Medical Pharmacology Chapter 16:  Pharmacology of Antipsychotics Drugs

• First Generation Antipsychotic Medications

  • Clinical Efficacy

  • Clinical Efficacy

    • Acute Psychosis

      • The evidence base for FGA efficacy in acute schizophrenia was established in part by the National Institute of Mental Health (NIMH) Collaborative Study Group, which published results in 1964 from one of the largest randomized, double-blind, placebo-controlled trials of antipsychotics conducted in the United States.⁵

        • Across ten Veterans Administration hospitals, patients hospitalized with acute schizophrenia were randomized to chlorpromazine, thioridazine, fluphenazine, or placebo.

          • All three phenothiazines significantly outperformed placebo on global improvement, symptom reduction, and rates of clinical remission. Crucially, the study demonstrated that antipsychotic efficacy was a class effect, not specific to any single agent.

      • In acute settings, FGAs reliably reduce positive symptoms, including hallucinations, delusions, disorganized thought, and agitated behavior, within days to weeks of initiation.

        • Response rates in acute schizophrenia typically range from 60% to 80% with adequate dosing.

        • Negative symptoms (affective blunting, alogia, avolition) and cognitive deficits are less responsive to FGAs and may, in some patients, be exacerbated by excessive D₂ blockade in the mesocortical pathway.

    •  Maintenance Therapy and Relapse Prevention

      • Davis's 1975 meta-analysis of 24 randomized controlled trials rigorously established the case for continuous antipsychotic maintenance therapy.⁶

        • Across studies, relapse occurred in approximately 55% of patients who discontinued antipsychotics, compared with 19% of those who remained on treatment, a clinically and statistically decisive difference.

          • This work provided the conceptual foundation for the modern standard of care: indefinite antipsychotic maintenance for patients with schizophrenia, particularly those with multiple prior episodes.

        • These findings were confirmed in a 2012 Cochrane-style systematic review and meta-analysis by Leucht and colleagues, which pooled data from 65 randomized controlled trials and over 6,000 participants.⁸

          • Antipsychotic drugs reduced the risk of relapse over one year by approximately 64% compared with placebo (relative risk 0.35, 95% CI 0.27–0.45).

            • The number needed to treat (NNT) to prevent one relapse was approximately 3.

              • These data provide a powerful argument for maintenance pharmacotherapy even in patients who have achieved remission.

    • Comparative Effectiveness: The CATIE Trial

      • The Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) study, published in 2005, was a landmark NIMH-funded pragmatic trial that enrolled 1,493 patients with chronic schizophrenia and randomized them to olanzapine, quetiapine, risperidone, ziprasidone, or the FGA perphenazine.⁷

        • The primary outcome, time to discontinuation of treatment for any cause, did not significantly differ between perphenazine and most of the second-generation agents.

        • Olanzapine had the longest time to discontinuation but was associated with substantially greater metabolic adverse effects.

          • Perphenazine was as effective as most Second generation antipsychotics (SGAs) in the trial and was notable for causing fewer metabolic side effects, though it did produce more EPS (Extrapyramidal symptoms), particularly in patients who had been excluded from the FGA arm due to prior Tardive Dyskinesia (TD).

      • The CATIE trial results were broadly corroborated by the 2009 meta-analysis by Leucht and colleagues, which compared nine SGAs against FGAs across 150 randomized controlled trials.¹⁴

        • Only four Second Generation Antipsychotics (SGAs), clozapine, amisulpride, olanzapine, and risperidone, demonstrated superior overall efficacy compared with FGAs, with effect sizes in the small-to-moderate range.

          • The remaining SGAs were not more efficacious than FGAs even for negative symptoms.

            • This meta-analysis firmly challenged the notion that SGAs, as a class, represent a fundamental therapeutic advance over FGAs in efficacy terms. therapeutic advance over FGAs in efficacy terms.

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