We read with interest the paper by Stone et al. (Reference Stone, Morrison, Koychev, Gao, Reilly, Kolanko, Mohammadinasab, Kapur and McGuire2016) about the effect of sodium nitroprusside (SNP) in patients with schizophrenia. It was a controlled trial where 20 subjects on antipsychotics received an infusion of SNP (0.5 µg/kg per min for 4 h) or placebo. The participants were assessed at baseline, immediately after the infusion, and 4 weeks later. No differences in outcomes were found between SNP and placebo (Stone et al. Reference Stone, Morrison, Koychev, Gao, Reilly, Kolanko, Mohammadinasab, Kapur and McGuire2016).

Previously, we reported that SNP displays antipsychotic activity in animal models of schizophrenia (Bujas-Bobanovic et al. Reference Bujas-Bobanovic, Bird, Robertson and Dursun2000; Maia-de-Oliveira et al. Reference Maia-de-Oliveira, Lobão-Soares, Ramalho, Gavioli, Soares, Teixeira, Baker, Dursun and Hallak2015a ) and in schizophrenia patients taking antipsychotics (Hallak et al. Reference Hallak, Maia-de-Oliveira, Abrao, Evora, Zuardi, Crippa, Belmonte-de-Abreu, Baker and Dursun2013; Maia-de-Oliveira et al. Reference Maia-de-Oliveira, Belmonte-de-Abreu, Bressan, Cachoeira, Baker, Dursun and Hallak2014). We found that SNP improved some cognitive deficits in schizophrenia patients (Maia-de-Oliveira et al. Reference Maia-de-Oliveira, Abrao, Evora, Zuardi, Crippa, Belmonte-de-Abreu, Baker, Dursun and Hallak2015 b) and long-term ketamine-induced memory deficits in rats (Kandratavicius et al. Reference Kandratavicius, Balista, Wolf, Abrao, Evora, Rodrigues, Chaves, Maia-de-Oliveira, Leite, Dursun, Baker, Guimaraes and Hallak2015). Trevlopoulou et al. (Reference Trevlopoulou, Touzlatzi and Pitsikas2016) reported that SNP attenuated ketamine-induced short-term recognition memory deficits and social isolation in rats.

Stone et al. (Reference Stone, Morrison, Koychev, Gao, Reilly, Kolanko, Mohammadinasab, Kapur and McGuire2016) were not able to replicate our main findings. The authors argued that beneficial effects of SNP may occur in patients with a shorter history of illness, or with more acute exacerbation of symptoms. Hallak et al. (Reference Hallak, Maia-de-Oliveira, Abrao, Evora, Zuardi, Crippa, Belmonte-de-Abreu, Baker and Dursun2013) used the Bech's version of the Brief Psychiatric Rating Scale that rates from 0 to 4 (Bech et al. Reference Bech, Kastrup and Rafaelsen1986), while Stone et al. (Reference Stone, Morrison, Koychev, Gao, Reilly, Kolanko, Mohammadinasab, Kapur and McGuire2016) used the Overall & Goram (Reference Overall and Goram1962) version, which rates from 1 to 7, suggesting that in the Stone et al. (Reference Stone, Morrison, Koychev, Gao, Reilly, Kolanko, Mohammadinasab, Kapur and McGuire2016) study participants were less symptomatic. Indeed, Hallak et al. (Reference Hallak, Maia-de-Oliveira, Abrao, Evora, Zuardi, Crippa, Belmonte-de-Abreu, Baker and Dursun2013) worked with subjects with less than 5 years of disease and who were so severely ill they were hospitalized; symptoms were also recorded at baseline and at multiple times between infusion and 4 weeks.

Stone et al. (Reference Stone, Morrison, Koychev, Gao, Reilly, Kolanko, Mohammadinasab, Kapur and McGuire2016) also seem to have worked with a population presenting other features that could potentially affect their final findings such as the presence of two schizo-affective disorder patients and seven subjects currently using cannabis; it was not clear if there was other illicit substance use. Furthermore, the majority of patients were current smokers (n = 12). Since it is well known that cigarette smoking induces a reduction in NO (Guo et al. Reference Guo, Oldham, Kleinman, Phalen and Kassab2006; Csordas & Bernhard, Reference Csordas and Bernhard2013), this characteristic may have influenced the SNP efficacy. Moreover, the majority of patients were black (n = 15, denoted as ‘black British and black other’). Since black Americans and black South Africans have been reported to present with attenuated SNP vascular effects (Stein et al. Reference Stein, Lang, Nelson, Brown and Wood1997; Pienaar et al. Reference Pienaar, Micklesfield, Gill, Shore, Gooding, Levitt and Lambert2014), perhaps the same happens concerning SNP's antipsychotic and cognitive effects; it may be inappropriate to compare these groups from three different countries, but it does raise the question of possible ethnic differences in responses to SNP.

In contrast to the Hallak et al. (Reference Hallak, Maia-de-Oliveira, Abrao, Evora, Zuardi, Crippa, Belmonte-de-Abreu, Baker and Dursun2013) study, Stone et al. (Reference Stone, Morrison, Koychev, Gao, Reilly, Kolanko, Mohammadinasab, Kapur and McGuire2016) found significant reduction of blood pressure and increase in heart rate during the SNP treatment. Could these cardiac alterations have negatively influenced the performance of the SNP group?

We believe that several variables could account for the different results reported, which points out the importance of avoiding possible confounding factors in future studies on this drug.