![[dr. bob]](/dr-bob-sm.gif)
Dr. Bob is Robert Hsiung, MD,
[email protected]Shown: posts 6 to 30 of 44. Go back in thread:
Posted by allisonm on December 31, 2000, at 11:45:02
In reply to Re: Bipolar type that cycles betw norm. and depressed?, posted by Noa on December 30, 2000, at 19:44:19
> For some people with double depression, mood stabilizers like lithium, depakote, lamictal, etc., do help.
>I have found that Neurontin (gabapentin), used for epilepsy but more recently as a mood stabilizer, has helped me. I take it with Wellbutrin for what my doctor terms chronic refractory major depression. I don't know whether this pairing is "enough," but seems to be the best combo so far.
I have sometimes wondered whether I had bipolar symptoms. I agree with Noa's opinion of finding the right drugs and disregarding the Dx.
Best wishes for the new year.
Allison
Posted by Ted R on December 31, 2000, at 18:56:31
In reply to Bipolar type that cycles betw norm. and depressed?, posted by S.D. on December 30, 2000, at 18:05:32
> For as long as I've believed I had a predominantly chemically/genetically -based mood disorder, I've thought it was Major Depression or Dysthymia (or both, a/k/a double depression).
>
> Someone asked me about Bipolar and I said I didn't know too much about it but that I didn't think there was anything that was recognized as being a type of Bipolar (meaning in practice, I suppose, that it responds to the typical treatments for Bipolar), having the feature that the cycles are only between 'normal' (or almost normal) and depressed - no mania or even hypomania.
>
> But I promised I'd investigate, so I'm asking.
>
> If there *is* recognized such a thing, how is it distinguished from plain old major depression that comes and goes? (response to classes of meds, maybe?)
>
> TIA
>
> peace and health,
>
> S.D.
> Dr. Jim Phelps at www.psycheducation.org has information, and appears to be a thought leader on this Bipolar type.It may be what he calls a further diagnostic classification of Bipolar 2 disorder.
Posted by S.D. on January 1, 2001, at 0:19:14
In reply to Re: Bipolar type that cycles betw norm. and depressed?, posted by Noa on December 30, 2000, at 19:44:19
> Yes, I read one abstract in which Akiskal defined this as Bipolar III. It is one way of looking at double depression.
>
> For some people with double depression, mood stabilizers like lithium, depakote, lamictal, etc., do help.
>
> I'll see if I can scrape up that abstract info....I couldn't find anything at all on pubmed about effectiveness of mood stabilizers for double depression or dysthymia. And the only thing that mentioned "Bipolar III" didn't have an abstract available. So if you can scrape up that abstract info, I'd really appreciate it.
Otherwise, I can't yet see how I could have any kind of bipolar, because everything I've read seems to require at least hypomanic episodes to rule it in (or, putting the Dx aside, to justify 'mood stabilizers').
I did find an old psychobabble post that said"... Dr. Akiskal has stated that up to 50% of patients diagnosed as having dysthymia are, in fact, suffering from a ‘soft bipolar’ disorder and would thus benifit from treatment with mood stabilizers",
which is very similar to what you said. But I definitely didn't find the source of that statement.peace and health,
S.D.
Posted by S.D. on January 1, 2001, at 1:44:28
In reply to Re: Bipolar type that cycles betw norm. and depressed? » S.D., posted by judy1 on December 31, 2000, at 0:27:06
> Hi,
> While Noa's finding the Akiskal abstracts
>(which she did remember correctly)-I hope she (I'll take your word for it; I don't think I ever knew if Noa was he or she) does - I looked at everything I could find from Akiskal and couldn't find what apparently is there (I found an old psychobabble post that refers to what sounds like 'it' - see my second reply to Noa ( http://www.dr-bob.org/babble/20001231/msgs/50662.html ))
>I thought I'd throw in my 2 cents.
>Do you ever have an agitated type of depression?Yes. I often have what I think would be called anxious depression or agitated depression or what Kraepelin called "depression with flight of ideas".
>Insomnia?
Oh, lord yes. often. See my recent post ( http://www.dr-bob.org/babble/20001130/msgs/50587.html )
>Irritability?
What's it to ya?!
(Guess that would be a yes.)>These are all on the bipolar spectrum, and
>with the cycling, you would fit the
>profile(and probably would benefit from a
>low dose mood stabilizer).Thanks for the ideas. I think I don't understand enough about the cycling part:
My mood and irritability can vary widely day to day or hour to hour, but I know that's not what is meant by bipolar cycling, nor even rapid cycling.
I go in and out of depression, but many people have depressions that remit (with or without treatment) and return. If that is bipolar cycling, even without ever going into mania, then anyone with recurring depressive episodes would be diagnosed bipolar.
The closest thing I think I have to a bipolar symptom relates to what you asked about agitated depression. That is, I have what might be considered a mixed state of some kind (although not DSM-IVs full-mania+full depression defn.), e.g. a "mixed depressive state, which consists of full syndromal depression and less than syndromal mania" ( http://www.medscape.com/medscape/cno/2000/APA/Story.cfm?story_id=1167 ).
And I may have been in a mild hypomanic state a few times in my life, but restricted to certain aspects (not euphoric or reckless).
In more recognizable bipolar, the mood stabilizers are supposed to prevent episodes of both mania and depression, right?. Are they also supposed to be able to prevent day-to-day mood swings, and/or suppress agitation or insomnia?
peace and health,
S.D.
Posted by S.D. on January 1, 2001, at 3:12:57
In reply to Re: Bipolar type that cycles betw norm. and depressed?, posted by Ted R on December 31, 2000, at 18:56:31
> Dr. Jim Phelps at
>www.psycheducation.org has information,
>and appears to be a thought leader on
>this Bipolar type.It may be what he calls
>a further diagnostic classification of
>Bipolar 2 disorder.Thanks. Actually his site is one that turned up in my search engine queries today. He does seem to be up on the latest research and theories, and obviously has had much personal clinical experience with it. I certainly can see myself in his description of "Depression with periods of severe insomnia" ( http://www.psycheducation.org/depression/02_diagnosis.html#Depression-Insomnia )
One seeming mistake I just noticed though, is in the section comparing GAD with Bipolar II ( http://www.psycheducation.org/depression/02_diagnosis_app.html#Anchor-GAD-20395 ). He lists profound insomnia as a Bipolar II symptom "using the broad criteria of...Dr. Akiskal" , but and article by Akiskal ( http://www.medscape.com/medscape/cno/1999/APA/Story.cfm?story_id=646 ) refers to a study where "It was found in this study that, insomnia was more common in unipolars and hypersomnia was more common in bipolar II."
