clozapine and Constipation

Constipation is a frequently overlooked side effect of clozapine treatment that can prove fatal. We conducted a systematic review and meta-analysis to estimate the prevalence and risk factors for clozapine-associated constipation. Two authors performed a systematic search of major electronic databases from January 1990 to March 2016 for articles reporting the prevalence of constipation in adults treated with clozapine. A random effects meta-analysis was conducted. A total of 32 studies were meta-analyzed, establishing a pooled prevalence of clozapine-associated constipation of 31.2% (95% CI: 25.6-37.4) (n = 2013). People taking clozapine were significantly more likely to be constipated versus other antipsychotics (OR 3.02 (CI: 1.91-4.77), p < 0.001, n = 11 studies). Meta-regression identified two significant study-level factors associated with constipation prevalence: significantly higher (p = 0.02) rates of constipation were observed for those treated in inpatient versus outpatient or mixed settings and for those studies in which constipation was a primary or secondary outcome measure (36.9%) compared to studies in which constipation was not a specified outcome measure (24.8%, p = 0.048). Clozapine-associated constipation is common and approximately three times more likely than with other antipsychotics. Screening and preventative strategies should be established and appropriate symptomatic treatment applied when required.

Topics: Antipsychotic Agents; Clozapine; Constipation; Humans; Odds Ratio; Prevalence; Schizophrenia; Serotonin Antagonists

This article reviews four of the milder but still bothersome side effects of clozapine that are fairly frequent and may have a negative impact on patients' compliance with the treatment regime. We reviewed the available literature on the rate and management of four non-life-threatening side effects of clozapine, including hypersalivation, constipation, tachycardia, and nocturnal enuresis. We found a variety of pharmacological and behavioral strategies to manage these four side effects. There is, however, no consensus on a preferred strategy to control these distressing side effects and there are no guidelines. Psychiatrists should be aware of the relatively high rate of hypersalivation, constipation, tachycardia, and nocturnal enuresis in clozapine-treated patients, of the impact that these side effects may have on patients' quality of life, and should be able to suggest management strategies to the patients.

Topics: Antipsychotic Agents; Clozapine; Constipation; Humans; Nocturnal Enuresis; Sialorrhea; Tachycardia

Clozapine is the preferred option for treatment-resistant schizophrenia. However, since 1975, clozapine has been known to cause agranulocytosis. In the clozapine screening guidelines, white blood cell count is mandatory. In the past 20 years, after its reintroduction, 3 other serious side effects, namely, diabetic ketoacidosis, gastrointestinal hypomotility, and myocarditis have been documented but have so far failed to be incorporated in the screening guidelines. The objective of this review is to determine whether an update of the screening guidelines for serious side effects with clozapine is evidence based.. The English-language literature, available via MEDLINE or PubMed, on the incidence of 4 clozapine-related side effects, using clozapine, agranulocytosis, diabetic ketoacidosis, and gastrointestinal hypomotility as keywords, that have been published over the period 1976-2010, was collected.. 16 studies that provided incidence rates or data from which these rates could be calculated were included.. We compared 1-year incidence rates, mortality rates in the whole study population and in the affected cases. When rates reflected longer periods of observation, the given rate was recalculated to obtain a 1-year incidence rate.. The incidence of clozapine-induced agranulocytosis varies between 3.8‰-8.0‰. The mortality rate is 0.1‰-0.3‰, and the case-fatality rate is 2.2‰-4.2‰. In diabetic ketoacidosis, the incidence was calculated at 1.2‰-3.1‰, and the case-fatality rate was 20%-31%. In gastrointestinal hypomotility, the incidence was 4‰-8‰, and the case-fatality rate was 15%-27.5%. The discrepancy in incidence rates between Australia (7‰-34‰) and the rest of the world (0.07‰-0.6‰) impairs a general approach of this side effect.. In 2 of the 3 studied side effects, diabetic ketoacidosis and gastrointestinal hypomotility, reduction of mortality to the level of agranulocytosis is both necessary and feasible. In order to obtain this outcome, the screening guidelines need to be modified; early detection of treatment-emergent hyperglycemia, that might-via diabetes mellitus-develop into diabetic ketoacidosis, requires obligatory monthly measurement of fasting plasma glucose. To prevent gastrohypomotility, and complications therefrom, the clinician should be required to choose between either weekly monitoring or standard coprescription of laxatives for prevention. The reported incidence of myocarditis (high in Australia, low in the rest of the world) is too divergent to allow for an overall recommendation outside Australia.

Topics: Agranulocytosis; Clozapine; Constipation; Diabetic Ketoacidosis; Humans; Incidence; Leukocyte Count; Mass Screening; Myocarditis; Practice Guidelines as Topic

Antipsychotics are the cornerstone in the management of psychotic disorders and schizophrenia. They are effective agents but also have a wide range of side effects. In the recent literature constipation as possible side effect has received little attention. A review of the literature concerning constipation associated with antipsychotics was performed. Overall constipation is a rarely studied or reported side effect of antipsychotic medication. Nevertheless constipation is a common side effect. Antipsychotic agents differ in their liability to induce constipation. Constipation can be severe and can lead to serious consequences such as paralytic ileus, bowel occlusion and death. Active screening, monitoring and treatment are recommended. Further research on incidence, prevalence, underlying mechanisms and preventive measures is required.

