-----------------------------7d52073a403e8 Content-Disposition: form-data; name="Upload"; filename="C:\Documents and Settings\Ayesha Ahmed\Desktop\Rapid Cycling Bipolar Disorder.htm" Content-Type: text/html Rapid Cycling Bipolar Disorder
Medscape www.medscape.com
To Print: Click your browser's PRINT button.
NOTE: To view the article with Web enhancements, go to:
http://www.medscape.com/viewarticle/512156


Rapid Cycling Bipolar Disorder: Update on Phenomenology and Treatment

Aditi Mehta, MD; Joseph R. Calabrese, MD 

Medscape Psychiatry & Mental Health.  2005;8(2) 2005 Medscape
Posted 09/13/2005

History/Definition

The rapid cycling pattern of bipolar disorder was first noted by Kraepelin in the early 1900s.[1] In 1974, Dunner and Fieve identified rapid cycling as a specific entity that could quite possibly predict nonresponse to treatment.[2] Many independent studies confirmed the existence of rapid cycling and, finally, in 1994, following a meta-analysis by Bauer and colleagues, the rapid cycling specifier was included in the fourth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) of the American Psychiatric Association.[3] The DSM-IV defines rapid cycling bipolar disorder as a pattern of presentation accompanied by 4 or more mood episodes in a 12-month period, with a typical course of mania or hypomania followed by depression or vice versa. The episodes must be demarcated by a full or partial remission lasting at least 2 months or by a switch to a mood state of opposite polarity.[4] Research shows that it is common for rapid cyclers to have frequent brief depressive episodes that do not necessarily meet duration criteria for full depressive episodes as per DSM-IV.[5]

Some investigators have further classified rapid cycling into ultrarapid (cycling every few days) and ultradian (cycling that occurs daily).[6,7] Kraepelin referred to these patterns of cycling as being the inherent mood lability seen in almost all patients with bipolar disorder; consequently, these additional specifiers have never been incorporated into the DSM-IV.[1] Initially, investigators hypothesized that rapid cycling predicted poor response to individual medications, but more recent data suggest that this entity is also accompanied by higher rates of recurrence and is more likely to be a nonspecific predictor of poor outcome, such as is the case for psychosis.[8,9]

Demographics and Risk Factors

A review of several studies demonstrates a wide range in prevalence rates (13% to 56%),[10,11] which may be due to confusion regarding interpretations of rapid cycling and recruitment bias.[12] Rapid cycling patients usually tend to be younger,[13] with illness onset before the age of 17 years.[14] Women are more likely than men to be rapid cyclers,[15] with prevalence rates of 70% (range, 58% to 92%) or even higher.[12,16,17] The higher prevalence of rapid cycling in women could be attributed to increased occurrence of hypothyroidism or menstrual cycle irregularities. Some researchers have asserted that hypothyroidism can cause rapid cycling,[18-20] while others question this theory.[21,22] According to Calabrese and colleagues,[23] rapid cycling is predominant in patients with bipolar II, which usually manifests as depression at onset. Since women are more prone to depression, they often may be diagnosed with rapid cycling.[12] Additionally, rapid cycling may be induced by the use of antidepressant drugs,[24,25] especially in women.[6] Finally, in patients with no psychiatric history, rapid cycling can emerge after varying kinds of trauma to the brain, such as subarachnoid hemorrhage,[26] diffuse cerebral damage following closed head injury,[27] or focal temporal pole damage.[28]

In a recent review article by Papadimitriou and colleagues,[29] rapid cycling was described as rare in unipolar patients, but considerably more common in bipolar patients. Rapid cyclers also suffer higher morbidity, which is evident in more serious suicide attempts,[14] more frequent hospitalizations,[13] and a greater tendency to seek treatment later in the course of illness.[15] Episodes also consist of more severe depression, less severe mania, and fewer psychoses compared with nonrapid cyclers.[13] In addition, rapid cyclers usually have a prior history of rapid cycling, substance abuse, and childhood physical and/or sexual abuse.[5,13] A family history of bipolar disorder, depression, and substance abuse usually exists as well.[13] In contrast to some other researchers, Kupka noted bipolar I disorder subtype to be more prevalent than bipolar II subtype in rapid cycling patients.[5] In short-term clinical trials, patients with rapid cycling tend to be placebo-responsive, but the available long-term data suggest that this pattern of presentation predicts poor long-term outcome.[13]

