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Clozapine
Terms modified by Clozapine Selected AbstractsAtypical antipsychotics and weightgain , a systematic reviewACTA PSYCHIATRICA SCANDINAVICA, Issue 6 2000D. M. Taylor Objective: To review systematically data relating to weight changes with atypical antipsychotics. Method: We conducted a Medline search on October 29 1999 and covered the period 1980,99. All recovered papers were examined for further relevant reports. In addition, we wrote to pharmaceutical manufacturers and 10 practising clinicians to ask them to provide other relevant reports known to them. Results: Eighty reports mentioning change in body weight were retrieved. Data relating to weight changes were of variable quality. Weight changes were indicated by a variety of measures. The majority of reports related to short-term changes. Conclusion: All atypical drugs, with the exception of ziprasidone, have been associated with weight increases. Clozapine seems to have the highest risk of weight gain, followed by olanzapine and quetiapine. There is probably a lower risk with risperidone, sertindole and zotepine and a still lower risk with amisulpride. Ziprasidone appears not to be associated with weight gain. In the absence of more compelling data, these rankings must be considered approximate and preliminary. Longer, more robust trials are needed. [source] Abstract no.: 2 The influence of clozapine on tone of isolated bovine retinal arteriesFUNDAMENTAL & CLINICAL PHARMACOLOGY, Issue 3 2005Koen Boussery Aims:, It has been suggested that the atypical antipsychotic drug clozapine might be helpful in the development of new antiglaucoma agents, since it combines lowering of the intra-ocular pressure after topical instillation with vasodilation. However, the vasoactive influence of clozapine on ocular blood vessels has never been analysed. Therefore, this study aimed to evaluate whether clozapine has direct vasodilatory effects in isolated bovine retinal arteries (BRA) and to characterise pharmacologically the mechanisms involved. Methods:, Retinal arteries were isolated from bovine eyes and mounted in a wire-myograph for isometric tension recording. Concentration-response curves were generated by cumulative addition of clozapine (1 nM to 10 ,M) to the organ bath. Results:, Clozapine elicited a concentration-dependent relaxation of the BRA. Removal of the endothelium of the BRA, inhibition of nitric oxide synthase with N, -nitro-L-arginine and inhibition of soluble guanylyl cyclase with ODQ (1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one) significantly attenuated the clozapine-response, whereas cyclo-oxygenase inhibition with indomethacin had no influence. The Ca2+ channel activator Bay k8644, the nonselective 5-hydroxytryptamine receptor antagonist methiothepin and the adenosine receptor antagonist 8-(p-sulfophenyl) theophylline also failed in affecting the clozapine-induced relaxations. Conclusion:, Clozapine clearly relaxes bovine retinal arteries in a direct way. Endothelium-derived NO is involved in this response. However, prostanoids, calcium entry blockade, 5-HT7 receptor stimulation and adenosine receptor stimulation all seem to be not involved. [source] Treatment of behavioural symptoms and dementia in Parkinson's diseaseFUNDAMENTAL & CLINICAL PHARMACOLOGY, Issue 2 2005Hasmet A. Hanagasi Abstract Behavioural symptoms such as anxiety, depression and psychosis are common in Parkinson's disease (PD), and dementia occurs in about 90% of the patients. These symptoms can be more disabling than the motor dysfunction and they negatively impact quality of life, increase caregiver distress and are more frequently associated with nursing home placement. Depression can be treated with counselling and pharmacotherapy. Tricyclic antidepressants or selective serotonin reuptake inhibitors are widely used, but there is still need for controlled clinical trials. Management of psychosis in PD is complex and includes elimination of identifiable risk factors, reduction of polypharmacy and administration of atypical neuroleptics, which can alleviate psychotic symptoms without worsening motor functions. Clozapine is the best documented atypical neuroleptic shown to be effective against psychosis in PD patients. Cholinesterase inhibitors may prove additional benefit in psychotic PD patients. Recent evidence from small double-blind and open-label trials suggests that cholinesterase inhibitors may be effective in the treatment of dementia associated with PD. [source] Haematological toxicity of drugs used in psychiatry,HUMAN PSYCHOPHARMACOLOGY: CLINICAL AND EXPERIMENTAL, Issue S1 2008Robert J. Flanagan Abstract Almost all classes of psychotropic agents have been reported to cause blood dyscrasias. Mechanisms include direct toxic effects upon the bone marrow, the formation of antibodies against haematopoietic precursors or involve peripheral destruction of cells. Agranulocytosis is probably the most important drug-related blood dyscrasia. The mortality from drug-induced agranulocytosis is 5,10% in Western countries. The manifestations of agranulocytosis are secondary to infection. Aggressive treatment with intravenous broad-spectrum antimicrobials and bone marrow stimulants may be required. Of drugs encountered in psychiatry, antipsychotics including clozapine (risk of agranulocytosis approximately 0.8%, predominantly in the first year of treatment) and phenothiazines (chlorpromazine agranulocytosis risk approximately 0.13%), and antiepileptics (notably carbamazepine, neutropenia risk approximately 0.5%) are the most common causes of drug-related neutropenia/agranulocytosis. Drugs known to cause neutropenia should not be used concomitantly with other drugs known to cause this problem. High temperature and other indicators of possible infection should be looked for routinely during treatment. Clozapine is