Dr. Zayfert is assistant professor of psychiatry and director of the Anxiety and Posttraumatic Stress Disorder Treatment Program in the Department of Psychiatry at Dartmouth Medical School in Hanover, NH.

Dr. Gillock is clinical associate in the Department of Psychiatry at Dartmouth Medical School.

Dr. Mellman is associate professor of psychiatry and director of the Psychopharmacology Program in the Department of Psychiatry at Dartmouth Medical School.

Acknowledgments: The authors would like to thank Carolyn Black Becker for her helpful comments. The authors report no financial, academic, or other support of this work.



Why is it important to detect posttraumatic stress disorder (PTSD) in medical settings and how can physicians help these patients obtain effective treatment? PTSD often manifests through physical symptoms and might be associated with a variety of medical problems. Unaware that such symptoms may be related to PTSD, many patients seek medical care only. This article discusses the critical role of medical professionals in ameliorating the deleterious effects of PTSD on physical and emotional well-being. Patients who present in medical settings often do not readily comprehend the complex role posttraumatic stress reactions can play in their health problems and are often reluctant to discuss their traumatic experiences. Thus, physician identification and management of PTSD is crucial for many patients. However, addressing PTSD presents unique challenges even for physicians skilled in addressing other mental health concerns. These challenges include recognizing signs of PTSD and developing effective strategies for communicating with patients about the role of PTSD in their overall health.



Recent epidemiologic data indicate that a substantial majority of Americans have experienced traumatic events.1 Posttraumatic stress disorder (PTSD) is a potentially debilitating anxiety disorder that affects many who are exposed to trauma. The current prevalence of PTSD in the general United States population is estimated to be 5%,2 and approximately 8% of the population meet criteria for PTSD at some point in their lives.3 However, the prevalence of PTSD among medical populations is substantially higher.4,5

The high rates of PTSD observed in medical populations are not surprising given that PTSD has been linked to poor health outcomes and functioning in a variety of domains. Studies have shown an association between PTSD, increased physical complaints, and poor overall health.6,7 PTSD has also been associated with an increased risk for medical conditions affecting the circulatory, digestive, musculoskeletal, nervous, respiratory, and immunological systems.8 Finally, available evidence suggests that individuals suffering from PTSD seek medical treatment more often than those without PTSD.7,9

Researchers have developed a variety of models to explain the association between PTSD and poor physical health. However, it is likely that a complex interaction of biological, behavioral, and psychosocial mechanisms leads to seeking of medical treatment among individuals with PTSD. For example, many traumatic events result in physical injury, some with lasting medical sequelae that require ongoing care.7,10 In addition, biologic dysregulation associated with PTSD, principally in the adrenergic and hypothalamic-pituitary-adrenal systems, has been implicated in the development of a variety of medical conditions for which patients seek care.11 PTSD has also been linked to behavioral risk factors (eg, smoking, substance use, poor diet, lack of exercise) for poor health.3,11 Finally, because PTSD involves avoidance of thinking about traumatic experiences, patients may selectively attend to physical symptoms that often accompany PTSD.7,12

In addition to the more straightforward medical presentations, PTSD is also associated with complex syndromes such as irritable bowel syndrome,13 fibromyalgia,14 and chronic fatigue syndrome.15 The primary care provider is in the optimal position to coordinate referrals for the multidisciplinary services that will best serve the needs of these patients. Thus, identification in the primary care setting has a pivotal role in meeting the treatment needs of individuals with PTSD. Even so, PTSD eludes detection in primary care in many cases. Thus, patients frequently present to specialized clinics such as those treating chronic pain, headaches, or epilepsy. Because these patients may be among those least likely to comply with recommendations to seek psychological services, it is important that clinicians become adept at drawing connections between PTSD and other disorders in a persuasive yet nonthreatening manner.

A variety of factors can interfere with identification of PTSD in clinical practice. Unfamiliarity and/or discomfort with the disorder and time constraints on clinicians may impede detection. Detection is also hindered by overlap between PTSD symptoms, diagnosable physical conditions, and the ambiguity in symptom presentation. Because there is often a gap of months or years between traumatic events and the onset of physical symptoms, individuals with physical complaints often do not link them to prior trauma. Many patients are reluctant to disclose traumatic events and discuss psychological symptoms. Avoidance of thoughts or reminders about the traumatic event is a core aspect of PTSD. Cultural influences, such as the belief that psychological symptoms are indicative of weakness, may dissuade some patients from revealing relevant diagnostic information.

Despite obstacles, enhancing detection of PTSD in medical settings is a worthy goal. Identification of PTSD offers physicians the opportunity to refer patients for effective intervention16 and alleviate suffering of those who might otherwise never seek mental health treatment. Thus, the remainder of this article will offer guidance to healthcare providers in meeting the needs of patients suffering from PTSD who present in medical settings.


Recognizing PTSD

The criteria for PTSD include the experience of a traumatic event, reexperiencing symptoms, avoidance symptoms, and hyperarousal.17 Events that may lead to PTSD typically involve a threat of serious harm to the individual or someone close to them and produce a sense of intense fear, helplessness, or horror. Clues from the patient’s history, behavior, and self-report are helpful for recognizing PTSD (Table). A diagnosis of PTSD is given when traumatic memories remain disturbing for 1 month or longer and persistently provoke fear, arousal, and avoidance behavior that is very distressing or that greatly interferes with a person’s life. PTSD is often accompanied by physical health complaints and feelings of depression, guilt, or shame.


Interviewing Strategies With Traumatized Patients

While there are a number of reasons why providers might be reluctant to ask about trauma, patients often welcome provider’s inquiries about their trauma experiences.18 When providers do not ask about abuse and assault, they can inadvertently send the message that this information is not important. Providers may be more inclined to assess patients’ exposure to trauma if they feel equipped to intervene effectively.

Once trauma has been identified as a significant concern, specialized psychiatric services are often indicated. Guiding patients with PTSD to seek appropriate services is typically a gradual process that takes place over multiple visits. The following strategies may facilitate identification and management of PTSD.
Ask about trauma directly and specifically. Taking the initiative shows that the clinician recognizes that trauma is a health issue. Using behaviorally specific and nonjudgmental questions maximizes the likelihood that the patient will disclose potentially embarrassing experiences such as abuse and assault.18
Interview the patient alone. Disclosure of trauma is sometimes more difficult or embarrassing in the presence of significant others. In addition, providers should alert themselves to the possibility of current abuse and avoid questioning in the presence of a possible perpetrator.
Summarize observations. Describing observations in simple and objective terminology can help the patient draw connections between experiences that previously appeared unrelated. Often, it is helpful to present this to the patient in a tentative manner (eg, “I’ve begun to wonder if what you are experiencing lately might be related to things that happened in your past”).
Normalize and validate posttraumatic reactions. Many patients with PTSD are aware that something is “not right,” but are fearful that their symptoms mean that they are abnormal, losing control, or “going crazy.” Communicating that the symptoms are understandable reactions experienced by many trauma survivors is a powerful method of managing traumatized patients. Validation can smooth subsequent steps, including medical procedures and referrals. Validation may include statements such as, “It’s not unusual to be bothered by stressful experiences long after they are over” and “It makes sense that you feel overwhelmed.”
Link to the presenting complaint. Patients with PTSD who present in medical settings are often concerned that the physician will not take their medical complaints seriously. For a variety of reasons, some patients are not ready to directly address their condition. Establishing a connection to the presenting complaint may enhance willingness to address psychological issues that affect the presenting problem. For example, the physician can make a statement such as, “It might be frightening to think about, yet the stress of ‘unfinished business’ can make it harder to deal with your back pain.”
Emphasize stress reduction. In making a referral for psychological services, it is important to communicate to patients that you take their symptoms seriously and to dispel the impression that you think the symptoms are “in their head.” Emphasize that stress can affect physical health and that a multidisciplinary approach may offer strategies to reduce stress and thereby alleviate suffering related to health concerns.
Offer optimism. PTSD patients often feel they have little control over many areas of their lives. Hopelessness interferes with taking steps to get help. Thus, an important goal of early intervention is to establish a sense of optimism by communicating to the patient that he or she can learn more effective ways of coping with stress. For example, the physician might say, “You can learn other ways to cope with your distress about the past. While we can’t change the awful things that have happened to you, I am hopeful that we will be able to help you feel less stressed by them.”
Enhance control. Using specific strategies to enhance the patient’s feeling of control can increase his or her willingness to adhere to recommendations. In addition to open and collaborative communication, this includes more extensive education about reproductive functioning, medical procedures, and offering choices whenever possible.


Screening Instruments

Given the high costs and burden on resources associated with undetected PTSD,19 formal screening processes may have utility in some settings. Several brief screening instruments for PTSD have recently been developed. Breslau and colleagues20 devised a seven-symptom screening tool based on a widely used diagnostic interview. Breslau and colleagues found that interview endorsement of four of the seven symptoms accurately detected 80% of cases classified as lifetime PTSD, based on the full diagnostic interview. However, follow-up assessment is recommended since the rate of false positives with this screening is 29%.

Meltzer-Brody and colleagues21 offered a four-item self-rating scale to screen for current PTSD diagnosis. The Startle, Physiologic arousal, Anger, and Numbness (SPAN) Test correctly identifies 84% of PTSD cases, and has a false positive rate of 11%. The use of these screening tools has the potential to enhance detection of PTSD when used in a population where the prevalence rate is 10% or higher.


Detection and Initial Management of PTSD in Populations With Increased Risk

As noted above, PTSD is overrepresented in medical populations and is associated with a higher rate of service utilization. This section reviews considerations relevant to the detection and initial management of PTSD in three populations for which it may be of particular significance: acute injury, obstetrics/gynecology (OB/GYN), and chronic pain clinics.


Acute Injury

Settings in which acute injury is treated are unique in that identification and management is aimed at prevention of PTSD soon after a trauma. Traumatic injury is a relatively common antecedent of PTSD.1 Psychiatric sequelae of traumatic injury often take the form of “subthreshold PTSD,” ie, posttraumatic symptoms that cause distress and impairment but fail to meet full PTSD diagnostic criteria.22,23

The significance of psychiatric complications of traumatic injury is underscored by findings that PTSD and depression significantly predict functional status and satisfaction with recovery after controlling for injury severity.24

Although serious injury is highly prevalent, only a minority of injury survivors will develop PTSD.25,26 Therefore, determining who is at future risk based on acute signs and symptoms is an important consideration for targeting interventions. The recently introduced diagnostic category of acute stress disorder emphasizes dissociation and the presence of PTSD symptoms as demarcating early risk for continuing PTSD. However, the data regarding the significance of dissociation for predicting PTSD in the aftermath of severe injury are mixed.23,26 Other factors that have been associated with increased risk for development of PTSD after injury include elevated heart rate within hours of the trauma,27 severity of early PTSD symptoms,26 and avoidant and maladaptive coping styles.22,23

Since it is not feasible for all injured patients at risk for PTSD to receive mental health interventions, it is important that providers in acute trauma settings have a general awareness of issues related to the disorder. Educating injured patients about possible PTSD symptoms is potentially a useful and cost-effective first-line intervention. Patients who begin to experience nightmares or flashbacks are often confused and frightened by their symptoms and can benefit from having a frame of reference for understanding them. The brief screening tools discussed above and patient information materials can provide this framework.

Injured patients who manifest intense reexperiencing, anxiety, sleep disturbance, dissociation, or appear to be trying hard to avoid thinking about what happened warrant the highest priority for mental health intervention. Research on interventions for preventing PTSD soon after trauma is in preliminary stages. Some of the most promising data support a modification of cognitive-behavioral therapy (CBT) for injury survivors.28 This suggests that some of the key components of CBT, such as educating the patient about the nature of PTSD and facilitating expression of trauma-related memories, thoughts, and feelings, are potential strategies for prevention of PTSD.



Women are at high risk for exposure to assaultive violence. Approximately 35% of those assaulted have experienced PTSD during their lifetime,29 warranting a skillful approach to detecting and managing PTSD in the OB/GYN setting. Abuse/assault and subsequent PTSD put women at greater risk for reproductive health problems, including sexual dysfunction, genital or nongenital physical injuries, sexually transmitted diseases,30 chronic pelvic pain (CPP),31 and complications during pregnancy and/or childbirth.32

OB/GYN providers should be especially cognizant of abuse/assault and PTSD because pelvic exams, labor, and delivery procedures can evoke feelings of loss of control and violation. In addition, both pregnancy and childbirth can trigger memories of past abuses, and childbirth itself is a potentially traumatic event.32 Being aware of a woman’s abuse history enables OB/GYN providers to adjust their interactions with the patient to enhance her sense of control and reduce her anxiety and posttraumatic symptoms during medical procedures.


Chronic Pain

Traumatic events, particularly sexual and physical abuse, are common experiences of patients seeking help for chronic pain problems. Such events have been implicated in the development and maintenance of chronic pain syndromes.33 Estimates of the prevalence of any form of abuse among patients with chronic pain have been as high as 65%.34,35 Despite the attention to trauma in the development and maintenance of chronic pain, the role of PTSD in chronic pain has only recently been investigated. However, available data suggests that the prevalence of PTSD among patients with chronic pain problems approximates 35%.5 Moreover, the presence of PTSD appears to adversely affect the adaptation to chronic pain.12,36

CPP, in particular, is a complex problem with multiple contributing factors. Approximately 58% of women who present with CPP report a history of assault or abuse,37 yet there is no conclusive evidence that psychological factors have a causative role.38 It is important to identify possible psychological contributions such as PTSD. However, CPP is a multifaceted problem, and communicating to the patient that physical complaints are to be taken seriously regardless of identifiable organic pathology promotes effective management.



PTSD is a highly prevalent disorder with pervasive effects on emotional and physical health. Despite this, many individuals do not seek appropriate interventions that can attenuate the aftereffects of trauma. Patients with PTSD present in medical settings with a wide range of physical health concerns, yet show little awareness of the role of their traumatic experiences in their presenting complaints. Attention to the detection of PTSD and the use of strategies suggested above would facilitate effective intervention for PTSD as an important adjunct to the patient’s medical care.  PP



1.    Breslau N, Kessler RC, Chilcoat HD, Schultz LR, Davis GC, Andreski P. Trauma and posttraumatic stress disorder in the community: the 1996 Detroit area survey of trauma. Arch Gen Psychiatry. 1998;55:626-631.
2.    Norris FH. Epidemiology of trauma: frequency and impact of different potentially traumatic events on different demographic groups. J Consult Clin Psychol. 1992;60:409-418.
3.    Kessler RC, Sonnega A, Bromet E, Hughes M, Nelson CB. Posttraumatic stress disorder in the national comorbidity survey. Arch Gen Psychiatry. 1995;52:1048-1060.
4.    Stein MB, McQuaid JR, Pedrelli P, Lenox R, McCahill ME. Posttraumatic stress disorder in the primary care medical setting. Gen Hosp Psychiatry. 2000;22:261-269.
5.    Asmundson G, Norton GR, Allerdings MD, Norton PJ, Larsen DK. Posttraumatic stress disorder and work-related injury. J Anxiety Disord. 1998;12:57-69.
6.    Clum GA, Calhoun KS, Kimerling R. Associations among symptoms of depression and posttraumatic stress disorder and self-reported health in sexually assaulted women. J Nerv Ment Dis. 2000;188:671-678.
7.    McFarlane AC, Atchison M, Rafalowicz E, Papay P. Physical symptoms in post-traumatic stress disorder. J Psychosom Res. 1994;38:715-726.
8.    Schnurr PP, Spiro A 3rd, Paris AH. Physician-diagnosed medical disorders in relation to PTSD symptoms in older military veterans. Health Psychol. 2000;19:91-97.
9.    Schnurr PP, Friedman MJ, Sengupta A, Jankowski MK, Holmes T. PTSD and utilization of medical treatment services among male Vietnam veterans. J Nerv Ment Dis. 2000;188:496-504.
10.    Beckham JC, Crawford AL, Feldman ME, et al. Chronic posttraumatic stress disorder and chronic pain in Vietnam combat veterans. J Psychosom Res. 1997;43:379-389.
11.    Schnurr PP, Jankowski MK. Physical health and post-traumatic stress disorder: Review and synthesis. Semin Clin Neuropsychiatry. 1999;4:1-11.
12.    Bryant RA, Marosszeky JE, Crooks J, Baguley IJ, Gurka JA. Interaction of posttraumatic stress disorder and chronic pain following traumatic brain injury. J Head Trauma Rehabil. 1999;14:588-594.
13.    Irwin C, Falsetti SA, Lydiard RB, Ballenger JC, Brock CD, Brener W. Comorbidity of posttraumatic stress disorder and irritable bowel syndrome. J Clin Psychiatry. 1996;57:576-578.
14.    Amir M, Kaplan Z, Neumann L, Sharabani R, Shani N, Buskila D. Posttraumatic stress disorder, tenderness, and fibromyalgia. J Psychosom Res. 1997;42:607-613.
15.    Katon W, Sullivan M, Walker E. Medical symptoms without identified pathology: relationship to psychiatric disorders, childhood and adult trauma, and personality traits. Ann Intern Med. 2001;134:917-925.
16.    Foa EB, Keane TM, Friedman MJ, eds. Practice Guidelines From the International Society for Traumatic Stress Studies: Effective Treatments for PTSD. New York, NY: The Guilford Press; 2000.
17.    Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition. Washington, DC: American Psychiatric Association; 1994.
18.    Acierno R, Resnick HS, Kilpatrick DG. Health impact of interpersonal violence. 1: Prevalence rates, case identification, and risk factors for sexual assault, physical assault, and domestic violence in men and women. Behav Med. 1997;23:53-64.
19.    Greenberg PE, Sisitsky T, Kessler RC, et al. The economic burden of anxiety disorders in the 1990s. J Clin Psychiatry. 1999;60:427-435.
20.    Breslau N, Peterson EL, Kessler RC, Schultz LR. Short screening scale for DSM-IV posttraumatic stress disorder. Am J Psychiatry. 1999;156:908-911.
21.    Meltzer-Brody S, Churchill E, Davidson JRT. Derivation of the SPAN, a brief diagnostic screening test for post-traumatic stress disorder. Psychiatric Res. 1999;88:63-70.
22.    Schnyder U, Moergeli H, Klaghofer R, Buddeberg C. Incidence and prediction of posttraumatic stress disorder in severely injured accident victims. Am J Psychiatry. 2001;158:594-599.
23.    Mellman TA, David D, Bustamante V, Fins A, Esposito K. Predictors of PTSD following severe injury. J Anxiety and Depression. 2001;14:226-231.
24.    Michels AJ, Michaels CE, Moon CH, Zimmerman MA, Peterson C, Rodriguez JL. Psychosocial factors limit outcomes after trauma. J Trauma. 1998;44:644-648.
25.    Ursano RJ, Fullerton CS, Epstein RS, et al. Acute and chronic posttraumatic stress disorder in motor vehicle accident victims. Am J Psychiatry. 1999;156:589-595.
26.    Harvey A, Bryant RA. The relationship between acute stress disorder and posttraumatic stress disorder: a 2-year prospective evaluation. J Consult Clin Psychol. 1999;67:985-988.
27.    Shalev AY, Sahar T, Freedman S, et al. A prospective study of heart rate response following trauma and the subsequent development of posttraumatic stress disorder. Arch Gen Psychiatry. 1998;55:553-559.
28.    Bryant RA, Harvey AG, Dang ST, Sackville T, Basten C. Treatment of acute stress disorder: a comparison of cognitive-behavioral therapy and supportive counseling. J Consult Clin Psychol. 1998;66:862-866.
29.    Breslau N, Chilcoat H, Kessler R, Peterson E, Lucia V. Vulnerability to assaultive violence: further specification of the sex difference in posttraumatic stress disorder. Psychol Med. 1999;29:813-821.
30.    Resnick HS, Acierno R, Kilpatrick DG. Health impact of interpersonal violence 2: medical and mental health outcomes. Behav Med. 1997;23:65-78.
31.    Savidge CJ, Slade P. Psychological aspects of chronic pelvic pain. J Psychosom Res. 1997;42:433-444.
32.    Allen S. A qualitative analysis of the process, mediating variables and impact of traumatic childbirth. J Reproductive & Infant Psychol. 1998;16:107-131.
33.    Rapkin AJ, Kames LD, Darke LL, Stampler FM, Naliboff BD. History of physical and sexual abuse in women with chronic pelvic pain. Obstet Gynecol. 1990;76:92-96.
34.    Taylor ML, Trotter DR, Csuka ME. The prevalence of sexual abuse in women with fibromyalgia. Arthritis Rheum. 1995;38:229-334.
35.    Haber J, Roos C. Effects on spouse abuse and/or sexual abuse in the development and maintenance of chronic pelvic pain in women. In: Fields HL, Dubner R, Cervero F, eds. Advances in Pain Research and Treatment. New York, NY: Raven Press; 1985.
36.    Hickling EJ, Blanchard EB, Schwarz SP, Silverman DJ. Headaches and motor vehicle accidents: results of the psychological treatment of post-traumatic headache. Headache Quarterly. 1992;3:285-289.
37.    Walker EA, Gelfand AN, Gelfand MD, Koss MP, Katon WJ. Medical and psychiatric symptoms in female gastroenterology clinic patients with histories of sexual victimization. Gen Hosp Psychiatry. 1995;17:85-92.
38.    Steege JF, Stout A. Chronic gynecologic pain. In: Stewart DE, Stotland NL, eds. Psychological Aspects of Women’s Health Care: The Interface Between Psychiatry and Obstetrics and Gynecology. Washington, DC: American Psychiatric Press; 1993.

