Side Effect Of Clozapine Research Articles

Clozapine-Associated Sialorrhea

Abstract Background Clozapine has demonstrated efficacy in treating treatment-resistant schizophrenia; however, it has a wide range of side effects. Sialorrhea is a common side effect of clozapine that causes the patient to withdraw from social life. This review aims to evaluate and summarize the prevalence, mechanism, risk factors, and management of clozapine-associated sialorrhea. Procedures The literature was explored for the prevalence, the mechanisms, the risk factors, and the management of sialorrhea. The following search strings and terms were used: “clozapine,” “sialorrhea,” “hypersalivation,” “clozapine induced sialorrhea,” and “clozapine induced hypersalivation”. Study Results Hypersalivation is one of the most common side effects of clozapine. Over the course of clozapine therapy, hypersalivation has been reported to have an incidence of 30% to –80%. Although different treatment approaches are applied on a case-by-case basis in the clinic, depending on the practitioners' preferences, there is a lack of clear guidelines for managing this common side effect that jeopardizes patients' social life. Conclusions It is important for healthcare professionals and patients that some clear treatment options for clozapine-associated sialorrhea are brought to the forefront and widely used, especially based on the research conducted to date.

Unexpected Falls in Schizophrenia: Clozapine-Induced Negative Myoclonus

Myoclonus, characterized by sudden involuntary muscle contractions, can occur in a variety of conditions, including as a side effect of clozapine, which is used in the treatment-resistant schizophrenia. This case study describes a 48-year-old female patient who developed negative myoclonus, manifested by knee flexion and falls, after starting clozapine. Despite dose reduction and the addition of valproic acid, symptoms persisted, highlighting the dose-dependent nature of clozapine-induced myoclonus and the need for clinicians to recognise this risk.

Long-term persistence of the risk of agranulocytosis with clozapine compared with other antipsychotics: a nationwide cohort and case–control study in Finland

Agranulocytosis is a life-threatening side-effect of clozapine, the only approved drug for treatment-resistant schizophrenia. The long-term profile of this complication has not yet been well established. Here we aim to describe the risk of clozapine-induced agranulocytosis over the long term. We used the entire population of Finland to identify people diagnosed with schizophrenia or schizoaffective disorder between 1972 and 2014 and developed a Kaplan-Meier model of time to diagnosis of agranulocytosis during clozapine versus non-clozapine treatment over a 22-year observation period (1996 to 2017). Next, we developed a nested case-control model for agranulocytosis matching by sex, age, time since diagnosis, and being in the incident cohort on a 1 to 5 ratio. Various durations of use for clozapine and non-clozapine antipsychotic treatment were compared to the modal antipsychotic use duration, deriving adjusted odds ratios (aORs) in a multivariable regression model. Recurrence and lethality rates for clozapine-induced agranulocytosis were described. These data reflect on all individuals with lived experience of schizophrenia in Finland during the study time, although individuals with lived experience were not included in the design of the study. We identified 61 769 people with schizophrenia or schizoaffective disorder (14 037 individuals treated with clozapine and 47 732 individuals treated with non-clozapine antipsychotics), with a mean age of 46·67 years (IQR 34·44-57·61), of whom 30 721 (49·7%) were female and 31 048 (50·3%) were male (data on ethnicity not available). Among those, 398 individuals were diagnosed with agranulocytosis (231 individuals treated with clozapine and 167 individuals treated with non-clozapine antipsychotics), representing a cumulative incidence of agranulocytosis for 1·37% (95% CI 0·58-3·16) on clozapine and 0·13% (0·04-0·23) on non-clozapine antipsychotics. In the case (n=398) versus control (n=1987) model, the risk of clozapine-induced agranulocytosis decreased steeply over time from an aOR of 36·01 (95% CI 16·79-77·22) for less than 6 months on clozapine to 4·38 (1·86-10·34) for clozapine use of 54 months or more. Only one of 3559 individuals starting clozapine died because of clozapine-induced agranulocytosis. The risk of clozapine-induced agranulocytosis decreases steeply over time but might be persistently greater than that of non-clozapine antipsychotics. This long-term risk excess seems small in absolute terms compared with the known magnitude of the advantages of clozapine in relevant outcomes, including life expectancy. Given the widespread underuse of clozapine, relaxing the long-term neutrophil monitoring could favour the advantages of long-term clozapine use, including greater life expectancy, without incurring the intolerable risk of clozapine-induced agranulocytosis. Northwell Health and Sigrid Jusèlius Foundation.