well known as a drug that can cause blood dyscrasias, but olanzapine and other atypicals may also cause similar problems. In addition to genetic factors, there are likely to be dose-related and immunological components to these phenomena. Important lessons have been learnt from the haematological monitoring that is necessary with clozapine and the monitoring has been very successful in preventing deaths related to clozapine-induced agranulocytosis. Continuing research into the mechanisms of drug-induced neutropenia and agranulocytosis may serve to further enhance the safe use not only of clozapine, but also of other agents. Copyright © 2007 John Wiley & Sons, Ltd. [source] Clinical correlates of clozapine prescription for schizophrenia in ChinaHUMAN PSYCHOPHARMACOLOGY: CLINICAL AND EXPERIMENTAL, Issue 1 2007Yu-tao Xiang Abstract Aims Few studies have investigated the prescription patterns of clozapine in outpatients with schizophrenia in China. It is an important issue due to clozapine's high efficacy and potentially fatal side effect profile. This study examined the use of clozapine and its correlates in China. Methods Three hundred ninety-eight clinically stable outpatients with schizophrenia were randomly selected and interviewed in Hong Kong (HK) and Beijing (BJ). Assessment instruments included the Structured Clinical Interview for DSM-IV, Brief Psychiatric Rating Scale, Simpson and Angus Scale of Extrapyramidal Symptoms, Barnes Akathisia Rating Scale and the Hong Kong and Mainland China World Health Organization Quality of Life Schedule-Brief version. Assessments were performed by the same investigator in both sites. Results Clozapine was prescribed to 15.6% of (n,=,62) patients. There was a wide inter-site variation between HK and BJ. Use of clozapine was associated with age, age at onset, extrapyramidal side effects (EPS), having health insurance, use of depot and typical antipsychotic and anticholinergic drugs and benzodiazepines as well as history of suicidal attempts. On multiple logistic regression analysis, the number of hospitalizations, site (HK vs. BJ), use of typical antipsychotics, polypharmacy and co-prescription with anticholinergics were significantly associated with the prescription of clozapine. No significant differences were found between the clozapine and non-clozapine groups with regard to any of the quality of life domains. Conclusion A combination of economical and clinical factors, health policies and the characteristics of the treatment settings plays important roles in determining clozapine use. Clozapine appears to have little significant influence on quality of life in clinical stable Chinese patients with schizophrenia. Copyright © 2007 John Wiley & Sons, Ltd. [source] Myocarditis, pericarditis and cardiomyopathy in patients treated with clozapineJOURNAL OF CLINICAL PHARMACY & THERAPEUTICS, Issue 1 2005P. M. Wehmeier MD Summary Clozapine is known to cause cardiac side-effects, including myocarditis, pericarditis and cardiomyopathy. Prompted by a case of clozapine-related pericarditis in our hospital we undertook a review of the literature for reports of myocarditis, pericarditis and cardiomyopathy occurring in patients treated with clozapine. This is the first comprehensive review of the literature on this topic. [source] Clozapine treatment of psychosis associated with velo-cardio-facial syndrome: benefits and risksJOURNAL OF INTELLECTUAL DISABILITY RESEARCH, Issue 7 2005S. Gladston Abstract Background Clozapine is licensed for the treatment of psychotic illnesses resistant to other antipsychotic medications. Velo-cardio-facial syndrome (VCFS) is associated with a vulnerability to psychotic illness that may be resistant to treatment with conventional typical and atypical antipsychotics. Patients and methods A 32-year-old man with intellectual disability (ID) and a long history of treatment-resistant psychosis was found to have VCFS. Treatment with typical antipsychotic drugs and with one atypical olanzapine produced no improvement. Results Treatment with clozapine produced an improvement in psychotic symptoms and associated behavioural abnormalities, but caused hypersalivation, constipation and a seizure disorder. The latter led to two fractures, one requiring surgery. The addition of sodium valproate stopped seizures. Conclusions Clozapine may improve psychotic symptoms for people with ID associated with VCFS, but clinicians should be alert for potential adverse effects. [source] Cardiovascular magnetic resonance in mild to moderate clozapine-induced myocarditis: Is there a role in the absence of electrocardiographic and echocardiographic abnormalities?JOURNAL OF MAGNETIC RESONANCE IMAGING, Issue 6 2010Vignendra Ariyarajah MD Abstract Clozapine is an atypical, neuroleptic medication that can cause myocarditis. While the "gold standard" for diagnosis of myocarditis is perceived to be via myocardial biopsy, cardiovascular magnetic resonance (CMR) has also proven its utility in this respect, primarily through its ability to detect myocardial scar by late-gadolinium enhancement (LGE). Until recently, however, clozapine-induced myocarditis specifically has not been known to be associated with LGE on CMR. In that particular case, LGE was demonstrated in a patient with clozapine-induced myocarditis. However, quite important, that patient also had specific abnormalities on the electrocardiogram (ECG) and echocardiogram that corresponded to the area of LGE demonstrated by CMR. We highlight a case series of three patients with clozapine-induced myocarditis and provide a literature review to discuss and critically appraise the true incremental diagnostic value of CMR in such patients with normal ECG and echocardiography. J. Magn. Reson. Imaging 2010;31:1473,1476. © 2010 Wiley-Liss, Inc. [source] Clozapine in schizophrenia patients with recurrent catatonia: Report of two casesPSYCHIATRY