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.


Abstract

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.

 

Introduction

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.

 

Conclusion

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

 

References

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

 

References

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. 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


 

Selecting the best strategy to optimize antidepressant response is a major ongoing clinical challenge. The need for more effective approaches for producing remission has been made clear by recent evidence that confirms treatment with any single antidepressant drug produces remission in only ~33% of patients, and that when antidepressants do work, they are of most benefit to those with more severe depressive symptoms. Patients with moderate levels of depression who seek care because they are either distressed or impaired by their symptoms may, paradoxically, be more difficult to bring into remission than those with a more pronounced disorder. An abundance of studies have shown that numerous augmentation or switching strategies may be effective for some patients, but no body of evidence demonstrates consistent superiority of any. In summarizing lessons learned from the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial, the most ambitious attempt to date to address the question of antidepressant enhancement options, Rush wrote that “the gap between what we do in practice and what we know is very large.”1 In the near future, another study should be published that looks at whether it is better to start treatment with a combination of antidepressants rather than monotherapy. In anticipation of that article, I want to review the STAR*D trial and its major finding and describe the Combining Medication to Enhance Depression Outcomes (CO-MED), which looks at whether it is better to start treatment with two drugs instead of one.

 

STAR*D

STAR*D focused on non-psychotic major depressive disorder (MDD) in adult outpatients. The primary purpose of this research study was to determine which treatments work best if the first treatment with medication does not produce an acceptable response. All participants at first received the selective serotonin reuptake inhibitor (SSRI) citalopram (open label). If symptoms remained after 8–12 weeks of treatment, up to four other levels of treatment were offered, including cognitive therapy and other medications (Table 1). There was no placebo treatment option.

The study involved a highly representative clinical sample of depressed outpatients. In that regard, the STAR*D population was different than the highly selective cohort usually enrolled in industry-sponsored clinical trials.

At each level change, participants were asked to indicate the unacceptability of the potential treatment strategies (eg, to augment or to switch medications). Participants were then be eligible for random assignment the next treatment options.

Level 2

Participants who either did not have an adequate response to or could not tolerate citalopram are eligible for Level 2. The Level 2 treatment strategies were:

 

i) Medication and Psychotherapy Switch: switch to sertraline, venlafaxine extended release (XR), bupropion sustained release (SR), or cognitive therapy (CT).
ii) Medication and Psychotherapy Augmentation: add to citalopram either a) buspirone, b) bupropion SR, or c) CT.
iii) Medication Only Switch or Medication Only Augmentation: options were available for participants for whom CT is
unacceptable.
iv) Psychotherapy Only Switch or Psychotherapy Only Augmentation: options were available for participants for whom additional medication is unacceptable at this point in the study (participants must be willing to continue citalopram)

 

Level 2A

Participants without a satisfactory response to their Level 2 treatment were eligible for random assignment to additional treatment at Level 2A. Level 2A was included so that all participants entering Level 3 had an opportunity to respond to at least two medications. Level 2A consisted of medication switch to one of two antidepressants (venlafaxine XR or bupropion SR).

 

Level 3

Participants without satisfactory response to Level 2 and, if appropriate Level 2A, were eligible for random assignment to one of the following treatments:
i) Medication Switch to: a) mirtazapine or b) nortriptyline, a tricyclic antidepressant.
ii) Medication Augmentation: add (to current Level 2 or Level 2A medication) either: a) lithium or b) thyroid hormone (T3).

 

Level 4

Participants without an adequate response to Level 3 were eligible for random assignment to Level 4 treatment. Level 4 includes two medication switch options: to tranylcypromine (a monoamine oxidase inhibitor), or to mirtazapine plus venlafaxine XR.

 

CO-MED

The study, which cost $35 million, failed to find any significant differences between drugs at each step in terms of the primary outcome measure, which was remission of depression. While there have been other significant findings from the study, the data did inform practitioners about “next step” management of patients with who fail on initial therapy.

CO-MED, like the STAR*D trial, was National Institute of Mental Health sponsored.2 Completed in late 2009, the results of this research have not been published. In contrast to STAR*D, this study compared whether a combination of antidepressants is better than one antidepressant alone when administered as initial treatment for people with chronic or recurrent MDD. CO-MED was designed to test whether two different medications when given in combination as the first treatment step, compared to one medication, enhances remission rates, increases speed of remission, is well tolerated, and provides better sustained benefits in the longer term. There were two arms to the study.

In Arm A, one of the following were given along with placebo: bupropion, escitalopram, mirtazapine, or venlafaxine.

In Arm B, two of the following drugs were given in combination: bupropion, escitalopram, mirtazapine or venlafaxine (Table 2).

Hopefully, the results of CO-MED will prove less nihilistic than those of the STAR*D trial with respect to answering the major question: Which treatment works best? One of the more disappointing aspects of both studies is that neither one looked at the use of a second-generation antipsychotic as an add-on treatment. Given that we now have increasing use of these drugs to augment antidepressants, it would be reassuring to have comparative data on both the safety and effectiveness of this approach.

 

Conclusion

Perhaps the answers we are looking for in terms of predicting treatment response may not come from large comparative clinical trials, but from molecular psychiatry research.

I want to thank David A. Mrazek, MD, FRCPsych, for serving as guest editor for this issue. Pharmacogenomic testing, he observes, may soon become standard practice based on the patient-specific evidence base that already exists. The four articles in this issue that address progress in individualized molecular psychiatry hint at the possibility, he notes, that we will be able to abandon our traditional trial and error approach to medication selection and begin providing our patients safer and more effective individualized psychopharmacologic treatments.

I also direct your attention to an article by Racha Nazir, MD, and colleagues regarding advice on starting the outpatient clinic. It touches on practical issues as office design, charting, knowledge of pharmacotherapy and psychotherapy, and individualization of patient care.

This issue marks the introduction of a new bi-monthly column titled “Clinical Updates in Child & Adolescent Psychiatry” by Margaret D. Weiss, PhD. Dr. Weiss is the head of the Provincial ADHD Program and clinical professor at the University of British Columbia Children’s & Women’s Health Centre in Vancouver, Canada. The column will highlight the clinical approaches, science, and new developments in child psychiatry. I look forward to her contributions and hope our reader-practitioners find the information useful.  PP

 

References

1. Rush AJ. STAR*D: what have we learned? Am J Psychiatry. 2007;164(2):201-204
2. Combining Medications to Enhance Depression Outcomes (CO-MED). Available at: http://clinicaltrials.gov/ct2/show/NCT00590863. Accessed April 19, 2010.

 

Researchers Analyze Prescription Rates for Psychiatric Medications

Tami K. Mark, PhD, and colleagues analyzed data from the 2005 National Disease and Therapeutic Index (NDTI) in order to examine which disease states psychiatric medications were being prescribed for. The NDTI is a continuing survey of over 4,000 office-based United States-based physicians. These physicians provide quarterly reports detailing their contact with patients and recording patient demographics, diagnosis, and therapies.
 

Via an e-mail interview, Dr. Mark stated their reasoning for conducting this research: “As part of an ongoing SAMHSA study to document how much is spent on mental health care in the US, we regularly conduct focused studies to better understand how specific types of mental health services are provided. In the area of psychotopic medications, we were frequently being asked whether most spending was for psychiatric illnesses, or whether it was often for medical illnesses, some of which may be off-label. We thus set out to better document the reasons why physicians were prescribing psychiatric medications.”
 

Mark and colleagues found that ~93% of antidepressants were prescribed for psychiatric conditions. Mood disorders accounted for 65.3% of mentions and anxiety disorders accounted for 16.4%. They also found that ~67% of anti-anxiety medications were prescribed for psychiatric conditions, with anxiety disorders accounted for ~40% of mentions and mood disorders accounted for ~19%.
 

They also found that ~99% of antipsychotics were prescribed for psychiatric conditions. Mood disorders, such as depression and bipolar disorder, accounted for 39% of mentions and schizophrenia or other psychiatric disorders accounted for 34.5% of mentions. Delirium, dementia, amnestic or other cognitive disorders accounted for 7.4% of drug mentions. Attention-deficit/hyperactivity disorder (ADHD) accounted for 5.7% of mentions and anxiety disorders accounted for 5.5%. Disorders diagnosed in infancy/childhood/adolescence, such as autism, accounted for 2.3% of mentions. Whether or not the prescription was on- or off-label was not part of the analysis.
 

“We were somewhat surprised at the small amount of non-psychiatric use of antidepressants (only ~7%) because some prior smaller studies found higher uses for medical purposes such as headache and chronic pain. The fact that ~33% of anti-anxiety medications were not prescribed for psychiatric diagnoses was also interesting. Approximately 6% of prescriptions were indicated as prescribed for a ‘medication examination/evaluation,’ thus presumably to relieve anxiety associated with the interventions.
 

“There has been considerable discussion in the scientific literature about the widening use of antipsychotics for a variety of psychiatric conditions and this study systematically documents this phenomenon. We found that the most common use for antipsychotics was not schizophrenia, but mood disorders, and that use for ADHD and dementia were common, despite being off-label,” Dr. Mark wrote.
 

The researchers hope that this analysis will be able to serve as a guide for future research, policy, and education about psychiatric medications, as well as their benefits, risks, and uses.
 

Funding for this research was provided by the Substance Abuse and Mental Health Services Administration to Thomson Reuters. (CNS Drugs. 2010;24(4):319-326). –CN
 

Rapid Cycling More Likely in Patients With Bipolar Disorder and Comorbid Substance Abuse

A recent study provided new evidence regarding specific characteristics that differentiate patients with bipolar disorder and comorbid substance use disorders (SUDs) from those who do not have comorbid SUDs.
 

Data were derived from the largest study on the treatment of bipolar disorder, the Systemic Treatment Enhancement Program, in which 2,154 patients with a diagnosis of bipolar I or II disorder who experienced a new-onset depressive episode were analyzed. Approximately 44% of patients had current or prior alcohol use, and 30% had a past or current drug use disorder. It was found that the likelihood of switching did not differ significantly between patients with prior SUDs and those with current SUDs. Therefore, the risk for direct switch in these patients was not induced or worsened by ongoing substance use.
 