A brief history of clozapine use in Taiwan

Blood concentrations of clozapine in Taiwanese patients appeared approximately 30–50 % higher than that from Caucasian patients, and women possessed a higher blood levels. Fluvoxamine was reported to increase the clozapine levels, reduce clozapine-related weight gain and metabolic disturbances, and improved general psychopathology. Clothiapine, a chemical structure analogue of clozapine, showed potential of benefitting patients who are unsuitable for clozapine treatment in Taiwan. Obsessive/compulsive symptom (OCS) is a common side effect of clozapine. Concentrations of clozapine were remarkably higher in patients with OCS than in those without. In conclusion, clozapine is a widely used in patients with schizophrenia in Taiwan.

Valproate-related neutropenia and lithium-related leukocytosis in patients treated with clozapine: a retrospective cohort study

BackgroundNeutropenia is a noteworthy side effect of clozapine, which might warrant this drugs’ discontinuance for safety. Studies have revealed that the risk of neutropenia increases with concurrent administration of valproate, but the evidence was limited. Conversely, lithium may have an ameliorating effect on clozapine-induced neutropenia. This study explored the effects of valproate and lithium on white blood cell counts in patients treated with clozapine.MethodsWe retrospectively investigated the electronic medical records from one tertiary psychiatric hospital in Taiwan and enrolled patients discharged between January 1, 2006, and December 31, 2017, with clozapine prescriptions. We scrutinized their demographic data, medications, and hematological results at discharge and during follow-up outpatient clinic visits over the subsequent 3 years. Patients were classified into four groups: clozapine only (CLO), clozapine and valproate (CLO + VAL), clozapine and lithium (CLO + Li), and clozapine, valproate, and lithium (CLO + VAL + Li). We also identified hematological events (neutropenia or leukocytosis) of these patients during outpatient follow-ups.ResultsOf the included 1084 patients, 55(5.1%) developed neutropenia. Concurrent valproate use (odds ratio [OR] = 3.49) and older age (p = .007) were identified as risk factors. Moreover, 453 (41.79%) patients developed leukocytosis. Younger age; male sex; and concurrent use of lithium (OR = 3.39, p < .001), clozapine daily dosage, and benzodiazepines were the risk factors for leukocytosis.ConclusionConcurrent valproate use and older age are associated with the development of neutropenia in patients treated with clozapine. Concurrent lithium usage, younger age, male sex, and concurrent benzodiazepine use might be related to leukocytosis.

Efficacy of sofpironium bromide gel on clozapine-induced hypersalivation in patients with treatment-resistant schizophrenia: double-blind, controlled crossover study.

Hypersalivation is a major side-effect of clozapine in patients with treatment-resistant schizophrenia. We investigated the efficacy of topical anticholinergic formulation sofpironium bromide gel for improving hypersalivation in patients with treatment-resistant schizophrenia receiving clozapine. A double-blind, controlled crossover study was conducted with sofpironium bromide gel and a placebo gel to treat clozapine-induced hypersalivation in 16 patients with treatment-resistant schizophrenia. Patients were randomly divided between groups A and B (each n = 8). Group A was treated with sofpironium bromide gel for 6 weeks, followed by a 2-week washout period and 6 weeks of placebo gel, after which they were observed for another 2 weeks. In contrast, group B was treated with placebo gel for 6 weeks, followed by a 2-week washout period, 6 weeks of sofpironium bromide gel and a 2-week observation period. One-minute saliva volume, objective salivation ratings (Drooling Severity and Frequency Scale and Nocturnal Hypersalivation Rating Scale) and subjective salivation ratings (Visual Analogue Scale) were assessed every 2 weeks. All patients completed the trials. Three patients reported mild, spontaneously resolved skin itching. Compared with baseline values, the 1-min saliva volumes of both groups were significantly decreased by approximately 30% at the second week of sofpironium bromide gel treatment (P < 0.001), and significantly decreased by >40% at the fourth and sixth weeks of treatment (P < 0.001). The effects were maintained for over 2 weeks even after the treatment was discontinued. We suggest that sofpironium bromide gel is effective in treating clozapine-induced hypersalivation in patients with treatment-resistant schizophrenia.

