Dr. Luo is associate clinical professor in the Department of Psychiatry and Biobehavioral Sciences at the University of California in Los Angeles; past president of the American Association for Technology in Psychiatry (AATP) in New York City; and Gores Informatics Advocacy chair at the AATP.

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

 


 

Consumers have help choosing products such as cars, dish washers, and stereos by reading newspaper and magazine reviews. Movie and book critics help consumers determine whether their time and money would be better spent before committing to potential hours of entertainment and intellectual stimulation. The Internet has changed the landscape of consumer information and decision making with direct feedback made available by many consumers online, creating knowledge of the masses versus depending on expert reviewers in traditional media. Amazon1 and Epinions2 have capitalized on this growing desire for direct consumer experience, with a greater need for “caveat emptor” regarding the relevancy of such information. Angie’s list3 has furthered this trend by creating a consumer community to evaluate and rate home improvement contractors, and RateMyProfessors4 has created buzz rating college class professors on difficulty and popularity. It is not surprising that physicians are also a rated “service’’ in the Internet age of Web 2.0.

 

Background

For many consumers, navigating the healthcare landscape has changed. The days of the traditional paternalistic care model where patients followed doctor’s advice without much questioning are practically gone. Many forces have led to this shift in healthcare behavior including increased consumer consumption of medical literature, shared consumer experiences found on patient support forums groups on the Internet, various online health information resources, and an increasing trend toward consumer empowerment and advocacy.

Patients and family members scour the Internet to find information on various symptoms and even diseases well before they see a physician. Numerous Websites even offer online screening tools for people to determine if they have a given condition such as depression and whether it is severe enough to warrant treatment. Once they have established a need to find a physician, the question becomes which physician to choose out of many.

 

Finding a Doctor

Traditionally, word of mouth was sufficient to find a doctor, such as by asking friends, relatives, and co-workers. However, if a specialist is needed, patients may be routed via several mechanisms. Many insurance plans use a primary care physician (PCP) as a gatekeeper to limit access to specialty care, while some plans allow patients to be self-referred. In the gatekeeper model, the referral is highly dependent on the PCP’s network of physician colleagues. Established physicians who have been practicing for a long time in a particular location develop these relationships geographically via medical school, residency training, working in the same building, utilizing the same hospital, medical society meetings, and even dinner events provided by the pharmaceutical industry. As health care becomes increasingly specialized, physicians may refer out on a national scale, utilizing national rankings of hospitals such as in US News and World Report5 and via professional networking.6

For the patients who directly choose a physician without a referral, who to choose may not be clear. In checking on the Internet for their health plan, there may be numerous physicians in various specialities listed. Proximity may be one reason to choose a physician, but many patients are willing to travel longer distances for an earlier appointment. Some patients will check the background of a physician on the Internet, looking at where they graduated and trained; however, these aspects are often less important in comparison to physician availability. A few motivated patients may search the medical literature and see if those physicians are available to them in their city.

There are many Websites that can help patients find a doctor, but often their list is incomplete and outdated. The American Medical Association (AMA) Doctor Finder7 tends to be the most accurate in terms of finding a physician and his or her most recent practice location. However, the AMA Doctor Finder lists AMA members first, and does not relay any information such as board certification or subspecialty. Other sites such as Locate A Doc8 and Web MD Physician Directory9 are examples of sites that list physicians by zip code or city. In addition, Web MD Physician Directory offers information on which insurance plans the physicians accept as well as the opportunity to request an appointment by filling out a form that is faxed to the doctor’s office.

 

Tips for Selecting a Physician

Savvy patients prefer to go on the Internet to find information about a physician to decide if that doctor is right for them. The Agency for Healthcare Research and Quality10 (AHRQ) has tips for consumers on how to choose a doctor. Among the quality measures are factors such as is the physician rated to give quality care, does the physician have the training and background to meet patient needs, is the physician willing to takes steps to prevent illness, does the physician have privileges at the hospital of choice, is the physician part of patient health plan, does the physician encourage patients to ask questions, does the physician listen to patients, does the physician explain things clearly, and does the physician treat patients with respect. The AHRQ also recommends that patients call to speak to the doctor and audit their manner.

 

Physician Rating Sites

Wellpoint generated much attention when it was announced that they would partner with Zagat to provide members of the health benefit company with physician reviews.11 Physicians would be rated on four domains including trust, communication, availability, and environment based on the Zagat 30-point scale. Members can benefit from sharing their notes on doctor visits and rank the usefulness of comments. This system is closed to Wellpoint members, making its usefulness limited.

RateMDs12 was established by the creator of RateMyProfessors,4 and it is open for all patients to comment on their doctor visits. Physicians are rated on staff, punctuality, helpfulness, and knowledge on a 5-star rating system. This Website depends on user-generated content, so it is no surprise that many physicians are not listed. They do not have a national database of physicians to validate whether that physician even exists or has a valid license. There is a link to the state medical board so that patients can check on any disciplinary action. The site publishes almost all comments, but does delete those that do not comment on professional ability. It logs the IP address and account of the posting so that multiple postings are not entered. This methodology was how the site owner caught one physician attempting to manipulate her ratings. Physicians are welcome to respond to ratings but must create an account.

DoctorsScorecard13 is another site for patients to rate their physicians; however, it has a different approach. It is a non-profit site that does not have ads compared to RateMDs, and its revenue comes from private donations. Each scorecard is reviewed to rule out spam, offensive language, or fake submissions. Patients can submit information anonymously and without an E-mail account. However, if they do enter their E-mail address, they can get messages when someone responds to their comments. As with RateMDs,12 physicians can respond to comments and patients can later retract or modify their comments as well. In addition, this site allows users to upload pictures and videos related to the physician.

Vimo14 is yet another Website to help consumers find physicians; however, its primary mission is to facilitate health insurance purchase. Consumers rate physicians on knowledge and skill, availability, punctuality, personal skills, and office staff. In contrast to the above sites, Vimo has a database of physicians compiled from public and private sources that includes years of practice, educational background, license information, and current practice location.

Careseek15 and its partner site NursesRecommendDoctors16 both utilize the same rating system. Physicians are rated on communication and rapport, competence and experience, responsiveness and efficiency, whether patients are likely to recommend them to others, and how well they treat staff with care and respect. These sites offer a key difference to other rating sites in that patients, caregivers, staff, and nurses can offer their rating and opinion. In addition, users with accounts can blog about their healthcare experiences and connect to one another to create a support network. Physicians can create an account to write comments on their reviews, but also to update their profile to include information such as areas of expertise, life accomplishments, languages spoken, hobbies, and care philosophy. Privacy settings limit who is able to see what information, such as reviews, hobbies, and so forth.

FindADoc17 takes a slightly different approach in that it offers a numerical rating based on various sources of information. Findadoc’s proprietary rating system strives to provide a fair and credible resource to patients and doctors by combining factual data with patient opinions. A doctor’s training, expertise, and patient care are taken into account to arrive at an overall numerical score out of a possible 100 points. Training (35 points) is based on medical school, residency, fellowship, and advanced training such as electroconvulsive therapy. Expertise (55 points) is based on hospital affiliation, doctor endorsements, and years of experience. Patient opinion (20 points) is based on ratings of office staff, office setting, wait time, medical knowledge, bedside manner, patient confidence, and patient satisfaction. Physicians can create an account to edit their profile, recommend other physicians, and ask other physicians to rate them in return. FindAdoc also has featured physicians who pay a subscription fee to be viewed by patients and physicians in their searches.

RemarkableDocs18 and NursesRecommendDoctors16 differ from other physician review Websites in that both sites do not accept negative reviews. They believe that negative reviews create a hostile environment, which is not in their philosophy. At NursesRecommendDoctors, nurses provide constructive criticism, which is more acceptable in that it avoids controversy and encourages the physician to make improvements that will ultimately benefit both physician and consumer. RemarkableDocs reviews all submissions to ensure that they fit their criteria with the ultimate goal of helping other patients find the right doctor.

RevolutionHealth19 and MDJunction20 are patient-focused Websites that offer support groups, tools, blogs, and health information but offer physicians reviews as a member benefit. BookOfDoctors21 also has physician ratings, but it is more of a doctor listing service that facilitates placement in search engines.

 

Other Selection Measures

To check on physician quality by examining if they have had license sanctions, suspensions, or lawsuits, several Websites make such information available to the consumer. Healthgrades22 provides information compiled from several federal-, state-, and physician-level data sources, including the lawsuits. For $29.95, their report includes information about any professional misconduct, specialty, area hospital rating, education, training, board certification, office location, and contact information. An additional report on a search of malpractice settlements in California, Connecticut, Florida, Idaho, Indiana, Maryland, Massachusetts, New Jersey, New York, North Dakota, Oregon, Tennessee, Vermont, Virginia, or West Virginia is available for $8.95. For $9.95, the Federation of State Medical Boards also provides a physician report on disciplinary sanctions, education, medical specialty, licensure history, and locations via its physician profile and disciplinary report site, DocInfo.23 Many state licensing boards such as California’s provide any physician disciplinary information to the public for free, but DocInfo will provide information on that physician from other states, the Drug Enforcement Agency, and other international licensing authorities. The Administrators in Medicine DocFinder,24 a free service, combines the search of many different state medical boards that are willing to share data with this site; however, >40 different state agencies do not.

Much of demographic information is available at different Websites so it is unlikely that patients check Healthgrades22 until they have a complaint or potential lawsuit. PhysicianReports25 is a partner site to Healthgrades in that it provides patient ratings based on ease of scheduling, office environment, friendliness of staff, wait time, and more in-depth aspects of the visit such as does the physician spend sufficient time with the patient, does the physician listen and answer questions, does the physician help explain the medical condition, do patients trust the recommendations and decisions made in the patient’s best interest, and would patients recommend the physician to family and friends. PhysicianReports also compiles demographic information on the patient such as insurance, age, ethnicity, marital status, education, and household income, which may be matched to physician ratings.

The American Board of Medical Specialities (ABMS)26 offers free physician board certification information to the public once an account on their Website has been created. Reports provided by this service are not accepted by The Joint Commission, National Committee for Quality Assurance, or Utilization Review Accreditation Commission to verify physician credentials because no dates are supplied and recent board certifications require re-certification. CertiFACTS Online27 also offers online information of board certification as a display agent of the ABMS, but it is geared toward institutions and agencies with access to the entire physician database and dates of certification on a yearly subscription basis.

 

Discussion

It is noteworthy that although many of these Websites exist, the majority of physician ratings has yet to reach critical mass in terms of numerous reviews. In a comparison of the various sites, RateMDs has one physician who was rated 97 times, but the vast majority are still in single digits. Other sites which form a national database often have no reviews for many physicians. One reason is that the Web 2.0 trend of user-generated content is still in its early stages, and patients are still relying on traditional methods to find a doctor. No one physician rating site appears to have the lead on the Internet, and each site has such different elements that make it difficult to create a physician-patient review meta-analysis.

With regard to the specific physician reviews sampled, many appear to be on the extreme end, ie, being either positive or negative. It seems that the extremely satisfied patient and the disgruntled patient are the ones who find time to comment online. The patient whose experience was average appears to not have a need to either vent frustrations or advocate on the physician’s behalf. In particular with mental health patients, it may be that transference and counter-transference have a significant impact on the patient experience. Physicians also must contend with how patients with mental illness may not be the most reliable or stable enough to comment in a constructive manner.

Socioeconomics also plays a role in that disadvantaged patients may not have sufficient access to the Internet, and they may have less education and technical savvy to utilize these health resources.

It is still quite early to determine whether patients will shift their online health behavior toward increasing dependence on other patient reviews of satisfaction and physician quality research. However, increasing demand on physicians to decrease medical errors with electronic prescribing and physician order entry as well as to fulfill certain screening requirements in pay for performance measures are part of the quality picture for the future.

 

Methods for Improvement

One immediate method to improve patient satisfaction is to offer online scheduling to improve access and wait time reviews. Xoova28 is a free service that helps patients find a physician using a search of its compiled national database. Physicians can create a profile that has basic information such as training, care philosophy, and hospital affiliation. On the physician page, Xoova creates a Google map rendering of the office location. The secure online scheduling feature has yet to be enabled but will provide the physician the ability to create several types of appointments in a schedule template.

DrScore29 is a service that in addition to providing patient physician ratings, creates a mechanism for physicians to monitor their practice in patient satisfaction and compare themselves to their peers. Ratings are conducted on the doctor, exam, staff, timeliness, and time to appointment. The yearly subscription service for $199 provides a desk placard to direct patients to the Internet review site, 500 cards for staff to hand out to patients, and four reports every 3 months.

Mystery shopping is another method to research and improve the quality of the patient experience. ExamineYourPractice30 and Devon Hill Associates31 are examples of healthcare mystery shopping evaluation services. They can evaluate the complete patient visit, walk-in visits, and telephone experiences. These assessments will improve the care and treatment of patients by determining why the practice is losing business, evaluating the staff on predetermined parameters, and identifying needs for diversity training. Even large hospital systems utilize these services to improve patient care.

 

Conclusion

Despite the ever-growing amount of information on the Internet, it continues to be the new and perhaps soon-to-be primary way that consumers find and share information as well as make decisions, be it which car to buy or which psychiatrist best fits their needs. The controversy of patient-generated physician ratings is not that it epitomizes the lower social stature of physicians, but that this information will be available to new and future patients in making current and future health-related decisions, such as deciding to comply with recommendations or staying with a new physician. The healthcare landscape in the Internet age requires physicians to adapt to the collaborate decision model which has been empowered by information. PP

 

References

1. Amazon. Available at: www.amazon.com. Accessed November 1, 2007.
2. Epinions. Available at: www.epinions.com. Accessed November 1, 2007.
3. Angie’s List. Available at: www.angieslist.com/AngiesList. Accessed November 1, 2007.
4. Rate My Professors. Available at: www.ratemyprofessors.com/index.jsp. Accessed November 1, 2007.
5. US News and World Report. America’s Best Hospitals 2007. Available at: http://health.usnews.com/sections/health/best-hospitals. Accessed November 2, 2007.
6. Luo J. Social networking: now professionally ready. Primary Psychiatry. 2007;14(2):21-24.
7. Doctor Finder. Available at: http://webapps.ama-assn.org/doctorfinder/home.html. Accessed November 3, 2007.
8. Locate A Doc. Available at: www.locateadoc.com. Accessed November 3, 2007.
9. WebMD Physician Directory. Available at: http://doctor.webmd.com. Accessed November 3, 2007.
10. Choosing a Doctor. Available at: www.ahrq.gov/consumer/qntascii/qntdr.htm. Accessed November 4, 2007.
11. WellPoint Taps Zagat Survey to Help Consumers Rate Experiences with Their Doctors. Available at: http://phx.corporate-ir.net/phoenix.zhtml?c=130104&p=irol-newsArticle_general&t=Regular&id=1065430&. Accessed Novmeber 5, 2007.
12. RateMDs. Available at: www.ratemds.com. Accessed November 5, 2007.
13. DoctorScorecard. Available at: www.doctorscorecard.com. Accessed November 5, 2007.
14. Vimo. Available at: www.vimo.com. Accessed November 5, 2007.
15. Careseek. Available at: www.careseek.com. Accessed November 5, 2007.
16. NursesRateDoctors. Available at: www.nursesratedoctors.com. Accessed November 5, 2007.
17. FindADoc. Available at: www.findadoc.com. Accessed November 6, 2007.
18. RemarkableDocs. Available at: www.remarkabledocs.org. Accessed November 7, 2007.
19. RevolutionHealth Doctor Finder. Available at: www.revolutionhealth.com/care-providers. Accessed November 7, 2007.
20. MDJunction. Available at: www.mdjunction.com. Accessed November 7, 2007.
21. BookOfDoctors. Available at: www.bookofdoctors.com. Accessed November 7, 2007.
22. Healthgrades. Available at: www.healthgrades.com. Accessed November 4, 2007.
23. DocInfo. Available at: www.docinfo.org. Accessed November 4, 2007.
24. DocFinder. Available at: www.docboard.org/docfinder.html. Accessed November 4, 2007.
25. PhysicianReports. Available at: www.physicianreports.com. Accessed November 4, 2007.
26. American Board of Medical Specialities Doctor Verification. Available at: www.abms.org/WC/login.aspx. Accessed November 4, 2007.
27. CertiFACTS Online. Available at: www.certifacts.org. Accessed November 5, 2007.
28. Xoova. Available at: www.xoova.com. Accessed November 8, 2007.
29. DrScore. Available at: www.drscore.com. Accessed November 8, 2007.
30. ExamineYourPractice. Available at: www.examineyourpractice.com. Accessed November 8, 2007.
31. Devon Hill Associates. Available at: www.devonhillassociates.com. Accessed November 9, 2007.

 
Needs Assessment: Primary care physicians have an opportunity to play an improved role in suicide prevention. Past studies have shown limitations in practice. Recent research has demonstrated that improved assessment and treatment techniques are available and may help to avert suicide.


Learning Objectives:
• Understand the importance of assessing and monitoring suicide risk in a primary care setting.
• List common suicide risk factors.
• Understand the current practices in the assessment and treatment of suicide.

• Understand the issues related to antidepressant management and suicidality.


Target Audience:
Primary care physicians and psychiatrists.


CME Accreditation Statement:
This activity has been planned and implemented in accordance with the Essentials and Standards of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of the Mount Sinai School of Medicine and MBL Communications, Inc. The Mount Sinai School of Medicine is accredited by the ACCME to provide continuing medical education for physicians.


Credit Designation:
The Mount Sinai School of Medicine designates this educational activity for a maximum of 3 AMA PRA Category 1 Credit(s)TM. Physicians should only claim credit commensurate with the extent of their participation in the activity.


Faculty Disclosure Policy Statement:
It is the policy of the Mount Sinai School of Medicine to ensure objectivity, balance, independence, transparency, and scientific rigor in all CME-sponsored educational activities. All faculty participating in the planning or implementation of a sponsored activity are expected to disclose to the audience any relevant financial relationships and to assist in resolving any conflict of interest that may arise from the relationship. Presenters must also make a meaningful disclosure to the audience of their discussions of unlabeled or unapproved drugs or devices. This information will be available as part of the course material.

This activity has been peer-reviewed and approved by Eric Hollander, MD, chair and professor of psychiatry at the Mount Sinai School of Medicine, and Norman Sussman, MD, editor of Primary Psychiatry and professor of psychiatry at New York University School of Medicine. Review Date: October 25, 2007.

Drs. Hollander and Sussman report no affiliation with or financial interest in any organization that may pose a conflict of interest.


To receive credit for this activity:
Read this article and the two CME-designated accompanying articles, reflect on the information presented, and then complete the CME posttest and evaluation. To obtain credits, you should score 70% or better. Early submission of this posttest is encouraged: please submit this posttest by December 1, 2009 to be eligible for credit. Release date: December 1, 2007. Termination date: December 31, 2009. The estimated time to complete all three articles and the posttest is 3 hours.

Dr. Posner is director of the Suicide Classification Center at Columbia University, assistant professor in the Division of Child & Adolescent Psychiatry at Columbia University College of Physicians & Surgeons, and research scientist at New York State Psychiatric Institute. in New York City. Dr. Melvin is research scientist at the New York State Psychiatric Institute. Dr. Stanley is director of the Suicide Intervention Center at the New York State Psychiatric Institute/Columbia University College of Physicians & Surgeons.

Disclosure: Dr. Posner has received funding from the Food and Drug Administration to develop and implement the suicidality classification system used in their child antidepressant safety analyses. This system was subsequently used in the adult antidepressant safety analyses. As part of an effort to help execute the FDA suicidality classification mandates, Dr. Posner has had and will have research support from Abbott, Bristol-Myers Squibb, Cephalon, Eli Lilly, GlaxoSmithKline, Johnson and Johnson, Merck, Novartis, Organon, Pfizer, sanofi-aventis, Schwarz Pharma, Shire, Vivus, and Wyeth Research. Dr. Melvin reports no affiliation with or financial interest in any organization that may pose a conflict of interest. Dr. Stanley receives grant support from the American Foundation for Suicide Prevention, the National Institute of Mental Health, and the National Institute on Alcohol Abuse and Alcoholism.

Please direct all correspondence to: Barbara Stanley, PhD, Division of Molecular Imaging, New York State Psychiatric Institute, Unit 42, 1051 Riverside Dr, New York, NY 10032; Tel: 212-543-5918; Fax: 212-543-6946; E-mail: bhs2@columbia.edu.

 


Abstract

Suicide is a leading cause of death and a public health priority. In an attempt to reduce suicide rates, efforts have focused on detection and management of suicidal patients in primary care settings, given that an estimated 45% of suicide victims see their physician in the month prior to their death. Previous research suggests that limitations exist in primary care physicians’ (PCPs’) assessment and treatment of suicidal risk. Training programs addressing the detection of suicidal patients and management of suicidal risk in primary care settings have demonstrated significant improvement in practice. Hence, treatments are available to help PCPs assist with suicide prevention. Recent safety warnings about suicidal ideation and behavior associated with youths and young adult antidepressant treatment have led to sharp declines in prescribing, particularly by PCPs. Concern now exists about under-treatment of depression and the subsequent impact on suicide rates. This article reviews recent literature and provides an overview of suicide risk factors and assessment of suicide risk. The importance of assessing and managing suicidal ideation and behavior and risk factors is highlighted.

 

Introduction

Suicide remains a leading cause of mortality, with elderly males at greatest risk.1 Training general medical professionals in the detection and management of suicide risk is a core component of national suicide prevention efforts.2 A review of studies found that on average 45% of individuals who commit suicide had contact with their primary care physician (PCP) in the month prior to suicide and 77% had contact in the previous year,3 placing PCPs in a unique position to prevent suicide. In addition, PCPs also regularly see patients with psychiatric disorders who are at risk of suicide. Olfson and colleagues4 reported that of those attending general medical care in the United States, 18.9% had major depressive disorder (MDD), 7.9% met criteria for substance abuse, and 7.1% experienced suicidal ideation. These three factors are major risks for suicide and suicide attempts. Epidemiologic studies have shown that the majority of suicide attempters will die on their first attempt.5 Given this, individuals who complete suicide on their first attempt are probably less likely to have been engaged by mental health professionals for specialist care but more likely to have been seen in the primary care setting. Moreover, a minority of suicide completers had contact with mental health services in the month prior to their suicide3 and almost 75% of those seeking help for depression will see their PCP rather than a mental health professional.6 Thus, PCPs are uniquely situated to play a critically important role in the prevention of suicide. This may be particularly the case in the at-risk population of elderly men, who may seek care for medical problems,7 providing the PCP with an opportunity to assess suicide risk.

A physician’s ability to assess, monitor, and treat suicide risk is dependent on his or her training, knowledge, skills, and attitudes. Previous studies have identified limitations in PCPs’ suicidal risk management skill and barriers that impede their practice.6,8,9 Gaps in suicide and depression training have been detected in primary care academic programs.10 However, with skills training, improved PCP management of suicidality has been demonstrated. The importance of assessment, monitoring, and treatment of suicidality in a primary care setting is discussed along with an overview of the current state of knowledge.

 

Assessment and Monitoring

Previous studies of suicide completers have demonstrated the need for routine suicide risk assessment in primary care. For example, in a retrospective review of the final primary care appointment prior to suicide, only two of 61 cases had a comment noted about suicide risk,11 potentially suggesting the need for more systematic practice in the assessment of suicide risk. In a retrospective review of completed suicide cases, Isometsa and colleagues12 found that 19% of PCPs knew about the suicidal intentions of their patients compared with 59% of psychiatric practitioners, perhaps highlighting that suicidality is not typically inquired about in general practice. However, assessment of psychiatric issues, including suicidality in primary care, is complicated by physician time pressure and competing needs to assess presenting medical issues.6 As previously mentioned, approximately 50% of suicide completers visit their PCP in the month prior to completing suicide. However, some demographic groups are less likely to be seen, such as males <35 years of age.3 Detecting those at risk may also be challenging because, while suicides may be seen before their death, it is usually for stated reasons quite unrelated to mental health or risk factors for suicide. However, Appleby and colleagues11 found 64% of 61 suicide completers reported psychological complaints at their visits to their general practitioner in the three months prior to suicide. The importance of improved detection is not diminished by suicide being a relatively rare event in primary care13 as some risk factors such as depressive disorders4 are quite common. Further risk assessment can detect and potentially prevent the more frequent suicide attempts, which are of significance on their own and are a cause of burden on the healthcare system.

The importance of suicide risk assessment in primary care and the challenges for PCPs in conducting this clinical task have prompted investigations into improved practices. Evidence suggests that significant improvements in PCP suicide assessment practices can be detected following the implementation of training programs.14,15 Within the Skills Training on Risk Management (STORM) project, PCPs and other professionals demonstrated a significant improvement following a 6-hour training course on the assessment and management of suicide risk.14 The focus of assessment training was on suicide risk, mental state, and psychosocial problems. Nutting and colleagues15 found that 41% of patients seen within programs designed to improve quality of depression care were identified with suicidal ideation compared with 21% within a usual care group.

Suicide risk factors are important for a PCP to consider when forming an opinion about suicide risk. Two of the strongest and most important risk factors for suicide are past suicidal behavior and ideation16,17 as well as MDD.18,19 Other psychiatric disorders known to raise risk include alcohol and substance use disorders, schizophrenia, bipolar disorder during depressive or mixed phase, and anxiety disorders.12,19,20 The psychological trait of hopelessness is also known to increase risk.21 Being male quadruples risk and those ≥65 years of age are in the age range typically at greatest risk.1 Those who have experienced sexual abuse22 or have a family history of suicide and/or sexual abuse are also at elevated risk.23 In addition to psychiatric and demographic factors, some chronic illnesses such as epilepsy,24 AIDS,25 multiple sclerosis,26 stroke,27 and myocardial infarction28 raise risk of suicide. Chronic illness has been found to be a greater risk factor in older men than older women.29 These risk factors should be determined in the first appointment with a patient when taking his or her history, along with the family history of mental health.

There is often reluctance on the part of physicians to ask about mental health issues, particularly suicidality. In conducting a risk assessment, physicians should not hesitate to ask the patient about both suicidal ideation and behavior. Gould and colleagues30 dispelled the clinical myth that asked if suicidality has iatrogenic effects, clearly demonstrating that asking does not cause distress or suicidal thinking. A risk assessment needs to include questions about suicidal ideation (eg, wishes to die, thoughts about committing suicide, any plans for suicide, and “intent” to act on such thoughts) and behavior (eg, preparations for a suicide attempt, past suicidal behavior) as well as risk factors previously described. If a patient reports a suicidal plan, any suicidal intent, and/or access to suicidal method (eg, gun), risk is likely elevated. An assessment of suicide risk is a clinical opinion valid for that point in time which the practitioner is required to reasonably act upon according to the level of risk that is present to ensure the safety of the patient (eg, schedule a further appointment for treatment or refer to a mental health professional).

Patients identified as being at risk of becoming suicidal or those who have a level of suicidal ideation or behavior judged appropriate for management in the primary care setting should be monitored for risk at regular intervals. It is important to remember that suicide risk should not be assumed to be stable over time. Schulberg and colleagues31 reported on a clinical trial in which patients with uncomplicated depression, including some with suicidal ideation, were monitored and managed within a primary care setting over a 6- or 12-month time frame. At a simple level, the trial demonstrated that PCPs could successfully monitor depressed patients with suicidal ideation over a sustained period, but it was also found that suicidal ideation largely declined or remained stable throughout the trial. The impact of monitoring suicidality was demonstrated recently in a study of subjects with borderline personality disorder.32 Participants received monitoring of their suicidal symptoms for 1 year and made 80% fewer attempts compared with the previous year.

The use of screening instruments can be a helpful technique to assess suicidal risk. Items that measure suicidal ideation and behavior are usually contained within measures of depression. Recommended depression measures include the Patient Health Questionnaire33 and the Beck Depression Inventory for Primary Care,34 both of which have demonstrated psychometric properties in primary care. For a specific measure designed to assess and track suicidal ideation and behavior (eg, suicide attempts, wish to die, thoughts of suicide, plan and intent) the Columbia-Suicide Severity Rating Scale (C-SSRS) is recommended as a helpful tool. The C-SSRS is a brief, low-burden questionnaire administered by the clinician.35

Screening for prominent suicide risk factors of depressive36 and alcohol use disorders37-39 can be effectively performed in primary care settings and leads to an improved rate of detection. Detection of these disorders provides an opportunity for the implementation of treatment intervention or referral that may be useful in reducing risk factors for suicidality. Psychometrically sound measures to screen for alcohol use disorders and hazardous drinking include the four-item CAGE questionnaire40,41 and the 10-item Alcohol Use Disorder Identification Test (AUDIT). Abbreviated versions of the AUDIT with similar psychometric properties42,43 such as five-item AUDIT-PC44 may be more practical in primary care settings.

 

Treatment

In recent years, treatment programs for depression with suicidal ideation specific to the general practice setting have been developed and demonstrated to be superior to usual care. Treatments typically involve a physician training component, antidepressant treatment, as well as an adjunctive counseling component provided by another practice staff member. Bruce and colleagues45 demonstrated that a depression and suicidal ideation management program comprising treatment guidelines (psychopharmacology, interpersonal psychotherapy), physician education, and care managers who monitored treatment and in some cases provided therapy, was superior to usual care in reducing suicidal ideation and depression in older patients with depression. Unützer and colleagues46 compared a collaborative care treatment comprising antidepressant medication plus a course of problem-solving treatment provided by a psychologist or registered nurse to treatment as usual in a sample of elderly depressed patients with or without suicidality. Significantly greater declines in suicidal ideation were evident in the collaborative care group compared to the treatment as usual group.

