Needs Assessment: Much to the chagrin of many, restraints are still being utilized in the acute care setting in order to reduce violent behavior. However, it is unknown if the use of restraints increases or decreased the level of agitation that patients experience. This study determines the effect of restraint use on patients’ levels of agitation.

Learning Objectives:
• Understand the level of agitation associated with the use of restraints.
• Review the methods to measure the level of agitation that patients exhibit.
• Determine the effect of the addition of chemical modulation to patients’ levels of agitation.

Target Audience: Primary care physicians and psychiatrists.

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

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

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

This activity has been peer-reviewed and approved by Eric Hollander, MD, chair and professor of psychiatry at the Mount Sinai School of Medicine, and Norman Sussman, MD, editor of Primary Psychiatry and professor of psychiatry at New York University School of Medicine. Review Date: January 14, 2008.

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

To receive credit for this activity: Read this article and the two CME-designated accompanying articles, reflect on the information presented, and then complete the CME posttest and evaluation. To obtain credits, you should score 70% or better. Early submission of this posttest is encouraged: please submit this posttest by February 1, 2010 to be eligible for credit. Release date: February 1, 2008. Termination date: February 28, 2010. The estimated time to complete all three articles and the posttest is 3 hours.

Dr. Zun is chairman and professor of emergency medicine in the Department of Emergency Medicine at Rosalind Franklin University of Medicine and Science/Chicago Medical School and chairman in the Department of Emergency Medicine at Mount Sinai Hospital in Chicago, Illinois. Dr. Downey is assistant professor in Public Policy at Roosevelt University in Chicago.

Disclosure: Dr. Zun is consultant to and on the speaker’s bureau of Eli Lilly. Dr. Downey reports no affiliation with or financial interest in any organization that may pose a conflict of interest.

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



Introduction: This study aimed to determine the effect of restraints on the level of agitation seen in patients restrained in the emergency department for behavioral reasons.
Methods: The convenience, observational study determined the level of patient agitation using the Overt Aggression Scale (OAS) and the Agitated Behavior scale (ABS) over a 2-hour period. The study was performed in a level 1 emergency department with 45,000 annual vis- its. The inclusion criteria included was any patient who presented to the emergency department in need of behavioral restraints; the exclusion criteria eliminated patients who were restrained for non-behavioral reasons. The study was Institutional Review Board approved.
Sixty-two physically restrained patients and 41 physically and chemically restrained patients were seen in the emergency department during the study. The average OAS score varied from 1.6935 at arrival, 1.9839 at application, and 1.4194 at 2 hours for physical restraint; and 1.9756 at arrival, 1.9512 at application, and 1.0732 at 2 hours for physical and chemical restraint. The average ABS score varied from 2.1795 on arrival, 2.20968 at application, and 1.7377 at 2 hours for physical restrained; and 2.4231 at arrival, 2.4516 at application, and 1.3793 at 2 hours for physical and chemical restrained patients. Using both the OAS (F=13.655, df=1, sig at .001) and the ABS (F=6.809, df=1, sig at .011) there was a statistically significant change at 120 minutes in the groups.
Discussion: The study demonstrated that patients who are physically and chemically restrained become more agitated when restraints are first applied, and have less agitation within 120 minutes. The addition of chemical restraint reduced the level of agitation even more than did physical restraints alone.
Conclusion: Restraint usage increased the amount of patient agitation of patients presenting to an emergency department.



Agitated patients frequently present to the emergency department for evaluation and treatment. Should their agitation escalate, such patients present a violence risk to themselves and others. Most emergency physicians and psychiatrists agree that these patients need to be treated as soon as possible in order to prevent violence escalation. These patients are frequently physically and chemically restrained in the acute healthcare setting.

The incidence of using various restraints for agitation in the acute care setting is not well documented in the literature. Soloff and colleagues1 reviewed 13 published studies of adults in an inpatient psychiatric setting and found a range of 1.9% to 66% patients had a need for seclusion and/or restraint. In another study, Robbins and colleagues2 used an average of two restraints on 17% of patients in an acute medical unit. In emergency medicine, it was found that 25.2% of teaching hospitals restrained at least 1 patient/day.3 The percent of patients restrained in a psychiatric emergency room (24% to 25%) was significantly higher than that in an inpatient facility (7% to 20%).4-7 A recent study8 found an average of 3.7% of all emergency department patients needed restraint and seclusion or restraint alone.

Little information exists on the number of patients in the acute care setting whom have been given chemical agents.9 No study identified the number of patients who were only given a chemical agent rather than physical restraint to control behavior. One study demonstrated that 29.1% of the studied patients received both chemical modulation and physical restraint.10 This study did not examine the effects of restraints, chemical or physical, on the level of agitation.

The medical literature is limited as to the effects of these treatments on controlling the level of agitation, either upon presentation or after treatment. The authors of this article proposed this study in order to better understand the role and effect of chemical and physical restraints on agitation in patients in the emergency department. The null hypothesis of the study was that restraint usage does not reduce the amount of patient agitation.



This observational study was performed in an inner-city community teaching hospital emergency department with 45,000 annual visits. Approximately 2,000 patients were categorized as psychiatric patients and 15.2% of this number were restrained. The city’s police department designated the hospital as a referral site for psychiatric patients in the southwest side of the city.

During the summer and fall of 2003, a convenience sample of patients who presented to the emergency department and needed restraints were enrolled when a research fellow was available. An agitation checklist was used for each patient enrolled in the study (Figure). The study was approved by the institutional review board. 


The patients’ level of agitation was evaluated upon arrival, at the time of initial application of restraint, 10 minutes thereafter, and 120 minutes thereafter. The authors of this article chose two validated tests of agitation to determine the patient’s level of agitation in the emergency department; namely, the Agitated Behavior Scale (ABS) and the Overt Aggression Scale (OAS).11-16 These scales were chosen because of their ease of use and their limited data requirements.

The data was inputted into a Statistical Package for the Social Sciences (SPSS) program for analysis (SPSS, version 12, Chicago). To analyze data, the scales were divided into slight (0–13), minimal (14–26), moderate (27–39), and severe (40–52) for the ABS, and none (0), minimal (1–4), moderate (5–8), and severe (9–12) for the OAS. The groups were compared using analysis of variance (ANOVA) and Pearson tests.



A total of 103 patients were enrolled in the study. More males than females, more African Americans than other racial groups, and more older than younger patients were enrolled in the study (Table 1). Some of the data fields in each case were not completed; therefore, not all of the numbers equaled the total. Sixty-two patients only received physical restraints. Forty-one patients received chemical restraints as well as physical restraint. Overall, most of the patients were 26–40 years of age (81 of 102), male (80 of 103), African American (67 of 103), restrained for <6 hours (35 of 77), schizophrenic (34 of 82), and presented with violence and agitation (18 of 101). The physical restraint group had similar characteristics overall except that the patients were >41 years of age (23 of 53) and had violent presentations (12 of 61). The chemical and physical restraint group had similar characteristics to the overall group except they presented with higher violence and agitation levels. The most common chemical agents used for restraint were haloperidol and lorazepam (19 of 41); the least was risperidone (4 of 41).



Among categories in ranking, the scores on the OAS of the patients who were physically restrained went from 1.6935 upon arrival, to 1.9839 at application, to 1.6452 at 10 minutes, and to 1.4194 at 120 minutes. For those who were physically and chemically restrained, the scores went from 1.9756 upon arrival, to 1.9512 at application, to 1.5366 at 10 minutes, and to 1.0732 at 120 minutes (Table 2). The intervals on the ABS of the patients who were physically restrained went from 2.1795 upon arrival, to 2.2097 at application, to 1.8871 at 10 minutes, and to 1.7377 at 120 minutes (Table 2). For those who were physically and chemically restrained, the scores went from 2.4231 upon arrival, to 2.4516 at application, to 1.9310 at 10 minutes, and to 1.3793 at 120 minutes.


In looking for differences among groups within the specific categories, the authors of this article used Pearson Chi squared correlation. After 120 minutes following application of  the OAS both groups had equal numbers (38) in the none category (Tables 3 and 4). However, during that same time period of 120 minutes, the physical alone group had 22, which is 35% of the total population in physical restraints group in the minimal 1–4 category, as compared with the physical and chemical group, with three (7%) in the same minimal category. The physical alone group also had two (3.2%) in the moderate category, as compared with none in that category for the physical and chemical group.


ANOVA was used in looking for differences between groups within the specific categories. A significant difference for OAS was only found at 120 minutes after restraints were done (F=13.655, df=1, sig at .001). The same was true for ABS with a significant difference at 120 minutes after restraints were applied (F=6.809, df=1, sig at .011). There was a significant difference, P=12.68, df=2, sig at .002, using the ABS, within groups upon arrival to the emergency department. Upon arrival, the two groups were about equal in the slight category, with three in the physical alone group, and four in the physical and chemical group. However, the physical alone group had 27 (69%) in the minimal category, as compared with only eight for the physical and chemical group. This pattern changed in the moderate category, with the physical alone group having eight (20%) and the physical and chemical group 13 (50%) in the same category. Using ABS at 120 minutes, there was also a difference, with P=6.58, df=2, sig at .037. At 120 minutes, the physical alone group had 23 (37%) and the chemical and physical group 18 (62%) at slight. The physical group had 31 (50%) at minimal, and the chemical and physical group only had 11 (38%) in the same category. After 120 minutes, the physical group still hadseven (11%) in the moderate category, whereas the physical and chemical group had none.



This study demonstrated three interesting phenomena. First, the level of agitation was high in the both groups. Second, the level of agitation initially increased in both groups during the application of restraints. Last, the level of agitation was reduced more in the physical and chemical group than in the physical restraint group alone. It was unexpected that the level of agitation increased upon application of the restraints. The authors of this article did expect to see that there was a greater reduction in agitation in the chemical and physical restraint group than the physical only.

This study found that the level of agitation was high in both treatment groups. There are few studies that have measured the level of agitation a patient exhibits upon arrival to the emergency department. The natural history of an agitated patient without treatment has not been evaluated and a study of the natural course of an agitated patient without treatment would be valuable. Analogous to pain treatment, the level of agitation over time as measured with one of the agitation tools could be used for the basis of treatment. The treatment and doses could be better metered by this method.

It was an unexpected finding that patients became more agitated when the restraints were first applied. This finding would question whether there are better means to reduce the patient’s level of agitation. If the mantra of medicine is to “first, do no harm,” then it is necessary to find better and more humane means to reduce a patient’s level of agitation instead of the use of restraints.

The scales used in this study have rarely been used in emergency medicine to determine a patient’s level of agitation. Battaglia and colleagues9 used the ABS to assess the differences among haloperidol, lorazepam, or both in the treatment of agitation. They found that all treatment groups showed significant reduction in baseline scores over a 12-hour treatment phase. They did not examine the effect of physical restraint only, nor did they document how many patients also received this intervention. Mock and colleagues10 used the OAS to measure the number of violence episodes encountered by an emergency medical service system.

It is understandable that the level of agitation was most reduced when the patient received both physical restraint and chemical treatment. The authors of this article did not evaluate whether chemical restraint alone might have been the optimal means to reduce a patient’s agitation. The study had initially been designed to examine the effect of chemical restraint only; however, only one patient received this treatment. Many studies have demonstrated the use of various agents to control agitation in the emergency department.9-22 Two atypical intramuscular antipsychotics have been approved for use in the agitated patients with schizophrenia and bipolar disorder. Most of these studies have been limited to comparison of a new atypical agent to haloperidol with or without lorazepam in patients with known schizophrenia or bipolar disorder. A randomized, double-blind, controlled trial of undifferentiated emergency department agitated patients would be more valuable. One randomized controlled trial compared atypical and typical antipsychotics on the undifferentiated patient to determine the best agent for use in the emergency department.23 Martel and colleagues23 compared droperidol, ziprasidone, and midazolam and found midazolam inferior to the other agents.

Both the Joint Commission for Accreditation Healthcare Organizations and the Center for Medicare and Medicaid Services require that alternatives be attempted prior to the initiation of restraints, whether they are physical or chemical.24-28 These alternatives may include negotiating with patients, putting them closer to the nursing station, and offering them food. A review of the literature found few helpful studies examining the effectiveness of the use of alternatives in the reduction of restraint use.

The measurement tools for agitation limited the study presented in this article. Although the validated tools have been used to determine the level of agitation in settings outside the emergency department, their usefulness in the acute care setting has not been determined.29-38 Prior studies using the tools administered in this study have been used to determine a patient’s risk of violence rather than the patient’s level of agitation. Arrango and colleagues29 and McNeil and colleagues30 have used the OAS to determine the risk of violence in patients. The ABS has been used to evaluate brain trauma patients and demented patients, but not in patients in the emergency department.36-38 Perhaps there are other measures of agitation that would have provided better information than those that were used in this study.

This study was limited by incomplete data collection for some of the patients and by the observational nature of the study. It would have been preferred to use a randomized, controlled trial evaluating different means of treating a patient’s level of agitation. The small number of patients in each group also limited this study. The groups were not homogenous in terms of diagnosis or indication for restraints. The study was also limited by the fact that individual physicians chose the form of treatment or restraint to place the patient in, rather than the choice being determined by study protocol.



This study sets the need for further inquiry regarding the agitated patient. The best and most humane means of modulating the agitated behavior of psychiatric patients is yet to be determined. A multi-faceted prospective study aimed at examining various approaches to patients with different agitation etiologies is needed, albeit difficult to accomplish in the acute care setting. It is essential to understand that a patient may become more agitated when restraints are initially applied, and the medical staff must be prepared to deal with this. Over time, these restrained patients will become significantly less agitated with the addition of chemical agents. PP



1.    Soloff PG, Gutheil TG, Wexler DB. Seclusion and restraint in 1985: a review and update. Hosp Community Psychiatry. 1985;36(6):652-657.
2.    Robbins L, Boyko E, Lane J, Cooper D, Jahnigen DW. Binding the elderly: A prospective study of the use of mechanical restraints in an acute care hospital. J Am Geriatr Soc. 1987;35(4):290-296.
3.    Lavoie FW, Carter GL, Danzl DF, Berg RL. Emergency department violence in United States teaching hospitals. Ann Emerg Med. 1988;17(11):1227-1233.
4.    Frengley JD, Mion LC. Incidence of physical restraints on acute medical wards. J Am Geriatr Soc. 1986;34(8):565-568.
5.    Telintelo, S, Kuhlman, TL, Winger, C. A study of the use of restraint in a psychiatric emergency room. Hosp Community Psychiatry. 1983;34(2):164-165.
6.    Dubin WR. Evaluating and managing the violent patient. Ann Emerg Med. 1981;10(9):481-484.
7.    Mion LC, Frengley JD, Jakovcic CA, Marino JA. A further exploration of the use of physical restraints in hospitalized patients. J Am Geriatr Soc. 1989;37(10):949-956.
8.    Lavoie FW. Consent, involuntary treatment and the use of force in an urban emergency department. Ann Emerg Med. 1992;21(1):25-32.
9.    Battaglia J, Moss S, Rush J, et al. Haloperidol, lorazepam, or both for psychotic agitation? A multicenter, prospective, double blind, emergency department study. Am J Emerg Med. 1997;15(4):335-340.
10.    Mock EF, Wrenn KD, Wright SW, Eustis TC, Slovis CM. Prospective field study of violence in emergency medicine services calls. Ann Emerg Med. 1998;32(1):33-36.
11.    Clinton JE, Sterner S, Stelmachers Z, Ruiz E. Haloperidol for sedation of disruptive patients. Ann Emerg Med. 1987;16(3):319-322.
12.    Reschke RW. Parental haloperidol for rapid control of severe, disruptive symptoms of acute schizophrenia. Dis Nerv Syst. 1974:35(3):112-115.
13.    Anderson WH, Kuehnle JC, Catanzano DM. Rapid treatment of acute psychosis. Am J Psychiatry. 1976;133(9):1076-1078.
14.    Neborsky R, Janowsky D, Munson E, Depry D. Rapid treatment of acute psychosis with high and low dose haloperidol. Arch Gen Psychiatry. 1981(2);42:195-199.
15.    Baldessarini RJ, Cohen BM, Teicher MH. Significance of neuroleptic dose and plasma level in the pharmacological treatment of psychosis. Arch Gen Psychiatry. 1988;45(1):79-81.
16.    Thomas H Jr, Schwartz E, Petrilli R. Droperidol versus haloperidol for chemical restraint of agitated and combative patients. Ann Emerg Med. 1992;21(4):407-413.
17.    Richards JR, Derlet RW, Duncan DR. Chemical restraint for the agitated patient in the emergency department: lorazepam versus droperidol. J Emerg Med. 1998;16(4):567-573.
18.    Chase PB, Biros MH. A retrospective review of the use and safety of droperidol in a large, high-risk, inner-city emergency department patient population. Acad Emerg Med. 2002;9(12):1402-1410.
19.    Breier A, Meehan K, Birkett M, et al. A double blind, placebo-controlled dose-response comparison of intramuscularly olanzapine and haloperidol in the treatment of acute agitation in schizophrenia. Arch Gen Psych. 2002;59(5):441-448.
20.    Meehan K, Zhang F, David S, et al.  A double-blind, randomized comparison of the efficacy and safety of intramuscularly injections of olanzepine, lorazepam or placebo in treating acutely agitated patients with bipolar mania. J Clin Psychopharmacol. 2001;21(1):389-397.
21.    Brook S, Lucey JV, Gunn KP. Intramuscular Ziprasidone compared with intramuscular haloperidol in the treatment of acute psychosis. J Clin Psychiatry. 2000;61(12):933-941.
22.    Geodon. In: Physicians’ Desk Reference. Montvale, NJ: Thomson; 2007:2529-2535.
23.    Martel M, Sterzinger A, Miner J, Clinton J, Biros M. Management of acute undifferentiated agitation in the emergency department: a randomized double blind trial of droperidol, ziprasidone and midazolam. Acad Emerg Med. 2006;12(12):1167-1172.
24.    Centers for Medicaid and Medicare Services: Medicare and Medicaid Programs: Hospital Conditions of Participation: Clarification of the Regulatory Flexibility Analysis for Patients Rights. Available at: Accessed January 7, 2008.
25.    Centers for Medicaid and Medicare Services Certification & Compliance: Hospitals. Available at:  Accessed January 8, 2008.
26.    Centers for Medicaid and Medicare Services: Medicare and Medicaid Programs; Hospital Conditions of Participation: Patients’ Rights; Final Rule. Available at: Accessed January 8, 2008.
27.    The Joint Commission. Sentinel Event Alert. Preventing Restraint Deaths. November 18, 1998. Available at: Accessed January 3, 2008.
28.    The Joint Commission on Accreditation of Hospitals and Healthcare Organizations. Comprehensive Manual on the Accreditation of Hospitals: The Official Handbook. Oak Brook, Illinois: JCAHO; 2007.
29.    Arango C, Calcedo BA, Gonzales-Salvador, Calcedo OA. Violence in inpatients with schizophrenia: a prospective study. Schizophr Bull. 1999;25(3):493-503.
30.    McNeil DE, Binder RL. Clinical assessment of the risk of violence among psychiatric patients. Am J Psych. 1991;14(10):1317-1321.
31.    Kafantaris V, Lee DO, Magee H, et al. Assessment of children with overt aggression scale. J Neuropsychiatry Clin Neurosci. 1996;8(2):186-193.
32.    Kopecky HJ, Kopecky CR, Yudofsky SC. Reliability and validity of the overt agitation severity scale in adult psychiatric inpatients. Psychiatr Q. 1998;69(4):301-323.
33.    Corrigan JD. Development of a scale for assessment of agitation following traumatic brain injury. J Clin Exp Neuropsychol. 1989;11(2):261-277.
34.    Yudofsky SC, Silver JM, Jackson W, Endicott J, Williams D. The overt aggression scale for objective rating of verbal and physical aggression. Am J Psychiatry. 1986;43(1):35-39.
35.    Silver JM, Yudofsky SC. The overt aggression scale: Overview and guiding principles. J Neuropsychiatry Clin Neurosci. 1991;3(2):S22-9.
36.    Bogner JA, Corrigan JD, Stange M, Rabold D. Reliability of agitated behavior scale. J Head Trauma Rehabil. 1999;14(1):91-96.
37.    Corrigan JD, Mysiw WJ. Agitation following traumatic head injury: equivocal evidence for a discrete stage of cognitive recovery. Arch Phys Med Rehabil. 1988;69(7):487-92.
38.    Bogner JA, Corrigan JD, Bode RK, Heinemann AW. Rating scale analysis of the Agitated Behavior Scale. J Head Trauma Rehabil. 2000;15(1):656-669.




