August 2010

The Generic Medication Question
Variability in the bioavailability of generic medications can affect efficacy and tolerability in some patients.

Anticonvulsants and Suicide Risk
Findings from a recent study support the US Food and Drug Administration's 2008 conclusion that anticonvulsants increase the risk of suicidal ideation and behavior.

Antidepressant-Induced Mania?
Evidence from a meta-analysis of controlled and open trials suggests that antidepressants increase the risk of a switch from depression into hypomania or mania in patients with bipolar disorder and in those with major depression.

Medications to Reduce Antipsychotic-Induced Weight Gain
The overall effect of medications as antidotes to antipsychotic-induced weight gain is modest; diet and exercise should be the first-line strategy.

In Brief
Veterans with PTSD Have Greater Risk of Dementia; Bupropion Safe and Effective Aid for Smoking Cessation in Schizophrenia

Smoking and Clozapine Levels
Elevations in plasma clozapine (Clozaril and others) concentrations following smoking cessation can be dramatic and potentially lead to serious toxicity.

Smoking and Clozapine Levels

August 2010

Among antipsychotics, only clozapine (Clozaril and others) has evidence for superior efficacy over other agents. Clozapine's clinical benefits, however, are purchased at the cost of numerous adverse effects—some life threatening.

The relationship between clozapine plasma levels and clinical effects are incompletely understood. Still, there are suggestions that (1) levels between 350 and 500 µg/L are therapeutic, and (2) the risk of seizure rises significantly when plasma levels exceed 1000 µg/L.

Clozapine is metabolized primarily via the 1A2 isoform of the cytochrome P450 (CYP) system, which is induced by tobacco smoke metabolites. Smoking tobacco, therefore, lowers plasma concentrations of clozapine and, conversely, smoking cessation raises them. Plasma clozapine levels may increase up to 50% in smokers following smoking cessation.1 Adverse events related to increased plasma clozapine levels have been reported in clozapine-treated patients who stopped smoking.

Cormac and others in the United Kingdom studied clozapine dosing and plasma clozapine levels before and after their hospital became smoke-free.2 At the time the policy was implemented, roughly 70% of their patients were heavy smokers. Investigators collected data on 48 smokers and 3 nonsmokers from 3 months before through 6 months after the policy change.

Before the hospital implemented its smoke-free policy, the mean plasma clozapine level was 500 µg/L in smokers and 700 µg/L in nonsmokers. As expected, clozapine levels in nonsmokers showed no significant change when smoking was forbidden. By contrast, the mean plasma clozapine level among former smokers increased from 500 to 900 µg/L (P = .0005). Before the ban, only 2 of the 48 clozapine-treated smokers had plasma clozapine levels above 1000 µg/L (considered hazardous). Six months after the ban, 20 of the 48 had plasma levels above 1000 µg/L. One of these patients experienced a seizure, and two others had myoclonic jerks. Another patient had a jump in plasma levels from 770 to 2150 µg/L. These striking increases in plasma clozapine concentrations occurred despite the fact that, when they stopped smoking, more than half of the patients had clozapine dosage reductions of up to 25% and some had dosages reduced more than 50%.

The authors conclude that elevations in plasma clozapine levels following smoking cessation can be dramatic and potentially lead to serious toxicity, sometimes despite substantial dosage reductions. Dosage decreases following smoking cessation may need to be more aggressive than in these patients. Certainly, patients should be observed carefully during this transition. The authors propose careful monitoring of plasma clozapine levels, pointing out that outpatient smokers who take clozapine and are admitted to a smoke-free facility are at risk of plasma concentration increases and potential adverse consequences. Conversely, a stabilized inpatient who is discharged and then resumes smoking may experience decreased plasma concentrations at a given dosage, with possible loss of clinical stability.

1De Leon J: Atypical antipsychotic dosing: The effect of smoking and caffeine. Psychiatr Serv 2004;55:491-493.

2Cormac I, Brown A, Creasey S, Ferriter M, Huckstep B. A retrospective evaluation of the impact of total smoking cessation on psychiatric inpatients taking clozapine. Acta Psychiatr Scand 2010;121:393-397.