Termination of Clozapine Treatment Due to Medical Reasons: When Is It Warranted and How Can It Be Avoided?

Presented By Dr Pavan Kumar Kadiyala Chaired By Dr P John Mathai

Authors
Jimmi Nielsen, MD; Christoph U. Correll, MD; Peter Manu, MD; and John M. Kane, MD

Corresponding author: Jimmi Nielsen, MD, Centre for Schizophrenia, Aalborg Psychiatric Hospital, Brandevej 5, 9210 Aalborg, N/A 9000, Denmark Email: jin@rn.dk
Journal of Clinical Psychiatry 2013;74(6):603613

Introduction
Clozapine remains the gold-standard for treatment-resistant

schizophrenia Its impressive efficacy has been demonstrated in several clinical trials and a meta-analysis. Unique efficacy in treatment-resistant schizophrenia Possesses anti-suicidal and anti-aggressive properties Efficacy for treatment resistant bipolar disorder. Highly cost-effective due to significant reductions in hospitalization. Many clozapine-treated patients and their relatives report a substantial positive effect on their lives and well-being.

 Associated with a wide range of side effects, some of which are

potentially fatal. The most salient among them, agranulocytosis, led to the suspension of clozapine treatment after 8 fatal cases in Finland in 1974 and demonstrated the need for the current mandatory hematological monitoring program. Other s/e, such as myocarditis, aspiration pneumonia, ileus, and weight gain have in fact caused more deaths than agranulocytosis

 Although the estimate of Fontaine et al remains untested in prospective

samples, overall, weight gain-induced mortality is balanced by clozapines antisuicidal properties, illustrated by 416 additional weight gain-induced deaths counteracted by saving 492 per every 100,000 patients from suicide

Because of the paucity of alternative treatments, the discontinuation of

clozapine remains an issue of utmost importance. Almost half of the patients who abruptly discontinue clozapine treatment experience rapid psychotic deterioration, Exposing some of them to an increased risk of suicide.

 With rates of up to 65%, discontinuation is highest during the first year

of treatment, but there is evidence of a 2- to 3-fold variation from study to study. There is growing evidence that psychiatrists lack of experience with clozapine contributes to the high discontinuation rate. A recent study found that medical reasons accounted for 20% of discontinuation decisions and cited as the most common reasons seizure (45.5%), severe constipation (36.4%), somnolence (27.3%), and neutropenia (18.2%). A cause for concern is that the literature provides consistent evidence that the overwhelming majority of decisions to discontinue clozapine treatment are on the basis of side effects, such as leukocytosis, seizures, and fever, which, under normal circumstances, can be managed and should not lead to such a decision.

 As strategies for counteracting many of the troublesome side effects are

available, it is highly likely that the termination of treatment is unwarranted in many cases. A lack of experience with clozapine seems to often explain why many psychiatrists are unaware of these strategies and unnecessarily discontinue clozapine treatment, thus depriving patients of what could be only effective intervention for them. Limited evidence combined with inexperience in using known remedies for side effects may thus jeopardize patients overall wellbeing.

 While the complexities of clozapine treatment, including potentially

life-threatening adverse events, may cause doctors to refrain from reintroducing clozapine after witnessing serious side effects, several case reports document that a rechallenge may offer patients another chance to benefit from clozapine treatment. However, the rarity of life-threatening side effects, on the one hand, and the prospect of increased risk of death following rechallenge, on the other hand, explain why this option has received only scant attention.

Need for the study

The severe clinical consequences of discontinuation of clozapine

treatment and the difficult questions facing psychiatrists have prompted this clinical overview, which aims to help psychiatrists handle the most pitfalls in treatment with clozapine, particularly with regard to decisions on the discontinuation or continuation of clozapine treatment.

Method
The authors conducted a structured search of PubMed and EMBASE

from database inception until september 10, 2012, without any language restrictions. References were imported to EndNote X4 (Thomson Reuters, New York), and duplicates were removed. On the basis of review of discontinuation studies and authors clinical experince, the following side effects were considered important for this review as potential grounds for discontinuation of clozapine treatment: neutropenia or agranulocytosis, leukocytosis, thrombocytopenia, thrombocytosis, eosinophilia, leukocytosis,

 QTc prolongation, electrocardiogram changes, atrial flutter, tachycardia, myocarditis, cardiomyopathy, fever, syncope, DM, DKA, diabetic hyperosmolar coma, NMS, ileus, liver enzyme elevation, or seizure. Although merely bothersome side effects may also have led to

discontinuation, these are not considered here.

