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Abstract

Background:

Ketamine, an N-methyl-D-aspartate antagonist, has been used for decades as an anesthetic agent, but more recently it has been studied in psychiatric illness. Though ketamine has been investigated for use in the general population, fewer studies have investigated the efficacy and tolerability of this treatment for older (age >60) adults.

Objectives:

This review sought to compile the randomized controlled trials (RCTs) investigating the evidence for ketamine treatment in older adults with psychiatric disorders.

Eligibility criteria:

Only RCTs published in English language journals, or with official English language translations, and human studies were included.

Sources of evidence:

Our team searched PubMed, Cochrane Database, and Ovid with the terms ketamine, depression, suicidal ideation, bipolar disorder, mania, anxiety, schizophrenia, psychotic disorders, dementia, delirium, and post-traumatic stress disorder.

Charting methods:

Covidence was used to extract and organize included studies.

Results:

Our review yielded 14 RCTs and 2 post-hoc analyses evaluating ketamine treatment in older patients. Eight of these studies examined ketamine for the treatment of delirium, while the remaining eight examined its use in depression. The studies had significant heterogeneity so direct comparisons of the results were challenging. However, five studies showed no significant impact of ketamine on delirium incidence. Two studies showed a lower incidence of delirium in the ketamine group, but another study showed a higher incidence of delirium with ketamine. Four studies showed improvement in depressive symptoms with ketamine treatment, while the others showed a lack of improvement. Most reported side effects were mild.

Conclusion:

Several studies have investigated ketamine for depression and delirium in older adults and show mixed results. This review reveals the paucity of current data on ketamine for other psychiatric conditions in older adults. It reaffirms that use of ketamine in older adults with psychiatric illness, including depression and delirium, remains an individual risk versus benefit analysis using shared decision making.

Plain language summary

Impact of ketamine treatment on mental illness in older adults

Introduction: Ketamine has been used for decades as anesthesia during surgeries and to treat pain. However, more recently scientists have been studying whether ketamine can be helpful for mental illness. How the study was done: Our team searched through medical databases to find studies that focused on ketamine and mental health issues like depression, suicidal thoughts, bipolar disorder, anxiety, schizophrenia, and post traumatic stress disorder (PTSD). What was found: We identified 16 studies that tested ketamine in older adults. Of these, 8 looked at how ketamine worked for treating delirium, and the other 8 studied its effects on depression. The results were mixed: For delirium, 5 studies found that ketamine did not decrease or increase the chance of developing delirium. Two studies showed fewer cases of delirium with ketamine, but one study showed more delirium with ketamine. For depression, 4 studies showed that ketamine helped improve depressive symptoms, but the other studies showed that ketamine did not help depression. The reported side effects from ketamine were usually mild and most often included disorientation, nausea, or vomiting. What it means: While ketamine has been tested for use in treating depression and delirium in older adults, the results are unclear, and more research is needed. This review shows that there is not enough information to say whether ketamine is a good treatment for older adults with mental health conditions. The risks and benefits of using ketamine need to be weighed for each individual who is considering using it.

Keywords

geriatric psychiatry ketamine

Introduction

Psychiatric illness, including depression, anxiety, psychosis, and post-traumatic stress disorder (PTSD), are common among older adults. According to the World Health Organization, approximately 14% of people over age 60 live with a psychiatric disorder, and this is likely an underestimate considering the under-recognition and undertreatment of mental illness in this population.¹ Additionally, delirium is highly prevalent in older adults and accounts for the greatest number of surgical complications in this age group.² Overall, mental health conditions in older adults confer high rates of morbidity and mortality. Data from the Global Health Estimates 2019 suggest that these conditions contribute to 10.6% of the total disability (in disability adjusted life years) in older adults, and around a quarter (27.2%) of all global suicide deaths are among people over age 60.¹ Moreover, older adults have been particularly vulnerable to psychosocial stress caused by the COVID-19 pandemic and lockdown, leading to decline in quality of life and negative mental health consequences.³

Despite these outcomes, older adults remain underrepresented in clinical trials across medical specialties.⁴ Consequently, we need additional research on our current psychiatric interventions in the geriatric population in order to ensure efficacious and safe treatment guidelines. Additionally, we need to identify treatments that are tolerable to older adults to ensure treatment adherence, especially considering that medication non-adherence may increase with age, and, in major depressive disorder (MDD), treatment side effects are the strongest predictor of non-adherence.^5,6

Ketamine, a non-competitive N-Methyl-D-Aspartate (NMDA) receptor antagonist, was first approved by the U.S. Food and Drug Administration (FDA) in 1970 as a general anesthetic.⁷ Ketamine is also used as an analgesic to treat chronic pain, postoperative pain,⁸ and acute trauma.⁹ Perioperative use of ketamine has also shown promising results in preventing postoperative delirium.¹⁰

Over the past two decades, ketamine has been gaining recognition for its off-label use to treat depression and suicidality.^11,12 Multiple routes of ketamine administration have been studied, including intravenous (IV), intramuscular, and intranasal administration.¹² Esketamine nasal spray was first approved by the FDA in March 2019 to be used in conjunction with an oral antidepressant for adults with treatment-resistant depression (TRD).¹³ In August 2020, it gained its second FDA approval to treat “depressive symptoms in adults with MDD with acute suicidal ideation or behavior.”¹³

The exact mechanism of ketamine’s antidepressant effects is unknown. One of the proposed mechanisms is that ketamine blocks the activation of GABA interneurons, leading to an increase in presynaptic glutamate release in the medial prefrontal cortex.^14,15 Another proposed mechanism is that ketamine enhances synaptic activity within the hippocampus by blocking NMDA receptors on excitatory neurons in the hippocampus.¹⁵

Since ketamine has shown effectiveness for a variety of psychiatric conditions, we sought to compile the current evidence for the use of ketamine in treating older adults with psychiatric illness.

