clozapine and Substance-Related-Disorders

Antipsychotic medications are the mainstay of treatment for schizophrenia and are associated with a reduction in psychiatric hospitalization and overall mortality. Some evidence suggest that antipsychotic medications might have a varying effect on the improvement of comorbid substance use disorders (SUDs), with clozapine showing more favorable outcomes.. We systematically reviewed all available evidence on effects of clozapine on the improvement of SUDs other than nicotine.. Electronic searches of MEDLINE, Embase, PsycINFO, and CINHAL were conducted up to March 1, 2022. Studies of any methodological design involving two concepts: (1) clozapine and (2) SUD terms (excluding nicotine) were included. For SUD outcomes with three or more comparative studies with available raw data meta-analysis was performed. SUD outcomes not meeting criteria for meta-analysis were described qualitatively. Risk of bias was examined using "Downs and Black," and "Q-Coh" instruments.. The majority of individuals in the included 31 studies were male and of European ancestry. Abstinence was the most common outcome. Most of the studies were of low-to-moderate quality, and none of the studies met all the quality criteria. Pooled findings from four observational studies in samples of patients with predominantly comorbid alcohol use disorder showed that clozapine treatment is associated with significantly higher odds of remaining abstinent. In addition clozapine was associated with decreased odds of psychiatric hospitalization in all but one observational study.. Our systematic review and meta-analysis builds upon previous reviews, and it suggests the association of clozapine treatment with significantly higher odds of remaining abstinent from substance use and decreased likelihood of psychiatric hospitalization, compared with continuing treatment with other antipsychotic medications. Still, the validity of this association needs greater exploration and providing recommendations for the utility of clozapine in individuals without treatment-resistant psychosis and comorbid SUDs would be premature.

Topics: Antipsychotic Agents; Clozapine; Female; Humans; Male; Nicotine; Observational Studies as Topic; Schizophrenia; Substance-Related Disorders

Lifetime prevalence of substance use disorders (SUD) in patients with schizophrenia is nearly 50%. Nicotine, alcohol, and cannabis are the substances most frequently used, with a high percentage of poly-substance users. There are few available data about pharmacological approaches in this population. Amongst antipsychotics, clozapine shows positive evidence in the literature. The aim of the present article is to provide systematic review on the efficacy of clozapine in SUD improvement in schizophrenic patients. PRISMA recommendations were followed (PROSPERO id: CRD42017059299). Five studies for nicotine use and nine studies for SUD (other than nicotine) were analyzed. Regarding nicotine use, results from randomized controlled trials (RCT) have found a decrease in nicotine use after 12 weeks of 200-600mg/day clozapine, as compared with lower doses. In SUD improvement (other than nicotine), RCT have shown superiority of clozapine when compared with risperidone, in short-term studies (from 4 to 12 weeks) performed in cannabis users. In long-term studies (1 year), clozapine was equal to ziprasidone in reducing cannabis use and equal to treatment as usual in reducing alcohol use. We conclude that positive results on nicotine use are scarce and derived from studies with a low degree of evidence. Evidence of clozapine on SUD (other than nicotine) is stronger, especially when clozapine is compared with first generation antipsychotics in poly-substance users. When compared with second generation antipsychotics, clozapine was superior to risperidone but equal to olanzapine or ziprasidone in poly-substance and cannabis users.

Topics: Antipsychotic Agents; Clozapine; Comorbidity; Diagnosis, Dual (Psychiatry); Humans; Schizophrenia; Substance-Related Disorders

Up to 75% of people with serious mental illness (SMI) such as schizophrenia and bipolar disorder have co-occurring substance use disorders (dual diagnosis). Dual diagnosis can have an adverse effect on treatment and prognosis of SMI.. To evaluate the effects of risperidone compared to treatment with other antipsychotics (first-generation and other second-generation antipsychotics) used in people with serious mental illness and co-occurring substance misuse.. On 6 January 2016 and 9 October 2017, we searched the Cochrane Schizophrenia Group's Study-Based Register of Trials (including trial registers).. We selected randomised trials of risperidone versus any other antipsychotic in people with SMI and substance abuse (dual diagnosis). We included trials meeting our inclusion criteria and reporting useable data. We excluded trials that either did not meet our inclusion criteria or met our inclusion criteria but did not report any useable data.. We independently inspected citations and selected studies. For included studies, we independently extracted data and appraised study quality. For binary outcomes we calculated the risk ratios (RRs) and their 95% confidence intervals. For continuous outcomes we calculated the mean differences (MDs) and their 95% confidence intervals. We pooled data using random-effects meta-analyses and assessed the quality of evidence, creating a 'Summary of findings' table using the GRADE approach.. We identified eight randomised trials containing a total of 1073 participants with SMI and co-occurring substance misuse. Seven of these contributed useable data to the review. There was heterogeneity in trial design and measurement. Risperidone was compared to clozapine, olanzapine, perphenazine, quetiapine and ziprasidone. Few trials compared risperidone with first-generation agents. Few trials examined participants with a dual diagnosis from the outset and most trials only contained separate analyses of subgroups with a dual diagnosis or were secondary data analyses of subgroups of people with a dual diagnosis from existing larger trials.For risperidone versus clozapine we found no clear differences between these two antipsychotics in the reduction of positive psychotic symptoms (1 randomised controlled trial (RCT), n = 36, mean difference (MD) 0.90, 95% CI -2.21 to 4.01, very low quality evidence), or reduction in cannabis use (1 RCT, n = 14, risk ratio (RR) 1.00, 95% CI 0.30 to 3.35, very low quality evidence), improvement in subjective well-being (1 RCT, n = 36, MD -6.00, 95% CI -14.82 to 2.82, very low quality evidence), numbers discontinuing medication (1 RCT, n = 36, RR 4.05, 95% CI 0.21 to 78.76, very low quality evidence), extrapyramidal side-effects (2 RCTs, n = 50, RR 2.71, 95% CI 0.30 to 24.08; I² = 0%, very low quality evidence), or leaving the study early (2 RCTs, n = 45, RR 0.49, 95% CI 0.10 to 2.51; I² = 34%, very low quality evidence). Clozapine was associated with lower levels of craving for cannabis (1 RCT, n = 28, MD 7.00, 95% CI 2.37 to 11.63, very low quality evidence).For risperidone versus olanzapine we found no clear differences in the reduction of positive psychotic symptoms (1 RCT, n = 37, MD -1.50, 95% CI -3.82 to 0.82, very low quality evidence), reduction in cannabis use (1 RCT, n = 41, MD 0.40, 95% CI -4.72 to 5.52, very low quality evidence), craving for cannabis (1 RCT, n = 41, MD 5.00, 95% CI -4.86 to 14.86, very low quality evidence), parkinsonism (1 RCT, n = 16, MD -0.08, 95% CI -1.21 to 1.05, very low quality evidence), or leaving the study early (2 RCT, n = 77, RR 0.68, 95% CI 0.34 to 1.35; I² = 0%, very low quality evidence).For risperidone versus perphenazine, we found no clear differences in the number of participants leaving the study early (1 RCT, n = 281, RR 1.05, 95% CI 0.92 to 1.20, low-quality evidence).For risperidone versus quetiapine, we found no clear differences in the number of participants leaving th. There is not sufficient good-quality evidence available to determine the effects of risperidone compared with other antipsychotics in people with a dual diagnosis. Few trials compared risperidone with first-generation agents, leading to limited applicability to settings where access to second-generation agents is limited, such as in low- and middle-income countries. Moreover, heterogeneity in trial design and measurement of outcomes precluded the use of many trials in our analyses. Future trials in this area need to be sufficiently powered but also need to conform to consistent methods in study population selection, use of measurement scales, definition of outcomes, and measures to counter risk of bias. Investigators should adhere to CONSORT guidelines in the reporting of results.

Topics: Antipsychotic Agents; Benzodiazepines; Clozapine; Diagnosis, Dual (Psychiatry); Humans; Mental Disorders; Olanzapine; Patient Dropouts; Perphenazine; Piperazines; Quetiapine Fumarate; Randomized Controlled Trials as Topic; Risperidone; Schizophrenia; Substance-Related Disorders; Thiazoles

Schizophrenia is a heterogenous and severe neuropsychiatric disorder that affects nearly 1% of the population worldwide. Antipsychotic drugs are the mainstay of treatment, but not all patients with schizophrenia respond to treatment with these agents. Clozapine, the first atypical antipsychotic, is a highly effective medication for patients with schizophrenia who do not respond to other antipsychotics. Although clozapine tends not to produce extrapyramidal symptoms, other side effects of the drug (e.g., agranulocytosis, myocarditis, seizures) limit its widespread use. This chapter reviews clozapine's unique clinical effects and unusual pharmacological profile. In addition to its effects in treatment-resistant schizophrenia, clozapine has been shown to decrease suicidality, which occurs at an increased rate in patients with schizophrenia. Still preliminary, but consistent data, also suggest that clozapine limits substance use in these patients, an important effect since substance use disorders are common in patients with schizophrenia and are associated with a poor outcome, including an increased risk for suicide and poor response to treatment. We have suggested, from animal studies, that clozapine's apparent ability to limit substance use may occur through its actions as a weak dopamine D2 receptor antagonist, a potent norepinephrine α-2 receptor antagonist and a norepinephrine reuptake inhibitor. Using animal models, we have built combinations of agents toward creation of safer clozapine-like drugs to reduce substance use in these patients. Future research into the mechanisms of action of clozapine toward the development of safe clozapine-like agents is of great public health importance.

