Clozapine s side-effects put into perspective. Dan Cohen, psychiatrist FACT-team Heerhugowaard, The Netherlands Mental Health Organization North-Holland North, Netherlands, Europe
Disclosure No conflict of interests Membership of the Dutch Clozapine Collaboration Group
The Low- or Netherlands ( Holland ) with 17 million inhabitants FACT NHN 3
The special effects of clozapine: when is it time for the drug of last resort? Grant your patient an adequate trial
Side-effects a) Uncommon dangerous side-effects: - definition - incidence - detection - treatment b) Common & harmless, potentially dangerous side-effects: - incidence - detection - treatment
a. Uncommon dangerous side-effects Side-effects that are - uncommon - emerge during clozapine treatment - lethal when not timely diagnosed and adequately treated
How lethal are these side effects? Review of literature between 1990-2010 - Agranulocytosis - DKA - Myocarditis/cardiomyopathy Cohen, Bogers, van Dijk, Bakker, Schulte. J Clin Psychiatry 2012
Leukopenia and agranulocytosis 1. The first thing that comes to mind. 2. Clozapine s best studied serious side-effect. 3. This side-effect has negatively affected clozapine prescription
Leukopenia and agranulocytosis: the cut-off points US UK Australia Moderate leukopenia WBC 3000 WBC 3000 or ANC < 2000 WBC 3000 Severe leukopenia WBC < 2000 WBC <2000 or ANC <1000 WBC < 2000 Agranulocytosis WBC 1000 or WBC: white blood cell count ANC: absolute neutrophil count ANC 500 WBC 1000 or ANC <500 WBC 1000 or ANC 500 V. Kumar. FDA.gov
Differential diagnosis of leukopenia 1. Benign ethnic neutropenia (BEN) 2. Intercurrent bacterial or viral infection 3. Diurnal variation: leucocytes counts in blood shows a diurnal variation: lowest in the morning, highest in the afternoon
Benign Ethnic Neutropenia Definition Lower mean white blood cell (WBC) count without any signs of illness = lower WBC count in the normal, healthy population. Population People of African, Caribbean or Middle-Eastern origin
BEN: cut-off points WBC Neutrophils BEN Regular BEN Regular Green (=satisfactory WBC) > 3,0 x 10 9 > 3,5 x 10 9 > 1,5 x 10 9 > 2,0 x 10 9 Amber (repeat WBC) 2,5 3,0 x 10 9 3,0-3,5 x 10 9 1,0-1,5 x 10 9 1,5-2,0 x 10 9 Red (= immediate cessation of clozapine) < 2,5 x 10 9 < 3,0 x 10 9 < 1,0 x 10 9 < 1,5 x 10 9 Rajagopal Postgrad Med J 2005
Intercurrent infection (Patho-)physiology Initial phase of infection Increased adherence of leucocytes to the vascular wall Leucocytes crossing the vascular wall Leucocyte migration towards the infected cell Death of leucocytes Result: lowered WBC plasma level = lowered WBC count Only later will infection result in increased production and levels of leucocytes (= leukocytosis)
Diurnal variation Diurnal variation: leucocytes counts in blood show diurnal variation lowest in the morning, highest in the afternoon Advise after the first leukopenia: - Rule out a mistake -> repeat WBC count from morning blood sample - Rule out diurnal variation -> WBC count from afternoon sample
Agranulocytosis Onset: 80-85% in the initial first 6 months Incidence Mortality Total population Affected cases 3,8 8.0 0,1 0,3 2,2%- 4,2% Cohen, Bogers, van Dijk, Bakker, Schulte. J Clin Psychiatry 2012
Treatment emergent agranulocytosis: general recommendation 1. Establish a working alliance with an internist and/or hematologist before initiation of clozapine treatment, whom you can consult if necessary. 2. When leukopenia emerges, consult the internist/hematologist.
