![[dr. bob]](/dr-bob-sm.gif)
Dr. Bob is Robert Hsiung, MD,
[email protected]Shown: posts 1 to 13 of 13. This is the beginning of the thread.
Posted by jrbecker on February 11, 2005, at 11:57:06
Journal of Affective Disorders
Volume 84, Issues 2-3 , February 2005, Pages 127-132
Bipolar Depression: Focus on Phenomenology
doi:10.1016/j.jad.2004.01.017
Copyright © 2004 Published by Elsevier B.V.
Research report
Bipolar II vs. unipolar depression: psychopathologic differentiation by dimensional measures
Elie G. Hantouche , a, , and Hagop S. Akiskalba Adult Psychiatry, Mood Center, Psychiatry Department, Pitiè-Salpêtrière Hôpital, 47 Bd de l'Hôpital, 75013, Paris, France
b International Mood Center, University of California at San Diego, La Jolla, CA, USAReceived 15 October 2003; accepted 15 January 2004. Available online 23 June 2004.
Abstract
Background: Clinical presentations of depression in bipolar disorder are varied, inconsistent and often confusing. Most previous studies have focused on bipolar I (BP-I). Given that bipolar II (BP-II) is the more common bipolar phenotype, which is often confused with unipolar (UP), the aim of the current analyses is to delineate the symptomalogic differences between BP II vs. UP MDD in a large national sample. Methods: The data derived from the French National EPIDEP study (n=452 DSM-IV major depressives), subdivided into BP-II (n=196) and UP (n=256). The BP II group included major depressives with both spontaneous and antidepressant-associated hypomania based on our finding of similarity in rates of familial bipolarity in the two subgroups. At index presentation, depression was assessed by the clinician (using HAM-D and the Rosenthal Atypical Depression Scale) and by the patient (using the Multi-Visual Analog Scale of Bipolarity, MVAS-BP). Principal component analyses (PCA with varimax rotation) were conducted on HAM-D and MVAS-BP in the total population and separately in BP-II and UP. We performed inter-group comparative tests (UP vs. BP-II) on factorial scores derived from PCAs and correlation tests between these factorial scores. Results: The PCA on "HAM-D+Rosenthal scale" showed the presence of nine major factors: F1-2 "weight changes", F3-4 "sleep disturbances", F5 "sadness–guilt", F6 "retardation–fatigue", F7 "somatic", F8 "diurnal variation" and F9 "insight–delusion". The PCA on MVAS-BP revealed the presence of eight principal components: F1 "psychomotor retardation", F2 "central pain", F3 "somatic", F4 "social contact", F5 "worry", F6 "loss of interest", F7 "guilt" and F8 "anger". Despite uniformity in global intensity of depression, significant differences were observed as follows: higher score on "psychomotor retardation" (p=0.03), "loss of interest" (p=0.057) and "insomnia" (p=0.05) in the UP group, and higher score on "hypersomnia" (p=0.008) in the BP-II group. Correlation analyses between clinician- and self-rating revealed the presence of higher number of significant coefficients in the UP vs. BP-II group (p≤0.001). Limitation: A three-way comparison between BP-I, BP-II and UP may have yielded somewhat different results. Conclusion: Our data indicate greater psychomotor retardation, stability and uniformity in the clinical picture of strictly defined UP depression. By contrast, bipolar II depression appeared to be characterized, despite the hypersomnic tendency, by psychomotor activation. This would indicate greater mixed features than those observed in UP. Moreover, in BP-II, there was less agreement between clinician vs. self-rating on the presence of various features of depression. Taken together, these findings explain why BP-II depression is missed by clinicians as a genuine depression.
Author Keywords: Bipolar II depression; Unipolar depression; Psychopathologic differentiation
Article Outline
1. Introduction
2. Methodology
3. Results
4. Discussion
Acknowledgements
References
1. Introduction
The debate on the clinical picture of bipolar depression is ongoing. For some, there is no difference between unipolar (UP) and bipolar (BP) depressions (Joffe et al., 1999). Previous studies, which have largely focused on bipolar I (BI-I), have suggested that psychomotor retardation is pathognomonic in comparison with UP (Akiskal, 1981; Akiskal, 1983; Akiskal and Mallya, 1987 and Mitchell et al., 2001). Other studies, which have largely derived from bipolar II (BP-II) samples, have concluded that bipolar depression has a distinct phenomenology with anxious, agitated, impulsive, irritable, and mixed features, as well as greater atypical manifestations such as reverse vegetative symptoms (Perugi et al., 1998 and Benazzi and Akiskal, 2003). In addition, hypersomnia is often considered the main sleep pathology in bipolar disorder (Detre et al., 1972 and Akiskal, 1983). The debate on these issues cannot be resolved unless bipolar I and II are considered separately (Akiskal, 1983 and Akiskal et al., 1995); and the unipolar group is "cleansed" by excluding depressives with antidepressant associated-hypomania, because the latter are familially bipolar (Akiskal et al., 2003a).
The EPIDEP French study showed that the rate of BP-II disorder nearly doubled from 21% at intake to 39.7% in a month's time, after systematic search for hypomania according to DSMIV criteria (Hantouche et al., 1998 and Allilaire et al., 2001). Without this prospective assessment of BP-II on at least two points in time, nearly 50% of all BP-II would have been misclassified as UP. In line with the reason given above, we also subsumed depressions with antidepressant-associated hypomania under BP-II. In the present analyses, we thereby succeeded to constitute appropriately defined groups of BP-II and UP patients, which enabled us to compare these groups on psychometric and phenomenological grounds.
2. Methodology
The EPIDEP is a national French multi-site study (15 sites and 48 trained investigators) conducted in a cohort of 537 patients with major depression (DSM-IV criteria). The aim of EPIDEP is to show the feasibility of validating the spectrum of BP-II. The full methodology can be found elsewhere (Hantouche et al., 1998; Akiskal et al., 2003b and Allilaire et al., 2001). From a total inclusion of 537 patients presenting a major depressive episode (DSM-IV), 493 (91,8%) completed the study (at least two visits 1 month apart). Cases presenting with BP-I disorder, with at least one manic episode (N=41) were excluded from the present analyses. Thus, the size of the current validated sample (UP+BP-II) was 452.
During the two visits, depression was assessed by the Hamilton Depression Rating Scale (21 items) plus additive Rosenthal Scale (8 items) for atypical features, and the multiple VAS of Bipolarity (MVAS-B; Ahearn and Carroll, 1996), which were filled out by patients. The definite categorization of mood disorder was obtained at the second visit according to a systematic screening of hypomania: 196 patients were ranked in the "BP-II" group (all cases with hypomania according to DSM-IV criteria; hypomania associated with antidepressant were also subsumed in this sub-population), and 256 in the "UP" sub-group, which included all the remaining patients.
Psychometric data on depression were obtained during intake (in other words, during the acute current depression). Principal component analyses (PCA) were separately conducted on the HAM-D (29 items) and the MVAS-BP (26 items), by using the varimax rotation method. Comparative tests of factorial scores of HAM-D and those of MVAS-BP were applied in UP vs. BP-II sub-groups (with a significance level at p≤0.05). Correlation tests (Pearson method) between the factorial scores of HAM-D and those of MVAS-BP were performed in the total sample, then separately in UP, and BP-II sub-populations (with significance level set at p≤0.001).
3. Results
The PCA conducted on "HAM-D+Rosenthal scale" (29 items) showed the presence of nine major factors: F1"weight loss" (two items: gastro-intestinal (GI) symptoms, weight loss), F2 "hyperphagia" (four items: weight gain, augmented appetite, hyperphagia, craving for carbohydrates), F3 "insomnia" (three items: initial, midnight and late insomnias), F4 "hypersomnia" (one item: hypersomnia), F5 "sadness–guilt" (five items: depressed mood, GI symptoms, guilt feelings, suicide thoughts, psychic anxiety), F6 "retardation–fatigue" (four items: work-activities, social withdrawal, fatigue, retardation) , F7 "somatic" (three items: general somatic symptoms, somatic anxiety, hypochondriasis), F8 "diurnal variation" (two items: diurnal variation types 1 and 2), and F9 "insight–delusion" (two items: insight, delusion).
The PCA on MVAS-BP revealed the presence of eight principal components that are clinically meaningful: F1 "psychomotor retardation" (eight items), F2 "central pain" (seven items), F3 "somatic" (three items), F4 "social contact" (three items), F5 "worry–anxiety" (two items), F6 "loss of interest" (two items), F7 "guilt" (one item) and F8 "anger" (one item).
Despite uniformity in global intensity of depression (equivalent global scores on HAM-D; Allilaire et al., 2001), significant differences (Table 1) were observed as follows: the UP group was characterized by higher score on the "psychomotor retardation," "loss of interest", and "insomnia"; by contrast, higher score on "hypersomnia" characterized the BP-II group.Correlation analyses between clinician- and self-ratings revealed in the combined UP–BP-II population the presence of significant coefficients (14 significant coefficients at p≤0.001), mainly between "sadness" and "retardation" (from HAM-D) and factors derived from MVAS-BP (Table 2).
The same analyses conducted separately in UP and BP-II sub-populations revealed the presence of higher number of significant coefficients (at p≤0.001) in the UP group: 13 vs. only 8 in the BP-II group (Table 3 and Table 4). Moreover, the "sadness" and "retardation" factors from HAM-D revealed 10 significant correlations with self-report in the UP group vs. only 5 in the BP-II group.
4. Discussion
Conservatively, it is difficult to differentiate unipolar from bipolar depressions on solely the clinical picture during acute depressive episode, without getting information about the patient's course of illness and the presence of prior hypomanic episodes (Akiskal, 1983; Akiskal et al., 1995; Angst and Preisig, 1995 and Swann, 1997). In fact, there is considerable overlap to render the two types of depression essentially indistinguishable. However, some clinical hints could help to differentiate between UP and BP depressions. For example, bipolar depressions tend to have shorter duration and are associated with greater anergy (Katz et al., 1982; Thase et al., 1992 and Himmelhoch, 1998). However, few studies separated BP-I, BP-II and related soft bipolar conditions, which may have contributed to this clinical impression of BP "retardation."
Data from past analyses in the EPIDEP study have revealed that, while clinically depressed, global depressive intensity is equivalent between UP and BP-II groups (Allilaire et al., 2001). However, the rate of certain depressive symptoms is differentially represented in the two groups: guilt feelings, suicide thoughts and psychomotor restlessness are more frequently observed in BP-II depression, and psychic anxiety and initial insomnia in the UP group. In the present analyses, we report on different clinical dimensions obtained from the HAM-D (filled out by clinicians) and the self-rated MVAS-BP. Factorial scores on dimensions such as psychomotor retardation, sleep and appetite disturbances did differentiate between UP (in which levels of retardation, loss of interest and insomnia were high) and BP-II (high level on hypersomnia, which is just one of the major features of atypical depression). These data are against prior observations that bipolar depression is globally more retarded or anergic (Akiskal, 1983; Himmelhoch et al., 1991 and Mitchell et al., 2001). In the latter studies the focus was on BP-I and not BP-II depression. In the present EPIDEP data, BP-II is activated, as if it were a mixed state, as suggested by Akiskal et al. (1995) and Benazzi and Akiskal (2003).
Hypersomnia appears more specifically related to bipolar depression, as observed in Perugi et al. (1998) in atypical depression that contained a very high rate of soft bipolar disorders. In related research (Benazzi and Akiskal, 2003), such features as irritability, racing or crowded thoughts, and inner tension characterized the mixed depressive episode, which was considered as prima facie evidence for the presence of soft bipolarity.
Interrelationships between clinician and patient ratings are rarely considered in clinical research. Our study showed more significant correlations between clinician's and patient's ratings in the UP group, than in the BP-II group, mainly on the assessment of sadness. Thus, in the UP group, the factor "sadness" from HAM-D was correlated with five factors from self-reporting vs. only two in the BP-II group. The assessment of "retardation" (clinician) and "central pain" (patient) was related only in the UP group. The discrepancy between depressive feelings, sadness and psychomotor function is then greater in BP-II (probably because of activation; Benazzi and Akiskal, 2003 and Koukopoulos and Koukopoulos, 1999). These findings suggest greater stability in the clinical picture of UP depression (greater congruency between depressive feelings and sadness, GI symptoms, guilt feelings, suicide thoughts, and psychic anxiety). By contrast, BP-II depression appeared to be characterized by "mood-incongruent" psychomotor disturbance (less retardation). However, hypersomnia, which is an atypical feature, we found more prevalent in bipolar II. Thus, clinical complexity, mood instability, and psychomotor activation despite hypersomnia would be the signatures of bipolar depression.
Bipolar depression is, by its very nature, more unstable and intense, and therefore misleading in everyday clinical practice. Many patients presenting bipolar II depression would be considered as "histrionic" or other personality disorder and the authenticity of depression would often appear questionable to the external observer. Previous data from EPIDEP (Hantouche et al., 1998) suggested that the clinical picture of BP-II disorder is best characterized by instability. This feature should be added to the clinical portrait of this disorder. Presently, clear-cut hypomania is the only cue to recognize soft bipolarity (Akiskal and Pinto, 1999); in clinical practice, it is often difficult to have access to this information (when obtained by history, hypomania is highly specific (Rice et al., 1986), but when absent, it does not rule out BP-II). Besides hypomania, the clinical interviewer should look for clinical instability of depressive manifestations and lesser conformity between clinician and patient's reporting (mainly on "sadness").
Like Dunner et al. (1976), we observed less conformity between clinician judgment and self-reporting in patients with BP-II vs. UP depression. This discrepancy should be added to other cues, such as tempestuous course, mixity, complex comorbidity, cyclothymic traits, or long-standing mood lability (Akiskal et al., 1995; Vieta et al., 1997; Hantouche et al., 1998 and Perugi et al., 1998), that are helpful to detect BP-II during acute depressive episodes, especially when at intake, history of hypomania is not obtainable.
Acknowledgements
The EPIDEP National French Study was conducted with Pr HS Akiskal as its international advisor, in collaboration with a French scientific committee which included Prs JF Allilaire (Paris), JM Azorin (Marseille), ML Bourgeois (Bordeaux) and D Sechter (Besançon). The study was coordinated by Dr EG Hantouche (Paris) and Dr L Châtenet-Duchêne (Sanofi-Syntelabo France), and supported by a unrestricted grant from Sanofi-Syntelabo France. Data management, computer monitoring and statistics were conducted by Sylia-Stat (Mrs S Lancrenon).
References
Ahearn, E.P. and Carroll, B.J., 1996. Short-term variability of mood ratings in unipolar and bipolar depressed patients. J. Affect. Disord. 36, pp. 107–115. Abstract | Abstract + References | PDF (579 K)
Akiskal, H.S., 1981. Subaffective disorders: dysthymic, cyclothymic and bipolar II disorders in the "border-line" realm. Psychiatr. Clin. North Am. 4, pp. 25–46. Abstract-EMBASE | Abstract-MEDLINE
Akiskal, H.S., 1983. The bipolar spectrum: new concepts in classification and diagnosis. In: Grinspoon, L., Editor, 1983. Psychiatry Update: The American Psychiatric Association Annual Review vol. 2, American Psychiatric Press, Washington, DC, pp. 271–292.
Akiskal, H.S. and Mallya, G., 1987. Criteria for the "soft" bipolar spectrum: treatment implications. Psychopharmacol. Bull. 23, pp. 68–73. Abstract-EMBASE | Abstract-MEDLINE
Akiskal, H.S. and Pinto, O., 1999. The evolving bipolar spectrum: prototypes I, II, III and IV. Psychiatr. Clin. North Am. 22, pp. 517–534. Abstract-EMBASE | Abstract-PsycINFO
Akiskal, H.S., Maser, J.D., Zeller, P., Endicott, J., Coryell, W., Keller, M., Warshaw, M., Clayton, P. and Goodwin, F.K., 1995. Switching from "unipolar" to bipolar II: an 11-year prospective study of clinical and temperamental predictors in 559 patients. Arch. Gen. Psychiatry 52, pp. 114–123. Abstract-EMBASE | Abstract-MEDLINE | Abstract-PsycINFO
Akiskal, H.S., Hantouche, E., Allilaire, J.F., Sechter, D., Bourgeois, M., Azorin, J.M., Chatenêt-Duchêne, L. and Lancrenon, S., 2003. Validating antidepressant-associated hypomania (BP-III): systematic comparison with spontaneous hypomania (BP-II). J. Affect. Disord. 73, pp. 65–74. SummaryPlus | Full Text + Links | PDF (86 K)
Akiskal, H.S., Hantouche, E. and Allilaire, J.F., 2003. BP-II with and without cyclothymia: "dark" and "sunny" expressions of soft bipolarity. J. Affect. Disord. 73, pp. 49–57. SummaryPlus | Full Text + Links | PDF (80 K)
Allilaire, J.-F., Hantouche, E.G., Sechter, D., Lancrenon, S., Chatenêt-Duchêne, L. and Akiskal, H.S., 2001. Frequency and clinical aspects of BP-II: data from the French multi-site study EPIDEP. Encéphale 27, pp. 149–158. Abstract-EMBASE | Abstract-MEDLINE | Abstract-PsycINFO
Angst, J. and Preisig, M., 1995. Course of a clinical cohort of unipolar, bipolar, and schizo-affective patients: results of a prospective follow-up from 1959 to 1985. Schweiz. Arch. Neurol. Psychiatr. 146, pp. 5–16. Abstract-EMBASE | Abstract-MEDLINE | Abstract-PsycINFO
Benazzi, F. and Akiskal, H.S., 2003. Refining the evaluation of bipolar II: beyond the strict SCID-CV guidelines for hypomania. J. Affect. Disord. 73, pp. 33–383.
Detre, T., Himmelhoch, J., Swartzburg, M., Anderson, C.M., Byck, R. and Kupler, D.J., 1972. Insomnia and manic-depressive disease. Am. J. Psychiatry 128, pp. 1303–1305. Abstract-MEDLINE | Abstract-PsycINFO
Dunner, D.L., Dwyer, T. and Fieve, R.R., 1976. Depressive symptoms in patients with unipolar and bipolar affective disorder. Comp. Psychiatry 17, pp. 447–451. Abstract
Hantouche, E.G., Akiskal, H.S., Lancrenon, S., Allilaire, J.F., Sechter, D., Azorin, J.M., Bourgeois, M., Fraud, J.P. and Châtenet-Duchêne, L., 1998. Systematic clinical methodology for validating bipolar-II disorder: data in mid-stream from a French national multisite study (EPIDEP). J. Affect. Disord. 50, pp. 163–173. SummaryPlus | Full Text + Links | PDF (87 K)
Himmelhoch, J.M., 1998. Social anxiety, hypomania and the bipolar spectrum: data, theory and clinical issues. J. Affect. Disord. 50, pp. 203–213. SummaryPlus | Full Text + Links | PDF (85 K)
Himmelhoch, J.M., Thase, M.E., Mallinger, A.G. and Houck, P., 1991. Tranylcypromine versus imipramine in anergic bipolar depression. Am. J. Psychiatry 148, pp. 910–916. Abstract-EMBASE | Abstract-MEDLINE | Abstract-PsycINFO
Joffe, R.T., Young, L.T. and MacQueen, G.M., 1999. A two-illness model of bipolar disorder. Bipolar Disord. 1, pp. 25–30. Abstract-MEDLINE | Full Text via CrossRef
Katz, M.M., Robins, E., Croughan, J., Secunda, S. and Swann, A.C., 1982. Behavioral measurement and drug response characteristics of unipolar and bipolar depression. Psychol. Med. 12, pp. 25–36. Abstract-EMBASE | Abstract-MEDLINE | Abstract-PsycINFO
Koukopoulos, A. and Koukopoulos, A., 1999. Agitated depression as a mixed state and the problem of melancholia. Psychiatr. Clin. North Am. 22, pp. 547–564. Abstract-EMBASE | Abstract-MEDLINE
Mitchell, P.B., Wilhelm, K., Parker, G., Austin, M.P., Rutgers, P. and Malhi, G.S., 2001. The clinical features of bipolar depression: a comparison with matched major depressive disorder patients. J. Clin. Psychiatry 62, pp. 212–216. Abstract-EMBASE | Abstract-PsycINFO
Perugi, G., Akiskal, H.S., Lattanzi, L., Cecconi, D., Mastrocinque, C., Patronelli, A., Vignoli, S. and Beni, E., 1998. The high prevalence of ‘soft’ bipolar (II) features in atypical depression. Compr. Psychiatry 39, pp. 63–71. SummaryPlus | Full Text + Links | PDF (787 K)
Rice, J.P., McDonald-Scott, P., Endicott, J., Coryell, W., Grove, W.M., Keller, M.B. and Altis, D., 1986. The stability of diagnosis with an application to bipolar II disorder. Psychiatry Res. 19, pp. 285–296. Abstract
Swann, A.C., 1997. Is bipolar depression a specific biological entity?. In: Young, L.T. and Joffe, R.T., Editors, 1997. Bipolar Disorder: Biological Models and their Clinical Applications, Marcel Dekker, New York, pp. 255–288.
Thase, M.E., Mallinger, A.G., McKnight, D. and Himmelhoch, J.M., 1992. Treatment of imipramine-resistant recurrent depression: IV. A double-blind cross-over study of tranylcypromine for anergic bipolar depression. Am. J. Psychiatry 149, pp. 195–198. Abstract-EMBASE | Abstract-MEDLINE | Abstract-PsycINFO
Vieta, E., Gasto, C., Otero, A., Nieto, E. and Vallejo, J., 1997. Differential features between bipolar I and bipolar II disorder. Compr. Psychiatry 38, pp. 98–101. SummaryPlus | Full Text + Links | PDF (346 K)
Corresponding author. Tel.: +33-1-43-25-08-07; fax: +33-1-43-25-06-35.
Posted by jrbecker on February 11, 2005, at 11:59:52
In reply to Bipolar II Series - Bipolar II vs. unipolar, posted by jrbecker on February 11, 2005, at 11:57:06
Journal of Affective Disorders
Volume 84, Issues 2-3 , February 2005, Pages 251-257
Bipolar Depression: Focus on Phenomenology
doi:10.1016/j.jad.2004.01.015
Copyright © 2004 Elsevier B.V. All rights reserved.
Research report
A closer look at treatment resistant depression: is it due to a bipolar diathesis?
Verinder Sharma , , Mustaq Khan and Angela SmithMood Disorders Program, Regional Mental Health Care London, 850 Highbury Avenue North, P.O. Box 5532, Station B, London, ON, Canada N6A 4H1
Received 21 August 2003; accepted 28 January 2004. Available online 25 May 2004.
Abstract
Background: Treatment resistant depression is a common clinical problem. Studies have shown that a large number of patients with depression do not have a satisfactory clinical outcome in spite of adequate trials of antidepressant drugs. In this study, we investigated demographic and clinical characteristics, diagnostic subtypes, and illness outcome of patients with resistant depression and a history of escape of response to adequate trials of at least two antidepressants for a previous episode. Method: Sixty-one patients who were seen consecutively at a mood disorders clinic with the diagnosis of "unipolar" treatment resistant depression, and followed up for at least one year, were interviewed using the Structured Clinical Interview for DSM-IV. Prospectively collected data including the occurrence of episodes of hypomania, and supplemental information from family members on illness course were also used for purposes of diagnostic re-evaluation. Results: At intake, 35% of the patients were diagnosed as having a bipolar disorder. At follow-up, there was a 59% prevalence of bipolar disorder. Of the patients with major depressive disorder, 52% were subsequently classified as having bipolar spectrum disorder. The most important finding was that 80% of patients were found to show evidence of bipolarity. Moreover, the most common change in medication was a switch to mood stabilizers. CGI ratings showed significant improvement in functioning from the time of initial consultation. Limitations: This was a naturalistic study, and the data were collected in a non-blind fashion. Conclusions: The findings suggest that the majority of cases of unipolar treatment resistant depression, occurring in the context of loss of antidepressant response, have a bipolar diathesis.
Author Keywords: Resistant depression; Antidepressants; Loss of response; Mood stabilizers; Bipolar disorder
1. Introduction
The pharmacological treatment of depression has been revolutionized since the introduction of antidepressant drugs five decades ago. The availability of safe and well-tolerated drugs, combined with a heightened awareness of the disabling and recurrent nature of depression, has led to a significant increase in the utilization of these drugs. Despite such a widespread use of antidepressants (Hemels et al., 2002), treatment resistance is a common clinical problem. A meta-analysis of clinical trials reported rates of partial response in 12–15%, and nonresponse in 19–34% among antidepressant-treated patients (Fava and Davidson, 1996). Authors of a recent study from England concluded that the long-term outcome of depression does not appear to have changed in the last 20 years (Kennedy et al., 2003).
Treatment resistance has a major impact on health care utilization and costs, due to the extensive use of depression and non-depression related medical services. Patients with treatment resistant depression require more hospitalizations and are likely to receive more psychotropic medications (Crown et al., 2002). Due to its ubiquitous nature and the associated functional impairment, major depression is a major cause of disease burden around the world (Murray and Lopez, 1996).
Variables associated with poor response to antidepressants include the presence of psychiatric or medical comorbidity, older age, chronicity, and greater illness severity (Kornstein and Schneider, 2001). The diagnosis of bipolar disorder is not an uncommon cause of treatment resistance (Fagiolini and Kupfer, 2003). Antidepressants are commonly prescribed to patients with bipolar depression, in spite of limited evidence for efficacy (Ghaemi et al., 1999; Ghaemi et al., 2001; Ghaemi et al., 2002a and Ghaemi et al., 2002b). In addition to risks such as induction of mania or rapid cycling associated with their use (Goodwin and Jamison, 1990 and Wehr and Goodwin, 1979), antidepressants are less effective for treating bipolar depression than major depressive disorder (Frankle et al., 2002). A study on the relationship between episode duration and antidepressant therapy concluded that over the past couple of decades little progress has been made in reducing the length of depressive episodes in bipolar disorder (Frankle et al., 2002).
There is also a concern that the use of antidepressants in some patients with major depression may lead to chronicity and treatment refractoriness. The majority of these patients, who experience a relapse in spite of the continued use of—or "overuse" of—antidepressants may have a bipolar diathesis or belong to a "soft" bipolar spectrum (Akiskal and Mallya, 1987) as suggested by irritable, cyclothymic or hyperthymic temperamental antecedents, depressive mixed states, antidepressant-induced alterations in the cyclic pattern of the illness, brief hypomanic features, and bipolar family history. These are the very patients those authors found to respond to lithium and/or low-dose neuroleptic augmentation. In another study, patients who relapsed on (an) apparently previous successful antidepressant(s) were more likely to have atypical symptoms of depression, postpartum episodes, and a family history of bipolarity (Sharma, 2001). Loss of antidepressant response or antidepressant "wear-off" usually refers to the phenomenon of acute but not prophylactic response (Ghaemi et al., 2002a and Ghaemi et al., 2002b). Results of a recent study showed that late loss of antidepressant response (defined as occurrence of major depression >6 months post resolution of symptoms) was significantly more common in bipolar as opposed to unipolar depression (Ghaemi et al., 2002a and Ghaemi et al., 2002b). The loss of antidepressant effect has been described with various drugs from different classes. A variety of strategies including dose optimization, substitution or combination with another antidepressant, or addition of an augmenting agent have been recommended (Sharma, 2001). Some patients nevertheless require discontinuation of antidepressant therapy and introduction of mood stabilizers for alleviation of depression (Sharma, 2001).
In this paper we describe the demographic and clinical characteristics of patients who were referred to a mood disorders program for refractory depression. The patients had a history of escape of antidepressant response to at least two adequate trials of antidepressants for a prior episode. We were particularly interested in determining the prevalence of bipolarity, as a previous study reported that treatment resistance in certain patients might represent a bipolar diathesis (Sharma, 2001).
2. Method
A chart review was conducted during June 2000–May 2001 on consecutive outpatients who attended a mood disorders clinic at a psychiatric hospital over the past 1–10 years. The hospital, with a catchment area of over one million people, serves as a tertiary care facility for the Southwestern region of the province. Family physicians and psychiatrists referred the patients for assessment and treatment of refractory unipolar depression. To be eligible for assessment, the patient must have received continuous follow-up care for at least 1 year. Eligible patients were approached to participate in the study. Their participation was required because the study involved collecting some new data from a diagnostic interview. The study received ethics approval from the institutional review board.
2.1. Definitions
For the index episode, treatment refractoriness was defined as failure to respond to two adequate trials of antidepressants. Adequacy of pharmacotherapy was determined using the criteria described by Amsterdam and Hornig-Rohan (1996). For example, treatment with imipramine≥250 mg or phenelzine≥60 mg for ≥6 weeks and fluoxetine≥20 mg for 8 weeks amounted to "adequate" therapy. For at least one previous episode of depression, our patients had shown an antidepressant response but were unable to achieve full remission on two separate adequate trials of medications from different classes. Response was defined as absence of significant symptoms with no functional impairment over a period of less than 2 months. Full remission required a 2-month period of absence of significant symptoms while the antidepressant dose remained constant. In keeping with the MacArthur guidelines for operationalizing relapse (Hart et al., 2001), a relapse was defined as fulfillment of DSM-IV criteria for a major depressive episode less than six months following resolution of depression. Patients who showed an inadequate response that was sustained for six or more months were therefore excluded. Patients initially referred with bipolar I disorder, schizoaffective disorder, concurrently comorbid substance abuse disorder, mental retardation, or major physical illness were also excluded.