An unexpected finding was that patients’ recovery time from a major depressive episode was not affected by whether patients had comorbid SUDs. Neither current nor prior substance use was thought to delay recovery from a depressive episode; therefore, patients did not suffer longer depressive episodes than patients without SUDs.
 

Lead researcher, Michael Ostacher, MD, MPH, of Massachusetts General Hospital and Harvard Medical School stated: “The results from this study suggest that treating patients with bipolar disorder for depression, even if they have a drug or alcohol problem, is no less successful than if they have no substance problem. This means that the standard guidelines for the treatment of bipolar disorder can be used for patients regardless of drug or alcohol problems.”
 

Defined as ≥4 mood episodes in the previous year, rapid cycling was more common in patients with prior or current alcohol use disorders, but had no significant correlation with prior or current drug use disorders. Based on these findings, the authors propose that patients with concomitant bipolar disorder and SUDs may have a set of inherent characteristics different from those of patients with bipolar disorder and no substance abuse.
 

“Patients with bipolar disorder and concomitant SUDs tend to be more ill. They are more likely to have attempted suicide, have more prior episodes, do not appear to function as well, are less likely to adhere to treatment, and are more likely to be violent,” explained Dr. Ostacher.
 

Regarding treatment of patients with SUDs, Dr. Ostacher added: “First, patients should be counseled to moderate or stop their use. Motivational interviewing techniques should be used to engage patients in a process of behavioral change, and referral for specialized treatment should be made. Treatments that are approved for drug or alcohol dependence should be used, especially considering the absence of data showing their ineffectiveness in comorbid bipolar disorder.”
 

Funding for this study was provided by the National Institute of Mental Health. (Am J Psychiatry. March 15, 2010 [Epub ahead of print]) –JV
 

Interpersonal Psychotherapy for Adolescent Girls at Risk for Adult Obesity

A recent study suggests that interpersonal psychotherapy (IPT) may help prevent weight gain and binge eating in adolescent girls at risk for adult obesity.
 

Marian Tanofsky-Kraff, PhD, at the Uniformed Services University of the Health Sciences in Maryland, and colleagues, evaluated the 1-year outcomes of IPT compared to general health education. Thirty-eight adolescent girls (12–17 years of age) at risk for adult obesity (body mass index in the 75th-97th percentile) were randomized to IPT or a health education group. Twenty of the 38 girls had out of control eating patterns at baseline.
 

According to previous studies, IPT can effectively reduce binge-eating behavior in obese adults and help stabilize the weight gain associated with binge eating. One goal of IPT is to demonstrate to patients the influences of social interaction, and especially negative social interaction. In this study, patients in the IPT group were encouraged to appreciate how their own spoken communication and, for example, body language, affects interaction with others. By moving toward more frequent positive social interactions, the goal was to lessen, or eliminate, any number of negative stimuli that might cause the patients to respond by eating.
 

Thirty-five patients returned to 1-year follow-up. Patients with out of control eating, who were in the IPT group, had greater reductions in those behaviors than those in the health education group (P=.036). Regardless of out of control eating status, IPT patients also showed greater weight stabilization at 1-year follow-up.
 

Funding for this study was provided by the National Institutes of Health and the Uniformed Services University of the Health Sciences. (Int J Eat Disord. Oct 30, 2009 [epub ahead of print]). –LS
 

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

 

Dr. Nazir is post-doctoral fellow and Dr. Sedky is associate professor of psychiatry at the Hershey Medical Center in Pennsylvania. Dr. Paladugu is an observer and Dr. Lippmann is professor of psychiatry at the University of Louisville School of Medicine in Kentucky.

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: Karim Sedky, MD, Department of Psychiatry, Hershey Medical Center, 500 University Drive, Mail Code H073, Hershey, PA 17033; Tel: 717-782-2180; Fax: 717-782-2190; E-mail: sedky66@hotmail.com.


Abstract

Residents benefit by being prepared for their outpatient rotation. Coming to the clinic with an understanding of the procedures, challenges, and how to meet educational objectives should promote confidence and a better educational experience. Learning how to adjust to this setting, arrange their office, get supervision, and provide good clinical service are important steps in the resident’s training. Assuring access to faculty guidance at pharmacotherapy and psychotherapy facilitates expertise and safety for the patient and trainee. Understanding administrative and practical aspects of psychiatric care in this setting fosters a good clinical approach and education in a supervised, productive manner.


Focus Points

• Office design is important and includes a focus on safety.
• Charting is important for clinical, insurance, and medico-legal reasons.
• Missed appointments are frequently encountered in outpatient settings.
• It is important to learn pharmacotherapy and psychotherapy.
• Patient care is individualized to specific patient needs.

 

Introduction

The outpatient clinic is one of the principal sites for training psychiatry residents. The Accreditation Council of Graduate Medical Education for psychiatry requires at least 1 year of outpatient experience for trainees.1

Most residencies start psychiatric training on inpatient services in the first postgraduate year. There, the resident acquires an understanding about psychopathology. Risk assessment, diagnostic evaluation, and formulating a differential diagnosis are mastered during this phase of training. It also offers an opportunity for prescribing medication under supervision and learning about aftercare options.

Residency may vary with respect to when residents begin to see outpatients. Before starting, it is important to learn about the clinic policies. Ambulatory patients exhibit a wide range of exposures. Certain conditions, such as obsessive-compulsive disorder (OCD), are seen in this setting more often than in a hospital service. Having residents continue clinic work as long as possible improves patient and physician satisfaction through a longer-term relationship. Therapeutic alliances are enhanced and it affords the resident an opportunity to observe the course of mental illness over time.2

Residents typically have at least one outpatient supervisor. Especially during the adjustment phase, supervisors provide orientation to the clinic. They offer professional advice, clinical guidance, and other assistance throughout the rotation. Discussion may include guidance on study of appropriate educational materials; prescribing pharmacotherapies; and help in handling referrals, complaints, and so forth. Residents also meet with their supervisors to review psychotherapeutic techniques and alternatives. Self-educational reading and attending lectures or conferences is usually required.

 

What About Your Office?

For safety reasons, the clinician’s chair should ideally be nearer to the door than is the patient’s chair. Some clinics place an emergency alarm button at the desk or some other alert system to call for help, if protection is needed. Extra seating is made available for family. A box of tissues should always be available.

The room should be well illuminated. There is controversy about whether to display pictures of one’s family. From a psychoanalytic point, this may not be advisable. Pictures on the wall should have a calmative theme. Plants beautify the room and promote a pleasant atmosphere, as long as they are healthy.

 

Schedules

Clinics differ in respect to scheduling of team meetings where referrals, clerical issues, and other problems are discussed. These meetings often review clinically difficult cases and administrative issues.

In cases of conjoint treatment with a psychotherapist, frequent contact between both clinicians is expected for information sharing. Billing is usually new to residents, but it is essential to learn the coding system for intakes, medication checks, psychotherapy sessions, and other patient contacts.

 

How To Chart

Legible documentation is important. Typing is clearer than handwriting, and printed clinical recording sheets for patient data also can simplify charting. Maintain appropriate eye contact with the patient when recording information. Note the date and time of each session, including the start and ending time and the duration of the visit. Document general content of the session, complaints, concerns, and therapy utilized. Include details about patient progress, efficacy of pharmacotherapy, and any side effects. Clinical data should support the type of session noted on the billing forms.

The chart should reflect a discussion of safety concerns and decisions about management. Safety includes suicidal or homicidal thoughts, inability to take care of oneself, abuse, or noncompliance with medical treatment. In these situations, consultation with the supervisor is advised and documented before ending the appointment. Child Protective Services must be notified whenever there is possible abuse to a minor. Adult Protective Services are informed if an adult is unable to care for him- or herself or is being abused.

 

About Tarasoff

It is important to be familiar with the Tarasoff ruling. In cases of expressed dangerous threats to others, clinicians have the duty to protect the potential victim by a direct warning to that individual and to the police; this can often be done without compromising the therapeutic relationship.3 When a patient refuses to reveal information about the possible victim, inform the local police department. These facts must always be documented in the chart.

 

First Appointment

Clinics differ with respect to who schedules the initial appointments, provides the clinic’s address and phone number, and answer questions, such as how to access parking. The first 1-hour session is dedicated to evaluating the patient with a history and mental status examination, followed by discussion of treatment plans. Laboratory tests may be ordered as needed. Therapeutic decisions are postponed in complex cases until the required information is obtained and reviewed with the supervisor. Collateral information from family members or a previous treatment team might be beneficial. Some patients may require more intensive treatment with referral to specialty clinics, as for persons with dangerous self-mutilation or substance abuse.

Written consents are obtained from patients before information is revealed to a third party, even to family or an insurance company. Special consents are obtained for video or audio taping a session.

Treatment discussions include pharmaceutical options as well as psychotherapy selections. Always tell patients whom to call in case of emergency, during working hours or when the clinic is closed. If there is overt concern for patient safety, involve family for monitoring. Although assessments are more accurate when the supervisor and the trainee conduct concluding parts of the initial interview together, this is usually not done for practical reasons.4

 

Follow Up

A follow-up visit is mutually agreed upon by the patient and resident. Some clinics depend on secretaries to schedule appointments, but the doctors must inform staff about their available times and planned visit dates. The clinic phone number, emergency contacts, and physician’s name should be provided to every patient. The next follow-up date and time should be given to the patient in written form.

 

Missed Visits

Residents should be aware of clinic policy towards individuals who frequently miss appointments. Every outpatient facility has its own way to deal with missed visits. Failure to appear for an appointment is most common among people seen by a resident, in younger patients, and for those individuals with a record of missed visits or living far from the facility.5

 

Pharmacotherapy

Prescribing medications is a frequent part of treatment. There are algorithms available for treatment of different syndromes6 and the American Psychiatric Association offers downloadable guidelines.7 Drug interactions between psychopharmaceuticals and other co-administered medical treatments must always be considered. Avoid polypharmacy when possible.8,9 The physiologic impact of medications must always be considered; for example, avoid lithium during pregnancy, lactation, renal dysfunction, or hypothyroidism.

Residents should know which medications cause weight gain.10 Patients taking antipsychotics should be monitored for the metabolic syndrome according to the current guidelines. Side effects should be discussed and charted.

