Successful treatment of tardive dystonia with clozapine and clonazepam

BACKGROUND: Tardive dystonia is an uncommon complication of neuroleptic treatment which is frequently disabling and poorly responsive to treatment. METHOD: The case is reported of a 28-year-old patient with schizophrenia who developed severe, generalised tardive dystonia after five years of neuroleptic treatment. Stopping neuroleptic medication and treatment with tetrabenazine, an anticholinergic and a benzodiazepine were ineffective. Treatment with clozapine and then the novel combination of clozapine plus clonazepam was instituted. RESULTS: Treatment with clozapine alone brought about limited improvement. Addition of clonazepam resulted in virtually complete disappearance of all abnormal movements. This remission has been sustained for nearly two years. CONCLUSIONS: This report adds to two other cases suggesting that the combination of clozapine and clonazepam may be an effective treatment for tardive dystonia.     

Cardiomyopathy associated with clozapine.

Clozapine is an atypical antipsychotic agent that is more effective than the standard neuroleptics currently used for treating refractory schizophrenia. In addition, clozapine is a drug with few extrapyramidal side effects. However, clozapine is also associated with potentially serious adverse effects, such as cardiac complications as well as agranulocytosis. Clozapine-related cardiomyopathy has not been previously reported in East Asia. This report describes a 31-year-old Korean male patient with schizophrenia who developed dilated cardiomyopathy on treatment with clozapine. The removal of clozapine caused subsequent physical improvement. However, the readministration of clozapine for managing relapse of psychosis caused a recurrence of dilated cardiomyopathy in this patient. Therefore, this is the 1st report showing that the 2nd trial of clozapine caused recurrence of cardiomyopathy associated with clozapine. Thus, this report adds important support for a causal relation between clozapine and cardiac complications. In conclusion, this report attempts to raise awareness of clozapine-related cardiomyopathy. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

The Grady Nia Project: A culturally competent intervention for low-income, abused, and suicidal African American women.

Background information is provided on the link between intimate partner violence and suicidal behavior, as this association sets the stage for interventions for this population. Attention then is paid to the theoretical components of an innovative culturally competent intervention for abused and suicidal, low-income African American women, entitled Grady Nia Project. The intervention is guided by the theory of triadic influence. Cultural competence components essential to implementing an intervention with this unique population and guided by this model are articulated. The Grady Nia Project is then described in detail, focusing on the context in which the intervention is conducted, the content of the 10 sessions, and treatment satisfaction and outcome data. Implications for culturally informed practice with abused, suicidal African American women are noted. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Reversible metabolism of clozapine and clozapine N-oxide in schizophrenic patients

1. To characterize the interconversion process between clozapine and its metabolite clozapine N-oxide (CNO), eight healthy male schizophrenics were administered a single dose of clozapine or CNO in a randomized crossover manner. 2. Using a general pharmacokinetic model for the interconversion process, the mean total clearances of clozapine and CNO were 28.45 L/hr and 45.30 L/hr, respectively. These values were similar to the values obtained by the usual model-independent method of pharmacokinetic analysis. 3. When administered clozapine, mean CNO plasma concentrations of 17.7 +/- 16.4 ng/ml were slightly lower than the other clozapine metabolite-desmethylclozapine (DCLOZ) plasma levels of 24.4 +/- 8.6 ng/ml at the 12 hour time point. When CNO was administered, plasma concentrations at the 12 hour time point of clozapine were twice the amount of CNO (28.1 +/- 8.9 ng/ml vs 14.4 +/- 8.8 ng/ml). 4. DCLOZ plasma concentrations were detected in all patients upon clozapine administration. Upon CNO administration, only one patient had detectable plasma DCLOZ levels. 5. The interconversion process of clozapine and CNO could partially account for the wide interpatient variability reported for clozapine plasma concentrations in schizophrenic patients.     

The expanding indications for clozapine.

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. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Chorea-like motor restlessness in clozapine

Clozapine is an antipsychotic drug that has a very low incidence of extrapyramidal side effects. Only few dyskinetic and dystonic motoric alterations are described. This brief review describes three patients who developed chorea-like symptoms during a Clozapine therapy. The possible causal mechanisms of these side effect are suggested.     

