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Department of Psychiatry
The primary rationale to test atypical antipsychotics in bipolar disorder was the extensive clinical experience and established usefulness of classical antipsychotics in manic disorder. Due to their rapid sedative and antipsychotic effect, these drugs proved to be useful in psychotic, agitated and hostile patients. However, their disadvantages are obvious. A significant shortcoming is the limited, or even the lack of, efficacy in prophylaxis.(1,2) While treating mania with a classical antipsychotic drug, the clinician fears the emergence of depressive symptoms.(3) The major disadvantages are the numerous side-effects, ranging from anticholinergic and cognitive side-effects to typical extrapyramidal syndromes (EPS)(4) and, in the worst cases, tardive dyskinesia.(5)
With their superior tolerability, atypical antiâ€‘psychotics may thus be more appropriate not only for schizophrenia but also for bipolar patients.
Monotherapy with atypical antipsychotics in bipolar disorder
Derivatives of clozapine: olanzapine and quetiapine
Clozapine can be considered as the very first atypical antipsychotic. Numerous case reports and several trials initiated by small investigators support its antimanic and antidepressive effects, as well as its good prophylactic efficacy, in bipolar patients.(6) However, all these data are derived from small and often poorly controlled investigator- initiated trials. Large-scale methodologically unambiguous studies are missing due to the lack of commercial interest and the potentially life-threatening side-effects of clozapine.
This situation is clearly different for the new generation of atypical antipsychotics, which emerged in the early 1990s. Two of these compounds, olanzapine and quetiapine, show receptor affinities similar to those of clozapine. Like clozapine, their D(2)-receptor occupancy level is lower than their affinity for histaminergic (H(1)) receptors, 5-HT(2A) receptors (for olanzapine) and Î±(1) receptors (for quetiapine). Both substances appear to be well tolerated. Agranulocytosis does not seem to be a problem; however, clinical experience from long-lasting use is still limited.
For acute mania, olanzapine has shown significant superiority over placebo in two double-blind placebo- controlled monotherapy studies.(7,8) This is of clinical importance, and similar studies with other atypical antipsychotics have shown that the improvement, as measured by the fall in the Young Mania Rating Scale (YMRS) scores, was not different in psychotic and nonpsychotic manic patients. Thus, improvement cannot be explained as a function of treatment of psychotic symptoms alone as, obviously, there are genuine effects on mood.
Every new potential mood stabiliser should not only beat placebo but also have efficacy at least comparable to that of clinical standards. Two double-blind placebo-controlled trials comparing olanzapine with valproate in acute mania led to inconclusive results,(9,10) with one demonstrating the superiority of olanzapine, while the other showed no difference in efficacy. These two trials may serve as examples that trial outcome, even if considered methodologically clean, clearly depends on dosing (which was different in both studies) and other methodological issues.
For quetiapine, two large-scale, placebo-controlled, double-blind monotherapy trials have just been published showing a significant advantage of quetiapine against placebo.(11,12) One trial additionally included haloperidol as a comparator arm, while the other used lithium as comparator. Haloperidol was superior to quetiapine at week 3, but the overall outcome after 12 weeks was similar for quetiapine and comparators.
Ziprasidone and risperidone
These two atypical antipsychotics are mainly defined by a pronounced serotonergic component of action, with both drugs having a similar occupancy profile for 5-HT(2A) receptors. Ziprasidone has additional occupancy for the 5-HT(1A) receptor. Dopaminergic D(2)-receptor affinity is relatively stronger than with clozapine, quetiapine or olanzapine, which may also result in higher incidence of EPS when overdosed.
Ziprasidone was tested for antimanic efficacy in two double-blind, placebo-controlled multicentre studies for three weeks,(13,14) and another study against placebo and haloperidol for 12 weeks.(15) In all three studies, ziprasidone was significantly superior to placebo in reducing manic symptomatology starting from day 2 until day 21, the endpoint of the study (p<0.01). In the PANSS positive subscale, the secondary outcome parameter, ziprasidone also showed a significant effect on psychotic symptoms in these manic patients. However, compared with haloperidol, ziprasidone was significantly less effective.
For risperidone, three double-blind placebo-controlled monotherapy trials have been conducted. All three trials showed a significant antimanic response with risperidone as compared with the placebo arm.(16-18) In one of these studies, conducted in India, a mean reduction of 21 points in the YMRS (Young Mania Rating Scale) was observed; this type of antimanic response has hardly ever been seen in any controlled phase III trial.(18) However, approximately one-third of patients had EPS (although rarely leading to study discontinuation). In another study, haloperidol served as an internal comparator, and no difference in efficacy was observed between risperidone and haloperidol.