Clozapine-induced myocarditis: a case report and literature review

IntroductionWe present the case of a male patient, 47 years old, diagnosed with schizophrenia, that was admitted at our hospital presenting a confusional state, with agitation, motor discoordination and difficulty breathing. At the blood analyses there was evidence of an increase in cardiac enzymes. The clinical manifestations had begun 5 days before, with slight leucocytosis showing in a routine blood test made after initiating clozapine, followed by fever, vomiting and progressive impairment of general clinical state.ObjectivesTo describe a case of clozapine-induced myocarditis, which is a known, but rare, side effect of clozapine and to do a brief review of the existing knowledge on this matter.MethodsThe authors undertook an article review using PubMed database and a thorough analysis of the clinical case.ResultsThe hypothesis of clozapine-induced myocarditis was the main diagnosis considered since the beginning, nevertheless, a thorough clinical examination and complementary tests were made and all the previous psychopharmacological treatment was suspended. The final diagnosis was based on the clinical presentation (fever, vomiting, shortness of breath, confusion and impairment of general state), the elevation of CRP, PCT and TnI and findings on echocardiogram that suggested myocarditis (moderate systolic dysfunction of the left ventricle due to global hypokinesia and a non dilated left ventricle).ConclusionsThe clinical manifestations observed, the results of the complementary diagnostic tests and the review of the existing literature, allowed to make the diagnosis of clozapine-induced myocarditis. We find of considerable importance to continue to publish and study this matter as it is still insufficiently known.DisclosureNo significant relationships.

Clozapine induced pneumonia: A case report of diagnostic difficulties in the time of Covid-19

IntroductionClozapine is a drug that can cause several side effects. Among the less commonly described is a drug-induced lung disease. Due to its non-specific clinical presentation, it represents a diagnostic challenge. The diagnosis is made based on: 1. Association of exposure to the agent and development of symptoms, 2. Pulmonary infiltration, 3. Exclusion of other causes, 4. Withdrawal of symptoms when the agent is excluded from therapy. To date, there have been only a few descriptions of this condition.ObjectivesCase report of rare side effect of clozapine.MethodsCase reportResultsCase report: male patient (37) with schizophrenia, was hospitalized after a brutal suicide attempt. The PCR test for COVID-19 that was routinely performed on admission was negative. After the introduction of clozapine into therapy, the patient became febrile. There was a drop in oxygen saturation, a Lung CT scan showed inflammatory changes („ground-glass opacities“), and COVID-19 pneumonia was suspected. Due to the worsening of the mental state, the dose of clozapine was increased. The physical condition further deteriorated: febrile, sO2 declining. After repeated PCR tests for COVID-19 (all negative), interstitial pneumonia caused by clozapine was suspected, and clozapine was excluded from therapy. The physical condition started to improve. Quetiapine was introduced, and occasional episodes of agitation were relieved with intramuscular diazepam. In the following days, the patient’s mental state improved and he was discharged.ConclusionsDespite its superiority over other antipsychotics, clozapine was with good rationale ranked third in treatment guidelines for schizophrenia.DisclosureNo significant relationships.

Clozapine-Related Thromboembolic Events.