Anticholinergics to treat clozapine withdrawal

Although some parents and health care staff believe that knowledge of impending death should be withheld from children to protect them, seriously ill children usually have an awareness of death. Denial of this by parents and staff may increase the child's stress. Nurses must address the question: asked by Rimmer (1993): 'To whom does the information of the diagnosis belong?'     

Neuroleptic malignant syndrome and clozapine monotherapy

OBJECTIVE: This report identifies neuroleptic malignant syndrome (NMS) occurring on a steady state dosage of clozapine monotherapy. CLINICAL PICTURE: An outpatient presented with a recent history of stiffness and soreness of his legs, dizziness, polydipsia, polyuria, abdominal and chest pains. After admission to a general hospital, further symptomatology was identified including: pallor, diaphoresis, nausea, confusion, agitation, decrease in normal reflexes, minimally reactive pupils and rigid limbs. TREATMENT: Intravenous (I/V) diazepam was administered but failed to decrease the agitation and confusion. He was sedated with the administered of I/V droperadol, intubated and placed on a ventilator with circulatory supports for 4 days. OUTCOME: On day five he was extubated and transfered to a medical ward. All laboratory values had returned to normal values by this time. The patient was subsequently discharged. CONCLUSIONS: Neuroleptic malignant syndrome can occur at any stage of clozapine treatment, and the patient can be rechallenged after such an episode. This person was rechallenged and after 6 months of treatment has suffered no further recurrence of NMS.     

Serotonin function and treatment response to clozapine in schizophrenic patients

OBJECTIVE: Clozapine is the only compound proven to be effective in the 20% of schizophrenic patients refractory to treatment with conventional neuroleptics. Although its mechanism of action has not been elucidated, clozapine appears, in contrast to most conventional neuroleptics, to be a potent serotonin (5-HT) antagonist. This study hypothesized that 5-HT function is increased in patients who benefit from clozapine treatment relative to patients who fail to improve on it. METHOD: The 5-HT receptor agonist m-chlorophenylpiperazine (MCPP) was used as a probe to examine 5-HT function. MCPP (0.35 mg/kg p.o.) was administered in a placebo-controlled design after a 3-week drug-free period to 19 schizophrenic patients. ACTH, prolactin, body temperature, behavior, and MCPP blood level were measured. Patients were then treated with a conventional neuroleptic, and, having failed to respond to it, were treated with clozapine for 5 weeks (up to 600 mg/day). RESULTS: Patients who responded to clozapine had significantly higher ACTH responses to MCPP during the drug-free state than the patients who failed to benefit from clozapine. Moreover, the degree of improvement with clozapine, particularly the improvement in psychotic symptoms, was strongly correlated with the magnitude of MCPP-induced ACTH release. Other MCPP-induced responses and MCPP blood level were similar for the two groups and did not correlate with the degree of symptomatic improvement with clozapine. CONCLUSIONS: Results of this study suggest that MCPP-induced ACTH release, and by inference 5-HT receptor function, may be increased in patients who benefit from treatment with clozapine relative to patients who fail to improve on this drug.     

Acute clozapine overdose: plasma concentration and outcome

The present study was designed to determine the effect of anisocytosis on the association of MCV values with HbA1c and reticulocyte counts as markers of red cell age. Normo-, micro- and macrocytic samples, fractionated by counterflow centrifugal elutriation were studied. The previously described correlation between MCV and HbA1c was only observed in normal samples and in the middle fractions of samples with anisocytosis. At both extremes of the elutriation profile, curves for HbA1c content and reticulocyte count levelled out. Furthermore, in fractions containing the largest red cells of the microcytic series and the smallest red cells of normo- and macrocytic samples, reticulocyte count decreased while HbA1c content increased with increasing MCV. From these data it is concluded that MCV is not an absolute determinant of red cell age in case of anisocytosis.     

