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IN THIS ISSUE:
March 2008

Topiramate for Alcohol Dependence
Topiramate (Topamax) has been found to be beneficial in treating alcohol dependence.

Early Intervention for Schizophrenia: A Role for Antidepressants?
Antidepressants may reduce the transition from a prodrome of pre-psychosis to schizophrenia in vulnerable individuals.

In Brief
Duloxetine Approved for GAD; Depression in Parkinson’s Disease; Asthma Linked to Psychiatric Disorder

Adjunctive Antipsychotics for MDD
Patients with treatment-resistant major depressive disorder may benefit from the addition of second-generation antipsychotics to an antidepressant medication regimen.

Antipsychotics in Youth with Schizophrenia
Early-onset schizophrenia-spectrum disorder requires long-term antipsychotic treatment, but children and adolescents are sensitive to antipsychotic side effects and should be monitored carefully.

Adjunctive Antipsychotics for MDD

March 2008

Many patients with major depressive disorder (MDD) fail to achieve remission with a single antidepressant. For them, clinicians often turn to adjunctive agents. In recent years, this has included the second-generation antipsychotics. Two posters present data on aripiprazole (Abilify) and one describes adding quetiapine (Seroquel) to augment antidepressants in MDD.1-3

Thase and coworkers conducted a pooled subpopulation analysis based on two identical studies of aripiprazole augmentation for MDD.1 In both studies, patients with MDD received 8 weeks of treatment with a doctor's choice of antidepressant: escitalopram (Lexapro), fluoxetine (Prozac and others), paroxetine CR (Paxil CR), sertraline (Zoloft and others), or venlafaxine XR (Effexor XR) under standard dosing guidelines. Patients also received a single-blind adjunctive placebo during this phase. Those who failed to achieve at least a 50% improvement in depression ratings were randomized to receive either placebo or aripiprazole, 2 to 20 mg/day, in addition to the antidepressant for another 6 weeks. Overall, patients taking adjunctive aripiprazole improved about 4 points more on the Montgomery-Asberg Depression Scale compared with those taking placebo.

A separate poster described a pooled safety and tolerability analysis of the same two studies with aripiprazole. Nelson and associates found that adjunctive aripiprazole was generally well tolerated.2 More common with aripiprazole than with placebo were insomnia, fatigue, blurred vision, and constipation. Particularly noted were akathisia, which occurred in 24.8% of aripiprazole subjects (versus 4.4% among those taking placebo), and restlessness, occurring in 12.1% and 1.9%, respectively. Also, the aripiprazole group gained more weight, increasing an average of 1.73 kg (3.84 lb) versus only 0.38 kg (0.84 lb) in the placebo group (P < .001). The percentage of patients who gained 7% or more body weight from baseline was 5% with aripiprazole versus 1% with placebo. Another concern about aripiprazole's safety emerges from a poster by Haney and coauthors.3 They stopped a clinical trial early when they discovered that aripiprazole actually increased the use of cocaine in a population of substance abusers.

Looking at another antipsychotic based on pilot data, Earley and collaborators enrolled 493 patients with MDD who had been incompletely responsive to an antidepressant: selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), a tricyclic, or bupropion (Wellbutrin and others).4 In a double-blind design, subjects were randomly assigned to receive, in addition to their single antidepressant, quetiapine XR, 150 mg/day; quetiapine XR, 300 mg/day; or placebo for 6 weeks.

Both quetiapine doses were statistically superior to placebo in decreasing average depression scores by the end of the first week and continued to be superior for the entire study. Both produced a greater number of responders, but only the higher dose achieved significance at the P = .05 level. Both doses reduced anxiety symptoms. The most common adverse effects with quetiapine were dry mouth, somnolence, fatigue, and sedation.

These positive data with aripiprazole and quetiapine as adjuncts for treatment-resistant MDD are encouraging. At the same time, adding a drug commonly adds side effects. Akathisia and restlessness are known side effects with aripiprazole, but they can often be attenuated by gradual dosage increases. Although aripiprazole is less likely to cause weight gain than other second-generation antipsychotics, it can cause some, with corresponding adverse health consequences. The suggestion from Haney et al that aripiprazole might spur cocaine abuse is worrisome. Clinicians treating psychotic patients who also may abuse cocaine should be cautious. Quetiapine similarly can cause adverse effects, including sedation and weight gain.

1Thase M, Trivedi MH, Swanink R, Tran QV, Pikalov A, Qi Y, Carlson BX, Marcus RN, Berman RM: Efficacy of adjunctive aripiprazole in major depressive disorder: A pooled subpopulation analysis (studies CN138-139 and CN138-163). Poster presented at the 46th annual meeting of the American College of Neuropsychopharmacology, Boca Raton, FL, December 9-13, 2007.

2Nelson JC, Kaplita S, Tran QV, Pikalov A, Qi Y, Carlson BX, Marcus RN, Berman RM: Safety and tolerability of adjunctive aripiprazole in major depressive disorder: A pooled analysis (studies CN138-139 and CN138-163). Poster presented at the 46th annual meeting of the American College of Neuropsychopharmacology, Boca Raton, FL, December 9-13, 2007.

3Haney M, Hart CL, Foltin RW: Aripiprazole increases smoked cocaine self-administration in humans. Poster presented at the 46th annual meeting of the American College of Neuropsychopharmacology, Boca Raton, FL, December 9-13, 2007.

4Early W, McIntyre A, Bauer M, Pretorius HW, Shelton R, Lindgren P, Brecher M: Efficacy and tolerability of extended release quetiapine fumarate (quetiapine XR) as add-on to antidepressants in patients with major depressive disorder (MDD): Results from a double-blind, randomized Phase III study. Poster presented at the 46th annual meeting of the American College of Neuropsychopharmacology, Boca Raton, FL, December 9-13, 2007.