Depression can occur either with or without alternation with periods of
mania. Depression that alternates with
mania (
bipolar depression) is a particularly difficult problem in clinical practice. The evidence base of the treatment for this condition is not strong and the choices at best are limited. Furthermore, although there are a number of effective
antidepressants for the non-cycling variety ('unipolar' major depression), > 50% of patients experience incomplete response to any given drug. Given the proportion of the population involved, these represent fairly sizeable markets. Studies over the last several years indicate that the combination of the novel
antipsychotic olanzapine and the
serotonin-selective re-uptake inhibitor (SSRI),
fluoxetine, may be effective for both conditions. One trial in 28 patients showed that this combination was an effective treatment, compared to the individual components with unipolar depressed patients who had not responded to two
antidepressants of different chemical classes. Two subsequent large-scale attempts at replication have resulted in failed trials. Patients randomly assigned to
antidepressant monotherapies showed a good response, indicating that the populations being studied were not actually treatment-resistant; therefore, more research is needed. Alternatively, a recent study showed that monotherapy with
olanzapine produced a greater effect than placebo in
bipolar depression and the combination of
olanzapine and
fluoxetine yielded an even more robust response. However, important questions remain, e.g., the issue of comparative effectiveness, that is to say, whether the same result could occur with combinations of other novel
antipsychotics and
SSRIs. In addition, there remain significant concerns regarding the safety and tolerability of
olanzapine in these populations. Essential questions about the potential for substantial
weight gain, Type II diabetes and for the development of
tardive dyskinesia (a syndrome of permanent, disfiguring abnormal
involuntary movements) remain. These problems will have to be vigorously addressed in order to achieve a substantial market penetration for these conditions.