Posted by jrbecker on June 21, 2003, at 11:03:20
Notes from the 5th International Bipolar conference, courtesy of our friend John McManamy at www.mcmanweb.com
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McMan's Depression and Bipolar Weekly
June 21, 2003 Vol 5 No 17Special Fifth International Bipolar conference issue
Lead story: Why bipolar continues to draw the short straw.
Also in this issue: Bipolar depression, Treating bipolar depression, Early STEP-BD data, Music therapy, Inositol for BP depression, Quality of life, BP kids on ADs, Gender differences, Galantamine for BP, UK and US authorities advise against kids taking Paxil, Lamictal for BP depression, Atypicals vs conventionals, Depression prevalence, Depression in the workplace, Depression and the heart, Suicide rates drop, New BP gene, US Supreme Court forced drugging decision, The Hours on DVD, Barrett Robbins, Introverts, AOL readers, NAMI conference, McMan's Web, Donation information.
Raw Deal?
When he started working at the NIMH back in the late 70s, Thomas Insel MD, the new director of the NIMH related, everyone seemed to be working on bipolar except for those in the child psychiatry area. On his return some 20 years later as head, however, the situation had seemingly reversed, with child psychiatry about the only group involved in bipolar research.
Things had started to change a few years before that, with the establishment of a mood and anxiety disorders program headed up by Dennis Charney MD, together with a new research agenda, but Dr Insel’s point is still valid. Partly due to the advent of lithium and its promise as a magic bullet, a lot of researchers lost interest in bipolar, resulting in a lengthy dry spell. And catching up is problematical, owing to that the fact that there is considerable debate about study designs, which leads to peer-review committees turning down grant requests, resulting in frustrated researchers leaving the field. "We eat our young," Dr Insel confessed to this writer.
The NIMH funds about $80 million a year in bipolar research compared to $280 million for schizophrenia, and that same ratio is reflected in the published literature.
What we need, Dr Insel told the Fifth International Conference on Bipolar Disorder held last week in Pittsburgh, is research that starts with genes then progresses to cells then to circuits and systems and finally to animal models. This is essentially the way new drugs are developed. Alzheimer’s has already jumped through these hoops, and not surprisingly the pharmaceuticals are burning the midnight oil to develop a blockbuster med.
So far, the literature has focused on less than one percent of the genome, representing a mere 300 or so genes. Writing in the American Journal of Psychiatry earlier this year, Dr Insel and co-author Francis Collins MD, PhD, head of the Human Genome Project observed: "We have a treasure trove of new genes to explore, including many that may prove more important than the few neurotransmitters and intracellular signaling molecules that have been studied so intensively these past 50 years."
Meanwhile, in another seminar, Husseini Manji MD, chief of molecular pathophysiology at the NIMH and no stranger to this Newsletter, explained how his research with lithium and Depakote on tissue samples and rats has led to the discovery of at least 10 potential new targets for the next generation of meds. This in turn drew a comment at another seminar from Fouzia Laghrissi-Thode MD, CNS director of new medicine strategy at F Hoffman Laroche, who said it was the first time she had seen new molecular targets for mood which could translate into animal models to develop new compounds.
In other words, the pharmaceutical industry could conceivably develop a legitimate bipolar drug from scratch rather than come up with yet another me-too, hand-me-down pill intended for treating schizophrenia or epilepsy.
But we can’t afford to wait until we figure out the neurobiology of the disorder, Dr Insel cautioned. We have to push forward with the treatments we have. STEP-BD, an NIMH-underwritten series of real world trials which has enrolled 3,000 bipolar patients in 22 centers to date, represents an important first step in looking to provide clinicians with some clear guidelines. But that study, along with its sister STAR*D for investigating various depression treatments, is set to wind down in another two years, with no commitment for successor trials. Genes and neurobiology may be the wave of the future, but the here and now demands our immediate attention, such as whether antidepressants should be part of the bipolar cocktail or if fish oil makes better salad dressing than mood food. Keep an eye on this space ...
Bipolar Conference
I spent three days in Pittsburgh at the Fifth International Conference on Bipolar Disorder hosted by the Western Psychiatric Institute and University of Pittsburgh, among people working very hard to crack our case, so without further ado ...
Bipolar Depression
The good news is this phase of the illness is finally getting attention. The bad news is we have little to go on. According to Paul Keck MD of the University of Cincinnati, at the Fifth International Conference on Bipolar Disorder, there are more review articles on bipolar depression than actual studies, meaning there’s more opinion than fact.
At the same seminar, Philip Mitchell MD of the University of New South Wales cited a 2002 NIMH study that found bipolar I patients were depressed 32 percent of weeks over a 12.8 year period as opposed to being manic or hypomanic for nine percent of weeks and mixed or cycling for six percent of weeks. For bipolar II patients, the same study found depression present in 50 percent of weeks over 13.4 years as opposed to one percent of weeks for mania or hypomania and 12 percent of weeks for mixed or cycling.
