Depression is a debilitating psychiatric disorder. Electroconvulsive therapy (ECT) and ketamine are effective treatments for severe depression, but target populations may differ. Systematic reviews on the few available trials show higher remission rates with ECT than with ketamine. Nonetheless, ketamine’s rapid onset of action is comparable to ECT but with less cognitive adverse effects. This makes ketamine a valuable option, particularly in outpatients or when ECT is unavailable. ECT and ketamine differ in side effects: ECT induces transient cognitive impairments, while ketamine commonly causes dissociative symptoms. Clinical factors can guide choices for ECT versus ketamine. Older patients and those with psychotic symptoms tend to respond better to ECT, while younger patients with longer episode duration may benefit similarly from ketamine. Although biological variables and brain imaging results hold promise as biomarkers to predict treatment outcomes, implementation in everyday practice remains limited due to inconsistent findings and technical challenges. This review underscores the importance of personalized approaches to managing severe depression, advocating the integration of clinical predictors with patient-specific characteristics to improve treatment outcomes.