Clozapine is an atypical antipsychotic used for treatment-resistant schizophrenia. Venous thromboembolism (VTE) is a rare side effect of clozapine which can be fatal. This article summarizes current evidence regarding the risk of VTE associated with the use of clozapine. We performed a PubMed (MeSH) and Google Scholar search for the last two decades. Studies or case reports performed in humans were included in the review, of which 42 case reports of patients taking clozapine at VTE onset were included in the analysis of this review. According to the articles reviewed, the mean age was 42.9 years, with more males (71.43%) than females (28.57%). The average clozapine dose was 285.62 mg/day. VTE onset occurred within the first six months in 71.8% of the cases. Overall, 70.37% of the patients had comorbidities, and 87.5% had risk factors for VTE. In total, 68.57% were prescribed other medications at VTE onset, and 60% were being treated with another antipsychotic concomitantly. Finally, 32.5% of the patients died, while 67.5% survived. In 60% of the cases, clozapine was discontinued after VTE. In our literature review, we observed that among clozapine users, VTE occurred at a wide dose range, and most of the events occurred within the first six months. As many patients who are prescribed clozapine have risk factors for VTE, the risk should be considered at the time of prescribing. Further research should be conducted to elucidate the risk of VTE in clozapine users and the benefits of thromboprophylaxis.

Clozapine-induced stuttering in the absence of known risk factors: a case report

BackgroundStuttering is a rare side effect of clozapine. It has been shown to occur in the presence of one or more factors such as abnormal electrophysiological findings and seizures, extrapyramidal symptoms, brain pathology, and a family history of stuttering. Few case reports have documented the occurrence of clozapine-induced stuttering in the absence of these risk factors.Case presentationA 29-year-old African male on clozapine for treatment-resistant schizophrenia presented with stuttering at a dosage of 400 mg/day that resolved with dose reduction. Electroencephalogram findings were normal, and there was no clinical evidence of seizures. The patient had no prior history or family history of stuttering, had a normal neurological examination, and showed no signs of extrapyramidal symptoms.ConclusionClinicians ought to be aware of stuttering as a side effect of clozapine, even in the absence of known risk factors. Further research should investigate the pathophysiology of clozapine-induced stuttering.

Pericardial effusion: a rare side effect of clozapine

The Sri Lanka Journal of Psychiatry (SLJP) is a peer-reviewed, open access journal published bi annually by the Sri Lanka College of Psychiatrists.The Journal publishes original papers, brief reports including case reports and commentaries relevant to psychiatry and allied sciences. The Sri Lanka Journal of Psychiatry is committed to maintaining and conforming to the editorial and ethical standards recommended by the International Committee of Medical Journal Editors.Cover“Perseverance”. These tenacious fishermen in Mannar continue their livelihood despite numerous difficulties. L. N. P. Samarasinghe, Acting Consultant Psychiatrist, Base Hospital Nikaweratiya, Sri Lanka.

Nocturnal Enuresis is an Under-recognised Side Effect of Clozapine: Results of a Systematic Review

Objectives Clozapine is an effective antipsychotic medication licenced for the management of treatment resistant schizophrenia. Due to its non-selective pharmacology, it has a broad range of side effects. Nocturnal enuresis secondary to the use of clozapine has been documented in the literature but may be overlooked, the link between drug and symptom being clinically unnoticed. Patients may not mention urinary symptoms due to supervening psychosis, co-existing symptomatology, embarrassment or shame. By raising awareness of the phenomenon, early recognition and patient support may improve compliance with clozapine medication, and consecutively, overall mental health. Consequently, this systematic review investigates the prevalence of nocturnal enuresis secondary to clozapine use. Methods A literature search on clozapine and nocturnal enuresis was used to identify the relevant papers. Papers providing the prevalence data on Clozapine associated nocturnal enuresis were selected for data extraction. Results 47 papers were initially identified. Eight papers focused on the prevalence of clozapine associated nocturnal enuresis (CANE). Point prevalence (nocturnal enuresis at the time of assessment), 1-month prevalence and episode prevalence (nocturnal enuresis since beginning of clozapine) were given. Papers included patients with schizophrenia, schizoaffective disorder, bipolar affective disorder and psychotic depression, taking clozapine medication. The prevalence of CANE ranged from 10–42%. Point prevalence was 21–27%, 1-month prevalence was 10–39% and episode prevalence was 15–42%. Clozapine was more likely to cause nocturnal enuresis compared to other psychotropic medication. Conclusion The prevalence of CANE may be greater than previously thought. However, in order to determine an accurate prevalence of clozapine associated nocturnal enuresis, larger studies with strict inclusion criteria, common definition of diagnosis and prevalence are required. By establishing an accurate prevalence, physician awareness can be improved, and patients can becounselled on the risk of developing the side effect, thus improving early identification and reducing discontinuation rates.