Topics: Animals; Antipsychotic Agents; Clozapine; Humans; Schizophrenia; Substance-Related Disorders; Suicide

The dopamine D

Topics: Animals; Drug Discovery; Humans; Ligands; Molecular Targeted Therapy; Neoplasms; Parkinson Disease; Receptors, Dopamine D4; Small Molecule Libraries; Substance-Related Disorders

Although the increased risk of violent behavior in individuals with schizophrenia is now well-established, there is considerable uncertainty in pharmacological strategies to reduce this risk. In this review, we performed a systematic search of three electronic databases from January 2000 to March 2010 of treatment research on the management of violence in schizophrenia. We identified eight randomized controlled trials. The main findings included the association of nonadherence to antipsychotic medication to violent outcomes, a specific anti-aggressive effect of clozapine and short-term benefits of adjunctive β-blockers. There was little evidence on the efficacy of adjunctive mood stabilizers, depot medication or electroconvulsive therapy. Future research should use validated outcomes, longer follow-up periods and investigate patients with comorbid substance misuse.

Topics: Adrenergic beta-Antagonists; Antipsychotic Agents; Clozapine; Comorbidity; Electroconvulsive Therapy; Female; Humans; Male; Medication Adherence; Randomized Controlled Trials as Topic; Schizophrenia; Substance-Related Disorders; Violence

In patients with a psychotic disorder, substance abuse is a major problem. Substance abuse is associated with changes in dopaminergic neurotransmission of dopamine D1 and D2 receptors. Differences in efficacy between antipsychotics on substance abuse could be explained by differences in D2 receptor occupancy rate, differences in dissociation rate of the dopamine D2 receptor and differences in D1/D2 receptor occupancy ratio. Since clozapine and risperidone show a maximal difference in these properties, we review the effect of these antipsychotics on substance abuse. The results suggest a superior effect of clozapine for the long-term treatment of substance abuse. This could support the hypothesis that low occupancy of the dopamine D2 receptor, a high dissociation rate and a high D1/D2 receptor ratio is related to efficacy on substance abuse. The results of this review suggest that clozapine could be considered as the medication of first choice in treating patients with substance use disorder.

Topics: Antipsychotic Agents; Clozapine; Humans; Psychotic Disorders; Receptors, Dopamine D1; Receptors, Dopamine D2; Risperidone; Substance-Related Disorders

Substance use disorder is common in patients with schizophrenia and dramatically worsens their outcome. The typical antipsychotic medications, introduced more than 50 years ago, are effective for the treatment of psychosis but may have only limited efficacy in patients with these co-occurring disorders because patients continue to use substances while taking them. In preliminary studies, however, several of the atypical antipsychotic medications have shown promise for reducing alcohol and drug use in patients with schizophrenia. A neurobiological formulation is discussed, suggesting that the use of substances in patients with schizophrenia may be based on a dysfunction within the dopamine-mediated brain reward circuitry and that clozapine, in particular, may potentially ameliorate this dysfunction and lessen the desire for substance use. Medications for the treatment of alcohol use disorders, such as disulfiram, naltrexone, and acamprosate, as well as other adjunctive medications, may also be useful. Further studies are required to establish a solid evidence base of best practices for the use of medications in these patients.

Topics: Acamprosate; Alcohol Deterrents; Antipsychotic Agents; Clozapine; Disulfiram; Drug Interactions; Humans; Naltrexone; Narcotics; Schizophrenia; Substance-Related Disorders; Taurine

The high rates of co-morbidity of drug addiction with depression may be attributable to shared neurobiology. Here, we discuss shared neurobiological substrates in drug withdrawal and depression, with an emphasis on changes in brain reward circuitry that may underlie anhedonia, a core symptom of depression and drug withdrawal. We explored experimentally whether clinical antidepressant medications or other treatments would reverse the anhedonia observed in rats undergoing spontaneous nicotine or amphetamine withdrawal, defined operationally as elevated brain reward thresholds. The co-administration of selective serotonin reuptake inhibitors with a serotonin-1A receptor antagonist, or the tricyclic antidepressant desipramine, or the atypical antidepressant bupropion ameliorated nicotine or amphetamine withdrawal in rats. Thus, increases in monoaminergic neurotransmission, or neuroadaptations induced by increased monoaminergic neurotransmission, ameliorated depression-like aspects of drug withdrawal. Further, chronic pretreatment with the atypical antipsychotic clozapine, that has some efficacy in the treatment of the depression-like symptoms of schizophrenia, attenuated nicotine and amphetamine withdrawal. Finally, a metabotropic glutamate 2/3 receptor antagonist reversed threshold elevations associated with nicotine withdrawal. The effects of these pharmacological manipulations are consistent with the altered neurobiology observed in drug withdrawal and depression. Thus, these data support the hypothesis of common substrates mediating the depressive symptoms of drug withdrawal and those seen in psychiatric patients. Accordingly, the anhedonic state associated with drug withdrawal can be used to study the neurobiology of anhedonia, and thus contribute to the identification of novel targets for the treatment of depression-like symptoms seen in various psychiatric and neurological disorders.

Topics: Adrenergic Uptake Inhibitors; Animals; Antipsychotic Agents; Central Nervous System Stimulants; Clozapine; Depressive Disorder; Dopamine Agents; Glutamic Acid; Humans; Norepinephrine; Selective Serotonin Reuptake Inhibitors; Substance Withdrawal Syndrome; Substance-Related Disorders

In recent years, there has been a growing interest in developing adequate treatments for patients with a diagnosis of schizophrenia and a comorbid substance use disorder (SUD). In the present paper we aim to critically review published reports on the use of conventional and second-generation antipsychotics in the treatment of patients with schizophrenia and comorbid SUD, to provide clinicians with a clearer view of the pharmacological treatment of this highly prevalent dual diagnosis based upon the evidence arising from the scientific literature.. A search of the relevant literature from Medline, PsycLIT and EMBASE databases, included in the Science Citation Index, and available up to November 2006 was conducted using the terms: 'schizophrenia', 'substance use disorder' and 'antipsychotics'.. While research on the use of conventional antipsychotics has remained limited, the majority of studies suggest the effectiveness of second-generation antipsychotics, particularly clozapine, for patients with schizophrenia and a comorbid substance use disorder.. In the absence of randomized controlled trials that could provide more reliable information, clinical decisions may need to rely on indirect data provided by the increasing number of case reports, open trials and retrospective studies showing a decrease in cigarette smoking, alcohol, cocaine or cannabis use and an improvement of overall psychiatric symptoms.

Topics: Alcoholism; Antipsychotic Agents; Clozapine; Cocaine-Related Disorders; Combined Modality Therapy; Comorbidity; Cross-Sectional Studies; Diagnosis, Dual (Psychiatry); Humans; Marijuana Abuse; Schizophrenia; Smoking Cessation; Substance-Related Disorders

Co-occurring substance use disorder is common among patients with schizophrenia, and its presence greatly worsens the course of schizophrenia. A number of theories have been introduced to explain the increased rate of substance use disorder in these patients. These theories include the notion that substance use could trigger psychotic symptoms in vulnerable individuals and the idea that the substances are used to self-medicate symptoms of schizophrenia. Our group and others have advanced a neurobiological hypothesis to explain this comorbidity-that a mesocorticolimbic brain reward circuit underlies the substance use disorder in patients with schizophrenia. Treatment of substance use disorder in these patients is best done with integrated treatment programs that combine psychosocial interventions with pharmacotherapy. Recent data suggest that the atypical antipsychotic clozapine and perhaps other atypical agents may lessen substance use in patients with schizophrenia. My colleagues and I have proposed that clozapine's effect in these patients may be related to its ability to decrease the brain reward circuit dysfunction. Research is continuing on the use of atypical antipsychotics in patients with schizophrenia and comorbid substance abuse. The adjunctive use of naltrexone or other agents also may be helpful. Further research on the optimal pharmacologic approach to patients with dual diagnosis is needed.

