Antipsychotic-treated Subjects Research Articles

α2A- and α2C-adrenoceptor expression and functionality in postmortem prefrontal cortex of schizophrenia subjects

Previous evidence suggests that α2-adrenoceptors (α2-AR) may be involved in the pathophysiology of schizophrenia. However, postmortem brain studies on α2-AR expression and functionality in schizophrenia are scarce. The aim of our work was to evaluate α2A-AR and α2C-AR expression in different subcellular fractions of prefrontal cortex postmortem tissue from antipsychotic-free (absence of antipsychotics in blood at the time of death) (n = 12) and antipsychotic-treated (n = 12) subjects with schizophrenia, and matched controls (n = 24). Functional coupling of α2-AR to Gα proteins induced by the agonist UK14304 was also tested. Additionally, Gα protein expression was also evaluated. In antipsychotic-free schizophrenia subjects, α2A-AR and α2C-AR protein expression was similar to controls in all the subcellular fractions. Conversely, in antipsychotic-treated schizophrenia subjects, increased α2A-AR expression was found in synaptosomal plasma membrane and postsynaptic density (PSD) fractions (+60% and +79% vs controls, respectively) with no significant changes in α2C-AR. [35S]GTPγS SPA experiments showed a significant lower stimulation of Gαi2 and Gαi3 proteins by UK14304 in antipsychotic-treated schizophrenia subjects, whereas stimulation in antipsychotic-free schizophrenia subjects remained unchanged. Gαo protein stimulation was significantly decreased in both antipsychotic-free and antipsychotic-treated schizophrenia subjects compared to controls. Expression of Gαi3 protein did not differ between groups, whereas Gαi2 levels were increased in PSD of schizophrenia subjects, both antipsychotic-free and antipsychotic-treated. Gαo protein expression was increased in PSD of antipsychotic-treated subjects and in the presynaptic fraction of antipsychotic-free schizophrenia subjects. The present results suggest that antipsychotic treatment is able to modify in opposite directions both the protein expression and the functionality of α2A-AR in the cortex of schizophrenia patients.

Opposite alterations of 5\xadHT2A receptor brain density in subjects with schizophrenia: relevance of radiotracers pharmacological profile

The status of serotonin 5­HT2A receptors (5­HT2ARs) in schizophrenia has been controversial. In vivo positron emission tomography neuroimaging and in vitro post-mortem binding studies have reported conflicting results about 5­HT2AR density. Radiotracers bind different receptor conformations depending on their agonist, antagonist or inverse agonist properties. This study investigates 5­HT2AR density in the post-mortem prefrontal cortex from subjects with schizophrenia and controls using three radiotracers with a different pharmacological profile. The specific binding parameters of the inverse agonist [18F]altanserin, the agonist [3H]lysergic acid diethylamide (LSD) and the antagonist [3H]MDL100907 to brain cortex membranes from 20 subjects with schizophrenia and 20 individually matched controls were evaluated under similar methodological conditions. Ten schizophrenia subjects were antipsychotic-free at death. Saturation curve analyses were performed by non-linear regression to obtain a maximal density of binding sites (Bmax) and the affinity of the respective radiotracers (Kd). In schizophrenia subjects, 5-HT2AR density was decreased when quantified by [18F]altanserin binding, whereas increased when evaluated by [3H]LSD binding. However, [3H]MDL100907 binding was unaltered. A slight loss of affinity (higher Kd) was observed exclusively in [3H]LSD binding. The findings were more evident in antipsychotic-free subjects than in antipsychotic-treated subjects. In conclusion, a higher proportion of the 5-HT2AR-active functional conformation, which is rather identified by agonist radiotracers, was observed in schizophrenia patients. A consequent reduction of the inactive 5-HT2AR conformation, which is preferentially identified by inverse agonist radiotracers, was also obtained. Antagonist radiotracers do not distinguish between molecular conformations of the receptor, and accordingly, the absence of changes was shown. These results are compatible with the proposed increased functional activity of brain cortical 5-HT2ARs in schizophrenia.

