Lamotrigine Sodium valproate

Introduced in clinical practice in the 1960s, lithium was the first mood stabilizer to be used in China. This was followed by carbamazepine and sodium valproate. For many years, these were the only treatment options available as mood stabilizers. Although lamotrigine was approved for maintenance treatment of bipolar I disorder in 2003 by FDA (Food and Drug Administration) in the USA, this indication has not yet been approved by the Chinese authorities. At present, only one atypical antipsychotic drug, risperidone, has been approved for treating acute mania (February 2005 by SFDA [State Food and Drug Administration]) in China (see Table 6.1). 

Lithium, divalproex sodium (valproate), aripiprazole, olanzapine, que-tiapine, risperidone, and ziprasidone are currently approved by the FDA for treatment of acute mania in bipolar disorder. Lithium, olanzapine, and lamotrigine are approved for maintenance treatment of bipolar disorder. Quetiapine is the only antipsychotic that is FDA approved for bipolar depression. 

Brodie, M.J. and Yuen, A.W (1997) Lamotrigine substitution study evidence for synergism with sodium valproate 105 Study Group. Epilepsy Res 26 423 32. 

Calabrese JR, Bowden CL, Sachs GS, et al A placebo-controlled 18-month trial of lamotrigine and lithium maintenance treatment in recently depressed patients with bipolar I disorder. Lamictal 605 Study Group. J Clin Psychiatry 64 1013-1024, 2003 Calabrese JR, Keck PE, Macfadden W, et al A randomized, double-blind, placebo-controlled trial of quetiapine in the treatment of bipolar 1 or 11 depression. Am J Psychiatry 162 1351-1360, 2005 Chen G, Manji HK, Hawver DB, et al Chronic sodium valproate selectively decreases protein kinase C alpha and epsilon in vitro. J Neurochem 63 2361-2364, 1994... 

Gidal BE, Tamura T, Hammer A, Vuong A. Blood homocysteine, folate and vitamin B12 concentrations in patients with epilepsy receiving lamotrigine or sodium valproate for initial monotherapy. Epilepsy Res 2005 64 161-6. 

Drug therapy includes the use of anticonvulsant or anti-epileptic drugs, such as sodium valproate, sodium phenytoin, lamotrigine, vigabatrin. 

Lithium salts are ineffective for prophylaxis of bipolar affective disorder in around 35% of patients and cause several unwanted effects. The search for alternatives has produced drugs that are more familiar as anticonvulsants, notably carbamazepine and sodium valproate, and possibly lamotrigine. 

Individual drugs carbamazepine, phenytoin, sodium valproate, lamotrigine, vigabatrin, gabapentin, clonazepam, topiramate, levetiracetam. 

Bromide (1857) was the first drug to be used for the treatment of epilepsy, but it is now obsolete. Phenobarbital, introduced in 1912, controlled patients resistant to bromides. The next success was the discovery in 1938 of phenytoin (a hydantoin) which is structurally related to the barbiturates. Since then many other drugs have been discovered, but phenytoin still remains a drug of choice in the treatment of major epilepsy. Over the past ten years there has been a dramatic increase in the number of new anticonvulsant drugs (vigabatrin, gabapentin, lamotrigine, topiramate, oxcarbazepine, levetiracetam), but none has been shown to be superior to the major standard anticonvulsants (phenytoin, carbamazepine and sodium valproate). 

Sodium valproate is extensively metabolised in the liver and has a t / of 13 h. It is 90% bound to plasma albumin. Sodium valproate is a nonspecific inhibitor of metabolism, and indeed inhibits its own metabolism, and that of lamotrigine, phenobarbitone, phenytoin and carbamazepine. Sodium valproate does not induce drug metabolising enzymes but its metabolism is enhanced by induction due to other drugs, including antiepileptics. 

Metabolic inhibition by valproate prolongs the action of co-administered antiepilepsy drugs (see above). The effect is significant and the dose of lamotrigine, for example, should be halved in patients who are also taking sodium valproate. 

Minor to modest falls in serum ethosuximide levels may occur if carbamazepine, primidone or phenytoin are also given, whereas methylphenobarbital or sodium valproate may cause a rise in ethosuximide levels. The effect of all these changes on seizure control is uncertain. Lamotrigine appears not to affect ethosuximide levels. 

Yuen AWC, Land G, Weatherley BC, Peck AW. Sodium valproate acutely inhibits lamotrigine metabolism, BrJ Clin Pharmacol (1992) 33,511-13. 

Reutens DC, Duncan JS, Patsalos PN. Disabling tremor after lamotrigine with sodium valproate. Lancet (1993) 342,185-6. 

Voudris K, Mastroyianni S, Skardoutsou A, Katsarou E, Mavrommatis P. Disabling tremor in epileptic children receiving sodium valproate after addition of lamotrigine. P2197. EurJ Neurol(2003) 10(Suppl. 1), 180. 

Pisani F, Di Perri R, Perucca E, Richens A. Interaction of lamotrigine with sodium valproate. Lancet(1993)3Al, 1224. 

Clozapine serum levels are approximately halved by car-bamazepine and possibly by phenobarbital and phenytoin. An isolated case of fatal pancytopenia has been seen in one patient taking clozapine and carbamazepine, and neuroleptic malignant syndrome occurred in another. Sodium valproate can apparently lower serum clozapine levels, and an isolated case report su ests that lamotrigine may raise them. 

Haematologic A case of quetiapine- and valproate-associated neutropenia and thrombocytopenia has been described after previous lamotrigine-induced Stevens-Johnson syndrome [226 ]. Two cases of neutropenia have been reported with the concomitant use of quetiapine and sodium valproate in elderly patients [227 ]. Another case of neutropenia in a 21-year-old male who was also on mirtazapine resolved following switch to ziprasidone is reported [228 ]. 

In addition to phenytoin, carbamazepine, and lamotrigine, metabolically optimized analogs of these drugs, such as fosphenytoin and oxcarbazepine, show clinical promise. Other anticonvulsants that block sodium channels, among several mechanisms of action, include zonisamide, felbamate, topiramate, and valproate (Fig. 5). 

Lamotrigine is similar in action to phenytoin. It appears to work on sodium ion channels to cause inhibition of the release of excitatory amino acids. Lamotrigine is considered to be first-line treatment for generalized and partial seizures and is considered more appropriate than valproate for women of childbearing age. 

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