Always consider the prospect of pregnancy to avoid teratogenicity from pharmaceutical exposure in female patients of child-bearing age. Pharmacotherapy is avoided if possible during pregnancy or lactation. The risk versus benefit of using medications during pregnancy mandates explicit indications and thorough discussion; consultation with a supervisor and an obstetrician is essential. Be aware that efficacy of oral contraceptives in preventing pregnancy is reduced when co-prescribed with hepatic enzyme-inducing drugs, like carbamazepine.

For patients taking benzodiazepines or other controlled substances, continued benefit should be consistently and specifically charted; taper off such medications when possible. Controlled substances, as in treatment for insomnia, should ideally be prescribed only for short periods. For patients with alcohol and/or drug abuse, sobriety is consistently stressed. Alcoholics Anonymous or Narcotics Anonymous are encouraged, buprenorphine administration is considered, and/or other chemical dependency intervention plans are implemented. Some programs offer special training to residents at handling drug abuse cases.11 Any controlled substances in the clinic, like buprenorphine, must be kept in a locked location. Needles and injectable medicines should be stored in secure places, with refrigeration as needed.

Always consider the cost of medication and insurance coverage in planning treatment. Pharmaceutical sales representative visits often inappropriately influence resident prescribing habits. Thus, this practice is now discouraged.12

 

Individual Versus Conjoint Treatment

Residents can do both medication management and psychotherapy. This allows more time to understand the patient and improves the therapeutic alliance. However, having two people share a case can also be clinically beneficial, and is often the reality.

 

Psychotherapy

After the assessment, the clinician and supervisor determine the type of psychotherapy indicated. Consider patient education, motivation, energy, and functional capacity. Availability, times for sessions, and financial aspects should be reviewed.

Supportive therapy is indicated, especially for those recently discharged from the hospital, after an acute relapse, or those with compromised function. Cognitive-behavioral therapy is a frequently chosen treatment that focuses on cognitive distortions and automatic thoughts.13 In cases of phobias, posttraumatic stress disorder, or OCD, exposure with response prevention is a frequent option. If there is a concern about self-harm, dialectical-behavioral therapy might be selected.14 This includes teaching interpersonal effectiveness, stress tolerance, acceptance skills, and emotional regulation.15 Mentalization therapy is an alternative for treating patients with borderline personality disorder by helping them develop stability within a secure attachment relationship.16 Learning psychodynamic psychotherapy is a core training requirement and utilized in selected cases.17 For those who have chemical dependence issues, one can encourage abstinence by motivational enhancement therapy through a guided review of ambivalences.

Other therapeutic options include group approaches, family or marital counseling, hypnotherapy, or other traditional or even less conventional therapies. It can be advantageous when different supervisors suggest alternative approaches, even in the same patient.18 Electroconvulsive therapy may be indicated as a somatic treatment in certain cases. Transcranial magnetic stimulation and vagal nerve stimulation are newer considerations.

 

Crisis Assesment And Community Treatment Team

During a psychiatric emergency, a crisis team or the regular clinical staff must provide an immediate assessment and/or referral to inpatient hospitalization. For chronically ill, low-functioning individuals, a referral to a community treatment program is appropriate since these agencies have an intense assistance program provided by multidisciplinary professionals.

 

Forms And Letters

Some patients may have forms for physician signature. Others may ask for social security or insurance papers to be filled out. Excuses for job or school absences are often requested. The same applies to notices about returning to work and clarifying occupational restrictions. Place copies of all forms and similar papers in the chart to document the transaction. An appreciation of disability regulations can be an aid in assisting patients.19

 

Referral

It is important that residents know how to access other services. These may include physician referrals such as securing a psychologist, social worker, nurse practitioner, Meals-on-Wheels, transportation services, or vocational rehabilitation. Knowledge of community resources is expected.20

 

Laboratory Tests

At the initial evaluation, laboratory screening is considered. This may include a complete blood count, lipid profile, comprehensive serum chemistry profile, urinalysis, or thyroid hormone assays. A serum pregnancy test is conducted in women of childbearing potential. Various tests may be repeated over time, eg, serum glucose or lipid monitoring when metabolic syndrome is a concern. Neuroimaging is requested when brain disease is in the differential. Syphilis or other infectious disease testing is indicated in demented or other selected people. Clozapine prescribing mandates hematologic follow up regularly with special attention to the neutrophil count. Lithium requires attention to serum levels, renal effects, and antithyroid properties as well as pre-treatment testing. Blood counts, liver or renal function tests, hepatic enzyme assays, or electrolytes are monitored regularly in patients taking medications with adverse potential in these areas. The procedures for ordering tests vary from clinic to clinic.
 

Samples/Returned Medications

It is important to be familiar with the policy for handling medication samples. Many clinics do not allow sampling of pharmaceuticals, but some facilities still do, under tight regulation.
 

Special Populations

Training residents about cultural differences is important.21-23 For example, African-American populations reportedly are often overdiagnosed with schizophrenia.24 Hispanic populations may have a higher incidence of anxiety disorders.25 Interpreter services are required in cases with a language barrier. Adjustment disorders and non-acceptance by family are frequent complaints by homosexuals.26 Training guidelines exist for women’s issues.27 When treating children or adolescents, family therapy is an integral part of the plan.28-30
 

Transfering Or Terminating

Sometimes a resident might need to transfer a patient. These situations could include transference or counter-transference issues, concern about physician safety, lack of progress, and always at times when the resident will no longer be available. It is important to explain the reasons for transfers. In long-term therapeutic relationships, discussion focuses on analysis of feelings and future plans. Self-esteem and abandonment issues should be addressed. At the end of the outpatient rotation, detailed discussions should ensue and consider even introducing the patient to the new therapist to avoid feelings of abandonment. A review of the newly arranged follow up is mandatory with names, dates, times, and phone numbers listed on a new appointment card.

 

Conclusion

The outpatient clinic is an important part of the psychiatric education. Preparing residents before they start the ambulatory rotation reduces anxiety and improves the educational experience. Understanding the practice policies of the clinic helps the resident to be comfortable and productive. Following patients for long duration offers trainees a long-term view of patient pathology, problems, and coping skills. Performing medication management and psychotherapy with expertise are important objectives. Education also focuses on forming therapeutic relationships, monitoring disease progression and/or effectiveness of treatment, and competently handling mental health emergencies. Learning about ambulatory care comes from practical experience in the clinic.  PP
 

References

1.    ACGME-Residency Review Committee Guidelines. Available at: www.acgme.org/acWebsite/downloads/RRC_progReq/400pr1104.pdf. Accessed on March 8, 2010.
2.    Steinbook R. Continuity clinics in psychiatric residency training. Acad Psychiatry. 2007;31(1):15-18.
3.    Binder RL, McNiel DE. Application of the Tarasoff ruling and its effect on the victim and the therapeutic relationship. Psychiatr Serv. 1996;47(11):1212-1215.
4.    Stein SP, Karasu TB, Charles ES, et al. Supervision of the initial interview. A study of two methods. Arch Gen Psychiatry. 1975;32(2):265-268.
5.    Campbell B, Staley D, Matas M. Who misses appointments? An empirical analysis. Can J Psychiatry. 1991;36(3):223-225.
6.    Texas Manuals and Algorithms. Available at: www.dshs.state.tx.us/mhprograms/disclaimer.shtm. Accessed on March 8, 2010.
7.    American Psychiatric Association Practice Guidelines. Available at: http://psych.org/psych_pract/treatg/pg/prac_guide.cfm. Accessed on March 8, 2010.
8.    Caine E, Lyness J. Delirium, dementia, and amnestic and other cognitive disorders. In: Sadock BJ, Sadock VA. Kaplan and Sadock’s Synopsis of Psychiatry. 10th ed. Pennsylvania, PA: Lippincott, Williams and Wilkins; 2007:323.
9.    Glezer A, Byatt N, Cook R Jr, Rothschild AJ. Polypharmacy prevalence in the treatment of unipolar depression in an outpatient clinic. J Affect Disord. 2009;117(1-2):18-23.
10.    Vanina Y, Podolskaya A, Sedky K, et al. Body weight changes associated with psychopharmacology. Psychiatr Serv. 2002;53(7):842-847.
11.    Renner JA Jr. How to train residents to identify and treat dual diagnosis patients. Biol Psychiatry. 2004;56(10):810-816.
12.    Schwartz TL, Kules DJ, Wade M, et al. Newly admitted psychiatric patients’ prescriptions and pharmaceutical sales visits. Ann Clin Psychiatry. 2001;13(3):159-162.
13.    Beck J. Cognitive Therapy: Basics and Beyond. New York, NY: Guilford Press; 1995.
14.    Linehan M. Cognitive-Behavioral Treatment of Borderline Personality Disorder. New York, NY: Guilford Press; 1993.
15.    Linehan MM, Armstrong HE, Suarez A, Allmon D, Heard HL. Cognitive-behavioral treatment of chronically parasuicidal borderline patients. Arch Gen Psychiatry. 1991;48(12):1060-1064.
16.    Bateman A, Fonagy P. Psychotherapy for Borderline Personality Disorder: Mentalization-based Treatment. Norfolk, UK: Oxford Medical Publication; 2004.
17.    Mullen L, Rieder R, Glick R, Luber B, Rosen PJ. Testing psychodynamic psychotherapy skills among psychiatric residents: the Psychodynamic Psychotherapy Competency test. Am J Psychiatry. 2004;161(9):1658-1664.
18.    Nestler EJ. The case of double supervision: a resident’s perspective on common problems in psychotherapy supervision. Acad Psychiatry. 1990;14:129-136.
19.    Mischoulon D. An approach to the patient seeking psychiatric disability benefits. Acad Psychiatry. 1999;23(3):128-136.
20.    Kramer T, Kennedy R. Educational computing. Useful websites for psychiatrist. Acad Psychiatry. 1998;22:141-143.
21.    Harris H, Felder D, Clark M. A psychiatric residency curriculum on the care of African American patients. Acad Psychiatry. 2004;28(3):226-239.
22.    Garza-Trevino ES, Ruiz P, Venegas-Samuels K. A psychiatric curriculum directed to the care of the Hispanic patient. Acad Psychiatry. 1997;21:1-10.
23.    Stein TS. A curriculum for learning in psychiatric residencies about homosexuality, gay men, and lesbians. Acad Psychiatry. 1994;18:59-70.
24.    Hausman K. Cultural factors affect success of African Americans’ MN care. Psych News. 2001;36(10):17.
25.    Hirai M, Stanley MA, Novy DM. Generalized anxiety disorder in Hispanics. Symptom characteristics and prediction of severity. J Psychopath Behav Assessment. 2006;28(1):49-56.
26.    Anhalt K, Morris T. Developmental and adjustment issues of gay, lesbian, and bisexual adolescents: a review of the empirical literature. Clin Child Family Psych Rev. 1998;1(4):215-230.
27.    Spielvogel AM, Dickstein LJ, Robinson GE. A psychiatric residency curriculum about gender and women’s issues. Acad Psychiatry. 1995;19:187-201.
28.    Celan M, Croft S, Morrissey-Kane E. Family Evaluation Clinic. Training psychiatrists to think systemically. Acad Psychiatry. 2002;26:17-25.
29.    Berman EM, Heru AM, Grunebaum H, et al. Family skills for general psychiatry residents: meeting ACGME core competency requirements. Acad Psychiatry. 2006;30:69-78.
30.    Berman EM, Heru AM, Grunebaum H, et al. Family-oriented patient care through the residency training cycle. Acad Psychiatry. 2008;32:111-118.

