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. He is also medical director of the Psychiatry Mobile Treatment Program at the Johns Hopkins Bayview Medical Center.

Disclosure: Dr. Neubauer is consultant to sanofi-aventis and Takeda.

Please direct all correspondence to: David N. Neubauer, MD, Johns Hopkins Bayview Medical Center, 4940 Eastern Ave, Box 151, Baltimore, MD 21224.


 

“Health consists of having the same diseases as one’s neighbors.” —Quentin Crisp

 

I am delighted to have the opportunity to write about sleep and sleep disorders in Primary Psychiatry. I aim to bridge the emerging neuroscience of sleep with the clinical realities of sleep disorders and, along the way, share with readers the stories of some of the patients I see at the Sleep Disorders Center at Johns Hopkins in Baltimore, Maryland. I am fortunate to be able to evaluate and treat such a diverse group of patients that have trouble sleeping at night or staying awake during the daytime. Even after nearly 25 years, I continue to learn from our patients every week in the sleep clinic and from our review of challenging cases in the staff conferences. Although there are dozens of defined sleep disorders, each patient seeking help for these problems is unique.1 I am fascinated by how people view their sleep problems and the assorted methods they use in trying to improve them. Their solutions sometimes help, but other times cause new problems.

People have many different motivations for consulting doctors and other healthcare professionals about their difficulties with sleep or wakefulness. Usually, the bottom line is some degree of suffering—a sense of daytime impairment, perhaps poor concentration or excessive sleepiness, or a feeling that nighttime sleep somehow is abnormal. Patients may come in complaining of difficulty getting to sleep or staying asleep, or that their sleep simply is not refreshing. They may also describe unusual experiences or behaviors that occur during their sleep, such as kicking, walking, screaming, or eating. Sometimes, concerned spouses or other family members bring in reluctant patients, and sometimes patients are referred by doctors concerned that their symptoms might be explained by a sleep disorder. Occasionally, employers or school administrators insist on evaluations when the patient obviously is functioning poorly due to excessive sleepiness.

One key issue that must be considered in evaluating people presenting with concerns about bothersome daytime sleepiness or poor concentration is the degree to which the cause is chronic sleep insufficiency. One of my patients had seen a television program on sleep apnea and was worried that it could be the reason that he was nodding off during afternoon meetings. However, most nights he was not getting to bed until nearly midnight and he had his alarm set for 5 AM so that he could exercise before going to his office. He was surprised when his revised schedule of getting to bed earlier and sleeping a little later in the morning had a big impact on his daytime alertness. Getting enough sleep seems obvious, but often it is overlooked.

We do tend to be a sleep-deprived society. The majority of working Americans are not getting an optimum amount of sleep most nights. That is true for students as well. Our culture in general does not value sleep and there are endless distractions that lure us from the time we should be devoting to sleep. Television and the Internet are chief offenders these days. For many, work schedules and commuting time significantly undermine the ability to get adequate sleep.

Evidence regarding the negative consequences of insufficient sleep has been growing rapidly. Certainly, the sleepiness and cognitive impairment resulting from acute or chronic sleep deprivation increase the risk for mistakes and accidents, which sometimes are catastrophic. However, numerous recent reports have emphasized other adverse health effects, such as impaired glucose utilization, diabetes, obesity, hypertension, cardiovascular disease, depression, and exacerbation of pain. These may be compounded further by the presence of sleep disorders that undermine sleep quality.

A 2006 Institute of Medicine (IOM) report2 highlighted the fact that 50–70 million Americans chronically suffer from a disorder of sleep and wakefulness, and that the cumulative effects of these conditions represent a major unrecognized public health problem. Recommendations in the report included strategies to increase the awareness of these sleep-related problems both in the general public and among healthcare professionals.

In December 2008, the IOM issued a new and highly relevant report3 in response to a request by the United States Congress. Medical training traditionally has required extended periods of work with no sleep or schedules that produce chronic sleep deprivation. The resulting fatigue and sleepiness during work hours are not conducive for safety or learning. Excellent lectures and other educational programs are worthless to the residents that are nodding off. The increase in medical errors with sleep deprivation is well documented.4 While patient safety is a critical issue, so is the health and safety of the trainees. I, for one, was one of very many residents involved in an automobile accident while driving home after a night on call.5 Fortunately, the 2003 Accreditation Council on Graduate Medical Education rules for resident working hours have offered some relief for the problem. The new IOM report, however, argues that further revisions are necessary. For example, the current guidelines limit the longest consecutive period of work at 30 hours, but the IOM report suggests that this still may be associated with significant fatigue and should be revised to include protected sleep time.3

While chronic sleep deprivation is a public health problem, there are many people who do have the opportunity to get enough sleep, but nevertheless are unable achieve adequate sleep or feel too sleepy during their waking hours. Lifestyle choices still may be part of the problem, as with the excessive use of caffeine or other stimulants, or use of sedating substances that cause daytime sleepiness. Various medications also may cause these problems. However, sleep-related symptoms often result directly from primary sleep disorders.

The Quentin Crisp quote wonderfully highlights the relativity in peoples’ perception of illnesses, and it captures an important aspect of many sleep disorders. That is, people need to conclude that their experience, or symptom, is different from most other people and, therefore, is abnormal and possibly treatable. Insomnia and excessive sleepiness are perfect examples. Insomnia fundamentally is the complaint when people feel that something is wrong with their ability to fall asleep, remain asleep, or achieve refreshing good quality sleep. Typically, the insomnia complaint incorporates presumed daytime consequences that would improve if the nighttime sleep would improve. However, there are no specific criteria of how long it takes to fall asleep, the number of awakening, the total amount of sleep, or the quality of sleep that define abnormality or clinical significance. The root of insomnia is the subjective complaint. From that point, history can be elucidated and a multitude of possible influences can be explored.

Similarly, the complaint of excessive daytime sleepiness begins with a subjective experience. Fortunately, one’s ability to remain awake during the daytime can be approached objectively in a sleep laboratory with the multiple sleep latency test or the maintenance of wakefulness test. Primary sleep disorders that may result in clinically significant daytime sleepiness include obstructive sleep apnea and narcolepsy, although there are several less well-defined syndromes that may incorporate chronic or episodic excessive sleepiness. Often overlapping complaints of fatigue and the presence of medical or psychiatric comorbidities, or even other sleep disorders, complicate the evaluation of patients reporting bothersome daytime sleepiness.

It is terrific that sleep medicine has evolved and that we now have a greater appreciation of the epidemiology and pathophysiology of sleep disorders. However, we still have the problem of the under-recognition and undertreatment of sleep disorders, whether it is a form of insomnia, circadian rhythm disorder, parasomnia, restless legs syndrome, sleep-disordered breathing, or disorder of excessive sleepiness. People may be unaware of their sleep disorder, as with obstructive sleep apnea, because it is occurring during their sleep, or they may not have been educated about disorders of sleep and wakefulness.

Healthcare professionals should screen patients routinely for sleep disorders and sleep deprivation. A few quick questions about nighttime sleep and daytime alertness will find those patients that should be evaluated further. Incorporating sleep-related questions into a review of systems form is a great idea. More detailed inquiries are appropriate for patients at higher risk for sleep disorders. For example, overweight and obese patients should be asked about symptoms of obstructive sleep apnea and patients with mood or and anxiety disorders should be asked about insomnia symptoms.

In future issues, I will cover sleep disorders in greater detail and highlight new and interesting research findings related to sleep. At times I will also take broad cultural and historic perspectives regarding sleep and discuss issues related to sleep in society. I will continue to argue that a sufficient amount of good quality sleep is essential for the health of our patients and for the population at large as well. It is important that enough time be devoted to sleeping and that problems with sleep and wakefulness be evaluated and treated. Exploring the causes of sleep problems may reveal other comorbid health conditions and treating sleep disorders may represent an opportunity to decrease other health risks. PP

References

1. American Academy of Sleep Medicine. The International Classification of Sleep Disorders: Diagnostic & Coding Manual, ICSD-2. 2nd ed. Westchester, IL: American Academy of Sleep Medicine; 2005.
2. Colten HR, Altevogt BM, eds. Sleep Disorders and Sleep Deprivation: An Unmet Public Health Problem. Washington, DC: The National Academic Press; 2006.
3. Ulmer C, Wolman DM, Johns, Michael M. E., eds. Resident Duty Hours: Enhancing Sleep, Supervision, and Safety. Washington, DC: The National Academic Press; 2008.
4. Barger LK, Ayas NT, Cade BE, et al. Impact of extended-duration shifts on medical errors, adverse events, and attentional failures. PLoS Med. 2006;3(12):e487.
5. Barger LK, Cade BE, Ayas NT, et al. Extended work shifts and the risk of motor vehicle crashes among interns. N Engl J Med. 2005;352(2):125-134.

 

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.

 

Needs Assessment: Schizophrenia and other forms of psychotic illness have plagued mankind for centuries. It causes a deterioration in patients afflicted. The current agents, though helpful, only diminish the frequency and severity of positive psychotic symptoms by 20% to 30% and have less of an effect on the negative symptoms and the cognitive deterioration. There is a tremendous need to develop novel agents with unique mechanisms of action for the treatment of psychotic disorders.  

Learning Objectives:
• Identify drugs in the pipeline for the treatment of schizophrenia
• Understand the need for new medication treatment of psychotic disorders
• Understand the mechanisms involved in the development of new antipsychotics

Target Audience: Primary care physicians and psychiatrists.

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

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

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

This activity has been peer-reviewed and approved by James C.-Y. Chou, MD, associate professor of psychiatry at the Mount Sinai School of Medicine, and Norman Sussman, MD, editor of Primary Psychiatry and professor of psychiatry at New York University School of Medicine. Review Date: November 20, 2008.

Dr. Sussman reports no affiliation with or financial interest in any organization that may pose a conflict of interest. Dr. Chou receives honoraria from AstraZeneca, Bristol-Myers Squibb, Eli Lilly, GlaxoSmithKline, Janssen, and Pfizer.

To receive credit for this activity: Read this article and the two CME-designated accompanying articles, reflect on the information presented, and then complete the CME posttest and evaluation. To obtain credits, you should score 70% or better. Early submission of this posttest is encouraged: please submit this posttest by December 1, 2010 to be eligible for credit. Release date: December 1, 2008. Termination date: December 31, 2010. The estimated time to complete all three articles and the posttest is 3 hours. 

Primary Psychiatry. 2008;15(12):57-64

 

Dr. Glick is professor of psychiatry in the Department of Psychiatry and Behavioral Sciences at Stanford University School of Medicine in California. Dr. Peselow is research professor at New York University School of Medicine in New York City.

Disclosures: Dr. Glick is a consultant to Bristol-Myers Squibb, Janssen, Lundbeck, Organon, Pfizer, Shire, Solvay, and Vanda; on the speaker’s bureaus of AstraZeneca, Bristol-Myers Squibb/Otsuka, Janssen, Pfizer, and Shire; receives research support from AstraZeneca, Bristol-Myers Squibb/Otsuka, Eli Lilly, GlaxoSmithKline, the National Institute of Mental Health, Shire, and Solvay; and owns stock in Forest and Johnson and Johnson. Dr. Peselow is on the speaker’s bureaus of Forest and Pfizer.

Off-label disclosure: This article includes discussion of investigational treatments for schizophrenia or psychotic illness.

Please direct all correspondence to: Ira D. Glick, MD, Professor of Psychiatry, Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford University Medical Center, 401 Quarry Rd, Rm 2122, Stanford, CA 94305-5543; Tel: 650-723-3519; Fax: 650-723-2507; E-mail: iraglick@stanford.edu.


Abstract

Due to the severity caused by schizophrenia, it is important to develop effective treatments. The current antipsychotics, including both typical and atypical, are at best effective only partially effective. Response is usually defined as a 20% to 30% reduction in the positive symptoms (delusions, hallucinations) with a lesser affect on the negative and cognitive symptoms. There has been a tremendous effort to develop newer antipsychotics to improve outcome. This article describes the current antipsychotics in the pipeline being clinically tested. The article also describes preclinical and clinical studies on a variety of agents that affect multiple receptors that are thought to be related to etioilogy.

Introduction

Schizophrenia and other forms of psychotic illness have plagued mankind for centuries. The conceptualization of psychosis as a “mental illness,” however, has only occurred recently. The development of effective pharmacotherapy began with the development of chlorpromazine in 1952,1 which revolutionized the treatment of schizophrenia. Older agents such as haloperidol and chlorpromazine (first-generation antipsychotics [FGAs]) are very effective for managing the positive symptoms of schizophrenia but display relatively poor long-term efficacy for negative symptoms, mood disturbances, and cognitive deficits. They are also associated with debilitating extrapyramidal symptoms (EPS) and tardive dyskinesia, thus often nullifying their therapeutic effect. There were no new agents approved by the Food and Drug Administration from 1977–1988. However, the introduction of clozapine from Europe in 19892 dispelled the notion that EPS and tardive dyskinesia were inevitable conclusions of antipsychotic therapy.

The FDA approval of clozapine led to a new generation of antipsychotics which seemed to provide a broader range of efficacy (both positive and negative symptoms and less cognitive decline) with a lower risk of EPS and tardive dyskinesia versus the older agents.3 Recent work4 has suggested that the newer agents cause a great risk for the metabolic syndrome—including diabetes, weight gain, and hyperlipidemia—which might be (in the long-run) more problematic than EPS or tardive dyskinesia. Thus, the continuing need for newer, safer, more efficacious antipsychotics continues.

Second-Generation Antipsychotics

The original agents, FGAs or typical antipsychotics, were thought to act by blocking striatal dopamine (D)2 receptors; indeed, the antipsychotic potency was positively correlated with in vitro potency of the D2 receptor.5,6 The evidence for this was that positron emission tomography positively demonstrated that N-methylspiperone (a radiolabeled ligand of the D2 receptor) blocked striatal dopamine receptors.

The second-generation antipsychotics (SGAs) which included risperidone, olanzapine, quetiapine, ziprasidone, and aripiprazole were characterized by strong or stronger antagonism for the serotonin (5-HT)2 receptor than for the D2 receptor.6 These newer agents (which also include clozapine) only partially block striatal dopamine receptors and more potently block serotonin receptors in the frontal cortex.

In addition, newer antipsychotics may have more unique actions. They appear to enhance glutamatergic function at the N-methyl-D-aspartate (NMDA) receptor and block the behavioral and physiologic effects of phencyclidine, a non-competitive NMDA receptor antagonist that produces a syndrome in normal individuals that closely mimics schizophrenia.7 In addition, SGAs, while alike, often show differences that may lead one to different mechanistic possibilities. For example, aripiprazole is a high affinity partial agonist of the dopamine receptor. It displays both dopamine agonist and antagonist properties.8 The partial dopamine agonist may thus reduce dopamine synthesis and release by stimulating presynaptic dopamine autoreceptors. They may also diminish the dopaminergic signal at postsynaptic sites by competing with dopamine for postsynaptic receptors.9

Newer Drugs and Strategies in Schizophrenia

A fundamental barrier to the discovery of novel treatments remains that our level of the biologic processes involved in schizophrenia is not sufficient to predict the therapeutic value of novel drug targets. Newer agents usually represent drugs that hit known and validated targets (“me too type drugs”). It is important to note that it is important to look at specific symptoms in schizophrenia. FGAs and SGAs are efficacious in treating the positive symptoms (delusions, hallucinations, thought disorganization, and loose associations), but even here the response rate is 67% to 75% with response being a 20% to 30% reduction in overall symptoms.

However, it is the negative symptoms (alogia, avolition, flat affect, and anhedonia) along with cognitive impairments that contribute disproportionately more to the long-term disability in patients with schizophrenia.10 The negative symptoms lead to particularly poor functional capacity and quality of life. Despite the fact that there was high optimism that the SGAs represented a breakthrough for the treatment of negative symptoms, a complete response has not been shown clinically.4,11 The cognitive impairments are significant in that patients with schizophrenia have been known to have documented problems with attention, working memory, and learning in addition to executive level functions such as abstract thinking and problem solving.12,13 Thus, improved efficacy with negative symptom relief and improvement in cognition remains unsolved.

Dopaminergic Approaches

Of note, all marketed drugs to date have efficacy at the D2 receptor. Many of the drugs in Phases II and III clinical trials have the same mechanism of action as the already available agents, that is, 5-HT2A and D2 antagonism.

Iloperidone

Iloperidone, which is currently in placebo-controlled, phase III trials, affects multiple receptor sites. It is an antagonist at D2 and D3 receptors, as well as an antagonist at the 5-HT2A and 5-HT1A receptor site. It has had a long developmental process after being dropped by Novartis due to concerns that the drug may cause cardiac arrhythmias (specifically, it might increase the QT interval of the heartbeat). A study14 in the November 2001 issue of Psychiatric Times noted no cardiac abnormalities in 10 patients receiving 0.5–6.0 mg of iloperidone; however, this is an extraordinarily small sample size, and the study was sponsored by Novartis. In other words, these safety concerns have yet to be resolved in the public domain. However, iloperidone is still in development (currently in phase III FDA clinical trials). Because it acts as an antagonist on many different receptors—including several different classes of dopamine, serotonin, and norepinephrine receptors—it has the potential to alleviate a wide range of symptoms.

