McMan's Depression and Bipolar Weekly 

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July 4, 2001 Vol 3 No 26 

MULTIPOLAR DEPRESSION 

Attendees at the Fourth International Conference on Bipolar held in June were just settling into their seats when the first speaker, Guy Goodwin MD, head of the Department of Psychiatry at Oxford, let drop: "There is a difference between unipolar and bipolar depression." 

Throw out your DSM-IV. Bipolar depression appears to be a completely different animal, with enormous implications for treatment, a theme taken up by other Conference speakers and presenters. A poster session paper by JF Alliliare of Pitie-Salpetriere Hospital in France and HS Akiksal of the University of California at San Diego and others pointed out some of the distinguishing characteristics based on a comparison of 493 subjects with either unipolar or bipolar II depression. For one, there was overrepresentation in the BP II group of "suicidal thoughts, guilt feelings, depersonalization and derealization, and atypical features such as hypersomnia and weight gain." The unipolar group experienced higher psychic anxiety and initial insomnia, and assessed themselves significantly higher in terms of slow thinking, feeling the worst, avoiding risks, life dull and dreary, dragging from day to day, and feeling to have no energy. 

A study by LG Schaffner and DF MacKinnon, both of Johns Hopkins, also found bipolar individuals were more likely than those with unipolar depression to display psychotic features during a depressive episode (30 percent vs six percent). Those with bipolar I had more ECTs (18 percent vs six percent) suggesting more severe depressions, and more suicidal episodes (33 percent vs eight percent). 

But unipolar depression is far from being "uni," either. Athanasios Koukopoulos MD of the University of Rome noted that agitated depression has been relegated to a symptom of depression in the DSM-IV ("psychomotor agitation or retardation"), meaning "major depressive episodes with or without agitation are treated in the same way, and the result is disastrous in many cases of agitated depression." Then there are psychotic depressions, excited and anxious depressions, and dysphoric moods, many induced by antidepressants, not to mention many who rapid-cycle after being prescribed an antidepressant. Toss in the various bipolar mixed states, and it is a virtual certainty that the next editors of the DSM will not meet their deadlines. 

Meanwhile, a study of the medication histories of 48 bipolar patients by JF Goldberg and others of Cornell University revealed "antidepressant-induced manias may arise in at least one-third of bipolar patients with comparable frequency across antidepressant classes, and regardless of the presence of concomitant mood stabilizers [emphasis mine]." Fortunately, most switches were of mild severity and tended to resolve themselves without hospitalization. Left unsaid was the chaos and uncertainty of yet more meds changes following those manias. 

Dr Koukopoulos categorized the many things that can go wrong when an antidepressant is unwittingly prescribed to someone in an agitated state or with an underlying hyperthymic or cyclothymic condition (which are not necessarily limited to those with bipolar). The first thing to diagnose, according to Dr Koukopoulos, is the patient's temperament. If the patient is agitated, the first course of treatment is "anything that calms him down." Sometimes, the depression stops along with the agitation. Other times, what follows is pure simple depression, which can be treated with antidepressants. "It is better," he says, "that things go slowly than trying to get well all at once." 

Obviously, psychiatry is making do with high-risk instruments not well-suited for the task at hand. But with the prospect of the ultimate magic bullet not yet a gleam in any researcher's eye, our best bet for now is working intelligently with what is available. Which leads to this crucial question: How smart is your psychiatrist? 

MEDS FASHION PARADE 

The drug companies were out in force at the poster sessions of the Fourth International Conference on Bipolar, held in June. Of the mood stabilizers, GlaxoSmithKline was pushing Lamictal hard, with at least six studies. The real battle, however, was being waged by Eli Lilly, Janssen, and AstraZeneca over their respective atypical antipsychotics, Zyprexa, Risperdal, and Seroquel. Eli Lilly was the first drug company to catch on to the fact that it could effectively double its market by putting Zyprexa to use treating bipolar, and last year it secured FDA approval for the treatment of acute mania. Now we have Eli Lilly pushing the envelope further, citing three studies that suggest its efficacy in bipolar depression. Janssen and AstraZeneca, meanwhile, show signs of pulling out all the stops in an effort to regain lost ground. In all, there were some 14 dueling posters involving atypical antipsychotics. 

