As with psychotic depression, dosing and duration of neuroleptic treatment are important concerns. In this context, Rifkin et al demonstrated that 10 mg of haloperidol per day had comparable efficacy but fewer adverse effects than did 30 or 80 mg per day in a group of acutely manic patients.12 Despite such data, high chlorpromazine-equivalent doses are often administered acutely and maintained for sustained periods. This can be a significant problem given the apparent great sensitivity of bipolar patients to the neurological sequelae of these antipsychotic agents.
Novel antipsychotics Early case series reports indicated that clozapine may benefit treatment-refractory bipolar patients. Given the inherent drawbacks of clozapine (e.g., agranulocytosis and seizure induction), attention now focuses on other novel agents with more benign adverse effect profiles than clopazine. Controlled trials with olanzapine and risperidone serve to reinforce the usefulness of these as well as other novel agents.
Tohen et al published the results of a 3-week, double-blind, placebo-controlled trial of olanzapine in 139 patients experiencing an acute bipolar manic or mixed episode.13 Olanzapine produced a statistically greater mean improvement than did the placebo on the Young Mania Rating Scale (YMRS) change scores. Further, 49% of the olanzapine-treated group (n=70) met the a priori criteria for response versus only 24% of the placebo-treated group (n=69). A second study using a higher starting dose of olanzapine, less rescue medication, and longer treatment duration than the first study resulted in a similar outcome.14
Sachs et al reported on the results of a 3-week, double-blind, placebo-controlled trial involving 156 patients with bipolar manic or mixed subtype who received a mood stabilizer (lithium or valproate) plus a placebo, risperidone (1 to 6 mg/d), or haloperidol (2 to 12 mg/d).15 The clinicians concluded that risperidone plus a mood stabilizer was statistically superior to a placebo plus a mood stabilizer, and produced more rapid reduction in manic symptoms, regardless of whether psychosis was present.
Sajatovic et al16 published the results of a prospective, open trial with quetiapine (mean dose = 203 ± 124 mg/d) as add-on therapy in 20 patients (10 bipolar, 10 schizoaffective; 19 male, 1 female) insufficiently responsive to their mood stabilizer or antipsychotic. Pre-post assessments indicated significant improvement in the BPRS, Mania Rating Scale (MRS), and HDRS scores. While the combination was generally well tolerated, there was a mean weight gain of 4.9 kg (10.8 lb). This raises the specter of complications associated with substantial weight gain produced by several of the novel antipsychotics.
A recent report indicates that ziprasidone may also be an effective antimanic agent. In a randomized, double-blind, placebo-controlled, multicenter trial involving 210 bipolar (manic or mixed episodes) patients, ziprasidone (80 to 160 mg/d; n=140) was compared to a placebo (n=70) for 3 weeks.17 By day 2 and all subsequent time points, ziprasidone was superior in terms of mean change scores from the baseline MRS; produced a more rapid and significantly greater improvement in overall psychopathology in both positive and negative symptoms; and did not produce significant adverse effects (including relevant ECG parameter changes) when compared with the placebo. Similar trials are being conducted for risperidone, aripiprazole, and iloperidone.
Finally, Meehan et al18 reported on the results of an acute parenteral formulation of olanzapine used to manage agitation in an acute manic or mixed episode. This was a 24-hour, double-blind, placebo-controlled trial comparing intramuscular olanzapine to intramuscular lorazepam. The following results were indicated:
- Olanzapine (doses of 5 to 10 mg) produced a significantly greater reduction in excitation than did the placebo or lorazepam at 30 minutes post-injection.
- Twice as many patients receiving lorazepam or a placebo versus olanzapine required more than one injection.
- Except for olanzapine-induced tachycardia in one patient, there were no significant changes in vital signs, ECG parameters, or laboratory assays among the three groups.
- Somnolence (13%) and dizziness (9%) were the most frequent side effects in the olanzapine group.
Treatment strategies for depression and mania
Considering the existing research data, clinical experience, and the risk/benefit ratio, treatment strategies that emphasize the role of antipsychotics in managing severe mood disorders are presented in the algorithms in Figures 1 and 2.
Figure 1 emphasizes the role of antipsychotics in the pharmacological management of patients with major depression. For unipolar depression with psychotic symptoms, options include an antidepressant plus an antipsychotic; amoxapine monotherapy; and possibly monotherapy with a novel agent such as ziprasidone. For bipolar depression with psychosis or schizoaffective disorder with depression, combining a mood stabilizer such as lithium plus an antipsychotic may be sufficient, but often an antidepressant must also be added. If the response is insufficient, consider switching to a novel antipsychotic (e.g., olanzapine or risperidone) plus a mood stabilizer (± antidepressant). In more serious exacerbations (e.g., high suicidality), ECT may be most appropriate. Secondary choices include clozapine with or without an antidepressant or novel antipsychotic such as risperidone combined with ECT.