Dr. Akiskal's much more inclusive view of bipolar, especially compared to DSM-IV, apparently is at least a bit controversial, but he seems to be "the man" on the leading edge of bipolar research (plus Dr. John Kelsoe regarding the genetics thereof. Both of them are are located in my city, San Diego. They are investigators for the MHCRC ( http://varesearch.ucsd.edu/gillin/mhcrc/default.htm ) which is associated with UCSD VA hospital, and Dr. Kelsoe is also a UCSD associate professor who is heading a genetics research program (regarding bipolar and depression) for UCSD psych. dept. ( http://www.bipolar.ucsd.edu/BPResearch.htm ).
I find it a bit ironic that I can hardly swing a dead cat in this town without hitting a major mental illness researcher, but it hasn't done me a bit of good. (I tried contacting Dr. Akiskal once; evidently he doesn't take patients anymore. Dr. Steven Stahl does, and he's plenty sharp, but I still ended up worse for having consulted him.)
peace and health,
S.D.
Posted by SLS on January 1, 2001, at 9:45:11
In reply to Bipolar type that cycles betw norm. and depressed?, posted by S.D. on December 30, 2000, at 18:05:32
> For as long as I've believed I had a predominantly chemically/genetically -based mood disorder, I've thought it was Major Depression or Dysthymia (or both, a/k/a double depression).
Someone asked me about Bipolar and I said I didn't know too much about it but that I didn't think there was anything that was recognized as being a type of Bipolar (meaning in practice, I suppose, that it responds to the typical treatments for Bipolar), having the feature that the cycles are only between 'normal' (or almost normal) and depressed - no mania or even hypomania.> But I promised I'd investigate, so I'm asking.
> If there *is* recognized such a thing, how is it distinguished from plain old major depression that comes and goes? (response to classes of meds, maybe?)
Hi S.D.Yes, there are bipolar and "soft" bipolar (not meeting strict diagnostic criteria for bipolar disorder) presentations that exhibit a cycling between depressed and normothymic states. I personally experienced a period of two years in which I was an ultra-rapid cycler, switching between severe depression and nearly normal (mild depressive) states regularly with a period of 11 days. 3 days up and 8 days down. Like clockwork. Damned biological clocks. Upon my first trial of lithium, rapid cyclicity ceased and left me chronically depressed thereafter.
At no time during my rapid-cycling period did mania or hypomania appear. In fact, the only time they do now is when a medication precipitates it. My manic states during these events have been either mixed or dysphoric. Depressions that include antidepressant-induced manias (but no spontaneous manias) has been proposed as bipolar type III (contradictory to the work cited by Noa) to be included in the DSM diagnostic manual for over a decade. Several years ago, someone on another site posted a diagnotic parsing that included five types of bipolar presentations.
Why do you think you have a cycle between states?
Can you describe the details of your cycle and what you feel in both states?
Personally, I feel that mood-stabilizer medications are a good idea in situations like this to help prevent the condition from evolving into a more severe and treatment-resistant course.
I agree in many ways with Noa regarding diagnosis based upon response or non-response to mood-stabilizers, especially when they seem to be helpful in cases currently thought to be unipolar. However, I think there is a place for charting the responses to various drugs as to be considered in a multimodal assessment.
A good starting point for you might be to throw away labels and conclusions and diagnostic terms and simply list in detail what you experience.
Examples:
1. How you feel now - both mentally and physically
2. Recall at what age you suffered your first unequivocal depressive episode.
3. Describe your baseline depression - how you felt and functioned before taking any psychotropic medications.
4. Describe the course of your mood states with regard to time:
- length of time for a complete cycle (beginning of depressive episode to the beginning of next depressive episode)
- cycling, length of time between depressive states
- the consistency or regularity of this cycling
- any seasonality; a tendency for changes in mood states to be associated with different times of the year.5. Describe what medications have been helpful, and how they helped.
I guess all of this garbage is my feeble attempt to squeeze out any true rapid cyclicity that might be indicative of a bipolar-spectrum disorder, or whether your illness is simply a recurrent unipolar depression that is best treated consistently and without "drug-holidays" indefinitely.No need to respond - just a few things to think about.
- Scott
Posted by judy1 on January 1, 2001, at 12:52:10
In reply to Re: Bipolar type that cycles betw norm. and depressed? » judy1, posted by S.D. on January 1, 2001, at 1:44:28
Hi Neighbor,
Yes, Dr. Akiskal and the full professors at UCSD (Zisook another bipolar expert there) do not accept patients anymore; I was able to get a consultation because I am "interesting", a treatment resistant rapid cycler with a loaded family history. Anyway, one of the important factors that came out of that meeting was a ban on antidepressants and a trial on lamictal- which worked TOO well. Have you tried it yet, it is considered the one mood stabilizer with an antidepressant effect and it really does work well in a lot of people. As far as the more mainstream mood stabilizers, no they don't prevent depression in most people dxed with bipolar- even lithium according to more recent developments. I'm glad you went to Dr. Phelp's site (sp?), he also hates AD's, even with someone who has a somewhat muddled picture like you. Although you did allude to possible hypomanic states, which people tend to downplay because they feel good. As far as cycles, I've cycled in 1 day- and there are people who do so hourly (ultra-rapid), and often get confused with borderline- another disorder Akiskal puts on the bipolar spectrum. I realize a lot of his stuff is presented as posters at meetings and may not be published. I think I'm drifting here, but as some one else suggested, don't worry about the semantics, just find something that works. And I would try lamictal- good luck, Judy
Posted by Ted R on January 1, 2001, at 13:12:40
In reply to phelps, Akiskal, insomnia and Bipolar II » Ted R, posted by S.D. on January 1, 2001, at 3:12:57
> > Dr. Jim Phelps at
> >www.psycheducation.org has information,
> >and appears to be a thought leader on
> >this Bipolar type.It may be what he calls
> >a further diagnostic classification of
> >Bipolar 2 disorder.
