Amerindians may need clozapine dosing similar to that of Asians

Dear Editor:

Clozapine is mainly metabolized by the cytochrome 1A2 (CYP1A2). CYP1A2 activity ranges from lowest in female non-smokers to highest in male smokers (estrogens are inhibitors and smoking is an inducer). To reach a therapeutic response requires 350 ng/ml of serum clozapine concentration. The concentration-to-dose (C/D) ratio¹ represents the linear relationship between clozapine dose and concentration.¹ A very high C/D ratio indicates a poor metabolizer (PM) phenotype^1,2 which can be explained by a potent inhibitor such as fluvoxamine, systemic inflammation and possibly obesity.^1,2 After excluding non-adherence, a very low clozapine C/D ratio indicates an ultrarapid metabolizer (UM) phenotype, possibly explained by powerful inducers such as carbamazepine.² Valproate is usually a mild inducer or inhibitor.^1,2

Having less CYP1A2 activity than Caucasians, Asians need lower clozapine doses according to: (1) a meta-analysis,³ (2) a study of 5 Asian samples,² and (3) a review of Asian dosing.⁴ Asians typically had clozapine C/D ratios from 1.2 to 2.4; Asian female non-smokers need 150 mg/day and male smokers 300 mg/day to reach 350 ng/ml.⁴

The Amerindians (the indigenous people from the Americas) are of East Asian origin.⁴ This reanalysis of a sample⁵ from Mexico City with trough steady-state levels identified 52 Mexican average metabolizers after excluding potential clozapine PMs and UMs. We explored the clozapine dosages needed to reach 350 ng/ml after stratification by sex and smoking (Table 1) and compared them with those from the 5 Asian samples.²

Table 1.

Comparing mean clozapine C/D ratios after stratification by sex and smoking status in 5 Asian samples (N = 508) and in a study in Mexico City (N = 52^a).

Group	Sample	N	Age (year)	Dose (mg/day)	C/D ratio		Dose to reach^b
					Clozapine	Total	>350 ng/ml (mg/day)
♂ smokers	Beijing 1	22	46.6	271	1.34 ± 0.59	1.98 ± 0.84	261
	Beijing 2	49	40.6	341	1.31 ± 0.95	1.90 ± 1.22	267
	Taipei	22	36.1	286	1.19 ± 0.54	1.82 ± 0.84	294
	Seoul	15	37.3	378	1.35 ± 0.71	2.05 ± 1.01	259
	Vellore	19	39.0	401	1.29 ± 1.07		271
Weighted mean		127			1.30		270
	Mexico City	10	38.9	275	1.29 ± 0.88		280
♀ smokers	Beijing 1	5	54.6	301	1.50 ± 0.58	1.90 ± 1.22	NC
	Beijing 2	2	39.0	313	1.11 ± 0.46	1.50 ± 0.46	NC
	Taipei	3	36.3	325	1.24 ± 0.48	2.03 ± 0.80	NC
	Seoul	1	38	450	0.88	1.59	NC
Weighted mean		11			1.30		270
	Mexico City	5	31.4	230	1.06 ± 0.24		330
♂ non-smokers	Beijing 1	35	37.2	230	1.71 ± 0.78	2.49 ± 1.04	205
	Beijing 2	65	42.8	262	1.50 ± 0.90	2.12 ± 1.12	233
	Taipei	29	36.0	300	1.80 ± 1.07	2.65 ± 1.42	194
	Seoul	26	31.0	347	1.70 ± 0.84	2.58 ± 1.02	206
	Vellore	54	33.8	329	1.78 ± 1.19		197
Weighted mean		209			1.67		210
	Mexico City	18	35.7	294	1.76 ± 1.13		199
♀ non-smokers	Beijing 1	64	45.1	202	2.11 ± 0.74	2.97 ± 1.00	166
	Beijing 2	75	46.5	297	2.03 ± 1.64	2.87 ± 2.12	172
	Taipei	31	39.1	254	2.38 ± 1.41	3.38 ± 2.00	147
	Seoul	25	32.4	282	2.41 ± 1.02	3.72 ± 1.52	145
	Vellore	28	36.2	323	1.85 ± 1.16		189
Weighted mean		233			2.12		166
	Mexico City	19	38.2	228	1.89 ± 1.14		185

C/D: concentration-to-dose; NC: not calculated due to the small sample size.

a

There were some patients with low doses (≤100 mg/day), which is a problem because they were frequently used for an indication other than treatment-resistant schizophrenia and they appear to be associated with non-linear kinetics. After eliminating those patients contaminated with valproate and those with low doses (≤100 mg/day), there were 52 patients left.

b

Mean dose needed to reach a concentration of 350 ng/ml was calculated by dividing 350 by mean clozapine C/D ratio.

In 19 female non-smokers from Mexico City, the recommended average clozapine dosage was 185 mg/day which is: (1) within the range of 145–189 mg/day in similar Asians, and (2) not far from the weighted mean of 166 mg/day in 233 Asian female non-smokers.

In 18 male non-smokers from Mexico City, the recommended average clozapine dosage was 199 mg/day which is: (1) within the range of 194–205 mg/day in similar Asians, and (2) not far from the weighted mean of 210 mg/day in 209 Asian male non-smokers.

In 5 female smokers from Mexico City, the recommended average clozapine dosage was 330 mg/day, but this group was too small for the authors to comment. In 10 male smokers from Mexico City, the recommended average clozapine dosage was 288 mg/day which is: (1) within the range of 259–294 in similar Asians, and (2) not far from the weighted mean of 270 mg/day in 127 Asian male smokers.

The sample of Mexico City fits within the Asian samples, suggesting similar clozapine clearance and need for the same low clozapine doses as Asians, but this data is limited by the lack of control for inflammation and obesity. Many American countries have populations of Amerindian origin; thus, future clozapine studies need to explore dosing after better control of variables and careful consideration of ancestry. Until then, psychiatrists working in the Americas may need to use clozapine doses ranging from 150 to 300 mg/day for average-metabolizer patients with predominant Amerindian ancestry. These clozapine doses are lower than those required for average-metabolizer patients of Caucasian and/or African ancestry.¹

Disclosure statement

This article was completed without any external funding. No commercial organizations had any role in the writing of this paper for publication. In the last 3 years, the authors had no conflicts of interest.

Acknowledgments

Lorraine Maw, M.A., at the Mental Health Research Center, helped with editing.