Anita S. Kablinger, MD

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.

 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.

 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.

 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 colleagues

 found that 86.4% of patients displayed altered function in the form of enhanced induction of the 

In the US, 49% of the general population is classified as ultrarapid or poor metabolizers of 

 The results regarding sex differences in 

 metabolism are mixed, with some studies failing to establish a statistically significant difference. However, a study conducted in 2000 by Ou-Yang and colleagues

 activity was generally higher in men than women. A study by Karjalainen and colleagues

 in 2008 supported these findings by demonstrating that certain oral contraceptives and female sex hormones are inhibitors of 

 activity. Thus, women are likely to have slower 

 metabolism than men. Because above-average metabolizers more quickly process 

 substrates, men may require higher doses of certain medications to achieve response.

Although on average, men may have faster 

 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 

, 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.

 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 colleagues

 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 colleagues

 suggest that women may actually need higher dosages of medications metabolized by CYP2D6 than men.

 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 Holloway

 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 colleagues

 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.

 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 (

). 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.

 Islam MM, Iqbal U, Walther BA, et al. Gender-based personalized pharmacotherapy: a systematic review. 

 Lamba V, Lamba J, Yasuda K. Hepatic CYP2B6 expression: sex and ethnic differences and relationship to CYP2B6 genotype and CAR (constitutive andro-stane receptor) expression. 

 Bebia Z, Buch SC, Wilson JW, et al. Bioequivalence revisited: influence of age and sex on CYP enzymes. 

 Laine K, Tybring G, Bertilsson L. No sex-related differences but significant inhibition by oral contraceptives of CYP2C19 activity as measured by the probe drugs mephenytoin and omeprazole in healthy Swedish white subjects. 

 Ramsey T, Griffin E, Liu Q. Use of pharmacogenetic testing in routine clinical practice improves outcome for psychiatry patients. 

. New York: Oxford University Press; 2010.

 Ou-Yang D, Huang S, Wang W. Phenotypic polymorphism and sex-related differences of CYP1A2 activity in a Chinese population. 

 Karjalainen MJ, Neuvonen, PJ, Backman JT. In vitro inhibition CYP1A2 by model inhibitors, anti-inflammatory analgesics and female sex steroids: predictability of in vivo interactions. 

 LabbÃ© L, Sirois C, Pilote S, et al. Effect of sex, sex hormones, time variables and physiological urinary pH on apparent CYP2D6 activity as assessed by metabolic ratios of marker substrates. 

 Haag S, Spigset O, Dahlqvist R. Influence of gender and oral contraceptives on CYP2D6 and CYP2C19 activity in healthy volunteers. 

 Waxman DJ, Holloway MG. Sex differences in the expression of hepatic drug metabolizing enzymes. 

 Wolbold R, Klein K, Burk O, et al. Sex is a major determinant of CYP3A4 expression in human liver. 

 Lynch T, Price A. The effect of cytochrome P450 metabolism on drug response, interactions, and adverse effects. 

Articles

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. 

Should We Prescribe Different Dosages of Psychotropic Medications to Men and Women?

Early intervention is key in psychiatry because it may improve prognosis. This has been especially difficult with schizophrenia. There is a strong basis for schizophrenia as a neurodevelopmental disorder, and the illness may result from several factors: genetic inheritance, disturbance of the in utero environment, and exposure to biological and psychosocial factors in infancy and early childhood, to name a few. Early environmental risk factors for schizophrenia include urban and winter birth, fetal malnutrition and hypoxia, and prenatal viral infections; diverse risk factors such as paternal age, drug abuse, immigrant status, social adversity, and isolation also appear to be contributing factors.

The prodromal phase of schizophrenia has received a great deal of attention, and multiple biological markers have been identified that may allow earlier diagnosis and treatment of patients with the disease. Biological markers are defined as objective, measurable phenomena that may identify subjects at increased risk for development of disease and are often found not only in the patients but also in first-degree relatives. Biological markers may target etiology of the disease (risk factors for development of the illness), pathophysiology (abnormalities associated with the illness), or expression of the disease itself (manifestations of the illness). The 

summarizes some of the more common findings in schizophrenia based on the triad of etiology, pathophysiology, and disease manifestations.