AND CLINICAL NEUROSCIENCES, Issue 2 2006YI-YUNG HUNG md Abstract, Prolonged catatonia can be a source of extremely serious morbidity and mortality. Lorazepam is effective in rapidly relieving most cases of catatonia. Reports have also shown that second-generation antipsychotic drugs are also efficacious in relieving catatonia. This report describes two schizophrenia patients who demonstrated recurrent catatonic features mutism and stupor. Both patients were treated with lorazepam, diazepam or electroconvulsive therapy (ECT). Patient 1 responded well and rapidly to lorazepam each time catatonia happened; but catatonia recurred once a year under treatment with many antipsychotic drugs. Patient 2 had catatonia features associated with discontinuing or decreasing clozapine. With each recurrent episode, the duration of catatonia increased, requiring an increased dosage of benzodiazepine. The patient's response to lorazepam and ECT gradually decreased, until the patient had almost no response to lorazepam, diazepam or ECT. Both patients had no recurrence during a period of 2-year follow up with continuous clozapine therapy. [source] Matrix-assisted laser desorption/ionization imaging mass spectrometry for direct measurement of clozapine in rat brain tissueRAPID COMMUNICATIONS IN MASS SPECTROMETRY, Issue 6 2006Yunsheng Hsieh Matrix-assisted laser desorption/ionization hyphenated with quadrupole time-of-flight (QTOF) mass spectrometry (MS) has been used to directly determine the distribution of pharmaceuticals in rat brain tissue slices which might unravel their disposition for new drug development. Clozapine, an antipsychotic drug, and norclozapine were used as model compounds to investigate fundamental parameters such as matrix and solvent effects and irradiance dependence on MALDI intensity but also to address the issues with direct tissue imaging MS technique such as (1) uniform coating by the matrix, (2) linearity of MALDI signals, and (3) redistribution of surface analytes. The tissue sections were coated with various matrices on MALDI plates by airspray deposition prior to MS detection. MALDI signals of analytes were detected by monitoring the dissociation of the individual protonated molecules to their predominant MS/MS product ions. The matrices were chosen for tissue applications based on their ability to form a homogeneous coating of dense crystals and to yield greater sensitivity. Images revealing the spatial localization in tissue sections using MALDI-QTOF following a direct infusion of 3H-clozapine into rat brain were found to be in good correlation with those using a radioautographic approach. The density of clozapine and its major metabolites from whole brain homogenates was further confirmed using fast high-performance liquid chromatography/tandem mass spectrometry (HPLC-MS/MS) procedures. Copyright © 2006 John Wiley & Sons, Ltd. [source] Comparison of clozapine and haloperidol on some autonomic and psychomotor functions, and on serum prolactin concentration, in healthy subjectsBRITISH JOURNAL OF CLINICAL PHARMACOLOGY, Issue 3 2001J. L. Pretorius Aims To compare the autonomic, neuroendocrine and psychomotor effects of single doses of the ,atypical' antipsychotic clozapine and the ,classical' antipsychotic haloperidol, in healthy male volunteers. Methods Clozapine (50 mg), haloperidol (3 mg) and placebo were administered to 12 healthy male volunteers at weekly intervals, according to a balanced double-blind design. Resting pupil diameter, salivary output, heart rate, blood pressure, plasma prolactin concentration, critical flicker fusion frequency and subjective ,alertness', ,contentedness' and ,anxiety' were measured at baseline and 2, 3, 4 and 5 h after drug ingestion. Data were analysed by analysis of variance with individual comparisons (Dunnett's test) with a significance criterion of P < 0.05. Results Significant treatment effects (difference from placebo [mean, 95% CI] 5 h after drug ingestion) were as follows: clozapine reduced pupil diameter (mm; ,3.02 [,3.56, ,2.47]), salivary output (g; ,0.34 [,0.60, ,0.08]), mean arterial blood pressure (mm Hg; ,8.7 [,14.3, ,3.1]), critical flicker fusion frequency (Hz; ,3.26 [,3.94, ,2.58]), and subjectively-rated ,alertness' (mm; ,20.94 [,29.21, ,12.67]) and ,contentedness' (mm; ,12.98 [,17.90, ,8.06]), whereas haloperidol increased prolactin concentration (mU l,1; 301.3 [196.7, 405.8]) and caused small reductions in pupil diameter (mm; ,0.68 [,1.23, ,0.14]), mean arterial blood pressure (mm Hg; ,7.0 [,12.6, ,1.4]) and critical flicker fusion frequency (Hz; ,1.15 [,1.83, ,0.47]). Conclusions The effects of the antipsychotics are in agreement with their receptor binding profiles: ,1 -adrenoceptor blockade by clozapine may contribute to reductions in pupil diameter, salivation, mean arterial blood pressure and sedation, and muscarinic cholinoceptor blockade by the drug may underlie the reduction in salivation. Conversely, D2 dopamine receptor blockade by haloperidol is likely to be responsible for the increase in prolactin secretion evoked by the drug. [source] Effects of phencyclidine (PCP) and MK 801 on the EEGq in the prefrontal cortex of conscious rats; antagonism by clozapine, and antagonists of AMPA-, ,1 - and 5-HT2A -receptorsBRITISH JOURNAL OF PHARMACOLOGY, Issue 1 2002Claude Sebban The electroencephalographic (EEG) effects of the propsychotic agent phencyclidine (PCP), were studied in conscious rats using power spectra (0 , 30 Hz), from the prefrontal cortex or sensorimotor cortex. PCP (0.1 , 3 mg kg,1 s.c.) caused a marked dose-dependent increase in EEG power in the frontal cortex at 1 , 3 Hz with decreases in power at higher frequencies (9 , 30 Hz). At high doses (3 mg kg,1 s.c.) the entire spectrum shifted to more positive values, indicating an increase in cortical synchronization. MK 801 (0.05 , 0.1 mg kg,1 i.p.) caused similar effects but