Methods

J.G., K.M., and H.S. searched PubMed, Ovid (Medline (1946–August 19, 2024], Embase (1974–August 19, 2024), and APA PsychInfo (1806–August Week 3, 2024)) and Cochrane collaboration on August 19, 2024. “Ketamine,” “bipolar disorder,” “schizophrenia,” “depression,” “anxiety,” “dementia,” “psychotic disorders,” “mania,” “suicidal ideation,” “post-traumatic stress disorders,” and “delirium.” were used as keywords. A total of 2994 abstracts were obtained for initial review (PubMed (Ketamine AND bipolar disorder, schizophrenia, depression, anxiety, dementia, psychotic disorders, mania, suicidal ideation, post-traumatic stress disorders, OR delirium = 640); Ovid (Ketamine AND bipolar disorder, schizophrenia, depression, anxiety, dementia, psychotic disorders, mania, suicidal ideation, post-traumatic stress disorders, OR delirium = 1822) and Cochrane (Ketamine AND bipolar disorder, schizophrenia, depression, anxiety, dementia, psychotic disorders, mania, suicidal ideation, post-traumatic stress disorders, OR delirium = 532)). J.G., K.M., and H.S. reviewed all abstracts to remove 1108 abstracts and select 440 studies for full-text review. After a full-text review, 16 articles were included in this analysis. We included all articles that evaluated the use of ketamine for the treatment of the above-mentioned psychiatric conditions in older adults. Articles were excluded if there were no stratified results for participants older than 60 years, articles were not treatment studies, studies were not randomized control trials (RCT), or there was no English language text or official translation. All disagreements regarding which reports to include were resolved with consensus discussion with K.M. and R.T. Covidence was used to screen articles for inclusion.¹⁶ Figure 1 describes the flow diagram for the identification of studies from the literature. Since this was a scoping review, a protocol was not prepared or registered. The PRISMA checklist was followed.¹⁷ The JADAD scale was independently used by K.M. and J.G. to assess study quality and risk of bias.¹⁸

Figure 1.

PRISMA diagram.

Results

A search of PubMed, Cochrane, and OVID yielded 14 RCTs and two post-hoc analyses of RCTs evaluating the use of ketamine for the treatment of psychiatric illness in older adults.

Delirium

A total of eight studies were found that evaluated the use of ketamine for the treatment of delirium in older adults. Table 1 summarizes the characteristics and results of these studies.

Table 1.

Study characteristics and results for the use of ketamine for the treatment of delirium.

Study	Study design	Intervention/dose	No. of participants	Population	Treatment duration	Follow up	Outcome measure/results	Adverse events
Hollinger et al. (2021)¹⁹	RCT	Four arms: 1 mg/kg of ketamine OR 5 μg/kg haloperidol OR a combination of both ketamine and haloperidol using the same dosing OR placebo	182	⩾65 undergoing surgery	One-time preoperative dose	Pre-op and POD 1–3	MMSE, DOS, Nu-DESC, ICDSC (all p values >0.1)	None reported
Hosseindoost et al. (2023)²⁰	RCT, open label	Two arms: one-time dose of 20 mg IV ketamine OR 2.5 mg of IM haloperidol	44	⩾65 non-intubated patients in the ICU	One-time dose	15 min for outcome measures, 60 min for adverse events	RASS (p = 0.168)	No significant difference in adverse events between groups
Lu et al. (2024)²¹	RCT	Two arms: 0.5 mg/kg IV esketamine OR 0.7 μg/kg IV dexmedetomidine (followed by 0.2–0.5 μg/kg/h for maintenance)	94	⩾60 and ⩽85 undergoing thoracic surgery	One time dose given over 20 min	14 days for mood/sleep scales, 5 days for MMSE, time of post-op delirium assessment not specified	MMSE (p value non-significant), RSS (p value non-significant), CAM scores not reported, but delirium incidence reported as lower in the esketamine group (p < 0.05)	GI upset (n = 2), respiratory depression (n = 1), and dizziness (n = 1)
Siripoonyothai (2021)²²	RCT	Two arms: 1 mg/kg/h IV ketamine OR IV propofol	64	⩾65 undergoing cardiopulmonary bypass	Duration of procedure	24 h post op	Thai version of CAM-ICU (p = 0.04 favoring lower incidence of delirium with ketamine, but p value not significant after multivariate analysis)	No nightmares or hallucinations were detected; no other events recorded
Avidan et al. (2017)²³	RCT	Three arms: 0.5 mg/kg IV ketamine OR 1 mg/kg IV ketamine or normal saline placebo	672	⩾60 undergoing surgery	Immediately after anesthesia induction	POD1 to POD 3	CAM, CAM-ICU, CAM-S (p = 0.92)	Hallucinations and nightmares increased with higher ketamine doses; no differences in major adverse events, including cardiovascular events
Ghazaly et al. (2023)²⁴	RCT	Three arms: 1 mg/kg IV ketamine OR 1 µg/kg IV dexmedetomidine OR 0.9% normal saline	60	⩾60 undergoing emergency surgery	Immediately prior to anesthesia induction	POD3	Scale not specified, delirium incidence reported as higher in the ketamine group (p < 0.013)	No mention of adverse events
Liu et al. (2024)²⁵	RCT	Two arms: 1 mg/kg IV esketamine plus sufentanil 1.5 µ g/kg OR sufentanil 2 µg/kg alone	60	⩾65 undergoing laparoscopic gastrointestinal surgery	Postoperative period	POD1, POD3	CAM (p < 0.05 favoring a lower incidence of delirium with ketamine)	Postoperative nausea and vomiting but no significant group differences
Ma et al. (2023)²⁶	RCT	Two arms: 0.25 mg/kg IV esketamine for induction, then 0.125 mg/kg/h IV for maintenance OR normal saline	62	⩾65 undergoing abdominal surgery for gastrointestinal tumors	Anesthesia induction and maintenance	POD1–POD3	CAM-ICU (p > 0.05)	Lower rates of hypotension and tachycardia in esketamine group

CAM, confusion assessment method; DOS, delirium observation screening; ICDSC, Intensive Care Delirium Screening Checklist; ICU, intensive care unit; IM, intramuscular; IV, intravenous; MMSE, mini mental status exam; Nu-DESC, Nursing Delirium Screening Scale; POD, postoperative day; RASS, Richmond Agitation Sedation Scale; RCT, randomized controlled trial.

