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1
Pardis, Parnian, Gary Remington, Roshni Panda, Milan Lemez, and Ofer Agid. "Clozapine and tardive dyskinesia in patients with schizophrenia: A systematic review." Journal of Psychopharmacology 33, no. 10 (July 26, 2019): 1187–98. http://dx.doi.org/10.1177/0269881119862535.
Повний текст джерелаАнотація:
Background: It is commonly recommended that a switch to clozapine be implemented in the face of tardive dyskinesia, even if current treatment involves another “atypical” agent. However, reports do indicate clozapine carries a liability for tardive dyskinesia. Aims: This review sought to evaluate clozapine in relation to tardive dyskinesia in the context of available evidence. Methods: Medline, Embase, and PsycINFO databases were searched for studies published in English, using the keywords: clozapine AND tardive dyskinesia OR TD. References from major review articles were searched for additional relevant publications. Studies were included if they investigated: tardive dyskinesia in clozapine-treated patients diagnosed with schizophrenia spectrum disorders, and reported on two or more assessments of tardive dyskinesia severity measured by the Abnormal Involuntary Movement Scale; or clozapine’s tardive dyskinesia liability. Results: In total, 513 unique citations were identified and 29 reports met the inclusion criteria. Thirteen studies suggest clozapine reduces dyskinetic symptoms over time ( n=905 clozapine-treated participants); however, the minimum required dose and effect of withdrawal requires further investigation. The majority of reports which address clozapine’s liability for tardive dyskinesia are case studies (11 of 14 reports, 79%), and clozapine was only the first-line treatment in one of the remaining three studies reporting treatment-emergent dyskinetic symptoms with clozapine in 12% of patients. No significant between-drug differences were identified comparing clozapine’s risk to other atypical antipsychotics. Conclusions: Research to date supports switching to clozapine for the purpose of reducing tardive dyskinesia risk and/or treating existing tardive dyskinesia, but prospective randomized controlled trials are necessary if we are to substantiate existing recommendations.
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Coward, D. M. "General Pharmacology of Clozapine." British Journal of Psychiatry 160, S17 (May 1992): 5–11. http://dx.doi.org/10.1192/s0007125000296840.
Повний текст джерелаАнотація:
Clozapine shows neuroleptic-like inhibition of locomotor activity and conditioned avoidance responding in rodents, although tolerance develops on repeated treatment. EEG-based studies show strong arousal-inhibiting activity of clozapine as well as neuroleptic-like effects on both caudate spindle duration and rat sleep-waking patterns. Effects such as apomorphine blockade, catalepsy and strong increases of plasma prolactin levels are not seen, however, and chronic treatment does not lead to dopamine D2 receptor supersensitivity. Binding studies show clozapine's highest affinities to be for dopamine D4, 5-HT1c, 5-HT2, α1, muscarinic and histamine H1 receptors, but moderate affinity is also seen for many other receptor subtypes. Microdialysis studies indicate a preferential interaction with striatal D1 receptors, whereas autoradiographical studies indicate upregulation of D1 and downregulation of 5-HT2 receptors after chronic clozapine. Clarification of the mechanisms underlying clozapine's special attributes is often hampered by a failure to examine compounds which show a close chemical relationship to clozapine, but which produce extrapyramidal side-effects in man, such as clothiapine, loxapine and amoxapine.
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Lieberman, Jeffrey A., Bruce L. Saltz, Celeste A. Johns, Simcha Pollack, Michael Borenstein, and John Kane. "The Effects of Clozapine on Tardive Dyskinesia." British Journal of Psychiatry 158, no. 4 (April 1991): 503–10. http://dx.doi.org/10.1192/bjp.158.4.503.
Повний текст джерелаАнотація:
This article reviews eight published studies that describe clozapine's effects on TD and examines the outcome of 30 patients with TD treated with clozapine for up to 36 months. These data indicate that TD response to clozapine is variable but that approximately 43% of cases, particularly those with dystonic features, improved after clozapine treatment. Methodological limitations of the studies described, however, preclude definitive conclusions, which must await appropriately controlled trials.
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Rajkumar, Anto P., B. Poonkuzhali, Anju Kuruvilla, Alok Srivastava, Molly Jacob, and K. S. Jacob. "Association betweenCYP1A2gene single nucleotide polymorphisms and clinical responses to clozapine in patients with treatment-resistant schizophrenia." Acta Neuropsychiatrica 25, no. 1 (February 2013): 2–11. http://dx.doi.org/10.1111/j.1601-5215.2012.00638.x.
Повний текст джерелаАнотація:
ObjectivesDespite clozapine's superior clinical efficacy in treatment-resistant schizophrenia (TRS), its adverse effects, need for periodic leukocyte monitoring, cost and variable clinical outcomes mandate a clinical need to predict its treatment response. Although cytochrome P450 1A2 (CYP1A2) is the principal determinant of metabolism of clozapine, the role ofCYP1A2gene in the clinical response to clozapine is uncertain. Hence, we investigated its association with treatment responses and adverse events of clozapine in TRS.MethodsWe evaluated four single nucleotide polymorphisms (SNP) in theCYP1A2gene, clinical responses and serum clozapine levels in 101 consecutive patients with TRS on stable doses of clozapine. We defined clozapine responsea prioriand investigated allelic and genotypic associations. We assessed the socio-demographic and clinical profiles, premorbid adjustment, traumatic life events, cognition and disability of the participants, using standard assessment schedules for appropriate multivariate analyses.ResultsOur results revealed thatCYP1A2gene SNP (*1C, *1D, *1Eand*1F) were not associated with clozapine treatment response, adverse effects, serum clozapine levels or with disability (pvalues > 0.10).ConclusionAsCYP1A2gene SNP do not help to predict the clinical response to clozapine, routine screening for them prior to start clozapine is currently unwarranted. We suggest future longitudinal genome-wide association studies investigating clinical and pharmacogenetic variables together.
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Oliveira-Souza, Ricardo de, Rogério Paysano Marrocos, and Jorge Moll. "Clozapine for severe ("kraepelinian") schizophrenia: Sustained improvement over 5 years." Dementia & Neuropsychologia 2, no. 1 (March 2008): 71–75. http://dx.doi.org/10.1590/s1980-57642009dn20100014.
