The Pharmacogenomics of Depression J Licinio and M-L Wong 176

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more of an element of subjectivity in The pharmacogenomics of the diagnosis of depression, particularly in mild cases, than in the diag- depression nosis of medical diseases that are based on objective test criteria such as elev- J Licinio and M-L Wong ated blood pressure (hypertension) or elevated blood sugar (diabetes Laboratory of Pharmacogenomics and Interdepartmental Clinical Pharmacology Center, mellitus). A key pre-requisite for suc- University of California, Los Angeles, School of Medicine, Los Angeles, CA, USA cessful research in pharmacogenomics is accurate phenotype assignment. As single nucleotide polymorphism (SNP) The contemporary treatment of effort trying to understand myself. I discovery progresses and a successful depression is marked by the interplay looked at those around me and SNP mapping is put together it is likely of clinical judgment, research, seren- thought they were all better off than I that biological and genetic criteria will 1 dipity, and marketing. Depression is a was. Life seemed to have a limit and I be identified as contributing markers 5 severe disorder that is the main cause saw no more reason to be alive’. for the diagnosis of depression. of suicide. Suicide is the eighth cause It is usually agreed that once a diag- of death in the US (the third cause of nosis of depression is made, treatment TREATMENT death for those between the ages of is needed. The question is then: what After diagnosing depression, the next 15–24 years and the fourth for the age treatment? While electroconvulsive step is to identify and prescribe a treat- group 25–44 years).2 The annual cost therapy is extremely effective,6 it is tra- ment. The choice of medication is of depression to the US economy ditionally reserved for refractory probably the area where pharmaco- exceeds 50 billion dollars.3 patients due to the need for multiple genomics will have its major impact. Even though there are no biological anesthesias, and possible memory loss. That will occur in two ways. Pharma- markers of depression the clinical pres- Medications are the first line of treat- cogenomics will contribute to increase entation is very characteristic and used ment for this highly common and available therapeutic targets and to to make a reliable diagnosis. According complex disorder of unknown cause. individualize treatment. to the Diagnostic and Statistical Man- While most patients respond well to ual of Mental Disorders of the Amer- existing treatments, a substantial min- IDENTIFICATION OF NOVEL can Psychiatric Association (DSM-IV),4 ority of those affected do not. Can THERAPEUTIC TARGETS FOR the cardinal symptoms of major pharmacogenomics contribute to DRUG DEVELOPMENT depression are depressed mood or loss improve the treatment of depression? Existing drugs target mostly monoam- of interest in pleasurable activities We will cover the multiple steps that ines in the brain. A key feature of anti- (anhedonia) that occur nearly every occur in antidepressant treatment, depressant treatment is that the effects day for at least 2 weeks, in conjunction identifying the pitfalls that occur on monoamines are nearly immediate, with other characteristic symptoms along the way and discussing the while clinical response takes at least 2– such as alterations in sleep, food potential of pharmacogenomics to 3 weeks to occur. Therefore, it is likely intake, body weight, decreased atten- overcome those obstacles. that their rapid effects on monoam- tion, inability to concentrate, feelings ines may not be the direct cause of the of guilt and suicidality. DIAGNOSIS clinical effects of antidepressants. A patient’s eloquent description of When a depressed person presents to Moreover, antidepressants of various how she experienced those diagnostic medical care, the physician is con- classes, affecting serotonin, norepi- features of depression brings the dis- fronted with a clinical entity that is nephrine, or dopamine7,8 have a com- order to life: ‘I did not know what was very characteristic but for which there mon clinical effect. It has been hypo- happening to me. I started to feel an is no identified cause, no identified thesized that the efficacy of the effects enormous sadness and I started to find pathognomonic biological abnor- of various types of antidepressants that nothing was of interest to me. I mality, and no accepted biological after chronic treatment is due to their stopped exercising, going out with marker. A diagnosis is made by clinical effects on new genomic targets. Phar- friends, driving, and I dropped out of observation and the determination macogenomics research is being con- school. I only wanted to stay home. I that the patient meets a set of stan- ducted by various groups worldwide to felt terrible inside, could not sleep, and dardized criteria that were put identify novel targets of antidepress- had an awful headache, I lost any together by a committee.4 Even ants. We have shown by differential interest in what I looked like, I would though the diagnostic criteria have mRNA display and validation with cry all the time, and spent a lot of been extensively validated there is reverse Northern blots that new tran- The pharmacogenomics of depression J Licinio and M-L Wong 176

