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Neuroimaging-derived biomarkers of the antidepressant effects of ketamine

Open AccessPublished:November 25, 2022DOI:https://doi.org/10.1016/j.bpsc.2022.11.005

      Abstract

      Major depressive disorder is a highly prevalent psychiatric disorder. Despite an extensive range of treatment options, about a third of patients still struggle to respond to available therapies. In the last 20 years, ketamine has gained considerable attention in the psychiatric field as a promising treatment of depression, particularly in patients who are treatment resistant or at high risk for suicide. At a sub-anesthetic dose, ketamine produces a rapid and pronounced reduction in depressive symptoms and suicidal ideation, where serial treatment appears to produce a greater and more sustained therapeutic response. However, the mechanism driving ketamine’s antidepressant effects is not yet well understood. Biomarker discovery may advance knowledge of ketamine’s antidepressant action, which could in turn translate to more personalized and effective treatment strategies. At the brain systems-level, neuroimaging can be used to identify functional pathways and networks contributing to ketamine’s therapeutic effects by studying how it alters brain structure, function, connectivity, and metabolism. In this review, we summarize and appraise recent work in this area, including 51 articles that use resting-state and task-based functional MRI, arterial spin labeling, positron emission tomography, structural MRI, diffusion MRI, or magnetic resonance spectroscopy to study brain and clinical changes 24 hours or longer after ketamine treatment in populations with unipolar or bipolar depression. Though individual studies have included relatively small samples, different methodological approaches and report disparate regional findings, converging evidence supports that ketamine leads to neuroplasticity in structural and functional brain networks that contribute to or are relevant to its antidepressant effects.

      Keywords(6)

      Introduction

      About 50% of patients with major depressive disorder (MDD) do not respond to first-line monoaminergic antidepressants(
      • Scott F.
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      Systematic review and meta-analysis of augmentation and combination treatments for early-stage treatment-resistant depression.
      ), and after multiple treatment failures are characterized as having treatment-resistant depression (TRD)(
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      • Stewart J.W.
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      Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR*D report.
      ). At a subanesthetic dose, ketamine produces profound and rapid reductions of depression symptoms(
      • Berman R.M.
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      • Anand A.
      • Oren D.A.
      • Heninger G.R.
      • Charney D.S.
      • Krystal J.H.
      Antidepressant effects of ketamine in depressed patients.
      ,
      • Wan L.-B.
      • Levitch C.F.
      • Perez A.M.
      • Brallier J.W.
      • Iosifescu D.V.
      • Chang L.C.
      • et al.
      Ketamine safety and tolerability in clinical trials for treatment-resistant depression.
      ,
      • Murrough J.W.
      • Perez A.M.
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      • Stern J.
      • Parides M.K.
      • aan het Rot M.
      • et al.
      Rapid and longer-term antidepressant effects of repeated ketamine infusions in treatment-resistant major depression.
      ) and suicidality(
      • Wilkinson S.T.
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      • Mathew S.J.
      • Murrough J.W.
      • Feder A.
      • et al.
      The Effect of a Single Dose of Intravenous Ketamine on Suicidal Ideation: A Systematic Review and Individual Participant Data Meta-Analysis.
      ) in over 60% of MDD patients(
      • Wan L.-B.
      • Levitch C.F.
      • Perez A.M.
      • Brallier J.W.
      • Iosifescu D.V.
      • Chang L.C.
      • et al.
      Ketamine safety and tolerability in clinical trials for treatment-resistant depression.
      ,
      • McGirr A.
      • Berlim M.T.
      • Bond D.J.
      • Fleck M.P.
      • Yatham L.N.
      • Lam R.W.
      A systematic review and meta-analysis of randomized, double-blind, placebo-controlled trials of ketamine in the rapid treatment of major depressive episodes.
      ). Though symptom relief is typically transient (<1 week), larger and more sustained antidepressant response and remission occur with serial ketamine therapy(
      • Phillips J.L.
      • Norris S.
      • Talbot J.
      • Birmingham M.
      • Hatchard T.
      • Ortiz A.
      • et al.
      Single, Repeated, and Maintenance Ketamine Infusions for Treatment-Resistant Depression: A Randomized Controlled Trial.
      ).
      In-vivo studies of brain structure, function, connectivity and metabolism can help discern the functional pathways and systems contributing to ketamine’s therapeutic effects at the macroscale(
      • Kotoula V.
      • Webster T.
      • Stone J.
      • Mehta M.A.
      Resting-state connectivity studies as a marker of the acute and delayed effects of subanaesthetic ketamine administration in healthy and depressed individuals: A systematic review.
      ,
      • Alexander L.
      • Jelen L.A.
      • Mehta M.A.
      • Young A.H.
      The anterior cingulate cortex as a key locus of ketamine’s antidepressant action.
      ) and may inform more effective individualized treatment approaches. Here, we synthesize findings identified using PRISMA methods(
      • Page M.J.
      • McKenzie J.E.
      • Bossuyt P.M.
      • Boutron I.
      • Hoffmann T.C.
      • Mulrow C.D.
      • et al.
      The PRISMA 2020 statement: an updated guideline for reporting systematic reviews.
      ) from neuroimaging studies in MDD published in English from 2011-2022 that investigate the effects of ketamine on functional and structural brain systems, or imaging biomarkers predictive of ketamine antidepressant response. Original research articles that collected brain imaging and clinical outcomes ≥24 hours post-ketamine administration in adult populations with unipolar or bipolar depression were included. Preclinical studies addressing the molecular and cellular mechanisms of ketamine(
      • Kraus C.
      • Wasserman D.
      • Henter I.D.
      • Acevedo-Diaz E.
      • Kadriu B.
      • Zarate Jr., C.A.
      The influence of ketamine on drug discovery in depression.
      ,
      • Zanos P.
      • Moaddel R.
      • Morris P.J.
      • Riggs L.M.
      • Highland J.N.
      • Georgiou P.
      • et al.
      Ketamine and Ketamine Metabolite Pharmacology: Insights into Therapeutic Mechanisms.
      ) or neuroimaging studies that only investigate the effects of ketamine during or shortly after (<24 hours) ketamine treatment were excluded(
      • Carlson P.J.
      • Diazgranados N.
      • Nugent A.C.
      • Ibrahim L.
      • Luckenbaugh D.A.
      • Brutsche N.
      • et al.
      Neural correlates of rapid antidepressant response to ketamine in treatment-resistant unipolar depression: a preliminary positron emission tomography study.
      ,
      • Li C.-T.
      • Chen M.-H.
      • Lin W.-C.
      • Hong C.-J.
      • Yang B.-H.
      • Liu R.-S.
      • et al.
      The effects of low-dose ketamine on the prefrontal cortex and amygdala in treatment-resistant depression: A randomized controlled study.
      ,
      • Nugent A.C.
      • Diazgranados N.
      • Carlson P.J.
      • Ibrahim L.
      • Luckenbaugh D.A.
      • Brutsche N.
      • et al.
      Neural correlates of rapid antidepressant response to ketamine in bipolar disorder.
      ,
      • Abdallah C.G.
      • De Feyter H.M.
      • Averill L.A.
      • Jiang L.
      • Averill C.L.
      • Chowdhury G.M.I.
      • et al.
      The effects of ketamine on prefrontal glutamate neurotransmission in healthy and depressed subjects.
      ,
      • Salvadore G.
      • van der Veen J.W.
      • Zhang Y.
      • Marenco S.
      • Machado-Vieira R.
      • Baumann J.
      • et al.
      An investigation of amino-acid neurotransmitters as potential predictors of clinical improvement to ketamine in depression.
      ,
      • Ballard E.D.
      • Lally N.
      • Nugent A.C.
      • Furey M.L.
      • Luckenbaugh D.A.
      • Zarate Jr., C.A.
      Neural correlates of suicidal ideation and its reduction in depression.
      ). Figure 1 elaborates search methods and inclusion criteria.
      Figure thumbnail gr1
      Figure 1Original research articles were identified and evaluated according to the PRISMA review method. Literature searches were performed in the PubMed and Google Scholar databases using key words (right) and the inclusion/exclusion criteria (bottom) provided. For more details regarding methods see Supplemental Material.

