Characteristics and clinical changes during hospitalization in bipolar and psychotic disorder patients with versus without substance-use disorders.

BACKGROUND: Co-morbid substance-use disorders (SUDs) are prevalent among patients with severe psychiatric disorders, but the characteristics of such patients remain incompletely defined, and their current treatments and responses, poorly documented. METHODS: We evaluated the records of 481 consecutive inpatients diagnosed with DSM-IV bipolar or schizoaffective disorders, or schizophrenia, admitted to McLean Hospital in 2004 or 2009. Demographic and clinical characteristics, and treatments, were extracted from hospital and pharmacy records for bivariate and multivariate analyses. RESULTS: SUD prevalence increased 1.84-times from 2004 (31.3%) to 2009 (57.6%). Patients with (n=204) versus without co-morbid SUDs (n=277) were similar in many respects, but in multivariate modeling, the following factors were more likely with SUD, in rank-order: co-morbid anxiety disorders > men more than women > greater prevalence in 2009 vs. 2004 > younger age > greater doses of mood-stabilizers > shorter hospitalization. CONCLUSIONS: Hospitalized patients with severe primary psychiatric disorders, and comorbid SUD were more likely to be young and have anxiety disorders, to receive more combinations and higher doses of mood-stabilizers, and show more improvement in impulsivity and hostility, but otherwise differed little in treatment-responses. Prevalence of SUD rose substantially in the past five years, with increased but largely unproved use of mood-stabilizers.

Comorbid substance-use in schizophrenia: relation to positive and negative symptoms.

As substance use disorders (SUD) are common in schizophrenia patients, we tested the hypothesis that comorbid patients (SUD[+]) have more positive vs. negative symptoms than non-comorbid (SUD[-]) patients. From reports identified by literature-searching we compared Positive and Negative Syndrome Scale (PANSS) ratings in schizophrenia patients with and without SUD using meta-analytic methods. Among 9 comparisons (N=725 subjects), SUD[+] patients were more often men, and abused alcohol>cannabis>cocaine. SUD[+] patients had very significantly higher PANSS-positive, and lower PANSS-negative scores. Comorbid SUD in schizophrenia patients was associated with male sex and higher PANSS positive to lower negative scores. Cause-effect relationships remain to be clarified.

Weight loss in overweight patients maintained on atypical antipsychotic agents.

BACKGROUND: Weight gain and associated medical morbidity offset the reduction of extrapyramidal side effects associated with atypical antipsychotics. Efforts to control weight in antipsychotic-treated patients have yielded limited success. METHODS: We studied the impact of an intensive 24-week program of diet, exercise, and counseling in 17 chronically psychotic patients (10 women, seven men) who entered at high average body weight (105.0+/-18.4 kg) and body mass index (BMI) (36.6+/-4.6 kg/m(2)). A total of 12 subjects who completed the initial 24 weeks elected to participate in an additional 24-week, less intensive extension phase. RESULTS: By 24 weeks, weight-loss/patient averaged 6.0 kg (5.7%) and BMI decreased to 34.5 (by 5.7%). Blood pressure decreased from 130/83 to 116/74 (11% improvement), pulse fell slightly, and serum cholesterol and triglyceride concentrations changed nonsignificantly. With less intensive management for another 24 weeks, subjects regained minimal weight (0.43 kg). CONCLUSIONS: These findings add to the emerging view that weight gain is a major health problem associated with modern antipsychotic drugs and that labor-intensive weight-control efforts in patients requiring antipsychotic treatment yield clinically promising benefits. Improved treatments without weight-gain risk are needed.

Delirium during clozapine treatment: incidence and associated risk factors.

