BEYOND THE ACUTE COURSE: EXPLORING THE DURABILITY OF KETAMINE'S ANTIDEPRESSANT EFFECTS IN THE MAINTENANCE PHASE OF TREATMENT

The acute antidepressant effects of ketamine for treatment resistant depression (TRD) have been well established with rapid reductions in depressive symptom severity observed within hours of a single ketamine infusion. Earlier studies evaluated a single infusion of ketamine and observed return of depressive symptoms within days to weeks of the single infusion. More recent studies employed an ‘acute course’ evaluating 4-8 doses over the course of 2-4 weeks. The acute course appeared to have greater antidepressant effects (compared to single dose studies), however, depressive symptoms were still observed to return within weeks of the last ketamine infusion. As such, the current standard of care for off label ketamine for depression typically employs a maintenance phase with ‘booster’ infusions administered every 2-8 weeks, with the frequency of booster infusions typically customized to individual patients based on the duration of benefits observed, which does appear to have significant variability between patients. A similar phenomenon is seen with nasal esketamine where an acute course consists of 8 doses over 4 weeks, with responders and remitters typically continuing on with maintenance treatments every 1-4 weeks for relapse-prevention. Indeed, phase 3 trials have demonstrated significant benefits for relapse prevention with continuing esketamine doses every 1-2 weeks compared to those stopping (ie randomized to placebo maintenance dosing) suggesting a role for maintenance treatment. Herein we will summarize the data on the durability of antidepressant effects of ketamine and esketamine, with a focus on maintenance ketamine and esketamine TRD studies. After providing an overview, we will present original data on TRD patients receiving maintenance ketamine infusions. We evaluated a cohort of 135 TRD patients (110 with major depressive disorder and 25 with bipolar depression), all of whom responded to an acute course of ketamine infusions and later received maintenance infusions. Linear mixed models found that depression and suicidality scores, as measured by the Quick Inventory of Depressive Symptomatology (QIDS-SR16) assessment, were significantly decreased after an acute course of ketamine infusions, with improvements persisting while patients continued to receive maintenance infusions over several months. Similar observations were seen after analyzing weekly patient-reported clinical global impression scores. Ketamine was determined to be relatively safe, with zero cases of suicidal behaviour and addiction behaviour throughout treatment. One patient diagnosed with bipolar I disorder underwent affective switching, with no further tolerability concerns following stabilization. These results provide preliminary support for the long-term clinical utility of maintenance ketamine infusions. Taken together, real world evidence supports the use of ketamine for relapseprevention in the maintenance phase of treatment. Additionally, clinical trial evidence support the use of esketamine in the maintenance phase, demonstrating superiority above those switched to placebo after an acute response.

References

Haikazian S, McIntyre RS, Meshkat S, Kratiuk K, Llach CD, Orsini DK, Di Luch SD, Rosenblat JD. Real world effectiveness of maintenance ketamine infusions for treatment-resistant depression in major depressive disorder and bipolar disorder. Psychiatry Res. 2025 Oct;352:116691. doi: 10.1016/j.psychres.2025.116691. Epub 2025 Aug