      Functional MRI

      Resting State fMRI

      Extensive neuroimaging evidence supports the pathophysiology of MDD includes the dysregulation of multiple large-scale brain networks. For example, connectivity within or between the default mode (DMN), salience (SN), cingulo-opercular (CON), frontoparietal/central executive network (FPN/CEN), orbito and ventromedial-affective (OAN and VMN) networks are repeatedly implicated in depression, and appear to influence treatment outcomes(
      • Dunlop K.
      • Talishinsky A.
      • Liston C.
      Intrinsic Brain Network Biomarkers of Antidepressant Response: a Review.
      ,
      • Dutta A.
      • McKie S.
      • Deakin J.F.W.
      Resting state networks in major depressive disorder.
      ,
      • Brakowski J.
      • Spinelli S.
      • Dörig N.
      • Bosch O.G.
      • Manoliu A.
      • Holtforth M.G.
      • Seifritz E.
      Resting state brain network function in major depression - Depression symptomatology, antidepressant treatment effects, future research.
      ,
      • Korgaonkar M.S.
      • Goldstein-Piekarski A.N.
      • Fornito A.
      • Williams L.M.
      Intrinsic connectomes are a predictive biomarker of remission in major depressive disorder.
      ). These networks and their nodes are pivotal for emotion processing, autonomic responses to emotion, memory and social cognition (hippocampal, amygdala, septal area, anterior thalamus and hypothalamus), higher cognition, motivation and mood regulation (dorsal and subgenual anterior cingulate cortex (dACC/sgACC) and dorsolateral (DLPFC) and parietal association regions), reward processing (ventral striatum, habenula) and vegetative states (midbrain/brainstem structures)(
      • Brakowski J.
      • Spinelli S.
      • Dörig N.
      • Bosch O.G.
      • Manoliu A.
      • Holtforth M.G.
      • Seifritz E.
      Resting state brain network function in major depression - Depression symptomatology, antidepressant treatment effects, future research.
      ,
      • Korgaonkar M.S.
      • Goldstein-Piekarski A.N.
      • Fornito A.
      • Williams L.M.
      Intrinsic connectomes are a predictive biomarker of remission in major depressive disorder.
      ,
      • Wang L.
      • Hermens D.F.
      • Hickie I.B.
      • Lagopoulos J.
      A systematic review of resting-state functional-MRI studies in major depression.
      ). Accordingly, the majority of recent ketamine imaging studies have used blood-oxygen-level-dependent (BOLD) resting-state functional magnetic resonance imaging (rsfMRI) to measure the temporal coherence of intrinsic brain activity across different functional brain systems in the absence of a specific task(
      • Damoiseaux J.S.
      • Rombouts S.A.R.B.
      • Barkhof F.
      • Scheltens P.
      • Stam C.J.
      • Smith S.M.
      • Beckmann C.F.
      Consistent resting-state networks across healthy subjects.
      ,
      • De Luca M.
      • Beckmann C.F.
      • De Stefano N.
      • Matthews P.M.
      • Smith S.M.
      fMRI resting state networks define distinct modes of long-distance interactions in the human brain.
      ). Network connectivity can be measured in many different ways with rsfMRI, each having its limitations(
      • Taylor J.J.
      • Kurt H.G.
      • Anand A.
      Resting State Functional Connectivity Biomarkers of Treatment Response in Mood Disorders: A Review.
      ,
      • Cole D.M.
      • Smith S.M.
      • Beckmann C.F.
      Advances and pitfalls in the analysis and interpretation of resting-state FMRI data.
      ,
      • Smith S.M.
      • Vidaurre D.
      • Beckmann C.F.
      • Glasser M.F.
      • Jenkinson M.
      • Miller K.L.
      • et al.
      Functional connectomics from resting-state fMRI.
      ). In this review, we report rsfMRI findings for large-scale cortical networks and nodes, and for whole brain and global brain connectivity (Table 1).
      Table 1Resting state fMRI studies of ketamine treatment in depressed populations.
      StudySampleOther MedicationsKetamine TreatmentData CollectionDepression AssessmentSummary of Findings
      Abdallah et al. 2017(49); NCT00768430NA: 22 Unipolar TRD***, 47 HC§NO

      Antidepressant and antipsychotics-free ≥1week prior to treatment.
      Cohort A++:

      •Single IV ketamine, 0.5mg/kg over 40 mins

      •Placebo: 0.45mg/kg midazolam over 40 mins

      Cohort B++:

      •Single IV ketamine, 0.23mg/kg in 2 mins followed by 0.58mg/kg over 70 mins

      •Placebo: oral placebo

      •Saline IV
      Cohort A:

      Neuroimaging:

      •Baseline

      •24 hours post

      Cohort B: Neuroimaging:

      •During infusion
      MADRS, QIDS, Brief psychiatric rating scale, Clinician-administered dissociative state scale(+) GBCr post ketamine in bilateral dmPFC and right dlPFC for TRD, normalizing to HC

      No significant change in GBCr detected in placebo group
      Abdallah et al., 2017(47); NCT00548964, NCT00768430, NCT01880593N: 18 Unipolar TRD**, 25 HCNO

      Antidepressant and antipsychotics-free ≥1week prior to treatment. Benzodiazepines witheld at day of each scan
      Single IV infusion 0.5mg/kg ketamine over 40 mins+Neuroimaging:

      •Baseline

      •24 hours post infusion

      Clinical Assessment:

      •Baseline

      •24 hours post infusion
      MADRS

      Response was defined as ⩾50% reduction in MADRS
      (+) GBCr in right lateral PFC after treatment for all TRD participants

      (-) GBCr in left cerebellum after treatment for all TRD participants

      (+) Change in GBCr (post-pre ketamine) in right lateral PFC and left anterior insula in Rs

      (+) GBCr postketamine in bilateral caudate, bilateral lateral PFC, and middle temporal of Rs

      (-) FC within PFC after ketamine

      (+) FC between PFC and other brain regions after ketamine
      Abdallah et al., 2018(48); NCT01046630N: 58 Unipolar MDDNOSingle IV infusion 0.5mg/kg ketamine, 100mg of lanicemine, or saline placebo over 60 mins++Neuroimaging & Clinical Assessment:

      •Baseline

      •During Infusion

      •24 hours post infusion
      BDI(+) PFC GBCr in ketamine during infusion and at 24hr post-treatment compared to baseline

      (+) GBCr in dlPFC, dmPFC, and fmPFC during ketamine infusion

      (+) GBCr in dorsolateral and dorsomedial PFC at 24 hrs post-treatment

      Vertex wise analysis showed depression improvement positively correlated with GBCr in dPFC during infusion and 24hrs post treatment but negative correlation with GBCr in ventral PFC during infusion
      Evans et al., 2018(31); NCT00088699N: 33 Unipolar TRD*, 25 HC§NO

      Medication free ≥2 weeks prior to treatment
      Single IV infusion 0.5mg/kg ketamine or saline placebo during first session followed by alternative treatment 2 weeks later+++Neuroimaging:

      •Baseline

      •2 and 10 days post infusion

      Clinical Assessment:

      •Baseline

      •40, 80, 120 and 230 mins post infusion on days 1, 2, 3, 7, 10 and 11
      MADRS(+) RSFC between bilateral insula, middle frontal gyrus, post-central gyrus, and occipital gyrus and DMN 2 days after ketamine infusion compared to placebo infusion that was no longer evident at day 10

      RSFC between insula (strongest in right posterior insula) and DMN normalized for MDD 2 days after ketamine- no significant difference between TRD and HC - that returned to baseline at day 10
      Chen et al., 2019(33); R000019001-UMIN000016985N: 48 Unipolar TRD**YES

      Permitted to remain on antidepressants
      Single IV infusion 0.5mg/kg ketamine, 0.2mg/kg ketamine, or saline placebo over 40 mins+++Neuroimaging & Clinical Assessment:

      •Baseline

      •48 hours post infusion
      MADRS(-) RSFC between left and right dACC after ketamine, associated with reduction in suicidal ideation

      (-) in RSFC between dlPFC and right frontal pole in 0.5mg/kg group

      (+) RSFC between right dlPFC and left superior parietal lobe associated with reduced suicidal ideation in 0.2mg/kg group

