The effect of adjunctive telmisartan treatment on psychopathology and cognition in patients with schizophrenia.

OBJECTIVE: This study examined the effect of adjunctive telmisartan on psychopathology and cognition in olanzapine- or clozapine-treated patients with schizophrenia. METHOD: In a 12-week randomized, double-blind, placebo-controlled study, patients diagnosed with schizophrenia or schizoaffective disorder received either telmisartan (80 mg once per day) or placebo. Psychopathology was assessed using the Positive and Negative Syndrome Scale (PANSS) and the Scale for Assessment of Negative Symptoms (SANS), and a neuropsychological battery was used to assess cognitive performance. Assessments for psychopathology and cognition were conducted at baseline and week 12. RESULTS: Fifty-four subjects were randomized, and 43 completed the study (22 in the telmisartan group, 21 in the placebo group). After 12-weeks of treatment, the telmisartan group had a significant decrease in PANSS total score compared withthe placebo group (mean ± SD: - 4.1 ± 8.1 vs. 0.4 ± 7.5, P = 0.038, SCohen's d = 0.57). There were no significant differences between the two groups in change from baseline to week 12 in PANSS subscale scores, SANS total score, or any cognitive measures (P > 0.100). CONCLUSION: The present study suggests that adjunctive treatment with telmisartan may improve schizophrenia symptoms. Future trials with larger sample sizes and longer treatment durations are warranted.

Metabolic effects of adjunctive aripiprazole in clozapine-treated patients with schizophrenia.

OBJECTIVE: This study examined the effects of adjunctive aripiprazole therapy on metabolism in clozapine-treated patients with schizophrenia. METHOD: In an 8-week randomized, double-blind, placebo-controlled study, subjects received either aripiprazole (15 mg/day) or placebo. At baseline and week 8, metabolic parameters were assessed by the frequently sampled intravenous glucose tolerance test, nuclear magnetic resonance spectroscopy and whole-body dual-energy X-ray absorptiometry (DXA). RESULTS: Thirty subjects completed the study (16 in the aripiprazole group and 14 in the placebo group). Glucose effectiveness measured by the frequently sampled intravenous glucose tolerance test improved significantly in the aripiprazole group (0.003 ± 0.006 vs. -0.005 ± 0.007/min, P = 0.010). The aripiprazole group showed significant reductions in both plasma low-density lipoprotein (LDL) levels (-15.1 ± 19.8 vs. 4.4 ± 22.5 mg/dl, P = 0.019) and LDL particle numbers (-376 ± 632 vs. -36 ± 301 nm, P = 0.035). Further, there was a significant reduction in the lean mass (-1125 ± 1620 vs. 607 ± 1578 g, P = 0.011) measured by whole-body DXA scan in the aripiprazole group. All values were expressed as mean ± standard deviation, aripiprazole vs. placebo. CONCLUSION: Adjunctive therapy with aripiprazole may have some metabolic benefits in clozapine-treated patients with schizophrenia.

A double-blind, placebo-controlled trial of rosiglitazone for clozapine-induced glucose metabolism impairment in patients with schizophrenia.

OBJECTIVE: The primary purpose of this 8-week double-blind, placebo-controlled trial of rosiglitazone 4 mg/day was to examine its effect on insulin sensitivity index (SI) and glucose utilization (SG) in clozapine-treated subjects with schizophrenia with insulin resistance. METHOD: Eighteen subjects were randomized and accessed with a Frequently Sampled Intravenous Glucose Tolerance Test (FSIVGTT) at baseline and at week 8 to estimate SG and SI. RESULTS: Controlling for the baseline, comparing the rosiglitazone group with placebo group, there was a non-significant improvement in SG (0.016 +/- 0.006-0.018 +/- 0.008, effect size = 0.23, P = 0.05) with a trend of improvement in SI in the rosiglitazone group (4.6 +/- 2.8-7.8 +/- 6.7, effect size = 0.18, P = 0.08). There was a significant reduction in small low-density lipoprotein cholesterol (LDL-C) particle number (987 +/- 443-694 +/- 415, effect size = 0.30, P = 0.04). CONCLUSION: Rosiglitazone may have a role in addressing insulin resistance and lipid abnormalities associated with clozapine.

A double-blind, placebo-controlled trial of sibutramine for clozapine-associated weight gain.

UNLABELLED: This study sought to examine the effectiveness of sibutramine, a weight loss agent, on clozapine-associated weight gain. METHOD: This was a 12-week double-blind, placebo controlled, randomized trial of sibutramine for weight loss in obese clozapine-treated schizophrenia or schizoaffective disorder subjects. RESULTS: Ten patients were enrolled into the placebo group and 11 patients into the sibutramine group. There were no significant baseline differences between the two groups on age, gender, education, ethnicity, diagnosis, weight, body mass index (BMI), and blood pressure. At week 12, there were no significant differences in changes in weight, BMI, abdominal and waist circumferences, Hba1c, fasting glucose, or cholesterol levels. CONCLUSION: Sibutramine treatment did not show significant weight loss compared with placebo in clozapine-treated patients with schizophrenia or schizoaffective disorder. Further research with a larger sample size and longer follow-up duration is warranted.

