clozapine and Mood-Disorders

The atypical antipsychotics have a low incidence of extrapyramidal side effects (EPS), have improved tardive dyskinesia profiles, and have a broad range of therapeutic efficacy. These agents offer important therapeutic advantages that extend beyond their initial regulatory approval in several conditions and patient groups. The use of atypical antipsychotics is most relevant in the treatment of mood disorders, where these medications are being used increasingly for acute mood stabilization and in patients who are resistant to other treatments. Similar circumstances and clinical advantages pertain to the use of atypical antipsychotics in the treatment of behavioral disturbances in patients with dementia and in the management of personality disorders-both circumstances where conventional antipsychotics were initially poorly tolerated because of EPS. The low incidence of EPS associated with atypical antipsychotics is highly beneficial in several neuropsychiatric conditions. The extent to which endocrine and metabolic dysregulations associated with atypical antipsychotics will influence antipsychotics' role remains to be determined. As therapeutic opportunities evolve and diversify, atypical antipsychotics, because of favorable adverse-effect profiles, will have enhanced patient tolerability and use in nonpsychiatric conditions.

Topics: Antipsychotic Agents; Basal Ganglia Diseases; Benzodiazepines; Child; Child Development Disorders, Pervasive; Clozapine; Dementia; Dibenzothiazepines; Humans; Mood Disorders; Olanzapine; Personality Disorders; Pirenzepine; Quetiapine Fumarate; Risperidone

Depression in schizophrenia may be partially responsible for the increased suicide rate in schizophrenic patients, which is more than 20 times higher than that found in the general population. Affective disorders in patients with schizophrenia are associated with a poor outcome, an increased risk of relapse, and a high rate of suicide. There is evidence that atypical antipsychotics may contribute to a reduction in suicidality, and although the new drugs are marketed for the treatment of schizophrenia, their novel psychopharmacologic effects suggest the possibility of other therapeutic applications. Recent studies of the efficacy of the novel antipsychotics found that these agents may produce an antidepressant effect in schizophrenia and may be used as either an adjunctive medication or an alternative to mood stabilizers in patients with affective disorders.

Topics: Antipsychotic Agents; Benzodiazepines; Bipolar Disorder; Clinical Trials as Topic; Clozapine; Comorbidity; Depressive Disorder; Humans; Mood Disorders; Olanzapine; Pirenzepine; Psychiatric Status Rating Scales; Risperidone; Schizophrenia; Schizophrenic Psychology; Suicide; Suicide Prevention

Atypical antipsychotics have become the treatment of choice for patients experiencing a first episode of schizophrenia. In addition, they are often prescribed for conditions such as bipolar disorder and dementia. While clinical trials have not yet established the efficacy of the atypical antipsychotics for these uses, a number of reports offer preliminary evidence that the atypical antipsychotics may be beneficial for affective disorders, substance abuse disorder, senile dementia, and pathologic aggression. Atypical agents may be particularly effective and tolerable in elderly patients who are especially susceptible to the adverse effects of conventional antipsychotic medication. Lower dosages are more necessary for the elderly than for younger adults. Current evidence suggests that clozapine is the most effective atypical antipsychotic for neuroleptic-resistant patients. Risperidone, olanzapine, and quetiapine may also be effective in a subset of these patients.

Topics: Adult; Age Factors; Aged; Algorithms; Antipsychotic Agents; Benzodiazepines; Bipolar Disorder; Clinical Trials as Topic; Clozapine; Decision Trees; Dementia; Dibenzothiazepines; Female; Humans; Male; Mood Disorders; Olanzapine; Pirenzepine; Quetiapine Fumarate; Risperidone; Schizophrenia

Clozapine is increasingly being used for clinical indications in addition to treatment-resistant schizophrenia; this article reviews the relevant literature. The first section reassesses the risks associated with clozapine treatment, particularly agranulocytosis. The next section discusses its use for schizophrenia in patients who are treatment resistant, not treatment resistant, and intolerant of traditional drug treatments. Subsequent sections address its use in mood disorders, neurologic conditions, comorbid substance abuse, aggressive behavior, and childhood schizophrenia. Each includes the initial rationale for the use of clozapine in the disorder, a critical evaluation of the relevant literature, and theories as to why clozapine's unique pharmacodynamic profile may be efficacious for the specific condition. This body of literature suggests clozapine may be an effective treatment for a wide range of disorders.