 The search term we used was clozapine because searches using the

above-mentioned side effects in conjunction with clozapine did not retrieve enough articles. Included in this review are studies that reported on the frequency of the specified clozapine-related adverse effects either reported on the grounds for or against clozapine discontinuation reported on management techniques to maintain patients on clozapine enable successful clozapine rechallenge.

 Review articles and meta-analysis were given precedence over case

series or individual studies. Case reports were excluded unless they provided important new evidence that was not contained in prior studies or reviews. Manuscripts were reviewed manually for relevance. Reference lists of the retrieved journal articles were cross-checked for additional relevant studies.

Results
Of a total of 13,385 search results, data from 81 studies were included

in this review. The remaining studies were excluded upon title or abstract review or full text review because they did not provide specific information for the topic of this review.

Cardiac Adverse Effects

QTc prolongation
Prolongation of the QTc interval to levels > 500ms associated with an increased risk of developing life-threatening

polymorphic ventricular arrhythmia, or torsade de pointes. The QTc interval is a measure of the time from the beginning of ventricular depolarization to the end of repolarization obtained from surface ECG. However, since a heart rate elevation has the effect of narrowing the QT interval, a correction formula is used. While a blockage of the fast rectifier potassium channel causes many antipsychotics to prolong the QTc interval (an effect most pronounced for ziprasidone and sertindole, with mean prolongation up to 20 ms), QTc intervals above 500 ms that should lead to discontinuation are rarely seen during clozapine treatment.

 Infact, the extent to which clozapine is capable of prolonging the QTc

interval remains largely unknown, as no studies have taken account of 2 important pitfalls: (1)tachycardia is common during treatment with clozapine and (2) the Bazett formula is valid only for heart rates below 80 bpm; since most machines use this formula for correcting the QT interval, overcorrections are likely to occur. For heart rates exceeding 80bpm, the Fredericica formula offers a more reliable correction. For a QT interval of 420 ms ,the QTc interval is HR Bazett Fridericia 70bpm 454ms 442 ms 90bpm 514 ms 481 ms

 Conclusion: a high number of cases with a QTc > 500ms during

treatment with clozapine represents an artifact of the Bazett formula rather than the Fredericia formula being employed. Another pitfall in clozapine treatment is presented by occasional changes in nonspecific T-wave morphology, in particular, flattening. This occurrence complicates both automatic and manual reading of the QT intervel in the lead where the T-wave exhibits the greatest amplitude. Termination of clozapine treatment on the grounds of QTc prolongation is rarely warranted Other causes of prolongation, such as concomitant medications or unrecognized cardiac disease, should therefore be sought.

Myocarditis
The absolute risk of clozapine-induced myocarditis is 0.015%-0.188%. It occurs within the 1st months of treatment and is diagnosed by ST-

segment elevation and tachycardia using an electrocardiogram or by increased troponin levels (twice the upper limit of normal warrant discontinuation) Flu-like symptoms, fever, fatigue, and dyspnea are the most common symptoms. A recent study found that, in most cases, patients had no symptoms of myocarditis before death, which raises the question of whether weekly monitoring of troponin levels is warranted. Clozapine should be discontinued immediately in case of myocarditis, and rechallenge is not recommended.

 Although, in a report of 4 cases, clozapine rechallenge was successful in

3 patients, a publication bias is likely. Moreever, with the addition of 8 additional cases published recently, 4 of which were successful, clozapine rechallenge would still not be recommended according to the metrics published by Manu et al for recommending rechallenge.

Cardiomyopathy
Clozapine-induced cardiomyopathy is a serious medical condition.

Typically, it is of dilated type, and sinus tachycardia may be accompanied by fatigue, dysnoea, and tachypnea. ECG signs are typically non-specific but frquently include T-wave and P-wave abnormalities and signs of left ventricular hypertrophy. A cardiomyopathy diagnosis confirmed by ECHO shoild lead to prompt discontinuation of clozapine.

