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July 2007

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

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.

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.

In Brief

July 2007

If a patient with schizophrenia fails to respond sufficiently to clozapine (Clozaril and others), what's the next step? In four randomized, placebo-controlled trials, 166 patients with schizophrenia who responded incompletely to clozapine received augmentation with a second antipsychotic—either risperidone (Risperdal) or sulpiride.* Paton and others conducted a meta-analysis of data from these studies and from eight open-label trials of clozapine nonresponders, in which the augmenting agent was risperidone, sulpiride, amisulpride,* ziprasidone (Geodon), or aripiprazole (Abilify) (J Clin Psychopharmacol 2007;27:198-204). They found that treatment duration was more important to outcome than choice of the augmenting drug. Taken together, the four controlled trials did not show a statistically significant advantage for active drug augmentation over placebo. However, pooled data from the two that lasted 10 weeks or longer favored clozapine augmentation, with response rates (a 20% or greater decrease in scores on the Brief Psychiatric Rating Scale or the Positive and Negative Syndrome Scale) of 42% for augmentation versus 9% for placebo. Response rates for augmentation versus placebo in the trials that lasted less than 10 weeks were virtually indistinguishable: 26% versus 27%. A similar pattern was seen in the open-label trials: those lasting at least 10 weeks had more positive results, whereas those lasting 6 weeks or less showed little effect of augmentation. The main side effects from treatment were extrapyramidal effects and raised serum prolactin. However, the investigators caution that these relatively small studies could have missed uncommon but severe adverse effects.

A recent multicenter, randomized, double-blind, placebo-controlled study investigated the efficacy, safety, and tolerability of quetiapine (Seroquel) to treat psychosis or agitation in patients with dementia complicated by coexisting parkinsonism (R Kurlan et al. Neurology 2007;68:1356-1363). This trial included 23 patients with dementia with Lewy bodies, 9 with Parkinson's disease with dementia, and 8 with Alzheimer's disease with parkinsonian features. Behavioral problems improved in both treatment groups, but quetiapine was not statistically superior to placebo. The authors opine that the lack of observed significant benefit of quetiapine might have resulted from their unexplained large placebo effect or from inadequate dosages. Their mean dosage was 120 mg/day, whereas other studies have suggested that 200 mg/day or greater may be needed to control agitation in demented patients. There was no significant increase in parkinsonism associated with quetiapine, and no drug sensitivity in patients with dementia with Lewy bodies. There was a trend towards worsening of functional abilities for those treated with quetiapine over placebo as measured by the Activities of Daily Living Scale.

*Not currently available in the United States.

Heather S. Hopkins