Ketamine for the Treatment of Depression and Other Selected Indications

Number: 0938

Table Of Contents

Policy
Applicable CPT / HCPCS / ICD-10 Codes
Background
References

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Policy

Scope of Policy

This Clinical Policy Bulletin addresses ketamine for the treatment of depression and other selected indications.

1. Experimental and Investigational

   Aetna considers ketamine (intramuscular, intranasal, intravenous, oral, or subcutaneous) experimental and investigational for the following indications because its clinical value and effectiveness for these indications has not been established:

   1. Acute pain
   2. Central body pain
   3. Chronic pain
   4. Generalized anxiety and social anxiety disorders
   5. Depression
   6. Neuropathic pain
   7. Post-concussion syndrome
   8. Post-traumatic stress disorder
   9. Sickle cell vaso-occlusive crises
   10. Substance use disorder
   11. Suicidal ideation.

2. Related Policies

   • CPB 0445 - Electroconvulsive Therapy
   • CPB 0447 - Complex Regional Pain Syndrome (CRPS) / Reflex Sympathetic Dystrophy (RSD): Treatments
   • CPB 0469 - Transcranial Magnetic Stimulation and Cranial Electrical Stimulation
   • CPB 0950 - Esketamine (Spravato)

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Table:

CPT Codes / HCPCS Codes / ICD-10 Codes

Code	Code Description
Information in the [brackets] below has been added for clarification purposes.   Codes requiring a 7th character are represented by "+" :
Other CPT codes related to the CPB:
96365 - 96368	Intravenous infusion administration
96372	Therapeutic, prophylactic, or diagnostic injection (specify substance or drug); subcutaneous or intramuscular
HCPCS codes not covered for indications listed in the CPB:
Ketamine - no specific code:
ICD-10 codes not covered for indications listed in the CPB:
D57.819	Other sickle-cell disorders with crisis, unspecified
F07.81	Post-concussional syndrome
F10.10 - F19.99	Substance related disorders
F32.0 - F33.9	Major depressive disorders
F40.10	Social phobia, unspecified
F40.11	Social phobia, generalized
F41.1	Generalized anxiety disorder
F43.10 - F43.12	Post-traumatic stress disorder (PTSD)
G89.0	Central pain syndrome
G89.29	Other chronic pain
M79.2	Neuralgia and neuritis, unspecified
R45.851	Suicidal ideations
R52	Pain, unspecified

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Background

Major depressive disorder (MDD) has one of the highest morbidities worldwide.  As reported in many clinical trials, standard anti-depressants are effective in only approximately 2/3 of patients.  Additionally, there is a substantial time-lag in response: 2 to 4 weeks for initial effect, and 6 to 12 weeks for maximal efficacy.  Treatment-resistant depression (TRD) is associated with substantial psychosocial dysfunction, morbidity, and mortality, due in part to suicide and under-treated medical co-morbidities.  Thus, there is a need for better and more rapid-acting anti-depressants to quickly alleviate the burden of depression for patients (Niciu et al, 2014; Fond et al, 2014).  Ketamine is a glutamate N-methyl-D-aspartate (NMDA) receptor antagonist; recent research has suggested that ketamine may be a novel, rapid-acting anti-depressant.

Schoevers and colleagues (2016) reviewed the literature about the dosing regimen, duration, effects and side-effects of oral, intravenous, intranasal and subcutaneous routes of administration of ketamine for TRD and pain.  Searches in PubMed with the terms “oral ketamine”, “depression”, “chronic pain”, “neuropathic pain”, “intravenous ketamine”, “intranasal ketamine” and “subcutaneous ketamine” yielded 88 articles.  They reviewed all papers for information about dosing regimen, number of individuals who received ketamine, number of ketamine days per study, results and side-effects, as well as study quality.  Overall, the methodological strength of studies investigating the anti-depressant effects of ketamine was considered low, regardless of the route of administration.  The doses for depression were in the lower range compared with studies that investigated analgesic use.  Studies on pain suggested that oral ketamine may be acceptable for TRD in terms of tolerability and side-effects.  The authors concluded that oral ketamine, given for longer time periods in the described doses, appeared to be well-tolerated, but few studies had systematically examined the longer-term negative consequences.  These researchers stated that the short- and longer-term depression outcomes as well as side-effects need to be studied with rigorous randomized controlled trials (RCT)s.

Al Shirawi and co-workers (2017) evaluated the effectiveness, tolerability, and safety of oral ketamine as an anti-depressant treatment in adults with TRD.  These investigators reviewed retrospective data on 22 patients with TRD, who failed at least 3 adequate anti-depressant treatment trials and 1 adequate trial of repetitive transcranial magnetic stimulation (TMS); subsequently, they received open-label treatment with oral ketamine, commenced at a dose of 50 mg every 3 days, titrated up by 25 mg every 3 days, according to response and tolerability.  The primary outcome measure was the Beck Depression Inventory (BDI)-II, which was used to rate subjective mood improvement at baseline and then at each follow-up visit.  Data about adverse effects related to ketamine and a self-harm risk assessment were also obtained.  Over the course of treatment, 18 % of the patients showed greater than 50 % reduction in the BDI-II scores, 14 % reported partial improvement in mood symptoms, while 45 % had no response to ketamine and 23 % showed a mild worsening in their depressive symptoms.  The most frequent adverse effects were acute dissociation, dizziness, blurred vision, numbness and sedation.  Neither serious adverse effects, nor any cases of abuse or dependence were observed.  The authors concluded that although this case series found oral ketamine to be safe and well-tolerated, the findings also showed rather modest effectiveness of oral ketamine in TRD, with only approximately 30 % reporting some benefit and approximately 70 % reporting no change or worsening of mood.  They stated that further investigation of the effectiveness of oral ketamine is needed.

Feifel and associates (2017) described the safety and efficacy of sub-anesthetic ketamine infusions in a TRD patient sample participating in a real-world TRD treatment program within a major university health system.  The effects of a sub-anesthetic dose (0.5 mg/kg) of ketamine infused intravenously over 40 minutes on TRD patients participating in a treatment program at the University of California, San Diego was investigated by retrospectively analyzing the medical charts of 41 adult TRD patients with a diagnosis of MDD or bipolar disorder (BD).  Subjects were aged 48.6 years, 78 % white, 36.6 % women, and 82.9 % had MDD.  Significant psychiatric co-morbidity existed in 73 %.  Average pre-infusion BDI score was 32.6 ± 8.4 (S.D) and dropped to 16.8 ± 3.1 at 24-hour post-infusion (p < 0.001).  The 24-hour response (greater than or equal to 50 % reduction from pre-infusion) and remission (BDI less than 13) rates were 53.7 % and 41.5 %, respectively; 3/4 of responders maintained responder status at 7-days.  Ketamine infusions were well-tolerated with occasional nausea or anxiety and mild hemodynamic effects during the infusion.  The authors concluded that this was the first published study of sub-anesthetic ketamine infusions in a real-world TRD population.  They stated that the results suggested that this treatment was effective and well-tolerated in this population.  These researchers stated that the main drawbacks of this study were its retrospective nature, lack of control group, and use of self-report depression ratings scales.

Kraus and colleagues (2017) reviewed available literature on efficacy, response rates and safety profile of ketamine for unipolar and bipolar depression -- 12 studies investigating unipolar depression, 7 on BD were included after search in Medline, Scopus and Web of science.  Randomized, placebo-controlled or open-label trials reported anti-depressant response rates after 24 hours on primary outcome measures at 61 %.  The average reduction of Hamilton Depression Rating Scale (HAM-D) was 10.9 points, BDI 15.7 points and Montgomery-Asberg Depression Rating Scale (MADRS) 20.8 points.  Ketamine was always superior to placebo.  Most common side effects were dizziness, blurred vision, restlessness, nausea/vomiting and headache, which were all reversible.  Relapse rates ranged between 60 % and 92 %.  The authors concluded that ketamine constituted a novel, rapid and efficacious therapeutic option for patients suffering from TRD and exhibited rapid and significant anti-suicidal effects.  New administration routes might serve as alternative to intravenous regimes for potential usage in out-patient settings.  Moreover, they stated that long-term side effects are unknown and short duration of anti-depressant response need ways to prolong ketamine's efficacy.

The authors stated that this study had several drawbacks.  First, all of patients in this series had highly resistant forms of depression, with failure of multiple treatment modalities (multiple anti-depressant medications, neuromodulation, and in most cases cognitive psychotherapy).  Second, adherence to the prescribed regimen could not be confirmed for at-home dosing regimens.  Third, because this report concerned a series of clinical cases rather than a RCT, standardized clinician ratings of mood symptom were not consistently obtained.  Fourth, a series of 22 patients was insufficiently large to assess the incidence of rare but serious adverse effects (medical or psychiatric) ensuing from the treatment.

