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Clinical Issues and Treatment Considerations for New Veterans: Soldiers of the Wars in Iraq and Afghanistan

Janice Hutchinson, MD, MPH, and Lisa Banks-Williams, APRN, BC


Primary Psychiatry. 2006;13(3):66-71

Dr. Hutchinson is assistant professor of psychiatry and pediatrics at Howard University Hospital in Washington, DC. Ms. Banks-Williams is a board certified clinical nurse specialist and runs a weekly group to address family reintegration issues in the Psychiatric Continuity Service at Walter Reed Army Medical Center in Washington, DC.

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

Disclaimer: The views expressed in this article are those of the authors and do not reflect the official policy of the Department of the Army, the Department of Defense, or the United States Government.

Please direct all correspondence to: Lisa Banks-Williams, APRN, BC, Psychiatric Continuity Services, Walter Reed Army Medical Center, 6900 Georgia Ave, N.W., Washington, DC 20302; Tel: 202-782-3358; Fax: 202-782-2306; E-mail:


Focus Points

• The stress of war follows the soldier from the war zone to home, where the response of family, friends, and the community can re-traumatize the returning soldier.

Expectations of returning soldiers and their family and friends may be mutually confusing.

The stigma of mental illness impairs the ability of soldiers and their families to seek psychiatric and mental health support.
Psychiatrists and mental health professionals must be prepared to provide diagnostic and treatment interventions to soldiers and their families individually and concurrently.



War can be traumatizing for some armed forces personnel and their families. It is widely accepted that soldiers exposed to combat may develop mental disorders, such as posttraumatic stress disorder, depression, and other emotional problems. Families of service personnel are also stressed and changed by the absence of their loved ones and fear for their loved one’s safety. This results in traumatically changed soldiers returning home to dramatically changed families. Psychiatrists and other mental health professionals are challenged to treat mentally distressed returning war veterans who are also responding to adaptations, adjustments, and alterations of mentally stressed families. The pathology of post-war soldiers may be much more complex than clinicians are prepared to acknowledge. This article examines the impact of family changes on the psyche of already stressed soldiers, and makes recommendations for individual and collaborative treatment of veterans and their families.



A patient presents to the emergency room (ER) with reports of flashbacks, poor appetite, depressed mood, and fleeting homicidal thoughts. Upon further interview, the patient reveals that he is hypervigilant, easily startled, and overly concerned about the safety and security of his family and friends. He has recently been discharged from the military and served in Iraq as a part of Operation Iraqi Freedom. He was treated at a military treatment facility prior to discharge from the service for major depressive disorder and posttraumatic stress disorder (PTSD). Upon return home, his children seemed more out of control than usual and his wife was managing the budget, children, homework, and household chores. The family members asked if the patient had killed anyone. Everyone seemed overly cautious in their approach to the returning soldier, in an effort to avoid conflict. Veterans Administration (VA) psychiatric services were either unavailable or required the patient to be put on a waiting list. People without military experience were unable to understand what the patient was going through. 

It is important to examine the major focus points in treating new post-war veterans as well as to prepare civilian providers for the challenge. The said patient is representative of a growing population of new war veterans who have returned to civilian life and will be in need of long-term care. A recent study by the Army Center for Health Promotion and Preventive Medicine1 revealed that approximately 1,700 service members returning from the war in 2005 proclaimed harbored thoughts of hurting themselves, or that they would be better off dead. More than 250 returnees reported that such thoughts were quite frequent. Nearly 20,000 reported nightmares or unwanted war recollection, and >3,700 said they had concerns of hurting others or losing control around others. The American public should review and reflect on this information as it may affect their soldier loved ones. It is imperative that privately practicing clinicians consider such statistics when working with post-war veterans. 

Many soldiers will be seeking psychiatric treatment outside of the military and/or VA systems, and the civilian psychiatric community must prepare to treat them. It has been reported that at least 17% of post-combat veterans have depression, anxiety, or PTSD.2 Many believe that the numbers are under-representative and that many will not be diagnosable until 6–12 months postcombat. Non-white, post-Vietnam soldiers reported a substantially higher incidence of PTSD.3 African-American and Hispanic veterans experienced more life adjustment problems after the Vietnam War than did white veterans. Minority soldiers are also less likely to accept and/or receive treatment. These families report a higher incidence of overall unhappiness, marital difficulties, and parenting problems. The stigma associated with seeking mental health services may appear great once the soldier has been discharged from the military. One soldier stated that asking for mental health services was like saying “I just could not cut it.”4

The opinion of the authors of this article is that soldiers’ responses to how their families and communities receive them may be as injurious as any battle wound and may have long-lasting effects. The purpose of this article is to educate psychiatric clinicians with little or no wartime experiences to the needs of the veterans returning from wars in Iraq and Afghanistan. This article examines the impact that a veteran’s family and community has on recovery, and identifies the critical areas of concern and focus for the psychodynamic treatment of the new post-war veteran.


Trauma and Relationships

According to the Pentagon’s Defense Manpower Data Center, a total of 3,325 army officers’ marriages ended in divorce in 2004.4 This represents 6% of all marriages among officers (including enlisted personnel). This also represents a 78% increase from 2003, when approximately 1,866 marriages of officers ended in divorce. The United States air force, navy, and marines saw increases in the divorce rate but to a lesser extent.5 

Research has indicated that the divorce rate for veterans is 62% greater than for civilians. Combat-exposed veterans also had a higher rate of divorce after the Korean, Vietnam, and Gulf wars.5 The implications are the same for each branch of service. Repeated deployments, especially to combat zones such as Iraq and Afghanistan, may have a impact on military families.

Soldiers suffering from PTSD have difficulty in their ability to manage and sustain relationships.2,3 Little research has been conducted on PTSD and other psychiatric symptoms expressed in the families of returning soldiers. PTSD symptoms in veterans may include flashbacks, a sense of self and family isolation, emotional distance from family and friends, depression and worthlessness, anger and rage, substance abuse, and extreme anxiety or nervousness. PTSD among loved ones may be expressed as constant anxiety, alienation from friends, low self-esteem, depression and hopelessness, resentment and bitterness, over-responsibility and enabling behaviors, and feelings of being overwhelmed and stressed. In many instances, a traumatized soldier is greeting a traumatized family, and neither is “recognizing” the other. Many soldiers are finding that neither they nor their spouses are able to cope with the changes in their relationships. Such changes result from both physical and psychologic battle-related injuries.

Besides severe marital adjustment issues leading to divorce, war veterans with PTSD engage in more physical and verbal aggression.6 The army is attempting to respond to these relationship issues through a multi-pronged approach. Chaplains have been encouraged to hold retreats and provide counseling to troubled couples. The Prevention and Relationship Enhancement Program utilizes a workshop approach on communication and conflict resolution. A 24-hour hotline is available for soldiers and their families who are not adapting or adjusting to post-war life. The army is recognizing the role of early prevention and intervention in addressing relationship post-war maladies, thereby aborting more traumatic outcomes of divorce and/or domestic violence.


Post-Deployment Disappointment

An in-depth look at some typical, yet difficult, issues to evaluate and address will put these soldier’s and their needs into perspective. The post-war veteran faces potential disappointment on many levels. First, there is a multi-layer, and sometimes profound, sense of disappointment. Reasons for disappointment include loss of military career, difficulty obtaining substantial employment, major changes in roles and responsibilities as parents and spouses, sequelae of physical and/or psychiatric injuries, and social isolation due to ambivalence regarding the mission. In some cases, veterans encounter a hostile climate about the war. Additionally, some veterans perceive that the military is not doing enough to help, despite all of the post-deployment initiatives to reduce the negative impact of the war.


The Return Home

Another major source of disappointment is the reception that some service members receive upon returning from deployment. The veteran is most likely to displace some of these feelings upon family and loved ones. This begins a vicious cycle that moves from disappointment to resentment, to distance and isolation, and then to depression. The post-war veteran faces potential disappointment, beginning with high expectation regarding reunion with families and reception from peers. One soldier indicated that he expected the country to rally around the troops and support the mission. He expected the “World War II spirit.” Instead, the response was the “Vietnam rejection.” There is a huge difference between the two sentiments in terms of self-esteem issues. One implies validation, praise, and support for their sacrifices and effort. The other implies criticism, dissatisfaction, and a lack of appreciation. 

Many soldiers who receive psychiatric injuries return to the US in the back of an army transport plane seated with other soldiers that have obvious physical injuries and deformities, making multiple stops. A bus then takes them to a large military hospital facility, hundreds of miles away from their families, where military medical personnel covered in gowns, gloves, and masks wait to triage them to the appropriate psychiatric units before clearing them to go home. A soldier expecting a ticker-tape parade and warm reception from family and friends might instead experience the sterility of the hospital as well as well-intended efforts to make the service members feel welcome.


Mental Injury Versus Physical Injury

The journey home may evoke uncomfortable, dystonic feelings. Some soldiers may experience guilt in returning from combat physically unscathed. Their psychiatric injuries may seem inapparent, even to themselves. Psychiatric injuries are regarded as less significant when compared to injuries that are physical. Tangible injuries are perceived as valid, while invisible injuries are not. Physical damage suggests strength, fearlessness, sacrifice, and honor. Mental damage may suggest weakness and dishonor. The stigma that characterizes attitudes toward mental illness also extends to military zones. Soldiers know they may be considered unfit for service if they acknowledge mental problems. Many will deny their emotional distress when specifically questioned. It has been determined that at least 60% of veterans are unlikely to seek help secondary to the fear of stigma or loss of career advancement opportunities.2 These soldiers must contend with navigating through the maze of clinics and appointments in order to be cleared to return home. In the meantime, their families typically wait until they are released, or some come to visit the service member at the military hospital. The initial reaction to the reunion is often one of exuberance, but many soldiers have reported that the reunion is bittersweet and that the excitement is short-lived. The fact that they returned home and some of their fellow soldiers did not, the reality of being thrust back into the role of spouse and/or parent, and receiving treatments for their injuries is often more than many soldiers can manage. Therefore, they withdraw from their families. They experience significant guilt and they suffer in silence with the symptoms of their injuries (ie, anxiety, depression, nightmares, fear, withdrawal, isolation, and/or hyper aggression). These unrevealed and unrecognized feelings may lead to alcohol and drug abuse/dependency; suicidal and homicidal behaviors; and depressive, dissociative, anxiety, and psychotic disorders.



The transition from military to non-military status can be emotionally disturbing. Even for a soldier who is leaving military service by choice, the move to civilian life can be laden with anxiety and uncertainty. However, for the most part, these post-war veterans are released from the military under three sets of conditions. They are medically retired via a medical evaluation board, they are administratively separated through an employment personnel procedure that is managed by the soldier’s command, or they come to the end of their tour of duty. Despite the existence of transition services, depending upon the circumstances surrounding departure from the military, soldiers can have a profound sense of disappointment. This can be related to soldiers not completing tours of duty and therefore not upholding their contracts, feeling disenfranchised from the service due to administrative action, or not being able to complete missions or commitments to serve their country. Others may feel like the military lifestyle and structure have been taken away from them, and they find that becoming a civilian is a very difficult and unwelcome transition.



Another area of concern is how post-war veterans address feelings about experienced images of war or the duties that they were expected to perform as a part of combat. Many soldiers find it difficult, if not impossible, to share their experiences with non-combat family, friends, and other civilians. They typically choose not to share details of their combat experiences with loved ones, thus causing further isolation due to the inability of loved ones to put such experiences into context. Even if a soldier does share some details of the war, there is no likely frame of reference for those who have not seen combat in the same proximity and/or intensity as the soldier. Therefore, it is often difficult to justify a soldier’s wartime actions. In a war veterans group, one female soldier told the group that she was haunted by one particular firefight. She stated that it was impossible to explain to her children how or why she had to cut an Iraqi insurgent in half with her M-16. While she indicated that she could barely explain it to herself, she said that in the end it was a matter of life or death, and she chose life. That the id, ego, and superego converged is a difficult concept to explain in this context to family members. Thus, communication was restricted for fear of negative judgment by her loved ones. It was difficult for the soldier to accept what she had done, let alone imagine that her family could accept her actions, justified as they may have been. This soldier was careful to protect her integrity as wife and mother. These were primary identities that she did not wish to be destroyed by negative perceptions of her as mother-turned-monster.

Some soldiers struggle with how their actions will be viewed by their family members and friends. A common complaint was that when soldiers return from leave, family and friends alike want to know if they had killed or seen someone killed. On some level, the media sensationalizes the war experience without reporting the day-to-day experiences and concerns that soldiers may have. Being part of human destruction as either warrior or witness is a devastating, emotionally compromising experience. The soldier may experience an inquiry like this as a re-traumatizing event. It can disrupt mental defenses of sublimation and/or denial of emotions related to horrifying events or actions. This type of reaction is common, but clinicians that work with these returning veterans must compassionately wait until a soldier is ready to tell his or her story. Through the development of a therapeutic alliance, the clinician gives the veteran permission to share war stories by creating a safe atmosphere by not forcing the soldier to open up. Insistence that the soldiers relive their combat experiences before they are emotionally ready can result in still further traumatization, thereby destroying any opportunity to establish a therapeutic alliance.


The Soldier, The Family, and PTSD

A young male strike team soldier in individual therapy for >8 months did not discuss his combat experiences until 6 months into treatment. The first 6 months were focused on getting him reintegrated into his family of origin and helping him to re-establish healthy intimate relationships. He experienced classic PTSD symptoms, including nightmares, flashbacks, hypervigilance, and anxiety attacks. He had close and loving parents who wanted their son back the way he had been prior to his deployment to Iraq. It is hard to comprehend the mental defenses and adaptation required to cope with danger and uncertainty on a daily, minute-to-minute basis. It causes extreme stress that often changes a person’s personality and character forever. The soldier’s challenge was to teach the family how he had matured, how he had been affected by his wartime experiences, and how to integrate those changes into their daily lives. Their challenge was to accept the physical and mental injuries that he sustained from the war.

Six months into therapy, the soldier shared a Web site that appeared benign on the surface, as he showed pictures of his battle buddies and members of his platoon posing at various campsites throughout Iraq. There were no gruesome pictures of mangled bodies or the expected carnage of war. With some apology, shame, and embarrassment, he stated that the hardest part for him was that he missed Iraq. He missed the action, the adrenaline rush, and the camaraderie of his fellow soldiers. Sharing the landscape of action with other soldiers was important for his emotional integrity. He experienced a feeling of safety that was elusive in the company of his family of origin. PTSD can cause changes in the chemistry and anatomy of the central nervous system that affect a person’s ability to feel safe in “normal” situations. Part of the isolation and withdrawal from the family emanated from the separation from fellow soldiers who understood the wartime experience. He and family members felt a mutual dissonance, but neither party understood why.

Having been separated from the military, a soldier seeking treatment will be hungry for a certain type of connection and camaraderie. Encouraging participation in veterans support groups can be helpful, as is encouraging the veteran to reconnect with wartime comrades to re-live, reflect, and re-think some of their wartime experiences in light of where they are at present. Reminiscing in this context is helpful to the soldier because he or she is encouraged to seek a personal frame of reference without insisting that a civilian therapist understand his or her plight. Cognitive-behavioral therapy has also been found useful in helping soldiers reframe their experiences and put them into context. It has become increasingly clear that the goal of treatment is not to ameliorate symptoms, but rather to teach veterans stress-management techniques and how to live with such symptoms. 

Another thought for consideration is the family member’s response to the expected symptoms of PTSD. According to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text-Revision,7 a persistent avoidance of stimuli is associated with the trauma and numbing of general responsiveness. Frequently, the soldiers report that their families complain that they are distant, detached, and unwilling to talk about their experiences. One focus of treatment is to help the service member develop a script of what can be talked about and under what terms. This intervention may reduce the veteran’s anxiety and relieve the curiosity of family and friends. The service members should also learn to set reasonable boundaries on the intrusion and inquisitive nature of those who, though well intentioned, actually may re-traumatize the veteran by insisting on hearing about wartime experiences. The veteran’s fear of experiencing re-traumatization may be the underlying dynamic for why there is social avoidance and withdrawal from, or diminished interest in, significant family events. One soldier recounted how hard it was to miss his daughter’s 16th birthday due to his deployment. The guilt of his absence from her special event coupled with his growing ambivalence about his wartime experience served as a catalyst for his withdrawal from the same daughter’s birthday the next year. Consequently, there was further conflict, avoidance, and withdrawal by the veteran, and further rejection by the daughter, even though he was only acting to protect them both from himself.



