Giovanni Muscettola

Extrapyramidal syndromes in neuroleptic-treated patients: prevalence, risk factors, and association with tardive dyskinesia.

Prevalence and risk factors for extrapyramidal syndromes (EPS) were investigated in a sample of 1,559 patients. The overall prevalence of EPS was 29.4% (N = 458). Among the EPS-diagnosed patients, parkinsonism as assessed by the presence of core parkinsonian symptoms (rigidity, tremor, bradykinesia) was present in 65.9% of patients (N = 302), akathisia in 31.8% (N = 145), and acute dystonia in 2.1% (N = 10). Old age and long-term neuroleptic drug (NL) treatment were significantly associated with EPS in both the univariate and the multivariate analyses, whereas no relationship was observed with average NL daily doses and current NL treatment. EPS was diagnosed in 50.2% of 285 patients with persistent tardive dyskinesia (TD). Distribution of EPS in patients with TD showed that tremor and akathisia were more frequent in peripheral TD cases than in orofacial TD cases. Furthermore, there was a stronger association of NL-induced parkinsonism with peripheral TD than with orofacial TD. This study suggests that the association between EPS and TD may be limited to specific subtypes of TD. Peripheral TD showed a higher association with parkinsonism and with akathisia, suggesting that these symptoms may share a common pathophysiology.

Urinary MHPG, stress response, personality factors and somatosensory evoked potentials in normal subjects and patients with major affective disorders.

Stressful procedures are reported to increase urinary MHPG in both normal and depressed patients. Bipolar depressed patients are also shown to be especially pain tolerant in comparison to normals. In the present study, 12 depressed patients (6 bipolar and 6 unipolar patients) and 10 normal volunteers had average evoked potentials recorded for visual and painful electrical stimuli. MHPG urinary excretion was measured during this session and during an unstimulated resting session on the home ward. Male normal volunteers showed a significant increase in urinary MHPG under stress, while no MHPG increment was noted for the depressed group. Depth of depression, assessed by the Zung and Beck scales, was found to be correlated with the reduced urinary MHPG response to stress. Possible interpretations of the results are discussed.

Homer 1a Gene Expression Modulation by Antipsychotic Drugs: Involvement of the Glutamate Metabotropic System and Effects of D-Cycloserine

N-methyl-D-aspartate receptor hypofunction has been suggested to play a role in the pathophysiology of schizophrenia. New glutamatergic mechanisms involving metabotropic receptors have been recently proposed to further expand this hypothesis. “Homer” is a family of postsynaptic density proteins functionally and physically attached to glutamate metabotropic receptors. We investigated the activation of the early gene form of Homer after acute treatment with typical or atypical antipsychotic drugs alone or with the adjunction of D-cycloserine. This activation was compared with that of c-fos, considered a putative molecular marker of brain regions activated by antipsychotics. Male Sprague-Dawley rats were treated intraperitoneally with haloperidol (0.8 mg/Kg) or clozapine (15 mg/Kg) alone or with the adjunction of D-cycloserine (20 mg/Kg). Rats were sacrificed ninety minutes after injection and the brains were processed for quantitative in situ hybridization histochemistry. Haloperidol induced a statistically significant increase of Homer both in caudate-putamen and nucleus accumbens compared with controls; clozapine induced Homer significantly only in the accumbens. The adjunction of D-cycloserine attenuated the haloperidol-induced increase of Homer expression in caudate-putamen and nucleus accumbens and attenuated the clozapine-induced increase in the accumbens. The c-fos gene expression was potently induced by haloperidol in caudate-putamen and nucleus accumbens, and by clozapine only in the accumbens. The adjunction of D-cycloserine enhanced c-fos expression only for clozapine in both regions of the forebrain. These results demonstrate a differential involvement of glutamatergic metabotropic system in gene expression modulation induced by typical or atypical antipsychotic drugs and may suggest new molecular basis for the augmentation strategy by a glycine site partial agonist.