Topics: Antipsychotic Agents; Clozapine; Constipation; Humans; Randomized Controlled Trials as Topic

Constipation is a common and potentially fatal side effect of clozapine treatment. Another important side effect of clozapine may also be significant weight gain. Orlistat is a weight-control medication that is known to induce loose stools as a common side effect. This study aimed to explore whether orlistat used to control clozapine-induced weight gain can simultaneously tackle clozapine-related constipation. In this 16-week randomized-controlled study, clozapine-treated patients received add-on orlistat (n=30) or add-on placebo (n=24). Colonic function was measured using the Bristol Stool Form Scale. There was a significant (P=0.039) difference in the prevalence of constipation in favor of orlistat over placebo in completers (n=40) at the endpoint. A decrease in the prevalence of constipation within the orlistat group (P=0.035) was observed (vs. no statistically significant changes in the placebo group). In clozapine-treated patients, orlistat may be beneficial not only for weight control but also as a laxative. As no established treatments for clozapine-induced constipation exist, orlistat can be considered for this population, although more studies are required.

Topics: Anti-Obesity Agents; Antipsychotic Agents; Benzodiazepines; Clozapine; Colon; Constipation; Cross-Sectional Studies; Diarrhea; Double-Blind Method; Finland; Humans; Incidence; Lactones; Laxatives; Obesity; Olanzapine; Orlistat; Overweight; Patient Dropouts; Prevalence; Psychotic Disorders; Schizophrenia; Severity of Illness Index; Weight Loss

Olanzapine is structurally similar to clozapine but has not been shown at routine doses to share the superiority of clozapine to traditional antipsychotics in treatment-resistant patients. Olanzapine, however, has been increasingly used in higher doses as clinicians attempt to find a more tolerable therapy for those refractory to conventional agents. This study examined the relationship of high-dose olanzapine plasma concentrations to symptoms, adverse effects, smoking, and gender. Thirteen patients participated in a double blind 16-week crossover study (8 weeks each arm) of olanzapine (50 mg/day) compared to clozapine (450 mg/day). Women had significantly higher plasma olanzapine levels than men at each time point in each arm (weeks 4, 6, and 8). At 8 weeks women had a steady-state olanzapine level of 278 +/- 62 ng/ml while men had a steady-state level of 127 +/- 47 ng/ml (p = 0.005). At week 4, olanzapine levels tended to be higher in those who had been on clozapine previously (205 ng/ml) compared to those who received olanzapine in the first arm (105 ng/ml). Cigarette intake was negatively correlated to olanzapine plasma concentrations (week 8: r = -0.86, p < 0.05). Plasma levels were significantly higher in those experiencing constipation (176 vs. 82 ng/ml; p = 0.022). Plasma levels of olanzapine were not associated with symptom response and anticholinergic effects were seen at greater frequency with higher olanzapine concentrations. In conclusion, this study reports plasma olanzapine levels at high fixed doses of olanzapine (50 mg/day) in relation to side effects, symptoms, smoking, and gender.

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Clozapine; Constipation; Cross-Over Studies; Double-Blind Method; Drug Monitoring; Female; Humans; Male; Olanzapine; Risk Factors; Schizophrenia; Severity of Illness Index; Sex Characteristics; Sex Factors; Smoking; Time Factors; Treatment Outcome; Vision Disorders; Xerostomia

Constipation, a clinical manifestation of gastrointestinal hypomotility, is a common and potentially serious complication of clozapine therapy, requiring laxatives for its prevention and treatment. We explored the predictive factors of the increased laxative use in inpatients receiving a long-term clozapine therapy.. In the cross-sectional study of 93 patients in a psychiatric rehabilitation hospital, we examined a four-week prevalence of laxative use and a range of demographic and clinical factors associated with the number of prescribed laxatives.. Seventy-four percent of inpatients with schizophrenia were prescribed laxatives, and they were statistically significant older and taking higher daily doses of clozapine. In generalized Poisson regression analysis, the clozapine dose, age, and comorbid diabetes mellitus and hypothyroidism were independently associated with the number of concurrently used laxatives. No association was found between the laxatives and gender, duration of clozapine treatment, and the number of other medications with a potential to cause constipation.. The clozapine dose, age, diabetes mellitus, and hypothyroidism were shown to be the independent predictors of the increased laxative use among inpatients on clozapine and might be associated with the increased risk of clozapine-induced constipation and gastrointestinal hypomotility.

Topics: Clozapine; Constipation; Cross-Sectional Studies; Humans; Inpatients; Laxatives; Schizophrenia

Topics: Adolescent; Antipsychotic Agents; Clozapine; Constipation; Female; Humans; Pediatric Obesity

Topics: Antipsychotic Agents; Clozapine; Constipation; Humans

Clozapine is one of the drugs that cause the highest level of weight gain. Additionally, obese patients are at higher risk of developing various physical co-morbidities, such as type 2 diabetes and cardiovascular diseases. Forty-nine percent of patients on clozapine suffer from constipation. Apple vinegar (AV) had been assigned health benefits, such as weight loss, laxative properties, blood glucose lowering effects, and reducing the risk of heart disease. Our hypothesis was that AV would lower the mean glycated haemoglobin level and reduce the level of constipation.. Pilot intervention study with a 12-week follow-up. All patients receiving clozapine treatment for schizophrenia at one outpatient clinic were eligible for inclusion. Intervention: Ten millilitres of AV diluted in 200 ml drinking water with breakfast and dinner.. Forty patients were suitable for inclusion and nine completed the intervention. Women had much higher-than-recommended body mass index. Scores for constipation were high. The reduction in constipation was of clinical interest (2.6 (. AV lower the constipation problems faced by patients with schizophrenia treated with clozapine. Further research, repeating this pilot study with a meaningfully larger sample size and randomized with placebo, is needed.