Dr. Cummings is the Augustus S. Rose Professor of Neurology, professor of psychiatry and biobehavioral sciences, director of the Mary S. Easton Center for Alzheimer Research at the University of California, Los Angeles (UCLA), and director of the Deane F. Johnson Center for Neurotherapeutics at the David Geffen School of Medicine at UCLA.

Disclosures: Dr. Cummings has served as a consultant for Acadia, Adamas, Astellas, Avanir, CoMentis, Eisai, EnVivo, Janssen, Forest, Lundbeck, Medivation, Merck, Merz, Myriad, Neurochem, Novartis, Ono, Pfizer, Prana, Sanofi-Aventis and Takeda. Dr. Cummings owns the copyright of the Neuropsychiatric Inventory. Dr. Cummings has been supported by a National Institute on Aging Alzheimer Disease Center grant (P50 AG 10157), an Alzheimer’s Disease Research Center of California grant, the Sidell-Kagan Foundation, and the August Rose Chair of the University of California.

Acknowledgements: Dr. Cummings thanks his colleagues at the UCLA Alzheimer Disease Center and the patients and caregivers who have given meaning to his commitment to find more effective treatments for Alzheimer’s Disease. He also thanks his wife Kate (Xue) Cummings (Zhong) without whose enthusiasm, love, and support this project would have been impossible.

Please direct all correspondence to: Jeffrey L. Cummings, MD, Alzheimer Disease Center, 10911 Weybrun Ave, #200, Los Angeles, CA 90095-7226; Tel: 310-794-3665; Fax: 310-794-3148; E-mail:



Focus Points

• Alzheimer’s disease is the most common cause of dementia in the elderly.
• Alzheimer’s disease and dementia are affected by genetics, neuropathology, and pathophysiology.
• The evaluation of the patient presenting for assessment of cognitive impairment includes clinical, laboratory, and imaging aspects.
• Clinical scales and inventories help to assess the presence of dementia.
• Warning signs of Alzheimer’s disease may help family members decide if an evaluation is warranted.



This educational review article is the first of a two-part adaptation of a clinical handbook that is useful in the diagnosis and treatment of Alzheimer’s disease and other dementias (The Black Book of Alzheimer’s Disease, J.L. Cummings, MD, 2008, publication pending). The classification of dementia, the expansion of diagnostic approaches to include more mild syndromes such as mild cognitive impairment (MCI), and the rapid evolution of new therapies make it difficult to remain informed about all critical progress relevant to Alzheimer’s disease and related conditions. The article provides information needed to manage patients using contemporary advances in diagnosis and management. It will be updated annually in the form of a Black Book to insure that it remains current.

This article is not intended as a comprehensive reference. It provides critical information only. In addition, it provides references and Web sites where more information can be found on each topic presented. Constructed for the clinician (primary care practitioner, neurologist, or psychiatrist) who needs rapid access to updated information, this article also contains information valuable to families (eg, Web sites) that the practitioner can provide in the course of discussions about Alzheimer’s disease and dementia.

Useful ratings scales and standardized assessments are described. Reference and resource sections complete the article. The presentations and discussions have been kept deliberately short, as the purpose is not to serve as a textbook but to provide information critical to patient care embedded in enough context to make management decisions coherent and logical.


Epidemiology of Alzheimer’s Disease and Dementia

Alzheimer’s disease is the most common cause of dementia in the elderly, accounting for 60% to 75% of cases. The frequency of dementia doubles every 5 years, increasing from affecting 1% of individuals 60–64 years of age; to 2% of those 65–69 years of age; 4% of individuals 70–74 years of age; 8% of those 75–79 years of age; 16% of those 80–84 years of age; and 35% to 45% of those >85 years of age (Figure 1).1 Most of these dementia patients have Alzheimer’s disease (Figure 2). An estimated 3.5–4.5 million Americans and 25 million worldwide have dementia.2 By 2040, these figures are expected to rise to 9.2 million (North America) and 81.1 million (global).2 The number of Alzheimer’s disease victims will have a striking impact on the global economy. The estimated cost of caring for dementia patients in 2003 was $156 billion3 and these costs will rise to staggeringly large numbers as the world population ages.




Risk and protective factors for Alzheimer’s disease have been identified through epidemiologic and case-controlled studies (Tables 1 and 2). A Mediterranean type-diet, dietary antioxidants, statins, and exercise are among the factors associated with reduced risk of Alzheimer’s disease, while low education levels, head injury, diabetes, and hypertension increase the risk of Alzheimer’s disease.4-9


Discussion of these risk and protective factors with relatives of Alzheimer’s disease patients interested in information about reducing their risk for Alzheimer’s disease is warranted. Lifestyle changes in midlife may have the greatest impact on the eventual development of Alzheimer’s disease. It is uncertain if factors that reduce the risk of Alzheimer’s disease will also decrease the progression of MCI to Alzheimer’s disease, or of the progression of established Alzheimer’s disease.


Genetics, Neuropathology, and Pathophysiology of Alzheimer’s Disease


Alzheimer’s disease is inherited as an autosomal dominant disorder in a small number of cases (3% to 5%) of the total number of Alzheimer’s disease patients. Most of the autosomal dominant forms of Alzheimer’s disease have an early onset dementia syndrome with symptoms appearing in the fifth and sixth decades of life. Mutations causing Alzheimer’s disease have been identified on chromosome 21 in the amyloid precursor protein (APP) and in the genes encoding presenilin 1 (chromosome 14) and preselinin 2 (chromosome 1), respectively.10 The presenilins form part of the g-secretase enzyme complex responsible for metabolizing APP to amyloid b protein. Triplication of the APP gene in trisomy Down syndrome is also associated with Alzheimer’s disease and all long-surviving individuals with Down syndrome develop Alzheimer’s disease-type brain pathology. Presenilin 1 mutations are the most common of the mutations causing early onset Alzheimer’s disease, and testing for this mutation is commercially available.

Polymorphisms of genes occurring in the population may increase the risk of developing Alzheimer’s disease. Apolipoprotein e4, encoded on chromosome 19, is the most well-established risk gene for Alzheimer’s disease.10 Clinical testing for e4 in asymptomatic individuals is not recommended since it does not provide definitive predictive information. There is increasing evidence of a role for a SORL1 polymorphism (chromosome 11) as a risk factor for Alzheimer’s disease.11



There is progressive atrophy of the brain in Alzheimer’s disease with loss of cerebral substance in temporal, parietal, and frontal regions. Primary motor and sensory cortices are relatively spared. The primary histopathologic lesions of Alzheimer’s disease are amyloid plaques, neurofibrillary tangles, and neuronal loss.12 Mature plaques consist of a central amyloid core with surrounding degenerating neurons affected by the toxic effect of the b-amyloid protein. Proliferating astrocytes and activated microglia are present in the plaque. Neurofibrillary tangles consist of hyperphosphorylated tau protein that has assumed a double helical filament conformation.12

Alzheimer’s disease is often complicated by other neuropathologic processes when patient brains are studied at autopsy.13 These studies demonstrate that comorbid conditions commonly coexist with Alzheimer’s disease at least by the time patients reach advanced stages of their disease (Figures 3–6; Table 3).





The β-amyloid peptide is derived from the APP through sequential proteolysis by b-secretase and γ-secretase. Monomeric peptides aggregate into increasing complex assemblies of oligomers, protofribrils, and fibrils, and are eventually deposited as insoluble plaques.14 It is the oligomeric intermediate species of amyloid to which neurotoxicity is attributed.15 β-amyloid initiates a cascade of events leading to synaptic dysfunction, neurodegeneration and neuron death.16 The elements of the cascade include oxidation, inflammation, excitotoxicty, and tau hyperphosphorylation leading to neurofibrillary tangle formation.


Assessment of Cognitive Impairment

Clinical Assessment

The evaluation of the patient presenting for assessment of cognitive impairment includes clinical, laboratory, and imaging aspects. The history of present illness, medical history, review of systems, social history, family history, and current medications should be discussed with the patients and corroborated by a caregiver or other knowledgeable informant. Caregiver mood and stress should be noted and evaluated.

The mental status examination is an essential part of the assessment of cognition and typically includes standardized assessments such as the Mini-Mental State Examination (MMSE)17 or the Montreal Cognitive Assessment (MoCA)18 and unstructured hypothesis-driven assessments based on findings that emerge in the course of the examination. The mental status examination should assess five basic cognitive domains, including attention, memory, language, visuospatial function, and executive function.

Results of the cognitive assessment are integrated with physical examination (ie, cardiac auscultation, carotid and peripheral pulse palpation, head and neck examination) and the neurologic examination (ie, cranial nerves, motor function, sensory function, coordination, muscle stretch reflexes, primitive reflexes, gait, station). A preliminary diagnostic formulation emerges and allows selection of appropriate laboratory tests and neuroimaging. Standardized mental status examinations are described below.


Laboratory Tests

The American Academy of Neurology (AAN) guidelines19 suggest that the routine laboratory assessment of cognitively impaired patients include basic laboratory studies of complete blood count, electrolytes, blood sugar, liver function tests, and blood urea nitrogen as well as thyroid stimulating hormone and serum B12 level (Table 4).19-21 Additional tests may be sought to clarify the clinical assessment. Lumbar puncture and examination of the cerebrospinal fluid is not a routine part of the evaluation for cognitive impairment but can be very helpful in assisting diagnosis in some cases (Table 5).







Brain imaging of patients with dementia is recommended by the AAN19 and the European Federation of Neurological Science.20 Computerized tomography or magnetic resonance imaging (MRI) provide structural information to exclude brain tumors, subdural hematomas, and obstructive hydrocephalus. Medial temporal atrophy can usually be discerned on MRI of patients with Alzheimer’s disease or amnestic MCI. Areas of high signal intensity are seen in the cerebral white matter on T2-weighted images in patients with small vessel disease associated with hypertension or diabetes. Obtaining T1, T2, and fluid-attenuated inversion-recovery imaging are the most useful in assessment of dementia syndromes.20 Magnetic resonance spectroscopy is a research instrument whose potential for more routine use is under investigation.

Single photon emission computed tomography demonstrates cerebral blood flow; patterns distinctive for Alzheimer’s disease (bilateral parietal hypoperfusion), frontotemporal dementia (frontal and temporal hypoperfusion), and vascular dementia (multifocal hypoperfusion with multiple infarctions) can be identified. Metabolic imaging with fluorodeoxyglucose positron emission tomography (PET) reveals distinctive metabolic profiles for different dementia syndromes21 (Figures 7–10).



PET imaging of amyloid with Pittsburgh Compound B22 or FDDNP23 is being studied but is not yet commercially available. Amyloid in the brain is synonymous with the presence of Alzheimer’s disease; with PET imaging, the amyloid may be identified before the patient meets criteria for Alzheimer type dementia.


Clinical Scales and Inventories

Brief Screening Tools

Mini-Mental State Examination
The MMSE17 is the most widely used brief mental status screening instrument. It consists of 30 questions, comprised of 10 orientation items, three recall items, five reverse spelling or serial subtraction items, three learning items, six oral language items (naming, repetition, comprehension), one reading item, one writing item, and one construction item. The MMSE best assesses disorders with important language and memory components such as Alzheimer’s disease. The examination changes at a rate of approximately three points per year in typical Alzheimer’s disease. The MMSE may be abnormal in dementia, delirium, aphasia, or amnesia syndromes. It is relatively insensitive to mild changes in well-educated individuals and is insensitive to change in advanced dementia. The MMSE lacks tests of executive function.

The Mini-Cog is a very brief assessment of memory and drawing skills. It is comprised of three memory items and a clock-drawing test (Figure 11). This very short assessment has similar sensitivity in specificity to the MMSE.25


Montreal Cognitive Assessment
The MoCA is a 30-item test similar to the MMSE but with less emphasis on language, memory, and orientation, and greater emphasis on executive function.18 Executive items included in the MoCA include Trails-B, clock drawing, word list generation, a continuous performance task, and abstraction of similarities. The naming items are lower frequency than those of MMSE and more likely to detect a mild anomia. The five-word learning test may be more sensitive to memory impairment than the three-word learning test of the MMSE (See example at www.mocatest.org28).

Functional Activity Questionnaire
The Functional Activity Questionnaire measures instrumental activities of daily living such as using transportation, balancing a checkbook, and preparing a meal.9 It provides a means of assessing mild impairment of higher level daily functions.

Neuropsychiatry Inventory–Questionnaire
The Neuropsychiatry Inventory-Questionnaire (NPI-Q)30 is the brief version of the Neuropsychiatric Inventory.31 The NPI-Q can be completed by a caregiver and provides information regarding 12 common behavioral changes and behavioral syndromes, including hallucinations, delusions, anxiety, depression, apathy, elation, disinhibition, irritability, abberrant motor behavior, agitation, sleep abnormalities, and appetite disturbances. The associated NPI-Q also allows the caregiver to indicate their level of distress with each behavior (Figure 12).


Other commonly used assessments of neuropsychiatric symptoms and behavioral abnormalities in patients with Alzheimer’s disease and other dementias include the Cohen-Mansfield Agitation Inventory,32 the Behavioral Pathology in Alzheimer’s Disease rating scale,33 and the Cornell Scale for Depression in Dementia.34

Neuropsychological Measures
Formal neuropsychological assessment allows standardized comprehensive evaluation of cognitive deficits and cognitive strength compared to age- and education-matched controls. Psychological testing is particularly useful when questions arise in regard to distinguishing normal aging from early cognitive abnormalities and MCI.

Neuropsychological testing can generate an intelligence quotient as well as assessments of memory and learning, language, visuospatial and constructional skills, executive function, and psychomotor speed.


