Lithium, Carbamazepine and Valproate in Acute Mania Lithium, Carbamazepine and Valproate in Acute Mania M. Erkan Ozcan M.D.1, A. Vahap Boztepe M.D.2 ABSTRACT: ÖZET: LITHIUM, CARBAMAZEPINE AND VALPROATE IN ACUTE MA- AKUT MAN‹ TEDAV‹S‹NDE L‹TYUM, KARBAMAZEP‹N VE VAL- NIA PROAT Objective: Mood stabilizers are frequently used in the manage- Amaç: Duygudurum düzenleyicileri akut mani tedavisinin vazge- ment of acute mania. Lithium has been used for this indication çilmez ilaçlar›d›r. Lityum psikotik eksitasyonda etkili oldu¤u, since Cade first described its effectiveness in psychotic exci- 1949 y›l›nda Cade taraf›ndan bildirildi¤inden beri kullan›lmakta- tation in 1949. Carbamazepine and valproate are also accepted d›r. Karbamazepin ve valproat da lityumun alternatifleri olarak as effective antimanic agents. Whether one of these agents is görülmektedirler. Bu ilaçlardan hangisinin akut manide daha et- more effective than others is still a matter of discussion. Our kili oldu¤u henüz yan›t› tam olarak verilemeyen bir soru olarak aims have been to clarify this issue and to see which one has a klinisyenleri meflgul etmektedir. Bu aç›k çal›flma akut manili has- faster onset of action. Methods: We compared the clinical effi- talarda lityum, karbamazepin ve valproat›n etkinli¤ini ve etkinin cacy of lithium, carbamazepine and valproate in 30 inpatients ortaya ç›kma süresini karfl›laflt›rmak için yap›lm›flt›r. Yöntem: Ça- with acute mania. Diagnoses were made according to DSM-IV l›flmaya tan›lar› DSM-IV s›n›fland›rmas›na göre konulmufl, akut criteria. There were 10 patients on each arm. Clinical efficacy manili, yatan 30 hasta al›nm›flt›r. Her bir grupta 10 hasta yer al- was assessed weekly by Bech-Rafaelsen Mania Scale, Brief m›fl, alt› hafta izlenen hastalara haftal›k olarak Bech-Rafaelsen Psychiatric Rating Scale, and Clinical Global Impressions Scale Mani Ölçe¤i, K›sa Psikiyatrik De¤erlendirme Ölçe¤i, Klinik Glo- for six weeks. Serum levels of study drugs were obtained weekly bal ‹zlenim Ölçe¤i uygulanm›fl ve ilaçlar›n kan düzeyleri ölçül- in order to maintain recommended serum levels. We referred to müfltür. Sadece zorunlu oldukça kullan›lan nöroleptikler klorpro- neuroleptics for excitation when really necessary, and the amount mazin eflde¤eri olarak kaydedilmifllerdir. Bulgular: Üç ilac›n et- used was recorded as chlorpromazine equivalents. Results: kinli¤i ve etki h›z› benzer bulunmufltur. Her üç grupta da klinik i- During weekly assessments and at the end of the study, none of yileflme üçüncü haftada bafllam›fl, çal›flma boyunca kullan›lan the drugs was superior to each other neither in antimanic effi- nöroleptiklerin miktar› istatistiksel aç›dan anlaml› bir farkl›l›k cacy nor in the week the efficacy began at. All of study drugs re- göstermemifl ve alt› haftal›k çal›flma tamamland›¤›nda hastalar- duced assessment scale scores significantly at the end of third daki iyileflme benzer bulunmufltur. Sonuçlar: Lityum, karbama- week. The amount of neuroleptics used was not different zepin ve valproat akut maninin tedavisinde etkili ilaçlard›r. Çal›fl- among the patient groups. Conclusions: Lithium, carbamazepine mam›zda bu ilaçlar›n hiçbirisi, di¤er ikisinden daha üstün bulun- and valproate are efficacious antimanic agents that have no su- mam›flt›r. periority on each other in treatment of acute mania, but these findings need to be replicated in larger studies. Anahtar sözcükler: akut mani, duygudurum düzenleyicileri, lityum, karbamazepin, valproat, etkinlik Key words: acute mania, mood stabilizers, lithium, carbamaze- pine, valproate, efficacy Klinik Psikofarmokoloji Bülteni 2001;11:90-95 Bull Clin Psychopharmacol 2001;11:90-95 INTRODUCTION treatment (3) since its antimanic (originally antipsy- chotic) activity has been described by Cade in 1949 ipolar disorder is a severe, highly prevalent disor- (4). In spite of the fact that patients described as Bder, which has an episodic nature, and is charac- having classic mania are being treated well by lithi- terized by manic or depressive episodes followed by um (5), it is now accepted that belonging to any of symptom-free periods (1). Although an untreated three diagnostic subgroups that is, dysphoric manic episode generally lasts from 2 to 8 months (2), manic/mixed states, rapid cycling, or comorbid sub- unwanted events that may complicate the patient's stance abuse is associated with a lower response rate life necessitates an effective and also quick treat- to lithium (6). Approximately 20-40% of patients ment. with acute mania fail to respond to lithium (7). For Lithium is drug of choice in bipolar disorder those, carbamazepine and valproate may be effective 1Department of Psychiatry, Inonu University School of Medical 2Malatya State Hospital Yaz›flma Adresi / Address reprint