Course of Illness

In the early years of the 20th century, Kraepelin reported an association between cycle length and the progression of illness.[1] Later research revealed that as the number of affective episodes increases, the length of each cycle decreases[30-32] and eventually stabilizes after 4-6 episodes.[33] Patients with a higher frequency of cycling usually spend more time in mania and hypomania with every subsequent episode, while depressive episodes appear to be unaffected by the frequency of cycling. This observation, however, is inconsistent with the growing impression that highly recurrent treatment-refractory depression is the hallmark of rapid cycling bipolar disorder.[23]

Treatment

Patients with rapid cycling bipolar disorder are difficult to treat, especially if complete mood stabilization is the goal.[34] Rapid cyclers are considered to be in remission if they stop cycling and their functioning returns to near normal in occupational, family, and social settings. Sleep patterns are reliable indicators of relapse, and if these patients have regular sleep, they may avoid cycling into mania.[35] In patients who have never been treated, mood stabilizers such as lithium are the first line of treatment.[9] Permissive definition of mood stabilizers characterizes medications as effective in the long-term management of at least 1 phase of bipolar disorder without worsening any other phase of the illness. Therefore, effective treatment should not precipitate mania, depression, or rapid cycling, and should minimize the burden of treatment-emergent side effects.[15] Sufficient evidence exists to support the use of lithium and lamotrigine in the prevention of cycling in bipolar disorder.[11] Lamotrigine is particularly efficacious in patients with predominant depression and rapid cycling bipolar II, while divalproex is a first-line option in rapid cycling bipolar I.[36,37]

The combination of lithium with carbamazepine, valproate, or lamotrigine for maintenance along with olanzapine as an adjunct also has some support from controlled studies.[9] Quetiapine monotherapy has also shown effectiveness in treating depression in patients with a rapid cycling course.[38]

Lithium

At least 8 placebo-controlled, randomized trials have demonstrated lithium to be prophylactic in bipolar disorder.[39] A meta-analysis of 16 studies of bipolar disorder by Tondo and colleagues[40] showed that lithium may be considered first-line treatment in the prophylaxis of rapid cycling bipolar disorder. Many studies support the efficacy of lithium as a mood stabilizer,[41-44] particularly in the maintenance of bipolar type II patients.[45] Conversely, other studies have illustrated poor efficacy of lithium in rapid cycling bipolar disorder,[2,24] especially compared with divalproex in the hypomanic and manic phases of rapid cycling bipolar disorder.[2,24,46-48] However, these studies may have been confounded by many variables (eg, concomitant antidepressant use), and therefore cannot be generalized.[15]

Most bipolar type II patients who have not been treated with antidepressants usually show a good response to lithium.[15] Response to lithium improves upon the discontinuation of antidepressant(s).[25] Other factors that need to be considered include gender, cycling history, and past use of lithium in treatment subjects. Women tend to respond better and longer to lithium, even though their serum levels are lower.[44] In addition, the response to lithium is usually lower in individuals with a history of 4 depressive or 12 manic episodes. This phenomenon may be related to neuropsychological changes due to increased incidents of lithium discontinuation.[49] Sometimes, poor response to lithium that is attributed to its poor efficacy actually exists due to treatment refractoriness of these patients as they have been cycling for a long time before lithium was administered.[50]

Divalproex

In an open, prospective study by Calabrese and colleagues, divalproex was markedly effective in mania for 72% of the sample, 94% for mixed states, and 33% for depression.[51] Divalproex has moderate-to-marked acute and prophylactic antimanic properties in rapid cyclers with only modest antidepressant effects.[46] It has proved effective in patients with a family history of affective disorder, no prior lithium therapy, and bipolar II or mixed states. Patients with more frequent or severe mania, or borderline personality disorder, usually do not respond as well.[51] Prior studies indicated that patients with mixed states or rapid cycling respond better to divalproex compared with lithium.[52] Calabrese and colleagues[41] recently reported on a 20-month double-blind study in which both lithium and divalproex had equal effect on time and rate of relapse. At the present time, the emerging consensus is that lithium and divalproex have similar efficacy in the long-term treatment of rapid cycling bipolar disorder.[41,53] Divalproex can sometimes be combined with lithium to improve response.[54,55] However, while the combination of lithium and divalproex administered over 6 months showed marked efficacy in mania for 85% of patients and in depression for 60% of patients, only 50% of patients showed bimodal stabilization.[23]

