Drs. Hall-Flavin and Schneekloth are assistant professors of psychiatry and consultants in psychiatry and Mr. Allen is research coordinator in psychiatry, all in the Department of Psychiatry and Psychology at the Mayo Clinic in Rochester, Minnesota.

Disclosure: The authors report no affiliation with or financial interest in any organization that may pose a conflict of interest.

Please direct all correspondence to: Daniel K. Hall-Flavin, MD, Assistant Professor of Psychiatry, Consultant in Psychiatry, Department of Psychiatry and Psychology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905; Tel: 507-255-7164; Fax: 507-284-3933; E-mail: flavin.daniel@mayo.edu.


Significant inter-individual variability exists in antidepressant response, therapeutic dosage, and adverse effect profile. Prolonged times to response or remission represent a period of suffering associated with increased risk for morbidity and mortality. Improving care in depression treatment using a more biologically informed selection of psychopharmacologic agents through genotyping has become a reality in psychiatric practice. Routine genotyping has now become available for gene variations that code for proteins involved in neurotransmission and for drug-metabolizing enzymes involved with the disposition of many pharmacologic agents including antidepressants. Clinical validation and reliability of genotyping, access to testing, uniformity and clarity in test interpretation, and clinician and patient education are critical to this process of innovation diffusion. This article focuses on the introduction of pharmacogenetic testing to the daily practice of psychiatry. Challenges inherent in innovation diffusion in general and in the application of pharmacogenetic testing in particular are addressed. Study data involving the introduction and integration of pharmacogenomic testing into two different types of community psychiatric practice are presented. The article concludes with a discussion of the ethical issues raised in this process and its impact on the physician-patient relationship.

Focus Points

• On average, there exists a 10-year gap between medically relevant bio-technological advances and appropriate application, or translation, of those technologies into routine medical practice.
• Pharmacogenetic testing represents a major advance for translational psychiatry and its goal of advancing personalized medicine.  
• Barriers to change are multifaceted and complex; enhancing the knowledge base of physicians will facilitate the process of clinical acceptance.
• Psychopharmacogenetic testing that leads to a comprehensible report which provides clinical guidance is a new tool that is now available for implementation in the clinical practice of psychiatry.



It has been over 60 years since antidepressants were introduced into clinical practice, and these medications have become among the most widely prescribed pharmacologic agents used in medicine today. Despite the number of agents available and recent advances in drug design, significant individual variability exists in drug response, therapeutic dosage, and adverse effect profile. Only 35% to 45% of depressed patients have a complete remission of their illness when initially treated with these medications.1 Variation in drug response is complex and is dependent upon numerous factors. These include other pharmaceutical use, age, gender, renal and hepatic function, medical comorbidity, nutritional status, substance use, and genetic factors.2 The selection of an appropriate agent is usually achieved through an informed trial and error process which considers these factors. The time to maximum therapeutic response can extend to 12 weeks. This delayed time to response contributes to the potential for substantial morbidity and mortality associated with depressive illness. The use of pharmacogenomic testing provides a new tool to improve time to response and remission, as well as decrease the likelihood of potential side effects.

Recent developments in pharmacogenomic testing allows for the more efficient and effective treatment of mood disorders that have proven difficult to manage in the clinical setting. Within the past 7 years, routine genotyping has become available to detect genetic variations that code for proteins that influence serotonergic and noradrenergic function, as well as drug-metabolizing enzymes that play a role in the disposition of many psychotropics, including antidepressants.3 Genotyping for the cytochrome P450 (CYP) 2D6, 2C19, and 1A2 drug-metabolizing enzymes, and genotyping of the serotonin transporter gene and the 5-HT2A and 5-HT2C receptors, is now available clinically, and the rationale for testing has been explicitly defined.4 Pharmacogenomic testing can be used to predict potential side effects, receptor sensitivity, and possible drug interactions. In its current iteration it cannot clearly predict response or remission in association with the use of a particular agent, and may not necessarily predict all side effects that a particular patient may experience.

The reliability of the genotyping, access to testing, and the usefulness of the interpretation of test results are critical to the process of innovation diffusion, which involves acceptance, adoption, and appropriate utilization of genomic testing in the clinical setting. It has been estimated that it is typical for a decade to pass between the discovery of applicable technology and its routine application in the clinical setting. This traditional delay in adoption represents a challenge for the implementation of powerful new technologies.

The use of genetic testing to improve the efficacy of psychotropics is a clear example of translational psychiatry. Given the promise of pharmacogenomic testing, it is prudent to analyze the barriers that may affect its adoption.5

Issues related to the introduction of pharmacogenetic testing in clinical practice are likely to result from the extension of testing at academic medical centers to surrounding community medical centers. After a discussion of concepts that are integral to translational medicine, the challenges inherent in implementation science will be discussed. This will be illustrated by a description of a pilot project that was designed to specifically address this process. This study examined the introduction of pharmacogenomic testing into two different community practice settings and documented the lessons learned from this experience.


Translational Psychiatry, Personalized Medicine, and Implementation Science

Recent advances in biotechnology, bioinformatics, and studying “real world” patients have improved our understanding of the biological underpinnings of depression as well as the treatment of depression. The sequencing of the human genome was a landmark event which was achieved shortly after the beginning of the new millennium. This was followed by technological advances in gene sequencing and functional genomics, proteomics, metabolomics, and epigenetics. The evolution of functional neuroimaging technology has provided even greater degrees of precision in the definition of biological vulnerabilities. Other advances include the documentation of brain neuroplasticity, an expanding armamentarium of psychopharmacologic agents with ever more specific disease targets, and a greater emphasis on the critical analysis of the extant research regarding treatment efficacy using evidence-based methodology. Additionally, the introduction of more creative research paradigms that involve “real world” patients, who are often not included in traditional research paradigms, adds to the applicability of many current studies.

Coupled with social forces of politics, economics, and cultural expectations, these multiple advances offer the promise of an “upstream shift” in the practice of medicine from primarily a reactive response to a more proactive approach to prevention in combination with informed treatment. Bidirectional communication and effective transmission of technology between researchers and clinicians which this implies is a process that has come to be known as translational medicine.6 Such a process applied to psychiatric patients is appropriately labeled translational psychiatry.

The use of genotypic information to stratify disease and select a therapy that is particularly suited to an individual patient is now described as personalized medicine.7 It is the ultimate goal of personalized medicine to identify individuals who are at-risk for a pathophysiologic process and to prevent the onset of symptoms of that process. As this knowledge base is still not well developed, the current goals include retardation, arrest, or even reversal of pathologic processes. Implementation research is the study of methods used to promote the incorporation of evidence-based research findings into routine practice in order to improve the quality and effectiveness of health services and care.8 The challenge in the implementation of evidence-based innovative technologies is to apply the right technology to the right person in the right way to effect clinical goals which are mutually defined by the physician and patient.


Barriers to Effective Implementation

Advancing pharmacogenetic medicine in clinical settings is an iterative process with many challenges. Barriers exist at the interface between research and practice that impede bidirectional discovery and communication. Foremost among these barriers are communication barriers that exist between researchers and clinicians. These communication barriers are influenced by pragmatic, economic, ideologic, informational, and training parameters.9 McGovern and colleagues10 has emphasized the importance of interdisciplinary communication between clinicians, administrators, regulatory agencies, and researchers. To this list, the input of patients should be added.

Bridging this divide calls for innovative and flexible thinking. It ultimately requires clinicians and researchers to participate in a dialogue. This innovation-to-organizational fit is influenced by the forces outlined by McGovern and colleagues.10 Mittman has likened the impact of these dynamic forces upon treatment as pliable bands representing semantics, advocacy, intellectual, regulatory, economic, ideologic, tradition, training, and social forces, which attach to and suspend a concrete block representing current treatment protocols (Willinbring M, personal communication, December, 2007). Ultimately, a transformation in treatment by novel scientific innovation requires a dynamically poised system.

Prochaska and DiClemente11 outlined how clinicians and patients are participating in the process of change. There exists a need for clinician scholars to bridge these gaps with their research colleagues. Similarly, basic scientists need to be rewarded for clinical communications initiatives. Clinicians who are often preoccupied with day to day clinical demands need to be provided with high quality, but concise scientific data in order to effect change. Finally, the use of evidence-based guidelines, identification of appropriate metrics of outcome, and delineation of performance gaps with feedback loops can powerfully improve treatment delivery.


Psychopharmacogenetic Testing: Implementation Issues

While psychopharmacogenetic testing is becoming more commonplace in academic and tertiary medical care centers, its use in clinical practice is not yet routine. As with other new technologies, ethical issues are important to consider.5 A recent article utilizing a clinical example from oncology demonstrates differences in patient outcome based upon access to testing. It also identifies disparities in our healthcare systems which negatively impacts access to testing.12

There is no simple pathway that leads from a novel technology to a change in the belief systems of clinicians providing care. This too is an iterative process that has an evolutionary pattern of its own. Important issues such as quantification of validity, establishment of regulatory policy, and insuring reimbursement must be resolved in order to provide these services.13-21

Key issues are provided in the Table. Responses to these challenges are underway. Research funded by the Pharmacogenetics Research Network of the National Institute of General Medical Sciences continues to define pharmacogenetic practices for specific disease treatment. Improved communications and cooperation between stakeholders at various levels with the support of public policy are leading to improved validation of research findings, the development of quality cost-effectiveness measures, the evolution of clinical guidelines for the application of testing in clinical practice, and the creation of appropriate incentives for use in clinical practice.

One objective of this article is to focus on innovation diffusion at the level of clinical practice. Specifically, the authors discuss the introduction of psychopharmacogenetic testing into two community practices. This discussion focuses on those issues which most directly face the community clinician. A report22 issued by the Consortium on Pharmacogenetics in the United Kingdom stated that:

     “Perhaps the greatest single factor affecting the penetration of pharmacogenomics into clinical practice and the pace at which it will occur will be the knowledge and acceptance of physicians. Studies indicated that many physicians lack basic knowledge of genetics and also frequently fail to take into account available information about drugs.”22

It is clear from empirical studies that effective behavioral change in established medical practices will require an enhancing of the knowledge base of physicians.23 However, more will be required than introducing new information. Making behavioral change in any clinical setting requires at least three cognitive steps. First, there must be a willingness to acknowledge that a problem or situation exists which can be improved. Second, there must be an awareness of the means to make the improvement. Third, one must believe that the individual or system can effect this change. Addressing these issues will require educational efforts targeted at physicians and patients. It will require the incorporation of guidelines for testing and interpretation as well as appropriate research incentives for testing. Addressing the time pressures facing primary practitioners will require a simplification of the means of transmission of this information. One option would be involvement of a focused liaison team from an academic institution which could present on-site information and evaluate outcomes of the introduction of testing. This team could also monitor related quality outcomes including patient satisfaction and quality of life.


Implementation of Psychopharmacogenomic Testing in Clinical Psychiatric Practice: A Pilot Project

A study designed to introduce pharmacogenomic testing into two clinical psychiatric practices has been initiated and is currently in progress with ongoing data collection. This testing utilizes a panel that includes five genes: three cytochrome P450 drug-metabolizing genes, as well as the serotonin transporter and serotonin receptors 2A genes. Results of the panel are summarized in a format designed to provide clinicians with useful clinical information. In the consent process what testing can and cannot provide at the present time is reviewed with patients and physician alike. It is important to note that such testing cannot clearly predict response or remission, and may not fully predict an individual’s psychotropic or other medication side-effect profile. Rather, it does provide information that may guide a physician’s choice of psychotropic agent that is likely to be tolerated by the patient and that would minimize the potential of adverse drug interaction and extended trial-and-error clinical attempts to find “the right drug.”

The two clinical practices chosen for this pilot study are structurally quite different. They serve patients from two different psychosocial and ethnic backgrounds. One practice primarily provides psychopharmacologic intervention. The second practice integrates medication management with psychotherapy in an ethnically diverse population. Continuity with practitioners is a core value in each program. At both institutions, testing is offered as an initial study arm examining “practice as usual.” Testing is conducted at the end of an 8-week period of standard treatment. The second phase introduces testing at the time of study entry and includes rapid feedback to both physicians and patients within 48 hours of specimen collection. Data points are then monitored to measure the potential impact of testing on practice, with attention given to the frequency of side effects experienced, need to change medications, usefulness of the interpretive report, time to response and remission, and impact on the utilization of resources both within the practice and associated settings such as the hospital emergency room or hospital. Perceptions of physicians and patients are measured. Variables include medication changes, number of visits to emergency rooms, and days in the hospital. Physician and patient satisfaction is also being documented.

A high level of physician satisfaction with the interpretive report is critical for the incorporation of this technology into clinical practice. A copy of this report is shown in the Figure. The report also includes specific genotyping results, an interpretation of these results, and practically categorized information on drug-drug interactions including drugs known to increase and decrease specific enzyme activity. The clinical usefulness of the report in patient education, guidance of medication choice, development of potential side effects and risk/benefit assessments, improvement in the rapport with patients, and confidence in medication choice by both physician and patient will be analyzed. Patient satisfaction evaluation includes assessing the quality of the explanation of the interpretive report, the ease of understanding of report findings, and the perception of benefit from this report in treatment. Overall satisfaction ratings for the report and the clinical visit are also being assessed.

A key to the overall success of clinical implementation is that medical directors at each practice are stakeholders in the process. These clinical leaders must be well-educated in the scientific rationale and supportive of the clinical objective of offering more personalized care for individual patients. The first practice consists primarily of psychiatrists offering brief counseling in conjunction with pharmacotherapy. In this group there is general acceptance among the physicians of the potential benefit of testing. This may be offset by limitations in training, time pressures, competing priorities, and difficulties inherent in making the cognitive changes necessary to incorporate a new concept into their practices. In this setting, patients themselves appear to be a more positive force for change as they expressed interest in testing as a means of dealing with the chronic frustration in the management of their depressive symptoms. However, it is critical to keep patients grounded in what the testing can and cannot offer. Both patients and physicians informally report finding the ease of the reporting process quite helpful in promoting elements of the healing relationship.

There has been some anxiety on the part of non-physician practitioners which have raised concerns about biological reductionism and the implications of genomic technology on their future practice opportunities. Educational research designed to define the role of these clinicians should be a high priority. The relationships between therapists and patients should be investigated in future study in a manner which would challenge Cartesian dualism. Pelletier and Dorval24 summarized some of these challenges in an article on the impact of translational psychiatry in the field of psychology.


Translational Psychiatry and the Physician-Patient Relationship

Ultimately, one of the most critical factors in the introduction of a new technology that may have an impact on the practice of medicine is the effect that the technology has on the physician-patient relationship. Traditionally, this relationship has accepted a Cartesian reductionism that views the body as a machine and the physician as a technician whose job it is to repair that machine. However, in recent years this way of thinking has given way to the more complex notion that the doctor-patient relationship is in its essence one of healing. In the philosophical model of medicine advanced by Pelligrino and Thomasma,25 the “center of medicine” is a relationship that has the central purpose of healing. Technical competence, including incorporation of appropriate new technologies, is not denied in this model because “the act of medical profession is inauthentic and a lie unless it fulfills the expectation of technical competence…however…Competence must itself be shaped by the end of a medical act, a right and good healing action for the patient.”

Scott and colleagues26 have built upon this foundation to describe the Healing Relationship Model. In this model, healing is defined as “being cured when possible, reducing suffering when cure is not possible, and finding meaning beyond the illness experience.” Critical to this relationship are mutual respect (valuing), a recognition of the inherent asymmetry of the relationship (appreciating power), and continuity (abiding). On the part of the patient three relational factors are critical. They include trust (a willingness to be vulnerable), hope (that some future beyond the present suffering is possible), and a sense of being known. (Parenthetically, the word “patient” is etymologically traced to the Latin verb patior, to suffer.) On the clinician’s side of this relational equation are four essential clinical competencies: self-confidence, emotional self-management, mindfulness, and clinical knowledge. Of particular import to the discussion of pharmacogenetic testing is what this latter competency implies: the store of knowledge of empirical medicine, and the ability to synthesize and tailor that knowledge for the benefit of a particular individual. These factors influence the bidirectional accuracy and flow of information between physician and patient, helping to ensure a cooperative spirit with mutually agreed upon treatment goals and components. Examples of this cooperation include receptivity to medication use and compliance. Other discussions of the physician-patient relationship have centered on the four pillars of ethical reasoning, which include beneficence, autonomy, non-maleficence, and justice. One could argue the forces of translational medicine have the potential to enrich the physician-patient relationship and move clinical practice beyond reactivity to a hybrid of reactivity and proactivity.



It is imprudent to allow a 10-year gap between research discovery and practice implementation. Pharmacogenetic testing represents a major advance for translational psychiatry and its goal of advancing personalized medicine. There is a need to proceed judiciously and focus on barriers to change that need to be addressed. The authors summarized challenges to a timelier implementation of personalized medicine with particular reference to psychopharmacogenetic testing. Enhancing the knowledge base of physicians will facilitate the process of clinical acceptance. The authors discussed efforts to address translational challenges. Their initial impressions offer a snapshot of key practical issues which occur in a “real world” setting. Psychopharmacogenetic testing that leads to a comprehensible report which provides clinical guidance is a new tool that is now available for implementation in the clinical practice of psychiatry.  PP



1.    Kemp AH, Gordon E, Rush AJ, Williams LM. Improving the prediction of treatment response in depression: integration of clinical, cognitive, psychophysiological, neuroimaging, and genetic measures. CNS Spectr. 2008;13(12):1066-1086.
2.    Bondy B. Pharmacogenomics in depression and antidepressants. Dialogues Clin Neurosci. 2005;7(3):223-230.
3.    de Leon J, Armstrong SC, Cozza KL. Clinical guidelines for psychiatrists for the use of pharmacogenetic testing for CYP450 2D6 and CYP450 2C19. Psychosomatics. 2006;47(1):75-85.
4.    Mrazek DA. Psychiatric Pharmacogenomics. New York, NY: Oxford University Press; 2010.
5.    Williams-Jones B, Corrigan OP. Rhetoric and hype: where’s the ‘ethics’ in pharmacogenomics? Am J Pharmacogenomics. 2003;3(6):375-383.
6.    Mankoff SP, Brander C, Ferrone S, Marincola FM. Lost in translation: obstacles to translational medicine. J Transl Med. 2004;2(1):14.
7.    Piquette-Miller M, Grant DM. The art and science of personalized medicine. Clin Pharmacol Ther. 2007;81(3):311-315.
8.    Madon T, Hofman KJ, Kupfer L, Glass RI. Public health. Implementation science. Science. 2007;318(5857):1728-1729.
9.    Stetler CB, Mittman BS, Francis J. Overview of the VA Quality Enhancement Research Initiative (QUERI) and QUERI theme articles: QUERI Series. Implement Sci. 2008;3:8.
10.  McGovern MP, Fox TS, Xie H, Drake RE. A survey of clinical practices and readiness to adopt evidence-based practices: Dissemination research in an addiction treatment system. J Subst Abuse Treat. 2004;26(4):305-312.
11.    Prochaska J, DiClemente CC. Toward a comprehensive model of change. In: Miller WR, Heather N, eds. Treating Addictive Behaviors: Processes of Change. New York, NY: Plenum Press; 1986:3-27.
12.    Griggs JJ. Personalized medicine: a perk of privilege? Clin Pharmacol Ther. 2009;86(1):21-23.
13.    Kirchheiner J, Bertilsson L, Bruus H, Wolff A, Roots I, Bauer M. Individualized medicine – implementation of pharmacogenetic diagnostics in antidepressant drug treatment of major depressive disorders. Pharmacopsychiatry. 2003;36 suppl 3:S235-243.
14.    Oscarson M. Pharmacogenetics of drug metabolising enzymes: importance for personalised medicine. Clin Chem Lab Med. 2003;41(4):573-580.
15.    Abrahams E, Ginsburg GS, Silver M. The Personalized Medicine Coalition: goals and strategies. Am J Pharmacogenomics. 2005;5(6):345-355.
16.    Manolopoulos VG. Pharmacogenomics and adverse drug reactions in diagnostic and clinical practice. Clin Chem Lab Med. 2007;45(7):801-814.
17.    Perlis RH. Pharmacogenetic studies of antidepressant response: how far from the clinic? Psychiatric Clinics of North America. 2007;30(1):125-138.
18.    Parkinson DR, Ziegler J. Educating for personalized medicine: a perspective from oncology. Clin Pharmacol Ther. 2009;86(1):23-25.
19.    Lin KM, Perlis RH, Wan YJ. Pharmacogenomic strategy for individualizing antidepressant therapy. Dialogues Clin Neurosci. 2008;10(4):401-408.
20.    Leeder JS, Spielberg SP. Personalized medicine: reality and reality checks. Ann Pharmacother. 2009;43(5):963-966.
21.    Ikediobi ON, Shin J, Nussbaum RL, et al. Addressing the challenges of the clinical application of pharmacogenetic testing. Clin Pharmacol Ther. 2009;86(1):28-31.
22.    Buchanan A, McPherson E, Brody B, et al. Pharmacogenetics: Ethical and Regulatory Issues in Research and Clinical Practice. Report of the Consortium on Pharmacogenetics, Findings and Recommendations; 2002.
23.    Mrazek M, Koenig B, Skime M, et al. Assessing attitudes about genetic testing as a component of continuing medical education. Acad Psychiatry. 2007;31(6):447-451.
24.    Pelletier S, Dorval M. Predictive genetic testing raises new professional challenges for psychologists. Canadian Psychology. 2004;45(1):16-30.
25.    Pellegrino ED, Thomasma DC. A Philosophical Basis of Medical Practice: Toward a Philosophy and Ethic of the Healing Professions. New York, NY: Oxford University Press; 1981.
26.    Scott JG, Scott RG, Miller WL, Stange KC, Crabtree BF. Healing relationships and the existential philosophy of Martin Buber. Philos Ethics Humanit Med. 2009;4:11.


Dr. Mrazek is chair in the Department of Psychiatry and Psychology at the Mayo Clinic in Rochester, Minnesota.

Disclosures: Dr. Mrazek has received research support from AssureRX.

Please direct all correspondence to: David A. Mrazek, MD, FRCPsych, Chair, Department of Psychiatry and Psychology, Mayo Clinic, 200 1st St SW, Rochester, MN 55905; Tel: 507-284-8891; Fax: 507-255-9416; E-mail: Mrazek.David@mayo.edu.


Individualized molecular psychiatry is one of the most exciting examples of successful translational research. Pharmacogenomic testing, which is designed to select psychotropics and adjust dosing, has been extensively studied and described.1 In order to appreciate the clinical implications of pharmacogenomic testing, it is useful to review some key technological issues. At this point in time, the focus of testing is to identify variations in the structure of relevant genes that have functional implications for medication response. While the principles that support pharmacogenomic testing have evolved over 30 years,2 the cost of testing has dropped as genotyping technology has advanced.

In 2003, the primary methodology to identify structural gene variations was to use early micro-array platforms. This technology was a major advance over earlier gel-based assays and provided clinicians with more information about the range of genetic variations in each gene that were associated with drug response and side effects. The micro-array platforms that are available today are much more sophisticated than earlier versions. Consequently, many more variants can be characterized at about the same cost.

Initially, psychiatric pharmacogenomic testing focused on the characterization of the cytochrome P450 (CYP) 2D6 gene. This gene codes for the 2D6 enzyme that is involved in the metabolism of 12 commonly used psychotropics, including paroxetine, fluoxetine, venlafaxine, atomoxetine, and desipramine. Within 1 year, the testing of CYP2C19 was also easily available. CYP2C19 plays a major role in the metabolism of escitalopram, citalopram, and diazepam. Over the past 5 years, the genotyping of other CYP drug metabolizing enzyme genes, such as CYP1A2, have become available. Additionally, a number of “target genes” that influence pharmacodynamic response are being genotyped. The serotonin transporter gene (SLC6A4) was the first widely genotyped target gene. Subsequently, the genotyping of neurotransmitter receptor genes associated with medication response such as the serotonin 2A receptor gene (HTR2A) or the dopamine 4 receptor gene (DRD4) have become clinically available.

Approximately 2 years ago, it became possible to order panels of multiple informative genes that could provide a more synthetic prediction of drug response and side effects. Amazingly, the cost of analyzing a panel of genes today is less than the cost of analyzing two genes just 5 years ago. While pharmacogenomic testing is universally available, the inclusion of recommendations of the testing of these genes in standardized treatment algorithms has been delayed as a consequence of a focus on defining their cost effectiveness. Demonstrations of improvements for efficacy of selected medications have not been established using traditional clinical trial designs. However, as the focus of clinical practice begins to shift towards insuring greater safety of psychotropics, it is predicted that pharmacogenomic testing will become standard practice based on the patient-specific evidence base that already exists.

The most exciting anticipated development for pharmacogenomic testing will be the implementation of total genome sequencing in clinical practice. Currently, there is no clinical laboratory that provides total genome sequencing. However, a number of specialty laboratories will provide this testing for ~$10,000. In February 2010, Francis Collins, who was recently appointed to be the Director of the National Institute of Health, predicted that the cost of sequencing the complete genome of a patient could be <$1,000 by 2013 and would almost certainly be <$1,000 by 2015. The implications of his predictions are astounding. If he is correct, within the next 5 years psychiatrists will be provided with reports defining the structural variations in all of the pharmacogenomically relevant genes of their patients.

Four articles in this issue of Primary Psychiatry address progress in individualized molecular psychiatry. There are now several examples in medical practice of the routine genotyping of drug metabolizing enzyme genes to manage patients taking medicines such as clopidogrel, tamoxifen, and warfarin. James R. Rundell, MD, and Gen Shinozaki, MD, highlight some of this progress and review the traditional application of evidence-based methodologies to establish clinical utility.

Given that the use of clinical pharmacogenomic testing of psychiatric patients has developed rapidly since its introduction,3 Daniel K. Hall-Flavin, MD, and colleagues describe the process by which the adoption of genotyping to guide the use of psychotropic drugs has proceeded in a specific clinical setting. Simon Kung, MD, and Xiaofan Li, MD, PhD, focus on the use of pharmacogenomic testing to treat patients with treatment-resistant depression and provide a concrete clinical example to illustrate a common indication for testing. Christopher A. Wall, MD, and colleagues, summarize the experiences of a team of child and adolescent psychiatrists over a 2-year period of treating children on an inpatient child and adolescent psychiatric unit using pharmacogenomic testing.

It will be some time before the implications of being able to detect all of the variations in our genome are fully worked out. However, all of the gene variations described in the four articles in this issue will soon be easily accessible as a component of the medical records of our patients. In the last decade, we made substantial progress in identifying the right drug for the right patient as a consequence of pharmacogenomic testing. It now seems highly likely that in the very near future we will be able to abandon our traditional trial-and-error approach to medication selection and begin providing patients safer and more effective individualized psychopharmacologic treatments.  PP



1.    Kirchheiner J, Nickchen K, Bauer M, et al. Pharmacogenetics of antidepressants and antipsychotics: the contribution of allelic variations to the phenotype of drug response. Mol Psychiatry. 2004;9(5):442-473.
2.    Weinshilboum R. Inheritance and drug response. N Engl J Med. 2003;348(6):529-537.
3.    Mrazek DA. Psychiatric Pharmacogenomics. New York, NY: Oxford University Press; 2010.


