Authors:
Madeline BrendleIntegrated Research Literacy Group, Draper, UT, USA
Department of Pharmacotherapy, University of Utah College of Pharmacy, SLC, UT, USA
Numinus Wellness, Draper, UT, USA
Department of Psychology and Neuroscience, Duke University, Durham, NC, USA

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Anya RagnhildstveitIntegrated Research Literacy Group, Draper, UT, USA
Department of Psychology and Neuroscience, Duke University, Durham, NC, USA
Department of Pyschiatry, University of Cambridge, Cambridge, England, UK

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Matthew SlaytonIntegrated Research Literacy Group, Draper, UT, USA
Department of Psychology and Neuroscience, Duke University, Durham, NC, USA

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Leo SmartIntegrated Research Literacy Group, Draper, UT, USA
Numinus Wellness, Draper, UT, USA
Department of Neuroscience, Bates College, Lewiston, ME, USA

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Sarah CunninghamIntegrated Research Literacy Group, Draper, UT, USA

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Mackenzie H. ZimmermanIntegrated Research Literacy Group, Draper, UT, USA

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Paul SeliDepartment of Psychology and Neuroscience, Duke University, Durham, NC, USA

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Michael Santo GaffreyDepartment of Psychology and Neuroscience, Duke University, Durham, NC, USA

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Lynnette Astrid AverillMenninger Department of Psychiatry, Baylor College of Medicine, Houston, TX, USA
Michael E. DeBakey Veterans Affairs Medical Center, Houston, TX, USA
Department of Psychiatry, Yale School of Medicine, New Haven, CT, USA
US Department of Veterans Affairs, National Center for PTSD – Clinical Neuroscience Division, West Haven, CT, USA

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Reid RobisonNuminus Wellness, Draper, UT, USA
Department of Psychiatry, University of Utah School of Medicine, UT, USA

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Open access

Abstract

Background and Aims

Ketamine and esketamine have garnered interest in both psychiatric research and clinical practice for treatment-resistant depression (TRD). In this review, we examined registered trials investigating the therapeutic use of ketamine or esketamine for TRD, with the aim of characterizing emerging trends and knowledge gaps.

Methods

The ClinicalTrials.gov electronic registry and results database was queried from inception to February 5, 2022, adhering to elements of the PRISMA guideline, we evaluated trial eligibility in the qualitative synthesis. Data regarding study design, drug regimens, and measures were subsequently abstracted and descriptively analyzed.

Results

The search returned 86 records, of which 56 trials were included in the final review. The number of trials investigating ketamine and esketamine for TRD increased since 2008, with higher peaks observed in 2015 (n = 9) and 2021 (n = 9). Most trials were Phase 2 (13, 23.2%) or Phase 3 (11, 19.6%), gathering preliminary data on efficacy and/or further data on safety and efficacy with variant dosing and pharmacological approaches. By and large, trials examined ketamine and esketamine as individual versus combination treatments (45% and 25%, respectively). The Montgomery-Asberg Depression Rating Scale (MADRS) was most commonly used to assess clinical outcomes (75%).

Conclusions

There are increasingly large-scale and late-phase trials of esketamine over ketamine for TRD, coupled with efforts to centralize evidence on these medications. Yet several trials do not assess patient characteristics that may affect treatment response, such as age, sex, and race. By understanding these design limitations, scientists and clinicians can avoid research waste and funding bodies can judiciously direct support towards high priority research.

Abstract

Background and Aims

Ketamine and esketamine have garnered interest in both psychiatric research and clinical practice for treatment-resistant depression (TRD). In this review, we examined registered trials investigating the therapeutic use of ketamine or esketamine for TRD, with the aim of characterizing emerging trends and knowledge gaps.

Methods

The ClinicalTrials.gov electronic registry and results database was queried from inception to February 5, 2022, adhering to elements of the PRISMA guideline, we evaluated trial eligibility in the qualitative synthesis. Data regarding study design, drug regimens, and measures were subsequently abstracted and descriptively analyzed.

Results

The search returned 86 records, of which 56 trials were included in the final review. The number of trials investigating ketamine and esketamine for TRD increased since 2008, with higher peaks observed in 2015 (n = 9) and 2021 (n = 9). Most trials were Phase 2 (13, 23.2%) or Phase 3 (11, 19.6%), gathering preliminary data on efficacy and/or further data on safety and efficacy with variant dosing and pharmacological approaches. By and large, trials examined ketamine and esketamine as individual versus combination treatments (45% and 25%, respectively). The Montgomery-Asberg Depression Rating Scale (MADRS) was most commonly used to assess clinical outcomes (75%).

Conclusions

There are increasingly large-scale and late-phase trials of esketamine over ketamine for TRD, coupled with efforts to centralize evidence on these medications. Yet several trials do not assess patient characteristics that may affect treatment response, such as age, sex, and race. By understanding these design limitations, scientists and clinicians can avoid research waste and funding bodies can judiciously direct support towards high priority research.

Introduction

Major depressive disorder (MDD) is one of the most common psychiatric conditions in the United States (US), and a leading cause of years lived with disability (YLD) worldwide (Johnston, Powell, Anderson, Szabo, & Cline, 2019; NIMH, 2022). First-line treatment for MDD is generally comprised of monoaminergic antidepressants, specifically selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) (NIMH, 2022). However, even when optimally delivered, up to 67% of patients show clinical non-response, a subset of whom progress to a chronic refractory state (Johnston et al., 2019; Warden, Rush, Trivedi, Fava, & Wisniewski, 2007). Moreover, each treatment failure is associated with a decline in successful intervention experience. A study evaluating the trajectory of antidepressant response to treatment found remission rates, based on a standard depression inventory, of 36.8, 30.6, 13.7, and 13.0% for the first, second, third, and fourth acute treatment steps, respectively (Rush et al., 2006). Furthermore, those who required additional treatment steps demonstrated higher relapse rates, even when benefit was eventually noted (Rush et al., 2006). Treatment-resistant depression (TRD) is characterized as failure to respond to two or more antidepressant trials of adequate dose and duration, aimed at treating the current depressive episode (Hough, 2019; Ionescu, Rosenbaum, & Alpert, 2015). The prevalence of TRD among patients with MDD is estimated at 30%, disproportionally accounting for MDD's burden of disease (Amos et al., 2018; Ionescu et al., 2015; Rush et al., 2006). Importantly, patients with TRD have an all-cause mortality rate that is 7–16 times higher than those responsive to first-line treatments (Brenner, Reutfors, Nijs, & Andersson, 2021).

At present, few interventions exist for TRD (Ionescu et al., 2015). Several pharmacotherapy regimens are thus used in clinical practice including switching or combining antidepressants as well as augmentation with second-generation antipsychotics or lithium (Ionescu et al., 2015; Luan, Wan, Wang, Li, & Zhang, 2017; NIMH, 2022). Olanzapine, an atypical antipsychotic, combined with fluoxetine is specifically indicated for TRD; though, this combination can produce undesired side effects, such as weight gain and extrapyramidal symptoms (i.e., tremors or involuntary muscle contraction) (Moser, 2018; Sanacora, Treccani, & Popoli, 2012). Further, most oral antidepressants take several weeks to initiate symptom improvement, resulting in considerable increased risk for suicidal behavior and mortality in the interim (Machado-Vieira et al., 2010; NIMH, 2022). Non-pharmacological treatment for TRD includes somatic therapies, namely transcranial magnetic stimulation (TMS), in addition to electroconvulsive therapy (ECT) and deep brain stimulation (DBS) (Cusin & Dougherty, 2012; Dandekar, Fenoy, Carvalho, Soares, & Quevedo, 2018; Li, Cui, Li, Liu, & Chen, 2021). However, TMS, ECT, and DBS are time-intensive and costly, with each carrying significant limitations (Cusin & Dougherty, 2012). First, TMS is not fully supported by trials on TRD, with small sample sizes, variable treatment schedules, and high drop-out rates (Cusin & Dougherty, 2012). Second, ECT, despite its efficacy, is linked to acute cognitive deficit as well as amnesia (Cusin & Dougherty, 2012). Finally, DBS is an experimental surgical procedure associated with substantial risk and slow onset of action to relieve depressive symptoms (Cusin & Dougherty, 2012). Taken together, there is a serious unmet need for novel, rapid-acting treatments for patients with TRD who may be at imminent risk of suicidal ideation (Hasin et al., 2018; Jakuszkowiak-Wojten et al., 2019; Kim, Farchione, Potter, Chen, & Temple, 2019).

Ketamine, which was first approved by the US Food and Drug Administration (FDA) in 1970 as an anesthetic and analgesic agent, has been increasingly used as an off-label treatment for psychiatric disorders when delivered at low doses (Sanacora et al., 2017). The drug is a non-competitive antagonist of N-methyl-d-aspartate (NMDA) glutamate receptors, and a 1:1 racemic mixture of its S- and R-enantiomers (Kim et al., 2019; Sanacora et al., 2017). Compared to the R-enantiomer, the S-enantiomer binds to the NMDA receptor with greater affinity and has stronger anesthetic and analgesic action, producing less lethargy and cognitive impairment (Agboola, Atlas, Touchette, Fazioli, & Pearson, 2020). Common reported physiological effects of ketamine include dissociation, changes in sensory perception, and slight increases in blood pressure (Szarmach, Cubała, Włodarczyk, & Wiglusz, 2019; Zanos & Gould, 2018). Ketamine can be administered through various routes; however, most research to date is on intravenous (IV) infusions, with dose ranges of 0.5–1.0 mg kg−1 over 40–60 min (Andrade, 2017; R. S. McIntyre et al., 2021). Of significance, the bioavailability (BA) of ketamine is a function of the route of administration (i.e., IV: BA = 100%, intramuscular (IM): BA = 90–95%, intranasal (IN): BA = 30–50%, oral: BA = 10–20%) (R. S. McIntyre et al., 2021).

While ketamine is administered off-label for psychiatric disorders, the S-enantiomer (esketamine) was synthesized into a prescription nasal spray by Janssen Pharmaceuticals, gaining FDA approval in March of 2019 for adults with TRD (Agboola et al., 2020; Janssen, 2019; Kim et al., 2019). This represented the first novel treatment for the condition since the advent of SSRIs in 1987. In terms of efficacy, a meta-analysis of four phase 3 randomized controlled trials (RCTs) on esketamine (initiated with an oral antidepressant) and TRD reported significant pooled risk ratios for response (RR = 1.40 P < 0.0001) and remission (RR = 1.45, P < 0.0001) compared to an oral antidepressant alone (Papakostas et al., 2020). Moreover, in a longer-term, randomized withdrawal study, esketamine reduced the risk of relapse by 51 and 70% among stable remitters and responders, respectively (Daly et al., 2019). In regard to, there have been several trials demonstrating its short-term efficacy for TRD (Murrough et al., 2013; Newport et al., 2015; Singh et al., 2016). A recent meta-analysis found that patients given a single ketamine infusion experienced rapid reduction in depressive symptoms during the first 24 h, with effects decreasing at seven days post-infusion (Marcantoni et al., 2020). These findings are especially pertinent to individuals requiring immediate intervention, as in the case of concurrent, active suicidality.