 Especially during up-titration of clozapine , orthostatic hypotension

may cause problems. The mechanism is extensive antagonism at the noradrenergic alpha1 receptor and is probably exacerbated by the sedating properties of clozapine. Slower up-titration may solve the problem, but if orthostatic hypotension is present in long-term treatment, patients are advised to drink plenty of fluid and eat a salt-containing diet. If this is recommendation doesnt solve the problem, compression socks and/or fludrocortisone may help.

Sinus Tachycardia
It is a frequent side effect of clozapine. It is most pronounced at the start of treatment and during the up-

titration phase. It is usually harmless but could be the first sign of life-threatening conditions, such as myocarditis, cardiomyopathy, or NMS. Newly occurring sinus tachycardia in apatient who has been in stable and unchanged treatment for at least month should raise suspicion of cardiomyopathy. Dose reduction should be attempted in case of idiopathic sinus tachycardia; if this attempt proves ineffective or if psychotic symptoms preclude dose reduction, a cardioselective beta-blocker may be tried after cardiomyopathy and myocarditis, as well as NMS, have been ruled out.

 Treatment with a beta blocker should not be initiated within the 1st

months of clozapine treatment because tolerane to the heart-rate inducing effect of clozapine is likely to develop after 4 to 6 weeks of treatment. Moreever, the use of beta blockers may complicate the diagnosis of myocarditis. Ivabradine may also be used in case of lack of response to or intolerability of beta-blockers. In conclusion idiopathic or drug-induced sinus tachycardia should not lead to clozapine discontinuation.

Other cardiac complications

Nonspecific ECG changes, such as ST- segment elevation, T-wave

flattening, or T-wave inversion, have been reported during treatment with clozapine in which no connection to cardiac disease was found. Provided that cardiac disease can be excluded, such symptoms appear to be of no clinical importance. Atrial flutter of unknown origin has also been reported and should lead to the discontinuation of clozapine or relevant medical treatment.

Hematological Adverse Effects

Eosinophilia
An increase in eosinophil production may indicate allergic reactions and is therefore considered to be a predictor of other clozapine-induced

side effects such as myocarditis, agranulocytosis, and toxic hepatitis. It is not predictive of other side effects, but, since many of these potentially life-threatening side effects are accompanied by concomitant eosinophilia, a thorough examination should be performed.

 Eosinophilia (eosinophil level > 3,000/cu mm) is usually transient and

occurs mainly during the first year of treatment The manufacturer of clozapine recommends discontinuation and eventually restarting when the level of eosinophilia is below 1,000/cumm The potential consequences of clozapine outweigh this risk if all other medical conditions are excluded.

Neutropenia or Agranulocytosis
Agranulocytosis indicates a condition in which the absolute neutrophil

count < 500/cumm, Neutropenia = ANC between 500 and 1500/cumm Risk of agranulocytosis is 0.7% Risk of neutropenia 3% approx Current mandatory monitoring system Made fatal agranulocytosis extremely rare with incidence as low as 00.03%. Occurrence of neutropenia typically provokes concern that the ANC willcontinue to drop and reach the agranulocytosis level, a development that is unpredictable. As clozapine treatment is generally terminated for safety reasons, the elucidation of this question is difficult.

 As a practical but unreliable rule of thumb, it can be assumed that neutropenia can occur at any time during

treatment with clozapine, whereas agranulocytosis tends to develop predominantly during the first 6 months of treatment. The problem is particularly pronunced with the so-called leukocyte and granulocyte dips, which can occur at any time during treatment with clozapine. Although the ANC may have been stable for months to years, it may suddenly drop and reach neutropenia levels, in which case clozapine should be interrupted. The treatment may be resumed under increased surveillance when ANC returns to normal levels.