Dr. Rundell is professor of psychiatry and Dr. Shinozaki has a collaborative research appointment, both in the Department of Psychiatry and Psychology at the Mayo Clinic in Rochester, Minnesota. Dr. Shinozaki is also a psychiatrist at the Sioux Falls Veterans’ Administration Medical Center in South Dakota.

Disclosure: The authors report no affiliation with or financial interest in any organization that may pose a conflict of interest.



Objective: This article identifies situations wherein an evidence base exists for informing the use of pharmacogenomic testing in treating comorbid medical and psychiatric disorders.
Method: A review of literature was conducted to identify medical conditions with frequent psychiatric comorbidity that had level 1 evidence or meta-analytic studies related to pharmacogenomic factors as they relate to safety, tolerability, efficacy, or cost.
Results: Three situations met inclusion criteria: tamoxifen clinical response, warfarin clinical management, and opioid pain management. Each of these situations is associated with elevated risk of mood or anxiety disorders. For tamoxifen, cancer recurrence risk is the primary indicator for the need for testing. For warfarin, patient safety is paramount. For opioid management, efficacy and tolerability are primary indications for pharmacogenomic testing.
Conclusion: Available clinical data and cost effectiveness data suggest that for tamoxifen patients, pharmacogenomic testing should be routine. In patients treated with warfarin, testing is supported by current safety and clinical evidence in patients who are unable to obtain a stable international normalized ratio level. Testing of analgesic patients is indicated if there is demonstrated treatment non-response or unexpected tolerability. Additional clinical applications of pharmacogenomic testing of patients with comorbid medical-psychiatric illness will be justified by the outcomes of future studies examining effects such as clinical outcome, patient safety, efficacy, and cost.

Focus Points

• Patients with comorbid medical and psychiatric problems often have polypharmacy.
• Polypharmacy increases drug interaction possibilities.
• Specific disease-drug and drug-drug interactions increase morbidity.
• Pharmacogenomic testing can optimize pharmacotherapy in comorbid disorder patients.



Pharmacogenomic testing is increasingly available to physicians to assist with clinical decision making and is probably most useful in cases that involve medication treatment resistance, intolerable adverse effects, or the potential for problematic drug-drug or drug-disease interactions.1-8 Though relatively well studied in psychiatry practice,5,9 the use of pharmacogenomic testing has not been as systematically investigated in patients who are treated for comorbid medical and psychiatric disorders.10 In these patients, additional challenges of medical comorbidities and polypharmacy are more prominent than in general psychiatry or routine primary care practice.11-16 Psychiatric medication polypharmacy is increasing despite concerns regarding multiple medication prescriptions. The percentage of patients being treated with >3 psychiatric medications simultaneously has increased more than 10-fold in the past 30 years.17

Personalized medicine, defined as the implementation of genetic variation to guide prescribing tailored to the individual, is considered to be an inevitable consequence of completion of the Human Genome Project. This is not a new concept, given that genetic factors have been recognized to influence individual responses to medications for >50 years.18 However, many conditions which were mysterious in terms of who was afflicted (eg, malignant hyperthermia) are now demystified because of pharmacogenomic studies.19 A striking failure of modern medical practice is the high morbidity and mortality associated with adverse drug reactions. These reactions are now one of the leading causes of death and illness in the United States. It is estimated that 100,000–200,000 deaths annually are the consequence of an adverse drug reaction.20-22 Adverse drug reactions are reported to account for 7% of all hospital admissions, but this estimate is believed to be low as a consequence of underreporting.20,23 Genetic variations in cytochrome P450 (CYP) enzymes explain some of the variation in patient tolerability and therapeutic response.9,24 However, catastrophic deaths have been the consequence of non-functional enzymes.25

Development of specific applications for the use of pharmacogenomic testing has been rapid in cancer chemotherapy, where associations between specific genetic markers and chemotherapy outcome are well documented.26,27 Similarly, metabolic enzyme genotype variability has been linked with tamoxifen outcome which has resulted in specific recommendations for clinically important genotyping.28 However, for most currently available medications, variability in drug response has been presumed to be the result of a complex interaction of multiple factors. It is relevant to consider the opioid individual response, variations in absorption and distribution, opioid receptor pharmacodynamics, and whether a medication is a prodrug.29 This article identifies clinical situations for which a well-developed evidence base exists to inform the use of pharmacogenomic testing in clinical practice settings which treat patients who are comorbid for medical and psychiatric disorders.



A MEDLINE review of literature was conducted to examine clinical situations in primary care and general medicine where pharmacogenomic clinical data have empirically demonstrated to be of relevance to clinical outcome. Search terms included pharmacogenomic testing, medication safety, medication tolerability, treatment-resistant depression, depressive disorder, drug-induced, treatment resistance, antidepressant treatment, medical-psychiatric comorbidity, antipsychotic treatment, and antipsychotic adverse effects. Meta-analyses and papers with level 1 evidence were included when there was available data about comorbid medical and psychiatric pharmacologic treatments. Over 400 papers were identified in the review; 65 papers meeting these inclusion criteria were reviewed to identify illustrative conditions that inform safety, tolerability, efficacy, or cost.



Three illustrative situations were identified that met the goals of this review and had sufficient scientific evidence to meet the study inclusion criteria. One is a situation where pharmacogenomic insights play a pre-eminent role in determining the outcome of tamoxifen clinical response. The clinical management of patients receiving warfarin and opioid pain management are additional treatments that have become more effective with testing. Treatment of all three situations is often complicated by the need to treat comorbid psychiatric disorders. For example, rates of mood and anxiety disorders are elevated among patients with breast cancer, cardiovascular disease, stroke, and chronic pain.30



Tamoxifen Clinical Response

Tamoxifen is a standard endocrine therapy for the prevention and treatment of estrogen receptor-positive breast cancer. It is a classic pro-drug, requiring metabolic activation to elicit pharmacologic activity. The CYP2D6 enzyme and other CYP isoenzymes catalyze the conversion of tamoxifen into metabolites with significantly greater affinity for the estrogen receptor and greater ability to inhibit cell proliferation than the parent drug.26 For example, 4-hydroxytamoxifen is 30- to 100-fold more potent than tamoxifen in suppressing estrogen-dependent cell proliferation.31

Major tamoxifen metabolites include N-desmethyltamoxifen, 4-hydroxytamoxifen, tamoxifen-N-oxide, a-hydroxytamoxifen, and N-didesmethyltamoxifen, all created by oxidation by CYP isoenzymes.26,32 These tamoxifen metabolites may then undergo secondary metabolism and further biotransformation. This is clinically important because the products of secondary metabolism may have concentrations several times higher than products of primary metabolism.31 One primary tamoxifen metabolite, N-desmethyltamoxifen, is biotransformed to at least four additional secondary metabolites, one of which is 4-hydroxy-N-desmethyl-tamoxifen (endoxifen). Endoxifen may be present in concentrations up to 10-fold higher than the primary metabolite. The transformation of N-desmethyltamoxifen to endoxifen is catalyzed exclusively by CYP2D6.

Since CYP2D6 is a highly polymorphic gene, CYP2D6 genotype can have a marked impact on clinical outcomes when there is exclusive catalysis, as with biotransformation to endoxifen from tamoxifen.28 Women homozygous for the most common allele associated with the CYP2D6 poor metabolizer phenotype (ie, CYP2D6 *4) tend to have worse relapse-free time (hazard ratio, 1.85; P=.176) and disease-free survival time (hazard ratio, 1.86; P=.089) than other tamoxifen patients, even after accounting for lymph node status and tumor size.33 As many as 10% of Caucasian women are CYP2D6 poor metabolizers.9 The relative decrement in biotransformation to endoxifen among women with this genotype was further demonstrated by the finding that none of the women with the poor metabolizer genotype experienced moderate or severe hot flashes, a characteristic tamoxifen adverse effect, compared with 20% of the women with more adequate production of the CYP2D6 enzyme. Most strikingly, for patients with either poor 2D6 metabolism or medication inhibition of CYP2D6, there was significantly higher risk for cancer relapse (hazard ration, 3.12; P=.007), shorter time to cancer recurrence (hazard ratio, 1.91; P=.034), and worse relapse-free survival (hazard ratio, 1.74; P=.017).34

Women with breast cancer often take antidepressants because of the elevated incidence and prevalence of depression.30 Selective serotonin reuptake inhibitors such as paroxetine and fluoxetine, which are strong CYP2D6 inhibitors, reduce plasma endoxifen concentrations.26,31,35 Other antidepressants exhibit varying degrees of CYP2D6 inhibition; until more is known, it may be best to prescribe antidepressants which appear to have little or no capacity for CYP2D6 inhibition. Examples of antidepressants which may avoid CYP2D6 inhibition are escitalopram, fluvoxamine, and desvenlafaxine. The combination of an intermediate CYP2D6 genotype status and CYP2D6 inhibition with medications can cause additive negative impact on survival and recurrence in tamoxifen-treated patients.28 CYP2D6 genotyping is now integrated into many breast cancer clinics and is recommended by expert panels as important in the management of estrogen receptor-positive breast cancer patients.28 The Food and Drug Administration is considering updating the product labeling for tamoxifen with recommendations regarding CYP2D6 genotyping.


Warfarin Clinical Management

Warfarin is a vitamin K antagonist used for >50 years as the most commonly prescribed antithrombotic medication in the US.36 Warfarin therapy presents numerous challenges in clinical practice.37 There are significant risks associated with over- and under-coagulation. Genetic variations account for some of the differences in achieving stable international normalized ratio (INR) levels. Fully 33% of the time the INR in patients receiving warfarin is outside of the target range,38 with 50% of the values being subtherapeutic and 50% being supratherapeutic. Researchers have focused on pharmacogenomic testing to individualize warfarin dosing and improve the safety, efficacy, and cost-effectiveness of warfarin therapy. Testing may be particularly helpful when patients are taking other concurrent medications, including psychotropic medications, which can affect how warfarin is utilized.

Genetic testing has focused on the genes that code for vitamin K epoxide reductase complex subunit 1 (VKORC1) and CYP2C9, which are enzymes involved in the mechanism of action of warfarin and the metabolism of S-warfarin, respectively. VKORC1 is responsible for the conversion of vitamin K epoxide to vitamin K, and is the rate-limiting step in the physiologic process of Vitamin K recycling.39 The CYP2C9 enzyme is largely responsible for metabolism of warfarin. The contribution of VKORC1 polymorphisms to warfarin dose variability has been estimated to be between 15% and 30%.40-42 A single CYP2C9 nucleotide polymorphism accounts for 6% to 18% of the difference in warfarin dose requirements among patients.40-42

Patients who are CYP2C9 intermediate or poor metabolizers have been found to have a lower warfarin dose requirement.40,41 CYP2C9 inhibitors, such as sertraline and fluvoxamine, can prolong bleeding time.43 The combination of being an intermediate metabolizer and taking a medication which inhibits CYP2C9 could potentially have catastrophic consequences. VKORC1 genetic variation is generally felt to have a more significant impact on early response to warfarin anticoagulation, and CYP2C9 a greater impact on achieving steady-state concentrations of warfarin,37,44 because of the different roles these enzymes play in warfarin effects.

Though a great deal of effort is going into the study of how genotyping of VKORC1 and CYP2C9 contribute to safer and more effective warfarin management algorithms,37 there is no single agreed upon recommendation. Numerous factors contribute to the complexity of creating a clinical algorithm.45 First, the interactions between effects of polymorphisms of VKORC1 and CYP2C9 have been difficult to quantify. Second, patients with different ancestry have different frequencies of polymorphisms.46 Third, cost-effective use of genotyping has not yet been demonstrated in terms of time to anticoagulation and improved out-of-range INRs. Fourth, there is some controversy regarding which variants should be included in a testing panel.47 Last, there are non-genetic factors that contribute ~20% to variance in warfarin dose, including age, sex, adherence, and weight.39

Despite the complexities related to pharmacogenomic testing and warfarin therapy, there are advocates who make the case that clinicians should not wait until there is an algorithm that covers all the permutations possible in decision making, or until there is profitability or cost neutrality, to start obtaining pharmacogenomic data when instituting warfarin therapy or when there is a patient on warfarin with unstable INRs.48 Because of the considerable medical risks of under- or over-coagulation, pharmacogenomic testing may make positive individual contributions to safety and efficacy, especially when warfarin is initiated or when medications known to affect CYP2C9 functioning are initiated in a patient receiving warfarin.

Sertraline has an evidence base supporting its use in cardiology patients, making its co-administration with warfarin a clinical event with considerable frequency. Though there is no clear consensus about whether to always order pharmacogenomic testing in a patient on both warfarin and sertraline, it is recommended by some experts, and would be important when there is difficulty with unstable INRs. Other antidepressants that are at least partly metabolized by CYP2C9 inhibition potential include fluoxetine and bupropion. Examples of antidepressants that largely avoid potential problems with CYP2C9 inhibition are citalopram, paroxetine, escitalopram, venlafaxine, and desvenlafaxine. Unfortunately, there are no current guidelines or algorithms that suggest how frequently an INR should be measured in a patient on a medication partly or largely metabolized by CYP2C9; there are too many patient-specific determinants of clinical effect apart from presence or absence of a single medication.


Opioid Pain Management

Many factors influence individual response to opioids. These include individual variations in absorption and distribution, opioid receptor pharmacodynamics, and drug metabolism.29 All these factors may be affected by the co-administration of another medication. Studies of genetic influences on the pharmacodynamic effects of variations in the μ-opioid receptor have been conducted. Factors which influence neurotransmitter pathways include variations in the catechol-O-methyltransferase (COMT) gene and drug transporter proteins.

Genetic polymorphisms that change mu-opioid receptor function result in variability in inter-patient opioid effects.29 COMT gene mutations can affect the perception of pain, as reduced COMT activity results in the up-regulation of opioid receptors.49 Clinical studies of COMT polymorphisms suggest that patients with low COMT activity who have the Met/Met genotype of the Val158Met polymorphism require smaller opioid doses.49 Drug transporter proteins facilitate passage of opioid drugs across biologic membranes such as the liver, kidneys, and intestines, as well as at the blood-brain barrier. Genetic variation in the production of these proteins affects both the efflux and uptake of opiod drugs and contributes to inter-patient variability in response to these drugs.29

Opioid metabolism by CYP enzymes and enzymes that regulate glucuronidation to active metabolites also influence drug concentrations and clinical efficacy. Psychotropic medications are metabolized by many of the same CYP enzymes that metabolize opioid analgesics and their metabolites. The higher incidence and prevalence of mood and anxiety disorders among patients with chronic pain30 creates pharmacologic scenarios that complicate the management of these patients.

The clinical effects of the weaker opioids codeine, hydrocodeine, tramadol, oxycodone, and hydrocodone rely upon formation of their more potent metabolites (eg, morphine, dihydromorphone, and oxymorphone) by a metabolic pathway mediated by CYP2D6.50 A number of in vivo retrospective or case studies51-53 of patients receiving codeine have demonstrated significant differences in plasma morphine concentrations between extensive and poor CYP2D6 metabolizers. Approximately 10% of patients of European ancestry are poor metabolizers and unlikely to gain full benefit from codeine administration, but are just as likely to suffer codeine-related side effects. These findings can be exacerbated when a patient is also on a CYP2D6 inhibitor, including many antidepressants, such as fluoxetine and paroxetine. However, ultrarapid CYP2D6 metabolism is associated with codeine intoxication.54 This phenomenon may extend to breastfeeding neonates of codeine-prescribed mothers who are ultra-rapid metabolizers.55

Tramadol exerts analgesia via the opioid agonist metabolite O-demethyl tramadol and via modulation of noradrenergic and serotonergic monoamine pathways. O-demethylation of tramadol to the opioid agonist O-demethyl tramadol is mediated by CYP2D6; there is lower plasma concentrations in poor metabolizers compared to extensive metabolizers, and there are reduced analgesic effects.56,57 Though the prevalence of CYP2D6 polymorphisms in the population undergoing pain management does not appear to be different from the general population,58 patient care may be improved by genotyping and following therapeutic drug concentrations when there is treatment resistance or poor tolerability.

Other opioid analgesics such as methadone are metabolized by other enzymes, such as the CYP3A4 enzyme. Although genetic polymorphisms occur in the enzyme CYP3A4, unlike CPY2D6, this has not yet been correlated with particular clinical phenotypes.59



The three illustrative clinical management situations reviewed in this paper demonstrate the potential value and complexity of pharmacogenomic testing in the clinical situation where comorbid medical and psychiatric disorders exist. Because of increasing frequency of psychiatric polypharmacy,17 patients with comorbid psychiatric and medical illness represent a growing and unique group of patients where pharmacogenomic testing may improve safety and clinical outcomes. The considerations presented in the three patient categories discussed in this paper highlight how complex the interactive contributions of genetic and non-genetic factors are in determining patient responses.

Available clinical data suggest that for tamoxifen patients, pharmacogenomic testing should be routine. Testing also appears to be clinically indicated when there are difficulties obtaining stable INR levels in patients receiving warfarin and when patients receiving opiate analgesic medications demonstrate treatment non-response or severe tolerability problems. Additional studies of cost effectiveness and clinical utility may identify additional clinical populations who could benefit.27 Studies of cost effectiveness may draw different conclusions over time; the cost of testing varies across laboratories and is currently in a phase of rapid decline. In addition to cost, variability in coverage by insurance providers and turnaround time for results (typically several days) may limit more widespread utilization of pharmacogenomic testing; these factors are likely to change with time.

As the scientific literature identifies clinical situations where pharmacogenomic testing can add value to healthcare, other medical specialists will begin to use this emerging technology. For example, within the field of infectious diseases, the genomes of both the host and the pathogen are relevant to antibiotic efficacy and resistance.60 Examples of host-relevant genetic polymorphisms include genes of antigen recognition molecules, pro-inflammatory cytokines, anti-inflammatory cytokines, and effectors molecules. Genetic mutations for these different factors could define a genetic profile of a high-risk patient for whom a specific treatment should be added urgently. However, co-treatment of the infection and concurrent psychiatric disorders may complicate clinical outcomes and require modifications of treatment algorithms.

Special patient populations may benefit from pharmacogenomic testing. Children and adolescents in particular may have unique considerations related to genomic variations that will translate into childhood-specific genomic testing algorithms. Examples of reported conditions relevant to childhood that are influenced by pharmacogenomic considerations are azathioprine-induced myelosuppression, codeine-induced infant mortality, warfarin-associated anti-phospholipid syndrome, and adverse drug reactions that appear to occur disproportionately in children and adolescents.22 Children are at even greater risk for adverse drug reactions than adults. An estimated 15% of pediatric hospitalizations are a consequence of adverse drug reactions, and 28% of these adverse reactions are severe.61,62 More than 75% of pharmaceuticals licensed in North America have never been tested in pediatric populations and are used without adequate guidelines for safety or efficacy.63

Patient satisfaction surveys indicate that patients are gradually becoming more aware of pharmacogenenomic testing and are beginning to expect their providers to be knowledgeable about the indications for testing.64 Specifically, they expect their providers to be able to interpret test results, provide education about the benefits and limits of testing, and to provide up-front education about cost. As knowledge about benefits of pharmacogenomic testing emerges, an increasing number of situations will be identified where it will prove cost effective and clinically beneficial to employ pharmacogenomic testing early in the course of treatment. Evidence-based pharmacogenomic testing will guide patients and providers in their selection of specific medications, and in implementation of safe and effective dosing strategies.15,65,66 Future development of clinical application of pharmacogenomic testing, in general and in the special setting of comorbid medical-psychiatric illness, will depend on future study outcomes measuring effects of testing on clinical outcome, patient safety, efficacy, and cost.  PP


1. Paulose-Ram R, Safran MA, Jonas BS, et al. Trends in psychotropic medication use among US adults. Pharmacoepidemiol Drug Saf. 2007;16(5):560-570.
2. Gelenter J, Cubells JF, Kidd JR. Population studies of polymorphisms of the serotonin transporter gene. Am J Med Genet. 1999;88(1):61-66.
3. Merikangas KR, Risch N. Will the genomics revolution revolutionize psychiatry? Am J Psychiatry. 2003;160(4):625-635.
4. Mrazek DA, Rush AJ, Biernacka JM, et al. SLC6A4 variation and citalopram response. Am J Med Genet B Neuropsychiatr Genet. 2009;150B(3):341-351.
5. Lin E, Chen PS. Pharmacogenomics with antidepressants in the STAR*D study. Pharmacogenomics. 2008;9(7):935-946.
6. Lesch KP, Bengel D, Heils A, et al. Association of anxiety-related traits with a polymorphism in the serotonin transporter gene regulatory region. Science. 1996;274(5292):1527-1531.
7. Murphy DL, Lerner A, Rudnick G, Lesch KP. Serotonin transporter: gene, genetic disorders, and pharmacogenetics. Mol Interv. 2004;4(2):109-123.
8. Seretti A, Mandelli L, Lorenzi C, et al. Serotonin transporter gene influences the time course of improvement of core depressive and somatic anxiety symptoms during treatment with SSRIs for recurrent mood disorders. Psychiatry Res. 2007;149(1-3):185-193.
9. Mrazek D. Psychiatric Pharmacogenomics. New York, NY: Oxford University Press; 2010.
10. Kohen R, Cain KC, Mitchell PH, et al. Association of serotonin transporter gene polymorphisms with poststroke depression. Arch Gen Psychiatry. 2008;65(11):1296-1302.
11. Henningsen P, Zimmermann T, Sattel H. Medically unexplained physical symptoms, anxiety and depression: a meta-analytic review. Psychosom Med. 2003;65(4):528-533.
12. Rundell JR, Amundsen K, Rummans TL, Tennen G. Toward defining the scope of psychosomatic medicine practice: psychosomatic medicine in an outpatient tertiary care practice setting. Psychosomatics. 2008;49(6):487-493.
13. Guthrie E. Medically unexplained symptoms in primary care. Advances in Psychiatric Treatment. 2008;14:432-440.
14. Rundell JR, Staab J, Shinozaki G, et al. Pharmacogenomic testing in a tertiary care outpatient psychosomatic medicine practice. Psychosomatics. In press.
15. Wu X, Hawse JR, Subramaniam M, Goetz MP, Ingle JN, Spelsberg TC. The tamoxifen metabolite, endoxifen, is a potent antiestrogen that targets estrogen receptor alpha for degradation in breast cancer cells. Cancer Res. 2009;69(5):1722-1727.
16. Deepak V, Eby C, Linder MW, Milligan PE, et al. Prospective dosing of warfarin based on cytochrome P450 2C9 genotype. Thromb Haemost. 2005;93(4):700-705.
17. Preskorn SH. Pharmacogenomics, informatics, and individual drug therapy in psychiatry: past, present and future. J Psychopharmacology. 2006;20(4 suppl):85-94.
18. Kalow W, Staron N. On distribution and inheritance of atypical forms of human serum cholinesterase, as indicated by dibucaine numbers. Can J Biochem Physiol. 1957;35(12):1305-1320.
19. Stowell KM. Malignant hyperthermia: a pharmacogenetic disorder. Pharmacogenomics. 2008;9(11):1657-1672.
20. Lazarou J, Pomeranz BH, Corey PN. Incidence of adverse drug reactions in hospitalized patients: a meta-analysis of prospective studies. JAMA. 1998;279(15):1200-1205.
21. Ernst FR, Grizzle AJ. Drug-related morbidity and mortality: updating the cost-of-illness model. J Am Pharm Assoc (Wash). 2001;41(2):192-199.
22. Ross CJ, Katzov H, Carleton B, Hayden MR. Pharmacogenomics and its implications for autoimmune disease. J Autoimmunity. 2007;28(2-3):122-128.
23. Fletcher AP. Spontaneous adverse drug reaction reporting vs event monitoring: a comparison. J R Soc Med. 1991;84(6):341-344.
24. McAlpine DE, O’Kane DJ, Black JL, Mrazek DA. Cytochrome P450 2D6 genotype variation and venlafaxine dosage. Mayo Clin Proc. 2007;82(9):1065-1068.
25. Koski A, Ojanpera I, Vuori E, Sajantila A. A fatal doxepin poisoning associated with a defective CYP2D6 genotype. Am J Forensic Med Pathol. 2007;28(3):259-261.
26. Brauch H, Murdter TE, Eichelbaum M, Schwab M. Pharmacogenomics of tamoxifen therapy. Clin Chem. 2009;55(10):1770-1782.
27. Ellingrod VL. Incorporating pharmacogenomics into practice. J Pharmacy Practice. 2007;30(3):277-282.
28. Goetz MP, Rae JM, Suman VJ, et al. Tamoxifen pharmacogenomics: the role of CYP2D6 as a predictor of drug response. Clin Pharmacol Ther. 2008;83(1):160-166.
29. Searle R, Hopkins PM. Pharmacogenomic variability and anaesthesia. Br J Anaesthesia. 2009;103(1):14-25.
30. Wise MG, Rundell JR. Effective consultation in a changing health care environment. In: Wise MG, Rundell JR. Clinical Manual of Psychosomatic Medicine: A Guide to Consultation-Liaison Psychiatry. Washington, DC: American Psychiatric Publishing, Inc; 2005:1-10.
31. Borges S, Desta Z, Li L, et al. Quantitative effect of CYP2D6 genotype and inhibitors on tamoxifen metabolism: implication for optimization of breast cancer treatment. Clin Pharmacol Ther. 2006;80(1):61-74.
32. Desta Z, Ward BA, Soukhova NV, Flockhart DA. Comprehensive evaluation of tamoxifen sequential biotransformation by the human cytochrome P450 system in vitro: prominent roles for CYP3A and CYP2D6. J Pharmacol Exp Ther. 2004;310(3):1062-1075.
33. Goetz MP, Rae JM, Suman VJ, et al. Pharmacogenetics of tamoxifen biotransformation is associated with clinical outcomes of efficacy and hot flashes. J Clin Oncol. 2005;23(36):9312-9318.
34. Goetz MP, Knox SK, Suman VJ, et al. The impact of cytochrome P450 2D6 metabolism in women receiving adjuvant tamoxifen. Breast Cancer Res Treat. 2007;101(1):113-121.
35. Jin Y, Desta Z, Stearns V, et al. CYP2D6 genotype, antidepressant use, and tamoxifen metabolism during adjuvant breast cancer treatment. J Natl Cancer Inst. 2005;97(1):30-39.
36. Shalansky S, Lynd L, Richardson K, Ingaszewski A, Kerr C. Risk of warfarin-related bleeding events and supratherapeutic international normalized ratios associated with complementary and alternative medicine: a longitudinal analysis. Pharmacotherapy. 2007;27(9):1237-1247.
37. Hynicka LM, Cahoon WD, Bukaveckas BL. Genetic testing for wafarin therapy initiation. Ann Pharmacother. 2008;42(9):1298-1303.
38. Jones M, McEwan P, Morgan CL, Peters JR, Goodfellow J, Currie CJ. Evaluation of the pattern of treatment, levels of anticoagulation control and outcome of treatment with warfarin in patients with non-valvular atrial fibrillation: a record linkage study in a large British population. Heart. 2005;91(4):472-477.
39. Owen RP, Gong L, Sagrieya H, Klein TE, Altman RB. VKORC1 pharmacogenomics summary. Pharmacogenet Genomics. Nov 24, 2009. [Epub ahead of print].
40. Gage BF, Lesko LJ. Pharmacogenetics of warfarin: regulatory, scientific, and clinical issues. J Thromb Thrombolysis. 2008;25(1):45-51.
41. Aithal GP, Day CP, Kesteven PJ, Daly AK. Association of polymorphisms in the P450 CYP2C9 with warfarin dose requirement and risk of bleeding complications. Lancet. 1999;353(9154):717-719.
42. Higashi MK, Veenstra DL, Kondo LM, et al. Association between CYP2C9 genetic variants and anticoagulation-related outcomes during warfarin therapy. JAMA. 2002;287(13):1690-1698.
43. Calhoun JW, Calhoun DD. Prolonged bleeding time in a patient treated with sertraline. Am J Psychiatry. 1996;153(3):443.
44. Schwarz UI, Ritchie MD, Bradford Y, et al. Genetic determinants of response to warfarin during initial anticoagulation. N Engl J Med. 2008;358(10):999-1008.
45. Wu AH. Use of genetic and nongenetic factors in warfarin dosing algorithms. Pharmacogenomics. 2007;8(7):851-861.
46. Wu AH, Wang P, Smith A, et al. Dosing algorithm for warfarin using CYP2C9 and VKORC1 genotyping from a multi-ethnic population: comparison with other equations. Pharmacogenomics. 2008;9(2):169-178.
47. McClain MR, Palomaki G, Piper M, Haddow J. A rapid-ACCE review of CYP2C9 and VKORC1 alleles testing to inform warfarin dosing in adults at elevated risk for thrombotic events to avoid serious bleeding. Genet Med. 2008;10(2):89-98.
48. Teagarden JR. Warfarin and pharmacogenomic testing: what would Pascal do? Pharmacotherapy. 2009;29(3):245-257.
49. Rakvåg TT, Klepstad P, Baar C, et al. The Val158Met polymorphism of the human catechol-O-methltransferase (COMT) gene may influence morphine requirements in cancer pain patients. Pain. 2005;116(1-2):73-78.
50. Selzer RR, Rosenblatt DS, Laxova R, Hogan K. Adverse effect of nitrous oxide in a child with 5,10-methlenetrahdrofolate reductase deficiency. N Engl J Med. 2003;349(1):45-50.
51. Chen ZR, Somogyi AA, Bochner F. Polymorphic O-demethylation of codeine. Lancet. 1988;2(8616:914-915.
52. Chen ZR, Somogyi AA, Reynolds G, Bochner F. Disposition and metabolism of codeine after single and chronic doses in one poor and seven extensive metabolisers. Br J Clin Pharmacol. 1991;31(4):381-390.
53. Yue QY, Svensson JO, Alm C, Sjöqvist F, Säwe J. Codeine-O-demethylation co-segregates with polymorphic debrisoquine hydroxylation. Br J Clin Pharmacol. 1989;28(6):639-645.
54. Gasche Y, Daali Y, Fathi M. Codeine intoxication associated with ultrarapid CYP2D6 metabolism. N Engl J Med. 2004;351(27):2827-2831.
55. Koren G, Cairns J, Chitayat D, Gaedigk, Leeder SJ. Pharmacogenetics of morphine poisoning in a breastfed neonate of a codeine-prescribed mother. Lancet. 2006;368(9536):704.
56. Enggard TP, Poulsen L, Arendt-Nielsen L, Brøsen K, Ossig J, Sindrup SH. The analgesic effect of tramadol after intravenous injection in health volunteers in relation to CYP2D6. Anesth Analg. 2006;102(1):146-150.
57. Poulsen L, Arendt-Nielsen L, Borsen K, Sindrup SH. The hypoalgesic effect of tramadol in relation to CYP2D6. Clin Pharmacol Ther. 1996;60(6):636-644.
58. Jannetto PJ, Bratanow NC. Utilization of pharmacogenomics and therapeutic drug monitoring for opioid pain management. Pharmacogenomics. 2009;10(7):1157-1167.
59. Rollason V, Samer C, Piguet V, Dayer P, Desmeules J. Pharmacogenetics of analgesics: Toward the individualization of prescription. Pharmacogenomics. 2008;9(7):906-933.
60. Sirgo G, Rello J, Waterer G. Pharmacogenomics and severe infections: the role of the genomes of both the host and the pathogen. Current Pharmacogenomics. 2006;4(4):321-329.
61. González-Martin G, Caroca CM, Paris E. Adverse drug reactions in hospitalized pediatric patients: A prospective study. Int J Clin Psychopharmacol Ther. 1998;36(10):530-533.
62. Martinez-Mir I, Garcia-Lopez V, Palop V, et al. A prospective study of adverse drug reactions in hospitalized children. Br J Clin Pharmacol. 1999;47:681-688.
63. Leeder JS. Developmental and pediatric pharmacogenomics. Pharmacogenomics. 2003;4(3):331-341.
64. Fargher EA, Eddy C, Newman W, et al. Patients’ and healthcare professionals’ views on pharmacogenetic testing and its future delivery in the NHS. Pharmacogenomics. 2007;8(11):1511-1519.
65. Holbrook AM, Pereira JA, Labiris R, et al. Systematic overview of warfarin and its drug and food interactions. Arch Intern Med. 2005;165(10):1095-1106.
66. Parrish RH, Pazdur DE, O’Donnell PJ. Effect of carbamazepine initiation and discontinuation on antithrombotic control in a patient receiving warfarin: case report and review of the literature. Pharmacotherapy. 2006;26(11):1650-1653.


