Lead story: Are antidepressants too risky for treating bipolar depression?

Also in this issue: More on ADs for BP depression, Symbyax approved for BP depression (what is it and what you need to know), Brain scans for BP depression, Riluzole for treatment-resistant depression, Ephedra RIP, Viagra for women, Shyness and health, Too many kids on meds?, Lonely lithium, Eskimo suicides, Rowan Atkinson, Extreme makeovers, Mind-bending margarine, The psychiatrist who became a patient, Personal note, McMan's Web, Donations.

Lots of Concerns, Precious Little Data

One would think modern medicine would have figured it out by now. After all we’re talking about a common illness and common meds. The issue is whether bipolar depression should be treated with an antidepressant (usually with a mood stabilizer). The relatively few studies we have to go on suggest that an antidepressant be prescribed with trepidation, if at all, but it is not as simple as all that, as the December 2003 "Bipolar Disorders" - which is largely devoted to the topic - makes clear:

The case for caution is set out in a review article by S Nassir Ghaemi MD of Harvard et al. Their analysis of previous studies points to both new and old antidepressants as complicit in inducing switches into mania and cycling. One could easily interpret several studies in support of the proposition that the risk is small (largely in single-figure percentages), say the authors, but when hypomania is factored in the rate climbs to 25 percent. Moreover, most studies exclude those with a co-occurring substance dependency, a major predictor of antidepressant-induced manic switching. Real world switch rates, the authors assert, are more like 40 percent for tricyclics and 20 percent for newer antidepressants.

A Stanley Foundation Bipolar Network study, cited in another article in the same issue, found manic (excluding hypomanic) switch rates of 12.6 percent in the first 12 weeks of treatment and 17.9 percent over one year, but could not establish how much of this was attributable to the antidepressant or the natural course of the illness. (Another SFBN study came to the surprising conclusion that there was no difference in switch rates between those who stayed on and those who went off their antidepressant.)

Ghaemi et al imply that the reward is not worth the risk. Four studies found that the tricyclics did not outperform lithium and another that lithium plus Paxil did no better than lithium alone. Also, discontinuing an antidepressant does not appear to pose the same kind of danger as it does for unipolar depression (17.6 percent of bipolar patients relapsing vs 83.3 percent of unipolar patients, according to one small study). Finally, Prozac poop-out appears to loom much larger for bipolar patients (a 57.5 percent relapse rate vs 18.4 percent for unipolar patients, according to another small study).

The picture may change, however, in the case of bipolar II, where mania by definition is not a feature of this shade of the illness, according to an article by Jay Amsterdam MD and David Brunswick MD of the University of Pennsylvania. Moreover, it may be safe to administer an antidepressant to this population without a mood stabilizer, say the authors. In one small open study, 61 percent of the bipolar II patients and 51 percent of the unipolar patients responded to Prozac alone after 12 weeks. Only 3.8 percent of the bipolar II patients switched into hypomania during that period. The second phase of the study (this time double-blinded) found 78 percent of the bipolar II patients who got well on Prozac stayed well on the med over six months vs 67 percent of unipolar patients, with only 3.6 of the bipolar II patients switching into hypomania. Another small trial involving Effexor produced similar results.

Which antidepressants are the safest? A review article in the same issue by Joseph Goldberg MD of the Zucker Hillside Hospital (Long Island) and Christine Truman of the Payne Whitney Clinic (New York) reports that studies suggest Wellbutrin and Paxil have a lower risk than other antidepressants, but caution that the risk may have more to do with the individual patient than the particular drug. The authors also advise that clinicians should not routinely assume that a concurrent mood stabilizer will prevent antidepressant-induced mania. One study found that lithium or Depakote helped against tricyclic antidepressants, but not against SSRIs and MAOIs. Another study found lithium but not Depakote lowered switch rates while another study still found that mood stabilizers made no difference.