Topics: Animals; Antipsychotic Agents; Clozapine; Humans; Mood Disorders; Nervous System Diseases; Schizophrenia

To compare plasma and red-cell selenium concentrations of schizophrenic patients treated with clozapine, with healthy controls and patients with mood disorders.. Plasma and red-cell selenium concentrations were measured in random venous blood samples from four groups: mood disorder (n = 36), schizophrenics treated with clozapine (n = 54), schizophrenics not treated with clozapine (n = 41) and a healthy control group (n = 56). Assays were performed by an independent laboratory that was blinded to the patient groups and specializes in estimating trace metal concentrations.. Selenium concentrations in plasma and red cells were found to be significantly lower in schizophrenic patients treated with clozapine as compared with all other groups.. Selenium is an essential antioxidant. Its deficiency has been implicated in myocarditis and cardiomyopathy. Low selenium concentrations in clozapine-treated patients may be important in the pathogenesis of life threatening cardiac side-effects associated with clozapine. Further clinical studies are being conducted to explore this important clinical observation and its therapeutic implications.

Topics: Adult; Antipsychotic Agents; Clozapine; Erythrocytes; Female; Humans; Male; Mood Disorders; Schizophrenia; Selenium; Serotonin Antagonists

Two separate studies were carried out to assess the effect of valproic acid on the steady-state plasma concentrations of clozapine and its major metabolites norclozapine and clozapine N-oxide in psychotic patients. In the first study, concentrations of clozapine and metabolites were compared between patients treated with clozapine in combination with sodium valproate (n = 15) and control patients treated with clozapine alone (n = 22) and matched for sex, age, body weight, and antipsychotic dosage. Patients comedicated with valproate tended to have higher clozapine levels and lower norclozapine levels, but the differences did not reach statistical significance. In a subsequent study, plasma concentrations of clozapine and its metabolites were determined in 6 patients with schizophrenia stabilized on clozapine therapy (200-400 mg/d) before and after treatment with sodium valproate (900-1200 mg/d) for 4 weeks. Mean plasma concentrations of clozapine and its metabolites did not change significantly throughout the study, but there was a trend for clozapine levels to be higher and for norclozapine levels to be lower after valproate. Overall, these findings suggest that valproic acid may have an inhibiting effect on the CYP1A2- or CYP3A4-mediated conversion of clozapine to norclozapine. However, the interaction is unlikely to be clinically significant.

Topics: Adult; Anticonvulsants; Antipsychotic Agents; Clozapine; Drug Interactions; Drug Therapy, Combination; Female; Humans; Male; Middle Aged; Mood Disorders; Schizophrenia; Valproic Acid

In this study, we aimed to investigate the effect of the clozapine on the course of the rapid cycling Bipolar Affective Disorder.. The study group was formed with the patients aged between 18 and 65 years of age, who met the criteria for the diagnosis of Bipolar Affective Disorder according to the Diagnostic and Statistical Manual of Mental Disorders 4th Edition, with rapid cycling characteristics. Variables like the number of mania and depressive episodes, the days spent in mania and in depression and the number of hospitalization and attempted suicide, in the year before starting clozapine were determined and compared with the annual data after starting the clozapine.. Eleven female and two male patients who met the inclusion criteria were included in this study. The group`s average daily use of clozapine was 180 mg (25-600 mg). There was a statistically significant difference in the number of days spent in the depression, the days spent in the mania, the number of depressive episodes and manic episodes, the number of hospitalizations and the suicide attempts after the clozapine use.. In this study, it was determined that clozapine was effective as a mood stabilizer in Bipolar Affective Disorder treatment. The results show that clozapine reduces the episode frequency and the duration in rapid cycling Bipolar Affective Disorder which does not respond to all conventional treatments, including lithium, valproic acid, carbamazepine and antipsychotic drugs.

Topics: Adolescent; Adult; Aged; Antipsychotic Agents; Bipolar Disorder; Clozapine; Diagnostic and Statistical Manual of Mental Disorders; Female; Humans; Male; Middle Aged; Mood Disorders; Young Adult