 Morning psudoneutropenia : a physiologic state with increased

neutrophill demargination as plasma cortisol levels reach their morning peak. So blood sampling should merely transferred to midmorning or afternoon In pts of African and Middle Eastern descent, benign ethnic neutropenia may be present with a low baseline count, a biological variation in which increased infection rates have not been recorded. In general, a low baseline ANC is a risk factor for neutropenia but not for agranulocytosis. In Great Britain, adjusted thresholds for neutropenia in pts with benign ethnic neutropenia that are 500/cu mm lower than in general guidelines, recommending clozapine discontinuation only if the ANC < 1,000/cumm

 Severe cases of ethnic neutropenia may require treatment with gCSF or

or long acting pegfilgastrim SC every 14 days. Li raise neutrophil count as it stimulates bone marrow and frequent cause of leukocytosis. The dosage should be therapeutic, (> 0.4mmol/L, 12-hr value) A period of 1-2 weeks should follow before the reinitiation of clozapine, if it was deemed necessary to discontinue clozapine Lithium inhibits MPO which reduce the aggressiveness of neutrophils No investigation of its effect on infection has been undertaken. Despite this fact, several studies report the successful use of lithium to boost neutrophils for leukopenia Others filgastrim- bonemarrow stimulating drugs

 Agranulocytosis should always lead to prompt discontinuation of

clozapine. Rechallenge shouldnt be attempted. Some pts have their clozapine treatment discontinued b/c they refuse to follow the hematological monitoring After 6 months of treatment, the risk of agranulocytosis is similar to other psychiatric drugs (mianserin) If pt accepts potential risk, an option may be to accept longer intervals b/w blood sampling or to draw blood only whenever infection is suspected. Another option- on-site hematologic monitoring using capillary blood.

Thrombocytopenia
Occur in isolation or accompanied by other cell line changes Sequelae petechiae, inc risk of bleeding Usually transient and Rarely merits a discontinuation of clozapine. Persistent thrombocytopenia is rare. PlC < 50,00/ cumm discontinuation until values return normal levels Li inc PlC Currently debated whether mandatory PlC should be introduced

Thrombocytosis
Extremely rare Predisopsis to thrombosis Mild transient thrombocytosis shouldnt lead to discontinuation But PlC > 750,000/ cumm to 10,00,000/cumm discontinue.

Leukocytosis
Paradoxically, clozapine may cause not only leukopenia, but also

leukocytosis Underlying mechanism not clear Benign and shouldnt lead to discontinuation An unreplicated study found an inc risk of AML, but the incidence was extremely low. Should rule out non-clozapine-related reason like NMS If there is none, leukocytosis shouldnt lead to clozapine discontinuation Occurs very often transiently in 1st few weeks of treatment Additional med examination is not warranted unless developing after years of treatment.

Cardiometabolic Adverse Effects

Weight Gain, Arterial hypertension, Dyslipidemia, and Metabolic syndrome:

Clozapine strongest lability for wt gain and lipid and glucose

abnormalities. Orthostatic hypotension - 1 blockade like most antipsychotics Also often severe wt gain can offset this effect, rising risk of BP over time Clozapine greatest risk for the development of metabolic syndrome A constellation of at least 3 of 5 WE = waist expanded (>35in F, 40in M)/ abdominal obesity IG = impaired glucose (>110mg/dl) H = hypertension (BP >130/85) H = HDL low (<50mg/dl F, <40mg M) T = TGs > 150mg/dl

 Metabolic syndrome or its components shouldnt generally lead to

discontinuation. Though of clinical concern, managed by medical guidelines like Healthy lifestyle guidance As dose related, the lowest effective dose If behavioral interventions fail, then treatment with metformin, topiramate, aripiprazole best evidence for wt loss in clozapine treated pts Novel drugs like lorcaserin or combination of phenertermine + topiramate or naltrexone + bupropion - no data on antipsychotic induced wt gain and metabolic syndrome If HTN, dyslipisemia, or hyperglycemia manage by medical guidelines by physician

DM, DKA, diabetic hyperosmolar coma (DHC, HONK)

DM- adverse effect of antipsychotic agents, clozapine most frequent In addition to diabetogenic effects of inc wt gain and adiposity Clozapine has unique molecular effects that inc risk of DM by M3 blockade decrease of cholinergic-dependent and glucose dependent

insulin secretion However, as pts on clozapine who develop DM have one or more risk factors for DM like diagnosis of schizophrenia, f/h/o DM Advanced age BMI >/= 25kg/m2 Dyslipdemia Central obesity, gestational DM or nonwhite ethnicity.

