Jose De Leon, MD

[[{"type":"media","view_mode":"media_crop","fid":"53266","attributes":{"alt":"","class":"media-image media-image-right","id":"media_crop_392538904725","media_crop_h":"0","media_crop_image_style":"-1","media_crop_instance":"6641","media_crop_rotate":"0","media_crop_scale_h":"120","media_crop_scale_w":"215","media_crop_w":"0","media_crop_x":"0","media_crop_y":"0","style":"float: right;","title":"Â©PAULISTA/SHUTTERSTOCK.COM","typeof":"foaf:Image"}}]]Just as others have become concerned about the use of nonvalidated pharmacogenetic (or genetic) tests in psychiatry, I too share that concern.

 If you do not like academic psychiatrists (“Ivory Tower” types), my second confession will seem like a confession. I started promoting pharmacogenetic tests in the 1990s-before they were fashionable-and now I am embarrassed after going through the 3 phases of pharmacogenetic testing (fear, failure, and hype).

Early in the 1990s, a couple of pharmacologists opened my eyes to cytochrome P450 (CYP), which is involved in clozapine metabolism. Then a patient taught me that a CYP-mediated drug-drug interaction between caffeine and clozapine was important.

 Thus, after 20 years of studying pharmacology and treating many complex patients, I reached the conclusion that drug-drug interactions are frequently important and that pharmacogenetic tests are occasionally indicated in psychiatry.

In the early 2000s (the fear phase), pharmaceutical companies were scared of pharmacogenetic tests. In the later 2000s (the failure phase), I figured out that I was not going to become famous, since the early pharmacogenetic tests failed. In the current hype phase, I am embarrassed that nonvalidated pharmacogenetic tests are aggressively promoted by some companies.

In January 2015, I was scheduled to lecture my department residents on psychopharmacology when one of them asked my opinion about a pharmacogenetic test that tells which drugs are good or bad for each patient. Another senior psychiatry resident had started ordering the test and was encouraging other residents to do so. My pharmacological arguments about the limitations of that test did not impress the resident. Who can blame him?

A company gave him a free test (saving him at least $2000) that told him in simple terms which psychiatric medication to use in each patient. Yet a professor lectured him about the need to study pharmacology and told him the following regarding selection of psychiatric drugs:

Using science to select the right drug for a patient is beyond our current scientific knowledge;

Once you choose a drug, selecting the right dosage may be relatively easy for some drugs; however,

Drug dosing is influenced not only by genetics, but also by environmental and personal factors.

This experience of failure to convince my psychiatry residents of the appropriate use of pharmacogenetics tests led me to design a PowerPoint presentation to teach residents which pharmacogenetic tests are indicated and the complexity involved in interpreting them.

Pharmacogenetic tests in the clinical environment should be limited to:

HLA-B*15:02 testing before starting carbamazepine in patients with Asian ancestry

CYP2D6 and/or CYP2C19 genotyping under the following conditions: always before prescribing tricyclic antidepressants, preferably combined with blood levels; and occasionally when seeing lack of effectiveness or adverse drug reactions with SSRIs, venlafaxine, pimozide, atypical antipsychotics dependent on CYP2D6 for their metabolism (aripiprazole, brexpiprazole, iloperidone, and risperidone), clozapine, or atomoxetine

On the other hand, genetic testing is not needed for CYP1A2, CYP2B6, CYP3A4, or CYP3A; brain neurotransmitters and/or transporter genes; and diagnosis of schizophrenia, depression, or bipolar disorder.

The embarrassed professor learns a few things

The PowerPoint presentation became useful when I was invited to speak on the same topic to confused clinicians in Spain and Italy. During the presentation, I attempted to explain to psychiatrists, who had no clue about CYP pharmacology, the various CYP alleles and the terminology differences among phenotypes: poor, intermediate, and ultrarapid metabolizers. Unfortunately, this does not explain that there is no need to test for normal alleles-the only tests required are for CYP abnormal variants. Unless an abnormal allele is found, the allele is normal by default.

If a lab tests 15 CYP2D6 alleles (although few test for so many), findings will show many patients with abnormal alleles and fewer with normal alleles; the 3 metabolizer phenotypes will also be identified. If a poorly equipped lab tests only 5 alleles associated with lack of activity, this lab will find only a few poor metabolizers and consider the remaining normal or almost normal.

