Carbamazepine (Tegretol) is an inexpensive seizure medication which was the first seizure medication widely used for bipolar patients.  Like divalproex (Depakote), its benefit is primarily on preventing manic swings and not on depression.  It actually has fewer side-effects than divalproex, is far less expensive, and works just as well.  One big advantage is that it doesn't cause the weight gain of divalproex or lithium.  However, lithium appears superior at lowering the suicide rate in bipolar patients.  Both lithium and carbamazepine can be used together for patients where lithium alone is not enough to block manic swings.  Carbamazepine's benefit on depression is quite minor.  There is no benefit to using extended release carbamazepine other than to enrich the pharmaceutical company which holds the patent.  Regular carbamazepine is fine.

Carbamazepine side-effects are usually fatigue, dizziness, and nausea. Occasionally, vomiting occurs. Elderly may get difficulty concentrating, double vision, and staggering (ataxia). Low sodium blood levels may occur with edema and weight gain early symptoms. In less than 1 in 100,000, it may cause aplastic anemia or agranulocytosis. Signs of infections, e.g. unexplained sore throats, should lead to a white blood cell test. Very severe liver damage is very rare but has occurred with fatal outcome. Benign, transient skin rashes occur infrequently with very rare cases of severe dermatological complications. Its half-life after auto-induction of liver enzymes is 10-20 hours. It reduces the concentration of most antipsychotics and antidepressants as well as lamotrigine. It can give a false positive pregnancy test. In increases valproate concentrations.

CBZ Works in Japan: Antimanic effect by a multi-institutional double-blind group comparison study with chlorpromazine as the control drug in the last 1970s. Prophylactic effect was confirmed by a double-blind study using inactive placebo as the control in 1981. The responses to CBZ and lithium were not always parallel each other and it was suggested that the mechanism of mood-stabilizing effect of CBZ and lithium may be different. It was also shown that patients who had not responded favorably to both of CBZ and lithium sometimes responded favorably to the combination of CBZ and lithium. During the course of our double-blind trials, the problem of different therapeutic dosages of psychotropic drugs between Japan and Western countries, i.e. lower dosage in Japan, emerged and caused the delay of publication of our results in Western journals. Okuma, Japan, Seishin Shinkeigaku Zasshi 2002;104(8):647-55

Extended Release Carbamazepine Better than Placebo for Acute Mania: In a 204-patient 3-week DB PC study of acute mania or mixed states, only 47% of patients completed the study. Carbamazepine dosage averaged 756 mg/day. Carbamazepine was better than placebo by week 2 with the responder rate (a 50% decrease in YMRS score) favoring carbamazepine (41.5% vs. 22.4%; p =.0074). In a post hoc analysis of mixed patients, HAM-D score was significantly improved in patients remaining on ERC-CBZ treatment on day 21 (p =.01). Adverse events included dizziness, nausea, and somnolence. A multicenter, randomized, double-blind, placebo-controlled trial of extended-release carbamazepine capsules as monotherapy for bipolar disorder patients with manic or mixed episodes. Weisler RH, Kalali AH, Ketter TA; SPD417 Study Group. Duke University. J Clin Psychiatry. 2004 Apr;65(4):478-84. 

CBZ=Lithium=Valproate Meta-analysis: The efficacy of lithium was compared with that of the antiepileptics, carbamazepine and valproic acid. Data sources include the Medline database and relevant references from articles. Only randomised controlled clinical trials with a double-blind assessment of outcomes were included. Lithium levels were required to be within the therapeutic range of 0.4-1.5 mmol/l. The effect sizes were measured by the odds ratio using the Mantel-Haenszel method. No significant difference was observed between the treatment effect of the 3 drugs compared. While the efficacy of the 3 treatments was identical, there is a general tendency in favour of the antiepileptics in the treatment of manic depression with regard to adverse events and treatment tolerance. Bristol Myers Squibb, Belgium, Eur Neuropsychopharmacol 1996 Aug;6(3):245-52

