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

Donald C Goff, Corinne Cather, Oliver Freudenreich, David C Henderson, A Eden Evins, Melissa A Culhane, Jared P Walsh, Donald C Goff, Corinne Cather, Oliver Freudenreich, David C Henderson, A Eden Evins, Melissa A Culhane, Jared P Walsh

Abstract

Background: 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.

Materials and methods: 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.

Results: 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.

Conclusion: 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.

Figures

Fig. 1
Fig. 1
Phosphodiesterase 5 (PDE5) inhibitors are believed to enhance memory and learning via facilitation of long-term potentiation (LTP) mediated by the “glutamate–nitric oxide–cyclic GMP intracellular pathway.” Glutamate binding to the N-methyl-d-aspartate (NMDA) receptor results in calcium (Ca2+) influx, which binds to calmodulin and activates nitric oxide synthase (NOS). NOS catalyzes the production of nitric oxide (NO) from arginine; NO activates guanylyl cyclase, which increases production of cyclic guanosine monophosphate (GMP) from guanosine triphosphate (GTP). Cyclic GMP mediates LTP and activates protein kinases (PK), which are believed to mediate memory consolidation via phosphorylation and protein formation. PDE5 inhibitors block the conversion of cGMP to 5′GMP; by elevating cGMP levels, LTP is facilitated

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