The same set of studies also found that dysthymia (minor depression) and subsyndromal (not full-blown) depression dominated, with bipolar II patients more likely to have major depression and a more chronic course.
A 2000 Australian study of 83 bipolar depressed and 904 unipolar depressed patients found bipolar patients were more likely to be melancholic (69 vs 37 percent), and were significantly more likely to demonstrate psychomotor disturbance and guilt. A 2001 study by Dr Mitchell of 270 depressed patients found those with bipolar were less tearful than those with unipolar depression, but felt more worthless, exhibited greater loss of pleasure, and experienced more subjective restlessness, leaden paralysis, and hypersomnia than their unipolar counterparts.
According to various studies cited by Dr Mitchell, suicidal ideation is present in 79 percent of those with bipolar depression, and attempted suicide is twice as high (26-29 percent vs 14-16 percent) as for those with unipolar depression.
Treating Bipolar Depression
At the same session Dr Keck cited recent drug trials for treating bipolar depression. These included:
A 2001 study that found no significant difference between Depakote and the placebo at week eight.
A 1999 study of 195 depressed bipolar I patients that found that 200 mg/day of Lamictal showed a greater than 50 percent response after seven weeks. The catch is Lamictal needs to be dosed gradually, with the full dose not being reached until three weeks into the study, but the same study also found the drug produced better than 40 percent response at 50 mg/day.
A 2002 Eli Lilly study of combination Zyprexa and Prozac (Zypzac, as one Canadian psychiatrist referred to it) that showed a 17-point drop in MADRS scores over eight weeks.
A 2003 unpublished study of combination Risperdal and Paxil that produced negative results. [Note: A positive Risperdal-Paxil pilot study was presented at last month’s American Psychiatric Association’s annual meeting.]
A 2000 study showing no difference between patients on two mood stabilizers and one mood stabilizer plus Paxil over six weeks, There were, however, significantly more dropouts in the two-mood stabilizer group.
A 2001 study showing little difference between Paxil or imipramine added to lithium vs lithium and a placebo, but lithium alone fared less well at lower levels.
A 2001 pilot study of the Parkinson’s drug pramipexole (Mirapex) found a 58 percent response after six weeks vs 17 percent on the placebo.
A 2003 NIMH study of patients on six gm/day EPA, one of the active ingredients in omega-3, found no significant efficacy.
A 2003 GSK study showing that Lamictal was superior to lithium in preventing the recurrence of depression over 18 months while lithium proved better at keeping mania at bay.
A 2002 Eli Lilly study that found that 25 percent of patients on Zyprexa added to lithium or Depakote relapsed into depression after 155 days compared to 27 days for those on lithium or Depakote alone.
Unanswered questions for the meds treatment of bipolar depression included: Duration and predictors of switching into mania vs depressive relapse; Efficacy of Lamictal with a mood stabilizer; Efficacy of Zyprexa with antidepressants; Efficacy of atypical antipsychotics alone or with antidepressants; Potential efficacy of new agents; Efficacy of talking therapy with meds; and optimal treatment for full and sustained remission.Early STEP Data
At the Fifth International Conference on Bipolar Disorder, Gary Sachs MD of Harvard and principal investigator of STEP-BD reported on some early data from bipolar patients enrolled in STEP in 22 centers throughout the US, including the fact that patients entering the program were being treated with an average of 4.2 meds. Five percent were on eight meds or more and four percent were on 10 meds or more, leading him to comment on "exotic polypharmacy." Less than 20 percent were on just one drug.
Five percent of patients relapsed each month, with 80 percent of the relapses into depression. Antidepressants did not enhance the rate of recovery, but did result in 18 percent of patients switching into mania vs 11 percent not on antidepressants.
Hospitalizations accounted for 14.2 patient years per 100.
Of the first 500 patients in the study, 52.8 percent of bipolar I patients and 46.1 percent of bipolar II patients had a co-occurring (comorbid) anxiety disorder. Dr Sachs suggested that in light of these numbers, comorbid may be a misnomer, that anxiety could actually be a manifestation of bipolar. About 60 percent of bipolar patients with a current anxiety disorder had attempted suicide as opposed to 30 percent with no anxiety. Among those with PTSD, more than 70 percent had attempted suicide.
From the Poster Sessions
A Colombian study of 85 patients with bipolar, schizophrenia, unspecified psychosis, and schizo-affective disorder were assigned either to eight 60-minute sessions of group music therapy, involving singing and playing the guitar, or group therapy with no music. Those taking music therapy were 73.8 percent meds compliant compared to 16.2 percent in the non-music group, and remained 69 percent compliant six months later compared to 16.3 for the non-music group. Patients with bipolar showed the greatest improvement.