Dr. Wall is instructor of psychiatry and consultant in child psychiatry and Dr. Swintak is instructor in psychiatry and senior associate consultant in child psychiatry, both in the Department of Psychiatry and Psychology at the Mayo Clinic in Rochester, Minnesota. Ms. Oldenkamp is a medical student at the Mayo Medical School in Rochester.

Disclosure: The authors report no affiliation with or financial interest in any organization that may pose a conflict of interest.

Please direct all correspondence to: Christopher A. Wall, MD, Instructor of Psychiatry, Consultant–Child Psychiatry, Dept of Psychiatry and Psychology, Mayo Clinic, 200 1st St, SW, Rochester, MN 55905; Tel: 507-284-3352; Fax: 507-533-5353; E-mail: wall.chris@mayo.edu.


Historically, clinicians have had few resources beyond empiric tools derived from population-based treatment algorithms and patient/family interviews to inform the “best choice” for psychopharmacologic intervention. Previously unappreciated interindividual variance in activity of cytochrome P450 enzymatic activity can lead to abnormal metabolism of many psychotropics and poor outcomes. Fortunately, advances in our understanding and application of psychiatric pharmacogenomic information have the potential to improve the quality of medical care for children at the level of the individual prescription.

Focus Points

• Advances in pharmacogenomics have the potential to improve the quality of medical care for children at the level of the individual prescription.
• Nearly 80% of all drugs in use today, along with most psychotropics, are metabolized via testable metabolic pathways.
• Children and adolescents with metabolic polymorphisms may be at greater risk for adverse drug events than children with normal metabolism.
• Pediatric psychotropic prescribers must consider treatment-resistant patients as potential abnormal metabolizers.



A large number of children and adolescents presenting for health care are affected by mental illness and many require psychotropic medications as a component of their overall care.1,2 Despite increasing choices in medication management, many of these patients still experience poor outcomes related to inadequate medication response and significant adverse drug events (ADEs).3 Given ongoing shortages in the specialty of child and adolescent psychiatry,4 the considerable challenge of prescribing psychotropics in the pediatric population is often managed by adult psychiatrists, family physicians, and pediatricians. In considering whether a medication is the “right” one for a given patient, all clinicians must weigh not only issues such as the potential for side effects, family responses to similar psychotropic medications, and the nature and intensity of the patient’s illness, but also psychosocial concerns. This is a process which is complicated by the knowledge that an incorrect choice could result in intolerable side effects, poor efficacy, and ultimately—perhaps most importantly—a negative view towards medication that may have proved helpful. Lack of efficacy and ADEs are frequently cited as reasons for noncompliance in pediatric psychopharmacology.

Currently, children who are treated without the benefit of individualized molecular genotyping have only a 60% chance of successful long-term treatment.5 Fortunately, advances in our understanding and application of individual pharmacogenetic profiles have the potential to improve the quality of medical care for children at the level of the individual prescription.6 Pickar7 has suggested that there is no specialty where the need for pharmacogenetics seems more compelling than for psychiatry. Psychiatric pharmacogenomics is an emerging tool to assist clinicians in developing strategies to personalize treatment and tailor therapy to individual patients, with the goal of optimizing efficacy and safety through better understanding of genetic variability and its influence on drug response. This article provides discussion of the role emerging pharmacogenomic advancement is playing in the clinical practice of individualized psychopharmacology: moving away from “trial and error” prescriptions to individualized prescribing. The article also highlights the growing literature and adoption of pharmacogenomic principles guiding modern psychotropic prescribing practices focusing on the pediatric population.


Background of Psychiatric Pharmacogenomics

Psychiatric pharmacogenomics is the study of how gene variations influence the responses of a patient to treatment with psychotropics. The most commonly studied cytochrome P450 (CYP) enzymes include 2D6, 2C19, and 2C9. Polymorphisms and gene duplications in these enzymes account for the most frequent variations in phase I metabolism of drugs since nearly 80% of all drugs in use today, along with most psychotropics (Tables 1 and 2),8 are metabolized via these pathways.9 It should also be noted that genetics may account for 20% to 95% percent of variability in drug disposition and effects.10


Historic and current literature divides metabolic phenotypes into four basic categories. These categories presented from least to most efficient metabolism are as follows: poor metabolism (PM; essentially no metabolism at a given enzyme pathway), intermediate metabolism (IM), extensive metabolism (EM; essentially “normal” metabolism), and ultra-rapid metabolism (UM). For the purpose of discussion, this article will highlight safety and efficacy concerns related to the 15% to 25% of pediatric patients that are either PM or UM metabolizers.11


Safety and Efficacy in Abnormal Metabolizers

The two primary tenets considered in all pediatric prescriptions are safety and efficacy, and both can be more precisely addressed through pharmacogenomics. “Safety pharmacogenomics” aims to avoid ADEs and side effects by identifying individuals who are likely to have difficulty with certain medications due to either increased activity of an enzymatic pathway (UMs), or lack of activity (PMs). “Efficacy pharmacogenomics” attempts to predict an individual’s likely response to a medication at the outset of treatment.12

Interindividual variance of activity of CYP enzymes can lead to abnormal metabolism of most antidepressants (Table 1) and antipsychotics (Table 2). These medications have been associated with a variety of ADEs, ranging from milder side effects, such as activation, irritability, sexual dysfunction, and sedation, to more significant ADEs, such as weight gain, extrapyramidal symptoms, metabolic syndrome, hyperprolactinemia, manic-induction, neuroleptic malignant syndrome, and even suicidality.13 Children and adolescents with polymorphisms leading to abnormal drug metabolism may be at greater risk for some of these ADEs than children with normal metabolism, as medications administered at normal therapeutic doses to poor metabolizers may result in toxicity, and consequently ADEs. Conversely, UMs may not attain therapeutic plasma levels on typical therapeutic doses of medications and the treatment may fail or lead to rapid conversion of prodrug to potentially toxic active metabolites.

Table 313-51 includes a list of ADEs that have been linked to abnormal metabolism of psychotropics by at least one study involving abnormal metabolizers. As pharmacogenomic testing is a relatively new technology, not many studies have been performed investigating these links, but identifying the at-risk population in advance could do much to positively affect quality of life, increase compliance with medications, and even circumvent death in rare cases. Pharmacogenomic testing has the potential to offer a more complete, individualized risk profile enabling tailored choices of medication with doses appropriately adjusted for individual metabolism and advanced screening for the propensity of certain undesirable effects.


Safety and Efficacy Implications in Poor Metabolism

Weight Gain and Metabolic Syndrome

There is no doubt that weight gain can be detrimental to a young person’s physical and mental health and can exacerbate problems with self-esteem during all developmental stages. Obesity, which is common among schizophrenic patients,52 may be further exacerbated by antipsychotics. It has been shown that decreased metabolism due to variations in several CYP genes may contribute to a patient’s risk profile while taking an antipsychotic. For example, decreased metabolism at CYP1A2, which is known to be involved in the metabolism of some antipsychotics, is associated with increased risk for weight gain and a cluster of clinical features including increased visceral adiposity, hyperglycemia, hypertension, and dyslipidemia known as “metabolic syndrome.”53 Prevalence of metabolic syndrome is higher in women than it is in men as demonstrated in the Clinical Antipsychotic Trials of Intervention Effectiveness schizophrenia trial.53 Lower activity of CYP1A2 may also contribute to the risk for metabolic syndrome by leading to increased serum concentrations of antipsychotics at standard doses. Children, especially young females, may be more susceptible to weight gain while on antipsychotics,53-55 and weight gain may lead to noncompliance and subsequent relapse.52-56

All of this evidence suggests that pediatric patients are likely to be at increased risk of weight gain and metabolic syndrome if carrying polymorphisms associated with decreased or absent 1A2 activity. Identifying poor metabolizers at this and other genes associated with atypical antipsychotic metabolism could allow a physician to be better informed of all risks when prescribing, and heighten awareness related to early signs of metabolic syndrome or weight gain. This may be especially pertinent to young female patients, who appear to carry the most risk.


Extrapyramidal Symptoms

Extrapyramidal symptoms (EPS) are frequent and serious acute adverse reactions to antipsychotics. These symptoms include pseudoparkinsonism, acute dystonia, akathisia, and tardive dyskinesia,34 which may be permanent even after removal of the drug.

Several hypotheses and studies indicate that PM at CYP2D6, which metabolizes several of the typical and atypical psychotropics, may increase the risk of developing EPS. Poor CYP2D6 metabolizers are likely to have higher than average plasma concentrations of neuroleptics with an increased risk for developing EPS, including tardive dyskinesia.14,34,57-59 PM or inhibition of CYP2D6 may be linked to the induction of EPS. CYP2D6 in the brain is involved in the metabolism of dopamine and has a possible functional association with the dopamine transporter.59,60 Several selective serotonin reuptake inhibiters and tricyclic antidepressants inhibit CYP2D6, as do a number of non-psychotropic drugs such as quinidine. Methylphenyltetrahydropyridine, a dopamine neurotoxin able to produce Parkinsonism, is metabolized by 2D6 and is also a 2D6 inhibitor. Vandel and colleagues59 concluded that inhibition of CYP2D6 may be involved in the genesis of EPS observed in treatment with 2D6 substrate psychotropics.

It follows that poor CYP2D6 metabolizers may be at increased risk for EPS while on certain antidepressants due to high plasma levels.59 Indeed, it has been shown that there is a significant association between EPS and the CYP2D6*4 and CYP2D6*6 polymorphisms that are both associated with the poor metabolizer phenotype.61,62 Furthermore, there may be a relationship between the degree of impaired CYP2D6 activity and the severity of EPS during neuroleptic treatment.34 One study14 demonstrating that the development of EPS or tardive dyskinesia while on antipsychotic medication is significantly more frequent among PMs than among matched IM and EM patients, also found a significantly higher prevalence of noncompliance among the same PM patients. These findings highlight the importance of identifying those at greater risk for experiencing these serious ADEs.


Neuroleptic Malignant Syndrome

Neuroleptic malignant syndrome (NMS) is a life-threatening ADE associated with antipsychotics, antidepressants, and other psychotropics. Signs of NMS include hyperthermia, EPS, altered consciousness, fluctuating blood pressure, incontinence, and dyspnea.48,63,64 While some studies were unable to find a significant link between reduced function of CYP2D6 and NMS,65,66 more recent case studies suggest pharmacogenomic factors cannot yet be excluded as risk factors for this serious condition. In two separate case studies, four patients who developed NMS were later determined to have mutations in CYP2D6 conferring the PM phenotype.48 It was concluded that while not all NMS patients have this poor metabolizer phenotype, poor metabolizers at CYP2D6 may be at increased risk for developing NMS.49



Conventional antipsychotics and certain atypical antipsychotics, such as risperidone, can cause significant elevations in prolactin.53 For risperidone, increases in prolactin levels are dose related.53,67 Though no studies have yet been conducted to show a link between PM phenotypes and ADEs related to hyperprolactinemia, this link remains not only possible, but an important consideration in the pediatric population. Amongst other potential developmental concerns, complications from early hyperprolactinemia may include bone loss, which in turn could lead to significant consequences upon reaching adulthood. Furthermore, if this increase in prolactin is dose related, PMs may have elevated risk as they may experience higher serum concentrations of poorly metabolized medication.


Additional Considerations

Prescribers should also bear in mind that over sedation, postural hypotension, and cardiovascular complications may be additional significant concerns in poor metabolizers.68 Likewise, as clinicians follow their natural tendency to optimize dosing in their treatment of psychiatric symptoms, it may be helpful to remember that, in the PM population, so called “somatic symptoms” associated with psychiatric diagnoses (and subsequent treatment) may in fact be medication intolerance exacerbated by dose titration. Without knowledge of the patient’s metabolic phenotype, the clinician must “guess” as to the cause of these symptoms and may incorrectly conclude that the patient is just “anxious” or “dramatic.” Furthermore, the clinician must also wonder whether or not the patient will be able to adequately tolerate the next medication choice.


Safety and Efficacy Implications in Ultra-Rapid Metabolism

UMs present their own set of treatment challenges as they may not attain therapeutic plasma levels on normal doses of medications, and thus treatment may have a higher propensity to fail.69 For example, a recent Swedish autopsy study13 found that among those who died of suicide, there was a higher number carrying >2 active CYP2D6 genes (UM phenotype) as compared with those who died of natural causes. Postulated explanations for this finding include accumulation of higher levels of metabolites at a faster rate which is a known risk of UM. This buildup may lead to adverse drug reactions if the metabolite is active or toxic. It could also be argued that in this population, UMs did not reach the desired therapeutic concentration of their prescribed medications and thus had not been treated effectively. This hypothesis is supported by Kawanishi and colleagues43 who found UMs as more likely to fail to respond to antidepressants. The ultra-rapid metabolizers in the study also had the worst scores on the Hamilton Rating Scale for Depression leading the authors to conclude that ultra rapid metabolism may be a risk factor for persistent mood disorders.

Case studies in UMs suggest that diphenhydramine may be converted to a compound which causes paradoxical excitation due to the abnormally high CYP2D6 activity.41 More serious consequences might be seen in children treated with other medications like codeine whose ultra-rapid conversion might result in toxic accumulation of morphine leading to death.23 It follows that UMs could be at increased risk of ADEs from higher levels of toxic or active metabolites from psychotropics.



To date, much of the available literature on pharmacogenomic testing in the pediatric population has focused on the spectrum of efficacy related to cancer treatments.70-75 Impressive results in leukemia remission rates have been described as partly due to advancements in pharmacogenomically derived individualized prescribing practices. Cheok and colleagues70 highlighted the progress made in the treatment of acute lymphoblastic leukemia in children noting the disease as being lethal 4 decades ago to current cure rates exceeding 80%. This progress is largely due to the optimization of existing treatment modalities rather than the discovery of new antileukemic agents. The literature regarding the pharmacogenomics of asthma treatment and research design has also been quite active in the pediatric population in the past few years.76-83 In both cancer and asthma research, there are clear outcomes and endpoints to define treatment response and the role that interindividual variability plays.

Historically, the process of initiating psychopharmacologic agents in the child and adolescent population has been empirically based and one in which the clinician considers many variables including age, gender, access to health care, and ability to remain compliant with the proposed treatment. Frequently factored into this consideration are quasi-genetic questions relating to family history of illness as well as family history of medication response. Until very recently, the use of family history has been the only tool available to better understand genetic makeup and its resultant interplay with efficacy and ADEs. In fact, as early as the 19th century, Holmes84 commented that, “All medications are directly harmful; the question is whether they are indirectly beneficial.” Fortunately, unlike in Holmes’ day, we now have the potential capability to resolve that very question; pharmacogenomic testing can help determine in advance whether an individual will respond favorably. Ongoing central nervous system maturation coupled with an increased risk for ADEs makes the utility of this advance most relevant in pediatric psychopharmacology.

Though most prescribing in pediatric psychiatry is still off label, treatment algorithms do currently exist for most classes of psychotropics. Unfortunately, none of these algorithms base their recommendations on psychiatric pharmacogenomics. Furthermore, since dosing recommendations are based on “normal” metabolizers, they do not include the estimated 15% to 25% of the population who is either UMs (and therefore at much higher risk for resultant noncompliance due to never reaching therapeutic and/or beneficial levels) or poor with non-compliance resulting from ADEs. These outliers, who frequently end up in treatment-resistant categories of patients, might have entirely different outcomes if medication management were tailored to their genetic—and therefore most fundamental—needs.

When considering the “stakes” involved in the early patient-physician-family relationship, it is clear that prescribing with improved confidence, and less risk of ADEs, will pay significant dividends. For example, if a clinician thoughtfully considers not only the symptoms involved in the patient’s illness process, but also the likelihood that the patient will experience difficulties with certain medications, the patient and family cannot help but be appreciative of the efforts involved at defining their particular risks. This transparency of process and subsequent conversations about the role for medications will allow for greater trust and a sense of improved objectivity.

Widespread adoption of pharmacogenomic testing will be hampered by several factors including costs, limited sample sizes in research reports, and ingrained practice habits fueled by understandable skepticism and access challenges. Each of these issues will need to be individually addressed and overcome in the foreseeable future. Several academic medical centers are incorporating this form of testing into the comprehensive biopsychosocial workup and results appear promising.11,85 Today, the cost of the genotyping of a single gene varies between $300–$700 depending upon the complexity of the variants that are being identified. Fortunately, panels of informative genes can now be ordered for between $800–$1,500. With the rapid improvement in sequencing technologies that is now occurring, these costs will inevitably decrease in the near future.

As psychiatric illnesses are increasingly recognized and treated in the pediatric population, clinicians now have access to an emerging set of pharmacogenomic principles to guide their prescribing practices. The primary principle is to use pharmacogenomic testing to increase the safety of psychotropics. A second principle is to use testing to identify medications that are unlikely to be effective. The ultimate goal of pharmacogenomic testing is to find the “right medication” on the first try. As pharmacogenomic testing becomes more sophisticated, it will be possible to abandon “trial and error” strategies and begin to provide individualized care utilizing metabolic and receptor pharmacogenomics. Using composite data, clinicians will have an unprecedented degree of molecular information available to help them choose effective medication-based treatments while minimizing the potential for ADEs.