In a pilot study, George and colleagues (2017) examined the safety and efficacy of subcutaneous ketamine for geriatric TRD.  Secondary aims were to examine if repeated treatments were safe and more effective in inducing or prolonging remission than a single treatment.  This was a controlled, double-blind, multiple-crossover study with a 6-month follow-up (RCT phase), 16 participants (greater than or equal to 60 years) with TRD who relapsed after remission or did not remit in the RCT were administered an open-label phase.  Up to 5 subcutaneous doses of ketamine (0.1, 0.2, 0.3, 0.4, and 0.5 mg/kg) were administered in separate sessions (greater than or equal to 1 week apart), with 1 active control (midazolam) randomly inserted (RCT phase); 12 ketamine treatments were given in the open-label phase.  Mood, hemodynamic, and psychotomimetic outcomes were assessed by blinded raters.  Remitters in each phase were followed-up for 6 months; 7 of 14 RCT-phase completers remitted with ketamine treatment; 5 remitted at doses below 0.5 mg/kg.  Doses greater than or equal to 0.2 mg/kg were significantly more effective than midazolam.  Ketamine was well-tolerated.  Repeated treatments resulted in higher likelihood of remission or longer time to relapse.  The authors concluded that these findings provided preliminary evidence for the safety and efficacy of ketamine in treating elderly depressed.  Dose titration was recommended for optimizing anti-depressant and safety outcomes on an individual basis.  These preliminary findings need to be validated by well-designed studies.

In a “Consensus statement on the use of ketamine in the treatment of mood disorders” from the American Psychiatric Association (APA), Sanacora and associates (2017) noted that several studies provided evidence of ketamine hydrochloride's ability to produce rapid and robust anti-depressant effects in patients with mood and anxiety disorders that were previously resistant to treatment.  Despite the relatively small sample sizes, lack of longer-term data on efficacy, and limited data on safety provided by these studies, they have led to increased use of ketamine as an off-label treatment for mood and other psychiatric disorders.  This review and consensus statement provided a general overview of the data on the use of ketamine for the treatment of mood disorders and highlighted the limitations of the existing evidence.  While ketamine may be beneficial to some patients with mood disorders, it is important to consider the limitations of the available data and the potential risk associated with the drug when considering the therapeutic option.  The authors concluded that the suggestions provided were intended to facilitate clinical decision making and encourage an evidence-based approach to using ketamine in the treatment of psychiatric disorders considering the limited information that is currently available.  This article provided information on potentially important issues related to the off-label therapeutic approach that should be considered to help ensure patient safety.

Short and co-workers (2018) provided the first systematic review of the safety of ketamine in the treatment of depression after single and repeated doses.  These investigators searched Medline, PubMed, PsycINFO, and Cochrane Databases and identified 288 articles, 60 of which met the inclusion criteria.  After acute dosing, psychiatric, psychotomimetic, cardiovascular, neurological, and other side-effects were more frequently reported after ketamine treatment than after placebo in patients with depression.  These findings suggested a selective reporting bias with limited assessment of long-term use and safety and after repeated dosing, despite these being reported in other patient groups exposed to ketamine (e.g., those with chronic pain) and in recreational users.  The authors recommended large-scale clinical trials that include multiple doses of ketamine and long-term follow-up to assess the safety of long-term regular use.

Wilkinson and associates (2018) conducted a systematic review and individual participant data meta-analysis examining the effects of a single dose of ketamine on suicidal ideation.  Individual participant data were obtained from 10 of 11 identified comparison intervention studies that used either saline or midazolam as a control treatment.  The analysis included only participants who had suicidal ideation at baseline (n = 167).  A 1-stage, individual participant data, meta-analytic procedure was employed using a mixed-effects, multi-level, general linear model.  The primary outcome measures were the suicide items from clinician-administered (the MADRS or the HAM-D) and self-report scales (the Quick Inventory of Depressive Symptomatology-Self Report [QIDS-SR] or the BDI), obtained for up to 1 week after ketamine administration.  Ketamine rapidly (within 1 day) reduced suicidal ideation significantly on both the clinician-administered and self-report outcome measures.  Effect sizes were moderate to large (Cohen's d = 0.48 to 0.85) at all time points after dosing.  A sensitivity analysis demonstrated that compared with control treatments, ketamine had significant benefits on the individual suicide items of the MADRS, the HAM-D, and the QIDS-SR but not the BDI.  Ketamine's effect on suicidal ideation remained significant after adjusting for concurrent changes in severity of depressive symptoms.  The authors concluded that ketamine rapidly reduced suicidal thoughts, within 1 day and for up to 1 week in depressed patients with suicidal ideation.  Ketamine's effects on suicidal ideation were partially independent of its effects on mood, although subsequent trials in trans-diagnostic samples are needed to confirm that ketamine exerts a specific effect on suicidal ideation.  They stated that additional research on ketamine's long-term safety and its efficacy in reducing suicide risk is needed before clinical implementation.

In a retrospective, case-series study, Archer and colleagues (2018) reported on the clinical use of ongoing maintenance ketamine infusions in a group of patients with TRD, beyond an acute course of 6 to 8 ketamine infusions.  This trial included 11 patients with TRD who received maintenance ketamine infusions, defined as treatments beyond an initial series of up to 8 infusions.  Charts were reviewed to collect data on response to treatment and side effects.  All 11 patients in this case series were noted to have a reduction in their BDI-II score after an acute course of treatment and a lower median BDI-II during their maintenance treatments than their baseline BDI-II.  At the study end-point, 4 patients were continuing maintenance ketamine and 1 patient had transitioned to maintenance intranasal ketamine; 4 patients discontinued ketamine due to loss of effect and 1 due to side effects, and the reason for discontinuation was not noted for the remaining 2 patients.  No major adverse events (AEs) were noted in these patients receiving maintenance treatments, and it was well-tolerated overall.  The authors concluded that maintenance ketamine treatments may be an effective way of maintaining therapeutic response in some ketamine responders.  Moreover, they stated that future research is needed to determine optimal length of treatment in those who respond to ketamine and to track ARs over a longer time.

An UpToDate review on “Unipolar depression in adults: Treatment of resistant depression” (Thase and Connolly, 2018a) does not mention ketamine as a therapeutic option.

Furthermore, an UpToDate review on “Unipolar depression in adults: Management of highly resistant (refractory) depression” (Thase and Connolly, 2018b) lists ketamine as an investigational procedures.

In a systematic review, Rosenblat and colleagues (2019) examined the safety, tolerability, efficacy, and dose range of oral ketamine for bipolar and unipolar depression in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA).  The Medline/PubMed, Embase, and Google Scholar databases were systematically searched for relevant articles, written in English, published prior to July 2018 using relevant keywords for all variants of ketamine, oral, and depression.  All clinical studies assessing oral ketamine for bipolar or unipolar depression were included.  A total of 13 published articles were identified, of which 2 were proof-of-concept RCTs; 1 was a prospective open-label trial; 5 were retrospective chart reviews; and 5 were case reports.  Included articles were qualitatively analyzed to determine anti-depressant safety, tolerability, efficacy, dose range, anti-suicide effects, time to effect, and efficacy in treatment-resistant depression and study bias.  Both RCTs demonstrated anti-depressant efficacy with good tolerability; however, significant changes in depressive symptom severity were observed only after 2 to 6 weeks of treatment (p < 0.05).  Both RCTs had high risk for bias, due to inadequate intent-to-treat (ITT) analysis and AE monitoring.  Rapid antidepressant effects (i.e., within 24 hours), anti-suicide effects, and efficacy in treatment-resistant depression were reported only in retrospective studies.  Dosages and frequency of administration were variable (i.e., 0.5 to 7.0 mg/kg thricely-daily to once-monthly), with most studies providing dosages of 1 to 2 mg/kg every 1 to 3 days.  No clinically significant AEs were reported.  The authors concluded that a small number of clinical studies assessed the anti-depressant effects of oral ketamine.  Initial results suggested that oral ketamine had significant anti-depressant effects with good overall tolerability; however, anti-depressant effects were not as rapid as those associated with intravenous (IV) ketamine.  Anti-suicide effects and efficacy in treatment-resistant depression have yet to be demonstrated.  These researchers stated that additional well-designed RCTs are needed.

