l-lysine as an adjunct to risperidone in patients with chronic schizophrenia: A double-blind, placebo-controlled, randomized trial
Introduction
Schizophrenia is a severely devastating brain disorder with significant personal, social and economic consequences. Despite growing numbers of antipsychotic drugs for the treatment of schizophrenia, the management of this disorder remains to be a major challenge. Therefore, there is a need to find new strategies to improve treatment plans for schizophrenia patients. Although the classic theories of dopamine neurotransmission involvement continue to be explored, studies have suggested existence of other neurobiological abnormalities in schizophrenia, including dysregulation of the nitric oxide system (Akbarian et al., 1993a, Akbarian et al., 1993b, Baba et al., 2004). Current antipsychotics have been mostly developed according to the dopaminergic hypothesis and primarily work on blocking dopamine D2 receptors. This may explain why currently available antipsychotics are unable to target all symptoms of schizophrenia.
Increasing evidence suggest that the nitric oxide (NO) signaling system of the brain may contribute to the pathophysiology of schizophrenia, making this system a potential target for developing novel treatments. Supporting evidence for this claim can be gathered from some findings indicating abnormal distribution of nitrinergic neurons in the temporal and prefrontal cortex of schizophrenic patients (Akbarian et al., 1993a, Akbarian et al., 1993b). More recent studies have shown that polymorphism of the nitric oxide synthase (NOS) gene may be associated with increased susceptibility to schizophrenia (Shinkai et al., 2002). Furthermore, abnormal levels of NO metabolites have been demonstrated in the serum and cerebral spinal fluid (CSF) of schizophrenic patients indicating a deregulated NO function in this disorder (Djordjevic et al., 2010, Lee and Kim, 2008, Ramirez et al., 2004, Taneli et al., 2004, Yilmaz et al., 2007). Clinical evidence of NO signaling system involvement in the pathophysiology of schizophrenia includes positive effects of methylene blue (MB), a NOS and guanylyl cyclase inhibitor, on the severity of psychopathology in schizophrenic patients and worsening of their symptoms after MB discontinuation (Deutsch et al., 1997). In addition, minocycline, which decreases inducible NOS and blocks NO induced neurotoxicity, is associated with robust clinical improvement in executive functioning as well as positive and negative symptoms in patients with schizophrenia (Khodaie-Ardakani et al., 2014, Levkovitz et al., 2010, Miyaoka et al., 2008). Notably, preclinical studies have demonstrated that pretreatment with NOS inhibitors blocks the phencyclidine (PCP)-induced disruption of prepulse inhibition (PPI), a measure of pre-attentive information processing, in mice (Klamer et al., 2001, Klamer et al., 2004). PCP is an N-methyl-D-aspartic acid (NMDA) receptor antagonist which has been proven to induce schizophrenia-like behaviors in experimental models.
NO is produced in a chemical reaction between amino acid l-arginine and a molecular oxygen which is catalyzed by NOS. l-lysine, an essential amino acid, and l-arginine share the same transport system named cationic amino acid transporter (CAT) in a competitive manner (White et al., 1982). l-lysine has been shown to inhibit cellular transport of l-arginine, deplete its intracellular concentration, and finally limits NO synthesis (Carter et al., 2004, Wu et al., 2000). Thereby, it may act as an indirect regulator of NO synthesis through competition with l-arginine for CAT. Wass et al. evaluated the efficacy of l-lysine as an adjunctive therapy in ten patients suffering from schizophrenia. They demonstrated significant improvement in positive symptoms and cognitive functioning after treatment with l-lysine. However, they concluded that further evaluation is required to determine the probable beneficial effects of l-lysine in the treatment of schizophrenia due to some limitations of their study such as limited number of participants and short follow-up period (Wass et al., 2011). According to the available data, we hypothesized that l-lysine might be an appropriate augmentative option for improving schizophrenia symptoms considering its dampening effect on NO signaling system and its acceptable safety profile. Therefore, a randomized, double-blind, placebo-controlled trial was designed to evaluate the efficacy and safety of l-lysine as an adjunctive to risperidone in alleviating the symptoms of schizophrenia.
Section snippets
Trial design and setting
An 8-week, randomized, double-blind, placebo-controlled, parallel-group study was performed in the Roozbeh Psychiatric Hospital (Tehran University of Medical Sciences, Tehran, Iran) and Qods Hospital (Kurdistan University of Medical Sciences, Sanandaj, Iran) from March 2012 to February 2014. The trial protocol was approved by the Institutional Review Board (IRB) of Tehran University of Medical Science (Grant No: 16005) and was conducted in agreement with the Declaration of Helsinki and its
Participants and baseline characteristics
A total number of 120 patients were assessed for eligibility, of whom 80 patients were enrolled in the study and randomized to receive either l-lysine or placebo. All drop-outs occurred before the first post-baseline visit. Seventy-two patients completed the study and participated in all follow-up visits so their data was included in the analyses (Fig. 1). Baseline characteristics of the patients as well as their baseline PANSS, HDRS, and ESRS are summarized in Table 1. Mean dose of risperidone
Discussion
The results of this randomized, double-blind, placebo-controlled trial demonstrated beneficial effects of l-lysine on total, negative and general psychopathology symptoms of schizophrenia without inducing serious AEs. However, positive symptoms did not significantly improve following l-lysine consumption compared to placebo treatment. The outcomes of this trial are relatively consistent with findings of Wass et al. which investigated the efficacy of l-lysine in a short-term, single-blinded,
Limitations
Although this study provided a valid assessment of l-lysine use in schizophrenic patients, it also has some limitations which should be considered. The sample size was relatively small and the study course and follow-up period were relatively short. Although PANSS has been widely used to measure the severity of schizophrenia symptoms, it is not a real life outcome measure which raises the question of whether statistically significant outcomes of this study would be also clinically prominent or
Conclusion
An 8-week course of l-lysine as adjunct to risperidone demonstrated a favorable tolerability and efficacy profile in patients suffering from chronic schizophrenia. However, the effects of higher doses and longer treatment periods with this medication as well as its impact on other aspects of schizophrenia remain to be elucidated in future studies.
Funding
This study was supported by a grant from Tehran University of Medical Sciences to Prof. Shahin Akhondzadeh (Grant No. 16005).
Authors contribution
Shahin Akhondzadeh was the principal investigator and provided statistical support. He was also the clinical neuropsychopharmacologist from March 2012 to February 2014. Morvarid Ahadi was the resident psychiatrist and trialist from March 2012 to February 2014. Farzin Rezaei was the clinical coordinators and psychiatrists from March 2012 to February 2014. Atefeh Zeinoddini, Mina Tabrizi and Mehdi Farokhnia were the methodologists from March 2012 to February 2014.
Conflict of interests
No conflict of interest exists for any of the authors associated with the manuscript and there was no source of extra-institutional commercial funding.
Acknowledgment
This study was Dr. Morvarid Ahadi's postgraduate thesis toward qualification for the Iranian Board of Psychiatry under supervision of Prof. Shahin Akhondzadeh. This study was supported by a grant from Tehran University of Medical Sciences to Prof. Shahin Akhondzadeh (Grant No. 16005). The trial was registered in Iranian registry of clinical trials (www.irct.ir): IRCT201202201556N33.
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