 Since DM can be managed medically, shouldnt lead to discontinuation But should address other diabetogenic conditions (infection, obesity,

hyperthyrodism) or medication effects (beta blockers, steroids) If FBS are too high(>350mg/dL) or if significant clinical symptoms (dizziness, syncope, lethargy, confusion) that cant be managed acutely with rehydration and lowering blood glucose, clozapine may need to be held until controlled. DKA & DHC are very rare s/e of antipsychotics, but clozapine most likely to be associated with this potentially lifethreatening effect.

 Can occur suddenly early in treatment or be late sign of unrecognized

and untreated DM Pts with dehydration, fruity-smelling breath, shortness of breath, lethargy and confusion. In more severe forms, pts can develop seizures, coma and death. Withheld clozapine immediately until contriol

Other adverse effects

Benign Hyperthermia
Benign fever, flu-like sym, hyperthermia 55% during 1st month Explained by increase in pyrogens Bear no relation to long term tolerability of clozapine Rule out other conditions Agranulocytosis TC and ANC Immunological conditions pancreatitis, polyserositis, colitis,

myocarditis Particularly myocarditis ECG, troponin enzymes These conditions discontinue clozapine abruptly Also consider NMS Infections as those on clozapine are easily prone

NMS
Rare but potentially life threatening Autonomic instability (ie tachycardia, HTN, or hypotension , shock) Altered conciousness Fever Leukocytosis Elveated CPK above 1000U/L Often sever parkinsonism but not always with atypical antipsychotics Pause clozapine and hydrate until symptoms resolve ECT if severe and refractory However, rechallenge can be attempted with slower titration.

Venous thromboembolism
Antispsychotics increase risk of venous thrombhoembolism Clozapine highest risk Mechanism not known Whether direct effect or additional risk factors obesity, lack of

exercise and smoking Prophylactic antithrombotic treatment Whether continue or discontinuing clozapine based on the expected consequnces involving pt A recurrence of thromboembolism despite prophylactic treatment should always lead to discontinuation.

Constipation
Possess extensive anticholinergic properties in combination with

sedative properties risk factor for constipation and subsequently ileus Ileus may be fatal and more deaths are caused by clozapine-induced ileus than by agranulocytosis Pts should be asked weekly during up-titration and every month during maintenance abt defecation frequency Frequency of less than 4 to 5 times/ wk should lead to intervention A high-fibre diet Plenty of fluid Exercise Often a laxative Contoversial of long term use of stimulant laxative as it may lead to cathartic colon.

Hepatic impairment
Ranging from asymptomatic inc in LFT to fulminant liver failure Up to 40% experience inc ALT 2 times the upper normal limit Icteric heapatitis in only 0.06% Abnormal LFT occurs in 1st months of treatment and transient in 60% of

cases Heaptitis also occurs in same period and reversible if clozapine terminated in timely manner

 No clear recommendations Routine LFT has occasionally recommended Clinical symptoms of rash, jaundice or malaise always check LFT 2-3 fold inc no discontinuation, but beyond 3 times the upper normal

warrant discontinuation Temporary disruption of clozapine may overcome subnormal LFT Dose reduction as dose dependent Cases of successful rechallenge of marked rise in LFT - described

Seizures
Lowers seizure threshold Dose-dependent fluctuation in EEG and risk of seizures Above 600mg/d - 4.4% 300- 600 mg/d- only 2.7% and <300 mg/d - 1%

A careful analysis of 101 clozapine- induced siezure indicated

Paroxysmal tonic-clonic activity -- 67 Myoclonic seizures ------- 27 Atonic seizure ---------1 Partial simple or complex --- 6

Mean daily dose for parital complex seizure 275mg while

Myoclonic activity-------------------------------535mg/ day

 A 50% dose reduction and assessment of other causes that decrease

threshold like Drug toxicity Withdrawal of BZDs or antiepileptics Electrolyte imbalances DKA Organic brain disorders Sleep deprivation must follow 1st seizure Seizures or EEG activity shouldnt lead to discontinuation even if refractory. Either a reduction or division of dosage (if giving OD) Treating with antiepileptic (Na valproate recommended, lamotrigine , gabapentin and others also tried with success).