Non-mental health professionals, including PCPs, trained in the STORM project showed significant improvement in their overall ability to manage suicidality, with specific gains in managing suicidal intent, removal of lethal means, and arrangement of appropriate support.14 Comparison of suicide rates in the district in which training was conducted in the years pre- and post-training did not differ.47 This is not surprising given only 39% of the district’s practitioners were trained, the rarity of suicide, and the tendency for suicide rates to be influenced by multiple factors.

In addition to the specifically developed treatments for suicidal depression, treatment of depression may also reduce risk of suicidality. In a review of effective primary care treatment strategies, Gilbody and colleagues48 found that collaborative care between a PCP and psychiatrist or psychologist was associated with improved treatment outcome and lower treatment cost for those with MDD. Models have been developed to enable best practice care of depression in primary care. Oxman and colleagues49 describe a three-component model that comprises education for clinicians and office staff about skills and procedures; care management, the focus of which is the use of telephone calls to educate and monitor progress and treatment compliance; and mental health interface, which includes involvement of a consulting psychiatrist who supervises clinicians and is available for consultation and referral.

Antidepressants are an effective treatment for depressive disorders in primary care settings.50 Ensuring that patients treated with antidepressants are receiving an adequate dose is an important treatment consideration as evidence points to the widespread practice of inadequate dosing.51 Evidence of inadequate dosing has been found in patients who completed suicide while in treatment in primary care11 as well as in depressed patients in community care.52 The Agency for Health Care Policy and Research Practice Guidelines provides guidelines for treatment of adult depression in primary care.53

Increasing selective serotonin reuptake inhibitor (SSRI) prescription rates have been associated with a significant decrease in suicide rates in many countries,54-58 and across the lifespan, and represent a reversal of the increasing suicide trend that preceded the introduction of SSRIs. In a large sample of treatment-seeking US veterans with MDD, Gibbons and colleagues59 demonstrated that risk of suicide attempt was reduced with antidepressant treatment. For example, risk of suicide attempt almost halved (221/100,000 to 123/100,000 participants) following the SSRI commencement, adding further support to the robustness of this relationship. In addition, completed suicide has been clearly associated with a lack of treatment or treatment non-compliance.60 Toxicology studies typically demonstrate that antidepressants are very rarely present in suicide victims at time of death.61,62

In recent years the Food and Drug Administration has analyzed the relationship between antidepressants and suicidality compared with placebo63 and released warnings about an increased risk of suicidal ideation and behavior initially in children and adolescents and subsequently in young adults up to 25 years of age.64 However, these conclusions were reached with studies not designed to measure suicidality, which limits the causal interpretations that can be drawn. Also included in this warning is acknowledgement of the role that depressive and other psychiatric disorders play in increasing risk of suicide. While the FDA aimed to educate prescribers and the general public of the possible risks of antidepressants to allow informed treatment decisions, an unintended consequence appears to have occurred. Prescription rates of antidepressants to youths have declined strikingly since the release of the warning,65,66 resulting in concern about even greater under-treatment of youth depression. Libby and colleagues65 estimated a 58% reduction in prescription fills compared with projected trends following the implementation of FDA warnings. Prescription by PCPs has declined markedly while psychiatrist prescription has inclined,65,66 indicating PCP hesitancy to prescribe. A further consequence of potential great harm has been a decline in diagnosis of youth depression and a decline in treatment of adult depression.65 Of particular concern, the first evidence of the consequences of these declines in prescription have started to manifest with a 49% increase in suicide recorded in the Netherlands (between 2003 and 2005) and a 14% increase recorded in the US (between 2003 and 2004), coinciding with an approximate 22% decline in prescriptions in both countries following the warnings.67 These findings may not be unexpected given the clear inverse relationship between SSRI prescription and suicide rate. These findings stress the importance of the management of depressive disorders in the prevention of suicide. The Texas Children’s Medication Algorithm Project provides treatment guidelines for antidepressant prescribing for children and adolescents.68

In addition to addressing depression, support exists for the use of brief behavioral interventions for alcohol problems in primary care settings, such as hazardous and harmful drinking69-71 and alcohol misuse.72 These cost-effective treatments73,74 typically include feedback on personal risk; advice; and self-help information on changing drinking behavior, goal setting, referral for further assistance, and ongoing monitoring.38,72 A meta-analysis found that brief interventions have a clear effect in men at reducing alcohol consumption but not in women.71 Specialized programs with demonstrated efficacy also exist for elderly populations.75

 

Conclusion

Primary care provides a unique opportunity for identification of those at risk for suicide and for the prevention of suicidal behavior. PCPs can serve at the front line in suicide prevention. Identification and treatment of conditions known to increase risk for suicide, particularly depression and alcohol use disorders, may help to avert suicidal crises. Furthermore, serious and chronic medical illness, managed often in the primary care setting, increases suicide risk. While some specialized training is needed, PCPs can be effectively trained in suicide assessment, risk management, and treatment strategies in an efficient manner. PP

 

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37.    Bradley KA, Kivlahan DR, Zhou X, et al. Using alcohol screening results and treatment history to assess the severity of at-risk drinking in veterans affairs primary care patients. Alcohol Clin Exp Res. 2007;28(3):448-455.
38.    Miller WR, Baca C, Compton WM, et al. Addressing substance abuse in health care settings. Alcohol Clin Exp Res. 2006;30(2):292-302.
39.    US Preventive Services Task Force. Screening for suicide risk: recommendation and rationale. Ann Intern Med. 2004;140(10):820-821.
40.    Ewing JA. Detecting alcoholism: the CAGE questionnaire. JAMA. 1984;252(14):1905-1907.
41.    Fleming M, Manwell LB. Brief intervention in primary care settings: a primary treatment method for at-risk, problem, and dependent drinkers. Alcohol Res Health. 1999;23(2):128-137.
42.    Aertgeerts B, Buntinx F, Ansoms S, Fevery J. Screening properties of questionnaires and laboratory tests for the detection of alcohol abuse or dependence in a general practice population. Br J Gen Pract. 2001;51(464):206-217.
43.    Gómez A, Conde A, Santana JM, Jorrín A. Diagnostic usefulness of brief versions of Alcohol Use Disorders Identification Test (AUDIT) for detecting hazardous drinkers in primary care settings. J Stud Alcohol. 2005;66(2):305-308.
44.    Piccinelli M, Tessari E, Bortolomasi M, et al. Efficacy of the alcohol use disorders identification test as a screening tool for hazardous alcohol intake and related disorders in primary care: a validity study. BMJ. 1997;314(7078):420-424.
45.    Bruce ML, Ten Have TR, Reynolds CF 3rd, et al. Reducing suicidal ideation and depressive symptoms in depressed older primary care patients: a randomized controlled trial. JAMA. 2004;291(9):1081-1091.
46.    Unützer J, Tang L, Oishi S, et al. Reducing suicidal ideation in depressed older primary care patients. J Am Geriatr Soc. 2006;54(10):1550-1556.
47.    Morriss R, Gask L, Webb R, Dixon C, Appleby L. The effects on suicide rates of an educational intervention for front-line health professionals with suicidal patients (the STORM project). Psychol Med. 2005;35(7):957-960.
48.    Gilbody S, Whitty P, Grimshaw J, Thomas R. Educational and organizational interventions to improve the management of depression in primary care: a systematic review. JAMA. 2003;289(23):3145-3151.
49.    Oxman TE, Dietrich AJ, Williams JW, Kroenke K. A three-component model for reengineering systems for the treatment of depression in primary care. Psychosomatics. 2002;43(6):441-450.
50.    Kroenke K, West SL, Swindle R, et al. Similar effectiveness of paroxetine, fluoxetine, and sertraline in primary care: a randomized trial. JAMA. 2001;286(23):2947-2955.
51.    Fernández A, Haro JM, Martinez-Alonso M, et al. Treatment adequacy for anxiety and depressive disorders in six European countries. Br J Psychiatry. 2007;190(2):172-173.
52.    Oquendo MA, Kamali M, Ellis SP, et al. Adequacy of antidepressant treatment after discharge and the occurrence of suicidal acts in major depression: a prospective study. Am J Psychiatry. 2002;159(10):1746-1751.
53.    Schulberg HC, Katon W, Simon GE, Rush AJ. Treating major depression in primary care practice: an update of the Agency for Health Care Policy and Research practice guidelines. Arch Gen Psychiatry. 1998;55(12):1121-1127.
54.    Gibbons RD, Hur K, Bhaumik DK, Mann JJ. The relationship between antidepressant prescription rates and rate of early adolescent suicide. Am J Psychiatry. 2006;163(11):1898-1904.
55.    Grunebaum MF, Ellis SP, Li S, Oquendo MA, Mann JJ. Antidepressants and suicide risk in the United States, 1985-1999. J Clin Psychiatry. 2004;65(11):1456-1462.
56.    Olfson M, Shaffer D, Marcus SC, Greenberg T. Relationship between antidepressant medication treatment and suicide in adolescents. Arch Gen Psychiatry. 2003;60(10):978-982.
57.    Henriksson S, Isacsson G. Increased antidepressant use and fewer suicides in Jamtland county, Sweden, after a primary care educational programme on the treatment of depression. Acta Psychiatr Scand. 2006;114(3):159-167.
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73.    Fleming MF, Mundt MP, French MT, Manwell LB, Stauffacher EA, Barry KL. Benefit-cost analysis of brief physician advice with problem drinkers in primary care settings. Med Care. 2000;38(1):7-18.
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Ms. Rodgers is pre-doctoral psychology intern at the Minneapolis Veterans Administration Medical Center in Minnesota. Ms. Norell is clinical research associate and Dr. Roll is director of the Washington Institute for Mental Illness Research and Training at Washington State University in Spokane. Dr. Dyck is vice chancellor of research and psychology professor at Washington State University.

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

Acknowledgments: The authors thank Dr. Robert Short for his comments on previous drafts of this article and wish to express their appreciation to consumers whose pursuit of recovery in spite of numerous challenges demonstrates tremendous strength and resiliency.

Please direct all correspondence to: Martina L. Rodgers, VA Medical Center (116A), One Veterans Drive, Minneapolis, MN 55417; Tel: 612-467-3049; Fax: 612-727-5964; E-mail: Martina.Rodgers@va.gov.

 


 

Focus Points

• Research evidence and subjective accounts support the notion that people with a severe and persistent mental illness can lead a meaningful life while managing the illness. This has been termed “recovery” in the mental health field.
• Numerous descriptions of recovery as a process and outcome have been proposed.
• Quantitative measures of recovery are currently being developed and studied. Qualitative methods have also come to the forefront in recovery research.
• Six evidence-based practices for people with severe and persistent mental illness have been identified. Although historically viewed as conflicting with the recovery concept, the integration of recovery ideals within an evidence-based framework has been recently endorsed.

 

Abstract

Empirical evidence and personal accounts have demonstrated that many people with severe and persistent mental illness can lead satisfying, meaningful lives. This phenomenon has been termed recovery. A variety of definitions of recovery have been proposed. Lack of consensus on conceptual and definitional issues complicate the measurement and study of recovery. The development of qualitative and quantitative measures of recovery is enriching research on recovery. The integration of recovery goals with evidence-based practices has recently been endorsed. However, relatively little empirical research has addressed the extent to which current evidence-based practices impact recovery. This article chronicles the history of the current focus on recovery in mental health, summarizes available process and outcome definitions, describes current research methods utilized in the recovery literature, and provides a clinical model that integrates recovery with an evidence-based practice perspective.

 

Introduction

The goal of recovery is well understood and appreciated in physical medicine and rehabilitation.1 People with a chronic medical condition (eg, diabetes) or disability (eg, paraplegia) may not expect an elimination of symptoms or the restoration of functioning. However, it is understood that treatment can help people manage the illness or disability and achieve the best life adjustment possible.2

The recovery construct from physical rehabilitation has over time been adopted by the public mental health system. Mental health consumers have shared their stories of recovery in the literature, and consumers and families alike are advocating recovery-oriented programs. In addition, researchers are evaluating the influence of mental health treatments on recovery outcomes, and mental health systems are attempting to develop policies that will enhance recovery outcomes.

What is meant by mental health recovery? Is recovery possible? How is recovery measured and studied? Can recovery be integrated with evidence-based practices? This article provides a historic overview, synopsis of the current thinking and research on recovery, and model that informs and guides the use of evidence-based mental health interventions to support recovery.

 

History of the Recovery Movement in Mental Health

Before the 1980s, treatment for people with severe and persistent mental illness (SPMI) focused solely upon symptom management.3 In addition, schizophrenia, an SPMI, was initially characterized by Kraepelin as a progressively deteriorating illness in which poor outcomes were expected.4 This prevailing viewpoint was challenged by two sources that demonstrated that people with SPMI were able to lead fulfilling lives while managing symptoms of the illness. First, personal stories of recovery emerged in the research literature, providing initial evidence that people with SPMI had the ability to move beyond the illness.5-8 Second, the possibility of recovery from mental illness was confirmed by landmark studies.9,10 These studies showed that 50% to 60% of people with schizophrenia significantly improved or recovered after an average of 32 years. A meta-analysis of international research literature reported that approximately 50% of people with schizophrenia included in studies during the 20th century evidenced substantial clinical improvement after an average of 6 years.11 Nine additional long-term studies found similar results.12 In a recent longitudinal study, recovery was repeatedly assessed over 15 years with results suggesting that almost 50% of the sample experienced one or more periods of recovery.13 Overall, these findings indicate that recovery may involve growth and setbacks as well as periods of rapid change and little change,1 and discredit the notion of SPMI being defined by an unrelenting, downhill course.

One of the first definitions of mental health recovery was proposed by Anthony1 as “a deeply personal, unique process of changing one’s attitudes, values, feelings, goals, skills, and/or roles…a way of living a satisfying, hopeful, and contributing life even with limitations caused by illness.” Anthony compared recovery from SPMI to recovery from physical illness and disability, noting that people can recover from illnesses without necessarily being cured.

The 1990s were subsequently declared the “decade of recovery” by Anthony.1 During the late 1990s, state mental health systems attempted to incorporate a recovery vision and promote recovery-oriented services. A system with a recovery vision is guided by the notion that people who are consumers of mental health services can lead personally satisfying lives beyond the illness.14,15 Many states initially developed recovery vision statements for their mental health systems, which explained recovery and showed a commitment to the goal. Some states redefined existing services as recovery oriented, while others developed new programs specifically designed to promote recovery. Common core elements of the recovery programs developed by these states included education about severe and persistent mental illness, consumer and family involvement such as peer-support and self-help networks, support for consumer-operated services, emphasis on relapse prevention and management, incorporation of crisis planning and advance directives, innovations in contracting and financing mechanisms, definition and measure of outcomes, review and revision of policies, and stigma reduction initiatives.16

In the current decade, the public mental health system in the United States is continuing to work toward the adoption of recovery principles. Some examples include the 2003 New Freedom Commission on Mental Health, which officially recognized the possibility of recovery from SPMI. The Veterans Administration has recently adopted a recovery model.4 An expert panel convened at the National Consensus Conference on Mental Health Recovery and Mental Health Systems drafted a national consensus statement on mental health recovery.17 A textbook devoted to the topic of recovery has been written in an effort to develop a knowledge base.18 An updated compendium of available recovery measures has been published to facilitate research.19 To promote system change, recent writings in the recovery literature have outlined characteristics of recovery-oriented systems of care. It has been suggested that recovery-oriented programs be person centered and strengths based by including the person in the design, plan, implementation, and evaluation of services; respecting the person’s rights to make his or her own decisions about treatment goals and services; and acknowledging the possibility of the person living a satisfying life beyond the disability.14 Davidson and colleagues20 articulated their vision of a recovery-oriented system:

What primarily will be different about recovery-oriented systems of care, as we envision them, is that these interventions and supports will be provided in ways much more similar to than different from other health care services for other health conditions. The people receiving these services will likewise continue on with their ordinary lives, either recovering from the illness when possible or, when not yet possible, gaining access to the technologies, tools, and environmental accommodations they need to incorporate the illness or disability into their lives as only one component of a multidimensional existence.20

Additional features of recovery-oriented services that have been proposed by researchers include communicating a sense of hope, focusing on all aspects of a consumer’s life (eg, spirituality, creativity), helping consumers develop skills and knowledge to effectively manage the illness, supporting efforts to move beyond the effects of the illness, nurturing the positive aspects of consumers’ lives in addition to decreasing symptoms and other difficulties, fostering a level of independence that suits the consumer, and promoting the development of support systems.15,17,21-24 Research has begun to demonstrate the benefits of such recovery-oriented practices.22

 

What is Recovery?

Since the initial conceptualization of recovery by Anthony,1 a variety of definitions have been proposed by consumers, families, practitioners, and researchers. There currently is no single definition,25 and some researchers have suggested that recovery defies definition.26

 

Process versus Outcome

The recovery literature is replete with definitions of recovery as both an outcome and a process. As an outcome, recovery refers to a measurable end point often defined by criteria such as being symptom-free, working or going to school for a specified length of time, socializing with peers during the week, or living independently in the community. However, many people with SPMI experience their recovery as a unique and dynamic process.

 

Recovery as a Process

Consumer Definitions
Given the subjective and highly personal nature of mental illness, consumers have had a stake in the description of recovery. Ralph27 provided a comprehensive review of consumer definitions of recovery. For example, recovery has been defined as a long process of learning how to live with a mental illness while struggling toward positive goals.28 Deegan29 noted, “To me, recovery means I try to stay in the driver’s seat of my life…I don’t let my illness run me.” Other consumers described hope, personal responsibility, education, advocacy, and peer support as being involved in recovery.30 Schiff31 commented, “…being recovered means feeling at peace, being happy, feeling comfortable in the world and with others, and feeling hope for the future…it is about knowing and being able to be who I am.”

Consumers have also embraced the concept of empowerment as being highly relevant to the process of recovery. This model of recovery emphasizes the principles of hope, achievement of self-defined goals, opportunities for consumers to speak for themselves, an end to discrimination, and healing from within.32 The Center for Mental Health Services recently invited consumer leaders to discuss and define recovery. Based upon their personal experiences and a review of the recovery literature, the Recovery Advisory Group described recovery as a nonlinear progression through phases of anguish; awakening; insight; action plan; determination to be well; and well-being, empowerment, and recovery.33 Additional consumer accounts of recovery include the importance of taking responsibility, having structure and organization, and “being like normal people.”34

Recovery Processes
Processes inherent in and relevant to recovery have been examined using primarily qualitative methodology. Jacobson35 examined 30 narratives by people who identified themselves as in recovery. Findings suggested four recovery processes, including recognizing the problem, transforming the self, reconciling the system, and reaching out to others. Another research group36 reviewed experiential accounts of recovery and subsequently identified the recovery processes of finding hope, re-establishing identity, finding meaning in life, and taking responsibility. Additional recovery processes extracted from personal stories include reawakening of hope after despair, breaking through denial and achieving understanding and acceptance, moving from withdrawal to engagement and active participation in life, active coping, no longer viewing oneself primarily as a person with a psychiatric disorder and reclaiming a positive sense of self, and moving from alienation to a sense of meaning and purpose.37

In another study,38 interviews were conducted with a small sample of people with schizophrenia. Their subjective experiences revealed three recovery processes, including controlling crisis, putting it in perspective, and coping with relapse. Based upon consumer accounts and focus group responses, other researchers proposed the recovery processes of having hope, taking personal responsibility, and getting on with life.39

Stage Models
Numerous authors have conceptualized stage models of recovery.40 Three “emotional stages” of recovery were proposed by Baxter and Diehl,41 who conducted interviews with 40 consumers involved in peer services. The stages included “crisis,” during which consumers attempt to recuperate; “decision,” such that consumers decide to rebuild the ability to care for themselves and to assume normal life roles; and “awakening,” in which consumers attempt to rebuild a healthy interdependence.

Over a 4-year period, consumers were interviewed about their personal experiences with schizophrenia or schizoaffective disorder.42 Their experiences were categorized into four phases, including being overwhelmed by the disability, struggling with the disability, living with the disability, and living beyond the disability.

Based upon data obtained from qualitative interviews and focus groups with consumers, Young and Ensing43 developed a three-stage model of recovery. The initial phase involves overcoming “stuckness,” which includes accepting the illness, finding hope, and having the desire to change. The middle phase entails regaining what was lost and moving forward. The last phase involves improving quality of life by striving for new potentials and achieving a sense of well being.

The findings from the above qualitative studies have been summarized in the form of a five-stage model of recovery.36 The first stage, moratorium, is characterized by denial, confusion, hopelessness, identity confusion, and self-protective withdrawal. The second stage, awareness, involves becoming aware of the potential to be someone other than the “sick person” and recognizing the possibility of recovery. The third stage is preparation, in which the person starts working on recovery by acknowledging his or her strengths and weaknesses, learning about mental illness and mental health services, and connecting with peers. The fourth stage, rebuilding, is characterized by the hard work of recovery, including setting and working toward personal goals, taking responsibility for managing the illness, and taking risks. The last stage, growth, is distinguished by knowing how to manage the illness and stay well, having a positive sense of self and confidence in one’s ability to manage setbacks, and looking toward the future.

The above definitions and stage models reflect a convergence of views about the fundamental nature of recovery. Recovery appears to involve dynamic and often non-linear movement through multiple stages as the consumer works to gain control of the illness in order to live life more fully. These stages progressively include the themes of hope, acceptance of the illness, and a renewed sense of self.26 Andresen and colleagues’36 five-stage model is one of the first attempts to succinctly incorporate a variety of conceptualizations of recovery into a single model and significantly contributes to this growing body of literature.

 

Recovery as an Outcome

Researchers have also attempted to operationalize recovery as an outcome. The outcome definitions are based on clinical experience as well as quantitative and qualitative research methodologies. Four specific operational definitions of recovery are summarized in Table 1.13,44-46 All definitions include the criterion of symptom remission or stabilization as well as improved psychosocial functioning, which has been defined in a variety of ways (eg, global rating versus assessment of involvement in social or employment activities). They also require that the criteria be met for varying lengths of time, ranging from 1–5 years. Furthermore, Liberman and Kopelowicz47 provided an expanded list of criteria for researchers to consider in operational definitions of recovery. This list included symptom remission; working or studying in a normative setting; independent living without supervision of money, self-care skills, and medication; social activities with peers; supportive family relations; recreational activity in normative settings; use of problem-solving skills when faced with a conflict; life satisfaction; positive self-esteem; and participation as a citizen in voting, self-advocacy, neighborliness, and other civic areas.

  

 
The above outcome definitions clearly facilitate the ability of researchers to measure recovery. However, they do not address subjective experience or phenomenology of recovery as emphasized by many consumers. To integrate the process and outcome perspectives on recovery, it may be beneficial to include both quantitative measurement of common recovery themes (eg, social relationships, employment) as well as qualitative measurement of the more phenomenologic aspects of recovery processes or stages, such as feelings of hope and empowerment. Most of the process and outcome definitions are not antithetical but inextricably linked and reflect different perspectives.

 

Measurement of Recovery

Quantitative Measurement of Recovery

The multiple definitions of the recovery construct complicate its measurement.37 There have been recent efforts to develop quantitative measures. The quantitative measures of recovery have been classified into two categories, including surveys and other scales as well as societal indicators.48 Surveys include measures that assess the absence of symptoms as well as direct measures of recovery and its related dimensions. Societal indicators address the ability to adapt to living in the community (eg, attainment of employment, reduction in hospitalizations).

In 2004, a group of consumers and researchers met to discuss the measurement of recovery. A variety of strategies were utilized to identify recovery instruments including review of the first volume of a compendium, review of the relevant literature, and professional networking. Critical information about each measure was systematically collected from the authors of the instruments. Current available measures are provided in the updated compendium entitled Measuring the Promise: A Compendium of Recovery Measures, Volume II.19 Two types of recovery assessment tools were included, that is, measures of individual recovery and recovery-promoting environments. Measures of individual recovery assess one or more aspects of individual-level recovery, while measures of recovery-promoting environments assess the recovery orientation of services and systems as well as the extent to which programs and services include processes thought to bring about recovery. To date, nine measures of individual recovery and four measures of recovery-promoting environments are available in this compendium. The measures vary in their stages of development with some having not yet been pilot tested, while others have undergone considerable psychometric testing. They also differ in length, method of administration (ie, interview versus self-administration), and source of information (ie, consumer versus family versus professional ratings). The compendium represents a major advancement in the measurement of recovery, and future efforts should be encouraged.

 

The Role of Qualitative Methodology

As noted above, researchers are also viewing recovery as a highly individualized, dynamic process.49 This view has received empirical support50 and validates the experiences of many consumers.25 This conceptualization, however, makes it difficult to study recovery using traditional quantitative methods, and increasingly qualitative methods are being recommended to understand the recovery process.50,51 Qualitative methods provide consumers the opportunity to tell their stories and describe the process in their own words, which is consistent with recovery values.

Davidson and Strauss52 were two of the early researchers to apply qualitative methodology in their study on the role of the sense of self in the recovery process. Qualitative inquiry has since come to the forefront in the study of recovery, 27,35,41,43,51,53-58 and a book has been published about qualitative studies of recovery in schizophrenia.59 Various qualitative methods have been used such as observation, semi-structured interviews, focus groups, and document analysis, as well as qualitative traditions such as grounded theory, ethnography, and phenomenology. For example, researchers have analyzed personal accounts of recovery to identify factors that play a role in coping and adaptation.27 Interviews have been used to examine the impact of treatment settings on recovery beliefs.58 Focus groups have been conducted to explore the meaning of recovery to people with severe and persistent mental illness.43 A multinational, qualitative study on the processes of recovery was recently completed with 12 individuals in four different countries.60 The main themes were elucidated in several papers and included how the person deals with difficulties, the role of material resources, the roles of formal and informal health systems, the roles of others, and the roles of social and cultural factors. The above research indicates that qualitative methods can effectively illuminate the process of recovery. However, this type of inquiry is limited by the length of time required to collect and interpret information, the inability to attribute causality to relationships, and potential biases due to differences in consumers’ abilities to articulate their experiences. Clearly, quantitative and qualitative methods each have inherent strengths and weaknesses and should be viewed as complementary approaches. Our understanding of recovery will be enriched when both methods are applied.

 

Recovery and Evidence-Based Mental Health Practices

As the recovery movement has grown in the mental health field, so has the development and implementation of evidence-based practices (EBPs). EBPs are interventions for which there is consistent research evidence of positive treatment outcomes.61 Six treatments for SPMI have been identified as having a strong empirical base. These include the use of medication guidelines, illness management and recovery, assertive community treatment, family psychoeducation, supported employment, and integrated substance abuse treatment.62

Both the recovery movement and EBPs are grounded in a growing research literature. Because the concepts of EBPs and recovery have originated from somewhat different traditions and stakeholder groups, they have sometimes been viewed as conflicting.63 Recently, however, the compatibility and integration of EBPs with recovery has been articulated in practice and research.40 Bellack4 summarized the extent to which current evidence-based treatment recommendations are in line with recovery. Similarly, Glynn and colleagues15 outlined ways in which the EBP of family psychoeducation is consistent with a recovery orientation.

Others have recommended that recovery goals be used to inform the development, evaluation, and provision of EBPs.3,14 Anthony and colleagues50 offered eight specific suggestions of how to incorporate a recovery orientation into EBP research. First, outcomes should reflect a recovery orientation and be endorsed by consumers. Current EBP research focuses upon symptoms and relapse rates at the expense of other important outcomes such as self-efficacy, valued work, decent housing, and enrollment in school, which may be deemed more important by consumers. Second, it is important to include subjective outcomes and qualitative methods since the recovery experience has been found to be unique. Qualitative inquiry is a research method designed to focus upon what the person perceives and experiences as the change process. Third, the use of quasi-experimental and correlational research designs should be continued. It is argued that these research designs can effectively inform the development of EBPs and the design of future clinical trials. Fourth, research should strive to understand why EBPs have not been shown to consistently affect recovery-oriented outcomes in order to modify and improve current EBPs as needed. Fifth, because first-person accounts of recovery indicate that the presence of another supportive person is an important factor in their success, future research should more closely examine the role of the helper/consumer relationship in EBPs. It is possible that non-specific factors may be viewed as more helpful than a particular technique or intervention. Sixth, since EBPs represent comprehensive programs that include several components, the use of dismantling studies will identify the specific components that are necessary and account for positive outcomes. This is an important issue to address given political and funding pressures. Seventh, EBP research should test the efficacy of treatments in a variety of cultures and contexts. There is currently a lack of evidence that points to positive outcomes using EBPs with minority groups and various geographic settings. Last, it is recommended that research examine features of EBPs that are based upon recovery values (eg, consumer involvement in the design of programs) to address their impact on outcomes. These values may determine the program’s potential in addition to the specific components and structure of the program itself.

The concept of community integration proposed by Bond and colleagues64 effectively clarifies the relationship between EBPs and recovery. Community integration has been defined as helping consumers “move out of patient roles, treatment centers, segregated housing arrangements, and work enclaves, enabling them to move toward independence, illness self-management, and normal adult roles in community settings.”64 It is viewed as the external manifestation of the recovery experience and has the potential to influence the internal experience of recovery such as having hope and self-confidence. The current EBPs are believed to promote community integration and maximum social and economic independence, which subsequently facilitates the internal experience of recovery, pointing to the potential role of EBPs in recovery. Bond and colleagues64 further outlined ways in which each EBP may contribute to community integration.