Bifeprunox

Bifeprunox was in phase III clinical trials until recently. It is a partial dopamine agonist/antagonist as well as a serotonin receptor agonist. It is expected that partial dopamine agonist action will have beneficial effects for positive, negative, and cognitive symptoms, while the serotonergic agonist action will help alleviate some side effects and possibly combat depression and anxiety that can accompany schizophrenia treatment. Early results report little to no weight gain, and no cardiac effects or EPS. Efficacy was uncertain, and the company investigating it has discontinued the trials.

Blonanserin

Blonanserin [AD 5423] is a combined D and 5-HT receptor antagonist currently undergoing development in Japan with Dainippon Sumitomo Pharmaceutical as a potential antipsychotic. Blonanserin is unrelated structurally to typical antipsychotics or to newer agents such as risperidone. It is hoped that the combination of receptor blockade possessed by blonanserin will be effective against both the positive and negative symptoms of schizophrenia, with a low tendency to cause EPS. Blonanserin is expected to have minimal sedative and hypotensive effects, as its adrenaline receptor-blocking function is weak.

Dainippon is conducting phase III clinical trials with oral formulations (tablet and powder) of the compound in psychotic disorders in the United States.

Ocaperidone

Ocaperidone is a D2 and 5-HT antagonist. Due to the dual-action mechanism of the drug, early research reports it to have “haloperidol-like effects” on the positive symptoms of schizophrenia, but with a lower incidence of EPS (more like the side-effect profile of risperidone). Neuro3d, the France-based developers of the medication, report that they are nearing the end of phase II clinical trials.

Nemonapride

Nemonapride (international nonproprietary name [INN]; tradename Emilace) is a dopamine receptor antagonist approved in Japan for the treatment of schizophrenia. Its mechanism of action is proposed to involve both D2 and D3 antagonism Nemonapride is a substituted benzamide antipsychotic with general antipsychotic properties–with effects on positive and negative symptoms of schizophrenia. The average daily dose of nemonapride was 18 mg/day. Plasma prolactin concentrations are significantly (P<·01) increased.

Perospirone

Perospirone (INN; trade name Lullan) is a neuroleptic in Japan. It is a D and 5-HT2A receptor antagonist. Clinical trials show that EPS tend to occur less often and were generally milder than with haloperidol.

Zuclopenthixol

Zuclopenthixol (marketed as Cisordinol, Clopixol, or Acuphase) is a typical antipsychotic neuroleptic of the thioxanthene group. It mainly acts by antagonism of D1 and D2 receptors, though it also has some antihistamine activity. It is produced and marketed by Lundbeck pharmaceutical company. It is available in three forms, namely, zuclopenthixol decanoate (clopixol), a long-acting intramuscular injection; zuclopenthixol acetate (clopixol acuphase), a shorter-acting intramuscular injection; and zuclopenthixol dihydrochloride (clopixol tablets), a tablet taken orally. Side effects, such as EPS and elevated prolactin levels, are similar to many other typical antipsychotics. In addition, the taking the drug may occasionally result in amenorrhoea or galactorrhoea in severe cases. Neuroleptic malignant syndrome is a rare but potentially fatal side effect. Zuclopenthixol is available wordwide. None of the findings suggest any clear difference between zuclopenthixol and other typical antipsycotics across a wide range of adverse effects. When compared with the newer generation of drugs, those taking zuclopenthixol were associated with no greater risk of being unchanged or worse compared with those taking risperidone.

Lurasidone

Lurasidone is an atypical antipsychotic in Japan. As of 2008, it is undergoing a Phase III clinical trial. Lurasidone blocks D1, D2 and 5-HT2A receptors. It seems to cause fewer EPS than current antipsychotics.

ACP-104

ACP-104, or N-desmethylclozapine, is the major metabolite of clozapine and is being developed by ACADIA as a novel, stand-alone therapy for schizophrenia. It combines an atypical antipsychotic efficacy profile with the added potential benefit of enhanced cognition, thereby addressing one of the major challenges in treating schizophrenia today. ACP-104 combines muscarinic (M)1 agonism, 5-HT2A inverse agonism, and D2 and D3 partial agonism in a single compound and, therefore, uniquely addresses what ACADIA believes are the three most promising target mechanisms for treating schizophrenia. As of this writing it is in phase II clinical trials. Two clinical studies15,16 showed the drug was safe with the major side effects being sleepiness, increased salivation, constipation, and tachycardia. No significant changes were observed in safety parameters such as electrocardiograph measures (including QT/QTc interval) and clinical chemistries. No EPS were observed in the patients. The Phase IIb study of ACP-104 for the treatment of schizophrenia did not meet its primary endpoint of antipsychotic efficacy (improvement in Positive and Negative Syndrome Scale (PANSS) or any of the secondary endpoints). Neither dose of ACP-104 600 mg or 800 mg demonstrated improved efficacy compared to a placebo. The drug’s future is uncertain.

BL-1020

BL-1020 is an orally available gamma-aminobutyric acid-enhanced antipsychotic clinical candidate for the treatment of schizophrenia. It is a dopamine receptor antagonist. Data from preclinical and Phase I studies demonstrated that the compound may retain the efficacy of currently available typical and atypical antipsychotics while achieving a much higher safety profile as evidenced by a lack of metabolic or EPS. In an open-label, multi-center, 6-week trial17 conducted in hospitalized patients with treatment-resistant schizophrenia, BL-1020 showed statistically significant efficacy with minimal side effects. Overall, BL-1020 treatment reduces the PANSS total score by 26.1 points from the baseline (P<.001; baseline=85.6, day 42=58.2). There was a significant (P<.001) improvement in PANSS negative score by 7.1 points when compared to baseline values (baseline=20.5, day 42=13.4). Furthermore, computer-generated imagery results showed that 92.35% of patients improved by at least one category by the end of this part of the study.

RGH-188

RGH-188 (INN; generic cariprazine), discovered by researchers at Gedeon Richter, is a novel antipsychotic which preferentially binds to D3 receptors and acts as a dopamine system stabilizer. It is also a D2 antagonist. A phase II study18 involving 389 schizophrenia patients. evaluating a primary endpoint change from baseline to Week 6 on the PANSS and RGH-188 demonstrated a nominally statistically significant (ie, not adjusted for multiple comparisons) therapeutic effect compared to placebo in the treatment of schizophrenia in the low-dose arm and a numerical improvement compared to placebo in the high dose arm that did not reach nominal statistical significance. RGH-188 was generally well tolerated and overall premature discontinuation rates (all causes including adverse event related) were 47% for patients receiving low dose of RGH-188 up to 4.5mg/day, 46% for patients receiving high dose RGH-188 up to 12 mg/day, and 47% for patients receiving placebo.

ACR-325

ACR-325 is a dopaminergic stabilizer (primarily a dopamine agonist), a new class of compounds with a unique ability to either enhance or inhibit dopamine-controlled functions depending on the initial level of dopaminergic activity. ACR-325 has also demonstrated an ability to strengthen the glutamatergic and noradrenalinergic (agonistic) functions, which is an important aspect in novel treatments of psychosis and motor dysfunctions.

In June 2008 NeuroSearch has completed Phase I evaluation ACR-325 with a highly positive outcome. The results of single- and multiple-dose studies19 in healthy volunteers show that ACR-325 has a linear and predictable pharmacokinetic profile after oral administration. Further, the compound proved very well tolerated at doses and plasma levels exceeding by far the predicted therapeutic levels.

SLV-313

SLV-313 is a combined D2 receptor antagonist and 5-HT1A receptor agonist that may improve efficacy and alleviate some side effects associated with classical antipsychotics. As a full 5-HT1A receptor agonist and full D2/3 receptor antagonist possessing characteristics of an atypical antipsychotic, it represents a potential novel treatment for schizophrenia. A phase I study randomizing patients to fixed doses of 2 mg, 5 mg, and 10 mg is currently underway.

YKP-1358

YKP-1358 is a novel 5-HT2A and D2 antagonist that, in preclinical studies, fits the general profile of an atypical antipsychotic. It is currently undergoing phase I trials.

Asenapine

Asenapine is a 5-HT and D2 antagonist, part of a class of atypical antipsychotics that have typically been more effective than medications that act only at D2 receptors. For example, clozapine, risperidone, and olanzapine all have serotonin-dopamine antagonist properties, and these drugs are popular for their low incidence of side effects (particularly EPS) and their efficacy against both positive and negative symptoms. Early data from previous trials shows good tolerability and superior efficacy when tested against placebo. Schering-Plough Corp. acquired Organon in 2007—now asenapine is currently pending FDA approval for both mania and schizophrenia.

The problem with the above drugs is that they have the same mechanism of action as the already available agents.

Attempts to Look at Various Neurotransmitter Systems to Develop New Antipsychotics

Other Dopamine Strategies: D1, D3, and D4 Receptors

The D1 receptor plays an important role in schizophrenic illness as it is thought to have a role in cognitive dysfunction.20 Chronic blockade of D2 receptors leads to down regulation of D1 receptors in the prefrontal cortex, and this produces severe working memory impairment in non-human primates. Thus, novel compounds targeted at stimulating the D1 receptor may be of great value in treating the cognitive symptoms of schizophrenia. Many drugs have been proposed, such as ZD-3638, a 5-HT2A/D2, D1 agent developed by AstraZeneca in phase II development; BSF-78438 (Abbott); and LE-300 (sanofi-aventis), the latter two in preclinical development.21

The D3 receptor is structurally similar to the D2 receptor and is, thus, a target for drug development. Interestingly, a study evaluating drug-free schizophrenics found elevated levels of D3 receptors with normal D2 receptors. A few agents are being evaluated. A-437203 is undergoing Phase II trials as is SB-773812. BP 4.879a (Bioproject), SB-277011 (GlaxoSmithKline), PD 157533 (Pfizer), U 99194A (Pfizer), and PNU 177864 are in preclinical development. The potential antipsychotic efficacy of D3 receptor antagonists remains unknown at this time but there is some suggestion that D3 receptor antagonists have a role in improving negative symptoms22 and working memory.23

The D4 receptor was initially cloned. It was noted that clozapine had a higher affinity for this receptor than for the D2 receptor, leading to speculation that the D4 receptor might be the receptor responsible for clozapine’s unique enhanced efficacy.24 However, clinical trials have not yet demonstrated any appreciable evidence of efficacy of D4 receptor antagonists in the treatment of schizophrenia.25,26 These clinical failures suggest that selective D4 antagonism alone is not responsible for the unique antipsychotic efficacy of clozapine but it is possible that D4 antagonism along with the action of other neurotransmitter receptors may be important in treating psychosis. There is some suggestion that D4 antagonism may play an important role in impulsivity and working memory.24 Pfizer has three D4 agents in clinical development, namely, PD 165167, PD 172760, and U99363E.

Serotonergic Issues

Since the atypical antipsychotics bind with higher affinity to the 5-HT2A receptors versus dopamine receptors, selective 5-HT2A receptor antagonists have been evaluated as possible antipsychotics.

Eplivanserin: A 5-HT2A/2C Receptor Antagonist

Adults with schizophrenia or schizoaffective disorder (N=481) were randomly assigned in a 3:1:1 ratio to receive fixed doses of investigational drug, placebo, or haloperidol for 6 weeks. Reductions in the PANSS total and negative scores in the group receiving the 5-HT2A/2C antagonist were equal to haloperidol and were significantly larger than those in the group receiving placebo.27

Another 5-HT2A selective antagonist, M100907, though more effective than placebo in two cumulative studies, was not as effective as haloperidol.28

The above studies suggest that although 5-HT2A receptor antagonists have antipsychotic properties, they are not superior to D2 antagonists. It does appear that 5-HT2A receptor antagonists may help with negative symptoms by elevating dopamine in the mesocortical region.29

5-HT1A agonists like clozapine have been suggested to boost dopamine levels in the prefrontal cortex. This may be responsible for clozapine’s efficacy with respect to negative symptoms and cognitive dysfunction in schizophrenics. So far, attemts to develop 5-HT1A agonists have not replicated the clinical efficacy profile of clozapine.30

The 5-HT2C, 5-HT4, and 5-HT6 receptors have also been targets of antipsychotic drug development. Selectively of the 5-HT2C receptor by decreasing dopamine in the mesolimbic and mesocortical region but not the nigrostriatal region suggests it might have antipsychotic efficacy without EPS.29 Since the 5-HT2C receptor antagonism has been shown to cause weight gain, a 5-HT2C receptor agonist may be useful in reducing food intake and weight in patients.31

The 5-HT4 receptor is prominent in the hippocampus, frontal cortex, and amygdala. This receptor is decreased in Alzheimer’s disease and, thus, 5-HT4 receptor agonists may be helpful in schizophrenia with the mechanism of increasing cholinergic transmission in the hippocampus. Thus, there is the possibility that these agents may be helpful in the cognitive dysfunction in schizophrenics.32 The affinity of clozapine and olanzapine on the 5-HT6 receptor, which preclinically improves cholinergic neurotransmission, may help with the neurocognitive deficits in schizophrenia.33

To date, human clinical studies involving the 5-HT1A, 5-HT2C, 5-HT4, and 5-HT6 agents have not been published.

Other Receptors

Alpha-adrenergic receptors may play a role in improving the cognitive functioning for schizophrenics. Indeed, alpha-adrenergic-2 receptor agonists such as clonidine and guanfacine have shown some efficacy in improving cognitive function in schizophrenics when added to standard antipsychotics.34,35 The problem with this is many alpha-adrenergic-2 receptor antagonists are traditional antipsychotics and thus a choice between alpha-adrenergic-2 receptor agonism and antagonism will be challenging.

Cholinergic Agents

Acetylcholine is important in various domains of cognition, including attention, learning, and memory. Cholinergic dysfunction is central to the treatment of Alzheimer’s disease as cholinesterase inhibitors have been shown to slow down the cognitive decline of Alzheimer’s disease and other neurodegenerative disease.36 These agents have been hypothesized to help with respect to cognitive dysfunction in schizophrenia, but the results have been disappointing.37

Muscarinic Acetylcholine Receptors

There are five types of muscarinic receptors (M1–M5), with M1 the most closely linked to schizophrenia. Clozapine and its metabolite N-desmethylclozapine bind to the M1 receptor with N-desmethylclozapine acting as a potent agonist.38

Xanomeline, an agonist at the M1 and M4 receptor with activity at 5-HT1A and 5-HT2A receptors, has shown improvement with active psychotic symptoms in a double-blind, placebo-controlled study39 assessing 10 patients receiving xanomeline versus 10 patients receiving placebo. Patients on xanomeline showed greater improvement on Brief Psychiatric Rating Scale (BPRS) and PANSS scores as well as verbal learning and short-term memory function compared with placebo.

Nicotinic-acetylcholine receptors have shown interest as schizophrenics have been shown to have significantly higher smoking rates than normal control40 and smoking has been shown to improve various measures of cognition while easing the side effects of antipsychotics.40 Considerable efforts are being made to explore the potential use of nicotinic agents in the treatment of schizophrenia.

Glutamate in Schizophrenia

The role of glutamate in schizophrenia is complex. Since phencyclidine and ketamine—both NMDA antagonists—may cause psychotic symptoms as well as worsen cognition and negative symptoms, it has been hypothesized that schizophrenia may be related to NMDA hypofunction.41 However, it is also thought that hyperactivity of the NMDA receptor may alleviate psychosis.

The NMDA receptors are ligand-gated ion channels with both a primary glutamate-binding site and an allosteric glycine-binding site. In view of the fact that a direct agonist to the glutamate-binding site may cause excessive excitation possibly giving rise to seizures, the glycine-binding site on the NMDA receptor has been the focus of much attention in the development of new antipsychotics.

NMDA receptor agonists attaching to the glycine site have been evaluated. These include the amino acids such as glycine, D-cycloserine, D-serine, and D-alanine. These agents have been added to either typical or atypical antipsychotics and show some significant benefits in reducing negative symptoms and cognitive impairment in schizophrenia.42

Other attempts to increase glycine is by inhibiting the glycine transporter. A low-potency glycine transport inhibitor, sarcosine, has been investigated in relation to schizophrenia. Early evidence suggests that intake of sarcosine 2 g/day as add-on therapy to certain antipsychotics43 in schizophrenia gives significant additional reductions in both positive and negative symptomatology as well as the neurocognitive and general psychopathologic symptoms that are common to the illness. This was not found to be the case when sarcosine was added on to clozapine.44 Sarcosine has been tolerated well. It is also under investigation for the possible prevention of schizophrenic illness during the prodromal stage of the disease. It acts as a type 1 glycine transporter inhibitor. It increases glycine concentrations in the brain, thus causing increased NMDA receptor activation and a reduction in symptoms. As such, sarcosine and other glycine transporters might be interesting treatment options and a possible new direction in the treatment of schizophrenia in the future.