>
> Thanks. Actually his site is one that turned up in my search engine queries today. He does seem to be up on the latest research and theories, and obviously has had much personal clinical experience with it. I certainly can see myself in his description of "Depression with periods of severe insomnia" ( http://www.psycheducation.org/depression/02_diagnosis.html#Depression-Insomnia )
>
> One seeming mistake I just noticed though, is in the section comparing GAD with Bipolar II ( http://www.psycheducation.org/depression/02_diagnosis_app.html#Anchor-GAD-20395 ). He lists profound insomnia as a Bipolar II symptom "using the broad criteria of...Dr. Akiskal" , but and article by Akiskal ( http://www.medscape.com/medscape/cno/1999/APA/Story.cfm?story_id=646 ) refers to a study where "It was found in this study that, insomnia was more common in unipolars and hypersomnia was more common in bipolar II."
>
> Dr. Akiskal's much more inclusive view of bipolar, especially compared to DSM-IV, apparently is at least a bit controversial, but he seems to be "the man" on the leading edge of bipolar research (plus Dr. John Kelsoe regarding the genetics thereof. Both of them are are located in my city, San Diego. They are investigators for the MHCRC ( http://varesearch.ucsd.edu/gillin/mhcrc/default.htm ) which is associated with UCSD VA hospital, and Dr. Kelsoe is also a UCSD associate professor who is heading a genetics research program (regarding bipolar and depression) for UCSD psych. dept. ( http://www.bipolar.ucsd.edu/BPResearch.htm ).
>
> I find it a bit ironic that I can hardly swing a dead cat in this town without hitting a major mental illness researcher, but it hasn't done me a bit of good. (I tried contacting Dr. Akiskal once; evidently he doesn't take patients anymore. Dr. Steven Stahl does, and he's plenty sharp, but I still ended up worse for having consulted him.)
>
> peace and health,
>
> S.D.
>These have been very interesting posts on the expanded criteria for Bipolar 2, soft and atypical etc. When my Pdoc first suggested that I might be Bipolar 2, instead of unipolar with panic-anxiety and suggested trying lamictal at hopefully not to high a dose, I was extremely skeptical. I see now where he is coming from. I definitely think trying the lamictal is worth a shot. I have to find something to improve my functioning, and other than the rash consideration, it appears lamictal is tolerated pretty well..Ted R
Posted by SLS on January 1, 2001, at 14:29:13
In reply to S.D.- some more thoughts, posted by judy1 on January 1, 2001, at 12:52:10
Hi Judy.
More semantics... :-)
> As far as cycles, I've cycled in 1 day- and there are people who do so hourly (ultra-rapid),
The type of ultra-rapid cyclicity that produces the type of 1-day cycling you describe is considered to be ultra-dian; dian meaning "day" (as in circadian - "circa-dian").
> Anyway, one of the important factors that came out of that meeting was a ban on antidepressants and a trial on lamictal- which worked TOO well.
I am not surprised that Lamictal caused in you a manic state, if that was what you are alluding to. It seems to have some true antidepressant effects that are separate and in addition to its mood-stabilizing properties. My hunch is that Lamictal exerts some sort of pro-dopaminergic effects. I have seen some reports of Lamictal inducing both mania and rapid-cyclicity. These things seem to be uncommon, though.
- Scott
Posted by judy1 on January 1, 2001, at 17:54:57
In reply to Re: S.D.- some more thoughts, posted by SLS on January 1, 2001, at 14:29:13
Hi Scott,
Thank you for the correct term- I was really thinking circadian, but then the insect kept coming to my mind. I think this is a result of my head injury or too many drugs- both legal and nonlegal. Anyway, yes I got manic on lamictal- actually they said I "overshot", which I rather like. To show my ignorance, when you said dopaminergic effects- does that mean an increase in dopamine? And if that is the case, I thought that was implicated in positive psychotic symptoms. If I'm way off base, please let me know. Take care- Judy
Posted by dj on January 1, 2001, at 17:59:04
In reply to S.D.- some more thoughts, posted by judy1 on January 1, 2001, at 12:52:10
> And I would try lamictal- good luck, Judy
While looking up lamictal I came across the following which, from a quick scan. looks like it has some interesting info. on: "Lamotrigine (Lamictal)for Depression and/or Mania"
:http://www.psycom.net/depression.central.lamotrigine.html
Posted by SLS on January 1, 2001, at 21:26:25
In reply to Re: S.D.- some more thoughts » SLS, posted by judy1 on January 1, 2001, at 17:54:57
> Hi Scott,
> Thank you for the correct term- I was really thinking circadian, but then the insect kept coming to my mind.> I think this is a result of my head injury or too many drugs- both legal and nonlegal.
You cannot blame a head injury on this one. Just think how confused lexicographers must have been to have chosen the word "etymology" to label their scholarly studies when the word "entomology" popped into their heads.
> Anyway, yes I got manic on lamictal- actually they said I "overshot", which I rather like.
> To show my ignorance, when you said dopaminergic effects- does that mean an increase in dopamine?
I guess we both are to show our ignorance. I don't know if Lamictal specifically increases the amount of dopamine available to receptors. Over these last five years, I have felt that Lamictal was pro-dopaminergic; it enhances or increases the activity of dopaminergic neurons. This is in addition to the inhibition of glutamate release, which has been considered the most likely mechanism for producing its anticonvulsant (and mood stabilizing?) effects.
1. Lamictal produces tics in individuals with and without diagnosed involuntery movement disorders. This is phenomenon seen with disorders thought to be mediated through dopaminergic neurons and produced by Ritalin and amphetamines, pro-dopaminergic drugs, when they are used to treat things like ADD AD/HD.
