Finding the right dosage of a psychotropic may be notoriously time consuming, but thought should be granted to the sexually dimorphic expression of CYP450 enzymes when prescribing medication.
SIGNIFICANCE FOR PRACTICING PSYCHIATRISTS
The human cytochrome P450 (CYP450) enzyme system operates primarily in the liver and is found in large amounts in the intestines. These enzymes are responsible for metabolizing a wide array of compounds from various classes, including many psychotropic medications. Variability in the performance of CYP450 enzymes is common and strongly affects how a person will react to medication. Pharmacogenomic tests can reveal the efficiency with which a patient’s CYP450 enzymes operate, providing classifications into metabolizer types: poor, intermediate, extensive, and ultrarapid. A person’s metabolizer type for an enzyme affects how he or she will respond to pharmacologic agents processed by that particular enzyme. Dosages inconsistent with a patient’s metabolizer type can be ineffective and/or increase the risk of adverse events.
Multiple recent studies suggest that there is a correlation between gender and metabolizer type for several of the most medically relevant CYP450 enzymes. When patients have above-average metabolism for a certain CYP450 enzyme they may need to take a higher dose of medication to achieve therapeutic efficacy. Similarly, patients who are slow enzyme metabolizers, and are prescribed too high a dose of medication, run the risk of experiencing significant adverse effects.
For many medications, dosage does not take gender into account with women and men receiving similar dosages relative to their size. Pharmacogenomic testing is (currently) primarily used on medically complex patients or those with treatment-resistant conditions and failed previous trials. Its utility and cost-effectiveness as a first step rather than a last resort has yet to be demonstrated.
Evidence exists to suggest that there may be a correlation between sex and metabolizer type for certain CYP450 enzymes.1 This knowledge can be used to inform the prescription of medications metabolized by these enzymes. Taking information about the expression of each metabolizer type by sex into account can increase the likelihood of initiating an effective dose of medication earlier in the course of illness without needing to conduct genetic testing on individual patients.
Psychotropic tests analyze roughly 16 genes to determine how they affect a person’s metabolism of psychotropic medications. Six of the genes encode CYP450 enzymes. There is significantly less evidence for sex differences in the metabolism of CYP2B6, CYP2C19, and CYP2C9 compared with the CYP450 enzymes discussed at length in this review. A 2003 study of CYP2B6 suggested that women have higher metabolic activity than men.2 There is little information available about the effect of gender on CYP2C9. Two studies have failed to establish a sex-related difference in CYP2C19 activity.3,4
CYP1A2. The CYP1A2 gene encodes a protein that metabolizes a large variety of antidepressants, antipsychotics, and sedative/hypnotics. It is one of the more frequently studied CYP450 enzymes and demonstrates large variability in populations tested. In general, extensive metabolism is considered normal enzyme activity and would be expected to be detected in a majority of the population. However, in a retrospective analysis of data gathered from a neuropsychiatric clinic, Ramsey and colleagues5 found that 86.4% of patients displayed altered function in the form of enhanced induction of the CYP1A2 enzyme.
In the US, 49% of the general population is classified as ultrarapid or poor metabolizers of CYP1A2.6 The results regarding sex differences in CYP1A2 metabolism are mixed, with some studies failing to establish a statistically significant difference. However, a study conducted in 2000 by Ou-Yang and colleagues7 established that CYP1A2 activity was generally higher in men than women. A study by Karjalainen and colleagues8 in 2008 supported these findings by demonstrating that certain oral contraceptives and female sex hormones are inhibitors of CYP1A2 activity. Thus, women are likely to have slower CYP1A2 metabolism than men. Because above-average metabolizers more quickly process CYP1A2 substrates, men may require higher doses of certain medications to achieve response.
Although on average, men may have faster CYP1A2 metabolism than women, individual differences should be taken into account. Many women may have faster than typical metabolism. With this knowledge, physicians may decide to start women on slightly lower dosages of medications metabolized by CYP1A2, hopefully limiting the risk of adverse effects but keeping in mind the possibility of a need to increase the dose. Similarly, physicians may decide to start men on a slightly higher dosage, limiting the number of adjustments before the patient starts responding to treatment.
CYP2D6. Although there are more than 50 different CYP450 enzymes, just six metabolize 90% of drugs. The two most significant enzymes of this class are CYP2D6 and CYP3A4. Studies on the effect of sex on CYP2D6 metabolism have yielded mixed results, but there is evidence to suggest that activity is slightly higher in females. A study conducted by LabbÃ© and colleagues9 in 2000 involved men who were phenotyped monthly over the course of a year and women phenotyped every other day over the course of one complete menstrual cycle. The results showed high variability in CYP2D6 activity regardless of sex and phenotype. The study reported that about 80% of observed variability was explained by urinary pH variations. Due to weight-based dosing, men are frequently prescribed higher doses of medication than women. Such dosing practices may be ineffective; the findings from Haag and colleagues10 suggest that women may actually need higher dosages of medications metabolized by CYP2D6 than men.
CYP3A4. As explained above, the CYP3A4 enzyme is one of the two most medically significant CYP450 enzymes. Multiple studies have found that CYP3A4 is predominantly expressed by women. Waxman explains that the temporal pattern of plasma growth hormone regulates genes expressed in the liver. Sex differences are seen in plasma growth hormone released by the pituitary gland, contributing to the difference in CYP450 expression by sex. Waxman and Holloway11 established that most variability in the metabolism of medications between men and women results from the uneven expression of CYP3A4 and the frequency of medications reacting with this enzyme. The CYP3A4 enzyme has arguably the most research to suggest sexually dimorphic expression of any CYP450 enzyme. Substrates of CYP3A4 have been found to have higher clearance levels in women than men. In 2003, Wolbold and colleagues12 found that surgical liver samples from women contained levels of CYP3A4 that were double those of men on average. The study showed that the findings were not due to higher drug exposure resulting in preferential induction.
Thought should be granted to the sexually dimorphic expression of CYP450 enzymes when prescribing medication. This family of enzymes is responsible for the metabolism of a wide variety of medications, including psychotropics. Finding the right dosage of a psychotropic may be notoriously time consuming, requiring multiple trials and errors. Knowledge about the differences in expression of CYP450 enzymes between the sexes can inform treatment direction and, in many cases, decrease the number of medication trials needed for patient response.
The three enzymes discussed (CYP1A2, CYP2D6, and CYP3A4) in this review are among the six cytochrome P450 enzymes that metabolize over 90% percent of drugs.13 Out of the enzymes in this family, these three have the most extensive research base suggesting gender differences in their expression.
Further research is needed to more firmly establish the sexual variance in metabolizer type for CYP450 enzymes as some studies fail to establish statistically significant differences. Still, multiple studies suggest that CYP3A4 and CYP2D6 are more predominantly expressed in women. Both of these enzymes are involved in the metabolism of a very large number of medications. This can inform the prescription of certain medications as women may need higher dosages relative to their size than men do.
Men have been found to more highly express the CYP1A2 enzyme, but the majority of people of either sex have above-average metabolism for CYP1A2. Paying attention to CYP450 enzyme activity differences between men and women may help physicians to prescribe accurate dosages of certain medications more quickly and with less trial and error (Table). Arguments for early pharmacogenomic testing are thus noteworthy.
Ms Chavira is an undergraduate, University of Virginia; Dr Kablinger is Professor and Director of Clinical Trials Research, and Dr Rahmani is PGY3 Resident, Department of Psychiatry and Behavioral Medicine, Virginia Tech Carilion School of Medicine and Research Institute, Roanoke, VA.The authors report no conflicts of interest concerning the subject matter of this article.
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