The literature on ketamine and esketamine for TRD is promising, yet there remain urgent questions regarding their comparative and long-term safety and efficacy, as well as patient suitability (R. S. McIntyre et al., 2021). Additionally, there are uncertainties around the infrastructure and personnel required for safe use, the appropriate setting for administration, and the dosing schedule for continued treatment (R. S. McIntyre et al., 2021; Sanacora et al., 2017). These concerns are further magnified by the rapid increase in healthcare providers who have introduced ketamine and esketamine into their scope of practice, despite the lack of real-world, evidence-based practice guidelines (R. S. McIntyre et al., 2021; Thielking, 2018; Wilkinson, Howard, & Busch, 2019; Wilkinson et al., 2017).

Given that trials frequently take years to conclude, publish results, and translate findings to clinical care, we chose to systematically investigate registered trials of ketamine and esketamine for TRD. This review aims to characterize pipeline trends, identify strengths and gaps in study design, and inform resource allocation. It also seeks to supplement existing knowledge on these medications published in the literature (Agboola et al., 2020; McIntyre et al., 2020; R. S. McIntyre et al., 2021; Papakostas et al., 2020).

Method

We performed a systematic review combining elements from the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guideline with methods for examining ongoing trials of serotonergic and classical psychedelics in psychiatric research (Peyrovian et al., 2020; Shamseer et al., 2015; Siegel et al., 2021). The review protocol was registered a priori through the Open Science Framework (Center for Open Science), which can be accessed via the digital object identifier (DOI): 10.17605/OSF.IO/BM6V4. Trial records were identified by searching the publicly available electronic database, ClinicalTrials.gov, operated by the U.S. National Library of Medicine (NLM) at the National Institute of Health (NIH). The query was executed from inception (i.e., establishment of the database) to February 5, 2022, using the following search string: ((“ketamine” [other terms] OR “esketamine” [other terms]) AND (“treatment-resistant depression” [condition or disease])). No publication date nor language restrictions were applied.

Inclusion criteria consisted of a) patients diagnosed with TRD of any age and biological sex, per trial eligibility criteria; b) ketamine or esketamine investigated as a primary intervention, either mechanistically (basic science) and/or therapeutically (treatment); c) non-randomized or randomized trials (Early Phase through Phase 4) that had concluded (status: “completed”), were active or active plus recruiting (status: “recruiting”, “enrolling by invitation”, or “active, not recruiting”), or were preparing for recruitment (status: “not yet recruiting”); and d) records posted in the English language. Trials failing to meet full inclusion criteria and/or were specified as “unknown”, “suspended”, “terminated”, or “withdrawn” were excluded.

Search results were independently screened by two authors (M.S. and S.C.) who examined titles (“official title”) and abstracts (“brief summary”). Relevant trials were subsequently identified for full text screening and assessed for eligibility. Discrepancies were resolved by discussion and involvement of a third member (M.B.) of the research team, as applicable. Data was then extracted from eligible trials, including: condition/disease, intervention/treatment, study population, groups/cohorts, study type and phase, target enrollment, estimated start and end date, allocation, interventional model, masking, outcome measures, drug regimen, sample characteristics, results, location, and funder type/sponsor. Following extraction of pertinent parameters, data were descriptively analyzed using STATA 16 (StataCorp, 2019).

Results

The initial search returned 86 records in ClinicalTrials.gov. Of these, 56 met criteria for inclusion in the final review (35% excluded) (Fig. 1). The number of trials investigating ketamine and esketamine for TRD increased since 2008, with higher peaks in 2015 (n = 9) and 2021 (n = 9) (Fig. 2). Most trials were Phase 2 (13, 23.2%) or Phase 3 (11, 19.6%), gathering preliminary data on efficacy and/or further data on safety and efficacy with variant dosing and pharmacological approaches (Table 1, Fig. 3).

Fig. 1.
Fig. 1.

PRISMA flow diagram

Citation: Journal of Psychedelic Studies 6, 3; 10.1556/2054.2022.00234

Fig. 2.
Fig. 2.

Number of new trials initiated each year investigating esketamine or ketamine for TRD

Citation: Journal of Psychedelic Studies 6, 3; 10.1556/2054.2022.00234

Table 1.

Characteristics of trial records

Characteristicsn (%)Characteristicsn (%)
TherapyIntervention model
Esketamine14 (25.0)Parallel31 (55.4)
Esketamine combination5 (8.9)Single Group20 (35.7)
Ketamine25 (44.6)Crossover4 (7.1)
Ketamine combination12 (21.4)Sequential1 (1.8)
SexMasking
Inclusive56 (100)Single3 (5.4)
Age groupDouble14 (25)
Child/adolescent (<18)2 (3.6)Triple5 (8.9)
Adult (18–64)16 (28.6)Quadruple9 (16.1)
Adult/older adult (18++)36 (64.3)None25 (44.6)
Older adult (>64)2 (3.6)Data monitoring committee
Primary purposeMonitoring committee26 (46.4)
Treatment51 (91.1)No monitoring committee30 (53.6)
Basic Science5 (8.9)Neuroimaging methods
Study typeNeuroimaging5 (8.9)
Interventional48 (85.7)No neuroimaging51 (91.1)
Observational6 (10.7)Site location (country)
Patient Registries1 (1.8)United States30 (53.6)
Expanded Access1 (1.8)Canada4 (7.1)
Study phaseAustria2 (3.6)
Early phase I1 (1.8)Poland2 (3.6)
Phase I3 (5.4)Japan1 (1.8)
Phase I/II1 (1.8)Mexico1 (1.8)
Phase II13 (23.2)Taiwan1 (1.8)
Phase II/III2 (3.6)United Kingdom1 (1.8)
Phase III11 (19.6)Multisite14 (25.0)
Phase IV8 (14.3)Sponsor type
Not applicable17 (30.4)Academic 26 (46.4)
Study statusIndustry20 (35.7)
Completed32 (57.1)Federal4 (7.1)
Recruiting15 (26.8)Other6 (10.7)
Enrolling by Invitation1 (1.8)Results posted
Active – Not Recruiting4 (7.1)Results20 (35.7)
Approved for Marketing1 (1.8)No results36 (64.3)
Not Yet Recruiting3 (5.4)Publications
AllocationPublications32 (57.1)
Randomized34 (60.7)No publications24 (42.9)
Non-randomized2 (3.6)
Not applicable20 (35.7)
Fig. 3.
Fig. 3.

Number of new trials initiated each year investigating esketamine or ketamine for TRD by study phase. NA, not applicable (i.e., observational study). a. Esketamine/Esketamine Combination. b. Ketamine/Ketamine Combination

Citation: Journal of Psychedelic Studies 6, 3; 10.1556/2054.2022.00234

By and large, trials investigated ketamine or esketamine as sole therapeutics (ketamine: 25 [45%], esketamine: 14 [25%]). The overwhelming majority were interventional in nature (91%), with a small number of mechanistic trials (9%) (Table 1). Others evaluated them as combination therapies (ketamine: 12 (21%), esketamine: 5 (9%)). In ketamine trials, this included clonidine (sedative, antihypertensive), lithium (mood stabilizer), brexpiprazole (atypical antipsychotic), and permpanel (antiepileptic) as well as TMS, ECT, cognitive behavioral therapy (CBT), and music therapy. Several routes of administration were employed, spanning IV (28, 76%), IN (6, 16%), and IM (1, 3%) (Supplementary Table S2). Two (5%) trials had unknown routes for ketamine administration. Comparatively, in esketamine trials, only oral antidepressants were used as a combination treatment. The IN administration route was leveraged most often for esketamine (17, 89%), except for two (11%) trials that utilized IV infusion.

To assess outcomes of ketamine or esketamine treatment, 22 (39%) trials used subjective measures, 3 (5%) used objective measures, and 31 (55%) employed both (Table 1). Of the trials utilizing subjective measures, the following were most prevalent: Montgomery–Åsberg Depression Rating Scale (MADRS; 42, 75%), Clinical Global Impressions Scale (CGI; 21, 38%), Patient Health Questionnaire-9 (PHQ-9; 12, 21%), European Quality of Life Five Dimension (EQ-5D-5L; 11, 20%), Clinician-Administered Dissociative States Scale (CADSS; 10, 18%), Generalized Anxiety Disorder-7 (GAD-7; 9, 16%), Columbia Suicide Severity Rating Scale (CSSRS; 8, 14%), Sheehan Disability Scale (SDS; 8, 14%), Hamilton Depression Rating Scale (HAM-D; 7, 13%), and Quick Inventory of Depression Symptomatology (QIDS; 5, 9%) (Supplementary Table S2). There were additionally 5 (8.9%) trials that leveraged neuroimaging techniques, including magnetic resonance spectroscopy, magnetic resonance imaging, and functional magnetic resonance imaging (Table 1).

No trials were exclusive based on sex, and the majority enrolled adults and/or older adults (36, 64.3%) (Table 1). Target trial enrollment ranged from 9 to 1,148 participants (Table 2). The largest number of estimated or actual participants in esketamine trials were enrolled in randomized, parallel assignment, Phase 3 trials among adults and/or older adults. The majority of participants in ketamine trials were enrolled in trials with the same characteristics as esketamine trials with majority enrollment except for the study phase. Most participants enrolled in ketamine trials were enrolled in Phase 2 trials or those wherein phase was not applicable (i.e., observational).

Table 2.