The American Psychiatric Association in its 2002 Practice Guideline for the Treatment of Patients with Bipolar Disorder recommends an antidepressant (with lithium) as a first option only for severely ill patients. The pioneering 2001 state of Texas TIMA Bipolar Algorithm advises adding an antidepressant to either Zyprexa or a mood stabilizer, but only after ensuring the patient is stabilized. The British Association for Psychopharmacology’s 2003 Evidence-based Guidelines for Treating Bipolar Disorder recommends an antidepressant plus an antimania agent. All three Guidelines are vague or tentative in regard to their suggestions for long-term treatment, all three acknowledge the paucity of data to guide them, and none of them distinguish bipolar I from bipolar II.

Which leads to the $64,000 question: Are you willing to put your life on the line choosing one way or the other whether an antidepressant should be in your cocktail? Basically, we already have.

A Crying Need

The critical necessity that psychiatry get treating bipolar depression right is underscored in a review article by Robert Post MD of the NIMH et al in the same issue of "Bipolar Disorders":

Despite being on an average of 4.1 meds, 258 Stanley Foundation Bipolar Network patients (76 percent bipolar I) were depressed three times more often than they were manic (121 days of the year vs 39.6).

A New Study

Keeping in tune with this week’s lead story, a study by Ghaemi et al appearing in this month’s American Journal of Psychiatry analyzed clinical records of 41 bipolar and 37 unipolar patients on antidepressants (mostly SSRIs). The bipolar patients where 1.6 times more likely not to respond to an antidepressant than the unipolar patients (51.3 vs 31.6 percent). Manic (including hypomanic) switching occurred in 48.8 percent of the bipolar patients vs none of the unipolar patients. Those who took mood stabilizers experienced less manic switching than those who did not (31.6 percent vs 84.2 percent). Antidepressant-induced cycle acceleration occurred in 25.6 percent of the bipolar patients and none with unipolar depression. Loss of response to treatment among bipolar patients was 3.4 times that of unipolar patients (53.8 percent vs 15.8 percent). Relapsing after antidepressant discontinuation was 4.7 times less frequent in bipolar than unipolar depression (17.6 vs 83.3 percent). Mood stabilizers did not prevent cycle acceleration, rapid cycling, or response loss.

Conclude the authors of the study: "The findings suggest an unfavorable cost/benefit ratio for antidepressant treatment of bipolar depression.^"

New Drug for Bipolar Depression

Eli Lilly has won its gamble that antidepressants - under the right conditions - are good for bipolar depression.

On Dec 29, 2003, the FDA approved Eli Lilly’s Symbyax to treat bipolar depression, the first drug indicated specifically for this purpose (Lamictal, which is also used for bipolar depression, is FDA-approved for bipolar maintenance). The drug combines low dose Zyprexa (6 mg) with normal dose Prozac (25 mg) and is taken once daily. Three other dosing options are 12/25 Zyprexa/Prozac, 6/50, and 12/50.

A 2003 Eli Lilly study of 833 patients with bipolar I depression found 48.8 percent of the Symbyax patients remitted after eight weeks vs 32.8 percent on Zyprexa vs 24.5 percent on a placebo. MADRS depression scores lowered by 18.5 points in the Symbiax group vs 15 percent in the Zyprexa group vs 11.9 points for those taking a placebo. Switches into mania were about the same for all three groups (about six percent). Two smaller studies submitted for FDA approval found a similar lowering of depression scores.

Eli Lilly advises that patients remain on the drug long-term.

Symbyax will be sold to wholesalers at the same price as Zyprexa alone, which could translate to $10 a pill retail. RX USA.com lists the unit cost of 5 mg Zyprexa of between $5.65 and $6.76, depending on quantity and whether dissolvable. The price range for 10 mg Zyprexa runs from $8.55 to $9.50. The drug should be in pharmacies in another week or two.

How Symbyax Works

The product labeling states that the exact mechanism of Symbyax is unknown, but that animal studies show that the Zyprexa-Prozac combination produces "synergistic increases in norepinephrine and dopamine release in the prefrontal cortex compared with either component alone, as well as increases in serotonin."

