by Andrew A. Nierenberg, MD; and Steven D. Targum, MD
Dr. Targum is on the editorial board of Psychiatry 2007. Presently, he is Chief Medical Officer at Brain Cells Inc., an executive-in-residence at Oxford BioScience Partners, and a consultant in psychiatry at the Massachusetts General Hospital, Boston, Massachusetts; and Dr. Nierenberg is Director, Bipolar Trials Network, Medical Director, Bipolar Clinic and Research Program, Associate Director, Depression Clinical Reserach Program, and Professor of Psychiatry, Harvard Medical School, Boston, Massachusetts.
Disclosure
Dr. Nierenberg discloses the following financial support: Research Support—Bristol Myers Squibb, Cederroth, Cyberonics, Forest Pharmaceuticals, Eli Lilly & Co., GlaxoSmithKline, Janssen Pharmaceutica, Lichtwer Pharma, NARSAD, NIMH, Pfizer Pharmaceuticals, Stanley Foundation, Wyeth-Ayerst; Speakers Bureau—Bristol Myers Squibb, Cederroth, Cyberonics, Forest Pharmaceuticals, Eli Lilly & Co., GlaxoSmithKline, Wyeth Ayerst; Advisory Board/Consultation—Abbott Laboratories, Brain Cells Inc., Bristol Myers Squibb, Cederroth, Eli Lilly & Co., GlaxoSmithKline, Genaissance, Innapharma, Janssen Pharmaceutica, Novartis Pharmaceuticals, Pfizer Pharmaceuticals, Sepracor, Shire, Somerset.
Introduction
Psychiatrists have always attempted to customize psychotropic drug selection for individual patients on the basis of their acute symptom profile, previous treatment response, and family history, within the context of empirical uncertainty inherent in the art of psychopharmacology. The recent emergence of pharmacogenomics based upon the human genetic polymorphisms and the availability of genetic testing suggests that there might be an objective method to inform treatment decisions. The cytochrome p450 system is implicated in these tests. We thought it would be of interest to the readers of Psychiatry 2007 to revisit the importance of p450 and consider the real value of genetic testing for drug selection.
In this column, I asked Andrew Nierenberg, MD, Professor of Psychiatry at Harvard Medical School and Medical Director of the Bipolar Clinic and Research Program at Massachusetts General Hospital to discuss his views regarding the importance of cytochrome p450 isoenzymes for psychopharmacology.
What is Cytochrome p450?
Dr. Nierenberg: p450 (also known as CYP450) is a very large family of hemoproteins identified in many living species that act as enzymes to cause oxidative metabolism. p450 enzymes are present in many body tissues, particularly the liver and GI tract and play important roles in hormone synthesis and breakdown, cholesterol synthesis, and vitamin D metabolism. There have been over 7000 distinct cytochrome p450 sequences identified, although there are only about 50 in humans. The hepatic cytochromes are the most widely studied because of their importance to drug metabolism.
Does p450 matter in man?
Dr. Nierenberg: p450 enzymes are important in drug metabolism facilitating solubility for excretion in the urine or bile. Many drugs affect the activity of p450 via enzyme induction or inhibition. Induction means that a drug stimulates the synthesis of more p450 enzyme to accelerate metabolic capacity. Inhibition means competition between drugs for the enzyme binding site. Two drugs taken together may interact differently with the CYP system and cause changes in CYP-mediated metabolism. The resulting metabolic changes can speed up or slow down drug clearance and contribute to drug-induced side effects or failure of the drug to achieve adequate blood levels. In the worst case, one drug may inhibit CYP-mediated metabolism of another drug leading to drug accumulation and toxicity.
Is p450 induction limited to drugs?
Dr. Nierenberg: No. In fact, grapefruit juice can inhibit CYP3A4 mediated metabolism. Alcohol, chronic cigarette smoking, and even charbroiled meats can induce hepatic CYP450 enzymes.
Does age affect p450?
Dr. Nierenberg: Yes. Not only does CYP differ between people, its presence and potency changes with age. For instance, CYP1A2 is not expressed at all in neonates making them highly susceptible to caffeine toxicity.
Which cytochrome enzymes are important in Psychiatry?
Dr. Nierenberg: CYP3A4, CYP2D6, CYP2C19, and CYP1A2 are most implicated with psychotropic medications. CYPD26 has genetic polymorphism resulting in marked variation in human metabolic activity. CYP2D6 can be inhibited competitively to affect drug metabolism although it cannot be induced. Approximately 10 percent of Caucasians are poor metabolizers of drugs metabolized by CYP2D6 putting them at some risk for drug accumulation particularly when they take competing drugs.[1]
Similarly, 15 to 20 percent of African-Americans and Asian-Americans are poor metabolizers of CYP2C19 compared with only 1 to 5 percent of Caucasians.[2]
Several antidepressant and antipsychotic drugs are metabolized by CYP2D6, which means that slow metabolizers given normal dosages may be at some risk for cardiotoxicity, postural hypotension, or oversedation. These drugs include most SSRIs and tricyclics, as well as conventional and atypical antipsychotic medications. Similarly, some SSRIs also inhibit CYP3A enzymes. However, it is important to emphasize that the potency of inhibition varies from drug to drug.
Can you test p450 in individuals?
Dr. Nierenberg: Yes. It is part of the emerging field of pharmacogenomics and a test has been approved by the FDA and is currently available on the market.
Can you use p450 tests to predict how people will respond to different psychotropic medications?
Dr. Nierenberg: Not really…p450 tests show us who will be a slow or fast drug metabolizer, but do not really tell us which drug will work for which individual patient. Essentially, p450 tests help to assess the risk of side effects and ascertain who might require slower titration or adjusted dosage levels. Thus, fast metabolizers might require higher doses of medication to achieve effective therapeutic levels, and slow metabolizers might require lower doses and slower titration.
What do you really think about the importance of p450 for psychopharmacology?
Dr. Nierenberg: In my opinion, p450 adds minimal clinical value in most cases. For instance, the metabolic effects of CYP450 isoenzymes between SSRIs are not substantial. Therefore, a focus on minute differences in p450 metabolism among these drugs may create a false impression that the potential side effect differences between these medications are larger than they really are. Frankly, most experienced clinicians make drug selection and dosing decisions without p450 testing by deliberate titration. p450 is not a replacement for careful evaluation of the acute symptom profile, previous treatment response, and family history.
The true value of p450 testing may be in the evaluation of potential drug-drug interactions. But drug-drug interactions involve much more than p450 isoenzymes. Numerous other factors including age, gender, dietary habits, smoking, alcohol use, and other genetic polymorphisms create considerable inter-individual variability beyond the cytochrome p450 system.[2]
Where can I get p450 drug interaction information on line?
Dr. Nierenberg: One good site to look at is from the University of Colorado, available at: www.uchsc.edu/sm/psych/ppfr/cyp_metabolism.htm
What do you see on the horizon for p450 and genomic testing for drug selection?
Dr. Nierenberg: In the not-too-distant future, broad genetic testing may allow us to re-classify patients by prognosis and facilitate our choice of optional treatments for our patients.
References
1. Cupp MJ, Tracy TS. Cytochrome p450: New nomenclature and clinical implications. Am Family Physician 1998;57:107–16.
2. Alpert JE. Drug-drug interactions in psychopharmacology. In: Stern TA, Herman JB (eds). Massachusetts General Hospital Psychiatry Update and Board Preparation, Second Edition. McGraw-Hill Companies, Inc., 2004:375–84.