with lesser changes in power. In contrast, the non-competitive AMPA antagonists GYKI 52466 and GYKI 53655 increased EEG power over the whole power spectrum (1 , 10 mg kg,1 i.p.) The atypical antipsychotic clozapine (0.2 mg kg,1 s.c.) synchronized the EEG (peak 8 Hz). The 5-HT2A -antagonist, M100907, specifically increased EEG power at 2 , 3 Hz at low doses (10 and 50 ,g kg÷1 s.c.), whereas at higher doses (0.1 mg kg,1 s.c.) the profile resembled that of clozapine. Clozapine (0.2 mg kg,1 s.c.), GYKI 53655 (5 mg kg,1 i.p.), prazosin (0.05 and 0.1 mg kg,1 i.p.), and M100907 (0.01 and 0.05 mg kg,1 s.c.) antagonized the decrease in power between 5 and 30 Hz caused by PCP (1 mg kg,1 s.c.), but not the increase in power at 1 , 3 Hz in prefrontal cortex. British Journal of Pharmacology (2002) 135, 65,78; doi:10.1038/sj.bjp.0704451 [source] A retrospective evaluation of the impact of total smoking cessation on psychiatric inpatients taking clozapineACTA PSYCHIATRICA SCANDINAVICA, Issue 5 2010I. Cormac Cormac I, Brown A, Creasey S, Ferriter M, Huckstep B. A retrospective evaluation of the impact of total smoking cessation on psychiatric inpatients taking clozapine. Objective:, To investigate the effect of a complete smoking ban on a group of psychiatric inpatients maintained on the antipsychotic medication clozapine. Method:, Retrospective data on clozapine dose and plasma levels were collected from a three month period before and a six month period after the introduction of the smoking ban. Results:, Before the ban only 4.2% of patients who smoked had a plasma clozapine level ,1000 ,g/l but after the ban this increased to 41.7% of the sample within the six month period following the ban despite dose reductions. Conclusion:, Abrupt cessation of smoking is associated with a potentially serious risk of toxicity in patients taking clozapine. Plasma clozapine levels must be monitored closely and adjustments made in dosage, if necessary, for at least six months after cessation. [source] Augmentation of clozapine with a second antipsychotic , a meta-analysis of randomized, placebo-controlled studiesACTA PSYCHIATRICA SCANDINAVICA, Issue 6 2009D. M. Taylor Objective:, Inadequate response to clozapine treatment is frequently encountered in practice and augmentation strategies have been developed in an attempt to improve response. Aims of the study were to evaluate the therapeutic effect of adding an antipsychotic drug to clozapine treatment. Method:, Meta-analysis of randomized, placebo-controlled studies of antipsychotic augmentation of clozapine treatment. Results:, Ten studies (including 522 subjects) met inclusion criteria. Antipsychotic augmentation showed significant benefit over the addition of placebo on only one outcome measure examined [mean effect size for rating scale score (BPRS/PANSS) ,0.180, 95% CI ,0.356 to ,0.004]. Antipsychotic augmentation showed no advantage on withdrawals from trials (risk ratio 1.261, 95% CI 0.679,2.345) or on CGI scores (effect size ,0.661, 95% CI ,1.475 to 0.151). Duration of study was not associated with outcome (P = 0.95). There was no evidence of publication bias. Conclusion:, In studies lasting up to 16 weeks, the addition of an antipsychotic to clozapine treatment has marginal therapeutic benefit. Longer and larger trials are necessary to demonstrate the precise therapeutic utility of antipsychotic co-therapy with clozapine. [source] A double-blind, placebo-controlled trial of rosiglitazone for clozapine-induced glucose metabolism impairment in patients with SchizophreniaACTA PSYCHIATRICA SCANDINAVICA, Issue 6 2009D. C. Henderson Objective:, The primary purpose of this 8-week double-blind, placebo-controlled trial of rosiglitazone 4 mg/day was to examine its effect on insulin sensitivity index (SI) and glucose utilization (SG) in clozapine-treated subjects with schizophrenia with insulin resistance. Method:, Eighteen subjects were randomized and accessed with a Frequently Sampled Intravenous Glucose Tolerance Test (FSIVGTT) at baseline and at week 8 to estimate SG and SI. Results:, Controlling for the baseline, comparing the rosiglitazone group with placebo group, there was a non-significant improvement in SG (0.016 ± 0.006,0.018 ± 0.008, effect size = 0.23, P = 0.05) with a trend of improvement in SI in the rosiglitazone group (4.6 ± 2.8,7.8 ± 6.7, effect size = 0.18, P = 0.08). There was a significant reduction in small low-density lipoprotein cholesterol (LDL-C) particle number (987 ± 443,694 ± 415, effect size = 0.30, P = 0.04). Conclusion:, Rosiglitazone may have a role in addressing insulin resistance and lipid abnormalities associated with clozapine. [source] A 12-month follow-up study of treating overweight schizophrenic patients with aripiprazoleACTA PSYCHIATRICA SCANDINAVICA, Issue 3 2008S. G. Schorr Objective:, To investigate the feasibility of switching overweight schizophrenic patients to aripiprazole and to assess the impact of 12 months of aripiprazole treatment on weight in routine practice. Method:, This was a non-controlled cohort study in overweight schizophrenic patients. Data were collected before treatment with aripiprazole was started and at 12-month follow-up. Results:, A total of 53 patients were included; of these 55% continued using aripiprazole for 12 months. Aripiprazole treatment for 12 months (P = 0.027) and stopping clozapine or olanzapine treatment (P = 0.038) predicted weight loss (,3 kg). Patients receiving aripiprazole monotherapy (n = 16, mean ,3.0 kg) had similar weight loss than patients receiving aripiprazole in addition to another antipsychotic drug (n = 13, mean ,4.4 kg). Conclusion:, In routine practice once aripiprazole treatment was started, more than half of the patients remained on aripiprazole and most of them lost weight. Adding aripiprazole to clozapine gave similar weight loss as monotherapy with aripiprazole. [source] Weight gain