Spinophilin expression in postmortem prefrontal cortex of schizophrenic subjects: Effects of antipsychotic treatment

Schizophrenia has been associated with alterations in neurotransmission and synaptic dysfunction. Spinophilin is a multifunctional scaffold protein that modulates excitatory synaptic transmission and dendritic spine morphology. Spinophilin can also directly interact with and regulate several receptors for neurotransmitters, such as dopamine D2 receptors, which play a role in the pathophysiology of schizophrenia and are targets of antipsychotics. Several studies have thus suggested an implication of spinophilin in schizophrenia. In the present study spinophilin protein expression was determined by western blot in the postmortem dorsolateral prefrontal cortex of 24 subjects with schizophrenia (12 antipsychotic-free and 12 antipsychotic-treated subjects) and 24 matched controls. Experiments were performed in synaptosomal membranes (SPM) and in postsynaptic density fractions (PSD). As previously reported, two specific bands for this protein were observed: an upper 120–130 kDa band and a lower 80–95 kDa band. The spinophilin lower band showed a significant decrease in schizophrenia subjects compared to matched controls, both in SPM and PSD fractions (-15%, p = 0.007 and -15%, p = 0.039, respectively). When schizophrenia subjects were divided by the presence or absence of antipsychotics in blood at death, the lower band showed a significant decrease in antipsychotic-treated schizophrenia subjects (-24%, p = 0.003 for SPM and -26%, p = 0.014 for PSD), but not in antipsychotic-free subjects, compared to their matched controls. These results suggest that antipsychotics could produce alterations in spinophilin expression that do not seem to be related to schizophrenia per se. These changes may underlie some of the side effects of antipsychotics.

Variants in the DRD2 locus and antipsychotic-related prolactin levels: A meta-analysis

BackgroundAlthough dopamine D2 receptor antagonists lead to dose-dependent prolactin (PRL) elevations proportionate to their D2 affinity, considerable inter-individual differences exist. We conducted a meta-analytic review of associations between genetic variations in the dopamine D2 receptor gene (DRD2) and PRL levels in antipsychotic-treated subjects. MethodsSystematic literature search (5/8/2015) was performed to find published studies of pharmacogenetic associations between two DRD2 variants, Taq1A (rs1800497) and −141C Ins/Del (rs1799732), and PRL levels during antipsychotic treatment (excluding aripiprazole). Patients were included independent of age or diagnosis. Random effects models were used and Hedges’ g was calculated as the effect size measure. Subgroup analyses explored the effect of sex and diagnosis, (males vs females; schizophrenia vs non-schizophrenia). ResultsAltogether, 11 studies (n=1034, schizophrenia-spectrum=475) for Taq1A polymorphism, and 4 studies (n=451, schizophrenia-spectrum=274) for −141C Ins/Del polymorphism, each reporting on PRL levels but not on the proportion of patients with hyperprolactinemia, were meta-analyzed. Across all patients, there was no statistically significant association between PRL levels and either DRD2 Taq1A genotype or DRD2 −141C Ins/Del genotype. However, in patients with schizophrenia, PRL levels were significantly higher in DRD2 Taq1A A1 carriers than A1 non-carriers (studies=5, n=475, Hedges’ g=0.250, 95% CI=0.068–0.433, p=0.007, I2=0%). DiscussionAlthough there was no significant association between either DRD2 Taq1A genotype or DRD2 −141C Ins/Del genotype and PRL levels in all included patients, our results suggest that DRD2 Taq1A genotype may affect antipsychotic-related PRL levels in patients with schizophrenia. Because of the small sample size, further studies are needed to confirm these results.

The metabolic syndrome and its constituting variables in atypical antipsychotic-treated subjects: Comparison with other drug treatments, drug-free psychiatric patients, first-degree relatives and the general population in Venezuela