Chronic psychosocial stress modulates brain antioxidant systems and causes neuroinflammation that plays a role in the pathophysiology of depression. Although the antidepressant fluoxetine (FLX) represents the first-line treatment for depression and the atypical antipsychotic clozapine (CLZ) is considered as a second-line treatment for psychotic disorders, the downstream mechanisms of action of these treatments, beyond serotonergic or dopaminergic signaling, remain elusive. We examined behavioral changes, glutathione (GSH)-dependent defense and levels of proinflammatory mediators in the prefrontal cortex (PFC) of adult male Wistar rats exposed to 21days of chronic social isolation (CSIS). We also tested the ability of FLX (15mg/kg/day) or CLZ (20mg/kg/day), applied during CSIS, to prevent stress-induced changes. CSIS caused depressive- and anxiety-like behaviors, compromised GSH-dependent defense, and induced nuclear factor-kappa B (NF-κB) activation with a concomitant increase in cytosolic levels of proinflammatory mediators cyclooxigenase-2, interleukin-1beta and tumor necrosis factor-alpha in the PFC. NF-κB activation and proinflammatory response in the PFC were not found in CSIS rats treated with FLX or CLZ. In contrast, only FLX preserved GSH content in CSIS rats. CLZ not only failed to protect against CSIS-induced GSH depletion, but it diminished its levels when applied to non-stressed rats. In conclusion, prefrontal cortical GSH depletion and the proinflammatory response underlying depressive- and anxiety-like states induced by CSIS were prevented by FLX. The protective effect of CLZ, which was equally effective as FLX on the behavioral level, was limited to proinflammatory components. Hence, different mechanisms underlie the protective effects of these two drugs in CSIS rats.

Topics: Animals; Antidepressive Agents; Clozapine; Cytokines; Defense Mechanisms; Disease Models, Animal; Fluoxetine; Glutathione; Glutathione Peroxidase; Glutathione Reductase; Male; Mood Disorders; NADP; NF-kappa B; Nitric Oxide Synthase Type II; Prefrontal Cortex; Rats; Rats, Wistar; Social Isolation

Two patients each developed a single, fixed somatic delusion complicating their existing bipolar disorder. Both failed to respond to a range of antidepressant and antipsychotic medications. They each showed a partial response to clozapine and to electroconvulsive therapy, with resolution of mood symptoms and diminution of their ongoing somatic preoccupation. A review of case reports suggests a possible relationship between somatic delusions and affective disorders.

Topics: Adult; Antipsychotic Agents; Bipolar Disorder; Clozapine; Delusions; Diagnosis, Differential; Electroconvulsive Therapy; Female; Humans; Male; Middle Aged; Mood Disorders; Mouth Diseases; Sleep Wake Disorders; Somatoform Disorders

To examine the neural correlates of emotion processing in treatment-resistant patients with schizophrenia (SCZ-TR).. Twenty-two SCZ-TR patients on clozapine, 24 schizophrenia patients on antipsychotics other than clozapine, and 39 healthy controls were scanned using functional neuroimaging while viewing positive, negative and neutral images.. Emotionally-laden images (positive and negative) elicited hyper-activations in the dorso-medial prefrontal cortex and left cerebellum in SCZ-TR patients, compared to the two other groups. Similarly, neutral images prompted hyper-activations in the cingulate gyrus in SCZ-TR patients, relative to the two other groups.. Treatment resistance is associated with neuro-functional hyper-activations in schizophrenia patients during emotion processing.

Topics: Adult; Antipsychotic Agents; Brain; Clozapine; Emotions; Female; Humans; Image Processing, Computer-Assisted; Magnetic Resonance Imaging; Male; Mood Disorders; Oxygen; Psychiatric Status Rating Scales; Schizophrenia

There is evidence that combining selective serotonin reuptake inhibitor (SSRI) antidepressant and antipsychotic drugs may improve negative symptoms in schizophrenia and resistant symptoms in obsessive-compulsive and affective disorders. To examine the mechanism of action of this treatment we investigated the molecular modulation of γ-aminobutyric acid-A (GABA(A)) receptor components and biochemical pathways associated with GABA(A) receptor function following administration of the SSRI fluvoxamine (Flu) combined with the first-generation antipsychotic haloperidol (Hal) and compared it to the individual drugs and the atypical antipsychotic clozapine (Clz). We analysed prefrontal cortices of Sprague-Dawley rats injected intraperitoneally (i.p.) with the combination of Flu (10 mg/kg) and Hal (1 mg/kg), each drug alone, or Clz (10 mg/kg) after 30 min and 1 h. We found that haloperidol plus fluvoxamine (Hal-Flu) co-administration, and Clz, decreased the level of GABAAβ2/3 receptor subunit in the cytosolic fraction, and increased it in the membrane compartment in rat PFC. Flu or Hal alone did not produce changes in GABAAβ2/3 receptor protein expression. Additionally, Hal-Flu and Clz regulated molecular signalling pathways that modulate GABA(A) receptor function, including protein kinase C (PKC) and extracellular signal-regulated kinase-2 (ERK2). In primary cortical culture, short-term treatment (15 min) with Hal-Flu combination and Clz increased GABAAβ subunit phosphorylation levels. Pretreatment of the cells with PKC inhibitor abolished the effect of the combined treatment, or Clz on phosphorylation of GABA(A) receptor. Inhibition of ERK2 did not alter the effect of drugs on GABA(A) receptor phosphorylation levels. Our findings provide evidence that the combined treatment regulates GABA(A) receptor function and does so via a PKC-dependent pathway.

