One of the first waves of results from the National Institute of Mental
Health's (NIMH) Systematic Treatment Enhancement Program for Bipolar Disorder
(STEP-BD) suggests that the anticonvulsant/mood stabilizer lamotrigine
(Lamictal) may have added value in treating patients with bipolar disorder for
A three-way head-to-head comparison of lamotrigine, risperidone
(Risperdal), and inositol as adjunct pharmacotherapy in the treatment of
bipolar depression in patients who have not adequately responded to
appropriate pharmacotherapy is believed to be the first trial of any
medication for treatment-resistant bipolar depression. The results of the
small trial appear in the February American Journal of
"This study was designed back in 1999, and it was felt then that we
really didn't know a lot about bipolar depression in general or about
treatment-resistant depression in particular," said lead author Andrew
Nierenberg, M.D., an associate professor of psychiatry at Harvard Medical
School and Massachusetts General Hospital.
STEP-BD was designed to include two randomized, controlled trials, one
looking at the treatment of acute depression (results of which should be
published in the next year) and this "smaller study of refractory
depression," Nierenberg told Psychiatric News.
At that time, lamotrigine had yet to be approved by the FDA for maintenance
treatment of bipolar I disorder. An anticonvulsant/mood stabilizer,
lamotrigine is currently indicated to "delay the time to occurrence of
mood episodes (depression, mania, hypomania, mixed episodes) in patients
treated for acute mood episodes with standard therapy."
While the efficacy of lamotrigine has not been established for the acute
treatment of mood episodes, a growing body of evidence indicates that the drug
may be particularly useful in treating depressive episodes associated with
Nierenberg and his STEP-BD co-investigators looked at a subset of 66 of the
nearly 4,500 patients enrolled in the larger study (see article above).
Participants in the head-to-head trial were patients with bipolar I or II and
were in a current major depressive episode that was not responsive to a
combination of adequate doses of established mood stabilizers plus at least
Patients were randomly assigned to open-label treatment with lamotrigine,
inositol, or risperidone for up to 16 weeks in addition to their existing mood
stabilizer and antidepressant therapy. The primary outcome measure was the
rate of recovery, with recovery defined as "no more than two symptoms
meeting DSM-IV threshold criteria for a mood episode and no
significant symptoms present for eight weeks."
Nierenberg and his colleagues found no statistically significant
differences between the rates of recovery of any two drugs compared
(lamotrigine versus risperidone, lamotrigine versus inositol, and inositol
versus risperidone). Nierenberg told PsychiatricNews this
is likely due to the small number of patients in each comparison. For example,
in the comparison of lamotrigine and inositol, only six patients were taking
lamotrigine compared with 11 patients taking inositol. The number of patients
in the other two paired comparisons were similar (15 on lamotrigine and 16 on
inositol; 13 on risperidone and eight on inositol).
However, using the same rigorous definition of sustained response for eight
weeks, secondary outcomes—in which all patients taking lamotrigine
(n=21), inositol (n=23), and risperidone (n=22) were considered—recovery
rates were different between the three groups. The overall recovery rates were
23.8 percent for those taking lamotrigine, 17.4 percent for those taking
inositol, and 4.6 percent for those taking risperidone; these medications were
taken in addition to the patients' existing pharmacotherapy.
"This study suggests, but by no means proves, that risperidone didn't
look particularly helpful," Nierenberg told Psychiatric News."
However, that would have to be looked at much more closely in a larger
study. Perhaps there was a role for inositol, and perhaps there was really a
role for lamotrigine."
"Treatment-Resistant Bipolar Depression: A STEP-BD Equipoise
Randomized Effectiveness Trial of Antidepressant Augmentation With
Lamotrigine, Inositol, or Risperidone" is posted at<http://ajp.psychiatryonline.org/cgi/content/full/163/2/210>.▪
Am J Psychiatry2005163210