Association Between N-Desmethylclozapine and Clozapine-Induced Sialorrhea: Involvement of Increased Nocturnal Salivary Secretion via Muscarinic Receptors by N-Desmethylclozapine.

Clozapine-induced sialorrhea (CIS) is a common side effect of clozapine. There is no established standard treatment of CIS since the underlying mechanism remains unknown. This study aimed to elucidate the mechanisms involved in CIS. In our clinical study, a prospective observational study evaluated the association between serum and saliva concentrations of clozapine or its metabolites and Drooling Severity and Frequency Scale (DSFS) score. In our in vivo study, we first developed a new CIS animal model; subsequently, we measured salivary secretion and concentrations of clozapine or its metabolites in the animal model. In our in vitro study, we measured the calcium ion (Ca2+) response to evaluate the effect of clozapine or its metabolites on human salivary gland cell line (HSY cells) and then examined whether their effect was inhibited by atropine. In our clinical study, serum and saliva N-desmethylclozapine concentrations were significantly correlated with nocturnal DSFS score. In our in vivo study, daily single oral administration of 100 mg/kg clozapine for 7 days significantly increased salivary secretion in rats. Furthermore, N-desmethylclozapine concentrations in serum and submandibular glands of the rats were higher than clozapine concentrations. In our in vitro study, N-desmethylclozapine only elicited an increase in the intracellular Ca2+ in HSY cells. N-desmethylclozapine-induced Ca2+ responses were inhibited by atropine. These results suggest that N-desmethylclozapine is implicated in CIS by increasing nocturnal salivation via the muscarinic receptors. Moreover, our developed animal model that reflects CIS in clinical condition plays a key role as a bridge between basic and clinical research. SIGNIFICANCE STATEMENT: Clozapine-induced sialorrhea (CIS) is a severe and frequent adverse reaction, but the mechanism underlying CIS is less well understood. This paper reports that N-desmethylclozapine, a metabolite of clozapine, is implicated in CIS by increasing nocturnal salivation via the muscarinic receptors and that oral administration of clozapine at 100 mg/kg once daily for 7 days to rat is the optimum method for establishing the new animal model reflecting the clinical scenario of CIS.

Increased sodium transporters in distal nephron segments are associated with clozapineinduced hypertension

Dopamine receptor subtype 4 (D4R) antagonists, such as clozapine, are used in the treatment of schizophrenia. A common side effect of clozapine is hypertension but the mechanism of the clozapine‐induced hypertension is unknown. D4R plays an important role in blood pressure (BP) regulation; deletion of the D4R gene in mice causes hypertension. To determine if renal mechanisms are involved in clozapine‐induced hypertension, we characterized the distribution of D4R in mouse kidney and measured BP, water and sodium balance, and renal protein expression of sodium transporters in clozapine‐ and vehicle‐treated mice. D4R (immunocytochemistry) was mainly located in thick ascending limb, distal convoluted tubule and cortical and medullary collecting ducts; there is slight staining of D4R in the proximal convoluted but not straight tubule. Clozapine (20mg/kg/day) or vehicle was delivered subcutaneously to adult male C57BL/6J mice for seven days via osmotic mini‐pump (n=5/group). In clozapine‐treated mice, systolic (110±0.5, mm Hg, under anesthesia) and diastolic BPs (76.6±1),) were elevated, relative to vehicle‐treated mice (SBP=97.6±1.6, DBP=69.5±2.3). Food and water intake, body weight, serum electrolytes and creatinine, urine volume, and creatinine clearance were similar in the two groups. The sodium excretion tended to decrease while sodium excretion and blood pressure plot in clozapine‐treated mice was shifted to the right of the vehicle‐treated mice. Renal protein expressions (immunoblotting) of sodium hydrogen exchanger 3 and sodium phosphate cotransporter 2 were similar in clozapine‐ and vehicle‐treated mice. However, the renal protein expressions of sodium potassium 2 chloride cotransporter (180±21, % of control) and sodium chloride cotransporter (171±22% ), and the three subunits of epithelial sodium channel, α (140±7%), β (166±21%) and γ (55 kDa=130±7%, 85kDa=114±10% ), were greater in clozapine‐than vehicle‐treated mice. Renal protein expression of a‐sodium potassium ATPase was also slightly increased (118±4%) in clozapine‐treated mice. These findings suggest that inhibition of D4R by clozapine increases sodium transporters in distal nephron segments. Furthermore, a similar increase in the protein expression of sodium chloride cotransporter was also found in the immortalized mouse renal distal convoluted tubule cells in vitro with inhibition of D4R with its siRNA and antagonists. Thus, inhibition of renal D4R may cause the impaired sodium excretion that may be responsible for the increased blood pressure in clozap‐inetreated mice.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Nocturnal Enuresis is an Under-recognised Side Effect of Clozapine: Results of a Systematic Review