We will review some well-known biological markers that have been studied, as well as ongoing research and where it is headed. The goal is to use biological markers to determine who is at risk for schizophrenia, to prevent the onset of schizophrenia in persons with prodromal symptoms, and, via early diagnosis and intervention, to reduce the severity of the illness in those who have schizophrenia. 

outlines a hypothetical model of how schizophrenia may be viewed along a continuum from neurodevelopmental phenomena to disease expression and its influences.


  Schizophrenia is a common disorder with a lifetime prevalence of approximately 1%. It is highly heritable, but the genetics are complex. Study findings have consistently demonstrated that the risk to relatives of a proband with schizophrenia is higher than that to relatives of controls. On review of chromosomal studies, there seems to be a particularly increased focus of interest involving chromosome 22q11, chromosome 1q22, and chromosome 1q42.

One of the genes that has received the most attention is that involving catechol-O-methyltransferase (COMT).

 The story of the COMT gene enlightens the pathway between gene and phenotype. This gene is located on chromosome 22q11, and COMT participates in the clearance of dopamine from synapses, a functional polymorphism involving the presence of either valine or methione altering enzyme activity. This protein product may be involved in regulation of neurotransmission related to schizophrenia. Studies evaluating the cognitive function of persons with different allele combinations at this gene have shown varying effects.

 Clinically, this information may help subcategorize patients, allowing for the tailoring of treatment to particular genetic types. One day, it may also provide the basis to screen for increased risk.


  Numerous studies have demonstrated that persons born in the winter and spring months have a 5% to 8% excess risk for schizophrenia, both in the northern and southern hemispheres, particularly for those with a negative family history. Further evidence suggesting the action of environmental factors in at least some forms of schizophrenia comes from associations with latitude, urban birth, household crowding, birth order, and famine during pregnancy.


  Minor physical anomalies have consistently been identified in those with early-onset schizophrenia and have helped differentiate patients from controls. These signs of poor neurologic maturation include high-steepled palate, hypertelorism, large head circumference, small nasal volumes, and soft signs such as a positive glabellar tap.


  A decline in scholastic abilities has been shown to identify children and adolescents in whom schizophrenia may develop.

 Research in this area has traditionally focused on neuropsychological testing; studies have shown that first-degree relatives have subtle impairments in attention, verbal memory, executive function, and working memory.

Working memory-the ability to maintain and use information in short-term memory modulated by the prefrontal cortex-has been the subject of increased focus, with deficits in working memory being reported in patients with schizophrenia. Harkavy-Friedman and associates

 evaluated the performance of patients with schizophrenia, their first-degree biological relatives, and nonpsychiatric controls and found that the patients were consistently impaired on working memory tasks. In contrast, their unaffected relatives were only impaired on working memory tasks with higher central executive processing requirements.


  Neuroimaging is on the cutting edge of schizophrenia research as techniques and resolution advance. CT scans consistently show ventricular enlargement in patients with schizophrenia. Structural MRI studies have shown reductions in the prefrontal cortex, the hippocampus, and the amygdala in patients with schizophrenia.

Positron emission tomography and single photon emission computed tomography techniques have been used to study neurotransmitter mechanisms. Magnetic resonance spectroscopy has also shown in vivo neurochemical changes in patients with schizophrenia, most notably a reduction in the concentration of N-acetylaspartate in the frontal and temporal cortical regions, indicating neuronal loss and supporting findings obtained using structural MRI studies of reduced gray matter in patients with schizophrenia.

In their study using functional MRI (fMRI), Holt and colleagues

 demonstrated that hippocampal and amygdala activity is elevated in persons with schizophrenia during the passive viewing of human faces. An interesting avenue of research would be possible if this is identified as the underlying pathophysiology of persecutory delusions.

In addition, there have been some studies that measure the relationship of the changes of specific brain structures both anatomically and functionally before and after antipsychotic treatment.

 The combination of neuroimaging and psychopharmacology is another stimulating area of research attempting to tie neuroimaging techniques such as MRI and fMRI to psychopharmacologic development and implementation.


