Demographic, Pharmaceutical & Genetic Factors Influencing Treatment Outcomes of Antidepressants

Abstract

Depression is a mood disorder that influences Quality of life (QoL), productivity and at its worst, it may lead to suicide. It is believed to be the leading cause of disability by 2030 that has been a concern for an individual and societal health. South Asia is considered among the most depressed regions and Pakistan is one of the countries having highest depression rate (6-34%) due to high vulnerability to many risk factors that may influence onset and treatment of depression. In spite of availability of many antidepressants, including new molecules with claimed less side-effects and high outcomes, very small percentage of patients (33-49%) achieve remission. Research revealed that there are many potential factors that can influence treatment outcomes; therefore, more personalized therapy in context to patient risk factors, is required rather than to adopt one size fits all formula. No national clinical practice guidelines available for Pakistan. International treatment guidelines exist and being updated but that have been drawn as a result of trials conducted in west, which has its own demographic, pharmaceutical and genetic background and these guidelines may not be equally effective for Pakistani population. Main aim of the study was related to the identification of different factors that may influence treatment outcomes of depression, as a very scarce data is published from Pakistan. Therefore, patients form Khyber Pakhtunkhwa (KPK) area of Pakistan, who reported to a tertiary care facility of provincial capital, was randomly included in the study. Because of the same ethnicity, these patients were expected to be having less diverse sociodemographic and genetic background compared to other regions of the country. For this longitudinal, prospective study, structured validated questionnaires have been used at different points of time to find out adherence, treatment outcomes and quality of life. In total, 348 patients were enrolled in the study; however, 274 patients meet the study criteria and were included in the final analysis of the study. Among these 274 patients, include 155 patients who were already on treatment (AOT) while 119 patients were treatment naïve at the time of enrollment. Based on the literature review and previous study of the lab, five single genetic Single nucleotide polymorphisms (SNPs); 5HTTLPR (SLC6A4) rs2234693 (ESR1), rs9340799 (ESR1), rs6265 (BDNF) and rs12936511 (CRHR1) were selected to study their role in treatment outcome. viii It was revealed on analysis that adherence decreased with time and AOT patients showed almost double adherence compared to those who were naïve for treatment at the time of enrollment (OR = 2.013; 95% CI = 1.218-3.6293). Further people living in rural areas showed significantly high adherence compared to those residing in urban areas (OR = 1.976; 95% CI = 1.146-3.407). Response among treatment naïve patients did not showed consistent trend of response. However, trends among all groups were similar in pattern. Female patients showed significantly better treatment response compared to males (OR = 2.014; 95% CI = 1.145-3.543). Patients addicted to tobacco (Naswar/sniffing, Cigarette), alcohol or any other drug substance were at 2.3 times more risk of non-responsiveness, compared to non-addicted patients. Over-all average response was 55% at 3 months from the day of enrollment which rose to 76% after 6 months. Statistically significant difference in response was observed between 3 months and 6 months among SSRIs (p=0.000), TCAs (p=0.005), SSRI+TCAs and other ADDs (p=0.008). Unmarried were at 3.21 times more risk of no-remission, compared to marrieds (OR = 3.205; 95% CI = 1.089-9.434). Patients on single antidepressant drug (ADD) were at high risk (2.19 times) of no-remission compared to those who took combination ADD therapy (OR = 2.190; 95% CI = 1.038-4.621). Although high response rate was observed in this study, remission after 90 days of treatment with antidepressants was shown by only 7% of total patients that rise to 14% after 6 months. Significant improvement was observed in Quality of life (QoL) with all treatment regimens (p=<0.001). Genetic polymorphisms analyzed in this study didn’t reveal any significant association with response or remission; however, for ESR1, rs9340799; A>G polymorphism there observed trends of remission for ‘A’ allele and non-remission for ‘G’ allele in the additive model. Similarly, 5-HTT, SLC6A4 Promotor polymorphism, a trend of good response was observed for “L” allele. The hypothesis was that demographic, pharmaceutical and genetic factors may affect treatment outcomes of ADDs. Result showed, some demographic factors like gender, job status, financial dependency, education level, marital status and pharmaceutical factors such as duration of treatment and combination of ADDs showed influence on treatment outcomes. Patient believes & perceptions have significant association while Genetic factors such as ESR1 & 5-HTT polymorphisms are potential factors influencing treatment outcomes of antidepressant drugs.