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. Dr. Olson is professor in the Department of Anatomy and Structural Biology at Albert Einstein College of Medicine.

Disclosure: Dr. Kennedy is a consultant to Myriad; is on the speaker’s bureaus of Forest and Pfizer; and has received grant support from Forest, Myriad, Novartis, Pfizer, and Takeda. Dr. Olson 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, Department of Geriatric Psychiatry, MMC, 111 East 210th St, Klau One, Bronx, NY 10467; Tel: 718-920-4236; Fax: 718-920-6538; E-mail: gjkennedy@msn.com.


 

Numerous medical schools in the United States and abroad have determined that anatomy taught through cadaver dissection is untenable. Concerns for cost effectiveness, educational efficacy, the shortage of trained anatomist teachers, the increasing demand for cadavers, and pressure to convert dissection rooms to research laboratories, all argue for minimizing or eliminating cadaver dissection. However, arguments against dissection tend to ignore the emotional growth students experience in the process. Cadaver dissection prepares them for one of the core dilemmas of patient care, namely, the need to be personally engaged yet clinically detached. This dilemma, traditionally encountered with the first incision in the dissection lab, will persist throughout professional life, and it must be addressed in order to provide humanistic care with scientific objectivity. What follows is one perspective on how to shape students’ self-awareness in the first weeks of dissection. The premise is simply that examination of the cadaver provides the student a unique opportunity to examine the self.

Background

From its origins, human dissection has been an emotionally charged topic.1 Although the morality of dissection for the advancement of medical science is widely accepted,2 the emotional impact on medical students is often ignored.3-5 Failure to provide an avenue for students to discuss their feelings misses a unique opportunity to explore the emotional relationship they will experience with subsequent patients. In addition, it misses a rare educational moment when a confluence of events provokes an openness and vulnerability in which students can reflect and grow. The Albert Einstein College of Medicine in New York City has developed several approaches within the Clinical and Developmental Anatomy Course to facilitate discussions of first-year student reactions to the dissection of a human cadaver. The stated goals for the course focus on a patient-centered approach to learning the basic human anatomy needed to prepare the student for preclinical course work as well clinical experience. Within the course are several opportunities to enhance the students’ capacity for empathy with subsequent patients by addressing empathically their reactions to their cadaver.

For the students’ initial encounter, “Introduction to the Cadaver,” they are asked to perform a physical examination of the body focused on surface anatomy under the supervision of non-anatomist clinical faculty. Students work in teams with one cadaver assigned to a table of four students. For this exercise, the nude cadaver is presented to the students face up, covered by a single shroud. Bed sores and entry wounds for tubes, infusions, and other evidence of invasive procedures are all clearly visible. After the introductory session, the team is required to write an essay describing their findings and speculating on the cause of death and quality of care at the end of life. Next, faculty facilitators not responsible for grading the students meet for 90 minutes with eight students during the second week of dissection for the “Cadaver Conference.” By the time of the conference the student teams will have dissected the back, and begun to work on the chest and most of the chest and thoracic viscera. During the conference, students are encouraged to speak freely of thoughts and feelings that have emerged during dissection. Finally, a memorial service acknowledging the gratitude students owe those who have donated their bodies for dissection is held at the end of the course. Memorial events such as the one held at the Albert Einstein College of Medicine are almost universal practice at medical schools across the US. The other course activities are not. The following describes how the Cadaver Conference facilitates student discussion of their sensory impressions as a prelude to the disclosure of deeper feelings.

Introduction

The volume of information as well as the pace at which it must be acquired leave the first-year student little time for reflection. As a result, asking students directly to reflect upon their reactions may evoke superficially protective responses. The session begins with brief introductions all around as an ice breaker followed by a purposefully vague description of the goal for the next 90 minutes. Students are reminded that the cadaver is their first patient6 and that the vivid initial impressions can be useful for subsequent encounters provided they have the opportunity for discussion. In some groups a student will seize the leadership with a deeply felt reaction which will propel all the students into the desired openness. More often the students are not prepared for the intensity of their reactions much less the invitation to share them with peers. It is then generally more productive to start with the least intimate perceptions before proceeding to more threatening fears and feelings. At critical junctures the clinical relevance of their reactions is highlighted.

First Sight

The first perception the students will have of the cadaver is visual. As a result, the facilitator begins by asking, “Who among you have seen or touched a dead body before the anatomy course?” Most students have done neither. However, they have performed a physical examination of the cadaver so that the next question focuses on their first glimpse of the body which the facilitator will call “the person” thereafter. The students are asked to describe what they saw, more specifically, “What was the gender, age, race, and condition of the body?” Students are asked if they have seen the hands, face, or genitals, each a more intimate part of the anatomy. These questions give permission for the students to voice their natural curiosity despite initial reservations. Some describe the appearance as “unreal or not human” or note that surgical scars, entry wounds for embalming fluids, bed sores, or compression of soft tissues due to positioning have distorted the anatomy. They are also asked again to speculate on the cause of death and state of the person’s care at the end of life. They are asked to determine whether the nails are manicured, the scalp hair is recently cut or dyed, or the appearance of the hands offers clues to the person’s work or self-care. In one instance, the person’s finger nails had been manicured shortly before death but the toenails “were in terrible shape.” In another, the boundary between dyed and natural hair color was nearly an inch. The hands of one of the bodies were heavily calloused prompting one student to say, “He must have worked hard right up to the end.” These observations allowed students to project themselves into the person’s immediate history to promote identification and lessen the interpersonal distance. Students are also asked how they left the body at the end of the initial dissection. In the initial stages of dissection with the body relatively intact, students are more meticulous in repositioning the cadaver’s anatomy prior to covering it with a shroud. When asked why, students generally respond it is simply matter of respect. This provides the clinically relevant observation that no matter what condition of the patient, living or dead, likable or not, admirable or not, the physician’s stance must always be one of respect. Starting with these more passive observations sets the stage for their responses to actual dissection.

Touch

The facilitator’s next line of inquiry starts with, “At your table, who made the first incision? Why were you chosen to be the first?” Students who have already identified themselves as future surgeons often initiate the dissection. However, on occasion a student will take the scalpel to overcome self doubt or embarrassment, saying that is easier to do it than to watch. The student who made the first cut is asked to describe the experience. “Was the flesh tough or difficult to incise? Was the force needed to retract the skin from the back greater or lesser than expected? Was a finger-sized stab wound opened to provide a better grip on the skin for retraction to reveal the anatomy below the surface?” Most students find the dissection of the back physically arduous. One mentioned, “When I first started it was really slow and I did not want to mess it up, but the instructor said I had to move along and not be so cautious. Then I got really into it; it was like I was just hacking away to get down to the spine. It was a little creepy.” Another student mentioned, “I was [dissecting] okay until I reached the scalp. It actually gave me a chill when I cut into the hair line.” Here the student is touching on the dread of inflicting harm, but also the latent sadism that doing so may be a source of delight. Yet, physicians are expected to enjoy their work and be proficient even if it means causing pain or disfigurement in order to prevent agony or death. Students are warned that no patient wants a surgeon who lacks confidence, is tentative, or is squeamish about making an incision.

Students are then reminded that this same push and pull, take action but do no harm, will recur throughout their professional lives. Sharing a dreaded diagnosis such as cancer, dementia, or terminal illness invariably distresses the patient and is unpleasant for the physician. But doing so in a skillful manner provides the patient and family a platform both to grieve and to act. To be an ongoing source of stability for patient and family unsettled by their realization of mortality is one of the more satisfying moments in medicine. Further, a seasoned, empathic physician can provide the leadership needed by the other members of the healthcare team as well. Confronting death in the person of a cadaver is the student’s first professional encounter with death and dying.7-9 The goal of the discussion, then, is to help students become aware of their own fears of death as well as fears of the inevitable errors in technique or judgment which they will commit.

Olfactory and Gustatory Dimensions of Dissection

The facilitator should ensure that no one in the group remains silent. Smell is a particularly effective sensation with which to elicit participation. Invariably, the students become animated when discussing smell. Most often the smell of the preservative receives the most discussion. When asked, “How did you manage to work on the person despite the smell?” most students, especially those who were first to make an incision, describe becoming habituated as concentration to the task at hand absorbs their attention. Others express an abiding revulsion which is present at the start of every class. However, asking how the odor is managed after class brings a wider range of responses. Some students retreat to their apartments, which are across the street from the anatomy room, to bathe and shampoo immediately after the dissection. For others, discarding their apron and washing their hands is sufficient. Some will admit to remembering the smell even when they know their clothing as well as their person has been thoroughly cleansed. Some will wear the same apparel to every dissection to contain fears of contamination. Asking questions about smell inevitably leads to a discussion of how dissection has affected appetite. Some leave class ravenous after the manual effort and prolonged standing at the dissection table. Others experience a temporary loss of appetite or forgo the consumption of meat.

Hearing

Added to the sight, smell, and feel of the cadaver is the sound associated with the procedures to free up bony parts of the anatomy using a Striker saw. A laminectomy performed during the early dissection assignments to view the spinal cord can provoke a noticeable reaction. One student was surprised by the amount of effort required to cut through the lamina. But the snap heard as the lamina was successfully sectioned was startling. The event made the student pause. “That was the first time it really got to me,” reflected the student. Thus, inquiring about the sound of the procedure also provides an opportunity to uncover complex feelings. The pause of self awareness is something to nurture rather than avoid.

Disavowals and Emotional Blunting

When shared among table mates, the sensory perception and emotional experiences promote openness and acceptance. However, equally important are expressions to the contrary by students who disavow strong feelings. There will be some who legitimately question the value of dissection to their individual careers. Even for them, hearing fellow students discuss the intense reactions can be enlightening. On rare occasions, students will deny strong reactions or even any reaction despite the facilitator’s questions. At times, students will form protective pairs to keep the discussion superficial by rationalizing emotional reactions as limited to the group setting and thereby artificial. This may well keep threatening feelings out of awareness, but is precisely what the conference is meant to prevent. Rather than allowing blunting to be a group norm, it may be helpful for the facilitator to express disappointment or surprise that what is usually an intense experience has eluded them. This normalizes the expression of feelings and allows the remaining students to continue the discussion uninhibited.

Shame and Authority

In contrast, some groups will dwell on difficult emotions as though they were mourning the loss of innocence rather than exploring a professionally important phenomenon. One student found herself in tears in her apartment after the first dissection, saying, “How could we do this? This could have been someone’s mom. I know we need to learn but it just does not feel right.” Indeed, the legitimacy of dissection has been questioned both before and after the 1832 Anatomy Act which allowed English hospitals to receive unclaimed dead bodies for dissection.1 At the Albert Einstein College of Medicine, many of the cadavers are provided by donors who have bequeathed their bodies for medical education. However, an equal and often greater number are donated annually by the decedent’s family members or estate executor. Thus, most cadavers used at the college of medicine are obtained without the informed consent of the living individual. This is most often the case for cadaveric organ donation as well. Nonetheless, this lack of prior permission is distressing for students already unsure of their “right” to dissect.

As a result, some students will continue to minimize contact with the body. The question, “Has everyone had a chance to make an incision?” helps students, such as the one mentioned above, to disclose their reasons. A more provocative question is, “How do you justify the mutilation of this person?” Here, the clinically relevant point is that dissection is a privilege performed so that others, not just the students, may benefit. It is a reminder that the moral authority of their profession is based on beneficence.

Alternatively, for groups stuck in their own mourning, it may be helpful to reflect, “Yes, these are inconvenient feelings, but was there nothing about the dissection that you enjoyed? Did not anybody have fun?” This often serves to uncover the students’ pride in newly acquired skills or an appreciation for the feel of anatomy that was absent from texts or Websites. Students will also mention the fascination of discovery. It also reminds students that cadaver dissection is only one among many of the challenges they will embrace to become effective, mature physicians. Mastering the work of dissection will facilitate mastery of the emotional work involved in patient care—both the successes and failures.

Other Considerations

Humor can create a protective distance from threatening reality but risks loss of sensitivity. One student admitted that for a moment he found himself too detached. As the heart was being excised from the chest cavity he humorously imagined passing it like a football. His ability to share this with the team added to rather than detracted from his moral stature. His insight had brought him closer, not farther, from the person, and closer to his classmates as well. He had, in effect, apologized to the cadaver and his classmates. The facilitator used the opportunity to reflect that when an error occurs, an apology delivered directly and without excuses more often sustains than ruptures the doctor-patient relationship. Patients can be remarkably forgiving, but not of sarcasm, indifference, or abandonment. Given the power, complexity, and cost of modern medicine, knowing how to apologize is a critical skill.

One student recalled being asked by a friend who was not a medical student what the dissection experience was like. The student welcomed the opportunity to discuss his feelings away from his instructors and classmates. However, as he began to describe his feelings, he became aware that his friend seemed distant, unable to relate to the experience. Similarly, patients will ask for personal information or express genuine concern when the physician cannot conceal the effects of personal illness or loss. Yet, the physician is responsible for maintaining a working distance that keeps the patient close without crossing the boundary of using the patient to meet the physician’s personal needs. Personal questions most often indicate a need to know what doctors think of their patients rather than what doctors think of themselves. Without the student’s example of the friend who could not relate, the boundary concept would have seemed little more than an ethical abstraction.

Finally, when asked, most students do not consider donating their bodies for dissection. Though for some this is the result of religious precepts, it is more often not the case. Throughout the session, the facilitator has sought to examine the boundary between the cadaver and the student in an effort to pave the way for a more empathically effective stance toward their patients. Yet, no matter how much they may identify with the cadaver, rarely do they identify themselves as future donors.

Conclusion

This column has focused on only one pedagogic technique and does not offer experimental evidence of beneficial outcomes associated with the experience. However, student evaluations of the experience are positive. One student commented at the end of the conference, “I never knew there was so much to this.” Another had a morbid fear of how she would respond to dissection, which seized her from the first moment she read her acceptance letter from the college of medicine. Two years later, during her clerkship, she told the facilitator how much she appreciated the opportunity to confront her fears in an open, non-judgmental arena. Admittedly, the sensitivities evoked by this technique may easily be blunted by overwork, cynical attendings, or clinical rotations that do not promote an empathic environment. In addition, there is no shortage of events during the clerkships that bring to light the dilemma of sustaining clinical detachment while remaining emotionally engaged. Yet, the intensity of the experience occurring as it does in the first year of medical education uniquely captures the duality and boundaries of patient care. For the patient’s sake, the physician cannot afford to be emotionally overwhelmed or unable to act. A physician paralyzed by fear or doubt has effectively abandoned the patient. Yet, unfeeling detachment is impersonal and unlikely to inspire trust. However anatomy is to be taught in the evolving medical school curriculum,10-13 student dissection provides a rare avenue to promote clinician self awareness and improve patient care. Dissection of the cadaver provokes an examination of the self. PP

References

1. Richardson R. The Making of Mr. Gray’s Anatomy: Bodies, Books, Fortune, Fame. London, UK: Oxford University Press; 2008.
2. Korf HW, Wicht H, Snipes RL, et al. The dissection course–necessary and indispensable for teaching anatomy to medical students. Ann Anat. 2008;190(1):16-22.
3. Finkelstein P, Mathers LH. Post-traumatic stress among medical students in the anatomy dissection laboratory. Clin Anat. 1990;3(3):219-226.
4. Lempp HK. Perceptions of dissection by students in one medical school: beyond learning about anatomy. A qualitative study. Med Educ. 2005;39(3):318-325.
5. Snelling J, Sahai A, Ellis H. Attitudes of medical and dental students to dissection. Clin Anat. 2003;16(2):165-172.
6. Coulehan JL, Williams PC, Landis D, Naser C. The first patient: reflections and stories about the anatomy cadaver. Teach Learn Med. 1995;7(1):61-66.
7. Druce M, Johnson MH. Human dissection and attitudes of pre-clinical students to death and bereavement. Clin Anat. 1994;7:42-49.
8. Nnodim JO. Preclinical student reactions to dissection, death, and dying. Clin Anat. 1996;9(3):175-182.
9. Marks SC, Bertman SL, Penney JC. Human anatomy: a foundation for education about death and dying in medicine. Clin Anat. 1997;10(2):118-122.
10. Aziz MA, McKenzie JC. The dead can still teach the living. The status of cadaver-based anatomy in the age of electronic media. Perspec Biol Med. 1999;42:402-421.
11. Dinsmore CE, Daugherty S, Zeitz HJ. Teaching and learning gross anatomy: dissection, prosection, or “both of the above?” Clin Anat. 1999;12(2):110-114.
12. Olson TR. A.D.A.M. Student Atlas of Anatomy. 2nd ed. Cambridge, MA: Lippincott, Williams & Wilkins; 2008.
13. McLachlan JC, Patten D. Anatomy teaching: ghosts of the past, present and future. Med Educ. 2006;40(3):243-253.