Clinical Trials

Clinical trial instrumentation overlaps with tools used in clinical practice but many of the outcome measures used in clinical trials are too time and labor intensive to be used in routine clinical practice.

The Food and Drug Administration requires that an agent produce a statistically significant advantage over placebo on a cognitive outcome and a global or functional outcome to be approved as an antidementia agent. Secondary outcomes commonly included in clinical trials assess behavioral changes and alterations in activities of daily living. Pharmacoeconomics, caregiver burden, and quality of life are assessed in some trials (Figure 13).



The cognitive assessment most commonly used in clinical trials is the Alzheimer’s disease Scale cognitive portion (ADAS-Cog).35 This instrument assesses memory, language, and praxis; higher scores indicate greater impairment.

The ADAS-Cog is used to assess patients with mild-to-moderate dementia. Clinical trials including patients with moderate-to-severe dementia are assessed with a Severe Impairment Battery.36

The Neuropsychological Test Battery has been used as an outcome measure in some clinical trials of patients with mild-to-moderate Alzheimer’s disease. The instrument has a memory and executive function factor, is reliable and sensitive to change, and may be particularly useful for patients with mild degrees of cognitive impairment.37

Global Assessments
Global assessments that may be used in clinical trials include the Clinical Interview-based Impression of Change scale37 or the Clinical Global Impression of Change scale.38 These global assessments provide a summary evaluation that includes cognition, function, and behavior. The Clinical Dementia Rating scale39 is sometimes used as a global outcome, particularly in longer clinical trials.

Activities of Daily Living

Activities of Daily Living (ADL) are an important outcome in clinical trials and are usually assessed as a secondary outcome measure. Commonly used assessments of ADL include the Alzheimer’s Disease Cooperative Study, ADL Inventory,40 or Disability Assessment for Dementia scale.41

The Neuropsychiatric Inventory29 is the behavioral measure most widely used as an outcome in clinical trials involving dementia patients.

Parkinsonism is assessed in many studies of patients with Parkinson’s disease or dementia with Lewy bodies. The Unified Parkinsonism Disease Rating Scale42 is the instrument most commonly incorporated into clinical trials where parkinsonism was an important outcome.


10 Warning Signs of Alzheimer’s Disease

Families may be uncertain and concerned if a loved one has the symptoms of Alzheimer’s disease. The warning signs may help them decide if an evaluation is warranted; the presence of any of these symptoms should lead to medical referral.


Memory Loss

Forgetting recently learned information is one of the most common early signs of dementia. A person begins to forget more often and is unable to recall the information later. However, forgetting names or appointments occasionally is normal.


Difficulty Performing Familiar Tasks

People with dementia often find it hard to plan or complete everyday tasks. Individuals may lose track of the steps involved in preparing a meal, placing a telephone call or playing a game. However, occasionally forgetting why one came into a room or what one planned to say is normal.


Problems with Language

People with Alzheimer’s disease often forget simple words or substitute unusual words, making their speech or writing hard to understand. For exmple, they may be unable to find the toothbrush and instead ask for “that thing for my mouth.” However, sometimes having trouble finding the right word is normal.


Disorientation to Time and Place

People with Alzheimer’s disease can become lost in their own neighborhood, forget where they are and how they got there, and not know how to get back home. However, it is normal to forget the day of the week or where one was going.


Poor or Decreased Judgment

Those with Alzheimer’s disease may dress inappropriately, wearing several layers on a warm day or little clothing in the cold. They may show poor judgment, like giving away large sums of money to telemarketers. However, making a questionable or debatable decision from time to time is normal.


Problems with Abstract Thinking

Someone with Alzheimer’s disease may have unusual difficulty performing complex mental tasks, like forgetting what numbers are for and how they should be used. However, it is normal to find it challenging to balance a checkbook.


Misplacing Objects

A person with Alzheimer’s disease may put objects in unusual places, such as an iron in the freezer or a wristwatch in the sugar bowl. However, misplacing keys or a wallet temporarily is normal.


Changes in Mood or Behavior

Someone with Alzheimer’s disease may show rapid mood swings, from calm to tears to anger, for no apparent reason.However, it is normal to occasionally feel sad or moody.


Changes in Personality

The personalities of people with dementia can change dramatically. They may become extremely confused, suspicious, fearful or dependent on a family member. However, people’s personalities do change somewhat with age.


Loss of Initiative

A person with Alzheimer’s disease may become very passive, sitting in front of the television for hours, sleeping more than usual, or not wanting to perform usual activities. However, it is normal to sometimes feel weary of work or social obligations.


Caregiver and Professional Resources

Contact information for caregiver and professional resources can be found in Tables 6 and 7.





Alzheimer’s disease research is forging ahead rapidly toward new therapies and the possibility of disease-modifying interventions. The second part of this review will appear in the March 2008 issue and will focus on diagnostic criteria for dementia and related disorders as well as treatment options for these disorders. PP



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20.    Lu PH, Masterman DA, Mulnard R, et al. Effects of testosterone on cognition and mood in male patients with mild Alzheimer disease and healthy elderly men. Arch Neurol. 2006; 63:(2)177-185.
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22. Waldemar G, Dubois B, Emre M, et al. Recommendations for the diagnosis and management of Alzheimer’s disease and other disorders associated with dementia: EFNS guideline. Eur J Neurol. 2007;14(1):e1-e26.
23. Silverman DH, Small GW, Chang CY, et al. Positron emission tomography in evaluation of dementia. JAMA. 2001;286(17):2120-2127.
24. Klunk WE, Engler H, Nordberg A, et al. Imaging brain amyloid in Alzheimer’s disease with Pittsburgh Compound-B. Ann Neurol. 2004;55(3):306-319.
25. Small G, Kepe V, Ercoli L, et al. PET of brain amyloid and tau in mild cognitive impairment. New Engl J Med. 2006;355(25):2652-2663.
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27. Borson S, Scanlan JM, Chen P, Ganguli M. The Mini-Cog as a screen for dementia: validation in a population-Bbased sample. J Am Geriatr Soc. 2003;51(10):1451-1454.
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Needs Assessment: Selective serotonin reuptake inhibitors and serotonin norepinephrine reuptake inhibitors are prescribed as first-line treatments for depression and other medical and psychiatric disorders. While most side effects are relatively minor, some uncommon complications may present in a medical or surgical context. Doctors who prescribe these medications should become aware of these adverse events and closely monitor these patients.

Learning Objectives:
• Familiarize with uncommon effects associated with selective serotonin reuptake inhibitors (SSRIs) and serotonin norepinephrine reuptake inhibitors (SNRIs).
• Comprehend why uncommon side effects associated with SSRIs and SNRIs are often not identified.
• Identify when close monitoring and use of appropriate alternative intervention is indicated.

Target Audience: Primary care physicians and psychiatrists.

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

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

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

This activity has been peer-reviewed and approved by Eric Hollander, MD, chair and professor of psychiatry at the Mount Sinai School of Medicine. Review Date: January 14, 2008.

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

To receive credit for this activity: Read this 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 February 1, 2010 to be eligible for credit. Release date: February 1, 2008. Termination date: February 28, 2010. The estimated time to complete all three articles and the posttest is 3 hours.

Dr. Sussman is the editor of this journal as well as professor of psychiatry and associate dean for Postgraduate Medical Programs at New York University School of Medicine in New York City.

Disclosure: Dr. Sussman reports no affiliation with or financial interest in any organization that may pose a conflict of interest.
Please direct all correspondence to: Norman Sussman, MD, 150 E 58th St, 27th Floor, New York, NY 10155; Tel: 212-588-9721; E-mail:



The selective serotonin reuptake inhibitors and serotonin norepinephrine reuptake inhibitors, drugs originally introduced as treatments for depression, are now extensively prescribed for a variety of other medical and psychiatric disorders as well. Their appeal as first-line agents derives from their simplicity of use and relative absence of life-threatening side effects. The most common adverse events associated with the use of these drugs tend to affect quality of life issues such as sexual function and desire, body weight, sleep, and emotional reactivity. However, there are some side effects that, while uncommon, can produce complications that present in a medical or surgical context. Consequently, patients may undergo unnecessary physical and laboratory examination as well as unneeded medical/surgical intervention. In some instances they may endure these side effects for extended periods.



The introduction of selective serotonin reuptake inhibitors (SSRIs) in the 1980s revolutionized the treatment of depressive illness. Better tolerated in terms of cholinergic and cardiovascular side effects, safer in overdose, and effective in treating a broad range of anxiety disorders, the SSRIs supplanted not only older classes of antidepressants such as the tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors, but anxiolytics such as benzodiazepines as well. Over time, and with extensive clinical experience, it became clear that some of the most common side effects associated with the SSRIs and serotonin norepinephrine reuptake inhibitors (SNRIs)—those that also have adverse effects on quality of life—had gone virtually undetected during clinical trials. These side effects include sexual dysfunction, weight gain, emotional blunting, and discontinuation syndrome. Looper1 called attention to other treatment-associated adverse events that, if undetected, can have potentially serious consequences for the patient. Some may be potentially fatal if not recognized. All may be a source of significant anxiety and unpleasant memories for the patient and may result in needless referral for consultation with medical specialists (who also may not be aware of these side effects) and subsequent medical tests.


Reasons for Under-recognition of Side Effects

It is difficult to arrive at accurate estimates of the true incidence of antidepressant side effects in clinical practice, even if the drugs are extensively prescribed. Even rigorous clinical trials routinely fail to detect treatment emergent events that are quite common. Perhaps the best examples of such failures involving SSRIs are the belated recognition that sexual dysfunction and weight gain are quite common.

One reason that pivotal clinical trials—those that determine whether a drug is effective and safe enough to market—exclude the kinds of patients who are likely to use the drugs once they are marketed is that those who are studied are not at all like the patients seen in the clinical setting. For example, patients who suffer from mild depression (ie, Hamilton Rating Scale for Depression score <18), those with a history of non-response to antidepressant treatment, and placebo cannot be enrolled. Excluded as well are alcohol or drug abusers, children, the elderly, pregnant women, those who are acutely suicidal, those with psychotic symptoms, subjects taking concomitant medications, and those with comorbid psychiatric or other medical illnesses. Another problem with pre-marketing clinical trials is that they are invariably too small or too short to detect rare side effects. For example, adverse events that occur in fewer than 1/1,000 patients or that take >6 months to appear tend to be missed. It would take a study with 3,000 patients at risk in order to detect an adverse drug reaction with an incidence of 1/1,000 (0.1%) with 95% certainty.2 No single pivotal trial has come close to this size, the largest usually consisting of 300 patients. Even if all preclinical trials were to be pooled, <3,000 patients have been studied.

Once a drug has been approved, it is assumed to be safe, and reports of safety and tolerability problems arise from the clinical setting. If side effects occur, it is not always clear that they are associated with the new drug. The first-line spontaneous reporting system is the Food and Drug Administration’s MedWatch. However, because it relies on physician initiative, using MedWatch (like similar systems in the United Kingdom where underreporting is common) only 1 in 10 cases are reported.3 Case reports/letters to editor, a very important kind of “heads-up” for clinicians, do not reveal the true incidence of adverse events because there is an uncertain numerator and denominator. In addition, after the first case reports and letters to the editor are published, the number of new reports decline. Manufacturer-initiated postmarketing (Phase 4) trials represent another means for determining a drug’s safety profile, but these are usually undertaken with a focus on efficacy and new clinical uses. They are rarely conducted to rule out a potential adverse event. As a result of these and other factors, there is typically a considerable delay between drug marketing and a full appreciation of its true side-effect profile

The examples of less common but potentially serious side effects that follow are discussed because there are a sufficient number of cases reported in the literature to warrant further scrutiny about their effects on important aspects of diverse physiologic systems. This article covers bleeding abnormalities, hyponatremia, hormonal disturbances, lipid elevation, bone loss, serotonin syndrome, and male reproductive effects.


Bleeding Risk

Platelets cannot synthesize aggregtion and serotonin; they store serotonin and release it in response to vascular injury, causing changes to the shape of the platelets. SSRIs and SNRIs inhibit the serotonin transporter (responsible for the uptake of serotonin into platelets), depleting platelet serotonin. It has never been clear how clinically significant the effects of serotonergic drugs might be on platelet function. However, one recent review4 noted that there are >120 MEDLINE-cited peer-reviewed research articles and >50,000 Web pages devoted to SSRI-related bleeding events. The medical literature abounds with case reports and study results attesting to the abnormal platelet aggregation associated with SSRI/SNRI therapy.5

Movig and colleagues6 presented evidence of the clinical relevance of bleeding and SSRIs in the surgical setting. Their study of 520 patients admitted for orthopedic surgery found that patients on SSRIs had twice the volume of intra-operative blood loss and an odds ratio (OR) of 3.7 for requiring blood transfusions during the admission. This risk was not observed with other antidepressants.

A study of patients 40–79 years of age without conditions that could cause gastrointestinal bleeding (UGIH) or disorders of coagulation found an association between SSRIs and upper gastrointestinal bleeding.7 In the patients with UGIH, 52 (3.1%) were current users of SSRIs, compared with only 1% of controls. The estimated crude incidence rate is one case per 1,300 patients taking SSRIs. The risk greatly increased by concomitant use of nonsteroidal anti-inflammatory drugs (NSAIDs) or aspirin. The adjusted relative risk for UGIH with SSRIs alone was 2.6 and with NSAIDs alone was 3.7. When SSRIs and NSAIDs were used together, the adjusted relative risk jumped to 15.6 compared with control subjects.8,9 SSRIs more than double the risk of UGIH. Concomitant NSAID use increases the risk by >500%. The statistical interaction is of similar magnitude to that seen with concurrent aspirin and NSAID use. The highest absolute risk is highest among older patients with depression. Clinicians should caution patients about combining SSRIs with aspirin, NSAIDs, or anticoagulants. The risk of bleeding is not predicted by standard blood tests and requires platelet aggregation studies (for patients with evidence of abnormal bleeding or bruising or who are pre-surgery). If findings are abnormal, taper SSRI prior to surgery.

Most cases of SSRI- or SNRI- associated bleeding events are not life threatening (eg, bruising, heavy menses, and gastrointestinal bleeds. Little evidence links SSRI use with intracerebral hemorrhage, and at least one analysis10 found no increased risk associated with SSRI use for intracerebral hemorrhage (OR=1.1, 95% CI: .7-1.8; P=.63) or subarachnoid hemorrhage (OR=0.6, 95% CI: .4-1.0; P=.054). In addition, potentiation of risk with warfarin or antiplatelets was not observed. In terms of possible clinical advantages for the hematologic effects of SSRIs an SNRIs on preventing stroke, none have been found.11

Unfortunately, there is little to no guidance in the literature as to how to avoid potential bleeding problems with these drugs. For example, how long before surgery should these agents be discontinued? Does serotonin withdrawal become a clinically significant problem post surgery?



SSRIs and SNRIs are among the most common causes of hyponatremia.12 The risk of hyponatremia is three times as high in patients taking SSRIs and SNRIs as it is in patients taking other antidepressants.13 Among elderly patients receiving SSRIs and SNRIs, 12% to 25% develop laboratory levels of hyponatremia, and 12% develop a clinical syndrome. The risk among youths is not known. Risk factors for hyponatremia, other than older age, include female gender, use of other medications, or medical conditions. The risk is highest during the first weeks of treatment, so early lab tests are recommended. As sodium levels drop, patients progress from confusion, to stupor, to coma, and then seizures. Death can occur due to herniation.

In mild cases, management of the syndrome of inappropriate antidiuretic hormone involves discontinuing the medication (if possible) and water restriction. The condition should normalize in approximately 2 weeks. In more extreme cases (sodium <110), sodium replacement may be necessary, but the intervention should not be too aggressive in order to avoid risk of central pontine myelinolysis. Once sodium reaches 120, only water restriction should be implemented.


Breast Enlargement and Lactation

In 1997, Amsterdam and colleagues14 reported significant rates of breast enlargement among women during treatment with SSRIs and venlafaxine. Rates varied among the different drugs, with rates being highest with paroxetine. Subsequent reports describe breast enlargement during the course of SSRI therapy.15,16

SSRI-associated gynecomastia can occur in males and is probably related to degree of reuptake inhibition. Symptoms and prolactin levels may respond to dose adjustment of SSRI/SNRI. Breast discharge may continue for a time after normalization of prolactin levels. It is especially likely when SSRIs/SNRIs are used in combination with risperidone and other dopamine antagonists.17


Lipid and Cholesterol Elevations

Severe hypertriglyceridemia secondary to SSRIs and SNRIs has been reported frequently in the literature.18 In one case series,19 cholesterol levels were measured during an 8-week trial of paroxetine in healthy men. Plasma levels of paroxetine were monitored to verify compliance with treatment. In 16 of 18 patients, paroxetine administration induced an 11.5% increase in low-density lipoprotein cholesterol (LDL-C). These levels normalized after paroxetine discontinuation. According to the authors, the magnitude of the paroxetine-induced increase in LDL-C would lead to a minor increase in coronary heart disease (CHD) risk in a minority of healthy male volunteers without associated CHD risk factors but might increase LDL-C sufficiently to warrant therapeutic intervention in patients with established CHD.