2.2. Clinical data
Detailed clinical information including demographic data, age of illness onset, duration and frequency of mood episodes, nature of symptoms, and DSM-IV diagnoses was obtained from 61 patients. Information regarding pharmacotherapy, including names, doses, and duration of use of antidepressants and other medications was gathered. At least one first-degree family relative was interviewed to obtain collateral information. Whenever possible, converging evidence from other sources—including previous treating physicians and hospital records—was obtained. Patients were diagnosed using DSM-IV criteria at the time of initial assessment. Diagnoses were modified according to our prospectively collected data on illness course as well as collateral information from family members.
Patients were re-evaluated in 2001–2002 using the Structured Clinical Interview for DSM-IV (SCID) (First et al., 1994). Patients were also diagnosed using the recently proposed criteria for bipolar spectrum disorder (Ghaemi et al., 2002a and Ghaemi et al., 2002b). We were interested in determining the prevalence of this disorder because some of the diagnostic criteria, including antidepressant "wear-off" and lack of response to antidepressant therapy, were the defining characteristics of our patient population.
2.3. Statistical analyses
Continuous variables were analyzed using an unequal groups one-way analysis of variance (ANOVA) or a non-directional dependent groups t-test. Categorical variables were analyzed with a chi-square goodness of fit test. All tests of significance were carried out at the 0.05 level.
3. Results
At intake, 35% of the patients were diagnosed as having a bipolar disorder. Patients with major depressive disorder (n=12) or bipolar spectrum disorder (n=13) were compared on clinical characteristics with patients who were diagnosed with a bipolar disorder (n=2 for bipolar I, n=26 for bipolar II, and n=8 for bipolar NOS). The demographic data for these two groups are presented in Table 1.
At follow-up, there was a 59% prevalence of bipolar disorder in our sample. The DSM-IV diagnostic breakdown was as follows: major depressive DISORDER=25 (41%), bipolar I=2 (3%), bipolar II=26 (43%), and bipolar NOS=8 (13.1%). Of the patients with major depressive disorder, 13 (52%) were subsequently classified as having bipolar spectrum disorder. The most striking finding is that 80% of our sample of patients, all of whom were referred initially for treatment resistant unipolar depression, was found on follow-up and our subsequent diagnostic interviews to show evidence of a bipolar diathesis.
For the continuous variables, the ANOVAs showed no group differences in any of the variables (all F (1,59)<1). In other words, the two patient groups were statistically equivalent on age, age of illness onset, and number of children. Table 1 shows the group means for these variables.
For the categorical variables, within each group there were more females than males (bipolar: 2(1)=60.48, p<0.01; major depressive+bipolar spectrum disorders combined: 2(1)=36.0, p<0.01). Consistent with our hypothesis, there were no group differences in any of the categorical variables. The only exception was the following: significantly more patients with current and lifetime comorbidity were found in the bipolar disorder group ( 2(1)=5.0, p<0.05) than in the bipolar spectrum+major depression group.
Table 2 shows, for each diagnostic group, the mean CGI rating at first visit and at the most recent visit with the psychiatrist. Non-directional dependent groups t-tests revealed that CGI ratings were significantly lower at the most recent visit compared to ratings at the first visit for the following groups: major depressive disorder, bipolar NOS, bipolar II, and bipolar spectrum (t(11)=3.0, p<0.01; t(7)=4.3, p<0.003; t(23)=9.0, p<0.001; respectively). The comparison for bipolar I involved only two patients, hence was not powerful enough to detect any difference that might exist (t(1)=1.0).
Table 2. Comparison of CGI ratings and class of medication at intake and at most recent visit, according to diagnostic category
Table 2 also summarizes the type of medication received by patients in each group. This data is subdivided into medication taken at the first consultation visit with the psychiatrist, and at the last visit. In each group, the percentage of patients receiving a change in medication from what they were taking at the time of initial consultation is as follows: 67% for the bipolar spectrum group, 67% for major depressive disorder, 100% for bipolar I, 83% for bipolar II, and 75% for the bipolar NOS group.
The most frequent change in medication appears to have been a switch to mood stabilizers alone, accounting for 36% of all the medication changes from the time of initial consultation. At time of initial consultation, 93% of patients were receiving an antidepressant (either alone or in combination with other types of medications). At last visit, over half (52%) of those who were initially receiving antidepressants was no longer receiving any antidepressant. This decrease in use of antidepressants is statistically significant (t(53)=7.6, p<0.001). Following the initial consultation, mood stabilizers and/or atypical neuroleptics were introduced at follow-up for two-thirds (66%) of patients who had been taking antidepressants at the time of initial consultation. This represents a significant increase in the use of mood stabilizers and/or atypical neuroleptics (t(37)=8.4, p<0.001).
4. Discussion
This study examined demographic and clinical characteristics, types of pharmacotherapy, and illness outcome of refractory depression in a cohort of 61 patients. The patients were seen consecutively at a specialty clinic, after having failed to respond to adequate trials of two antidepressants. These patients additionally had a history of inability to attain full remission on two adequate trials of antidepressant for at least one prior episode. We also studied in this sample the prevalence of bipolar II and other types of bipolarity, as well as the presence of comorbid psychiatric disorders.
The main finding was that the majority of patients with a clear history of treatment resistant "unipolar" depression actually suffered from bipolar disorders, with bipolar II as the most common diagnosis, followed by bipolar spectrum disorder. Our findings extend the preliminary report by Akiskal and Mallya (1987) suggesting that the "soft bipolar spectrum" may underlie treatment resistance. Assessment of demographic and clinical features differentiating bipolar spectrum disorders is beyond the purpose of this study.
Akiskal's group has provided both the clinical description (Akiskal and Pinto, 1999) and the validation status of the bipolar spectrum (Akiskal, 1996 and Akiskal, 2002). Previous studies have reported that many patients with a bipolar disorder are initially treated for major depression. Ghaemi et al., 2002a and Ghaemi et al., 2002b reported a 40% rate of misdiagnosis of major depression among patients with bipolar disorder. Similar findings were described in a French study of 250 patients with major depression (Hantouche et al., 1998). In that study, 28% of the patients initially met the DSM-IV diagnosis of bipolar disorder; but the rate jumped to 55% when more in-depth assessments were conducted. The much higher figure of 80% in the present study was likely due to our sample being biased towards having an overrepresentation of patients with a bipolar diathesis. Specifically, our patients experienced an escape of antidepressant response and failed to show a favorable response to trials of several antidepressants. Both of these clinical features are among the proposed criteria for the diagnosis of bipolar spectrum disorder (Ghaemi et al., 2002a and Ghaemi et al., 2002b). Other factors might help account for our 80% rate; that is, the uncovering of occult bipolarity. These factors arise from the regular gathering of supplemental information. They include systematic follow-up over a long period, expert questioning to elicit symptoms of hypomania, and routine interviews with family members to obtain supplemental information (including family history of psychiatric disorders).
Another important finding was that the two groups—the "nonbipolar" (major depressive disorder+bipolar spectrum disorder) and the bipolar (I, II, and NOS)—were remarkably similar on most of the variables examined. There are some possible reasons for this similarity. A large number of patients in this study met the criteria for bipolar spectrum disorder. Such a change in diagnosis occurred because the DSM-IV does not recognize that antidepressant-induced hypomanic episodes should be subsumed under the rubric of bipolar disorder. In addition, some patients received the diagnosis of bipolar NOS, as their episodes of hypomania were not long enough to reach the DSM-IV duration threshold. While the nosological status of recurrent major depression with non-spontaneous episodes of hypomania remains a contentious issue, it has recently been argued that some of these cases (e.g., those with antidepressant-induced episodes of hypomania) may have a genetically less penetrant version of bipolar II illness.
The findings from this study have important clinical and research implications. Patients who have treatment resistant depression occurring in the context of loss of antidepressant response should have a thorough assessment to rule out bipolarity. Close monitoring of clinical condition over a period of time may be required in some patients to clarify the diagnosis. During episodes of depression, patients may have difficulty recalling any hypomanic spells, or may tend to report these as periods of well-being. Because the use of antidepressants in individuals with a bipolar diathesis may convert their "atypical" presentation into an agitated, anxious state with accompanying insomnia and racing of thoughts, it is important to make a distinction between their symptoms before and after the introduction of antidepressants.
There should be caution regarding the use of antidepressants in patients with histories of repeated loss of antidepressant response, due to the risk of inducing treatment refractoriness. The use of mood stabilizers at the time of initial referral was quite low in our sample. However, there was no evidence that illness outcome in patients on mood stabilizers combined with antidepressants was any different from those patients receiving antidepressant monotherapy. Some patients do benefit from discontinuation of antidepressants, to be treated instead with mood stabilizers alone. By contrast, other patients require the use of an antidepressant with their mood stabilizer. A trial of a monoamine oxidase inhibitor should be considered for some patients who have persistent depression in spite of adequate trials of mood stabilizers.
There are some limitations of this descriptive study that should be acknowledged. The present results might not necessarily generalize to the entire population of patients who show a loss of antidepressant response. Our sample represents a select group referred from primary care settings. There are conceivably many more patients showing a loss of response, who do not receive specialized consultation. Because this was not a randomized study, confounding factors were not ruled out. For example, those who are referred for consultation might possess illness characteristics that differentiate them from the larger population of patients with treatment resistant depression. Treatment was not controlled, which makes the data vulnerable to experimenter and participant expectancy effects. For instance, the experimenter's bias to discover bipolarity could have affected the judgment about whether a particular symptom is indicative of mood elevation. Such bias was reduced by use of structured interviews; nevertheless, clinical judgment was eventually used in arriving at a diagnosis. From the patient's perspective, there could have been a strong expectancy to improve due to a placebo effect; that is, the change in diagnosis as a result of the consultation reduced the patient's uncertainty over why their depression did not remit. The new diagnosis and/or change in medication likely elicited increased hope. Another limitation concerns the measure of treatment outcome. More indicators than the CGI alone are required in order to strengthen the conclusion that treating for bipolarity produces improved outcomes.
Due to poor response of bipolar depression to antidepressants, controlled studies with other drugs including mood stabilizers are urgently needed. Studies are also needed to determine whether there is also a loss of response to other treatment modalities such as electroconvulsive therapy.
Acknowledgements
The authors thanks M. Hesch and C. Corpse for their help in the preparation of this manuscript.
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Akiskal, H.S. and Mallya, G., 1987. Criteria for the "soft" bipolar spectrum: treatment implications. Psychopharmacol. Bull. 23, pp. 68–73. Abstract-EMBASE | Abstract-MEDLINE
Akiskal, H.S. and Pinto, O., 1999. The evolving bipolar spectrum: prototypes I, II, III, IV. Psychiatr. Clin. North Am. 22, pp. 517–534. Abstract-EMBASE | Abstract-PsycINFO
Amsterdam, J.D. and Hornig-Rohan, M., 1996. Treatment algorithms in treatment-resistant depression. In: Hornig-Rohan, M. and Amsterdam, J.D., Editors, 1996. Psychiatr. Clin. North Am., Saunders, Philadelphia, pp. 371–386. Abstract-EMBASE | Abstract-MEDLINE | Abstract-PsycINFO
Crown, W.H., Finkelstein, S., Berndt, E.R., Ling, D., Poret, A.W., Rush, A.J. and Russell, J.M., 2002. The impact of treatment-resistant depression on health care utilization and costs. J. Clin. Psychiatry 63 11, pp. 963–971. Abstract-EMBASE | Abstract-MEDLINE | Abstract-PsycINFO
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Journal of Affective Disorders
Volume 84, Issues 2-3 , February 2005, Pages 251-257
Bipolar Depression: Focus on Phenomenology
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Posted by jrbecker on February 11, 2005, at 12:14:46
In reply to Bipolar II Series - treatment-resistant depression, posted by jrbecker on February 11, 2005, at 11:59:52
Journal of Affective Disorders
Volume 84, Issues 2-3 , February 2005, Pages 267-272
Bipolar Depression: Focus on Phenomenology
doi:10.1016/j.jad.2004.08.004
Copyright © 2004 Elsevier B.V. All rights reserved.
Preliminary communication
Antidepressant-associated chronic irritable dysphoria (acid) in bipolar disorder: a case series
Rif. S. EI-Mallakh , and Anoop KarippotMood Disorders Research Program, Department of Psychiatry and behavioral Science, University of Louisville School of Medicine, Louisville, KY, United States
Received 28 July 2003; accepted 18 August 2004. Available online 12 October 2004.
Abstract
Background
Antidepressants administered to bipolar subjects may induce manias, mixed states, or rapid cycling. More recently, we have noted that long-term use of antidepressants may induce a chronic dysphoric, irritable state.
Method
A case series is presented in which six type I bipolar subjects receiving antidepressants continuously for several years developed chronic irritable dysphoria.
Results
A triad of dysphoric mood, irritability, and middle insomnia that is frequently associated with occupational and social dysfunction can occur in some bipolar patients receiving antidepressants for at least 3 years. Typically, initial treatments with antidepressants for the index episode were effective. Over time, depressive symptoms returned and would transiently improve with dose increase or change of agents. Ultimately, the dysphoria and associated symptoms became chronic and resulted in dysfunction. Concomitant mood stabilizer did not appear to alter this pattern. Discontinuation of antidepressants was associated with a slow and gradual improvement in these symptoms over the ensuing year.
Conclusion
Additional studies are required to investigate safety of long-term use of antidepressants in bipolar illness.
1. Introduction
Depression in bipolar disorder may be particularly problematic. Judd et al., 2002 and Judd et al., 2003 found the duration of depression accounts for three to four times the duration of mania or hypomania. Antidepressants appear to be beneficial in the short-term management of bipolar depression (Himmelhoch et al., 1982, Himmelhoch et al., 1991, Cohn et al., 1989, Simpson and DePaulo, 1991, Thase et al., 1992, Amsterdam, 1998, Amsterdam et al., 1998 and Biederman et al., 2000). Unfortunately, over the last three decades, evidence has accumulated that antidepressants may induce mania or rapid cycling in some bipolar subjects (Kukopulos et al., 1980, Ghaemi et al., 2000, Wehr and Goodwin, 1987, Stoll et al., 1994 and Altshuler et al., 1995).
While the absolute rate of induction of mania secondary to antidepressant treatment is quite variable, it is consistently two to three times the background rate (Angst, 1985 and El-Mallakh and Karippot, 2002). Additionally, subjects with cyclothymia may convert to a type II illness when given antidepressants (Akiskal et al., 1977). Antidepressant-induced manias have a significant irritable component (Stoll et al., 1994). They resolve relatively quickly once the antidepressant is discontinued (Stoll et al., 1994). However, not all studies have found an increase in manic induction, and this remains a debated topic in psychiatry. In an influential study performed by Lewis and Winokur (1982), antidepressants did not appear to increase manic relapse risk.
In the pre-antidepressant era (pre-1950s), rapid cycling among bipolar subjects was quite rare (Kukopulos et al., 1983). Since then, several studies have now confirmed that antidepressants are associated with rapid cycling (Kukopulos et al., 1983, Wehr et al., 1988, Altshuler et al., 1995 and Ghaemi et al., 2000). Kukopulos et al. (1983) found that in 80 subjects, onset of rapid cycling was associated with antidepressant treatment that continued through euthymic periods (n=17), or persisted at least 1 year (n=33), 2 years (n=14.), or longer (n=5). Rapid cycling faded quickly in 29% of 5l subjects studied by Wehr et al. (1988), and in 8 of 9 subjects studied by Altshuler et al. (1995). Altshuler et al. (1995) also noted that individuals who had previously experienced antidepressant-induced manic induction were the ones most likely to have antidepressant-associated rapid cycling.
We have noted a phenomenon that is probably related to rapid cycling. Several bipolar individuals who received long-term antidepressant treatment developed a chronic, dysphoric, irritable state [Antidepressant-associated Chronic Irritable Dysphoria (ACID)]. Improvement following antidepressant discontinuation was slow, gradual, and usually required months. A similar phenomenon was noted by Akiskal and Mallya (1987). They described 25 patients with bipolar spectrum illness who were referred for treatment-resistant depression, and in whom chronic use of tricyclic antidepressants was associated with a chronic irritable, dysphoric state (Akiskal and Mallya, 1987).
2. Case series
We are reporting on six individuals with a remarkably consistent pattern of antidepressant-associated worsening. Most had type I illness with an average duration of illness of 9.7 years. All received continuous antidepressant treatment for a protracted period of time (mean 6.6 years, range 3–7 years). They were followed for 13.7 months after discontinuation of antidepressant. All subjects had experienced significant dysphoria, irritability, and middle insomnia and exhibited severe social and occupational dysfunction. Prior to antidepressant discontinuation, five had stopped working, two lost their homes, and one had declared bankruptcy. Two had terminated long-term relationships, and two had significant relationship problems. The following case histories provide a better understanding of the course of these events.
2.1. Case 1
Mr. A is a 29-year-old married man with a 6-year history of bipolar illness. For the preceding 5 years, he had received lithium and a variety of serotonin reuptake inhibiting (SRI) antidepressants (paroxetine, sertraline, fluoxetine). Despite ongoing antidepressants and several attempts at optimization of treatment, he noted slowly increasing depressed mood, frustration and irritability, amotivation, middle insomnia, and difficulty at work. At the time of antidepressant discontinuation, the patient had been unable to work for 6 months and was experiencing significant marital discord. Discontinuation of antidepressant was not associated with an immediate change in symptoms and low-dose quetiapine (25–100 mg/day) was used to provide mild tranquilization. Approximately 4 months after discontinuation of antidepressants, the patient began working (in temporary and part-time jobs). He noted a significant improvement in mood, irritability, and his ability to concentrate. At 1 year after discontinuation of antidepressants, he was working (in a permanent job) with no marital problems. The only residual symptom was ongoing early insomnia (the middle insomnia had resolved).
2.2. Case 2
Mr. B is a 45-year-old divorced man with a certificate in public accountancy. He had a type II bipolar illness which was diagnosed 7 years previously. He was initially treated with sertraline. Lithium was added when his hypomanic episodes were recognized after 4 years of antidepressant treatment. Prior to sertraline discontinuation, he was experiencing persistent dysphoria, irritability and decreased frustration tolerance, labile mood, and a sleep disturbance with both early and middle insomnia. These symptoms had previously improved transiently with sertraline dosage increases, but had become continuous for at least 1 year. He became unable to maintain continuous employment and declared bankruptcy. His mother supplemented his income so that he was able to keep his house. He separated from his girlfriend and his infant son. Sertraline was tapered and lamotragine was added to lithium and advanced to 200 mg/day. There was minimal initial change in his symptoms. After 1 year off sertraline, the patient was able to work full time. He improved his financial situation and reconciled with his girlfriend. Despite the notable improvement in his quality of life, he continued to complain of dissatisfaction with life and to experience mild variations in mood and energy.
2.3. Case 3
Ms C is a 48-year-old lesbian attorney with type I bipolar illness for 5 years. Following onset of her illness, she was treated with divalproex, paroxetine, and amitriptyline. She experienced initial improvement. Her symptoms appeared to recur with worsening depressed mood, irritability, middle insomnia, lethargy, and poor motivation. Changes in antidepressant treatment resulted in progressively briefer transient improvements. She became unable to work, lost her home, and broke up with her lover. Ultimately, after 4 years of continuous antidepressant exposure, her most recent regiment was discontinued (paroxetine, nefazodone, and trazadone). Divalproex was continued and quetiapine (25–75 mg/day) was added transiently. She became asymptomatic 4 months later, restarted a private practice as an attorney, and reestablished her lesbian relationship.
2.4. Case 4
Mr. D is a 61-year-old married man with a type I bipolar illness for over 13 years. He had initially done quite well with lithium alone for 8 years. When he experienced a depressive episode, antidepressants were started. Initial nonresponse to SRIs was followed by a good response to doxepin. However, 2 years after continuous treatment with lithium and doxepin, he noted a crescendo of depressive episodes to a rapid cycling pace of 4 per year for two consecutive years. This was followed by a great increase in the number (1–2/month), but briefer duration of depressive episodes for the last 2 years. In addition, the interepisode period was characterized by a continuous dysphorlc, irritable, low-energy state. He took a leave of absence from his work, and was making plans to discontinue his job as a minister. Doxepin was discontinued and zolpidem or lorazepam used intermittently for insomnia. The brief depressive episodes continued for 5 months and then became less frequent. Interepisode mood improved markedly but residual mild irritability and dysphoria persisted. Insomnia was episodic. Over the 16 months off doxepin, he experienced two significant depressive episodes that responded well to transient, brief (2 months) use of bupropion. He returned to work full time and felt he was more effective.
2.5. Case 5
Ms E is a 34-year-old woman with a type I bipolar disorder since age 19. She was treated over the previous 6 years with a mood stabilizer (lithium or divalproex) and an antidepressant (most recently sertraline). She complained of persistent depression, irritability, middle insomnia, and loss of motivation. She slowly withdrew from all her friends, became unable to work, and failed at attempts to return to school. Her financial state declined and she had to sell her house and move in with her parents. Sertraline was discontinued and she was maintained on lithium with occasional alprazolam for anxiety. There was no immediate change in her symptoms, but 7 months later, she felt more energetic and returned to work. At 1-year follow-up, she had obtained and maintained a full-time job, moved out of her parents' home and married. She continued to have ongoing unhappiness and anxiety, but the irritability and middle insomnia resolved. One episode of mild mania was treated as an outpatient with transient use of olanzapine.
2.6. Case 6
Ms F is a 52-year-old married woman with type I bipolar illness for 12 years. Most recently, she was treated with bupropion for depression, clonazepam for anxiety, and maintained on divalproex for her bipolar illness. After initial resolution of the depression, she noted a gradual onset of persistent depressed mood, significant irritability, middle insomnia, and anxiety. Antidepressant was discontinued. At 4 months, there was a noted mild improvement; at 6 months, she had total resolution of the dysphoria, insomnia, and irritability. Ongoing anxiety prevented taper of clonazepam.
3. Discussion
These patients share several characteristics. All received antidepressants for protracted periods of time. All had a good antidepressant response for their index depressive episodes which persisted for at least several months. All had recurrent depressive symptoms while still taking the antidepressant, which would transiently improve with optimization of antidepressant treatment. And all experienced severe work or social dysfunction. A triad of irritability, dysphoria, and middle insomnia was noted in all six subjects. There was minimal change in clinical status immediately after antidepressants were discontinued. Beginning at 2 months, and slowly increasing thereafter, the subjects noted an improvement in dysphoria, irritability, middle insomnia, and other symptoms. Return of occupational function occurred relatively late in the course of recovery and was frequently associated with difficulties.
A similar phenomenon was described by Akiskal and Mallya a quarter of a century ago (1987). They presented 25 subjects with bipolar spectrum disorder who had been treated with tricyclic antidepressants for an extended period of time. After an initial good response, these subjects entered into a chronically symptomatic state. Similar to our sample they developed the following: “(1) unrelenting dysphoria, (2) severe agitation, (3) refractory anxiety, (4) unendurable sexual excitement, (5) intractable insomnia, (6) suicidal obsessions and impulses, and (7) ‘histrionic’ demeanor” (Akiskal and Mallya, 1987). Similar to our subjects, these patients also improved after discontinuation of antidepressants and initiation of lithium or carbamazepine.
The process leading to these symptoms is probably related to the one leading to rapid cycling. Previous workers have noted that cycling may accelerate to the point that the illness becomes continuous (Crane, 1956, Amold and Kryspin-Exner, 1965, Kukopulos et al., 1980 and Wehr et al., 1988, pp. 23–26). In other words, as cycling accelerates, the course of bipolar illness is altered from episodic to chronically continuous (Amold and Kryspin-Exner, 1965 and Kukopulos et al., 1980). It is possible that ACID is a milder manifestation of this same phenomenon. Alternatively, this may represent a process that is parallel to the observation of loss of antidepressant efficacy in unipolar depression (reviewed in Byrne and Rothschild, 1998).
The slow time course of both onset and resolution suggests that the process may involve antidepressant-induced neuroplastic changes (EI-Mallakh et al., 1999 and EI-Mallakh et al., 2000). Studies with the simple nervous systems of snails show that alteration of synaptic serotonin levels alters axonal branching. Specifically, increasing synaptic serotonin (Baker and Croll, 1996) (as probably occurs with antidepressants; Bel and Artigas, 1992). For example, one can hypothesize that a relative serotonin deficit (depression) might transiently improve with a serotonin reuptake inhibitor. However, the excess synaptic serotonin may reduce serotonergic neuron branching thereby aggravating the original problem, or inducing a chronically similar state (dysphoria).
These observations are clearly tentative. A small sample and numerous uncontrolled factors raise the possibility that alternative explanations may exist. The course of bipolar illness can be quite varied and spontaneous remissions of symptomatic states cannot be ruled out. ACID superficially resembles the depressive mixed states in type I bipolar patients of Perugi et al. (2001) and some unipolar depressive patients (Benazzi, 2001); it is important to note that such states are episodic while ACID is continuous. In type II bipolar patients, depressive mixed states occur in the absence of antidepressant treatment and may be either episodic or fluctuating-chronic (Benazzi and Akiskal, 2001 and Akiskal and Benazzi, 2003). Furthermore, the unfailing presence of the symptomatic triad of dysphoria, irritability, and middle insomnia is notable. Larger, randomized, prospective studies of patients treated continuously (as is currently recommended for recurrent major depression) or intermittently (as is currently the practice for patients who experience antidepressant worsening but still require antidepressant treatment) with antidepressant may answer the question. Our data run contrary to the recommendations of Altshuler et al. (2003), who suggested that bipolar patients who respond to antidepressants should continue receiving them, if they are on mood stabilizers. Our patients did initially respond to antidepressants, and despite coverage with mood stabilizers, developed the ACID syndrome. Large naturalistic data bases [such as is currently being amassed in the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) Study] may yield useful information on this unresolved issue.
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Corresponding author. Tel.: +1 502 852 1124; fax: +1 502 852 1115.
Posted by jrbecker on February 11, 2005, at 12:16:18
In reply to Bipolar II Series -Antidepressnt-induced dysphoria, posted by jrbecker on February 11, 2005, at 12:14:46
Journal of Affective Disorders
Volume 84, Issues 2-3 , February 2005, Pages 209-217
Bipolar Depression: Focus on Phenomenology
doi:10.1016/j.jad.2004.05.004
Copyright © 2004 Elsevier B.V. All rights reserved.
Research report
Atypical depression: a variant of bipolar II or a bridge between unipolar and bipolar II?
Hagop S. Akiskala, , and Franco Benazzib, caInternational Mood Center, University of California at San Diego, V.A. Hospital, 3350 La Jolla Village Dr. 116-A, La Jolla, San Diego, CA 92161, USA
bE. Hecker Outpatient Psychiatry Center, Ravenna, Italy
cNational Health Service, Forli, ItalyReceived 10 February 2004; accepted 13 July 2004. Available online 10 February 2005.
Abstract
Background
Although increasing data link atypical depression (AD) to the bipolar spectrum, controversies abound about the extent of the overlap. In particular, the Columbia group, which has pioneered in providing data on operational clarity and pharmacological specificity of atypical depressions, has nonetheless consistently avoided studying its discriminatory validity from bipolar II (BP-II). Accordingly, we undertook a full scale validation of such a link in a large clinical sample of BP-II and unipolar (UP) major depressive disorder (MDD).
Methods
Consecutive 348 BP-II and 254 MDD outpatients presenting with major depressive episodes (MDE) were interviewed off psychoactive drugs with a modified Structured Clinical Interview for DSM-IV, the structured Family History Screen and the Hypomania Interview Guide. We used the DSM-IV criteria for “atypical features” specifier. Depressive mixed state was defined as ≥3 concurrent hypomanic signs and symptoms during MDE. Bipolar validators were age at onset, high depressive recurrence, depressive mixed state and bipolar family history (types I and II). Univariate and multivariate logistic regression were used to examine associations and control for confounding variables.
Results
Frequency of AD was 43.0% in the combined BP-II and MDD sample. AD, versus non-AD, had significantly higher rates of BP-II. AD was significantly associated with all bipolar validators, among which family history was the most robust. A dose–response relationship was found between number of atypical symptoms during MDE and bipolar family history loading. The association between bipolar family history and number of atypical symptoms remained significant after controlling for the confounding effect of BP-II. Bipolar family history was strongly associated with the atypical symptoms of leaden paralysis and hypersomnia.
Conclusion
These results confirm a strong link between AD and bipolar validators along psychopathologic and familial grounds. From a practical standpoint, AD is best viewed as a variant of BP-II. Clinicians confronted with MDE patients presenting with atypical features should strongly consider a BP-II diagnosis. In a more hypothetical vein, atypicality—or some associated features thereof—might serve as a nosologic bridge between UP and BP-II.
Keywords: Atypical depression; Bipolar II; Leaden paralysis; Hypersomnia
Article Outline
1. Introduction
2. Methods
3. Results
4. Discussion
References
1. Introduction
According to DSM-IV-TR (American Psychiatric Association, 2000), AD is not a distinct disorder but a specifier of the major depressive episode (MDE) of bipolar and major depressive disorders (MDD) (and dysthymia). DSM-IV-TR criteria for the “atypical feature” specifier require mood reactivity plus overeating or weight gain, oversleeping, leaden paralysis and interpersonal rejection sensitivity (at least two), and absence of melancholic or catatonic features. The diagnostic validity and optimal definition of AD is currently unclear. The diagnostic validity of the Columbia group's definition of AD (the basis of DSM-IV-TR criteria) is justified by treatment response studies (better to MAOIs than to TCAs, Quitkin et al., 2003) and on latent class analysis (Kendler et al., 1996 and Sullivan et al., 1998). This definition of AD is being increasingly questioned (Perugi et al., 1998, Perugi et al., 2003, Nierenberg et al., 1998, Posternak and Zimmerman, 2001, Posternak and Zimmerman, 2002, Angst et al., 2002, Benazzi, 2002a, Benazzi, 2002b and Parker et al., 2002). In particular, many studies supporting the diagnostic validity of atypical depression (AD) had the important limitation of insufficient attention paid to discriminatory validity from bipolar II (Horwath et al., 1992, Kendler et al., 1996, Rabkin et al., 1996, Levitan et al., 1997, Sullivan et al., 1998, Sullivan et al., 2002, Sotsky and Simmens, 1999, Williamson et al., 2000, McGrath et al., 2000 and Matza et al., 2003). Furthermore, key AD symptoms (oversleeping, overeating, weight gain) were found to be more characteristic of bipolar as compared with unipolar depression (Detre et al., 1972, Akiskal et al., 1983, Hantouche et al., 1998, Serretti et al., 1998 and Mitchell et al., 2001).