Lamotrigine

In an open-label study of lamotrigine as add-on or monotherapy, patients with more severe symptoms of mania did not improve, but subgroups of patients with rapid cycling who also had both depressive and hypomanic symptoms showed significant improvement.[56,57] In the first double-blind, placebo-controlled study of a homogeneous cohort of prospectively enrolled patients with rapid cycling bipolar disorder, lamotrigine monotherapy over a 6-month study period exhibited evidence of mood-stabilizing efficacy, especially in patients with bipolar II. Compared with placebo, lamotrigine at an average dose of 288 94 mg/day showed higher median survival and effectiveness (time to drop out for any reason).[58] When comparing lithium with lamotrigine in bipolar patients, patients taking lamotrigine showed lower rates of rapid cycling.[59] Frye and colleagues[60] compared lamotrigine, gabapentin, and placebo in treatment-refractory patients with a high percentage (92%) of rapid cycling and found marked antidepressant response in lamotrigine-treated patients. Even though lamotrigine has limited efficacy in the manic phase, its moderate-to-marked efficacy in depression and hypomania makes it a good complement to lithium and divalproex in the treatment of rapid cycling.[61] In addition, lamotrigine has a relatively weight-neutral profile, which is a potential advantage over other mood stabilizers such as lithium or divalproex.[60]

Carbamazepine

Early studies of the efficacy of carbamazepine showed that a diagnosis of rapid cycling predicts a positive response to carbamazepine.[62] More recently, this observation has been persuasively refuted by a series of studies.[63] Carbamazepine has been found to have a very limited scope in the treatment of rapid cycling, especially as monotherapy. It has moderate-to-marked efficacy in the manic phase, and poor-to-moderate efficacy in the depressed phase.[64] When carbamazepine was added to another mood stabilizer, particularly lithium, it was more advantageous than monotherapy.[15] It was seen that the response rate in bipolar patients on carbamazepine alone was half that of the response with lithium monotherapy. However, both lithium and carbamazepine achieved earlier response and twice the response rate as lithium alone.[65] Now the use of a congener, oxcarbazepine, has increased in an effort to avoid potential adverse reactions from carbamazepine; however, oxcarbazepine has not been studied enough in the treatment of rapid cycling to make any conclusive statements.[15]

Olanzapine

Tohen and colleagues[66] compared olanzapine and the combination of olanzapine plus fluoxetine to placebo in acute bipolar I depression and found that both monotherapy and combination therapy showed significant improvement in depression. In addition, the improvement on combination therapy occurred as early as the first week of treatment and neither therapy caused an elevation in treatment-emergent mania.[66] Recent randomized, double-blind trials comparing the short-term efficacy of olanzapine vs placebo in acute mania have shown good response. The patient population consisted of current rapid cyclers[67] and also those with a history of a rapid cycling course.[68] Vieta and colleagues[13] recently looked at long-term outcomes from pooled data of the prior randomized studies and found that even though the rapid cycling patients are more likely to relapse in the long term, olanzapine improves their overall outcome.

Quetiapine

Quetiapine is a bimodal mood stabilizer effective for treatment of both bipolar mania and depression.[15] In an open-label study, quetiapine was found to be effective and well tolerated as monotherapy or as an add-on to a mood stabilizer in treatment of Type I rapid cycling bipolar disorder.[69] In the first randomized, placebo-controlled trial to evaluate the efficacy of quetiapine in depressed patients with and without rapid cycling bipolar disorder, significant improvement was seen independent of the rapid cycling pattern.[70] A 3-month follow-up study in which quetiapine was given to patients on lithium and/or divalproex or concomitant lamotrigine showed improvement in rapid cycling in groups with quetiapine.[15] Additionally, Vieta and colleagues[71] reported that quetiapine is an efficacious add-on therapy to other mood stabilizers for rapid cycling and is more effective for mania. The dosage of quetiapine for acute illness ranged from 720 84 mg/day for mania vs 183 29 mg/day for depression.[71]

