Small Differences in Efficacy Among Second-Generation Antipsychotics for Schizophrenia  CME/CE

News Author: Marlene Busko
CME Author: Hien T. Nghiem, MD

Release Date: December 1, 2008; Valid for credit through December 1, 2009

Learning Objectives
Upon completion of this activity, participants will be able to:

Report the common adverse effects associated with certain second-generation antipsychotics in the treatment of schizophrenia.
Report the meta-analysis of blinded trials comparing each second-generation antipsychotic vs other second-generation antipsychotics in the treatment of schizophrenia.
Authors and Disclosures
Marlene Busko
Disclosure: Marlene Busko has disclosed no relevant financial relationships.

 

Hien T. Nghiem, MD
Disclosure: Hien T. Nghiem, MD, has disclosed no relevant financial relationships.

 

Laurie Scudder, MS, NP-C
Disclosure: Laurie Scudder, MS, NP-C, has disclosed no relevant financial information.

 

Brande Nicole Martin
Disclosure: Brande Nicole Martin has disclosed no relevant financial information.

 

 

December 1, 2008 — A meta-analysis examining the efficacy of second-generation antipsychotics in the treatment of schizophrenia shows that there are small differences, a finding that suggests other factors, including adverse effects and cost, should be considered in treatment choice.

"In tailoring drug treatment to the individual patient, small efficacy superiorities must be weighed against large differences in side effects and cost," the authors, led by Stefan Leucht, MD, Technical University of Munich, Germany, write.

The study is published online November 17 in the American Journal of Psychiatry.

High Stakes

Second-generation antipsychotics have become the most frequently prescribed antipsychotics for schizophrenia drugs in the United States.

According to the investigators, the stakes are high for patients, because the 4 second-generation antipsychotics that have been shown to be more efficacious than first-generation antipsychotics carry significant adverse effects, including substantial weight gain (clozapine and olanzapine), or substantially increase prolactin levels (amisulpride and risperidone).

While adverse effects are important, the researchers note that because schizophrenia is a lifelong illness, even a small increase in efficacy could increase the chances of living a healthier life.

To determine whether there are differences in efficacy among second-generation antipsychotics in the treatment of schizophrenia, the researchers conducted a meta-analysis of blinded, randomized studies with head-to-head comparisons of these drugs.

The analysis included 78 studies with 167 relevant groups and 13,558 participants.

The studies compared 2 or more of 9 drugs: amisulpride (9 studies), aripiprazole (4), clozapine (28), olanzapine (48), quetiapine (21), risperidone (44), sertindole (2), ziprasidone (9), and zotepine (2).

Most participants had relatively chronic illness, and their mean age was in the mid-30s.

Consistent Results

The primary outcome was the change in total score on the Positive and Negative Syndrome Scale (PANSS). Secondary outcomes included PANSS scores for positive symptoms such as hallucinations and delusions, PANSS scores for negative symptoms such as loss of pleasure and energy, and rate of dropout due to insufficient efficacy.

The PANSS total scores showed that olanzapine was more efficacious than aripiprazole, quetiapine, risperidone, and ziprasidone, and its efficacy was similar to that of amisulpride and clozapine.

Risperidone was less efficacious than olanzapine but more efficacious than quetiapine and ziprasidone.

Clozapine was superior to zotepine and, in doses greater than 400 mg/day, to risperidone.

These differences were due to improvements in positive symptoms rather than negative symptoms.

These efficacy findings are similar to those in phase 1 of the Clinical Antipsychotic Trials in Intervention Effectiveness, which found that olanzapine was more efficacious than risperidone, quetiapine, or ziprasidone.

The results are also consistent with a recent meta-analysis that compared second-generation with first-generation antipsychotics and showed that clozapine, amisulpride, olanzapine, and risperidone were significantly more effective than first-generation antipsychotics, while aripiprazole, quetiapine, ziprasidone, and zotepine were only as efficacious as the older drugs.

The most likely explanation of not finding clozapine superior here is that most studies used low or very low doses, they note.

Clinical Implications

The study has several clinical implications. First, the magnitude of the efficacy differences was small to medium. "On the other hand, schizophrenia affects patients for life, and even a small benefit may be important."

