Clozapine and body mass change.

BACKGROUND: Patients treated with clozapine have been reported to gain weight. We hypothesized that patients would also experience an increase in body mass, which can be more directly related to cardiovascular morbidity. METHODS: Forty-two patients who had been treated with clozapine for at least 1 year were weighed and measured, and waist-hip ratios (WHR) and body mass index (BMI), measured as kg/m2, were calculated. Patients were also asked about a series of factors potentially related to change in body mass. RESULTS: Female patients gained both weight and body mass. Their WHR after 37 months of clozapine therapy was .83, with a significant increase in BMI from 23.2 to 29.1 kg/m2 (p = .001). Male subjects also gained weight and body mass. Their WHR after 39 months of clozapine therapy was .93, with a significant increase in BMI from 26.4 to 29.7 kg/m2 (p < .001). Stepwise multiple-regression analysis showed that factors related to final body mass were initial body mass, dose of clozapine, and decrease in smoking. Baseline BMI contributed most to the final BMI, but the addition of dose and decrease in smoking made significant contributions to the model. CONCLUSIONS: Both female and male patients treated with clozapine gain body mass. This may place them at greater risk for cardiovascular morbidity.

Olanzapine: a new antipsychotic agent with efficacy in the management of schizophrenia.

OBJECTIVE: To review the pharmacology, pharmacokinetics, efficacy data, and adverse effects of olanzapine as a treatment for schizophrenia and to determine the advantages and disadvantages of this atypical antipsychotic agent compared with currently marketed agents. DATA SOURCES: A MEDLINE computer literature search was conducted to retrieve all English-language studies and review articles involving olanzapine published as of October 1, 1996. The manufacturer of the drug, Eli Lilly and Company, provided the clinical investigator's brochure and abstracts of unpublished Phase III clinical trials. STUDY SELECTION: Animal studies evaluating the pharmacology of olanzapine were evaluated, as were all open-label and double-blind studies involving the evaluation of olanzapine for the treatment of patients with schizophrenia. DATA EXTRACTION: All available clinical studies were reviewed and the interpretation of data for each study was influenced by the size of the study sample, the nature of the inclusion and exclusion criteria, and the data analysis techniques used. DATA SYNTHESIS: Olanzapine is a thienobenzodiazepine analog with an in vitro receptor affinity profile similar to that of clozapine. Olanzapine exhibits linear kinetics over the dosage range studied and is extensively metabolized in humans. Clinical evaluations to date have shown olanzapine to be at least as efficacious as typical antipsychotic agents in the treatment of the acute phase of schizophrenia. The drug was well tolerated, with significantly fewer extrapyramidal adverse effects than haloperidol. Current data suggest that olanzapine may be more effective than haloperidol for the treatment of negative symptoms; moreover, preliminary data suggest that fewer relapses occur over the course of treatment in patients treated with olanzapine compared with those taking haloperidol. CONCLUSIONS: The exact place of olanzapine in the therapy of psychotic patients remains unclear, as more data are needed to evaluate the long-term efficacy of this agent, its impact on negative symptoms, and its potential use in patients resistant to the standard agents. Despite limitations in the current database, olanzapine is a promising treatment option for patients with schizophrenia.

Transfer of psychiatric inpatients to a general hospital due to adverse drug reactions.

The authors review their experience with transfers of hospitalized psychiatric inpatients to general hospitals because of adverse drug reactions (ADRs). A total of 29 medical transfers related to ADRs were found in a review of 10,994 psychiatric inpatient admissions that occurred in a 30-month period between 1990 and 1993 (0.264%). Most cases involved neurological syndromes (76%), particularly delirium (31%). Low-potency antipsychotic agents were most frequently implicated (31%). Most ADRs were of moderate severity, but 8 cases required medical hospitalization (0.07% incidence). These findings indicate that ADRs leading to transfer of hospitalized psychiatric patients to a general medical facility were infrequent (< 0.3% of psychiatric admissions) and rarely led to medical hospitalization (< 0.1%).