in bipolar disorder: pharmacological treatment as a contributing factorACTA PSYCHIATRICA SCANDINAVICA, Issue 1 2008C. Torrent Objective:, The aim of this paper was to review the association of most commonly used psychopharmacological drugs with weight gain in bipolar disorder. Method:, Information was retrieved from a PubMed/Medline literature search reviewing weight gain in pharmacological studies in bipolar disorder. Results:, Obesity and overweight in bipolar disorder are partly related to prescribed drugs with a strong effect of clozapine and olanzapine. Lesser but still relevant weight gain is caused by quetiapine, risperidone, lithium, valproate, gabapentin and by some antidepressants. Ziprasidone, aripiprazole, carbamazepine and lamotrigine do not seem to cause significant overweight. Conclusion:, Careful monitoring of weight changes in patients before and after drug prescription should be implemented in the clinical routine and drugs which potentially cause weight gain should be avoided in overweight patients with bipolar disorder. Furthermore, eating habits and daily activities should be targeted as they may also have a significant impact on overall health and weight-related issues. [source] Does antipsychotic withdrawal provoke psychosis?ACTA PSYCHIATRICA SCANDINAVICA, Issue 1 2006Review of the literature on rapid onset psychosis (supersensitivity psychosis), withdrawal-related relapse Objective:, To examine the evidence that discontinuation of long-term antipsychotic medication, including clozapine, may provoke a psychotic episode. Method:, Databases were searched and citations scrutinised. Results:, Evidence for a rapid onset psychosis (supersensitivity psychosis) following clozapine withdrawal was found and weaker evidence that this might occur with some other antipsychotic drugs. Some cases were reported in people without a psychiatric history. It appears that the psychosis may be a feature of drug withdrawal rather than the re-emergence of an underlying illness, at least in some patients. Meta-analyses of withdrawal studies have suggested that antipsychotic discontinuation may also increase the risk of relapse over and above the risk because of the underlying disorder, but not all individual studies show this effect. Mechanisms may relate to brain adaptations to long-term drug use but data are sparse. Conclusion:, These effects require further urgent research. Interventions to reduce morbidity after drug withdrawal need to be developed. [source] Medication decisions and clinical outcomes in the Canadian National Outcomes Measurement Study in SchizophreniaACTA PSYCHIATRICA SCANDINAVICA, Issue 2006R. Williams Objective:, To evaluate over a 2-year period, patients from academic/non-academic centres, from each region of Canada, to determine whether location or other variables such as medication type, gender or income was associated with outcome as defined by non-hospitalization and persistence on original treatment. Method:, A total of 448 patients were recruited from academic and non-academic centres across all provinces of Canada and followed up for 2 years. Results:, Patients from British Columbia had significantly lower rates of hospitalization than patients from other provinces. Male patients showed greater symptomatic improvement at 2 years from initial assessment compared to females. Patients on clozapine, risperidone and olanzapine were least likely to be hospitalized. Conclusion:, There were some regional differences noted in both utilization of types of antipsychotic medications and hospitalization rates. In this sample of stable out-patients over 70% who started on monotherapy with clozapine, risperidone, olanzapine and quetiapine remained on the same medication over the 2-year study period. [source] Antipsychotic combination therapy in schizophrenia.ACTA PSYCHIATRICA SCANDINAVICA, Issue 5 2002A review of efficacy, risks of current combinations Objective:, To review the literature on efficacy and risks of combining antipsychotics (atypical with atypical or conventional) and suggest a rationale and strategies for future clinical trials. Method:, A computerized Medline search supplemented by an examination of cross-references and reviews was performed. Results:, Empirical evidence for the efficacy of combining antipsychotics is too limited to draw firm conclusions. The practice of augmenting clozapine with more ,tightly bound' D2 receptor antagonists as exemplified by risperidone augmentation of clozapine has some empirical and theoretical support. The risks of augmentation strategies have not been studied systematically. No study has examined the economic impact of combination treatment. Conclusion:, Further trials of antipsychotic combination therapies are needed before this currently unsupported practice can be recommended. Rationales for combination treatment include a broadening of the range of receptor activity or an increase in D2 receptor occupancy with certain atypical agents. Trial methodology needs to take into account subject characteristics, duration of treatment, optimization of monotherapy comparators, and appropriate outcome measures. [source] Augmentation with sulpiride for a schizophrenic patient partially responsiveto clozapineACTA PSYCHIATRICA SCANDINAVICA, Issue 5 2000Jean H. Stubbs Objective:,Schizophrenic patients who are only partially responsive to clozapine pose a therapeutic challenge. In these circumstances some clinicians would consider adding in a second antipsychotic. We present a case report and review evidence for the efficacy of such augmentation strategies. Method:,Single case report and literature review. Results:,The total number of patients in studies and case reports of combining clozapine with other antipsychotics is small. There has been only one randomized controlled trial. This found the addition of sulpiride to clozapine resulted in clinical