Hollinger et al.¹⁹ performed a multicenter, double-blind, placebo-controlled clinical trial examining the efficacy of preoperative ketamine administration in the prevention of postoperative cognitive dysfunction and delirium. The trial included 182 participants (age ⩾65, mean (standard deviation) age = 73.7 (6.1) years) scheduled for visceral, orthopedic, gynecological, cardiac, or thoracic surgery. Participants were assigned to one of four study arms where they received a one-time dose of either: 1 mg/kg body weight of ketamine, 5 μg/kg body weight of haloperidol, a combination of both ketamine and haloperidol using the same dosing, or placebo immediately preceding the induction of anesthesia. Participants were then followed for 3 days beginning on postoperative day 1. Cognitive function was assessed pre- and postoperatively using the Mini Mental State Examination (MMSE), the Delirium Observation Screening Scale, and the Nursing Delirium Screening Scale (Nu-DESC) or the Intensive Care Delirium Screening Checklist. Scores on all of these scales did not show significant differences between any of the groups (p > 0.1 for all scales and time periods) in the preoperative period or postoperative day 1–3. No reports of adverse events were mentioned.¹⁹

Hosseindoost et al.²⁰ conducted an open-label RCT assessing the efficacy of ketamine in preventing delirium. The trial included 44 non-intubated participants (age ⩾65, mean 69.2 years in the ketamine group and 70.2 years in the haloperidol group) in a general intensive care unit. Baseline Richmond Agitation Sedation Scale (RASS) scores were ⩾+2 in order to meet the inclusion criteria. Participants were randomly assigned to receive a one-time dose of either 20 mg of IV ketamine or 2.5 mg of intramuscular haloperidol. The primary outcome was RASS scores, obtained at 5, 10, and 15 min posttreatment. Adverse events and physician satisfaction with the control of agitation were assessed for 60 min following treatment. There was no significant difference in delirium score between the groups after treatment (p = 0.168). However, the ketamine group had significantly lower delirium incidence at 5 min (p = 0.002), but the difference was not statistically significant between groups at 10 and 15 min. No significant adverse effects were reported in either treatment arm, and there was no significant difference in physician satisfaction with agitation control after treatment.²⁰

Lu et al.²¹ published an RCT comparing the efficacy of esketamine and dexmedetomidine in the prevention of postoperative delirium and hyperalgesia. The trial included 94 participants (age ⩾60 and ⩽85; mean 69.25 years in the ketamine group and 70.05 years in the dexmedetomidine group) who underwent thoracic surgery. Participants were randomly assigned to either the esketamine group (0.5 mg/kg IV for 20 min) or the dexmedetomidine group (0.7 μg/kg IV for >10 min after anesthesia induction then 0.2–0.5 μg/kg/h for maintenance until the completion of the procedure). Cognitive function was assessed using the MMSE preoperatively, postoperative day 3, and postoperative day 5; there were no significant differences between groups at any of these time points. Anxiety, depression, and sleep quality were assessed using the Self-Rating Anxiety Scale (SAS), the Self-Rating Depression Scale (SDS), and Pittsburgh Sleep Quality Index (PSQI), respectively, preoperatively, postoperative day 5, and postoperative day 14. SAS and SDS scores were lower in the esketamine group on postoperative day 5 (p < 0.05) with no statistical differences between the groups by postoperative day 14. PSQI scores were lower in the dexmedetomidine group compared to the esketamine group at days 5 and 14 compared to preoperative scores (p < 0.05). Sedation was assessed using Ramsay Sedation Scale at 1, 6, 12, and 24 h postoperatively, but there were no significant differences between groups. The CAM was used to assess rates of delirium between groups. CAM scores were not reported, but the incidence of postoperative delirium was reported as significantly lower in the esketamine group compared to the dexmedetomidine group (4.26% (2/47) vs 19.15% (9/47), respectively, (p < 0.05)). Adverse events in the esketamine group included GI upset (2), respiratory depression (1), and dizziness (1).²¹

Siripoonyothai and Sindhvananda²² performed an RCT comparing the efficacy of ketamine to propofol in preventing postoperative delirium. Sixty-four participants aged 65 years and older who were undergoing cardiac surgery with cardiopulmonary bypass completed the study. After the induction of anesthesia was complete, participants were assigned to receive either IV ketamine at 1 mg/kg/h or IV propofol at 1.5–6 mg/kg/h during the procedure. The primary outcome was postoperative delirium identified using the Thai version of CAM-ICU, which was administered 8–24 h after being admitted to the ICU postoperatively. There were significantly lower rates of postoperative delirium in the ketamine group compared to the propofol group within the first 24 h following surgery (10 (31.25%) and 18 (56.25%), respectively, (p = 0.04)). After performing multivariate analysis, the risk of postoperative delirium was higher in the propofol group but this was not statistically significant (OR = 2.67, p = 0.061). No nightmares or hallucinations were detected in either group during the 24-h monitoring; no other adverse event monitoring was conducted.²²

Avidan et al.²³ completed the PODCAST trial: a multicenter, double-blinded, RCT examining the effect of ketamine on postoperative delirium and pain in older adults undergoing major open cardiac or non-cardiac (thoracic, vascular, abdominal, gynecologic, orthopedic, or otolaryngologic) surgeries under general anesthesia. The study included 672 participants aged 60 years and older who were randomized to three groups: placebo, IV ketamine 0.5 mg/kg, or IV ketamine 1 mg/kg. Following induction of anesthesia and prior to surgical incision, a dose of ketamine (0.5 mg/kg or 1 mg/kg) or placebo was administered. The primary outcomes were the CAM or CAM-ICU, and the severity of delirium was assessed with CAM-S. Assessments were completed twice daily on the first to the third postoperative day. There was no significant difference in postoperative delirium incidence between the combined ketamine groups and placebo (19.45% vs 19.82%, respectively; absolute difference; 0.36%; 95% CI, −6.07% to 7.38%; p = 0.92)). There was a greater incidence of nightmares and hallucinations in the high-dose ketamine group. Major adverse events, including cardiovascular events, did not differ significantly between the groups.²³

Ghazaly et al.²⁴ conducted a double-blind, randomized placebo-controlled trial examining the impact of ketamine versus dexmedetomidine versus placebo on postoperative delirium after emergency surgery. A total of 60 participants aged 60 years and older who were scheduled for emergent gastrointestinal, orthopedic, vascular, obstetric, urologic, or plastic surgeries completed the trial. Participants were randomized to receive 0.9% normal saline, IV dexmedetomidine 1 µg/kg, or IV ketamine 1 mg/kg immediately prior to anesthesia induction. The primary outcome was the incidence of delirium within 3 days of surgery. The assessment method or scale used for delirium assessment was not specified. The multivariate analysis conducted showed that the ketamine group had three times the risk of postoperative delirium (OR = 3.012; 95% CI, 1.185–9.68; p = 0.013) and 4.5 times the risk of postoperative cognitive dysfunction (OR = 4.501; 95% CI, 1.161–8.817; p = 0.006). However, delirium occurred in 1, 2, and 15 participants in the dexmedetomidine, ketamine, and placebo groups, respectively. The presence or absence of adverse events is not mentioned.²⁴

