Can Antipsychotic Agents be Considered as Real Antimanic Treatments?

Until now, in various parts of the world, no consensus has been reached with regard to the treatment of acute mania. Controlled clinical trials have at last provided irrefutable evidence for the effectiveness of lithium, which had long been used alone, as well as that of divalproate or its derivatives and, to a lesser extent, carbamazepine (1). In Europe, haloperidol is still the reference compound used in clinical trials while it has never been officially approved in the treatment of mania. In the USA, lithium, divalproate, or second-generation-antipsychotics can be prescribed as first-line treatments. As dopamine was reported to be involved in the pathophysiology of mania in the 1970s and as changes in dopaminergic neurotransmission have consistently been reported in bipolar disorders (BDs), the question of the antimanic properties of antidopaminergic drugs such as antipsychotics is a fair one (2). In Europe, lithium remains the first-line medication, whereas divalproate and atypical antipsychotic agents are mainly used as second-line treatments. Yet, manic inpatients are frequently released from hospitals while on neuroleptics or antipsychotics even in the absence of psychotic symptoms or aggressive behavior (3). Although both types of medications (antipsychotics, mood stabilizer agents, and/or anticonvulsants) have proved their effectiveness in the management of mania by reducing the mania scores overall, they do not reduce all manic symptoms with the same intensity. The British Association of Psychopharmacology (BAP) guidelines reports that, in placebo-controlled trials, the atypical antipsychotics used in monotherapy, including aripiprazole, have been shown to be effective in the treatment of acute manic or mixed episodes (4). Factorial approaches to mania have all shown that since there are several clinical subtypes of mania, several clusters of manic symptoms can be identified. Antipsychotic and mood stabilizer agents and/or anticonvulsants do not appear to have equivalent effects on each of these identifiable clusters of symptoms, especially on psychotic features. We think that it is vitally important for future clinical trials conducted in mania treatment to focus on the treatment effects using a factorial approach and an appropriate methodological structure. This question highlights the uncertainty surrounding manic episodes, namely their predominant mood or psychotic nature. The Europeans consider mania to be more of a mood episode and prefer lithium as first-line treatment, whereas the Americans believe that psychotic symptoms dominate and widely use antipsychotic agents. However, according to the clinical trials currently available, even though antipsychotic agents are certainly effective in reducing the scores on the mania scales, it is not clear whether they can be considered purely as antimanic treatments. Nowadays, there is no clear consensus regarding mania treatment. The question as to whether mood stabilizer agents such as lithium or anticonvulsants (even a combination of both) or antipsychotic agents should preferably be used as first-line treatment of mania remains unanswered and neither the American nor the European guidelines provide an entirely satisfactory answer to this crucial question. Indeed, these two classes can have a somewhat different impact on the underlying symptoms of mania (1). Both therapeutic strategies are feasible and effective (5). With regard to the American approach (6), three classes of compounds are used as first-line chemotherapy in the management of mania: lithium, sodium divalproate, and antipsychotic agents. In case of severe and purely manic or of mixed episode, the APA advocates the use of a combination of lithium and an antipsychotic or lithium and sodium divalproate. Monotherapy using one of these three compounds (lithium, sodium divalproate, or an antipsychotic) is recommended for less severe episodes. Atypical antipsychotics (olanzapine and risperidone) are preferably used compared to typical antipsychotics due to their better safety profile. Carbamazepine or oxcarbazepine is used only as second-line treatment option. Finally, clozapine is restricted to refractory mania. In case of psychotic mania or combined episodes, the APA recommends the use of antipsychotic treatment. The 2nd edition of the APA guideline for BDs issued in 2010 do not modify its recommendation regarding the treatment of acute mania. The recommendations for the management of acute mania remain largely unchanged in Canada. Lithium, valproate, and several atypical antipsychotic agents are first-line treatments for acute mania. Monotherapy with asenapine, paliperidone extended release (ER), and divalproex ER have been recently considered as first-line options, as well as adjunctive asenapine (7).