The Experts below are selected from a list of 42114 Experts worldwide ranked by ideXlab platform
David Taylor - One of the best experts on this subject based on the ideXlab platform.
-
management of Clozapine treatment during the covid 19 pandemic
Therapeutic Advances in Psychopharmacology, 2020Co-Authors: Siobhan Gee, Eromona Whiskey, James H Maccabe, Sukhi Shergill, Fiona Gaughran, David TaylorAbstract:Clozapine is the only available treatment for refractory schizophrenia but its use involves frequent physical contact with healthcare workers for the purpose of mandatory blood monitoring. During the COVID-19 pandemic, patients taking Clozapine will be self-isolating to reduce the risk of infection, not least because these patients are at high risk of serious illness and fatality because of high rates of diabetes, obesity and pulmonary disease and an increased risk of pneumonia. Problems may also arise because both Clozapine-induced myocarditis and neutropenic sepsis share signs and symptoms with COVID-19 (fever, chest pain, dyspnoea, etc.). We recommend decreasing the frequency of physical contacts by extending the blood monitoring interval to 12 weeks in those patients taking Clozapine for more than 1 year. To distinguish COVID-19 from Clozapine-related physical adverse effects, we suggest an urgent antigen test alongside a full blood count. In those taking Clozapine who develop COVID-19, we suggest continuing with Clozapine whenever possible (even during ventilation), reducing the dose if necessary in line with blood assay results. Blood monitoring should continue but Clozapine should only cease if there is a significant fall in neutrophils (COVID-19 is linked to lymphopenia but not neutropenia). To protect against the likelihood and severity of respiratory infection, we recommend the use of vitamin D in all Clozapine patients. Initiation of Clozapine is likely to remain problematic while the risk of infection remains, given the degree of physical contact required to assure safety.
-
Patient attitudes to Clozapine initiation.
International Clinical Psychopharmacology, 2017Co-Authors: Siobhan Gee, Sukhwinder S. Shergill, David TaylorAbstract:Clozapine is widely underused. No study has assessed views of patients suitable for, but not yet receiving, Clozapine. We aimed to assess views of Clozapine in patients eligible for Clozapine but not yet prescribed it by conducting semistructured interviews with acutely unwell hospital in-patients. We interviewed 61 of 116 eligible patients and 50 (82%) answered all questions. At interview, 33 (54%) of 61 participants had heard of Clozapine and 17 (30%) of 57 participants said they would take it if asked. Overall, 31 (57%) of 54 respondents said blood testing would not preclude them taking Clozapine. The necessity for hospital admission was seen as the greatest barrier to receiving Clozapine - 25 (49%) of 51 respondents stated this would be a reason for their refusing Clozapine. Concerns about adverse effects of Clozapine were considered sufficient to refuse Clozapine in 23 (43.4%) of 53 respondents. Overall, 12 (24%) of 50 respondents felt that Clozapine would be helpful to them. Patients' acceptance of Clozapine is likely to be improved by offering the opportunity to start Clozapine at home and by improved education about the therapeutic benefits of Clozapine and the management of its adverse effects. Blood testing does not appear to be an important barrier to the initiation of Clozapine.
-
Practitioner attitudes to Clozapine initiation.
Acta Psychiatrica Scandinavica, 2013Co-Authors: Siobhan Gee, Oliver D Howes, F. Vergunst, David TaylorAbstract:Objective Clozapine is the most effective antipsychotic for treatment-resistant schizophrenia. It is recommended as third-line treatment for schizophrenia in national and local guidelines. Despite this, it is underutilised. This survey aimed to clarify barriers to prescribing and elucidate factors that may improve patient access to Clozapine. Method A questionnaire was made available to all staff members at South London and Maudsley NHS Foundation Trust. Results In total, 144 clinical staff completed the questionnaire. The majority (81%) of respondents were ‘fairly’ or ‘very’ familiar with Clozapine prescribing guidelines. Barriers to prescribing most commonly stated as being ‘very frequently’ a problem were patient concerns about tolerability of Clozapine or patient refusal to adhere to blood test monitoring. Staff members also felt medical complications frequently prevented Clozapine prescription. Dedicated staff or day hospital placements devoted to Clozapine initiation were identified as factors most likely to increase prescribing of Clozapine. Conclusion Professionals identified the dominant barriers to prescribing as being patient focussed – refusal of blood test monitoring or concerns about tolerability. Clinician fears about compliance or medical complications were also important. The development of out-patient services specifically tasked with initiating Clozapine may help to increase the frequency of prescribing of Clozapine earlier in treatment than is currently seen.