Acute administration of antipsychotics modulates Homer striatal gene expression differentially

Typical and atypical antipsychotics, the mainstay of schizophrenia pharmacotherapy, have been demonstrated to affect differently neuronal gene expression in several preclinical paradigms. Here we report the differential gene expression of the glutamatergic post-synaptic density proteins Homer and PSD-95 in rat forebrain following acute haloperidol or olanzapine treatment. Moreover, considering the extensive interactions between dopaminergic and opioidergic systems we also measured striatal preproenkephalin mRNA. Male Sprague-Dawley rats were treated with haloperidol 1 mg/kg or olanzapine 0.5 mg/kg or vehicle, i.p. and sacrificed 3 h after the injection. Homer gene expression was significantly increased in caudate putamen and nucleus accumbens of rats treated with haloperidol and in the core of accumbens of rats treated with olanzapine. No changes were detected for Homer in prefrontal and parietal cortex in any of the experimental groups. PSD-95 gene expression was not modulated in our paradigm by administration of either typical or atypical antipsychotics. These results (1) suggest a differential modulation of Homer by typical and atypical antipsychotics; (2) confirm that Homer can be induced as an early gene with putative direct effect on neuronal plasticity and (3) demonstrate different response to antipsychotics by different classes of postsynaptic density proteins at glutamatergic synapses.

Dopamine receptor subtypes contribution to Homer1a induction: insights into antipsychotic molecular action.

The inducible gene Homer1a has been considered a candidate gene for schizophrenia. Drugs efficacious in schizophrenia and acting as dopamine receptor antagonists induce Homer1a expression, although the specific role of the different dopamine receptors in its induction is not completely known. In this study, we explored Homer1a expression induced by selective antagonists at dopamine receptors (SCH-23390, D(1) receptor selective antagonist, 0.5 mg/kg; L-741,626, D(2) receptor selective antagonist, 2 mg/kg; U-99194, D(3) receptor selective antagonist, 5 mg/kg; L-745,870, D(4) receptor selective antagonist, 3 mg/kg), haloperidol (0.8 mg/kg), and terguride (0.5 mg/kg), a partial agonist at D(2) receptors. Moreover, we evaluated the expression of two Homer1a-related genes which play essential roles in synaptic plasticity: mGluR5 and Homer1b. Gene expression was analyzed in brain regions relevant for schizophrenia pathophysiology and therapy, namely the striatum, the cortex, and the hippocampus. In striatum, Homer1a was induced by D(2) receptor antagonists and, with a different distribution, by SCH-23390. In the cortex, Homer1a was differentially induced by D(1), D(2), and D(3) receptors antagonists, while haloperidol and terguride did not affect or reduced its expression. Homer1b expression was reduced by L-741,626, L-745,870, terguride, and haloperidol in the ventral caudate-putamen, in the nucleus accumbens and in the cortex, while SCH-23390 increased the expression in the core of the accumbens. mGluR5 expression was increased by SCH-23390 in the dorsomedial putamen, the core of the accumbens, and in some hippocampal subregions. A reduction of gene expression by terguride and an increase by L-745,870 was observed in the dorsomedial putamen. The changes in expression suggest that these gene transcripts are differentially regulated by antagonism at different dopamine receptors.

Platelet 3H-imipramine binding in bipolar patients

Platelet 3H-imipramine binding was investigated in 31 control subjects and 19 hospitalized bipolar patients, either in the hypomanic or the depressed phase of illness. The mean Bmax value in the bipolar depressed patients did not differ significantly from that in the control subjects or the hypomanic patients. Differences in timing of the assay after blood collection, membrane preparation, protein content used in the assay, or binding of radioactive ligand to the equipment do not appear to explain the discrepancy between these results and previous findings.

Persistent tardive dyskinesia: demographic and pharmacological risk factors

The demographic, clinical and pharmacological risk factors for persistent tardive dyskinesia (TD) were investigated in a sample of 1745 patients. When simultaneously adjusting for the effects of demographic and pharmacological factors using multivariate logistic regression, female sex and advanced age were positively and significantly associated with increased risk of TD. Interaction between these two variables, investigated by cross‐stratification, was significant. Furthermore, high neuroleptic dose and concomitant use of neuroleptic and antiparkinsonian drugs were both significantly associated with increased risk of TD. The results support the view that both vulnerability factors and high neuroleptic doses contribute to the occurrence of TD and further stress the relevance of a conservative use of antipsychotic medication, particularly in older women.

