In the past decade, lithium's limitations as an acute and prophylactic treatment for patients with several subtypes of manic-depressive illness have been recognized. However, a substantial number of studies have now revealed that about 50% of patients may show only a partial therapeutic response and inadequate prophylactic effect. Certain diagnostic subtypes (dysphoric mania, rapid cycling) have notably poor response rates to lithium therapy, while a significant number of patients cannot tolerate its side effects, or are unable to achieve suitable degrees of compliance at blood levels that are necessary for complete suppression of symptomatology. The foregoing has necessitated the study of both adjunctive and alternative treatment options to lithium.

A series of anticonvulsants have emerged as major mood stabilizing alternatives to lithium therapy for bipolar illness. Data on carbamazepine and valproate indicate that, although they appear to prevent manic and depressive episodes in patients inadequately responsive to lithium carbonate, they may not be sufficient for monotherapy. Two newer anticonvulsant agents, gabapentin and lamotrigine have shown promise in the treatment of patients with bipolar disorders. Both gabapentin and lamotrigine differ from other mood regulators in two major ways - (1)their reported frequent effectiveness for treatment resistant patients, and (2)their relatively benign side effect profiles, that make discontinuation due to side effects rare.

Gabapentin increases GABA(gamma amino butyric acid) turnover and whole blood serotonin, increases breakdown of glutamic acid, and modulates norepinephrine and dopamine in vivo. Case reports have described its potential psychiatric indications in bipolar disorder, panic disorder, generalized anxiety disorder and behavioral dyscontrol. The post-absorption half-life is 5-7 hours with rapid crossing of the blood brain barrier. Usual starting dose of gabapentin is 300 mg once a day, and the dose is increased and rapidly titrated every three to five days to the usual mood stabilizing dose, which is most often between 900-2700 (up to 4800 reported) mg a day typically taken in divided doses. Therapeutic effect is noticed from within a week up to a month. Gabapentin is generally well tolerated. The most common side effects are sedation, dizziness, unsteadiness, nystagmus, ataxia, fatigue, tremor and diplopia.

Lamotrigine acts upon the voltage dependent sodium channels, resulting in inhibited release of the excitatory neurotransmitters glutamate and aspartate, and stabilization of the neuronal membranes. Early reports suggest that lamotrigine may be beneficial in patients with treatment resistant bipolar disorders, including mixed and rapid cycling illness. Its use in treating unipolar depression and anxiety disorders has not been extensively studied. The inhibition of glutamate may suggest a role for lamotrigine in mania following ischemic stroke. Usual initiating dose of lamotrigine is 25 mg once or twice a day, and this is increased by 25-50 mg every 1-2 weeks, to reach the usual effective dose range of 100-200 mg per day. Therapeutic effect is generally noticed within a month of starting treatment. The most commonly reported adverse effects of lamotrigine are dizziness, diplopia, ataxia, blurred vision, nausea, and vomiting. A severe morbilliform or maculopapular rash, developing within the first six weeks which is related to starting dose and escalation of titration, can be a special clinical hazard (rate in adults one in every thousand patients with higher incidence below age sixteen).

The principal advantage of gabapentin and lamotrigine over lithium is that routine serum monitoring of drug levels is not essential during therapy. However, as with all bipolar patients, one should be aware of a possible paradoxical switch to mania or provocation of rapid cycling. Also, while gabapentin may be safely used in combination with depakote and carbamazepine, their doses need adjustment when lamotrigine is initiated. Valproic acid should be reduced in dosage prior to starting lamotrigine to decrease inhibition of metabolism and reduce the risk of rash. Due to enzyme induction, the dose of carbamzepine may need to be reduced when lamotrigine treatment is initiated. The relatively recent use of gabapentin and lamotrigine for mood disorders limits the information regarding their long term therapeutic efficacy, and potential emergent side effects. Since many patients with bipolar disorders resist or show incomplete response to standard treatment regimens, further clinical studies of these novel agents are anticipated.

Other modalities being researched for mood stabilizers include calcium channel blockers, and TRH (thyrotropin releasing hormone) plus other endogenous neuropeptides. The calcium channel blockers like verapamil and nimodipine are showing special promise for rapid and ultra rapid cycling. Preliminary findings have suggested that the dihydropyridine class of L-type calcium channel blockers, which includes nimodipine, isradipine etc., compared to the phenylalkalamine verapamil may have greater mood stabilizing effects, and potential as an alternative or adjunct to lithium. Highly preliminary data on TRH have raised the possibility of its possible acute anti-depressant, anti-anxiety, and anti-suicide effects.

It is thus clear that although the search for safer alternatives to lithium therapy in affective disorders, is getting increasingly promising, extensive further research of the newer mood stabilizing medications is warranted in order to firmly establish their safety and efficacy both as adjunctive medications and monotherapeutic alternatives to lithium.

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