Background Few studies on the association between atypical antipsychotic drug (AAP) administration and metabolic dysfunction have concurrently evaluated the general population (GP), other psychotropic drug treatments and drug-free psychiatric patients. Methods We assessed the frequency of the metabolic syndrome (MS) according to the National Cholesterol Education Program criteria (NCEP) and its constituting variables in a GP sample (n = 271) and in patients receiving, for at least three consecutive months, antiepileptic drugs (n = 93), olanzapine (n = 162), clozapine (n = 105), typical antipsychotics (n = 117), other AAP (n = 58), other psychotropic drugs (n = 185), and drug-free individuals (n = 636). Subjects were clinically classified as schizophrenia, bipolar or other axis I disorders (DSM-IV-RT), and as first-degree relatives of each diagnostic group. Results The MS was detected in 26.6% of the GP (95% confidence interval: 21.5–31.8). No diagnostic or treatment group had a significantly higher age-adjusted frequency than the GP (p > 0.05). Treatment duration did not significantly affect the results. However, significant differences were observed in the frequency of abnormal MS constituting variables in comparison to the GP. For example, schizophrenia patients and their relatives, bipolar subjects and olanzapine- and clozapine-treated patients had higher abnormal waist circumference values. In addition, bipolar patients and their relatives and subjects treated with olanzapine and other AAPs had higher frequencies of abnormal glucose levels. Neither schizophrenia nor bipolar patients in the diagnostic categories nor the olanzapine or the clozapine groups displayed higher proportions of abnormal triglycerides, high density cholesterol or blood pressure levels than the GP. Conclusions While we did not demonstrate an increased frequency of the MS in AAP-treated subjects, our results confirm that specific metabolic variables must be monitored in psychiatric patients. Besides they stress the importance, in epidemiological studies, of concurrently comparing the figures recorded in AAP-treated patients with those obtained in the local GP, other drug treatment groups and drug-free subjects when referring to the magnitude of the metabolic effects of specific antipsychotic agents.

Immunodensity and mRNA expression of A2A adenosine, D2 dopamine, and CB1 cannabinoid receptors in postmortem frontal cortex of subjects with schizophrenia: effect of antipsychotic treatment

Dopamine D2 receptors are the main target of antipsychotic drugs. In the brain, D2 receptors coexpress with adenosine A2A and CB1 cannabinoid receptors, leading to functional interactions. The protein and messenger RNA (mRNA) contents of A2A, D2, and CB1 receptors were quantified in postmortem prefrontal cortex of subjects with schizophrenia. The study was performed in subjects suffering schizophrenia (n=31) who mainly died by suicide, matched with non-schizophrenia suicide victims (n=13) and non-suicide controls (n=33). The density of receptor proteins was evaluated by immunodetection techniques, and their relative mRNA expression was quantified by quantitative real-time polymerase chain reaction. In schizophrenia, the densities of A2A (90+/-6%, n=24) and D2-like receptors (95+/-5%, n=22) did not differ from those in controls (100%). Antipsychotic treatment did not induce changes in the protein expression. In contrast, the immunodensity of CB1 receptors was significantly decreased (71+/-7%, n=11; p<0.05) in antipsychotic-treated subjects with schizophrenia but not in drug-free subjects (104+/-13%, n=11). The relative mRNA amounts encoding for A2A, D2, and CB1 receptors were similar in brains of drug-free, antipsychotic-treated subjects with schizophrenia and controls. The findings suggest that antipsychotics induce down-regulation of CB1 receptors in brain. Since A2A, D2, and CB1 receptors coexpress on brain GABAergic neurons and reductions in markers of GABA neurotransmission have been identified in schizophrenia, a lower density of CB1 receptor induced by antipsychotics could represent an adaptative mechanism that reduces the endocannabinoid-mediated suppression of GABA release, contributing to the normalization of cognitive functions in the disorder.

Homozygosity for the Gly-9 variant of the dopamine D3 receptor and risk for tardive dyskinesia in schizophrenic patients.

This study was undertaken to re-examine whether homozygosity for the Gly-9 variant (allele 2) of the dopamine D3 receptor gene (DRD3) is associated with increased risk for tardive dyskinesia (TD) in schizophrenic patients. Seventy-one antipsychotic-treated subjects with schizophrenia from Newcastle upon Tyne, UK, were genotyped for the presence of allele 1 (Ser-9) and allele 2 (Gly-9) of the dopamine D3 receptor (DRD3) Ser-9-Gly polymorphism. Among 32 patients with TD, 7 subjects (22 %) were homozygous for the Gly-9 variant (2-2 genotype), whereas 4 out of 39 patients (10 %) without TD had this genotype. The non-significant tendency in this sample towards an over-representation of allele 2 and the 2-2 genotype among schizophrenic patients with TD is in line with our initial report as well as recent studies by others, indicating that the Gly-9 allele of DRD3 may be a susceptibility factor for the development of TD in neuroleptic-treated individuals with schizophrenia. There are, however, some recent non-supportive reports, and since the trend in our present study failed to reach statistical significance, further studies on larger samples and future meta-analysis may be necessary to establish the role of the DRD3 in the pathogenesis of TD.