clozapine and Heroin-Dependence

Drug addiction is a chronic disorder characterized by compulsive drug seeking, and involves repetitive cycles of compulsive drug use, abstinence, and relapse. In both human and animal models of addiction, chronic food restriction increases rates of relapse. Our laboratory has reported a robust increase in drug seeking following a period of withdrawal in chronically food-restricted rats compared with sated controls. Recently, we reported that activation of the paraventricular nucleus of the thalamus (PVT) abolished heroin seeking in chronically food-restricted rats. However, the precise inputs and outputs of the PVT that mediate this effect remain elusive. The goal of the current study was to determine the role of corticothalamic and thalamo-accumbens projections in the augmentation of heroin seeking induced by chronic food restriction. Male Long-Evans rats were trained to self-administer heroin for 10 d. Next, rats were removed from the self-administration chambers and were subjected to a 14 d withdrawal period while sated (unlimited access to food) or mildly food-restricted (FDR). On day 14, rats were returned to the self-administration context for a 3 h heroin-seeking test under extinction conditions during which corticothalamic and thalamo-accumbens neural activity was altered using chemogenetics. Surprisingly, chemogenetic activation or inhibition of corticothalamic projections did not alter heroin-seeking behavior. Chemogenetic activation of thalamo-accumbens shell, but not core, projectors attenuated heroin seeking in FDR rats. The results indicate an important role for the PVT to nucleus accumbens shell projections in the augmentation of heroin seeking induced by chronic food restriction.

Topics: Animals; Behavior, Addictive; Cerebral Cortex; Clozapine; Drug-Seeking Behavior; Food Deprivation; Heroin; Heroin Dependence; Male; Motor Activity; Narcotics; Neural Pathways; Nucleus Accumbens; Rats; Rats, Long-Evans; Recurrence; Self Administration; Substance Withdrawal Syndrome; Thalamus

A young male presented with many years of delusions and hallucinations, with concurrent heroin use and subsequent amphetamine uses. There were no depressive or manic symptoms and psychotic symptoms prior to the amphetamine use. After the trials of two atypical antipsychotics and later clozapine due to treatment resistance, adherence and functionality were poor and there was still persistent drug use. As a result, a long acting injectable adjunct was commenced, but only minimal effects were observed. However after initiation of directly observed treatment of clozapine with methadone, there has been functional and clinical response and drug use has ceased.

Topics: Adult; Antipsychotic Agents; Clozapine; Directly Observed Therapy; Drug Administration Schedule; Heroin Dependence; Humans; Male; Medication Adherence; Methadone; Opiate Substitution Treatment; Schizophrenia; Social Environment; Treatment Outcome

Negative affect is critical for conferring vulnerability to opiate addiction as reflected by the high comorbidity of opiate abuse with major depressive disorder (MDD). Rodent models implicate amygdala prodynorphin (Pdyn) as a mediator of negative affect; however, evidence of PDYN involvement in human negative affect is limited. Here, we found reduced PDYN mRNA expression in the postmortem human amygdala nucleus of the periamygdaloid cortex (PAC) in both heroin abusers and MDD subjects. Similar to humans, rats that chronically self-administered heroin had reduced Pdyn mRNA expression in the PAC at a time point associated with a negative affective state. Using the in vivo functional imaging technology DREAMM (DREADD-assisted metabolic mapping, where DREADD indicates designer receptors exclusively activated by designer drugs), we found that selective inhibition of Pdyn-expressing neurons in the rat PAC increased metabolic activity in the extended amygdala, which is a key substrate of the extrahypothalamic brain stress system. In parallel, PAC-specific Pdyn inhibition provoked negative affect-related physiological and behavioral changes. Altogether, our translational study supports a functional role for impaired Pdyn in the PAC in opiate abuse through activation of the stress and negative affect neurocircuitry implicated in addiction vulnerability.

Topics: Adult; Amygdala; Animals; Clozapine; Corticosterone; Depressive Disorder, Major; Designer Drugs; Enkephalins; Female; Fluorine Radioisotopes; Fluorodeoxyglucose F18; GTP-Binding Protein alpha Subunits, Gi-Go; Heroin Dependence; Humans; Hungary; Limbic System; Male; Middle Aged; Neuroimaging; Neurons; Positron-Emission Tomography; Protein Precursors; Radiopharmaceuticals; Rats; Rats, Long-Evans; Recombinant Fusion Proteins; RNA, Messenger; United States

Methadon maintenance therapy with opiate addicts who suffer from a comorbid schizophrenia in an outpatient treatment setting of a psychiatric hospital is described. We examined five patients looking for periods of inpatient treatment, drug free urine tests, social integration and illegal activities before and after neuroleptic treatment. In comparison with standard neuroleptics patients show under the therapy with atypical neuroleptics better outcome in drug urine tests especially concerning cannabis and benzodiazepines. According to these findings, the best improvements seem to occur with a combination of methadone and clozapine.

Topics: Adult; Ambulatory Care; Antipsychotic Agents; Clozapine; Comorbidity; Drug Therapy, Combination; Female; Follow-Up Studies; Heroin Dependence; Hospitals, Psychiatric; Humans; Methadone; Outpatient Clinics, Hospital; Patient Readmission; Schizophrenia; Secondary Prevention; Treatment Outcome

Little is known about possibilities of chronic hepatitis C treatment with interferon-alpha (IFN-alpha) in psychiatric patients continuously taking antipsychotics. We report on a 28-year-old hepatitis C-positive man with paranoid psychosis. He was successfully treated with clozapine, an atypical antipsychotic drug which is known for the risk of granulocytopenia and agranulocytosis. With doses up to 200 mg/day over 3 years, he showed no remarkable changes in WBC. Because of the chronic hepatitis C with genotype 3a, additional treatment was started with IFN-alpha (s.c., 3 x 6 million IU/week). After 2 months of therapy he developed a severe agranulocytosis. Both clozapine and IFN-alpha were discontinued, and his WBC returned to normal. Results from bone marrow examination were compatible with a toxic reaction possibly caused by either or both medications. We discuss possible problems with IFN-alpha during the treatment of psychiatric patients, interactions with psychiatric medication, and hematotoxic side effects like those from clozapine. We recommend combining IFN-alpha with less "toxic" antipsychotics and weekly checks of WBC.

Topics: Adult; Agranulocytosis; Cannabinoids; Clozapine; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Interactions; Drug Therapy, Combination; Follow-Up Studies; Hepatitis C; Heroin Dependence; Humans; Interferon alpha-2; Interferon-alpha; Lysergic Acid Diethylamide; Male; Psychoses, Substance-Induced; Recombinant Proteins; Substance Abuse, Intravenous

Topics: Antipsychotic Agents; Chronic Disease; Clozapine; Cost Control; Delivery of Health Care; Diffusion of Innovation; Feeding and Eating Disorders; Heroin Dependence; Humans; Quality Assurance, Health Care; Schizophrenia; United Kingdom