Increases in LDL cholesterol levels have been reported among patients taking SSRIs for panic disorder. In one published case report20 of a patient with panic disorder before and after successful treatment with sertraline, fasting baseline concentrations of serum total (total-C), low-density lipoprotein (LDL-C), and high-density lipoprotein cholesterol (HDL-C) and triglycerides were determined prior to and after successful naturalistic treatment with SSRIs in 11 medically healthy patients.20 All patients studied were free of psychotropic medication and were not heavy smokers, coffee drinkers, excessive alcohol users, or street drug users. Eight panic disorder patients were treated with sertraline 100–300 mg/day, two with citalopram 30–60 mg/day, and one with paroxetine 30 mg/day over a period of 4.5–13.5 months. Contrary to the authors’ hypothesis, “mean fasting levels of total, LDL, and HDL cholesterol were all significantly increased from baseline after successful SSRI treatment of panic disorder.”


Bone Loss

The most recent adverse event to join the list of medically significant side effects possibly caused by SSRI/SNRI treatment is osteoporosis. There have been numerous animal studies showing an interaction between the inhibition of serotonin reuptake and osteoblast (bone-forming cells) and osteoclast (bone resorbing cells). Mice with genetic disruption of the serotonin transporter gene have lower bone-mineral density when compared with wild-type mice. These were the first findings to suggest that there might be clinical correlations between the presence of functional serotonin transporters in osteoblasts, osteocytes, and osteoclasts, and treatment with compounds that inhibit the serotonin reuptake transporter. A more recent animal study21 suggests that there may be multiple factors involved in bone mass changes during SSRI treatment. Systemic fluoxetine, administered to mice for 6 weeks, was shown to increase trabecular bone volume and bone volume fraction in femurs and vertebrae. This correlated with an increase in trabecular number, connectivity, and decreased trabecular spacing. Fluoxetine treatment was also shown to increase volume in vertebral trabecular bone. However, the study found that fluoxetine-treated mice were not protected against bone loss after ovariectomy. This obviously raises a question about whether the anabolic effect of SSRIs require the presence of estrogen.

In the same study, the effect of a challenge with an inflammatory agent that stimulated osteoclast-mediated bone resorption was investigated. The effect of on bone loss following a lipopolysaccharide (LPS)-mediated inflammatory challenge was also investigated. Subcutaneous injections of LPS over the calvariae for 5 days increased the numbers of osteoclasts and net bone loss, but new bone formation and a net gain in bone mass was seen when LPS was given together with fluoxetine.

Two major studies published in 2007 raised alarms because they were prospective, involved human subjects (not mice), were large (involving thousands of patients), and showed that there was significant bone loss among the elderly taking SSRIs. One study was an investigation of 2,722 women with an average age of approximately 80 years.22 Checks on bone mineral density were made initially and again approximately 5 years later. The authors adjusted for other factors, such as the severity of depression and use of calcium supplements. Mean total hip bone mineral density (BMD) decreased .47% per year in nonusers compared with .82% in SSRI users (P=.<00) and .47% in TCA users (P=.99). In a second study,23 readings of the hip and bone density of approximately 6,000 men ≥65 years of age were conducted. Further readings were taken 2 years later. Mean BMD (hip readings) among SSRI users were 3.9% lower, and spine readings were 5.9% lower among SSRI users than those reporting no SSRI use. There were no differences among trazodone and TCA users and non-antidepressant users.

Many questions remain unanswered. Does depression itself represent a risk factor for osteoporosis? Human studies conducted so far warrant caution when using these drugs in the elderly. Although peak bone mass develops during adolescence, it remains to be seen if there is a need for monitoring when prescribing SSRIs to children, adults, or premenopausal women. The benefit of medications for osteoporsis is not known.


Serotonin Toxicity

Unlike the neuroleptic malignant syndrome associated with use of antipsychotics, serotonin toxicity (ie, serotonin syndrome) is not idiosyncratic, but an extension of the SSRIs and SNRIs pharmacologic effect. Ostensibly, it is caused by an excess of serotonin, with the susceptibility to this side effect varying considerably among individuals, with some patients experiencing symptoms even at modest therapeutic doses of a single agent at the start of treatment. Serotonin syndrome symptoms include restlessness, hallucinations, loss of coordination, fast heart beat, rapid changes in blood pressure, increased body temperature, overactive reflexes, nausea, vomiting, and diarrhea.

Most often the sydrome is dose dependent, often occurring at high doses when combining these drugs with other serotonergic agents or adding serotonergic agents to ongoing SSRI therapy. Adding some opioids such as meperidine, fentanyl, tramadol, and pentazocine to SSRIs and SNRIs has been associated with the serotonin toxicity.

Anesthesiologists should recognize the potential for and manifestations of serotonin syndrome for a reaction even when there is a remote possibility of the syndrome, with patients being monitored accordingly.24

A potentially frequent drug combination in clinical practice is the use of a triptan to treat migraine along with an SSRI or SNRI to treat anxiety, depression, or pain. Concurrent use of a triptan and an SSRI or SNRI is normally uneventful, but serotonin toxicity occurs occasionally. There is a pharmacodynamic (additive effects on the serotonin system) as well as pharmacokinetic (inhibition of triptan metabolism by SSRIs) interaction between triptans and SSRIs. Responding to multiple reports of serious reactions, in 2006 the FDA issued a Public Health Advisory.25 The FDA requested that all manufacturers of triptans, SSRIs, and SNRIs update their prescribing information to warn of the possibility of serotonin syndrome when triptans and SSRIs or SNRIs are taken together. In view of the FDA position on triptans, physicians should monitor patients for signs and symptoms of serotonin syndrome (eg, restlessness, sweating, tremor, shivering), particularly during treatment initiation, with dose increases, or with the addition of another serotonergic medication. Nevertheless, it is important to bear in mind that there have been millions of patients exposed to SSRI/SNRI combinations, with very few cases of serotonin syndrome reported.26 It would be unfortunate if these patients were to be denied efficacious treatments for a highly distressing and disabling condition. Indeed, extent of potential for serotonin syndrome remains unknown.

There are no accepted guidelines for serotonin syndrome treatment. The best approach is to be aware of potential interactions, and weigh the benefits and risks of treatment. The main intervention once a reaction occurs is to stop the offending drugs. Benzodiazepines can be used for patient comfort and rigidity. Patients should be monitored closely for rhabdomyolysis and metabolic acidosis. In severe cases patients may require intubation. Once the offending medication is discontinued there is usually dramatic improvement within 24–48 hours.


Reproductive Effects

A new focus of some studies is the possible adverse impact of SSRIs on male fertility. Several recent reports raise the possibility that SSRIs and SNRIs may have an effect on sperm. To date, most studies of reproductive health have focused on egg health rather than sperm. Few if any studies have been performed on the effects of prescription medication on sperm chromatin. In general, FDA studies conducted before approval of a new medication address only limited assays of sperm counts and motility, not the health of the sperm’s DNA.

One report27 presents evidence that the SSRIs may have varying degrees of spermicidal and antitrichomonas activity in vitro. Another publication28 links low sperm count to SSRI therapy. The authors28 report that 14 patients reported reduction in sperm counts from antidepressants. The authors speculate that because SSRI drugs affect both sperm count and the ability of sperm to move, the antidepressants may be preventing sperm from reaching the semen. A controlled study by investigators at Cornell has been completed, but the results have not been published by the time this issue went to press.



Treatment-emergent physiologic changes associated with use of SSRIs and SNRIs, while rare, are nevertheless clinically significant. The possibility of these side effects should not deter clinicians from diagnosing and treating depression or anxiety with these a drugs. These are serious and debilitating disorders that need to be treated, with the benefits of treatment well established. However, those who prescribe or are prescribed antidepressants should be aware of what can go wrong during treatment. When problems arise, closer monitoring and use of an appropriate alternative intervention is indicated. This reduces risk to the patient and prevents complicated medical work-ups. PP



1.    Looper KJ. Potential medical and surgical complications of serotonergic antidepressant medications. Psychosomatics. 2007;48(1):1-9.
2.    Phillips B. Rule of three. Arch Dis Child. 2005;90(6):642.
3.    Rawlins MD. Pharmacovigilance: paradise lost, regained or postponed? The William Withering Lecture. 1994. J R Coll Physicians Lond. 1995;29:41-49.
4.    Serebruany VL. Selective serotonin reuptake inhibitors and increased bleeding risk: are we missing something? Am J Med. 2006:119(2):113-116.
5.    Alderman CP, Moritz CK, Ben-Tovim DI. Abnormal platelet aggregation associated with fluoxetine therapy. Ann Pharmacother. 1992;26(12):1517-1519.
6.    Movig KL, Janssen MW, de Waal Malefijt J, Kabel PJ, Leufkens HG, Egberts AC. Relationship of serotonergic antidepressants and need for blood transfusion in orthopaedic surgical patients. Arch Intern Med. 2003;163(19):2354-2358.
7.    de Abajo FJ, Rodríguez LA, Montero D. Association between selective serotonin reuptake inhibitors and upper gastrointestinal bleeding: population based case-control study. BMJ. 1999;319(7217):1106-1109.
8.    Meijer WE, Heerdink ER, Nolen WA, Herings RM, Leufkens HG, Egberts AC. Association of risk of abnormal bleeding with degree of serotonin reuptake inhibition by antidepressants. Arch Intern Med. 2004;164(21): 2367-2370.
9.    Loke YK, Trivedi AN, Singh S. Meta-analysis: gastrointestinal bleeding due to interaction between selective serotonin uptake inhibitors and non-steroidal anti-inflammatory drugs. Aliment Pharmacol Ther. 2007;27(1):31-40.
10.    Kharofa J, Sekar P, Haverbusch M, et al. Selective serotonin reuptake inhibitors and risk of hemorrhagic stroke. Stroke. 2007;38(11):3049-3051.
11.    Weinrieb RM, Auriacombe M, Lynch KG, Lewis JD. Selective serotonin re-uptake inhibitors and the risk of bleeding. Expert Opin Drug Saf. 2005;4(2):337-344.
12.    Goh KP. Management of hyponatremia. Am Fam Physician. 2004;69(10):2387-2894.
13.    Jacob S, Spinler SA. Hyponatremia associated with selective serotonin-reuptake inhibitors in older adults.  Ann Pharmacother. 2006;40(9):1618-1622).
14.    Amsterdam JD, Garcia-España F, Goodman D, Hooper M, Hornig-Rohan M. Breast enlargement during chronic antidepressant therapy. J Affect Disord. 1997;46(2):151-156.
15.    Marcus P. SSRIs and mammoplasia. Am J Psychiatry. 2001;158(6):967.
16.    Ashton AK, Longdon MC. Hyperprolactinemia and galactorrhea induced by serotonin and norepinephrine reuptake inhibiting antidepressants. Am J Psychiatry. 2007;164(7):1121-1122.
17.    Sahin M, Yilmaz H, Guvener ND. A possible case of gynecomastia with fluoxetine. Ann Pharmacother. 2005;39(7-8):1369.
18.    Teitelbaum M. Severe hypertriglyceridemia secondary to venlafaxine and fluoxetine. Psychosomatics. 2001;42(5):440-441.
19.    Lara N, Baker GB, Archer SL, Le Mellédo JM. Increased cholesterol levels during paroxetine administration in healthy men. J Clin Psychiatry. 2003;64(12):1455-1459.
20.    Bailey PD, Le Melledo JM. Effects of selective serotonin reuptake inhibitors on cholesterol levels in patients with panic disorder. J Clin Psychopharmacol. 2003;23(3):317-319.
21.    Battaglino R, Vokes M, Schulze-Späte U, et al. Fluoxetine treatment increases trabecular bone formation in mice. J Cell Biochem. 2007;100(6):1387-1394.
22.    Diem SJ, Blackwell TL, Stone KL, et al. Use of antidepressants and rates of hip bone loss in older women: the study of osteoporotic fractures. Arch Intern Med. 2007;167(12):1240-1245.
23.    Haney EM, Chan BK, Diem SJ, et al. Association of low bone mineral density with selective serotonin reuptake inhibitor use by older men. Arch Intern Med. 2007;167(12):1246-1251.
24.    Keegan MT, Brown DR, Rabinstein AA. Serotonin syndrome from the interaction of cyclobenzaprine with other serotoninergic drugs. Anesth Analg. 2006;103(6):1466-1468.
25.    FDA public health advisory: combined use of 5-hydroxytryptamine receptor agonists (triptans), selective serotonin reuptake inhibitors (SSRIs) or selective serotonin/norepinephrine reuptake inhibitors (SNRIs) may result in life-threatening serotonin syndrome. U.S. Food and Drug Administration. Available at: Accessed January 10, 2008.
26.    Evans RW. The fda alert on serotonin syndrome with combined use of ssris or snris and triptans: an analysis of the 29 case reports. Medscape General Medicine. Available at: Accessed January 10, 2008.
27.    Yirmiya R, Goshen I, Bajayo A, et al. Depression induces bone loss through stimulation of the sympathetic nervous system. Proc Natl Acad Sci U S A. 2006;103(45):16876-16881.
28.    Tanrikut C, Schlegel PN. Antidepressant-associated changes in semen parameters. Urology. 2007;69(1)185.


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

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



Telemedicine is generally viewed as use of video conferencing in the delivery of health care. However, it encompasses the various technologies, including E-mail and the telephone, in creating a connection between the provider and patient. Despite its clear potential to deliver health care to patients in rural settings or facilitate the reach of specialty providers to a larger patient population, telemedicine has somewhat faded in the technology and medicine limelight. This column reviews some of the early promises for telemedicine, examines various barriers in implementation and adoption of telemedicine, and explores the opportunities to return telemedicine to the forefront of medical care.



The 1990s were the beginnings of telemedicine that grew along side of the development of the World Wide Web. Balch and Tichenor1 described how at East Carolina University (ECU) School of Medicine telemedicine was used to reach rural areas of eastern North Carolina, where there was a shortage of healthcare providers. From 1992–1996, they conducted >1,000 consultations, with 55% in dermatology. In addition to consultations to rural clinics, specialists at ECU provided consultations to the emergency rooms. The network also provided family medicine grand rounds to the rural sites.

One of the major benefits of telemedicine is its ability to reach special populations such as rural patients who need deaf services. In South Carolina, the program for the Deaf and Hard of Hearing used a video conferencing program to provide psychiatric care.2 Jill Afrin, MD, an American Sign Language fluent psychiatrist, would normally travel 14 hours per week to treat clients around South Carolina. Using a desktop video conferencing system from PictureTel, she could communicate with patients in three community health centers without leaving her office, instead of traveling 50% of her time and seeing significantly fewer patients.

Zarate and colleagues3 studied the use of video conferencing for evaluating patients with schizophrenia, with particular emphasis on the impact of the video quality on assessment rating measures such as the Brief Psychiatric Rating Scale (BPRS), the Scale for the Assessment of Positive Symptoms (SAPS), and the Scale for the Assessment of Negative Symptoms (SANS). They compared in-person patient visits to low-quality (182 kilobits/second bandwidth) and high-quality (384 kilobits/second bandwidth) telemedicine sessions. Patients with schizophrenia were actually quite satisfied with their virtual visit and preferred the telemedicine visit over the in-person visit. Total scores on the BPR and SAPS were comparable to live rating for both low and high quality. SANS was comparable to live rating only at high quality since at low quality sessions there is difficulty rating negative symptoms.

Shea and colleagues,4 in the Informatics for Diabetes Education and Telemedicine project, studied the difference in diabetes management for usual care versus telemedicine intervention in an older, ethnically-diverse, and medically underserved patient population in New York City. Patients in the intervention group had home telemedicine units installed with dial-up Internet access, which also had blood glucose monitors attached to upload data. Nurses made visits via telemedicine to check on patients and implemented both direct video conference-based educational modules and store-forward self-paced modules from the Website established for the project. Although both groups demonstrated reductions in hemoglobin A1C, blood pressure, and low-density lipoprotein levels, the telemedicine intervention group achieved statistically significantly greater levels. Although many pilot studies demonstrate the impact of telemedicine, this study had much more statistical power with its 1,665 participants, 884 of whom had the telemedicine intervention.



Hardware issues are an obvious barrier to implementing and establishing telemedicine. In 1996, the average personal computer cost $2,500 and video conferencing systems, such as the PictureTel, Compression Laboratories, Sony, and VTEL, ranged from $20,000–$60,000.5 At that time, Integrated Service Digital Networks (ISDN) were the primary most reliable and direct data transmission service, which provided 384 Kbps rates both upstream and downstream. A listserv posting indicated that Bell Atlantic charged from $120–$240 of usage charges for 100 hours of residential ISDN service.6 In comparison, monthly dial-up Internet access by America Online in 1996 was $50 for unlimited number of hour’s access at 28.8 Kbps. Today, Web cameras which transmit video and audio are quite inexpensive at $30, but in 1996, Creative Labs Inc. sold the ShareVision PC3000 for $9,995. This product worked over regular analog phone lines but was compatible only with other ShareVision setups.