Homocysteine levels and glucose metabolism in non-obese, non-diabetic chronic schizophrenia.

OBJECTIVE: We studied a sample of schizophrenia out-patients to test the hypotheses that serum homocysteine concentrations would correlate positively with measures of glucose metabolism. METHOD: Subjects underwent a nutritional assessment and fasting plasma, serum insulin and homocysteine tests. RESULTS: Males had a significantly higher homocysteine levels than females (7.69 +/- 1.42 microM vs. 6.63 +/- 1.40 microM; P = 0.02). Comparing subjects with normal fasting glucose (NFG) (glucose < 100 mg/dl) and impaired fasting glucose (IFG) (> or = 100 mg/dl) subjects with IFG (mean 8.2 +/- 1.5 microM) had significantly higher homocysteine levels than those with NFG (mean 7.2 +/- 1.4 microM, P = 0.03). IFG was also associated with greater mean values for a Homeostatic Model Assessment-Insulin Resistance (HOMA-IR) (P = 0.002) and diastolic blood pressure (P = 0.045). CONCLUSION: The group with IFG had higher fasting serum homocysteine concentrations than those with NFG which supports a connection to an important cardiovascular risk factor.

An exploratory open-label trial of aripiprazole as an adjuvant to clozapine therapy in chronic schizophrenia.

OBJECTIVE: We conducted this 6-week open-label trial to examine the effects of adjunctive aripiprazole in clozapine-treated subjects on weight, lipid and glucose metabolism, as well as positive and negative symptoms of schizophrenia. METHOD: Ten clozapine-treated subjects received aripiprazole augmentation; eight completed the 6-week trial and two ended at week 4. Eighty percent were male, the mean age was 38.7 +/- 8.9 years and the mean clozapine dose was 455 +/- 83 mg daily. RESULTS: There was a significant decrease in weight (P = 0.003), body mass index (P = 0.004), fasting total serum cholesterol (P = 0.002) and total triglycerides (P = 0.04) comparing baseline to study endpoint. There was no significant change in total Positive and Negative Syndrome Scale scores. CONCLUSION: This combination may be useful for clozapine-associated medical morbidity and must be studied in placebo-controlled double-blind randomized trials to determine efficacy and safety.

Insight into current symptoms of schizophrenia. Association with frontal cortical function and affect.

OBJECTIVE: Examine whether frontal lobe dysfunction or affective experiences correlates with lack of symptom awareness in schizophrenia. METHOD: A total of 122 consecutive adult schizophrenia outpatients were assessed cross-sectionally with standard rating scales of psychopathology and of insight, and underwent neuropsychological assessment with a battery of tests sensitive to frontal lobe dysfunction. Correlational analyses were used to determine relationships between variables. RESULTS: About 62% of patients had at least partial awareness of symptoms. Anxiety correlated modestly with insight into the abnormal nature of positive and negative symptoms. No cognitive variable was significantly correlated with symptom awareness. CONCLUSION: The pathological nature of symptoms is better recognized by patients who experience dysphoric affect. Neither severity of psychotic symptoms nor frontal lobe cognitive deficits correlates to symptom awareness. Lack of insight, which can be partial for symptoms of the illness, might be a non-reducible symptom of schizophrenia.

Antipsychotic combination therapy in schizophrenia. A review of efficacy and risks of current combinations.

OBJECTIVE: To review the literature on efficacy and risks of combining antipsychotics (atypical with atypical or conventional) and suggest a rationale and strategies for future clinical trials. METHOD: A computerized Medline search supplemented by an examination of cross-references and reviews was performed. RESULTS: Empirical evidence for the efficacy of combining antipsychotics is too limited to draw firm conclusions. The practice of augmenting clozapine with more 'tightly bound' D2 receptor antagonists as exemplified by risperidone augmentation of clozapine has some empirical and theoretical support. The risks of augmentation strategies have not been studied systematically. No study has examined the economic impact of combination treatment. CONCLUSION: Further trials of antipsychotic combination therapies are needed before this currently unsupported practice can be recommended. Rationales for combination treatment include a broadening of the range of receptor activity or an increase in D2 receptor occupancy with certain atypical agents. Trial methodology needs to take into account subject characteristics, duration of treatment, optimization of monotherapy comparators, and appropriate outcome measures.

Schizophrenia.

To provide the most effective care for this difficult patient population, it is helpful to remember that patients with schizophrenia have disease-intrinsic limitations that limit their ability to participate in their care. These limitations are symptoms of a disease and not volitional. For the physician to substitute for these deficits, a certain degree of flexibility as well as the willingness to use unorthodox interventions is necessary. Good medical care is as important for the patient with schizophrenia as for any other patient.

