All - I have posted several messages on this board as a Non-BP who was in a long term relationship with a BP, and have read many of the posts here. While there are some excellent medical resources on this web site, I recommend reading the information below assembled by Mr. John McManamy, a BP who has his own web site (referenced at the end). It contains information and statistics regarding medication important for both BP's and Non-BP's. I verified most of his cited references until I was confident that his research & statistics were credible before posting here.
Take care - G
Treating Bipolar Depression
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According to the Stanley Foundation Bipolar Network, patients with bipolar I spend three times as many days in depression as they do in mania. For bipolar II, the ratio is 50 to one. If you find this figure deifies credibility, Hagop Akiskal MD of the University of California, San Diego arrived at a more conservative 37 to one ratio. In addition, Dr Akiskal, with corroboration from Jules Angst MD of the University Zurich and others, found evidence that the bipolar II population could conceivably be widened to include as many as half of those currently diagnosed with unipolar depression.
But do we know how to treat all these people? Recent developments indicate throwing out the current psychiatric treatment guidelines and starting afresh.
Two Illness Phases
Psychiatry, like the rest of medicine, divides treating illnesses into two phases.
The acute phase involves the illness as it first presents itself to the clinician. The object of treatment is to get the patient well.
The maintenance phase involves keeping the patient well, which means preventing relapses. Often, what gets a patient well doesn’t necessarily keep him well. At the very least, the treatment strategy needs to be reassessed as the patient enters the maintenance phase.
Meds for Acute Phase Bipolar Depression
Lamictal, Yes or No?
Lamictal’s FDA indication is for bipolar maintenance treatment, not bipolar depression. Basically, according to the clinical evidence, it is a mood stabilizer rather an antidepressant, though there is more to this than meets the eye.
Lamictal’s manufacturer, GSK, tested Lamictal for treating depression in the short-term, and achieved encouraging results in one published 1999 trial. But, according to trial data listed on GSK’s web-based clinical trial register (see article), the drug failed to outperform the placebo in seven unpublished trials ranging from seven to ten weeks. One of these trials involved unipolar depression. Two were for recurring unipolar depression, the type of cycling depression considered by many a close cousin of bipolar depression. The other four trials involved populations with bipolar I and bipolar II depression.
Despite the evidence (and three of the four guidelines purport to be evidence-based), four North American treatment guidelines (TIMA, APA, CANMAT, and Expert Consensus) recommend Lamictal for the acute phase. All four guidelines cite the one published study, but fail to acknowledge the unpublished studies.
By contrast, a UK guideline (NICE), evinced extreme skepticism over the one published study (the trial failed on its primary endpoint). NICE also had issues with the slow dosing of the drug (six weeks to achieve full strength). Accordingly, NICE was adamant that the drug should not be used to treat acute bipolar depression. Unlike the North American guidelines, NICE's panel of experts had no ties to the drug industry.
Ironically, the best proof of Lamictal's efficacy for acute depression came in the form of a 2006 seven-week trial sponsored by Eli Lilly, which compared Lamictal to its own Symbyax. The study was apparently designed to make Lilly's own Symbyax come out a winner (by using as a primary measure a scale - the CGI - that does not specifically measure for depression). This allowed the Eli Lilly to spin the study to show that those on Symbyax "had significantly greater improvement than lamotrigine-treated patients."
But on secondary depression measures (the MADRS scale), Eli Lilly was obliged to concede, "response rates did not differ significantly between groups" (69 percent for Symbyax to 60 percent for Lamictal). Additionally, time to response was only marginally better for Symbyax (17 days vs 23 days for Lamictal). Moreover, patients on Symbyax had a raft of side effects (including weight gain and cholesterol) not evident in those on Lamictal.
The head-to-head study did not use a placebo for comparison.
In conversations with this writer, clinicians attest to the efficacy of Lamictal in their practices. They see their patients getting better on the med. That is not the same thing as clinical proof, but, provided you trust your psychiatrist, perhaps a far more important indicator.
Seroquel
In October 2006, the FDA approved AstraZeneca’s Seroquel for treating bipolar depression. The indication does not distinguish between acute and maintenance treatment. Seroquel is an atypical antipsychotic first used to treat schizophrenia. In 2004, the FDA approved its use for acute mania. The latest approval was based on two eight-week clinical trials involving 1,045 patients with either bipolar I or bipolar II experiencing a major depressive episode.