 

Dr. Aggarwal is senior resident, Dr. D.D. Sharma is assistant professor, Dr. R.C. Sharma is professor and head, and Dr. Kumar is associate professor, all in the Department of Psychiatry at Indira Gandhi Medical College in Shimla, India.
 

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: Ashish Aggarwal, MD, Senior Resident, Department of Psychiatry, Indira Gandhi Medical College, Shimla-171001, Himachal Pradesh, India; Tel: +91-0-9218832616; Fax: 91-177-2658339; E-mail: drashish1980@gmail.com.


 

Abstract

Clozapine is an atypical antipsychotic used for treatment-resistant schizophrenia. It has also been used for other disorders, such as obsessive-compulsive disorder, especially as an augmenting agent. Paradoxically, there are few reports of clozapine-induced obsessive-compulsive symptoms (OCS). The authors report on a patient with schizophrenia who developed OCS twice when clozapine was initiated, and responded positively to lowering the dose of clozapine.


Focus Points

• Clozapine is the drug of choice for patients with treatment-resistant schizophrenia.
• Obsessive-compulsive symptoms (OCS) can occur during the course of schizophrenia.
• Clozapine can cause OCS in patients with schizophrenia.
• It is important to clarify the relation of OCS with antipsychotic medications, including clozapine, in patients with schizophrenia.
• Clozapine-induced OCS needs to be managed either by lowering the dose or adding an anti-obsessive medication like serotonin reuptake inhibitors. 

 

Introduction

Clozapine is an atypical antipsychotic used for managing patients with treatment-resistant schizophrenia. Unlike other antipsychotics, it has potent antagonistic activity at the serotonin (5-HT)2 receptor and has less affinity for dopamine-2 receptors. Development of obsessive-compulsive symptoms (OCS) with atypical antipsychotics, including clozapine, have been reported in the literature.1,2 On the contrary, these atypical antipsychotics, including clozapine, have been used for the management of treatment-resistant obsessive-compulsive disorder (OCD).3,4 A large retrospective review5 did not find any worsening or emergence of OCS/OCD with clozapine treatment. The authors report on a patient with schizophrenia who developed OCS twice when clozapine was initiated, and responded positively to lowering the dose of clozapine.

 

Case Report

Mr. P, a 20-year-old unmarried male presented with a history of violent aggressive behavior, smiling and muttering to himself, suspiciousness, decreased sleep, and decrease in self care for the last 2 years. There was no significant past, family, or personal history. He was well adjusted premorbidly. He was diagnosed as a case of undifferentiated schizophrenia, as per the International Statistical Classification of Diseases and Health Related Problems, Tenth Revision.6 The patient was receiving treatment for the last 1.5 years but tended to be non-compliant. Currently, the patient had exacerbated his illness after he stopped treatment for 2 months. No records of his treatment were currently available. This time, he was started on olanzapine 10 mg/day increased to 20 mg/day, along with chlorpromazine 200 mg/day. There was no improvement at all for a period of ~3 weeks.

In view of marked aggression, adamant behavior, and hostility, the patient was started on clozapine 25 mg/day gradually increased to 250 mg/day over a period of 2 weeks; simultaneously, other drugs were gradually tapered over a period of 1 week. After ~5 days of clozapine 250 mg, it was observed that, in addition to previous symptoms, the patient also started doing things repeatedly. He would repeatedly touch some objects such as glass and doors and would get irritable if asked not to do so. He would lie down on the floor and, after a few minutes, would get up and repeat the cycle 4–5 times before finally lying on the bed. On asking, he would report that he felt compelled to do it again and again, although he knew that these actions were irrational and that he was doing this himself, without any external influence. The Yale-Brown Obsessive Compulsive Scale score was 20. Review of the patient’s treatment record revealed that ~8 months ago, he was started on clozapine, in view of non-response to haloperidol and risperidone in adequate doses for an adequate time period. The patient started developing similar OCS at that time when he was on clozapine 250 mg/day; however, thinking it to be related to psychosis, the dose of clozapine was increased further up to 400 mg/day, leading to further exacerbation of OCS. Capsule fluoxetine up to 40 mg/day was added to the treatment without much relief in the symptoms. Since the patient developed marked sedation and increased OCS, clozapine was stopped and the patient was started on trifluperazine and amisulpride at that time. The OCS remitted within a period of ~3 weeks.

In view of appearance of OCS at clozapine 250 mg/day on both occasions, it was decided to decrease the dose of clozapine to 200 mg/day, and amisulpride up to 400 mg/day was added to the treatment. The patient’s OCS decreased and subsided after ~1 week of decreasing the dose.

 

Discussion

In this case, during both instances, the symptoms developed when a dose of clozapine >200 mg and abated on decreasing the dose. Alhough during the first scenario fluoxetine was also added, it did not lead to significant improvement in symptoms and the OCS improved after stopping clozapine. Thus, in this patient, OCS were definitely related to clozapine and were a dose-related phenomenon. This case differs from earlier reported cases of clozapine-induced OCS because the patient developed OCS after a short period of clozapine treatment (<3 weeks) and the patient developed OCS at clozapine 250 mg/day.
 

Previous reports of clozapine-induced OCS have been at comparatively higher doses of clozapine (300–900 mg/day)2,7,8 and after a long period of clozapine treatment (ranging from 10 weeks to 2 years).2,7-9 In adition, this patient did not have any OCS prior to clozapine treatment, though there have been reports of clozapine exacerbating already existing OCS in schizophrenia.2
 

A recent study10 of OCD in clozapine-treated patients with schizophrenia or schizoaffective disorder revealed a prevalence of 24% of clinically significant OCS. However, the temporal relationship between the onset of obsessional and schizophrenic symptoms and clozapine treatment was not established. Approximtely 50% of these patients had OCS prior to clozapine treatment.
 

Multiple hypotheses have been offered to explain the development of OCS during antipsychotic treatment. For clozapine-induced OCS, both 5-HT2A and 5-HT2C receptor antagonisms11 have been postulated to play a role in the generation of OCS. Other mechanisms that have been reported are the role of dopamine in the pathogenesis of OCS and the serotonergic modulation of dopaminergic system.12,13
 

It is important to clarify the relationship with antipsychotics while evaluating a patient of schizophrenia presenting with OCS. This is of importance for the management of such patients. Cases of spontaneous self-remission of clozapine-induced OCS within 1–3 weeks have also been described in the literature.14 Other options for clozapine-induced OCS include lowering the dose of clozapine as in this case, or adding a serotonin reuptake inhibitor. Switching to another antipsychotic might also be an option, but one should be careful for the exacerbation of psychosis as clozapine is generally used for treatment-resistant patients.

 

Conclusion

Given the paradoxical efficacy of clozapine in resistant cases with OCD, the overlapping neurobiology of OCD and psychosis, and the increasing use of clozapine for the management of treatment-resistant patients with schizophrenia, it is recommended that one should be vigilant and cautious while using clozapine. In addition, proper treatment history and delineation of symptoms in relation to drugs is important for correct management of patients and also to avoid polypharmacy.  PP
 

 

References

1.    Khullar A, Chue P, Tibbo P. Quetiapine and obsessive compulsive symptoms (OCS): case report and review of atypical antipsychotics induced OCS. J Psychiatry Neurosci. 2001;26(1):55-59.
2.    Chong SA, Wong KE. Clozapine and obsessive compulsive symptoms in schizophrenia. Hong Kong Journal of Psychiatry. 1996;6(1):45-47.
3.    Young CR, Bostic JQ, McDonald CL. Clozapine and refractory obsessive compulsive disorder. A case report. J Clin Psychopharmacol. 1994;14(3):209-211.
4.    Keuneman RJ, Pokos V, Weerasundera R, et al. Antipsychotic treatment in obsessive compulsive disorder: a literature review. Aust N Z J Psychiatry. 2005;39(5):336-343.
5.    Ghaemi SN, Zarate CA, Popli AP, Pillay SS, Cole JO. Is there a relationship between clozapine and obsessive-compulsive disorder?: a retrospective chart review. Compr Psychiatry. 1995;36(4):267-270.
6.    International Statistical Classification of Diseases and Health Related Problems. 10th rev. 2nd ed. Geneva, Switzerland: World Health Organization; 2004.
7.    Patel B, Tandon R. Development of obsessive compulsive symptoms during clozapine treatment. Am J Psychiatry. 1993;150(5):836.
8.    Rahman MS, Grace JJ, Pato MT, Priest B. Sertraline in the treatment of clozapine-induced obsessive-compulsive behavior. Am J Psychiatry. 1998;155(11):1629-1630.
9.    Levkovitch Y, Kronnenberg Y, Gaoni B. Can clozapine trigger OCD? J Am Acad Child Adoles Psychiatry. 1995;34(3):263.
10.    Mukhopadhaya K, Krishnaiah R, Taye T, et al. Obsessive-compulsive disorder in UK clozapine-treated schizophrenia and schizoaffective disorder: a cause for clinical concern. J Psychopharmacol. 2009;23(1):6-13
11.    Dursun SM, Reveley MA. Obsessive-compulsive symptoms and clozapine. Br J Psychiatry. 1994;165(2):267-268.
12.    Goodman WK, McDougle CJ, Price LH, et al. Beyond the serotonin hypothesis: a role for dopamine in some forms of obsessive-compulsive disorder? J Clin Psychiatry. 1990;51(suppl):36-43.
13.    Dewey SL, Smith GS, Logan J, et al. Serotonergic modulation of striatal dopamine measured with positron emission tomography (PET) and in vivo microdialysis. J Neurosci. 1995;15(1 pt 2):821-829.
14.    Patil, VJ. Development of transient obsessive-compulsive symptoms during treatment with clozapine. Am J Psychiatry. 1992;149(2):272.

