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. Lamotrigine in treatment-resistant schizophrenia: a randomized placebo-controlled crossover trial. Augmenting atypical antipsychotics with a cognitive enhancer (donepezil) improves regional brain activity in schizophrenia patients: a pilot double-blind placebo controlled BOLD fMRI study. A double-blind, placebo controlled, cross-over trial of adjunctive donepezil for cognitive impairment in schizophrenia. Randomized controlled trial of brief cognitive-behavioural interventions among regular users of amphetamine. Randomized, placebo-controlled study of ethyl-eicosapentaenoic acid as supplemental treatment in schizophrenia.
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. There is no evidence from randomized, controlled trials that demonstrate effectiveness for any pharmacological treatment in clozapine-resistant schizophrenia. Since the introduction of chlorpromazine, all antipsychotics with proven efficacy on positive symptoms have been dopamine antagonists, but recent experimental data suggest that ketamine-induced positive schizophreniform symptoms in healthy subjects can be controlled by a glutamate antagonist lamotrigine. The hypothesis tested was that lamotrigine is more effective than placebo in the treatment of positive schizophrenic symptoms when combined with clozapine.
                Thirty-four hospitalized treatment-resistant patients having chronic schizophrenia participated in a double-blind, placebo-controlled, 14-week, crossover trial where 200 mg/day lamotrigine was gradually added to their ongoing clozapine treatment. Clinical assessments were made by the Positive and Negative Syndrome Scale at the beginning and end of each treatment period.
                In intention-to-treat analysis, lamotrigine treatment was more effective in reducing positive (effect size.7, p =.009) and general psychopathological (effect size.6, p =.030) symptoms, whereas no improvement was observed in negative symptoms.
                These results provide the first evidence from a randomized controlled trial of an effective pharmacological treatment with an anticonvulsant agent in treatment-resistant schizophrenia and indicate that both positive and general psychopathological symptoms in patients with schizophrenia can be controlled by a drug that is not a dopamine antagonist. The results are in line with previous experimental data suggesting that excessive glutamate neurotransmission contributes to the positive symptoms of schizophrenia. Cognitive impairments are cardinal features of schizophrenia and predictors of poor vocational and social outcome. Imaging studies with verbal fluency tasks (VFT) lead some to suggest that in schizophrenia, the combination of a failure to deactivate the left temporal lobe and a hypoactive frontal lobe reflects a functional disconnectivity between the left prefrontal cortex and temporal lobe. Others have theorized that an abnormal cingulate gyrus modulates such fronto-temporal connectivity. Thus addition of a cognitive enhancing medication to current antipsychotic therapy might improve functionality of networks necessary in working memory and internal concept generation. To test this hypothesis, we serially measured brain activity in 6 subjects on stable atypical antipsychotics performing a VFT, using BOLD fMRI. Measurements were made at baseline and again after groups were randomized to receive 12 weeks of donepezil (an acetylcholinesterase inhibitor) and placebo in a blind cross-over design. Donepezil addition provided a functional normalization with an increase in left frontal lobe and cingulate activity when compared to placebo and from baseline scans. This pilot study supports the cingulate's role in modulating cognition and neuronal connectivity in schizophrenia. Although there have been several case reports suggesting the beneficial effect of acetylcholinesterase inhibitors in the cognitive deficits seen in schizophrenia, controlled studies have revealed contradictory results. The aim of this study was to investigate if donepezil could improve cognitive functions in schizophrenia. Twelve schizophrenic patients, who were diagnosed according to DSM-IV criteria and who had been on a stable dose of a high-potency typical antipsychotic for a minimum period of 3 months, participated in this 12-wk double-blind, placebo controlled, cross-over study of donepezil adjunctive treatment. Patients were randomly assigned under double-blind conditions to receive 5 mg/d donepezil or placebo for 6 wk, and then were crossed over to the alternate condition for 6 additional weeks. At baseline, 6 and 12 wk, patients were evaluated with the Positive and Negative Syndrome Scale (PANSS), Calgary Depression Scale, the Wechsler Memory Scale Revised (WMS-R), a test for Verbal Fluency, Trail Making Test, Parts A and B, and Wisconsin Card Sorting Test (WCST). Treatment effect was not significant in any of the cognitive measures. There were also no significant changes in the PANSS and depression scores. Nicotinic receptor desensitization may cause non-responsiveness to acetylcholine as previously suggested, but the most likely explanation appears to be that defects in other neurotransmitter systems account for the cognitive deficits seen in schizophrenic patients. To identify whether brief cognitive-behavioural interventions are feasible among regular users of amphetamine, to assess the effectiveness of intervention overall and to pilot two- and four-session interventions.
                Subjects were assigned randomly to individually receive a cognitive-behavioural intervention (n = 32) of either two or four sessions' duration or a self-help booklet (control condition; n = 32).
                Subjects were volunteers recruited from needle exchange schemes and treatment centres in Newcastle, Australia.
                Regular (at least monthly) users of amphetamine were recruited.
                Either four sessions of cognitive-behaviour therapy, consisting of a motivational interview and skills training in avoidance of high-risk situations, coping with craving and relapse prevention, or two sessions consisting of a motivational interview and discussion of skills.
                The Opiate Treatment Index was the main measure at pre-treatment and 6-month follow-up.
                There was a significant reduction in amphetamine use among the sample as a whole, with inconclusive differences between intervention subgroups. There was a moderate overall intervention effect, with the intervention group reporting over twice the reduction in daily amphetamine use as the control group. Significantly more people in the cognitive-behavioural intervention condition abstained from amphetamine at 6-month follow-up compared to the control condition.
                Brief cognitive-behavioural interventions appear feasible among regular users of amphetamine. A larger randomised controlled trial of the effectiveness of such interventions appears warranted. The study investigated the efficacy and tolerability of ethyl-eicosapentaenoic acid (E-EPA) as add-on treatment in chronic, severe schizophrenia.
                A randomized, parallel-group, double-blind, placebo-controlled, fixed-dose, add-on study was conducted over 12 weeks. Forty patients with persistent symptoms after at least 6 months of stable antipsychotic treatment received E-EPA or placebo, in addition to their existing treatment.
                At 12 weeks, the E-EPA group had significantly greater reduction of Positive and Negative Syndrome Scale total scores and of dyskinesia scores than the placebo group.
                EPA may be an effective and well-tolerated add-on treatment in schizophrenia.
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.