-
adherence to treatment guidelines in clinical practice study of antipsychotic treatment prior to Clozapine initiation
British Journal of Psychiatry, 2012Co-Authors: Oliver D Howes, Siobhan Gee, Francis Vergunst, Philip Mcguire, Shitij Kapur, David TaylorAbstract:Background Clozapine is the only antipsychotic drug licensed for treatment-resistant schizophrenia but its use is often delayed. Since previous studies, national guidelines on the use of Clozapine and other antipsychotics have been disseminated to clinicians. Aims To determine the theoretical delay to Clozapine initiation and to quantify the prior use of antipsychotic polypharmacy and high-dose antipsychotic treatment. Method Clinico-demographic data were extracted from the treatment records of all patients commencing Clozapine in our centre between 2006 and 2010. Results Complete records were available for 149 patients. The mean theoretical delay in initiating Clozapine was 47.7 months (s.d. = 49.7). Before commencing Clozapine, antipsychotic polypharmacy and high-dose treatment was evident in 36.2 and 34.2% of patients respectively. Theoretical delay was related to illness duration (β = 0.7, P <0.001) but did not differ by gender or ethnicity. Conclusions Substantial delays to Clozapine initiation remain and antipsychotic polypharmacy and high doses are commonly used prior to Clozapine, despite treatment guidelines.
-
Clozapine-related EEG Changes and Seizures: Dose and Plasma-Level Relationships
Therapeutic Advances in Psychopharmacology, 2011Co-Authors: Seema Varma, Delia Bishara, Frank Besag, David TaylorAbstract:Clozapine is a widely used atypical antipsychotic with a unique effectiveness in treatment-resistant schizophrenia. An important adverse effect is seizures, which have been observed at all stages of Clozapine treatment. Valproate has traditionally been considered the drug of choice for the prophylaxis of Clozapine seizures, however it may not be the most suitable choice for all patients. There is disagreement as to the best point to prescribe valproate or a suitable antiepileptic: as seizure prophylaxis at a certain Clozapine dose or level, or only as remedial treatment. In this review, we examine the relevant literature with an aim to evaluate the following relationships: Clozapine dose and electroencephalogram (EEG) abnormalities, plasma levels and EEG abnormalities, dose and occurrence of seizures and plasma levels and occurrence of seizures. Weighted linear regression models were fitted to investigate these relationships. There was a strong relationship between Clozapine dose and plasma level and occurrence of Clozapine-induced EEG abnormalities. However, a statistically significant relationship between dose and occurrence of seizures was not found. A relationship between Clozapine plasma level and occurrence of seizures was not established because of the scarcity of useful data although our review found three case reports which suggested that there is a very substantial risk of seizures with Clozapine plasma levels exceeding 1300 μg/l. Seizures are more common during the initiation phase of Clozapine treatment, suggesting a slow titration to target plasma levels is desirable. An antiepileptic drug should be considered when the Clozapine plasma level exceeds 500 μg/l, if the EEG shows clear epileptiform discharges, if seizures, myoclonic jerks or speech difficulties occur and when there is concurrent use of epileptogenic medication. The antiepileptics of choice for the treatment and prophylaxis of Clozapine-induced seizures are valproate (particularly where there is mood disturbance) and lamotrigine (where there is resistance to Clozapine).
Steve Kisely - One of the best experts on this subject based on the ideXlab platform.
-
elevated Clozapine levels associated with infection a systematic review
Schizophrenia Research, 2017Co-Authors: Scott R Clark, Steve Kisely, Nicola Warren, Gajin Kim, David Jankowiak, Klaus Oliver Schubert, Tori G Forrester, Bernhard T Baune, Dan SiskindAbstract:Clozapine is the most effective anti-psychotic medication for treatment refractory schizophrenia. A growing number of case reports have linked infection to high Clozapine levels and associated adverse outcomes. We present a systematic review of published cases to clarify the relationship between infection and elevated Clozapine levels. The case reports were located through PubMed and Embase. In addition, 8 new cases from two Australian states were included. Demographics, psychiatric diagnoses and medical morbidities, medications, clinical symptoms, Clozapine levels, inflammatory markers and final clinical outcome were extracted. 40 cases were identified in 23 publications that demonstrated elevated Clozapine levels associated with infection. Infections were commonly respiratory in origin. Adverse events, typically sedation, were associated with raised Clozapine levels during infection. In many cases the signs of infection such as fever and white blood cell count were reduced. Severe adverse effects were uncommon, with one case each of seizure, myocarditis and neutropenia. The relationship between infection, Clozapine levels and adverse events is complex and multi-factorial. Monitoring of Clozapine levels is essential during hospitalisation for infection and consideration should be given to gradual dose reduction to minimise dose related side effects.
