No Evidence to Support Recommendation to Use Atypicals Over First-Generation Antipsychotic

American Psychiatric Association Practice Guideline Needs Updating, Researcher Says

Deborah Brauser

October 22, 2010

October 22, 2010 — Second-generation antipsychotics (SGAs), also known as aytypicals, are not superior to the first-generation antipsychotic perphenazine in treating depression in patients with chronic schizophrenia — a finding that contradicts the American Psychiatric Association Clinical Practice Guidelines, which specifically recommend SGAs in this population.

Using data from the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE), the investigators compared the SGAs olanzapine, quetiapine, risperidone, and ziprasidone with perphenazine, but found no significant between-class differences in improvement of depressive symptoms.

These finding "do not lend empirical support" to the recommendation by the American Psychiatric Association in its Clinical Practice Guidelines for schizophrenia that SGAs "may be specifically indicated for the treatment of depression" for this disorder, write the researchers.

Although a significant improvement in depressive symptoms was found in all treatment groups over time, subanalyses found that quetiapine was significantly more effective than risperidone in the patients having a major depressive episode (MDE) at study entry (P = .0056).

"I wasn't surprised at the overall findings, which went against Clinical Practice Guidelines," lead author Donald E. Addington, MD, professor in the Department of Psychiatry at the University of Calgary in Alberta, Canada, told Medscape Medical News.

The recommendation "generally said that [SGAs] are better than first-generation antipsychotics, based on their review of the studies that had been published prior to 2005," added Dr. Addington, was also involved in writing the Canadian clinical practice guidelines for schizophrenia.

"The recommendation needs to be updated," he added. "I think that when using antipsychotics for patients with schizophrenia and depression, clinicians should optimize the reduction in positive and negative symptoms as a first strategy and avoid high doses of antipsychotics that cause extrapyramidal side effects."

The study was published online September 21 in the Journal of Clinical Psychiatry.

The CATIE Project

"Since their introduction in the 1990s, [SGAs] have become the drugs of choice in the treatment of schizophrenia, despite a lack of conclusive evidence of superior efficacy as assessed by measures of general psychopathology," the investigators write.

There were many claims and meta-analyses that suggested that there were some benefits to the [SGAs], but there were very few large, rigorous studies designed to make fair comparisons.

Most SGA trials, "were designed as registration studies, usually having 3 arms: a new antipsychotic, a control active treatment — which was usually haloperidol, and placebo," said Dr. Addington. "With those studies, there were many claims and meta-analyses that suggested that there were some benefits to the [SGAs], but there were very few large, rigorous studies designed to make fair comparisons."

The original CATIE project was designed to compare the effectiveness of perphenazine to all SGAs available in January 2002 in the United States for the treatment of chronic schizophrenia, with the exception of clozapine.

A total of 1460 patients with schizophrenia between the ages of 18 and 65 years were enrolled between January 2001 and December 2004 at 57 US sites. Of these patients, 1428 were randomly assigned to receive 1 to 4 capsules daily, containing a total of 8 mg perphenazine (n = 256), 7.5 mg olanzapine (n = 328), 200 mg quetiapine (n = 326), 1.5 mg risperidone (n = 332), or 40 mg ziprasidone (n = 182).

"Ziprasidone was approved for use by the US Food and Drug Administration during the trial and was added in January 2002, after 40% of the sample had been recruited," note the study authors.

In addition, "patients with tardive dyskinesia were excluded from the randomization that included perphenazine," they write.

The main results, which were first published in 2005, showed no significant differences in efficacy, tolerability, or neurologic adverse effects between the SGA and perphenazine groups.

However, "patients treated with olanzapine remained on treatment with their medicine longer than those treated with quetiapine or risperidone and were less likely than all of those receiving other drugs to switch drugs for lack of efficacy," report the investigators. The olanzapine-treated patients also experienced substantial weight gain.

Depression Analysis

For this analysis, the investigators sought to specifically examine the effect of the different treatments on depressive symptoms in the same overall study population, as well as in a subgroup meeting criteria for a MDE at baseline (n = 448).

Depression was assessed using the Calgary Depression Scale for Schizophrenia, which was developed by Dr. Addington. All patients were evaluated at baseline and followed-up for 18 months.

Although the results showed no significant differences between any of the treatment groups, there was "a significant interaction found between treatment and experiencing an MDE at baseline (P = .05)," the investigators report.

"The main finding of this study is that we found no evidence of a class benefit of the use of SGAs compared with [first-generation antipsychotics] in the treatment of symptoms of depression, even in the subset that was above the baseline threshold for MDD," they summarize.

However, "depression was not the primary outcome measure for this study, and the sample size was not powered for this outcome. Thus, these analyses should be considered descriptive," they add.

Dr. Addington reported that he would now like to see research on the relationship between patients and extrapyramidal symptoms.

"We also need to look more carefully at the antidepressant effects of the different antipsychotics. That merits further basic laboratory and animal studies to understand whether this is a general property of antipsychotics or whether it's more specific to some of them rather than others," he explained.

Slight Depression Reduction "Distressing"

"These results were very similar to the primary results found in the earlier CATIE study, where basically the first-generation drug did pretty much as well as second-generation drugs," Ed Pigott, PhD, a psychologist with NeuroAdvantage LLC in Clarksville, Maryland, told Medscape Medical News.

Dr. Pigott, who was not involved in this study, noted that the overall CATIE project showed that 74% of the patients discontinued the study by the end of the 18-month trial either because of lack of efficacy or intolerable adverse effects.

"What's interesting to me in this study is that there's a slight decrease in overall depressive symptoms over the course of the 18 months, but that's really only for those who were continuing in the study," he said. "By definition, those should be the ones who are doing better. So that slight decline in symptoms over time is really underwhelming."

He also noted interest in the subgroup with MDE. "By the end of 18 months, they basically only had a 1- to 2-point reduction on their depressive score, which again is distressing because I would think you would expect much more.

Overall, clearly we haven't made much improvement in terms of going from first-generation meds to second-generation meds.

"Overall, clearly we haven't made much improvement in terms of going from first-generation meds to second-generation meds."

Dr. Pigott recently conducted a review of 4 meta-analyses of FDA trials, including the large Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study, which found that antidepressants were only marginally better than placebo.

He noted that this new study reminds him of a recent paper written by the director of the National Institute of Mental Health, Thomas R. Insel, MD (J Clin Invest. 2009;119:700-705).

"In 1 portion of it, Dr. Insel basically reviews various comparative effectiveness studies that the National Institute of Mental Health has funded, including the CATIE and the STAR*D studies. He makes the observation that despite their added costs, the second-generation psychotropic medications have been found to be no better than first-generation ones," said Dr. Pigott.

"His quote that resonates with me is, 'the unfortunate reality is that current medications help too few people to get better and very few people to get well.' And what we concluded in the STAR*D analysis was similar."

We really need to take more seriously looking at different combination therapies, different kinds of approaches to treatment if we're going to be able to make some meaningful improvement in patients' lives.

"I think we really need to [start] more seriously looking at different combination therapies, different kinds of approaches to treatment, if we're going to be able to make some meaningful improvement in patients' lives," said Dr. Pigott.

The original CATIE project was supported by the National Institute of Mental Health. Dr. Addington has disclosed no relevant financial relationships. However, 5 of the other 7 study authors report several potential conflicts, which are listed in the original article. Dr. Pigott reported consulting for CNS Response, Amen Clinics, EEG Spectrum, Neuronetics, and International Society of Neurofeedback and Research.

J Clin Psychiatry. Published online September 21, 2010.


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