Dr. Marshall is director of trauma studies and services at the New York State Psychiatric Institute and associate professor of clinical psychiatry at Columbia University College of Physicians and Surgeons, both in New York City.

Dr. Sinha is research fellow in the Department of Psychiatry at Columbia University College of Physicians and Surgeons.

Acknowledgments: This work was supported in part by National Institute of Mental Health Grant#MH01412. 



The history of the recognition of psychological impairment after severe trauma is, in many ways, a microcosm of the history of clinical psychiatry and psychology. Until recently, etiological assumptions about clinical manifestations have confounded the field. However, current research regarding the central nervous system’s plasticity in both the developing and adult human links severe psychological trauma with enduring alterations in brain function. These recent studies offer a rationale for administering medication to patients with posttraumatic stress disorder (PTSD). More importantly, adults diagnosed with PTSD can receive a number of different medications that have demonstrated efficacy. However, the real priority is to achieve full remission in patients rather than merely improvement in symptoms. Hence, further study of new compounds as well as longer and combined treatments will be necessary and will likely improve our management of patients with this often refractory disorder.



There is … no a priori reason why drugs should not be discovered which have a wholly beneficial effect. I have never myself observed any but good effects to flow from the drinking of tea, at any rate if it is China tea.

Bertrand Russell1

For several centuries, medical literature has documented the relationship between traumatic experiences and enduring, debilitating psychological suffering. However, only recently has this association been incorporated in the psychiatric literature (Diagnostic and Statistical Manual of Mental Disorders, Third Edition2 [DSM-III]). The history of this phenomenon is revealing in itself and pertinent to contemporary debate in the field.3 The structure of arguments proposing a connection between trauma and psychological stress seem consistent with the Hegelian model of the evolution of “thesis, antithesis, synthesis.” Initial theoretical explanations focused on the biological perspective in the 18th and 19th centuries. The early 20th century witnessed the psychoanalysis debate with psychological explanations brought to the forefront.

In the past 10 years, proof of both somatic and psychological approaches have emerged, along with evidence of biological vulnerabilities and a genetic predisposition to posttraumatic stress disorder (PTSD). Once all the data are synthesized, we suspect that a true biopsychosocial model of PTSD will emerge as the most accurate and clinically useful model.

Throughout this debate, propositions about the etiology of PTSD symptoms have often polarized between two models.4 A more biologically based model posits that vulnerability factors explain why some individuals develop PTSD while other persons, despite the same severity of trauma, spontaneously recover. A psychologically based model driven by stigmatization proposes that all individuals with PTSD possess a universal vulnerability to severe trauma and objects to the medicalization of posttraumatic reactions as “symptoms” rather than normal reactions to abnormal events.

In the 19th and early 20th centuries, a common belief was maintained that PTSD-like syndromes resulted from neurological damage (eg, minimal brain damage during an accident, damaged heart tissue, or concussion-like effects of explosive shells leading to “shell shock”).5 The alternative viewpoint—that clinical symptomatology might be better explained as a psychological consequence of trauma—came to the forefront during the psychoanalytic era, in which all mental illness was reconceptualized as having a psychological and developmentally rooted etiology. However, even this perspective presumed the existence of constitutional vulnerabilities. We now know that both biological alterations and vulnerability factors are associated with PTSD. For example, in a large study of United States Vietnam veterans, genetic models accounted for about one third of symptom liability.6

After World War II, psychoanalysis was the dominant paradigm. In 1947, after treating many war veterans, Kardiner and Spiegel7 noticed striking physiologic symptoms in patients who seemed to suffer from damage and/or dysregulation of the autonomic nervous system. They termed this condition “physioneurosis.”

During this era, physicians primarily treated psychiatric illness by analyzing neurotic conflicts that were rooted in the patients’ early development; physicians assumed that the patients’ symptoms represented regression under stress.

Pharmacotherapy for Physioneurosis

After World War II, experts advocated the use of sedatives in patients with chronic conditions to facilitate the psychotherapeutic process of dealing with memories of trauma. Only barbiturates were available then, and their disadvantages often outweighed their usefulness. Dr. Kardiner8 explained it thus:

Barbiturates have the advantage of being simultaneously an anesthetic and a device to render the subject accessible. It has however the disadvantage of blunting the sensorium, so that, although it is possible to dissolve a good many peripheral defenses, the chances of complete integration of the reconstructive efforts are diminished.

Although researchers recognized that biological factors played a role in physioneurosis, they did not believe that medications contributed toward recovery, which was presumably a psychological process.

Empirical Findings to Date

Pharmacotherapy for patients with PTSD has demonstrated direct usefulness over the past 10–15 years, despite the fact that the mechanism of action for most psychiatric medications remains unknown. Although medications are categorized by their pharmacodynamic properties (eg, selective serotonin reuptake inhibitor [SSRI]) and molecular structure (eg, heterocyclic antidepressants), none of these designations explain the mechanism of action. This is a very important research issue because premature closure regarding the relationship between the psychobiology of PTSD and the putative mechanisms of pharmacotherapy can be damaging to scientific progress in this area.

Early medication trials were conducted exclusively with war veterans who usually demonstrated modest results with the exception of a single trial of phenelzine.9 Tricyclic agents also seemed to have modest effectiveness in this population.9,10

Since the discovery of the SSRIs, the study of PTSD caused by combat or other types of trauma has shifted to progressively larger, more rigorous trials. Five large multicenter trials using the SSRIs sertraline, paroxetine, and fluoxetine have demonstrated efficacy compared with placebo in adults who had chronic PTSD due to a wide range of traumas.10-14 These findings replicated and extended the results of two previous single-site studies with fluoxetine.15,16

Negative trials with SSRIs have also been reported.17-19 Three of the four negative trials were conducted primarily using US war veterans as subjects. To date, the only multinational trial conducted in Africa and Europe showed efficacy for war veterans. This suggests that recruitment patterns in US studies probably differ from those abroad and may be biased toward enrolling treatment-refractory individuals who have failed several prior treatment attempts.14

Three earlier pioneering trials demonstrated superiority over placebo for the tricyclic antidepressants amitriptyline9 and imipramine,9 and the monoamine oxidase inhibitor phenelzine.9 Smaller early trials conducted with phenelzine20 and similar drugs (alprazolam21 and inositol22) produced negative results, although the studies were probably inadequately powered.

A large number of case reports have reported therapeutic efficacy for other drug categories including mood stabilizers such as valproate, topiramate, carbamazepine, gabapentin, and lithium, and α-agonists (eg, clonidine).23 Of course, double-blind, placebo-controlled trials must be conducted before a drug can be considered effective. The history of medicine is replete with humbling examples of the post hoc fallacy. The scientific literature is biased toward positive reports because negative trials are less likely to be submitted for publication.

Treatment-Response Patterns

Many clinically relevant observations have emerged from the new large-scale SSRI trials that answer longstanding questions, sometimes overturn previously held assumptions, and often point investigators toward important and new directions such as the following:

• Medication is effective for PTSD. Although this point may seem obvious to many readers, only a decade ago this controversial assertion was maintained by only a minority of experts in the field. The Food and Drug Administration (FDA) has approved sertraline and paroxetine for PTSD. The largest paroxetine trials to date have now demonstrated efficacy for all three symptom clusters analyzed.13,14 It was initially surprising that a medication could help to reverse entrenched behavioral avoidance patterns that had often been maintained for years.
• Medication is effective for PTSD arising from a wide range of trauma types. Early literature focused largely on the type of trauma, rather than the universal features that most trauma survivors shared. Thus, there was a railway spine syndrome, a rape trauma syndrome, battle fatigue, irritable heart syndrome, and so forth. A major contribution of the DSM was the focus on defining universal features of syndromes, such as longitudinal course.3 Thereafter, clinical trials demonstrated that drugs were effective for treating individuals with PTSD resulting from all types of traumas ranging from car accidents to domestic violence.
• SSRIs appear to be equally effective for men and women. A major controversy in the literature has been the question of whether there are gender differences in treatment response. Approximately twice as many women as men report a lifetime history of PTSD.24 However, until recently, the literature was confounded by the fact that most of the negative trials with SSRIs were conducted in US war veterans, who were almost entirely males. A recent trial13 with paroxetine demonstrated equal treatment efficacy in both genders, the majority of whom had experienced nonwar-related trauma.
For most individuals, medication alone will not lead to remission, at least in the short-term. On the whole, the mean reduction in symptoms in large SSRI trials is approximately 50% compared with a 30% reduction in symptoms observed in patients who received a placebo. Similar findings are seen in time-limited psychotherapy trials that use the same methodology for outcome analysis (ie, intent-to-treat analysis). This deserves emphasis because the psychological literature has traditionally published more complete analyses which tend to be more favorable than intent-to-treat analyses. These results suggest that additional treatment will be needed for most individuals. In double-blind, placebo-controlled trials, the response pattern suggests a flattening of the response curve at 6–8 weeks of treatment with adequate doses of an SSRI (in the higher range).

However, a recent report by Londborg and colleagues25 suggested that therapeutic benefits can continue for more than 12 weeks in at least a subgroup of individuals. Patients were offered the opportunity to receive open treatment with sertraline in a continuation phase (24 weeks) after completing a double-blind, placebo-controlled trial. The authors included in the analysis only those patients who had been randomized to receive the active medication. Of those patients who received sertraline during the trial and opted to receive open treatment (n=128), about half of those who had been rated as nonresponders (28/52) became responders during this phase over the next 24 weeks.

This response pattern stands in contrast to those observed in all acute controlled trials to date—a clear plateau in treatment response seen in patients who received medication alone after 6–8 weeks. It is possible that individuals who could not tolerate sertraline or had a minimal response did not enter the open trial, thereby altering the sample composition. Nevertheless, this study25 provides the first evidence that at least some patients can show ongoing improvement over 6 months, and that partial responders should probably continue medication beyond the usual 12 weeks if other treatments that might accelerate recovery are unavailable or are refused.
The clinical need for additional treatments exceeds our empirical knowledge. Case reports and open trials document the fact that many patients do not achieve full recovery after treatment with medications of established efficacy. This finding is apparent to most clinicians who manage and treat PTSD patients. Until further research is available, the recommended strategy is to target specific symptom clusters or problems that may be responsive to certain types of medications. For example, patients who have problems with affect dysregulation, irritability, and aggressive impulses and who have not responded to SSRIs might experience symptom reduction by taking a mood stabilizer. Patients with persistent reexperiencing in the form of nightmares and/or vivid imagery might respond to α-agonists. Patients with depressive symptoms that have only partially responded to the first antidepressant agent might improve with the addition of a second medication of complementary antidepressant action. In all clinical situations, the combination of medication with supportive psychotherapy has been recommended.26

Treatment Versus Referral

Most experts working with PTSD patients, including those involved in research in primary care settings, have stated that the primary care provider’s preferred role is identification, provision of education, and referral to a specialist.27

The most efficient and successful way to detect PTSD is to assess for lifetime traumatic experiences. Brief questionnaires such as the Life Events Questionnaire28 or Short PTSD Rating Interview (SPRINT)29 offer a natural lead into questions about the consequences of the traumatic experience. The physician’s assessment might include questions about reexperiencing (eg, “Was it on your mind a lot afterward?” or “Did you keep seeing it in your mind and dreaming about it?”), avoidance (eg, “Did you find yourself withdrawing from other people afterward?” or “Do you feel less interested in things you enjoyed before?”), and arousal (eg, “Were you very jumpy or jittery afterward?”, “Are you more cautious or fearful in general?”, “Are you having trouble sleeping?”, or “Do you startle easily?”). Relationship problems are also common (eg, “Did you find you were more irritable, having trouble getting along with others? If so, did this affect your sex life?”).

If the diagnosis of PTSD is made, it is crucial to mention that there are safe and effective treatments, in order to give the patient hope and motivation for seeking help. Referral to a specialist is preferable for patients who are willing. If patients are reluctant to meet with a mental health practitioner or if none are available, providing information about treatment options is still important because a subsequent partial response to medication may require revisiting the option of psychotherapy.

A number of typical questions can arise during medication treatment. Because trauma patients have a heightened sense of caution, they may have exaggerated fears about side effects of medications. Reviewing research findings with these patients may provide reassurance. Patients may misperceive the offer of medication treatment as an expression of unwillingness to talk about their traumatic experience.

On the other hand, many patients seek help based on the assumption that the medical model is most appropriate when they feel severely ill. In nonwestern countries, depression and anxiety primarily present with somatic symptoms. The fact that there is a biological model for PTSD can be experienced as legitimizing their suffering. Patients may experience the biological model as a positive connection to their physicians  and, hopefully, as a way of taking positive action to improve their lives. However, patients may sometimes rely heavily on the medication based on an idealized wish to erase the trauma from their memory. We believe it is important to present the medication as an adjunct to the patients’ efforts toward recovery.

If a first medication is only partially effective, the physician can again recommend the option of psychotherapy. Although guidelines have been recently published26 concerning the next steps in a treatment algorithm, a psychiatrist’s assistance is highly advisable at this point, if possible.


The history of treatment for chronic PTSD reflects the vicissitudes of our field. Although we still have no coherent and validated theory to explain PTSD symptoms, emerging ethological and clinical research strongly supports the power of pharmacotherapy to correct alterations in multiple systems that modulate affect and perception. The SSRIs offer the most optimal and validated empirical treatments to date. The FDA has approved both sertraline and paroxetine in the US.