But what initially got this writer's attention was a little-known drug being developed by a lesser-known drug company ... EPA Ethyl-eicosapentaenoate (Lax-101) is a fatty acid with an ethyl group added to it to purify it and make it more tolerable. Eicosapentaenoic acid (EPA) is one of the active ingredients of omega-3 fish oil. Unlike fish oil, however, there is no fishy aftertaste. Lax-101 is being developed by Laxdale Ltd, a Scottish company, for the treatment of Huntington's Disease, but the company is also exploring the drug's potential in the treatment of depression and bipolar. A recent study of 70 depressed patients who had not responded to other treatments were randomized into three groups taking different doses of Lax-101 (one, two, or four grams a day) or a placebo. Six of the 52 patients on Lax-101 dropped out before 12 weeks. The one gram group did "dramatically better" than the placebo group, but surprisingly the two and four gram groups fared only modestly better than the placebo group. Much higher doses (eight to 10 grams a day) have been found effective in treating bipolar. 

The drug acts as a messenger for signal transduction pathways in the brain. According to the company: "Impaired fatty acid and phospholipid metabolism may be a primary cause of depression in many patients and may explain ... interactions with other diseases." 

WARNING 

Most of the studies below were funded by the pharmaceutical companies, and can be expected to contain the kind of results that portray their products in the best possible light. By the same token, much of the research was conducted by some of the leading lights in the field. 

LAMICTAL 

Safety issues - Two studies were aimed at countering Lamictal's bad rap for inducing rash. A study of adverse events from several trials involving more than 2,000 patients concluded the drug "at daily doses of 50-400 mg is well-tolerated in patients with mood disorders." A re-examination from a database of 2,469 bipolar patients concluded, "The risk of ... serious dermatologic events can be significantly reduced by adherence to dosing instructions (including starting dose and rate of escalation) contained in the package insert." 

Weight - A 32-week trial of epilepsy patients found the mean weight increase for Depakote was 12 pounds vs one pound for Lamictal, with moods consistently higher in the Lamictal group. 

Mania prevention - A study of 175 stabilized patients over 18 months found that Lamictal compared favorably to lithium in treating and preventing relapses of mania or hypomania. 

Rapid-cycling - Five difficult to treat rapid-cycling patients were tracked for three years on Lamictal, which showed "promising efficacy in limiting depression and manic episodes." In a study of 177 rapid-cycling patients, 41 percent of the Lamictal monotherapy patients completed six months without additional clinical intervention vs 26 percent in the placebo group. 

Depression and mania - A study of 462 patients on Lamictal, combined with other studies, concluded that, "these data ... suggest that [Lamictal] possesses a unique spectrum of efficacy that includes both antidepressant and mood stabilizing properties." 

ZYPREXA 

Mania and depression - In two double-blind trials of 78 bipolar I patients with mania, a subset of depressed patients was analyzed. The study concluded Zyprexa "effectively treats mania and may reduce depressive symptoms as well. Another study of 16 bipolar patients - 10 with elevated and six with depressed moods - found all six depressed patients responded to Zyprexa. Another study comparing Zyprexa with Haldol found Zyprexa may be superior in treating depression in patients with acute manic or mixed episodes. 

Weight gain - The last study above found a weight gain of 3.55 kg over 12 weeks for Zyprexa patients vs .72 kg for the Haldol group. 

Safety - Two studies involving 254 patients showed that although mania rating scores worsened for some patients during Zyprexa therapy, the "results do not support the clinical speculation that [Zyprexa] may cause mania-like states in patients with pre-existing bipolar disorder." 

Remission/clinical outcomes - Two studies found that Zyprexa had higher rates of remission and better clinical outcomes in bipolar I (manic or mixed) patients than Haldol. Another study found bipolar I patients on Zyprexa achieved better response for acute mania after three weeks than those on Depakote. 

RISPERDAL 

Add-on for mixed mania - Thirty-one mixed mania patients were treated with Risperdal with a mood stabilizer for six months. Of the 26 who stayed in the study, 73 percent were asymptotic or only slightly ill compared to six percent at the beginning of the study. There were no reports of mania-inducing and only one of depression. 

Add-on for mania - Two double-blind placebo-controlled studies involving 293 bipolar patients with acute mania over three weeks found those taking Risperdal plus a mood stabilizer showed greater improvement than the mood stabilizer with a placebo group. Further improvements were shown in 209 patients who entered a 10-week open label follow-up. A third double-blind placebo-controlled study involving 156 bipolar patients (manic or mixed) found Risperdal plus a mood stabilizer was "more efficacious than a mood stabilizer alone for the rapid control of manic symptoms and was well tolerated." Two more similar studies involving 106 patients found the same thing. 

Dose/cost - The studies above also highlighted the comparatively low dose required of Risperdal. In the first study the mean dose was 4.2 mg a day at the end of the study; in the second set of studies the mean dose during the open label phase was 3.4 mg a day. A retrospective chart review comparing Risperdal to Zyprexa on bipolar and schizo-affective patients found no significantly different clinical and side effect outcomes, but did note the total acquisition cost for Zyprexa was $11.84 a day vs $5.81 for Risperdal. 