Topics: Animals; Antidepressive Agents; Antipsychotic Agents; Cells, Cultured; Clozapine; Dopamine; Drug Therapy, Combination; Fluvoxamine; Haloperidol; Male; Mitogen-Activated Protein Kinase 1; Mood Disorders; Obsessive-Compulsive Disorder; Phosphorylation; Prefrontal Cortex; Protein Kinase C; Rats; Rats, Sprague-Dawley; Receptors, GABA-A; Schizophrenia; Selective Serotonin Reuptake Inhibitors

Medication is a necessary part of treatment for severe psychiatric illnesses such as schizophrenia and nonadherence to prescribed medication is one of the most important public health issues in psychiatry today. The devastating consequences of nonadherence have motivated the development of novel therapeutic strategies, including a new long-term implantable medication delivery system.. The current study assesses attitudes towards implantable medication in psychiatric patients and their family members. Patients included in the study had diagnoses of Schizophrenia, Schizoaffective Disorder, Mood or Anxiety related disorders.. 49.62% of patients and 74.47% of family members endorse support for implantable medication.. This study demonstrates that implants may be an acceptable alternative to oral and injectable medication for a subset of psychiatric patients and their families.

Topics: Adult; Attitude to Health; Clozapine; Cross-Cultural Comparison; Data Collection; Drug Implants; Family; Female; Haloperidol; Humans; Male; Mental Disorders; Middle Aged; Mood Disorders; Patient Compliance; Psychotic Disorders; Psychotropic Drugs; Schizophrenia; Schizophrenic Psychology; Treatment Outcome; United States

Topics: Antipsychotic Agents; Basal Ganglia Diseases; Clozapine; Humans; Mood Disorders; Neuroleptic Malignant Syndrome; Randomized Controlled Trials as Topic; Schizophrenia; Treatment Outcome

To compare prescribed daily doses (PDDs) of psychotropic drugs in several European centres.. A one-day census of psychotropic drug prescriptions to 613 patients in 39 acute psychiatric wards in ten countries.. Patients in Spain were on most drugs; patients in Germany were on the fewest. Chlorpromazine equivalents in Denmark, England, Germany and Spain were at high levels as were diazepam equivalents in Belgium, Finland, The Netherlands and Norway. Newer anti-psychotics were used in the majority of centres, although older anti-psychotics were used commonly in three centres.. The high doses of psychotropic drugs patients receive in some centres may be having little additional therapeutic effect and could increase their risk of side effects. The use of older anti-psychotics in some centres may be causing side effects that could be reduced by using newer anti-psychotics.

Topics: Adult; Benzodiazepines; Biperiden; Chlorpromazine; Clozapine; Cyclohexanols; Diazepam; Drug Administration Schedule; Drug Prescriptions; Drug Therapy, Combination; Drug Utilization Review; Europe; Female; Humans; Male; Mood Disorders; Olanzapine; Pharmacoepidemiology; Practice Patterns, Physicians'; Psychiatric Department, Hospital; Psychotropic Drugs; Schizophrenia; Time Factors; Venlafaxine Hydrochloride

Asterixis (flapping tremor) can be induced by treatment with psychopharmacologic agents. We observed 10 cases of asterixis in psychiatric inpatients, most with affective spectrum disorders being treated with combination therapy. The drugs most often used were clozapine (eight cases), lithium (seven cases), and carbamazepine (seven cases). There were neither metabolic disorders nor structural brain lesions that might explain the occurrence of asterixis. Because dosage in general was moderate and serum levels were within therapeutic boundaries in most cases, the symptom seemed to have been caused by an interaction of drugs rather than by a single agent. Therefore clozapine, carbamazepine, and lithium should be combined with each other only with great care.

Topics: Adult; Aged; Carbamazepine; Clozapine; Female; Humans; Male; Middle Aged; Mood Disorders; Psychotropic Drugs; Tremor