This can be confusing for psychiatrists. During the question period, one of the top Spanish researchers suggested to me that it may better to order the test and have the company tell you what medication to use than to try to learn how to interpret CYP testing. Instead of being cool-headed, this professor responded that his children frequently accuse him of being demented, and maybe the researcher was getting demented too and could not learn to interpret CYP testing.

The end of 2015 brought further embarrassment. Some of the residents reported attending a dinner lecture supported by one of the pharmacogenetic companies because they receive no training in this area. Not having access to unbiased information about new products highlights the potential risk of receiving misinformation about these products by way of the company’s marketing messages. A pharmacogenetics expert told me that each test costs “only” $2000 (one article quotes a higher price of $3800). Nevertheless, whether it is $2000 or $3800, one test ordered by a resident is sufficient to pay for dinner for all my program residents at the best restaurant in town.

In the spring of 2016, I again started lecturing residents on psychopharmacology. My embarrassment over the continued failure to convince my psychiatry residents of the appropriate use of pharmacogenetics tests led me to the foolish idea of using, as my first lecture, the one titled “Pharmacogenetic Testing in Psychiatry.”

 I had to start with the confession that my wife thinks I am incompetent in marketing. I then acknowledged that this was a complex issue, mainly interesting to experts in CYP testing but relevant for patient care. I also conceded that hearing this lecture at 4 pm after a full day of lectures couldn’t possibly beat an enticing sales pitch (“You do not need to worry about psychiatric drug selection! Our test gives you all the answers!) during dinner at a nice restaurant.

Analytic validity, clinical validity, and clinical utility

Analytic and clinical validity as well as clinical utility are required to market a genetic test. Analytic validity addresses accurate and reliable measurement of the gene variations; clinical validity, the ability to detect or predict the associated disorder-in this case, that genetic variations predict drug response in the clinical environment; and clinical utility, the risks and benefits of the test in clinical practice.

The FDA has tried to control pharmacogenetic testing by limiting the promotion of genetic tests to the general population. It has not had success in limiting the genetic tests offered to clinicians. US clinical laboratories are regulated not by the FDA but by the Clinical Laboratory Improvement Amendments (CLIA). Following CLIA, accreditation by the College of American Pathologists, the Joint Commission on Accreditation of Healthcare Organizations, or state health departments allows any laboratory to legally offer pharmacogenetic testing in the US. Unfortunately, CLIA regulations only deal with very basic aspects of analytic validity.

Any US clinical lab can offer CYP genotyping without the need to demonstrate clinical validity or clinical utility, and the FDA cannot do anything about it. Some US managed care companies pay in some cases for CYP testing. This professor cannot understand why Medicare has approved payment for one of these tests in psychiatry, even though the test has problems with analytic validity and shows no demonstrated clinical validity or clinical utility.

 In my view, Medicare should not get involved in approving complex pharmacogenetic tests that should be regulated by the FDA.

This professor of psychiatry believes that personalized prescription in psychiatry is a complex pharmacological puzzle that:

 Can focus on drug dosing or drug selection

 Requires combining genetic, environmental, and personal variables

 Necessitates understanding pharmacokinetic and pharmacodynamic mechanisms to predict efficacy and safety

Furthermore, as each patient is a unique individual with different drug responses governed by pharmacological laws, each drug may also be a different individual governed by its specific pharmacological mechanisms. The most frequent cause of being a poor metabolizer is not a genetic variant but rather taking an inhibitor, such as an antidepressant; and the most frequent cause of being an ultrarapid metabolizer is not a genetic variant but taking an inducer, such as an antiepileptic. Genetic testing does not tell you about these very frequent and clinically relevant drug-drug interactions. However, as stated above, it can help in a few psychiatric patients.

As there is no way that this set of conclusions is going to satisfy you and you may prefer to order a pharmacogenetic test that provides an easy answer (eg, a red, yellow, or green signal for each drug), you will need to read the sequel to this piece-about the consequences of ordering pharmacogenetic tests. Look for it in the next issue of 

Dr. de Leon is Professor of Psychiatry at the University of Kentucky College of Medicine in Lexington, KY. He reports no conflicts of interest concerning the subject matter of this article.