Повний текст джерелаАнотація:
Abstract Clozapine has become a keystone in the treatment of schizophrenia because of its efficacy as an antipsychotic with negligible neuroleptic effects. The long-term stability of its effects, however, is poorly understood, because most studies have probed the usefulness of clozapine over a period of weeks to several months at the most. Knowing whether clozapine's benefits are sustained over the very long-term, i.e., more than 5 years, may be critical for cost-benefit analyses. Objective: To report the results of an open study on the efficacy of clozapine over the very long-term. Methods: Thirty-three adults (26 men) with severe (kraepelinian) schizophrenia were assessed at regular intervals using a brief neuropsychiatric battery over a 5-year period. Results: A significant improvement was observed between the pre-clozapine and the first "on-clozapine" evaluation. This improvement was paralleled by a remarkable conversion of schizophrenia from "active" (mostly paranoid) into "residual" in 70% of all patients. Eight patients became functionally productive to the point of being capable of living an independent life. Roughly one-third of our cases showed no improvement. Conclusions: Clozapine is a safe and effective drug for patients with severe schizophrenia who have failed to improve on other antipsychotic drugs. Clozapine's maximal benefit is established by the end of the first year of treatment and continues unabated for many years thereafter. Clozapine-resistant patients remain a major challenge calling for the discovery of new treatments for schizophrenia.
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Orejas, O., C. Masferrer Herrera, C. Macías Castellví, and P. Flores Martínez. "Subacute psychiatric hospitalization unit: The role of clozapine." European Psychiatry 33, S1 (March 2016): S548—S549. http://dx.doi.org/10.1016/j.eurpsy.2016.01.2026.
Повний текст джерелаАнотація:
IntroductionSeveral studies report that Clozapine is more effective in reducing symptoms of schizophrenia, producing clinically meaningful improvements and postponing relapse than other antipsychotic strategies.ObjectivesTo analyze the prescription of Clozapine in a sample of 88 inpatients admitted to a subacute psychiatric hospitalization unit.MethodsThis is a transversal study. All patients admitted for a medium-term psychiatric treatment since 01/06/2014 to 30/11/2015 were included. Data about socio-demographical status and clinical situation were obtained and compiled in a database. This study compares patients receiving clozapine treatment with those who receive other psychopharmacologic treatment. Statistics were performed using SPSS Software.ResultsEighty-eight patients (52% men; mean age: 48.6 years) composed the sample. In 58% of cases, schizophrenia and schizoaffective disorder were the diagnoses motivating the admission. Within the 51 patients with Schizophrenia o Schizoaffective Disorder, 16 of them (31.4%) received Clozapine. Comparing clozapine group vs non-clozapine group, there were no significant differences between the groups in terms of sex, civil state or working state. Instead, Clozapine group patients were older, had a major number of previous hospitalization admissions and had a larger trajectory of their disorder.ConclusionsPatients requiring treatment with Clozapine had a major number of hospital admissions and had more often committed suicide attempts, suggesting a more severe course of the disorder. They were older than the non-clozapine group. Clozapine is delayed in its use among resistant-treatment patients. It is worth highlighting that only 16 cases of Schizophrenia inpatients received Clozapina. It could mean that Clozapine is underprescribed.Disclosure of interestThe authors have not supplied their declaration of competing interest.
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Stanton, Robert J., Chris Paxos, Werner J. Geldenhuys, B. Pharm, Jessica L. Boss, Mark Munetz, Altaf S. Darvesh, and M. Pharm. "Clozapine underutilization in treatment-resistant schizophrenia." Mental Health Clinician 5, no. 2 (March 1, 2015): 63–67. http://dx.doi.org/10.9740/mhc.2015.03.063.
Повний текст джерелаАнотація:
Abstract It has been shown that up to one third of patients with schizophrenia do not respond to antipsychotic therapy. Thus, treatment-resistant schizophrenia (TRS) remains a major mental health care challenge. Clozapine has been shown to provide superior therapeutic benefits and is approved as first-line therapy for TRS. These benefits include improvement in both positive and negative symptoms, and reduction of suicidal behavior in patients with schizophrenia. Clozapine, however, remains significantly underused for TRS. A major reason for clozapine's underuse is its substantial adverse effect profile, mainly the risk of life-threatening agranulocytosis which necessitates regular hematologic monitoring. Another factor contributing to reduced clozapine prescribing is the increased use of other second-generation antipsychotics. In TRS patients, there is often a considerable delay in clozapine use, which is prescribed only after other unsuccessful second-generation antipsychotic trials. To combat this trend, there is a push for increased awareness to optimize clozapine prescribing. An important aspect in improving the use of clozapine therapy is physician and patient education. Furthermore, pharmacist involvement can improve clozapine prescription trends in TRS.
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Fehsel, K., K. Schwanke, BA Kappel, E. Fahimi, E. Meisenzahl-Lechner, C. Esser, K. Hemmrich, T. Haarmann-Stemmann, G. Kojda, and C. Lange-Asschenfeldt. "Activation of the aryl hydrocarbon receptor by clozapine induces preadipocyte differentiation and contributes to endothelial dysfunction." Journal of Psychopharmacology 36, no. 2 (January 3, 2022): 191–201. http://dx.doi.org/10.1177/02698811211055811.
Повний текст джерелаАнотація:
Background: The superior therapeutic benefit of clozapine is often associated with metabolic disruptions as obesity, insulin resistance, tachycardia, higher blood pressure, and even hypertension. Aims: These adverse vascular/ metabolic events under clozapine are similar to those caused by polycyclic aromatic hydrocarbons (PAHs), and clozapine shows structural similarity to well-known ligands of the aryl hydrocarbon receptor (AhR). Therefore, we speculated that the side effects caused by clozapine might rely on AhR signaling. Methods: We examined clozapine-induced AhR activation by luciferase reporter assays in hepatoma HepG2 cells and we proved upregulation of the prototypical AhR target gene Cyp1A1 by realtime-PCR (RT-PCR) analysis and enzyme activity. Next we studied the physiological role of AhR in clozapine’s effects on human preadipocyte differentiation and on vasodilatation by myography in wild-type and AhR-/- mice. Results: In contrast to other antipsychotic drugs (APDs), clozapine triggered AhR activation and Cyp1A1 expression in HepG2 cells and adipocytes. Clozapine induced adipogenesis via AhR signaling. After PGF2α-induced constriction of mouse aortic rings, clozapine strongly reduced the maximal vasorelaxation under acetylcholine in rings from wild-type mice, but only slightly in rings from AhR-/- mice. The reduction was also prevented by pretreatment with the AhR antagonist CH-223191. Conclusion: Identification of clozapine as a ligand for the AhR opens new perspectives to explain common clozapine therapy-associated adverse effects at the molecular level.