The chemical structure and the receptor occupancy profile of aripiprazole appear slightly different from other atypical antipsychotics. Aripiprazole is a partial agonist of D(2) and 5-HT(1A) receptors. Its receptor binding affinity is high for D(2), D(3), 5-HT(1A) and 5-HT(2A), and moderate for D(4), alpha and H(1), while it has no affinity for M(1). Three acute mania studies have so far been published(19,20) or presented in scientific meetings.(21) They include two three-week studies against placebo and one 12-week study against haloperidol. Aripiprazole was superior, showing clear, significant separation from placebo at day 4 in one study, whereas in the other only a trend to higher efficacy was observed, mainly due to an extraordinarily high placebo response rate of 38%. No difference in efficacy was observed in the haloperidol comparator study at endpoint; however, aripiprazole was clearly better tolerated.
Atypical antipsychotics in combination treatment in acute mania
Monotherapy trials are needed to show unambiguous efficacy of a drug, even though combination treatment is the clinical reality. However, until recently, only a few controlled trials were designed to test efficacy in combination treatment. Some studies on this issue are now available for olanzapine, risperidone and quetiapine.(22-24) In at least one trial, all three agents could prove additional benefit when added to mood stabilisers (lithium or valproate) compared with mood stabiliser monotherapy. Studies have also been carried out on ziprasidone and aripiprazole, but have not been published yet.
Atypical antipsychotics in combination treatment for bipolar depression
So far, data are available for olanzapine and quetiapine. In a combined analysis of two double-blind eight-week trials, both olanzapine and the combination of olanzapine and fluoxetine differed significantly from placebo response in the Montgomery Asberg Depression Rating Scale (MADRS), the primary outcome criterion. However, the effect size of olanzapine monotherapy was low and reached statistical significance only from week 4 onwards, whereas the combination was clearly more efficacious.
For quetiapine, two randomised, double-blind, placebo-controlled studies (BOLDER I and II) have been conducted, of which one has recently been published.(25) Both studies proved significant ï¿½superiority of quetiapine (300 and 600mg) over placebo in reducing depressive symptoms. In contrast to the ï¿½olanzapine study, the effect size was much greater in both studies. In addition, quetiapine also showed significant effects on secondary outcomes, such as reduction of anxiety, quality of life and sleep.
Maintenance treatment with atypical antipsychotics
Olanzapine has been approved in several countries for long-term continuation treatment in patients responsive to olanzapine in acute mania.(26-28) Aripiprazole has also proven efficacy in preventing new manic episodes in a 26-week study.(29) Controlled long-term studies with other atypical antipsychotics are currently in progress. For risperidone and quetiapine, published controlled data are available for 12 weeks.(11,12,17) In addition, several atypical antipsychotics have been studied in open-extension trials (up to one year) after initial treatment for acute mania in a double-blind randomised design.
Tolerability and safety of atypical antipsychotics in bipolar patients
In general, there seems to be a consensus that the side-effects with atypical antipsychotics are lower than with typical antipsychotics, especially with respect to extrapyramidal motor symptoms.(30) This is an important issue, as it may determine patients’ compliance. Weight gain is clearly a disadvantage of clozapine and olanzapine; this effect is less pronounced in risperidone and quetiapine, whereas ziprasidone and aripiprazole are almost weight-neutral. Weight gain is also associated with the increased risk of cardiovascular mortality, which is 1.6 times higher in treated bipolar patients and 2.1 times higher in untreated bipolar patients, compared with the general population.(31) Thus, when choosing the appropriate atypical antipsychotic for treating bipolar patients, this issue should be kept in mind and discussed openly with the patient. The comprehensive character of this review does not allow a more detailed discussion of tolerability issues, but a review has recently been published on the topic.(32)
Atypical antipsychotics are an emerging treatment for bipolar patients. Both controlled and “real-life” studies with risperidone, olanzapine, ziprasidone, quetiapine and aripiprazole showed efficacy in treating acute mania. The atypical antipsychotics olanzapine and quetiapine also improve depressive symptoms in bipolar depressed patients. Controlled data support prophylactic efficacy, especially for olanzapine. A main advantage of atypical antipsychotics is their relatively good tolerability, at least compared with conventional antipsychotics. However, we still need more experience about efficacy and safety in long-term treatment. Large-scale, but simple, trials with atypical antipsychotics may broaden our knowledge about the “real-life” clinical effectiveness of this class of agents and also give us more information about long-term safety of these novel compounds.