Glutamate Receptor

The glutamate receptor family is subdivided into ionotropic receptors and metatropic receptors which activate G-protein coupled intracellular metabolic processes.45 NMDA, alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), and kainate are ionotropic receptors. The NMDA receptor is mainly coupled to the calcium channel while AMPA and kainate are coupled to sodium channels. Allosteric potentiation of the AMPA receptor by a group of compounds known as ampakines may help in alleviating some symptoms of schizophrenia. Indeed, the ampakine CX-516, when added to clozapine, yielded significant improvement in memory and attention,46 although when given as monotherapy it had no benefit.47

Currently, there are eight metabotropic receptors divided into three classes. Group 1, classified as mGLU R 1 and mGLU R 5, uses inositol 3P as its second messenger; Group 2, classified as mGLU R 2 and mGLU R 3, uses cyclic adenosine monophosphate (cAMP) as its second messenger; Group 3, which includes mGLU R 4, mGLU R 6 (mainly confined to the retina), mGLU R 7, and mGLU R 8, also uses cAMP as its second messenger. Selective allosteric modulators of these mGLU R receptors are being examined in schizophrenia.

Neurokinin Receptors

First identified in the 1930s, neurokinins are neurotransmitters found in the substantia nigra and striatum areas of the brain. Unlike most of the neurotransmitters identified to date, they are made from peptides rather than amino acids. They are believed to be involved in the control of movement. Their potential as therapeutic targets for drug development has only recently been suggested, but these receptors are seen as an area of rich research. The neurokinins NK1 and NK3 have been identified as suitable targets for drug development. Several antagonists to these neurokinins are now in development. Talnetant and osanetant are the two NK3 antagonists in development for schizophrenia.

NK1 has been studied with respect to depression but NK3 receptor antagonists have been evaluated in the treatment of schizophrenia. In one study,27 the group receiving the NK3 antagonist osanetant showed significantly greater improvement over baseline than the group receiving placebo as measured by PANSS total score, Clinical Global Impressions (CGI) severity of illness score, and BPRS psychosis cluster score. Talnetant has not been evaluated in clinical studies with respect to schizophrenia.

Cannabinoid Receptors

In view of the fact that there appears to be significant correlation between prior cannabis use and the development of schizophrenia, the study of the endogenous cannabinoid system has been of interest.48,49 There are two cannabinoid receptors, namely, CB1 and CB2. A selective CB1 antagonist SR 141716, while showing some preclinical antipsychotic efficacy, did not show antipsychotic efficacy versus placebo.27

Neurotensin Receptors

Neurotensin is a 13 amino acid neuropeptide that is implicated in the regulation of luteinizing hormone and prolactin release and has significant interaction with the dopaminergic system. There is evidence that since neurotensin agonists may reverse amphetamine-induced effects on hyperactivity, neurotensin may have a potential for use in schizophrenia. Clinical trials on neurotensin agonists need to be evaluated. Since there is neurotensin tone in schizophrenia, a neurotensin antagonist may be useful in schizophrenia. A recent study,27 however, showed that the neurotensin antagonist compared with haloperidol and placebo did not equal the group receiving haloperidol or differ from the group receiving placebo on any outcome measure (PANSS total score, CGI severity of illness score, and BPRS psychosis cluster score).

Conclusion

Generally, with clozapine being the ideal drug, it seems we need to develop drugs that mirror clozapine without its side-effect profile. Clozapine as the “ideal drug” has affinities for numerous receptors, including 5-HT1A, 5-HT2A, 5-HT2C, D1, D2, D3, D4, alpha-1, alpha-2, M1, M2, and H1 receptors. It would seem that this might require the use of polypharmacy and augmentation strategies, but the hope is for the development of non-selective single compounds that can target multiple domains, while decreasing side effects. Pursuing diverse molecular targets and validating these targets as effective in the treatment of schizophrenia appears to be the future for developing antipsychotics in the treatment of schizophrenia. PP

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33. Reavill C, Rogers DC. The therapeutic potential of 5-HT6 receptor antagonists. Curr Opin Investig Drugs. 2001;2(1):104-109.
34.    Fields RB, Van Kammen DP, Peters JL, et al. Clonidine improves memory function in schizophrenia independently from change in psychosis. Preliminary findings. Schizophr Res. 1988;1(6):417-423.
35.    Friedman JI, Adler DN, Howanitz E, Harvey PD, Brenner G, Temporini H, White L, Parrella M, Davis KL. A double blind placebo controlled trial of donepezil adjunctive treatment to risperidone for the cognitive impairment of schizophrenia. Biol Psychiatry. 2002;51(5):349-357.
36.    Sarter M, Bruno JP. Cognitive functions of cortical acetylcholine: toward a unifying hypothesis. Brain Res Brain Res Rev. 1997;23(1-2):28-46.
37.    Ferreri F, Agbokou C, Gauthier S. Cognitive dysfunctions in schizophrenia: potential benefits of cholinesterase inhibitor adjunctive therapy. J Psychiatry Neurosci. 2006;31(6):369-376.
38.    Sur C, Mallorga PJ, Wittmann M, et al. N-desmethylclozapine, an allosteric agonist at muscarinic 1 receptor, potentiates N-methyl-D-aspartate receptor activity. Proc Natl Acad Sci U S A. 2003;100(23):13674-13679.
39.    Shekhar A, Potter WZ, Lightfoot J, et al Selective muscarinic receptor agonist xanomeline as a novel treatment approach for schizophrenia. Am J Psychiatry. 2008;165(8):1033-1039.
40.    Kumari V, Postma P. Nicotine use in schizophrenia: the self medication hypotheses. Neurosci Biobehav Rev. 2005;29(6):1021-1034.
41.    Javitt DC. Glutamate as a therapeutic target in psychiatric disorders. Mol Psychiatry. 2004;9(11):984-997.
42.    Javitt DC. Is the glycine site half saturated or half unsaturated? Effects of glutamatergic drugs in schizophrenia patients. Curr Opin Psychiatry. 2006;19(2):151-157.
43.    Tsai G, Lane H, Yang P, Chong M, Lange N. “Glycine transporter I inhibitor, N-methylglycine (sarcosine), added to antipsychotics for the treatment of schizophrenia”. Biol Psychiatry. 2004;55(5):452-456.
44.    Lane H, Huang C, Wu P, et al. “Glycine transporter I inhibitor, N-methylglycine (sarcosine), added to clozapine for the treatment of schizophrenia”. Biol Psychiatry. 2006;60(6):645-649.
45.    Kew JN, Kemp JA. Ionotropic and metabotropic glutamate receptor structure and pharmacology. Psychopharmacology (Berl). 2005;179(1):4-29.
46.    Goff DC, Leahy L, Berman I, Posever T, Herz L, Leon AC, Johnson SA, Lynch G. A placebo-controlled pilot study of the ampakine CX516 added to clozapine in schizophrenia. J Clin Psychopharmacol. 2001;21(5):484-487.
47.    Marenco S, Egan MF, Goldberg TE, Knable MB, McClure RK, Winterer G, Weinberger DR. Preliminary experience with an ampakine (CX516) as a single agent for the treatment of schizophrenia: a case series. Schizophr Res. 2002;57(2-3):221-226.
48.    Henquet C, Murray R, Linszen D, van Os J. The environment and schizophrenia: the role of cannabis use. Schizophr Bull. 2005;31(3):608-612.
49.    Vinod KY, Hungund BL. Cannabinoid-1 receptor: a novel target for the treatment of neuropsychiatric disorders. Expert Opin Ther Targets. 2006;10(2):203-210.

 

Dr. Luo is associate clinical professor in the Department of Psychiatry and Biobehavioral Sciences at the University of California in Los Angeles; past president of the American Association for Technology in Psychiatry (AATP) in New York City; and Gores Informatics Advocacy chair at the AATP.
Disclosure: Dr. Luo is consultant to S.M.A.R.T. Link Medical, Inc., on the speaker’s bureau of Epocrates, and on the advisory board of Spyglass Consulting.


 

Today’s computers actually have more power and memory than most users need. Ten years ago, a high-end computer with the fastest processor, most memory, and large capacity hard drive would cost over $3,000, destined primarily for computer gamers and video editing. Today, even the most basic computers (under $1,000) have sufficient computing power for the majority of users, who typically only use office productivity software such as a word processor, spreadsheet, and database programs, as well as a Web browser to access information on the Internet. As health information and medical software increasingly become Web based, such as the National ERx initiative,1 maximizing the Web-browsing experience has become a must for medical professionals.

Issues

The medical office needs a variety of tools, which have increasingly become dependent on the Internet for delivery. Today’s practice can no longer maintain high levels of productivity with just practice management software and a word processor for documentation. Electronic communication with patients is increasingly becoming the norm, and eventually Web-based appointment scheduling will be the predominant appointment booking method. Patients will rely more upon e-mail appointment reminders with subsequent integration into their iPhone or Blackberry calendar than the traditional phone call confirmation. Just as the need for intense computing power has diminished over the years, the medical office will depend less upon medical software and information installed on office-based computers and rely heavily on subscriptions to Web-based applications such as electronic health records.

There are many reasons for this switch from office-based computing to Web-based delivery. Access is easier for multiple providers at different locations if the electronic health record system is centralized on the Internet. Timely backup and data integrity is improved since the busy practice manager or physician is no longer responsible for daily backup of records, billing, and scheduling. Communication between multiple health plans and healthcare service providers to streamline financial, clinical, and administrative transactions has now gone online. To enhance the experience with these services requires the optimization of the Web browser.

Security

In the medical setting, the security of the browsing experience is of paramount importance beyond the Health Insurance Portability and Accountability Act. Although the Web is a portal to web-based medical software and medical information, it is also the gateway for vulnerability of computers to viruses and hackers. Phishing is the type of attack that uses both social engineering and technical subterfuge to steal personal identity data and financial account credentials.2 These social-engineering schemes use “spoofed” e-mails, which appear to be from a credible Website, to lead victims to counterfeit Websites designed to trick them into divulging financial data or providing account information. Medical offices are vulnerable because they often have demographic information such as social security number, birthday, and address that hackers may use for other purposes. Technical subterfuge schemes implore users to click on a button on a Website, which plants “crimeware” onto computers. This software, usually a Trojan keylogger, basically captures keystrokes and sends them to phishers so that they can steal information directly.

AntiPhishing.org3 provides general advice to consumers to avoid phishing tactics. These include recommendations such as not to use links embedded in e-mails if there is suspicion that the e-mail is not authentic, and checking on the URL to determine if the site is authentic. Even the yellow lock on a URL and its “https://” can be forged by phishers. It is highly recommended that instead of clicking on e-mail links, enter the web site URL directly in the browser to avoid being sent to a phishing site.

There are a variety of tools to avoid phishing sites. Earthlink4 and Netcraft5 provide free toolbars that can be embedded into Internet Explorer or Firefox browsers to alert users if they have entered a site that may be risky. GreenBorder is a Windows-based Web browser that provided secured browsing by using virtualization technology to keep the Web browser from being hijacked and taking over the operating system. Google purchased GreenBorder in 2006, and its developers helped contribute to Google’s own Web browser, Chrome.6

Chrome is an open-source browser compiled by Google from a variety of sources.7 It uses components from Apple’s WebKit, which is incorporated into Apple’s Safari browser, and elements from Mozilla’s Firefox. These components have been tweaked to run complex Web applications better and to run clean as well as fast. Elements from GreenBorder’s technology help Chrome keep each tab in a secure “sandbox” so that they do not crash the browser and improve protection from phishing sites. At present, this product is still in beta and only for the Windows operating system, but Mac OS X and Linux versions are promised.

Microsoft has not been idly watching the secure browsing phenomenon. The new version 8 of Internet Explorer (IE8), now in beta testing, also offers secure Web browsing features.8 IE8 has a SmartScreen Filter that detects phishing sites, and domain highlighting which focuses the user’s attention to the domain name in the URL to spot misleading addresses.

Speed

Even 20 seconds waiting for a Website to load can create frustration for the medical office. Google’s Chrome browser and Microsoft’s IE8 are faster than earlier versions of Internet Explorer and Mozilla’s Firefox by incorporating various technologies to enhance the speed of access to information. Chrome has a simple interface and a revamped JavaScript engine to improve speed of Web-based applications. Application shortcuts in Chrome are specialized windows in the Chrome browser just for Web applications. They can be invoked from the desktop once the shortcut is created and they also do not display tabs, menus, and the address bar to maximize the application speed and appearance. IE8 has “Web slices,” which are favorite Websites that are routinely checked by IE8 for updates and then highlighted for the user. IE8 also has Web accelerators, installed mini-applications that help users copy information on one Website to be used on another with one click.

Fans of Firefox who desire speed but do not want to give up their favorite browser still have options. For the Microsoft Windows operating system, K-Meleon9 is an extremely fast, lightweight Web browser based on the Gecko layout engine used in Firefox. For Mac OS X, Camino10 is a specifically compiled web browser based on the same Gecko engine. These browsers, in essence, are similar to Firefox but have fewer features and add-ons. Additionally, their tighter integration with the specific operating system makes a significant improvement in speed.

Bookmarks

One of the issues with current Web browsers is many users have important bookmarks on home computers and work computers, and it is a challenge to synchronize the two. An easy solution for Firefox Web browser users is Foxmarks.11 This product is a free add-on extension to the Firefox browser that enables users to synchronize specific bookmarked sites between different computers as well as access and edit these bookmarks online from a third computer. Bookmarks can be shared between members as well as accessed on a mobile device such as an iPhone. Bookmarks are saved on the server, which functions as a backup. For Internet Explorer, there are many services that work as Foxmarks, but BookmarkSync12 is recommended because it can sync between IE and Firefox.

For the adventurous, to share bookmarks is a novel way to discover new Websites that have relevant information. Stumbleupon13 is a Website where members rate other Websites with a thumb up or down and then share this opinion with friends. Stumbleupon will then recommend Websites based on search topics chosen by users. Delicious.com14 is another popular bookmark-sharing Website. Here, users bookmark Websites and tag them on search terms of their own choosing. Users can then create their own network of colleagues with whom to share favorite Websites or they can search for Websites tagged by other members based on keywords.

Web Applications

As mentioned in a previous “Tech Advisor,”15 there are numerous Web-based office productivity software programs such as Google Docs16 and Thinkfree.17 These Web applications free users from dependence on specific productivity software on a computer as well as from carrying files on a USB flash drive. One advantage of using Google Docs is that a Microsoft PowerPoint presentation slideshow can be run directly from the Web browser. Glide OS18 takes this premise one step further toward desktop replacement. Glide OS offers Microsoft Office-compatible programs for word processing, spreadsheets, and presentations, but also offers photo and video management, e-mail, calendar, contact manager, and bookmark management. Eye OS19 is another desktop “operating system” where all software functions on a computer are delivered via the Web browser. Eye OS offers its software via the GNU Affero Public License version 3, which means that one can have one’s own private eye OS server for family, company, or network completely free. The source code is available and with eye OS development tools. The software can be customized with new applications that fit specific needs.

Conclusion

At first thought, the Web browser appears to be a limited tool for medical information and office management. However, with proper customization, it can be the portal to all functions of the medical office such as communication with health insurance companies using NaviNet,20 an electronic medical record system such as ValentMed,21 e-prescribing with NationalERx,1 medication information with Epocrates Online,22 and numerous medical content sites such as PsychiatryOnline.23 Once WiMax, the full wireless Internet for mobile access, arrives, basic Internet tablet devices and inexpensive ultramobile PCs may be sufficient for the daily medical practice. PP

References

1.    National ERx. National ePrescribing Patient Safety Initiative. Available at: www.nationalerx.com. Accessed October 8, 2008.
2.    APWG. What is Phishing and Pharming? Available at: www.antiphishing.org. Accessed October 8, 2008.
3.    APWG. Consumer Advice: How to Avoid Phishing Scams. Available at: www.antiphishing.org/consumer_recs.html. Accessed October 8, 2008.
4.    Earthlink Toolbar. Available at: www.earthlink.net/earthlinktoolbar. Accessed October 8, 2008.
5.    Netcraft Toolbar. Available at: http://toolbar.netcraft.com. Accessed October 8, 2008.
6.    Methvin D. Google chrome answers the greenborder mystery. Information Week. September 1, 2008. Available at: www.informationweek.com/blog/main/archives/2008/09/google_chrome_a.html. Accessed October 8, 2008.
7.    Google Chrome. A fresh take on the browser. Available at: www.google.com/chrome/intl/en/why.html?hl=en. Accessed October 8, 2008.
8.    Internet Explorer 8: More secure, private, and reliable. Available at: www.microsoft.com/windows/internet-explorer/beta/features/stay-safer-online.aspx?tabid=2&catid=1. Accessed October 8, 2008.
9.    K-Meleon. Available at: http://kmeleon.sourceforge.net. Accessed October 8, 2008.
10.    Camino. Available at: http://caminobrowser.org. Accessed October 8, 2008.
11.    Foxmarks. Available at: www.foxmarks.com. Accessed October 8, 2008.
12.    BookmarkSync. Available at: www.sync2it.com/bms/default.php. Accessed October 8, 2008.
13.    StumbleUpon. Available at: www.stumbleupon.com. Accessed October 8, 2008.
14.    Delicious. Available at: www.delicious.com. Accessed October 8, 2008.
15.    Luo JS. Free Software Tools for the Medical Practice. Primary Psychiatry. 2007;14(6):23-28.
16.    Google Docs. Available at: http://docs.google.com. Accessed October 8, 2008.
17.    ThinkFree. Available at: www.thinkfree.com. Accessed October 8, 2008.
18.    Glide OS. Available at: www.glideos.com. Accessed October 8, 2008.
19.    Eye OS. Available at: www.eyeos.com. Accessed October 8, 2008.
20.    NaviNet. Available at: www.aboutnavinet.com. Accessed October 8, 2008.
21.    ValantMed. Available at: www.valantmed.com. Accessed October 8, 2008.
22.    Epocrates Online. Available at: http://online.epocrates.com. Accessed October 8, 2008.
23.    Psychiatry Online. Available at: www.psychiatryonline.com. Accessed October 8, 2008.