      (+) RSFC between right dACC and right anterior middle temporal gyrus in 0.2mg/kg group
      Gärtner et al., 2019(39); NCT02099630, NCT03609190NB: 24 Unipolar TRD**YES

      Prior antidepressant medication remained unchanged
      Site A: Single IV infusion 0.5mg/kg racemic ketamine+

      Site B: Singe IV infusion 0.25mg/kg S-ketamine+
      Neuroimaging & Clinical Assessment:

      •Baseline

      •24 hours post infusion
      MADRS, HDRS(+) RSFC between sgACC and 4 regions (SMA, dlPFC, anterior PFC, and OFC) associated with symptom reduction

      ↓Whole-brain connectivity at baseline associated with (-) depressive symptoms 24 hrs after ketamine
      Chen et al., 2020(41); UMIN000016985N: 48 Unipolar TRD**YES

      Concomitant stable antidepressant treatment ≥2 weeks prior
      Single IV infusion at 0.5mg/kg or 0.2mg/kg ketamine or saline placebo over 40 mins+++Neuroimaging:

      •Baseline

      Clinical Assessment:

      •Baseline

      •40, 80, 120, and 240 mins post infusion

      •2, 3, 4, 5, 6, 7, and 14 days post infusion
      HDRS↓Baseline RSFC between bilateral superior frontal cortex and striatum associated with (-) depressive symptoms after 0.2mg/kg ketamine infusion
      Kraus et al., 2020(50); NCT00088699N: 28 Unipolar TRD*, 22 HC§NO

      Medication free ≥2 weeks prior to treatment
      Single IV infusion 0.5mg/kg ketamine or saline placebo during first session followed by alternative treatment 2 weeks later+++Neuroimaging:

      •Baseline

      •2 and 3 days post infusion

      •Baseline

      Clinical Assessment:

      •Before, during, and after each infusion
      MADRS,

      BID,

      Hamilton Anxiety Rating Scale
      Could not replicate (+) connectivity observed in Abdallah et al. 2017 in Neuropsychopharmacology after ketamine treatment
      Sahib et al., 2020(46); NCT02165449N: 61 Unipolar TRD**, 40 HCYES

      Monoaminergic antidepressants allowed if stable ≥6 weeks prior to treatment

      No Benzodiazapine ≤72 hours prior to treatment
      Four serial IV infusions of 0.5mg/kg ketamine over 40 mins+Neuroimaging & Clinical Assessment:

      •Baseline

      •24 hours post first infusion

      •24-72 hours post fourth infusion
      HDRS-17

      Rm: post-treatment HDRS ≤7
      (+) RSFC within SMN after ketamine, normalizing towards HC

      (-) RSFC between ventral node and visual node after ketamine, normalizing towards HC. ↑RSFC between visual cortex and DMN at baseline that (-) with each infusion

      (-) RSFC between cerebellum and SN between first and fourth ketamine treatment, normalizing towards HC

      (-) RSFC between cerebellum and striatum for Rm, normalizing towards HC.

      Opposite effect in NRm pre- and post-treatment change in whole brain FC significantly different between Rs and NRs
      Zhuo et al., 2020(51)N: 38 Bipolar TRD**YES

      Remained on mood stabilizer or antipsychotic medication if clinically stable
      Serial IV infusion of 0.5mg/kg ketamine over 40-50 mins on days 2, 4, 6, 8, 10, 12, 15, 18, and 20 of study+Neuroimaging:

      •Baseline

      •Day 2, 7, 14, and 21 after beginning treatment
      HDRS-17Changes in GBCd after first day of ketamine and peaked at day 7. Effects mostly gone by end of third week.

      (-) GBCd in bilateral insula, right caudate nucleus and bilateral inferior frontal gyrus

      (+) GBCd in bilateral postcentral gyrus, sgACC, bilateral thalamus, and cerebellum.

      No significant associations with clinical measure
      Mkrtchian et al., 2020(42); NCT00088699N: 33 Unipolar TRD*, 25 HC§NO

      Medication free ≥2 weeks prior to treatment
      Single IV infusion of 0.5mg/kg ketamine or saline placebo during first session followed by alternative treatment 2 weeks later+++Neuroimaging:

      •2 days post infusions

      Clinical Assessments:

      •Baseline

      •40, 80, 120, and 230 mins on 1, 2, 3, 7, 10, and 11 days post infusions
      MADRS, SHAPS(+) RSFC between VS-left dlPFC, DC-right ventrolateral PFC, DC-pgACC, and VRP-OFC in TRD but (-) in HC post-ketamine.

      (+) RSFC in DC-right vlPFC correlated with improved day 2 SHAPS

      (+) RSFC in DC-pgACC correlated with improved day 10 SHAPS
      Nakamura et al., 2021(40); UMIN-CTR No. UMIN000017529N: 14 unipolar TRD***, 1 bipolar TRD*NO

      Discontinuation of antidepressant medications
      Serial IV infusions of ketamine over 40 mins twice a week over 2 weeks (4 total) with concurrent daily oral placebo or lithium carbonate (600-800mg) daily++Neuroimaging:

      •Baseline

      •6-24 hours post infusions

      Clinical Assessments:

      •4 hours post final infusion
      MADRS,

      Young Mania Rating Scale,

      Rs: Decrease in MADRS ≥50%
      Significant cluster defining Rs and NRs between the amygdala and sgACC in the right AN

      (-) RSFC between amygdala and sc/sgACC in the right hemisphere at baseline associated with (+) depressive symptoms (MADRS)

      RSFC between amygdala and sc/sgACC in the right hemisphere Rs>NRs both at baseline and followup
      Siegel et al., 2021(30); NCT01179009N: 23 Unipolar TRD**, 27HCYES

      SSRI and SNRI allowed if constant for ≥6 weeks prior to infusion
      Continuous 96h IV infusion of ketamine started at 0.15mg/kg/h at 10am on day 1 and titrated to tolerance twice daily to target rate of 0.6mg/kg/h+Neuroimaging:

      •Baseline

      •2 weeks post infusion

      Clinical Assessments:

      •2, 4, 6, and 8 weeks post infusion
      MADRS(-) RSFC within DMN 2 weeks after ketamine

      (-) RSFC between sgACC and DMN 2 weeks after ketamine across hemispheres

      (+) RSFC between sgACC and bilateral cACC and bilateral anterior insula

      (-) RSFC within limbic system especially with anterior thalamus

      (+) RSFC between limbic regions and cortical areas, especially cingulo-opercular network
      Rivas-Grajales et al., 2021(44); NCT00768430, NCT01880593N: 35 Unipolar TRD**NO

      Antidepressant free ≥1 week prior to treatment
      Single IV infusion of 0.5mg/kg ketamine over 40 mins+Neuroimaging & Clinical Assessments:

      •Baseline

      •24 hours post infusion
      MADRS

      QIDS-SR
      (+) RSFC between right habenula and right frontal pole of dlPFC associated with (-) MADRS scores

      (+) RSFC between right habenula and right occipital pole, right temporal pole, right parahippocampal gyrus, and left lateral occipital cortex associated with (-) QIDS-SR
      Vasavada et al., 2021(34); NCT02165449N: 44 Unipolar TRD**, 50 HCYES

      Monoaminergic antidepressants allowed if stable ≥6 weeks prior to treatment

      No Benzodiazapine ≤72 hours prior to treatment
      Four serial IV infusions of 0.5mg/kg ketamine over 40 mins+Neuroimaging & Clinical Assessments:

      •Baseline

      •24 hours post first infusion

      •24-72 hours post fourth infusion
      HDRS-17

      SHAPS

      DASS

      BIS
      (+) RSFC between right amygdala and right CEN normalizing towards HC with each infusion

      (-) RSFC between left amygdala and SN with each infusion and correlated with improved BISS.