 

Dr. Grodberg is clinical instructor in the Department of Psychiatry at the Seaver and New York Autism Center of Excellence and Dr. Kolevzon is assistant professor of psychiatry and pediatrics in the Department of Psychiatry, both at Mount Sinai School of Medicine in New York City.

Disclosures: Dr. Grodberg receives research support from the National Institutes of Health. Dr. Kolevzon receives grant support from the Beatrice and Samuel A. Seaver Foundation, Bristol-Myers Squibb, Johnson and Johnson, the National Institutes of Health, and Neuropharm.

Please direct all correspondence to: David M. Grodberg, MD, Clinical Instructor, Department of Psychiatry, Seaver and N.Y. Autism Center of Excellence, Mount Sinai School of Medicine, One Gustave L. Levy Place, Box 1230, New York, NY 10029-6574; Tel: 212-241-3276; Fax: 212-241-5670; E-mail: david.grodberg@mssm.edu.


 

Autism is a severe neuropsychiatric disorder characterized by delays or deviation in the development of social and communication skills and the presence of restricted patterns of interests and/or stereotypic motor mannerisms. Autistic disorder is categorized under the pervasive developmental disorders (PDD) in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition–Text Revision.1 The other PDDs include Asperger’s disorder, Rett’s disorder, childhood disintegrative disorder, and pervasive developmental disorder not otherwise specified (PDD-NOS).1 The term “autism spectrum disorder” (ASD) has recently taken hold in medical practice and research and is considered to be synonymous with PDD, though not a formal DSM-IV-TR diagnosis.

Symptoms of inattention, hyperactivity, and impulsivity are common in individuals with ASD, and may be the primary reason for referral among less impaired patients with Asperger’s disorder and PDD-NOS. In fact, the earliest published accounts of autism2 extensively describe attention deficits, and these symptoms continue to be an important area of clinical focus and ongoing research. This is despite the fact that the DSM-IV-TR currently prohibits the diagnosis of attention-deficit/hyperactivity disorder (ADHD) when an underlying PDD is present.

In a recent survey3 of 487 children and adolescents with ASD, >50% had moderate to severe symptoms of inattention and hyperactivity. In another sample of 101 children with ASD,4 95% exhibited attention deficit, 50% demonstrated impulsive behavior, and 75% were found to manifest symptoms consistent with ADHD. The presence of ADHD symptoms in children with ASD is particularly important to clarify because comorbidity may predict greater impairment in activities of daily life4 and higher rates of hospitalization than otherwise exist for children with ASD alone.5

It may be possible in several ways to distinguish symptoms of ADHD in ASD from ADHD in typically developing children. For example, individuals with ASD may exhibit selective inattention to social stimuli while sustaining focus on idiosyncratic interests or inanimate objects. This type of inattention may be differentiated from the more pervasive inattention and distractibility seen in uncomplicated ADHD. Similarly, hyperactivity seen in ASD can often be manifestations of motor stereotypy, social anxiety, or agitation. In ADHD, however, typically developing children are often impulsive and motorically hyperactive as a result of inhibitory deficits.

The complex neurodevelopmental syndrome of ASD appears to contain a subgroup of affected individuals who display significant inattention, hyperactivity, and impulsivity. Yet, the precise mechanisms and treatment for these symptoms in individuals with ASD remain to be elucidated.

In this issue, Ellen J. Hoffman, MD, offers an important comprehensive review of the clinical features of ASD and of the diagnostic challenges in identifying comorbid conditions such as ADHD. Latha V. Soorya, PhD, and Danielle Halpern, PsyD, review behavioral interventions for this complicated group of patients. Alexander Kolevzon, MD, reviews the pharmacologic treatment of ADHD symptoms in patients with ASD. PP

References

1.    Diagnostic and Statistical Manual of Mental Disorders. 4th ed, text rev. Washington, DC: American Psychiatric Association; 2000.
2.    Kanner L. Autistic disturbances of affective contact. Nerv Child. 1943;2:217-250.
3.    Lecavalier L. Behavioral and emotional problems in young people with pervasive developmental disorders: relative prevalence, effects of subject characteristics, and empirical classification. J Autism Dev Disord. 2006;36(8):1101-1114.
4.    Goldstein S, Schwebach AJ. The comorbidity of pervasive developmental disorder and attention deficit hyperactivity disorder: results of a retrospective chart review. J Autism Dev Disord. 2004;34(3):329-339.
5.    Frazier JA, Biederman J, Bellordre CA, et al. Should the diagnosis of attention-deficit/hyperactivity disorder be considered in children with pervasive devlopmental disorder? J Atten Disord. 2001;4(4):203-211.

 

An expert review of clinical challenges in primary care and psychiatry

 

This supplement is supported by Pamlab.

 

Dr. Farah is chief of Psychiatry at High Point Regional Health Systems, High Point NC, and is clinical faculty at Wake Forest University, Winston-Salem NC.

Disclosures: Dr. Farah serves as consultant to and receives honoraria from Pamlab.

 

Abstract

Major depressive disorder (MDD) is a debilitating and often recurrent illness. An initial antidepressant trial is effective at achieving remission for ~30% of patients when prescribed as monotherapy, with the majority of patients returning as partial or non-responders. Switching antidepressants or adding augmentation agents are standard therapeutic options used to achieve and maintain remission. Suboptimal serum and red blood cell folate levels have been associated with a poorer response to antidepressant therapy, a greater severity of symptoms, later onset of clinical improvement, and overall treatment resistance. This Expert Review Supplement reviews the evidence for L-methylfolate as an augmentation agent in depression and discusses its clinical use elaborated by three clinical presentations.

 

Introduction

Major depressive disorder (MDD) is a debilitating illness affecting 7% to 12% of men and 20% to 25% of women.1,2 It is usually a recurrent illness, with up to 30% of patients experiencing a depressive episode lasting over 2 years.3 Depression may also increase the morbidity and mortality of numerous medical conditions, such as cardiac disease, myocardial infarction, chronic pain, diabetes, cerebrovascular events, and respiratory illnesses.4-11 The goal of antidepressant therapy is to achieve full remission and functional recovery, and continuing treatment beyond the acute phase is usually necessary to maintain remission. In contrast with full remission, individuals who experience residual symptoms, however mild, have a higher chance of experiencing one or more additional episodes.

An initial antidepressant trial is effective at achieving remission for ~30% of patients when prescribed as monotherapy, with the majority of patients returning as either partial or non-responders.12 Switching antidepressants or adding augmentation agents are standard therapeutic options used to achieve and maintain remission. Adequate levels of central nervous system (CNS) folate are likely essential for a patient to fully recover from a depressive episode. Suboptimal serum and red blood cell (RBC) folate levels have been associated with a poorer response to antidepressant therapy, a greater severity of symptoms, later onset of clinical improvement, and overall treatment resistance.13-20 Lower systemic levels of folate  can result from poor dietary intake, diabetes, various gastrointestinal disorders, hypothyroidism, renal failure, nicotine dependence, alcoholism, and a particular genetic polymorphism prevalent in 50% of the United States population,21,22 and up to 70% of depressed patients.23-26 Folate may also be depleted by numerous medications including oral contraceptives, metformin, as well as first generation anticonvulsants and lamotrigine, which are commonly used in psychiatry.

This article reviews the evidence for L-methylfolate as an augmentation agent in depression and discusses its clinical use elaborated by three clinical presentations. L-methylfolate offers a safe and tolerable alternative to traditional agents, particularly for patients at risk for lower systemic folate levels.

The Need for Improved Treatment Strategies

Depression has been traditionally considered one of the most “treatable” of all illnesses, with authors commonly citing study response rates of 50% to 70%. However, “response” as measured and defined by clinical trials has traditionally meant a reduction in score (usually 50%) on a Hamilton Rating Scale for Depression (HAM-D) or a Montgomery-Åsberg Depression Rating Scale (MADRS). A reduction in score may reflect symptomatic improvement but not full remission. In a long-term study following MDD patients, 76% of subjects who did not attain full remission (HAM-D>7) had relapsed by month 15, while a HAM-D of ≤7 was associated with a far lower likelihood of relapse (25%), by month 15.27 Thus, if recovery is only partial, patients remain at high risk for a relapse, possibly as severe as their initial episode.

Upon follow-up, patients generally fall into three categories: full remission, some response but not full remission (thus “partially responding” to antidepressants), and non-responders (Slide 1). Recent attention to the reality of low remission rates in studies and clinical practice, as well as drop-out rates, highlight the fact that a significant number of patients fail to benefit from advances in depression treatment. It is well documented that many patients discontinue antidepressant therapy due to side effects, the most common being sexual dysfunction and weight gain. Further, a perceived lack of efficacy may often lead to antidepressant discontinuation [unpublished data]. Long-term investigations of MDD patients (>10 years) indicate that depressive symptoms will often persist beyond the initial treatment phase, up to 60% of the time during long-term follow-up. The resultant disability is pervasive and chronic, and even a few depressive symptoms, though below the diagnostic threshold for MDD or even dysthymia, are associated with a significant increase in psychosocial disability compared to months in which the same patients are asymptomatic.28,29

 

 
Achieving and maintaining remission, rather than a reduction in symptom severity, should be the goal of therapy. Clinicians are faced daily with the question of what steps to take in order to achieve a full response for patients on antidepressant therapy. When no response is reported after an adequate time (generally accepted to be at least 4 weeks), and side effects are minimal, increasing the dose is a common strategy. However, if no response is reported but side effects are significant, switching agents would be preferred over dose escalation because most side effects are dose-dependent. For partial and non-responders, augmentation of antidepressants may have several advantages over dose escalation or switching.

Augmentation of Antidepressants

Practitioners currently have many effective options for depressed patients including several Food and Drug Administration approved antidepressants and several effective psychotherapies, the most common being cognitive-behavioral. Because no one treatment is universally effective, and many depressed patients do not experience a satisfactory clinical benefit from the initial treatment they receive, a series of therapies or a combination may be required.  Augmentation/combination has been generally defined as the addition of one or more agents to existing antidepressant therapy to enhance recovery and speed response. Traditional agents have included lithium, thyroid hormone (T3), buspirone, bupropion, stimulants, pindolol, and in recent years, atypical antipsychotics, and modafinil. Currently, aripiprozole is the only drug FDA-approved for adjuvant therapy in depression.

The Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial was a longitudinal, multi-center, 5-year study of common strategies for treating depression. To date, it is the United States’ largest National Institute of Mental Health funded study including over 4,000 patients. This four level trial compared traditional augmentation strategies with switching agents (Slide 2).30-34 Unlike most depression studies, in STAR*D the outcome measure was full remission. 

 

 

 
In Level 1, the initial monotherapy phase, citalopram (mean dose of 41.8 mg) was effective at achieving remission for only ~30% of subjects. This finding has been accepted as an accurate reflection of clinical experience with any initial monotherapy. The remaining 70% were randomized to either receive bupropion or buspirone augmentation, or switched to one of three antidepressants as monotherapy—bupropion, venlafaxine, or sertraline. Augmentation resulted in a 30% response, while switching antidepressants resulted in ~20% of patients achieving remission. Level 3 included those non-remitters from Level 2 who were then randomized to either T3 or lithium augmentation, resulting in remission rates of 25% and 16% respectively. A Level 3 switch to nortriptyline (NTP) or mirtazapine (MTZ) was in general less successful than Level 3 augmentation, with 20% of NTP patients and 12% of MTZ patients remitting. Level 4 treatment options (monoamine oxidase inhibitors [MAOIs] or venlafaxine–mirtazapine-combination therapy) were provided to patients who had not responded satisfactorily to previous levels of the treatment protocol, and very few experienced full remission (14% and 7% respectively).12,35

An overall analysis of STAR*D results indicates that the chances of achieving and maintaining remission in patients with difficult-to-treat depression diminishes with every additional strategy needed.  Those who fully remit early in the course of treatment have a better chance of remaining well than those who experience only symptomatic improvement. STAR*D does not tell us which treatment works better as a first or second adjunct, simply that the greatest chance of recovery appears to lie with the first two sequential treatments.

While there are advantages to switching antidepressants in some cases, augmentation has several advantages over switching antidepressants as well. It eliminates the need to taper some medications that pose a risk of withdrawal, and augmentation may allow the patient to build on the partial response already achieved rather than risk losing that response, which can occur when switching the primary agent to a newer choice. Further, some augmentation agents can often ameliorate the side effects of primary agents (such as sexual side effects) or have other benefits (eg, lower anxiety or help with insomnia). Clinicians must also be aware that potential benefits of augmentation may be countered by issues arising from polypharmacy, such as higher costs to patients and a greater potential for side effects and possible drug interactions. 

Association of Low Folate with Depression

Since the early 1960s, reports have shown a correlation between low folate levels and MDD. Since these initial findings, community studies have strengthened the association between low folate and depressive illnesses.36 Whether measuring serum, plasma, or RBC folate, patients diagnosed with MDD have been shown to have significantly lower folate levels when compared to non-depressed controls. RBC folate levels will generally reflect CNS folate levels,37 and have been demonstrated to be low in as many as 56% of depressed patients.19,38 Folate deficiency has also been linked to courses of depressions that are more severe, longer in duration, and treatment resistant.20,39-47 Suboptimal folate may also predict non-responders and partial responders, as patients with low RBC folate are 6 times more likely not to respond to antidepressant therapy and are less likely to achieve and maintain remission.15,48 The connection between folate and MDD is believed to be L-methylfolate, a necessary cofactor in the synthesis of monoamine neurotransmitters. Thus, a deficiency may result in inadequate CNS synthesis of serotonin, norepinephrine, and dopamine.49

Folate and L-methylfolate

Folate is a water soluble B vitamin (B9), considered one of the 13 essential vitamins. The primary function of folate is the transfer of methyl and formyl groups, thus, it is essential for cell growth and reproduction, the breakdown and utilization of proteins, the formation of nucleic acids, red blood cell maturation, and a variety of CNS reactions. Dihydrofolate is the dietary form found in orange juice, spinach, asparagus, beans, liver, yeast, whole grain cereals, and eggs. Folic acid is the synthetic form of folate in over-the-counter vitamins and used to fortify the food supply (to help prevent neural tube defects, the FDA mandated folic acid fortification of flour in 1998). Folic acid is also the predominant form used in prescription strength prenatal vitamins. Both folic acid and dihydrofolate are not biologically active forms of folate, but are essentially pro-drugs, and must undergo enzymatic transformation to L-methylfolate in order to be used by cells, and unlike other forms of folate, L-methylfolate readily crosses the blood-brain barrier for use in the CNS.

Almost 85% of dietary folate and nearly all supplemental folic acid is absorbed into the venous system in the proximal small intestine. The enzymatic conversion begins in the intestinal wall—it is a three step process for dihydrofolate, and a four step process for folic acid (Slide 3). Folic acid is converted to dihydrofolate (DHF) by dihydrofolate reductase enzyme (DHFR), and DHF is then converted to tetrahydrofolate (THF). The conversion of THF to 5,10-methyleneTHF follows. Finally, the conversion of 5,10-methyleneTHF to L-methylfolate is achieved by the methyltetrahydrofolate reductase enzyme (MTHFR). This last step completes the four step transformation process by which the bioactive cofactor, L-methylfolate, is made available to the brain to be used in the synthesis of monoamine neurotransmitters associated with mood regulation (serotonin, norepinephrine, and dopamine).50

 

 

 
For many, dietary folate will result in adequate delivery of L-methylfolate to the brain, however, inhibition of any of the above enzymes, or having defective, less functional forms of enzymes could result in inadequate CNS L-methylfolate levels. There are over 40 identified mutations of the MTHFR gene that codes for the enzyme responsible for the last step in the conversion of folate to L-methylfolate,51 but the three main genotypes are of particular interest. The most common genotype is the C/C which codes for a normally functioning enzyme. The C/T and T/T polymorphisms are less functional forms that result in suboptimal amounts of L-methylfolate. This variant is known as C677T polymorphism.

