Lurasidone and bipolar disorder.

Lurasidone is a new atypical antipsychotic developed by Sunovion Pharmaceuticals, Inc., that was approved for use in schizophrenia in the United States in 2010. It was approved for use in bipolar depression in July 2013, and the two backto-back articles in this month’s Journal constitute pivotal studies for medication approval for bipolar depression by the FDA (1, 2). Lurasidone is a strong dopamine D2 receptor blocker, as are almost all currently known antipsychotics used in schizophrenia, so its development and approval came as no surprise. Consistent with the major thrust of development in the schizophrenia treatment area today, lurasidone’s preclinical development was associated with the search for a dopamine D2 blocker with little or no extrapyramidal symptoms and little or no prolactin rise. Sometimes an absence of cholinergic muscarinic blockade and a felicitous balance of agonism and antagonism at some of the large number of serotonin receptor subtypes can achieve this desirable side effect profile. It has been achieved already in some other compounds, but the big prize today in pharmaceutical development of atypical antipsychotics is avoidance of the metabolic side effects such as weight gain, hyperlipidemia, and impaired glucose metabolism. The molecular basis of this cardiovascular profile is not fully known, so it has not been possible to use designer medicinal chemistry to create the ideal compound from basic principles. Some trial and error is necessary both in animals and eventually in clinical trials. Lurasidone may fit this basic bill. Bipolar disorder or manic-depressive illness has been distinguished from schizophrenia since Kraeplin over 100 years ago, although a persistent group of psychiatrists, scientists, and accompanying facts seems to turn up in every generation to resurrect the concept of “a unitary psychosis” that may even include depression (3). The discovery of lithium as a simple ion effective in bipolar disorder and not in schizophrenia presaged an era in which the distinction between bipolar disorder and schizophrenia was a foundation of psychiatric treatment, and a prediction of lithium response a clinical tour de force to make any psychiatrist proud. The later discovery that some anticonvulsants, such as valproate and carbamazepine, are also effective in bipolar disorder did not undermine the essential concept. However, the rise of atypical antipsychotic use in bipolar disorder and the large quantity and quality of the evidence justifying its use over the last 10 years is having a major impact on clinical diagnostic thinking (4). This is not yet evident in DSM-5, but I predict that it will be evident in DSM-6. Most, if not all, of the new atypical antipsychotics are effective in mania and in the prophylaxis of new episodes in bipolar disorder. But what about bipolar depression? Bipolar depression is a major clinical problem, and the evidence that antidepressants can be useful seems less and less convincing (5). Like a brave knight on a white horse, atypical antipsychotics have rushed in to save us, the psychiatric maidens. It could be said that we have rediscovered the wheel. But it could be a better wheel.