-
Clozapine v first and second generation antipsychotics in treatment refractory schizophrenia systematic review and meta analysis
British Journal of Psychiatry, 2016Co-Authors: Dan Siskind, Lara Mccartney, Romi Goldschlager, Steve KiselyAbstract:Background Although Clozapine is the ‘gold standard’ for treatment-refractory schizophrenia, meta-analyses of Clozapine for this condition are lacking. Aims We conducted a systematic review and meta-analysis of Clozapine treatment for people with treatment-refractory schizophrenia. Method We searched the Cochrane Schizophrenia Group's trial register, PubMed and EMBASE and hand-searched key papers for randomised controlled trials of Clozapine for treatment-refractory schizophrenia. Results Twenty-one papers with 25 comparisons were included. The number needed to treat was 9. Clozapine was superior for positive symptoms in both the short and long term. In the short term only Clozapine was superior for total and negative symptoms, with higher response rates. Both funding source and dosage affected results. Higher baseline psychosis scores predicted better outcomes for Clozapine in a meta-regression. Conclusions Clozapine is superior for treatment-refractory disorder but if there is no response by 6 months medications with lower adverse reactions should be considered.
Dan Siskind - One of the best experts on this subject based on the ideXlab platform.
-
elevated Clozapine levels associated with infection a systematic review
Schizophrenia Research, 2017Co-Authors: Scott R Clark, Steve Kisely, Nicola Warren, Gajin Kim, David Jankowiak, Klaus Oliver Schubert, Tori G Forrester, Bernhard T Baune, Dan SiskindAbstract:Clozapine is the most effective anti-psychotic medication for treatment refractory schizophrenia. A growing number of case reports have linked infection to high Clozapine levels and associated adverse outcomes. We present a systematic review of published cases to clarify the relationship between infection and elevated Clozapine levels. The case reports were located through PubMed and Embase. In addition, 8 new cases from two Australian states were included. Demographics, psychiatric diagnoses and medical morbidities, medications, clinical symptoms, Clozapine levels, inflammatory markers and final clinical outcome were extracted. 40 cases were identified in 23 publications that demonstrated elevated Clozapine levels associated with infection. Infections were commonly respiratory in origin. Adverse events, typically sedation, were associated with raised Clozapine levels during infection. In many cases the signs of infection such as fever and white blood cell count were reduced. Severe adverse effects were uncommon, with one case each of seizure, myocarditis and neutropenia. The relationship between infection, Clozapine levels and adverse events is complex and multi-factorial. Monitoring of Clozapine levels is essential during hospitalisation for infection and consideration should be given to gradual dose reduction to minimise dose related side effects.
-
Clozapine v first and second generation antipsychotics in treatment refractory schizophrenia systematic review and meta analysis
British Journal of Psychiatry, 2016Co-Authors: Dan Siskind, Lara Mccartney, Romi Goldschlager, Steve KiselyAbstract:Background Although Clozapine is the ‘gold standard’ for treatment-refractory schizophrenia, meta-analyses of Clozapine for this condition are lacking. Aims We conducted a systematic review and meta-analysis of Clozapine treatment for people with treatment-refractory schizophrenia. Method We searched the Cochrane Schizophrenia Group's trial register, PubMed and EMBASE and hand-searched key papers for randomised controlled trials of Clozapine for treatment-refractory schizophrenia. Results Twenty-one papers with 25 comparisons were included. The number needed to treat was 9. Clozapine was superior for positive symptoms in both the short and long term. In the short term only Clozapine was superior for total and negative symptoms, with higher response rates. Both funding source and dosage affected results. Higher baseline psychosis scores predicted better outcomes for Clozapine in a meta-regression. Conclusions Clozapine is superior for treatment-refractory disorder but if there is no response by 6 months medications with lower adverse reactions should be considered.
James G Scott - One of the best experts on this subject based on the ideXlab platform.