Topics: Acetic Acid; Antipsychotic Agents; Clozapine; Constipation; Diabetes Mellitus, Type 2; Female; Humans; Malus; Pilot Projects; Schizophrenia

Clozapine intoxication can be life-threatening. Outside of the common drug-drug interactions, tobacco smoking, and caffeine consumption, infectious and inflammatory processes are important contributors to clozapine intoxication. Although this relationship has been reported previously, the literature is scant of proper research articles describing the presentation and management of this unpredictable interaction. Therefore, clinicians need to rely heavily on case reports describing clozapine intoxication caused by inflammation and/or infection.. A 64-year-old Caucasian woman known for schizophrenia was brought to the emergency department (ED) with severe signs and symptoms of clozapine intoxication (general deterioration, drowsiness, neutropenia, and ileus). She was on clozapine 700 mg daily amongst other medications. The clozapine dose was stable for over 3 years, and there were no recent changes in her medications. The initial culprit was determined to be an infectious/inflammatory process of gastrointestinal origin with contribution from dehydration and constipation. Clozapine and norclozapine serum concentrations confirmed the intoxication: 1315 ng/mL and 653 ng/mL, respectively. She drastically improved with clozapine dose reduction and antibiotic therapy. She remained stable for years with clozapine 600 mg daily with stable clozapine serum levels.. This case report illustrates the possibility of severe toxicity associated with an acute infectious and/or inflammatory process in patients on clozapine therapy. Clinicians must maintain a high level of suspicion in patients taking clozapine who develop and an infectious and/or inflammatory process. Constipation secondary to clozapine intoxication can exacerbate the initial intoxication process.

Topics: Antipsychotic Agents; Clozapine; Constipation; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Middle Aged; Schizophrenia

Clozapine-induced constipation is a frequently overlooked side effect that can prove fatal. This study aimed to investigate the prevalence of constipation and the breakdown of laxatives, and to identify whether use of laxative may be predicted by demographics or baseline metabolic markers in 53 Japanese treatment-resistant schizophrenia inpatients switched to clozapine. Differences of present age, onset age and duration of illness, previous antipsychotic dose using the chlorpromazine equivalent, and 10-items of metabolic markers, including fasting plasma glucose and ratio of triglyceride to high-density lipoprotein cholesterol levels were compared between the laxative and nonlaxative user groups. Sequential changes of defecation scores using Bristol stool form scale, and clozapine dosage at 1, 2 and 3 months were evaluated within each group. Multiple linear stepwise regression analysis was performed to assess the predicting use of laxatives. Half of subjects required treatment with laxative, were significantly older and had longer durations of illness than nonlaxative users. Magnesium oxide and lubiprostone were mainly used singly or in combination. Longer disease duration, and lower levels of fasting blood glucose and insulin resistance were predicting the use of laxatives. Screening and preventive strategies for minimizing clozapine-related constipation should be established in future study.

Topics: Clozapine; Constipation; Humans; Laxatives; Prevalence; Schizophrenia, Treatment-Resistant

Topics: Adult; Antipsychotic Agents; Appendicitis; Clozapine; Constipation; Humans; Male; Retrospective Studies; Schizophrenia

Topics: Adult; Antipsychotic Agents; Clozapine; Constipation; Gastrointestinal Agents; Gastrointestinal Diseases; Gastrointestinal Motility; Humans; Male; Middle Aged; Psychiatric Department, Hospital; Retrospective Studies; Schizophrenia

Clozapine is the favoured antipsychotic for treatment-refractory schizophrenia but its safe use requires careful adverse-effect management. Clozapine-induced gastrointestinal hypomotility (CIGH or 'slow-gut') is one of the most common and serious of clozapine's adverse effects. CIGH can lead to paralytic ileus, bowel obstruction, gastrointestinal ischaemia, toxic megacolon, and death. Enquiring about constipation is a simple and commonly used screening method for CIGH but its diagnostic accuracy has not previously been assessed.. First, we examined the reliability of asking about constipation compared with asking about Rome constipation criteria in inpatients treated with clozapine (n = 69). Second, we examined the diagnostic accuracy of (1) self-reported constipation and (2) the Rome criteria, compared with the reference standard of gastrointestinal motility studies.. After 30 motility tests, it was clear constipation screening had very poor diagnostic properties in this inpatient group and the study was terminated. Although 73% of participants had objective CIGH on motility testing, only 26% of participants self-reported constipation, with sensitivity of 18% (95% CI: 5-40%). Specificity and positive predictive values were higher (95% CI: 63-100% and 40-100%, respectively). Adding in Rome criteria improved sensitivity to 50% (95% CI: 28.2-71.8%), but half the cases were still missed, making this no more accurate than tossing a coin.. CIGH is often silent, with self-reported constipation having low sensitivity in its diagnosis. Treating CIGH based on self-reported symptoms questions will miss most cases. However, universal bowel motility studies are impractical. In the interests of patient safety, prophylactic laxatives are suggested for people taking clozapine.

