clozapine and Alzheimer-Disease

To systematically assess the safety and efficacy of olanzapine versus clozapine when treating senile dementia and to provide evidence-based medicine basis for its promotion and use.. PubMed, Embase, ScienceDirect, Cochrane Library, China Knowledge Network Database (CNKI), China VIP Database, Wanfang Database, and China Biomedical Literature Database (CBM) online database were searched for randomized controlled trials (RCT) of olanzapine and clozapine when treating senile dementia. The retrieval time limit is from the establishment of the database to the present. The data were extracted independently by two researchers, and the bias risk of each contained literature was analyzed in accordance with the standard of Cochrane Handbook 5.3. RevMan 5.4 statistical software was used to analyze the collected data by meta-analysis.. Finally, 6 randomized controlled trial articles were included, with a total of 490 samples. Meta-analysis of clinical efficacy showed that the clinical efficacy was similar and there was no significant difference (. Olanzapine and clozapine have similar efficacy when treating mental and behavioral disorders in patients with senile dementia, in which olanzapine is more effective in improving the symptoms of patients with Alzheimer's disease (AD), with less adverse reactions and high safety, which is worth popularizing in clinical practice. However, more studies and follow-up with higher methodological quality and longer intervention time are needed to further verify.

Topics: Alzheimer Disease; Antipsychotic Agents; Clozapine; Humans; Olanzapine; Randomized Controlled Trials as Topic; Treatment Outcome

Topics: Aged, 80 and over; Alzheimer Disease; Antipsychotic Agents; Clozapine; Dose-Response Relationship, Drug; Drug Substitution; Female; Humans; Randomized Controlled Trials as Topic

Psychotic symptoms are seen in numerous psychiatric illnesses afflicting the elderly. This article reviews the efficacy of the pharmacologic management of psychotic symptoms in primary psychotic disorders, affective disorders, and neurodegenerative disorders.. A comprehensive literature review.. Evidence to support the use of pharmacologic interventions to manage psychotic symptoms in elderly patients afflicted with primary psychotic disorders and affective disorders is limited by the absence of randomized, placebo-controlled trials (RCTs). The use of low-dose clozapine is supported by RCTs in Parkinson's disease. The efficacy of risperidone and olanzapine for the treatment of psychotic symptoms has been demonstrated by large RCTs in Alzheimer's disease.. There is evidence of the efficacy of antipsychotic medications to manage psychotic symptoms in elderly patients. However, the absence of published evidence from RCTs in primary psychotic and affective disorders, and the limited evidence in the neurodegenerative illnesses, is notable.

Topics: Aged; Alzheimer Disease; Benzodiazepines; Bipolar Disorder; Clozapine; Depressive Disorder; Drug Administration Schedule; Humans; Lewy Body Disease; Olanzapine; Parkinson Disease; Pirenzepine; Psychotic Disorders; Risperidone

Drug-induced iatrogenic hallucinations and psychosis occur in about 30% of Parkinson's disease (PD) patients and are the single most important precipitant for nursing home placement, which carries a grave prognosis. In addition, parkinsonism is a frequent accompaniment to the more common dementing syndromes, Alzheimer's disease (AD), vascular dementia, and dementia with Lewy bodies (DLB). The five most recent antipsychotic drugs approved by the Food and Drug Administration in the United States have been marketed as "atypical" antipsychotics (AA) due to their relative freedom from extrapyramidal symptoms when used in schizophrenia patients. The use of these newer antipsychotic drugs in PD and other parkinson-sensitive populations represents the most stringent test to their freedom from motor side effects. To date, clozapine, risperidone, olanzapine, and quetiapine have been studied in parkinson-vulnerable populations. This article reviews the data and highlights the differences that these four drugs have on motor function. It also emphasizes the challenges in evaluating the available data on the motor effects of AA, especially on the non-PD elderly and cognitively impaired population. Suggestions are made for future research to improve the interpretability of these studies.