Compatibility of various systems was clearly a problem. A direct data transmission connection between setups using ISDN provided security since the network was private although quite expensive. Present day cable and digital subscriber line (DSL) modems provide up to 3 Mbps (equals 3,000 kilobits) per second downstream and up to 300 Kbps upstream or upload for only $20/month. Although Verizon’s FiOS fiber optic Internet access is extremely fast at 30 Mbps download and 5 Mbps upload speeds for $42.99/month, it is not readily available.7 In remote rural areas, DSL and cable access are often not available. The bandwidth requirement for video and audio is certainly not met with dial-up Internet speeds of 56 Kbps. Satellite transmissions, such as HughesNet, can reach download speeds of 2 Mbps and 500 Kbps upload for their business plan, but costs $199.99/month.8 Lower speeds are available via satellite as well, such as WildBlue’s Value Pak at 512 Kbps download and 128 Kbps upload for $49.99/month.9 Clarke and colleagues10 have demonstrated in a simulation that even with low bandwidth satellite links, packet-switched protocols such as TCP/IP can support telemedicine well if not too may concurrent sessions are running.

Video transmission standards have made it possible to decrease costs by utilizing public networks such as the Internet in lieu of direct connections as well as utilizing different equipment at each site. The International Telegraph Union (ITU),11 a United Nations agency, creates international standards for telecommunications services. Standard video protocols supported by web cameras include H.263 and H.264, which involve different levels of compression of the audio and video data. H.263 is an ITU standard, designed for low bitrate communications such as video-conferencing and video-telephony applications, but it can be used for a wide range of bitrates. H.264, also an ITU standard, is a high-quality video compression algorithm and is suited for all types of applications with different ranges of bit rates. This technology is also known as AVC (Advanced Video Coding) or MPEG-4 Part 10 (ISO/IEC 14496-10).

Although the Internet provides an existing and inexpensive infrastructure to conduct telemedicine, security is of concern. For consultations conducted between urban and rural health clinics, the use of a virtual private network (VPN) connection ensures that any data exchange is conducted over a private channel on the public Internet. This setup requires knowledgeable staff to setup the VPN hardware or software as well as a fast Internet connection and video system to compensate for the performance degradation secondary to the encryption. This technical demand is one barrier to why telemedicine visits have largely been between medical facilities and not direct to patients in the comfort of home. Chen and colleagues12 have described a way to utilize a discrete key encryption/decryption system to enable telemedicine visits from providers at hospitals to patients at home.

One of the technological issues raised with telemedicine versus the “plain old telephone system” is reliability. Balch and Tichenor1 indicated that their center had to employ staff at each site in order to manage the daily operation of their network in order to troubleshoot any difficulties. In addition to technical staff, healthcare staff needed time to develop familiarity with the equipment, and good interpersonal communication between the technical staff and clinical staff is essential.

Technical difficulties with telemedicine, such as choppy video or prolonged latency in audio reception, are significant drawbacks to a satisfactory session.13 Staff and patients need to learn proper “etiquette” in how to conduct a video conferencing session to avoid confusion and distraction in the session, which may detract from the experience.14 Such etiquette includes avoiding rapid movements, awaiting turns to speak, and speaking slower if needed.

Backup systems need to be in place to address potential failures in areas such as data transmission, video and audio, and power. Pre-visit testing to validate a connection is important, particularly if telemedicine is conducted over the Internet with equipment from different manufacturers. At East Carolina University’s telemedicine program, the developers discovered that due to the technical requirements for their network connections, their own staff had to design and build their own alarm system to inform the engineering staff when their data connection was lost instead of relying on the phone company.1

Nesbitt and colleagues15 noted that in California, reimbursement was one barrier to the use of telemedicine, and in 1996, the Welfare and Institutions Code 14132.72 was passed that mandated reimbursement of telemedicine services. The experience at University of California (UC) Davis Telemedicine Program is that in rural areas, the majority of patients had Medicaid insurance coverage, whereas in suburban and urban areas private insurance and Medicare were the majority. Their experience has been that many private insurance companies have not developed a reimbursement policy for telemedicine and have made it difficult to get reimbursement by requiring significant explanation of the telemedicine visit, the role of the presenting provider, the role of the consultant, and paying the telecommunications costs. The Center for Telehealth and E-Health Law notes that only five states have a statutory requirement that private insurance cover telehealth services. These include Louisiana (1995), California (1996), Oklahoma (1997), Texas (1997), and Kentucky (2000).16

Licensure is a particularly significant barrier to the adoption of telemedicine by many practitioners. Most state medical boards have agreed that the practice of medicine occurs in the state where the patient is located.17 Therefore, physicians who wish to practice telemedicine are required to obtain a license in the state where the patient is located, which may be an expensive and time-consuming endeavor. Only 15 states have adopted an abbreviated licensing process for the purpose of telemedicine. Even this legislation does not help in eleven states that have laws explicitly requiring physical examination before the physician can prescribe.

East Carolina University discovered that scheduling is important in telemedicine. With their multiple sites and limited resources, they needed an Online scheduling system so that rural sites could request specialty consults.1 Nesbitt and colleagues15 reported that specialties involving unique examination procedures or imaging techniques such as otolaryngology, dermatology, and orthopedics required only 30 minutes of examination time for initial and follow-up visits in contrast to interview-based consultations such as nutrition, behavioral health, and endocrinology, which required 60 minutes for the initial evaluation and 30 minutes for follow-up appointments. With this limited resource, UC Davis had an overall cancellation rate of 11.1% with great variability of 21% for infectious disease to 0% for rheumatology.

Emergencies are a challenging situation in telemedicine, in particular if the patient is out of state. The disadvantages are obvious in that the provider may not be familiar with local resources for emergency services. It makes sense that most telemedicine programs adopt the consultation model where there is a health practitioner available locally with the patient to manage any emergency. Hilty and colleagues18 describe new models of care via telemedicine, which include cross-cultural consultation to rural primary care, secured E-mail and telephone consultation for telepsychiatry and telepsychological services, and direct physician to physician consults.

Shore and colleagues19 describes how emergency telepsychiatry which provides direct psychiatric care requires protocols for emergency coverage after hours as well as ways to address legal issues such as involuntary commitments and duty to warn.



The slow rate of telemedicine adoption has many other facets to consider. The California Healthcare Foundation in 1999 forecasted that telemedicine as part of communication infrastructure and transaction services would be a trend in health care; however, it accurately predicted that telemedicine applications would develop slowly.20 The report cited lack of reimbursement and bandwidth limitations as barriers toward more widespread adoption.

Besides licensure, recruitment of specialists is a significant barrier since primary care physicians (PCPs) have many patients to refer.21 Some administrators also see that recruitment of PCPs is a barrier, especially since their traditional referral habits are difficult to break. Grigsby and colleagues21 also cite how a conundrum may exist if PCPs do not feel comfortable writing a prescription recommended by a specialist, who additionally do not feel comfortable writing a prescription based on a videoconference visit.

Although not explicitly described above, cost is a significant issue barrier to more widespread use of telemedicine. Many of the programs serving rural areas have been funded by grants, which are necessary to pay for videoconferencing equipment, peripheral devices such as dermatology cameras and digital stethoscopes, data transmission charges, maintenance contracts, clinical staff, technical staff, and professional fees.

Despite the many barriers toward more widespread usage of telemedicine beyond the rural area specialty consultation, some specialties thrive with the use of telemedicine. The Nighthawk radiology service based in Idaho is a perfect example where telemedicine meets a defined need extremely well.22 These radiologists provide consultation remotely by reading x-rays, magnetic resonance imaging scans, and computerized axial tomography scans. Licensure is not an issue since the physicians are licensed in the state where they provide consultation, and evening and early hours are not an issue since the remote radiologist is located in a different time zone.

The continuing trend toward new technologies every year helps decrease cost barriers. At the January 2008 Consumer Electronics Show in Las Vegas, Nevada, Creative introduced its In Person handheld videoconferencing unit.23 This device retails for <$1,000, and it has a 7” video screen with a built-in camera and microphone. It does not require a separate personal computer to run, and it connects to the Internet either wirelessly with 802.11g or wired local area network. It is compatible with the common H.263 and H.264 video standards.

Wireless Metropolitan Area Networks, a telecommunications technology aimed at providing wireless data transmission over long distances in a variety of ways, is an IEEE 802.16 standard known as Wireless MAN.24 It is also known by WiMAX, which was created by the WiMAX Forum, to promote conformance and interoperability of this standard. WiMAX is a long-range system, covering many kilometers and providing high bandwidth services that normally would be handled if DSL or cable modems were available. It typically uses licensed spectrum to deliver a point-to-point connection to the Internet from an Internet Service Provider to an end user. Different 802.16 standards provide different types of access, from mobile to fixed access. WiMAX will eventually eliminate the need for wireless Internet access via the cellular phone network.



Telemedicine certainly is not a technology whose time has passed nor has it been relegated to strictly serving the rural communities of the world. With today’s trends toward increasing consumer familiarity with technology, availability of hardware and Internet access at reasonable cost, and the growing consumer utilization of health care on the Internet, telemedicine is certainly poised to become more mainstream and widely adopted. Traffic problems and schedule conflicts may encourage patients to occasionally visit their physician via video conferencing. Corporate America has already invested significant dollars in videoconferencing technology to facilitate multi-site meetings, which reduce downtime from travel and impact on the environment. Videoconference-based treatment, such as EGetGoing’s Online group-therapy service for drug and alcohol addiction, has already been in place for 5 years.25 Perhaps the portrayal of health care in Star Trek is not too far away. PP



1.    Balch DC, Tichenor JM. Telemedicine Expanding the Scope of Health Care Information. J Am Med Inform Assoc. 1997;4(1):1-5.
2.    Straub K. Health care videoconferencing options cover wide range of applications, price, quality. Health Manag Technol. 1997;18(5):52-53,55-56.
3.    Zarate CA Jr, Weinstock L, Cukor P, et al. Applicability of telemedicine for assessing patients with schizophrenia: acceptance and reliability. J Clin Psychiatry. 1997;58(1):22-25.
4.    Shea S, Weinstock RS, Starren J, et al. A randomized trial comparing telemedicine case management with usual care in older, ethnically diverse, medically underserved patients with diabetes mellitus. J Am Med Inform Assoc. 2006;13(1):40-51.
5.    Baig EC. A World of Talking Heads? Lower costs and more compatibility bring videoconferencing within everyone’s reach. Businessweek. Available at: Accessed January 15, 2008.
6.    Love J. Pretty Good ISDN Cost Study. Available at: Accessed January 15, 2008.
7.    Verizon FiOS. Available at: Accessed January 15, 2008.
8.    HughesNet. Available at: Accessed January 15, 2008.
9.    WildBlue. Available at: Accessed January 13, 2008.
10.    Clarke M, Fragos A, Jones RW, Lioupus D. Optimum Delivery of Telemedicine Over Low Satellite Links. Available at Accessed January 15, 2008.
11.    International Telecommunication Union: Audiovisual and Multimedia systems. Available at: Accessed January 15, 2008.
12.    Chen Z, Yu X, Feng D. A Telemedicine System Over the Internet. Available at: Accessed January 15, 2008.
13.    Hsiung R. E-Therapy. London, UK: Norton & Co; 2002.   
14.    Maheu M, Whitten P, Allen A. E-Health, Telehealth, and Telemedicine. San Francisco, CA: Josse-Bass; 2001.
15.    Nesbitt TS, Hilty DM, Kuenneth Ca, Siefkin A. Development of a telemedicine program: a review of 1,000 videoconferencing consultations. West J Med. 2000;173(3):169-174.
16.    Mandatory Private Payer Telehealth Reimbursement in States. The Center for Telehealth and E-Health Law. Available at: Accessed January 15, 2008.
17.    Physician Licensure. The Center for Telehealth and E-Health Law. Available at:     Accessed January 15, 2008.
18.    Hilty DM, Yellowlees PM, Cobb HC, Bourgeois JA, Neufeld JD, Nesbitt TS. Models of Telepsychiatric Consultation–Liaison Service to Rural Primary Care. Psychosomatics. 2006;47(2):152-157.
19.    Shore JH, Hilty DM, Yellowlees P. Emergency management guidelines for telepsychiatry. Gen Hosp Psychiatry. 2007;29(3):199-206.
20.    Mittman R, Cain M. The Future of the Internet in Health Care: Five-Year Forecast. California Healthcare Foundation. Available at: Accessed January 15, 2008.
21.    Grigsby B, Brega AG, Bennett RE, et al. The slow pace of interactive video telemedicine adoption: the perspective of telemedicine program administrators on physician participation. Telemed J E Health. 2007;13(6):645-656.
22.    NightHawk Radiology Services. Available at: Accessed January 15, 2008.
23.    Creative inPerson. Available at: Accessed January 15, 2008.
24.    The IEEE 802.16 Working Group on Broadband Wireless Access Standards. IEEE WirelessMAN 802.16. Available at: Accessed January 15, 2008.
25.    eGetGoing. Available at: Accessed January 15, 2008.


Needs Assessment: Suicide prevention is a public health priority but is hampered by the scarcity of data on the relationship between ethnicity and suicidal behaviors. An important first step is to identify groups at increased risk for suicidal ideation and attempts. Clinicians need to be aware of the existence of high-risk groups.

Learning Objectives:
• Identify the rates of suicidal ideation/attempts across ethnic groups in the United States.
• Recognize individuals at high risk for suicidal behaviors across ethnic groups.
• Recognize specific risk factors for individuals of a given ethnic group.

Target Audience: Primary care physicians and psychiatrists.

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

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

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

This activity has been peer-reviewed and approved by Eric Hollander, MD, chair and professor of psychiatry at the Mount Sinai School of Medicine, and Norman Sussman, MD, editor of Primary Psychiatry and professor of psychiatry at New York University School of Medicine. Review Date: January 14, 2008.

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

To receive credit for this activity: Read this article and the two CME-designated accompanying articles, reflect on the information presented, and then complete the CME posttest and evaluation. To obtain credits, you should score 70% or better. Early submission of this posttest is encouraged: please submit this posttest by February 1, 2010 to be eligible for credit. Release date: February 1, 2008. Termination date: February 28, 2010. The estimated time to complete all three articles and the posttest is 3 hours.

Dr. Perez-Rodriguez is clinical researcher in the Department of Psychiatry at Ramón y Cajal University Hospital in Madrid, Spain. Dr. Baca-Garcia is adjunct assistant professor, Dr. Oquendo is professor of clinical psychiatry, and Dr. Blanco is associate professor of clinical psychiatry at Columbia College of Physicians and Surgeons in New York City.

Disclosure: Drs. Perez-Rodriguez, Baca-Garcia, and Oquendo report no affiliation with or financial interest in any organization that may pose a conflict of interest. Dr. Blanco receives grant support from the American Foundation for Suicide Prevention, the National Institutes of Health, and the New York State Psychiatric Institute.

Acknowledgments: The authors thank Elizabeth M. Langer for contributing to the literature search and article drafting.

Please direct all correspondence to: Carlos Blanco, MD, PhD, Department of Psychiatry, Columbia University, 1051 Riverside Dr, Box 69, New York, NY 10032; Tel: 212-543-6533; Fax: 212-543-6515; E-mail:




Suicide is one of the leading causes of death, and suicidal ideation and attempts are a major public health concern. However, little is known about the relationship between ethnicity and suicidal behaviors. This article provides an update on the relationship between ethnicity and suicidal ideation and attempts. It reviews the rates of suicidal ideation/attempts across ethnic groups in the United States as well as the risk factors associated with suicide attempts in each ethnic group. The results of published studies have been inconsistent. Some studies have suggested that non-Hispanic Whites have significantly higher suicide attempt risk than other ethnic groups, while two studies using national data did not find any significant relationship between race/ethnicity and suicidal ideation or attempts. From the epidemiologic point of view, these findings underscore the need to conduct large studies in general population samples that include enough individuals from all ethnic groups and that are large enough to detect significant effects among those groups. From the clinical point of view, mental health professionals should focus on factors consistently found to be strongly associated with suicide attempts across different populations, including major depressive disorder and other psychiatric disorders, female gender, and young age.



In the United States, suicide is the 11th cause of death for all ages, the third cause of death in individuals 10–24 years of age, and the second in those 25–34 years of age.1 Every year, >300,000 individuals (112–145 per 100,000 population) are treated for suicide attempts in emergency departments in the US.1 Suicidal ideation strongly increases the risk for suicide attempts.2

Studies have consistently documented that women2-5 and young adults2,5-7 are at increased risk for suicidal behavior. In contrast, much less is known about the relationship between ethnicity and suicidal ideation and attempts. Some studies have suggested that non-Hispanic Whites have significantly higher risk for suicide attempts than other ethnic groups,4 such as Blacks2 and Hispanics,8 although some9 but not all10 studies have suggested that different subgroups among Hispanics have divergent rates of suicide attempts. In contrast, two studies using national data did not find any significant relationship between race/ethnicity and suicidal ideation or attempts.2,6 It is debatable whether these inconsistencies are due to the fact that ethnic groups as usually conceptualized are rather heterogeneous. There are also some questions as to whether risk factors for suicidal ideation and attempts among the general population may not apply to specific ethnic groups such as African Americans, American Indians, or Hispanics.11

This article provides an update on the relationship between race/ethnicity and suicidal ideation/attempts. The article reviews the rate of suicidal ideation and attempts across races and ethnic groups in the US as well as the specific risk factors associated with suicide attempts in each race and ethnic group. Rates of suicidal ideation and attempts across ethno-racial groups are presented in Table 1.2,4-10,12-18 Risk factors for suicide attempts across races and ethnic groups are presented in Table 2.8-10,13,15-35



This article uses the five racial classifications used by the US Census Bureau to collect and present federal data on race and ethnicity. These classifications include American Indian and Alaska Native; Asian; Black or African American; Native Hawaiian and Other Pacific Islander; and White.36 There are also two categories for ethnicity, namely, Hispanic or Latino and Non-Hispanic/non-Latino (Hispanics and Latinos may be of any race).36 Rates and risk factors for suicidal ideation and attempts in each of these groups are presented in alphabetical order.