      Greater negative connectivity between right hippocampus and left CN correlated with improved SHAPS
      Zhang et al. 2020(32)N: 36 Unipolar TRD**-Six serial IV infusions of 0.5mg/kg over 40 mins followed by propofol-ECT treatment 24 hours later+Neuroimaging:

      •Baseline

      •1st, 3rd, 7th, 10th, and 14th day after first treatment

      Clinical Assessment:

      •Baseline

      •7th and 14th day of treatment
      HAMD(-)GBCd in medial prefrontal lobe, sgACC, posterior cingulate, thalamus, hippocampus, and orbitofrontal lobe on day 7

      (-) FC within DMN through third day
      *≥1 failed treatment

      **≥2 failed treatment

      ***≥3 failed treatment

      TRD: Treatment resistant depression

      MDD: Major Depressive Disorder

      HC: Healthy Control

      §: HC received ketamine

      +: Open Label

      ++: Randomized Placebo

      +++: Randomized Crossover

      IV: Intravenous

      Hrs: Hours

      Mins: Minutes

      MADRS: Montgomery-Åsberg Depression Rating Scale

      QIDS: Quick Inventory of Depressive Symptomatology

      QIDS-SR: Quick Inventory of Depressive Symptomatology Self Report (+): Increase

      (-): Decrease

      ECT: Electroconvulsive therapy
      HDRS: Hamilton Depression Rating Scale

      BDI: Beck Depression Inventory

      DASS: Depression Anxiety and Stress Scale

      BISS: Behavioral Inhibition System Scale

      SHAPS: Snaith-Hamilton Pleasure Scale

      Rs: Responders

      NRs: Non responders

      Rm: Remitters

      NRm: Non remitters

      GBCr: Global brain connectivity regression

      GBCd: Global functional connectivity density

      RSFC: Resting state functional connectivity

      PFC: Prefrontal cortex dmPFC: Dorsomedial Prefrontal cortex

      fmPFC: Frontomedial Prefrontal cortex

      ↑: Higher

      ↓: Lower
      dlPFC: Dorsolateral PFC

      vlPFC: ventrolateral FPC

      dPFC: dorsal PFC

      dACC: Dorsal anterior cingulate cortex

      sgACC: Subgenual anterior cingulate cortex

      scACC: Subcallosal anterior cingulate cortex

      cACC: Caudal anterior cingulate cortex

      OFC: Orbitofrontal cortex

      VS: Ventral striatum

      DC: Dorsal cingulate

      AN: Affective network

      DMN: Default mode network

      SN: Salience network

      CEN: Central executive network

      SMN: Somato-motor network

      VRP: Ventral rostral putamen
      ATwo studies were pooled. Cohort A conducted at one site in Houston as an add on to a ketamine clinical trial. Cohort B was conducted at a different site in New Haven CT to investigate modulation of ketamine effects by lamotrigine and only included healthy controls
      BTwo different scanners used to collect rsfMRI data. Scanning site used as a covariate in the analysis. Post-hoc analysis found similar results when testing sites individually

      Large-Scale Cortical Networks and Nodes

      Several independent rsfMRI studies report changes in resting-state functional connectivity (RSFC) in MDD in the days following ketamine treatment. The DMN, engaged during introspective activities and consisting of anterior/dorsal (medial PFC, precuneus, and inferior parietal cortex) and ventral subsystems (hippocampus/parahippocampus), is perhaps the most widely studied large-scale network in depression(
      • Dutta A.
      • McKie S.
      • Deakin J.F.W.
      Resting state networks in major depressive disorder.
      ). Several studies have reported ketamine-related changes in DMN RSFC. For example, 2 weeks following a continuous 96-hour intravenous (IV) ketamine infusion (0.6mg/kg/hour), RSFC decreased within ventral DMN limbic nodes, but increased between subcortical and cortical DMN/CON nodes(
      • Siegel J.S.
      • Palanca B.J.A.
      • Ances B.M.
      • Kharasch E.D.
      • Schweiger J.A.
      • Yingling M.D.
      • et al.
      Prolonged ketamine infusion modulates limbic connectivity and induces sustained remission of treatment-resistant depression.
      ). However, these patterns did not vary based on ketamine response. A separate study similarly observed increased RSFC between the DMN and the insula, a key node of the CON and SN, as well as with frontal, parietal and occipital cortices 2 days after single IV ketamine compared with placebo in MDD(31). Here, increased DMN-insula connectivity normalized towards control levels 2-days post-ketamine but reversed 10-days following treatment. Another study found when adding ketamine to propofol-electroconvulsive treatment, RSFC within the DMN decreased(
      • Zhang J.
      • Tian H.
      • Li J.
      • Ji S.
      • Chen S.
      • Zhu J.
      • et al.
      Ketamine plus propofol-electroconvulsive therapy (ECT) transiently improves the antidepressant effects and the associated brain functional alterations in patients with propofol-ECT-resistant depression.
      ).
      The FPN/CEN, comprised of dorsal and ventral frontal-parietal subsystems, is a large resting-state network active during attention, cognitive states and emotion-regulation frequently linked with depression. Also implicated in ketamine MRI studies, decreased RSFC has been reported within the frontal component of the CEN 48 hours following single dose ketamine in PFC and dACC seed-based analysis(
      • Chen M.-H.
      • Lin W.-C.
      • Tu P.-C.
      • Li C.-T.
      • Bai Y.-M.
      • Tsai S.-J.
      • Su T.-P.
      Antidepressant and antisuicidal effects of ketamine on the functional connectivity of prefrontal cortex-related circuits in treatment-resistant depression: A double-blind, placebo-controlled, randomized, longitudinal resting fMRI study.
      ). Negative and positive correlations with suicidal ideation were observed for RSFC between left-right dACC, and DLPFC-left superior parietal cortex for each dose respectively. Explicitly examining RSFC between the hippocampus and amygdala with the DMN, FPN/CEN and SN, increased and normalized RSFC was observed between the right amygdala and the right CEN 24 hours after patients received four serial ketamine infusions(
      • Vasavada M.M.
      • Loureiro J.
      • Kubicki A.
      • Sahib A.
      • Wade B.
      • Hellemann G.
      • et al.
      Effects of Serial Ketamine Infusions on Corticolimbic Functional Connectivity in Major Depression.
      ). Further, decreased left amygdala-SN RSFC associated with improved behavioral inhibition, while negative connectivity between the right hippocampus and the left CEN correlated with improved anhedonia(
      • Vasavada M.M.
      • Loureiro J.
      • Kubicki A.
      • Sahib A.
      • Wade B.
      • Hellemann G.
      • et al.
      Effects of Serial Ketamine Infusions on Corticolimbic Functional Connectivity in Major Depression.
      ,
      • Snaith R.P.
      • Hamilton M.
      • Morley S.
      • Humayan A.
      • Hargreaves D.
      • Trigwell P.
      A scale for the assessment of hedonic tone the Snaith-Hamilton Pleasure Scale.
      )
      The sgACC, considered a node of the VMN and reciprocally connected with limbic, ventral striatum, habenula, and thalamic structures, is involved in modulating emotion and reward response(
      • Drevets W.C.
      • Savitz J.
      • Trimble M.
      The subgenual anterior cingulate cortex in mood disorders.
      ) and linked with antidepressant response following behavioral, pharmacological and brain stimulation interventions(
      • Dunlop K.
      • Talishinsky A.
      • Liston C.
      Intrinsic Brain Network Biomarkers of Antidepressant Response: a Review.
      ). Increased RSFC between the sgACC, caudate and insula was observed two weeks after single 96-hour ketamine IV treatment(
      • Siegel J.S.
      • Palanca B.J.A.
      • Ances B.M.
      • Kharasch E.D.
      • Schweiger J.A.
      • Yingling M.D.
      • et al.
      Prolonged ketamine infusion modulates limbic connectivity and induces sustained remission of treatment-resistant depression.
      ), though RSFC between the sgACC and DMN decreased. At least two studies have linked sgACC connectivity with overall antidepressant response post ketamine. Specifically, a multi-site study reported associations between depression symptom improvement(
      • Hamilton M.
      A rating scale for depression.
      ,
      • Montgomery S.A.
      • Asberg M.
      A new depression scale designed to be sensitive to change.
      ) and increased RSFC between the sgACC and supplementary motor area, and DLPFC 24 hours following single IV ketamine(
      • Gärtner M.
      • Aust S.
      • Bajbouj M.
      • Fan Y.
      • Wingenfeld K.
      • Otte C.
      • et al.
      Functional connectivity between prefrontal cortex and subgenual cingulate predicts antidepressant effects of ketamine.
      ). However, another study found symptom improvement(
      • Montgomery S.A.
      • Asberg M.
      A new depression scale designed to be sensitive to change.
      ) was associated with lower RSFC between the sgACC and right amygdala(
      • Montgomery S.A.
      • Asberg M.
      A new depression scale designed to be sensitive to change.
      ,
      • Nakamura T.
      • Tomita M.
      • Horikawa N.
      • Ishibashi M.
      • Uematsu K.
      • Hiraki T.
      • et al.
      Functional connectivity between the amygdala and subgenual cingulate gyrus predicts the antidepressant effects of ketamine in patients with treatment-resistant depression.
      ). Lower sgACC-right amygdala RSFC at baseline was also found present in patients subsequently identified as treatment responders(
      • Nakamura T.
      • Tomita M.
      • Horikawa N.
      • Ishibashi M.
      • Uematsu K.
      • Hiraki T.
      • et al.
      Functional connectivity between the amygdala and subgenual cingulate gyrus predicts the antidepressant effects of ketamine in patients with treatment-resistant depression.
      ).
      Prior data also suggest fronto-striatal circuitry influences ketamine response. Here, lower PFC-striatal RSFC at baseline has been found to associate with subsequent improvements in depressive symptoms(
      • Hamilton M.
      A rating scale for depression.
      ,
      • Chen M.-H.
      • Chang W.-C.
      • Lin W.-C.
      • Tu P.-C.
      • Li C.-T.
      • Bai Y.-M.
      • et al.
      Functional Dysconnectivity of Frontal Cortex to Striatum Predicts Ketamine Infusion Response in Treatment-Resistant Depression.
      ). Additionally, a seed-based study showing increased frontal-striatal connectivity 2-days after single IV ketamine(
      • Mkrtchian A.
      • Evans J.W.
      • Kraus C.
      • Yuan P.
      • Kadriu B.
      • Nugent A.C.
      • et al.
      Ketamine modulates fronto-striatal circuitry in depressed and healthy individuals.
      ), found increased connectivity between the VLPFC and caudate to associate with improved anhedonia(
      • Snaith R.P.
      • Hamilton M.
      • Morley S.
      • Humayan A.
      • Hargreaves D.
      • Trigwell P.
      A scale for the assessment of hedonic tone the Snaith-Hamilton Pleasure Scale.
      ).
      The habenula, part of the epithalamus with direct connections to limbic structures and the basal ganglia, plays a role in emotion, reward and motivation(
      • Hikosaka O.
      • Sesack S.R.
      • Lecourtier L.
      • Shepard P.D.
      Habenula: crossroad between the basal ganglia and the limbic system.
      ). Increased RSFC has been reported between the habenula and the right DLPFC, which associated with improved antidepressant response(
      • Montgomery S.A.
      • Asberg M.
      A new depression scale designed to be sensitive to change.
      ) 24 hours after single IV ketamine(
      • Rivas-Grajales A.M.
      • Salas R.
      • Robinson M.E.
      • Qi K.
      • Murrough J.W.
      • Mathew S.J.
      Habenula Connectivity and Intravenous Ketamine in Treatment-Resistant Depression.
      ). Further, increased RSFC between the right habenula and right and left occipital cortex, right temporal pole, and right parahippocampal gyrus associated with improved subjective mood ratings(
      • Rush A.J.
      • Trivedi M.H.
      • Ibrahim H.M.
      • Carmody T.J.
      • Arnow B.
      • Klein D.N.
      • et al.
      The 16-Item Quick Inventory of Depressive Symptomatology (QIDS), clinician rating (QIDS-C), and self-report (QIDS-SR): a psychometric evaluation in patients with chronic major depression.
      ).