Despite these suggestions, the extent to which EBPs foster recovery is presently unclear.65 There is simply a lack of studies that have asked the relevant questions. Due to the paucity of data, researchers have drawn contradictory conclusions about the impact of EBPs on recovery-related outcomes.50,64 Thus, there is a critical need for future researchers to systematically address the influence of EBPs on recovery processes and outcomes.

It is important to acknowledge that the EBP movement is not without its critics. Most notably, the criteria for establishing the status of treatments as evidence based have been said to reflect priorities of the research community rather than consumer preferences (eg, relapse rates versus empowerment). This approach also downplays potentially effective treatments that have yet to reach EBP standards, particularly consumer-run services.66

 

The Role of Evidence-based Practices in Recovery

As researchers begin to evaluate the ways in which recovery is facilitated by current evidence-based practices, it is important for consumers to receive services that improve the ability to function in their environments.67 The basic needs of food, clothing, safety, and shelter must first be met, which serve as a secure base from which to move forward in recovery.68 For some consumers, this may involve offering assistance in accessing Social Security benefits as well as supervised housing programs or subsidized housing. In addition, although medications are necessary in managing symptoms, medications alone have been found to be insufficient.69

Peer support, in the form of mutual support groups, consumer-run services, or consumers as providers within treatment settings may promote recovery by countering stigma and offering hope and motivation to work toward a better future.70 Throughout a person’s recovery, it may additionally be useful to provide EBPs because research has shown that they reduce symptoms and relapse, promote stabilization, provide education, build skills, and encourage the realization of consumer goals. EBPs may also play a role in promoting the specific processes involved in recovery, which is currently being examined. The authors of this article have proposed a model in which the selection of EBPs are linked to each stage of recovery (Table 2). The stages of recovery proposed by Andresen and colleagues36 guided the development of this model. Their work is based upon research and represents an integration of all stage models currently available in the recovery literature. 

 

The proposed model is intended to call attention to the relative contribution of EBPs during the various recovery stages and to stimulate thinking about the role of EBPs throughout recovery. While the EBPs may contribute quite broadly to all stages, some EBPs are likely to play a larger role during certain phases of recovery, which is reflected in the model presented. This authors of this article also recognize that the path to recovery is not linear and that consumers may move back and forth among the various stages. Therefore, frequent assessment of the consumer’s involvement in the recovery stages may be helpful throughout the course of treatment and will better inform treatment planning.

Andresen and colleagues36 note that consumers experience denial and confusion in the initial recovery stage, identified as “moratorium.” They may feel hopeless about their future, confused about the biologic and cognitive changes they are experiencing, and withdraw from others in order to protect themselves. At this beginning point in recovery, pharmacologic treatments according to established guidelines71 are generally useful in diminishing the impact of symptoms. The EBP of assertive community treatment72 (ACT) may be of particular benefit because it is designed for people facing the most challenges73; further, its assertive outreach approach entails working with the person in his or her own environment, providing assistance with activities of daily living, and assisting the person in obtaining needed services. During this stage, not only does the consumer experience a sense of confusion and hopelessness, but the family does as well. Thus, the EBP of family psychoeducation74 is of use in the “moratorium” stage. Family psychoeducation is an EBP which invites the family to participate fully in the treatment process and encourages a strong support network for the consumer.

During the second stage of recovery, called “awareness,” consumers begin to feel hopeful about leading a better life and realize that recovery is possible. They learn that one can be viewed as a person with many different aspects, including an illness, rather than viewed wholly as a “sick person.”36 Medication management services, ACT, and family psychoeducation are useful in this stage. Medications are continued particularly since it has been found that they not only reduce symptoms but also help to prevent the recurrence of symptoms. The provision of ACT services may help maintain the person’s psychiatric stabilization and engagement in mental health services. In addition, family psychoeducation may engender hope as well as facilitate awareness of recovery by providing opportunities for consumers to meet others who are progressing in recovery and by presenting information about the recovery concept and its supporting research literature during an educational workshop.

The third stage of recovery, “preparation,” involves preparing for the work involved in recovery. This work may involve evaluating values, strengths, and challenges; beginning to learn about mental illness and strategies for managing the illness; and becoming more involved with treatment groups or peers.36 Medication management and ACT services again play a role in helping the person maintain stability and treatment involvement. To help consumers develop individualized coping skills, ACT works with consumers individually, while family psychoeducation offers information to families and consumers through a workshop and structured problem-solving exercises. The highly structured EBP of illness management,75 which may be provided individually or as a group, is particularly useful during this recovery stage. Illness management is designed to provide consumers information about mental illness and how to cope more effectively.

During the fourth stage of “rebuilding,” consumers begin the “hard work of recovery.” They strive to develop a positive self identity and pursue personally meaningful goals, which may require a re-evaluation of previous goals and dreams. Consumers also take responsibility for managing the mental illness and resuming control of their lives, which may involve taking risks and managing potential setbacks without losing hope.36 Medications and ACT continue to assist consumers in maintaining stability. Members of the ACT team may also provide educational and/or employment services for consumers who have a desire to pursue these goals. Family psychoeducation promotes rebuilding by assisting consumers with setting and working toward goals in a step-by-step fashion. Illness management provides opportunities for consumers to explore areas of their lives in which they are most and least satisfied and teaches the importance of establishing one or two obtainable goals during recovery. This EBP also provides information about how to develop a detailed relapse prevention plan, which may assist in managing a potential setback. Personal76 and cognitive therapy for schizophrenia,77 which have been identified as two specific illness-management programs, may assist the person in forging a positive identity and exploring meaningful life goals. The EBP of supported employment78 may be introduced during this stage to assist consumers in finding job placements if their goals involve employment.

The last stage of recovery has been referred to as “growth.” At this stage, consumers are able to manage the illness effectively and are, thus, able to lead a life with meaning, resiliency, and a sense of confidence in their ability to manage potential setbacks. They are also able to hold a positive self identity and realize that the experience of having a mental illness has strengthened them.36 Each of the EBPs may play a role during this stage of recovery. For example, medications and ACT are naturally designed to assist the person in managing the illness and symptoms, though the ACT team’s focus will most likely shift to supporting recovery-oriented goals. Family psychoeducation and illness management provide opportunities for the person to learn strategies to manage the illness effectively and make progress toward goals. The EBP of supported employment may assist consumers who find meaning in holding a job. Employment provides several benefits for people in recovery, including “additional income…improved self-esteem…a daily structure, a reason to get out of bed in the morning, an identity, and an extended social network.”69 Employment may also positively influence the internal experiences of recovery, such as feelings of hope and self-confidence.64

The EBP of integrated substance abuse treatment is a necessary treatment for many consumers. More than 50% of people with SPMI are further challenged by substance abuse, creating a high risk for numerous negative outcomes. Research has shown that treating the substance use disorder and mental illness together promotes recovery.79 It is recommended that one core team provide integrated services through all stages of recovery from “moratorium” to “growth” and promote consumer motivation to reduce or abstain from the negative effects of substance abuse.

Because ACT in particular has been viewed by some consumers as restrictive and paternalistic, it is important to note that ACT was specifically developed for a subset of consumers who were unable to function independently in the community. ACT was intended to provide the structure and support necessary for successful community life. Therefore, it is essential to recognize that ACT is utilized as the consumer identifies or requests a need for it, and while engaged in ACT, consumers maintain a decisive voice in which services they receive and the way in which they receive them.73

For example, one consumer, who will be named Mary, was positively affected by the use of a combination of EBPs in her recovery process. Initially, the effects of illness caused Mary to be unable to take of her basic needs and self independently, requiring that she live with her family for support. In the “moratorium” stage, Mary accepted her need for medications and recognized the negative effects of substances use. Although an ACT program was not available, intensive case-management services and family psychoeducation were provided. As Mary and her family learned about the illness, they entered the stages of “awareness” and “preparation,” where they came to understand and accept the illness process as well as learn strategies to cope with illness effects. Individual illness-management sessions with Mary’s therapist significantly facilitated this process. The stage of “rebuilding” emerged as Mary and her family began to apply the learnd coping strategies in everyday life in a step-by-step manner. Although the “rebuilding” stage had forward and backward movement, over time the accumulative effect of improved coping facilitated a sense of hope and confidence in Mary. She was able to seek supportive employment and educational opportunities, which encouraged her independence in the “growth” stage. Currently, Mary lives independently with the support of friends and family, works part-time, and attends school. She engages in public speaking related to mental illness and has become a peer counselor. Most importantly, Mary reports being happy and satisfied in her life.

The framework described represents an attempt to clinically integrate EBPs with a stage model of recovery.36 EBPs and the recovery construct are not contradictory but instead can be viewed as complementary when offering treatment services during certain phases of recovery. In addition, when offering EBPs as treatment options to consumers, it is important to utilize such recovery principles as self-direction, empowerment, and respect. Both EBPs and recovery can be used to inform mental health policy and research.

 

Conclusion

Recovery is a recent movement in the mental health field that provides much hope and inspiration to consumers and families. The personal accounts of consumers and longitudinal studies demonstrate that recovery clearly is possible. A variety of definitions of recovery have been proposed and there is some debate as to whether it is more appropriate to view recovery as an outcome or a process. The integration of the recovery movement within an evidence-based practice framework has also been recently discussed in the literature. Although quantitative and qualitative methods are frequently viewed as incompatible, both methods may be of most benefit in recovery research.

However, the recovery movement has its critics. Practitioners and some researchers are concerned that the term is overused and that the case for recovery is overstated, setting unrealistic expectations and promoting additional stigma.80,81 Thus, future research efforts that include all stakeholders have the best chance for a balanced perspective and will establish a solid research base for recovery.

A recovery vision has been articulated. Consumers, families, practitioners, and researchers now share the common goals of educating other stakeholders about the possibility of recovery and developing systems of care that promote recovery. For many people with severe and persistent mental illness, recovery is not only a possibility but a reality. PP

 

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68.    Borg M, Sells D, Topor A, Mezzina R, Marin I, Davidson L. What makes a house a home: the role of material resources in recovery from severe mental illness. Am J Psychiatr Rehabil. 2006;8(3):243-256.
69.    Torrey EF. Surviving Schizophrenia: a Manual for Families, Consumers, and Providers. New York, NY: Quill; 2001.
70.    Davidson L, Chinman M, Kloos B, Weingarten R, Stayner D, Kraemer Tebes J. Peer support among individuals with severe mental illness: a review of the evidence. Clin Psychol Sci Prac. 1999;6(2):165-187.
71.    Rush AJ, Crismon L, Kashner TM, et al. Texas medication algorithm project, phase 3 (TMAP-3): rationale and study design. J Clin Psychiatry. 2003;64(4):357-369.
72.    Stein LI, Test MA. Alternative to mental hospital treatment: i. conceptual model, treatment program, and clinical evaluation. Arch Gen Psychiatry. 1980;37(4):392-397.
73.    Phillips SD, Burns BJ. Assertive Community Treatment Workbook. Substance Abuse Mental Health Services Administration; 2003.
74.    McFarlane WR, Dixon L, Lukens E, Lucksted A. Family psychoeducation and schizophrenia: a review of the literature. J Marital Fam Ther. 2003;29(2):223-245.
75.    Mueser KT, Corrigan PW, Hilton DW, et al. Illness management and recovery: a review of the research. Psychiatr Serv. 2002;53(10):1272-1284.
76.    Hogarty GE. Personal Therapy for Schizophrenia & Related Disorders. New York, NY: The Guilford Press; 2002.
77.    Kingdon DG, Turkington D. Cognitive Therapy of Schizophrenia. New York, NY: The Guildford Press; 2005.
78.    Bond GR, Becker DR, Drake RE, et al. Implementing supported employment as an evidence-based practice. Psychiatr Serv. 2001;52(3):313-322.
79.    Drake RE, Essock SM, Shaner A, et al. Implementing dual diagnosis services for clients with severe mental illness. Psychiatr Serv. 2001;52(4):469-476.
80.    Roe D, Rudnick A, Gill KJ. The concept of “being in recovery.” Psychiatr Rehabil J. 2007;30(3):171-173.
81.    Remington G, Shammi C. Overstating the case about recovery? Psychiatric Serv. 2005;56(8):1022.

 

Dr. Robinson is a consultant with Worldwide Drug Development in Burlington, Vermont.

Disclosure: Dr. Robinson has served as a consultant to Bristol-Myers Squibb, CeNeRx, Epix, Genaissance, Medicinova, Ono Pharmaceuticals, Pfizer, and Somerset.

 


 

Deficiency of monoamine neurotransmitter levels was proposed as the underlying cause of depressive disorders over 40 years ago. Extensive biochemical studies and pharmacologic evidence show that all antidepressants modulate functional levels of monoamine neurotransmitters implicated in depression (ie, serotonin, norepinephrine, and dopamine). Evidence of norepinephrine, serotonin, and, more recently, dopamine’s key roles in the biology of depression is compelling; however, the primary mechanism of monoamine depletion in depression remains unresolved.


The leading targets for the cause of depression include deficient monoamine neurotransmitter synthesis and dysregulation of both monoamine neuroreceptors and monoamine neuronal transporters. Despite intense study, none of these etiologies have emerged as the primary factor underlying monoamine deficiency. Recently, investigators from the University of Toronto conducted a series of positron emission tomography (PET) studies providing compelling evidence that elevated brain monoamine oxidase A (MAO-A) levels could be the primary monoamine-lowering mechanism in major depressive disorder (MDD).
1

 

Possible Causes of Monoamine Deficiency in Depression

Studies of postmortem brain tissues from patients with depression or suicidal behavior have failed to detect a deficiency in either tyrosine hydroxylase, the rate-limiting enzyme for norepinephrine synthesis, or tryptophan hydroxylase, the rate-limiting enzyme for serotonin synthesis.2-5 The post-mortem studies’ results are inconsistent, either detecting no change or in some cases modest increases in enzymatic pathways for monoamine synthesis in brain tissues of affected individuals.

Since many studies find no decrement in monoamine transporter density indices in brain tissues of depressed and suicidal patients, loss of  monoamine-releasing neurons appears to be an unlikely mechanism of neurotransmitter deficiency. Even those studies reporting a reduction found decreases in monoamine transporter indices of only modest magnitude (≤25%)5-8 in contrast to much greater monoamine transporter loss associated with the neurodegenerative disorders.9

In a comprehensive review of the evidence relating to mechanisms of serotonin (5-HT) depletion in depression, Stockmeier10 commented on the many sources of biologic variance in postmortem and brain imaging studies, which confound interpretation of results. In addition to postmortem degradation of brain monoamines and enzymes, other uncontrolled variables need to be considered, such as absent or retrospective diagnoses; exposure to smoking, drugs or alcohol; and other sources of biologic and demographic variance.

Extensive evidence supports the notion that a functional 5-HT deficiency plays a role in depression, but investigations still fail to identify the cause of this monoamine deficiency. A wealth of evidence documents that biochemical abnormalities are present in depression, including low 5-hydroxy-indoleacetic acid in the cerebrospinal fluid of patients with suicidal behavior, decreased 5-HT uptake and 5-HT transporter- (5-HTT) binding sites in brain and platelets of depressed subjects, and blunted neuroendocrine response to serotonergic stimuli. Alterations of 5-HT receptor densities have been documented in the prefrontal cortex of subjects with depression and suicide; 5-HT2A receptors were increased and 5-HT1A receptors decreased in cerebral cortical regions of both drug-free and antidepressant-treated patients.11

Assessing current understanding of the various biochemical abnormalities reported in postmortem and brain imaging studies, Stockmeier10 concluded that the methodologic heterogeneity of these investigations, with their often inconsistent and conflicting results, precludes attempts at identifying the underlying pathophysiology of serotonin dysfunction in depression.

 

5-HT Transporter in Depression

Neuroimaging studies utilizing an 11C-labeled specific ligand for monoamine transporter-binding sites now permit in vivo 5-HTT density measurement in brain regions of subjects experiencing a major depressive episode (MDE).12 Brain 5-HTT binding potential, which serves as an index of transporter-receptor density, may be a key function during an MDE because the monoamine transporter regulates extracellular 5-HT levels within the central nervous system (CNS). 5-HTT binding potential was assessed in 22 nonsmoking, medication-free (≥3 months) patients with MDEs and 20 age-matched controls. No overall group differences in binding potential between patients and healthy patients were observed in any of the brain regions studied by PET. However, a post hoc analysis of the data found a correlation between highly negativistic attitude and increased transporter-binding potential (mean increase=21%).12

 

PET Study of Brain MAO-A

This same group of investigators employed a positron emission tomography (PET) radiotracer selective for the monoamine oxidase (MAO)-A isozyme, 11C-labeled harmine, to assess the amount present of this enzyme, which serves as the major catabolic pathway in the CNS for the monoamine neurotransmitters serotonin and norepinephrine. Studies in animal models and in humans at clinically relevant doses indicate that harmine is a specific and reversible ligand for the MAO-A form of the enzyme.13-15 Harmine’s specific distribution volume, which is derived from the ratio of brain and plasma harmine concentrations at equilibrium, provides a measure of MAO-A enzyme density and serves as an index for the amount of enzyme present in various brain regions.

This milestone study found consistent and marked differences in the specific distribution volume of MAO-A in untreated, depressed patients with MDD and matched healthy controls in several areas of the brain.1 Methodologic strengths of this study include the fact that PET testing involved living, non-smoking, medication-free patients who were carefully diagnosed by structured interview for presence of MDE. The increase in MAO-A distribution volume in MDE patients was highly significant compared with normal controls, with a mean increase of 34% (P<0.001) and an effect size of two standard deviations. This difference in MAO-A levels represents a striking disparity between patients and healthy subjects. MAO-A enzyme levels were elevated in MDE patients throughout every brain region tested, including the prefrontal cortex, temporal cortex, anterior and posterior cingulated cortex, thalamus, caudate, putamen, hippocampus, and midbrain.

Since MAO-A metabolizes all three major monoamine neurotransmitters (selectively, for norepinephrine and serotonin) and serves as the major catabolic pathway in the CNS for each of these transmitters, it is plausible that elevated MAO-A density constitutes the primary factor leading to monoamine deficiency. No prior study has convincingly explained why monoamine levels are deficient in depression. The presence of elevated MAO-A levels, by enhancing the catabolism of monoamine neurotransmitters, may produce a basal state of monoamine depletion predisposing to depression. Other secondary influences, eg, differences in monoamine transporters and receptor sensitivity, may further modulate extracellular monoamine concentrations, affecting symptom type, severity, and response to treatment.

 

Conclusion

It is postulated that a state of functional monoamine deficiency underlies depressive disorders, but the primary cause has not been elucidated despite extensive investigation. A recent PET neuroimaging study of brain MAO-A levels in patients with MDD found a marked increase in this catabolic enzyme compared with healthy subjects. Methodologic strengths of this study include the fact that measurements were conducted in living, nonsmoking, and medication-free patients carefully screened for presence of an MDE. Both the effect size and the ubiquitous nature of this increase in MAO-A enzyme levels in all brain regions studied suggest that elevated MAO-A levels may be the primary cause of monoamine depletion in depression. PP

 

References

1. Meyer JH, Ginovart N, Boovariwala A, et al. Elevated monoamine oxidase a levels in the brain: an explanation for the monoamine imbalance of major depression. Arch Gen Psychiatry. 2006;63(11):1209-16.
2. Zhu MY, Klimek V, Dilley GE, et al. Elevated levels of tyrosine hydroxylase in the locus coeruleus in major depression. Biol Psychiatry. 1999;46(9):1275-86.
3. Boldrini M, Underwood MD, Mann JJ, Arango V. More tryptophan hydroxylase in the brainstem dorsal raphe nucleus in depressed suicides. Brain Res. 2005;1041(1):19-28.
4. Bonkale WL, Murdock S, Janosky JE, Austin MC. Normal levels of tryptophan hydroxylase immunoreactivity in the dorsal raphe of depressed suicide victims. J Neurochem. 2004;88(4):958-64.
5. Mann JJ, Huang YY, Underwood MD, et al. A serotonin transporter gene promoter polymorphism (%-HTTLPR) and prefrontal cortical binding in major depression and suicide. Arch Gen Psychiatry. 2000;57(8):729-738.
6. Meyer JH, Kruger S, Wilson AA, et al. Lower dopamine transporter binding potential in striatum during depression. Neuroreport. 2001;12(18):4121-4125.
7. Austin MC, Whitehead RE, Edgar CL, et al. Localized decrease in serotonin transporter-immunoreactive axons in the prefrontal cortex of depressed subjects commiting suicide. Neuroscience. 2002;114(3):807-815.
8. Neumeister A, Willeit M, Praschak-Rieder N, et al. Dopamine transporter availability in symptomatic depressed patients with seasonal affective disorder and healthy controls. Psychol Med. 2001;31(8):1467-1473.
9. Hornykiewicz O. Biochemical aspects of Parkinson’s disease. Neurology. 1998;51(2 suppl 2):2-9.
10. Stockmeier CA. Involvement of serotonin in depression: evidence from postmortem and imaging studies of serotonin receptors and the serotonin transporter. J Psychiatr Res. 2003;37(5):357-373.
11. Mann JJ. Role of serotonin system in the pathogenesis of major depression and suicide. Neuropsychopharmacology. 1999;21(2 suppl):99-105.
12. Meyer JH, Houle S, Sagrati S, et al. Brain serotonin transporter binding potential measured with carbon 11-labeled DASB positron emission tomography: effects of major depressive episodes and severity of dysfunctional attitudes. Arch Gen Psychiatry. 2004;61(12):1271-1279.
13. Bergstrom M, Westerberg G, Langstrom B. 11C-harmine as a tracer for monoamine oxidase A (MAO-A): in vitro and in vivo studies. Nucl Med Biol. 1997;24(4):287-293.
14. Bergstrom M, Westerberg G, Kihlberg T, Langstrom B. Synthesis of some 11C-labelled MAO-A inhibitors and their in vivo uptake kinetics in rhesus monkey brain. Nucl Med Biol. 1997;24(5):381-388.
15. Ginovart N, Meyer JH, Boovariwala A, et al. Positron emission tomography quantification of [11C]-harmine binding to monoamine oxidase-A in the human brain. J Cereb Blood Flow Metab. 2005;26(3):330-344.

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David L. Ginsberg, MD


Primary Psychiatry.
2007;14(12):19-23

 

Dr. Ginsberg is vice-chair of clinical affairs in the Department of Psychiatry at New York University Medical Center in New York City.


Disclosure: Dr. Ginsberg receives honoraria for lectures, papers, and/or teaching from AstraZeneca and GlaxoSmithKline; and receives research support from Cyberonics.

 


 

Do Antidepressants Reduce Male Fertility?

Over the past 2 decades, serotonin reuptake inhibitors (SRIs) have become mainstays in the pharmacologic treatment of depression and anxiety disorders. Surprisingly, given their widespread use around the world, few studies have been conducted to evaluate the impact of SRIs on male fertility. The following is a report of two men treated at a high-volume male infertility practice at New York Hospital-Cornell Medical Center in New York City who presented with a clear temporal association between selective seretonin reuptake inhibitor (SSRI) use and impairment in sperm motility and/or sperm transport (emission). Both men subsequently showed improvement in sperm counts and motility after discontinuation of their SSRIs, with one of the men also showing a similar association with the norepinephrine-dopamine reuptake inhibitor (NDRI) bupropion.1

 The first patient was a 44-year-old man with a 7-month history of primary infertility. He was taking citalopram for the treatment of depression. He did not consume alcohol, use tobacco or illicit drugs, or have any toxin exposures. General physical examination was unremarkable. A genitourinary examination revealed a normal testicular volume, normal epididymides bilaterally, no varicoceles, and normal rectal findings. The serum testosterone, estradiol, follicle-stimulating hormone, luteinizing hormone, and prolactin levels were all normal. Scrotal ultrasonography revealed no abnormalities. The sperm antibody test was negative, while Y chromosome testing revealed no microdeletions.

During the course of the 15 months in which he was evaluated, the patient underwent multiple semen analyses. His initial semen analysis, performed while he was taking citalopram, revealed marked oligospermia and 1% motility. A repeat semen analysis 1 month after he had discontinued citalopram showed a marked improvement in all parameters to within the normal range. Shortly thereafter, bupropion was initiated for treatment of his depression. Semen analysis on bupropion showed a decrease in sperm concentration to 21 million/mL with 10% motility.

After two failed in vitro fertilization attempts, the patient was reassessed approximately 1 year after his initial presentation. He was still taking bupropion. A sperm chromatin structural assay revealed 76% DNA fragmentation. He was advised to taper off bupropion to determine whether his semen parameters would improve. A follow-up semen analysis performed 1 month after bupropion discontinuation showed 75% motility and a marginally normal sperm concentration of 41 million/mL. A second semen analysis performed 2 months after he had stopped taking bupropion demonstrated normal sperm concentration and motility.

The second patient was a 35-year-old man who presented for evaluation of primary infertility. He was taking sertraline for the past 5 years for treatment of depression. Previous surgery included left orchiopexy with left inguinal hernia repair at 6 years of age. He did not use tobacco or illicit drugs, nor had he any toxin exposures. His physical examination revealed a normally masculine, healthy-appearing male. His right testis measured 25 cm3, his left measured 18 cm3, and the bilateral vasa deferentia were palpable. He had no evidence of epididymal induration or obstruction and no varicoceles, and the rectal findings were normal. Results of an endocrinologic evaluation were also normal. The scrotal ultrasound findings were normal. The sperm antibody test was negative, and his genetic evaluation was normal.

The patient’s initial semen sample while on sertraline was of normal volume but had a sperm concentration of 20,000 and showed no motile sperm. A repeat semen analysis immediately after he discontinued sertraline revealed similar results. However, after 3 months, all parameters were normal, with 40 million total motile sperm in his ejaculate.

Due to relapse of the patient’s depression, bupropion was prescribed shortly after the third semen analysis. Venlafaxine was added to the regimen for augmentation due to refractory depression. Semen analyses performed while the patient was taking both medications in April and May of that year again revealed no motile sperm. In anticipation of an in vitro fertilization cycle early that summer, both medications were stopped after the May analysis. A follow-up semen analysis 1 month after discontinuation of both bupropion and venlafaxine showed a return to normal sperm parameters.

The medical literature assessing the impact of antidepressants on male fertility is sparse. In 1966, a preliminary study performed to assess the use of the tricyclic antidepressant (TCA) trimipramine in patients with schizophrenia revealed the incidental observation of a possible adverse effect on spermatogenesis.2 To further evaluate this finding, a study was designed to investigate trimipramine’s effect on semen samples in 11 healthy adult men.3 After 8 weeks of medication administration, a general decrease in sperm concentration and motility was noted, although this trend did not achieve statistical significance. Over a decade later, in vitro studies revealed that the TCAs imipramine, nortriptyline, and desmethylimipramine were potent inhibitors of sperm motility.4,5 However, an in vivo study failed to demonstrate a significant change in sperm concentration or motility after 3 weeks of treatment with desmethylimipramine. Another study6 Compared the semen analysis results of nine patients after 3 months of clomipramine therapy with those of a control group of 11 patients with erectile dysfunction. While approximately 66% of the control group had normal semen parameters, none of the patients taking clomipramine had normal semen analysis results.

While it is well established that SSRIs may delay or impair ejaculation, few studies assessing the potential impact of SSRIs on sperm quality have yet been studied. An abstract by St. Dennis and colleagues7 indicated a marked increase in sperm DNA fragmentation in smokers taking fluoxetine compared with nonsmokers taking fluoxetine, though no differences in sperm motility were identified. Given the association between SSRIs and delayed ejaculation, it is possible that SSRIs may negatively influence sperm transport as well. If that were the case, then sperm motility and eventually, sperm concentrations and even sperm DNA integrity, might also be adversely affected. The authors of the case report presented here1 suggest that in the patients described, the time course of recovery to normal semen parameters is more consistent with a drug effect on sperm transport than with an effect on sperm production.

Finally, in a recent study by Kumar and colleagues,8 the SSRIs fluoxetine, sertraline, paroxetine, citalopram, and fluvoxamine all exhibited spermicidal activity in vitro. Among SSRIs, fluoxetine demonstrated the most potent spermicidal activity, evaluated as comparable to that of the over-the-counter contraceptive Nonoxynol-9. According to the authors of this study, the spermicidal action of SSRIs does not appear to be mediated by serotonin transporters but rather by their effect on adenosine triphosphate synthesis via inhibition of oxidative phosphorylation in sperm mitochondria.9 Such inhibition may be mediated by the interaction of SSRIs with phospholipids in the inner mitochondrial membrane or possibly due to an interaction of SSRIs with sulfhydryl groups present over the sperm membrane. This is sometimes characterized as a non-detergent mode of action.

Regardless of mechanism of action, it appears that SRIs, and even the NDRI bupropion, may reversibly suppress male fertility in susceptible individuals through an effect on sperm quality and/or number. At this point, how widespread or severe are these effects is not precisely known, but based on clinical experience with these drugs over the last 20 years, it appears to be limited to a relatively small percentage of individuals.

