Ketamine or Esketamine in Special Populations of Patients With Treatment-Resistant Depression

Conventional antidepressant drugs are effective in only approximately 50% of patients with treatment-resistant depression (TRD). Ketamine, a non-competitive N-methyl-D-aspartate receptor antagonist, offers a promising alternative with an exceptionally rapid antidepressant effect. Although its efficacy in the general TRD population is well established, its use in specific patient subpopulations warrants further investigation. We conducted a comprehensive, non-systematic review of preclinical and clinical evidence regarding ketamine and esketamine in patients with TRD and various comorbidities. We also discuss the pharmacodynamics, pharmacokinetics, and neurobiological mechanisms underlying ketamine's antidepressant effects. Both ketamine and esketamine demonstrated efficacy in multiple TRD subpopulations, including geriatric, psychiatric, neurologic, oncologic, pediatric, and obstetric patients. Key challenges include management of psychotomimetic effects, potential for substance abuse, and cardiovascular adverse effects. Preliminary data concerning arketamine (R-ketamine) suggest potential advantages, such as longer-lasting antidepressant effects with fewer psychomotor adverse effects and lower abuse potential, opening avenues for future research. In conclusion, esketamine and ketamine show promise as effective and relatively safe treatments for selected sensitive subgroups of patients with TRD, provided that appropriate monitoring is implemented. Although preliminary results in patients with multiple comorbidities are encouraging, these findings are often derived from very small samples, underscoring the urgent need for larger, well-designed clinical trials to establish definitive efficacy and safety profiles across diverse populations. Further arketamine-focused research remains essential to fully define its therapeutic potential.