Treatment‑resistant depression ladder

Depression treatment usually starts with talk therapy, medicine, or both. When symptoms do not improve after full trials, psychiatrists use a step-by-step ladder instead of jumping straight to ketamine or brain stimulation. (nice.org.uk) (va.gov) That ladder starts with a basic check: was the antidepressant taken at an adequate dose, for an adequate length of time, and often enough to judge whether it worked. The U.S. Department of Veterans Affairs defines treatment-resistant depression as a major depressive episode that does not remit after at least 2 proven treatments of adequate dose and duration. (va.gov) Psychotherapy stays in the picture at every stage, not just the first one. The National Institute for Health and Care Excellence says its adult depression guideline covers first episodes, further-line treatment, relapse prevention, and treatment-resistant depression, including cognitive behavioral therapy and other structured therapies. (nice.org.uk) The next steps usually mean changing the drug plan before moving to more intensive procedures. In practice, that can mean switching antidepressants, adding an augmenting drug such as quetiapine, or using older classes such as tricyclic antidepressants when newer selective serotonin reuptake inhibitors or serotonin-norepinephrine reuptake inhibitors have not worked. (nejm.org) (nice.org.uk) Ketamine and esketamine sit higher on that ladder, not at the bottom. NICE’s technology appraisal on esketamine is specific to adults with treatment-resistant depression, and the Veterans Affairs clinical material says clinicians should consider ketamine or esketamine after several past treatment options have failed. (nice.org.uk) (va.gov 1) (va.gov 2) The evidence for esketamine is stronger than a social-media sketch can show. In a 2023 New England Journal of Medicine trial, 336 patients were assigned to esketamine plus a selective serotonin reuptake inhibitor or serotonin-norepinephrine reuptake inhibitor and 340 to quetiapine augmentation; remission at week 8 was 27.1% with esketamine and 17.6% with quetiapine. (nejm.org) Brain stimulation is higher still on the ladder. The Veterans Affairs guide says electroconvulsive therapy should be considered for patients who cannot tolerate or have not responded to several antidepressant trials, and says repetitive transcranial magnetic stimulation can be offered during a major depressive episode in treatment-resistant depression. (va.gov) The American Psychiatric Association’s July 2024 position statement calls transcranial magnetic stimulation a safe and effective evidence-based medical treatment for appropriately selected patients when delivered by TMS-trained psychiatrists. The same document says insurance limits still block access for some patients. (psychiatry.org) The point of the ladder is sequencing, not delay for its own sake. Before calling depression “resistant,” clinicians are being pushed to confirm the earlier steps were real treatment trials, then combine the next medication step with psychotherapy and move upward only as needed. (nice.org.uk) (va.gov)