C677T polymorphism is characterized by a mutation at position 677 of the MTHFR gene resulting in a single amino acid substitution, rendering the MTHFR enzyme thermolabile, thus significantly reducing its activity (Slide 4).52 Numerous studies indicate an association between the C677T polymorphism and depression.52-60 In one study, 70% of depressed individuals were positive for either the heterozygous or homozygous from of the C677T polymorphism (14% T/T, 56% C/T). The C/T, or heterozygous polymorphism reduces the MTHFR activity by 35%, while for the homozygous, T/T form, enzyme activity is decreased by more than 70%. Thus depressed patients may be at significant risk for inadequate levels of CNS L-methylfolate, and thus, lower synthesis of serotonin, norepinephrine, and dopamine.26,52-58

 

 

The Evidence for L-methylfolate in Depression

There are five trials that examine folate therapy in depressive disorders. In a study59 with patients who had low or borderline low RBC folate, depressed patients on tricyclic antidepressants or MAOIs were augmented with methylfolate 15 mg (L-methylfolate 7.5 mg) experienced significantly greater clinical improvement and social improvement at 3 months (P<.02) and 6 months (P<.01) compared to patients treated with antidepressants alone. The methylfolate-augmented patients continued to improve for 6 months compared to patients augmented with placebo, and none experienced relapse. In a separate double-blind, controlled trial60 comparing methylfolate 50 mg/day  to trazodone 100 mg/day, depressed patients experienced a significant decrease in HAM-D scores at 4 and 8 weeks in both groups, with response rates in the methylfolate group at 45%, and in the trazodone group (not statistically significant) at 29%.

An open label trial61 of methylfolate as monotherapy in elderly depressed subjects demonstrated an 81% response rate (>50% reduction in HAM-D) by 6 weeks of therapy. A second monotherapy study examined a depressed population of 36 chronic alcoholics. After a week of placebo wash-out, subjects received 4 weeks of 90 mg methylfolate therapy. This dosing (30 mg TID) significantly improved depressive symptoms based on the HAM-D scale with the majority reporting improved mood and less fatigue (P<.01).62 Alpert and colleagues63 conducted an open label trial augmenting selective serotonin reuptake inhibitor (SSRIs) with folinic acid in patients who had failed at least 4 weeks of SSRI therapy. The response to folinic acid was not robust (P<.01, n=22), but it was well tolerated overall.

Clinical Presentations

Clinical Presentation # 1

EF is a 62-year-old female with Parkinson’s disease who was taking ropinirole when she presented with significant depressive symptoms. She had failed to respond to citalopram 20 mg/day at 5 weeks, and due to past weight gain and excessive anxiety while taking serotonin reuptake inhibitor and serotonin-norepinephrine reuptake inhibitors she requested no dose escalations. Symptoms included dysphoria, poor concentration, short term memory deficits, fatigue, hypersomnia, and irritability. Mindful of her request to maintain the current SRI dose, L-methylfolate was started at 7.5 mg/day. By week 4 she reported a resolution in most of her symptoms, but still had residual fatigue and felt her concentration was not baseline. L-methylfolate was doubled to 7.5 mg BID, and within 2 weeks she was in remission. L-methylfolate augmentation was well tolerated and EF remains well after 9 months of therapy.

Clinical Presentation #2

JL is a 28-year-old female who presented with severe depression of rapid postpartum onset. Symptoms included crying spells, guilty ruminations, poor memory and concentration, insomnia, fatigue, and intrusive thoughts of harming her infant. She had failed to fully respond to sertraline 150 mg/day for 4 weeks, and L-methylfolate was added, as well as lorazepam PRN. After 3 weeks of combination therapy, she had achieved remission (HAM-D of 5), and reported no further intrusive thoughts. She remains stable and euthymic at 7 months of sertraline 150 mg/day and L-methylfolate 7.5 mg/day therapy. She continues breast feeding while on these agents.

Clinical Presentation # 3

BR is a 54-year-old male who met the Diagnostic and Statistical Manual, Fourth Edition, criteria for MDD, severe without psychosis, and was suffering from fatigue, insomnia, excessive anxiety and ruminations, and suicidal thoughts. He reported stress at work and recently had placed his mother in a nursing home due to rapidly progressing dementia. He was already on escitalopram 10 mg/day without benefit. After 5 weeks, his dose was escalated to 20 mg/day, and clonazepam 1 mg TID PRN was added. He was on this new regimen for three weeks when he presented to our clinic with only modest improvement in symptoms. He reported sedation when he took clonazepam. The dose of his benzodiazepine was cut in half, and L-methylfolate was added at 7.5 mg/day. At day 10 he phoned to report he was nearly baseline, and by day 14 was euthymic. He remains stable at 10 weeks of therapy reporting no additional side effects with L-methylfolate augmentation.

Specific Populations that May Benefit

Depressed patients are known to be at risk for C677T polymorphism, which translates into lower serum levels of L-methylfolate64 and possibly lower CNS folate, and thus lower monoamine levels. Specific ethnic groups are at higher risk for the less functional forms of MTHFR. The T/T genotype is present in as many as 10% of whites, and up to 22% of samples of Hispanic or Mediterranean populations.26,54 Several other groups are also at risk for lower L-methylfolate levels, including substance abusers, smokers, and those with gastrointestinal disorders (Slide 5).   

 

Medications that are known to reduce folate levels include all first-generation anticonvulsants (phenytoin, valproic acid products, carbamazepine, primidone, and phenobarbital) and the second-generation anticonvulsant lamotrigine, which is a specific inhibitor of dihydrofolate reductase (DHFR) (Slide 6). DHFR activity is the first step necessary for the conversion of dietary folate or supplemental folic acid to L-methylfolate. Other second-generation anticonvulsants are not known to be folate depleting (though information is limited, and this cannot be ruled out). This may explain why traditional mood stabilizers have had less success at preventing or treating depression and perhaps why the antidepressant effects of lamotrigine can be lost with continued therapy over a period of weeks to months and dose escalation is not usually helpful. Other medications associated with folate depletion include oral contraceptives, acne medicine, metformin, lithium, dopaminergic medications for Parkinson’s disease and methotrexate, which, like lamotrigine, is a specific inhibitor of DHFR.

 

 

 

Mechanism of Action and Clinical Use of L-methylfolate

There are numerous CNS roles for L-methylfolate, and those affecting neurotransmitter production are believed to be critical to its antidepressant properties. L-methylfolate is thought to exert its action by enhancing synthesis of monoamine neurotransmitters, and has been categorized as a “trimonoamine modulator” because it is necessary for serotonin, dopamine, and norepinephrine synthesis.50 

Depression is well known to involve dysregulation of one or more monoamines—­serotonin (5-HT), norepinephrine (NE), and dopamine (DA). L-methylfolate  acts as an important regulator of a critical cofactor needed for neurotransmitter synthesis. The cofactor is known as tetrahydrobiopterin (BH4). L-methyloflate combines with BH2 utilizing MTHFR to synthesize BH4. The trimonoamine synthetic enzymes that require BH4 as a cofactor are tryptophanhydroxylase, the rate-limiting enzyme for 5-HT synthesis, and tyrosine hydroxylase, the rate-limiting enzyme for DA and NE synthesis (Slide 7).49,50

 

 
Another mechanism of antidepressant activity of L-methylfolate is its role in the homocysteine cycle. High CNS homocysteine levels are associated with depression, dementia, and stroke,65 as well as negative symptoms of schizophrenia.66 Homocysteine is transformed to methionine utilizing B12 and L-methylfolate, both necessary cofactors for this transformation. Methionine is then converted to s-adenyl-methionine, which serves as the methyl donor for all three monoamines—serotonin, norepinephrine, and dopamine. Thus, patients with low CNS L-methylfolate are less able to convert homocysteine to methionine, the first necessary step of the homocysteine cycle.65

Unlike antidepressants, which block the re-uptake of neurotransmitters in short supply, L-methylfolate allows necessary methyl donation for adequate formation of trimonoamines.  Results are often seen within 2 weeks, sometimes even remission. As is common with other traditional augmentation strategies, some form of early response is encouraging. Drop-out rates due to side effects are consistently similar to placebo.59-62

Safety of L-Methylfolate

The standard dose of L-methylfolate for the augmentation of antidepressants is one 7.5 mg tablet/day. No titration is necessary, and it is not associated with withdrawal symptoms at discontinuation. The maximum amount of L-methylfolate that can be absorbed in one dose is ~15 mg.67 If more than one 7.5 mg tablet/day is needed, it may be prudent to give in divided doses. All reported adverse events occur at placebo rates or lower, and overall it is an extremely well tolerated agent, allowing patients to continue L-methylfolate therapy as long as necessary to maintain remission.  There are no known contraindications and no known drug interactions. 

L-methylfolate is available by prescription and is regulated by the FDA as a prescription medical food for the specific nutritional requirements of depressed individuals with suboptimal serum, RBC, or CNS folate. It is specifically intended as adjunctive therapy for depressed patients who have only partially responded to antidepressant therapy. However, L-methylfolate may provide benefit to patients with or without serum or RBC folate deficiency, particularly if they are at risk for low neurotransmitter production. 

Placement Among Augmentation Agents

Adding an additional therapy to augment an antidepressant effect usually carries the concern of adding additional side effects or potential drug interactions.  Although buproprion and buspirone are considered well tolerated, discontinuation due to side effects in the STAR*D trial ranged from 13% to 21%. Response rates to these therapies in STAR*D approximated 30% when added to existing antidepressant therapy, and discontinuation rates were ~15%.12 The recent trend of adding antipsychotics as augmenters is worrisome as it assumes that all newer agents (those launched after clozapine) qualify as “atypical,” and this assumption has recently been challenged in the literature.68 The importance of this debate is underscored by the fact that patients with affective disorders are at higher risk for tardive dyskinesia (TD). Thus, when giving antipsychotic medications to non-psychotic individuals, one must not only consider weight and metabolic concerns, but also risks of extrapyramidal symptoms, akathisia, and TD.

There have been recent concerns about the safety of very high levels of circulating unmetabolized synthetic folic acid.69 In one study, high amounts of unmetabolized folate did lower the effectiveness of natural killer cells in postmenopausal women, yet other forms of folate, such as L-methylfolate have not been associated with such risks. High dose folic acid has been associated with toxic effects in healthy subjects70 and an increase in depressive symptoms in some studies.71

There have been eight folate studies (including all forms of folate) published thus far that evaluate the use of folate in depression,44,45,48,59-62,72 and though various forms have been used, L-methylfolate appears to be the optimal compound for augmentation, as it is the active form utilized by the CNS, and readily crosses the blood-brain barrier. It is a necessary cofactor for the synthesis of monoamine neurotransmitters. Many depressed patients are at risk for low levels of CNS folate due to lifestyle, medications, and genetics, but even those with normal CNS folate may benefit from L-methylfolate augmentation. There are no known drug interactions and no case reports to date of mania induction. L-methylfolate is a well tolerated agent which stands out as one of the safest of available augmentation options. 

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36. Morris MS, Fava M, Jacques PF, et al. Depression and folate status in the US Population. Psychother Psychosom. 2003;72(2):80-87.
37. Obeid R, Kostopoulos P, Knapp JP, et al. Biomarkers of folate and vitamin B12 are related in blood and cerebrospinal fluid. Clin Chem. 2007;53(2):326-333.
38. Alpert JE, Fava M. Nutrition and depression: the role of folate. Nutr Rev. 1997;55(5):145-149.   
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43. Gilbody S, Lewis S, Lightfoot T. Methylenetetrahydrofolate reductase (MTHFR) genetic polymorphism and psychiatric disorders: a HuGE review. Am J Epidemiology. 2007;165:1-13.
44. Coppen A, Bailey J. Enhancement of the antidepressant action of fluoxetine by folic acid: a ramdomised placebo controlled trial. J Affect Disord. 2000;60:121-130.
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46. Carney NW, Chary TK, Laundy M, et al. Red cell folate concentrations in psychiatric patients. J Affect Disord. 1990;19:207-213
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48. Alpert M, Silva RR, Pouget ER. Prediction of treatment response in geriatric depression from baseline folate level: interaction with an SSRI or a tricyclic antidepressant. J Clin Psychopharmacology. 2003;23(3):309-13.
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54. Arinami T, Yamada N, Yamakawa-Kobayashi K, et al. Methylenetetrahydrofolate reductase variant and schizophrenia/depression. Am J Med Genet. 1997;74:526-528.
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Dr. Kolevzon is assistant professor of psychiatry and pediatrics in the Department of Psychiatry at Mount Sinai School of Medicine in New York City.

Disclosure: Dr. Kolevzon receives grant support from the Beatrice and Samuel A. Seaver Foundation, Bristol-Myers Squibb, Johnson and Johnson, the National Institutes of Health, and Neuropharm.

Please direct all correspondence to:  Alexander Kolevzon, MD, Assistant Professor of Psychiatry and Pediatrics, Department of Psychiatry, Mount Sinai School of Medicine, One Gustave L. Levy Place, Box 1230, New York, NY 10029; Tel: 212-659-9134; Fax: 212-659-8710; E-mail: alexander.kolevzon@mssm.edu.


 

Focus Points

• Methylphenidate and atomoxetine can be useful in the treatment of attention-deficit/hyperactivity disorder (ADHD) symptoms in autism spectrum disorders (ASD).
• Response rates and tolerability may be lower than in typically developing individuals with ADHD.
• Patients with ASD and symptoms of ADHD, aggression, and/or self-injury may benefit from risperidone if cautiously administered and monitored.

 

Abstract

Autism is a pervasive developmental disorder defined by social impairment, language impairment, and repetitive patterns of behavior. Symptoms of attention deficit and hyperactivity frequently occur in autism and autism spectrum disorders (ASD), yet current Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision criteria prohibit the diagnosis of attention-deficit/hyperactivity disorder (ADHD) in the presence of an underlying pervasive developmental disorder. Autism is characterized by broad heterogeneity in symptoms and associated features and may be a challenge to diagnose clinically. Yet, the accurate identification of ADHD symptoms in ASD has important implications for treatment. There is a significant body of evidence to support the use of medications to treat ADHD in typically developing populations, but a relative dearth of research to explore the effect of pharmacotherapy in populations with ASD and symptoms of ADHD. This article focuses on the medication management of ADHD symptoms in ASD to evaluate the current state of evidence and help guide providers in their clinical judgment.

Introduction

Autism is a severe neurodevelopmental disorder characterized by social impairment, language impairment, and repetitive patterns of behavior. The autism spectrum, also called pervasive developmental disorders, includes Asperger’s disorder, Rett’s disorder, childhood disintegrative disorder, and pervasive developmental disorder not otherwise specified.1 Symptoms of attention deficit, impulsivity, and hyperactivity are extremely common in autism spectrum disorders (ASD), with some surveys reporting estimates of 50%2 to 75%.3 However, the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision1 precludes the diagnosis of attention-deficit/hyperactivity disorder (ADHD) if symptoms occur in the context of an underlying pervasive developmental disorder (ie, ASD). Nevertheless, some clinical symptoms of ASD and ADHD clearly overlap and the boundaries between the disorders are sometimes unclear.4

In the absence of biologic markers, clinicians must rely on behavioral characteristics using a variety of diagnostic tools in addition to a comprehensive developmental history to evaluate individuals with ASD. The use of validated diagnostic instruments, cognitive testing, and assessment of adaptive behavior functioning are crucial in developing individualized treatment plans in ASD. Symptoms of ADHD should be specifically explored and rating scales, such as the Conners’ Rating Scale5 can be distributed to parents and teachers both for diagnostic purposes and also as a means to measure improvement from baseline.

The first line of treatment in ASD is behavioral and educational interventions, though their consideration is beyond the scope of this article. Pharmacotherapy in ASD is used to target symptom domains and is not curative. While much evidence supports the use of medications to treat symptoms of ADHD in typically developing children, questions remain as to their utility in patients with developmental delays. There is a paucity of research to examine the effect of pharmacotherapy in populations with co-occurring ASD and symptoms of ADHD, with minimal data to guide providers in their clinical judgment. The following article focuses on the medication management of ADHD-related symptoms in ASD with the goal of providing clinicians with a systematic evaluation of the evidence to date.

Methods

Relevant studies were identified by searching the PubMed database for English-language articles on clinical trials of medication in the treatment of autism and autism spectrum disorders, and screening reference lists of original studies. PubMed is a National Library of Medicine service that includes citations from Medline and additional life science journals that date back to the 1950s. For inclusion in this article, identified studies used randomized controlled designs of agent versus placebo or active agent; a well-defined sample of subjects that included children, adolescents, or adults with autism or autism spectrum disorders; and at least one outcome measure with an assessment of inattention, hyperactivity, or impulsivity. Retrospective and open-label studies were also reviewed when relevant to controlled trials.

Results

Methylphenidate

Methylphenidate is a psychostimulant that binds to the presynaptic dopamine transporter decreasing reuptake and increasing synaptic dopamine in the striatum and other brain regions. Several randomized, placebo-controlled trials have explored the use of methylphenidate in ASD. Quintana and colleagues6 used 20–40 mg/day doses in 10 children with ASD and found that methylphenidate produced significant improvement in hyperactivity as compared to placebo. No significant differences in the occurrence of side effects were noted between groups, although higher doses appeared to produce a greater likelihood of insomnia and irritability. Another placebo-controlled trial by Handen and colleagues7 of 13 children with ASD and symptoms of ADHD compared doses of 0.3 and 0.6 mg/kg given 2–3 times/day. Hyperactivity improved significantly as compared to placebo and eight of the 13 children (62%) were considered responders. Five of the 13 (38%) children experienced significant side effects as compared to placebo, including social withdrawal, dullness, sadness, and irritability.

