Introduction
Schizophrenia affects approximately 0.5-1% of the global population, with a prevalence increased from 14.2 million cases in 1990 to 23.6 million in 2019, highlighting its growing public health concern. While positive symptoms (hallucinations, delusions) generally respond to antipsychotic medications, negative symptoms (blunted affect, anhedonia, alogia, asociality, avolition) remain largely treatment-resistant despite their profound impact on functional outcomes and quality of life. Evidence indicates that approximately 30-40% of patients experience persistent negative symptoms despite appropriate pharmacological treatment.
Neurobiological research has consistently demonstrated functional abnormalities in the dorsolateral prefrontal cortex (DLPFC) in schizophrenia patients. The phenomenon of hypofrontality (reduced activity in the frontal brain regions) correlates significantly with negative symptom severity, with greater activity reduction associated with more severe symptoms. Given the key role of DLPFC in negative symptom pathophysiology, non-invasive brain stimulation techniques have emerged as potential therapeutic approaches. One of these methods is transcranial direct current stimulation (tDCS), which uses weak electrical current to modulate cortical excitability and may address the interhemispheric imbalance and hypofrontality observed in schizophrenia. 
While international evidence shows tDCS efficacy for negative symptoms, research in Iranian populations remains limited. This study aimed to investigate the effects of tDCS on positive, negative, and depressive symptoms in schizophrenia patients with predominant negative symptoms. We hypothesized that anodal stimulation of the left DLPFC and cathodal stimulation of the right orbitofrontal cortex significantly improve negative symptoms compared to sham tDCS, with effects persisting for one month.

Method
This double-blind, sham-controlled randomized clinical trial was conducted on 40 patients aged 18-65 years diagnosed with schizophrenia having predominant negative symptoms. Sample size was calculated using G*Power software, version 3.1.9.7 and based on previous studies, considering an effect size of 0.9, test power of 0.80, and significance level of 0.05. Accounting for a potential 10% dropout rate, the final sample size was determined to be 40 (20 per group). Participants were recruited via convenience sampling from among inpatients and outpatients of Shahid Beheshti Hospital in Zanjan, Iran.
Inclusion criteria were age 18-65 years, diagnosis of schizophrenia with predominant negative symptoms according to the DSM-5 criteria, and stable antipsychotic medication uptake for at least four months. Exclusion criteria were substance dependence, comorbid psychiatric disorders, neurological diseases, pregnancy, severe physical illnesses, having implants, and scalp skin diseases.
The patients were randomly assigned to either active tDCS (n=20) or sham tDCS (n=20) using the block randomization method. The intervention consisted of 15 daily sessions of tDCS. In the active group, the anode was placed over the left DLPFC (F3) and the cathode over the right orbitofrontal region (Fp2) and a 2mA current was applied for 20 minutes. In the sham group, electrode placement was identical, but the device automatically turned off after 30 seconds. Assessments were done using the positive and negative syndrome scale (PANSS), scale for the assessment of negative symptoms (SANS), and Calgary depression scale (CDSS) at baseline, post-intervention, and one-month follow-up by a blinded clinical psychologist.

Results 
There was an equal gender distribution in both groups (50% male, 50% female). The mean age in the active tDCS group was 40.40±8.00 years and in the sham group 44.70±8.42 years. Statistical tests showed no significant differences between groups in demographic variables (P>0.05), indicating homogeneous groups at baseline. Independent t-tests confirmed no significant differences between groups in pretest scores for positive symptoms (t=0.05, P=0.962), negative symptoms (t=-0.41, P=0.683), and depression (t=1.73, P=0.92), demonstrating balanced symptom severity at baseline.
Repeated measures ANOVA showed significant changes in dependent variables across the three time points in both groups (P<0.05). However, the effect size was substantially larger in the active tDCS group compared to the sham group. In the active tDCS group, 78.5% of the variance in positive symptoms (F=69.40, P<0.001, η²=0.785), 68.1% of the variance in negative symptoms (F=40.59, P<0.001, η²=0.681), and 33.6% of the variance in depression (F=9.62, P<0.001, η²=0.336) was explained by the intervention (Table 1).


ANCOVA results showed that after controlling for baseline scores, the active tDCS group demonstrated significant reductions in positive symptoms (F=6.59, P=0.004, η²=0.207) and negative symptoms (F=5.22, P=0.028, η²=0.124) in the post-test phase compared to the sham group (Table 2). These therapeutic effects persisted for one month only on positive and negative symptoms.



Conclusions 
This study demonstrated that tDCS significantly improved negative and positive symptoms and depression in patients with schizophrenia, with therapeutic effects persisting for one month only on negative and positive symptoms. Despite promising findings, limitations of this study included a relatively small sample size, short follow-up period, and lack of assessment of cognitive function and quality of life. In conclusion, tDCS is an effective, safe, and non-invasive method for improving negative and positive symptoms in schizophrenia, suggesting its potential as an adjunctive treatment along with antipsychotic medications.

Ethical Considerations

Compliance with ethical guidelines
The study received approval from the Ethics Committee of Zanjan University of Medical Sciences (Code: IR.ZUMS.REC.1398.102) and was registered by the Iranian Registry of Clinical Trials (ID: IRCT20200203046366N1).

Funding
This study was funded by Zanjan University of Medical Sciences, Zanjan, Iran. 

Authors contributions
Conceptualization, Paria Jalili Khiavi, Mina Shabani, Omid Saed; Methodology, Omid Saed; Formal Analysis, Amirhossein Rasouli; Investigation, Fatemeh Ghaffari; Writing – Original Draft Preparation, Paria Jalili Khiavi, Amirhossein Rasouli; Writing – Review & Editing, all author; Supervision, Mina Shabani, Omid Saed; Validation, All Authors.

Conflicts of interest
The authors declared no conflict of interest.

Acknowledgments
"We would like to thank all participants for their participation in this research.