Liu et al.²⁵ completed an RCT assessing the effect of esketamine on postoperative delirium in patients undergoing laparoscopic gastrointestinal surgeries. Sixty participants aged 65 years and older were enrolled and randomized to sufentanil 2 µg/kg or sufentanil 1.5 µg/kg plus IV esketamine 1 mg/kg. Sufentanil and esketamine were administered as analgesia during the immediate postoperative period. The incidence of delirium on postoperative day 1 and postoperative day 3 was assessed using the CAM; the incidence of postoperative delirium was higher in the placebo group compared to the esketamine group (40% vs 13.3%; 95% CI, 20.5–46.3; p < 0.05). The number of patients with postoperative nausea and vomiting was high in both groups but not statistically different. No other adverse events were mentioned.²⁵

Ma et al.²⁶ conducted a randomized, double-blind controlled trial investigating the impact of esketamine on postoperative cognitive dysfunction after abdominal surgery for gastrointestinal tumors. A total of 62 participants aged 65 years and older completed the study. One group received IV esketamine 0.25 mg/kg for induction and then 0.125 mg/kg/h for maintenance. The placebo group received normal saline. Participants were assessed with CAM-ICU if they were arousable with RASS score ⩾−3 one to three days after surgery. The postoperative delirium incidence was 12.9% (day 1), 9.68% (day 2), and 6.45% (day 3) in the placebo group and 9.68% (day 1), 3.23% (day 2), and 0% (day 3) in the esketamine group. However, the difference was not statistically significant. Compared to placebo, there was significantly lower incidence of hypotension and tachycardia in the esketamine group and no significant difference in bradycardia or hypertension, though the study also notes that the control group used more analgesics.²⁶

Depression

A total of eight studies were found that evaluated the use of ketamine for the treatment of depression in older adults. Table 2 summarizes the characteristics and results of these studies.

Table 2.

Study characteristics and results for the use of ketamine for the treatment of depression.

Name of study	Study design	Intervention/dose	# of participants	Population	Treatment duration	Follow up	Outcome measure/results	Adverse events
George et al. (2017)²⁷	RCT, crossover study, open-label secondary phase	Two arms: Ascending doses of subcutaneous ketamine (0.1,0.2, 0.3, 0.4, 0.5 mg/kg) AND one-time dose of midazolam (0.01 mg/kg)	16	Age ⩾60; Diagnosed with MDD or Bipolar Disorder and a current treatment-resistant, depressive episode of duration ⩾4 weeks	Ascending doses one week apart for up to 6 weeks in RCT phase	Four hours post-treatment; days 2, 4, and 7; 6 months	MADRS (p-value < 0.01 for 0.2 mg/kg dose, p-values < 0.001 for 0.3 and 0.4 mg/kg doses, and p-value = 0.06 for 0.1 mg/kg dose)	No serious adverse events; most common side effects = mild perceptual disturbance, derealization, altered body perception, altered time perception, transient increases in heart rate and blood pressure; 1 participant with mild liver enzyme elevations at study end
Ochs-Ross et al. (2020)²⁸	RCT	Two arms: Esketamine 28 mg on day one followed by flexible doses (28, 56, or 84 mg); Plus initiation with SSRI/SNRI OR placebo nasal spray plus initiation with SSRI/SNRI	138 randomized (esketamine/antidepressant (n = 72); antidepressant/placebo (n = 66))	Age ⩾65 years old; diagnosed with treatment-resistant, recurrent, MDD without psychotic features	Twice weekly esketamine for 4 weeks	Day 28 and 2 weeks following last intervention dose	MADRS (p-value = 0.059), CGI-S (Odds ratio = 5.3 (1.85, 15.85))	Common side effects = dizziness, nausea, transient elevation in BP, fatigue, headache, and dissociation; Two patients with serious adverse events likely due to ketamine: BP elevation (n = 1), anxiety (n = 1)
Jones et al. (2022)²⁹	Post-hoc analysis	See Ochs-Ross et al.²⁸	See Ochs-Ross et al.²⁸	See Ochs-Ross et al.²⁸	See Ochs-Ross et al.²⁸	See Ochs-Ross et al.²⁸	MADRS (no statistically significant sex effects or treatment-by-sex interactions)	See Ochs-Ross et al.²⁸
Zarate et al. (2006)³⁰	RCT, crossover study	Two arms: 0.5 mg/kg IV ketamine OR IV saline	18 participants, 2 aged ⩾60	Age 18–65; Diagnosed with MDD without psychotic features	One time dose	40, 80, 110, and 230 min and 1, 2, 3, and 7 days post-treatment	HDRS (p value < 0.001 in sample as a whole); BPRS (p value = 0.06 at 1 day post-treatment in sample as a whole)	No serious adverse events; Mild events included perceptual disturbances, confusion, transient elevations in BP, euphoria, dizziness, increased libido
Rascon-Martinez et al. (2022)³¹	RCT	Two arms: IV ketamine 0.5 mg/kg OR IV normal saline	90 randomized to ketamine group (N = 46) and control group (n = 44)	Age ⩾60; undergoing ophthalmic surgery (e.g., cataracts, retinal detachment, or vitreous hemorrhage); no history of mental illness or previous antidepressant use	One time dose	120 min and 24 h post-surgery	Spanish version of the Geriatric Depression Scale – Short Form (p-value = 0.003 at 24 h follow-up)	No reported adverse events
Zou et al. (2020)³²	RCT	Two arms: IV ketamine 0.3 mg/kg with propofol OR propofol only	157 randomized to ketamine group (N = 76) and control group (n = 81)	Age ⩾60 undergoing ECT; diagnosed with MDD	Dosed with each ECT treatment (average of 10 sessions)	One day after ECT sessions 1, 2, 4, and 6, and 1 day after the last treatment	HAMD-24 (p = 0.002 and 0.011) fourth and sixth sessions, respectively, no significant difference after final session; MMSE (p-values > 0.05)	No serious adverse events; common side effects were hallucination (n = 4), myalgia/headache (n = 14), nausea and vomiting (n = 7), and delirium (n = 2); no significant between-groups differences
Finnegan et al. (2019)³³	RCT	Two arms: IV ketamine 0.5 mg/kg OR 0.045 mg/kg midazolam	6 but none completed the trial	3 participants over age 80 with unipolar depression (n = 2 in ketamine group)	4 once-weekly treatments	Before, 20 min after, 240 min after infusions; Relapse assessed 6 months after ECT completion	Results of mood scales were not stratified by age	Dissociation and nausea in both 80-year-olds
Mashour et al. (2018)³⁴	RCT, post hoc analysis	See Avidan et al.²³	See Avidan et al.²³	See Avidan et al.²³	See Avidan et al.²³	Pre-op, POD3, POD30	PHQ-8 (p value not-significant)	See Avidan et al.²³