Grabski and associates (2020) noted that esketamine was recently licensed by the Food and Drug Administration (FDA) and European Drug Agency (EDA) for use in TRD, and further research indicates ketamine as a possible treatment in other mental health conditions.  While the underlying mechanisms remain unclear, it has been hypothesized that ketamine's acute psychoactive effects may be associated with psychiatric treatment efficacy.  These investigators systematically reviewed the evidence for this association.  The data-bases Medline, Embase and PsychInfo were searched up to June 2019.  Studies were included if they enrolled adults with a psychiatric diagnosis, assessed acute psychoactive effects using a quantitative measure, and reported on the relationship between acute effects and treatment outcome.  They included 21 studies, totaling 891 patients; 17 studies examined patients with depression (TRD [k = 14]), 3 evaluated substance use disorders, and 1 assessed social anxiety disorder.  Overall, 41 associations were assessed, of which 26 % were significant.  The studies reviewed displayed great variability in terms of methodology and quality of reporting.  The most commonly assessed effect was dissociation, measured by the Clinician Administered Dissociative States Scale (CADSS).  The authors concluded that these findings suggested that the CADSS total was not consistently associated with anti-depressant outcomes.  Apart from this, the current literature is too limited to draw definite conclusions on the presence of an association between acute psychoactive effects and mental health outcomes.  Moreover, these researchers stated that the field would benefit from consistently employing a priori hypotheses, more transparent reporting and sufficiently powered statistical analyses.  Furthermore, the use of a broader range of assessments tools of acute psychoactive effects during ketamine administration would be beneficial.

Kim and co-workers (2020) noted that suicide is the 2nd leading cause of death in the U.S. among individuals aged 10 to 24 years of age; and severe youth depression is often refractory to the current standards of care.  In a systematic review, these researchers examined the current state of evidence for the use of ketamine in children with treatment-resistant mood disorders.  They carried out a search utilizing 2 electronic data-bases for English-language studies examining the therapeutic effects and side effect profile of ketamine in youth less than or equal to 19 years of age with a diagnosis of a treatment-resistant mood disorder.  Analysis included subjects with TRD with and without psychotic features and with bipolar disorder.  Primary outcome measures included the following scales: MADRS, Children's Depression Rating Scale, Children's Depression Rating Scale Revised, Child Bipolar Questionnaire, Overt Aggression Scale, Yale-Brown Obsessive-Compulsive Scale, and Scale for Suicidal Ideation.  A total of 4 studies were identified that examined the use of ketamine in youth for the primary purpose of treating a treatment-resistant psychiatric disorder; 3 additional studies that did not meet eligibility criteria were identified and discussed.  The authors concluded that ketamine was shown in youth to generally improve depressive symptoms, decrease acute suicidality, and reduce mood lability, although a number of subjects remained resistant to its treatment.  Moreover, these researchers stated that these findings substantiated the need for further longitudinal studies examining ketamine's long-term safety, its efficacy, and abuse potential in the youth.

Memon and colleagues (2020) stated that MDD is a common psychiatric disorder with major implications for healthcare system and socioeconomic burden.  For chronic and treatment-resistant depression, ketamine has emerged as a possible therapeutic option.  In a systematic review, these researchers examined the evidence for the effectiveness and tolerability of ketamine in patients with MDD.  This systematic review was carried out following the guidelines of PRISMA check-list.  A total of 8 electronic data-bases were searched by using search terms: (ketamine) AND (trial OR RCT OR clinical-trial) AND (depressive OR depression OR "depressive-disorder").  After a rigorous screening process against the pre-determined eligibility criteria, 35 RCTs were included.  Quality assessment of included studies was performed by using the Cochrane risk-of-bias tool for RCTs.  The majority of the included studies came from the U.S., Iran, and China.  Intravenous ketamine was effective in 70 % (21/30) of the included studies whereas oral and intra-nasal (IN) ketamine were effective in 2 and 3 studies, respectively.  The majority of studies (6/8) using ketamine as anesthetic agent during electroconvulsive therapy (ECT) failed to show an improvement compared to the subjects receiving ECT and placebo.  The most common reported side effects were nausea, vomiting, dizziness, diplopia, drowsiness, dysphoria, hallucinations, and confusion.  The authors concluded that ketamine is an effective therapeutic option for patients with MDD with undesirable effects when administered via oral, IV and IN routes.  Augmentation of ECT with ketamine requires further investigation in well-designed studies with adequate sample size.  Moreover, these researchers stated that the short-lived anti-depressant effect of ketamine is a potential limitation; further studies administering multiple infusions for acute treatment and maintenance are needed.

Moeller et al (2022) noted that difficult-to-treat-depression (DTD) is a clinical challenge.  The interventions that are well-established for DTD are not suitable or effective for all the patients; thus, more therapeutic options are needed.  These investigators formulated an evidence-based guideline concerning 6 interventions not well-established for DTD in Denmark.  Selected review questions were formulated according to the PICO principle with specific definitions of the patient population (P), the intervention (I), the comparison (C), and the outcomes of interest (O), and systematic literature searches were carried out stepwise for each review question to identify relevant systematic reviews/meta-analyses, and RCTs.  The GRADE system was used to evaluate the methodological quality of the included studies.  Clinical recommendations were formulated based on the evidence, the risk-benefit ratio, and perceived patient preferences.  These researchers found sufficient evidence for a weak recommendation of repetitive transcranial magnetic stimulation (rTMS) and cognitive behavioral analysis system of psychotherapy (CBASP).  The use of bright light therapy in DTD was not sufficiently supported by the evidence; however, it should be considered as good clinical practice.  The interventions should be considered in addition to ongoing anti-depressant treatment.  These investigators did not find sufficient evidence to recommend IV ketamine/esketamine, rumination-focused psychotherapy, or cognitive remediation to patients with DTD.  The authors concluded that the evidence supported 2 of the 6 reviewed interventions; however, it was generally weak which emphasized the need for more good quality studies.  This guideline does not cover all therapeutic options and should be regarded as a supplement to relevant DTD-guidelines.

In a systematic review, Vaccarino et al (2022) determined the objective neurocognitive effects of single-dose ketamine, repeated-dose ketamine, ketamine adjunct to ECT, and ketamine as the anesthetic for ECT in MDD and depression in BD.  Cochrane, Medline, Embase, and PsycINFO databases were searched on March 19, 2020 (updated July 2, 2020), using the terms major depressive disorder bipolar disorder and ketamine and their synonyms.  Clinical trial registries (search date May 4, 2020) and reference sections of included articles were also searched.  There was no restriction on language or year of publication.  Of 4,035 identified articles, 17 met inclusion criteria.  Controlled and open-label studies of adults who received at least 1 ketamine treatment for a current major depressive episode, as part of MDD or BD, were included.  Only studies measuring cognition using at least 1 validated, objective neurocognitive assessment were eligible.  Results were presented using a narrative review format.  Data regarding change in cognitive performance from baseline to end-of-treatment and/or differences in cognition between ketamine and control groups were extracted.  There were no negative effects of single- or repeated-dose IV ketamine up to 2 weeks post-treatment in MDD.  Limited data were available for BD populations, as well as on other routes of ketamine administration.  The authors concluded that data to definitively answer the question of whether ketamine has substantive or persistent cognitive effects are insufficient; therefore, larger controlled trials measuring cognition as the primary outcome are needed.  Moreover, these investigators stated that future research should focus on different routes of ketamine administration, ketamine enantiomers, and BD populations.

Xiao et al (2023) discussed outcomes of their single-center, randomized, double-blind pilot study that compared the safety and efficacy of a single subanesthetic dose of “esketamine” (ketamine) versus intravenous midazolam in boosting the efficacy of oral antidepressants for treating fluctuating antidepressant response (FAD) in major depressive disorder (MDD). This trial included 30 adult patients with FAD, defined as patients with MDD experiencing fluctuating symptoms after symptom relief and stabilization. All patients in the esketamine-treated group (n=15) received intravenous esketamine at 0.2 mg/kg in 40 minutes. Patients in the midazolam control group (n=15) received intravenous midazolam at 0.045 mg/kg in 40 minutes. The primary outcome was the response rate at 2 weeks, defined as a 50% reduction in Montgomery-Åsberg Depression Rating Scale (MADRS). Secondary outcomes included response rate at 6 weeks, remission rates at 2 and 6 weeks, and change in MADRS and Clinical Global Impression–Severity score from baseline to 6 weeks; remission was defined by a MADRS score of 10 or lower. Of the 30 patients, 29 patients completed the study. The authors found that response rates at 2 weeks were significantly higher in the esketamine-treated group than in the midazolam control group (10 patients [66.7%] vs 1 patient [6.7%]; p < .001). Patients treated with IV esketamine experienced significantly greater reduction in MADRS score from baseline to 2 weeks compared with those treated with midazolam (mean [SD] reduction, 15.7 [1.5] vs 3.1 [1.3]; p < .001). There were no serious adverse events observed in their trial, and no psychotogenic effects or clinically significant manic symptoms were reported. The authors concluded that their pilot study found that a single subanesthetic dose of esketamine could boost the efficacy of oral antidepressants in treating fluctuating antidepressant response, with a good safety profile; however, future larger trials with longer follow-up are required to confirm these findings.