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Davis, Erica A. K., and Deanna L. Kelly. "Clozapine-associated renal failure: A case report and literature review." Mental Health Clinician 9, no. 3 (May 1, 2019): 124–27. http://dx.doi.org/10.9740/mhc.2019.05.124.
Повний текст джерелаАнотація:
Abstract One of clozapine's unrecognized potential side effects is renal insufficiency and nephritis. Although most clinicians are aware of the possibility of clozapine-induced myocarditis, less is known about other inflammatory disorders due to clozapine treatment. This patient was started on lithium and clozapine within 4 days of each other although lithium was discontinued after 7 days due to tremor. Routine labs showed an increase in serum creatinine, which was initially attributed to the recent lithium. However, the patient's kidney function continued to worsen, requiring discontinuation of clozapine despite a robust response to a low dose. Several years later, the patient's kidney function improved but has not returned to baseline. This literature review and case report illustrates the similarities in diagnostic presentation of clozapine-associated renal insufficiency as well as potential risk factors. More research should be conducted into the role concomitant sodium valproate and/or lithium play in the risk of clozapine-associated renal insufficiency.
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Jalenques, Isabelle, and André-Julien Coudert. "Clozapine for the treatment of levodopa-induced psychosis and dyskinesia in Parkinson's disease." Irish Journal of Psychological Medicine 11, no. 2 (June 1994): 83–88. http://dx.doi.org/10.1017/s0790966700012404.
Повний текст джерелаАнотація:
AbstractThe treatment of psychosis in patients with Parkinson's disease (PD) is one of the most difficult problems in clinical psychiatry. Clozapine's low propensity to induce extrapyramidal side effects makes it an attractive treatment for psychotic patients with PD. A number of published uncontrolled studies suggest that low-dose clozapine is effective in these patients. However, the dose range, side effect profiles and length of treatment have varied in these reports. In this article, the authors review the literature and report on the effects of clozapine in a patient with Parkinson's disease and psychosis. Clozapine (50mg per day) resulted in a complete resolution of psychosis, improvement of motor function, reduction of “off” time and a major improvement in levodopa-induced dystonic dyskinesias. The only adverse effect was mild sedation during the first two weeks of clozapine treatment. The lack of acute blockade of striatal D2 receptors by clozapine and the failure of chronic clozapine treatment to suppress striatal dopamine release may account for its beneficial effect in Parkinson's disease. Additionally, an ameliorating effect of clozapine on parkinsonism might be due to its action on serotonergic systems leading to release of striatal dopamine.
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Marcelino, Carla R. B., and Clarissa de R. Dantas. "Clozapine-induced severe eosinophilia: report of a case with good outcome." Jornal Brasileiro de Psiquiatria 62, no. 3 (September 2013): 240–43. http://dx.doi.org/10.1590/s0047-20852013000300009.
Повний текст джерелаАнотація:
INTRODUCTION: Clozapine is the antipsychotic of choice in the treatment of refractory schizophrenia. However, its side effects, such as eosinophilia, may preclude its use. METHODS: Case report and literature review. RESULTS: Young woman, 19 years old, diagnosed with hebefrenic schizophrenia, admitted at Unicamp's psychiatry ward after psychotic symptoms relapse. Clozapine was started after unsuccessful attempts with risperidon and olanzapine. By the fourth week of clozapine use, eosinophils began to increase. Drug titration was stopped, but eosinophils counts continued to rise up, reaching the mark of 5200/mm³. Due to severity of psychotic symptoms and to the good response obtained with clozapine, we decided to investigate organs involvement before withdrawing the medication. As the patient had no organs involvement, clozapine was maintained and one month after eosinophils peak, it was already normalized. CONCLUSION: Eosinophilia should not necessarily lead to clozapine's withdrawal. Patients who present eosinophilia must be at rigorous observation for organs involvement, and if there is no such involvement, clozapine might be maintained, considering the possible benign and transitory nature of the eosinophils count elevation.
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Sulejmanpasic, G., and S. Bise. "Clozapine augmented with risperidone in treatment-resistant schizophrenia." European Psychiatry 41, S1 (April 2017): S385. http://dx.doi.org/10.1016/j.eurpsy.2017.02.424.
Повний текст джерелаАнотація:
IntroductionThe evolution of various pharmacological therapies for schizophrenia has given rise to several pharmacological models for the neuroreceptor targets of antipsychotics and the influence of various neuroreceptors on specific symptoms and side effects.ObjectivesExperience in clinical practice affirms clozapine's position as the treatment of choice for patients with treatment-refractory schizophrenia. Unlike clozapine, risperidone has a more targeted profile of neurotransmitter binding, with particular predilection for dopamine and serotonin receptors. Risperidone is, to date, the most extensively documented clozapine augmentation agent.AimThe aim was to evaluate clinical efficacy, safety and tolerability of augmenting clozapine with risperidone in patients with treatment-resistant schizophrenia.MethodsIn a randomized, double-blind, placebo-controlled 8-week trial, 10 patients unresponsive or partially responsive to 300 mg/day of clozapine monotherapy (n = 5) received a steady dose of 450 mg/day clozapine combined with or up to 4 mg/day of risperidone (n = 5). Patient psychopathology was assessed at 2-week intervals with the Brief Psychiatric Rating Scale (BPRS), the Scale for the Assessment of Negative Symptoms (SANS) and Clinical Global Impression (CGI) improvement scale.ResultsFrom baseline to week 4 and week 8, mean BPRS total and positive symptom subscale scores were reduced significantly in both groups, but the reductions were significantly greater with clozapine/risperidone treatment. Reductions in SANS scores were also significantly greater with clozapine/risperidone treatment than with clozapine monotherapy group. Clozapine/risperidone treatment did not induce additional weight gain or agranulocytosis compared with clozapine monotherapy treatment.ConclusionsClozapine augmentation with risperidone appears to be well tolerated, safe and may provide additional clinical benefit for patients who are nonresponsive or only partially responsive to clozapine alone.Disclosure of interestThe authors have not supplied their declaration of competing interest.
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Kirwan, P., L. O’Connor, K. Sharma, and C. McDonald. "The impact of switching to clozapine on psychiatric hospital admissions: a mirror-image study." Irish Journal of Psychological Medicine 36, no. 4 (July 18, 2017): 259–63. http://dx.doi.org/10.1017/ipm.2017.28.
