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Effects of Long-Term Treatment With Topiramate on Mood and Body Weight in Patients With Bipolar Disorders

David B. Marcotte, MD

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Primary Psychiatry. 2003;10(3):63-68

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Fibromyalgia and Psychopathology in a Community Hospital Emergency Room

P. Waverly Davidson III, MD, FACP

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Primary Psychiatry. 2003;10(3):69-73

 

Dr. Davidson is clinical professor of psychiatry and behavioral sciences in the Department of Psychiatry at the University of Southern California School of Medicine, and consulting psychiatrist at the Pacific Hospital of Long Beach Outpatient Psychiatric Clinic, in Long Beach California.

Disclosure: The author reports no financial, academic, or other support was received for this work.

Please direct all correspondence to: P. Waverly Davidson, MD, PO Box 15778; Beverly Hills, CA 90929.



Abstract

Objective: Using a retrospective chart review, the authors investigated the rate of occurrence of primary and posttraumatic fibromyalgia among 204 patients being assessed for pain management at a community hospital emergency room (ER). The presence of psychopathology was investigated as well.

Background: The relevant medical literature was summarized in regard to the comorbidity of fibromyalgia and depressive disorders, the comorbidity of fibromyalgia and somatoform disorders, and the comorbidity of fibromyalgia and other neurologic and medical syndromes.

Methods: This study was conducted at Pacific Hospital of Long Beach, CA. The author reviewed 204 charts of patients with musculoskeletal pains who were assessed in the ER between July 1999 and March 2001, 10 of whom had been previously diagnosed with fibromyalgia.

Results: Although fibromyalgia constitutes 20% to 30% of a typical rheumatologist’s practice, only 5% of the ER patients were diagnosed with the condition. As was summarized in the literature review, there were multiple psychiatric diagnoses in the 10 fibromyalgia patients, as well as disabilities, multiple outpatient psychiatric treatments, and use of analgesics and psychotropic medications. All 10 patients were receiving some form of monetary compensation and none were currently employed.

Conclusion: It would appear that fibromyalgia is a somatoform disorder more aptly described as a “multisomatoform disorder” because of the basic symptoms of widespread musculoskeletal pain, fatigue, tender points on physical examination, and due to its association with victimization attitudes, family history of alcoholism, depression, or somatization, childhood sexual abuse, and association with certain neurologic syndromes such as carpel tunnel syndrome, chronic fatigue syndrome, work absenteeism, and disability.

Discussion: Guidelines to help primary care physicians distinguish which acute fibromyalgia patients are likely to become chronic fibromyalgia patients are presented, followed by guidelines for future investigations into the psychopathology associated with fibromyalgia.

 

Introduction

Fibromyalgia is a common, complex, chronic, and controversial condition of unestablished etiology,1 that is characterized by widespread musculoskeletal pain, multiple tender pressure points, and profound fatigue. Although the condition is distinct from articular joint disease, ironically it is referred to as “rheumatism of the muscles.” The condition may be associated with other syndromes of uncertain etiology such as chronic fatigue syndrome (CFS), irritable bowel syndrome (IBS), and carpel tunnel syndrome (CTS), and is often accompanied by headaches, insomnia, depression, and exhaustion.

This study is a retrospective chart review investigating the occurrence rate of fibromyalgia among patients assessed for pain management in the emergency room (ER) of a general hospital. The study also investigates the comorbid psychopathology of fibromyalgia patients, which can help primary care physicians better treat such patients or know when to refer them to specialists.

 

Background

Ayd2 found that fibromyalgia had an estimated prevalence of 15% to 20% in rheumatology clinics and is the most common cause of widespread chronic pain. The estimated prevalence of fibromyalgia in the general community is 2% for both sexes; 3.4% for women and 0.5% for men.3,4 Marden and colleagues5 pointed out that fibromyalgia is the second most common diagnosis in American rheumatology clinics, while Schultes and colleagues6 indicated that 1% to 7% of the German population suffer from fibromyalgia. According to Hadler,7 20% of Americans awaken frequently with “morning stiffness” lasting as along as 30 minutes and seek no medical attention at all. In pointing out the difficulty of determining the presence of focal “tender points,” Sola and colleagues8 reported that 50% of their patients can be made to be aware of such tender points during a physical exam, especially of the pectoral girtle muscles, and still be in robust good health.

In the past, a wide spectrum of chronic and subchronic musculoskeletal conditions had been commonly called “fibrositis.”9 In 1990, based on a multi-center study,10 the American College of Rheumatology (ACR) set the criteria for the classification and diagnosis for the favored, more descriptive term, “fibromyalgia.” At present, the diagnosis of fibromyalgia must include the finding of widespread, chronic musculoskeletal pain, and mild (or greater) tenderness in at least 11 of 18 specified tender points located by digital palpation.11

In a study by Andersson and colleagues,12 22% of 1,609 Swedes with widespread pain of >3 months’ duration fit the ACR criteria for fibromyalgia. However, the 78% who did not fulfill the fibromyalgia criteria had similar profiles to the group with fibromyalgia in regard to fibromyalgia spectrum of problems, including depression, anxiety, work, absenteeism, and pain intensity.

In terms of prognosis, McFarlane and colleagues13 studied 141 English men and women in Manchester and found that only 35% of their subjects with chronic widespread pain still had pain 2 years later. Thus they speculated that most fibromyalgia patients who do not receive treatment for their symptoms, tend to make spontaneous recoveries. How then, can a primary care physician predict which fibromyalgia patients will improve with little or no treatment and which ones will need specialized rheumatological care?

 

Posttraumatic Fibromyalgia

Before the ACR published their report in 1990, the terms “fibrositis” and “fibromyalgia” were used interchangeably.10 The term “primary fibromyalgia” was introduced when describing a patient without any other medical disorder or disease that could affect fibromyalgia symptoms; the terms “secondary fibromyalgia” or “concomitant fibromyalgia” was used when other medical disorders or diseases were also present. The multicenter committee of the ACR which had devised the two terms, then disavowed the existence of any significant clinical difference between the two. The term “posttraumatic fibromyalgia” (PT fibromyalgia) refers to the fibromyalgia symptoms present which have arisen only after trauma (usually motor vehicular accidents), and are not synonymous with “secondary fibromyalgia.”

Nielsen and Merskey14 reported that the diagnosis of PT fibromyalgia has not been adequately validated and that reports of high rates of PT fibromyalgia among those fibromyalgia patients are not well designed and are often derived from uncontrolled studies. In contrast, Buskila and colleagues,15 in a well-designed study, reported 102 patients with nonspecific soft tissue neck injuries, 90% of whom had classical “whiplash” symptoms, and compared the occurrence of PT fibromyalgia in these patients with the occurrence of PT fibromyalgia in 59 patients with leg fractures. They offered no clear explanation as to why there was a higher prevalence of PT fibromyalgia (21.7%) in the neck injury patients, but only a prevalence of 1.7% of PT fibromyalgia in the more severely injured leg fracture patients, after 12.4 months from the time of injury.

Turk and colleagues16 described three distinct profiles of fibromyalgia patients: dysfunctional, interpersonally distressed, and adaptive copers. In a second study by Turk and colleauges,17 the researchers explored the differences between PT fibromyalgia patients and fibromyalgia patients, with 46 patients in each diagnostic category matched for age and duration of pain. While they found that the PT fibromyalgia patients used more narcotic analgesics, more nerve blocks, more transcutaneous electric nerve stimulator units, more physical therapy, and were more likely to fall into the “dysfunctional” and interpersonally distressed” profiles, the fibromyalgia patients were more often classified as “adaptive copers.” There were no significant differences between the two groups in terms of legal-financial incentive, suggesting that the PT fibromyalgia patients were not merely seeking monetary gains, but perhaps indicating that these PT fibromyalgia patients had more subconscious unmet needs, as in the psychodynamics of somatoform disorders.

 

Comorbidity of Fibromyalgia and Depression

Goldenberg and Don18 administered the Diagnostic Interview Schedule (DIS) to 31 fibromyalgia patients at the Newton-Wellsley Hospital in Boston, using 14 patients with rheumatoid arthritis as controls. In 1989, this was the first time that a structured interview using criteria of the Diagnostic and Statistical Manual of Mental Disorders, Third Edition19 was used with fibromyalgia patients. When the researchers expanded their fibromyalgia patient pool from 31 to 82, they found that 60% had a lifetime history of major depression and 21% had current major depression, in contrast to the current rate of 8.7% in the rheumatoid arthritis group. However, 3 years later, Ahles and colleagues20 and Yunus and colleagues21 made similar studies and did not find significant difference in major depression between groups of patients with fibromyalgia and rheumatoid arthritis.

In a 1999 study22 involving four tertiary care centers in Washington, DC, San Diego, CA, Stonybrook, NY, and Charleston, SC, 73 patients were evaluated for major depression based on criteria of the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV)23 using the Structured Clinical Interview, the Raad 36-Item Health Survey, and multiple self-report measures. The fibromyalgia patients were found to have a high lifetime prevalence and current incidence of major depression (68% and 22%, respectively). In addition, 16% had a lifetime prevalence of panic disorder as well as a 7% incidence of current panic disorder.

Katz and Krabitz24 evaluated 425 first-degree relatives of 55 females and 5 males with fibromyalgia and concluded that there was a subgroup of fibromyalgia patients with major depression, whose family members had both depression and alcoholism, and who were more likely to have had an abusive childhood as a result of this family dysfunction. This theme of physical and emotional abuse and neglect is also reported by Van Houdenhove and colleagues,25 who showed a higher prevalence of abuse in 96 patients with fibromyalgia and CFS compared with two other control groups—a chronic disease group and a healthy group.

 

Comorbidity of Fibromyalgia and Somatoform Disorders

Kirmayer and colleagues26 studied 20 fibromyalgia patients and 23 rheumatoid arthritis controls and found no significant difference in current or lifetime depression. While they did not conclude, as other investigators did, that fibromyalgia was a type of somatized depression, they did report that the fibromyalgia patients had “more somatic symptoms of obscure origin,” had more numerous somatic complaints, had endured more surgical procedures, and had sought medical help more frequently.

In 1991, Maccrocchi27 reported a case of conversion disorder presenting as fibromyalgia in which he was able to trace the fibromyalgia symptoms to specific psychological trauma. He speculated that his case, unlike those of classical conversion disorder, wherein psychological events lead to neurologic symptoms, had shown that psychological events had led to fibromyalgia symptoms.

Kroenke and colleagues28 have also noted that fibromyalgia patients are not classical cases of somatization disorder, but have proposed that a new disorder be added to the spectrum of DSM-IV somatoform disorders; this new disorder, to be called “multisomatoform disorder,” would fall between “full” and “abridged” somatization criteria, and would include functional impairment, psychiatric comorbidity, family dysfunction, and health care utilization costs. He opined that fibromyalgia would be properly included in this new multisomatoform designation.

McBeth and colleagues29 completed a prospective population-based study of 1,658 adults, using the General Health Questionnaire, the Somatic Symptom Checklist, the Fatigue Questionnaire, and the Illness Attitude Scale. Half of his subjects were pain-free and half had pain symptoms, but not widespread or chronic pain. At 1-year follow-up, 825 subjects with pain were re-evaluated, and it was found that 8% of these individuals, who had displayed many aspects of somatization earlier, were the ones who developed widespread chronic pain, a cardinal symptom of fibromyalgia.

 

Comorbidity of Fibromyalgia and Other Disorders

Sleep disturbances, tension headaches, and migraine headaches occur commonly in fibromyalgia patients. Malt and colleagues30 reported that 27% of 45 female patients studied had lifetime prevalence of panic disorder. Sivri and colleagues31 reported that 42% of IBS patients had fibromyalgia, whereas Veale and colleagues32 reported a much higher occurrence (65%) of fibromyalgia among IBS patients. Yunus and Aldag33 reported restless legs syndrome in 31% of fibromyalgia patients compared to 15% in rheumatoid arthritis patients and 2% in control subjects. Andreu and colleagues34 reported that CTS is common in fibromyalgia patients, but that fibromyalgia was very rare in the 102 CTS patients he studied. Dohrenbusch and Gruterich35 reported an association between fibromyalgia and Sjogren’s syndrome.

 

Method

The purpose of this study was to determine the rates of patients diagnosed with primary fibromyalgia and with PR fibromyalgia occurring in a community hospital ER by use of a retrospective chart review, and to determine the nature of any psychopathology co-occurring in these patients.

Pacific Hospital of Long Beach, CA, is a full-service 171-bed hospital with a 24-hour ER. Between July 1999 and March 2001, 204 individuals presented themselves to the ER with the International Classification of Diseases, Ninth Edition diagnostic code of 729.1.36 This code covers the following categories: unspecified myalgia and myositis, fibromyositis, and fibromyositis not otherwise specified. The charts of these 204 patients were reviewed to determine which among them were diagnosed with fibromyalgia or PT fibromyalgia and to determine if any psychopathology was present in the fibromyalgia and PT fibromyalgia patients.

Many of the 204 patients had made multiple presentations to the ER for treatment of their pain symptoms so that the total number of ER visits was 309.

 

Results

Of the 204 patients, 22 had musculoskeletal chest pains for which cardiac pathology was ruled out. Nevertheless, these 22 charts had been retrieved with the 729.1 diagnostic code. Thirteen patients presented with myositis as a result of a motor vehicular accident or a slip-and-fall accident; 40 patients had musculoskeletal pains or myositis in addition to acute panic episodes with hyperventilation symptoms; 43 patients were acutely intoxicated with alcohol and/or drugs and had minor lacerations in addition to painful musculoskeletal soft tissue injuries or myositis directly related to their intoxication; 76 patients had various types of musculoskeletal pains associated with osteoarthritis, lower back pain, disc disease, migraine headaches, or other forms of myositis, and had previously been diagnosed with a major mental illness such as schizoaffective disorder, schizophrenia, bipolar disorder, or major unipolar depression. Ten patients, representing 5% of the total group, had been previously diagnosed as having fibromyalgia prior to their visits to the ER.

Of the 10 fibromyalgia patients whose charts were retrieved, 8 were female (average age=49 years) and 2 were male (ages 56 and 31). Both males and two of the females had been diagnosed with PT fibromyalgia. Of the six females with primary fibromyalgia, three had comorbid diagnoses for generalized anxiety disorder, four had been also diagnosed with minor depression, and one was diagnosed with current drug addiction and had been previously diagnosed with schizoaffective disorder. Three females had lifetime histories of alcohol or drug addiction; two females had diagnoses of temporomandibular joint syndrome; one female was also diagnosed with IBS.

A careful new chart review of the 10 fibromyalgia patients showed that all patients with PT fibromyalgia (two males and two females) were currently receiving social security disability benefits or workers’ compensation benefits; one of the males had received five epidural blocks for his fibromyalgia during the 21 months of the study. The schizoaffective female had two inpatient psychiatric hospitalizations during the study. Two of the six females with primary fibromyalgia had previous treatments for CTS and four primary fibromyalgia females had been treated for their comorbid psychopathology with a total of 15 outpatient psychiatric clinic visits in addition to their ER visits during the time frame of the study.

All eight females were treated with analgesics for their fibromyalgia or PT fibromyalgia symptoms and psychotropic medications for their psychiatric symptoms; the two males were receiving analgesic medications for their PT fibromyalgia symptoms. In addition to the four patients receiving some form of monetary compensation or benefits on the basis of their PT fibromyalgia symptoms, all of the remaining six primary fibromyalgia females were also recipients of monetary benefits, based not just on primary fibromyalgia alone, but on the totality of their several comorbid diagnoses as well.

 

Discussion

One of the 2-fold purposes of this study was to investigate the rate of occurrence of fibromyalgia among patients assessed for pain management in a community hospital ER. With a retrospective chart review of 204 patients over a 21-month period, 5% had been diagnosed with fibromyalgia. If patients with fibromyalgia constitute 20% to 30% of the clinical practice of some rheumatologists, it would appear that they present themselves to local ER only for pain management and not for diagnoses.

Due to the comorbidity of so many varying neurologic syndromes and psychiatric conditions, one can begin to understand the controversy that often surrounds the validity of the diagnosis of this chronic widespread pain syndrome. It is because of this comorbidity and chronicity that so many fibromyalgia patients seek the emotional support of fibromyalgia self-help groups, fibromyalgia advocacy groups, and more sympathetic rheumatologists.37-41 It can also be speculated that fibromyalgia patients who do not feel that they get adequate management for their symptoms turn to the ERs for pain relief. Many turn to litigation as well, making inadequate medical treatment a financial burden on the population at large; it is estimated that $10 billion is spent annually in America on health care for the 6 million fibromyalgia patients, including litigation costs.42,43

All 10 of the fibromyalgia patients whose charts were reviewed in this study (96 primary fibromyalgia and 4 PT fibromyalgia patients) were receiving monetary benefits.

 

Conclusion

It is clear that a wide range of psychopathology existed in the background of these 10 patients, perhaps in their families as well, and in the multiple neurologic and psychiatric diagnoses most of them have in addition to the fibromyalgia /PT fibromyalgia.

Fibromyalgia was described in the early 1880s but it only recently emerged as a distinct syndrome in 1990 when fibromyositis was renamed by a committee of the American College of Rheumatology. Seven of the 10 patients (70%) reported here who habitually use a local ER for pain flare-ups but who report to rheumatologists or primary care physicians for diagnostic validation of their symptoms, have either a current or lifetime comorbidity for psychiatric diagnoses, mostly depression. This percentage is comparable with that of Goldenberg and Don,11,18 Crook and colleagues,44 and Granges and colleagues.45

There seems to be a subgroup of fibromyalgia patients prone to depression themselves, with family histories of depression, as reported in the studies by Epstein and colleagues22 and Katz and Krabitz.24 There are other fibromyalgia subgroups with CFS, IBS, sleep disturbances, restless legs syndromes, and other disorders.

Since both patients with depression and those with fibromyalgia respond often to antidepressants, there is a tendency to link them in terms of causation. However, most fibromyalgia patients seen in rheumatology clinics do not have treatable major depression nor are they seeking treatment for depression from their rheumatologists. Thus, Ayr2 referred to an Iowa study reporting that “fibromyalgia has been associated with anxiety and depression in 50% to 90% of patients seeking treatment for fibromyalgia.” There is no suggestion that these fibromyalgia patients also sought treatment for their depression, but they may have reported depressive symptoms when asked about their lifetime experience.

The question of somatization is an important one in terms of prognosis, as noted by the studies of Kirmayer and colleagues,26 Macciocchi,27 Kroenke and colleagues,28 and McBeth and Selman,46 which note that the more likely it is that the basic symptoms of fibromyalgia (widespread musculoskeletal pain, fatigues, and tender points) are associated with work, absenteeism, disability, victimization attitudes, psychiatric comorbidity, family history of alcoholism, depression or somatization, childhood sexual abuse, and/or neurological syndromes (such as CTS, degenerative disc disease, or migraine headaches), the more likely it is that those fibromyalgia symptoms will become chronic. This seems to be true for both primary fibromyalgia and PT fibromyalgia.

In addition, it it noted that once the fibromyalgia symptoms have become chronic, it is more likely that those fibromyalgia patients will be referred to rheumatologists. It is also more likely that their symptoms will fit into the multisomatoform disorder (MSD)described by Kroenke and colleagues28 in 1998, when they combined data from two studies (N=1,258) and proposed that MSD was an intermediate diagnosis between the abridged and full somatization disorder. The MSD?diagnosis included a patient’s disabilities, comorbid psychiatric diagnosis, family dysfunction, and use of health care facilities.

Guided by these insights, the primary care physician can more quickly predict which fibromyalgia patients will become pain-free with only the “morning stiffness” that Hadler7 describes, and which patients will require rheumatologists and/or psychiatrists for longer periods of care and pain management.

Future investigators should compare primary and PT fibromyalgia patients being currently treated for their comorbid psychiatric disorders, and those being treated in rheumatology clinics who are not in current psychiatric treatment (even though some psychiatric symptoms may be present), with matched groups of nonpatients in the community who were treated for primary or PT fibromyalgia in the past (including subgroups of patients who had and who did not have psychiatric disorders in the past) but who have completely recovered.

There should also be two distinct control groups: healthy individuals matched for age and gender with the other groups, who have never experienced any treatment for psychiatric symptoms or any pain syndromes, and another group of individuals, also age and gender matched, who currently or in the past have had painful musculoskeletal diseases other than primary fibromyalgia or PT fibromyalgia. Family history, various psychological tests, and pain inventory tests, should be obtained on all groups in such an extensive retrospective and prospective study. PP

 

References

1. Carette J, Bell MJ, Reynolds WJ, et al. Comparison of amitriptyline, cyclobezaprine, and placebo in the treatment of fibromyalgia: a randomized double-blind clinical trial. Arthritis Rheum. 1994;37:32-40.

2. Ayd FJ Jr. 1998 American Psychiatric Association Report. Psychiatr Times. 1998;8:4.

3. Wolfe F, Toss K, Anderson J, Russell IJ, Hebert L. The prevalence and characteristics of fibromaylgia in the general population. Arthritis Rheum. 1995;1:19-28.

4. Croft P, Schollum J, Silman A. Population study of tender point counts and pain as evidence of fibromyalgia in the general population. BMJ. 1994;6956:696-699.

5. Marden WD, Meenan RF, Felson DT, et al. The present and future adequacy of rheumatology manpower: a study of health care needs and physician supply. Arthritis Rheum. 1991;10:1209-1217.

6. Schultes H, Pirk O, Berger K, Schramm B, Pongratz D. Cost of illness in fibromyalgia: results of a feasibility study. Abstract presented at: 64th Annual Meeting of the American College of Rheumatology; May 2000; Neurenberg, Germany.

7. Hadler NM. Occupational Musculoskeletal Disorders. 2nd ed. Philadelphia, Pa: Lippincott Williams and Wilkins; 1999.

8. Sola AE, Rodenberger ML, Gettys BB. Incidence of hypersensitive areas in posterior shoulder muscles. Am J Phys Med. 1955;34:585-590.

9. Hudson JI, Hudson MS, Pliner LF, Goldenberg DL, Pope HG Jr. Fibromyalgia and major affective disorders: a controlled phenomenology and family history study. Am J Psychiatry. 1985;4:441-446.

10. Wolfe F, Smythe HA, Yunus MB, et al. The American College of Rheumatology 1990 Criteria for the Classification of Fibromyalgia: Report of the Multicenter Criteria Committee. Arthritis Rheum. 1990;2:160-172.

11. Goldenberg DL. Fibromyalgia syndrome a decade later: what have we learned? Arch Intern Med. 1999;8:777-785.

12. Andersson H, Ejlertsson G, Leden I, Rosenberg C. Characteristics of subjects with chronic pain, in relation to local and widespread pain reports. Scand J Rheumatol. 1996;3:146-154.

13. MacFarlane GJ, Thomas E, Papageiorgiou AC, Schollum J, Croft PR, Silman AJ. The natural history of chronic pain in the community: a better prognosis than in the clinic? J Rheumatol. 1966;9:1617-1620.

14. Nielsen WR, Merskey H. Psychosocial aspects of fibromyalgia. Curr Pain Headache Rep. 2001;4:330-337.

15. Buskila D, Neumann L, Vaisberg G, Alkalay D, Wolfe F. Increased rates of fibromyalgia following cervical spine injury: a controlled study of 161 cases of traumatic injury. Arthritis Rheum. 1997;3:446-452.

16. Turk DC, Okifuji A, Sinclair JD, Starz TW. Pain, disability, and physical functioning in subgroups of patients with fibromyalgia. J Rheumatol. 1996;7:1255-1262.

17. Turk DC, Okifuji A, Starz TW, Sinclair JD. Effects of type of symptom onset on psychological distress and disability in fibromyalgia syndrome patients. Pain. 1996;2-3:423-430.

18. Goldenberg DL. Psychiatric and Psychological Aspects of the Fibromyalgia Syndrome. Vol 15. Newton, MA: Arthritis-Fibrositis Center, Newton-Wellesley Hospital; 2000:105-114.

19.Diagnostic and Statistical Manual of Mental Disorders. 3rd ed. Washington, DC: American Psychiatric Assocation; 1980.

20. Ahles TA, Khan SA, Yunus MB, Spiegel DA, Masi AT. Psychiatric status of patients with primary fibromyalgia, patients with rheumatoid arthritis, and subjects without pain: a blind comparison of DSM-III diagnoses. Am J Psychiatry. 1991;12:1721-1726.

21. Yunus MB, Ahles TA, Aldag JC, Masi AT. Relationship of clinical features with psychological status in primary fibromyalgia. Arthritis Rheum. 1991;1:15-21.

22. Epstein SA, Kay G, Clauw D, et al. Psychiatric disorders in patients with fibromyalgia: a multicenter investigation. Psychosomatics. 1999;1:57-63.

23.Diagnostic and Statistical Manual of Mental Disorders. 4th ed. Washington, DC: American Psychiatric Association; 1994.

24. Katz RS, Kravitz HM. Fibromyalgia, common depression, and alcoholism: a family history study. J Rheumatol. 1996;1:149-154.

25. Van Houdenhove B, Neerinckx E, Lysens R. Victimization in chronic fatigue syndrome and fibromyalgia patients in tertiary care: a controlled study on prevalence and characteristics. Psychosomatics. 2001;1:21-28.

26. Kirmayer LJ, Robbins JM, Kapusta MA. Somatization and depression in fibromyalgia syndrome. Am J Psychiatry. 1988;8:950-954.

27. Macciocchi SN. Conversion disorder presenting as primary fibromyalgia. Psychosomatics. 1993;3:267-270.

28. Kroenke K, Spitzer RL, deGruy FV, Swindle R. A symptom checklist to screen for somatoform disorders in primary care. Psychosomatics. 1998;3:263-272.

29. McBeth J, McFarlane GJ, Benjamin S, Silman AJ. Features of somatization predict the onset of chronic widespread pain: results of a large population-based study. Arthritis Rheum. 2001;4:940-946.

30. Malt EA, Berle JE, Olafsson S, Lund A, Ursin H. Fibromyalgia is associated with pain disorders and functional dyspepsia with mood disorders: a study of women with random sample population controls. J Psychosom Res. 2000;5:285-289.

31. Sivri A, Cindas A, Dincer F, Sivri B. Irritable bowel syndrome. Clin Rheumatol. 1996;3:283-286.

32. Veale D, Kavanagh G, Fielding JF, Fitzgerald O. Primary fibromyalgia and the irritable bowel syndrome: different expressions of a common pathogenic process. Br J Rheumatol. 1991;3:220-222.

33. Yunus MD, Aldag JC. Restless legs syndrome and leg cramps in fibromyalgia syndrome: a controlled study. Br Med J. 1996;312:1339-1341.