Enrollment based on trial characteristics

All trialsEsketamine/Esketamine combinationKetamine/Ketamine combination
Trials (n = 19)ParticipantsTrials (n = 37)Participants
n (%)MedianMinimumMaximumSumn (%)MedianMinimumMaximumSum
Age group
Child/adolescent2 (5)34145468
Adult9 (47)202307192,0117 (19)369110341
Adult/older adult8 (42)320101,1483,38326 (70)3194001,445
Older adult1 (5)1391391391391 (3)30303030
Primary purpose
Treatment18 (95)196101,1485,53331 (84)3394001,685
Basic Science5 (14)36970199
Study Type
Interventional17 (89)202301,1485,52331 (84)3094001,570
Observational1 (5)101010105 (14)6013120314
Patient Registries1 (3)NANANANA
Expanded Access1 (5)NANANANA
Study Phase
Early phase I1 (3)20202020
Phase I3 (8)10162460
Phase I/II1 (3)70707070
Phase II4 (21)98302024289 (24)60999465
Phase II/III2 (5)2059400409
Phase III10 (53)299301,1484,3851 (3)33333333
Phase IV2 (11)3201904506406 (16)412062244
Not applicable2 (11)4010708013 (35)2813120583
Study Status
Completed11 (58)202108022,93221 (57)28999773
Recruiting4 (21)1303745074710 (27)6020400877
Enrolling by Invitation1 (3)20202020
Active – Not Recruiting2 (11)9126761,1481,8242 (5)7030110140
Approved for Marketing1 (5)NANANANA
Not Yet Recruiting1 (5)303030302 (5)37205474
Allocation
Randomized13 (68)202307193,34621 (57)46154001,349
Non-randomized2 (5)45306090
Not applicable5 (26)190101,1482,18713 (35)209120445
Intervention model
Parallel13 (68)202307193,34618 (49)57154001,303
Single Group5 (26)190101,1482,18713 (35)209120445
Crossover4 (11)221646106
Sequential1 (3)30303030

Sponsor type varied across trials included in this review, with 26 (46.4%) university sponsored, 20 (35.7%) industry sponsored, 4 (7.1%) federally-sponsored, and 6 (10.7%) sponsored by other organizations. Moreover, the majority of trials were single site and located in the US (30, 53.6%). Other single site locations included Canada (4, 7.1%), Austria (2, 3.6%) Poland (2, 3.6%), Japan (1, 1.8%), Mexico (1, 1.8%), Taiwan (1, 1.8%), and England (1, 1.8%). The remaining 14 (25%) trials were multiple site (Table 1).

Discussion

Registered trials of ketamine and esketamine for TRD revealed critical trends in the research pipeline. Compared to ketamine, there are more large-scale and late-phase trials investigating esketamine for TRD. This reflects the time period initiated in 2015 of large Phase 3 trials on esketamine, which are included in this review, leading to the FDA approval of esketamine for TRD in 2019 (FDA, 2019b). However, due to economic factors and patent law in the pharmaceutical industry, it is unlikely that such trials on ketamine will be conducted (Sanacora et al., 2017). Ketamine's expired patent is specifically unprofitable for pharmaceutical companies to conduct further research under, given its anesthetic and analgesic use for over half a century (Wei, Chang, & Hashimoto, 2020). Without large-scale trials to provide data on safety and efficacy, as required by the FDA, a TRD indication for ketamine will likely not be subject to FDA review (FDA, 2019a). Hence, there are major knowledge gaps surrounding the acute and maintenance use of ketamine for this condition (R. S. McIntyre et al., 2021; Sanacora et al., 2017).

Furthermore, there is a paucity of research on combination approaches to ketamine, namely with psychotherapy. This is otherwise known as ketamine-assisted psychotherapy (KAP). As a prototypical psychoplastogen, ketamine has been shown to rapidly promote structural and functional neuroplasticity, which may enhance (or be enhanced by) the effects of psychotherapy to maximize treatment outcomes (Joneborg et al., 2022; Olson, 2018). The formation of new neural connections, restructuring of thought patterns, and promotion of emotional learning are potential mechanisms of behavior change within this context (Drozdz et al., 2022; Hasler, 2020). Additionally, ketamine may enhance treatment adherence and patient engagement, carrying high capacity as a psychotherapeutic adjunct (Drozdz et al., 2022). In clinical practice, KAP often comprises preparatory therapy, the ketamine experience, and integration therapy; however, several approaches exist and are being explored. One method is administering a low dose ketamine prior to psychotherapy as a way of decreasing fear and resistance to exploring psychological material (Dore et al., 2019). Of the trials included in this review, one trial that utilized CBT following IV ketamine to sustain antidepressant effects, a current primary goal in the field (R. S. McIntyre et al., 2021; S. Wilkinson, 2020). Yet, no trials utilized ketamine prior to or during therapy. More open-label, pilot, and randomized trials are thus warranted to determine whether ketamine and psychotherapy act synergistically, are efficacious together, and are superior to ketamine alone. Future trials should also examine these questions at variant dosing schedules to best capture response rates and durability (Drozdz et al., 2022).

Descriptive analyses further revealed important gaps in demographic and clinical characteristics. Patients with TRD have increased rates of psychiatric comorbidity, the most common being anxiety, substance use, post-traumatic stress disorder (PTSD), personality disorders, and non-organic psychosis (Abdallah et al., 2019, 2022; Huang et al., 2020). In this review, only one trial clearly examined ketamine for TRD with a psychiatric comorbidity, PTSD (Albott et al., 2018). Thus, more definitive trials investigating the safety and efficacy of these mediations in TRD with psychiatric comorbidities are needed.

Importantly, there is limited knowledge regarding age- and sex-specific response to ketamine and esketamine (Benitah et al., 2022; Di Vincenzo et al., 2021). The majority of trials in this review enrolled adults (18 + years of age), per eligibility criteria, while only two trials examined ketamine for adolescents (12–19 years of age) and two trials examined ketamine or esketamine for older adults (>64 years of age) (Doty et al., 2021; Lenze, 2020; Mu-Hong, 2021; Roy et al., 2021). Conversely, trials were not exclusive based on sex; however, it is unclear whether the investigators plan to evaluate sex differences and/or have the statistical power to do so. These are noteworthy considerations, as pre-clinical data suggests the underlying mechanisms ketamine's antidepressant response could be differential based on sex (Herzog, Wegener, Lieb, Müller, Treccani, 2019; Ponton, Turecki, & Nagy, 2022; Wright, 2018). Although, at this time, few published studies have directly investigated sex differences in ketamine or esketamine treatment; and of those that have, strong differences in antidepressant response were not detected (Benitah et al., 2022; Freeman et al., 2019; Jones et al., 2022; Williams, 2018). However, these trials may not have been sufficiently powered to detect sex differences (Williams, 2018). This has significant implications on health disparity, as understanding the processes driving sex differences in response to treatment is necessary for developing effective intervention protocols. Future research is thus encouraged to assess the safety and efficacy of ketamine and esketamine for TRD across sexes, as well as consider other confounding factors such as ethnicity, age, gender, and their interplay in addition to menstruation and pregnancy (Gerhard & Duman, 2018; Williams, 2018).

Ethnoracial health disparities were also evident in the samples included in the large-scale, phase 3 trials investigating esketamine for TRD. There was a particular lack of inclusion of black, indigenous, and people of color (BIPOC). This was shown, for example, in two short-term RCTs evaluating esketamine (i.e., TRANSFORM-1 and -2) where the study population was 79% White, 6% Black or African American, 2% Asian, 7% other, 0% American Indian or Alaskan Native, and 0% multiple races (Hudgens et al., 2021). Sexual and gender minorities were also excluded and/or unreported in trials. This reflects existing evidence, or the lack thereof, on ketamine or esketamine for TRD among these minority populations, such as non-binary or transgender individuals (Herzog et al., 2019). Future research stands to benefit from more inclusive study designs, and targeted recruitment strategies in underrepresented communities, that likely translate to and influence real-world access, quality, and affordability of care.

Notwithstanding the foregoing, there are several trials aiming to increase the knowledge base of ketamine for TRD, as demonstrated in this review. Importantly, one trial is establishing a psychiatric service registry for patients receiving ketamine infusions or esketamine nasal spray (Niciu, 2020). This is a critical development, as there is pressing need to centralize evidence on ketamine and esketamine for mood disorders, which can inform long-term safety and effectiveness, as well as populations that are most likely to benefit (Sanacora et al., 2017). This can also aid in efforts surrounding reproducibility of evidence with clarity in clinical and methodological characteristics of treatment. Additionally, the registry can be extended to other institutions, providing a path to collaborative research among scientists and clinicians, and be leveraged to develop clinical practice guidelines.

Limitations

This review was limited to trials registered with ClinicalTrials.gov, which is principally based in the US. There are likely other trials, not included in this review, that were not registered in this database and/or registered outside of the US. Additionally, some trials that assessed TRD may not have been identified with the search strategy if they did not explicitly state TRD as the condition under study. Furthermore, some trials had missing information that affected the overall analysis and subsequent interpretation, including data regarding intervention protocol as well as route of administration. Finally, there is a possibility that ongoing trials are withdrawn and/or terminated with incomplete, unpublishable data and, therefore, should be examined cautiously.

Conclusion

The research pipeline for ketamine and esketamine for TRD shows increasing trends in the number of trials investigating their safety and efficacy, with a larger proportion of late phase esketamine trials compared to ketamine. Trials were heterogeneous in methodological and clinical characteristics. Trials further underscore limitations in assessing patient characteristics that may affect treatment response, such as age, sex, and race. While replication plays a role in accumulating evidence to support these treatments for TRD, the field serves to benefit from making trial inclusion more equitable, particularly for developing evidence-based practice guidelines. By understanding these emerging gaps, scientists and clinicians can avoid research waste (i.e., squandering limited resources by asking low priority questions), and funding bodies agencies can judiciously direct support towards high priority research.

Ethics approval

Not applicable. This was a review of the literature.

Availability of data and materials

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Competing interests

A.R. is the Founding Director of the Integrated Research Literacy Group. R.R. serves as Chief Clinical Officer of Numinus Wellness and is an equity holder in the company. He is also the Co-Founder of Cedar Psychiatry, the Medical Director of Center for Change, and an Investigator for MAPS-sponsored trials. L.A.A serves as a Consultant, Speaker and/or Advisory Board Member for Guidepoint, Transcend Therapeutics, Source Research Foundation, Reason for Hope, and Ampelis. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Funding

This study was not funded.

Authors' contributions

M.B. and A.R. conceptualized and designed the study. M.B., M.S., and L.S. extracted and analyzed data and completed the manuscript writeup. A.R., M.Z., P.S., M.S.G., L.A.A., and R.R. reviewed the data analysis and presentation and critically reviewed/revised the manuscript writeup. All authors have read and approved the final article.

Supplementary materials

Supplementary data to this article can be found online at https://doi.org/10.1556/2054.2022.00234.

References

  • Abdallah, C. G., Averill, L. A., Akiki, T. J., Raza, M., Averill, C. L., Gomaa, H., et al. (2019). The neurobiology and pharmacotherapy of posttraumatic stress disorder. Annual Review of Pharmacology and Toxicology, 59, 171189. https://doi.org/10.1146/annurev-pharmtox-010818-021701.

