The dopamine hypothesis of schizophrenia proposes that hyperactivity of dopaminergic transmission is associated with this illness, but direct observation of abnormalities of dopamine function in schizophrenia has remained elusive. We used a newly developed single photon emission computerized tomography method to measure amphetamineinduced dopamine release in the striatum of fifteen patients with schizophrenia and fifteen healthy controls. Amphetamine-induced dopamine release was estimated by the amphetamine-induced reduction in dopamine D2 receptor availability, measured as the binding potential of the specific D2 receptor radiotracer [1231] The dopamine hypothesis of schizophrenia, formulated over 30 years ago, proposes that hyperactivity of dopaminergic transmission is associated with this illness (1). This hypothesis is based on the observation that dopamine D2 receptor antagonists alleviate symptoms of the illness (mostly positive symptoms), while dopamine agonists can induce psychotic states characterized by some salient features of schizophrenia (2). These pharmacological effects suggest, but do not establish, a dysregulation of dopamine systems in schizophrenia. Despite decades of effort to validate this hypothesis, documentation of abnormalities of dopamine function in schizophrenia has remained elusive. Postmortem studies measuring dopamine and its metabolites in the brain of schizophrenic patients have yielded inconsistent results (for review, see ref.3). Increased density of striatal dopamine D2 and D2-like receptors has been reported in postmortem studies, but this observation is difficult to interpret, given that neuroleptic drugs upregulate these receptors (4, 5). Positron emission tomography and single photon emission computerized tomography (SPECT) studies of striatal D2 and D2-like receptors density in neurolepticnaive schizophrenic patients have been inconclusive. While one group reported increased striatal D2-like receptors density in schizophrenia (6, 7), other groups reported negative results (8-12). The lack of clear evidence for increased dopaminergic indices in schizophrenia might indicate that dopaminergic transmission is enhanced only relative to other systems, such as serotonergic or glutamatergic systems (13,14). On the other hand, the absence of data supporting the dopamine hypothesis of schizophrenia might be due to the difficulty of obtaining direct measurement of dopamine transmission in the living human brain.Over the past few years, several groups have provided evidence that competition between neurotransmitters and radioligands for neuroreceptor binding allows measuring changes in synaptic neurotransmitter levels with in vivo binding techniques. In rodents, decreased uptake of D2 radioligands has been measured following amphetamine and other dopamine enhancing drugs, whereas the opposite effect (i.e., increased tracer accumulation) has been induced by drugs that decrease dopamine concentration (15)(16)(17). In baboons, decreased specific uptake of positron emission to...

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Background D-serine is an allosteric modulator of the brain N-methyl-D-aspartate (NMDA) receptor and a potential novel treatment of schizophrenia. Double-blind studies have been performed at 30 mg/kg/day (~2 g/day) with encouraging results, but no formal dose escalation studies have been performed. We describe the first evaluation of the efficacy and safety of D-serine at doses >30 mg/kg/day; a 4-week, open-label trial of adjunctive D-serine (30, 60 or 120 mg/kg/day). Methods 42 antipsychotic-stabilized patients with schizophrenia or schizoaffective disorder participated. PANSS was obtained bi-weekly and neuropsychological (MATRICS) was obtained pre- and post medication phase. The pharmacokinetics/pharmacodynamics (PK/PD), and safety of doses ≥30 mg/kg was also evaluated. Results Significant improvement in symptoms and neuropsychological measures was noted across doses. On the PANSS, improvement was observed for positive (p=0.006;d=0.46), negative (p<0.001;d=0.68), general (p=0.001;d=0.53), and total (p<0.0001;d=0.74) symptoms. On MATRICS, while only non-significant improvement was noted at 30 mg/kg, highly significant, large effect size improvement was noted on the composite score (p<0.01;d=1.0) for doses ≥60 mg/kg, leading to a significant dose-by-time interaction (p<0.01). In PK analyses, significant dose-dependent increases in plasma D-serine levels were seen during the study, predictive of significantly increased brain levels. Furthermore, increases in plasma levels correlated with improved symptomatic and neuropsychological function. Discussion These findings support double-blind investigation of D-serine at doses ≥60 mg/kg/d, and suggest effectiveness in treatment of both persistent symptoms and neurocognitive dysfunction.

Objective This randomized trial addressed risks and benefits of staying on antipsychotic polypharmacy versus switching to monotherapy. Method Adult outpatients with schizophrenia taking two antipsychotics (127 participants across 19 sites) were randomly assigned to Stay on Polypharmacy or Switch to Monotherapy by discontinuing one antipsychotic. The trial lasted for 6 months, with a 6-month naturalistic follow-up. Kaplan-Meier and Cox regression analyses examined time to discontinuation of assigned antipsychotic treatment, and random regression models examined additional outcomes through time. Results Individuals assigned to Switch to Monotherapy had shorter times to all-cause treatment discontinuation than those assigned to Stay (p <.05). By month 6, 86% (n=48) of those assigned to Stay on Polypharmacy were still taking both medications whereas 69% (n=40) of those assigned to Switch to Monotherapy were still taking that monotherapy. Most monotherapy discontinuations entailed returning to the original polypharmacy. Groups did not differ with respect to psychiatric symptomatology or hospitalizations. The monotherapy group lost weight whereas the polypharmacy group gained weight. Conclusions Discontinuing one of two antipsychotics was followed by treatment discontinuation more often and more quickly than when both antipsychotics were continued. However, two thirds of participants successfully switched, groups did not differ with respect to symptom control, and switching to monotherapy resulted in weight loss. This supports the reasonableness of prescribing guidelines encouraging trials of antipsychotic monotherapy for individuals receiving antipsychotic polypharmacy, with the caveat that individuals should be free to return to polypharmacy if an adequate trial on antipsychotic monotherapy proves unsatisfactory.

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Deficits in gamma-amino-butyric acid (GABA) neurotransmitter systems have been implicated in the

These results are inconclusive about the role of monoaminergic dysregulation in recovering alcoholics. They also question the utility of these CSF measures to predict alcohol cue reactivity in patients who have been sober at least 1 month.