Add-on for depression - A 24-week study of 21 bipolar I patients with depression suggests that Risperdal can be used in combination with Zoloft "with good results and safety." One patient switched into mania. 

SEROQUEL 

Dual diagnosis treatment - An open-label study of 12 outpatients with bipolar and cocaine dependence found "improvement in mood and drug cravings" after 12 weeks. 

Adolescent mania - A retrospective chart review of 26 adolescent bipolar patients concluded that Seroquel as add-on treatment "resulted in decreased symptoms for most patients." The most common side effect was sedation. 

Safety - A study of 30 manic bipolar adolescents on Depakote with Seroquel suggests that Seroquel is "safe and well-tolerated." 

Mania and depression - Preliminary findings of a pilot study of rapid-cycling bipolar I patients using Seroquel, either with a mood stabilizer or without one, found patients "improving" after eight weeks on their depression scores and experiencing "significant improvement" on their mania scores. 

TOPAMAX 

A retrospective chart review of 76 patients treated with Topamax found mild to moderate improvement in 36 individuals and marked improvement in 10. Patients who received a higher mean dose (180 mg a day) fared better than nonresponders (83.2 mg a day). Higher dose patients also lost more weight, a mean amount of 14.2 pounds. 

Long-term treatment - A study of 150 patients over six months to three years concluded that Topamax "is an effective agent ... both as a stand-alone therapy and as additive therapy." No patients dropped out due to serious adverse events or exacerbation of psychiatric symptoms. . 

Depression - An eight-week study of 36 depressed outpatients found that Topamax compared favorably to Wellbutrin. The Wellbutrin group experienced a mean 1.2 kg weight loss vs 5.8 kg for Topamax. Another study of 65 depressed bipolar patients over 30 months found of the 41 patients completing the study, 80.5 percent were full responders and 19.5 partial responders on depression rating scores. 

TRILEPTAL 

Forty-two percent of 12 patients in a pilot study showed a good antimanic response, but the benefits seemed restricted to those with mild or moderate manic episodes. 

LITHIUM 

A retrospective study of 114 patients on lithium for four to 30 years found 24 showed excessive blood creatinine levels associated with renal failure, but the study emphasized the drug's safety for the overwhelming majority of patients. Another study found responses to lithium seem to be inherited. 

GABATRIL 

A six-month study of 22 patients considered nonresponders or partial responders to medication found seven responded to Gabatril as add-on therapy, two were partial responders, and 13 were nonresponders. 

NEURONTIN 

A study of refractory depressed patients with a history of bipolar in the family found that treatment with Neurontin as an add-on showed "significant clinical improvement." 

WHO TAKES WHAT 

An Institute of Psychiatry study of 63 bipolar I patients in the UK found: a.. 28.57 percent were on antipsychotics, with 71.42 percent having been prescribed this class of drugs in the past. Only 20.6 percent had ever been treated with an atypical agent. b.. 50.8 percent were prescribed a mood stabilizer (30.2 percent lithium, 14.3 percent Tegretol, and 9.5 percent Depakote). c.. 12.3 percent of the sample were on antidepressants. d.. 28.6 percent of the sample were on combination therapy, most commonly lithium plus a typical antipsychotic (11.11 percent). 

MORE 

More on medications, this time from Medscape ... 

HOW THEY WORK 

We know SSRIs have something to do with the enhancement of serotonin in the brain, but even the experts are at a loss to account for the several weeks time lag between when an antidepressant sets the chemical process in motion and when one's depression starts lifting. At the APA Annual Meeting in New Orleans in May, Pierre Blier MD, PhD of the University of Florida offered this explanation: When the 5-HT-1A autoreceptor in the brain is stimulated by an increase in the amount of serotonin, it will decrease the firing of the serotonin neurons. An SSRI will initially increase serotonin levels by blocking the 5-HT uptake transporter, but this is offset by the decreased firing at the autoreceptor end of the synapse. After a few weeks, however, the autoreceptors are desensitized and full firing resumes. The reuptake action, in the meantime, is still blocked, which results in a positive serotonin balance sheet.  

For more information see:

Antidepressant Treatment and the Biology of Depression on Medscape (you must complete the free medscape registration for this link to work)

GEODON 

A three-week double-blind study of 210 bipolar I patients (manic or mixed) found the new atypical antipsychotic drug Geodon to be similar to other atypical antipsychotics in the treatment of acute mania. Discontinuation due to adverse effects occurred in 7.1 percent of the patients taking the drug. None of the adverse effects were considered severe by the investigators. Unlike the other antipsychotics, the drug is not associated with significant weight gain. 