As clinicians continue to treat pediatric patients with psychotropics, every relevant clinical observation and laboratory assessment should be considered to increase the likelihood of achieving remission of symptoms with minimal ADEs. Reviewing the results of pharmacogenomic testing prior to writing an initial prescription now provides clinicians useful individualized data that can be reviewed with the patient and family to inform them about the role that metabolism may play in treatment response as well as the possibility of ADEs. It is the authors’ belief that pharmacogenomic testing has a significant role in modern psychopharmacologic practice and that the associated expenses are already outweighed by the potential benefits of more individualized prescriptions.  PP



1.    Kessler RC, Wang PS. The descriptive epidemiology of commonly occurring mental disorders in the United States. Annu Rev Public Health. 2008;29:115-129.
2.    McVoy M, Findling R. Child and Adolescent Psychopharmacology Update. Psychiatr Clin North Am. 2009;32(1):111-133.
3.    Bourgeois FT, Mandl KD, Valim C, Shannon MW. Pediatric adverse drug events in the outpatient setting: An 11-year national analysis. Pediatrics. 2009;124(4):e744-e750.
4.    Thomas CR, Holzer CE. The continuing shortage of child and adolescent psychiatrists. J Am Acad Child Adolesc Psychiatry. 2006;45(9):1023-1031.
5.    Mrazek DA. Pharmacogenomics of methylphenidate response: making progress. J Am Acad Child Adolesc Psychiatry. 2009;48(12):1140-1142.
6.    Husain A, Loehle JA, Hein DW. Clinical pharmacogenetics in pediatric patients. Pharmacogenomics. 2007;8(10):1403-1411.
7.    Pickar D. Pharmacogenomics of psychiatric drug treatment. Psychiatr Clin North Am. 2003;26(2):303-321.
8.    Mrazek D. Psychiatric Pharmacogenomics. New York, NY: Oxford University Press; 2010.
9.    Zhou SF, Di YM, Chan E, et al. Clinical pharmacogenetics and potential application in personalized medicine. Curr Drug Metab. 2008;9(8):738-784.
10.    Kalow W, Tang BK, Endrenyi L. Hypothesis: comparisons of inter- and intra-individual variations can substitute for twin studies in drug research. Pharmacogenetics. 1998;8(4):283-289.
11.    Wall CA, Wells L, Mohan A, Odegarden S, Drews M, Mrazek DA. Pharmacogenomics and its emerging role in individualized pediatric psychopharmacology. Poster presented at the 55th Annual Meeting of the American Academy of Child and Adolescent Psychiatry; Chicago, IL; October 28-November 2, 2008.
12.    Roses AD. Pharmacogenetics and drug development: The path to safer and more effective drugs. Nat Rev Genet. 2004;5(9):645-656.
13.    Zackrisson AL, Lindblom B, Ahlner J. High frequency of occurrence of CYP2D6 gene duplication/multiduplication indicating ultrarapid metabolism among suicide cases. Clin Pharmacol Ther. November 11, 2009. [Epub ahead of print].
14.    Kobylecki CJ, Jakobsen KD, Hansen T, Jakobsen IV, Rasmussen HB, Werge T. CYP2D6 genotype predicts antipsychotic side effects in schizophrenia inpatients: a retrospective matched case-control study. Neuropsychobiology. 2009;59(4):222-226.
15.   Subuh Surja AA, Reynolds KK, Linder MW, El-Mallakh RS. Pharmacogenetic testing of CYP2D6 in patients with aripiprazole-related extrapyramidal symptoms: a case-control study. Per Med. 2008;5(4):361-365.
16.   Scordo MG, Spina E, Romeo P, et al. CYP2D6 genotype and antipsychotic-induced extrapyramidal side effects in schizophrenic patients. Eur J Clin Pharmacol. 2000;56(9-10):679-683.
17.   Inada T, Senoo H, Iijima Y, Yamauchi T, Yagi G. Cytochrome P450 II D6 gene polymorphisms and the neuroleptic-induced extrapyramidal symptoms in Japanese schizophrenic patients. Psychiatr Genet. 2003;13(3):163-168.
18.   Kobylecki CJ, Hansen T, Timm S, et al. The impact of CYP2D6 and CYP2C19 Polymorphisms on suicidal behavior and substance abuse disorder among patients with schizophrenia: a retrospective study. Ther Drug Monit. 2008;30(3):265-270.
19.    Köhnke MD, Griese EU, Stösser D, Gaertner I, Barth G. Cytochrome P450 2D6 deficiency and its clinical relevance in a patient treated with risperidone. Pharmacopsychiatry. 2002;35(3):116-118.
20.  Jaanson P, Marandi T, Kiivet RA, et al. Maintenance therapy with zuclopenthixol decanoate: Associations between plasma concentrations, neurological side effects and CYP2D6 genotype. Psychopharmacology. 2002;162(1):67-73.
21.    Ellingrod VL, Schultz SK, Arndt S. Association between cytochrome P4502D6 (CYP2D6) genotype, antipsychotic exposure, and abnormal involuntary movement scale (AIMS) score. Psychiatr Genet. 2000;10(1):9-11.
22.    Koski A, Sistonen J, Ojanperä I, Gergov M, Vuori E, Sajantila A. CYP2D6 and CYP2C19 genotypes and amitriptyline metabolite ratios in a series of medicolegal autopsies. Forensic Sci Int. 2006;158(2-3):177-183.
23.    Ciszkowski C, Madadi P, Phillips MS, Lauwers AE, Koren G. Codeine, ultrarapid-metabolism genotype, and postoperative death. N Engl J Med. 2009;361(8):827-828.
24.    Stamer UM, Stüber F, Muders T, Musshoff F. Respiratory depression with tramadol in a patient with renal impairment and CYP2D6 gene duplication. Anesth Analg. 2008;107(3):926-929.
25.    He YJ, Brockmöller J, Schmidt H, Roots I, Kirchheiner J. CYP2D6 ultrarapid metabolism and morphine/codeine ratios in blood: was it codeine or heroin? J Anal Toxicol. 2008;32(2):178-182.
26.    Madadi P, Ross CJD, Hayden MR, et al. Pharmacogenetics of neonatal opioid toxicity following maternal use of codeine during breastfeeding: a case-control study. Clin Pharmacol Ther. 2009;85(1):31-35.
27.    Madadi P, Koren G, Cairns J, et al. Safety of codeine during breastfeeding: fatal morphine poisoning in the breastfed neonate of a mother prescribed codeine. Can Fam Physician. 2007;53(1):33-35.
28.    Gasche Y, Daali Y, Fathi M, et al. Codeine intoxication associated with ultrarapid CYP2D6 metabolism. N Engl J Med. 2004;351(27):2827-2831.
29.    Voronov P, Przybylo HJ, Jagannathan N. Apnea in a child after oral codeine: a genetic variant – an ultra-rapid metabolizer. Paediatr Anaesth. 2007;17(7):684-687.
30.    Kirchheiner J, Schmidt H, Tzvetkov M, et al. Pharmacokinetics of codeine and its metabolite morphine in ultra-rapid metabolizers due to CYP2D6 duplication. Pharmacogenomics J. 2007;7(4):257-265.
31.    de Wildt SN, Koren G. Re: Apnea in a child after oral codeine: a genetic variant – an ultra-rapid metabolizer [corrected]. Paediatr Anaesth. 2008 Mar;18(3):273-276. Erratum in: Paediatr Anaesth. 2008;18(5):454.
32.    De Leon J, Dinsmore L, Wedlund P. Adverse drug reactions to oxycodone and hydrocodone in CYP2D6 ultrarapid metabolizers. J Clin Psychopharmacol. 2003;23(4):420-421.
33.    Dalén P, Frengell C, Dahl ML, Sjöqvist F. Quick onset of severe abdominal pain after codeine in an ultrarapid metabolizer of debrisoquine. Ther Drug Monit. 1997;19(5):543-544.
34.    Arthur H, Dahl ML, Siwers B, Sjoqvist F. Polymorphic drug metabolism in schizophrenic patients with tardive dyskinesia. J Clin Psychopharmacol. 1995;15(3):211-216.
35.    Zhou SF. Polymorphism of human cytochrome P450 2D6 and its clinical significance: part II. Clin Pharmacokinet. 2009;48(12):761-804.
36.    Arranz MJ, De Leon J. Pharmacogenetics and pharmacogenomics of schizophrenia: a review of last decade of research. Mol Psychiatry. 2007;12(8):707-747.
37.    Kirchheiner J, Keulen JTHA, Bauer S, Roots I, Brockmöller J. Effects of the CYP2D6 gene duplication on the pharmacokinetics and pharmacodynamics of tramadol. J Clin Psychopharmacol. 2008;28(1):78-83.
38.    Pollock BG, Mulsant BH, Sweet RA, Rosen J, Altieri LP, Perel JM. Prospective cytochrome P450 phenotyping for neuroleptic treatment in dementia. Psychopharmacol Bull. 1995;31(2):327-332.
39.    Meyer JW, Woggon B, Baumann P, Meyer UA. Clinical implications of slow sulphoxidation of thioridazine in a poor metabolizer of the debrisoquine type. Eur J Clin Pharmacol. 1990;39(6):613-614.
40.    Spina E, Ancione M, Di Rosa AE, Meduri M, Caputi AP. Polymorphic debrisoquine oxidation and acute neuroleptic-induced adverse effects. Eur J Clin Pharmacol. 1992;42(3):347-348.
41.    de Leon J, Nikoloff DM. Paradoxical excitation on diphenhydramine may be associated with being a CYP2D6 ultrarapid metabolizer: three case reports. CNS Spectr. 2008;13(2):133-135.
42.    Michelson D, Read HA, Ruff DD, Witcher J, Zhang S, McCracken J. CYP2D6 and clinical response to atomoxetine in children and adolescents with ADHD. J Am Acad Child Adolesc Psychiatry. 2007;46(2):242-251.
43.    Kawanishi C, Lundgren S, Ågren H, Bertilsson L. Increased incidence of CYP2D6 gene duplication in patients with persistent mood disorders: Ultrarapid metabolism of antidepressants as a cause of nonresponse. A pilot study. Eur J Clin Pharmacol. 2004;59(11):803-807.
44.    Gorny M, Röhm S, Läer S, Morali N, Niehues T. Pharmacogenomic adaptation of antiretroviral therapy: overcoming the failure of lopinavir in an African infant with CYP2D6 ultrarapid metabolism. Eur J Clin Pharmacol. 2010;66(1):107-108.
45.   Breil F, Verstuyft C, Orostegui L, et al. Non-response to consecutive antidepressant therapy caused by CYP2D6 ultrarapid metabolizer phenotype. Int J Neuropsychopharmacol. 2008;11(5):727-728.
46.    Ellingrod VL, Miller D, Schultz SK, Wehring H, Arndt S. CYP2D6 polymorphisms and atypical antipsychotic weight gain. Psychiatr Genet. 2002;12(1):55-58.
47.    Lane HY, Liu YC, Huang CL, et al. Risperidone-related weight gain: genetic and nongenetic predictors. J Clin Psychopharmacol. 2006;26(2):128-134.
48.    Kawanishi C, Shimoda Y, Fujimaki J, et al. Mutation involving cytochrome P450IID6 in two Japanese patients with neuroleptic malignant syndrome. J Neurol Sci. 1998;160(1):102-104.
49.    Kato D, Kawanishi C, Kishida I, et al. Effects of CYP2D6 polymorphisms on neuroleptic malignant syndrome. Eur J Clin Pharmacol. 2007;63(11):991-996.
50.    Kato D, Kawanishi C, Kishida I, et al. CYP2D6 gene deletion allele in patients with neuroleptic malignant syndrome: preliminary report. Psychiatry Clin Neurosci. 2005;59(4):504-507.
51.   Tang SW, Helmeste D. Paroxetine. Expert Opin Pharmacother. 2008;9(5):787-794.
52.    Allison DB, Mentore JL, Heo M, et al. Antipsychotic-induced weight gain: a comprehensive research synthesis. Am J Psychiatry. 1999;156(11):1686-1696.
53.    Aichhorn W, Whitworth AB, Weiss EM, Marksteiner J. Second-generation antipsychotics: Is there evidence for sex differences in pharmacokinetic and adverse effect profiles? Drug Saf. 2006;29(7):587-598.
54.    Correll CU. Weight gain and metabolic effects of mood stabilizers and antipsychotics in pediatric bipolar disorder: A systematic review and pooled analysis of short-term trials. J Am Acad Child Adolesc Psychiatry. 2007;46(6):687-700.
55.    Safer DJ. A comparison of risperidone-induced weight gain across the age span. J Clin Psychopharmacol. 2004;24(4):429-436.
56.    Bernstein JG. Induction of obesity by psychotropic drugs. Ann N Y Acad Sci. 1987;499:203-215.
57.    Topic E, Stefanovic M, Ivanisevic AM, Blazinic F, Culav J, Skocilic Z. CYP2D6 genotyping in patients on psychoactive drug therapy. Clin Chem Lab Med. 2000;38(9):921-927.
58.    de Leon J, Susce MT, Pan RM, Fairchild M, Koch WH, Wedlund PJ. The CYP2D6 poor metabolizer phenotype may be associated with risperidone adverse drug reactions and discontinuation. J Clin Psychiatry. 2005;66(1):15-27.
59.    Vandel P, Bonin B, Vandel S, Sechter D, Bizouard P. CYP 2D6 PM phenotype hypothesis of antidepressant extrapyramidal side-effects. Med Hypotheses. 1996;47(6):439-442.
60.    Niznik HB, Tyndale RF, Sallee FR, et al. The dopamine transporter and cytochrome P450IID1 (debrisoquine 4-hydroxylase) in brain: resolution and identification of two distinct [<sup>3</sup>H]GBR-12935 binding proteins. Arch Biochem Biophys. 1990;276(2):424-432.
61.    Crescenti A, Mas S, Gassó P, Parellada E, Bernardo M, Lafuente A. CYP2D6*3, *4, *5 and *6 polymorphisms and antipsychotic-induced extrapyramidal side-effects in patients receiving antipsychotic therapy. Clin Exp Pharmacol Physiol. 2008;35(7):807-811.
62.    Sachse C, Brockmöller J, Bauer S, Roots I. Cytochrome P450 2D6 variants in a Caucasian population: allele frequencies and phenotypic consequences. Am J Hum Genet. 1997;60(2):284-295.
63.    Pope Jr HG, Keck Jr PE, McElroy SL. Frequency and presentation of neuroleptic malignant syndrome in a large psychiatric hospital. Am J Psychiatry. 1986;143(10):1227-1233.
64.    Kawanishi C, Furuno T, Onishi H, et al. Lack of association in Japanese patients between neuroleptic malignant syndrome and a debrisoquine 4-hydroxylase genotype with low enzyme activity. Psychiatr Genet. 2000;10(3):145-147.
65.    Kawanishi C, Hanihara T, Maruyama Y, et al. Neuroleptic malignant syndrome and hydroxylase gene mutations: No association with CYP2D6A or CYP2D6B. Psychiatr Genet. 1997;7(3):127-129.
66.    Iwahashi K, Yoshihara E, Nakamura K, et al. CYP2D6 HhaI genotype and the neuroleptic malignant syndrome. Neuropsychobiology. 1999;39(1):33-37.
67.    Volavka J, Czobor P, Cooper TB, et al. Prolactin levels in schizophrenia and schizoaffective disorder patients treated with clozapine, olanzapine, risperidone, or haloperidol. J Clin Psychiatry. 2004;65(1):57-61.
68.    Dahl ML. Cytochrome P450 phenotyping/genotyping in patients receiving antipsychotics: useful aid to prescribing? Clin Pharmacokinet. 2002;41(7):453-470.
69.    Bertilsson L, Dahl ML, Sjöqvist F, et al. Molecular basis for rational megaprescribing in ultrarapid hydroxylators of debrisoquine. Lancet. 1993;341(8836):63.
70.    Cheok MH, Pottier N, Kager L, Evans WE. Pharmacogenetics in acute lymphoblastic leukemia. Semin Hematol. 2009;46(1):39-51.
71.    Pottier N, Cheok M, Kager L. Antileukemic drug effects in childhood acute lymphoblastic leukemia. Expert Rev Clin Pharmacol. 2008;1(3):401-413.
72.    Ansari M, Krajinovic M. Pharmacogenomics in cancer treatment defining genetic bases for inter-individual differences in responses to chemotherapy. Curr Opin Pediatr. 2007;19(1):15-22.
73.    Ansari M, Krajinovic M. Pharmacogenomics of acute leukemia. Pharmacogenomics. 2007;8(7):817-834.
74.    Cheok MH, Evans WE. Acute lymphoblastic leukaemia: A model for the pharmacogenomics of cancer therapy. Nat Rev Cancer. 2006;6(2):117-129.
75.    Brenner TL, Pui CH, Evans WE. Pharmacogenomics of childhood acute lymphoblastic leukemia. Curr Opin Mol Ther. 2001;3(6):567-578.
76.    Rogers AJ, Tantisira KG, Fuhlbrigge AL, et al. Predictors of poor response during asthma therapy differ with definition of outcome. Pharmacogenomics. 2009;10(8):1231-1242.
77.    Qing LD, Tantisira KG. Pharmacogenetics of asthma therapy. Curr Pharm Des. 2009;15(32):3742-3753.
78.    Koster ES, Raaijmakers JA, Koppelman GH, et al. Pharmacogenetics of anti-inflammatory treatment in children with asthma: Rationale and design of the PACMAN cohort. Pharmacogenomics. 2009;10(8):1351-1361.
79.    Warrier MR, Hershey GK. Asthma genetics: personalizing medicine. J Asthma. 2008;45(4):257-264.
80.    Szalai C, Ungvári I, Pelyhe L, Tölgyesi G, Falus A. Asthma from a pharmacogenomic point of view. Br J Pharmacol. 2008;153(8):1602-1614.
81.    Weiss ST, Litonjua AA, Lange C, et al. Overview of the pharmacogenetics of asthma treatment. Pharmacogenomics J. 2006;6(5):311-326.
82.   Wechsler ME. Managing asthma in the 21st century: the role of pharmacogenetics. Pediatr Ann. 2006;35(9):660-669.
83.    Drazen JM, Yandava CN, Dubé L, et al. Pharmacogenetic association between ALOX5 promoter genotype and the response to anti-asthma treatment. Nat Genet. 1999;22(2):168-170.
84.    Holmes OW. Currents and Counter-Currents in Medical Science: Medical Essays. 1842-1882. Boston, MA: Houghton-Mifflin; 1891.
85.    Oldenkamp C, Wall CA, Mrazek DA. An analysis of the clinical usefulness of psychiatric pharmacogenomic testing in children and adolescents. Poster presented at: the 56th Annual Meeting of the American Academy of Child and Adolescent Psychiatry; October 27-November 1, 2009; Honolulu, HI.


Dr. Kung is assistant professor of psychiatry and consultant in psychiatry, and Dr. Li is psychiatry resident, both in the Department of Psychiatry and Psychology at the Mayo Clinic in Rochester, Minnesota.

Disclosures: The authors report no affiliation with or financial interest in any organization that may pose a conflict of interest.

Please direct all correspondence to: Simon Kung, MD, Mayo Clinic, 200 First St SW, Rochester, MN 55905; Tel: 507-255-7184; Fax: 507-284-3933; E-mail: kung.simon@mayo.edu.


Pharmacogenomic testing is clinically available to assist with medication selection in treatment-resistant depression (TRD). Common tests include the cytochrome P450 (CYP) 2D6 and 2C19 enzymes, the serotonin transporter gene, and the serotonin receptor gene. There are practical recommendations of interventions which can be supported from the literature. Identification of a CYP2D6 poor metabolizer would result in recommending a lower dosage of medications metabolized by CYP2D6, or avoiding the use of CYP2D6 medications. Identification of a serotonin transporter gene short/short genotype suggests more adverse effects, less response, or longer time to respond to selective serotonin reuptake inhibitors (SSRIs), and may warrant focusing treatment with non-SSRIs. Numerous other genotypes have been studied but with mixed implications. The use of pharmacogenomic testing can help the clinician rationalize medication selection and reduce the numerous medication combinations used in TRD. Further research and clinical experience will continue to define the clinical utility of this testing.

Focus Points

• Pharmacogenomic testing can be clinically used in guiding medication selection for treatment-resistant depression.
• Cytochrome P450 metabolizer status can guide whether the clinician uses medications metabolized by a specific pathway or uses different dosing ranges.
• The serotonin transporter gene short/short genotype has been associated with adverse reactions and less response to selective serotonin reuptake inhibitors (SSRIs), thus clinicians might choose a non-SSRI for such patients.
• Further research and clinical practice will help define the utility of pharmacogenomic testing.



Treatment-resistant depression (TRD) is a common occurrence in clinical practice. Depending on the operational definitions, studied populations and analytic methods used, prevalence ranges from 15% to 80%.1 Results from the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study suggest that ~50% of “real world” patients with psychiatric and medical comorbidity who meet criteria for major depressive disorder (MDD) fail to achieve remission, even after four carefully monitored sequenced treatments.2

The most commonly adopted definition of TRD evolved from >15 historic definitions is “major depression with poor response to two adequate trials with different classes of antidepressants, given in an adequate dose for sufficient time.”3 Staging models of TRD reflect the severity of treatment resistance, factoring in the number of failed trials and intensity or optimization of each trial.4

Numerous strategies are used in TRD, including psychotherapy, pharmacotherapy using augmentation strategies, and brain stimulation techniques such as transcranial magnetic stimulation, vagus nerve stimulation, and electroconvulsive therapy. Deep brain stimulation and magnetic seizure therapy are investigational treatments.5 However, the most common treatment for TRD is the selection of alternative antidepressant trials. Algorithms have been developed to guide pharmacotherapy.6

Given the trial-and-error nature of medication treatment for TRD, a method which could decrease the number of trials needed to achieve remission would be valuable. There has been much research into the use of genotyping to predict drug metabolism (pharmacokinetic) and genotyping to determine serotonin gene variants (pharmacodynamic) associated with drug response. Both strategies provide information that can increase the likelihood that a medication trial will be helpful.

This article reviews our current knowledge of pharmacogenomic testing designed to predict antidepressant adverse effects and response. Clinical implications for the care of patients with MDD and TRD are discussed.



Cytochrome P450 (CYP) enzymes are involved with the metabolism of most medications, including antidepressants. Some medications, such as codeine and tamoxifen, are pro-drugs which require activation by CYP enzyme. Several CYP isoenzymes are involved with antidepressant metabolism, mainly the 2D6 and 2C19, and to a lesser extent, 2C9 and 1A2.7 Polymorphisms in the genes that code for these enzymes result in varying drug levels in an individual. The phenotypes typically range from a “poor” metabolizer (PM) with little or no enzyme activity, to an “intermediate” metabolizer with less than normal activity, to the “extensive” normal type, and to the “ultra-rapid” metabolizer (UM) with greatly increased activity. In patients of European ancestry, the distribution for CYP2D6 is ~10% PMs and 2% to 3% UMs. The phenotype frequencies for patients of European ancestry for CYP2C19 are ~3% PMs and 4% UMs. Drug metabolizing enzyme gene polymorphisms play a role in the interethnic variations in drug metabolism given that up to 20% of patients of Asian ancestry are CYP2C19 PMs.8 Generally, poor metabolizers experience more side effects and ultra-rapid metabolizers are less likely to respond to treatment with an antidepressant that is a substrate of the enzyme.

A clinical laboratory test for CYP2D6 genotyping has been available since 2003. Subsequently, clinical laboratory tests for CYP enzymes 2C19, 2C9, and 1A2 have become available. CYP 3A4 is an important enzyme involved in medication metabolism as well, but does not have many polymorphisms of functional significance.9

A current problem is that there is not a single standard for predicting the phenotype based on genotype. Consequently, different laboratories provide differing phenotype interpretations for the same genotype. This problem is compounded because different laboratories analyze for different sets of alleles. Another less problematic issue is that new alleles continue to be identified.10


Associations with Plasma Concentrations, Adverse Effects, and Treatment Response

The consequence of the CYP genotype on the pharmacokinetics of many antidepressants has been demonstrated. Desipramine,11 venlafaxine,12,13 nortriptyline,14 doxepin,15 imipramine,16 paroxetine,17 fluvoxamine,18 fluoxetine and paroxetine,19 and amitriptyline and nortriptyline20 have significant correlations between CYP2D6 genotypes and their plasma concentrations. However, the implications of these variable serum concentrations are not completely correlated with side effects or therapeutic response.11,13,21-23

CYP2C19 genotypes have been associated with metabolism of imipramine,24 sertraline,25,26 citalopram/escitalopram,27 and clomipramine.28 A study combining genotypes 2D6, 2C19, and 2C9 found significant influence of the 2D6 genotype, minor influence of the 2C19 genotype, and no influence of the 2C9 genotype on plasma concentrations of citalopram, paroxetine, fluvoxamine, and sertraline.29

Many studies show that poor and intermediate 2D6 metabolizers have been associated with more adverse effects to CYP2D6-dependent antidepressants.30-35 However, in some reports the risk for adverse effects have not reached statistical significance.13,36-38 These negative studies have had issues related to comprehensiveness of genotyping and sample size.

There are mixed reports of CYP2D6 genotyping associations with antidepressant response. UMs have been associated with non-response to antidepressants in several studies.17,31,39 However, in a retrospective study40 of 81 responders and 197 non-responders, CYP2D6 metabolizer status was not associated with either response or remission rates.


Practical Recommendations

Pharmacokinetic genotyping provides probabilistic estimates of side effects and efficacy in patients with PM and UM phenotypes. Its usefulness includes guiding certain antidepressant dosage and understanding and avoiding drug-drug interactions (DDIs), especially when 34% of patients in a primary care setting are on an antidepressant and ≥3 medications.41 The current standard clinical practice in using tricyclic antidepressants (TCAs) is to dose until reaching a pre-determined “therapeutic” serum drug level. For newer antidepressants, clinicians sometimes titrate the dose until a patient experiences benefit or uncomfortable side effects. Consequently, patients can be placed on dosages exceeding the manufacturer’s recommended usual dosages. The determination that a patient is an ultra-rapid metabolizer provides a rationale for a patient’s capacity to tolerate higher than recommended doses. Conversely, clinicians should be more cautious with substrate medications if a patient is not able to produce sufficient active enzyme necessary for the metabolism of the drug.

Pharmacokinetic reviews have suggested decreasing by ~50% the dosages of TCAs and risperidone in patients who are CYP2D6 PM, and using higher dosages of a TCA in UM.42-45 More specific dose adjustments have been proposed for the antidepressants imipramine, desipramine, nortriptyline, clomipramine, paroxetine, venlafaxine, amitriptyline, buproprion, citalopram, sertraline, and fluvoxamine, as well as the antipsychotics perphenazine, thioridazine, olanzapine, aripiprazole, haloperidol, and risperidone.44 Another review41 estimates the potential for antidepressants to be the perpetrator of a DDI mediated by effects on CYP2D6 enzymes as substantial (>150%) for paroxetine and fluoxetine; moderate (50% to 150%) for duloxetine; and mild (20% to 50%) for venlafaxine, sertraline, citalopram, and escitalopram.

Fortunately, for the newer antidepressants, clinically significant drug interactions from CYP inhibition are less frequent.46 Psychotropic medications which are not metabolized by CYP2D6 have been developed (eg, desvenlafaxine).

There is one psychotropic medication for which the Food and Drug Administration has made a firm recommendation for genetic testing (HLA-B*1502). Carbamazepine in patients with Asian ancestry with this variant have been shown to be at increased risk of life-threatening skin reactions such as Stevens-Johnson syndrome.47



In addition to CYP enzyme genes, several genes in the serotonin pathway have been studied for their potential role in the susceptibility to depression, adverse effects, and treatment response to psychotropic medications. Commonly studied genes include the 5-HTTLPR promoter region of the serotonin transporter gene (SLC6A4) and the serotonin receptor gene subtypes 5-HT2A and 5-HT2C.


Adverse Effects of Psychotropic Medications

Several studies reported that 5-HTTLPR L alleles are associated with fewer selective serotonin reuptake inhibitor (SSRI) side effects.48 In a study49 comparing the SSRI paroxetine versus the non-SSRI mirtazapine, patients with 5-HTTLPR S alleles had worse side effects with paroxetine but tolerated mirtazapine better. A possible interaction of 5-HTTLPR L allele and oral contraceptives associated with sexual side effects has also been reported.50 5-HTTLPR S alleles have also been associated with antidepressant-induced mania.51

The serotonin receptor genes 5-HT2A and 5-HT2C have also been associated with psychotropic adverse effects. Paroxetine side-effect severity and discontinuation was associated with the number of 5-HT2A C alleles.38 Various 5-HT2A polymorphisms have also been associated with fewer SSRI side effects including gastrointestinal side effects52 or increased side effects such as sexual side effects.53 An 5-HT2C polymorphism was reported to be protective against significant antipsychotic-induced weight gain54 and associated with tardive dyskinesia, although the association was not significant.55


Response to Treatment

A 2007 meta-analysis of 5-HTTLPR and SSRI treatment reported that the L allele is associated with a better response independent of ethnic differences, and patients with the S/S genotype take >4 weeks to respond and have difficulties reaching remission.56 While there is conflicting data related to the effects of SLC6A4 in patients of African-American or Hispanic ancestry,57,58 an analysis of STAR*D patients restricted to the white non-Hispanic subgroup confirmed an association of SLC6A4 activity level and remission with citalopram.59

Ethnic and gender differences can be seen in various reports. A 2009 study60 of Mexican Americans reported a SLC6A4 haplotype associated with remission using desipramine or fluoxetine. Korean patients with the SLC6A4 S/S genotype responded better to mirtazapine compared to those with the L/L or L/S genotype.61 Chinese patients with the L/L genotype experienced better clinical response to SSRIs compared to serotonin norepinephrine reuptake inhibitors.62 Regarding gender, in women with the SLC6A4 S/S genotype, lower efficacy was reported for SSRIs as well as non-SSRIs.63,64

Other reports of SLC6A4 associations with antidepressant response are interesting. In geriatric patients, SLC6A4 was reported to interact with serum paroxetine levels to influence antidepressant response.65 In a positron emission tomography imaging study, higher serotonin transporter occupancy was associated with clinical improvement with paroxetine in patients with L/L.66 In patients with S/S genotype, antidepressant augmentation with pindolol and lithium was associated with better response.67,68

For 5-HT2A, meta-analysis of antidepressant treatment response showed a contribution to better response with a specific polymorphism, particularly in Asians.52 In the STAR*D data,69 participants who were homozygous for the 5-HT2A A allele of a newly identified variant (rs7997012) had an 18% reduction in absolute risk of having no response to treatment, compared with those homozygous for the other allele. The A allele was over six times more frequent in white than in black participants, and treatment was less effective among black participants.


