July 2007

As Depression Becomes More Treatment-Resistant…
For patients who do not respond to initial antidepressant therapy, augmentation, or switch strategies, further augmentation or switching with different agents can bring about remission—but at a lower rate.

New Studies on GAD
Pregabalin and duloxetine (Cymbalta) may be efficacious for adults and venlafaxine (Effexor) for children with generalized anxiety disorder.

Methadone Prolongs QTc Interval
Long-term, high-dose methadone treatment is linked to prolonged QTc intervals.

In Brief
Augmentation for Clozapine Nonresponders; Quetiapine Ineffective for Psychosis/Agitation in Dementia

Effects of Antidepressants on 2D6 Enzymes
Duloxetine (Cymbalta) has substantial and escitalopram (Lexapro) and sertraline (Zoloft and others) more modest inhibiting effects on CYP 2D6.

New Studies on GAD

July 2007

Generalized anxiety disorder (GAD) is a chronic condition with symptoms waxing and waning over many years. Per the DSM-IV criteria, its cardinal symptoms are excessive anxiety and worry, which need to persist for at least 6 months. Venlafaxine (Effexor and others) and several selective serotonin reuptake inhibitors (SSRIs) carry labeling from the US Food and Drug Administration (FDA) for the treatment of GAD. Most likely, all serotonergic antidepressants would be efficacious if tested. A form of cognitive behavioral therapy also is effective for GAD symptoms.

Montgomery and colleagues conducted a comparative trial of pregabalin (Lyrica) versus venlafaxine and placebo for patients with GAD.1 A relatively new drug, pregabalin has high-affinity binding to the α2-δ subunit protein of voltage-gated calcium channels and is believed to act by inhibiting excited neurotransmitter release. Its FDA-labeled indications are epilepsy and pain.

In this study, patients with GAD were randomly assigned in double-blind fashion to 6 weeks of treatment with pregabalin, 400 or 600 mg/day; venlafaxine, 75 mg/day; or placebo. Both doses of pregabalin, as well as venlafaxine, were statistically superior to placebo in relieving anxiety symptoms. Pregabalin appeared to work faster.

In another trial, Rynn and associates studied duloxetine (Cymbalta) in a 10-week, double-blind, flexible-dose trial.2 Patients were assigned to duloxetine, 60 to 120 mg daily, or placebo. The active agent showed statistical superiority to placebo.

In another study led by Dr Rynn, children and adolescents with GAD took either venlafaxine, flexibly dosed up to 225 mg/day, or placebo for 8 weeks.3 As in adults, venlafaxine appeared efficacious for GAD in this younger population.

As noted at the beginning, GAD is a chronic condition. There is a high lifetime comorbidity with major depression. All of the medications currently labeled by the FDA for the treatment of GAD are antidepressants. The study by Rynn et al shows that young people are as likely to benefit from venlafaxine as adults. Of course, venlafaxine is not approved for use in this population, and concerns have been raised that children and adolescents are at a higher risk than older patients to develop suicidal impulses with venlafaxine and SSRIs. Although it is not yet labeled for GAD, there is every reason to believe that duloxetine, with a mechanism of action similar to that of venlafaxine, also will be shown efficacious in GAD. Pregabalin is an interesting compound, which works by a novel mechanism of action. It is available by prescription but not labeled for any psychiatric indication. Data so far suggest that it has a faster onset of anti-anxiety action than antidepressants. Whether it will treat comorbid depression remains to be seen.

1Montgomery SA, Tobias K, Zornberg GL, Kaspar S, Pande AC: Efficacy and safety of pregabalin in the treatment of generalized anxiety disorder: A 6-week, multicenter, randomized, double-blind, placebo-controlled comparison of pregabalin and venlafaxine. J Clin Psychiatry 2006;67:771-782.

2Rynn M, Russell J, Erickson J, Detke MJ, Ball S, Dinkel J, Rickels K, Raskin J: Efficacy and safety of duloxetine in the treatment of generalized anxiety disorder: A flexible-dose, progressive-titration, placebo-controlled trial. Depress Anxiety, in press.

3Rynn MA, Riddle MA, Yeung PP, Kunz NR: Efficacy and safety of extended-release venlafaxine in the treatment of generalized anxiety disorder in children and adolescents: Two placebo-controlled trials. Am J Psychiatry 2007;164:290-300.