      Whole Brain and Global Brain Connectivity

      The larger literature suggests that several interacting brain networks underlie the pathophysiology of depression, and that multiple functional networks contribute to antidepressant response(
      • Korgaonkar M.S.
      • Goldstein-Piekarski A.N.
      • Fornito A.
      • Williams L.M.
      Intrinsic connectomes are a predictive biomarker of remission in major depressive disorder.
      ). Prior ketamine rsfMRI studies have mostly focused on targeting major networks or components thereof, potentially missing other changes in the functional connectome. To address this limitation, one study employed a data-driven whole-brain approach before and 24 hours after serial ketamine therapy(
      • Sahib A.K.
      • Loureiro J.R.
      • Vasavada M.
      • Anderson C.
      • Kubicki A.
      • Wade B.
      • et al.
      Modulation of the functional connectome in major depressive disorder by ketamine therapy.
      ) to show RSFC within and between the somatomotor network (SMN), and FPN/CEN and visual networks (VN) normalized with treatment and distinguished controls from patients at baseline. This study also showed a normalization of circuitry between the cerebellum, SN and striatum, which correlated with antidepressant response(
      • Hamilton M.
      A rating scale for depression.
      ).
      Global brain connectivity (GBC), which measures the connectivity strength between each voxel to all other gray matter voxels, has been investigated in four ketamine studies. One study(
      • Abdallah C.G.
      • Averill L.A.
      • Collins K.A.
      • Geha P.
      • Schwartz J.
      • Averill C.
      • et al.
      Ketamine Treatment and Global Brain Connectivity in Major Depression.
      ) found ketamine-related GBC increases in the PFC and reduced GBC in the cerebellum. Treatment responders showed greater GBC changes in the lateral PFC, caudate, and insula 24 hours post single-dose ketamine. Follow-up seed-based analysis suggested ketamine reduced hyper-connectivity within the PFC and enhanced hypo-connectivity between the PFC and other brain regions. In a larger sample, the same investigators found an increase in PFC GBCr 24 hours after ketamine when compared to placebo and baseline(

      Abdallah CG, Dutta A, Averill CL, McKie S, Akiki TJ, Averill LA, Deakin JFW (2018): Ketamine, but Not the NMDAR Antagonist Lanicemine, Increases Prefrontal Global Connectivity in Depressed Patients. Chronic Stress (Thousand Oaks) 2. https://doi.org/10.1177/2470547018796102

      ,
      • Abdallah C.G.
      • Averill C.L.
      • Salas R.
      • Averill L.A.
      • Baldwin P.R.
      • Krystal J.H.
      • et al.
      Prefrontal Connectivity and Glutamate Transmission: Relevance to Depression Pathophysiology and Ketamine Treatment.
      ), which negatively correlated with symptom improvement. However, a separate study(
      • Kraus C.
      • Mkrtchian A.
      • Kadriu B.
      • Nugent A.C.
      • Zarate Jr., C.A.
      • Evans J.W.
      Evaluating global brain connectivity as an imaging marker for depression: influence of preprocessing strategies and placebo-controlled ketamine treatment.
      ) did not find significant changes to GBC when neuroimaging was performed 2-3 days post-ketamine. Finally, a study investigating GBC density after serial ketamine in treatment resistant bipolar depression(
      • Zhuo C.
      • Ji F.
      • Tian H.
      • Wang L.
      • Jia F.
      • Jiang D.
      • et al.
      Transient effects of multi-infusion ketamine augmentation on treatment-resistant depressive symptoms in patients with treatment-resistant bipolar depression - An open-label three-week pilot study.
      ) found decreased density in the bilateral insula, right caudate and bilateral VLPFC and increased density in the bilateral postcentral gyrus, sgACC, thalamus, and cerebellum. These changes appeared 24 hours post-ketamine, peaked at one week, and diminished by the third week; significant associations with clinical measures were not detected.