34. Andreu JL, Ly-Pen D, deBias G, Sanchey-Olaso A. Prevalence of fibromyalgia in patients with carpel tunnel syndrome: a prospective primary case based study. Abstract presented at: the 64th Annual Meeting of the College of Rheumatology; May 2000; Neurenberg, Germany.

35. Dohrenbusch R, Gruterich M, Genth Z. Fibromyalgia and sjogren’s syndromes: clinical and methodological aspects. Rheumatology. 1996;55:19-27.

36. American Medical Association. International Classification of Diseases. 9th ed. Jones MK, ed. N. Valley City, UT: INGENIX Press; 2001.

37. McIlwain H, Bruce DF. The Fibromyalgia Handbook. New York, NY: Henry Holt & Co.; 1996.

38. Fransen J, Russell IJ. The Fibromyalgia Helpbook.St. Paul, MN: Smith House Press; 1996.

39. Starlanyl D, Copeland ME. Fibromyalgia and Chronic Myofascial Pain Syndrome. Oakland, CA: New Harbinger Publications; 1996.

40. Starlanyl D. The Fibromyalgia Advocate. Oakland, CA: New Harbinger Publishers; 1998.

41. Amand RP, Marek CC. What Your Doctor May Not Tell You About Fibromyalgia. Boston, MA:?Little, Brown, and Co.; 1999.

42. Aronoff GM, Markovitz A. AADEP position paper: fibromyalgia impairment and disability issues. Disability. 1998;8:1-10.

43. Wallace DJ, Hallegua DS. Quality of life, legal-financial, and disability issues in fibromyalgia. Curr Pain Head Rep. 2001;5:313-319.

44. Crook J, Weir R, Tunks E. An epidemiological follow-up survey of persistent pain sufferers in a family group practice and specialty pain clinic. Pain. 1989;36:49-61.

45. Granges G, Zilko P, Littlejohn G. Fibromyalgia syndrome assessment of the severity of the condition 2 years after diagnosis. J Rheumatol. 1994;21:523-529.

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Successful Concomitant Treatment of Raynaud’s Phenomena, Premenstrual Dysphoric Symptoms, and Bipolar Disorder With Oxcarbazepine and Venlafaxine

Hayne McMeekin, MD

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Primary Psychiatry. 2003;10(3):53-56

 

Dr. McMeekin is in private practice at Piedmont Psychiatric Associates in Rock Hill, South Carolina.

Disclosure: Dr. McMeekin is a regional speaker for Novartis Pharmaceuticals.

Please direct all correspondence to: Hayne McMeekin, MD, Piedmont Psychiatric Associates, PO Box 36024, Rock Hill, SC 29732-0500; Tel: 803-327-6103 ext. 233; Fax: 803-328-5443; E-mail: hmcmeekin@comporium.net.


 

Abstract

Stress in association with depression and anxiety has been increasingly defined in relation to the hypothalamic-pituitary axis, which regulates physical and emotional processes. Thus, is it possible that there are physical as well as emotional consequences to depression and anxiety associated with stress? This case study describes a patient’s psychological and physical findings during the process of successful resolution of the illness. Adiscussion of modulation of the hypothalamic pituitary adrenal axis and the sympathetic nervous system in relation to mood, anxiety, and pharmacotherapy follows.

 

Introduction

Perceived internal or external stress affects organ function via the hypothalamic-pituitary-adrenal axis (HPA) and the sympathetic nervous system. The central nervous system components of these two systems interact with each other on a regular basis.1 Stress causes the release of corticotrophin-releasing-factor (CRF) and subsequently adrenocorticotropic hormone (ACTH), which stimulates the adrenals to release cortisol. Cortisol at first acts to protect neurons from the chemical results of stress. With continued stress the body’s ability to control the HPA axis becomes impaired and with that, levels of cortisol, CRF, and glutamate become elevated. This increases the chance of neuronal toxicity and may be the reason for the hippocampal atrophy seen in chronic depression. Sympathetic activation from the locus ceruleus increases peripheral catecholamines. The circulating glucocorticosteroids and catecholamines (primarily norepinephrine) then act at diverse sites to produce wide-ranging effects across a number of systems.1-3 Many of these changes such as increases in alertness, respirations, and heart rate, and decreases in feeding, digestion, and sexual behavior, result in the fight-or-flight response to threat.1

Glutamate is the major excitatory neurotransmitter in the central nervous system. Mathew and colleagues3 have postulated that glutamate plays an important role in modulating the HPA axis and, therefore, mood and anxiety. Skolnick4 has proposed that tricyclic antidepressants (TCAs) and selective serotonin reuptake inhibitors (SSRIs) may stabilize the HPA axis in two ways. The first would be through the process of reuptake inhibition of norepinephrine and serotonin, thereby promoting the production of protective and growth-enhancing neurochemicals such as brain-derived neurotropic factor (BDNF). BDNF causes stabilization of the neuron’s cell membranes, increased branching and connections between neurons, and reverses the potential overstimulatory and cytotoxic effects of the glutaminergic system by stabilization of glutamate sensitive receptors. This promotes healing of neurons which then improves mood and anxiety. Drugs that modulate the effects of glutamate (such as lamotrigine and oxcarbazepine) may also increase BDNF by protecting neurons from overstimulation.4,5 The anticonvulsant oxcarbazepine modulates sodium channels, calcium channels, reduces glutaminergic transmission, and enhances dopaminergic neurotransmission.6 Oxcarbazepine has been reported effective in bipolar disorders.7

Intense vasospastic phenomena have been noted in anorexia nervosa. Bhanji and Mattingly8 examined an unselected series of 155 anorectics and found acrocyanosis in 32 patients. The patients with intense vasospastic phenomena were judged more ill than their counterparts. The characteristic cyanosis and coldness of the hands and feet in acrocyanosis is caused by constriction of the skin arterioles and venous dilatation.8 Anorexia nervosa, like migraine, has been genetically linked to bipolar disorder.9 Vasospastic phenomena have also been noted in bipolar disorder.

Endicott10 studied 400 patients who fell within the bipolar spectrum. He noted a significant positive correlation with migraine headaches, Raynaud’s “disease,” enuresis, “episodic phenomena,” (which may have been migraine auras), fingernail biting, and learning disorders. Forearm blood flow has been noted to be reduced compared to controls in depersonalization disorder.9

In a study of 186 bipolar I women, Blehar and colleagues11 found that 6% reported regular mood changes in the menstrual or premenstrual phase of their cycles. In addition, 75% described their premenstrual symptoms primarily as increased irritability, anger outbursts, and mood lability; 25% reported that their chief symptom was depression. Only five women reported symptoms as minor, while 20 described them as severe. Other disturbances related to hormonal changes were reported as well. Of those bipolar I women who reported a pregnancy, 45.3% reported experiencing severe emotional problems during pregnancy or within 1 month after childbirth and 19.3% reported increased symptoms during perimenopause or menopause. Blehar and colleagues11 also noted a higher rate of migraine headache in their sample of bipolar women than reported in the general population.

Intense vasospastic and/or vasodilatory phenomena has been reported in anxiety and affective disorders, koro, eating disorders, depersonalization disorder and disorders genetically linked to bipolar disorder, such as migraine, and Raynaud’s phenomenon.8,10,12,13 The following patient presented with severe premenstrual psychiatric symptoms, Raynaud’s phenomenon, and migraine headaches. All resolved or improved following successful concomitant treatment of the patient’s affective syndrome.

 

Case Report

A 42-year old married, white female was referred for anxiety attacks, chronic generalized anxiety, and severe premenstrual symptoms only partially responsive to sertraline.

She had originally noted the onset of distractibility following the birth of her children. Her anxiety began at 32 years of age following a severe case of Bell’s palsy. The anxiety persisted and gradually worsened so that she became increasingly more “on guard” when leaving home, driving, or seeing others outside her home. In retrospect, she also noted during that time the onset of Raynaud’s phenomena in her hands and feet when she was anxious, and a feeling of sporadic sadness sometimes without reason. Three years later she experienced her first panic attack during a business meeting. She noted shortness of breath, feelings of terror, loss of feeling in her arms and legs, and a feeling of being overwhelmed (Table).

This intensified her level of anxiety and she shortly became frightened to drive or to leave her home except to walk next door to the family business and, as a result, became socially isolated. The vasoconstriction in her extremities intensified during her attacks and she began to feel pain in her extremities as though “someone was pouring hot oil over her hands and feet” (while her hands and feet would become “icy cold”). She also noted her nose, ears, and nipples would be affected and that her nipples would become erect and cold, and then excruciatingly painful, as did her hands and feet. These symptoms would reliably occur when she would become frightened, such as when forced to make a sales call or go outside the home to shop. She would also often have an urgent bowel movement accompanied by diarrhea.

None of these autonomic phenomena would be preceded by aura-like phenomena, but were triggered by fear. The pattern of her baseline psychiatric symptoms included problems concentrating due to distractibility, being easily startled, her mind being flooded with thoughts (or, as she described it, “rushing”), a mixture of anxiety and painful awareness (a sensation of being overwhelmed by events, noises, and movement around her), and restlessness. The restlessness could gradually increase to overactivity, agitation, and mild elation with a decreased need for sleep. This was followed by periods of depression, during which she had difficulty falling and staying asleep. These cycles were unpredictable and brief in duration, sometimes lasting only 5 days.

The cycles often began following the patient’s menses. Her premenstrual symptoms were an intensification of her basic mixed anxiety and depressive symptoms and began 7 days prior to her menses as tracked using a calendar. The patient’s gynecologist had prescribed sertraline that helped her depression at a dosage of 50 mg/day, and helped her premenstrual symptoms at a dosage of 100 mg/day 2 days prior to her menses. However, the increased dose of sertraline intensified her anxiety and mood swings at other times. She became severely depressed when the sertraline was discontinued. The patient was referred for psychiatric evaluation.

 

Medical, Social, and Family History

The patient’s medical history was significant for occasional hemicranial migraine headaches that were accompanied by nausea and photophobia. Her aura consisted of nonspecific “vision changes” in her left eye and lessened sensation in her tongue. Computerized axial tomography (CAT) and magnetic resonance imaging (MRI) scans of her brain were read as normal and her neurologist reported her examination as unremarkable. She had not been given an electroencephalogram (EEG). No migraine-specific treatment was required. Her Bell’s palsy was mostly resolved and not noticeable. She was unable to take oral contraceptives as they increased her blood pressure. She was allergic to levofloxacin, trimethoprin and/or sulfamethoxazole, and erythromycin. She had gained 20 pounds since treatment with sertraline began and was unable to reach orgasm. Her two preadolescent children were in good health. She had no accidents, head injuries, operations, or hospitalizations other than for childbirth. She denied a history of fainting or any phenomena reminiscent of seizure activity.

There was a family history of diabetes mellitus, hypertension, cardiovascular disease, and a history of depression in her mother, both sisters, and her maternal aunt. Two family members had been treated successfully with sertraline.

The patient was in a successful second marriage. Both of her children were symptom-free and successful in their academic and social life. The family business was successful. The patient was a college graduate, denied alcohol or drug abuse, and reported no problems with authority figures during her life, but had a difficult relationship with her mother, whom she described as critical and dominating. There was no history of sexual or physical abuse.

 

Mental Status Exam

At initial evaluation the patient presented as an anxious, hyperactive, overstimulated woman who spoke rapidly and whose speech was poorly modulated. She was neatly dressed and of average weight. She tended to become distracted easily and lose her train of thought. Her eyelids were over-retracted and her pupils were 5 mm in diameter and reacted sluggishly to distance and changes in light. Her eyes moved in jerky arcs and she tended to glance quickly about the room as she became distracted.14 Her movements were hesitant and poorly modulated. Her hands, ears, and nose were cool and her hands showed slowed capillary filling after pressure was placed against the skin; they also had a curious pale dusky hue.

She was intelligent, well informed, pleasant, and frustrated by her symptoms. She described herself as easily angered, often losing control of her temper to her later embarrassment and shame. She described herself as being depressed at times but not suicidal, and felt that her main problem was her anxiety. She described her premenstrual symptoms as an intensification of her basic symptom pattern complete with increased irritability and racing of her thoughts. She was unable to stop her anxiety and panic attacks once they started and arranged her life to minimize those activities and situations that she thought triggered the attacks. She described herself as feeling almost constantly “on guard.”

 

Treatment

Due her mood swings, irritability, racing thoughts, and increased anxiety following the increases in her sertraline, a diagnosis of comorbid or primary bipolar disorder was considered and oxcarbazepine 300 mg BID was prescribed with instructions to increase the dose by 300 mg/week to a maximum of 1,200 mg/day. Sertraline was continued and alprazolam 0.5–1.0 mg/day was added as needed to help with panic attacks. At her return in 1 month, she was taking oxcarbazepine 600 mg BID and had noticed improved concentration; her mind had “stopped rushing,” and her extremities (and nipples) were warm and no longer painful. Her premenstrual symptoms had been much improved, but she was still having difficulty sleeping and still felt moderate anxiety in stressful situations.

Her oxcarbazepine dosage was changed to 600 mg in the morning and 900 mg in the evening with remission resulting. The only side effect noted was mild morning sedation. Attempts to decrease the total dosage, or to further decrease the morning dose and increase the evening dose (to maintain the same total daily dose) resulted in an increase in her premenstrual symptoms and a return of her peripheral vasospasm. Returning to her previous dosing schedule brought the patient to her asymptomatic state. Her sedation has gradually abated. Attempts to stop the sertraline to help with weight loss resulted in a return of sustained depressive symptoms. Venlafaxine 37.5 mg BID was substituted with resulting normalization of mood, weight, and sexual functioning. She reported no further need for the alprazolam.

This combination of medications has resulted in a near complete remission of the patient’s affective and depressive psychiatric symptoms, her Raynaud’s phenomenon, and a marked decrease in her migraine headaches. She had earlier noted some “bloating” prior to menses, but has increasingly had no premenstrual symptoms. She is now able to drive about freely and go to public gatherings such as church and shopping malls and has joined her church choir. She has had a decrease in the severity of her allergic reactions to bee, wasp, and fire ant bites. Although she used to required steroid and epinephrine injections, she now responds to diphenhydramine injections alone. Her improvement has been maintained for over 9 months.

 

Discussion

The case patient presented with mixed, rapidly-cycling mania, Raynaud’s phenomenon, peripheral pain accompanying vasoconstriction, migraine, and severe premenstrual discomfort. All these syndromes resolved or improved with treatment, suggesting some commonality of process.

There is evidence of an interaction between the hypothalamic-pituitary-ovarian axis and the HPA axis. Stress can induce amenorrhea and women normally show a hyperresponsiveness of the HPA axis when compared to men.15 Interestingly, when estradiol patches are given to normal men, they then show an increase in plasma cortisol, ACTH, and norepinephrine from baseline when subjected to unexpected stress.16 This patient’s premenstrual symptoms were best described as a cyclical exacerbation of her basic manic process and her panic attacks as a painful, intense exacerbation of the flight-or-flight process causing sensory overload.

In a 10-year study of 135 patients diagnosed with obsessive-compulsive disorder, Perugi and colleagues17 noted that in 27.4% of their patients, symptoms followed an episodic course with periods of remission and exacerbation and that those patients were more likely to respond to mood stabilizers such as lithium. While the patient discussed in this case study did not have periods of remission, her symptoms did vary in intensity and on closer investigation brief cyclical episodes were noted. Perugi and colleagues17 suggested that in some patients obsessive and compulsive symptoms were the “phenotypic expression of an underlying affective genotype.” The case patient’s premenstrual, anxiety, and panic symptoms may well fit that pattern of an affective syndrome mimicking other disorders or making latent syndromes overt.17

In an open case series, Blumer and colleagues18 reported that premenstrual dysphoria responded to a combination of anticonvulsants and antidepressants in both patients diagnosed with and without epilepsy. They noted that chronic epilepsy involving the mesial temporal lobe often results in hippocampal sclerosis and that interictal dysphoria in those patients often results in a syndrome which varies in intensity and presents in a characteristic pleomorphic and intermittent pattern of depressed mood, anergia, irritability, euphoric mood, insomnia, pain, anxiety, and fears. They reported that this syndrome often responded to the addition of modest doses of antidepressants to the optimal antiepileptic regimen. While an EEG was not performed for the case patient, both MRI and CAT scans of her brain were negative and there were no symptoms or history suggestive of a seizure disorder.

 

Conclusion

There is increasing evidence that dysregulation and hyperresponsiveness of the HPA axis plays a role in psychiatric disorders and symptoms.3,19 As the brain structures involved in the HPA are involved in the regulation of physical and emotional equilibrium one might expect to see somatic symptoms as well as emotional distress in such patients’ presentation.1

From the work of Bhanji and Mattingly8 one might suspect that a subgroup of more ill psychiatric patients would show such symptoms. The case patient presented demonstrated or reported mixed, rapid-cycling mania, Raynaud’s phenomena, peripheral pain accompanying vasoconstriction, migraine, severe premenstrual discomfort, and symptoms suggestive of the fight-or-flight process. All these syndromes resolved or improved with treatment. PP

 

References

1. Gohil BC, Rosenblum LA. Hypothalamic-pituitary-adrenal axis function and the metabolic syndrome X of Obesity. CNS Spectr. 2001;7:581-589.

2. Smith, ELP, Batuman OA, Coplan JD, Rosenblum LA. Stress, peer affiliation, and transforming growth factor-B 1 in differentially reared primates. CNS Spectr. 2001;7:573-578.

3. Mathew SJ, Coplan JD, Smith ELP, Schoepp DD, Rosenblum LA, Gorman JM. Glutamate-hypothalamic-pituitary-adrenal axis interactions: implications for mood and anxiety disorder. CNS Spectr. 2001;7:555-654.

4. Skolnick P. Antidepresants for the new millennium. Eur J Pharmacol. 1999;375:31-40.

5. Leowe-Ponsford FL, Nutt DJ. Pathophysiology of depression. Primary Psychiatry. 2001;11:43-48.

6. Schacter SC. Tricyclic anticonvulsants: mechanisms of action. Epilepsy Behav. 2002;2:7-8.

7. Ghaemi SN, Ko YJ. Oxcarbazepine treatment of bipolar disorder. a review of the literature. Primary Psychiatry. 2002;1:55-59.

8. Bhanji S, Mattingly D. Acrocyanosis in anorexia nervosa. Postgrad Med J. 1991;67:33-35.

9. Kelly DH, Walter CJ. The relationship between clinical diagnosis and anxiety, assessed by forearm blood flow and other measurements. Br J psychiatry. 1968;114:611-626.

10. Endicott NA. Psychophysiological correlates of “bipolarity.” J Affect Disord. 1989;17:47-56.

11. Bleher MC, Depaulo JR jr, Gershon ES, Reicht T, Simpson SG, Nurnberger J. Women with bipolar disorder: findings from the NIMH genetics initiative sample. Psychopharmacol Bull. 1998;3:239-243.

12. Bohn P, Sternbach H. Physical symptoms associated with social phobia. Primary Psychiatry.1998;2:59-63.

13. Oyebode F, Jamieson R, Mullaney J, Davison K. Koro–a psychophysiological dysfunction? Br J Psychiatry. 1986;148:212-214.

14. Goodwin, GK, Jamison KR. Manic Depressive Illness. New York, NY: Oxford University Press; 1990.

15. Chrousos GP, Torpy DJ, Gold PW. Interactions between the hypothalamic-pituitary-adrenal axis and the female reproductive system: clinical implications. Ann Intern Med. 1998;129:229-240.

16. Kirschbaum C, Schommer, Federenko I, et al. Short-term estradiol treatment enhances pituitary-adrenal axis and sympathetic responses to psychological stress in healthy young men. J Clin Endocrinol Metab. 1996;81:39-43.

17. Perugi G, Akiskal HS, Gemignani A, et al. Episodic course in obsessive-compulsive disorder. Eur Arch Psychiatry Clin Neurosci. 1998;248:240-244.

18. Blumer D, Herzog AG, Himmelhoch J, Salgueiro CA, Ling FW. To what extent do premenstrual and interictal dysphoric disorder overlap? significance for therapy. J Affect Disord. 1998;48:215-225.

19. Newport DJ, Stowe ZN, Nemeroff CB. Parental depression: animal models of an adverse life event. Am J Psychiatry. 2002;159:1265-1283.

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Genetics and Genomics in Schizophrenia

Ming T. Tsuang, MD, PhD, DSc, Stephen J. Glatt, PhD,
and Stephen V. Faraone, PhD

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Primary Psychiatry. 2003;10(3):37-40,50

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The Bipolar Spectrum in Psychiatric and General Medical Practice

Hagop S. Akiskal, MD

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Primary Psychiatry. 2004;11(9):30-35

Focus Points

• Bipolar disorder is more prevalent than previously believed.

• This higher prevalence is largely accounted for by a spectrum of bipolar disorders, which include bipolar type I, type II, and beyond.

• In different community studies, 5% of individuals on average are estimated to have bipolar spectrum disorders.

• Although counterintuitive, 30% to 70% of all depressions seen in various clinical settings, including both psychiatric and general medical practices, have been found to belong to the bipolar spectrum.

• The bipolar spectrum frequently presents clinically in association with panic, anxious-phobic, bulimic, addictive, and erratic personality disorders.

Abstract

This introductory article examines the emerging scientific and clinical literature on bipolar types beyond those in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV). These include new “softer” expressions of bipolarity, such as type II with briefer hypomanias, type II½, type III, and type IV. Patients within the soft spectrum beyond the DSM-IV prototypes are highly prevalent in private psychiatric, community mental health, and general medical practice. Thus, identifying bipolar disorder as a spectrum has clinically meaningful implications for comorbid conditions, the nature of a putative shared underlying pathophysiology, clinical management, and public health.

Introduction

Until recently, it was believed that bipolar disorder occurred in 1% of the general population. This figure pertains to what is known as bipolar I disorder (manic-depressive illness). However, the current bipolar schema in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV),1 also includes bipolar II, cyclothymia, and bipolar not otherwise specified. Thus, it should not come as a surprise that, in a wave of new epidemiologic studies, the prevalence of the entire spectrum has been revised up to at least 5% of the general population.2 Although the DSM-IV does not use the construct of “bipolar spectrum,” its bipolar subtypes implicitly adhere to such a broad schema.

The work reviewed in this article examines the emerging scientific and clinical literature on bipolar types beyond DSM-IV bipolar I and II. These include new “softer” expressions of bipolarity, such as type II with briefer hypomanias, type II½ (depression superimposed on cyclothymia), type III (depression plus antidepressant-associated hypomania), and type IV (depression superimposed on a hyperthymic temperament).2,3

Patients within the soft spectrum beyond the DSM-IV prototypes are highly prevalent in psychiatric and primary care community and private practice settings. However, they often present clinically with a volatile mix of depression and biographical instability (ie, so-called erratic personality disorders), along with addictive, phobic-anxious, panic, and bulimic comorbidities. History of hypomania is more often than not overshadowed by the lifelong nature of these complex manifestations. It is important for psychiatrists, other mental health professionals, and general medical practitioners to be vigilant concerning the bipolar spectrum in patients presenting with the foregoing conditions. They should therefore conduct a diligent search for hypomania.

There is credible evidence that, depending on the study and the setting, somewhere between 30% and 70% of all depressions observed in clinical settings belong to this complex spectrum.2 The atheoretical position of the DSM-IV diagnostic system may serve as a blueprint for a research document, but regrettably it does not do justice to the clinical complexity of bipolarity as seen by the practitioner, nor does the DSM-IV provide any guidance on how to make sense of the conditions that accompany bipolar illness. Reformulating bipolar disorder as a spectrum has clinically meaningful implications for comorbidity, the nature of a putative shared underlying pathophysiology, clinical management, and public health.

Defining the Bipolar Spectrum

There is an emerging international consensus2 that bipolar disorder extends beyond the boundaries of an illness historically defined by an alternation of mania and depression. Indeed, between the extremes of full-blown manic-depressive illness (ie, bipolar I, where the patient has at least one acute manic episode) and strictly-defined unipolar depression (without personal or family history of mania or hypomania), there exists a prevalent spectrum of soft bipolar conditions with various admixtures of depression, hypomania, and temperamental instability.3

Those with spontaneous hypomania are now formally considered bipolar II in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition Text Revision (DSM-IV-TR).4 Moreover, in many clinically depressed patients, elements of hypomanic activation can occur during an episode of major depressive disorder (MDD), resulting in “depressive mixed states” (which are not officially recognized in the DSM-IV). These patients pose diagnostic and therapeutic challenges for clinicians.3,5,6 Depressions with antidepressant-associated hypomania also appear, on the basis of extensive recent work,2,7 to be related to bipolar II (although some refer to them as bipolar III, also not an official rubric in the DSM-IV). Premorbid and interepisodic cyclothymic (a variant of bipolar II8) or hyperthymic traits (ie, bipolar type IV, consisting of overcheerful, overenergetic, and overconfident people who succumb to depression in their 40s and 50s9) represent prominent characteristics of other soft expressions of this spectrum. Patients across the soft spectrum may present with depression, anxiety, or mood swings. These mood swings are recurrent, biphasic, and abrupt, and are frequently induced by antidepressants (or stimulant and alcohol abuse) and/or by seasonal changes.3 Falling in and out of love and other excitements that could lead to sleep deprivation represent common contributory factors to the instability of these patients.3,9 Table 1 presents this proposed bipolar spectrum schema.

Although the DSM-IV-TR only includes bipolar types I and II, the aforementioned schema provides characterization for the remainder of the spectrum types, which in the DSM-IV are dubbed under the nondescript rubric of “bipolar not otherwise specified.” The proper specification of the entire spectrum is important for clinical practice. It makes little sense for a diagnostic manual developed for clinicians to categorize patients as having an unspecified disorder. Most physicians diagnose and manage conditions on the border of prototypical disorders. This is where the DSM-IV fails them. For a more in-depth description of this schema, the reader is referred to work by Akiskal and Pinto.9

Bipolar Disorder in Clinical and Community Settings

There has been a major recent research thrust in the study of bipolar disorder in its psychotic and ambulatory variants. It is now well accepted that mania can manifest in extreme psychotic forms,10 including “schizobipolar” phenotypes.11 Careful research has also delineated mixed or dysphoric forms of mania that also frequently reach psychotic proportions.12-17 Patients with such intense activation typically require psychiatric hospitalization. Current data indicate that at least two depressive symptoms exclusive of insomnia and agitation are sufficient for defining dysphoric mania. More provocatively, such mixed manic forms have been shown to arise from the baseline of a dysthymic (depressive) temperament, whereas pure mania is more typically superimposed on a hyperthymic temperament.

