Bipolar: It's Everywhere!

I have mentioned earlier that Big Pharma needs a new market for antipsychotics. After all, they’re generally under patent protection for a little while longer, and since there is little sign of making any new drugs which may actually improve outcomes for patients with psychiatric conditions, they are just expanding the market for existing medications. Bipolar disorder is the next big frontier, and one important part of finding a new frontier in psychiatry is to emphasize how this frontier represents an undetected epidemic. This is where a nice article from David Healy in PLoS Medicine comes in. It will be quoted at some length interspersed with my commentary…

Healy reminds us that the term “mood stabilizer” is a relatively recent phenomenon, as the term was rarely mentioned to the use of valproate (Depakote) to treat bipolar in 1995. By 2001, Healy points out that there were over 100 articles being published annually that had a subject heading of “mood stabilizer.”

“Repeated reviews make it clear that the academic psychiatric community still has not come to a consensus on what the term “mood stabilizer” means [5–7]. But this lack of consensus did not get in the way of the message that patients with bipolar disorders needed to be detected and once detected needed mood stabilizers, and perhaps should only be given these drugs and not any other psychotropic drugs [8,9].”

--SNIP—

“Bipolar disorders entered the DSM (Diagnostic and Statistical Manual of Mental Disorders) in 1980. At the time, the criteria for bipolar I disorder (classic manic-depressive illness) involved an episode of hospitalization for mania. Since then, the community based disorders bipolar II disorder, bipolar disorders NOS (not otherwise specified), and cyclothymia have emerged. With their emergence, estimates for the prevalence of bipolar disorders have risen from 0.1% of the population having bipolar I disorder (involving an episode of hospitalization for mania) [11] to 5% or more when the definition of bipolar disorders includes the aforementioned community disorders [12]. A range of academic institutions has also grown more interested in the condition.”

Now, there is a case to be made that antipsychotics reduce symptoms in the case of acute mania (though, as I've shown earlier, it is not necessarily a very impressive effect). This, however, carves out a limited market, as acute manic states are generally short in duration. The trick, then, is to make sure that physicians and patients are convinced that they must use the medications indefinitely to prevent relapse. In other words, to profit immensely from the use of antipsychotics, people must be convinced that there is a prophylactic effect. Of course, if there really is a strong long-term positive effect for these meds, then everyone stands to benefit. Patients improve and drug companies’ bottom lines are justifiably enhanced.

Indeed, this is just what Big Pharma is attempting to do —persuade people that antipsychotic meds have an excellent long-term benefit:

“There is a growing amount of patient Web site and patient support materials that in the case of Zyprexa state that “bipolar disorder is often a lifelong illness needing lifelong treatment; symptoms come and go, but the illness stays; people feel better because the medication is working; almost everyone who stops taking the medication will get ill again and the more episodes you have, the more difficult they are to treat” [17]. Information available from Janssen (the makers of Risperdal) states “medicines are crucially important in the treatment of bipolar disorders. Studies over the past twenty years have shown beyond the shadow of doubt that people who receive the appropriate drugs are better off in the long term than those who receive no medicine” [18].

“There is, however, much less evidence than many might think to support these claims for the prophylactic drug treatment of manic-depressive illness (bipolar I). And there is almost no evidence to support such claims in the case of whatever community disorders (bipolar II, bipolar NOS, cyclothymia) are now being pulled into the manic-depressive net by the lure of bipolar disorder.

With the possible exception of lithium for bipolar I disorder, there are no randomized controlled trials to show that patients with bipolar disorders in general who receive psychotropic drugs are better in the long term than those who receive no medicine [19]. This may stem in part from difficulties in conducting trials on psychotropic drugs that last more than a few weeks in conditions as complex as manic-depressive illness. One short-term, randomized, placebo-controlled trial (in which patients were only followed for up to 48 weeks) that some see as a basis for claiming that olanzapine may be prophylactic in bipolar disorder [2] has been regarded by others as indicating that this drug produces a withdrawal-induced decompensation when stopped [20]. Even in the case of lithium, there is some dispute over what has been demonstrated [19], with the best evidence stemming from large open studies in dedicated lithium services rather than from randomized trials [21].

This evidence of benefit for one agent (lithium) and possible benefit for one more (olanzapine) must be weighed against two harms associated with use of antipsychotics: (1) a consistent body of evidence indicates that regular treatment with antipsychotics in the longer run increases mortality [22–26]; and (2) there is evidence that in placebo-controlled trials of antipsychotics submitted in application for schizophrenia licenses there is a statistically significant excess of completed suicides on active treatment [27]. A range of problems associated with antipsychotics, from increased mortality to tardive dyskinesia, never show up in the short-term trials aimed at demonstrating treatment effects in psychiatry.

But aside from these hazards, there are also grounds to question whether the treatment effects that some think have been demonstrated in bipolar disorder trials translate into therapeutic efficacy. If use of these agents based on demonstrated effects leads on to efficacy, admissions for bipolar disorder might be expected to fall, but the evidence for this is difficult to find. In North Wales before the advent of modern pharmacotherapy, patients with bipolar I disorder had on average four admissions every ten years. In contrast, against a background of a constant incidence of bipolar I disorder, and dramatic improvements in service provision, bipolar I patients show a 4-fold increase in the prevalence of admissions despite being treated with the very latest psychotropic medications [11]. This is not ordinarily what happens when treatments “work,” but quite often is what happens when treatments have effects.”

Healy goes on to point out in more detail that the risk of suicidal acts is apparently significantly higher among users of mood stabilizers…

“Two suicides (493/100,000 person- years of exposure) and eight suicide attempts (1,969/100,000 person-years of exposure) occurred in the group given an active drug (943 patients), but no suicides and two suicide attempts (1,467/100,000 person-years of exposure) occurred in the placebo group (418 patients). Based on these absolute numbers from these four trials, I have calculated … that active agents are most likely to be associated with a 2.22 times greater risk of suicidal acts than placebo (95% CI 0.5, 10.00).”

The article then points out that there is a groundswell of bipolar diagnoses among children in the United States though the question of whether this represents disease awareness or disease mongering is still open. I strongly suspect it is the latter, as bipolar disorder has generally been thought to not emerge until adolescence except in extremely rare cases. At least that was the case prior to the latest "epidemic" in psychiatry. Bipolar diagnoses, especially of children, are often based on quite subjective criteria and may reflect inaccurate reporting by parents. How far will the mania for bipolar go?

“Experts that appear willing to go so far as to accept the possibility that the first signs of bipolar disorder may be patterns of overactivity in utero [32] can only further compound these problems.”

Antipsychotics are potent sedative agents, so, as Healy points out, they will likely slow down overly active children (see trial results for antipsychotics in autism, for example) as measured on a rating scale, resulting in apparent efficacy. Who needs limit setting, boundaries, and warm but firm parenting when you can simply sedate kids with very powerful tranquilizers? I am not meaning to state that parenting and/or behavior therapy can solve the problems of all bipolar, er, overly active children. I am saying that practitioners would be wise to attempt many other treatment options prior to using these meds, whose long-term impact on children is likely to be deleterious from a health standpoint.

Please read Healy’s article here. Read a critique of his paper (which doesn’t even attempt to refute the main points of his arguments) and then read his reply here. You can also see my prior post on the future of antipsychotic meds (hint: distribute them much more widely) here.