Lamotrigine in Treatment Resistant Depression in Adolescents

Mood disorders in youth, which include Major Depressive Disorder (MDD) and Bipolar Disorder
(BPD), are highly prevalent, and are associated with significant mortality and morbidity.
Many youths with major depression fail first-line treatments with psychotherapy and
psychotropic medications. Lamotrigine (Lamictal®) recently gained approval by the FDA for
maintenance treatment of bipolar disorder in adults. A few pilot studies have also shown
promising results for lamotrigine (LTG) in treatment refractory mood disorders in both youth
and adults, especially for depressive symptoms (Carandang et al., 2003; Frye et al., 2000).

For this proposed study, the modified design begins with adolescents with major depressive
disorder who have not responded to a trial of a selective serotonin reuptake inhibitor
antidepressant (SSRI), fluoxetine, of adequate dose and duration, and randomizes them either
to a second SSRI or to fluoxetine augmented by lamotrigine. Non-responders to 8 weeks of
fluoxetine, on at least 40 mg/day, who have not had to discontinue fluoxetine because of
adverse effects, would be randomized to: (A) continue fluoxetine with lamotrigine
augmentation, for 8 weeks, as in the active arm of the original Stage 2, or (B) discontinue
fluoxetine and begin a second SSRI, for 8 weeks. We will use sertraline as the second SSRI,
because of the data supporting efficacy from the randomized placebo-controlled trial by
Wagner, et.al. (JAMA, '03). Citalopram is also a possibility (Wagner et.al, Am J. Psychiatry
'04), but it has been in use for a shorter period of time than sertraline.

To maintain the blind, the B group will receive placebo augmentation.

The assessments and outcome measures would be the same as in the original study. We will
consult with primary care offices to coach them through doing the initial, Stage 1,
fluoxetine trial in their offices, and we will monitor the progress of adolescents started
on fluoxetine in our clinic. Consent will be discussed only with those who are not
responding, and treatment in the study will involve only the post-randomization treatment.

Background

Mood disorders in youth are common and debilitating. Early-onset of mood disorders often
indicates a severe illness, with high likelihood of recurrence into adulthood. For
prepubertal children, point prevalence of MDD is 2%, and 6% in adolescents, while the
lifetime prevalence for MDD in adolescents is 20% (Birmaher et al., 2002). The duration of a
Major Depressive Episode in youth ranges from 3 to 9 months, with 10% lasting more than 2
years, 60-70% recurring in adulthood, and 20-40% developing Bipolar Disorder within 5 years
(Weller and Weller, 2000). The prevalence of prepubertal bipolar disorder is estimated at
0.5%. Prevalence of bipolar disorder in adolescents is 1% (Lewinshon et al., 1995). Suicide
is the third leading cause of death in the 15 - 24 year old age group (10.1 per 100,000) and
the fifth leading cause in the 5 - 14 year old group (0.7 per 100,00), and is highly
correlated with MDD and BPD (Pfeffer, 2002). In addition, mood disorders in youth can impair
functioning, often characterized by poor school performance, impaired relationships,
delinquent behavior, and substance abuse.

Inclusion Criteria:

1. Adolescents (13-17) diagnosed with a major depressive episode (MDE) (DSM-IV criteria)
from either major depressive disorder (MDD) or bipolar disorder (BPD). BPD can
present as a major depressive episode, with previous or subsequent cycling into a
hypomanic, manic, or mixed episode. By definition, major depressive disorder MDD
requires the presence of a major depressive episode, without cycling into a
hypomanic, manic, or mixed episode.

2. CDRS (Children's Depression Rating Scale) > 40.

3. CGAS (Children's Global Assessment Scale) < 60.

- Exclusion Criteria:

Adolescents who meet the following criteria will be excluded from the study:

1. Prior medically serious suicide attempt, within 3 months of enrollment into study or
a score of 3 on suicide questions within KSADS at initial visit or the side effect
checklist on follow up visits regarding current state.

2. Known or suspected mental retardation. For patients with known mental retardation,
full scale IQ below 70 should be documented.

3. Current significant physical illnesses (e.g. diabetes mellitus, asthma, cystic
fibrosis, congenital heart defects, genetic disorders). Patients with seizure
disorders taking anticonvulsants will be excluded (no concomitant anticonvulsants).

4. Current drug or alcohol abuse. No active abuse will be permitted within two weeks of
beginning the study trial (confirmed by urine testing in all cases of suspected
abuse).

5. Females who are sexually active and are unwilling or considered unable to use
appropriate contraception.

6. Use of benzodiazepines and other anxiolytics, antipsychotic medications, other
antidepressants, stimulant medication, other mood stabilizers (e.g., lithium,
valproate), and other sedative-hypnotics will not be permitted