The largest controlled trial8 with methylphenidate to date was done by the Research Units of Pediatric Psychopharmacology (RUPP) Autism Network using a double-blind, placebo-controlled, crossover design in 72 children and adolescents with ASD. Methylphenidate was administered in low (.125 mg/kg), medium (.250 mg/kg), and high (.5 mg/kg) doses TID. Methylphenidate was superior to placebo on measures of inattention and hyperactivity and 49% of subjects were classified as responders. Side effects were significantly more likely to occur in patients on methylphenidate, including decreased appetite, difficulty falling asleep, irritability, and emotional outbursts. A total of 13 out of 72 subjects (18%) withdrew from the study due to adverse events and the most common reason for discontinuation was irritability (six subjects). A follow-up of the RUPP methylphenidate study by Posey and colleagues9 confirmed results from the original study using secondary outcomes to measure core symptoms of ADHD but found that hyperactivity and impulsivity were more likely to improve than inattention. Higher doses (.25–.50 mg/kg) were also more consistently effective than low doses (.125 mg/kg).

Atomoxetine

Atomoxetine is a non-stimulant, norepinephrine reuptake inhibitor which also enhances prefrontal dopaminergic transmission because the norepinephrine transporter is sensitive to dopamine in the frontal cortex. Retrospective10 and open-label studies11 of atomoxetine found significant effects on measures of hyperactivity and inattention in children and adolescents with ASD. One double-blind, placebo-controlled, crossover study12 examined the safety and efficacy for symptoms of ADHD in 16 children and adolescents with ASD. Atomoxetine was started at doses of .25 mg/kg/day and increased to a maximum dose of 1.4 mg/kg/day given in divided doses. Atomoxetine significantly improved symptoms of hyperactivity and impulsivity as compared to placebo, but results only approached significance on measures of inattention. Patients who received atomoxetine exhibited significantly more side effects, including gastrointestinal distress, fatigue, and tachycardia. Other side effects such as decreased appetite and irritability were reported but rates did not differ significantly from placebo.

Haloperidol

Haloperidol is a first-generation antipsychotic that acts by blocking postsynaptic dopamine receptors. Antipsychotics have been used extensively in developmentally disabled populations and typically developing children with ADHD. Aman and Langworthy13 identified 11 clinical trials that evaluated antipsychotics for hyperactivity in children with ASD. Four of these were controlled trials that examined the use of haloperidol.14-17 Haloperidol appears to improve hyperactivity in ASD, although results were not always consistent, depending on the outcome measure utilized.

Risperidone

Risperidone is a second-generation antipsychotic that acts by blocking postsynaptic dopamine and serotonin receptors. The remaining seven studies identified in the article by Aman and Langworthy13 used open-label designs; six were with risperidone18-23 and one examined the use of olanzapine.24 Results of these open-label trials were mostly positive and found that risperidone significantly reduces hyperactivity in ASD.

The RUPP Autism Network later conducted a large placebo-controlled trial25 of risperidone in 101 children and adolescents (5–17 years of age) to examine impact on tantrums, aggression, and self-injury. The Aberrant Behavior Checklist Irritability subscale was the primary outcome measure but the Hyperactivity subscale was also used. Risperidone was initiated at 0.5 mg/day and titrated to a maximum of 2.5 mg/day in divided doses (mean=1.8 mg/day). Risperidone significantly improved hyperactivity as compared to placebo (effect size=1). Irritability also improved significantly (effect size=1.2). Sixty nine percent of patients receiving risperidone were considered responders according to global ratings as compared to 12% of patients who received placebo. Risperidone was significantly more likely to produce side effects, including mild (49%) to moderate (24%) increases in appetite, fatigue (59%), drowsiness (49%), drooling (27%), dizziness (16%), and weight gain (2.7±2.9 kg). There was no evidence of extrapyramidal symptoms and no child required discontinuation due to side effects.

Overall, there have been at least five additional controlled trials26-30 of risperidone with positive results in patients with ASD, though not all systematically assessed symptoms of ADHD.

Clonidine

Clonidine is an alpha-2 adrenergic agonist that reduces sympathetic discharge and lowers levels of catecholamine production. Several studies31-33 have found clonidine effective in improving inattention, hyperactivity, and impulsivity in children with ADHD. In patients with ASD, clonidine has been examined in two controlled studies34,35 with a total of 15 males. The first study34 did not show improvement on measures of hyperactivity but did find improvement on global ratings of change according to both parents and clinicians. The second study35 found improvement on parent and teacher ratings of hyperactivity, irritability, and oppositional behavior, but not on the clinician ratings. Side effects included sedation and hypotension. Hyperactivity may improve due to initial sedation, and benefit appears to diminish in some cases after 6–8 weeks.35

Guanfacine

The efficacy of guanfacine, another alpha-2 agonist, was examined in two open-label studies.36,37 The first study36 was a large retrospective review of 80 children and adolescents with ASD and symptoms of ADHD. Doses ranged from 0.25–9.0 mg/day administered in divided doses (mean=2.6 mg/day) and treatment duration ranged 7–1,776 days. Twenty-seven percent of patients showed improvement in hyperactivity and 21% showed improvement in symptoms of inattention. Twenty-four percent of patients were considered responders based on global improvement scores and there was a small but statistically significant improvement on global severity ratings. Later, Scahill and colleagues37 conducted a prospective open-label trial of guanfacine in 25 children with ASD and hyperactivity with a history of non-response to methylphenidate. Doses ranged from 1–3 mg/day in divided doses. Forty-eight percent of children were considered responders and results from parent and teacher ratings of inattention and hyperactivity showed significant improvement for both symptoms across two different measures, although parent ratings demonstrated a larger effect. Both studies36,37 suggest that guanfacine was well tolerated and no serious adverse events occurred. Side effects included sedation, irritability, increased aggression and self-injury, decreased appetite, sleep disturbance, constipation, headache, and nocturnal enuresis. Heart rate, blood pressure, and electrocardiogram changes were not deemed clinically significant and did not require discontinuation for any cases in either of the studies of guanfacine.

Amantadine

Amantadine is a noncompetitive N-methyl-D-aspartate (NMDA) antagonist indicated for the treatment of Parkinson’s disease. A placebo-controlled study of amantadine by King and colleagues38 in 43 children and adolescents with ASD assessed the impact on behavioral symptoms. Amantadine was started at doses of 2.5 mg/kg/day and increased to 5 mg/kg/day BID. Significant improvement was found on clinician-rated measures of hyperactivity but not on parent-rated measures. Fifty-three percent of patients demonstrated response on measures of global improvement as compared to 25% of patients receiving placebo; however, this difference was not statistically significant. There were no significant differences in side effects between groups but the most common side effects in patients taking amantadine were insomnia and somnolence. There were no reports of hallucinations, which have been associated with higher doses of amantadine.38

Naltrexone

Naltrexone is an opiate antagonist studied in children and adolescents with ASD using open-label designs39-41 and is found to effectively reduce autistic symptoms, including hyperactivity and inattention. At least six randomized, placebo-controlled studies have also examined its efficacy,42-47 although results from these trials are mixed. Campbell and colleagues42 found that hyperactivity was significantly improved according to parent and teacher ratings on the Conners Rating Scale, whereas Willemsen-Swinkels and colleagues43 reported no significant improvement according to parent ratings, but teacher ratings did find improvement in hyperactivity. In contrast, Kolmen and colleagues44 found significant improvement on parent ratings, but not on teacher ratings. Both the Willemsen-Swinkels and colleagues45 and Kolmen and colleagues44 also measured activity level using an actometer and no difference was found between the naltrexone and placebo groups. Bouvard and colleagues46 examined the use of naltrexone in 10 children with ASD using a placebo-controlled design and again no significant differences were found. None of the controlled trials with naltrexone reported significant differences in side effect profiles as compared to placebo.

Other Medications

Many other medications have been studied in ASD, but few specifically measured symptoms of ADHD, and a list of these trials is beyond the scope of this article. Some studies have shown promise for several selective serotonin reuptake inhibitors, tianeptine, divalproex sodium, lamotrigine, and omega-3 fatty acids, among others. However, to date, no additional randomized controlled trials have found evidence to support their use for symptoms of ADHD in ASD.

Conclusion

Methylphenidate and atomoxetine are both typically used to treat ADHD and are also effective in ASD. Recently, Santosh and colleagues48 conducted a retrospective and an open-label prospective trial to compare response to stimulants (methylphenidate or dextroamphetamine) between children with ASD and ADHD and children with ADHD alone, and found no significant differences in treatment response or side-effect profiles between groups. However, other studies suggest that response rates of methylphenidate may differ in ASD as compared to what is reported in typically developing children with ADHD alone. The National Institute of Mental Health Collaborative Multisite Multimodal Treatment Study of Children with ADHD (MTA) reported response rates of 70% to 80% as compared to the 49% reported in the RUPP Autism Network trial of methylphenidate.8 In terms of tolerability, 18% of subjects in the RUPP trial withdrew, yet discontinuation rates were quite low in the MTA study (1.4%). While methylphenidate may improve irritability in ADHD without ASD, it appears to worsen irritability in some patients with ASD. In the only controlled study of atomoxetine,12 results were significantly better than placebo, but the sample size was small and only seven of 16 children (43%) were considered responders. Overall, both methylphenidate and atomoxetine appear to effectively treat ADHD-related symptoms in ASD. However, response rates may be lower in ASD plus ADHD than in ADHD alone, and symptoms of inattention may be less likely to respond than symptoms of hyperactivity and impulsivity. Finally, treatment success may be limited by tolerability.

Many studies have demonstrated efficacy for antipsychotics, and since the RUPP trial with risperidone25 this medication in particular has consistently shown benefit for hyperactivity in ASD.26,27,49,50 In 2006, The United States Food and Drug Administration approved risperidone for the treatment of irritability in ASD in children and adolescents 5–16 years of age. Symptoms of aggression and self-injury are especially distressing for patients with ASD and their families, and risperidone is an effective pharmacotherapeutic option for this symptom constellation. However, significant concerns about tolerability remain and suggest that benefits of this medication must be carefully weighed against the risks. Metabolic monitoring, nutritional counseling, and a physical activity regimen should be included for all children treated with risperidone.

Evidence from controlled studies of alpha-2 agonists for ADHD-related symptoms in ASD is inconsistent and response rates are relatively low. Open-label studies of guanfacine appear promising but additional controlled studies are needed. alpha-2 agonists may, nevertheless, be a reasonable alternative or augmentation strategy and have the advantage of being relatively benign. Amantadine and other NMDA antagonists are interesting compounds to consider in the treatment of ASD but their use for ADHD-related symptoms is limited by a relative dearth of evidence and only one controlled trial to date. Despite multiple controlled trials, naltrexone appears to exert minimal benefit and inconsistent results indicate that isolated findings should be interpreted with caution.

Regardless of medication choice, treatment of children and adolescents with ASD should be initiated at very low starting dosages using very slow titration schedules. Benefits must be carefully weighed against risks, and future research would benefit from systematic assessment of side effects to clarify safety profiles and identify patients who are most vulnerable. Future studies to specifically examine treatment of ADHD symptoms in ASD should utilize specific outcome measures that clearly assess medication impact on symptoms of inattention, hyperactivity, and impulsivity.

Several weaknesses of this article are important to note. First, its focus is primarily on studies of children and adolescents because inattention and hyperactivity occur more commonly in this population. Second, mental retardation has not been adequately addressed. The presence of mental retardation may play a role in predicting treatment response and some studies suggest a trend for lower response rates for patients with mental retardation. Despite this, many studies have demonstrated the efficacy of stimulant medications, for example, in patients with mental retardation,51-56 though some investigators have suggested that an IQ of ≥45 is required in order to see favorable effects.53,54 However, among the studies reviewed above which specifically examined IQ as a moderator of methylphenidate response, none showed a significant effect.7,8,57 Third, there is limited discussion of methodologic weaknesses of the studies reviewed because the focus has been primarily on randomized controlled trials. This selection bias does not imply that controlled trials are beyond criticism, and is not intended to dismiss the value of case reports, case series, and open-label trials. Finally, and despite best efforts, some relevant studies may not have been included in this article. PP

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e-mail: ns@mblcommunications.com

 

Dr. Sussman is editor of Primary Psychiatry as well as professor of psychiatry and interim chairman in the Department 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.


 

The function of any medical journal is to provide readers with information that can be translated into better understanding their patients, their illnesses, and the most effective ways to prevent or treat those conditions. As editor of Primary Psychiatry, I endeavor each month to ensure that the content of the publication is accurate and balanced. Topics for issues and individual articles are selected based on their merits. Despite the efforts of myself and the editorial staff, there is much more that clinicians need to know than we can print or put on our Website. Thus, like our readers, I am constantly looking for sources of easily accessed information that may be relevant to clinical decision making, teaching, and writing. 

One problem that I encounter with many psychiatry Websites is a content bias. Most contain information that is unduly weighted toward therapeutic areas or disease states that are associated with medications that are still on patent. I have been searching for a Website that I can log onto every morning, or whenever I want to scope out what is new in the field. For the most part, I have set up Google alerts to notify me about reports involving topics I follow.

However, just last week I was pleasantly surprised when my colleague at the New York University School of Medicine, David L. Ginsberg, MD, alerted me to a Website I had never visited called MedlinePlus.1 There is no advertising on this Website. The home page has a feature on current health news, which provides access to late-breaking articles of interest. A person can search for specific topics as well. For example, I was interested in anticonvulsants and birth defects, mainly because these drugs are frequently used to treat bipolar disorder. My search directed me to a very helpful article2 from a neurology journal that I would not otherwise run across. I read the following:

“The finding of worse anatomic and neurodevelopmental outcomes following fetal valproate exposure in multiple studies suggests that it poses a special risk. Thus, it seems prudent not to use valproate as a first choice antiepileptic drug in women of childbearing age. When valproate is employed in women of childbearing potential, dosage should be kept as low as possible since its effect appears to be dose dependent…. Lamotrigine and carbamazepine may have a specific risk for cleft lip/palate but with an overall modest risk for major malformations.”

MedlinePlus gathers information from National Library of Medicine, the National Institutes of Health, and other government agencies and health-related organizations. Preformulated MEDLINE searches are included and link to medical journal articles. There are numerous links to other sites that are very useful. To test the Website, I clicked on the topic “Panic Disorder” on the link to ClinicalTrials.gov. It provided specific information about 36 clinical trials that are currently recruiting subjects. This Website will prove very helpful for clinicians who want to refer patients to research protocols.

While I hope that readers continue to consider Primary Psychiatry and its Website3 as a regular source of information, the fact is that in the Internet age, no single Website can provide comprehensive access to emerging clinical and research publications. I would appreciate readers letting me know of Websites that they find helpful, and in a future issue we can publish a list of these sites.

I want call attention to a review article in this issue by Jagoda Pasic, MD, and colleagues, discussing factitious disorders, a puzzling, curious, but nevertheless serious illness. Patients with factitious disorder perplex caregivers in terms of accounting for the patient’s motivation in feigning illness, making the diagnosis, and determining how to treat the disorder once it is recognized. As the authors note, these cases are especially challenging in the initial, emergency department setting, where clinicians have no access to historic data. Even if factitious illness is suspected, genuine illness needs to ruled out. The authors present two patients who sought emergency psychiatric care and discuss diagnostic and treatment issues. They offer psychological explanations for staff and clinicians’ reactions and suggest interventions that may prove useful in the emergency setting.

I also want to welcome David N. Neubauer, MD, who, starting with this issue, will contribute a regular column entitled “Clinical Updates in Sleep Medicine.” Dr. Neubauer is associate director of the Johns Hopkins Sleep Disorders Center and assistant professor in the Department of Psychiatry at the Johns Hopkins University School of Medicine in Baltimore, Maryland.

Finally, I would like to thank the excellent and hard work of our peer reviewers, without whom we could not maintain the high standards of the journal. PP

References

1.    MedLinePlus. Available at: http://medlineplus.gov. Accessed December 10, 2008.
2.    Meador KJ, Pennell PB, Harden CL, et al. Pregnancy registries in epilepsy: a consensus statement on health outcomes. Neurology. 2008;71(14):1109-1117.
3.    Primary Psychiatry. Available at: www.primarypsychiatry.com. Accessed December 16, 2008.

 

Dr. Soorya is assistant professor of psychiatry and Dr. Halpern is clinical instructor in the Department of Psychiatry at the Mount Sinai School of Medicine in New York City.