Practical Recommendations

Pharmacodynamic reviews of SLC6A4 suggest that patients with the S/S genotype do not respond as well to SSRI antidepressants, and may experience more side effects.48,52,70 Thus, a practical approach is to use a non-SSRI in a patient who is SLC6A4 S/S or S/L. A decision analytic model of pre-treatment testing for SLC6A4 concluded that such testing would result in more patients experiencing remission earlier in treatment.71

Knowledge of 5-HT2A alleles might suggest the clinician try citalopram, or if generalization is possible, an SSRI, in patients who are homozygous for the 5-HT2A A allele.69 If a clinician is making a decision whether to augment an antidepressant with an antipsychotic, results of the 5-HT2C might not support an antipsychotic if the patient has the allele associated with increased weight gain with antipsychotics.


Pharmacogenomics in the Perspective of TRD

TRD represents a major public health concern, since it is associated with higher rates of relapse, poorer quality of life, deleterious personal and societal economic ramifications, and increased mortality rates.72,73 In the biopsychosocial model of depression treatment, the biologic standard of care is the medication trial. Numerous algorithms are available for guidance.6,74 Using the example of the Texas Medication Algorithm Project (TMAP), given that each adequate medication trial is ~2 months, and if a patient tries at least 3 SSRIs and 3 non-SSRIs, that would already be 1 year of medication trials. For each antidepressant, augmenting with two different medications such as a mood stabilizer or an antipsychotic for each of the antidepressants tried increases each medication trial by a few more months, and one can appreciate how patients might go through 4 or 5 years of medication trials. By incorporating genotyping results into an algorithm such as TMAP, one should be able to reduce the number of medication trials needed.

Genotyping can also explain some of the adverse events associated with medications. Consider the case example of a 58-year-old Caucasian woman with depression who has not responded to citalopram and bupropion. The clinician selects nortriptyline as the next medication trial, and titrates to a therapeutic dose based on serum level. As her depression is not improving, the clinician adds fluoxetine, noting that the combination of an SSRI and a TCA is listed in Stage 3 of the TMAP. Two weeks later, the patient experiences lethargy and unsteadiness, to the point of falling and sustaining a wrist fracture. A nortriptyline serum level shows it is now in the toxic range, and both medications are held. Two weeks later, the patient returns to her baseline state. Genotyping is obtained, and reveals that the patient is an intermediate metabolizer of CYP2D6. The explanation in this situation is that nortriptyline and fluoxetine are both metabolized by CYP2D6, and additionally, fluoxetine is a strong inhibitor of 2D6. The patient was already an intermediate metabolizer, and by inhibiting that state, effectively converted the patient to a poor metabolizer, which resulted in the nortriptyline toxicity and side effects. Adverse effects are common reasons for switching antidepressants, which leads to more medication trials and a sense of medication “resistance.” Understanding and predicting adverse effects can improve the patient’s experience and compliance with medications, leading to a better outcome.

A patient’s genetic makeup is only one of the many complex factors involved in his or her response to antidepressants. Other factors include diet, caffeine, nicotine, age, medical illness, and concurrent medications. In addition, appropriate attention should be given to the psychological and social stresses aspects of the patients’ illness. Psychotherapies such as cognitive behavioral therapy and acceptance and commitment therapy can be helpful.75,76 Patients with aversive social contexts for their depression also have consistently lower remission rates, indicating the need for social interventions.77



Depression can be difficult to treat, especially with its biopsychosocial contributors. From the biologic perspective, clinicians rely on medication trials which might span several years because of the large number of antidepressants available and the various augmentation strategies. Patients understandably become frustrated with such treatment techniques and look towards methods which might help them identify the optimal medication or combination to treat their depression.

There has been much research into whether pharmacogenomic testing might provide sufficient clinical information to guide psychotropic medication choices and thus decrease the trial and error approach of medication management. With regards to pharmacokinetic testing, specifically CYP2D6 and CYP2C19, identifying poor metabolizers in order to help with medication selection and dosage adjustments can be helpful. In patients presenting with numerous side effects, it can also confirm whether a patient is experiencing side effects because of metabolizer status. From the pharmacodynamic perspective, many genes have been studied, with the most common being the serotonin transporter and serotonin receptor genes. Patients of European ancestry with a serotonin transporter gene S/S or S/L genotype seem to not tolerate or not respond as well to SSRIs compared to patients with the L/L genotype. Various serotonin receptor gene alleles have also been associated with increased or decreased response to SSRIs as well as side effects.

The response of an individual to antidepressant treatment is not only influenced by the limited number of genes that are currently tested. Genome-wide association studies (GWAS) to investigate the entire genome without focus on a specific hypothesis and genomic area represent a new and promising methodologic strategy. A recent GWAS found remission associated with the number of predicted “response” alleles, and supported that antidepressant response emerges from a multitude of genetic variants.78,79 Further research is predicted to reveal additional clinical applications to guide treatment.  PP


1.    Fava M, Davidson KG. Definition and epidemiology of treatment-resistant depression. Psychiatr Clin North Am. 1996;19(2):179-200.
2.    Warden D, Rush AJ, Trivedi MH, Fava M, Wisniewski SR. The STAR*D Project results: a comprehensive review of findings. Curr Psychiatry Rep. 2007;9(6):449-459.
3.    Souery D, Amsterdam J, de Montigny C, et al. Treatment resistant depression: methodological overview and operational criteria. Eur Neuropsychopharmacol. 1999;9(1-2):83-91.
4.    Berlim MT, Turecki G. Definition, assessment, and staging of treatment-resistant refractory major depression: a review of current concepts and methods. Can J Psychiatry. 2007;52(1):46-54.
5.    Kennedy SH, Giacobbe P. Treatment resistant depression–advances in somatic therapies. Ann Clin Psychiatry. 2007;19(4):279-287.
6.    Trivedi MH, Fava M, Marangell LB, Osser DN, Shelton RC. Use of treatment algorithms for depression. J Clin Psychiatry. 2006;67(9):1458-1465.
7.    Black JL 3rd, O’Kane DJ, Mrazek DA. The impact of CYP allelic variation on antidepressant metabolism: a review. Expert Opin Drug Metab Toxicol. 2007;3(1):21-31.
8.    Bradford LD. CYP2D6 allele frequency in European Caucasians, Asians, Africans and their descendants. Pharmacogenomics. 2002;3(2):229-243.
9.    Lamba JK, Lin YS, Thummel K, et al. Common allelic variants of cytochrome P4503A4 and their prevalence in different populations. Pharmacogenetics. 2002;12(2):121-132.
10.    Gaedigk A, Bradford LD, Alander SW, Leeder JS. CYP2D6*36 gene arrangements within the cyp2d6 locus: association of CYP2D6*36 with poor metabolizer status. Drug Metab Dispos. 2006;34(4):563-569.
11.    Spina E, Gitto C, Avenoso A, Campo GM, Caputi AP, Perucca E. Relationship between plasma desipramine levels, CYP2D6 phenotype and clinical response to desipramine: a prospective study. Eur J Clin Pharmacol. 1997;51(5):395-398.
12.    Veefkind AH, Haffmans PM, Hoencamp E. Venlafaxine serum levels and CYP2D6 genotype. Ther Drug Monit. 2000;22(2):202-208.
13.    Whyte EM, Romkes M, Mulsant BH, et al. CYP2D6 genotype and venlafaxine-XR concentrations in depressed elderly. Int J Geriatr Psychiatry. 2006;21(6):542-549.
14.    Murphy GM Jr, Pollock BG, Kirshner MA, et al. CYP2D6 genotyping with oligonucleotide microarrays and nortriptyline concentrations in geriatric depression. Neuropsychopharmacology. 2001;25(5):737-743.
15.    Kirchheiner J, Henckel HB, Franke L, et al. Impact of the CYP2D6 ultra-rapid metabolizer genotype on doxepin pharmacokinetics and serotonin in platelets. Pharmacogenet Genomics. 2005;15(8):579-587.
16.    Schenk PW, van Fessem MA, Verploegh-Van Rij S, et al. Association of graded allele-specific changes in CYP2D6 function with imipramine dose requirement in a large group of depressed patients. Mol Psychiatry. 2008;13(6):597-605.
17.   Gex-Fabry M, Eap CB, Oneda B, et al. CYP2D6 and ABCB1 genetic variability: influence on paroxetine plasma level and therapeutic response. Ther Drug Monit. 2008;30(4):474-482.
18.    Watanabe J, Suzuki Y, Fukui N, et al. Dose-dependent effect of the CYP2D6 genotype on the steady-state fluvoxamine concentration. Ther Drug Monit. 2008;30(6):705-708.
19.    Charlier C, Broly F, Lhermitte M, Pinto E, Ansseau M, Plomteux G. Polymorphisms in the CYP 2D6 gene: association with plasma concentrations of fluoxetine and paroxetine. Ther Drug Monit. 2003;25(6):738-742.
20.    Steimer W, Zopf K, von Amelunxen S, et al. Allele-specific change of concentration and functional gene dose for the prediction of steady-state serum concentrations of amitriptyline and nortriptyline in CYP2C19 and CYP2D6 extensive and intermediate metabolizers. Clin Chem. 2004;50(9):1623-1633.
21.    Kuhs H, Schlake HP, Rolf LH, Rudolf GA. Relationship between parameters of serotonin transport and antidepressant plasma levels or therapeutic response in depressive patients treated with paroxetine and amitriptyline. Acta Psychiatr Scand. 1992;85(5):364-369.
22.    Amsterdam JD, Fawcett J, Quitkin FM, et al. Fluoxetine and norfluoxetine plasma concentrations in major depression: a multicenter study. Am J Psychiatry. 1997;154(7):963-969.
23.    Beasley CM, Jr., Bosomworth JC, Wernicke JF. Fluoxetine: relationships among dose, response, adverse events, and plasma concentrations in the treatment of depression. Psychopharmacol Bull. 1990;26(1):18-24.
24.    Schenk PW, van Vliet M, Mathot RA, et al. The CYP2C19*17 genotype is associated with lower imipramine plasma concentrations in a large group of depressed patients. Pharmacogenomics J. Nov 3, 2009. [Epub ahead of print].
25.    Wang JH, Liu ZQ, Wang W, et al. Pharmacokinetics of sertraline in relation to genetic polymorphism of CYP2C19. Clin Pharmacol Ther. 2001;70(1):42-47.
26.    Rudberg I, Hermann M, Refsum H, Molden E. Serum concentrations of sertraline and N-desmethyl sertraline in relation to CYP2C19 genotype in psychiatric patients. Eur J Clin Pharmacol. 2008;64(12):1181-1188.
27.    Jin Y, Pollock BG, Frank E, et al. Effect of age, weight, and CYP2C19 genotype on escitalopram exposure. J Clin Pharmacol. 2010;50(1):62-72.
28.    Yokono A, Morita S, Someya T, Hirokane G, Okawa M, Shimoda K. The effect of CYP2C19 and CYP2D6 genotypes on the metabolism of clomipramine in Japanese psychiatric patients. J Clin Psychopharmacol. 2001;21(6):549-555.
29.    Grasmader K, Verwohlt PL, Rietschel M, et al. Impact of polymorphisms of cytochrome-P450 isoenzymes 2C9, 2C19 and 2D6 on plasma concentrations and clinical effects of antidepressants in a naturalistic clinical setting. Eur J Clin Pharmacol. 2004;60(5):329-336.
30.    Chen S, Chou WH, Blouin RA, et al. The cytochrome P450 2D6 (CYP2D6) enzyme polymorphism: screening costs and influence on clinical outcomes in psychiatry. Clin Pharmacol Ther. 1996;60(5):522-534.
31.    Rau T, Wohlleben G, Wuttke H, et al. CYP2D6 genotype: impact on adverse effects and nonresponse during treatment with antidepressants-a pilot study. Clin Pharmacol Ther. 2004;75(5):386-393.
32.    Grzesiak M, Beszlej A, Lebioda A, Jonkisz A, Dobosz T, Kiejna A. Retrospective assessment of the antidepressants tolerance in the group of patients with diagnosis of depression and different CYP2D6 genotype [Polish]. Psychiatr Pol. 2003;37(3):433-444.
33.    Laika B, Leucht S, Heres S, Steimer W. Intermediate metabolizer: increased side effects in psychoactive drug therapy. The key to cost-effectiveness of pretreatment CYP2D6 screening? Pharmacogenomics J. 2009;9(6):395-403.
34.    McAlpine DE, O’Kane DJ, Black JL, Mrazek DA. Cytochrome P450 2D6 genotype variation and venlafaxine dosage. Mayo Clin Proc. 2007;82(9):1065-1068.
35.    Shams ME, Arneth B, Hiemke C, et al. CYP2D6 polymorphism and clinical effect of the antidepressant venlafaxine. J Clin Pharm Ther. 2006;31(5):493-502.
36.    Roberts RL, Mulder RT, Joyce PR, Luty SE, Kennedy MA. No evidence of increased adverse drug reactions in cytochrome P450 CYP2D6 poor metabolizers treated with fluoxetine or nortriptyline. Hum Psychopharmacol. 2004;19(1):17-23.
37.    Gillman PK. Re: no evidence of increased adverse drug reactions in cytochrome P450 CYP2D6 poor metabolizers treated with fluoxetine or nortriptyline. Hum Psychopharmacol. 2005;20(1):61-62.
38.    Murphy GM, Jr., Kremer C, Rodrigues HE, Schatzberg AF. Pharmacogenetics of antidepressant medication intolerance. Am J Psychiatry. 2003;160(10):1830-1835.
39.    Kawanishi C, Lundgren S, Agren H, Bertilsson L. Increased incidence of CYP2D6 gene duplication in patients with persistent mood disorders: ultrarapid metabolism of antidepressants as a cause of nonresponse. A pilot study. Eur J Clin Pharmacol. 2004;59(11):803-807.
40.    Serretti A, Calati R, Massat I, et al. Cytochrome P450 CYP1A2, CYP2C9, CYP2C19 and CYP2D6 genes are not associated with response and remission in a sample of depressive patients. Int Clin Psychopharmacol. 2009;24(5):250-256.
41.    Preskorn SH FD. 2010 guide to psychiatric drug interactions. Primary Psychiatry. 2009;16(12):45-74.
42.    de Leon J, Armstrong SC, Cozza KL. Clinical guidelines for psychiatrists for the use of pharmacogenetic testing for CYP450 2D6 and CYP450 2C19. Psychosomatics. 2006;47(1):75-85.
43.    de Leon J, Susce MT, Johnson M, et al. DNA microarray technology in the clinical environment: the AmpliChip CYP450 test for CYP2D6 and CYP2C19 genotyping. CNS Spectr. 2009;14(1):19-34.
44.    Kirchheiner J, Nickchen K, Bauer M, et al. Pharmacogenetics of antidepressants and antipsychotics: the contribution of allelic variations to the phenotype of drug response. Mol Psychiatry. 2004;9(5):442-473.
45.    Thuerauf N, Lunkenheimer J. The impact of the CYP2D6-polymorphism on dose recommendations for current antidepressants. Eur Arch Psychiatry Clin Neurosci. 2006;256(5):287-293.
46.    DeVane CL. Antidepressant-drug interactions are potentially but rarely clinically significant. Neuropsychopharmacology. 2006;31(8):1594-1604.
47.    FDA News Release. December 12, 2007. Carbamazepine prescribing information to include recommendation of genetic test for patients with asian ancestry. Available at: www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/2007/ucm109038.htm. Accessed February 11, 2010.
48.    Horstmann S, Binder EB. Pharmacogenomics of antidepressant drugs. Pharmacol Ther. 2009;124(1):57-73.
49.    Murphy GM Jr, Hollander SB, Rodrigues HE, Kremer C, Schatzberg AF. Effects of the serotonin transporter gene promoter polymorphism on mirtazapine and paroxetine efficacy and adverse events in geriatric major depression. Arch Gen Psychiatry. 2004;61(11):1163-1169.
50.    Bishop JR, Ellingrod VL, Akroush M, Moline J. The association of serotonin transporter genotypes and selective serotonin reuptake inhibitor (SSRI)-associated sexual side effects: possible relationship to oral contraceptives. Hum Psychopharmacol. 2009;24(3):207-215.
51.    Ferreira Ade A, Neves FS, da Rocha FF, et al. The role of 5-HTTLPR polymorphism in antidepressant-associated mania in bipolar disorder. J Affect Disord. 2009;112(1-3):267-272.
52.    Kato M, Serretti A. Review and meta-analysis of antidepressant pharmacogenetic findings in major depressive disorder. Mol Psychiatry. Nov 4, 2008. [Epub ahead of print].
53.    Bishop JR, Moline J, Ellingrod VL, Schultz SK, Clayton AH. Serotonin 2A -1438 G/A and G-protein Beta3 subunit C825T polymorphisms in patients with depression and SSRI-associated sexual side-effects. Neuropsychopharmacology. 2006;31(10):2281-2288.
54.    Reynolds GP, Zhang Z, Zhang X. Polymorphism of the promoter region of the serotonin 5-HT(2C) receptor gene and clozapine-induced weight gain. Am J Psychiatry. 2003;160(4):677-679.
55.    Reynolds GP, Templeman LA, Zhang ZJ. The role of 5-HT2C receptor polymorphisms in the pharmacogenetics of antipsychotic drug treatment. Prog Neuropsychopharmacol Biol Psychiatry. 2005;29(6):1021-1028.
56.    Serretti A, Kato M, De Ronchi D, Kinoshita T. Meta-analysis of serotonin transporter gene promoter polymorphism (5-HTTLPR) association with selective serotonin reuptake inhibitor efficacy in depressed patients. Mol Psychiatry. 2007;12(3):247-257.
57.    Kraft JB, Peters EJ, Slager SL, et al. Analysis of association between the serotonin transporter and antidepressant response in a large clinical sample. Biol Psychiatry. 2007;61(6):734-742.
58.    Hu XZ, Rush AJ, Charney D, et al. Association between a functional serotonin transporter promoter polymorphism and citalopram treatment in adult outpatients with major depression. Arch Gen Psychiatry. 2007;64(7):783-792.
59.    Mrazek DA, Rush AJ, Biernacka JM, et al. SLC6A4 variation and citalopram response. Am J Med Genet B Neuropsychiatr Genet. 2009;150B(3):341-351.
60.    Dong C, Wong ML, Licinio J. Sequence variations of ABCB1, SLC6A2, SLC6A3, SLC6A4, CREB1, CRHR1 and NTRK2: association with major depression and antidepressant response in Mexican-Americans. Mol Psychiatry. 2009;14(12):1105-1118.
61.    Kang RH, Wong ML, Choi MJ, Paik JW, Lee MS. Association study of the serotonin transporter promoter polymorphism and mirtazapine antidepressant response in major depressive disorder. Prog Neuropsychopharmacol Biol Psychiatry. 2007;31(6):1317-1321.
62.    Min W, Li T, Ma X, et al. Monoamine transporter gene polymorphisms affect susceptibility to depression and predict antidepressant response. Psychopharmacology (Berl). 2009;205(3):409-417.
63.    Smits KM, Smits LJ, Peeters FP, et al. The influence of 5-HTTLPR and STin2 polymorphisms in the serotonin transporter gene on treatment effect of selective serotonin reuptake inhibitors in depressive patients. Psychiatr Genet. 2008;18(4):184-190.
64.    Gressier F, Bouaziz E, Verstuyft C, Hardy P, Becquemont L, Corruble E. 5-HTTLPR modulates antidepressant efficacy in depressed women. Psychiatr Genet. 2009;19(4):195-200.
65.    Lotrich FE, Pollock BG, Kirshner M, Ferrell RF, Reynolds Iii CF. Serotonin transporter genotype interacts with paroxetine plasma levels to influence depression treatment response in geriatric patients. J Psychiatry Neurosci. 2008;33(2):123-130.
66.    Ruhe HG, Ooteman W, Booij J, et al. Serotonin transporter gene promoter polymorphisms modify the association between paroxetine serotonin transporter occupancy and clinical response in major depressive disorder. Pharmacogenet Genomics. 2009;19(1):67-76.
67.    Zanardi R, Serretti A, Rossini D, et al. Factors affecting fluvoxamine antidepressant activity: influence of pindolol and 5-HTTLPR in delusional and nondelusional depression. Biol Psychiatry. 2001;50(5):323-330.
68.    Stamm TJ, Adli M, Kirchheiner J, et al. Serotonin transporter gene and response to lithium augmentation in depression. Psychiatr Genet. 2008;18(2):92-97.
69.    McMahon FJ, Buervenich S, Charney D, et al. Variation in the gene encoding the serotonin 2A receptor is associated with outcome of antidepressant treatment. Am J Hum Genet. 2006;78(5):804-814.
70.    Luddington NS, Mandadapu A, Husk M, El-Mallakh RS. Clinical implications of genetic variation in the serotonin transporter promoter region: a review. Prim Care Companion J Clin Psychiatry. 2009;11(3):93-102.
71.    Smits KM, Smits LJ, Schouten JS, Peeters FP, Prins MH. Does pretreatment testing for serotonin transporter polymorphisms lead to earlier effects of drug treatment in patients with major depression? A decision-analytic model. Clin Ther. 2007;29(4):691-702.
72.    Greden JF. The burden of disease for treatment-resistant depression. J Clin Psychiatry. 2001;62 suppl 16:26-31.
73.    Fekadu A, Wooderson SC, Markopoulo K, Donaldson C, Papadopoulos A, Cleare AJ. What happens to patients with treatment-resistant depression? A systematic review of medium to long term outcome studies. J Affect Disord. 2009;116(1-2):4-11.
74.    TMAP. Texas Medication Algorithm Project. Available at: www.dshs.state.tx.us/mhprograms/disclaimer.shtm. Accessed February 11, 2010.
75.    Markowitz JC. Evidence-based psychotherapies for depression. J Occup Environ Med. 2008;50(4):437-440.
76.    Pull CB. Current empirical status of acceptance and commitment therapy. Curr Opin Psychiatry. 2009;22(1):55-60.
77.    Brown GW, Harris TO, Kendrick T, et al. Antidepressants, social adversity and outcome of depression in general practice. J Affect Disord. 2010;121(3):239-246.
78.    Sabbagh A, Darlu P. Data-mining methods as useful tools for predicting individual drug response: application to CYP2D6 data. Hum Hered. 2006;62(3):119-134.
79.    Ising M, Lucae S, Binder EB, et al. A genomewide association study points to multiple loci that predict antidepressant drug treatment outcome in depression. Arch Gen Psychiatry. 2009;66(9):966-975.

High Rates of Psychiatric Disorders Found in the Wives of Deployed Soldiers

Active military deployment can be a stressful period for both the family member on active deployment as well as family members at home waiting for a safe return. The mental health status of the wives of active military personnel, including those soldiers that are still at home and those that are deployed, has not frequently been studied.

Alyssa Mansfield, PhD, and colleagues reviewed the electronic medical records of >250,000 female spouses of active duty Army personnel receiving outpatient care between 2003 and 2006. Of the wives studied, ~31% had husbands that were currently home, ~34% were stationed overseas between 1–11 months, and 35% were deployed for >12 months.

Mansfield and colleagues found higher rates of mental health diagnosis in the wives of soldiers who were deployed for >12 months compared to those deployed for shorter periods of time or still stationed at home. The Table provides the adjusted analysis of wives whose husbands were not deployed and whose husbands were deployed between 1–11 months compared to the wives whose husbands were deployed for >12 months. When converting the excess cases to potential patients, Mansfield and colleagues found that the 41.3 excess cases would attribute to 3,474 mental health diagnoses and the 60.7 excess cases would attribute 5,370 mental health diagnoses.


Although there are limitations to this study, Mansfield and colleagues believe that this data proves that treatment options and preventive measures not only need to be offered to returning soldiers, but also to all military family members. (N Eng J Med. 2010;362(2):168-170.) –CN


Hypertension, White Matter Brain Lesions, and Dementia Risk in Older Women

Older women with hypertension may be at greater risk for abnormal white matter lesions in the brain that can cause dementia. The relationship between hypertension, blood pressure, and blood pressure control with white matter abnormalities in the Women’s Health Initiative (WHI) Memory Study—MRI Trial was studied by Lewis H. Kuller, MD, PhD, at the University of Pittsburgh.

The study’s sample included 1,403 women, ≥65 years of age, from the WHI study. All participants had no dementia at baseline and received blood pressure, cognitive, and magnetic resonance imaging (MRI) assessments.

According to MRI, women receiving hypertension treatment, with blood pressure ≥140/90 mm Hg, had the greatest number of abnormal white matter lesions. Women receiving no hypertension treatment, with blood pressure ≥140/90 mm Hg, had “intermediate” levels of abnormal white lesions. The white matter lesions were more likely to appear in the frontal lobe, compared to the occipital, parietal, or temporal lobes, and baseline blood pressure was strongly associated with white matter lesion volumes.

Previous evidence, combined with the current study, continues to suggest that maintaining health blood pressure levels consistently and sooner in life is the best preventive measure against dementia.

The WHI program is funded by the National Heart, Lung, and Blood Institute of the National Institutes of Health. (J Clin Hypertens. Epub Dec. 16, 2009) –LS


Sudden Infant Death Syndrome Linked to Lower Levels of Serotonin

Sudden infant death syndrome (SIDS) is the leading cause of postneonatal infant death in the United States. During a critical developmental period, SIDS is speculated to result from abnormalities in brainstem control of autonomic function and breathing. It has been reported that irregularities of serotonin (5-HT) and tryptophan hydroxylase (TPH2) receptor binding in regions of the medulla oblongata have been documented in infant deaths resulting from SIDS.

The hypothesis that SIDS is connected with reductions in tissue levels of 5-HT, TPH2, or both was tested by Jhodie R. Duncan, PhD, and colleagues at the Children’s Hospital Boston and Harvard Medical School in Massachusetts. For biochemical analysis, the study involved 35 infants who had died from SIDS, five infants with acute death from known causes, and five hospitalized infants with chronic hypoxia-ischemia. Through autopsy, tissue samples were obtained and several enzymes, including 5-HT and TPH2, were analyzed and measured.

In the raphé obscurus and the paragigantocellularis lateralis regions of the brain, the researchers found that 5-HT levels were 26% lower in SIDS cases compared with age-adjusted controls. TPH2 levels were 22% lower in the raphé obscurus in the SIDS cases, and 5-HT levels were 55% higher in the raphé obscurus and 126% higher in the paragigantocellularis lateralis in the hospitalized group compared with the SIDS group.

According to the authors, SIDS can be viewed as possibly being caused by a defect in one or more parts of the medullary 5-HT system.

Funding for this research was provided by Children’s Hospital Boston and Harvard Medical School in Massachusetts.  (JAMA. 2010;303(5):430-437). –JV

Psychiatric dispatches is written by Christopher Naccari, Lonnie Stoltzfoos, and Jennifer Verlangieri.


Dr. Haq is house officer in the Department of Psychiatry at the University of Michigan in Ann Arbor.

Disclosure: Dr. Haq reports no affiliation with or financial interest in any organization that may pose a conflict of interest.