BP, blood pressure; BPRS, Brief Psychiatric Rating Scale; CGI-S, Clinician Global Impression Scale; ECT, electroconvulsive therapy; HRSD/HAMD, Hamilton Rating Scale for Depression; IV, intravenous; MADRS, Montgomery-Asberg Depression Rating Scale; MDD, major depressive disorder; MMSE, Mini Mental Status Exam; PHQ-8, Patient Health Questionnaire-8; POD, Postoperative day; RCT, randomized controlled trial; SNRI, serotonin norepinephrine reuptake inhibitor; SSRI, selective serotonin reuptake inhibitor.

George et al.²⁷ in a double-blind, placebo-controlled, multiple-crossover trial examined the efficacy and safety of subcutaneous ketamine for TRD. The trial included 16 participants (age ⩾60, mean (standard deviation) age = 65.6 (5.7) years) with diagnoses of MDD or bipolar disorder in a current depressive episode lasting ⩾4 weeks, not responsive to ⩾1 adequate antidepressant trial. Baseline Montgomery-Asberg Rating Scale (MADRS) scores were ⩾20. In the RCT phase, participants received ascending doses of ketamine (0.1, 0.2, 0.3, 0.4, 0.5 mg/kg) starting with the lowest dose on day 1 and receiving subsequent treatments at least 1 week apart. Participants also received one dose of midazolam (0.01 mg/kg), which was randomly inserted into the first three treatment sessions. Participants exited the study if they received the highest dose (0.5 mg/kg) or achieved remission on day 7 after treatment, defined as MADRS <10. Remitters were assessed with the MADRS weekly for 4 weeks and then monthly for 5 months. Any participant who did not achieve remission or who relapsed was subsequently included in the open-label phase.

The primary outcome of the RCT was MADRS score, obtained at pretreatment, 4 h post-treatment, and days 2, 4, and 7 post-treatment. In this phase, 14 participants completed the trial (two withdrew after the first dose due to reasons unrelated to the trial). Seven participants remitted at varying doses: one at 0.1 mg/kg, one at 0.3 mg/kg, three at 0.4 mg/kg, and two at 0.5 mg/kg. Five of these seven subsequently relapsed. The remaining seven participants did not remit after 0.5 mg/kg. In the intention to treat analyses, MADRS scores were significantly lower after the ketamine 0.2 (p < 0.01), 0.3 (p < 0.001) and 0.4 mg/kg (p < 0.001) doses compared to midazolam but not significantly different for 0.1 mg/kg (p = 0.06) (the 0.5 mg/kg dose was not included in these analyses due to a small n receiving this dose). There was no significant linear trend across the five follow-up times within the week after each treatment; however, there was a significant quadratic trend, suggesting initial improvement followed by attenuation of effect. During the open-label phase, participants received 12 injections twice weekly for 4 weeks and once weekly for 4 weeks at the dose at which they had remitted. A total of 12 participants enrolled in the open-label phase, during which 7 participants remitted (n = 1 on 0.3 mg/kg; n = 3 on 0.4 mg/kg; n = 3 on 0.5 mg/kg); however, only two did not relapse after 6 months of follow-up. Overall, subcutaneous ketamine was safe and well-tolerated, with some of the most common adverse effects being perceptual disturbance, derealization, and a transient increase in blood pressure.²⁷

Ochs-Ross et al.²⁸ in their phase III, double-blind, active-controlled trial examined the efficacy and safety of ketamine in participants aged 65 years and older with treatment-resistant, moderate to severe major depression. Participants were randomly assigned (1:1) to receive either esketamine plus a newly initiated oral antidepressant or a placebo nasal spray plus a newly initiated oral antidepressant. Participants were tapered off their prior antidepressant during an observational phase and initiated on duloxetine, escitalopram, sertraline, or venlafaxine XR based on clinical judgment and prior treatment history. Participants received twice-weekly ketamine or placebo treatments for 4 weeks. All ketamine group participants received 28 mg on day 1 followed by flexible doses (28, 56, or 84 mg) on subsequent days per investigator’s judgment about safety and efficacy. Participants were followed for 2 weeks post-treatment to monitor vitals and electrocardiograms.

A total of 138 participants were randomized (mean age (SD) = 70.0 (4.5)), and 122 completed all treatments. Six participants dropped out due to non-serious, treatment-related adverse effects (four in ketamine arm and two in placebo). The primary outcome variable, change in MADRS from baseline to day 28, was not statistically significant. However, when stratifying by age and age of depression onset, participants aged 65–74 years versus 75 years and older had faster and greater improvement in MADRS with ketamine, and those with earlier depression onset (age <55) had significantly greater improvement with ketamine. Additionally, the ketamine group had a significantly higher odds of improved Clinician Global Impression Scale score (OR = 5.3 (1.85, 15.85)). The numbers needed to treat for response and remission at day 28 were 8 and 10, respectively. The most common side effects were dizziness, nausea, transient blood pressure elevation, fatigue, headache, and dissociation. There were five reported serious adverse events, two of which were likely due to ketamine and consisted of anxiety (n = 1) and elevation in blood pressure (n = 1).²⁸

Jones et al.²⁹ performed a post-hoc analysis of the TRANSFORM 1, 2, and 3 trials to explore sex differences in response to esketamine. In TRANSFORM-3, more females (20.5%) than males (12.5%) remitted, but this numerical difference was not substantiated by statistical analyses. Across the three trials, there were no statistically significant sex effects or treatment-by-sex interactions comparing MADRS on baseline to day 28.²⁹