Topics: Antipsychotic Agents; Clozapine; Constipation; Gastrointestinal Motility; Humans; Reproducibility of Results

Topics: Antipsychotic Agents; Clozapine; Constipation; Humans; Male; United States; United States Food and Drug Administration

Topics: Antipsychotic Agents; Clozapine; Constipation; Humans; Schizophrenia

Despite being a very effective treatment for resistant schizophrenia and bipolar disorder, use of clozapine is limited by adverse effects. Constipation is a common but potentially life-threatening adverse effect of clozapine that is understudied. The objective was to study the prevalence and factors associated with constipation in those receiving clozapine compared with control subjects.. Fifty patients in age group of 18 to 55 years receiving clozapine were compared with 50 patients in the same age group receiving medications other than clozapine. Presence of constipation was ascertained using the World Gastroenterology Organization Practice Guidelines definition. The severity of constipation was assessed using Constipation Assessment Scale and Bristol Stool Form Scale, and anticholinergic burden was assessed using Anticholinergic Burden Scale.. Among clozapine-treated patients, 28 (56%) had constipation as compared with 11 (22%) in the control subjects (P < 0.001); the odds of developing constipation was 4.5 (95% confidence interval, 1.9-10.8). Kaplan-Meier survival analysis showed median time to onset of constipation in clozapine-treated patients was 60 days (SE, 13.1 days; 95% confidence interval, 34.3-85.7 days) and median dose of clozapine was 300 mg/d (interquartile range, 312 mg/d). Clozapine group had high Constipation Assessment Scale scores (P = 0.005, Cohen d = 1.17) and higher prevalence of types 1 and 2 Bristol stool types (Fisher exact P = 0.005, Cramer V = 0.59).. Constipation was prevalent in more than half of patients receiving clozapine, which was severe and took longer time for recovery. Limitations include using a hospital-based sample and that dietary habits and lifestyle factors were not studied.

Topics: Adult; Antipsychotic Agents; Clozapine; Constipation; Cross-Sectional Studies; Female; Humans; Male; Middle Aged; Prevalence; Young Adult

Clozapine impairs gastrointestinal motility owing to its anticholinergic and antiserotonergic properties. This commonly leads to constipation and potentially to more severe complications such as bowel obstruction and ischemia. The aim of this study was to determine whether genetic variations in the genes encoding muscarinic and serotonergic receptors (CHRM2, CHRM3, HTR2, HTR3, HTR4, and HTR7) explain the variations in incidence of constipation and anticholinergic symptoms during clozapine treatment. Genes associated with opiate-induced constipation were also included in this analysis (TPH1, OPRM1, ABCB1, and COMT).. Blood samples from 176 clozapine-treated, Finnish, white patients with schizophrenia were genotyped. Constipation and anticholinergic symptoms were rated using the Liverpool University Neuroleptic Side Effect Rating Scale self-report questionnaire. In total, 192 single-nucleotide polymorphisms (SNPs) were detected and grouped to formulate a weighted genetic-risk score (GRS).. No significant associations between individual SNPs or GRSs and constipation or laxative use were observed. A GRS of 19 SNPs in CHRM2, CHRM3, HTR3C, HTR7, ABCB1, OPRM1, and TPH1 was associated with anticholinergic symptoms in a generalized linear univariate model, with body mass index, clozapine monotherapy, and GRS as explaining variables (permuted P = 0.014). Generalized linear univariate model analysis performed on the opiate-induced constipation-associated SNPs and a single CHRM3 SNP revealed an association between anticholinergic symptoms and a score of 8 SNPs (adjusted P = 0.038, permuted P = 0.002).. Two GRSs are able to predict the risk of anticholinergic symptoms in patients receiving clozapine and possibly an increased risk of gastrointestinal hypomotility.

Topics: Adult; Antipsychotic Agents; Cholinergic Antagonists; Clozapine; Constipation; Female; Finland; Gastrointestinal Motility; Genotype; Humans; Male; Middle Aged; Polymorphism, Single Nucleotide; Schizophrenia; Serotonin Antagonists; Surveys and Questionnaires

Topics: Benzofurans; Clozapine; Constipation; Humans; Male; Middle Aged

Purpose of the article: Clozapine is the only evidence based treatment for treatment-resistant schizophrenia. Constipation is a well known side effect of clozapine treatment. The aims of this study are to describe the prevalence of constipation and ileus during clozapine treatment of patients with schizophrenia in Iceland and to assess the concomitant use of medication that can cause constipation, and laxatives used to treat constipation.. We identified 188 patients treated with clozapine by searching the electronic health records of Landspitali, the National University Hospital, during the study period 1.1.1998 - 21.11.2014. Cases of constipation and ileus were identified using an electronic search with keywords related to ileus in the patients' electronic health records. Detailed medication use was available for 154 patients that used clozapine for at least one year.. Four out of 188 patients were diagnosed with ileus that resulted in admission to hospital. Two of these required a permanent stoma as a consequence of their ileus. Laxatives were prescribed for 24 out of 154 patients (15.4%) while on clozapine. In total 40.9% of the patients either had laxatives prescribed or had constipation documented in the medical records. Apart from clozapine, other medications known to cause constipation were prescribed to 28 out of 154 patients (18.2%).. Constipation is a common problem during clozapine treatment which can progress to full-blown ileus which can be fatal. Clinicians need to monitor signs of constipation during treatment with clozapine and respond to it with lifestyle advice and laxative treatment.