The effect of clozapine on saliva flow rate: a pilot study.

This study examined the effect of clozapine on saliva flow rate. Unstimulated whole saliva was collected from 9 patients taking clozapine (dose range = 50-400 mg/day) and from 8 controls who had never used clozapine. There was no significant difference between the average saliva flow rates in the two groups (p > .10), nor was there significant correlation between saliva flow rate and daily clozapine dose (p > .10). Alternative explanations for observations or complaints of excessive salivation, drooling, or a choking feeling while taking clozapine are proposed.

The use of valproate in an elderly population with affective symptoms.

BACKGROUND: Little is known about the efficacy and tolerability of valproate in the elderly population with affective disorders. This pharmacoepidemiologic study was undertaken to determine the side effect profile and efficacy of valproate in an elderly population with psychiatric symptomatology. METHOD: This was a retrospective chart review of all elderly inpatients at McLean Hospital who received valproate between May 8, 1989, and May 8, 1992. Charts were reviewed to determine gender, discharge diagnosis, indication for the agent, and length of time on each medication. Charts were also reviewed for abnormalities in liver function tests, blood cell dyscrasias, sedation, nausea and vomiting, weight gain, impairment of cognition, tremor, and hair loss. The efficacy of the medication was also determined. RESULTS: Thirty-five elderly subjects who suffered from an affective disorder and who had received valproate were identified. The mean age was 71.3 years. The mean length of time the patient received valproate was 32.7 days. The mean dose was 743 mg/day, and the mean blood drug level was 52.9 mg/L. The valproate was rated as efficacious in 18 (62%) of the 29 patients who had had an adequate drug trial at discharge. Overall the medication was well tolerated. There were no reports of liver function test abnormalities. One patient experienced transient leukopenia. Other adverse events included two reports of nausea, two reports of sedation, and one complaint of confusion. None of the variables examined were found to be statistically significant in regard to efficacy. CONCLUSION: Valproate was well tolerated and efficacious in this elderly population with affective disorders. Further controlled studies are needed to confirm our results.

Serum levels of clozapine and norclozapine in patients treated with selective serotonin reuptake inhibitors.

OBJECTIVE: The selective serotonin reuptake inhibitor (SSRI) fluoxetine can increase serum levels of clozapine and norclozapine, but effects of other SSRIs are unknown. Thus, the authors evaluated interactions of clozapine with fluoxetine, paroxetine, and sertraline. METHOD: Serum clozapine and norclozapine concentrations were assayed in 80 psychiatric patients, matched for age and clozapine dose, given clozapine (mean dose = 279 mg/day) alone or with fluoxetine (mean dose = 39.3 mg/day), paroxetine (mean = 31.2 mg/day), or sertraline (mean = 92.5 mg/ day). Each patient's dose of clozapine was stable for at least a month before serum sampling. RESULTS: Concentrations of clozapine plus norclozapine averaged 43% higher, and the risk of levels higher than 1000 ng/ml was 10-fold greater (25%), in the patients taking SSRIs, with minor differences between patients taking the individual SSRIs. CONCLUSIONS: SSRIs can increase circulating concentrations of clozapine and norclozapine, sometimes to potentially toxic levels.

Does intolerance or lack of response with fluoxetine predict the same will happen with sertraline?

BACKGROUND: The purpose of this study was to determine whether sertraline would be well tolerated and effective in patients who had failed fluoxetine therapy or were unable to tolerate the medication. METHOD: Hospital records were reviewed for 88 consecutive patients started on sertraline treatment at McLean Hospital from February 11, 1992 to August 28, 1992. Forty-two patients were identified who had received sertraline treatment and who had had previous trials of fluoxetine. Patients were contacted after discharge to determine sertraline efficacy and side effects. A variety of patient characteristics and outcome measures were compared. RESULTS: Thirty-nine subjects (93%) were available for follow-up interviews. The DSM-III-R diagnoses at discharge were as follows: major depression (N=25), bipolar depression (N=6), schizoaffective disorder (N=4), and obsessive-compulsive disorder (N=4). The sertraline discontinuation rate was 64% (25/39) by a mean +/- SD of 2.3 +/- 2.1 months. In patients with major depression (N=25) and bipolar depression (N=6) discharged on sertraline, only 13 (42%) were considered responders to sertraline therapy, and at follow-up, only 8 (26%) of 31 were considered responders to sertraline therapy. Patients who had previously discontinued fluoxetine because of side effects were significantly more likely to have side effects during sertraline treatment (p = .027), and to have discontinued sertraline at follow-up (p = .018). CONCLUSION: Sertraline was found to be modestly efficacious and associated with numerous side effects and discontinuation rates in patients who had previously discontinued fluoxetine.

