Table 2.

Summary of retrospective studies, including case series and case reports on prolonging ketamine treatment

Study	No. of cases	Dose and duration	Description	Prolonged	TRD
Best et al. [2]	28	Frequency of treatment was dependent on patient responsiveness (10–30 sessions) CTK included pre-treatment with rTMS, ketamine 0.4–2.3 mg/kg IV until patient stiffened, and then TMS was administered	Chart review of patients with TRD who received combination therapy with TMS and ketamine (CTK) to determine the efficacy of the combined antidepressant therapies. A significant mean reduction in CGI severity following CTK treatment completion was observed (P ≤ 0.0001). This reduction was sustained for 2 years following treatment completion (P ≤ 0.0001). CTK allowed for greater TMS intensities than would otherwise be tolerated. CTK was well tolerated, with no treatment-limiting adverse outcomes throughout the study	Y	Y
Messer et al. [38]	2	Patient A: 6 doses of ketamine 0.5 mg/kg IV (on days 1, 3, 5, 7, 9, 11) Patient B: 2 doses of 0.5 mg/kg IV (on days 1, 7) and 4 saline infusions (on days 3, 5, 9, 11)	A 50-year-old man with a history of depression and concomitant suicidal ideation with comorbid sleep apnea and obesity was treated with 11 medication trials and seven right unilateral ECTs and reported no change in mood. He received six doses of ketamine intravenously every other day during a 12-day period. He achieved a sustained clinical response (BDI ≤ 18) on day 4 with only mild, transient adverse effects; his response lasted until day 39. Repeated treatments of ketamine every other day for 12 days produced sustained remission of his depressive symptoms A 45-year-old man with a history of treatment-resistant major depressive disorder with comorbid hypertension was treated with 9 medication trials and 105 ECT treatments, producing short-term and long-term memory loss, and an incomplete recovery from depression. He also received implantation of a vagal nerve stimulator 5 years prior. He received two doses of ketamine intravenously on days 1 and 7 within the 12-day period, and saline on days 3, 5, 9, and 11. His MMSE score was 30 at baseline. He achieved a sustained clinical response (BDI ≤ 18) on day 2 with only mild, transient adverse effects; his response lasted until day 24. Repeated treatments of ketamine twice produced sustained remission of his depressive symptoms	Y	Y
Messer et al. [39]	1	Three doses of ketamine 0.5 mg/kg IV every other day for 5 days, followed by 3 series of 6 doses of ketamine 0.5 mg/kg IV given over 16 weeks, followed by a maintenance dose of ketamine 0.5 mg/kg IV given every 3 weeks over 15 months	A 46-year-old woman with a history of treatment-resistant major depressive disorder was treated with 24 medication trials and 273 ECT treatments, producing short-term and long-term memory loss and an incomplete recovery from depression. All interventions have produced only short-lived remission. Her long-term use of ECT caused significant problems with memory loss and focused attention. She received ketamine 0.5 mg/kg IV which led to a dramatic improvement in her depressive symptoms (DBI 22 to 6). She then received three additional infusions every other day for 5 days. This produced a remission lasting for 17 days after the last infusion. Three series of six infusions were given on alternating business days over the following 16 weeks. These three series produced remissions lasting 16, 28, and 16 days, respectively. A maintenance dose of ketamine 0.5 mg/kg IV was then established at a 3-week inter-dose interval. She then remained in remission for > 15 months with only mild, transient adverse effects typical of ketamine	Y	Y
Szymkowicz et al. [40]	3	Up to 6 doses of ketamine 0.5 mg/kg IV with doses occurring every other day followed by an individualized maintenance dose of ketamine 0.5 mg/kg IV	Three cases of TRD with suicide ideation are reported in which repeated doses of ketamine IV were provided. The first patient had rapid and moderately sustained depression symptom relief 4 h post-infusion 1 (MADRS ≤ 8). The second patient only achieved MADRS scores of a moderate level of depression 4 h post-infusion 4. The third patient also only achieved MADRS scores of a moderate level of depression 4 h post-infusion 4; however, significant functional improvement was observed. The total number of ketamine treatments varied from 16, 34, and 32, respectively. Dissociative effects of worsened cognitive difficulties and insomnia post-ketamine treatment in patient 2; however, no other adverse effects were noted	Y	Y

TRD the study sample was treatment resistant to depression, rTMS repetitive transcranial magnetic stimulation, TMS transcranial magnetic stimulation, CGI the Clinical Global Impression Scale, Y yes (meets criteria for satisfaction), ECT electroconvulsive therapy, BDI Beck Depression Inventory, MMSE Mini-Mental State Examination, MADRS Montgomery–Asberg Depression Rating Scale

*Intravenously administered racemic ketamine was used unless otherwise specified