Clinical use of carbamazepine for bipolar disorders.
ABSTRACT Two recently completed large, randomised, double-blind, placebo-controlled trials supporting the efficacy of carbamazepine (CBZ) extended-release capsules (ERC) for the treatment of acute manic and mixed episodes have resulted in US FDA approval of CBZ-ERC, and have reinvigorated the importance of understanding the role of CBZ in bipolar disorder (BD) pharmacotherapy. Additional data suggest that CBZ may have a use in BD maintenance treatment and possibly in acute BD depression. Optimal use of CBZ requires sound knowledge of adverse effects and pharmacokinetic interactions with this agent. Adverse effects commonly involve benign side effects but can rarely include serious haematological, dermatological and hepatic manifestations. On the other hand, metabolic adverse effects (thyroid, glucose, lipid disturbances and significant weight gain) can be less problematic with CBZ, compared with lithium, valproate and atypical antipsychotics. Pharmacokinetic considerations (cytochrome P450 3A3/4 metabolism, active epoxide metabolite and catabolic enzyme induction) can influence the clinical use of CBZ. Managing adverse effects and pharmacokinetic complexities is important for optimising pharmacotherapy with CBZ in patients with BD. This paper reviews the chemistry, pharmacodynamics and pharmacokinetics of CBZ, as well as reviews of the controlled trials of CBZ in acute bipolar mania, acute bipolar depression and bipolar maintenance treatment.
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ABSTRACT: Carbamazepine (CBZ) is a first-line antiepileptic agent with mood-stabilizing effects in bipolar disorder. It has been reported to influence extracellular concentrations of serotonin and dopamine, suggesting an interaction with monoamine transporters. We have investigated this effect using in vivo single photon emission computed tomography (SPECT) in rats. Adult male rats received 3 mg/kg/h CBZ via mini-osmotic pump. After 14 days continuous treatment, animals underwent two consecutive SPECT scans, using 125I beta-CIT as a radiotracer to label serotonin transporter (SERT) and dopamine transporter (DAT) sites in the brain. Pharmacologic distinction was enabled by 125I beta-CIT SPECT imaging in rats acutely exposed to the serotonin and dopamine transporter inhibitors, fluoxetine and GBR12909. The interaction between CBZ and 125I beta-CIT binding to SERT and DAT was investigated using in vitro autoradiography. Carbamazepine (10 microm) did not affect binding of 125I beta-CIT to isolated rat brain slices, thereby excluding a direct effect on ligand binding to SERT and DAT. SPECT studies with fluoxetine and GBR12909 highlighted SERT binding in thalamus, hippocampus, centromedial nuclei, and occipital cortex, and DAT binding in the caudate. Prolonged treatment with CBZ failed to influence 125I beta-CIT binding to either SERT or DAT in any of the brain regions examined. This study employed the novel technique of small animal SPECT imaging to investigate the effects of CBZ on monoamine transporters in rat brain. Following prolonged treatment, the drug was without effect on SERT or DAT availability. The mechanism by which CBZ exerts its mood stabilizing effects remains elusive.Epilepsia 06/2009; 50(8):1962-70. DOI:10.1111/j.1528-1167.2009.02095.x · 4.58 Impact Factor
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ABSTRACT: This review assesses the parallel data on the role of gamma-aminobutyric acid (GABA) in depression and anxiety. We review historical and new data from both animal and human experimentation which have helped define the key role for this transmitter in both these mental pathologies. By exploring the overlap in these conditions in terms of GABAergic neurochemistry, neurogenetics, brain circuitry, and pharmacology, we develop a theory that the two conditions are intrinsically interrelated. The role of GABAergic agents in demonstrating this interrelationship and in pointing the way to future research is discussed.Depression and Anxiety 01/2007; 24(7):495-517. DOI:10.1002/da.20262 · 4.29 Impact Factor
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ABSTRACT: In December 2004, an extended-release capsule formulation of carbamazepine was approved by the U.S. Food and Drug Administration for the treatment of acute manic or mixed episodes associated with bipolar I disorder. This formulation allows twice-daily dosing and minimizes plasma carbamazepine fluctuations. The efficacy, safety and tolerability of the product were demonstrated with two pivotal randomized, placebo-controlled, double-blind monotherapy trials. These studies showed efficacy in bipolar I mania in patients with acute manic or mixed episodes. Pooled post hoc analyses documented a significant onset of effect within seven days, an incremental response of about 25% over placebo and a moderate effect size of 0.61 with no treatment-emergent depression. Carbamazepine's mode of action in mania is unknown, but a variety of effects on receptors, neurotransmitters, ion channels and binding sites have been documented. It has a complex pharmacokinetic profile due to autoinduction and a long-acting active metabolite. Carbamazepine's most frequent adverse events comprise dizziness, somnolence, nausea and vomiting, although these tend to diminish over time. It is effectively weight neutral and can provide an acceptable and efficacious treatment option for bipolar I mania.Drugs of today (Barcelona, Spain: 1998) 06/2006; 42(5):283-9. DOI:10.1358/dot.2006.42.5.985635 · 1.00 Impact Factor