Off-label disclosure: This article includes discussion of treatments for insomnia and anxiety disorders in patients with chronic alcohol-use disorders which are not approved by the United States Food and Drug Administration.

Acknowledgments: The author would like to thank Kirk Brower, MD, for his valuable editorial assistance; Michelle Riba, MD, Michael Jibson, MD, PhD, and Theadia Carey, MD, for their support; and Edward Jouney, DO, for his inspiration for this article.

Please direct all correspondence to: Aazaz Haq, MD, Department of Psychiatry, University of Michigan, MCHC F6135, 1500 E Medical Center Drive, Ann Arbor, MI 48109; Tel: 734-764-6875; Fax: 734-936-9116; E-mail: ahaq@med.umich.edu.



Insomnia and anxiety are frequently encountered problems in patients with chronic alcohol use disorders. The use of benzodiazepines and benzodiazepine-receptor agonists in post-withdrawal patients is discouraged due to their abuse potential and cross-reactivity with alcohol, and clinicians should be aware of what alternate medications are available. For the treatment of insomnia, trazodone, low-dose tricylic antidepressants, gabapentin, and quetiapine can all be used effectively in this population. For common anxiety disorders (panic disorder, generalized anxiety disorder, social anxiety disorder, and posttraumatic stress disorder), selective serotonin reuptake inhibitors, buspirone, venlafaxine, quetiapine, and gabapentin all have varying levels of evidence of efficacy. These medications have their greatest effect when used in conjunction with continued behavioral and other non-pharmacologic therapy.

Focus Points

• Some antidepressants at low doses (trazodone, tricyclic antidepressants), at least one antiepileptic (gabapentin), and atypical antipsychotics (particularly quetiapine) can all be used to treat insomnia in patients with chronic alcohol use disorders.
• For the treatment of common anxiety disorders in alcohol-dependent patients, there is varying degrees of evidence supporting the use of selective serotonin reuptake inhibitors, venlafaxine, buspirone, quetiapine, and gabapentin.
• Large-scale, placebo-controlled trials assessing the efficacy of common anxiolytics in the treatment of anxiety disorders in alcohol-dependent patients are generally lacking.
• Benzodiazepines and benzodiazepine receptor agonists should be used in patients with alcohol-use disorders only with extreme caution.



Alcohol use disorders are known to be frequently comorbid with insomnia, anxiety, and depression.1,2 While depression can be difficult to treat in alcoholics, the medications used to treat depressive symptoms in this population are no different than those used in the general population.3 In contrast, the treatment of insomnia and anxiety in alcoholic patients is made particularly challenging by the relative contraindication of benzodiazepines in this population due to their abuse liability.4 Clinicians who treat patients with alcohol use disorders should be aware of what options are available to treat insomnia and anxiety.

A significant association between alcohol dependence and insomnia has been shown in several community samples.5,6 Moreover, disturbed sleep has been shown to be a strong predictor of relapse in alcoholics after detoxification,7,8 and alcoholic patients are much more likely to use alcohol to self-medicate for their insomnia.8 During acute withdrawal, alcoholics have short and fragmented sleep with long sleep latencies, very small amounts of delta (stages 3 and 4) sleep, and vivid dreams.9 Sleep continues to be significantly disrupted during the first month of sobriety and slowly improves over the next few months. Some measures of sleep quality remain abnormal at ≥14 months after abstinence, with continued decreased delta-wave sleep, increased rapid eye movement (REM) percentage, and increased REM latency.10

Alcoholism is also frequently comorbid with anxiety disorders. In some patients with a genetic predisposition to an anxiety disorder, ingestion of alcohol can “unmask” anxiety symptoms.11 Other patients with preexisting anxiety disorders frequently use alcohol to self-medicate. The National Comorbidity Study found that in 8,000 respondents with alcohol use disorders in the United States between 15–54 years of age, 37% had at least one anxiety disorder, most commonly social anxiety disorder (18%).12 Independent community studies from Germany and Australia have reported rates of comorbid anxiety disorders among alcoholic patients of 42.3% and 15%, respectively, with the most common disorders being generalized anxiety disorder (GAD) and specific phobia.13,14 Significantly higher degrees of anxiety are found in patients who subsequently relapse within 6 months of initiating abstinence than those who manage to stay sober.15

This article discusses the alternatives to benzodiazepine treatment in the management of insomnia and anxiety in post-withdrawal alcohol-dependent patients. For the treatment of insomnia in these patients, trazodone, tricyclic antidepressants (TCAs), gabapentin, and quetiapine are commonly used. For anxiety disorders, selective serotonin reuptake inhibitors (SSRIs), buspirone, venlafaxine, quetiapine, and gabapentin can all generally be used with efficacy, depending on the specific type of anxiety disorder.




The sedative properties of some antidepressants, typically at low doses, can be used to treat insomnia in alcoholic patients. Trazodone is the second most common medication used by clinicians for insomnia (after zolpidem), despite the relative absence of convincing evidence of its efficacy in non-depressed patients with insomnia.16 It is the agent most commonly used by addiction specialists to treat insomnia in alcoholic patients.17 Trazodone has a relatively benign side-effect profile (most common side effects being drowsiness, dizziness, dry mouth), appears to have few interactions with alcohol,18 and does not have abuse potential.19 Some data suggest that tolerance to the sedative effects of trazodone may develop over long-term use.16 For example, two studies20,21 looking at objective measurements of the sedative effects of trazodone show a slight decrease in the total sleep time in subjects using trazodone after week 3 in one study20 and week 4 in the other.21 However, further studies are needed to clarify this effect.

A small (n=16), double-blind, placebo-controlled study22 assessing the efficacy of trazodone in improving sleep in post-withdrawal alcoholics found that, after 4 weeks, patients receiving nightly trazodone (50 mg/night, titrated up to 200 mg) had significantly increased sleep efficiency, less frequent night-time awakenings, and increased non-REM sleep percentage, than those receiving placebo. A later double-blind, placebo-controlled study19 with a larger sample size (n=173) confirmed that trazodone improves sleep quality and overall mental health during its administration. However, the study19 also found that the patients in the trazodone group had less improvement in the proportion of abstinent days during 3 months of treatment and drank a greater number of drinks per drinking day following the cessation of the medication than the placebo group. Therefore, trazodone was not recommended with confidence for the routine treatment of insomnia in alcohol-dependent patients.

Sedating TCAs can be used at low doses for their anti-histaminergic properties to treat insomnia. For example, doxepin, whose antidepressant effects are typically seen at daily doses of 50–300 mg, has been shown to produce effective hypnotic effects at doses of 1–6 mg/day.23,24 At these low doses, doxepin is selective for blocking only histamine (H)1 receptors and has no effect on serotonin or norepinephrine transporters or muscarininc acetylcholine receptors.25 Selective H1 blockade is not associated with rebound insomnia, loss of hypnotic efficacy over time, or daytime sedation; these undesirable effects of many “antihistamine” medications are largely due to their actions on muscarinic, cholinergic, and adrenergic receptors.25,26 Because muscarinic receptors are not affected at such low doses, the anticholinergic side effects of confusion, dry mouth, blurred vision, constipation, and urinary retention, which are commonly associated with TCAs, are not seen with low dose doxepin. TCAs also have the benefit of not producing euphoria as a side effect, not causing physical tolerance or dependence, and not being controlled substances.23 TCAs should be used with caution in alcohol-dependent patients; even mild overdoses can cause cardiotoxicity or severe orthostatic hypotension and can be fatal, something to be wary of in a population that is at an increased risk for suicide attempts. Moreover, TCAs can lower the seizure threshold, so they should be used with caution in patients undergoing alcohol withdrawal.

SSRIs are generally not used to treat insomnia, as they can frequently worsen sleep and increase the number of nighttime awakenings.24 Nefazodone, an antidepressant with a similar structure to trazodone, has some sleep-promoting properties, but it is rarely used today because of its risk of serious hepatic toxicity.



Gabapentin has recently been gaining favor for the treatment of alcohol dependence and alcohol-related insomnia. Gabapentin is an antiepileptic medication that has a relatively benign side-effect profile, little abuse potential, and does not affect the metabolism or excretion of other medications. Gabapentin has been studied for alcohol-related insomnia during both acute withdrawal and after several weeks of abstinence. During acute withdrawal, gabapentin was shown to be superior to lorazepam in reducing nighttime insomnia and daytime sleepiness among subjects with a history of repeated withdrawal episodes.27 In a preliminary non-blinded, uncontrolled study of post-withdrawal insomnia, Karam-Hage and Brower28 showed that 15 alcohol-dependent patients had improved sleep quality as per the Sleep Problems Questionnaire (SPQ) with an average gabapentin dose of 953 mg/day.

In another non-randomized, non-blinded, uncontrolled study29 (n=50) comparing gabapentin with trazodone for the treatment of post-withdrawal insomnia in patients with alcohol dependence, both medications were shown to improve sleep quality, as per the SPQ, although gabapentin improved sleep quality significantly more than trazodone and was associated with less sedation the next day. However, in a recent double-blind, placebo-controlled pilot trial30 (n=21) of post-withdrawal alcohol-dependent subjects, the same authors found no significant difference in the sleep quality of the gabapentin versus placebo group, as measured by the SPQ, sleep diary parameters, and polysomnography parameters. Of note, gabapentin significantly delayed the onset of relapse to drinking in this study.



Of the typical and atypical antipsychotics, quetiapine is the one most commonly used clinically in patients with alcohol use disorders to reduce cravings and promote sleep. A small-scale retrospective review31 of male alcoholic patients at a Veterans Administration (VA) hospital showed that, in patients with difficulty initiating sleep, quetiapine initiated at a dose of 25–50 mg and titrated up to 200 mg increased the total number of days of abstinence and significantly lowered the rate of hospital admissions. The study did not comment on sleep differences between the two groups. Another retrospective chart review32 of data from patients admitted to a 28-day residential rehabilitation program showed significant improvement in insomnia in alcoholic patients given quetiapine. In an open-label pilot trial33 of 28 dually diagnosed alcoholics, quetiapine significantly decreased middle and late insomnia. A randomized control trial34 by the Department of Veterans Affairs to study the use of quetiapine for insomnia during alcohol abstinence is currently recruiting participants. Of note, the use of quetiapine as a drug of abuse has been rising; it is the antipsychotic most commonly implicated in the literature in case reports of antipsychotic abuse.35 It has several street names, such as “quell,” “Susie-Q,” and “baby heroin.”



Any of the common anxiety disorders (panic disorder, GAD, social anxiety disorder, and posttraumatic stress disorder [PTSD]) can be comorbid with alcohol abuse or dependence. Below, evidence regarding treatment will be reviewed by disorder. When assessing these disorders in the context of alcoholism, it is important to distinguish them from transient anxiety states related to alcohol intoxication or withdrawal, as these may improve with abstinence alone. The best way to approach this task is by observation of the patient during a period of abstinence, generally after 3 or 4 weeks of sobriety for patients recovering from chronic alcohol use.36


Panic Disorder

Several types of antidepressants, including SSRIs, TCAs, monoamine oxidase inhibitors (MAOIs), and venlafaxine, have been shown to be effective in the treatment of panic disorders in patients without substance use disorders, but they have not been studied systematically for use in patients with alcohol or other substance use disorders. Given the unfavorable side-effect profiles of TCAs and MAOIs, SSRIs and venlafaxine are logical choices among antidepressants for the treatment of panic disorder in patients in remission from alcohol.11 SSRIs have a relatively benign side-effect profile, are safe in overdose, and have little abuse potential. To avoid increased anxiety with the initial activation associated with SSRIs, they should be started at a low dose and titrated upwards slowly. Patients should be monitored for relapse in the 4-to-6-week window it takes for the SSRIs to have an effect. As these medications are metabolized by the liver, lower doses should be used in chronic alcoholic patients who have compromised liver function.37 Venlafaxine, a serotonin-norepinephrine reuptake inhibitor, is approved by the US Food and Drug Administration for the treatment of panic disorder38; however, trials of its use in alcohol-dependent patients are lacking.

Gabapentin may be a novel alternative to SSRIs in the treatment of severe panic disorder. In a double-blind, placebo-controlled study (n=103), gabapentin (dosed from 600–3,600 mg/day) was not found to be more effective than placebo in reducing scores on the Panic and Agoraphobia Scale (PAS).39 However, in the severely ill subset of patients with baseline PAS≥20, the patients treated with gabapentin showed significant improvement in PAS scores. Gabapentin has not been studied for treatment of panic disorder in alcoholic patients; however, it has a favorable risk-benefit profile and may be a good option for alcoholic patients with severe panic symptoms for whom SSRIs or venlafaxine are not good options or are ineffective.



Diagnosis of GAD in patients with substance abuse disorders is challenging, as many symptoms of intoxication and withdrawal, such as anxiety, restlessness, difficulty concentrating, fatigue, and sleep disturbance, are similar to the symptoms of GAD. Of the anxiolytic medications, buspirone has been studied most extensively for treatment of GAD in alcoholic patients.40 This is a generally well-tolerated medication with a favorable side-effect profile (most common side effects being dizziness, nausea, headache, nervousness, lightheadedness, and insomnia). Patients given buspirone (average daily dose 20 mg/day) in a double-blind, placebo-controlled trial41 (n=50) in outpatients with mild-to-moderate alcohol abuse demonstrated decreased scores on the Hamilton Rating Scale for Anxiety (HAM-A) as well as lower discontinuation rate and decreased cravings. In another trial42 evaluating 51 patients with dual diagnoses of alcohol abuse or dependence and GAD, the buspirone treatment group had decreased overall anxiety, less number of days desiring alcohol, and overall clinical global improvement. However, in a double-blinded, placebo-controlled study43 (n=67) of alcohol-dependent patients with high levels of generalized anxiety in a Veteran’s Administration hospital, there was no significant difference on scores between the treatment and placebo groups on the HAM-A or the Speilberger State Anxiety Scale. Lastly, in a randomized, 12-week, placebo-controlled trial,44 buspirone was found to be associated with reduced anxiety, greater retention rate, a slower return to heavy alcohol consumption, and fewer drinks during the follow-up period compared to placebo. Anxiolytic effects with this medication may only be seen at relatively higher doses (above 30 mg/day) after 2–4 weeks of treatment.45

SSRIs, TCAs, venlafaxine, and some anticonvulsants are also effective in treating symptoms of GAD in the general population. However, trials studying these medications in the treatment of GAD specifically in alcoholic patients are lacking. Based on side effects, metabolic profiles, and data from non-alcoholic patients, buspirone, SSRIs, and venlafaxine are likely the most reasonable choices in alcohol-dependent patients for the treatment of GAD.


Social Anxiety Disorder

Kessler and colleagues46 found the rate of comorbidity of social anxiety and alcohol abuse to be 22%. Patients with social anxiety disorder often use alcohol to self-medicate and ease anxiety in social situations. In the general population, MAOIs (phenelzine, brofaromine, and moclobemide), SSRIs (sertraline and fluvoxamine), benzodiazepines (clonazepam), and one antiepileptic (gabapentin), have been shown to be effective in treating social anxiety in placebo-controlled trials.47 Buspirone is not effective in treating social anxiety.48 Placebo-controlled trials studying these medications in patients with comorbid alcohol use disorders and social anxiety are lacking, with the exception of one study49 examining the use of paroxetine. In this 8-week, double-blind, placebo-controlled trial (n=18), alcohol-dependent patients in the treatment group (paroxetine titrated to 60 mg/day) showed a significant improvement in social anxiety symptoms (as per the Clinical Global Index and the Liebowitz Social Anxiety Scale) by week 6 of the trial. Of note, no significant difference on any of the quantity/frequency measures of alcohol use was seen between the two groups.



PTSD is associated with a greatly increased risk of alcohol dependence.50 SSRIs have been widely shown to be successful in the treatment of PTSD in the non-substance-abusing population. In a preliminary open-label trial of sertraline in patients with comorbid alcohol-dependence and PTSD, PTSD symptom scores (per the Impact of Event Scale) and average number of drinks during the follow-up period decreased, while the number of days of abstinence increased.51 In a follow-up randomized, placebo controlled trial (n=94) of sertraline in PTSD patients with comorbid alcohol-use disorders, the same authors52 found a significant decrease in alcohol use in both the treatment and placebo groups. Of note, in this study, a subgroup of patients with less severe alcohol dependence and early-onset PTSD had significantly fewer drinks per drinking day with sertraline treatment than other groups.

Several atypical antipsychotics, including risperidone,53 olanzapine,54 and quetiapine,55 have been shown to be effective as adjunctive agents to SSRIs in alleviating PTSD symptoms in the general population. However, they have not been studied in patients with co-morbid PTSD and alcohol-use disorders. In a retrospective study31 assessing quetiapine treatment in alcohol-dependent patients in a VA hospital, 90% of whom had PTSD, the authors found a decrease in the number of detoxifications needed per year, increase in the total number of abstinent days, and longer mean time to relapse in patients receiving quetiapine for sleep. These improvements were attributed at least partially to reduction in PTSD symptoms from quetiapine.


Benzodiazepines and Benzodiazepine-Receptor Agonists

The use of benzodiazepines in alcoholic patients merits special discussion. These medications are frequently used to treat anxiety and insomnia in the general population. However, except in the treatment of acute alcohol withdrawal, use of these medications in patients with alcohol use disorders is generally discouraged.4 They share a similar mechanism of action on gamma-aminobutyric acid  receptors to alcohol and have a high abuse potential.56 Even in patients without substance use problems, they are generally recommended only for short-term usage and in conservative dosages.57

Benzodiapzepine receptor antagonists (BzRAs), like zolpidem and zaleplon, present an interesting scenario in the treatment of insomnia in alcoholic patients. These medications are generally well tolerated, and studies have shown that they do not cause tolerance or dependence at physiologic doses over short-term (4-week) nightly use58 or long-term (12-week) non-nightly use.59 A very large percentage of patients who use BzRAs for primary nighttime insomnia do not go on to develop dependence or to abuse the drug in the daytime for non-therapeutic reasons.60 In 2002, a systematic review of all published case studies of BzRA dependence found only 36 cases of zolpidem dependence and 22 cases of zoplicone dependence, almost all of which involved former drug or alcohol abusers or patients with other recognized psychiatric disorders.61 This relatively low number of published cases of dependence was in marked contrast to the much higher incidence of dependence known with benzodiazepines. The authors concluded that zolpidem and zoplicone are relatively safe medications, but “extreme caution” should be utilized when prescribing them to patients with a history of substance abuse, dependence, or other psychiatric illness.

It is worth mentioning that withholding benzodiazepines or BzRAs from all post-withdrawal alcoholic patients as a rule may not be an optimal strategy. According to Lejoyeux and colleagues,4 an anxiolytic agent might help to improve the quality of life and adherence to treatment in patients with severe anxiety. A recent prospective study62 monitoring 545 patients with comorbid anxiety and alcohol-use disorder receiving benzodiazepines over 12 years showed that benzodiazepine usage did not predict recovery or relapse. However, the authors were cautious in generalizing their results to all patients or the set of patients who present for addiction treatment. The judicious use of benzodiazepines in a given patient should be decided on a case-by-case basis after a careful assessment of the alternatives as well as the risks and benefits involved.



The management of insomnia and anxiety in the alcohol-dependent population can be challenging. With the relative contraindication of benzodiazepines and BzRAs, clinicians have to turn to alternative medications to treat these symptoms. It is important to keep in mind that none of the medications discussed above are FDA-approved for treatment of insomnia or anxiety disorders in alcohol-dependent patients. Moreover, they have their greatest effects when used in conjunction with continued behavioral and non-pharmacologic therapy.63 Continued research is needed to further identify the safety and efficacy of these medications in this unique patient population.  PP



1.    Grant BF, Stinson FS, Dawson DA, et al. Prevalence and co-occurrence of substance use disorders and independent mood and anxiety disorders: results from the National Epidemiologic Survey on Alcohol and Related Conditions. Arch Gen Psychiatry. 2004;61(8):807-816.
2.    Conway KP, Compton W, Stinson FS, Grant BF. Lifetime comorbidity of DSM-IV mood and anxiety disorders and specific drug use disorders: results from the National Epidemiologic Survey on Alcohol and Related Conditions. J Clin Psychiatry. 2006;67(2):247-257.
3.    Nunes EV, Levin FR. Treatment of depression in patients with alcohol or other drug dependence: a meta analysis. JAMA. 2004;291(15):1887-1896.
4.    Lejoyeux M, Solomon J, Ades J. Benzodiazepine treatment for alcohol dependent patients. Alcohol Alcohol. 1998;33(6):563-575.
5.    Brower KJ. Insomnia, alcoholism, and relapse. Sleep Med Rev. 2003;7(6):523-539.
6.    Takamatsu S, Sekine M, Tatsuse T, Kagamimori S. Alcohol drinking patterns and sleep quality of Japanese civil servants. Sangyo Eiseigaku Zasshi. 2009 Nov 27 [Epub ahead of print].
7.    Foster JH, Marshall EJ, Peters TJ. Predictors of relapse to heavy drinking in alcohol dependent subjects following alcohol detoxification: the role of quality of life measures, ethnicity, social class, cigarette and drug use. Addiction Biology. 1998;3:333-343.
8.    Brower KJ, Aldrich MS, Robinson EA, Zucker RA, Greden JF. Insomnia, self-medication, and relapse to alcoholism. Am J Psychiatry. 2001;158(3):399-404.
9.    Gillin JC, Smith TL, Irwin M, Kripke DF, Schuckit M. EEG sleep in “pure” primary alcoholism during subacute withdrawal: Relationships to normal controls, age, and other clinical variables. Biol Psychiatry. 1990;27(5):477-488.
10.    Drummond SPA, Gillin JC, Smith TL, DeModena A. The sleep of abstinent pure primary alcoholic patients: natural course and relationship to relapse. Alcohol Clin Exp Res. 1998;22(8):1796-1802.
11.    Brady KT, Verduin ML. Pharmacotherapy of comorbid mood, anxiety, and substance abuse disorders. Subst Use Misuse. 2005;40(13-14):2021-2041,2043-2048.
12.    Kessler R, Crum R, Warner L, Nelson C, Schulenberg J, Anthony J. Lifetime co-occurrence of DSM-III-R alcohol abuse and dependence with other psychiatric disorders in the National Comorbidity Survey. Arch Gen Psychiatry. 1997;54(4):313-321.
13.    Burns L, Teesson M. Alcohol use disorders comorbid with anxiety, depression, and drug use disorders: findings from the Australian National Survey of Mental Health and Well Being. Drug Alcohol Depen. 2002;68(3):299-307.
14.    Schneider U, Altmann A, Baumann M, et al. Comorbid anxiety and affective disorder in alcohol-dependent patients seeking treatment: the first multicenter study in Germany. Alcohol Alcohol. 2001;36(3):219-223.
15.    Driessen M, Meier S, Hill A, Wetterling T, Wolfgang L, Junghanns K. The course of anxiety, depression, and drinking behaviors after complete detoxification in alcoholics with and without comorbid anxiety and depressive disorders. Alcohol Alcohol. 2001;36(3):249-255.
16.    Mendelson WB. A review of the evidence for the efficacy and safety of trazodone in insomnia. J Clin Psychiatry. 2005;66(4):469-476.
17.    Friedmann PD, Herman DS, Freedman S, Lemon SC, Ramsey S, Stein MD. Treatment of sleep disturbance in alcohol recovery: a national survey of addiction medication physicians. J Addict Dis. 2003;22(2):91-103.
18.    Warrington SJ, Ankler SI, Turner P. An evaluation of possible interactions between ethanol and trazodone or amitriptyline. Br J Clin Pharmacol. 1984;18(4):549-557.
19.    Friedmann PD, Rose JS, Swift R, Stout RL, Millman RP, Stein MD. Trazodone for sleep disturbance after alcohol detoxification: a double-blind, placebo-controlled trial. Alcohol Clin Exp Res. 2008;32(9):1652-1660.
20.    Van Bemmel AL, Havermans RG, van Diest R. Effects of trazodone on EEG sleep and clinical state in major depression. Psychopharmacology. 1992;107(4):569-574.
21.    Moon CA, Davey A. The efficacy and residual effects of trazodone (150 mg nocte) and mianserin in the treatment of depressed general practice patients. Psychopharmacology. 1988;95(suppl):S7-S13.
22.    Le Bon OL, Murphy JR, Staner L, et al. Double-blind, placebo-controlled study of the efficacy of trazodone in alcohol post-withdrawal syndrome: polysomnographic and clinical evaluations. J Clin Psychopharmacol. 2003;23(4):377-383.
23.    Goforth HW. Low dose doxepin for the treatment of insomnia: emerging data. Expert Opin Pharmacother. 2009;10(10):1649-1655.
24.    Hajak G, Rodenbeck A, Voderholzer U, et al. Doxepin in the treatment of primary insomnia: A placebo-controlled, double-blind, polysomnographic study. J Clin Psychiatry. 2001;62(6):453-463.
25.    Stahl SM. Selective histamine H1 antagonism: novel hypnotic and pharmacologic actions challenge classical notions of antihistamines. CNS Spectr. 2008;13(12):1027-1038.
26.    Roth T, Rogowski R, Hull S, et al. Efficacy and safety of doxepin 1 mg, 3 mg, and 6 mg in adults with primary insomnia. Sleep. 2007;30(11):1555-61.
27.    Malcolm R, Myrick LH, Veatch LM, Boyle E, Randall PK. Self-reported sleep, sleepiness, and repeated alcohol withdrawals: a randomized, double blind, controlled comparison of lorazepam vs gabapentin. J Clin Sleep Med. 2007;3(1):24-32.
28.    Karam-Hage M, Brower KJ. Gabapentin treatment for insomnia associated with alcohol dependence. Am J Psychiatry. 2000;157(1):151.
29.    Karam-Hage M, Brower KJ. Open pilot study of gabapentin versus trazodone to treat insomnia in alcoholic outpatients. Psychiat Clin Neuros. 2003;57(5):542-544.
30.    Brower KJ, Kim HM, Strobbe S, Karam-Hage MH, Consens F, Zucker RA. A randomized, double-blind pilot trial of gabapentin vs placebo to treat alcohol dependence and comorbid insomnia. Alcohol Clin Exp Res. 2008;32(8)1429-1438.
31.    Monnelley EP, Ciraulo DA, Knapp C, LoCastro J, Sepulveda I. Quetipatine for the treatment of alcohol dependence. J Clin Psychopharmacol. 2004;24(5):532-535.
32.    Sattar SP, Bhatia CB, Petty F. Potential benefits of quetiapine in the treatment of substance dependence disorders. Rev Psychiatr Neurosci. 2004;29(6)452-457.
33.    Martinotti G, Andreoli S, Di Nicola M, Di Giannantonio M, Sarchiapone M, Janiri L. Quetiapine decreases alcohol consumption, craving, and psychiatric symptoms in dually diagnosed alcoholics. Hum Psychopharmacol. 2008;23(5):417-424.
34.    Clinicaltrials.gov. The effects of quetiapine (Seroquel XR) on sleep during alcohol abstinence. Available at: http://clinicaltrials.gov/ct/show/nct00434876?order=31. Accessed February 1, 2010.
35.    Hanley MJ, Kenna GA. Quetiapine: treatment for substance abuse and drug of abuse. Am J Health Syst Pharm. 2008;65(7):611-618.
36.    Brady KT. Evidence-based pharmacotherapy for mood and anxiety disorders with concurrent alcoholism. CNS Spectr. 2008;13:4(suppl 6):6-9.
37.    Micromedex Health Care Series. DrugPoint Summary: Fluoxetine Hydrochloride, Paroxetine Hydrochloride. Thompson Reuters, 2009. Updated April 30, 2009. Available at: www.thomsonhc.com. Accessed February 2, 2010.
38.    US Food and Drug Administration. Drug details for venlafaxine. Washington, DC: US Dept of Health and Human Services; 2007. Available at: http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.Overview&DrugName=VENLAFAXINE%20HYDROCHLORIDE. Accessed February 1, 2010.
39.    Pande AC, Pollack MH, Crockatt JM, et al. Placebo-controlled study of gabapentin treatment of panic disorder. J Clin Psychopharmacol. 1999;20(4):341-348.
40.    Goldstein BI, Diamontouros A, Schaffer A, Naranjo CA. Pharmacotherapy of alcoholism in patients with comorbid psychiatric disorders. Drugs. 2006;66(9):1229-1237.
41.    Bruno F. Buspirone in the treatment of alcoholic patients. Psychopathology. 1989;22(suppl 1):49-59.
42.    Tollefson GD, Montague-Clouse J, Tollefson SL. Treatment of comorbid generalized anxiety in a recently detoxified alcoholic population with a selective serotonergic drug (buspirone). J Clin Psychopharmacol. 1992;12(1):19-26.
43.    Malcom R, Anton RF, Randall CL, Johnston A, Brady K, Thevos A. A placebo-controlled trial of buspirone in anxious inpatient alcoholics. Alcoholism Clin Exp Res. 1992;16(6):1007-1013.
44.    Kranzler HR, Burleson JA, DelBoca FK, et al. Buspirone treatment of anxious alcoholics – a placebo-controlled trial. Arch Gen Psychiatry. 1994;51:720-731.
45.    Micromedex Health Care Series. DrugPoint Summary: Buspirone. Thompson Reuters, 2009. Updated February 6, 2009. Available at: www.thomsonhc.com. Accessed February 2, 2010.
46.    Kessler RC, Crum RM, Warner LA, Nelson CB, Schulenberg J, Anthony JC. Lifetime co-ocurrence of DSM-III-R psychiatric disorders in the United States. Results from the National Comorbidity Survey. Arch Gen Psychiatry. 1997;54(4):313-321.
47.    Pande AC, Davidson JR, Jefferson JW, et al. Treatment of social phobia with gabapentin: a placebo-controlled study. J Clin Psychopharmacol. 1999;19(4):341-348.
48.    Van Vliet IM, Den Boer JA, Westenberg HG, Pian KL. Clinical effects of buspirone in social phobia: A double-blind, placebo controlled study. J Clin Psychiatry. 1997;58(4):164-168.
49.    Randall CL, Johnson MR, Thevos AK, et al. Paroxetine for social anxiety and alcohol use in dual-diagnosed patients. Depress Anxiety. 2001;14(4):255-262.
50.    Pierce JM, Kindbom KA, Waesche MC, Yuscavage AS, Brooner RK. Posttraumatic stress disorder, gender, and problem profiles in substance-dependent patients. Subs Use Misuse. 2008:43(5):596-611.
51.    Brady KT, Sonne SC, Roberts JM. Sertraline treatment of comorbid posttraumatic stress disorder and alcohol dependence. J Clin Psychiatry. 1995;56(11):502-505.
52.    Brady KT, Sonne S, Anton RF, Randall CL, Back SE, Simpson K. Sertraline in the treatment of co-occurring alcohol dependence and posttraumatic stress disorder. Alcohol Clin Exp Res. 2005;29(3):395-401.
53.    Monnelly EP, Ciraulo DA, Knapp C, Keane T. Low dose risperidone as adjunctive therapy for irritable aggression in posttraumatic stress disorder. J Clin Psychopharmacol. 2003;23(2):193-196.
54.    Stein MB, Kline NA, Matloff JL. Adjunctive olanzapine for SSRI-resistant combat-related PTSD: a double-blind, placebo-controlled study. Am J Psychiatry. 2002;159(10):1777-1779.
55.    Hamner MB, Deitsche SE, Brodrick PS, Ulmer HG, Lorberbaum JP. Quetiapine treatment in patients with posttraumatic stress disorder: an open trial of adjunctive therapy. J Clin Psychopharmacol. 2003;23(1):15-20.
56.    Feldman RS, Meyer JS, Quenzer LF. Sedative-hypnotic and anxiolytic drugs. In: Feldman RS, Meyer JS, Quenzer LF. Principles of Neuropsychopharmacology. Sunderland. MA: Sinauer Associates, Inc. 1997:673-729.
57.    Lader MH. Limitations on the use of benzodiazepines in anxiety and insomnia: are they justified? Eur Neuropsychopharmacol. 1999:9(suppl 6)S399-S405.
58.    Fry J, Scharf M, Mangano R, et al. Zaleplon imporves sleep without producing rebound effects in outpatients with insomnia. Zaleplon Clinical Study Group. Int Clin Psychpharmacol. 2000;15(3):141-152.
59.   Perlis ML, McCall WV, Krystal AD, Walsh KJ. Long-term, non-nightly administration of zolpidem in the treatment of patients with primary insomnia. J Clin Psychiatry. 2004;65(8):1128-1137.
60.    Zammit G. Comparative tolerability of newer agents for insomnia. Drug Saf. 2009;32(9):735-748.
61.    Hajak G, Müller WE, Wittchen HU, Pittrow D, Kirch W. Abuse and dependence potential for the non-benzodiazepine hypnotics zolpidem and zoplicone: a review of case reports and epidemiological data. Addiction. 2003;98(10):1371-1378.
62.    Mueller TI, Pagano ME, Rodriguez BF, Bruce SE, Stout RL, Keller MB. Long-term use of benzodiazepines in participants with comorbid anxiety and alcohol use disorders. Alcohol Clin Exp Res. 2005;29(8):1411-1418.
63.    Arnedt JT, Conroy DA, Brower KJ. Treatment options for sleep disturbances during alcohol recovery. J Addict Dis. 2007;26(4):41-54.


