Severe mental illness is usually marked by periods of remission, when symptoms are absent or well controlled, and of exacerbation, when symptoms return or worsen. Relapse of these severe illnesses costs a lot for patients and their families and imposes a financial burden on hospital and community services. Costs for relapse cases were four times higher than that of non-relapse cases. There is a dearth of evidence in on relapse rate on these vulnerable population in Sub-Saharan Africa, therefore this study assessed relapse rate and predictors among people with severe mental illnesses at Debre Markos Comprehensive specialized hospital, Northwest Ethiopia. Prospective follow up study design was employed among 315 people with severe mental illnesses who were selected by systematic random sampling technique. Epi.data version 4.2 was used for data entry and exported to STATA 14 for analysis. The Kaplan-Meier curve was used to estimate the median duration of occurrence and the Log rank test was used to compare survival curves between different categories of explanatory variables. A survival analysis was used to estimate the cumulative rate of relapse, Cox proportional hazards models was used to examine independent factors associated with time to develop relapse. To estimate the association between predictors and relapse, hazard ratio with 95% confidence intervals was used. Variables score p value < 0.25 with in the Bivariable analysis was entered in to the multivariable analysis model. The statistical significance was accepted at p-value < 0.05. Around 119 (37.78%) had develop relapse, and the remaining 196 (62.22%) were censored. The overall incidence rate of relapse was 3.66 per 100 person-month (95% CI:3.06-4.38) with a total of 3250 patient-month observations. Variables such as: age (18-36 years) [(AHR) = 3.42:95% (CI) :1.67,6.97)], marital status (single and widowed) 1.87 [AHR: 1.87; 95% CI: (1.06 ,3.27)] and 2.14 [AHR: 2.14; 95% CI: (1.03 ,4.44)], duration of delay in getting treatment ( > = 1 year) [(AHR = 2.55:CI:1.20, 5.38)], types of diagnosis (Major Depressive Disorder) (AHR = 2.38, CI:1.37 ,4.14), medication adherence (low adherence) (AHR = 5.252.45, 11.21) were statistically significant (P value < 0.05). Nearly two-fifth of people diagnosis with severe mental illnesses had develop relapse and the median survival time to develop relapse was nine months. It is advised that early detection of severe mental illness and early initiation of treatments are very crucial to prevent relapse. Psycho education, counseling that alleviates poor treatment adherence are highly recommended.

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