What to Watch Out For

The same worries about diabetes and hyperglycemia, drowsiness, and weight gain - and to a lesser extent tardive dyskinesia - in Zyprexa also apply to Symbyax. The product labeling carries a similar diabetes/hyperglycemia warning to the one found on the Zyprexa labeling (a remote risk). The labeling also says somnolence occurred in 25 percent of Symbyax patients, leading to discontinuation in two percent. In the eight-week clinical trials, Symbyax patients gained 7.9 pounds (3.6 kg), 14 percent of them adding more than ten percent their baseline weight. The labeling reports that the incidence of tardive dyskinesia for Symbyax was infrequent (perhaps due to the low Zyprexa dose).

Ten percent of patients discontinued Symbiax due to adverse events compared to 4.6 in the placebo group.

The labeling advises that women who are pregnant or intend to get pregnant notify their physician, further advising to stay on the med only if the benefit outweighs the risks. Breast-feeding is not recommended.

Other Clinical Uses

Eli Lilly is also investigating Symbyax for treatment-resistant depression and psychotic depression. One 2001 study for treatment-resistant depression found "significantly-greater" improvement compared to either Prozac or Zyprexa alone.

Meanwhile, what works for combining Zyprexa and Prozac may also work for other atypical antipsychotics and SSRIs. At least other pharmaceutical companies are looking into it, including Janssen Pharmaceutica, which is experimenting with Risperdal and Celexa. At a Janssen symposium (surf and turf main course) at last year’s American Psychiatric Association meeting, Charles Nemeroff MD, PhD of Emory University reported on a small Risperdal-Celexa study, indicating "ironclad evidence of efficacy" for treatment-resistant depression, and that combination antipsychotic-antidepressant treatment has "in my practice moved up to a number one strategy."

Brain Scans for Bipolar Depression

If Symbyax doesn’t work, try getting your brain scanned.

A McLean Hospital study of 40 depressed bipolar patients found 23 of 30 who received Echo-Planar Magnetic Resonance Spectroscopic Imaging (EP-MRSI), a form of MRI brain scan, reported significant mood improvement compared to three of ten patients receiving sham EP-MRSI. The electric fields generated by EP-MRSI extend uniformly throughout the head. The Boston Globe reports that the study began by accident when investigators noticed that study subjects being scanned for other studies came out feeling better than they went in.

Riluzole for Treatment-Resistant Depression

An NIMH open pilot study of 19 treatment-resistant depressed patients has found that the glutamate inhibitor riluzole, used to treat ALS, resulted in "significant improvements" during weeks three through six for all patients.

Last Exit to Ephedra

The FDA will be banning the sale of the herbal stimulant Ephedra in the US, probably sometime in March. The supplement has been linked 155 deaths and 16,000 health complaints from Ephedra users.

Quiz

What psychiatric medication is the result of a quest to find a butter substitute? Answer further down.

Viagra for Women

A UCLA study of 202 postmenopausal women with "female sexual arousal disorder" without concomitant "hypoactive sexual desire disorder" and on hormone therapy found that Viagra resulted in "significantly greater improvement" in five of six indicators, including greater genital sensation and increased satisfaction with intercourse and/or foreplay.

Why Shyness is Unhealthy

A Newsletter poll last year revealed that an astonishing 83 percent of readers were introverts, which raised serious issues concerning the destructive interplay between our illness and our personality. Two new studies highlight the physical toll:

A Swiss study of 3,736 HIV patients found those in a stable partnership had a slower rate of progression to AIDS or death. The authors of the study cited studies on heart patients in support of the notion that "having fewer close friends or relatives, less frequent contact with other people, and reduced social participation have all been associated with increased mortality, especially in elderly people and in men."

In the second study, researchers from the University of Chicago found that lab rats with a fear of anything new were more likely to die from cancer. The average lifespan for the bolder rats was 701 days vs 599 for the more timid ones.

Too Many Kids on Meds?

A Columbia University survey that tracked depressed children and teen outpatients over four years has found 79 percent received psychotherapy and 56.9 percent received antidepressants, leading the authors of the study to conclude: "Antidepressant medications are used far more commonly than would be expected on the basis of published treatment recommendations.^"

Lonely Lithium

The authors of UCLA study have proposed "two by two" criteria for a mood stabilizer: Efficacy in treating acute manic and depressive symptoms, and in prevention of manic and depressive symptoms. A review of 111 placebo-controlled trials according to FDA standards (ie at least two successful trials for say mania prevention) found only lithium met their standards as a mood stabilizer.