Dr. Sussman is editor of Primary Psychiatry as well as Associate Dean for Post-Graduate Programs and professor of psychiatry at the New York University School of Medicine in New York City.

Dr. Sussman reports no affiliation with or financial interest in any organization that may pose a conflict of interest.

Email questions or comments to ns@mblcommunications.com


Most of the articles in this issue of Primary Psychiatry address different ways to diagnose mental disorders and their manifestations. Given the reliance on diagnostic criteria and rating scales, our understanding of what clinical entities represent are constantly evolving. It is important that we keep current about any data that improve our efforts to understand the disorder at hand.

It is well known that patients with panic disorder are frequent visitors to emergency departments, usually with fears they are having a heart attack. Geneviève Belleville, PhD, and colleagues describe how the characteristics of patients with panic disorder in an emergency room differ from patients seen in psychiatric settings with respect to panic symptoms, comorbid psychiatric disorders, and psychological correlates of panic disorder. They assessed >2,000 patients seen either in an emergency department or anxiety disorder clinics. The authors report that men were more likely than women to go to an emergency room. Those in the emergency room sample were also more likely to have recently experienced suicidal ideation. Of interest was the finding that patients from the emergency department had less severe panic symptoms, but had higher rates of psychiatric comorbidity, most notably other anxiety disorders and major depressive disorder. Other differences between the groups are discussed in the article.

As a reminder, the American Psychiatric Association (APA) has just released the draft disorders and disorder criteria that have been proposed by the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) Work Groups.1 As part of the development process of the DSM-5, set for publication in May 2013, the preliminary draft revisions to the current diagnostic criteria for psychiatric diagnoses are now available for public review and comment. The draft criteria are listed in Table 1.


Another anxiety disorder addressed in this issue is obsessive-compulsive disorder (OCD). Ashish Aggarwal, MD, and colleagues provide a case report of obsessive-compulsive symptoms following administration of clozapine. There have been numerous reports of OCD emerging or becoming exacerbated during the treatment of schizophrenia with atypical antipsychotics. In the reported case, these symptoms were dose related. The authors discuss possible explanations for this phenomenon. Incidentally, the APA work group is recommending that this OCD be included under a grouping of anxiety and obsessive-compulsive spectrum disorders, with the diagnostic criteria listed in Table 2.


The common dilemma of how to treat anxiety and insomnia in patients with chronic alcohol use disorders is addressed by Aazaz U. Haq, MD. Using an evidence-based approach, he describes many pharmacologic strategies that rely on off-label use of various agents and advocates concurrent use of cognitive behavioral therapy.

David Goodman, MD, and colleagues report on interpreting attention-deficit/hyperactivity disorder rating scale scores. The article supports the evidence that improvement on a rating scale translates into clinically significant symptom reduction. Conversely, Leo Baestiaens, MD, notes that measurement-based approaches to patient care that rely on validated rating scales may in fact be less helpful than believed. Addressing the care of patients with schizoprenia, he argues that professionals interact more with their patients and spend more time with them. This, of course, would require higher reimbursement rates.

In a case report, Ravi C. Sharma, MD, and Rajeshwar S. Thakur, MS, offer a reminder that conversion symptoms do indeed still occur. They report the case of a woman with acute urinary retention manifesting as a conversion symptom.

Finally, I want to share with you a communication I received from one of our readers about a December 2009 article by Galit Ben-Amitay, and colleagues2 about the psychiatric assessment of children with poor verbal capacities using a sandplay technique. Erno Daniel, MD, PhD, at the Sansum Clinic in Santa Barbara, CA wrote:

“An interesting offshoot of the study you reported could be the following. When my children were young, we built a sandcastle on the beach. When we tired of playing with it, we sat away from it in the sand doing other things. A little child came by. As he approached the sandcastle, it occurred to me that he had several choices: 1. Sit and play with it. 2. Add on to the sandcastle and make it better to suit his own imagination. 3. Kick it to bits and walk away.

The latter is what happened. It occurred to me that the ‘sandcastle test’ may have predictive correlates with future behavior: fit-in personality versus creative/progressive personality versus destructive personality. I would welcome a study to see if such is true.”  PP



1.     Proposed Draft Revisions to DSM Disorders and Criteria. Available at: www.dsm5.org/Pages/Default.aspx. Accessed February 17, 2010.
2.    Ben-Amitay G, Lahav R, Toren P. Psychiatric assessment of children with poor verbal capacities using a sandplay technique. Primary Psychiatry. 2009;16(12):38-44.


Dr. Kennedy is professor in the Department of Psychiatry and Behavioral Sciences at Albert Einstein College of Medicine, and director of the Division of Geriatric Psychiatry at Montefiore Medical Center in the Bronx, New York.

Disclosure: Dr. Kennedy has received grant support from Forest.

Please direct all correspondence to: Gary J. Kennedy, MD, Director, Division of Geriatric Psychiatry, Montefiore Medical Center, 111 East 210th St, Bronx, NY 10467; Tel: 718-920-4236; Fax: 718-920-6538; E-mail: gjkennedy@msn.com.


The identification of genetic risk factors for the familial dementias has been a productive area of scientific study, but the clinical impact for the far more common sporadic dementias has been modest at best. As a result, interest in the characterization of biomedical and psychosocial protective factors is intense as evidenced by the April 2010 National Institutes of Health (NIH) consensus conference on Preventing Alzheimer’s Disease and Cognitive Decline. If genetic polymorphisms associated with exceptional longevity are associated with lessened incidence of dementia, their characterization may suggest novel pharmacologic interventions to prevent Alzheimer’s disease. 



The most common heritable dementias, familial Alzheimer’s disease and Huntington’s disease, exhibit an early age of onset and have a well described genetic profile. Genetic testing can inform family members of their risk status with near certainty. However, the search for genetic risk in the more common later-onset sporadic Alzheimer’s disease has had little clinical impact. Moreover, pharmacologic strategies to counter cholinergic deficits, cerebral amyloidosis, and neurofibrillary tangles—the major neuropathologic manifestations of Alzheimer’s dementia—have yet to show genuine disease-modifying effects. Failure to find a breakthrough in treatment has lead to intense interest in prevention as evidenced by the April 26–28, 2010 NIH consensus conference on “Preventing Alzheimer’s Disease and Cognitive Decline”.1 Risk factors for vascular disease are often cited as risk factors for Alzheimer’s disease such that a heart-healthy diet and lifestyle are advocated by the Alzheimer’s Association as reasonable steps to reduce one’s chances of developing dementia.2 In addition, studies of exceptional longevity suggest that polymorphisms involved in lipid transport may also provide protection against Alzheimer’s disease.


Longevity Genes and Heart Disease

Apolipoprotein (APOE) and cholesterol ester transfer protein (CETP) are both involved in central nervous system cholesterol homeostasis. The APOE ε4 allele is associated with late onset sporadic Alzheimer’s disease while the APOE ε2 allele is associated with increased life span as well as reduced risk of heart disease. A functional single-nucleotide polymorphism (SNP) substitution of valine for isoleucine at codon 405 in the CETP gene has been associated with reduced CETP serum activity and an increase in high-density lipoprotein, both of which are thought to convey protection against heart disease. Additionally, like the APOE ε2 allele, the valine CETP SNP is associated with exceptional longevity. Thus, APOE ε2 and CETP V405 may be called “longevity genes”,3 but the mechanism with which they provide benefits is unclear.


Longevity Genes and Dementia     

In addition to conferring benefits for increased life span, evidence suggests that that they also protect against cognitive decline and dementia. Most recently, investigators with the Einstein Aging Study4 examined the genotypes of 523 community residents ≥70 years of age who were dementia free at baseline. The mean age was 87 years, 69% were white, 25.6% were African American and 5.4% were of other ethnicity. Those who were either homozygous for the CETP valine SNP made up 66% of the group. Those homozygous or heterozygous for APOE ε4 numbered 23%. There were 40 people who developed dementia over the period of observation. Valine CETP homozygotes but not heterozygotes experienced a relative 51% less decline in memory compared to the isoleucine homozygotic reference group after adjusting for gender, race/ethnicity, education, medical comorbidities, and APOE status. After controlling for these same variables, the hazard ratios for any dementia and for Alzheimer’s disease specifically were less among both valine homo- and heterozygotes compared to the isoleucine homozygotic group. However, the results were statistically significant only among the valine homozygotes. Importantly, the protective effect remained after adjusting for APOE status.


The Cholesterol Hypothesis

Carter has suggested that there is a convergence of polymorphic genes implicated in Alzheimer’s disease, including those associated with the amyloid precursor protein, cholesterol, lipoproteins, and atherosclerosis.5 Cholesterol and its transport system have also been associated with amyloid production as well as tau hyperphosphorylation and neurofibrillary tangles.6 Thus, both of the signature pathologic findings of Alzheimer’s disease are related in some way to cholesterol homeostasis. 

Moreover, a number of retrospective and case control studies comparing individuals prescribed statins for hypercholesterolemia have detected a small but statistically reliable protective effect against Alzheimer’s disease.6 Statins have anti-inflammatory effects and reliably prevent cardiovascular disease and stroke which has a direct impact on dementia.7 Yet, despite the hypothetical appeal of cholesterol as a target for intervention, large-scale prospective studies of two statins, simvastatin and pravastatin, failed to prevent dementia. In both studies, total cholesterol and LDL cholesterol were significantly and substantially decreased compared to placebo. But there were no differences in cognitive performance over time or in the incidence of dementia.8 However, both studies were designed to examine cardiovascular events rather than dementia as the primary outcome. The sample sizes and periods of observation may not have been sufficient to detect protection against dementia.7 In his 2008 Public Policy forum for the Alzheimer’s Association, Dekosky9 described the challenge of finding a protective effect of any medication against Alzheimer’s disease. The requisite sample size would approach 3,000 individuals and require a 5-year period of observation in order to detect a difference between drug and placebo. In contrast, the Cholesterol Lowering Agent to Slow Progression of Alzheimer’s disease study [CLASP] included 400 people with mild to moderate Alzheimer’s disease randomized to receive placebo or simvastatin. People with vascular disease and those whose cholesterol level met criteria for lipid-lowering medications were excluded. Change measured by the cognitive portion of the Alzheimer’s Disease Assessment Scale is the primary outcome. The CLASP study10,11 is the only double-blind, randomized controlled trial specifically designed to detect reduced cognitive decline among people with Alzheimer’s disease who would not have been prescribed a statin for cardiovascular indications. Prior studies have examined whether the cerebral cholesterol shuttle plays a role in initiating dementia. CLASP, if positive, will determine whether it sustains the disease.



Studies of longevity genes such as CETP and APOE add to the argument that aggressively targeting cardiovascular risk factors may be the most effective public health approach against Alzheimer’s disease at present. Cardiovascular mortality declined substantially between 1970 and 2000 representing nearly 800,000 lives saved from heart disease.9 If this trend continues and if the CLASP study is positive, the threatened pandemic of disability due to dementia may well be abated. Use of the current Food and Drug Administration-approved medications to combat the symptoms of dementia combined with lipid-modifying agents could then push the disability of Alzheimer’s disease to the end of the naturally occurring life span. The personal and societal benefit would then be similar to that observed for interventions which postpone the disability of diabetes. If genetic polymorphisms associated with exceptional longevity are associated with lessened incidence of dementia, their characterization may suggest novel pharmacologic interventions to prevent Alzheimer’s disease as well. PP



1.     NIH State-of-the-Science Conference Preventing Alzheimer’s Disease and Cognitive Decline. Available at: http://consensus.nih.gov/2010/alz.htm. Accessed February 2, 2010.
2.    alz.org. Brain Health. Available at: www.alz.org/we_can_help_brain_health_maintain_your_brain.asp. Accessed February 2, 2010.
3.    Barzilai N, Atzmon C, Schecter C, et al. Unique lipoprotein phenotype and genotype in humans with exceptional longevity. JAMA. 2003;290(15):2030-2040.
4.    Sanders AE, Wang C, Katz M, et al. Association of a functional polymorphism in the cholesteryl ester transfer protein (CETP) gene with memory decline and incidence of dementia. JAMA. 2010;303(2):150-158.
5.`Carter CJ. Convergence of genes implicated in Alzheimer’s disease on the cerebral cholesterol shuttle: APP, cholesterol, lipoproteins, and atherosclerosis. Neurochem Int. 2007;50(1):12-38.
6.    Kandiah N, Feldman HH Therapeutic potential of statins in Alzheimer’s disease. J Neurol Sci. 2009;283(1-2):230-234.
7.    Haan MN. Review: statins do not protect against development of dementia. Evidence Based Mental Health. 2009;12(4):114.
8.    McGuinness B, Craig D, Bullock R, Passmore P. Statins for prevention of dementia. Cochrane Database Syst Rev. 2009;(2):CD003160.
9.    DeKosky ST. Alzheimer’s Disease: Current and Future Research. Available at: www.alz.org/publicpolicyforum/08/downloads/Dekosky_Slides.pdf. Accessed February 2, 2010.
10.    Sano M. Multi-centre, randomised, double-blind, placebo controlled trial of simvastatin to slow the progression of Alzheimer’s disease. Alzheimer’s & Dementia. 2008;4(4 suppl 1):T200.
11. CLASP. Cholesterol lowering agent to slow progression of Alzheimer’s disease study. Clinical Trials.gov, National Institutes of Health/National Library of Medicine Web site. Available at: www.clinicaltrials.gov/show/NCT00053599. Accessed February 2, 2010.


Dr. Goodman is director and assistant professor in the Department of Psychiatry and Behavioral Sciences at Johns Hopkins University School of Medicine in Baltimore, Maryland. Dr. Faraone is a professor in the Department of Psychiatry and Department of Neuroscience and Physiology at SUNY Upstate Medical University in Syracuse, New York. Dr. Adler is a professor in the Department of Psychiatry and Child Adolescent Psychiatry at New York University School of Medicine and Psychiatry Service, and New York VA Harbor Healthcare System in New York City. Dr. Dirks is associate medical director and Mr. Hamdani is associate director at Shire Development Inc. in Wayne, Pennsylvania. Dr. Weisler is an adjunct professor at Duke University Medical Center in Durham, North Carolina and University of North Carolina at Chapel Hill.

Dr. Goodman has been a consultant to Avacat, Clinical Global Advisors, Eli Lilly, Forest, McNeil, New River Pharmaceuticals, Major League Baseball, Novartis, Schering-Plough, Shire, and Thompson Reuters; has received research support from Cephalon, Eli Lilly, Forest Labs, McNeil, New River Pharmaceuticals, and Shire; has received honoraria from Eli Lilly, Forest Labs, McNeil, Shire, and Wyeth; has been on the speaker’s bureaus of the American Professional Society of ADHD and Related Disorders, the Audio-Digest Foundation, CME Inc, Forest Labs, JB Ashton Associates, McNeil, Medscape, Shire, Synermed Communications, Temple University, the Veritas Institute, WebMD, and Wyeth; and receives royalties from MBL Communications. Dr. Faraone is consultant to and is on the advisory boards of Eli Lilly, McNeil, and Shire; and receives research support from Eli Lilly, the National Institutes of Health, Pfizer, and Shire. Dr. Adler is consultant to AstraZeneca, Eli Lilly, Epi-Q, i3 Research, INC Research, Mindsite, Organon/Schering-Plough/Merck, Ortho-McNeil/Janssen/Johnson & Johnson, Otsuka, Shire, United Biosource; receives research support from Bristol-Myers Squibb, Chelsea Therapeutics, Eli Lilly, Organon/Schering-Plough/Merck, Ortho-McNeil/Janssen/Johnson & Johnson; and is on the advisory boards of Eli Lilly, i3 Research, INC Research, Mindsite, Organon/Schering-Plough/Merck, Ortho-McNeil/Janssen/Johnson & Johnson. Dr. Dirks is a full-time Shire employee and has stock and/or stock options from Shire and Johnson & Johnson. Mr. Hamdani is a full-time Shire employee and has stock and/or stock options from Shire. Dr. Weisler has been a consultant to Abbott, Ayerst, Bioavail, Bristol-Myers Squibb, the Centers for Disease Control and Prevention, Corcept, Eli Lilly, Forest Labs, GlaxoSmithKline, Johnson & Johnson, Novartis, Organon, Ostuka America Pharma, Pfizer, Sanofi-Synthelabo, Shire, Solvay, the Agency for Toxic Substances Disease Registry, Validus, and Wyeth; has been on the speaker’s bureaus of Abbott, AstraZeneca, Bioavail, Bristol-Myers Squibb, Cephalon, Eli Lilly, Forest Labs, GlaxoSmithKline, Organon, Pfizer, sanofi-aventis, Shire, Solvay, Validus, and Wyeth Ayerst; has received research support from Abbott, AstraZeneca, Ayerst, Bioavail, Bristol-Myers Squibb, Burroughs Wellcome, Cenerx, Cephalon, Ciba-Geigy, CoMentis, Corcept, Dainnpon-Sumitomo, Eisai, Eli Lilly, Forest Labs, GlaxoSmithKline, Janssen, Johnson & Johnson, Lundbeck, McNeil, MediciNova, Merck, the National Institute of Mental Health, Neurochem, New River Pharmaceuticals, Novartis, Organon, Parke Davis, Pfizer, Pharmacia, Repligen, Saegis, Sandoz, Sanofi-Synthelabo, Schwabe/Ingenix, Sepracor, Shire, SmithKline Beecham, Solvay, Synaptic Pharmaceutical Incorporated, Takeda, TAP Pharmaceutical, UCB Pharma, Upjohn, Vela, and Wyeth; and has been a financial stockholder of Bristol-Myers Squibb, Cortex, Merck, and Pfizer.

Acknowledgments: Supported by funding from Shire Development Inc. Although the study sponsor was involved in the study design as well as collection, analysis, and interpretation of data, the ultimate interpretation of the data was made by the independent authors, as was the writing of this manuscript and the decision to submit it for publication in Primary Psychiatry. Writing assistance was provided by Margaret McLaughlin, PhD, a former employee of Health Learning Systems, and Michael Pucci, PhD, an employee of Health Learning Systems. Editorial assistance in the form of proofreading, copy editing, and fact checking was provided by Health Learning Systems.

Please direct all correspondence to: David Goodman, MD, Johns Hopkins at Green Spring Station, 10751 Falls Rd, Suite 306, Lutherville, MD 21093; Tel: 410-583-2726; Fax: 410-583-2724;
E-mail: dgoodma4@jhmi.edu.



Objective: To provide additional understanding of the clinical significance of Attention-Deficit/Hyperactivity Disorder Rating Scale, Version IV (ADHD-RS-IV) total and change scores in relation to Clinical Global Impressions-Severity or -Improvement (CGI-S/-I) levels.
Methods: Using two similarly designed pivotal trials of lisdexamfetamine dimesylate (Vyvanse, Shire US Inc), equipercentile linking was used to identify scores on the ADHD-RS-IV and CGI that have the same percentile rank.
Results: As assessed by CGI-S levels, moderately, markedly, severely, and extremely ill adults had mean (SD) baseline ADHD-RS-IV scores of 36.2 (4.9), 42.1 (6.1), 45.4 (5.1), and 53.0, respectively. A similar relationship was observed in children. At endpoint, children categorized as minimally, much, or very much improved by CGI-I demonstrated mean (SD) ADHD-RS-IV changes from baseline of -9.9 (6.8), -25.5 (7.2), and -33.2 (9.3), respectively. Adults demonstrated a similar relationship between ADHD-RS-IV change scores and CGI-I ratings. Based on equipercentile link function, a change from baseline in ADHD-RS-IV total score of ~10–15 points or 25% to 30% corresponded to a change of 1 level in CGI-I score.
Conclusion: This analysis makes possible the establishment of a clinical impression of severity of illness from total ADHD-RS-IV scores and may facilitate the clinical interpretation of improvement of ADHD-RS-IV change scores.

Focus Points

• Linking the Clinical Global Impressions-Severity (CGI-S) ratings with Attention-Deficit/Hyperactivity Disorder Rating Scale, Version IV (ADHD-RS-IV) scores at baseline, two trials of lisdexamfetamine dimesylate demonstrated that a difference of ~8–10 points in baseline ADHD-RS-IV score is appreciated clinically as a 1-point difference in CGI-S score.
• An improvement in ADHD-RS-IV score of ~50% to 60% is needed to achieve a rating of much improved (2-level improvement) on the CGI-Improvement scale.
• For all three pairs of linkages, the relationship between ADHD-RS-IV scores and CGI levels was consistent across the age groups.