Acute treatment trials of medication or psychotherapy demonstrate that a substantial proportion of patients remain symptomatic at the conclusion of the trial. Unfortunately, most individuals with trauma-related symptoms or problems never seek and/or receive effective treatment. Public health efforts and clinical trials are equally important in diminishing the suffering of trauma survivors.   PP


1. Russell B. The Scientific Outlook. New York, NY: W.W. Norton; 1931:184.
2.    Diagnostic and Statistical Manual of Mental Disorders. 3rd ed. Washington, DC:?American Psychiatric Association; 1980.
3.    Marshall RD, Klein DF. Diagnostic classification of anxiety disorders: historical context and implications for neurobiology. In: Charney DS, Nestler EJ, Bunney BS, eds. Neurobiology of Mental Illness. Oxford, England: Oxford University Press; 1999:437-450.
4.    Yehuda R, McFarlane AL. Conflict between current knowledge about posttraumatic stress disorder and its original conceptual basis. Am J Psychiatry. 1999;152:1705-1713.
5.    Kinzie JD, Goetz RR. A century of controversy surrounding posttraumatic stress-spectrum syndromes: the impact on DSM-III and DSM-IV. J Traumatic Stress. 1996;9:159-179.
6.    True WR, Rice J, Eisen SA, et al. A twin study of genetic and environmental contributions to liability for posttraumatic stress symptoms. Arch Gen Psychiatry. 1993;50:257-264.
7.    Kardiner A, Spiegel H. War Stress and Neurotic Illness. 2nd ed. New York, NY: Paul B. Hoeber, Inc; 1947.
8. Kardiner A, Spiegel H. War Stress and Neurotic Illness. 2nd ed. New York, NY: Paul B. Hoeber, Inc; 1947:364.
9.    Kosten TR, Frank JB, Dan E, McDougle CJ, Giller EL. Pharmacotherapy for posttraumatic stress disorder using phenelzine or imipramine. J Nerv Ment Dis. 1991;179:366-370.
10.    Davidson J, Kudler H, Smith R, et al. Treatment of posttraumatic stress disorder with amitriptyline and placebo. Arch Gen Psychiatry. 1990;47:259-266.
11.    Brady K, Pearlstein T, Asnis GM, et al. Efficacy and safety of sertraline treatment of posttraumatic stress disorder: a randomized controlled trial. JAMA. 2000;283:1837-1844.
12.    Davidson JRT, Rothbaum BO, van der Kolk B, Sikes CR, Farfel GM. Multi-center, double-blind comparison of sertraline and placebo in the treatment of posttraumatic stress disorder. Arch Gen Psychiatry. 2001;58:485-492.
13.    Marshall RD, Beebe KL, Oldham M, Zaninelli R. Efficacy and safety of paroxetine treatment of chronic PTSD: a fixed-dosage, multi-center, placebo-controlled study. Am J Psychiatry. 2001;158:1982-1988.
14.    Martenyi F, Brown E, Zhang H, Prakash A, Koke S. Fluoxetine vs placebo in posttraumatic stress disorder. Poster presented at: Annual Meeting of the American Psychiatric Association; May 2001; New Orleans, La.
15.    Connor KM, Sutherland SM, Tupler LA, Malik ML, Davidson JR. Fluoxetine in post-traumatic stress disorder. Randomised, double-blind study. Brit J Psychiatry. 1999;175:17-22.
16.    van der Kolk BA, Dreyfuss D, Michaels M, et al. Fluoxetine in posttraumatic stress disorder. J Clin Psychiatry. 1994;55:517-522.
17.    Nagy LM, Southwick SM, Charney DS. Placebo-controlled trial of fluoxetine in PTSD. Poster presented at: International Society for Traumatic Stress Studies 12th Annual Meeting; November 11, 1996; San Francisco, Calif.
18.    Hertzberg MA, Feldman ME, Beckham JC, Kudler HS, Davidson JR. Lack of efficacy for fluoxetine in PTSD: a placebo controlled trial in combat veterans. Ann Clin Psychiatry. 2000;12:101-105.
19.    Physicians’ Desk Reference. 55th ed. Montvale, NJ: Medical Economics Company, Inc; 2001.
20.    Shestatzky M, Greenberg D, Lerer B. A controlled trial of phenelzine in posttraumatic stress disorder. Psychiatric Res. 1988;24:149-155.
21.    Braun P, Greenberg D, Dasberg H, Lerer B. Core symptoms of posttraumatic stress disorder unimproved by alprazolam treatment. J Clin Psychiatry. 1990;51:236-238.
22.    Kaplan Z, Amir M, Swartz M, Levine J. Inositol treatment of post-traumatic stress disorder. Anxiety. 1996;2:51-52.
23.    Yehuda R, Marshall RM, Wong CM, Penkower A. Psychopharmacological treatment of PTSD. In: Nathan PE, Gorman JM, eds. A Guide to Treatments that Work. 2nd ed. Oxford, England: Oxford University Press. In press.
24.    Kessler RC, Sonnega A, Bromet E, Hughes M, Nelson CB. Posttraumatic stress disorder in the National Comorbidity Survey. Arch Gen Psychiatry. 1995;52:1048-1060.
25.    Londborg PD, Hegel MT, Goldstein S, et al. Setraline treatment of posttraumatic stress disorder: results of 24 weeks of open-label continuation treatment. J Clin Psychiatry. 2001;62:325-331.
26.    Foa EB, Keane TM, Friedman MJ. Effective Treatment for PTSD: Practice Guidelines From the International Society for Traumatic Stress Studies. Gilford Press: New York, NY; 2000.
27.    Doyle B, Foa EB, Keane TM, Marshall RD. Posttraumatic stress disorder: changing the perspective of primarys care. Med Crossfire. 2001; 33:33-43.
28.    Johnson JH, McCutcheon S. Assessing life stress in older children and adolescents: preliminary findings with the Life Events Checklist. In: Sarason IG, Spielberger CD, eds. Stress and Anxiety. Washington, DC: Hemisphere; 1980:111-125.
29.    Connor KM, Davidson JR. SPRINT: a brief global assessment of post-traumatic stress disorder. Int Clin Psychopharmacol. 2001;5:279-284.

Dr. Yehuda is professor of psychiatry in the Department of Psychiatry at Mount Sinai School of Medicine in New York City.

Acknowledgments: This work was supported in part by National Institute of Mental Health Grant #R02-MH49555 and Veterans Administration Merit Review funding.



Posttraumatic stress disorder (PTSD) is associated with a somewhat unique and paradoxical neuroendocrine profile in that corticotropin-releasing factor (CRF) levels appear to be increased in this disorder even though ambient cortisol levels have generally been found to be low. This set of findings distinguishes the hypothalamic-pituitary-adrenal (HPA) axis alterations in PTSD from those observed in studies of acute and chronic stress and major depressive disorder (MDD), as the latter conditions are associated with increase in both CRF and cortisol levels. A consistent observation in PTSD has been that of a hypersuppression of cortisol in response to dexamethasone administration. In contrast, MDD studies have observed nonsuppression following dexamethosone administration. These findings have led to the idea that PTSD may be characterized by an enhanced negative feedback inhibition of the HPA axis. This review summarizes the evidence for the enhanced negative feedback model in PTSD and discusses some of the implications of this alteration for understanding the phenomenology of PTSD.



Hypothalamic-pituitary-adrenal (HPA) axis alterations in posttraumatic stress disorder (PTSD) are different from those observed in studies of acute and chronic stress and major depressive disorder; the latter conditions are associated with increase in both corticotropin-releasing factor (CRF) and cortisol levels, whereas in PTSD, CRF levels have been shown to be increased while cortisol levels have often been found to be lowered.1

There is converging evidence to support the idea that the HPA axis is particularly sensitive to negative feedback inhibition in PTSD subjects. The increased sensitivity to negative feedback inhibition is reflected by a hypersuppression of cortisol in response to dexamethasone administration,2-7 an increased concentration and sensitivity of lymphocyte glucocorticoid receptors (GRs),2,8 and an augmented adrenocorticotropin hormone (ACTH) response to metyrapone test administration.9 The enhanced negative feedback of cortisol is also accompanied by a more dynamic circadian release of cortisol under basal conditions.10 This review will summarize the evidence for the enhanced negative feedback model in PTSD and discuss some of the implications of this alteration.


The Neuroendocrine Response to Stress

One of the immediate neuroendocrine responses to stress involves the coordinated sympathetic discharge that causes increases in heart rate and blood pressure, initially described as the “fight or flight” reaction. This response allows a greater perfusion of blood glucose to muscles and vital organs and results in increased energy to skeletal muscles, allowing the organism to better fight or flee adverse situations. The HPA axis response to stress involves a more complex set of chemical reactions, in which brain neuropeptides stimulate the release of CRF, or corticotropin-releasing hormone (CRH) vasopressin, and other regulatory neuropeptides from the hypothalamus that stimulate the pituitary to release ACTH. In turn, ACTH stimulates the release of cortisol from the adrenal glands. This is the basic HPA-axis stress-response cascade.11

Typically, the greater the severity of the stressor, the higher the levels of both catecholamines and cortisol. However, whereas catecholamines facilitate the availability of energy to the body’s vital organs, cortisol’s role in stress is to help contain or dampen sympathetic activation and other neuronal defensive reactions that have been initiated by stress.12 As these stress-activated biological reactions begin to shut down, cortisol levels also suppress the HPA axis via the negative feedback inhibition of cortisol on the pituitary, hypothalamus, hippocampus, and amygdala.13

In classic stress theory, stressors that result in the activation of CRF release from the hypothalamus also result in elevated cortisol levels, whereas lower levels of cortisol are thought to result directly from a cessation of activation by CRF. Thus, one paradox in PTSD—which is clearly a disorder in which exposure to stress is a critical feature—is the presence of low cortisol levels.


Neuroendocrine Alterations in PTSD

Brain CRF concentrations appear to be elevated in PTSD subjects, as indicated by increased concentrations of this peptide in the cerebrospinal fluid.14,15 There is also specific evidence of increased hypothalamic CRF release, as determined by the ACTH response to metyrapone administration.9 However, in several studies, cortisol concentrations have been found to be lower in PTSD subjects than in normal comparison groups, other psychiatric patients, or similarly exposed non-PTSD groups.1,8,16 Some studies of 24-hour urinary cortisol excretion have not replicated the finding that cortisol levels are lower in PTSD subjects17-19 compared to other subject groups. This may reflect differences in the type of subjects studies, the type of methods used in these studies, or may suggest that low cortisol levels are only present in a subgroup of trauma survivors with PTSD.

We have been able to confirm our observations of low urinary cortisol with a 24-hour plasma cortisol study in which blood samples were obtained every 30 minutes around the clock.10 These data demonstrated lower cortisol levels in the evening in combat Vietnam veterans with PTSD, whereas morning levels were comparable to normal groups. Other changes in circadian rhythm were also noted. PTSD subjects showed a greater dynamic range of cortisol over the diurnal cycle compared to normal groups as estimated by the amplitude-to-mesor (“signal-to-noise”) ratio. PTSD subjects also demonstrated evidence of a stronger circadian rhythm, as evidenced by an increased goodness-of-fit of the 24-hour single oscillator cosinor model to the raw cortisol data (Figure).

Studies examining single-point cortisol levels in plasma and salivary samples have also found some evidence of low cortisol. Boscarino20 reported significantly lower cortisol levels in combat veterans with the heaviest combat exposure, including a subset of 293 veterans with PTSD.

In addition, Goenjian and colleagues5 demonstrated that basal salivary cortisol levels were lower in children who had been close to the epicenter of the Armenian earthquake 5 years earlier, and who still had substantial PTSD symptoms, compared to children who had been further away from the epicenter and who, as a group, had fewer symptoms. Furthermore, Heim and colleagues6 found lower basal salivary cortisol in women with chronic pelvic pain who had a high prevalence of sexual trauma and PTSD, compared to women without sexual trauma or PTSD. Finally, Jensen and colleagues21 reported lower basal plasma cortisol levels in combat veterans before and after sodium lactate infusion.22,23 Some investigators reported elevated morning cortisol levels in PTSD.

Other studies have demonstrated low plasma cortisol in trauma survivors who appear to have been symptomatic at the time of assessment, but were not specifically evaluated for PTSD. Low plasma cortisol levels were also observed in a sample of detainees who were studied shortly after being liberated from a prisoner-of-war camp in Bosnia,24 in refugees who had fled from East to West Germany and were still symptomatic 6 weeks after their arrival in West Berlin,25 detainees released from Bosnian concentration camps, displaced persons evacuated from their Croatian town after occupation by the Serbians, and civilians living in Zagreb during the war in Bosnia who were found to “express a severe psychological response.”26


Why Are Cortisol Levels Low in PTSD?

The presence of low cortisol levels in trauma survivors has been intriguing because it is counterintuitive to the idea that stress would be associated with high cortisol levels. One important question that has raised concerns in the course of adaptation to trauma is: when are low basal cortisol levels first observable? In the abovementioned studies, cortisol levels were generally obtained several months, years, or even decades following exposure to the stressor, which leads to the hypothesis that the low basal cortisol levels in PTSD reflect a chronic adaptation of the HPA axis. Implicit in this idea was that if cortisol levels would have been obtained while the individual was undergoing the traumatic event, or at least in the immediate aftermath of it, then they might have been found to be elevated—particularly in individuals who would subsequently develop long-term psychiatric problems and/or PTSD.

As early as 1968, Bourne and colleagues27 reported surprisingly lower urinary cortisol metabolite 17-hyroxycorticosteroid levels in Vietnam soldiers during a threat of imminent enemy attack while they were stationed in Vietnam. This study raised the possibility that cortisol levels can be low in response to an extremely traumatic experience. These observations were confirmed nearly 30 years later by recent studies.28-30

In one study, McFarlane and colleagues28 measured the cortisol response to motor vehicle accidents in persons appearing in the emergency room in the immediate aftermath (usually within 1–2 hours) of this trauma. Six months later, subjects were evaluated for the presence or absence of psychiatric disorder. In subjects who had developed PTSD, the cortisol response in the immediate aftermath of the motor vehicle accident was significantly lower than the cortisol response of those who subsequently developed major depression. This study suggests that PTSD-like HPA axis alterations are present in the immediate aftermath of a traumatic event. These findings were similar to those reported by Delahanty and colleagues.29

Resnick and colleagues30 demonstrated that women with a prior history of rape or assault had lower cortisol levels immediately after rape than women without such histories.30 Cortisol levels did not predict the subsequent development of PTSD in these women (possibly owing to the small sample size). Thus, there is a possibility that cortisol levels in the immediate aftermath of a traumatic event might be predicted by factors that precede trauma exposure, or by previous exposure.

The prospective longitudinal studies discussed above demonstrate that the acute cortisol responses to trauma in individuals who develop PTSD, or who show characteristic risk factors for PTSD such as prior exposure to trauma, could be different from those of individuals who do not develop PTSD in response to a similar trauma or who do not have a prior history of trauma. These studies raise the provocative question of whether some individuals might have had low cortisol levels even before the traumatic event, or had some abnormality that would account for their aberrant response to the traumatic event they sustained. Evidence for this is currently scant. However, we have recently demonstrated that cortisol levels are low in adult children of Holocaust survivors, who are at increased risk for the development of PTSD.31


Implications of Low Cortisol in the Immediate Aftermath of a Trauma

If cortisol levels are low in the immediate aftermath of a traumatic event, this might result in a failure of cortisol to completely contain the sympathetic nervous system (SNS) response, resulting in an initial problem of a failure of normal memory consolidation. Indeed, there is evidence that catecholamines, particularly epinephrine, enhance memory consolidation in laboratory rats.32 This effect appears to be modulated at least in part by adrenal steroids, since removing the adrenal glands of animals makes them more sensitive to the effects of epinephrine on memory consolidation.32 Furthermore, when such animals are given replacement doses of glucocorticoids, they become less sensitive towards the memory-enhancing effects of epinephrine.32

It has been hypothesized that PTSD results from an exaggerated response of neuropeptides and catecholamines at the time of the trauma,33 and that increased levels of these stress hormones initiate a process in which memories of the traumatic event might be “overconsolidated” or inappropriately remembered due to an exaggerated level of distress. The failure of cortisol to contain other neuropeptides would facilitate this effect. It would also explain why non-PTSD patients do not overconsolidate their traumatic memories and why reminders of the traumatic event are accompanied by distress in individuals with PTSD. However, this process might represent only one of many pathways to the development of PTSD.

Shalev and colleagues34 collected heart rate data from trauma survivors who appeared in the emergency room in the immediate aftermath of a traumatic event, but who did not have significant physical injury. Mean heart rate levels at the time of the trauma were significantly higher in the subjects who developed PTSD, as determined at a 4-month follow-up. The mean heart rate in the PTSD group remained higher at the 1-week follow-up. However, by 1 month and 4 months, there were no group differences. Importantly, subjects who did not develop PTSD also had elevated heart rate in the emergency room because they were expressing a stress response.

It is interesting to consider both the observations of low cortisol and elevated heart rate, particularly in light of the role of SNS-HPA interactions in stress. Under normal stress-activated conditions, cortisol levels would ultimately inhibit the adrenergic system. However, it could be that some trauma survivors have higher heart rates in the immediate aftermath of a traumatic event because cortisol has failed to contain this specific response.

In support of this idea was the observation that cortisol and methoxy-hydroxy-phenylglycol (MHPG) levels—measured from the same blood sample in the aforementioned rape survivors—appeared to be related to different aspects of the traumatic experiences.35 While cortisol levels were related to prior history, MHPG levels in these rape victims were associated with the severity of the trauma. Moreover, in the women who did not subsequently develop PTSD, there was a significant correlation between cortisol and MHPG levels, which is consistent with the normal stress response. In the women who did subsequently develop PTSD, this relationship was lacking. Thus, the HPA and SNS responses to trauma might literally be disassociated in those who subsequently develop PTSD. These preliminary data suggest a possible mechanism for why some individuals would develop PTSD-like responses, whereas others recover.

One could further theorize that the increased dose of distress every time there are traumatic reminders might activate stress responsive hormones and neuromodulations such as CRF. Thus, CRF might be hyper-released due to the anxiety brought about by memories that have been experienced while persons were distressed. We have previously suggested that CRF hypersecretion activates the pituitary to release ACTH. However, because of an increased sensitivity of GRs, the HPA axis may become progressively more sensitive to cortisol (and stress) as it continues to be exposed to CRF.1,2 An increased responsiveness of GRs may facilitate a stronger negative feedback inhibition.

The enhanced negative feedback response contrasts to the well-known cascade in depression, in which chronic CRF release results in an erosion of negative feedback inhibition, resultant hypercortisolism, and GR downregulation.11 This would imply that low cortisol may be a downstream manifestation of a more primary alteration—an enhanced negative feedback inhibition resulting from an increased GR sensitivity. However, this hypothesis has not been adequately tested to date.


GR Responsiveness in PTSD

The binding of cortisol to GRs initiates the transcription of mRNA and the synthesis of proteins that alter the structure and function of cells. Our group has demonstrated that urinary cortisol concentrations and lymphocyte GR numbers are not always inversely correlated,8 which supports the notion that there can be critical individual differences in the number and functional activity of the receptor. In turn, individual differences in GR sensitivity would also potentially explain why individuals do not respond to stress in the same manner.

In major depression, the number and sensitivity of lymphocyte type II GRs in lymphocytes are lower than normal.36 Therefore, although high cortisol levels are present in major depression, the decreased sensitivity of the receptor might actually result in an attenuation of the normal biobehavioral effects of steroids. This phenomenon has been referred to as “glucocorticoid resistance.”1,31 The occurrence of a glucocorticoid resistance explains why depressed patients with very high cortisol levels do not show evidence of endocrinological disorders such as Cushing’s syndrome (a disease characterized by excessively high release of cortisol).

In contrast to the decreased number of GRs observed in major depression and stress, the number of lymphocyte GRs appears to be increased in PTSD subjects compared to normal subjects and other psychiatric groups.3,9,10 That GRs might also be more sensitive is implied by the fact that dexamethasone administration resulted in a significant decrease or downregulation of the lymphocyte GR number in combat veterans with PTSD but not in trauma survivors without PTSD or in normal controls. This suggests that the GRs of PTSD subjects show a greater response to the administration of the synthetic steroid.2

Diminished glucocorticoid sensitivity in major depression is primarily observed by the reduced cortisol negative-feedback inhibition of the HPA axis on the dexamethosone suppression test.11 In contrast, subjects with PTSD show an augmented suppression following dexamethasone compared to both similarly exposed subjects without PTSD and nonexposed subjects.3-7 Further evidence for the idea of an enhanced negative feedback theory has been provided by the results of the metyrapone stimulation test.

Metyrapone administration resulted in an augmented ACTH response in combat veterans with PTSD compared to nontraumatized men who showed ACTH increases in the normal endocrinologic range.8 The increased ACTH response to metyrapone demonstrates that when the pituitary is unconstrained by negative feedback inhibition, there is clearly evidence of suprapituitary activation (increased CRF). Therefore, under basal conditions, the increased negative feedback inhibition at the level of the pituitary results in lower ambient cortisol levels.