Local monitoring center for clozapine (Leponex) treatment

A local centre for monitoring clozapine therapy has been in operation in the Pharmacy Department at Asg?rd Hospital in Troms? since 1994. The centre utilizes an electronic reporting system and is available to clozapine-prescribers in the three northernmost countries in Norway: Nordland, Troms and Finnmark. The system fosters early detection of poor compliance with frequent blood tests and for signs of white blood cell suppression. This is a new concept in Norway and one way of assuring the quality of clozapine treatment. The purpose of the centre is to improve patient safety by facilitating early detection of potentially dangerous white blood cell suppression, thereby avoiding fatal consequences.     

Ganglioside vaccines with emphasis on GM2

OBJECTIVE: To investigate the impact of an educational intervention on knowledge and anxiety level of women scheduled for colposcopy after an abnormal Papanicolaou (Pap) test. DESIGN: Experimental, randomized controlled study. SETTING: An inner-city medical school. PARTICIPANTS: The final sample consisted of 58 women in the intervention group and 55 women in the control group. Exclusion criteria included any previous colposcopy. INTERVENTIONS: The women in the intervention group received in the mail, approximately 1 week before their appointment, a one-page handout about colposcopy. The control group received no mailed handout. After arriving for the visit, women were asked to participate in the study and then were interviewed. MAIN OUTCOME MEASURES: Knowledge of reason for visit and knowledge of colposcopy as measured by content analysis of interview; and anxiety as measured by the Spielberger State/Trait Anxiety Inventory. RESULTS: Women in the intervention group demonstrated significantly more knowledge about the reason for their visit and about colposcopy than did the other women. No significant difference in mean anxiety score was found between the groups. CONCLUSIONS: The intervention increased knowledge about colposcopy for this population. Because patient education is an essential nursing function, these results are encouraging. This intervention can be replicated by nurses in other settings. Further research is necessary to understand how nurses can best help women alleviate anxiety before colposcopy.     

A fatal drug interaction between clozapine and fluoxetine

A case is presented of a fatal drug interaction caused by ingestion of clozapine (Clozaril) and fluoxetine (Prozac). Clozapine is a tricyclic dibenzodiazepine derivative used as an "atypical antipsychotic" in the treatment of severe paranoid schizophrenia. Fluoxetine is a selective serotonin reuptake inhibitor used for the treatment of major depression. Clinical studies have proven that concomitant administration of fluoxetine and clozapine produces increased plasma concentrations of clozapine and enhances clozapine's pharmacological effects due to suspected inhibition of clozapine metabolism by fluoxetine. Blood, gastric, and urine specimens were analyzed for fluoxetine by gas chromatography/mass spectrometry (GC/MS) and for clozapine by gas-liquid chromatography (GLC). Clozapine concentrations were: plasma, 4.9 micrograms/mL; gastric contents, 265 mg; and urine, 51.5 micrograms/mL. Fluoxetine concentrations were: blood, 0.7 microgram/mL; gastric contents, 3.7 mg; and urine 1.6 micrograms/mL. Norfluoxetine concentrations were: blood, 0.6 microgram/mL, and none detected in the gastric contents or urine. Analysis of the biological specimens for other drugs revealed the presence of ethanol (blood, 35 mg/dL; vitreous, 56 mg/dL; and urine 153 mg/dL) and caffeine (present in all specimens). The combination of these drugs produced lethal concentrations of clozapine and high therapeutic to toxic concentrations of fluoxetine. The deceased had pulmonary edema, visceral vascular congestion, paralytic ileus, gastroenteritis and eosinophilia. These conditions are associated with clozapine toxicity. The combined central nervous system, respiratory and cardiovascular depression of these drugs was sufficient to cause death. The death was determined to be a clozapine overdose due to a fatal drug interaction.     

N-oxygenation of clozapine by flavin-containing monooxygenase

The involvement of FMO in the N-oxygenation of CLZ was investigated by use of purified FMOs and human liver microsomes that contained the mean amount of immunoreactive FMO3 relative to other human liver microsomal preparations in a liver bank. In the microsomal preparation the involvement of FMO was indicated through enzyme inhibition by methimazole, heat inactivation, and protection against heat inactivation by NADPH. Also the Michaelis-Menten kinetic constant; KM determined for CLZ N-oxidation catalyzed by purified human FMO3 (324 microM) was very similar to the mean value obtained in these laboratories for the microsomal preparations of seven human livers.     