Topics: Alcohol Deterrents; Alcoholism; Antipsychotic Agents; Clozapine; Comorbidity; Diagnosis, Dual (Psychiatry); Disulfiram; Drug Therapy, Combination; Humans; Naltrexone; Narcotic Antagonists; Schizophrenia; Substance-Related Disorders; Treatment Outcome

Schizophrenia is noted for the remarkably high prevalence of substance use disorders (SUDs) including nicotine (>85%), alcohol and stimulants. Mounting evidence supports the hypothesis that the endophenotype of schizophrenia involves hypofunction of a subpopulation of cortico-limbic NMDA receptors. Low doses of NMDA receptor antagonists such as ketamine replicate in normal volunteers positive, negative and cognitive symptoms of schizophrenia as well as associated physiologic abnormalities such as eye tracking and abnormal event related potentials. Genetic studies have identified putative risk genes that directly or indirectly affect NMDA receptors including D-amino acid oxidase, its modulator G72, proline oxidase, mGluR3 and neuregulin. Clinical trials have shown that agents that directly or indirectly enhance the function of the NMDA receptor at its glycine modulatory site (GMS) reduce negative symptoms and in the case of D-serine and sarcosine improve cognition and reduce positive symptoms in schizophrenic subjects receiving concurrent anti-psychotic medications. Notably, the GMS partial agonist D-cycloserine exacerbates negative symptoms in clozapine responders whereas full agonists, glycine and D-serine have no effects, suggesting clozapine may act indirectly as a full agonist at the GMS of the NMDA receptor. Clozapine treatment is uniquely associated with decreased substance use in patients with schizophrenia, even without psychologic intervention. Given the role of NMDA receptors in the reward circuitry and in substance dependence, it is reasonable to speculate that NMDA receptor dysfunction is a shared pathologic process in schizophrenia and co-morbid SUDs.

Topics: Acamprosate; Alcohol Deterrents; Animals; Antipsychotic Agents; Clozapine; Diagnostic Imaging; Glutamates; Humans; Receptors, N-Methyl-D-Aspartate; Schizophrenia; Substance-Related Disorders; Taurine

It is known that 9-13% of individuals with a diagnosis of schizophrenia commits suicide. In addition, patients with schizophrenia have approximately a 50% lifetime risk for attempting suicide. The authors review the identified risk factors for suicide in schizophrenia. The most significant risk factors include the age of the patient, male gender, depression, presence of positive symptoms and substance abuse. There is evidence that implicates the serotonin system in the suicide of individuals with schizophrenia. Overactivity of the hypothalamo-pituitary-adrenal axis has also been reported in individuals who went on to attempt suicide. The authors review the molecular biology of suicide in schizophrenia. With regard to prevention of suicide, pharmacological intervention with typical antipsychotics and antidepressants may be helpful. It is suggested that atypical anti-psychotics, in particular clozapine may provide additional benefit in reducing the rate of suicide attempts. The authors emphasise the importance of early treatment of individuals with a diagnosis of schizophrenia, the role of maintenance therapy and the importance of a collaborative approach between in- and outpatient services.

Topics: Age Factors; Antidepressive Agents; Antipsychotic Agents; Clozapine; Depression; Female; Humans; Male; Neuropeptide Y; Polymorphism, Genetic; Risk Factors; Schizophrenia; Schizophrenic Psychology; Serotonin Plasma Membrane Transport Proteins; Sex Factors; Substance-Related Disorders; Suicide; Suicide Prevention

Although life prevalence of substance use disorders among patients with schizophrenia is close to 50%, few studies have been carried out to date to identify an integrated pharmacological treatment for this comorbidity. So far, the most promising results, that we report here, have been obtained with clozapine. To a lesser extent, quetiapine and olanzapine, both clozapine analogues, have also shown promising results. Further to these observations, the present paper critically reviews the advantages associated with clozapine, quetiapine and olanzapine, and their relevance to the treatment of addiction among schizophrenic patients. Six characteristics seem to distinguish clozapine, quetiapine and olanzapine from the first-generation antipsychotics: (1) acting preferentially on the reward system, these second-generation antipsychotics (mainly clozapine and quetiapine) induce almost no extrapyramidal symptoms; (2) quickly dissociating from D(2), theses drugs (mainly clozapine and quetiapine) seem not to induce dysphoria, unlike conventional antipsychotics like haloperidol;(3) these drugs (mainly clozapine) seem more effective in the treatment of negative symptoms than conventional antipsychotics; (4) because of a diversified activity on several serotoninergic and noradrenergic receptors, these drugs positively alter mood, which does not seem to be the case with conventional antipsychotics, except for flupenthixol; (5) these drugs have a positive impact on cognition, which is not the case with the first-generation antipsychotics; (6) unlike conventional antipsychotics, these drugs seem to have a moderate affinity for 5-HT(3), the receptor on which ondansetron, an anti-craving medication, acts.

Topics: Affect; Antipsychotic Agents; Basal Ganglia Diseases; Benzodiazepines; Clozapine; Cognition; Comorbidity; Dibenzothiazepines; Drug Therapy, Combination; Humans; Olanzapine; Pirenzepine; Quetiapine Fumarate; Receptors, Serotonin; Receptors, Serotonin, 5-HT3; Schizophrenia; Substance-Related Disorders; Treatment Outcome

Research on the optimal pharmacotherapy for people with schizophrenia and co-occurring substance use disorders remains in its infancy. This report reviews existing data and provides an update on recent research. The confluence of findings is consistent with a model of a reward dysfunction inherent in the neuropathology of schizophrenia, leading to a heightened vulnerability of people with schizophrenia to substance use disorders. Studies indicate that patients with dual disorders have difficulty tolerating conventional antipsychotics, have higher rates of medication nonadherence, and have greater impulsivity and sensation seeking. Limited evidence suggests that clozapine treatment may be associated with reduced substance abuse, with weaker evidence suggesting that other novel antipsychotics may have similar, but potentially less potent, effects. Controlled trials to test the effects of these medications are underway. A number of recent studies indicate that bupropion can facilitate reduced tobacco smoking among patients with schizophrenia. The preferential use of novel antipsychotics, a lower threshold for prescription of clozapine, the use of bupropion for smoking cessation, careful monitoring of compliance, and possible use of other medications for substance use disorders when indicated are recommended in pharmacologic management for people with co-occurring substance use disorders and schizophrenia.

Topics: Antidepressive Agents, Second-Generation; Antipsychotic Agents; Bupropion; Clozapine; Humans; Schizophrenia; Smoking Cessation; Substance-Related Disorders; Treatment Outcome

The past 5 years have witnessed an intense period of change in the pharmacotherapy of schizophrenia. Several new antipsychotic agents have become available for clinical use, and more are likely to appear over the next few years. The new agents require that clinicians treating patients with schizophrenia adopt new ways of thinking regarding the pharmacotherapy of this illness. Longer drug trials than have traditionally been used may be required to determine response to the newer agents, and response should be measured across negative symptoms, cognitive symptoms, and broader rehabilitative dimensions. Clozapine has an established role in treatment-resistant schizophrenia. Other new antipsychotics are being used with broader clinical indications. The relative efficacy of these agents, particularly in treatment-refractory patients, remains to be determined. The availability of the newer agents may represent an opportunity to reduce the incidence of tardive dyskinesia and to gain better management of comorbid substance abuse and aggression among schizophrenic patients. Significant cost savings could accrue from more effective disease management.

Topics: Aggression; Antipsychotic Agents; Clinical Trials as Topic; Clozapine; Comorbidity; Cost-Benefit Analysis; Drug Costs; Dyskinesia, Drug-Induced; Health Care Costs; Humans; Schizophrenia; Schizophrenic Psychology; Substance-Related Disorders; Treatment Outcome

Aggressive behavior in schizophrenic patients, although infrequent, is a serious problem. It is, however, a relatively common reason for psychiatric admission and poses an increasing threat as more patients are cared for in the community. There is a strong association between substance abuse and violent behavior, and comorbid substance abuse in schizophrenia is also a major problem. The recent introduction of the atypical antipsychotics has brought hope for the pharmacologic management of this group of patients. These newer agents are thought to have antiaggressive effects and perhaps decrease cravings for illicit substances and alcohol. Data from a number of studies have demonstrated that clozapine has antiaggressive effects. A retrospective analysis of 331 schizophrenic patients assessed the effects of clozapine on hostility and aggression. At baseline, 31.4% of patients showed overt physical aggression, and after an average of 47 weeks of treatment with clozapine, this rate had fallen to 1.1%. The antiaggressive effects of clozapine were relatively specific and could not be explained by sedation or general antipsychotic effects. These effects were more pronounced than the effects on other symptoms and were also present in those patients who showed the highest pretreatment levels of hostility and aggression. Clozapine may also be of benefit in the treatment of schizophrenic patients with comorbid substance abuse. After 6 months of treatment with clozapine, substance abusers and nonabusers with schizophrenia or schizoaffective disorder showed similar improvements on measures of psychopathology and psychosocial functioning.

Topics: Adult; Aggression; Antipsychotic Agents; Clozapine; Comorbidity; Humans; Psychotic Disorders; Quality of Life; Retrospective Studies; Schizophrenia; Schizophrenic Psychology; Social Adjustment; Substance-Related Disorders; Treatment Outcome; Violence

Approximately half of the patients who suffer from schizophrenia are also substance abusers at some time during their illness. The motivational drive toward abusive consumption is compounded in individuals with schizophrenia who turn toward substances with reinforcing properties to alleviate aspects of psychosis. This review examines the prevalence, etiology, and clinical effects of substance abuse (e.g., alcohol, nicotine, cocaine) among individuals with schizophrenia. Clearly, substance abuse persists despite and in spite of treatment with typical antipsychotics. The efficacy of newer generation antipsychotics in the reduction of substance abuse among the schizophrenic population has yet to be established, but clozapine has been shown to reduce alcohol, smoking, and cocaine use. Hence, clozapine is a therapeutic option for dually diagnosed patients because of its superior efficacy relative to conventional neuroleptics and its capacity to control substance abuse.