Current official systems of classification (such as the DSM-IV) are couched within the unipolar-bipolar distinction, yet a newer conceptual framework, in development since 1977,3,9,18-21 has accumulated data in favor of the existence of a prevalent group of intermediary, predominantly ambulatory, conditions. Recent studies in psychiatric settings,3,22-24 in general medical practice,25 and in the community26-29 have revealed a large spectrum of patients with soft or subtle signs of bipolarity. Bipolar II, the best known of these conditions, was first delineated by Dunner and colleagues.30 Typically these patients present with MDD, but upon expert interviewing31 reveal a history of activated behavior, mood lability, explosive behavior, or marked irritability.32 The soft bipolar spectrum, which is more prevalent than full-blown manic-depressive illness, constitutes a “clinical bridge” between unipolar and psychotic bipolar disorders,3 indicating the need for a partial return to Kraepelin’s33 broad concept of manic-depressive illness.

Based on the finding that depressive forms exceed definite bipolar cases in manic-depressive pedigrees by 4–5-fold,11 Akiskal and Mallya3 estimated in 1987 that the rates for the bipolar spectrum should be 4% to 5%. Epidemiologic studies have actually shown that these softer expressions of bipolarity have a prevalence range of 3.7% to 8.3%,26-29 as opposed to the conventionally reported rate of 1% for manic-depressive illness.34 Most interestingly, in private psychiatric, community mental health,2,3 and general medical25 settings, somewhere between 30% and 70% of patients presenting with MDD belong to the bipolar spectrum.

Focus on the Soft Spectrum

There are several intermediary conditions between bipolar I and strictly-defined unipolar MDD. The common feature of these intermediate bipolar conditions is the occurrence of manic activation at a subthreshold level.3,9 Bipolar II, the most prototypical of the soft bipolar spectrum, appears to be the most prevalent clinical expression of bipolar disorders.35 Spontaneous hypomania is needed for the diagnosis of bipolar II. Because bipolar II patients present clinically with depression and almost never with hypomania, the diagnosis of bipolar II requires skillful interviewing about history of such episodes. Current clinical guidelines2 indicate that the duration of hypomanic episodes is less important when numerous such episodes have occurred in the past. Hypomania is a distinct episode of mild elevation of mood, positive thinking, and increased activity level occurring over at least a few days. It is distinguished from ordinary happiness by the tendency of episodes to recur (happiness usually does not, unfortunately) and by the fact that it can be mobilized by antidepressants.3 Despite DSM-IV conventions to the contrary, the preponderance of evidence based on family history for bipolar disorder and clinical course2,7 indicates that hypomania during antidepressant treatment of an episode of MDD merits a bipolar designation (ie, bipolar III).

Individual hypomanic episodes may also be associated with positive emotions and creative thinking.36 However, the judgment of patients may be impaired. Repeated episodes of hypomania in association with mood swings may cumulatively contribute to the unstable course of bipolar II disorder, as well.2 Moreover, the experience of hypomania itself is often that of a “nervous high,” with marked irritable and hostile admixtures. According to the DSM-IV, hypomania typically presents without the marked impairment characteristic of manic episodes. Judging from the above symptoms of hypomania, however, the DSM-IV characterization of bipolar II as a milder condition is misleading. Table 2 provides a summary of findings on hypomanic episodes taken from clinical experience.3,9,18

Another characteristic of some, but not all, bipolar II patients is their labile cyclothymic temperamentality8 prior to and between MDD episodes.24 These patients, who can be considered “cyclothymic depressives,” exhibit a great deal more instability than bipolar II patients who present without cyclothymia; in fact, they are often mistaken for patients with borderline personality disorder. Prospective follow-up leading to MDD and/or hypomania rather than mania,18 and familial bipolar history, are the strongest evidence for the inclusion of these patients within the bipolar spectrum.8 One might consider them bipolar II variants or bipolar II½.9 The validated self-rated criteria for cyclothymia37 are summarized in Table 3. Patients with MDD endorsing at least six of these criteria are likely to belong to this bipolar variant.

In yet another soft bipolar subgroup, hypomanic and cyclothymic episodes as such are absent; instead, the individual has a persistent upbeat disposition, is overoptimistic, and functions at a high level of energy and confidence premorbidly and between depressive episodes. Unlike hypomania, which is an episode distinct from the patient’s habitual self, the hyperthymic traits of bipolar IV patients represent their habitual baseline.38 These traits have been found to define a subtype of MDD with bipolar family history indistinguishable from other disorders in the spectrum.9,22 The criteria for the hyperthymic temperament3 are summarized in Table 4. It is usually best to elicit these traits by clinical interview or from significant others; a patient with MDD meeting at least four of these criteria can be clinically assigned to bipolar type IV.

Evidence for the importance of temperamental attributes in defining bipolar spectrum subtypes has come from the National Institute of Mental Health Collaborative Study of Depression (CDS) database. As demonstrated in a 12-year prospective examination of bipolar switching in the CDS,39 trait attributes consisting of “mood-lability” and “energetic-activity” permit a more precise characterization of the bipolar spectrum than the hypomanic periods emphasized in the DSM-IV and the International Statistical Classification of Diseases and Related Health Problems, Tenth Revision (ICD-10).40 To properly diagnose soft bipolar conditions, the clinician must therefore carefully assess lifelong cyclothymic (mood-labile) or hyperthymic (active-energetic) traits. MDD episodes often complicate the life course in these individuals, and during these episodes, their conditions would therefore warrant the additional diagnosis of bipolar spectrum disorders.

In official diagnostic systems, bipolarity is characterized by the presence of alternating manic (or hypomanic) and depressive phases. However, a more fundamental characteristic of bipolarity is the reversal of the basic temperament into its opposite episode.41 Research22,24 has actually shown that the MDD expression in bipolar II disorder commonly arises from cyclothymic temperament. On the other hand, bipolar I disorder, characterized by a predominance of manic attacks, is more likely to arise from a dysthymic or hyperthymic temperament and, in bipolar I, a hyperthymic baseline is typically limited to patients with a predominantly manic course. Thus, the biphasic disturbance in bipolar illness often consists of the development of episodes that can be considered opposite in polarity to that of the antecedent temperament.41

As a result, the depressive episodes of many patients with soft bipolarity arising from cyclothymic and/or hyperthymic baseline are often mixed in nature (ie, isolated hypomanic symptoms, such as psychomotor acceleration, flight of ideas, and intense sexual arousal, intrude into MDD).3,5,42 Clinicians, when confronted with activated (labile, aroused, hostile, or agitated) MDD patients in psychiatric or general medical settings, must first rule out a bipolar spectrum condition. The same is true for a proportion of major depressions with intense anxious-phobic arousal.43

Comorbidity Within the Bipolar Spectrum

Mixed bipolar depressive states are ignored in both the DSM-IV and the ICD-10. This failure to recognize the bipolar nature of the volatile mix of temperament, depression, and anxious-phobic features often gives rise to such misleading characterologic diagnoses as borderline, histrionic, psychopathic,18,44 or atypical depressions.45

In the offspring of bipolar patients, affective storms can be misconstrued as attention-deficit/hyperactivity disorder (ADHD) and/or conduct disorder.46-48 ADHD and bipolar are distinct disorders, yet they often coexist. Thus, if family history is bipolar, considering these patients as a special ADHD-bipolar subtype is justified. Although such overlap is most common in manic or mixed manic children, it is at times observed in adults across the bipolar spectrum.

Substance and alcohol abuse are particularly prevalent among soft bipolar conditions.18,49,50 They often represent an attempt to enhance the hyper periods (with stimulants), rather than an attempt to self-medicate during depressed periods.32 Often comorbid appetitive behaviors, such as bulimia,51 can also be considered to have relevance to the bipolar spectrum. McElroy and colleagues51 contend that other impulse-control disorders, such as kleptomania and gambling, might have affinities to the bipolar spectrum as well. This is not to say that addictive, bulimic, and impulse-control disorders are secondary to bipolarity. Their common coexistence with bipolar disorder raises the possibility of shared underlying neurobiologic mechanisms. This is analogous to the common coexistence of obesity, diabetes, and hypertension, which are all diseases in their own right that are linked by the metabolic syndrome.

Bipolar spectrum patients with prominent temperamental dysregulation also appear vulnerable to the cycling effect of antidepressants.18,52,53 The excesses of bipolar II patients and the associated circadian disruptions appear relevant to the irregular cycling so often encountered in ambulatory bipolar patients today. A soft bipolar diagnosis is crucial, precisely because these patients need protection from antidepressant monotherapy (eg, with mood-stabilizing anticonvulsants or atypical antidepressants).

Interestingly, current data also suggest an intriguing association between soft bipolar conditions, especially cyclothymic conditions, and artistic creativity. Individuals with hyperthymic temperament are also over-represented among prominent individuals in leadership positions.54 In the same vein, professional achievement is over-represented among healthy relatives of bipolar patients.55,56 Thus, high achievement in various professional domains, or family history for such achievement, in the patient presenting with clinical depression can be used as a clinical pointer in favor of soft bipolarity.

On a more clinical note, pointers toward bipolarity include certain course, episode, phenomenological, and familial characteristics listed in Table 5.3,9,19

Discussion

Since bipolar spectrum was first proposed,18,19 the literature has been enriched by conceptual extensions, modifications, and/or research in favor of the spectrum of bipolarity.57-68 The material reviewed in this article refers to the phenomenology, course, and familial aspects of the spectrum. It is likely that genetic heterogeneity exists, underlying the bipolar spectrum.69-71 This does not rule out the possibility that biological commonalities may be shared by the spectrum.

Although the concept of bipolar spectrum has been criticized on methodologic grounds,72 the evidence reviewed herein has documented that the spectrum and its comorbidities are prevalent conditions in both psychiatric and general medical settings. In the differential diagnosis of depressive, anxious-phobic, and panic states, the clinician must consider bipolar II and its variants. Comorbidity is high with addictive, bulimic, and borderline conditions. Migraine73 can also coexist with soft bipolar disorders, as can other psychophysiological disorders61 beyond the scope of this review. This means that bipolarity can present clinically with the foregoing nonaffective features. Given emerging data on the link between bipolarity and suicidality,74 the recognition and proper management of the bipolar spectrum and its comorbidities is relevant to suicide prevention.75,76

The emerging literature on the bipolar spectrum is beginning to impact psychiatric practice worldwide,77 as well as pathophysiologic understanding of putative common temperamental and molecular genetic mechanisms underlying the spectrum and its comorbidities.78 The bipolar spectrum is also relevant to family and general medical practice,79-82 which represents the de facto field for prevalent affective disorders, ADHD, and substance and alcohol use disorders.

Conclusion

It has not been the purpose of this overview on the bipolar spectrum concept and its adjoining conditions to demolish the edifice of the diagnostic prototypes embodied in the DSM-IV. The clinician should use these prototypic descriptions as a guide to identify the most likely diagnosis that best fits a patient presenting with an elusive and complex array of affective manifestations subthreshold to the classical bipolar type. In adults, these manifestations are typically comorbid with anxious, migrainous, addictive, bulimic, and erratic personality disturbances. The DSM-IV provides no guidance as to why these disorders often coexist with bipolar illness, nor does it provide any rationale for prioritizing one diagnosis over another. To focus on the presenting condition exhorted by the DSM-IV, while sensible, is not necessarily always the best diagnostic solution. Because of its therapeutic and prognostic implications, it is important not to miss a bipolar spectrum diagnosis in the patients described in this review. Early age of onset, episodic or cyclic course, marked seasonality, mixity, and bipolar family history can serve as markers for a bipolar diathesis in such patients.

It is meaningful to consider that this illness, while operationally distinct from its commonly co-occurring disorders, may nonetheless share underlying neurobiologic mechanisms with them. This style of thinking is an incentive to contemporary molecular oligogenic studies in the field of bipolar and related disorders.78 This model postulates various combinations of shared genes among the adjoining disorders of bipolarity and the bipolar spectrum itself.

Taking these factors into account, the concept of the bipolar spectrum can serve to bridge practice, clinical research, and more basic research in psychiatry.83 In fact, spectrum concepts of mental illness may represent a promising alternative to the DSM-IV.84 PP

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28. Judd LL, Akiskal HS. The clinical and public health relevance of current research on subthreshold depressive symptoms to elderly patients. Am J Geriatr Psychiatry. 2002;10(3):233-238.

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37. Akiskal HS, Mendlowicz MV, Rapaport MH, Kelsoe JR, Gillin JC, Smith TL. TEMPS-A: validation of a short version of a self-rated instrument designed to measure variations in temperament. J Affect Disord. In press.

38. Akiskal HS. Delineating irritable and hyperthymic variants of the cyclothymic temperament. J Personal Disord. 1992;6:326-342.

39. Akiskal HS, Maser JD, Zeller PJ, et al. Switching from ‘unipolar’ to bipolar II. An 11-year prospective study of clinical and temperamental predictors in 559 patients. Arch Gen Psychiatry. 1995;52(2):114-123.

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42. Akiskal HS, Benazzi F. Delineating depressive mixed states: their therapeutic significance. Clin Approaches Bipolar Disord. 2003;2:41-47.

43. Perugi G, Toni C, Akiskal HS. Anxious-bipolar comorbidity. Diagnostic and treatment challenges. Psychiatr Clin North Am. 1999;22(3):565-583.

44. Deltito J, Martin L, Riefkohl J, et al. Do patients with borderline personality disorder belong to the bipolar spectrum? J Affect Disord. 2001;67(1-3):221-228.

45. Perugi G, Akiskal HS, Lattanzi L, et al. The high prevalence of “soft” bipolar (II) features in atypical depression. Compr Psychiatry. 1998;39(2):63-71.

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48. Dilsaver SC, Henderson-Fuller S, Akiskal HS. Occult mood disorders in 104 consecutively presenting children referred for the treatment of attention-deficit/hyperactivity disorder in a community mental health clinic. J Clin Psychiatry. 2003;64(10):1170-1176.

49. Maremmani I, Pacini M, Lubrano S, Lovrecic M, Perugi G. Dual diagnosis heroin addicts. The clinical and therapeutic aspects. Heroin Add Relat Clin Probl. 2003;5:7-98.

50. Camacho A, Akiskal HS. Proposal for a bipolar stimulant spectrum. Temperament, diagnostic validation and therapeutic outcomes with mood stabilizers. J Affect Disord. In press.

51. McElroy SL, Keck PE Jr, Phillips KA. Kleptomania, compulsive buying, and binge-eating disorder. J Clin Psychiatry. 1995;56(suppl 4):14-26. Discussion in: J Clin Psychiatry. 1995;56(suppl 4):27

52. Kukopulos A, Reginaldi D, Laddomada P, Floris G, Serra G, Tondo L. Course of the manic-depressive cycle and changes caused by treatment. Pharmakopsychiatr Neuropsychopharmakol. 1980;13(4):156-167.

53. Wehr TA, Goodwin FK. Can antidepressants cause mania and worsen the course of affective illness? Am J Psychiatry. 1987;144(11):1403-1411.

54. Akiskal HS, Akiskal K. Re-assessing the prevalence of bipolar disorders: clinical significance and artistic creativity. Psychiatrie Psychobiologie. 1998;3:29-36.

55. Coryell W, Endicott J, Keller M, et al. Bipolar affective disorder and high achievement: a familial association. Am J Psychiatry. 1989;146(8):983-988.

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57. Taylor MA, Abrams R. Reassessing the bipolar-unipolar dichotomy. J Affect Disord. 1980;2(3):195-217.

58. Klerman GL. The spectrum of mania. Compr Psychiatry. 1981;22(1):11-20.

59. Egeland JA. Bipolarity: the iceberg of affective disorders? Compr Psychiatry. 1983;24(4):337-344.

60. Tsuang MT, Faraone SV, Fleming JA. Familial transmission of major affective disorders. Is there evidence supporting the distinction between unipolar and bipolar disorders? Br J Psychiatry. 1985;146:268-271.

61. Endicott NA. Psychophysiological correlates of ‘bipolarity’. J Affect Disord. 1989;17(1):47-56.

62. Himmelhoch JM. Social anxiety, hypomania and the bipolar spectrum: data, theory and clinical issues. J Affect Disord. 1998;50(2-3):203-213.

63. Ghaemi SN, Ko JY, Goodwin FK. “Cade’s disease” and beyond: misdiagnosis, antidepressant use, and a proposed definition for bipolar spectrum disorder. Can J Psychiatry. 2002;47(2):125-134.

64. Angst J, Gamma A. A new bipolar spectrum concept: a brief review. Bipolar Disord. 2002;4(suppl 1):11-14.

65. Dunner DL. Clinical consequences of under-recognized bipolar spectrum disorder. Bipolar Disord. 2003;5(6):456-463.

66. Benazzi F. High frequency of bipolar spectrum in outpatients with depression. Can J Psychiatry. 2004;49(4):279-280.

67. Hirschfeld RM. Bipolar spectrum disorder: improving its recognition and diagnosis. J Clin Psychiatry. 2001;62(suppl 14):5-9.

68. Cassano GB, Rucci P, Frank E, et al. The mood spectrum in unipolar and bipolar disorder: arguments for a unitary approach. Am J Psychiatry. 2004;161(7):1264-1269.

69. Gershon ES. Bipolar illness and schizophrenia as oligogenic diseases: implications for the future. Biol Psychiatry. 2000;47(3):240-244.

70. MacKinnon DF, Xu J, McMahon FJ, et al. Bipolar disorder and panic disorder in families: an analysis of chromosome 18 data. Am J Psychiatry. 1998;155(6):829-831.

71. Alda M. The phenotypic spectra of bipolar disorder. Eur Neuropsychopharmacol. 2004;14(suppl 2):S94-S99.

72. Baldessarini RJ. A plea for integrity of the bipolar disorder concept. Bipolar Disord. 2000;2(1):3-7.

73. Oedegaard KJ, Fasmer OB. Is migraine in unipolar depressed patients a bipolar spectrum trait? J Affect Disord. 2004.

74. Rihmer Z, Pestality P. Bipolar II disorder and suicidal behavior. Psychiatr Clin North Am. 1999;22(3):667-673.

75. Goodwin FK, Fireman B, Simon GE, Hunkeler EM, Lee J, Revicki D. Suicide risk in bipolar disorder during treatment with lithium and divalproex. JAMA. 2003;290(11):1467-1473.

76. Yerevanian BI, Koek RJ, Mintz J. Lithium, anticonvulsants and suicidal behavior in bipolar disorder. J Affect Disord. 2003;73(3):223-228.

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78. Kelsoe JR. Arguments for the genetic basis of the bipolar spectrum. J Affect Disord. 2003;73(1-2):183-197.

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83. Akiskal HS. From dysthymia to the bipolar spectrum: bridging practice and research (Jean Delay Prize Paper). Paper presented at: XII World Congress of Psychiatry; August 24–29, 2002; Yokahama, Japan.

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Dr. Akiskal is director of the International Mood Center in the Department of Psychiatry at the University of California, and chief of the Mood Disorders Program in the Veterans Administration Healthcare System, both in San Diego.

Disclosure: Dr. Akiskal is a consultant for and is on the speaker’s bureaus of Abbott, AstraZeneca, Bristol-Myers Squibb, Eli Lilly, GlaxoSmithKline, Janssen, and Sanofi-Synthelabo.

Please direct all correspondence to: Hagop S. Akiskal, MD, University of California, San Diego, International Mood Center, Department of Psychiatry, 3350 La Jolla Village Dr, La Jolla, CA 92161-0603; Tel: 619-552-8585; Fax: 619-534-8598; E-mail: hakiskal@ucsd.edu.


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Are Some Forms of Substance Abuse Related to the Bipolar Spectrum? Hypothetical Considerations and Therapeutic Implications

Alvaro Camacho, MD

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Primary Psychiatry. 2004;11(9):42-46
 

Dr. Camacho is a research fellow with the International Mood Center in the Department of Psychiatry at the University of California in San Diego, and is attending psychiatrist at Imperial County Behavioral Health in El Centro, California.

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

Please direct all correspondence to: Alvaro Camacho, MD, University of California, San Diego, International Mood Center, Department of Psychiatry, 9500 Gilman Dr, Mail Code 0603, La Jolla, CA 92037-0603; Tel: 619-252-0428; Fax: 619-497-6686; E-mail: acamacho@ucsd.edu.
 

Focus Points

• Substance abuse is the most common comorbid condition in individuals diagnosed with bipolar disorder.
• Alcohol and stimulants are the most commonly abused substances in patients with bipolar disorder.
• Patients with bipolar disorder and substance abuse should be started sooner rather than later on a mood stabilizer, despite the risks and side effects associated with the particular medication.
• Clinicians should pay close attention to premorbid dysphoria and irritability associated with states of withdrawal from substances, which could be the prodromal phase of a bipolar depressive episode; if left untreated, further relapse and exacerbation of mood symptoms is possible.
• Bipolar and substance abuse conditions may share a common diathesis, which may in part explain the overlap in therapeutic modalities.

 

Abstract

The use of addictive substances is prevalent among individuals with bipolar disorder (the so-called “dual diagnosis” phenomenon). New studies have led to the proposal that the two groups of disorders exist on a continuum. The Akiskal-Pinto bipolar spectrum schema describes this continuum as bipolar type III 1/2. This review explores the possibility that some forms of substance abuse, especially stimulant abuse, can belong to the bipolar spectrum. These forms of substance abuse respond to anticonvulsant medications used as mood stabilizers. The review is divided into the following sections: neurobiology of addictive disorders, epidemiology of bipolar illness and comorbid substance abuse (particularly stimulant abuse), and clinical correlation with proposed treatment options. The proposed spectrum, with emphasis on stimulant use and bipolar disorder, provides an alternative understanding to a phenomenon that otherwise remains a diagnostic dilemma and therapeutic quagmire. Anticonvulsant medications appear to be a viable joint option for a proportion of patients with this condition.

 

Introduction

 

Patients with comorbid mental illness and substance abuse disorders (SUD) frequently present for treatment with a confusing array of psychiatric and physical findings. The importance of identifying the association between mental illness and SUD in these patients was recognized as early as 1979 by McLellan and colleagues.1 Assessment of comorbid mental illness and SUD can be difficult; it begins with an open mind to avoid premature closure of diagnostic possibilities, lest the patient be left without adequate treatment.2 Given the high frequency of substance abuse among patients with mental disorders, clinicians should use a probing diagnostic approach.2-4 In order to clarify the relationship between SUD and mental illness it is recommended that they assess: when the initial mental symptoms began, and, in the case of an exacerbation, under which circumstances the symptoms began again; when the SUD started and whether the symptoms preceded the development of substance abuse; which subjective effects the substance has on the psychiatric symptoms (relief, exacerbation or cessation); and whether or not patterns of substance use alleviate the underlying psychiatric phenomena.

 

Of all Axis I mental disorders, mood disturbances—especially bipolar disorder—are most likely to co-occur with SUD. Studies5,6 have described that an earlier onset of bipolar disorder is seen in patients who develop SUD compared to those who do not, suggesting that an earlier age at onset of mood symptoms may put individuals at risk for developing an addiction disorder.

 

This review attempts to inform the clinician about the increasing evidence of comorbidity between bipolar disorder and substance use, with a particular emphasis on stimulant use disorders. The article will review the neurobiology of addiction and then the epidemiology of bipolar disorder and addictions, both of which should aid in building clinical correlations, especially with regard to emerging treatments. Stimulant abuse will again be the main focus of the model of bipolar disorder proposed in this article.

 

Neurobiology of Addiction

 

Addiction can be viewed as a form of drug-induced neuronal plasticity. Many studies identifying possible transcription factors that could contribute to the developing of tolerance and eventual dependence on addictive substances are currently underway. Two of the most studied transcription factors are the cyclic adenosine monophosphate (cAMP) response element binding protein (CREB) and the ΔFosB. These transcription factors are responsible for the autoregulation of intracellular transmission, which promotes the biosynthesis of certain neurotransmitters, such as norepinephrine, dopamine, glutamate, and γ-aminobutyric acid, among others, that are responsible for stable adaptations of neuronal function and the reward effects of addictive substances.7

 

Research has shown that the upregulation of the cAMP pathway and the eventual activation of CREB occurs in response to the administration of several drugs of abuse, including opiates, stimulants, and ethanol. The same has been described for the ΔFosB transcription factor.8-10 Thus, these transcription factors play a role in the acute and chronic administration of addictive substances. The activation of CREB is the result of the upregulation of the second messenger pathway of cAMP, which has been described as an adaption to chronic exposure to drugs of abuse, leading to tolerance and dependence. On the other hand, ΔFosB has been implicated in the acute adaptations of addictive substances or sensitization, which refers to the enhanced response to the substance use.7-11

 

CREB and ΔFosB seem to balance each other. CREB has been implicated in drug inhibition and states of withdrawal, depression, and dysphoria, whereas the Fos family of transcription factors has been associated with euphoria, increased locomotor responses to drugs, and rewarding responses to drugs, especially morphine and cocaine.7,8,12 These features bear some resemblance to the biphasic cyclothymic phenomenology of the bipolar spectrum.13 However, whether these underlying mechanisms are similar is speculative at this point.

 

Epidemiology

 

Data from the Epidemiological Catchment Area study14 reported that the lifetime prevalence of any substance abuse or dependence among individuals with bipolar disorder types I and II is 56.1%, and is 60.7% in patients with only bipolar I disorder.2,14 Patients with more complicated forms of bipolar disorder (eg, mixed or rapid-cycling) are also more likely to have SUD.5,15 Antisocial personality disorder is the only psychiatric condition with a reported higher rate of comorbid SUD.2,16,17

 

A recent study done by Copeland and Sorensen18 found that mood disorders accounted for 71% of the diagnoses among individuals with methamphetamine use disorders. A previous study by Winokur and colleagues19 found that individuals with bipolar disorder not only have a higher incidence of alcoholism but also a considerable tendency toward stimulant abuse and dependence. Additionally, these investigators postulated the hypothesis between a common familial-genetic diathesis for a subtype of bipolar disorder and stimulant abuse. This was corroborated in another study,20 which reported that 72% of individuals with a history of alcohol use disorder had a lifetime prevalence of stimulant use (26% with powder cocaine and 46% with crack cocaine). McElroy and colleagues21 described a cohort of 288 bipolar patients in which 33% had lifetime prevalence of alcohol use disorder, followed by an 18% lifetime prevalence of stimulant (including cocaine) use disorder. Moreover, there was no significant difference between patients with bipolar I and bipolar II disorder and their comorbid substance use.

 

Dalton and colleagues22 reported a lifetime rate of 40% of suicide attempts in a cohort of 336 subjects with bipolar I disorder, bipolar II disorder, schizoaffective disorder, and comorbid substance abuse. The authors described that the use of drugs among this cohort was a significant predictor for suicide attempts (P=.037); they described cannabis as the most frequently used substance (74%), followed by hallucinogens (18%), sedatives (18%), and cocaine (18%).