  Eye tracking dysfunction (ETD) is a well-researched phenomenon that includes both the smooth pursuit and saccade systems. Saccades are very rapid movements used to move the eye quickly toward a target. During smooth pursuit, patients with schizophrenia follow a target slowly (ie, the speed of the eye is slowed in comparison to normal speed) and then show compensatory saccades to correct the error in eye position. Studies have shown that patients with schizophrenia and their family members have ETD.

Neurochemical findings of note include decreased plasma homovanillic acid (pHVA), the major metabolite of dopamine. Unfortunately, it is unclear whether and to what degree pHVA is a measure of central dopamine activity.

 Future neurochemical studies will focus on more specific proteins involved in dopamine uptake and metabolism in patients and unaffected relatives. One such example is the regulator of G protein signaling (RGS) molecules, which are a class of proteins that modulate the signaling activity of G protein coupled receptors. Because RGS4 is associated with the dopamine receptor, it is of particular interest in schizophrenia. RGS4 expression is altered in affected CNS tissue, and polymorphisms in the RGS4 gene are being examined as risk factors for the disease.

Another interesting neurophysiologic response in schizophrenia is prepulse inhibition (PPI) of startle. Reduced or abnormal PPI in schizophrenia is among the most consistent markers of brain-based inhibitory deficits in this disorder; however, studies vary in their findings. Cadenhead and colleagues

 showed that patients with schizophrenia, their relatives, and subjects with schizotypal personality disorder all had abnormal PPI relative to comparison subjects. Others report deficient PPI only in symptomatic patients that partially or completely resolves with medication treatment.

 It is hoped that further research will clarify these issues and that the clinical usefulness of measuring PPI in screening or treatment will be found.


  Endophenotypes, a subset of biological markers, are measurable components unseen by the unaided eye. They can be neurophysiologic, biochemical, endocrinologic, neuroanatomic, cognitive, or neuropsychological in nature. As described by Prathikanti and Weinberger,

 to be considered an endophenotype, the putative deficits that compromise the endophenotype must be stable over time. The deficits should be found in mildly ill and psychiatrically healthy relatives to establish that these phenotypes are related to risks for the illness rather than being a result of the illness. 

 indicates the multiple sources of influence from gene to phenotype in a schematic that incorporates the above factors and how the disease of schizophrenia may manifest itself in multiple ways.


  Discovering ways to put findings into practice will be the challenge in the future, not only to predict risk of disease but also to use changes in biomarkers to monitor response to treatment. One of the ways this will likely be done is by correlating the various biological markers, thereby strengthening the ability to predict risk. Investigators in Europe, particularly in Germany, are starting to address these issues.

The European Prediction of Psychosis Study is the first large European multicenter study that is focused on early detection of persons at risk for psychosis, particularly schizophrenia; it incorporates the use of biological markers.

 found that impairments in olfactory identification and verbal memory appear to represent 2 correlated risk markers for schizophrenia. They hypothesized that frontotemporal deficits likely account for both impairments.

In summary, the goal is to use biological markers to determine who is at risk for schizophrenia and perhaps to prevent the onset of schizophrenia in people with prodromal symptoms or reduce the severity of the illness in those who have schizophrenia via early diagnosis and aggressive intervention. Yet we need to be mindful of the ethical dilemmas; those who are shown to have a propensity for schizophrenia must not be marginalized or discriminated against. Finally, we can use this information to understand the complex interplay between biological and environmental factors in the development and maintenance of this chronic disease and lower the burden on those living with schizophrenia.

Dr Saran and Dr Phansalkar are residents in the department of psychiatry and Dr Kablinger is associate professor in the department of psychiatry and pharmacology at Louisiana State University Health Science Center in Shreveport. They report that they have no conflicts of interest concerning the subject matter of this article. 
  

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Biological Markers and the Future of Early Diagnosis and Treatment in Schizophrenia

Author | Anita S. Kablinger, MD

Articles

Should We Prescribe Different Dosages of Psychotropic Medications to Men and Women?

Biological Markers and the Future of Early Diagnosis and Treatment in Schizophrenia