Topics: Alzheimer Disease; Antipsychotic Agents; Benzodiazepines; Clozapine; Dementia, Vascular; Dibenzothiazepines; Hallucinations; Humans; Iatrogenic Disease; Lewy Body Disease; Olanzapine; Parkinson Disease; Pirenzepine; Psychotic Disorders; Quetiapine Fumarate; Risperidone

In addition to their neurochemical effects, antipsychotic (neuroleptic) drugs produce structural brain changes. This property is relevant not only for understanding the drugs' mode of action, but because it complicates morphological studies of schizophrenia. Here the histological neuropathological effects of antipsychotics are reviewed, together with brief mention of those produced by other treatments sometimes used in schizophrenia (electroconvulsive shock, lithium and antidepressants). Most data come from drug-treated rats, though there are also some human post-mortem studies with broadly congruent findings. The main alteration associated with antipsychotic medication concerns the ultrastructure and proportion of synaptic subpopulations in the caudate nucleus. In rats, synapses and dendrites in lamina VI of the prefrontal cortex are also affected. The changes are indicative of a drug-induced synaptic plasticity, although the underlying mechanisms are poorly understood. Similarly, it is unclear whether the neuropathological features relate primarily to the therapeutic action of antipsychotics or, more likely, to their predisposition to cause tardive dyskinesia and other motor side-effects. Clozapine seems to cause lesser and somewhat different alterations than do typical antipsychotics, albeit based on few data. There is no good evidence that antipsychotics cause neuronal loss or gliosis, nor that they promote neurofibrillary tangle formation or other features of Alzheimer's disease.

Topics: Alzheimer Disease; Animals; Antidepressive Agents, Second-Generation; Antipsychotic Agents; Caudate Nucleus; Clozapine; Dyskinesia, Drug-Induced; Humans; Neuronal Plasticity; Rats; Schizophrenia

This article reviews the nature and prevalence of Lewy bodies (LBs) found during postmortem examination of demented individuals. Neuropathologic findings associated with diffuse Lewy body disease (DLBD) are contrasted with those of other causes of dementia (e.g., Pick's disease and Alzheimer's disease). A sufficiently specific clinical syndrome is suggested to enhance the antemortem diagnosis of DLBD. Current and speculative clinical management strategies of DLBD are discussed.

Topics: Alzheimer Disease; Antipsychotic Agents; Brain Stem; Clozapine; Dopamine Antagonists; Humans; Lewy Bodies; Neuropsychological Tests; Parkinson Disease; Risperidone

Schizophrenia, a complex psychiatric disorder, is often associated with cognitive, neurological and neuroimaging abnormalities. The processes underlying these abnormalities, and whether a subset of people with schizophrenia have a neuroprogressive or neurodegenerative component to schizophrenia, remain largely unknown. Examining fluid biomarkers of diverse types of neuronal damage could increase our understanding of these processes, as well as potentially provide clinically useful biomarkers, for example with assisting with differentiation from progressive neurodegenerative disorders such as Alzheimer and frontotemporal dementias.. We found no differences in NfL levels between treatment-resistant schizophrenia (mean NfL, M = 6.3 pg/mL, 95% confidence interval: [5.5, 7.2]), first-degree relatives (siblings, M = 6.7 pg/mL, 95% confidence interval: [5.2, 8.2]; parents, M after adjusting for age = 6.7 pg/mL, 95% confidence interval: [4.7, 8.8]), controls (M = 5.8 pg/mL, 95% confidence interval: [5.3, 6.3]) and not treated with clozapine (M = 4.9 pg/mL, 95% confidence interval: [4.0, 5.8]). Exploratory, hypothesis-generating analyses found weak correlations in treatment-resistant schizophrenia, between NfL and clozapine levels (Spearman's. Treatment-resistant schizophrenia does not appear to be associated with neuronal, particularly axonal degeneration. Further studies are warranted to investigate the utility of NfL to differentiate treatment-resistant schizophrenia from neurodegenerative disorders such as behavioural variant frontotemporal dementia, and to explore NfL in other stages of schizophrenia such as the prodome and first episode.