In the first first trial, patients achieved virtually similar outcomes on either 300 mgs or 600 mgs (58.2 and 57.6 percent response rates respectively on the MADRS scale vs 36.1 percent in the placebo group). "Response" signifies a 50 percent or better reduction in symptoms. Fifty-three percent of the combined Seroquel groups achieved remission (virtual elimination of symptoms) vs 36.1 percent in the placebo group. Some clinical benefit was observed at week one. Switches into mania were virtually identical to the placebo group (3.9 percent vs 3.2 percent).
The second trial replicated the results of the first. Forty-one percent did not complete the study. The product labeling (going off a slightly different database) attributes 12.3 percent dropping out of the bipolar depression 300 mg Seroquel group due to adverse events vs 19 percent in the 600 mg group vs 5.2 percent in the placebo group. The labeling lists 30 percent of the patients being treating for bipolar depression reporting sedation and 28 percent reporting somnolence vs eight and seven percent respectively on a placebo.
The labeling carries the same black box warning regarding suicidal thinking and behavior in children and adolescents that appears on SSRIs and other antidepressants. An additional bolded warning advises that antidepressants may increase suicidal thinking in some pediatric and adult patients and urges close clinical monitoring.
Symbyax
The first drug approved by the FDA to treat bipolar depression (in Dec 2003) was Eli Lilly's Symbyax (combination Zyprexa-Prozac). A 2003, Eli Lilly study of 833 patients with bipolar depression found that those on Symbyax showed greater improvement than the Zyprexa alone group and those on a placebo. Nearly 49 percent of the Symbyax patients remitted vs 32.8 percent of the Zyprexa alone patients vs 25.5 percent on a placebo. The first, Eli Lilly’s Symbyax (combination Zyprexa and Prozac) received an indication for this use in Dec 2003.
The drug has been a major earnings disappointment for Eli Lilly, with $53.9 million in sales in 2005 (the last year available), down from $70.2 million in 2004. (By contrast, Lilly's antidepressant Cymbalta, introduced around the same time, raked in $680 million in sales in 2005. Over the same period Zyprexa generated $4.2 billion in sales.)
Zyprexa
Zyprexa proved no slouch in the Symbyax studies cited above. Those who are uneasy about an antidepressant in the mix may prefer their Zyprexa "straight up."
An Experimental Med
A 2004 NIMH double-blind study of 21 depressed bipolar II patients found 60 percent of those taking the dopamine agonist pramipexole (Mirapex), used for treating Parkinson’s, achieved a therapeutic response vs nine percent in the placebo group. One subject on the drug and two on the placebo developed hypomania.
Meds for Maintenance Phase Bipolar Depression
Lamictal, Yes or No?
In two 2003 published trials lasting 18 months, Lamictal proved superior to lithium at delaying relapses into depression in patients with bipolar I with recently occurring manic or hypomanic episodes (while lithium proved superior at staving off relapses into mania). These results proved to be the ticket to an FDA indication. Significantly, the indication was for bipolar maintenance treatment, not bipolar depression, though GSK was allowed to put on its labeling that the findings were more robust for bipolar depression treatment.
Despite the FDA seal of approval, many psychiatrists regard the studies as suspect. This is because the trials used "enriched" populations, which leave room for manipulation. In this case, the patients in the study had all gotten better on Lamictal (a more true sampling would have included patients who had also gotten better on lithium). According to the skeptics, it stands to reason that those already responsive to Lamictal would fare batter on the same drug rather than being switched to lithium.
Lithium
Lithium is regarded as having some antidepressant effect, but comes into its own as a mood stabilizer.
The Antidepressant Controversy
Antidepressants pose a real risk of switching a bipolar patient (and possibly a patient with recurrent unipolar depression) into mania or hypomania or rapid-cycling.
The case for caution is set out in a review article by Ghaemi et al in the December 2003 Bipolar Disorders. 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 use, 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 2004 study by Ghaemi et al appearing in the Jan American Journal of Psychiatry analyzed clinical records of 41 bipolar and 37 unipolar patients on antidepressants (mostly SSRIs). The bipolar patients were 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 concurrent 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.
Concluded the authors of the study: "The findings suggest an unfavorable cost/benefit ratio for antidepressant treatment of bipolar depression."
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).