 

Dr. Peselow is research professor at New York University School of Medicine in New York City.

Disclosure: Dr. Peselow is on the speaker’s bureaus of Forest and Pfizer.

Please direct all correspondence to: Eric D. Peselow, MD, Research Professor, School of Medicine, Psychiatry, New York University School of Medicine, 550 First Ave, New York, NY 10016-8304; Tel: 917-376-6755; Fax: 718-763-1677; E-mail: ericpes@mindspring.com.


 

Over the past 50 years, psychotropic agents have revolutionized the field of psychiatry. With the discovery of lithium,1 typical antipsychotics,2 tricyclic antidepressants,3 and benzodiazepine anxiolytics,4 psychiatry has advanced from a psychoanalytic to a biologic field. The discovery of newer agents for mood stabilization (carbamazepine, divalproex sodium), atypical antipsychotics, selective serotonin reuptake inhibitors (SSRIs), and buspirone has led to incremental improvement in treating these disorders. However, despite these remarkable advances, a large number of patients still do not respond to treatment. This issue discusses agents currently being tested for major psychiatric syndromes.

Eric D. Peselow, MD, and colleagues evaluate historic treatments that are no longer used, holistic medical techniques involving an orthomolecular strategy, and “natural” herbal products which are used despite lack of evidence-based trials. In addition, the authors assess the current state of these agents to identify whether these agents will prove to be safe and effective in various disorders or whether they will pass into history.

Yujuan Choy, MD, and  Franklin R. Schneier, MD, present findings of recent controlled trials that examine the evidence of efficacy of various classes of drugs (SSRIs, typical and atypical antipsychotics, anticonvulsants, and novel drug treatments of anxiety disorders) which effect the gamma-aminobutyric acid-ergic, serotonergic, and glutamatergic systems.

Ira D. Glick, MD, and Eric D. Peselow, MD, describe the current antipsychotics in the pipeline that are being clinically tested. They describe preclinical and clinical studies on a variety of agents that affect multiple receptors, including serotonin (5-HT)1A, 5-HT2A, 5-HT2C, dopamine (D)1, D2, D3, D2/D4, alpha-adrenergic receptors (alpha-1 and alpha-2) muscarinic (M)1 and M2 and histamine-1 receptors that are thought to be related to etiology. The authors point out that pursuing diverse molecular targets and validating these targets as effective in the treatment of schizophrenia appears to be the future for developing antipsychotics in the treatment of schizophrenia.

Patrick Ying, MD, evaluates new medications in mood disorders. Some of these medications continue in the existing paradigm of modifying serotonin, norepinephrine, and/or dopamine. Others employ novel mechanisms of action and hold the potential to improve the treatment of patients, such as by modifying the hypothalamic-pituitary-adrenal axis, affecting the tachykinin neuropeptide transmitters, and modulating the glutamatergic system. These drugs may not only improve the efficacy of treatment, but could potentially improve the speed and tolerability of pharmacotherapy.

Laurence M. Westreich, MD, and Deborah Finklestein, MD, evaluate the pipeline of investigational medications and vaccines used in the treatment of various illicit drugs. In addition to  these vaccines and the Food and Drug Administration-approved medications, other addiction remedies need to be understood by the general physician. The authors note that clinicians can provide substantial benefit to their addicted patients by making newly developed medications part of the treatment package.

Understanding these newer agents and treatment strategies may provide enhanced efficacy for patients with various psychiatric disorders. PP

References

1.    Cade JF. Lithium salts in the treatment of psychotic excitement. Med J Aust. 1949;2(10):349-352.
2.    Bower WH. Chlorpromazine in psychiatric illness. N Engl J Med. 1954;251(17):689-692.
3.    Kuhn R. The treatment of depressive states with G 22355 (imipramine hydrochloride). Am J Psychiatry. 1958;115(5):459-464.
4.    Kerry RJ, Jenner FA. A double blind crossover comparison of diazepam (Valium, Ro5-2807) with chlordiazepoxide (Librium) in the treatment of neurotic anxiety. Psychopharmacologia. 1962;3:302-306.

 

NeuroStar TMS Therapy Approved by FDA for MDD

The NeuroStar Transcranial Magnetic Stimulation (TMS) Therapy system was approved by the United States Food and Drug Administration for the treatment of major depressive disorder (MDD). Mark George, MD, of the Medical University of South Carolina (MUSC) initiated research on the treatment.

“I began researching prefrontal TMS as a potential treatment for depression back in 1993, reasoning from the effects of electroconvulsive therapy, emerging brain imaging findings in depression and sadness, and new papers describing corticothalamic regulator loops,” Dr. George said. “The ideas were heretical at first, as most people wrongly assumed that a seizure was needed for an electrical stimulation method to work.”

NeuroStar TMS Therapy is a non-systemic, non-invasive form of neuromodulation that requires no anesthesia or sedation. The 40-minute outpatient procedure involves magnetic resonance imaging-strength magnetic pulses that stimulate nerve cells in areas of the brain associated with depression. These pulses should be administered daily for 4–6 weeks.

The randomized controlled trial conducted for the FDA showed no systemic side effects (eg, sedation, nausea, dry mouth) and no adverse effects on concentration and memory. TMS treatments were safely performed with no seizures and no device-drug interactions. Mild-to-moderate scalp pain at the treatment area was experienced during treatment but dissipated after the first week. This option is for adults with MDD who failed to receive benefit with other treatments. It is not recommended for patients with implanted metallic devices or non-removable metallic objects in or around the head.

Despite over 15 years of research, a rigorous trial sponsored by the National Institute of Mental Health is being conducted at MUSC and three other sites to test the efficacy of prefrontal TMS in depression.

“We have extensive imaging, genetic, demographic, and neuropsychological testing in these patients to help understand the mechanism of action and determine who best responds, and whether biomarkers might help monitor or predict response,” Dr. George said.

The NeuroStar TMS Therapy has not been studied in patients who have received previous antidepressant treatment. Further, efficacy has not been established in patients whose condition did not improve after ≥2 prior antidepressant treatments at minimal effective dose and duration in the current episode.

Funding for this research was provided by the National Alliance for Research on Schizophrenia and Depression. (Further information can be found at http://clinicaltrials.gov/ct2/show/NCT00149838) –ML

Researchers Determine Rates of Child and Adolescent Bipolar I Disorder Becoming Adult Bipolar I Disorder

Current research has found that approximately 1% of the United States population <20 years of age suffers from bipolar disorder. With the onset of bipolar I disorder generally occurring in late adolescence or young adulthood, research is needed to determine whether child bipolar I disorder would become continuous adult bipolar I disorder.

Barbara Geller, MD, and colleagues from the Washington University in St. Louis, Missouri studied 115 children whose average age was 11.1±2.6 years to determine these potential prevalence rates. All of the children met the criteria for a first episode Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition bipolar I disorder mixed or manic phase; had one or both of the cardinal symptoms of bipolar I disorder (elation or grandiosity); and scored <60 on the Children’s Global Assessment Scale (CGAS). Geller and colleagues assessed the patients using the Washington University in St. Louis Kiddie Schedule for Affective Disorders and Schizophrenia, the Psychosocial Schedule for School Age Children-Revised, and the CGAS. 

Over an 8-year period there were nine follow-up visits and approximately 94% of patients completed the study. Geller and colleagues found that these patients spent approximately 60% of weeks with any mood episodes and approximately 40% of weeks with episodes of mania. Approximately 88% of patients recovered from mania; however, approximately 73% of these patients relapsed. Geller and colleagues found that approximately 44% of these children with bipolar I disorder became young adults with bipolar I disorder. These patients continued to have manic episodes while 35.2% had a substance use disorder. This rate is similar to the rate found in adults.

“As we found, these data add to the validation of child bipolar I disorder as a similar illness to the adult form,” Dr. Geller said. “These data are consistent with our earlier publication showing that both child onset and adult onset bipolar I disorder occur within the same families.”

Geller and colleagues plan on following the sample into adulthood. They believe that the rate was similar in young adults because “these prospective longitudinal data and family psychopathology data support that they are the same illness and therefore would have similar comorbidity with substance use disorders. These are the first data to prospectively demonstrate continuity between child and adult bipolar I disorder.”

Funding for this research was provided by the National Institute of Mental Health. (Arch Gen Psychiatry. 2008;65(10):1125-1133.) –CDN

Adolescent Insomnia May Indicate Depression and Substance Abuse in Young Adulthood

Brandy Roane, MS, and Daniel J. Taylor, MD, of the University of North Texas in Denton conducted a study suggesting signs of adolescent insomnia symptoms are linked to depression, suicide, and substance abuse. This study is the first to longitudinally evaluate adolescent insomnia symptoms as a risk factor for mental health problems in young adulthood.

The researchers chose 145 middle, junior, and high schools in the United States based on size, school type, census region, urbanization level, percentage of Caucasian and African-American students, grade span, and curriculum. The sample consisted of 4,494 participants 12–18 years of age at baseline and 3,582 young adults 18–25 years of age at 6- to 7-year follow up. Self-report measures were used to assess mental health conditions. A cross-sectional, prospective design was used to evaluate the association between adolescent insomnia and mental health during adolescence and young adulthood.

Results indicated that 9.4% of adolescents reported insomnia symptoms (ie, difficulty falling asleep every day or almost every day). Cross-sectional analysis showed that these symptoms were associated with use of alcohol (ie, binge drinking; drinking ≥5 alcoholic beverages consecutively), cannabis, and other drugs (eg, cocaine) as well as suicide ideation or attempts. In addition, gender differences emerged for substance abuse and depression. Males were more likely to endorse substance abuse while females were twice as likely to develop depression. Sex and baseline depression were controlled for a prospective analysis that indicated adolescent insomnia symptoms were a significant risk factor for young adult depression (odds ratio=2.3). In addition, when participants suffering from depression and suicide at baseline were excluded, the insomnia cohort showed greater risk of experiencing recurrences of depression and suicidal activities.

These findings indicate that insomnia is a prevalent problem for adolescents. Roane and colleagues argue for future treatment-outcome studies to evaluate the efficacy and effectiveness of various insomnia interventions in this age group. (Sleep. 2008;31(10):1351-1356.) –ML

Children May Present With Course of OCD Similar to Older Peers and Adolescents

Marked by recurrent, unwanted thoughts and/or repetitive behaviors often aimed at relieving these obsessions, obsessive-compulsive disorder (OCD) is not only present in adult populations, but has also been found in children <3 years of age. Prior studies have shown that OCD development in childhood and adolescence features a unique presentation and poses risks to later growth and development.

Despite the differed presentation and risk, there have been few studies into the development of OCD in children. In addition, studies of youths with OCD often do not distinguish between those who present with the disorder as children and patients who develop OCD later in life. Researchers at the Bradley Hasbro Children’s Research Center Pediatric Anxiety Research Clinic in Providence, Rhode Island, recently sought to determine differences in OCD presentation among youths with the disorder.

Abbe M. Garcia, PhD, and colleagues studied 58 children (4–8 years of age; 23 male and 35 female) for distinguishing factors of early-onset OCD presentation. Early-onset OCD was defined as the presence of OCD, according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, prior to the 8 years of age, and was determined (along with comorbid conditions) by use of a structured interview. OCD severity was evaluated using the Children’s Yale-Brown Obsessive Compulsive Scale.

Garcia and colleagues found that the mean age of OCD onset was approximately 5 years and the mean age of presentation was 6–7 years. Mean symptom severity was in the moderately severe range while, among all children studied, approximately 19% had been previously treated with medication and 24% had received previous psychotherapy for OCD. Approximately 22% of children in the study also had comorbid attention-deficit/hyperactivity disorder and approximately 20% had comorbid generalized anxiety disorder. In addition, 20% of children in the study reported a first-degree family history of the disorder.

Regarding OCD symptoms of children in the study, common obsessions included contamination and aggressive/catastrophic thoughts, such as death or harm to family members, and common compulsive behaviors included washing and checking. The authors found that children with OCD presented with similar symptoms, severity levels, and family history as adolescents with the disorder, which may indicate that children can progress to the mature OCD course typically found in adults.

Garcia and colleagues concluded that presence of various obsessions and compulsions as well as multiple comorbid conditions indicate that, for some children with OCD, the disorder is not in a beginning phase that will progress as children age. However, they found that children can be affected with similar OCD severity as older children and adolescents. They added that researchers need to have a more developed understanding of the course of OCD in children in order to reduce the severity of symptoms that can impair patients’ quality of life.

Funding for this research was provided by the National Institute of Mental Health. (J Psychopathol Behav Assess. 2008. [Epub ahead of print].) –CP

10-Year Study on Smoking and Depression in Women

A longitudinal study investigated the strength of smoking as a risk factor for major depressive disorder (MDD). One thousand forty-three Australian women, participants in the Geelong Osteoporosis Study, had been monitored for 10 years. At the 10-year mark, participants were given a psychiatric examination. Julie Pasco, BSc(Hons), at the University of Melbourne, and colleagues conducted their assessment using case-control and retrospective cohort methods. MDD was diagnosed using Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision criteria; smoking was self-reported. Pasco and colleagues found that smoking and depression had a significant association, especially for heavy smokers (>20 cigarettes/day).

There were 165 women with a diagnosis of MDD with 806 controls. Smoking was associated with a significantly higher odds ratio for MDD (1.46, 95% CI 1.03–2.07). For heavy smokers (>20 cigarettes/day), the odds ratio for MDD was more than twice that of non-smokers. Among the 671 women with no history of MDD at baseline, 13 out of 87 smokers (14.9%) and 38 out of 584 non-smokers (0.07%) developed MDD during the 10-year study period. Overall, after controlling for alcohol consumption and physical activity, smoking increased the risk of MDD by 93% (hazard ratio 1.93, 95% CI 1.02–3.69).

Funding for this research was provided by Eli Lilly. (Br J Psychiatry. 2008;193(4):322-326) –LS

US Youths More Commonly Prescribed Psychotropic Drugs Compared to Western European Counterparts

Prescriptions for psychotropic medications have been increasing throughout Western Europe and the United States for the last 10 years. In addition, previous research indicates that use of psychotropic medications is higher in the US. According to a cross-sectional study by Julie M. Zito, PhD, of the University of Maryland School of Pharmacy in Baltimore, and colleagues, youths 0–19 years of age are more likely to receive prescriptions for psychotropic drugs in the US than in Western Europe.

The researchers investigated administrative claims data from the year 2000 on insured youths from  Germany (n=356,520), the Netherlands (n=110,944), and the US (n=127,157). A population-based analysis of psychotropic medication use was performed according to children’s age group, gender, drug subclass pattern, and concomitant use. Results found that annual prevalence of any psychtropic medication in youths was 6.7% in the US, which is substantially greater than in both the Netherlands (2.9%) and Germany (2%). The US demonstrated ≥3 times greater antidepressant and stimulant prevalence than the Netherlands and Germany; antipsychotic prevalence was 1.5–2.2 times greater. While the atypical antipsychotic subclass represented 48% in the Netherlands and 5% in Germany, the US represented 66%. Though psychotropic drugs such as α-agonists, lithium agents, and antiparkinsonian agents were prescribed less in all three countries, rarely used anxiolytics were twice as prevalent in Dutch youths as in US and German youths. Prescription hypnotics were 50% as common as anxiolytics in Dutch and US youths; they were uncommon in German youths the most. Concomitant drug use was twice as prevalent in youths in the US (19.2%) as those in the Netherlands, and three times as those in Germany.

