clozapine and Cocaine-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

Because clozapine may be prescribed to cocaine abusing patients with schizophrenia, we studied cocaine-clozapine interactions in a controlled setting. Eight male cocaine addicts underwent four oral challenges with ascending doses of clozapine (12.5, 25 and 50 mg) and placebo followed 2 h later by a 2-mg/kg dose of intranasal cocaine. Subjective and physiological responses, and serum cocaine levels were measured over a total 4-h period. Clozapine pretreatment increased cocaine levels during the study and significantly increased the peak serum cocaine levels in a dose dependent manner. In spite of this elevation in blood levels, clozapine pretreatment had a significant diminishing effect upon subjective responses to cocaine, including 'expected high', 'high' and 'rush', notably at the 50 mg dose. There was also a significant effect upon 'sleepiness', 'paranoia' and 'nervous'. Clozapine caused a significant near-syncopal episode in one subject in the study, requiring his removal from the study. Clozapine had no significant effect on baseline pulse rate and systolic blood pressure, but it attenuated the significant pressor effects of the single dose of intranasal cocaine. These data suggested a possible therapeutic role for clozapine in the treatment of cocaine addiction in humans, but also suggests caution due to the near-syncopal event and the increase in serum cocaine levels.

Topics: Adult; Arousal; Clozapine; Cocaine; Cocaine-Related Disorders; Comorbidity; Dose-Response Relationship, Drug; Drug Interactions; Euphoria; Humans; Male; Risk Factors; Schizophrenia; Syncope

The purpose of this study was to determine if social vs nonsocial cues (peer vs light/tone) can serve as discriminative stimuli to reinstate cocaine seeking. In addition, to assess a potential mechanism, an oxytocin (OT) promoter-linked hM3Dq DREADD was infused into the paraventricular nucleus of the hypothalamus to determine whether peer-induced cocaine seeking is decreased by activation of OT neurons. Male rats underwent twice-daily self-administration sessions, once with cocaine in the presence of one peer (S+) and once with saline in the presence of a different peer (S-). Another experiment used similar procedures, except the discriminative stimuli were nonsocial (constant vs flashing light/tone), with one stimulus paired with cocaine (S+) and the other paired with saline (S-). A third experiment injected male and female rats with OTp-hM3Dq DREADD or control virus into PVN and tested them for peer-induced reinstatement of cocaine seeking following clozapine (0.1 mg/kg). Although acquisition of cocaine self-administration was similar in rats trained with either peer or light/tone discriminative stimuli, the latency to first response was reduced by the peer S+, but not by the light/tone S+. In addition, the effect of the conditioned stimulus was overshadowed by the peer S+ but not by the light/tone S+. Clozapine blocked the effect of the peer S+ in rats receiving the OTp-hM3Dq DREADD virus, but not in rats receiving the control virus. These results demonstrate that a social peer can serve as potent trigger for drug seeking and that OT in PVN modulates peer-induced reinstatement of cocaine seeking.

Topics: Animals; Clozapine; Cocaine; Cocaine-Related Disorders; Cues; Extinction, Psychological; Female; Male; Neurons; Oxytocin; Paraventricular Hypothalamic Nucleus; Rats; Self Administration

The reinforcing efficacy of cocaine is largely determined by its capacity to inhibit the dopamine transporter (DAT), and emerging evidence suggests that differences in cocaine potency are linked to several symptoms of cocaine use disorder. Despite this evidence, the neural processes that govern cocaine potency

Topics: Animals; Axons; Clozapine; Cocaine; Cocaine-Related Disorders; Dopamine Agonists; Dopamine Plasma Membrane Transport Proteins; Dopamine Uptake Inhibitors; Dopaminergic Neurons; Male; Microinjections; Phosphorylation; Rats; Rats, Long-Evans; Self Administration; Ventral Tegmental Area

Cocaine-associated environmental cues elicit craving and relapse to cocaine use by recalling the rewarding memory of cocaine. However, the neuronal mechanisms underlying the expression of cocaine-associated memory are not fully understood. Here, we investigated the possible contribution of γ-aminobutyrate (GABA)ergic neurons in the nucleus accumbens (NAc), a key brain region associated with the rewarding and reinforcing effects of cocaine, to the expression of cocaine-associated memory using the conditioned place preference (CPP) paradigm combined with designer receptors exclusively activated by designer drugs (DREADD) technology. The inhibitory DREADD hM4Di was selectively expressed in NAc GABAergic neurons of vesicular GABA transporter-Cre (vGAT-Cre) mice by infusing adeno-associated virus (AAV) vectors. Ex vivo electrophysiological recordings revealed that bath application of clozapine-N-oxide (CNO) significantly hyperpolarized membrane potentials and reduced the number of spikes induced by depolarizing current injections in hM4Di-positive NAc neurons. Additionally, systemic CNO injections into cocaine-conditioned mice 30 min before posttest session significantly reduced CPP scores compared to saline-injected mice. These results indicate that chemogenetic inhibition of NAc GABAergic neurons attenuated the expression of cocaine CPP, suggesting that NAc GABAergic neuronal activation is required for the environmental context-induced expression of cocaine-associated memory.

