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A placebo-controlled study of sildenafil effects on cognition in schizophrenia.

ABSTRACT: Phosphodiesterase 5 (PDE5) inhibitors increase cyclic guanosine monophosphate (cGMP) concentrations in the intracellular pathway activated by N-methyl-D-aspartic acid receptors which is believed to mediate long-term potentiation and memory consolidation. The PDE5 inhibitor sildenafil has been shown to enhance memory in animal models. In addition, neuronal nitric oxide synthase, another component of the NMDA/nitric oxide/cGMP intracellular pathway, has been reported to be dysregulated in schizophrenia patients.Seventeen adult schizophrenia outpatients treated with a stable dose of antipsychotic received a single oral dose of placebo, sildenafil 50 mg, and sildenafil 100 mg in random order with a 48-h interval between administrations. Psychiatric symptom ratings and a cognitive battery were performed at baseline and 1 hour following each administration of the study drug. In addition, memory consolidation was examined by testing recall 48 h later, prior to the next administration of the study drug.Fifteen subjects completed all three treatment conditions. One subject developed irritability and required hospitalization 2 days after receiving sildenafil 100 mg. Neither dose of sildenafil significantly affected cognitive performance or symptom ratings compared to the placebo.Despite evidence for cognitive-enhancing effects of sildenafil in animal models, the strategy for treating putative NMDA receptor-mediated memory deficits in schizophrenia with sildenafil 50 and 100 mg was not successful. It is possible that the doses used in this study were not optimal or that repeated dosing may be necessary to achieve therapeutic effects. Agents under development that inhibit other subtypes of PDE remain promising for schizophrenia and dementia.

SUBMITTER: Goff DC

PROVIDER: S-EPMC2704618 | biostudies-other | 2009 Jan

REPOSITORIES: biostudies-other

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Project description:ImportancePatients' previous experience with performance-based cognitive tests in clinical trials for cognitive impairment associated with schizophrenia can create practice-related improvements. Placebo-controlled trials for cognitive impairment associated with schizophrenia are at risk for these practice effects, which can be difficult to distinguish from placebo effects.ObjectivesTo conduct a systematic evaluation of the magnitude of practice effects on the Measurement and Treatment Research to Improve Cognition in Schizophrenia Consensus Cognitive Battery (MCCB) in cognitive impairment associated with schizophrenia and to examine which demographic, clinical, and cognitive characteristics were associated with improvement in placebo conditions.Design, setting, and participantsA blinded review was conducted of data from 813 patients with schizophrenia who were treated with placebo in 12 randomized placebo-controlled clinical trials conducted mostly in outpatient clinics in North America, Europe, Asia, and Latin America from February 22, 2007, to March 1, 2014. A total of 779 patients provided data for the primary outcome measure at baseline and at least 1 follow-up. Seven trials had prebaseline assessments wherein the patients knew that they were not receiving treatment, allowing a comparison of practice and placebo effects in the same patients.InterventionsPlacebo compared with various experimental drug treatments.Main outcomes and measuresComposite score on the MCCB.ResultsOf the 813 patients in the study (260 women and 553 men; mean [SD] age, 41.2 [11.5] years), the mean MCCB composite score at baseline was 22.8 points below the normative mean, and the mean (SEM) total change in the MCCB during receipt of placebo was 1.8 (0.2) T-score points (95% CI, 1.40-2.18), equivalent to a change of 0.18 SD. Practice effects in the 7 studies in which there was a prebaseline assessment were essentially identical to the postbaseline placebo changes. Baseline factors associated with greater improvements in the MCCB during receipt of placebo included more depression/anxiety (F1,438?=?5.41; P?=?.02), more motivation (F1,272?=?4.63; P?=?.03), and less improvement from screening to baseline (F1,421?=?59.32; P?<?.001).Conclusions and relevancePlacebo effects were minimal and associated with the number of postbaseline assessments and several patient characteristics. Given that the patients performed 2.28 SDs below normative standards on average at baseline, a mean placebo-associated improvement of less than 0.2 SD provides evidence that ceiling effects do not occur in these trials. These minimal changes in the MCCB could not be responsible for effective active treatments failing to separate from placebo.

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A placebo-controlled study of sildenafil effects on cognition in schizophrenia.

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