A Massachusetts General Hospital study of 16 depressed bipolar patients found a 33 percent response in those who augmented their lithium or Depakote with the simple carbohydrate, inositol, vs zero in the placebo group. Inositol naturally occurs in the body, is necessary for the formation of lecithin, and may reverse desensitization of serotonin receptors.
A Turkish study of 28 euthymic bipolar patients and 30 diabetic patients found both shared a similar perceived quality of life, which was lower on a number of measures than the controls in the study.
A Juvenile Bipolar Research Foundation study of 134 bipolar children and adolescents exposed to antidepressants found 75.4 percent experienced "clinically significant adverse effects," including increased cycling within the day (79 percent), increased aggression (70.9 percent), and increased psychotic symptoms (23.1 percent) over four months.
A Stanford and other centers study of 84 bipolar patients over 5,179 days found men were depressed 15.9 percent of the time, normal 79.6 percent of the time, and manic 4.5 percent of the time while for women the percentages were 24.8, 67, and 8.2, respectively. Women reported severe depression twice as often (17.1 vs 10.9 percent), and severe mania five times as often (18.7 vs 3.2 percent). Sixty-five percent of premenopausal women also experienced mood changes across the menstrual cycle.
A University of Pittsburgh chart review of four bipolar patients on the Alzheimer’s drug, galantamine, found that the two on higher doses (24 and 32 mg/day) experienced "marked cognitive improvement."
SEGUEMuch more on the Bipolar Conference in future issues. And now back to normal programming ...
Paxil Kids Warning
The FDA has just advised that no one under age 18 should be prescribed Paxil for depression, owing to the risk of suicide. Three studies found the drug did not help for pediatric depression, and an analysis of the data showed a three times greater risk of suicidal thoughts and attempts among mostly teens taking the drug vs those on a placebo. There were no deaths in the studies.
The warning follows similar action by the Medicines and Healthcare Products Regulatory Authority in the UK, where the drug is marketed as Seroxat.
Children and teens already on the drug should not suddenly stop the drug, the FDA cautioned, as a long tapering period is required to avoid withdrawal effects.
Prozac is the only antidepressant FDA approved to treat depression in children. For more information:
http://www.fda.gov/cder/drug/infopage/paxil/paxilQ&A.htm
Lamictal Approval Due Soon
The FDA is expected to formally approve Lamictal for the prevention of bipolar depression any day now. Two studies involving 583 bipolar I patients who were stabilized, then put on either lithium, Lamictal, or a placebo for 18 months, found that Lamictal was superior to lithium at delaying time to intervention for a depressive episode while lithium was superior to Lamictal at delaying time to intervention for a manic episode.
A 1999 study involving 195 patients found 200 mg/day effective after seven weeks for acute bipolar depression, but manufacturer GlaxoSmithKline is not seeking an indication for this phase of the illness.
The drug is recommended as first-line acute bipolar depression treatment in both the APA Practice Guideline for the Treatment of Patients with Bipolar Disorder and the pioneering TIMA algorithm put out by the state of Texas. Both the APA and TIMA are vague with regard to treating bipolar depression in the maintenance phase.
Better Than Haldol? - Revisited
After the Jayson Blair scandal, I should have known better than to rely on a NY Times account. Newsletter 5#16 reported on a NY Times article that cited three meta-analyses in support of the proposition that the atypical antipsychotics had at best a marginal advantage over their conventional predecessors. It turns out that one of those studies, published in the current Archives of General Psychiatry, came to a completely different conclusion:
A University of Chicago/Stanford meta-analysis of 124 trials found Clozaril, amisulpride (available in Europe), Risperdal, and Zyprexa "significantly more efficacious than first generation antipsychotics." Clozaril produced the best results. Other atypicals, however, including Seroquel, Geodon, Abilify, remoxipride, and sertindole were similar in efficacy to the older drugs such as Haldol.
The authors of the study took issue with a 2000 study by Geddes et al, also cited in the NY Times article. No attempt was made to compare side effects and tolerability.
Making an Issue of It
JAMA has devoted a whole issue to depression. Among the highlights:
A National Comorbidity Survey Replication survey of 9,090 US residents has found that the prevalence for lifetime major depression was 16.2 percent, equating to 32.6 to 35.1 million US adults, and for the past 12 months was 6.6 percent, representing 13.1 to 14.2 million US adults. Thirty-eight percent of the episodes were severe and 12.9 percent very severe, with mean duration of 16 weeks. Three-quarters had co-occurring psychiatric illnesses, with major depression only rarely the primary illness. Half of the 12-month individuals had received care for their depression, but treatment was only adequate in 41.9 of the time, resulting in just 21.7 percent receiving adequate treatment.