Haloperidol induces higher Homer1a expression than risperidone, olanzapine and sulpiride in striatal sub-regions

Homer1a and Yotiao are two post-synaptic density proteins at the crossroad of dopamine-glutamate neurotransmission. Homer1a has been implicated in the pathophysiology of schizophrenia and is differentially induced by typical and atypical antipsychotics, perhaps according to their dopaminergic profile. Yotiao has been involved in glutamate and dopamine post-synaptic signalling. Here, we seek to determine whether Homer1a and Yotiao might be implicated in post-synaptic response to antipsychotics with affinity to different dopamine D(2) receptors: haloperidol (0.8mg kg(-1)), risperidone (3mg kg(-1)), olanzapine (2.5mg kg(-1)) and (-)-sulpiride (50mg kg(-1)). Homer1a expression was significantly induced by haloperidol compared to vehicle and to atypical antipsychotics in almost all striatal sub-regions. Atypical antipsychotics induced the gene in the lateral putamen and in the core of the accumbens only. All antipsychotics, with the exclusion of sulpiride, elicited a dorsolateral-to-ventromedial distribution pattern of Homer1a expression. No significant induction was detected for Yotiao. These results suggest that the quantitative and topographical pattern of Homer1a expression may putatively be related to antipsychotics affinity and/or occupancy at dopamine D(2) receptors.

Revision of the Italian psychiatric reform: North/South differences and future strategies

The Italian psychiatric reform of 1978 shifted the care of the mentally ill from the asylum to the community, by prohibiting new admissions to asylums and providing new community-oriented services. Ten years later, the Italian government is reviewing the effects of the psychiatric reform and is considering drastic revisions of the Law. However, few data are available to evaluate the impact of the new legislation on a national basis. The present cross-sectional study, conducted in North-Central and Southern Italy, showed that a more socially disadvantaged patient population was treated in Southern Italian mental health services. In both geographic regions, the probability of being currently treated in mental hospitals as compared to community services was increased by poor education, being unmarried, having a schizophrenia or organic diagnosis, a long psychiatric history, a long previous hospitalization, or a poor prognosis. However, a long psychiatric history was the main factor associated with current mental hospital treatment in Southern Italy but not in the North-Center, thus suggesting that the psychiatric reform has had different impacts on Northern and Southern mental hospitals. The inadequate provision of community-oriented services in Southern Italy regions, and the presence of private mental hospitals that are publicly reimbursed, contribute importantly to the unsatisfactory situation of mental health care delivery in Southern Italy. The reinstitutionalization of mental patients is currently proposed by some political parties in Italy. This article argues that new legislation must address the provision of effective community services in the South, better definition of the role of the private sector, and the creation of an effective information system to monitor the implementation of the proposed measures.

Association of antipsychotic induced weight gain and body mass index with GNB3 gene: A meta-analysis

It has been reported that C825T variant in the gene encoding the G-protein subunit beta3 (GNB3) is associated with antipsychotic-induced weight gain and obesity. We investigated the association of the GNB3 and antipsychotic-induced weight gain as well as body mass index (BMI) using meta-analytical techniques. Our analysis of 402 schizophrenia subjects showed a trend (p=0.072) only under a fixed-model. As it was observed heterogeneity among the studies (p=0.007), we re-analyzed using a random-effects framework and no significance was found (p=0.339). No evidence for bias publication was reported (p=0.868). Our analysis of 18,903 subjects showed a trend (p=0.053) associating CC and lower BMI under a fixed model. Although no significant association was found, the same pattern (CC and lower antipsychotic-induced weight gain) was observed. Our meta-analysis indicates that firmly establishing the role of pharmacogenetics in clinical psychiatry requires much larger sample sizes that have been reported.