improvement in some patients. Conclusion:,Further randomized controlled studies of augmentation of clozapine therapy are needed to provide scientific justification for this clinical practice. [source] Early intervention with second-generation antipsychotics in first-episode psychosis: results of an 8-week naturalistic studyEARLY INTERVENTION IN PSYCHIATRY, Issue 1 2010Richard C. Josiassen Abstract Objective: The objective was to compare short-term effectiveness of aripiprazole with three other second-generation antipsychotics (SGAs) in the treatment of first-episode psychosis. Method: In a naturalistic, ,single-blind' design, 60 subjects experiencing their first psychotic episode were treated for 8 weeks with aripiprazole (n = 19), risperidone (n = 16), olanzapine (n = 14) or quetiapine (n = 11). Medication and dosing decisions were made by treating psychiatrists, constrained to once-a-day dosing, low initial doses and no clozapine. Weekly ratings were obtained using the Positive and Negative Syndrome Scale (PANSS), Simpson-Angus Rating Scale and Barnes Akathasia Rating Scale. Weight and vital signs were also collected weekly. Results: The group presented with severe psychotic symptoms (mean baseline PANSS total score of 105.2), which were reduced rapidly (P < 0.0005). The between-group and group by time interaction terms were non-significant. Similar reductions were seen across all PANSS sub-scales. At Week 1 the mean PANSS Activation Scale score was reduced more with olanzapine than in the other groups (P < 0.002). Few instances of extrapyramidal symptoms occurred; all were sporadic and did not require treatment. Group body weight increased by 7.3% over the study. Vital signs remained unchanged. Conclusions: Early intervention with low doses of four SGAs led to rapid symptom reduction in first-episode psychotic patients with severe psychopathology. Although no clear medication advantages were observed in the short term, longer duration studies with larger samples will be required for determining efficacy, rates of compliance, relapse prevention and diminished incidence of extrapyramidal signs and symptoms. [source] Electrophysiological characterization of laminar synaptic inputs to the olfactory tubercle of the rat studied in vitro: modulation of glutamatergic transmission by cholinergic agents is pathway-specificEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 9 2001G. S. Owen Abstract We have exploited the complementary arrangement of afferents in a coronal slice (300,400 µm) of the rat olfactory tubercle (OT) maintained in vitro to investigate transmission in two separate synaptic pathways. We recorded extracellular responses within the OT dense cell layer in slices and stimulated either the outermost layer to activate primary olfactory fibres or deeper to activate secondary input. Superficial stimulation produced a synaptic potential with superimposed population spike. This interpretation was based on blockade by calcium removal from the bathing medium and the use of the glutamate antagonist DNQX (10 µm); the spike was found to be selectively suppressed by tetrodotoxin applied near the cells. The spike, but not the synaptic wave, was depressed by 12 mm Ca2+ and enhanced by 1 mm Ba2+ in the bathing medium. Deep stimulation to activate association and intrinsic fibres elicited a nerve volley followed by a later response, also blocked by Ca2+ removal or 10 µm DNQX. It was unaffected by high Ca2+ or Ba2+, hence resulting from synaptic and not action current flow. Removal of Mg2+ from the bathing medium revealed an NMDA component of synaptic transmission at both loci that was selectively blocked by D-AP-5. The deep synaptic response, only, was depressed by carbachol IC50 7 µm or muscarine IC50 13 µm. This depression was also induced by AChE inhibitors eserine or tacrine and was antagonized by 1 µm atropine or 5,10 µm clozapine. These results characterize transmission in the OT and demonstrate a role for muscarinic modulation of deeper synapses in the OT that is influenced by psychotherapeutic drugs. [source] Abstract no.: 2 The influence of clozapine on tone of isolated bovine retinal arteriesFUNDAMENTAL & CLINICAL PHARMACOLOGY, Issue 3 2005Koen Boussery Aims:, It has been suggested that the atypical antipsychotic drug clozapine might be helpful in the development of new antiglaucoma agents, since it combines lowering of the intra-ocular pressure after topical instillation with vasodilation. However, the vasoactive influence of clozapine on ocular blood vessels has never been analysed. Therefore, this study aimed to evaluate whether clozapine has direct vasodilatory effects in isolated bovine retinal arteries (BRA) and to characterise pharmacologically the mechanisms involved. Methods:, Retinal arteries were isolated from bovine eyes and mounted in a wire-myograph for isometric tension recording. Concentration-response curves were generated by cumulative addition of clozapine (1 nM to 10 ,M) to the organ bath. Results:, Clozapine elicited a concentration-dependent relaxation of the BRA. Removal of the endothelium of the BRA, inhibition of nitric oxide synthase with N, -nitro-L-arginine and inhibition of soluble guanylyl cyclase with ODQ (1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one) significantly attenuated the clozapine-response, whereas cyclo-oxygenase inhibition with indomethacin had no influence. The Ca2+ channel activator Bay k8644, the nonselective 5-hydroxytryptamine receptor antagonist methiothepin and the adenosine receptor antagonist 8-(p-sulfophenyl) theophylline also failed in affecting the clozapine-induced relaxations. Conclusion:, Clozapine clearly relaxes bovine retinal arteries in a direct way. Endothelium-derived NO is involved in this response. However, prostanoids, calcium entry blockade, 5-HT7 receptor stimulation and adenosine receptor stimulation all seem to be not