Serious respiratory infections can increase clozapine levels and contribute to side effects: a case report

Clozapine is mainly metabolized by the cytochrome P450 1A2 (CYP1A2), which may be inhibited by serious respiratory infections. This case report supports that a serious respiratory infection may increase clozapine levels and contribute to side effects. Plasma clozapine and norclozapine levels were monitored 17 times during 1 year. The concentration-to-dose ratio (C/D), an index of metabolic activity, was obtained by dividing the sum of plasma clozapine and norclozapine concentration (total clozapine concentration) by clozapine dose. The coefficient of variation (CV) of the total clozapine concentrations was calculated at different doses to provide a measure of the noise associated with determining clozapine concentrations in clinical practice. During a respiratory infection, the patient was taking 600 mg/day of clozapine. Clozapine levels were 1245 ng/ml (norclozapine 472 ng/ml), reflecting a decrease in clozapine metabolism by approximately a factor of 2. The high clozapine levels were associated with side effects (myoclonus and increased sedation). The C/D during the infection was 2.9, while the rest of C/Ds ranged between 1.0 and 1.6. CVs before and after the infection, at different doses, were always lower than 20%. When the level during the infection was included to calculate the CV on 600 mg/day, the CV increased to 54%. The theophylline literature, a prior case report and this case all suggest that if a clozapine patient develops a severe respiratory infection with fever, the psychiatrist must pay particular attention to any signs suggestive of major clozapine toxicity associated to a decrease in clozapine metabolism. If any of these signs appear, the psychiatrist may need to consider cutting the clozapine dose in half until the patient has recovered from the infection.     

Hyperglycemia, hyperlipemia, and periodic paralysis: a case report of new side effects of clozapine

1. 1. This case report of a Chinese male schizophrenic patient describes new side effects that have not been documented previously for patients treated with clozapine. At certain doses of clozapine, the patient showed direct adverse reactions, which include a combination of hyperglycemia, hyperlipemia, and periodic paralysis.

2. 2. In a four-year study of this patient who had no previous episodes of diabetes in his or his family history, the authors found that these symptoms disappeared upon withdrawal of clozapine and relapsed with re-treatment of the drug.

3. 3. This study indicates that hyperglycemia, hyperlipemia, and periodic paralysis may need to be monitored on patients treated with clozapine.

     

Combination of clozapine and amisulpride in treatment-resistant schizophrenia--case reports and review of the literature

BACKGROUND: The clinical outcome of patients suffering from schizophrenic psychoses has been considerably improved by atypical antipsychotics like clozapine and amisulpride. In patients whose symptomatology cannot be ameliorated by monotherapy, it might be necessary to combine two atypical antipsychotics. While clozapine interacts with a variety of neurotransmitter receptors, amisulpride predominantly binds with high affinity to D3/D2-dopamine receptors. Combination can be considered if a supplementary dopamine-receptor blockade is desired. METHODS: We report on the therapy of 15 patients using a combination regimen of amisulpride and clozapine. Data were collected from patient records. The case reports document previous treatment attempts, describe the reason for the combination therapy, and determine its effect. RESULTS: Major (six cases) or at least marked (eight cases) improvement of previously treatment-resistant positive and negative symptoms could be achieved by using a mean clozapine dose of 375 mg/day (serum level 0.38 mg/l) and an amisulpride dose of 527 mg/day. Additionally, by reducing the clozapine dose compared to monotherapy by 24 %, a significant reduction of side effects was observed. CONCLUSIONS: The combination of amisulpride with clozapine considerably enriches the therapeutic arsenal in cases of severe schizophrenic psychoses. Additional prospective studies are needed in order to systematically evaluate this new treatment strategy.     

Benefits of combining aripiprazole to clozapine: three case reports

OBJECTIVE: A substantial number of patients treated with clozapine shows insufficient response. The author presents the results of adding aripiprazole in patients resistant to clozapine. METHOD: Three cases of individuals with psychotic symptoms despite clozapine use and with significant side effects that were treated via this combination are presented. Response was evaluated by clinical assessment. RESULTS: Good clinical results were obtained in all three patients, with improvement of psychotic symptoms and of some of the side effects of clozapine. CONCLUSION: The findings from this case series suggest that adjunctive therapy with aripiprazole can be of benefit for treating clozapine resistant schizophrenic patients.     

Clinical analysis in the main side effects of clozapine: enclosed 600 cases report]

The main side effects of 7921 hospitalized patients taken clozapine from July in 1980 to October in 1988 were investigated. In these cases, there were 600 patients with the main side effects caused by clozapine. They included 312 patients with leukocytosis (52.0%), 114 patients with leukopenia (19.0%), (included 16 patients with agranulocytosis), 53 patients with EEG abnormal (8.9%), 35 patients with fever (5.9%), 32 patients with EKG abnormal (5.3%), 14 patients with rash (2.3%), 12 patients with epileptic seizure (2.0%), 11 patients with posture hypotension (1.8%), 8 patients with paralytic intestinal obstruction (1.3%), 6 patients with SGPT raised (1.0%) and 3 patients with conscious disturbances (0.5%). The causes and treatments of the main side effects mentioned above were discussed.     

Verapamil treatment in clozapine-induced sleep-related enuresis: a case report

Enuresis is an embarrassing rare side effect of clozapine treatment. Using single-blind placebo-control design, the antienuretic activity of the calcium channel blocker verapamil (up to 80 mg/day per os, at 21.00 hours) was evaluated in a schizophrenic patient with comorbid obsessive-compulsive disorder (OCD) who developed nocturnal functional enuresis during clozapine treatment. Verapamil (80 mg/day) displayed antienuretic activity. No correlation between the bradycardiac effect and the antienuretic activity of verapamil was detected.     