Topics: Antipsychotic Agents; Clozapine; Comorbidity; Cost-Benefit Analysis; Diagnosis, Dual (Psychiatry); Drug Monitoring; Humans; Precipitating Factors; Prevalence; Schizophrenia; Substance-Related Disorders

Neuroleptics were the first modern class of pharmacotherapeutic agents available for the treatment of schizophrenia. Although they were effective in reducing florid psychotic symptoms, up to 90% of treated individuals subsequently developed extrapyramidal symptoms (EPS) (akathisia, dystonia, or parkinsonism), and about 20% developed tardive dyskinesia (TD). When clozapine became commercially available for treatment-resistant and treatment-intolerant (i.e., prone to EPS and TD) schizophrenic individuals, it became apparent that an antipsychotic need not induce motor side effects to be efficacious in reducing the symptomatology of schizophrenia. Sociodemographic, behavioral, and clinical predictors of TD are useful in identifying a subset of schizophrenic individuals who would benefit from treatment with clozapine, the prototype atypical antipsychotic whose efficacy and motor side effect profile are superior to those of chlorpromazine. This favorable motor side effect profile of clozapine contributes to improved patient outcomes by reducing noncompliance, substance abuse, and suicide, resulting in improved quality of life and savings on health care costs.

Topics: Age Factors; Aged; Basal Ganglia Diseases; Clozapine; Dyskinesia, Drug-Induced; Female; Humans; Male; Middle Aged; Prevalence; Risk Factors; Schizophrenia; Substance-Related Disorders; Suicide; Suicide Prevention; Treatment Outcome; Treatment Refusal

Tardive dyskinesia (TD) is the most feared and troublesome extrapyramidal side-effect of prolonged neuroleptic (NL) treatment. We present a review of TD. Its pathophysiology remains elusive, although extrapyramidal symptoms (EPS) increase the liability for TD. Nowadays, therefore, avoidance of all EPS remains the best preventive strategy, as it is not possible to predict which liable patients will develop TD, or of what type or severity. TD frequently includes dystonic features, and is more disabling when these dystonias are present. Clozapine (CLZ) has been reported to be effective in suppressing nearly 60% of TD syndromes, specially those with dystonic features. Based on the few reports in the literature on CLZ and TD by the early 1980s, we started to videotape the first severe TD patient treated with CLZ in 1984. We present the first three case reports of severe TD, with prominent disabling dystonic features, treated with CLZ and videotaped since pretreatment and then periodically for 12, 8 and 5 years of follow-up, respectively. The patients' current diagnosis, gender and age are: Case 1, DSM-IV Schizophrenia Residual Type, male, 39 years; Case 2, DSM-IV Polysubstance Related Disorder, Borderline Personality Disorder, female, 28 years; Case 3, DSM-IV Schizoaffective Disorder, male, 40 years. Two of them presented with a recurrence of TD because of CLZ interruption within the first 2 months of treatment, with no further breakthrough to date. The first two cases have complete remission of TD; the third case is still improving after 5 years of CLZ treatment, with only minor dystonic features persisting that constitute no impairment for work or daily routines at present. All patients, independent of their psychiatric primary diagnosis, have shown significant and progressive improvement in both motor and psychosocial aspects. None of them has been rehospitalized. Long-term treatment and follow-up is required to avoid TD recurrence and to assure full assessment of treatment effectiveness. Ideally, periodic video recording with standardized examination is advisable for long-term follow-up and outcome assessment. At present, CLZ could be regarded as the drug of choice for patients with TD, specially for those with disabling and or dystonic features and who require ongoing NL therapy. The use of novel antipsychotic agents for TD treatment and prevention, with their low EPS liability, is promising, but has yet to be tested.

Topics: Adult; Antipsychotic Agents; Clozapine; Dyskinesia, Drug-Induced; Female; Follow-Up Studies; Humans; Male; Schizophrenia; Substance-Related Disorders; Videotape Recording

Topics: Adult; Antipsychotic Agents; Clozapine; Drug Therapy, Combination; Female; Humans; Male; Middle Aged; Psychotic Disorders; Risperidone; Substance-Related Disorders; Treatment Outcome

Several case studies indicate that clozapine use is associated with reductions in the use of nicotine, alcohol, or illicit drugs. Although not designed to assess clozapine, this study explored a posteriori the effects of clozapine on alcohol and drug use disorders among schizophrenia patients. Among 151 patients with schizophrenia or schizoaffective disorder and co-occurring substance use disorder who were studied in a dual-disorder treatment program, 36 received clozapine during the study for standard clinical indications. All participants were assessed prospectively at baseline and every 6 months over 3 years for psychiatric symptoms and substance use. Alcohol-abusing patients taking clozapine experienced significant reductions in severity of alcohol abuse and days of alcohol use while on clozapine. For example, they averaged 54.1 drinking days during 6-month intervals while off clozapine and 12.5 drinking days while on clozapine. They also improved more than patients who did not receive clozapine. At the end of the study, 79.0 percent of the patients on clozapine were in remission from alcohol use disorder for 6 months or longer, while only 33.7 percent of those not taking clozapine were remitted. Findings related to other drugs in relation to clozapine were also positive but less clear because of the small number of patients with drug use disorders. This study was limited by the naturalistic design and the lack of prospective, standardized measures of clozapine use. The use of clozapine by patients with co-occurring substance disorders deserves further study in randomized clinical trials.

Topics: Adult; Alcoholism; Antipsychotic Agents; Clozapine; Comorbidity; Female; Humans; Male; Schizophrenia; Substance-Related Disorders; Treatment Outcome

To describe (i) the clinical characteristics of individuals referred to the Tertiary Referral Service for Psychosis (TRSP) and (ii) the recommendations TRSP made for future treatment across psychopharmacological and other intervention domains.. Retrospective audit of clinical data collected during the assessment process of individuals who accessed TRSP between 02/06/2020 and 31/12/2022. Categories of recommendations made following collaborative care planning comprised psychopharmacological, neuropsychological, psychological, psychosocial, physical health, substance misuse and other domains.. Eighty-two individuals were included, with diagnoses most commonly of schizophrenia (54.9%) and schizoaffective disorder (30.5%). The median PANSS score was 88.0 (73-100). Social occupational functioning was very poor (SOFAS M = 37.0, SD = 15.1). Cognitive functioning was poor (RBANS: M = 74.6; SD: 15.0). 67.1% had physical health comorbidities, with high prevalence of smoking (52.4%) and substance misuse (25.6%). Psychopharmacological recommendations (made for 81.7%) included clozapine trial (25.6%), clozapine dose change/augmentation (22.0%) and rationalisation of polypharmacy (12.2%). Neuropsychological (73.2%), psychological (39.0%) and psychosocial (85.4%) recommendations included access to cognitive remediation, psychological therapy and disability support. Physical health and substance misuse interventions were recommended for 91.5% and 20.7%, respectively.. Individuals referred to the TRSP had marked clinical and functional impairments. Holistic collaborative care planning complemented psychopharmacological interventions with psychological, psychosocial and physical healthcare recommendations.

Topics: Clozapine; Humans; Psychotic Disorders; Retrospective Studies; Schizophrenia; Substance-Related Disorders

Preliminary evidence suggest clozapine is associated with more favorable impact on concurrent substance use disorder related outcomes in patients with concurrent schizophrenia spectrum disorders (SSD). At the same time, there is a dearth of evidence with regards to clozapine outcomes in the context of concurrent methamphetamine or amphetamine use disorder (MAUD).. To examine whether clozapine use decreases rate of methamphetamine or amphetamine (MA) relapses and increases the likelihood of maintaining abstinence from any MA use.. A descriptive-analytic retrospective cohort study was conducted on individuals with SSD-MAUD in an inpatient provincial treatment and rehabilitation center for concurrent disorders. Antipsychotic exposure was categorized as "on clozapine" or "on other antipsychotic(s)." Data were collected using electronic health records. Logistic regression was used to examine association of clozapine treatment with likelihood of complete abstinence from MA use for the duration of antipsychotic exposure. Negative binomial regression was used to examine association of clozapine treatment with rate of MA relapses for the duration of antipsychotic exposure.. In this study, clozapine use compared with other antipsychotics in SSD was associated with improved outcomes related to severe concurrent MAUD. Co-prescription of psychostimulant medications was associated with a poor outcome.