Rates and Risk Factors for Suicidal Ideation and Attempts Among American Indians and Alaska Natives (Native Americans)

The broader term, “Native Americans,” potentially includes American Indians, Alaska Natives, Native Hawaiians, and all indigenous people of Canada, Mexico, and Central and South America. In contrast with the common view that Native Americans are a homogeneous group, according to Census reports there are >561 tribes speaking over 220 indigenous languages with various dialects living in the US.37 Relatively little is known about suicidal ideation and attempts among Native Americans, with most of the studies being based on student populations.13,38-40

In 1977, the National Congress of American Indians and National Tribal Chairman’s Association issued a joint resolution that preferred the term “American Indian” over “Native American” for the indigenous population of the “lower 48.” The term “Alaska Native” was reserved for the indigenous population of Alaska. Native Hawaiians were not included in either of these groups.13 A more recent survey by the US Department of Labor41 indicated that approximately 50% of the Indians sampled preferred the term “American Indian” over “Native American.” Therefore, the more specific term “American Indian” will be used throughout this article.

According to the US Census, 4.1 million American Indians/Alaska Natives live in the US, comprising approximately 1.5% of the US population.42 Studies have reported a high prevalence of suicidal ideation and attempts among American Indians, particularly among females, adolescents, and young adults.13 Data on adults are scarce but suggest that there is a high prevalence of suicidal ideation and attempts among American Indians.13 According to the Alaska Trauma Registry,43 rates of suicide attempts, particularly those using firearms, were significantly higher for Alaska Natives than Alaska Whites between 1994 and 1999. In a study of a sample of urban Native Americans ≥50 years old, 31% of those who had been physically abused and 12% of those who had not been abused reported a history of depression or suicide attempts. The authors failed to provide rates for history of suicide attempts only, making it difficult to compare their results with those of other studies.19

Although the reasons for the high rates of suicidal ideation and attempts among American Indians are unknown, they are likely related to the high prevalence of depression, substance use disorders, including alcohol, and posttraumatic stress disorder in this population.44,45 Chester and collegues45 studied 235 off-reservation Native Americans and found high rates of mental health problems, but low levels of service use. Alcoholism has been described as “epidemic” among Alaska Natives.46 Hill and colleagues43 reported that alcohol was involved in 60.8% of intentional injuries involving Alaska Natives, compared to only 27.1% for Alaska Whites. May and colleagues21 observed that two-thirds of all self-destructive acts in the Western Athabaskan Tribal Nation reservation were alcohol related and occurred among unemployed individuals. This is particularly relevant given that in some reservations 80% of those ≥16 years of age are unemployed. Moreover, physical abuse may be particularly prevalent in some Native American communities and has been associated with depression and suicide attempts.47 The lack of culturally appropriate models of mental health in Native Americans and the barriers to providing effective mental health services to Native Americans may also be related to the high rates of suicidal acts in this population.48

Some studies have found that a greater percentage of American Indians had attempted suicide in their lifetime than had reported suicidal ideation or planning. This suggests that in this population suicide attempts may be more impulsive than previously hypothesized.13 Alternatively, the wish to die, which has been understudied so far, as opposed to the presence of suicidal ideation, may be a key factor related to the risk for attempting suicide.49


Rates and Risk Factors for Suicidal Ideation and Attempts Among Asians

Asian Americans are also an extremely diverse group of people with varying cultures, histories, views of mental illness, and views of suicide, although they comprise slightly >2% of the US population.50

Suicide attempts and suicidal ideation among Asian Americans have been understudied to date.50 Part of the problem is that most epidemiologic studies examining this topic collapse Asian Americans and American Indians into a single category, precluding the examination of the suicidal behavior in those groups independently.2,6 Asian Americans and American Indians represent very small percentages of the general population (2.0% and 1.5%, respectively), and some of the outcomes are sufficiently rare that most epidemiologic surveys may not have enough power to detect differences in such small group sizes.6 Iribarren and colleagues12 analyzed rates of hospitalization for suicide attempt in a sample of White, Asian, and African American men and women. Among women, the rate of hospitalization for suicide attempts was highest among Whites, while rates for Asian and African American women were lower (Table 1). Among men, the rate of hospitalization for suicide attempt was highest among Whites, intermediate among African Americans, and lowest among Asians. By contrast, Kennedy and colleagues14 reported no differences in rates of suicide attempts across Europeans, Chinese, and Indo-Asians. Studies in other Western countries have generally reported significantly lower rates of suicidal behaviors among individuals of Asian origin than among individuals of other ethnic groups.51-53 Furthermore, some groups of Asian Americans, such as southeast Asian refugees, appear to have increased needs for mental health services compared to the general population.54-56 Overall, these data suggest that clinicians and researchers should pay more attention to Asian American communities.54


Rates and Risk Factors for Suicidal Ideation and Attempts Among Blacks

Two large national epidemiologic studies have suggested that Blacks are at lower risk for suicide attempt than non-Hispanic Whites.2,4 However, another recent national study indicated that there may have been an increase in the rate of suicide and nonfatal suicidal behaviors among Blacks, particularly among youths.16 Studies based on Black samples have reported high rates of suicidal ideation and attempts among Blacks, particularly among young individuals.15,16 Moreover, it has been suggested that suicidal behavior among African Americans is often underreported or misclassified.30 These contradictory findings need to be explored in national studies with large samples that include all other ethnic groups.

Regarding subgroups within the Black community, Joe and colleagues16 reported that the lifetime prevalence of suicide attempts among Caribbean black men (7.5%) was the highest among the four ethnic-sex groups analyzed (African American and Caribbean American men and women). The authors of this article have not found any other studies comparing suicide attempts in different groups within the African American community.

Blacks share some of the risk factors for suicide attempt identified in the general population, such as life events, female gender, depression and other psychiatric disorders, and hopelessness.15,16,26-29,31-34,57 According to data from the National Hospital Ambulatory Medical Care Survey, African Americans had significantly higher rates of psychiatric-related emergency department visits compared with Whites.58 There are also some indications that Blacks may also have specific risk factors such as lower ethnic identity, alienation from family, and fragmentation of social support.26 By contrast, other authors have reported that religious well being, but not acculturation, was related to history of suicidal ideation and attempt.59 Some studies have found that Blacks report suicidal ideation or depression as a possible precursor to suicide attempts less often than non-Hispanic Whites. Similarly, it has been hypothesized that Black youths may act out and attempt suicide as a defense against feelings of sadness.60,61


Rates and Risk Factors for Suicidal Ideation and Attempts Among Hispanics

It is estimated that by 2020 Hispanics will be the largest racial/ethnic minority group in the US and that by that time they will represent 17% of the US population.62 However, research on suicidal ideation and attempts among Hispanics in the US is limited and rarely analyzes different Hispanic groups separately. In addition, many Hispanic individuals are undocumented workers who are not represented in epidemiologic studies.63

Some studies have suggested that suicide attempts may be less common among Hispanics than in other ethnic groups.8 In contrast, two large nationwide surveys did not find any significant relationship between race/ethnicity and suicide ideation or attempts,2,6 and studies focused on Hispanic samples have reported rates of suicidal ideation and attempts that are similar to those reported in White populations or even higher among some subgroups of Hispanics.9,10

Studies have also reported that rates of suicidal ideation and attempts are different across Hispanic ethnic subgroups,9,18 while others have not found any significant differences in rates of suicidal ideation or attempts across Hispanic subgroups after adjusting for demographic, psychiatric, and sociocultural factors.10 The most consistently reported findings are a higher rate of lifetime suicide attempts among Puerto Ricans and a lower rate among Cuban Americans.9,10,18,64

This variability in suicide attempt rates across Hispanic subgroups has been attributed to many factors such as the impact of the migration process, socioeconomic status, acculturation, cultural differences in norms and attitudes, and different rates of psychiatric disorders, among others.9,10 This is supported by the fact that the Hispanic population is heterogeneous in terms of ethnicity, geography, acculturation, migration patterns, education, and socioeconomic status.10

The variability in suicide attempt rates across Hispanic subgroups is consistent with the differences in the prevalence of major depressive disorder (MDD) observed among Hispanic subgroups. Non-Hispanic Whites and Puerto Ricans have higher rates of MDD compared to other Hispanic ethnic groups.9,65 Fortuna and colleagues10 observed that any lifetime Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition,66 psychiatric diagnoses were associated with an increased risk of lifetime suicidal ideation and suicide attempt among Hispanics.

Acculturation may also be related to suicidal behavior among Hispanics.10,67 Fortuna and colleagues10 observed that different aspects of acculturation, such as language spoken as a child, current English proficiency, and parental US nativity may be risk factors for suicidal behaviors. The prevalence of suicidal ideation and attempts appear to be higher among Puerto Ricans and Mexican Americans17 with higher levels of acculturation than among those with lower levels of acculturation. It has been reported that US-born Hispanics have a higher rate of mental health and substance abuse problems than recent immigrant Hispanic populations.68 The mechanism by which acculturation is a potential risk factor for psychiatric disorders and suicidality may be related to culturally influenced coping strategies and cultural values such as moral objections to suicide, which may be less prominent as acculturation progresses.10,69

Despite the existence of some specific risk factors such as acculturation or family cultural conflict, Hispanics appear to share some of the risk factors for suicidal behavior found in the general population, such as female gender and presence of psychiatric disorders, particularly MDD.8-10



The findings of studies examining suicide attempt and suicidal ideation rates in specific ethnic groups should be viewed with two limitations in mind. First, some of the groups analyzed are heterogeneous in terms of ethnicity, geography, acculturation, education, migration patterns, socioeconomic status, and access to health care.9,10 The second limitation is that studies have different designs and target populations. For example, the results reported in studies of clinical populations whose data are based on discharge diagnoses rather than self-reports may reflect issues such as access to care, which may vary across ethnic groups and may have excluded suicidal behavior not requiring medical attention.9 It has been reported that immigrants may under-use psychiatric services.70 A third limitation is that some of the ethnic groups analyzed may be too small (<5% of the general population) for the differences to achieve statistical significance in epidemiologic surveys in the general population.6



The published studies indicate that the prevalence of suicidal ideation and attempts vary widely across ethnic groups. However, many of these studies were focused on a single ethnic group or used relatively small or local samples sizes, suggesting caution in their interpretation. Overall, these existing findings underscore the need to conduct large studies in general population samples that include enough individuals from all ethnic groups and that are large enough to detect significant effects among those groups.

This stresses the importance of focusing on factors that have been consistently found to be strongly associated with suicide attempts across different populations, such as MDD and other psychiatric disorders, female gender, and young age.2-7

Besides examining associations between suicide and risk factors such as demographic variables (eg, female gender, young age), future research should aim at identifying factors that may be modifiable with interventions, including the treatment of psychiatric disorders such as MDD.71 A better understanding of risk factors may allow the implementation of selective suicide prevention programs that could then be tested empirically.63 These programs are more likely to be effective if they are culturally sensitive. More research is needed to examine which aspects of the prevention programs can be universally applied and which have to be tailored for the specific target groups.

Another key issue is the identification of protective factors that may act upon individuals of different ethnicities and may help explain the lower rates of suicide attempts found among some of them. For example, Oquendo and colleagues69 found that several factors protective against suicidal behaviors (those regarding survival and coping beliefs, responsibility to family, and moral objections to suicide) were significantly more common among Hispanics than non-Hispanics. Since this may reflect cultural norms endorsed by Hispanic groups, it would be of interest for further studies to examine the impact of protective factors on suicidal behavior and their relationship to specific cultural constructs.69 The protective role of African American culture has been consistently reported.72 Culture-based strengths like spiritually based coping, extended social support networks, flexible family roles, strong family ties, and positive ethnic group identity have been suggested as protective factors against suicide risk.26,72 Female kinship networks have been suggested as a protective factor against suicidal behaviors among African American women.34 In a sample of 1,456 Northern Plains American Indians, Garroutte and colleagues73 observed that high levels of cultural spiritual orientation had a protective effect against suicide attempts. Although most suicide prevention strategies so far have been aimed at decreasing the suicide risk factors, research should also focus on increasing the effects of factors that protect against suicide.

Despite recent progress in the area, the examination of the relationship between ethnicity and suicidal ideation and attempts is still in its infancy. As the ethnic diversity of the US continues to increase, the identification of common and specific risk and protective factors for suicidal ideation and attempts and the development of effective preventive interventions offer important opportunities and challenges for clinicians, researchers, and policy-makers. PP



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73.    Garroutte EM, Goldberg J, Beals J, Herrell R, Manson SM, AI-SUPERPFP Team. Spirituality and attempted suicide among American Indians. Soc Sci Med. 2003;56(7):1571-1579.



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

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



There is no theme to this issue of Primary Psychiatry. Instead, This issue features a series of articles that help fill some gaps involving common clinical situations that confront clinicians who treat psychiatric patients. A self-authored article provides a brief overview of medical complications that may arise in the course of treatment with selective serotonin reuptake inhibitors and selective norepinephrine reuptake inhibitors. Unlike common side effects, such as sexual dysfunction or weight gain, less common adverse reactions may have serious consequences for the patient. Among the possible side effects discussed are bleeding abnormalities, hyponatremia, bone loss, and serotonin toxicity. Because most of our readers are non-psychiatrists and might encounter patients exhibiting these problems, it is useful to increase awareness of these events. In this way, patients might be spared unncessary work-ups and prolonged suffering due to non-recognition of the side effects discussed.

Suicide is difficult to predict and prevent. Knowledge of any risk factors relevant to the patient evaluation could prove crucial to making the correct decision in terms of intervention and degree of special precautions used with a person who is potentially suicidal. M. Mercedes Perez-Rodriguez, MD, and colleagues, address this issue. Suicide is one of the leading causes of death, and suicidal ideation and attempts are a major public health problem. In the United States, suicide is the eleventh cause of death for all ages, the third cause of death in individuals between 10 and 24 years of age, and the second in those 25–34 years of age. However, little is known about the relationship between ethnicity and suicidal behaviors. The goal of this article is to provide an update on the relationship between ethnicity and suicidal ideation and attempts. The authors review the rates of suicide ideation attempts across ethnic groups in the US, and the risk factors associated with suicide attempts in each ethnic group. They also argue that mental health professionals should focus on factors consistently found to be strongly associated with suicide attempts across different populations, including major depressive disorder and other psychiatric disorders, female gender, and young age. The authors provide an update on the relationship between race and ethnicity and suicidal ideation and attempts.

At one time, restraints were commonly used to manage aggressive or agitated patients. Although the advent of medications and behavioral interventions have reduced both the frequency and duration of restraints in the acute care setting, restraints are still utilized. A study by Leslie S. Zun, MD, MBA, and LaVonne Downey, PhD, discusses the level of agitation associated with the use of restraints, reviews the methods to measure the level of agitation that patients exhibit, and suggests ways of determining the effect of the addition of chemical modulation to patients’ level of agitation.

There were 62 physically restrained patients and 41 physically and chemically restrained patients seen in the emergency department during the study. Zun and Downey report that the findings demonstrated physically and chemically restrained patients become more agitated when restraints are first applied and have less agitation by 120 minutes. The addition of chemical restraint reduced the level of agitation more than physical restraints alone. It had not been expected that patients would become more agitated when the restraints were first applied. The authors comment on this finding and ask whether there are better means to reduce a patient’s level of agitation. The authors note that “[i]f the mantra of medicine is to ‘first, do no harm,’ then we need to find better and more humane means to reduce a patient’s level of agitation instead of the use of restraints.”

Jeffrey Cummings, MD, contributes the first of two concise educational reviews on the diagnosis and treatment of Alzheimer’s disease and other dementias. This first part discusses epidemiology, genetics, neuropathology, and pathophysiology of Alzheimer’s disease and other dementias. It also discusses the assessment of cognitive impairment, clinical scales and inventories, and warning signs of Alzheimer’s disease, and provides contact information for caregiver and professional resources. The second part will appear in next month’s Primary Psychiatry and will discuss diagnosis and management of Alzheimer’s disease and dementia.

Dr. Cummings mentions that the two articles are not meant to be a comprehensive reference. Rather, they are meant to provide critical information and references that contain information on each topic presented. Constructed for the clinician (primary care practitioner, neurologist, or psychiatrist) who needs rapid access to updated information, these articles also contain information valuable to families that the practitioner can provide through a course of discussions about Alzheimer’s disease and dementia. PP



This interview took place on September 7, 2007, and was conducted by Norman Sussman, MD.