Experience with clozapine in a community mental health care setting

BACKGROUND: Clozapine has been heralded as the first major breakthrough in antipsychotic drug therapy for treatment-resistant schizophrenia in 40 years. This study reports on the experience with clozapine in an outpatient, community mental health care setting. METHODS: All clinic patients receiving clozapine during the 4-year period 1992 to 1996 were retrospectively studied. Measures of improvement were changes in the Clinical Global Improvement (CGI) Scale and reduction in the number of hospital days after clozapine therapy. RESULTS: Testing with the CGI scale showed moderate or marked improvement in 63% of patients. Hospital days dropped from 7,919 to 1,833 for comparable time periods. Clozapine therapy had to be discontinued in only 21% of patients, and no serious side-effects occurred. CONCLUSION: Clozapine is an effective medication for treatment-resistant schizophrenia and can be safely used in chronic mental illness. Although the drug is expensive, the cost is offset by a remarkable reduction in hospital days.     

Forgiveness as an intervention goal with incest survivors

An intervention, with forgiveness toward their abuser as the goal, was implemented with 12 female incest survivors. The women, from a midwestern city, were 24 to 54 years old, and all were Caucasian. A yoked, randomized experimental and control group design was used. The participants were randomly assigned to an experimental group (receiving the forgiveness intervention immediately) or a waiting-list control group (receiving the intervention when their matched experimental counterpart finished the intervention). Each participant met individually with the intervener once per week. The average length of the intervention for the 12 participants was 14.3 months. A process model of forgiveness was used as the focus of intervention. Dependent variables included forgiveness, self-esteem, hope, psychological depression, and state-trait anxiety scales. After the intervention, the experimental group gained more than the control group in forgiveness and hope and decreased significantly more than the control group in anxiety and depression. When the control group then began the program they showed similar change patterns to the above, as well as in self-esteem improvement.     

Time to clozapine response in a standardized trial

OBJECTIVE: The authors sought to determine the time to clozapine response in treatment-refractory patients with schizophrenia. METHOD: Antipsychotic response to a clozapine trial was examined in 50 treatment-refractory schizophrenic inpatients. Subjects were treated with clozapine for at least 12 months, regardless of response status, according to a standardized, increasing dose protocol. Behavioral changes were measured through monthly assessments with the Brief Psychiatric Rating Scale. RESULTS: Thirty-four subjects (68%) met clinical response criteria by the end of the trial. Response was achieved at a mean dose of 468 mg/day (SD = 168). The dose of 30 (88%) of the responding patients was 600 mg/day or less. The mean time to response was 82 days (SD = 100, range = 10-401). It took an average of 60 days (SD = 87) for subjects to reach the dose at which clozapine response was achieved. Once this dose was reached, the average response time was 17 days (SD = 14, range = 2-56). All 34 subjects who responded met criteria within 8 weeks of a clozapine dose escalation. No late response was found in the remaining 16 subjects despite a mean follow-up period of 75 weeks (SD = 50). CONCLUSIONS: In this study, all patients who responded to clozapine did so within 8 weeks of a change in dose. Thus, there appears to be little clinical gain in prolonging exposure to clozapine beyond 8 weeks at any particular dose if no response is seen.     

Risperidone as an adjunct to clozapine therapy in chronic schizophrenics

BACKGROUND: Some treatment-resistant schizophrenic patients improve enough to remain out of the hospital but continue to have significant positive or negative symptoms. METHOD: The goal of this study was to assess the safety and potential efficacy of risperidone as an adjunct for schizophrenic patients treated with clozapine. In an open 4-week trial involving 12 DSM-III-R-diagnosed patients, the addition of risperidone to clozapine was well tolerated and did not affect serum clozapine concentrations significantly. RESULTS: Total Brief Psychiatric Rating Scale (BPRS) scores and subscales measuring positive symptoms, negative symptoms, and depressive symptoms were significantly reduced from baseline. Ten of 12 participants had a 20% or greater reduction in the total BPRS score. CONCLUSION: In this open trial, the addition of risperidone to clozapine was well tolerated and produced significant reduction of symptoms, suggesting that this may be a useful clinical approach. Because this was an open trial, the improvement we observed must be replicated in a controlled trial.