Meltzer presents an informative review of antipsychotic drug action and serotonin (Meltzer 1999). However, his conclusion that new generation drugs with serotonin antagonism are efficacious for the primary negative symptoms of schizophrenia contrasts with our view (Carpenter 1995; Carpenter et al. 1995) and merits further consideration.

It is important to distinguish primary, or disease-based, negative symptoms from negative symptoms secondary to other sources (e.g., depressive anhedonia, neuroleptic akinesia, paranoid social withdrawal, sedative anergia) (Carpenter et al. 1998, 1993). The clinical trials cited by Meltzer (1999) do not make this distinction. Other studies have addressed primary negative symptoms by design and fail to support the efficacy hypothesis for clozapine (Buchanan et al. 1998; Conley et al. 1994; Rosenheck et al. 1999). A meta-analysis of these and other studies reaches similar conclusions (Wahlbeck et al. 1999). The view that new generation medications are not a therapeutic answer for trait negative symptoms of schizophrenia is further reinforced in the six-month controlled study in outpatients where neither haloperidol nor clozapine was associated with negative symptom improvement (Schooler et al. 1999), and in studies by Lieberman et al. (1994) and Tandon et al. (1993) where improvement appeared to be accounted for by secondary negative symptoms. Conley et al. (1998) also failed to observe negative symptom improvement with olanzapine. It is important to note that superior efficacy for psychosis was shown in each of the clozapine studies, so the lack of efficacy for negative symptoms was not a non-responsive cohort effect.

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