This interview is also available as an audio PsychCastTM at

Disclosure: Dr. Janicak is consultant to and/or on the advisory boards of AstraZeneca, Bristol-Myers Squibb, Janssen, Neoronetics, and Solvay; is on the speaker’s bureaus of Abbott, AstraZeneca, Bristol-Myers Squibb, Janssen, and Pfizer; and receives grant support from AstraZeneca, Bristol-Myers Squibb, Janssen, Neuronetics, sanofi-aventis, and Solvay.



Dr. Janicak is professor of Psychiatry at Rush University in Chicago, Illinois, medical director of the Rush Psychiatric Clinical Research Center, and distinguished fellow at the American Psychiatric Association. He has been listed in Best Doctors of America since 1996 and Who’s Who in America since 2002. In 2003, the Illinois chapter of the National Alliance for the Mentally Ill named Dr. Janicak “Psychiatrist of the Year.” With a strong interest in the assessment and treatment of mood and psychotic disorders, he has been a National Institute of Mental Health grant awardee as both principal and co-investigator. Dr. Janicak is editor of the Psychopharm Review and has authored >250 publications in psychiatric literature, including Principles and Practice of Psychopharmacotherapy.


What types of neuromodulation are available for clinical use?

Using electrical or magnetic stimulation to alter neurocircuits in the brain is the core concept associated with neuromodulation. This is possible through a variety of device-based therapies, including electroconvulsive therapy (ECT), vagus nerve stimulation (VNS), deep brain stimulation (DBS), and repetitive transcranial magnetic stimulation (TMS). ECT has been available for >60 years and remains the standard for therapeutic neuromodulation. In 1997, the Food and Drug Administration approved DBS for patients with neurologic disorders such as Parkinson’s disease and dystonic reactions. VNS is another way to alter activity in the central nervous system for treatment-resistant depression (TRD) and epilepsy. TMS has been used for moderately severe TRD. Only ECT and VNS have FDA-approved indications for specific types of depression. The FDA is presently considering the approval of a TMS device.


What are the approved indications for VNS?

VNS was approved as an adjunctive treatment for depression since studies were done in combination with other pharmacologic agents. In addition, those studies involved a more resistant group of patients who, according to the FDA-approved indication, should have failed ≥4 adequate antidepressant trials during the index episode. This could include medication, cognitive behavioral therapy, or ECT.


What is the time course of improvement?

The pivotal trial1,2 was a sham control versus active design, in which VNS served as an adjunctive treatment to stable ongoing medication regimens over a 3-month period. The trial demonstrated a statistically significant difference between the active and sham procedure only on the secondary outcome measure, the Inventory of Depressive Symptomatology. Based on these results, the safety/tolerability profile, and patients who did not benefit from previous treatments improving, the advisory panel advised the FDA to approve VNS. However, the division within the FDA that makes the final decision initially chose to not take the panel’s advice. The FDA and Cyberonics (the company that makes the device) continued to discuss the potential advantages of VNS. In the meantime, the company continued to collect data after the 3-month sham-controlled trial. Response and remission rates continued to increase over extended periods of time (eg, 6 months, 1 year, 2 years) with more prolonged exposure to VNS. This improvement occurred in patients who generally did not experience lasting benefit from previous treatment strategies. The FDA decided that it would be better to provide VNS for these patients, and it became clinically available in July 2005.


Have parallel-like functional brain imaging studies been conducted to see whether or not clinical improvement correlates with changes in brain chemistry patterns?

Most of the imaging data are from animal studies. When ECT, VNS to the left vagus nerve, and TMS were used, all seemed to alter activity in structures of the mesolimbic system implicated in symptoms associated with depression. These observations are also supported by human imaging data. This evidence argues that neuromodulation, regardless of the approach (eg, electrical stimulation or magnetic pulses to the brain), affects areas known to modulate the symptoms of depression.


What factors contribute to the controversy over VNS?

Concern has focused on the efficacy of VNS. Numerous factors contribute to this. First, pharmacologic agents must meet certain FDA requirements to be approved. This usually requires two large, placebo-controlled, positive trials demonstrating that a drug is useful and safe for the treatment of depression. Second, there is a lack of experience with devices for the treatment of depression. Prior to VNS, ECT was the last form of neuromodulation to be approved. This means the division within the FDA that assesses devices is more accustomed to looking at a variety of devices for medical conditions. Third, discussions between Cyberonics representatives and the FDA did not go smoothly. Ultimately, the division that rejected the advisory panel’s suggestion to approve VNS had this decision overridden. Fourth, third-party payers such as Medicare and Medicaid have decided not to reimburse the cost of VNS implantation, still considering it an investigational device. The average cost is $25,000 for the implantation plus additional costs for follow-up visits and adjustments. As a result, the device may not have adequate use in a sufficient sample of patients over an extended period of time to assess its true benefit.


Has anyone reported getting manic on VNS?

Yes. The studies included both unipolar and bipolar patients, and a few patients became manic. However, it is hard to know if they spontaneously moved into a manic episode or if VNS induced it. One positive perspective is that most known effective antidepressant therapies have a propensity to increase the switch rate from depression to mania. Thus, if VNS were an effective antidepressant treatment for bipolar depression, one might expect some of these switches to occur. However, I think the bipolar group was too small to make any meaningful conclusions.


If a patient shows signs of TRD, when should the clinician recommend VNS?

The clinician should follow the FDA-approved indications for TRD. The patient should have a history of chronic, recurrent depression and failed ≥4 adequate antidepressant therapies during the index episode. In addition, based on the clinical trials, clinicians may expect response and remission rates after 2 years in the 15% to 25% range in a patient group that did not benefit from multiple prior treatments. In the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study, chances of achieving remission dramatically dropped after two failed adequate antidepressant trials.3,4 This demonstrates that this level of treatment-resistant patient has limited options. Since the data is not encouraging, the STAR*D results make VNS an appealing intervention for this population. If VNS works, it may be most effective with longer exposure.


What makes VNS a more desirable treatment than periodic ECT?

VNS is primarily a maintenance treatment strategy. It appears that the longer a patient is exposed the greater the benefit. ECT is usually an acute treatment. Treatment-resistant patients could possibly use both approaches, treating the acute episode with a course of ECT and then using VNS as a maintenance strategy.


What risks are associated with VNS?

The risks associated with VNS involve the electrical stimulation of the left vagus nerve. The most common complications include voice alteration such as hoarseness and other related symptoms which occurred in approximately 50% of patients. These symptoms, however, were not serious enough to require large numbers of patients to withdraw from the studies. In the sham controlled trial, shortness of breath, neck pain, dysphasia, and parethesias occurred in >10% of patients, and 25% to 35% experienced a cough. Most of those symptoms gradually subsided, and the percentage of patients who experienced cough dropped to <10% at 2 years. Of note, in the acute pivotal trial, both sham control and active VNS patients reported similar rates of mild, moderate, or severe adverse effects. Overall, VNS appears to be a safe treatment.

Stimulation to the nerve occurs in an on- and off-duty cycle. Thus, stimulation is on for a period of time then off for several minutes. The patient can also stop the device by placing a magnet over the chest area where it was implanted. Generally, patients do not go through that process unless a side effect is troublesome.

VNS does not result in any systemic effects (eg, weight gain, sexual dysfunction, sedation, and other common issues associated with pharmacologic treatments). When the device is implanted and the stimulus electrodes first attached to the left vagus nerve, rarely the device can cause a cardiac rhythm disturbances when initially turned on. If this happens, the surgeon can readjust the electrodes to prevent this.


Why is the approval for TMS taking a long time?

In January 2007, an FDA advisory panel discussed concerns about the a priori primary outcome measure (ie, Montgomery-Asberg Depression Rating Scale change score) comparing active TMS to a sham control in the Neuronetics-sponsored 6-week trial. At the 4-week juncture, the difference between active TMS and sham control achieved a P-value of .057, just missing the conventional level of statistical significance. However, several secondary measures demonstrated that active TMS achieved statistical separation from the sham procedure at the 4-week period, including the 24-item and 17-item Hamilton Rating Scale for Depression and the Inventory of the Depressive Symptomatology. At the 6-week juncture, both change scores and categorical response rates demonstrated statistical separation for the active versus sham procedure.

The panel also considered the absolute difference between the active TMS and sham control scores (ie, 3–5 points). Because of the modest differences, the clinical relevance was discussed. It is important to note that the patients in the TMS trial were a moderately treatment-resistant group who had failed one to four antidepressant trials during the index or a previous episode. In drug trials, pharmaceutical companies usually do not include patients with this level of TRD because it could skew the outcome against the investigational agent. In this study, even though the mean number of adequate antidepressant trials during the current episode was approximately 1.5, the TMS effect sizes were larger in comparison to those achieved in antidepressant placebo-controlled trials. Thus, studies involving patients who have similar levels of treatment resistance need to be conducted before meaningful comparisons can be made between TMS and other approved treatments.


Have people had an unmistakable effect with TMS?

We conducted a study comparing ECT to TMS.5 Patients in this study had to be clinically appropriate for ECT. Often, they were reluctant to go forward with ECT for a variety of reasons, including potential adverse effects, the treatment’s cost, and the social stigma associated with it. Some of these patients had dramatic improvement with TMS. While TMS will not replace ECT, I think a proportion of patients who are referred for ECT may benefit from TMS as an alternative. We also reviewed the ECT-TMS literature which consists of several small, primarily single-site trials.6 Six out of eight studies reported that TMS was comparable to ECT and two studies found ECT superior. If these data are distilled into a clinically meaningful picture there may be a proportion of patients referred for ECT not because they are highly suicidal, psychotically depressed, in need of hospitalization, or having substantial compromise of their physical status but because they have not benefited from psychotherapy, medication, or a combination of the two. In addition, some may not tolerate adequate trials of medication for their depression. Presently, ECT may be the only option for them. Based on the data from the eight ECT-TMS comparison studies, the large Neuronetics-sponsored trial7 and several other sham control studies, as many as 30% to 40% of patients referred for ECT might benefit from TMS.


What are the side effects of TMS?

The Neuronetics’ trial has the largest database on adverse effects associated with TMS for treatment of depression.8 The most common were headaches and discomfort at the site of the application of the magnetic pulses. Both usually subsided in the first week of treatments. The discontinuation rate due to these adverse events was quite low. In terms of serious adverse events, no seizures or deaths occurred in >10,000 sessions involving >300 patients. Further, this study used the most aggressive set of parameters in terms of the intensity of the stimulation, number of stimulations per treatment session, number of sessions, and total number of stimulations over a course of treatment. For example, previous studies typically averaged 15,000–30,000 total magnetic pulses over an entire course of TMS. In the Neuronetics trial, the average number of pulses was 90,000. A small number of serious adverse events (primarily related to an exacerbation of the illness process) occurred primarily in patients who received the sham rather than the active procedure. From a safety tolerability point of view, TMS appears to be a benign treatment. The Neuronetics’ trial showed no evidence of cognitive deficits, consistent with the findings in the ECT-TMS comparison studies.

Over extended periods of time, the loud clicking sound that occurs near the acoustic nerve could potentially cause damage. However, all patients were required to wear ear plugs during the procedure and changes in the auditory threshold between the sham and active procedure did not differ. In terms of safety and tolerability, TMS looks much better than ECT or VNS. TMS may be even better tolerated than many antidepressants because there are no adverse systemic effects. In the Neuronetics’ trial, responders could enter a third phase transitioning from TMS to maintenance antidepressant monotherapy for 6 months. Some patients needed TMS reintroduced when they started to relapse. Two thirds of these patients benefited and returned to their prior stable mood levels. Further, these patients did not experience an increase in adverse events when TMS was combined with their antidepressant. Prior studies that used TMS as an augmentation strategy in partially but insufficiently responsive patients also reported that it was safe to combine TMS with various medications for depression.


Do you think DBS is a practical treatment?

DBS is an alternative to psychosurgery. It is a procedure neurosurgeons use for a variety of conditions because it is potentially reversible and causes minimal tissue damage, most of which involves the procedure placing the stimulating electrodes in the brain. The device is similar to the one used with VNS and is implanted in the upper chest region. Two wires run subcutaneously from the device behind the ears to the head where two small burr holes are drilled. The wires are implanted under stereotactic observation in the part of the brain that may be involved with a particular disease process (eg, Parkinson’s disease, dystonias, obsessive compulsive disorder, depression, Tourette’s syndrome). The level of electrical stimulation can be adjusted. Some patients who have had the electrical stimulation turned on report an almost immediate relief of symptoms which return when the electrical stimulation is turned off.

Medtronics makes the device most frequently used for DBS and is planning a multicentered trial for intractable depression. Mayberg and colleagues conducted an open-label pilot trial in which very seriously depressed patients had stimulating electrodes placed in Brodman’s Area-25.9 The study reported four of six patients who were unresponsive to a variety of treatment strategies experienced “striking and substantial remission” in their mood symptoms when the device was activated. PP



1.    Rush AJ, George MS, Sackeim HA, et al. Vagus nerve stimulation (VNS) for treatment-resistant depression:  a multicentered study. Biol Psychiatry. 2000;47(4):276-286.
2.    Sackeim HA, Rush AJ, George MS, et al. Vagus nerve stimulation (VNS) for treatment-resistant depression: Efficacy, side effects, and predictors of outcome. Neuropsychopharmacology. 2001;25(5):713-728.
3.    Rush AJ, Trivedi MH, Wisniewski SR, et al. Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR*D report. Am J Psychiatry. 2006;163(11):1905-1917.
4.    Trivedi MH, Fava M, Wisniewski SR, et al. Medication Augmentation after the failure of SSRIs for depression. New Engl J Med. 2006;354(12):1243-1252.
5.    Janicak PG, Dowd SM, Martis B, et al. Repetitive transcranial magnetic stimulation versus electroconvulsive therapy for major depressive: preliminary results of a randomized trial. Biol Psychiatry. 2002;51(8):659-667.
6.    Janicak PG, Dowd SM, Rosa M, Marcolin MA. Transcranial magnetic stimulation versus electroconvulsive therapy for the treatment of more severe major depression. In: Marcolin MA, Padberg F, eds. Transcranial Brain Stimulation for Treatment of Psychiatric Disorders. (Advances in Biological Psychiatry). Basel, Switzerland: Karger. 2007;23:97-109.
7.    O’Reardon JP, Solvason B, Janicak PG, et al. Efficacy and safety of repetitive transcranial magnetic stimulation (rTMS) in the acute treatment of major depression: results of a multicenter randomized controlled trial. Biol Psychiatry. 2007;62(11):1208-1216.
8.    Janicak PG, O’Reardon JP, Sampson SM, et al. Transcranial magnetic stimulation in the treatment of major depressive disorder: a comprehensive summary of safety experience from acute exposure, extended exposure and reintroduction treatment. J Clin Psychiatry. In press.
9.    Mayberg HS, Lozano AM, Voon V, et al. Deep brain stimulation for treatment-resistant depression. Neuron. 2005;45(5):651-660.


Babies with Low Birth Weight More Prone to Future Depression and Anxiety

An important chapter reopened in the controversial “nature versus nurture” debate, as a study by Ian Colman, PhD, at the University of Cambridge, and colleagues, suggests atypical neurodevelopment may lead to future profiles of depression and anxiety.

The study involved data collected from a nationally representative sample of 4,627 members of the Medical Research Council National Survey of Health and Development from the British 1946 birth group. Measures of the depression and anxiety levels of the members at 13, 15, 36, 43, and 53 years of age were examined through a longitudinal latent variable analysis. Results revealed heavier babies show less depressive and anxious symptoms as adults. Even within the range of normal birth weight, babies slightly smaller than others had a slightly increased risk of depression and anxiety. This suggests that fetal programming may induce future depression and anxiety.

“The fetal programming hypothesis postulates that when pregnant mothers encounter stressful environments, they pass on information to the developing fetus in order for it to be prepared for a hostile environment,” Dr. Colman said. “If, however, the adverse environment that existed during pregnancy does not persist, the permanent alterations in the development of the fetus may become maladaptive.”

In addition, the study found that people who exhibited worse mental health throughout their lives reached “motor developmental milestones,” such as standing or walking for the first time, later in life compared to people with better mental health, implying possible stressful social factors and life events during childhood.

The study’s biggest limitation to this study was the lack of data on the gestational age of the babies when they were born. As the study was initiated in 1946, data was limited to what was collected at that time. Birth weight adjusted for gestational age would have been ideal; however, that the researchers found significant relationships using crude birth weight strengthens the study’s conclusions.

“Prenatal conditions have a significant impact on the long-term health of the developing fetus, and we need to do our best to take care of pregnant mothers,” Dr. Colman said.

Funding for this research was provided by the Institute for Social Studies in Medical Care, the United Kingdom Medical Research Council, the Stanley Medical Research Institute, the Leverhulme Foundation, and the Isaac Newton Trust. (Biol Psychiatry. 2007;62(11):1265-1271.) –ML


Increased Risk of Depressive and Anxiety Disorders for Relatives of Parkinson’s Disease Patients

Parkinson’s disease affects approximately 1.5% to 2% of the population >60 years of age. Recent evidence suggests that family members of Parkinson’s disease patients are at increased risk for dementia or essential tremor. A new study conducted by investigators at the Mayo Clinic revealed that first-degree relatives of Parkinson’s disease patients are also at increased risk for mood and anxiety disorders, especially when the family member with Parkinson’s disease develops the condition before 75 years of age.