As a follow-up investigation to these initial case reports, Tanrikut and Schlegel1 have recently completed a 5-week, crossover pilot study of 30 normal healthy men to ascertain possible effects of the SSRI paroxetine on semen parameters. In this trial, serial semen analyses were obtained for each subject both while on paroxetine and 1 month after its discontinuation. Comparisons between semen parameters on and off paroxetine will be used to evaluate the frequency and significance of semen analysis changes during SSRI treatment. The data analysis for this study is currently ongoing, with results expected in the coming months. PP

 

References

1. Tanrikut C, Schlegel PN. Antidepressant-associated changes in semen parameters. Urology. 2007;69(1):185.e5-e7.
2. Simpson GM, Blair JH, Iqbal J, Iqbal F. A preliminary study of trimipramine in chronic schizophrenia. Curr Ther Res Clin Exp. 1966;8(5):225-231.
3. Kurland AA, Pinto A, Destounis N, Babikow PW. Effects of trimipramine (surmontil) on spermatogenesis and mood in normal volunteers. Curr Ther Res Clin Exp. 1970;12(4):186-191.
4. Levin RM, Shofer J, Greenberg SH. A quantitative method for determining the effects of drugs on spermatozoal motility. Fertil Steril. 1980;33(6):631-635.
5. Levin RM, Amsterdam JD, Winokur A, Wein AJ. Effects of psychotropic drugs on human sperm motility. Fertil Steril. 1981;36(4):503-506.
6. Maier U, Koinig G. Andrological findings in young patients under long-term antidepressive therapy with clomipramine. Psychopharmacology (Berl). 1994;116(3):357-359.
7. St. Dennis C, Schimmels J, Short R, et al. Selective serotonin reuptake inhibitor (SSRI) causes sperm chromatin damage in smoking men. Abstract presented at: the Annual Meeting of the American Society of Andrology; April 2-5, 2005; Seattle, WA.
8. Kumar VS, Sharma VL, Tiwari P, Singh D. The spermicidal and antitrichomonas activities of SSRI antidepressants. Bioorg Med Chem Lett. 2006;16:2509-2512.
9. Curti C, Mingatto FE, Polizello AC, Galastri LO, Uyemura SA, Santos AC. Fluoxetine interacts with the lipid bilayer of the inner membrane in isolated rat brain mitochondria, inhibiting electron transport and F1F0-ATPase activity. Mol Cell Biochem. 1999;199(1-2):103-109.

 

Low-Dose Aripiprazole to Treat Ephedrine Dependence

Ephedrine is a sympathomimetic amine similar in structure to the synthetic derivatives amphetamine and methamphetamine. Ephedrine is commonly used as a stimulant, appetite suppressant, concentration aid, and decongestant as well as to treat hypotension associated with regional anesthesia. Chemically, it is an alkaloid derived from various plants in the genus Ephedra (family Ephedraceae). It is most usually marketed in the hydrochloride and sulfate forms.

Aripiprazole is an atypical neuroleptic indicated for the treatment of schizophrenia and acute manic and mixed episodes associated with bipolar disorder. A potent dopamine partial agonist, aripiprazole acts as an antagonist at dopamine (D)2 receptors under hyperdopaminergic conditions and as a D2 agonist under hypodopaminergic conditions. It has been theorized that dopamine partial agonists may be able to stabilize the dopaminergic system without inducing a hypodopaminergic state, thereby reducing the risk of side effects associated with pure blockade of dopamine receptors. In addition to these effects, aripiprazole also acts as a partial agonist at serotonin (5-HT)1A and as an antagonist at 5-HT2A receptors.1 Aripiprazole has a low incidence of clinically significant weight gain and hyperlipidemia.2,3 The following is a report in which use of low-dose aripiprazole resulted in unexpected remission of a 20-year history of ephedrine dependence.4

A 37-year-old woman with an eating disorder and major depressive disorder, initially presented in 2005 to the University of New Mexico Mental Health Center  when she was forced into treatment by her probation officer after a routine urine drug screen was positive for methamphetamine. The patient adamantly denied having ever used methamphetamine but did acknowledge a 20-year history of abusing over-the-counter medications to maintain her weight. Subsequent hair analysis confirmed the presence of ephedrine but not methamphetamine.

The patient reported having an eating disorder since she was 17 years of age, characterized by binge eating and vomiting as well as overuse of laxatives and over-the-counter stimulants. Other problems included recurrent episodes of major depression, impulsive and compulsive shopping, and forgery. The forgery resulted in her arrest, conviction, time in jail, and subsequent probation. The patient also described a 20-year history of use of as much as 1.5 mg/day of ephedrine. During this period, her ephedrine dependence continued despite comprehensive psychiatric care including inpatient hospitalization and outpatient medication management (bupropion, sertraline, lithium, paroxetine, and venlafaxine) as well as individual and group psychotherapy.

At the time of initial presentation, the patient exhibited significant depression, daily vomiting, impulsive and compulsive spending, and ephedrine dependence. Her body mass index was 18.5 kg/m2. There was no evidence of bipolar spectrum disorder. Fluoxetine 40 mg/day was initiated, then gradually increased to 80 mg/day. The patient also received cognitive-behavioral therapy. After 6 months, her depression completely remitted. However, her daily vomiting, impulsive/compulsive shopping, and ephedrine dependence continued unabated.

The patient had limited insight into the problems associated with her ephedrine dependence. She refused to consider the risk of cardiac complications that could result from excessive ephedrine intake. Moreover, she continued to use ephedrine despite having to spend 3 nights in the county jail after a second urine drug screen was positive for methamphetamine. Subsequent hair analysis demonstrated this to be a false positive.

The patient gave consent for off-label use of aripiprazole, which was started at a dosage of 2.5 mg/day. During the next 8 weeks, the patient’s spending behaviors as well as her bingeing and vomiting did not change significantly. Surprisingly, however, during this same period she completely tapered herself off ephedrine, proclaiming that it was not helping her anymore. Subsequently, the patient explained that while for years ephedrine had helped her maintain a very high energy level, she was able to achieve the same effect with aripiprazole. Eight weeks later, the patient elected to discontinue aripiprazole, as she was concerned about gaining weight from it. She reported that her clothes were tighter, which she attributed to aripiprazole-induced weight gain rather than to the discontinuation of ephedrine. At last follow-up, 5 months after first taking aripiprazole, the patient remained ephedrine-free, fulfilling criteria for ephedrine dependence in early full remission.

Data on the pharmacologic treatment of stimulant dependence is limited. Some have suggested that dopamine partial agonists, including aripiprazole, might be useful for treating withdrawal and craving symptoms in cocaine-dependent patients.5 Rats administered aripiprazole show fewer cocaine-dependent behaviors than do controls.6 Others have shown that aripiprazole can attenuate the effects of d-amphetamine in people as well.7-9

If aripiprazole has utility in the treatment of cocaine and d-amphetamine dependence, then it may also be useful for dependence on over-the-counter stimulants. Currently, there are no Food and Drug Administration-approved medications for stimulant dependence. Patients with eating disorders not infrequently use amphetamines and other stimulants to maintain weight loss.10,11 Given its relatively favorable side-effect profile and low risk of weight gain compared to other second-generation atypical antipsychotics, aripiprazole in low dose may be beneficial for the treatment of ephedrine dependence in eating-disordered patients. Randomized controlled trials are indicated to confirm these preliminary findings. PP

 

References

1. Abilify [package insert]. San Francisco, CA: Otsuka Pharmaceutical Group; 2005.
2. McQuade RD, Stock E, Marcus R, et al. A comparison of weight change during treatment with olanzapine or aripiprazole: results from a randomized, double-blind study. J Clin Psychiatry. 2004;65(suppl 18):47-56.
3. Potkin SG, Saha AR, Kujawa MJ, et al. Aripiprazole, an antipsychotic with a novel mechanism of action, and risperidone vs placebo in patients with schizophrenia and schizoaffective disorder. Arch Gen Psychiatry. 2003;60(7):681-690.
4. Arnold KK, Yager J. A case of unexpected and selective remission of a 20-year history of ephedrine dependence following treatment with low-dose aripiprazole. J Clin Psychiatry. 2007:68(10):1620-1621.
5. Childress AR, O’Brien CP. Dopamine receptor partial agonists could address the duality of cocaine craving. Trends Pharmacol Sci. 2000;21(1):6-9.
6. Feltenstein MW, Altar CA, See RE. Aripiprazole blocks reinstatement of cocaine seeking in an animal model of relapse. Biol Psychiatry. 2007;61(5):582-590.
7. Lile JA, Stoops WW, Vansickel AR, Glaser PE, Hays LR, Rush CR. Aripiprazole attenuates the discriminative-stimulus and subject-rated effects of d-amphetamine in humans. Neuropsychopharmacology. 2005;30(11):2103-2114.
8. Stoops WW. Aripiprazole as a potential pharmacotherapy for stimulant dependence: human laboratory studies with d-amphetamine. Exp Clin Psychopharmacol. 2006;14(4):413-421.
9. Stoops WW, Lile JA, Glaser PE, Rush CR. A low dose of aripiprazole attenuates the subject-rated effects of d-amphetamine. Drug Alcohol Depend. 2006;84(2):206-209.
10. Wiedrman MW, Pryor T. Substance use among women with eating disorders. Int J Eating Disord. 1996;20(2):163-168.
11. Piran N, Robinson SR. Associations between disordered eating behaviors and licit and illicit substance use and abuse in a university sample. Addict Behav. 2006;31(10):1761-1775.

 

Topiramate-Induced Facial Myoclonus

Topiramate is a sulfamate-substituted monosaccharide indicated for adjunctive treatment of adult partial-onset epilepsy.1 It blocks voltage-gated sodium channels, enhances γ-aminobutyric acid (GABA) via its actions on the GABAA receptor, antagonizes the kainate aminomethyl phosphonic acid subtype of the glutamate receptor, and inhibits carbonic anhydrase.1 Due to its ability to suppress appetite and cause weight loss, it has gained increasingly widespread use among clinicians as a treatment for psychotropic-induced weight gain, binge-eating disorder, and even bulimia nervosa.2-5 Other research suggests that topiramate may also be effective for the treatment of posttraumatic stress disorder,6 obstructive sleep apnea,7 opiate and benzodiazepine withdrawal,8,9 kleptomania,10 alcohol dependence,11 self-injurious behavior,12 aggression,13 nonparaphilic sexual addiction,14 olfactory hallucinations,15 vascular hemichorea/hemiballism,16,17 vascular generalized chorea,18 and even the promotion of scar healing.19

In studies of epilepsy, the most frequently reported side effects of topiramate were somnolence, dizziness, paresthesias, ataxia, speech disorders, cognitive dysfunction, psychomotor slowing, headache, nausea, nystagmus, tremor, fatigue, gastrointestinal upset, visual disturbances, and renal calculi.1 Dose-related side effects include difficulty concentrating, tremor, mood lability, fatigue, confusion, and weight loss.20,21 There are also reports post-marketing of topiramate-induced bilateral angle-closure glaucoma,22 topiramate-induced depression,23 and of oligohidrosis and metabolic acidosis.20 The following is a report of two patients who developed reversible facial myoclonus in association with use of topiramate.24

The first patient was a 28-year-old man with posttraumatic frontal lobe epilepsy who was switched to topiramate monotherapy after failure on phenytoin. Topiramate was initiated at 25 mg/day, then increased by 25 mg every week. Phenytoin was tapered to discontinuation. Four days after a topiramate dose of 75 mg BID was reached, the patient started to experience symmetrical and synchronous twitchings of his facial muscles predominantly involving his forehead. An electromyography (EMG) documented that the twitches occurred in clusters lasting up to 10 seconds and had a frequency of 6–8 Hz, with each jerk lasting between 50 and 100 milliseconds. The twitches were not associated with any epileptiform activity on the electroencephalogram (EEG). Neurologic examination and routine blood work were normal. Upon reduction of the topiramate dose, there was a gradual improvement in the twitches that disappeared when topiramate was lowered to 100 mg/day. Over the next few weeks, topiramate was gradually discontinued, with no recurrence of facial myoclonus over the last 10 months on a subsequent course of oxcarbazepine monotherapy.

The second patient was a 49-year-old woman who presented with new-onset complex partial seizures. Topiramate was initiated at 25 mg BID, then increased by 25 mg every week. Three days after a daily dose of 150 mg/day was reached, the patient started to experience clusters of symmetrical and synchronous facial twitches involving her forehead and periorbital muscles. The episodes were very frequent, with no provoking factors, and were quite distressful to the patient. Her neurologic exam and routine blood work were normal. Upon reduction of the topiramate dose to 100 mg/day, the facial myoclonus disappeared and did not recur over the next 7 months.

In both patients described above, facial myoclonus appears to be a dose-related adverse event associated with topiramate. Further, the myoclonus appears to be of subcortical origin based on its segmental distribution and periodicity, the absence of concomitant spikes on EEG, and the relatively long duration of the twitches on EMG.25 Given the widespread, including off-label use of topiramate, clinicians ought to be aware of these possible effects. PP

 

Reference

1. Markind JE. Topiramate: a new antiepileptic drug. Am J Health Syst Pharm. 1998;55(6):554-562.
2. Van Ameringen M, Mancini C, Pipe B, Campbell M, Oakman J. Topiramate treatment for SSRI-induced weight gain in anxiety disorders. J Clin Psychiatry. 2002;63(11):981-984.
3. Dursun SM, Devarajan S. Clozapine weight gain, plus topiramate weight loss. Can J Psychiatry. 2000;45(2):198.
4. Shapira NA, Goldsmith TD, McElroy SL. Treatment of binge-eating disorder with open-label topiramate. Paper presented at: the Annual Meeting of the American College of Neruropsychopharmacology; December 14, 1999; Acapulco, Mexico. Poster session II, no. 36.
5. Knable M. Topiramate for bulimia nervosa in epilepsy. Am J Psychiatry. 2001;158(2):322-323.
6. Berlant J. Topiramate in chronic civilian post-traumatic stress disorder: an open-label study of a novel treatment. Poster presented at: the 41st Annual Meeting of the New Clinical Drug Evaluation Unit; May 28-31, 2001; Phoenix, AZ. Session II-35.
7. Weber MV. Topiramate for obstructive sleep apnea and snoring. Am J Psychiatry. 2002;159(5):872-873.
8. Zullino DF, Cottier AC, Besson J. Topiramate in opiate withdrawal. Prog Neuropsychopharmacol Biol Psychiatry. 2002;26(6):1221-1223.
9. Cheseaux M, Monnat M, Zullino DF. Topiramate in benzodiazepine withdrawal. Hum Psychopharmacol.  2003;18(5):375-377.
10. Dannon PN. Topiramate for the treatment of kleptomania: a case series and review of the literature. Clin Neuropharmacol. 2003;26(1):1-4.
11. Komanduri R. Two cases of alcohol craving curbed by topiramate. J Clin Psychiatry. 2003;64(5):612.
12. Shapira NA, Lessig MC, Murphy TK, Driscoll DJ, Goodman WK. Topiramate attenuates self-injurious behaviour in Prader-Willi Syndrome. Int J Neuropsychopharmacol. 2002;5(2):141-145.
13. Nickel MK, Nickel C, Kaplan P, et al. Treatment of aggression with topiramate in male borderline patients: a double-blind, placebo-controlled study. Biol Psychiatry. 2005;57(5):495-499.
14. Fong TW, De La Garza R 2nd, Newton TF. A case report of topiramate in the treatment of nonparaphilic sexual addiction. J Clin Psychopharmacol. 2005;25(5):512-514.
15. Johnson J, Bourgeois JA, Quanbeck C. Treatment of olfactory hallucinations with topiramate. J Clin Psychopharmacol. 2006;26(3):340-341.
16. Gatto EM, Uribe Roca C, Raina G, Gorja M, Folgar S, Micheli FE. Vascular hemichorea/hemiballism and topiramate. Mov Disord. 2004;19(7):836-838.
17. Driver-Dunckley E, Evidente VG. Hemichorea-hemiballismus may respond to topiramate. Clin Neuropharmacol. 2005;28(3):142-144.
18. Siniscalchi A, Gallelli L, Davoli A, De Sarro G. Efficacy and tolerability of topiramate in vascular generalized chorea. Ann Pharmacother. 2007;41(11):1915.
19. Shapira NA, Lessig M, Murphy TK, Annis AM, Lazoritz M. Evaluation of open-label topiramate for scar therapy. Dermatol Online J. 2003 Dec;9(5):3.
20. Topamax [package insert]. Titusville, NJ: Ortho-McNeil Pharmaceutical, Inc.; 2003.
21. Shorvon SD. Safety of topiramate: adverse events and relationships to dosing. Epilepsia. 1996;37(suppl 2):S18-S22.
22. Sankar PS, Pasquale LR, Grosskreutz CL. Uveal effusion and secondary angle-closure glaucoma associated with topiramate use. Arch Ophthalmol. 2001;119(8):1210-1211.
23. Klufas A, Thompson D. Topiramate-induced depression. Am J Psychiatry. 2001;158(10):1736.
24. Kutluay E, Pakoz B, Beydoun A. Reversible facial myoclonus with topiramate therapy for epilepsy. Epilepsia. 2007;48(10):2001-2002.
25. Shibasaki H, Hallett M. Electrophysiological studies of myoclonus. Muscle Nerve. 2005;31(2):157-174.

 

e-mail: ns@mblcommunications.com

 

Dr. Sussman is editor of Primary Psychiatry and professor of psychiatry at the New York University School of Medicine in New York City.

Dr. Sussman is a consultant to and on the advisory boards of GlaxoSmithKline and Wyeth; and has received honoraria from AstraZeneca, Bristol-Myers Squibb, GlaxoSmithKline, and Wyeth.


 

This issue of Primary Psychiatry contains Part 2 of our review of emerging insights into the causes and management of suicidal patients. Eric A. Fertuck, PhD, and colleagues provide an overview of the nature of suicidality in borderline personality disorder (BPD). They note that this common condition is associated with one of the highest rates of healthcare utilization in both the psychiatric and primary care setting. BPD is characterized by suicidal ideation and behavior.

The approximately 10% rate for suicide completion in BPD is 400 times greater than the rate in the general population. This article is written with the needs of primary care physicians (PCPs) in mind, so that they become better able to recognize the clinical manifestations of BPD and the treatment options for those patients who are suicidal. The article emphasizes that primary care is often the best setting for both the identification of those at risk for suicide and for the prevention of suicidal behavior.

Kelly Posner, PhD, and colleagues expand on this theme. The authors describe PCPs as being in the “front line” of suicide prevention. They note that an estimated 45% of suicide victims see their physician in the month prior to their death. They also describe factors known to increase risk for suicide, such as depression and alcohol use disorders as well as serious and chronic medical illness. Improved detection of suicidal patients and management of suicidal risk in primary care settings have demonstrated significant improvement in practice.

Katharine A. Phillips, MD, underscores that suicidal ideation, suicide attempts, and completed suicide are common in individuals with body dysmorphic disorder (BDD). Remarkably, approximately 80% of individuals with BDD experience lifetime suicidal ideation, and 24% to 28% have attempted suicide. Nevertheless, BDD is under-recognized in clinical settings. The article reviews available evidence on suicidality in BDD and discusses how to recognize and diagnose this often-secret disorder.

Heidi Combs, MD, and Sharon Romm, MD, note that psychiatric inpatient suicide is rare, with a prevalence of between 0.1% and 0.4% of all psychiatric admissions. However, the authors note that such an event carries an especially powerful emotional charge, since a psychiatric inpatient unit is supposed to be a safe refuge from the destructive sequelae of mental illness. The authors continue that in-hospital suicides cause additional legal problems for the care delivery system and providers, and that the most frequent legal action involving a psychiatric service is the failure to protect patients from harming themselves. This article reviews the literature on inpatient suicide to see if such events can be predicted and forestalled. It identifies patients at especially high risk and explores risk factors in the care-delivery environment, such as staffing, length of stay, and physical surroundings. Articles were chosen that evaluated suicides occurring while patients were hospitalized in an acute psychiatric unit or soon after discharge. The authors excluded studies addressing outpatient suicide or suicide in correctional settings.

Unrelated to suicide, Martina L. Rodgers, MS, and colleagues examine the empirical evidence and personal accounts showing that many people with severe and persistent mental illness can lead satisfying, meaningful lives. That is, they recover. The authors describe the emergence of qualitative and quantitative measures of recovery, summarize available process and outcome definitions, describe current research methods utilized in the recovery literature, and provide a clinical model that integrates recovery with an evidence-based practice perspective. PP

 

Expert Roundtable Supplement

 

An expert panel review of clinical challenges in psychiatry and primary care

  

Funding for this activity has been provided by an educational grant from Bristol-Myers Squibb.

 

Accreditation Statement

This activity has been planned and implemented in accordance with the Essentials and Standards of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of the Mount Sinai School of Medicine and MBL Communications, Inc. The Mount Sinai School of Medicine is accredited by the ACCME to provide continuing medical education for physicians. 

 

Credit Designation

The Mount Sinai School of Medicine designates this educational activity for a maximum of 2 AMA PRA Category 1 Credit(s)TM. Physicians should only claim credit commensurate with the extent of their participation in the activity.

 

Faculty Disclosure Policy Statement

It is the policy of the Mount Sinai School of Medicine to ensure objectivity, balance, independence, transparency, and scientific rigor in all CME-sponsored educational activities. All faculty participating in the planning or implementation of a sponsored activity are expected to disclose to the audience any relevant financial relationships and to assist in resolving any conflict of interest that may arise from the relationship. Presenters must also make a meaningful disclosure to the audience of their discussions of unlabeled or unapproved drugs or devices. This information will be available as part of the course material.

This activity has been peer reviewed and approved by Eric Hollander, MD, Chair and Professor of Psychiatry at the Mount Sinai School of Medicine. Review Date: November 9, 2007.

 

Statement of Need and Purpose

Major depressive disorder (MDD) is the fourth largest contributor to the worldwide burden of disease and is expected to be second only to ischemic heart disease by the year 2020. Over 60% of suicide deaths in the United States are directly attributable to MDD, and >300,000 people successfully commit suicide in the US annually. Despite its prevalence, 50% of MDD cases go undetected, undiagnosed, and untreated. The impairment of depression can lead to decreased productivity, alcohol and substance abuse, and an increased risk of suicide.  Treatment resistant depression (TRD) is frequently defined as depressive illness that does not fully remit after a single initial treatment failure. Patients who only achieve partial response or continue to experience residual symptoms are likely to show reduced functioning and an increased risk of relapse. Up to 50% of patients do not show a full response to their first antidepressant treatment. This has led to a re-emergence of interest in treatment augmentation research. There is a higher frequency of suicide in patients with TRD as opposed to those with treatment responsive MDD. Although the results of several open-label trials suggest a potential role of second-generation antipsychotics (SGAs) in TRD, there has been a paucity of double-blind, placebo-controlled studies confirming whether this treatment strategy is truly effective. New data continue to emerge and it is important to determine how these findings apply to each of the SGAs. It is also important to report on the safety, tolerability, and efficacy of augmenting with SGAs versus other augmentation or switching strategies for TRD.

Target Audience

This activity is designed to meet the educational needs of primary care physicians and psychiatrists.

Learning Objectives

• Recognize the efficacy, safety, and tolerability of augmenting pharmacologic treatment of major depressive disorder (MDD) with atypical antipsychotics.
• Discuss the challenges of limited response to MDD treatment and its impact on the course of illness.

 

Faculty Disclosures

Michael E. Thase, MD, is a consultant to AstraZeneca, Bristol-Myers Squibb, Cephalon, Cyberonics, Eli Lilly, GlaxoSmithKline, Janssen, MedAvante, Neuronetics, Novartis, Organon, Sepracor, Shire, Supernus, and Wyeth; is on the speaker’s bureaus of AstraZeneca, Bristol-Myers Squibb, Cyberonics, Eli Lilly, GlaxoSmithKline, Organon, sanofi-aventis, and Wyeth; has equity in MedAvant; and receives book royalties from American Psychiatric Publishing, Guilford Publications, and Herald House. Dr. Thase discloses that he will discuss investigational uses of older pharmacologic agents for the treatment of major depressive disorder (MDD).

J. Craig Nelson, MD, is a consultant to and/or on the advisory boards of Abbott, Biovail, Bristol-Myers Squibb, Corcept, Eli Lilly, Forest, GlaxoSmithKline, Novartis, Orexigen, Organon, and Pfizer. Dr. Nelson discloses that he will discuss unapproved/investigational uses of pharmacologic agents for the treatment of MDD.

George I. Papakostas, MD, has served as a consultant to Aphios, Bristol-Myers Squibb, GlaxoSmithKline, Evotec, Inflabloc, Jazz, PAMLAB, Pfizer, and Wyeth; has received honoraria from Bristol-Myers Squibb, Evotec, GlaxoSmithKline, Inflabloc, Jazz, Lundbeck, PAMLAB, Pfizer, Titan, and Wyeth; and has received research support from Bristol-Myers Squibb, PAMLAB, and Pfizer. Dr. Papakostas discloses that he will discuss unapproved/investigational uses of aripiprazole, buspirone, olanzapine, pindolol, quetiapine, risperidone, triiodothyronine, and ziprasidone for the treatment of MDD.

Michael J. Gitlin, MD, has received honoraria from AstraZeneca, Bristol-Myers Squibb, Cephalon, Eli Lilly, GlaxoSmithKline, Pfizer, and Takeda. Dr. Gitlin discloses that he will discuss unapproved/investigational use of aripiprazole, clozapine, olanzapine, quetiapine, risperidone, and ziprasidone for the treatment of MDD.
   

Acknowledgment of Commercial Support

Funding for this activity has been provided by an educational grant from Bristol-Myers Squibb.

 

Peer Reviewers

David L. Ginsberg, MD, receives honoraria from AstraZeneca and GlaxoSmithKline.

Eric Hollander, MD, reports no affiliation with or financial interest in any organization that may pose a conflict of interest.

 

To Receive Credit for this Activity

Read this expert roundtable supplement, reflect on the information presented, and complete the CME posttest and evaluation. To obtain credit, you should score 70% or better. Early submission of this posttest is encouraged. Please submit this posttest by December 1, 2009 to be eligible for credit.

Release date: December 1, 2007
Termination date: December 31, 2009

The estimated time to complete this activity is 2 hours.

Abstract

Under optimal circumstances, patients respond to treatments for major depression only 60% to 70% of the time. Therefore, there is a critical need for effective treatment strategies that augment available depression treatment. Currently, such strategies augment primary antidepressants with agents that increase the likelihood of treatment response. Augmentation agents include thyroid hormones, which are used to augment tricyclic antidepressants (TCAs); lithium, which also improves response to TCAs; and second-generation antipsychotics (SGAs), which are used to augment selective serotonin reuptake inhibitors and serotonin norepinephrine reuptake inhibitors. Other, less common, strategies include augmentation with stimulants, folate, and buspirone. Unfortunately, studies of augmentation efficacy are often limited or equivocal. Studies may overestimate the magnitude of effect, as augmentation may be attempted while patients still experience an initial response. Prescribers must be sure treatment strategies are not undermined by safety or tolerability concerns. Lithium, in particular, is not well tolerated by patients, and SGAs pose the risk of tardive dyskinesia, metabolic syndrome, and extrapyramidal symptoms. Clinicians must weigh these issues against a relatively limited base of knowledge.   

In this Expert Roundtable Supplement, Michael E. Thase, MD, discusses the history of augmentation strategies for depression. J. Craig Nelson, MD, reviews recent findings on augmentation with thyroid hormone, lithium, buspirone, and modafinil. George I. Papakostas, MD, reviews the efficacy of augmentation with SGAs. Finally, Michael J. Gitlin, MD, provides an overview of safety and tolerability issues.

 

 

Augmentation Strategies for Depression: History and Concepts

By Michael E. Thase, MD — Moderator

Dr. Thase is professor of psychiatry at the University of Pennsylvania School of Medicine in Philadelphia, the Philadelphia Veterans Affairs Medical Center and the University of Pittsburgh Medical Center.

Disclosures: Dr. Thase is a consultant to AstraZeneca, Bristol-Myers Squibb, Cephalon, Cyberonics, Eli Lilly, GlaxoSmithKline, Janssen, MedAvante, Neuronetics, Novartis, Organon, Sepracor, Shire, Supernus, and Wyeth; is on the speaker’s bureaus of AstraZeneca, Bristol-Myers Squibb, Cyberonics, Eli Lilly, GlaxoSmithKline, Organon, sanofi-aventis, and Wyeth; has equity in MedAvant; and receives book royalties from American Psychiatric Publishing, Guilford Publications, and Herald House.


 

Introduction: Need for Augmentation Strategies

Depression is one of the world’s great public health problems. As there are no perfect or uniformly effective treatments for depression, it is not surprising that treatment-resistant depression (TRD) is likewise an important public health problem. Although the potential benefits of antidepressants are now well documented, no widely used antidepressant can be expected to be effective in more than half the patients who begin to take it. Even under optimal circumstances (ie, a patient who is fully adherent to 12 weeks of treatment), there is only a 60% to 70% chance that the first choice of medication will be effective. The need for effective alternate strategies for TRD, as well as the need for innovations in service delivery systems to ensure those strategies are implemented in a timely manner, are foremost to fully realizing the potential benefits of antidepressant therapies.

Over the years, hierarchies of treatment strategies for TRD have been based on the widespread use of particular treatments, their ease of use, and their safety or complexity. One of the strategies consistently used since its introduction 20 years ago has been augmentation of the ineffective antidepressant by a second medication. The second agent may or may not have antidepressant effects of its own, but when used in combination with a primary antidepressant the agent reliably increases a patient’s likelihood of response and symptom remission.

When augmentation strategies were first implemented, only three classes of medication—the tricyclic antidepressants (TCAs), the heterocyclic alternatives to the TCAs (eg, trazodone, amoxapine, and maprotiline), and the monoamine oxidase inhibitors (MAOIs)—were available. These original antidepressants have since declined in use, largely replaced by a raft of newer antidepressants that, while no more effective on average, have more favorable profiles with respect to ease of use, tolerability, and safety in overdose. The number of options available to patients who do not respond to first-line treatments has thus also increased, multiplying the potential combinations of antidepressant medications and augmenting agents. Ironically, some of the most gratifying responses to pharmacotherapy observed among patients with TRD are observed with “old school” medications such as the TCA clomipramine and the MAOI tranylcypromine.