In a tertiary-care AD sample (Perugi et al., 2003), close links have been recently reported between AD and bipolar-II disorder (BP-II), and between these disorders and the (possible) bipolar traits of mood lability, interpersonal sensitivity and cyclothymic temperament. Follow-up, too, has shown a relationship between AD and BP-II (Ebert and Barocka, 1991). Cross-sectional studies have shown that DSM-IV AD is more common in BP-II (Perugi et al., 1998, Perugi et al., 2003, Benazzi, 2000, Agosti and Stewart, 2001 and Angst et al., 2003). The inclusion of BP-II in AD studies is important because BP-II is common (around 50%) among depressed outpatients (Akiskal and Mallya, 1987, Dunner and Tay, 1993, Hantouche et al., 1998, Perugi et al., 1998, Akiskal et al., 2000, Benazzi, 2000, Angst et al., 2002, Angst et al., 2003, Akiskal and Benazzi, 2003 and Benazzi, 2003a). In an Australian study, Parker et al. (2002) curiously focused on their inpatient psychiatric setting—which is not where atypical depressives ordinarily come for treatment. We therefore submit that the relationship between AD and the bipolar spectrum should be further investigated in non-tertiary care settings, which are more representative of usual clinical practice.
An important diagnostic validator for AD would be diagnostic stability over time, yet such has not been realized (Kendler et al., 1996, Levitan et al., 1997 and Angst et al., 2002). Finding more BP-II than MDD in AD is not by itself a strong validator of the bipolar nature of AD, as a significant percentage of AD is reported in MDD patients (Angst et al., 2003, Benazzi, 2002a and Benazzi, 2002b). Such diagnostic validators as family history, age at onset, gender, comorbidity, temperament, treatment response, outcome and putative biology are more relevant (Robins and Guze, 1970, Akiskal, 1980, Kendler, 1990, Kendler et al., 1996 and Kendell and Jablensky, 2003). According to Kendell and Jablensky (2003), finding a bimodal distribution (zone of rarity) of key symptoms between two related syndromes would support a categorical distinction. BP-II is the closest of the bipolar disorders to MDD. Atypical features were reported to be more common in BP-II versus MDD, but no zone of rarity in the distribution of atypical symptoms was found in a mixed BP-II and MDD sample (Benazzi, 2003b), a finding not supporting AD as a distinct disorder. The strongest validator of the bipolar nature of AD would be a shared bipolar diathesis (Perugi et al., 2003). Such familial validation can be further strengthened by a dose–response relationship between number of atypical symptoms present during depression and bipolar family history loading (Rothman and Greenland, 1998). The few studies on familial bipolarity in AD versus non-AD were based on nonbipolar samples of AD (Rabkin et al., 1996, Sullivan et al., 1998 and Matza et al., 2003). The only study including BP-II and MDD in an AD sample found more bipolar family history in BP-II AD (Perugi et al., 1998), but this study was conducted in a tertiary care center.
Our aim then was to test the relationship between AD and the bipolar spectrum, by studying its association with bipolar validators—particularly on the basis of familial grounds, in an outpatient private practice setting where the bulk of AD patients present for care.
2. Methods
The present analyses were designed by both authors, but data collection itself was accomplished in FB's private practice. The methods in this outpatient setting are detailed in previous reports (Benazzi and Akiskal, 2003, Akiskal and Benazzi, 2003 and Benazzi, 2003c). Patients were consecutive 348 BP-II and 254 MDD outpatients, presenting voluntarily for treatment of a MDE, assessed in the last 5 years. Sample features are presented in Table 1, whereby BP-II vs. MDD had significantly younger index age and age at onset, higher depressive recurrences, depressive mixed states, number of atypical symptoms, individual atypical symptoms and bipolar family history. Substance-related and borderline personality disorders—which are anyway quite rare in FB's private setting—were excluded. Patients had to be off psychoactive drugs for at least 2 weeks when presenting for treatment. During the assessment visit the following instruments were used:
(1) The Structured Clinical Interview for DSM-IV Axis I Disorders-Clinician Version (First et al., 1997) (SCID-CV, reported inter-rater reliability k=0.70–1.0) as modified by Benazzi and Akiskal (2003);
(2) The Global Assessment of Functioning Scale (GAF, in the SCID-CV) for index MDE severity;
(3) The structured Family History Screen (Weissman et al., 2000) for assessing bipolar disorders family history in probands' first-degree relatives;
(4) The Hypomania Interview Guide (Williams et al., 1994) to assess intra-MDE hypomanic symptoms. Often, family members or close friends supplemented clinical information during interview, increasing validity of BP-II diagnosis and family history (Akiskal et al., 2000 and American Psychiatric Association, 2000).
Table 1.
Sample features
Variables: mean (S.D.), % BP-II, n=348 MDD, n=254 T/X2, df=600, df=1 p
Index age, years 41.5 (13.2) 46.7 (14.7) 4.4 0.000
Age at onset first MDE, years 22.8 (10.7) 31.8 (13.8) 8.9 0.000
Index GAF 50.3 (9.3) 50.6 (9.6) 0.4 0.652
N atypical symptoms 2.8 (1.5) 2.1 (1.4) 6.3 0.000
Female gender 67.8 61.4 2.6 0.104
≥5 MDEs 80.1 57.8 35.2 0.000
Index MDE symptoms>2 years 38.5 35.8 0.4 0.502
Axis I comorbidity 53.7 46.8 2.7 0.095
Index psychotic features 8.0 8.6 0.0 0.787
Index melancholic features 12.0 14.1 0.5 0.448
Index atypical features 52.8 29.5 32.6 0.000
Index depressive mixed state 62.3 33.4 49.0 0.000
Bipolar (type I+II) family history 47.7 16.5 46.4 0.000Atypical symptoms
Mood reactivity 89.6 82.2 6.8 0.009
Increased weight 21.8 10.2 14.0 0.000
Increased eating 27.0 14.1 14.2 0.000
Increased sleep 37.6 24.0 12.5 0.000
Leaden paralysis 47.1 33.4 11.2 0.001
Interpersonal sensitivity 65.8 46.8 21.6 0.000
Bipolar II disorder versus major depressive disorder.
BP-II=bipolar II disorder, MDD=major depressive disorder, GAF=Global Assessment of Functioning Scale, MDE=major depressive episode.
Systematic interviews about history of hypo-manic episodes were routinely conducted after the diagnosis of MDE, before the assessment of study variables, thereby avoiding a possible bias. We also made appropriate modifications of the SCID-CV administered in semi-structured format (Dunner and Tay, 1993, Brugha et al., 2001, Simpson et al., 2002 and Benazzi, 2003c), focusing first on overactive behaviours before evaluating mood change (Benazzi and Akiskal, 2003). We have found that patients are more likely to remember euphoric and/or irritable mood after hypomanic behaviors are elicited (Benazzi and Akiskal, 2003). Despite this sequence in our procedures giving precedence to hypomanic behavior, the final diagnosis of BP-II always required eliciting recall of hypomanic mood change occurring at the time of the activated period. We used a 2-day minimum duration threshold for hypomania for BP-II diagnosis (Akiskal et al., 1977, Akiskal et al., 1978, Akiskal et al., 1979, Akiskal, 2000, Benazzi, 2001, Simpson et al., 2002, Dunner, 2003, Angst et al., 2003 and Judd et al., 2003). This lower cut-off for hypomania duration is unlikely to have led to overdiagnosing BP-II, as most BP-II in our study setting have hypomanias lasting more than 2 days (Benazzi and Akiskal, in press).
We used DSM-IV-TR diagnostic criteria for the atypical features specifier of the MDE: mood reactivity plus increased eating or weight, increased sleeping, leaden paralysis, interpersonal rejection sensitivity (at least two) and no melancholic or catatonic features. Atypical depression was defined as an MDE with this specifier.
Depressive mixed state was defined as ≥3 hypomanic signs and symptoms during an MDE, following Akiskal and Benazzi definition (2003). Other bipolar diagnostic validators were age at onset, depressive recurrences, bipolar (type I+II) family history, following previous reports (Robins and Guze, 1970, Akiskal, 1980, Kendler, 1990, McMahon et al., 1994, Ghaemi et al., 2002, Angst et al., 2003 and Akiskal and Benazzi, 2003). We conducted a dose–response relationship analysis (Rothman and Greenland, 1998) between the number of atypical symptoms and bipolar family history.
For pairwise comparisons of continuous variables we used the t-test and the chi-squared test for categorical variables. We also used univariate, multivariate and forward stepwise logistic regression to study associations and to control for confounding. STATA Statistical Software, Release 7, was used (Stata, College Station, TX, USA, 2001). P-values were two-tailed and α level was set at 0.05, given the exploratory nature of the study.
3. Results
Frequency of AD in the combined MDD and BP-II sample was 43.0% (259/602). AD, versus non-AD (Table 2), had significantly younger index age and age at onset, higher rate of BP-II, females, depressive mixed states, axis I comorbidity, fewer psychotic features and higher bipolar family history.
Table 2.
Comparison between AD and non-AD
Variables: mean (S.D.), % AD, n=259 Non-AD, n=343 T/X2, df=600, df=1 p
Index age, years 40.3 (12.9) 46.3 (14.3) 5.2 0.000
Age at onset first MDE, years 22.9 (10.7) 29.5 (13.7) 6.4 0.000
Index GAF 51.5 (8.0) 49.6 (10.3) 2.4 0.015
MDD 28.9 52.1 32.6 0.000
BP-II 71.0 47.8 32.6 0.000
Female gender 73.3 58.8 13.5 0.000
≥5 MDEs 74.9 67.6 3.7 0.052
Index MDE symptoms>2 years 41.6 34.1 3.6 0.057
Depressive mixed state 65.2 38.7 41.3 0.000
Axis I comorbidity 58.3 45.1 10.1 0.001
Index psychotic features 3.8 11.9 13.9 0.000
Bipolar (type I+II) family history 45.5 24.1 85.7 0.000
BP-II=bipolar II disorder, MDD=major depressive disorder, GAF=Global Assessment of Functioning Scale, MDE=major depressive episode.
Table 3 shows a dose–response relationship between number of atypical symptoms during the MDE (in the BP-II and MDD combined sample) and bipolar family history loading: the higher the bipolar family history loading, the higher was the number of atypical symptoms during MDE (chi-squared test for trend=21.9, df=1, p<0.0001).
Table 3.
Dose–response relationship between number of atypical symptoms during the MDE and bipolar family history in the entire 602 sample
Variables: % BP-FH MR IW IE IS LP IRS
MDE+0, n=29 27.5 0.0 0.0 0.0 0.0 0.0 0.0
MDE+1, n=141 21.9 78.0 0.0 0.0 1.4 6.3 14.1
MDE+2, n=161 26.7 89.4 0.6 3.1 13.0 26.0 67.7
MDE+3, n=117 41.0 98.2 6.8 10.2 39.3 65.8 80.3
MDE+4, n=72 51.3 97.2 34.7 47.2 75.0 70.8 75.0
MDE+5, n=53 41.5 100.0 73.5 94.3 75.4 77.3 79.2
MDE+6, n=29 48.2 100.0 100.0 100.0 100.0 100.0 100.0
MDE=major depressive episode, BP-FH=bipolar (type I+II) family history, MR=mood reactivity, IW=increased weight, IE=increased eating, IS=increased sleep, LP=leaden paralysis, IRS=interpersonal rejection sensitivity.
Chi-squared test for trend=21.9, df=1, p<0.0001.
Table 4 shows that, within the MDD subsample, MDD plus AD had a significantly higher bipolar family history loading and lower age at onset than MDD without AD.
Table 4.
Comparison of bipolar family history in the major depressive disorder group with (MDD+AD) and without (MDD-AD) depression with atypical features
Variables MDD+AD, n=75 MDD-AD, n=179 T/X2, df=252, df=1 p=0
Bipolar family history% 24.0 12.8 4.8 0.028
Age at onset first MDE, years, mean (S.D.) 25.8 (11.6) 34.4 (13.9) −4.7 0.000
The association between AD and bipolar validators was tested (Table 5) by univariate logistic regression. AD was significantly associated with all bipolar validators. In order to test which were the strongest bipolar validator predictors of AD and to control for confounding, multiple logistic regression was used (Table 6). All possible interactions were tested: These analyses showed that depressive mixed state, BP-II and bipolar family history were significant predictors. Logistic regression of bipolar family history versus number of atypical symptoms during the MDE gave an odds ratio (OR)=1.3, 95% CI=1.1–1.4, z=3.7, p=0.000. The same analysis, controlled for BP-II (a confounding factor as it was associated with both atypical features and bipolar family history), revealed an OR=1.1, 95% CI=1.0–1.3, z=2.4, p=0.013.
Table 5.
Univariate logistic regression of atypical depression versus bipolar diagnostic validators
Variables Odds ratio 95% CI
Age at onset 0.9 0.9–0.9**BP-II 2.6 1.9–3.7**
≥5 MDEs 1.4 0.9–2.0*
Depressive mixed state 2.9 2.1–4.1**
Bipolar (type I+II) family history 2.6 1.7–3.9**
CI=confidence interval, BP-II=bipolar II disorder, MDE=major depressive episode.
* Means p≤0.05.
** Means p≤0.01.
Table 6.
Multiple logistic regression of atypical depression versus all bipolar diagnostic validators
Variables Odds ratio 95% CI
Age at onset 0.9 0.9–0.9*BP-II 1.3 0.8–2.1
≥5 MDEs 0.9 0.2–2.9
Depressive mixed state 1.9 1.2–3.0**Bipolar (type I+II) family history 1.7 1.0–2.7*
CI=confidence interval, BP-II=bipolar II disorder, MDE=major depressive episode.
* Means p≤0.05.
** Means p≤0.01.
In order to find which were the atypical symptoms most strongly associated with bipolar family history, we resorted to forward stepwise multiple logistic regression of bipolar family history versus all the atypical symptoms. The only selected atypical symptoms were leaden paralysis, increased sleep and interpersonal sensitivity. Multiple logistic regression of bipolar family history versus these variables confirmed leaden paralysis OR=1.6, 95% CI=1.1–2.5, z=2.4, p=0.015, and increased sleep OR=1.6, 95% CI=1.0–2.4, z=2.1, p=0.029 as significant predictors.
4. Discussion
The rate of 43% of AD in MDD in our study is nearly identical to that of the Angst et al.'s (2002) community study and that found by Perugi et al. (2003) in a tertiary-care sample. Unlike these three studies, age at onset of AD versus non-AD was not significantly different in a unipolar sample (Asnis et al., 1995), and no gender differences were reported in several mainly MDD community samples (Horwath et al., 1992, Levitan et al., 1997 and Sullivan et al., 2002). In the latter community studies, which did not systematically assess BP-II and used an AD definition requiring only oversleeping and overeating, AD did not have a higher rate of bipolar I than non-AD. Since specialized experience in the diagnosis of BP-II improves its detection (Dunner and Tay, 1993, Brugha et al., 2001, Ghaemi et al., 2002, Simpson et al., 2002 and Benazzi, 2003c), nonclinician interviewers appear to have led to gross underestimates of this diagnosis in all of these AD studies.
Our comparison between AD and non-AD showed that AD had features reported in previous studies, such as young age at onset, higher rate of females, BP-II and depressive mixed states, as well as axis I comorbidity; these are in line with previous studies from both clinical and epidemiological settings (Perugi et al., 1998, Benazzi, 2000 and Angst et al., 2002). Most importantly, bipolar family history was more common in AD versus non-AD. These findings support a link between AD and the bipolar spectrum. This link was more strongly shown by the dose–response relationship found between number of atypical symptoms during depression and the bipolar family history loading. A dose–response relationship supports a causal link, according to Rothman and Greenland (1998). Furthermore, number of atypical symptoms and bipolar family history were closely associated even when controlling for the confounding effect of BP-II. The latter finding suggests that AD is not simply a subset of BP-II, that indeed it may have its own distinguishing features. The AD symptoms most strongly associated with bipolar family history were leaden paralysis and increased sleep. On the other hand, the fact that even in the MDD sample, AD had more bipolar family history than non-AD, suggests that AD could be a marker of the bipolar nature of a subgroup of MDD, thereby supporting a continuity between BP-II and MDD. The present results follow closely previous analyses (Benazzi, 2003b), showing lack of bimodality in the distribution of atypical symptoms between BP-II and MDD. More tersely stated, atypicality—or some features thereof—may represent a bridge in a spectrum subsuming BP-II and UP disorders. Such temperamental characteristics, as cyclothymia and interpersonal sensitivity (both of which were not measured in the present study) might, hypothetically, subserve the proposed relationship between UP, atypicality and soft bipolarity (Perugi et al., 2003). Quitkin (2002) has proposed that “despite aspects of the disorder resembling a maladaptive, persistent mode of behavior”, AD patients do respond to psychopharmacotherapy. This statement implies that the persistent maladaptive style is a trait affective measure. Whether this trait is best described as interpersonal sensitive anxiousness (Parker et al., 2002), trait mood lability (Akiskal et al., 1995 and Akiskal, 1996) or the related construct of cyclothymia (Perugi et al., 2003) is presently unknown. It is nonetheless likely that all three temperaments are interwoven concepts (Perugi et al., 2003 and Kochman et al., 2005), in press.
The findings of the present analyses must be placed in the context of methodological assets and limitations. Ours was a solo private practice in the outpatient setting. However, interviewer bias is unlikely, because study variables were part of a larger set of data systematically and routinely assessed during the first visit (for MDE) in all new patients during the last 5 years. The interview was conducted by a clinician (FB) studying and treating mood disorders for over two decades, using reliable and validated structured and semi-structured interviews, buttressed by information from key informants. All state-of-the-art instruments were administered in a systematic manner, in a very large clinical population. The finding of a high BP-II versus MDD ratio in the present analyses is due to the use of systematic methods for probing for hypomania (Benazzi and Akiskal, 2003). Finally, the rate of bipolar family history was in line with previous family history studies (Dunner, 2003 and Hirschfeld et al., 2003).
Studies from other research centers would be desirable to confirm, modify or extend our results. But for now, our data from psychopathologic and familial validation strategies strongly support the link between BP-II and atypical depression. The two affective subtypes, while not isomorphic, appear intimately linked diagnostically and probably by an underlying pathogenetic diathesis (Perugi et al., 2003). There is little justification, on clinical grounds, to diagnose atypical depression as a UP MDD preferentially over BP-II. Our data seem to also suggest that to the extent AD is related to BP-II, it might, phenomenologically, serve as a “proxy” for depressive mixed states. Alternatively, from a nosologic perspective, AD might be conceptualised as a bridge between UP and BP-II.
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Corresponding author. Tel.: +1 858 552 8585x2226; fax: +1 858 534 8598.
Posted by jrbecker on February 11, 2005, at 12:18:52
In reply to Re: Bipolar II Series -Atypical depression, posted by jrbecker on February 11, 2005, at 12:16:18
Journal of Affective Disorders
Volume 84, Issues 2-3 , February 2005, Pages 187-196
Bipolar Depression: Focus on Phenomenology
doi:10.1016/S0165-0327(02)00172-6
Copyright © 2002 Elsevier B.V. All rights reserved.
Research report
Irritable psychomotor elation in depressed inpatients: a factor validation of mixed depression
T. Sato , , R. Bottlender, N. Kleindienst and H. -J. MöllerPsychiatrische Klinik, Ludwig-Maximilians-Universität München, Nussbaumstrasse 7 80336, Munich, Germany
Received 10 January 2002; accepted 6 May 2002. Available online 10 February 2005.
Abstract
Background: Early authors described hypomanic symptoms as mixed features in depressive episode, but this syndrome has not been sufficiently explored in previous studies. Methods: 958 consecutive depressed patients were assessed by using a standardized method in terms of 43 psychiatric symptoms at hospitalization. Results: A principal component analysis, followed by varimax rotation, extracted six interpretable factors: typical vegetative symptoms, depressive retardation/loss of feeling, hypomanic syndrome, anxiety, psychosis, and depressive mood/hopelessness. The extracted factor structure was relatively stable among several patient groups. There was no evidence that the hypomanic factor was exaggerated by antidepressant pretreatments before hospitalization. Bipolar diagnoses were associated with higher scores on depressive retardation and hypomanic symptoms, and a lower score on anxiety. Limitations: Psychiatric syndromes and their interrelationships, found in the present study, may be strongly influenced by the rating instrument used. The sample of this study was depressed inpatients. The results should not be generalized for depressed outpatients or epidemiological depressed populations. Conclusions: Hypomanic symptoms, as characterized by the flight of ideas, racing thought, increased drive, excessive social contact, irritability, and aggression are a salient syndrome in acutely ill depressed patients, lending support to the factor validity of mixed depression. The symptoms may not be related to pretreatments with antidepressants, or comorbidity of substance abuse, suggesting that they reflect various natural phenomenological manifestations of depressive episodes. Anxiety is unlikely to play a major role in the core phenomenological features of mixed depression. Hypomanic symptoms during a depressive episode were more represented in bipolar disorders, which may serve for further clarifications of latent bipolarity in unipolar depression, and prediction of switch into maniform states under biological depression treatments.
Author Keywords: Mixed states; Mixed depression; Depression; Bipolar disorder; Anxiety; Hypomania
1. Introduction
Since early classic authors, it has long been recognized that some depressed patients demonstrate considerable hypomanic symptoms such as flight of idea and increased drive, mostly accompanied by irritable mood (Kraepelin, 1921 and Himmelhoch et al., 1976; Braden and Qualls, 1979; Abrams and Taylor, 1980, a review by Koukopoulos and Koukopoulos, 1999). The classical authors described these affective states as mixed states, which are not a transient phenomenon such as a cycling process in manic–depressive illness, but relatively long lasting affective states. However, an intensive exploration of these hypomanic symptoms during a depressive episode has rarely been made. Traditional authors occasionally referred to agitated depression, an extremely high level of anxiety, in relation to hypomanic symptoms during a depressive episode (see Koukopoulos and Koukopoulos, 1999): but the relationship between hypomanic features and anxiety has not been systematically investigated in depressed patients. Many studies with multivariate techniques have been conducted to seek for evidence supporting depressive subtypes, especially melancholic and nonmelancholic subdivisions of depressive episodes (see a review by Nelson and Charney, 1981); but most of these studies did not include a broad range of hypomanic symptoms. To our knowledge, only two of such studies included hypomanic symptoms in their analyses: these studies found a symptom cluster related to psychomotor elation ( Raskin et al., 1969) and a depressive subtype characterized by hypomanic symptoms ( Andreasen and Grove, 1982) in depressed patients. However, potential implications of these findings have occupied nearly no interest in the literature.
Recent findings indicating the differential nature between mixed and pure mania in terms of phenomenological presentations (McElroy et al., 1992; Swann et al., 1993; Dilsaver et al., 1994; Dilsaver et al., 1999; Cassidy et al., 1998; Cassidy et al., 2000 and Sato et al., 2002a), natural course ( Bauer et al., 1994; Arnold et al., 2000; Perugi et al., 2000 and Sato et al., 2002b); and specific treatment responses ( Swann et al., 1997 and Greil et al., 1998) have newly aroused our interest in hypomanic symptoms during a depressive episode. Several researchers have begun to report that hypomanic symptoms are not infrequent during a major depressive episode. Akiskal and Pinto (1999) were the first to turn researchers’ attention to the potential clinical implications of hypomanic symptoms during a major depressive episode. Other authors report that these hypomanic symptoms may be associated with bipolar diagnoses, in particular bipolar II diagnosis, and atypical depressive features in their study groups ( Benazzi, 2000 and Benazzi, 2001). Depressed patients with hypomanic features, called mixed depression, have been implied to have a similar natural course to mixed mania ( Perugi et al., 1997), and to possibly demonstrate less beneficial response to tricyclics ( Koukopoulos et al., 1995), although clinical implications of these features in depressive episodes have to date not been well investigated ( Akiskal et al., 2000). These recent authors used differently defined criteria for hypomanic symptoms admixed in depressive episode. A potential role of anxiety was stressed by several authors (see Koukopoulos and Koukopoulos, 1999), while irritable mood, combined with flight of idea and increased drive, was suggested to be the core of these hypomanic symptoms ( Perugi et al., 1997). This may be because the boundary and the relationship of hypomanic symptoms to other depressive syndromes have not been systematically studied in depressed patients.
Factor analysis is one way of clarifying a psychiatric syndrome underlying various manifestations in depressed patients. We therefore carried out a factor analysis of 43 symptoms including a broad range of depressive as well as hypomanic symptoms, systematically assessed them by using a standardized method in 958 acutely ill depressed patients.
2. Methods
2.1. Patients
All patients, who were consecutively hospitalized at the Psychiatric Hospital of the Ludwig-Maximilian University in Munich, Germany for treatments of depressive states during the period of 1995–2000, were considered as subjects in this study. Clinical diagnoses of these patients were made according to ICD-10 (WHO, 1992) by means of a consensus among three experienced psychiatrists including at least one person with a professor degree. Patients, who were diagnosed as currently having major depressive episode (ICD-10 diagnoses: depressive episode F32.0–32.3; recurrent depressive episode F33.0–33.3; and bipolar affective disorder, current depressive episode F31.3–31.5), were included. Patients older than 70 years were excluded. If a patient experienced more than one hospitalization during the whole study period, only data for the last admission were included. Finally, 958 depressed patients were included. Of these patients, 863 had no lifetime history of hypomania or mania that occurred spontaneously (i.e. without effects of depression treatments) (nonbipolar depressives, UP), while 25 had experienced spontaneous hypomania that continued for at least 4 days without requirement of hospitalization (bipolar II disorder, BPII). The remaining 70 patients had a history of mania that required treatments in psychiatric hospitals (bipolar I disorder, BPI).
The demographic and clinical variables of the patients included are shown in Table 1. Among the three diagnostic groups, there was significant difference in onset age (younger onset in patients with bipolar disorders), as shown by previous studies (Cassano et al., 1992 and Hantouche et al., 1998). The frequency of antidepressant pretreatments before admission was also significantly different among the three groups.
2.2. Clinical assessments
A broad range (198 symptoms) of psychiatric symptoms were systematically assessed at admission. The AMDP system (Association for Methodology and Documentation in Psychiatry, 1981) was used for assessing psychiatric symptoms. All included patients gave informed consent to be assessed by using this instrument. The AMDP system is a comprehensive rating instrument, developed on the basis of German traditional descriptive psychopathology on functional psychoses: it is commonly used in most psychiatric institutes in German-speaking countries. Each psychiatric symptom of the AMDP system is scored from 0 (absent) to 3 (severe) with defined anchor statements by using a semi-structured interview method. Several studies indicated moderate to high inter-rater agreements for included symptoms ( Renfordt et al., 1983 and Kuny et al., 1983). Among the psychiatric symptoms assessed, 43 symptoms, which were considered from a careful review of the literature as being related to various depressive manifestations and manic features in depressed patients, were selected.
Suicidality at admission was defined in this study as a score on the AMDP suicide item higher than 1 (mild: ‘the patient repeatedly expresses the feeling that her/his life has no meaning to live’). The depression severity was measured by using the AMDP depression scale, which is calculated by summing up 13 AMDP item scores for rumination, loss of feeling, loss of vitality, depressed mood, hopelessness, feeling of inadequacy, feeling of guilt, inhibition of drive, worse in the morning, interrupted sleep, shortened sleep, early waking, and decreased appetite. This scale was previously validated in large psychiatric samples (Baumann et al., 1983 and Pietzcker et al., 1983). The coefficient for this scale in our study group was 0.793, indicating substantial internal consistency.
2.3. Statistical analyses
Principal component analysis, followed by varimax rotation, was carried out for included symptoms. The extracted factor structure was examined in terms of model fit by using confirmatory factor analyses, with factors to be correlated. This calculation was made for all subjects, for UP patients only (n=863), and for subjects without a lifetime history of drug and alcohol abuse only (n=902). The invariance of the factor structure was explored across subjects with and without antidepressant pretreatments before admission (n=732 and 226, respectively), across younger (younger than 51 years, n=458) and older (n=500) subjects, and across male (n=394) and female (n=564) subjects. Two indices for measures of fit, the goodness-of-fit index (GFI) and the adjusted goodness-of-fit index (AGFI), were used to estimate the degree to which the models fit the data. The GFI usually ranges from zero to unity, where values >0.9 indicate a good fit (Bentler, 1990). The AGFI ranges from zero to unity, where a value >0.8 indicates an acceptable fit ( Cuttance, 1987 and Cole, 1987).