requests to: Doç.Dr.M.Erkan Özcan, Turgut Özal T›p Merkezi Psikiyatri Bölümü 44069 Malatya, Turkey Tel: +90 (422) 341 0660/5403 Fax: +90 (422) 341 0728 E-mail: [email protected] Kabul tarihi: 26 Ocak 2001 90 Klinik Psikofarmakoloji Bülteni, Cilt: 11, Say›: 2, 2001 / Bulletin of Clinical Psychopharmacology, Vol: 11, N.: 2, 2001 M. E. Ozcan, A. V. Boztepe alternatives. Although lithium and valproate have valproate. Daily dosage was between 900-1500 mg been approved by Food and Drug Administration for for lithium, 600-1000 mg for carbamazepine and treatment of mania in the United States, efficacy of 750-1500 mg for valproate. Total daily dosage was carbamazepine in acute mania is also well docu- divided into two or three, and was administered orally. mented (1). Serum levels of drugs were obtained weekly, Emerging questions are whether one of these is beginning within the end of the first treatment more effective or has a faster onset of action in week. Targeted serum levels were between 1.0-1.4 acute treatment of mania. This study was performed mmol/L for lithium and 4-12 mg/ml for carba- to test whether the clinical effectiveness and the mazepine and 50-150 mg/ml for valproate. time for onset of action of lithium, carbamazepine Intramuscular injections of neuroleptics were admin- and valproate in acute mania is different or not. The istered in cases of excitation. The amount of neu- patients involved in this study will also be followed roleptics administered to each patient was recorded for five years during maintenance treatment. This as chlorpomazine equivalents. BRMS, BPRS and CGI will enable us to evaluate the prophylactic efficacious scores were obtained repeatedly at the end of each of lithium, carbamazepine and valproate. week until the end of the 6 weeks study period. Wilcoxon and Kruskal-Wallis tests were used for sta- METHODS tistical analyses. The study was designed as an open label, clinical RESULTS comparative study with inpatients. Acutely ill manic patients were hospitalized at Mood Disorders Unit of Demographic data: There were 10 patients on Psychiatry Department of Turgut Ozal Medical each treatment arm. Two of 30 patients were expe- Center, in Malatya, one of eastern provinces of riencing their first manic attacks, while the remain- Turkey. Diagnoses were made according to ing had had previous manic attacks. Mean age was Diagnostic and Statistical Manual of Mental 36.60±11.49, and mean number of episodes was Disorders (8) (DSM-IV) criteria. The study was 2.70±0.82 in the lithium group. Mean age was approved by the Ethical Comittee of Inonu 30.50±16.07 and mean number of episodes was University. 4.80±2.34 in the carbamazepine group. Mean age Inclusion and exclusion criteria were as follows: was 38.00±12.20 and mean number of episodes was patients who were between 18-65 years and meet- 3.70±2.58 in the valproate group. (Table 1) ing DSM-IV criteria for manic episode; that were without substance abuse history in the previous year Tablo 1. Demographic data and who had not been treated with any psychotropic N Age (mean±SD) # of episodes agent during the previous month entered the study. Lithium 10 36.60±11.49 2.70±0.82 Rapid cycling patients and patients with mixed Carbamazepine 10 30.50±16.07 4.80±2.34 episode were also excluded. Valproate 10 38.00±12.20 3.70±2.58 After initial evaluation and informed consent, Bech-Rafaelsen Mania Scale (9) (BRMS), Brief Efficacy data: Mean BPRS score in the lithium Psychiatric Rating Scale (10) (BPRS) and Clinical group was 31.20±7.83 before treatment, 17.70±4.74 Global Impressions Scale-Severity Subscale (CGI) at the end of week 1, and 1.20±3.16 at the end of scores were obtained before institution of any phar- week 6. Mean BPRS score in the carbamazepine macological treatment. Patients were randomized in group was 28.40±5.91 before treatment, 19.30±8.10 the following rank: the first patient was in lithium at the end of week 1, and 4.80±6.60 at the end of group, the second in carbamazepine, the third in val- week 6. Mean BPRS score in the valproate group was proate group, the fourth patient was again in lithi- 31.80±10.69 before treatment, 18.50±8.92 at the um group and so on. There were 10 patients on each end of week 1, and 0.60±1.90 at the end of week 6. treatment arm. The difference among these values was statistically Study drugs were 300 mg capsules of lithium not significant (p>0.05). (Table 2) carbonate, 200 and 400 mg tablets of carba- Mean BRMS score in the lithium group was mazepine, and 200 and 500 mg tablets of sodium 29.80±3.82 before treatment, 18.70±5.29 at the end Klinik Psikofarmakoloji Bülteni, Cilt: 11, Say›: 2, 2001 / Bulletin of Clinical Psychopharmacology, Vol: 11, N.: 2, 2001 91 Lithium, Carbamazepine and Valproate in Acute Mania Tablo 2.