Topiramate

A limited number of open-label studies have supported the use of topiramate in rapid cycling bipolar disorders. Double-blinded, placebo-controlled studies have been unable to demonstrate the mood-stabilizing effects of topiramate in general cohorts of patients with bipolar disorder. It has an advantage of reversing increased body weight, however, as well as normalizing glycemic control and blood pressure, which are side effects of some of the other medications for rapid cycling.[72]

Summary

Rapid cycling bipolar disorder is defined as 4 or more mood episodes alternating between depression and mania over a 12-month period. Patients with rapid cycling are usually managed through the use of multiple mood stabilizers in combination that target minimizing the frequency of the cycles without worsening any phase of the disorder. Lithium and divalproex are considered first-line treatments for acute and long-term management of rapid cycling in bipolar I (especially for mania) and lamotrigine for bipolar II patients who usually present with depression. Prior notions that lithium is ineffective in rapid cycling are not supported by recently conducted maintenance studies. Other drugs such as olanzapine and quetiapine are currently being studied in the long-term treatment of rapid cycling bipolar disorder. Although the acute treatment of patients with rapid cycling bipolar disorder is satisfactory, the long-term management of this variant of illness is quite challenging, with response rates frequently being very modest and rates of comorbidity quite high. There is emerging evidence to suggest that highly recurrent, treatment-refractory depression is the hallmark of rapid cycling bipolar disorder, and that many patients presenting in this way are being incorrectly diagnosed and treated with selective serotonin reuptake inhibitors used as monotherapy.