 

Augmentation Strategies   

Benzodiazepines
The earliest augmentation strategies were first employed in the 1960s, almost coincident with the introduction of the first antidepressants (Slide 1). For example, benzodiazepines were commonly used to enhance the anxiolytic or sedative hypnotic effects experienced by patients taking TCAs or MAOIs. Evidence from studies performed in the 1960s indicated that anxiolytic medications rapidly and reliably reduced anxiety symptoms and insomnia associated with depressive states and, when administered from the outset, might hasten treatment response.1-3 However, concomitant prescription of anxiolytics did not greatly increase the likelihood of patient response or symptom remission, and their longer-term utility (in combination with antidepressants) was never systematically confirmed. Although even greater use was limited by concerns about abuse liability, many experts believe that concerns about the risk of benzodiazepine addiction in this instance have been overstated4 and a large number of patients with difficult-to-treat forms of depression continue to receive palliative benefit from concomitant prescription of benzodiazapines.

 

 

 

First-Generation Antipsychotics
Combinations of antipsychotics and antidepressants were also fairly widely used in the 1960s and 1970s to treat more severe depressive episodes, particularly those characterized by agitation, anxiety, and of course psychosis (Slide 2).5,6 In fact, a proprietary combination of perphenazine and amitriptyline, the most prevalent such combination in the United States, remained in use well into the 1980s, although the fixed-dose combination formulation was more popular in primary care than psychiatric settings, perhaps because the specialists preferred to titrate the component medications separately. Other combinations were used both in the US and abroad, including the antipsychotic trifluperazine and the MAOI tranylcypromine.7 In retrospect, the amitriptyline plus perphenazine combination capitalized on pharmacokinetic interactions: perphenazine increased amitriptyline and, to a lesser extent, nortriptyline blood levels, functionally doubling the dose of the TCA for the average patient. However, with the growing recognition that first-generation antipsychotics conveyed the risk of tardive dyskinesia (TD), coupled with the still controversial observation that patients with mood disorders were even more likely to develop TD than patients with schizophrenia, these combinations were used with increasing reluctance. By the 1990s, this strategy was no longer widely used.

 

 

Psychiatrists thus have known for nearly 50 years that antipsychotics have the potential to enhance antidepressant effects, particularly for severely ill patients. This augmentation strategy was largely discontinued, partly because of the introduction of other options and partly for fear of TD. The availability of the second-generation (atypical) antipsychotics (SGAs) has, of course, changed the therapeutic landscape considerably. As is discussed in subsequent sections of this supplement, even though SGAs are less associated with TD in short- and intermediate-term studies of schizophrenia, there continues to be uncertainty about whether patients with resistant depression who respond to augmentation with SGAs will require long-term administration and, if so, whether they are indeed at greater risk for development of TD.

 

Thyroid Hormone Augmentation

Beginning in the 1960s, reports suggested that thyroid hormone, when added to a TCA at the beginning of a treatment regimen, could accelerate or increase the likelihood of response.8-10 Interestingly, the original observations suggested the strategy was more useful for depressed women, and efficacy specifically in depressed men was never established.11 As women are at higher risk for undetected thyroid disease, one parsimonious explanation for the therapeutic activity of adjunctive thyroid hormone was correction of “pre-clinical” hypothyroidism.12 Consistent with this view, the performance of thyroid augmentation has been disappointing in studies of euthyroid depressed patients.13

These observations reinforced a long-abiding interest in the role of the thyroid axis in the etiopathogenesis of mood disorders. One view is that the thyroid axis responds to the stress of an affective disorder with increased hypothalamic drive, ie, elevated levels of thyroid releasing hormone (TRH). This, over time, results in increased thyroid tone, ie, higher-than-usual levels of circulating thyroid hormone and blunted thyroid stimulating hormone response to TRH. As more recent observations suggest that even patients with low normal levels of thyroid hormone have greater rates of depression14 and slower or less robust responses to antidepressants (Slide 3),15,16 it has been speculated that depressed patients may require a higher-than-usual level of thyroid activity to benefit fully from antidepressant therapy. The efficacy of thyroid augmentation thus may be linked to induction of a higher-than-usual thyroid state, which in turn may selectively benefit patients with low-normal thyroid functions.

 

 

It remains unknown whether better results are obtained with triiodothyronine (T3), the centrally active form of thyroid hormone, or whether thyroxine (T4), the normal thyroid replacement hormone, is equally useful. More evidence exists indicating that T3 can be used to enhance an incompletely effective antidepressant, but only because T3 has been more extensively studied than T4.

 

Lithium Augmentation

Since the 1960s, lithium augmentation has been used to enhance the effects of antidepressants. One of the early case series reported on the utility of the combination of lithium with MAOIs in a group consisting predominantly of patients with bipolar disorder.17 On the basis of several studies in the early 1980s,18-20 lithium augmentation became the preferred augmentation strategy for unipolar patients not adequately responding to TCAs. Several initial reports suggested dramatic antidepressant effects within 24–72 hours.18,19 Results of subsequent studies, however, reported that this kind of rapid and dramatic augmentation response is less common than a slower emerging response over 4–6 weeks (Slide 4),21,22 which is certainly more suggestive of a primary antidepressant effect.22 As lithium salts have antidepressant effects for a subset of depressed people,23 it is difficult to say whether lithium’s therapeutic effects are actually due to augmentation of the antidepressant or a primary antidepressant effect.24 Unfortunately, despite more than 20 years of research, the proper experiment to answer this question still has not been undertaken.

 

 

Conclusion

The challenging problem of treating people who do not benefit from first-line antidepressant medications has not been solved by the availability of newer classes of drugs. Over the years one strategy used by physicians treating depressed people are not benefiting from antidepressant monotherapy has been to add a second medication thought to augment or enhance the actions of the primary medication. The concepts that guided selection of the first strategies used for this purpose—anxiolytics, antipsychotics, thyroid hormone, and lithium—continue to be relevant to the treatment of depression and guide clinicians’ choices of medications in an effort to enhance the effects of newer-generation antidepressants.

 

References

1. Blackman B. The adjunctive role of diazepam in the treatment of depression. Clin Med (Northfield Il). 1963;70:1495-500.
2. Hare HP Jr. Comparison of chlordiazepoxide-amitriptyline combination with amitriptyline alone in anxiety-depressive states. J Clin Pharmacol New Drugs. 1971;11(6):456-460.
3. Feighner JP, Brauzer B, Gelenberg AJ, et al. A placebo-controlled multicenter trial of Limbitrol versus its components (amitriptyline and chlordiazepoxide) in the symptomatic treatment of depressive illness. Psychopharmacology (Berl). 1979;61(2):217-225.
4. Shader RI, Greenblatt DJ. Benzodiazepine overuse-misuse. J Clin Psychopharmacol. 1984;4(3):123-124.
5. Robertson MM, Trimble MR. Major tranquillisers used as antidepressants. A review. J Affect Disord. 1982;4(3):173-193.
6. Spiker DG, Weiss JC, Dealy RS, et al. The pharmacological treatment of delusional depression. Am J Psychiatry. 1985;142(4):430-436.
7. Mena A, Heistad G, Schiele BC, Janecek J. A comparison of tranylcypromine alone with tranylcypromine plus trifluoperazine in the treatment of chronic outpatients: a double-blind controlled study. J Neuropsychiatr. 1964;5:542-550.
8. Prange AJ Jr, Wilson IC, Rabon AM, Lipton MA. Enhancement of imipramine antidepressant activity by thyroid hormone. Am J Psychiatry. 1969;126(4):457-469.
9. Prange AJ Jr, Wilson IC, Lipton MA, Rabon AM, McClae TK, Knox AE. Use of a thyroid hormone to accelerate the action of imipramine. Psychosomatics. 1970;11(5):442-444.
10. Wilson IC, Prange AJ Jr, McClane TK, Rabon AM, Lipton MA. Thyroid-hormone enhancement of imipramine in nonretarded depressions. N Engl J Med. 1970;282(19):1063-1067.
11. Altshuler LL, Bauer M, Frye MA, et al. Does thyroid supplementation accelerate tricyclic antidepressant response? A review and meta-analysis of the literature. Am J Psychiatry. 2001;158(10):1617-1622.
12. Haggerty JJ Jr, Stern RA, Mason GA, Beckwith J, Morey CE, Prange AJ Jr. Subclinical hypothyroidism: a modifiable risk factor for depression? Am J Psychiatry. 1993;150(3):508-510.
13. Thase ME, Kupfer DJ, Jarrett DB. Treatment of imipramine-resistant recurrent depression: I. An open clinical trial of adjunctive L-triiodothyronine. J Clin Psychiatry. 1989;50(10):385-388.
14. Frye MA, Denicoff KD, Bryan AL, et al. Association between lower serum free T4 and greater mood instability and depression in lithium-maintained bipolar patients. Am J Psychiatry. 1999;156(12):1909-1914.
15. Cole DP, Thase ME, Mallinger AG, et al. Slower treatment response in bipolar depression predicted by lower pretreatment thyroid function. Am J Psychiatry. 2002;159(1):116-121.
16. Gitlin M, Altshuler LL, Frye MA, et al. Peripheral thyroid hormones and response to selective serotonin reuptake inhibitors. J Psychiatry Neurosci. 2004;29(5):383-386.
17. Himmelhoch JM, Detre T, Kupfer DJ, Swartzburg M, Byck R. Treatment of previously intractable depressions with tranylcypromine and lithium. J Nerv Ment Dis. 1972; 155(3):216-220.
18. de Montigny C, Grunberg F, Mayer A, Deschenes JP. Lithium induces rapid relief of depression in tricyclic antidepressant drug non-responders. Br J Psychiatry. 1981;138:252-256.
19. de Montigny C, Cournoyer G, Morissette R, Langlois R, Caille G. Lithium carbonate addition in tricyclic antidepressant-resistant unipolar depression. Correlations with the neurobiologic actions of tricyclic antidepressant drugs and lithium ion on the serotonin system. Arch Gen Psychiatry. 1983;40(12):1327-1334.
20. Heninger GR, Charney DS, Sternberg DE. Lithium carbonate augmentation of antidepressant treatment. An effective prescription for treatment-refractory depression. Arch Gen Psychiatry. 1983;40(12):1335-1342.
21. Price LH, Charney DS, Heninger GR. Variability of response to lithium augmentation in refractory depression. Am J Psychiatry. 1986;143(11):1387-1392.
22. Thase ME, Kupfer DJ, Frank E, Jarrett DB. Treatment of imipramine-resistant recurrent depression: II. An open clinical trial of lithium augmentation. J Clin Psychiatry. 1989b;50(11):413-417.
23. Kupfer DJ, Pickar D, Himmelhoch JM, Detre TP. Are there two types of unipolar depression? Arch Gen Psychiatry. 1975;32(7):866-871.
24. Thase ME, Howland RH, Friedman ES. Treating antidepressant nonresponders with augmentation strategies: an overview. J Clin Psychiatry. 1998;59(suppl 5):5-12.

 

 

Recent Findings and Current Status of Augmentation Strategies

By J. Craig Nelson, MD

Dr. Nelson is the Leon J. Epstein professor of psychiatry and director of geriatric psychiatry in the Department of Psychiatry at the University of California San Francisco.

Disclosures: Dr. Nelson is a consultant to and/or on the advisory boards of Abbott, Biovail, Bristol-Myers Squibb, Corcept, Eli Lilly, Forest, GlaxoSmithKline, Novartis, Orexigen, Organon, and Pfizer.


 

Introduction

Augmentation strategies have become popular in patients with a partial response or residual symptoms. In a survey conducted by the American Society of Consultant Pharmacists, 65% of 169 psychiatrists indicated that they would augment treatment as the next step in a partial responder in contrast to non-responders in whom they would switch to another drug (J.C. Nelson, unpublished data). This decision is based on common sense and practicality rather than empirical evidence. Many clinicians and patients think that if a patient achieves at least a partial response to a medication, it makes sense to continue that drug and add a second.  To some extent, the patient preferences for treatment shown in the Systematic Treatment Alternatives to Relieve Depression (STAR*D) study  reflect this approach.1 This discussion will update clinicians on the use of augmentation agents for the treatment of major depressive disorder (MDD).

 

Lithium Augmentation   

Lithium augmentation has been used since it was first described by de Montigny and colleagues2 in 1981. This strategy is based on a rational neurochemical hypothesis that lithium has a synergistic effect when added to a tricyclic antidepressant (TCA). Lithium increases serotonin turnover and the TCA increases postsynaptic serotonin receptor sensitivity.3 Recent debates have focused on whether lithium is as effective combined with selective serotonin reuptake inhibitors (SSRIs) as it is combined with a TCA. The rapid effects sometimes observed with lithium augmentation of TCAs does not seem to occur with SSRIs, conceivably because SSRIs do not increase postsynaptic serotonin receptor sensitivity.

A recent meta-analysis by Crossley and Bauer4 found  10 placebo-controlled lithium augmentation studies.  Augmentation with lithium was significantly more effective than augmentation with placebo. Forty percent of study participants on lithium responded versus 17% on placebo. However, many of the studies included in this meta-analysis were quite small. While one study had 61 patients, the other samples had ≤35 patients. Usual doses of lithium during augmentation were 600–900 mg/day, which translates into a lithium level of ≥0.4 mEq/L. Most recently, lithium augmentation was compared with triiodothyronine (T3) augmentation as a Level 3 strategy in the STAR*D study.5 Patients achieved a reasonable final lithium dose of about 900 mg/day; however, remission rates, while not significantly different, appeared to favor T3 (25% versus 13% to 16%) (Slide 1).6  Lithium was significantly less well tolerated than T3, with more patients discontinuing treatment.

 

Placebo-controlled study of the use of lithium for patients with treatment-resistant depression (TRD) is limited. Several early studies added lithium after 4 weeks of limited response to the initial antidepressant, and it is not clear that these patients were really treatment resistant. A recent study by Nierenberg and colleagues6 found lithium augmentation was not  more effective than placebo in a group of 35 patients who had failed a 6-week prospective nortriptyline trial.  

Another possible explanation of the apparent reduced effectiveness of lithium augmentation is the increased recognition of bipolar spectrum illness. We found, in patients with psychotic depression, that lithium was particularly effective for augmentation in patients with first-degree relatives with bipolar illness or probable histories of hypomania.7 It is possible that as clinicians have become more alert to the diagnosis of bipolar disorder and exclude these patients from studies, the efficacy of lithium augmentation has declined. 

 

Thyroid Augmentation   

Thyroid augmentation is another commonly employed augmentation strategy. Several controlled studies have suggested this strategy may accelerate response. Altshuler and colleagues8 performed a meta-analysis of six studies using T3 to accelerate response. Five of these showed a significant effect in increasing the speed of response. The effect was particularly notable in women. Three placebo-controlled studies subsequent to the meta-analysis have examined acceleration of response with T3, with two finding an advantage for T3.9,10 

The evidence for the effectiveness of T3 in patients with TRD is less clear. Aronson and colleagues11 performed a meta-analysis of eight controlled studies of T3 augmentation (Slide 2). Four of the studies were placebo-controlled, and those that were not used other controls or comparisons. For example, one study compared T3 and T4, and three of the other studies used a historical control for comparison. Overall, the studies indicated that T3 had a significant effect, with an odds ratio of 2 in 292 patients. However, in the four placebo-controlled trials, T3 was not superior to placebo. The placebo-controlled studies included 75 patients, and the odds ratio was 1.5 with a wide confidence interval.

 

The nature of the thyroid trials varied widely, and there are limitations to the studies. A small placebo-controlled trial reported by Gitlin and colleagues12 used a crossover design after randomizing patients to T3 or placebo. Crossover designs in depression are limited by the lingering effects of the prior treatment. Goodwin and colleagues13 substituted T3 for placebo in a blinded fashion, but without randomization to a parallel comparison. Arguably the best designed study was conducted by Joffe and colleagues.14 This was a placebo-controlled parallel comparison of T3, lithium and placebo in 50 patients receiving TCAs. Both T3 and lithium were more effective than placebo but augmentation occurred after only 5 weeks of failure to respond to the first antidepressant. The use of T3 in patients we would now consider treatment resistant is limited. There are no placebo-controlled studies of T3 in SSRI-resistant patients. The best evidence for the efficacy of T3 augmentation of SSRIs in TRD comes from STAR*D which found that ~25% of patients who had failed two prior antidepressant trials, remitted with T3.5 Forty-seven of the 70 patients receiving T3 were taking citalopram or sertraline.  

The dose of T3 for thyroid augmentation is typically 25–50 μg/day. T3 has relatively few side effects. As is the case with almost all augmentation strategies, it is unknown how long thyroid augmentation should be continued. Although no significant problems have yet been identified with long-term treatment, this has not been well studied in depression.

 

Stimulant Augmentation   

Stimulants are also commonly used to augment antidepressants but this strategy is not as well studied as lithium or thyroid augmentation. Several open studies, previously reviewed,15 with <100 total patients reported that the addition of methylphenidate or dextroamphetamine to a TCA or MAOI could be useful in the addressing TRD. Stimulants were usually employed in patients who were anergic or fatigued.  A recent study by Patkar and colleagues16 examined methylphenidate augmentation in 60 patients with MDD who had been resistant to at least one trial with various antidepressants, primarily SSRIs (Slide 3). These patients were randomly assigned to extended-release methylphenidate, 18–54 mg/day, or to placebo for a duration of 4 weeks. The response rates were 40% with methylphenidate and 23% with placebo, but this difference was not significant. Of note, the sample of 60 patients may have been too small to  detect subtle differences.

 

Modafinil has also been used to improve alertness or energy in targeted populations of sedated or fatigued patients. Several open trials support the use of modafinil as an augmentation agent. A double-blind study by Fava and colleagues17 looked at patients with MDD who experienced a partial response to 8 weeks of SSRI monotherapy and had residual fatigue or sleepiness (Slide 4). The study also implemented scales for sleepiness and fatigue. The patients were randomized to modafinil or placebo for 8 weeks. Approximately 150 patients participated in each arm of the study. Patients receiving modafinil showed significantly greater improvement on the Clinical Global Impression (CGI) scale.

 

 

Thase and colleagues18 performed a 12-week, open-label, dose-titration extension study of the study by Fava and colleagues.17 Patients who had received placebo in the randomized phase had the option to switch to modafinil. The response was sustained in patients, and some patients who had failed to respond to modafinil during the initial 8-week trial responded during the 12-week treatment with modafinil.

The mechanism of action for modafinil is less clear than that of other stimulants, and some clinicians have limited experience with this agent. It has thus far been used to treat specific residual symptoms. The usual dose has been 200–300 mg/day. A randomized trial by Fava and colleagues17  is one of the largest augmentation studies conducted and showed modafinil to be quite effective in treating patients with specific residual symptoms. 

 

Buspirone Augmentation   

Buspirone was the first augmentation strategy proposed for use with the SSRIs in 1991.19,20 Several previously reviewed15 open studies, with samples ranging up to 30 patients, suggested efficacy. However, a controlled study by Landen and colleagues21 found that buspirone augmentation was not more effective than placebo after 4 weeks of SSRI treatment failure in 119 patients. The high placebo response rate of 47% suggested that patients were continuing to improve with the initial SSRI. 

Buspirone augmentation was employed in Level 2 of the STAR*D study.1 While the overall remission rate, 32.9%, looked promising, patients who  elected to receive augmentation had fewer symptoms at the start of Level 2 treatment than the patients who elected or were randomized to switch.  The ultimate efficacy of buspirone for augmentation has yet to be determined.

 

Other Augmentation Strategies

Although pindolol has shown efficacy when used to accelerate initial SSRI treatment,15 it has not been effective in patients with TRD. In two studies of TRD patients, particularly the larger study by Perez and colleagues,22 augmentation with pindolol was no more effective than augmentation with placebo.

An emerging body of evidence suggests lamotrigine may be useful as an augmentation strategy. In addition to case reports, three retrospective series of cases (N=14, 34, and 37) suggest the value of the addition of lamotrigine to an ongoing antidepressant in unipolar patients who have been resistant to treatment.23-25 In addition, one placebo-controlled trial in 23 patients, who had failed at least one prior antidepressant, randomly assigned patients to the addition of lamotrigine or placebo to fluoxetine 20 mg/day.26 The sample included 8 patients with bipolar II depression and 15 patients with unipolar MDD.  In both groups lamotrigine failed to show superiority on the primary outcome measure, the Hamilton Rating Scale for Depression, but did show an advantage on the CGI scale. Lamotrigine would appear to be a promising but not established strategy.  

Several studies have examined the use of testosterone in depressed men. A report of five cases suggested testosterone replacement therapy might be useful in hypogonadal men with SSRI-resistant depression.27 The results of placebo-controlled studies have been mixed. Pope and colleagues28 randomly assigned 22 depressed men who had failed 4 weeks of antidepressant treatment and had low or borderline testosterone levels, to the addition of either testosterone gel or placebo to their ongoing antidepressant and found this strategy effective. The authors noted that the effect was only observed in patients whose serum testosterone levels rose appreciably.  A second randomized controlled trial (RCT) in 18 hypogonadal depressed men who were partial responders to prior treatment added testosterone gel or placebo to the continuing antidepressant. The study employed a 12-week trial followed by a crossover. No advantage for testosterone was observed.29 The third RCT examined intramuscular testosterone or placebo in 26 depressed subjects who had failed two prior antidepressant trials and were now receiving an SSRI.30 Again testosterone augmentation was not found to be superior to placebo. At this point, the usefulness of testosterone in depressed men with either low or adequate testosterone levels remains unclear.

Estrogen has been examined as a potential augmentation agent in women. Various comparisons have been performed with monotherapy, augmentation, estrogen versus an antidepressant, and in peri- and post-menopausal women. Two large retrospective analyses of SSRI trials found that postmenopausal women receiving hormone replacement therapy were more likely to respond to the SSRI.31,32 However, results of prospective studies have been mixed.  A small (N=16) study of perimenopausal women, who were partial responders and who were experiencing other perimenopausal symptoms, found that adding estrogen to antidepressant treatment elicited a better response than adding placebo.33 Two other placebo-controlled studies, however, in postmenopausal women, found no advantage of augmenting sertraline with an estrogen patch (N=22)34 or adding an estrogen/progesterone combination to venlafaxine (N=56).35 These studies illustrate the need for a placebo control as all groups in both studies improved. The controlled data to date suggest that estrogen augmentation in postmenopausal women is not effective but may be useful in symptomatic perimenopausal women who are depressed. 

Several studies have indicated that high homocysteine levels and low B12 and folate levels are associated with depression. Papakostas and colleagues36 found that low folate serum levels were associated with reduced response to fluoxetine. In a 10-week RCT by Coppen and Bailey,37 127 subjects with MDD who were receiving fluoxetine but were not treatment resistant were randomly assigned to folate 500 μg or placebo (Slide 5). Female patients taking folate were more likely to respond than those taking placebo. This effect was not observed in men and it was suggested this dose may be too low in men. Although the value of folate has not been established in TRD, given the minimal side effects observed, this simple strategy ought to be considered in women. Alternatively it is not clear if this effect is limited to women with low folate or if additional folate would be useful to women already taking multi-vitamins that often contain about 400 μg of folic acid.

 

 

Conclusion   

Currently several augmentation strategies have been described for use in patients with TRD. Unfortunately, with the exception of STAR*D, almost all of these studies have been conducted in samples of <100 subjects. Only recently have studies employed designs that more carefully assure that patients have received adequate prior treatment and are in fact treatment resistant. Seldom have two augmentation strategies been compared with each other under similar conditions, thus the relative magnitude of their effects is largely unknown.  The lack of large comparison studies also limits what is known about predictors of response to these treatments. Thus selection of a particular agent is based more on clinical experience than empirical data. Some strategies—augmentation with T3, estrogen, testosterone, and folate—would appear to make sense in patients deficient in that substance, but that rational hypothesis has not been confirmed. Finally, the following question remains: If the patient responds to augmentation, should the augmenting agent be continued? This question has seldom been studied.

 

References

1. Rush AJ, Trivedi MH, Wisniewski SR, et al. Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR*D report. Am J Psychiatry. 2006;163:1905-1917.
2. Dé Montigny C, Grunberg F, Mayer A, Deschenes JP. Lithium induces rapid relief of depression in tricyclic antidepressant drug non-responders. Br J Psychiatry. 1981;138:252-256.
3. Nelson JC. Lithium augmentation in refractory depression. In: Roose SP, Glassman.AH. Treatment Strategies for Refractory Depression. Washington, DC: American Psychiatric Press, Inc; 1990:35-49.
4. Crossley NA, Bauer M. Acceleration and augmentation of antidepressants with lithium for depressive disorders: two meta-analyses of randomized, placebo-controlled trials. J Clin Psychiatry. 2007;68:935-940.
5. Nierenberg AA, Fava M, Trivedi MH, et al. A comparison of lithium and T(3) augmentation following two failed medication treatments for depression: a STAR*D report. Am J Psychiatry. 2006;163(9):1519-1530.
6. Nierenberg AA, Papakostas GI, Petersen T, et al. Lithium augmentation of nortriptyline for subjects resistant to multiple antidepressants. J Clin Psychopharmacol.2003;23:92-95.
7. Nelson J C, Mazure C. Lithium augmentation in psychotic depression refractory to combined drug treatment. Am J Psychiatry. 1986;143:363-366.
8. Altshuler LL, Bauer M, Frye MA, et al. Does thyroid supplementation accelerate tricyclic antidepressant response? A review and meta-analysis of the literature. Am J Psychiatry. 2001;158(10):1617-1622.
9. Posternak M, Novak S, Stern R, et al. A pilot effectiveness study: placebo-controlled trial of adjunctive L-triiodothyronine (T3) used to accelerate and potentiate the antidepressant response. Int J Neuropsychopharmacol. 2007;13:1-11.
10. Cooper-Kazaz R, Apter JT, Cohen R, et al. Combined treatment with sertraline and liothyronine in major depression: a randomized, double-blind, placebo-controlled trial. Arch Gen Psychiatry. 2007;64:679-688.
11. Aronson R, Offman HJ, Joffe RT, Naylor CD. Triiodothyronine augmentation in the treatment of refractory depression. A meta-analysis. Arch Gen Psychiatry. 1996;53(9):842-848.
12. Gitlin MJ, Weiner H, Fairbanks L, Hershman JM, Friedfeld N. Failure of T3 to potentiate tricyclic antidepressant response. J Affect Disord. 1987;13(3):267-272.
13. Goodwin FK, Prange AJ Jr, Post RM, Muscettola G, Lipton MA. Potentiation of antidepressant effects by L-triiodothyronine in tricyclic nonresponders. Am J Psychiatry. 1982;139(1):34-38.
14. Joffe RT, Singer W, Levitt AJ, MacDonald C. A placebo-controlled comparison of lithium and triiodothyronine augmentation of tricyclic antidepressants in unipolar refractory depression. Arch Gen Psychiatry. 1993;50:387-393.
15. Nelson JC. Augmentation strategies in depression 2000. J Clin Psychiatry. 2000;61(suppl 2):13-19.
16. Patkar AA, Masand PS, Pae CU, et al. A randomized, double-blind, placebo-controlled trial of augmentation with an extended release formulation of methylphenidate in outpatients with treatment-resistant depression. J Clin Psychopharmacol. 2006;26(6):653-656.
17. Fava M, Thase ME, DeBattista C. A multicenter, placebo-controlled study of modafinil augmentation in partial responders to selective serotonin reuptake inhibitors with persistent fatigue and sleepiness. J Clin Psychiatry. 2005;66(1):85-93.
18. Thase ME, Fava M, DeBattista C, Arora S, Hughes RJ. Modafinil augmentation of SSRI therapy in patients with major depressive disorder and excessive sleepiness and fatigue: a 12-week, open-label, extension study. CNS Spectr. 2006;11(2):93-102.
19. Jacobsen FM.  Possible augmentation of antidepressant response by buspirone. J Clin Psychiatry. 1991;52:217-220.
20. Bakish D. Fluoxetine potentiation by buspirone: Three case histories. Can J Psychiatry. 1991;36:749-750.
21. Landén M, Björling G, Agren H, Fahlén T. A randomized, double-blind, placebo-controlled trial of buspirone in combination with an SSRI in patients with treatment-refractory depression. J Clin Psychiatry. 1998;59(12):664-668.
22. Pérez V, Soler J, Puigdemont D, Alvarez E, Artigas F, Grup de Recerca en Trastorns Afectius. A double-blind, randomized, placebo-controlled trial of pindolol augmentation in depressive patients resistant to serotonin reuptake inhibitors. Arch Gen Psychiatry. 1999;56(4):375-379.
23. Gabriel A. Lamotrigine adjunctive treatment in resistant unipolar depression: an open, descriptive study. Depress Anxiety. 2006;23:485-488.
24. Gutierrez RL, McKercher RM, Galea J, Jamison KL. Lamotrigine augmentation strategy for patients with treatment-resistant depression. CNS Spectr. 2005;10:800-805.
25. Barbee JG, Jamhour NJ. Lamotrigine as an augmentation agent in treatment-resistant depression. J Clin Psychiatry. 2002;63:737-741.
26. Barbosa L, Berk M, Vorster M. A double-blind, randomized, placebo-controlled trial of augmentation with lamotrigine or placebo in patients concomitantly treated with fluoxetine for resistant major depressive episodes. J Clin Psychiatry. 2003;64:403-407.
27. Seidman SN, Rabkin JG. Testosterone replacement therapy for hypogonadal men with SSRI-refractory depression. J Affect Disord. 1998;48:157-161.
28. Pope HG, Cohane GH, Kanayama G, et al. Testosterone gel supplementation for men with refractory depression: a randomized, placebo-controlled trial. Am J Psychiatry. 2003;160:105-111.
29. Orengo CA, Fullerton L, Kunik ME. Safety and efficacy of testosterone gel 1% augmentation in depressed men with partial response to antidepressant therapy. J Geriatr Psychiatry Neurol. 2005;18:20-24.
30. Seidman SN, Miyazaki M, Roose SP. Intramuscular testosterone supplementation to selective serotonin reuptake inhibitor in treatment-resistant depressed men: randomized placebo-controlled clinical trial. J Clin Psychopharmacol. 2005;25:584-588.
31. Schneider LS, Small GW, Hamilton SH, et al. Estrogen replacement and response to fluoxetine in a multicenter geriatric depression trial. Fluoxetine Collaborative Study Group. Am J Geriatr Psychiatry. 1997;5:97-106.
32. Schneider LS, Small GW, Clary CM. Estrogen replacement therapy and antidepressant response to sertraline in older depressed women. Am J Geriatr Psychiatry. 2001;9:393-399.
33. Morgan ML,Cook IA, Rapkin AJ, Leuchter AF. Estrogen augmentation of antidepressant in perimenopausal depression: a pilot study. J Clin Psychiatry. 2005;66:774-780.
34. Rasgon NL, Altshuler LL, Fairbanks LA, et al. Estrogen replacement therapy in the treatment of major depressive disorder in perimenopausal women. J Clin Psychiatry. 2002;63(suppl 7):45-48.
35. Dias RS, Kerr-Correa F, Moreno RA, et al. Efficacy of hormone therapy with and without methyltestosterone augmentation ov venlafaxine in the treatment of postmenopausal depression: a double-blind controlled pilot study. Menopause. 2006;13:202-211.
36. Papakostas GI, Petersen T, Mischoulon D, et al. Serum folate, vitamin B12, and homocysteine in major depressive disorder, Part 1: predictors of clinical response in fluoxetine-reistant depression. J Clin Psychiatry. 2004;65:1090-1095.
37. Coppen A, Bailey J. Enhancement of the antidepressant action of fluoxetine by folic acid: a randomised, placebo controlled trial. J Affect Disord. 2000;60(2):121-130.