involved. [source] Metabolic drug interactions with new psychotropic agentsFUNDAMENTAL & CLINICAL PHARMACOLOGY, Issue 5 2003Edoardo Spina Abstract New psychotropic drugs introduced in clinical practice in recent years include new antidepressants, such as selective serotonin reuptake inhibitors (SSRI) and ,third generation' antidepressants, and atypical antipsychotics, i.e. clozapine, risperidone, olanzapine, quetiapine, ziprasidone and amisulpride. These agents are extensively metabolized in the liver by cytochrome P450 (CYP) enzymes and are therefore susceptible to metabolically based drug interactions with other psychotropic medications or with compounds used for the treatment of concomitant somatic illnesses. New antidepressants differ in their potential for metabolic drug interactions. Fluoxetine and paroxetine are potent inhibitors of CYP2D6, fluvoxamine markedly inhibits CYP1A2 and CYP2C19, while nefazodone is a potent inhibitor of CYP3A4. These antidepressants may be involved in clinically significant interactions when coadministered with substrates of these isoforms, especially those with a narrow therapeutic index. Other new antidepressants including sertraline, citalopram, venlafaxine, mirtazapine and reboxetine are weak in vitro inhibitors of the different CYP isoforms and appear to have less propensity for important metabolic interactions. The new atypical antipsychotics do not affect significantly the activity of CYP isoenzymes and are not expected to impair the elimination of other medications. Conversely, coadministration of inhibitors or inducers of the CYP isoenzymes involved in metabolism of the various antipsychotic compounds may alter their plasma concentrations, possibly leading to clinically significant effects. The potential for metabolically based drug interactions of any new psychotropic agent may be anticipated on the basis of knowledge about the CYP enzymes responsible for its metabolism and about its effect on the activity of these enzymes. This information is essential for rational prescribing and may guide selection of an appropriate compound which is less likely to interact with already taken medication(s). [source] Genetic association between TNF-, ,308 G>A polymorphism and longitudinal weight change during clozapine treatmentHUMAN PSYCHOPHARMACOLOGY: CLINICAL AND EXPERIMENTAL, Issue 4 2010Ying-Chieh Wang Abstract Objective The aim of the study was to investigate the association between genetic variation in the tumor necrosis factor-alpha (TNF-,) gene and longitudinal weight change during long-term clozapine treatment. Methods Fifty-five patients with refractory schizophrenia treated with clozapine for 8 years were recruited. Gender, age, treatment response to clozapine in the first 14 months, baseline BMI, clozapine dose, concomitant use of mood stabilizers and other antipsychotics, and ,308 G,>,A polymorphism in the human TNF-, gene were analyzed using generalized estimating equations. Results In addition to having a lower baseline BMI (p,=,0.0013) and a longer treatment time (p,=,0.050), the ,308 GG carriers gained significantly more weight than the ,308 A allele carriers (p,=,0.0084) during 8 years of clozapine treatment, after controlling for other non-genetic factors. Conclusions The ,308 G,>,A genetic variant of the TNF-, gene is associated with longitudinal weight change during clozapine treatment. Follow-up duration is an important factor to consider when performing pharmacogenetic study of clozapine-induced weight gain. Copyright © 2010 John Wiley & Sons, Ltd. [source] Augmentation of atypical antipsychotics with valproic acid.HUMAN PSYCHOPHARMACOLOGY: CLINICAL AND EXPERIMENTAL, Issue 8 2009An open-label study for most difficult patients with schizophrenia Abstract Objective Most difficult inpatients with schizophrenia are in serious needs but obviously underrepresented in clinical trials. Methods Very challenging patients received open-label treatment with atypical antipsychotics concurrently augmented with valproic acid. The primary outcome was the newly developed Functional Assessment for Comprehensive Treatment of Schizophrenia (FACT-Sz). Patients improving more than 20 points were classified as responders. Results Mean age and illness duration of 28 participants (22male) were 42 y.o. and 20 years, respectively. They had spent a half of their life admitted after the onset. The average Brief Psychiatric Rating Scale (BPRS) and Clinical Global Impression-Severity (CGI-S) were very severe at 79 and 6.1, respectively, with the baseline Global Assessment of Functioning (GAF) of as low as 21. As a result of augmentation, there were nine responders, 12 partial responders, and seven non-responders including only two patients who got worse. The main antipsychotics were mostly either risperidone or olanzapine. Mean maximum oral dose and blood level of valproic acid were 1907,mg and 91.7,µg/ml, respectively. Overall significant improvements whilst to an inadequate degree were noted in clinical parameters. Valproate augmentation was generally well tolerated but serious adverse effects included thrombocytopenia, anaemia and sedation/falls. Conclusions While these preliminary results need to be tested against tenacious monotherapy or polypharmacy involving clozapine, augmenting atypical antipsychotics with valproic acid can be useful for very severe schizophrenia. Copyright © 2009 John Wiley & Sons, Ltd. [source] Effectiveness of antipsychotic polypharmacy for patients with treatment refractory schizophrenia: an open-label trial of olanzapine plus risperidone for those who failed to respond to a sequential treatment with olanzapine, quetiapine and risperidoneHUMAN PSYCHOPHARMACOLOGY: CLINICAL AND EXPERIMENTAL, Issue 6 2008Takefumi Suzuki Abstract Objective To evaluate the effectiveness of antipsychotic polypharmacy in a methodologically sound manner. Methods In this open-label