Topics: Amphetamine; Antipsychotic Agents; Central Nervous System Stimulants; Clozapine; Female; Humans; Male; Methamphetamine; Recurrence; Retrospective Studies; Schizophrenia; Substance-Related Disorders

Research on the effectiveness of pharmacotherapies for schizophrenia and comorbid substance use disorder (SUD) is very sparse, and non-existent on the prevention of the development of SUDs in patients with schizophrenia.. To compare the real-world effectiveness of antipsychotics in schizophrenia in decreasing risk of developing an initial SUD, and psychiatric hospital admission and SUD-related hospital admission among patients with an SUD.. Two independent national cohorts including all persons diagnosed with schizophrenia (. For patients with schizophrenia without an SUD, clozapine use (Finland: aHR 0.20, 95% CI 0.16-0.24,. Clozapine and antipsychotic polytherapy are most strongly associated with reduced risk of developing SUDs among patients with schizophrenia, and with lower relapse rates among patients with both diagnoses.

Topics: Antipsychotic Agents; Chronic Disease; Clozapine; Humans; Recurrence; Schizophrenia; Substance-Related Disorders

Patients with psychotic disorders often have substance use disorders and other addictions. The objective of this study was to know the current treatment situation of these patients focusing on clozapine, which was proposed in most consensus as antipsychotic of first choice in this indication.. A survey with 14 questions on aspects related to the treatment and management of the dual disorders was developed, emphasizing the role of clozapine in this disease.. The survey was answered by 199 experts in mental illnesses (90.5% physicians and 9.5% psychologists). A total of 88.4% of experts were able to prescribe clozapine, but the majority (89.4%) administered the drug to patients with resistant schizophrenia without considering a dual disorder. Only 30.8% considered the use of clozapine in patients with dual psychosis. The underutilization of clozapine in these patients was mainly attributed to controls of the pharmacovigilance plan, including frequent leukocyte count (57.1%), and lack of drug education (35.6%). The main measures proposed to increase its use are fewer blood tests (29.3%), more training (27.8%), and fewer administrative problems (25.1%).. In order to improve the treatment of patients with dual psychosis, it is necessary to simplify the therapy and increase the training of professionals in the use of atypical antipsychotics, especially clozapine, designed to be the drug of choice in the main expert consensus.

Topics: Antipsychotic Agents; Attitude of Health Personnel; Clozapine; Cross-Sectional Studies; Diagnosis, Dual (Psychiatry); Humans; Leukocyte Count; Perception; Practice Patterns, Physicians'; Psychotic Disorders; Schizophrenia; Substance-Related Disorders

Novel psychoactive substances (NPS), or 'legal highs' are becoming more commonly used as recreational substances in the UK. Their clinical effects are little known and vary considerably between substances. This case discusses a psychiatric inpatient who repeatedly used a stimulant NPS called 'el blanco' while on leave, precipitating relapses of his schizophrenia. The patient initially denied drug use, considering legal highs as different from drugs. The relationship between NPS use and mental state was eventually revealed on careful direct questioning. He recovered and was discharged following treatment with clozapine and education about NPS use. We suggest that specific questioning about NPS usage is added to routine psychiatric history taking and that patients using NPS should be educated about the substances' use.

Topics: Adult; Antipsychotic Agents; Central Nervous System Stimulants; Clozapine; Humans; Illicit Drugs; Male; Psychotropic Drugs; Recurrence; Schizophrenia, Paranoid; Substance-Related Disorders

The efficacy of clozapine for the treatment of schizophrenia has been demonstrated. However, a range of adverse events have been associated with its use. To date, there remains a paucity of data regarding the prevalence of clozapine-induced cardiovascular (CV) and parameters associated with the development of metabolic syndrome, alongside associated risk factors for their development.. An observational, clinical cohort study design of 355 clozapine patients who were enrolled in the Barwon Health Clozapine Program at Geelong Hospital, Victoria, Australia, between 2008-12. Medical records were accessed retrospectively. Multivariate logistic regression was used to determine associations with adverse event(s).. Older age of commencement with clozapine was consistently associated with increased risk of CV abnormalities, with the exception of tachycardia where older age was protective (Odds Ratio [OR]: 0.97; 95% Confidence Intervals [CI]: 0.95, 0.99). Males had significantly greater odds of most metabolic disturbances with the exception of being obese (BMI: ≥30 OR: 0.45; 95% CIs: 0.24, 0.85). Older age of commencement was a significantly associated variable with High- Density Lipoprotein-cholesterol (OR: 1.03; 95% CIs: 1.01, 1.07) and fasting glucose (OR:1.04; 95% CIs: 1.02, 1.07). An increase in BMI was consistently and significantly associated with all metabolic events.. Male patients who are obese at any point during treatment and older at treatment commencement may be the most vulnerable to adverse CV and metabolic events. While future studies using a matched case-control design may be required to verify these findings, we recommend that treating clinicians consider these risks when assessing patient suitability to clozapine therapy.

Topics: Adult; Age Factors; Aged; Antipsychotic Agents; Blood Glucose; Cardiovascular Diseases; Cholesterol, HDL; Clozapine; Cohort Studies; Female; Humans; Male; Metabolic Diseases; Middle Aged; Prevalence; Retrospective Studies; Risk Factors; Schizophrenia; Sex Factors; Substance-Related Disorders; Victoria

Co-occurring substance use disorders (SUD), including alcohol, are common in schizophrenia (SZ) and are associated with poor outcome. Emerging data suggest that individuals with SZ have a dysfunctional brain reward circuit that may underlie their frequent use of alcohol and other substances, and further, that the atypical antipsychotic, clozapine (CLOZ), limits alcohol/substance use in these individuals, potentially by ameliorating this brain reward circuit dysfunction. To explore this hypothesis, reward functioning in a SZ sample with a history of co-occurring SUD, treated with either CLOZ (n=13) or typical antipsychotic agents (TYP), haloperidol or fluphenazine (n=14), as well as healthy controls (n=16), was evaluated through ratings of pleasurable and aversive odors, stimuli that are processed by several neural structures thought to play a key role in processing rewarding stimuli. Results suggest that CLOZ treatment is associated with broadening and strengthening the hedonic experience of these rewarding olfactory stimuli, both of a pleasant and unpleasant nature. This hedonic appraisal of odors appeared to be independent of odor perception (intensity ratings) and clinical symptoms. These preliminary findings provide important new data in support of the hypothesis that CLOZ ameliorates some aspects of abnormal brain reward functioning in individuals with co-occurring SZ and SUD. Further research may have valuable treatment implications for this population including interventions for other reward-associated deficits in learning, social interactions and other aspects of behavior and cognition.

Topics: Adult; Antipsychotic Agents; Clozapine; Female; Fluphenazine; Haloperidol; Humans; Male; Middle Aged; Odorants; Psychiatric Status Rating Scales; Reward; Schizophrenia; Schizophrenic Psychology; Smell; Substance-Related Disorders

The purpose of this study was to measure the effectiveness of two alternative care pathways for managing patients treated with clozapine.. Medical records for 90 clozapine patients managed via three care pathways were audited for a 24 month period (30 per group). The three care pathways established to manage patients prescribed clozapine include: (1) remaining in public mental health service case management; (2) transitioning to general practitioner-mental health service shared care; or (3) transitioning to private psychiatry sole care. Demographic, illness, medication compliance, service utilisation and performance on clinical outcome measures were collected in the 12 months prior to and following transition.. Across both the private psychiatry and general practitioner (GP) shared care transitioned groups, only one patient had a psychiatric hospital admission in the 12 months following transition, and transitioned patients also had fewer mental health service clinician contacts. Good medication compliance, better skills of daily living, lower levels of illicit substance abuse and a lower intensity of case management history were seen in transitioned patients.. Transitioning appropriate patients taking clozapine to less intensive care pathways like private psychiatrists and GP shared care can be effectively achieved if appropriate supports are in place for both the clinicians and their patients.

Topics: Activities of Daily Living; Adult; Antipsychotic Agents; Clozapine; Female; Humans; Male; Medication Adherence; Middle Aged; Patient Acceptance of Health Care; Patient Care; Retrospective Studies; Schizophrenia; Schizophrenic Psychology; Substance-Related Disorders

This study tested the hypothesis that among patients with schizophrenia the risk and correlates of aggressive behavior differ depending on the level of positive symptoms. Two hundred and fifty-one adults with schizophrenia who were living in the community were assessed by psychiatrists using validated instruments. Patients and collaterals reported aggressive behavior. In a final multivariate model, aggressive behavior was significantly and positively associated with childhood conduct disorder, current use of illicit drugs, positive, threat-control-override (TCO), and depression symptoms. While 16% of the patients with two or fewer positive symptoms engaged in aggressive behavior in the previous six months, this was true of 28.4% of those with three or more positive symptoms (X2 (n=251,1)=5.48, P=0.019). Among patients with high positive symptoms, even univariate analyses failed to detect any factors associated with aggressive behavior other than medication non-compliance, typical antipsychotic medication, and clozapine. By contrast, among patients with few positive symptoms, aggressive behavior was associated with TCO and depression symptoms, young age, male sex, the number of childhood conduct disorder symptoms, prior aggressive behavior, and current illicit drug use. In phases of illness characterized by different levels of positive symptoms, the risk of aggressive behavior and the associated factors differ.

