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Antipsychotics Effective and Safe in Patients With Chronic Schizophrenia: Presented at ECNP

By Chris Berrie

PARIS, FRANCE -- September 20, 2006 -- The second-generation antipsychotic olanzapine and the gold standard therapy clozapine appear to be more efficacious than the other second-generation antipsychotics in non-refractory patients with schizophrenia, with olanzapine also particularly associated with weight gain and metabolic changes.

The intermediate potency first-generation antipsychotics, like perphenazine (and potentially loxapine, molindone and thiothizene) appear comparably effective to the second-generation antipsychotics, and in moderate doses, they are also as well tolerated as the newer drugs.

These data were presented here on September 18^th at the 19^th Congress of the European College of Neuropsychopharmacology (ECNP) on behalf of the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) investigators.

Investigator Ira D. Glick, MD, professor of psychiatry and behavioural sciences, department of psychiatry, Stanford University School of Medicine, Stanford, California, said that the CATIE Trial is, "A National Institute of Mental Health (NIMH)-sponsored research programme to evaluate the effectiveness of antipsychotic medications for schizophrenia and Alzheimer's disease in broad patient populations and real-world settings."

This multicentre study was conducted in 3 well-defined phases, to compare relative effectiveness and costs among and between first-generation and second-generation antipsychotics. The primary outcome throughout is all-cause treatment discontinuation, with secondary outcomes including reasons for discontinuation, psychopathology, safety, service utilisation and costs, and neurocognition.

The study enrolled subjects aged 18 to 65 years of age diagnosed with schizophrenia using Diagnostic and Statistical Manual of Mental Disorders, Revision IV (DSM-IV) criteria. The study excluded subjects who were having a first episode, were treatment resistant, but allowed patients who were on concomitant medications, had medical illness, or substance use disorders. No adjunctive antipsychotics were allowed after randomisation.

The 1,460 patients who were assessed initially had an average age of 40.6 years, 74% were male; mean age at first psychiatric treatment was 24 years, and 28% had a schizophrenia exacerbation in the past 3 months. Mean Positive and Negative Syndrome Scale (PANSS) total score was 75.7; the clinically rated Clinical Global Impression of Severity (CGI-S) score was 4.0, indicating moderately illness. At baseline, patients were on a range of antipsychotic medications and under a number of medical diagnoses.

In phase 1 of the study, patients followed a double-blind, randomised treatment assignment to 1 of the following 5 antipsychotics: the second-generation antipsychotics, olanzapine 7.5 to 30 mg/day, quetiapine 200 to 800 mg/day, risperidone 1.5 to 6.0 mg/day or ziprasidone 40 to 160 mg/day, or the first-generation antipsychotics perphenazine 8 to 32 mg/day.

Results of phase 1 show a 74% rate of discontinuation, with olanzapine significantly showing the best efficacy (P </= .002 for all others), but worst adverse effects (including significantly higher weight and triglyceride increases; P < .001 for both). Perphenazine was comparable to the second-generation antipsychotics, which themselves showed no differential effects on symptoms.

Dr. Glick noted that there were differences in types and severities of adverse effects, and the results were consistent across multiple measures within domains.

All-cause discontinuations from phase 1 could then be randomised into the chosen pathway of phase 2, which provided the 2-fold choice for: (i) randomisation to open-label clozapine or a double-blinded second-generation antipsychotic (efficacy pathway); or (ii) double-blinded randomisation to ziprasidone or another second-generation antipsychotic (tolerability pathway).

For the efficacy pathway, there was a 65% rate of discontinuation. For primary, any-cause, outcome, after 18 months, clozapine showed significant efficacy over the others, at a 44% rate of efficacy without event (overall, P = .028); olanzapine followed at 29%, then risperidone at 14% and quetiapine at 7%.

With discontinuations for lack of efficacy, clozapine was again preferred (overall, P = .010), with its 11% discontinuation at 18 months producing significant hazard ratios in favour of clozapine: olanzapine, 0.24 (95% confidence interval [CI], 0.07-0.78; P = .019; 35% discontinuation); quetiapine, 0.16 (95% CI, 0.04-0.54; P = .004; 43% discontinuation); and risperidone, 0.16 (95% CI, 0.05-0.54; P = .003; 43% discontinuation).

The phase 2 tolerability pathway also showed high rates of all-cause discontinuation (70%), with risperidone (n = 104; 36% without event) and olanzapine (n = 108; 33%) showing more promise than ziprasidone (n = 137; 23%) and quetiapine (n = 95; 16%) (overall, P = .004).

There were significant weight gains (>7% from phase 2 baseline to last observation) across the treatment groups: olanzapine, 27%; risperidone, 13%; quetiapine, 6%; ziprasidone, 6% (overall, P = .009). Similarly, there were significant increases in cholesterol and triglyceride levels for olanzapine over the other treatments (P < .001 for both).

Dr. Glick said that all the tested drugs resulted in a slight improvement in cognition, with perphenazine being the most effective in this regard at the end of 18 months, although this was not a significant improvement.

Overall, all agents studied were generally effective, but they also all have various limitations, as seen in high rates of discontinuation, intolerable side effects and failure to control symptoms adequately, he concluded. However, for patients whose symptoms do not improve with initial treatment, clozapine, is the most effective alternative, followed by olanzapine. However, for patients who must switch medication due to adverse effects, the best choice alternative will depend on the individual adverse effects.

"Treatments for persons with schizophrenia must be individualised and [doctors] and patients must carefully evaluate the trade-offs between efficacy and side effects in choosing an appropriate medication," Dr. Glick said. He added that perphenazine is significantly less costly than the other medications in the study, while it is not significantly or substantially less effective than some of the alternative second-generation antipsychotics.

Dr. Glick received a grants from Bristol-Myers Squibb, GlaxoSmithKline, Janssen, Pfizer, Adadia, BMS, honoraria from AstraZeneca, Lilly, Janssen, Shire, Pfizer, BMS, owns shares of Forest, Johnson & Johnson, is on advisory boards for Janssen, Pfizer, BMS, Shire, Organon, Lilly, and holds a patent for the biopharmaceutical company Repligen.

*The initial safety and efficacy results for phases 1 and 2 have been reported in Lieberman et al., 2005, NEJM, 353, 1209-1223; McEvoy et al., 2006, Am J Psychiatry, 163, 600-610; Stroup et al., 2006, Am J Psychiatry, 163, 611-622.


[Presentation title: Effectiveness of Antipsychotic Drugs in Patients With Chronic Schizophrenia: Efficacy and Safety Outcomes of the CATIE Trial. Abstract S.14.04]

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