 

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. 

 

Introduction

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.

 

Conclusion

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

 

References

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. Belleville is professor in the School of Psychology at Université Laval. Dr. Foldes-Busques is research associate at Centre Hospitalier Affilié Universitaire Hôtel-Dieu de Lévis. Dr. Marchand is professor in the Department of Psychology at the Université du Québec à Montréal.

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: Geneviève Belleville, PhD, École de Psychologie, Pavillon Félix-Antoine-Savard, Bureau 1334, 2325, rue des Bibliothèques, Québec (Québec), G1V 0A6; Tel: 1-418-656-2131 ext. 4226; Fax: 1-418-656-3646; E-mail: Genevieve.Belleville@psy.ulaval.ca


 

Abstract

Objective: The objective of this article is to describe the characteristics of patients with panic disorder from an emergency department by comparing them to patients with panic disorder from psychiatric settings on panic symptoms, psychiatric comorbidity, and psychological correlates of panic disorder.
Methods: Eighty-four consecutive patients consulting an emergency department with noncardiac chest pain and diagnosed as having panic disorder, and 126 patients with panic disorder seen in two specialized clinics for anxiety disorders, were assessed with validated clinical interview and questionnaires.
Results: Panic disorder patients recruited in the emergency department were older and reported fewer panic symptoms than their psychiatric settings counterparts. They also had less severe agoraphobic cognitions and less sensitivity to anxiety. The two samples displayed similar rates of psychiatric comorbidities and similar rates of suicidal ideation, with 24.3% to 31.3% of panic disorder patients overall having had thoughts of killing themselves.
Discussion: Panic disorder patients encountered in the emergency department tend to report physical, rather than psychological, symptoms of panic. This finding could explain the extremely low rates of panic disorder recognition in the emergency department.
Conclusion: Despite showing less severe panic symptoms, and sometimes no emotional or cognitive signs of fear at all, emergency department patients with panic disorder have elevated rates of psychiatric comorbidities and suicidal ideation and need adequate clinical attention.


Focus Points

• Male patients with panic disorder were more likely to be encountered in the emergency department of a general hospital than in clinics specialized in anxiety disorders.
• Patients with panic disorder from the emergency department displayed less numerous and severe panic symptoms, agoraphobic cognitions, and sensitivity to anxiety than patients with panic disorder from psychiatric settings.
• One-third of panic disorder patients from the emergency department had non-fear panic disorder, a condition characterized by the physical symptoms of panic but the absence of fear, whether of dying, losing control, or going crazy.
• Despite showing less severe symptoms, panic disorder patients from the emergency department had high rates of psychiatric comorbidity, particularly other anxiety disorders and major depressive disorder.
• In the emergency department sample, one panic disorder patient out of four had suicidal ideation within the past 7 days.

 

Introduction

Chest pain is one of the 13 symptoms that may occur during a panic attack. It is the symptom most likely to prompt consultation at an emergency department.1 Accordingly, 17% to 32% of patients who consult an emergency department with chest pain have panic disorder.2-4 However, despite increasing knowledge about panic in the emergency room, panic disorder remains virtually unidentified.2

The discrepancy between the incidence of panic disorder in the emergency department and the emergency department professionals’ failure to detect it raises important questions regarding the clinical profile of panic disorder patients consulting in the emergency department. These patients may present a different profile compared to panic disorder patients encountered in psychiatric settings. Exploratory data have suggested that panic disorder patients from the emergency department are older, are more likely to be male, have less severe panic symptoms, and have lower rates of agoraphobia than their psychiatric counterparts.5 Reports of clinical experiences also suggested that it is likely for people with panic disorder to initially present to their general practitioner or hospital emergency department with a focus on somatic symptoms and concerns.6 These preliminary findings need to be replicated.

Another concern is the proportion of patients in the emergency department that appear to have a subtype of panic disorder, referred to as non-fearful panic disorder (NFPD). This subtype is characterized by no report of either fear of dying or fear of going crazy or losing control during panic attacks.7 In the emergency department of a hospital specialized in cardiology, Fleet and colleagues8 found that 44% of panic disorder patients seeking treatment for chest pain could be categorized as having NFPD. Using the National Comorbidity Survey database, Chen and colleagues9 found that 30% of panic attacks occurred without fear of dying or going crazy. The prevalence of this variant of panic disorder in the emergency department of general hospitals is not known.

The principal objective of the present study is to compare panic disorder patients from the emergency department versus in psychiatric settings on panic symptoms, psychiatric comorbidity, and psychological correlates of panic disorder. Another objective is to identify the proportion of patients displaying NFPD in a sample of panic disorder patients consulting for chest pain in an emergency department of a general hospital.

 

Method

Participants and Procedure

The emergency department sample consisted of “quasi” consecutive patients consulting an emergency department with non-cardiac chest pain. Although efforts were made to approach every patient admitted to the emergency department with a complaint of chest pain on weekdays from 8am to 4pm, several patients (1,101 out of 3,234; 34%) could not be reached for various reasons (as described in the Figure). Inclusion criteria for the study were: ≥18 years of age, French or English speaking, and consulted the emergency department for chest pain non-associated with chest trauma. Exclusion criteria were: presented results outside the normal ranges on the electrocardiogram or blood tests, suggesting coronary artery disease; and presented a clear medical cause for the chest pain (eg, pulmonary embolism). Patients were assessed with self-report questionnaires and a clinical diagnostic interview conducted by a research assistant while they were in medical observation or waiting for tests results. Self-report questionnaires were completed on site or at home and returned to the research team with a prepaid envelope (if patients had insufficient time to complete the forms or if they were too tired). For the purpose of this study, the authors included data from participants meeting criteria for panic disorder based on the Diagnostic and Statistical Manual of Mental Disorder, Fourth Edition.10 Significant interference with at least one area of functioning was defined by a clinical score of ≥4 on the Anxiety Disorder Interview Schedule for DSM-IV (ADIS-IV; n=84).11

 

The psychiatric settings sample was composed of 126 patients recruited for a panic disorder treatment delivered in a specialized anxiety clinic through newspapers and referrals by healthcare professionals. This sample included patients referred by family physicians, general practitioners and psychiatrists working in a psychiatric hospital, and psychiatrists working in a specialized anxiety clinic, as well as self-referred patients. Inclusion criteria were: 18–65 years of age; diagnosis of panic disorder with agoraphobia, based on DSM-IV criteria, for at least 1 year; onset of panic disorder prior to 40 years of age; and had not participated in cognitive-behavioral therapy for panic disorder within the last year. The severity of the disorder for the psychiatric settings sample was moderate to severe, interfering significantly with at least one area of functioning, in accordance with a clinical score of ≥4 on the ADIS-IV, and a score of ≥3 on the Global Assessment of Severity Scale. Following a telephone screening interview, all eligible patients completed an assessment battery and underwent a psychological assessment conducted by a research assistant. Patients were assessed using a clinical interview, and self-report questionnaires were completed before receiving treatment.

 

Measures

The ADIS-IV

The ADIS-IV is a semi-structured interview assessing anxiety disorders according to DSM-IV criteria. It also includes a series of questions targeting mood, somatoform, and substance-related disorders. The ADIS-IV is widely used in research and clinical settings, and is considered a gold standard measure for the assessment of panic and other anxiety disorders.12 The ADIS-IV was used in both samples to screen and assess the severity of panic disorder and comorbid psychiatric diagnoses. A French version of this instrument was used, but no information on its psychometric validation is currently available. In the psychiatric settings sample, participants were also administered the Global Assessment of Severity Scale (GASS).13 The GASS is a clinician-administered five-point scale assessing impairment caused by panic and agoraphobic symptoms within the occupational, social, and recreational spheres.

 

BDI-II

The Beck Depression Inventory, Second Edition (BDI-II),14 includes 21 items that assess symptoms of depression; for each item, four statements describe increasing levels of symptom intensity. The respondent chooses the statement that best reflects his or her state of the last 7 days. The BDI-II has been extensively validated, and good psychometric properties have been reported for the French version used in this study.15 Item #9 (suicidal ideation) was singled out to assess suicidal ideation.

 

The ACQ

The Agoraphobic Cognitions Questionnaire (ACQ)16 measures the presence of 14 catastrophic thoughts related to panic (eg, “I will have a heart attack”; “I am going to go crazy”). Each thought is rated on a scale from one (very rarely) to five (very often). The total score ranges from one to five, and is computed by averaging the scores on the 14 items. Higher scores indicate greater frequency catastrophic thoughts. The French translation of the ACQ has demonstrated good internal consistency (a=.75) and temporal stability (r=.71).17

 

The ASI

Anxiety Sensitivity Index (ASI)18 is a 16-item self-report questionnaire that assesses the way that respondents react to anxious arousal (eg, “It is important to me not to appear nervous”; “Unusual body sensations scare me”; “It scares me when I am nervous”). Each item is rated on a scale from zero (very little) to four (very much). Total score is obtained by summing the scores from each item and ranges from 0–64, with higher scores indicating greater sensitivity to anxiety. Psychometric properties of the French translation17 are adequate (internal consistency: a=.87; temporal stability: r=.91).

