clozapine and Stress-Disorders--Post-Traumatic

Although impaired extinction of fear memory (EFM) is a hallmark symptom of posttraumatic stress disorder (PTSD), the mechanisms underlying the impairment are unknown. Activation of the infralimbic cortex (IL) in the medial prefrontal cortex (mPFC) has been reported to predict successful fear extinction, whereas functionally disrupting this region impairs extinction. We examined whether chemogenetic activation of the IL could alleviate impaired EFM in a single prolonged stress (SPS) rat model of PTSD.. Chemogenetic activation of IL and prelimbic (PL) excitatory neurons was undertaken to evaluate EFM using a contextual fear conditioning paradigm. Neuronal activity in the IL was recorded using a 32-multichannel silicon electrode. To examine histological changes in the mPFC, apoptosis was measured by TUNEL staining.. Chemogenetic activation of excitatory neurons in the IL, but not the PL, enhanced EFM in sham rats and resulted in alleviation of EFM impairment in SPS rats. The alleviation of impaired EFM in SPS rats was observed during the extinction test session. Neuronal activity in the IL of SPS rats was lower than that of sham rats after clozapine-n-oxide administration. Increased apoptosis was found in the IL of SPS rats.. These findings suggest that a decreased excitatory response in the IL due, at least in part, to an increase in apoptosis in SPS rats leads to impaired EFM, and that neuronal activation during extinction training could be useful for the treatment of impaired EFM in PTSD patients.

Topics: Animals; Antipsychotic Agents; Clozapine; Disease Models, Animal; Extinction, Psychological; Fear; Genetic Vectors; Male; Memory; Piperazines; Prefrontal Cortex; Rats; Rats, Sprague-Dawley; Stress Disorders, Post-Traumatic

No systematic study has focused on the characteristics and outcome of acute clozapine intoxication, although clozapine is the most widely used antipsychotic agent in China. The study reported herein examined the features of clozapine intoxication and the therapeutic effect of hemoperfusion (HP).. In a retrospective chart review, the notes of 47 patients who attempted suicide by ingesting large amounts of clozapine and were treated at the only psychiatric emergency service in Beijing were analyzed. Of the 20 unconscious patients with plasma clozapine concentrations of more than 2000 ng/mL, 14 received a combination of HP and symptomatic treatment, whereas the other 6 and the remaining 27 patients received only symptomatic treatment. Patients' psychiatric conditions and both plasma clozapine and norclozapine concentrations were closely monitored and registered.. One patient died of pulmonary edema and subsequent heart failure, but the rest of the patients recovered without any sequelae. Patients who received HP regained consciousness significantly faster than their counterparts with the same level of clozapine plasma concentration (>2000 ng/mL) who did not receive HP.. A combination of HP and symptomatic treatment is the best therapeutic option when plasma clozapine concentration is high.

Topics: Acute Disease; Adult; Alprazolam; Antipsychotic Agents; China; Clonazepam; Clozapine; Depressive Disorder; Dose-Response Relationship, Drug; Drug Overdose; Emergency Service, Hospital; Hemoperfusion; Humans; Medical History Taking; Middle Aged; Pulmonary Edema; Retrospective Studies; Schizophrenia; Stress Disorders, Post-Traumatic; Suicide, Attempted; Sulpiride; Unconsciousness; Wine

There are limited data in the literature regarding clozapine use in adolescents with diagnoses other than schizophrenia. This report describes the use of clozapine in adolescents with diagnoses of bipolar disorder, intermittent explosive disorder (IED), and posttraumatic stress disorder (PTSD).. A chart review of 39 adolescents treated with clozapine at two residential facilities was undertaken. Data extraction included demography, illness variables, medication information, and clinical outcomes. Categorical outcomes were analyzed using contingency statistics, and continuous variables were analyzed using a paired t test.. The cohort included 26 females and 13 males with a mean age of 14 years. Clozapine was titrated slowly, and the mean daily dose was 102 mg. The diagnoses included bipolar disorder (n = 7), IED (n = 9), and PTSD (n = 19). There were significant reductions in polypharmacy once the clozapine dosage was stabilized. Prior to clozapine treatment, nearly 70% of the subjects were receiving either mood-stabilizing or antidepressant agents in combination with the previous antipsychotic drug. Once the clozapine dosage was stabilized, only 24% of the subjects required concomitant mood stabilizers (p < 0.001), and only 21% of the subjects required concomitant antidepressants (p < 0.001). Anxiolytic medication use was also significantly reduced during clozapine treatment. Most patients were discharged to a less restrictive setting. Eight subjects discontinued clozapine due to agranulocytosis (n = 1), neutropenia (n = 2), excessive weight gain (n = 2), or not requiring it long term (n = 1), and data were unavailable in 2 subjects. Significant weight gain (5% or greater change from baseline) was noted in 20 subjects.. Clozapine, in relatively modest doses, appears to have clinical benefits for adolescent with bipolar disorder, IED, and PTSD. There is no labeled indication for clozapine use in these disorders. Clozapine is also associated with serious side effects in subsets of individuals. Therefore, a very careful evaluation of the risk-to-benefit ratio in each individual subject being considered for clozapine is highly recommended.

Topics: Adolescent; Bipolar Disorder; Chi-Square Distribution; Child; Clozapine; Disruptive, Impulse Control, and Conduct Disorders; Female; Humans; Male; Retrospective Studies; Stress Disorders, Post-Traumatic; Weight Gain

This study investigates the efficacy of clozapine in treatment-resistant abused adolescents detained in a secure environment who present with chronic posttraumatic stress disorder and psychotic symptoms. All participants had received at least 2 trials of conventional neuroleptic medication prior to starting clozapine. Efficacy was assessed by using single case methodology across 6 participants employing predependent and postdependent measures of psychiatric symptoms and behavioral observations. Subjective self-reports were also sought after treatment had been established. Evaluation of the data suggests that 4 of the participants demonstrated substantial improvements in psychiatric symptoms and behavioral presentation once a therapeutic dose of clozapine had been achieved. Questionnaire responses from 5 participants indicated that clozapine treatment was associated with a reduction in hallucinatory experiences. The most troubling side effects were those of excessive salivation, dizziness, and weight gain. These findings indicate that clozapine may be effective in decreasing psychiatric symptoms and risk behaviors in traumatized adolescents presenting with psychotic symptoms.

Topics: Adolescent; Aggression; Antipsychotic Agents; Clozapine; Depressive Disorder; Female; Humans; Inpatients; Male; Prospective Studies; Psychiatric Status Rating Scales; Psychotic Disorders; Risk-Taking; Self-Injurious Behavior; Stress Disorders, Post-Traumatic

Topics: Clozapine; Comorbidity; Humans; Male; Psychotic Disorders; Stress Disorders, Post-Traumatic; Treatment Outcome; Veterans