Clozapine Initiation Research Articles

The effect of clozapine therapy on frontal lobe dysfunction in schizophrenia: neuropsychology and event-related potential measures

There are several reports that performance-based measures as well as symptom ratings improve with clozapine in patients with schizophrenia who previously responded poorly to typical neuroleptic treatment. It is not clear whether improved cognitive function following initiation of clozapine is simply related to relief of psychotic symptoms and extrapyramidal side-effects associated with prior use of typical neuroleptics, or reflects another dimension of the greater efficacy of clozapine compared with typical neuroleptics. To elucidate this issue and better specify the cognitive changes associated with use of clozapine, the authors have assessed cognitive function psychometrically and using event-related potentials (ERPs), pre- and 8-12 wk post-initiation of clozapine treatment. Patients were rated on the BPRS, the SAPS and the SANS and completed a number of tests tapping aspects of frontal lobe function. ERP recordings were conducted using an auditory task twice, which was repeated under passive and active attention conditions. It was found that clozapine differentially affects tests reflecting executive and planning function, and not stimulus-driven cognitive functions. The results were not consistent with the hypothesis that these effects were simply due to relief of medication side-effects but could be related to the D(1) receptor antagonist actions of clozapine.

Monitoring of plasma clozapine levels and its metabolites in refractory schizophrenic patients.

Plasma concentrations of clozapine and its metabolites desmethylclozapine and clozapine N-oxide were measured in 61 patients with refractory schizophrenia. Before the initiation of clozapine, each patient was given haloperidol (HL) up to 60 mg/day for at least 4 weeks without improvement. Patients were then given a fixed dose of clozapine 400 mg/day. Patients were assessed with the Brief Psychiatric Rating Scale (BPRS) at baseline before HL therapy, at the end of HL at 6 weeks, before clozapine, and after 6 weeks of clozapine therapy. Clozapine and its metabolites were measured by high-performance liquid chromatography with ultraviolet detection. The mean plasma concentrations of clozapine, desmethylclozapine, and clozapine N-oxide were 598 +/- 314, 281 +/- 140, and 90 +/- 29 ng/ml, respectively. The mean decrease in the total BPRS scores from baseline clozapine to the 6-week treatment period was 11 +/- 4. Clinical improvement was noted to occur in most patients with clozapine plasma levels > 300 ng/ml. Improvement diminished in patients with clozapine plasma levels > 700 ng/ml. The most common adverse effects were sedation and hypersalivation. Significant correlations between plasma clozapine concentrations and adverse side effects were not found.

The Clozapine Experience from a Family Perspective

To examine how the lives of family members of clozapine-treated patients with schizophrenia have been affected by this treatment. Through the use of a questionnaire and an interview of family members, this qualitative study focused on the families' perceptions of change in their family member and the impact on the family unit. Fourteen patients and their family members participated. The family interview was conducted an average of 1.78 years after clozapine initiation (range 0.58 years to 3.73 years). Global ratings of behavioural change were positively and significantly correlated between all raters: patients, family members, and clinicians. Family members were positive about clozapine's effect on their relatives and the impact on the family. A positive response to clozapine decreases the burden on the family. This is in part the result of a decreased need for rehospitalization.

Clozapine Therapy and Clinical Outcomes in Kentucky Psychiatric Hospitals

We reviewed the protocol for determining patient eligibility to receive clozapine in Kentucky state psychiatric facilities. Results of a retrospective review of the clinical outcomes of the initial 42 patients who received clozapine under this protocol are reported. Patients receiving clozapine were severely ill patients with a mean duration of illness and mean length of current hospitalization of 11 years and 2 years, respectively. Symptomatic response was dramatic with a reduction in total Brief Psychiatric Rating Scale (BPRS) and Clinical Global Impression (CGI) ratings of 48.4% and 36.3%, respectively. The time patients spent in restraints decreased significantly following clozapine initiation. Clozapine was well tolerated, with sedation being the most common adverse effect reported. One patient experienced a seizure and another developed leukopenia. Following 12 weeks of clozapine treatment, the patient discharge rate was 42.9%.

