Acute Mania: Not All Antipsychotics Are Created Equal

Deborah Brauser

August 16, 2011

August 16, 2011 — Although antipsychotic medications overall are significantly more effective than mood stabilizers in treating acute mania, some are much better than others, new research suggests.

In a meta-analysis of 68 randomized, controlled trials (RCTs), investigators showed that treatment with the antipsychotics haloperidol, risperidone, olanzapine, quetiapine, aripiprazole, asenapine, and ziprasidone (and the mood stabilizers lithium, carbamazepine, and valproate) significantly decreased mania rating scores after 3 weeks compared with placebo.

However, the mood stabilizers gabapentin, lamotrigine, and topiramate were not significantly more effective than placebo.

Dr. Andrea Cipriani

Haloperidol provided the most significant score differences compared with placebo as well as many of the other study drugs. However, risperidone and olanzapine appeared to have had the lowest discontinuation rates.

"Risperidone, olanzapine, and haloperidol should be considered as among the best of the available options for the treatment of manic episodes," write Andrea Cipriani, MD, PhD, lecturer of Psychiatry at the University of Verona, Italy, and visiting fellow at the University of Oxford, United Kingdom, and colleagues.

Risperidone, olanzapine, and haloperidol should be considered as among the best of the available options for the treatment of manic episodes.

"These results should be considered in the development of clinical practice guidelines."

The study is published online August 17 in the Lancet.

Haloperidol Tops the List

According to the analysis, mania affects about 1% of the population, but "conventional meta-analyses have shown inconsistent results" for the efficacy of medications in treating acute mania.

"It is already known that many antimanic agents are more effective than placebo, but this was the first time all antimanic agents licensed for acute mania were compared each other and ranked according to efficacy and acceptability," Dr. Cipriani told Medscape Medical News.

They evaluated data on 16,073 adults from 68 RCTs conducted between January 1980 and November 2010. All participants had a primary diagnosis of bipolar 1 disorder with manic or mixed episodes.

The primary outcome measures were mean change scores on the Young Mania Rating Scale and number of patients who discontinued treatment at 3 weeks.

Results showed that 10 of the 13 medications studied were significantly more effective than placebo.

Table 1. Mean Change Score on Young Mania Rating Scale With Placebo

Medication Standardized Mean Difference (95% CI)
Haloperidol -0.56 (-0.69 to -0.43)
Risperidone -0.50 (-0.63 to -0.38)
Olanzapine -0.43 (-0.54 to -0.32)
Lithium -0.37 (-0.63 to -0.11)
Quetiapine -0.37 (-0.51 to -0.23)
Aripiprazole -0.37 (-0.51 to -0.23)
Carbamazepine -0.36 (-0.60 to -0.11)
Asenapine -0.30 (-0.53 to -0.07)
Valproate -0.20 (-0.37 to -0.04)
Ziprasidone -0.20 (-0.37 to -0.03)

CI = confidence interval

Haloperidol had the highest number of significant differences and was significantly more effective than all study drugs except for risperidone and olanzapine.

Table 2. Mean Change Score on Young Mania Rating Scale for Haloperidol vs Other Medications

Haloperidol vs: Standardized Mean Difference (95% CI)
Gabapentin -0.88 (-1.40 to -0.36)
Topiramate -0.63 (-0.84 to -0.43)
Lamotrigine -0.48 (-0.77 to -0.19)
Ziprasidone -0.36 (-0.56 to -0.15)
Valproate -0.36 (-0.56 to -0.15)
Asenapine -0.26 (-0.52 to -0.01)
Carbamazepine -0.20 (-0.36 to -0.01)
Aripiprazole -0.19 (-0.36 to -0.02)
Quetiapine -0.19 (-0.37 to -0.01)
Lithium -0.19 (-0.36 to -0.01)

CI = confidence interval

"Risperidone and olanzapine had a very similar profile [to haloperidol] of comparative efficacy, being more effective than valproate, ziprasidone, lamotrigine, topiramate, and gabapentin," report the investigators.

Patients treated with olanzapine, risperidone, and quetiapine had significantly fewer discontinuations (odd ratio [OR], 0.57, 0.61, and 0.64, respectively) than did patients treated with placebo. They also had fewer dropouts than those treated with lithium (OR, 1.05), lamotrigine (OR, 1.22), topiramate (OR, 1.51), and gabapentin (OR, 1.76).

Haloperidol had a dropout rate OR of 0.85, which was significantly inferior to olanzapine.

The researchers report that they found "no usable data" for the antipsychotic chlorpromazine, so did not include it in this analysis.

"All statements comparing the merits of 1 medicine with another must be tempered by the potential biases and uncertainties that result from choice of dose and choice of patients," they write.

"Our results apply only to the acute manic phase of bipolar disorder and do not inform the clinically important issue of which pharmacological treatments best prevent relapse and stabilized mood in the medium and long term," add the investigators.

Still, they note that the findings underscore "the need for new treatments to show either greater efficacy or acceptability than the existing best standard treatments and serve as a disincentive to the development of drugs that offer little to patients other than increased costs."

"In the field of psychopharmacology, there are new treatments that have been recently marketed for acute mania. This study shows that clinicians should be aware that these new compounds are not better — and possibly worse — than the older ones [and] are much more expensive," said Dr. Cipriani, noting that their analysis received no funding, including anything from the pharmaceutical industry.

A Clear Winner?

Dr. Michael Berk

"These findings are likely to attract much interest and have a substantial effect both on clinical practice guidelines and real-world treatment," write Michael Berk, MD, PhD, professor of psychiatry in the School of Medicine at Deakin University, Geelong, Australia, and Gin S. Malhi, MD, from the CADE Clinic, Department of Psychiatry at the Royal North Shore Hospital in Sydney, in an accompanying editorial.

These findings are likely to attract much interest and have a substantial effect both on clinical practice guidelines and real-world treatment.

This makes the understanding of the "true comparative effectiveness" of these medications crucial, they add.

"Haloperidol seems to have won the race for pole position in the treatment of acute mania. However, the management of manic episodes…is not the overriding therapeutic imperative in this polyphasic and capricious disorder," write the editorialists.

"Instead, the main goals of treatment are attention to long-term mood stability and prophylaxis."

They note that promoting haloperidol as a first-line treatment for acute mania is therefore "problematic" because it lacks maintenance efficacy for depression and may increase the risk for incident depression.

"In this context, the successful management of bipolar disorder requires the implementation of therapeutic strategies that balance long-term tolerability and effectiveness. Although the findings of this analysis are undoubtedly important, the results have to be interpreted within a wider clinical context."

Dr. Cipriani and 7 study authors have disclosed no relevant financial relationships. The 2 other investigators and the editorialists report several disclosures, which are listed in the original article.

Lancet. Published online August 17, 2011.


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