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

Please direct all correspondence to: Latha V. Soorya, PhD, Department of Psychiatry, Mount Sinai School of Medicine, One Gustave Levy Place, Box 1230, New York, NY 10029; Tel: 212-241-7250; E-mail: latha.soorya@mssm.edu.


 

Focus Points

• Autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD) share several similar cognitive and behavioral impairments including motor functions, executive functions/behavioral regulation, and socialization.
• Behavioral interventions for shared deficits across ASD and ADHD include socialization skills therapies and behavior management strategies.
 

Abstract

Autism spectrum disorders (ASDs) and attention-deficit/hyperactivity disorder (ADHD) are among the most commonly diagnosed psychiatric syndromes in childhood. While the syndromes have unambiguous distinctions, ADHD and ASD share several common cognitive and behavioral disturbances including deficits in behavior regulation, deficits associated with executive functions impairments (planning, inattention, behavioral regulation), motor coordination problems, and impairments in peer relationships/socialization. This article provides an overview of the available clinical research data on the shared cognitive and behavioral symptoms in ASD and ADHD, with a focus on implications for psychosocial treatments. Evaluating the overlap between these common developmental disorders, as well as the subset of individuals exhibiting comorbid ADHD and ASD, has potential to advance conceptualizations of each disorder including factors influencing treatment response.

Introduction

This article provides an overview of the emerging scientific literature on the shared and disassociated symptoms across autism spectrum disorders (ASDs) and attention-deficit/hyperactivity disorder (ADHD). Both neurodevelopmental disorders share several characteristics, including strong genetic liabilities and heterogeneous presentations. Findings from genetics, neurobiology, and neuropsychological studies have found intriguing overlaps between the disorders. Molecular genetics studies suggest that some genes may influence both ADHD and ASDs, with some studies finding an overlap in linkage peaks in ASD and ADHD in genome-wide scans.1 Genetic syndromes such as Fragile X also have strong associations with both ASDs and ADHD.2 Findings also support commonalities in brain abnormalities associated with both conditions, including structural and functional abnormalities of the front-striatal systems.3,4 Brieber and colleagues5 reported findings of structural abnormalities in gray matter in both ADHD and autism compared to typically developing controls, with reduced gray matter in left medial temporal lobe and higher gray matter volumes in left inferior parietal cortex. The study also reported dissociation between ASD and ADHD in volumetric gray matter development; ASD (but not ADHD) individuals exhibited increased gray matter volume in the right temporo-parietal junction, a region which may be associated with perspective-taking abilities. Such research has potential to inform conceptualizations of endophenotypes that span diagnostic categories and provide insight into variability observed in treatment response in both disorders.

This article focuses on the substantial overlap between cognitive and behavioral symptoms in ASD and ADHD, with an emphasis on psychosocial interventions which target these symptom domains across disorders. The article inherently adopts a dimensional perspective since available psychological and psychiatric interventions, particularly in ASDs, have been most successful when aimed at treating specific symptom domains (eg, impulsivity, repetitive behaviors) rather than the broad syndrome. A review of shared phenotypic features in ASD and ADHD is complicated, and tempered, by the heterogeneity within ASDs and ADHD as well as the high rates of comorbidity between the disorders.6 Leyfer and colleagues,6 in a study piloting their Autism Comorbidity Interview-Present and Lifetime Version, found that ADHD was diagnosed with autism in 31% of their sample. This rate was increased to ~55% when subsyndromal cases were included. Within their sample, 65% of the children diagnosed with ADHD had the inattentive sub-type. Furthermore, empirical literature providing joint evaluations of ASD and ADHD is in its early stages. Thus, this article draws from the available empirical and clinical literature within and across disorders, with the aim of identifying areas of potential overlap and future directions for conceptualizations of ASDs and psychosocial intervention research.

Cognitive and Behavioral Phenotypes and Interventions in ASD and ADHD

Several cognitive and behavioral domains have been evaluated in both ASDs and ADHD, including motor coordination, executive functions/behavioral regulation, and social cognition/social skills. Research questions have addressed shared versus disassociated symptoms across disorders as well as the specificity of symptom domains to either ASD or ADHD (Table).7-32

 

 

Motor Coordination

Motor coordination deficits are a well-known neurologic soft sign associated with ADHD and have been associated with various childhood disorders including ASDs.33 In ADHD, motor coordination deficits include but are not limited to manual dexterity, fine-motor speed, and hand-eye coordination, and may be more prominent in the ADHD-inattentive subtype and combined subtype.7 Neurocognitive research in ASDs have found impairments in tasks of motor speed and dexterity,8,9 gross motor development,10 posture,11 and skilled motor actions.12,13

A few studies with negative findings suggest deficits in basic motor skills may not be specific to autism, but rather are associated with delayed development.14,15 Studies with negative findings to date utilized developmental disability control groups (vs. typically developing controls). The failure to find ASD-specific deficits in studies utilizing controls for delay or disability may provide support to the intriguing, yet controversial concept of DAMP (deficits in attention, motor control, and perception),16 which proposes a syndrome characterized by deficits in motor coordination, inattentive symptoms, and deficits in visual-perceptual abililities, and which has a high co-occurance with ASDs. Such dimensional concepts may imply common treatment approaches across disorders.

Targeted Treatments for Motor Coordination

To date, targeted psychosocial treatments addressing motor coordination problems in ADHD and ASD, including physical therapy and sensory integration therapies (SIT), have received limited attention in the empirical literature. Physical therapy involves the treatment of injuries, disorders, or delays, using physical methods such as exercising specific parts of the body, in an effort to strengthen these parts or improve their range of motion. Watemberg and colleagues18 conducted a randomized trial comparing outcomes of physical therapy (vs. no treatment) in a group of 28 children with ADHD and developmental coordination disorder with findings suggesting improvements on standardized motor testing for the treatment group. Similar controlled trials of physical therapy are not available to date for individuals with ASD, nor are controlled studies of the widely used SIT. SIT involves gradually exposing a child to various sensory stimuli so as to encourage the nervous system to process, integrate, and organize sensory input. The available data on SIT is not promising; the only meta-analytic study17 of SIT suggests children receiving the therapy improved no more than children who received no treatment at all. When SIT has been compared to alternative treatments such as perceptual motor therapy and academic tutoring, there has been no difference in effect.

Executive Functions

Executive functions are among the most well-studied neurocognitive deficit in the ASD and ADHD literature. Across disorders, executive function is a broad construct consisting of several higher-order cognitive abilities (eg, working memory, response inhibition, set-shifting, planning, and monitoring skills), which govern one’s ability to perform adaptive responses to complex or novel situations. Executive function deficits are at the core of the neurocognitive profile in ADHD with findings supporting deficits in inattention, inhibition, and working memory. Less conclusive evidence is available for deficits in other executive function domains such as fluency, perseveration, and self-regulation/monitoring. The neurocognitive deficits in ADHD are present across the lifespan, familial, and specific (not associated with comorbid symptoms).19

While the presence of executive function deficits in ASD has been the subject of several investigations, the nature of the executive function problems in ASD are less established. For example, several questions remain; the profile of executive function deficits,20,22 specificity of executive function deficits to ASD, and presence across the lifespan remain to be established. Ozonoff and colleagues21 provide a comprehensive review of executive function research in ASD and suggest that when evaluating components of executive function in ASD, a consistent pattern of abilities and disabilities appear. Generally, the literature suggests that sustained attention and response inhibition are two components of executive function that are relatively preserved in ASD. In contrast, set-shifting/flexibility and planning are commonly found deficits. Deficits in other executive functions are more mixed, particularly in the area of working memory. Certain studies have found no deficits in working memory,34 with others suggesting verbal35 or spatial36 working memory deficits.

Happé and colleagues22 investigated executive function in males ages 8–16 years with ASD or ADHD and in typically developing children. The study utilized multiple measures of skills in three executive function domains, namely, response selection, flexibility, and planning/working memory. Results indicated the clinical groups performed below typically developing children on all but one variable measuring response selection. Additionally, the ADHD patients exhibited greater impairments than the ASD patients and typically developing children groups on measures of response inhibition (eg, go–no go) and planning/working memory. Specific impairments in cognitive flexibility in children with ASD were not found, in contrast to previous research. The results also found age-related improvements in executive function in children with ASD, but not ADHD. These findings suggest that observed problems in executive function in ASD may relate to delayed brain maturation, in which the frontal cortices are the last to achieve full functionality, rather than an autism-specific executive function deficit.

Targeted Treatments for Executive Functions

Psychosocial treatments of executive function deficits are emerging in the ADHD literature and are not available to date in the ASD literature. Functional impairments associated with the executive function domains of attention and inhibition are cardinal features of ADHD and common associated symptoms of ASD. Of the available psychosocial treatments for executive functions in both disorders, interventions targeting behavioral regulation are among the most well established and widely used. Studies24,25 overwhelmingly support the use of behavior therapies based on operant conditioning paradigms, focused on contingency management and identification of common predictors of problem behaviors.

In ADHD, a large pool of studies support the efficacy of behavioral parent training and behavioral classroom management in managing the core symptoms of inattention and behavioral regulation,37 although the additive value of behavioral interventions to the standard of care (ie, medication treatment) remains a contentious debate in the field.19 The behavioral interventions involve parent or teacher training in the use of effective reinforcement (eg, token systems) and punishment procedures (eg, time-out) for target behaviors (eg, following directions, completing homework). The rationale for these behavioral interventions is to provide compensatory systems for the executive function deficits found in ADHD (eg, behavioral regulation, working memory, internalized/self-directed speech).

Behavioral interventions for inattention and impulsivity in ASD generally utilize similar contingency management approaches, in combination with antecedent-based (or preventative) interventions. For example, children may appear impulsive or inattentive but the function of such outward behaviors may be related to accessing/engaging in a preoccupation. Interventions which create scheduled access to a child’s intense interests (eg, through picture activity schedules) may be helpful.

Research in ADHD includes cognitive remediation programs targeting a broad range of functional deficits associated with executive function26,37 and computerized attention training programs.23 Stevenson and colleagues23 conducted the only randomized controlled trial of targeted executive function interventions in ASD utilizing an 8–12-week psychosocial program targeting time management, organization, and planning skills in adults. Findings suggest clinically significant improvements in ADHD symptomology and organization skills, with maintenance seen 12 months post-intervention. Studies of computerized attention training have shown promise in clinic settings and untrained tasks, but have failed to show generalization outside of the lab (eg, academic settings, teacher/parent ratings of ADHD symptoms).23 Interventions directly targeting organization and planning skills in ASD have not been published to date.

Socialization Deficits and Interventions in ASD and ADHD

Social dysfunction is the central, unifying feature of ASDs and may be among the most debilitating functional impairments in both ASD and ADHD. A few recent studies38 evaluating the overlap in socialization impairments in ADHD and ASD suggest that individuals with clinically significant symptoms in both ASD and ADHD may be at greater risk for peer rejection and significant social dysfunction than individuals with ASD or ADHD alone. Furthermore, social impairment and peer rejection have been found to be predictors of long-term outcomes (eg, academic achievement and mental health).39

While similar functional outcomes are associated with the social skills deficits across ASD and ADHD, it is important to note the considerable differences in socialization problems found between disorders. In particular, children and adolescents with ADHD do not demonstrate social avoidance or deficits in social motivation; in fact, they often initiate social exchanges and often direct attention to peers during play activities. However, these individuals are frequently excitable and the intensity of their overtures is often not consistent with social situation. Research has found various deficits including difficulties with social-cognitive skills (eg, inattention to and misinterpretation of social cues), inappropriate behaviors (eg, impulsivity), and poor interpersonal skills (eg, less social involvement during conversations).40

In ADHD, social dysfunction appears in early childhood and adolescence, resulting in fewer friendships and high levels of peer rejection,27 with social dysfunction clearly exacerbated by comorbidity with aggression and conduct problems.28 Further, research has demonstrated behavioral and social differences between children and adolescents with different subtypes of ADHD as well as differences in treatment response. In particular, children with combined type ADHD, especially those who are impulsive and hyperactive, tend to be rejected and disliked, whereas children with only inattention tend to be ignored.41

In ASD, social impairments are evident from infancy and include difficulty with eye gaze, emotion recognition, play skills, social motivation, and understanding communicative intent.29 High-functioning individuals with ASD also have substantial socialization deficits, particularly in discerning subtleties of complex social interactions. For example, individuals with high functioning autism (HFA) and Asperger’s syndrome can often identify basic emotions, but research on visual scanning patterns in social situations suggest these individuals may use alternative strategies that may not be sufficient when social requirements are more complex and dynamic.42,43 Similarly, while high-functioning children with ASD may pass basic theory of mind (ie, understanding the perspectives/intentions of others), they continue to have difficulty understanding the intent behind nonliteral speech.44,45

It has been hypothesized that the basis of social problems in children with ADHD is associated with performance rather than knowledge or skills deficits. Thus, interventions in ADHD would emphasize determining when and where such skills would be useful rather than skills training, as is seen in social skills interventions in ASD.19 Further, as social impairment and peer acceptance are predictors of long-term outcome, including later peer acceptance, academic achievement, and mental health,39 these skills are also critical treatment targets for intervention in both disorders. However, at present, empirical support for existing interventions for socialization skills are limited in ASD and ADHD, although some studies suggest improvements in third-party ratings of socialization skills in children with ADHD treated with stimulants.30

Targeted Treatments: Social Skills Interventions in ASD

Treatment targets for children and adolescents with ASDs are broad and reflect the diversity of problems seen across the autism spectrum. Many of these treatments focus on the variety of socialization deficits present in individuals in this population. In lower functioning individuals deficits and treatment targets include: initiation of speech, use of appropriate speech intonation, use of appropriate facial affect and initiation and modulation of eye contact. Many of these difficulties persist into adulthood and without intervention, may increase rather than diminish with age.46

For higher functioning individuals, deficits and treatment targets include initiation of social interactions, interpretation of social cues (both verbal and nonverbal),47 and theory of mind (a skill essential to the development of friendships).48 Children with Asperger’s syndrome or HFA often do not outgrow these deficits; rather, these social difficulties may persist into adulthood, where they continue to negatively impact social, emotional, and occupational functioning. Adults with Asperger’s syndrome/HFA are far more likely than the general population to be unemployed or have jobs that are not commensurate with their cognitive skills and level of education. In addition, these adults are far less likely to have satisfying social relationships.49,50

Although social skills therapy groups are widely used in the community for individuals with Asperger’s syndrome/HFA, empirical support for these programs is limited and do not include randomized controlled trials. Preliminary studies suggest promise for social skills group therapies in Asperger’s syndrome/HFA, particularly for structured approaches such as cognitive-behavioral therapy.31 A recent article reported ~70% of studies yielded positive treatment effects for targeted social skills.32 Specific group therapies targeting social cognitive skills (eg, emotion recognition, theory of mind) are also showing promise in small-scale pilot studies (eg, social cognition training).51,52

Aside from social skills training, other commonly utilized psychosocial interventions for individuals with HFA and Asperger’s syndrome are inclusion with typically developing peers and peer-mediated social skills interventions. Research on inclusion strategies suggests that although inclusion may improve the frequency of interactions, this approach may not develop the quality of these social exchanges. Further, without concurrent targeted skills training, inclusion may not be sufficient in treating the core deficits of autism.53 As a result, a combination of target-child (addressing specific social skills) and peer-mediated approaches (teaching typical children to engage their peers with ASDs) are recommended and have some support from preliminary studies.54

While preliminary studies in both group and peer-mediated interventions suggest promise, the efficacy of these psychosocial interventions remains to be tested in controlled treatment trials. Both group therapies and peer-mediated interventions need to address the central questions of generalizability of treatment effects across settings and maintenance of treatment gains across time.

Targeted Treatments: Socialization Interventions in ADHD

Research on social skills training for children and adolescents with ADHD has produced mixed results.19 Certain studies yield positive outcomes; for example, Frankel and colleagues55 compared two groups of children with ADHD treated with stimulant medication, one group receiving concurrent social skills treatment and the other group a wait-list control. Results indicated significant benefits on both parent and teacher ratings.56 However, results of other studies are less encouraging. Sheridan and colleagues56 found no evidence that social skills training generalized to improved peer interaction in an educational setting.57 In addition, others studies yielded mixed results. Pfiffner and McBurnett57 found that short-term social skills training combined with parent training was superior to a wait-list control but only on parent ratings.

The Multimodal Treatment Study of Children with ADHD,58 the most comprehensive ADHD treatment study to date, suggests a limited role for social skills interventions in children with ADHD. Findings from this study indicated that “in young children with ADHD, there is no support for clinic-based social skills training as part of a long-term psychosocial intervention to improve social behavior.” Although children treated with stimulant medication (methylphenidate) did evidence certain social improvements when social skills intervention was integrated with methylphenidate treatment, these children demonstrated no gains in social functioning beyond those associated with stimulant treatment alone, except for the finding of greater positive responses to positive behaviors by peers and teachers in the second year of the study.