    • Search Google Scholar
    • Export Citation
  • Abdallah, C. G., Roache, J. D., Gueorguieva, R., Averill, L. A., Young-McCaughan, S., Shiroma, P. R., et al. (2022). Dose-related effects of ketamine for antidepressant-resistant symptoms of posttraumatic stress disorder in veterans and active duty military: A double-blind, randomized, placebo-controlled multi-center clinical trial. Neuropsychopharmacology, 47(8), 15741581. https://doi.org/10.1038/s41386-022-01266-9.

    • Search Google Scholar
    • Export Citation
  • Agboola, F., Atlas, S. J., Touchette, D. R., Fazioli, K., & Pearson, S. D. (2020). The effectiveness and value of esketamine for the management of treatment-resistant depression. Journal of Managed Care & Specialty Pharmacy, 26(1), 1620. https://doi.org/10.18553/jmcp.2020.26.1.16.

    • Search Google Scholar
    • Export Citation
  • Albott, C. S., Lim, K. O., Forbes, M. K., Erbes, C., Tye, S. J., Grabowski, J. G., et al. (2018). Efficacy, safety, and durability of repeated ketamine infusions for comorbid posttraumatic stress disorder and treatment-resistant depression. Journal of Clinical Psychiatry, 79(3). https://doi.org/10.4088/JCP.17m11634.

    • Search Google Scholar
    • Export Citation
  • Amos, T. B., Tandon, N., Lefebvre, P., Pilon, D., Kamstra, R. L., Pivneva, I., et al. (2018). Direct and indirect cost burden and change of employment status in treatment-resistant depression: A matched-cohort study using a US commercial claims database. Journal of Clinical Psychiatry, 79(2). https://doi.org/10.4088/JCP.17m11725.

    • Search Google Scholar
    • Export Citation
  • Andrade, C. (2017). Ketamine for depression, 4: In what dose, at what rate, by what route, for how long, and at what frequency? Journal of Clinical Psychiatry, 78(7), e852-e857. https://doi.org/10.4088/JCP.17f11738.

    • Search Google Scholar
    • Export Citation
  • Benitah, K., Siegel, A. N., Lipsitz, O., Rodrigues, N. B., Meshkat, S., Lee, Y., et al. (2022). Sex differences in ketamine's therapeutic effects for mood disorders: A systematic review. Psychiatry Research, 312, 114579. https://doi.org/10.1016/j.psychres.2022.114579.

    • Search Google Scholar
    • Export Citation
  • Brenner, P., Reutfors, J., Nijs, M., & Andersson, T. M. (2021). Excess deaths in treatment-resistant depression. Therapeutic Advances in Psychopharmacology, 11, 20451253211006508. https://doi.org/10.1177/20451253211006508.

    • Search Google Scholar
    • Export Citation
  • Cusin, C., & Dougherty, D. D. (2012). Somatic therapies for treatment-resistant depression: ECT, TMS, VNS, DBS. Biology of Mood & Anxiety Disorders, 2, 14. https://doi.org/10.1186/2045-5380-2-14.

    • Search Google Scholar
    • Export Citation
  • Daly, E. J., Trivedi, M. H., Janik, A., Li, H., Zhang, Y., Li, X., et al. (2019). Efficacy of esketamine nasal spray plus oral antidepressant treatment for relapse prevention in patients with treatment-resistant depression: A randomized clinical trial. JAMA Psychiatry, 76(9), 893903. https://doi.org/10.1001/jamapsychiatry.2019.1189.

    • Search Google Scholar
    • Export Citation
  • Dandekar, M. P., Fenoy, A. J., Carvalho, A. F., Soares, J. C., & Quevedo, J. (2018). Deep brain stimulation for treatment-resistant depression: An integrative review of preclinical and clinical findings and translational implications. Molecular Psychiatry, 23(5), 10941112. https://doi.org/10.1038/mp.2018.2.

    • Search Google Scholar
    • Export Citation
  • Di Vincenzo, J. D., Siegel, A., Lipsitz, O., Ho, R., Teopiz, K. M., Ng, J., et al. (2021). The effectiveness, safety and tolerability of ketamine for depression in adolescents and older adults: A systematic reviewJournal of Psychiatric Research, 137, 232241. https://doi.org/10.1016/j.jpsychires.2021.02.058.

    • Search Google Scholar
    • Export Citation
  • Dore, J., Turnipseed, B., Dwyer, S., Turnipseed, A., Andries, J., Ascani, G., et al. (2019). Ketamine assisted psychotherapy (KAP): Patient demographics, clinical data and outcomes in three large practices administering ketamine with psychotherapy. Journal of Psychoactive Drugs, 51(2), 189198. https://doi.org/10.1080/02791072.2019.1587556.

    • Search Google Scholar
    • Export Citation
  • Doty, R. L., Popova, V., Wylie, C., Fedgchin, M., Daly, E., Janik, A., et al. (2021). Effect of esketamine nasal spray on olfactory function and nasal tolerability in patients with treatment-resistant depression: Results from four multicenter, randomized, double-blind, placebo-controlled, phase III studies. CNS Drugs, 35(7), 781794. https://doi.org/10.1007/s40263-021-00826-9.

    • Search Google Scholar
    • Export Citation
  • Drozdz, S. J., Goel, A., McGarr, M. W., Katz, J., Ritvo, P., Mattina, G. F., et al. (2022). Ketamine assisted psychotherapy: A systematic narrative review of the literature. Journal of Pain Research, 15, 16911706. https://doi.org/10.2147/jpr.S360733.

    • Search Google Scholar
    • Export Citation
  • FDA (2019a). Development & approval process | drugs. https://www.fda.gov/drugs/development-approval-process-drugs.

  • FDA (2019b). Psychopharmacologic drugs advisory committee (PDAC) and drug safety and risk management (DSaRM) advisory committee meeting; agenda topic: The committees will discuss the efficacy, safety, and risk-benefit profile of new drug application (NDA) 211243, esketamine 28 mg single-use nasal spray device, submitted by Janssen pharmaceuticals, inc., for the treatment of treatment-resistant depression. https://www.fda.gov/media/121376/download.

    • Search Google Scholar
    • Export Citation
  • Freeman, M. P., Papakostas, G. I., Hoeppner, B., Mazzone, E., Judge, H., Cusin, C., et al. (2019). Sex differences in response to ketamine as a rapidly acting intervention for treatment resistant depression. Journal of Psychiatric Research, 110, 166171. https://doi.org/10.1016/j.jpsychires.2019.01.010.

    • Search Google Scholar
    • Export Citation
  • Gerhard, D. M., & Duman, R. S. (2018). Rapid-acting antidepressants: Mechanistic insights and future directions. Current Behavioral Neuroscience Reports, 5(1), 3647.

    • Search Google Scholar
    • Export Citation
  • Hasin, D. S., Sarvet, A. L., Meyers, J. L., Saha, T. D., Ruan, W. J., Stohl, M., et al. (2018). Epidemiology of adult DSM-5 major depressive disorder and its specifiers in the United States. JAMA Psychiatry, 75(4), 336346. https://doi.org/10.1001/jamapsychiatry.2017.4602.

    • Search Google Scholar
    • Export Citation
  • Hasler, G. (2020). Toward specific ways to combine ketamine and psychotherapy in treating depression. CNS Spectrums, 25(3), 445447. https://doi.org/10.1017/S1092852919001007.

    • Search Google Scholar
    • Export Citation
  • Herzog, D. P., Wegener, G., Lieb, K., Müller, M. B., & Treccani, G. (2019). Decoding the mechanism of action of rapid-acting antidepressant treatment strategies: Does gender matter? International Journal of Molecular Sciences, 20(4), 949. https://www.mdpi.com/1422-0067/20/4/949.

    • Search Google Scholar
    • Export Citation
  • Hough, D. (2019). Esketamine. https://www.fda.gov/media/121379/download.

  • Huang, S. S., Chen, H. H., Wang, J., Chen, W. J., Chen, H. C., & Kuo, P. H. (2020). Investigation of early and lifetime clinical features and comorbidities for the risk of developing treatment-resistant depression in a 13-year nationwide cohort study. BMC Psychiatry, 20(1), 541. https://doi.org/10.1186/s12888-020-02935-z.

    • Search Google Scholar
    • Export Citation
  • Hudgens, S., Floden, L., Blackowicz, M., Jamieson, C., Popova, V., Fedgchin, M., et al. (2021). Meaningful change in depression symptoms assessed with the patient health Questionnaire (PHQ-9) and montgomery-Åsberg depression rating scale (MADRS) among patients with treatment resistant depression in two, randomized, double-blind, active-controlled trials of esketamine nasal spray combined with a new oral antidepressant. Journal of Affective Disorders, 281, 767775. https://doi.org/10.1016/j.jad.2020.11.066.

    • Search Google Scholar
    • Export Citation
  • Ionescu, D. F., Rosenbaum, J. F., & Alpert, J. E. (2015). Pharmacological approaches to the challenge of treatment-resistant depression. Dialogues in Clinical Neuroscience, 17(2), 111126. https://doi.org/10.31887/DCNS.2015.17.2/dionescu.

    • Search Google Scholar
    • Export Citation
  • Jakuszkowiak-Wojten, K., Gałuszko-Węgielnik, M., Wilkowska, A., Słupski, J., Włodarczyk, A., Górska, N., et al. (2019). Suicidality in treatment resistant depression: Perspective for ketamine use. Psychiatria Danubina, 31(Suppl 3), 258260.

    • Search Google Scholar
    • Export Citation
  • Janssen. (2019). Spravato (esketamine) nasal spray prescribing information.

  • Johnston, K. M., Powell, L. C., Anderson, I. M., Szabo, S., & Cline, S. (2019). The burden of treatment-resistant depression: A systematic review of the economic and quality of life literature. Journal of Affective Disorders, 242, 195210. https://doi.org/10.1016/j.jad.2018.06.045.

    • Search Google Scholar
    • Export Citation
  • Joneborg, I., Lee, Y., Di Vincenzo, J. D., Ceban, F., Meshkat, S., Lui, L. M. W., et al. (2022). Active mechanisms of ketamine-assisted psychotherapy: A systematic review. Journal of Affective Disorders, 315, 105112. https://doi.org/10.1016/j.jad.2022.07.030.

    • Search Google Scholar
    • Export Citation
  • Jones, R. R., Freeman, M. P., Kornstein, S. G., Cooper, K., Daly, E. J., Canuso, C. M., et al. (2022). Efficacy and safety of esketamine nasal spray by sex in patients with treatment-resistant depression: Findings from short-term randomized, controlled trials. Archives of Women's Mental Health, 25(2), 313326. https://doi.org/10.1007/s00737-021-01185-6.