The authors note several limitations to their study, which include the following: (i) symptom fluctuation was evaluated retrospectively using the VAS tool, (ii) the definition of FAD was empirical without a reference standard, which may have introduced bias and affected data accuracy, and (iii) study included a small sample size in a single center, which may limit the generalizability of the results. The authors state that “including patients with first-episode depression and patients with recurrent depression in the sample may limit the internal and external validity. Furthermore, collecting data during the COVID-19 pandemic may have impacted the results of this study. Additionally, a significant difference in dissociation levels at 40 minutes was observed and blinding assessment was lacking, which could potentially affect the integrity of blinding”.

Prevention of Emergence Agitation in Children Undergoing Surgery or Imaging Procedures

Ng and colleagues (2019) noted that ketamine is believed to reduce the incidence of emergence agitation in children undergoing surgery or procedure.  However, recent RCTs reported conflicting findings.  In a meta-analysis, these investigators examined the effect of ketamine on emergence agitation in children.  Medline, Embase, and CENTRAL were systematically searched from their start date until February 2019; RCTs comparing IV ketamine and placebo in children were sought.  The primary outcome was the incidence of emergence agitation; secondary outcomes included post-operative pain score, duration of discharge time, and the adverse effects associated with the use of ketamine, namely post-operative nausea and vomiting, desaturation, and laryngospasm.  A total of 13 studies (1,125 subjects) were included in the quantitative meta-analysis.  The incidence of emergence agitation was 14.7 % in the ketamine group and 33.3 % in the placebo group.  Children receiving ketamine had a lower incidence of emergence agitation, with an odds ratio (OR) being 0.23 (95 % confidence interval [CI]: 0.11 to 0.46), certainty of evidence: low.  In comparison with the placebo, ketamine group achieved a lower post-operative pain score (OR: -2.42, 95 % CI: -4.23 to -0.62, certainty of evidence: very low) and lower pediatric anesthesia emergence delirium scale at 5 mins after operation (OR: -3.99, 95 % CI: -5.03 to -2.95; certainty of evidence: moderate).  However, no evidence was observed in terms of incidence of post-operative nausea and vomiting, desaturation, and laryngospasm.  The authors concluded that in this meta-analysis of 13 RCTs, high degree of heterogeneity and low certainty of evidence limited the recommendations of ketamine for the prevention of emergence agitation in children undergoing surgery or imaging procedures.  However, the use of ketamine was well-tolerated without any notable adverse effects across all the included trials.

Treatment of Suicidal Ideation

Chen et al (2019) stated that increasing evidence suggested that infusion of a sub-anesthetic dose of ketamine exerts anti-depressant and anti-suicidal effects in patients with TRD.  In a double-blind, placebo-controlled, randomized, longitudinal study, these researchers used the resting functional connectivity magnetic resonance imaging (fcMRI) to examine the effects of ketamine on the functional connectivity (FC) of pre-frontal cortex (PFC)-related circuits in patients with TRD.  A total of 48 patients with TRD were recruited and randomly divided into 3 groups on the basis of ketamine infusion dose: 0.5 mg/kg (standard-dose), 0.2 mg/kg (low-dose), or normal saline (a placebo infusion).  Resting functional MRI data and clinical data were recorded at the baseline and on the 3rd day after ketamine infusion treatment.  The standard-dose group showed a reduction in the FC of the left dorsal anterior cingulate cortex (dACC) and right dorsolateral (dl) PFC with the other frontal regions.  The low-dose group demonstrated a more pervasive reduction of FC in the bilateral dACC with other frontal and parietal regions.  A negative correlation was observed between the reduction in suicidal ideation and the reduction in the FC between the left dACC and right ACC regions in the standard-dose group, whereas a positive correlation was observed between the reduction in suicidal ideation and the increase in the FC between the right dlPFC and left superior parietal region in the low-dose group.  The authors concluded that these findings supported the hypothesis that PFC-related circuit modulation was crucial to the anti-depressant and anti-suicidal effects of the ketamine infusion treatment.

Ionescu and co-workers (2019) noted that the extent to which repeated doses of ketamine (versus placebo) reduce depression in the short- and long-term among out-patients with TRD and chronic, current suicidal ideation remains unknown.  In a randomized, double-blind, placebo-controlled trial, a total of 26 medicated out-patients with severe MDD with current, chronic suicidal ideation were randomized to 6 ketamine infusions (0.5 mg/kg over 45 mins) or saline placebo over 3 weeks.  Depression and suicidal ideation were assessed at baseline, 240 mins post-infusion, and during a 3-month follow-up phase.  During the infusion phase, there was no differences in depression severity or suicidal ideation between placebo and ketamine (p = 0.47 and p = 0.32, respectively).  At the end of the infusion phase, 2 patients in the ketamine group and 1 in the placebo group met criteria for remission of depression.  At 3-month follow-up, 2 patients in each group met criteria for remission from depression.  The authors concluded that repeated, non-escalating doses of ketamine did not out-perform placebo in this double-blind, placebo controlled study of patients with severe TRD and current, chronic suicidal ideation.  This result may support the authors’ previously published open-label data that, in this severely and chronically ill outpatient population, the commonly used dose of 0.5 mg/kg is insufficient.  These researchers stated that limitations of this trial included the small sample size (n = 26), uncontrolled out-patient medication regimens, and restriction to out-patients, which may have resulted in lower levels of suicidal ideation than would be observed in emergency or in-patient settings.

In a preliminary study, Zhan et al (2019) examined the anti-suicidal efficacy of repeated ketamine infusions for Chinese depressed suicidal patients, especially distinguished between low suicidal ideation (SI) group and high SI group.  A total of 86 unipolar and bipolar depressive patients with current suicidal ideation received 6 ketamine infusions during a 12-day period.  Hamilton Depression Rating Scale (HAMD) and Beck Scale for Suicide Ideation (SSI) were measured at baseline, 4 hours and 24 hours after each infusion, and 2-week naturalistically follow-up.  A total of 49 (57.0 %) patients found relief of suicidal ideation after 1st infusion and 56 (65.1 %) after 6 infusions.  Anti-suicidal response rate in low SI group were higher than high SI group, and anti-suicidal response at 4 hours after 1st infusion was significant predictor of response at 24 hours after 6th infusion.  Furthermore, at 24 hours after the 6th infusion, correlation between changes in suicidal ideation and depression was 0.23, accounting for 7.4 % in the variance of suicidal ideation change.  The authors confirmed that 6 repeated ketamine infusions for Chinese suicidal depressed patients were effective in generating a rapid response of suicidal ideation, especially low SI achieved more benefits from ketamine infusions.  These researchers stated that the main drawback of this study was that lack of a placebo or other control group, which limited the interpretation of efficacy.

Witt and associates (2020) noted that ketamine may reduce suicidal ideation in TRD.  But it is unclear how quickly this occurs and how long it persists.  These researchers carried out a systematic review and meta-analysis to determine the short- and long-term effectiveness of ketamine for suicidality.  CENTRAL, Embase, Medline, and PsycINFO were searched until December 12, 2018; RCTs of ketamine or esketamine reporting data on suicidal ideation, self-harm, attempted or completed suicide in adults diagnosed with any psychiatric disorder were included.  Two reviewers independently extracted data, and certainty of evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) tool.  Standardized mean difference was used for continuous outcomes.  A total of 25 reports from 15 independent trials, with a total of 572 subjects diagnosed with predominately affective disorders, were included.  The evidence was rated moderate-to-low.  In most trials, ketamine was administered at 0.5 mg/kg via a single IV infusion over a 30- to 45-min period.  Only a single trial of IN esketamine was identified.  At 4 hours post-infusion, treatment with ketamine was associated with a significant reduction in suicidal ideation scores (standardized mean difference [SMD] = -0.51, 95 % CI: -1.00 to -0.03), which persisted until 72 hours post-infusion (time-points between 12 and 24 hours: SMD = -0.63, 95 % CI: -0.99 to -0.26; between 24 and 72 hours: SMD = -0.57, 95 % CI: -0.99 to -0.14]), but not thereafter.  However, there was marked heterogeneity of results.  In a single trial of esketamine, marginal effects on suicidal ideation were observed.  In terms of actual suicidal behavior, there were virtually no data on effects of ketamine or esketamine.  The authors concluded that a single infusion of ketamine may have a short-term (up to 72 hours) beneficial impact on suicidal thoughts.  These researchers stated that while confirmation of these results in further trials is needed, they suggested possible use of ketamine to treat acute suicidality.  Means of sustaining any anti-suicidal effect need to be found.