The use of rating scales to quantify subjects’ response to treatment for attention-deficit/hyperactivity disorder (ADHD) is commonplace in clinical trials. These scales are less commonly used in clinical practice and, as such, the clinical implications of total or change scores on these scales may not be readily apparent to clinicians. Additionally, the measures of response used in clinical trials may not mimic the standards used by clinicians in practice.

The ADHD Rating Scale, Version IV (ADHD-RS-IV),1 has been widely used as a measure of efficacy in clinical trials of ADHD treatments in children and adolescents.2,3 Derived from the 18 inattentive and hyperactive/impulsive diagnostic criteria for ADHD from the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition,4 the parent and teacher versions of the ADHD-RS-IV have a large base of normative data and have demonstrated reliability and discriminant validity in children and adolescents.1,3 A validated, clinician-administered version of the ADHD-RS-IV using adult prompts was developed at New York University/Massachusetts General Hospital (NYU/MGH) and has been used in adult populations.5-8 Despite extensive use in clinical trials, the meaning of a reduction (ie, improvement) in ADHD-RS-IV scores in response to treatment, with regard to an overall clinical effect, remains unclear.

Global rating scales of disease severity or improvement such as the Clinical Global Impressions-Improvement (CGI-I) and Severity (CGI-S) scales9 are typically more intuitive to clinicians,10 and may better correspond to the global judgments made by clinicians in practice than the item-by-item scores of rating scales. While sometimes adapted for a specific domain of symptoms,11 these scales typically ask clinicians to make a global assessment of function, symptoms, and adverse events (AEs) to rate a patient’s severity of symptoms (ie, CGI-S) and change in symptoms from baseline (ie, CGI-I) based on their experience with the patient population and baseline status, respectively.9 While the psychometric properties of the CGI have not been fully explored, preliminary studies12,13 demonstrate that it is sensitive to differences in treatment responses and possesses good internal consistency and concurrent validity. The CGI scales, however, lack well-defined, consistently applied ADHD-specific anchor points and may not yield consistent results across raters as highlighted by a recent study14 in which clinicians differed considerably in which factors (eg, side effects) they considered when determining a CGI rating.10,14,15

Given the widespread use of the CGI in clinical trials and the potential that such a global assessment of patients may be more contextually applicable and generally understandable to clinicians,10 several analyses have explored the relationship between disorder-specific psychiatric rating scales commonly used in trials (eg, the Positive and Negative Syndrome Scale, the Panic Disorder Severity Scale, and the Brief Psychiatric Rating Scale) and scores on the CGI.16-19 Such analyses typically use the equipercentile linking technique described by Kolen and Brennan.20

The goal of this analysis was to use the equipercentile linking technique to better understand the relationship between scores on the ADHD-RS-IV and scores on the CGI using data from pivotal clinical trials of lisdexamfetamine dimesylate (LDX) in adults and children with ADHD.21,22 LDX is the first long-acting prodrug stimulant and is indicated in the United States for the treatment of ADHD in children 6–12 years of age and in adults. LDX is a therapeutically inactive molecule. After oral ingestion, LDX is converted to l-lysine and active d-amphetamine, which is responsible for the therapeutic effect.23,24



Data Sources

This analysis was conducted using data from two pivotal trials of LDX, one in adults21 and one in children22 with ADHD. Complete descriptions of both studies have been published previously. Briefly, both studies were 4-week, randomized, double-blind, placebo-controlled, forced-dose escalation, parallel-group trials. In the adult trial, subjects were 18–55 years of age, while in the pediatric trial, subjects were 6–12 years of age. In both trials, subjects had to meet DSM-IV-TR25 diagnostic criteria for a primary diagnosis of ADHD and were excluded from the trial if they had a comorbid psychiatric diagnosis with significant symptoms, any medical condition that could interfere with the study or increase risk to the subject, history of seizures (excluding febrile seizures), tic disorder, or Tourette’s disorder. Additional exclusion criteria included any cardiac abnormality that may affect cardiac performance, a clinically significant electrocardiogram or laboratory abnormality, hypertension, pregnancy, lactation, and concomitant use of any medication with central nervous system or blood pressure effects (excluding ADHD treatments, which were washed out). Adults were required to have baseline ADHD-RS-IV total scores of at least 28 assessed using NYU/MGH adult prompts, and children were required to have ADHD-RS-IV total scores of at least 28 at baseline.

Each study began with a screening and washout period during which ADHD medications were discontinued. At the baseline visit, adult subjects were randomized to receive once-daily LDX 30, 50, or 70 mg or placebo for 4 weeks in a 2:2:2:1 ratio. In the pediatric trial, subjects were randomized 1:1:1:1 to placebo or once-daily doses of LDX 30, 50, or 70 mg. Subjects followed a forced-dose titration schedule with those randomized to receive 70 mg/day being titrated to that dose over 2 weeks.



In the pediatric study,22 the primary efficacy measure was the ADHD-RS-IV; in the adult study21 it was the ADHD-RS-IV with adult prompts. In both trials, the ADHD-RS-IV was administered by experienced investigators at each study visit. Whereas the ADHD-RS-IV was originally designed to assess a patient’s behavior over a period of 6 months,1 in these trials it was used to capture behavior over the preceding week. Each item on the 18-item measure is scored on a 4-point scale ranging from 0 (no symptoms) to 3 (severe symptoms), yielding a possible total score of 0–54. Both versions of the scale assess the 18 DSM-IV diagnostic criteria for ADHD, but the individual items are phrased slightly differently. For example, in the pediatric trial, one item asked raters to evaluate if subjects had “difficulty sustaining attention in tasks or play activities.” In the adult trial, the analogous item asked whether the subject had “difficulty sustaining attention in tasks or fun activities.”

The CGI scale was a secondary efficacy measure in both trials. At the baseline visit, clinicians completed the CGI-S and were asked to evaluate the severity of subjects’ illness with respect to ADHD symptoms based on the clinician’s experience with this particular population. Possible scores ranged from 1 (normal, not ill at all) to 7 (among the most extremely ill subjects). At all subsequent study visits, clinicians used the CGI-I to rate the subjects’ total improvement based on comparison with their baseline assessment from 1 (very much improved) to 7 (very much worse).


Statistical Analysis

The procedure for finding corresponding scores on different measurement instruments is called linking.26 Equating procedures, originally described as a method intended to provide interchangeable scores, are the strongest form of linking and can be performed on parallel, yet distinct scales, as in the present analysis. When used in such a manner, the results lead to scores that are not necessarily interchangeable but, rather, are concordant.26,27

The present trial used the equipercentile linking technique detailed by Kolen and Brennan20 at two time points (baseline and endpoint) in each LDX clinical trial to derive percentile rankings of baseline scores on the ADHD-RS-IV and CGI-S ratings as well as endpoint change scores on the ADHD-RS-IV and CGI-I ratings, and to identify scores at each time point in each study that had the same percentile rank. The equipercentile linking technique is not a comparison by subject, where the absolute score on the CGI is compared with the absolute score on the ADHD-RS-IV. Rather, equipercentile linking is a technique that identifies scores on two measures that have the same percentile rank (irrespective of which subjects had particular scores on either measure). So, for every score on one scale, there is a corresponding score on the other scale that has the same percentile rank. Percentile rank functions are calculated for both the ADHD-RS-IV and CGI in the present analysis.

Analyses were performed to compare baseline ADHD-RS-IV scores with CGI-S scores as well as the absolute change and percentage change from baseline in ADHD-RS-IV scores with CGI-I scores. The process of equipercentile linking begins with the calculation of percentile rank function for each variable. A graph is then generated using a score on one measure and the score on the other as the X and Y variables for each point, based on each having the same percentile rank.20 For example, if on Measure 1, 50% of subjects score X or below while on Measure 2, 50% score Y or below; the point X,Y is plotted on a new graph. The X and Y axes are the respective measure scores, not the percentiles. Similar points are generated for each matched percentile ranking, and the resulting line is the equipercentile link function.

Although scores on the CGI scales are discrete, the equipercentile link function is continuous. Therefore, for this analysis, CGI levels are understood to encompass a range. For example, a CGI-S level of markedly ill (a score of 5 on the scale) is equivalent to any score from 4.5–5.5, rather than simply 5. Similarly, CGI-S scores of 2.5–4.5 represent mildly ill (3) to moderately ill (4), 4.5–5.5 represent markedly ill (5), and scores >5.5 represent severely ill (6) to extremely ill (7). On a continuous plot of the CGI-I scale, scores <2.5 represent very much (1) to much (2) improved while scores ranging from 2.5–3.5 represent minimally improved (3), and those >3.5 signify no change (4) or a worsening (5, 6, or 7) compared with the baseline assessment.

Analyses were conducted on the intention-to-treat (ITT) populations of both trials, defined as all subjects randomized to receive treatment who had both a baseline and at least one post randomization ADHD-RS-IV total score available. For all analyses, endpoint was defined as the last post randomization treatment week for which a valid ADHD-RS-IV and CGI-I score was obtained. Only subjects with ADHD-RS-IV scores and CGI-I ratings at endpoint were included in the analysis. Additional analyses by gender were conducted to assess whether there were differences between male and female subjects in link analysis of ADHD-RS-IV scores and CGI ratings.



The demographic and baseline characteristics of the pediatric and adult study populations have been detailed in publications by Biederman and colleagues22 and Adler and colleagues,21 respectively. The treatment groups within each study were generally well matched at baseline. The ITT populations of the trials consisted of 285 children (213 randomized to receive LDX and 72 randomized to receive placebo) and 414 adults (352 randomized to receive LDX and 62 randomized to receive placebo).

As previously reported, significant treatment effects were observed in the primary efficacy measure, the mean change from baseline to endpoint in ADHD-RS-IV total scores compared with placebo for all LDX doses (adult and pediatric studies, P<.0001; Figure 1).21,22 The proportion of subjects with a CGI-I score of 1 (much improved) or 2 (very much improved) at endpoint was significantly higher in all LDX treatment groups compared with the respective placebo groups (adult study P<.01; pediatric study, P<.0001). Among patients receiving LDX, AEs were generally mild or moderate in severity and typical of those observed in trials of other amphetamine-based ADHD treatments. The most common AEs associated with LDX in children included decreased appetite, insomnia, abdominal pain, and irritability, and in adults included dry mouth, decreased appetite, and insomnia.


Linking ADHD-RS-IV Total Scores and CGI-S Levels

The summary statistics for baseline ADHD-RS-IV total scores by baseline CGI-S levels from both studies are presented in Table 1. In the adult study, mean (SD) ADHD-RS-IV scores of 36.2 (4.9), 42.1 (6.1), 45.4 (5.1), and 53.0 corresponded with CGI-S scores of 4 (moderately ill), 5 (markedly ill), 6 (severely ill), and 7 (extremely ill), respectively. It should be noted that these statistics include one subject who had an ADHD-RS-IV total score of 14 (and a CGI-S of markedly ill) at baseline. This subject had an ADHD-RS-IV total score of 35 at screening and 34 after 1 week of treatment. In the pediatric study, mean (SD) ADHD-RS-IV scores of 28.0, 38.7 (6.3), 45.5 (5.8), 48.2 (4.1), and 50.5 (4.0) corresponded with CGI-S scores of 3 (mildly ill), 4 (moderately ill), 5 (markedly ill), 6 (severely ill), and 7 (extremely ill), respectively. Also included in Table 1 are the ADHD-RS-IV quartile scores corresponding to each CGI-S level and the range of ADHD-RS-IV scores corresponding to each CGI-S level that were used in creating the equipercentile link function.


The equipercentile link function for CGI-S and ADHD-RS-IV baseline scores are presented in Figure 2. Data from the adult study demonstrated that a change in the baseline ADHD-RS-IV score of ~8–10 corresponded to a change of 1 in CGI-S level (Figure 2A). Based on the link function from the adult study, baseline ADHD-RS-IV scores ranging from 13.5–37.4 are expected to correspond to CGI-S levels of mildly to moderately ill. Scores ranging from 37.5–48.3 and from 48.4–54.5 corresponded to CGI-S ratings of markedly ill and severely to extremely ill, respectively (Table 2).


Similar to the adult study, the equipercentile link function for CGI-S and ADHD-RS-IV baseline scores derived from the pediatric study also demonstrated that a change in the baseline ADHD-RS-IV score of ~8–10 corresponded to a change of 1 in CGI-S score (Figure 2B). In addition, based on the equipercentile link function, in children a baseline ADHD-RS-IV score of 28.2–41.2 is expected to correspond to a CGI-S level of mildly or moderately ill; an ADHD-RS-IV score of 41.3–50.7 to a CGI-S level of markedly ill; and an ADHD-RS-IV score of 50.8–54.5 corresponded to a CGI-S level of severely to extremely ill (Table 2).


Linking ADHD-RS-IV Total Score Changes From Baseline and CGI-I Levels

The CGI-I levels at endpoint and the corresponding absolute change from baseline to endpoint in ADHD-RS-IV total score are presented in Table 3. In the adult trial, 317 patients were rated improved by CGI-I at endpoint while 97 were rated as no change or worse. Of the 317 adults who improved with treatment, CGI-I scores of 1 (very much improved), 2 (much improved), and 3 (minimally improved) corresponded with mean (SD) changes from baseline in ADHD-RS-IV total scores of -30.4 (7.8), -20.6 (7.2), and -11.2 (5.9), respectively. Adults assessed by CGI-I at endpoint as exhibiting no change demonstrated a mean (SD) change in ADHD-RS-IV total score of -2.1 (3.8).


In the pediatric trial, as assessed by the CGI-I, 217 children showed improvement with treatment while 68 showed no change or worse. Of the children demonstrating improvement, the mean (SD) change from baseline in ADHD-RS-IV scores at endpoint were -33.2 (9.3), -25.5 (7.2), and -9.9 (6.8) for subjects with CGI-I scores of 1 (very much improved), 2 (much improved), and 3 (minimally improved), respectively.

The graph of the equipercentile link function in Figure 3 shows the relationship between CGI-I levels at endpoint and the absolute change from baseline to endpoint in ADHD-RS-IV scores derived from the adult study (Figure 3A) and the pediatric study (Figure 3B). Both graphs indicate that a change from baseline to endpoint in ADHD-RS-IV total score of roughly 10–15 corresponded to a change of 1 in CGI-I score at endpoint.


Based on the above link function, a change from baseline to endpoint in ADHD-RS-IV score of -13.6 to -49.5 corresponded to a CGI-I level at endpoint of much improved or very much improved in adults. Using the link function from the pediatric study, an improvement in ADHD-RS-IV total scores from baseline at endpoint of -17.3 to -50.5 would have been expected to result in a CGI-I score of 2 or 1 (ie, much improved or very much improved) among children. Additional ranges of ADHD-RS-IV scores and their corresponding CGI-I levels are presented in Table 4. In the pivotal trials included in the present analysis, the mean ADHD-RS-IV total score change from baseline at endpoint associated with LDX treatment ranged from -16.2 to -18.6 in the adult study and -21.8 to -26.7 in the pediatric study. According to the link function, these mean scores corresponded to a CGI-I level of much improved.


When the equipercentile link function was carried out for CGI-I scores at endpoint and the percent change from baseline at endpoint in ADHD-RS-IV, CGI-I scores of 1, 2, and 3 (very much improved, much improved, and minimally improved) roughly corresponded to percent changes in ADHD-RS-IV scores of -80% and -80%, -48%, and -52%, and -25% and -27% (adult and pediatric studies, respectively; Figure 4). A percent change from baseline to endpoint in ADHD-RS-IV total score of ~25% to 30% corresponded to a change of 1 in CGI-I score at endpoint. Therefore, an improvement in ADHD-RS-IV score of ~50% to 60% and >75% is needed to achieve a rating of much improved and very much improved, respectively.


Post hoc analyses found no gender differences in linking ADHD-RS-IV and CGI in relation to either baseline severity or change from baseline at endpoint.



In this analysis, the linking between CGI levels and ADHD-RS-IV scores was established using the equipercentile link function and was based on LDX trial data from adults and children with ADHD. To the authors’ knowledge, this is the first time a reliable and valid ADHD-specific rating scale,7,8 the ADHD-RS-IV, has been linked to a clinically meaningful global assessment such as the CGI. This analysis generated three sets of link functions, each containing one linkage for adult subjects and one for pediatric subjects with ADHD. For all three pairs of linkages, the relationship between ADHD-RS-IV scores and CGI levels were consistent across the age groups. This is noteworthy because ADHD symptoms are often variable across the life span and the goals of treatment may be distinct in adults compared with children.28 Such a consistent relationship between the ADHD-RS-IV and CGI across age groups, however, should allow for a valid and consistent means of treatment titration even as children grow into adulthood.

The ability to link ADHD-RS-IV score changes to global improvements as assessed by the CGI-I has several implications for the interpretation of clinical trial results. For example, absolute changes in ADHD-RS-IV scores associated with a given treatment should be interpreted with the understanding that an absolute change of ~10–15 is required to be detected as a change of 1 level on the CGI-I. Clinicians may find such global assessments more clinically useful than reports of mean changes in rating scale scores compared with placebo, the measure usually reported in clinical trials, to understand the likely impact of a treatment on their patients. Furthermore, given that clinicians may not routinely use rating scales such as the ADHD-RS-IV, these results facilitate interpretation of the results of trials of ADHD treatments by healthcare providers and patients because more widely used and readily understood clinical terms may be applied to ADHD-RS-IV scores.

Based on this analysis, a clinically detectable response to treatment, that is, a change in CGI-I score of at least 1 level, requires at least a 25% to 30% change in ADHD-RS-IV score. Historically, clinical trials have often used a 25% to 30% reduction in symptoms as assessed by the ADHD-RS-IV as a threshold for response.29 Interestingly, this threshold has not been fully substantiated by statistical support for the adequacy of this cutoff. Clinical trials have also defined response as a global rating of much or very much improved. The results of this analysis suggest that these two definitions of response are not concordant and that the benchmark of a 25% to 30% reduction in symptoms as a barometer of efficacy, while satisfactory, may not be optimal for future development of useful treatments for ADHD. This also raises the possibility that more stringent criteria, perhaps a 50% reduction in ADHD-RS-IV total score, might be considered as a new standard for response in clinical trials.

The results of the present analysis should be viewed in light of several limitations. Although the results obtained from the adult and pediatric trial were similar, it should be noted that the versions of the ADHD-RS-IV used in these trials were not identical. In the adult study, the ADHD-RS-IV was a semistructured scale and used adult ADHD prompts,5 whereas the pediatric scale was a more structured assessment. In both trials, the scoring of the CGI and ADHD-RS-IV were not independent since they were completed by the same investigator based on behavior observed and reported during the same study visit. Because neither trial included adolescent patients, relationship between ADHD-RS-IV scores and CGI levels in that population remains unknown.

The present analysis contains both potential ceiling and floor effects. The CGI-S was only assessed at baseline, at which point subjects were required to have ADHD-RS-IV scores of ≥28. The lack of CGI-S scores available at endpoint precludes the establishment of a threshold for normalization. Relatively few subjects represented the low and high ends of the ADHD-RS-IV and CGI scales, which likely accounts for the abrupt changes observed in the slopes of the equipercentile link function showing the relationship between ADHD-RS-IV scores at baseline and CGI-S levels (Figures 2A and 2B). For example, only one patient in the adult study had a CGI-S score of 7 and none had a CGI-S score of 3; in the pediatric trial, only one subject was assessed as mildly ill (ie, CGI-S score of 3) and four were assessed as being extremely ill (ie, CGI-S score of 7).

The data from the present analysis originated from two studies with very similar methodologies and included data from ~700 subjects with ADHD. As pivotal trials, both studies had rigorous inclusion and exclusion criteria such as the exclusion of subjects with most medical and psychiatric comorbidities. Such limitations result in a patient population distinct from that seen in clinical practice and may limit generalization of the present results to broader patient populations. Additional analyses using similar methods across other data sets should attempt to confirm and extend these findings, perhaps providing data at the ends of the scales or demonstrating that these findings are similar in other patient populations.



Clinical studies of ADHD often employ rating scales to assess symptom improvement associated with a given treatment. Such measures, while psychometrically sound, are less intuitive and may be assessed by clinicians less frequently than global assessments of improvement since it is often unclear how much of a change in symptom-based scores corresponds to a change that can be observed clinically. In this preliminary analysis, ADHD-RS-IV scores were linked to CGI ratings using the equipercentile linking technique and produced results that were consistent between children and adults. A change of ~10–15 points in ADHD-RS-IV score corresponded to a change of 1 level in CGI-I rating. When analyzed by percent change, each change of ~25% to 30% in ADHD-RS-IV score resulted in a 1 level change in CGI-I. These results may further the clinical understanding of severity levels and change scores on the ADHD-RS-IV and suggest new thresholds for defining clinical response when evaluating ADHD treatments.  PP


1.    DuPaul GJ, Power TJ, Anastopoulos AD, Reid R. ADHD Rating Scale–IV: Checklists, Norms, and Clinical Interpretation. New York, NY; Guilford Press; 1998.
2.    Spencer TJ, Wilens TE, Biederman J, Weisler RH, Read SC, Pratt R. Efficacy and safety of mixed amphetamine salts extended release (Adderall XR) in the management of attention-deficit/hyperactivity disorder in adolescent patients: a 4-week, randomized, double-blind, placebo-controlled, parallel-group study. Clin Ther. 2006;28(2):266-279.
3.    Collett BR, Ohan JL, Myers KM. Ten-year review of rating scales. V: scales assessing attention-deficit/hyperactivity disorder. J Am Acad Child Adolesc Psychiatry. 2003;42(9):1015-1037.
4.    Diagnostic and Statistical Manual of Mental Disorders. 4th ed. Washington, DC: American Psychiatric Association; 1994.
5.    Adler L, Cohen J. Diagnosis and evaluation of adults with attention-deficit/hyperactivity disorder. Psychiatr Clin North Am. 2004;27(2):187-201.
6.    Weisler RH, Biederman J, Spencer TJ, et al. Mixed amphetamine salts extended-release in the treatment of adult ADHD: a randomized, controlled trial. CNS Spectr. 2006;11(8):625-639.
7.    Spencer TJ, Adler LA, Qiao M, et al. Validation of the Adult ADHD Investigator Symptom Rating Scale (AISRS). J Atten Disord. 2009 Sep 30. [Epub ahead of print].
8.    Adler LA, Spencer TJ, Biederman J, et al. The internal consistency and validity of the Attention-Deficit/Hyperactivity Disorder Rating Scale (ADHD-RS) with adult ADHD prompts as assessed during a clinical treatment trial. J ADHD Relate Disord. 2009;1(1):14-24.
9.    Guy W. Clinical global impressions. In: ECDEU Assessment Manual for Psychopharmacology. Rockville, MD: US Department of Health, Education, and Welfare; Public Health Service, Alcohol, Drug Abuse and Mental Health Administration, NIMH Psychopharmacology Research Branch; 1976;218-222.
10.    Nierenberg AA, DeCecco LM. Definitions of antidepressant treatment response, remission, nonresponse, partial response, and other relevant outcomes: a focus on treatment-resistant depression. J Clin Psychiatry. 2001;62(suppl 16):5-9.
11.    Huber CG, Lambert M, Naber D, et al. Validation of a Clinical Global Impression Scale for Aggression (CGI-A) in a sample of 558 psychiatric patients. Schizophr Res. 2008;100(1-3):342-348.
12.    Leon AC, Shear MK, Klerman GL, Portera L, Rosenbaum JF, Goldenberg I. A comparison of symptom determinants of patient and clinician global ratings in patients with panic disorder and depression.
 J Clin Psychopharmacol. 1993;13(5):327-331.
13.    Leucht S, Engel RR. The relative sensitivity of the Clinical Global Impressions Scale and the Brief Psychiatric Rating Scale in antipsychotic drug trials. Neuropsychopharmacology. 2006;31(2):406-412.
14.    Busner J, Targum SD, Miller DS. The Clinical Global Impressions scale: errors in understanding and use. Compr Psychiatry. 2009;50(3):257-262.
15.    Kadouri A, Corruble E, Falissard B. The improved Clinical Global Impression Scale (iCGI): development and validation in depression. BMC Psychiatry. 2007;7:7.
16.    Leucht S, Kane JM, Kissling W, Hamann J, Etschel E, Engel R. Clinical implications of Brief Psychiatric Rating Scale scores. Br J Psychiatry. 2005;187:366-371.
17.    Leucht S, Kane JM, Etschel E, Kissling W, Hamann J, Engel RR. Linking the PANSS, BPRS, and CGI: clinical implications. Neuropsychopharmacology. 2006;31(10):2318-2325.
18.    Leucht S, Kane JM, Kissling W, Hamann J, Etschel E, Engel RR. What does the PANSS mean? Schizophr Res. 2005;79(2-3):231-238.
19.    Furukawa TA, Shear KM, Barlow DH, et al. Evidence-based guidelines for interpretation of the Panic Disorder Severity Scale. Depress Anxiety. 2009;26(10):922-929.
20.    Kolen MJ, Brennan RL. Observed score equating using the random groups design. In: Kolen MJ, Brennan RL. Test Equating Methods and Practices. New York, NY: Springer Verlag New York, Inc.; 1995.
21.    Adler LA, Goodman DW, Kollins SH, et al. Double-blind, placebo-controlled study of the efficacy and safety of lisdexamfetamine dimesylate in adults with attention-deficit/hyperactivity disorder. J Clin Psychiatry. 2008;69(9):1364-1373.
22.    Biederman J, Krishnan S, Zhang Y, McGough JJ, Findling RL. Efficacy and tolerability of lisdexamfetamine dimesylate (NRP-104) in children with attention-deficit/hyperactivity disorder: a phase III, multicenter, randomized, double-blind, forced-dose, parallel-group study. Clin Ther. 2007;29(3):450-463.
23.    Pennick M. Hydrolytic conversion of lisdexamfetamine dimesylate to the active moiety, d-amphetamine. Poster presented at: the 64th Annual Scientific Convention and Meeting of the Society of Biological Psychiatry; May 14-16, 2009; Vancouver, British Columbia, Canada.
24.    Pennick M. Absorption of lisdexamfetamine dimesylate and hydrolysis to form the active moiety,
d-amphetamine. Poster presented at: the 49th Annual Meeting of the New Clinical Drug Evaluation Unit; June 29-July 2, 2009; Hollywood, FL.
25.    Diagnostic and Statistical Manual of Mental Disorders. 4th ed, text rev. Washington, DC: American Psychiatric Association; 2000.
26.    Lim RL. Linking results of distinct assessments. J Applied Measure Ed. 1993;6(1):83-102.
27.    Pommerich M, Hanson BA, Harris DJ, Sconing JA. Issues in creating and reporting concordance results based on equipercentile methods. ACT Research Report Series 2000-1. Iowa City, IA: ACT, Inc.; 2000.
28.    Weiss MD, Weiss JR. A guide to the treatment of adults with ADHD. J Clin Psychiatry. 2004;65(suppl 3):27-37.
29.    Steele M, Jensen PS, Quinn DMP. Remission versus response as the goal of therapy in ADHD: a new standard for the field? Clin Ther. 2006;28(11):1892-1908.