The Long Dark Winter of the Soul

The AP reports that the suicide rate among Alaska Natives in 2000 was about four times the US national average, 42.9 per 100,000 people, while for Alaskan Native males it was more than six times the national average at 68.5 per 100,000 people. Loss of cultural identity, poverty, climate, isolation, boredom, and the availability of firearms put the population at risk. At Brevig Mission, a remote Inupiat village on the Bering Strait, Robert Tokeinna, 21, resorts to traditional Eskimo dance when he gets down, and is teaching others. Said Robert to the AP: "I didn't think dancing was preventing suicide. I thought it was just an activity. Now, I look at it differently. It lifts up the spirit and makes the person happier."

Pagliacci

Rowan Atkinson - the rubber-faced UK comic of "Not the Nine O’Clock News," "Blackadder," and "Mr Bean" fame - recently checked himself into an Arizona clinic for deep depression over the poor reception in the US of his most recent film, "Johnny English." The film was a box office success in Europe, but was panned by critics on both sides of the Atlantic before bombing in the US. The London Mail on Sunday reported that he said recently: "Acting is so personally exposing. You invest a lot of yourself in your work and if people don't like it, you feel they won't like you either. I think everybody wants to please people and be liked. I find work very stressful and I'm always convinced that whatever I've just finished working on has never been as good as it could have been."

Extreme Makeovers

Can makeovers change you from the inside-out? Time magazine reports on four people who underwent liposuction, plastic surgery and other procedures and regimens, and personal coaching on the ABC TV series, "Extreme Makeover." Stacey, who was transformed into a raving beauty, returned to a young niece who failed to recognize her and jealous co-workers, forcing her to seek new employment. Dan suffered a similar cold reception from his daughter after his bionic repair job, but felt like an action hero, lifting him from a multiyear depression. Tammy’s marriage received a shot in the arm following her retooling into a glamorpuss, but soon things went back to normal. Karen, on the other hand, went from being a grouch to being cheerful and gregarious.

Mind-Bending Margarine

According to David Healy MD et al of the University of Wales in an article in the Dec 2003 "Bipolar Disorders," valproate was initially developed by the Germans in World War II as a butter substitute, then was used as a diluent for other drugs. In 1963, its anticonvulsant properties became apparent when an experimental anticonvulsant was dissolved in valproic acid (thus revealing the true agent). European asylums in the 1960s had large populations of epileptic patients, and when synthesized valproate (Depakote) was given to these patients - voila! - the next mood stabilizer. Tegretol’s mood stabilizing properties were discovered in a similar fashion when it was used in Japanese asylums in the 1960s and 1970s for treating epilepsy.

When Doctor Becomes Patient

"After taking bupropion, I describe potential side effects to my patients in much greater detail. Even though I continue to prescribe it, I'm hypervigilant about any signs of distress. If a patient complains of symptoms similar to mine, I switch meds immediately. In the past, I would have encouraged the patient to stick it out, anticipating that most side effects would eventually pass. I wonder where I'd be now if I had followed my own advice."

Nanette Gartrell MD, a San Francisco psychiatrist who experienced an extreme awakening after becoming a patient, in an article this week’s New York Times Sunday Magazine.

A Personal Note

Next week, my 25-year old daughter from New Zealand will be visiting. The reason for her visit is that her Dad is getting married on Jan 18 (for the second time). I met my fiancée online when she emailed me with several outstanding articles after visiting my website. A long period of emails and phone calls resulted in a personal meeting and a much shorter time in deciding we were right for each other. Five years ago at this time, I was in the throes of a suicidal depression, which led to my diagnosis of bipolar I. To any of you facing a similar crisis or just feeling overwhelmed, please don’t abandon hope. You have so much to look forward to. My good fortune - which my depression had perversely convinced me was beyond imagination - is proof of that.

You can expect your next Newsletter sometime around the end of January or early February, following a brief honeymoon in New York City. Till then ...

McMan's Web

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"Knowledge is necessity."