 

Clinical Correlation

 

The question that many clinicians face on a daily basis is which disorder accounts for the symptomatology that the patient is experiencing. Based on the literature reviewed, and building on the Akiskal-Pinto formulation,23 Camacho and Akiskal24 hypothesized the existence of a bipolar-stimulant spectrum. Just as in some depressives with familial-genetic permission for bipolarity who manifest hypomania upon antidepressant challenge,25,26 they suggested that in another group of potential bipolar depressives, stimulant use can bring about the first overt hypomanic or manic episode. They also suggested that anticonvulsants can stabilize the underlying bipolar dysregulation, treat the withdrawal phenomena from substances of abuse, and reduce the craving for the substance.

 

Emerging Treatment Approaches

 

Treatment with Mood Stabilizers

 

Divalproex Sodium

 

The use of divalproex sodium has provided promising results not only in the treatment of patients with comorbid bipolar and SUD, but also as an aid for preventing further relapse. It can be used as an adjunctive agent for detoxification, as well. Starting doses can be 500 mg at night, increased up to 2,000 mg in divided doses. It is important to monitor liver function, pancreatic function, and serum levels when using divalproex.27-29 More longitudinal studies are needed to assess the length of abstinence in these patients.

 

Carbamazepine

 

A preclinical study using carbamazepine posed interesting questions about the utility of this mood stabilizer in treating methamphetamine-related bipolar symptoms and in reducing associated methamphetamine cravings.30 Brady and colleagues31 postulated the utility of this mood stabilizer in patients with cocaine dependence and comorbid affective disorders, and found a trend toward fewer positive urine drug tests. Another study32 demonstrated improvement on self-ratings of depression and irritability. Doses of carbamazepine start at 300 mg BID, and can be increased up to 1,600 mg/day. Patients on carbamazepine should be monitored for hyponatremia and thrombocytopenia.

 

Lithium

 

Lithium has shown some efficacy in reducing amphetamine-related locomotor activation.33 Larger epidemiological trials are needed to validate this finding. Lithium has also been used safely in the treatment of bipolar adolescents with secondary substance dependence.34,35 A recent study36 demonstrated that bipolar patients treated with lithium have a lower risk for suicide than those treated with divalproex (after controlling for comorbid medical and psychiatric conditions). Usual starting doses of lithium are 300 mg twice daily, with doses up to 1,200 mg/day or higher. It is important to monitor lithium levels (usually between 0.6–1.2 mEq/L), and thyroid and renal function. Future studies need to address this medication specifically in those patients with comorbid bipolarity and some types of substance abuse.

 

Gabapentin

 

Gabapentin has been extremely useful for treatment of comorbid bipolar, anxiety, and substance abuse disorders.37 A recent study reported that gabapentin appeared to be safe and efficacious in reducing the use of cocaine in a group of psychiatric patients.38

 

Oxcarbazepine

 

Since oxcarbazepine may be considered a prodrug,39 it may be less likely to cause drug-drug interactions. Treatment with oxcarbazepine is started at 600 mg BID, with doses up to 2,400 mg/day. Current consensus states that the dose of oxcarbazepine should be 50% higher than that of carbamazepine. Oxcarbazepine does not have the same well-established record as carbamazepine in the treatment of comorbid substance abuse with bipolar disorder, although the literature has reported its promising use.40,41

 

Topiramate

 

Dosing for topiramate ranges from 300–800 mg. It has been reported that this medication has minimal drug interactions, and may cause weight loss (a potential “virtue”); however, it can cause cognitive dulling.42 This agent can potentially be used for the augmentation treatment bipolar disorder.43 Additionally, it has been reported that topiramate might help as an adjunct treatment in diminishing the impulsive cravings in patients with alcohol use disorders.44,45

 

Lamotrigine

 

Brown and colleagues46 described the potential benefit of lamotrogine in the treatment of patients with bipolar disorder and comorbid cocaine use. This finding is important, since lamotrigine appears to possess antidepressant properties that may be beneficial for patients who are experiencing protracted dysphoria from stimulant withdrawal and who have a comorbid bipolar diathesis.46,47

 

Zonisamide

 

This newer anticonvulsant differs mainly from the others because of its beneficial side-effect profile and reduced risk of drug-drug interactions.41 Studies have reported some benefit of zonisamide in the treatment of bipolar disorder and other psychiatric conditions.48,49 However, as reported by McElroy and Keck,50 it is necessary to guide clinical practice on evidence-based medicine, leaving enough flexibility to tailor the appropriate treatment to each individual patient. Although the medications described above, including zonisamide and the other mood stabilizers, are helpful in treating patients that fall into the substance abuse bipolar spectrum, there is a need for more studies that will further validate the importance of adequately treating this complicated disorder.

 

Other Potential Treatments

 

Several short-term trials using antidepressants demonstrated some reduction in the consumption of stimulants, and showed potential in achieving abstinence.51 These trials have been performed using imipramine, desipramine, fluoxetine, and pramipexole.52-55

 

However, it is generally best to avoid antidepressants in stimulant abuse patients, since these patients could be switched to a mixed or manic state. Treatment of these patients with an anticonvulsant first to control their increased irritability, dysphoria, racing thoughts, insomnia, and agitation beyond the expected phase of a withdrawal episode is therefore recommended.

 

New-generation antipsychotics have also been also used for the treatment of the proposed spectrum of bipolar and addictive disorders. Brown and colleagues56 reported that quetiapine could be used to stabilize patients with bipolar disorder and to reduce their cocaine use. Recently, a pilot trial showed that olanzapine was not effective in the treatment of primary cocaine dependence without baseline mood disorder.57 Future clinical trials need to elucidate the use of these medications in patients with comorbid bipolar disorder and substance abuse, especially stimulant use.

 

Discussion

 

This review has presented information about two conditions, bipolar disorder and SUD, which could be considered as a continuum of a bipolar spectrum. This model of a continuum of bipolar and substance abuse disorders was exemplified using stimulant abuse as a case in point.24

 

A similar hypothesis involving the heroin-bipolar connection has been proposed by Maremmani and colleagues.58 Additionally, the proposed hypothesis by Khantzian and colleagues59 on “self-medication” in individuals with stimulant use disorders has raised several questions regarding possible associations between temperament and stimulant addiction. Aharonovich and colleagues60 recently tested a similar hypothesis: the investigators used the State-Trait Anger Expression Inventory in 60 individuals with SUD, including cocaine, heroin, and marijuana use disorders, and found that individuals with cocaine use disorders reported a trend toward more angry temperament compared with individuals with opioid addiction. Studies done by Helfrich and colleagues61 and Craig62 found that patients with cocaine abuse problems had increased problems with impulsive behavior, acting out, and authority figures, according to patients’ scores on the Minnesota Multiphasic Personality Inventory.61,62

 

When prescribing for such conditions, the clinician should keep in mind the possibility of increased side effects associated with the concomitant use of medications and addictive substances, especially stimulants,63,64 although it is also important to provide the care necessary to avoid devastating behavioral consequences of substance-related mood and psychotic disorders, particularly if there are stimulants involved. It is also important to treat comorbid bipolar disorder and substance abuse as a continuum and not as isolated disorders.24,65

 

Furthermore, experts in the field of addiction have emphasized the importance of a detailed lifetime evaluation for independent psychiatric problems and SUD. In this process, careful attention should be placed on patients with bipolar disorder, as they may not provide a reliable information about their comorbid substance abuse.66-68

 

Increasing training in the early identification of individuals with a bipolar-addiction diathesis could avoid problems, such as overprescribing stimulants or antidepressants in susceptible individuals whose initial presentation is depression.69 Despite reported stabilization of bipolar-related electroencephalographic changes with methylphenidate, the clinician should be cautious in prescribing stimulants to bipolar patients.70 With documented attention-deficit/hyperactivity disorder history preceding and/or co-existing with bipolar and substance abuse, mood-stabilizing anticonvulsants should be the mainstay of a treatment regimen; the difficult clinical judgment to add a stimulant to this regimen should be deferred to experts with a great deal of experience in this area.

 

Prospective studies on this subject should assess the risks and benefits of long-term use of stimulants for conditions such as attention-deficit disorder, which could be the initial presentation of a bipolar diathesis.71-74 Adequate follow-up and constant review of the working diagnosis is important to prevent the possible development of a complicated bipolar-stimulant use diathesis.75-78 The use of standardized questionnaires to estimate levels of cravings for substances and early identification of a bipolar spectrum could also possibly prevent devastating outcomes in these individuals.79,80

 

Conclusion

 

To summarize, this article presents co-occurring SUD and bipolar disorder as part of the bipolar spectrum, although it recognizes that knowledge on this subject is still limited. Understanding and identifying the different faces of the bipolar spectrum is necessary in order to offer prompt treatment, avoid suicide episodes, and educate patients about the detrimental effect of addictive substances.81,82 This clinically heuristic model to reconceptualize the relationship between bipolar spectrum and substance abuse disorders opens therapeutic opportunities to co-occurring bipolar and substance abuse disorders in both psychiatric and general medical settings. PP

 

References

 

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48. McElroy SL, Kotwal R, Hudson JI, Nelson EB, Keck PE. Zonisamide in the treatment of binge-eating disorder: an open-label, prospective trial. J Clin Psychiatry. 2004;65(1):50-56.
49. Kanba S, Yagi G, Kamijima K, et al. The first open study of zonisamide, a novel anticonvulsant, shows efficacy in mania. Prog Neuropsychopharmacol Biol Psychiatry. 1994;18(4):707-715.
50. McElroy SL, Keck PE Jr. Pharmacologic agents for the treatment of acute bipolar mania. Biol Psychiatry. 2000;48(6):539-557.
51. Gawin F, Kleber H. Pharmacologic treatments of cocaine abuse. Psychiatr Clin North Am. 1986;9(3):573-583.
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55. Batki SL, Moon J, Delucchi K, et al. Methamphetamine quantitative urine concentrations during a controlled trial of fluoxetine treatment. Preliminary analysis. Ann N Y Acad Sci. 2000;909:260-263.
56.  Brown ES, Nejtek VA, Perantie DC, Bobadilla L. Quetiapine in bipolar disorder and cocaine dependence. Bipolar Disord. 2002;4(6):406-411.
57.  Kampman KM, Pettinati H, Lynch KG, Sparkman T, O’Brian CP. A pilot trial of olanzapine for the treatment of cocaine dependence. Drug Alcohol Depend. 2003;70(3):265-273.
58. Maremmani I, Pacini M, Lubrano S, Lovrecic M, Perugi G. Dual diagnosis heroin addicts. The clinical and therapeutic aspects. Heroin Addict Relat Clin Probl. 2003;5(2):7-98.
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62. Craig RJ. Psychological functioning of cocaine free-basers derived from objective psychological tests. J Clin Psychol. 1988;44(4):599-606.
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Are Some Forms of Substance Abuse Related to the Bipolar Spectrum? Hypothetical Considerations and Therapeutic Implications

Alvaro Camacho, MD

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Primary Psychiatry. 2004;11(9):42-46
 

Dr. Camacho is a research fellow with the International Mood Center in the Department of Psychiatry at the University of California in San Diego, and is attending psychiatrist at Imperial County Behavioral Health in El Centro, California.

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

Please direct all correspondence to: Alvaro Camacho, MD, University of California, San Diego, International Mood Center, Department of Psychiatry, 9500 Gilman Dr, Mail Code 0603, La Jolla, CA 92037-0603; Tel: 619-252-0428; Fax: 619-497-6686; E-mail: acamacho@ucsd.edu.
 

Focus Points

• Substance abuse is the most common comorbid condition in individuals diagnosed with bipolar disorder.
• Alcohol and stimulants are the most commonly abused substances in patients with bipolar disorder.
• Patients with bipolar disorder and substance abuse should be started sooner rather than later on a mood stabilizer, despite the risks and side effects associated with the particular medication.
• Clinicians should pay close attention to premorbid dysphoria and irritability associated with states of withdrawal from substances, which could be the prodromal phase of a bipolar depressive episode; if left untreated, further relapse and exacerbation of mood symptoms is possible.
• Bipolar and substance abuse conditions may share a common diathesis, which may in part explain the overlap in therapeutic modalities.

 

Abstract

The use of addictive substances is prevalent among individuals with bipolar disorder (the so-called “dual diagnosis” phenomenon). New studies have led to the proposal that the two groups of disorders exist on a continuum. The Akiskal-Pinto bipolar spectrum schema describes this continuum as bipolar type III 1/2. This review explores the possibility that some forms of substance abuse, especially stimulant abuse, can belong to the bipolar spectrum. These forms of substance abuse respond to anticonvulsant medications used as mood stabilizers. The review is divided into the following sections: neurobiology of addictive disorders, epidemiology of bipolar illness and comorbid substance abuse (particularly stimulant abuse), and clinical correlation with proposed treatment options. The proposed spectrum, with emphasis on stimulant use and bipolar disorder, provides an alternative understanding to a phenomenon that otherwise remains a diagnostic dilemma and therapeutic quagmire. Anticonvulsant medications appear to be a viable joint option for a proportion of patients with this condition.

 

Introduction

 

Patients with comorbid mental illness and substance abuse disorders (SUD) frequently present for treatment with a confusing array of psychiatric and physical findings. The importance of identifying the association between mental illness and SUD in these patients was recognized as early as 1979 by McLellan and colleagues.1 Assessment of comorbid mental illness and SUD can be difficult; it begins with an open mind to avoid premature closure of diagnostic possibilities, lest the patient be left without adequate treatment.2 Given the high frequency of substance abuse among patients with mental disorders, clinicians should use a probing diagnostic approach.2-4 In order to clarify the relationship between SUD and mental illness it is recommended that they assess: when the initial mental symptoms began, and, in the case of an exacerbation, under which circumstances the symptoms began again; when the SUD started and whether the symptoms preceded the development of substance abuse; which subjective effects the substance has on the psychiatric symptoms (relief, exacerbation or cessation); and whether or not patterns of substance use alleviate the underlying psychiatric phenomena.

 

Of all Axis I mental disorders, mood disturbances—especially bipolar disorder—are most likely to co-occur with SUD. Studies5,6 have described that an earlier onset of bipolar disorder is seen in patients who develop SUD compared to those who do not, suggesting that an earlier age at onset of mood symptoms may put individuals at risk for developing an addiction disorder.

 

This review attempts to inform the clinician about the increasing evidence of comorbidity between bipolar disorder and substance use, with a particular emphasis on stimulant use disorders. The article will review the neurobiology of addiction and then the epidemiology of bipolar disorder and addictions, both of which should aid in building clinical correlations, especially with regard to emerging treatments. Stimulant abuse will again be the main focus of the model of bipolar disorder proposed in this article.

 

Neurobiology of Addiction

 

Addiction can be viewed as a form of drug-induced neuronal plasticity. Many studies identifying possible transcription factors that could contribute to the developing of tolerance and eventual dependence on addictive substances are currently underway. Two of the most studied transcription factors are the cyclic adenosine monophosphate (cAMP) response element binding protein (CREB) and the ΔFosB. These transcription factors are responsible for the autoregulation of intracellular transmission, which promotes the biosynthesis of certain neurotransmitters, such as norepinephrine, dopamine, glutamate, and γ-aminobutyric acid, among others, that are responsible for stable adaptations of neuronal function and the reward effects of addictive substances.7

 

Research has shown that the upregulation of the cAMP pathway and the eventual activation of CREB occurs in response to the administration of several drugs of abuse, including opiates, stimulants, and ethanol. The same has been described for the ΔFosB transcription factor.8-10 Thus, these transcription factors play a role in the acute and chronic administration of addictive substances. The activation of CREB is the result of the upregulation of the second messenger pathway of cAMP, which has been described as an adaption to chronic exposure to drugs of abuse, leading to tolerance and dependence. On the other hand, ΔFosB has been implicated in the acute adaptations of addictive substances or sensitization, which refers to the enhanced response to the substance use.7-11

 

CREB and ΔFosB seem to balance each other. CREB has been implicated in drug inhibition and states of withdrawal, depression, and dysphoria, whereas the Fos family of transcription factors has been associated with euphoria, increased locomotor responses to drugs, and rewarding responses to drugs, especially morphine and cocaine.7,8,12 These features bear some resemblance to the biphasic cyclothymic phenomenology of the bipolar spectrum.13 However, whether these underlying mechanisms are similar is speculative at this point.

 

Epidemiology

 

Data from the Epidemiological Catchment Area study14 reported that the lifetime prevalence of any substance abuse or dependence among individuals with bipolar disorder types I and II is 56.1%, and is 60.7% in patients with only bipolar I disorder.2,14 Patients with more complicated forms of bipolar disorder (eg, mixed or rapid-cycling) are also more likely to have SUD.5,15 Antisocial personality disorder is the only psychiatric condition with a reported higher rate of comorbid SUD.2,16,17

 

A recent study done by Copeland and Sorensen18 found that mood disorders accounted for 71% of the diagnoses among individuals with methamphetamine use disorders. A previous study by Winokur and colleagues19 found that individuals with bipolar disorder not only have a higher incidence of alcoholism but also a considerable tendency toward stimulant abuse and dependence. Additionally, these investigators postulated the hypothesis between a common familial-genetic diathesis for a subtype of bipolar disorder and stimulant abuse. This was corroborated in another study,20 which reported that 72% of individuals with a history of alcohol use disorder had a lifetime prevalence of stimulant use (26% with powder cocaine and 46% with crack cocaine). McElroy and colleagues21 described a cohort of 288 bipolar patients in which 33% had lifetime prevalence of alcohol use disorder, followed by an 18% lifetime prevalence of stimulant (including cocaine) use disorder. Moreover, there was no significant difference between patients with bipolar I and bipolar II disorder and their comorbid substance use.

 

Dalton and colleagues22 reported a lifetime rate of 40% of suicide attempts in a cohort of 336 subjects with bipolar I disorder, bipolar II disorder, schizoaffective disorder, and comorbid substance abuse. The authors described that the use of drugs among this cohort was a significant predictor for suicide attempts (P=.037); they described cannabis as the most frequently used substance (74%), followed by hallucinogens (18%), sedatives (18%), and cocaine (18%).

 

Clinical Correlation

 

The question that many clinicians face on a daily basis is which disorder accounts for the symptomatology that the patient is experiencing. Based on the literature reviewed, and building on the Akiskal-Pinto formulation,23 Camacho and Akiskal24 hypothesized the existence of a bipolar-stimulant spectrum. Just as in some depressives with familial-genetic permission for bipolarity who manifest hypomania upon antidepressant challenge,25,26 they suggested that in another group of potential bipolar depressives, stimulant use can bring about the first overt hypomanic or manic episode. They also suggested that anticonvulsants can stabilize the underlying bipolar dysregulation, treat the withdrawal phenomena from substances of abuse, and reduce the craving for the substance.

 

Emerging Treatment Approaches

 

Treatment with Mood Stabilizers

 

Divalproex Sodium

 

The use of divalproex sodium has provided promising results not only in the treatment of patients with comorbid bipolar and SUD, but also as an aid for preventing further relapse. It can be used as an adjunctive agent for detoxification, as well. Starting doses can be 500 mg at night, increased up to 2,000 mg in divided doses. It is important to monitor liver function, pancreatic function, and serum levels when using divalproex.27-29 More longitudinal studies are needed to assess the length of abstinence in these patients.

 

Carbamazepine

 

A preclinical study using carbamazepine posed interesting questions about the utility of this mood stabilizer in treating methamphetamine-related bipolar symptoms and in reducing associated methamphetamine cravings.30 Brady and colleagues31 postulated the utility of this mood stabilizer in patients with cocaine dependence and comorbid affective disorders, and found a trend toward fewer positive urine drug tests. Another study32 demonstrated improvement on self-ratings of depression and irritability. Doses of carbamazepine start at 300 mg BID, and can be increased up to 1,600 mg/day. Patients on carbamazepine should be monitored for hyponatremia and thrombocytopenia.

 

Lithium

 

Lithium has shown some efficacy in reducing amphetamine-related locomotor activation.33 Larger epidemiological trials are needed to validate this finding. Lithium has also been used safely in the treatment of bipolar adolescents with secondary substance dependence.34,35 A recent study36 demonstrated that bipolar patients treated with lithium have a lower risk for suicide than those treated with divalproex (after controlling for comorbid medical and psychiatric conditions). Usual starting doses of lithium are 300 mg twice daily, with doses up to 1,200 mg/day or higher. It is important to monitor lithium levels (usually between 0.6–1.2 mEq/L), and thyroid and renal function. Future studies need to address this medication specifically in those patients with comorbid bipolarity and some types of substance abuse.

 

Gabapentin

 

Gabapentin has been extremely useful for treatment of comorbid bipolar, anxiety, and substance abuse disorders.37 A recent study reported that gabapentin appeared to be safe and efficacious in reducing the use of cocaine in a group of psychiatric patients.38

 

Oxcarbazepine

 

Since oxcarbazepine may be considered a prodrug,39 it may be less likely to cause drug-drug interactions. Treatment with oxcarbazepine is started at 600 mg BID, with doses up to 2,400 mg/day. Current consensus states that the dose of oxcarbazepine should be 50% higher than that of carbamazepine. Oxcarbazepine does not have the same well-established record as carbamazepine in the treatment of comorbid substance abuse with bipolar disorder, although the literature has reported its promising use.40,41

 

Topiramate

 

Dosing for topiramate ranges from 300–800 mg. It has been reported that this medication has minimal drug interactions, and may cause weight loss (a potential “virtue”); however, it can cause cognitive dulling.42 This agent can potentially be used for the augmentation treatment bipolar disorder.43 Additionally, it has been reported that topiramate might help as an adjunct treatment in diminishing the impulsive cravings in patients with alcohol use disorders.44,45

 

Lamotrigine

 

Brown and colleagues46 described the potential benefit of lamotrogine in the treatment of patients with bipolar disorder and comorbid cocaine use. This finding is important, since lamotrigine appears to possess antidepressant properties that may be beneficial for patients who are experiencing protracted dysphoria from stimulant withdrawal and who have a comorbid bipolar diathesis.46,47

 

Zonisamide

 

This newer anticonvulsant differs mainly from the others because of its beneficial side-effect profile and reduced risk of drug-drug interactions.41 Studies have reported some benefit of zonisamide in the treatment of bipolar disorder and other psychiatric conditions.48,49 However, as reported by McElroy and Keck,50 it is necessary to guide clinical practice on evidence-based medicine, leaving enough flexibility to tailor the appropriate treatment to each individual patient. Although the medications described above, including zonisamide and the other mood stabilizers, are helpful in treating patients that fall into the substance abuse bipolar spectrum, there is a need for more studies that will further validate the importance of adequately treating this complicated disorder.

 

Other Potential Treatments

 

Several short-term trials using antidepressants demonstrated some reduction in the consumption of stimulants, and showed potential in achieving abstinence.51 These trials have been performed using imipramine, desipramine, fluoxetine, and pramipexole.52-55

 

However, it is generally best to avoid antidepressants in stimulant abuse patients, since these patients could be switched to a mixed or manic state. Treatment of these patients with an anticonvulsant first to control their increased irritability, dysphoria, racing thoughts, insomnia, and agitation beyond the expected phase of a withdrawal episode is therefore recommended.

 

New-generation antipsychotics have also been also used for the treatment of the proposed spectrum of bipolar and addictive disorders. Brown and colleagues56 reported that quetiapine could be used to stabilize patients with bipolar disorder and to reduce their cocaine use. Recently, a pilot trial showed that olanzapine was not effective in the treatment of primary cocaine dependence without baseline mood disorder.57 Future clinical trials need to elucidate the use of these medications in patients with comorbid bipolar disorder and substance abuse, especially stimulant use.

 

Discussion

 

This review has presented information about two conditions, bipolar disorder and SUD, which could be considered as a continuum of a bipolar spectrum. This model of a continuum of bipolar and substance abuse disorders was exemplified using stimulant abuse as a case in point.24

 

A similar hypothesis involving the heroin-bipolar connection has been proposed by Maremmani and colleagues.58 Additionally, the proposed hypothesis by Khantzian and colleagues59 on “self-medication” in individuals with stimulant use disorders has raised several questions regarding possible associations between temperament and stimulant addiction. Aharonovich and colleagues60 recently tested a similar hypothesis: the investigators used the State-Trait Anger Expression Inventory in 60 individuals with SUD, including cocaine, heroin, and marijuana use disorders, and found that individuals with cocaine use disorders reported a trend toward more angry temperament compared with individuals with opioid addiction. Studies done by Helfrich and colleagues61 and Craig62 found that patients with cocaine abuse problems had increased problems with impulsive behavior, acting out, and authority figures, according to patients’ scores on the Minnesota Multiphasic Personality Inventory.61,62

 

When prescribing for such conditions, the clinician should keep in mind the possibility of increased side effects associated with the concomitant use of medications and addictive substances, especially stimulants,63,64 although it is also important to provide the care necessary to avoid devastating behavioral consequences of substance-related mood and psychotic disorders, particularly if there are stimulants involved. It is also important to treat comorbid bipolar disorder and substance abuse as a continuum and not as isolated disorders.24,65

 

Furthermore, experts in the field of addiction have emphasized the importance of a detailed lifetime evaluation for independent psychiatric problems and SUD. In this process, careful attention should be placed on patients with bipolar disorder, as they may not provide a reliable information about their comorbid substance abuse.66-68

 

Increasing training in the early identification of individuals with a bipolar-addiction diathesis could avoid problems, such as overprescribing stimulants or antidepressants in susceptible individuals whose initial presentation is depression.69 Despite reported stabilization of bipolar-related electroencephalographic changes with methylphenidate, the clinician should be cautious in prescribing stimulants to bipolar patients.70 With documented attention-deficit/hyperactivity disorder history preceding and/or co-existing with bipolar and substance abuse, mood-stabilizing anticonvulsants should be the mainstay of a treatment regimen; the difficult clinical judgment to add a stimulant to this regimen should be deferred to experts with a great deal of experience in this area.

