Second-Generation Antipsychotics May Not Always Be Best Option

Second-Generation Antipsychotics May Not Always Be Best Option

 

 

News Author: Pauline Anderson
CME Author: Charles Vega, MD

 

 

April 1, 2008 — Newer and more costly atypical antipsychotic drugs are not necessarily a better choice in first-episode schizophrenia and related disorders than the older agent haloperidol, according to the results of a new study.

The open, randomized controlled trial of daily oral doses of the first-generation antipsychotic medication haloperidol vs 4 second-generation antipsychotic medications showed that although compliance was substantially better with the newer drugs vs haloperidol, reduction in symptoms was virtually identical in all of the groups, at a clinically meaningful 60%.

"The importance of this study is that it shows that the pessimism that has pervaded the treatment options and drug response in schizophrenia (following large discontinuation rates in previous research) is not justified, at least in the early stages of the illness," René S. Kahn, MD, from the University Medical Centre, Utrecht, the Netherlands, one of the study's principal investigators, told Medscape Psychiatry. "Schizophrenia can be treated effectively."

The study, supported by funding from AstraZeneca, Pfizer, and sanofi-aventis, was published in the March 28 issue of The Lancet.

 

 

 

 

 

Pessimism Not Justified

 

Introduced more than a decade ago, second-generation antipsychotics were assumed to be more effective than previous drugs and were less likely to induce adverse effects such as dystonia and parkinsonism, the study authors write. However, research comparing the various drugs has not been conclusive. Studies used restrictive criteria leading to overrepresentation of men and underrepresentation of patients with comorbidities such as drug abuse, used doses of haloperidol that were too high, or had relatively short follow-up, the study authors note.

Among the strengths of this current study is its length (12 months), the inclusion of a broad range of patients (40% of whom were women, a percentage corresponding to the general population), and its clinically meaningful outcome measures, the study authors write. As well, it included patients in the early stages of schizophrenia who might respond differently to antipsychotic drugs than patients with chronic schizophrenia.

The study enrolled 498 patients aged 18 to 40 years at 50 sites in 14 countries (13 European countries and Israel) who were diagnosed with schizophrenia, schizophreniform disorder, or schizoaffective disorder. Patients were randomly assigned to 1 of 5 treatment groups: haloperidol (1 - 4 mg), amisulpride (200 - 800 mg), olanzapine (5 - 20 mg), quetiapine (200 - 750 mg), and ziprasidone (40 - 160 mg).

For the study, the researchers obtained baseline data on psychopathologic characteristics using the positive and negative syndrome scale (PANSS), severity of illness using the clinical global impression scale, overall functioning using the global assessment of functioning score, depression, quality of life, and sexual dysfunction. They also recorded various other parameters including weight, height, fasting blood glucose levels, and cholesterol.

A relatively low dose of haloperidol was used in the study because, according to the study authors, patients with first-episode schizophrenia tend to respond to low doses of antipsychotic drugs. Higher doses do not boost the antipsychotic effect and may increase adverse effects.

After 12 months, treatment discontinuation was substantially lower in all of the second-generation antipsychotic medication groups — especially among olanzapine users — vs the haloperidol group.

 

 

 

 

 

 

Table. Number of Patients Discontinuing Treatment by Antipsychotic Drug and Risk for Any-Cause Discontinuation vs Haloperidol

 

Drug	No. (Kaplan-Meier Estimate, %)	Hazard Ratio (95% CI)
Haloperidol	63 (72)	Referent
Amisulpride	32 (40)	0.37 (0.24 - 0.57)
Olanzapine	30 (33)	0.28 (0.18 - 0.43)
Quetiapine	51 (53)	0.52 (0.35 - 0.76)
Ziprasidone	31 (45)	0.51 (0.32 - 0.81)

 

"Patients clearly stayed on olanzapine much longer than on haloperidol, which is an important consideration," commented Dr. Kahn in an email interview.

 

 

 

 

 

 

Clinically Meaningful Response

 

Reduction in symptoms (PANSS) and rates of admission to the hospital did not differ significantly among groups. PANSS recordings were reduced approximately 35 points from a baseline total of 88.5, which translates into a symptom reduction of approximately 60%, a response the study authors called "clinically meaningful."

"Although patients stayed longer on SGAs [second-generation antipsychotics] than on the FGA [first-generation antipsychotic] haloperidol, in symptomatic improvement the drugs showed no difference," said Dr. Kahn. "Thus in some respects — compliance for instance — the newer drugs may be better but in other respects, they may not be."

Adverse effects varied depending on treatment. It is noteworthy that more patients taking haloperidol showed signs of parkinsonism. "Haloperidol induces — even in this low dose — more motor side-effects than some of the SGAs, for example, olanzapine and quetiapine," commented Dr. Kahn.

"We conclude that although the high continuation rates for several of the second-generation antipsychotic drugs suggest that clinically meaningful long-term antipsychotic treatment is achievable in the first episode of schizophrenia, it cannot be concluded that second-generation antipsychotic drugs are more efficacious than is haloperidol in the treatment of these patients," the study authors write.

