ACP-103, a 5-HT2A/2C inverse agonist, potentiates haloperidol-induced dopamine release in rat medial prefrontal cortex and nucleus accumbens.

Rationale: Atypical antipsychotic drugs (APDs) such as clozapine, olanzapine, quetiapine, risperidone, and ziprasidone are serotonin (5-HT)(2A) antagonists and relatively weaker dopamine (DA) D(2) antagonists, with variable 5-HT(2C) antagonist properties. The ability of atypical APDs to preferentially increase DA release in the cortex compared to the limbic system is believed to be due in part to their antagonism of 5-HT(2A) and D(2) receptors and believed to contribute to their beneficial effects on cognition, negative, and psychotic symptoms. Previous studies from this laboratory using microdialysis have shown that pretreatment of the 5-HT(2A) antagonist M100907 with the typical APD and D(2) antagonist haloperidol produced an increase in the medial prefrontal cortex (mPFC), but not in the nucleus accumbens (NAC), DA release.

Suggestive association between the C825T polymorphism of the G-protein beta3 subunit gene (GNB3) and clinical improvement with antipsychotics in schizophrenia.

G-proteins are composed of alpha, beta and gamma subunits. Once activated, these subunits play a major role in the conversion of external receptor activation into intracellular signals. The functional C825T polymorphism of the beta3 subunit gene (GNB3) has recently been shown to modulate antidepressant response, with the T-allele conferring an increased signaling and being associated with favorable antidepressant response.

Prevalence of the metabolic syndrome in patients with schizophrenia: baseline results from the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) schizophrenia trial and comparison with national estimates from NHANES III.

Unlabelled: One important risk factor for cardiovascular disease is the metabolic syndrome (MS), yet limited data exist on its prevalence in US patients with schizophrenia.

Methods: Using baseline data from the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) Schizophrenia Trial, assessment of MS prevalence was performed based on National Cholesterol Education Program (NCEP) criteria, and also using a fasting glucose threshold of 100 mg/dl (AHA). Subjects with sufficient anthropometric data, data on use of antihypertensives, hypoglycemic medications or insulin, and fasting glucose and lipid values >8 h from last meal were included in the analysis.

Occupancy of striatal and extrastriatal dopamine D2/D3 receptors by olanzapine and haloperidol.

There have been conflicting reports as to whether olanzapine produces lower occupancy of striatal dopamine D(2)/D(3) receptor than typical antipsychotic drugs and preferential occupancy of extrastriatal dopamine D(2)/D(3) receptors. We performed [(18)F] fallypride PET studies in six schizophrenic subjects treated with olanzapine and six schizophrenic subjects treated with haloperidol to examine the occupancy of striatal and extrastriatal dopamine receptors by these antipsychotic drugs. [(18)F] setoperone PET studies were performed in seven olanzapine-treated subjects to determine 5-HT(2A) receptor occupancy.

Valproic acid potentiates both typical and atypical antipsychotic-induced prefrontal cortical dopamine release.

Antipsychotic drugs (APD)s and anticonvulsant mood-stabilizers are now frequently used in combination with one another in treating both schizophrenia and bipolar disorder. We have recently reported that the atypical APDs, e.g.

Association study between a functional glutathione S-transferase (GSTP1) gene polymorphism (Ile105Val) and tardive dyskinesia.

A possible role for oxidative stress in the pathophysiology of tardive dyskinesia (TD) has previously been proposed (reviewed in Andreassen and Jorgensen [O.A. Andreassen, H.

Lithium differs from anticonvulsant mood stabilizers in prefrontal cortical and accumbal dopamine release: role of 5-HT(1A) receptor agonism.

Anticonvulsant mood stabilizers, e.g., valproic acid and carbamazepine, and atypical antipsychotic drugs (APDs), e.

N-desmethylclozapine, a major metabolite of clozapine, increases cortical acetylcholine and dopamine release in vivo via stimulation of M1 muscarinic receptors.

The active moiety of clozapine, the prototypical antipsychotic drug, consists of clozapine and its major metabolite, N-desmethylclozapine (NDMC). Previous studies have suggested that NDMC may be more important than the patent compound itself for the improvement in cognition in patients with schizophrenia treated with clozapine. While the pharmacology of clozapine and NDMC are similar in most respects, NDMC has been shown to be an M1 muscarinic receptor partial agonist whereas clozapine is an M1 antagonist in vitro and in vivo.

Combined analysis of 635 patients confirms an age-related association of the serotonin 2A receptor gene with tardive dyskinesia and specificity for the non-orofacial subtype.

Tardive dyskinesia (TD) is an important limiting factor in the use of typical antipsychotic drugs. Genetic variability in the serotonin 2A (5-HT(2A)) receptor may influence risk for TD but the results of prior studies are not confirmatory. The objective of this study was to determine association of T102C and His452Tyr polymorphisms in the 5-HT(2A) receptor gene (HTR(2A)) with TD in a large, multicentre patient sample.

Association study of 12 polymorphisms spanning the dopamine D(2) receptor gene and clozapine treatment response in two treatment refractory/intolerant populations.