 Klitzman R. The need for vigilance in the marketing of genomic tests in psychiatry. 

 Howland RH. Pharmacogenetic testing in psychiatry: not (quite) ready for primetime. 

 Dubovsky SL. The limitations of genetic testing in psychiatry. 

 Preskorn SH. Genetic and related laboratory tests in psychiatry: what mental health practitioners need to know. 

 de Leon J. Pharmacogenetic tests in psychiatry: from fear to failure to hype (editorial). 

 Odom-White A, de Leon J. Clozapine levels and caffeine. 

 de Leon J. Pharmacogenetic testing in psychiatry. 2016. 

http://inhn.org/fileadmin/Programs/DE_Leon_Pharmcgenetic_testing.pdf

 The Secretary’s Advisory Committee on Genetics, Health and Society (SACGHS). Coverage and Reimbursement of Genetic Tests and Services, 2006. 

http://osp.od.nih.gov/office-clinical-research-and-bioethics-policy/genetics-health-and-society/sacghs-archives/documents

Articles

I started promoting pharmacogenetic tests in the 1990s-before they were fashionable-and now, after going through the 3 phases of pharmacogenetic testing (fear, failure, and hype), I am embarrassed. 

Nonvalidated Pharmacogenetic Tests, Part I: Confessions of an Embarrassed Psychiatry Professor

Psychiatric Times May 2005 Vol. XXII Issue 6

The prevalence of smoking in severe mental disorders is higher than the normal population. In worldwide schizophrenia studies, the rate is approximately six times higher than in the general population (de Leon and Diaz, in press). Many patients with severe mental disorders are heavy smokers (Dalack et al., 1998; de Leon et al., 2002). Patients with severe mental disorders also tend to have high intake of caffeine (Hughes et al., 1998). This may, in part, be explained by the high coprevalence of heavy smoking, which increases caffeine metabolism (Gurpegui et al., 2004). Smoking and caffeine intake can affect the metabolism of some psychotropic medications with implications for clinical dosage adjustment.

Nicotine is mainly metabolized to cotinine by cytochrome P450 (CYP) 2A6 (CYP2A6) (Nakajima et al., 2002). Byproducts of tobacco smoke such as polycyclic aromatic hydrocarbons are inducers of cytochrome P450 isoenzyme 1A2 (CYP1A2) and of the less-understood UDP-glucuronosyl-transferases (UGTs) (de Leon, 2003; Zevin and Benowitz, 1999). This enzyme induction occurs with marijuana smoking as well. The effects of these inducers depend on the turnover of the hepatic enzymes and production of new enzymes. Thus, it takes several weeks for their maximum effect to occur and, similarly, for their enzyme-inducing effect to resolve after cessation of smoking.

Caffeine is highly dependent (>90%) on CYP1A2 for its metabolism (de Leon et al., 2003). It competitively inhibits CYP1A2 and increases the levels of medications metabolized by this enzyme. Thus the effects of caffeine are opposite that of smoking. Due to the metabolic inductive effects of smoking, smokers require three to four times the caffeine doses compared to non-smokers to get similar plasma caffeine levels and hence caffeine intake is usually higher in smokers (de Leon et al., 2003).

Second-generation antipsychotics that are not metabolized by CYP1A2 should not be affected by either smoking or caffeine. Thus, smoking or caffeine intake should not influence dosing of aripiprazole (Abilify) and risperidone (Risperdal) (the metabolism of both depends on CYP2D6 and CYP3A4) (Prior and Baker, 2003; Swainston Harrison and Perry, 2004), quetiapine (Seroquel) (mainly metabolized by CYP3A4), and ziprasidone (Geodon) (mainly metabolized by an aldehyde oxidase and CYP3A4) (Prior and Baker, 2003). On the other hand, the metabolism of clozapine (Clozaril) and olanzapine (Zyprexa) is mainly dependent on CYP1A2 and UGTs, and hence their levels are affected by smoking and caffeine. The 

 lists the effects of smoking and caffeine on second-generation antipsychotics.