Another source of concern is the restricted range of affect as exhibited by the returning soldier. Several soldiers have returned from a home visit and reported an inability to experience intimacy. One soldier even reported that he was unable to be touched by his son because the child’s touch seemed intrusive and unpredictable. Touching seemed scary and unsafe because touch, in the context of war, holds new meaning and memories. Training service members to be less sensitive to touch and more responsive to physical affection from their loved ones is also influenced by another common symptom—increased arousal. Hearing that the soldier is afraid to sleep in the same bed as his or her spouse upon return from combat is especially disconcerting, since having a patient return to a pre-combat level of intimacy would be a reasonable goal for treatment. However, due to repeated exposure to violence and perceived threat of danger, soldiers develop increased sense of arousal and hypervigilance. Therefore, close contact associated with sleeping with another person is shunned by service members because of the great potential for a violent response to inadvertent contact. The closeness and intimacy of the marital bed has thus been redefined emotionally as a fearful battleground. Hate and fear replace love and intimacy. The anxiety and fear of injuring loved ones outweighs the rejection soldiers communicate to their families while attempting to protect them from harm. An investigation of psychiatric symptomatology among wives of combat-stressed soldiers suggests there is diminished sexual interest.6 This may heighten tension and decrease the development of intimacy.

It is becoming apparent that returning soldiers have experienced a great deal of trauma. The severity and intensity of their presenting symptoms is indicative of that trauma. One psychiatrist describes this condition as “complex PTSD.”8 It is an injury to character in which the capacity for social trust is destroyed. Often inapparent is the degree of mistrust and hostility projected onto civilian providers just because they “were not there” to experience what the soldiers saw and felt. Therefore, to some degree, such clinicians are disqualified as credible agents of healing and change. Although the new post-war veterans are entering offices, clinics, and ERs with a wide variety of symptoms and complaints, the stated concerns are just the tip of the iceberg. These soldiers are coming back with more than the apparent war wound, and they are going to need clinicians and therapists who can hear their stories and decipher the sources of their pain. There is a growing number of soldiers that have sustained psychiatric injuries while deployed that have rendered them unfit for duty and therefore separated from the military either through medical retirement or administrative separation. Some of these soldiers, for a variety of reasons, may be released from the military without medical benefits and therefore are not entitled to care at their local VA hospitals. Others have been unable or unwilling to wait for the services to be made available to them through the VA. Some veterans choose not to engage in the military/VA system once they are released from service; these soldiers are most often resistant to treatment and are likely to be taxing to any primary care provider or healthcare facility.



Most Americans, whether civilian, non-civilian, medical, or non-medical, recognize the physical and emotional toll that war takes on the soldier. Physical and psychiatric injuries are common outcomes of war. However, many do not recognize or understand how war impacts the family and the subsequent interplay between returning soldier and waiting family. The loss of a loved one to war creates stress in relationships and changes in roles. Mutual readjustment difficulties occur, as both soldier and family have changed and each is experiencing the other from a different prism. To some extent, neither knows the other. One soldier commented that returning home was like walking around in a bubble. No one knew what to say to him or how to respond. He stated that the best thing for him was kindness, respect, patience, and some time to come out of the combat zone and return to safe and familiar surroundings. Effective treatment strategies must include both soldiers and their families. Therapy should be concurrently individual, family, couples, and group oriented.9 Returning soldiers and their families need to learn about the effects of trauma on individuals and families. It is extremenly important to help both the returning soldiers and their family members establish realistic expectations about recovery and healing. Family members need assistance in learning how to incorporate a soldier’s disability into their normal lives and daily routine.

All of these approaches can facilitate communication and develop coping interventions. Because of the separation that can occur between armed forces and soldiers, it has become important that VA personnel train and assist non-military clinicians in therapeutic management of post-war veterans. Effective management and treatment of these soldiers and families requires sensitive and empathic interventions, which may not be a military affiliation. There are many available resources for civilian clinicians to review in preparation for working with new post-war veterans. One informative collection of articles and treatment recommendations is the Iraq War Clinician Guide, Second Edition.10

Perhaps the most critical prevention and treatment is understanding the stigma of mental illness. Many cultures do not support psychiatric diagnoses and treatment. Soldiers and families misrepresent the nature and extent of their mental maladies post war, in an effort to sustain the expectations of self and family. Consequently, chronic emotional maladies, dysfunctional families, and sometimes divorce may be the outcome. PP



1. Zoroya G. 1 in 4 Iraq vets ailing on return. USA Today. October 18, 2005:4. 

2. Hoge CW, Castro CA, Messer SC, McGurk D, Cotting DI, Koffman RL. Combat duty in Iraq and Afghanistan, mental health problems, and barriers to care. N Engl J Med. 2004;351(1):13-22. 

3. Kulka RA, Schlenger WE, Fairbanks JA, et al. Trauma and the Vietnam War Generation: Report of Findings from the National Vietnam Veterans Readjustment Study (NVVRS). New York, NY: Brunner/Mazel; 1990. 

4. Pentagon’s Defense Manpower Data Center (DMDC). Available at: Accessed January 27, 2006. 

5. Byrne CA, Riggs DS. The cycle of trauma; relationship aggression in male Vietnam veterans with symptoms of posttraumatic stress disorder. Violence Vict. 1996;11(3):213-225. 

6. Solomon Z, Waysman M, Avitzur E, Enoch D. Psychiatric symptomatology among wives of soldiers following combat stress reaction: The role of the social network and marital relations. Anxiety Res. 1991;4:213-223. 

7. Diagnostic and Statistical Manual of Mental Disorders. 4th ed text rev. Washington, DC: American Psychiatric Association; 2000. 

8. Shay J, Cleland M, McCain JS. Odysseus in America: Combat Trauma and the Trials of Homecoming. New York, NY: Scribner; 2002. 

9. Nelson BS, Wright DW. Understanding and treating post-traumatic stress disorder symptoms in female partners of veterans with PTSD. J Marital Family Ther. 1996;22:455-467. 

10. Schnurr PP, Cozza SJ, eds. The Iraq War Clinician Guide. 2nd ed. National Center for PTSD. Department of Veteran’s Affairs; 2004. Available at: Accessed January 27, 2006.



Dr. Zun is chairman and professor of Emergency Medicine in the Department of Emergency Medicine at Rosalind University of Medicine and Science/Chicago Medical School and chairman of the Department of Emergency Medicine at Mount Sinai Hospital in Chicago, Illinois. Dr. Downey is assistant professor of public administration in the Department of Political Science and Public Administration at the College of Arts and Sciences at Roosevelt University in Chicago.

Disclosures: The authors report no affiliation with or financial interest in any organization that may pose a conflict of interest.
Acknowledgments: The authors thank Joseph T. Klempner for editorial assistance; Michael Sachman for statistical help; and the Medical Clearance Workgroup, including Roma Hernandez, Louis Shicker, MD, Jerrold Leikin, MD, and Randy Thompson.

Please direct all correspondence to: Leslie Zun, MD, MBA, Chair, Department of Emergency Medicine, Mount Sinai Hospital, Chicago, IL 60608; Tel: 773-257-6957; Fax: 773-257-6447; E-mail:



Focus Points

• There is a need for medical clearance protocol of psychiatric patients presenting to acute care settings.
• There is controversy concerning the need for testing as part of the medical clearance process.
• This medical clearance protocol can reduce costs but not patient throughput times when the protocol is applied to the emergency medicine setting.



Introduction: The objective of the study was to determine if the use of a medical clearance protocol reduces costs and the throughput times for emergency department psychiatric patients undergoing medical clearance. 
Methods: A retrospective, chart review of all emergency department patients with psychiatric complaints transferred to a state-operated psychiatric facility using the medical clearance protocol from January through June 2001 was compared to the usual medical clearance that was performed in 2000. 
Results: Thirty-three charts were reviewed for 2000 and 64 charts for 2001. The total cost of ancillary testing was $269 in 2001 and $352 in 2000, and was found to be significantly different (analysis of variance F=7.894,
P=.006). The throughput time was not statistically different in the 2 years (P<.05).
Discussion: A medical clearance protocol was applied to patients with psychiatric symptoms presenting to an emergency department for evaluation. The protocol did not mandate testing but recommended testing if it was clinically indicated.  
Conclusion:  The application of standardized medical clearance protocol resulted in reduced cost but unchanged throughput time.


The process of medical clearance of patients who present to the emergency department with psychiatric symptoms is one that is commonly performed without standardization.1,2 The need to perform tests as part of the medical clearance process on the psychiatric patient have run the gamut from extensive evaluation and testing to limited evaluation and no testing. Retrospective studies have demonstrated that selected patients with a past psychiatric history, negative physical examination, and normal vital signs without medical problems do not need laboratory testing.3,4 In contrast, prospective studies of patients presenting with new psychiatric symptoms demonstrated the need to perform extensive testing including drug screen and cranial computed tomography, and, in patients with a fever, a lumbar puncture.5,6 With significant overcrowding in many emergency departments in the United States, reduction of the number of tests performed for each patient is thought to reduce the patient throughput.

To address this confusion, a team of emergency physicians and psychiatrists developed a consensus protocol for this medical clearance.7 The protocol for the evaluation of patients presenting with psychiatric symptoms includes both a psychiatric assessment and clinically indicated physical assessment. The protocol did not dictate the performance of any routine laboratory tests rather the decision was based on clinical indications.

The effect of this protocol on the cost of test ordering and throughput time in the emergency department is unknown. The objective of the study was to determine if the use of a medical clearance protocol reduces the cost and throughput time for emergency department psychiatric patients undergoing medical clearance.



The medical clearance protocol was used as the basis for this study. A checklist was developed from the protocol to provide a foundation for documentation of the medical clearance of patients with psychiatric illness (Figure). This checklist extensively walks the physician through the process of medical clearance.



The medical clearance checklist was applied to all patients presenting with psychiatric complaints from January to July 2001 and compared to the usual medical clearance process used during the same time period in the prior year. The medical clearance protocol checklist was completed prospectively in the emergency department. The inclusion criteria were presentation of psychiatric complaint and the need for admission to a state operated psychiatric facility (SOF). The exclusion criteria included patients who were transferred to another psychiatric facility, patients with intoxication, and juveniles.

A retrospective chart review was performed of all patients with psychiatric complaints presenting to an inner-city teaching level I emergency department with an annual volume of 44,000, who were then transferred to a state-operated psychiatric facility in the 6-month period of January through June 2001. The patients were transferred to one of three state-operated psychiatric facilities. The medical clearance, clinically driven, non-routine–based protocol was administered in 2001 and the usual medical clearance was performed in 2000. The ancillary test costs were obtained from billing data and based on 50% of hospital charges. The throughput time was calculated from the time the patient was triaged to the time the patient was discharged from the emergency department. The data was analyzed using SPSS statistical package, version 10 (Chicago, Illinois). Analysis of the data was performed using the t-test or analysis of variance (ANOVA) and chi when this analysis was not possible. The study was Internationl Review Board approved.



One hundred twenty-one patients were transferred to psychiatric facilities in 2000 and 270 in 2001. Thirty-three of the 41 patient charts (80.5%) were reviewed for transfer to a state-operated facility in 2000 and 64 of 81 charts (79.0%) for 2001. The other eight charts were incomplete or could not be located for review. The mean age was 33.6 years (34.9 in 2000 and 35.1 in 2001) and 70.8% were male (68.2% in 2001 and 76.0% in 2000). The most frequent race was African American (48% in 2000 and 56.8% in 2001) followed by Hispanic (36% in 2000 and 25% in 2001). A chi square analysis was performed because of limited variability and did not determine any differences between the groups for age, gender, or race.

The mean total cost of ancillary testing was $169 in 2001 and $352 in 2000 and was found to be significantly different (ANOVA F=7.894, P=.006) (Table). The mean laboratory cost was $238 in 2000 and $156 in 2001; radiology cost was $151 in 2000 and $93 in 2001; and electrocardiogram cost was $120 in 2000 and $113 in 2001. In 2000, one patient received an ultrasound and one received a stress test. The total cost of laboratories was correlated with the year of testing (Pearson coefficient .305, P=.006), age (Pearson coefficient .381, P=.003), and race (Pearson coefficient .288, P=.028) in both years. It was not correlated with length of stay nor which hospital the patient was transferred to (P<.05).


The throughput time ranged from 3.1 hours to 24.6 hours with a mean of 9.7 hours in 2000, and ranged from 2.2 hours to 20.0 hours with a mean of 9 hours in 2001. The throughput time was not statistically different in the 2 years (P<.05). The length of stay in the emergency department was correlated with age (Pearson coefficient .304, P=.012) but not with year, receiving SOF, gender, or race (P<.05).



This study demonstrated that the use of a medical clearance protocol reduces the number and cost of testing but does not affect the throughput time for psychiatric patients. The medical clearance protocol used in this study did not require testing of psychiatric patients, rather left the option of testing to the emergency physician. The use of medical clearance protocol reduced the mean cost of total testing. The rationale for this difference is not defined; however, since more tests were performed it is more likely that fewer expensive tests were used. The limited effect on throughput time for this study may have been due to the transfer process rather than the workup in the emergency department. The presumption that emergency department throughput would be reduced by the use of a medical clearance protocol was not supported in this study.

The American College of Emergency Physicians has published numerous guidelines and protocols for use in the emergency department recommendations. These guidelines take into consideration the need to reduce the costs of testing for many conditions such as seizures, acute mental status change, and headache.8-11 Such guidelines have not been published for the medical evaluation of psychiatric patients. However, the American College of Emergency Physicians’ statement on evaluation of psychiatric patients states that most of the time the physician can identify medical problems on the history and physical evaluation alone without laboratory testing. This recommendation, however, is not evidence based.10

Emergency physicians tend to order tests on patients for various reasons.12 The two major factors affecting emergency physician testing of psychiatric patients are the variable disease prevalence and relatively little rigorous research on the topic. Many times an accepting psychiatric institution requires that certain tests be performed by the transferring hospital emergency department prior to transfer. Even the emergency physician’s perception of required testing from the gatekeeper at the accepting psychiatric institution may influence testing of psychiatric patients in the emergency department. Neither of these presumptions was queried in this study.

Emergency physicians are concerned about transferring unstable patients to another facility. Since Emergency Medical Treatment and Active Labor Act (EMTALA) legislation does apply to psychiatric patients, it behooves the emergency physician to ensure that the patient is medically stable prior to transfer. EMTALA does not require the patient to have laboratories or radiographies performed to ensure medical stability. It does require that psychiatric patients with medical problems are transferred to a psychiatric facility that is equipped to handle the patients’ medical problem.13 The SOFs in Illinois can perform many, albeit limited, medical-care functions at their facilities.7

This study has numerous limitations. Unavailable, incomplete, or inadequate charts provided for a potential bias. The hospital did not use cost accounting; therefore, the costs of tests were estimated. The authors of this study enrolled only patients who were going to be transferred to a state-operated facility and not admitted to the authors’ own hospital or transferred to another institution. The study was performed in one location on one population of psychiatric patients. There was no observation of the type of evaluation that was performed to determine if the protocol was actually followed. Further delineation of the protocol to establish an algorithm for testing ordering, using the protocol and outcome analysis, would be valuable.


Although the throughput time was not affected, this study demonstrated a significant cost savings in utilizing a medical clearance protocol for psychiatric patients in the emergency department. PP


1. Tintinalli JE, Peacock FW, Wright MA. Emergency medical evaluation psychiatric patients. Ann Emerg Med. 1994;23(4):859-862.
2. Broderick KB, Lerner B, McCourt JD, et al. Emergency physician practices and requirements regarding the medical screening examination of psychiatric patients. Acad Emerg Med. 2002;9(1):98-92.
3. Olshaker JS, Browne B, Jerrard DA, Prendergast H, Stair TO. Medical clearance and screening of psychiatric patients in the emergency department. Acad Emerg Med. 1997;4(2):124-128.
4. Korn CS, Currier GW, Henderson SO. Medical clearance of psychiatric patients without medical complaints in the emergency department. J Emerg Med. 2000;18(2):173-176.
5. Adhikari P, Haydel MJ. Computerized tomography in patients with new onset psychosis [abstract]. Acad Emerg Med. 2001;8:508.
6. Henneman PL, Mendoza R, Lewis RJ. Prospective evaluation of emergency department medical clearance. Annals Emerg Med. 1994;24(4):672-677.
7. Zun LS, Leikin JB, Stotland NL, Blade L, Marks RC. A Tool for the emergency medicine evaluation of psychiatric patients. Am J Emerg Med. 1996;14(3):329-333.
8. American College of Emergency Physicians. Clinical policy: critical issues in the evaluation and management of patients presenting to the emergency department with acute headache. Ann Emerg Med. 2002;39(1):108-122.
9. ACEP Clinical Policies Committee, Clinical Policies Subcommittee on Seizures. Clinical policy: issues in the evaluation and management of adult patients presenting to the emergency department with seizures. Ann Emer Med. 2004;43(5):605-625.
10. American College of Emergency Physicians. Clinical policy for the initial approach to patients presenting with altered mental status. Ann Emer Med. 1999:33(2):251-281.
11. Lukens TW, Wolf SJ, Edlow JA, et al. Clinical policy: critical issues in the diagnosis and management of adult psychiatric patient in the emergency department. Ann Emerg Med. 2006;47(1):79-99.
12. Fontanarosa PB. An evidence based approach to diagnostic testing in emergency medicine. Emer Med Clin North Am. 1999;17(1):1-8.
13. Moy, MM. EMTALA and Psychiatry in The EMTALA Answer Book. 2nd ed. Gaithersburg, MD: Aspen; 2000.