Topics: Alzheimer Disease; Biomarkers; Child; Clozapine; Frontotemporal Dementia; Humans; Intermediate Filaments; Neurodegenerative Diseases; Neurofilament Proteins; Schizophrenia; Schizophrenia, Treatment-Resistant

Dysphagia has been reported as an adverse event for patients receiving rivastigmine for Alzheimer's disease (AD) treatment.. The purpose of this study was to determine the association between dysphagia and the usage of rivastigmine by using the pharmacovigilance data from the FDA Adverse Event Reporting System (FAERS).. The risk of dysphagia in patients who took rivastigmine was compared with those of patients who took other medications. In addition, this study sought to determine if the dysphagia risk was influenced by sex, age, dosage, and medication routes of administration.. When compared to patients prescribed donepezil, galantamine, or memantine, individuals prescribed rivastigmine were almost twice as likely to report dysphagia as an adverse event. The dysphagia risk in individuals prescribed rivastigmine is comparable to individuals prescribed penicillamine but significantly higher than clozapine, drugs of which have been previously shown to be associated with elevated dysphagia likelihood. Individuals older than 80 were 122% more likely to report having dysphagia after being prescribed rivastigmine than patients that were 50-70 years of age. Oral administration of rivastigmine was associated with approximately 2 times greater likelihood of reporting dysphagia relative to users of the transdermal patch. In addition, dysphagia showed higher association with pneumonia than other commonly reported adverse events.. Patients prescribed rivastigmine were at greater risk of reporting dysphagia as an adverse event than patients prescribed many other medicines. This increase in dysphagia occurrence may be attributed to the dual inhibition of both acetylcholinesterase and butyrylcholinesterase.

Topics: Acetylcholinesterase; Alzheimer Disease; Butyrylcholinesterase; Cholinesterase Inhibitors; Clozapine; Deglutition Disorders; Donepezil; Galantamine; Humans; Memantine; Penicillamine; Risk Management; Rivastigmine; United States; United States Food and Drug Administration

To study the antioxidant profile of blood plasma in patients with paranoid schizophrenia and Alzheimer disease (AD).. Thirty-three patients with paranoid schizophrenia and 18 patients with AD were included in the study. Patients with schizophrenia were stratified into two subgroups by response to therapy. The indicators of the antioxidant profile were determined using methods based on chemiluminometry and spectrofluorimetry.. Systemic oxidative stress due to insufficiency of low molecular weight plasma antioxidants is not determined neither in AD nor in treatment resistant schizophrenia. At the same time, a «thiol» oxidative stress, which indirectly indicates a deficiency of the glutathione system, is present in both groups. In patients with paranoid schizophrenia responsive to treatment, systemic oxidative stress is more pronounced and «thiol» oxidative stress is less significant. Among the antipsychotics studied, haloperidol, zuclopenthixol, risperidone and ziprasidone do not exhibit antioxidant properties, but periciazine, clozapine and especially chlorpromazine exhibit strong antioxidant properties, but they unlikely affect the antioxidant potential of blood plasma.. The glutathione part of the antioxidant system is mostly affected, but systemic oxidative stress is not significant in patients with treatment resistant paranoid schizophrenia and AD. Oxidative disorders are more pronounced in treatment responsive paranoid schizophrenia.. Изучение показателей антиоксидантного профиля плазмы крови пациентов с параноидной шизофренией и болезнью Альцгеймера (БА).. В исследование включены 33 пациента с параноидной шизофренией и 18 пациентов с БА. Выделены группы пациентов с шизофренией, резистентных к терапии и положительно отреагировавших на терапию. Параметры антиоксидантного профиля определяли методами хемилюминометрии и спектрофлуометрии.. При БА системный окислительный стресс, обусловленный недостаточностью низкомолекулярных антиоксидантов плазмы крови, отсутствует, но выявлен «тиоловый» белковый окислительный стресс, косвенно свидетельствующий о недостаточности системы глутатиона. Для пациентов с параноидной шизофренией, резистентной к терапии, системный окислительный стресс также нехарактерен при выраженности «тиолового» окислительного стресса. У пациентов с параноидной шизофренией, поддающихся терапии, ситуация обратная — более выражен системный окислительный стресс и менее выражен «тиоловый» окислительный стресс. Из изученных нейролептиков галоперидол, зуклопентиксол, рисперидон и зипрасидон не обладают антиоксидантными свойствами, перициазин, клозапин и особенно хлорпромазин обладают выраженными антиоксидантными свойствами, однако их влияние на антиоксидантный потенциал плазмы крови маловероятно. Сделан вывод, что при резистентной к терапии параноидной шизофрении и БА страдает прежде всего глутатионовое звено антиоксидантной системы, а системный окислительный стресс не выражен. При параноидной шизофрении, успешно поддающейся терапии, окислительные нарушения выражены сильнее.

