February 2010

Second-Generation Antipsychotics: New Information
Second-generation antipsychotics differ from each other, offering options for patients.

Cognitive Effects of Antipsychotic Drugs: Are All Created Equal?
First- and second-generation antipsychotics appear comparable in their ability to lessen cognitive dysfunction associated with schizophrenia.

In Brief
Long-acting Injectable Olanzapine Approved in US; High-potency Cannabis May Increase Risk of Psychosis

Olanzapine and Sertraline Combined for Psychotic Depression
In a short-term trial, sertraline (Zoloft and others) combined with olanzapine (Zyprexa) was more efficacious than olanzapine plus placebo for psychotic depression in both young and elderly patients.

Second-Generation Antipsychotics: New Information

February 2010

It often takes decades to truly comprehend new medications. Gradually, we are coming to understand the diverse attributes of the second generation of antipsychotic agents. These drugs differ among themselves more than antipsychotics of the first generation. Their pharmacology, adverse effects, and possibility of patient response are more variable, presumably reflecting their different effects on neuronal systems. As more studies are conducted and disseminated, and the field gains more experience in a wide range of settings, new information is emerging about second-generation antipsychotics.

Three recent Cochrane reviews focused on these agents, and other data continue to come forward. Komossa and collaborators examined clinical trials comparing ziprasidone (Geodon) with other second-generation antipsychotics.1 In nine randomized controlled trials with over 3000 participants, the investigators found a surprisingly high discontinuation rate: 59.1%. Substantially more patients dropped out of studies early (for any reason) when they were taking ziprasidone compared with olanzapine (Zyprexa) or risperidone (Risperdal and others). Differences with other second-generation antipsychotics in early dropouts were not statistically significant. Comparisons also showed that ziprasidone was less efficacious than olanzapine or risperidone.

Turning to side effects, ziprasidone caused less weight gain and was associated with less cholesterol increase than olanzapine, quetiapine (Seroquel), or risperidone. Ziprasidone caused more extrapyramidal side effects than olanzapine and more prolactin increase than quetiapine, but fewer movement disorders and less prolactin increase than risperidone. Ziprasidone and clozapine were comparably tolerable.

Responding to a request by the U.S. Food and Drug Administration, Pappadopulos and coauthors analyzed all data on weight, lipids, and glucose from the manufacturer’s studies on ziprasidone.2 Double-blind trials included 1605 patients who took ziprasidone, 2 to 200 mg/day, and another 677 who took placebo. Subjects were 18 to 98 years old, and two-thirds were men. Confirming previous conclusions, the investigators found no clinically relevant negative mean changes in the metabolic parameters examined.

In another Cochrane review, Komossa and collaborators compared aripiprazole (Abilify) with other second-generation antipsychotics.3 Examining four trials with over 1400 participants, the investigators discovered a 38.5% early dropout rate (for any reason), but there was no significant difference in this measure between aripiprazole and comparison antipsychotics. Compared with olanzapine, aripiprazole was associated with less cholesterol increase, weight gain, sedation, and prolactin elevation, but it was also less efficacious. Aripiprazole was comparable in efficacy to risperidone and produced less dystonia, QTc abnormalities, and prolactin and cholesterol increases, but it did cause more tremor.

Kane and coworkers compared 16 weeks of adjunctive aripiprazole, 2 to 15 mg/day, with placebo for 323 patients with schizophrenia or schizoaffective disorder who had responded inadequately to quetiapine or risperidone.4 Adjunctive aripiprazole failed to produce added clinical benefits.

Reviewing optimal dosing of risperidone, Li and coworkers found that doses below 2 mg/day produced a higher early dropout rate due to insufficient response.5 Doses in excess of 10 mg/day were associated with more frequent extrapyramidal side effects. The authors conclude that for most patients, a target range between 4 and 6 mg/day optimizes clinical response versus adverse effects. There is weak evidence that doses between 2 and 4 mg/day may benefit patients in a first psychotic episode. Doses at or above 10 mg/day did not appear to confer any advantage over lower doses and caused more adverse effects, especially movement disorders. The authors deem doses below 2 mg/day to be “useless.”