Factor scores for each subject were saved, and were then compared among the three diagnostic groups (UP, BPII, and BPI). Factor scores were firstly adjusted for sex and age, and these adjusted factor scores were used for the group comparisons. An overall difference in factor scores was examined by means of the discriminant function analysis with the three diagnostic groups being used as the dependent variable, and all adjusted factor scores being used as independent variables. As posthoc univariate comparisons, Kruskal–Wallis tests or analyses of variance (ANOVA) were used, according to whether or not statistical assumptions for ANOVA were violated. The significance level for each univariate comparison was adjusted by using Bonferroni’s method. Significant statistics, produced by univariate analyses, were followed by multiple group comparisons by using Scheffe’s simultaneous confidence intervals. All statistical statements were two-tailed. Statistical packages, SPSS (1995) and AMOS ( SPSS, 1997).
3. Results
The principal component analysis produced eight eigenvalues greater than unity. However, scree-test and parallel analysis (Lautenschlager et al., 1989) indicated that a six-factor solution was more appropriate to extract interpretable factors. We therefore chose a six-factor solution. The six factors explained 49.4% of the total variance. Rotated factor loadings greater than 0.4 and percentage variance explained by each extracted factor are shown in Table 2. All symptoms loaded on only one factor each. The first factor isolated eight typical vegetative symptoms. The second factor represented depressive retardation/loss of feeling. On the third factor, hypomanic symptoms such as flight of idea, logorrhea, aggression, excessive social contact, increased drive had high loadings. Irritability also had high loading on this factor, while symptoms representative of classic mania, such as euphoria, grandiosity, and distractivity, did not have high loading on this factor. The fourth factor isolated five symptoms related to anxiety. The fifth factor represented psychotic symptoms, while symptoms related to depressive mood and hopelessness loaded on the sixth factor. None of these six factors showed bimodal distribution. Several symptoms (reverse vegetative function, morning worsening, euphoria, grandiosity, and distractivity) had no loading higher than 0.4 on any extracted factor, as shown in Table 2.
The results of confirmatory factor analyses are shown in Table 3. For these analyses, items without a clear loading on any extracted factor (reverse vegetative function, morning worsening, euphoria, grandiosity, and distractivity) were not used. The fit-indices for the factor structure were in a range, suggestive of an acceptable or good fit for all subjects, for UP patients only, and for subjects without a lifetime history of drug or alcohol abuse only. The fit-indices for the hypothesis of invariance of the factor structure across subjects with and without antidepressant pretreatments, across female and male subjects, and across younger and older subjects also remained in a similar range, indicating that the hypothesis is statistically supported.Table 4 demonstrates results of comparisons of the computed factor scores among the three diagnostic groups. The discriminant function analysis, with the diagnostic groups being used as the dependent variables, and all computed factor scores being used as independent variables, produced a significant F value (Wilks’ =0.95, F=3.20, DF=14,1894, P=0.000), indicating that factor scores significantly differed among the three groups. Posthoc univariate analysis for each factor score was carried out with a significance level of P<0.0083 (0.05/6: Bonferroni’s correction). A significant effect of diagnosis was found in factor scores 3 (hypomanic factor) and 4 (anxiety factor). Multiple comparison procedures showed that BPI patients scored higher than UP patients on hypomanic factor; and that UP patients scored higher than bipolar patients on anxiety factor. The psychomotor retardation factor (factor 2) tended to differ among the three diagnoses, with a higher score in bipolar patients.
Scores on the hypomanic factor were also compared between patients with and without antidepressant pretreatments by using an ANOVA, with diagnosis, age and gender being used as covariates. Since the number of BPII patients without pretreatments was quite small (n=2), this diagnostic group was combined with BPI patients in this analysis. The mean scores on this factor were −0.06 (S.D.=0.92) and 0.18 (S.D.=1.2) for patients with and without antidepressant pretreatments, respectively, indicating a significant difference (F=8.11, DF=1, 953, P=0.005). Patients without pretreatments scored even higher on this factor than did patients with pretreatments, suggesting that the hypomanic factor was unlikely to be exaggerated by antidepressant pretreatments in this study group.
4. Discussion
The factor analysis in the present study isolated six independent factors. The extracted factor structure appeared relatively stable across several patient groups, as shown by the confirmatory factor analyses. The fit indices computed for patients without a lifetime history of abuse were suggestive of a good or an acceptable fit. The invariance of the factor structure across patients with and without antidepressant pretreatments was also statistically supported: these suggest that the factor structure is relatively robust against effects of having a history of abuse and antidepressant pretreatments. The extracted factors were typical vegetative symptoms, depressive retardation/loss of feeling, hypomanic symptoms, anxiety, psychosis, and depressive mood. Besides several factors, which were repeatedly identified by previous factor analyses for depressed patients (Nelson and Charney, 1981; Mullaney, 1984; Rush et al., 1986 and Enns et al., 1998), hypomanic symptoms were extracted as the third factor: this indicates that hypomanic symptoms are not negligible but rather a salient syndrome in depressed patients. Our results indicated lower scores on the hypomanic factor in patients with antidepressant pretreatments: this suggests that the successful identification of this factor in the present study is unlikely to be exaggerated by antidepressant pretreatments, but is likely to reflect various natural manifestations of depressed patients. Several early studies with multivariate techniques included hypomanic symptoms in their analyses. Consistent with our results, they found a factor related to hypomanic symptoms ( Raskin et al., 1969) and a depressive subtype characterized by hypomanic features ( Andreasen and Grove, 1982) in depressed patients, although these authors did not discuss potential implications of their findings. Our results, combined with these previous investigations, indicate that some depressed patients demonstrate hypomanic symptoms in their natural course, lending support to the factor validity of mixed depression.
Symptoms composing the hypomanic factor in the present study appear somewhat different from typical manic symptoms. Recently, four studies have conducted a factor analysis for psychiatric symptoms including a broad range of atypical features in manic patients (Cassidy et al., 1998; Dilsaver et al., 1999; Rossi et al., 2001 and Sato et al., 2002a). Besides several factors associated with atypical manic features, these studies consistently found a factor representative of the typical manic syndrome, on which euphoria, grandiosity, and psychomotor elation had high loadings. Compared to the typical manic factor in manic patients, the hypomanic factor in the present study clearly lacked high loadings of euphoria and grandiosity. Instead of euphoria and grandiosity, irritability and aggression, which are usually thought to be associated with atypical manic manifestations ( Beigel and Murphy, 1971a), had high loadings on the factor. This suggests that hypomanic features in mixed depression qualitatively differ from the typical manic syndrome in manic patients. The phenomenology of mixed depression may be characterized not by a simple admixture of depressive syndromes and the typical manic syndrome, but by a relatively specific presentation composed of irritable aggressive mood and psychomotor elation.
Some factors, identified in the present study, were associated with bipolar diagnoses. Patients with bipolar disorders were more likely to present lower anxiety, slightly higher psychomotor retardation and higher hypomanic symptoms, although the results for the retardation factor did not reach a significance level after Bonferroni’s correction (F=4.53, DF=2,955, P=0.011). The findings regarding the former two factors in the present study are consistent with well-established evidence, which has repeatedly been replicated by a large number of studies (see a review by Mitchell et al., 1992; Mitchell et al., 2001 and Beigel and Murphy, 1971b). The finding that a higher score on hypomanic symptoms was associated with bipolar diagnoses in acutely ill depressed patients has firstly been reported by an early study ( Abrams and Taylor, 1980). Their study found that bipolar endogeneous depressives scored higher on a manic scale than did unipolar endogeneous depressives, although it is unclear whether or not the manic symptoms assessed in their study have similar contents, compared to the hypomanic factor identified in our present study. Since then, only Perugi et al. (1997) and Benazzi (2000) provided similar results. The consistency between these previous studies and ours strongly indicates the affinity with bipolar disorder of depresses patients with hypomanic symptoms suggesting the clinical importance of hypomanic symptoms in differentiating between bipolar and unipolar depressives. Hypomanic symptoms may also be associated with the hypothesised latent bipolarity in unipolar depressives ( Akiskal, 1996 and Akiskal and Pinto, 1999), which requires future studies investigating family history, comorbidity, specific treatment responses and natural history in unipolar depressives with hypomanic symptoms. A recent study reports that manic patients with several depressive symptoms (i.e. patients with broadly defined mixed mania) are more likely to experience a cycling into depressive episode from a first manic episode in bipolar disorder ( Zarate et al., 2001). On the analogy of this finding, one may speculate that a switch from a depressive episode into a hypomanic or manic episode under biological depression treatments is more likely to occur in depressed patients with hypomanic symptoms. This definitely requires further study since such a switch is not infrequent at least in bipolar depressives ( Bottlender et al., 2001), and is believed to be associated with phenomena suggestive of deteriorated outcome such as rapid cycling in depressed patients ( Wehr and Goodwin, 1979 and Wehr, 1993).
Hypomanic symptoms and anxiety loaded on two separate factors in our results, where only hypomanic symptoms were associated with bipolar diagnoses. This finding requires some comment, since traditional authors occasionally referred to agitated depression (an extreme pole of anxiety) in relation to a potential mixed state in depressed patients. Our results did not provide evidence that higher anxiety is likely to be accompanied by hypomanic symptoms, indicating that agitated depression (i.e. an affective state, where extremely high anxiety is accompanied by psychomotor elation) is probably heterogeneous in terms of statistically refined phenomenological factors. Some depressive patients may present both high anxiety and hypomanic symptoms, as these two syndromes were orthogonal in our results. However, our findings appear to suggest that this complex affective state can only be called a mixed depression, as far as hypomanic symptoms are accompanying. It is likely from our results that anxiety plays only a minor role in the core phenomenological features of mixed depression.
One of possible limitations in the present study is that our subjects were composed of depressed inpatients only, which raises a question as to the generalizability of our results. In particular, atypical depressive features, which are thought to be more common in outpatient or epidemiological populations (Rabkin et al., 1996), were very infrequent in our study group. Only 26 patients (2.7%) of our subjects showed reverse vegetative function, which may have resulted in our failure in clarifying relationships between atypical features and other identified factors. Several studies with multivariate techniques succeeded in identifying a factor or a depressive subtype related to atypical depressive features in outpatient and epidemiological populations ( Rush et al., 1986; Davidson et al., 1989; Kendler et al., 1996 and Sullivan et al., 1998), though some did not obtain similar results in an outpatient population ( Paykel et al., 1983) or in a sample of out- and inpatients combined ( Robertson et al., 1996). Some recent studies reported that atypical features might be correlated to hypomanic symptoms in outpatients with major depressive episode ( Benazzi, 2001). Our results indicate that this is not the case in depressed inpatients. These different findings are definitely related to different populations studied. Our sample consists of relatively few patients with bipolar diagnoses. Further study with a large outpatient or epidemiological cohort may help further clarify the relationships between atypical depressive features and other depressive syndromes including hypomanic symptoms during depressive episodes. Psychiatric syndromes and their interrelationships, found in the present study, may be strongly influenced by the rating instrument used (the AMDP-system). Further study using other rating instruments is required to confirm our findings.
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Corresponding author. Tel.: 89-5160-5505; fax: 89-5160-5520
Posted by jrbecker on February 11, 2005, at 12:20:07
In reply to Bipolar II Series -irritable/psychomotr agitation, posted by jrbecker on February 11, 2005, at 12:18:52
Journal of Affective Disorders
Volume 84, Issues 2-3 , February 2005, Pages 197-207
Bipolar Depression: Focus on Phenomenology
doi:10.1016/j.jad.2004.07.006
Copyright © 2004 Elsevier B.V. All rights reserved.
Research report
Irritable-hostile depression: further validation as a bipolar depressive mixed state
Franco Benazzia, b, , , and Hagop AkiskalcaE. Hecker Outpatient Psychiatry Center, Ravenna, Italy
bDepartment of Psychiatry, National Health Service, Forli, Italy
cDepartment of Psychiatry and Director, International Mood Center, University of California at San Diego, La Jolla, CA, USAReceived 10 February 2004; accepted 13 July 2004. Available online 27 September 2004.
Abstract
Background
“Hostile depression” has unofficially long been described as a depressive subtype, but since DSM-III, the affect has been made a defining characteristic of borderline personality disorder. The related affect of irritability in DSM-IV-TR subsumes various hostile nuances and is included in the stem question for mood disorders—especially for hypomanic episodes; in children, it is nonetheless a sign of depression. Then, there is the unofficial more general concept of depression with anger attacks, until recently ostensibly a “unipolar” (UP) disorder. A veritable tower of Babel indeed. In the present analyses, our aim was to extend previous research on irritable-hostile depression to more specific parameters of bipolarity and depressive mixed state (DMX).
Methods
Consecutive 348 bipolar-II (BP-II) and 254 unipolar (UP) major depressive disorder (MDD) outpatients (off psychoactive agents, including substances of abuse), were interviewed with the Structured Clinical Interview for DSM-IV, the Hypomania Interview Guide, and the Family History Screen. Borderline personality, a confounding variable, rare in the FB setting, was excluded. Irritability was defined according to DSM-IV-TR, which includes various features of hostility and anger. Depressive mixed state (DMX) was defined as a major depressive episode (MDE) plus three or more concurrent intradepressive hypomanic symptoms, whether it occurred in BP-II or MDD.
Results
MDE with irritability was present in 59.7% (208/348) of BP-II and in 37.4% (95/254) of MDD (p=0.0000). In BP-II, MDE with, versus MDE without, irritability had significantly younger index age, higher rates of axis I comorbidity, atypical depressive features, and DMX. Upon logistic regression, we found a significant independent association between BP-II MDE with irritability and DMX. In UP, MDE with, versus without, irritability had significantly younger age and age at onset, higher rates of atypical depression, DMX, and bipolar family history. Logistic regression revealed a significant independent association between MDE with irritability and DMX. Given that we had excluded patients with borderline personality, the high prevalence of irritable-hostile depressives in this outpatient population means that hostility cannot be considered the signature of that personality. Factor analysis revealed independent “psychomotor activation” and “irritability-mental activation” factors. Odds ratios of irritability for DMX were highest in the “UP” MDD group (=12.2); for predicting DMX, irritability had the best psychometric profile of sensitivity of 66.3% and a specificity of 86.1% for this group as well.
Limitation
We did not use specific instruments to measure irritable, hostile, and angry affects.
Conclusions
These analyses show that irritable-hostile depression is distinct from agitated depression. Whether arising from a BP-II or MDD baseline, irritable-hostile depression emerges as a valid entity with strong links to external bipolar validators, such as bipolar family history. Irritable-hostile phenomenology in depression appears to be a strong clinical marker for a DMX. Irritable-hostile depression as a variant of DMX deserves the benefit of what seems to work best in practice, i.e., anticonvulsant mood stabilizers and/or atypical antipsychotics. Formal treatment studies are very much needed.
Keywords: Hostile depression; Bipolar II disorder; Atypical depression; Depressive mixed state; Major depressive disorder
1. Introduction
Hostile depressions have long been known as an unofficial nosologic subtype of depression (Paykel and Henderson, 1977 and Overall and Zisook, 1980). Recently, it has been the subject of more formal research (reviewed in Fava and Rosenbaum, 1999). Yet it is not an official subtype since DSM-III, where hostility and anger appear as the signature of borderline personality (Snyder and Pitt, 1985 and Gardner et al., 1991). The confusion does not stop here! According to DSM-IV-TR criteria (American Psychiatric Association, 2000), a major depressive episode (MDE) must have depressed mood (or loss of interest) in adults, and mood can be irritable only in children and adolescents. In the differential diagnosis section of the MDE, it is reported that there may be MDEs “with prominent irritable mood”, which can occur in bipolar and in depressive disorders (as MDE criteria are identical). In the text description of the MDE, it is stated that “many individuals report or exhibit increased irritability (e.g., persistent anger, a tendency to respond to events with angry outbursts or blaming others, or an exaggerated sense of frustration over minor matters).” Irritability is present in the diagnostic criteria of hypomania as a criterion A.
To resolve the foregoing issues, we set off with the hypothesis that in adults, irritable-hostile depression would be linked to a bipolar depressive mixed state (DMX). In an earlier report (Benazzi, 2003a) from the present database, this hypothesis was upheld. However, due to the sample size, in that study, it was not possible to test this hypothesis in unipolar (UP) MDE patients separately from bipolar II (BP-II). In addition, it was uncertain from the results of that study whether irritable-hostile depression was distinct from agitated depression; in an earlier study, the two constructs had appeared in the same factor of “excited depression (Akiskal and Benazzi, 2004).
The hypothesis being entertained by us was actually anticipated by Kraepelin (1921, 1913 English translation by Barclay). According to him, irritability was a hypomanic (excitement) symptom, which could be present in depression (inhibition) only when it was a depressive mixed state (i.e., when symptoms of excitement and inhibition were present in the same episode). Kraepelin and Weygandt (English translation by Marneros, 2001) described a depressive mixed state, the “excited depression, which included irritability and the other excitement symptoms psychomotor agitation and more talkativeness. These ideas are also in line with the views of the Vienna School (Berner et al., 1992).
Fava et al., 1990 and Fava et al., 1993 have extensively published on depressions with anger attacks within a “unipolar” MDD framework. Only recently do they appear to have become aware that such patients might be more prevalent among bipolar patients (Perlis et al., 2004). Interestingly, Deckersbach et al. (2004) found, in bipolar-I depression, that irritability was present in 26–68%, depending on how strict were the criteria used, and that it was associated with psychomotor agitation. This study, however, had several limitations, including being based on chart review, small sample, and strict definitions of hypomanic symptoms; as a result, they could not unravel the relevance of irritable depression to mixed states. Two recent studies, using better methods, found that irritability often had a clustering of hypomanic symptoms in bipolar-I depression (Maj et al., 2003 and Perugi et al., 2001). Irritability is also seen as a core feature of depressive mixed states (Koukopoulos and Koukopoulos, 1999, Dayer et al., 2000, Akiskal et al., 2003 and Akiskal and Benazzi, 2004).
In a recent series of studies on depressive mixed states in bipolar-II (BP-II) and major depressive disorder (MDD), we found that irritability was one of the most common hypomanic symptoms present (and appearing) during depression (Akiskal and Benazzi, 2003, Benazzi, 2002, Benazzi, 2003a, Benazzi, 2003b and Benazzi, 2003c). The definition of depressive mixed states used in these studies (i.e., three or more concurrent intra-MDE hypomanic symptoms) was validated by its strong association with BP-II and bipolar family history.
The DSM-IV-TR definition of the symptom “irritability” includes anger and anger outbursts. Fava et al., 1990 and Fava et al., 1993 described, in 30–40% of MDD, a syndrome of long-lasting irritability and anger attacks, defined as spells of anger with autonomic and behavioral outbursts. Anger attacks and anger (irritability) were reported to be more common (53–62% versus 26–36%; Perlis et al., 2004 and Posternak and Zimmerman, 2002) or not (Fava and Rosenbaum, 1999) in bipolar-I depression versus MDD. Anger was found in 33% of BP-II depressions (Posternak and Zimmerman, 2002). Anger attacks responded to antidepressants in MDD (Fava and Rosenbaum, 1999 and Tedlow et al., 1999), while antidepressants were reported to induce/increase irritability/anger in bipolar depression, especially when mixed (Koukopoulos and Koukopoulos, 1999, Akiskal and Pinto, 1999, Baldessarini, 2001, Ghaemi et al., 2003, Goldberg and Truman, 2003 and Bottlender et al., 2004).
The aim of the present analyses was to shed light on the nosologic status of hostile-irritable depressions, by comparing MDE with and without irritability in BP-II and MDD samples, and by examining the relationship between MDE and irritability with bipolar validators in an MDD sample. To the best of our knowledge, this is the first study including BP-II as a comparison sample versus UP MDD.
2. Methods
The present analyses in the Ravenna–San Diego Collaborative Study were conducted on the extensive and systematically collected database of FB. The specific design of the present analyses on hostile-irritable depression were designed by HSA. We highlight herein the essential features of our overall methodology, which are generic to our collaborative studies. For full documentation, we refer the reader to previous reports (Akiskal and Benazzi, 2003, Benazzi and Akiskal, 2003a and Benazzi, 2003d). We then enlarge upon those features in our methods most relevant to defining irritable-hostile depressions.
2.1. Study setting
An outpatient psychiatry private practice, which is more representative of mood disorders usually seen in clinical practice in Italy (apart from bipolar-I).
2.2. Interviewer
A senior clinical (20 years in practice) and mood disorder research psychiatrist.
2.3. Patient population
Consecutive 348 BP-II and 254 MDD outpatients, presenting voluntarily for major depressive episode (MDE) treatment (off psychopharmacotherapy and without substance-related problems), were included in the last 5 years. Borderline personality and clinically significant general medical illnesses and cognitive disorders, which too can confound the phenomenology of labile-irritable depressions, were also excluded.
2.4. Assessment instruments
During the index assessment visit, the following instruments were used: (1) the Structured Clinical Interview for DSM-IV Axis I Disorders-Clinician Version (First et al., 1997; SCID-CV), as modified by Benazzi and Akiskal (2003a) to improve detection of BP-II; the question on racing thoughts was supplemented by the Koukopoulos and Koukopoulos' definition (1999) of crowded thoughts (i.e., mind continuously full of nonstop thoughts); (2) the Global Assessment of Functioning scale (GAF, in the SCID-CV) for index MDE severity; (3) the Hypomania Interview Guide (HIGH; Williams et al., 1994) to assess intra-MDE hypomanic symptoms; (4) the structured Family History Screen (Weissman et al., 2000) for assessing bipolar disorders family history in probands' first-degree relatives. Often, family members or close friends supplemented clinical information during the interview, increasing validity of BP-II diagnosis and family history (Akiskal et al., 2000).
2.5. Interview procedures
Systematic interviews about history of hypomanic episodes were always conducted soon after MDE diagnosis before the assessment of study variables, thereby avoiding a possible bias related to knowledge of bipolar signs (Ghaemi et al., 2002). The SCID-CV is partly semistructured and based on clinical evaluation, thus wording of the sentences can be changed to improve and to check the understanding by the interviewed. This is an important advantage versus fully structured interviews, because it reduces the false negative BP-II and mood disorders (Dunner and Tay, 1993, Brugha et al., 2001, Simpson et al., 2002, Benazzi, 2003e and Benazzi, 2004). The skip out instruction of the stem question on history of mood changes was not followed, in order to assess all past hypomanic symptoms, especially overactivity (increased goal-directed activity), this procedure being in line with previous reports (Dunner and Tay, 1993, Akiskal et al., 2001, Simpson et al., 2002, Angst et al., 2003, Benazzi and Akiskal, 2003a, Benazzi and Akiskal, 2003b and Benazzi, 2003f).
2.6. Diagnostic definitions
Irritability was defined according to DSM-IV-TR. In the SCID-CV for DSM-IV, irritability is defined only for mania, by the question “you were so irritable that you found yourself shouting at people, or starting fights or arguments”. There is no similar structured question for irritability in hypomania, but the features must be similar, apart from severity. DSM-IV-TR text description of irritability is “easily annoyed and provoked to anger”, “persistent anger, a tendency to respond to events with angry outbursts or blaming others, or an exaggerated sense of frustration over minor matters”. The anger attacks described by Fava et al., 1990 and Fava et al., 1993 in MDD are included by DSM-IV-TR in the definition of irritability. In the present study, irritability was scored present if at least one of the above features was positive. Depressive mixed state was defined as an MDE plus three or more concurrent intra-MDE hypomanic symptoms (DMX3, according to Akiskal and Benazzi, 2003). Hypomanic symptoms had to appear during the MDE (i.e., a hypomanic symptom-free interval of at least 1 month before the MDE was required), to last at least 1 week and to be present at the time of the interview (to increase reliability).
2.7. Statistics
Univariate and multivariate logistic regression were used to study associations and to control for confounding. The two-sample test of proportion was used to compare proportions. Principal component factor analysis (varimax rotation, eigenvalue>1, item loading>0.40) was used to study the relationships among the intra-MDE hypomanic symptoms (those present in more than 10%, to reduce the “noise” effect of low-frequency symptoms), following previous factor analysis studies of hypomania (Hantouche et al., 2003, Benazzi and Akiskal, 2003b, Cassidy et al., 1998, Dilsaver et al., 1999 and Bauer et al., 1991). ROC analysis was used to study predictive power. STATA Statistical Software, Release 7, was used (Stata Corporation, College Station, TX, USA, 2001). P values were two-tailed, and alpha level was set at 0.05, given the exploratory nature of the study.
Comparisons were made between MDE with and without irritability, independently, in both the BP-II and MDD samples, on clinical and family history variables. As diagnostic and bipolar validators were used age at onset, number of MDE recurrences, frequency of atypical depressions and depressive mixed states, and bipolar (type I and type II) family history, following previous reports (Kraepelin, 1921, Robins and Guze, 1970, Kendler, 1990, McMahon et al., 1994, Ghaemi et al., 2002, Akiskal, 2003, Angst et al., 2003, Akiskal and Benazzi, 2003, Sato et al., 2003, Coryell, 1999, Dunner, 2003 and Goodwin and Jamison, 1990).
3. Results
3.1. Prevalence
MDE with irritability was present in 59.7% (208/348) of BP-II, and 37.4% (95/254) of MDD (z=5.4, p=0.0000).
3.2. Comparisons in the BP-II sample
Comparisons between MDE with and without irritability are presented in Table 1. MDE with irritability had significantly lower index age, more axis I comorbidity, and more atypical depressions. Among the intra-MDE hypomanic symptoms, it had significantly more depressive mixed states and more psychomotor agitation. Among the MDE symptoms, it had significantly more weight gain, increased eating, and more leaden paralysis.
Forward stepwise logistic regression of MDE with irritability (dependent variable) versus the variables found significantly different in the pairwise comparisons of Table 1, found significant independent associations with DMX (coefficient=0.4, 95% CI=0.3–0.5, p=0.000), increased eating (coefficient=0.1, 95% CI=0.0–0.2, p=0.024), and psychomotor agitation (coefficient=−0.1, 95% CI=−0.2–0.0, p=0.029). The odds ratio of irritability for DMX was 7.3.
Factor analysis (Table 2) found two factors: a motor activation factor 1 and irritability-mental activation factor 2 (risky activities present only in 21.6%).
Sensitivity, specificity, and area under the ROC curve of irritability for predicting depressive mixed state were sensitivity=80.2%, specificity=64.2%, ROC area=0.72.
3.3. Comparisons in the MDD sample
Comparisons between MDE with and without irritability are presented in Table 3. MDE with irritability had significantly lower index age, lower age at onset, more atypical depressions, and more bipolar family history. Among the intra-MDE hypomanic symptoms, it had significantly more depressive mixed states, more distractibility, racing/crowded thoughts, psychomotor agitation, and risky activities. Among the MDE symptoms, it had significantly more hypersomnia, psychomotor agitation, leaden paralysis, and difficulty concentrating.
Forward stepwise logistic regression of MDE with irritability (dependent variable) versus the variables found significantly different in the pairwise comparisons of Table 3, found significant independent associations with DMX (coefficient=0.7, 95% CI=0.6–0.9, p=0.000), psychomotor agitation (coefficient=−0.2, 95% CI=−0.4–0.1, p=0.000), racing/crowded thoughts (coefficient=−0.1, 95% CI=−0.3–0.0, p=0.005), and age (coefficient=−0.0, 95% CI=−0.0–0.0, p=0.006). The odds ratio of irritability for DMX was 13.8.
Factor analysis (Table 4) found two factors: a motor activation factor 1 and an irritability-mental activation factor 2 (risky activities present only in 14.7%).
Sensitivity, specificity, and area under the ROC curve of irritability for predicting depressive mixed state were sensitivity=66.3%, specificity=86.1%, ROC area=0.76.
3.4. MDE with irritability in BP-II and MDD
Comparisons on bipolar validators between BP-II and MDD major depressive episode with irritability are presented in Table 5. There were significant differences on all validators.
4. Discussion
In the present analyses, we have observed a great many strong associations linking irritable-hostile depressions to various parameters of bipolarity. Given that the interview was conducted by one psychiatrist (FB), unintended biases cannot be entirely excluded. However, systematic biases are unlikely, because all patients underwent rigorous diagnostic work-up with the use of reliable and validated instruments. Finally, as the designs of these analyses were enunciated by HA, FB could not have been aware of the potential use of this database in the present manner. The main limitation of our study is that we did not use a validated instrument specifically geared to measure hostility and anger attacks (Fava et al., 1991).
Frequency of MDE with irritability in this outpatient BP-II and MDD sample was high (ranging from 37% in MDD to 60% in BP-II), suggesting that irritability is a common symptom of MDE. It was however significantly more common in BP-II MDE. The finding is in line with the less conservative frequency of irritability in bipolar-I depression found by Deckersbach et al. (2004), and with the frequency of anger attacks (included in the DSM-IV-TR definition of irritability) in bipolar-I depression found by Perlis et al. (2004). Factor analysis, done independently in the BP-II and in the MDD samples, supported the subtyping MDE with and without irritability.
In the BP-II sample, MDE with irritability was strongly associated with many intra-MDE hypomanic symptoms (depressive mixed state), a finding buttressed by multivariate logistic regression. A higher rate of psychomotor agitation in MDE with irritability was found also in a bipolar-I sample by Deckersbach et al. (2004). Atypical features were also more common in MDE with irritability, a finding which may account for the association found between atypical depression and hypomanic symptoms (Benazzi, 2001).
Our results indicate that, in BP-II, MDE with irritability is highly likely to have several concurrent hypomanic symptoms (OR=7.3), in brief that irritability may be a marker of depressive mixed state. ROC analysis supported this finding, showing an area under the ROC curve of 0.72 (meaning adequate predictive power, with high sensitivity, and relatively high specificity).