2. Lamictal, unlike other "mood-stabilizers" has shown to infrequently produce mania, a state thought by many to involve an increase in dopaminergic neurotransmission.
3. Lamictal, unlike the other anticonvulsants, has shown a positive therapeutic effect in Parkinson's Disease, a disorder involving too little dopamine, when it is combined with l-dopa. This is a property shared with selegiline, a dopaminergic MAO-inhibitor. The inhibition of glutamate release by Lamictal has been discounted by several studies as being the mechanism by which it exerts its positive effects.
> And if that is the case, I thought that was implicated in positive psychotic symptoms.
It is. This might be why anti-dopaminergic drugs that block dopamine receptors are effective in treating positive symptoms.
> If I'm way off base, please let me know.
:-)
> Take care- JudyYou do the same- Scott
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1: Epilepsia 2000 Jul;41(7):862-7Lamotrigine-induced tic disorder: report of five pediatric cases.
Sotero de Menezes MA, Rho JM, Murphy P, Cheyette S
Department of Neurology, University of Washington School of Medicine, Seattle, Washington, USA. [email protected]
PURPOSE: To describe the clinical spectrum of lamotrigine (LTG)-induced tics (an uncommon side effect) in children. METHODS: Retrospective analysis of patients from our hospital-based practice who developed tics while on LTG. Data obtained from medical records, interviews with parents, video-EEGs, and homemade videotapes. RESULTS: Three males and two females (range, 2.5-12 years; mean, 6.9 years) developed a movement disorder within the first 10 months of therapy (maintenance doses, 4-17 mg/kg/day). Four patients exhibited simple motor tics; one patient experienced mostly vocal (i.e., gasping sounds) tics. Laryngoscopic evaluation of one 2.5-year-old with repetitive gasping sounds was normal. In three cases, tics resolved completely within 1 month of drug cessation; tics recurred in two of these patients after reintroduction of LTG. A fourth patient experienced gradual improvement after stopping LTG over 4 months; the fifth patient's simple motor tics improved spontaneously with a reduction in medication. None of the patients had clinical features of a neurodegenerative disorder, and none met diagnostic criteria for Tourette syndrome. Two patients, however, had a diagnosis of acquired epileptic aphasia syndrome, and one patient had nonprogressive expressive and receptive language dysfunction. A fourth patient had global static encephalopathy, and the fifth patient had only attentional problems. In all patients, tics were not associated with ictal EEG changes. CONCLUSIONS: LTG may infrequently induce simple motor tics, vocal tics, or both. Patients with severe language dysfunction may be particularly susceptible to this uncommon side effect. Further studies are necessary to clarify the population at risk.
PMID: 10897158, UI: 20357679
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15: Eur J Pharmacol 1996 May 23;304(1-3):1-6Motor effects of lamotrigine in naive and dopamine-depleted mice.
Kaur S, Starr M
Department of Pharmacology, School of Pharmacy, London, UK.
Lamotrigine (3,5-diamino-6-[2,3-dichlorphenyl]-1,2,4-triazine) has been hypothesised to possess antiparkinsonian activity, by inhibiting the release of glutamate from basal ganglia neurones. This study therefore examined the motor effects of lamotrigine in naive and reserpine-treated mice and its interactions with dopaminergic agonists. In normal mice, lamotrigine (5-80 mg/kg i.p.) decreased spontaneous locomotor activity with high doses ( > or = 40 mg/kg) causing moderately severe impairment to posture and gait. In mice treated 24 h beforehand with reserpine (5 mg/kg i.p.), lamotrigine (5-40 mg/kg i.p.) had no effect on akinesia by itself and did not alter the locomotion induced with the selective dopamine D1 receptor agonist 2,3,4, 5-tetrahydro-7,8-dihydroxy-1-phenyl-1 H-3-benzazepine hydrochloride (SKF 38393, 30 mg/kg i.p.). By contrast, motor responses to the dopamine D2 receptor-selective agonist N-n-propyl-N-phenylethyl-p-(3-hydroxyphenyl)ethylamine (RU 24213, 5 mg/kg s.c.) and to the dopamine precursor L-3,4-dihydroxyphenylalanine (L-DOPA, 150 mg/kg i.p. in the presence of benserazide, 100 mg/kg i.p.), were significantly potentiated by 10 and 40 mg/kg i.p. lamotrigine respectively. It is suggested that lamotrigine may enhance the antiakinetic action of L-DOPA in parkinson-like mice by increasing motor responding mediated by dopamine D2 but not dopamine D1 receptors. This interaction profile of lamotrigine with dopamine D1 and D2 receptor mechanisms is opposite to what one sees with antagonists of glutamate receptors.
PMID: 8813577, UI: 96408570
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20: Life Sci 1994;54(4):245-52The novel anticonvulsant lamotrigine prevents dopamine depletion in C57 black mice in the MPTP animal model of Parkinson's disease.
Jones-Humble SA, Morgan PF, Cooper BR
Wellcome Research Laboratories, Department of Pharmacology, Research Triangle Park, NC 27709.
The effect of the novel anticonvulsant Lamotrigine (LTG) was studied on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) induced dopamine depletion in C57BL/6 mouse brain. Whole brain dopamine levels were measured by HPLC-ED 2 days after treatment with MPTP (15 mg/kg s.c.). While LTG alone had no direct effect on dopamine levels at two hours or two days after treatment, MPTP induced dopamine depletion was significantly less in mice pretreated with LTG (approximate ED50: 6 mg/kg). LTG (38 mg/kg) was shown to completely protect against dopamine depletion when given 1 or 2 hours prior to MPTP administration. The effect of LTG (38, 100 mg/kg) on MPTP toxicity was compared to the effects of the anticonvulsants phenytoin (67 mg/kg), carbamazepine (156 mg/kg), and riluzole (33 mg/kg) and the Ca++ channel blocker nicardipine (0.1 mg/kg). Only phenytoin and LTG showed significant protection against MPTP. Results suggest LTG prevents MPTP induced dopamine depletion via a novel mechanism.