Abstract Objectives Clozapine is an effective antipsychotic medication licenced for the management of treatment resistant schizophrenia. Due to its non-selective pharmacology, it has a broad range of side effects. Nocturnal enuresis secondary to the use of clozapine has been documented in the literature but may be overlooked, the link between drug and symptom being clinically unnoticed. Patients may not mention urinary symptoms due to supervening psychosis, co-existing symptomatology, embarrassment or shame. By raising awareness of the phenomenon, early recognition and patient support may improve compliance with clozapine medication, and consecutively, overall mental health. Consequently, this systematic review investigates the prevalence of nocturnal enuresis secondary to clozapine use. Methods A literature search on clozapine and nocturnal enuresis was used to identify the relevant papers. Papers providing the prevalence data on Clozapine associated nocturnal enuresis were selected for data extraction. Results 47 papers were initially identified. Eight papers focused on the prevalence of clozapine associated nocturnal enuresis (CANE). Point prevalence (nocturnal enuresis at the time of assessment), 1-month prevalence and episode prevalence (nocturnal enuresis since beginning of clozapine) were given. Papers included patients with schizophrenia, schizoaffective disorder, bipolar affective disorder and psychotic depression, taking clozapine medication. The prevalence of CANE ranged from 10–42%. Point prevalence was 21–27%, 1-month prevalence was 10–39% and episode prevalence was 15–42%. Clozapine was more likely to cause nocturnal enuresis compared to other psychotropic medication. Conclusion The prevalence of CANE may be greater than previously thought. However, in order to determine an accurate prevalence of clozapine associated nocturnal enuresis, larger studies with strict inclusion criteria, common definition of diagnosis and prevalence are required. By establishing an accurate prevalence, physician awareness can be improved, and patients can becounselled on the risk of developing the side effect, thus improving early identification and reducing discontinuation rates.

Clozapine and Gastrointestinal Hypomotility.

Gastrointestinal hypomotility (GIH) is an under-reported but highly prevalent and potentially dangerous side effect of clozapine. In a comprehensive meta-analysis of clozapine-treated patients, the prevalence of GIH was 32%. In general, GIH has consistently been reported to have a negative impact on quality of life, and there is no reason to believe this will be different in clozapine-treated patients with therapy-resistant schizophrenia. GIH is dangerous; in a comparative review of lethal side effects of clozapine, the mortality of agranulocytosis was 2.2-4.2% compared with 15.0-27.5% for GIH. The mortality rate in our review of all published case reports of ileus was 43.7%. (Co-)Prescription of anticholinergic drugs in patients treated with clozapine should be avoided as anticholinergics are associated with increased incidence and fatality of ileus. Prevention of GIH can best be obtained by frequent and targeted questioning by the mental healthcare providers of the patients' defecation pattern and this is therefore strongly recommended for timely detection and treatment of treatment-emergent GIH throughout clozapine treatment. Treatment approaches can be either preventive laxative prescription with every clozapine prescription in all clozapine-treated patients or targeted treatment of treatment-emergent GIH. First-line treatments of GIH are the osmotic laxative macrogol, stool softener docusate and bowel stimulant senna. As the occurrence of severe cases of GIH is not restricted to a certain treatment duration, alertness for and/or treatment of GIH is required for the whole duration of clozapine treatment.