 

Data Analyses

A series of statistical analyses were performed to compare the emergency department and psychiatric settings samples. Mean differences on continuous variables (questionnaires scores) were assessed with independent t tests or Analysis of Variance (ANOVA) tests. Frequency differences on dichotomous variables (presence of symptoms and diagnoses) were evaluated with chi square analyses. Each analysis was tested with a .05 a-level. While no corrections were systematically conducted to adjust the a-level for multiple statistical tests, differences associated with a P value inferior to .05, .01, and .001 were distinctly reported. More importantly, effect sizes were computed each time a statistical test was associated with a P value <.05 in order to assess the strength of the association. Effect sizes of mean differences on continuous variables were evaluated using Cohen’s d (.2=small; .5=moderate; .8=large). Significant chi square analyses were followed by the calculation of Cramér’s V, a measure of the strength of the association between two categorical variables. A Cramér’s V between .20 and .25 reflects a moderate strength of association, and between .30 and .35, a strong one.

 

Results

The sociodemographic characteristics of the participants in the emergency department and psychiatric settings samples are presented in Table 1. Significant differences were observed between samples regarding age, proportion of women to men, and level of education achieved. The emergency department sample was nearly equally composed of men and women (47.6% women), while the psychiatric settings sample had a greater proportion of women (77.0%). Patients from emergency department were, on average, 10 years older than patients from psychiatric settings (48.73 and 38.60 years old, respectively), and had a slightly higher level of education. To ensure that the age difference was not an artifact due to different selection criteria (18–65 years of age in the psychiatric settings sample versus ≥18 years of age in the emergency department sample), the comparison was repeated with participants >65 years of age (n = 13) removed from the emergency department sample. Participants in the emergency department sample were still significantly older than those from the psychiatric settings sample (44.48 vs. 38.60, respectively; P<.001).

 

Table 2 presents the frequency of DSM-IV panic attack symptoms reported by patients with panic disorder, ie, rated ≥4 on a zero-to-eight scale during the administration of the ADIS-IV, according to sample of origin. Eleven out of 13 symptoms were more frequently reported by psychiatric settings patients than by emergency department patients. Cramér’s V values ranged from .14 (fear of dying) to .50 (fear of losing control or going crazy), indicating effect sizes of moderate to large magnitude for most differences (Table 2). Only paresthesia was evenly encountered in both groups. Although participants from the emergency department sample consulted for chest pain, they may have reported not having it during panic attacks; thus, most (83.1%), but not every, panic disorder patients from the emergency department reported chest pain. On average, psychiatric settings patients reported three more symptoms during panic attacks than emergency department patients (9.21 vs. 6.61; Table 2).

 

Rates of psychiatric comorbidity among both samples are presented in Table 3. Agoraphobia was encountered in 32.1% of emergency department patients. The high prevalence of agoraphobia in the psychiatric settings sample (100%) only reflected the selection criteria used to recruit this sample. Rates of comorbid anxiety disorders were similar in both groups, with the exceptions of specific phobia and posttraumatic stress disorder (PTSD), which were more frequent among emergency department patients. Mood disorders, particularly major depressive disorder (MDD), were also more frequent among emergency department patients than among psychiatric settings patients (Table 3). Comorbid somatoform or substance-related disorders were rarely encountered in either group.

 

Further differences emerged regarding psychological aspects related to panic disorder (Table 4). Emergency department patients had lower ACQ and ASI scores, indicating less severe agoraphobic cognitions and less sensitivity to anxiety. Corresponding effect sizes were large. To ensure that the difference in ACQ scores was not an artefact due to different selection criteria (only participants in the psychiatric settings sample had to suffer from agoraphobia to be included in the study), the comparison was repeated with participants without agoraphobia (n=57) removed from the emergency department sample. Participants remaining in the emergency department sample still reported significantly lower ACQ scores than those from the psychiatric settings sample (2.019 vs. 2.649, respectively; P<.001). Severity of depressive symptomatology and presence of suicidal ideation were similar in both groups. BDI mean scores indicated the presence of mild depressive symptoms in both groups. Between 24.6% and 31.3% of all panic disorder patients reported suicidal ideation.

 

The characteristics of panic disorder patients that could be categorized as having NFPD, ie, that reported no fear of dying or of losing control during panic attacks, are reported in Table 5. The proportion of NFPD patients in the emergency department sample (32.1%) was almost three times that observed in the psychiatric settings sample (11.9%). In order to assess differences between panic disorder and NFPD while partitioning out the variance attributable to the sample of origin (emergency department or psychiatric settings), three 2X2 ANOVAs were performed, on the ACQ score, the ASI scores, and the number of “non-fear” panic symptoms. Independent variables were “type of panic disorder (panic disorder or NFPD)” and “sample of origin (emergency department or psychiatric settings).” NFPD patients had lower ACQ and ASI scores, as well as fewer panic symptoms. Interactions were not statistically significant, except for the ACQ scores. Inspection of the means indicated that the difference between panic disorder and NFPD patients was more important in the psychiatric settings sample than in the emergency department sample.

 

Discussion

The objective of this study was to compare panic disorder patients from emergency department and psychiatric settings on panic symptoms, psychiatric comorbidity, and psychological correlates of panic disorder. Panic disorder patients recruited in the emergency department were older, reported fewer panic symptoms, and had less severe agoraphobic cognitions and less sensitivity to anxiety than their psychiatric settings counterparts. The two samples displayed similar rates of psychiatric comorbidities, with the exceptions of MDD, specific phobia, and PTSD, which were more frequent among patients from the emergency department. Both samples reported alarmingly high rates of suicidal ideation.

Fleet and colleagues5 compared panic disorder patients from the emergency department of a hospital specialized in cardiology to a sample recruited in psychiatric settings, with results that were very similar to those of the present study. This study’s findings were replicated regarding older age, low prevalence of agoraphobia in the emergency department, and the absence of difference in severity of depressive symptomatology and suicidal ideation. Adding to these findings, the authors observed that panic disorder patients from the emergency department reported fewer symptoms during their attacks, and that NFPD was more frequently encountered in the emergency department.

The reasons for the differences between the clinical portrait of panic disorder patients from the emergency department and panic disorder patients from psychiatric settings are not known. Observed differences may reflect the chronicity of panic disorder symptoms. Onset of panic disorder in psychiatric settings patients occurred at least 1 year prior to the study, while symptoms were present for at least the past month for the emergency department sample. Moreover, one of the most frequently cited reasons for consulting an emergency department during a panic attack is that the panic symptoms are part of a first episode, or that a new or more intense symptom has appeared.1 Panic disorder may develop progressively, with few symptoms during earlier panic attacks and increasing symptoms as the panic experience repeats itself over time. First episodes may lead patients to consult the emergency department because they believe their symptoms to be of organic origin. As they receive multiple negative results from medical exams and accumulate a history of impairment due to panic, patients with recurrent and aggravating panic attacks may be more likely to be directed toward mental health care. Early screening of these patients and referral to appropriate treatment could prevent this progression of symptoms. However, the stigma attached to mental illness may prevent emergency department patients from disclosing emotional symptoms, rendering even more difficult for emergency department physicians to recognize the emotional disorder causing chest pain.

The inclusion of NFPD patients may be an additional explanation for the appearance of less severe symptoms of panic disorder in emergency department patients. NFPD patients displayed genuine panic attacks, without reporting fear of dying or fear of going crazy or losing control. They also displayed less severe agoraphobic cognitions and less sensitivity to anxiety. Although these differences were observed in NFPD patients from psychiatric settings as well as from the emergency department, NFPD patients were nearly three times more likely to be encountered in the emergency department than in psychiatric settings. In fact, nearly one out of three (32.1%) panic disorder patients recruited in the emergency department could be categorized as having NFPD.

One implication of these findings is that, as a result of their less severe symptoms, infrequent manifestations of agoraphobia, less reported overall impairment, and a less “psychiatric” presentation, patients with panic disorder in the emergency room may not be adequately screened and offered appropriate therapeutic options. Indeed, recognition of panic disorder by healthcare providers has been associated with severity of fear experienced during the worse panic attack and overall symptom severity during the panic attack that led to consultation.19 Failure to recognize panic among chest pain patients is associated with serious consequences in terms of phobic avoidance, quality of life, and healthcare utilization.20-22 The current results have indicated that these patients suffer from significant depressive comorbidity, to an even greater degree than psychiatric patients, and that they present an elevated level of depressive symptomatology and suicidal ideation, replicating findings observed in their counterparts from psychiatric settings.21-23 In light of these data, it is essential that panic disorder be adequately identified and addressed and not merely considered as a residual category for noncardiac chest pain of unknown origin.

These findings are to be interpreted with caution as the study includes some methodologic limitations. First, due to the different settings, the selection criteria across both samples were not exactly the same. However, the authors performed statistical analyses on selected subsamples aiming to reduce the likeliness of rival explanations. Another limitation is that the emergency department sample did not include panic disorder patients that did not consult for chest pain (eg, patients consulting for hyperventilation, palpitations). As such, the observed differences may generalize only to panic disorder patients consulting the emergency department for chest pain. However, it has been observed that 91% of panic disorder patients presenting at an emergency department consult initially for chest pain.1 Finally, panic disorder patients without agoraphobia were not originally included in the psychiatric settings sample. This certainly explains the difference in prevalence of agoraphobia between the two samples (100% in psychiatric settings and 32.1% in emergency department). These figures do not reflect the true prevalence of agoraphobia among panic disorder patients in psychiatric settings. However, the fact that <33% of patients with panic disorder recruited in the emergency department reported agoraphobia is noteworthy.