Zito and colleagues concluded that there are great differences in psychotropic medication treatment patterns between US youths and Western European youths. It is possible that such differences raise from direct-to-consumer (DTC) drug advertising, government regulation, reimbursement policies, diagnostic classification systems, and cultural beliefs concerning medication’s role in emotional and behavioral treatment. Further, a demographic explanation of this phenomenon suggests that the number of child psychiatrists per capita is higher in the US than in Western Europe.

The study was limited by the cross-sectional nature of the investigation and lack of diagnostic information of enrollees. In addition, that DTC advertising is allowed only in the US among the three countries is confounding as is the fact that US data were confined to children covered under the State Children’s Health Insurance Program. Lack of information on reimbursement patterns, differences in access to specialist care, and lack of information on over-the-counter drugs limited the study as well. (Child Adolesc Psychiatry Ment Health. 2008;2(1):26.) –ML

MDD and Anxiety May Worsen COPD Symptoms Leading to Increased Hospitalizations

Major depressive disorder (MDD) and other depressive disorders as well as generalized anxiety are frequently occurring comorbid conditions for patients with chronic obstructive pulmonary disease (COPD). Although the increased prevalence of these psychiatric conditions in patients with COPD is widely known, few studies have investigated the link between these conditions and COPD disease course, including frequency of COPD exacerbation and subsequent hospital stays. The effect of MDD and anxiety on COPD presentation is of particular importance as the mental health conditions can be treated, which may potentially alter the disease outcome for a patient with COPD.

Jean Bourbeau, MD, of the Respiratory Epidemiology and Clinical Research Unit of McGill University in Montreal, Canada, and colleagues, studied 491 patients with stable COPD for symptoms of MDD and/or anxiety. The authors hypothesized that COPD patients with comorbid MDD or anxiety would be at increased risk for a greater number of exacerbations and hospitalizations. All patients were gathered from respiratory departments of 10 hospitals in Beijing, China and were evaluated for MDD and anxiety symptoms as well as COPD progression at the study beginning. For study inclusion, patients had to be ≥30 years of age, have physician-diagnosed COPD, have no worsening of respiratory symptoms 4 weeks prior to study beginning, and have an expected survival rate of ≥6 months, among other criteria.

MDD and anxiety symptoms were assessed using the Hospital Anxiety and Depression Scale, which assesses symptom severity among hospital and primary care patients. COPD progression was measured by spirometry and bronchodilator response tests, assessment of cough production and chest wheeze, and self-report. Exercise capacity and quality of life were also evaluated. Patients were then evaluated once-a-month for 12 months to assess occurrence of exacerbations or hospitalizations.

Bourbeau and colleagues found that 112 patients had probable MDD while 47 had probable anxiety. During the study period, 876 symptom-based and 450 event-based exacerbations were recorded, and 183 of these symptom exacerbations led to hospitalization. When compared to patients without psychiatric disorders, patients with probable MDD had significantly increased rates of symptom-based and event-based exacerbations, increased mortality, and increased hospital stays that were longer than non-depressed patients. Patients with anxiety experienced more frequent symptom-based exacerbations and longer hospital stays, when compared to non-anxious patients.

They also found that depressed patients had a higher percentage of concurrent anxiety, had lower levels of education attained, were less likely to be married, and had increased rates of past exacerbations and hospitalizations. Patients with both probable MDD and anxiety had lower levels of self-efficacy and social support. These results also persisted after adjusting for confounding variables.

Bourbeau and colleagues concluded that their findings show that symptoms of depression and anxiety are causally linked to increased rates of exacerbations and hospitalizations for patients with COPD. This relationship may be due to depression effecting change in the immune system or affecting a patient’s ability to adapt to chronic symptoms as well as decreasing self-confidence, which may lead to poorer medication adherence. Thus, clinicians should note that treatment of MDD and anxiety may lead to better COPD treatment outcomes.

Funding for this research was provided by the Canadian Institute of Health Research. (Am J Respir Crit Care Med. 2008;178(9):913-920.) –CP

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

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.


 

Generations of physicians have been accustomed to receiving pens, pads, mugs, and assorted models of the spine, the brain, and other organs, all courtesy of pharmaceutical and medical device manufacturers. Most, if not all, of these gifts will cease as of January 2009, when a new guideline for interactions of pharmaceutical companies with health care professionals goes into effect.1 This code is voluntary, but if brand name drug manufacturers follow this code of the Pharmaceutical Research and Manufacturers of America, freebies will be history. Tickets to shows, concerts, and sporting events are also banned. However, there will be some exceptions. For example, educational items without company logos or drug names are permissible if they are valued at <$100. Drug representatives can still provide meals for physicians, but they must be inexpensive, infrequent, and must take place in a clinical setting such as an office or hospital. When meals are provided, they must be accompanied by the presentation of information about the product belonging to the sponsor of the meal. Thus, this code is not as severe as it would seem as first, and it is not mandatory, so pharmaceutical companies can elect to participate, or not. 

The new code does not mention sampling, however, this is under assault as well. According to some observers, after January 1, 2009 free drug samples will be the last form of in-office marketing. For those of us in clinical practice, samples are helpful in getting people started on medications. Often, I have patients take the first pill in my office because I sense they might be ambivalent about taking medication or they are concerned about the side effects. The major objection to samples is that they get patients started on more expensive branded medications instead of more economical generics.  In most cases the less expensive, generic medication is as effective as the brand medication.

Apart from the ethical questions raised about the provision of samples and starter coupons, there is the fact that that many of you have already noticed that the variety of drug samples in your cabinets has decreased in the past few years. This is because many widely prescribed psychotropic medications have lost patent protection over the past two years and they have not been replaced by newer agents. The United States Food and Drug Administration has not approved any new psychotropic agents recently, and those that have been approved are not radically different from existing agents. 2008 may have been the year with the fewest introduction of new psychiatric medications in the past two decades.

Conflicts of Interest and Consulting Arrangements

The past year has also seen a number of highly publicized findings involving influential psychiatric “thought leaders.” The Senate Finance Committee found highly visible researchers had not fully disclosed the extent of financial relationships they had with industry.2-4 These reports are embarrassing to the field, however, more importantly, they disturbing because they call into question the motives and accuracy presentations and publications by these individuals. Although prominent academics have gotten the headlines, much of the abuse of this system probably involves arrangements where high-prescribing local clinicians are retained as consultants or speakers simply to win their loyalty to a product. This can also be seen as a kickback. Under the new guidelines, consultants who provide advisory services may “be offered reasonable compensation for their time, considering the value of the type of services provided, and to be offered reimbursement for reasonable travel, lodging, and meal expenses.” Also, “Any compensation or reimbursement made…in conjunction with a consulting arrangement should be reasonable and based on fair-market value.” 

On balance, I think these changes will result in less promotional/marketing driven distortion of clinical decision-making. It will also make whatever information is disseminated more credible. Greater transparency regarding conflicts of interest in publications and Continuing Medical Education programs is long overdue. PP

References

1.     Code on Interaction with Healthcare Professionals. http://www.phrma.org/code_on_interactions_with_healthcare_professionals. Accessed November 25, 2008. 
2.    Psychiatric Group Faces Scrutiny Over Drug Industry Ties. http://www.nytimes.com/2008/07/12/washington/12psych.html. Accessed November 25, 2008.
3.     Researchers Fail to Reveal Full Drug Pay. http://www.nytimes.com/2008/06/08/us/08conflict.html?scp=3&sq=%20Grassley%20psychiatry&st=cse. Accessed November 25, 2008.
4.     Top Psychiatrists Didn’t Report Drug Makers’ Pay. http://www.nytimes.com/2008/10/04/health/policy/04drug.html?scp=5&sq=%20Grassley%20psychiatry&st=cse Accessed November 25, 2008.

 

 

Needs Assessment: Many clinicians have little information about the newer medications used to treat addiction, and often hold biases against using medications in the treatment of addiction. This paper places medications within the full context of addiction treatment and provides guidance on how to select and use the anti-addiction medications.

Learning Objectives:
• Place medications within the context of full treatment for addiction
• List the Food and Drug Administration-approved medications for alcohol dependence
• Give an example of common side effects for varenicline
• Know the usual effective dose for buprenorphine

Target Audience: Primary care physicians and psychiatrists.

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

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

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

This activity has been peer-reviewed and approved by James C.-Y. Chou, MD, associate professor of psychiatry at the Mount Sinai School of Medicine, and Norman Sussman, MD, editor of Primary Psychiatry and professor of psychiatry at New York University School of Medicine. Review Date: November 20, 2008.

Dr. Sussman reports no affiliation with or financial interest in any organization that may pose a conflict of interest. Dr. Chou receives honoraria from AstraZeneca, Bristol-Myers Squibb, Eli Lilly, GlaxoSmithKline, Janssen, and Pfizer.

To receive credit for this activity: Read this article and the two CME-designated accompanying articles, reflect on the information presented, and then complete the CME posttest and evaluation. To obtain credits, you should score 70% or better. Early submission of this posttest is encouraged: please submit this posttest by December 1, 2010 to be eligible for credit. Release date: December 1, 2008. Termination date: December 31, 2010. The estimated time to complete all three articles and the posttest is 3 hours. 

Primary Psychiatry. 2008;15(12):73-80

 

Dr. Westreich is an associate professor of clinical psychiatry and Dr. Finklestein is an instructor in clinical psychiatry in the Department of Psychiatry’s Division on Alcoholism and Drug Abuse at New York University School of Medicine in New York City.

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

Off-label disclosure: This article contains discussion of the following unapproved medications for the treatment of addiction: baclofen, citalopram, flumazanil, fluoxetine, gabapentin, gamma-vinyl GABA, hydralazine, modafinil, propranolol, tiagabine, and topiramate.

Please direct all correspondence to: Deborah Finklestein, MD, Instructor in Clinical Psychiatry, Division on Alcoholism and Substance Abuse, Department of Psychiatry, New York University School of Medicine, 550 First Ave, New York, NY 10016; Tel: 212-579-4142; Fax: 212-579-7849; E-mail: debbefink@yahoo.com.


 
Abstract

Can new medications help in the treatment of substance use disorders? The short answer to that question is yes. Despite the historical resistance of addiction treaters to using medications in their treatment of addicted people, recent advances and more sophisticated methods for integrating medications into standard addiction treatment have led to a surge in new anti-addiction medications available to the addicted person. Medications like depot naltrexone and acamprosate have shown substantial effects in decreasing alcohol craving, while suboxone has provided relief to opiate addicts who simply would not have come to treatment in the past. Despite the apparent post-marketing emergence of side effects like agitation and nightmares, varenicline is a step in the right direction for those looking for help with their nicotine addiction. Although not yet available to the public, the pipeline of investigational medications includes several cocaine vaccines. In addition to these vaccines and the Food and Drug Administration-approved medications, other addiction remedies have been touted in the press and should be understood by the general physician; in this widely publicized but unproven category is the proprietary medication “cocktail” offered by Prometa. Clinicians can provide substantial benefit to their addicted patients by making newly developed medications part of the treatment package. This article reviews the clinical use of these new medications.

 Introduction

The Epidemiologic Catchment Area study1 noted that 7.9% of the general population suffered from alcohol dependence over their lifetime, while 4.4% suffered from drug dependence. Despite some leveling off of teenager’s use of addictive substances over the past decade, 9.2% of all high school seniors acknowledged illicit use of non-heroin narcotics such as acetaminophen plus hydrocodone.2 However, these numbers do not reflect the desperation that addicted people, their loved ones, and their clinicians feel when confronted with a life-threatening addiction. Their anguish often engenders hope for a “magic pill” which will cure the addiction and return the sufferer to his or her previous state of health.

Despite the promise of some older medications as well as the medications reviewed below, no such panacea exists. The absence of such a curative biologic remedy arises in part from the remedial nature of understanding of addiction’s biology, and in part from the inherent impossibility of the task. No biologic substance will cure addiction since addiction is not (purely) a biologic condition. The successes of relapse prevention psychotherapy,3 network therapy,4 and other biopsychosocial treatments as well as peer-led support groups like Alcoholics Anonymous5 attest to the potential for effective non-biologic treatment of addiction.

However, biologic treatments like the medications in this article can substantially benefit the addicted person. Despite some resistance in the field of addiction psychiatry, most clinicians now see medications as a useful adjunct, if not the mainstay of treatment. Considerable controversy remains about the use of maintenance prescription of opiates, as with buprenorphine. But there is little disagreement about the need for more and better biologic approaches to the treatment of addiction. The medications below represent the newest and best of those approaches.

Alcohol

Since the 1970s, behavioral treatments6-8 have proven the most prevalent form of treatment in the United States. However, in the last several years, pharmacologic research has introduced some new medications as another means to enhance abstinence and prevent relapse.

The US Food and Drug Administration has approved disulfiram, acamprosate, and naltrexone (the latter in both daily oral and monthly injectable formulations) for the treatment of alcohol dependence. Previous articles1,2 have outlined the clinical uses of disulfiram and oral naltrexone. This article provides an update on the above medications as well as describes the applications of depot naltrexone and acamprosate, medications that are currently being used in the treatment of alcohol dependence.

Disulfiram

Since the 1970s, disulfiram has been widely used as a deterrent to alcohol use secondary to its unpleasant side effects when alcohol is consumed. As a result, disulfiram primarily benefits patients who are adherent or receive medication under supervision. Controlled studies9-11 of disulfiram have revealed mixed results. Some provide evidence that drinking frequency is reduced, but the data show no convincing and sustained improvement in continuous abstinence rates. However, it still appears to be one of the most used pharmacotherapies available in the market and is dosed daily at 500 mg/day.

Naltrexone Oral Formulation

In 1994, naltrexone was approved by the FDA to treat alcohol dependence. An opioid antagonist, naltrexone is thought to dampen the pleasurable effects of alcohol-induced endogenous upload activity in the brain, thus reducing drinking frequency and the likelihood of relapse to heavy drinking.12,13 The standard regimen is one 50-mg tablet per day; duration of treatment can vary depending on the patient’s needs, but usually does not exceed 12 months. Initial nausea usually subsides after a few days, and other side effects (eg, heightened liver enzymes) are rare but necessitate monitoring of liver function tests.

Multiple controlled studies12,14-16 have shown naltrexone’s superiority over placebo, as patients receiving naltrexone were shown to be less likely to relapse to heavy drinking and more likely to drink on fewer days. Additionally, several meta-analyses17,18 have added support for the efficacy of naltrexone for improved abstinence. Other studies, however, have reported no or minimal effectiveness, attributing the outcome to poor medication adherence and adverse effects, especially nausea.19,20

Despite these findings, some patients find naltrexone helpful in itself or as an adjunct to other psychopharmacologic or psychosocial treatments. Clinicians should consider it as possiblity in treating their alcohol-dependent patients.

Naltrexone Depot Formulation

In an attempt to improve patient adherence and avoid some of the adverse effects associated with oral naltrexone, a monthly injectable formulation was approved by the FDA in April 2006. This formulation is administered by intramuscular (IM) injection of 380 mg and lasts for up to 30 days. Patients are advised to abstain from alcohol 3–7 days prior to first dose, but one study18 reported positive results in actively drinking patients with little to no abstinence period. Although FDA guidelines indicate that naltrexone should be used for up to 3 months to treat alcoholism, the Substance Abuse and Mental Health Administration (SAMHSA) recommends that treatment providers individualize the length of naltrexone treatment according to each patient’s needs. Certain patients may be appropriate candidates for long-term (eg, up to 1 year) naltrexone treatment if they demonstrate evidence of compliance with medication and psychosocial treatment regimens.

To date, the most reported adverse event has been injection site reactions. The FDA has received 196 reports of injection site reactions including cellulitis, induration, hematoma, abscess, sterile abscess, and necrosis, 16 of which required surgical intervention. In response to this, the FDA has recently issued an alert to healthcare professionals who are administering naltrexone to their patients. The recommendations are as follows:

Physicians who administer naltrexone should refer a patient who develops pain, swelling, bruising, pruritus, and redness at the injection site that does not improve within 2 weeks of naltrexone administration to a surgeon. Naltrexone should be administered as directed as an intramuscular (IM) gluteal injection. Naltrexone should not be administered intravenously, subcutaneously, or inadvertently into fatty tissue. Healthcare providers should ensure that the naltrexone injection is given correctly with the pre-packaged 1.5-inch needle that is specifically designed for this drug. In addition, the FDA reports data that shows women may be physiologically at higher risk for injection site reactions due to typically higher gluteal fat thickness.3

Several studies4,5 demonstrate that long-acting naltrexone is well tolerated and associated with a significant reduction in heavy drinking in a population of actively drinking patients. In one recent study,21 the abstinence rate was significantly higher for IM naltrexone compared with placebo: median time to first drink was 41 days versus 12 days, respectively, and rate of continuous abstinence at end of the study was 32% versus 11% (P=.02). In addition, the patients who received naltrexone extended release (ER) showed substantially increased time to first heavy drinking event (>180 days vs. 20 days; P=.04) and decreased the median number of any drinking days per month by 90% (0.7 days vs. 7.2 days; P=.005) and heavy drinking days per month by 93% (0.2 days vs. 2.9 days; P=.007).