CBZ Almost as Good as Lithium in Small DB: 13 (31.0%) of 42 failed to complete a full year of lithium therapy owing to lack of efficacy, and 2 dropped out because of side effects; 13 (37.1%) of 35 withdrew from carbamazepine within the first year owing to lack of efficacy, and 10 dropped out because of side effects (9 of the 10 had a rash); 7 (24.1%) of 29 withdrew from the combination therapy owing to lack of efficacy. The percentage of the evaluable patients who had marked or moderate improvement on the Clinical Global Impressions scale was 33.3% on lithium. 31.4% on carbamazepine, and 55.2% on the combination treatment, which was not significantly different. By a variety of measures, lithium was more effective than carbamazepine in the prophylaxis of mania. Patients with a past history of rapid cycling did poorly on monotherapy (28.0% responded to lithium; 19.0% responded to carbamazepine), but significantly better on the combination (56.3%, p < .05). NIMH, J Clin Psychiatry 1997 Nov;58(11):470-8

Lithium = Carbamazepine in Small DB Bipolar II: 57 pts 2 ½ yr f/u randomized. Lithium averaged 960 mg/d, Carbamazepine 630mg/d. Hospitalization carbamazepine 17%, lithium 33% not signif difference. 2/3 free of recurrences. Greil W, Kleindienst N: Lithium vsersus barbamazepine in the maintenance treatment of bipolar II disorder and bipolar disorder not otherwise specified. Int Clin Psychoph 99;14:283-5, U Munich.

Carbamazepine = Lithium in 3 Yr Study: DB 3 yr 83 patients. incidence of side effects was similar in both treatment groups, and side effects generally responded well to dosage reduction. Both drugs were effective in two thirds of the patients and appeared about equal in most outcome measures, except for a significantly higher dropout rate for patients with mood-incongruent psychotic features who were assigned to the lithium group. Both drugs appeared more effective in preventing excited rather than depressive symptoms. The comparative efficacy and safety of carbamazepine versus lithium: a randomized, double-blind 3-year trial in 83 patients. Placidi GF, Lenzi A, Lazzerini F, Cassano GB, Akiskal HS. J Clin Psychiatry 1986 Oct;47(10):490-4

Lithium & Carbamazepine: #16 average difference after 1 year: 31 patients who were stable on lithium had half switched to carbamazepine in a DB for one year. There was a 9# weight gain on lithium vs. 7# loss on carbamazepine. Relapses occurred in 6 on carbamazepine and 8 on lithium, but most on carbamazepine occurred near the beginning suggesting withdrawal effect. Carbamazepine versus lithium in the prophylaxis of bipolar affective disorder. Coxhead N, Silverstone T, Cookson J. Acta Psychiatr Scand 1992 Feb;85(2):114-8

Carbamazepine 19 DB Studies: Nineteen double-blind studies utilizing a variety of designs suggest that carbamazepine, or its keto-congener oxcarbazepine, is effective in acute mania; six controlled studies report evidence of the efficacy of valproate in the treatment of acute mania as well. Fourteen controlled or partially controlled studies of prophylaxis suggest carbamazepine is also effective in preventing both manic and depressive episodes. Valproate prophylaxis data, although based entirely on uncontrolled studies, appear equally promising. NIMH, The place of anticonvulsant therapy in bipolar illness. Post RM, Ketter TA, Denicoff K, Pazzaglia PJ, Leverich GS, Marangell LB, Callahan AM, George MS, Frye MA. Psychopharmacology (Berl) 1996 Nov;128(2):115-29

Lithium + Carbamazepine = Lithium + Haldol: In a DB 8-week study of manics after two week wash-out in hospital, there was no difference in efficacy at 8 weeks between lithium with carbamazepine compared to lithium plus haldol. Authors favor lithium-carbamazepine because of fewer neurological side-effects. Indiana U. Lithium combined with carbamazepine or haloperidol in the treatment of mania. Small JG, Klapper MH, Marhenke JD, Milstein V, Woodham GC, Kellams JJ. Psychopharmacol Bull 1995;31(2):265-72