 

Conclusion

This study added to earlier findings in demonstrating that panic disorder encountered in the emergency department presents different clinical characteristics than panic disorder seen in psychiatric settings. Despite reporting fewer and less severe symptoms than their counterparts from psychiatric settings, panic disorder patients consulting the emergency department for noncardiac chest pain presented a wide array of distressing symptoms and psychiatric comorbidities that warrant clinical attention, including suicidal ideation. There is a need for valid and “user-friendly” instruments to help emergency department physicians and nurses, who are not extensively familiar with psychiatric nosologies and subtle diagnostic particularities, to rapidly and efficiently identify panic disorder. Panic disorder is a treatable disorder; the efficacy and efficiency of interventions for panic disorder, whether cognitive-behavioral,24 pharmacologic,25 or a combination of both strategies,26 have been extensively demonstrated. Panic disorder patients could benefit from more sensitive panic disorder detection capacities in the emergency department, as well as a stronger bridge between emergency department healthcare providers and the mental health professionals that possess the therapeutic tools to help panic disorder patients.  PP

 

References

1.    Katerndahl DA. Factors associated with persons with panic attacks seeking medical care. Fam Med. 1990;22(6):462-466.
2.    Fleet RP, Dupuis G, Marchand A, Burelle D, Arsenault A, Beitman BD. Panic disorder in emergency department chest pain patients: prevalence, comorbidity, suicidal ideation, and physician recognition. Am J Med. 1996;101(4):371-380.
3.    Srinivasan K, Joseph W. A study of lifetime prevalence of anxiety and depressive disorders in patients presenting with chest pain to emergency medicine. Gen Hosp Psychiatry. 2004;26(6):470-474.
4.    Wulsin L, Liu T, Storrow A, Evans S, Dewan N, Hamilton C. A randomized, controlled trial of panic disorder treatment initiation in an emergency department chest pain center. Ann Emerg Med. 2002;39(2):139-143.
5.    Fleet RP, Marchand A, Dupuis G, Kaczorowski J, Beitman BD. Comparing emergency department and psychiatric setting patients with panic disorder. Psychosomatics. 1998;39(6):512-518.
6.    Austin D, Blashki G, Barton D, Klein B. Managing panic disorder in general practice. Aust Fam Physician. 2005;34(7):563-571.
7.    Beitman BD, Basha I, Flaker G, DeRosear L, Mukerji V, Lamberti J. Non-fearful panic disorder: panic attacks without fear. Behav Res Ther. 1987;25(6):487-492.
8.    Fleet RP, Martel JP, Lavoie KL, Dupuis G, Beitman BD. Non-fearful panic disorder: a variant of panic in medical patients? Psychosomatics. 2000;41(4):311-320.
9.    Chen J, Tsuchiya M, Kawakami N, Furukawa TA. Non-fearful vs. fearful panic attacks: a general population study from the National Comorbidity Survey. J Affect Disord. 2009;112(1-3):273-278.
10.    Diagnostic and Statistical Manual of Mental Disorders. 4th ed, text rev. Washington, DC: American Psychiatric Association; 2000.
11.    DiNardo PA, Brown TA, Barlow DH. Anxiety Disorders Interview Schedule for DSM-IV (ADIS-IV): Lifetime Version (ADIS-IV-L). San Antonio, TX: Psychological Corporation; 1994.
12.    Shear MK, Maser JD. Standardized assessment for panic disorder research. A conference report. Arch Gen Psychiatry. 1994;51(5):346-354.
13.    Mavissakalian M, Michelson L, Greenwald D, Kornblith S, Greenwald M. Cognitive-behavioral treatment of agoraphobia: paradoxical intention vs self-statement training. Behav Res Ther. 1983;21(1):75-86.
14.    Beck AT, Steer RA, Ball R, Ranieri W. Comparison of Beck Depression Inventories -IA and -II in psychiatric outpatients. J Pers Assess. 1996;67(3):588-597.
15.    Gauthier J, Morin C, Thériault F, Lawson JS. French adaptation of a self-administered measure of depression severity [French]. Revue Québécoise de Psychologie. 1982;3:13-27.
16.    Chambless DL, Caputo GC, Bright P, Gallagher R. Assessment of fear of fear in agoraphobics: the body sensations questionnaire and the agoraphobic cognitions questionnaire. J Consult Clin Psychol. 1984;52(6):1090-1097.
17.    Stephenson R, Marchand A, Lavallée MC. French-Canadian adaptation of the Agoraphobic Cognitions Questionnaire: cross-cultural validation and gender differences. Scandinavian Journal of Behaviour Therapy. 1999;28(2):58-69.
18.    Reiss S, Peterson RA, Gursky DM, McNally RJ. Anxiety sensitivity, anxiety frequency and the prediction of fearfulness. Behav Res Ther. 1986;24(1):1-8.
19.    Katerndahl DA. Predictors and outcomes in people told that they have panic attacks. Depress Anxiety. 2003;17(2):98-100.
20.    Katerndahl DA. Panic plaques: panic disorder & coronary artery disease in patients with chest pain. J Am Board Fam Pract. 2004;17(2):114-126.
21.    Roy-Byrne PP, Stein MB, Russo J, et al. Panic disorder in the primary care setting: comorbidity, disability, service utilization, and treatment. J Clin Psychiatry. 1999;60(7):492-500.
22.    Markowitz JS, Weissman MM, Ouellette R, Lish JD, Klerman GL. Quality of life in panic disorder. Arch Gen Psychiatry. 1989;46(11):984-992.
23.    Weissman MM, Klerman GL, Markowitz JS, Ouellette R. Suicidal ideation and suicide attempts in panic disorder and attacks. N Engl J Med. 1989;321(18):1209-1214.
24.    Otto MW, Deveney C. Cognitive-behavioral therapy and the treatment of panic disorder: efficacy and strategies. J Clin Psychiatry. 2005;66(suppl 4):28-32.
25.    Pollack MH, Doyle AC. Treatment of panic disorder: focus on paroxetine. Psychopharmacol Bull. 2003;37(suppl 1):53-63.
26.    Furukawa TA, Watanabe N, Churchill R. Combined psychotherapy plus antidepressants for panic disorder with or without agoraphobia. Cochrane Database Syst Rev. 2007(1):CD004364.

 

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.


 

Abstract

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.

 

Introduction

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.

 

Insomnia

Antidepressants

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

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.

 

Quetiapine

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.”

 

Anxiety

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.

 

GAD

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

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.

 

Conclusion

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

 

References

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.

 

This interview took place on November 30, 2009 and was conducted by Norman Sussman, MD.

 

Dr. Weintraub is Associate Professor of Psychiatry and Fellow at the Institute of Aging at the University of Pennsylvania in Philadelphia. His areas of research interest include the psychiatric and cognitive complications of Parkinson’s disease. Dr. Weintraub recently completed a 5-year Career Development Award from the National Institute of Mental Health titled “Depression Diagnosis and Treatment in Parkinson Disease.” In addition, he was coordinating investigator for a multi-site, international, industry-sponsored study of the frequency and correlates of impulse control disorders in Parkinson’s disease.

 

What is Parkinson’s Disease and Why Does Dementia with Lewy Bodies (DLB) Tend to get Clustered in with it in Discussions?

Parkinson’s disease is defined by its motor characteristics, whereas DLB is defined primarily by its cognitive and other non-motor deficits.

To meet criteria for idiopathic Parkinson’s disease, a person must have primary motor symptoms, the most common ones being tremor (upper extremity tremor in particular, usually asymmetric at the time of disease onset); bradykinesia, or slowness of movement; stiffness; and, at times, impairments in balance, although that tends to happen later in the course of the illness. Some combination of those types of motor symptoms is what helps patients meet criteria for Parkinson’s disease, often supported by a response to dopamine-replacement therapy.

In contrast, DLB is characterized at disease onset by a dementing illness consisting of impairment in memory and other cognitive abilities. Supporting features include psychotic symptoms, particularly visual hallucinations. Impairments in attention or fluctuations in alertness are also characteristic. Parkinsonism—some of the same features that I mentioned before—is also characteristic of DLB, although the response to dopamine-replacement therapy is typically less in DLB than in Parkinson’s disease.

 

Would it be confusing for a non-neurologist to distinguish between one or the other?

There is the potential for confusion. One main reason is that a fair number of Parkinson’s disease patients, even at the time of illness onset or diagnosis of motor symptoms, are already demonstrating some level of cognitive impairment.

The two can go hand in hand fairly early in the course of either illness, and therefore there is sometimes a blurring between diagnostic categories. Expert opinion is that if there is an established diagnosis of Parkinson’s disease and at least 1 year has gone by before the patient meets criteria for dementia, then the diagnosis is Parkinson’s disease dementia. If that dementia diagnosis either predates the onset of the motor symptoms or comes within the first year of the parkinsonism, then the patient would meet criteria for DLB.

The reason there seems to be so much overlap is that from a neuropathologic standpoint, the illnesses are very similar. The core neuropathology and even the brain regions that are affected appear to significantly overlap between Parkinson’s disease, Parkinson’s disease dementia, and DLB.

 

Compared to a decade ago, is there better understanding of the pathophysiology of Parkinson’s disease and DLB?

There has been some evolution in terms of understanding. One change to highlight over the past 10 years is that the neurotransmitter deficits really are beyond dopamine in Parkinson’s disease. The noradrenergic deficits are probably as significant or close to as significant as the dopaminergic deficits. In addition, serotonergic deficits can be prominent in the illness. However, it appears that all of the brain stem monoamines are affected to some degree in Parkinson’s disease, so it really is more than just a dopamine disorder.

Another prominent neurotransmitter deficit is in acetylcholine. The cholinergic deficits in Parkinson’s disease dementia are greater than in Alzheimer’s disease. Even non-demented Parkinson’s disease patients have significant cholinergic loss, so that probably helps explain the high frequency of cognitive impairments in Parkinson’s disease.

 

Have Anticholinergics been used to treat Parkinson’s Disease?

Yes, and they still are, though less commonly now. They have to be used cautiously in patients who are more likely to suffer the side effects of anticholinergics, which would include older patients or patients with preexisting cognitive impairment. Younger patients who are more intact cognitively still receive those treatments.

 

How Common are Parkinson’s Disease and DLB?

The primary risk factor for Parkinson’s disease and DLB is increasing age. Accurate prevalence and incidence estimates for Parkinson’s disease are hard to come by. The general estimate of Parkinson’s disease in the United States is anywhere between 500,000 and 1 million people. In Western societies, it is the second most common neurodegenerative disease after Alzheimer’s disease.
 

Looking at only the dementia end, DLB is thought to be the second most common dementing illness after Alzheimer’s disease. Part of the problems with the prevalence estimates are the overlapping diagnoses of DLB and Parkinson’s disease, so it is sometimes difficult to disentangle those two groups. Still, those are the general prevalence estimates. Increasing age is the main risk factor; however, compared with Alzheimer’s disease, it is not as uncommon for patients in their thirties, forties, or even fifties, to develop Parkinson’s disease, much more common relatively than in Alzheimer’s disease.

