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.

 

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

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


 

Abstract

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


Focus Points

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

 

Introduction

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

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

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

 

Method

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

 

Results

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

 

Discussion

Tamoxifen Clinical Response

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

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

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

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

 

Warfarin Clinical Management

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

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

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

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

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

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

 

Opioid Pain Management

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

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

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

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

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

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

 

Conclusion

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

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

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

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

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

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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.

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

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

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

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

 

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

 

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

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

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

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

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

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

 

Sudden Infant Death Syndrome Linked to Lower Levels of Serotonin

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

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

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

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

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

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


 

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

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

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

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

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


 

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

 

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

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

Email questions or comments to ns@mblcommunications.com


 

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

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

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

 

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

 

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

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

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

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

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

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

 

References

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

 

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

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

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


 

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

 

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.