References

  1. Kraepelin E. Manic Depressive Insanity and Paranoia. Translation of selections from Psychiatrie. Reprint of the 1921 ed. Edinburgh, Scotland: E & S Livingstone, Edinburgh; 2002.
  2. Dunner DL, Fieve RR. Clinical factors in lithium carbonate prophylaxis failure. Arch Gen Psychiatry. 1974;30:229-233. Abstract
  3. Bauer MS, Calabrese JR, Dunner DL, et al. Multisite data reanalysis of the validity of rapid cycling as a course modifier for bipolar disorder in DSM-IV. Am J Psychiatry. 1994;151:506-515. Abstract
  4. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision. Washington, DC: American Psychiatric Association; 2000.
  5. Kupka RW, Luckenbaugh DA, Post RM, et al. Comparison of rapid-cycling and non-rapid-cycling bipolar disorder based on prospective mood ratings in 539 outpatients. Am J Psychiatry. 2005;162:1273-1280. Abstract
  6. Barrios C, Chaudhry TA, Goodnick PJ. Rapid cycling bipolar disorder. Expert Opin Pharmacother. 2001;2:1963-1973. Abstract
  7. Tillman R, Geller B. Definitions of rapid, ultrarapid, and ultradian cycling and of episode duration in pediatric and adult bipolar disorders: a proposal to distinguish episodes from cycles. J Child Adolesc Psychopharmacol. 2003;13:267-271. Abstract
  8. Maj M, Magliano L, Pirozzi R, et al. Validity of rapid cycling as a course specifier for bipolar disorder. Am J Psychiatry. 1994;151:1015-1019. Abstract
  9. Coryell W. Rapid cycling bipolar disorder: clinical characteristics and treatment options. CNS Drugs. 2005;19:557-569. Abstract
  10. Akiskal HS, Bourgeois ML, Angst J, et al. Re-evaluating the prevalence of and diagnostic composition within the broad clinical spectrum of bipolar disorders. J Affect Disord. 2000;59(suppl 1):S5-S30. Abstract
  11. Coryell W, Endicott J, Keller M. Rapidly cycling affective disorder. Demographics, diagnosis, family history, and course. Arch Gen Psychiatry. 1992;49:126-131. Abstract
  12. Mackin P, Young AH. Rapid cycling bipolar disorder: historical overview and focus on emerging treatments. Bipolar Disord. 2004;6:523-529. Abstract
  13. Vieta E, Calabrese JR, Hennen J, et al. Comparison of rapid-cycling and non-rapid-cycling bipolar I manic patients during treatment with olanzapine: analysis of pooled data. J Clin Psychiatry. 2004;65:1420-1428. Abstract
  14. Coryell W, Solomon D, Turvey C, et al. The long-term course of rapid-cycling bipolar disorder. Arch Gen Psychiatry. 2003;60:914-920. Abstract
  15. Muzina DJ, Elhaj O, Gajwani P, Gao K, Shelton MD, Calabrese JR. Advances in treatment of rapid cycling bipolar disorders. Oldham JM, Riba MB, Ketter TA, eds. Review of Psychiatry, Volume 24. Arlington, Va: American Psychiatric Publishing Inc; 2005:147-178.
  16. Leibenluft E. Women with bipolar illness: clinical and research issues. Am J Psychiatry. 1996;153:163-173. Abstract
  17. Leibenluft E. Issues in the treatment of women with bipolar illness. J Clin Psychiatry. 1997;58(suppl 15):5-11. Abstract
  18. Cowdry RW, Wehr TA, Zis AP, et al. Thyroid abnormalities associated with rapid-cycling bipolar illness. Arch Gen Psychiatry. 1983;40:414-420. Abstract
  19. Bauer MS, Whybrow PC. Rapid cycling bipolar affective disorder. II. Treatment of refractory rapid cycling with high-dose levothyroxine: a preliminary study. Arch Gen Psychiatry. 1990;47:435-440. Abstract
  20. Bauer MS, Whybrow PC, Winokur A. Rapid cycling bipolar affective disorder. I. Association with grade I hypothyroidism. Arch Gen Psychiatry. 1990;47:427-432. Abstract
  21. Post RM, Kramlinger KG, Joffe RT, et al. Rapid cycling bipolar affective disorder: lack of relation to hypothyroidism. Psychiatry Res. 1997;72:1-7. Abstract
  22. Joffe RT, Kutcher S, MacDonald C. Thyroid function and bipolar affective disorder. Psychiatry Res. 1988;25:117-121. Abstract
  23. Calabrese JR, Shelton MD, Bowden CL, et al. Bipolar rapid cycling: focus on depression as its hallmark. J Clin Psychiatry. 2001;62(suppl 14):34-41. Abstract
  24. Koukopoulos A, Reginalsi D, Laddomada P. Course of the manic-depressive cycle and changes caused by treatments. Pharmacopsychiatry. 1980;13:156-167.
  25. Wehr TA, Sack DA, Rosenthal NE, et al. Rapid cycling affective disorder: contributing factors and treatment responses in 51 patients. Am J Psychiatry. 1988;145:179-184. Abstract
  26. Blackwell MJ. Rapid-cycling manic-depressive illness following subarachnoid haemorrhage. Br J Psychiatry. 1991;159:279-280. Abstract
