American Journal of Psychiatry Reviews and Overviews

Clinical Trials Design Lessons From the CATIE Study [Reviews and Overviews]

Kraemer, H. C., Glick, I. D., Klein, D. F. — Mon, 02 Nov 2009 10:01:53 PST

The Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) study was funded by the National Institute of Mental Health to compare the effectiveness of drugs for schizophrenia. The focus here is not on its conclusions but on the knotty issues of design and methods, in order to support appropriate clinical interpretation of the conclusions, and on using the CATIE experience to indicate directions for improvement of future clinical trials. While many of the CATIE design and implementation decisions are excellent and serve as models for future research, other decisions resulted in a study with a large study group but inadequate power. Multiple treatment interventions, unbalanced randomization within and across clinical sites, and multiple secondary outcomes are among the issues that require even more serious consideration in future large multisite clinical trials. Moreover, it is crucial to clarify whether the intent of a study is to establish superiority of some treatments or to establish equivalence, for the appropriate designs and analyses differ in these situations. If the study is designed, as was CATIE, to demonstrate some treatments’ superiority, statistically nonsignificant results should not be misinterpreted as evidence of "equivalence." For establishing either superiority or equivalence, future treatment comparisons might better be designed with fewer sites, more subjects per site, fewer treatments, and fewer outcomes, in order to have the power for definitively establishing superiority or equivalence at a lower cost.

Clinical Messages From the Treatment for Adolescents With Depression Study (TADS) [Reviews and Overviews]

March, J. S., Vitiello, B. — Thu, 01 Oct 2009 10:01:37 PDT

OBJECTIVE: The purpose of this report was to summarize the key clinical messages from the Treatment for Adolescents with Depression Study (TADS). METHODS: TADS is a National Institute of Mental Health (NIMH)-funded randomized controlled trial designed to evaluate the relative effectiveness of fluoxetine, cognitive-behavioral therapy (CBT), and the combination of fluoxetine plus CBT across acute treatment, maintenance treatment, and naturalistic follow-up periods among adolescents with major depressive disorder. RESULTS: Findings revealed that 6 to 9 months of combined fluoxetine plus CBT should be the modal treatment from a public health perspective as well as to maximize benefits and minimize harms for individual patients. CONCLUSION: The combination of fluoxetine and CBT appears to be superior to both CBT monotherapy and fluoxetine monotherapy as a treatment for moderate to severe major depressive disorder in adolescents.

Atypical Antipsychotic Augmentation in Major Depressive Disorder: A Meta-Analysis of Placebo-Controlled Randomized Trials [Reviews and Overviews]

Nelson, J. C., Papakostas, G. I. — Tue, 01 Sep 2009 10:01:41 PDT

OBJECTIVE: The authors sought to determine by meta-analysis the efficacy and tolerability of adjunctive atypical antipsychotic agents in major depressive disorder. METHOD: Searches were conducted of MEDLINE/PubMed (1966 to January 2009), the Cochrane database, abstracts of major psychiatric meetings since 2000, and online trial registries. Manufacturers of atypical antipsychotic agents without online registries were contacted. Trials selected were acute-phase, parallel-group, double-blind controlled trials with random assignment to adjunctive atypical antipsychotic or placebo. Patients had nonpsychotic unipolar major depressive disorder that was resistant to prior antidepressant treatment. Response, remission, and discontinuation rates were either reported or obtained. Data were extracted by one author and checked by the second. Data included study design, number of patients, patient characteristics, methods of establishing treatment resistance, drug doses, duration of the adjunctive trial, depression scale used, response and remission rates, and discontinuation rates for any reason or for adverse events. RESULTS: Sixteen trials with 3,480 patients were pooled using a fixed-effects meta-analysis. Adjunctive atypical antipsychotics were significantly more effective than placebo (response: odds ratio=1.69, 95% CI=1.46–1.95, z=7.00, N=16, p<0.00001; remission: odds ratio=2.00, 95% CI=1.69–2.37, z=8.03, N=16, p<0.00001). Mean odds ratios did not differ among the atypical agents and were not affected by trial duration or method of establishing treatment resistance. Discontinuation rates for adverse events were higher for atypical agents than for placebo (odds ratio=3.91, 95% CI=2.68–5.72, z=7.05, N=15, p<0.00001). CONCLUSIONS: Atypical antipsychotics are effective augmentation agents in major depressive disorder but are associated with an increased risk of discontinuation due to adverse events.

Prefrontal Activation Deficits During Episodic Memory in Schizophrenia [Reviews and Overviews]

Mon, 03 Aug 2009 10:01:40 PDT

OBJECTIVE: Episodic memory impairments represent a core deficit in schizophrenia that severely limits patients’ functional outcome. This quantitative meta-analysis of functional imaging studies of episodic encoding and retrieval tests the prediction that these deficits are most consistently associated with dysfunction in the prefrontal cortex. METHOD: Activation likelihood estimation (ALE) was used to perform a quantitative meta-analysis of functional imaging studies that contrasted patients with schizophrenia and healthy volunteers during episodic encoding and retrieval. From a pool of 36 potential studies, 18 whole-brain studies in standard space that included a healthy comparison sample and low-level baseline contrast were selected. RESULTS: As predicted, patients showed less prefrontal activation than comparison subjects in the frontal pole, dorsolateral and ventrolateral prefrontal cortex during encoding, and the dorsolateral prefrontal cortex and ventrolateral prefrontal cortex during retrieval. The ventrolateral prefrontal cortex encoding deficits were not present in studies that provided patients with encoding strategies, but dorsolateral prefrontal cortex deficits remained and were not secondary to group performance differences. The only medial temporal lobe finding was relatively greater patient versus comparison subject activation in the parahippocampal gyrus during encoding and retrieval. CONCLUSIONS: The finding of prominent prefrontal dysfunction suggests that cognitive control deficits strongly contribute to episodic memory impairment in schizophrenia. Memory rehabilitation approaches developed for patients with frontal lobe lesions and pharmacotherapy approaches designed to improve prefrontal cortex function may therefore hold special promise for remediating memory deficits in patients with schizophrenia.