Lithium + Carbamazepine Better Than Monotherapy of Either: 52 outpatients ages 19-75 in an NIMH study were half Bipolar I, half Bipolar II. Half were rapid cycling, and half had a history of psychosis. They were treated with monotherapy for 1 year, and crossed to the other medication the second year, and received the combo the third year. One-third did well on each monotherapy and one half did well on the combo. There was no difference in the three treatments for depression. Denicoff K et al: Comparative prophylactic efficacy of lithium, carbamazepine, and the combination in bipolar disorder. J Clin Psyc 97;58:470-8.

Carbamazepine = Valproate on Cognitive Side-Effects: VA DB study of new epileptics. behavioral toxicity battery was administered prior to treatment and again 6 and 12 months after the initiation of antiepileptic medication. RESULTS: There were no significant differences in the effect of carbamazepine vs valproate on motor speed and coordination, memory, or concentration and mental flexibility, and there was no significant decline in neuropsychological performance from pretreatment baseline levels for either drug. No significant differences in performance were found between patients with low (mean, 52.8 micrograms/mL) vs high (mean, 94.4 micrograms/mL) serum valproate levels within the therapeutic range. Patients treated with either carbamazepine or valproate did not show practice effects experienced by normal controls, a finding that may reflect a subtle compromise in cognitive functioning. Effect of valproate on cognitive functioning. Comparison with carbamazepine. The Department of Veterans Affairs Epilepsy Cooperative Study 264 Group. Prevey ML, Delaney RC, Cramer JA, Cattanach L, Collins JF, Mattson RH

Carbamazepine-CR Loading Dose: CBZ-CR and PHT were administered to 42 adult patients (21 each) at a dosage of 20 mg/kg with a minimum and maximum dosage of 1,200 and 1,600 mg in patients weighting < 60 and > 80 kg, respectively. CBZ-CR was given as single loading dose; PHT was split, with two thirds of the dose administered at 0 h and one third administered 2 h later. The 24- and 36-h doses were assessed according to the nystagmus status at 24 h. Mean CBZ serum levels (percentage of subjects with level > 4 micrograms/ml shown in parentheses) were 0.0 (0%), 5.2 (62%), 6.7 (81%), 6.8 (95%), and 6.1 micrograms/ml (95%) at 0, 4, 8, 24, and 48 h after loading, respectively, and mean PHT levels (percentage of subjects with PHT level > 10 micrograms/ml in parentheses) were 0.1 (0%), 13.2 (86%), 16.3 (100%), 16.3 (100%), and 15.4 micrograms/ml (82%). One subject in the CBZ group and 3 in the PHT group vomited. Clinical effects did not differ significantly between treatment groups and are reported. Acute doses of CBZ-CR 20 mg/kg and PHT 20 mg/kg (two-thirds at 0 h and one-third at 2 h) provided therapeutic levels in most patients in < or = 4 h and were well tolerated. Acute oral loading of carbamazepine-CR and phenytoin in a double-blind randomized study of patients at risk of seizures. Van Der Meyden CH, Kruger AJ, Muller FO, Rabie W, Schall R. Epilepsia 1994 Jan-Feb;35(1):189-94

Loading Dose Strategies for Carbamazepine, Lithium, Valproate: Pharmacologic loading in the treatment of acute mania. U Cinn: Keck PE Jr, McElroy SL, Bennett JA. Bipolar Disord 2000 Mar;2(1):42-6

False-Positive TCA: In ER after overdose, carbamazepine toxicity can cause a false + tricyclic screen and should be thought of. Matos, Harvard, Pediatrics 00;105:e66

Carbamazepine S-e: 6/1,000,000 patients /year get agranulocytosis and 2/1,000,000/year aplastic anemia. Carbatrol is a new extended release capsule formulation.