Topics: Adult; Antipsychotic Agents; Clozapine; Cohort Studies; Constipation; Female; Follow-Up Studies; Humans; Iceland; Ileus; Laxatives; Male; Middle Aged; Prevalence; Retrospective Studies; Schizophrenia; Treatment Outcome; Young Adult

Clozapine is known to cause fecal impaction and ileus with resultant colonic necrosis due to compression of colonic mucosa. There are rare reports of clozapine causing necrosis of other portions of the gastrointestinal tract unrelated to constipation. We describe a case of acute necrosis of the upper gastrointestinal tract and small bowel to due to clozapine and quetiapine.. A 66-year-old white man with a past medical history of schizophrenia, maintained on clozapine and quetiapine, presented with hypoxic respiratory failure caused by aspiration of feculent emesis due to impacted stool throughout his colon. His constipation resolved with discontinuation of clozapine and quetiapine, and his clinical condition improved. These medicines were restarted after 2 weeks, resulting in acute gastrointestinal necrosis from the mid esophagus through his entire small bowel. He died due to septic shock with Gram-negative rod bacteremia.. Clozapine may cause acute gastrointestinal necrosis.

Topics: Aged; Antipsychotic Agents; Clozapine; Constipation; Endoscopy, Digestive System; Esophagus; Fatal Outcome; Fecal Impaction; Gastrointestinal Diseases; Gram-Negative Bacterial Infections; Humans; Intestine, Small; Male; Necrosis; Respiratory Aspiration; Respiratory Insufficiency; Schizophrenia; Shock, Septic; Stomach; Vomiting

Constipation and dyspepsia are disturbing gastrointestinal symptoms that are often ignored in research on physical comorbidities of schizophrenia. The aim was to assess dyspepsia and constipation in a sample of outpatients with schizophrenia spectrum psychoses. A general practitioner performed a thorough physical health check for 275 outpatients and diagnosed constipation and dyspepsia. This study assessed the possible contribution of several sociodemographic, lifestyle, and clinical variables to constipation and dyspepsia using logistic regression analysis. This study also assessed whether these symptoms were associated with abnormal laboratory findings. The prevalence of constipation was 31.3%, and of dyspepsia 23.6%. Paracetamol (OR =3.07, 95% CI =1.34-7.02) and clozapine use (OR =5.48, 95% CI =2.75-10.90), older age (OR =1.04, 95% CI =1.01-1.06), and living in sheltered housing (OR =2.49, 95% CI =1.16-5.33) were risk factors for constipation. For dyspepsia the risk factors were female sex (OR =2.10, 95% CI =1.15-3.83), non-steroidal anti-inflammatory drugs (OR =2.47, 95% CI =1.13-5.39), and diabetes medication (OR =2.42, 95% CI =1.12-5.25). Patients with dyspepsia had lower haemoglobin and haematocrit and higher glucose values than those without dyspepsia. Patients with constipation had lower thrombocyte values than patients without constipation. However, these findings were explained by factors pre-disposing to constipation and dyspepsia. Clozapine use markedly increases the risk of constipation and may lead to life-threatening complications. In addition, analgesics and diabetes medication were related to gastrointestinal symptoms. These medications and their association to gastrointestinal symptoms should be kept in mind when treating patients with schizophrenia.

Topics: Adult; Analgesics; Antipsychotic Agents; Clozapine; Comorbidity; Constipation; Diabetes Mellitus; Dyspepsia; Female; Humans; Male; Schizophrenia

Clozapine, an antipsychotic used in treatment-resistant schizophrenia, causes slow gastrointestinal transit in 50-80% of patients. Clozapine-induced gastrointestinal hypomotility is both common and serious, and potential complications include severe constipation, ileus, bowel obstruction and related complications, with a higher mortality rate than clozapine-related agranulocytosis. Little evidence exists on its prevention and management.. Using a well-validated radiopaque marker ('Metcalf') method, we compared colonic transit times (CTTs) of clozapine-treated inpatients not receiving laxatives with their transit times when receiving laxatives, with treatment prescribed according to the Porirua Protocol for clozapine-related constipation (docusate and senna augmented by macrogol 3350 in treatment-resistant cases).. The median age of participants was 35 years, and median clozapine dose, plasma level and duration of treatment were 575 mg/day, 506 ng/mL and 2.5 years, respectively. Overall, 14 participants (10 male) were enrolled and all completed the study. Transit times improved markedly with laxative treatment. Median colonic transit without laxatives was 110 h (95% confidence interval [CI] 76-144 h), over four times longer than normative values (p < 0.0001). Median CTT with laxatives was 62 h (95% CI 27-96 h), a 2-day reduction in average transit time (p = 0.009). The prevalence of gastrointestinal hypomotility decreased from 86% pre-treatment to 50% post-treatment (p = 0.061). Severe gastrointestinal hypomotility decreased from 64 to 21% (p = 0.031). Subjective reporting of constipation did not correlate well with objective hypomotility, and did not change significantly with treatment.. Treating clozapine-treated patients with docusate and senna augmented by macrogol appears effective in reducing CTTs in clozapine-induced constipation. Randomised controlled trials are the next step. Australian New Zealand Clinical Trial Registry ACTRN12616001405404 (registered retrospectively).