      Summary

      Subanesthetic ketamine leads to plasticity in multiple resting state networks and their components (Figure 2). Since existing investigations have used different analysis approaches (e.g., theory-driven seed-based vs data-driven whole brain analysis methods), sample sizes are typically small and have overlapped amongst reports, and study designs (open-label, randomized controlled trial, post-ketamine assessment time points) and clinical populations vary, convergence amongst findings remains relatively low. However, this work still provides important insight and future leads concerning the influence of subanesthetic ketamine on functional brain circuity and clinical outcomes. For example, existing data supports that ketamine leads to decreased activity within the DMN(20,34,35) and within the FPN/CEN(24), potentially affecting behaviors associated with negatively-biased self-referential processing and executive functions/emotional regulation in depression, respectively. When generalizing findings, RSFC instead appears to increase between different large-scale cortical networks such as the DMN and FPN/CEN with nodes including the sgACC, anterior insula, striatum, amygdala, habenula)(
      • Siegel J.S.
      • Palanca B.J.A.
      • Ances B.M.
      • Kharasch E.D.
      • Schweiger J.A.
      • Yingling M.D.
      • et al.
      Prolonged ketamine infusion modulates limbic connectivity and induces sustained remission of treatment-resistant depression.
      ,
      • Gärtner M.
      • Aust S.
      • Bajbouj M.
      • Fan Y.
      • Wingenfeld K.
      • Otte C.
      • et al.
      Functional connectivity between prefrontal cortex and subgenual cingulate predicts antidepressant effects of ketamine.
      ,
      • Mkrtchian A.
      • Evans J.W.
      • Kraus C.
      • Yuan P.
      • Kadriu B.
      • Nugent A.C.
      • et al.
      Ketamine modulates fronto-striatal circuitry in depressed and healthy individuals.
      ,
      • Rivas-Grajales A.M.
      • Salas R.
      • Robinson M.E.
      • Qi K.
      • Murrough J.W.
      • Mathew S.J.
      Habenula Connectivity and Intravenous Ketamine in Treatment-Resistant Depression.
      ,
      • Rush A.J.
      • Trivedi M.H.
      • Ibrahim H.M.
      • Carmody T.J.
      • Arnow B.
      • Klein D.N.
      • et al.
      The 16-Item Quick Inventory of Depressive Symptomatology (QIDS), clinician rating (QIDS-C), and self-report (QIDS-SR): a psychometric evaluation in patients with chronic major depression.
      ,
      • Abdallah C.G.
      • Averill L.A.
      • Collins K.A.
      • Geha P.
      • Schwartz J.
      • Averill C.
      • et al.
      Ketamine Treatment and Global Brain Connectivity in Major Depression.
      ). Together, these patterns suggest ketamine modulates circuitry that may be both under- and over-reactive prior to treatment. Data-driven results also emphasize the contribution of sensory systems and cortico-striatal-cerebellar loops that encompass the SN, as a potential biomarker for ketamine response(
      • Sahib A.K.
      • Loureiro J.R.
      • Vasavada M.
      • Anderson C.
      • Kubicki A.
      • Wade B.
      • et al.
      Modulation of the functional connectome in major depressive disorder by ketamine therapy.
      ,
      • Abdallah C.G.
      • Averill L.A.
      • Collins K.A.
      • Geha P.
      • Schwartz J.
      • Averill C.
      • et al.
      Ketamine Treatment and Global Brain Connectivity in Major Depression.
      ). Notably, individual studies have shown that changes in RSFC in nodes including the amygdala, sgACC and habenula to other subcortical or higher cortical association regions relate to clinical response(
      • Gärtner M.
      • Aust S.
      • Bajbouj M.
      • Fan Y.
      • Wingenfeld K.
      • Otte C.
      • et al.
      Functional connectivity between prefrontal cortex and subgenual cingulate predicts antidepressant effects of ketamine.
      ,
      • Nakamura T.
      • Tomita M.
      • Horikawa N.
      • Ishibashi M.
      • Uematsu K.
      • Hiraki T.
      • et al.
      Functional connectivity between the amygdala and subgenual cingulate gyrus predicts the antidepressant effects of ketamine in patients with treatment-resistant depression.
      ,
      • Rivas-Grajales A.M.
      • Salas R.
      • Robinson M.E.
      • Qi K.
      • Murrough J.W.
      • Mathew S.J.
      Habenula Connectivity and Intravenous Ketamine in Treatment-Resistant Depression.
      ). Changes in limbic RSFC (amygdala, hippocampus) have also been linked to improved behavioral inhibition(
      • Vasavada M.M.
      • Loureiro J.
      • Kubicki A.
      • Sahib A.
      • Wade B.
      • Hellemann G.
      • et al.
      Effects of Serial Ketamine Infusions on Corticolimbic Functional Connectivity in Major Depression.
      ), anhedonia(
      • Vasavada M.M.
      • Loureiro J.
      • Kubicki A.
      • Sahib A.
      • Wade B.
      • Hellemann G.
      • et al.
      Effects of Serial Ketamine Infusions on Corticolimbic Functional Connectivity in Major Depression.
      ,
      • Mkrtchian A.
      • Evans J.W.
      • Kraus C.
      • Yuan P.
      • Kadriu B.
      • Nugent A.C.
      • et al.
      Ketamine modulates fronto-striatal circuitry in depressed and healthy individuals.
      ), and suicidality(
      • Chen M.-H.
      • Lin W.-C.
      • Tu P.-C.
      • Li C.-T.
      • Bai Y.-M.
      • Tsai S.-J.
      • Su T.-P.
      Antidepressant and antisuicidal effects of ketamine on the functional connectivity of prefrontal cortex-related circuits in treatment-resistant depression: A double-blind, placebo-controlled, randomized, longitudinal resting fMRI study.
      ).
      Figure thumbnail gr2
      Figure 2This illustration synthesizes results across functional MRI studies that have addressed the effects of subanesthetic ketamine on resting state functional connectivity (RSFC) in patients with major depression. Here, connectograms are used to describe increasing (top) and decreasing (bottom) changes in RSFC between specific brain regions and resting state networks observed across studies following ketamine treatment. Corresponding atlases that are color coordinated with the resting state networks (top) and brain regions (bottom) represented in the connectograms are shown on the right. A table detailing the connections and their corresponding references can be found in Supplemental Table 1. Acronyms: DMN=Default Mode Network, CEN=Central Executive Network, CON=Cingulo-opercular Network, SMN=Somatomotor Network, vlPFC= Ventrolateral Prefrontal Cortex, dlPFC=Dorsolateral Prefrontal Cortex, SMA=Sensorimotor Area, aPFC=Anterior Prefrontal Cortex, dACC=Dorsal Anterior Cingulate Cortex, pgACC= Pregenual Anterior Cingulate Cortex, sgACC=Subgenual Anterior Cingulate Cortex, SN=Salience Network, OFC=Orbitofrontal Cortex, Striatum= Caudate and Putamen

      Task fMRI

      Disturbances in emotion regulation and processing and other cognitive functions linked with depression can be probed by examining fMRI BOLD signal as participants actively engage in functional tasks(
      • Rock P.L.
      • Roiser J.P.
      • Riedel W.J.
      • Blackwell A.D.
      Cognitive impairment in depression: a systematic review and meta-analysis.
      ,
      • Gudayol-Ferré E.
      • Peró-Cebollero M.
      • González-Garrido A.A.
      • Guàrdia-Olmos J.
      Changes in brain connectivity related to the treatment of depression measured through fMRI: a systematic review.
      ,

      Palmer SM, Crewther SG, Carey LM, START Project Team (2014): A meta-analysis of changes in brain activity in clinical depression. Front Hum Neurosci 8: 1045.