In a randomized, double-blind, placebo-controlled, proof-of-concept trial, Domany et al (2020) examined the effectiveness of ketamine for the treatment of acute suicidal ideation.  A total of 18 depressed subjects with acute suicidal ideation, who required hospitalization, were randomized to either an IV ketamine 0.2 mg/kg group or a saline placebo group.  Safety and effectiveness evaluations were scheduled for 15, 30, 60, 90, 120, 180, and 240 mins, and on days 1, 2, 3, 7, and 14 after infusion.  The main outcome measure was suicidal ideation with secondary measures of depression.  A total of 9 subjects were randomized to each group.  There were no differences between groups at baseline in any demographic or assessment scales.  A reduction in suicidal ideation was noted at 90 to 180 mins (p < 0.05); 90 mins after infusion, 88 % of the ketamine group had achieved remission of suicidal ideation compared with 33 % in the placebo group (p < 0.05).  No serious AEs were noted.  The authors concluded that ketamine was safe and effective for rapid reduction in suicidal ideation in depressed, highly suicidal subjects presenting to the emergency department.  These researchers stated that future larger‐scale studies should consider using a higher dose of ketamine (0.5 mg/kg) and addressing a trans-diagnostic approach.

The authors stated that this study had several drawbacks.  First, the small sample size (n = 9 in each group) resulting from the early termination of recruitment; thus, in spite of the statistically significant benefit, the ability to draw conclusions from such a sample was limited.  Second, while participants and study evaluators were blinded to randomization, there were subjective (dissociation, dizziness) and objective (pulse and BP) effects that were diverse and may impair blindness.  To that end, some studies have used midazolam as an active placebo.  These investigators, however, were concerned that the anxiolytic effect of midazolam may influence suicidal ideation and other Research Domain Criteria (RDoC) elements (i.e., anxiety) and might cause a different bias (type 2 error).  Future studies should consider active and non-active placebo.  Third, follow‐up was limited in time and not always complete, as participants were difficult to contact after discharge from the hospital.  Fourth, these researchers did not examine the hospital length of stay (Los), an outcome that could reflect the clinical benefit of ketamine.

In a prospective, randomized, double-blind, placebo-controlled, superiority, trial Abbar et al (2022) confirmed the rapid onset anti-suicidal benefits of ketamine in the short-term and at 6weeks, overall and according to diagnostic group.  A total of 7 French teaching hospitals participated in this trial between April 13, 2015, and March 12, 2019.  Subjects were of age 18 years or older with current suicidal ideation, admitted to hospital voluntarily.  Exclusion criteria included a history of schizophrenia or other psychotic disorders, substance dependence, and contraindications for ketamine.  A total of 156 subjects were recruited and randomized to placebo (n = 83) or ketamine (n = 73), stratified by center and diagnosis: bipolar, depressive, or other disorders.  Two 40-min intravenous infusions of ketamine (0.5 mg/kg) or placebo (saline) were administered at baseline and 24 hours, in addition to usual treatment.  The primary outcome was the rate of patients in full suicidal remission at day 3, according to the scale for suicidal ideation total score of 3 or less.  Analyses were carried out on an ITT basis.  More subjects receiving ketamine reached full remission of suicidal ideas at day 3 than those receiving placebo: 46 (63.0 %) of 83 subjects in the ketamine arm and 25 (31.6 %) of 73 in the placebo arm (OR of 3.7 (95 % CI: 1.9 to 7.3; p < 0.001).  This effect differed according to the diagnosis (treatment: p < 0.001; interaction: p = 0.02): bipolar (OR 14.1 (95 % CI: 3.0 to 92.2; p < 0.001), depressive (1.3 (0.3 to 5.2), p = 0.6), or other disorders (3.7 (0.9 to 17.3, p = 0.07)).  Side effects were limited; no manic or psychotic symptom was observed.  Moreover, a mediating effect of mental pain was found.  At week 6, remission in the ketamine arm remained high, although non-significantly versus placebo (69.5 % versus 56.3 %; OR of 0.8 (95 % CI: 0.3 to 2.5; p = 0.7).  The authors concluded that the findings of this study indicated that ketamine was rapid, safe in the short-term, and exhibited persistent benefits for acute care in suicidal patients.  Co-morbid mental disorders appeared to be important moderators.  An analgesic effect on mental pain might explain the anti-suicidal effects of ketamine.  Moreover, these researchers stated that studies with larger sample size, longer follow-up are needed to examine benefits on suicidal behaviors; and drugs with different mechanisms of action will have to be investigated for non-responders.

The authors stated that his study had several drawbacks.  First, although this was a large study and sufficiently powered, analyses within diagnostic groups were on smaller samples, which might explain both the large effect size of ketamine in bipolar disorder, and the lack of significant differences in the depressive disorder group.  Second, as ketamine could induce recognizable effects (depersonalization, dizziness), masking might have been compromised for both the patients and the investigators; however, this was not formally measured.  It should, however, be noted that only 9.6 % of patients in the ketamine group experienced depersonalization and 4.1 % dizziness (versus 2.4 % in the placebo group) while other side effects were unspecific and found in the placebo group.  Midazolam has been used instead of placebo in a few studies and should be considered as a suitable control in the future.  Third, the rapid resolution of suicidal ideas after receiving ketamine did not equate to a reduced risk of suicidal acts, notably after hospital discharge.  Indeed, the rates of suicidal attempts during follow-up were similar between the groups.  Moreover, ketamine is a drug with a potential for abuse.

Adjunctive Ketamine and Electroconvulsive Therapy

Zheng and colleagues (2019) noted that adjunctive ketamine with electro-convulsive therapy (ECT) has been examined for treating MDD, however, the findings have been inconsistent.  These investigators provided an updated meta-analysis on the safety and efficacy of ketamine augmentation of ECT in the treatment of MDD; RCTs reporting on the safety and efficacy of ketamine and ECT were identified and analyzed.  A total of 17 RCTs (n = 1,035) compared ketamine alone or ketamine plus other anesthetic drugs (n = 557) with other anesthetic agents (n = 478) in MDD patients who received ECT.  Ketamine + other anesthetic drugs was superior in improving depressive symptoms over other anesthetic medications at early study time-point, but not at post-ECT or end of study time-points.  Ketamine alone was not more effective in treating depressive symptoms than other anesthetic drugs at early study, post-ECT and end of study time-points.  Sensitivity analysis and 19 of the 20 subgroup analyses also confirmed the lack of significance of these findings.  A total of 11 RCTs testing the effects of ketamine on neurocognitive functions with various test batteries found mixed results.  Ketamine alone significantly increased blood pressure (BP) more than other anesthetic drugs in MDD treated with ECT.  The authors concluded that compared to other anesthetic agents, ketamine alone did not appear to improve the efficacy of ECT.  However, ketamine + other anesthetic combinations may confer a short-term advantage in improving depressive symptom at the early stages of ECT.

Ketamine in the Treatment of Generalized Anxiety and Social Anxiety Disorders

Glue and colleagues (2020) previously reported that ketamine has anxiolytic effects in patients with treatment-resistant generalized anxiety disorder (GAD) and social anxiety disorder (SAD).  In a double-blind, psychoactive-controlled, ascending dose study, these researchers attempted to replicate their earlier findings regarding ketamine's anxiolytic activity, using a more robust study design.  This trial included 12 patients with treatment-resistant GAD and SAD who were not currently depressed.  Ascending doses of ketamine (0.25, 0.5, 1 mg/kg) were administered at weekly intervals, and midazolam 0.01 mg/kg, the control, was randomly inserted into the ketamine dose sequence.  Assessments included ratings of anxiety and dissociation, safety and tolerability, and blood samples for ketamine pharmacokinetics and brain-derived neurotrophic factor (BDNF) concentrations.  Improvements in anxiety ratings occurred within an hour of ketamine dosing, and persisted for up to 1 week.  A dose-response profile was noted for anxiolytic effects, dissociative side effects, and changes in blood pressure and heart rate after ketamine dosing.  Midazolam had minor brief effects on anxiety ratings; ketamine was safe and well-tolerated.  Ketamine pharmacokinetics were correlated with dissociation ratings.  Serum BDNF concentrations declined over time and were similar for all treatments.  The authors concluded that ketamine may be a potential therapeutic option for patients with treatment-resistant GAD and SAD.