Abstract P321: Clozapine-induced Hypertension: Role of the Dopamine Type 4 Receptor (D4R) in Human Renal Proximal Tubule Cells (RPTC)

Clozapine (CLZ), a potent D 4 R antagonist that is an effective antipsychotic drug for the treatment of schizophrenia, is associated with hypertension. The hypertensive side effect of CLZ may be through inhibition of the D 4 R because germline deletion of D 4 R in mice causes hypertension. The hypertension caused by germline deletion of D 4 R may, in part, be due to increased renal expression of the angiotensin type 1 receptor (AT 1 R) and renal expression of sodium exchangers, transporters, and pumps, e.g., NHE3, NKCC2, NCC, and Na + K + /ATPase, α subunit. CLZ administered subcutaneously (20mg/kg/day/x3 days, n=5) in mice induced hypertension, shifted the pressure-natriuresis plot to the right, and increased the renal expressions of NCC and Na + K + /ATPase, α subunit, relative to vehicle-treated mice (n=5). Activation of D 4 R decreased AT 1 R expression and Na + K + /ATPase activity in rat renal proximal tubule cells (RPTCs). Therefore, we studied two groups: subjects 18 to 75 years old with a DSM-IV diagnosis of schizophrenia or schizoaffective disorder treated with CLZ for &gt;2 months (CLZ, N=32) and untreated healthy controls ( HC , N=20) without psychiatric illness. There were no significant differences in blood pressure (BP) between the two groups since more than half of the CLZ participants received antihypertensive medication. We studied RPTCs cultured from the participant’s urine (CLZ, N=18; HC, N=9) and treated those cells with 100 nM CLZ. CLZ decreased D 4 R expression in both HC and CLZ groups ( HC , VEH 1.04±0.17 vs CLZ 0.73±0.09, n=9, paired t-test, P&lt;0.05; CLZ, VEH 1.02±0.09 vs CLZ 0.75±0.06, n=16, paired t-test, P&lt;0.01). CLZ also increased reactive oxygen species (Rosstar550 assay) in the HC but not CLZ-treated group ( HC , VEH 0.92±0.07 vs CLZ 1.02±0.09, n=8, paired t-test , P&lt;0.05; CLZ VEH 1.09±0.18 vs CLZ 1.07±0.18, n=14). The density of plasma membrane AT 1 R tended to be higher in CLZ-treated hypertensive (CLX HP) than the CLZ-treated normotensive participants (CLZ NP): ( HC , 0.28±0.08 n=8; CLZ NP, 0.10±0.02 n=4; CLZ HP, 0.81±0.31 n=7). Thus, CLZ may induce hypertension through a D 4 R/AT 1 R-mediated mechanism similar to that reported in D 4 R knockout mice. Additional studies will determine if CLZ increases sodium transport in human RPTCs.

Clozapine-associated Pisa syndrome: A rare type of tardive dystonia.