BACKGROUND: Incidence and risk factors for delirium during clozapine treatment require further clarification. METHODS: We used computerized pharmacy records to identify all adult psychiatric inpatients treated with clozapine (1995-96), reviewed their medical records to score incidence and severity of delirium, and tested associations with potential risk factors. RESULTS: Subjects (n = 139) were 72 women and 67 men, aged 40.8 +/- 12.1 years, hospitalized for 24.9 +/- 23.3 days, and given clozapine, gradually increased to an average daily dose of 282 +/- 203 mg (3.45 +/- 2.45 mg/kg) for 18.9 +/- 16.4 days. Delirium was diagnosed in 14 (10.1 % incidence, or 1.48 cases/person-years of exposure); 71.4 % of cases were moderate or severe. Associated factors were co-treatment with other centrally antimuscarinic agents, poor clinical outcome, older age, and longer hospitalization (by 17.5 days, increasing cost); sex, diagnosis or medical co-morbidity, and daily clozapine dose, which fell with age, were unrelated. CONCLUSIONS: Delirium was found in 10 % of clozapine-treated inpatients, particularly in older patients exposed to other central anticholinergics. Delirium was inconsistently recognized clinically in milder cases and was associated with increased length-of-stay and higher costs, and inferior clinical outcome.

Factors associated with noncompliance with psychiatric outpatient visits.

Adherence to recommended services is essential for long-term effectiveness of ambulatory treatment programs, but factors associated with such adherence are not securely established. We evaluated attendance at 896 scheduled psychiatric clinic visits for 62 patients at a major psychiatric teaching hospital. Visit adherence was found to be significantly higher among patients in an acute stage of illness, those with a personality disorder, those with a post-high-school education, and those living alone. Adherence was also higher when visits were routinely scheduled, when the intervisit interval was shorter, and when the visit entailed psychotherapy rather than pharmacotherapy.

Olanzapine versus placebo in the treatment of acute mania. Olanzapine HGEH Study Group.

OBJECTIVE: The primary intent of this study was to compare the efficacy and safety of olanzapine and placebo in the treatment of acute mania. METHOD: The design involved a random-assignment, double-blind, placebo-controlled parallel group study of 3 weeks' duration. After a 2- to 4-day screening period, qualified patients were assigned to either olanzapine (N = 70) or placebo (N = 69). Patients began double-blind therapy with either olanzapine, 10 mg, or placebo given once per day. After the first day of treatment, the daily dose could be adjusted upward or downward, as clinically indicated, by one capsule (olanzapine, 5 mg/day) within the allowed range of one to four capsules. The primary efficacy measure in the protocol was defined as a change from baseline to endpoint in total score on the Young Mania Rating Scale. Clinical response was defined a priori as a decrease of 50% or more from baseline in Young Mania Rating Scale total score. RESULTS: The olanzapine group experienced significantly greater mean improvement in Young Mania Rating Scale total score than the placebo group. On the basis of the clinical response criteria, significantly more olanzapine-treated patients (48.6%) responded than those assigned to placebo (24.2%). Somnolence, dizziness, dry mouth, and weight gain occurred significantly more often with olanzapine. There were no statistically significant differences between the olanzapine-treated and placebo-treated patients with respect to measures of parkinsonism, akathisia, and dyskinesias. No discontinuations of treatment due to adverse events occurred in the olanzapine treatment group. CONCLUSIONS: The results from this study suggest that compared with placebo, olanzapine has superior efficacy for the symptoms of acute mania.

Polymorphisms of the dopamine D4 receptor and response to antipsychotic drugs.

The dopamine D4 receptor may be a site through which the clinical effects of antipsychotic drugs are mediated. Polymorphisms of a 48 base pair repeat in the third exon of the DRD4 gene code for different length segments in the third intracytoplasmic loop of the D4 receptor. The most common long (seven repeat) form of the D4 receptor has been shown in both physiologic and pharmacologic experiments to respond differently to dopamine agonists and antagonists than do shorter forms of D4. Thus, variants of D4 may partly determine patient response to antipsychotic drugs and, in particular, response to typical neuroleptics, which have a relatively low affinity for the D4 receptor, as compared to clozapine, which has a relatively high affinity for D4. DRD4 polymorphisms in the third intron were characterized in 28 patients with chronic psychosis who responded well to typical neuroleptics, 32 patients who responded well to clozapine, and 57 healthy comparison subjects. Patients responding to typical neuroleptics carried the allele for the long (seven repeat) form of the D4 receptor (allele frequency 8.9%) less frequently than patients responding to clozapine (allele frequency 23.4%, P = 0.046) or healthy comparison subjects (allele frequency 26.3%, P = 0.004). The results of this study suggest that inherited variants of D4 may explain some of the interindividual variation seen in patient response to different classes of antipsychotic medication.

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.

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.

Clinically significant interactions of psychotropic agents with antipsychotic drugs.