In the UP sample, MDE with irritability had significant associations with bipolar validators, such as young age at onset, atypical depression, depressive mixed state, and, most importantly, bipolar family history. Also in the UP sample, MDE with irritability was significantly highly likely to have many concurrent hypomanic symptoms (OR=12.2), such as distractibility, racing/crowded thoughts, psychomotor agitation, and risky activities, again suggesting that it may serve as a marker of depressive mixed state in MDD. This association was supported by multivariate logistic regression. ROC analysis showed that the area under the ROC curve was 0.76 (meaning adequate predictive power, with relatively high sensitivity, and high specificity). Overall, these findings suggest that MDE with irritability in MDD may be related to the bipolar spectrum (as described by Akiskal and Pinto, 1999), and that it may be even a more robust marker of bipolarity in MDD.
That both BP-II and MDD with irritable cross-sectional symptoms have underlying bipolar familial diathesis is of great significance in classification and genetics. That depressions with anger attacks have more offspring with delinquency and aggressive behavior (Alpert et al., 2003) could reflect the passing on of “mood genes” of bipolar nature from one generation to another.
The analyses done independently in the two samples of BP-II and MDD showed that MDE with irritability had several important common features, such as the association with depressive mixed state. This finding represents further strong independent association, as shown by multivariate logistic regression. These results suggest that MDE with irritability may be associated with many concurrent hypomanic symptoms independently of the BP-II and MDD distinction, in brief that irritability by itself is likely to be associated with a clustering of hypomanic symptoms.
Among the atypical symptoms significantly more common in MDE with irritability (in the MDD sample) there was hypersomnia. In classic textbooks (Goodwin and Jamison, 1990 and Akiskal, 2002), in Hecker's description of “cyclothymia” (corresponding to DSM-IV-TR BP-II; 1898, English translation by Koukopoulos, 2003), and in more recent studies (Mitchell et al., 2001), hypersomnia was reported to be a typical feature distinguishing bipolar depression versus MDD. This is another finding supporting the bipolar nature of MDE with irritability in MDD.
MDE with irritability in BP-II versus MDD had significant differences on bipolar validators. A finding suggesting that MDE with irritability may lie along a continuum linking MDD and BP-II, thereby bridging the gap created by DSM-IV-TR between bipolar and depressive disorders.
Kraepelin described irritability only in hypomania (i.e., as an excitement symptom), which could be present in depression only when depression was mixed (i.e., it had concurrent inhibition and excitement symptoms), like in the depressive mixed state he termed “excited depression”. Both irritability and psychomotor excitement were core features of this depressive subtype. However, the present analyses suggest that agitated depression and irritable depression might be distinct. Our findings further suggest that 60% of BP-II MDE (a similar percentage was found by other studies in bipolar-I MDE) may have concurrent irritability, running against the DSM-IV-TR criteria for MDE, which are the same in bipolar and depressive disorders and do not include irritability in adults. The results of our studies in both BP-II and UP suggest that irritability may be a symptom distinguishing bipolar depression from MDD. Curiously, a recent study (Posternak and Zimmerman, 2002) found anger limited in mood disorders to BP-I and MDD; however, given that very few patients in their sample of 1300 outpatients had BP-II diagnosis, one can conclude that these authors seem to have a systematic bias against this diagnosis.
Despite the DSM-IV-TR description of hostility as the signature affect in borderline personality, there is no evidence that this affect is unique to this particular personality disorder. At any rate, such anger in borderline personality responds significantly to fluoxetine (Salzman et al., 1995), divalproex (Frankenburg and Zanarini, 2002), and lamotrigine (Pinto and Akiskal, 1998). Such pharmacologic response suggests that the anger in these patients has affect disorder origins. Finally, the fact that in the present study we demonstrated a high prevalence of irritability in an outpatients sample from which we had excluded borderline personality disorder indicates that hostile affect should not be viewed as a pathognomonic indication of borderline personality disorder. Our patients instead were suffering from depressive mixed states with bipolar substrate—an entity to be yet recognized by the official classification of both the American (DSM-IV-TR, 2000) and International (ICD-10) classifications.
Whereas validating MDE with irritability as a bipolar spectrum disorder needs further studies, from what we know already, it seems to have important diagnostic and therapeutic utility. Actually, thioridazine is FDA indicated for depression with hostile features (Schatzberg and Nemeroff, 2004, p. 432). More recently, in MDD, at least one controlled trial has shown that anger attacks in bipolar patients respond well to a combination of an SSRI added to a mood stabilizer (Mammen et al., 2004). Further studies are needed to determine the optimal short-term and long-term treatment of hostile depressions. Antidepressants were effective in MDE with anger attacks (included in DSM-IV-TR definition of irritability) in the short term (Fava et al., 1993). Instead, in bipolar depression, many open reports showed that antidepressants can induce hypomanic symptoms (Akiskal et al., 1977, Goodwin and Jamison, 1990, Altshuler et al., 1995, Baldessarini, 2001, Ghaemi et al., 2003 and Goldberg and Truman, 2003), and bipolar-I mixed depression was shown to have a higher risk of switching with antidepressants versus nonmixed bipolar-I depression (Bottlender et al., 2004).
5. Conclusion
These findings suggest that depression with irritability is associated with many intradepressive hypomanic symptoms (depressive mixed state) and with external bipolar validators. It is noteworthy that this was so both in BP-II and MDD, suggesting that MDD with irritability may lie along a continuum linking BP-II and nonirritable MDD. The finding of a strong association between irritable-hostile depression and numerous noneuphoric concurrent hypomanic symptoms suggests that its treatment may first (or concurrently) require mood-stabilizing agents and not antidepressant monotherapy, in order to reduce a possible worsening of irritability (and of the other often present intradepressive hypomanic symptoms). Atypical antipsychotics would also be relevant. Controlled trials are required to test the possible treatment impact of subtyping depression on the basis of irritability.
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Corresponding author. Via Pozzetto 17, 48010 Castiglione di Cervia RA, Italy. Tel.: +39 335 6191 852; fax: +39 054 330 069.
Posted by jrbecker on February 11, 2005, at 12:21:36
In reply to Bipolar II Series - irritable-hostile depression, posted by jrbecker on February 11, 2005, at 12:20:07
Journal of Affective Disorders
Volume 84, Issues 2-3 , February 2005, Pages 233-242
Bipolar Depression: Focus on Phenomenology
doi:10.1016/j.jad.2003.11.007
Copyright © 2004 Elsevier B.V. All rights reserved.
Research report
Is migraine in unipolar depressed patients a bipolar spectrum trait?
Ketil Joachim Oedegaard , and Ole Bernt FasmerDepartment of Psychiatry, Haukeland Hospital, University of Bergen, N-5021, Bergen, Norway
Received 29 September 2003; accepted 12 November 2003. Available online 22 January 2004.
Abstract
Background: It is well known that affective disorders and migraine often coexist in the same patients, and some information is available indicating that migraine is particularly prevalent in bipolar II disorder. The aims of this study were to compare the clinical features in unipolar depressed patients with and without comorbid migraine to bipolar patients. Methods: Semi-structured interview of 201 patients with major affective disorders, using DSM-IV criteria for affective disorders combined with Akiskal's criteria for affective temperaments, and IHS-criteria for migraine. Results: Compared to the group of patients having unipolar depressions without comorbid migraine (n=51) the group with unipolar depression and migraine (n=63) had a higher number of depressive episodes (4.5 vs. 2.5, P=0.017), significantly higher prevalences of affective temperaments (46% vs. 16%, P=0.001), irritability (70% vs. 45%, P=0.008), seasonal variation (22% vs. 5%, P=0.017), agoraphobia (44% vs. 26%, P=0.036), asthma (25% vs. 6%, P=0.006) and migraine in family (59% vs. 29%, P=0.002). The clinical features of unipolar depressed patients with comorbid migraine resemble the bipolar II patients (n=51) in this sample. Limitations: Non-blind, cross-sectional assessment. Conclusions: These results indicate that there may be important clinical differences between unipolar depressed patients with and without comorbid migraine, possibly indicating that migraine in depressed patients is a bipolar spectrum trait.
Author Keywords: Affective disorders; Affective temperaments; Migraine
Article Outline
1. Introduction
2. Methods
3. Results
4. Discussion
References
1. Introduction
Patients with major affective disorders often have comorbid migraine (Breslau et al., 1994 and Merikangas and Stevens, 1997). The prevalence of migraine and depression in the general population is similar, around 10%, and females are more often affected with either disease (Silberstein and Lipton, 1993 and Thase and Kupfer, 1996). Both migraine (Gardner, 1999) and bipolar affective disorders (Gelernter, 1995) have an apparent genetic background, but it has been hard to identify a single genetic locus. Moreover, there is a strong association between migraine and anxiety disorders (Breslau et al., 1994 and Swartz et al., 2000), and there seems to be a syndrome characterized by an early occurring anxiety disorder, followed by migraine and depression over the life time course (Merikangas and Stevens, 1997).
There are few studies of migraine in patients presenting primarily with psychiatric disorders. In a study from his private specialist practice in New York, Endicott (1989) found that between 20% and 50% of patients with major affective disorders also had migraine. Concerning patients with bipolar disorders a 26% prevalence of migraine has been reported (Mahmood et al., 1999). In two papers from a previous study of 102 patients we have reported that there seems to be a preferential association between migraine and bipolar II disorder, and we have suggested that the presence of migraine may be used to delineate a distinct subgroup of the major affective disorders (Fasmer, 2001 and Fasmer and Oedegaard, 2001). According to the present classification systems in psychiatry, the presence or absence of hypomania separates bipolar II from unipolar disorder. However, hypomania may be difficult to separate from mania, and depressed patients may on follow up develop mania or hypomania (Akiskal, 1996). In an extension of the previous study we have identified another 99 patients with a major affective syndrome. The purpose of this has been to collect a sufficient amount of patients to separate unipolar depressed patients with migraine from unipolar patients without comorbid migraine with regards to the type and characteristics of the clinical symptoms, looking for signs of bipolarity that might be associated with the presence of migraine.
2. Methods
The study group (n=201) comprised 177 psychiatric patients at one of the University hospitals of Bergen and 24 psychiatric patients from private praxis in the county of Fusa outside Bergen. One hundred and nineteen subjects were consecutively admitted patients to a 12 bed open psychiatric ward (62 in the first study and 57 in the second study). The remaining patients were either inpatients at other wards of the hospital (n=19), from the outpatient department or the day care unit (n=39). The mean age in the whole group was 36.9±10.2 years (range 18–64). One hundred and thirty-nine patients (69%) were female. Patients were included if they presented with a major affective syndrome (major depression or mania), which was not clearly secondary to an organic or substance abuse disorder, were between 18 and 65 years old, and gave informed consent to participate. Patients that did not speak Norwegian with sufficient fluency to be interviewed without interpreter were excluded. The patients that were psychotic at intake were not psychotic when interviewed. The local ethics committee has approved the study protocol.
We used a semi-structured interview based on DSM-IV criteria (American Psychiatric Association, 1994) for affective disorders (major depressive episode, mania, hypomania), anxiety disorders (panic disorder, agoraphobia, specific phobia, social phobia, generalized anxiety disorder, obsessive compulsive disorder) and eating disorders (anorexia nervosa and bulimia nervosa). Hyperthymic, irritable and depressive temperaments were diagnosed according to the criteria of Akiskal and Mallya (1987), and cyclothymic temperament according to Akiskal and Akiskal (1992). Criteria for the cyclothymic temperament requires at least three of five attributes of each of the following two sets, with an indeterminate early onset (<21 years). First group: (1) Hypersomnia versus decreased need for sleep. (2) Introverted self-absorption versus uninhibited people-seeking. (3) Taciturn versus talkative. (4) Unexplained tearfulness versus buoyant jocularity. (5) Psychomotor inertia versus restless pursuit of activities. Second group: (1) Lethargy and somatic discomfort versus eutonia. (2) Dulling of senses versus keen perceptions. (3) Slow-witted versus sharpened thinking. (4) Shaky self-esteem alternating between low self-confidence and overconfidence. (5) Pessimistic brooding versus optimism and carefree attitudes. The hyperthymic temperament requires at least five of the following characteristics, with an indeterminate early onset (<21 years): (1) Irritable, cheerful, overoptimistic, or exuberant. (2) Naive, overconfident, self-assured, boastful, bombastic, or grandiose. (3) Vigorous, full of plans, improvident, and rushing off with restless impulse. (4) Overtalkative. (5) Warm, people-seeking, or extroverted. (6) Overinvolved and meddlesome. (7) Uninhibited, stimulus-seeking, or promiscuous. The irritable temperament requires at least five of the following characteristics, with an indeterminate early onset (<21 years): (1) Habitually moody, irritable and choleric, with infrequent euthymia. (2) Tendency to brood. (3) Hypercritical and complaining. (4) Ill-humored joking. (5) Obtrusiveness. (6) Dysphoric restlessness. (7) Impulsive. The depressive temperament requires at least five of the following characteristics, with an indeterminate early onset (<21 years): (1) Gloomy, pessimistic, humorless, or incapable of fun. (2) Quiet, passive, and indecisive. (3) Sceptical, hypercritical, or complaining. (4) Brooding and given to worry. (5) Conscientious or self-disciplining. (6) Self-critical, self-reproaching, and self-derogatory. (7) Preoccupied with inadequacy, failure, and negative events to the point of morbid enjoyment of ones failures. Unipolar depressive, bipolar I disorder and bipolar II disorder were diagnosed according to DSM-IV criteria.
With regard to affective disorders the following information was recorded: age of onset of the first major affective episode and the first depressive episode, the number of depressive episodes, the presence of melancholic or atypical symptoms (DSM-IV criteria) in the present or in previous episodes, seasonal variability of depressive episodes, current or previous suicide attempt, suicidal thoughts, psychotic symptoms, and the presence of prominent irritability or suspiciousness in the current or previous major depressive episodes.
For the anxiety disorders, the age of onset was recorded for each.
Symptoms of the following psychiatric disorders were also recorded (DSM-IV criteria): attention-deficit/hyperactive disorder, dyslexia and abuse of alcohol and drugs. Use of tobacco currently or previously was noted. History of characteristic symptoms of the following somatic symptoms was asked for: allergic rhinitis or other allergic disorders, asthma, atopic eczema, Raynaud's syndrome (Miller et al., 1981) and thyroid disorders. Hand preference was assessed according to the method of Oldfield (1971).
The criteria of the Headache Classification Committee of the International Headache Society (1988) were used to establish the diagnosis of migraine. In addition to migraine with and without aura the occurrence of migraine aura without headache was specifically asked for and recorded. Age of onset of migraine and the frequency of attacks (>1 per week, >1 per month, <1 per month, no attacks last year) were recorded.
Information about serious psychiatric disorders (major depression, bipolar disorder, psychosis, suicide) or migraine in first-degree family members was obtained from interviews of patients or from hospital records.
The first 102 patients were interviewed by the second author (O.B.F.), and the last 99 patients by the first author (K.J.O.). To assure an identical diagnostic approach both authors interviewed 10 patients together.
Chi-square test, t-test (two-tailed) or Fischer's exact test were used to calculate differences between groups. SPSS version 11.0 was used for the statistical analyses.
3. Results
The mean age of the patients was 36.9±10.2 years. Sixty-nine percent were female. The index episode was depression in 90% of the patients and mania in 10%. During the index episode 69% of the patients were inpatients. One hundred and seventeen patients had migraine (57%), and among these, 57 (28%) patients had migraine with aura, 41 (20%) had migraine without aura and 18 (9%) patients had migraine aura without headache. A majority of patients had suffered from migraine within the last 12 months (86%), and most of these patients (64%) had experienced at least one attack within the last month. Characteristics of the sample, grouped according to the diagnosis unipolar, bipolar I, and bipolar II disorder are detailed in Table 1. Furthermore, the unipolar patients are subdivided into two groups, depending on the presence or not of migraine. The presentations of the bipolar groups are given as a demonstration of the sample. All significances are calculated for the comparison between the two unipolar groups with or without migraine. There were no significant differences in age, gender distribution, marital status, work activity, alcohol or substance abuse or family history of serious psychiatric illness. Concerning serious psychiatric illness in first grade relatives, a bipolar I disorder was reported by 4.8% (3/63) of the unipolar patients with migraine and in none of the unipolar patients without migraine (0/51). The frequency of depressive episodes was 52.4% (33/63) and 41.2% (21/51) in first grade relatives of unipolar patients with and without migraine, respectively. No attempt was made to discriminate possible bipolar II disorder in these relatives. As expected there were more patients in the migraine group with a family history of migraine.
Table 1. Characteristics of the whole sample (n=201), and the comparison of the of unipolar patients with and without migraine
In Table 2 the somatic characteristics of the sample are shown. The only significant difference between the unipolar groups is that the frequency of asthma is four times higher among the patients with comorbid migraine (25% vs. 6%). Concerning all the other somatic features demonstrated, the two groups are surprisingly similar, except for the higher prevalence of left- or mixed-handedness among the migraine patients, although this was not significant.
Table 2. Some somatic characteristics of the whole sample, and the comparison of unipolar disorders with and without migraine
The characteristics of depressions are demonstrated in Table 3. Several differences emerge between the unipolar patients with migraine when compared to those without migraine. The patients with migraine had a higher total number of depressive episodes (4.5 vs. 2.5, P=0.017), they had significantly more often an affective temperament (46% vs. 16%, P=0.001), irritability (70% vs. 45%, P=0.008) and seasonal variation of depressions (22% vs. 3%, P=0.017). Regarding the type of affective temperaments, the unipolar patients with migraine most often were cyclothymic (n=13), or depressive (n=12), whereas few were hyperthymic (n=3) and only one patient had an irritable temperament. In the eight unipolar patients without migraine who had an affective temperament the distribution in the groups above were, respectively 3, 4, 1 and 0. Whereas patients in both groups commonly report irritability as a symptom occurring during depressions, this must not be confused with irritable mood as an affective temperament since this was only found in one unipolar patient. Even in bipolar I and bipolar II patients the presence of an irritable temperament was rare (one and two patients, respectively), while both BP I and BP II patients most often had a cyclothymic temperament (13 vs. 18 patients) and quite seldom a hyperthymic (two vs. three patients) or depressive temperament (five vs. two patients). Notice that the characteristics of bipolar II patients resemble those found in the unipolar patients with migraine concerning both number of depressive episodes (4.9), affective temperaments (49%), irritability (77%) and seasonality (33%), whereas the bipolar I patients seem to have more depressive episodes (6.6) and affective temperaments (58%) and less irritability (56%). The presence of seasonal variation is the same in both types of bipolar disorder. On the other hand, the unipolar patients have about the same prevalences of psychotic symptoms, suspiciousness, melancholia, guilt, suicidal behavior, rejection sensitivity or other atypical features, and treatment response to SSRI's, weather they suffer from migraine or not. Concerning most of these features the bipolar I and bipolar II patients have more symptoms than the unipolar patients, although there are some obvious differences since psychotic symptoms seem to be more pronounced in bipolar I patients, and suspiciousness in bipolar II patients. It might be noteworthy that particularly bipolar I patients report to be non-responders to SSRI's during depressions. There is no significant difference between the unipolar patients with and without migraine concerning the age at onset of first depressive episode, but it might be worth mentioning that the age of onset of depressions is significantly earlier in both bipolar I (22.3 vs. 28.1; t-test, P=0.008) and bipolar II patients (23.1 vs. 28.1, t-test, P=0.007) when compared to the whole sample of unipolar patients. Moreover, the bipolar II patients appear to report an earlier onset of hypomania than of depression (age 20.9 vs. 23.1).
Table 3. Characteristics of depressions in the whole sample and the comparison of unipolar disorders with and without migraine
As shown in Table 4, unipolar patients with comorbid migraine had an overall tendency towards a higher number of anxiety disorders (2.4 vs. 1.9, NS) than the patients that did not have migraine, but this was only significant for agoraphobia (44% vs. 26%, P=0.036). Unipolar patients with migraine seem to be more akin with bipolar II patients concerning comorbid anxiety disorders than with bipolar I patients or unipolar patients without migraine, although the total burden of anxiety appears to be even higher in bipolar II patients who have a total number of anxiety disorders of 2.8. Regarding obsessive-compulsive disorder or eating disorders, however, the bipolar II patients seem to be more affected than both bipolar I patients and unipolar patients, and no significant impact related to the presence of migraine is found in the latter group.
Table 4. Anxiety and eating disorders in the whole sample and the comparison of unipolar disorders with and without migraine
4. Discussion
The present findings indicate that the unipolar depressions associated with migraine are different from unipolar depressions without comorbid migraine in several important clinical features. It is noteworthy that almost half of the patients (46%) in the migraine group had an affective temperament. In addition most of them (70%) reported increased irritability as an important symptom during depressions, and nearly one-forth (22%) stated that they had seasonal variations in their depressive symptoms. This constellation was significantly different from that seen in unipolar patients without migraine. The patients with migraine furthermore had a higher number of depressive episodes, even though they were slightly older than the non-migraine patients when the first depression started (28.7 vs. 27.4), and insignificantly older at the time of inclusion (38.5 vs. 36.4, P=0.299) in the study. Additionally, the migraine patients had a tendency towards an increased number of comorbid anxiety disorders, although this was only significant for agoraphobia. Concerning the somatic conditions recorded in this study, the only difference associated with migraine was an increased prevalence of asthma. Other characteristics such as gender distribution, age, age of onset of depressive episodes, marital status and frequency of alcohol or substance abuse were not significantly different.
Unipolar disorder in this study is defined according to DSM-IV criteria. There is substantial evidence supporting the separation of patients with cyclothymic temperament from the unipolar depressive group (Akiskal and Akiskal, 1992), and it might be argued that there are several subgroups in this realm of "soft bipolar" conditions (Akiskal and Mallya, 1987), including patients with either shorter hypomanic episodes and even hyperthymic temperament. A link between migraine and neuroticism has been reported in several epidemiological studies (Breslau and Andreski, 1995; Merikangas et al., 1993 and Merikangas et al., 1994) and Wolff introduced the notion of migraine personality more than 60 years ago, including increased mood lability and depressions characterized by anergia and particularly panic disorder and phobia (Wolff, 1937). The contemporary equivalent to these features is the atypical subtype of depression. The high prevalence of affective temperaments in the unipolar patients with migraine, which is in line with the prevalence found in the bipolar II group, may possibly reflect increased mood lability in migraine patients and represent a linkage to bipolar disorders. We did not find more atypical depressions among the unipolar migraine patients, but irritability as a prominent symptom was more common in this group. Depressive mixed states (major depressive episodes with some hypomanic symptoms) have been found to be more prevalent in atypical depressions than in non-atypical depressions (Benazzi, 2001), and both irritability, agitation, racing thoughts and increased talking are reported as common features of a mixed state (Akiskal, 1992; Akiskal and Mallya, 1987; Goodwin and Jamison, 1990; Koukopoulos et al., 1992 and Perugi et al., 1997), and repeatedly associated with bipolar II and cyclothymic or hyperthymic temperament ( (Akiskal, 1996 and Akiskal et al., 1998). It is well known that prodromal and accompanying symptoms of migraine attacks are often psychiatric in nature, such as depression, elation, racing thoughts, irritability and anxiety (Davidoff, 1995). Irritability may be both a part of the prodrome that often precedes migraine headache, and a prominent symptom during hypomanic/manic or mixed state affective episodes. The increased frequency of irritability among the unipolar migraine patients in the present study, may possibly relate them to bipolar patients.
In a study from 1984, Rosenthal found that 90% of patients who suffered from winter depressions had a bipolar disorder (Rosenthal et al., 1984). Several studies have later opposed this finding. But, in the present study seasonal variation was more common in bipolar than in unipolar disorder. However, the unipolar patients with migraine reported significantly more seasonal variation of depressions than those without migraine, and in this regard they are more in line with the bipolar patients.
Both suicidal ideation and suicide attempts have been reported to be increased in patients having migraine with aura and major depression compared to patients having major depression without migraine (Breslau, 1992). In the present study the number of patients with suicide attempts was not significantly different between the unipolar groups with and without migraine. The most probable explanation is the high baseline frequency of suicide attempts in the whole sample, obscuring any preferential association with migraine. However, we found that the rate of prior suicide attempts were 30%, 50% and 61%, respectively, in unipolar, bipolar I and bipolar II patients. This is in good agreement with recent reviews showing that bipolar II patients carry the highest suicide risk, followed by bipolar I and unipolar disorder (Rihmer and Kiss, 2002). This may be interesting, since both migraine and suicide are strongly related to serotonin disturbance, and therefore, it is not surprising that the most suicidal form of major mood disorders (bipolar II) is most strongly related to migraine.
It is well established that bipolar patients have more comorbid anxiety than found in the general population (Angst, 1998 and Kessler et al., 1997) and this comorbidity may be higher for bipolar than unipolar depression (Chen and Dilsaver, 1995). In addition, there may be more comorbid anxiety disorders found in bipolar II patients when compared to bipolar I patients (Judd et al., 2003 and Rihmer et al., 2001). In the present study the highest total number of anxiety disorders was seen in bipolar II (2.8) patients, followed by unipolar (2.2) and finally bipolar I patients (1.8). However, dividing the unipolar groups into those with and without migraine shows that the migraine patients tend to have more anxiety disorders than the non-migraineurs (2.4 vs.1.9). Although this difference was not significant, it shows a tendency towards a linkage between migraine and anxiety disorders. The migraine patients had significantly more often agoraphobia (44% vs. 26%), and the same trend was seen in panic disorder and social phobia, with differences just dropping out of significance. The association between migraine and anxiety disorders has been found in several studies (Marazziti et al., 1999a and Marazziti et al., 1999b) and patients with migraine and major depression most often have a comorbid anxiety disorder (Merikangas and Stevens, 1997). Breslau and Davis (1992) found in a community study a doubled frequency of anxiety disorders among migraine patients, and the association was especially strong for panic disorder, with a 6-fold increase. The temporal association between the onset of the different anxiety disorders, migraine and major depression is also similar to previous findings (Merikangas and Stevens, 1997). In the present study, the unipolar patients with comorbid migraine present a constellation with an early onset of an anxiety disorder, 16.5 years, followed by migraine (21.5 years) and major depression (28.7 years). In a previous study (Fasmer and Oedegaard, 2001) we found that migraine was associated with bipolar II disorder, affective temperaments and an increased number of anxiety disorders, particularly panic disorder and agoraphobia. The present study indicates that even unipolar patients with comorbid migraine share this particular symptom cluster.
We found a high frequency of asthma (25%) among the unipolar migraine patients in this study, compared to only 6% among the migraine free individuals. There may be a link between migraine and asthma since children born to mothers with migraine seem to have an increased risk for asthma (Chen and Leviton, 1990). Even in this regard unipolar patients with migraine were similar to the bipolar II patients (22% prevalence of asthma), while there was a low frequency of asthma in the bipolar I group (8%). But of course it has to be kept in mind that most bipolar II patients in this sample had migraine (78.4%), whereas this was far less common among the bipolar I patients in this sample (36.1%). Migraine has a clear genetic background (Russel et al., 1995) and this is reflected in a high prevalence of migraine in first-degree relatives both in the unipolar group with migraine (59%) and in the bipolar II group (57%).
The major limitation of the present study is a non-blind cross-sectional assessment. On the other hand two interviewers included patients separately and the distribution of diagnosis of affective disorders, affective temperaments and migraine did not vary between the investigators. The results may not be applied to the general population since the patients interviewed in this study clearly represent a selected group. Relatives were not systematically interviewed. If this had been done it could perhaps have permitted a better delineation of affective temperaments and hypomania. Regarding the statistics we have chosen to present P-values without trying to correct for multiple comparisons. The number of comparisons increased the risk of type I error. However, the main differences between the unipolar patients with and without migraine concerning affective temperaments, irritability and seasonality were highly significant, and seem robust since they point in the same direction and also are in line with previous reports on the comorbidity of migraine, affective and anxiety disorders. The present findings underscore the importance of including questions on migraine in patients with affective disorders. If the presence of migraine in unipolar patients is a bipolar spectrum trait, this finding may have treatment implications, as antidepressants may worsen the mood instability, and mood stabilizers may improve it. Besides, there is strong evidence of a prophylactic effect of valproate in the prevention of migraine headache (Klapper, 1997 and Mathew et al., 1995), and a documented effect of valproate in the treatment of panic attacks (Lum et al., 1990), additionally increasing the worth of using a drug that is effective in the treatment of bipolar disorders (Bowden et al., 1994) as well.
The serotonergic system may be involved in the pathogenesis of migraine and affective disorders (Gardner, 1999 and Gelernter, 1995). There could be a basic derangement responsible both for the short-lasting, episodic phenomena seen in these patients (migraine, panic attacks, hypomania) and for the longer-lasting disturbances (major depression, affective temperaments), possibly linked to disturbances in either the serotonergic (Chugani et al., 1999 and Wang et al., 1996) or the dopaminergic system (Peroutka, 1997). Mckinnon has in several studies established a pattern of bipolar disorder with comorbid panic disorder as a possible genetic subtype of bipolar disorders (Mckinnon et al., 1998 and Mckinnon et al., 2002) and recently even in a subphenotype with rapid mood switching (Mckinnon et al., 2003). The present classification systems group patients with affective disorders according to a clinically expressed affective dysregulation. A non-psychiatric disorder like migraine, where the underlying commonality could be the dysregulation of 5HT-metabolism, may prove useful in establishing more homogenous subgroups of the affective disorders for further neurophysiological and molecular genetic investigations.
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Journal of Affective Disorders
Volume 84, Issues 2-3 , February 2005, Pages 233-242
Bipolar Depression: Focus on Phenomenology
Posted by jrbecker on February 11, 2005, at 12:24:38
In reply to Bipolar II Series -Antidepressnt-induced dysphoria, posted by jrbecker on February 11, 2005, at 12:14:46
Journal of Affective Disorders
Volume 84, Issues 2-3 , February 2005, Pages 279-290
Bipolar Depression: Focus on Phenomenology
doi:10.1016/j.jad.2004.06.002
Copyright © 2004 Elsevier B.V. All rights reserved.
