1. Introduction
Antipsychotics or dopamine receptor antagonists are the major components of treatment for schizophrenia but about 10-20% of patients do not benefit from antidopaminergic agents, indicating that other neuronal systems may be involved in this disorder [2]. Dysregulation of both excitatory and inhibitory mechanisms N-Methyl-D-aspartic acid (NMDA) and γ-Amino butyric acid (GABA) are implicated in psychopathology of schizophrenia [4]. GABAergic neurons alter dopaminergic function by inhibiting presynaptic dopamine release, particularly in the mesolimbic system [5]. As gabaergic drugs act on the mesoprefrontocortical region and reduce dopaminergic activity, they may reduce both the positive and negative symptoms of schizophrenia [5, 6]. Pregabalin is the structural analog of GABA that binds to the alpha-2/delta subunit of voltage-dependent calcium channels and regulates the release of neurotransmitters such as glutamate, noradrenaline, and substance P in hyperactive neurons too [4, 10]. The role of pregabalin as an adjunctive substance in the treatment of psychotic symptoms in patients with schizophrenia has been evaluated in few studies [4, 5, 6, 11]. These trials are associated with contradictory results partly due to differences in the sample size, patients’ antipsychotic regimen, and severity of psychotic symptoms at baseline. This pilot clinical trial aims to investigate the efficacy and safety of adding pregabalin to standard antipsychotic treatment in patients with chronic schizophrenia for 6 weeks.
2. Materials and Methods 
In this randomized, double-blind, placebo-controlled clinical trial (Code: IRCT2015092711885N7), 48 male inpatients aged 18-65 years with chronic schizophrenia diagnosed based on the structured clinical interview and Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5) [12] in Sari, Mazandaran, Iran, who were under treatment with antipsychotics for at least two years and had clinically stable conditions in the past three months (no need for change in medication/dose of current antipsychotic agent). Patients who received anticholinergic medication (biperiden or trihexyphenidyl) for extrapyramidal symptoms and lorazepam for agitation or insomnia, as benzodiazepine prior to the trial were also included were at stable conditions for at least one month before and during the study. Exclusion criteria were existence of physical and neurological diseases or any other comorbid psychiatric disorders according to the DSM-5, mental retardation, electroconvulsive therapy in the past six months, history of substance use disorder (except for nicotine) as defined by DSM-5 and relapse within the past six months before screening or positive urine drug test prior to study, history of receiving pregabalin in the past six months, and sensitivity to pregabalin and its derivatives or placebo. The antipsychotic agents and their dosages were unchanged during the study. After obtaining informed consent from participants, they were divided into two groups of intervention and control randomly using a computerized random number generator, to receive either pregabalin or placebo. Patients in the intervention group received 75 mg of pregabalin (Sobhan Co, Iran) per day for three weeks and increased to 150 mg per day from the fourth week to the end of the study, in addition to standard antipsychotic medication for six weeks. Patients in the control group received placebo capsules similar to  pregabalin capsules in terms of shape, odor, color, size, and taste in addition to standard antipsychotic medication for six weeks. The severity of psychotic symptoms was assessed by the Positive and Negative Syndrome Scale (PANSS), and their movement disorder symptoms were evaluated by the Barnes Akathisia Rating Scale (BARS) [14] and Simpson-Angus Scale (SAS) [15]. These assessments were done at baseline and at 3th and 6th weeks of the intervention. Collected data were analyzed using repeated measures ANOVA in SPSS v.20 software, considering P<0.05 as the statistically significance level.
3. Results
 No significant differences were observed in demographic or clinical variables between both groups at baseline. There were no significant differences in the PANSS total score and its three subscales of positive scale, negative scale and general psychopathology at 3th and 6th weeks within and between two groups. Moreover, the difference between the two groups was not significant in the SAS and BARS scores at 3th and 6th weeks. 
4. Discussion 
Results of this study showed that the effectiveness of adding pregabalin (150 mg per day) to standard antipsychotic treatment in improving psychotic symptoms in patients with chronic schizophrenia was similar to that of placebo. The pregabalin use was associated with an incidence of side effects similar to placebo, most of which were mild. It seems that adding 150 mg pregabalin to antipsychotic medication is safe and well tolerated. The effectiveness of adding pregabalin to antipsychotic medications in patients with schizophrenia has been evaluated in few studies and different results have been achieved in this regard [1, 4, 11]. 
Results of the current study on psychotic symptoms are consistent with the results of Javahery et al. [6] and against the results of Schönfeldt-Lecuona et al. [5] and Englisch et al. [4]. This discrepancy can be due to differences in the type of study, pregabalin dose, sample size, patients’ antipsychotic regimen and severity of psychotic symptoms at baseline. Pregabalin caused no new psychotic symptoms or worsening of these symptoms during the study. Nevertheless, it may be possible that the study sample size was relatively small to determine the differences in amount of side effects. The limitations of the present study included the slow duration of pregabalin dose titration (which decreased the duration of receiving full dose of pregabalin by the patients), the short period of study, and no female patients. Further studies using larger sample sizes, longer duration, and different dosage in female patients with schizophrenia are recommended. Pregabalin cannot be used as an adjunctive treatment for psychotic symptoms in patients with schizophrenia. 

Ethical Considerations
Compliance with ethical guidelines
This study was approved by the Ethics Committee of Mazandaran University of Medical Sciences (Code: 95.1809.REC.MAZUMS.IR). Also, this article has been registered in the Clinical Trial Registration Center of Iran (Code: IRCT2015092711885N7). Written informed consent was obtained from eligible patients and their legally authorized guardian. Participants were informed that they were free to withdraw from the study at any time without any negative effect on their standard treatment process.

Funding
This study was postgraduate thesis of Elham Mahtian toward the Iranian Board of Psychiatry under supervision of. Samaneh Farnia and was supported by a grant from the research council of Mazandaran University of Medical Sciences to Samaneh Farnia [Grant No: 1809].

Authors contributions
Study design, interpretation of the obtained data, preparation of the initial draft of the article: Samaneh Farnia, Mehran Zarghami, Narjes Hindu; Supervision of research: Samaneh Farnia, Mehran Zarghami; Writing the initial proposal of the research project, collecting data, preparing the initial draft of the article: Elham Mahtian. Statistical analysis, interpretation of the obtained data: Parisa Eslami, Aida Emadian, Narjes Hindu; Review of the original draft article: All authors

Conflicts of interest
The authors declared no conflict of interest.


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