 

Prospective studies on this subject should assess the risks and benefits of long-term use of stimulants for conditions such as attention-deficit disorder, which could be the initial presentation of a bipolar diathesis.71-74 Adequate follow-up and constant review of the working diagnosis is important to prevent the possible development of a complicated bipolar-stimulant use diathesis.75-78 The use of standardized questionnaires to estimate levels of cravings for substances and early identification of a bipolar spectrum could also possibly prevent devastating outcomes in these individuals.79,80

 

Conclusion

 

To summarize, this article presents co-occurring SUD and bipolar disorder as part of the bipolar spectrum, although it recognizes that knowledge on this subject is still limited. Understanding and identifying the different faces of the bipolar spectrum is necessary in order to offer prompt treatment, avoid suicide episodes, and educate patients about the detrimental effect of addictive substances.81,82 This clinically heuristic model to reconceptualize the relationship between bipolar spectrum and substance abuse disorders opens therapeutic opportunities to co-occurring bipolar and substance abuse disorders in both psychiatric and general medical settings. PP

 

References

 

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38. Raby WN, Coomaraswamy S. Gabapentin reduces cocaine use among addicts from a community clinic sample. J Clin Psychiatry. 2004;65(1):84-86.
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41. LaRoche SM, Helmers SL. The new antiepileptic drugs: scientific review. JAMA. 2004;291(5):605-614.
42. Nemeroff CB. Safety of available agents used to treat bipolar disorder: focus on weight gain. J Clin Psychiatry. 2003;64(5):532-539.
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44. Komanduri R. Two cases of alcohol craving curbed by topiramate. J Clin Psychiatry. 2003;64(5):612.
45. Johnson BA, Ait-Daoud N, Bowden CL, et al. Oral topiramate for the treatment of alcohol dependence: a randomized controlled trial. Lancet. 2003;361(9370):1677-1685.
46. Brown ES, Nejtek VA, Perantie DC, Orsulak PJ, Bobadilla L. Lamotrigine in patients with bipolar disorder and cocaine dependence. J Clin Psychiatry. 2003;64(2):197-201.
47. Southam E, Kirkby D, Higgins GA, Hagan RM. Lamotrigine inhibits monoamine uptake in vitro and modulates 5-hydroxytryptamine uptake in rats. Eur J Pharmacol. 1998;358(1):19-24.
48. McElroy SL, Kotwal R, Hudson JI, Nelson EB, Keck PE. Zonisamide in the treatment of binge-eating disorder: an open-label, prospective trial. J Clin Psychiatry. 2004;65(1):50-56.
49. Kanba S, Yagi G, Kamijima K, et al. The first open study of zonisamide, a novel anticonvulsant, shows efficacy in mania. Prog Neuropsychopharmacol Biol Psychiatry. 1994;18(4):707-715.
50. McElroy SL, Keck PE Jr. Pharmacologic agents for the treatment of acute bipolar mania. Biol Psychiatry. 2000;48(6):539-557.
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Return

Focus Points

• The tolerability and adverse-effect profiles of the newer psychotropic drugs for bipolar disorder affect the therapeutic benefits of these agents.

• The ability of clinicians to provide optimal treatments after considering differential adverse effects and tolerability increases medication compliance in patients who might otherwise discontinue treatment due to adverse effects.

• Strategies exist for either minimizing or counteracting the adverse effects of most psychotropic agents.

• Clinical decisions to switch primary medications due to adverse effects—rather than treat through adverse effects—must reflect careful balancing of drug efficacy (benefits) versus side-effect liability (costs).

Abstract

How do the tolerability and adverse-effect profiles of newer psychotropic drugs for bipolar disorder balance against their enhanced therapeutic benefits? The growing range of pharmacotherapy options across all phases of bipolar illness should, ideally, enhance the ability of clinicians to provide optimal treatments while considering differential adverse effects and drug tolerability. Such approaches help to increase medication adherence in patients who might otherwise discontinue treatment due to adverse effects. Clinically diverse, often significant adverse effects are evident with both older and newer drug therapies for bipolar illness. Most notably, problems related to gastrointestinal upset, weight gain, glucose dysregulation, sexual dysfunction, cognitive impairment, dermatologic reactions, and central nervous system effects are a potential liability with numerous compounds. Strategies exist for either minimizing or counteracting the adverse effects of most psychotropic agents. These include slow-dose escalations, preferential use of delayed-release formulations, and adjunctive treatments with additional agents. Clinical decisions to switch primary medications due to adverse effects—rather than treat through adverse effects—must reflect careful balancing of drug efficacy (benefits) versus side-effect liability (costs).

Introduction

Rates of medication nonadherence among patients with bipolar disorder are unacceptably high, ranging from 10% to 60% (median 40%) of patients discontinuing treatment.1 Evidence of this high rate was shown in a recent study of the bipolar medication lithium,2 which found that health maintenance organization enrollees with bipolar disorder discontinued lithium a median of only 72 days after starting it. With such high rates of treatment nonadherence in bipolar patients, it is therefore critical for clinicians to understand how the tolerability and adverse-effect profiles of newer psychotropic drugs for bipolar disorder balance against their enhanced therapeutic benefits. As such, this article provides an overview of common adverse effects associated with current pharmacotherapies for bipolar disorder, and describes strategies for their management in order to optimize treatment outcomes.

Paradoxically, while psychotropic medications are prescribed in efforts to enhance patient functionality and quality of life, they may actually create new physical, cognitive, or other problems that can jeopardize treatment adherence and physical well-being (Table). In fact, patients may interpret the adverse effects of medications such as lithium as problems that mimic physical illness and may obscure diagnostic issues related to patients with bipolar disorder.3

Additionally, while current texts and guidelines caution against or limit the use of antidepressants in patients with bipolar disorder,4,5 data from the National Disease and Therapeutic Index indicate that antidepressants are prescribed more frequently than mood stabilizers.6 Therefore, common side effects associated with antidepressant use are also enumerated in this article.

Adverse Effects and Treatment Adherence

Among bipolar patients, attitudes and expectations about adverse effects appear to contribute more to medication nonadherence than do actual adverse effects themselves.7 That aside, the balance between therapeutic efficacy and adverse effects is illustrated in clinical trials that compare benefits versus dropout rates due to adverse effects. For example, a recent 18-month comparison of bipolar relapse prevention8 compared lithium or divalproex plus placebo or olanzapine. Although one might expect more dropout due to adverse effects among those taking more medications, trial completion was three times more likely for those on combination therapy (31.4%) than monotherapy (10.4%), while adverse effects were more common for those on monotherapy (9.8%) than combination therapy (16.7%). Similarly, Keck and colleagues9 found significantly greater medication adherence during combined maintenance treatment with lithium plus divalproex compared to either one alone, again suggesting that if combinations produce better efficacy than monotherapies, better efficacy in turn may help to promote treatment adherence.

Adverse Effects Associated with Medications Used in Bipolar Disorder

Gastrointestinal Disturbances

Nausea, vomiting, and diarrhea are commonly seen with lithium, valproate, and selective serotonin reuptake inhibitors (SSRIs). Bowden and colleagues10 demonstrated that nearly 50% of patients treated with lithium experienced nausea and diarrhea. The onset of nausea tends to be related to peak serum levels and may reflect the rapidity with which plasma levels are increased.4,11 Therefore, temporarily reducing the dose (as long as clinical efficacy is not compromised) or prescribing a slow-release formulation may alleviate nausea and other upper gastrointestinal (GI) effects. However, in some patients, diarrhea is reportedly increased by some slow-release formulations due to more distal absorption.12,13 Nausea may also be alleviated by taking lithium with meals.4 Use of lithium citrate syrup is also reported to decrease GI side effects.14

Similarly, GI disturbances are the most frequent adverse events associated with valproate. Zarate and colleagues15 demonstrated that approximately 63% of patients discontinued generic valproate treatment due to GI side effects; subsequent treatment with the enteric-coated formulation of divalproex was better tolerated. The extended-release formulation of divalproex may be associated with less nausea than the delayed-release preparation.16

All SSRIs have been shown to produce some degree of nausea and GI disturbance. Such effects appear to be transient and typically resolve within the first month of treatment.17 Gradual dose titration may be helpful in avoiding onset of these symptoms.

Weight Gain

Although weight gain is not the most common side effect associated with bipolar medication use, it may be the most distressing.18 In addition, overweight and obesity are significant public health concerns in the United States: they affect >61% of all American adults19 and are associated with hypertension, type II diabetes, and cardiovascular disease, as well as many other medical conditions.20 Independent of pharmacotherapy, rates of overweight and obesity are substantially elevated among individuals with bipolar disorder and may be directly related to recurrent depressive episodes as well as poorer functional outcome.21

The majority of agents currently used to treat bipolar disorder have been associated with some degree of weight gain, although variability may exist across compounds. Data from a 1-year monotherapy study10 of relapse prevention comparing lithium, divalproex, and placebo demonstrate that only patients treated with divalproex experienced significantly more weight gain than those taking placebo. However, weight gain has been associated with lithium use in other reports.22 In early reports, carbamazepine was associated with less weight gain than lithium,23 although data from a more recent controlled maintenance trial24 revealed appetite increases as occurring more often with carbamazepine (33%) than lithium (17%). Weight has been shown to remain stable or slightly decrease with the anticonvulsant lamotrigine.25

In both short- and long-term comparative studies of olanzapine or divalproex monotherapy in bipolar disorder, patterns of weight gain have differed with each treatment. For example, more weight gain was evident with olanzapine than divalproex during a 12-week acute mania study,26 and total weight was more extensive with olanzapine than divalproex monotherapy over a 1-year relapse prevention study.27 When weight gain occurs with olanzapine it tends to arise rapidly during the first few weeks and months, plateauing by 9 months.28 By contrast, weight gain with divalproex appears to occur more gradually (such that, for example, the magnitude of weight gain with divalproex matched that seen with olanzapine after 9 months in a trial by Tohen and colleagues27).

An inherent problem in attributing weight increases to psychotropic drug therapy involves judging the extent to which it may alternatively reflect illness-specific phenomena, such as hyperphagia, lethargy, and other vegetative signs. Further complicating the picture is the observation that some patients may be genetically predisposed to gain more weight when taking an atypical antipsychotic, such as clozapine.29 This indicates that not all patients may share the same adverse effect vulnerability.

Generalizations about weight changes associated with second-generation antipsychotics are limited by intermixed data involving patients with bipolar disorder, schizophrenia, and other diagnoses.20,28 Across diagnoses, clozapine and olanzapine appear to be associated with the most weight gain (ranging from approximately 2.7–5.3 kg).20 Ziprasidone produces nominal weight gain (approximately 0.5 kg), while risperidone and quetiapine have been associated with intermediate gain (approximately 1.6–2.4 kg).20,30 Aripiprazole appears to be associated with minimal weight gain in the existing short-term studies for bipolar disorder31; longer-term (ie, 1-year) trials in schizophrenia patients reveal a >7% increase in body weight for 30% of patients with low (<23) body mass index (BMI), 19% for those with normal BMI (23–27), and 8% for those with BMI >27.32

Adjunctive treatment with the anticonvulsant topiramate may be beneficial in reducing psychotropic drug-induced weight gain. Data show that patients treated with topiramate in combination with lithium, valproate, carbamazepine, or an antipsychotic lost an average of 9.4 pounds over 5 weeks.33 However, topiramate itself is associated with a range of side effects, including paresthesias, renal calculi, increased intraocular pressure, secondary narrow-angle glaucoma, and cognitive dysfunction.34 Preliminary findings with the anticonvulsant zonisamide, which is potentially useful in bipolar disorder,35 suggest that it too may be associated with weight loss.36

It is often difficult for clinicians to know when it is more advantageous to attempt remedial strategies aimed at overcoming an adverse effect, such as weight gain, and when it is preferable to substitute an alternative agent. The obvious limitation of this latter strategy is that therapeutic efficacy for a given patient cannot be assumed across diverse agents, even within a given class (as exemplified by the variable efficacy across antimicrobials, antiarrhythmics, antiepileptics, and other types of medication classes).

Nonpharmacologic interventions that have shown success for psychotropic-induced weight gain include dietary counselling prior to prescribing medications,37 diet programs,38 exercise programs,39 and behavior modification programs, although the success of behavioral programs may not always be sustained long-term.7,40

Dyslipidemias and Glucose Dysregulation

Awareness has grown regarding the potential for individuals with bipolar disorder to be at risk for cardiovascular disease,41 as well as adult-onset diabetes mellitus.42 Both conventional and atypical antipsychotics have been associated with an increased risk for new-onset type II diabetes,43,44 and some second-generation antipsychotics may impose a heightened risk for elevated low-density lipoprotein cholesterol and triglyceride levels.44,45 The mechanisms by which conventional or second-generation antipsychotics may be associated with glucose dysregulation are likely complex and not merely the byproduct of peripheral insulin resistance due to weight gain.31 Serious instances of diabetic ketoacidosis have been described within weeks of beginning some second-generation antipsychotics.31,45 A nested case study43 in the United Kingdom observed that antipsychotic exposure may increase risk for type II diabetes alongside a range of other baseline risk factors, including psychiatric diagnosis, hypertension, and alcoholism.

Recently, the Food and Drug Administration requested updated product labeling for all atypical antipsychotics; this labeling includes a warning regarding the risk of hyperglycemia and diabetes.46 However, the FDA did not address the differing amounts of risk relevant to each agent. Rather, the label only states that patients who develop suggestive symptoms during treatment with an atypical antipsychotic should be tested for diabetes. Patients at risk for diabetes (eg, those with obesity or family history of diabetes) should undergo fasting glucose testing at baseline, and periodically throughout treatment, and patients with a history of diabetes who begin taking atypical antipsychotics should be monitored for a worsening of glucose control.46

Sexual Dysfunction

Effects on sexual function ranging from diminished libido to orgasmic and erectile dysfunction are considered to be relatively prevalent with SSRIs (incidence rates reported have been as high as 34%)47; however, they may also occur with other psychotropics. Depression and other severe psychiatric disorders can themselves obviously contribute to loss of sexual interest, requiring careful clinical evaluation to differentiate iatrogenic from illness-related symptoms.

A number of pharmacologic and nonpharmacologic strategies have been described, each with varying degrees of success. In the case of SSRIs, undesired pharmacologic agonism at the postsynaptic 5-HT2A receptor has been implicated in the mechanism of sexual dysfunction,48 suggesting that agents which block this receptor, such as nefazodone, mirtazapine, or second-generation antipsychotics, may entail fewer sexual side effects.

SSRI dosage reductions have been advocated by some authors as one possible strategy, although no controlled trials exist to examine this approach rigorously.47 Drug holidays have been reported to have a modest degree of success with some SSRIs,49 although periodic planned drug cessation interferes with spontaneity and may discourage overall patient compliance. Moreover, in the case of SSRIs with a longer half-life, such as fluoxetine, this approach may be of little value. Using medications that either modify or compensate for the increased genitourinary serotonergic tone, such as cyproheptadine,50,51 represents another plausible strategy, particularly for patients who have shown good response and otherwise tolerate the SSRI well. Varying degrees of evidence, from controlled trials to clinical reports, exist to support the use of numerous adjunctive agents, including granisetron,52 sildenafil,53 yohimbine,54 ginkgo biloba,55 methylphenidate,56 amantadine,57 or buspirone,58 although most controlled trials with these agents have yielded only modest success. The antidepressant bupropion also has been suggested as a possible substitution strategy for an SSRI, based on its relatively lower incidence of sexual side effects,59 although clinicians should not automatically assume that the substitution of any one antidepressant for another will show equal efficacy. Open trials augmenting serotonergic drugs with bupropion also suggest its value as an adjunctive strategy to help diminish SSRI-associated sexual dysfunction.60 A recent placebo-controlled trial61 of bupropion augmentation of SSRIs found improved sexual desire and frequency but no global change in sexual functioning with bupropion compared to placebo.

Cognitive Impairment and Sedation

Cognitive dysfunction—particularly impaired attention and executive function—have increasingly become recognized as common features that are intrinsic to bipolar disorder across its illness phases.62 Thus, clinicians must discern the extent to which subjective complaints involving memory, attention, or concentration are reflections of a genuine neurocognitive deficit,63 or likely the result of the illness or of medication.

Mental sluggishness is often described as an adverse effect associated with lithium, even among healthy individuals.64 One uncontrolled study65 reported improvement in the cognitive complaints associated with lithium after switching to divalproex. Among anticonvulsant agents, cognitive impairment appears to be less likely to occur with either lamotrigine or gabapentin among both epilepsy and bipolar patients.66 Topiramate is associated with somnolence, impaired concentration or attention, word-finding difficulties, and subjective cognitive dulling.66 In the authors’ experience, adverse effects such as these occur most often when dosages are escalated too rapidly above 50–100 mg/day. In the aftermath of several negative randomized controlled trials to assess the antimanic efficacy of topiramate for bipolar mania, increasing attention has focused on its potential value for ancillary problems related to bipolar illness, such as weight gain.

Cognitive dysfunction is well established with the use of first-generation antipsychotics, particularly low-potency neuroleptics that possess significant anticholinergic effects. Cognitive impairment has generally been described as less extensive with second-generation antipsychotics in schizophrenics67 or in healthy volunteers,68 although little information is available specifically for patients with bipolar disorder. In one of the few existing preliminary studies of neurocognitive function and pharmacotherapy for bipolar disorder, Reinares and colleagues69 observed better attentional functioning in bipolar patients taking risperidone than conventional antipsychotics.

Dermatologic Effects

Many psychotropic drugs have been associated with cutaneous reactions. In the case of lamotrigine, skin rashes have been the most frequent adverse event leading to drug discontinuation in controlled trials in epilepsy.70,71 However, in nearly all instances, such rashes have been benign and likely the result of rapid dose escalation strategies which were previously recommended in the first few years lamotrigine was available. Currently, rashes of any kind occur in approximately 10% of patients treated with lamotrigine; severe cases resulting in hospitalization occur in 0.3% of adults and 1% of children. Importantly, the revised slower-dose escalation schedule established in 1994 has led to a marked reduction in the incidence of skin rash. The incidence of rash is higher when given with concomitant valproate due to their pharmacokinetic interaction, although lamotrigine can be safely co-prescribed with valproate when doses are escalated twice as slowly as with monotherapy.34 Rash and Stevens-Johnson syndrome have also been associated with use of divalproex72 and carbamazepine.34

In the case of lithium, case reports have described exacerbations or first occurrences of psoriasis,73 which may be improved with the use of appropriate dermatologic preparations or by lowering the lithium dose. Severe pustular acne that does not respond well to dermatologic treatment is also associated with lithium treatment and resolves only with lithium discontinuation.3

Tremor

Tremor, whether resting or exacerbated by activity, is a common problem for patients taking lithium. Incidence rates range from 4% to 65%. The wide variability is due to differences in definition and reporting and possibly also to differences in peak lithium levels.74 Lithium-induced tremor is frequently treated successfully with β-blockers, such as propranolol, although patients should be monitored for bradycardia due to this combination.74

Symptomatic tremor also occurs in approximately 10% of patients treated with valproate.75 Valproate-induced tremor may be treated with amantadine or propranolol, both of which are associated with side effects of their own.76

Mania Induction and Rapid Cycling

Antidepressants have been reported to induce mania in approximately one-third of patients overall with bipolar disorder,77-80 although the likelihood that any given antidepressant trial might lead to a manic or hypomanic episode in a known bipolar patient is probably <15% to 20%.79,81 Although practitioners frequently assume that SSRIs or other newer-generation antidepressants are substantially less likely than older antidepressants to induce mania, the database from which this impression has arisen is not extensive.80-85 Growing evidence has begun to suggest that some patients with bipolar disorder may inherently be at higher risk for developing antidepressant-induced mania; such vulnerability factors may include a history of prior antidepressant-induced mania, a family history of bipolar disorder or other genetic factors, exposure to multiple antidepressant trials, and comorbid substance abuse.79,80 Recent naturalistic studies86-88 have begun to challenge a prior literature linking antidepressant overuse with mood destabilization or cycle acceleration. However, while these reports attest to the persistence of depression in bipolar disorder, it is difficult to conclude from such noncontrolled, nonrandomized studies which bipolar patients are or are not suitable candidates for receiving standard antidepressants to manage their depression.

Standard mood stabilizers, such as lithium or valproate, are thought to confer some protection against the possibility of antidepressant-induced mania, although this assumption is not robustly reported within the literature.80,89,90 By contrast to standard antidepressants or standard mood stabilizers, the compound lamotrigine has demonstrated antidepressant efficacy both acutely91 and long term,92,93 without a greater risk than placebo for inducing mania.

Depressive episodes in bipolar disorder are traditionally difficult to treat. The depressive episodes in bipolar patients often do not respond favorably to many of the mood stabilizers currently approved for use in bipolar disorder, and this may encourage antidepressant use. On the other hand, both lithium and valproate have some antidepressant properties.3,96,97 The magnitude of lithium’s protective effect against recurrent depression appears substantially smaller than its efficacy to prevent manias,98 although lithium and lamotrigine are nonetheless both considered appropriate first-line pharmacotherapies for bipolar depression according to the revised American Psychiatric Association’s “Practice Guidelines for the Treatment of Patients with Bipolar Disorder.”4

Special Considerations in Women

While epidemiologic studies indicate that bipolar disorder equally afflicts men and women,99 a number of gender differences have been observed, including a higher incidence of rapid cycling and mixed states among women than men,100 as well as a higher likelihood of comorbid alcohol abuse or dependence among bipolar women than bipolar men compared to proportional rates in the general population.101 Therapeutic outcomes with certain core treatments, such as lithium, appear comparable in both men and women,102 although gender differences become important when considering adverse-effect profiles across existing psychotropic agents.

First-generation (and some second-generation) antipsychotics, and to some extent SSRIs, may elevate serum levels of prolactin, leading to galactorrhea, sexual dysfunction, impaired fertility, and menstrual disorders.4 In addition, menstrual disturbances associated with valproate use are common among female epileptic populations.103 It has been suggested that polycystic ovarian syndrome (PCOS) and/or hyperandrogenism occur at increased rates among females taking valproate for epilepsy.103,104 Links between PCOS and valproate use remain controversial among nonepileptic women, such as those with migraine or bipolar disorder.105-108

Carbamazepine, oxcarbazepine, and topiramate all increase the metabolism of oral contraceptives, reducing their effectiveness and necessitating the use of other forms of birth control.4 A case series of seven women with epilepsy who received oral contraceptives while being treated with lamotrigine demonstrated that the oral contraceptives reduced lamotrigine plasma levels by 41% to 64% (mean 49%), leading the authors to recommend serum level monitoring of lamotrigine when prescribed concomitantly with an oral contraceptive.109

Laboratory Monitoring

Periodic laboratory testing has the potential to negatively impact patient compliance. In addition, there is no clear agreement even among experts as to the frequency with which laboratory monitoring should be conducted when prescribing lithium, divalproex, or other anticonvulsant drugs used for bipolar disorder.110 The revised APA practice guideline for bipolar disorder4 notes that most psychiatrists obtain hematologic and hepatic function tests at least every 6 months for stable patients taking divalproex, or more often based on clinical status. Among patients taking lithium, the APA practice guideline recommends monitoring renal function every 2–3 months during the first 6 months of treatment, and thyroid function once or twice during this time; these parameters may be checked every 6–12 months thereafter in stable patients, or more often if clinically indicated. In the case of carbamazepine, the APA practice guideline advises obtaining a complete blood count, platelet measures, and liver function tests every 2 weeks during the first 2 months of treatment, and every 3 months thereafter in stable patients.4

At present, atypical antipsychotic agents, as well as newer-generation anticonvulsants, such as topiramate and lamotrigine, do not require monitoring for these side effects, nor is regular monitoring of serum levels required.4 However, in September 2003, the FDA called for the manufacturers of all atypical antipsychotics to include a product warning label regarding the potential increased risk for diabetes and hyperglycemia, particularly among patients with intrinsic background factors for diabetes, such as obesity or a family history of Type II diabetes.46

Clinicians should always give female patients a pregnancy test before initiation of any psychotropic medication, due to the risks of teratogenesis.

Conclusion

Aside from acquiring a sound knowledge of the efficacy of a drug, it is the responsibility of the clinician to closely consider the side-effect profile of a given medication, as well as the unique concerns of the individual patient.

While medications used in treating bipolar disorder have traditionally been associated with numerous adverse events, new information is emerging regarding ways to reduce the incidence and severity of side effects. In addition, new treatment options for treating bipolar disorder continue to emerge. Many of these offer safer side-effect profiles and do not require laboratory monitoring, although the risks and benefits of choosing any pharmacotherapy must be individually tailored to a patient based on their unique clinical circumstances. Safe and appropriate pharmacotherapy for bipolar illness today involves the thoughtful integration of evidence-based efficacy with the anticipation and management of potential adverse effects.

Controversies persist about the potential for antidepressants to worsen the course of bipolar disorder by inducing mania or potentially accelerating cycle frequency in a subgroup of patients. Current practice guidelines advise against the use of antidepressants without mood stabilizers for bipolar I disorder, and caution is warranted when clinicians augment mood stabilizers with standard antidepressants in order to minimize the risk for destabilizing mood both short-term and long-term. PP

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97. Winsberg ME, DeGolia SG, Strong CM, Ketter TA. Divalproex therapy in medication-naive and mood-stabilizer-naive bipolar II depression. J Affect Disord. 2001;67(1-3):207-212.

98. Geddes JR, Burgess S, Hawton K, Jamison K, Goodwin GM. Long-term lithium therapy for bipolar disorder: systematic review and meta-analysis of randomized controlled trials. Am J Psychiatry. 2004;161(2):217-222.

99. Leibenluft E. Women with bipolar illness: clinical and research issues. Am J Psychiatry. 1996;153(2):163-173.

100. Arnold LM. Gender differences in bipolar disorder. Psychiatr Clin North Am. 2003;26(3):595-620.

101. Frye MA, Altshuler LL, McElroy SL, et al. Gender differences in prevalence, risk, and clinical correlates of alcoholism comorbidity in bipolar disorder. Am J Psychiatry. 2003;160(5):883-889.

102. Viguera AC, Tondo L, Baldessarini RJ. Sex differences in response to lithium treatment. Am J Psychiatry. 2000;157(9):1509-1511.

103. Isojarvi JI, Tauboll E, Pakarinen AJ, et al. Altered ovarian function and cardiovascular risk factors in valproate-treated women. Am J Med. 2001;111(4):290-296.

104. Isojarvi JI, Laatikainen TJ, Pakarinen AJ, Juntunen KT, Myllyla VV. Polycystic ovaries and hyperandrogenism in women taking valproate for epilepsy. N Engl J Med. 1993;329(19):1383-1388.

105. Ernst CL, Goldberg JF. The reproductive safety profile of mood stabilizers, atypical antipsychotics, and broad-spectrum psychotropics. J Clin Psychiatry. 2002;63(suppl 4):42-55.

106. Rasgon NL, Altshuler LL, Gudeman D, et al. Medication status and polycystic ovary syndrome in women with bipolar disorder: a preliminary report. J Clin Psychiatry. 2000;61(3):173-178.

107. O’Donovan C, Kusumakar V, Graves GR, Bird DC. Menstrual abnormalities and polycystic ovary syndrome in women taking valproate for bipolar mood disorder. J Clin Psychiatry. 2002;63(4):322-330.

108. McIntyre RS, Mancini DA, McCann S, Srinivasan J, Kennedy SH. Valproate, bipolar disorder and polycystic ovarian syndrome. Bipolar Disord. 2003;5(1):28-35.

109. Sabers A, Buchholt JM, Uldall P, Hansen EL. Lamotrigine plasma levels reduced by oral contraceptives. Epilepsy Res. 2001;47(1-2):151-154.

110. Sachs GS, Printz DJ, Kahn DA, Carpenter D, Docherty JP. The expert consensus guideline series: medication treatment of bipolar disorder 2000. Postgrad Med. 2000;(spec)


Dr. Anderson is assistant professor of psychiatry in the Department of Psychiatry at the University of Illinois College of Medicine in Chicago.