Researchers from the AdvancePCS Center for Work and Health and other centers have extrapolated from survey results of more than 1,100 US workers to conclude that depression in the work place costs employers $44 billion a year in lost productive time, which represents $31 billion more than their peers without depression.
A Washington University (St Louis)/Harvard/Mayo Clinic study that followed 2,481 heart attack patients for 29 months has found that treating them for depression did not reduce the risk of death or a second heart attack. Seventy-five percent of patients were still alive with no heart attack in both the depression-treatment and control groups, though quality of life was higher in the depression-treatment group.
Suicide Rate DropAccording to the Swiss-based Institute of Social and Preventive Medicine, the suicide rate for males fell in the European Union by more than 10 percent over the past two decades, while the rate for women in Western Europe and North America has dropped by 40 percent since the 1970s. Japan and Eastern Europe, with higher rates, showed proportionate drops. Suicide is increasing in Ireland, Australia, and New Zealand, with suicide death rates of 35 to 40 per 100,000, while in Russia suicide mortality skyrocketed over the past decade by more than 50 percent for males (66 fatalities per 100,000) and 10 percent for women. According to the report’s lead author, Fabio Levi MD, speaking to Reuters, the downward trend may be due to changes in the management of depression and other disorders.
Blue Genes
Many of you may have read reports in the popular press of the possible discovery of a bipolar gene by John Kelsoe MD and his team at the University of California at San Diego. Some readers of this Newsletter could have experienced a since of deja vu, as that story was reported nearly three years ago here. A gene on chromosome 22 appears to switch on the protein GRK3, whose normal role is to regulate a number of neurotransmitters, including dopamine. Disruption of this function can result in psychosis for both bipolar and schizophrenia patients. Researchers believe bipolar is the result of at least several genes, each with a modest effect. For a full account of GRK3 on my website, see: http://www.mcmanweb.com/article-89.htm
Pyrrhic Victory
The US Supreme Court has ruled that the government may not drug Charles Sell, a dentist who sees leopards and believes the FBI is trying to kill him, to make him stand trial on fraud charges. The court, however, did not rule out forced drugging in the case of someone charged with a violent crime. Charles has spent more than four years in a prison hospital.
The Hours
The film based on a fictional day in the life of Virginia Woolf, and starring Nicole Kidman in an Oscar-winning performance, is set to come out in DVD June 24. For a review on my website, please see: http://www.mcmanweb.com/article-224.htm
Back in the Saddle
Oakland Raiders center Barrett Robbins, who went AWOL prior to the Super Bowl as the result of a manic episode and drinking binge, has rejoined his team for a workout following several months of recovery. The NY Times reports that teammate Frank Middleton, one of Barrett’s strongest critics initially, walked into the locker room singing, "We Are Family."
The Introvert Question
Last Newsletter asked if psychiatrists and therapists should use a shortened version of the Myers-Briggs to screen their patients and clients for introversion. One reader replied that it would be very helpful, as "I was more introverted when depressed and suicidal. I learned after those experiences that I had to actively link myself with others in the community, to in effect protect myself. It was a hard lesson, but I did it through volunteer activities, and it worked."
Another wrote that "being an introvert isn't necessarily bad, and doesn't automatically mean a person is pathologically ill. It can show changes, if a previous score is available. My periods of mild introversion are actually quite pleasant."
Another reported that she found the test useful in assisting her introverted nursing students to be more outgoing in a clinical setting, noting "the use of valid and reliable tools are helpful in any helping situation. So again, sure why not?"
Another wrote that "introversion/withdrawal/isolation/social anxiety can very quickly be assessed without taking the time to do a Jungian personality inventory."
AOL Readers
AOL is bouncing all Newsletters I send using a bulk email program, resulting in considerable delays in your receiving this Newsletter. Apparently, AOL has classified the Newsletter as spam when it is sent using bulk email. I would greatly appreciate it if all of you notified AOL that you have specifically requested this Newsletter, that it is not spam, and for them to stop blocking its transmission. Please let me know what kind of reply you get, if any.
NAMI Conference
It’s off to another conference at the end of June. I will try to get out a short Newsletter beforehand. Otherwise, I look forward to seeing a lot of you in Minneapolis.
McMan's Web
I've given my website a complete makeover, featuring a cleaner look and easier navigation. Check out more than 250 articles on all aspects of depression and bipolar, plus a bookstore, readers' forum, message boards, and other features at:
http://www.mcmanweb.comNew: Taking it Personally, an expanded treatment of the personality types survey that appeared in Newsletter 5#14..
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"Knowledge is necessity."Copyright 2003 John McManamy
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