Changes in cerebral blood flow and mental state after amphetamine challenge in schizophrenic patients. Why olanzapine beats risperidone, risperidone beats quetiapine, and quetiapine beats olanzapine: an exploratory analysis of head-to-head comparison studies of second-generation antipsychotics. Acute d-amphetamine challenge in schizophrenia: effects on cerebral glucose utilization and clinical symptomatology. A single-blind study of clocapramine and sulpiride in hospitalized chronic schizophrenic patients.
Changes in regional cerebral blood flow and behavioral and physiological indices were monitored after intravenous administration of d-amphetamine sulfate and placebo in groups of patients with schizophrenia and normal volunteers. Amphetamine administration was associated with decreased anxiety, emotional withdrawal, depressed mood, blunted affect and increased excitement in the patients. Subjects who received amphetamine showed significant increases in systolic and diastolic blood pressure and reduction in end-tidal carbon dioxide. Post-amphetamine cerebral blood flow was decreased equally in both patients and controls. The blood flow change, however, did not show any regional variations. In many parts of the world, second-generation antipsychotics have largely replaced typical antipsychotics as the treatment of choice for schizophrenia. Consequently, trials comparing two drugs of this class--so-called head-to-head studies--are gaining in relevance. The authors reviewed results of head-to-head studies of second-generation antipsychotics funded by pharmaceutical companies to determine if a relationship existed between the sponsor of the trial and the drug favored in the study's overall outcome.
                The authors identified head-to-head comparison studies of second-generation antipsychotics through a MEDLINE search for the period from 1966 to September 2003 and identified additional head-to-head studies from selected conference proceedings for the period from 1999 to February 2004. The abstracts of all studies fully or partly funded by pharmaceutical companies were modified to mask the names and doses of the drugs used in the trial, and two physicians blinded to the study sponsor reviewed the abstracts and independently rated which drug was favored by the overall outcome measures. Two authors who were not blinded to the study sponsor reviewed the entire report of each study for sources of bias that could have affected the results in favor of the sponsor's drug.
                Of the 42 reports identified by the authors, 33 were sponsored by a pharmaceutical company. In 90.0% of the studies, the reported overall outcome was in favor of the sponsor's drug. This pattern resulted in contradictory conclusions across studies when the findings of studies of the same drugs but with different sponsors were compared. Potential sources of bias occurred in the areas of doses and dose escalation, study entry criteria and study populations, statistics and methods, and reporting of results and wording of findings.
                Some sources of bias may limit the validity of head-to-head comparison studies of second-generation antipsychotics. Because most of the sources of bias identified in this review were subtle rather than compelling, the clinical usefulness of future trials may benefit from minor modifications to help avoid bias. The authors make a number of concrete suggestions for ways in which potential sources of bias can be addressed by study initiators, peer reviewers of studies under consideration for publication, and readers of published studies. The effects of d-amphetamine (0.5 mg/kg orally) on regional cerebral glucose utilization were measured with positron emission tomography (PET) in 17 schizophrenics (along with a placebo-control group of an additional six schizophrenic patients). The acute d-amphetamine challenge tended to decrease glucose utilization throughout much of the brain, with a regional effect that was statistically significant in the left temporal cortex. There was no apparent relationship between the effects of amphetamine-induced changes in regional cerebral metabolism and psychotic symptom exacerbation. An exploratory analysis suggested that features characteristic of Crow's type II syndrome were significant predictors of cerebral hyporesponsivity to stimulant challenge, however. The therapeutic effects, safety and side-effects of clocapramine and sulpiride were evaluated in 52 hospitalized chronic schizophrenic patients using a single-blind method during an 8-week trial period. While the final global improvement rating showed clocapramine to be superior to sulpiride, the differences were not statistically significant. The time course of the total psychiatric rating scales (PRS) showed a progressive decline during treatment for both drugs, and at the end of treatment clocapramine proved significantly lower in total PRS than did sulpiride. In the improvement of psychotic symptoms, clocapramine seemed to be superior to sulpiride with respect to motor retardation, delusion, hallucination or disturbance of self-consciousness, social isolation or withdrawal, and recreation or work. Side-effects appeared more frequently with clocapramine than with sulpiride, but abnormal laboratory-test results appeared less in clocapramine-treated patients than in sulpiride-treated ones. Neither side-effects nor abnormal laboratory-test results induced by the two drugs were severe enough to terminate administration. Clocapramine is concluded to have a more favourable effect on negative symptoms, as well as on some positive symptoms of chronic schizophrenia, than sulpiride.
Understandably amphetamines are rarely formally evaluated in randomised studies and therefore unpublished work in this area is likely to exist. Addition of more studies may clarify reasons why people with schizophrenia persist in taking these harmful stimulants.