Повний текст джерелаАнотація:
BackgroundClozapine is an atypical antipsychotic agent used primarily in the management of treatment-resistant schizophrenia. Previous studies have demonstrated clozapine’s superior efficacy over other antipsychotic medications in treating this population of patients. The aim of this study was to assess if the number of hospital admissions and days spent in hospital reduced with the initiation of clozapine, compared with when the same sample of patients were prescribed other antipsychotics prior to clozapine initiation.MethodA mirror-image study design was adopted. In this case the intervention under study was the initiation of clozapine. Information was collected retrospectively from the charts of patients attending the University Hospital Galway clozapine clinic. The number of admissions and number of hospital days were collected for each patient over the 3 years before and after clozapine initiation. Wilcoxon’s signed-rank test was used to test for statistical significance.ResultsThe total sample size comprised of 62 patients, of which the majority were male (74.2%) and had a diagnosis of schizophrenia (82.3%). The mean dose of clozapine was 417 mg, and mean age of the sample was 38 years. Mean number of hospital admissions reduced from 2.8 to 0.8 (p<0.0001) following initiation of clozapine. Mean number of days spent in hospital reduced from 116.4 to 17.1 (p<0.0001).ConclusionAfter initiation of clozapine treatment, patients experience a substantial reduction in number of hospital admissions and number of days spent in hospital when compared with a similar period prior to clozapine initiation.
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Kubota, Takashi, Itsuki Jibiki, Akira Ishikawa, Tomomi Kawamura, Sonoko Kurokawa, and Man Wang. "Increase in extracellular dopamine levels during clozapine-induced potentiation in the hippocampal dentate gyrus of chronically prepared rabbits." Canadian Journal of Physiology and Pharmacology 86, no. 5 (May 2008): 249–56. http://dx.doi.org/10.1139/y08-036.
Повний текст джерелаАнотація:
We previously found that 20 mg/kg clozapine i.p. potentiated the excitatory synaptic responses elicited in the dentate gyrus by single electrical stimulation of the perforant path in chronically prepared rabbits. We called this phenomenon clozapine-induced potentiation and proved that it was an NMDA receptor-mediated event. This potentiation is presumably related to clozapine’s clinical effect on negative symptoms and cognitive dysfunctions in schizophrenia. In the present study, to investigate the mechanisms underlying clozapine-induced potentiation, we examined whether extracellular dopamine and 5-HT levels changed during the potentiation by using a microdialysis technique in the dentate gyrus. The extracellular concentrations of dopamine and 5-HT levels were measured every 5 min during all experiments. Extracellular 5-HT levels did not change, but dopamine levels eventually increased significantly during clozapine-induced potentiation. The increase in the dopamine levels occurred almost simultaneously with the induction of clozapine-induced potentiation. These results suggest that clozapine-induced potentiation is at least partly attributable to a dopamine-mediated potentiation of excitatory synaptic transmission. The present study implies that such phenomena occur also in the perforant path–dentate gyrus pathway.
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Freudenreich, O. "Augmentation strategies for treatment-refractory clozapine patients." European Psychiatry 64, S1 (April 2021): S31. http://dx.doi.org/10.1192/j.eurpsy.2021.109.
Повний текст джерелаАнотація:
BackgroundClozapine can be a life-saving and course-altering treatment for patients with psychosis, particularly treatment-resistant schizophrenia. Unfortunately, clozapine monotherapy rarely leads to a full symptomatic remission.AimsThis talk outlines key decision points in the use of clozapine: how to select patients for clozapine treatment and how to optimize clozapine’s efficacy in patients with a poor response to an adequate clozapine monotherapy trial.ConclusionsClozapine’s main indication is for treatment-resistant schizophrenia. Therapeutic drug monitoring (TDM) should be used to optimize clozapine dosing during a clozapine trial and to rule-out pseudo-resistance. Up to 50% of patients do not respond to clozapine monotherapy and augmentation strategies can be utilized in such cases. Pharmacological add-on treatments are selected based on the most prominent symptom cluster (refractory psychosis, negative symptoms, depression and suicidality, aggression). Electroconvulsive therapy is the most effective augmentation strategy for refractory psychosis and suicidality. Non-pharmacological interventions and a focus on quality of life become important considerations in clozapine non-responders.CommentsClozapine is an important and underutilized tool in the management of treatment-resistant schizophrenia. It should be offered timely, as soon as treatment-resistance becomes apparent. Clinicians can use personalized augmentation strategies as part of a comprehensive treatment plan in order to achieve improvements even in patients with a poor response to clozapine alone. However, polypharmacy should be used judiciously, keeping in mind medical morbidity and quality of life.DisclosureI have the following financial relationship with a commercial interest to disclose (recipient SELF; content area SCHIZOPHRENIA): Alkermes – Research grant (to institution), consultant honoraria (Advisory Board); Avanir – Research grant (to institution);
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Bunney, Benjamin S. "Clozapine: A Hypothesised Mechanism for its Unique Clinical Profile." British Journal of Psychiatry 160, S17 (May 1992): 17–21. http://dx.doi.org/10.1192/s0007125000296864.
Повний текст джерелаАнотація:
Clozapine's clinical profile is unique among antipsychotic drugs. What makes it different? For almost two decades researchers have been attempting to answer this question. Based on various data, many hypotheses have been proposed. Using electrophysiological techniques we have found that clozapine, like typical antipsychotic drugs, inactivates most midbrain dopamine cells secondary to the induction of depolarisation block. However, unlike classical antipsychotic drugs, clozapine does not inactivate the nigrostriatal dopamine system. Based on these and other findings the hypothesis of ‘depolarisation block‘ is reviewed and presented as an explanation for clozapine's unique clinical profile. Research data both for and against the hypothesis are then discussed.
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Cairns, Rebecca, and Stephen Guy. "Clozapine initiation in the Belfast Health and Social Care Trust (BHSCT)." BJPsych Open 7, S1 (June 2021): S177. http://dx.doi.org/10.1192/bjo.2021.482.