This interview took place on September 6, 2007, and was conducted by Norman Sussman, MD.


This interview is also available as an audio PsychCastTM at

Disclosure: Dr. Goldberg is consultant to Abbott, AstraZeneca, Cephalon, Eli Lilly, and GlaxoSmithKline; on the speaker’s bureaus of Abbott, AstraZeneca, Eli Lilly, and GlaxoSmithKline; and on the scientific advisory boards of Eli Lilly and GlaxoSmithKline.


 Dr. Goldberg is director of the Affective Disorders Program at Silver Hill Hospital in New Canaan, Connecticut, and associate clinical professor of psychiatry at the Mount Sinai School of Medicine in New York City. His research focuses on the treatment and clinical features of bipolar disorder. He is a co-investigator in the National Institute of Mental Health (NIMH) Systematic Treatment Enhancement Program for Bipolar Disorder and has received a Career Development Award from the NIMH. He has also received research grants from the National Alliance for Research in Schizophrenia and Depression, the American Foundation for Suicide Prevention, and the Stanley Foundation.

How has the approach to the diagnosis of bipolar disorder changed in recent years?

The rigor of the diagnosis and the systematic approach to making a diagnosis have changed. Bipolar disorder is not just about mood; rather, it is a disorder with components that involve disregulation of mood, the sleep-wake cycle, impulse control, cognitive disturbances, and behavioral problems. Some of these phenomena persist independent of the mood state. For example, cognition or impulsivity are present much of the time but that may flare during a mood state.

When assessing a patient, I conduct a systematic overview of the patient’s pathology and symptoms in the sense of differential diagnosis. I also describe the systematic approach of recognizing dimensions of psychopathology and symptom constellations, alongside differential diagnosis.

We think about mood disorders in terms of their polarity of mood, cyclicity, recurrence rates over time, pharmacologic response, environmental correlates, cognitive aspects, and sleep aspects. This mode of thinking correlates with the idea of the spectrum, as well, where we step outside the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV).1

My approach to diagnosis includes not just a cross-sectional survey of DSM-IV symptoms—though that is obviously a part of it— but a longitudinal, panoramic, perspective of how symptoms fit together. Does the context suggest a bipolar illness based on age of onset, family history, aspects that may better or worsen the illness, or medication response? Taking a systematic approach and incorporating these dimensions can give us a best-informed assessment of a likely diagnosis.


How is bipolar disorder generally diagnosed?

How much rigor goes into a diagnosis usually depends on what kind of specialist is conducting the assessment. For example, some base the diagnosis on mood swings alone. Thus, there is potential for misdiagnosis, incomplete diagnosis, quasi diagnosis, or nonsystematic diagnosis if one fails to take all symptoms into account. Mood instability is not diagnostic and occurs in many psychiatric disorders including bipolar disorder, among others. However, if we identified it all as synonymous with bipolar disorder, we would miss a lot of posttraumatic stress disorder, substance abuse, adjustment disorders, and personality disorders.

In the last 5–10 years, our sensitivity has gone up, meaning we are more often asking mood disorder patients about current and past symptoms of mania or hypomania, paying more attention to patterns of high recurrence, and considering when cyclical mood disorders are not unipolar depression. We are doing a better job overall in recognizing non-unipolar patients, but we are not necessarily encouraging our colleagues to think as critically about the differential diagnoses among these patients. The DSM-IV defines clinical subtypes of bipolar disorder quite strictly, and as all-or-none categories. For example, mixed episodes are defined only as occurring in bipolar I (not II) disorder, and require the presence of a full manic and depressive syndrome for at least 1 week. The “not otherwise specified (NOS)” designation thus has meaning when DSM-IV duration criteria or numbers of symptoms may not be fulfilled, but clinically important symptoms differentiable from unipolar depression are nonetheless present. Nosology advances and good clinical care occurs when we encourage clinicians to go beyond a DSM-IV diagnosis.

Mixed states are an excellent example because in the case of bipolar depression most depressed bipolar patients have some mania symptoms alongside their depression. Data from the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) program (JF Goldberg, unpublished data, May 2007) has demonstrated that two-thirds of fully-depressed bipolar patients have at least some manic symptoms. This may not catch a clinician’s attention unless the patient has enough manic symptoms to call it a mixed state. However, if it is subsyndromal mania one must determine whether it is an agitated depression or a subsyndromal mania within a depression. The condition is considered NOS and not a DSM-IV entity, but it is extremely common.


Are antidepressants effective for bipolar patients?

No controlled study has ever shown antidepressants to be more effective than mood stabilizers alone for bipolar depression. According to recent STEP-BD data,2 antidepressants on an overall basis add very little benefit for patients with bipolar depression and minimal manic symptoms. They neither help nor hurt. However, there are subgroups for whom the antidepressants may be detrimental. Our recent article3 examining concomitant mania symptoms with depression, found that manic symptoms of patients with bipolar depression with some mania are worsened by antidepressants. Further, the depression is not managed with these drugs. Other reports note that patients with a history of prior switch with an antidepressant are more prone to switch into mania. A forthcoming study from the STEP-BD program by our site at Cornell Medical Center in New York City4 found that patients who have previously experienced mania with an antidepressant have double the chance of that occurring in the future with any antidepressant.

Goldstein and colleagues5 described the abrupt cessation of antidepressants triggering a manic state. It is sometimes difficult to tell whether a withdrawal phenomenon is a physiologic phenomenon as opposed to a psychiatric one. An abrupt change in an equilibrium state could destabilize mood. Therefore, I have become a proponent of gradual tapers whenever possible with almost all psychotropics.


Is there a relationship between bipolar disorder and alcoholism?

There is an extraordinarily high comorbidity with substance abuse in general and alcohol abuse or dependence in particular for people with bipolar disorder. The National Comorbidity Survey reported approximately 70% comorbidity.6 Other studies place comorbidity of alcohol use or dependence and bipolar disorder at 40% to 60%. There is no simple explanation for why that co-occurrence is so high. One theory is that people with bipolar disorder are reckless, impulsive, and likely to engage in hedonistic behaviors of high-risk consequence, such as excessive spending, gambling, drinking, or drugs. For some, the potential for alcohol is in the context of a mania. Other people might use alcohol to ward off depression. There is also a genetic component, where some research suggests that alcoholism tends to run in families with bipolar members.

Alcohol acts as a stimulant and then acts as a central nervous system depressant. It is very difficult to diagnose a mood disorder in someone with active substance abuse because the psychotropic effects of alcohol or drugs can mimic depression or mania. Overdiagnosis of bipolar disorder is partially a result of the high co-occurrence with substance or alcohol use. It can be challenging for a clinician to know the extent to which a patient’s mood symptoms are artifacts of substance use or consequences of withdrawal. The most systematic diagnostic approach is to obtain a longitudinal history, assessing the presence of mood symptoms during sustained periods of abstinence. Our group7 recently conducted a study attempting to disentangle “true” bipolar diagnoses from “non-bipolar I or II” mood instability among inpatients with substance use disorders and found that only approximately one-third met DSM-IV criteria for bipolar I or II disorder. Approximately half the time, we could not identify a period of abstinence in which to evaluate mood symptoms, pointing to the complexity of accurately differentiating and diagnosing separate mood disorders in patients with active substance abuse or dependence. A related study by Stewart and El-Mallakh8 recently reported similar findings.


Which disorders are comorbid with bipolar disorder?

According to Susan McElroy, MD, from the Stanley Network, two-thirds of people with bipolar disorder have at least a second DSM-IV psychiatric disorder. Approximately 50% have a third psychiatric disorder, and approximately 25% have a fourth. Comorbidity is the rule rather than the exception. There is less prevalence of first-episode patients with substance or alcohol abuse than there are multi-episode patients. According to the McLean-Harvard First-Episode Mania Study, the prevalence of drug or alcohol abuse in first-episode mania patients is approximately 33%—much lower than the rate seen in multi-episode patients with bipolar disorder.9 Thus, if bipolar disorder is caught early and treated effectively, the progression to alcohol and substance abuse can likely be prevented.

The second most common comorbidity, which is not mutually exclusive from alcohol or drugs, is anxiety. Rates vary for any anxiety disorder. The National Epidemiologic Study on Alcohol-related Conditions (NESARC) study by Grant and colleagues10 reports that approximately 50% of people with bipolar disorder have an anxiety disorder. It can be difficult to distinguish between agitation, psychomotor acceleration, and goal directness of mania from free-floating anxiety, generalized anxiety disorder, or panic. Therefore, we must be guided by other features as well—such as sleep patterns, cognitive features, and mood features—bearing in mind that this may represent anxiety or hypomanic activation.

Seasonal affective disorder and postpartum mood disorders are also more common in patients with bipolar disorder than in the general population.


Is there any evidence to support that people with recurrent manic episodes and major depressive episodes get worse cognitively after each episode?

There is evidence that cognitive functioning is poorer in patients with multiple prior affective episodes, particularly manic episodes.11 As to whether or not repeated affective episodes lead to a progressive worsening of cognitive function has not been demonstrated; however, some reports do suggest that eventual risk for dementia is higher among bipolar patients with more prior episodes.12

We are just beginning to appreciate the cognitive problems that are inherent in bipolar disorder. Much interest has focused on how much those cognitive problems are an epiphenomenon of mood symptoms (eg, depression), how much is iatrogenic from pharmacology and the long-term effects of certain medications like lithium, and how much is a neurodegenerative phenomenon. We think of mood stabilizers as being neuroprotective. It in part addresses this concern for a potential neurotoxic effect of multiple episodes. Some research discusses structural brain changes in multi-episode patients in the hippocampus and the amygdala.

Some recent cognitive data show the potential for decline over time. However, I would not encourage patients to worry and anticipate a decline in course. The kinds of deficits we see in most patients are subtle. They tend to involve things like verbal learning, practice effects, and attention. They may be trait features passed along genetically, and even seen in unaffected relatives, as a kind of “hidden” biologic marker or “endo”phenotype. A person’s actions also play a role. As mentioned, alcohol is not neuroprotective. It is difficult to know the extent to which alcohol comorbidity is having a direct neurotoxic effect. It is difficult to distinguish how much of the cognitive potential decline occurs because of the illness, treatment, delays to treatment, or comorbidities. The message for patients is to recognize the illness early, treat it early, and strive to ward off the comorbidities. If a patient takes care of oneself, the outcome can be quite good.


When should lithium be used?

Lithium deserves special consideration in the treatment of any first-episode mania patient. There is some suggestion in the literature that if lithium is going to work, it will do so early on coupled with the neuroprotective effects. Unfortunately, I often see patients who have already gone on 10–15 other medications. I use lithium in mania-prone patients. Patients who are more prone toward depression than mania probably struggle more with effective treatments for the depression side of the illness than the mania side. Hence, lithium may not work as well with these patients. Also, we are often fond of asking if relatives benefited from a given psychotropic agent, thinking this may help to guide treatment response for our own patient. Lithium is one of the very few drugs where this has in fact proven to be true, and so family history of lithium responsiveness is a useful parameter. In addition, one must not forget that the anti-suicide properties of lithium may be unique to that drug and can even occur regardless of whether lithium is effective for preventing manias or depressions. Lithium, therefore, deserves consideration in the regimen of any mood-disordered patient with a longitudinal suicide risk.

With so many drugs being approved for the treatment of bipolar disorder, is the term “mood stabilizer” now obsolete?
The term is imprecise and incomplete more than obsolete. Contrary to our assumptions from a decade ago, anticonvulsants do not appear to show robust effects as a class to treat or prevent manias or depressions; those psychotropic properties seem to be confined to divalproex, carbamazepine, and lamotrigine. Meanwhile, all atypical antipsychotics treat mania regardless of the presence of psychosis, and at least some have value for bipolar depression or long-term prevention of episodes. Thus, rather than identify whether or not a drug is a “mood stabilizer” based on its pharmacologic class, it may be more useful to talk about the extent to which any treatment has mood-stabilizing properties and the extent to which those properties are predominantly anti-manic, antidepressant, or both.

We can talk about the extent to which a drug derives its mood-stabilizing properties by virtue of treating or preventing one pole or the other, or both. Classic examples are lithium and lamotrigine. Neither drug has been shown in rigorous controlled studies to induce the opposite polarity of the illness. Lamotrigine is an example of a drug that does not seem to induce the opposite polarity, has a robust effect on the depression side, and a more modest effect on the mania side. It can be described as a mood-stabilizing antidepressant or an agent that has mood-stabilizing properties that are predominantly depression related. It is in many ways the complement or mirror image of lithium—which is an excellent drug choice to minimize cyclicity and polarity change, particularly in patients who are prone to recurrent manias. However, lithium is less robust against recurrent bipolar depressions than bipolar manias.13


What off-label drugs for treatment of bipolar symptoms have value?

Many anticonvulsants have not borne out in clinical trials to treat mania or depression or to forestall polarity changes, but they act in other relevant ways to treat the illness. Topiramate, which has not been shown in placebo-controlled studies to help severe mania, has significant effects in alcohol dependence, binge eating, and neuropathic pain, all of which are common problems for patients with bipolar disorder. Comparably, gabapentin, a drug in which two placebo-controlled studies14,15 looked at its usefulness as an add-on treatment or monotherapy in severely ill patients, did not significantly reduce manic or depressive symptoms; however, the drug helps to treat anxiety disorders, alcohol dependence, and neuropathic pain.

Comorbidity is a descriptor in helping to create a regimen that is informed by what is being treated. For example, a clinician may choose to include topiramate “off-label” in the regimen of a patient with bipolar disorder, not for mood symptoms but to target comorbid obesity, binge eating,16 alcoholism,17 or migraines. Similarly, one might include gabapentin “off label” in a regimen as a possible alternative to benzodiazepines to treat anxiety symptoms. When comorbidities are considered in addition to mood symptoms, off-label uses from evidence-based controlled studies help guide clinicians to which medications are valuable for treating each patient with bipolar disorder.


What are the clinical features that help differentiate between unipolar and bipolar depression?

Mania is in many ways not just a mood disorder but also a rate disorder, with the speeding up of thought, action, behavior, cognition, and so forth. Sleep duration, rate of thinking, and goal-directed activity help differentiate the polarity distinctions, rate of disturbance, and cyclicity phenomenon. Highly-recurrent or cyclical phenomena are probably a variant of bipolar disorder, or at least a separation from unipolarity. As a diagnosis, bipolar disorder can broadly encompass cyclical mood recurrences, polarity changes, impulsivity, cognitive dysfunction, possible psychosis, chronobiologic or sleep disruptions, common psychiatric comorbidities, and consequent behavioral or interpersonal problems. These factors create a complex that is not simple. A longitudinal perspective is neccessary for an accurate diagnosis. PP



1. Diagnostic and Statistical Manual of Mental Disorders. 4th ed. Washington, DC: American Psychiatric Association; 1994.
2. Sachs GS, Nierenberg AA, Calabrese JR, et al. Effectiveness of adjunctive antidepressant treatment for bipolar depression. N Engl J Med. 2007;356(17):1711-1722.
3. Goldberg JF, Perlis RH, Ghaemi SN, et al. Adjunctive antidepressant use and symptomatic recovery among bipolar depressed patients with concomitant manic symptoms: findings from the STEP-BD. Am J Psychiatry. 2007;164(9):1348-1355.
4. Truman CJ, Goldberg JF, Ghaemi SN, et al. Self-reported history of manic/hypomanic switch associated with antidepressant use: Data from the STEP-BD. J Clin Psychiatry. In press.
5. Goldstein TR, Frye MA, Denicoff KD, et al. Antidepressant discontinuation-related mania: critical prospective observation and theoretical implications in bipolar disorder. J Clin Psychiatry. 1999;60(8):563-576.
6. Regier DA, Farmer ME, Rae DS, et al. Comorbidity of mental disorders with alcohol or other drug abuse. Results from the Epidemiologic Catchment Area (ECA) study. JAMA. 1990;264(19):2511-2518.
7. Goldberg JF, Garno JL, Callahan AC, Kearns DL. Validity of bipolar diagnoses among inpatients with substance use disorders. Poster presented at: the 7th International Conference on Bipolar Disorder; Pittsburgh, PA; June 7, 2007.
8. Stewart C, El-Mallakh RS. Is bipolar disorder overdiagnosed among patients with substance abuse? Bipolar Disord. 2007;9(6):646-648.
9. Baethge C, Baldessarini RJ, Khalsa HM, Hennen J, Salvatore P, Tohen M. Substance abuse in first-episode bipolar I disorder: indications for early intervention. Am J Psychiatry. 2005;162(5):1008-1010.
10. Grant BF, Stinson FS, Dawson DA, et al. Prevalence and co-occurrence of substance use disorders and independent mood and anxiety disorders: results from the National Epidemiologic Survey on Alcohol and Related Conditions. Arch Gen Psychiatry. 2004;61(8):807-816.
11. Robinson LJ, Ferrier IN. Evolution of cognitive impairment in bipolar disorder: a systematic review of cross-sectional evidence. Bipolar Disord. 2006;8(2):103-116.
12. Kessing LV, Andersen PK. Does the risk of developing dementia increase with the number of episodes in patients with depressive disorder and in patients with bipolar disorder? J Neurol Neurosurg Psychiatry. 2004;75(12):1662-1666.
13. Geddes JR, Burgess S, Hawton K, Jamison K, Goodwin GM. Long-term lithium therapy for bipolar disorder: systematic review and meta-analysis of randomized controlled trials. Am J Psychiatry. 2004;161(2):217-222.
14. Pande AC, Crockatt JG, Janney CA, Werth JL, Tsaroucha G. Gabapentin in bipolar disorder: a placebo-controlled trial of adjunctive therapy. Gabapentin Bipolar Disorder Study Group. Bipolar Disord. 2000;2(3 Pt 2):249-255.
15. Frye MA, Ketter TA, Kimbrell TA, et al. A placebo-controlled study of lamotrigine and gabapentin monotherapy in refractory mood disorders. J Clin Psychopharmacol. 2000;20(6):607-614.
16. McElroy SL, Hudson JI, Capece JA, et al. Topiramate for the treatment of binge eating disorder associated with obesity: a placebo-controlled study. Biol Psychiatry. 2007;61(9):1039-1048.
17. Johnson BA, Ait-Daoud N, Bowden CL, et al. Oral topiramate for treatment of alcohol dependence: a randomised controlled trial. Lancet. 2003;361(9370):1677-1685.