Augmentation strategies in the treatment of schizophrenia.

Use of augmenting agents in schizophrenia is a common practice in response to resistant symptoms or comorbid illness. Increasingly, clinicians are combining more than one antipsychotic agent, despite a lack of evidence from controlled studies to support this approach. A rationale can be made for adding higher-potency agents to clozapine in an attempt to optimize D2 dopamine receptor blockade, but this strategy requires further study before it should be adopted in clinical practice. Older reports have explored the use of antidepressants, mood stabilizers, and anxiolytics as augmenting agents. These agents appear to improve comorbid affective or anxiety symptoms, but earlier evidence of improvement in psychotic or negative symptoms has not been replicated consistently. Glutamatergic agents acting at the glycine coagonist site of the N-methyl-d-aspartate receptor, including glycine, d-cycloserine, and d-serine, have demonstrated impressive therapeutic effects for negative symptoms when added to conventional neuroleptic agents, but do not appear to enhance clozapine efficacy. Given the high rates of symptom persistence and disability associated with schizophrenia, the need for augmentation strategies is great, but no approach has clearly emerged as effective for a substantial portion of patients. Although certain approaches may prove helpful for individual patients, augmentation should not be used unless monotherapy has been optimized, and should not be continued long-term unless benefits are clear.

Smoking and therapeutic response to clozapine in patients with schizophrenia.

BACKGROUND: Of patients with schizophrenia, 70 to 80% smoke. Nicotine corrects certain information processing and cognitive psychomotor deficits seen in many patients with schizophrenia. Clozapine, but not conventional antipsychotics, has been shown to correct some of these deficits. METHODS: We assessed psychopathology and smoking in 70 patients with treatment refractory schizophrenia (55 smokers and 15 nonsmokers) at baseline when they were receiving conventional antipsychotics and again after they were switched to clozapine. RESULTS: Smokers showed significantly greater therapeutic response to clozapine than nonsmokers. Smokers smoked less when treated with clozapine than when treated with conventional antipsychotics. CONCLUSIONS: Certain patients with schizophrenia have contributing pathophysiologic mechanisms that respond favorably to either nicotine or clozapine.

Clozapine-induced electroencephalogram changes as a function of clozapine serum levels.

Specific electroencephalogram (EEG) changes during clozapine therapy were prospectively studied in a cohort of 50 chronic state hospital patients with schizophrenia who were randomly assigned to one of three nonoverlapping clozapine serum level ranges (50-150 ng/mL, 200-300 ng/mL, and 350-450 ng/mL). EEGs were obtained before clozapine was instituted, and after 10 weeks of treatment. Fifty-three percent of patients showed EEG changes during the 10-week study period. We observed three seizures (6%), one in a patient on 900 mg (serum level 320 ng/mL) clozapine, and two in patients with lower clozapine serum levels (200-300 ng/mL) who had prior histories of seizures and inadequate valproate coverage. Thirteen percent of patients developed spikes with no relationship to dose or serum level of clozapine. Fifty-three percent of patients developed slowing on EEG. Compared to plasma levels below 300 ng/mL, a clozapine serum level between 350 and 450 ng/mL led to more frequent and more severe slowing. The EEG slowing correlated with observed sleepiness, although this factor was not sufficient to explain the severity of high-dose effects.

Response of patients with treatment-refractory schizophrenia to clozapine within three serum level ranges.

OBJECTIVE: This study sought to determine the relationships between serum clozapine levels and therapeutic response. METHOD: Fifty-six inpatients who met the DSM-III-R criteria for chronic schizophrenia and who had not responded to extended treatment with classical antipsychotics were randomly assigned to 12 weeks of double-blind treatment with clozapine at one of three serum level ranges: low (50-150 ng/ml), medium (200-300 ng/ml), or high (350-450 ng/ml). Baseline clinical assessments were completed before the patients' regular antipsychotic and anticholinergic drugs were discontinued. During clozapine treatment, serum levels were ascertained weekly to allow adjustment of clozapine doses so as to maintain each patient near the midpoint of his or her assigned serum level range. Clinical assessments were completed after 6 and 12 weeks of treatment. RESULTS: The analyses of the results of treatment supported the superior efficacy of the 200-300 ng/ml and 350-450 ng/ml serum clozapine level ranges over the 50-150 ng/ml range, with no advantage for 350-450 ng/ml over 200-300 ng/ml. Sleepiness increased with increasing serum levels. CONCLUSIONS: Serum clozapine levels per unit of daily dose were at the lower end of the range noted in previous reports, possibly reflecting the current study's dosing schedules of twice or three times a day, the 11- to 13-hour postdose sampling time, and the moderate doses given. Serum clozapine levels, if interpreted in relation to daily clozapine dosing schedules, postdose sampling time, and total daily dose, may help to guide dosing to provide adequate opportunities for therapeutic response and to limit certain side effects of clozapine treatment.