Lori Altshuler MD of UCLA in a grand rounds lecture delivered at UCLA in Jan 2003 suggested that the switch rates into mania attributed to antidepressants may in fact be the result of the natural course of the illness. She also called into question the APA's and TIMA's bias against continuing treatment with antidepressants after full response has been achieved.
In a study published in the July 2003 American Journal of Psychiatry, Dr Altshuler and colleagues examined data from the Stanley Foundation Bipolar Network (comprising six treatment locales in the US and Europe). Of the 549 bipolar patients who received antidepressants (with their mood stabilizers, it goes without saying), only 189 remained on these meds 60 days or more, and only 84 (44 percent) had a successful response, which is not exactly a ringing endorsement for antidepressants. Nevertheless, those who did respond to these meds were far better off staying on them, namely:
Seventy-one percent of those who discontinued their antidepressants before six months had a relapse into depression after 12 months compared to 57 percent who stayed on their antidepressants between six and 12 months, and to 29 percent who at follow-up stayed on their antidepressants for more than a year. Equally as significant, the 18 percent who switched into mania were equally divided among the three groups, suggesting the antidepressants had little or no role.
“Discontinuing people’s antidepressants after they get better,” Dr Altshuler concluded, “puts them at serious risk for depression relapse,” a greater danger, she asserted, than that posed by antidepressant-induced mania.
Nevertheless, it needs to be emphasized that Dr Altshuler is talking about a very small population, about 15 percent of bipolar patients. At a symposium at the 2003 APA meeting, Dr Ghaemi acknowledged there is a small percentage of bipolar patients who would benefit from staying on their antidepressants, so here, at least, there is some form of consensus. The problem, of course, is we don't know which 15 percent of bipolar patients would benefit from antidepressants.
Treatment Strategy
Oregon psychiatrist Jim Phelps MD, in his book Why Am I Still Depressed? (see article), emphasizes treating the cycle rather than the "symptom du jour." Bipolar depressions and recurrent unipolar depressions tend to cycle in contrast to classic unipolar "chronic" depression. Thus, even if a patient is in dire need of acute treatment, the clinician needs to be looking ahead to steadying the cycle in the maintenance phase.
Even if a patient is manic, the clinician needs to be thinking ahead to preventing cycling back into depression, as relapses into depression are far more common than relapses into mania.
The object is to stabilize the cycle to prevent depressions from returning rather than going for a quick treatment fix. As Dr Phelps points out, an antidepressant may lift one out of a depression, only to speed up one's cycling and reduce the intervals between episodes, ironically resulting in more depression.
Some General Principles
The meds that make you well may not the same meds that will keep you well. Seroquel and Symbyax are proven in the short term only. Moreover, their respective side effects profiles make them problematic in the long term. Obviously, if one's depression has psychotic features, then staying on an antipsychotic is prudent.
Lamictal's clinical efficacy is equivocal at best, but because of its favorable side effect profile may represent a legitimate first choice.
If nothing seems to work in the short term, then it might be wise to try an antidepressant (in conjunction with a mood stabilizer), but probably only for a short time.
Dr Phelps advises that in some cases it may pay not to push the panic button, to instead allow the patient to cycle naturally out of his or her depression and look ahead to stabilizing the cycling.
For the long term, as a general rule, the object is to wean off the antipsychotic or antidepressant and go with a mood stabilizer. With Lamictal, again the evidence is equivocal.
Non Meds Approaches
There are many articles on this site about managing one's illness through smart lifestyle choices involving diet, exercise, and sleep, and so on. The various coping and mindfulness techniques mentioned on this site can work wonders as natural mood stabilizers. Cognitive therapy, which works to address erroneous thoughts, is also indispensable. Although the evidence on omega-3 is not conclusive, its main effect is prevention against depression, though there may be some risk of manic switch.
Conclusion
Since launching this site in late 2000, I have made by far more changes to this page than any other page on my site. As of Feb 6, 2006, this page is far more up to date and based upon the available known evidence than the current treatment guidelines. But since we are constantly chasing a moving target, that is not the same as saying we know what we're doing.
In the final analysis, you know yourself best. Establish a good working relationship with your psychiatrist and therapist, learn suitable coping skills, make smart lifestyle choices, and develop a reliable support network. Be well.
http://www.mcmanweb.com/treating_bipolar_depression.htm
Bipolar Community 