Dr. Kennedy is professor in the Department of Psychiatry and Behavioral Sciences at Albert Einstein College of Medicine, and director of the Division of Geriatric Psychiatry at Montefiore Medical Center in the Bronx, New York.
Disclosure: Dr. Kennedy has received research support or honoraria from AstraZeneca, Eli Lilly, Forest, Janssen, Myriad, and Pfizer.

Please direct all correspondence to: Gary J. Kennedy, MD, Director, Department of Geriatric Psychiatry, MMC, 111 East 210th St, Klau One, Bronx, NY 10467; Tel: 718-920-4236; Fax: 718-920-6538; E-mail:



Present treatments for dementia are largely palliative, providing symptomatic but temporary improvement. In contrast, agents that promise disease modification offer the hope of prevention, arrest, or deceleration of decline. However, enthusiasm for these new agents must be tempered by acknowledgment of their inevitable limitations within the present standard dementia care.

Two recent reviews1,2 of treatments being developed for Alzheimer’s disease describe a substantial number of agents in randomized clinical trials, not only to demonstrate safety or determine effective dosing, but to test efficacy and tolerability as well. Although some of the medications are targeted at neurotransmitter systems, which may be the innocent bystanders in dementia pathogenesis, several address amyloid and tau pathologies thought to be central to neurodegeneration of the Alzheimer’s type. These latter agents offer the promise of preventing, arresting, or slowing decline through disease modification. However, disease-modifying agents will have to overcome even greater challenges faced by the present generation of medications for dementia if they are to be approved by the Food and Drug Administration. Moreover, they are not expected to be curative and their preventive potential depends on as yet unrealized preclinical diagnostics. Thus, they are unlikely to supplant symptomatic treatments. Without the continued evolution in collaborative models of dementia care, it is difficult to see how disease modifiers will ever meet their full public health potential. What follows is an effort to prepare practitioners and policy makers to better address the implications of disease modification in dementia (Table).




Disease Modification and Symptomatic Treatments Defined

The concept of disease modification is graphically portrayed in the accompanying Figure. With the start of a symptomatic treatment such as donepezil, galantamine, rivastigmine, or memantine, measures of benefit diverge initially from placebo but ultimately parallel the rate of decline of untreated patients. When withdrawn from treatment, within weeks patients who initially benefited perform no better than the placebo group. Thus, the effect is beneficial but palliative. In contrast, disease-modifying agents would either arrest or slow the progressive loss in quality of life. The result is an altered slope or velocity of decline which diverges at an acute angle from placebo. The larger the effect, the greater the divergence and the sooner the benefits become clinically apparent. Smaller effects may be reliably detected only after prolonged treatment. With the introduction of diagnostic tests to identify at-risk people prior to the onset of illness, disease modifiers may also be preventive.2


It is the mechanism of action that distinguishes symptomatic from modifying therapy. The present medications for mild, moderate, or severe Alzheimer’s disease either enhance cognitive performance or retard cognitive decline through the manipulation of neurotransmitter systems. They either boost the signal between cholinergic neurons or reduce the background noise from excessive neuronal excitation. Although the signal is enhanced, the receiver continues to fail at the same rate. In disease modification, the pathology being modified is upstream from events leading to the loss of neurons and neurotransmitters. Both the neurotransmitter signals and receivers continue to decline, though less rapidly. Disease modification does not imply that function will be restored permanently to premorbid levels. Hence, unless the modification occurs prior to neurotransmitter deficits, symptomatic agents would still have a role to play. By analogy, analgesics may be necessary both before and after an osteoarthritic joint is replaced with a mechanical prosthesis. Similarly, cholesterol-lowering agents are indicated both before and after myocardial infarction. Indeed, statin therapy is one possible model of disease modification in both coronary artery disease as well as Alzheimer’s dementia.1


How Would Disease Modification Be Measured?

The development of measures for disease modification in dementia has involved at least three elements. First, a human biomarker at or near the cause of the illness needed to be identified. Second, an animal model of the illness in which the biomarker could be experimentally manipulated needed to be developed. Third, agents which reduce the pathogenic effects of the biomarker in animals need to show the same or similar actions in humans but with clinical significance. It is clinical significance which has to be defined if the agent is to be prescribed. However, the definition of meaningful clinical significance is not straightforward. Although FDA-approved medications for dementia reliably demonstrate cognitive benefits superior to placebo, a significant minority of treated patients experience no benefit. These agents may delay the emergence of behavioral problems, but their capacity to reduce them once present is unreliable.3,4 Further, a significant minority of providers find the benefits neither socially meaningful nor economically valuable.5,6

Based on analyses of medical expenditures and the increase in life expectancy between 1960 and 2000 in the United States, Cutler and colleagues7 found that the value extracted from dollars spent was substantial. However, further expenditures are expected to yield decreasing value, meaning that increased spending will likely be accompanied by smaller and smaller increases in the life span. Thus, the quality of existence in the latter part of life takes on greater importance. If disease modification can extend the quality of life (eg, independence, productivity) for the patient and family caregivers, increased life span need not be the measure by which value is determined. Indeed, pushing dementia-related disability to the end of the life span would be nearly as desirable as the more distant goal of outright prevention. Complicating the equation is the amount of time necessary to demonstrate a reduction in the slope of cognitive decline or quality of life that must be demonstrated to argue for the presence of modification. As a result, an accounting of the social and economic benefits will follow at some distance from the expense of initiating disease modification.


Unanticipated Consequences

Post and Whitehouse’s8 cautionary examples of dementia treatment following the introduction of donepezil at first reading appear not to apply to disease-modifying therapies. In the cases cited, improved cognition following cholinesterase therapy was accompanied by a return of obsessive worry, agitation, painful and unwelcome insight, and awareness of limitations. For the patients’ caregivers, burden increased rather than declined and the quality of life for both parties was degraded rather than enhanced. In an accompanying editorial, Sachs9 advised that while the vignettes cited by Post and Whitehouse8 are exceptions rather than the norm, they are nonetheless familiar to physicians who treat patients and their families coping with dementia. The cases highlight the need to communicate clear, realistic goals of treatment. If symptomatic improvement in one domain is associated by symptom exacerbation in another, the balance of harm and benefit may not favor continued treatment. Because the cholinesterase inhibitors are not thought to increase the life span of people with dementia, they are not seen as prolonging their disability or exacerbating suffering except in the rare cases cited by Post and Whitehouse.8

However, if disease modification does indeed prolong life by delaying cognitive decline, the expected delay in loss of independence and emergence of behavioral disturbances may not result in a lesser duration of dependency and discomfort. Thus, the question remains of when to stop treatment whether it is merely symptomatic or genuinely disease modifying. Similarly, once the process of neuronal death is well underway there may be little gained from modification agents even if they were to arrest the process entirely. Again, the goals of care must be made explicit to insure that modified disease means more than prolonged dependency.


Disease Modification and Diagnosis With Biomarkers

Symptomatic treatment is recommended across the array of common dementias including Alzheimer’s, mixed (Alzheimer’s disease with vascular components), and Parkinson’s dementia.10 However, for disease modification to be effective, particularly for prevention, precise diagnosis is needed to distinguish Alzheimer’s disease from the prevalent but less frequent vascular and Parkinson’s dementias. Dubois and colleagues11 recommend new research diagnostic criteria for Alzheimer’s disease which would require the presence of significant impairment in episodic memory plus at least one abnormal biomarker as detected by either structural neuroimaging with magnetic resonance imaging, functional imaging with positron emission tomography, cerebrospinal fluid analyses of b-amyloid, or hyperphosphorylated tau proteins. If any of the agents currently in clinical trials demonstrate clinically significant disease modification as well as favorable alteration in biomarkers, the research criteria proposed by Fillit and colleagues10 may well take their place in standard clinical practice. Biomarkers sensitive to early effects or lack thereof from disease modifiers would also be useful for the determination of treatment failure. Because disease modification will require long-term treatment, minimizing the expense and disappointment when the treatment fails is critical.

A breakthrough in risk identification through personal genomics12 might justify the prescription of disease-modification agents prior to any phenotypic evidence of illness. However, a statistically significant association between a personal genetic variation and an illness does not mean that it is clinically significant. Simply knowing about one’s risk status does not always lead to better health decisions. Some patients may over-interpret a relative increase in risk as absolute certainty that disease will follow. Others, finding they are at relatively less risk than expected, may forego health-promoting behaviors. As a result, patient education coupled with provider counseling would be required to ethically address the uncertainties of risk and benefit. The costs of a personal genome, even if current prices fall precipitously, will add expense and inevitable concerns about inequities in care and insurance coverage. Finally, at what threshold of risk should medication be started? Further, what evidence will physicians use to declare a disease-modifying treatment is ineffective or has lost efficacy after initial benefit? These are scientific questions of probability but the emotional weight attached to them will be personal to the patient. Thus, tact, time, and counseling will be necessary to help patients and their families make informed, personalized decisions.



Advances in preclinical diagnosis may transform disease modification into disease prevention. However, in the interim, disease modification, if shown to be efficacious, will impose substantial burdens before the desired benefits are evident. Disease-modifying agents may fail to demonstrate their full potential unless they are incorporated into a model of disease-modifying care. The collaborative model is supported by several randomized controlled trials but is not the current standard.13-15 Nonetheless, if disease-modifying agents delay the onset of dementia-related disability until the end of the life span, the economic value would be substantial even if they cannot cure or prevent the disease. In summary, enthusiasm for the next-generation medications should be tempered by an awareness of the implications of disease modification for dementia care. PP



1. Grossberg GT, Pejovic V, Miller ML. Current strategies for the treatment and prevention of Alzheimer’s disease. Primary Psychiatry. 2007;14(8):39-54.
2. Christensen DD. Changing the course of Alzheimer’s disease: anti-amyloid disease-modifying treatments on the horizon. Prim Care Companion J Clin Psychiatry. 2007;9(1):32-41.
3. Howard RJ, Juszczak E, Ballard CG, et al. Donepezil for the treatment of agitation in Alzheimer’s disease. N Eng J Med. 2007;357(14):1382-1392.
4. Yaffe K. Treatment of neuropsychiatric symptoms in patients with dementia. N Engl J Med. 2007;357(14):1441-1443.
5. Birks JS, Harvey R. Donepezil for dementia due to Alzheimer’s disease. Cochrane Database Syst Rev. 2003;(3):CD001190.
6. Kmietowicz Z. NICE proposes to withdraw Alzheimer’s drugs from NHS. BMJ. 2005;330(7490):495.
7. Cutler DM, Rosen AB, Vijan S. The value of medical spending in the United States, 1960-2000. N Engl J Med. 2006;355(9):920-927.
8. Post SG, Whitehouse PJ. Emerging antidementia drugs: a preliminary ethical view. J Am Geriatr Soc. 1998;46(6):784-787.
9. Sachs GA. Dementia and the goals of care. J Am Geriatr Soc. 1998;46(6):782-783.
10. Fillit HM, Doody RS, Binaso K, et al. Recommendation for best practices in the treatment of Alzheimer’s disease in managed care. Am J Geriatr Pharmacother. 2006;4(suppl A):S9-S24.
11. Dubois B, Feldman HH, Jacova C, et al. Research criteria for the diagnosis of Alzheimer’s disease: revising the NINCDS-ADRDA criteria. Lancet Neurol. 2007;6(8):734-746.
12. McGuire AL, Cho MK, McGuire SE, Caulfield T. The future of personal genomics. Science. 2007;317(5845):1687.
13. Callahan CM, Boustani MA, Unverzagt FW, et al. Effectiveness of collaborative care for older adults with Alzheimer disease in primary care: a randomized controlled trial. JAMA. 2006;295(18):2148-2157.
14. Vickrey BG, Mittman BS, Connor KI, et al. The effect of a disease management intervention on quality and outcomes of dementia care: a randomized controlled trial. Ann Intern Med. 2006;145(10):713-726.
15. Mittelman MS, Roth DL, Clay OJ, Haley WE. Preserving health of Alzheimer caregivers: impact of a spouse caregiver intervention. Am J Geriatr Psychaitry. 2007;15(9):780-789.




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

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

Please direct all correspondence to: Gary J. Kennedy, MD, Director, Division of Geriatric Psychiatry, MMC, 111 East 210th St, Klau One, Bronx, NY 10467; Tel: 718-920-4236; Fax: 718-920-6538; E-mail:


Criteria for Alzheimer’s disease and preclinical dementia have been proposed recently, which include potential biomarkers of the illness. Nonetheless, the etiology of the illness remains uncertain despite consistent associations described for cerebral amyloid and hyperphosphorylated tau pathologies. As a result, further progress toward understanding age-related changes in cognition that are not related to dementia is critical both to characterize healthy aging but also to develop interventions that will sustain cognitive performance. This will be the case even if proposed biomarkers become powerful predictors of the presence of disease.


Preliminary criteria for diagnosis of Alzheimer’s disease in both its clinical and pre-clinical forms have appeared in the proposed Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition,1,2 and subsequently by work groups convened by the National Institute on Aging and the Alzheimer’s Association.3-5 Both suggest that bio-markers related to amyloid or the microtubule protein tau soon may be incorporated into the diagnostic process. The appeal of putative biomarkers of dementia is their promise of signaling the presence of a disease process before cognition or brain topography become noticeably impaired. In addition to anteceding the onset of symptoms, biomarkers might be less subject to variations seen in healthy cognitive performance related to education, vocation, or innate intelligence. The proponents of biomarker research assume that amyloid is the signal event in Alzheimer’s disease. Amyloid and hyperphosporylated tau are pathology consistently associated with Alzheimer’s disease. But how distal are these pathologies from the pathoetiology of the illness?

Uncertainty about the primary pathophysiology of Alzheimer’s disease has raised skepticism about the use of biomarkers.6 Yet, interventions applied once synaptic atrophy and neuronal death are manifest as cognitive impairment may be too late to be effective. Further, intervention trials to test the amyloid hypothesis among patients selected on the basis of these preliminary criteria could take a decade to complete. Even if the spread of amlyoid in the brain can be reduced or reversed, the demonstration of preserved or improved cognition will be required to establish efficacy. As a result, attention to progress in the characterization age-related changes in cognition is critical to refining criteria for preclinical dementia. The study of working memory and executive function now underway in the Research Domain Criteria initiative of the National Institute of Mental Health7,8 may further advance the assessment of cognitive processes and neural circuits sensitive to the earliest signs of Alzheimer’s disease.

Cognitive Constructs and Aging

Cognitive constructs refer to mental processes which have both scientific and clinical utility yet are approximations of reality based on observation and theory. Functional imaging has revealed age-related changes relevant to the theoretical constructs, but no unified phenomenon which might represent a simple theory of aged cognition has emerged. Nonetheless, awareness of these constructs and how they are changed for better or worse with age will have clinical implications when genuinely therapeutic agents arrive for the treatment of dementia. Prominent constructs recently reviewed by Reuter-Lorenz and Park9 appear in bold followed by descriptions.