study, 17 patients with treatment-refractory schizophrenia, who failed to respond to a sequential monotherapy with olanzapine, quetiapine and risperidone, were subsequently treated with a combination therapy with olanzapine plus risperidone for at least 8 weeks. Results Seven responded according to the primary endpoint defined as the post-treatment Brief Psychiatric Rating Scale being less than 70% of the pretreatment values, and they were classified as such an average of 10 weeks after the initiation of polypharmacy. Two of them were successful in a later conversion to monotherapy. None dropped out prematurely. Four (out of 13 inpatients) got better enough to be discharged from the hospital, while six patients did not show any response. The Global Assessment of Functioning score improved from 37.1 to 53.0 in responders (mean maximum dose: olanzapine 12.9,mg; risperidone 3.14,mg), while it showed non-significant changes among others (mean maximum dose: olanzapine 14.5,mg; risperidone 5.50,mg). Body weight, prolactin, and total cholesterol increased significantly. Conclusions Antipsychotic polypharmacy might be sometimes helpful for difficult populations but at the cost of adverse effects. More studies of antipsychotic combination therapy versus clozapine, augmentation strategies or tenacious longer- term monotherapy are warranted for refractory schizophrenia. Copyright © 2008 John Wiley & Sons, Ltd. [source] Cardiac side effects of psychiatric drugs,HUMAN PSYCHOPHARMACOLOGY: CLINICAL AND EXPERIMENTAL, Issue S1 2008Paul Mackin Abstract This review describes the common effects of psychotropic drugs on the cardiovascular system and offers guidance for practical management. Selected reports from the literature describing common side effects associated with psychotropic drugs are reviewed, and suggestions for further reading are given throughout the text. Orthostatic hypotension is the most common adverse autonomic side effect of antipsychotic drugs. Among the atypical antipsychotics the risk of orthostatic hypotension is highest with clozapine and among the conventional drugs the risk is highest with low potency agents. Rarely, orthostatic hypotension may result in neurocardiogenic syncope. QTc prolongation can occur with all antipsychotics but an increased risk is seen with pimozide, thioridazine, sertindole and zotepine. QTc prolongation is a marker of arrhythmic risk. Torsade de pointe, a specific arrhythmia, may lead to syncope, dizziness or ventricular fibrillation and sudden death. Heart muscle disease presents most commonly in the elderly as chronic heart failure, but myocarditis and cardiomyopathy, although relatively rare, are devastating, but potentially reversible complications of psychotropic drug therapy have been particularly linked to clozapine treatment. Patients with severe mental illness (SMI) are a ,high risk' population with regard to cardiovascular morbidity and mortality. It is probable that many patients accumulate an excess of ,traditional' risk factors for the development of cardiovascular disease, but other mechanisms including psychotropic drugs may also be influential in increasing risk in this vulnerable group. These risks need to be seen in the context of the undoubted therapeutic efficacy of the psychotropic armamentarium and the relief that these drugs bring to those suffering from mental disorder. Copyright © 2007 John Wiley & Sons, Ltd. [source] Neurological complications of psychiatric drugs: clinical features and management,HUMAN PSYCHOPHARMACOLOGY: CLINICAL AND EXPERIMENTAL, Issue S1 2008Peter M. Haddad Abstract This paper reviews the main neurological complications of psychiatric drugs, in particular antipsychotics and antidepressants. Extrapyramidal syndromes include acute dystonia, parkinsonism, akathisia, tardive dyskinesia and tardive dystonia. Extrapyramidal symptoms (EPS) are less frequent with atypical than with conventional antipsychotics but remain common in clinical practice partly due to lack of screening by health professionals. Neuroleptic malignant syndrome (NMS) consists of severe muscle rigidity, pyrexia, change in conscious level and autonomic disturbance but partial forms also occur. NMS is particularly associated with the initiation and rapid increase in dose of high-potency antipsychotics but it has been reported with all the atypical antipsychotics and rarely with other drugs including antidepressants. Serotonin toxicity comprises altered mental state (agitation, excitement, confusion), neuromuscular hyperactivity (tremor, clonus, myoclonus, hyper-reflexia) and autonomic hyperactivity and occurs on a spectrum. Severe cases, termed serotonin syndrome, usually follow the co-prescription of drugs that increase serotonergic transmission by different pathways, for example a monoamine oxidase inhibitor (MAOI) and a selective serotonin reuptake inhibitor (SSRI). Most antipsychotics and antidepressants lower the seizure threshold and can cause seizures; the risk is greater with clozapine than with other atypical antipsychotics and greater with tricyclic antidepressants (TCAs) than with SSRIs. In randomised controlled trials in elderly patients with dementia atypical antipsychotics are associated with a higher risk of stroke and death than placebo. Cohort studies suggest that conventional drugs carry at least the same risk. Cessation of treatment with antipsychotics and antidepressants can lead to a wide range of discontinuation symptoms which include movement disorders and other neurological symptoms. Clinicians need to be familiar with strategies to reduce the risk of these adverse events and to manage them when they arise. Their occurrence needs to be balanced against the benefits of psychiatric drugs in terms of efficacy and improved quality of life in a range of disorders. Copyright © 2007 John Wiley & Sons, Ltd. [source] | |||||||||||||||||||||||||||||||||||||