    • Search Google Scholar
    • Export Citation
  • Kim, J., Farchione, T., Potter, A., Chen, Q., & Temple, R. (2019). Esketamine for treatment-resistant depression – first FDA-approved antidepressant in a new class. The New England Journal of Medicine, 381(1), 14. https://doi.org/10.1056/NEJMp1903305.

    • Search Google Scholar
    • Export Citation
  • Lenze, E. (2020). Ketamine for older adults pilot. Clinicaltrials.gov. clinicaltrials.gov/ct2/show/study/NCT04504175?term=NCT04504175&draw=2&rank=1.

    • Search Google Scholar
    • Export Citation
  • Li, H., Cui, L., Li, J., Liu, Y., & Chen, Y. (2021). Comparative efficacy and acceptability of neuromodulation procedures in the treatment of treatment-resistant depression: A network meta-analysis of randomized controlled trials. Journal of Affective Disorders, 287, 115124. https://doi.org/10.1016/j.jad.2021.03.019.

    • Search Google Scholar
    • Export Citation
  • Luan, S., Wan, H., Wang, S., Li, H., & Zhang, B. (2017). Efficacy and safety of olanzapine/fluoxetine combination in the treatment of treatment-resistant depression: A meta-analysis of randomized controlled trials. Neuropsychiatric Disease and Treatment, 13, 609620. https://doi.org/10.2147/NDT.S127453.

    • Search Google Scholar
    • Export Citation
  • Machado-Vieira, R., Baumann, J., Wheeler-Castillo, C., Latov, D., Henter, I. D., Salvadore, G., et al. (2010). The timing of antidepressant effects: A comparison of diverse pharmacological and somatic treatments. Pharmaceuticals (Basel, Switzerland), 3(1), 1941. https://doi.org/10.3390/ph3010019.

    • Search Google Scholar
    • Export Citation
  • Marcantoni, W. S., Akoumba, B. S., Wassef, M., Mayrand, J., Lai, H., Richard-Devantoy, S., et al. (2020). A systematic review and meta-analysis of the efficacy of intravenous ketamine infusion for treatment resistant depression: January 2009–January 2019. Journal of Affective Disorders, 277, 831841. https://doi.org/10.1016/j.jad.2020.09.007.

    • Search Google Scholar
    • Export Citation
  • McIntyre, R. S., Carvalho, I. P., Lui, L. M. W., Majeed, A., Masand, P. S., Gill, H., et al. (2020). The effect of intravenous, intranasal, and oral ketamine in mood disorders: A meta-analysis. Journal of Affective Disorders, 276, 576584. https://doi.org/10.1016/j.jad.2020.06.050.

    • Search Google Scholar
    • Export Citation
  • McIntyre, R. S., Rosenblat, J. D., Nemeroff, C. B., Sanacora, G., Murrough, J. W., Berk, M., et al. (2021). Synthesizing the evidence for ketamine and esketamine in treatment-resistant depression: An international expert opinion on the available evidence and implementation. American Journal of Psychiatry, 178(5), 383399. https://doi.org/10.1176/appi.ajp.2020.20081251.

    • Search Google Scholar
    • Export Citation
  • Moser, G. (2018). Pink sheet: Major depressive disorder patients emphasize long-term nature of disease in feedback meeting. Pharma Intelligence. https://pink.pharmaintelligence.informa.com/PS124402/Major-Depressive-Disorder-Patients-Emphasize-Long-Term-Nature-Of-Disease-In-Feedback-Meeting.

    • Search Google Scholar
    • Export Citation
  • Mu-Hong, C. (2021). Low-dose ketamine infusion among adolescents with treatment-resistant depression. Clinicaltrails.gov. https://www.clinicaltrials.gov/ct2/show/record/NCT05045378?term=NCT05045378&draw=2&rank=1.

    • Search Google Scholar
    • Export Citation
  • Murrough, J. W., Iosifescu, D. V., Chang, L. C., Al Jurdi, R. K., Green, C. E., Perez, A. M., et al. (2013). Antidepressant efficacy of ketamine in treatment-resistant major depression: A two-site randomized controlled trial. American Journal of Psychiatry, 170(10), 11341142. https://doi.org/10.1176/appi.ajp.2013.13030392.

    • Search Google Scholar
    • Export Citation
  • Newport, D. J., Carpenter, L. L., McDonald, W. M., Potash, J. B., Tohen, M., & Nemeroff, C. B. (2015). Ketamine and other NMDA antagonists: Early clinical trials and possible mechanisms in depression. American Journal of Psychiatry, 172(10), 950966. https://doi.org/10.1176/appi.ajp.2015.15040465.

    • Search Google Scholar
    • Export Citation
  • Niciu, M. (2020). University of Iowa interventional Psychiatry service patient registry. Clinicaltrials.gov. https://www.clinicaltrials.gov/ct2/show/NCT04480918?term=NCT04480918&draw=2&rank=1.

    • Search Google Scholar
    • Export Citation
  • NIMH (2022). Major depression. https://www.nimh.nih.gov/health/statistics/major-depression.

  • Olson, D. E. (2018). Psychoplastogens: A promising class of plasticity-promoting neurotherapeutics. Journal of Experimental Neuroscience, 12, 1179069518800508. https://doi.org/10.1177/1179069518800508.

    • Search Google Scholar
    • Export Citation
  • Papakostas, G. I., Salloum, N. C., Hock, R. S., Jha, M. K., Murrough, J. W., Mathew, S. J., et al. (2020). Efficacy of esketamine augmentation in major depressive disorder: A meta-analysis. Journal of Clinical Psychiatry, 81(4). https://doi.org/10.4088/JCP.19r12889.

    • Search Google Scholar
    • Export Citation
  • Peyrovian, B., McIntyre, R. S., Phan, L., Lui, L. M. W., Gill, H., Majeed, A., et al. (2020). Registered clinical trials investigating ketamine for psychiatric disorders. Journal of Psychiatric Research, 127, 112. https://doi.org/10.1016/j.jpsychires.2020.03.020.

    • Search Google Scholar
    • Export Citation
  • Ponton, E., Turecki, G., & Nagy, C. (2022). Sex differences in the behavioral, molecular, and structural effects of ketamine treatment in depression. International Journal of Neuropsychopharmacology, 25(1), 7584. https://doi.org/10.1093/ijnp/pyab082.

    • Search Google Scholar
    • Export Citation
  • Roy, A. V., Thai, M., Klimes-Dougan, B., Westlund Schreiner, M., Mueller, B. A., Albott, C. S., et al. (2021). Brain entropy and neurotrophic molecular markers accompanying clinical improvement after ketamine: Preliminary evidence in adolescents with treatment-resistant depression. Journal of Psychopharmacology, 35(2), 168177. https://doi.org/10.1177/0269881120928203.

    • Search Google Scholar
    • Export Citation
  • Rush, A. J., Trivedi, M. H., Wisniewski, S. R., Nierenberg, A. A., Stewart, J. W., Warden, D., et al. (2006). Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: A STAR*D report. American Journal of Psychiatry, 163(11), 19051917. https://doi.org/10.1176/ajp.2006.163.11.1905.

    • Search Google Scholar
    • Export Citation
  • Sanacora, G., Frye, M. A., McDonald, W., Mathew, S. J., Turner, M. S., Schatzberg, A. F., et al. (2017). A consensus statement on the use of ketamine in the treatment of mood disorders. JAMA Psychiatry, 74(4), 399405. https://doi.org/10.1001/jamapsychiatry.2017.0080.

    • Search Google Scholar
    • Export Citation
  • Sanacora, G., Treccani, G., & Popoli, M. (2012). Towards a glutamate hypothesis of depression: An emerging frontier of neuropsychopharmacology for mood disorders. Neuropharmacology, 62(1), 6377. https://doi.org/10.1016/j.neuropharm.2011.07.036.

    • Search Google Scholar
    • Export Citation
  • Shamseer, L., Moher, D., Clarke, M., Ghersi, D., Liberati, A., Petticrew, M., et al. (2015). Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015: Elaboration and explanation. BMJ: British Medical Journal, 349, g7647. https://doi.org/10.1136/bmj.g7647.

    • Search Google Scholar
    • Export Citation
  • Siegel, A. N., Meshkat, S., Benitah, K., Lipsitz, O., Gill, H., Lui, L. M. W., et al. (2021). Registered clinical studies investigating psychedelic drugs for psychiatric disorders. Journal of Psychiatric Research, 139, 7181. https://doi.org/10.1016/j.jpsychires.2021.05.019.

    • Search Google Scholar
    • Export Citation
  • Singh, J. B., Fedgchin, M., Daly, E. J., De Boer, P., Cooper, K., Lim, P., et al. (2016). A double-blind, randomized, placebo-controlled, dose-frequency study of intravenous ketamine in patients with treatment-resistant depression. American Journal of Psychiatry, 173(8), 816826. https://doi.org/10.1176/appi.ajp.2016.16010037.

    • Search Google Scholar
    • Export Citation
  • StataCorp (2019). Stata statistical software: Release 16. StataCorp LLC.

  • Szarmach, J., Cubała, W. J., Włodarczyk, A., & Wiglusz, M. S. (2019). Short-term ketamine administration in treatment-resistant depression: Focus on cardiovascular safety. Psychiatria Danubina, 31(Suppl 3), 585590.

    • Search Google Scholar
    • Export Citation
  • Thielking, M. (2018). Ketamine gives hope to patients with severe depression. But some clinics stray from the science and hype its benefits. STAT News. https://www.statnews.com/2018/09/24/ketamine-clinics-severe-depression-treatment/.

    • Search Google Scholar
    • Export Citation
  • Warden, D., Rush, A. J., Trivedi, M. H., Fava, M., & Wisniewski, S. R. (2007). The STAR*D project results: A comprehensive review of findings. Current Psychiatry Reports, 9(6), 449459. https://doi.org/10.1007/s11920-007-0061-3.

    • Search Google Scholar
    • Export Citation
  • Wei, Y., Chang, L., & Hashimoto, K. (2020). A historical review of antidepressant effects of ketamine and its enantiomers. Pharmacology, Biochemistry and Behavior, 190, 172870. https://doi.org/10.1016/j.pbb.2020.172870.

    • Search Google Scholar
    • Export Citation
  • Wilkinson, S. (2020). Cognitive therapy to sustain the antidepressant effects of intravenous ketamine in treatment-resistant depression. Clinicaltrials.gov. https://clinicaltrials.gov/ct2/show/record/NCT03027362.

    • Search Google Scholar
    • Export Citation
  • Wilkinson, Howard, D. H., & Busch, S. H. (2019). Psychiatric practice patterns and barriers to the adoption of esketamine. JAMA, 322(11), 10391040. https://doi.org/10.1001/jama.2019.10728.