Topics: Adult; Antipsychotic Agents; Clozapine; Constipation; Female; Gastrointestinal Motility; Gastrointestinal Transit; Humans; Laxatives; Male; Middle Aged; Schizophrenia; Young Adult

Topics: Antipsychotic Agents; Clozapine; Constipation; Fatal Outcome; Humans; Male; Middle Aged; Schizophrenia

Topics: Administration, Rectal; Antipsychotic Agents; Clopenthixol; Clozapine; Constipation; Drug Administration Schedule; Drug Monitoring; Drug Therapy, Combination; Humans; Intensive Care Units; Laxatives; Methotrimeprazine; Plant Gums; Polyethylene Glycols; Severity of Illness Index; Sterculia; Surface-Active Agents

The clinical records of 190 patients with schizophrenia who discontinued clozapine between 1990 and 2012 in the county of Northamptonshire were examined, in an attempt to answer the following questions. Why do patients stop clozapine? What do physicians prescribe as an alternative? What is the mortality in this patient group?. Patients' data were extracted using their electronic records, then analysed using descriptive statistical methods.. Non-compliance with treatment, or with the mandatory white blood cell monitoring, was the most common reason (55.3%) for clozapine cessation, followed by neutropaenia and other adverse effects (25.2%). Death (mean age 48 years) was the third most common reason (10%), with respiratory infections accounting for more than a quarter of the deaths. 13% of the patients had died (mean age 49 years) at some point following clozapine discontinuation. In terms of the alternative antipsychotic prescribing, olanzapine was the most commonly prescribed (37.1%) drug in patients who were still under the care of the local psychiatric service (n=121), at the time of data extraction. Clozapine had been reinstated in 19% of these patients.. Our findings are generally consistent with previous studies, and they demonstrate the need for physicians to address their patients' concerns regarding clozapine treatment, and to effectively manage any adverse effects. Sialorrhea and constipation seem to be particularly of concern, as they may be linked to clozapine- related mortality. Olanzapine was the most commonly prescribed alternative to clozapine, which suggests that it may possibly have a role in refractory schizophrenia.

Topics: Adult; Aged; Antipsychotic Agents; Benzodiazepines; Clozapine; Constipation; Electronic Health Records; Female; Humans; Male; Middle Aged; Olanzapine; Prescription Drugs; Retrospective Studies; Schizophrenia; Sialorrhea

Constipation occurs in 25-60% of the subjects during administration of the antipsychotic drug (AP) clozapine (CLZ).. We used a colonic transit diagnostic test that quantifies in a single abdominal X-ray the number of silver O-ring markers out of 25 units ingested five days before. The quantity of markers is directly proportional to the degree of gastrointestinal hypomotility, and elimination of over 80% of the markers is considered normal. The test was applied to three groups of AP-treated subjects for at least three consecutive months: CLZ alone (n=45), CLZ+Other APs (n=28), and Other APs (n=64).. The number of remaining markers at day 5 (mean±S.D.) was significantly higher in the CLZ alone (10.8±10.6) and in the CLZ+Other APs (9.7±9.7) groups than in the Other AP group (4.5±6.7), Kruskal-Wallis test: p=0.004. No significant associations were found between the number of markers, age, AP dose and treatment duration. All subjects who passed <80% of markers - which approximately corresponds to the 60th percentile of marker elimination - showed a scattered marker distribution along the colon, thus suggesting colon inertia. In subjects with hypomotility, 38.5% of the CLZ group, 25% of the CLZ+Other APs group, and 25% of the Other APs group were negative for the Rome III clinical criteria of constipation, thus showing objective, not subjective, hypomotility.. This study objectively confirms significant gastrointestinal hypomotility associated with CLZ administration.

Topics: Adult; Antipsychotic Agents; Bipolar Disorder; Clozapine; Constipation; Diagnostic Techniques, Digestive System; Female; Gastrointestinal Tract; Humans; Male; Middle Aged; Radiography, Abdominal; Schizophrenia; Silver Compounds

Clozapine is often the drug of choice within patients suffering from treatment-resistant paranoid schizophrenia. It has a complex side effects profile which includes potentially fatal agranulocytosis. Clozapine has also become increasingly associated with a range of other side effects including constipation and pneumonia. We report on a case of clozapine-induced severe constipation leading to a silent presentation of pneumonia with a subsequent respiratory arrest. To our knowledge, this is the first case report of pneumonia secondary to severe constipation occurring in the absence of respiratory aspiration of feculent vomitus. We suggest a new pathological mechanism by way of severe constipation leading to diaphragmatic dysfunction and subsequent clozapine-induced pneumonia. In addition, implications for clinical practice are outlined.

Topics: Adult; Antipsychotic Agents; Clozapine; Constipation; Fecal Impaction; Humans; Male; Pneumonia; Respiratory Insufficiency; Schizophrenia, Paranoid; Sigmoidoscopy

Topics: Adult; Alprostadil; Antipsychotic Agents; Chloride Channel Agonists; Clozapine; Constipation; Humans; Lubiprostone; Male; Schizophrenia; Treatment Failure

Although many patients with schizophrenia fail to respond adequately to trials of 2 or more antipsychotics, utilization of clozapine for these patients remains low, despite recommendations for its use by accepted treatment guidelines. Some experts estimate that 5-10 times more patients could benefit from clozapine than who are now receiving it. Learning how to manage the unique side effect profile of clozapine can potentially remove barriers to prescribing this agent and thus unlock its unique therapeutic efficacy for more patients.