Dr. Goldberg is research scientist in the Department of Psychiatry Research at the Zucker Hillside Hospital of the North Shore–Long Island Jewish Health System in Glen Oaks, New York.

Dr. Harrow is professor in the Department of Psychiatry at the University of Illinois College of Medicine.

Disclosure: Dr. Anderson is on the speaker’s bureau of AstraZeneca. Dr. Goldberg is a consultant for Abbott, AstraZeneca, Bristol-Myers Squibb, Eli Lilly, GlaxoSmithKline, Johnson & Johnson, Novartis, Organon, Ortho-McNeil, Pfizer, and UCB Pharma; is on the speaker’s bureaus of Abbott, AstraZeneca, Bristol-Myers Squibb, Eli Lilly, GlaxoSmithKline, and Novartis; and has received grant and/or research support from Abbott, AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Forest, GlaxoSmithKline, Novartis, Pfizer, The Robert Wood Johnson Foundation, Shire, and UCB Pharma.

Funding/support: This work was supported in part by grant nos. MH-26341 and MH-01936 from the National Institute of Mental Health awarded to Drs. Goldberg and Harrow, by a National Allegiance for Research on Schizophrenia and Depression Young Investigator Award to Dr. Goldberg, and by an unrestricted grant from GlaxoSmithKline.

Please direct all correspondence to: Joseph F. Goldberg, MD, The Zucker Hillside Hospital, 75-59 263rd St, Glen Oaks, NY 11004; Tel: 718-470-4134; Fax: 718-343-1659; E-mail: Jgoldber1@lij.edu.


Return

Focus Points

• Many of the recommendations in the American Psychiatric Association’s “Practice Guideline for the Treatment of Patients with Bipolar Disorder” are supported by a limited evidence base.

• Guideline recommendations may change rapidly as new evidence is generated.

• Some treatments, including antipsychotics, benzodiazepines, and arguably newer antidepressants, could be considered mood stabilizers.

• The frequent recommendation in the guideline of adding medications to nonresponsive patients does not consider the possibility that switching medications is also reasonable.

• Olanzapine and lamotrigine have new evidence of efficacy beyond that which is described in the guideline.

• Directional response is important in choosing medications for bipolar patients.

Abstract

The American Psychiatric Association’s “Practice Guideline for the Treatment of Patients with Bipolar Disorder” represents a major synthesis of the available research and expert clinical opinion on bipolar disorder. The guideline extends beyond the clinical research evidence base and bridges the highly-controlled conditions of clinical trials and the broader range of clinical situations encountered in practice. However, any practice guideline is inevitably outdated by the time it is published, due to the time required in the process of its creation and publication. This article summarizes the recommendations in the APA bipolar practice guideline and reviews new relevant research available since its publication. The concept of a “mood stabilizer,” which is not incorporated in the guideline, is reviewed. In addition, the numerous clinical assumptions underlying the recommendations in the guideline are described, and the strength of the research evidence supporting them is reviewed. These include the assumptions that lithium and anticonvulsants are preferred treatments while antipsychotics and benzodiazepines are not, that nonresponding patients should always have additional medication added rather than switching to a new medication, that all antidepressants have a significant liability for causing switching into mania, and that all bipolar patients should receive long-term maintenance. New research with lamotrigine, olanzapine, and other atypical antipsychotics in bipolar disorder is reviewed, as well as the implications of this research on the recommendations in the guideline. The concept of directional efficacy of mood stabilizers, only briefly mentioned in the guideline, is discussed and expanded. Finally, the importance of understanding the research basis of the guideline before applying its recommendations to clinical practice is described.

Introduction

The current American Psychiatric Association (APA) “Practice Guideline for the Treatment of Patients with Bipolar Disorder”1 was published in 2002 and is a revision of an earlier version published in 1994. The latest revision represents a summary of a much larger evidence base than the previous version and is a distillation of both available research and expert opinion.

Unfortunately, the guideline has several problems: first, such an endeavor, by nature, is outdated by the time it is published. Second, while the guideline contains descriptors that indicate the level of author confidence in the evidence supporting its recommendations, many of the recommendations are based essentially on opinion and are not supported by well-designed trials. Recommendations primarily based on expert opinion or clinical consensus with either no evidence basis or an uncontrolled case series may be erroneous. Such untested or unproven treatments that are popular among clinicians may find their way into the practice guideline simply on the basis of their popularity, which can lead to the widespread perpetuation of clinical myth and folklore. For example, topiramate and gabapentin are common treatments for acute mania that have failed to demonstrate efficacy in placebo-controlled trials. Their popularity developed from numerous case series suggesting efficacy in mania. Despite the negative trial data, clinicians have already become familiar with using these medications; currently, ancillary uses include prescribing topiramate for drug-induced weight gain and gabapentin for insomnia or anxiety. Unfortunately, neither the practice guideline nor Food and Drug Administration product labels are designed to discuss such ancillary uses. Should such a treatment or practice be included in the guideline simply because it is popular?

A third problem with the practice guideline is that it is indirectly impacted by commercial influences. While any obvious influence can be reduced by mechanisms such as those utilized in the development of the APA guideline, such as independent review and full disclosure of potential conflicts, both subtle and conspicuous influences from the industry still make their way into the guideline. For example, clinical trial data from pharmaceutically-funded projects is often considered proprietary; theoretically, the industry sponsor could conduct multiple controlled trials and suppress any negative results. Recent proposals to create an inclusive registry of all clinical trials may reduce this problem. Even the recommendations arising from scientifically high-caliber, placebo-controlled, double-blind studies are based overwhelmingly on industry-sponsored trials, which are subject to bias introduced through both study design and selective reporting of results. Thus, the myriad of choices made in designing any clinical trial are often driven by potential drug sales rather than science. Furthermore, the use of leading academics as authors seldom reflects the independent control of the design, the statistical analysis, or the reported results of the study, as is perhaps implied.

Clearly, limiting recommendations exclusively to medications derived from high-quality, placebo-controlled clinical trials is impractical. Unfortunately, solely using clinical practice as a guide can also be risky, since the majority of clinical practice involves patients who do not meet the inclusion criteria of highly-controlled clinical trials, and the majority of clinical decisions are beyond the tightly-defined conditions of clinical trials. The practice guideline, though, despite its many problems, represents an important effort to bridge the gap between clinical trials and clinical practice.

This review summarizes the APA guideline’s strengths and weaknesses (Table 1), and introduces new research completed since its publication. In addition, it examines many of the guideline’s recommendations that are not evidence based. It discusses alternative rationales that warrant consideration and presents several key questions, which have not as yet been studied but are important for the development of future standards of treatment for bipolar disorder.

What is a Mood Stabilizer?

Despite its widespread use, the term “mood stabilizer” was intentionally omitted from the APA practice guideline due to a lack of consensus on a definition. Simplistically speaking, the term is most often used to describe a first-line treatment for bipolar disorder that would not destabilize the disorder. Beyond this, though, there is disagreement about whether both acute antimanic and antidepressant (for bipolar depression) efficacy are required or whether both acute and maintenance efficacy are required. While the term is technically based on use of treatments in bipolar disorder, medications identified as mood stabilizers are also often used for lability, impulsivity, and aggression in bipolar patients and in patients with other psychiatric disorders. Clinicians can benefit from a clarification of this term.

If the term mood stabilizer is a proxy for a “first-line treatment for any phase of bipolar disorder,” as is often the intent with clinicians who use it, then both uni-directional antimanic treatments, as well as uni-directional bipolar depression treatments, could be considered mood stabilizers regardless of whether bi-directional or maintenance efficacy has been convincingly demonstrated. This is, of course, assuming that the treatment does not worsen the course of the illness by causing a switch to the other pole or by exacerbating rapid cycling.

Lithium, divalproex, valproate, and carbamazepine have been shown to have efficacy in mania without exacerbating depression and are generally considered mood stabilizers (Figure 1).2 Likewise, lamotrigine has been shown to have efficacy in bipolar depression without exacerbating mania.3 Paroxetine has shown some evidence of efficacy in bipolar depression4 with little liability of inducing switching. Buproprion may also have efficacy in bipolar depression with a low liability for switching,5 although its efficacy has never been tested in a placebo-controlled trial.

Switching is the most relevant problem for many treatments of bipolar depression. One review that attempted to examine switching in more detail compiled data from placebo-controlled trials of sertraline, paroxetine, tricyclic antidepressants (TCAs), and placebo in bipolar depression. This review included a post-hoc analysis of 242 cases of bipolar depression treated under controlled conditions with selective serotonin reuptake inhibitors (SSRIs) and found an associated switch rate into mania of 3.7%, which was no different from the switch rate on placebo. The 125 bipolar depressed patients treated with TCAs had a switch rate of 11.2%, which was clearly greater than the switch rate on placebo.6 This report supports the well-documented and clearly demonstrated risk of switching with TCAs (primarily imipramine). Monoamine oxidase inhibitors were also found in controlled trials to have significant risks of switching. Thus, the logical conclusion is that the risk of switching caused by SSRIs is comparatively low.

It is important to separate evidence from controlled trials and anecdotal reports or case series, especially in the case of induction of mania, which occurs naturally in bipolar depressed patients anyway. In fact, to address this issue, it is critical to estimate the expected switch rate on placebo. While there is no single large set of data that allows for a direct comparison of switch rates on antidepressants versus placebo, switch rates on placebo from smaller sets of data are as high as 5%.3

Whether drugs traditionally considered tranquilizers (specifically typical antipsychotics, benzodiazepines, and atypical antipsychotics) should also be considered safe first-line treatments for bipolar disorder is a controversial issue. There is extensive evidence of the efficacy of typical antipsychotics in acute mania,7 and indeed these drugs are used for acute and maintenance treatment of bipolar disorder. While typical antipsychotics are often described as causing depression, the evidence for this is unconvincing and derived largely from two early reports on flupenthixol decanoate. Both reports had design problems and did not statistically test for this side effect.8,9 Furthermore, there are case reports of bipolar patients who became more depressed when a typical antipsychotic was discontinued. The benzodiazepines clonazepam and lorazepam have also been shown to have efficacy for acute mania10-15 with no suggestion of any aggravation of depressive symptoms. Thus, typical antipsychotics, clonazepam, and lorazepam could arguably be considered mood stabilizers.

Typically, though, these medications are not regarded as mood stabilizers because of tolerability issues. The risk of tardive dyskinesia from typical antipsychotic use and substance dependence with benzodiazepines may relegate these drugs to second-line choices. It is notable that reports of an increased risk of tardive dyskinesia in bipolar patients on typical antipsychotics compared to schizophrenic patients were based on methodologically limited studies,16 and the question of how likely dependence on benzodiazepines occurs in bipolar patients under medical supervision, even for long periods of time, has never been studied. Furthermore, it is clear that many bipolar patients do use benzodiazepines chronically with apparently good efficacy and without any dependence problems.

More interesting is the question of whether atypical antipsychotics are mood stabilizers. Olanzapine has demonstrated efficacy in acute mania (Figure 2),17 bipolar depression, and bipolar maintenance.17-20 Quetiapine, risperidone,21 ziprasidone, and aripiprazole (Figure 3)22 also have been shown to be effective in treating acute mania, either as monotherapy or in combination with lithium or divalproex (Figures 4 and 5).21,23-26 The liability of such atypical antipsychotics for inducing depression or tardive dyskinesia seems to be low. These drugs are commonly used for bipolar disorder but only olanzapine is listed in the guideline as a first-line treatment for mania. Generally, the atypical antipsychotics as a class are not recommended as first-line treatments because of limited available research regarding long-term use, although such data is emerging rapidly. They are recommended for patients with persistent psychosis or for those who relapse in spite of other treatments.

The industry-supported research on atypical antipsychotics for bipolar disorder has to some degree avoided this question by designing studies that combine atypical antipsychotics with an accepted mood stabilizer, specifically lithium or divalproex. The implication is that the other medication (ie, lithium or divalproex) is the primary treatment and the atypical antipsychotic is the added tranquilizer. Unfortunately, most of these trials have underdosed lithium or divalproex, which further leads to difficulty in interpreting the results. Trials of atypical antipsychotics in mania, bipolar depression, and maintenance treatment should consider monotherapy designs to avoid the need to interpret the effects of the other drug.

The question remains: should atypical antipsychotics be considered first-line treatments for bipolar disorder? Their potential to be useful in this role is clear, but more research is needed. On the other hand, anticonvulsants such as divalproex and lamotrigine have, in some ways, been considered mood stabilizers despite only slight or no evidence of bi-directional effects.

Other mood-stabilizing treatments that are considered by the practice guideline include electroconvulsive therapy (ECT) and psychotherapy. ECT may be effective for both mania and bipolar depression, and psychotherapies are generally accepted as helpful in bipolar depression, although controlled data for this is lacking. A comprehensive index of possible mood stabilizers (ie, treatments that do not exacerbate bipolar disorder) is listed in Table 2 and Table 3.1

Combination Therapy Versus Sequential Monotherapy

Important to consider when using mood stabilizers is the concept of adding rather than switching treatments, which is one of the key underpinnings of the guideline. This practice has been studied only minimally due to the many logistical problems associated with attempting to research this topic. At issue is whether multiple medications should be used early or if they should be utilized only after sequential monotherapy has failed.

The answer to this question relates to some degree to culture: the tradition of psychopharmacology in the United States has for decades emphasized monotherapy. Monotherapy was largely driven by the FDA approval process, which has principally required placebo-controlled monotherapy studies due to their clear interpretability. Clinicians in many other countries, however, routinely prescribe multiple medications and can be highly respected for their skills at safely combining medications. US practices have shifted toward polypharmacy, as reflected in the bipolar practice guideline. Combination therapy or polypharmacy can hold theoretical benefits of enhanced efficacy and reduced side effects with lower doses of multiple medications, but is fraught with the risks of additive side effects and, most importantly, subtherapeutic dosing of medications.

There appears to be a growing clinical impression reflected in the practice guideline that response rates to multiple medications are greater than response rates to a single medication. This is based on case reports, uncontrolled case series, and very few actual clinical trials. This impression has led to widespread recommendations for combination therapy and polypharmacy, with the implication that combinations work together synergistically. However, from a scientific viewpoint, such conclusions may be premature since two medications used at adequate doses in sequence could theoretically produce comparable response rates. Consider a scenario in which two treatments, Drug A and Drug B, have both been shown to be effective as monotherapy for some specific disorder. Each achieved a response rate of 70% based on some predetermined definition of response, such as a reduction in symptoms. This means that 30% of subjects given each drug did not achieve the predefined response. However, the 30% of exposed subjects who are nonresponsive to each of the two medications differs in each study. In fact, while Drug A and Drug B could each produce efficacy in 70% of subjects, these are not the same subjects. In other words, while there may have still been a 70% response rate had the subjects in the study of Drug A instead been in the study of Drug B, it would have been different subjects who responded.

Another study starts similar subjects on a combination of Drugs A and B and achieves a response rate of >70%. This is often interpreted as either additive or synergistic efficacy of combination treatment. However, even without any synergistic or additive efficacy, a higher rate of response would be expected from two efficacious treatments because some of the nonresponders to Drug A are responders to Drug B and vice versa. Had the study started with Drug A and then given Drug B to the Drug A nonresponders, a total response rate might have equaled that of combination treatment. Thus, higher response rates in combination treatment could be explained simply by individual differences in drug responsiveness, rather than by additive or synergistic efficacy.

A small number of reports on synergistic effects and differences in individual drug responsiveness have led to widespread recommendations for combination treatments. The effort to achieve higher efficacy rates is clearly desirable, and the side effects may not necessarily be worse with more medications, especially if they are all underdosed. On the other hand, if clinicians plan to combine medications either at the start of treatment or shortly thereafter, there is a strong likelihood that the dosing of each medication will be lower, which leads to an inadequate trial of the first treatment in terms of both dose and duration. Such an approach may also minimize clinical efficacy of each medication and is clearly a divergence from the largely FDA-driven American practice of using a single drug at a high enough dose to better determine either drug responsivity or drug refractoriness.

Combining or switching medications is difficult to address in clinical trials, but as a routine clinical practice is legitimate material for a consensus-based guideline. However, the add versus switch question is complex and may not only reflect scientific issues, but also philosophical and cultural ones beyond the scope of such a guide. Essentially, adding additional medications for nonresponders makes sense, but switching to another medication is also a reasonable option that has not been considered. While combination therapy is common in other specialties such as oncology and infectious disease, such treatments are recommended based on clinical trial evidence. Combination treatments for psychiatric disorders work, but their superiority over sequential use of monotherapies has not been clearly demonstrated by clinical trials. In the absence of better-designed studies on the efficacy of combination therapies that address the questions of proper dosing of each medication and adding versus switching, it is likely that use of combination therapy for bipolar disorder will become arbitrary and without a credible evidence base.

Treatment of Manic or Mixed Episode

The bipolar practice guideline recommends lithium, divalproex, and olanzapine as first-line treatments for mild to moderate mania or mixed episode of bipolar disorder. For severe mania or mixed episode, a combination of either lithium or divalproex with an antipsychotic is recommended. For mixed episode, divalproex is preferred over lithium (Figure 6).2 Alternatives to lithium and divalproex include carbamazepine and oxcarbazepine. In addition, short-term use of benzodiazepines is recommended. Tapering of antidepressants and psychosocial treatments is also recommended.

There are many assumptions regarding treatment of manic or mixed episode that underlie these recommendations (Table 4).1 While these assumptions may reflect standard clinical care, the rationale behind them is based on limited research. The first assumption is that lithium and divalproex are appropriate for both acute and maintenance treatment, while antipsychotics and benzodiazepines are not. Supporting this is the fact that substantially more clinical and research trials with lithium and divalproex in bipolar maintenance have been performed. Although the guideline avoids calling such medications mood stabilizers, the authors clearly consider lithium and divalproex mood stabilizers, but do not consider other antipsychotics or benzodiazepines as such (Table 5).

This conceptual dichotomy between anticonvulsants and antipsychotics arises out of the long history of lithium as the primary treatment for mania, and the assumption that anticonvulsants should be used like lithium while antipsychotics should not. The dichotomy developed in the era of typical antipsychotics and was largely driven by concerns about acute extrapyramidal side effects, tardive dyskinesia, and the unproven perception that typical antipsychotics could make patients depressed. This dichotomy seemed sensible since the development, FDA labeling, and early use of anticonvulsants and antipsychotics had previously been for completely different disorders, specifically epilepsy and schizophrenia. Today, the dichotomy makes less sense, as atypical antipsychotics clearly have a reduced risk of both acute extrapyramidal side effects and tardive dyskinesia. Also, as more clinical trials of atypical antipsychotics in bipolar disorder are made available, the potential use of atypicals for all phases of bipolar disorder will become more apparent. The point is that a dichotomy separating anticonvulsants and atypical antipsychotics is not fundamentally driven by any research that has been done in bipolar disorder. Recent clinical trials, with a few exceptions,18,19,26 have done little to reduce the perpetuation of this now-outdated conceptual dichotomy.

Furthermore, the question of whether lithium and divalproex are better tolerated than atypical antipsychotics in long-term treatment has never actually been addressed by a clinical trial. Since many medications are effective for mania, suitability for long-term treatment is a key issue in drug selection. Antipsychotics may have long-term side effects, but the long-term effects of lithium and divalproex are also considerable. Lithium is associated with tremor, weight gain, acne, cognitive impairment, hypothyroidism, diabetes insipidus, nephrotoxicity, gastrointestinal problems, alopecia, and edema. Divalproex is associated with tremor, weight gain, alopecia, hepatotoxicity, leukopenia, thrombocytopenia, pancreatitis, and possibly polycystic ovarian syndrome. Thus, the preference of lithium and divalproex over atypical antipsychotics for maintenance treatment is partly based on an assumption of better tolerability that has never been tested and is questionable at best.

A second assumption underlying treatment of a manic or mixed episode maintains that if a patient is nonresponsive to a single treatment, other treatments should be added rather than substituted. Adding versus switching has not been well addressed by clinical trials, and the few studies that have addressed it primarily studied a combination of lithium and carbamazepine or divalproex and had small numbers or methodological limitations.27-32 One small study found a lithium-divalproex combination superior to lithium alone for maintenance treatment,33 but there were only five subjects on the combination. Systematic attempts to address adding or substituting other drugs have failed to consistently show that combination treatment produces superior efficacy compared to a single efficacious treatment, especially if the treatment is an adequately dosed antipsychotic for mania.34-37 One large well-designed multicenter acute mania study38 found that the addition of valproate to a flexible-dose typical antipsychotic allowed lower antipsychotic dosing and superior efficacy, but the antipsychotic in the study was dosed openly. The finding of superior efficacy in the combined valproate plus antipsychotic group is one of the rare examples of a demonstrated advantage to combination over antipsychotic alone.

Adding another medication for an unresponsive or partially-responsive patient may be a clinically reasonable approach, and the practice guideline has clearly endorsed this approach as a routine recommendation. However, the research evidence supporting the idea that combination treatments produce greater efficacy than optimal dosing of both drugs separately and sequentially is quite limited. Whether automatically prescribing combination treatments makes sense for completely unresponsive patients is questionable, as most treatments cause some adverse events.

The recommendation to combine either lithium or divalproex with an antipsychotic for severe mania also does not consider the option of antipsychotic monotherapy. This is one of several examples in the practice guideline that favors combination therapy or polypharmacy over monotherapy with a different medication. The clinical trials of antipsychotics in mania have included at least moderately ill subjects, which suggests that antipsychotic monotherapy may be efficacious for these patients. Furthermore, the addition of lithium has never been demonstrated to produce additional efficacy for acute manic patients who receive an efficacious dose of an antipsychotic.34,35,37

The possibility that using lithium or divalproex together with an antipsychotic might reduce antipsychotic dosing has been studied at least twice under controlled conditions. One haloperidol study34 found that combining lithium with a low dose of haloperidol for acute mania produced efficacy comparable to a higher dose of haloperidol monotherapy. Muller-Oerlinghausen and colleagues38 also found in a multicenter placebo-controlled acute mania study that when adding valproate versus placebo to typical antipsychotics dosed openly, the antipsychotic-valproate group was treated with lower doses of antipsychotic and had a greater clinical response than the antipsychotic-placebo group. Thus, considering a reduced-dose antipsychotic as the primary treatment and lithium or divalproex as the added treatment may be an alternative approach to combination therapy. For manic patients not fully responsive to atypical antipsychotic monotherapy, it might be reasonable to increase the dose of the antipsychotic first, and then consider adding lithium or divalproex (similar to what is often done with antidepressants and lithium in unipolar depression).

The practice guideline has also avoided considering the possibility of adding carbamazepine to either lithium or divalproex instead of an antipsychotic, in the case of severe or nonresponding patients. This combination is not considered despite the fact that double-blind data, albeit from a small number of subjects, suggests that it has efficacy in refractory patients.30

The practice guideline for mania recommends considering oxcarbazepine as an alternative to carbamazepine, under the assumption that oxcarbazepine has comparable efficacy. Oxcarbazepine has never been tested in a placebo-controlled clinical trial for acute mania. The available double-blind literature for oxcarbazepine and mania is limited to two small studies from the same principal investigator who found oxcarbazepine comparable in efficacy to either haloperidol or lithium.39 These two studies have limited utility in determining the antimanic efficacy of oxcarbazepine, due to the absence of a placebo control. Why the practice guideline has elevated oxcarbazepine to a prominence which has been reserved only for other treatments that have been tested in placebo-controlled trials is unclear (Table 6). The assumption that oxcarbazepine is as efficacious as carbamazepine for treatment of mania should be considered unproven at best.

The role of benzodiazepines has also been largely ignored. Despite the evidence that clonazepam and lorazepam are efficacious in mania, albeit at high doses (clonazepam 16 mg/day and lorazepam 30 mg/day), their use has been largely discouraged due to concerns about dependence. There are many cases, however, in which benzodiazepines have been used for long-term treatment with apparent prolonged efficacy. The true incidence rate and risk of dependence with chronic use when prescribed under the supervision of a psychiatrist is unknown and may have been overestimated in the interest of being cautious.

Treatment of Refractory Mania

The same concerns described above for mania or mixed episode also apply to the refractory mania recommendations. The guideline recommends lithium, divalproex, or an antipsychotic for refractory patients, followed by carbamazepine and oxcarbazepine, as well as clozapine or ECT (Table 7).1 Again, the question of the definition of an adequate trial of monotherapy for mania is avoided. It is notable that neither lithium nor divalproex was shown to have efficacy in treatment of a manic episode in <7 days,2 suggesting that >1 week may be necessary to define nonresponse. The guideline for refractory mania does not clearly define the condition itself. Should clinicians wait for 7–10 days before considering a patient refractory? If this decision is made sooner, has lithium or divalproex been given a reasonable opportunity to work? What blood level of lithium or valproate should be achieved before a patient is considered refractory? Should the same duration criteria be used for atypical antipsychotics that appear to have more rapid onset of efficacy?25

The recommendation to add an antipsychotic to lithium or divalproex for refractory mania suffers from the same problems as discussed for manic episode. Specifically, why should an atypical antipsychotic be added to lithium or divalproex instead of substituted? If lithium or divalproex alone is not working, why would they be continued if an antipsychotic is going to be used anyway? Haloperidol and lithium data suggest that if an adequate dose of antipsychotic is used, adding lithium produces no additional benefit.34

Treatment of Bipolar Depressive Episode

The early research basis of treatments for bipolar depression has been thoroughly reviewed by Zornberg and Pope.40 Many problems have limited the interpretability of these earlier studies, though, including the use of both unipolar and bipolar depressed subjects in early lithium trials; slow antidepressant response to either antidepressants or lithium in bipolar depression; and low overall rates of response. The guideline makes several assumptions about bipolar depression treatment (Table 8). The practice guideline recommends lithium or lamotrigine as first-line treatments, although it places a higher level of confidence in lithium, followed by a combination of an antidepressant with lithium or electroconvulsive therapy. In addition, interpersonal and cognitive-behavioral psychotherapies are suggested, although the limited evidence of their efficacy is acknowledged (Table 9).1

Since the guideline was published, a new pivotal study (Figure 7)20 has led to the first FDA approval for a treatment for acute bipolar depression, a combination of olanzapine and fluoxetine. This study, with over 700 randomized subjects, showed that both olanzapine and an olanzapine/fluoxetine combination have acute antidepressant efficacy in bipolar depression.20 Olanzapine alone was statistically superior to placebo in acute efficacy but had a relatively small clinical effect. More interestingly, a combination of olanzapine and fluoxetine was superior to both placebo and olanzapine monotherapy. The average dose of olanzapine was 9.7 mg/day. The average doses of olanzapine and fluoxetine in combination were 7.4 mg/day and 39.3 mg/day, respectively. Neither active treatment caused more switching into mania than placebo.20

This is the first study to show acute antidepressant efficacy for an antipsychotic in bipolar depression. It seems likely that studies of other atypical antipsychotics for acute bipolar depression will be conducted rapidly, hopefully creating more treatment options. Prospective studies in this area should consider whether to use atypical antipsychotic monotherapy; a combination of an atypical antipsychotic with an antidepressant; or an atypical antipsychotic combined with lithium, divalproex, or lamotrigine.