Topics: Animals; Clozapine; Cocaine; Cocaine-Related Disorders; GABAergic Neurons; Humans; Male; Mice; Mice, Transgenic; Nucleus Accumbens; Patch-Clamp Techniques; Reinforcement, Psychology; Reward; Synaptic Potentials

A case of acute dyskinesia in a 42-year-old man with a history of cocaine use and schizophrenia is described. He had discontinued clozapine approximately 1 month before presenting to the emergency department displaying signs of psychosis, with generalised choreiform and dystonic movements. Urinary toxicology was positive for cocaine. Clozapine treatment was reinitiated, and within 2 weeks the dyskinesia had subsided. Review of his records revealed two previous episodes of similar dyskinesia, both of which were temporally associated with cocaine use. Dyskinesia occurring in the context of cocaine use, and clozapine withdrawal-associated dyskinesia were considered to be the main differential diagnoses. A range of differential diagnoses should be considered in patients presenting with an acute-onset movement disorder who have a history of long-term exposure to antipsychotic medication.

Topics: Adult; Antipsychotic Agents; Clozapine; Cocaine-Related Disorders; Crack Cocaine; Dyskinesia, Drug-Induced; Humans; Magnetic Resonance Imaging; Male; Neuroimaging; Schizophrenia; Substance Withdrawal Syndrome; Treatment Outcome

Drug addiction is a chronic disease that is shaped by alterations in neuronal function within the cortical-basal ganglia-thalamic circuit. However, our understanding of how this circuit regulates drug-seeking remains incomplete, and relapse rates remain high. The midline thalamic nuclei are an integral component of the cortical-basal ganglia-thalamic circuit and are poised to mediate addiction behaviors, including relapse. It is surprising that little research has examined the contribution of midline thalamic nuclei and their efferent projections in relapse. To address this, we expressed inhibitory, G

Topics: Animals; Clozapine; Cocaine-Related Disorders; Cues; Designer Drugs; Drug-Seeking Behavior; Efferent Pathways; Male; Neurons; Nucleus Accumbens; Rats; Rats, Sprague-Dawley; Receptors, G-Protein-Coupled; Repetition Priming; Thalamic Nuclei

Glial cells of the central nervous system directly influence neuronal activity by releasing neuroactive small molecules, including glutamate. Long-lasting cocaine-induced reductions in extracellular glutamate in the nucleus accumbens core (NAcore) affect synaptic plasticity responsible for relapse vulnerability.. We transduced NAcore astrocytes with an adeno-associated virus vector expressing hM3D designer receptor exclusively activated by a designer drug (DREADD) under control of the glial fibrillary acidic protein promoter in 62 male Sprague Dawley rats, 4 dominant-negative soluble N-ethylmaleimide-sensitive factor attachment protein receptor mice, and 4 wild-type littermates. Using glutamate biosensors, we measured NAcore glutamate levels following intracranial or systemic administration of clozapine N-oxide (CNO) and tested the ability of systemic CNO to inhibit reinstated cocaine or sucrose seeking following self-administration and extinction training.. Administration of CNO in glial fibrillary acidic protein-hM3D-DREADD transfected animals increased NAcore extracellular glutamate levels in vivo. The glial origin of released glutamate was validated by an absence of CNO-mediated release in mice expressing a dominant-negative soluble N-ethylmaleimide-sensitive factor attachment protein receptor variant in glia. Also, CNO-mediated release was relatively insensitive to N-type calcium channel blockade. Systemic administration of CNO inhibited cue-induced reinstatement of cocaine seeking in rats extinguished from cocaine but not sucrose self-administration. The capacity to inhibit reinstated cocaine seeking was prevented by systemic administration of the group II metabotropic glutamate receptor antagonist LY341495.. DREADD-mediated glutamate gliotransmission inhibited cue-induced reinstatement of cocaine seeking by stimulating release-regulating group II metabotropic glutamate receptor autoreceptors to inhibit cue-induced synaptic glutamate spillover.

Topics: Animals; Astrocytes; Calcium Channels, N-Type; Central Nervous System Agents; Clozapine; Cocaine; Cocaine-Related Disorders; Cues; Dietary Sucrose; Disease Models, Animal; Dopamine Uptake Inhibitors; Drug-Seeking Behavior; Extinction, Psychological; Genetic Therapy; Glutamic Acid; Male; Mice, Transgenic; Nucleus Accumbens; Rats, Sprague-Dawley; Receptors, G-Protein-Coupled; Receptors, Metabotropic Glutamate; Self Administration; SNARE Proteins

The factors causing the transition from recreational drug consumption to addiction remain largely unknown. It has not been tested whether dopamine (DA) is sufficient to trigger this process. Here we use optogenetic self-stimulation of DA neurons of the ventral tegmental area (VTA) to selectively mimic the defining commonality of addictive drugs. All mice readily acquired self-stimulation. After weeks of abstinence, cue-induced relapse was observed in parallel with a potentiation of excitatory afferents onto D1 receptor-expressing neurons of the nucleus accumbens (NAc). When the mice had to endure a mild electric foot shock to obtain a stimulation, some stopped while others persevered. The resistance to punishment was associated with enhanced neural activity in the orbitofrontal cortex (OFC) while chemogenetic inhibition of the OFC reduced compulsivity. Together, these results show that stimulating VTA DA neurons induces behavioral and cellular hallmarks of addiction, indicating sufficiency for the induction and progression of the disease.