  

Examining the Evidence on Augmentation with Atypical Antipsychotics

By George I. Papakostas, MD

 
Dr. Papakostas is assistant professor of psychiatry at Harvard Medical School, and staff psychiatrist in the Department of Psychiatry at Massachusetts General Hospital in Boston.

Disclosures: Dr. Papakostas has served as a consultant to Aphios, Bristol-Myers Squibb, GlaxoSmithKline, Evotec, Inflabloc, Jazz, PAMLAB, Pfizer, and Wyeth; has received honoraria from Bristol-Myers Squibb, Evotec, GlaxoSmithKline, Inflabloc, Jazz, Lundbeck, PAMLAB, Pfizer, Titan, and Wyeth; and has received research support from Bristol-Myers Squibb, PAMLAB, and Pfizer.


 

Introduction: Efficacy of Current Treatment Strategies for Depression   

There is mounting evidence to suggest that the efficacy of all available antidepressants when used as monotherapy to treat major depressive disorder (MDD) is, at best, modest. For example, a meta-analysis1 of all double-blind placebo-controlled studies of antidepressants published since 1980 revealed response rates of 53% for antidepressants versus 36% for placebo (difference in response rate of 16.8%) (Slide 1). To make matters worse, if one is to assume that “negative trials” (ie, trials which do not demonstrate the superiority of a drug over placebo) are less likely to be published than “positive trials” (trials which demonstrate the superiority of a drug versus placebo), it is quite possible that the margin of efficacy of antidepressants when compared to placebo is <16.8%. Thus, if one were to include all unpublished along with published double-blind, placebo-controlled trials of antidepressants for MDD, this efficacy margin could be <10%.

 

At the present time, it is unclear to what extent conclusions drawn from randomized, double-blind, placebo-controlled trials (ie, efficacy studies) also apply to “real-world” treatment settings. However, preliminary studies focusing on the use of antidepressants in “real-world” clinical settings present discouraging results. For example, Petersen and colleagues2 report remission rates as low as 20% to 23% following each successive treatment among patients with MDD enrolled in one of two academically-affiliated, depression-specialty clinic (Slide 2). In fact, only ~50% of patients enrolled achieved full remission of their depression. Similarly, only about one in three patients with MDD experienced a remission of their depression following treatment with the selective serotonin reuptake inhibitor (SSRI) citalopram during the first-level of the large, multicenter, Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial.3 Clearly, there is an urgent need to develop safer, better tolerated, and more effective treatments for MDD.

 

 

Augmentation of Antidepressants with Second-Generation Antipsychotics: A Novel Approach

There are three major “paths” toward the development of novel pharmacotherapeutic strategies for MDD (Slide 3). The first approach involves developing new drugs. The second approach involves identifying subpopulations of depressed patients that are more likely to experience the benefits of a given treatment versus placebo. Attempts have been made to identify such “subpopulations” with the use of either biological markers (ie, genetic markers), or clinical markers (ie, the presence of symptoms, symptoms clusters, or comorbid disorders). Finally, a third approach involves combining two pharmacologic treatments: either two antidepressants or an antidepressant with a novel agent. The case of augmenting antidepressants with second-generation (atypical) antipsychotics (SGAs) for treatment-resistant depression (TRD) falls under the third “path” of treatment development. Other examples which also fall under this category include the combination of SSRIs or serotonin norepinephrine reuptake inhibitors (SNRI) with other antidepressants including mirtazapine (a 5-HT2 receptor antagonist and α2-adrenergic receptor antagonist), bupropion (a norepinephrine dopamine reuptake inhibitor), tricyclic antidepressants, or with non-antidepressant agents including lithium, triiodothyronine (T3), pindolol, or buspirone.4

 

  
The preclinical rationale for the use of the SGAs in MDD derives from their complex neuropharmacologic effects at various monoaminergic receptors and transporters.4 Specifically, all SGAs appear to be 5-HT2 receptor antagonists.4 SGAs also vary in terms of neuropharmacologic effects. Ziprasidone and aripiprazole possess affinity for the 5-HT1A receptor, while ziprasidone and risperidone possess affinity for the 5-HT1D receptor.4 Ziprasidone has also been shown to inhibit the reuptake of serotonin and norepinephrine, while aripiprazole has been shown to possess mixed agonist and antagonist effects at various dopamine receptors.4 These effects were thought to be suggestive of antidepressant activity.4

Early clinical studies focusing on augmentation with SGAs in depression demonstrated mixed findings. The first clinical report ever to be published focusing on this treatment strategy was a case series describing eight patients with SSRI-resistant depression who experienced remission of symptoms following the addition of low doses of risperidone (0.5–1 mg).5 What was also notable in that report was that all patients achieved remission of symptoms of depression quite rapidly (within 1 week of combined treatment). This preliminary report was soon followed by a double-blind placebo-controlled study that focused on adding olanzapine to fluoxetine among fluoxetine nonresponders.6 A greater improvement in depressive symptoms was reported among patients treated with the combination of these two agents than either agent alone.6 

However, soon thereafter, doubt was cast on the potential utility of this treatment strategy when two subsequent studies combining olanzapine with fluoxetine for nortriptyline- or venlafaxine-resistant MDD failed to show that combining olanzapine with fluoxetine was more effective than monotherapy with either venlafaxine, fluoxetine, or nortriptyline.7,8 More recently, however, several double-blind, placebo-controlled studies focusing on augmenting antidepressants with either risperidone,9,10 quetiapine,11-13 or olanzapine14 for TRD re-kindled clinicians interest in this treatment strategy. Specifically, six of these seven trials9,10,12-14 demonstrated greater efficacy in TRD among patients treated with adjunctive SGAs than placebo (Thase and colleagues14 reported two separate but identical trials of olanzapine augmentation of fluoxetine, and found olanzapine augmentation to be effective in the first but not the second study). 

In order to reconcile the discrepancy in results between “positive” and “negative” studies, we conducted a random-effects model meta-analysis pooling all 10 randomized, double-blind, placebo-controlled clinical trials focusing on augmentation of antidepressants with SGAs for TRD.15 In that meta-analysis, the difference in remission rates between the SGAs and placebo was found to be statistically significant, with a 47.4% remission rate for augmentation with SGAs versus a 37% remission rate for augmentation with placebo (Slide 4). Though the difference in efficacy in favor of this augmentation strategy over placebo was pronounced, tolerability appeared to be a considerable limitation. Specifically, the difference in the rates of discontinuation due to intolerance for patients treated with SGAs compared to placebo was also statistically significant (22.3% for the SGAs and 12% for placebo, respectively).

 

 

 

Second-Generation Antipsychotic Augmentation for MDD: Questions Unanswered

Although the results of our meta-analysis provided evidence in support of the use of SGAs as adjuncts for TRD, two major questions remain: (A) is this evidence generalizeable to all SGAs; and (B) is there evidence supporting the long-term efficacy for this treatment strategy as there is for standard antidepressants?

Regarding the issue of generalizability, it is important to note that at the time the meta-analysis was conducted, evidence supporting the use of adjunctive ziprasidone in MDD derived exclusively from open-label, but not placebo-controlled trials. In one such study, Papakostas and colleagues16 treated 20 patients with SSRI-resistant MDD with adjunctive ziprasidone. Twenty-five percent of patients remitted during the trial and 50% experienced a clinical response (Slide 5).

 

However, more recently, two positive, double-blind, placebo-controlled trials investigating the use of adjunctive aripiprazole in MDD were either been published17 or presented at major scientific meetings (Slide 6).18 In the first study, Berman and colleagues17 focused on the use of aripiprazole augmentation for patients resistant to up to 1–3 retrospective antidepressant trials. To confirm treatment resistance, those patients underwent an 8-week, open-label trial with an SSRI (fluoxetine, sertraline, paroxetine or escitalopram) or an SNRI (venlafaxine). The patients who made insufficient symptom improvement had either aripiprazole or placebo added to their SSRI or SNRI regimen, under double-blind conditions for 6 weeks. A statistically significant difference in remission rates was observed, with 26% remission for aripiprazole versus 15.7% remission for placebo (P<.05). This study also reported relatively low rates of discontinuation due to intolerance in the treatment groups (2% for aripiprazole and 1.7% for placebo [P>.05]). The results of a separate study of identical design also demonstrated greater remission rates for adjunctive aripiprazole- than placebo-treated patients.18

 

Much less is know regarding long-term efficacy.  Rapaport and colleagues19 examined 386 MDD patients who failed to experience sufficient symptom improvement following treatment with citalopram. These patients then received adjunctive treatment (open-label) with risperidone for 4–6 weeks. Of these patients, 241 (63%) experienced significant symptom improvement. These patients were randomized under double-blind conditions to continue to receive the combination of risperidone and citalopram or to continue with citalopram but to undergo a substitution of risperidone for placebo (double-blind) for 24 weeks. Relapse rates between the two groups were not statistically significant (Slide 7).

 

 

 

Conclusion

From the evidence available to date, it appears that augmentation of standard, first-line antidepressants with SGAs is effective in some cases of TRD, at least during the acute phase of treatment. However, there are limitations in the tolerability of this combination strategy, while the long-term efficacy, tolerability, and safety of this treatment are not yet understood. Further research is required into how this compares with other augmentation strategies and other strategies for addressing TRD.

 

References

1. Papakostas GI, Fava M. Does the probability of receiving placebo influence the likelihood of responding to placebo or clinical trial outcome? A meta-regression of double-blind, randomized clinical trials in MDD. Neuropsychopharmacology. 2006;31(suppl 1):s158.
2. Petersen T, Papakostas GI, Posternak MA, et al. Empirical testing of two models for staging antidepressant treatment resistance. J Clin Psychopharmacol. 2005;25(4):336-341.
3. Trivedi MH, Rush AJ, Wisniewski SR, et al; STAR*D Study Team. Evaluation of outcomes with citalopram for depression using measurement-based care in STAR*D: implications for clinical practice. Am J Psychiatry. 2006;163(1):28-40.
4. Papakostas GI. Augmentation of standard antidepressants with atypical antipsychotic agents for treatment-resistant major depressive disorder. Essent Psychopharmacol. 2005;6(4):209-220.
5. Ostroff RB, Nelson JC. Risperidone augmentation of selective serotonin reuptake inhibitors in major depression. J Clin Psychiatry. 1999;60(4):256-259.
6. Shelton RC, Tollefson GD, Tohen M, et al. A novel augmentation strategy for treating resistant major depression. Am J Psychiatry. 2001;158(1):131-134.
7. Shelton RC, Williamson DJ, Corya SA, et al. Olanzapine/fluoxetine combination for treatment-resistant depression: a controlled study of SSRI and nortriptyline resistance. J Clin Psychiatry. 2005;66(10):1289-1297.
8. Corya SA, Williamson D, Sanger TM, Briggs SD, Case M, Tollefson G. A randomized, double-blind comparison of olanzapine/fluoxetine combination, olanzapine, fluoxetine, and venlafaxine in treatment-resistant depression. Depress Anxiety. 2006;23(6):364-372.
9. Keitner GI, Garlow SJ, Ryan CE, et al. Risperidone augmentation for patients with difficult-to-treat major depression. Poster presented at: 159th Annual Meeting of the American Psychiatric Association; May 20-26, 2006; Toronto, Canada.
10. Gharabawi G, Canuso C, Pandina G, et al. A double-blind, placebo-controlled trial of adjunctive risperidone for treatment-resistant major depressive disorder. Poster presented at: 25th Collegium Internationale Neuropsychopharmacologicum; July 9-13, 2006; Chicago, Illinois.
11. Khullar A, Chokka P, Fullerton D, McKenna S, Blackman A. Quetiapine as treatment of non-psychotic unipolar depression with residual symptoms: double blind, randomized, placebo controlled study. Poster presented at: 159th Annual Meeting of the American Psychiatric Association; May 20-26, 2006; Toronto, Canada.
12. Mattingly G, Ilivicky H, Canale J, Anderson R. Quetiapine augmentation for treatment-resistant depression. Poster presented at: 159th Annual Meeting of the American Psychiatric Association; May 20-26, 2006; Toronto, Canada.
13. McIntyre AW, Gendron A, Mcintyre A. Quetiapine augmentation of SSRIs/SNRIs in major depression with anxiety. Poster presented at: 159th Annual Meeting of the American Psychiatric Association; May 20-26, 2006; Toronto, Canada.
14. Thase ME, Corya SA, Osuntokun O, et al. A randomized, double-blind comparison of olanzapine/fluoxetine combination, olanzapine, and fluoxetine in treatment-resistant major depressive disorder. J Clin Psychiatry. 2007;68(2):224-236.
15. Papakostas GI, Shelton RC, Smith J, Fava M. Augmentation of antidepressants with atypical antipsychotic medications for treatment-resistant major depressive disorder: a meta-analysis. J Clin Psychiatry. 2007;68(6):826-831.
16. Papakostas GI, Petersen TJ, Nierenberg AA, et al. Ziprasidone augmentation of selective serotonin reuptake inhibitors (SSRIs) for SSRI-resistant major depressive disorder. J Clin Psychiatry. 2004;65(2):217-221.
17. Berman RM, Marcus RN, Swanink R, et al. The efficacy and safety of aripiprazole as adjunctive therapy in major depressive disorder: a multicenter, randomized, double-blind, placebo-controlled study. J Clin Psychiatry. 2007;68(6):843-583.
18. Thase ME, Marcus RN, Hennicken D, et al. Efficacy and safety of aripiprazole as adjunctive therapy in major depressive disorder: a multicenter, randomized, double-blind, placebo-controlled study (Study CN 138-163). Poster presented at: 61st Annual Convention of the Society of Biological Psychiatry; May 18-20, 2006; San Diego, California.
19. Rapaport MH, Gharabawi GM, Canuso CM, et al. Effects of risperidone augmentation in patients with treatment-resistant depression: Results of open-label treatment followed by double-blind continuation. Neuropsychopharmacology. 2006;31(11):2505-2513.


 

Clinical Considerations with Atypical Antipsychotic Augmentation

By Michael J. Gitlin, MD
 

Dr. Gitlin is professor of clinical psychiatry at the University of California, Los Angeles (UCLA) School of Medicine and director of the Mood Disorders Clinic at the Neuropsychiatric Clinic at UCLA.

Disclosures: Dr. Gitlin has received honoraria from AstraZeneca, Bristol-Myers Squibb, Cephalon, Eli Lilly, GlaxoSmithKline, Pfizer, and Takeda.


 

Introduction: Practical Clinical Applications

In spite of the tremendous advances made in developing antidepressant treatments and exploring augmentation with second-generation antipsychotics (SGAs), significant obstacles remain for psychiatrists: How should clinicians make use of cutting-edge augmentation studies? How should they use the antipsychotics in their treatment algorithm? How should they think about dosing and side effects?

The first major problem is there have been no great algorithmic studies on adjunctive strategies. In fact, the most useful algorithmic study was the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study, from which SGAs were entirely absent. The second problem is that STAR*D showed a clear pattern in which the efficacy of an augmentation agent depended on its placement in the algorithm. Those agents occurring later in the algorithm, such as monoamine oxidase inhibitors (MAOIs), adjunctive triiodothyronine (T3), and adjunctive lithium, appeared to be less effective than adjunctive buspirone, which occurred earlier in the algorithm. This was not the result of a direct comparison. Because of these two problems, it is therefore difficult to determine how to rank the efficacy of SGAs among the agents investigated by the STAR*D study. Among clinical treatment strategies, SGAs might appear toward the end of first-line strategies, perhaps after combinations and stimulants but before buspirone.

As a field, we also know very little about optimal dosing of SGAs when used as adjunctive treatments for depression. In general, however, doses used in adjunctive strategies are lower than those used for either acute mania or acute psychotic states. These are usually dosed in the range of 2.5–10 mg for aripiprazole, 20–60 mg for ziprasidone, 2.5–10 mg for olanzapine, 0.5–3 mg for risperidone, and 50–200 mg for quetiapine. However, these doses are based more on clinical experience than evidence-based data.

 

Side-Effect Concerns

Considering what is currently known about augmentation with SGAs, clinicians must consider how to make decisions within a relatively limited base of knowledge. Another factor to consider in making these decisions are side effects. There are class concerns, such as tardive dyskinesia (TD), and concerns that differ across agents, such as weight gain and propensity for metabolic syndrome. Many of these side-effect concerns have caused hesitation among clinicians regarding the use of SGAs earlier in the algorithm of treatment-resistant depression (TRD).

It is clear that SGAs are less associated with TD than first-generation antipsychotics (FGAs). In the best meta-analysis conducted on the subject thus far, the occurence of TD with SGAs was one seventh its occurence with FGAs.1 However, this study was conducted several years ago, and therefore did not include more recent medications such as ziprasidone and aripiprazole. In addition, TD studies are conducted with schizophrenia patients who have received full doses of antipsychotics. It is not known how relevant those data are to low-dose strategies in mood disorders patients. While it seems likely that TD risk is reduced with low-dose strategies, it has not yet been proven. It is also unknown whether rates of TD vary across SGAs. In theory, quetiapine, with its fast dopamine (D)2 dissociation; aripiprazole, with its D2 partial agonism; and clozapine should have the lowest risks of TD. However, there is not enough data to show that these agents are less likely to be associated with TD than any other SGA.

Prolactin is another concern for clinicians. It is clear that risperidone has a unique propensity to increase prolactin levels, whereas other SGAs increase prolactin rarely, if at all. Clinicians prescribing SGAs should look for side effects such as menstrual abnormalities in women; galactorrhea and gynecomastia in both men and women; and certainly sexual dysfunction in men.

Risperidone is far more likely to cause extrapyramidal symptoms (EPS) than the other SGAs, for all symptoms except agitation. Quetiapine seldom causes EPS, and clozapine is not associated with EPS at all. Ziprasidone and aripiprazole are most linked to agitation. A restlessness syndrome, often diagnosed as agitation or akathisia, occurs in ~10% of people taking ziprasidone or aripiprazole.

 

Metabolic Syndrome and Weight Gain

Even though medications that increase weight have existed since the beginning of modern psychopharmacology, starting with chlorpromazine and amitriptyline, it has become a greater concern in recent years. This is especially true with SGAs. The definition of metabolic syndrome is polythetic; it must meet three of five criteria (Slide 1).2 No one criterion is weighted more than another. Other risk factors for cardiovascular disease, such as cigarette smoking, are not typically included in the definition of metabolic syndrome but are considered additive risk factors. Obesity is clearly a strong mediating variable for a number of these factors, but it is not the only one. Some patients have suddenly and dramatically developed diabetic ketoacidosis early in the course of treatment with an SGA (specifically clozapine, olanzapine, or quetiapine) without gaining any weight at all. Treatment with SGAs causes both obesity-mediated metabolic syndrome and non-obesity–related concerns.

 

 

Metabolic syndrome in psychiatrically ill patients mirrors epidemiologic trends in society at large, where rates of type 2 diabetes among children and adults have increased markedly over the past 20 years. It is widely presumed that this is related to dietary factors, although a concrete cause has not yet been established. Clinicians must also remember that chronically psychiatrically ill patients, whether afflicted with schizophrenia, bipolar disorder, or major depressive disorder, tend to have very unhealthy habits. These habits may contribute to, or even cause, patients’ metabolic disturbances. It is also significant to note that abdominal obesity, not simple weight gain, is the relevant criterion. Truncal weight gain correlates with cardiovascular risk more than fat deposits elsewhere, making this specific type of obesity of greater concern.

A study by Allison and colleagues3 showed differential weight gain across antipsychotics (Slide 2). Aripiprazole was not included in the study because data were not available at the time, though its weight gain effects might be similar to those of ziprasidone and fluphenazine. It is clear, in any case, that weight gain is not uniform across agents.

 

 

The Consensus Development Conference on Antipsychotic Drugs and Obesity and Diabetes investigated the differential concern for weight gain, risk for diabetes, and worsening lipid profile.4 These can be divided into three groups: the clozapine-olanzapine group, which clearly has the highest propensity toward metabolic syndrome; the risperidone-quetiapine group, which has a medium propensity; and the ziprasidone-aripiprazole group, which has the lowest propensity (Slide 3).

 

 

Analyses of the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) study also demonstrated that olanzapine has the greatest weight gain concern (Slides 4 and 5) and is associated with the highest glucose levels (Slide 6).5 Clinicians might be disinclined to use agents with greater weight gain propensity and metabolic syndrome concerns. However, they must bear in mind that some patients do much better on olanzapine, and some patients experience the most symptom improvement with clozapine.

 

 

 

Recommendations for Monitoring

Clinicians must be vigilant about monitoring patients taking antipsychotics as adjunctive antidepressants. The Consensus Development Conference recommended monitoring for a number of risk factors, such as family history, waist circumference, fasting plasma glucose, and fasting lipid glucose (Slide 7).4 Unfortunately, many clinicians do not rigorously follow these guidelines. Clinicians in institutional settings, with ample assistance from nurses and ancillary personnel, may have less difficulty drawing blood and following these extensive guidelines. However, clinicians in smaller practices face obstacles to carrying out the recommendations, both because they often lack the infrastructure to obtain frequent lab tests and because because they simply do not have a tradition of doing them. The formal recommendations are lofty but burdensome, and because the majority of clinicians in the community may not follow them, those doctors are left without practicable guidelines.

 

Should clinicians receive a second set of guidelines? It seems that there are practical measures clinicians can take to monitor their patients without undue burden. Though they will miss some rare diabetic ketoacidoses without consistently monitoring weight gain or other laboratory parameters, clinicians can safely assume that patients who have experienced significant weight gain—≥7% of baseline body weight, or ≥10 pounds for a 150-pound person—belong to a higher-risk group. When using SGAs as adjunctive antidepressants, identifying high-risk groups might best involve monitoring weight gain and testing glucose, lipid profiles, and blood pressure for those patients who have gained ≥7% of their baseline body weight.

Clinicians should be reminded that using lower doses of the SGAs does not mean they can be dismissive about weight gain. While there are some data indicating that weight gain is dose-related, at least for olanzapine and quetiapine, there has been no conclusive evidence. However, adjunctive therapy with an SGA does utilize relatively low doses of SGAs, which may give clinicians some peace of mind. This is a topic that clinicians will have to address more in the future as SGAs are increasingly used as adjunctive antidepressants.

 

Conclusion

In summary, the use of SGAs as adjunctive antidepressants has increased substantially. At this point, the data has not kept up with the clinical interest but we can anticipate a number of controlled studies in this area emerging over the next few years. With the use of these medications for depression comes the obligation to carefully consider side effect issues in choosing specific agents.

 

References

1. Correll Cu, Leucht S, Kane JM. Lower risk for tardive dyskinesia associated with second-generation antipsychotics: a systematic review of 1-year studies. Am J Psychiatry. 2004;161(3):414-425.
2. Ford ES, Giles WH, Dietz WH. Prevalence of the metabolic syndrome among US adults: findings from the third National Health and Nutrition Examination Survey. JAMA. 2002;287(3):356-359
3. Allison DB, Mentore JL, Heo M, et al. Antipsychotic-induced weight gain: a comprehensive research synthesis. Am J Psychiatry. 1999;156(11):1686-1696.
4. American Diabetes Association; American Psychiatric Association; American Association of Clinical Endocrinologists; North American Association for the Study of Obesity. Consensus development conference on antipsychotic drugs and obesity and diabetes. Diabetes Care. 2004;27(2):596-601.
5. Lieberman JA, Stroup TS, McEvoy JP, et al. Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. N Engl J Med. 2005;353(12):1209-1223.


 

Question-and-Answer Session

Q: I have long been interested in using thyroid hormone as adjunctive treatment for depression, but I am consistently disappointed with the results in my patients. What has your experience been?

 
Dr. Thase: In my clinical experience, thyroid augmentation is the treatment of choice for a depressed patient with an underfunctioning thyroid gland, but it is not high on my list for anyone else with refractory depression. Simply said, I believe this treatment works by enhancing thyroid function and patients who have high normal thyroid function to begin with do not benefit. In a study of bipolar depression,1 the cutoff for thyroid-stimulating hormone (TSH) was ~2.5 and a below 50 percentile value for the free thyroxin index (FTI). Patients with one or both of these were less likely to respond to antidepressants. Since that time I have since been targeting those patients with a slightly higher-than-average TSH and a slightly lower than average FTI for thyroid augmentation.

Dr. Nelson: Many studies have looked at augmentation very early in the course of treatment, at ~4 weeks. This may overestimate the effect of augmentation since patients may still be in the midst of responding to initial treatment. Not many studies have carefully selected patients who are truly refractory to initial treatment. A study by Thase and colleagues2 was one of the only studies that incorporated a 12-week period of treatment with imipramine and psychotherapy. Augmentation with thyroid did not seem to add efficacy. In my own experience, I have been similarly disappointed with thyroid augmentation for people who are really treatment resistant.

 

Q: Have the studies focusing on augmenting tricyclic antidepressants (TCAs)  with first-generation (conventional) antipsychotics (FGAs) for major depressive disorder largely evaluated them as first-line treatments?

Dr. Thase: The original set of studies looked at FGAs as first-line treatments. In that era, FGAs were often used as augmentation agents because psychiatrists did not want to use benzodiazepines. Lower doses of FGAs showed good anxiolytic effects as long as they did not induce akathisia. The evidence of FGA efficacy in depression primarily comes from studies of their first-line use, not their use as augmentation strategies.

Dr. Nelson: There are several positive studies showing that FGAs have an advantage over placebo in the treatment of depression, especially with severely ill patients. The reason they are not considered “antidepressants,” however, is because they were less effective than imipramine for treating loss of interest or motor retardation—symptoms the field considers to be central to the concept of depression.3 However, antipsychotics are useful for treating many other symptoms of depression such as feelings of guilt, anxiety-tension, sleep disturbance, and of course, depressive delusions.3 Hollister and Overall4 argued that some depressed patients have a complete response to antipsychotics alone.

 

Q: Consider a hypothetical patient with moderately severe nonpsychotic depression, with no clear family history or worrisome historical factors suggestive of bipolar disorder, who has not responded to a second-line antidepressant. The clinician has tried one monotherapy after another, and the patient has experienced a 25% to 30% symptom reduction. The clinician now has decided to augment rather than go to a third favorite monotherapy. Given the state of the evidence, which strategy would you pick?   

 
Dr. Nelson: That is a difficult question at this point. Should one pick an augmentation strategy or a combination treatment strategy? If the patient remained generally depressed, I would use an antidepressant combination. I would use augmentation agents for specific prominent residual symptoms such as lack of energy and fatigue, or insomnia, or anxiety and agitation and select the agent most likely to help with those symptoms.   
  
Dr. Gitlin: There is a reasonable amount of positive data for lithium augmentation, most of it with tricyclic antidepressants (TCAs), but clinician and patient acceptance of lithium augmentation is very poor. There are also stimulants for which we do not have any supportive double-blind evidence, yet stimulant augmentation is the single most common augmenting technique clinicians use. It is quite difficult to make research-informed decisions when the findings do not translate into practices acceptable to clinicians and patients.    

Dr. Nelson: It would be nice to have a study similar to the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study, with a more extensive comparison of common augmentation and combination strategies, as well as a placebo arm. This kind of study would allow psychiatrists to compare the efficacy of these strategies. 