Neuroendocrine alterations in PTSD, particularly those relating to the HPA axis, do not typically resemble those that have been described in classic studies of stress or major depression. If one considers these findings in the context of the fact that PTSD is not a universal stress response, the data can be more readily understood. Indeed, PTSD represents a situation where there has been a failure of restitution of the body to its pre-stress baseline. The biological findings appear to mirror this phenomenon; there may be biological risk factors that determine the responses that are most likely to result in a PTSD syndrome. These biological risk factors could be related to the prior stress history of the person experiencing a traumatic event. As our knowledge of the biology of PTSD grows, we will be able to better understand the developmental biological progression of PTSD, as well as its implications for the pathophysiology and treatment of the disorder.  PP



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Dr. Fukutaki is head of the psychiatric team at the Infectious Disease Clinic in the Department of Behavioral Health Services at the Denver Health Medical Center in Colorado, and clinical instructor in the Department of Psychiatry at the University of Colorado School of Medicine, also in Denver.

Dr. Allen is director of inpatient psychiatry in the Department of Behavioral Health Services at the Colorado Psychiatric Hospital in Denver and assistant professor of psychiatry in the Department of Psychiatry at the University of Colorado School of Medicine.

Acknowledgments: The authors report no financial, academic, or other support of this work.



For both clinical and economic reasons, accelerated strategies for the control of manic symptoms are desirable. Today, significant improvement is expected within 3–4 days of treatment initiation. This article reviews the use of various classes of medications with this time frame in mind. Evidence is presented for methods of rapid loading of mood stabilizers and combinations of mood stabilizers and antipsychotics.



Rapid stabilization of the acutely manic patient has become a more urgent task in both outpatient and acute care settings. Currier and Allen1 found that patients with bipolar disorder accounted for 13.2% of presentations to 51 psychiatric emergency services, suggesting that this diagnosis is disproportionately represented in emergency rooms compared to the general population. The economics of health care have shortened the length of psychiatric hospital stays and reduced the number of available psychiatric beds in hospitals, fostering a more aggressive approach to the treatment of mania.2 Classically, onset of therapeutic effects at 1 week has been the standard, but this is now outside the average length of stay in most settings. Treatments that produce substantial benefit in 3–4 days are required.

Treatment can be thought of as occurring in several phases with somewhat different priorities. The initial focus in acute care of the manic patient is on controlling behavior that may place the patient and others at risk. At this point in the treatment, route of administration for uncooperative patients and speed of onset for critical target symptoms are the drivers. In the next phase, rapid resolution of core manic symptoms that require continued hospitalization and impair functioning in the community take precedence. Finally, in the continuation and maintenance phase, evidence of prophylaxis and side-effect burden become the central considerations.

A number of medications have been shown to be useful in treating mania. However, many of these (lithium, topiramate, lamotrigine, carbamazepine) require gradual titration to avoid side effects, thus delaying the onset of therapeutic action. The safety and tolerability of orally-loading divalproex sodium has been demonstrated.3-7 Typical and atypical antipsychotics appear to be useful in stabilizing mania, in some cases at the initial dosage.5,8-19 Benzodiazepines (BZDs) have also been shown to have therapeutic effects in the treatment of mania and can be delivered intramuscularly with a minimal side-effect burden.20 Electroconvulsive therapy (ECT) is an effective treatment for acute mania21 but may be difficult to arrange in emergency circumstances. Unless maintenance ECT is available, medication therapy will still be needed for continuation and maintenance.

Given the severity of manic behavioral symptoms and the complexity of the longitudinal course of bipolar disorder, it is perhaps the exception when patients can be treated efficiently with a single agent. This article will review the acute management of mania from the standpoint of the most rapid and complete resolution of serious symptoms with the best tolerability and most seamless transition to continuation and maintenance.


Behavioral Emergency

A recently published expert consensus guideline for the management of behavioral emergencies found that emergency psychiatrists give very similar ratings to intramuscular (IM) BZDs alone or in combination with a high-potency conventional antipsychotic as the treatment of choice for the agitated manic patient. If the patient is cooperative enough to take oral medication, combining a BZD with an atypical is also considered first line. Typical strategies include lorazepam 2 mg IM or PO alone, or combined with haloperidol 5 mg IM or risperidone 2 mg PO.22 There is little evidence that parenteral combinations are superior to lorazepam alone in equivalent total doses.23 If oral medication is possible and repeated use is anticipated, clonazepam may be a good choice. The drug also has the advantage of longer half-life and less frequent administration.24


Acute Phase

Mood Stabilizer Monotherapy

Orally-loading divalproex sodium at 20–30 mg/kg/day for the first 2 days (divided into two doses separated by at least 4 hours) and continuing at 20 mg/kg/day thereafter, has been shown to be safe, tolerated, and effective in reducing mania.3-7 In one study,3 84% of the patients loaded with 30 mg/kg/day of divalproex sodium for the first 2 days and then treated with 20 mg/kg/day achieved therapeutic levels by day 3 with a mean of 83.8 mg/mL. Only 30% of the titrated divalproex patients had valproate serum levels above 50 mg/mL at day 3 of the study, and no lithium-treated patient had reached 0.8 mEq/L. No increase in the frequency or types of adverse events was noted between this group and the groups receiving titrated doses of divalproex sodium or lithium.

Another study5 compared oral loading of divalproex sodium 20 mg/kg/day with haloperidol 0.2 mg/kg/day, using lorazepam up to 4 mg/day to control agitation. The greatest rate of improvement for both drug regimens occurred over the first 3 days of treatment. Divalproex sodium was as effective as haloperidol in reducing mania and psychosis during the 6-day study, and produced fewer side effects. In a recent consensus guideline for the management of behavioral emergencies, approximately half the panel of emergency psychiatrists endorsed the 30 mg/kg strategy and half endorsed the 20 mg/kg strategy.25

Therapeutic efficacy with intravenous loading of valproate has also been reported.26,27 One report26 states parenteral valproate loading was effective in reducing manic symptoms in an 81-year-old woman in 2 days. Valproate 125 mg was infused in 100 cc of 5% dextrose in water over an hour, every 6 hours, for two doses. The dosage was then increased to 200 mg every 6 hours. The patient received nine doses of valproate before stabilizing, at which time her serum valproate level was 53 mg/mL. No side effects were noted. Grunze and colleagues27 treated seven bipolar patients, five of whom were in manic or mixed states, with parenteral valproate. They noted reduction in mania occurred without side effects in four of the five manic or mixed-state patients, one of whom had been nonresponsive to oral valproate loading.

In addition to its quick action, divalproex has a number of other advantages in the acute setting. Swann and colleagues28 correlated the number of previous affective episodes in 154 manic patients to therapeutic response to lithium and divalproex sodium. They found that divalproex was more effective than lithium in stabilizing manic patients with more than 10 prior affective episodes, and that response to lithium resembled that of placebo in this group of patients. Several other factors, such as substance use, may limit the usefulness of lithium in acute settings.


Typical Antipsychotics

Typical antipsychotics have been shown to be effective in the treatment of mania.5,10,11,16 Chou and colleagues16 examined the effect of haloperidol 5–25 mg/day, with and without lithium, in a double-blind, placebo-controlled study of 63 acutely psychotic bipolar manic inpatients. They found that low-dose haloperidol was insufficient as monotherapy in reducing mania, but when combined with lithium was as effective as high-dose haloperidol at clinical outcome. Studies by Chou16 and Rifkin29 suggest haloperidol 10 mg/day is effective as monotherapy. However, the risks of extrapyramidal side effects, sedation, dysphoria, and tardive dyskinesia with typical antipsychotics impact tolerability and safety in the long-term.


Atypical Antipsychotics

Evidence is emerging in support of the therapeutic benefits of atypical antipsychotics in the treatment of mania.8,9,12-15,18,19,30 Two double-blind, placebo-controlled studies8,12 have shown olanzapine to be superior to placebo in reducing mania. Tohen and colleagues8 found this difference appeared 1 week after randomization. More weight gain and somnolence were noted with olanzapine than with placebo. Sanger and colleagues19 continued one of the studies12 into a 49-week open-label trial of olanzapine at a mean modal dose of 13.9 mg/day and found that 88.3% of patients experienced a remission of manic symptoms, while 25.5% subsequently relapsed. Forty-one percent of patients were maintained on olanzapine monotherapy. Somnolence, depression, and weight gain were the most common side effects noted.

Zarate and colleagues9 suggest that quetiapine 300 mg/day is effective in reducing symptoms of mania. Dunayevich and colleagues17 treated seven hospital inpatients who had bipolar disorder, manic or mixed, with psychotic features using quetiapine, either as monotherapy (n=1) or as an adjunct to treatment with a mood stabilizer (either lithium, carbamazepine, valproate, and/or divalproex sodium) in a retrospective study. The patients were generally titrated from dosages of 50 mg BID/TID per day up to 200–500 mg/day within 3–8 days (mean dosage=421 mg/day). Two patients were considered “very much improved” by Clinical Global Impression-Change score, three were “much improved” (including the patient treated with quetiapine monotherapy), and two were “minimally improved.” The most common side effects were sedation and dizziness.

Ghaemi and colleagues15 published a small study suggesting risperidone at a dosage of 2.75±1.8 mg/day may be an effective treatment in patients with bipolar disorder. Segal and colleagues18 studied 45 inpatients diagnosed with mania in a randomized, double-blind trial of either 6 mg/day of risperidone (n=15), 10 mg/day of haloperidol (n=15), or 800–1,200 mg/day of lithium (n=15, lithium levels=0.6–1.2 mmol/L). At the end of the 28-day trial, all three groups showed significant improvement, with similar rates of improvement at days 7, 14, 21, and 28. The authors concluded that monotherapy with risperidone appears to be comparable to lithium and haloperidol in the treatment of mania.

Ziprasidone is a new novel antipsychotic that has recently been reported to be effective in mania.31 In keeping with the focus on rapid improvement, ziprasidone 80–160 mg/day separated from placebo at day 2 in this study. Keck and colleagues32 conducted a randomized, double-blind, placebo-controlled study of 34 hospitalized patients with schizoaffective disorder (bipolar type), and found that ziprasidone 160 mg/day was significantly better than placebo (P<.001) in reducing manic symptoms over the 6-week study period. The time required for ziprasidone to separate from placebo was not provided.


Drug Combinations

As suggested previously, medication combinations may offer advantages in terms of response time and may also reduce the side-effect burden to the extent that lower doses of component drugs may be utilized. One study relevant to the acute setting compared treatment with a mean of 3.83 mg/day of risperidone, 6.23 mg of haloperidol, or placebo in combination with either lithium or divalproex for 3 weeks. Over two thirds of subjects in each group received divalproex as their mood stabilizer.30 At weeks 1 and 2, the risperidone-mood stabilizer combination was associated with significantly greater improvement compared to a mood stabilizer alone and was numerically superior to the haloperidol combination at some points. Levels of psychosis in the three groups were similar and, as expected, did not affect outcome.


Continuation and Maintenance

Aggressive treatment is better tolerated in the acute phase. Moving into continuation and maintenance, side-effect burden and its impact on adherence becomes a major consideration. Sedation, movement disorders, and weight gain may reduce the long-term usefulness of some drugs. However, adjunctive medications should be tapered and discontinued cautiously only after the estimated end of a typical manic phase, based either on the individual’s history or a minimum of 12 weeks.

Bipolar patients may appear to have fairly stable mood but continue to complain of anxiety. This may be evidence of an incompletely stabilized mood disorder that might be better treated with an atypical antipsychotic, even in the absence of psychotic symptoms, than with a BZD. Atypical antipsychotics do not cause the habituation sometimes seen with BZDs and may have greater benefits in mood stability over time.

Longer-term considerations argue for maintenance treatment with a traditional mood stabilizer as the foundation, possibly in combination with an atypical antipsychotic rather than with an atypical antipsychotic alone. Only one open-label trial33 of atypical antipsychotic monotherapy maintenance has been published. In that study, which lacked a comparison drug and suffered a 39.8% drop-out rate, an average of 6.6 months of olanzapine monotherapy was associated with a 25% relapse rate.



Finding ways to stabilize the acutely manic patient is desirable from the standpoint of both patient care and cost-effectiveness. Bipolar disorder will often require multiple medications in any given phase and alterations between phases of different types. Treatment should always include a traditional mood stabilizer, if tolerated, with additional medications as required for each presentation. Current data suggest that oral loading with divalproex, augmented with an atypical antipsychotic and/or a BZD for agitation, may be the most rapid and best-tolerated strategy for the broadest spectrum of acutely manic patients.  PP



1.     Allen MH, Currier GW. Diagnosis and treatment of mania in the psychiatric emergency service. Psychiatr Ann. 2000;30:258-266.
2.     Allen MH. Definitive treatment in the psychiatric emergency service. Psychiatr Q. 1996;67:247.
3.     Hirschfeld RM, Allen MH, McEvoy JP, et al. Safety and tolerability of oral loading divalproex sodium in acutely manic bipolar patients. J Clin Psychiatry. 1999;60:815-818.
4.     Martinez JM, Russell JM, Hirschfeld RM. Tolerability of oral loading of divalproex sodium in the treatment of acute mania. Depress Anxiety. 1998;7:83-86.
5.     McElroy SL, Keck PE, Stanton SP, et al. A randomized comparison of divalproex oral loading versus haloperidol in the initial treatment of acute psychotic mania. J Clin Psychiatry. 1996;57:142-146.
6.     Keck PE Jr, McElroy SL, Tugrul KC, Bennett JA. Valproate oral loading in the treatment of acute mania. J Clin Psychiatry. 1993;54:305-308.
7.     McElroy SL, Keck PE Jr, Tugrul KC, Bennett JA. Valproate as a loading treatment in acute mania. Neuropsychobiology. 1993;27:146-149.
8.     Tohen M, Jacobs TG, Grundy SL, et al. Efficacy of olanzapine in acute bipolar mania: a double-blind, placebo-controlled study. Arch Gen Psychiatry. 2000;57:841-849.
9.     Zarate CA, Rothschild A, Fletcher KE, Madrid A, Zapatel J. Clinical predictors of acute response with quetiapine in psychotic mood disorders.
J Clin Psychiatry. 2000;61:185-189.
10.     Prien R, Caffey EJ, Klett C. Comparison of lithium carbonate and chlorpromazine in the treatment of mania: report of the Veterans’ Administration and National Institute of Mental Health Collaborative Study Group. Arch Gen Psychiatry. 1972;26:146-153.
11.     Braden W, Fink EB, Qualls CB, Ho CK, Samuels WO. Lithium and chlorpromazine in psychotic inpatients. Psychiatry Res. 1982;7:69-81.
12.     Tohen M, Sanger TM, McElroy SL, et al. Olanzapine versus placebo in the treatment of acute mania. Olanzapine HGEH Study Group. Am J Psychiatry. 1999;156:702-709.
13.     Soutullo CA, Sorter MT, Foster KD, McElroy SL, Keck PE. Olanzapine in the treatment of adolescent acute mania: a report of seven cases. J Affect Disord. 1999;53:279-283.
14.     Barbini B, Scherillo P, Benedetti F, Crespi G, Colombo C, Smeraldi E. Response to clozapine in acute mania is more rapid than that of chlorpromazine. Int Clin Psychopharmacol. 1997;12:109-112.
15.     Ghaemi SN, Sachs GS, Baldassano CF, Truman CJ. Acute treatment of bipolar disorder with adjunctive risperidone in outpatients. Can J Psychiatry. 1997;42:196-199.
16.     Chou JC, Czobor P, Charles O, et al. Acute mania: haloperidol dose and augmentation with lithium or lorazepam. J Clin Psychopharmacol. 1999;19:500-505.
17.     Dunayevich E, Tugrul KC, Strakowski SM. Quetiapine in the treatment of mania. Poster presented at: The American Psychiatric Association’s 52nd Institute on Psychiatric Services; October 25-29, 2000; Philadelphia, Pa.
18.     Segal J, Berk M, Brook S. Risperidone compared with both lithium and haloperidol in mania: a double-blind randomized controlled trial. Clin Neuropharmacol. 1998;21:176-180.
19.     Sanger TM, Grundy SL, Gibson PJ, Namjoshi MA, Greaney MG, Tohen MF. Long-term olanzapine therapy in the treatment of bipolar I disorder: an open-label continuation phase study.
J Clin Psychiatry. 2001;62:273-281.
20.     Bradwejn J, Shriqui C, Koszycki D, Meterissian G. Double-blind comparison of the effects of clonazepam and lorazepam in acute mania.
J Clin Psychopharmacol. 1990;10:403-408.
21.     Grunze H, Erfurth A, Schafer M, Amann B, Meyendorf R. Electroconvulsive therapy in the treatment of severe mania. Case report and a state-of-art review. Nervenarzt. 1999;70:662-667.
22.     Currier GW, Simpson GS. Risperidone liquid concentrate and oral lorazepam versus intramuscular haloperidol and intramuscular lorazepam for treatment of psychotic agitation. J Clin Psychiatry. 2001;62:153-157.
23.     Allen MH. Managing the agitated psychotic patient: a reappraisal of the evidence. J Clin Psychiatry. 2000;61:11-20.
24.     Chouinard G, Young SN, Annable L. Antimanic effect of clonazepam. Biol Psychiatry. 1983;18:451-466.
25.     Allen MH, Currier GW, Hughes DH, et al. The Expert Consensus Guideline Series. Treatment of behavioral emergencies. Postgrad Med. 2001;May(Spec No):1-90.
26.     Herbert PB, Nelson JC. Parenteral valproate for control of acute mania. Am J Psychiatry. 2000;157:1023-1024.
27.     Grunze H, Erfurth A, Amann B, Giupponi G, Kammerer C, Walden J. Intravenous valproate loading in acutely manic and depressed bipolar I patients. J Clin Psychopharmacol. 1999;19:303-309.
28.     Swann AC, Bowden CL, Calabrese JR, Dilsaver SC, Morris DD. Differential effect of number of previous episodes of affective disorder on response to lithium or divalproex in acute mania. Am J Psychiatry. 1999;156:1264-1266.
29.     Rifkin A, Doddi S, Karajgi B, Borenstein M, Munne R. Dosage of haloperidol for mania. Br J Psychiatry. 1994;165:113-116.
30.     Sachs G. Safety and efficacy of risperidone vs placebo as add-on therapy to mood stabilizers in the treatment of manic phase of bipolar disorder. Poster presented at: Annual Meeting of the American College of Neuropsychopharmacology; December 1999; San Juan, Puerto Rico.
31.     Giller EL, Mandel F, Ziprasidone in Mania Investigators. Ziprasidone in the acute treatment of mania: a double-blind, placebo-controlled, randomized trial. Poster presented at: Annual Meeting of the American College of Neuropsychopharmacology; December 13, 2000; San Juan, Puerto Rico.
32.     Keck PE, Reeves KR, Harrigan EP. Ziprasidone in the short-term treatment of patients with schizoaffective disorder: results from two double-blind, placebo-controlled, multicenter studies. J Clin Psychopharmacol. 2001;21:27-34.
33. Sanger TM, Grundy SL, Gibson PJ, Namjoshi MA, Greaney MG, Tohen MF. Long-term olanzapine therapy in the treatment of bipolar I?disorder: an open-label continuation phase study. J Clin Psychiatry. 2001;62:273-281.