Working memory, that component of the cognitive system which retains information for immediate use, is an area of intense interest for clinicians caring with older adults but for neuroscientists as well. Memory screening tests most often rely on working memory by requiring the patient to register, retain (learn), and recall (remember) new information such as a recited list of words or set of image presentations. Older adults perform as well as younger provided the memory load does not exceed four items or require marked executive function to inhibit, reorder, or refresh the list. Thus, when older adults are asked to select from the assortment of recently learned memories or to alternate categories of items, working memory becomes fatigued. Unlike consolidated memory, which seems to have infinite shelf space, working memory is volume dependent and vulnerable to overload. As the memory load increases, both younger and older adults recruit prefrontal cortical areas to manage the load. Older adults reach overload sooner and show a drop in prefrontal activation, suggesting the system has met its limit.

Inhibitory control deficits appear when older adults are given memory tasks in which distractors are also presented. In comparison to a younger adult, the older person is less likely to ignore, screen out, or delete irrelevant stimuli. When instructed to remember a sequence of words or images followed by items to be ignored, older adults show greater brain activation for the latter than do younger adults. When instructed to generate a list of words starting with the letter “S” followed by an instruction to list words starting with the letter “A,” older adults are more likely to insert S-words into the A-word list. Thus, age-related inhibitory dysfunction mediated by prefrontal processes results in impairments in the initial stage of information processing, placing further limits on working memory capacity and efficiency.

Processing speed decrements are the most widely accepted explanation for decline in cognitive processes during late life. Changes in white matter structure and integrity are largely responsible. It is as though age and cardiovascular illness fray the insulation in neural circuits. However, the effects are not uniform. Some neural circuits and the cognitive processes they serve may be more intact and more capable of compensating for those with less integrity. As a result, slowed processing speed is not considered a sufficient explanation for cognitive decline during aging.

Long-term memory deficits have been ascribed to a number of age-related changes in brain structure and cognitive function. Older adults are less effective at encoding new information for memory tests. However, when given contextual or categorical cues associated with the memory item, their performance improves. Such tests of episodic memory are also sensitive to loss of volume and under-activation of the hippocampus and parahippocampus, two areas affected early in Alzheimer’s disease. Implicit, automatic, or procedural memory functions out of awareness and is related to previously learned material that can be applied to current tasks with little conscious effort. This form of effortless recall, particularly when associated with semantic processing, involves left inferior prefrontal regions and is relatively preserved in older people.

Constructs from Imaging Studies of Brain Regions and Neural Circuitry

Functional imaging studies with positron emission tomography or functional magnetic resonance imaging scans have provided a number of discoveries about regional differences in the aging brain. For example, compared to younger people, older adults will activate a greater number of brain regions to meet the same cognitive challenge. Hemispheric dominance, whether for verbal processing on the left or spatial processing on the right, is diminished such that functional asymmetry and localization are reduced. Over-activation is also seen in both posterior and anterior regions of cortex accompanied by a general posterior to anterior shift in activation. The phenomenon is thought not to be a result simply of cerebrovascular aging. Over-activation may be associated with superior cognitive performance and represent compensatory enhancement of neural circuitry. However compensation has its price.

The medial prefrontal, medial, and lateral parietal brain areas are known as the default network. These regions are highly interconnected, more active at rest than during purposeful activity, and associated with internal rather than external stimuli. The default network manages ongoing attention to the environment, self-focus, and reflective memories. However, with advancing age, the network loses interconnectivity and over-reacts to external stimuli. As a result, frontal areas are recruited to compensate, causing loss of efficiency and accuracy.

De-differentiation is the result of lost topographic specificity and decline in neural plasticity. Additional regions of cortex have to be recruited, not to reach a new equilibrium, but rather to respond to loss of specialization. For example, face recognition is specific to the ventral visual cortex, but as this area loses functionality with age, prefrontal areas are recruited to manage the work load placed on working memory. There is a general posterior to anterior activation in the cortex with the medial, lateral, and anterior prefrontal cortex being over-activated to compensate for under-activation in the medial temporal lobe and ventral visual cortex.

Frontal over-activation makes older adults vulnerable to age- and illness-related prefrontal deficits. In addition, there is an increased noise to signal ratio. As dopamine levels decline with age, the strength of synaptic signaling falls while the background neural noise does not.

Older adults are also more likely to exhibit difficulties with proactive versus reactive cognitive control. Because of changes in executive function and prefrontal structures, older adults are less able to benefit from cues and context that might precede a sequence of stimuli. Rather, they rely more than younger people on cognitive procedures that occur during stimulus presentation. This reduces processing speed as well as the stimulus load that can be successfully processed. Thus, their executive function is more reactive than proactive or anticipatory. They multi-task with difficulty.

From “CRUNCH” to “STAC”

How, then, do we explain the increasing proportion of older adults who maintain sufficient cognitive function to remain independent into late life?”10 Reuter-Lorenz and Park9 present two hypothetical mechanisms to account for the maintenance of cognitive performance in late life, shown in the Figure. The Compensation-Related Utilization of Neural Circuits hypothesis suggests that cognitive processes become rerouted to new or additional circuits as age and illness wear the brain down. As one area of mental hardware deteriorates, another is recruited to take its place. A virtual scaffold gradually emerges and is made possible by the distribution of cognitive processes to frontal and other areas, including both hemispheres, and to new neurons via neurogenesis. The Scaffolding Theory of Aging and Cognition adds the notion that the brain’s software may be enhanced at the same time that the circuitry is being upgraded. The scaffold is enhanced by learning, physical exercise, cognitive stimulation, and social engagement. The impact on cognitive performance will vary as a result of both the quality of the structure of the scaffold and personal behavior. In this way, not only do age and illness affect cognition, but so do personal history, ongoing mental activity, and the environment.




Advances in cognitive neuroscience buttressed by interest in dementia biomarkers and functional imaging techniques promise to increase the measurement of risk for the development of Alzheimer’s disease. However, equally important are insights into compensatory mechanisms and the plasticity of neural circuitry that may argue for interventions which might sustain if not improve cognitive performance to the end of the life span.11 This will be particularly important when treatments emerge to modify the disease process and slow the rate of decline among people with dementia. An understanding of how biomarkers might predict dementia will not obviate the need to advance our understanding of aging and cognition in healthy active older adults. PP


1. Diagnostic and Statistical Manual of Mental Disorders. 5th ed. Washington, DC: American Psychiatric Association. In press.
2. Kennedy GJ. Proposed revisions for the diagnostic categories of dementia in the DSM-5. Primary Psychiatry. 2010;17(5):26-28.
3. Proposed criteria for Alzheimer’s disease dementia. Available at: Accessed August 10, 2010.
4. Proposed criteria for mild cognitive impairment due to Alzheimer’s disease. Available at: Accessed August 10, 2010.
5. Proposed criteria for preclinical Alzheimer’s disease. Available at: Accessed August 10, 2010.
6. Kolata G. In Alzheimer’s research, hope for prevention. The New York Times. August 5, 2010: A18.
7. Insel T, Cuthbert B, Garvey M, et al. Research domain criteria (RDoC): toward a new classification framework for research on mental disorders. Am J Psychiatry. 2010;167(7):748-751.
8. NIMH Research Domain Criteria (RDoC). Available at: Accessed August 12, 2010.
9. Reuter-Lorenz PA, Park DC. Human neuroscience and the aging mind: a new look at old problems. Journal of Gerontology: Psychological Sciences. 2010;65B(4):405-415.
10. Fries JF. Aging, natural death, and the compression of morbidity. N Engl J Med. 1980;303(3):130-135.
11. Rae MJ, Butler RN, Campisi J, et al. The demographic and biomedical case for late-life interventions in aging. Sci Transl Med. 2010;2(40):40cm21.



This interview took place on June 10, 2010 and was conducted by Norman Sussman, MD.

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

If you would like to access this interview online, please visit

Are we at a point where neuroimaging or neural biomarkers of psychiatric illness can help us identify and even start treating diseases early in their development?

One central goal in neuroimaging research in psychiatric illness is to define the neural correlates of particular psychiatric illnesses so that they can be used as biomarkers of the illness. The basic assumption is that at least some of the brain abnormalities found in people with an illness should also be seen in people who are at risk for that illness but not yet ill. These neural abnormalities could be used as biomarkers of risk; they could work just like stress tests, Papanicolaou smears, or other methods used for early risk detection by other fields of medicine. Then, these biomarkers would allow us to treat people at risk in a targeted, cost-effective way with preventive interventions.

Neuroimaging research in psychiatry is still a relatively young field. It started in the mid-1970s, with the development of computerised tomography scan. The high-resolution magnetic resonance imaging (MRI)-based methods that we use now have only been used since the mid- to late-90s. We have only been conducting this kind of research for the past 10–15 years. The spatial and temporal resolution of these methods are still improving. We have come a long way in identifying neural correlates of psychiatric illness, but we still have a way to go.

Does evaluating multiple aspects of illness in addition to neuroimaging provide a better prediction tool?

Yes. The key may be to use multiple methods in combination to develop a risk signature of psychiatric illnesses. However, it is challenging because a lot of the neural correlates of illness turn out to be somewhat nonspecific. They often overlap with what is seen in healthy people. Also, the different illnesses can show similar abnormalities. This may say more about our diagnostic and classification systems than the biology of the illnesses we study.

There has been a recent set of breakthroughs that will help push forward this line of research. There have been recent studies showing that certain treatments, like cognitive-behavioral therapy1,2 and fish oil,3 may actually prevent the development of certain major mental illnesses, such as schizophrenia and depression.

Can neural dysfunction predict who in combat might experience posttraumatic stress disorder (PTSD)?

PTSD has been associated with a set of abnormalities in brain function, including impaired function of the medial prefrontal cortex (PFC), exaggerated amygdala responses, and dysfunctional connections between the medial PFC and the amygdala. Risk for PTSD has been studied extensively by a group at Massachusetts General Hospital in Boston led by Roger K. Pitman, MD, using various neuroimaging methods including functional MRI (fMRI) as well as psychophysiologic techniques.4,5 They have measured skin conductance responses in response to emotional stimuli and during fear conditioning. They have used these methods to study brain function of combat veterans who do or do not have PTSD. The elegant aspect of their design is that each of the combat veterans they have studied also has an identical twin brother who has not been exposed to combat. The idea is that any abnormalities they find in the veterans with PTSD that they also find in those veterans’ twin brothers could be related to risk for PTSD.

They found several abnormalities in the veterans with PTSD and their twins, such as elevated dorsal anterior cingulate gyrus activity and an enlargement of a space in the middle of the brain called the cavum septum pellucidum. Now that they have found these abnormalities that could be related to risk, they can examine them prospectively in soldiers before they go into combat, to see if these actually are risk markers for PTSD.

Is it true that when patients with neuronal loss in areas like the hippocampus are effectively treated with an antidepressant, neuronal sprouting occurs because of an increase in brain-derived neurotropic factor?

The rat model of the effects of stress on the hippocampus differs from what we see in humans to some extent. Still, there is a lot of evidence for the effects of neurotrophic factors on brain regions affected in psychiatric illness and that antidepressants increase the release of these factors and possibly affect medial temporal lobe volume and neurogenesis. This is an active area of study right now, in research dedicated to developing novel treatments for depression and schizophrenia.

Addictive disorders are common. What do we know about reward circuitry responses?

There has been much research on the reward system of the brain, both in rats and monkeys as well as in humans. Research in humans has mostly been conducted using fMRI and positron emission tomography. There is a network of regions which includes the ventral striatum, orbital frontal cortex, dorsal lateral PFC, and dopaminergic cell groups of the midbrain, which are involved in the pursuit of reward and the experience, and anticipation of rewarding stimuli—all aspects of reward-related responses.

Addiction, major depressive disorder, and schizophrenia have each been associated with a different type of abnormality in the circuitry. For example, addiction may be most related to an impairment in what we call “top-down control” by the PFC of the function of subcortical reward circuitry. Schizophrenia, particularly the negative symptoms of the disorder,  may be related to an impairment in the anticipation, or memory, of rewarding experiences, which may have a slightly different mechanism. We are still in the process of understanding what the specific neural correlates are of these behavioral abnormalities associated with the reward system. Luckily, this system has been very well-characterized in animal models.

If it really turns out to be the case that addiction is associated with a reduction in the top-down control of reward-related responses, there may be a way to augment the activity of the PFC and its modulation of subcortical activity in the striatum and other centers that may be dysregulated in these patients.

Have you done any work on understanding delusions of schizophrenia from a neural point of view?

Yes. Our model comes from several lines of converging evidence that suggest that delusions result from an abnormality in emotional learning and memory.

The idea is that we have a somewhat flexible neural system that tells us whether something in the environment is important, dangerous, or relevant to us in some way. It actually appears that we have two interacting systems that evaluate the emotional meaning of information in the environment. There is a fast, sometimes inaccurate system, and then a slow but more detail-oriented and precise system. Sometimes the fast system misfires, even in healthy non-delusional people. Then, the second more accurate system kicks in to correct these errors.

When people develop delusional ideas, the system misfires frequently, telling the person that something in his or her environment is important, relevant, or dangerous. Yet, there is no mechanism that comes in to correct these misperceptions.

Our lab, among others, has found neuroimaging evidence to support this hypothesis. We have found that delusions are associated with misfiring of certain regions of the brain, such as the cingulate gyrus, in response to information that is not personally relevant or emotionally significant for most people.6-8

Is there a correlation between treatment, elimination of delusions, and changes in these areas?

Neuroimaging studies that conduct this type of within-subject comparison represent the best approach to testing this model of delusions, but it is difficult to do this kind of study well. If you are not careful, there will be several things that are changing at the same time, like doses of medication and symptom severity. We are conducting a study like this right now to see if we can tease out the effects of treatment on delusions and the associated changes in brain function.

Is quantitative electroencephalogram (EEG) valuable in your work?

I have done some event-related potential (ERP) work and I think it is extremely valuable. It can be a very good companion to fMRI because it has very good temporal resolution. However, the spatial resolution is not very good, while fMRI has the opposite set of strengths.

fMRI essentially measures blood flow by taking advantage of the fact that the  deoxygenated hemoglobin (deoxyhemoglobin) is paramagnetic. Because deoxyhemoglobin is paramagnetic, we can measure where it is going in the brain because it disrupts the MRI signal in a predictable way.

EEG measures electrical activity of pyramidal neurons. Because it is directly measuring neuronal activity, the electrical discharge of neurons, it is very accurate temporally, on the order of milliseconds. However, because it can only measure activity that is near the surface of the scalp, it can only measure activity of neurons that are near the cortical surface; it cannot provide the sort of spatial resolution that we have with MRI-based methods.

Has there been work on the circuits involved with anxiety disorders?

This brings up a current question in psychiatric neuroimaging research that many are grappling with, which is whether to continue to use the Diagnostic and Statistical Manual of Mental Disorders classification schemes in our research, since these classifications may not reflect unique biologic or neurophysiologic characteristics. For example, social anxiety disorder may be difficult to distinguish neurophysiologically from generalized anxiety disorder or other types of phobias.

Obsessive-compulsive disorder (OCD), however, appears to have a neural signature that is somewhat distinct in comparison to other anxiety disorders. It seems to be associated with more prominent orbital frontal-striatal abnormalities. This is interesting because it is consistent with the impression of many clinicians, that the clinical features of OCD are somewhat distinct from the clinical features of other anxiety disorders. This is in the line with the general idea that the DSM-IV-TR may have it right in some cases but not in others.

What is the major message for our clinical audience at this point?

I believe that we are slowly moving closer to being able to use neuroimaging as a clinical tool to identify people at risk and to measure effects of treatment. A large benefit of neuroimaging research that we have already seen clinically is that it has contributed to the reduction of the stigma associated with psychiatric disorders. It is really helpful for patients to understand that we have identified abnormalities of the brain associated with these disorders. These are medical disorders, which you can see evidence of, in research studies, on an MRI scan.

Have there been any major findings related to the PFC?

The frontal lobe is the part of the cerebral cortex that is most relevant for psychiatric illness. It is the control center of the brain. The dorsal and lateral PFC are involved in decision-making, planning, and task switching—any process that involves conscious choice. The medial and ventral portions of the PFC are involved in emotional perception, introspective activity, and integrating internal states with incoming sensory information. Many psychiatric disorders appear to be associated with abnormalities of the PFC, including schizophrenia, bipolar disorder, major depression, and PTSD.

Are there other brain areas of interest that you would like to comment on?

Neuroimaging researchers are very interested currently in understanding what the midline cortical network does and whether there are abnormalities in the functioning of this network in psychiatric disorders. This network includes the medial PFC and posterior cingulate gyrus. These regions show elevated activity during what people call “stimulus-independent thought,” which you have during times when you are not really engaged in thinking about anything going on in your surrounding environment. Instead, you may be daydreaming or thinking about the past or future. This network is of interest to psychiatric researchers because certain psychiatric disorders are associated with abnormal introspective thinking—either too much or too little of it. So far, it has been shown that this network functions abnormally in schizophrenia and depression.