However, more data are needed to determine whether this treatment would similarly benefit alcohol-dependent women. Adverse events associated with the depot formulation appear to be milder than those associated with the use of oral naltrexone, but a direct comparison between the oral and depot formulations within the same clinical trial has yet to be studied.

Acamprosate

In 2004, following use of acamprosate in Europe for more than a decade, the FDA approved this drug for treatment of alcohol dependence. Acamprosate targets the brain’s glutamate system and has been shown in European metanalyses to reduce the motivation to drink.22 However, several US studies23,24 have found it to have little efficacy, especially in non-motivated and non-abstinent populations. The reason for these contradictory results is unclear, but researchers speculate that they may reflect differences in patient characteristics included in the European and US studies as well as study designs. One early observational study25 suggested that acamprosate is useful in heavy drinking populations and is safe for use even early in the alcohol detoxification process. Trials continue and many researchers in the US and abroad continue to support the efficacy of acamprosate in maintaining abstinence and reducing alcohol consumption.26,27

Acamprosate is dosed as a 333-mg tablet TID and treatment duration can vary from 3–12 months. It is generally well tolerated and adverse events tend to be mild and transient, primarily involving the gastrointestinal tract with diarrhea and abdominal discomfort in approximately 10% of patients. Acamprosate should not be taken by those with kidney problems or allergies to the drug.28

Opioids

Despite the overall plateau in illicit drug use in the US, opioid dependence remains a growing and deadly affliction. The number of current US heroin users rose from 136,000 in 2005 to 338,000 in 2006,29 while admissions for heroin dependence treatment actually decreased over the same 2 years.30 One out of every 20 high school seniors reported having tried oxycodone over the previous year31 and many, if not most, opioid-related deaths were due to misuse and abuse of prescription opioids.32   

In the 50 years since the introduction of methadone, clinicians have had few other effective medications for opioid addiction until the FDA’s approval of suboxone in October 2002. Previous articles have outlined the clinical applications of methadone for detoxification and opioid maintenance,33 naltrexone for opioid blockade,34 and clonidine for opioid detoxification.35 Levo-a-acetyl-methadol, a previously available opioid agonist, was taken off the market in early 2004 because of cardiac side effects.36 This article reviews the clinical usage of the newer medications buprenorphine and injectable depot naltrexone and outlines the case against Prometa in the treatment of opioid addiction.

Buprenorphine

Buprenorphine, a partial opioid agonist, was approved by the FDA and became commercially available in January 2003 with a sublingual tablet as a sole agent as well as in a preparation mixed with naloxone, designed to prevent illicit intravenous use.

Under the auspices of the Drug Addiction Treatment Act of 2000,37 office-based physicians with special licenses were permitted to prescribe buprenorphine and other opioid medications for the treatment of addiction for the first time. The required training for these special licenses, in the form of an 8-hour course, is available from professional organizations like the American Academy of Addiction Psychiatry.38

Like methadone, buprenorphine can be used in a tapering protocol for detoxification or at stable dose for opioid maintenance. The differences between buprenorphine and methadone are substantial; buprenorphine can be prescribed in a private physician’s office, it has a “ceiling effect” which makes overdose unlikely, and its partial opioid agonism makes addictive use less likely, though far from impossible. Buprenorphine does not, as yet, engender the same sort of societal stigma as methadone, so the medication is acceptable to a cohort of opioid-dependent individuals who would avoid methadone clinics.

After determining that the patient is appropriate for either buprenorphine detoxification or maintenance, the treating clinician arranges a medication induction. One good source for treatment planning, SAMHSA’s Clinical Guide for the Use of Buprenorphine in the Treatment of Opioid Addiction,39 recommends (amongst other things) that the prospective patient choose buprenorphine after reviewing all the treatment options, be reasonably complaint, understand the risk and benefits of treatment, and not be dependent on other central nervous system (CNS) depressants like benzodiazepines and alcohol.

Induction onto buprenorphine can be complicated, especially with a patient who is less than fully compliant. Standard recommendations for induction40 suggest that the patient show actual withdrawal symptoms before a test dosage of buprenorphine 2–4 mg is administered, followed by close observation of withdrawal symptoms, with a first-day total maximum dosage of 8 mg and a second-day maximum dosage of 16 mg.

Once stabilized on buprenorphine, patients clearly benefit in terms of opioid avoidance. One outpatient study41 compared buprenorphine, buprenorphine/naloxone, and placebo in the treatment of 326 opiate-addicted people. The high efficacy of both buprenorphine preparations necessitated in preventing illicit opioid use necessitated an early end to the study; the subjects’ urine toxicologies at 4 weeks and self-reported opioid craving were both so low that the study was stopped and the placebo group was offered active medication.

In comparison to methadone, buprenorphine is similarly effective at the higher dosage range. One study42 of 116 opioid-dependent subjects compared high and low doses of both buprenorphine and methadone and found (predictably) that at 24 weeks, opioid positive urine toxicologies were highest (77% and 72%) in those randomly assigned to take the low doses of methadone 20 mg/day and buprenorphine 4 mg/day. Conversely, opioid-positive urine toxicology rates were lowest for those assigned to high doses of methadone 65 mg/day and buprenorphine 12 mg/day, at 45% and 58%, respectively.

One exciting possibility for buprenorphine is a depot preparation which can last 6 months. In Phase III FDA clinical trials,43 the 6-month depot form of buprenorphine was found to be better than placebo in preventing opioid use and very unlikely to be used illicitly, both to a very high degree of statistical significance (P=.0117 and P=.0004, respectively).

Depot Naltrexone

Naltrexone, a highly effective and long-lasting opioid receptor antagonist, is approved by the FDA, as noted above, as an anti-craving agent for alcohol. The 2008 Physician’s Desk Reference notes that naltrexone “…is not indicated for the purpose of opioid blockade or the treatment of opiate dependence…”44 because of the possibility that patients will attempt to overwhelm the opiate blockade and suffer respiratory collapse. Despite this rather overstated warning, (those taking oral naltrexone could try to overwhelm the blockade also,) clinicians have made the obvious maneuver of using naltrexone in their opioid-addicted patients. One preliminary study45 of IM naltrexone ER in 27 opioid-using adults found that blockade of hydromorphone as measured by pupil size and a visual analog scale of reported drug effect was complete for 28 days, based on dosages of IM naltrexone ER 150 mg and 300 mg. (Naltrexone is sold in 380 mg vials.)

Another randomized, double-blind, placebo-controlled study46 noted oral naltrexone’s “high dropout rates during treatment and poor compliance with medication ingestion.” At 8 weeks, the investigators found a 39% retention in treatment for those receiving placebo, while those receiving IM naltrexone 192 mg had a 60% retention rate and those receiving IM naltrexone 384 mg were retained in treatment at the rate of 68%. The article concludes that there is “…new evidence of the feasibility, efficacy, and tolerability of long acting antagonist treatments for opioid dependence.”46

Nicotine   

While smoking rates have leveled off or declined in developed nations, tobacco use in the developing world continues to rise at a rate of approximately 3.4% per year.47 The US Centers for Disease Control and Prevention6 describes tobacco use as “the single most important preventable risk to human health in developed countries and an important cause of premature death worldwide.”

Since the early 1990s, clinicians have been able to help their patients quit or to temporarily abstain from smoking by using a variety of nicotine-containing tobacco substitutes, or nicotine-replacement therapy (NRT). Most nicotine-replacement products are available over the counter and are fundamental tools for physicians helping patients taper themselves off of nicotine. The most popular are options such as the nicotine patch, nicotine gum, and nicotine inhaler. The patch which is placed on the upper body (usually the upper arm/deltoid) delivers nicotine through the skin to the bloodstream for approximately 24 hours. The treatment period may last for ≥8 weeks. The nicotine gum is a gum-like resin that delivers nicotine to the bloodstream, available in a 2-mg dose for regular smokers and a 4-mg dose for heavy smokers. The maximum number of pieces per day is 20 and treatment is recommended for 1–3 months, with a maximum of 6 months. The nicotine lozenge is a tablet that dissolves in the mouth and is available in 2-mg and 4-mg doses. The recommended dose is one lozenge every 2–3 hours for 6 weeks, with a gradual increase in intervals between lozenges over the next 6 weeks. Some prefer a nicotine inhaler that is shaped somewhat like a cigarette holder; when inhaled, it gives off nicotine vapors which help to relieve withdrawal symptoms. A nicotine nasal spray available with prescription has a quicker delivery system than most of the other NRTs. It is usually prescribed for 3-month periods, for a maximum of 6 months.

For many, these substitutes temporarily lessen the physical withdrawal symptoms of smoking cessation, along with peer support often in the form of groups and telephone helplines. However, for many, these treatments have fallen short of relieving symptoms and helping them to attain or maintain abstinence. This article reviews the clinical uses of two new medications that are currently being used for the treatment of nicotine addiction, bupropion and varenicline.

Bupropion

Bupropion is an atypical antidepressant that acts as a norepinephrine and dopamine reuptake inhibitor and nicotinic antagonist. Initially researched and marketed as an antidepressant, bupropion was subsequently found to be effective for smoking cessation and in 1997 was approved by the FDA for use as a smoking cessation aid.48

Bupropion is widely reported to reduce the severity of nicotine cravings and withdrawal symptoms that accompany smoking cessation. After a seven-week treatment,49 27% of subjects who received bupropion reported that an urge to smoke was a problem, versus 56% of those who received placebo. In the same study,49 the patients taking bupropion reported fewer mood swings than the placebo group (21% vs. 32%, respectively).

Bupropion for smoking cessation treatment was originally recommended as a 7–12-week course, with the patient stopping the use of tobacco approximately 10 days into the course. However, many patients find that a longer course (possibly several months) has proven beneficial so clinicians can tailor treatment to patients’ needs as long as they continue to monitor for adverse effects. Dosing should begin at 150 mg/day given every day for the first 3 days, followed by a dose increase for most patients to the recommended usual dose of 300 mg/day. In comparison to nicotine replacement therapy, bupropion is similarly efficacious. Bupropion approximately doubles the chance of quitting smoking successfully after 3 months. One study50 demonstrated that 1 year after the treatment, the odds of sustaining smoking cessation were 1.5 times higher in the bupropion group than in the placebo group.

Varenicline

Varenicline is a more recently introduced medication indicated for smoking cessation. It is a partial agonist of the α4β2 subtype of the nicotinic acetylcholine receptor that was approved for the treatment of smoking cessation in May 2006 after demonstrating superior efficacy over NRT and bupropion with a minimal side-effect profile.

The FDA approved its use as a 12-week trial51 that, if proven successful, can be continued for another 12 weeks. However, if the patient is not successful at completely stopping smoking within the first 12-week period, continued use is not recommended.

In early comparison studies,50,52 varenicline was more effective than other strategies in helping to reduce nicotine craving and maintain abstinence. One metanalysis study50 identified varenicline to be more effective in reducing craving to both placebo and bupropion and in indirect comparisons with NRT. Another study52 demonstrated that after 1 year, the rate of continuous abstinence was 10% for placebo, 15% for bupropion, and 23% for varenicline. Varenicline has not been tested in children, those <18 years of age, or pregnant or breastfeeding women, and, therefore, is not recommended for use by these populations.

The side effects that are most commonly reported are nausea, headache, insomnia, and abnormal dreams. However, in late 2007 the FDA reported receiving several post-marketing reports of patients experiencing more serious symptoms such as suicidal ideation, erratic and suicidal behavior, and extreme drowsiness.

In early 2008 the FDA issued an alert7 to further clarify its findings, noting that “it appears increasingly likely that there is an association between varenicline and serious neuropsychiatric symptoms.” In spite of this, many patients have reported success with the medication and may decide with their physician that the short- and long-term health risks of smoking outweigh the possible dangers of a trial of this smoking cessation therapy.53 As with all new medications, clinicians are recommended to exercise caution in the use of varenicline and consider the use of alternative approaches to smoking cessation while more research is being conducted to further understand the short- and long-term risks associated with the medication.

Stimulants/Cocaine

Stimulant and cocaine dependence continue to present a major health and societal concern despite increasing public awareness of the dangers that accompany illicit drug use. According to a SAMHSA report54 in 2006, “the demand for treatment for cocaine dependence remained roughly level from 1992–2005, while the demand for treatment for amphetamine dependence increased about eight-fold.” As a result, the National Institute on Drug Abuse has pushed the scientific research community to develop treatments aimed at combating the craving, addiction, and overdose of the drug. To date, however, no treatment has been approved by the FDA.

Cognitive-behavioral therapy, motivational therapy, contingency management, and group therapy (such as 12-step programs) are behavioral therapies empirically proven to be effective in treating cocaine addiction.55-57 However, these treatments could be significantly augmented by pharmacotherapeutic agents to help patients attain initial abstinence or prevent relapse. Medications that ease the symptomatology of cocaine withdrawal (often characterized by anxiety, depression, and fatigue) are options currently available to clinicians, but they still fall far short of treating the greater problem.

Previous articles58,59 have outlined the clinical applications of the antidepressant desipramine and the anti-epileptic carbamazepine for minimizing craving for cocaine. These, however, along with several other antidepressants such as citalopram,60 bupropion,61,62 and fluoxetine,63 have shown insufficient results in treating those with cocaine dependence.

Recently, numerous medications have been shown in placebo-controlled, double-blind, randomized-controlled trials to significantly decrease cocaine dependence (BH Herman, PhD, A Elkashef, MD, and F Vocci PhD, personal communication, July 29, 2008). The focus has mostly been on substitution with stimulant medications to decrease cocaine use by inhibiting craving, reducing withdrawal, and producing tolerance to the acute reinforcing effects of cocaine.

Modafinil and propanolol have demonstrated their potential to attain abstinence by minimizing withdrawal symptoms and reducing cocaine reinforcement.64-67 Other prospective agents minimize relapse by reducing cocaine-induced euphoria and cue-induced craving. These include disulfiram68 and several gamma-aminobutyric acid (GABA)-ergic agents like baclofen,69 tiagabine,70 gamma-vinyl GABA,71 and topiramate.72

A novel approach being studied for relapse prevention is the development of a cocaine vaccine that has been shown to produce cocaine-specific antibodies that bind the drug and prevent it from crossing the blood-brain barrier.73 Similarly, another alternative method being studied is a CNS immunopharmacotherapy for the treatment of cocaine addiction. Intranasal administration of an engineered bacteriophage with cocaine sequestering antibodies on its surface is proposed to bind cocaine in the CNS and block its behavioral effects.74

The pursuit for medications to treat amphetamine and methamphetamine dependence has only recently begun. Thus, fewer medications have been tested and none approved. However, the similarities between the actions of amphetamines and those of cocaine in the brain suggest that the same medications may help with both addictions.75 As a result, studies are underway to examine many of the above proposed treatments for amphetamine and methamphetamine dependence.

Prometa

The Prometa program is a heavily advertised75,76 proprietary program for the treatment of alcohol and stimulant dependence, which, according to promotional materials “…integrates physiological, nutritional, and psychosocial therapies, designed to help patients meet their individual recovery goals….”77 Although the actual medications used in the treatment are not mentioned in the promotional materials, one article78 describes the off-label use of flumazenil, hydralazine, and gabapentin in an open-label study of 50 methamphetamine addicts. During the 12-week, open-label, single-group study, the subjects received, for 3 consecutive days, hydoxyzine 50 mg, followed by flumazenil .1–.3 mg, followed by gabapentin 300 mg/day up to 1,500 mg/day, as tolerated. On days 21 and 22 of the study, the subjects were given “booster” injections of flumazenil. Among the patients treated in this study, there was a 47% reduction in self-reported use over 84 days of treatment as well as significant reductions in urine toxicology results and self-reported craving. However, since no randomized, placebo-controlled studies have been published in the peer-reviewed literature, there is no acceptable evidence that the Prometa program’s risk and expense are justified by its benefits.