Valproate Good for Sex, Carbamazepine Bad: Val increases sex hormones and carbamazepine does the opposite with lower DHEA-S. 19% of 21 valproate men reported improved sex functioning and 19% of 40 reported worse with carbamazepine. Neurol 01;56:31. 

Carbamazepine, But not Valproate, Induces Metabolism of Bupropion: Small study of a single 150mg dose bupropion found marked effect. Carbamazepine but not valproate induces bupropion metabolism. Ketter TA, Jenkins JB, Schroeder DH, Pazzaglia PJ, Marangell LB, George MS, Callahan AM, Hinton ML, Chao J, Post RM. J Clin Psychopharmacol 1995 Oct;15(5):327-33

QD Dosing OK with Extended Release: Double dummy comparison between once and twice daily dosing with modified-release carbamazepine in epileptic patients. McKee PJ, Blacklaw J, Carswell A, Gillham RA, Brodie MJ. Br J Clin Pharmacol 1993 Sep;36(3):257-61

QD Dosing OK with Regular Carbamazepine: 14 male 16-18 year old epileptics stable on carbamazepine were given trials of TID, BID and QD carbamazepine and experienced no difference in fits and minimal difference on EEG with BID and QD same as BID on EEG. Carbamazepine is probably effective as a single daily dose, but further long-term controlled clinical trial in necessary. Once daily dosage versus divided daily doses of carbamazepine therapy in epileptic patients: a pilot study. Ghose K, Dawson M, Fry DE, Christofides JA. Pharmatherapeutica 1981;3(1):71-8

Carbamazepine Rash: Carbamazepine-induced rash is common, occurring in 13 (12%) of 113 patients. Benign rashes can occasionally progress to more fulminant and life-threatening eruptions. NIMH, Rash complicating carbamazepine treatment. Kramlinger KG, Phillips KA, Post RM. J Clin Psychopharmacol 1994 Dec;14(6):408-13

Valproate More Side-effects Than Carbamazepine: In a DB study of 480 seizures patients over 1 year, valproate was as effective as carbamazepine for the treatment of generalized tonic-clonic seizures, but carbamazepine provided better control of complex partial seizures and has fewer long-term adverse effects. Valproate weight gain (20% gained over 12#), hair loss (12%), tremor (45%). Carbamazepine rash (11% vs. 1%). A comparison of valproate with carbamazepine for the treatment of complex partial seizures and secondarily generalized tonic-clonic seizures in adults. The Department of Veterans Affairs Epilepsy Cooperative Study No. 264 Group. Mattson RH, Cramer JA, Collins JF. N Engl J Med 1992 Sep 10;327(11):765-71

Quetiapine Raised Carbamazepine Levels Dramatically: Two cases of very high carbamazepine after starting quetiapine but OK when switched to oxcarbazepine. If carbamazepine and quetiapine are administered concurrently, clinicians should consider monitoring CBZ-E concentrations. Pharmacotherapy. 2002 Nov;22(11):1500-3

Carbamazepine May Suppress Folic Acid and B-12 Levels: In a study of 25 carbamazepine patients followed for 5 years, folic acid and B-12 levels appeared decreased and may have been the reason for an increased in the size of red blood cells (MCV) and GGT liver enzymes. Basic haematological parameters, serum gamma-glutamyl-transferase activity, and erythrocyte folate and serum vitamin B12 levels during carbamazepine and oxcarbazepine therapy. Isojarvi JI, Pakarinen AJ, Myllyla VV. Univ Oulu. Seizure. 1997 Jun;6(3):207-11

Carbamazepine Reduces Anti-psychotic Blood Levels Much More than Oxcarbazepine: Carbamazepine reduces clozapine blood levels by 47%. Pharmacopsychiatry. 1995 Jan;28(1):26-8. The same more be true for haloperidol and chlorpromazine. Psychopharmacology (Berl). 1994 Sep;116(1):115-6. Much less enzyme induction with oxcarbazepine. Br J Clin Pharmacol. 1991 Jan;31(1):65-71