Hospital use of antipsychotic agents in 1989 and 1993: stable dosing with decreased length of stay.

OBJECTIVE: This study evaluated recent and current use of antipsychotics by psychiatric inpatients. METHOD: Computer-based hospital pharmacy records identified prescriptions for antipsychotics in 1993. Medical records were reviewed to verify prescription and clinical data, and these were compared with similar data from 1989. RESULTS: In 1993, antipsychotics were prescribed for 299 (42%) of 709 hospitalized patients. Treatment usually started within 24 hours of admissions averaging 18 days. High-potency agents were used 2.4 times more frequently than low-potency drugs; 13% received clozapine. The mean chlorpromazine-equivalent daily dose, corrected for as-needed supplements, was 305 mg; peak doses were 32% higher. Doses of the most potent agents (fluphenazine and haloperidol) were only 22%-33% above the overall mean. Rarely were two neuroleptics given simultaneously, but cotreatment with an anticonvulsant (84% of patients, 92% of whom received valproate), a potent benzodiazepine (81%), lithium (70%), one CNS depressant (84%), or more (45%) was common. Doses averaged 20% higher for men, 42% lower at age > 50 years versus 20-30 years, and 53% greater for schizophrenia or schizoaffective disorder versus other conditions. Comparison with 1989 admissions (N = 50) averaging 73 days indicated few differences in use of neuroleptics or benzodiazepines but less frequent use of anticonvulsants and lithium. CONCLUSIONS: High-potency antipsychotic agents and clozapine were used most often in 1993; doses of high-potency agents were only slightly higher than doses of low-potency agents, but combinations with mood stabilizers were more common in 1993, when length of stay was one-fourth that in 1989.

Prescribing trends of antidepressants in bipolar depression.

BACKGROUND: This study utilizing pharmacoepidemiologic methods was undertaken to determine the prescribing patterns of antidepressants particularly in bipolar depression. METHOD: From pharmacy records of the McLean Hospital, the number of patients receiving antidepressants and given electroconvulsive therapy (ECT) from June 1, 1987, to May 8, 1993, was determined. We later linked these data bases with patients who were diagnosed with DSM-III-R bipolar depression (296.5) during the same period of time. RESULTS: During the 6-year period, it was determined that 3829 inpatients had received tricyclic antidepressants (TCAs), 2981 fluoxetine, 2603 trazodone, 809 bupropion, 743 monoamine oxidase inhibitors (MAOIs), 592 stimulants, 588 sertraline, 48 paroxetine, and 894 ECT. There were significant increases over time in prescriptions of MAOIs compared with fluoxetine (chi 2 = 14.36, p = .006), and bupropion compared with TCAs (chi 2 = 6.45, p = .04). There was a trend for bupropion to be prescribed more over time compared with fluoxetine (chi 2 = 5.09, p = .08). There were no significant changes in the prescribing of other antidepressants or in the use of ECT. CONCLUSION: At our center, prescribing of bupropion and MAOIs in bipolar depression has increased significantly. This may be related to the reports in the literature of the low switch rates to mania with the use of these drugs.

Occurrence of seizures related to psychotropic medication among psychiatric inpatients.