Second, the authors point out, rising healthcare costs are making medication cost an increasingly important consideration. They added that amisulpride, risperidone, zotepine, and the first-generation antipsychotics are all off-patent.

Third, large differences in adverse effects are often more important than small differences in efficacy in individual patients.

Finally, they write, there are substantial differences in how patients respond to these medications, and therefore clinicians need to balance efficacy and adverse effects according to each individual patient, the setting, and the health system.

The study was supported by grants from the German Federal Ministry of Education and Research, the National Institute for Mental Health's Advanced Center for Intervention and Services Research Center, and the Maryland Psychiatric Research Center. Dr. Leucht has received speaker and/or consultancy honoraria from sanofi-aventis, Bristol-Myers Squibb, Eli Lilly, Janssen/Johnson & Johnson, Lundbeck, and Pfizer and has received research funding from Eli Lilly and sanofi-aventis. Another study author (Christine Rummel-Kluge, MD) has received lecture honoraria and travel grants to attend scientific meetings from AstraZeneca, Janssen-Cilag, Eli Lilly, and Pfizer. The other study authors have disclosed no relevant financial relationships.

Am J Psychiatry. Published online November 17, 2008.

Clinical Context
Introduced in the 1990s, second-generation antipsychotic drugs became favored for the treatment of schizophrenia vs the first-generation antipsychotics because of their low propensity to cause extrapyramidal adverse effects. Moreover, meta-analyses have shown that some second-generation antipsychotics are more efficacious than first-generation antipsychotics. However, the stakes are high for patients because the 4 antipsychotics that have turned out to be more efficacious than first-generation antipsychotics are responsible for inducing substantial weight gain, glucose and lipid abnormalities (clozapine and olanzapine), or substantially increasing prolactin levels (amisulpride and risperidone). Despite these adverse effects, second-generation antipsychotics have become the most frequently prescribed drugs in some countries, including the United States. Whether there are differences in efficacy among second-generation antipsychotics in the treatment of schizophrenia is a matter of heated debate.

The authors conducted a systematic review and meta-analysis of blinded studies comparing second-generation antipsychotics head-to-head.

Study Highlights
In this meta-analysis, searches of the Cochrane Schizophrenia Group's register (May 2007) and MEDLINE (September 2007) were conducted for randomized, blinded studies comparing 2 or more of 9 second-generation antipsychotics in the treatment of schizophrenia.
Nonblinded studies were excluded because open studies favored the sponsor.
All data were extracted by at least 3 reviewers independently. Most studies available for analysis involved olanzapine (N = 48), followed by risperidone (N = 44), clozapine (N = 28), and quetiapine (N = 21), whereas few or no studies compared the other second-generation antipsychotics vs one another.
The primary outcome measure was change in total score on the PANSS; secondary outcome measures were positive and negative symptom subscores and rate of dropout from inefficacy.
Various sensitivity analyses and meta-regressions were used to examine bias.
The analysis included 78 studies with 167 relevant groups and 13,558 participants.
Olanzapine proved superior to aripiprazole, quetiapine, risperidone, and ziprasidone; its efficacy was similar to that of amisulpride and clozapine.
Risperidone was more efficacious than quetiapine and ziprasidone.
Clozapine proved superior to zotepine and, in doses of more than 400 mg/day, to risperidone.
For secondary outcome measures, these differences were because of improvement in positive symptoms vs negative symptoms.
The rates of dropout from poor efficacy were consistent with the primary outcome measure, except that clozapine was significantly more effective than risperidone and amisulpride was superior to ziprasidone.
Meta-regression did not detect significant effects of study duration, antipsychotic dosages or dose ratios, or study quality.
The 5 first-episode studies showed no difference between second-generation antipsychotics.
The results were rather robust with regard to the effects of industry sponsorship, study quality, dosages, and trial duration.
Limitations of meta-analyses must be considered to assess the findings.
Pearls for Practice
Despite being more efficacious than first-generation antipsychotics, the 4 second-generation antipsychotics are responsible for inducing substantial weight gain, glucose and lipid abnormalities (clozapine and olanzapine), or substantially increasing prolactin levels (amisulpride and risperidone).
The findings suggest that some second-generation antipsychotics may be somewhat more efficacious than others, but the limitations of meta-analysis must be considered.