Повний текст джерелаАнотація:
AimsThe aim of this project is to improve the quality of documentation and recording of the assessment and monitoring of patients commencing clozapine in BHSCT.BackgroundClozapine is an effective treatment for patients with schizophrenia who have not responded to at least two other antipsychotics. Due to clozapine's significant side effect profile patients must be carefully assessed prior to treatment initiation with close monitoring of their physical observations and reported side effects during initiation.The BHSCT Clozapine Pathway currently uses a Clozapine Assessment Integrated Care Pathway (ICP) common to inpatient and outpatient clozapine titrations and a Clozapine Titration ICP which varies slightly between inpatient and outpatient titrations.MethodThe Clozapine ICPs of patients commenced on clozapine in BHSCT in a 9 month period commencing January 2019 were reviewed. Handwritten clinical records were used to collect data on rates of completion of all aspects of the pathway.These results were used to identify areas of the pathway that were being poorly completed and the “Method for Improvement Model” used to trial changes to the pathway using Plan-Do-Study-Act (PDSA) cycles.Result20 patients in BHSCT were commenced on clozapine in the 9 month period. 1 Clozapine Initiation Pathway could not be located; therefore data were collected on 19 patients. 2 patients were initiated in the community and 17 patients initiated as inpatients.The results showed that sections of the Clozapine Assessment ICP were poorly completed; for example only 27% of the “Patient Baseline Preparation Checklist” were complete, with 60% partially complete and 13% completely blank.In the inpatient clozapine titration ICP the physical observations record was complete in only 20% of patients and the side effects monitoring record complete in only 13% of patients. Conversely the physical observations and side effects monitoring records were complete in 100% (n = 2) of patients.ConclusionBHSCT Clozapine Pathways were being poorly completed, with outpatient pathways being completed better than inpatient pathways. Analysis of the data shows that repetition of information in various parts of the pathway leads to gaps in documentation.Parts of the pathway that were poorly completed have been redesigned and the impact of these changes assessed using the PDSA cycle method. It is hoped that this along with education of staff will lead to an improvement in the assessment and monitoring of patients being commenced on clozapine.
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Chang, Geng-Ruei, Hsien-Yueh Liu, Wei-Cheng Yang, Chao-Min Wang, Ching-Fen Wu, Jen-Wei Lin, Wei-Li Lin, et al. "Clozapine Worsens Glucose Intolerance, Nonalcoholic Fatty Liver Disease, Kidney Damage, and Retinal Injury and Increases Renal Reactive Oxygen Species Production and Chromium Loss in Obese Mice." International Journal of Molecular Sciences 22, no. 13 (June 22, 2021): 6680. http://dx.doi.org/10.3390/ijms22136680.
Повний текст джерелаАнотація:
Clozapine is widely employed in the treatment of schizophrenia. Compared with that of atypical first-generation antipsychotics, atypical second-generation antipsychotics such as clozapine have less severe side effects and may positively affect obesity and blood glucose level. However, no systematic study of clozapine’s adverse metabolic effects—such as changes in kidney and liver function, body weight, glucose and triglyceride levels, and retinopathy—was conducted. This research investigated how clozapine affects weight, the bodily distribution of chromium, liver damage, fatty liver scores, glucose homeostasis, renal impairment, and retinopathy in mice fed a high fat diet (HFD). We discovered that obese mice treated with clozapine gained more weight and had greater kidney, liver, and retroperitoneal and epididymal fat pad masses; higher daily food efficiency; higher serum or hepatic triglyceride, aspartate aminotransferase, alanine aminotransferase, blood urea nitrogen, and creatinine levels; and higher hepatic lipid regulation marker expression than did the HFD-fed control mice. Furthermore, the clozapine group mice exhibited insulin resistance, poorer insulin sensitivity, greater glucose intolerance, and less Akt phosphorylation; their GLUT4 expression was lower, they had renal damage, more reactive oxygen species, and IL-1 expression, and, finally, their levels of antioxidative enzymes (superoxide dismutase, glutathione peroxidase, and catalase) were lower. Moreover, clozapine reduced the thickness of retinal cell layers and increased iNOS and NF-κB expression; a net negative chromium balance occurred because more chromium was excreted through urine, and this influenced chromium mobilization, which did not help overcome the hyperglycemia. Our clozapine group had considerably higher fatty liver scores, which was supported by the findings of lowered adiponectin protein levels and increased FASN protein, PNPLA3 protein, FABP4 mRNA, and SREBP1 mRNA levels. We conclude that clozapine can worsen nonalcoholic fatty liver disease, diabetes, and kidney and retinal injury. Therefore, long-term administration of clozapine warrants higher attention.
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Hirsch, Steven R., Christopher G. G. Link, Jeffrey M. Goldstein, and Lisa A. Arvanitis. "ICI 204, 636: A New Atypical Antipsychotic Drug." British Journal of Psychiatry 168, S29 (May 1996): 45–56. http://dx.doi.org/10.1192/s0007125000298310.
Повний текст джерелаАнотація:
The therapeutic effects of ‘classic’ (typical) antipsychotic agents lie in their ability to block central dopaminergic receptors – a property that is also responsible for the frequent occurrence of undesirable extrapyramidal side-effects (EPS). In contrast to these typical agents, clozapine alone has distinguished itself in humans – by virtue of its enhanced antipsychotic action and lack of concurrent EPS – as an atypical antipsychotic. However, the use of clozapine has been limited by the occurrence of agranulocytosis and, to a lesser extent, seizures (Alvir et al, 1993; Haring et al, 1994). The mechanism underpinning the atypical profile of clozapine remains elusive. One hypothesis suggests that it lies in clozapine's higher serotonin 5-HT2: D2 binding ratio, when compared with typical agents – a factor being considered as a predictor of atypicality (Meltzer, this issue; Meltzer et al, 1989). However, an emerging view is that it is not a single pharmacological action, but rather multiple properties that may define an atypical, clozapine-like compound (Lieberman, 1993).
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Haile, Kibrom, and Halima Umer. "The use of clozapine and clonazepam co-administration in the treatment of a severe tardive dyskinesia: A case report." SAGE Open Medical Case Reports 7 (January 2019): 2050313X1983325. http://dx.doi.org/10.1177/2050313x19833254.
Повний текст джерелаАнотація:
This is a case report of a patient who was treated with clozapine and clonazepam after he developed neuroleptic-induced tardive dyskinesia following treatment for schizophrenia. There are reports of clozapine treatment itself causing tardive dyskinesia; however, more reports have shown clozapine’s benefit for patients with neuroleptic-induced tardive dyskinesia. This is a case report of a patient with neuroleptic-induced tardive dyskinesia who benefitted from clozapine treatment with adjuvant use of clonazepam – the first such case report from Ethiopia. A 43-year-old male patient developed severe involuntary abnormal body movements mainly involving the trunk after he received chlorpromazine for 8 years for the diagnosis of schizophrenia. When the movement disorder became intolerable and disabling, the diagnosis of severe neuroleptic-induced tardive dyskinesia was established and the patient was started on clozapine with adjuvant clonazepam treatment. Following such management, the patient responded well and the dyskinetic movements were fully controlled, and the patient was able to work. Patients with severe and disabling neuroleptic-induced tardive dyskinesia can be treated and be productive if they receive treatment with clozapine, with adjuvant use of clonazepam.