Zarate et al.³⁰ conducted a placebo-controlled, double-blind, crossover study that examined the efficacy of IV ketamine for TRD. The trial included 18 patients (age 18–65, mean (standard deviation) age = 46.7 (11.2) years, with 2 patients aged 60 years and older) who were receiving inpatient care for major depressive disorder without psychotic features. Baseline Hamilton Depression Rating Scale (HDRS) scores were ⩾18. Participants were randomly assigned to receive IV saline solution followed by 0.5 mg/kg of ketamine 1 week later, or vice versa. The primary outcome was HDRS scores, obtained 60 min pretreatment and at 40, 80, 110, and 230 min, as well as 1, 2, 3, and 7 days post-treatment. Secondary outcome measures include the Brief Psychiatric Rating Scale (BPRS) positive symptoms subscale. The two older patients, aged 60 and 62 years, had a more robust improvement in HDRS scores with the ketamine infusion compared to placebo (change from baseline HDRS score with ketamine vs placebo = 39 vs10 points for the 62-year-old and 36 vs 26 for the 60-year-old). These two older participants also experienced a slight increase (1–3 points) in BPRS scores while they received the ketamine infusion. The authors only report analysis of the data as a whole and not a stratified analysis of the two older adults. There were no serious adverse events reported, and the most common ketamine side effects were transient perceptual disturbances, confusion, elevations in blood pressure, euphoria, dizziness, and increased libido.³⁰

Rascón-Martínez et al.³¹ in their double-blind, dose-controlled trial examined the efficacy, safety, and feasibility of IV ketamine on reducing depressive symptoms in patients aged 60 years or older undergoing ophthalmic surgery. Ophthalmic indications included cataracts, retinal detachment, or vitreous hemorrhage. Participants were excluded if they had a documented history of mental illness or previous antidepressant use. Ninety participants (mean age (SD) = 69.5 (6.7) years) were randomized to one of two groups: (1) the ketamine group, which received a single dose of ketamine 0.5 mg/kg (n = 46) or the control group, which received a single dose of normal saline (n = 44). Both treatments were infused during the surgery. Depressive symptoms were assessed using the Spanish version of the Geriatric Depression Scale – Short Form (GDS-SF) at three timepoints: time of hospitalization, 120 min post-surgery, and 24 h after surgery. Five participants in both groups were lost at the study’s final assessment stage due to reasons unrelated to the treatment. Baseline mean (SD) GDS-SF score was 4.3 (2.8) for the ketamine group and 3.5 (3.3) for the control (for reference GDS-SF score 0–4 = normal, 5–8 = mild depression). At 24 h post-operation, the difference reported in symptom improvement was significantly greater in the ketamine group than control (mean change −1.6 (2.0) in ketamine vs −0.3 (1.4) in control; p = 0.003). There were no hemodynamic differences observed between the groups, and no additional adverse effects were noted.³¹

Zou et al.³² in their randomized, double-blind trial examined the efficacy and safety of IV ketamine in participants with major depression aged 60 years and older undergoing electroconvulsive therapy (ECT). One-hundred fifty-seven participants were randomized to one of two groups: (1) subanesthetic ketamine (0.3 mg/kg) before propofol (n = 76), or (2) propofol only (n = 81). Depressive symptoms (HAMD-24) and global cognitive function (MMSE) were assessed at baseline, 1 day after sessions 1, 2, 4, and 6 and 1 day after the last treatment. Both groups received a similar mean number of treatments (ketamine = 9.9 (1.5) vs control = 10.0 (2.0)). Seizure time was higher in the ketamine group during the first, second, and fourth sessions but not the sixth or last sessions. Twenty patients (9 in the ketamine group and 11 in control) dropped out due to reasons unrelated to the treatment. At study end, there was no statistically significant difference between depression scores; however, the ketamine group had significantly lower depression scores after treatments four (p = 0.002) and six (p = 0.011). There was no significant change in MMSE scores between the groups. There were no significant differences in adverse events between the groups.³²

Finnegan et al.³³ completed a randomized controlled pilot trial examining the impact of ketamine on depression relapse prevention after receiving ECT. Six patients were eligible and consented to participate in the study: three were randomized to ketamine and three to midazolam as placebo. However, no participants completed the 4-week treatment protocol. Two 80-year-old participants received one ketamine infusion and both reported adverse reactions of dissociation. One of these participants dropped out due to reported adverse reactions, the other due to travel. One of the 80-year-olds who received a single ketamine infusion relapsed 26 weeks after completing ECT; the other did not relapse at the 6-month follow-up period. No other results were stratified by age.³³

Mashour et al.³⁴ completed a post-hoc analysis of the PODCAST trial (discussed above) in order to assess whether ketamine had an impact on postoperative depressive symptoms. The PHQ-8 (Patient Health Questionnaire) was used to dichotomize patients into two groups using a threshold score of greater than 10 or higher. Scores were compared from the preoperative period to postoperative day 3 and postoperative day 30. Their analysis showed that there were no significant differences in depressive symptoms between the combined ketamine (17.5%) and placebo (14.7%) groups on postoperative day 3 (difference −2.7%; 95% CI, 5% to −9.5%; p = 0.446). Severity of depressive symptoms between combined ketamine groups and placebo was also not significant at postoperative day 3 (p = 0.773) and postoperative day 30 (p = 0.271).³⁴

Other psychiatric conditions

No RTCs were found for ketamine in older adults with schizophrenia, mania, anxiety, PTSD, or dementia.

Discussion

This scoping review provides an up-to-date summary of the evidence for the use of ketamine in psychiatric conditions in older adults. The studies had significant heterogeneity, so direct comparisons of the results were challenging. However, five studies showed no significant impact of ketamine on delirium incidence. Two studies showed a lower incidence of delirium in the ketamine group, but another showed a higher incidence of delirium with ketamine. Four studies showed improvement in depressive symptoms with ketamine treatment, while the others showed a lack of significant improvement.

The JADAD scale was used to systematically assess the quality of the included studies. This is a five-point scale that assesses for randomization, blinding, and account of withdrawals; studies are considered high quality when they have a score of 3 or greater and low quality when they have a score of 0–2.¹⁸ Based on this scale, 12 studies in this review were considered high-quality RCTs (Table 3).