    • Search Google Scholar
    • Export Citation
  • Wilkinson, S. T., Toprak, M., Turner, M. S., Levine, S. P., Katz, R. B., & Sanacora, G. (2017). A survey of the clinical, off-label use of ketamine as a treatment for psychiatric disorders. American Journal of Psychiatry, 174(7), 695696. https://doi.org/10.1176/appi.ajp.2017.17020239.

    • Search Google Scholar
    • Export Citation
  • Williams, A. V, & Trainor, B. C. (2018). The impact of sex as a biological variable in the search for novel antidepressants. Frontiers in Neuroendocrinology, 50, 107117. https://doi.org/10.1016/j.yfrne.2018.05.003.

    • Search Google Scholar
    • Export Citation
  • Wright, K. N., & Kabbaj, M. (2018). Sex differences in sub-anesthetic ketamine's antidepressant effects and abuse liability. Current Opinion in Behavioral Sciences, 23, 3641. https://doi.org/10.1016/j.cobeha.2018.02.001.

    • Search Google Scholar
    • Export Citation
  • Zanos, P., & Gould, T. D. (2018). Mechanisms of ketamine action as an antidepressant. Molecular Psychiatry, 23(4), 801811. https://doi.org/10.1038/mp.2017.255.

    • Search Google Scholar
    • Export Citation

Appendix: List of abbreviations

TermDefinition
BABioavailability
CADSSClinician-Administered Dissociative States Scale
CGIClinical Global Impressions
CSSRSColumbia Suicide Severity Rating Scale
DBSDeep Brain Stimulation
DOIDigital Object Identifier
ECTElectroconvulsive Therapy
EQ-5D-5LEuropean Quality of Life Five Dimension
FDAFood and Drug Administration
GAD-7Generalized Anxiety Disorder-7
HAM-DHamilton Depression Rating Scale
IMIntramuscular
INIntranasal
IVIntravenous
KAPKetamine-assisted psychotherapy
MADRSThe Montgomery-Asberg Depression Rating Scale
MDDMajor Depressive Disorder
NMDAN-methyl-d-aspartate
NIHNational Institute of Health
NLMNational Library of Medicine
PHQ-9Patient Health Questionnaire-9
PRISMAPreferred Reporting Items for Systematic Reviews and Meta-Analyses
PTSDPost-Traumatic Stress Disorder
QIDSQuick Inventory of Depression Symptomatology
RCTRandomized Controlled Trials
SDSSheehan Disability Scale
SSRISelective Serotonin Reuptake Inhibitor
SNRISerotonin-Norepinephrine Reuptake Inhibitor
TMSTranscranial Magnetic Stimulation
TRDTreatment Resistant Depression
USUnited States
YLDYears Lived with Disability

Supplementary Materials

  • Abdallah, C. G., Averill, L. A., Akiki, T. J., Raza, M., Averill, C. L., Gomaa, H., et al. (2019). The neurobiology and pharmacotherapy of posttraumatic stress disorder. Annual Review of Pharmacology and Toxicology, 59, 171189. https://doi.org/10.1146/annurev-pharmtox-010818-021701.

    • Search Google Scholar
    • Export Citation
  • Abdallah, C. G., Roache, J. D., Gueorguieva, R., Averill, L. A., Young-McCaughan, S., Shiroma, P. R., et al. (2022). Dose-related effects of ketamine for antidepressant-resistant symptoms of posttraumatic stress disorder in veterans and active duty military: A double-blind, randomized, placebo-controlled multi-center clinical trial. Neuropsychopharmacology, 47(8), 15741581. https://doi.org/10.1038/s41386-022-01266-9.

    • Search Google Scholar
    • Export Citation
  • Agboola, F., Atlas, S. J., Touchette, D. R., Fazioli, K., & Pearson, S. D. (2020). The effectiveness and value of esketamine for the management of treatment-resistant depression. Journal of Managed Care & Specialty Pharmacy, 26(1), 1620. https://doi.org/10.18553/jmcp.2020.26.1.16.

    • Search Google Scholar
    • Export Citation
  • Albott, C. S., Lim, K. O., Forbes, M. K., Erbes, C., Tye, S. J., Grabowski, J. G., et al. (2018). Efficacy, safety, and durability of repeated ketamine infusions for comorbid posttraumatic stress disorder and treatment-resistant depression. Journal of Clinical Psychiatry, 79(3). https://doi.org/10.4088/JCP.17m11634.

    • Search Google Scholar
    • Export Citation
  • Amos, T. B., Tandon, N., Lefebvre, P., Pilon, D., Kamstra, R. L., Pivneva, I., et al. (2018). Direct and indirect cost burden and change of employment status in treatment-resistant depression: A matched-cohort study using a US commercial claims database. Journal of Clinical Psychiatry, 79(2). https://doi.org/10.4088/JCP.17m11725.

    • Search Google Scholar
    • Export Citation
  • Andrade, C. (2017). Ketamine for depression, 4: In what dose, at what rate, by what route, for how long, and at what frequency? Journal of Clinical Psychiatry, 78(7), e852-e857. https://doi.org/10.4088/JCP.17f11738.

    • Search Google Scholar
    • Export Citation
  • Benitah, K., Siegel, A. N., Lipsitz, O., Rodrigues, N. B., Meshkat, S., Lee, Y., et al. (2022). Sex differences in ketamine's therapeutic effects for mood disorders: A systematic review. Psychiatry Research, 312, 114579. https://doi.org/10.1016/j.psychres.2022.114579.

    • Search Google Scholar
    • Export Citation
  • Brenner, P., Reutfors, J., Nijs, M., & Andersson, T. M. (2021). Excess deaths in treatment-resistant depression. Therapeutic Advances in Psychopharmacology, 11, 20451253211006508. https://doi.org/10.1177/20451253211006508.

    • Search Google Scholar
    • Export Citation
  • Cusin, C., & Dougherty, D. D. (2012). Somatic therapies for treatment-resistant depression: ECT, TMS, VNS, DBS. Biology of Mood & Anxiety Disorders, 2, 14. https://doi.org/10.1186/2045-5380-2-14.

    • Search Google Scholar
    • Export Citation
  • Daly, E. J., Trivedi, M. H., Janik, A., Li, H., Zhang, Y., Li, X., et al. (2019). Efficacy of esketamine nasal spray plus oral antidepressant treatment for relapse prevention in patients with treatment-resistant depression: A randomized clinical trial. JAMA Psychiatry, 76(9), 893903. https://doi.org/10.1001/jamapsychiatry.2019.1189.

    • Search Google Scholar
    • Export Citation
  • Dandekar, M. P., Fenoy, A. J., Carvalho, A. F., Soares, J. C., & Quevedo, J. (2018). Deep brain stimulation for treatment-resistant depression: An integrative review of preclinical and clinical findings and translational implications. Molecular Psychiatry, 23(5), 10941112. https://doi.org/10.1038/mp.2018.2.

    • Search Google Scholar
    • Export Citation
  • Di Vincenzo, J. D., Siegel, A., Lipsitz, O., Ho, R., Teopiz, K. M., Ng, J., et al. (2021). The effectiveness, safety and tolerability of ketamine for depression in adolescents and older adults: A systematic reviewJournal of Psychiatric Research, 137, 232241. https://doi.org/10.1016/j.jpsychires.2021.02.058.

    • Search Google Scholar
    • Export Citation
  • Dore, J., Turnipseed, B., Dwyer, S., Turnipseed, A., Andries, J., Ascani, G., et al. (2019). Ketamine assisted psychotherapy (KAP): Patient demographics, clinical data and outcomes in three large practices administering ketamine with psychotherapy. Journal of Psychoactive Drugs, 51(2), 189198. https://doi.org/10.1080/02791072.2019.1587556.

    • Search Google Scholar
    • Export Citation
  • Doty, R. L., Popova, V., Wylie, C., Fedgchin, M., Daly, E., Janik, A., et al. (2021). Effect of esketamine nasal spray on olfactory function and nasal tolerability in patients with treatment-resistant depression: Results from four multicenter, randomized, double-blind, placebo-controlled, phase III studies. CNS Drugs, 35(7), 781794. https://doi.org/10.1007/s40263-021-00826-9.

    • Search Google Scholar
    • Export Citation
  • Drozdz, S. J., Goel, A., McGarr, M. W., Katz, J., Ritvo, P., Mattina, G. F., et al. (2022). Ketamine assisted psychotherapy: A systematic narrative review of the literature. Journal of Pain Research, 15, 16911706. https://doi.org/10.2147/jpr.S360733.

    • Search Google Scholar
    • Export Citation
  • FDA (2019a). Development & approval process | drugs. https://www.fda.gov/drugs/development-approval-process-drugs.

  • FDA (2019b). Psychopharmacologic drugs advisory committee (PDAC) and drug safety and risk management (DSaRM) advisory committee meeting; agenda topic: The committees will discuss the efficacy, safety, and risk-benefit profile of new drug application (NDA) 211243, esketamine 28 mg single-use nasal spray device, submitted by Janssen pharmaceuticals, inc., for the treatment of treatment-resistant depression. https://www.fda.gov/media/121376/download.

    • Search Google Scholar
    • Export Citation
  • Freeman, M. P., Papakostas, G. I., Hoeppner, B., Mazzone, E., Judge, H., Cusin, C., et al. (2019). Sex differences in response to ketamine as a rapidly acting intervention for treatment resistant depression. Journal of Psychiatric Research, 110, 166171. https://doi.org/10.1016/j.jpsychires.2019.01.010.

    • Search Google Scholar
    • Export Citation
  • Gerhard, D. M., & Duman, R. S. (2018). Rapid-acting antidepressants: Mechanistic insights and future directions. Current Behavioral Neuroscience Reports, 5(1), 3647.

    • Search Google Scholar
    • Export Citation
  • Hasin, D. S., Sarvet, A. L., Meyers, J. L., Saha, T. D., Ruan, W. J., Stohl, M., et al. (2018). Epidemiology of adult DSM-5 major depressive disorder and its specifiers in the United States. JAMA Psychiatry, 75(4), 336346. https://doi.org/10.1001/jamapsychiatry.2017.4602.

    • Search Google Scholar
    • Export Citation
  • Hasler, G. (2020). Toward specific ways to combine ketamine and psychotherapy in treating depression. CNS Spectrums, 25(3), 445447. https://doi.org/10.1017/S1092852919001007.

    • Search Google Scholar
    • Export Citation
  • Herzog, D. P., Wegener, G., Lieb, K., Müller, M. B., & Treccani, G. (2019). Decoding the mechanism of action of rapid-acting antidepressant treatment strategies: Does gender matter? International Journal of Molecular Sciences, 20(4), 949. https://www.mdpi.com/1422-0067/20/4/949.