What have we learned from the research on the neuropsychology of epilepsy?

It is interesting that medial temporal lobe epilepsy is sometimes associated with psychotic symptoms. Abnormalities in the medial temporal lobe are likely involved in the psychosis associated with schizophrenia too.9 A lot of evidence now supports this possibility. There has been some recent evidence showing abnormally elevated activity in a part of the hippocampus, which is within the medial temporal lobe, in people who have schizophrenia, as well as in people who are at risk for schizophrenia and later develop it.10

Epilepsy is an interesting model in that in some cases it has a very specific neuroanatomical correlate associated with psychiatric symptoms. It suggests that we are on the right track and that, at some point, we will understand psychiatric illnesses just as well as neurologists understand epilepsy. PP


1.    Morrison AP, French P, Walford L, et al. Cognitive therapy for the prevention of psychosis in people at ultra-high risk: randomised controlled trial. Br J Psychiatry. 2004;185:291-297.
2.    Garber J, Clarke GN, Weersing VR, et al. Prevention of depression in at-risk adolescents: a randomized controlled trial. JAMA. 2009;301(21):2215-2224.
3.    Amminger GP, Schafer MR, Papageorgiou K, et al. Long-chain omega-3 fatty acids for indicated prevention of psychotic disorders: a randomized, placebo-controlled trial. Arch Gen Psychiatry. 2010;67(2):146-154.
4.    Pitman RK, Gilbertson MW, Gurvits TV, et al. Clarifying the origin of biological abnormalities in PTSD through the study of identical twins discordant for combat exposure. Ann N Y Acad Sci. 2006;1071:242-254.
5.    Shin LM, Lasko NB, Macklin ML, et al. Resting metabolic activity in the cingulate cortex and vulnerability to posttraumatic stress disorder. Arch Gen Psychiatry. 2009;66(10):1099-1107.
6.    Holt DJ, Titone D, Long LS, et al. The misattribution of salience in delusional patients with schizophrenia. Schizophr Res. 2006;83(2-3):247-256.
7.    Holt DJ, Lebron-Milad K, Milad MR, et al. Extinction memory is impaired in schizophrenia. Biol Psychiatry. 2009;65(6):455-463.
8.    Holt DJ, Lakshmanan B, Freudenreich O, Goff DC, Rauch SL, Kuperberg GR. Dysfunction of a cortical midline network during emotional appraisals in schizophrenia. Schizophr Bull. In press.
9.    Holt DJ, Phillips ML. The human amygdala in schizophrenia. In: Phelps EA, Whalen PJ, eds. The Human Amygdala. New York, NY: Guilford; 2009:344-361.
10.    Schobel SA, Lewandowski NM, Corcoran CM, et al. Differential targeting of the CA1 subfield of the hippocampal formation by schizophrenia and related psychotic disorders. Arch Gen Psychiatry. 2009;66(9):938-946.


Dr. Levenson is professor in the Departments of Psychiatry, Medicine, and Surgery, chair of the Division of Consultation-Liaison Psychiatry, and vice chair for clinical affairs in the Department of Psychiatry at Virginia Commonwealth University School of Medicine in Richmond.
Disclosure: Dr. Levenson is on the depression advisory board for Eli Lilly.



Important psychiatric issues affecting diagnosis and management arise in patients with neurologic illness more often than any other area of medicine. These include cognitive impairment either as a primary feature or a secondary complication of a known neurologic disorder, such as multiple sclerosis; other psychiatric symptoms as a manifestation or complication of neurologic disease; and physical neurologic symptoms that do not correspond to any recognized pattern of neurologic disease, ie, conversion disorder or somatization disorder. In addition, behavioral, cognitive, or emotional symptoms may occur as a complication of drug therapy of neurologic disease. More detailed coverage of these topics can be found elsewhere.1,2 In a previous column in Primary Psychiatry, psychiatric issues in stroke were reviewed.3 In this issue, psychiatric issues related to Parkinson’s disease and multiple sclerosis are reviewed.


Parkinson’s Disease

Parkinson’s disease is an idiopathic degenerative disorder characterized by tremor, rigidity, and bradykinesia. Its estimated prevalence is 10–20 cases per 100,000 and its incidence increases with age. While it is thought of as primarily a disease of the elderly, Parkinson’s disease occurs even in adolescents, albeit rarely. Resting tremor (especially “pill-rolling” tremor) is the most obvious feature of Parkinson’s disease and is found in 75% of patients. However, bradykinesia is the most common initial sign, with insidious onset, and is therefore easily misdiagnosed as depression or apathy; bradykinesia is ultimately the most disabling feature. “Cogwheeling” is the result of tremor superimposed on rigidity. Postural instability due to rigidity as Parkinson’s disease progresses results in increased risk for falls. Abnormal involuntary movements are a result both of Parkinson’s disease and of dopaminergic therapy. Freezing of movement is particularly distressing to patients. In addition to the classic motor symptoms, other common manifestations of Parkinson’s disease include autonomic dysfunction (particularly orthostatic hypotension, bladder and gastrointestinal dysfunction), cognitive dysfunction, depression, and other psychiatric symptoms.



Parkinson’s disease is accompanied by dementia in a substantial minority of cases, and the boundary between Parkinson’s disease with dementia (PD-D) and dementia with Lewy bodies (DLB) is not a clear one. Psychotic symptoms (hallucinations and delusions) occur in 50% to 75% of patients with DLB, 30% to 50% with PD-D, and 5% to 15% of patients with Parkinson’s disease without dementia.1 Hallucinations are usually visual and delusions are most often paranoid. While limited psychotic symptoms with retained insight in Parkinson’s disease have been regarded as benign, a recent study suggests this is not the case and that most individuals’ psychotic symptoms progress over a period of years.4

In the early days of L-dopa treatment, adverse psychiatric reactions, particularly psychotic symptoms, were frequent after initiation of therapy and reported in up to 50% of patients after several years of treatment.1 The addition of carbidopa to L-dopa made this much less common. Psychotic symptoms have been reported as adverse reactions to other dopaminergic drugs in Parkinson’s disease, including bromocriptine, pramipexole, and ropinirole, but have not been clearly related to dose or length of exposure. Anticholinergic drugs are beneficial for Parkinsonian symptoms but pose the risk of aggravating cognitive dysfunction if dementia is also present. Anticholinerigc drugs also may cause psychotic symptoms as part of delirium, whereas the hallucinations and delusions induced by dopaminergic drugs are usually isolated psychotic symptoms unaccompanied by delirium.

Typical neuroleptics, especially high-potency ones, are contraindicated in Parkinson’s disease because they exacerbate symptoms and block the effect of dopaminergic drugs. Clozapine is the only antipsychotic shown in a randomized controlled trial (that also included olanzapine and risperidone) to be effective against psychosis, without aggravation of Parkinson’s disease.5 Quetiapine appeared beneficial for psychotic symptoms without worsening Parkinson’s disease in an open trial,6 but two small randomized controlled trials were negative. Despite its mixed dopamine agonist-antagonist profile, open trials of aripiprazole have not supported its use for psychosis in Parkinson’s disease.7 While there are case reports of psychotic symptoms responding to cholinesterase inhibitors in patients who have PD-D, without aggravating Parkinson’s disease,8 others have reported they caused significant worsening of Parkinson’s disease motor symptoms (which is not surprising since anticholinergic drugs reduce Parkinson’s disease motor symptoms).



Depression is very common in Parkinson’s disease, with a prevalence of up to 40% to 50%.1 Depression may antedate the development of motor symptoms in Parkinson’s disease and is associated with cognitive dysfunction.9,10 Depression and other psychological factors interact to affect the course and outcome of Parkinson’s disease, with depression resulting in impairment of functional capacity and quality of life, but not motor function in Parkinson’s disease.9 It is not known to what extent depression results from brain pathology as opposed the psychological consequences of the progressive disabling nature of Parkinson’s disease. Early in the course of unrecognized Parkinson’s disease, depression may be misdiagnosed because of the patient’s lack of facial expression and motor slowing. Later in Parkinson’s disease, the diagnosis of depression may be missed when fatigue, psychomotor slowing, impaired attention, poor sleep, and sexual dysfunction—all of which can be caused by Parkinson’s disease—are attributed to Parkinson’s disease. The presence of psychological symptoms of depression (eg, dysphoric mood, anhedonia, negativism, guilt) that are out of proportion to the degree of disability in Parkinson’s disease, and of course suicidal ideation, support the diagnosis of major depressive disorder (MDD).11 Mood lability (both unipolar and bipolar) has been described during the late-stage fluctuations known as on-off phenomena that occur after years of L-dopa therapy.1

For treatment of depression in Parkinson’s disease, tricyclic antidepressants (TCAs) may have the side benefit of reducing Parkinson’s disease motor symptoms because of their anticholinergic effects, but this must be balanced against the risk of their aggravating cognitive or autonomic dysfunction. Selective serotonin reuptake inhibitors (SSRIs) have occasionally been reported to exacerbate Parkinson’s disease motor symptoms and rarely have caused extrapyramidal side effects in patients without Parkinson’s disease. Mirtazapine may be a good choice for depression in Parkinson’s disease and may even reduce symptoms of Parkinson’s disease.12 Finally, dopamine agonists like pramipexole may be an alternative to antidepressants in Parkinson’s disease.13

Electroconvulsive therapy (ECT) may produce simultaneous remission of comorbid depression and Parkinson’s disease. Case reports, case series, and one sham-ECT controlled trial indicate that ECT is effective for depression in Parkinson’s disease and may also improve motor function.14 Many patients will experience improvement in motor symptoms but the magnitude (sometimes dramatic) and duration (sometimes many months) of benefit are variable and unpredictable. Maintenance ECT has also been used to extend the motor benefits. The potential benefits of ECT in patients with Parkinson’s disease and depression must be balanced against the common side effects of delirium and treatment-emergent dyskinesia.



Anxiety is very common in Parkinson’s disease,15 particularly as the disease progresses with anticipatory anxiety about motor freezing. Whether antiparkinsonian medications themselves contribute to anxiety is not clear. Treatment with antidepressants and cognitive-behavioral therapy (CBT), particularly if delivered along with physical therapy, can be helpful, and benzodiazepines sometimes may be required. However, the optimal pharmacologic treatment for anxiety in patients with Parkinson’s disease has not been established.1,15


Multiple Sclerosis

Multiple sclerosis is the most prevalent chronic disabling central nervous system disease in young adults, with a variable and unpredictable course. Common symptoms include motor and sensory dysfunction, visual loss, incontinence, and fatigue as well as cognitive impairment and mood symptoms. Psychiatric symptoms are common in multiple sclerosis and have significant effects on patients’ lives. (A more detailed review of psychiatric aspects of multiple sclerosis can be found elsewhere.16)



MDD occurs in patients with multiple sclerosis at approximately double the prevalence in the general population of comparable gender and age mix, and subsyndromal depressive symptoms are even more common. Between 25% and 50% of multiple sclerosis patients will have MDD sometime in their lives. However, depression remains underdiagnosed and undertreated in patient with multiple sclerosis. Suicide usually preceded by depression is not uncommon in multiple sclerosis, with one study estimating it may account for as many as 15% of deaths in patients with multiple sclerosis.17 Research to date has not clearly established whether the likelihood of depression is proportional to the degree of neurologic disability or duration of multiple sclerosis. As in stroke, there has been an attempt to differentiate “biologic” depression from “reactive” depression and to link the former to specific brain lesion sites. However, the literature remains unclear as to whether the risk of depression in multiple sclerosis can be related to lesions in specific brain areas.1,16

In patients with multiple sclerosis, depression causes greater cognitive dysfunction, poorer health-related quality of life and functional status, disruption of social networks, and reduced adherence with treatment. Such effects have been found in many other chronic diseases and it has not been demonstrated that depression affects the demyelination pathophysiology of multiple sclerosis, although depression may increase and its treatment decrease production of pro-inflammatory cytokines.18 The study of depression as an independent risk factor affecting the onset or course of multiple sclerosis is challenging because depression may also be a direct physiologically mediated consequence of the disease, a psychological reaction to the illness, or a complication of pharmacotherapy.19 Depression is especially difficult to study in multiple sclerosis because of its uncertain relationship to the multiple sclerosis-fatigue syndrome (discussed below).20

Both psychotherapy and pharmacotherapy appear to be effective for decreasing depressive symptoms in patients with multiple sclerosis,21 but studies to date have been few and small. In those studies, response rates to CBT have been equal to or better than than with antidepressant pharmacotherapy.


Bipolar Disorder

It has been long recognized that multiple sclerosis sometimes presented with mania, at times before other neurologic signs. However, some reported cases of bipolar disorder caused by multiple sclerosis may have been due to corticosteroid treatment, and some have represented other types of emotional lability caused by multiple sclerosis, such as emotional incontinence (see below). A limited epidemiologic literature has indicated that multiple sclerosis and bipolar disorder occur together at more than twice the expected rate based on their prevalence in the general population, but there have been no large, population-based epidemiologic studies of the prevalence of bipolar disorder in multiple sclerosis patients.16


Emotional Incontinence

Emotional incontinence (also referred to as pathologic crying or laughing, emotional diarrhea, emotional lability, pseudobulbar affect, or, more recently, involuntary emotional expression disorder [IEED]22) is a syndrome of uncontrollable episodes of emotional expression that occurs in up to 10% of multiple sclerosis patients23 and in a variety of other neurologic conditions including stroke.3 IEED is characterized by episodes of crying or laughing that are unrelated to or disproportionate to the patient’s actual emotional state. The crying and/or laughing are disinhibited and experienced by the patient as ego-dystonic and a struggle to stop. This form of emotional lability has been theorized to result from damage to inhibitory neurons projecting from the frontal lobes to limbic areas. Pathologic crying or laughing can have a significant impact on individuals’ social functioning and their relationships with others. Unpredictable and uncontrollable outbursts of affect often cause severe embarrassment and avoidance of social interactions and may result in subsequent agoraphobia. Treatment has usually been with TCAs or SSRIs, but dopamine agonists and a combination of dextromethorphan and quinidine have also been reported to be helpful.24



While anxiety symptoms and disorders are common in multiple sclerosis, as with most chronic medical illnesses they have received much less study than depression. Clinically significant current anxiety has been reported in 25% to 40% of multiple sclerosis patients, and the lifetime risk of Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition,25 anxiety disorders is approximately 50% greater than in the general population.16,26 Like depression, anxiety disorders are underrecognized and undertreated in multiple sclerosis.


Cognitive Dysfunction

Cognitive impairment may ultimately affect 50% of all patients with multiple sclerosis, with the deficits reflecting the subcortical location of the demyelination, including impairment of attention, speed of processing, and executive functions.1 Disorders of working memory may be prominent, and a minority of patients become frankly demented. However, cognitive impairment in multiple sclerosis may also be due to fatigue, depression, anxiety, or medication side effects. Neuropsychological assessment in multiple sclerosis patients with cognitive dysfunction can be helpful in this differential diagnosis as well as prognosis.



Fatigue is the most common symptom in multiple sclerosis, affecting 80% of patients and ranging from mild to disabling. While it is aggravated by heat and exertion, it is not eliminated by their avoidance. It should be distinguished from depression,20 medication side effects, and physical exhaustion and deconditioning attributable to motor impairment, though such distinctions are usually difficult and many patients have more than one of these contributing to their fatigue. The cause of multiple sclerosis-fatigue is unknown. Pharmacologic treatments include amantadine (100 mg twice daily), amphetamines and related stimulants (including pemoline, which is no longer available in the United States), SSRIs, and most recently modafinil,27 which is Food and Drug Administration-approved for the treatment of multiple sclerosis-related fatigue. A very gradually progressive exercise program, as in chronic-fatigue syndrome,28 can also be very helpful in multiple sclerosis.29



Both acute and chronic pain are common in multiple sclerosis and can be disabling. One study found that 25% of a large community-based sample of people with multiple sclerosis had severe chronic pain.30 Mechanisms may include dysesthesia, altered cognitive function, and other multiple sclerosis complications such as spasticity. Of the acute pain syndromes, trigeminal neuralgia is the most common and usually responds to carbamazepine.31 Widespread chronic pain is more common and harder to manage. Dysesthetic limb pain is particularly troublesome and treatment is usually with amitriptyline or gabapentin.


Psychiatric Side Effects of Treatment

Pharmacotherapy for multiple sclerosis may include corticosteroids, interferon, and other drugs. Corticosteroids have dose-related psychiatric adverse effects, including mania, depression, mixed states, psychosis, anxiety, insomnia, and delirium. A previous psychiatric reaction to corticosteroids does not necessarily predict recurrent reactions with subsequent steroids. The onset of psychiatric symptoms is typically within the first 2 weeks of treatment. Mild psychiatric side effects include insomnia, hyperexcitability, mood lability, mild euphoria, irritability, anxiety, agitation, and racing thoughts. Mood disorders are the most common psychiatric reaction to corticosteroids. Mania is also common and patients may experience both mania and depression during a single course of corticosteroid therapy. Affective symptoms are often accompanied by psychotic symptoms. Delirium and psychosis (without mood symptoms) are less common. Cognitive dysfunction also has been reported.