PMID: 8289584, UI: 94118795
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Posted by AndrewB on January 2, 2001, at 1:31:43
In reply to Re: S.D.- some more thoughts » judy1, posted by SLS on January 1, 2001, at 21:26:25
Scott,
Thank you for the provocative info. on lamotrigine's dopaminergic effects.
Though it not clear to me how lamotrigine achieves its mood and antidepressive actions I thought I would add some possibly relevant factoids to the discussion.
Antidepressants (when effective) cause upregulation of the D2/(D3?) receptors in the shell of the nucleus accumbums (a site associated with mood and anxiety) and downregulation of the NMDA receptors.
The major neurotransmitter pathways to the shell of the nucleus accumbuns are dopaminergic, of course, and glutaminergic.
NMDA is one of the three glutaminergic receptors subtypes along with the AMPA and Kainate receptors.
Possibly NMDA antagonism is the route by which antidepressants upregulate the D2/D3 receptors.
NMDA antagonists can exhibit antidepressant effects.Abnormal glutaminergic transmission, especially involving the NMDA receptor, is associated with depression.
Abnormal glutaminergic transmission is associated with bipolar disorder.
Combined AMPA and Kainate receptors antagonists are potent anticonvulsants.
AMPA and NMDA receptor antagonists can act synergistically to provide robust anticonvulsant action at doses that do not produce behavioral side effects.
(It seems that glutamate receptor antagonists hold great promise for side effect free control of bipolar cycling.)
The partial NMDA antagonist Memantine (available from overseas) increases the effectiveness of Depakote for bipolar disorder without extra side effects.
(I wonder if Memantine may also increase the effectiveness of Lamotrigine. One study showed that Lamotrigine increased the mood elevating effects of ketamine, a total NMDA antagonist, and decreased its cognitive impairment.)
In sum, Lamotrigine’s effectiveness in controlling cycling may well involve actions on all the glutamate receptors, while its mood effects may be primarily dopaminergic mediated through the NMDA receptors.
Posted by Noa on January 2, 2001, at 9:46:49
In reply to Re: Bipolar type that cycles betw norm. and depressed? » judy1, posted by S.D. on January 1, 2001, at 1:44:28
I think there are some researchers who believe that recurrent major depression IS in the bipolar "family".
Posted by SLS on January 2, 2001, at 10:34:27
In reply to Re: Scott- Lamotrigine's AD/dopaminergic action, posted by AndrewB on January 2, 2001, at 1:31:43
Hi Andrew.
You have invited quite a questions regarding your "factoids" :-)> Antidepressants (when effective) cause upregulation of the D2/(D3?) receptors in the shell of the nucleus accumbums (a site associated with mood and anxiety)
All antidepressants, all of the time when they do work?
> and downregulation of the NMDA receptors.
Where can I find some material regarding this?
> NMDA is one of the three glutaminergic receptors subtypes along with the AMPA and Kainate receptors.
> Possibly NMDA antagonism is the route by which antidepressants upregulate the D2/D3 receptors.
Through what mechanisms?
> NMDA antagonists can exhibit antidepressant effects.
Ketamine? Which others?
> Abnormal glutaminergic transmission, especially involving the NMDA receptor, is associated with depression.
> Abnormal glutaminergic transmission is associated with bipolar disorder.
Is there something on Medline I could look at. To what degree is this considered to be putative?
> Combined AMPA and Kainate receptors antagonists are potent anticonvulsants.
> AMPA and NMDA receptor antagonists can act synergistically to provide robust anticonvulsant action at doses that do not produce behavioral side effects.
> (It seems that glutamate receptor antagonists hold great promise for side effect free control of bipolar cycling.)
> The partial NMDA antagonist Memantine (available from overseas) increases the effectiveness of Depakote for bipolar disorder without extra side effects.
> (I wonder if Memantine may also increase the effectiveness of Lamotrigine. One study showed that Lamotrigine increased the mood elevating effects of ketamine, a total NMDA antagonist, and decreased its cognitive impairment.)
> In sum, Lamotrigine’s effectiveness in controlling cycling may well involve actions on all the glutamate receptors, while its mood effects may be primarily dopaminergic mediated through the NMDA receptors.
This sounds pretty good. I hadn't realized the extent to which glutamatergic function was a focus in the research of depressive disorders.
I read something that indicated that unlike phenytoin and gabapentin, lamotrigine appeared to act presynaptically to reduce electrically-evoked action potentials measured along cortico-striatal excitatory neurons, but had no effect upon the magnitude of depolarization when glutamate was applied directly, as did the former two. I don't yet know how to interpret this, except that it supports the notion that lamotrigine acts, in part, via glutamate-release inhibition. I think recall reading that glutamate, and perhaps aspartate, serve to modulate the reuptake of dopamine. Therefore, a reduction in the amount of glutamate rather than a muting of postsynaptic stimulation to glutamate would allow lamotrigine to be uniquely dopaminergic.
Amantadine.
- Scott
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6: Br J Pharmacol 1999 Feb;126(3):689-96An in vitro electrophysiological study on the effects of phenytoin,
lamotrigine and gabapentin on striatal neurons.Calabresi P, Centonze D, Marfia GA, Pisani A, Bernardi G
Dip. Sanita, Universita di Roma Tor Vergata, Rome, Italy.
[email protected]We performed intracellular recordings from a rat corticostriatal
slice preparation in order to compare the electrophysiological
effects of the classical antiepileptic drug (AED) phenytoin (PHT)
and the new AEDs lamotrigine (LTG) and gabapentin (GBP) on striatal
neurons. PHT, LTG and GBP affected neither the resting membrane
potential nor the input resistance/membrane conductance of the
recorded cells. In contrast, these agents depressed in a
dose-dependent and reversible manner the current-evoked repetitive
firing discharge. These AEDs also reduced the amplitude of
glutamatergic excitatory postsynaptic potentials (EPSPs) evoked by
cortical stimulation. However, substantial pharmacological
differences between these drugs were found. PHT was the most
effective and potent agent in reducing sustained repetitive firing
of action potentials, whereas LTG and GBP preferentially inhibited
corticostriatal excitatory transmission. Concentrations of LTG and
GBP effective in reducing EPSPs, in fact, produced only a slight
inhibition of the firing activity of these cells. LTG, but not PHT
and GBP, depressed cortically-evoked EPSPs increasing paired-pulse
facilitation (PPF) of synaptic transmission, suggesting that a
presynaptic site of action was implicated in the effect of this
drug. Accordingly, PHT and GBP, but not LTG reduced the membrane
depolarizations induced by exogenously-applied glutamate,
suggesting that these drugs preferentially reduce postsynaptic
sensitivity to glutamate released from corticostriatal terminals.
