Simultaneous Use of Carbamazepine and Lithium in the Treatment of Outpatients with Rapid Cycle Bipolar Disorder: Randomized, Double-Blind Placebo-Controlled Study

Purpose: rapid cycle bipolar disorder may be more resistant to treatment than other bipolar disorders. However, the effect of the synergistic use of carbamazepine and lithium in the treatment of outpatients with rapid cycle bipolar disorder without psychiatric comorbidity has not been studied in a double-blind, placebo-controlled design.

Patients and methods: participants in a double-blind, placebo-controlled study met DSM-5 criteria for bipolar disorder with a rapid cycle between the ages of 18 and 65 years. The response and side effects of carbamazepine, lithium, and placebo were compared using analysis of variance (ANOVA) and chi-square tests. The respondent underwent F2, demonstrating superiority with respect to carbamazepine and lithium than in the case of placebo. Carbamazepine and lithium were generally well tolerated by the study patients, although a larger number of patients receiving carbamazepine and lithium (n = 2) early discontinued the study due to side effects.

Results: twenty-seven of the 36 participants taking the combined carbamazepine and lithium regimen responded at 12 weeks, compared with six of 38 participants who received a placebo (p < 0.001). Two common side effects that led to discontinuation of carbamazepine and the lithium group were allergic reaction and drowsiness. Frequent complaints of sweating and headache during placebo treatment occurred in two out of 38 men. There were no unexpected or serious adverse events.

Conclusions: the combined use of carbamazepine and lithium in the treatment of outpatients with rapid cycle bipolar disorder has demonstrated superior use of carbamazepine and lithium than placebo.

1. Blanco C, Compton WM, Saha TD, Goldstein BI, Ruan WJ, Huang B, Grant BF. Epidemiologic Survey on Alcohol and Related Conditions-III. J. Psychiatr. Res. 2017;84:310–317. PMID: 27814503 PMCID: PMC7416534 DOI: 10.1016/j.jpsychires.2016.10.003

2. Cloutier M, Greene M, Guerin A, Touya M, Wu E. The economic burden of bipolar I disorder in the United States in 2015. J. Affect. Disorder. 2018;226:45–51. PMID: 28961441 DOI: 10.1016/j.jad.2017.09.011

3. Maj M, Pirozzi R, Magliano L, Bartoli L. The long-term result of lithium prophylaxis in bipolar disorder: a 5-year prospective study of 402 patients in a lithium clinic. Am. J. Psychiatry. 1998;155:30–35. PMID: 9433335 DOI: 10.1176/ajp.155.1.30

4. Fountoulakis KN, Kontis D, Gonda X, Yatham LN. A systematic review of the evidence on the treatment of rapid cycling bipolar disorder.BipolarDisord. 2013;15:115–137. PMID: 23437958 DOI: 10.1111/bdi.12045

5. Carvalho AF, Dimellis D, Gonda X, Vieta E, Mclntyre RS, Fountoulakis KN. Rapid cycling in bipolar disorder: a systematic review. J. Clin. Psychiatry. 2014;75:e578–586. PMID: 25004199 DOI: 10.4088/JCP.13r08905

6. Goldberg JF, Bowden CL, Calabrese JR, Ketter TA, Dann RS, Frye MA, Suppes T, Post RM. Six-month prospective life charting of mood symptoms with lamotrigine monotherapy versus placebo in rapid cycling bipolar disorder. Biol. Psychiatry. 2008;63:125–130. DOI: 10.1016/j.biopsych.2006.12.031

7. Aditya H, Aditi S, Malvika R, Janardhanan CN, Suresh BM. Pramipexole in the treatment of refractory depression in a patient with rapid cycling bipolar disorder. Indian J. Psychol. Med. 2015;37:473–474. PMCID: PMC4676223 PMID: 26702189 DOI: 10.4103/0253-7176.168614

8. Chen P, Huang Y. Remission of classic rapid cycling bipolar disorder with levothyroxine augmentation therapy in a male patient having clinical hypothyroidism. Neuropsychiatr Dis. Treat. 2015;11:339–342. DOI: 102147/NDT.S76973

9. 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. PMID: 11903207 DOI: 10.1034/j.1399-5618.2001.30503.x

10. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5). American Psychiatric Association. 2013.

11. Glantz SA. Primer of Biostatistics. Seventh Edition. 2012:321. ISBN-13: 978-0071781503; ISBN-10: 0071781501

12. Huber J, Burke D. ECT and lithium in old age depression —cause or treatment of rapid cycling? Australas Psychiatry. 2015;23:500–502. PubMed DOI: 10.1177/1039856215591328

13. Maj M, Pirozzi R, Formacola AMR, Tortrella A. Reliability and validity of four alternative definitions of bipolar disorder with fast cycling. Am. J. Psychiatry. 1999;158:303–305. PMID: 10484955. DOI: 10.1176/ajp.156.9.1421

14. Sampath H, Sharma I, Dutta S. Treatment of suicidal depression with ketamine in rapid cycling bipolar disorder. Asia Pac. Psychiatry. 2016;8:98–101. PMID: 26871425 DOI: 10.1111/appy.12220

15. Goldberg JF, Bowden CL, Calabrese JR, Ketter TA, Dann RS, Frye MA, Suppes T, Post RM. Six-month prospective life charting of mood symptoms with lamotrigine monotherapy versus placebo in rapid cycling bipolar disorder. Biol. Psychiatry. 2008;63:125–130. DOI: 10.1016/j.biopsych.2006.12.031

16. Bobo WV, Vande Voort JL, Croarkin PE, Leung JG, Tye SJ, Frye MA. Ketamine for treatment-resistant unipolar and bipolar major depression: critical review and implications for clinical practice. Depress Anxiety. 2016;33(8):698–710. DOI: 10.1002/da.22505. Epub 2016 Apr 6. PMID: 27062450

17. Calabrese JR, Fatemi SH, Kujawa M, Woyshville MJ. Predictors of response to mood stabilizers. J. Clin. Psychopharmacol. 1996;16:24–31. PMID: 8707997 DOI: 10.1097/00004714-199604001-00004

18. Baldessarini RJ, Tondo L, Hennen J, Viguera AC. Is Lithium Still Worth Using? An Update of Selected Recent Research. Harvard Review of Psychiatry. 2002; 10(2):59–75. DOI: 10.1080/hrp.10.2.59.75

19. Calabrese JR, Shelton MD, Rapport DJ, Youngstrom EA, Jackson K, Bilali S, Ganocy SJ, Findling RL. A 20-month, double-blind, maintenance trial of lithium versus divalproex in rapid-cycling bipolar disorder. Am. J. Psychiatry. 2005;162:2152–2161. PMID: 16263857. DOI: 10.1176/appi.ajp.162.11.2152

20. Koukopoulos A, Reginalsi D, Laddomada P, Floris G, Serra G, Tondo L. Course of the manic-depressive cycle and changes caused by treatments. Pharmacopsychiatry. 1980;13:156–167. PMID: 6108577. DOI: 10.1055/s-2007-1019628

21. Health at a Glance: Europe 2018. State of Health in the EU Cycle. OECD Publishing. 2018:216.

22. Calabrese JR, Rappor t 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(2):92–95. PMID: 15797691 DOI: 10.1016/j.eurpsy.2004.12.003

23. Kostyukova EG, Shafarenko AA, Ladyzhenskii MJ. Сhallenges and opportunities of differentiated therapy of patients with bipolar disorder. Sovremennaya terapiya psihicheskih rasstrojstv. 2014;4:8–14. (In Russ.).