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


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.


CONCLUSIONS
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.
Goff
Donald C
DC
Department of Psychiatry, MGH Schizophrenia Program, Freedom Trail Clinic, Massachusetts General Hospital, Harvard Medical School, 25 Staniford St., 2nd Floor, Boston, MA, 02114, USA, goff@psych.mgh.harvard.edu.
Cather
Corinne
C
Freudenreich
Oliver
O
Henderson
David C
DC
Evins
A Eden
AE
Culhane
Melissa A
MA
Walsh
Jared P
JP
D003072:Cognition Disorders / Q000188:drug therapy* / Q000209:etiology* / Q000523:psychology; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D008297:Male; D008568:Memory / Q000187:drug effects; D008875:Middle Aged; D009483:Neuropsychological Tests; D010726:Phosphodiesterase Inhibitors / Q000009:adverse effects / Q000627:therapeutic use*; D010879:Piperazines / Q000009:adverse effects / Q000627:therapeutic use*; D011569:Psychiatric Status Rating Scales; D011597:Psychomotor Performance / Q000187:drug effects; D011687:Purines / Q000009:adverse effects / Q000627:therapeutic use; D012559:Schizophrenia / Q000150:complications*; D012565:Schizophrenic Psychology; D000068677:Sildenafil Citrate; D013450:Sulfones / Q000009:adverse effects / Q000627:therapeutic use*
D010726:Phosphodiesterase Inhibitors; D010879:Piperazines; D011687:Purines; D013450:Sulfones; D000068677:Sildenafil Citrate