Drug Information Request
Resident: Jen Houser
Requested by: Dr. Resch
Date Requested: October 11, 2011
Date Information needed by: October 18, 2011
Question: Is there evidence to support a correlation between clozapine (or norclozapine levels) and
therapeutic efficacy?
A review article published in 2003 regarding this topic stated that the clinical application of therapeutic
drug monitoring for clozapine is unclear.1 There is significant inter- and intra-individual variations in
clozapine levels for a given dose due to its complicated metabolism. One study reported an eight-fold
inter-individual variation in patients on 400 mg of clozapine daily.2 It has been suggested that this may
be partly due to the genetic variability of CYP450 activity.3 However, a number of studies have
demonstrated a link between clinical response and a therapeutic range for clozapine. The range for
therapeutic efficacy supported by several studies is between 350 and 420 mcg/L.4-8
Specifically examining norclozapine levels, a study was performed in 2000.9 Clozapine was administered
up to 500 mg/day for 12 weeks. Steady-state plasma concentrations of clozapine and norclozapine were
measured at the end of the study period. The Brief Psychiatric Rating Scale (BPRS) was used to assess
response and administered at baseline and at week 12. Patients were considered responders if they
showed a greater than 20% reduction in total BPRS score compared with baseline and a final BPRS score
of 35 or less. At the end of the study, mean plasma clozapine concentrations were higher in responders
(n=18) than in non-responders (n=27) (472 ± 220 vs. 328 ± 128 ng/ml, p<0.01), whereas plasma
norclozapine levels did not differ between the two groups (201 ± 104 vs. 156 ± 64 ng/ml, NS). A
significant positive correlation between plasma levels and percent decrease in total BPRS score was
found for clozapine (p<0.02), but not for norclozapine (NS). The cutoff value of 350 ng/ml for clozapine
differentiated responders from non-responders with a sensitivity of 72% and a specificity of 70%. The
incidence of side effects was twice as high at clozapine concentrations greater than 350 ng/ml compared
with lower concentrations (38% vs. 17%). It was recommended to avoid initially dosing clozapine with
the aim of 350 ng/ml or greater due to the fact that many patients respond well at lower plasma
clozapine concentrations. However, increasing the dosage to achieve plasma levels above 350–400
ng/ml may be indicated in patients without side effects who fail to show improvement at standard
dosages or at lower drug concentrations.
Unlike the range of clozapine for efficacy, the range that corresponds with toxicity remains unclear.
According to one study, it was found that CNS side effects such as seizures, delirium and confusion may
correlate with a serum level greater than 1000 ng/ml.10 However, other adverse effects of clozapine
appear to be unrelated to plasma levels, including hematological (i.e. agranulocytosis) and cardiac
events.11
It is important to keep in mind factors that can affect serum clozapine levels such as adherence, timing
of blood samples, nicotine/caffeine and concurrent medications. According to the review article
published in 20031, although routine monitoring is not recommended, there are several indications for
therapeutic monitoring of clozapine which include:
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Poor clinical response to routine doses
Concern about non-adherence
Patient is changing his/her usual intake of caffeine or nicotine
Signs of toxicity or adverse events
Use of concurrent medications that are known to interact with CYP450 (particularly CYP1A2)
Patient is suspected/known to have liver disease
References
1. Greenwood-Smith C, Lubman DI, Castle DJ. Serum clozapine levels: a review of their clinical
utility. J Psychopharmacol 2003; 17(2):234-8.
2. Olesen OV, Thomsen K, Jensen PN, et al. Clozapine serum levels and side effects during steady
state treatment of schizophrenic patients: a cross sectional study. Psychopharmacology 1995;
117:371-8.
3. Mitchell PB. Therapeutic drug monitoring of psychotropic medications. Br J Clin Pharmacol 2000;
49:303-12.
4. Hasegawa M, Gutierrez-Esteinou R, Way L, et al. Relationship between clinical efficacy and
clozapine concentrations in plasma in schizophrenia: effect of smoking. J Clin Psychopharmacol
1993; 13:383-90.
5. Kronig MH, Munne RA, Szymanski S, et al. Plasma clozapine levels and therapeutic response for
treatment refractory schizophrenic patients. Am J Psychiatry 1995; 152:179-82.
6. Perry PJ, Miller DD, Arndt SV, et al. Clozapine and norclozapine plasma concentrations and
clinical response of treatment-refractory schizophrenic patients. Am J Psychiatry 1991; 148:2315.
7. Potkin SG, Bera R, Gulasekaram B, et al. Plasma clozapine concentrations predict clinical
response in treatment-resistant schizophrenia. J Clin Psychiatry 1994; 55(Suppl B):133-6.
8. Miller DD, Fleming F, Holman TL, et al. Plasma clozapine concentrations as a predictor of clinical
response: a follow-up study. J Clin Psychiatry 1994; 55(Suppl B):117-21.
9. Spina E, Avenoso A, Facciola G, et al. Relationship between plasma concentrations of clozapine
and norclozapine and therapeutic response in patients with schizophrenia resistant to
conventional neuroletpics. Psychopharmacology 2000; 148(1):83-9.
10. Freeman DJ, Oyewumi LK. Will routine therapeutic drug monitoring have a place in clozapine
therapy? Clin Pharmacokinet 1997; 32:93-100.
11. Coulter DM, Bate A, Meybroom RHB, et al. Antipsychotic drugs and heart muscle disorder in
international pharmacovigilance: data mining study. BMJ 2001; 322:1207-9.
Completion Date: October 14, 2011
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Christopher Thomas Pharm.D., BCPP, BCPS, CGP, FASCP