In an independent report, Boter and associates describe an open randomized clinical trial—the European First-Episode Schizophrenia Trial (EUFEST)—in 14 countries comprising almost 500 patients with first-episode schizophrenia.6 Over 12 months, they found substantially higher response rates in patients treated with amisulpride,* olanzapine, quetiapine, or ziprasidone compared with haloperidol (Haldol and others). Of interest, olanzapine produced substantially higher 12-month remission rates (41%) than quetiapine (24%), ziprasidone (28%), or haloperidol (17%).

Leucht and coauthors reviewed the latest findings about second-generation antipsychotics, including data from the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE; BTP 2009;32:21-22, 34-35), the Cost Utility of the Latest Antipsychotic Drugs in Schizophrenia Study (CUtLASS; BTP 2009;32:34-35), and EUFEST.7 Comparing meta-analyses of these three large effectiveness trials, Dr Leucht’s group advises that second-generation antipsychotics are not homogeneous, and that, in fact, classifying them together is misleading. They note that experts interpret the same results differently, with some placing greater emphasis on cost, while others focus on adverse effects. Leucht et al conclude that second-generation antipsychotics are not the “breakthrough” that the pharmaceutical industry believes, but clinicians and patients together can individualize and, ideally, optimize treatment, taking advantage of the full range of medications available.

We concur with Leucht et al. Second-generation antipsychotics are not all we had hoped for and unquestionably different from each other. But these medicines do give patients with severe psychiatric conditions more options than they had earlier. With the second-generation, patients may respond to one drug who have not benefited or could not tolerate a different one. It falls to clinicians to discuss options with patients and family members and to dose these agents cautiously and knowledgeably.

*Not available in the United States.

1Komossa K, Rummel-Kluge C, Hunger H, Schwarz S, Bhoopathi PS, Kissling W, Leucht S: Ziprasidone versus other atypical antipsychotics for schizophrenia. Cochrane Database Syst Rev 2009;4:CD006627.

2Pappadopulos E, Kolluri S, Newcomer J: Changes in metabolic parameters in adult subjects in randomized, placebo-controlled studies of ziprasidone included in FDA-requested analyses. Poster presented at the 48th annual meeting of the American College of Neuropsychopharmacology, Hollywood, FL, December 6-10, 2009.

3Komossa K, Rummel-Kluge C, Schmid F, Hunger H, Schwarz S, El-Sayeh HGG, Kissling W, Leucht S. Aripiprazole versus other atypical antipsychotics for schizophrenia. Cochrane Database Syst Rev 2009;4:CD006569.

4Kane JM, Correll CU, Goff DC, Kirkpatrick B, Marder SR, Vester-Blokland E, Sun W, Carson WH, Pikalov A, Assunção-Talbott S: A multicenter, randomized, double-blind, placebo-controlled, 16-week study of adjunctive aripiprazole for schizophrenia or schizoaffective disorder inadequately treated with quetiapine or risperidone monotherapy. J Clin Psychiatry 2009;70:1348-1357.

5Li C, Xia J, Wang J: Risperidone dose for schizophrenia. Cochrane Database Syst Rev 2009;4:CD007474.

6Boter H, Peuskens J, Libiger J, Fleischhacker WW, Davidson M, Galderisi S, Kahn RS; EUFEST study group: Effectiveness of antipsychotics in first-episode schizophrenia and schizophreniform disorder on response and remission: An open randomized clinical trial (EUFEST). Schizophr Res 2009;115:97-103.

7Leucht S, Kissling W, Davis JM: Second-generation antipsychotics for schizophrenia: Can we resolve the conflict? Psychol Med 2009;39:1591-1602.