Ketamine in the Treatment of Substance Use Disorders

Ivan Ezquerra-Romano and associates (2018) examined the pre-clinical and clinical research into ketamine's ability to treat addiction.  Despite methodological limitations and the relative infancy of the field, results thus far are promising.  Ketamine has been shown to effectively prolong abstinence from alcohol and heroin in detoxified alcoholics and heroin dependent individuals, respectively.  Moreover, ketamine reduced craving for and self-administration of cocaine in non-treatment seeking cocaine users.  However, further RCTs are urgently needed to confirm ketamine's efficacy.  Possible mechanisms by which ketamine may work within addiction include: enhancement of neuroplasticity and neurogenesis, disruption of relevant functional neural networks, treating depressive symptoms, blocking reconsolidation of drug-related memories, provoking mystical experiences and enhancing psychological therapy efficacy.  Identifying the mechanisms by which ketamine exerts its therapeutic effects in addiction, from the many possible candidates, is crucial for advancing this treatment and may have broader implications understanding other psychedelic therapies.  The authors concluded that ketamine showed great promise as a treatment for various addictions, but well-controlled research is urgently needed.

Jones and colleagues (2018) stated that despite advances in behavioral and pharmacotherapy interventions, substance use disorders (SUDs) are frequently refractory to treatment.  Glutamatergic dysregulation has received increasing attention as one common neuropathology across multiple substances of abuse.  These investigators reviewed the literature on the efficacy of ketamine in the treatment of SUDs.  A systematic review of the PubMed, Scopus, and ClinicalTrials.gov databases was undertaken to identify completed and ongoing human studies of the effectiveness of ketamine in the treatment of SUDs between January 1997 and January 2018.  A total of 7 completed studies were identified; 2 focused on alcohol use disorder, 2 focused on cocaine use disorder, and 3 focused on opioid use disorder.  Both cocaine studies found improvements in craving, motivation, and decreased cocaine use rates, although studies were limited by small sample sizes, a homogeneous population and short follow-up.  Studies of alcohol and opioid use disorders found improvement in abstinence rates in the ketamine group, with significant between-group effects noted for up to 2 years following a single infusion, although these were not placebo-controlled trials.  The authors noted that these findings suggested that ketamine may facilitate abstinence across multiple substances of abuse and warrants broader investigation in addiction treatment.  They concluded with an overview of the 6 ongoing studies of ketamine in the treatment of alcohol, cocaine, cannabis, and opioid use disorders and discussed future directions in this emerging area of research.  These researchers stated that further studies are urgently needed.

Ketamine in the Treatment of Acute Pain

In a systematic review and meta-analysis, Li and colleagues (2021) compared the efficacy of intra-nasal (IN) ketamine for pain control with placebo and other analgesics in an emergency setting.  Electronic databases of PubMed, Embase, and CENTRAL were searched for RCTs comparing IN ketamine with placebo or other analgesics up to January 1, 2021.  Studies were to be conducted on adults and in an emergency setting; pain outcomes and AEs were compared.  A total of 7 RCTs were included; 3 compared IN ketamine with placebo while others with opioids.  Comparing IN ketamine with opioids, the pooled analysis demonstrated no significant difference in pain scores between the 2 groups at 15 mins, but better pain reduction with opioids at 30 mins.  Comparing IN ketamine with placebo, the analysis demonstrated a non-significant difference but a tendency for better pain relief with IN ketamine at 15 mins and 60 mins.  Pain scores at 30 mins were, however, significantly lower with IN ketamine as compared to placebo.  The need for rescue analgesics was significantly lower with IN ketamine as compared to placebo.  There was no significant difference in the incidence of dizziness and nausea/vomiting between IN ketamine and opioids.  As compared to placebo, IN ketamine was associated with an increased incidence of dizziness but not nausea/vomiting.  Emergence reactions were significantly increased with IN ketamine as compared to opioids and placebo.  The authors concluded that there may be a role of IN ketamine for acute pain management in adults in an emergency setting.  There is a tendency for better pain control with IN ketamine as compared to control and the possibility of similar efficacy of IN ketamine as compared to opioids.  However, the results were not unequivocal and were limited by the low number of studies in literature and limited pain indications studied.  These researchers stated that further RCTs are needed to strengthen the evidence.

The authors stated that this review had several drawbacks.  First, only 7 RCTs were available for analysis.  Furthermore, due to heterogeneity in the comparator drug and limited availability of data, only a few studies could be included in the meta-analysis.  Second, the study population in the included studies was different.  Among the 3 studies comparing IN ketamine versus placebo, 2 included only traumatic pain patients while in the 4 studies comparing IN ketamine with IV opioids 3 included only renal colic patients.  Thus, the generalization of these findings for other pain indications should be performed with caution.  Lastly, as a consequence of imprecision of results and risk of bias due to blinding in 1 trial, the certainty of the evidence for the comparison of IN ketamine and opioids were not high.  Even for the comparison of pain scores between IN ketamine versus placebo, the certainty of the evidence was deemed to be moderate for comparisons at 15 mins and 60 mins.

Ketamine in the Treatment of Central Body Pain

Lo et al (2016) stated that Ehlers-Danlos syndrome frequently causes acute and chronic pain because of joint subluxations and dislocations secondary to hyper-mobility.  Current treatments for pain related to Ehlers-Danlos syndrome and central pain syndrome are inadequate.  In a case report, these researchers discussed the therapeutic use of ketamine intravenous infusion as an alternative.  A 27-year old Caucasian woman with a history of Ehlers-Danlos syndrome and spinal cord ischemic myelopathy resulting in central pain syndrome, presented with severe generalized body pain refractory to multiple pharmacological interventions.  After a 7-day course of ketamine intravenous infusion under controlled generalized sedation in the intensive care unit (ICU) the patient reported a dramatic reduction in pain levels from 7 to 8 out of 10 to 0 to 3 out of 10 on a numeric rating scale (NRS) and had a significant functional improvement.  The patient tolerated a reduction in her pain medication regimen, which originally included opioids, gabapentin, pregabalin, tricyclic anti-depressants, and non-steroidal anti-inflammatory drugs (NSAIDs).  The authors concluded that ketamine infusion treatment has been used in various pain syndromes, including central neuropathic pain, ischemic pain, and regional pain syndrome.  Reports have suggested that ketamine modulates pain by the regression of N-methyl-D-aspartate receptor to a resting state.  As such, propagation of nociceptive signal to brain is interrupted allowing for the restoration of physiological balance between pain inhibition and facilitation.  The present report showed that this therapeutic option can be used in patients with refractory central pain syndrome in the setting of spinal cord myelopathy secondary to Ehlers-Danlos syndrome.  Furthermore, as observed in this case, this protocol could potentially decrease the chronic use of pain medication, such as opioids.  Moreover, these researchers stated that further investigation is needed to establish an evidence-based treatment for pain related to Ehlers-Danlos syndrome.

Wang et al (2021) noted that treatment of central pain syndrome (CPS) is known to be extremely challenging.  Current therapies are unsatisfactory as patients report only mild-to-moderate pain relief.  These investigators reported a case of using ketamine as a patient-controlled analgesia (PCA) for the treatment of CPS.  A 58-year old man with CPS presented with severe generalized body pain refractory to multiple pharmacological interventions.  He was started on a basal infusion rate at 0.3 mg/kg/h with a ketamine PCA bolus of 10 mg with a 10-min lock-out period.  Over the next 7 days, the basal infusion rate was titrated up to 2.1 mg/kg/hour relative to the number of times the patient pressed the PCA.  At the end of the trial, the patient reported 0/10 pain with light-headedness on the 1st day being the only side effect reported.  He was discharged home with his regular pain regimen, with significant decrease in pain over the next few months.  The authors concluded that rather than trying to establish a "one size fits all" protocol for ketamine infusions, this case illustrated a shift in pain management focus by allowing patients to self-titrate and demonstrated the potential for using ketamine PCA as a therapeutic option for CPS.  Again, this was a single-case report.

Furthermore, an UpToDate review on “Central neuropathic facial pain” (Garza, 2021) does not mention ketamine infusion as a management / therapeutic option.