Critical comments

TITLE Adequate , short, accurate, informative AUTHORS Dr Jimmi Nielsen MD Corresponding author address and email for correspondence given Dr Christoph U. Corell MD Dr John M Kane MD These authors are department of psychiatry Dr Peter Manu is from the department of medical services Dr John M Kane - He was a pioneer in the study of first episode schizophrenia and also conducted groundbreaking work with clozapine for treatment resistant schizophrenia.

 All the authors except Dr Manu has received research support from

various drug companies Dr kane also received grant support from the NIMH. One of the CME articles for the educational needs on a variety of topics. By the CME Institute of Physicians Postgraduate Press, Inc; part of Journal of Clinical Psychiatry. No member of the CME Institute staff reported any relevant personal finanacial relationships. FUNDING None Reported.
No mention about the ethical approval of the study

ABSTRACT: Brief and concise Fair and unbiased account of the paper INTRODUCTION AND REVIEW OF LITERATURE Brief and comprehensive Correct and necessary No important citations missing Has cited prior articles and their limitations. Has described reasons and need for the research project No Explicit hypothesis was made.

AIMS AND OBJECTIVES (Research Questions) Clear and unambiguous METHODOLOGY Place and period of the study havent been mentioned. Type of study: Mentioned as review study but what type of review not mentioned

 Publications on individual studies may be summarized in various forms: Narrative reviews Systematic review articles Meta-analyses of published data Pooled re-analyses (meta-analyses with individual data) Prospectively planned meta-analysis

 Based on methodology, it can be considered as systematic review.

Because relevant information is extracted from the publications and

the results are not quantitatively summarized using statistical methods and pooled effect estimates

 A "review" is the qualitative summary of the results of individual

studies systematic review articles claim that, if possible, they consider all published studies on a specific themeafter the application of previously defined inclusion and exclusion criteria. The aim is to extract relevant information systematically from the publications. analyze the methodological quality of the included publications and to investigate the reasons for any differences between the results in the different studies. The results of each study are presented and analyzed according to defined criteria, such as study design and mode of recruitment.

EBM
Sometimes an RCT may fail to give a clear result, or results from multiple

studies may yield different estimates of treatment effect. By systematic review, possible to arrive at a more precise estimate of treatment effect, all evidence in the field of interest to be taken into account danger exists that a poorly executed systematic review and metaanalysis may give deceptive results.

 Checklist for the analysis of a systematic summary Was there an a priori study protocol? Was there an a priori hypothesis? Was there a detailed description of the literature search used? Were prospectively specified inclusion and exclusion criteria clearly

described and applied? Was the possible heterogeneity between the studies considered? Was there a clear description of the statistical methods used? Were the limitations of the summary discussed?

Study protocol: Mentioned in the form of objectives and method of study No explicit hypothesis Selection of studies, study design and mode of recruitment. Structured search of PubMed and EMBASE from database inception psycINFO specific database for psychiatry not considered Cochrane library source of systematic reviews not considered Until September 10, 2012 Without any language restrictions avoding some bias

 Reference lists of retrieved journal articles cross checked unpublished studies in congress volumes, as well as with search

machines on the Internet not taken into account In their limitations, reported that most of studies are based on small samples, uncontrolled observations and clinical guidelines rather than RCTs or population based register studies.

 Only Clozapine is used as search term Only certain side-effects that led for dicontinuation of clozapine are

considered in the study Other side-effects that are merely bothersome are not considered like Sedation, nausea, nocturnal eneureis, hypersalivation, which are common Other uncommon s/e like colitis, delirium, pancreatitis Other neurological s/e like parkinsonism, akathisia, tardive dyskinesia They agreed this as limitation of the study.

 Mentioned but not fully analyzed the methodological quality of the

included publications nor investigated the reasons for any differences between the results in the different studies. Inclusion and exclusion criteria clearly described and applied Heterogeneity between the studies is considered Descriptive analysis of the data Overview tables mentioning important characteristics of the individual studies not there

Publication bias: Publication bias means that studies which failed to find any influence of exposure on the target disease ("negative studies") are more rarely published than studies which showed a positive or statistically significant association. Publication bias can be visualized with funnel plots. Considered publication bias in reviewing publications Funnel Plot not constructed as it is a systematic review.