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Murphy, Kate, Ian Coombes, Sara McMillan, and Amanda J. Wheeler. "Clozapine and shared care: the consumer experience." Australian Journal of Primary Health 24, no. 6 (2018): 455. http://dx.doi.org/10.1071/py18055.
Повний текст джерелаАнотація:
Clozapine is a high-risk medication with restrictions that may increase consumer treatment burden. Shared care may improve access, reduce burden and promote primary care management. However, knowledge about the consumer experience of clozapine treatment within a shared-care setting has not been previously reported to the authors’ knowledge. The aim of this study was to explore the consumer experience within the shared-care setting. This mixed-methods study examined consumers’ experiences with a clozapine shared-care program in an urban setting in Queensland, Australia. Eligible consumers (n=35) participated in a semi-structured interview, including a survey. Analysis was descriptive and thematic. Ten (28.6%) consumers participated. Survey results found a strong belief in the necessity for clozapine, with a low level of reported treatment burden and minimal adverse effects. Four themes were identified from the interviews: (i) understanding of illness and recovery; (ii) positive outcomes of treatment; (iii) acceptance of treatment burden; and (iv) communication pathways. Participants reported positive experiences in the clozapine shared-care program, citing clozapine’s efficacy and the GP relationship as key benefits, however communication between clinicians and consumers must be enhanced to reduce risk of suboptimal treatment and adverse drug events.
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Peinado, A. Gomez, P. Cano Ruiz, S. Cañas Fraile, M. Gonzalez Cano, and G. E. Barba Fajardo. "Clozapine induced blood dyscrasias and a therapeutical approach." European Psychiatry 33, S1 (March 2016): S613. http://dx.doi.org/10.1016/j.eurpsy.2016.01.2293.
Повний текст джерелаАнотація:
IntroductionClozapine is a neuroleptic commonly used in treatments resistant to schizophrenia. However, despite the benefits, clozapine might cause some serious side effects. Hence, it is of the utmost necessity to keep an exacting control of the patients.ObjectivesTo study some of the therapeutical approaches to the treatment of clozapine induced neutropenia and agranulocytosis.MethodsReview of some articles in Mental Health Journals.ResultsThe treatment with clozapine, substratum of aminergic and muscarinic receptors, entails a 0.9% risk of causing agranulocytosis, and approximately a 2.7% risk of causing neutropenia. Both occur, over 80% of them, during the first 18 weeks of treatment. Thus, before starting it, it is necessary to draw some blood and analyze the complete blood count (CBC). Also, we must analyze CBCs weekly during the first 18 weeks. Other dyscrasias like leukopenia, leukocytosis, anaemia, eoshinophilia, thrombocythaemia or thrombocytopenia can also be observed. When agranulocytosis appears, it can be treated by discontinuing the clozapine treatment, but also using granulocyte-colony stimulating factor or lithium, both separated or combined with clozapine. Lithium produces reversible leukocytosis onceplasma levels of > 0.4 mmol/L are reached. Despite the simultaneous treatment with lithium, clozapine can trigger some neurological side effects, it seems that seizure risk remains invariable.ConclusionsSome of the clozapine's side effects, like neutropenia or agranulocytosis, are potentially lethal. Their treatment consists of discontinuing clozapine or initiating granulocyte-colony stimulating factor or lithium. These are good options that can give rise to a later continued treatment with clozapine.Disclosure of interestThe authors have not supplied their declaration of competing interest.
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Dickson, Ruth A., Richard Williams, and J. Thomas Dalby. "The Clozapine Experience from a Family Perspective." Canadian Journal of Psychiatry 40, no. 10 (December 1995): 627–29. http://dx.doi.org/10.1177/070674379504001010.
Повний текст джерелаАнотація:
Objective To examine how the lives of family members of clozapine-treated patients with schizophrenia have been affected by this treatment. Methods Through the use of a questionnaire and an interview of family members, this qualitative study focused on the families' perceptions of change in their family member and the impact on the family unit. Results Fourteen patients and their family members participated. The family interview was conducted an average of 1.78 years after clozapine inititation (range 0.58 years to 3.73 years). Global ratings of behavioural change were positively and significantly correlated between all raters: patients, family members, and clinicians. Family members were positive about clozapine's effect on their relatives and the impact on the family. Conclusion A positive response to clozapine decreases the burden on the family. This is in part the result of a decreased need for rehospitalization.
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Fernando, Tharushi, Ritesh Bhandarkar, and Graham Meadows. "Clinical Audit of Clozapine Prescribing Practice and Monitoring Process in an Australian Community Mental Health Service." BJPsych Open 8, S1 (June 2022): S4—S5. http://dx.doi.org/10.1192/bjo.2022.83.
Повний текст джерелаАнотація:
AimsClozapine, a well-established treatment of choice for treatment-resistant schizophrenia is known to reduce suicidality, lessen the risk of tardive dyskinesia and reduce relapse risk. It contributes to a higher quality of life by reducing cognitive clouding. Patients taking Clozapine have improved social and work functioning. But Clozapine's significant side effects require regular, intense monitoring to minimize mortality and morbidity. To improve current practice of clozapine prescribing and monitoring, a systematic audit of service practices against guidelines of local hospital / Monash Health Clozapine patient management guidelines and the Royal Australian and New Zealand College of Psychiatrists (RANZCP) clinical practice guidelines will identify any deficits and inform measures to overcome them.MethodsAn audit was conducted to compare the current clozapine prescribing practice and monitoring process compared with local hospital / Monash Health Clozapine patient management guidelines and RANZCP clinical practice guidelines among clozapine prescribed patients in an Australian community mental health service.ResultsMedical records of thirty-three eligible adult patients on clozapine were audited. All the patients were prescribed dosages within the recommended daily clozapine range. Clozapine was used for appropriate indications (treatment of treatment resistant-schizophrenia or schizoaffective disorder). Of the 33 patients, clozapine level was subtherapeutic on 54.5% of patients. 54.5% of patients were on an adjunct psychotropic with clozapine. Aripiprazole and sodium valproate were used by eight patients each, and nine patients were identified using selective serotonin reuptake inhibitors. The most common side effect was hypersalivation (57.6%), followed by weight gain (39.4%), sedation (21.2%) and constipation (12.1%). Monthly weight monitoring, physical examination, medical officer monthly review and full blood examination, at 97% compliance met these standards. However, monitoring of Body Mass Index (BMI) (66.7%) and six-monthly consultant reviews (42.4%) showed poor compliance (<70%) with the standards. Most metabolic blood investigations were in moderate compliance (70–90%) except for relatively high compliance for lipid profile (90.1%). Monitoring cardiac functions by echocardiogram were only 75.8% met the standard.ConclusionMost patients in this clinic receive recommended monthly monitoring practice but for BMI monitoring, six-monthly consultant review, most blood investigations and annual or 2 yearly echocardiogram findings indicated need for improvement. Polypharmacy of psychotropics increases the side effect burden and further increases the need to closely monitor the physical health and prescriptions of this cohort of patients. The next stage of this project will involve a codesign approach to developing a response to these findings that will be outlined here.
