GABA carbamazepine

Drugs acting on GABA/glutamate - hypnotics/anxiolytics barbiturates, benzodiazepines, chlormethiazole, chloral derivatives, baclofen - anticonvulsants phenobarbitone, primidone, phe-nytoin, sodium, valproate, carbamazepine - alcohol, phencyclidine, ketamine... 

Baclofen, labeled as a skeletal muscle relaxant binds to GABA receptors and depresses excitation. It is also useful in the treatment of paroxysms of trigeminal neuralgia. Baclofen is effective in patients with carbamazepine-resistant pain and has been used successfully to relieve attacks in patients previously unresponsive to carbamazepine or phenytoin. 

Belelh D, Lan N, Gee KW Anticonvulsant steroids and the GABA/benzodiazepine receptor-chloride ionophore complex. Neurosci Biobehav Rev 14 315-322, 1990 Bellaire W, Demisch K, Stoll K-D Carbamazepine vs. lithium. Application in the prophylaxis of recurrent affective and schizoaffective psychoses. Muenchener Medizinische Wochenschrift 132 S82-S86, 1990 Belmaker RH Receptors, adenylate cyclase, depression, and lithium. Biol Psychiatry 16 333-350, 1981... 

Clark M, Massenburg GS, Weiss SRB, et al Analysis of the hippocampal GABA, receptor system in kindled rats by autoradiographic and in situ hybridization techniques contingent tolerance to carbamazepine. Brain Res Mol Brain Res 26 309-319, 1994... 

Post RM, Ballenger JC, Hare TA, et al Cerebrospinal fluid GABA in normals and patients with affective disorders. Brain Res Bull 5 (suppl 2 755-759, 1980 Post RM, Uhde TW, Ballenger JC, et al Prophylactic efficacy of carbamazepine in manic-depressive illness. Am J Psychiatry 140 1602-1604, 1983 Post RM, Ballenger JC, Uhde TW, et al Efficacy of carbamazepine in manic-depressive illness implications for underlying mechanisms, in Neurobiology of Mood Disorders. Edited by Post RM, Ballenger JC. Baltimore, MD, Williams Wilkins, 1984, pp 777-816... 

FIGURE 7—24. Shown here is an icon of carbamazepine s pharmacologic actions. By interfering with sodium and potassium, carbamazepine is thought to enhance the inhibitory actions of gamma aminobutyric acid (GABA). 

Carbamazepine. The anticonvulsant carbamazepine was actually the first to be shown to be effective in the manic phase of bipolar disorder, but it has not been approved for this use by regulatory authorities such as the U.S. Food and Drug Administration (FDA). Its mechanism of action may be to enhance GABA function, perhaps in part by actions on sodium and/or potassium channels (Fig. 7—24). Because its efficacy is less well documented and its side effects can include sedation and hematological abnormalities, it is not as well accepted for first-line use in the treatment of mood disorders as either lithium or valproic acid. 

Topiramate blocks repetitive firing of cultured spinal cord neurons, as do phenytoin and carbamazepine. Its mechanism of action, therefore, is likely to involve blocking of voltage-dependent sodium channels. Topiramate also appears to potentiate the inhibitory effect of GABA, acting at a site different from the benzodiazepine or barbiturate sites. Topiramate also depresses the excitatory action of kainate on AMPA receptors. It is possible that all three of these actions contribute to topiramate s anticonvulsant effect. 

Carbamazepine is licenced as an alternative to lithium for prophylaxis of bipolar affective disorder, although clinical trial evidence is actually stronger to support its use in the treatment of acute mania. Carbamazepine appears to be more effective than lithium for rapidly cycling bipolar disorders, i.e. with recurrent swift transitions from mania to depression. It is also effective in combination with lithium. Its mode of action is thought to involve agonism of inhibitory GABA transmission at the GABA-benzodiazepine receptor complex (see also Epilepsy, p. 417). 

Carbamazepine continues to be studied with regard to its actions on primary and secondary neurotransmitter systems and on sodium and potassium ion channels. It has a limited ability to block norepinephrine reuptake (Hollister 1992) and has been reported to decrease norepinephrine release (Post, Weiss, and Chuang 1992). Dopamine release is enhanced, and reuptake is blocked. As with lithium and valproate, long-term administration causes an increase in GABA receptors (upregula-tion) in the hippocampus, but not in the cortex (Post, Weiss, and Chuang 1992). 

Even though valproic acid shares with carbamazepine many of the properties described above, the more likely mechanism of valproate in bipolar disorder is through increased GABA levels in the CNS. 

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