-
a review of the use of Clozapine levels to guide treatment and determine cause of death
Australian and New Zealand Journal of Psychiatry, 2012Co-Authors: Anne Stark, James G ScottAbstract:Objective To review the literature to examine the use of Clozapine levels to (i) guide therapy and prevent toxicity in clinical care and (ii) determine cause of death in post-mortem examination of patients who were treated with Clozapine. Methods MEDLINE was searched in December 2010 using the following keywords: 'Clozapine levels', 'Clozapine and toxicity', 'Clozapine and death', 'Clozapine and mortality' and 'post-mortem redistribution'. Data was also collected from the 2010 MIMS Annual. Results The literature reported significant variation in Clozapine levels attained with any given dose, and considerable variability in the clinical response achieved at any given Clozapine level. The lowest effective Clozapine levels ranged from 250 to 550 µg/L, while the recommended upper limit to prevent toxicity varied from 600 to 2000 µg/L. There was minimal correlation between Clozapine levels and side effects, with the exception of sedation, hypotension and seizure activity. The risk of seizures increased with plasma Clozapine levels greater than 600 µg/L or rapid upward titration. In addition to prescribed dose, there are many factors that influence plasma Clozapine levels. After death, the process of post-mortem drug redistribution resulted in 3.00 to 4.89 times increases in Clozapine levels in central blood vessels and 1.5 fold increases in peripheral vessels compared to ante-mortem levels. Conclusions The exact range of Clozapine levels that corresponds to toxicity remains unclear. However, levels between 350 µg/L and 1000 µg/L achieved with gradual upward titration are more likely to be effective and less likely to cause toxicity. Ongoing Clozapine level monitoring is indicated, especially when (i) prescribing higher doses (> 600 mg/day) of Clozapine, (ii) there has been a change in a patient's concomitant pharmacotherapy or cigarette use and (iii) there has been a suboptimal response to treatment. The use of post-mortem Clozapine levels to determine Clozapine toxicity as a cause of death is unreliable.
Harriet M. Bryson - One of the best experts on this subject based on the ideXlab platform.
-
Clozapine
CNS Drugs, 1995Co-Authors: Antona J. Wagstaff, Harriet M. BrysonAbstract:Synopsis Clozapine is an atypical antipsychotic agent whose mode of action is thought to pertain to its interactions with dopamine and serotonin (5-hydroxytryptamine) neurotransmitter systems. Clinical efficacy may be related to plasma Clozapine concentrations. Response rates have varied widely on short term therapy (30 to 100%); during longer term treatment, 60% of patients unresponsive to or intolerant of previous antipsychotic therapy responded to Clozapine. Significant improvement in both positive and negative psychotic symptoms, quality of life, social functioning and suicidality has been demonstrated. Clozapine has demonstrated superior efficacy to that of chlorpromazine, haloperidol andfluphenazine in treatment-resistant patients, and improvements were maintained with long term treatment. Economic savings may be realised after the first 1 to 2 years of Clozapine therapy. Extrapyramidal symptoms occur less frequently and appear to be less severe in patients receiving Clozapine than in those receiving classical antipsychotic agents. The incidence of tardive dyskinesia and neuroleptic malignant syndrome is very low. Agranulocytosis appears to occur in about 0.8% of Clozapine recipients, and the incidence has been reported to decrease after the first year of therapy. Regular blood monitoring is mandatory. More frequent adverse events associated with Clozapine include tachycardia, sedation, hypersalivation and orthostatic hypotension. With regular blood monitoring, Clozapine is the drug of choice for patients with schizophrenia who are unresponsive to or intolerant of previous antipsychotic therapy. Pharmacodynamic Properties The atypical antipsychotic drug Clozapine is a tricyclic dibenzodiazepine, whose clinical efficacy is thought to be associated with its interactions with both dopaminergic and serotonergic neurotransmitter systems. The affinity of Clozapine for the dopamine D_2 receptor is relatively weak compared with classical antipsychotic agents, and it has a relatively high affinity for dopamine D_1 and D_4 receptors, acting preferentially on mesolimbic rather than neostriatal dopaminergic neurons. Clozapine also has appreciable affinity for cholinergic muscarinic, serotonin (5-hydroxytry ptamine), histamine and adrenergic receptors. Clozapine has anxiolytic and antiaggressive effects and appears to improve cognition and smooth pursuit eye movements in patients with schizophrenia. Various immunological changes have been noted with Clozapine treatment. Electroencephalogram abnormalities have been reported in 52 to 100% of patients receiving