Ketamine in the Treatment of Chronic Pain / Neuropathic Pain

Pickering and associates (2020) stated that ketamine is often used for the management of refractory chronic pain; however, there is a paucity of studies examining its analgesic effect several weeks after IV administration or in association with magnesium.  In a randomized, double-blind, cross-over, placebo-controlled study, these researchers hypothesized that ketamine in neuropathic pain may provide pain relief and cognitive-emotional benefit versus placebo and that a combination with magnesium may have an additive effect for 5 weeks.  This trial included 20 patients with neuropathic pain.  Each ketamine-naive patient received 1 infusion every 35 days in a random order: ketamine (0.5 mg/kg)/placebo or ketamine (0.5 mg/kg)/magnesium sulfate (3 g) or placebo/placebo.  The primary endpoint was the area under the curve (AUC) of daily pain intensity for a period of 35 days after infusion.  Secondary endpoints included pain (at 7, 15, 21 and 28 days) and health-related, emotional, sleep, and quality of life (QOL) questionnaires.  Daily pain intensity was not significantly different between the 3 groups (n = 20) over 35 days (mean AUC = 185 ± 100, 196 ± 92, and 187 ± 90 pain score-days for ketamine, ketamine/magnesium, and placebo, respectively, p = 0.296).  The effect size of the main endpoint was -0.2 (95 % CI: -0.6 to 0.3; p = 0.425) for ketamine versus placebo, 0.2 (95 % CI: -0.3 to 0.6; p = 0.445) for placebo versus ketamine/magnesium and -0.4 (95 % CI: -0.8 to 0.1; p = 0.119) for ketamine versus ketamine/magnesium.  There were no significant differences in emotional, sleep, and QOL measures.  During placebo, ketamine, and ketamine/magnesium infusions, 10 %, 20 %, and 35 % of patients respectively reported at least 1 AE.  The authors concluded that the findings of this study in neuropathic pain refuted the hypothesis that ketamine provided pain relief at 5 weeks and cognitive-emotional benefit versus placebo and that a combination with magnesium had any additional analgesic effect.

van Velzen and colleagues (2021) noted that in humans, proof of long-term efficacy of ketamine treatment in neuropathic pain is lacking.  To improve the understanding of ketamine behavior under various administration conditions, these researchers carried out a systematic review and meta-analyses of controlled studies on the efficacy of ketamine in mice and rats with a disease model of nerve injury on relief of allodynia.  Searches in PubMed and Embase identified 31 unique studies; 4 meta-analyses were performed.  The first analysis included 19 comparisons on a single ketamine dose and measurement of effect within 3 hours of dosing and showed an appreciable effect (standardized mean difference [SMD] 1.6, 95 % CI: 1.1 to 2.1).  Subgroup analyses showed no effect of species, administration route, or dose.  A single administration was insufficient to sustain relief of allodynia at 24 or 72 hours after dosing, as observed in the second analysis (7 comparisons) with similar effects in ketamine-treated and control animals.  Chronic ketamine administration (9 comparisons) resulted in profound relief of allodynia when tested during ketamine exposure (effect size 5.1, 3.7 to 6.5).  The final analysis (6 comparisons) showed that chronic administration caused a slow loss of relief of allodynia with 70 % loss of effect 24 days after end of treatment.  No subgroups analyses were possible in the last 3 meta-analyses due to small group sizes.  The authors concluded that these findings indicated long-term ketamine anti-allodynic effects after chronic exposure (greater than 3 days) but not after a single administration.  Moreover, these researchers stated that given several limitations, extrapolation of the animal data to the human condition is tenuous.

Corriger and colleagues (2022) stated that ketamine is often used in pain clinics for refractory chronic pain; however, its long-term efficacy is poorly reported.  In a prospective, multi-center, 1-year follow-up observational study, these researchers examined the long-term effect of ketamine on pain and health variables in patients with refractory chronic pain.  This trial was carried out in 30 French pain clinics where ketamine is commonly prescribed.  This study focused on patients with one ketamine delivery procedure (n = 256).  The primary endpoint was pain intensity (0 to 10 numerical pain rating scale) before and after ketamine every month for 1 year.  Secondary outcomes aimed to identify pain trajectories by semi-parametric mixture models and to collect AEs.  The following data were obtained for 256 patients: pain intensity decreased significantly (6.8 ± 1.8, n = 240 at baseline versus 5.7 ± 1.8, n = 93 at 12 months, p < 0.001).  The effect size of the main endpoint was 0.61 (95 % CI: 0.40 to 0.80; p < 0.001).  A total of 3 pain trajectories were identified: 16.0 % of patients in "mild pain" (mostly neuropathic pain), 35.3 % in "moderate pain" and 45.7 % in "severe pain" (mostly fibromyalgia) trajectory.  Neuropathic pain and fibromyalgia presented opposite outcomes, pain severity being associated with anxiety, depression and a poorer QOL; AEs occurred at 1 week in 108/218 (50 %) patients and this rate gradually decreased throughout the follow-up.  The authors concluded that this real-life study in chronic pain identified distinct pain trajectories and predictive variables of ketamine efficacy.  It is now pivotal to further study and optimize the subtyping of patients to provide the most safe and effective ketamine treatment in this vulnerable population.

Ketamine in the Treatment of Post-Concussion Syndrome

An UpToDate reviews on “Postconcussion syndrome” (Evans, 2021) does not mention ketamine infusion as a management / therapeutic option.

Ketamine in the Treatment of Sickle Cell Vaso-Occlusive Crises

Hagedorn and Monico (2019) noted that sickle cell disease (SCD) is the most common hemoglobin variant in the world and can present with recurrent painful vaso-occlusive crises (VOC).  Pain control in these patients is often difficult and requires a multi-modal approach.  In patients with uncontrolled pain after traditional pain control methods, ketamine infusions have been used.  Unfortunately, no source alone had described ketamine infusions for pediatric patients with SCD.  These investigators provided a thorough definitive reference for health care providers regarding the use of ketamine infusion for pain control in pediatric painful VOC.  Low-dose ketamine infusions for pediatric patients with SCD painful crises resulted in improved pain scores and reduced opioid usage.  The authors concluded that ketamine infusions have shown promise in aiding physicians in appropriately treating pediatric sickle cell painful crises.

In a Cochrane review on pharmacological interventions for painful VOC in adults with SCD, Cooper and colleagues (2019) noted that they found no difference in mean pain scores between ketamine/hydromorphone and placebo/hydromorphone on a VAS (1 to 10 cm): ketamine/hydromorphone (5.2 cm; 95 % CI: 4.01 to 6.46; 40.2 % decrease from baseline), placebo/hydromorphone (5.6 cm; 95 % CI: 4.27 to 6.93; 34.1 % decrease from baseline) (1 study, very low‐quality evidence).  The authors concluded that this review identified only 9 studies, with insufficient data for all pharmacological interventions for analysis.  The available evidence is very uncertain regarding the efficacy or harm from pharmacological interventions used to treat pain related to sickle cell VOC in adults.  These researchers stated that this area could benefit most from more high-quality, certain evidence, as well as the establishment of suitable registries that record interventions and outcomes for this group of individuals.

Alghamdi and Al-Shahrani (2020) stated that VOC is one of the main causes of hospital admission in patients with SCD.  Ketamine is often used as adjuvant to opioids to control sickle cell crisis, however, there is a lack of class I evidence regarding its safety and efficacy for VOC in SCD patients.  In a systematic review and meta-analysis, these researchers examined the evidence from published reports about the safety and efficacy of ketamine in the management of acute painful VOC in both children and adult SCD patients.  They carried out a systematic literature search of PubMed, Scopus, Web of Science, EBSCO, and Cochrane library up to March 2019; and selected studies reporting the analgesic effects and side effects of ketamine in the management of acute painful VOC in both children and adult sickled patients.  The primary outcome measure was the improvement in pain scale; and the secondary outcomes were opioid use and side effects.  Case reports and case series were narratively summarized while comparative studies were pooled in meta-analysis models.  A total of 14 studies (n = 581 patients) were included in the final analysis.  Several case reports and case series showed that ketamine significantly reduced pain scales and opioid use in children and adults with VOCs.  However, meta-analysis of 2 studies on children showed no significant difference between ketamine and control group in terms of change on pain scales (MD 0.42, 95 % CI: -0.25 to 1.09, p = 0.22).  In terms of side effects, ketamine was associated with more AEs than the control group (OR 15.9, 95 % CI: 5.85 to 43.33, p < 0.0001).  The authors concluded that this systematic review of the published literature showed that ketamine has a potentially comparable efficacy with other opioids in reducing the pain during VOC in SCD patients.  However, a higher rate of transient AEs was reported in the ketamine group.  Moreover, these researchers stated that due to the lack of published RCTs, current evidence is insufficient to confirm the safety and efficacy ketamine.  They stated that future well-designed RCTs are strongly recommended.

