Neuropsychiatric complications of medications have always been important and challenging issues that interfere with diagnosis and management of patients [
6]. In this paper, we report a psychotic episode associated with the use of sildenafil in a subject without personal or family history of mental illness. Although different neuropsychiatric side effects of sildenafil such as aggressive behavior, depression, abnormal dreams and nervousness, rape, and suicidal attempt have been published so far [
7], literature about sildenafil-induced psychosis is scanty. In 2004, Baggot and Singh reported a relapse of mixed affective state with paranoid delusions and elevated mood in a bipolar patient treated with sildenafil. In this patient, affective symptoms improved with discontinuation of sildenafil and prescription of antipsychotics. The authors focused on the role of NO in the pathophysiology of psychotic disorders and hypothesized that an excess of NO-stimulated cGMP due to the inhibition of PDE led directly to the relapse [
8]. In the same vein, Özdemiroğlu
et al. reported on a patient who first developed mania while taking pramipexole, and some additional psychotic symptoms further emerged when panax ginseng and sildenafil were added to the ongoing pramipexole treatment. Although a link between sildenafil and psychosis has been suggested in this article, concomitant medications such as ginseng and pramipexole were other possible causes of psychotic symptoms. Besides, the patient had Parkinson’s disease, which is associated with a predisposition to psychosis [
9]. In terms of pathophysiology, there is some evidence available to suggest a possible association between sildenafil and psychotic symptoms. As mentioned earlier, the main pharmacological action of sildenafil is the inhibition of the cGMP-specific PDE5. PDE5 is present in substantial concentrations in the smooth muscles of the systemic vasculature and cerebral neurons and vessels [
10]. Inhibition of cGMP degradation by selective PDE5 raises nitric oxide (NO) levels by increasing the ratio of nitrite to nitrate and by stimulating transcription of mRNA for nitric oxide synthase (NOS) [
11]. NO is a key component in many processes occurring in the nervous system such as regulation of synaptic plasticity [
12], neurotransmission [
13], and development of nervous tissue [
14]. However, nitric oxide can be considered a double-edged blade. In fact, in the low, regulated mode, NO has favorable effects, mediating and protecting neuronal function. On the other hand, in the high, unregulated mode, it has neurotoxic effects [
15]. A growing body of evidence suggests that NO is involved in cerebrovascular diseases, seizures, neurodegenerative disorders, and pain [
16]. Previous studies have also concentrated on the association between NO and psychotic disorders (
17,
18). It is not unlikely that sildenafil’s inhibition of PDE5, accumulation of cGMP, and alterations in the concentrations of NO in the brain would result in psychotic symptoms. Accordingly, it is plausible that other PDE5 inhibitors such as tadalafil, vardenafil, and avanafil would be able to cause such symptoms through a similar mechanism. Nonetheless, in reviewing the literature, we found no reports on other PDE5 inhibitors causing psychotic symptoms. There are, therefore, other possible mechanisms behind the central nervous system adverse effects of the sildenafil that until now have not been recognized. In our case, there was a close temporal relationship between the use of sildenafil and emergence of psychotic symptoms. Furthermore, discontinuation of the sildenafil led to quick and full recovery from psychotic symptoms. These data strongly support a causative role for sildenafil in the development of psychotic symptoms. Taken together, this case demonstrates an episode of psychosis arising as a possible side effect of sildenafil and highlights the importance of watchful observation for the occurrence of this rare but serious side effect. Further studies are needed to clarify the precise mechanism that causes sildenafil-induced psychosis.