Sir, Tardive dystonia are delayed-onset drug-induced movement disorders associated with traditional neuroleptic agents, characterized by involuntary muscle contraction, which may be tonic, spasmodic, patterned, or repetitive.[1] Pleurothotonus or Pisa syndrome is a rare type truncal dystonia, first described by Ekbom et al. in the 1970s.[2] Recent data show that factors such as female gender, old age, previous treatment with classical neuroleptics, the presence of an organic brain disorder, and a combination of pharmacologic treatment increase the risk of this condition.[3] In contrast to other atypicals, such as olanzapine,[4] which have been reported to cause tardive dystonia, clozapine has been used in treating tardive dystonia, including blepharospasm.[5] A 52-year-old woman, with schizophrenia, was on regular treatment with clozapine monotherapy for the last 2 years. Past and family history revealed no psychiatric or neurological illness. She was initially treated with risperidone 8 mg/day and due to partial response switched to quetiapine 200 mg/day for 1 year which was replaced with clozapine due to partial response. The dose of clozapine was increased from 50 mg to 200 mg/day over 6 months and was maintained on the same for 1½ years. In the past 6 months, she developed back pain and frequent, forceful bending of spine to the left along with difficulty to walk, and a leaning posture towards the left side which was gradual and progressive. Medical history was significant for adult onset diabetes. Orthopedic, ophthalmic, and neurological examinations were normal. Computed tomography scan of the brain and magnetic resonance imaging of both brain and spine were normal. Full biochemistry profile, liver function test, serum ceruloplasmin, and thyroid functions were normal. The appearance of dystonia with monotherapy of clozapine for 2 years strongly implicates the role of clozapine. The diagnosis of tardive dystonia can be made based on the criteria by Burke et al. in 1982.[6] The fact that this patient was on clozapine monotherapy for 2 years clearly rules out the involvement of other antipsychotics. It is possible that previous antipsychotic exposure resulted in long-term functional dopamine receptor abnormalities through chronic dopamine receptor blockade. This could have created a sensitizing or priming effect on this patient's striatum. Thus, clozapine exposure alone may not be sufficient to cause dystonia; it may be necessary for the substrate of an abnormal striatum to be already in place.[7] While reviewing the literature, we found only few reports[7891011] of possible tardive dystonia associated with clozapine. Davé[8] reported a patient with the recurrent oculogyric crisis while on clozapine. Although this is considered to be a type of tardive dystonia, this patient had previously experienced this while taking perphenazine, calling into question the relationship of these symptoms to clozapine. In 1996, Peacock et al.[9] reported mild finger dystonia in one of 100 patients treated (>5 years) with clozapine. In 1999, Molho and Factor reported a case of cervical tardive dystonia in a patient while on clozapine monotherapy.[10] With the increasing use of clozapine in treatment resistant schizophrenia, the issue of its potential association with tardive syndromes gathers importance. Reporting of similar cases will lead to a more accurate understanding of the incidence of this potential side effect of clozapine. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.

Leukocytosis after Clozapine Treatment in a Patient with Chronic Schizophrenia

Clozapine is an atypical antipsychotic drug that is approved by the US Food and Drug Administration (FDA) for the treatment of psychotic disorders. Agranulocytosis is a well-established side effect of clozapine; clozapine has also been associated with other blood dyscrasias like leukocytosis, albeit rarely. In this paper, we aim to report a case of possible clozapine-associated leukocytosis in a 41-year-old woman.

Clozapine and Ileus: a Case Report

Introduction An under-recognized life-threatening adverse effect of clozapine is the gastrointestinal hypomotility. It represents a serious problem. Clozapine is an atypical antipsychotic which commonly produces ileus. The risk is higher when we associate clozapine to drugs, such us anticholinergic and tricyclic. Ileus can produce the death in our patients, therefore we will check constipation in our daily clinical practice as a measure to avoid these side effectS. Methods We looked through Medline for articles published since 2005 regarding Clozapine and Ileus. We will present the case of a patient who developed Ileus as the side effect of clozapine. Results Constipation is very common in patients with schizophrenia (until 50%). Risk factors developing ileus in psychotic patients are: women, age, anticholinergic drugs, first generation of antipsychotics, clozapine, opioids and tricyclic antidepressants. Taking into account that this side effect can be mortal some recommendations that can reduce gastrointestinal hipomotility in this population are: a high fiber diet, exercise and the use of a softening laxative. In the case a patient treated with clozapine suffers from ileus we should shift the clozapine to aripiprazole or Amisulpride treatment. Moreover, we can use prokinetic drugs and surgery in the most complicated cases. Then, clozapine can be introduced after the ileus problem has been solved. Conclusion 1 Gastrointestinal hypomotility has a high prevalence in psychotic treatments. 2 Avoiding the use of other drugs that produce constipation. 3 Offer advice to avoid the constipation. 4 If ileus is present, stop the clozapine treatment and shift it to aripiprazole or Amisulpride.