The clear and robust efficacy of the olanzapine-fluoxetine combination for acute bipolar depression may suggest a wider role for antidepressants in bipolar depression. However, as the first study showing acute efficacy of either an antipsychotic or an antipsychotic-antidepressant combination, the study raises many new questions. Unfortunately, this study did not have a cell on fluoxetine alone. Is antidepressany monotherapy a reasonable option? If not, and if antidepressants should always be combined with an antimanic drug, is lithium the logical choice, or are other mania treatments, such as olanzapine, worth considering? Furthermore, how long should the antidepressant be continued following remission? Perhaps the biggest question raised by this study is that of whether the terminologies of antipsychotic and antidepressant are really relevant to bipolar disorder.

Other research in this area includes an acute bipolar I depression trial of lamotrigine (Figure 8), which demonstrated clinically significant antidepressant efficacy and an overall mania switch rate equal to placebo.3 This study led to the inclusion of lamotrigine as a first-line treatment in the guideline. The onset of efficacy was seen by 3 weeks, although at that point the lamotrigine dose was only 50 mg/day; response increased further with subsequently increased doses up to 200 mg/day. This trial provides evidence of antidepressant efficacy in bipolar depression and suggests that lamotrigine could be considered as a first-line treatment. Furthermore, although lamotrigine must be titrated slowly to reduce the risk of serious rash, the statistically significant separation from placebo by 3 weeks of treatment, even at a dose of only 50 mg/day, indicates that the antidepressant response to lamotrigine may be no slower than that of antidepressants. Unfortunately, there is no evidence of efficacy in acute mania.

On the other hand, there are several arguments supporting the preference of lithium over lamotrigine for acute bipolar depression. These include the demonstrated efficacy of lithium in both acute mania and acute bipolar depression, efficacy in prevention of mania in both responder-enriched and nonresponder-enriched samples, strong antisuicide efficacy based on retrospective comparisons to suicide attempts prior to taking lithium, and extensive clinical experience. There is no available trial directly comparing lithium and lamotrigine in acute bipolar depression.

The recommendation against using antidepressant monotherapy for treatment of bipolar depressive episodes is so widespread and well-accepted that it warrants inclusion in the practice guideline. Even the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition,41 allows the savvy clinician to easily diagnose substance-induced mood disorder (mania) secondary to an antidepressant. The question of whether the manic episode was caused by the antidepressant is left to the clinician’s judgement—specifically, no minimum dose of antidepressant or duration of exposure is required. Without a controlled trial, the individual clinician faced with an antidepressant-treated patient who becomes manic assumes that the manic episode is antidepressant induced because there is no way to determine if the patient would have become manic even without an antidepressant. The rate of switching of bipolar depressed patients receiving acute treatment with placebo has ranged from 2% to 5%.3,4,6

Research evidence supporting this recommendation is not as convincing as might be assumed. While TCAs clearly have a high rate of switching into mania, the data for newer antidepressants is far from convincing. Recommendations for using bupropion and paroxetine arise from one small non-placebo–controlled study of bupropion suggesting a lower switch rate than desipramine,5 and one larger study of paroxetine.4 Notably, in the paroxetine trial, there was no switching at all reported in paroxetine-exposed depressed patients, although it is possible that some subjects had other adverse events that were consistent with mania but were not reported as such (Figure 9).4 Even if these are considered switches, the rate of switching on paroxetine is still low. It seems likely that different antidepressants have different liabilities for causing switching into mania and that newer antidepressants are safer. One report of a large series of 242 bipolar patients treated with SSRIs6 suggests a switch rate of only 3.7%, which was comparable to placebo.

The recommendation to use antidepressants with lithium (if antidepressants are used at all) to “cover” and reduce the possibility of switching into mania is more widely accepted. Unfortunately, the evidence basis for this recommendation in controlled trials is, at best, limited. In fact, in a paroxetine versus imipramine versus placebo in acute bipolar depression study,4 all patients were given combination treatment with lithium in addition to the study drug. In this trial, imipramine-treated patients had a switch rate of 8% despite being on lithium, while placebo-treated patients had a switch rate of only 2%. Imipramine-treated patients did have a lower switch rate when lithium was at a serum level of >0.8 mEq/L, but it was still higher than placebo. The fact that the switch rates reported in this trial represent a total of only four switches out of 117 subjects in the entire study should be considered.

A new study with >700 randomized subjects showed that both olanzapine and a combination of olanzapine-fluoxetine have antidepressant efficacy in bipolar depression.20 In this study, olanzapine alone was statistically superior to placebo but had a relatively small clinical effect. More interestingly, a combination of olanzapine and fluoxetine was superior to both placebo and to olanzapine monotherapy. This study suggests that both olanzapine monotherapy and an olanzapine-fluoxetine combination should be recommended as first-line acute bipolar depression treatments also.

The recommendation for psychosocial treatments in bipolar depression, including psychotherapy, has been essentially universally accepted by the academic community. Unfortunately, there is almost no controlled research on psychotherapy in bipolar disorder. The guideline recommendations on psychosocial or psychotherapeutic treatments are largely derived from the unipolar depression literature, where cognitive-behavioral therapy (in addition to medication) has been shown to be helpful. Psychodynamic psychotherapy, while widely used, also remains untested for bipolar depression.

Treatment of Rapid Cycling

The practice guideline recommendations for treatment of rapid cycling (Table 10)1 are based on a very small and incomplete research database (Table 11). The majority of the literature on treatments for rapid cycling is either in the form of case series or retrospective analyses and only clearly shows that rapid cycling is associated with poor response to lithium and also possibly carbamazepine. Hence, the assumptions that are made elsewhere in the practice guideline reappear in the rapid-cycling section (Table 12). For example, while efficacious mania treatments including lithium and valproate are recommended, atypical antipsychotics and benzodiazepines are omitted despite their documented efficacy in mania. The widely accepted notion that antidepressant use is associated with rapid cycling has been consistently documented in retrospective analyses of current rapid-cycling patients42,43 but has never been tested in a prospective trial (Table 13).42,44-56 The concept of adding rather than substituting, which was discussed earlier, is repeated in this section of the guideline.

The guideline for rapid cycling also discusses whether bipolar I and bipolar II rapid cycling are different. A recently published and well-designed study of rapid-cycling suggests that, in fact, they are quite distinct.57 In this trial, rapid-cycling subjects who were able to tolerate withdrawing from most of their medications took at least 100 mg/day of lamotrigine, and were randomly assigned to either continue on flexible-dose lamotrigine or placebo (withdrawal of lamotrigine) for 6 months. Lamotrigine was efficacious in reducing rapid cycling, and was found in a post hoc analysis be effective in the bipolar II subset but not the bipolar I subset (Figure 10). Due to the use of outcome measures which were not primarily related to relapse into either mania or depression, the potential efficacy of lamotrigine to selectively prevent depression but not mania could not be assessed from the study. However, the results suggest a differential drug response between bipolar I and II rapid-cycling patients.

Maintenance Treatment of Bipolar Disorder

The research literature about maintenance treatment is certainly more modest than that available for manic episode. The most important new development since the publishing of the practice guideline is the FDA approval of lamotrigine for maintenance treatment of bipolar I disorder. Since lithium and lamotrigine are now the only two FDA-approved medications for bipolar maintenance, clearly they should both be considered first-line treatments.

One important and often underappreciated feature of the literature for maintenance treatment is that nearly all of the controlled trials showing that any treatment has maintenance efficacy superior to placebo have done so based on responder-enriched samples. In other words, maintenance studies have tested medications primarily in subjects who were either known acute responders to that medication or had at least been shown to tolerate the study drug before being randomized. For example, the early studies documenting lithium efficacy in maintenance used subjects who had been acutely stabilized on lithium. Recent olanzapine and lamotrigine bipolar maintenance trials have selected only subjects who were either known drug responders or at least able to tolerate the drug being studied.19,57-59

In fact, the one major study that did not select a responder-enriched sample was the divalproex maintenance trial.60 Using an unselected study sample, divalproex could not be shown to have convincing and statistically significant maintenance efficacy when compared to lithium or placebo. However, when a post hoc subanalysis was performed on subjects treated with divalproex in their acute episode prior to the maintenance trial (and hence enriched with divalproex responders) divalproex was found to be efficacious.

Two lamotrigine maintenance trials58,59 selected lamotrigine-tolerating subjects for randomization and what could be considered lamotrigine-responder–enriched samples. The two studies differed in terms of the patients entered: one trial enrolled recently manic subjects, while the other enrolled recently depressed subjects. Both trials found lithium and lamotrigine superior to placebo in maintenance of bipolar disorder when relapse to either mania or depression was analyzed. More interestingly, when the direction of relapse was analyzed separately, lithium was superior to placebo in preventing mania (while lamotrigine was not), and conversely, lamotrigine was superior to placebo in preventing depression (while lithium was not). These studies also provide convincing confirmation of lithium’s efficacy in prophylaxis of mania since the study samples were definitely not enriched with lithium responders.

The results of these well-designed maintenance trials raise two important clinical points. The first is that results were similar regardless of whether the most recent episode was mania or depression. This could have important clinical implications. Common sense might suggest that the most important type of episode to prevent in each patient would be the same as the most recent episode (in other words, recently manic patients should have maintenance treatment focused primarily on prevention of mania while recently depressed patients should have maintenance treatment focused primarily on prevention of depression). These trial results suggest that this distinction may not be necessary and that long-term tendencies to relapse in either direction may be more important.

Secondly, the two active treatments, lithium and lamotrigine, have differences in the direction of their prophylactic efficacy. This may indicate that patients who historically had primarily manic or hypomanic episodes require one type of treatment (either lithium or valproate), while those with a history of depressive episodes require a different type of treatment (either lamotrigine or lithium). Thus, longitudinal course may be more important than recent history in terms of choosing a maintenance treatment. Furthermore, those having both types of episodes may require two treatments simultaneously.

There is nothing inherently unacceptable about using responder-enriched samples in a maintenance trial; in fact, this reflects the almost universal clinical practice of continuing efficacious acute treatments during maintenance. The principal conclusion from all of the bipolar maintenance trials confirms this practice by demonstrating that the first-choice maintenance treatment should be whatever worked for the acute episode. The exception to this observation is the finding that lithium was shown to be an efficacious maintenance treatment for prophylaxis of mania in the lamotrigine trials,59,60 which did not use a lithium-responder–enriched design. This demonstrates that lithium has mania prophylaxis efficacy even in nonresponder-enriched samples.

The inclusion of oxcarbazepine in this section of the guideline is highly questionable. There is no maintenance study of this medication at all in bipolar disorder, much less a placebo-controlled trial. Again, apparently the assumption is that oxcarbazepine works as well as carbamazepine for maintenance. This assumption has never been tested in bipolar disorder.

The issue of antipsychotics in maintenance treatment has largely been avoided by the practice guideline, which recommends antipsychotics only for psychosis or relapse prevention. These drugs, although commonly used for bipolar disorder, lack a clear role in maintenance treatment because there is little clinical research on their effectiveness. Recently, two large trials documented olanzapine’s maintenance efficacy in responder-enriched samples.19,61 The first trial randomly assigned olanzapine mania responders to continue on olanzapine or to withdraw from olanzapine, and to be treated with placebo. Olanzapine was superior to placebo in preventing both mania and depression.19 In the second trial,61 olanzapine combined with either lithium or valproate was compared to placebo combined with either lithium or valproate in maintenance treatment of recently manic responders. The olanzapine plus lithium or valproate was superior to the lithium or valproate alone (olanzapine withdrawal) in preventing relapse to mania.

These studies suggest that olanzapine is a legitimate first-line candidate for both acute and maintenance treatment and that olanzapine should clearly be considered a mood stabilizer. A major concern, though, particularly for olanzapine, is long-term tolerability with regard to metabolic side effects. Olanzapine has been associated with significant weight gain, diabetes, and hyperlipidemia in long-term studies of schizophrenia. Moreover, the magnitude of weight gain is greater than that estimated for lithium or divalproex. Other atypical antipsychotics with fewer long-term metabolic concerns may be important options for maintenance treatment, but there are no data yet available to demonstrate efficacy.

Lithium, carbamazepine, divalproex, lamotrigine, and olanzapine all have some placebo-controlled evidence of maintenance efficacy (Table 14). However, there is limited data available allowing direct comparisons of the efficacy of these medications in bipolar maintenance (Tables 15 and 16). Therefore, treatment choices are typically made based on tolerability and continuing the medication that worked in the acute episode.

Who Should Receive Maintenance Treatment?

The practice guideline recommends maintenance treatment for all bipolar patients. While this common sense recommendation is clearly popular, at least among mental health providers who prescribe medication, it should be considered in the context of the supporting research data. Obviously, all clinical maintenance trials have been conducted only with clearly identified bipolar patients and have included subjects with moderate and severe histories. Clinical trials nearly always intentionally attempt to exclude mildly ill patients because of the likelihood that such subjects may have a high placebo response rate, potentially undermining the ability of the study to show drug-placebo differences.

There are several rationales that suggest that maintenance medication may not be helpful for all patients. First, subjects in clinical trials may not actually represent the patients seen in standard clinical care. It is certainly likely that milder patients may benefit less from maintenance treatment. Second, while placebo has often performed worse than active medication in bipolar maintenance trials, this has not always been the case. For example, a lower-than-expected placebo relapse rate in the divalproex maintenance trial was one of several factors leading to the overall negative results of the study. Lithium was also unable to produce efficacy greater than placebo.61 Finally, the recommendation considers only efficacy in relapse prevention and ignores side effects. It is left to the individual clinician to decide whether the tolerability issues of any specific medication outweigh the potential benefits.

Conclusion

Bipolar disorder is a complex disorder often requiring a complex treatment plan. The APA practice guideline has summarized the research literature and expanded its conclusions on the basis of standard clinical practice. However, the guideline makes assumptions that have limited supporting evidence, including: atypical antipsychotics are more poorly tolerated than lithium or divalproex; combining a new treatment with one that is not working is preferable to switching to a new treatment; oxcarbazepine works as well as carbamazepine; all antidepressants cause mania; and adding lithium to an antidepressant will reduce chances of switching.

The practice guideline does represent a major synthesis of research and clinical opinion distilled into easily understood recommendations. However, most patients do not fit perfectly into any of its recommendations. In order to apply the practice guideline, it is important to understand the underlying assumptions, as well as the limitations of, the evidence on which the guideline is based. Only then can the clinician make a more educated decision about when to go beyond the recommendations in the guideline. PP

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26. Sachs GS, Grossman F, Ghaemi SN, Okamoto A, Bowden CL. Combination of a mood stabilizer with risperidone or haloperidol for treatment of acute mania: a double-blind, placebo-controlled comparison of efficacy and safety. Am J Psychiatry. 2002;159(7):1146-1154.

27. Inoue K, Arima S, Tanaka K, Fukui Y, Kato N. A lithium and carbamazepine combination in the treatment of bipolar disorder—a preliminary report. Folia Psychiatr Neurol Jpn. 1981;35(4):465-475.

28. Nolen WA. Carbamazepine, a possible adjunct or alternative to lithium in bipolar disorder. Acta Psychiatr Scand. 1983;67(4):218-225.

29. Lipinski JF, Pope HG Jr. Possible synergistic action between carbamazepine and lithium carbonate in the treatment of three acutely manic patients. Am J Psychiatry. 1982;139(7):948-949.

30. Kramlinger KG, Post RM. Adding lithium carbonate to carbamazepine: antimanic efficacy in treatment-resistant mania. Acta Psychiatr Scand. 1989;79(4):378-385.

31. Desai NG, Gangadhar BN, Channabasavanna SM, Shetty KT. Carbamazepine hastens therapeutic action of lithium in mania. Paper presented at: International Conference on New Directions in Affective Disorders; April 5–9, 1987; Jerusalem, Israel.

32. Keck PE Jr, McElroy SL, Vuckovic A, Friedman LM. Combined valproate and carbamazepine treatment of bipolar disorder. J Neuropsychiatry Clin Neurosci. 1992;3:319-322.

33. Solomon DA, Ryan CE, Keitner GI, et al. A pilot study of lithium carbonate plus divalproex sodium for the continuation and maintenance treatment of patients with bipolar I disorder. J Clin Psychiatry. 1997;58(3):95-99.

34. Chou JC, Czobor P, Charles O, et al. Acute mania: haloperidol dose and augmentation with lithium or lorazepam. J Clin Psychopharmacol. 1999;19(6):500-505.

35. Biederman J, Lerner Y, Belmaker RH. Combination of lithium carbonate and haloperidol in schizo-affective disorder. Arch Gen Psychiatry. 1979;36(3):327-333.

36. Prien RF, Kupfer DJ, Mansky PA, et al. Drug therapy in the prevention of recurrences in unipolar and bipolar affective disorders. Report of the NIMH Collaborative Study Group comparing lithium carbonate, imipramine, and a lithium carbonate-imipramine combination. Arch Gen Psychiatry. 1984;41(11):1096-1104.

37. Garfinkel PE, Stancer HC, Persad E. A comparison of haloperidol, lithium carbonate and their combination in the treatment of mania. J Affect Disord. 1980;2(4):279-288.

38. Muller-Oerlinghausen B, Retzow A, Henn FA, Giedke H, Walden J, for the European Valproate Mania Study Group. Valproate as an adjunct to neuroleptic medication for the treatment of acute episodes of mania: a prospective, randomized, double-blind, placebo-controlled, multicenter study. J Clin Psychopharmacol. 2000;20(2):195-203.

39. Emrich HM. Experience with oxcarbazepine in acute mania. In: Modigh K, Robak OH, Vestergaard P, eds. Anticonvulsants in Psychiatry. Petersfield, UK: Wrightson Biomedical Publishing; 1994:29-36.

40. Zornberg GL, Pope HG Jr. Treatment of depression in bipolar disorder: new directions for research. J Clin Psychopharmacol. 1993;13(6):397-408.

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42. Altshuler LL, Post RM, Leverich GS, Mikalauskas K, Rosoff A, Ackerman L. Antidepressant-induced mania and cycle acceleration: a controversy revisited. Am J Psychiatry. 1995;152(8):1130-1138.

43. Wehr TA, Sack DA, Rosenthal NE, Cowdry RW. Rapid cycling affective disorder: contributing factors and treatment responses in 51 patients. Am J Psychiatry. 1988;145(2):179-184.

44. Crane GE. The psychiatric side-effects of iproniazid. Am J Psychiatry. 1956;112(7):494-501.

45. Arnold OH, Kryspin-Exner K. The problem of control of manic-depressive processes by antidepressants [in German]. Wien Med Wochenschr. 1965;115(45):929-934.

46. Till E, Vukovic AJ. Int Pharmacopsychiatry. 1970;5:13-17.

47. Coppen A, Brooksbank BW, Peet M. Tryptophan concentration in the cerebrospinal fluid of depressive patients. Lancet. 1972;1(7765):1393.

48. van Scheyen JD, van Kammen DP. Clomipramine-induced mania in unipolar depression. Arch Gen Psychiatry. 1979;36(5):560-565.

49. Siris SG, Chertoff HR, Perel JM. Rapid-cycling affective disorders during imipramine treatment: a case report. Am J Psychiatry. 1979;136(3):341-342.

50. Kukopulos A, Reginaldi D, Laddomada P, Floris G, Serra G, Tondo L. Course of the manic-depressive cycle and changes caused by treatment. Pharmakopsychiatr Neuropsychopharmakol. 1980;13(4):156-167.

51. Lerer B, Birmacher B, Ebstein RP, Belmaker RH. 48-hour depressive cycling induced by antidepressant. Br J Psychiatry. 1980;137:183-185.

52. Ko GN, Leckman JF, Heninger GR. Induction of rapid mood cycling during L-dopa treatment in a bipolar patient. Am J Psychiatry. 198;138(12):1624-1625.

53. Mattsson A, Seltzer RL. MAOI-induced rapid cycling bipolar affective disorder in an adolescent. Am J Psychiatry. 1981;138(5):677-679.

54. Extein I, Pottash AL, Gold MS. Does subclinical hypothyroidism predispose to tricyclic-induced rapid mood cycles? J Clin Psychiatry. 1982;43(7):290-291.

55. Oppenheim G. Drug-induced rapid cycling: possible outcomes and management. Am J Psychiatry. 1982;139(7):939-941.

56. Ghaemi SN, Boiman EE, Goodwin FK. Diagnosing bipolar disorder and the effect of antidepressants: a naturalistic study. J Clin Psychiatry. 2000;61(10):804-808.

57. Calabrese JR, Suppes T, Bowden CL, et al, for the Lamictal 614 Study Group. A double-blind, placebo-controlled, prophylaxis study of lamotrigine in rapid-cycling bipolar disorder. J Clin Psychiatry. 2000;61(11):841-850.

58. Bowden CL, Calabrese JR, Sachs G, et al, for the Lamictal 606 Study Group. A placebo-controlled 18-month trial of lamotrigine and lithium maintenance treatment in recently manic or hypomanic patients with bipolar I disorder. Arch Gen Psychiatry. 2003;60(4):392-400.

59. Goodwin FK, Bowden CL, Calabrese JR, et al. Maintenance treatments for bipolar I depression (lithium, lamotrigine, and placebo). Poster presented at: Annual Meeting of the American Psychiatric Association; May 17–22, 2003; San Francisco, CA.

60. Bowden CL, Calabrese JR, McElroy SL, et al, for the Divalproex Maintenance Study Group. A randomized, placebo-controlled 12-month trial of divalproex and lithium in treatment of outpatients with bipolar I disorder. Arch Gen Psychiatry. 2000;57(5):481-489.

61. Tohen M, Chengappa KN, Suppes T, et al. Relapse prevention in bipolar I disorder: 18-month comparison of olanzapine plus mood stabiliser v. mood stabiliser alone. Br J Psychiatry. 2004;184:337-345.


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

Disclosure: Dr. Chou is a consultant for Abbott, Bristol-Myers Squibb, GlaxoSmithKline, and Pfizer; is on the speaker’s bureaus of Abbott, AstraZeneca, Bristol-Myers Squibb, GlaxoSmithKline, Hoechst, Janssen, Merck, Novartis, Ortho-McNeil, Otsuka, and Pfizer; receives grant and/or research support from Abbott, AstraZeneca, Bristol-Myers Squibb, GlaxoSmithKline, Hoechst, Janssen, Merck, Novartis, Ortho-McNeil, Otsuka, and Pfizer; and is a major stock holder in Bristol-Myers Squibb and Pfizer.

Please direct all correspondence to: James C-Y. Chou, MD, New York University School of Medicine, Department of Psychiatry, NBV 20 20W 13A, 462 1st Ave, New York, NY 10016; Tel: 212-263-6202; Fax: 914-359-7029; E-mail: chou@nki.rfmh.org.


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Pediatric Bipolar Disorder or Disruptive Behavior Disorder?

Joseph Biederman, MD, Eric Mick, ScD, Stephen V. Faraone, PhD, and Janet Wozniak, MD

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Primary Psychiatry. 2004;11(9):36-41
 

 

Faculty Affiliations and Disclosures

Dr. Biederman is professor of psychiatry at Harvard Medical School and chief of the Pediatric Psychopharmacology Research Unit at Massachusetts General Hospital in Boston.

Dr. Mick is assistant professor of psychiatry at Harvard Medical School and assistant director of research in the Pediatric Psychopharmacology Research Unit at Massachusetts General Hospital.

Dr. Faraone is professor in the Department of Epidemiology at Harvard School of Public Health, clinical professor of psychiatry at Harvard Medical School, and director of research in the Pediatric Psychopharmacology Research Unit at Massachusetts General Hospital.

Dr. Wozniak is assistant professor of psychiatry at Harvard Medical School and director of the bipolar program in the Pediatric Psychopharmacology Research Unit at Massachusetts General Hospital.

Disclosure: Dr. Biederman serves on the speaker’s bureaus for Cephalon, Eli Lilly, Novartis, Ortho-McNeil, Pfizer, Shire, and Wyeth; receives research support from Cephalon, Eli Lilly, Janssen, National Institute of Child Health and Human Development (NICHD), National Institute on Drug Abuse, National Institute of Mental Health (NIMH), Novartis, Pfizer, Shire, the Stanley Foundation, and Wyeth; and is on the advisory boards of CellTech, Cephalon, Eli Lilly, Janssen, Johnson & Johnson, Novartis, Noven, Ortho-McNeil, Pfizer, and Shire. Dr. Mick is a consultant for Janssen, receives grant and/or research support from NIMH, and receives honoraria and/or expenses from Ortho-McNeil. Dr. Faraone is a consultant for Eli Lilly, Noven, Ortho-McNeil, and Shire; serves on the speaker’s bureaus for Eli Lilly, Ortho-McNeil, and Shire; and receives research support from Eli Lilly, NICHD, NIMH, National Institute of Neurological Diseases and Stroke, Ortho-McNeil, and Shire. Dr. Wozniak is a consultant for Shire; serves on the speaker’s bureaus of Eli Lilly and Janssen; and receives grant and/or research support from Eli Lilly. 

Funding/support: This work was supported in part by grant #98-325B from the Theodore and Vada Stanley Foundation awarded to Dr. Biederman.

Acknowledgment: Aspects of this work were presented at the conference, “Bipolar Disorder: From Preclinical to Clinical, Facing the New Millennium,” held January 19–21, 2000 in Scottsdale, Arizona. The conference was sponsored by the Society of Biological Psychiatry through an unrestricted education grant provided by Eli Lilly.

Please direct all correspondence to: Joseph Biederman, MD, Pediatric Psychopharmacology Unit (ACC 725), Massachusetts General Hospital, 15 Parkman St, Boston, MA 02114-3139; Tel: 617-726-1731; Fax: 617-724-1540; E-mail: jbiederman@partners.org.

 

Focus Points

• Bipolar disorder is a highly morbid and disabling disorder that can afflict children and adolescents.

• Studies of children with bipolar disorder document a high overlap with attention-deficit/hyperactivity disorder.

• A bi-directional and robust overlap between bipolar disorder and conduct disorder has also been documented in studies of bipolar youth and studies of conduct disorder youth.

 

Abstract

Despite ongoing controversy, the view that pediatric mania is rare or nonexistent has been increasingly challenged by case reports and systematic research. This research suggests that pediatric mania is more common that previously assumed, although it may be difficult to diagnose. Since children with mania are likely to become adults with bipolar disorder, the recognition and characterization of childhood-onset mania may help identify a meaningful developmental subtype of bipolar disorder worthy of further investigation. The major difficulties that complicate the diagnosis of pediatric mania include a pattern of comorbidity that may be unique by adult standards, especially due to its overlap with attention-deficit/hyperactivity disorder and conduct disorder.