Topics: Agranulocytosis; Antipsychotic Agents; Clozapine; Constipation; Diabetes Mellitus; Eosinophilia; Humans; Myocarditis; Neuroleptic Malignant Syndrome; Neutropenia; Practice Guidelines as Topic; Practice Patterns, Physicians'; Schizophrenia; Sialorrhea; Tachycardia; Weight Gain

Topics: Antipsychotic Agents; Bethanechol; Clozapine; Constipation; Defecation; Humans; Laxatives; Male; Middle Aged; Parasympathomimetics; Schizophrenia, Paranoid; Schizophrenic Psychology; Treatment Outcome

Topics: Antipsychotic Agents; Clozapine; Constipation; Diabetic Ketoacidosis; Humans; Mass Screening; Myocarditis; Practice Guidelines as Topic

To highlight some problems that may occur when investigating clozapine-associated deaths including (i) that death may be related to gastrointestinal hypomotility and (ii) that post-mortem blood clozapine and norclozapine concentrations may not reflect ante-mortem concentrations.. A 41-year-old male died 40 min after admission to hospital as a result of aspiration complicating severe, clozapine-induced constipation. At post-mortem the small bowel was dilated and contained bloodstained mucus, particularly within the jejunum. The large bowel was considerably dilated and contained large quantities of foul-smelling, bloodstained fluid and a small amount of stool. Its lining was focally congested, but there was no other obvious abnormality. Analysis of serum obtained on admission revealed clozapine and norclozapine concentrations of 0.56 and 0.43 mg/L, respectively, whereas post-mortem femoral whole blood obtained <34 h after death showed clozapine and norclozapine concentrations of 3.73 and 1.75 mg/L, respectively. In 6 out of a further 12 clozapine-associated deaths investigated 2002-9 there were reports of gastrointestinal tract problems of varying severity.. Severe constipation or paralytic ileus in clozapine-treated patients may lead to intestinal necrosis and/or perforation, or pulmonary aspiration. In some such cases the immediate cause of death may be obvious, but in others only careful assessment of the clinical course of the terminal illness may reveal gastrointestinal hypomotility as a likely underlying cause of death.

Topics: Adult; Antipsychotic Agents; Brain Edema; Clozapine; Constipation; Gastrointestinal Motility; Humans; Intestinal Pseudo-Obstruction; Intestines; Lung; Male; Pulmonary Edema; Respiratory Aspiration; Spleen

Antipsychotic are the cornerstone in the treatment of schizophrenia. They also have a number of side-effects. Constipation is thought to be common, and a potential serious side-effect, which has received little attention in recent literature.. We performed a retrospective study in consecutively admitted patients, between 2007 and 2009 and treated with antipsychotic medication, linking different electronic patient data to evaluate the prevalence and severity of constipation in patients with schizophrenia under routine treatment conditions.. Over a period of 22 months 36.3% of patients (99) received at least once a pharmacological treatment for constipation. On average medication for constipation was prescribed for 273 days. Severe cases (N = 50), non-responsive to initial treatment, got a plain x-ray of the abdomen. In 68.4% fecal impaction was found.. A high prevalence of constipation, often severe and needing medical interventions, was confirmed during the study period. Early detection, monitoring over treatment and early intervention of constipation could prevent serious consequences such as ileus.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antipsychotic Agents; Aripiprazole; Clozapine; Constipation; Enema; Fecal Impaction; Female; Gastrointestinal Agents; Humans; Lactulose; Male; Middle Aged; Piperazines; Polyethylene Glycols; Prevalence; Quinolones; Retrospective Studies; Risperidone; Schizophrenia; Severity of Illness Index; Young Adult

Topics: Adult; Antipsychotic Agents; Clozapine; Constipation; Drug Utilization; Female; Humans; Hyperlipidemias; Inpatients; Male; Polypharmacy; Schizophrenia; Sialorrhea

The aim of this paper was to describe the association of clozapine with life-threatening constipation.. Case report.. A 53-year-old man presented to the emergency department with severe abdominal pain and bilious vomiting after being on clozapine for over a year for schizoaffective disorder. Surgery revealed severe faecal impaction in the large and small bowel. Clozapine was ceased. There were significant difficulties in the subsequent psychiatric management. Clozapine was gradually reintroduced with concurrent laxative administration, which resulted in another episode of severe constipation with faecal impaction.. Clozapine can be associated with potentially life-threatening constipation. Psychiatrists, especially consultation liaison psychiatrists, physicians, surgeons and radiologists, should be aware of the seriousness of clozapine-induced constipation and its potentially fatal complications.

Topics: Antipsychotic Agents; Clozapine; Constipation; Drug Therapy, Combination; Fecal Impaction; Humans; Laxatives; Male; Middle Aged

Aim of this article is to describe the first italian case reported in literature of a clozapine-induced intestinal occlusion with previous severe constipation in a 45-year-old male patient who had been treated with daily clozapine for 5 months because of treatment-resistant residual schizophrenia. When conservative treatment (intravenous fluids, fleet enema and rectal washout) was used and clozapine therapy was decreased, gastrointestinal symptoms rapidly improved and the patient had regular bowel motions within a week. Preventive measures (high-fiber diet, adequate fluid intake, stool softeners and exercise) was also used to ensure that clozapine therapy could be safely continued. Although constipation is a common and usually benign side effect of treatment with clozapine, this case-report highlights the consequences of undertreated and unrecognized marked constipation progressing to severe bowel obstruction (a complication which deserves more attention because it can lead to hospitalization and might be potentially fatal).