The use of Chloral Hydrate and Sodium Amytal during Clozapine Initiation

Sedative hypnotics are frequently a necessary adjunctive to neuroleptic treatment. The recently released antipsychotic agent clozapine poses a challenge in this regard since the manufacturer advises caution when using clozapine with patients receiving benzodiazepines. The effectiveness of alternate agents sodium amytal and chloral hydrate when initiating clozapine was evaluated in a group of 15 patients suffering from schizophrenia. These medications were observed to be both safe and effective.

Starting Patients on Clozapine in a Partial Hospitalization Program

The authors' aim was to assess the safety and efficacy of starting clozapine in a structured, long-term, partial hospitalization program that included protocols for detecting and managing side effects and adverse reactions to the drug as well as therapeutic programming to enhance patients' reintegration into community life. Medical records of 47 patients with schizophrenia or schizoaffective disorder who were started on clozapine in the partial hospitalization program were analyzed. Data on incidence and management of adverse reactions, number of hospitalizations, status of symptoms, and changes in patients' social functioning for periods up to 12 months after initiation of clozapine were collected. Although adverse reactions were common in the first weeks of treatment, they were managed with dosing strategies, monitoring, and concomitant medication so that no patient had to discontinue the medication. Psychotic symptoms and symptoms of tardive dyskinesia decreased significantly during the study period. At 12-month follow-up, most patients were able to attend school, hold paying or volunteer jobs, and live independently. Clozapine can be safely initiated outside an inpatient setting. Partial hospitalization programs can enhance patients' reintegration into the community through a combination of treatment with clozapine and rehabilitative and psychotherapeutic programming.

Improvement in cognitive functions and psychiatric symptoms in treatment-refractory schizophrenic patients receiving clozapine

Cognitive functions and psychopathology were assessed in 36 treatment-refractory schizophrenic patients before initiation of clozapine, and at 6 weeks and 6 months, thereafter. Before treatment, cognitive impairment was found in each measure of memory, attention, and executive function as compared with 26 normal controls. After both 6 weeks and 6 months of treatment, significant improvement occurred in the Controlled Oral Word Association Test, a measure of retrieval from reference memory. Improvement was also noted as 6 months in the Category Instance Generation Test, another measure of retrieval from reference memory, and in some, but not all, tests of executive function, attention, and recall memory. Clozapine treatment also resulted in significant improvement in Brief Psychiatric Rating Scale (BPRS) Total and Positive symptom scores at both 6-week and 6-month assessment points. There was some evidence for a relationship between improvement in psychopathology and cognitive function. The improvement in cognitive function during clozapine treatment could have consequences for capacity to work and social function.

Obstetric complications in schizophrenia

Early onset schizophrenia (EOS) begins in childhood or adolescence. EOS is associated with poor treatment response and may benefit from timely use of clozapine. This study aimed to identify the predictors of clozapine use in EOS and characterize the clinical profile and outcome of clozapine-treated youths with schizophrenia. We conducted a nationwide population-based study using linked data from Danish medical registries. We examined all incident cases of EOS (i.e., cases diagnosed prior to their 18th birthday) between December 31st 1994 and December 31st 2006 and characterized their demographic, clinical and treatment profiles. We then used multivariable cox proportional hazard models to identify predictors of clozapine treatment in this patient population. We identified 662 EOS cases (1.9% of all schizophrenia cases), of whom 108 (17.6%) had commenced clozapine by December 31st 2008. Patients had on average 3 antipsychotic trials prior to clozapine initiation. The mean interval between first antipsychotic treatment and clozapine initiation was 3.2 (2.9) years. Older age at diagnosis of schizophrenia [HR=1.2, 95% CI (1.05–1.4), p=0.01], family history of schizophrenia [HR=2.1, 95% CI (1.1–3.04), p=0.02] and attempted suicide [HR=1.8, 95% CI (1.1–3.04), p=0.02] emerged as significant predictors of clozapine use. The majority of patients (n=96, 88.8%) prescribed clozapine appeared to have a favorable clinical response as indicated by continued prescription redemption and improved occupational outcomes. Our findings support current recommendations for the timely use of clozapine in EOS.