 

When people lose 80% of their neurons they get clinical manifestations of Parkinson’s Disease. Does everybody as they get older lose these neurons? Is it only a matter of time?

Parkinson’s disease is a disorder of aging. It is unclear if the incidence of Parkinson’s disease will peak at a certain age or whether it just continues to go up. All evidence to this point is that it continues to go up with advanced age. A person needs to lose ~80% of the neurons in the substantia nigra before clinically manifesting the motor symptoms of Parkinson’s disease. Another advancement in the past decade has been the work of Professor Heiko Braak and other neuropathologists that have not only staged Alzheimer’s disease, but also showed a staging process for Parkinson’s disease. Clearly, the brain stem changes in the majority of patients occur even before 80% of those neurons are lost in the substantia nigra, which helps explain some of the pre-motor symptoms that can occur. Beyond the substantia nigra in the later stages of the illness, the pathology spreads to cortical areas; by then it really becomes very much a diffuse brain disease.

 

Are there certain non-motor cognitive or psychiatric symptoms in Parkinson’s disease that will present before any movement disturbance is detected?

Yes, there has been significant research conducted in that area in the past decade, both from large European databases where patients are followed prospectively from young adulthood annually, as well as from case-controlled studies. There is now convincing evidence that patients with Parkinson’s disease compared to non-Parkinson patients are more likely to have a lifetime history of either depression or an anxiety disorder in the 5–10-year period, and perhaps even up to 20 years for anxiety, preceding the onset of Parkinson’s disease.
 

Another common psychiatric or non-motor disorder reported to occur prior to Parkinson’s onset is rapid eye movement behavior disorder, which is a parasomnia where patients are able to verbally or physically act out their dreams. This has been reported to occur up to 20 years prior to the onset of Parkinson’s disease. When most of us dream we are in an atonic state; we cannot physically or verbally act out our dreams. This atonia seems to be lost in a fair percentage of Parkinson’s patients, and apparently may be lost prior to the onset of Parkinson’s disease, which is thought to represent a brain stem dysfunction.
 

Other non-motor symptoms that have been reported to occur prior to Parkinson’s disease include impaired smell or olfaction, which is very common in Parkinson’s disease; constipation; and altered sympathetic intervention of the heart. All are testable.
 

What are some of the cognitive symptoms you observe in patients with Parkinson’s disease?

It was taught in the past that Parkinson’s disease patients compared with Alzheimer’s disease patients are less likely to have memory or language deficits and more likely to have deficits in other domains. For patients that have memory deficits, it is less likely to be an encoding deficit, as seen with Alzheimer’s disease, but more of a retrieval deficit, which was thought to reflect more subcortical dysfunction.
 

However, accumulating research has found that Parkinson’s disease patients can have impairments in a range of cognitive domains, including memory, attention, executive abilities, and visual-spatial abilities. This has been one major shift in the perception of the disease.
 

The other major shift is the recognition that, whereas cross-sectional studies have demonstrated that ~30% of Parkinson’s disease patients have dementia, more careful longitudinal studies1,2 have shown that the overwhelming majority of patients with Parkinson’s disease do develop dementia if followed long enough. Early stages of these deficits can be detectable often at the time of diagnosis in 20% of patients. If the clinician asks the right questions and uses appropriate assessment instruments, the disease can be detected early.

 

What kind of visual-spatial disturbances are involved?

A common example would be the judgment of line orientation tests, which is the ability to conceptualize lines in three dimensions, so to speak. However, it can be detectable even at a much simpler level, just with pentagon or clock drawing. Another difficulty for Parkinson’s patients is drawing a cube. The disease can be detected even on simple paper-and-pencil tests.
 

Are some subtle dysfunctions picked up early and more inevitable ones later on?

Yes. Heterogeneity is the one word that I use more than any to describe all the motor and non-motor features of Parkinson’s disease. There is such a range of presentations of Parkinson’s in patients from both a non-motor and a motor standpoint. This is one area where I think our research has failed us to some extent, in that most studies will present means and averages for patients on a particular score or domain; however, the individual presentation of patients is really lost that way. The means really mean less in Parkinson’s disease than how individual patients present.
 

Some patients do have cognitive deficits early on, and others do not for 15 years. Somebody may have a primary memory deficit, while another may have impairment in multiple domains. Presentations are all over the board.
 

Do treatments for psychiatric symptoms and Parkinson’s disease adversely affect each other?

This is a very controversial and complex area. Early in the course of Parkinson’s disease, a de novo case, for example, who has not been treated ever, often would respond with exposure to dopamine-replacement therapies, whether it is levodopa or dopamine agonists. For instance, some patients show improvements in psychomotor speed, attention, and concentration. However, the results are mixed, with some patients or cognitive abilities improving, and others worsening.  Thus, it is difficult to offer a generalization in this regard.
 

As patients advance in the course of their illness, where they age and the pathology becomes more severe, it seems more likely that the medications, if anything, are not beneficial to cognition. Rather, they may be potentially harmful, particularly with higher dosages when patients can become delirious or psychotic, which certainly has an effect on the cognition, as well.
 

Deep brain stimulation (DBS), which is increasingly used as a treatment for Parkinson’s disease, is thought to perhaps impair verbal fluency and some aspects of memory. That may be a complicating effect of that specific treatment. The anticholinergics and amantadine are probably the most notorious medications in terms of worsening cognition.
 

In terms of psychiatric medications, in general the newer antidepressants are thought to be safe and well tolerated from both a motor and cognitive standpoint. Recent studies show benefit for tricyclic antidepressants in Parkinson’s disease.3,4 One concern there, of course, is that with a heavier anticholinergic load, cognition could potentially worsen.
 

It is unclear from a cognitive standpoint whether antipsychotics have deleterious effects on Parkinson’s disease, but certainly there is concern about them worsening motor symptoms in Parkinson’s patients.
 

Finally, the last class of psychiatric medications commonly used is benzodiazepines. These medications must be used very cautiously in Parkinson’s disease patients because common side effects include impaired gait, sedation, and worsening cognition.
 

Are any therapies currently available for Alzheimer’s disease effective in improving cognitive symptoms in patients with Parkinson’s disease and DLB?

The cholinesterase inhibitor rivastigmine actually has Food and Drug Administration approval for the treatment of Parkinson’s disease dementia. This was on the basis of one large European study5 that showed significant, but modest, benefits in the treatment of Parkinson’s disease dementia, similar to what would be present in Alzheimer’s disease patients. A more recent placebo-controlled study6 in patients with both Parkinson’s disease dementia and DLB showed benefit for memantine. Those are really the two large-scale studies that have been positive to date for the treatment of cognitive dysfunction in Parkinson’s disease.
 

Another common non-motor disturbance in Parkinson’s disease is apathy, often in the context of cognitive impairment, but not always. We really do not have good treatments for apathy in the context of any other disorder. We extrapolate what people use in other populations, including the use of stimulants. Clinicians, myself included, may use methylphenidate and dextroamphetamine as a trial for apathy in particular. Bupropion is also used to some extent because of its stimulant-like properties, the reason being that it has some dopamine-enhancing effects, as well.
 

Have there been any meaningful advances in the treatment of the motor symptoms of these disorders in recent years?

The one class that was not available 10 years ago that is readily available now and used as a first-line agent in younger patients particularly are the dopamine agonists. The ones being used now are more selective and better tolerated overall than the older ones. This class of medication has been added to the armamentarium, in addition to levodopa, although levodopa still is the most potent in terms of its motor effects.
 

DBS has been a significant advancement, particularly for patients with more advanced disease, because those patients really had no option previously. Once they developed dyskinesias and other motor fluctuations, they were really at a dead end in terms of treatment. This often can be a successful treatment for patients that enables them to make a significant decrease in their dopamine-replacement therapy. Other fine tuning has been the increased use of catechol-O-methyl transferase inhibitors, that do allow a better management of motor fluctuations in off periods.
 

That being said, I think treatment has not advanced so significantly. I do think patients are better managed overall. Clinicians are able to go deeper into the course of their illness without significant complications compared with previously.

 

Does using these other, more indirect interventions delay some of the secondary complications of taking levodopa, such as the dyskinesias?

Yes. A preferred medication choice in this day and age would be to start with a dopamine agonist, or even for milder symptomatic benefit something like an monoamine oxidase-B inhibitor early in the course of the illness, and to delay the introduction of levodopa as long as possible.

 

Is there anything you would like to add?

One other interesting area for psychiatrists that has come to the forefront recently—and we have been involved in a fair amount of research with this—is impulse control disorders in response to dopamine agonist treatment. Parkinson’s patients can develop compulsive behaviors (the four that have been reported have been gambling, sexual behavior, buying, and eating) in connection with their Parkinson’s treatment. It is quite a problematic disorder, but also an interesting one from a psychiatric standpoint in that the disorder can be essentially induced by these dopaminergic medications. PP

 

References

1.    Aarsland D, Andersen K, Larsen JP, Lolk A, Kragh-Sørensen P. Prevalence and characteristics of dementia in Parkinson disease: an 8-year prospective study. Arch Neurol. 2003;60(3):387-392.
2.    Hely MA, Reid WG, Adena MA, Halliday GM, Morris JG. The Sydney multicenter study of Parkinson’s disease: The inevitability of dementia at 20 years. Mov Disord. 2008;23(6):837-844.
3.    Menza M, Dobkin RD, Marin H, et al. A controlled trial of antidepressants in patients with Parkinson’s disease and depression. Neurology. 2009;72(10):886-892.
4.    Devos D, Dujardin K, Poirot I, et al. Comparison of desipramine and citalopram treatments for depression in Parkinson’s disease: a double-blind, randomized, placebo-controlled study. Mov Disord. 2008;23(6):850-857.
5.    Emre M, Aarsland D, Albanese A, et al. Rivastigmine for dementia associated with Parkinson’s disease. N Engl J Med. 2004;351(24):2509-2518.
6.    Aarsland D, Ballard C, Walker Z, et al. Memantine in patients with Parkinson’s disease dementia or dementia with Lewy bodies: a double-blind, placebo-controlled, multicentre trial. Lancet Neurol. 2009;8(7):613-618.