Topics: Alzheimer Disease; Antioxidants; Antipsychotic Agents; Clozapine; Humans; Risperidone; Schizophrenia, Paranoid

Topics: Aged; Alzheimer Disease; Antipsychotic Agents; Cholinesterase Inhibitors; Clozapine; Drug Therapy, Combination; Dystonic Disorders; Female; Humans; Rivastigmine; Schizophrenia

Alzheimer's disease (AD) is a progressive degenerative condition. In order to treat AD, the use of a "drug repositioning" or "repurposing" approach with potential disease-modifying compounds has been increased. The new generation antipsychotics are commonly used in AD and other dementias for the treatment of psychosis and behavioral symptoms, and several animal models have shown the effects of these potential disease-modifying compounds. In this study, we examined whether long-term clozapine treatment could reduce amyloid beta (Aβ) deposition and cognitive impairment in transgenic mice of AD, Tg-APPswe/PS1dE9. AD mice were fed clozapine at 20 mg/kg/day for 3 months from 4.5 months of age. Intake of clozapine improved the Aβ-induced memory impairment and suppressed Aβ levels and plaque deposition in the brain of AD mice. Clozapine upregulated Trk, brain-derived neurotrophic factor, cyclin-dependent kinase-5, and p35 in the cortex and hippocampus of AD mice and activated AMP-activated protein kinase (AMPK). As a downstream effector of AMPK, beta-secretase expression was decreased by clozapine administration. Moreover, clozapine-phosphorylated synapsin I at Ser9 and Ser549 sites in the hippocampus and cortex of AD mice, which may be involved in synaptic strength. This study suggests that as one of candidate for multi-target approach of AD treatment, clozapine is proposed as a therapeutic drug for treatment of AD patients.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Animals; Clozapine; Male; Memory Disorders; Mice; Mice, Inbred C57BL; Mice, Transgenic; Peptide Fragments; Presenilin-1

Aberrant neural hyperactivity has been observed in early stages of Alzheimer's disease (AD) and may be a driving force in the progression of amyloid pathology. Evidence for this includes the findings that neural activity may modulate β-amyloid (Aβ) peptide secretion and experimental stimulation of neural activity can increase amyloid deposition. However, whether long-term attenuation of neural activity prevents the buildup of amyloid plaques and associated neural pathologies remains unknown. Using viral-mediated delivery of designer receptors exclusively activated by designer drugs (DREADDs), we show in two AD-like mouse models that chronic intermittent increases or reductions of activity have opposite effects on Aβ deposition. Neural activity reduction markedly decreases Aβ aggregation in regions containing axons or dendrites of DREADD-expressing neurons, suggesting the involvement of synaptic and nonsynaptic Aβ release mechanisms. Importantly, activity attenuation is associated with a reduction in axonal dystrophy and synaptic loss around amyloid plaques. Thus, modulation of neural activity could constitute a potential therapeutic strategy for ameliorating amyloid-induced pathology in AD.. A novel chemogenetic approach to upregulate and downregulate neuronal activity in Alzheimer's disease (AD) mice was implemented. This led to the first demonstration that chronic intermittent attenuation of neuronal activity in vivo significantly reduces amyloid deposition. The study also demonstrates that modulation of β-amyloid (Aβ) release can occur at both axonal and dendritic fields, suggesting the involvement of synaptic and nonsynaptic Aβ release mechanisms. Activity reductions also led to attenuation of the synaptic pathology associated with amyloid plaques. Therefore, chronic attenuation of neuronal activity could constitute a novel therapeutic approach for AD.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Animals; Calcium-Binding Proteins; Clozapine; Designer Drugs; Disease Models, Animal; Humans; Insulysin; Lysosomal Membrane Proteins; Male; Mice; Mice, Transgenic; Microfilament Proteins; Nerve Tissue Proteins; Neurotoxicity Syndromes; Presenilin-1; Proto-Oncogene Proteins c-fos; Styrenes; Transduction, Genetic

