Lamotrigine and Lithium in Manic or Hypomanic Patients with Bipolar I Disorder
From MindLinc Wiki
LAMOTRIGINE AND LITHIUM IN MANIC OR HYPOMANIC PATIENTS WITH BIPOLAR I DISORDER
Bottom line: Lamotrigine is effective in prolongating the recurrence of depressive episodes in bipolar I d/o in patients with a recent manic or hypomanic episode.
Clinical Question: How efficacious are lamotrigine and lithium as monotherapy in delaying the recurrence of mood episodes in patients with bipolar I d/o who had a recent manic or hypomanic episode?
Methods
Design: A randomized double-blind, parallel-group, placebo-controlled, multi center study comparing efficacy and tolerability of lamotrigine and lithium monotherapy vs. placebo for the prevention of relapse or recurrence of mood episodes in recently manic or hypomanic patients. The screening phase occurred within 2 weeks after the pt's entry into the open label phase. During this phase, pt received physical exam, psychiatric and medical histories and laboratory tests were performed, and scores on psychiatric rating scales (MRS, HAMD, CGI-S, CGI-I and GAS. Eligible pts were enrolled in the open-label phase, which lasted 8 to 16 weeks and during which all patients received open-label lamotrigine (target dosage, 200 mg/d, minimum 100mg/d) as adjunctive therapy or monotherapy. Pts who met criteria for response to lamotrigine (defined as a CGI-S scale score of 3 or less maintained for at least 4 weeks) were eligible to enroll in the double-blind phase. Pts not meeting criteria for response at end of 16 week open-label phase, were discontinued from the study. Setting: 64 centers (Australia, Greece, New Zealand, Norway, UK, US, Yugoslavia), outpatient settings.
Patient Population: mean age in the early 40's, equally men and women.
Enrolled vs. screened: Of 349 pts enrolled in the open-label phase, 175 were randomized to maintenance treatment during the double-blind phase (lomotrigine: 59, lithium: 46; placebo: 70 pts).
Interventions: Pts who responded to tx with lamotrigine were randomized 1:1:1 to receive double-blind tx with lamotrigine (100-400 mg/d, depending on clinical response, starting dosage, 200 mg/d), lithium (titrated to serum levels of 0. 8- 1. 1 mEq/L), or placebo for up to 76 weeks. No other psychotropic meds were permitted, with exception of shortterm, intermittent use of chloral-hydrate, ativan, temazepam or oxazepam pm agitation, insomnia, irritability.
Inclusion criteria: patients aged 18 yo or older with dx of bipolar I d/o were eligible if they 1) were currently manic or hypomanic per DSMIV or 2) had been manic or hypomanic within 60 days of screening visit, had manic or hypomanic sx at enrollment, and had at least I additional manic or hypomanic episode and 1 depressed episode (including those of a mixed episode per DSMIV) within 3 years of enrollment.
Exclusion criteria: pts with more than 6 DSMIV manic, hypomanic, mixed, or depressive episodes in the year prior to enrollment, pts with panic d/o, OCD, social phobia, bulimia, h/o epilepsy, significant cardiac, renal, hepatic, neoplastic, cerebrovascular disease, pts who were actively suicidal or had a score of 3 or more on item 3 of the 31-item HAMD. Blinding: double-blind
Main outcome measures: Primary efficacy end point was the time to intervention (defined as addition of pharmocotherapy or ECT) for any mood episode
Secondary efficacy measures: time to early discontinuation for any reason (i.e. survival in study), time to intervention for a manic, hypomanic, or mixed episode; time to intervention for a depressive episode; mean change from baseline (defined as day I of the double-blind phase) in scores of the MRS, HAMD, CGI, GAS scales during double-blind treatment.
Analysis: Kaplan-Meier survival curves, mean change scores for psychiatric evaluations between groups were analyzed using last observation carried forward, and mean change data.
Follow-up: Complete.
Validity Randomized? Yes. Randomization list concealed? No comment.
Treatment groups similar at baseline? Yes.
Patients starting trial accounted for at conclusion? 1 pts each in the lamotrigine and placebo group and 2 pts in the lithium group were excluded due to missing postbaseline assessments following entry into the double-blind phase.
Patients analyzed in groups to which they were randomized? Yes.
Patients and clinicians blinded to treatment? Yes.
Groups treated similarly outside of intervention? No comment.
Results For primary outcomes: Both lamotrigine and lithium were significantly superior to placebo on time to intervention for any mood episode (lamotrigine vs. placebo, p=0.02; lithium vs. placebo, p=0.003) (median survival times in table 3).
Secondary outcomes: In the analysis of overall survival in the study (i.e. categorizing all early discontinuations as events), lamotrigine was superior to placebo (lamotrigine vs. placebo, p=0.03; lithium vs. placebo, p=0.07). Lamotrigine, but not lithium, was superior to placebo at prolonging the time to a depressive episode (lamotrigine vs. placebo, p=0.02; lithium vs. placebo, p=0.17). Lithium, but not lamotrigine, was superior to placebo at prolonging the time to a manic, hypomanic or mixed episode (lithium vs. placebo, p=0.006; lamotrigine vs. placebo, p=-0.28). Change from baseline scores for the HAMD indicated lesser overall degrees of worsening with lamotrigine vs. placebo (p=0.03; table 4). Change from baseline scores for the MRS indicated lesser overall degrees of worsening with lithium vs. placebo (p=0.001).
Compliance with Therapies: No comment.
Adverse Effects: most common adverse event during open-label or double-blind phases was headache. During doubleblind phase of study, the incidence of headache was significantly higher in lamotrigine group compared with lithium. The incidence of diarrhea was significantly higher in the lithium group compared with lamotrigine group. One case with rash during open-label phase which resolved after discontinuation of lamotrigine.
Presented by Simone Litsch, MD
