Gabitril fails to improve GAD symptoms in three controlled trials
Cephalon’s selective GABA reuptake inhibitor, the antiepileptic drug tiagabine (Gabitril), was assessed for the treatment of generalized anxiety disorder in adults in three large 10-week placebo-controlled studies. Gabitril failed to beat placebo on the primary outcome measure (change on the Hamilton Rating Scale for Anxiety) in any of the trials, which included one fixed dose trial and two flexible-dose trials. Gabitril was superior to placebo on some secondary measures, though some of these analyses included only participants who completed the study. As dropout rates on Gabitril were high, ranging from 29% to 47%, it is problematic to rely on any analysis that included only participants who completed treatment. The authors reported that the rates of serious adverse events did not differ between drug and placebo; however, dropout rates from adverse events in the flexible dose studies were about twice as high on Gabitril than on placebo. In the fixed dose trial, these rates were 60% higher for the 8mg and 12mg groups compared to the placebo group. The authors did not report whether these differences were statistically significant, but the percentages certainly seem clinically significant. Dizziness, nausea, fatigue and somnolence were the most commonly reported adverse events that occurred more frequently on Gabitril relative to placebo (Pollack MH et al., J Clin Psychopharmacol 2008;28:308-316).
TCPR’s Take: The results are clear: Gabitril is not more effective than a placebo for GAD. If it has any role in psychiatry, it would be as an add-on agent for patients with anxiety who are not improving with standard treatment, though the evidence for this is based on small uncontrolled studies (see TCPR March 2006). Across four double-blind trials, various doses of iloperidone (4 mg – 24 mg/day) were compared to ziprasidone (Geodon), risperidone (Risperdal), haloperidol, and placebo. As reported in the June 2008 issue of TCPR, risperidone and haloperidol were numerically superior to iloperidone on several outcome measures in some trials, though whether these differences were statistically significant was not reported by the company. Iloperidone generally outperformed placebo to a statistically significant extent and seemed about on par with Geodon in terms of efficacy, though their safety profiles differed somewhat. What’s next for iloperidone? To generate more convincing data on efficacy, the FDA asked Vanda to conduct a trial comparing iloperidone to an active comparator and a placebo. More safety data will also be required for the 20-24 mg doses of the drug.
TCPR’s Take: While iloperidone seemed roughly equivalent to Geodon, the less favorable results versus Risperdal suggest that the drug is not a breakthrough in therapeutic efficacy. Perhaps the collection of more data will yield a better understanding of how this drug stacks up to current popularly prescribed medications.
Placebo response is usually long-lasting
Based on data from eight randomized double-blind, placebo-controlled trials, researchers found that 79% of patients who responded to placebo in the initial phase of the trial maintained their response while continuing to take placebo during the continuation phase of the trial. The continuation phases varied from four months to a year in duration. The 79% maintenance response rate was significantly less than the 93% maintenance response rate on antidepressants (Khan A et al, J Psychiatr Res 2008;42:791-796).
TCPR’s Take: These results contradict the common belief that the placebo response can be distinguished from active medication response by a shorter time course. In line with prior research, these results reinforce the notion that there is more to antidepressant response than a medication’s pharmacological properties. Factors common to both psychopharmacological treatment and psychotherapy, including the relationship between doctor and patient, the doctor’s credibility as an expert, and the provision of an explanation for the patient’s distress, are likely key elements in determining patient outcomes. Clinical trials have consistently found that the placebo response is robust in depression and several other psychiatric conditions; thus, clinicians should make sure to maintain a strong sense of rapport and credibility with their clients – the so-called “human element” in psychiatric practice should not be overlooked.
Intensive early intervention benefits fade after treatment discontinued
An intensive two-year-long early intervention for first episode psychosis showed early promise relative to standard care, yielding superior improvement in both positive and negative symptoms, as well as lower rates of substance abuse and lower antipsychotic medication doses. This intensive intervention consisted of multidisciplinary case management tailored to each client’s preferences, psychoeducational family treatment, and social skills training (Petersen L et al., BMJ, 2005(331):602). Unfortunately, three years after the program was discontinued, most of the benefits appear to have faded substantially. At three year follow-up, intensive intervention participants showed improved outcomes (vs. standard care) only regarding fewer days in supported housing and, depending on how the data are analyzed, perhaps fewer hospital days (Bertelsen et al., Arch Gen Psychiatry 2008;65:762-771).
TCPR’s Take: On many outcomes, the benefits at the end of the two-year intensive program were statistically significant, with small to moderate effect sizes. Some might wonder about increased costs for such an intensive program, but the authors state that the increased costs of early intervention are offset by reduced spending for health services, though they provided no cost data to support this claim. There appears to be little risk associated with such a program, and several studies have found that psychosocial interventions are often useful in the management of schizophrenia and related disorders in the short-term, though longer-term data are not as convincing.