The association between etiology, symptoms, biochemical processes and responses to the treatment of MDD is still not sufficiently explained. The efficacy of antidepressants is not satisfactory in nearly 50% of patients. The effect of these drugs is weaker in patients with MDD who had elevated proinflammatory cytokine levels prior to the treatment. several studies have shown that periodontitis may be a factor in therapeutic resistance by increasing proinflammatory cytokine levels such as IL-1b and IL-6, that is by modifying SIPSS activity and reducing serotonin activity in the brain. The hypothesis of our study was that periodontal parameters are associated with a weaker effect of pharmacotherapy of MDD with SSRI after three and six months of treatment, independently of other clinical, vital and sociodemographic parameters. We performed a six-month long prospective cohort study at Psychiatric Hospital "Sveti Ivan". The main outcome was the change in the overall score of HAM-D17. The main independent variable was the condition of the periodont. In our studies, we partially confirmed the hypothesis that periodontitis was made weaker by the performance of VDP SIPPS pharmacotherapy after three and six months of treatment, independent of other clinical, vital, and sociodemographic parameters. After adjusting for all treatment effects, the overall results of HAM-D17 were measured, and the results were subjected to major depressive symptoms, dimensions of depression, and anxiety from the fourfactor model HAM-D17 was statistically safe with CAL. The adverse effect of CAL in the treatment of VDP starts at approximately 4.5 mm. This correlation was not mediated by the proinflammatory cytokines IL-6 and TNFα. This study contributes to a better understanding of the pathogenesis of VDP and periodontitis as a comorbidity associated with a weaker effect of VDP treatment. Periodontitis may have predictive significance in the treatment of VDP SIPPS.