PROZAC DROOP 

From Healthscout comes a more detailed account of the sexual side effects study published at the APA Annual Meeting in May. That study found the rate of sexual dysfunction among ten of the newer antidepressants averaged 37 percent. The lowest rates were for Wellbutrin (22 and 25 percent for IR and SR, respectively) and Serzone at 28 percent. The anti-Viagras of the lot were Paxil at 43 percent, Remeron at 41 percent, and Prozac with 37 percent. Falling in between were Zoloft, Effexor, Effexor XR, and Celexa. 

THAT FIVE PERCENT MAY INCLUDE SOME OF US 

The Centers for Disease Control and Prevention reports that the number of suicides in the US fell more than five percent, from 30,575 in 1998 to 29,041 in 1999, dropping from the eighth leading cause of death to eleventh. Homicide also dropped by a similar rate, and the decrease in both is being attributed to the decrease in death caused by guns. For those aged 15 to 24, suicide is the second-leading cause of death, and for those 65 and over the rate is 16.9 suicides per 100,000, which goes up to 19.7 per 100,000 for those 75 to 84 years and 21 for 85-plus. 

TEXAS TRAGEDY 

There's a lot we don't know about postpartum psychosis, but that hasn't stopped various people from speaking out anyway. With reference to the Susan Smith, the South Carolina mother who drowned her two children but was spared the death penalty, NY Post columnist Andrea Peyser felt inclined to write: "Pity, too, will save the life of Andrea Yates, the Texas mother who methodically and diabolically drowned her five young children in the family bathtub. But it shouldn't." After accusing Andrea Yates of killing her kids because she didn't love them, and ridiculing Marie Osmond who experienced a severe case of postpartum depression, she concluded: "Still, blaming a mother for murder is heresy among the talking heads who fill the airwaves with psycho-babble about postpartum depression." 

Click here for more on the Texas tragedy.

DOWN, DOWN UNDER 

One in 20 Australian high school students suffer from clinical depression, according to a University of Sydney/Adelaide University survey of 1,300 teenagers. Only 18.5 percent of those who reported themselves as depressed had attended a service for help, and only three percent received antidepressants. Co-author Dr Michael Sawyer said up to 14 percent of Australian children and adolescents suffered some form of mental health problem. 

EMBRYO SCREENING 

Will bipolar parents one day be repeating this scene? Matt Raminger carries the gene for Huntington's Disease. He has seen the illness first rob the sanity, then strike the final blow, of his aunts, uncles, and his mother. Barring a cure or a miracle, his fate will be the same as theirs, and any child he sires the normal way will have a 50 percent chance of carrying the gene. Five years ago, Matt and his wife, Denise became the first couple to use embryo screening - preimplantation genetic diagnosis, or PGD - to ensure the birth of a healthy child. The results are four-year-old twins who need not share their father's worry. Matt's story is part of a much larger feature in the Washington Post on the shape of things to come. THE 

PRICE OF DEPRESSION 

According to an article in Medscape, major depression accounts for 50 to 100 percent higher costs, even after controlling the patient's associated medical illness. One study of 2,500 elderly patients found at every level of medical co-occurrence, depression was associated with 30 to 50 percent higher costs. Depressed patients complain more about physical symptoms, but studies suggest that depression is also a risk factor for diabetes mellitus and coronary heart disease. Free registration is required to access the above link. 

NDMDA CONFERENCE 

The National Depressive and Manic-Depression Association is hosting its annual conference, "Empowering Our Future," at the Renaissance Cleveland Hotel in Cleveland Aug 17-Aug 19. Speakers include some of the field's top researchers, psychiatrists, therapists, wellness practitioners, and advocates. For more details, go here. 

BIPOLAR KIDS 

Last week's Newsletter noted that, "These days the illness seems to catch kids at a very young age." Joanne writes: That sounds funny to me. It seems more like the psychiatrists are catching the disorder earlier. It seems sometimes we forget that this is a biologically, genetically based illness, not environmental. I was born with bipolar disorder. I had symptoms as a kid that nobody knew what to do with. And it was so scary being that kid without treatment. I'm so happy that diagnoses are happening earlier. But, don't forget if you have bipolar now, you were born with it. The symptoms are varied, though, with different people and different ages. 

MCMAN'S WEB 

Check out more than 120 articles on all aspects of depression and bipolar, plus a bookstore, readers' forum, and other features. 

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