Various psychotropic drugs are commonly combined with antipsychotic agents. Such combinations can induce pharmacodynamically based, presumably additive, beneficial (e.g. sedative or mood-altering) effects or adverse autonomic, cardiac depressant and CNS intoxicating effects. Clinically significant interactions also arise through competition with or induction of hepatic microsomal cytochrome P450 (CYP) enzymes, particularly the CYP1A2 and CYP2D6 isozymes by which most antipsychotics are oxidised. Such pharmacokinetic interactions can elevate circulating concentrations of antipsychotics (both typical agents and the atypical antipsychotic clozapine) to potentially toxic ranges, which may lead to increased risks of adverse effects. Such interactions occur particularly with serotonin (5-hydroxytryptamine; 5-HT) reuptake inhibitor antidepressants. Metabolic interactions that lead to lesser increases in antipsychotic concentrations may arise in combining these drugs with other antidepressants, benzodiazepines or propranolol. In contrast, most anticonvulsants, except valproic acid (sodium valproate), induce the oxidative metabolism of antipsychotics and can lower their plasma concentrations to potentially subtherapeutic levels, with unpredictable increases after their discontinuation. Since simultaneous use of multiple psychotropic agents is increasingly common, special caution is required to avoid untoward consequences of interactive adverse effects due to drug interactions, which can sometimes be severe or life-threatening.

Risperidone in the treatment of mania.

BACKGROUND: Risperidone, a 5-HT2 and D2 antagonist, has been shown to be an effective antipsychotic in the treatment of schizophrenia but has unclear efficacy in the treatment of psychotic affective disorders. The purpose of the study was to assess the efficacy of risperidone in the treatment of acute mania with psychotic features. METHOD: We conducted an open-label pilot study of risperidone and concurrent mood-stabilizing drugs in the treatment of acute mania with psychotic features. Patients were diagnosed with the Structured Clinical Interview for DSM-III-R (SCID). Efficacy was measured weekly with the use of the Young Mania Rating Scale (YMRS) and the Brief Psychiatric Rating Scale (BPRS). RESULTS: Ten women and 5 men (mean age = 38 years) were included in the study. Of the 13 patients who completed 2 weeks of treatment, 8 of these 13 had a 50% improvement of the BPRS, and all 13 had at least a 25% improvement (p = .002, 95% confidence interval [CI] = 46.0 to 57.8). Of the 8 patients who completed 6 weeks of treatment, 7 of the 8 had a 50% improvement, and all 8 had a 25% improvement (p = .012, 95% CI = 52.4 to 69.3). Similar results were obtained with the YMRS. By the second week of treatment, 10 of the 13 patients remaining in treatment had at least a 50% improvement, and 12 of these 13 had a 25% improvement (p = .002, 95% CI = 55.1 to 89.9). By the sixth week, all of the 8 patients remaining in treatment had a 75% improvement (p = .012, 95% CI = 90.5 to 102.8). The medication was well tolerated, and no case worsened. CONCLUSION: When used with concomitant mood-stabilizing drugs, risperidone may be effective and well tolerated in patients with acute mania with psychotic features. Considering the open design, small sample size, and limited period of observation, further studies need to be conducted.

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.

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.

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.

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.

Tissue concentrations of clozapine and its metabolites in the rat.

Clozapine (CLZ) and its metabolites norclozapine (NOR) and clozapine-N-oxide (NOX) were assayed in rat serum and brain tissue after intraperitoneal injection of CLZ. Clozapine levels rose with dose, averaging 28 ng/ml (87 nmol/L) serum per milligram/kilogram dose. Brain- and serum-CLZ levels correlated closely, averaging 24-fold higher in brain. Norclozapine and NOX averaged approximately 58% and 13% of CLZ in serum, respectively, whereas in brain, NOR was detected only at doses greater than or equal to 10 mg/kg (approximately 5.6% of CLZ) and NOX was undetectable. Levels peaked within 30 minutes, and elimination of CLZ from brain and CLZ or NOR from blood was very rapid (half-life = 1.5 to 1.6 hours). A week of daily dosing with CLZ led to no accumulation of drug in brain; a week of fluoxetine pretreatment increased analyte concentrations (serum, 86%; brain, 61%), but valproate had little effect.