Social problems in children with ADHD are heterogeneous; as a result, research outcomes may vary with subtype. Certain research demonstrates that behaviorally based psychosocial treatment, when specifically adapted for ADHD-Inattentive subtype (ADHD-I), may be effective in reducing symptoms and impairment associated with ADHD-I, especially when parents, teachers, and children are involved. For example, Pfiffner and colleagues57 designed a social skills treatment (the Child Life and Attention Skills program) that led to statistically and clinically significant reductions in attention problems and improvement in organizational and social skills at posttreatment relative to the control group. These improvements were maintained at follow-up. The inclusion of teachers in the treatment protocol and the more intensive parent intervention likely enhanced generalization.

Although certain studies may yield promising outcomes, empirical research is limited and results are inconsistent. In particular, there are a limited number of studies using randomized assignment to treatment groups, the majority of studies involve parent and teacher awareness of treatment conditions, and studies involve an absence of alternative treatment groups and limited evidence of generalization to the school setting.

Conclusion

The study of the overlap in symptom domains of motor coordination, executive functions, and socialization skills in ASD and ADHD is relatively recent, and few conclusions can be drawn. Data on motor coordination difficulties suggests the presence of motor dysfunction across many developmental disorders, including ADHD and autism. These findings may relate to the relative vulnerability of the motor system to developmental insult. Additional research on this symptom domain may have implications for motor skills as a shared endophenotype across disorders. Research on executive functions deficits is well established with regards to its central role in the neurocognitive profiles of individuals with ADHD. In contrast, research continues to evaluate the presence and specificity of executive functions deficits in ASDs. Available data suggest the nature of executive function impairments may be qualitatively different in ADHD and ASD. Psychosocial treatments for behavioral dysregulation related to executive function in both disorders have strong empirical support and primarily include behavioral interventions based in operant conditioning theory. Promising psychosocial treatments for other executive function domains such as attention and organizational/planning skills are emerging in ADHD and may provide interesting avenues for applications in ASD.

 In the domain of socialization impairments, while both ASD and ADHD are associated with deficits in social perception and poor peer relationships, the cause and nature of these deficits appear fundamentally different. In ASD, social perceptual deficits are apparent from infancy in fundamental social skills (eg, joint attention, eye gaze), are pervasive through development, and are a defining feature of the disorder. In ADHD, social perceptual deficits are highly specific (overly negative interpretation of social cues) and appear largely related to problems with performance, rather than knowledge, of appropriate social skills. Subsequently, psychosocial interventions showing promise in ASD tend to be structured, skills-based interventions, while similar approaches have not been successful in the ADHD literature.

The present article highlights the need for ongoing research on these symptom domains, including iterative studies advancing the knowledge of efficacy of commonly used psychosocial interventions as well as investigations evaluating adapted therapies across these similar disorders. Furthermore, increased focus on the subset of individuals exhibiting clinically significant or comorbid ADHD and ASD symptoms may prove useful in understanding the variability in treatment response associated with psychosocial interventions in both disorders. PP

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Researchers Determine Rates of Self-Medication in Mood Disorders Patient

Self-medication, defined as using alcohol and/or drugs to alleviate emotional distress, is a dangerous habit for patients suffering from mood disorders. Although rates of self-medication have previously been found to be fairly high in mood disorders patients, research on this topic has been at a minimum.

James Bolton, MD, and colleagues from the University of Manitoba in Canada, studied 43,093 patients >18 years of age enrolled in the National Epidemiologic Survey on Alcohol and Related Conditions. Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, criteria was used to determine the self-medication prevalence rates for patients suffering from bipolar I disorder, bipolar II disorder, dysthymia, and major depressive disorder (MDD).

Bolton and colleagues found 2,184 patients had dysthymia, 7,822 had MDD, 1,546 had bipolar I disorder, 538 bipolar II disorder, and 8,420 had any mood disorder. Of these patients, ~24% of patients with mood disorders were self-medicated with drugs and/or alcohol. Self-medication prevalence rates by disease state were as follows: 41% of bipolar I disorder patients; ~35% of bipolar II disorders patients; ~23% of dysthymic patients; and ~23% of MDD patients.  Regarding comorbidities, the researchers found significant amounts of panic disorder and dependent personality disorder in men and high rates of generalized anxiety disorder and dependent personality disorder in women.

Due to the high rates of self-medication found in bipolar I disorder, the researchers further reviewed this subset of the overall patient population. They found that self-medication was at its highest rates during depressive episodes (~41% for bipolar I patients and ~32% for bipolar II patients). They also found patients self-medicating ~29% of the time during manic episodes and ~8% of the time during hypomanic symptoms.

 Bolton and colleagues believe that it is up to the clinician to monitor each patient’s medication misuse as well as drug and alcohol intake during treatment. They also recommend that the clinician inquire as to each patient’s reason for using drugs and alcohol during treatment.  (J Affect Disorder. 2008; epub ahead of print) –CDN

Smoking Cessation More Difficult for Patients with ADHD

For patients with attention-deficit/hyperactivity disorder (ADHD), rates of tobacco use are higher than in the general population, and smoking cessation is less likely for ADHD patients than for those without the disorder. Prior studies have shown that use of tobacco and nicotine is not only related to the presence of ADHD but may also differ in presentation depending on the increased presence of inattentive or hyperactive/impulsive symptoms, which comprise the core symptomology of ADHD. Additional studies into ADHD symptoms and smoking cessation have not been conducted. An improved understanding of the associations between ADHD subtypes, tobacco use, and smoking cessation could lead to improved smoking cessation and decreased tobacco-related mortality for patents with ADHD.

Lirio Covey, PhD, and colleagues at the Columbia University Medical Center and New York State Psychiatric Institute in New York City evaluated smoking cessation patterns of 583 adult smokers, who were treated with bupropion and nicotine patch during the 8-week study period. They sought to determine if the separate domains of ADHD—inattention or hyperactivity—affected rates of smoking cessation differently. 

All patients were evaluated for ADHD using the ADHD Current Symptom Scale. Two subtypes of ADHD were identified among all patients with the disorder: ADHD with predominate inattentive symptoms (ADHD-inattention) and ADHD with predominate hyperactive/impulsive symptoms with or without inattention (ADHD-hyperactivity/impulsivity with or without inattention). To aid smoking cessation, patients were treated with bupropion, nicotine patch, and cessation counseling. Study outcome was rate of smoking abstinence, which was measured by amount of expired carbon monoxide.

Covey and colleagues found that among all patients, 540 showed no symptoms of ADHD, 20 patients met criteria for ADHD-inattention, and 23 patients met criteria for ADHD-hyperactivity/impulsivity with or without inattention. When compared to patients without ADHD, patients with both subtypes of the disorder showed lower rates of smoking cessation. The authors also found that patients with ADHD-hyperactivity/impulsivity with or without inattention had the lowest rates of smoking cessation when compared to patients without ADHD or with ADHD-inattention. The proportion of patients without ADHD or with ADHD-inattention who abstained from smoking were also similar (55% compared to 54%).

In addition, the treatment approach of bupropion and nicotine patch was more helpful for patients with ADHD-inattention than those with ADHD-hyperactivity/impulsivity with or without inattention. Study data also found that the frequency of past major depressive disorder was highest in patients with ADHD-inattention, and the frequency of past alcohol dependence was highest in patients with ADHD-hyperactivity/impulsivity with or without inattention.

They concluded that more research is necessary for an improved understanding of ADHD, particularly the ADHD-hyperactivity/impulsivity with or without inattention subtype, and tobacco use, which could lead to early prevention of one or both of these conditions. Prior studies have shown that nicotine improves attentiveness and other performance deficits for patients with ADHD and may be used as a form of self-medication for patients, although more data in needed to understand the mechanism behind ADHD and tobacco use.  

Funding for this research was provided by the National Institute on Drug Abuse. (Nicotine Tob Res. 2008;10(12):1717-1725.) –CP

Psychiatric Diagnoses and Treatment Seeking in College Students: Findings from the NESARC

Psychiatric disorders are not uncommon among young, college-aged adults. Those attending college, however, are less likely to seek psychiatric treatment than their non-college-attending peers. This finding was reported in a recent study that assessed the differences in 1-year prevalence of psychiatric disorders, sociodemograhic correlates, and rates of treatment in United States college students, compared to peers not attending college for at least the previous year. Carlos Blanco, MD, PhD, at Columbia University Medical Center in New York City, and colleagues used data from the large (N=43,093) National Epidemiologic Survey on Alcohol and Related Conditions to conduct their subsample analyses.

The subsample comprised 2,188 college attending, and 2,904 non-college-attending adults 19–25 years of age. Approximately 50% of the subsample had at least one Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition psychiatric disorder in the previous year. The unadjusted risk for alcohol use disorders was significantly greater for college students (odds ratio=1.25; 95% CI, 1.04–1.50) than non-college-attending peers, but not after adjusting for sociodemographic characteristics (adjusted odds ratio=1.19; 95% CI, 0.98–1.44).

Diagnosis of a drug use disorder, nicotine dependence, or tobacco use were all significantly less likely to occur in those attending college, although non-college-attending subjects were more likely to receive relevant psychiatric treatment—especially regarding alcohol-use disorders.

The authors note that, overall, <25% of those with a psychiatric disorder sought treatment within the year preceding the survey. This statistic suggests that a more centralized mental healthcare structure may be helpful for college and university campuses.

This study is supported by grants from the American Foundation for Suicide  Prevention, the National Institutes of Health, and the New York State Psychiatric Institute. (Arch Gen Psychiatry. 2008;65(12):1429-1437). –LS

Association Between MDD and Adverse Cardiovascular Events May Be Due to Changes in Patient Behavior

Despite lacking data on causality, researchers have long established that major depressive disorder (MDD) and other depressive disorders increase the risk of cardiovascular disease for physically healthy patients as well as increase the likelihood of recurring adverse cardiac events for patients with existing cardiovascular disease. Understanding the causality of the relationship between MDD and adverse cardiovascular symptoms would allow for primary care physicians (PCPs), psychiatrists, and other healthcare professionals to develop treatments that would slow or stop the progression of cardiovascular disease in patients with MDD.

Mary A. Whooley, MD, of the Veteran’s Affairs Medical Center in San Francisco, California, and colleagues, evaluated 1,017 patients with stable coronary heart disease to determine why depressive symptoms are associated with an increased risk of cardiovascular events in patients with cardiovascular disease. All patients were gathered from area hospitals and followed by researchers for an average of 4.8 years after study beginning.

Depressive symptoms were assessed using the Patient Health Questionnaire (PHQ), and presence of depressive symptoms was defined as a PHQ score of ≥10. Various analyses were used to determine the rate of cardiovascular events in patients with MDD symptoms as compared to patients without MDD. Recorded cardiovascular events included heart failure, heart attack, stroke, transient ischemic attack—a temporary reduction of blood supply to the brain—or death.

Whooley and colleagues found that 341 cardiovascular events occurred during the study period. Patients with MDD symptoms had an ~50% increased risk of cardiovascular events than patients without MDD. The annual rate of cardiovascular events was 10% for the 199 patients with MDD when adjusted for age. For the 818 patients without MDD, the annual rate of cardiovascular events was 6.7% during the study period. When adjusted for the severity of cardiac disease and other factors, the authors found that patients with MDD symptoms were at a 31% increased risk of experiencing adverse cardiac events as compared to patients with depression.

In addition, after adjusting findings for particular health behaviors, including lack of physical activity, Whooley and colleagues found that there was no significant difference between patients with or without MDD and subsequent development of adverse cardiac events. However, lack of physical exercise was associated with a 44% increase in cardiovascular events for all patients. The authors concluded that although depressive symptoms are associated with cardiovascular events, this association may be due to changes in behavior—particularly lack of exercise—due to MDD symptoms.

Whooley and colleagues said that the relationship between MDD and cardiovascular events may be caused when patients with MDD symptoms do not adhere to exercise, dietary, and other recommendations by PCPs and other medical professionals, which leads to cardiovascular events. Medication adherence for this group may also be reduced when compared to patients without MDD. The authors added that these findings are useful for PCPs as they illustrate that adverse cardiovascular events could potentially be prevented if depressed patients modify certain health behaviors, such as increasing amount of exercise. (JAMA. 2008;300(20):2379-2388.) –CP


Psychiatric dispatches is written by Christopher Naccari, Carlos Perkins, Jr, and Lonnie Stoltzfoos.

 

Dr. Pasic is associate professor of psychiatry in the Department of Psychiatry and Behavioral Sciences at the University of Washington School of Medicine and medical director of the Psychiatric Emergency Services at Harborview Medical Center in Seattle, Washington. Dr. Combs is clinical assistant professor and Dr. Romm is clinical associate professor in the Department of Psychiatry at Harborview Medical Center at the University of Washington.

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

Please direct all correspondence to: Jagoda Pasic, MD, PhD, Associate Professor of Psychiatry, Department of Psychiatry and Behavioral Sciences, Harborview Medical Center, 325 Ninth Ave, Box 359896, Seattle, WA 98104-2499; Tel: 206-744-2377; Fax: 206-744-8615; E-mail: jpasic@u.washington.edu.


 

Focus Points

• The hallmark of factitious disorder is motivation to assume a sick role.
• Deception is an integral part of factitious disorder.
• Care providers must be attentive to their own responses to patients who might have the diagnosis of factitious disorder.

 

Abstract

Factitious disorders can represent diagnostic and treatment dilemmas for all clinicians who come in contact with these perplexing patients. Presentations are unusual; symptoms may be incongruent with known diagnoses or match textbook descriptions. As demanding as it may be to care for such patients in the long term, it is equally challenging to assess a case in the initial emergency department where patients can present without historic data, demonstrate the ability to deceive, have unclear motivation, and exhibit puzzling symptoms. Missing a serious condition can be disastrous but there can also be sequelae of inadvertently ordered expensive and potentially harmful treatment. This article presents two patients who sought care in the psychiatric emergency services of a large, county hospital and discusses diagnostic and treatment issues. The authors propose psychological explanations for staff and clinicians’ reactions and suggest interventions useful in the emergency setting. The article emphasizes the necessity of caring for the patient in an ethical and appropriate manner and raises issues of risk management.

Introduction

Factitious disorders, classified as major mental illnesses by the American Psychiatric Association (APA),1 can represent diagnostic and treatment dilemmas for all who come in contact with these perplexing patients. Psychiatrists and medical practitioners are confronted with individuals whose presentations are unusual, with symptoms either incongruent with known diagnostic categories or that match textbook descriptions with surprising precision. As demanding as it may be to care for such patients in the long term, it is equally challenging to assess a case in the initial, emergency treatment setting.

Identifying factitious disorder is difficult in the emergency department where patients may present without available historic data, unclear motivation, and puzzling symptoms. The literature is a less helpful diagnostic aid than with other conditions. Because deception is integral, accurate epidemiologic data is unavailable2 and causes are equally puzzling.3 Missing a serious condition can be disastrous but there can also be sequelae of inadvertently ordered expensive and potentially harmful treatment.4

This article presents two patients, one with chiefly psychological symptoms and the second whose symptoms were predominantly physical, who sought care in the psychiatric emergency services of a large, county hospital. The authors discuss diagnostic and treatment issues, propose psychological explanations for staff and clinicians’ emotional reactions,5-7 and suggest interventions useful in the emergency setting.8 The authors also emphasize the necessity of caring for the patient in an ethical and appropriate manner and raise issues of risk management.9,10

Clinical Case Reports

Case Report 1

Mr. X is a 28-year-old male who presented multiple times to the psychiatric emergency services of Seattle, Washington’s Harborview Medical Center; he had also sought care at local emergency rooms. He presented with bizarre behavior and confusion, though he showed no signs of internal preoccupation or responding to internal stimuli which would have be indicative of a true psychotic state. He was noted to be uncooperative during prior visits. Disorganized, he had been brought by ambulance at the request of the police. Medical and psychiatric history was unknown except for indication that in the past he had “lived in an institution.” Mr. X remained mute on questioning so, for considerations of safety, he was referred to the County Designated Mental Health Professionals for involuntary psychiatric admission; however, he was not detained due to insufficient evidence as required by Washington State Mental Health Law.

Although discharged, the patient declined to leave the area. He also refused to walk although he had been previously observed to ambulate. When he left the hospital, he did so with the assistance of security officers. He yelled and spat throughout the discharge process, insisting there was “something seriously wrong.” A similar scenario had occurred in previous visits; on reluctant discharge from emergency services, he publicly disrobed, walked in front of a moving car, and jumped into a construction site, dangerous and bizarre behaviors that caused the police to return him to the emergency room.