. The breadth of therapeutic index for a drug determines the clinical significance of plasma level changes associated with smoking or caffeine intake. Clozapine has a much narrower therapeutic index compared to olanzapine. Several of clozapine's side effects are dose related (levels >1000 ng/mL have been associated with toxicity, including seizure risk and severe sedation) (Greenwood-Smith et al., 2003). In a patient on clozapine who smokes, smoking cessation would probably cause an average patient's blood clozapine level to increase by 1.5-fold two to four weeks later. Similarly, if a patient stabilized in a non-smoking environment starts to smoke heavily (more than one pack/day), the clinician may need to consider increasing the clozapine dose by a factor of 1.5 over two to four weeks. Checking for side effects and measuring a clozapine level may then be prudent, since the 1.5 factor is only a rough approximation.

Caffeine competitively inhibits CYP1A2, and a correction factor of 0.6 has been recommended for those who are on clozapine and begin to consume significant quantities of caffeine (de Leon, 2004). If a patient stabilized on clozapine in a caffeine-free environment begins to regularly consume high quantities of caffeine, it may be safest to decrease the clozapine dose (e.g., from 400 mg/day to 250 mg/day [400 x 0.6=240]). Low levels of caffeine intake may not have clinically significant interactions with clozapine. The 

 illustrates the amount of caffeine in selected beverages in the United States. There are no data on what level of caffeine intake is safe in patients taking clozapine. Steady caffeine doses in a patient stabilized on clozapine should not be of concern for clinicians. It is important to warn patients to avoid significant changes in caffeine intake without discussion with their psychiatrist. Although there are no published data on what a significant change in caffeine intake is, de Leon (2004) recommended caution with changes (increases or decreases) of daily caffeine intake more than three cups (or six caffeinated soda cans) in smokers, and with changes more than one cup of coffee (or two caffeinated soda cans) in non-smokers. For example, when a smoker taking clozapine increases caffeine intake by three cups of coffee (e.g., from two cups/day to five cups/day), clinicians should watch for increased side effects due to increased clozapine levels. When a non-smoker taking clozapine decreases caffeine intake by two cans of soda (e.g., from four cans/day to two cans/day), clinicians should watch for possible loss of clozapine response due to decreased clozapine levels.

Skogh et al. (1999) reported a case of a 38-year-old white male patient with schizophrenia stabilized on 725 mg of clozapine for seven years. The patient stopped smoking and two weeks later was admitted to the hospital with hypotension and generalized tonic-clonic seizure. The authors attributed this episode to smoking cessation. Subsequently, the patient was stabilized on 425 mg of clozapine while remaining a non-smoker.

Odom-White and de Leon (1996) reported a case of a 31-year-old African-American woman on 550 mg of clozapine consuming about 1200 mg of caffeine a day and showing plasma clozapine level of 1500 ng/mL and norclozapine of 630 ng/mL. One week after discontinuation of caffeine, the same dosage of 550 mg/day showed a much lower clozapine level of 630 ng/mL and norclozapine level of 330 ng/mL.

. The enzyme-inducing effects of smoking and inhibiting effects of caffeine on olanzapine levels are probably very similar to clozapine. Smoking may lower olanzapine levels by 40% (Botts et al., 2004). The clinical significance of this change may be limited in comparison to clozapine, as olanzapine has a much broader therapeutic index and high levels of olanzapine are not associated with the serious toxicity described with clozapine. However, higher than recommended doses of olanzapine may be required for some heavy smokers due to low olanzapine levels (Carrillo et al., 2003).

Smoking status may also influence a patient's liability to develop adverse effects. For example, it may have a protective effect against antipsychotic-induced parkinsonism (Jabs et al., 2003). On the other hand, smoking has been shown to increase Abnormal Involuntary Movement Scale (AIMS) scores in some patients (Ellingrod et al., 2002). However, some of these effects may be pharmacodynamic in nature and explained by the influence of nicotine on dopaminergic function.

. Haloperidol (Haldol) is metabolized by CYP2D6 and possibly by CYP3A5 and UGTs (de Leon et al., 2004). As CYP1A2 is not involved in haloperidol metabolism, changes in haloperidol dosage due to caffeine intake are generally not recommended. Some studies suggest that smoking reduces haloperidol levels; this effect may be explained by induction of UGTs, but it has not been well studied.