 

Q: The findings of the meta-analysis by Crossley and Baur5 favor lithium augmentation. However, the authors do not highlight the discrepancies in study durations. Many of these durations are ≤2 weeks. Clinical effects of lithium appear very early, but are not very apparent later. Might this meta-analysis indicate an early acceleration effect which might not appear as robust at week 2?  

Dr. Nelson: There are two duration issues that are variable and limited. One is the duration of prior treatment, which often was only 4 weeks. The other is the duration of the augmentation phase, which in some studies was only 48 hours. The short duration of these studies was based on de Montigny’s6 report of rapid response. There may indeed have been a rapid effect (acceleration) independent of long-term efficacy. Alternatively, Dr. Thase’s historical comparison7 had a longer duration of treatment (6 weeks) during which patients continued to improve.   
  
Dr. Thase: It is important to keep in mind the source of the patients in the study. Ours was part of a study of highly recurrent depression, and our patients had an average of seven prior episodes. The clinic was strict in its definition of bipolar disorder, and many of our patients would today be said to fall in the bipolar spectrum. Of the lithium responders, 20% to 30% had relatively fast responses, while the other lithium responders experienced slow, gradual, 4–6-week responses.7 For patients with difficult-to-treat depression, lithium can enhance antidepressant effect. This seems more likely to occur with a TCA than with a selective serotonin reuptake inhibitor (SSRI) because TCAs are primarily noradrenergic medications and lithium is a relatively weak serotonergic enhancer.

Q: Is there evidence of an advantage for the use of second-generation (atypical) antipsychotics (SGAs) as an adjunct in more severely depressed patients? It is my impression that severely ill patients are usually more willing to tolerate side effects.

  
Dr. Papakostas: Unfortunately, in our meta-analysis8 we did not have data that would allow us to look at whether the treatment difference is more robust in patients with severe depression versus those with mild depression. It would be interesting as a post-hoc analysis. However, in my clinical practice, when a patient has very severe depression with suicidal ideation or with irritability, using SGAs certainly comes to mind sooner than it would for a patient who is nearly remitted, whose initial treatment had a low side-effect burden.
 
Dr. Gitlin: I agree. We have difficulty telling patients with significant residual symptoms, but without severe depression, that we want to put them on antipsychotics. That can be quite jarring for patients. In the less severe patients who presumably have less agitation, we must be careful about using more sedating agents, such as quetiapine and olanzapine. A moderately residually depressed patient might prefer to try aripiprazole or ziprasidone than more sedating and weight-gaining agents.    
 
Dr. Nelson: It is still quite difficult to determine which augmentation agents will work best with which patients. The data on predictors of response to augmentation are very limited. These decisions are currently based on clinical experience.  It does seem that depression severity interacts with ability to tolerate side effects. Early studies of lithium augmentation were primarily done in more severely ill inpatients who were started on lithium 900 mg/day (300 mg TID). In these hospitalized patients, lithium was relatively well tolerated. In the STAR*D sample, however, which consisted of outpatients who were less ill, lithium was considered quite problematic in terms of patient tolerability.   

 

References

1. Cole DP, Thase ME, Mallinger AG, et al. Slower treatment response in bipolar depression predicted by lower pretreatment thyroid function. Am J Psychiatry. 2002;159(1):116-121.
2. Thase ME, Kupfer DJ, Jarrett DB. Treatment of imipramine-resistant recurrent depression: I. An open clinical trial of adjunctive L-triiodothyronine. J Clin Psychiatry. 1989;50(10):385-388. 
3. Raskin A, Schulterbrandt JG, Reatig N, McKeon. Differential response to chlorpromazine, imipramine, and placebo. Arch Gen Psychiatry. 1970;23:164-173.
4. Hollister LE, Overall JE. Reflections on the specificity of action of anti-depressants. Psychosomatics. 1965;6(5):361-365.
5. Crossley NA, Bauer M. Acceleration and augmentation of antidepressants with lithium for depressive disorders: two meta-analyses of randomized, placebo-controlled trials. J Clin Psychiatry. 2007;68(6):935-940.
6. Dé Montigny C, Grunberg F, Mayer A, Deschenes JP. Lithium induces rapid relief of depression in tricyclic antidepressant drug non-responders. Br J Psychiatry. 1981;138:252-256.
7. Thase ME, Kupfer DJ, Frank E, Jarrett DB. Treatment of imipramine-resistant recurrent depression: II. An open clinical trial of lithium augmentation. J Clin Psychiatry. 1989;50(11):413-417.
8. Papakostas GI, Shelton RC, Smith J, Fava M. Augmentation of antidepressants with atypical antipsychotic medications for treatment-resistant major depressive disorder: a meta-analysis. J Clin Psychiatry. 2007;68(6):826-831.

Needs Assessment: Borderline personality disorder (BPD) is a psychiatric disorder often associated with suicidal behavior, thoughts, and urges. Primary care physicians are very likely to encounter and treat individuals with BPD and, therefore, need to be educated about the characteristics, risk factors of suicidality, and treatment options in individuals with BPD.

Learning Objectives:
• Describe the characteristics of individuals with borderline personality disorder (BPD).

• Recognize risk factors for suicidal behavior that should be considered and assessed in patients with BPD.
• Identify treatment options for patients with BPD who are at risk for suicidal behavior.

Target Audience: Primary care physicians and psychiatrists.

CME Accreditation Statement: This activity has been planned and implemented in accordance with the Essentials and Standards of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of the Mount Sinai School of Medicine and MBL Communications, Inc. The Mount Sinai School of Medicine is accredited by the ACCME to provide continuing medical education for physicians.
 


Credit Designation:
The Mount Sinai School of Medicine designates this educational activity for a maximum of 3 AMA PRA Category 1 Credit(s)TM. Physicians should only claim credit commensurate with the extent of their participation in the activity.

Faculty Disclosure Policy Statement: It is the policy of the Mount Sinai School of Medicine to ensure objectivity, balance, independence, transparency, and scientific rigor in all CME-sponsored educational activities. All faculty participating in the planning or implementation of a sponsored activity are expected to disclose to the audience any relevant financial relationships and to assist in resolving any conflict of interest that may arise from the relationship. Presenters must also make a meaningful disclosure to the audience of their discussions of unlabeled or unapproved drugs or devices. This information will be available as part of the course material.
 

This activity has been peer-reviewed and approved by Eric Hollander, MD, chair and professor of psychiatry at the Mount Sinai School of Medicine, and Norman Sussman, MD, editor of Primary Psychiatry and professor of psychiatry at New York University School of Medicine. Review Date: October 25, 2007.

Drs. Hollander and Sussman report no affiliation with or financial interest in any organization that may pose a conflict of interest.



To receive credit for this activity:
Read this article and the two CME-designated accompanying articles, reflect on the information presented, and then complete the CME posttest and evaluation. To obtain credits, you should score 70% or better. Early submission of this posttest is encouraged: please submit this posttest by December 1, 2009 to be eligible for credit. Release date: December 1, 2007. Termination date: December 31, 2009. The estimated time to complete all three articles and the posttest is 3 hours.

Dr. Fertuck is assistant professor of clinical psychology in the Department of Psychiatry at Columbia University College of Physicians & Surgeons and the New York State Psychiatric Institute in New York City. Ms. Makhija is assistant research scientist at Columbia University. Dr. Stanley is director of the Suicide Intervention Center at the New York State Psychiatric Institute/Columbia University College of Physicians & Surgeons.

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

Funding/support: This article was supported in part by grants from the American Foundation for Suicide Prevention (AFSP), the Fund for Psychoanalytic Research through the American Psychoanalytic Association, and the National Institute of Mental Health (NIMH; 1 K23 MH077044-01A2) to Dr. Fertuck; and in part by grants from the AFSP, the NIMH (R01 MH061017 and MH62665), and the National Institute on Alcohol Abuse and Alcoholism (P20 AA015630) to Dr. Stanley.

Please direct all correspondence to: Eric A. Fertuck, PhD, Department of Psychiatry, Columbia University College of Physicians and Surgeons, NYSPI Unit 42, 1051 Riverside Dr, New York, NY 10032; Tel: 212-543-6926; Fax: 212-543-6946; E-mail: ef304@columbia.edu.

 


Abstract

Borderline personality disorder (BPD) is a common but often misunderstood and stigmatized psychiatric condition. Furthermore, BPD is a psychiatric disorder associated with one of the highest rates of healthcare utilization. Accordingly, the prevalence of BPD in primary care settings is high. The most pressing and lethal dimension of BPD is suicidal behavior. There is an almost 10% rate for suicide completion in BPD, which is 400 times greater than the rate in the general population. Primary care physicians (PCPs) are very likely to encounter and treat individuals with BPD at risk for suicide. However, most PCPs have not been educated about this diagnosis. This article aims to orient and familiarize PCPs with the unique characteristics and risk factors of suicidality and treatment options for individuals with BPD.

 

Introduction

This article has two aims. First, to orient and familiarize primary care physicians (PCPs) with the unique characteristics and risk factors of suicidality in borderline personality disorder (BPD).1 Second, to inform PCPs about treatment options for suicidal individuals with this diagnosis. Given the prevalence and high rate of healthcare utilization associated with BPD, it is likely that in their day-to-day clinical work, PCPs in both psychiatric and other primary care settings will encounter individuals with BPD, some of whom may be acutely suicidal. Consequently, it is essential that PCPs understand the symptomatic manifestations and treatment options for suicidal individuals with BPD.

 

Prevalence of Borderline Personality Disorder

BPD is a common but often misunderstood and stigmatized psychiatric condition. Up to 2.8 million adults in the United States meet criteria for BPD,2 approximately three times higher than the rate of schizophrenia.3 In clinical settings, most individuals with BPD are women; however, in the general population the gender ratio appears equal.2 This suggests that more women than men with BPD seek treatment in psychiatric settings.

 

Characteristics of Borderline Personality Disorder

Individuals with BPD are profoundly sensitive to perceived abandonment, rejection, and betrayal by significant others. Further, stormy and turbulent emotional states tend to occur in the context of perceived disruption and threats to relationships with significant others. Consequently, the relationships of those with BPD are often fraught with conflict, anger, and disappointment. Individuals with BPD also have impairments in regulating and modulating their intense emotional experiences. For these individuals, emotions can quickly spiral out of control, leading to intense states of anxiety, tension, and anger. Concurrently, disruption in the sense of self or identity is frequent in individuals with BPD. Accordingly, many people with BPD struggle with a chronic sense of emptiness and alienation. Individuals with BPD tend to view themselves critically and to expect to be emotionally hurt by others. Poor impulse control is a core feature of BPD. Impulsive behavior in BPD is most often self-directed and takes the form of suicide attempts, non-suicidal self-injury (NSSI; such as cutting), substance abuse, and high-risk behaviors (such as reckless driving). When emotionally stressed, dissociation and brief psychotic-like symptoms can occur. The psychotic-like symptoms do not take the form of hallucinations seen in schizophrenia. Rather, they are usually the product of interpersonal sensitivity and are exaggerations of the perceived hurtful intentions of others.

 

Suicide Completion in Borderline Personality Disorder

The high rate of completed suicide in major depressive disorder (MDD), bipolar disorder, and schizophrenia is well recognized by most clinicians. However, there is not yet widespread appreciation that the nearly 10% rate for suicide completion in BPD is comparable to these other disorders4-10 and is 400 times greater than the rate in the general population. Of all completed suicides, 9% to 33% are by individuals with BPD.11,12 Moreover, 60% to 84% of patients with BPD have made at least one suicide attempt,13,14 indicating that attempts outnumber completions by approximately 8 to 1.

 

Assessing Suicide Risk in Borderline Personality Disorder

There are several risk factors for suicide in BPD, some of which are unique to this patient population. Regrettably, none of these factors allow clinicians to confidently predict risk for completed suicide. Nonetheless, the following sections summarize the risk factors that the PCP should consider and assess when attempting to identify and prevent suicide attempts in patients with BPD.

Many clinicians are reluctant to ask patients direct question about suicide out of concern that it may actually trigger an attempt. There is no evidence for this concern.15 On the contrary, not assessing the possibility of suicidality may lead to a preventable suicide attempt. With individuals with BPD, a thorough, calm, and concerned inquiry of suicidality is required.

 

Differentiating Suicidal Behavior from Non-Suicidal Self-Injury in Borderline Personality Disorder

For clinicians, one of the most confusing features of BPD is NSSI and self-injury with only partial suicidal intent (see Posner and colleagues16 for a typology of suicidal behavior). Most individuals with BPD have cut, burned, hit, or otherwise injured themselves at some point in the course of their illness. For many, this is a frequent, recurrent behavior. Less obvious forms of self-injury include impulsive substance use, over- or under-eating, risky driving, and high-risk sexual behavior. The most common reported motivations for these behaviors among individuals with BPD are self-punishment as a consequence of extreme anger and self-hatred, to interrupt dissociative symptoms and to feel “real,” to communicate distress, to avoid making a suicide attempt, to reduce unbearable negative emotions (usually manifest as anxiety or tension), and to restore a sense of emotional equilibrium (ie, “to feel better”).17

NSSI and suicide attempts and completions often co-occur; however, those patients with both may be a unique sub-population.18 Suicide attempters with cluster B personality disorders such as BPD who also have a history of NSSI tend to exhibit more depressive symptoms, anxiety, and impulsivity. As a result, clinicians may assess the suicide risk of those who engage in NSSI as less serious than it actually is.18

Individuals who present with BPD and NSSI need to be assessed for the degree of suicidal intent associated with this behavior. NSSI doubles a BPD patient’s risk for suicide.19 With this in mind, individuals with BPD often underestimate the lethality and danger of NSSI and may put their lives at risk without full intent.20 Furthermore, clinicians treating an individual with repeated NSSI may overlook genuine suicidal intent when it occurs. If the individual with BPD has NSSI without acute suicidal intent and this is low in lethality and risk, then specialized outpatient treatment for BPD is indicated (see below). Given the high rate of treatment non-compliance, recommendations for specialized treatment should be followed up with an inquiry to the patient and with consistent encouragement to seek treatment for this behavior. While it is outside the scope of this paper to focus on primary care intervention for NSSI, others have recommended an approach for use in the psychiatric emergency room.21

 

Differentiating Chronic Suicidal Ideation from Acute Suicidal Intent and Risk

Individuals with BPD often have chronic suicidal ideation. For some, chronic suicidal ideation with recurrent attempts and self-injurious behaviors becomes a “way of life” that seems to allow these individuals to cope with emotions and life circumstances that feel intolerable and uncontrollable. While distressing to these patients and those around them, suicidal ideation without acute suicidal intent, a plan, and realistic means (eg, the availability of a firearm) can best be addressed in specialized outpatient or partial hospital treatment.

 

The Importance of Interpersonal Context and Experience in Suicidality in Borderline Personality Disorder

In keeping with the interpersonal turbulence associated with BPD, environmental triggers of highly lethal suicide attempts by people with BPD and MDD are more likely to be interpersonal stressors than in patients with MDD alone.22 Despite this difference, lethality of attempts in BPD is equal to that of MDD, indicating that the type of precipitant is unrelated to the lethality of the suicidal behavior. It is crucial for the clinician to inquire about environmental triggers to suicide, both perceived and actual, when evaluating suicidality, particularly in BPD.

 

Other Co-Occurring Disorders that Increase Suicide Attempt and Completion Risk in Borderline Personality Disorder

The presence of several other Axis I and II psychiatric disorders can also increase suicide risk in BPD. The most concerning is a current or past substance use disorder.23-27 Whether or not the patient meets criteria for a current substance use disorder, substance abuse prior to an attempt can disinhibit individuals who may be ambivalent about suicide, leading to more lethal attempts. Substance abuse can impair judgment so that suicidal actions instigated with a low level of intent can result in lethal consequences. Further, substance use disorders which may be linked to the trait of impulsivity—a suicide risk factor even after substance abuse or MDD is controlled for—are associated with increased lifetime suicide attempts in patients with BPD.20,26,28

Co-occurring MDD and other mood disorders are common in BPD. However, the quality of the mood disturbance is different from MDD without BPD.29 Suicide attempters with co-occurring BPD and MDD have more lifetime suicide attempts, make their first attempt at a younger age, report more interpersonal triggers to attempts, and have higher levels of lifetime aggressive behaviors, hostility, and impulsivity compared with depressed attempters without BPD.22 In BPD, depressive moods and affects are reactive to interpersonal and other environmental stressors and are usually of briefer duration. By contrast, in MDD, the severity of depression and suicidality build up more gradually and can persist for weeks or months. Suicide attempts in MDD, then, are often done in a planned manner after extended dysphoric periods that conclude in a sense that the only option is to end one’s life.30

Consequently, the impact of depression severity on suicide is less clear in BPD than in MDD. In one study, emotional dysregulation in BPD was the strongest predictor of prospectively assessed suicidal behaviors and suicide attempts; severity of depression at baseline did not predict later suicidality.31 However, current severity of MDD is associated with increased risk for a greater number of suicide attempts that are more lethal in BPD.23,28,32 Moreover, sub-threshold depressive symptoms and hopelessness can increase suicide attempt risk in BPD. Consequently, assessment of the severity of current depressive symptoms is crucial when assessing suicide attempt risk in BPD.

The majority of suicide victims with antisocial personality disorder have co-occurring BPD. Moreover, the more individuals with BPD have characteristics of antisocial personality, the greater their risk for making suicide attempts. Though the risk of suicide associated specifically with antisocial personality disorder remains unclear, it is estimated that the lifetime suicide risk associated with this diagnosis is 5%.20,23,25

 

Other Risk Factors

Other risk factors for suicidal behavior in BPD include prior suicide attempts25,27,33-35 and having past suicide attempts of high medical lethality.27,36 However, these risk factors are not unique to BPD. A younger age, most specifically from adolescence through the third decade of one’s life,26 is associated with increased suicide risk in BPD. However, some have proposed that more suicide attempts occur at a younger age, whereas more suicide completions occur between 30 and 37 years of age. This may be due to increased hopelessness as treatments have failed the individual. A history of sexual or physical abuse is a strong risk factor for suicide attempts as well.14,20 Other family and developmental factors such as parental absence or separation during childhood, employment or financial problems, or a lack of a permanent home in early life are associated with suicide attempts in BPD. Finally, prior hospitalizations33 and a higher level of education9 have been linked to suicide attempts in BPD.

 

Treatment of Borderline Personality Disorder

It is estimated that 11% of all psychiatric outpatients and 19% of psychiatric inpatients meet diagnostic criteria for BPD.37 One study38 found that individuals with BPD make up only 1% of the patient population seen in the psychiatric emergency room yet accounted for 12% of all visits. Moreover, the prevalence of BPD in primary care is high (6.4%), approximately four times higher than that found in general community studies.39 Accordingly, BPD is a psychiatric disorder associated with the highest rates of healthcare utilization.40

BPD is difficult to treat.41 Individuals with BPD are prone to feeling disappointed and angry with treatment providers as well as to ending treatment under the influence of unfulfilled expectations. The recurrent interpersonal difficulties, NSSI, and suicidality associated with BPD can lead clinicians to stigmatize BPD and feel burnt out and non-empathic toward BPD. Most mental health clinicians have no specialized training in working with this population. Without specialized training, clinicians often provide less than optimal assessment and care.

 

The Circumscribed Role of Hospitalization in Preventing Suicide in Borderline Personality Disorder

Most forms of suicidal behavior and NSSI in BPD can be managed and treated in an outpatient or partial hospital setting, provided such a treatment is in place. Even though the individual with BPD may desire and request hospitalization at times, regular hospitalization for suicidal threats, minor overdoses, and self-injurious behavior can actually reinforce these behaviors and be counter-therapeutic.42 Furthermore, because individuals with BPD are often chronically suicidal, much of their lives could be spent hospitalized if this was routinely employed. At the same time, the high suicide rate in BPD must be kept in mind and suicidal feelings should not be dismissed as simply threats.

 

Recommended Principles for Hospitalization in Borderline Personality Disorder with Suicidality

Specialized treatments for BPD have protocols for deciding when to hospitalize individuals with BPD. Primary therapists of individuals with BPD use their clinical judgment and the principles of their treatment approach to make a decision to hospitalize during an acute suicidal episode. As a result, close communication with the primary therapist is recommended before deciding to hospitalize an individual with BPD who is suicidal.

If an individual with BPD presents in a primary care setting with suicidality and he or she does not have a primary clinician with whom to immediately consult, the PCP is responsible for deciding whether hospitalization is warranted. There are discrete circumstances when brief inpatient treatment is necessary, such as when a patient with BPD appears to be at an extremely high risk for suicide and is not responding to therapy. Additionally, an acute episode of an Axis I condition such as MDD, bipolar disorder, or a psychotic disorder may require hospitalization to intensively evaluate and monitor the immediate effects of any treatment change.27,43

In general, if a patient reports the intent, plan, and available means for suicide attempt, they are at high risk for a suicide attempt and hospitalization is recommended. If the patient reports suicidal ideation without intent, plan, and means, then a “safety contract” (ie, an agreement between the clinician and patient that the patient will not harm him- or herself) and a treatment referral with a follow up call by the PCP to ensure the referral was utilized is recommended. In the event that a patient with BPD refuses a recommended hospitalization, involuntary admission may be necessary to ensure the patient’s immediate safety. For all decisions, thorough documentation of the decision and its clinical rationale is essential.

 

Manualized Psychosocial Treatments for Borderline Personality Disorder with Suicidality

Due to the complicated clinical picture and difficult-to-treat dimensions, BPD requires expert assessment and treatment, usually from a clinician or treatment team with specialized training. In the last 15 years, several manualized psychosocial treatments and medications now have varying empirical support in treating BPD from randomized controlled trials (RCTs). In addition, the American Psychiatric Association treatment guidelines for BPD were updated in 2005.44,45 All of the psychosocial treatments include strategies for managing and treating suicidality in BPD.

 

Dialectical-Behavioral Therapy

Dialectical-behavioral therapy (DBT) is a cognitive-behavioral treatment with two components, namely, individual therapy and weekly group skills training. The treatment balances “acceptance” and “change” strategies to help individuals with BPD improve emotion regulation capacities, and has a strong focus on helping individuals master skills to diminish suicidal urges and cope more effectively with their interpersonal relationships and emotional states. DBT has been found efficacious for reducing suicidal behavior, NSSI, and substance abuse in several RCTs.46

 

Cognitive-Behavioral Therapy

Cognitive-behavioral therapy (CBT) is a structured, time limited, individual treatment that focuses on altering core dysfunctional beliefs specific to BPD. In one RCT, CBT plus treatment as usual for BPD had better outcomes in suicide prevention and other symptom domains compared to treatment as usual without CBT.47

 

Schema-Focused Therapy

Schema-focused therapy (SFT), a modified form of CBT for personality disorders, posits the existence of schema modes (conceptions of self in relation to significant others) common and specific to BPD. The putative mechanism of change in SFT is to help the patient become less influenced by these pervasive schemas. In one RCT, this therapy demonstrated efficacy in multiple domains of symptoms and function, including suicidal behavior.48

 

Mentalization-Based Therapy

Mentalization-based therapy (MBT) for BPD is a psychoanalytically oriented treatment in the context of a partial hospital program. MBT focuses on increasing “mentalization” in BPD. Mentalization entails making sense of the actions of oneself and others on the basis of intentional mental states such as desires, feelings, and beliefs. MBT has been found to be efficacious in reducing depression, suicidal acts, NSSI, inpatient days, and social functioning in one RCT.49,50

 

Transference-Focused Psychotherapy

Transference-focused psychotherapy (TFP) is a psychoanalytic treatment rooted in object relations theory. TFP addresses disturbance in identity and conceptions of significant others in BPD. It is has received empirical support in one RCT, where it reduced self-injurious behavior comparably to DBT and more than supportive psychotherapy.51

 

Efficacy of Medication in Borderline Personality Disorder

No single pharmacologic agent has emerged as the treatment of choice for BPD.46,52 Moreover, medications for BPD have not been evaluated with a focus on their efficacy for reducing suicidal behaviors. As is often the case in psychopharmacology trials, the acutely suicidal patients are excluded. Thus, there is a pressing need to evaluate these agents for their efficacy in specifically reducing suicidal behavior, ideation, and intent. Prescribing medication to an acutely suicidal BPD patient with suicidality requires careful management and consideration and may be contraindicated if the prescribed medication can be used for a high lethality overdose.

Atypical neuroleptics show promise for reducing quasi-psychotic symptoms and the other dimensions of BPD,53 although their side effects, particularly weight gain, can make them unacceptable to patients. Placebo-controlled studies provide preliminary support for the efficacy of selective serotonin reuptake inhibitors (SSRIs) on mood dysregulation, irritability and hostility, and anxiety. Importantly, the relative efficacy of SSRIs, a common treatment for BPD, compared with psychosocial treatment has not been established. Mood stabilizers,54 particularly valproic acid55 and topiramate,56,57 and lamotrigine, show efficacy in the treatment of dimensions of BPD such as impulsive aggression.58 There is also support for the use of omega-3 fatty acids in the treatment of BPD,59 with better compliance, fewer side-effects, and less stigma than conventional mood stabilizers.

 

Case Vignettes Illustrating Suicidality and Non-Suicidal Self-Injurious Behavior in Borderline Personality Disorder

The following vignettes are examples of patients who have presented to the emergency department for suicide or NSSI. Included are a case with a suicide attempt and one with NSSI to illustrate the similarities and differences between these two clinical presentations. These two presentations have different treatment implications for the PCP.

 

Borderline Personality Disorder Suicide Attempter

The first vignette is of a patient with BPD who had multiple suicide attempts. This patient is illustrative of a BPD attempter because of the recurrent suicide attempts she has made throughout her life.

A 26–year-old Hispanic female who was separated from her husband and who had one daughter presented to a psychiatric emergency department with an angry and irritable mood. She complained of disturbed sleep, stating she had not slept in the past 2 weeks. At the same time she reported increased energy, distractibility, and having suicidal and homicidal ideation. She stated that she was “indifferent” as to whether she lived or died. She reported a history of physical and sexual abuse as a child. The patient had been unemployed for the last 4 months, receiving disability; prior to this she was working as a convenience store manager. She had nine lifetime suicide attempts and eight psychiatric hospitalizations that lasted between 1 week and 1 month. Four of her suicide attempts were overdoses (the first three attempts consisted of 25–30 pills each attempt). One of her attempts involved cutting her wrist with “little” cuts, and for one attempt she hung herself on a bus door for two seconds with a scarf before the scarf broke. Two of her attempts were interrupted (her friends stopped her from trying to jump in front of train tracks and trying to run into traffic), and one was aborted (she stopped herself before jumping into train tracks). Her most recent attempt was 3 weeks prior to the emergency room visit when she ingested 40 1-mg clonazepam capsules with the intent to die. The attempt was prompted by her feeling distraught after her husband moved away. After the overdose, she reported feeling dizzy and throwing up two or three times and then sleeping for 1.5 days.

The patient’s treatment history is as follows. She first began therapy at 7 years of age. Since 23 years of age she had eight psychiatric hospitalizations that lasted between 1 week and 1 month. She had been prescribed a variety of medication and at present is prescribed lithium carbonate and clonazepam but is non-compliant with these medications. She is not currently and had never been in any specialized treatment for BPD.

 

Borderline Personality Disorder Self-Injurer without Suicide Attempts

The second vignette is that of a woman with BPD who never had a suicide attempt but has had recurrent NSSI that she engages in impulsively when feeling upset. The patient sees this behavior as a way to feel more alive, release her tension, and punish herself. Note her underestimation of the medical risk and lethality inherent in her self-injury.

A 25-year-old Caucasian female brought herself to a psychiatric emergency department after cutting her right thigh with an Exacto knife. She stated that she became afraid of all the blood, realized that she had cut too deeply, and needed to get medical attention. She denied any suicidal ideation or intent. She has a history of sexual abuse by a family friend between the ages of five and seven. She reported no history of suicidal ideation in the last 2 years and no history of suicide attempts; she reported active suicidal ideation throughout her childhood with intent to act only once while sitting on a rooftop. On the roof she reported that she thought she would like to jump but a friend told her it was a bad idea. She had a history of NSSI. As a child she recalled jumping out of trees that were two stories high so she could hurt herself. She once tried to burn herself but stopped because of the pain. She has a history of picking the skin around her nails until it bleeds and of cutting herself on her arms, thighs, and stomach. She had stopped NSSI for some time in early adulthood, but resumed intermittently cutting herself 2 years ago. In the 2 months before presenting to the emergency room (ER), she had been cutting herself daily. She reported that she engages in superficial cutting because afterwards she “feels better, feels something and feels less numb” and that “it helps [her] sleep.” Her latest cutting episode stemmed from a phone call with her mother in which her mother told her she was too busy to speak with her. The patient reports that she was “mad at [her]self” because she felt that she was “hassling her mother.” Upon cutting herself this time she realized the cuts were much deeper than she normally made them and brought herself to the ER.

The patient’s treatment history is as follows. Her first experience with psychiatric treatment was for a few months when she was 8 years of age. She then began individual therapy again approximately 24 years of age. She had no prior psychiatric hospitalizations. She is currently in outpatient therapy and takes paroxetine 10 mg/day.