Topics: Adult; Age Factors; Aggression; Antipsychotic Agents; Clozapine; Conduct Disorder; Depression; Female; Humans; Male; Medication Adherence; Middle Aged; Psychiatric Status Rating Scales; Risk Assessment; Risk Factors; Schizophrenia; Schizophrenic Psychology; Sex Factors; Substance-Related Disorders; United Kingdom; Violence

Clozapine has superior efficacy for treating patients with schizophrenia. Its discontinuation could have detrimental consequences. We attempted to identify the clinical parameters that could predict clozapine discontinuation in patients diagnosed as having schizophrenia by conducting a retrospective analysis of all of those who started on clozapine treatment during their hospitalization in our institution between 2002 and 2008 (n=100). Demographic and clinical parameters were analyzed and compared between the 58 patients who continued and the 42 who discontinued clozapine treatment during a follow-up period of 8.1 years. Twenty of the latter patients (47.6%) discontinued clozapine because of nonadherence and 11 (26.2%) because of side effects. Thirty-three of them (78.6%) stopped taking clozapine during the first year of treatment. The duration of clozapine use correlated significantly with the time to readmission (P<0.001). The decrease in number of suicide attempts was higher in those who continued clozapine treatment compared with those who discontinued it (P=0.02). Predictors for drug discontinuation were old age at clozapine initiation and comorbid substance abuse. These findings indicate that patients with schizophrenia with those risk factors need special incentives to be compliant during the first year of clozapine treatment to minimize the negative sequelae of clozapine discontinuation.

Topics: Adolescent; Adult; Aged; Antipsychotic Agents; Clozapine; Comorbidity; Female; Follow-Up Studies; Hospitalization; Humans; Longitudinal Studies; Male; Middle Aged; Patient Compliance; Retrospective Studies; Risk Factors; Schizophrenia; Substance-Related Disorders; Suicide, Attempted; Time Factors; Universities; Young Adult

Clozapine, a poorly tolerated antipsychotic drug, is widely recognized as the only efficacious option in treatment-resistant psychosis. The United Kingdom (U.K.) National Institute of Clinical Excellence (NICE) guidance for its consideration defined a threshold for treatment resistance substantially more liberal than that utilized in seminal studies of efficacy. This study documented adherence to NICE guidance in a patient group likely to be enriched for treatment resistance: 150 consecutive assertive outreach and former rehabilitation inpatients. Evidence of a NICE-compliant treatment trial was adduced from case notes: treatment resistance was determined through discussion with key workers about ongoing clinical problems, including treatment-resistant patients already on clozapine. Reasons for treatment-resistant patients not receiving clozapine were documented. Levels of ongoing clinical problems were compared between treatment-resistant patients on clozapine, treatment-resistant patients not on clozapine, and non-treatment-resistant patients.. Patients' mean age was 41, with illness duration of 16 years. Twelve percent (18 patients) had not had a NICE-compliant trial of treatment, but all 3 treatment-resistant patients in this subgroup were on clozapine already. Forty-five percent of the whole group was treatment resistant: 54% of the treatment-resistant group was treated with clozapine. Of the remaining 46% (i.e., 31 treatment-resistant patients not taking clozapine), 16 refused and 15 could not be treated for medical reasons including the failure of previous trials and neutropenia. Levels of ongoing clinical problems were generally similar between clozapine-treated patients and nontreatment-resistant patients, with significantly greater problems in treatment-resistant patients not taking clozapine. However, positive symptoms remained relatively high in the clozapine group, while substance abuse was actually lower than in the other two groups, and there were no differences between any of the groups in depression and suicide risk.. Tertiary referral assertive outreach and rehabilitation services include a higher proportion of treatment-resistant patients than secondary services, as appropriate. Most patients receive a NICE-compliant trial for the determination of pharmacological treatment resistance, but only just over half of the patients who need clozapine on clinical grounds are taking it. While half of these refuse, the rest encounter insuperable obstacles to treatment. In general, clozapine reduces levels of ongoing clinical problems to those of nontreatment-resistant patients. In view of the difficulties of delivering clozapine to treatment-resistant patients, the development of treatment resistance should be avoided if possible.

Topics: Adult; Aged; Antipsychotic Agents; Clozapine; Comorbidity; Drug Resistance; England; Evidence-Based Medicine; Female; Health Services Accessibility; Humans; Male; Medication Adherence; Middle Aged; Psychiatric Status Rating Scales; Psychotic Disorders; Quality Assurance, Health Care; Schizophrenia; Schizophrenic Psychology; Secondary Prevention; State Medicine; Substance-Related Disorders; Young Adult

Topics: Antipsychotic Agents; Cause of Death; Clozapine; Comorbidity; Humans; Schizophrenia; Substance-Related Disorders

To document and measure various parameters and outcomes in patients prescribed clozapine in a forensic psychiatric setting.. A retrospective file review was conducted on patients prescribed clozapine. Parameters and outcomes were recorded and compared against a group prescribed other antipsychotics, matched for sex and diagnosis.. Patients prescribed clozapine had higher rates of substance misuse syndromes and comorbidity when compared to patients prescribed other antipsychotics. Clozapine was found to be effective in treatment of psychosis. High rates of adverse effects were noted. Discontinuation of clozapine for a variety of reasons was common.. Patients identified as treatment resistant who are prescribed clozapine are often more complex in the pattern of illness and subsequent needs. Clozapine is effective in the treatment of psychosis in this forensic service. Its benefits need to be balanced against the potential for adverse effects and problems ensuring adherence. Regular, objective monitoring of clinical and adverse effects would aid patient safety, clinical decision-making and future research.

Topics: Adult; Antipsychotic Agents; Clozapine; Crime; Diagnosis, Dual (Psychiatry); Drug Monitoring; Drug Resistance; Forensic Psychiatry; Health Status; Hospitals; Humans; Incidence; Male; Middle Aged; Neutropenia; New South Wales; Patient Dropouts; Prisoners; Psychotic Disorders; Retrospective Studies; Risk Factors; Schizophrenia; Schizophrenic Psychology; Seizures; Substance-Related Disorders

A panel of academic psychiatrists and pharmacists, clinicians from the Texas public mental health system, advocates, and consumers met in June 2006 in Dallas, Tex., to review recent evidence in the pharmacologic treatment of schizophrenia. The goal of the consensus conference was to update and revise the Texas Medication Algorithm Project (TMAP) algorithm for schizophrenia used in the Texas Implementation of Medication Algorithms, a statewide quality assurance program for treatment of major psychiatric illness.. Four questions were identified via premeeting teleconferences. (1) Should antipsychotic treatment of first-episode schizophrenia be different from that of multiepisode schizophrenia? (2) In which algorithm stages should first-generation antipsychotics (FGAs) be an option? (3) How many antipsychotic trials should precede a clozapine trial? (4) What is the status of augmentation strategies for clozapine? Subgroups reviewed the evidence in each area and presented their findings at the conference.. The algorithm was updated to incorporate the following recommendations. (1) Persons with first-episode schizophrenia typically require lower antipsychotic doses and are more sensitive to side effects such as weight gain and extrapyramidal symptoms (group consensus). Second-generation antipsychotics (SGAs) are preferred for treatment of first-episode schizophrenia (majority opinion). (2) FGAs should be included in algorithm stages after first episode that include SGAs other than clozapine as options (group consensus). (3) The recommended number of trials of other antipsychotics that should precede a clozapine trial is 2, but earlier use of clozapine should be considered in the presence of persistent problems such as suicidality, comorbid violence, and substance abuse (group consensus). (4) Augmentation is reasonable for persons with inadequate response to clozapine, but published results on augmenting agents have not identified replicable positive results (group consensus).. These recommendations are meant to provide a framework for clinical decision making, not to replace clinical judgment. As with any algorithm, treatment practices will evolve beyond the recommendations of this consensus conference as new evidence and additional medications become available.

Topics: Algorithms; Antipsychotic Agents; Basal Ganglia Diseases; Clozapine; Drug Therapy; Humans; Mental Health Services; Schizophrenia; Substance-Related Disorders; Suicide, Attempted; Texas; Violence; Weight Gain

Previous correlational research with schizophrenic patients has suggested that the second-generation antipsychotic medication clozapine helps to induce remissions of substance use disorder in patients with co-occurring psychosis and substance abuse. This research, however, could be biased by selection factors. Studying patients who are currently in substance abuse remission could control for level of motivation to stop using substances and other methodological confounds.. To test whether clozapine was associated with prevention of substance abuse relapses, we examined patients with schizophrenia or schizoaffective disorder who were in their first 6-month remission of substance use disorder during a prospective 10-year follow-up study. All patients received yearly multimodal assessments of substance use. Antipsychotic medications were prescribed by community doctors as part of usual clinical care.. Patients using clozapine at the first 6-month period of substance abuse remission (n = 25) were much less likely to relapse over the next year compared with those on other antipsychotic medications (n = 70): 8.0% vs 40.0%, chi(2) = 8.73 (df = 1), P = .003. Although medication assignment was not randomized, several potential confounders were similar between the groups.. Clozapine should be considered for the treatment of patients with schizophrenia and co-occurring substance use disorder to prevent relapses to substance abuse.