These data indicate that in the striatum PHT, LTG and GBP decrease
neuronal excitability by modulating multiple sites of action. The
preferential modulation of excitatory synaptic transmission may
represent the cellular substrate for the therapeutic effects of new
AEDs whose use may be potentially extended to the therapy of
neurodegenerative diseases involving the basal ganglia.PMID: 10188980, UI: 99202863
Posted by Noa on January 2, 2001, at 11:18:11
In reply to Re: Scott- Lamotrigine's AD/dopaminergic action, posted by SLS on January 2, 2001, at 10:34:27
SLS, you are right--the term Bipolar III is being used to describe depressions with AD-induced hypomania. I just read this in the following abstract:
I could swear I remember reading a previous abstract of work by Akiskal in which he uses BPIII to refer to recurrent depression. Oh well.
I also thought I would mention, as I was reminded when perusing the abstracts, that one of the reasons why these researchers believe there is a diagnostic relationship between recurrent depression and bipolar is that for many people, recurrent depression takes the so called "atypical" form--with "reverse vegetative signs", like hypERsomnia, INcreased appetite, and also have some mood reactivity, whereas "typical" (to me "typical" vs. "atypical" are misnomers) depression, usually non-recurrent, is more often associated with vegetative signs like DEcreased appetite, INsomnia, etc. and very little reactivity (ie, can your depression loosen a bit to allow you to laugh at a joke, etc.).
So, it might also help to ask if your depression falls into either of these types.
And, I also want to say that sometimes mood stabilizers do have AD effect, on their own, or in combo with ADs, regardless of diagnosis.
Regardless of Diagnosis is a point I keep repeating, because I agree with SLS about focusing on the specific experience and treating symptoms or clusters of symtoms and not worrying too much about diagnosis. Every few years, the dx categories change a bit anyway.
Posted by Ted R on January 2, 2001, at 23:51:54
In reply to S.D.- some more thoughts, posted by judy1 on January 1, 2001, at 12:52:10
> Hi Neighbor,
> Yes, Dr. Akiskal and the full professors at UCSD (Zisook another bipolar expert there) do not accept patients anymore; I was able to get a consultation because I am "interesting", a treatment resistant rapid cycler with a loaded family history. Anyway, one of the important factors that came out of that meeting was a ban on antidepressants and a trial on lamictal- which worked TOO well. Have you tried it yet, it is considered the one mood stabilizer with an antidepressant effect and it really does work well in a lot of people. As far as the more mainstream mood stabilizers, no they don't prevent depression in most people dxed with bipolar- even lithium according to more recent developments. I'm glad you went to Dr. Phelp's site (sp?), he also hates AD's, even with someone who has a somewhat muddled picture like you. Although you did allude to possible hypomanic states, which people tend to downplay because they feel good. As far as cycles, I've cycled in 1 day- and there are people who do so hourly (ultra-rapid), and often get confused with borderline- another disorder Akiskal puts on the bipolar spectrum. I realize a lot of his stuff is presented as posters at meetings and may not be published. I think I'm drifting here, but as some one else suggested, don't worry about the semantics, just find something that works. And I would try lamictal- good luck, Judy
> With anxious depression being the main symptomology, could lamictal really exacerbate the anxiety? I suppose I should really follow my doc's advice and see if my problem is this Special Bipolar 2 diagnosis, but the overactivating possibility of lamictal concerns me. I hate to be vague, but whether or not a person is considered to be unipolar depressed or this newer Bipolar explanation,the control and management of the painful symptoms is all that I want.
Posted by AndrewB on January 3, 2001, at 3:05:41
In reply to Re: Scott- Lamotrigine's AD/dopaminergic action, posted by SLS on January 2, 2001, at 10:34:27
Scott,
I am very busy this week, I will try to answer your questions as soon as possible. Glutaminergic dysfunction is inplicated in physical ailments (i.e gluacoma, hearing loss, neuropathic pain), neurologal deterioration (neuron die off due to excess calcium influx), depression, seizure and cycling activity, cognitive impairiment, schizpophrenia and the list goes on.
Perhaps it is relevant that the glutaminergic system is the largest nuerotramitter system in the brain. Moreover, it has significant pathways into and between the hippocampus, medial prefrontal cortex and the shell of the nucleus accumbens. These are areas of the brain amoung the most responsive and vulnerable (to damage from) stress. For example it was recently shown that excitoxic lesions in the hippocampus impair the emotional conditioning and led to additional glutamate release in the n. accumbens.
Anyway, some drugs are out there to halt in some aspects the damage of various types of glutaminergic dysfunction and restore normal function. Many more are in the investigational stage. I plan to try to learn further what meds are curently available for the beneficial manipulation of parts of the glutaminergic system in order to deal with certain health disorders.