Conclusion

Many new medications offer efficacious and effective clinical options to the general physician. The next generation of treatments (including vaccines and “cocktails”) in the pipeline also show exciting potential for further relieving these complex conditions. However, medication management alone remains limited. Comprehensive treatment of substance use disorders can only be maximized by a full biopsychosocial plan which mutually reinforces medication compliance, more traditional psychotherapy, and peer-led help groups. PP

References

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25.    Brasser SM, McCaul, ME, Houtsmiller EJ. Alcohol effects during acamprosate treatment: A dose-response study in humans. Alcohol Clin Exp Res. 2004;28(7):1074-1083.
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42.    Schottenfeld RS, Pakes JR, Oliveto A, Ziedonis D, Kosten TR. Buprenorphine vs. methadone maintenance treatment for concurrent opioid dependence and cocaine abuse. Arch Gen Psych. 1997;54(8):713-720.
43.    Titan Pharmaceuticals Announces Positive Results From Phase III Clinical Trial Of Probuphine For The Treatment Of Opioid Addiction. Available at: www.medicalnewstoday.com/articles/116538.php. Accessed November 4, 2008.
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45.    Preston GE, Kenzie L, Schmittner J, et al. A randomized, single dose, opioid challenge study of extended release naltrexone in opioid-using adults. Poster presented at: the 45th Annual Meeting of the American College of Neuropsychopharmacology; December 3-7, 2006; Hollywood, FL.
46.    Comer SD, Sullivan MA, Yu E, et al. Injectable, sustained-release naltrexone for the treatment of opioid dependence: a randomized, placebo-controlled trial. Arch Gen Psychiatry. 2006;63(2):210-218.
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51.    Food and Drug Administration. FDA Approves Novel Medication for Smoking Cessation. Rockville, Md: National Press Office. May 11, 2006. Press Release P06-67.
52.    Jorenby DE, Hays JT, Rigotti NA, et al. Efficacy of varenicline, an alpha4beta2 nicotinic acetylcholine receptor partial agonist, vs placebo or sustained-release bupropion for smoking cessation: a randomized controlled trial. JAMA. 2006;296(1):56-63. Erratum in: JAMA. 2006;296(11):1355.
53.    Centers for Disease Control and Prevention. Annual smoking-attributable mortality, years of potential life lost, and productivity losses—United States, 1997-2001. MMWR Morb Mortal Wkly Rep. 2005;54(25):625-628.
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55.    Hoffman JA, Caudill BD, Koman JJ 3rd, Luckey JW, Flynn PM, Hubbard RL. Comparative cocaine abuse treatment strategies: enhancing client retention and treatment exposure. J Addict Dis. 1994;13(4):115-128.
56.    Higgins ST, Budney AJ, Bickel WK, Foerg FE, Donham R, Badger GJ. Incentives improve outcome in outpatient behavioral treatment of cocaine dependence. Arch Gen Psychiatry. 1994;51(7):568-576.
57.    Kosten T, Poling J, Oliveto A. Effects of reducing contingency management values on heroin and cocaine use for buprenorphine- and desipramine treated patients. Addiction. 2003;98(5):665-671.
58.    Campbell J, Nickel EJ, Penick EC, et al. Comparison of desipramine or carbamazepine to placebo for crack cocaine-dependent patients. Am J Addict. 2003;12(2):122-136.
59.    McDowell D, Nunes EV, Seracini AM, et al. Desipramine treatment of cocaine-dependent patients with depression: a placebo-controlled trial. Drug Alcohol Depend. 2005;80(2):209-221.
60.    Moeller FG, Schmitz JM, Steinberg JL, et al. Citalopram combined with behavioral treatment reduces cocaine use: A double-blind, placebo-controlled trial. Am J Drug Alcohol Abuse. 2007;33(3):367-378.
61.    Poling J, Oliveto A, Petry N, et al. Six-month trial of bupropion with contingency management for cocaine dependence in a methadone-maintained population. Arch Gen Psychiatry. 2006;63(2):219-228.
62.    Shoptaw S, Heinzerling KG, Rotheram-Fuller E, et al. Bupropion hydrochloride versus placebo, in combination with cognitive behavioral therapy, for the treatment of cocaine abuse/dependence. J Addict Dis. 2008;27(1):13-23.
63.    Grabowski J, Rhoades H, Elk R, et al. Fluoxetine is ineffective for treatment of cocaine dependence or concurrent opiate and cocaine dependence: two placebo-controlled, double blind trials. J Clin Psychopharmacol. 1995;15:163-174.
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Dr. Levenson is professor in the Departments of Psychiatry, Medicine, and Surgery, chair of the Division of Consultation-Liaison Psychiatry, and vice chair for clinical affairs in the Department of Psychiatry at Virginia Commonwealth University School of Medicine in Richmond.
Disclosure: Dr. Levenson reports no affiliation with or financial interest in any organization that may pose a conflict of interest.


 

This column continues a series reviewing the interface between dermatology and psychiatry. Dermatologists and primary care physicians frequently encounter important psychiatric issues affecting diagnosis and management of patients with dermatologic complaints. Psychological factors affect many dermatologic conditions, including atopic dermatitis, psoriasis, alopecia areata, urticaria and angioedema, and acne vulgaris. Some dermatologic conditions are best considered as idiopathic functional disorders, such as idiopathic pruritus, which can be generalized or focal (eg, pruritus ani, vulvae, and scroti). Some primary psychiatric disorders present with primarily physical symptoms to dermatologists, including body dysmorphic disorder (BDD) and delusional disorder, somatic type (eg, delusions of parasitosis, delusions of a foul body odor). Indeed, most patients with delusions of parasitosis or BDD avoid seeing psychiatrists or other mental health professionals, and resist referral. Dermatologists also see patients with compulsive behaviors that may be part of obsessive-compulsive disorder, or that stand alone, eg, trichotillomania, psychogenic excoriation, and onychophagia. Factitious skin disorders include factitious dermatitis (also called dermatitis artefacta) and psychogenic purpura. Another important aspect of the interface between psychiatry and dermatology is the range of dermatologic adverse reactions to psychotropic drugs. More detailed coverage of these topics can be found elsewhere.1,2 The first part of the series focused on atopic dermatitis and psoriasis,3 and the second reviewed alopecia areata, urticaria, and angioedema.4 This third installment reviews acne vulgaris and chronic idiopathic pruritus.

Acne Vulgaris

Acne vulgaris, a common skin disease affecting sebaceous glands with sebum blocking hair follicles, is characterized by a variety of lesions, including comedones, inflammatory papules, pustules, and nodules. The face and upper neck are the most common sites, but the chest, back, and shoulders may also be involved. Most cases of acne vulgaris develop in early adolescence, affecting 85% of teenagers, and it frequently continues into adulthood. During adolescence, the frequency of acne increases with age and pubertal development. In girls, the commencement of menstruation is associated with increased frequency of acne. Perhaps this explains why adolescent girls may be more vulnerable than boys to the negative psychological effects of acne.5 The course of acne vulgaris is usually self-limited, with gradual improvement and spontaneous disappearance after several years, but it may persist into the thirties and forties. Possible complications include development of pitted or hypertrophic scars as well as psychological adverse effects, discussed below. Although women are more likely than men to have persistent acne, it tends to be more severe in men.1,2

Although the cause of acne vulgaris is unknown, many factors are probably involved in its pathogenesis, including genetics, inflammation, skin flora, hormonal activity, and stress. The relationship with stress has long been observed, but there are few prospective studies. One study6 reported that patients with acne may experience worsening of the disease during academic examinations. While there is a significant association between psychological stress and severity of acne, it does not appear to be mediated by increased sebum production.7 A variety of neuroendocrine mediators may be involved in the precipitation or aggravation of acne by stress, including adrenal steroids, corticotropin-releasing hormone, melanocortins, beta-endorphin, vasoactive intestinal polypeptide, neuropeptide Y, insulin-like growth factor, and calcitonin gene-related peptide.1,2,8 It has also been long recognized that lithium can cause or aggravate acne,9 and there have been case reports of acne resulting from aripiprazole,10 lamotrogine,11 valproate,12 and other anticonvulsants, as well as the atypical tricyclic antidepressant amineptine13 (not available in the United States).

Severe acne is associated with increased depression, anxiety, poor self-image, and poor self-esteem.1,2 Not surprisingly, psychiatric symptoms are more common in more severe acne and in the later stages of puberty.14 A cross-sectional study15 of approximately 10,000 teenagers in New Zealand found that “problem acne” was associated with an increased risk of depressive symptoms (odds ratio 2.04), anxiety (odds ratio 2.3), and suicide attempts (odds ratio 1.83). The association of acne with suicide attempts remained after controlling for depressive symptoms and anxiety (odds ratio 1.5). One study16 has estimated the incidence of suicidal ideation in patients with acne as 7.1%. However, psychiatric comorbidity may even occur with milder acne. A Turkish study17 found that patients with acne were at increased risk for anxiety and depression compared to the normal population, irrespective of the degree of severity.

Acne can substantially interfere with social and occupational functioning and result in impairment in quality of life (QOL). There are numerous available rating scales for quantifying QOL in patients with acne.18 Acne negatively affects quality of life, and there is not always a correlation between the severity of acne and its impact on QOL. The magnitude of anxiety and depression is proportional to degree of impairment of QOL due to acne.17 Acne patients with greater social sensitivity experience poorer QOL compared to other patients with the same severity of acne.19 Anger, similarly, is associated with poorer QOL and less satisfaction with treatment, independent of other variables.20

Successful treatment of acne with isotretinoin leads to reduction in anxiety and depression and significant improvement in self-image.1,2 However, patients’ perceptions of the results of treatment for acne can differ from their physician’s judgment, with more pessimistic self-assessment in those with emotional distress.21

Anecdotal reports of depression, suicidal ideation, suicide attempts, and suicide with the use of isotretinoin for treatment of acne vulgaris were widely reported in the media and led the US Food and Drug Administration to expand the label warning to include that “accutane may cause depression, psychosis and, rarely, suicidal ideation, suicide attempts, suicide, and aggressive and/or violent behaviors.”22 However, a recent systematic review23 of nine controlled trials found that rates of depression among isotretinoin users were similar to the rates in oral antibiotic control groups, ranging from 1% to 11%. Trials that compared depression before and after isotretinoin treatment did not show a statistically significant increase in depression symptoms or diagnoses. Some even found a trend toward reduction in depressive symptoms after isotretinoin therapy, particularly in patients with higher pretreatment depression scores. Similar reductions have been reported in uncontrolled trials.24 Another recent study25 in Canada using a retrospective case-crossover design found that, the relative risk for those exposed to isotretinoin of developing a depression diagnosis was 2.68 (95% CI=1.10–6.48), after adjusting for confounders. In contrast, another Canadian group26 recently reported a prospective controlled cohort study that concluded that isotretinoin does not appear to be associated with the development of depression. The literature to date has not proven a causative association between isotretinoin use and depression or suicidal behavior. Interpretation of the literature is complicated both by important methodologic limitations in many of the studies and by the association of acne itself with depression, anxiety, and possibly suicidal behavior.

The FDA and isotretinoin’s manufacturer subsequently added a warning regarding the possible development of aggressive and/or violent behavior to the psychiatric disorder warning section of the package insert previously focused on depression and suicidality. While there have been reports of several cases of manic psychosis in association with isotretinoin treatment,27 large population-based cohort studies have found no evidence that use of isotretinoin is associated with an increased risk for psychosis.28

One may ask how clinicians should proceed, given the FDA’s black box warning and the case reports suggesting an association between isotretinoin and depression and suicide, yet an overall lack of support for these associations in the more rigorous observational and epidemiologic studies. It is prudent to continue to prescribe isotretinoin to treat severe acne, while at the same time educating patients (and the parents of minor patients) of the importance of actively monitoring for depressive symptoms; if symptoms appear, referral to a psychiatrist and discontinuation of isotretinoin should be considered. In addition, patients should be cautioned not to self-medicate for depression with St. John’s Wort both because it is ineffective and because its metabolic interaction with hormonal contraceptives may reduce their effectiveness.

Numerous reports attest to the benefits of a wide variety of psychiatric and psychological treatments for acne, including paroxetine,29 olanzapine,30 relaxation techniques, hypnosis, cognitive-behavioral therapy, and biofeedback,31,32 but no controlled clinical trials except for one.33

Chronic Idiopathic Pruritus

Pruritus, or itchiness, is a common symptom of dermatologic diseases, several systemic diseases (eg, hepatic or renal failure, HIV), and advanced age,1,2 but the cause in chronic pruritus is often not identifiable. Such idiopathic pruritus is typically experienced on a daily basis, especially at night and in the evening, resulting in mostly having difficulty falling asleep. Generalized idiopathic pruritus mainly involves the legs, arms, and back. The most common focal presentations of idiopathic pruritus are pruritus ani, vulvae, and scroti. Idiopathic pruritus may be described as crawling, tickling, stinging, or burning.34,35 In one study,34 idiopathic pruritus patients described the itching as unbearable (73%), bothersome (72%), annoying (67%) and/or worrisome (45%). The pathophysiology of pruritus is not well understood, and it is unclear why it is worse at night.36 While psychiatric symptoms are common in idiopathic pruritus, and idiopathic pruritus is common in psychiatric patients, idiopathic pruritus should be considered as a functional disorder rather than a psychogenic one. New onset of unexplained pruritus should lead to evaluation for occult medical disease before considering it to be idiopathic pruritus.

Recent stressful life events, and degree of anxiety and/or depressive symptoms have been correlated with an increased ability to experience itching.1,2 In a study37 of 100 psychiatric inpatients, idiopathic pruritus was reported by 42% of the subjects, 34% of the men, and 58% of the women, with increased prevalence in those without adequate social support and in those without regular employment. It is not surprising that depression is common in patients with idiopathic pruritus, especially given the chronicity and sleep disturbance.38

For focal idiopathic pruritus (eg, pruritus ani, vulvae, and scroti), topical treatments are used. For both generalized and focal idiopathic pruritus, the most commonly prescribed oral medications are antihistamines, which usually provide some short-term relief. Tricyclic antidepressants, especially doxepin, can relieve chronic idiopathic pruritus. Paroxetine has also been reported to be helpful.39 Opiate receptor antagonists and anticonvulsants (gabapentin, pregabalin, carbamazepine) have also been suggested as possible remedies.40 Behavioral treatment, such as habit-reversal training and cognitive-behavioral therapy, may also be helpful in interrupting the itch-scratch cycle,1,2 and there is one case report of the benefits of hypnosis.41 PP

 

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10. Mishra B, Praharaj SK, Prakash R, Sinha VK. Aripiprazole-induced acneiform eruption. Gen Hosp Psychiatry. 2008;30(5):479-481
11. Nielsen JN, Licht RW, Fogh K. Two cases of acneiform eruption associated with lamotrigine. J Clin Psychiatry. 2004;65(12):1720-1722.
12. de Vries L, Karasik A, Landau Z, Phillip M, Kiviti S, Goldberg-Stern H. Endocrine effects of valproate in adolescent girls with epilepsy. Epilepsia. 2007;48(3):470-477.
13. De Gálvez Aranda MV, Sánchez PS, Alonso Corral MJ, Bosch García RJ, Gallardo MA, Herrera Ceballos E. Acneiform eruption caused by amineptine. A case report and review of the literature. J Eur Acad Dermatol Venereol. 2001;15(4):337-339.
14. Kilkenny M, Stathakis V, Hibbert ME, Patton G, Caust J, Bowes G. Acne in Victorian adolescents: associations with age, gender, puberty and psychiatric symptoms. J Paediatr Child Health. 1997;33(5):430-433.
15. Purvis D, Robinson E, Merry S, Watson P. Acne, anxiety, depression and suicide in teenagers: a cross-sectional survey of New Zealand secondary school students. J Paediatr Child Health. 2006;42(12):793-796.
16. Picardi A, Mazzotti E, Pasquini P. Prevalence and correlates of suicidal ideation among patients with skin disease. J Am Acad Dermatol. 2006;54(3):420-426.
17. Yazici K, Baz K, Yazici AE, et al. Disease-specific quality of life is associated with anxiety and depression in patients with acne. J Eur Acad Dermatol Venereol. 2004;18(4):435-439.
18. Dréno B. Assessing quality of life in patients with acne vulgaris: implications for treatment. Am J Clin Dermatol. 2006;7(2):99-106.
19. Krejci-Manwaring J, Kerchner K, Feldman SR, Rapp DA, Rapp SR. Social sensitivity and acne: the role of personality in negative social consequences and quality of life. Int J Psychiatry Med. 2006;36(1):121-130.
20. Rapp DA, Brenes GA, Feldman SR, et al. Anger and acne: implications for quality of life, patient satisfaction and clinical care. Br J Dermatol. 2004;151(1):183-189.
21. Jones-Caballero M, Pedrosa E, Peñas PF. Self-reported adherence to treatment and quality of life in mild to moderate acne. Dermatology. 2008;217(4):309-314.
22. FDA Approved Drug Products. Available at: www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.Label_ApprovalHistory. Accessed September 24, 2008.
23. Marqueling AL, Zane LT. Depression and suicidal behavior in acne patients treated with isotretinoin: a systematic review. Semin Cutan Med Surg. 2007;26(4):210-220.
24. Kaymak Y, Kalay M, Ilter N, Taner E. Incidence of depression related to isotretinoin treatment in 100 acne vulgaris patients. Psychol Rep. 2006;99(3):897-906.
25. Azoulay L, Blais L, Koren G, LeLorier J, Bérard A. Isotretinoin and the risk of depression in patients with acne vulgaris: a case-crossover study. J Clin Psychiatry. 2008;69(4):526-532.
26. Cohen J, Adams S, Patten S. No association found between patients receiving isotretinoin for acne and the development of depression in a Canadian prospective cohort. Can J Clin Pharmacol. 2007;14(2):e227-e233.
27. Barak Y, Wohl Y, Greenberg Y, et al. Affective psychosis following Accutane (isotretinoin) treatment. Int Clin Psychopharmacol. 2005;20(1):39-41. Erratum in: Int Clin Psychopharmacol. 2005;20(3):182.
28. Jick SS, Kremers HM, Vasilakis-Scaramozza C. Isotretinoin use and risk of depression, psychotic symptoms, suicide, and attempted suicide. Arch Dermatol. 2000;136(10):1231-1236.
29. Moussavian H. Improvement of acne in depressed patients treated with paroxetine. J Am Acad Child Adolesc Psychiatry. 2001;40(5):505-506.
30. Gupta MA, Gupta AK. Olanzapine may be an effective adjunctive therapy in the management of acne excoriée: a case report. J Cutan Med Surg. 2001;5(1):25-27.
31. Shenefelt PD. Using hypnosis to facilitate resolution of psychogenic excoriations in acne excoriée. Am J Clin Hypn. 2004;46(3):239-245.
32. Shenefelt PD. Biofeedback, cognitive-behavioral methods, and hypnosis in dermatology: is it all in your mind? Dermatol Ther. 2003;16(2):114-122.
33. Hughes H, Brown BW, Lawlis GF, Fulton JE Jr. Treatment of acne vulgaris by biofeedback relaxation and cognitive imagery. J Psychosom Res. 1983;27(3):185-191.
34. T-J Goon A, Yosipovitch G, Chan YH, Goh CL. Clinical characteristics of generalized idiopathic pruritus in patients from a tertiary referral center in Singapore. Int J Dermatol. 2007;46(10):1023-1026.
35. Yosipovitch G, Ansari N, Goon A, Chan YH, Goh CL. Clinical characteristics of pruritus in chronic idiopathic urticaria. Br J Dermatol. 2002;147(1):32-36.
36. Patel T, Ishiuji Y, Yosipovitch G. Nocturnal itch: why do we itch at night? Acta Derm Venereol. 2007;87(4):295-298.
37. Kretzmer GE, Gelkopf M, Kretzmer G, Melamed Y. Idiopathic pruritus in psychiatric inpatients: an explorative study. Gen Hosp Psychiatry. 2008;30(4):344-348.
38. Sheehan-Dare RA, Henderson MJ, Cotterill JA. Anxiety and depression in patients with chronic urticaria and generalized pruritus. Br J Dermatol. 1990;123(6):769-774.
39. Zylicz Z, Krajnik M, Sorge AA, Costantini M. Paroxetine in the treatment of severe non-dermatological pruritus: a randomized, controlled trial. J Pain Symptom Manage. 2003;26(6):1105-1112.
40. Lynde CB, Kraft JN, Lynde CW. Novel agents for intractable itch. Skin Therapy Lett. 2008;13(1):6-9.
41. Rucklidge JJ, Saunders D. Hypnosis in a case of long-standing idiopathic itch. Psychosom Med. 1999;61(3):355-358.