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&NA;. "Clozapine see Imipramine/clozapine." Reactions Weekly &NA;, no. 309 (July 1990): 4. http://dx.doi.org/10.2165/00128415-199003090-00013.
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Remington, Gary J., Donald Addington, Evan J. Collins, Barry D. Jones, Pierre Lalonde, Duncan J. MacCrimmon, and G. William MaCewan. "Clozapine: Current Status and Role in the Pharmacotherapy of Schizophrenia." Canadian Journal of Psychiatry 41, no. 3 (April 1996): 161–66. http://dx.doi.org/10.1177/070674379604100306.
Повний текст джерелаАнотація:
Objective: This study evaluates clozapine and its present role in the pharmacotherapy of schizophrenia. Method: Clozapine's current clinical status is reviewed, as is its position with respect to other treatment options. Results: Clozapine represents the prototype of “atypical” neuroleptics, with evidence of clinical efficacy in both positive and negative symptoms, as well as a diminished risk of extrapyramidal side effects. It is the only neuroleptic to date that has established itself as having little, if any, risk of tardive dyskinesia. More recent research has focused on its potential for overall savings in health care costs, as well as possible benefits in the area of neuropsychological functioning. Conclusion: Evidence suggesting that the course of schizophrenia can be altered by effective treatment favours a systematic approach that optimizes treatment options. While clozapine does not represent a 1st-line agent because of its risk of agranulocytosis, it has an integral role to play in treatment-resistant schizophrenia or in individuals experiencing intolerable side effects with conventional neuroleptics. Objectif: La présente étude vise à évaluer la clozapine et son rôle actuel dans la pharmacothérapie de la schizophrénie. Méthode: On évalue l'emploi clinique actuel de la clozapine ainsi que sa position par rapport à d'autres options de traitement. Résultats: La clozapine constitue le prototype des neuroleptiques «atypiques,» révélant une efficacité clinique autant sur les symptômes positifs que négatifs ainsi qu'un risque réduit d'effets secondaires extrapyramidaux. Elle constitue le seul neuroleptique à ce jour associé à peu, voire pas du tout, de risque de dyskinésie tardive. De récentes recherches se sont penchées sur son potentiel d'économies globales en soins de santé ainsi que sur ses avantages en matière de fonctionnement neuropsychologique. Conclusion: L'information qui suggère que l'évolution de la schizophrénie peut être modifiée par un traitement efficace encourage une approche systématique optimisant les options de traitement. Bien que la clozapine ne soit pas un médicament d'élection étant donné le risque d'agranulocytose, elle joue un rôle important dans le traitement de la schizophrénie résistante au traitement ou chez les personnes pour qui les effets secondaires des neuroleptiques conventionnels sont intolérables.
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de Leon, Jose, Violet Henighan, Joseph K. Stanilla, and George M. Simpson. "Clozapine Levels After Clozapine Discontinuation." Journal of Clinical Psychopharmacology 16, no. 2 (April 1996): 193–94. http://dx.doi.org/10.1097/00004714-199604000-00016.
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Edinoff, Amber N., Emily Sauce, Carolina O. Ochoa, Jordan Cross, Mark Cogburn, Elyse M. Cornett, Adam M. Kaye, Alex D. Pham, and Alan D. Kaye. "Clozapine and Constipation: A Review of Clinical Considerations and Treatment Options." Psychiatry International 2, no. 3 (September 1, 2021): 344–52. http://dx.doi.org/10.3390/psychiatryint2030026.
Повний текст джерелаАнотація:
Psychosis, a break in reality which is manifested as hallucinations, delusions or the disruption in thought process, is the hallmark of schizophrenia. Despite novel pharmacotherapy advancements of antipsychotic medications that have resulted in some patients having the ability to return to social settings and thereby decreasing psychotic symptoms and reducing hospital admissions, there is still a sub-population of patients who remain symptomatic. Treatment-resistant schizophrenia is defined as failure of treatment with at least two different antipsychotics with the proper length of treatment and titration. Clozapine has been heralded as a drug to resolve the puzzle of treatment-resistant schizophrenia. Clozapine has one side effect that is well known, being the development of agranulocytosis. However, there is another side effect that can limit clozapine’s use and can also be life-threatening. Recently, at the end of January 2020, the FDA issued a communications statement which “[strengthened] an existing warning that constipation caused by the schizophrenia medicine clozapine can, uncommonly, progress to serious bowel complications.” After identifying ten cases of constipation from between 2006 to 2016 that progressed to hospitalization, surgery, and even death, the FDA focused their attention on this often overlooked, common side effect, especially when considering the strong anticholinergic effects of clozapine. Although patients are screened by their physicians for agranulocytosis by weekly lab monitoring, constipation is also a complication that needs to be identified and treated. Much like opioid-induced constipation, constipation can also be reduced with the use of laxatives and reduction in the co-prescribing of anticholinergic therapies with clozapine.
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de Leon, Jose, Can-Jun Ruan, Hélène Verdoux, and Chuanyue Wang. "Clozapine is strongly associated with the risk of pneumonia and inflammation." General Psychiatry 33, no. 2 (April 2020): e100183. http://dx.doi.org/10.1136/gpsych-2019-100183.