1.a. Other uncommon serious side-effects - Diabetic Keto-Acidosis (DKA) - Myocarditis
Diabetic Keto-Acidosis Rarely occurring severe disruption of the glucose homeostasis or severe worsening of pre-existing DM Cause: acute shortage of insulin Pathophysiological mechanisms are unclear
Diabetic Keto-Acidosis Outcome: - metabolic acidosis - metabolic ketosis - if undetected and therefore untreated: coma and death
Diabetic Keto-Acidosis Reported cases occurred most frequently with olanzapine or clozapine But Cases have been reported with all atypical antipsychotics
Diabetic Keto-Acidosis in clozapine treatment Onset seems to be restricted to the initial 3 months of treatment Diagnosis may occur later, after the hyperglycemia has become more severe and has lead to metabolic complications. Cohen, Bogers, van Dijk, Bakker, Schulte. J Clin Psychiatry 2012
Diabetic Keto-Acidosis in clozapine treatment Incidence Mortality Total population Affected cases 1,2-3,1 0,2-4,4 20,0%- 31,0% Cohen, Bogers, van Dijk, Bakker, Schulte. J Clin Psychiatry 2012
Myocarditis Onset: restricted to the initial 1 month of treatment Incidence Mortality Total population Affected cases Australia 7,0 34.0 0-1,2 0%- 13% Rest of world 0,07 0,6 0-0,2 0%- 68%
b. Common & harmless: the case of constipation Constipation occurs in 25,1% of clozapine-treated patients. Danger: severe constipation can result in (sub-)ileus and eventually death. Meltzer InterSept Trial. Arch Gen Psychiatry 2003
Risk factors of GIH 1. Co-medication: anticholinergic drugs or other drugs that cause constipation. Caveat: medication is only co-medication from a psychiatric point of view, not from that of the GP or somatic specialist. 2. Dosage: more risk with higher dosage 3. Treatment duration: conflicting results. initial phase: 36% < 4 months, 50% < 1 year (Palmer) maintenance phase: mean duration 1528 days (Nielsen) Palmer J Clin Psych 2008; Nielssen & Meyer Schizophr Bull 2011
GIH: (sub-)ileus Incidence Mortality Total population Affected cases 4-8 0,98 1,19 15,0%- 27,5%
Comparison of incidence ( ) & mortality rates of all 4 dangerous side effects of clozapine. Incidence Mortality Total population ( ) Total population ( ) Incident cases Agranulocytosis 3,8 8,0 0,1-0,3 2,2-4,2% DKA 1,2-3,1 0,2-4,4 20,0-31,0% GIH 4,0-8,0 0,98-1,19 15,0-27,5 % Myocarditis: Australia 7,0 34,0 0-1,2 0-13% Rest of the world 0,07-0,6 0-0,2 0-68% Cohen, Bogers, van Dijk, Bakker, Schulte. J Clin Psychiatry 2012
Uncommon serious side-effects: agranulocytosis In general, psychiatrists are excessively worried over the chances and risks of agranulocytosis. They tend to be less worried about - some even unaware of other serious side effects. Both positions are wrong.
Incidence and mortality of agranulocytosis put into perspective Incidence Country Study pop Agranulocytosis Incidence USA N=99.500 382 cases 0.382% Australia N=11.000 33 cases 0.3% In the US-study, 12 patients died. Honigfeld J Clin Psych 1998; Drews Australasian Psych 2013
Incidence and mortality of agranulocytosis put into perspective Mortality rate - Affected population(12/382) = 3,14% - Total population (12/99.500) = 0,1 (= 1:10.000 patients) Honigfeld J Clin Psych 1998
Uncommon serious side-effects: incidence and mortality of agranulocytosis put into perspective Conclusion Within the framework of mandatory WBC monitoring, the risk of agranulocytosis is low and kept within acceptable borders.
Uncommon serious side-effects: agranulocytosis incidence and mortality in perspective Obligatory WBC-count has shown to be effective in preventing death as complications of agranulocytosis. What about the other 3 serious side-effects?
Screening advise for DKA, GIH and myocarditis Aim Reduction of the current high mortality rates to that of agranulocytosis
Screening advise DKA Baseline measurement of fasting plasma glucose (FPG) Monthly FPG measurement during the months at risk = the first 3 months of clozapine treatment Thereafter: yearly measurement of FPG
Screening advise DKA: the role of HbA1c HbA1c is a reliable predictor of long term DM complications reflects mean plasma glucose of the previous 2 months is therefore unsuitable for detection of rapidly developing new-onset DM and DKA
Screening advise GIH: two options and one obligation: Two options Option 1. Patients defecation pattern is a standard topic at every visit. Option 2. Patients defecation pattern is a standard topic at every visit and preventive prescription of macrocol laxative in all clozapine patients.
Screening advise GIH: two options and one obligation: Obligation Warn and inform the GP on - the risk of GIH as a side-effect of clozapine - the possibility of additional risk of constipation due to constipating effect of somatic (co-)medication.
Screening advise myocarditis 1. For reasons unknown, myocarditis in clozapine treatment is mainly a problem of Australia and New-Zealand. 2. There is no evidence that warrants routinely monitoring of treatment emergent myocarditis outside Australia and New- Zealand.
The special effect of clozapine: what is the right moment for prescription of this drug of last resort? Grant your patients a safe treatment with clozapine!
Thank you for your attention! d.cohen@ggz-nhn.nl
Questions?