Clozapine. A period of 3 to 9 months of Clozapine treatment appears to be necessary in order to effect a therapeutic response in many patients. Pharmacokinetic Properties Plasma Clozapine concentrations increase proportionally with dosage (although wide interpatient variability has been recorded), reaching a peak in 1.5 to 3.6 hours. The initial and terminal plasma elimination half-lives range from 0.2 to 2.0 hours and 8.1 to 15.8 hours, respectively. The drug is widely distributed in the body, and the oral bioavailability ranges from 27 to 47%. Metabolism occurs extensively, mainly via liver cytochromes, and results in several derivatives. Recent research indicates that plasma Clozapine concentrations ≥350 or 420 μg/L are associated with optimal clinical efficacy. The concomitant administration of drugs metabolised by or inhibiting cytochrome P450 enzymes may result in altered plasma concentrations of Clozapine and subsequent adverse effects. Plasma Clozapine concentrations may also be altered by coadministration of drugs which are highly protein-bound. Therapeutic Efficacy The efficacy of Clozapine in patients with schizophrenia who are unresponsive to or intolerant of classical antipsychotic agents has been demonstrated in both open noncomparative trials and randomised double-blind comparative trials against classical antipsychotic agents. Response rates to Clozapine in trials of 4 to 10 weeks’ duration varied from 30 to 100% of patients (depending on study design and definition of response), with significant improvement in both positive and negative symptoms, including cognitive, psychomotor and depressive symptoms. During longer term treatment (1 year), a response rate of 60% was reported, mostly occurring during the first 4 months of treatment. Superior efficacy in comparison with chlorpromazine, haloperidol and fluphenazine has been demonstrated over a treatment period of 1 to 2.5 months in patients resistant to previous antipsychotic agents, and also in comparison with chlorpromazine in patients intolerant of previous therapy (because of extrapyramidal symptoms or tardive dyskinesia). An earlier onset of action was noted in Clozapine recipients than in those receiving chlorpromazine. Long term treatment has resulted in sustained clinical improvement; relapse occurred in 4 of 21 patients over a year of Clozapine treatment, compared with 18 of the same 21 patients while receiving other antipsychotic agents in the preceding year. Pharmacoeconomic Considerations Studies investigating quality of life have demonstrated a significant improvement over baseline with Clozapine therapy, including improvement in psychosocial functioning. 40 to 56% of patients returned to work or school on Clozapine therapy, compared with 15% on previous antipsychotic agents. A decrease in the level of suicidality among schizophrenic patients (39.8% showed improvement) has also been demonstrated. Despite increased use of outpatient services during the first year of therapy with Clozapine, reduced use of psychiatric and general hospital services (arising from improved psychopathology, social functioning and quality of life) is likely to result in cost savings to psychiatric institutions and insurers after the first 1 to 2 years of therapy. Tolerability The most common adverse events associated with Clozapine therapy include tachycardia, body weight gain, sedation, orthostatic hypotension, hypersalivation and disturbance in urinary function. Seizures can occur with high dosages or if the dose is increased too quickly. While extrapyramidal symptoms have been recorded in most patients receiving classical antipsychotic drugs, tremor or bradykinesia (3 to 24% in Clozapine recipients vs 15 to 35% with classical antipsychotics) and akathisia (6 to 7% vs 18 to 75%) occur relatively seldom in patients receiving Clozapine, and tend to be less severe. Acute dystonia (40 to 90% with classical antipsychotics) and rigidity (parkinsonism occurs in 15 to 35% of patients receiving classical antipsychotics) have not been associated with Clozapine treatment. Tardive dyskinesia can occur in 5 to 56% of patients receiving classical antipsychotic drugs, but in many patients this resolves on substitution with Clozapine. Tardive dyskinesia occurs rarely in Clozapine recipients. An atypical form of neuroleptic malignant syndrome, without rigidity, has been rarely reported in Clozapine recipients. Although transient changes in blood counts are relatively common, the incidence of agranulocytosis associated with Clozapine is about 0.8% (a range of 0.05 to 2% has been reported), decreasing 10-fold after the first year of therapy. Dosage and Administration It is recommended that Clozapine is initiated at a dosage of 12.5mg once or twice daily, increased by 25 to 50 mg/day over 2 to 3 weeks to 300 to 450 mg/day. Subsequent increases should be made gradually and individualised according to symptoms. Regular monitoring of white blood cell counts is required during therapy.