Table 3.

JADAD scale.

Name of study	Randomization mentioned	Appropriateness of randomization	Blinding mentioned	Appropriateness of blinding	Account of all withdrawals/dropouts	Total score
Hollinger et al. (2021)¹⁹	1	1	1	1	1	5
Hosseindoost et al. (2023)²⁰	1	1	0	0	0	2
Lu et al. (2024)²¹	1	1	0	0	0	2
Siripoonyothai (2021)²²	1	1	0	0	1	3
Avidan et al. (2017)²³	1	1	1	1	1	5
Ghazaly et al. (2023)²⁴	1	1	1	1	1	5
Liu et al. (2024)²⁵	1	1	1	1	1	5
Ma et al. (2023)²⁶	1	1	1	1	1	5
George et al. (2017)²⁷	1	1	1	1	1	5
Ochs-Ross et al. (2020)²⁸	1	1	1	1	1	5
Zarate et al. (2006)³⁰	1	1	1	1	1	5
Rascon-Martinez et al. (2022)³¹	1	1	1	1	1	5
Zou et al. (2020)³²	1	1	1	0	1	4
Finnegan et al. (2019)³³	1	1	1	1	1	5

A total of 8 RCTs examined the impact of ketamine on delirium. Most of the studies (n = 6) examined the use of ketamine in the preoperative and/or perioperative period by administering a one time dose of ketamine or maintenance ketamine during the operation.^{19,21–24,26} Five of the studies reported no impact of ketamine compared to control (either placebo or additional anesthetic agent) on delirium.^{19,21–23,26} The study by Liu et al.²⁵ reported a reduction in delirium incidence in the ketamine group compared to the placebo group (both groups received sufentanil). Lu et al.²¹ also reported decreased delirium incidence in the ketamine group compared to dexmedetomidine; however, the scale used to assess delirium was not reported, so the assessment method for delirium is not known. The study by Ghazaly et al.²⁴ showed a higher incidence of postoperative delirium in the ketamine group compared to placebo and dexmedetomidine. However, only two patients in the ketamine group developed delirium, limiting the conclusions that can be drawn from this data. Overall, these studies demonstrate significant heterogeneity, both in control groups and assessment scales, so the results cannot be aggregated. The follow-up periods are also short, often 15 min to postoperative day 3. While most of these studies were observing postoperative delirium incidence, the heterogeneity in the type of surgeries varied to such an extent that conclusions cannot be reliably drawn about the positive and negative effects of ketamine on postoperative delirium. Overall, the differences in study design, conflicting results, and limited follow-up time make it challenging to evaluate whether ketamine helps reduce delirium in the postoperative period or in the intensive care setting.

Though there were two studies showing some decreased incidence of delirium with perioperative ketamine, a systematic review of 8 RCTs by Fellous et al.¹⁰ showed that there was no difference in postoperative delirium incidence between ketamine compared to placebo. The main age of patients in this pooled analysis was 71.1 ± 9 years. Some studies have proposed that ketamine has an anti-inflammatory effect, and this may be the mechanism of decreased delirium incidence seen in some ketamine studies. For example, Hudetz et al.³⁵ found a decreased delirium incidence and significantly reduced C-reactive protein concentration after ketamine treatment compared to placebo when administered during anesthesia induction. At the same time, animal studies have shown that ketamine may interfere with intracellular protein tau trafficking and promote delirium-like behavior.³⁶ Overall, additional large RCTs are needed to further assess the impact of ketamine on delirium and guide anesthetic selection to optimize postoperative cognitive function, especially in older adults.

Six RCTs and two post-hoc analyses investigated the use of ketamine in treating depressive symptoms. The majority of these studies (n = 6) examined populations with current unipolar or bipolar depressive episodes.^{27–30,32,33} One of these studies examined low-dose ketamine as an adjunctive anesthetic for ECT and did not identify a significant change in remission compared to placebo.³² Another study examined treatment with IV ketamine among patients receiving ECT, but no participants completed their protocol, preventing analyses.³³ Four studies examined ketamine for treatment-resistant depression with mixed results.^27–30 First, George et al.²⁷ did identify a significant reduction in depressive symptoms with ketamine at IV doses of 0.2, 0.3, and 0.4 mg/kg; however, the significant quadratic trend of their results suggested initial improvement in depressive symptoms followed by attenuation of the effect a week following treatment. Additionally, in the open-label phase, only 2 of 12 participants did not relapse after 6 month of follow-up. Second, Ochs-Ross et al.²⁸ found no significant between-groups difference in depressive symptoms 28 days following treatment with intranasal ketamine; although, younger participants (ages 65–74 vs ⩾75) and those with earlier depression onset (age <55) had greater improvement with ketamine. Moreover, the post-hoc analysis by Jones et al. using data from Ochs-Ross et al.’s RCT identified no significant sex differences in these results.²⁹ Finally, the two older participants with TRD in the study by Zarate et al. both exhibited an improvement in HDRS scores from baseline with IV ketamine; however, there were no statistical analyses examining the significance of these findings.³⁰

Among the studies related to depression, two did not specifically select populations with current depressive episodes.^31,34 Rascon-Martinez et al.³¹ found a mild but statistically significant reduction in symptoms on the GDS in a sample of patients without clinical depression 24 h after ketamine treatment compared to control, although the mean GDS scores from baseline to post-treatment were in the range of mild to no depression. The second study was a post-hoc analysis of the RCT by Avidan et al.,²³ examining ketamine for post-operative delirium, and identified no significant effect on post-operative depression when ketamine had been administered.³⁴

Overall, the results of these studies on ketamine for depression in older adults were mixed and without conclusive data on the long-term antidepressant effects. This finding is consistent with that of another systematic review,³⁷ which identified eight retrospective and prospective studies (including the RCTs by George et al.²⁷ and Ochs-Ross et al.²⁸), which examined ketamine for treatment of depression among patients aged 60 years and older. Their review concluded that there was contradicting evidence regarding the safety, tolerability, and efficacy of ketamine as an antidepressant in older adults.