Rationale: Dopamine D(2) receptor blockade is the major basis for the antipsychotic action of typical antipsychotic drugs (AP) and a necessary but not sufficient basis for the antipsychotic action of atypical APs such as clozapine and other multireceptor antagonists which rely, in part, upon 5-HT(2A) antagonism. Genetic factors affecting the density and/or function of D(2) receptors may therefore affect AP response.

Objectives: This exploratory study investigates the effect of 12 single nucleotide polymorphisms (SNPs) spanning the entire dopamine D(2) gene on clozapine response in two distinct schizophrenic populations (Caucasian and African-American) refractory or intolerant to conventional APs.

Prediction of the ability of clozapine to treat negative symptoms from plasma glycine and serine levels in schizophrenia.

We previously reported that plasma levels of glycine, a co-agonist at N-methyl-D-asparate (NMDA)-type glutamate receptors, are decreased in patients with schizophrenia, and that glycine levels are negatively correlated with negative symptoms. The aim of the present study was to determine if glycine, or its ratio to serine, a precursor of glycine, predicts change in negative symptoms in subjects with schizophrenia during treatment with clozapine, an atypical antipsychotic drug with multiple effects on glutamatergic activity. Plasma levels of glycine, serine, and their ratio, were measured in 44 patients with schizophrenia who were subsequently treated with clozapine.

A meta-analysis of neuropsychological change to clozapine, olanzapine, quetiapine, and risperidone in schizophrenia.

Cognitive impairment is a core feature of schizophrenia and a major impediment to social and vocational rehabilitation. A number of studies have claimed cognitive benefits from treatment with various atypical antipsychotic drugs (APDs). The currently available evidence supporting cognitive improvement with atypical APDs was evaluated in two meta-analyses.

The FOCIS international survey on psychiatrists' opinions on cognition in schizophrenia.

Background: The goal of this project was to develop an interview to evaluate psychiatrists' views on the nature of cognitive dysfunction in schizophrenia, its importance as a potential treatment target, and its relative importance as a treatment target across different phases of schizophrenia.

Materials And Methods: A survey (available in paper or on-line) consisting of 27 questions, was developed by the Focus on Cognition in Schizophrenia (FOCIS) group, and distributed in a single wave mailing to 63,295 psychiatrists in 21 countries worldwide.

Results: The overall response rate was 4.

A double-blind controlled study of adjunctive treatment with risperidone in schizophrenic patients partially responsive to clozapine: efficacy and safety.

Background: Several open trials and case studies have reported beneficial effects following the addition of risperidone for partial responders to clozapine. The purpose of this study was to carry out a placebo-controlled, randomized, double-blind trial of the efficacy, safety, and tolerability of adjunctive treatment with risperidone in patients with schizophrenia partially responsive to clozapine.

Method: In this 6-week double-blind study, 30 patients with DSM-IV schizophrenia who had partial response to clozapine despite being treated for a mean of 32 months were randomly assigned to risperidone (N = 16) up to 6 mg/day or placebo (N = 14).

Cellular changes in the postmortem hippocampus in major depression.

Background: Imaging studies report that hippocampal volume is decreased in major depressive disorder (MDD). A cellular basis for reduced hippocampal volume in MDD has not been identified.

Methods: Sections of right hippocampus were collected in 19 subjects with MDD and 21 normal control subjects.

Cognitive factors in schizophrenia: causes, impact, and treatment.

Greater attention has been given to the cognitive dimension in schizophrenia in recent years. This has resulted from increased recognition that cognitive impairment and negative symptoms of the disease have a greater impact on quality of life (QOL) compared to positive symptoms. Successful treatment of positive symptoms in patients with schizophrenia has not been shown to robustly translate into improvements in employment status or social relationships, while cognitive improvements are strongly associated with these important aspects of QOL and independence.

Cognitive functioning predicts outpatient service utilization in schizophrenia.

Aim of the study was to evaluate the cognitive and symptom predictors of outpatient service utilization in schizophrenia. The relationships between cognitive functioning (verbal learning and memory, executive functions), symptoms (positive symptoms, negative symptoms), and outpatient service utilization (case management, medication monitoring), were examined in 20 patients receiving outpatient services at a psychosocial clubhouse over a 12-month period. Executive functions, as measured on the Wisconsin Card Sorting Test (WCST), were the only significant predictor of outpatient service utilization, accounting for over 20% of the variance in total outpatient services used, with greater impairment associated with higher service utilization.

Clozapine increases both acetylcholine and dopamine release in rat ventral hippocampus: role of 5-HT1A receptor agonism.

Atypical antipsychotic drugs (APDs) such as clozapine, but not the typical APD haloperidol, improve some aspects of cognition in schizophrenia. This advantage has been attributed, in part, to the ability of the atypical APDs to markedly increase acetylcholine (ACh) and dopamine (DA) release in rat medial prefrontal cortex (mPFC), while producing a minimal effect in the nucleus accumbens (NAC) or striatum. The atypical APD-induced preferential release of DA, but not ACh, in the mPFC is partially inhibited by the selective 5-HT(1A) antagonist WAY100635.