Tools and Instruments References were imported to EndNote X4 EndNote is the industry standard software tool for publishing and managing bibliographies, citations and references on the Windows and Macintosh desktop.
Procedure has been well described Ethical but not mentioned about ethical clearance.

RESULTS Presented and described adequately in form of tables and graphs. Statistical methods not used as systematic review. In implications and abstract leukocytosis mentioned in two statements Leukocytosis (increase by 15%) may be a nonspecific predictor of subsequent of agranulocytosis within 75 days. (Meylers S/e of psy drugs)

 Pg 606 in last paragraph on eosinophilia 1st and 2nd statements - Contradictory statements (eosinophilia

?predictive or accompanied by life threatening side effects) 3rd and 4th statements manufacturer recommends discontinuation when eosinophil count > 3,000 and restart when below 1,000/cumm

DISCUSSION
Interpretation of data is justifiable & appropriate to study. No comparisons with previous reviews (may be not there). Limitations of the study described Further work need to be done was explained No important omissions Conclusions are reasonable Clinical implications of the study mentioned.

REFERENCES Adequate No important omissions

Conclusion ( take over message)

Research Implications An almost systematic review on most of clozapine induced medical

adverse effects All the previous reviews on side effects of clozapine are comprehensive or narrative reviews. May be first systematic review on clozapine side effects but not done completely like a systematic review.

 Clinical Implications Psychiatrists should be aware that the discontinuation of clozapine

treatment may exclude pts from effective treatment and can increase the risk of relapse, aggression and suicidal behavior. Neutropenia, leukocytosis, seizures, orthostatic hypotension, severe constiaption, wt gain, and metabolic abnormalities, including matabolic syndrome and its components, as well as moderately prolonged myocardial repolarization need to be managed but do not genarally warrant clozapine discontinuation. S/e eosinophilia, leukocytosis, drug induced fever without any medical cause and sunus tachycardia can be managed and should rarely lead to discontinuation of clozapine treatment.

 Clozapine discontinuation with potential rechallenge (providing there

is appropriate surveillance and management or prophylactic therapy) is indicated for ileus or subileus , NMS, venous thromboembolism, DKA or DHC. Other s/e such as agranulocytosis, myocarditis, cardiomyopathy, and a QTc Interval > 500ms that is confirmed and derived with appropriate correction method warrant the immediate discontinuation of clozapine treatment Mentioned in discussion Many of the s/e are idiosyncratic with no dependency (agranulocytosis, myocarditis) whereas some dose dependency for others (tachycardia and seizure) Clozapine is susceptible to severe pharmacokinetic interactions

 Smoking Smoking increases clozapine levels, may in extreme cases increase by

80% and have caused seizures Steady state plasma concentration for clozapine calculated Clozapine (in ng/ml)= 0.464D+111S+145 (men) =1.590D+111S 149 (women) Where D= dosage (mg/day) and S = 1 for smoker and S=0 for non smokers Advice abt smoking cessation most important as it is highly prevalent in pts with schizophrenia Infection and infalmmation also cause exteme plasma levels Addition of p450 inhibitors like fluoxamine or ketoconazole inc clozapine levels Dose reduction may solve the problem.

 Discontinuation of clozapine should be tapered off over a period of

weeks to months , depending on variables like size of dosage, psychotic symptoms, and duration of treatment If terminating abruptly increases the risk of rebound psychosis and anticholinergic withdrawal syndrome Can be overcome by adding another anticholinergic drug And olanzapine can be used for preventing rebound psychosis (though some case reports concern that olanzapine could prolong neutropenia period)

Suggestions
To consider a more structured systematic review overcoming the

limitations of this study To consider a meta-analysis and pooled analysis by using statistical methods To consider almost all the side effects for the review To consider review of psychiatric side effects of clozapine like OC symptoms, worsening of bulimia nervosa,

Thank you
Further comments ????

Further suggestions ???