Special article
Searching for behavioral indicators of bipolar II in patients presenting with major depressive episodes: the “red sign,” the “rule of three” and other biographic signs of temperamental extravagance, activation and hypomania
Hagop S. Akiskal ,International Mood Center, University of California at San Diego, V.A. Hospital 3350, La Jolla Village Dr. (116-A), San Diego CA 92161, USA
Received 12 January 2004; accepted 3 June 2004. Available online 10 February 2005.
Abstract
Background
Since 1977, the work of the author has shown the primacy of behavioral activation, flamboyance, and extravagance in detecting hypomania, the historical hallmark of cyclothymic and the broader spectrum of bipolar II (BP-II) disorders. In other words, the soft spectrum is more likely to declare itself in behavioral rather than mood disturbances. The obligatory search for elation and related mood changes à la DSM-IV (and its interview form, the SCID) during the clinical interview is often doomed to failure, thereby “condemning” the patient to a unipolar diagnosis, and hence to sequential and often tragic failures with antidepressants or combinations thereof.
Methods
To characterize behavioral signs of good specificity, though individually of low sensitivity for BP-II in patents presenting with major depression, the author undertook a chart review of over 1000 depressive patients he had examined extending over a period of nearly three decades. The Mood Clinic Data Questionnaire (MCDQ) used in the author's Memphis mood clinic permitted systematization of unstructured observations. BP-II had been independently confirmed by hypomania of ≥2 days and/or cyclothymia over the course of the index illness (both of which were validated by family history for bipolarity in earlier research in our clinic).
Results
Triads of behavior or traits in the patients' biographical history—as well as in the biologic kin—involving polyglottism, eminence, creative achievement, professional instability, multiple substance/alcohol use, multiple comorbidity (axis I and axis II), multiple marriages, a broad repertoire of sexual behavior (including brief interludes of homosexuality), impulse control disorders, as well as ornamentation and flamboyance (with red and other bright colors dominating) were specific for BP-II. Temperamentally, many of these individuals thrive on activity—they are indeed “activity junkies.”
Limitation
The reported findings pertain primarily to the differential diagnosis between BP-II and unipolar depression. Replication of the approach espoused herein will require quantification of the operational definitions of the observed phenomenology.
Conclusion
The findings, which make sense in an evolutionary model of the advantage that “dilute” bipolar traits confer to human biography and erotic life, suggest that such behavioral traits can be useful provisionally in assigning a depressive episode to the realm of the bipolar II spectrum. Overall, the perspective espoused in this paper indicates that temperamental excesses and, more generally, a biographical approach, represent a more coherent approach than hypomanic episodes in the diagnosis of BP-II patients. Finally, such a diagnostic approach underscores the importance of incorporating evolutionary considerations and principles in understanding the origin of affective disorders.
Keywords: Bipolar II; Major depression; Bipolar spectrum; Temperament; Ethology
Article Outline
1. Introduction
2. Clinical rationale
2.1. Methodologic innovation
2.2. Prospective investigations
2.3. Structuring unstructured observations
2.4. Modifications of the diagnostic process
2.5. Emphasis on the social/behavioral phenotype
3. Results and interpretation
3.1. Polyglottism
3.2. Eminence
3.3. Creativity
3.4. Biographic instability and/or excesses
3.5. “Activity junkies”
3.6. Multiple substances of use
3.7. Multiple comorbidity
3.8. Multiple outrageous behaviors
3.9. Sexual excesses
3.10. Marital history
3.11. Flamboyance and ornamentation
4. Discussion
References
1. Introduction
Although bipolar I (BP-I) disorder may still pose diagnostic problems (Bowden, 2001)—especially in its differentiation from schizophrenia—there exists a rich literature about this classical boundary question (Taylor and Abrams, 1973, Carlson and Goodwin, 1973, Pope and Lipinski, 1978 and Akiskal and Puzantian, 1979; Andreasen and Akiskal, 1983; Berner et al., 1992). Nonetheless, recent data from the US (Ghaemi et al., 2002 and Hirschfeld et al., 2003) and France (Hantouche et al., 2003) indicate that BP-I disorder is still subject to misdiagnosis, but now as major depressive disorder (MDD), as well as anxiety and personality disorders. Diagnostic errors are even more formidable in bipolar II (BP-II) disorder (Hantouche et al., 1998). Current data indicate that the BP-II spectrum is much more prevalent than BP-I in the community (Szadoczky et al., 1998; Angst, 1998 and Judd and Akiskal, 2003), and may account for at least 50% of all depressions observed in clinical practice (Akiskal and Mallya, 1987, Benazzi, 1997, Manning et al., 1997, Hantouche et al., 1998 and Akiskal et al., 2000). This paper will focus on a new diagnostic approach to this prevalent bipolar subtype.
BP-II was first described by Dunner and Gershon (1976), as a bipolar patient who had had hospitalization for depression, but not for mania; this meant that hypomanic signs and symptoms were almost always to be obtained by history. Although finally sanctioned by DSM-IV (1994), clinical assessment of BP-II presents formidable problems, principally because of the low reliability of the diagnosis of hypomania by history (Rice et al., 1986), which in turn is due in part to the vagaries of the patient’s state-dependent memory (difficulty to remember hypomanic mood during clinical depression), as well as failure to obtain history from significant others (Akiskal et al., 2000). The diagnostic process is complicated by inter-episodic instability (Akiskal, 1981) and comorbidity (Perugi and Akiskal, 2002), both of which contribute to the failure of recognizing it as a bipolar disorder (Akiskal and Pinto, 1999 and Akiskal et al., 2000): Such patients are then diagnosed as major depressives arising from cluster B personality disorders and/or substance-induced mood disorders. There also exist unmistakable, even severe major depressions without marked personality pathology, apparently “unipolar,” who nonetheless exhibit intra-episodic signs of submanic activation, flight of ideas, irritability, hostibility and agitation (Akiskal and Mallya, 1987, Koukopoulos and Koukopoulos, 1999 and Benazzi and Akiskal, 2001). Although not so-classified in the official International Classification of Mental and Behavioral Disorders (ICD-10, 1992) and theAmerican Psychiatric Association (DSM-IV, 2000) nomenclature of mental disorders, there is increasing evidence that such patients belong to the bipolar spectrum (Akiskal and Benazzi, 2003 and Sato et al., 2003).
Clinical diagnosis of BP-I is relatively easy, because when patients do not provide history of mania, past records are often decisive in this regard (Hantouche et al., 1998). This is rarely the case for BP-II. The best documented ways to improve the diagnostic process in evaluating depressed patients for BP-II are semi-structured interviewing by clinicians experienced in the diagnosis of bipolar II (Dunner and Tay, 1993) specifically geared for the signs and symptoms of hypomania; the diagnostic process can be further enhanced by obtaining information from significant others, and re-interviewing the patient as he or she is recovering from depression (Hantouche et al., 1998). Re-interviewing the patient at this time is helpful because the lifting of depression—sometimes accompanied by sudden brightening of mood and/or antidepressant associated hypomania (Akiskal et al., 2003)—helps the patient in recalling past episodes of hypomania (Akiskal et al., 2000). However, undue emphasis on elated and/or labile moods may lead to false negative diagnoses; a more fruitful approach is to inquire about behaviors suggestive of hypomania which patients are more likely to endorse (Akiskal et al., 1977).
The foregoing considerations suggest that objective features of hypomania or its behavioral manifestations should be given greater diagnostic weight in the evaluation of BP-II disorder. The purpose of this paper is to propose such an observational clinical framework in the differential diagnosis of “unipolar” major depressive vs. BP-II disorder that the author has developed in his clinical practice over the past several decades.
2. Clinical rationale
2.1. Methodologic innovation
What will be proposed here is a list of discreet observational signs and features outside the officially sanctioned clinical picture of BP-II in DSM-IV (1994) and ICD-10 (1992), and which can be useful in detecting “cryptic” bipolarity. These have been observed by the author during systematic interviewing of a very large depressive patient population extending over the three decades of the 1970s, 1980s and the 1990s. These findings emerged from four methodologic features in our systematic diagnostic interview process which we have used as of our earliest studies in the Memphis Mood Clinic (Akiskal et al., 1978) and in subsequent private practice and/or consultations.
1. The development of operational criteria for temperaments, such as the cyclothymic, irritable and hyperthymic (Akiskal et al., 1979a and Akiskal and Mallya, 1987), permitted broad assessment of behavioral traits underlying bipolarity. These are quite distinct from personality disorders—particularly because, in addition to emotional reactivity patterns which make people vulnerable to affective disorders, they describe their positive attributes.
2. Our interview schedule itself, the Memphis Mood Clinic Data questionnaire (MCDQ), was liberally semi-structured in format, permitting the clinician to probe biographical domains of interest beyond specified operational criteria. The MCDQ is particularly well suited for clinicians, because it represents systematization of what they normally do in evaluating patients. The MCDQ was filled routinely by trainees, fellows and visiting clinical scientists to our clinic and was eventually exported overseas. This is one of the reasons there now exists a cadre of clinical researchers (e.g., Manning et al., 1997, Akiskal and Pinto, 1999, Hantouche et al., 1998, Perugi et al., 1999, Haykal and Akiskal, 1999 and Benazzi and Akiskal, 2003) who think differently than the DSM-IV (and SCID) fixated “majority” in our field.
3. In the main, the MCDQ does not adhere to hierarchical rules. This means for instance that a patient can be diagnosed as having both a depressive episode and simultaneously meet criteria for hypomania during that episode, or; a patient presenting with depressive disorder can also be diagnosed as having a lifelong cyclothymic temperament. More generally, multiple diagnoses can be made in depressive disorders, including, for instance, anxiety disorders, substance use and alcohol disorders. To the post-DSM-III-R reader, the latter may seem like nothing new. Yet it is important to understand that suspension of hierarchical rules (DSM-III-R, American Psychiatric Association, 1987) was not the practice during much of the 1970s and 1980s when we conducted the bulk of the studies in our Mood Clinic. It is also noteworthy that in the Washington University Schema (Feighner et al., 1972), patients meeting the criteria for multiple co-existing mental disorders were considered “undiagnosed.”
4. Our Mood Clinic was different from the Lithium clinics of the 1970s and the bipolar clinics of today in a fundamental respect. The latter clinics admit well known or perhaps, in some instances, suspected bipolar patients. Our mood clinic admitted all consecutive depressive as well as bipolar patients referred to our service. This meant that we had the opportunity to study predictors of switching from depressive to bipolar disorders on a prospective basis. In brief, the bipolar status of patients reported in this paper does not represent cross-sectional entities, but prospectively validated diagnoses. Such a system with prospective diagnostic rigor can only be accomplished in a large service of both public and private patients. They do not typically attract—at least in those days—research dollars. The modus operandi of such a clinical service are typically labeled by conventional research standards as a “fishing expedition”, yet it represents clinical reality of everyday practice. However, our procedures did differ from routine practice in one crucial respect: data both at baseline or entry and during follow-up were collected systematically and rigorously. Conventional research methodology has consistently failed to account for the most common types of depressed patients encountered in private and public practice settings. The present report is an attempt to correct the narrow scope of the former.
2.2. Prospective investigations
Several systematic investigations during this period conducted in the author's mood clinics in Memphis led to the “rule of three” regarding the differential diagnosis of BP vs. MDD. For instance, we had found that BP-II patients arising from a cyclothymic baseline (Akiskal et al., 1977) often had a triad of past diagnoses from the dramatic cluster of personality disorders, e.g., “psychopathic,” histrionic, and “borderline.” In a subsequent study (Akiskal et al., 1983), we found that switching of depressed patients to bipolar I disorder could be prospectively predicted, among others, on the basis of a familial triad involving bipolar family history, “loaded” family history for affective disorder (>3 affected members in a pedigree), and consecutive generation family history for affective disorder (typically ≥3 generations). In this study, we computed sensitivity (which ranged from 32–42%) and specificity (which ranged from 83% to 98%) for these familial features in predicting who would switch to bipolar. In still a third study, which derived from the NIMH depression database (Akiskal et al., 1995), a triad of trait “mood lability,” “energy activity,” and “daydreaming (mental activation)” emerged as the best predictors of switching of “unipolar” major depression to BP-II over a long prospective observational period. In this study, in some ways reminiscent of our work on cyclothymic disorder summarized earlier, we reported excellent sensitivity (91% for the triad); the single best diagnostic predictor for BP-II was mood lability (sensitivity of 42% and specificity of 86%).
2.3. Structuring unstructured observations
The foregoing systematic and psychometrically validated observations were further enhanced by sporadic clinical observations, originally made in Memphis in the author’s Mood Clinic. These are best described as systematization of unstructured observations. For instance, we noted that some patients who presented with depression exhibited a triad involving the color red, e.g., drove to the clinic in a red sports car, wore either a bright red hat or a colorful necktie, or used a red pen in signing their names. This led to the unofficial use of the “red sign” of (bipolar) melancholia in our mood clinic. But in reality, this was a “red flag” for bipolarity because nearly all of those patients either gave past history of hypomania or developed it subsequently. The clinical rationale for considering the “red sign” as an indicator of bipolarity was that such colorful flamboyance was incompatible with the dark or blue mood of melancholia.
2.4. Modifications of the diagnostic process
On the basis of what has been already summarized, during diagnostic assessments of clinically depressed patients, the author would specifically inquire about these and related features in search for soft bipolarity. For purposes of this report, based on retrospective chart review of over 1000 interviews of affectively ill patients, I have compiled a preliminary list of triads of signs and characteristics which, while having relatively low sensitivity values (rates of 5–30%), appeared to have high specificity for a BP-II diagnosis in the sense that they were rarely observed (5%) or encountered among (unipolar) major depressive disorder. The validating independent clinical diagnosis of unipolar vs. BP-II was made on the basis of hypomania, and/or cyclothymic disorder, which conforms to DSM-IV (2000) definitions with one exception: 2 days of hypomania was considered sufficient for a diagnosis of BP-II in line with old and new evidence validating this duration threshold (e.g., Akiskal et al., 1977, Akiskal et al., 1979b, Cassano et al., 1992, Manning et al., 1997, Akiskal et al., 2000 and Benazzi and Akiskal, 2003). It is important to emphasize that the patients were evaluated during a clinically depressed state, and observations and/or history for the triads were made at this time; hypomania and other required evidence documenting bipolar disorder were obtained subsequently, as they became available. This is the sequence of events that happens in clinical practice. In other words, I am proposing these signs as discreet features as a preliminary approach in the differential diagnosis of unipolar vs. BP-II disorders when a clear-cut history of hypomania is not available or has not yet been obtained.
2.5. Emphasis on the social/behavioral phenotype
It would be useful to recapitulate the methodology of obtaining information from patients based on our mood clinic data questionnaire more fully described elsewhere (Akiskal et al., 1978). It is derived from the Feighner et al. (1972) framework, enriched by subthreshold diagnoses such as BP-II (Dunner and Gershon, 1976), and depressive subtypes in the RDC or research diagnostic criteria (Spitzer and Endicott, 1979), as well as temperament traits along hyperthymic, irritable and cyclothymic lines (Akiskal et al., 1979a). Systematic data is also collected on psychopathologic, demographic, developmental, social, educational and professional aspects, and family pedigrees based on the Winokur approach as incorporated into the RDC (Andreasen et al., 1977).
The interview is semi-structured and permits open-ended questions about aspects that the clinician will find relevant—striking or unusual, and in need of further probing—which would be faithfully recorded in the present or past history. This is how observational and behavioral features beyond the conventional diagnostic criteria have been noted. Finally, our procedures permit the perusing of signs and symptoms of hypomania during an index depressive episode, even in the absence or uncertainty about history of hypomanic episodes. As noted, the latter was made possible because the MCDQ suspended diagnostic hierarchies both within and outside the boundary of mood disorders.
3. Results and interpretation
What is summarized here are observations that would aid clinical differential diagnosis between a unipolar major depressive and a BP-II patient and, whenever available, supporting evidence from the literature. The bipolar indicators to be described here broadly fall into two groups: Those which pertain to the depressed patient's social traits obtained by history, and those observed at the index depressive episode which brought the patient to clinical consultation.
3.1. Polyglottism
People with proficiency ≥3 languages are rare among the US-born: among the affectively ill, it is also uncommon, but when it occurs, it appears limited to BP-II disorder. This probably does not apply to most European patients, where the base rate of multilingualism is quite high. In brief, when a US-born depressed patient lists in his biography competence in three or more languages, bipolarity should be searched diligently.
It is of interest that Rihmer et al. (1982) reported that in Hungary, three languages were the threshold for bipolarity. This study was conducted at a time when Hungary was less open to the West and, unless somebody had a special reason to learn more than a few languages, such as belonging to the family of a diplomat, three languages were significantly associated with bipolarity.
Language is for communication between people, and it makes good sense that the extroverted traits of individuals with bipolar disorder would lead to special abilities to learn languages. Also, extroverted and novelty-seeking individuals travel more and are more likely to encounter the opportunity to learn other languages.
3.2. Eminence
Diplomats would also qualify for bipolar traits by virtue of their belonging to an extroverted profession. The latter include political or other leadership, journalism, media and/or entertainment. All require interpersonal charm and eloquence, well-known features of the hyperthymic temperament (Gardner, 1982 and Akiskal, 1992). All such individuals, when clinically depressed, should be examined for bipolarity. When examining a depressed individual, history of eminence in the family, especially that for extroverted professions, should also lead to the search for bipolarity. When members of the family meet criteria for eminence along these lines, the connection to bipolarity is strengthened.
It is of interest in this regard that Coryell et al. (1989), examining the large database of the NIMH collaborative study of depression, found that achievement was significantly higher in the families of bipolar, as opposed to unipolar, patients. Using different methodology, Verdoux and Bourgeois, 1995a and Verdoux and Bourgeois, 1995b have replicated this find in France with respect to social class.
3.3. Creativity
Although most BP-II are not extraordinarily creative, and many individuals who are accomplished in an artistic domain do not meet criteria for full-blown affective disorders, artists who do present with clinical depression are more often BP-II than unipolar (Akiskal and Akiskal, 1988 and Akiskal and Akiskal, 1992). Indeed, those rare artists who excel in three domains, e.g., poetry, painting, and music, when clinically depressed, are more likely to belong to BP-II. Also, depressed individuals with extensive family history for artistic creativity should be carefully examined for BP-II disorder. There is some support for this in the literature in a study by Richards et al., 1988, demonstrating that creativity scores were significantly higher among relatives of bipolars as opposed to unipolars. Finally, the work ofAndreasen (1987) and Jamison (1995) on the connection between artistic creativity and bipolarity can be cited in general support for the foregoing suggestions.
3.4. Biographic instability and/or excesses
Instabilities in three areas of life, such as going to three universities and not obtaining a degree, or changing line of work and/or city of residence frequently have all been reported as strong correlates of the cyclothymic temperament (Akiskal et al., 1977). Should a clinically depressed individual give such history, the diagnosis of BP-II has to be entertained. Those individuals who shift from one profession to another, and then yet to another, such as law, medicine, and music, should be considered to be in the bipolar spectrum, at least temperamentally. For instance, a professor of medicine who practices law, and regularly sings in the opera. The foregoing consideration is also true for those who are boarded in three or more distinct medical subspecialties. All such individuals when clinically depressed should be examined for other clinical hints for bipolarity. Athletes who excel in three distinct sports, from such a list as basketball, soccer, baseball, tennis or skiing, when presenting clinically with a depression, must be examined for possible bipolarity. Finally, although one may have sound economic reasons for maintaining three jobs on a daily basis, when such a person develops clinical depression (which is not uncommon among such individuals), bipolarity should be high on the list of differential diagnoses, especially since such individuals often sleep no more than a few hours per day, or use stimulants towards this purpose. Individuals who have such orientation to work that requires both energy and obsessoid traits are typically in the realm of hyperthymic temperament (Akiskal, 1992 and Sakai et al., 2005).
3.5. “Activity junkies”
Individuals who travel long distance more than three times a month for whatever reasons, scientists who write three papers per month, and novelists who write three books per year are typically individuals with great energy for their line of work. These are desirable characteristics and help in climbing the ladder of professional success; they do not constitute mental illness. However, if and when these people present clinically with altered sleep patterns and fatigue, one should search for signs of depressive illness and then proceed to elicit signs of hypomania, which should prove not difficult in most such instances. Again, the rationale here is that the boundless energy, characteristic of such individuals, and their obsessoid traits are features of the hyperthymic temperament (Akiskal, 1992 and von Zerssen et al., 1998). While hyperthymic traits per se do not represent pathology, the development of clinical depression in individuals with such traits would suggest a bipolar spectrum disorder (Akiskal and Pinto, 1999).
3.6. Multiple substances of use
Comorbidity with substance abuse at the polysubstance level (three or more major drugs, such as nicotine, stimulants, alcohol and/or opiates) should also raise suspicion of bipolarity in an individual presenting with depression beyond the period of detoxification (Akiskal et al., 1977 and Angst et al., 2005). This is a complex issue, which will require much better documentation, but it is useful to think along these lines, both for familial-genetic (Winokur, et al.,1998), clinical (Akiskal and Pinto, 1999), and therapeutic reasons (Brady and Sonne, 1995).
3.7. Multiple comorbidity
As far as comorbid diagnoses, depressed individuals with at least three anxiety disorder diagnoses (panic-agoraphobic, social phobic, and obsessive-compulsive) are commonly BP-II (Perugi et al., 1999). Those with the triad of bulimic, atypical, and seasonal depressions also seem to belong to the realm of BP-II (Perugi and Akiskal, 2002). Related to the latter are depressions with rapid onset, short duration, and rapid offset, almost always associated with BP-II (Strober and Carlson, 1982 and Akiskal et al., 1983).
3.8. Multiple outrageous behaviors
Depressed individuals who have in the past received controversial diagnoses with an impulsive component such as “borderline personality,” “compulsive gambling,” and “sexual addiction” are paramount among those who should be evaluated for bipolarity. The same applies to individuals who, with some regularity, take extreme risks for thrills such as gambling, car racing, sky diving, and wildlife safaris. Whether all impulse control disorders are bona fide bipolar disorders is an unsettled question, but association of a triad of such activities is reported by many (Akiskal et al., 1995, McElroy et al., 1996, Cassano et al., 2000 and Deltito et al., 2001).
The boundary between “psychopathic” behavior and bipolar temperaments is not always easy to draw (Pukrop et al., 1998). In a study of 559 depressives to predict those “unipolars” who switched to BP-II over prospective observation (Akiskal et al., 1995), we reported that certain “outrageous” behaviors, particularly occasional “anti-social” acts were significantly over-represented in the minority (8.6%) who switched. In this light, it would not be surprising that clinically depressed individuals who give history of three such “anti-social” acts—e.g., shoplifting, a paraphilia, and arrest for participation in a riot—might after all belong to the bipolar spectrum. If for nothing else, this would open therapeutic opportunities (Nelson et al., 2001), as discussed earlier in relation to controversial diagnostic categories involving impulsivity. We are neither arguing for decriminalizing certain behaviors, nor romanticizing them. The point is that prisons are full of people for “offenses” or felonies that can be perhaps one day understood in a broader humane perspective based on temperamental excesses—along hypomanic or cyclothymic lines—operating within a certain social context that did not provide the socialization and education to harness their energy and drive to socially desirable goals and achievement.
3.9. Sexual excesses
As far as erotic life, depressed individuals who give history of having engaged, with more than occasional frequency, in sexual behavior with the same sex and both sexes at the same time or different times, are in our clinical experience, over-represented among the BP-II. Brief homosexual liaison during hypomania—sometimes protracted beyond—underscores the disinhibition that BP-II brings to the lives of these individuals (Akiskal and Pinto, 1999); alcohol use is often contributory to such behaviors.
Moreover, those with excesses in sexual behavior such as simultaneously dating three or more individuals for extended periods of time, or on the same day (such as breakfast, lunch, and dinner), indeed those who actually repeatedly engage in sex with three different individuals on the same day, must all be suspect for bipolar traits. Along these lines, someone whose sexual desire is so excessive that they would regularly engage in sex with their own spouse as well as visiting prostitutes, in addition to repeated masturbation on a daily basis, should be evaluated for bipolarity. Finally I must mention individuals who date in three faraway cities in the same week (for instance, Memphis, Hawaii, and New York; or Chicago, London, and Bali); obviously this is confounded by one's financial resources, which, as discussed earlier, represents another factor in favor of bipolarity (Verdoux and Bourgeois, 1995b).
Sexual prowess and openness to different forms of expression of the sexual passion may, hypothetically, represent the evolutionary rationale for the emergence of genes which contribute to bipolarity (Gardner et al., 1982; Hamer and Copeland, 1998 and Akiskal, 2001). As such, they have an essential role in human biology, and obviously do not constitute pathology; from such a perspective, they may be regarded as an advantage, representing a greater repertoire of sexual behavior and responding. The clinical claim we make here is that in an individual presenting clinically with depressive illness, history of the type of sexual behaviors described herein should be taken as a hint of bipolarity. A perusal of the criteria for bipolar disorder in official classification systems (ICD-10, 1992; DSM-IV, 1994) leaves no doubt that excessive involvement in any activity with major potential for risk due to seeking of pleasure, including sexual hedonism, is in the realm of trait bipolarity.
3.10. Marital history
Related to the above considerations are individuals with three or more marriages and/or divorces (Akiskal et al., 1995). The same is true for family history for more than three divorces in one or both parents. Individuals—and these are usually men—who are legally married and have children, but maintain two or more families in other cities without having been married or in polygamous relationships (Akiskal, 2000). Again, such individuals may never suffer from affective illness, but if and when they present with clinical depression, bipolarity should be high on the list of differential diagnosis.
Individuals who dare into trans-ethnic marriages are bold and unconventional—and certainly a trend of the future in the rapidly shrinking travel distances between countries, and the expansion of diasporas. As discussed above for erotic life and openness to experience, this behavior probably has advantages from a cultural and evolutionary point of view. Thus, those who consummate three or more marriages, each to distinctly different ethnic groups from their own, are probably making a statement about their novelty-seeking temperament. This temperament is close to the hyperthymic and the cyclothymic (Maremmani et al., 2005). Therefore, we contend that when clinically depressed, their depressions are likely to belong to the soft bipolar realm.
3.11. Flamboyance and ornamentation
The “red sign” of bipolarity has already been mentioned. It goes along with the flamboyance of the cyclothymic temperament (Akiskal, 1992). At least in the Western world, women are more likely to wear colorful clothing; this is generally less so in men. Therefore, a depressed female must be observed to have a marked degree of flamboyance to be considered for BP-II; on the other hand, a pink watchband or pink socks or shoes would each alone probably suffice in raising ones diagnostic suspicion for bipolarity in a depressed male patient!
A particular development in certain youth subcultures in recent years are individuals who wear pierced rings in unusual parts of their body such as the tongue, nipples, navel and external genitalia. Other individuals have tattoos, both visible and discreet. Again, by themselves these are not necessarily indicators of any specific mental condition. However, when a depressed individual is examined in a clinical setting and is wearing three or more such rings, or three or more elaborate tattoos, bipolarity should be kept in mind.
Of all the observations made about discreet bipolarity, this is the most susceptible to cultural and subcultural influences and, hence, least secure from a diagnostic standpoint. The origin of such ornamentation might, hypothetically, by traced to an era in human evolution when their use conveyed a certain status in the territory of a tribe or a clan. Alternatively, their power status in the hierarchy might have lent to its bearer certain aphrodisiac or erotic qualities. Even today, the latter seems to represent the implicit, if not explicit, message of ornamentation, tattooing and piercing.
4. Discussion
The main findings are summarized in Table 1 in the form of a mnemonic of 3 to facilitate their didactic use, but also to emphasize the excessive nature of the listed behaviors as bipolar indications. I comment on selected aspects.
The clinical observations reported in this paper suggest that temperamental excesses or instabilities underlying or associated with the BP-II spectrum are more useful in the diagnostic assessment of these patients than attempts to elicit hypomania during the clinical interview (see Akiskal et al., 1995).
The findings further indicate that behavioral activation is more important than mood change per se in diagnosing BP-II hypomania. This has been verified in both clinical (Benazzi and Akiskal, 2003) and epidemiological studies (Angst et al., 2003). I would like to expand on this methodologic point, because it is contrary to the diagnostic algorhythms of research interviewing in the SCID (First et al., 1997). In a recent Ravenna-San Diego Collaboration (Benazzi and Akiskal, 2003), bypassing the stem question A on mood change in hypomania in SCID interviews, and first eliciting hypomanic behaviors (indicative of activation), yielded a significant increase in BP-II diagnoses; because once such behaviors were elicited, patients (and significant others) upon re-questioning could recall positive mood changes. This collaborative study also suggested that, rather than obtaining history for hypomanic signs and symptoms, the clinician could more profitably search for signs of hypomanic activation during the index depression, in effect supporting the diagnosis of a depressive mixed state (a diagnosis regrettably “forbidden” in the DSM-IV schema and its SCID derivative).
Phenomenologically, perhaps the most provocative of the findings reported, “the red sign,” finds partial validation in an NIMH study (Donnelly et al., 1975). These authors wrote: “The color-reactive style of the bipolar group on the Rorschach underscores the potential for manic (impulsive) behavior in the midst of depressive episode.”