There are two types of interferon (IFN)-β used for the treatment of multiple sclerosis (IFN-β 1a and IFN-β 1b). While IFN-β commonly cause some of the same side effects as IFN-α (eg, flu-like symptoms), in contrast to IFN-α there is no clear evidence that IFN-β increase the risk for depression in patients with multiple sclerosis. Other drugs used to treat multiple sclerosis, including glatiramer acetate, mitoxantrone, and natalizumab, have not been reported to have neuropsychiatric side effects (except with the very rare cases of progressive multifocal leukoencephalopathy that occurred after natalizumab).16 PP



1. Carson AJ, Zeman A, Myles L Sharpe MC. Neurology and neurosurgery. In: Levenson JL, ed. American Psychiatric Publishing Textbook of Psychosomatic Medicine. Washington, DC: American Psychiatric Publishing; 2005:701-732.
2. Carson AJ, Zeman A, Myles L Sharpe MC. Neurology and neurosurgery. In: Levenson, JL, ed. Essentials of Psychosomatic Medicine. Washington, DC: American Psychiatric Publishing; 2007:313-342.
3. Levenson JL. Psychiatric issues in neurology, part I: stroke. Primary Psychiatry. 2007;14(9):37-40.
4. Goetz CG, Fan W, Leurgans S, Bernard B, Stebbins GT. The malignant course of “benign hallucinations” in Parkinson disease. Arch Neurol. 2006;63(5):713-716.
5. Low-dose clozapine for the treatment of drug-induced psychosis in Parkinson’s disease. The Parkinson Study Group. N Engl J Med. 1999;340(10):757-763.
6. Mancini F, Tassorelli C, Martignoni E, Moglia A, Nappi G, Cristina S, Pacchetti C. Long-term evaluation of the effect of quetiapine on hallucinations, delusions and motor function in advanced Parkinson disease. Clin Neuropharmacol. 2004;27(1):33-37.
7. Friedman JH, Berman RM, Goetz CG, et al. Open-label flexible-dose pilot study to evaluate the safety and tolerability of aripiprazole in patients with psychosis associated with Parkinson’s disease. Mov Disord. 2006;21(12):2078-2081.
8. Sobow T. Parkinson’s disease-related visual hallucinations unresponsive to atypical antipsychotics treated with cholinesterase inhibitors: a case series. Neurol Neurochir Pol. 2007;41(3):276-279
9. Holroyd S, Currie LJ, Wooten GF. Depression is associated with impairment of ADL, not motor function in Parkinson disease. Neurology. 2005;64;2134-2135.
10. Errea JM, Ara JR. Depression and Parkinson disease [Spanish]. Rev Neurol. 1999;28(7);694-698.
11. Brooks DJ, Doder M. Depression in Parkinson’s disease. Curr Opin Neurol. 2001;14:465-470.
12. Pact V, Giduz T. Mirtazapine treats resting tremor, essential tremor, and levodopa-induced dyskinesias.Neurology. 1999; 22;53(5):1154.
13. Barone P, Scarzella L, Marconi R, et al. Pramipexole versus sertraline in the treatment of depression in Parkinson’s disease: a national multicenter parallel-group randomized study. J Neurol. 2006;253(5):601-607.
14. Rasmussen KG, Rummans TA, Tsang TSM, Barnes RD. Electroconvulsive therapy. In: Levenson JL, ed. American Psychiatric Publishing Textbook of Psychosomatic Medicine. Washington, DC: American Psychiatric Publishing; 2005:957-978.
15. Richard IH. Anxiety disorders in Parkinson’s disease. Adv Neurol. 2005;96:42-55.
16. Chwastiak LA, Ehde DM. Psychiatric issues in multiple sclerosis. Psych Clin N Am. In press.
17. Sadovnick AD, Eisen K, Ebers GC, Paty DW. Cause of death in patients attending multiple sclerosis clinics. Neurology. 1991;41(8):1193-1196.
18. Gold SM and Irwin MR. Depression and immunity: inflammation and depressive symptoms in multiple sclerosis. Neurol Clin. 2006;24(3):507-519.
19. Zorzon M, de Masi R, Nasuelli D, et al. Depression and anxiety in multiple sclerosis. A clinical and MRI study in 95 subjects. J Neurol. 2001;248(5):416-421
20. Bakshi R, Shaikh ZA, Miletich RS, et al. Fatigue in multiple sclerosis and its relationship to depression and neurologic disability. Mult Scler. 2000;6(3):181-185.
21. Mohr DC, Goodkin DE. Treatment of depression in multiple sclerosis: review and meta-analysis. Clinical Psychology: Science and Practice. 1999;6:1-9.
22. Cummings JL, Arciniegas DB, Brooks BR, et al. Defining and diagnosing involuntary emotional expression disorder. CNS Spectr. 2006;11(6):1-7.
23. Feinstein A, Feinstein K, Gray T, O’Connor P. Prevalence and neurobehavioral correlates of pathological laughing and crying in multiple sclerosis. Arch Neurol. 1997;54(9):1116-1121.
24. Brooks BR. Involuntary emotional expression disorder: treating the untreated. CNS Spectr. 2007;12(4 suppl 5):23-27.
25. Diagnostic and Statistical Manual of Mental Disorders. 4th ed. Washington, DC: American Psychiatric Association; 1994.
26. Korostil M, Feinstein A. Anxiety disorders and their clinical correlates in multiple sclerosis patients. Mult Scler. 2007;13(1):67-72.
27. Stankoff B, Waubant E, Confavreux C, et al. Modafinil for fatigue in MS: a randomized placebo-controlled double-blind study. Neurology. 2005;64(7):1139-1143.
28. Powell P, Bentall RP, Nye FJ, Edwards RH. Randomised controlled trial of patient education to encourage graded exercise in chronic fatigue syndrome. BMJ. 2001;322(7283):387-390.
29. Petajan JH, Gappmaier E, White AT, Spencer MK, Mino L, Hicks RW. Impact of aerobic training on fitness and quality of life in multiple sclerosis. Ann Neurol. 1996;39(4):432-433.
30. Ehde DM, Gibbons LE, Chwastiak L, Bombardier CH, Sullivan MD, Kraft GH. Chronic pain in a large community sample of persons with multiple sclerosis. Mult Scler. 2003;9(6):605-611.
31. Thompson AJ. Symptomatic treatment in multiple sclerosis. Curr Opin Neurol. 1998;11(4):305-309.




Dr. Haridas is a final year resident, Dr. Oluwabusi is a Child Fellow, and Dr. Gurmu is Chief resident in the Psychiatry Program at Drexel University College of Medicine in Philadelphia. Dr. Kushon is Clinical Associate Professor of Psychiatry at Drexel University College of Medicine and Medical Director of the Psychiatric-Medical Care Unit at Hahnemann University Hospital in Philadelphia, Pennsylvania.

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

Off-label disclosure: This article includes discussion of investigational treatments for major depression.

Please direct all correspondence to: Arun Haridas, MD, MRCPsych, Drexel University College of Medicine, Department of Psychiatry, 1427 Vine St, 8th Floor, Philadelphia, PA 19107; Tel: 215-762-6660; Fax: 215-762-6673; E-mail:

Focus Points

• Several case reports point to quetiapine’s abuse potential on the black market.
• Oral, intravenous, and intranasal routes of abuse have been reported.
• The inhalational method of quetiapine abuse is novel and counter-intuitive.
• Polysubstance abuse history may bring combinations of abuse, eg, quetiapine with cocaine-“Q” ball, quetiapine with marijuana “Maq ball.”



Quetiapine abuse has been a cause for increased concern among clinicians. Several reports have highlighted this in the past. Reports of quetiapine abuse have varied in their routes of administration. The authors have had experience in managing several patients who have admitted to the use of quetiapine outside of prescription settings. This article examines the case of a recent patient on the authors’ inpatient unit who admitted to a novel route of abuse. While quetiapine’s abuse potential in the black market is well known, motivations for the abuse of quetiapine have varied in the past. Anxiety and insomnia has been amongst the reported motivations. Combination abuse of quetiapine with cocaine, called “Q ball,” have been reported previously. Quetiapine serves as a substitute for heroin when used in this combination. This article highlights a previously unreported combination of quetiapine with marijuana used in the inhalational route in what is termed a “Maq ball.”


Quetiapine has been cited in several recent reports of being abused, especially in prison settings under the name “baby heroin” and “quell.”1,2  Reports of quetiapine abuse have varied in their routes of administration from the intravenous,1 intranasal,3,4 and oral.5 The authors have had experience in managing numerous patients in the in-patient unit who have admitted to obtaining and using quetiapine outside of prescription settings. A recent patient in an in-patient unit is highlighted below, illustrating this worrisome trend.

Case Report

A 27-year-old Hispanic male was admitted to the in-patient unit with a history of worsening depressed mood with suicidal ideation. He described polysubstance abuse involving marijuana, crack cocaine, alprazolam, and quetiapine; his preferred drug of choice was marijuana. He described smoking 1 oz. of marijuana daily. Approximately 1–2 times per week, he smoked crushed quetiapine tablets mixed with one ounce of marijuana. In addition, he smoked crack cocaine 3 times/week and alprazolam 5–10 mg/day orally up to 5 times/week.

Efforts to stop his quetiapine on this admission were unsuccessful on the unit, though he agreed to a tapered discharge dosage of quetiapine 100 mg/day. He requested to be discharged to a local drug and alcohol recovery house. Examination of prior admission records revealed that 5 months earlier, he had admitted to using quetiapine from the black market. At the time, he abused quetiapine orally, taking ~2–3 pills of quetiapine 100 mg/day, in addition to being prescribed quetiapine 100 mg BID by his primary care physician for his mood symptoms.


Quetiapine is a drug of known value on the black market of antipsychotics.6 Its use is motivated by anxiety and insomnia.4 Quetiapine, amongst olanzapine, anticholinergics, and tricyclic antidepressants, have been a favored method to “zone out” or “take the edge off” amongst buyers in the black market.6 This may be related to the fact that quetiapine is associated with a better subjective response than its conventional antipsychotic counterparts.7

Quetiapine, crushed and mixed with cocaine and water, and taken intravenously, has been previously recorded in the literature as a “Q ball.”8 The strategy aims to mitigate the dysphoria associated with cocaine withdrawal through the sedative and anxiolytic effects of quetiapine. Quetiapine in the described case served as a substitute for heroin and the more classic cocaine and heroin “speed ball” combination.8


There have been no reports of quetiapine  combined with marijuana and serving as what we term a “Maq ball.” Unlike combining cocaine and quetiapine, which carries the risk for QT prolongation,8 lethal side effects are unlikely with this combination. However, it once again draws attention to this worrying trend of quetiapine becoming an increasing favorite for novel and hitherto unknown methods of abuse. Clinicians would do well to keep this fact in mind when deciding on an appropriate antipsychotic for individuals with comorbid substance use disorders. PP


1.    Hussain MZ, Waheed W, Hussain S. Intravenous quetiapine abuse. Am J Psychiatry. 2005;162(9):1755-1756.
2.    Del Paggio D. Psychotropic medication abuse in correctional facilities. The Bay Area Psychopharmacology Newsletter. 2005;8(1):5.
3.    Morin AK. Possible intranasal quetiapine misuse. Am J Health Syst Pharm. 2007;64(7):723-725.
4.    Pierre JM, Shnayder I, Wirshing DA, Wirshing WC. Intranasal quetiapine abuse. Am J Psychiatry. 2004;161(9):1718.
5.    Reeves RR, Brister JC. Additional evidence for the abuse potential of quetiapine. South Med J. 2007;100(8):834-836.
6.    Tarasoff G, Osti K. Black market value of antipsychotics, antidepressants and hypnotics in Las Vegas, Nevada. Am J Psychiatry. 2007;164(2):350.
7.    Voruganti L, Cortese L, Oyewumi L, Cernovsky Z, Zirul S, Award A. Comparative evaluation of conventional and novel antipsychotic drugs with reference to their subjective tolerability, side effects profile and impact on quality of life. Schizophr Res. 2000;43(2-3):135-145.
8.    Waters BM, Joshi KG. Intravenous Quetiapine-Cocaine Use (“Q- Ball”). Am J Psychiatry. 2007;164(1):173-174.





Dr. IsHak is Director of Psychiatry Residency Training and Medical Student Education in Psychiatry at Cedars-Sinai Medical Center (CSMC) and Associate Clinical Professor of Psychiatry at the University of California, Los Angeles (UCLA), the University of Southern California, and CSMC, all in Los Angeles, California. Dr. Rasyidi is the CSMC Psychiatry Chief Resident. Dr. Saah is former research physician volunteer at CSMC and current psychiatry resident at Emory University in Atlanta, Georgia. Dr. Vasa is on medical staff at CSMC. Dr. Ettekal is Research Psychiatrist at California Clinical Trials in Glendale, California. Dr. Fan is Associate Director of Inpatient Psychiatry at CSMC and Assistant Clinical Professor of Psychiatry at UCLA and CSMC.

Disclosures: Dr. IsHak receives grant support from the National Alliance for Research on Schizophrenia and Depression and Pfizer. Drs. Saah, Rasyidi, Vasa, Ettekal, and Fan report no affiliation with or financial interest in any organization that may pose a conflict of interest.

Please direct all correspondence to: Waguih William IsHak, MD, FAPA, Cedars-Sinai Medical Center, Department of Psychiatry and Behavioral Neurosciences, 8730 Alden Dr, Thalians W-157, Los Angeles, CA 90048; Tel: 310-423-3515; Fax: 310-423-3947; E-mail:

Focus Points

• Factitious disorder is the intentional production of symptoms to assume the sick role in the absence of secondary gain.
• Factitious disorder could present with physical, psychological, or combined symptoms.
• Factitious disorders are commonly misdiagnosed with medical conditions, somatoform disorders, or malingering.
• Medical records from previous hospitalizations and healthcare providers are essential.
• Factitious disorder needs to be suspected in frequent acute care utilizers with atypical presentations and negative results.



In the clinical setting, factitious disorder is often mistaken for malingering or somatoform disorders. Three cases of factitious disorder with physical, psychological, and combined symptoms are reported. Comparing these patients may help facilitate identification of factitious disorder, especially with improving recognition in patients who are high utilizers of acute medical and psychiatric services. A high level of suspicion regarding the diagnosis of factitious disorder is needed, especially in cases with frequent utilizers of emergency room and inpatient services, atypical presentations, and negative diagnostic results.


The Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition-Text Revision,1 refined the diagnosis for factitious disorder by providing three diagnostic criteria (Table 1).2 Studies indicate a .5% to .8% prevalence of factitious disorders in hospital patients, with a prevalence of up to 6% to 8% on psychiatric units.2-5 However, patients with factitious disorders are commonly misdiagnosed with medical conditions, somatoform disorders, or malingering. Due to diagnostic difficulties, only the most severe cases of factitious disorder are diagnosed correctly. In other cases, factitious disorder may be suspected but not diagnosed. The following three cases of factitious disorder with disparate presentations are based on the subtypes described in the DSM-IV-TR (Table 2).1 Patient A presented with mainly physical symptoms. Patient B presented with physical and psychological symptoms. Patient C presented with mainly psychological symptoms. The patients presented depict the wide spectrum of severity and presentations in factitious disorders that contribute to the difficulty of accurate diagnosis. The management of these cases also demonstrates the diagnostic strategy needed for improving diagnosis of factitious disorder.


Factitious Disorder Case Reports

Patient A: Factitious Disorder with Predominantly Physical Signs and Symptoms

Patient A, a 27-year-old female, would often present to the emergency department with vague complaints of abdominal pain and bright red blood per rectum, which she stated was typical for her Crohn’s disease. The patient also freely reported a psychiatric history with multiple diagnoses, including bipolar disorder, posttraumatic stress disorder (PTSD), obsessive-compulsive disorder (OCD), panic disorder, a history of anorexia nervosa, and Asperger’s syndrome, as well as a history of suicide attempts and self-injurious behaviors. The patient had a stable income through state disability and lived in a comfortable home with her parents in an affluent neighborhood. Psychiatric consultation was requested on her third admission to the medical center and after 13 previous presentations to the emergency department. At that point she had undergone extensive diagnostic testing, including computed tomography scans, upper gastrointestinal (GI) endoscopy with small bowel follow through, colonoscopy, and biopsies, all of which had been unsuccessful in finding the cause of GI bleeding. She was transferred to the inpatient psychiatric hospital for complaints of depressed mood and her diagnosis was refined to PTSD and borderline personality disorder. During hospitalization, a nurse found the patient in the bathroom one night inserting a toothbrush into her rectum, producing the bloody stools that she had been complaining of for the past several days. When confronted, the patient articulated that she desired the attention that came with her medical work-ups and that it instilled a sense of control over her environment. This behavior was different from previous suicide attempts in that there was no intent to die. It was also distinct from her self-injurious behaviors which were performed openly and freely admitted to. As for the discrepancy between reported psychiatric diagnoses and those at time of discharge, this was due to diagnostic errors on the part of previous treatment teams, not due to misrepresentation by the patient. The patient thus met criteria for factitious disorder with predominantly physical symptoms.