 

This interview took place on September 24, 2008, and was conducted by Norman Sussman, MD.

 

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

Disclosure: Dr. Perkins is a consultant to Dainippon Sumitomo Pharma Co., Ltd; is on the speaker’s bureaus of AstraZeneca and Eli Lilly; and receives grant support from Janssen.


 

Dr. Perkins is professor of psychiatry in the Department of Psychiatry at the University of North Carolina (UNC) School of Medicine in Chapel Hill. She is medical director of Outreach and Support Intervention Services at UNC Hospitals and the UNC-Chapel Hill School of Medicine. Dr. Perkins’ research emphasizes treatment of the prodromal period and early intervention of the first episode of schizophrenia. Currently investigating pharmacologic and psychotherapeutic treatments for psychosis, she focuses on managing side effects of atypical antipsychotics and the weight gain mechanism in patients taking psychotropic medications. In addition, Dr. Perkins is investigating the genetic basis of schizophrenia.

 

How has the pathogenesis of schizophrenia evolved in the last century?

It is known that both gene and environment contribute to schizophrenia risk. For example. when an identical twin has schizophrenia, his or her counterpart has a 50% chance of having schizophrenia as well.1 This compares to the population risk of .01%. It is also likely that genetic or environmental risk factors act by changing when and how much protein is made.2

In addition, some forms of schizophrenia are likely neurodevelopmental disorders, meaning that the brains of some people who developed schizophrenia may have developed differently from those unaffected with schizophrenia. It may also be that an environmental event is needed to trigger the disorder in an at-risk person.3 There is also strong evidence that neurocircuits involving the front of the brain, especially the prefrontal cortex, are involved in schizophrenia. Much work needs to be conducted, however, to determine the underlying causes of schizophrenia.

It has been found that schizophrenia is a heterogeneous disorder similar to pneumonia; it is likely that there are hundreds of independent causes to schizophrenia. Such heterogeneity makes it challenging to further decipher the pathogenesis of schizophrenia.

How do parents influence their children having schizophrenia?

One epidemiologic finding is that schizophrenia risk is associated with higher paternal age at the time of conception.  We do not know the reason for this association, but I could speculate that perhaps it is because men make sperm throughout their life, and as they age genetic mistakes may accumulate in the germ line, including variations in the number of copies of genomic regions as well as point mutations. New evidence suggests that the genetic risk of schizophrenia may be due to de novo mutations in the patient.4,5 This may explain why approximately 70% of people who develop schizophrenia do not have a relative with the disorder.6

Is there anything specific about viruses implicated in early development that might be associated with schizophrenia?

There is a wealth of epidemiologic research showing increased risk in individuals who had certain prenatal environmental exposures. An example is maternal starvation where the risk of schizophrenia in offspring doubles.7 While data show most people whose mothers starved did not develop schizophrenia, there is still a small group that may have a biologic vulnerability. Some leading hypotheses suggest it is micro nutrium, meaning some critical nutrients (eg, vitamins D or B) were not received in utero. The second epidemiologic observation involves the fetus’ exposure to an infectious disease process in utero. As a result of this exposure, risk of schizophrenia in adulthood increases by 2–3 fold. Research on that relationship has tried to determine whether it is brain infection with the virus or the maternal immune response that affects brain development, increasing later risk of schizophrenia. Numerous animal models point to the immune maternal response. For example, if there is an infection or something provoking the maternal immune response, then antibodies, cytokines, or other aspects of the immune system response cross the placenta, enter the fetus, and affect brain development. Epidemiologic studies also find that maternal exposure to a traumatic event during pregnancy is associated with an increased risk of schizophrenia. One mechanistic theory involves stress hormones affecting brain development in utero, making a person vulnerable to schizophrenia in adulthood.

There have been studies investigating viral exposures in childhood  and later risk of schizophrenia. For example,  one recent population-based epidemiologic study8 found that childhood cytomegalovirus in the central nervous system was associated with a 16-fold increase in schizophrenia risk.

Is there a connection with gene expression?

One percent of a genome codes for a protein. Until recently, the remaining 99% was considered “junk deoxyribonucleic acid (DNA).” There was no explanation for its function; junk DNA was considered an evolutionary relic. However, in the past 5 years, it has been found that ≥50% of DNA is transcribed into ribonucleic acid (RNA), but this RNA is not translated into protein. Instead, this RNA regulates when and how much of the protein-coding genes are expressed. Numerous post-mortem studies of schizophrenia find altered levels of specific RNAs or proteins, suggesting that some process regulating the expression of a protein is impaired. There is no firm evidence of what regulatory processes might be altered, but research is now focusing on the variety of factors that impact protein expression.

Is there evidence that antipsychotics used earlier are neuroprotective?

Eighty-five percent of patients with schizophrenia will report prodromal symptoms; for example, they may report having weird ideas, illusions, or transient hallucinations (eg, hearing clicking noises, someone calling their name when no one was around). In the prodromal stage of psychosis, people may also complain of increased distractability, problems in school, and social problems. Researchers have been looking at the kinds of symptoms that can help distinguish people at highest increased vulnerability to schizophrenia. The best predictors of psychosis risk appear to be altered thought process (eg, ideas of reference) and abnormal perceptions (eg, illusions or brief hallucinations) that also interfere with social or vocational function.

Current estimates are that approximately 35% to 40% of people experiencing these “clinical high-risk” symptoms will develop a psychotic disorder within 2 years.9 Note that most people who are experiencing these “psychosis-like” symptoms do not go on to develop a psychotic disorder. Some (approximately 20%) will remit; here the symptoms may have been the result of a rough time or a glitch in adolescent brain development that self-corrected. Other times the person was experiencing early symptoms of anxiety disorders, depression, or a personality disorder, but not schizophrenia.

There is great interest in improving the ability to predict risk. One factor that has emerged is functional impairment. The more severe the symptoms, the more they significantly interfere with function. Environmental factors, such as marijuana use or severe stress may further increase psychosis vulnerability. However, more research is required to appropriately identify symptoms before prevention is possible. Studies10-12 examined people experiencing prodromal symptoms who have investigated an antipsychotic, an antipsychotic plus psychotherapy, or psychotherapy alone. In these studies, all interventions were equally successful in preventing psychosis, meaning both pharmacologic and psychotherapeutic interventions could benefit patients.

When the clinician is faced with an adolescent or young adult having clinical high risk symptoms and also struggling in school, treatment decisions are complicated by the fact that most (>50%) will not develop a psychotic illness. While preventative antipsychotic treatment may benefit the approximately 40% who are truly in the earliest stages of illness, antipsychotics are not appropriate for the other 60% of patients. These patients would be unnecessarily exposed to the risks of antipsychotics, such as metabolic or neurologic side effects. In addition, the clinical trials find that patients who are clinically at risk for psychosis are only protected from psychosis while they are taking the antipsychotic. When the antipsychotic is discontinued, the patients continue to be at high risk, and eventually 35% to 40% will develop a psychotic disorder. I think treating clinical high-risk symptoms with an antipsychotic is premature and should only be used when a patient is suffering severe functional impairment. Psychotherapy, however, is a relatively benign and effective treatment. Clinicians should consider some form of psychotherapy, especially a cognitive-behavioral type to help people cope with symptoms, manage stress, and deal with life issues conducive to stress.

Do atypical antipsychotics cause less risk of tardive dyskinesia than the older treatments?

Despite the ongoing debate on this issue, I think they do. In the early part of my career, only typical antipsychotics were available. Tardive dyskinesia was not at all unusual. In my clinical practice tardive dyskinesia is unusual.  Many medical or nursing students rotating through inpatient and outpatient settings will not see a single case of tardive dyskinesia.

Studies on tardive dyskinesia risk are difficult to conduct. Unmedicated people with schizophrenia will develop dyskinetic movements that are indistinguishable from tardive dyskinesia. While dyskinetic movements are not necessarily caused by antipsychotics, there is clear evidence showing antipsychotics increase the risk of developing those movements. In order to understand the difference between the two treatments, patients may have to be followed for several years. Unfortunately, studies of that length are almost impossible to conduct. The reinterpretation of short-term clinical studies suggest that tardive dyskinesia happens less often  with patients treated with atypical antipsychotics. Tardive dyskinesia can certainly emerge in people treated with atypical antipsychotics, but it appears less likely than in patients treated with typical antipsychotics.

Why do antipsychotics tend to cause weight gain and metabolic syndrome?

These adverse effects are seen mostly with newer antipsychotics. For example, patients taking quetiapine, olanzapine, or risperidone have increased risk of weight gain while aripiprazole or ziprasidone might not cause weight gain (at least in adults). In children, there is some increased risk of weight gain and metabolic syndrome with ziprasidone.

There are three possible mechanisms that could explain weight gain and metabolic syndrome in antipsychotic treatment patients. First, the patient’s appetite might increase once starting the antipsychotic. Second, patients using sedative drugs experience increased sleep time, resulting in a decrease in the amount of calories spent in a 24-hour period. Decreased activity is conducive to weight gain. Third, there may be changes in metabolism—for example, how readily a person may tap into fat stores.

I advise patients to exercise regularly and go on a low carbohydrate diet such as the American Diabetic Association diet or the Atkins diet. I have had patients who were able to follow that kind of diet and lose weight associated with antipsychotics. However, weight loss and behavioral change is a difficult task to accomplish, even for people who have schizophrenia. In addition to lifestyle changes, there is emerging evidence from clinical trials13 that metformin may attenuate or even reverse antipsychotic-related weight gain. In addition, there are clinical trials13 suggesting similar benefits from topirimate and amantadine.

Are there developing treatments that may benefit people who are not being treated effectively?

We are learning more about how to best use available treatments. Most clinical trials with antipsychotics were conducted by pharmaceutical industries. As the studies are highly regulated, the data are valid. However, the problem with industry-sponsored studies is that they are initially designed in favor of the company’s drugs. For example, if there is a drug that could cause weight gain, the researchers might not weigh people in the study. There is a fundamental problem with depending on the people who may profit from the drug conducting all of the studies with that drug.

The Clinical Antipsychotic Trials in Intervention Effectiveness (CATIE) study14 involved the atypical antipsychotics that were FDA approved at the time, namely risperidone, quetiapine, and olanzapine. Ziprasidone was added once it was approved by the Food and Drug Administration. Perphenazine was chosen as a typical antipsychotic comparator because the researchers wanted a drug that was unfamiliar and not used. The outcome measure in the CATIE study was all-cause treatment discontinuation. This was picked because it was thought to reflect both clinicians’ and patients’ judgment on how well a medication was working. If a patient experiences enough benefit from a medication and the side effects are not too troublesome, he or she is willing to continue using it. However, if the benefits seem negligible or the side effects are too much relative to the benefit, the patient will stop taking that medication. This was a novel outcome measure that is still somewhat controversial, but it was chosen as a measure of overall effectiveness. The study was large; it randomized 1,400 patients from the United States. Unlike most pharmaceutical industry studies, the CATIE study did not restrict inclusion to those patients who are very healthy, who do not use street drugs, and/or who do not require treatment with other medications, making the findings generalizable to routine clinical practice.

Overall, the study found that 74% of patients discontinued treatment prior to the end of the 18-month study. The time to discontinuation was significantly longer for olanzapine compared to risperidone and quetiapine, and was longer at a trend level compared to perphenazine- and ziprasidone-treated patients. However, olanzapine-treated patients were more likely to gain weight and have lipid abnormalities, so that the improved effectiveness came at the price of more severe side effects. One of the surprising findings of the CATIE study was how well the typical antipsychotic perphenzine peformed compared to the other antipsychotics, especially since other studies had shown that other typical antipsychotics, like haloperidol and chlorpromazine, were not as efficacious as the atypical antipsychotics. Perphenazine prescribing has increased since the publication of the CATIE study.

 What can also be concluded from the CATIE study is that none of the study drugs are optimal, and that treatment discontinuation rates overall are very high. There are now efforts to develop better strategies to improve medication treatment adherence, both with schizophrenia as well as other chronic diseases. Only approximately 50% of patients being treated for chronic illness are compliant with that treatment by 1 year,15 and the reasons for poor adherence are similar in schizophrenia and other chronic disease. We know that there will be a low rate of treatment adherence if a clinician simply writes a prescription and hands that prescription to the patient. A different kind of therapeutic model is needed.

There is growing evidence of a “concordance” model of care, where the patient’s experience of the illness and how treatment affects his or her life is taken into consideration. The clinician may engage in a negotiation with the patient until both agree with the treatment plan. However, it is important to note that even the best-intended patient will likely have difficulties in complying long term. It is difficult to remember to take a medication every day. To be successful, patients usually need to actively work on medication adherence, and the clinician can help. For example, the clinician can keep the medication regimin as simple as possible and also encourage the use of “cognitive adaptive strategies,” where patients develop environmental cues, like pill boxes or alarms to help with adherence.16 The lessons from the CATIE study reveal more than just the need for a new drug. Better ways to use available medication and optimize treatment are needed as well.

There may be breakthrough drugs on the horizon, however. There is a recent clinical trial of a drug that is a selective agonist at certain glutamate receptors (mGluR2 and mGluR3), but that does not affect dopamine receptors. The first published clinical trial17 is promising, and this new drug, at this point called “LY2140023,” may open up a new strategy for treating schizophrenia. Other promising areas include drugs targeting nicotinic receptors. PP

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2.    Perkins et al. microRNA expression in the prefrontal cortex of individuals with schizophrenia and schizoaffective disorder. Genome Biol. 2007;8(2):R27.
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4.    Stefansson H, Rujescu D, Cichon S, et al. Large recurrent microdeletions associated with schizophrenia. Nature. 2008;455(7210):232-236.
5.    International Schizophrenia Consortium. Rare chromosomal deletions and duplications increase risk of schizophrenia. Nature. 2008;455(7210):237-241.
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12.    McGlashan TH, Zipursky RB, Perkins D, et al. Randomized, double-blind trial of olanzapine versus placebo in patients prodromally symptomatic for psychosis. Am J Psychiatry. 2006;163(5):790-799.
13.    Baptista T, ElFakih Y, Uzcátegui E, et al. Pharmacological management of atypical antipsychotic-induced weight gain. CNS Drugs. 2008;22(6):477-495.
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