. Fluphenazine (Permitil, Prolixin) clearance is increased significantly in smokers, and lower levels of fluphenazine decanoate have been reported (Jann et al., 1985). Chlorpromazine (Thorazine) levels are also reported lower in smokers (Desai et al., 2001). It is not clear if the effects of smoking on phenothiazine levels are due to CYP1A2 and/or UGT induction. The effects of caffeine intake on phenothiazines have not been studied, but some effect is possible since phenothiazines are probably partly metabolized by CYP1A2.

. Antidepressants that have increased metabolism and clearance from smoking include imipramine (Tofranil), clomipramine (Anafranil), fluvoxamine (Luvox) and trazodone (Desyrel) (Desai et al., 2001). It is likely that these inductive effects may be explained by CYP1A2 and/or UGT induction (de Leon, 2003). The effect of smoking on the plasma concentrations of amitriptyline and nortriptyline (Aventyl, Pamelor) is variable, and buproprion (Wellbutrin) is unaffected by smoking (Desai et al., 2001). Fluvoxamine is a powerful CYP1A2 inhibitor and may cause clinically relevant inhibition of caffeine metabolism (Yoshimura et al., 2002).

. Increased clearance of the benzodiazepines alprazolam (Xanax), demethyldiazepam, diazepam (Valium), lorazepam (Ativan) and oxazepam (Serax) is found in cigarette smokers, whereas chlordiazepoxide (Libritabs, Librium, Mitran) does not appear to be affected by smoking (Desai et al., 2001; Greenblatt et al., 1980). Induction of UGTs probably explains the effects of smoking on benzodiazepine metabolism.

Further Considerations and Concluding Thoughts

There are specific environments and situations that impact smoking and caffeine intake and thereby influence medication dosages. Hospital restrictions are one example that may have clinical importance. Smoking is banned inside U.S. hospitals; thus, clinicians need to carefully question patients and consider smoking's effects on some antipsychotic doses in the hospital (limited or no smoking) versus those in the community (unrestricted smoking). Many hospital environments also restrict caffeinated beverages. There are no simple correction factors for patients stabilized in a non-smoking and caffeine-free hospital environment when they go to environments allowing smoking and caffeine intake. Clinicians should be aware of the time course of changes in enzyme activity and monitor patients closely for reduced efficacy or increased risk of side effects. Also, clinicians should be aware of the pharmacokinetic implications of situations in which patients reduce or quit smoking or cut down their intake of caffeine.

Recent guidelines to promote physical health recommend that efforts toward nicotine cessation be part of regular psychiatric treatment (Goff et al., 2005). Psychiatrists should assess patients' motivation to quit on a routine basis, strengthen their motivation, offer full array of pharmaceutical treatments like buproprion (Zyban) and nicotine replacement, and psychosocial treatment like group and individual counseling. Involving family members and referring patients to quit groups can increase family and community support and the likelihood of smoking cessation.

In summary, cigarette smoking and caffeine intake significantly impact the metabolism of a number of psychotropic medications and hence these factors should be routinely considered in prescribing decisions. While patients should be routinely encouraged to quit smoking they also need to be educated about the importance of informing their treating psychiatrist of changes in their caffeine intake or smoking. Research in new drug development should include studies to determine the impact of smoking and caffeine intake on dosages and clinical response.

Dr. Pinninti is assistant professor of psychiatry at the University of Medicine and Dentistry of New Jersey School of Osteopathic Medicine and medical director of Steininger Behavioral Care Services, Inc.

Dr. Mago is assistant professor of psychiatry, director of the mood disorders program and associate director of consultation-liaison psychiatry at the Thomas Jefferson University.

Dr. de Leon is associate professor of psychiatry at the University of Kentucky College of Medicine and medical director of the University of Kentucky Mental Health Research Center at Eastern State Hospital in Lexington, Ky.

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Heavy smoking and caffeine intake are highly prevalent in patients with psychiatric disorders, both of which significantly impact the metabolism of a number of psychotropic medications. Hence, these factors should be routinely considered in making prescribing decisions.

Jose De Leon, MD

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Nonvalidated Pharmacogenetic Tests, Part I: Confessions of an Embarrassed Psychiatry Professor

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