The reported observations also suggest, but do not prove, a relationship between homosexual behavior and the bipolar spectrum. In a written personal communication (June 5, 2004), Richard C. Pillard, M.D. expressed the opinion that such a relationship could be formulated in terms of greater mood variability (at least among homosexual men) at the lower thresholds of the bipolar spectrum. Homosexuals are often of upper middle or upper class and flamboyant (Saghir, 1973), both of which accord with the proposed putative link with the BP-II spectrum (at least temperamentally). On the other hand, the proposed hypothetical link between homosexual behavior and the bipolar spectrum might be due to the confounding variables of higher education and higher class status; in addition, individuals with homosexual orientation from such socio-economic background are more likely to participate in interview research. Finally, homosexual behavior and bisexual behavior are not synonymous. For all these reasons, the relationship between homosexual behavior and the bipolar spectrum is still an open question that deserves further study. Nonetheless, the following conclusions appear warranted: (1) The bipolar spectrum appears associated with a greater repertoire of sexual behavior, including homosexual and bisexual behavior, and (2) among individuals with homosexual or bisexual orientation presenting clinically with a depressive episode, the differential diagnosis should include BP-II.
On a more theoretical note, bipolar II, associated with other forms of affective dysregulation, impulse control disorders, as well as alcohol and stimulant abuse might share genetic underpinnings. This is a challenge for the future.
The diagnostic approach itself illustrates the enriching of psychiatric formulation by evolutionary theory (Kramer and McKinney, 1979, McGuire et al., 1992, Nesse, 1998, Wilson, 1998 and Stevens and Price, 2004). This valuable perspective is regrettably omitted in psychiatric education (Abed, 2000).
Finally, this paper illustrates the intimate link between one’s temperament, biography and the form of depression one will suffer from (Possl and von Zerssen, 1990, Kraus, 1996 and Akiskal, 1996). This is a desirable feature for the interview process in modern psychiatry which, in its quest for “objectivity”, is distancing itself from the person who is ill. Psychiatry without a biographical perspective misses the richness of human experience and behavior in their positive and tragic expressions. It also may miss the opportunity to learn a great deal about the patient that can be uniquely useful in the diagnostic process. Patients presenting to psychiatrists are not just a constellation of signs and symptoms. These merely provide a systematic framework for a diagnosis, but unless understood in the context of the patient's life and experiences, they do not provide a coherent and adequate information for an optimum understanding of the individual patient. I will close in going as far as to submit that psychiatry without a biographical perspective is not psychiatry at all.
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Posted by jrbecker on February 11, 2005, at 12:30:55
In reply to Bipolar II Series -behavioral indicators, posted by jrbecker on February 11, 2005, at 12:24:38
Journal of Affective Disorders
Volume 84, Issues 2-3 , February 2005, Pages 133-139
Bipolar Depression: Focus on
doi:10.1016/S0165-0327(02)00103-9
Copyright © 2002 Published by Elsevier B.V.
Research report
Dimensional psychopathology of depression: detection of an ‘activation’ dimension in unipolar depressed outpatients
M. Biondi , , a, A. Picardib, M. Pasquinia, P. Gaetanoa and P. Pancheriaa Clinica Psichiatrica III, Dipartimento di Scienze Psichiatriche e Medicina Psicologica, University ‘La Sapienza’ of Rome, Viale dell’Università, 30-00185, Rome, Italy
b Department of Epidemiology and Biostatistics, Italian National Institute of Health, Rome, ItalyReceived 3 January 2001; accepted 3 April 2002. Available online 9 May 2002.
Abstract
Background: Despite the high prevalence of bipolar spectrum disorders, most instruments currently available for the assessment of depression do not explore symptoms of ‘activation’ such as anger, irritability, aggressiveness, hostility, and psychomotor activation. Methods: Two samples of adults with unipolar depression were studied. They had no comorbid DSM-IV disorder, and they were free from antidepressant drugs. The first sample (n=380) was assessed with the SVARAD, a validated scale for the rapid assessment of the main psychopathological dimensions. The second sample (n=143) was assessed with the MMPI-2. Factor analysis was performed on SVARAD items and MMPI-2 clinical scales. Results: In both samples, we obtained a three-factor solution with factors interpreted as a depressive dimension, an anxious dimension, and an activation dimension. The latter dimension appeared to be clinically relevant in 20–27% of patients. Limitations: The presence of a comorbid disorder may have been missed in some cases. Also, some bipolar II patients might have been misdiagnosed as unipolar and included in the study. Further, our findings apply only to a selected psychiatric population, and it should be tested whether they generalize to other settings of care and other countries. Conclusions: Our results suggest that depressive mixed states are not rare even in patients diagnosed as unipolar, and that some unipolar patients might actually be ‘pseudounipolar’ and belong to the bipolar spectrum. More in general, our findings suggest that some depressed patients have prominent symptoms of activation that can easily go unnoticed using instruments that do not explore such symptoms. Detecting these symptoms has important treatment implications.
Author Keywords: Depression; Assessment instruments; Factor analysis; Dimensional psychopathology; Activation
1. Introduction
Current nosography of depression emphasizes a few prototypes of depressive disorder. However, in practice, it is common to observe that clinical manifestations vary widely around these prototypes. The diverse combination of a limited number of symptom clusters, also called ‘psychopathological dimensions’ (Van Praag et al., 1990; Pancheri, 1995; Goldberg, 2000), differs from patient to patient, and gives rise to the wide variety of clinical pictures that can be observed in depressed patients.
Currently, standardized assessment of depression is imperative, and various instruments are available to this purpose. However, a frequent problem with instruments for the assessment of depressed patients is that most of them do not cover symptoms of ‘activation’ such as anger, irritability, aggressiveness, hostility, and psychomotor activation. The accurate assessment of this psychopathological dimension in depressed patients is important, because an increasing body of literature suggests that the prevalence of bipolar disorders is much higher than usually believed (Hirschfeld, 2001). Already in the 1980s, authors such as Akiskal ( Akiskal, 1983; Akiskal and Mallya, 1987) and Klerman (1981) underscored the need to broaden the concept of bipolarity in order to include various bipolar conditions beyond classic mania. It has also been pointed out that many patients who do not satisfy the DSM-IV or ICD-10 criteria for bipolar II disorder belong to a broad bipolar spectrum which includes depression with brief hypomanic episodes, cyclothymic depression, hypomania induced by antidepressants or other somatic treatments, and hyperthymic depression ( Akiskal and Pinto, 1999). Recent epidemiological studies have shown that the lifetime prevalence of bipolar spectrum disorders might be as high as 5% ( Akiskal et al., 2000). The relevance of symptoms of ‘activation’ has been repeatedly emphasized even in cases of unipolar depression ( Fava et al., 1986; Fava et al., 1991). This study was designed to assess the importance of this psychopathological dimension in unipolar depressed outpatients free from antidepressant drugs.
2. Methods
2.1. Setting
The study was performed on two different samples of depressed outpatients, recruited at the Outpatient Center of the 3rd Psychiatric Clinic of the University of Rome between 1997 and 2000. In this Center, patients undergo a careful psychiatric examination of about 90 min duration, and then are diagnosed according to DSM-IV criteria by resident physicians. All diagnoses are confirmed and the patients’ clinical course supervised by a faculty psychiatrist with more than 20 years of clinical experience.
2.2. Subjects
All newly admitted patients who met the criteria specified below were included in the study: a current diagnosis of DSM-IV axis I depressive disorder, with the exception of diagnoses pertaining to the bipolar spectrum; no comorbid psychiatric diagnosis on DSM-IV axis I or II; no treatment with antidepressant drugs in the preceding 2 months; absence of severe medical illness; and at least 18 years of age.
Two independent samples of patients were enrolled in the study. The first sample included 380 patients. Their mean age was 47.4±15.4 years, and 61.6% were female. The DSM-IV diagnosis was major depressive disorder in 154 patients (40.5%), dysthymic disorder in 125 (32.9%), depressive disorder not otherwise specified in 56 (14.7%), adjustment disorder with depressed mood in 20 (5.3%), and adjustment disorder with mixed anxiety and depressed mood in 25 (6.6%).
The second sample consisted of 143 patients. Their mean age was 43.0±15.4 years, and 67.1% were female. The DSM-IV diagnosis was major depressive disorder in 37 patients (25.9%), dysthymic disorder in 60 (42.0%), depressive disorder not otherwise specified in 30 (21.0%), and adjustment disorder with depressed mood in 16 (11.2%).
Gender distribution did not differ significantly between the two groups ( 2-test), while mean age was higher in the first sample than in the second sample (P<0.01, t-test). Diagnostic distribution was also found to be different between the two samples (P=0.01, 2-test), with a greater proportion of cases of major depressive disorder in the first sample and of dysthymic disorder in the second sample.
2.3. Study instruments
The first sample was assessed with the Scala Valutazione Rapida Dimensionale (SVARAD) by their physician at the end of the visit. All resident physicians had been instructed in the proper use of this instrument as part of their training in psychiatry. The SVARAD is a 10-item instrument specifically developed for rapid assessment of the main psychopathological dimensions (Pancheri et al., 1999a). All items are rated on a five-point scale ranging from 0 to 4, with higher scores indicating greater severity. Scores of 1 indicate a severity level at the border between normality and psychopathology, whereas scores of 2 or more attest the presence of clinically relevant symptoms. A validation study has provided evidence of inter-rater reliability, content validity, and criterion validity ( Pancheri et al., 1999b). It has also been shown that, thanks to its brevity and ease of use, the SVARAD can be extensively used even in clinical settings where there is only a very limited amount of time allotted to research ( Pancheri et al., 2001). The items of the instrument explore the following dimensions: (1) apprehension/fear; (2) sadness/demoralization; (3) rage/aggressiveness; (4) obsessionality; (5) apathy; (6) impulsiveness; (7) reality distortion; (8) thought disorganization; (9) somatic preoccupation/somatization; (10) activation. Of these, three (items 3, 6, 10) assess symptoms pertaining to the ‘activation’ dimension, and hence will be described in more detail. The definition of item 3 (rage/aggressiveness) is as follows: irritation, anger, resentment; irritability, litigiousness, hostility; verbal or physical violence. The content of item 6 (impulsiveness) is defined as the tendency to suddenly behave in an inadequate or potentially harmful way, without reflecting enough on the causes or the consequences of one’s own actions. Finally, item 10 (activation) is defined as follows: increased motor activity, acceleration of ideas, disinhibition, increased energy and self-confidence, euphoria or irritability.
The second sample was assessed with the Minnesota Multiphasic Personality Inventory 2 (MMPI-2) (Butcher et al., 1989). Patients completed the inventory in the waiting room of the Outpatient Center, just before being visited. The MMPI-2 is one of the most widely used psychometric instruments. It consists of a long series of statements to which the subject must respond with ‘true’ or ‘false’, and it gives scores on three validity scales and 10 clinical scales, providing information on both personality and psychopathology. Scale scores are computed in the form of standardized T-scores, with scores higher than 70 indicating a considerable departure from the norms. Symptoms of ‘activation’ are mainly assessed by three clinical scales that will be described in more detail. The scale Ma (hypomania) measures elevated or unstable mood, psychomotor activation, acceleration of ideas. High scores on the scale Pd (psychopathic deviance) indicate intolerance towards social rules, impulsiveness, sensitivity, aggressiveness. Finally, high scores on the scale Pa (paranoia) indicate vigilance, sensitivity, litigiousness, distrust, suspicion, and possibly paranoid delusions.
2.4. Data analysis
Factor analysis was performed on all SVARAD items in the first sample, and on all MMPI-2 clinical scales except scale 5 ‘Mf’ (masculinity–femininity) in the second sample. The number of factors to be extracted was determined according to the scree-plot method (Cattell, 1966). In the first sample, factors were extracted using the principal axis method. Principal component analysis was used in the second sample. All analyses were run under SPSS, version 8.0 for Windows ( Norusis, 1998).
3. Results
3.1. First sample
Three factors were extracted, explaining a total variance of 33.4%. Orthogonal rotation was performed using the Varimax method. The cutoff for size of loading to be interpreted was set at 0.32. This cutoff corresponds to 10% of common variance between a variable and a factor, and it is widely used in factor analysis (Tabachnick and Fidell, 1996). Factor I was saturated by items such as rage/aggressiveness, impulsiveness, and activation. It was interpreted as an ‘activation’ dimension. Factor II was clearly a ‘pure depression’ dimension, with high loadings on items such as sadness/demoralization and apathy. Factor III was defined by items such as apprehension/fear and somatic preoccupation/somatization. It was interpreted as an ‘anxiety’ dimension. The rotated factor matrix is reported in Table 1, where variables are ordered and grouped by size of loading to facilitate interpretation. Blank spaces indicate loadings of 0.32 or under.
The activation dimension appeared to be clinically relevant in a sizable proportion of patients, because 104 patients (27.4%) scored 2 or more on at least one of the items with high loadings on the activation dimension. In detail, 98 patients scored 2 or more on item 3 (rage/aggressiveness), 36 on item 6 (impulsiveness), and three on item 10 (activation).
3.2. Second sample
Three factors were extracted, accounting for 73.2% of total variance. Orthogonal solution with the Quartimax method was performed. This method minimizes complexity of variables and was preferred to Varimax rotation because there were two complex variables, that is, variables with high loadings on two different factors. With a cutoff for size of loading to be interpreted of 0.32, Factor I was defined by scales Si (social introversion), Pt (psychasthenia), Sc (schizophrenia), and D (depression). It was interpreted as a ‘depression’ dimension. Factor II included scales Ma (hypomania), Pa (paranoia), Pd (psychopathic deviance), and Sc (schizophrenia). It was interpreted as an ‘activation’ dimension. Factor III was saturated by scales Hs (hypochondriasis), Hy (hysteria), and D (depression). It was interpreted as an ‘anxiety’ dimension. The rotated factor matrix is reported in Table 2, where variables are ordered and grouped by size of loading to facilitate interpretation. Blank spaces indicate loadings of 0.32 or under.Also in this analysis, the activation dimension appeared to be clinically relevant in a substantial proportion of patients. A total of 29 patients (19.9%) scored above 70 on the Ma scale, or on both the Pa and Pd scales. In detail, six patients scored high on the Ma scale, 46 on the Pd scale, and 45 on the Pa scale.
4. Discussion
Overall, our findings seem to indicate that depressive disorders are characterized by three fundamental psychopathological dimensions: a pure depressive dimension, an anxious dimension, and an activation dimension characterized by anger, irritability, aggressiveness, hostility, and psychomotor activation. It is worth noting that these three dimensions emerged consistently in two distinct groups of unipolar depressed patients, using two different instruments. Interestingly, such dimensions correspond to three basic human emotions: sadness, fear, and anger (Plutchik, 1980).
A strong point of our study is that, when the assessment took place, patients were free from antidepressant drugs, which may induce hypomania or mania (Wehr and Goodwin, 1987) and precipitate mixed states ( Akiskal and Mallya, 1987). Hence, it is unlikely that our detection of an activation dimension in depressed patients is to be ascribed to concurrent pharmacological treatment.
However, it should also be acknowledged that our study has some limitations. First, patients were not assessed using a structured diagnostic interview. However, the diagnoses were probably reliable, because they were made after an accurate psychiatric examination and were confirmed by a faculty psychiatrist with more than 20 years of clinical experience who reviewed all clinical charts. Although the presence of a comorbid disorder may have been missed in some cases, this should not have substantially affected the results.
Another issue is the possible misdiagnosis of bipolar II patients in our sample. A recent study has found that a sizable proportion of bipolar patients are misdiagnosed as unipolar (Ghaemi et al., 2000). Indeed, apparent unipolar depression might turn out to be bipolar II disorder on careful questioning ( Akiskal, 1996), and a study has shown that clinicians specifically trained to recognize bipolar II disorder outperform structured instruments such as the SADS or the SCID in the diagnosis of bipolar II disorder ( Dunner and Tay, 1993). We cannot rule out the possibility that some bipolar patients might have been included in our study, because the residents lacked the long training required to be able to identify past hypomanic episodes with high reliability. However, they had been instructed to ask systematically about a history of mood swings, hypomania or mania in all patients presenting with depression. This should have reduced the risk of misdiagnosis.
It should also be recognized that our findings apply only to a selected psychiatric population. It remains to be tested whether they generalize to other settings of care and other countries. Our results need to be replicated in different cultures, using the same instruments or other instruments that include items exploring symptoms of activation.
The presence of a depressive dimension and of an anxious dimension was not unexpected. Their cardinal importance in psychiatric patients is well recognized, even in consulting samples in primary care (Goldberg et al., 1987). The most interesting finding of our study is probably the detection of an activation dimension in a sample of unipolar depressive patients. This finding might at first come as a surprise. However, the presence of symptoms of activation in depression had already been emphasized by ancient Greek physicians such as Hippocrates and Aretaeus of Cappadocia, as well as by Kraepelin and Weygandt at the end of the nineteenth century ( Angst and Marneros, 2001). Also, psychoanalysts ( Abraham, 1948; Freud, 1975) and cognitive psychotherapists ( Guidano, 1987) have underscored the importance of aggressive impulses, anger, and rage in depressed patients. Moreover, several psychometric studies have detected an activation dimension in depressed patients who were assessed with psychometric instruments that explore symptoms of activation ( Pull et al., 1979; Overall and Hollister, 1980; Fava et al., 1986; Riley et al., 1989; Fava et al., 1991; Moreno et al., 1994).
The observation of cases of depression characterized by anger, irritability, aggressiveness, hostility, and psychomotor activation casts some doubts over the classical psychoanalytic aggression-turned-inward model as an universal explanation for depressive behavior (Akiskal, 2000). More likely, the observation of depressed patients with prominent symptoms of activation might be related to factors such as the patient’s cognitive and emotional organization ( Guidano and Liotti, 1983; Arciero and Guidano, 2000), and his or her temperament ( Akiskal, 1995). At least partial confirmation of the role of temperament has been recently provided ( Perugi et al., 1997). Psychobiological disposition might also play a part, especially in cases of loss-induced depression ( Biondi and Picardi, 1996).
In our study, we used multivariate statistical techniques. However, the activation dimension was not a statistical artifact. Rather, it was found to be clinically relevant in a substantial proportion of patients. Some of them might specifically belong to a distinct group of angry hostile depressed patients (Fava et al., 1991), an hypothesis that has received partial support ( Bagby et al., 1997). However, many of these patients with clinically relevant symptoms of activation were probably experiencing a depressive mixed state. Until recently, depressive mixed states have been under-recognized and under-researched. However, in the last decade there has been renewed interest in these psychiatric conditions ( Perugi et al., 1997; Koukopoulos and Koukopoulos, 1999) which seem to be much more prevalent than commonly believed, even in patients diagnosed as unipolar ( Benazzi and Akiskal, 2001).
The results of our study suggest that depressive mixed states are not rare even in patients receiving a diagnosis of unipolar depression, and that a number of unipolar patients might actually be ‘pseudounipolar’ (Akiskal, 1996) and belong to the bipolar spectrum. More in general, our findings suggest that in a substantial proportion of depressed patients diagnosed as unipolar there are symptoms of activation that can easily go unnoticed using instruments that do not include items dealing with such symptoms. Indeed, the majority of the rating scales for depressive symptomatology do not include items exploring these symptoms. For instance, in a similar sample of unipolar depressed patients, we were not able to detect an activation dimension with a factor analysis of the 17-item Hamilton Depression Rating Scale ( Pancheri et al., 2002). The inadequate assessment of symptoms of activation by the majority of rating scales for depression raises some concern, because the proper identification of these symptoms is important and has considerable implications for the choice of treatment. First, in depressive mixed states antidepressants should be used with caution, while the use of mood stabilizers is imperative ( Montgomery et al., 2000). Second, symptoms of activation may preferentially respond to treatment with serotonergic antidepressants, though further studies are needed to substantiate this recommendation ( Fava, 1998).
In conclusion, the activation dimension in depressive disorders deserves greater clinical recognition and research. Our study corroborates the opinion that the use of dimensional models of psychopathology in addition to categorical models might be profitable (Van Praag et al., 1990; Costello, 1992; Pancheri, 1995; Angst et al., 2000; Goldberg, 2000). A dimensional assessment might help clinicians to recognize symptoms of activation in their patients presenting with a depressive disorder.
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Posted by jrbecker on February 11, 2005, at 12:35:06
In reply to Bipolar II Series - Activation dimension, posted by jrbecker on February 11, 2005, at 12:30:55
Journal of Affective Disorders
Volume 84, Issues 2-3 , February 2005, Pages 159-166
Bipolar Depression: Focus on Phenomenologydoi:10.1016/j.jad.2003.09.011
Copyright © 2005 Published by Elsevier B.V.
Research report
Profiles of "manic" symptoms in bipolar I, bipolar II and major depressive disorders
Alessandro Serretti , and Paolo OlgiatiDepartment of Psychiatry, Vita-Salute University, San Raffaele Institute, Via Stamira D'Ancona 20, 20127, Milan, Italy
Received 25 February 2003; accepted 9 September 2003. Available online 19 November 2003.
Abstract
Background: Classical authors such as Kraepelin, as well as the emerging literature during the past decade, indicate that manic-like signs and symptoms are present to a variable degree in all mood disorders. Current nosography does not differentiate between them and only the number of symptoms or severity is used for classification. This is particularly true for mania and hypomania. This paper will analyze the patterns of manic symptoms in bipolar I (BP-I), bipolar II (BP-II) and major depressive disorders (MDD), to test the hypothesis that mania and hypomania have different profiles, and ascertain which excitatory manic phenomena do occur in unipolar MDD. Methods: Six hundred and fifty-two inpatients (158 BP-I, 122 BP-II and 372 MDD) were assessed using the operational criteria for psychotic illness checklist (OPCRIT) [Arch. Gen. Psychiatry 48 (1991) 764] with a lifetime perspective. Manic or hypomanic symptoms were investigated and compared between BP-I, BP-II and MDD. Results: When compared with BP-II, BP-I disorder had a higher prevalence of reckless activity, distractibility, psychomotor agitation, irritable mood and increased self-esteem. These five symptoms correctly classified 82.8% of BP-I and 80.1% of BP-II patients. One or two manic symptoms were observed in more than 30% of major depressive patients; psychomotor agitation was the most frequent manifestations present in 18% of the MDD group. Limitations: We did not control for severity of symptoms, nor for neuroleptic use that could produce akathisia. Conclusions: This study suggests that mania and hypomania can be differentiated in their symptom profiles, and highlights the presence of few manic symptoms, particularly psychomotor agitation, in MDD. From the standpoint of number of manic signs and symptoms, controlling for psychomotor agitation did not substantially change the predictive power of the remaining manic symptoms. Given that excitatory manic signs and symptoms are present to a decreasing degree in BP-I, BP-II and MDD, these disorders can be proposed to lie along a dimensional model. Overall, these data are compatible with the concept of a bipolar spectrum, whereby each of the affective subtypes requires specific genetic factors.
Author Keywords: Bipolar disorder; Hypomania; Symptomatology; Affective disorders
1. Introduction
According to DSM IV (American Psychiatric Association, 1994), mania and hypomania, which respectively identify bipolar I (BP-I) and bipolar II (BP-II) disorder, have the same clinical profile (apart from psychotic symptoms, that can occur in mania alone) and differ only in the degree of severity. In fact, the diagnosis of mania requires a longer minimum duration (7 vs. 4 days), more functional impairment or hospitalization. Yet different lines of evidence, including family history, long-term diagnostic stability and linkage studies (Coryell et al., 1995; Coryell, 1999; Angst, 1998; Akiskal et al., 1977; Akiskal et al., 2000; Cassano et al., 1992; MacKinnon et al., 1998 and Benazzi, 1999), support the distinction between BP-I and BP-II disorder. This suggests that hypomania is not merely a less severe form of mania and different clinical phenomenology might characterize the two syndromes (Benazzi and Akiskal, 2003 and Hantouche et al., 2003a).
Manic and depressive symptoms co-exist in "Mixed States", originally described by Kraepelin (1909–1915). The recent literature focused on depressive mixed state (DMX), consisting of a major depressive episode (MDE) with few (at least three) manic symptoms (Akiskal, 1996 and Benazzi and Akiskal, 2001). Common features of this syndrome, not specifically identified in DSM IV, are agitation, irritability, racing thoughts and talkativeness (Akiskal and Mallya, 1987; Akiskal, 1992; Akiskal, 1996 and Perugi et al., 1997). An increasing body of evidence supports its inclusion under bipolar disorders (Benazzi, 2000; Benazzi, 2001a; Benazzi, 2001b and Benazzi and Akiskal, 2001). Koukopoulos and Koukopoulos (1999) have actually suggested that agitated depressions should be classified as mixed states. The foregoing results and considerations might depend on the use of high diagnostic thresholds. In fact, DMX2 (MDE plus no more than two manic symptoms) was much less specific for bipolar disorders, and much more frequent among unipolar depressives than DMX3, the form with a higher threshold of three manic symptoms (Benazzi, 2000; Benazzi, 2001a; Benazzi, 2001b and Benazzi and Akiskal, 2001).
This suggests that few (e.g. one or two) manic symptoms might be relatively common in unipolar depression, which would question the traditional bipolar–unipolar distinction. Most available data on DMX were achieved from cross-sectional studies performed on outpatients (Benazzi, 2000; Benazzi, 2001a and Benazzi, 2001b). This setting might have underestimated the prevalence of certain manic manifestations. In particular psychomotor agitation was found to occur more frequently among inpatients (Sobin and Sackeim, 1997 and Schatzberg and DeBattista, 1999). We are aware of only one previous paper specifically examining manic symptoms in bipolar and unipolar inpatients (Sato et al., 2003).
The current paper will compare manic symptoms occurring in BP-I and BP-II disorders to test the hypothesis that mania and hypomania differ in their clinical profiles. Furthermore, we will analyze the prevalence of few (one or two) manic symptoms in unipolar MDD inpatients.
2. Patients and method
2.1. Clinical sample
This study was conducted on subjects admitted to the Center for Mood Disorders of St. Raffaele Hospital in Milan, a specialized institution for treatment of mood disorders with 50 acute inpatients and about 3000 outpatients. Over 2000 new cases visited our center during the study period (1992–2000). Of those, we selected 652 inpatients, excluding individuals with mental retardation, dementia, substance abuse/dependence, neurological disorder or clinical/laboratory indications of severe organic disease. These subjects so-selected had participated in previous genetic studies (Serretti and Smeraldi, 1999; Serretti et al., 1998a; Serretti et al., 1998b; Serretti et al., 1999a; Serretti et al., 1999b and Serretti et al., 1999c), and were a part of a greater patient pool analyzed in clinical and demographic comparisons which did not involve manic symptomatology (Serretti et al., 2002).
Data were collected after obtaining informed consent for studies like the present one and the procedure was reviewed by the local ethical committee. The sample for the present analyses consisted of 223 males and 429 females, all of Caucasian origin: 158 patients were BP-I, 122 were BP-II and 372 had major depressive disorder (MDD). Of the MDD, 117 had one or two manic symptoms and were classified as "manic major depressives" (MMD).
2.2. Diagnostic procedures
Lifetime diagnoses were assigned by two independent psychiatrists on the basis of clinical interviews and medical records (Leckman et al., 1982), according to DSM-III-R and DSM-IV criteria (American Psychiatric Association, 1987; American Psychiatric Association, 1994 and Spitzer et al., 1990). All patients were assessed using the operational criteria for psychotic illness checklist (OPCRIT). This scale, described in detail elsewhere (McGuffin et al., 1991), was administered with a lifetime perspective to ascertain manic symptoms ever occurred during the course of illness (Farmer et al., 1994). Information was obtained not only from patients, interviewed during hospitalization, but also from their relatives and, whenever possible, from medical records. Out of a list of 90 OPCRIT items, we selected those 10 corresponding to symptoms included in DSM IV Criteria A and B for hypomanic/manic episode—elevated mood, irritable mood, increased self-esteem, reduced need for sleep, pressured speech, thoughts racing, distractibility, excessive activity, agitated activity, reckless activity, and other four items providing information on key variables reported to distinguish bipolar from unipolar disorders—gender, age at onset, mode of onset and familiarity.
2.3. Statistical analyses
Clinical and demographic variables were compared in BP-I, BP-II and major depressive patients (subdivided into MMD and pure MDD) by means of ANOVA and 2-test. Unipolar patients were subdivided into psychotic and non-psychotic groups. Fisher's exact test was used to test differences in the clinical pictures of manic (BP-I) and hypomanic (BP-II) episodes. Owing to the large number of comparisons, alpha was considered significant when <0.01. Finally a Wilkes-lambda discriminant analysis was performed on those manifestations which most differed between bipolar groups. The analysis was conducted with and without the inclusion of agitated activity (see Section 4).
3. Results
On demographic and general clinical characteristics (i.e. age and manner of onset), compared with MDD, BP-I disorder had a higher prevalence of males (X2=18.99, P<0.001), a lower age at onset (t=7.10, P<0.001), and a more rapid onset (X2=46.97, P<0.001) and a more frequent family history of mental diseases (X2=13.31 P<0.001).
Although there were more females in BP-II disorder the difference with BP-I this finding, however, was not statistically significant (X2=4.87 P=0.027). MMD was similar to pure major depression on all demographic comparators (not shown).
On manic symptomatology, when compared with BP-II, BP-I disorder had higher rates of reckless activity, distractibility, agitated activity, irritable mood and increased self-esteem (see Table 1). These five symptoms correctly classified 82.8% of BP-I and 80.8% of BP-II patients. After the exclusion of agitated activity, 80.2% of BP-I and 71.3% of bipolar II patients could still be assigned to correct diagnostic groups (see Table 2).
Agitated activity was the most frequent "manic symptom" in the major depressive group, followed by irritable mood, distractibility, reduced need for sleep and reckless activity. In psychotic depression, the rate of agitated activity was about three times higher than in non-psychotic major depression (see Table 3).