Topics: Antipsychotic Agents; Clozapine; Constipation; Fecal Impaction; Humans; Male; Middle Aged; Schizophrenia; Time Factors

Monitoring plasma clozapine concentrations may play a useful role in the management of patients with schizophrenia, but information on the relationship between the plasma levels of the drug and response is still controversial.. The purpose of this study was to assess the relationship between plasma concentrations of clozapine and its weakly active metabolite norclozapine and clinical response in patients with schizophrenia resistant to conventional neuroleptics.. Forty-five patients, 35 males and ten females, aged 19-65 years, were given clozapine at a dosage up to 500 mg/day for 12 weeks. Steady-state plasma concentrations of clozapine and norclozapine were measured at week 12 by a specific HPLC assay. Psychopathological state was assessed at baseline and at week 12 by using the Brief Psychiatric Rating Scale, and patients were considered responders if they showed a greater than 20% reduction in total BPRS score compared with baseline and a final BPRS score of 35 or less.. Mean plasma clozapine concentrations were higher in responders (n=18) than in non-responders (n=27) (472+/-220 versus 328+/-128 ng/ml, P<0.01), whereas plasma norclozapine levels did not differ between the two groups (201+/-104 versus 156+/-64 ng/ml, NS). A significant positive correlation between plasma levels and percent decrease in total BPRS score was found for clozapine (r(s)=0.371, P<0.02), but not for norclozapine (r(s)=0.162, NS). A cutoff value at a clozapine concentration of about 350 ng/ml differentiated responders from non-responders with a sensitivity of 72% and a specificity of 70%. At a cutoff of 400 ng/ml, sensitivity was 67% and specificity 78%. The incidence of side effects was twice as high at clozapine concentrations above 350 ng/ml compared with lower concentrations (38% versus 17%).. These results suggest that plasma clozapine levels are correlated with clinical effects, although there is considerable variability in the response achieved at any given drug concentration. Because many patients respond well at plasma clozapine concentrations in a low range, aiming initially at plasma clozapine concentrations of 350 ng/ml or greater would require in some patients use of unrealistically high dosages and imply an excessive risk of side effects. Increasing dosage to achieve plasma levels above 350-400 ng/ml may be especially indicated in patients without side effects who failed to exhibit amelioration of psychopathology at standard dosages or at lower drug concentrations.

Topics: Adult; Aged; Antipsychotic Agents; Clinical Trials as Topic; Clozapine; Conscious Sedation; Constipation; Dizziness; Dose-Response Relationship, Drug; Drug Resistance; Female; Follow-Up Studies; Humans; Male; Middle Aged; Psychiatric Status Rating Scales; Schizophrenia; Sialorrhea; Tachycardia; Treatment Outcome; Weight Gain

Topics: Antipsychotic Agents; Clozapine; Constipation; Death, Sudden; Drug Therapy, Combination; Fecal Impaction; Humans; Male; Middle Aged; Pneumonia, Aspiration; Schizophrenia; Schizophrenic Psychology

Topics: Adult; Clozapine; Constipation; Humans; Male; Mental Disorders; Prevalence

Clozapine has an unusual profile of adverse effects; among them, gastrointestinal (GI) side effects are important management concerns. The charts of patients in a state hospital who received clozapine for at least 3 months were reviewed. We compared the pre- and post-clozapine weights and changes in frequency and intensity of use of drugs prescribed for gastrointestinal symptoms for each subject (n = 99). There were statistically significant increases in the use of antacids (p < 0.02) and both bulk and non-bulk laxatives (p < 0.05, p < 0.03). Seventy-three percent of patients gained weight, of whom 27% gained over 10% body weight. This study confirms clozapine's association with weight gain, constipation, and upper GI symptoms. The literature concerning weight gain, and the mechanisms underlying GI adverse effects were reviewed.

Topics: Adult; Antacids; Antipsychotic Agents; Body Weight; Cathartics; Clozapine; Constipation; Female; Histamine H2 Antagonists; Humans; Male; Middle Aged; Weight Gain; Weight Loss

Clozapine, as the model agent for the atypical antipsychotic drugs, is currently recommended as effective regarding negative symptoms of schizophrenia and treatment-resistant schizophrenic patients. This study focuses on the clozapine-induced side-effects in 100 hospitalized schizophrenic patients (negative and therapy-resistant forms), followed-up for a four year period. Clinically relevant side-effects occurred in 73% of all patients. Tachycardia (67%), the increase of liver enzymes (36%), hypotension (29%) and sedation (27%) were most frequent. Tachycardia, hypotension and sedation disappeared during the initial phase of treatment (i.e. 4-6 weeks), as tolerance developed with continuation of therapy. The increase of liver enzymes appeared to be dose related, since the reduction of daily clozapine dose led to the normalization of transaminases values. The other side-effects (constipation, nausea and vertigo) were rare and transient. Leucopenia was not registered in any patient during the follow-up period. Therefore, clozapine is efficient and, with some precautions concerning hepatotoxicity, is safe for in- and outpatient long-term treatment in appropriately selected patients.

Topics: Adult; Blood Pressure; Body Temperature; Clozapine; Constipation; Drug Resistance; Female; Follow-Up Studies; Humans; Liver; Male; Middle Aged; Nausea; Pulse; Salivation; Schizophrenia; Schizophrenic Psychology