scripts are elicited by chronic antide- ant treatment response in a different bolizing enzymes are involved in pressant treatment with drugs of dif- manner in different populations. determining the bioavailability of ferent classes.9 Currently, the limiting Of course, many more polymor- antidepressant drugs.14 Of particular factor in drug development is the phisms in various other genes should importance to antidepressant metab- identification of new therapeutic tar- be considered. A key dilemma for olism are cytochrome P 450 enzymes, gets. This line of investigation will those investigating this area is whether particularly CYP2D6 (see Table 1). identify targets for the development of to intensively examine the effects of as CYP2D6 activity is generally lower in new classes of antidepressant drugs. many polymorphisms as possible in a Oriental than in Caucasian popu- few genes or to set a broader net look- lations, because of a frequent ing at a few key polymorphisms in a mutation causing decreased enzyme Individualization of Drug Choice variety of genes. Additional questions activity.15 In contrast, up to 29% of Importantly, pharmacogenomics will of relevance include how to handle East Africans, particularly Ethiopians, contribute to individualize drug the statistical challenges presented by have duplication of the CYP2D6 gene choice by using genotype to predict the need for multiple comparisons. resulting in the translation of multiple positive clinical outcomes, adverse Traditional statistical approaches may copies of the enzyme and in ultra- reactions, and levels of drug metab- need to be re-examined. It is likely that rapid metabolism of drugs that are olism. pharmacological efficacy in depression metabolized by that pathway.16 Anti- will depend on the sum of small effects depressant treatment of patients with Prediction of Clinical from multiple genes. As hundreds of duplication of the CYP2D6 gene may Antidepressant Effects SNPs of potential interest are ident- therefore require a very high level of The serotonin transporter is the initial ified, it becomes increasingly difficult drug for the achievement of adequate target of the widely-used selective to scientifically justify studying just bioavailability. The patient’s drug met- serotonin reuptake inhibitors (SSRIs). one or a handful of SNPs. On the other abolizing status should be taken into Lesch et al identified a functional poly- hand, if multiple SNPs comparisons consideration in the treatment of morphism in the upstream regulatory are made, the level of statistical correc- depression. This is exemplified by the region that affects transcriptional tion required for significance will be so following teaching case: efficiency. The short variant of the high that even contributions of small polymorphism reduces the transcrip- effect that are occurring at the biologi- Patient is a 45-year-old research tional efficiency of the 5-HTT gene cal level may not be detected. Novel nurse, whose parents are from East promoter, resulting in decreased 5- statistical approaches to handle the Africa. She has a history of major depression and presents to clinic HTT expression and 5-HT uptake in assessment of multiple SNPs in large with passive suicidal ideation. Resi- 10 lymphoblasts. This polymorphism but realistic samples are needed. dent, supervised by attending phys- has been associated with the antide- Ideal candidates will include anti- ician, prescribes paroxetine, in reg- pressant effects of SSRIs and of sleep depressant regulated genes that are ular doses. Patient is seen two weeks deprivation. Smeraldi et al studied discovered by pharmacogenomic stud- after initial visit. Her condition con- depressed inpatients who were treated ies. tinues to worsen, but she denies any with a fixed dose of fluvoxamine. Both plans to harm self. Because antide- homozygotes for the long variant (l/l) Prediction of Drug Metabolism pressants can take up to 4–6 weeks to act, and she is not a danger to self, of the 5-HTT promoter and hetero- Before an antidepressant can exert its nor others, nor is she gravely dis- zygotes (l/s) showed a better response effects on central nervous system abled, she is scheduled to be seen in to fluvoxamine than homozygotes targets, it must reach those targets in two weeks, and instructed to call for the short variant (s/s). They con- sufficient levels for sufficient time. A doctors should symptoms worsen. cluded that fluvoxamine efficacy in variety of genes encoding drug meta- Ten days later patient committed delusional depression seems to