Lamotrigine and Lithium in Bipolar Mania
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LAMOTRIGINE AND LITHIUM IN BIPOLAR MANIA
Bottom Line: In this randomized double-blind controlled trial of 30 patients admitted with bipolar mania, an escalating dose of lamotrigine demonstrated similar efficacy to lithium 800mg/day over 28 days of treatment, measured by reduced MRS, BPRS, CGI and improved GAF. This study is most limited by its small size and lack of placebo group (ethical limitations).
Background: Multiple newer anticonvulsants are purported to work in treatment of bipolar patients. Some of the best evidence to date is for lamotrigine. Lamotrigine is an antifolate phenyltriazine w/ a similar basic structure to carbamazepine & phenytoin. It stabilizes certain Na+ channels & inhibits glutamate release.
Methods: 30 subjects with admission for acute mania (via DSM-IV structured clinical interview), randomized in double-blind fashion to lamotrigine (n=15) or Li (n=15) treatment groups, planned for 28 days. All psychotropics discontinued for >1 day before entering study. Lithium dosed 400mg bid, monitored by independent clinician. Lamotrigine dosed 25mg qhs 1st wk, 50mg qhs 2nd wk, 100mg qhs 3`d & 4`h wks. Lamotrigine groups also received qam placebo. Lorazepam 4-12mg qd prn aggression used as rescue medication. No other psychotropics permitted. Measured weekly Manic Rating Scale (MRS), Brief Psychiatric Rating Scale (BPRS), CGI, & GAF for 28 days. If subject dropped out, these were measured that day, & analyzed using last observation carried forward. Setting - academic tertiary referral center in South Africa. Included - M & F, ages 18-65, admitted w/ acute manic episode. Excluded, - Abnormal LFTs, TFTs, CBC; acute medical d/o, depot neuroleptic in past month, fluoxetine in past 5 wks, did not or unable to give informed consent.
Validity: Randomized, double-blind design. 28 day follow-up sufficient. All subjects were analyzed in the group to which they were assigned. Groups were treated equally & similar at start of trial. No placebo group, so cannot differentiate a genuine medication effect. Small study, n=30. Low power means small differences between groups may not have been detected. Lithium dose chosen to minimize side effects & dropouts, but may be considered low. Lamotrigine required dose escalation. Likely setting selection bias toward more severe/refractory cases. Subjects must have been able to give informed consent. Regression to mean?
Results: Ages ranged from 20 to 59yo. With exception of length of index episode before hospitalization, no significant baseline differences between groups. Mean duration of index episode longer in lithium group due to an outlier of 38 days. No difference without the outlier. Reported results included outlier. Lithium level 0.743 on average. 2 dropouts in lamotrigine group, 3 in lithium group. Lorazepam 2.65mg/day in lamotrigine group, and 2.66mg/day in lithium group. No rashes. No other significant adverse effects. Absolute score & change from baseline reported for MRS, BPRS, CGI, GAF. No significant difference b/w treatment groups in any measure at baseline or week 4. No significant difference between Li +0.21 in 9 MRS responders, and Li 0.71 +0.25 in 6 MRS non-responders.
Comments: In this small study it appears lamotrigine is comparable to lithium in treatment of acute mania. Larger controlled trials are needed to confirm this result.
Presented by Heath Penland, MD