Topics: Acetylcholine; Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Animals; Clozapine; Conditioning, Psychological; Disease Models, Animal; Fear; Glutamate Decarboxylase; Hippocampus; Interneurons; Memory Disorders; Mice; Mice, Transgenic; Neuroanatomical Tract-Tracing Techniques; Neuronal Plasticity; Somatostatin; Synapses

Comprehensive structure activity relationship (SAR) studies were conducted on a focused screening hit, 2-(methylthio)-3-(phenylsulfonyl)-4H-pyrido[1,2-a]pyrimidin-4-imine (1, IC50: 4.0 nM), as 5-HT6 selective antagonists. Activity was improved some 2-4 fold when small, electron-donating groups were added to the central core as observed in 19, 20 and 26. Molecular docking of key compounds in a homology model of the human 5-HT6 receptor was used to rationalize our structure-activity relationship (SAR) findings. In pharmacokinetic experiments, compound 1 displayed good brain uptake in rats following intra-peritoneal administration, but limited oral bioavailability.

Topics: Alzheimer Disease; Animals; Humans; Imines; Molecular Docking Simulation; Rats; Receptors, Serotonin; Structure-Activity Relationship

We have devised a chemocentric informatics methodology for drug discovery integrating independent approaches to mining biomolecular databases. As a proof of concept, we have searched for novel putative cognition enhancers. First, we generated Quantitative Structure-Activity Relationship (QSAR) models of compounds binding to 5-hydroxytryptamine-6 receptor (5-HT(6)R), a known target for cognition enhancers, and employed these models for virtual screening to identify putative 5-HT(6)R actives. Second, we queried chemogenomics data from the Connectivity Map ( http://www.broad.mit.edu/cmap/ ) with the gene expression profile signatures of Alzheimer's disease patients to identify compounds putatively linked to the disease. Thirteen common hits were tested in 5-HT(6)R radioligand binding assays and ten were confirmed as actives. Four of them were known selective estrogen receptor modulators that were never reported as 5-HT(6)R ligands. Furthermore, nine of the confirmed actives were reported elsewhere to have memory-enhancing effects. The approaches discussed herein can be used broadly to identify novel drug-target-disease associations.

Topics: Alzheimer Disease; Cell Line, Tumor; Cloning, Molecular; Cognition; Drug Discovery; Drug Evaluation, Preclinical; Genomics; Humans; Informatics; Ligands; Nootropic Agents; Quantitative Structure-Activity Relationship; Raloxifene Hydrochloride; Receptors, Serotonin; Reproducibility of Results; Selective Estrogen Receptor Modulators; Serotonin Antagonists; User-Computer Interface

Atypical antipsychotics (AA) are generally associated with weight gain. We determined body mass index (BMI) change in Parkinson's disease (PD) before and after taking AA and compared against PD controls and Alzheimer's disease (AD) patients on AA. In 66 consecutive PD subjects started on AA who had accurate weights for more than 6 months before and after initiation of AA, we compared weight change before and after AA use, against a control group of sixty-one sex-matched PD subjects, and against twenty-eight AD subjects taking AA. A linear regression model was created to compare weight changes. Fifty-nine PD subjects had complete data, quetiapine (n=53) and clozapine (n=6). The mean BMI change in the period before starting AA was 0.00 kg/m(2)/month over 1.95+/-1.41 years. After starting AA, subjects lost 0.03 kg/m(2)/month (95% CI 0.62-1.21, P<0.0001), comparing PD before AA to the same PD patients after AA. In 61 PD controls, the mean BMI loss was 0.01 kg/m(2)/month (95% CI 0.15-0.94, P=0.007) comparing PD on AA vs. PD controls. The BMI for 28 AD subjects on AA increased 0.01 kg/m(2)/month (95% CI 0.26-0.83, P<0.0001), comparing PD on AA vs. AD on AA. The weight loss seen in the PD/AA group, compared to AD, suggest uniquely altered weight homeostasis in PD.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Antipsychotic Agents; Body Mass Index; Body Weight; Case-Control Studies; Clozapine; Confidence Intervals; Dibenzothiazepines; Female; Humans; Male; Middle Aged; Odds Ratio; Parkinson Disease; Quetiapine Fumarate

Topics: Alzheimer Disease; Antipsychotic Agents; Clozapine; Dibenzothiazepines; Humans; Mental Disorders; Quetiapine Fumarate