be related to allelic variation within the CYP450 enzymes that metabolize antidepressants14 promoter of the 5-HTT gene.11 The same group found that those carrying Drug CYP1A2 CYP2D6 CYP2C19 CYP3A4 two copies of the long variant were also more likely to respond to sleep Amitripyline * * * * deprivation, a short-term treatment of Nortriptyline * depression.12 In contrast, Kim et al in Imipramine * * * * Korea, studied 120 depressed subjects Desipramine * and showed that those who were Citalopram * * Fluoxetine * homozygous s/s in the promoter Fluvoxamine * * region showed better responses than Paroxetine * 13 all others. These conflicting results Sertraline * are puzzling, but suggest that this Venlafaxine * * polymorphism may affect antidepress-

The Pharmacogenomics Journal The pharmacogenomics of depression J Licinio and M-L Wong 177

suicide. Antidepressant levels meas- effect profiles. Pharmacogenomics can 7 Charney DS. Monoamine dysfunction and ured postmortem were barely detect- also be used to predict level of drug the pathophysiology and treatment of depression. J Clin Psychiatry 1998; 59:11– able, in spite of the fact that a pill metabolism and bioavailability, which count from the patient’s prescription 14. are key elements of clinical pharma- 8 Pani L, Gessa GL. On the mechanism of bottle suggested that she had been cology. action of the substituted benzamides and taking medication as prescribed. their clinical potential on dysthymia and on Genetic studies revealed CYP2D6 the negative symptoms of schizophrenia. gene duplication. DUALITY OF INTEREST Mol Psychiatry (in press). None declared. 9 Wong M-L et al. Identification of hypothal- This case dramatically illustrates the amic transcripts upregulated by antide- fact that genetic substrate can have Correspondence should be sent to pressants. Biochem Biophys Res Commun profound effects on drug metabolism, J Licinio, MD, Laboratory of 1996; 229: 275–279. consequently impacting on bioavail- Pharmacogenomics, 3357A Gonda Center, 10 Lesch KP et al. Association of anxiety- related traits with a polymorphism in the 695 Charles Young Dr South, Los Angeles, ability, and treatment efficacy. This is serotonin transporter gene regulatory CA 90095–1761, USA. particularly relevant to the treatment region. Science 1996; 274: 1527–1531. Tel: +1 310 206 6207 of depression, which has the potential 11 Smeraldi E et al. Polymorphism within the Fax: +1 310 206 6715 to lead to suicide. promoter of the serotonin transporter gene E-mail: licinioȰucla.edu and antidepressant efficacy of fluvoxamine. Mol Psychiatry 1998; 3: 508–511. CONCLUSIONS REFERENCES 12 Benedetti F et al. Influence of a functional Antidepressant treatment represents 1 Wong M-L, Licinio J. Research and treat- polymorphism within the promoter of the an ideal target for pharmacogenomics. ment approaches to depression. Nat Rev serotonin transporter gene on the effects of total sleep deprivation in bipolar disorder. Depression is a common disorder Neurosci 2001; 2: 343–351. 2 Murphy SL. Deaths: Final data for 1998. Am J Psychiatry 1999; 156: 1450–1452. affecting over 10% of the North-Amer- National Vital Statistics Reports (CDC) 2000; 13 Kim DK et al. Serotonin transporter gene ican population. If inadequately 48:1–106. polymorphism and antidepressant treated, depression can result in sui- 3 Greenberg PE, Stiglin LE, Finkelstein SN, response. NeuroReport 2000; 11: 215–219. cide, a common cause of death. Treat- Berndt ER. The economic burden of 14 Bertilsson L, Dahl M-L, Tybring G. Pharma- depression in 1990. J Clin Psychiatry 1993; cogenetics of antidepressants: clinical ment for depression is expensive and 54: 405–418. aspects. Acta Psychiatric Scand 1997; 96 protracted, and there are no biological 4 American Psychiatric Association. Diagnostic (suppl 391): 14–21. markers of treatment response. The and Statistical Manual of Mental Disorders, 15 Bertilsson L et al. Pronounced differences identification of genomic markers of 4th edn American Psychiatric Association: between native Chinese and Swedish populations in the polymorphic hydroxylations treatment response would constitute Washington DC, 1994. 5 Paparounis D. I wanted to die. Tudo 2001; of debrisoquin and S-mephenytoin. Clin an enormous clinical advance of pub- 28:28–32. Pharmacol Ther 1992; 51: 388–397. lic health importance. Moreover, phar- 6 Wong M-L et al. Pronounced and sustained 16 Aklillu E et al. Frequent distribution of ultrar- macogenomics may lead to the identi- central hypernoradrenergic function in apid metabolizers of debrisoquine in an Ethiopian population carrying duplicated fication of targets for the development major depression with melancholic features: relation to hypercortisolism and and multiduplicated functional CYP2D6 of novel and hopefully more effi- corticotropin-releasing hormone. Proc Natl alleles. J Pharmacol Exp Ther 1996; 278: cacious drugs that have favorable side Acad Sci USA 2000; 97: 325–330. 441–446.