    • Search Google Scholar
    • Export Citation
  • Hough, D. (2019). Esketamine. https://www.fda.gov/media/121379/download.

  • Huang, S. S., Chen, H. H., Wang, J., Chen, W. J., Chen, H. C., & Kuo, P. H. (2020). Investigation of early and lifetime clinical features and comorbidities for the risk of developing treatment-resistant depression in a 13-year nationwide cohort study. BMC Psychiatry, 20(1), 541. https://doi.org/10.1186/s12888-020-02935-z.

    • Search Google Scholar
    • Export Citation
  • Hudgens, S., Floden, L., Blackowicz, M., Jamieson, C., Popova, V., Fedgchin, M., et al. (2021). Meaningful change in depression symptoms assessed with the patient health Questionnaire (PHQ-9) and montgomery-Åsberg depression rating scale (MADRS) among patients with treatment resistant depression in two, randomized, double-blind, active-controlled trials of esketamine nasal spray combined with a new oral antidepressant. Journal of Affective Disorders, 281, 767775. https://doi.org/10.1016/j.jad.2020.11.066.

    • Search Google Scholar
    • Export Citation
  • Ionescu, D. F., Rosenbaum, J. F., & Alpert, J. E. (2015). Pharmacological approaches to the challenge of treatment-resistant depression. Dialogues in Clinical Neuroscience, 17(2), 111126. https://doi.org/10.31887/DCNS.2015.17.2/dionescu.

    • Search Google Scholar
    • Export Citation
  • Jakuszkowiak-Wojten, K., Gałuszko-Węgielnik, M., Wilkowska, A., Słupski, J., Włodarczyk, A., Górska, N., et al. (2019). Suicidality in treatment resistant depression: Perspective for ketamine use. Psychiatria Danubina, 31(Suppl 3), 258260.

    • Search Google Scholar
    • Export Citation
  • Janssen. (2019). Spravato (esketamine) nasal spray prescribing information.

  • Johnston, K. M., Powell, L. C., Anderson, I. M., Szabo, S., & Cline, S. (2019). The burden of treatment-resistant depression: A systematic review of the economic and quality of life literature. Journal of Affective Disorders, 242, 195210. https://doi.org/10.1016/j.jad.2018.06.045.

    • Search Google Scholar
    • Export Citation
  • Joneborg, I., Lee, Y., Di Vincenzo, J. D., Ceban, F., Meshkat, S., Lui, L. M. W., et al. (2022). Active mechanisms of ketamine-assisted psychotherapy: A systematic review. Journal of Affective Disorders, 315, 105112. https://doi.org/10.1016/j.jad.2022.07.030.

    • Search Google Scholar
    • Export Citation
  • Jones, R. R., Freeman, M. P., Kornstein, S. G., Cooper, K., Daly, E. J., Canuso, C. M., et al. (2022). Efficacy and safety of esketamine nasal spray by sex in patients with treatment-resistant depression: Findings from short-term randomized, controlled trials. Archives of Women's Mental Health, 25(2), 313326. https://doi.org/10.1007/s00737-021-01185-6.

    • Search Google Scholar
    • Export Citation
  • Kim, J., Farchione, T., Potter, A., Chen, Q., & Temple, R. (2019). Esketamine for treatment-resistant depression – first FDA-approved antidepressant in a new class. The New England Journal of Medicine, 381(1), 14. https://doi.org/10.1056/NEJMp1903305.

    • Search Google Scholar
    • Export Citation
  • Lenze, E. (2020). Ketamine for older adults pilot. Clinicaltrials.gov. clinicaltrials.gov/ct2/show/study/NCT04504175?term=NCT04504175&draw=2&rank=1.

    • Search Google Scholar
    • Export Citation
  • Li, H., Cui, L., Li, J., Liu, Y., & Chen, Y. (2021). Comparative efficacy and acceptability of neuromodulation procedures in the treatment of treatment-resistant depression: A network meta-analysis of randomized controlled trials. Journal of Affective Disorders, 287, 115124. https://doi.org/10.1016/j.jad.2021.03.019.

    • Search Google Scholar
    • Export Citation
  • Luan, S., Wan, H., Wang, S., Li, H., & Zhang, B. (2017). Efficacy and safety of olanzapine/fluoxetine combination in the treatment of treatment-resistant depression: A meta-analysis of randomized controlled trials. Neuropsychiatric Disease and Treatment, 13, 609620. https://doi.org/10.2147/NDT.S127453.

    • Search Google Scholar
    • Export Citation
  • Machado-Vieira, R., Baumann, J., Wheeler-Castillo, C., Latov, D., Henter, I. D., Salvadore, G., et al. (2010). The timing of antidepressant effects: A comparison of diverse pharmacological and somatic treatments. Pharmaceuticals (Basel, Switzerland), 3(1), 1941. https://doi.org/10.3390/ph3010019.

    • Search Google Scholar
    • Export Citation
  • Marcantoni, W. S., Akoumba, B. S., Wassef, M., Mayrand, J., Lai, H., Richard-Devantoy, S., et al. (2020). A systematic review and meta-analysis of the efficacy of intravenous ketamine infusion for treatment resistant depression: January 2009–January 2019. Journal of Affective Disorders, 277, 831841. https://doi.org/10.1016/j.jad.2020.09.007.

    • Search Google Scholar
    • Export Citation
  • McIntyre, R. S., Carvalho, I. P., Lui, L. M. W., Majeed, A., Masand, P. S., Gill, H., et al. (2020). The effect of intravenous, intranasal, and oral ketamine in mood disorders: A meta-analysis. Journal of Affective Disorders, 276, 576584. https://doi.org/10.1016/j.jad.2020.06.050.

    • Search Google Scholar
    • Export Citation
  • McIntyre, R. S., Rosenblat, J. D., Nemeroff, C. B., Sanacora, G., Murrough, J. W., Berk, M., et al. (2021). Synthesizing the evidence for ketamine and esketamine in treatment-resistant depression: An international expert opinion on the available evidence and implementation. American Journal of Psychiatry, 178(5), 383399. https://doi.org/10.1176/appi.ajp.2020.20081251.

    • Search Google Scholar
    • Export Citation
  • Moser, G. (2018). Pink sheet: Major depressive disorder patients emphasize long-term nature of disease in feedback meeting. Pharma Intelligence. https://pink.pharmaintelligence.informa.com/PS124402/Major-Depressive-Disorder-Patients-Emphasize-Long-Term-Nature-Of-Disease-In-Feedback-Meeting.

    • Search Google Scholar
    • Export Citation
  • Mu-Hong, C. (2021). Low-dose ketamine infusion among adolescents with treatment-resistant depression. Clinicaltrails.gov. https://www.clinicaltrials.gov/ct2/show/record/NCT05045378?term=NCT05045378&draw=2&rank=1.

    • Search Google Scholar
    • Export Citation
  • Murrough, J. W., Iosifescu, D. V., Chang, L. C., Al Jurdi, R. K., Green, C. E., Perez, A. M., et al. (2013). Antidepressant efficacy of ketamine in treatment-resistant major depression: A two-site randomized controlled trial. American Journal of Psychiatry, 170(10), 11341142. https://doi.org/10.1176/appi.ajp.2013.13030392.

    • Search Google Scholar
    • Export Citation
  • Newport, D. J., Carpenter, L. L., McDonald, W. M., Potash, J. B., Tohen, M., & Nemeroff, C. B. (2015). Ketamine and other NMDA antagonists: Early clinical trials and possible mechanisms in depression. American Journal of Psychiatry, 172(10), 950966. https://doi.org/10.1176/appi.ajp.2015.15040465.

    • Search Google Scholar
    • Export Citation
  • Niciu, M. (2020). University of Iowa interventional Psychiatry service patient registry. Clinicaltrials.gov. https://www.clinicaltrials.gov/ct2/show/NCT04480918?term=NCT04480918&draw=2&rank=1.

    • Search Google Scholar
    • Export Citation
  • NIMH (2022). Major depression. https://www.nimh.nih.gov/health/statistics/major-depression.

  • Olson, D. E. (2018). Psychoplastogens: A promising class of plasticity-promoting neurotherapeutics. Journal of Experimental Neuroscience, 12, 1179069518800508. https://doi.org/10.1177/1179069518800508.

    • Search Google Scholar
    • Export Citation
  • Papakostas, G. I., Salloum, N. C., Hock, R. S., Jha, M. K., Murrough, J. W., Mathew, S. J., et al. (2020). Efficacy of esketamine augmentation in major depressive disorder: A meta-analysis. Journal of Clinical Psychiatry, 81(4). https://doi.org/10.4088/JCP.19r12889.

    • Search Google Scholar
    • Export Citation
  • Peyrovian, B., McIntyre, R. S., Phan, L., Lui, L. M. W., Gill, H., Majeed, A., et al. (2020). Registered clinical trials investigating ketamine for psychiatric disorders. Journal of Psychiatric Research, 127, 112. https://doi.org/10.1016/j.jpsychires.2020.03.020.

    • Search Google Scholar
    • Export Citation
  • Ponton, E., Turecki, G., & Nagy, C. (2022). Sex differences in the behavioral, molecular, and structural effects of ketamine treatment in depression. International Journal of Neuropsychopharmacology, 25(1), 7584. https://doi.org/10.1093/ijnp/pyab082.

    • Search Google Scholar
    • Export Citation
  • Roy, A. V., Thai, M., Klimes-Dougan, B., Westlund Schreiner, M., Mueller, B. A., Albott, C. S., et al. (2021). Brain entropy and neurotrophic molecular markers accompanying clinical improvement after ketamine: Preliminary evidence in adolescents with treatment-resistant depression. Journal of Psychopharmacology, 35(2), 168177. https://doi.org/10.1177/0269881120928203.

    • Search Google Scholar
    • Export Citation
  • Rush, A. J., Trivedi, M. H., Wisniewski, S. R., Nierenberg, A. A., Stewart, J. W., Warden, D., et al. (2006). Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: A STAR*D report. American Journal of Psychiatry, 163(11), 19051917. https://doi.org/10.1176/ajp.2006.163.11.1905.

    • Search Google Scholar
    • Export Citation
  • Sanacora, G., Frye, M. A., McDonald, W., Mathew, S. J., Turner, M. S., Schatzberg, A. F., et al. (2017). A consensus statement on the use of ketamine in the treatment of mood disorders. JAMA Psychiatry, 74(4), 399405. https://doi.org/10.1001/jamapsychiatry.2017.0080.

    • Search Google Scholar
    • Export Citation
  • Sanacora, G., Treccani, G., & Popoli, M. (2012). Towards a glutamate hypothesis of depression: An emerging frontier of neuropsychopharmacology for mood disorders. Neuropharmacology, 62(1), 6377. https://doi.org/10.1016/j.neuropharm.2011.07.036.