Dr. Ghaemi is director of the Bipolar Disorder Research Program at Cambridge Hospital in Massachusetts and assistant professor of psychiatry at Harvard Medical School in Boston.

Mr. Ko is research coordinator at the Bipolar Disorder Research Program at Cambridge Hospital.

Acknowledgments: This research was supported by the National Institute of Mental Health Research Career Development Award, Grant #K-23-MH-64189.



The anticonvulsant oxcarbazepine is a keto-analog of carbamazepine that has been studied as a possible treatment for bipolar disorder. European literature reports oxcarbazepine efficacy in treating manic symptoms while confirming its tolerability. Existing prophylaxis studies seem to indicate some benefit with oxcarbazepine, but small sample sizes limit the ability to generalize the findings. Naturalistic pilot data examining the treatment of bipolar disorder in a North American setting suggest some benefit with oxcarbazepine in treating a very refractory sample with depressive and rapid-cycling features. These studies are encouraging because they suggest that the drug may have some mood-stabilizing effects. However, controlled studies and more clinical experience with oxcarbazepine in the United States are required before we can assess the potential utility of the agent with any clarity.



Since the 1980s, the anticonvulsant oxcarbazepine has been available for use in some parts of Europe. A handful of European studies have examined oxcarbazepine treatment of bipolar disorder, but its use in a North American setting is yet to be studied extensively. This is partly due to the fact that oxcarbazepine is relatively new to the United States; the Food and Drug Administration (FDA) first approved the drug for marketing in January 2000. In this article, we review the European literature on oxcarbazepine treatment of bipolar disorder and provide pilot data on its use in an American setting. We also provide recommendations for the clinical use of oxcarbazepine for bipolar disorder.


Pharmacology of Oxcarbazepine

Oxcarbazepine, a 10-keto-analog of carbamazepine, is FDA indicated for partial seizures with or without secondary generalization. The pharmacologic properties of oxcarbazepine are summarized in Table 1. A major advantage of oxcarbazepine over carbamazepine is its tolerability. Unlike carbamazepine, oxcarbazepine has not been associated with increased risk of leukopenia, aplastic anemia, agranulocytosis, elevated liver function test results, or Stevens-Johnson syndrome.

Biochemically, oxcarbazepine has a minimal effect on most major cytochrome P450 (CYP) enzymes (such as 2D6), except for mild induction of CYP 3A4.1 As such, although oxcarbazepine has fewer drug interactions than carbamazepine, it can reduce levels of oral contraceptives by up to 50% and levels of calcium channel blockers by up to 30%. Thus, particular caution should be exercised when this agent is used in women of childbearing age. Oxcarbazepine also inhibits CYP 2C19, which can increase phenytoin levels by up to 40%.1 However, oxcarbazepine does not increase lithium or valproate blood levels.

The most significant medical risk to using oxcarbazepine is its association with a 2.5% clinically significant hyponatremia rate (sodium level <125 mmol/L) based on placebo-controlled clinical trials.1 Most cases of hyponatremia occur in the first 3 months of treatment. Thus, it is probably wise to check serum sodium levels monthly in the first 3 months of treatment, and every 6–12 months thereafter. Given the potential for selective serotonin reuptake inhibitors (SSRIs) to also reduce serum sodium levels (due to an increased risk of the syndrome of inappropriate antidiuretic hormone production), patients treated with combinations of SSRIs and oxcarbazepine should be particularly carefully monitored in the early stages of treatment. However, unlike with carbamazepine, routine laboratory tests for blood levels, hepatic function, and blood counts are not necessary with oxcarbazepine.

The pharmacologic effect of oxcarbazepine is mainly related to the 10-monohydroxy (MHD) metabolite.1 Both the pro-drug and this metabolite are active agents thought to block sodium channels. No effects on neurotransmitter systems or receptors have been shown. The half-life of oxcarbazepine itself is 2 hours and that of MHD is 9 hours, thus requiring at least twice-daily dosing. Oxcarbazepine is rather quickly metabolized to mostly MHD in plasma, and MHD is poorly plasma-protein bound (only 40% bound). Blood levels increase linearly and, though dose related, have not been associated with treatment response. Thus, laboratory testing is not required to establish a therapeutic blood level. Oxcarbazepine is metabolized by the liver to MHD, then glucuronidated and excreted in the kidney. Renal impairment is associated with increased half-life of MHD, up to 19 hours. However, mild-to-moderate hepatic impairment has not been associated with changes in oxcarbazepine or MHD pharmacokinetics. The agent has not been studied in severe hepatic impairment. Effective blood concentrations of MHD are lower in children younger than 8 years of age and higher in the elderly (60–82 years of age) than in adults.

It is generally thought that doses of oxcarbazepine need to be about one third higher than those of carbamazepine for similar effects. Research has suggested that many of the side effects of carbamazepine, which are lower with oxcarbazepine, have to do with the major metabolite 10,11-epoxide.2 In a study of 20 healthy volunteers, a single dose of oxcarbazepine (600 mg) was compared with carbamazepine (400 mg). Each dose led to fatigue in 7 of 10 persons in each group, but dizziness was lower in the oxcarbazepine group than in the carbamazepine group (2/10 versus 7/10, respectively; P<.05). Overall, reported tolerance of oxcarbazepine was greater than that of carbamazepine.2

In the epilepsy clinical trials that led to oxcarbazepine’s FDA indication, the most common side effects reported in one trial (N=172) with monotherapy at 2,400 mg/day (compared with a control group given 300 mg/day) included headache (31% versus 15% in controls), dizziness (28% versus 8% in controls), nausea (22% versus 7% in controls), and fatigue (21% versus 5% in controls). Discontinuation rates due to side effects were much higher in combination treatment clinical trials than in oxcarbazepine monotherapy studies; 1% or fewer patients discontinued in monotherapy studies, compared with 65% in combination treatment studies (using the same dose of 2,400 mg/day in both cases). Sedation and ataxia markedly increased the likelihood of discontinuation.

Oxcarbazepine has a lower rash rate than carbamazepine. A study conducted in Denmark found that skin rash reactions to carbamazepine resolved in 75% of patients with epilepsy after treatment was switched to oxcarbazepine.3 Thus, it is estimated that 25% of individuals who experience rash with carbamazepine will also experience it with oxcarbazepine. In a placebo-controlled monotherapy study (N=104), rash was reported in 4% of oxcarbazepine-treated subjects, compared with 2% of controls.

Oxcarbazepine is a pregnancy category C drug, with fetal abnormalities noted in animals treated at doses similar to recommended human doses.1 Fertility was also impaired in animal studies. Oxcarbazepine and MHD are excreted in human breast milk, with a milk:plasma concentration ratio of 0:5. This agent should probably be avoided during preconception, pregnancy, and breast-feeding.

There are no other known serious medical risks associated with oxcarbazepine, although studies in rats suggest increased 2-year rates of hepatocellular adenomas or carcinomas at doses near human recommended doses. In more than a decade of human use in Europe, no known increase in cancer risk has been reported with this agent.


European Studies of Bipolar Disorder

Clinical effectiveness studies with oxcarbazepine are summarized in Table 2.

Treatment of Acute Mania

In an open pilot study2 in which 48 patients with acute mania were treated with oxcarbazepine alone, 50% (n=24) were maintained on 600–900 mg/day, 37.5% (n=9) on 1,200–1,500 mg/day, and 6% (n=3) on 1,800–3,000 mg/day. Neuroleptics or lithium were needed in only 7 patients (15%), and oxcarbazepine was used by itself or only with hypnotic agents in the remaining 41 patients (85%). Patients were followed for a mean of 39 days, and based on clinicians’ assessments, 83% had a marked improvement and 94% tolerated the medication without adverse reactions.

A double-blind, placebo-controlled study used an on-off-on design in six acutely manic patients.4 All patients received an oxcarbazepine dose of 1,800 mg/day, and one patient received a second trial at 2,100 mg/day. The only side effect reported was dizziness at the higher dose (2,100 mg/day). A 49.9% reduction in manic symptoms (using the Inpatient Multidimensional Rating Scale—a psychopathology measure13) was shown on the drug, compared with only a 26.1% reduction off the drug (P<.10).

Another controlled study in mania (N=20) involved double-blind randomized treatment for 2 weeks to either oxcarbazepine (900–1,200 mg/day) or haloperidol (15–20 mg/day).2 Using the Bech-Rafaelsen Mania Scale (BRMS), both groups experienced equal and marked improvement in manic symptoms (from an initial mean score ~20 to a final mean score ~8). This study strongly suggests that the onset of action of oxcarbazepine rivals that of neuroleptic agents. Side-effect data were not reported.

A third double-blind study6 compared 19 manic patients on oxcarbazepine with 19 manic patients on haloperidol at high doses (2,400 mg/day of oxcarbazepine versus 42 mg/day of haloperidol). Both drugs were equally effective in 2 weeks of treatment, with reductions in the BRMS score from about 22 initially to less than 10 at 2 weeks. Although notable adverse effects occurred in 35% of haloperidol-treated patients, only 10% of oxcarbazepine-treated patients experienced adverse effects (n=3; one each with vomiting, lack of coordination, and parkinsonian symptoms). The researchers judged tolerability of oxcarbazepine to be excellent in 18%, good in 76%, moderate in 6%, and poor in none. In comparison, 25% of the haloperidol group was judged to have moderate or poor tolerability.

A fourth double-blind study6 examined 28 acutely manic patients on oxcarbazepine (mean dose=1,400 mg/day) with a control group of 24 patients receiving lithium (mean dose=1,100 mg/day) over 2 weeks. Again, efficacy was similar with both agents; there was improvement in the BRMS score from ~27 initially to ~11 at endpoint. Twenty-eight percent of the oxcarbazepine group had adverse effects, compared with 18.5% in the lithium group. However, this difference was not statistically significant. Two patients experienced hypotension, sedation, and sialorrhea. One patient each experienced skin rash, sedation, vertigo, akathisia, slurred speech, and oculogyric movements. Researchers judged the two medications to be equally tolerable, with excellent tolerability reported in 79% of both groups and good tolerability in 14% of the oxcarbazepine group, compared with 13% of the lithium group. Only 3% of the oxcarbazepine group and 6% of the lithium group were thought to have tolerated the medications poorly.

An open-label German study5 treated 10 hospitalized patients with acute psychotic mania or schizoaffective psychosis with 900 mg/day of oxcarbazepine, along with neuroleptics. All patients showed improvement with 3 weeks of treatment, including psychotic and agitated symptoms. Lower mean haloperidol doses (12.3 mg/day) were lower in the oxcarbazepine group, compared with a matched control group (24.9 mg/day). Factor analyses of global psychopathology ratings provided evidence for improvement in manic-like symptoms and in hostility and paranoid symptoms. No statistically significant improvement in hallucinatory symptoms was seen. Electroencephalograms were monitored in this study, and only one case of some slowing with generalized theta waves was noted. Only one patient dropped out due to a rash (this person was excluded from the analysis).

Prophylaxis Treatment

The only controlled prophylaxis study (open, not double-blind) was conducted in 10 patients, 4 of whom were randomized to oxcarbazepine and 6 to lithium.7 In the oxcarbazepine group, two depressive relapses and one manic relapse were noted over 10 months of follow-up, compared with two manic relapses and one depressive relapse in the lithium group over 12 months of follow-up. In mirror-image comparisons of relapse before and after treatment with the two drugs, both groups also appeared to improve similarly. Interestingly, all four oxcarbazepine-treated patients (versus only one lithium-treated patient) discontinued treatment eventually, three due to noncompliance and one due to leukopenia. Side effects were limited despite this dropout rate. However, the small numbers greatly limit the ability to interpret these results. It should also be noted that four other lithium-refractory patients who were nonrandomly assigned to oxcarbazepine treatment (mean dose=1,050 mg/day, for a mean duration of 16 months) appeared to do rather well, with only two depressive relapses in that time frame.

Another prophylaxis study, which was open but uncontrolled, assessed outcome in nine lithium nonresponders who received add-on treatment with oxcarbazepine. Six patients were treated with 600 mg/day, two with 900 mg/day, and one with 1,200 mg/day; mean duration of treatment was 5.4 months. Naturalistic treatment with neuroleptics and antidepressants was allowed. No robust benefit was seen overall in terms of reduction in the number of mood episodes, but a few patients appeared to have reduced severity of symptoms and fewer hospitalizations. Standardized outcome measures were not used. Side effects were reported to be limited and transient, with some dizziness, sedation, and ataxia. One patient dropped out after 2 months of treatment due to dizziness, nausea, and headache. Interestingly, lithium-related polyuria improved in two patients treated with adjunctive oxcarbazepine, and thyrotropin-releasing hormone stimulation test results normalized on oxcarbazepine plus lithium in three patients who previously had abnormal results when treated with lithium alone.8

Other Studies

A recent scientific report from Italy focused on the effect of switching patients from carbamazepine to oxcarbazepine.9 Thirteen patients reported to meet Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition14 criteria for bipolar disorders or cyclothymia were treated openly with oxcarbazepine; nine of the patients had been switched from carbamazepine. All carbamazepine-treated patients had to be switched to oxcarbazepine due to hepatic or blood count abnormalities, dermatitis, electrocardiogram abnormalities, or noncompliance. Overall, liver-function test results and hematologic parameters improved into the normal range on oxcarbazepine. The researchers also reported improvement in mood based on the Global Assessment Scale in all patients, all of whom were also treated with SSRIs at 8-week follow-up. Details regarding the clinical indications for treatment and statistical comparisons were not provided.

North American Studies of Oxcarbazepine in Bipolar Disorder

Treatment of Depression and Rapid Cycling

The European literature on oxcarbazepine mostly focuses on mania, with a few small prophylaxis studies and no published data on depression. Since its indication for use in epilepsy in the US, oxcarbazepine has been increasingly used for psychiatric purposes as well.

In a recent study for the Stanley Foundation Bipolar Network, 12 manic patients received oxcarbazepine alone in an open on-off-on design (14 days on, 7 days off, 14 days on).10 Using the Young Mania Rating Scale (YMRS), 42% were judged responders (with the standard definition of ≥50% improvement on the YMRS). Side effects occurred in four patients (30%) and constituted the usual findings of sedation and nausea. The most severely manic and psychotic patients appeared to experience less improvement in their YMRS scores on oxcarbazepine monotherapy.

Another recent large study11 compared oxcarbazepine (n=30) with divalproex sodium (n=30) in an open-label, prospective, nonrandomized fashion. All patients were acutely manic and assessed at 5 and 10 weeks with the Clinician-Administered Rating Scale for Mania (CARS-M). The two drugs were similar in efficacy, but there was more weight gain and cognitive side effects (based on the Mini Mental State Examination) with divalproex. While the results suggest enhanced tolerability with oxcarbazepine, the study was not randomized and therefore the drug’s efficacy data should be viewed with caution.

We also report preliminary data here on our experience using this agent for the treatment of mostly depressive and rapid-cycling symptoms in patients with bipolar disorder. Our research group has recently completed a chart review of oxcarbazepine treatment of refractory bipolar disorder in a naturalistic North American setting. The charts of 13 outpatients treated with oxcarbazepine were examined and clinical response was assessed retrospectively using the Clinical Global Impressions Scale– Improvement. All patients had failed treatment with at least one previous mood stabilizer, and most were experiencing depressive or rapid-cycling symptoms. The mean maintenance dose of oxcarbazepine was ~600 mg/day, and patients were followed for a mean duration of treatment of ~3 months. Mild-to-moderate improvement was seen in about one half of patients. The most common side effect was sedation, occurring in slightly more than one half of patients. Although the efficacy of oxcarbazepine remains to be established in larger, controlled studies with monotherapy in a North American setting, these naturalistic data suggest some benefit in this very refractory, difficult-to-treat sample with depressive and rapid-cycling features.12

Clinical Recommendations

Based on the previously mentioned research in bipolar disorder, the typical dose range for oxcarbazepine appears to be 600–1,200 mg/day in divided doses, although it seems tolerable and often effective in doses as high as 3,000 mg/day. Most of the controlled studies conducted with this agent have occurred in the 1980s and have been limited to studies of acute mania. Only one placebo-controlled study has been conducted, and that study used an on-off design (rather than the typical randomized, parallel group design) in only six subjects. Nonetheless, that report suggested benefit, and double-blind comparisons suggest similarity in efficacy with haloperidol (two studies) or lithium (one study), with the same or lower rates of side effects. Despite the suggestiveness of these studies, straightforward, placebo-controlled, parallel-design data would be more compelling.

Long-term benefit with oxcarbazepine has only been assessed in two small, open, prospective studies, one of which was controlled with a lithium comparison group. However, the extremely small size of these studies and their lack of standardized outcome criteria make them extremely difficult to interpret.

No studies have yet been published on the use of oxcarbazepine for depressive symptoms of bipolar disorder or for the rapid-cycling subtype. However, our recent pilot data12 suggest some benefit, albeit mild to moderate, in a very refractory population which had previously failed at least one fair trial of lithium, valproate, or carbamazepine.

Although far from definitive, these studies are encouraging. They suggest that oxcarbazepine may have some antimanic and/or mood-stabilizing effects. Further, its chemical similarity to carbamazepine, a well-proven antimanic and mood-stabilizing agent, provides some biochemical rationale for the likely efficacy of oxcarbazepine.

Perhaps most importantly, in practical terms, oxcarbazepine rather clearly appears to be better tolerated than carbamazepine and possesses fewer drug interactions. Given that most patients with bipolar disorder do not respond to a single mood stabilizer and thus require polypharmacy with two or more agents, the availability of oxcarbazepine for adjunctive use with lithium, valproate, or other agents provides a potentially useful alternative. Our initial pilot American data suggest that the limiting factor to its use in this setting may be sedation.


