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 back- to-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. Quetiapine is clearly effective in bipolar depression, and its evidence base is backed up by clinical satisfaction. However, weight gain, hyperlipidemia, and glucose impairment are striking, although not as striking as with olanzapine, another atypical antipsychotic clearly shown to be useful not only in bipolar mania and in the prophylaxis of bipolar episodes but also in the treatment of bipolar depression with or without an adjunctive mood stabilizer.

In this month's Journal, Loebel and colleagues from Sunovion Pharmaceuticals along with distinguished university research collaborators have studied two large groups, one with about 500 patients and one with about 350 patients, all with the bipolar I diagnosis in the depressed phase. The first group of patients were not currently receiving any mood stabilizer treatment, and the second group of patients were receiving lithium or valproate mood-stabilizer treatment at the time of entrance to the study. In both studies, patients were randomly assigned to receive placebo, low-dose lurasidone, or high-dose lurasidone and were followed for 6 weeks and rated using the Montgomery-Åsberg Depression Rating Scale (MADRS) and the depression severity score on the Clinical Global Impressions scale for use in bipolar illness (CGI-BP). There were few dropouts because of adverse events and minimal changes in weight, lipids, or measures of glycemic control in the lurasidone groups compared with placebo. Lurasidone-treated patients had significantly more improvement in depression than the placebo-treated patients whether they were currently receiving a mood stabilizer (lithium or valproate) or not. There were no differences between low-dose lurasidone treatment (20–60 mg/day) or higher-dose lurasidone (80–100 mg/day). The size of the effect was moderate, clinically relevant. The monotherapy trial does not include an active comparator against which to assess the efficacy of lurasidone, but the adjunctive trial indicates that it adds to the effects of lithium or valproate.

Does this mean that all atypical antipsychotics are effective in all phases of bipolar disorder? Perhaps not. Aripiprazole and ziprasidone do not seem to be effective in bipolar depression. Could there be some more practical mechanism in play here such that perhaps only sedative atypical antipsychotics are useful in depression? It is too early to tell. Trial data on the incidence of sedative side effects do not suggest that lurasidone is a particularly sedating antipsychotic, but in my experience depressed patients are often relieved to be sedated, and only prophylactic studies in the euthymic phase will really give us information as to whether the sedative component distinguishes between dopamine blockers that are useful in bipolar depression and those that are not.

Is this a new era in psychiatry and psychopharmacology? The history of psychopharmacology certainly saw some periods of discovery of entirely new principles, such as the first antipsychotic (chlorpromazine), the first antidepressant (imipramine), the first benzodiazepine, and lithium, the first mood stabilizer . On the other hand clinicians have become a bit jaded during a long era of “me too” compounds where new antipsychotics and new antidepressants seem to appear daily—hailed by leaders of the field and feted with dinners and weekends for clinicians willing to attend, later to lose their patents and be discarded on the scrap heap of history.

Lurasidone may be somewhere between those two situations. Sometimes incremental progress in psychopharmacology can gradually add up after much preclinical work, many clinical trials, and tinkering with several different compounds to an advance that is real. The discovery of a D₂ blocker with a concomitant receptor profile that avoids extrapyramidal symptoms, avoids hyperprolactinemia, avoids cardiovascular side effects, and is also effective in bipolar disorder—this could be a serious advance of the field. Together with the large number of overlapping genetic linkages between schizophrenia and bipolar disorder (6), one might envision an impact on the battle over unitary psychosis theory that could even affect DSM-6.

What would a historian say? A historian might note that in the first edition of Diagnosis and Drug Treatment of Psychiatric Disorders by Klein and Davis (7), the first textbook of psychopharmacology, the usefulness of typical old-fashioned neuroleptics such as chlorpromazine in many forms of depression was emphasized and use of other typical neuroleptics for prophylaxis of bipolar disorder was widespread around the world, especially for patients who were nonadherent with lithium or in areas where blood testing was unavailable (8). It could be said that we have rediscovered the wheel. But it could be a better wheel than chlorpromazine or fluphenazine (9) were in their times.