Patient B: Factitious Disorder with Combined Psychological and Physical Signs and Symptoms

Patient B, a 52-year-old female with bipolar depression, was admitted to the inpatient unit for the fifth time in 6 months after presenting with suicidality and depressed mood. The patient stated that she had been diagnosed with OCD, PTSD, and attention-deficit/hyperactivity disorder. She also stated that she was blind and had a guide dog. During hospitalization, she consistently reported that her depression and suicidality were worsening. However, observations showed that the patient joked, laughed, and regaled others with far-fetched stories. She ate and slept well, and ambulated without difficulty. It also became increasingly obvious that Patient B was not blind. She was observed reading, looking in the mirror, and dialing numbers from her phone book. In daily sessions, inconsistencies were noted in her elaborate recollections of traumas. The management plan consisted of performing a diagnostic work-up including medical, neurologic, and neuropsychological evaluations, in addition to a trial of citalopram 40 mg PO and lamotrigine 200 mg PO, both at bedtime, as well as psychotherapy. Ophthalmology and neurology consults did not reveal any visual loss. The psychological and neuropsychological testing confirmed suspicions about the presence of significant antisocial, narcissistic, and borderline personality traits, and showed intact neuro-cognitive functioning. Additional information confirmed the patient’s tendency to move from hospital to hospital, leave against medical advice, and express inconsistent medical and psychiatric complaints, which gave evidence to the diagnosis of a factitious disorder. The most important two differential diagnoses were conversion disorder and malingering. Conversion disorder was ruled out because the patient was shown to have intact vision on medical consultations. Regarding malingering, there were no specific secondary gains as she had a stable housing and financial situation. It became clear that Patient B was intentionally producing both physical (blindness) and psychological (worsening of depression) symptoms in order to assume the sick role. She was informed of the diagnostic possibility of factitious disorder with combined psychological and physical signs and symptoms, and was recommended for continuation of both psychotherapy and pharmacotherapy.

Patient C: Factitious Disorder with Predominantly Psychological Signs and Symptoms

Patient C, a 38-year-old male, presented complaining of a 3–4-month history of depressed mood, poor energy, difficulty sleeping, poor appetite, psychomotor retardation, increasing hopelessness, and suicidal ideation with a plan to walk into traffic. Once on the inpatient wards, the patient remained compliant with his medications; however, no change in mood was seen. Throughout his stay, Patient C demonstrated, on a consistent basis, a discrepancy between what he stated to staff and what was observed on the wards. The patient consistently reported depressed mood and suicidality, but was observed to be euthymic, in good spirits, and carousing with the other patients. The patient’s stay was also significant for two suicide attempts both with low lethality and high possibility of rescue. Elaborate stories regarding the death of his best friend, as well as his previous married life, employment status, and relations with his family, were for the most part later repudiated by the patient’s father. Eventually, the patient was so disruptive to the inpatient milieu that he was placed in seclusion. Within a few hours he arranged to be picked up by a friend and was successful in finding a place to stay. Before being discharged, the patient admitted to never being suicidal and that the two suicide attempts had both been feigned. The treatment team noticed that the patient had traits of antisocial, narcissistic, borderline, and histrionic personality disorders. The likelihood of malingering was low because the patient had stable income and was offered numerous housing options, which he refused. The treatment team concluded that this patient was willing to assume the sick role, by intentionally manifesting psychological symptoms, to gain the social interaction of being in a psychiatric unit.


Although factitious disorders have been formally recognized for >30 years, diagnostic criteria have evolved significantly since the recognition of the disorder. From the DSM-II6 through the DSM-III7 and DSM-III-R,8 factitious disorders had no clear inclusion or exclusion criteria for diagnosis.9 The advent of the DSM-IV10 and DSM-IV-TR11 advanced the diagnosis of factitious disorder by defining three diagnostic criteria: A) intentional production of physical or psychological signs or symptoms, B) motivation to assume the sick role, and C) absence of external incentives or secondary gain.1,12-14 Criterion A differentiates factitious disorder from somatoform disorders by requiring the intentional production of signs or symptoms. Criterion C differentiates factitious disorder from malingering by eliminating the presence of secondary gains for the patient.15 It is also important to note that while patient cases B and C were also clear examples of pseudologia fantastica, where embellished truth and colorful fantasies are presented as fact in order to gain the interest of the listener, this phenomenon is neither pathognomonic nor necessary under our current nosology for the diagnosis of factitious disorder.14

The three cases presented elucidate several effective diagnostic strategies. With Patient A, psychiatric consultation led to psychiatric hospitalization and a careful review of the medical and psychiatric history. The treating psychiatrist had thoughtful discussions with the patient’s other doctors, which confirmed her history of high health services, utilization, and a lack of evidence for a medical etiology. The close observation of the psychiatric nursing staff then caught the patient in an act of self-injury. With Patient B, the treating psychiatrist also had a thorough diagnostic plan, which included consultation with the neurology, medicine, ophthalmology, and neuropsychological testing services. Nursing observations on the inpatient psychiatric unit revealed that the patient did not have the visual or depressive symptoms that she claimed to have. The treating psychiatrist was also able to obtain valuable medical and psychiatric history from collateral sources to confirm a pattern of multiple hospitalizations, inconsistent medical and psychiatric presentations, and hospital discharges against medical advice. With Patient C, nursing observations also found that the patient’s behavior on the psychiatric unit were inconsistent with his reported symptoms. The treating psychiatrist was able to obtain collateral history from the patient’s father, which confirmed that the patient had falsified his symptoms and psychiatric history to gain admission to the psychiatric unit.

The growing literature on factitious disorder indicates that patients have certain common traits. Understanding these traits may help in accurate diagnosis and management. Some studies have found that factitious disorder patients often have work experience in healthcare fields. They can use their medical knowledge to deceive and confuse the treatment team in their search for an accurate diagnosis. Factitious disorder patients are fearful of abandonment and highly sensitive to rejection.16 They usually have comorbid Axis I and II diagnoses. They use the hospital setting to find support, safety, and social relationships that they cannot obtain otherwise. Confronted with their falsification of history and intentional production of symptoms, factitious disorder patients have increased risk of self-harm and exacerbation of psychiatric disorders. They become extremely difficult to manage as the therapeutic rapport is broken.

From the three patients presented and a review of the literature, several recommendations to facilitate the accurate diagnosis and proper management of factitious disorder patients have been provided. In cases in which factitious disorder is suspected, always ask the patient for permission to obtain medical records from previous hospitalizations and healthcare providers. After Patient A had been caught in the act of producing her physical symptoms, she conceded consent. However, even in situations where patients are caught “red-handed,” there may be an impressive level of denial with patients going so far as to assert that events never actually took place. With Patients B and C, consent was obtained by explaining to the patients that access to sufficient information was necessary in providing appropriate treatment. Again, there may be scenarios where patients balk at this proposal. Refusal by the patient of a well-presented, reasonable request should make the treating physician suspicious of a non-medical diagnosis. Similarly, the treating physician should also ask the patient for permission to collect history from collateral sources such as family members, spouses, and friends. A refusal by the patient may indicate a fear of discovering a falsification. In a hospital, the treating physician should ask the nursing staff to closely monitor a patient suspected of factitious disorder. Close observation can reveal a patient’s surreptitious production of clinical signs. The treating physician should also seek consultations from specialists in other fields to exclude a medical etiology for the patient’s signs and symptoms. In a psychiatric unit, the treatment team, including nurses and therapists, needs to be reminded to set appropriate limits and boundaries for suspected factitious disorder patients. These limits and boundaries may decrease the social and psychological gains that a patient may want from a hospitalization.


The dearth of information available on factitious disorder and the difficulty in obtaining epidemiologic and diagnostic information should not preclude the possibility of more accurate diagnosis and better management. Large descriptive and longitudinal studies with adequate diagnostic work-ups, including medical, neurologic, neuropsychological, and personality testing evaluations, are needed in order to develop a clear understanding of factitious disorders. Unfortunately, such studies are very difficult to undertake in a patient population that is adverse to discovery. Nonetheless, factitious disorder should be considered in patients with atypical presentations and negative diagnostic results who are high utilizers of acute care facilities such as the emergency room and inpatient services. PP


1. Diagnostic and Statistical Manual of Mental Disorders. 4th ed, text rev. Washington, DC: American Psychiatric Association; 2000:513-516.
2. Hamilton JC, Feldman MD, Janata JW. The A, B, C’s of factitious disorder: a 220 response to Turner. Medscape J Med. 2009;11(1):27.
3. Catalina ML, Gómez Macias V, de Cos A. Prevalence of factitious disorder with psychological symptoms in hospitalized patients. Actas Esp Psiquiatr. 2008;36(6):345-349.
4. Sutherland AJ, Rodin GM. Factitious disorders in a general hospital setting: clinical features and a review of the literature. Psychosomatics. 1990;31(4):392-399.
5. Gregory RJ, Jindal S. Factitious disorder on an inpatient psychiatry ward. Am J Orthopsychiatry. 2006;76(1):31-36.
6. Diagnostic and Statistical Manual of Mental Disorders. 2nd ed. Washington, DC: American Psychiatric Association; 1968.
7. Diagnostic and Statistical Manual of Mental Disorders. 3rd ed. Washington, DC: American Psychiatric Association; 1980.
8. Diagnostic and Statistical Manual of Mental Disorders. 3rd ed rev. Washington, DC: American Psychiatric Association; 1987.
9. Rogers R, Bagby RM, Rector N. Diagnostic legitimacy of factitious disorder with psychological symptoms. Am J Psychiatry. 1989;146(10):1312-1314.
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14. Turner MA. Factitious disorders: reformulating the DSM-IV criteria. Psychosomatics. 2006;47(1):23-32.
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Dr. Sussman is editor of Primary Psychiatry as well as Associate Dean for Post-Graduate Programs and professor of psychiatry at the New York University School of Medicine in New York City.

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

Please e-mail questions or comments for Dr. Sussman to

It is a point I have made before, but the content of this month’s Primary Psychiatry reminds me of how important it is for those who diagnose and treat patients with mental disorders know those disorders and their treatments well. As primary care physicians (PCPs) increasingly treat psychiatric disorders, it is important to remember that many conditions and their treatment require full knowledge of differential diagnoses, even of rarely occurring disorders, as well as infrequent but potentially serious side effects of treatment.

Four years ago, a case report1 in our sister publication, CNS Spectrums, described a case of tardive dyskinesia (TD) associated with the long-term use of adjuvant aripiprazole in a patient with refractory depression. The authors wrote:

“Prior to the case of Mrs. C, there were no reports of aripiprazole-associated TD. In this report, however, we described the case of a woman who developed TD after 18 months of treatment with aripiprazole, and suggest that use of aripiprazole may be associated with this adverse effect. Clinicians who choose to prescribe aripiprazole as a primary antipsychotic agent or as an adjuvant treatment should be aware of the risk of TD.”

Shortly after the publication of this case report, aripiprazole became the first drug of any kind to be approved by the Food and Drug Administration as an addition to antidepressants for adults with major depressive disorder. Even though aripiprazole is an atypical antipsychotic, and there is a known risk of TD associated with these agents, published data have suggested that this risk is significantly lower than the risk of TD associated with older antipsychotics. This has made may clinicians comfortable using atypical antipsychotics as adjuncts in place of other add-on strategies. In fact, some early reports2,3 indicated that aripiprazole could cause improvement of TD.

In a Web-exclusive Letter to the Editor, Joseph H. Friedman, MD, and Daniel Tarsy, MD, express concern that increased use of aripiprazole by PCPs—a consequence of its FDA-approved indication for depression—increases the incidence of TD cases because, unlike psychiatrists, PCPs are not adequately accustomed to monitoring their patients for early signs of TD and do not counsel their patients about this risk.

They note that TD may occur in patients never treated with another dopamine antagonist, and even at the low doses recommended for treating depression. Although aripiprazole-associated TD may be reversible in some cases, in other cases the movement disorder may be permanent. They emphatically conclude that aripiprazole should only be used for refractory cases by doctors knowledgeable about antipsychotics. The dose should be as low as possible, and once the patient has achieved a stable improvement attempts should be made to wean off the drug. Alternatives include switching to other antidepressants, including the tricyclics, combined therapy with drugs of different chemical families, adjunctive exercise, and psychotherapy. They further note that psychiatrists should consider other alternatives, such as lithium or thyroid augmentation and that TD should be specifically evaluated and commented upon at each office visit so that the drug may be stopped if TD begins. It is worth noting that there are no data that compare either the safety or efficacy of long-term adjunctive atypical antipsychotic therapy with alternative combinations mentioned above.

In this issue, Waguih William IsHak, MD, and colleagues, in a case series on factitious disorder, describe three cases in which there is the intentional production of symptoms to assume the sick role in the absence of secondary gain. The disorder can present with physical, psychological, or combined symptoms. Like panic disorder, factitious disorders are commonly misdiagnosed with medical conditions or diagnosed as somatoform disorders or malingering. The authors note a .5% to .8% prevalence of factitious disorders in hospital patients, and a prevalence of up to 6% to 8% on psychiatric units. However, patients with factitious disorders are commonly misdiagnosed with medical conditions, somatoform disorders, or malingering. They nevertheless feel that only the most severe cases of factitious disorder are diagnosed correctly. They report on three cases of factitious disorder subtypes, each with a unique disparate presentation, but yet sharing some common clinical features. They also provide several recommendations to facilitate the accurate diagnosis and proper management of factitious disorder in patients. Most importantly, in cases in which factitious disorder is suspected, always ask the patient for permission to obtain medical records from previous hospitalizations and healthcare providers. The authors conclude that factitious disorder should be considered in patients with atypical presentations and negative diagnostic results who are high utilizers of acute care facilities such as the emergency room and inpatient services.

Raymond A. Lorenz, PharmD, and colleagues review the safety of varenicline in patients with mental illness. Varenicline is the most recently FDA-approved smoking cessation aid. However, it carries a boxed warning on its package labeling detailing the increased risk of psychiatric adverse events. Although the risk of developing psychiatric adverse events in the general population is relatively rare, the data presented in this article suggest that the risk for developing psychiatric adverse events is greater for those with pre-existing mental illness. This may not have been evident immediately after the drug came to market because patients with psychiatric conditions were excluded from the phase III clinical trials. Recognition of these rare adverse drug events are thus a result of post-marketing experiences. Thus, the authors caution that while varenicline is effective for facilitating smoking cessation, it may carry some serious risks, particularly for patients with preexisting mental illness. In the absence of clinical trials involving psychiatric patients, they conclude, the data reviewed in this article should lead to cautious use of varenicline in patients with mental illness, especially when the drug is used for extended periods of time.

A different type of smoking-related problem is discussed by Arun Haridas, MD, and colleagues. Quetiapine has been cited in several reports as being abused. This case report highlights a patient with a unique method of abusing quetiapine. The drug is relatively unique among antipsychotics in that it has value in the black market. It is used illicitly mainly as an anxiolytic or hypnotic, or to “take the edge off” amongst buyers in the black market. Quetiapine crushed and mixed with cocaine and water and taken intravenously has been termed a “Q ball,” and is used to mitigate the dysphoria associated with cocaine withdrawal. The authors describe quetiapine combined with marijuana, serving as what they term a “Maq ball.” They note that unlike the cocaine and quetiapine combination, which carries the risk for QT prolongation, lethal side effects are unlikely with this combination. However, they caution that clinicians would do well to keep the street use of quetiapine in mind when selecting antipsychotics for individuals with comorbid substance use disorders.

Robert Lasser, MD, and colleagues, all employees of Shire Development Inc., as disclosed in their conflict of interest disclosure, present an analysis of data—not the results of prospective and quantitative comparison studies—that suggests that lisdexamfetamine dimesylate may offer advantages over mixed amphetamine salts-extended release for the treatment of adults with attention-deficit/hyperactivity disorder.

I also encourage you to read the exchange of letters between Roger Z. Samuel, MD, and Kiki Chang, MD, regarding my recent interview with Dr. Chang on the topic of bipolar disorder in youths. PP


1. Maytal M, Michael Ostacher M, Stern TA. Aripiprazole-Related Tardive Dyskinesia. CNS Spectr. 2006;11(6)435-439.
2. Witschy JK, Winter AS. Improvement in tardive dyskinesia with aripiprazole use. Can J Psychiatry. 2005;50(3):188.
3. Duggal HS. Aripiprazole-induced improvement in tardive dyskinesia. Can J Psychiatry. 2003;48(11):771-772.