In a review on “Integrative approaches to treating pain in sickle cell disease” (Sagi et al, 2020), ketamine is not mentioned as a therapeutic option.

An UpToDate review on “Acute vaso-occlusive pain management in sickle cell disease” (DeBaun, 2021) states that “Ketamine may be appropriate in individuals with severe pain not responsive to standard opioid analgesics … Ketamine should only be used by programs experienced and trained with its use and following a standardized protocol”.  However, ketamine is not listed in the “Summary and Recommendations” section of this UTF review.

Ketamine in the Treatment of Post-Traumatic Stress Disorder

Feder et al (2021) noted that post-traumatic stress disorder (PTSD) is a chronic and disabling disorder, for which available pharmacotherapies have limited effectiveness.  These investigators' previous proof-of-concept RCT of single-dose IV ketamine infusion in individuals with PTSD showed significant and rapid PTSD symptom reduction 24 hours post-infusion.  Theis trial was the 1st RCT to test the safety and effectiveness of repeated IV ketamine infusions for the treatment of chronic PTSD.  Patients with chronic PTSD (n = 30) were randomly assigned (1:1) to receive 6 infusions of ketamine (0.5 mg/kg) or midazolam (0.045 mg/kg) (psycho-active placebo control) over 2 consecutive weeks.  Clinician-rated and self-report assessments were administered 24 hours after the 1st infusion and at weekly visits.  The primary outcome measure was change in PTSD symptom severity, as assessed with the Clinician-Administered PTSD Scale for DSM-5 (CAPS-5), from baseline to 2 weeks (after completion of all infusions).  Secondary outcome measures included the Impact of Event Scale-Revised, the Montgomery-Asberg Depression Rating Scale (MADRS), and side effect measures.  The ketamine group showed a significantly greater improvement in CAPS-5 and MADRS total scores than the midazolam group from baseline to week 2.  At week 2, the mean CAPS-5 total score was 11.88 points (SE = 3.96) lower in the ketamine group than in the midazolam group (d = 1.13, 95 % CI: 0.36 to 1.91); 67 % of subjects in the ketamine group were treatment-responders, compared with 20 % in the midazolam group.  Among ketamine responders, the median time to loss of response was 27.5 days following the 2-week course of infusions.  Ketamine infusions were well-tolerated overall, without serious AEs.  The authors concluded that this RCT provided the 1st evidence of effectiveness of repeated ketamine infusions in reducing symptom severity in individuals with chronic PTSD.  Moreover, these researchers stated that further research is needed to examine the effectiveness of novel interventions to prevent PTSD symptom relapse over time, including clinical trials to evaluate the safety, tolerability, and efficacy of periodic IV ketamine (or intra-nasal esketamine) administration as maintenance over several months, which has been studied in patients with treatment-resistant depression, and studies examining whether combining repeated ketamine administration with evidence-based psychotherapy for PTSD can help reduce the likelihood of relapse following cessation of ketamine infusions.

The authors stated that among the limitations of this study was the exclusion of patients with co-morbid psychotic, bipolar, or current alcohol or substance use disorders in order to protect against worsening of psychotic symptoms or abuse potential, which may limit the generalizability of these findings.  Patients with active suicidal ideation were also excluded, because examining the effectiveness of repeated ketamine administration in reducing suicidality in patients with PTSD was beyond the scope of this study.  Other limitations included the relatively small sample size (n = 15 in the treatment group), as well as the higher rate of transient dissociative symptoms in the ketamine group potentially affecting the blind.  Although 3 subjects in the ketamine group used marijuana, only 1 of them continued to use marijuana during the 2-week treatment phase, and the remaining 2 resumed use only after the primary outcome assessment day, during the follow-up phase.  Finally, although use of concomitant psychotropic medications was permitted, this study was not designed to evaluate the effectiveness of repeated ketamine infusions in patients with treatment-resistant PTSD, which should be examined in future studies.  Of note, intra-nasal esketamine, the S-enantiomer of ketamine, is FDA-approved as an adjunctive treatment for patients with TRD and also for the treatment of depressive symptoms in adults with MDD with acute suicidal ideation or behavior.

Shiroma et al (2022) stated that ketamine has been studied for its rapid anti-depressant effect and, more recently, for its potential use in PTSD.  The proposal that ketamine's anti-depressant and anti-suicidal mechanism may be in part due to its pro-cognitive effect contrasts with the well-established decreased performance on spatial working memory and pattern recognition memory among long-term frequent users.  These investigators reviewed the neurocognitive effects of sub-anesthetic doses of IV ketamine in pharmacological studies among healthy subjects and patients with PTSD or depression.  They included studies in English, among healthy adults, or with PTSD or unipolar or bipolar depression where the primary or secondary cognitive outcomes were measured by means of validated neuropsychological test.  These researchers excluded studies that examined the use of ketamine only in combination with other drugs or psychotherapy, or studies examining emotion-laden cognitive functions.  Ketamine administration among patients with depression and possibly with PTSD did not show significant impairment of cognitive functions in the short-term, in contrast with the immediate altered cognitive dysfunction found in healthy subjects.  The potential pro-cognitive effects of ketamine appeared more pronounced in cognitive domains of executive function, which is in line with the putative molecular, cellular, and synaptic mechanisms of ketamine's therapeutic action.  The authors concluded that the potential pro-cognitive effect of ketamine deserves further exploration.  Whether ketamine has transient or sustained neurocognitive benefits beyond its anti-depressant effects is unknown.  Improved cognition by ketamine might be used to facilitate psychotherapy interventions for PTSD and depression.

In an open-label study, Albott et al (2022) examined changes in neurocognitive performance following a repeated ketamine dosing regimen, and baseline neurocognitive performance as a predictor of ketamine treatment effect.  Veterans with co-morbid PTSD and MDD (n = 15) received 6 infusions of 0.5 mg/kg ketamine over a 12-day period.  Neurocognitive and clinical outcomes assessments occurred at baseline and within 7 days of infusion-series completion using the CogState battery.  Repeated ketamine infusions did not significantly worsen any measures of cognition.  Rather, significant improvement was observed in working memory following completion of the infusion series.  furthermore, greater improvements in PTSD and MDD symptoms were associated with lower working memory, slower processing speed and faster set shifting at baseline.  Lower verbal learning was also predictive of improvement in depression.  The authors concluded that this was the 1st study to examine the neurocognitive effects of repeated ketamine in patients with co-morbid PTSD and MDD.  These researchers stated that these findings suggested potential baseline neurocognitive predictors of ketamine response for co-morbid PTSD and MDD symptoms.   Moreover, they stated that this study applied an open-label design without a placebo control.  As such, it is unclear to what extent the correlations or improvement in neurocognitive performance may have occurred under placebo conditions.

Elsouri et al (2022) stated that the psychopharmacology of psychedelics has been extensively examined over the last 2 decades.  For many years, research has focused on the pernicious effects of psychedelics while disregarding the clinical benefits these drugs may serve.  The more recent shift in policies and public opinion provides a new horizon for the use of psychoactive drugs in managing PTSD.  The prevalence rate for PTSD ranges between 6 % to 8 % among the general public and significantly higher amongst veterans.  Effects of PTSD could involve intrusive thoughts and images, phobic avoidance, pathological hyper-arousal, hyper-vigilance, irritability and anger, and depression.  Traditional treatments employ trauma-focused cognitive behavioral therapy (CBT) and/or pharmacotherapy to modify and treat PTSD behavior.  Approximately 2/3 of patients have shown a response rate to traditional treatment with pharmacotherapy; however, 40 % or less have shown remission.  This forms the basis on which other agents such as 3,4-methylenedioxymethamphetamine (MDMA), ketamine, and psilocybin are being researched.  These investigators noted that a systematic review (Abdallah et al, 2019) found that the quality of evidence supporting the use of ketamine as a stand-alone treatment for co-morbid PTSD with depression was “very low”.  However, when ketamine was used in combination with psychotherapy, improvement of symptoms was sustained for approximately 1 month.  Furthermore, results from this systematic review showed the evidence for 3,4-methylenedioxymethamphetamine (MDMA) in combination with psychotherapy was graded as “moderate”.  The authors concluded that ketamine use shows promise in PTSD patients as well as co-morbid TRD.  They stated that more studies need to be carried out to demonstrate the resolution and remission in comparison to a placebo.

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References