Walter Rocca, MD, of the Mayo Clinic, and colleagues, led a population-based study that included 1,000 first-degree relatives of 162 patients with Parkinson’s disease. The control population included 850 first-degree relatives of 147 age-matched, healthy controls. All subjects were from Olmsted County, Minnesota, where the Mayo Clinic’s Rochester campus is located. Psychiatric disorders were documented for all relatives—in both control and Parkinson’s disease groups—by conducting individual assessments including separate telephone interviews and review of existing medical records. Other interviews were conducted with a proxy, in the case of a death of a subject or incapacitation.

The overall risk of psychiatric disorder for first-degree relatives of Parkinson’s disease patients was greater than that of first-degree relatives of healthy controls (hazard ratio, 1.54; 95% CI, 1.21–1.95; P<.001). More specifically, there was an increased risk of depressive disorders (hazard ratio, 1.45; 95% CI, 1.11–1.89; P=.006) and anxiety disorders (hazard ratio, 1.55; 95% CI, 1.05–2.28; P=.03).

The investigators controlled for type of interview, and excluded relatives who developed Parkinson’s disease or those who developed both an anxiety and depressive disorder. (Arch Gen Psychiatry. 2007;64(12):1385-1392.) –LS


Live, Online CBT Helps Service Members with PTSD

Posttraumatic stress disorder (PTSD) develops after a severely distressing, psychologically taxing occurrence. According to a study by Brett Litz, PhD, of Boston Veterans Affairs Healthcare, Boston University School of Medicine, and the National Center for PTSD, and colleagues, self-managed cognitive-behavioral therapy (CBT) live over the Internet may broaden treatment options for military personnel suffering from PTSD.

The controlled proof-of-concept trial involved Department of Defense service members who developed PTSD after the September 11, 2001 Pentagon attack or combat in the Middle East. From the pool of 141 volunteers, the researchers recruited 45 patients after an initial face-to-face assessment by therapists using the PTSD Symptom Scale-Interview Version, the Beck Depression Inventory-II, and the Beck Anxiety Inventory.

These patients were then randomly assigned to one of two arms in the DElivery of Self-Training and Education for Stressful Situations (DESTRESS) program, ie, the Internet-based self-management CBT arm or the Internet-based supportive counseling arm. Patients in the CBT arm acquired coping skills for everyday life through homework assignments, applied them during exposure to trauma-inducing triggers, and discussed their traumas during seven online sessions. The supportive counseling arm included a control group of 21 patients who wrote about non-trauma–related, present-day concerns. Both groups were able to access the Internet, allowing for independent research on PTSD, stress, anger management, and depression.

Patients were evaluated after 8 weeks of treatment (≤56 sessions), and at 3 and 6 months after baseline. Patients showed an overall similar reduction in PTSD, depression, and anxiety scores at 3 months. However, those who completed the self management in the CBT arm (N=33) achieved high-end state functioning at 6 months.

The results suggest online CBT is an effective treatment. People with PTSD learn how to independently manage challenges and DESTRESS made good use of the therapists’ time. Patients met with therapists for approximately 15 minutes per week, making the treatment convenient for large numbers that do not have conventional access to care. (Am J Psychiatry. 2007;164(11):1628-1630.) –ML


Treatment Discontinuation Increases Risk of Symptom Recurrence for Pregnant Women with Bipolar Disorder

For the approximately 5.7 million American adults with bipolar disorder, dramatic shifts in mood and other symptoms related to the disorder can be alleviated and/or stabilized with proper treatment, which typically includes the use of anticonvulsants and antidepressants as well as anti-epilepsy medications, according to the National Institute of Mental Health. Despite the benefit patients often find in the use of these medications, women with bipolar disorder who become pregnant commonly discontinue medication use in order to avoid uncertain medication side effects or risks, such as abnormal fetal development. This discontinuation leads to a lack of knowledge among researchers concerning the course of bipolar disorder and the effects and safety of mood stabilizers during pregnancy.

Adele Viguera, MD, MPH, at the Department of Psychiatry and Psychology at the Cleveland Clinic Neurological Institute in Ohio, and colleagues, studied pregnant women with bipolar disorder to determine the risk of mood episode recurrence for those who continued or discontinued treatment during pregnancy. According to the authors, such knowledge could affect clinicians’ care decisions for a patient who is or is not taking typically used medication during pregnancy.

Eighty-nine pregnant women with bipolar disorder as defined by the Diagnostic and Statistical Manual of Mental Disorder, Fourth Edition, Text Revision, participated in the study. Among the participants, 62 women discontinued treatment with mood stabilizers after becoming pregnant. Researchers examined time to first symptom recurrence and overall recurrence risk to assess affect of treatment continuation or discontinuation. 

All patients in the study were euthymic at conception and continued or discontinued treatment with mood stabilizers following an approximate date of conception. The most commonly used medication was lithium, which was taken by 61.8% of all patients in the study. Among all patients, 51.6% of those who discontinued treatment and 85.2% of those who continued treatment were taking lithium. In addition, 70.8% of patients were taking ≥2 psychotropics for bipolar disorder. The mean age of patients in the study was 32.7 years.

Viguera and colleagues found that the risk of symptom recurrence (defined as a patient experiencing ≥1 mood episode) during pregnancy was 71%. For women who discontinued treatment during pregnancy, 85% experienced symptom recurrence as compared to the 37% of patients who continued treatment. Most recurrences were depressive or mixed (74%). Predictors of recurrence included diagnosis of bipolar disorder type II, earlier first-episode onset, recent illness, and experiencing more recurrences per year. Antidepressant use and use of anticonvulsants instead of lithium were also predictors of symptom recurrence.

When comparing patients who continued or discontinued treatment, median time to first recurrence was four times shorter (40 weeks for the continuation group; 9 weeks for the discontinuation group) and the proportion of weeks patients experienced symptoms was five times greater for those who discontinued treatment. Women who discontinued treatment experienced symptoms for 40% of the duration of pregnancy as compared to the 8.8% for women who continued treatment.

Viguera and colleagues found that, for all recurrences, 47% occurred during the first trimester of pregnancy. Median time to recurrence was 11 times greater for patients who discontinued abruptly compared to patients who discontinued gradually. Patients who discontinued treatment within 14 days of approximate conception had a 50% risk of recurrence within 2 weeks. However, women who discontinued treatment at ≥15 days after conception did not reach a 50% risk of recurrence until 22 weeks. The authors concluded that abrupt discontinuation of bipolar disorder treatment for pregnant women created a high risk for new morbidity, particularly for early depressive and dysphoric states. Based on these findings, the authors recommend that clinicians practice a more balanced consideration of all risks and benefits associated with the illness management for patients during pregnancy. (Am J Psychiatry. 2007;164(12):1817-1824.) –CP

Dispatches is written by Michelisa Lanche, Carlos Perkins, Jr., and Lonnie Stoltzfoos.



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

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



This past December, the United States Food and Drug Administration approved duloxetine for the maintenance treatment of major depressive disorder in adults. Long overlooked, the issue of delaying or preventing a return of depressive illness has become a focus of both clinical and research interest. Until now, compared to acute efficacy trials, few maintenance studies have evaluated the efficacy of pharmacotherapy for the prevention of recurrence. One reason is that maintenance and relapse prevention studies take significantly longer to conduct than acute efficacy studies, making them difficult to complete and expensive. These studies, if they are done, occur after the drug is approved for acute treatment, so requiring completion of such studies at New Drug Application filing will delay approvals and patient access to novel treatments. Many patients need to be enrolled because discontinuation rates after 3 months in most studies are approximately 50%. In most trials, the drop-out rate at 6 months is 70%. In a study of the elderly, approximately one-third of patients who originally responded to paroxetine alone or in combination psychotherapy relapsed within 2 years.1 Relapse rates in the Sequenced Treatment Alternatives to Relieve Depression study were also high.2

There are many possible reasons people break through. Some include pharmacodynamic or pharmacokinetic tolerance (eg, tachyphylaxis), side effects (eg, apathy, anhedonia, emotional blunting), onset of a comorbid medical disorder, increase in disease severity or change in disease pathogenesis (eg, progression), depletion of effector substance (eg, neurotransmitter), serum drug levels that have drifted below or above that drug’s therapeutic window, accumulation of detrimental metabolites, misdiagnosis (eg, bipolar disorder), loss of placebo response.

Defective or counterfeit medication can be added to this list. For example, the FDA is currently reviewing the formulation of a generic form of Wellbutrin XL. Called Budeprion XL, the drug was found in tests to have significant bioavailability problems. The tests were conducted as a result of complaints by hundreds of patients that the drug caused severe headaches, digestive problems, anxiety, tremors, and insomnia.

Keep in mind that the active ingredient of a generic medication is chemically identical to the active ingredient of the corresponding branded medication. It is supposed to be identical, or bioequivalent, to a brand name drug in dosage form, safety, strength, route of administration, quality, performance characteristics, and intended use. However, the FDA does permit a variation of approximately 20% either way in the bioavailability of the active ingredient. In addition, any filler used in compounding the pill may be different than that found in the branded product. I have had several patients who complained of loss of efficacy or allergic reaction when switching from Wellbutrin XL to a generic preparation.

On a related note to that of bupropion above, a recent article appeared on the front page of the New York Times3 concerning increase in counterfeit products that reach pharmacies. Fake, subpotent, or adulterated drug products are reaching the market. Among counterfeit drugs recently seized by the FDA were Actonel, Arimidex, Celebrex, Crestor, Diovan, Hyzaar, Lipitor, Nexium, Propecia and Zetia. This is relevant because if there is a sudden change in a patient’s clinical status, either in terms of response or side effects, questions should be triggered about whether the medication looks different than those used or whether a new bottle of medication was started.

 In addition to thanking all the authors in this issue of Primary Psychiatry, I want to acknowledge the contribution of my colleague, Jean-Pierre Lindenmayer, MD. Dr. Lindenmayer is a member of the faculty at the New York University School of Medicine and has spent his career looking for ways to improve the treatment of individuals with schizophrenia. His article notes that patient function is often a neglected aspect of the disease. Although used in clinical trials, scales of functioning are not routinely used in clinical practice for the assessment of schizophrenia. He argues that an improved understanding of the spectrum of patient dysfunction and the development and increased use of specific assessment scales should improve long-term prognoses for schizophrenia patients.

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



1. Reynolds CF 3rd, Dew MA, Pollock BG, et al. Maintenance treatment of major depression in old age. N Engl J Med. 2006;354(11):1130-1138.
2. Rush AJ, Trivedi MH, Wisniewski SR, et al. Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR*D report. Am J Psychiatry. 2006;163(11):1905-1917.
3. Bogdanich W. A Toxic Pipeline Counterfeit Drugs’ Path Eased by Free Trade Zones. The New York Times. December 17, 2007:A1.


Dr. Novak is assistant professor in the Department of Psychiatry at the University Health Network at the University of Toronto and associate professor at the Institute of Behavioral Sciences at Semmelweis University in Budapest.

Disclosure: Dr. Novak reports no affiliation with or financial interest in any organization that may pose a conflict of interest.
Please direct all correspondence to: Marta Novak, MD, PhD, Department of Psychiatry, University Health Network, Toronto General Hospital, 200 Elizabeth St. EN 8-212, Toronto, ON, M5G 2C4, Canada; Tel: 416-340-3043; Fax: 416-340-4198; E-mail:



This issue of  Primary Psychiatry includes articles related to psychosocial and psychiatric problems in patients with chronic kidney disease (CKD). CKD is defined by structural or functional abnormalities of the kidney, with or without decreased glomerular filtration rate (GFR), that persists for >3 months.

In its early stages the condition is indolent but in more advanced stages (when the GFR is <60% and CKD stage 3–5) an increasing number of symptoms will appear. When the GFR drops ≤10% to 15%, the patient will need renal replacement therapy (RRT) in the form of peritoneal or hemodialysis, or kidney transplantation (KTx). This stage of the disease is called CKD stage 5 or end-stage renal disease (ESRD).

Currently, >1.5 million people worldwide and approximately 350,000 patients in the United States are treated with dialysis therapy. In the US, another 150,000 patients live with a functioning kidney transplant.2 The prevalence of stage 3–5 CKD is largely unknown but it may well be approximately 10–50 times higher than the prevalence of ESRD.3

CKD is a complex medical problem. Patients not only experience symptoms of the declining kidney function but also suffer from a variety of serious comorbid conditions (eg, cardiovascular disorders, diabetes, bone diseases, eye diseases). Significant restrictions in fluid intake and diet affect the everyday life and medical management of patients. The pharmacologic management of these medical conditions results in a complex system of numerous medications.

The mortality of patients with CKD is substantially increased and in stage 5 CKD it could be 10–100 times higher than in the general population. The 5-year survival of patients on dialysis therapy is <50% in the US. CKD and RRTs not only increase mortality and morbidity of these patients but they are also associated with severely impaired quality of life (QOL).

Dialysis is a stressor in itself on biologic, psychological, and social levels alike. KTx does not cure CKD either and people who live with transplants are constantly under the risk of rejection and may experience medication side effects. When the transplanted kidney fails, the patients have to return to dialysis again. Dialysis, in any form, cannot fully replace kidney function, and patients inevitably experience the symptoms of CKD chronically. Both dialysis and renal transplantation are fairly invasive, and intrusive procedures which may involve pain, discomfort, and distress for the patients and their families.

As the variety of psychosocial and mental health issues related to patients with chronic renal disease and RRT are increasingly acknowledged, psychonephrology has become an emerging interdisciplinary field between nephrology, transplantation, and psychosocial medicine and psychiatry.

Psychosocial and psychiatric aspects of CKD not only affect patients but have effects on family members and caregivers; a complex and difficult psychological and lifestyle adaptation to the disease, and its treatment is required from the individuals involved. Selected topics for this issue are important in assisting patients and families in this process and improving the care of patients with CKD.

Assessing the outcome of CKD, comparing the effectiveness of various RRTs has become increasingly important over the past decades. Istvan Mucsi, MD, PhD, notes in his article that in addition to the traditional “hard outcome measures” (ie, mortality, morbidity, and hospitalization), patient-reported outcomes and, specifically, health-related quality of life, have increasingly been recognized as equally important aspects of healthcare delivery, measures of effectiveness, and patient experience in chronic medical conditions such as CKD. He emphasizes that RRTs are very intrusive therapies and have a significant impact on patient lives. Sometimes this is similar in magnitude to the effect of the disease itself on QOL. Consequently, QOL of the patients with ESRD is substantially impaired in the physical, mental health, and social domains.

Sleep disorders clearly contribute to impaired QOL and might even affect survival in patients with CKD. Sleep disorders and complaints regarding sleep are among the most frequent problems in patients with CKD. Mark Unruh, MD, MSc, provides an overview of the most frequent and significant sleep disorders, including insomnia, sleep apnea, and restless legs syndrome. He also notes that sleep disorders are still understudied in this high risk population.

Mood disorders and anxiety are the most common psychiatric problems in patients with kidney diseases. Stressful life events can trigger depression at any point of the CKD, especially in those who are susceptible to mood disorders. Specific disease-related factors might also contribute to depression or emotional distress in these patients.

Both patients and physicians often tend to attribute the physical problems, emotional distress, and functional decline to the kidney disease, and depressive disorders may be overlooked. Treatment of depressive disorders may be one important step toward a life not fully dominated by the perceived intrusiveness of the illness. Dora M. Zalai, MD, and Marta Novak, MD, PhD, emphasize that a complex biopsychosocial approach is needed to fully understand mood disorders in medically ill patients in general, and in CKD patients in particular.

The fact that no outcome studies are available that assess the effect of depression treatment on survival or QOL in this patient population points to a disturbing clinical knowledge gap. Based on the association of depression and mortality and the well-documented relationship between depression and compliance as well as between depression and conditions such as malnutrition, cardiac events, and inflammation, we can speculate that effective treatment of depression would improve the outcome of patients with CKD. Treatment of psychiatric disorders deserves special consideration in the medically ill patient. Often, patients receive suboptimal pharmacologic management due to the lack of information in this specific area. Roger S. McIntyre, RS, MD, FRCPC, and colleagues, provide a comprehensive review on the use of psychotropic drugs in patients with impaired renal function. After a detailed theoretical overview, they discuss “tactics and strategies” with a special focus on lithium and antidepressants and an extended Table synthesizing the available information of pharmacokinetics of psychotropic medications.

It is hoped that readers will find these articles useful for everyday practice. PP



1.    National Kidney Foundation: K/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification, and stratification. Am J Kidney Dis. 2002;39(2 Suppl 1):S1-266.
2.    U.S. Renal Data System. USRDS 2007 Annual Data Report: Atlas of Chronic Kidney Disease and End-Stage Renal Disease in the United States. Bethesda, MD: National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases; 2007.
3.    Coresh J, Astor BC, Greene T, Eknoyan G, Levey AS. Prevalence of chronic kidney disease and decreased kidney function in the adult US population: Third National Health and Nutrition Examination Survey. Am J Kidney Dis. 2003;41(1):1-12.