Case Report 2

Mr. Y is a 38-year-old male with an esophageal stricture previously dilated on several occasions. He presented to the emergency department because he was experiencing difficulty swallowing. His history included ingestion of objects such as tacks and safety pins, behaviors which lacked obvious external incentives. On the current occasion, a computed axial tomography scan showed the presence of a coin in his esophagus which was subsequently removed by endoscopy. His post-operative course was complicated by intentional ingestion of a pulse oximeter which had lodged in his cervical esophagus and caused respiratory difficulty. Surgeons removed this with a rigid endoscope. After evaluation by psychiatry, he was deemed neither suicidal nor homicidal and was discharged. Within 24 hours, he presented to an affiliated hospital with a razor blade in his esophagus. Psychiatric evaluation was repeated and this time he was detained by the County Designated Mental Professionals as a danger to himself.

Discussion

Factitious disorder is classified as a major mental illness by the APA.1 The Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, offers three diagnostic criteria for this condition (Table 1), including the intentional production of physical or psychological symptoms; the motivation to assume the sick role; and the absence of external incentives for this behavior. The condition can present with either physical or psychological symptoms by themselves or by a combination of the two. Variants exist and are classified as factitious disorder not otherwise specified. Munchausen’s syndrome, a chronic variant, most often presents with numerous physical symptoms. It was first described by Asher2 in 1951, who identified patients traveling from hospital to hospital to dramatically offer their complaints. Munchausen’s syndrome by proxy3 is another version of the disease in which a person, typically a parent, intentionally creates symptoms in their child so enabling the adult to identify with the sick role.

 

Prevalence and Etiology

Because of difficulty in diagnosing the disorder and deception is a prominent componant, accurate epidemiologic data is absent and long-term follow-up is almost impossible to obtain.4 Estimated prevalence rates vary from 0.1% in an Italian community study5 of 2,363 people to 9.3% of referrals of fever of unknown origin to the National Institute for Allergy and Infectious Disease. Causes are equally puzzling. One theory is that the condition develops as a result of stressful life events such as early loss and abandonment. The resulting use of the medical arena to enact life’s dramas allows them to gain control over situations where previously there was none.6

Demographics

The majority presenting with what ultimately proves to be factitious disorder are women 20–40 years of age, often employed in the medical field as nurses, medical technicians, or other health-related jobs. Common presenting conditions are self-induced wounds or infections and simulated disease states.7,8

Making the Correct Diagnosis

Accurate diagnosis is difficult. There are no specific tests to aid in assessment. Clinical acumen is vital. The patient may tell a story that seems almost unbelievable; laboratory finding may be inconsistent; and there may be inexplicable gaps in the record or the patient may refuse to allow gathering of historic data. In spite of the impulse to collect as much information as possible, regulations regarding privacy and confidentiality must be respected.9

Differential diagnosis can be perplexing. Diagnostic boundaries blur between factitious disorder, the somatoform disorders where symptoms are unconsciously generated, and malingering with its accompanying external incentives. Foremost, a genuine organic etiology of the condition must be eliminated.10

Unlike the outpatient setting where patients, after exhaustive medical work-up, are referred to a psychiatrist who diagnoses factitious disorder, several visits to an emergency department may take place before this occurs. According to one study11 of psychiatrists providing emergency services at an urban general hospital, 13% of patients were suspected of feigning symptoms.

Emergency room providers are familiar with homeless or substance-abusing patients who produce symptoms to obtain food and shelter. These individuals evoke frustration and negative reactions from the staff. However, malingerers, unlike those with factitious disorder, intentionally produce or feign symptoms by which to benefit such as economic gain in the form of disability payment or the avoidance of legal responsibility.1 Assumption of the sick role is benefit enough for those with factitious disorder. Because factitious disorders are often diagnoses of exclusion, an individual presenting in the emergency setting with physical complaints is entitled to medical screening for acute illness and stabilization. Similarly, a thorough psychiatric evaluation is warranted for a patient with psychological symptoms.

Psychodynamics Associated with Diagnosis and Treatment

Countertransference, or feelings evoked in the treator, poses problems for both patient and provider. Patients who feign illness to gain privileges afforded those in the sick role stir up strong negative reactions. Clinicians and staff respond with despair, anger, and frustration. Patients are pejoratively labeled “chronic complainers,” “difficult,” and “frequent flyers,” because they repeatedly seek healthcare services. Staff reaction may be so strong that they lose ability to respond with empathy.12

Countertransference complicates treatment. Clinicians may harbor a conviction that all patients with factitious disorder are untreatable, causing the patient to feel not only incurable but worthless. Anger, fear, aversion or disgust undermines a therapeutic alliance. The inherent drama of factitious behaviors can create inappropriate levity, titillation, or gossip, reflecting the provider’s underlying rage caused by the patient’s manipulation of his peers and practitioners. Providers, in turn, may treat the patient or referring physician with undue harshness.13 If feelings go unrecognized, there is the potential danger of missing a diagnosis of an accompanying condition or that the care provider’s anger or resignation will mobilize the patient’s resistance.13,14 Furthermore, clinicians may over-identify with the patients, who often are healthcare providers themselves, which can interfere with diagnosis and appropriate treatment.

Groves12 identified four subtypes of difficult patients. (Table 2) These descriptions can promote insight into patient behavior and clinician response. Case Report 1 may, at first, be seen as a malingerer, but on closer scrutiny can be identified as a “manipulative help-rejecter.” Case Report 2 is identified as “self-destructive denier” in combination with “dependant clinger.”

 

 

Providing Necessary Medical or Surgical Care

Surgeons are used to operating on patients for truly emergent reasons, sometimes even without obtaining consent as an urgent intervention. However, with patients who deliberately create pathology, surgeons may feel less inclined to intervene. In such cases, psychiatry consultation can be a great resource. Helpful techniques include assessment of danger to self and/or decisional capacity, validation of the surgical team’s concerns, setting limits for the patient, and maintaining a safe setting which can include assigning a constant observer or placing the patient in a room monitored by camera.

The challenge comes with a surgical team reluctant to operate because of concern that self-injurious behavior will continue. This did not occur when Case Report 2 required urgent surgical intervention because of risk of airway obstruction.

In Case Report 2, the patient exhibited disturbing behavior necessitating the involvement of more than one discipline, ie, emergency medicine, psychiatry, and otorhinolaryngology. The initial assessment was conducted by the emergency medical physician who deemed necessary the consultation for dysphagia. Because a history of self-injury and swallowing objects was noted, referral to psychiatry was also made. The psychiatrist found the patient not suicidal so recommended neither hospitalization nor involuntary detention.

Treatment: Emergency Room Interventions Beyond Medical Interventions

The literature on reports on emergency room treatment of factitious disorder patients is limited. Outside of clear-cut emergent medical procedures or medication administration, interventions with factitious disorder patients are problematic at best and carry the risk for iatrogenic harm at worst.

The authors of this article have found recommendations in the literature for office treatment and suggest that they may be adapted for use in the emergency room. Either a confrontational or non-confrontational approach has been tried by the primary physician or in conjunction with a psychiatrist.15 Reich and Gottfried9 studied 12 patients with factitious disorder confronted with their behaviors. Although it has been reported that psychosis can occur,16 none became suicidal or psychotic using this approach yet only one patient acknowledged his conduct.9 If the patient feels humiliated and exposed by confrontation, no matter how sensitively handled, proceeding with any therapy is difficult.

Hollender and Hersh15 advocate the non-confrontational approach. They recommend that the consulting psychiatrist avoid the role of prosecutor and try to help the patient understand behaviors identified by the primary physician.

Another technique that can be employed to allow narcissistically vulnerable patients to relinquish symptoms without threat of exposure and humiliation was developed by Eisendrath.17 He originated a “double-bind” approach. The patient is informed that his failure to respond to the next offered treatment will prove the illness is faked. The patient can simultaneously make his recovery and save face. This approach is based on the hypothesis that confrontation fails because symptoms of factitious disorder serve as an important psychological defense and can be relinquished only in an atmosphere of safety.18

There is an absence of robust research supporting the effectiveness of any management technique for factitious disorder. Eastwood and Bisson5 reviewed treatment outcomes in 32 case reports and 13 case series. They found no significant difference between confrontational and non-confrontational approaches, between treatment with psychotherapy compared to treatment with none, and with the addition or avoidance of medications. They concluded that long-term management plans which include consistent care and a holistic approach are beneficial, a model difficult to achieve in an acute hospital setting. The authors5 suggest that various strategies may be helpful but there is no definitive way to help select a particular management plan. Of note is a report of two cases ending in suicide, a reminder of the necessity of vigilance.5 One management goal is to modify patient’s often unrealistic expectations of the medical profession. The clinician should offer encouragement to cope with symptoms rather than expect a cure19 and acknowledge that the patient is manifesting physical symptoms for psychic distress. It is this distress that must be identified and treated.

It is not unreasonable to refer the patient to psychotherapy, a treatment that may be interpersonal or psychoanalytically oriented.20-23 Realistically, a referral to therapy by an emergency room provider may be immediately rejected by the patient for emotional or financial reasons.

System Interventions

While there are no evidence-based studies to suggest interventions in the emergency department, in the case of suspected or presumed factitious disorder, the authors of this article recommend the creation of a care plan, the consideration of psychiatric consultation, and, if possible, the assignment of the same provider on repeated emergency room visits (Table 3).

 

Risk Assessment

Patients with factitious disorder engage in behaviors endangering themselves. Researchers24,25 propose three types of self-harm, including direct self-harm such as self-inflicted burns; self-created disease, including symptoms produced by the application of noxious agents, such as self-inflicted hypoglycemia (Case Report 1 best fits this category); and indirect or delegated harm, which includes damage or health risks created by medical interventions provoked by the patient. In such cases, the medical staff is “delegated” to carry out a procedure due to feigned symptoms or manipulated findings as exemplified by Case Report 2.

In Case Report 1, the patient engaged in behavior that put himself at risk of serious harm (eg, jumping from a high place; inviting being hit by a car) and created his own disease. In Case Report 2, the otolaryngology team initially hesitated to operate on this patient using a procedure that by itself has potential for an adverse outcome. Controversy may exist around the question of whether patients with feigned symptoms or illness should have the same kind of treatment administered to patients with “legitimate” symptoms or diseases. However, it is the physician’s ethical duty to provide adequate care if a patient’s symptoms pose a risk of serious harm if left without intervention. The two patients received care that met community standards. In Case Report 1, an evaluation for involuntary psychiatric treatment was indicated due to self-harm behaviors, and in Case Report 2 surgery was required for foreign body removal to prevent bleeding, infection, and perforation. While hospitalization would rarely be appropriate for cases of malingering, it may be indicated for patients with factitious disorders when there is an acute medical issue or a psychiatric issue that poses imminent risk of harm to self, or the patient’s symptoms are causing grave disability. Factitious disorders are rarely associated with risk of harm to others except in cases of Munchausen’s by proxy; hence, hospitalization on this ground is not indicated.

Risk Management

Tempting as it may be to dismiss patients in the emergency department who are suspected of factitious disorder, stabilization must be provided according to the Emergency Medical Treatment and Active Labor Act (Social Security Act: Sections 1866 and 1867). An individual suspected of factitious disorder has the same rights as any patient, ie, the right to reasonable care, respect, privacy, safety, and confidentiality.26 The clinician must adequately document physical and psychological findings and include positive and negative laboratory results. If confusion is an issue, decisional capacity must be established. If the standard of care is ignored, clinicians are vulnerable for risk management review and possible litigation.

Patients with factitious disorder may refuse treatment because of anger and humiliation; they may leave against medical advice or consider themselves wronged, feelings that can motivate them to sue. While no physician is immune to a lawsuit, abiding by federally mandated regulations, adhering to the standard of care, and keeping accurate documentation are the best protective measures.

Conclusion

From personal experiences combined with a literature review, the authors of this article conclude the following. First, in spite of provider reaction, a thorough medical and psychiatric assessment should be performed on patients whether or not they are suspected of having a factitious disorder. Serious acute problems must not be overlooked. Second, every effort must be made to engage the patient in care in the acute setting to help with immediate assessment and to encourage appropriate follow-up. Third, although there is absence of robust support for any treatment, there is some evidence for trying either a confrontational or non-confrontational approach or Eisendrath’s “double-bind” technique.5,8,15,18 Fourth, hospitalization or consideration for involuntary detainment is strongly recommended when there is potential for the patient harming him or herself or when the patient lacks decisional capacity. Fifth, creation of a care plan, easily accessible in the medical record, gives the opportunity for consistent, informed assessment and treatment. Last, all involved with patient care must accurately and neutrally provide thorough documentation to minimize legal risk for the provider and accomplish good patient care. PP

References

1.    Diagnostic and Statistical Manual of Mental Disorders. 4th ed. Washington, DC: American Psychiatric Association; 1994:471-472.
2.    Asher R. Munchausen’s syndrome. Lancet. 1951;1(6650):339-341.
3.    Meadow R. Munchausen syndrome by proxy. The hinterland of child abuse. Lancet. 1977;2(8033):343-345.
4.    Fehnel CR, Brewer EJ. Munchausen’s syndrome with 20-year follow-up. Am J Psychiatry. 2006;163(3):547.
5.    Eastwood S, Bisson JI. Management of factitious disorders: a systematic review. Psychother Psychosom. 2008;77(4):209-218.
6.    Jones RM. Factitious disorders. In: Kaplan HI, Sadock BJ, eds. Comprehensive Textbook of Psychiatry. 6th ed. Baltimore, MD: Williams & Wilkins; 1995:1271-1279.
7.    Lipsitt DR. Factitious disorder and Munchausen syndrome. In: UpToDate. Schwenk TL, ed. UpToDate. Waltham, MA: 2008. Available at: www.uptodate.com. Accessed December 3, 2008.
8.    Eisendrath S. Current overview of factitious physical disorders. In: Feldman MD, Eisendrath SJ, eds. The Spectrum of Factitious Disorders. Washington, DC: American Psychiatric Association Press; 1996:195-213.
9.    Reich P, Gottfried LA. Factitious disorders in a teaching hospital. Ann Intern Med. 1983;99(2):240-247.
10.    Wise MG, Ford CV. Factitious disorders. Prim Care. 1999;26(2):315-326.
11.    Yates BD, Nordquist CR, Schultz-Ross RA. Feigned psychiatric symptoms in the emergency room. Psychiatr Serv. 1996;47(9):998-1000.
12.    Groves JE. Taking care of the hateful patient. N Engl J Med. 1978;298(16):883-887.
13.    Willenberg H. Countertransference in factitious disorder. Psychother Psychosom. 1994;62(1-2):129-134.
14.    Nadelson T. Victim, victimizer: interaction in the psychotherapy of borderline patients. Int J Psychoanal Psychother. 1976;5:115-129.
15.    Hollender MH, Hersh SP. Impossible consultation made possible. Arch Gen Psychiatry. 1970;23(4):343-345.
16.    Fras I, Coughlin BE. The treatment of factitial disease. Psychosomatics. 1971;12(2):117-122.
17.    Eisendrath SJ. Factitious physical disorders: treatment without confrontation. Psychosomatics. 1989;30(4):383-387.
18.    Weiss J. The integration of defences. Int J Psychoanal. 1967;48(4):520-524.
19.    Bass C, May S. Chronic multiple functional somatic symptoms. BMJ. 2002;325(7359):323-326.
20.    Schoenfeld H, Margolin J, Baum S. Munchausen syndrome as a suicide equivalent: abolition of syndrome by psychotherapy. Am J Psychother. 1987;41(4):604-612.
21.    Tucker LE, Hayes JR, Viteri AL, Liebermann TR. Factitial bleeding: successful management with psychotherapy. Dig Dis Sci. 1979;24(7):570-572.
22.    Mayo JP Jr, Haggerty JJ Jr. Long-term psychotherapy of Munchausen syndrome. Am J Psychother. 1984;38(4):571-578.
23.    Spivak H, Rodin G, Sutherland A. The psychology of factitious disorders. A reconsideration. Psychosomatics. 1994;35(1):25-34.
24.    Willenberg H, Eckhardt A, Freyberger H, Sachsse, U, Gast U. Self-destructive behavior: classification, and basic documentation. Psychotherapeut. 1997;42:211-217.
25.    Fliege H, Scholler G, Rose M, Willenberg H, Klapp BF. Factitious disorder and pathological self-harm in a hospital population: an interdisciplinary challenge. Gen Hosp Psychiatry. 2002;24(3):164-171.
26.    Medical-Legal Survival: A Risk Management Guide for Physicians. Oak Brook, IL: University Health System Consortium; 2007.

 

An expert review of clinical challenges in primary care and psychiatry

 

This supplement is supported by Pamlab.