In summary, more clinical experience with oxcarbazepine in the US is required before we can assess the potential utility of this agent (particularly for depressive and prophylactic benefit) with any clarity. It has been available in Europe for almost two decades and researchers there have produced some double-blind evidence, albeit limited, that oxcarbazepine is an effective antimanic agent. Given its biochemical similarity to carbamazepine, future research may find evidence of broad utility in bipolar disorder.  PP


1. Physician’s Desk Reference. 55th ed. Montvale, NJ: Medical Economics Company; 2001.
2. Muller AA, Stoll KD. Carbamazepine and oxcarbazepine in the treatment of manic syndromes: studies in Germany. In: Emrich HM, Okuma T, Muller AA, eds. Anticonvulsants in Affective Disorders. Amsterdam, the Netherlands: Excerpta Medica; 1984:139-147.
3. Dam M, Jakobsen K. Oxcarbazepine in patients hypersensitive to carbamazepine. Acta Neurol Scand. 1984;70:223.
4.  Emrich HM, Altmann H, Dose M, von Zerssen D. Therapeutic effects of GABA-ergic drugs in affective disorders. A preliminary report. Pharmacol Biochem Behav. 1983;19:369-372.
5. Velinkoja M, Heinrich K. Effect of oxcarbazepine on affective and schizoaffective symptoms: a preliminary report. In: Emrich H, Okuma T, Mueller A, eds. Anticonvulsants in Affective Disorders. Amsterdam, the Netherlands: Excerpta Medica; 1984:208-210.
6. Emrich H. Studies with oxcarbazepine (Trileptal) in acute mania. Int Clin Psychopharmacol. 1990;5(suppl 1):83-88.
7. Cabrera J, Muehlbauer H, Schley J, Stoll K, Muller-Oerlinghausen B. Long-term randomized clinical trial on oxcarbazepine vs lithium in bipolar and schizoaffective disorders: preliminary results. Pharmacopsychiatry. 1986;19:282-283.
8. Greil W, Krueger R, Rossnagl G, Schertel M, Walther A. Prophylactic treatment of affective disorders with carbamazepine and oxcarbazepine: an open clinical trial. In: Pichot P, Berner P, Wolf R, Thau K, eds. Psychiatry: The State of the Art. New York, NY: Plenum Publishing; 1985:491-494.
9. Tavormina G. Oxcarbazepine as a mood regulator. its efficacy, safety, and tolerability vs carbamazepine. Paper presented at: Collegium Internationale Neuropsychopharmacologium; July 9-13, 2000; Brussels, Belgium.
10. Hummel B, Stampfer R, Grunze H, et al. Acute antimanic efficacy and safety of oxcarbazepine in an open trial with an on-off-on design. Paper presented at: Fourth International Conference on Bipolar Disorder; June 14-16, 2001; Pittsburgh, Pa.
11. Reinstein MJ, Sonnenberg JG, Chasanov MA, et al. Oxcarbazepine and divalproex sodium: a comparison of efficacy and side effects for mania [abstract]. Poster presented at: The 154th Annual Meeting of the American Psychiatric Association; May 5-10, 2001; New Orleans, La.
12. Ghaemi SN, Ko JY, Katzow JJ. Oxcarbazepine treatment of refractory bipolar disorder: a retrospective chart review. Bipolar Disord. 2001. In press.
13. Lorr M, Klett CJ, McNair DM, Lasky JJ. Inpatient Multidimensional Rating Scale. Palo Alto, Ca: Consulting Psychologists Press; 1962.
14. Diagnostic and Statistical Manual of Mental Disorders. 4th ed. Washington, DC: American Psychiatric Association; 1994.

Dr. Marcotte is director of the psychiatric outpatient clinic Marcotte and Associates in Fayetteville, NC.

Acknowledgments:The author reports no financial, academic, or other support of this work.  



Are there safe treatments for elderly patients with dementia and aggression? This article describes the use of gabapentin, a nonmetabolized antiepileptic drug, for control of aggression in the elderly patient with dementia. The drug’s relative safety and ease of use are demonstrated to assist in the control of aggressive behavior. The objective of the study was to determine the effectiveness of gabapentin in the acute management of behavioral disturbance in patients who had failed to respond to previous medications and had failed their nursing home placement.


With the aging of our population, psychiatrists will increasingly be called upon to provide services to nursing homes, general hospitals, and families of loved ones with dementia and aggression. Although traditional and atypical antipsychotics are commonly employed in the management of aggression, antiepileptic drugs are being used with growing frequency.

Dementia is a major health concern today. It is expected that in the next 50 years, the worldwide population of people >80 years of age will increase by 6-fold, to 370 million.1 With the aging of our population and enhanced life expectancy, the large number of baby boomers will shortly reach the ages at which dementia tends to occur, presenting a greater challenge to medical resources and the economic welfare of families.2,3 Those of us who have worked with families that maintain an elderly demented patient in their home are witness to the emotional stress and financial burden that caretaking involves. Factors that affect the family’s ability to care for an elderly relative in the home include incontinence, aggressive behaviors toward others, behaviors resulting in self-injury (eg, falling), or wandering from the premises.

Many nursing homes are equipped with devices that monitor a patient’s whereabouts (eg, anklet or door alarms). However, while nursing home staff may be familiar with patients who wander or are incontinent, they may not be equipped to handle aggressive behaviors that threaten staff members or other residents of the nursing home. Aggressive behavior, considered an immediate crisis within the patient’s home or the nursing home, frequently leads to psychiatric hospitalization. To maintain the possibility of having the patient return to the nursing home, families are often taxed with additional costs, such as paying for the vacant nursing home bed during the patient’s hospitalization in a psychiatric unit.

Patients with dementia hospitalized for other medical procedures in a general hospital have longer lengths of stay.4 Lyketsos and colleagues4 studied 823 patients in a general hospital and found that the average length of stay for patients with dementia exceeded that for patients without dementia by 4 days. There were higher costs of hospitalization and greater complications. Unfortunately, that study did not differentiate delirium from dementia. A substantial portion of those patients who exhibited demented behavior may have qualified for the diagnosis of delirium.5 Patients with a diagnosis of dementia who were admitted to a general hospital were found not to have higher rates of mortality in the hospital. Another study by Lyketsos and colleagues6 noted that of patients with dementia, 27% had apathy, 24% had depressive disorders, and 24% had aggression and agitation. Although apathy and depression were noted to have significant effects on the individual and earlier nursing home referral, a worse prognosis accompanied those patients who had aggression and agitation. Such symptoms also increased the cost of caregiver burden.7

Not only does aggressive and behavioral disturbance such as agitation lead to early nursing home placement, it can lead to expulsion from the nursing home. Behaviors that include aggression toward others result in more costly expenditure, greater morbidity, higher mortality, and increased financial burden.4,6 In addition, the symptoms of agitation and aggression become more significant and frequent as dementia becomes more advanced. Lyketsos and colleagues6 studied patients with symptoms of aggression and agitation and found that 13% had mild dementia, 24% had moderate dementia, and 39% had severe dementia.

The large expected increase in patients with dementia and aggression will produce significant burden for psychiatric hospitals and nursing homes.  Psychiatric care and management of aggressive symptoms must be obtained before the patient can return to the nursing home, even after the hostile behaviors have been ameliorated. Thus, length of hospital stay for general medical purposes is expected to increase.

This article examines the use of gabapentin in a traditional inpatient setting, including patients ≥65 years of age who were both demented and aggressive. Gabapentin, a relatively nontoxic, nonmetabolized, nonplasma-bound antiepileptic drug, was used in addition to a minimal amount of atypical antipsychotics. The results indicate that gabapentin offers a safe alternative to metabolized, plasma-bound antiepileptic agents.


Recent treatment of behavioral disturbance with aggression in the elderly has included anticonvulsants, traditional antipsychotics, and novel antipsychotics. The use of anticonvulsants has a substantial advantage over antipsychotics; anticonvulsants are less anticholinergic, thus they are less likely to contribute to increasing dementia.8-16 Anticholinesterase medications have been used to decrease the enzyme acetylcholinesterase to preserve acetylcholine (ACH) and increase mental acuity. Anticonvulsants have less impact on ACH and may be less harmful to memory, attention, and concentration in demented patients. There have been more reports of the use of gabapentin in the treatment of behavioral disturbance in the elderly.17-22 Gabapentin has a unique advantage because it does not plasma bind, displace other medications, or cause drug-medication interactions. Gabapentin is not metabolized in the body and 95% of the drug is excreted in the urine. This obviates problems associated with liver toxicity or other metabolic concerns in the cytochrome P450 system. Because it is excreted in the urine, excessive quantities of gabapentin can be accumulated in those patients with renal failure. Gabapentin doses must be reduced in such patients.


Patients treated with gabapentin over 3 years (N=210) through a small community hospital service were retrospectively reviewed. Gabapentin blood levels were obtained from a small number of patients during the course of this study (BJ Wilder, MD, oral communication, 1996). All patients who underwent treatment with gabapentin were selected from this pool. Only patients ≥65 years of age were identified and those with dementia and behavioral disturbance were included in the study. Of the patients >65 years of age, 48 were identified and 13 were excluded. Although the 13 patients excluded from the study did indeed meet criteria for a diagnosis of dementia, they did not display sufficiently aggressive or disturbing behaviors to result in expulsion from a nursing home. Several of the patients had frequently experienced paranoid ideations, suspiciousness/distrust of others, and cognitive psychotic disturbance, but were not overtly physical or disruptive in their behavior. However, 35 patients were identified as having significant behavioral problems resulting in their expulsion from nursing homes. All patients in the study were treated with gabapentin throughout the course of hospitalization. During the course of treatment, ancillary medications were used (Table). Eleven patients had small-to-moderate dosages of risperidone, up to a maximum of 6 mg/day, added to their course of treatment. Most had much more modest dosages. Many of the medications patients were taking before hospitalization were withdrawn for the study.

Patient charts were reviewed by an independent research assistant who recorded frequency of the following behaviors: yelling, moaning, screaming, crying, and verbal or physical threats of aggression. Sexually inappropriate behaviors (grabbing, fondling, or sexually provocative comments) were also recorded.

Length of hospital stay was divided into the first and second halves of hospitalization. Each patient served as his or her own control. Charts were reviewed on each patient, and the number of aggressive events that occurred during each patient’s first and second half of hospitalization was recorded (Table).


The average age of all 35 patients was 78 years, and the average length of stay in the hospital was 14.37 days. The number of aggressive events occurring in the first half of the hospitalization was 102; in the second half there were 34. Three patients accounted for 61.8% of the aggressive behavior in the second half of the hospitalization.

The data were analyzed by pairing each observation in the second half of hospitalization with an observation in the first half. The mean difference in aggressive events between the first and second samples was 1.94, with a standard error of 0.518. The probability of observing such a difference in aggressive behaviors by chance alone between the first and second observation period is less than .001. The value of the t statistic for this test was 3.747, thus we can say with 99.9% confidence that the behavioral change exhibited between the first and second half of the hospital stay was not a result of chance.

Although 17 patients accounted for 100% of the disturbing behaviors in the first half of the hospitalization, 11 patients accounted for all of the aggressive behaviors in the second half of hospitalization. Both frequency and intensity of aggressive acts diminished during the course of hospitalization for 16 patients. Only one patient had more events in the second portion of the hospitalization than in the first. Although 17 patients (48%) had aggressive behaviors that continued during hospitalization, 18 patients who had aggressive behaviors before hospitalization had no aggressive behaviors during either their first or second half of the hospitalization. This result is possibly associated with a good response to medication management or the result of hospitalization itself. All of the patients were managed with gabapentin throughout the entire course of hospitalization. Risperidone was the most common medication given as an add-on throughout hospitalization, although one patient received haloperidol. The addition of risperidone was employed in the 11 patients exhibiting aggressive behaviors. Other antipsychotics, antidepressants, and benzodiazepines were avoided. The use of risperidone does not account for the positive results in this study because only 11 of the 35 patients took risperidone during the study. Six of the 11 patients had no aggression in both halves of the hospitalization, whereas 5 exhibited aggressive behaviors in the first half and 4 continued to be aggressive in the second half. The total number of aggressive episodes for the risperidone- and gabapentin-treated group was 30 in the first half and 11 in the second. These figures represent a 36% reduction in aggressive behaviors, whereas in the gabapentin-treated group there was a 30% reduction (102 aggressive events occurred in the first half of hospitalization and 34 in the second).


It is highly likely that the removal of a patient from his or her environment and the placement of that patient in a hospital with staff who are highly trained to manage aggressive behaviors does have a salutary effect on the diminishing aggression in a patient with dementia. This may contribute to the fact that 18 of the patients had no disturbing behaviors in the first half of their hospitalization. It is also possible, however, that medication management at the inception of treatment in the first hospital stay could account for some of the diminishment in aggression.

This was a retrospective, open-label study of gabapentin. As such, it is limited to noncontrolled conditions. Although the data were retrospectively examined, results must be replicated in a controlled, blind experiment.


The use of gabapentin in demented patients with aggressive behaviors has been shown to be effective in the management and control of aggressive, hostile symptoms. Gabapentin had no substantial side effects other than mild sedation in one patient,4 who tolerated only 300 mg/day secondary to renal insufficiency with elevated serum urea nitrogen levels and increased creatinine clearance, both of which were in the abnormal range. One other patient could tolerate only 600 mg due to sedation. Both patients were noted to have sedation on higher doses. No adverse events (eg, falling) were noted in the treatment cohort. Aggressive behaviors have a substantial impact on caregivers, and can lead to expulsion from nursing homes and mandatory psychiatric hospitalization. Gabapentin represents a safe medication for elderly patients with dementia and aggressive behaviors. This study employed an average gabapentin dosage of 1,400 mg/day in an elderly population (mean age=78.8 years), demonstrating the drug’s effectiveness in high dosages without any deleterious side effects other than mild sedation. The use of antipsychotics, such as risperidone, did not substantially improve aggressive behaviors more than gabapentin.  PP


1.     Aging and the Oldest Old. Geneva, Switzerland: United Nations, Population Division, Department of Economics and Social Affairs; 1998.
2.     Ernst RL, Hay JW. US economic and social costs of Alzheimer’s disease revisited. Am J Public Health. 1994;84:1261-1264.
3.     Weiner M, Powe NR, Weller WE, Shaffer TJ, Anderson GF. Alzheimer’s disease under managed care: implications from Medicare utilization and expenditures patterns. J Am Geriatr Soc. 1998;46:762-770.
4.     Lyketsos CG, Sheppard JM, Rabins PV. Dementia in elderly persons in a general hospital. Am J Psychiatry. 2000;157:704-707.
5.     Kolbeinsson H, Jonsson A. Delirium and dementia in acute medical admissions of elderly patients in Iceland. Acta Psychiatr Scand. 1993;87:123-127.
6.     Lyketsos CG, Steinberg M, Tschanz J, Norton MC, Steffens DC, Breitner JC. Mental and behavioral disturbances in dementia: findings from the Cache County study on Memory in Aging. Am J Psychiatry. 2000;157:708-714.
7.     Mega MS, Cummings JL, Fiorello T, Gombein J. The spectrum of behavioral changes in Alzheimer’s disease. Neurology. 1996;46:130-135.
8.     Finkel S. Research methodologic issues in evaluating behavioral disturbances of dementia. Int Psychogeriatr. 1996;8(suppl 2):149-150.
9.     Tariot PN, Erb R, Podjorski CA, et al. Efficacy and tolerability of carbamazepine for agitation and aggression in dementia. Am J Psychiatry. 1998;155:54-61.
10.     Tariot PN, Frederiksen K, Erb R, et al. Lack of carbamazepine toxicity in frail nursing home patients: a controlled study. J Am Geriatr Soc. 1995;43:1026-1029.
11.     Cooney C, Mortimer A, Smith A, Newton K, Wrigley M. Carbamazepine use in aggressive behavior associated with senile dementia. Int J Geriatr Psychiatry. 1996;11:901-905.
12.     Sandborn WD, Benfeldt F, Hamdy R. Valproic acid for physically aggressive behavior in geriatric patients. Am J Geriatr Psychiatry. 1996;3:239-242.
13.     Herrmann N. Valproic acid treatment of agitation in dementia. Am J Psychiatry. 1998;43:69-72.
14.     Mazure CM, Druss BH, Cellar JS. Valproate treatment of older psychotic patients with organic mental syndromes and behavioral dyscontrol. J Am Geriatr Soc. 1991;42:906-909.
15.     Mellow A, Solano-Lopez C, Davis S. Sodium valproate in the treatment of behavioral disturbance in dementia. J Geriatr Psychiatry Neurol. 1993;6:205-209.
16.     Raskind MA. Evaluation and management of aggressive behavior in the elderly demented patient. J Clin Psychiatry. 1999;60:45-49.
17.     Herrmann N, Lanctot K, Myszak M. Effectiveness of gabapentin for the treatment of behavioral disorders in dementia. J Clin Psychopharmacol. 2000;20:90-93.
18.     Roane DM, Feinberg TE, Meckler L, Miner CR, Scicutella A, Rosenthal RN. Treatment of dementia-associated agitation with gabapentin. J Neuropsychiatry Clin Neurosci. 2000;12:40-43.
19.     Dallocchio C, Buffa C, Mazzarello P. Combination of donepezil and gabapentin for behavioral disorders in Alzheimer’s disease [letter]. J Clin Psychiatry. 2000;61:64.
20.     Goldenberg G, Kahaner K, Bassavaraju N, Rangu S. Gabapentin for disruptive behaviour in an elderly demented patient [letter]. Drugs Aging. 1998;13:183-184.
21.     Sheldon LJ, Ancill RJ, Holliday SG. Gabapentin in geriatric psychiatry patients [letter]. Can J Psychiatry. 1998;43:422-423.
22.     Regan WM, Gordon SM. Gabapentin for behavioral agitation in Alzheimer’s disease [letter]. J Clin Psychopharmacol. 1997;17:59-60.

Dr. Wilder is Professor Emeritus in the Department of Neurology and Neuroscience at the University of Florida College of Medicine in Gainesville.

Acknowledgments: The author reports no financial, academic, or other support of this work. 



Why and how do antiepileptic drugs (AEDs) work in so many neurological and psychiatric disorders? AEDs are highly effective in various neurological and psychiatric disorders. They are the drugs of choice in several mood disorders (including bipolar disorder), neurological disorders, and neuropathic pain syndromes; they are also choice drugs for the prevention of migraine and cluster headaches and restless legs syndrome. AEDs work by altering neuronal excitability, increasing inhibition, and decreasing excitation. They act on neurotransmitters, primarily those involved in excitation (glutamate) and inhibition (γ-aminobutyric acid) and those that may be associated with mood and pain, such as serotonin, dopamine, and norepinephrine. The AEDs approved for the treatment of epilepsy during and after 1993 have created a profound change in the pharmacotherapy of many neurological and psychiatric syndromes.



