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Use of high doses of quetiapine in
Réunion
Ambulatoires
SAS,
8.5.2006
bipolar disorder episodes is not linked to
high activity of cytochrome P4503A4
and/or cytochrome P4502D6
Yasser
1
Khazaal ,
Daniele Fabio
1
Zullino ,
Chin
2
Eap
1Division
of Substance Abuse, University Hospitals of Geneva
2Department of Psychiatry, University Hospitals of Lausanne
Results
Introduction


Quetiapine as monotherapy (Vieta et al., 2005; Bowden et al.,
2005; McIntyre et al., 2005) or in combination with other mood
stabilizers (Sachs et al., 2004; Yatham et al., 2004) is efficacious in
the treatment of acute mania, as well as monotherapy in bipolar
depression (Calabrese et al., 2005). Although the maximal
quetiapine doses in the published studies have been restricted to
800mg/day, higher quetiapine doses are not unusual in clinical
practice. Quetiapine is predominantly metabolized by cytochrome
P450 3A4 (CYP3A4) and to a lesser extent by CYP2D6. The large
interindividual variability of these isozyme activities could contribute
to the variability observed in quetiapine dosage.
The aim of the present study was to evaluate if the use of high
dosages of quetiapine clinical practice could be explained by a high
activity of CYP3A4 and/or of CYP2D6

Demographic and metabolic data measured in the high and
normal dose groups are shown in Table one

One patient in the high dose and one patient in the normal
dose groups were genotyped as CYP2D6 ultrarapid
metabolizers.

CYP3A4 activities were not significantly different between
the two groups, with even a trend for a higher CYP3A4
activity in the normal dose group as compared to the high
dose group (midazolam metabolic ratio: 9.4 ± 8.2 ; 6.2; 1.726.8 versus 3.9 ± 2.3 ; 3.8; 1.5-7.6, respectively, p = 0.06).

The results were not due to concomitant medications
Table 1 Group comparisons
Age


(n = 12)
43±12
p=0.86
22%
75%
p<0.001
Smokers
78%
75%
p=0.6
1467;1200
433;350
p=0.002
Quetiapine serum/plasma concentrations (mean; median)[ng/ml]
303;287
64;44
p=0.006
Midazolam metabolic ratio
3.9;3.8
9.4;6.2
p=0.06
11%
8.30%
p=0.28
CYP3A4
Methods

(n = 9)
Female
CYP2D6 ultrarapid metabolizer
Quetiapine
Normal dose
44±12
Maximum quetiapine doses (mean; median)[mg/d]
CYP2D6
High dose
CYP3A4 activities were determined using the midazolam metabolic
ratio in 21 bipolar and schizoaffective bipolar patients genotyped for
CYP2D6. 9 patients were treated with a high quetiapine dosage
(mean ± SD, median; range: 1467 ± 625,1200; 1000-3000 mg/day)
and 12 with a normal quetiapine dosage (433 ± 274, 350; 100-800
mg/day).
CYP3A4 activity was measured using the midazolam metabolic
ratio (MR) as previously described (Eap et al., 2004). In summary,
following oral administration, midazolam is oxidized to 1’-OH
midazolam by CYP3A4. The test measures the 1’OH-midazolam /
midazolam plasma MR half an hour after oral intake of 0.075 mg of
midazolam (Eap et al., 2004)
Genotyping of CYP2D6 was performed by real-time polymerase
chain reaction with the use of 5’-nuclease allelic discrimination
assays
Limitations
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Lack of concomitant clinical data on mood episodes
One recruitment center
Sample size is too small to detect differences due to
CYP2D6
Conclusions
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The present study shows that, the use of higher than
licensed range of quetiapine cannot be explained by a high
activity of CYP3A4 and/or CYP2D6, the two main enzymes
involved in quetiapine metabolism.
The present results did not contest that individual patients
may receive a high quetiapine dose in relation to high
activity of CYP3A4 and/or of CYP2D6.
Further studies are needed to explore the influence of other
genetic variability and of clinical factors (Khazaal et al.,
2007) which could contribute to the interindividual variation
of administered quetiapine doses for bipolar disorders and
for schizoaffective episodes.
References
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Sachs G, Chengappa KN, Suppes T, Mullen JA, Brecher M, Devine NA, Sweitzer DE: Quetiapine with lithium or divalproex for the treatment of bipolar mania: a randomized, double-blind, placebo-controlled study. Bipolar Disord 2004, 6: 213-223.
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Yatham LN, Paulsson B, Mullen J, Vagero AM: Quetiapine versus placebo in combination with lithium or divalproex for the treatment of bipolar mania. J Clin Psychopharmacol 2004, 24: 599-606.
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Calabrese JR, Keck PE, Jr., Macfadden W, Minkwitz M, Ketter TA, Weisler RH, Cutler AJ, McCoy R, Wilson E, Mullen J: A randomized, double-blind, placebo-controlled trial of quetiapine in the treatment of bipolar I or II depression. Am J
Psychiatry 2005, 162: 1351-1360.
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Eap CB, Buclin T, Cucchia G et al. Oral administration of a low dose of midazolam (75 microg) as an in vivo probe for CYP3A activity. Eur.J Clin.Pharmacol. 2004;60:237-46.
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Khazaal Y, Tapparel S, Chatton A, Rothen S, Preisig M, Zullino D. Quetiapine dosage in Bipolar disorder episodes and mixed states. Progress in Neuro-Psychopharmacology & Biological Psychiatry 2007 (in press).
Service d’abus de substances
Département de Psychiatrie
WHO Collaborating Center
for Training and Research in
Substance abuse