Background: Many patients with SCZ discontinue antipsychotics, frequently due to dose related multiple and severe adverse effects. This clinical trial was designed to investigate the efficacy, safety, and tolerability of adding sertraline to ziprasidone in order to substantially reduce its dose and potential side effects in first-episode and drug-naive (FEDN) patients with SCZ. Methods: This 24-week randomized, double-blinded controlled clinical trial randomly allocated 452 FEDN SCZ patients to receive a usual dose of ziprasidone (control group) or half the dose of ziprasidone in combination with sertraline (ZS group). Treatment outcome included the Positive and Negative Syndrome Scale (PANSS), the Hamilton Depression Rating Scale (HAMD), CGI-Severity (CGI-S) and the Personal and Social Performance Scale (PSP) at baseline and weeks 2, 4, 8, 12 and 24. Findings: Repeated measures ANCOVA showed significant treatment by time interactions on the PANSS negative symptom, general psychopathology and total scores, as well as CGI-S, HAMD and PSP scores (all p<0.05). Furthermore, the ZS group had greater reductions in PANSS negative symptoms, general psychopathology and total scores (all p<0.05) and greater increases in the PSP total score (p<0.01) than the control group. Importantly, adverse effects were lower in the ZS than control group. The reduction in PANSS, CGI-S or HAMD scores was not correlated with the increase in PSP. Sex and duration of disease predicted PSP improvement from baseline to week 24 in the ZS group. Interpretation: Our FEND patients with SCZ were effectively treated for their psychotic and depressive symptoms while experiencing significantly fewer adverse effects using half the usual ziprasidone dose when combined with sertraline. The implications for long term improved retention and compliance with treatment using this combination therapy are substantial for introducing them to life saving chronic care that will be optimally effective and minimally aversive due to antipsychotic side effects including cardiac problems. Trial Registration: The clinical trial was registered with ClinicalTrials.gov (ClinicalTrials.gov Identifier NCT04076371). Funding: Funding for this study was provided by the CAS Pioneer Hundred Talents Program. Declaration of Interest: None to declare. Ethical Approval: The study protocol was approved by the Institutional Review Board of First Hospital of Shanxi Medical University