Since 1993, eight new antiepileptic drugs (AEDs) have been approved for the treatment of epilepsy. We can now assess the use of these drugs not only in epilepsy, but in many other neurological and psychiatric disorders. AEDs have been used in mood disorders and chronic neuropathic pain syndromes for decades. Valproic acid (VPA) is the drug of choice for the treatment of bipolar disease, and topiramate (TPM) and lamotrigine (LTG) are also effective; LTG is especially efficacious in the depressive side of the disorder without tripping the patient back into mania. Valproate and carbamazepine (CBZ) have been used extensively in the management of aggression and episodic dyscontrol syndrome. CBZ was introduced in the United States for the treatment of trigeminal neuralgia more than 2 decades ago.

The new AEDs (those approved after 1993) have opened a Pandora’s box for the widespread use of certain AED drugs for neurological and psychiatric disorders. At present, 38% of AED prescriptions are written for the management of epilepsies and 62% for nonepilepsy uses. AEDs are the drugs of choice in the treatment of chronic neuropathic pain, trigeminal neuralgia, and prevention of migraine. They are also of value in the management of cluster headaches, familial tremor, restless legs syndrome, anxiety, depression, drug and alcohol withdrawal, posttraumatic mood stabilization, spasticity, tics, dystonia, and social phobias. Gabapentin (GP) is the most commonly prescribed AED, although only 12% of prescriptions are written for the treatment of epilepsy. TPM is gaining acceptance as an effective drug for weight loss, in addition to neurological and psychiatric disorders. Some AEDs are undergoing clinical trials for neuroprotection in acute brain and spinal ischemia and certain progressive neurological diseases. How can we account for the widespread use of these drugs? AEDs modulate brain activity by decreasing excitability, enhancing inhibition, and raising the threshold for neuronal firing. They also alter central nervous system (CNS) neurotransmitters, and two of the drugs are carbonic anhydrase inhibitors. This review includes a discussion of the mechanisms of action of the AEDs and provides general comments on efficacy, adverse effects, drug interactions, and dosing parameters of the newer AEDs.


Antiepileptic Drugs

How They Work: Neuronal Targets and Mechanisms of Action

AEDs decrease excitation and enhance inhibition by various mechanisms. AEDs act on specific neuronal targets (Table 1), and many of them block voltage-sensitive sodium channels. This action decreases the frequency of action potentials, raises the threshold for repetitive action-potential generation, and prevents burst firing of neurons.1 In the treatment of epilepsy, this mechanism is thought to prevent the spread of the electrical discharge from an epileptic seizure focus, thereby preventing the spread and generalization of epileptic discharge into a tonic-clonic or grand mal seizure. In the case of neuropathic pain, prevention of repetitive discharge may prevent the windup phenomenon thought to be characteristic of the development of changes in lamina II of the dorsal horn of the spinal cord, which may be important in the development of neuropathic pain.

Some of the AEDs block different types of voltage-sensitive calcium channels. A partial block of slow-conducting calcium channels (T type) decreases thalamocortical reverberating circuits and thereby controls absence seizures.2 Another target by which AEDs reduce excitation of cortical neurons is by reducing calcium entry by blocking L-type calcium channels.3,4 Excitation can be further reduced by blocking N-type calcium channels, which reduce neurotransmitter release.3

Secondly, AEDs target the γ-aminobutyric acid (GABA) inhibitory neurotransmitter system by augmenting the action of GABA at GABAA receptors. This increases the inward flow of chloride ions (Cl-), resulting in neuronal hyperpolarization.5 Other AEDs increase the synthesis and release of GABA. One of the AEDs specifically blocks the reuptake of GABA,6 while another reverses GABA reuptake when the neuron is depolarized. Two of the AEDs trigger the release of serotonin (5-hydroxytryptamine [5-HT]), which in turn stimulates the release of GABA from neurons.7,8

A third target for decreasing excitation of cortical neurons is inhibitory by blocking excitatory receptors. Several of the AEDs either inhibit N-methyl-D-aspartate (NMDA)-type or non-NMDA-type a-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) or kainic acid receptors.9

A fourth target is a reduction of the concentration of neuronal glutamate. One of the AEDs decreases the amount and release of glutamate, the major excitatory transmitter in the CNS.1,5

TPM and zonisamide are carbonic anhydrase inhibitors. This results in CNS acidosis, with a reduction in excitatory NMDA activity and enhancement of inhibitory GABA activity.

Although AEDs used to be commonly characterized as having one or perhaps several main modes of action,2 it has become increasingly clear that most AEDs have multiple modes of action, many of which may be clinically relevant to various neurological and psychiatric disorders10 (Tables 2 and 3).

It is well known that both barbiturates and benzodiazepines bind to the GABAA receptor at different sites, resulting in the augmentation of inhibitory neurotransmission.1,11 However, barbiturates also block non-NMDA-type glutamate receptors.12 Similarly, phenytoin and CBZ are well known as sodium channel blockers.1 They both have a range of other actions, including L- and N-type calcium-channel blockade, blocking NMDA receptors, and, for CBZ, an indirect GABA-ergic effect via increasing the release of 5-HT.10 Valproate has effects on all of the key antiepileptic mechanisms.

As shown in Table 3, a number of the newer AEDs, namely felbamate, TPM, LTG, and GP, have effects on all of the key antiepileptic mechanisms; the effect of GP in blocking action potentials is not via sodium channel blockade.5 After exposure to GP (intracellular injection or extracellular application), the neuron has a time delay before sodium (Na+) channels are affected and burst firing decreases. This is in contrast to other Na+ channel blockers with which the effect is instantaneous. TPM has a direct effect on Na+ channels and L-type calcium ion (Ca++) channels and also blocks non-NMDA glutamate receptors.13 TPM and GP increase the metabolism of glutamate to GABA by stimulating the enzyme glutamic acid decarboxylase and increasing the intracellular concentration of GABA. TPM is a GABA agonist at the receptor site that is different from the phenobarbital and benzodiazepines sites. Tiagabine (TGB) was designed to inhibit the reuptake of GABA by presynaptic neurons and glial cells, and this is its only known mode of action.14 The mechanism of action of levetiracetam (LVT) is unknown.15 It blocks kindling in the kindling model of epilepsy, although it is not effective in blocking seizures in other models of epilepsy. For example, LVT does not block seizures induced by electrical stimulation or seizures induced by pentylene tetrazole in animal models of epilepsy.

The newer AEDs offer a number of advantages over the older drugs. They are just as efficacious as the older drugs in treating the epilepsies and in the treatment of various other neurological and psychiatric conditions. As a group, they are safer and produce fewer idiosyncratic reactions. GP has been chronically administered to over 5,000,000 patients without a serious life-threatening reaction. TPM, likewise, appears to be very safe, with approximately 1,000,000 chronic patient exposures. Felbamate, the first of the new drugs, is not safe and is treated as a third-line agent for the treatment of epilepsy. The remaining new drugs, with the exception of LTG, appear safe from serious idiosyncratic reactions, although they have not received the same usage as GP and TPM. When initiated at low doses and titrated slowly, LTG rarely produces allergic epidermal reactions. The package insert16 for LTG dosing and titration should be carefully followed. The pharmacokinetic profiles for the newer drugs are superior. Bioavailability is better, protein binding is very low, metabolism is more simple, and many of the new AEDs are predominately excreted by the kidneys. The newer drugs produce far fewer drug interactions than the older drugs. Phenytoin (PHT), CBZ, and phenobarbital (PB) are potent enzyme inducers that interact not only with other AEDs but also with many non-AEDs. VPA is a potent enzyme inhibitor for many AEDs (particularly LTG and CBZ epoxide) and non-AEDs. GP and LVT do not interact with other AEDs or non-AEDs. TPM, LT, zonisamide, oxcarbazepine (OX), and TGB are relatively free from producing drug interactions, although they are acted on by the enzyme-inducing drugs. The adverse-effect profiles of the newer AEDs are generally mild and depend on dosing and titration. The general rule of “start low and go slow” applies to AEDs in general. Doses required to treat many neurological and psychiatric conditions are far less than the doses recommended to treat refractory epilepsy.

Neuropathic Pain

Unlike nociceptive pain, which emanates from the activation of the pain receptors, neuropathic pain is the outcome of injury to the pain-conducting nervous system; traditional therapies provide little relief. AEDs have become the drugs of choice for the management of neuropathic pain syndromes. The older anticonvulsants have been used for the treatment of various neuropathic pain and mood syndromes for 40 years.17-20 When appropriate, CBZ (the drug of choice for lancinating pain associated with trigeminal neuralgia) and occasionally phenytoin have been used, although there are only a few randomized clinical studies to support their use for this purpose.21,22 Clinical efficacy for these agents has also been reported for diabetic neuropathy and poststroke pain. However, the general lack of efficacy, along with significant side-effect profiles, has limited the overall use of these drugs.18 GP and TPX have emerged as effective in many chronic pain syndromes, and OX has shown efficacy in trigeminal neuralgia. Controlled studies for other neuropathic pain syndromes are underway.


Approved in 1993 as add-on therapy for the treatment of generalized and partial seizures for adults, GP was synthesized as a structural GABA analog that would cross the blood-brain barrier. GP blocks the tonic phase of nociception and exerts a powerful inhibitory effect in neuropathic pain models of mechanical and thermal hyperalgesia and allodynia. A number of open-label studies have shown positive results in the effect of GP on various pain conditions, including tonic spasms associated with multiple sclerosis, trigeminal neuralgia, neuropathic cancer pain, reflex sympathetic dystrophy, and human immunodeficiency syndrome-related peripheral neuropathy.23

Two large multicenter, randomized, placebo-controlled trials have demonstrated the efficacy of GP in relieving neuropathic pain and associated symptoms (eg, sleep, mood, and quality of life) in patients with postdiabetic neuropathy (PDN) and postherpetic neuropathy (PHN). Dosages ranged from 900–3,600 mg/day in three divided doses. Pain relief was observed during the second week when the dosage reached 1,800 mg/day. The median effective dosage in the two studies was 900–1,200 mg. The drug was well tolerated with no significant differences in adverse effects between the drug and placebo in patients with PDN, with a slightly higher withdrawal rate (13.3% versus 9.5%) in patients with PHN. The most frequent tolerable adverse events were somnolence and dizziness.24,25

Increasing evidence from experimental and clinical studies has shown that GP is efficacious in the treatment of neuropathic pain, particularly pain due to PDN and PHN. Clinical trials are needed to evaluate the efficacy of the agent in other painful conditions such as facial neuralgias (including trigeminal and glossopharyngeal neuralgias), central pain syndromes secondary to cerebrovascular disease, phantom-limb pain, spinal cord injury, and central poststroke pain syndrome.23,26


TPM, a broad-spectrum anticonvulsant, was approved in 1997 for the adjunctive treatment of partial and secondary generalized seizures in adults. Unlike LTG and GP, TPM was used as an anti-nociceptive drug for humans before systematic research on animal models of pain was undertaken. Thus far, published clinical experience with TPM is limited. One case report describes a 60-year-old male patient with post-thoracotomy pain syndrome that remained unresponsive to a host of other treatments for more than 3 years. Two daily doses of TPM, gradually increased up to 50 mg and 75 mg, provided consistent 80% pain relief around the clock without intolerable side effects for more than 6 months.23,27

A single-center, double-blind, randomized, placebo-controlled, 14-week study designed to evaluate the efficacy and safety of TPM in 27 patients with painful diabetic neuropathy reported a statistically significant reduction in average pain scores as measured on the Short-Form McGill Pain Questionnaire (SFMPQ) and the 100-mm visual analog scale of the SFMPQ. TPM (or placebo) was initiated at 25 mg/day and titrated over a 9-week period to 200 mg BID or a maximum tolerated dose. The most common adverse effects of the drug were asthenia, more than 10% weight loss, and confusion. The results suggest that TPM may represent a new option for the treatment of painful diabetic neuropathy.28

TPM may be a reasonable alternative treatment for patients experiencing various neuropathic pain syndromes, particularly for those who were unresponsive to other neuropathic analgesics (including anticonvulsants). TPM is well tolerated at low dosages (100–200 mg/day) and has few interactions with other drugs. Weight loss has been reported in all controlled clinical trials of TPM.

Migraine Headache Prevention

Migraine headache is a chronic, disabling disorder that affects some 30 million Americans and accounts for 20% of all outpatient visits to neurologists. According to the American Migraine Study29,30 (a 1989–1999 landmark population-based survey), 13% of the United States population (18% of all women and 6% of men) suffer from this disorder. The current concept of migraine pathophysiology holds that the underlying mechanism of migraine (with and without aura) is neurovascular in origin and that the primary dysfunction arises in the CNS. The neurovascular theory emphasizes the essential interaction between nerves and vessels, and integrates the known physiologic and pathophysiologic mechanisms. Migraine responds to various treatments, but tryptans are the drugs of choice for the acute attack. A number of treatments are available for the prevention of migraine, although AEDs are the choice drugs. VPA is approved for migraine prevention, and GP and TPX have had clinical acceptance as excellent preventatives.

Valproic Acid

The efficacy and safety of this established AED as prophylactic monotherapy was evaluated in a multicenter, double-blind, placebo-controlled, parallel-group study of 176 patients. The primary efficacy variable was 4-week migraine attack frequency, and the daily dosages were 500 mg, 1,000 mg, 1,500 mg, or placebo. Mean reductions in migraine attack were 1.7, 2.0, 1.7, and 0.5, respectively (P=.05 versus placebo). The 1,000-mg dosage was superior to the 500- and 1,500-mg dosages. Approximately 45% of the three groups treated with divalproex sodium achieved a >50% reduction in attack frequency versus 21% of the placebo group (P<.05).31

The results of two 12-week, double-blind, placebo-controlled studies and one 36-month open-label extension study (N=248) were as follows: 37% of patients reported nausea, 34% reported tremor, 24% reported weight gain, and 12% reported alopecia. Although nausea and alopecia subsided over time, tremor and weight gain persisted.32


After positive observations in an open-label study, 145 patients were randomized to receive GP in a multicenter, double-blind, placebo-controlled trial. Initial dosages of 300 mg/day were gradually increased to 1,800 or 2,400 mg/day, and patients remained at these fixed dosages for an 8-week stabilization period. Analysis showed that the median headache rate during the last 4 weeks was significantly lower in patients receiving GP versus those receiving placebo (2.7 versus 3.5 attacks, respectively; P=.006). Compared with placebo, GP was also associated with a significantly greater number of patients achieving a >50% reduction in migraine rate (16% versus 46%, respectively; P=.008).33

Somnolence, dizziness, and asthenia were observed in more than 10% of the GP-treated patients in the above study. However, only somnolence occurred significantly more often with the active treatment versus placebo (24.5% versus 8.9%; P=.04).33


Based on positive findings in open-label investigations of patients with refractory migraine or intractable daily headache, two single-center, double-blind, placebo-controlled trials were undertaken.34,35 Although the former evaluated TPM as monotherapy, concomitant prophylaxis medication was permitted in the latter. The target dosage was 100 mg BID. In both studies, a 4-week baseline period was followed by a titration phase of 6–8 weeks and a maintenance phase of 8–12 weeks. The results of the studies showed a mean reduction in migraine frequency per 28 days of 1.2 and 1.8 versus 0.4 and 0.5, respectively, for the placebo groups.

The 50% responder rate was higher in the TPM monotherapy group (46.7% versus 6.7% for placebo) than in the add-on treatment group (26.3% versus 9.5% for placebo). A subsequent analysis of two subsets of patients (with and without prophylactic migraine medications at baseline or during the study) showed no significant difference between treatment groups in patients receiving prophylactic medications. In contrast, the mean reduction (2.1) in 28-day headache frequency for the TPM group was significantly greater than that for the placebo group (0.3, P=.00006) in patients with a washout of baseline prophylactic medications.34 (TPM is currently being evaluated as monotherapy in a large, multicenter, placebo-controlled trial to determine its response.)

Adverse effects were mild to moderate and included paresthesias, drowsiness/ somnolence, decreased appetite/anorexia, diarrhea, weight loss, altered taste, and memory impairment. In contrast to divalproex sodium and GP, weight loss is a characteristic feature; TPM-treated patients in the two studies showed a statistically significant mean weight reduction (compared with placebo) of 4.7% to >10% of their body weight.34

Other Neurological Disorders

The AEDs are effective in various other disorders. GP and TPX given before bedtime in doses of 300–900 mg and 50–100 mg, respectively, are effective in nighttime restless legs syndrome and muscle cramps. Primidone, one of the older drugs, and TPX significantly reduce benign essential tremor.36 Dosages range from 250–500 mg/day for primidone and 200–400 mg/day for TPX. AEDs may be helpful in spasticity. GP has been anecdotally reported to be helpful as adjunctive therapy to baclofen. TG, a GABA reuptake inhibitor, has been very effective both alone and as adjunctive therapy to baclofen in refractory spasticity.

Weight gain is prominent with several of the AEDs, such as VPA, CBX, and GP. VPA has resulted in significant weight gain in many of the neurological and psychiatric disorders for which it is used. TPX results in weight loss when used in these disorders. The drug has also been used primarily for weight loss in dosages of 50–200 mg/day. Zonisamide has also been reported to result in weight loss in controlled clinical trials for epilepsy treatment.