Several meta-analyses^38–40 in the general adult population have identified more conclusively the positive effects of ketamine on depression, but, similar to this review, identified variability in outcomes depending on forms and dosages of ketamine. For instance, two meta-analyses identified greater response and remission rates with racemic ketamine versus esketamine, and higher (⩾0.5 mg/kg) versus lower (<0.5 mg/kg) doses were also more effective.^39,40 Notably, in our review, the study by George et al.,²⁷ which looked at ascending doses of subcutaneous ketamine, demonstrated that older adults can remit at doses <0.5 mg/kg. While other studies included in this review^30,31,33 started at doses of 0.5 mg/kg, the study by George et al.²⁷ suggests that starting at a lower dose and following a dose-titration model may be particularly beneficial in older adults to identify the lowest effective dose. Few studies in the current review looked at sustained response to ketamine; the longest follow-up period in these studies was 6 months.²⁷ A 2022 systematic review of maintenance ketamine (IV, intranasal, oral, and intramuscular) for depression in the general population identified sustained remission rates ranging from 33% to 100% over <6 month periods and 22% to 100% over 6–12 months in open-label studies, case series, and case reports.⁴¹ Similar longitudinal data is required to evaluate sustained response in older adults, specifically. Additionally, the findings by George et al.²⁷ suggested that repeated treatments with ketamine, as compared to single doses, may facilitate sustained remission in TRD. However, data from a meta-analysis on ketamine for TRD in the general population suggests that the duration and frequency of treatment do not significantly predict outcomes.³⁸

Studies have also noted age-related differences in ketamine response when treating depression. In our review, the study by Ochs-Ross et al.²⁸ found that patients aged 65–74 years had a greater response than those ⩾75. Several studies have found mixed results when comparing older versus younger cohorts in the general population.^42,43 One of these studies, a post-hoc analysis using data from Ochs-Ross et al.’s study,²⁸ found comparable improvements in depressive symptoms in those aged 65 years and older versus 18–64.⁴² Whereas, another study found a greater response and improvement in depressive symptoms among younger (age <50) versus older (age ⩾50) participants.⁴³ Altogether, data from the current review and from studies on the general adult population reveal inconsistencies; therefore, given the limited current data on ketamine for older adults with depression, the decision to utilize this treatment should be an individual risk versus benefit analysis.

There are several limitations to the studies examining depression. First, all of the studies had relatively short durations of treatment and short follow-up times, none longer than 6 months post-treatment, precluding assessment of long-term antidepressant effects. Second, the studies varied significantly in the route of ketamine utilized (intranasal vs IV vs subcutaneous), ketamine dosage, and outcome measures, so results could not be aggregated. Finally, two of the studies^30,33 included only two participants over age 60 in each trial, limiting meaningful analysis of the treatment response in older patients. There are similar limitations to the ketamine studies examining the impact on delirium. The delirium studies varied significantly in the study population, dosage, timing, and assessment measurements utilized. While most studies used the CAM to assess for delirium, two did not report the assessment scores or the scales used for assessment, which is a significant weakness.^21,24 Additionally, there are some limitations to using the CAM for delirium assessment since prior studies have shown that it can miss a significant portion of patients who do have delirium.⁴⁴ Combining the use of multiple scales (CAM, Nu-DESC) with clinical assessment by an experienced provider and assessing at multiple time points could increase sensitivity for delirium detection.

There were no studies identified for the use of ketamine in treating psychiatric conditions other than depression or delirium. Research on the general adult population does suggest that ketamine may be effective for other disorders. Several meta-analyses have examined ketamine for PTSD with overall beneficial effect, particularly in those with chronic, and not early or combat, PTSD.^45,46 A systematic review by Tully et al. did show ketamine may have some benefit for treating refractory anxiety disorders.⁴⁷ Though ketamine should not be used for treatment of schizophrenia, prior studies have found that ketamine could be used as a model for studying schizophrenia since it induces psychotic symptoms, especially when administered in bolus doses.⁴⁸

The short-term safety data collected in these trials suggest that ketamine is relatively safe and well-tolerated in older adults. The majority of studies did not report any serious adverse events. The study by Ochs-Ross et al.²⁸ did report two incidents of serious adverse events, one for anxiety and the other for blood pressure elevation, but further details of these events were not reported. The other most commonly reported side effects were perceptual disturbance/hallucination/dissociation, confusion, headache, dizziness, gastrointestinal upset, and transient elevations in blood pressure. The majority of these effects lasted only up to a few hours and spontaneously terminated without additional intervention. Some studies did note several participant drop-outs due to these treatment-related side effects.^28,33 There were no lasting cognitive changes noted, though not all studies reported on these results.

There are several limitations to this review. There were no RCTs for the use of ketamine in older adults with psychiatric conditions other than depression or delirium, so we cannot comment on the impact of ketamine on other psychiatric disorders in later life. Studies that were not RCTs or English language translations were excluded, which means some data may have been missed. Due to the significant heterogeneity of these studies, including variation in treatment route, dose, timing of administration, frequency, and timing of follow-up assessment, as well as methods of assessment, a meta-analysis could not be completed, and it is difficult to draw collective conclusions from the studies. Non-English language studies or studies with an English translation were also excluded, which may have resulted in missed data.

Conclusion

Several randomized trials have investigated ketamine for the treatment of depression and delirium in older adults and show mixed results for both conditions. Though there was significant study heterogeneity, it appears that ketamine does not necessarily decrease delirium incidence, and in one study, the participants actually had an increased incidence of delirium. Therefore, the use of ketamine for delirium prevention alone should be reconsidered. For depression in older adults, the results were nearly evenly split between a positive and a negative response to ketamine. Despite these mixed results, the side effects were mild in this population, so ketamine may be presented as a reasonable option when depressive symptoms are severe and other treatment options have been exhausted. This review reveals the paucity of current data on ketamine for other psychiatric conditions in older adults. It reaffirms that further research is needed, and the use of ketamine in older adults with psychiatric illness remains an individual risk versus benefit analysis.

Footnotes

Acknowledgements

None.

Declarations

ORCID iDs

Kayla Murphy

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The evidence for ketamine treatment in older adults with psychiatric illness: a scoping review

Abstract

Background:

Objectives:

Eligibility criteria:

Sources of evidence:

Charting methods:

Results:

Conclusion:

Plain language summary

Keywords

Introduction

Methods

Results

Delirium

Depression

Other psychiatric conditions

Discussion

Conclusion

Footnotes

Acknowledgements

Declarations

ORCID iDs

References