 

 

 

 

 

 

 

Even Less Ground for Enthusiasm

 

 

In an accompanying editorial, Robert A. Rosenheck, MD, from the Veterans Administration Connecticut Health Care System, in West Haven, noted that the reduced risk for neurologic adverse effects associated with the newer drugs may not justify their added expense and that this benefit may be offset by metabolic risk and weight gain, although differences in weight gain in this study were not significant.

"There clearly seems to be much less, if any, ground for enthusiasm about these costly drugs now than in 2002" when the study began, he writes.

Researchers need to face "head on" whether newer atypical antipsychotics should be limited to cases in which they are specifically indicated (eg, in the presence of tardive dyskinesia). "Addressing this question poses a major challenge to both cost-effectiveness assessment and to mental-health policy making," Dr. Rosenheck concludes.

The study was supported by funding from AstraZeneca, Pfizer, and sanofi-aventis. Dr. Kahn has received grants, honoraria for education programmes, or served as a consultant for Astellas, AstraZeneca, Bristol-Meyers Squibb, Eli Lilly, Janssen-Cilag, Pfizer, Roche, and sanofi-aventis. The complete list of disclosures is available in the original article.

Dr. Rosenheck has disclosed no relevant financial relationships.

The Lancet. 2008:371:1048-1049, 1085-1097.

Clinical Context

Although second-generation antipsychotics were introduced to improve both the efficacy and tolerability in the treatment of schizophrenia, the authors of the current study question the evidence supporting these benefits. They note that previous studies of second-generation antipsychotics overrepresented men and excluded patients with comorbid conditions, such as substance abuse. Many studies evaluated patients for less than 2 months' duration and may have used doses of haloperidol (as a comparator medication) that were unnecessarily high.

The current study uses a primary outcome important in clinical practice — continuation of antipsychotic medication at 1 year — to compare first-generation and second-generation antipsychotics among patients with a first episode of schizophrenia or schizophreniform disorder.

Study Highlights

• Study participants were between the ages of 18 and 40 years and were recruited from 1 of 50 centers in Europe and Israel. All subjects had schizophrenia, schizophreniform disorder, or schizoaffective disorder according to criteria from the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition.
• Subjects with positive symptoms of schizophrenia for more than 2 years or who had received antipsychotic medications for 6 weeks at any time were excluded from study participation.
• Participants were randomized to receive daily doses of 1 of the following antipsychotic medications: haloperidol 1 to 4 mg, amisulpride 200 to 800 mg, olanzapine 5 to 20 mg, quetiapine 200 to 750 mg, or ziprasidone 40 to 160 mg.
• The primary outcome of the study was the rate of treatment discontinuation at 1 year. Treatment discontinuation was defined as the use of a medication dose outside of the range defined above, the use of an additional antipsychotic medication, or complete discontinuation of the medication. Secondary outcomes included multiple measures of antipsychotic efficacy and adverse events.
• 498 participants underwent randomization. Baseline data were similar among study groups. The mean age was 26 years, and 40% of subjects were women. Schizophrenia and schizophreniform disorder were diagnosed in 53% and 40% of participants, respectively.
• The mean daily doses of haloperidol, amisulpride, olanzapine, quetiapine, and ziprasidone before discontinuation of treatment were 3.0, 450.8, 12.6, 498.6, and 107.2 mg, respectively.
• Overall discontinuation of treatment was less likely with second-generation antipsychotics vs haloperidol. The respective rates of treatment discontinuation for haloperidol, amisulpride, olanzapine, quetiapine, and ziprasidone were 72%, 40%, 33%, 53%, and 45%.
• Rates of treatment discontinuation from a lack of efficacy also favored the second-generation antipsychotics.
• Discontinuation of treatment caused by adverse events was lower with olanzapine and quetiapine vs haloperidol.
• There was no difference between haloperidol and the second-generation antipsychotics in the rate of treatment discontinuation from nonadherence.
• The second-generation antipsychotics promoted reduced severity of illness and improved functioning vs haloperidol, but several other measures of treatment efficacy were similar when the second-generation antipsychotics and haloperidol were compared.
• Rates of hospitalization did not differ between treatment groups.
• Haloperidol was associated with higher rates of parkinsonism than the second-generation antipsychotics, and haloperidol and ziprasidone increased the rate of akathisia vs the other drugs.
• More subjects receiving olanzapine used antidepressants vs the other study medications. The incidence of significant weight gain was high in the study cohort but did not differ between among the medications, although olanzapine was associated with the highest mean weight gain.

Pearls for Practice

• Previous studies of second-generation antipsychotic medications for the treatment of schizophrenia may have overrepresented men and excluded patients with comorbid conditions, such as substance abuse. Many studies were less than 2 months' duration and used doses of haloperidol (as a comparator medication) that were too high.
• In the current study of patients with first-episode schizophrenia, haloperidol was associated with a higher rate of treatment discontinuation vs second-generation antipsychotic medications, although these medications were generally similar in terms of treatment efficacy.