Topics: Adult; Antipsychotic Agents; Clozapine; Comorbidity; Diagnosis, Dual (Psychiatry); Female; Follow-Up Studies; Humans; Male; New Hampshire; Prospective Studies; Psychotic Disorders; Recurrence; Remission Induction; Schizophrenia; Substance-Related Disorders

There is an extensive literature documenting that people with schizophrenia have marked impairments in social role functioning and social skill. One of the most widely employed strategies for assessing social skill has been role-play tests: simulated social interactions that are videotaped for subsequent behavioral coding. There has been considerable discussion of the validity of the approach in the literature, but there has not been adequate consideration of other psychometric characteristics of role-play tests. This paper examines the psychometric characteristics of a representative role-play measure: the Maryland Assessment of Social Competence (MASC). Data from 5 large schizophrenia studies that included the MASC were examined: a study of victimization in women who abuse drugs, a study of health care among people with diabetes, a study of vocational outcomes, a study of social skill among drug abusers, and a clinical trial comparing two antipsychotic medications. Data were examined in terms of five questions: (1) Can role-play scenes be rated reliably? (2) How are role-play ratings distributed across populations? (3) How many and which behaviors should be rated? (4) How many role-play scenes are required? (5) Is role-play behavior temporally stable? Overall, the data suggest that the MASC, and by implication other similar role-play procedures, does have good psychometric properties. However, several things often taken for granted in the literature warrant careful consideration in the design of research using role-play. Implications of the results for design of research are discussed.

Topics: Adult; Antipsychotic Agents; Clozapine; Comorbidity; Crime Victims; Diabetes Mellitus, Type 2; Female; Health Behavior; Humans; Problem Solving; Psychometrics; Risperidone; Role Playing; Schizophrenia; Social Behavior; Social Perception; Substance-Related Disorders

Acute poisonings by medical, narcotic substances and alcohol are actual in Russia in the recent years. Comparison of analytic facilities of modern analytical techniques: chromatographic (HPLC, GC, GC-MS) and immuno-chemical (FPIA) in clinical toxicology for urgent diagnostics, assessment of the severity of acute poisoning and the efficacy of the treatment in patients with acute poisonings by psychotropic drugs, narcotics and alcohol have been done. The object of the study were serum, blood, urine of 611 patients with acute poisonings by amitriptyline, clozapine, carbamazepine, opiates and also alcohol. Threshold concentrations (threshold, critical and lethal) of the toxicants and their active metabolites which corresponded to different degrees of poisoning severity have been determined. The most comfortable and informative screening method for express diagnostics and assessment of severity of acute poisonings by psychotropic drugs and narcotics showed the HPLC with using automatic analyzers. FPIA using the automatic analyzer could be applied for screening studies, if group identification is enough. GC-FID method is advisable in case of poisoning by medical substances and narcotics in view of repeated investigation for assessment of the efficacy of the therapy. GC-MS could be advisable for confirming the results of other methods. GC-TCD possess high sensitivity and specificity and is optimal for express differential diagnostics and quantitative assessment of acute poisoning by ethanol and other alcohols.

Topics: Acute Disease; Amitriptyline; Carbamazepine; Central Nervous System Agents; Clozapine; Ethanol; Female; Humans; Immunoenzyme Techniques; Male; Mass Spectrometry; Narcotics; Poisoning; Reproducibility of Results; Russia; Severity of Illness Index; Substance Abuse Detection; Substance-Related Disorders; Toxicology

Severe impulsiveness in the absence of apparent neurological signs has rarely been reported as a clinical presentation of multiple sclerosis (MS). An 11-year-old female developed progressive and sustained personality disturbances including disinhibition, hypersexuality, drug abuse, aggressiveness and suicide attempts, without neurological signs. She was given several unsuccessful psychopharmacological and psychotherapeutic interventions. At age 21, a diagnosis of MS was made, confirmed by imaging, laboratory and neurophysiological studies. Although unusual, MS may produce pure neurobehavioral disturbances. In the present case, widespread demyelinization produced a complex behavioral disorder, with features compatible with orbitofrontal and Klüver-Bucy syndromes.

Topics: Adolescent; Adult; Antimanic Agents; Antipsychotic Agents; Child; Clozapine; Female; Homicide; Humans; Impulsive Behavior; Magnetic Resonance Imaging; Masturbation; Multiple Sclerosis; Personality; Psychotropic Drugs; Sex Work; Sexual Behavior; Substance-Related Disorders; Suicide; Valproic Acid

Topics: Adult; Antipsychotic Agents; Behavior, Addictive; Clozapine; Dimenhydrinate; Female; Humans; Male; Schizophrenia; Schizophrenic Psychology; Substance-Related Disorders; Treatment Outcome

There are not many studies on the use of clozapine in patients with intellectual disability (ID). The authors describe a case series of patients treated with clozapine, drawn from a medium secure unit, a low secure assessment and treatment service and a community team in the London region.. A retrospective file-review of patients treated in these three settings during the time period March-June 2002 was performed (n = 24). Information was collected using a semistructured proforma.. Of the 24 patients, 67% had schizophrenia, 17% had schizoaffective disorder and 8% had bipolar disorder. Patients had been unwell for a mean of 6 years and had been tried on a mean of four antipsychotics. The mean maximum dose of clozapine was 488 mg. The outcomes on the clinical global impression (CGI) scale showed 29% very much improved, 42% much improved, 21% minimally improved and 8% no change. 54% of the whole sample and 53% of those from the medium secure unit were discharged to homes in the community. The drug had to be stopped in four patients, of which three were because of neutropaenia.. Clozapine appears to be safe and efficacious in many people with ID. Careful monitoring of side-effects is needed during therapy.

Topics: Adult; Antipsychotic Agents; Bipolar Disorder; Child; Child Development Disorders, Pervasive; Clozapine; Cognition Disorders; Drug Resistance; Drug Utilization; Epilepsy; Female; Humans; Male; Middle Aged; Personality Disorders; Psychotic Disorders; Retrospective Studies; Schizophrenia; Substance-Related Disorders

Alcohol and cannabis use disorders worsen the course of schizophrenia. While the typical antipsychotics are of limited value in controlling substance use in schizophrenic patients, previous studies suggest that the novel antipsychotic clozapine (CLOZ) may decrease their substance use. We describe a retrospective study of the effects of the novel antipsychotics risperidone (RISP) and clozapine on alcohol and cannabis use in patients with schizophrenia or schizoaffective disorder and comorbid alcohol and/or cannabis use disorder.. This study involved retrospective assessment of abstinence (cessation of alcohol and cannabis use) in 41 patients treated with either risperidone (n=8) or clozapine (n=33) for at least 1 year. In 32 of these 41 patients, information was available on whether abstinence occurred during the 1-year period.. Abstinence rates were significantly higher in patients treated with clozapine than in those treated with risperidone (54% vs. 13%, p=0.05). The nine patients treated for at least 1 year, but excluded from the analysis because time of cessation of use was not known, had all stopped alcohol/cannabis use during clozapine treatment.. While the limitations of this retrospective study must be recognized, the data suggest that comorbid patients treated with clozapine are more likely to abstain from alcohol and cannabis use than are those treated with risperidone. Further prospective studies will be required to confirm these intriguing results.

Topics: Adult; Aged; Alcohols; Antipsychotic Agents; Cannabis; Clozapine; Female; Humans; Male; Middle Aged; Psychiatric Status Rating Scales; Retrospective Studies; Risperidone; Schizophrenia; Substance-Related Disorders; Treatment Outcome

This study examined outcomes following discharge on clozapine for treatment-resistant schizophrenia patients with and without diagnosed substance abuse histories.. Those discharged on clozapine from a research unit between April 1991 and March 1996 were followed with respect to hospitalization status. Of the treatment-resistant patients with schizophrenia, 19 were diagnosed as individuals with substance abuse, while 26 patients had no history of abuse. Patients were openly treated with clozapine and were included in the study if they were stabilized and discharged on the medication.. Patients who had histories of abuse exhibited a better treatment response and a lower total Brief Psychiatric Rating Scale (BPRS) score at discharge, compared with the non-substance abuse group. One-year readmission rates were 21% and 23% in patients with and without prior substance abuse histories, respectively (P = ns).. Clozapine may be a therapeutic option for the dually diagnosed population and may offer benefits to patients with schizophrenia who have a history of substance abuse.

