Evaluation of the efficacy and safety of pregabalin as an adjuvant to antipsychotics in patients with chronic schizophrenia: a six-week pilot double-blind placebo-controlled trial

Introduction and objectives: Antipsychotics or dopamine receptor antagonists are the major components of treatment but about 10-20% of patients with schizophrenia do not benefit from treatment with antidopaminergic agents, indicating 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 a GABA structural analog 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 (4-6, 11). These trials were associated with contradictory results partly due to differences in the sample size, patients' antipsychotic regimen and severity of psychotic symptoms at baseline. This pilot double blind, randomized clinical trial study was designed to investigate the efficacy and safety of pregabalin add on standard antipsychotic treatment in patients with chronic schizophrenia for 6 weeks. Methods: In a randomized, double-blind, placebo-controlled clinical trial, 48 inpatient male patients aged 18 to 65 years who fulfilled the chronic schizophrenia diagnosis, based on the structured clinical interview developed by the criteria from DSM-5(12), and had received antipsychotics for at least two years and were clinically stable on their current antipsychotic agent (no change in medication/dose of current antipsychotic agent) for a minimum of three months included in the study in Sari, Mazandaran, Iran. Exclusion criteria were existence of serious medical, neurological or any other comorbid psychiatric disorders in terms of DSM-5, electroconvulsive therapy in the last 6 months, history of substance use disorder (including alcohol, but exept nicotine) as defined by DSM-5 and relapse within the past six months before the screening visit or positive urine test for illicit drugs prior to entering the trial, history of treatment with pregabalin during the past six months, and hypersensitivity to pregabalin and its derivatives or placebo. Also, patients received anticholinergic medication (biperiden or trihexyphenidyl) for extrapyramidal symptoms and lorazepam for agitation or insomnia, as benzodiazepine of choice in study centers prior to entering the trial, were included if being stable (no change in medication/dose) for a minimum of one month before starting the study and during the study. The antipsychotic agents and their dosages were constant during the study. After giving informed consent, participants were placed in 4 blocks and randomized in a 1: 1 ratio by using a computerized random number generator, to receive either pregabalin or placebo. Patients in the intervention group received pregabalin (Sobhan Co, Tehran, Iran) with an initial dose of 75mg/d for the three weeks, if tolerated; it increased to 150 mg/d on the fourth week and continued until the end of the study along with their antipsychotic regimen for 6 weeks. Patients in the placebo group received the same identical capsules (with the same shape, color, and taste as pregabalin) along with their antipsychotic regimen for 6 weeks. The efficacy of treatment was assessed by PANSS. Extrapyramidal symptoms were evaluated by Barnes Akathisia Rating Scale (BARS) (14) and Simpson-Angus Scale (SAS) (15). Patients were assessed at baseline and weeks 3 and 6 after the medication started. Collected data were analyzed using ANOVA with repeated measures in SPSS software Version 20, and p values of less than 0.05 were considered as statistically significant. Results: No significant differences were observed in demographic or clinical variables between both groups at baseline. An insignificant difference was observed on the PANSS total, positive, negative and general psychopathology subscale scores at weeks 3 and 6 of study within and between two groups. Also, the difference between the two protocols was insignificant on the SAS and BARS scores at weeks 3 and 6 of study and frequency of other adverse effects between two groups (Table 1). Discussion: Results of this study showed that adding pregabalin 150 mg per day to standard antipsychotic treatment in patients with chronic schizophrenia had no greater benefit than placebo on the improvement of psychotic symptoms. The pregabalin therapy was associated with an incidence of adverse events similar to placebo, and most of these were of mild intensity. It appeared that 150 mg pregabalin add-on antipsychotic medication was safe and well tolerated. To the best of our knowledge, the effectiveness of pregabalin add-on antipsychotic medications in patients with schizophrenia has been evaluated in few studies and different results have been achieved in this regard (4-1, 11). Results of the current study on psychotic symptoms are in line with the results of the study by Javahery et al. (6) and in contrast with the studies by Schönfeldt-Lecuona et al. (5) and Englisch et al. (4). Possibly, this difference can be due to the differences in type of study, pregabalin dose, sample size, patients' antipsychotic regimen and severity of psychotic symptoms at baseline. Pregabalin was well tolerated and no new symptoms of psychosis or worsening of psychotic symptoms occurred during the study (7,8,14,22,23). Nevertheless, it may be possible that the study was relatively small to determine differences in side-effect rates. The limitations of the present study  were the long rate of pregabalin titration, which decreased the duration of receiving full dose of pregabalin by the patients, the short period of study and male patients. Further studies with larger sample sizes, longer durations, different dosage in patients with schizophrenia of both sexes is necessary. Conclusion: Our findings do not support a clinical role for pregabalin as an adjunctive treatment for psychotic symptoms in patients with schizophrenia.