 

Conclusion

BPD is a serious disorder that puts an individual at increased risk for suicidal attempts and completions. The PCP is very likely to encounter individuals with this diagnosis in psychiatric and non-psychiatric settings, and suicidal behavior and urges may be present. It is crucial for the PCP to maintain an empathic and concerned clinical stance with individuals with BPD, in particular in the context of acute suicidality. A thorough assessment of suicidality in BPD focuses on suicidal intent, any suicidal plans, and the presence of a realistic means to complete the plan. Further, the degree of emotion dysregulation, interpersonal triggers to suicidality, and degree of suicidal versus non-suicidal intent in self-injurious urges and behaviors needs to be assessed to provide a complete picture of acute suicide risk. Given the complications that can arise in this multifaceted disorder, close communication and follow up with treatment providers who have expertise in the assessment and treatment of BPD is crucial as well. PP

 

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FDA Approves Aripiprazole for the Treatment of Schizophrenia in Adolescents

The United States Food and Drug Administration approved aripiprazole (Abilify, Bristol-Myers Squibb) for the treatment of schizophrenia in adolescents between 13 and 17 years of age.

The recent approval for adolescents was based on a 6-week, double-blind study conducted at 101 centers in 13 countries. It enrolled 302 ethnically diverse pediatric patients who were experiencing an acute episode of schizophrenia and required hospitalization at the time of enrollment. After 3 days without any antipsychotic treatment, patients were randomly assigned to receive either aripiprazole 10 mg/day or 30 mg/day or placebo. The study demonstrated significant improvement with aripiprazole compared to placebo on the primary efficacy endpoint, Positive and Negative Syndrome Scale Total Score.

The recommended oral target dose of aripiprazole for adolescents is 10 mg/day with or without food.

The most common side effects found in ≥5% of pediatric patients receiving aripiprazole were somnolence (ie, drowsiness), tremor, and various extrapyramidal symptoms.

For more information, please consult the medication’s full prescribing information. (www.abilify.com). —ML

 

Psychosocial Intervention Improves Physical and Mental Health of Spouses Who Care for Patients with Alzheimer’s Disease

Patients with Alzheimer’s disease typically present with dementia and other symptoms related to brain damage, such as disorientation and confusion as well as neglect of personal hygiene, safety, and nutrition. Those with Alzheimer’s disease often require specialized care that is commonly provided by spouses and other family members in the home environment. Although such care can be beneficial for patients with Alzheimer’s, those providing that care may be suffering from negative physical and mental health effects and may not seek adequate treatment for their own conditions.

In a recent study, Mary S. Mittelman, DPH, of the Department of Psychiatry of the New York University School of Medicine, and colleagues, sought to determine the effects of counseling and support interventions on the physical health of spouses who acted as caregivers for patients with Alzheimer’s disease. The efficacy of mental health support interventions was evaluated in prior studies by Mittelman and colleagues.

Researchers studied the outcomes from psychosocial interventions or usual care for 406 spouse caregivers of patients with Alzheimer’s over the course of 9.5 years between 1987 and 2006. Interventions included six sessions of individual and family counseling, support group participation, and telephone counseling continuously available to caregivers over a 4-month period. Caregivers in the intervention group were also encouraged to join weekly support groups following the 4-month study period. Usual care included providing caregivers with intervention information and assistance upon request. Structured questionnaires, such as self-reported health measures and number of reported illnesses, were administered at baseline and at regular follow-up periods to assess outcomes.

The authors found that caregivers in the intervention group had significantly better self-reported health than those receiving usual care at the study endpoint (6.87 vs 7.21, in self-reported health measures; mean=7.24). This result was also maintained for 2 years following the study endpoint (6.70 vs 7.01). Mittelman and colleagues found that caregivers began to show improvement in physical health after 4 months of intervention. In addition, positive results due to the interventions remained significant when the authors controlled for nursing home placement, Alzheimer’s disease patient death, caregiver depression symptoms, and caregiver satisfaction with social support.

The authors concluded that counseling and support preserved the self-reported physical health in vulnerable caregivers. They added that interventions may provide more support for caregivers, provide increased education on potential health risks while caring for a spouse, reduce depression symptoms, and help caregivers devote attention to their own health, which may improve caregiver health overall.

Prior studies by the New York University School of Medicine have shown that interventions result in a reduction of depression among caregivers and delayed nursing home placement for spouses with Alzheimer’s disease, when compared to those receiving usual care. The authors believe future studies should focus on psychosocial interventions with biological measures of physical health outcomes. (Am J Geriatr Psychiatry. 2007;15(9):780-789.) —CP

 

Outcome of Relationship-based Child-Parent Counseling to Reduce Abuse

A pilot study, undertaken in inner-city childcare centers in Miami, Florida, measured the effectiveness of several counseling strategies and curricula in reducing child abuse rates in high-risk families with young children. The study concentrated on families with children <5 years of age because, as the authors note, this age group is at the highest risk for abuse.

Ruby Natale, PhD, PsyD, at the Miller School of Medicine, in Miami, and colleagues, assessed the risk of abuse by screening the caretakers or parents of 150 families with the Parenting Stress Index (PSI) and, using a two-tiered approach, enrolled higher risk families in the Tier-2 cohort (n=53); the remaining families were enrolled in the Tier-1 cohort (n=90).

Parents in the Tier-2 cohort completed the PSI and the Adult-Adolescent Parenting Inventory, 2nd edition (AAPI), as pre-post measures. The PSI assesses parental stress levels broadly, but specifically measures stress levels related to the child’s adaptability, acceptability, demandingness, mood, distractibility, hyperactivity, and parent reinforcement. The AAPI assesses the methods of parental discipline as well as the parents’ expectations of their children, whether they use corporal discipline or create oppressive environments for their children.

Families enrolled in Tier-1 management—those at lower risk for abuse—participated in five group-parenting sessions on child brain development and attachment behaviors. Families at higher risk for abuse, Tier-2 families, received 20 individualized parent-child dyadic sessions of responsive training, an intervention designed to target children’s development, specifically highlighting a child’s cognition, communication, social-emotional awareness, and motivation. Another target of the responsive training curriculum is to increase the frequency and quality of parent-children interactions by educating parents and caregivers of the “pivotal developmental behaviors” of their children and how those behaviors contribute to the child’s development.

A demographic profile of this study reveals that 74.1% of the families were headed by the mother, 18.5% by the father, and 3.8% by a maternal guardian; 42.7% of caregivers were aged 26–30 years of age, and 66.7% of the caregivers were African American.

All pre-post measures, tests initially administered at Time 1, were administered again for follow up at Time 2 for both cohorts. Overall, PSI scores improved from Time 1 to Time 2, but only the PSI subscale measuring the attachment relationship to the child was significantly improved; attachment at Time 1 (mean=46.62, SD=29.43) was significantly reduced at Time 2 (mean=38.55, SD=31.20). On the AAPI scale, however, there was a significant improvement in the caregivers’ attitudes toward corporal punishment, eg, caregivers valued alternative disciplinary methods.

With the highly replicable nature of this study, the authors encourage the proliferation of this model to improve maternal response and nurturing in high-risk communities. In addition, by emphasizing alternatives to corporal punishment, the authors report a lower likelihood of abuse from families who undertake similar programs. (US Psychiatry and Mental Health Congress 2007, Poster 127). –LS

 

Divalproex Extended Release and Dialectical-Behavior Therapy Effective in the Treatment of Borderline Personality Disorder

Characterized by instability in personal relationships, chronic feelings of emptiness, impulsivity, and dissociative experiences, borderline personality disorder (BPD) affects 1% to 2% of the United States population, 10% of psychiatric outpatients, and 20% of hospitalized psychiatric patients. Medication—including divalproex extended release (ER) which is commonly used to treat bipolar disorder—has been shown to target three symptom clusters of the disorder, including aggression and impulsivity, mood instability, and psychotic-like symptoms. Treatment with antidepressants, neuroleptics, benzodiazepines, and mood stabilizers may also aid in the efficacy of psychotherapy. Nevertheless, as patients with BPD are more sensitive to and may discontinue treatment because of medication side effects, additional empirical studies aid in researchers understanding of medication treatment response in patients with BPD.

Richelle Moen-Moore, PhD, at the University of Minnesota Medical School in Minneapolis, and colleagues, examined the efficacy of a new formulation of divalproex ER on BPD symptoms in 17 patients. Prior studies have shown that previous formulations of divalproex ER were effective in reducing symptoms of impulsivity and aggression.

Moen-Moore and colleagues utilized a study design beginning with a 4-week “run in” period of condensed dialectical-behavior therapy (DBT) that sought to identify patients as “placebo responders” among patients who responded to psychotherapy early. DBT involves both individual and group counseling focused on training and development of various skills, such as mindfulness, interpersonal effectiveness, emotion regulation, and distress tolerance.

For patients who did not respond early to DBT, other study exclusion criteria included no current or prior history of bipolar disorder, schizophrenia, major depressive disorder (MDD) with psychotic features as well as symptoms of MDD without psychotic features present in the past 12 weeks, and presence of substance abuse, seizure disorder, or pregnancy. All patients who completed the study (n=11) were between 21 and 55 years of age, diagnosed with BPD as defined by the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, and had not taken any mood-stabilizing or psychiatric medications prior to the study beginning.

Blood concentration of divalproex ER was measured at 4, 8, and 16 weeks in order to maintain the medication at a therapeutic range for all patients. In order to determine divalproex ER efficacy, patients were separated into three groups; one group received divalproex ER plus condensed DBT, another group received placebo plus condensed DBT, and the third group received condensed DBT only for 12 weeks.

Moen-Moore and colleagues found that there were no significant differences in treatment response among groups at weeks 4, 8, and 12. However, the authors did find that, for the study period, patients in all three groups improved significantly over time. Examining data from the “run in” phase of the study, Moen-Moore and colleagues found that 12% (two out of 17 patients) improved with condensed DBT alone.

The authors concluded that this finding is unique in that it mirrors actual treatment conditions for most patients whose pharmacotherapy is determined by response to psychotherapy. They added that more studies are needed to increase researchers’ understanding of subcategories of BPD. Study limitations included the small sample size and lack of data validation via the replication of study conditions. (2007 US Psychiatry and Mental Health Congress 2007). —CP

Posters were drawn from the 20th Annual Meeting of the US Psychiatry and Mental Health Congress (October 11–13, 2007, Orlando, Florida). Psychiatric Dispatches is written by Michelisa Lanche, Carlos Perkins, Jr., and Lonnie Stoltzfoos.

 
Dr. Combs is acting instructor and Dr. Romm is associate clinical professor in the Department of Psychiatry and Behavioral Sciences at the University of Washington in Seattle.
Disclosures: The authors report no affiliation with or financial interest in any organization that may pose a conflict of interest.
Acknowledgments: The authors are grateful for the manuscript review and suggestions of Peter P. Roy-Byrne, MD, professor and vice-chair in the Department of Psychiatry at the University of Washington in Seattle and Chief of Psychiatry at Harborview Medical Center in Seattle.

Please direct all correspondence to: Sharon Romm, MD, Harborview Medical Center, 325 Ninth Ave, Office box number 359896, Seattle, WA 98104; Tel: 206-744-4517; E-mail: romm@comcast.net.

 


 

Focus Points

• Although an infrequent occurrence, psychiatric inpatients are at particular risk for suicide.
• Risk factors associated with inpatient suicide are identified; however, current ability to predict who will commit suicide while in the hospital is poor.
• Precautions can be taken to reduce the risk of inpatient suicide.
• In the aftermath of suicide, one must consider the impact on family, other patients, staff, and physicians.

 

Abstract

Suicides that occur while a patient is hospitalized are tragic events causing immense distress to relatives, peers, and professional caregivers. The prevalence of this infrequent occurrence is between 0.1% and 0.4% of all psychiatric admissions. This article reviews the literature to see if such events can be predicted and prevented; attempts to identify high-risk patients through demographics, diagnoses, medication treatments, and patient social situations; and examines the care-delivery environment such as length of stay and physical surroundings. This article also examines the means patients used to end their lives and when in their hospital course they did so. The authors ask if standard predictors are applicable to hospitalized patients, speculate on potential preventive measures, examine the effect on care providers, and explore what might ease the aftermath. Affective disorders or schizophrenia are most frequently associated with inpatient suicide. Most occur while patients are off the psychiatric unit. Suicides on-ward are usually accomplished by hanging; off-ward suicides are also often violent. Most patients denied suicidal ideation prior to the act. Factors associated with suicide in the general population are not consistently associated with inpatient suicides. Patient monitoring is not always effective. The first week of hospitalization and the days immediately after discharge are when patients are most vulnerable to end their lives. The authors conclude that the potential for suicide may be present from the initiation of hospitalization, but the ability to determine individuals at risk is, at best, poor.

 

Introduction

Suicides are tragic events causing immense distress to relatives, peers, and professional caregivers. Taking one’s own life is often carried out in private and rarely in public. Suicides occur even less frequently while a patient is hospitalized and under the watchful eyes of care providers. Such an event carries an especially powerful emotional charge since a psychiatric inpatient unit is supposed to be a safe refuge from the destructive sequelae of mental illness. In-hospital suicides cause additional legal problems for the care delivery system and providers; the most frequent legal action involving a psychiatric service is the failure to protect patients from harming themselves.1-3

Although an infrequent occurrence, psychiatric inpatients are at particular risk for suicide.4-7 The prevalence of inpatient suicide is between 0.1% and 0.4% of all psychiatric admissions.8 This article reviews the literature pertaining to inpatient suicide to examine whether such events can be predicted and forestalled. The authors identify patients who are at especially high risk by examining demographics, diagnoses, medication treatments, and patient social situations associated with suicide. The article explores risk factors in the care-delivery environment such as length of stay and physical surroundings.1 Also examined are the means patients used to end their lives and when in their hospital course they did so. The authors question if standard predictors of suicide are applicable to hospitalized patients and speculate on potential preventive measures. Finally, the authors examine the effect on care providers and explore what might be done to ease the aftermath.

The databases of PubMed and PsyINFO were searched using the terms “psychiatry inpatient suicide,” “coping inpatient suicide,” “acute inpatient suicide,” and “psychiatric ward suicide.” A total of 821 articles are cited. After a review of titles, abstracts, or text, the authors included 41 articles published between 1982 and 2007 documenting 5,396 patients successful in ending their lives. Studies are drawn from various countries and cultures in the United States, Europe, and Asia. Articles were chosen that evaluated suicides occurring while patients were hospitalized on an acute psychiatric unit or soon after discharge. Studies addressing suicide in the outpatient setting or in correctional settings were excluded as were studies of single cases and single diagnoses.

 

Epidemiology of Suicide in Hospitalized Patients

The inpatient suicide rate in the US, China, New Zealand, Australia, Austria, and the United Kingdom ranges from 100–400 per 100,000 inpatient psychiatric admissions.8-11 Three percent to 28% (median 23.5%) of inpatient suicides occur during the first week of hospitalization, while 17% to 71% (median 39.5%) occur within the first month (Table 1).3,6-9,11-25 Several studies discussed length of stay, a factor crucial for data interpretation. Sharma and colleagues21 identified the mean length of stay of patients who killed themselves at 185 days compared to 124.2 days for controls. Shah and Ganesvaran3 found a median stay of 44.5 days, while Erlangsen and colleagues14 noted a median length of stay of 28 days. Even with accounting for distribution of patient days, Erlangsen and colleagues14 described a significantly higher proportion of suicides occurring within 7 days of admission.

 

 

The majority of studies show that affective disorders1,5-9,15,22 or schizophrenia1,5,10 are most frequently associated with inpatient suicide (Table 1). Multiple studies also find schizophrenia and affective disorders to be the most common diagnoses of inpatient psychiatric patients (Table 2).3,6,8,11,16,22,23,26 Given that schizophrenia and affective disorders are the most common diagnoses, it would be expected that these diagnoses would be heavily represented in patients that commit suicide. However, in multiple studies the incidence of schizophrenia is higher in the suicide cohorts compared to controls.11,16,22,23 The prevalence rates of diagnoses vary as they reflect the heterogeneous sites of study. The studies cited in Table 1 include data from state, private, university, and public hospitals. Proportionally, more schizophrenic patients are usually found in state hospitals providing care for the chronically mentally ill,23,27,28 while those with affective disorders are more frequently hospitalized in facilities caring for acutely ill patients.10,23 

 

Most suicides occur while patients are off the psychiatric unit.3,4,6,7,13,19,22,23,25,27 Studies show that 7% to 65% (median 36%) of patients were out of the hospital without permission at time of death and 19% to 81% (median 30%) were on approved leave when they killed themselves. Meehan and colleagues25 reported that the majority of all patients who committed suicide on or off unit were judged to be at no or low immediate risk at last contact with staff. This finding highlights the difficulty in assessing suicide risk in inpatient psychiatric patients.

Methods of suicide depend on whether the patient is on or off unit at time of death. Substances potentially employed for overdose are typically unavailable for an inpatient so this method is rarely used. Suicides on ward are usually accomplished by hanging,13,22 an accessible means. Off-ward suicides are often violent: hanging or jumping from a height or in front of a moving vehicle  (Table 1).3,6,7,10,19,25,28

 

Inpatient Suicide Risk Factors

Multiple risk factors have been identified for risk of inpatient suicide. Patients who kill themselves might have previously indicated to others that they were considering suicide. Busch and colleagues15 note that 78% of patients denied suicidal ideation prior to the act, and Deisenhammer and colleagues10 found that 40.9% patients had not expressed any suicidal thoughts. Furthermore, Fawcett and colleagues29 identified suicidal ideation more often in patients who did not kill themselves compared to those who actually took their own lives. However, Powell and colleagues9 identified suicidal ideation and attempts at self harm as the most predictive risk factor in their study of 112 inpatient suicides.

Patients may indicate that their suicidal symptoms abated yet progress to self harm. Dong and colleagues8 identified 40.9% patients, Goh and colleagues18 identified 40%, Morgan and Priest24 cited 51%, and Deisenhammer and colleagues10 found that 22.7% of patients had improved psychiatric symptoms prior to suicide. Deisenhammer and colleagues10 also noted that 44% of patients had discharge plans in progress at time of death, indicating hopefulness for life after hospitalization.

Suicide risk for inpatients is unique. Numerous factors associated with suicide in the general population such as substance abuse as well as being single, unemployed, or living alone are not consistently associated with inpatient suicides.9 However, other factors linked with suicide in the general population appear to be associated with inpatient suicide. Chronic mental illness including mood and psychotic disorders are most consistently predictive of inpatient suicide.1,3,4,6,8,11,13,15,16,18,22,23,27 Previous episodes of self-abusive behaviors and history of suicide attempts, especially during the index admission, are also significant predictors.3,4,6,11,13,17,18,22 Several studies11,18,23,26 identified increased length of hospital stay, multiple previous admissions,22,24 longer duration of illness,20,22 and male gender.6-8,19 Meehan and colleagues25 note that the majority of patients are hospitalized by their own choice with involuntary admission identified as an inconclusive risk factor.8,22,27 Identified risk factors including those less commonly noted are listed in Table 3.3,6-12,13,14,16-25,30-32

 

 

Predicting Inpatient Suicides

Several researchers have attempted to predict inpatient suicide using identified risk factors. Powell and colleagues9 identified five predictive risk factors. However, upon review only two of the 97 patients in their data set that committed suicide had a predicted risk of suicide >5%. The authors9 concluded that although several factors identified were strongly associated with suicide, their clinical utility is limited by low sensitivity and specificity, a product of the minimal rate of suicide even in this high-risk group. Spiessl and colleagues23 found that although they also could identify five significant predictors, their model failed to identify any of the patients who committed suicide. Other researchers have tried to develop predictive schema but have been unable to generate models with sufficiently high sensitivity and specificity.33 A study by Hunt and colleagues6 found that a multivariate model included three independent predictors of suicide, including being male, having a diagnosis of affective disorder, and previous deliberate self harm. Thirteen percent of suicide cases had all three compared to 5% of controls (P=.003).

 

Impact of Medications

The relationship of pharmacotherapy to inpatient suicide was not a focus of most articles reviewed. Of 41 articles in the survey, only 13 identified either drug choice or compliance. A German study16 compared medication treatment of 61 suicide victims to an age-, gender-, and diagnosis-matched control group taken from 27,078 admissions over a 20-year period. Half the patients who killed themselves had schizophrenia and four of the 27 patients in the suicide group had been off their antipsychotics for ≥10 days. Lorazepam had been more often reduced or withdrawn than in the controls in the 10 days preceding suicide. The highest suicide risk was in patients with schizoaffective disorder who had a recent change in antidepressant or dose. The authors concluded that if an antidepressant was to be changed, accompanying benzodiazepines should be more liberally prescribed. They advised the use of mood stabilizers, especially lithium, which has been shown in a controlled study to prevent suicide in patients with a history of previous suicide attempts.34 The author of another German study35 noted that only clozapine proved effective in bringing about stabilization in a patient who twice tried to kill himself by jumping from a tall building during hospitalization. This is consistent with evidence of clozapine’s efficacy in reducing suicidal risk in schizophrenic patients.36

Dong and colleagues8 reviewed 93 hospitalized patients who had committed suicide and found that the number of patients prescribed antidepressants was similar to that of controls. All had expressed depressive symptoms within 2 weeks of suicide whether their diagnosis was major depressive disorder, substance-induced depression, bipolar depression, or depression associated with a psychotic disorder. Twenty-two percent of patients were on antidepressants but all were taking less than the maximum dose. Sixty-six percent of patients were taking oral antipsychotics and 37% were on a depot form of these drugs. Fourteen percent experienced extrapyramidal symptoms or akathisia. Dong and colleagues8 surmised that a relationship between suicidal impulses and akathesia can only be hypothetical.

Medication noncompliance is thought to contribute to relapse, a factor considered to increase suicide risk in the short term.30 Cassells and colleagues4 note that 20% of inpatients with schizophrenia and 40% to 70% of outpatients with schizophrenia are estimated to be medication noncompliant.

Anxiety disorders are an independent risk factor for suicide.37 In a review of 76 patients who had committed suicide during hospitalization, Busch and colleagues15 note use or non-use of anxiolytics. These medications were usually offered after staff assessment rather than by patient request. In some instances, helpful anxiolytics were discontinued. In general, doses were low and often inadequate to control severe anxiety.

Sharma and colleagues21 speculated that mood instability could be associated with increased risk of suicide. They proposed that treatment with antidepressants and even electroconvulsive therapy can induce both mixed states and rapid cycling, thereby elevating the possibility of suicide.

 

Suicide in Older Individuals

Few studies have examined suicide events in elderly inpatients. Erlangsen and colleagues14 reviewed 37,172 people ≥60 years of age admitted to a psychiatric inpatient unit in Denmark between 1990 and 2000. One-hundred ten patients died by suicide during hospitalization. Men comprised 43% and women 57%. The authors concluded that patients with dementia had a lower suicide risk, but patients who committed suicide were more likely to have a greater number of comorbid diagnoses of physical illness and accompanying affective disorders.

Shah and Ganesvaran38 found that only 8% of all inpatient suicides in a large psychiatric hospital in Melbourne, Australia over a 21-year period were by patients >60 years of age. When compared to younger inpatient suicides, elderly patients were more likely to be depressed, less likely to have schizophrenia, have more children, and have a longer interval between the age of onset of the illness and the index admission. A high degree of vigilance in those elderly patients with depression, alcohol abuse, and expressed suicidal ideation is advised.

 

In-Hospital Risk Monitoring

Numerous studies reviewed the association of patient monitoring with inpatient suicide. This includes constant staff observation or checks by staff at short intervals. Busch and colleagues15 noted nine of 45 patients who killed themselves had been monitored every 30 minutes or seen by staff within 30 minutes of suicide, nine were checked every 15 minutes or observed at least 15 minutes before the event, and four were continuously observed. Powell and colleagues9 found that 25 patients (26%) who killed themselves were on formal nursing observation, and two were continuously observed at time of death. Meehan and colleagues25 found that 57 of 754 (8%) patients ended their lives after absconding while on medium- or high-level observation.

 

Suicide Risk Post-Hospitalization

A group of patients did not attempt suicide during hospitalization but chose to end their lives almost immediately or soon after discharge. Meehan and colleagues25 evaluated risk of suicide during the 3 months following discharge. Of 1,100 patients committing suicide within this period, 337 (32%) occurred within the first 2 weeks and 32 (3%) died on the first day following discharge. The most common methods were hanging and overdose. Furthermore, 397 deaths (40%) occurred before the patients’ first post-discharge mental health follow-up appointment in the community. This group was often homeless and had severe mental illness, multiple previous admissions, and a history of previous self harm. Erlangsen and colleagues14 evaluated 77 patients who committed suicide after discharge and found that 34% died within the first week.

Deisenhammer and colleagues20 evaluated suicides between 1996 and 2002 in Tyrol, Austria. Of 665 suicides 109 (16.4%) had been hospitalized in the year prior to death. Of these patients, 12.8% killed themselves on the day of discharge, 28% ended their lives within 7 days of discharge, and 48% committed suicide within 1 month of discharge.

 

Impact on Staff and Patients

Little research exists on how mental health professionals cope with everyday stress on an inpatient ward. Norwegian authors Hummelvoll and Severinsson39 described interviews with 16 mental health professionals who emphasized the pressures experienced in routine, everyday work life. They cited an unpredictable and demanding work climate, diffuse responsibilities, occasional lack of clinical supervision, and inadequate or dangerous surroundings as contributing to anxiety and eventual burnout.

In an already tense inpatient environment, patient suicide engendered increased stress. Spitzer and Burke40 enumerated multiple symptoms experienced by staff following a critical incident, including cognitive impairments with inability to make decisions as well as anger, irritability, paranoia, inattention, guilt, and depression. Staff also reported physical problems such as fatigue and headaches following the death of a patient in their care. Joyce and Wallbridge41 considered the effects of several suicides on nine nursing staff members on an adult acute care psychiatric unit and reflected on which supportive activities related to the incidents were helpful. Most staff felt shocked, stressed, and sad. Many identified with the patient or the patient’s family. One employee interviewed said, “I was good at masking my feelings at work, but when I left, I’d just sit alone in my car and cry.” Workers were often angry, vigilant, tense, and critical of colleagues’ management of the incident. Some felt ostracized and blamed. Those who adhered to spiritual beliefs appeared to cope better. Some could, after time, say how dealing with death affirmed their regard for life.

Approaches to staff reactions to patient suicide varied. Joyce and Wallbridge41 noted that some found post-event debriefing helpful while others felt overwhelmed by a meeting and wanted to be left alone. Many needed to have their guilt assuaged. Cotton and colleagues42 noted that informal peer contact was the most valuable intervention for staff. They emphasized acceptance of the suicide as the patient’s personal choice. Blythe and Pearlmutter43 argued that patient safety while hospitalized is important and it is unreasonable to assume that staff is ultimately responsible for the patient’s life.

Researchers concluded that before any intervention, good background information pertaining to the incident must be obtained. Team members’ psychological resilience, experience with similar episodes, and worker cohesiveness must be assessed. They stressed that participation in debriefing should be voluntary and follow-up with mental health services should be offered. Midence and colleagues44 recommended providing support from senior nurses and psychiatrists and suggested scheduling follow-up staff meetings to review assessment and prevention policies.

Patients on the ward at the time of the incident need special attention. Those with a history of suicidal behavior may be principally affected. Bowers and colleagues45 stressed how surviving patients are often ignored and not provided with sufficient support. Kayton and Freed46 recommended patient-staff meetings. Olin47 suggested offering memorial service and scrutinizing patient off-ward privileges. Kaye and Soreff47 underscored the role of psychiatrist as leader with numerous responsibilities in the aftermath of suicide including notifying family; meeting with family, staff and patients to open discussion and vent feelings; documenting events; and possibly attending the funeral.

 

Conclusion

Suicides on the inpatient unit are infrequent but tragic and generally unpredictable events. Although studies have identified risk factors for this occurrence, the ability to employ them to effectively predict which individuals will end their lives as inpatients has proven difficult. Interpretation of the data is challenging given inconsistent design methods and heterogeneity in the populations studied. However, some findings including diagnoses associated with inpatient suicide, method chosen to end one’s life, site of death, high risk periods, and incidence are consistent and, therefore, can improve management of inpatient psychiatric patients.

Although the ability to predict which individuals will commit suicide is poor, there are possible precautions to reduce risk. Medications should be offered in adequate doses. For patients considered at high risk, direct, individual supervision while hospitalized is advised. Suicides in a locked ward are fewer compared to those taking place while patients are off unit. A significant number of patients were off unit at time of death because they had eloped. Suicides might have been avoided by preventing patients leaving the unit without permission. Absconded patients must be actively sought because of their high risk for self harm.23 Given the first week of hospitalization is a time of increased vulnerability, careful assessment of patients given permission to go off ward may also reduce deaths.

Changes in the immediate hospital environment can also help prevent inpatient suicides. Access to potentially lethal means should be reduced. Meehan and colleagues25 found that of 236 deaths in the inpatient unit, 73% were by hanging. Nineteen patients hung themselves with a belt. Patients at risk should be denied access to belts, bathrobe cords, and shoe laces. Safety features such as shower heads that give way when pressure is applied and eliminating wall hooks reduce access to means. Meehan and colleagues25 also reported that in 184 cases, staff were unable to keep patients in view secondary to poor ward design.

Patients are particularly vulnerable in the week following discharge. With the current trend for short hospital stays, clinicians may feel pressure to release patients before they are stable enough to cope with the outside environment. Detailed disposition planning with close follow up post-discharge may help ease the transition to the stress outside of the hospital and reduce risk of suicide.

The potential for suicide may be present from the initiation of hospitalization, but our ability to determine individuals at risk is, at best, poor. Factors linked with suicide in the general population appear to differ from those associated with inpatient suicide. However, measures can be taken to try to reduce risk in the inpatient setting and during the time immediately after discharge. The hope is that with further study, we will find improved methods of identifying those at risk and preventing a fatal outcome. PP

 

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