Topics: Adult; Antipsychotic Agents; Brief Psychiatric Rating Scale; Clozapine; Diagnostic and Statistical Manual of Mental Disorders; Female; Humans; Male; Prevalence; Schizophrenia; Substance-Related Disorders; Time Factors

Substance use disorders, particularly those involving alcohol, marijuana, and cocaine, are highly prevalent among patients with schizophrenia and contribute markedly to its overall morbidity. Unfortunately, standard (typical) antipsychotic medications do not seem to reduce substance use in patients with schizophrenia and may even increase it. Recently, however, a few anecdotal case reports and two previous small "N" surveys have found that clozapine, an atypical antipsychotic medication, seems to decrease substance use in patients treated with this drug for their psychoses. The authors report data from a retrospective survey of substance use in 58 patients treated with clozapine who had a history of comorbid schizophrenia (or schizoaffective disorder) and substance use disorder. Of these 58 patients, 43 were being treated with clozapine at the time of the survey; the remaining 15 patients had discontinued clozapine before the survey. The survey involved chart review and clinician interview to assess change in substance use and global clinical symptoms while receiving treatment with clozapine. More than 85% of the patients who were active substance users at the time of initiation of treatment with clozapine decreased their substance use over the course of clozapine administration. For patients who continued treatment with clozapine up to the present, the decrease in substance use was strongly correlated with a decrease in global clinical symptoms. Data from this retrospective survey further support the previous observations that clozapine reduces substance use among patients with schizophrenic disorders. Moreover, the data suggest the need for prospective controlled studies of the effects of clozapine on substance use in this population.

Topics: Adult; Antipsychotic Agents; Clozapine; Diagnosis, Dual (Psychiatry); Female; Humans; Male; Medical Records; Middle Aged; Pilot Projects; Psychotic Disorders; Retrospective Studies; Schizophrenia; Substance-Related Disorders

Topics: Antipsychotic Agents; Clozapine; Diagnosis, Dual (Psychiatry); Humans; Schizophrenia; Schizophrenic Psychology; Substance-Related Disorders

In schizophrenics, clozapine has been reported to induce various withdrawal signs and rapid onset relapse to psychosis on cessation of chronic treatment.. The study was designed to develop an animal model of one aspect of clozapine tolerance and withdrawal using core body temperature measures.. Two groups of 15 female Wistar rats were treated chronically (b.i.d.) with clozapine at 6 or 12 mg/kg per injection for 21 days prior to cessation of drug treatment, withdrawal being studied over 4 consecutive days. Body temperatures were assessed daily throughout the study.. Acutely, clozapine induced dose-related hypothermia, to which complete tolerance developed in both groups, the development of tolerance being more rapid in the group treated with 6 mg/kg per injection of clozapine. During withdrawal only the group treated chronically with 12 mg/kg per injection of clozapine showed rapid onset significant hyperthermia. This dissipated progressively over days, and was completely absent after 4 days of withdrawal.. Clozapine induced a clear somatic withdrawal sign after chronic treatment. It is suggested that, in future research in both humans and animals, it is important to attempt to differentiate between clozapine withdrawal and clozapine withdrawal-induced relapse to psychosis. It is also important to characterise the clozapine withdrawal syndrome fully in animals; to establish the neurochemical mechanisms involved in such withdrawal; and to determine which novel antipsychotics are most efficacious in inducing clozapine-like withdrawal effects, in suppressing clozapine withdrawal, and in preventing relapse to psychosis in patients being transferred from clozapine to novel atypical antipsychotic drugs.

Topics: Animals; Antipsychotic Agents; Body Temperature; Clozapine; Dose-Response Relationship, Drug; Drug Tolerance; Female; Rats; Rats, Wistar; Substance Withdrawal Syndrome; Substance-Related Disorders

Forced nicotine intake was previously found to decrease a subsequent free choice selection, whereas clozapine (CL) caused a marked increase in its consumption. Here these findings are extended to ethanol, cocaine, morphine and amphetamine. Forced intake of ethanol, cocaine, morphine and amphetamine had no major effect on a subsequent voluntary intake. CL, a dopamine D4 antagonist, increased the voluntary consumption of amphetamine and morphine with no effects on ethanol or cocaine intake. Only for cocaine was it found that low-consuming rats increased but high-consuming rats decreased their voluntary cocaine intake by CL. Thus, forced drug exposure per se does not lead to subsequent enhancement of voluntary intake; CL exerts differential effects on intake of these drugs, and a specific dopaminergic set point may govern the voluntary intake of cocaine by individual rats.

Topics: Administration, Oral; Amphetamine; Animals; Central Nervous System Depressants; Clozapine; Cocaine; Dopamine Agents; Ethanol; Male; Morphine; Narcotics; Rats; Rats, Sprague-Dawley; Self Administration; Substance-Related Disorders

Topics: Adult; Antipsychotic Agents; Clozapine; Comorbidity; Diagnosis, Dual (Psychiatry); Drug Administration Schedule; Humans; Male; Schizophrenia; Substance-Related Disorders; Treatment Outcome

Topics: Adult; Clozapine; Female; Humans; Male; Schizophrenia; Serotonin Antagonists; Substance-Related Disorders

Topics: Adult; Antipsychotic Agents; Clozapine; Humans; Male; Schizophrenia; Schizophrenic Psychology; Substance-Related Disorders

Topics: Administration, Intranasal; Adult; Blood Pressure; Clozapine; Cocaine; Drug Interactions; Heart Rate; Humans; Male; Schizophrenia; Substance-Related Disorders; Syncope

Topics: Adult; Aged; Antipsychotic Agents; Bipolar Disorder; Clozapine; Diagnosis, Dual (Psychiatry); Female; Humans; Male; Middle Aged; Psychotic Disorders; Substance-Related Disorders

Topics: Alcohol Drinking; Caffeine; Clozapine; Comorbidity; Diagnosis, Dual (Psychiatry); Ethanol; Humans; Schizophrenia; Substance-Related Disorders

The goal of this study was to determine if demographic or clinical factors collected at baseline on patients treated with clozapine would increase the risk of having clozapine discontinued for (a) lack of response, (b) side effects, (c) noncompliance, (d) concomitant illness, or (e) death. The subjects were 805 patients treated with clozapine at 96 Department of Veterans Affairs Hospital System facilities. Multiple logistic regression was used to determine if any of the baseline variables predisposed patients to discontinuation from treatment. Factors which were studied include age, race, history of inadequate response to traditional neuroleptics, history of substance abuse, and DSM-III-R Axis I diagnosis. Of the 805 patients started on clozapine 167 (20.7%) were discontinued from treatment. The only significant variable in the logistic regression model was race. This study finds that African American patients are more likely to have clozapine discontinued than non-African American patients, and there is a trend for prior history of inadequate response to traditional neuroleptics to predict clozapine discontinuation. We found no effect of substance abuse or dependence, diagnosis, or age on outcome in the overall patient group. In a post hoc analysis the African American patients had a significantly lower baseline white blood count than the non-African American patients, which could have explained the difference in clozapine discontinuation. The findings of this study support further investigation into the causes of ethnic differences in treatment outcome with clozapine.

Topics: Adult; Antipsychotic Agents; Clozapine; Female; Hospitalization; Hospitals, Veterans; Humans; Leukocyte Count; Male; Middle Aged; Psychotic Disorders; Racial Groups; Schizophrenia; Substance-Related Disorders

Topics: Adult; Clozapine; Cocaine; Comorbidity; Diagnosis, Dual (Psychiatry); Drug Therapy, Combination; Fluphenazine; Humans; Lithium; Male; Psychotic Disorders; Substance-Related Disorders; Treatment Outcome

Among 118 patients with DSM-III-R diagnoses of schizophrenia or schizoaffective disorder who received treatment with clozapine, 29 patients had an antecedent or current history of substance abuse. Substance abusers and nonabusers showed similar improvements on measures of psychopathology and psychosocial functioning after 6 months of clozapine therapy. The implications of this finding are discussed.

Topics: Adult; Clozapine; Comorbidity; Female; Humans; Male; Psychotic Disorders; Schizophrenia; Substance-Related Disorders

The goals of this study were 1) to determine the extent of substance abuse in patients with treatment-resistant schizophrenia and 2) to assess the relevance of such abuse to subsequent response to treatment with clozapine.. The subjects were 118 treatment-resistant patients with DSM-III-R diagnoses of schizophrenia or schizoaffective disorder who underwent detailed demographic, clinical, and psychopathological evaluations before commencing treatment with clozapine. Lifetime and current histories of substance abuse were also systematically evaluated and characterized according to the Research Diagnostic Criteria and DSM-III-R. Response to clozapine treatment at 6 months was determined with measures of psychopathology and psychosocial function.. An antecedent or current history of substance abuse was determined for 29 patients. Although predominantly male, the abusers did not differ from the nonabusers on other demographic features. The substance abusers actually showed less psychopathology (negative and disorganization symptoms) and better psychosocial functioning at baseline; however, both groups attained similar improvements on these measures after 6 months of clozapine therapy.. A modest extent of previous or current substance abuse was observed among neuroleptic-resistant schizophrenic patients who subsequently received treatment with clozapine. This antecedent history of substance abuse did not appear to negatively influence subsequent response to clozapine treatment.

Topics: Adult; Clozapine; Comorbidity; Female; Humans; Male; Prevalence; Psychiatric Status Rating Scales; Psychotic Disorders; Schizophrenia; Schizophrenic Psychology; Substance-Related Disorders; Treatment Outcome

Topics: Adult; Chronic Disease; Clozapine; Humans; Male; Schizophrenia, Paranoid; Substance-Related Disorders

Topics: Clozapine; Dibenzazepines; Humans; Schizophrenia; Substance-Related Disorders