Best wishes,
AndrewB
Posted by judy1 on January 3, 2001, at 19:20:02
In reply to Re: S.D.- some more thoughts, posted by Ted R on January 2, 2001, at 23:51:54
Hi Ted,
I started lamictal with depakote and klonopin in place, so I really didn't experience any increase in panic attacks or anxiety. Are you on a benzo for anxiety? If you start out low and slow- 25mgs for the first week (actually I did 12.5 because of the depakote), you should be able to judge your rx pretty well. At 100mgs, I was absolutely euphoric, gee maybe I should take it again- Judy
Posted by Ted R on January 3, 2001, at 23:35:39
In reply to Re: S.D.- some more thoughts » Ted R, posted by judy1 on January 3, 2001, at 19:20:02
> Hi Ted,
> I started lamictal with depakote and klonopin in place, so I really didn't experience any increase in panic attacks or anxiety. Are you on a benzo for anxiety? If you start out low and slow- 25mgs for the first week (actually I did 12.5 because of the depakote), you should be able to judge your rx pretty well. At 100mgs, I was absolutely euphoric, gee maybe I should take it again- Judy
>Judy, thanks for your advice. I have on hand tranxene and also xanax when a PA may develope, but lately I have been taking more of the xanax with the Welbutrin, because xanax was offering some additional AD effect, and taking the normal dose of tranxene began to add to the depression. I believe that a trial on lamictal may well be worth it. Because with the exception of 150 to 200mgs a day of Wellbutrin SR, the entire realm of ADs, I have already tried, I have not gotten through the side effects, loss of libido, spaciness etc. thanks again...Ted
Posted by S.D. on January 5, 2001, at 15:38:23
In reply to Re: S.D.- some more thoughts, posted by Ted R on January 3, 2001, at 23:35:39
>Because with the exception of 150 to 200mgs a day
>of Wellbutrin SR, the entire realm of ADs, I
>have already tried, I have not gotten through the
>side effects, loss of libido, spaciness etc.The "150 to 200mgs a day of Wellbutrin SR" got my attention because they always say 300mg qd is the minimum therapeutic dose. Though in reality I guess it is the amount in one's body that matters, and 300mg/day is only the amount believed needed to achieve that for most people with normal metabolism.
So I was wondering, were you getting a significant antidepressant effect from 150-200/day?
I wasn't sure if I should post this becaus no doubt your doctor knows this already and there's a reason for it, like that something else you were/are taking decreases the metabolism of the Wellbutrin.
S.D.
Posted by S.D. on January 5, 2001, at 17:30:24
In reply to Re: Bipolar type that cycles betw norm. and depressed? » S.D., posted by SLS on January 1, 2001, at 9:45:11
> Hi S.D.
>
> Yes, there are bipolar and "soft" bipolar (not meeting strict diagnostic criteria for bipolar disorder) presentations that exhibit a cycling between depressed and normothymic states. I personally experienced a period of two years in which I was an ultra-rapid cycler, switching between severe depression and nearly normal (mild depressive) states regularly with a period of 11 days. 3 days up and 8 days down. Like clockwork. Damned biological clocks. Upon my first trial of lithium, rapid cyclicity ceased and left me chronically depressed thereafter.
>
> At no time during my rapid-cycling period did mania or hypomania appear. In fact, the only time they do now is when a medication precipitates it. My manic states during these events have been either mixed or dysphoric. Depressions that include antidepressant-induced manias (but no spontaneous manias) has been proposed as bipolar type III (contradictory to the work cited by Noa)
>to be included in the DSM diagnostic manual for
>over a decade.
>
>I suppose I'm dysphoric or mixed much of the time that I'm depressed. Only sometimes is it *pure* depression, but I may be splitting hairs. It is pure enough to be Dx'd that way by any pdoc (with a side of anxiety, but that is traditionally always considered separate, and in my case subsyndromal anyway).
It's rather like this quote the abstract Noa referenced:
( http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11121824&dopt=Abstract )
< blockquote >...depressive mixed states consisting of few hypomanic symptoms (i.e., racing thoughts, sexual arousal) during full-blown major depressive episodes - included in Kraepelin's schema of mixed states, but excluded by DSM-IV.
< /blockquote >> Why do you think you have a cycle between states?
Maybe 'cycle' is not the right word, although my pdoc told me yesterday that cycling even in classic bipolars does not have to be regular (constant period). I've never had shifts that were anything like yours or that had a constant period (unless a very long one so I haven't perceived it).
**
If cycle doesn't imply constant period, then anyone who has had more than one Major Depressive episode 'has a cycle between states'. I've not found any abstracts about trials showing 'mood stabilizers' (other than adjunctive lithium) are significant for people with this Dx/presentation. (That was my essential purpose in posting the query that started this thread.) But if not, I don't know what would be the point of broadening the idea of bipolar, or the "spectrum of bipolar", as sumarized in these words from the abstract Noa referenced:( http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11121824&dopt=Abstract )
< blockquote >'softer' clinical expressions of bipolarity situated between the extremes of full-blown bipolar disorder where the person has at least one manic episode (bipolar I) and strictly defined unipolar major depressive disorder without personal or family history for excited periods
< /blockquote >
**> Can you describe the details of your cycle and
> what you feel in both states?What I originally described was just Vanilla major depression as one state and either normal or dysthymic as the other. The paragraphs above, between the '**' marks, explains why someone like that would be bothering about all this.
In my case what I called almost normal I really feel is dysthymia. Which I guess is a way of saying "I hope this isn't really as good as it gets, because this is pretty lame. Whatever happiness is, I don't think I'm experiencing what normal people experience.")
To put it in more detail... since age 8 or earlier, maybe always, I think I've had dysthymia; and that since age 14 I've had what history-taking doctors have considered a few distinct major depressive episodes that have lasted around 3 months to 2 years.
( http://www.graylab.ac.uk/cgi-bin/omd?query=dysthymia )
I could elaborate to say I could maybe identify 5 'states' that don't necessarily corrospond to anything and may have different periods (probably no consistant period):
1) Major depressive episode, of the ho-hum DSM kind.
2) Mixed state of depression mostly as above, but also two or more of agitation, irritability, anxiety, racing thoughts. Similar to "depression with flight of ideas" first described by Kraepelin.
3) my normal dysthymic self. I can distinguish it from (1), above, because I don't spend as much time thinking about being better off dead. But fatigue and anhedonia and tendency toward anxiety remain.
4) disturbed sleep only - multi-week or multi-month stretches. Usually insomnia, but a long hypersomnia once and probably a few shortish ones.
5) What I'll call euthymic. Cured, if it would stay that way. I guess that doesn't have to be the same thing as 'happy', so I don't have to try to figure out what that feels like. This has probably happened a few times, for up to maybe several months. Most recently while on an AD.> Personally, I feel that mood-stabilizer medications are a good idea in situations like this to help prevent the condition from evolving into a more severe and treatment-resistant course.