AEDs are effective in a wide variety of neurological and psychiatric disorders. Their mechanisms of action serve to control neuronal excitation. AEDs are generally safe and well tolerated, and when dosed and titrated properly have a low adverse-effect profile.   PP


1.    Macdonald RL. Inhibitory synaptic transmission. In: Engel J, Pedley TA, eds. Epilepsy: A Comprehensive Textbook. Philadelphia, Pa: Lippincott–Raven Publishers; 1997:1383-1391.
2.    Taylor CP. Mechanisms of action of new antiepileptic drugs. In: Chadwick D, ed. New Trends in Epilepsy Management: The Role of Gabapentin. London, England: Royal Society of Medicine Services Limited; 1993:13-40.
3.    Stefani A, Spadoni F, Bernardi G. Voltage-activated calcium channels: targets of antiepileptic drug therapy. Epilepsia. 1997;38:959.
4.    Snutch TP, Reiner PB. Ca2+ channels: diversity of form and function. Curr Opin Neurobiol. 1992;2:247-253.
5.    McLean MJ. Gabapentin in the management of convulsive disorders. Epilepsia. 1999;40(suppl 6):S39-S50.
6.    Taylor CP, Gee NS, Su TZ. A summary of mechanistic hypotheses of gabapentin pharmacology. Epilepsy Res. 1998;29:233-249.
7.    Yan QS, Mishra PK, Burger RL, Bettendorf AF, Jobe PC, Dailey JW. Evidence that carbamazepine and antiepilepsirine may produce a component of their anticonvulsant effects by activating serotonergic neurons in genetically epilepsy-prone rats. J Pharmacol Exp Ther. 1992;261:652-659.
8.    Ropert N, Guy N. Serotonin facilitates GABAergic transmission in the CA1 region of rat hippocampus in vitro. J Physiol. 1991;441:121-136.
9.    Loscher W. Pharmacology of glutamate receptor antagonists in the kindling model of epilepsy. Prog Neurobiol. 1998;54:721-741.
10.     White HS. Mechanisms of action of antiepileptic drugs. Epilepsia. 1999;40(suppl 5):S2-S10.
11.     Olsen RW, DeLorey TM. GABA and glycine. In: Siegel MJ, Agronoff BW, Albers RW, Molinet PB, eds. Basic Neurochemistry: Molecular, Cellular and Medical Aspects. 6th ed. Philadelphia, Pa: Lippincott–Raven Publishers; 1999:335-346.
12.     Marshalec W, Narahashi T. Use-dependent pentobarbital block of kainate and quisqualate currents. Brain Res. 1993;608:7-15.
13.     Kramer LD, Reife RA. Topiramate. In: Engel J, Pedley TA, eds. Epilepsy: A Comprehensive Textbook. Philadelphia, Pa: Lippincott–Raven Publishers; 1997:1593-1598.
14.     Sommerville K. Tiagabine. In: Engle J, Pedley TA, eds. Epilepsy: A Comprehensive Textbook. Philadelphia, Pa: Raven Press; 1997:1645-1653.
15.     Genton P, Van Vleymen B. Piracetam and levetiracetam: close structural similarities but different pharmacological and clinical profiles. Epilepsy Disord. 2000;2:99-105.
16. Lamotrigine [package insert]. Research Triangle Park, NC: Glaxo Wellcome, Inc; 1999.
17.     Calabrese JR, Bowden CL, Sachs GS, Ascher JA, Monaghan E, Rudd GD. A double-blind placebo-controlled study of lamotrigine monotherapy in outpatients with bipolar I depression. J Clin Psychiatry. 1999;60:79-88.
18.     Collins SL, Moore RA, McQuay HJ, Wiffen P. Antidepressants and anticonvulsants for diabetic neuropathy and postherpetic neuralgia: a quantitative systematic review. J Pain Symptom Manage. 2000;20:449-458.
19.     Pande AC, Davidson JR, Jefferson JW, et al. Treatment of social phobia with gabapentin: a placebo-controlled study. J Clin Psychopharmacol. 1999;19:341-348.
20.     Sindrup SH, Jensen TS. Efficacy of pharmacological treatments of neuropathic pain: an update and effect related to mechanism of drug action. Pain. 1999;83:389-400.
21.     Bloom S. Trigeminal neuralgia: its treatment with a new anticonvulsant drug. Lancet. 1962;1:839-840.
22.     Bloom S. Tic douloureux treated with new anticonvulsant drug. Lancet. 1963;9:285-290.
23.     Tremont-Lukats IW, Megeff C, Backonja MM. Anticonvulsants for neuropathic pain syndromes. Drugs. 2000;60:1029-1052.
24.     Backonja M, Beydoun A, Edwards KR, Bernstein P, Magnus-Miller L. Gabapentin for the symptomatic treatment of painful neuropathy in patients with diabetes mellitus: a randomized controlled trial. JAMA. 1998;280:1831-1836.
25.     Rowbotham M, Harden N, Stacey B, Bernstein P, Magnus-Miller L. Gabapentin for the symptomatic treatment of postherpetic neuralgia: a randomized controlled trial. JAMA. 1998;280:1837-1842.
26.     Nicholson B. Gabapentin use in neuropathic pain syndromes. Acta Neurol Scand. 2000;101:359-371.
27.     Bajwa ZH, Sami N, Warfield CA, Wootton J. Topiramate relieves refractory intercostal neuralgia. Neurology. 1999;52:1917.
28.     Edwards KR, Glantz MJ, Button J, et al. Efficacy and safety of topiramate in the treatment of painful diabetic neuropathy: a double-blind, placebo-controlled study. Neurology. 2000;54(suppl 3):147.
29.     Lipton RB, Stewart WF. Migraine in the United States: a review of epidemiology and health care use. Neurology. 1993;43(suppl 3):S6-S10.
30.     Lipton RB, Stewart WF, Simon D. Medical consultation for migraine: results from the American Migraine Study. Headache. 1998;38:87-96.
31.     Klapper J. Divalproex sodium in migraine prophylaxis: a dose-controlled study. Cephalalgia. 1997;17:103-108.
32.     Silberstein SD, Collins SD. Safety of divalproex sodium in migraine prophylaxis: an open-label, long-term study. Headache. 1999;39:633-643.
33.     Matthew NT, Rapoport A, Saper J, et al. Efficacy of gabapentin in migraine prophylaxis. Headache. 2001;41:119-128.
34.     Edwards KR. Migraine treatment and prophylaxis. Paper presented at: Headache World 2000; September 2000; London, England.
35.     Potter DL. A double-blind, randomized, placebo-controlled study of topiramate in the prophylactic treatment of migraine with and without aura. Paper presented at: Headache World 2000; September 2000; London, England.
36.     Connor, G. Treatment of benign essential tremor with topiramate. Paper presented at: The 28th Annual Meeting of the Southern Clinical Neurological Society; January 13, 2001; Puntarenas, Costa Rica.

Dr. Shelton is assistant professor of psychiatry and head of clinical drug trials in the Mood Disorders Program in the Department of Psychiatry at Case Western Reserve University School of Medicine in Cleveland, Ohio.

Dr. Calabrese is professor of psychiatry and director of the Mood Disorders Program in the Department of Psychiatry at Case Western Reserve University School of Medicine.

Acknowledgments: Drs. Shelton and Calabrese have received grant support and honoraria from Glaxo- SmithKline Pharmaceuticals. No financial support was received for this particular work. 



What was the rationale behind the development of lamotrigine (LTG) as a mood stabilizer? Patients demonstrated improvements in mood and sense of well-being during the clinical trials phase of LTG development as an antiepileptic drug. There were theoretical reasons to suppose that LTG might possess mood-stabilizing properties; mood swings may be associated with the kindling process, as are seizures. The different phases of bipolar disorder are not equally amenable to treatment. Pharmacotherapy of bipolar disorder must address both stabilization “from above” and “from below.” Bipolar depression and rapid-cycling bipolar disorder are particularly refractory to treatment with lithium and carbamazepine, and it is evident that further treatment options are needed for refractory mood states. Bipolar I depressed patients receiving LTG dosages of 200 mg/day and 50 mg/day showed significant improvement compared with placebo on several measures of depression. In addition, LTG was shown to be a useful treatment for patients with rapid-cycling bipolar II disorder. Furthermore, LTG was shown to be effective in preventing depressive episodes associated with bipolar I disorder over an 18-month randomized phase. LTG has not been shown to be effective in the treatment of mania or unipolar depression. Primary care providers and psychiatrists have been reluctant to prescribe LTG for bipolar disorder because of the drug’s tendency to cause rash; improved titration schedules have resulted in a dramatic reduction in the incidence of this side effect. A series of controlled studies investigating the use of LTG in bipolar disorder is in progress.



During the clinical development of lamotrigine (LTG) as a treatment for intractable seizures, anecdotal reports of mood improvements in LTG-treated patients were obtained.1,2 In 1994, Smith and colleagues2 pointed out that although reduced seizure frequency is an established benefit of LTG treatment, it remained unclear how to determine whether the reduction justified any inherent toxicity. They reasoned that resources are limited in treatment-refractory epilepsy. Thus, passing up an antiepileptic drug (AED) that might be of value to specifically defined patient subgroups is undesirable. Smith and colleagues concluded that there was a need to evaluate other AED efficacy measures that might be more sensitive than seizure frequency. Reasonable candidates, they thought, might be seizure severity and quality-of-life reports.

Using a crossover design, the investigators administered add-on LTG to 81 patients with various types of epilepsy. The patients were already receiving either enzyme-inducing AEDs (n=56) or both enzyme inducers and valproate (n=25). The principle variable of interest was seizure frequency. Among the secondary response variables were patients’ subjective reports of seizure severity, anxiety, depression, self-esteem, mastery, happiness, and mood. Results indicated no difference in the levels of depression reported by patients receiving LTG and those receiving placebo (PBO), but LTG-treated patients reported significantly higher levels of happiness and mastery, or perceived internal locus of control. There was no correlation between perceived happiness and changes in seizure frequency or severity.

The investigators concluded that LTG has an effect on mood independent of its antiepileptic effect. However, the study was limited by its choice of affective measures and the results were open to interpretation. There was no explanation offered for the fact that improvements were reported in self-esteem, mastery, and happiness, yet no comparable effect was seen on measures of anxiety and depression. The results of the mood analysis were discarded entirely because of a large variance. Because the study was constructed by a “standard design” we presume it was double-blinded, although that was not explicitly stated.


Lamotrigine and Bipolar Depression

Open Studies

To date, there have been approximately 16 open studies of LTG in the treatment of bipolar depression. The largest and most recent3 was an open 48-week trial of LTG as either add-on (n=60) or monotherapy (n=15) in patients with bipolar I and bipolar II disorder. Forty-one of the patients (55%) were rapid cyclers and 34 were not. Improvement from baseline was seen in patients with and without rapid cycling. Rapid cyclers showed less improvement than nonrapid cyclers in severe mania, but about equal improvement in mild-to-moderate mania and depression. Nonrapid cyclers showed greater improvement in severe manic symptoms than in depressive symptoms. This result is consistent with findings on valproate reported from this laboratory in the early 1990s4,5; evidence suggested more antimanic than antidepressant effects.


Controlled Studies

In the first double-blind, PBO-controlled, parallel-group evaluation of the efficacy of LTG monotherapy in bipolar depression, Calabrese and colleagues6 examined 195 depressed adult outpatients with bipolar I (not bipolar II) disorder for 7 weeks at 12 sites in the United States, 2 sites in the United Kingdom, and 2 sites in Australia. Sixty-six patients received PBO tablets, 63 received LTG 50 mg (25 mg BID), and 66 received LTG 200 mg/day (100 mg BID). Patients were “stratified” to balance the presence or absence of recent treatment with lithium, defined as presence or absence of plasma levels of at least 0.4 mmol/L or dosing of 600 mg/day for at least 1 month.

In contrast to early work by Smith and colleagues,2 response variables consisted of measures customarily used in studies of mood disorders—the Hamilton Rating Scale for Depression (HAM-D), the Montgomery-Asberg Depression Rating Scale (MADRS), the Mania Rating Scale (MRS, consisting of the first 11 items from the Schedule for Affective Disorders and Schizophrenia–Change Version), and the Clinical Global Impression Scales for Severity and Improvement (CGI-S and CGI-I, respectively). Analysis of variance was used to test for group differences in response variables at screening, baseline, day 4 of treatment, and weekly thereafter. A last observation carried forward (LOCF) analysis was also employed at the same points, as well as a responder analysis to detect any differences in the rate of response.

The LOCF analysis corrected any bias introduced by patients who dropped out of the study early, possibly before a drug effect was detectable. Results of the study showed significant differences between groups on most efficacy variables in both the LOCF and the observed endpoint data. Patients on LTG 200 mg showed improvement over PBO on all measures except the LOCF analyses of the 17-item and the 31-item HAM-D, and the 17-item HAM-D-observed analyses. Patients receiving LTG 50 mg also showed responses on major efficacy variables, but not as marked as those shown by the group taking LTG 200 mg. The effect of lithium pretreatment stratification was noncontributory. Importantly, LTG was not associated with switch rates that exceeded those of PBO, suggesting that an antidepressant effect was observed without evidence of destabilization.

Frye and colleagues7 have published the results of a controlled comparative study on the efficacy of LTG and gabapentin compared to PBO. Thirty-one patients with refractory bipolar and unipolar mood disorders were randomly assigned and then crossed over to each of the three 6-week monotherapy evaluations. LTG, but not gabapentin, was shown to possess acute antidepressant properties in depressed patients with bipolar disorder, compared with PBO.


Lamotrigine and Mania

In two separate PBO-controlled multicenter trials, LTG failed to demonstrate efficacy superior to that of PBO in acutely manic patients. The first trial lasted 3 weeks and compared LTG 50 mg with PBO, whereas the second trial employed 6 weeks of blinded augmentation and compared LTG 200 mg with PBO.8


Long-Term Efficacy of Lamotrigine

The long-term mood-stabilizing properties of LTG have been compared with lithium and PBO. Recently, manic patients (N=349) were enrolled in an 18-month maintenance study and randomized to maintenance therapy after stabilization on LTG monotherapy.9 Patients were then randomized to LTG (n=59), lithium (n=46), or PBO (n=70). Both LTG and lithium were shown to be significantly better than PBO in both analysis of survival and time to intervention for a mood episode. However, LTG was primarily effective in the prevention of depressive episodes, whereas lithium was primarily effective in the prevention of manic episodes.

A 27-site randomized, double-blind, PBO-controlled study of LTG prophylaxis in rapid cyclers was recently published,10 constituting the first controlled study of rapid cyclers. A pure cohort of 182 patients with bipolar I and bipolar II disorder was stabilized on LTG adjunctive therapy; the initial and ancillary psychotropic medications were then gradually withdrawn. At that point, 93 patients were randomized to LTG (titrated up to 500 mg/day) and 89 to PBO. Seventy-one percent had bipolar I disorder; stratification ensured a balanced assignment of patients with bipolar I and bipolar II disorder to each treatment group. Efficacy variables were time to a relapse-preventing intervention, survival time in study (time to dropout for any reason, including intervention), the 17-item HAM-D, MADRS, MRS, CGI-S, GAS, and retrospective life charting.

There was no significant difference  between LTG and PBO groups in time to intervention, but the median LTG time to intervention was 18 weeks, compared with 12 weeks for PBO. The intergroup survival analysis was significant (P<.04). Median survival times were 14 weeks for LTG and 8 weeks for PBO. Importantly, stratification analyses showed consistently greater affective improvement in patients with bipolar II disorder compared to those with bipolar I disorder—an unexpected result in light of previously documented efficacy of LTG in bipolar I disorder. This finding supports the validity of bipolar II as a legitimate bipolar subtype according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition11 (DSM-IV). It also underscores the observation by Smith and colleagues,2 who suggested that it is important to examine drugs for efficacy in specific patient subgroups, even in the face of possible undesirable side effects.


Lamotrigine and Unipolar Depression

There has been one case study reported12 of a positive response to LTG when added to buspirone. The response was maintained after the discontinuation of buspirone at 6 weeks and for 16 months thereafter. To date, 371 unipolar depressed patients have received LTG monotherapy in three controlled studies.13,14 All three studies failed to show significant LTG treatment effects. One study7 examined the efficacy of LTG and gabapentin in a mixed cohort of 38 patients with treatment-refractory unipolar or bipolar depression, using a double-blind, randomized, crossover design. Patients in the LTG cohort showed significantly more improvement in symptoms than those taking PBO; patients taking gabapentin showed an intermediate degree of improvement. Improvement appeared to increase with increasing bipolarity (ie, unipolar<bipolar II<bipolar I.)



The use of LTG has been shown to be associated with an increased prevalence of benign rash and, rarely, more serious rashes. In all PBO-controlled, multicenter studies comparing LTG (n=979) with PBO (n=935), benign rash rates were 9.4% versus 8.2%, serious rash rates were 0.1% versus 0%, and no cases of Stevens-Johnson syndrome or toxic epidermal necrolysis were observed. Rash occurring within 5 days of beginning treatment is usually benign and often caused by other factors such as contact dermatitis and insect bites. Benign rash (present in 9% of adults) shows no systemic involvement, changes in complete blood cell count, or changes in differential cell count. A reasonable response is to retain or reduce and maintain the current dose for 10–14 days and follow clinically. Loratadine (10 mg/day) plus a topical agent such as 0.5% betamethasone can be used for pruritus. It is important to engage the patient in the treatment process. Patients must report any rash to the psychiatrist, and unexplained rashes should immediately be referred to a dermatologist.

Of greater concern are serious rashes, which necessitate the discontinuation of LTG treatment. Presentations and risk factors in the occurrence of such patients have been described. Initial risk factors include having tested positive for the human immunodeficiency virus (a 100-fold increase in incidence), the presence of systemic lupus erythematosus (a 10-fold higher incidence), corticosteroid treatment (a 4.4-fold increase), and history of a primary relative having manifested a serious rash after LTG treatment (as with other AED hypersensitivity reactions, as much as a 25% increase).15-17 Symptoms include fever, sore throat, malaise, facial involvement (eg, edema, involvement of lips, mouth, or eyes), and cervical lymphadenopathy. The rash may also be generalized (confluent). Hematologic changes may include neutropenia, thrombocytopenia, atypical lymphocytosis, leukocytosis, delayed eosinophilia, a left shift with toxic neutrophils present, and liver function test results that may be three times their normal values. Urinalysis may be remarkable for proteinuria and the presence of white blood cells.18 Treatment is by discontinuation of LTG and any concurrently administered enzyme inhibitor.



During the clinical development of LTG as an AED, anecdotal evidence suggested that the drug might improve the quality of life for many patients. Later, case studies, open trials, and blinded, PBO-controlled, randomized studies demonstrated clearly that LTG is effective in the treatment of bipolar disorder. The drug does not appear to be equally effective in all phases of the illness. Both open and PBO-controlled data suggest that LTG is more effective in the acute and prophylactic management of the depressed phase than in mania; double-blinded, PBO-controlled data suggest that the drug is useful in the treatment of patients with rapid-cycling bipolar disorder, particularly in those with bipolar II. This finding supports the validity of both rapid cycling and bipolar II as valid modifications to the DSM-IV diagnosis of bipolar disorder. The efficacy of LTG monotherapy in these two subgroups may be due to the frequent presentation of such patients in the depressed phase of the illness.

It has long been understood that treatment of bipolar disorder requires “stabilization from above” (ie, amelioration of manic and hypomanic symptoms), and that available medications such as divalproex and lithium are more effective in the treatment of (hypo-) mania than in depression. It is becoming equally clear that treatment must provide “stabilization from below” (ie, improvement in neurovegetative signs), with agents effective in depression.14 There is emerging consensus that complex regimens of combination therapy will be necessary in order to accomplish this in the immediate future. The possibility that there may exist an agent equally effective in the management of both phases of the illness awaits further investigation.  PP



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