Reversible Pisa syndrome induced by clozapine: a case report

Pisa syndrome, manifested with persistent lateral flexion of the trunk, is most commonly associated with prolonged treatment with typical antipsychotics. However, it was also reported as occurring with atypical antipsychotics. To our knowledge, there have been very few reports of clozapine-associated Pisa syndrome. Here we report 1 case of Pisa syndrome in a 39-year-old woman with schizoaffective disorder who developed tonic flexion of trunk and head toward the left side after clozapine treatment (400 mg/d) for 5 months. Clozapine was reduced to 25 mg/d within 15 days; the dystonic reaction then completely resolved within the next 3 to 4 weeks. Caution should be taken while prolonged use of clozapine in patients with risk factors of Pisa syndrome.     

氯氮平的心脏不良反应

目的：探讨氯氮平治疗精神疾病时的心脏不良反应及危险因素。方法：分析400例服用氯氮平治疗的患者心电图异常改变及其影响因素。结果：服用氯氮平的患者中出现窦性心动过速(发生率79％)、心律失常及传导障碍(4、5％)、ST段压低(3、8％)、T波异常(36．5％)、QTc间期延长(16．3％)等心电图异常。其严重异常发生率为24．3％。服氯氮平出现心脏严重不良反应的危险因素有：男性、合并心血管疾病、治疗前T波异常、服药剂量较大、服药早期。结论：氯氮平的心脏不良反应较常见，约1／4患者可出现严重心电图异常。氯氮平不宜作为首选用药，使用时应定期监测心电图。     

Reduction of clozapine-induced hypersalivation by pirenzepine is safe

INTRODUCTION: Hypersalivation is known as a frequent, disturbing, and socially stigmatizing side effect of therapy with the atypical antipsychotic clozapine. It has been shown that the addition of the anticholinergic pirenzepine is able to reduce clozapine-induced hypersalivation, probably by blocking M4-receptors. Nevertheless, a pharmacokinetic interaction between both compounds cannot be excluded. METHODS: In this pilot study, 29 schizophrenic patients (ICD-10; 51.7 % female; age: 36.7 +/- 8.7 years [mean +/- SD]) were included. Serum concentrations of clozapine and its pharmacologically active metabolite N-desmethylclozapine were determined under steady-state conditions by automated HPLC with UV detection before and after addition of pirenzepine for 3 days. RESULTS: Significantly fewer patients reported hypersalivation after addition of pirenzepine (69 % vs. 34.5 %, P = 0.002). No significant differences of clozapine and N-desmethylclozapine serum levels before (329 +/- 181 ng/ml and 218.0 +/- 123.4 ng/ml, respectively) and 3 days after (336 +/- 215 ng/ml and 235.9 +/- 164.4 ng/ml, respectively) addition of pirenzepine were found. In three patients, however, clozapine serum levels increased; this was probably unrelated to pirenzepine. CONCLUSION: In conclusion, treatment of clozapine-induced hypersalivation with pirenzepine is a recommendable combination with low risk of additional side effects.     

Quetiapine-Induced extrapyramidal side effects in patients with Parkinson's disease: case report.

Although quetiapine is the antipsychotic of choice for the psychosis associated with Parkinson's disease (PD) and often is also helpful for sleep, we report two cases of quetiapine-induced extrapyramidal side effects. The patients described were unusual in their frailty and severity of illness and may not represent the majority of patients with PD.     

Results and side effects of treatment with clozapine (leponex R)

In the basle Psychiatric University Out-Patient-Clinic 93 randomly chosen patients treated with clozapine were specially examined from 1973–1975. (The percentages are mentioned even when the numbers are small, to give possibilities of comparison.)In schizophrenics the same results were registered when clozapine was given alone or when it was combined with other psychotropic drugs. The young age group of these patients, however, showed more often a deterioration (p < 0.01) in patients treated with clozapine alone. Out of the schizophrenics we had the best results with pure paranoid states, with hebephrenics and catatonics, the least success with paranoid-depressive states (p < 0.01) who showed the same results under clozapine alone and under a combined treatment. The paranoid schizophrenics showed less often a deterioration under treatment with clozapine alone (p < 0.05).The patients with mixed psychoses, manic-depressive psychoses, and involutional depressions showed the same results under clozapine alone and when clozapine was combined with antidepressants and lithium salts.In the treatment of abnormal psychic developments, including neuroses, the same results were obtained when clozapine was given alone or in combination with other drugs. But in this realm it can never be decided definitely what is the psychotherapeutic and what the psychopharmacological effect.Among the side-effects the most serious are the disturbances of hematopoesis. In 9 (25%) of the 36 patients examined with respect to their hematological status, disturbances were registered: 5 patients suffered from leukopenia (except for one all of them had had previous treatments with other major tranquilizers), 6 showed a decrease in polymorphonuclear neutrophils, 2 and eosinophilia, 1 an increase of the number of platelets, 1 an increase of the hemoglobin rate pro erythrocyte (the same patient could have some side-effects). Hematological disturbances were more frequent (p < 0.01) in the young age group (<40 years) if the patients were treated with clozapine alone, and more frequent (p < 0.01) in the group above 40 years if clozapine was combined with other major tranquilizers and other psychotropic drugs.