 

Dr. Shelton is the James G. Blakemore Research Professor and Vice Chair for Research in the Department of Psychiatry at the Vanderbilt University School of Medicine.

Disclosures: Dr. Shelton serves as consultant to Eli Lilly, Pamlab, Pfizer, and Sierra; serves on the speakers bureau of Abbott, Bristol-Myers Squibb, Eli Lilly, GlaxoSmithKline, Janssen, Pfizer, Sierra, and Wyeth; and receives research support from Abbott, Eli Lilly, GlaxoSmithKline, Janssen, Pamlab, Pfizer, and Wyeth.

 

Abstract

Major depressive disorder (MDD) is a debilitating and often recurrent illness. An initial antidepressant trial is effective at achieving remission for ~30% of patients when prescribed as monotherapy, with the majority of patients returning as partial or non-responders. Switching antidepressants or adding augmentation agents are standard therapeutic options used to achieve and maintain remission. Suboptimal serum and red blood cell folate levels have been associated with a poorer response to antidepressant therapy, a greater severity of symptoms, later onset of clinical improvement, and overall treatment resistance. This Expert Review Supplement reviews the evidence for L-methylfolate as an augmentation agent in depression and discusses its clinical use elaborated by three clinical presentations.

 

Recent research, particularly the data coming out of the National Institute of Mental Health Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study,1 have highlighted the reality that depression is a difficult condition to treat to remission and even more troublesome to maintain in a remitted state. Several problems with currently available modalities emerged from that landmark study. The STAR*D program provided high quality, multi-level treatment using the best evidence-based treatments, including both medications and cognitive behavioral psychotherapy.2 Only a small proportion of patients remitted with any of the treatments at any level. A very low proportion of patients responded to treatment after Level 3 (ie, three treatment trials). At all levels, relapse rates were high even after achieving remission.

These data suggest several conclusions. Despite notions to the contrary, depression is a very difficult condition to treat to sustained remission. In addition, there appear to be significant problems with current treatment modalities; although most produce a degree of improvement, there appear to be countervailing influences that either prevent remission in the first place or that “defeat” wellness in the long run. This may be explainable by a fundamental biological substrate that resists correction to a normal baseline mood.

The accompanying article by Farah reviews the evidence for the possible effectiveness of L-methylfolate as a novel alternative to achieve remission in treatment resistant depression. Folic acid is a normal dietary constituent; unlike the past, deficiency is uncommon in the United States because of the fact that grain products are fortified with folic acid. However, simple addition of folic acid does not solve the “true folate deficiency” problem; the conversion of folic acid to its active metabolite, L-methylfolate is of low efficiency in humans, requiring four metabolic steps. Moreover, as noted by Farah, a common single nucleotide polymorphism of one of the metabolic enzymes, methyltetrahydrofolate reductase, reduces the conversion of folic acid to L-methylfolate. L-methylfolate, in turn, is involved in the synthesis of tetrahydrobiopterin, a cofactor in the synthesis of the three key neurotransmitters involved in the regulation of mood: serotonin, norepinephrine, and dopamine.

This is significant because of the fact that all of the currently available treatments require sufficient quantities of one or more of these transmitters. A synthetic deficiency of the key monoamines involved in mood regulation may, in fact, explain several of the findings noted earlier. For example, take Level 1 treatment in STAR*D: citalopram was dosed as high as 50 mg/day, which would achieve saturation levels of the serotonin transporter in most people. Clearly, sustained serotonin signaling is required to achieve and maintain the antidepressant response of serotonin selective reuptake inhibitors (SSRIs). This has been demonstrated by research that has shown that acute depletion of tryptophan, the amino acid precursor of serotonin, leads to rapid relapse in people who have achieved sustained response to an SSRI.3 Under normal conditions, serotonin is taken up presynaptically following release by the serotonin transporter, and repackaged in synaptic vesicles. However, since SSRIs block the reuptake mechanism, ongoing synthesis of serotonin is required to provide adequate levels of the transmitter to response to depolarization-dependent release. A deficiency of synthesis of serotonin, then, could be expected to either prevent remission in the first place, or increase risk of relapse.

Although there is a clear therapeutic rationale for L-methylfolate, the clinical trials data supporting its effectiveness are very limited. Five studies have evaluated the effectiveness of L-methylfolate treatment in major depression, most of which are of questionable relevance to L-methylfolate in typical treatment-resistant depression. One early report4 showed open treatment with methylfolate of patients with depression or schizophrenia with low red blood cell folate levels. Another study5 evaluated the effectiveness of 15 mg of racemic methylfolate in persons with “organic mental disorders with depression,” who also had low red blood cell folate levels. The third6 involved a monotherapy trial of 50 mg of methylfolate (roughly 25 mg of L-methylfolate) compared against an inadequate dose of trazodone (100 mg/day) in elderly depressed patients. The fourth7 was, again, a open monotherapy trial of 90 mg of methylfolate (45 mg of L-methylfolate) in depressed alcoholic patients. The closest to a real augmentation trial is the study by Alpert and colleagues8 using folinic acid, a 5-formyl derivative of folic acid that is metabolized to racemic methylfolate without the action of methyltetrahydrofolate reductase. In this project, persons who were non-responders to SSRIs were given 15-30 mg/day of folinic acid. The Hamilton Rating Scale for Depression score reduced, on average, from 19.1 to 12.8 points, a significant but modest effect. This is reflected by only 27% achieving response status—a 50% reduction in depression scores. Although suggestive of benefit, larger scale controlled clinical trials are needed before L-methylfolate can be recommended as a first-line treatment. 

References

1. Rush AJ, Trivedi MH, Wisniewski SR, et al. Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR*D report. Am J Psychiatry. 2006;163:1905-1917.
2. Fava M, Rush AJ, Trivedi MH, et al. Background and rationale for the sequenced treatment alternatives to relieve depression (STAR*D) study. Psychiatr Clin North Am. 2003;26:457-494.
3. Delgado PL, Miller HL, Salomon RM, et al. Tryptophan-depletion challenge in depressed patients treated with desipramine or fluoxetine: implications for the role of serotonin in the mechanism of antidepressant action. Biol Psychiatry. 1999;46:212-220.
4. Godfrey PS, Toone BK, Carney MW, et al. Enhancement of recovery from psychiatric illness by methylfolate. Lancet. 1990;336:392-395.
5. Passeri M, Cucinotta D, Abate G, et al. Oral 5’-methyltetrahydrofolic acid in senile organic mental disorders with depression: results of a double-blind multicenter study. Aging (Milano ). 1993;5:63-71.
6. Guaraldi GP, Fava M, Mazzi F, La Greca P. An open trial of methyltetrahydrofolate in elderly depressed patients. Ann Clin Psychiatry. 1993;5:101-105.
7. Di Palma C, Urani R, Agricola R, Giorgetti V, Della Verde G. Is methylfolate effective in relieving major depression in chronic alcoholics? A hypothesis of treatment. Curr Ther Res. 1994;55:559-568.
8. Alpert JE, Mischoulon D, Rubenstein GE, et al. Folinic acid (Leucovorin) as an adjunctive treatment for SSRI-refractory depression. Ann Clin Psychiatry. 2002;14:33-38.

 

 

This interview took place on September 23, 2008, and was conducted by Norman Sussman, MD.

 

This interview is also available as an audio PsychCastTM at http://psychcast.mblcommunications.com.

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


 

Jerome M. Siegel, PhD, is professor of psychiatry at the University of California, Los Angeles, former president of the Sleep Research Society, and the recipient of Merit and Javits awards from the National Institutes of Health and the Distinguished Scientist award from the Sleep Research Society. His laboratory has made discoveries concerning the role of hypocretin in human narcolepsy and Parkinson’s disease. He has studied the phylogeny of sleep as a clue to sleep function, discovering that the primitive mammal platypus has rapid eye movement sleep and that marine mammals can go without extended periods of sleep for long periods without ill effects.

 

What is narcolepsy?

Narcolepsy is a disorder characterized by excessive sleepiness. The four classic symptoms of narcolepsy are excessive daytime sleepiness, cataplexy, sleep paralysis, and hypnagogic hallucinations. For diagnostic purposes, excessive daytime sleepiness is usually followed up with a multiple sleep latency test. That is, the patient is given repeated opportunities to go to sleep. Narcoleptics have very short latency to the onset of rapid eye movement (REM) sleep. In clinical practice, persistent sleepiness combined with short latency to the onset of REM sleep is sufficient to diagnose narcolepsy.

What is cataplexy?

Cataplexy is a sudden loss of muscle tone triggered by the sudden onset of strong emotion. The most common trigger for cataplexy is laughter, but in some patients sudden anger and other rapid-onset emotions will trigger it as well. There is a spectrum of intensity of cataplexy. A person might fall to the floor for seconds or even minutes. More typically, there is weakness, such as the jaw or head dropping, which may be transient.

Most cases of narcolepsy with cataplexy are caused by a deficit in the peptide hypocretin (ie, orexin). In autopsy material, patients with narcolepsy with cataplexy showed a 90% loss of hypocretin cells on average. However, most patients with narcolepsy without cataplexy do not have a complete loss of hypocretin in the cerebrospinal fluid. This has lead to the question of whether these two groups, in fact, have the same disease.

Is narcolepsy adequately diagnosed?

Narcolepsy occurs in ~1 in 2,000 people in the United States. It is underdiagnosed. It used to be that >15 years would pass between the onset of symptoms and a correct diagnosis. Though that lag has been reduced, I think many patients with excessive sleepiness are not correctly diagnosed and may just be told that they need to sleep more or that they should get more exercise. Thus, they are not adequately treated. The age of onset is typically in the teens or twenties. In many cases children will not be able to stay awake in school and may be ridiculed for these symptoms. It is very important that they get correctly diagnosed and treated so that their educational and social development are not impaired.

Once narcolepsy manifests, do the intensity and frequency of symptoms change over time?

There is a progression during the year or two after the onset. Typically, the sleepiness presents first and cataplexy comes later. The onset of cataplexy can be delayed by up to 2 years or, in a few cases, more than that. Many patients with narcolepsy with cataplexy report that they have learned to reduce the cataplexy, mostly by avoiding situations that trigger it, such as anything which causes one to laugh. That in itself is quite sad.

However, I am not certain that this cognitive explanation is adequate, because in narcoleptic dogs we see the same progression. That is, the symptoms appear and then as the animal ages, the cataplexy in particular gets more and more infrequent. There is no reason to think that the dogs have any incentive to avoid cataplexy. They are not embarrassed, and the condition does not cause injury or “social” problems. Thus, it appears that with aging there may be some brain reorganization or some normal maturational change that may counter the effect of hypocretin loss on cataplexy. All in all, the general picture is that once the symptoms are established they do not continue to worsen.

Certainly, there is no generalized degeneration leading to other symptoms such as Parkinson’s disease or Alzheimer’s disease. However, a recent article1 showed that Parkinson’s disease patients do have a depletion of hypocretin cells. Though this depletion is not quite as extensive as in narcolepsy, it is still quite severe. This may account for the sleepiness that characterizes Parkinson’s disease, which is quite similar to narcolepsy in many ways. However, it is clear from examining the brains of Parkinson’s disease patients that the cause of the cell loss is not the same as in narcolepsy.

Is narcolepsy related to abnormalities in REM sleep?

In normal REM sleep, several groups of monoaminergic cells become silent. Norepinephrine-, serotonin-, and histamine-containing neurons are inhibited. This is partially responsible for the phenomena of REM sleep. In narcolepsy, these cells are no longer so well coordinated. That is, they do not all stop being active at the same time. Norepinephrine cells become inactive during waking, which never happens in the normal animal. This loss of norepinephrine activity is responsible for the loss of muscle tone in cataplexy. This presumably occurs because of the loss of hypocretin. Normally, hypocretin, an excitatory peptide, keeps the norepinephrine cells active in waking. In the absence of hypocretin, which is the case in narcolepsy, these cell groups can fall silent in waking when strong emotions are triggered. That, then, causes cataplexy.

Have you been able to identify any genetic markers for narcolepsy?

Genetic mutations can cause narcolepsy but that is extremely rare. There are only one or two human cases identified in which there is a mutation in genes synthesizing hypocretin or its receptors. Most narcoleptics do not have such mutations and do not have first-order relatives with narcolepsy. In addition, 87% of identical twins are discordant for narcolepsy, even many years after onset. One identical twin may have narcolepsy but 30 years later the other twin will still be symptom free. However, in the case of some animal models, it is entirely genetic. Two narcoleptic dogs with a mutation that inactivates a hypocretin receptor produce only narcoleptic offspring.

However, there is a genetic risk factor in human narcolepsy, namely, a particular human leukocyte antigen (HLA) subtype called DQB-10602. The HLA system is related to the immune system and mediates tissue compatibility. Most HLA-linked disorders are autoimmune in nature. Ninety-five percent of Caucasian narcoleptics have this particular HLA subtype, whereas in the general population only 20% to 30% have it. Certainly, the HLA subtype by itself is not sufficient to produce the disease. The HLA correlation suggests that narcolepsy may be an autoimmune disease. There is some direct evidence in the postmortem brains of narcoleptics of gliosis in the region of cell loss, which is an indication of prior inflammation. This suggests that something happened at symptom onset that caused these particular cells to be destroyed. In fact, adjacent cells are left untouched. This points to an immune mechanism that would recognize particular cell types, rather than just the destruction of a particular area of the brain as the cause of most human narcolepsy.

Are there any characteristic psychiatric symptoms associated with narcolepsy?

There appears to be a greater incidence of depression in narcolepsy. Although this has not been very well documented or quantified, it has been reported in an anecdotal manner. However, now that we understand that the hypocretin system is the key to this disorder, and we can work with narcoleptic animals, we notice behavioral signs that seem to be similar to depression. For example, it has long been known that narcoleptics tend not to get addicted to various drugs. They very seldom abuse drugs of treatment, such as amphetamines and g-hydroxybutyrate. It has also been documented that mice without hypocretin do not get addicted to agents that produce addiction in normal mice. We know that the hypocretin system connects very strongly to the dopamine system, which has been implicated in addictive behavior and in pleasure. Therefore, the loss of hypocretin may cause depression. This may also be the case of Parkinson’s disease, which has a similar loss of hypocretin cells and similar symptoms of depression.

Should a practitioner who suspects someone might have narcolepsy start treating it or first send the patient to a sleep lab?

I think it is always desirable to go to a sleep lab. The drugs that are prescribed are potential drugs of abuse so it is certainly highly desirable to get objective evidence that the patient has the symptoms that are diagnostic for narcolepsy before prescribing these drugs. Typically, patients will take these drugs for the rest of their lives. In the sleep center, narcolepsy with cataplexy is easily diagnosed. For narcolepsy without cataplexy it is certainly desirable to have the full electroencephalographic workup that can document that the patient has sleep-onset REM periods. Of course, excessive daytime sleepiness is quite common, and other potential causes, particularly sleep apnea, must be ruled out. Another disease category which can look like narcolepsy is idiopathic hypersomnia, where people are just sleepy all the time but do not have cataplexy or REM sleep near sleep onset.

What are the treatments for narcolepsy?

Sleepiness in narcolepsy has traditionally been treated by dextroamphetamine and methamphetamine. Methylphenidate and modafinil are also used. Tricyclic antidepressants are used if cataplexy is a major complaint. More recently, selective serotonin reuptake inhibitors such as fluoxetine have been used. Antidepressants, such as venlafaxine, protriptyline, and imipramine are also commonly used to treat cataplexy. Typically, a narcoleptic will be treated with both anticataplectic drugs and stimulants.

A relatively new drug being used is sodium oxybate (ie, g-hydroxybutyrate). Its mode of action is not well understood but it seems to help both the sleepiness and the cataplexy. It is taken in liquid form, in very large doses of up to approximately 8 grams per night. The patient has to wake up in the middle of the night to take the second half of the dose. It is inconvenient to use but it can be uniquely effective on both symptoms.

The hope is that hypocretin itself or hypocretin agonists will be used as a treatment since that is the underlying deficit. We have shown that hypocretin given to narcoleptic dogs can reverse symptoms. Deadwyler and colleagues2 showed that hypocretin can be administered by nasal inhalation to monkeys that were sleepy. It reversed the sleep deficits very effectively. Potentially, that would be a very useful treatment, but to my knowledge it has not been tested in human narcoleptics. PP

References

1.    Thannickal TC, Lai YY, Siegel JM. Hypocretin (orexin) cell loss in Parkinson’s disease. Brain. 2007;130(Pt 6):1586-1595.
2.    Deadwyler SA, Porrino L, Siegel JM, Hampson RE. Systemic and nasal delivery of orexin-A (Hypocretin-1) reduces the effects of sleep deprivation on cognitive performance in nonhuman primates. J Neurosci. 2007;27(52):14239-14247.