4. Discussion
The distinction between BP-I and BP-II disorders has been supported by biological variables, such as the distribution of *BO blood type (Rihmer and Arato, 1981), the red blood cell/plasma ratio of lithium (Rihmer et al., 1982) and serum dopamine-beta-hydroxylase activity (Rihmer et al., 1984), as well as clinical variables including characteristics of prior episode, family history and risk for suicide attempts (Dunner et al., 1976; Heun and Maier, 1993; Coryell, 1996; Cassano et al., 1992; Angst, 1998; Goldring and Fieve, 1984; Goodwin and Jamison, 1990 and Rihmer and Pestality, 1999). More recently, BP-IIs revealed a significantly higher lifetime prevalence of anxiety disorders, in particular social and simple phobias, and a substantially more chronic course, with more major and minor depressive episodes and shorter inter-episode intervals (Judd et al., 2003). Interestingly we found that also the patterns of manic symptoms could differentiate these two forms. Based on five manifestations—reckless activity, distractibility, psychomotor agitation, irritable mood and increased self-esteem—more than 80% of patients were correctly classified as manic (BP-I) or hypomanic (BP-II). In these analysis, one important confounding factor was antipsychotic treatment. In fact, psychomotor agitation can hardly be distinguished from akathisia, a well recognized side effect of conventional neuroleptics. The OPCRIT checklist does not assess drug therapy and detailed lifetime treatment information was not available for the sample. However even excluding psychomotor agitation still 80% of BP-I and 70% of BP-II patients could be correctly classified. Such results appear contrary to DSM IV (American Psychiatric Association, 1994), that describes manic episodes as nearly identical to hypomanic ones apart from a higher degree of severity and the possible occurrence of psychotic symptoms. In the literature, a number of factor analyses assessed the structure of mania (Cassidy et al., 1998; Serretti et al., 1999d; Swann et al., 2001; Hantouche et al., 2001; Akiskal et al., 2001; Rossi et al., 2001 and Sato et al., 2002) and hypomania (Benazzi and Akiskal, 2003 and Hantouche et al., 2003a). Overall, these studies displayed more dimensions (three to six) and a broader spectrum of symptoms in manic states. In particular, psychomotor agitation and poor judgment, often leading to involvement in reckless activities, were reported to be common in manic (Akiskal et al., 2003), but not in hypomanic patients (Benazzi and Akiskal, 2003). These findings are consistent with ours, and can serve to address the question of two disorders: it could be hypothesized that the different manic profiles are a manifestation of a greater severity, or that they reflect different physiopathology.
We also found one or two manic symptoms in more than 30% of patients with MDD, whose diagnostic assessment was integrated with the analysis of clinical and demographic variables which enabled to differentiate between bipolar and unipolar subjects. Psychomotor agitation, irritability and distractibility were the most prevalent manic-like manifestations in this unipolar subgroup. Interestingly this pattern of symptoms was similar to that observed in bipolar DMX (Benazzi and Akiskal, 2001), except for a higher prevalence of agitation. This might be due to the different characteristics of the samples. In fact Benazzi and Akiskal (2001) examined outpatients, whereas psychomotor agitation was shown to occur more frequently among inpatients (Sobin and Sackeim, 1997 and Schatzberg and DeBattista, 1999). Nonetheless, Sato et al. (2003) did replicate among inpatients the findings of Benazzi and Akiskal (2001).
Altogether our findings point to manic-like symptoms being present in all mood disorders, which contradicts the concept of the bipolar–unipolar distinction. A dispute exists between those who regard bipolar and unipolar disorders as different diseases (splitters), and those who include bipolar and unipolar forms in the same continuum (lumpers). Our results are more consistent with the latter position.
One possible remark is that our unipolar group might actually consist of "pseudo-unipolar" patients (Akiskal, 1983). Indeed 34.9% of MDD patients had psychotic manifestations and some authors have reported that psychotic delusional depression is more likely to occur in bipolar disorders (Akiskal et al., 1983 and Mitchell et al., 2001).
Nonetheless a relatively high prevalence of manic-like symptoms (26%) was found in non-psychotic MDD patients as well. Those may be the subjects with higher bipolar family history (Akiskal and Benazzi, 2003), unfortunately we had no data to test this possibility.
The presence of psychomotor agitation in a high proportion of unipolar depressions might have important consequences for clinical practice. In fact psychomotor agitation was listed among factors increasing the probability of suicide in depression (Fawcett, 1992 and Angst et al., 1999) and it was reported to be exacerbated by some antidepressant treatments (Akiskal and Pinto, 1999 and Koukopoulos and Koukopoulos, 1999).
In our sample, agitation was 3-fold commoner in psychotic than in non-psychotic depression. Such a difference might be in part the effect of drug therapy. But in our department antidepressant monotherapy is the routine, and the combination with antipsychotics is a second choice, thus, only in the psychotic group, a small proportion of agitated behaviors could be better understood as expressions of akathisia (Muscettola et al., 1999 and Berardi et al., 2000). Anyway even with the removal of such percentages attributable to drugs, psychotic depressives would maintain an almost twice higher prevalence rate of agitation (20.7% vs. 11.9% observe in non-psychotic MDD). This supports the association between psychotic depression and psychomotor agitation independently of neuroleptic use. Besides incomplete information about drug treatment, another limitation of our study is that symptoms were not rated on their severity. This is a problem because hypomania is regarded as a milder form of mania, thus the same manifestations might be less severe. Moreover we did not include other symptoms such as anxiety or obsessive symptoms, both of which have a bearing on bipolarity and its subtyping (Perugi et al., 1999 and Hantouche et al., 2003b). Indeed, there is linkage analysis data to support some uniqueness to the BP-I and BP-II subtype (MacKinnon et al., 1998 and Collier et al., 1996).
A strength of our study is that a lifetime perspective was applied to assess current and past symptoms gathered from various sources: patients themselves, interviewed during hospitalization, members of patients’ families and, when available, medical charts. In addition the use of complementary sources of information (relatives, medical records) reduced biases related to self-report of symptoms.
In conclusion, this study unveiled specific clinical profiles in mania and hypomania and the occurrence of few manic symptoms, particularly psychomotor agitation, in a relatively high proportion of unipolar inpatients. The latter finding might be interpreted in support of the hypothesis of bipolar-unipolar clinical continuity or spectrum (Akiskal, 1983 and Akiskal, 2002), with some common susceptibility genes modifying the presentation of the two forms (Gershon et al., 1982; Serretti et al., 1996 and Kelsoe, 2003).
Acknowledgements
The authors thank Cristina Cusin for her help in writing the manuscript.
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Corresponding author. Tel.: +39-02-2643-3250; fax: +39-02-2643-3265.
Posted by jrbecker on February 11, 2005, at 12:41:00
In reply to Bipolar II Series - differences in +mania+ by dx, posted by jrbecker on February 11, 2005, at 12:35:06
Journal of Affective Disorders
Volume 84, Issues 2-3 , February 2005, Pages 107-115
Bipolar Depression: Focus on Phenomenologydoi:10.1016/j.jad.2004.06.003
Copyright © 2004 Elsevier B.V. All rights reserved.
Introcduction
The dark side of bipolarity: detecting bipolar depression in its pleomorphic expressions
Hagop S. Akiskal ,VA Psychiatry Service (116A), International Mood Center, University of Caifornia, 3550 La Jolla Village Drive, San Diego, CA 92161, USA
Received 15 March 2004. Available online 1 September 2004.
Abstract
The depressive expressions of bipolar disorders have long been neglected. Current data, from both clinical and epidemiologic studies, indicate that such expressions far exceed the manic forms in both cross-section and during follow-up course. Thus, mania occurs in 1% of the population at large; bipolar depression afflicts at least 5 times more people. Much of the new literature on this subject has emphasized its high prevalence, morbidity, and mortality. There has been relatively less attention paid to the phenomenology of bipolar depression as it presents clinically. This special issue (volume 84/2–3, 2005) is devoted to a systematic data-based in-depth examination of the different clinical expressions of bipolar depression including, among others, retarded depression, agitated and/or activated depression, mood-labile depression, irritable-hostile depression, atypical depression, anxious depression, depressive mixed state, and resistant depression. Both bipolar I (BP-I), and the more prevalent yet relatively understudied bipolar II (BP-II), are covered. We trust that this extensive coverage of the “darker” side of bipolarity will set the stage for a much needed renaissance in its complex phenotypic expressions—and its delimitation from unipolar depression (UP).
The phenomenology of BP-I depression ranges from depressive stupor to agitated psychosis, whereas UP depression expresses itself in psychic anxiety, and insomnia, as well as retardation. BP-II compared with UP is more likely to have atypical features, mood lability, hostility, activation, biographical instability, multiple anxiety comorbidities, suicidal tendencies, and to be rated as less “objectively” depressed. These findings are complex and do not fully agree with the conventional characterization of BP as retarded and UP as anxious and agitated. The inconsistency between the conventional and the phenomenology described herein is largely due to depressive mixed states, which tend to destabilize BP-II, and may account for the “contradictory” relationships of affect, sleep, drive, and psychomotor activity in mood disorders.
Keywords: Bipolar I; Bipolar II; Atypical depression; Mixed state; Retarded depression; Agitated depression
1. Introduction
Although much has been published about the clinical features of mania, there has been a comparative paucity of research on the depressive phase of bipolar disorder. This paper provides an overview of recent developments on the clinical features of the depressive phase of bipolar disorder. We term it the “dark side” of bipolarity because it is often missed in diagnostic assessments and has long been neglected. Such neglect, in turn, reflects the complexities of its clinical presentation and the instability, lability, and mixity of its clinical phenomenology in the BP-II subtype (Akiskal et al., 2003a). Such patients may be regarded as less depressed on clinician versus self-evaluation (Dunner et al., 1976a). Tragically, the dark side of these patients may lead to suicide (Rihmer and Pestality, 1999).
There is considerable confusion in the current literature about the clinical portrait of bipolar depression (Beigel and Murphy, 1971, Dunner et al., 1976a, Akiskal et al., 1983, Akiskal et al., 1995, Joffe et al., 1999 and Mitchell et al., 2001). In particular, it is uncertain whether bipolar depression manifests with psychomotor retardation or agitation. Indeed, both have been reported. Table 1 summarizes what we know from the literature about the validating differential features of bipolar and unipolar disorders in their depressive phases (Goodwin and Jamison, 1990 and Akiskal, 2000). To be further discussed in the present review is to what extent these features pertain to bipolar II (BP-II), the more common form of bipolar disorder (Akiskal et al., 2000). The present introductory review is undertaken as background material for the new data-based reports compiled for the present special issue.2. Bipolar I depression
It is generally believed that bipolar I (BP-I) disorder, the prototype of bipolar disorder, exemplifies the classical features listed in Table 1. This traditional view is supported in its main elements by two prospective studies, one in adolescents (Strober and Carlson, 1982), the other in adults (Akiskal et al., 1983). However, temperament was not tested in these two studies. Prospective assessment of temperamental attributes in the NIMH Collaborative Depression Study (Akiskal et al., 1995) has actually shown that MDE patients who switch to BP-I are more likely to be “sanguine” compared to those who do not switch; the latter tend to be anxious-neurotic (i.e. dysthymic). Similar findings have been reported by Angst and Clayton (1986) from the Zurich cohort. Such data suggest that most BP-I are not cyclothymic—this is certainly the case for BP-I with euphoric mania. However, BP-I with dysphoric mania may arise from depressive and cyclothymic temperaments (Perugi et al., 1997 and Akiskal et al., 1998).
Psychomotor retardation with hypersomnia (Detre et al., 1972, Himmelhoch, 1998 and Mitchell et al., 2001), touted as “pathognomonic” for bipolar illness, is characteristic of the “pure” depressive phase of the illness. Psychotic, agitated-irritable depression, the hallmark of bipolar mixed depression, is not uncommonly observed in BP-I (Perugi et al., 2001). Contrary-wise, as to be discussed later in this paper, anxious agitation in “unipolar” depression might be due to contamination by bipolar II mixed states.
Thus, the phenomenology of BP-I depression ranges from depressive stupor to agitated psychosis, whereas unipolar depression (UP) expresses itself in guilt and insomnia, as well as retardation (Allilaire et al., 2001). To further complicate matters, agitation can coexist with retardation (Greden and Carroll, 1981), a phenomenon which might be more characteristic of bipolar disorder. Such “paradoxical” coexisting psychomotor phenomenology is perhaps best understood when one considers that it is acceleration, not agitation, which is the opposite of retardation.
In conclusion, the distinguishing features of full-blown bipolar (BP-I) from UP depressions shown in Table 1 are largely accurate except for the foregoing qualifications for temperament and psychomotor activity.
3. The clinical spectrum of bipolarity
Current data indicate that classical manic-depressive illness (BP, type I) involves 1% of the population. These patients reach the threshold of mania, typically a condition which requires hospitalization; much of the course of BP-I, however, is dominated by depressive episodes and/or subthreshold depression (Judd et al., 2002). Bipolar type II is characterized by alternation of depression with more subtle periods of excitement known as hypomania which, by itself, does not warrant hospitalization (Dunner et al., 1976b); depression dominates its course. Type II, which is 5 times more common than type I, is poorly recognized by both researchers and clinicians (Akiskal et al., 2000), which explains the relative paucity of research on it.
Recent research has nonetheless shown reliable methods of clinical ascertainment in public, private, and national samples (Hantouche et al., 1998 and Benazzi and Akiskal, 2003). There is indeed a “hidden epidemic” in the making, consisting of major depressive disorders whose bipolar nature is unrecognized (Akiskal and Pinto, 1999). Failure to recognize the bipolar nature of bipolar II and its variants often leads to inappropriate treatments of the depression—and long delays in instituting effective treatments.
A new paradigm of bipolar spectrum is shaping up in the research literature and in clinical practice (Akiskal, 2002). It represents a partial return to the Kraepelinian (1921) broad concept of manic depression which included many recurrent depressions. Although bipolar I, bipolar II, and cyclothymia are now part of the official nomenclature of DSM-IV, the breadth of bipolarity is not represented in this manual. Old and new evidence indicate that the most common form of bipolar II is characterized by hypomanias of shorter duration than the arbitrary threshold of 4 days (Akiskal et al., 2000), and that cyclothymic depressions (major depressions arising from a cyclothymic baseline) represent a prevalent variant of the bipolar II pattern. Furthermore, evidence is now compelling that hypomania in association with antidepressant treatments (bipolar III) requires familial bipolar diathesis for bipolar disorder (Akiskal et al., 2003b). There also exist clinical depressions superimposed on hyperthymic temperament (bipolar IV), referring to individuals with subthreshold hypomanic traits rather than episodes (Akiskal, 1992 and Cassano et al., 1992). Given emerging data for a population prevalence of at least 5% for a broadly conceived bipolar spectrum (Akiskal and Mallya, 1987, Angst, 1998, Szadoczky et al., 1998, Judd and Akiskal, 2003 and Hirschfeld et al., 2003)—and 6% for the cyclothymic temperament (Placidi et al., 1998)—we estimate that 1 of 10 individuals in the community either has bipolar disorder or is at risk for it.
A provocative new development is the emergence of extensive clinical and research evidence for the comorbidity of panic, social phobic, and related anxiety states with bipolar, especially bipolar II, disorder (Perugi et al., 1999). In addition, prevalent mixed states beyond dysphoric mania have been described, consisting of hypomanic intrusions into major depressive states (Akiskal and Benazzi, 2003 and Sato et al., 2003).
The net effect of the broadened boundaries of bipolarity is encroachment into the terrain of so-called “unipolar” anxious depressions and that of axis II cluster B personality disorders predicted by us as early as the early 1980s (Akiskal, 1983). This is an evolving reformulation of the subclassification of affective disorders, validated on the basis of phenomenology, comorbidity, epidemiology, course, family history, twin studies, and molecular genetics and an evolutionary perspective (Akiskal, 2002). These considerations—especially the fact that depression is the most prevalent expression of the bipolar spectrum—have major implications for clinical practice, methodology of genetic investigations, pharmaceutical trials of putative bipolar agents in affective disorders, and public health.
Because bipolarity impacts on all aspects of life, the spectrum would be of great interest to all mental health clinicians, general practitioners, nurses, educators, and public health officials.
4. Prevalence of bipolar II in major depression
The clinical diagnosis of bipolar II is crucial, not only for psychopathology and its therapeutic implications, but also for prognostic reasons (e.g., high suicidality; Rihmer and Pestality, 1999). Accordingly, it is gratifying that a great deal of recent research has been conducted on the clinical prevalence of bipolar II among patients presenting with major depressive disorder in various psychiatric clinics—both public and private—worldwide (summarized in Akiskal et al., 2000). These data show that up to 50% of all major depressions conform to bipolar II or its variants. Simpson et al (1993) stated this fact most eloquently: bipolar II represents the most common phenotype of bipolar disorder. Recent epidemiologic studies both in the U.S. (Judd and Akiskal, 2003 and Hirschfeld et al., 2003) and Europe (Angst, 1998 and Szadoczky et al., 1998) have extended these findings to the community.
The French EPIDEP study (Hantouche et al., 1998), based on a representative national clinical sample, has provided the most compelling data on the high prevalence of bipolar II among major depressive patients. The overarching purpose of this study was to assist practicing psychiatrists to recognize bipolarity in all of its varieties. The main finding was that at index interview, 22% of major depressive patients could be diagnosed as bipolar II based on history of hypomania; a month later, upon reinterview, 40% of patients were diagnosed as bipolar II on the basis of more in-depth evaluation and collateral information from significant others, as well as observed hypomania by the clinician. These figures must be contrasted with the 6% at both index and follow-up for BP-I (which remained stable because it depends on history of manic episodes, readily available from past patient records).
To recapitulate, the EPIDEP study demonstrated that clinicians in diverse practice settings can document the diagnosis of BP-I with relative ease; however, they required the institution of systematic assessment methods to recognize bipolar II and its variants. Thus, specialized training can lead to changes in diagnostic practice at the national level.
5. Assessing hypomania
Bipolar II patients present with a major depressive episode, and upon further inquiry, history for hypomanic episodes is elicited. Accurate diagnostic subtyping then depends on the vagaries of the patient's memory and how systematically the clinician pursues lead questions about hypomania and whether relatives are interviewed.
Rice et al (1986), reporting from the NIMH collaborative study of depression, found low reliability of the bipolar II diagnosis. However, all such diagnoses occurred in pedigrees with bipolar disorder, suggesting that once history for hypomania was obtained, it did carry significant diagnostic specificity. In practice, then, the diagnosis of bipolar II requires repeated evaluation at different time points to obtain more reliable history for hypomania. Dunner and Tay (1993) found that clinicians specifically trained to recognize bipolar II outperformed those using structured instruments such as the SADS or the SCID in the diagnosis of bipolar II disorder. This finding has been replicated (Brugha, 2003). Although the foregoing consideration runs against the usual tenets in the literature on structured diagnostic interviewing, they are consistent in suggesting that the proper identification of bipolar II requires a sophisticated approach in the clinical evaluation of these patients.
Among the major reasons for diagnostic inconsistency in bipolar II is the underlying cyclothymic dysregulation, resulting in clinical presentations of a labile-variable nature, which can be confusing in cross section (Akiskal et al., 2003a). That is, these patients could present with cross-sectional features of atypical depression and lifelong history of anxiety states, bulimia, substance abuse, and cluster B personality disorder such as “borderline” (Perugi et al., 1999). A prospective study has also demonstrated that atypical depressions more often than not progress to bipolar spectrum disorders (Ebert et al., 1993). Hypersomnia, weight gain, and related atypical features then represent an important clinical marker of bipolar II, observed in cross-sectional studies as well; such features may actually serve as a clinical marker for bipolar II (Benazzi, 2000 and Akiskal and Benazzi, 2005, this issue).
Recent work has shown that the stem question on mood (euphoric or irritable) in the SCID and the DSM-IV is not understood by patients, either because it reflects the way they usually feel or they do not believe that there is anything wrong with it. In a study in the Ravenna–San Diego Collaboration, we found that bypassing this question and inquiring first about the behavioral or activation signs and symptoms of hypomania can better accomplish the diagnosis of bipolar II (Benazzi and Akiskal, 2003). After such activation symptoms are elicited, the patient can then be queried about their moods, who better remember that they were irritable or euphoric during such an activated period, thereby supporting a bipolar II diagnosis.
Another interesting development in the complexity of bipolar II is panic attacks. There have been stronger lod score estimates in molecular linkage in bipolar II patients with familial panic versus those without (MacKinnon et al., 1998). Thus, the affective dysregulation of bipolar disorder extends beyond elation and depression—to include, among others, such negative affective arousal states as panic, irritability, and mood lability (Akiskal et al., 1995).
6. The specificity of mood lability and related life disruptions in bipolar II
Analyses from the NIMH Collaborative Depression Study on 559 “unipolar” patients showed that 48 converted to bipolar II during a prospective observation period of 11 years. What characterized these bipolar II converters at entry were early age at onset of first depression, recurrent depression, high rates of divorce or separation, high rates of scholastic and/or job maladjustment, isolated “antisocial acts,” and drug abuse—in brief, a more tempestuous affective and life history. In addition, the index depressive episode was further characterized by such features as phobic anxiety, interpersonal sensitivity, obsessive-impulsive symptoms, somatization (often with subpanic symptoms), worse in evening, self-pity, demandingness, subjective or overt anger, jealousy, suspiciousness, and ideas of reference—again testifying to a broad mélange of “atypical” depressive symptoms with “borderline” features. Temperamental attributes obtained at index interview proved decisive (sensitivity=91%) in identifying those who switched from depression to hypomania: these attributes consisted of trait “mood lability,” “energy activity,” and “daydreaming”—all characteristic of Kretschmer's (1936) description of the cyclothymic temperament; mood lability was the most specific predictor (specificity=86%) of which depressions will prospectively transform to bipolar. This study testifies to the fact that bipolar II is a complex affective disorder with biographical instability—deriving from an intense temperamental dysregulation. Mood lability—with rapid shifts, often in a depressive polarity—was the hallmark of “unipolar” patients who switched to bipolar II. Unfortunately, our formal diagnostic systems (e.g., ICD-10 and DSM-IV) are symptom-oriented and do not consider extreme temperamental dispositions in clinical evaluation. Instead—and regrettably this is particularly true for the DSM-IV schema—such patients often get labeled “borderline.”
7. Bipolar II depressive mixed states
Because history for hypomanic episodes often proves difficult to obtain from a depressive patient, one may examine hypomanic features during a depressive phase. Hypomanic symptoms such as racing and grandiose thoughts, sexual arousal, and psychomotor acceleration have been described in major depressive episodes in contemporary psychiatry, thereby testifying to Kraepelin's diagnostic acumen—yet, the number of studies reporting on “bipolar depressive mixed states” are too few (reviewed in Akiskal and Benazzi, 2003). A recent study by Benazzi (2000) demonstrated that irritability, distractibility, and racing thoughts were the most common hypomanic features during depression, mostly among bipolar II depressives. Unfortunately, such studies have not commanded sufficient interest in official nosologic systems nor in the clinical literature. The nonrecognition of depressive mixed state is nothing short of a clinical tragedy because these are the very “unipolar” depressive patients who are likely to do poorly on antidepressants and require mood stabilizers, antipsychotics, or electroconvulsive therapy (Akiskal and Mallya, 1987 and Akiskal and Benazzi, 2003). Koukopoulos and Koukopoulos (1999) have recently written a superb clinical article on agitated depression as a mixed state. This is an instance where clinical acumen has outpaced the conventional scientific literature. Validation of the bipolar nature of agitated depression represents a new frontier (Akiskal and Benazzi, 2005 and Benazzi et al., 2004).
8. Characterizing the phenomenology of bipolar II depression
In the French national collaborative study on depression (EPIDEP. Hantouche et al., 1998 and Allilaire et al., 2001), analyses in midstream demonstrated that hypersomnia and suicidal ideation were more common in bipolar II (BP-II) versus unipolar (UP) disorder, which had more insomnia. In the most recent analyses based on dimensional measures in the entire sample of 493 patients, the differential features of the two disorders emerged more clearly (see Hantouche and Akiskal, 2005, this issue):
• BP-II depressives were rated higher on suicidal thoughts, guilt, depersonalization, and derealization, and yet, despite hypersomnia and weight gain, had high ratings on psychomotor activation, suggesting the picture of an activated or mixed depressive state. These findings, in turn, showed why BP-II patients were deemed as less “objectively” depressed, revealing greater discrepancy between clinician versus self-rated measures of depression.
• Strictly UP major depressives did have more psychic anxiety and insomnia on various self-assessment [including Multiple Analog Visual Scale for bipolar on the Ahearn-Carroll scale (1996)] and were higher on slow thinking, anergia, feeling worst, avoiding risks, life dull, and dreary. Indeed, “psychomotor retardation” was highest in UP, and this difference appeared most significant when compared with cyclothymic BP-II.
9. Diagnostic implications for the clinician
Depression is the more common expression of the bipolar spectrum. Bipolar II is actually the most common clinical phenotype of this disorder.
Apart from demographic, familial, and course differences between unipolar and bipolar disorders, the literature has emphasized differences in psychomotor function. Most studies have reported higher psychomotor retardation in bipolar than unipolar disorder. However, this depends on whether mixed features are permitted in bipolar depression and whether or not the comparison with unipolar is between bipolar I or bipolar II. The data overall indicate that in bipolar II depression, irritability, distractibility, racing thoughts, and mood lability are quite common, despite the presence of hypersomnia. Once bipolar II is properly diagnosed and excluded from broadly defined unipolar major depression, not only are atypical features less common in strictly defined unipolar patients, but also the mixed features documented above become the clinical signature of bipolar II. It is therefore not surprising that psychomotor retardation per se might be more marked in unipolar depressive patients once BP-II are excluded from it.
On the other hand, psychic anxiety and insomnia, long known for their state association with unipolar disorder (Beigel and Murphy, 1971), continue to accompany this subtype of depression. The situation, however, is more intricate because of increasing reports about high prevalence of multiple comorbid anxiety states during the course of bipolar II (Perugi et al., 1998 and Rihmer et al., 2001). This means that the presence of anxiousness and/or anxiety comorbidity does not automatically suggest unipolarity. Such comorbidity appears to be a marker of even childhood onset bipolar disorder (Masi et al., 2001). These conclusions are complex and suggest that heterogeneity of depressive states, particularly in bipolar II, should be taken into consideration in describing the differentiating characteristics of unipolar and bipolar disorders.
This special issue provides an in-depth data-based collection of reports that expand upon and go beyond the present introductory review. DSM-IV is not of great help in the differential diagnosis of bipolar from major depressive disorders. This cannot be merely achieved in cross-sectional symptomatologic basis or past episodes of mania or hypomania. The clinician must also consider, among other validators, family history, temperament, switching on antidepressants, cyclicity, mixity, and seasonal patterns (Akiskal, 2002).
On the basis of the foregoing validators, the “depressive” presentations listed in Table 2 should be considered as putative soft bipolar disorders. These conditions are not officially recognized as bipolar. They are often misconstrued as recurrent major depressive in nature. The author submits that they have affinity to bipolar disorder, yet are not listed in the bipolar NOS category in DSM-IV. I would like to highlight recent evidence that anxious inhibition may partly replace the depressive phase in certain patients with cyclothymic tendencies (Perugi et al., 1999), resulting in social phobic, panic, and obsessive-compulsive variants of bipolarity; these patients are often considered to have anxious depressions with mood instability and, regrettably, more often than not, delegated to cluster B erratic personality disorders.
It is important to consider soft bipolarity in the listed conditions because such patients often show mediocre response to monotherapy; indeed, they often fail multiple (≥3) antidepressants from different classes (Akiskal and Mallya, 1987). This is upheld by clinical experience in specialized mood and bipolar clinics (Akiskal and Pinto, 1999 and Ghaemi and Goodwin, 2001). In particular, activated depressions respond poorly to antidepressants (Caligiuri et al., 2003). We obviously need more rigorous studies to demonstrate the efficacy of mood stabilizer augmentation in such patients.
10. Concluding remarks
The concept of a bipolar spectrum is a heuristic concept that is rooted in the descriptive clinical tradition and is validated by a new wave of epidemiologic studies demonstrating the high prevalence of subthreshold cases, familial aggregation studies, high-risk offspring studies, analysis of monozygotic “discordance,” and molecular linkage studies (Akiskal, 2002).
Family history for bipolar disorder, cyclothymic temperament, and switching on antidepressants represent the most useful validating principles in clinical practice when examining depressed patients without antecedent frank hypomania. Early age at onset, postpartum onset, mixity, high rate of recurrence, cyclicity, and seasonality can also serve as clinical validators. Specific comorbid patterns of depression with alcohol and multiple drug abuse, as well as social phobic, panic, and obsessive-compulsive disorder, should also raise clinical suspicion of a bipolar diathesis. The thrust of arguments made in this report suggests that the clinical management of affective disorders will not improve significantly until there is recognition that most depressions presenting clinically are, at some level, bipolar. As counterintuitive as this suggestion might be, there is increasing evidence in its support.
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Posted by KaraS on February 11, 2005, at 16:48:30
In reply to Bipolar II Series - Bipolar II vs. unipolar, posted by jrbecker on February 11, 2005, at 11:57:06
There's a lot of great information here. Thanks for posting these!
Kara
Posted by Phillipa on February 11, 2005, at 17:58:59
In reply to Re: Bipolar II Series - Bipolar II vs. unipolar » jrbecker, posted by KaraS on February 11, 2005, at 16:48:30
It will take a year to absorb all this. Fondly, Phillipa
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