  27. Zwil AS, McAllister TW, Cohen I, et al. Ultra-rapid cycling bipolar affective disorder following a closed-head injury. Brain Inj. 1993;7:147-152. Abstract
  28. Murai T, Fujimoto S. Rapid cycling bipolar disorder after left temporal polar damage. Brain Inj. 2003;17:355-358. Abstract
  29. Papadimitriou GN, Calabrese JR, Dikeos DG, Christodoulou GN. Rapid cycling bipolar disorder: biology and pathogenesis. Int J Neuropsychopharmacol. 2005;8:281-292. Abstract
  30. Roy-Byrne PP, Post R, Uhde TW. The longitudinal course of recurrent affective illness: Life chart data from research patients at the NIMH. Acta Psychiatr Scand. 1985;71(suppl 317):1-34.
  31. Zis AP, Grof P, Webster M, et al. Prediction of relapse in recurrent affective disorder. Psychopharmacol Bull. 1980;16:47-49.
  32. Angst J. Unsolved problems in the indications for lithium prophylaxis in affective and schizoaffective disorders. Bibl Psychiatr. 1981;161:32-44. Abstract
  33. Goodwin FK, Jamison KR. Manic Depressive Illness. New York, NY: Oxford University Press; 1990.
  34. Cole AJ, Scott J, Ferrier IN, et al. Patterns of treatment resistance in bipolar affective disorder. Acta Psychiatr Scand. 1993;88:121-123. Abstract
  35. Keck PE Jr. Defining and improving response to treatment in patients with bipolar disorder. J Clin Psychiatry. 2004;65(suppl 15):25-29. Abstract
  36. Hirschfeld RM, Bowden CL, Gitlin MJ, et al. Practice guideline for the treatment of patients with bipolar disorder (revision). Am J Psychiatry. 2002;159(Suppl):1 50.
  37. Keck PE Jr, Perlis RH, Otto MW, Carpenter D, Ross R, Docherty JP. The Expert Consensus Guideline Series: Treatment of Bipolar Disorder 2004. Postgrad Med Special Report. 2004;(December):1-120.
  38. Calabrese JR, Elhaj O, Gajwani P, Gao K. Clinical highlights in bipolar depression: focus on atypical antipsychotics. J Clin Psychiatry. 2005;66(suppl 5):26-33. Abstract
  39. Goodwin FK. Rationale for long-term treatment of bipolar disorder and evidence for long-term lithium treatment. J Clin Psychiatry. 2002;63(suppl 10):5-12. Abstract
  40. Tondo L, Hennen J, Baldessarini RJ. Rapid-cycling bipolar disorder: effects of long-term treatments. Acta Psychiatr Scand. 2003;108:4-14. Abstract
  41. Calabrese JR, Shelton MD, Rapport DJ, et al. A 20-month, double-blind, maintenance trial of lithium vs. divalproex in rapid-cycling bipolar disorder. Am J Psychiatry. In Press.
  42. Baldessarini RJ, Tondo L, Hennen J, et al. Is lithium still worth using? An update of selected recent research. Harv Rev Psychiatry. 2002;10:59-75. Abstract
  43. Tondo L, Baldessarini RJ, Floris G. Long-term clinical effectiveness of lithium maintenance treatment in types I and II bipolar disorders. Br J Psychiatry. 2001;178:S184-190. Abstract
  44. Viguera AC, Baldessarini RJ, Tondo L. Response to lithium maintenance treatment in bipolar disorders: comparison of women and men. Bipolar Disord. 2001;3:245-252. Abstract
  45. Tondo L, Baldessarini RJ, Hennen J, et al. Lithium maintenance treatment of depression and mania in bipolar I and bipolar II disorders. Am J Psychiatry. 1998;155:638-645. Abstract
  46. Calabrese JR, Delucchi GA. Spectrum of efficacy of valproate in 55 patients with rapid-cycling bipolar disorder. Am J Psychiatry. 1990;147:431-434. Abstract
  47. Bowden CL. Clinical correlates of therapeutic response in bipolar disorder. J Affect Disord. 2001;67:257-265. Abstract
  48. Post RM, Frye MA, Denicoff KD, et al. Emerging trends in the treatment of rapid cycling bipolar disorder: a selected review. Bipolar Disord. 2000;2:305-315. Abstract
  49. Swann AC, Bowden CL, Calabrese JR, et al. Mania: differential effects of previous depressive and manic episodes on response to treatment. Acta Psychiatr Scand. 2000;101:444-451. Abstract
  50. Baldessarini RJ, Tondo L, Floris G, et al. Effects of rapid cycling on response to lithium maintenance treatment in 360 bipolar I and II disorder patients. J Affect Disord. 2000;61:13-22. Abstract
  51. Calabrese JR, Markovitz PJ, Kimmel SE, et al. Spectrum of efficacy of valproate in 78 rapid-cycling bipolar patients. J Clin Psychopharmacol. 1992;12:53S-56S. Abstract
  52. Swann AC. Prediction of treatment response in acute mania: controlled clinical trials with divalproex. Encephale. 2001;27:277-279. Abstract
  53. Calabrese JR, Rapport DJ, Youngstrom EA, Jackson K, Bilali S, Findling RL. New data on the use of lithium, divalproate, and lamotrigine in rapid cycling bipolar disorder. Eur Psychiatry. 2005;20:92-95. Abstract