Topics: Animals; Channelrhodopsins; Clozapine; Cocaine; Cocaine-Related Disorders; Conditioning, Operant; Disease Models, Animal; Dopamine Plasma Membrane Transport Proteins; Dopamine Uptake Inhibitors; Dopaminergic Neurons; Food Deprivation; GABA Antagonists; Glutamate Decarboxylase; Limbic System; Mice; Mice, Inbred C57BL; Mice, Transgenic; Receptors, Dopamine D1; Self Administration; Sucrose; Synaptic Transmission; Time Factors

To determine the prevalence rates of hepatitis C in patients with schizophrenia and schizoaffective disorder being treated with clozapine.. Clozapine-treated outpatients and inpatients were recruited from the Centre for Addiction and Mental Health Schizophrenia Program in Toronto, Canada. All subjects had liver function tests, and positive HCV status was defined as a positive qualitative HCV RNA assay. Subjects completed a self-report questionnaire assessing HCV risk factors, past history of liver disease, previous diagnosis of human immunodeficiency virus (HIV), past hepatitis B virus (HBV) infection and current alcohol use.. 110 subjects participated in the study and the HCV prevalence rate (antibody and viremia-positive) was 2.7%, compared to a 0.8% prevalence rate in Canada. All study subjects had established housing, none reported a history of HIV, and only one patient had a history of HBV infection. A total of 9% drank two or more drinks on a typical day drinking and 7% endorsed having six or more drinks on one occasion at least monthly. Two of 3HCV-viremia positive subjects had HCV risk factors, specifically intravenous drug use and intranasal cocaine use. There was no difference between HCV infected and HCV negative subjects on liver function tests.. Our study demonstrates elevated rates of HCV in clozapine-treated patients compared to the general population in Canada and are congruent with reports from United States centres. Our study highlights the importance of homelessness and patterns of high-risk behaviour when interpreting HCV prevalence rates in this sub-population of patients and should be explored in future studies.

Topics: Administration, Intranasal; Adult; Alcoholism; Antipsychotic Agents; Canada; Clozapine; Cocaine-Related Disorders; Cohort Studies; Female; Hepacivirus; Hepatitis C; Humans; Male; Middle Aged; Prevalence; Psychotic Disorders; Risk Factors; Risk-Taking; Schizophrenia; Substance Abuse, Intravenous; Surveys and Questionnaires

Topics: Akathisia, Drug-Induced; Alcoholism; Antipsychotic Agents; Aripiprazole; Clozapine; Cocaine-Related Disorders; Comorbidity; Delayed-Action Preparations; Diabetic Ketoacidosis; Drug Therapy, Combination; Female; Humans; Injections, Intramuscular; Middle Aged; Molindone; Piperazines; Quinolones; Schizophrenia, Paranoid; Substance Withdrawal Syndrome

Clozapine was found to be effective in attenuating cocaine-induced neurochemical effects. We investigate whether clozapine influences in utero cocaine exposure-induced changes in striatal dopamine levels and cortical N-methyl-D-aspartate (NMDA) receptor density in mouse and rat brains. Pregnant mice or rats were injected with cocaine (5 or 10 mg/kg intraperitoneally) or saline every 24 h throughout gestation and continued for 6 weeks following the delivery. Striatal dopamine levels measured by high-pressure liquid chromatography were found to decrease 24 to 33% in gestational cocaine exposed between the ages of 3 to 15 days, but not in 42-day-old pups. The cortical NMDA receptor densities assessed either in the presence of 100 microM glutamate or 30 microM glycine were significantly increased in 15-day-old gestational cocaine-exposed rats. Simultaneous daily administration of 3 mg/kg clozapine with 5 mg/kg cocaine to pregnant mice protected against the decrease in striatal dopamine levels or an increase in the concentration of NMDA receptor measured in the presence of 100 microM glutamate in 15-day-old pups. Clozapine did not affect striatal dopamine levels by itself or when coadministered with cocaine in 42-day-old pups. The results show gestational cocaine may induce neurochemical abnormalities in brain exhibited as an increased glutamate NMDA receptor density together with a decreased striatal dopamine level. These effects of gestational cocaine exposure may be prevented by simultaneous administration of clozapine. Thus clozapine, which is a partial agonist at the NMDA receptor, may be of value in protecting against gestational cocaine-induced adverse effects in the brain.

Topics: Animals; Brain; Clozapine; Cocaine; Cocaine-Related Disorders; Dopamine; Dopamine Uptake Inhibitors; Female; Male; Mice; Pregnancy; Prenatal Exposure Delayed Effects; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Uterus