OBJECTIVE: Seizures associated with psychotropic medication are serious and reportable adverse drug reactions. This study examined the occurrence of seizures associated with psychotropic medication during psychiatric hospitalization. METHODS: Among 10,994 admissions to a psychiatric teaching hospital over a 30-month period between 1990 and 1993, 29 patients were identified by a specially trained quality assurance nurse as having seizures that were probably related to psychotropic medication. These cases were verified by a clinical pharmacist and a psychopharmacologist. Two patients were excluded, and the records of 27 patients were reviewed in detail. RESULTS: Nineteen of the 27 patients (70 percent) whose seizures were related to psychotropic medication had a preexisting seizure disorder, and eight had new-onset seizures. Psychotropic medications were primarily implicated as being associated with seizures in the cases of three of the 19 patients with preexisting seizure disorders (15.8 percent) and five of the eight patients with new-onset seizures (62.5 percent). In the group with preexisting seizure disorders, six patients (32 percent) had subtherapeutic blood levels of antiseizure medication, and four (21 percent) experienced pseudoseizures. CONCLUSIONS: Seizures among inpatients on psychotropic medication were infrequent (.3 percent of psychiatric admissions); the majority (70 percent) occurred in patients with preexisting seizure disorders. Seizures were directly attributed to psychotropic medications in less than .1 percent of admissions.

Relation of leukocyte counts during clozapine treatment to serum concentrations of clozapine and metabolites.

OBJECTIVE: This study was done to test the hypothesis that serum concentration of norclozapine is a risk factor for leukopenia during treatment with clozapine. METHOD: Maximum decreases in leukocyte counts in 44 unselected patients treated with clozapine were determined and then correlated with drug doses and serum concentrations of clozapine, norclozapine, and clozapine-N-oxide. RESULTS: White cell and granulocyte counts decreased by up to 60%-73%, but there were no positive correlations between these decrements and drug dose, drug level, ratio of drug level to drug dose, or ratio of norclozapine level to clozapine level, nor were the decreases related to age or gender. CONCLUSIONS: While these results do not suggest in vivo hemotoxicity of norclozapine, further study of patients with clinically significant leukopenia is required.

Blood dyscrasias with carbamazepine and valproate: a pharmacoepidemiological study of 2,228 patients at risk.

OBJECTIVE: The purpose of this study was to determine the occurrence of leukopenia and other blood dyscrasias associated with psychiatric use of carbamazepine and valproate. METHOD: Rates of WBC counts of 3,000-4,000/mm3 (moderate leukopenia) and < 3,000/mm3 (severe leukopenia), platelet counts of < 100,000/mm3, and hematocrit < 30% were identified among 2,228 treated patients at risk among 11,720 patients admitted to McLean Hospital over 4 years (1989-1993). Patients who received carbamazepine or valproate and had a blood dyscrasia not associated with a relevant medical condition were compared to patients treated with imipramine or desipramine. RESULTS: Of 977 patients treated with carbamazepine, 2.1% experienced leukopenia (16 moderate cases, five severe). Time to 50% risk was 16 days, and recovery occurred within about 6 days after carbamazepine was stopped. For 1,251 patients given valproate, the occurrence of leukopenia was 0.4% (three moderate cases, two severe). The occurrence of leukopenia in 1,031 patients given the tricyclic antidepressants was 0.3% (two moderate cases, one severe). The observed occurrence of moderate leukopenia with carbamazepine was 6.9 and 7.3 times higher than that with valproate and antidepressants, respectively. CONCLUSIONS: Severe blood dyscrasias were uncommon in psychiatric patients given carbamazepine and were about as rare with valproate as with imipramine or desipramine. Most important, in this cohort of 2,228 patients exposed to carbamazepine and valproate, there were no life-threatening cases.

Concurrent use of clozapine and valproate in affective and psychotic disorders.