Повний текст джерелаАнотація:
Clinicians need to remember that (1) systemic inflammations can increase clozapine level; (2) clozapine, by itself, can cause inflammation, particularly during titration that is too rapid for that patient; (3) clozapine may increase the risk of infection; and (4) more specifically, clozapine may be particularly strongly associated with the risk of pneumonia. Pneumonia appears to be associated with high mortality in clozapine patients around the world. Clinicians who are alert to the risk of pneumonia in clozapine patients may significantly decrease mortality in clozapine patients. There is no data on COVID-19 infections in clozapine patients, but based on what we know about clozapine pharmacology, we can hypothesise that clozapine, possibly by impairing immunological mechanisms, may increase the risk of pneumonia in infected patients. More importantly, once fever and/or pneumonia develops, the clozapine dose should be cut in half to decrease the risk of clozapine intoxication. If there is any doubt that in spite of halving the dose there are still signs of clozapine intoxication, completely stopping clozapine may be indicated. Once the signs of inflammation and fever have disappeared, the clozapine dose can be increased to the prior dosage level.
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Ktari, H., A. Ouertani, S. Madouri, A. Aissa, Y. Zgueb, U. Ouali, and R. Jomli. "Clozapine cessation." European Psychiatry 65, S1 (June 2022): S730. http://dx.doi.org/10.1192/j.eurpsy.2022.1884.
Повний текст джерелаАнотація:
Introduction Approximately 30% of individuals diagnosed with schizophrenia suffer from treatment-resistant or refractory schizophrenia. The gold standard for treatment is clozapine. However, a significant number of patients discontinue clozapine treatment and this carries a poor prognosis. Objectives This study explores patients’ motives for cessation of clozapine therapy and its prevalence. Methods A longitudinal, retrospective and descriptive study on a period of 20 years, at the psychiatry department A of the Razi hospital in Tunisia. Data was collected from the medical files of patients trated by clozapine using a pre-established sheet. Results The studied sample included 64 patient records. Treatment with clozapine was stopped spontaneously or following a medical decision in 37 patients (57.8%). The total number of clozapine stops in these 37 patients was 70. Indeed, each one of these patients had stopped treatment at least once. Clozapine was discontinued by some patients in the study sample for poor compliance(45.9%), for adverse side effects of treatment (16.2%) and by treating physicians for poor response treatment (8.1%). Clozapine was discontinued by 11 patients for hematological adverse reactions, representing 27.9% of the total number of clozapine discontinuations. Withdrawal of clozapine was indicated in 2 cases of agranulocytosis(18.2%), in 2 cases of moderate neutropenia(18.2%), in 3 cases of eosinophilia (27.2%), in 3 cases of thrombocytopenia (27.2%) and in 1 case of severe anemia (9.2%). Conclusions Clozapine discontinuation was essentially caused by poor patients’ observation and hematological adverse reactions appearance.Future research should seek to further investigate clozapine cessation factors in order to better benefit from the medical virtues of this molecule. Disclosure No significant relationships.
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Meltzer, Herbert Y. "Clozapine." Clinical Schizophrenia & Related Psychoses 6, no. 3 (October 2012): 134–44. http://dx.doi.org/10.3371/csrp.6.3.5.
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Hill, Michele, and Oliver Freudenreich. "Clozapine." Clinical Schizophrenia & Related Psychoses 6, no. 4 (January 2013): 177–85. http://dx.doi.org/10.3371/csrp.hifr.01062013.
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&NA;. "Clozapine." Reactions Weekly &NA;, no. 1377 (November 2011): 15. http://dx.doi.org/10.2165/00128415-201113770-00044.
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&NA;. "Clozapine." Reactions Weekly &NA;, no. 1383 (January 2012): 17. http://dx.doi.org/10.2165/00128415-201213830-00055.
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&NA;. "Clozapine." Reactions Weekly &NA;, no. 1384 (January 2012): 20. http://dx.doi.org/10.2165/00128415-201213840-00073.
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&NA;. "Clozapine." Reactions Weekly &NA;, no. 1384 (January 2012): 20. http://dx.doi.org/10.2165/00128415-201213840-00076.
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&NA;. "Clozapine." Reactions Weekly &NA;, no. 1385 (January 2012): 15–16. http://dx.doi.org/10.2165/00128415-201213850-00048.
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&NA;. "Clozapine." Reactions Weekly &NA;, no. 1385 (January 2012): 16. http://dx.doi.org/10.2165/00128415-201213850-00052.
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&NA;. "Clozapine." Reactions Weekly &NA;, no. 1386 (January 2012): 15. http://dx.doi.org/10.2165/00128415-201213860-00050.
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&NA;. "Clozapine." Reactions Weekly &NA;, no. 1389 (February 2012): 18. http://dx.doi.org/10.2165/00128415-201213890-00058.
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&NA;. "Clozapine." Reactions Weekly &NA;, no. 1391 (March 2012): 17. http://dx.doi.org/10.2165/00128415-201213910-00059.
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&NA;. "Clozapine." Reactions Weekly &NA;, no. 1392 (March 2012): 18. http://dx.doi.org/10.2165/00128415-201213920-00055.
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&NA;. "Clozapine." Reactions Weekly &NA;, no. 1393 (March 2012): 15–16. http://dx.doi.org/10.2165/00128415-201213930-00047.
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&NA;. "Clozapine." Reactions Weekly &NA;, no. 1394 (March 2012): 17. http://dx.doi.org/10.2165/00128415-201213940-00060.
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&NA;. "Clozapine." Reactions Weekly &NA;, no. 1395 (March 2012): 17. http://dx.doi.org/10.2165/00128415-201213950-00055.
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&NA;. "Clozapine." Reactions Weekly &NA;, no. 1395 (March 2012): 17. http://dx.doi.org/10.2165/00128415-201213950-00058.
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&NA;. "Clozapine." Reactions Weekly &NA;, no. 1396 (April 2012): 16. http://dx.doi.org/10.2165/00128415-201213960-00053.
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&NA;. "Clozapine." Reactions Weekly &NA;, no. 1396 (April 2012): 16. http://dx.doi.org/10.2165/00128415-201213960-00055.
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&NA;. "Clozapine." Reactions Weekly &NA;, no. 691 (March 1998): 7. http://dx.doi.org/10.2165/00128415-199806910-00020.
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&NA;. "Clozapine." Reactions Weekly &NA;, no. 696 (April 1998): 7. http://dx.doi.org/10.2165/00128415-199806960-00020.
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