Three second-generation antipsychotic (SGA) agents have received FDA approval for adjunctive treatment, to antidepressant, of major depressive disorder: quetiapine, aripiprazole, and olanzapine. Additionally, quetiapine and lurasidone have been approved for the treatment of bipolar depression. There are data suggesting that quetiapine is effective for major depressive disorder as monotherapy. These agents are effective for depression only at subantipsychotic doses. Receptor profiles predict that all SGA will have anxiolytic effects as subantipsychotic doses but that all will be dysphorogenic at full antipsychotic doses (i.e., produce a depression-like clinical picture). The antidepressant effect appears to be unique to some agents, with direct evidence of insignificant antidepressant action for ziprasidone. Three general principles can guide the use of antipsychotics as antidepressants: (i) All SGAs may have anxiolytic effects; (ii) full antipsychotic doses are dysphorogenic, and therefore, subantipsychotic doses are to be used; and (iii) SGAs do not have a general antidepressant effect, rather, this appears to be unique to quetiapine and aripiprazole, and possibly lurasidone.

Bipolar disorder is a complex condition to treat because agents that may be effective for a specific phase may not be effective for other phases, or may even worsen the overall course of the illness. Over the last decade there has been an increase in research activity in the treatment of bipolar illness. There are now several agents that are well established for the treatment of acute mania (lithium, divalproex, carbamazepine, nearly all antipsychotics), acute bipolar depression (lamotrigine, quetiapine, olanzapine/fluoxetine combination), and relapse prevention (lithium, lamotrigine, divalproex, most second generation antipsychotics). There are also novel treatments that are being studied for all three phases. These include eslicarbazepine, cariprazine, MEM-1003, memantine, tamoxifen and pentazocine for acute mania; pramipexole, modafinil, armodafinil, divalproex, lurasidone, agomelatine, cariprazine, lisedexamfetamine, riluzole, RG-2417, bifeprunox, ropinirole, GSK1014802, and magnetic stimulation for bipolar depression; and asenapine, lurasidone, and cariprazine for relapse prevention. Additionally, there are accumulating data that antidepressants, particularly serotoninergic ones, are not particularly effective in acute bipolar depression and may worsen the course of the illness.

There has been a recent increase in the number of clinical trials and treatment options for bipolar disorder. This research has resulted in new treatment options. Most second-generation antipsychotics have demonstrated efficacy in the treatment of mania, both in monotherapy and as adjuncts to mood stabilizers. For bipolar depression, nearly all randomized, placebo-controlled studies have demonstrated that antidepressants do not provide any additional benefit to ongoing mood stabilizers. Additionally, antidepressants carry a risk of destabilization of bipolar disorder with an increase in mania, cycling, and chronic irritable dysphoria. Newer non-antidepressant treatments for depression include quetiapine, lamotrigine, modafinil, and pramipexole. These agents are effective for acute treatment and appear to be effective in maintenance. The least-studied phase of bipolar disorder is the maintenance phase. The use of multiple agents appears to be superior to monotherapy in relapse prevention. Despite the many advances in the pharmacotherapy of bipolar disorder, the overall prognosis of this severe illness does not appear to have changed.

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