  54. Calabrese JR, Sullivan JR, Bowden CL, et al. Rash in multicenter trials of lamotrigine in mood disorder: clinical relevance and management. J Clin Psychiatry. 2002;63:1012-1019. Abstract
  55. Sharma V, Persad E, Mazmanian D, et al. Treatment of rapid cycling bipolar disorder with combination therapy of valproate and lithium. Can J Psychiatry. 1993;38:137-139. Abstract
  56. Bowden CL, Calabrese JR, McElroy SL, et al. The efficacy of lamotrigine in rapid cycling and non-rapid cycling patients with bipolar disorder. Biol Psychiatry.1999;45:953-958. Abstract
  57. Calabrese JR, Bowden CL, McElroy SL, et al. Spectrum of activity of lamotrigine in treatment refractory bipolar disorder. Am J Psychiatry. 1999;156:1019-1023. Abstract
  58. Calabrese JR, Suppes T, Bowden CL, et al. A double-blind, placebo-controlled, prophylaxis study of lamotrigine in rapid-cycling bipolar disorder. Lamictal 614 Study Group. J Clin Psychiatry. 2000;61:841-850. Abstract
  59. Walden J, Schaerer L, Schloesser S, et al. An open longitudinal study of patients with bipolar rapid cycling treated with lithium or lamotrigine for mood stabilization. Bipolar Disord. 2000;2:336-339. Abstract
  60. Frye MA, Ketter TA, Kimbrell TA, et al. A placebo-controlled study of lamotrigine and gabapentin monotherapy in refractory mood disorders. J Clin Psychopharmacol. 2000;20:607-614. Abstract
  61. Calabrese JR, Bowden CL, Sachs GS, et al. A double-blind placebo-controlled study of lamotrigine monotherapy in outpatients with bipolar I depression. Lamictal 602 Study Group. J Clin Psychiatry. 1999;60:79-88. Abstract
  62. Post RM, Uhde TW, Roy-Byrne PP, et al. Correlates of antimanic response to carbamazepine. Psychiatry Res. 1987;21:71-83. Abstract
  63. Okuma T. Effects of carbamazepine and lithium on affective disorders. Neuropsychobiology. 1993;27:138-145. Abstract
  64. Calabrese JR, Bowden CL, Woyshville M. Lithium and anticonvulsants in the treatment of bipolar disorder. In: Psychopharmacology: The Third Generation of Progress. New York, NY: Raven Press; 1995.
  65. Denicoff KD, Smith-Jackson EE, Disney ER, et al. Comparative prophylactic efficacy of lithium, carbamazepine, and the combination in bipolar disorder. J Clin Psychiatry. 1997;58:470-478. Abstract
  66. Tohen M, Vieta E, Calabrese JR, et al. Efficacy of olanzapine and olanzapine-fluoxetine combination in the treatment of bipolar I depression. Arch Gen Psychiatry. 2003;60:1079-1088. Abstract
  67. Baldessarini RJ, Hennen J, Wilson M, et al. Olanzapine versus placebo in acute mania: treatment responses in subgroups. J Clin Psychopharmacol. 2003;23:370-376. Abstract
  68. Sanger TM, Tohen M, Vieta E, et al. Olanzapine in the acute treatment of bipolar I disorder with a history of rapid cycling. J Affect Disord. 2003;73:155-161. Abstract
  69. Ghaemi SN, Goldberg JF, Ko J, et al. Seroquel treatment of rapid cycling bipolar disorder: an open prospective study. Program and abstracts of the Fourth International Conference on Bipolar Disorder; June 14-16, 2001; Pittsburgh, Pennsylvania.
  70. Calabrese JR, Keck PE Jr, Macfadden W, et al. A randomized, double-blind, placebo-controlled trial of quetiapine, in the treatment of bipolar I or II depression. Am J Psychiatry. 2005;162:1351-1360. Abstract
  71. Vieta E, Parramon G, Padrell E, et al. Quetiapine in the treatment of rapid cycling bipolar disorder. Bipolar Disord. 2002;4:335-340. Abstract
  72. Arnone D. Review of the use of topiramate for treatment of psychiatric disorders. Ann Gen Psychiatry. 2005;4:5.
Funding Information

Supported by an independent educational grant from GlaxoSmithKline


Aditi Mehta, MD, Resident, Psychiatry, University Hospitals of Cleveland, Cleveland, Ohio

Joseph R. Calabrese, MD, Professor of Psychiatry, Case Western Reserve University School of Medicine; Director, Mood Disorders Program; Director, Division of Ambulatory Care, University Hospitals of Cleveland, Cleveland, Ohio

Disclosure: Aditi Mehta, MD, has disclosed no relevant financial relationships.

Disclosure: Joseph R. Calabrese, MD, has disclosed that he has received grants for clinical research and/or educational activities from Abbott, AstraZeneca, Merck, GlaxoSmithKline, Janssen, Eli Lilly, and Pfizer. Dr. Calabrese has also disclosed that he serves on an advisory board for Abbott, AstraZeneca, Bristol-Myers