 

Introduction

The atypicality (by adult standards) of the clinical picture of childhood mania has long been recognized.1,2 Notably, the literature consistently shows that mania in children is seldom characterized by euphoric mood.3,4 Rather, the most common mood disturbance in manic children is severe irritability, with “affective storms,” or prolonged and aggressive temper outbursts.2 This irritability observed in manic children is very severe, persistent, and often violent.5 The outbursts include threatening or attacking behavior toward family members, other children, adults, and teachers. In between outbursts, these children are described as constantly irritable or angry in mood.3,4,6 Thus, it is not surprising that these children frequently receive the diagnosis of conduct disorder (CD). These aggressive symptoms may be the primary reason for the high rate of psychiatric hospitalization noted in manic children.5

In addition to the predominant abnormal mood in pediatric mania, its natural course is also atypical compared with the natural course of adult mania. The course of pediatric mania tends to be chronic and continuous rather than episodic and acute.3,4,7,8 For example, in a recent review of the past 10 years of research on pediatric mania, Geller and Luby6 concluded that childhood-onset mania is a nonepisodic, chronic, rapid-cycling, mixed manic state. Such findings have also been reported by Wozniak and colleagues,5 who found that the overwhelming majority of 43 children from an outpatient psychopharmacology clinic who met diagnostic criteria for mania on a structured diagnostic interview presented with chronic and mixed presentation. Furthermore, Carlson and colleagues9 reported that early-onset manic subjects were more likely to have comorbid behavior disorders in childhood and to have fewer episodes of remission in a 2-year period than those with adult-onset cases of mania. Thus, pediatric mania appears to present with an atypical picture characterized by predominantly irritable mood, mania mixed with symptoms of major depression, and a chronic—as opposed to euphoric, biphasic, and episodic—course.

The chronicity of pediatric mania has been documented by an emerging, although limited, literature. Using data from a 2-year follow-up study, Geller and colleagues10 recently reported high levels of persistence and recurrence of manic symptomatology in children with bipolar disorder. Similar findings were reported by Biederman and colleagues11 in a longitudinal sample of children with attention-deficit/hyperactivity disorder (ADHD) and comorbid bipolar disorder. These investigators documented that 90% of these children failed to attain euthymia over a 10-year course.11 The findings suggest that pediatric cases with mania may develop into adults with mixed mania.

 

Bipolar Comorbidity with Attention-Deficit/Hyperactivity Disorder

A leading source of diagnostic confusion in childhood mania is its symptomatic overlap with ADHD. Systematic studies of children and adolescents show that rates of ADHD range from 60% to 90% in pediatric patients with mania.5,12-14 Although the rates of ADHD in samples of youth with mania are universally high, the age of onset modifies the risk for comorbid ADHD. For example, while Wozniak and colleagues5 found that 90% of children with mania also had ADHD, West and colleagues14 reported that only 57% of adolescents with mania had comorbid ADHD. Examining further developmental aspects of pediatric mania, Faraone and colleagues15 found that adolescents with childhood-onset mania had the same rates of comorbid ADHD as manic children (90%) and that both of these groups had higher rates of ADHD than adolescents with adolescent-onset mania (60%). Most recently, Sachs and colleagues16 reported that, among adults with bipolar disorder, a history of comorbid ADHD was only evident in those subjects with onset of bipolar disorder before 19 years of age. The mean onset of bipolar disorder in those with a history of childhood ADHD was 12.1 years of age.16 Similarly, Chang and colleagues17 studied the offspring of patients with bipolar disorder and found that 80% of manic children had comorbid ADHD and that the onset of mania in adults with bipolar disorder and a history of ADHD was 11.3 years of age. These findings suggest that age of onset of mania, rather than chronological age at presentation, may be the critical developmental variable that identifies a highly virulent form of the disorder that is heavily comorbid with ADHD. 

Although ADHD has a much earlier onset than pediatric mania, the symptomatic and syndromatic overlap between pediatric mania and ADHD raises a fundamental question: do children presenting symptoms that are suggestive of mania and ADHD have ADHD, mania, or both? One method to address these uncertainties has been to examine the transmission of comorbid disorders in families.18,19 If ADHD and mania are associated due to shared familial etiologic factors, then family studies should find mania in families of ADHD patients and ADHD in families of manic patients.

Studies that have examined rates of ADHD (or attention-deficit disorder) among the offspring of adults with bipolar disorder all found higher rates of ADHD among these children compared with controls.20 Although the difference in rates attained statistical significance in only one study, the meta-analysis of Faraone and colleagues20 documented a statistical and bi-directional significant association between bipolar disorder in parents and ADHD in their offspring, as well as between ADHD in a child proband and mania in relatives.

Wozniak and colleagues21 used familial risk analysis to examine the association between ADHD and mania within families of manic children. They found that relatives of children with mania were at high risk for ADHD; this risk was indistinguishable from the risk in relatives of children with ADHD and no mania. However, rates of mania and comorbid ADHD selectively aggregated among relatives of manic youth were comparable to those of ADHD and comparison children.21 Almost identical findings were obtained in two independently defined family studies of ADHD probands with and without comorbid mania.20,22 Taken together, this pattern of transmission in families suggests that mania in children might be a familially distinct subtype of either bipolar disorder or ADHD. The existence of a familial, developmental subtype is consistent with the work of Strober and colleagues,23 Strober,24 and Todd and colleagues,25 who proposed that pediatric mania might be a distinct subtype of bipolar disorder with a high familial loading.

One problem facing studies of ADHD and mania is that these disorders share diagnostic criteria. Of seven Diagnostic and Statistical Manual of Mental Disorders, Third Edition-Revised (DSM-III-R)26 criteria for a manic episode, three are shared with DSM-III-R criteria for ADHD: distractibility, motoric hyperactivity, and talkativeness. To avoid counting symptoms twice toward the diagnosis of both ADHD and mania, two different techniques of correcting for overlapping diagnostic criteria have been used to evaluate the association between ADHD and pediatric mania.27

In the first technique, the subtraction method, overlapping symptoms are simply not counted when making the diagnosis. In the proportion method, overlapping symptoms are not counted but the diagnostic threshold is lowered. However, the same proportion of symptoms is required in both the reduced set and the original diagnosis.28 Using these methods, Biederman and colleagues27 showed that 48% of children with mania continued to meet criteria by the subtraction method and 69% by the proportion method. Eighty-nine percent of children with mania maintained a full diagnosis of ADHD using the subtraction method and 93% maintained the ADHD diagnosis by the proportion method. These results suggest that the comorbidity between ADHD and pediatric mania is not a methodological artifact due to diagnostic criteria shared by the two disorders.

The potential for different rates of comorbidity with mania in the combined subtype, the inattentive subtype, and the hyperactive-impulsive subtype of ADHD is in need of further research. Faraone and colleagues20 studied 301 ADHD children and adolescents consecutively referred to a pediatric psychopharmacology clinic. Among these, 185 (61%) had the combined type of ADHD, 89 (30%) had the inattentive type, and 27 (9%) had the hyperactive-impulsive type. Bipolar disorder was highest among combined-type youth (26.5%) but was also elevated among hyperactive-impulsive (14.3%) and inattentive (8.7%) youth.

 

Bipolar Comorbidity with Conduct Disorder

An emerging literature documents an elevated risk for CD among children with bipolar disorder. Kovacs and Pollock29 reported a 69% rate of CD in a referred sample of bipolar youth. In that study, the presence of CD heralded a more complicated course of bipolar disorder. Similarly, Kutcher and colleagues30 found that 42% of hospitalized youth with bipolar disorder had comorbid CD; Wozniak and colleagues5 showed that preadolescent children satisfying structured interview criteria for bipolar disorder very frequently had comorbid CD. Notably, an epidemiologic study of children and adolescents31 found high rates of comorbidity between bipolar and disruptive behavior disorders. These findings in children, which report a nearly 7-fold increase in the risk for bipolar disorder among individuals with antisocial personality disorder (ASPD), are consistent with those in adults.32

While the reasons for these intriguing associations between CD and bipolar disorder remain unknown, a close inspection of the characteristics of juvenile bipolar disorder offers some clues. The literature indicates that juvenile bipolar disorder is frequently mixed, and that the most common mood disturbance in manic children is irritability, with “affective storms,” or prolonged, aggressive, and frequently violent temper outbursts.2-4 The irritable outbursts include threatening or attacking behavior toward others, including family members, children, adults, and teachers.

In conceptualizing the overlap between bipolar disorder and CD, Kovacs and Pollock29 suggested that the high prevalence of comorbid CD in bipolar youth might confuse the clinical presentation of childhood bipolar disorder and possibly account for some of the documented failure to detect bipolarity in children. Thus, the heterogeneity of bipolar disorder and that of CD may have important implications in helping to identify a subtype of bipolar disorder with early onset characterized by high levels of comorbid CD,29 as well as a subtype of CD with high levels of dysphoria and explosiveness.

Although these aberrant behaviors are consistent with the diagnosis of CD, they may be due to the behavioral disinhibition of bipolar disorder, or the irritability and low frustration tolerance that frequently accompanies pediatric bipolar disorder. Considering the extreme severity of juvenile bipolar disorder, its emergence in CD children (and, conversely, the emergence of CD in bipolar children) seriously complicates their already compromised condition.

Biederman and colleagues33 attempted to delineate this relationship between bipolar and CD in a series of studies. These studies relied on systematic evaluation of clinical correlates in affected youth and their relatives. Biederman and colleagues33 first tested the hypothesis that subtypes of CD with and without bipolar disorder could be distinguished from one another in a family study of 140 ADHD probands and 120 controls without ADHD ascertained from psychiatric and pediatric clinics. All probands were Caucasian, non-Hispanic males who were 6–17 years of age. Of 140 ADHD probands, 38 (27%) also met diagnostic criteria for CD and 30 (23%) for bipolar disorder at either baseline or follow-up assessments; of those, 21 (55% of CD cases and 71% of bipolar disorder cases) had both CD and bipolar disorder. The researchers reexamined the degree of overlap in a larger sample of clinically referred children that were not selected to participate in a study of ADHD.34 In this sample, the prevalence of bipolar disorder was 17% and the prevalence of CD was 18%. Of the pool of consecutively referred youth evaluated comprehensively with a structured diagnostic interview as described above, 186 subjects with mania and 192 subjects with CD were identified. Seventy-six patients satisfied criteria for both CD and bipolar disorder (ie, 40% of CD youth [76 of 192] and 41% of youth with bipolar disorder [76 of 186] also had the other disorder). This larger study of children with bipolar disorder and/or CD conducted outside the context of an ADHD sampling scheme34 provided greater precision and more clearly demonstrates the bi-directional overlap of these two disorders in clinical samples.

Further examination of the symptoms of bipolar disorder and CD indicated that the presence of one disorder did not alter the presentation of the other.34 The symptom profile of bipolar disorder was the same in bipolar disorder children and children with comorbid CD and bipolar disorder, just as the symptoms of CD were strikingly similar in children with bipolar disorder and CD irrespective of the comorbidity with the other disorder. Similarly, there were few differences in the frequency of CD symptoms between CD youth with and without comorbid bipolar disorder. These findings lend support to the notion that this may be true comorbidity and not simply the misdiagnosis of both conditions due to aggressive behavior endorsed in both modules of the interview. CD was also not found to modify the course of mania, with equal numbers of subjects reporting a chronic course (≥1 year duration) irrespective of the comorbidity with CD (65% versus 71% for bipolar disorder alone and comorbid bipolarity and CD, respectively).34 This pattern of symptoms, onset, and course suggests that the disorders behave similarly whether they are comorbid or exist separately from each other, and do not necessarily overlap concurrently. Longitudinal studies that examine the course of the disorders repeatedly over brief intervals are needed to disentangle this difficult clinical diagnostic confusion.

Rates of psychiatric hospitalization also differed dramatically in CD youth with and without comorbid bipolar disorder, with children with both CD and bipolar disorder accounting for most of the psychiatric hospitalizations in youth with CD. Psychiatric hospitalization was very low outside the context of bipolar disorder. Since many children in psychiatric hospitals with the diagnosis of CD commonly have a profile of severe aggressiveness, it is likely that these children required psychiatric hospitalizations because of the manic picture and not necessarily due to the CD. More work is needed to better test this hypothesis and to determine other factors that lead to hospitalization in children with either CD or bipolar disorder.

Because both CD and bipolar disorder are known to be familial disorders, one useful approach to disentangling these diagnoses and answering questions regarding the nature of their association is the use of family aggregation data.19,35-38 Such an approach can provide evidence external to the complicated diagnostic questions posed by the complex comorbid phenotype of individual patients. In other words, examining familial patterns of psychopathology can help answer whether children with a mix of mood and antisocial symptoms have bipolar disorder, CD, or both. Familial risk analysis showed that bipolar disorder probands had significantly higher rates of familial bipolar disorders and CD probands had higher rates of familial antisocial disorders compared with ADHD probands, irrespective of the presence of comorbidity with the other disorder.33

Wozniak and colleagues39 confirmed and expanded these findings in a second familial risk analysis that pooled resources from smaller studies in order to estimate the risk in relatives from a study with an increased sample size. This study pooled data from two samples of youth with DSM-III-R bipolar disorder (n=45) and their first-degree relatives (n=145), who were evaluated with identical methodologies. These were stratified into two proband groups defined by the presence or absence of CD and bipolar disorder. The first group contained 26 probands with both CD and bipolar disorder and 92 relatives, and the second group contained 19 probands with bipolar disorder without CD and 53 relatives. Compared with controls, the rate of bipolar disorder was significantly higher in relatives of both bipolar proband groups, irrespective of comorbidity with CD. The rate of CD/ASPD was significantly higher in relatives of both CD proband groups, irrespective of comorbidity with bipolar disorder. In addition, the rate of CD/ASPD in relatives of CD and bipolar disorder probands was nearly twice as large as the rate of CD/ASPD in relatives of CD probands (34% versus 19%, P<.05).39,40

The researchers also found significant co-segregation between antisocial disorders and bipolar disorder among the relatives of CD and bipolar disorder probands. That is, nearly all the bipolar disorder among relatives of co-occurring CD and bipolar disorder probands occurred in those relatives who also had CD or ASPD (χ2=10.9, P=.001). Two types of CD/ASPD were identified in relatives of co-occurring CD and bipolar disorder probands: those with and those without comorbid bipolar disorder. While relatives of CD and bipolar disorder probands had almost exclusively the comorbid type of bipolar disorder, the overrepresentation of CD/ASPD in relatives of CD probands consisted exclusively of CD/ASPD individuals without comorbid bipolar disorder.39 These findings were consistent with prior work suggesting a three-way familial association among bipolar disorder, CD/ASPD, and ADHD.20 The results from these family studies support the concept of heterogeneity of bipolar disorder and CD and provide compelling evidence that subtypes of CD and of bipolar disorder can be identified based on patterns of comorbidity with the other disorder.

 

Treatment Implications

Biederman and colleagues41 systematically reviewed the clinical records of all pediatrically referred patients who, at initial intake, satisfied diagnostic criteria for mania based on a structured diagnostic interview with the mother. Mood stabilizers were frequently used in these children and their use was associated with significant improvement of manic-like symptoms (as recorded by their psychiatrists in the medical record). However, although treatment with mood stabilizers was associated with a statistically significant decrease in manic-like symptoms, this improvement was slow to develop and was associated with frequent relapses. Antidepressants, typical antipsychotics, and stimulants were not associated with improvement of manic-like symptoms. 

Kowatch and colleagues,42 using an 8-week open study design, compared the effectiveness and tolerability of lithium carbonate, divalproex sodium, and carbamazepine in children with bipolar disorder. They found a 53% rate of improvement for divalproex sodium and much lower rates for lithium carbonate and carbamazepine. Likewise, Wagner and colleagues43 reported similarly modest effects in another trial of divalproex sodium in pediatric bipolar disorder.

Recently, somewhat more optimistic findings have resulted from investigations of atypical neuroleptics in the treatment of juveniles with bipolar disorder. In a retrospective chart review study of 28 youths with bipolar disorder, 82% of subjects showed improvement in both manic and aggressive symptoms with risperidone treatment.44 In contrast to the duration of treatment required for improvement with mood stabilizers, the average time to optimal response was 1.9±1.0 months of therapy. Moreover, no serious adverse effects were observed.

Similarly encouraging results were reported by Frazier and colleagues45 in an open trial of olanzapine monotherapy. They found that treatment with olanzapine was associated with significant improvements in 23 manic children after 8 weeks of monotherapy on doses ranging from 2.5–20 mg/day, according to both the Children’s Depression Inventory and the Young Mania Rating scale. Using the same prospective 8-week open study design, Biederman and colleagues46 reported that treatment with risperidone monotherapy improved both manic and depressive symptoms in youth with bipolar I, bipolar II, or bipolar spectrum disorder in youth. Also, DelBello and colleagues47 recently reported results from a randomized clinical trial that documented that the combination of divalproex sodium plus quetiapine was superior to divalproex sodium alone in the treatment of an inpatient sample of adolescents with bipolar disorder.47,48 

Because pediatric bipolar disorder is frequently mixed and comorbid with ADHD, its pharmacologic management can be complicated, as treatments for bipolar disorder do not treat ADHD, treatments for ADHD do not treat bipolar disorder, and antidepressants can precipitate mania. Biederman and colleagues41,49 used a novel chart review methodology to systematically evaluate the clinical records of psychiatrically referred youth with a diagnosis of bipolar disorder and comorbid ADHD. The results showed that the presence of mania interfered with the improvement of ADHD symptomatology during anti-ADHD pharmacotherapy and that ADHD symptoms were much more likely to improve after mood stabilization. These results suggest that the successful management of children with both mania and ADHD requires the deployment of disorder-specific treatments and that treatment of ADHD symptomatology is only possible after mood stabilization.48 However, because of the severe disruption in functioning associated with exacerbation of manic symptoms, caution is needed in prescribing anti-ADHD treatments to ADHD children with mania.

The diagnosis of bipolar disorder in some CD children offers important therapeutic possibilities, since sociopathy and bipolar disorder may require very different treatment strategies. A series of controlled clinical trials50-54 documented the efficacy of mood stabilizers (lithium carbonate and carbamazepine) in the treatment of aggressive CD children. However, these psychiatrically hospitalized CD youth were treated for severe, uncontrollable, and disorganized aggression and not necessarily for delinquency. Thus, it is possible that the therapeutic benefits observed in these children could have been due to the effects of these well known antimanic medications in treating aggressive manic children satisfying criteria for CD.51,55

Findling and colleagues56 recently reported that risperidone was effective in treating aggression in children with conduct disorder and Aman and colleagues57 reported results from a double-blind study that documented that risperidone was superior to placebo in the treatment of youth with CD and subaverage intelligence. A recent secondary analysis of the study results of Aman and colleagues57 documented the efficacy of risperidone in improving both manic and depressive symptoms in this population (Biederman and colleagues, unpublished data, 2004). Taken together, these initial results support the need for additional short- and long-term controlled trials of atypical neuroleptics in the treatment of juvenile bipolar disorder, either as monotherapy or in combination with mood stabilizers.

 

Conclusion

The emerging literature indicates that mania can be identified in a substantial number of referred children using systematic assessment methodology. Thus, this disorder may not be as rare as previously considered. Children with mania tend to show an atypical picture by adult standards, with a chronic course, severely irritable mood, and a mixed picture with depressive and manic symptoms co-occurring. Most children with childhood-onset mania may also have ADHD and CD, which requires additional treatment. Initial clinical evidence suggests that atypical neuroleptics may play a therapeutic role in the management of such youth. The high levels of comorbidity with other disorders is common, further requiring the cautious use of a combined pharmacotherapy approach. PP

 

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55. Campbell M, Gonzalez NM, Silva RR. The pharmacologic treatment of conduct disorders and rage outbursts. Psychiatr Clin North Am. 1992;15(1):69-85. 

56. Findling RL, McNamara NK, Branicky LA, Schluchter MD, Lemon E, Blumer JL. A double-blind pilot study of risperidone in the treatment of conduct disorder. J Am Acad Child Adolesc Psychiatry. 2000;39(4):509-516. 

57. Aman MG, De Smedt G, Derivan A, Lyons B, Findling RL, for the Risperidone Disruptive Behavior Study Group. Double-blind, placebo-controlled study of risperidone for the treatment of disruptive behaviors in children with subaverage intelligence. Am J Psychiatry. 2002;159(8):1337-1346.

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 e-mail: ns@mblcommunications.com

 

Dr. Sussman is editor of Primary Psychiatry as well as professor of psychiatry and interim chairman in the Department of Psychiatry at the New York University School of Medicine in New York City. Dr. Nelson is Leon J Epstein Professor of Psychiatry and director of Geriatric Psychiatry at the University of California, San Francisco.

Dr. Sussman reports no affiliation with or financial interest in any organization that may pose a conflict of interest. Dr. Nelson is a consultant to Bristol-Myers Squibb, Corcept, Merck, Orexigen, and Sierra Neuropharmaceuticals; is on the advisory boards of Bristol-Myers Squibb, Eli Lilly, and Shire; is on the Data, Safety Monitoring Boards of Medtronics, the National Institute of Mental Health (NIMH), and Orexigen; and receives grant support from the Health Resources and Services Administration and the NIMH.


 

Both clinicians and researchers have long known that the majority of depressed patients do not achieve or sustain a complete recovery from their disorders on most therapies. This has led to anecdotal reports and to clinical trials that suggest a broad range of interventions involving some combination of medications. The Sequenced Treatment Alternatives to Relieve Depression study1 examined response to treatment in a large sample of 3,671 patients with major depressive disorder. The patients were those typically encountered in primary care and psychiatry settings. The study found that even after 12–14 weeks of adequately dosed citalopram, only 37% of the patients achieved remission. The study indicates that most patients will require additional treatments. The common choices after initial treatment failure are to switch to another antidepressant, add a second antidepressant, start psychotherapy, or augment with a compound not approved for use as an antidepressant. Many different compounds have been used for augmentation including stimulants, modafinil, buspirone, pindolol, estrogen, and testosterone.2,3 Few controlled studies of these agents have been performed, and with the exception of a single modafinil study,4 the controlled studies have failed to show an advantage for augmentation with these agents. Thyroid augmentation has been more extensively studied. Reviews and meta-analyses indicate thyroid augmentation does accelerate response but the placebo-controlled trials in resistant depression fail to show an advantage.5,6

Lithium augmentation also has a long history. The idea for lithium augmentation was suggested by the observation in animal studies that the tricyclic antidepressants (TCAs) increased post-synaptic serotonin receptor sensitivity.4 Because lithium increases serotonin turnover, the thought was that lithium might have rapid effects when added to an ongoing TCA. In fact, the first study of lithium augmentation in depressed human subjects did report improvement within 48 hours in several patients.7 The other observation that supported the idea of a synergistic effect was the induction of mania after the addition of lithium noted in a few case reports.8 This effect would not be expected if lithium were acting independently. In this issue, Lawrence Price, MD, and colleagues provide a comprehensive and critical review of the lithium augmentation literature.

The use of atypical antipsychotics as adjunctive treatments for treatment-resistant depression has a relatively recent history. The use of adjunctive risperidone was first reported in eight patients who had failed selective serotonin reuptake inhibitor treatment in 1999.9 Since 2003, more than a dozen placebo-controlled augmentation trials of atypical antipsychotics in treatment-resistant non-psychotic depression have been reported or presented at meetings. George Papakostas, MD, provides an up-to-date and thoughtful review of this literature, which clinicians will find useful.

A brief case report by Anna Yusim, MD, describes a patient with phantom testicular pain. Like any form of phantom sensation, symptoms involving the genitalia are distressing to patients and difficult for the physician to both explain and treat. As Dr. Yusim notes, <10% of phantom pain patients receive relief with prescribed medication. There is clearly a need for additional research into the psychology and neurobiology of sensory disturbances. This additional information might lead to improved interventions.

Richard H. Weisler, MD, and David W. Goodman, MD, contribute an article on the assessment and diagnosis of adult attention-deficit/hyperactivity disorder (ADHD). They emphasize the need to rule out and factor into treatment decisions the presence of medical conditions and especially to consider cardiovascular risks before initiating treatment of adults with this disorder. Nevertheless, they note that adult ADHD remains under-recognized, underdiagnosed, and undertreated. Improved recognition and treatment should result in improved productivity in school and work as well as lead to better interpersonal relations, especially among family members.

Nadeem Bhanji, MD, and colleagues share the results of a survey of psychiatric physicians about direct-to-consumer (DTC) marketing. They report that surveyed psychiatrists believed that DTC had little significant effect on their prescribing practices, but that over 80% of respondents said they had prescribed medications specifically requested by their patients, often the result of their having seen a DTC advertisement. Among their conclusions is that there is a continued need for clinicians to play an active role about disease states and available treatments. PP

References

1.     Rush AJ, Trivedi MH, Wisniewski SR, et al. Acute and longer-term outcomes in depressed outpatients who required one or several treatment steps: a STAR*D report. Am J Psychiatry. 2006;163(11):1905-1917.
2.    Nelson JC. Augmentation strategies in depression 2000. J Clin Psychiatry. 2000;61(suppl 2):13-19.
3.    Fava M, Rush AJ. Current status of augmentation and combination treatments for major depressive disorder: a literature review and a proposal for a novel approach to improve practice. Psychother Psychosom. 2006;75(3):139-153.
4.    de Montigny C, Aghajanian GK. Tricyclic antidepressants: long-term treatment increases responsivity of rat forebrain neurons to serotonin. Science. 1978; 202(4374):1303-1306.
5.    Altshuler LL, Bauer M, Frye MA, et al. Does thyroid supplementation accelerate tricyclic antidepressant response? A review and meta-analysis of the literature. Am J Psychiatry. 2001;158(10):1617-1622.
6.    Aronson R, Offman HJ, Joffe RT, et al. Triiodothyronine augmentation in the treatment of refractory depression. A meta-analysis. Arch Gen Psychiatry. 1996;53(9):842-848.
7.    de Montigny C, Grunberg F, Mayer A, Deschenes JP. Lithium induces rapid relief of depression in tricyclic antidepressant drug non-responders. Br J Psychiatry. 1981;138(3):252-256.
8.    Nelson JC. Use of lithium augmentation in refractory depression. In: Treatment Strategies in Refractory Depression. S. Roose and A. Glassman eds. Washington, DC: American Psychiatric Press, Inc.; 1990;35-49.
9.    Ostroff RB, Nelson JC. Risperidone augmentation of selective serotonin reuptake inhibitors in major depression. J Clin Psychiatry. 1999;60(4):256-259.

 

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