Topics: Aged; Alzheimer Disease; Clozapine; GABA Antagonists; Hiccup; Humans; Male

This paper examines the effects of medical center budget stress on the use of expensive atypical antipsychotic medications for the treatment of schizophrenia in the Department of Veterans Affairs (VA). VA prescription drug records were collected for patients diagnosed with schizophrenia. Generalized estimation equations were used to identify patient and facility characteristics (especially fiscal stress) that are associated with the use of atypical antipsychotics. Of the 34,925 patients in the final sample, over half received an atypical antipsychotic, usually either olanzapine or risperidone. Unexpectedly, increased fiscal stress was associated with increased likelihood of receiving atypical antipsychotics. Among patients who receive atypicals, however, fiscal stress was associated with reduced likelihood of receiving the more expensive atypicals (clozapine and olanzapine) but positively associated with receiving the least expensive atypical (risperidone). Institutional fiscal pressure does not seem to reduce the broad availability of these medications overall but does affect which drug is prescribed.

Topics: Alzheimer Disease; Antipsychotic Agents; Benzodiazepines; Budgets; Clozapine; Comorbidity; Depressive Disorder; Drug Costs; Female; Health Care Costs; Health Facilities; Humans; Male; Middle Aged; Olanzapine; Pirenzepine; Practice Patterns, Physicians'; Regression Analysis; Risperidone; Schizophrenia; Treatment Outcome; United States; United States Department of Veterans Affairs

Neuroleptic-induced tardive dyskinesia, which often appears in middle-aged and older adults early in the course of treatment with low doses of conventional antipsychotics, is 5 to 6 times more prevalent in elderly than in younger patients. In addition to age, other risk factors for tardive dyskinesia include early extrapyramidal symptoms (EPS), cumulative amounts of neuroleptics, duration of neuroleptic treatment, and history of alcohol abuse and/or dependence. The atypical antipsychotics, which have a low liability for EPS, are likely to also have low potential for tardive dyskinesia, despite the paucity of controlled studies. Starting and maintenance doses of the atypical antipsychotics should generally be lower in older than in younger adults.

Topics: Adult; Age Factors; Aged; Alzheimer Disease; Antipsychotic Agents; Basal Ganglia Diseases; Benzodiazepines; Clinical Trials as Topic; Clozapine; Dibenzothiazepines; Drug Administration Schedule; Dyskinesia, Drug-Induced; Female; Humans; Incidence; Male; Middle Aged; Olanzapine; Pirenzepine; Psychotic Disorders; Quetiapine Fumarate; Risk Factors; Risperidone

Topics: Alzheimer Disease; Antipsychotic Agents; Benzodiazepines; Clozapine; Double-Blind Method; Drug Costs; Drugs, Investigational; Humans; Olanzapine; Pirenzepine; Placebos; Pyridines; Randomized Controlled Trials as Topic; Schizophrenia; Thiadiazoles

Topics: Aged; Alzheimer Disease; Antipsychotic Agents; Clozapine; Drug Costs; Humans; Isoxazoles; Nursing Homes; Piperidines; Psychotic Disorders; Research; United States

The short- and long-term treatment tolerance of low-dose clozapine was retrospectively investigated in 18 psychogeriatric patients. Discontinued use of the drug because of side effects or inefficiency was required for only four patients. In the long-term treatment group leukopenia was not observed, and disturbances of liver function appeared to be very infrequent. A second group of seven severely demented psychogeriatric inpatients who were currently being treated with low-dose clozapine underwent a withdrawal study in order to evaluate the therapeutic efficacy of the drug, measured by the NOSIE and the SCAG scales. The results indicate that for patients such as these, with paranoid or socially disturbing behavior who also tend to develop severe neurological side effects with classical neuroleptics, a low-dose administration of clozapine is an acceptable alternative treatment.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Clozapine; Dementia; Dementia, Multi-Infarct; Dose-Response Relationship, Drug; Female; Geriatric Assessment; Hospitalization; Humans; Hydrocephalus, Normal Pressure; Long-Term Care; Male; Neuropsychological Tests; Psychiatric Status Rating Scales; Psychotic Disorders; Retrospective Studies; Schizophrenia; Schizophrenic Psychology; Social Behavior; Substance Withdrawal Syndrome