BACKGROUND: This pharmaco-epidemiologic study was undertaken to determine if the combination of clozapine and valproate poses an increased risk of blood dyscrasias, liver function abnormalities, or other side effects and to develop dosing guidelines when the combination is utilized. METHOD: The charts of 55 patients receiving clozapine and valproate concurrently between May 8, 1989, and May 8, 1992, were reviewed to determine the indication for and length of time on each medication, abnormalities in liver function test results, blood cell dyscrasias, seizures, nausea, vomiting, sedation, sialorrhea, and enuresis. In addition, the efficacy of the combination was measured. RESULTS: The combination of clozapine and valproate was efficacious and well tolerated in the majority of patients. Major adverse effects such as blood dyscrasias or seizures were not experienced by the study population. The side effect that led to discontinuation of the combination most frequently was sedation. CONCLUSION: The combination of clozapine and valproate is safe and efficacious.

Clozapine and metabolites: concentrations in serum and clinical findings during treatment of chronically psychotic patients.

Clozapine (CLZ) and metabolites norclozapine and clozapine-N-oxide were assayed with a new, sensitive (2 pmol), and selective method in 68 serum samples from 44 psychotic subjects, 20 to 54 years old, ill 16 years, and treated with CLZ for 2.2 years (currently at 294 mg, 3.4 mg/kg daily). CLZ levels averaged 239 ng/ml (0.73 microM; 92 ng/ml per mg/kg dose) or 48% of total analytes (norclozapine = 41% [91% of CLZ] and clozapine-N-oxide = 11%); metabolite and CLZ levels were highly correlated (rs = 0.9), and CLZ levels varied with daily dose (rs = 0.7). Sampling twice yielded similar within-subject analyte levels (r = 0.8 to 0.9; difference = 24% to 33%). Range and variance narrowed when levels were expressed per weight-corrected dose (ng/ml per mg/kg). Levels per dose were 40% higher in nonsmoking women than men, despite a 60% lower milligram per kilogram dose in women, and did not vary by diagnosis or age in this limited sample. Fluoxetine increased serum CLZ analytes by 60%; valproate had less effect. Patients rated treatment very positively; observer-assessed benefits typically were more moderate. Common late side effects were sialorrhea (80%), excess sedation (58%), obesity (55% > 200 lb), mild tachycardia (51%), constipation (32%), and enuresis (27%); there were no seizures or leukopenia. There was little evident relationship of drug dose or serum level to current clinical measures or side effect risks.

Serum concentrations of clozapine and its major metabolites: effects of cotreatment with fluoxetine or valproate.

Serum concentrations of clozapine, norclozapine, and clozapine-N-oxide were assayed in psychotic patients treated with clozapine alone (N = 17), clozapine with fluoxetine added (N = 6), or clozapine with valproic acid added (N = 11). Subjects were matched for age and other treatments, and concentrations were corrected for daily dose of clozapine (milligrams per kilogram of body weight). With valproic acid, there was a minor increase in total clozapine metabolites, which was even less with dose correction. Fluoxetine increased all clozapine analytes, in some cases to twice the levels in the subjects given only clozapine.

Adverse behavioral events reported in patients taking alprazolam and other benzodiazepines.

A review of the published case reports of adverse behavioral episodes or unexpected psychopathology in patients taking benzodiazepines was undertaken in an attempt to determine if these adverse or unexpected events are more likely to occur with alprazolam when compared with other currently marketed benzodiazepines. Adverse behavioral phenomena and unexpected psychopathology were divided into the following categories: (1) anger or violence, (2) impulsive, suicidal, or self-harming behavior, (3) depression, (4) mania, (5) schizophrenia, (6) withdrawal syndromes and (7) physical dependence and abuse liability. It is difficult to draw conclusions from this literature because of the limitations of spontaneously reported cases and the lack of epidemiologic studies. Despite these limitations, it appears that some differences between alprazolam and older benzodiazepines may exist. The older benzodiazepines are more commonly reported to have adverse events than alprazolam (with the exception of mania or hypomania). On the other hand, worsening in post-traumatic stress disorder and an increase in impulsive behavior in patients with borderline personality disorder have only been reported in patients receiving alprazolam. This is probably explained by the fact that only alprazolam has been used to any great extent in these conditions.