    • Search Google Scholar
    • Export Citation
  • Shamseer, L., Moher, D., Clarke, M., Ghersi, D., Liberati, A., Petticrew, M., et al. (2015). Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015: Elaboration and explanation. BMJ: British Medical Journal, 349, g7647. https://doi.org/10.1136/bmj.g7647.

    • Search Google Scholar
    • Export Citation
  • Siegel, A. N., Meshkat, S., Benitah, K., Lipsitz, O., Gill, H., Lui, L. M. W., et al. (2021). Registered clinical studies investigating psychedelic drugs for psychiatric disorders. Journal of Psychiatric Research, 139, 7181. https://doi.org/10.1016/j.jpsychires.2021.05.019.

    • Search Google Scholar
    • Export Citation
  • Singh, J. B., Fedgchin, M., Daly, E. J., De Boer, P., Cooper, K., Lim, P., et al. (2016). A double-blind, randomized, placebo-controlled, dose-frequency study of intravenous ketamine in patients with treatment-resistant depression. American Journal of Psychiatry, 173(8), 816826. https://doi.org/10.1176/appi.ajp.2016.16010037.

    • Search Google Scholar
    • Export Citation
  • StataCorp (2019). Stata statistical software: Release 16. StataCorp LLC.

  • Szarmach, J., Cubała, W. J., Włodarczyk, A., & Wiglusz, M. S. (2019). Short-term ketamine administration in treatment-resistant depression: Focus on cardiovascular safety. Psychiatria Danubina, 31(Suppl 3), 585590.

    • Search Google Scholar
    • Export Citation
  • Thielking, M. (2018). Ketamine gives hope to patients with severe depression. But some clinics stray from the science and hype its benefits. STAT News. https://www.statnews.com/2018/09/24/ketamine-clinics-severe-depression-treatment/.

    • Search Google Scholar
    • Export Citation
  • Warden, D., Rush, A. J., Trivedi, M. H., Fava, M., & Wisniewski, S. R. (2007). The STAR*D project results: A comprehensive review of findings. Current Psychiatry Reports, 9(6), 449459. https://doi.org/10.1007/s11920-007-0061-3.

    • Search Google Scholar
    • Export Citation
  • Wei, Y., Chang, L., & Hashimoto, K. (2020). A historical review of antidepressant effects of ketamine and its enantiomers. Pharmacology, Biochemistry and Behavior, 190, 172870. https://doi.org/10.1016/j.pbb.2020.172870.

    • Search Google Scholar
    • Export Citation
  • Wilkinson, S. (2020). Cognitive therapy to sustain the antidepressant effects of intravenous ketamine in treatment-resistant depression. Clinicaltrials.gov. https://clinicaltrials.gov/ct2/show/record/NCT03027362.

    • Search Google Scholar
    • Export Citation
  • Wilkinson, Howard, D. H., & Busch, S. H. (2019). Psychiatric practice patterns and barriers to the adoption of esketamine. JAMA, 322(11), 10391040. https://doi.org/10.1001/jama.2019.10728.

    • Search Google Scholar
    • Export Citation
  • Wilkinson, S. T., Toprak, M., Turner, M. S., Levine, S. P., Katz, R. B., & Sanacora, G. (2017). A survey of the clinical, off-label use of ketamine as a treatment for psychiatric disorders. American Journal of Psychiatry, 174(7), 695696. https://doi.org/10.1176/appi.ajp.2017.17020239.

    • Search Google Scholar
    • Export Citation
  • Williams, A. V, & Trainor, B. C. (2018). The impact of sex as a biological variable in the search for novel antidepressants. Frontiers in Neuroendocrinology, 50, 107117. https://doi.org/10.1016/j.yfrne.2018.05.003.

    • Search Google Scholar
    • Export Citation
  • Wright, K. N., & Kabbaj, M. (2018). Sex differences in sub-anesthetic ketamine's antidepressant effects and abuse liability. Current Opinion in Behavioral Sciences, 23, 3641. https://doi.org/10.1016/j.cobeha.2018.02.001.

    • Search Google Scholar
    • Export Citation
  • Zanos, P., & Gould, T. D. (2018). Mechanisms of ketamine action as an antidepressant. Molecular Psychiatry, 23(4), 801811. https://doi.org/10.1038/mp.2017.255.

    • Search Google Scholar
    • Export Citation
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Attila Szabo - University of Oslo

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  • Zsolt Demetrovics - Eötvös Loránd University, Budapest, Hungary
  • Ede Frecska, founding Editor-in-Chief - University of Debrecen, Debrecen, Hungary
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  • Gábor Andrássy - University of Debrecen, Debrecen, Hungary
  • Tiago Arruda-Sanchez - Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
  • Paulo Barbosa - State University of Santa Cruz, Bahia, Brazil
  • Michael Bogenschutz - New York University School of Medicine, New York, NY, USA
  • Petra Bokor - University of Pécs, Pécs, Hungary
  • Jose Bouso - Autonomous University of Madrid, Madrid, Spain
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  • Susana Bustos - California Institute of Integral Studies San Francisco, USA
  • Robin Carhart-Harris - Imperial College, London, UK
  • Valerie Curran - University College London, London, UK
  • Alicia Danforth - Harbor-UCLA Medical Center, Los Angeles, USA
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  • Lajos Horváth - University of Debrecen, Debrecen, Hungary
  • Robert Jesse - Johns Hopkins University School of Medicine, Baltimore, MD, USA
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  • István Kelemen - University of Debrecen, Debrecen, Hungary
  • Eli Kolp - Kolp Institute New, Port Richey, FL, USA
  • Stanley Krippner - Saybrook University, Oakland, CA, USA
  • Evgeny Krupitsky - St. Petersburg State Pavlov Medical University, St. Petersburg, Russia
  • Rafael Lancelotta - Innate Path, Lakewood, CO, USA
  • Anja Loizaga-Velder - National Autonomous University of Mexico, Mexico City, Mexico
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  • David Nichols - Purdue University, West Lafayette, IN, USA
  • David Nutt - Imperial College, London, UK
  • Torsten Passie - Hannover Medical School, Hannover, Germany
  • Janis Phelps - California Institute of Integral Studies, San Francisco, CA, USA
  • József Rácz - Semmelweis University, Budapest, Hungary
  • Christian Rätsch - University of California, Los Angeles, Los Angeles, CA, USA
  • Jordi Riba - Sant Pau Institute of Biomedical Research, Barcelona, Spain
  • Sidarta Ribeiro - Federal University of Rio Grande do Norte, Natal, Brazil
  • William Richards - Johns Hopkins School of Medicine, Baltimore, MD, USA
  • Stephen Ross - New York University, New York, NY, USA
  • Brian Rush - University of Toronto, Toronto, Canada
  • Eduardo Schenberg - Federal University of São Paulo, São Paulo, Brazil
  • Ben Sessa - Cardiff University School of Medicine, Cardiff, UK
  • Lowan H. Stewart - Santa Fe Ketamine Clinic, NM, USA (Medical Director)
  • Rebecca Stone - Emory University, Atlanta, GA, USA
  • Rick Strassman - University of New Mexico School of Medicine, Albuquerque, NM, USA
  • Attila Szabó - University of Oslo, Oslo, Norway
  • Csaba Szummer - Károli Gáspár University of the Reformed Church, Budapest, Hungary
  • Manuel Torres - Florida International University, Miami, FL, USA
  • Luís Fernando Tófoli - University of Campinas, Campinas, Brazil State
  • Malin Uthaug - Maastricht University, Maastricht, The Netherlands
  • Julian Vayne - Norwich, UK
  • Nikki Wyrd - Norwich, UK

Attila Szabo
University of Oslo

E-mail address: attilasci@gmail.com

Indexing and Abstracting Services:

  • Web of Science ESCI
  • Biological Abstracts
  • BIOSIS Previews
  • APA PsycInfo
  • DOAJ
  • Scopus
  • CABELLS Journalytics

2021  
Web of Science  
Total Cites
WoS
not indexed
Journal Impact Factor not indexed
Rank by Impact Factor

not indexed

Impact Factor
without
Journal Self Cites
not indexed
5 Year
Impact Factor
not indexed
Journal Citation Indicator not indexed
Rank by Journal Citation Indicator

not indexed

Scimago  
Scimago
H-index
2
Scimago
Journal Rank
not yet available
Scimago Quartile Score Anthropology (Q3)
Biological Psychiatry (Q4)
Clinical Psychology (Q4)
Health (social science) (Q4)
Pharmacology (medical) (Q4)
Psychiatry and Mental Health (Q4)
Social Psychology (Q4)
Scopus  
Scopus
Cite Score
0,9
Scopus
CIte Score Rank
Anthropology 186/443 (Q2)
Health (social science) 234/323 (Q3)
Clinical Psychology 213/292 (Q3)
Pharmacology (medical) 190/255 (Q3)
Psychiatry and Mental Health 419/529 (Q4)
Social Psychology 243/296 (Q4)
Biological Psychiatry 38/43 (Q4)
Scopus
SNIP
0,381

2020  
CrossRef Documents 8
WoS Cites 37
WoS H-index 4
Days from submission to acceptance 95
Days from acceptance to publication 75
Acceptance Rate 41%

2019  
WoS
Cites
11
CrossRef
Documents
35
Acceptance
Rate
77%

 

Journal of Psychedelic Studies
Publication Model Gold Open Access
Submission Fee none
Article Processing Charge none
Subscription Information Gold Open Access

Journal of Psychedelic Studies
Language English
Size A4
Year of
Foundation
2016
Volumes
per Year
1
Issues
per Year
3
Founder Akadémiai Kiadó
Debreceni Egyetem
Eötvös Loránd Tudományegyetem
Károli Gáspár Református Egyetem
Founder's
Address
H-1117 Budapest, Hungary 1516 Budapest, PO Box 245.
H-4032 Debrecen, Hungary Egyetem tér 1.
H-1053 Budapest, Hungary Egyetem tér 1-3.
H-1091 Budapest, Hungary Kálvin tér 9.
Publisher Akadémiai Kiadó
Publisher's
Address
H-1117 Budapest, Hungary 1516 Budapest, PO Box 245.
Responsible
Publisher
Chief Executive Officer, Akadémiai Kiadó
ISSN 2559-9283 (Online)

Monthly Content Usage

Abstract Views Full Text Views PDF Downloads
Aug 2022 0 0 0
Sep 2022 0 0 0
Oct 2022 0 0 0
Nov 2022 0 0 0
Dec 2022 0 0 0
Jan 2023 0 315 233
Feb 2023 0 0 0