While we have considerable data supporting the antidepressant effects of intravenous ketamine, considerably less is known about the long-term outcomes of repeated ketamine infusions in patients treated for depression. Specifically, how effective is ketamine for treatment-resistant depression? How long do the antidepressant effects of ketamine last? And what side effects may emerge over time?
In order to answer these important questions, Dr. Hitoshi Sakurai, PhD, MD, along with colleagues from the Depression Clinical and Research Program at MGH, conducted a retrospective chart review investigating outcomes of patients receiving intravenous ketamine treatment for depression.
Their analysis included 85 patients with treatment-resistant depression (TRD) who started intravenous ketamine therapy between October 2018 and November 2019 in Intravenous Ketamine Clinic for Depression at MGH. In this clinic, ketamine is offered to patients with severe and refractory major depressive disorder or bipolar depression who have failed at least two or more adequate antidepressant treatment trials. Because ketamine infusions are not covered by insurance, patients seen in the clinic must pay out of pocket for each infusion.
The initial ketamine dose was typically 0.5 mg/kg infused over 40 minutes. Intravenous ketamine was administered twice-weekly for three weeks in an induction phase, followed by maintenance treatment with a variable administration schedule and dose. Depending on response and tolerability, the dose was adjusted during the induction up to 1.2 mg/kg. Symptom severity was evaluated prospectively using the 16-item Quick Inventory of Depressive Symptomatology-Self Report scale (QIDS-SR16) at each visit prior to ketamine administration.
In this cohort, 40 (47.1%) of the 85 patients who initiated ketamine discontinued treatment during or immediately after completing the induction phase. The most common reasons for early discontinuation of treatment included insufficient improvement (n=23), transition to intranasal ketamine treatment (n=6), loss to follow-up (n=4), and side effects (n=3), including dissociative symptoms, agitation, and migraine.
In this group, 42 (49.4%) transitioned into maintenance treatment after completing the induction phase. Three patients (3.5%) were still in the induction phase at the time of this report. In the maintenance group, 14 (16.5%) ultimately discontinued ketamine treatment and 28 (32.9%) continued on maintenance treatment. The mean ketamine dosage during maintenance was 0.91 ± 0.28 mg/kg.
Response was defined as a ≥ 50% reduction in depressive symptoms as measured using the total QIDS-SR16 score compared to baseline. Fifteen out of 82 patients (18.3%) responded to induction treatment and 6 (7.3%) of the patients receiving maintenance treatment remained in responder status at the time of data analysis. Despite the apparent low response rate on the QIDS-SR16 score, more than one third of patients reported a reduction in suicidality.
Repeated administrations of intravenous ketamine were well tolerated without serious adverse events. Only 3 of 85 patients (3.5%) dropped out during the induction phase because of side effects. While 81 patients (93.1%) experienced transient dissociative symptoms and 31 (35.6%) experienced anxiety during the infusions, intravenous lorazepam (1 mg) helped to improve tolerability of the infusion.
The response rate in patients participating in this study appears to be lower than observed in randomized controlled trials (RCTs) of IV ketamine; however, it is important to note that the patients seen in this clinic have more severe or refractory illness than those typically participating in RCTs. Patients in the MGH sample had an average duration of the current depressive episode of 6.7 ± 11.1 years, 69.0% had at least one comorbid psychiatric disorder, and had at least 7.4 ± 3.7 failed antidepressant trials, which reflects a high level of treatment resistance in this population. In addition, because ketamine infusions are currently not covered by insurance, the high cost of repeated intravenous ketamine ($530/infusion at this clinic) is a major contributor to early discontinuation if the perceived benefit is not sufficient to justify continuing treatment. Nonetheless, almost 50% of these real-world patients with TRD elected to continue with this treatment because of perceived improvement of their depression and suicidal ideation.
Sakurai H, Jain F, Foster S, Pedrelli P, Mischoulon D, Fava M, Cusin C. Long-term outcome in outpatients with depression treated with acute and maintenance intravenous ketamine: A retrospective chart review. J Affect Disord. 2020 Nov 1; 276:660-666.