>
> I agree in many ways with Noa regarding diagnosis based upon response or non-response to
>mood-stabilizers, especially when they seem to be
>helpful in cases currently thought to be unipolar.
>
My pdoc also said they (and not just lithium) are used this way. But I still can't find any trial results (e.g. valproate, carbamazepine, lamictal).> I guess all of this garbage is my feeble attempt to squeeze out any true rapid cyclicity ...
> ... or whether your illness is simply a recurrent unipolar depression that is best treated consistently and without "drug-holidays" indefinitely.
>
>Definitely no true rapid cyclicity. It can certainly be seen as simple recurrent unipolar depression, comorbid with an anxiety disorder ( I have other anxiety too, but 'subsyndromal' I guess since it doesn't seem to qualify as GAD ).
And it may not even be all that treatment-resistant if I can find an AD I can tolerate.
> No need to respond - just a few things to think about.*Now* you tell me.
>
> - ScottS.D.
Posted by S.D. on January 5, 2001, at 18:00:41
In reply to S.D.- some more thoughts, posted by judy1 on January 1, 2001, at 12:52:10
> Hi Neighbor,
> Yes, Dr. Akiskal and the full professors at UCSD
>(Zisook another bipolar expert there) do not accept patients anymore;Another San Diegan! cool.
I think I read in another of your posts that you are married which is great because your husband is probably a great source of support for you.I'm guessing you know about this already, but if a typical support group kind of thing is something you'd be interested in there's a chapter of the NDMDA that meets Every monday at 6pm in room 2011 of the UCSD VA hospital in LJ.
Every other meeting there's a speaker the first hour.BTW I'm curious about something you posted in a reply about clon.:
"my pdoc feels panic/bipolar is intertwined with seizure disorders. "
When I posted asking if a normal-to-depressed cycle could be bipolar it was at the prompting of my mother who had heard something to that effect. I had never considered it (no family history, although my mother's ancesters are unknown.) and probably wouldn't have gone ahead and inquired except for one tidbit: my father and brother had/have some form of epilepsy/seizure.
I had a hunch about that since "mood stabilizer" == "Anticonvulsant/AED" in several cases.
I don't know if epilepsy has been shown to be hereditary similar to Bipolar but if so, then if 'bipolar genes' are found it could also confirm the connection to epilepsy.I was wondering who that pdoc is. I'll understand if you don't want to say.
peace and health,
S.D.
Posted by SLS on January 5, 2001, at 21:08:44
In reply to Re: Bipolar type that cycles betw norm. and depressed? » SLS, posted by S.D. on January 5, 2001, at 17:30:24
Dear S.D.,
> > No need to respond - just a few things to think about.
>
> *Now* you tell me.I always read the punchline first so that I can better understand the rest of the joke when I read it for the first time. :-)
Frustrating, isn't it. I wish I could help you pinpoint the right treatment for you to be "cured". Me too, while I'm at it.
> And it may not even be all that treatment-resistant if I can find an AD I can tolerate.
With which ADs have you experienced a significant antidepressant effect? What side effects of these drugs did you find intolerable? Very often, the side effects themselves need to be treated. If there is one drug that is a standout as far as improvement of your depression is concerned, perhaps you could get some feedback here as to how to remedy the side effects. For instance, I could not tolerate a combination of Nardil + imipramine. My blood pressure was so low, that I had to crawl around the house to avoid passing-out. I would just about bust a gut every time I tried to urinate. Florinef fixes #1 and bethanecol fixes #2. Over time, after the body makes some adjustments, one can often tolerate such a combination and discontinue the remedial drugs.
> Definitely no true rapid cyclicity. It can certainly be seen as simple recurrent unipolar depression, comorbid with an anxiety disorder ( I have other anxiety too, but 'subsyndromal' I guess since it doesn't seem to qualify as GAD ).
Rapid cyclicity is defined by the DSM IV as being the occurrence of four or more mood episodes (not cycles) over a one year period. I guess you gotta start somewhere. It seems a bit arbitrary to me, but I think it has value. There is no mention of a regularity of cycles.
If you are looking for accurate diagnoses for the purpose of choosing those treatments most likely to fix the problem, I should think that it was worth the effort to have made your inquiry. It is relevant. However, sometimes it comes down to a best guess. Sometimes not even that. Things can get pretty fuzzy. That's why the idea of a spectrum is useful.
Perhaps you suffer from an agitated major depression superimposed upon dysthymia - a double depression. The "agitated" would help explain the anxiety and even the racing thoughts. You haven't mentioned sex. That's O.K. I'm not in the mood anyway. However, the presence of hypersexuality would help differentiate an agitated depression from a bipolar mixed-state. Either way, perhaps Depakote or lithium would help. For agitated depressions, I think tricyclics are worth pursuing. Right now, I wouldn't know which of them to recommend - maybe nortriptyline or Sinequan.
Do you eat too much or too little when you are in the middle of a serious depression?
Do you experience insomnia, particularly in the early morning (3:00am-5:00am) when seriously depressed?
- Scott
Posted by judy1 on January 9, 2001, at 11:46:30
In reply to Re: Hi neighbor (was Re: S.D.- some more thoughts) » judy1, posted by S.D. on January 5, 2001, at 18:00:41
Hi S.D,
Sorry for not getting back sooner, I have had somewhat of a setback. The pdoc I am seeing is connected with UCLA and prominant (you'll figure it out). Anyway, with your background of epilepsy I think a THOROUGH neuro work-up should be considered (not just an EEG). Even though the treatment for bipolar and complex partial seizures, what they think I have is the same, and AED's are effective in panic disorder, I'm sure you feel it would be nice to have a precise dx. Thank you for the NDMDA info, I have tried group sessions and failed- I have had some of my worst panic attacks then. I hope you find them helpful. I am going to see someone local today (recommended by the UCSD group), I'll let you know how it works out. Thank you for posting the info on Dr. Stahl, I have heard the name- did he give you the wrong meds? Take care- Judy
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