      ). Here, we summarize findings from ketamine studies using task-based fMRI organized by brain activation task, including response inhibition, reward processing, emotional judgment, and emotional face recognition (Table 2).
      Table 2Task-based fMRI studies of ketamine treatment in depressed populations.
      StudyDemographicsOther MedicationsKetamine TreatmentData CollectionDepression AssessmentSummary of Findings
      Sahib et al., 2020(55); NCT02165449N: 47 Unipolar TRD**, 32 HCYES

      Monoaminergic antidepressants allowed if stable ≥6 weeks prior to treatment

      No Benzodiazapine ≤72 hours prior to treatment
      Four serial IV infusions 0.5mg/kg ketamine over 40 mins+Neuroimaging & Clinical Assessments:

      •Baseline

      •24 hours post first infusion

      •24-72 hours post fourth infusion
      HDRS-17

      Rm: End of treatment HDRS≤ 7
      Conditioned Approach Response Inhibition (CARIT):

      (-) activation between baseline and fourth infusion in inferior frontal cortex and dlPFC along superior and inferior parietal regions and right cerebellum

      (-) in activation in visual cortex and superior parietal regions of left hemisphere after fourth infusion

      (-) BOLD activity for DMN, FPN, DAN, and SN in right hemisphere following ketamine

      (-) NoGo>Go activity in bilateral precentral gyrus for NRm after serial ketamine

      (+) NoGo>Go activity in bilateral precentral gyrus for Rm after serial ketamine

      Average baseline contrast values in bilateral precentral gyrus show negative correlation with % change in HDRS score after serial treatment

      (-) in contrast values in bilateral precentral gyrus 24 hrs post ketamine significantly associated with serial HDRS improvement
      Loureiro et al., 2021(56); NCT02165449CN: 46 Unipolar TRD**, 32 HCYES

      Monoaminergic antidepressants allowed if stable ≥6 weeks prior to treatment

      No Benzodiazapine ≤72 hours prior to treatment
      Four serial IV infusions 0.5mg/kg ketamine over 40 mins+Neuroimaging & Clinical Assessments:

      •Baseline

      •24 hours post first infusion

      •24-72 hours post fourth infusion
      HDRS-17

      QIDS

      DASS
      Conditioned Approach Response Inhibition (CARIT):

      (-) connectivity between cerebellum and FPN and the SMN in Rm only

      Baseline connectivity between cerebellum and FPN and cerebellum and SN significantly correlated with ketamine related %change QIDS for both Rm and NRm
      Murrough et al., 2015(68); NCT00548964, NCT00768430, NCT01880593N: 18 Unipolar TRD**, 20 HCNO

      Antidepressant medication free ≥1 week prior to treatment
      Single IV infusion of 0.5mg/kg ketamine over 40 mins+Neuroimaging & Clinical Assessments:

      •Baseline

      •24 hours post infusion
      MADRSFacial emotion perception task:

      (+) neural response to positive emotions (happy 100% > neutral) following ketamine centered in the right caudate but not correlated with pre-ketamine depressive symptoms

      (+) in post-ketamine right caudate connectivity associated with improved MADRS score
      Sterpenich et al., 2019(60); NCT01135758N: 10 Unipolar TRD**YES

      Stable medications ≥6 weeks prior to treatment
      Single bolus IV infusion 0.5mg/kg ketamine over 1 min+Neuroimaging:

      •Baseline

      •1 day post infusion

      Clinical Assessments:

      •Baseline

      •40, 80, 110, and 230 post infusion
      MADRS

      HDRS-21

      BDI-II
      Reward task adapted from Monetary Inventive Delay Task:

      (+) changes in insula and OFC during anticipatory phase of reward task one day after ketamine compared to baseline and in ventral striatum and OFC 7 days after ketamine compared to baseline (more activated for positively cued trials)

      (+) activation of VS and OFC in response to winning vs losing when comparing day 7 with baseline

      (+) more active substantia nigra/ventral tegmental area when winning than losing one day after ketamine and 7 days after ketamine compared to baseline

      Emotional Judgement Task:

      patient reaction time faster after ketamine (baseline vs day 1 and day 7) but not effect of emotion

      (-) activation of amygdala and insula response to negative pictures after 1 day after ketamine

      (-) activation of insula and dACC 7 days after ketamine in response to negative pictures

      (+) medial substantia nigra/ventral tegmental area more active for negative than positive pictures at baseline and then become (+) active for positive than negative pictures at day 7
      Morris et al., 2020(59)N:

      •Study 1: 28 Unipolar MDD, 20 HC

      •Study 2: 16 Unipolar TRD**
      NO

      Antidepressant and other medication free at time of scan
      Single IV infusion 0.5mg/kg ketamine over 40 mins+Neuroimaging:

      •Baseline

      •5 days post infusion
      MADRS, TEPS, STICSAReward Incentive Flanker Task:

      (-) sgACC activation to positive feedback with ketamine but not negative feedback

      Higher pre-ketamine sgACC activation to positive feedback associated with better improvements in anhedonia after ketamine
      Reed et al., 2018(66); NCT00088699N: 33 Unipolar TRD*, 26 HC§NO

      Medication free ≥2 weeks prior to treatment
      Single IV infusion 0.5mg/kg ketamine over 50 mins or saline placebo followed by alternative treatment two weeks later+++Neuroimaging:

      •Baseline

      •Immediately after infusion

      •1-3 days post infusion

      Clinical Assessments:

      •Baseline

      •40, 80, 120, 240 mins post infusion

      •1, 2, 3, 7, and 10 days post infusion
      MADRSDot probe task with emotional face stimuli:

      (+) activation post-ketamine compared to post-placebo in left middle occipital gyrus across groups

      (-) activation post-ketamine compared to post-placebo in left temporal and inferior frontal cortices across groups

      (-) in activation post-ketamine vs post-placebo in MDD patients in right frontal cortex, dACC, and left inferior occipital gyrus

      Medial prefrontal and anterior cingulate cluster showed deactivation to angry trials and activation to happy trials in MDD participants post placebo and reversed after ketamine %change in MADRS significantly associated with magnitude of activation (positive post ketamine and negative post placebo)

      (-) MADRS score associated with (-) activation to angry trials and greater activation to happy trials in left parahippocampal gyrus and amygdala, bilateral cingulate gyri, precuneus, and left medial and middle frontal gyri
      Reed et al., 2019(67); NCT00088699N: 33 Unipolar TRD*, 24 HC§NO

      Medication free ≥2 weeks prior to treatment
      Single IV infusion of 0.5mg/kg over 50 mins and single IV of saline solution placebo two weeks apart+++Neuroimaging:

      •Baseline

      •Immediately after infusion

      •1-3 days post infusion

      Clinical Assessments:

      •Baseline

      •40, 80, 120, 240 mins post infusion

      1, 2, 3, 7, and 10 days post infusion
      MADRSFacial Recognition Task:

      (-) activation post ketamine in bilateral frontal, temporal, precuneus and posterior cingulate regions in MDD, normalizing towards HC when compared to placebo

      Greater difference in activity pattern in the left temporal gyri and bilateral precuneus/posterior cingulate between explicit and implicit processing conditions in MDD participants after ketamine
      Loureiro et al., 2020(70); NCT02165449N: 27 Unipolar TRD**, 31 HCYES

      Monoaminergic antidepressants allowed if stable ≥6 weeks prior to treatment

      No Benzodiazapine ≤72 hours prior to treatment
      Four serial IV infusions of 0.5mg/kg ketamine over 40 mins+Neuroimaging & Clinical Assessments:

      •Baseline

      •24 hours post first infusion

      •24-72 hours post fourth infusion
      HDRS

      SHAPS

      DASS
      Emotional faces task:

      Post-treatment change in fearful>objects contrast correlated with %DASS and %SHAPS change in right amygdala
      Downey et al. 2016(71); NCT01046630N: 56 Unipolar MDDNOSingle IV 0.5mg/kg ketamine, 100mg lanicemine, or saline placebo over 60 mins++Neuroimaging:

      •Baseline

      •During infusion

      Clinical Assessments:

      •Baseline

      •Immediately post infusion

      •4 hours and 24 hours post infusion
      BDI

      MADRS
      PHMRI



      (+) BOLD response by both drugs in ACC predicted symptomatic improvement 24 hours and 1 week following infusion but no antidepressant effect when compared to placebo

      McMillan et al. 2020(72); ACTRN12615000573550N: 26 Unipolar MDDYES

      Stable medications ≥4 weeks prior
      Single IV 0.25mg/kg bolus ketamine followed by 0.25mg/kg over 45 minutes or placebo separated by 3 week period+++Neuroimaging:

      •During infusion

      Clinical Assessments:

      •Baseline

      •3 hours, 1 day, 1 week, and 2 weeks post infusion
      MADRSPHMRI

      (+) BOLD in right insula and left post-central gyrus during ketamine infusion associated with antidepressant response
      Stippl et al. 2021(69)N: 16 unipolar MDDYES

      Patients permitted to remain on psychopharmacological medication
      Single IV 0.25mg/kg S-ketamine or 0.5mg/kg racemic ketamine+Neuroimaging:

      Baseline

      Clinical Assessments:

      Baseline

      24 hours post infusion
      HDRS

      BDI
      Emotional Working Memory Task:

      No significant association with change in depressive symptoms
      *≥1 failed treatment

      **≥2 failed treatment

      ***≥3 failed treatment

      TRD: Treatment resistant depression

      MDD: Major Depressive Disorder

      HC: Healthy Control

      §: HC received ketamine

      +: Open Label

      ++: Randomized Placebo

      +++: Randomized Crossover

      IV: Intravenous

      Hrs: Hours

      Mins: Minutes

      BOLD: Blood oxygen level dependent

      HDRS: Hamilton Depression Rating Scale

      MADRS: Montgomery-Åsberg Depression Rating Scale

      QIDS: Quick Inventory of Depressive Symptomatology (+): Increase

      (-): Decrease
      SHAPS: Snaith-Hamilton Pleasure Scale

      BDI: Beck Depression Inventory

      DASS: Depression Anxiety and Stress Scale

      TEPS: Temporal Experience of Pleasure Scale

      STICSA: State-trait Inventory of Cognitive and Somatic Anxiety dlPFC: Dorsolateral Prefrontal Cortex

      DMN: Default mode network

      FPN: Frontoparietal network

      DAN: Dorsal attention network

      SN: Salience network

      SMN: Somato-motor network

      OFC: Orbitofrontal cortex

      VS: Ventral striatum dACC: Dorsal anterior cingulate cortex

      sgACC: Subgenual anterior cingulate cortex

      Rm: Remitter

      NRm: Nonremitter
      CLoureiro et al 2021 report different sample sizes for each time point. T1 represents baseline, T2 represents 24 hours after single infusion and T3 represents 24 hours after fourth infusion
      Two fMRI studies probed changes in response inhibition (NoGo>Go) as a proxy for cognitive control(
      • Sahib A.K.
      • Loureiro J.R.
      • Vasavada M.M.
      • Kubicki A.
      • Wade B.
      • Joshi S.H.
      • et al.
      Modulation of inhibitory control networks relate to clinical response following ketamine therapy in major depression.
      ,
      • Loureiro J.R.A.
      • Sahib A.K.
      • Vasavada M.
      • Leaver A.
      • Kubicki A.
      • Wade B.
      • et al.
      Ketamine’s modulation of cerebro-cerebellar circuitry during response inhibition in major depression.
      ). Decreased activation in the inferior/dorsolateral PFC and parietal regions, the right cerebellum, and visual cortex were observed during response inhibition pre-post serial ketamine treatment, which normalized towards healthy controls(
      • Sahib A.K.
      • Loureiro J.R.
      • Vasavada M.M.
      • Kubicki A.
      • Wade B.
      • Joshi S.H.
      • et al.
      Modulation of inhibitory control networks relate to clinical response following ketamine therapy in major depression.
      ). Decreased activation in prefrontal-parietal inhibitory control networks and motor and insular regions 24 hours post-single and serial treatment, were associated with and predicted subsequent improvements in mood and rumination. In an overlapping sample, investigators used psychophysiological-interaction models (PPI) to interrogate relationships between the cerebellum, and FPN, SMN, and SN networks(
      • Loureiro J.R.A.
      • Sahib A.K.
      • Vasavada M.
      • Leaver A.
      • Kubicki A.
      • Wade B.
      • et al.
      Ketamine’s modulation of cerebro-cerebellar circuitry during response inhibition in major depression.
      ). Results revealed significant decreases in PPI-connectivity between the cerebellum, FPN and SMN in remitters only. Baseline values of cerebellar-FPN and cerebellar-SN PPI were Would associated with clinical outcomes(
      • Rush A.J.
      • Trivedi M.H.
      • Ibrahim H.M.
      • Carmody T.J.
      • Arnow B.
      • Klein D.N.
      • et al.
      The 16-Item Quick Inventory of Depressive Symptomatology (QIDS), clinician rating (QIDS-C), and self-report (QIDS-SR): a psychometric evaluation in patients with chronic major depression.
      ).
      MDD is linked with dysfunctional reward processing, including motivation, reinforcement learning, and hedonic capacity(
      • Keren H.
      • O’Callaghan G.
      • Vidal-Ribas P.
      • Buzzell G.A.
      • Brotman M.A.
      • Leibenluft E.
      • et al.
      Reward Processing in Depression: A Conceptual and Meta-Analytic Review Across fMRI and EEG Studies.
      ,
      • Admon R.
      • Pizzagalli D.A.
      Dysfunctional Reward Processing in Depression.
      ). A study using an Incentive Flanker Task showed reduced sgACC activation to positive and negative feedback 5 days following single-dose ketamine, normalizing towards healthy controls(
      • Morris L.S.
      • Costi S.
      • Tan A.
      • Stern E.R.
      • Charney D.S.
      • Murrough J.W.
      Ketamine normalizes subgenual cingulate cortex hyper-activity in depression.
      ). Greater pre-ketamine sgACC hyperactivity to positive feedback also associated with larger post-treatment improvements in anhedonia. Using a modified Monetary Incentive Delay Task, an independent study found increased insula and orbitofrontal activation during the anticipatory phase of reward 24 hours post-ketamine(
      • Sterpenich V.
      • Vidal S.
      • Hofmeister J.
      • Michalopoulos G.
      • Bancila V.
      • Warrot D.
      • et al.
      Increased Reactivity of the Mesolimbic Reward System after Ketamine Injection in Patients with Treatment-resistant Major Depressive Disorder.
      ). Increased ventral striatum and orbitofrontal cortex activity involved in reward processing(
      • Kahnt T.
      • Heinzle J.
      • Park S.Q.
      • Haynes J.-D.
      The neural code of reward anticipation in human orbitofrontal cortex.
      ,
      • Daniel R.
      • Pollmann S.
      A universal role of the ventral striatum in reward-based learning: evidence from human studies.
      ) (often hypo-active in MDD(63)) was observed 7 days post-infusion.
      Several studies have used variants of the emotion recognition task to probe ketamine’s effects on emotion networks. Using the Emotional Judgment Task, during which participants rate the emotional valence of pictures, decreased amygdala and insula response was observed during negatively-valanced picture ratings 24 hours post-ketamine; insula and dACC response decreased 7 days post-ketamine(
      • Sterpenich V.
      • Vidal S.
      • Hofmeister J.
      • Michalopoulos G.
      • Bancila V.
      • Warrot D.
      • et al.
      Increased Reactivity of the Mesolimbic Reward System after Ketamine Injection in Patients with Treatment-resistant Major Depressive Disorder.
      ). Additionally, the substantia nigra/ventral tegmentum appeared more active for negative than positive picture ratings pre-treatment, a pattern that reversed 7 days following ketamine(
      • Sterpenich V.
      • Vidal S.
      • Hofmeister J.
      • Michalopoulos G.
      • Bancila V.
      • Warrot D.
      • et al.
      Increased Reactivity of the Mesolimbic Reward System after Ketamine Injection in Patients with Treatment-resistant Major Depressive Disorder.
      ). Since the amygdala, insula, and dACC are often found overreactive when processing negatively valanced stimuli in MDD(64,65), these findings suggest ketamine may normalize this particular hyperactive signature of MDD.
      Using an Attentional Bias Dot Probe task with emotional face stimuli to investigate attentional bias pre-to-post ketamine, MDD participants showed a reversal of PFC and dACC activity for happy and angry trials 1-3 days post-ketamine versus placebo(
      • Reed J.L.
      • Nugent A.C.
      • Furey M.L.
      • Szczepanik J.E.
      • Evans J.W.
      • Zarate Jr., C.A.
      Ketamine normalizes brain activity during emotionally valenced attentional processing in depression.
      ). Reductions in depressive symptoms(
      • Montgomery S.A.
      • Asberg M.
      A new depression scale designed to be sensitive to change.
      ) associated with decreased and increased activation for angry and happy trials respectively in the left parahippocampus and amygdala, bilateral ACC, precuneus, and left PFC. Using an implicit and explicit Facial Recognition task, the same group showed reduced activity post‐ketamine in frontal, temporal, and precuneus regions in patients that normalized towards healthy controls(
      • Reed J.L.
      • Nugent A.C.
      • Furey M.L.
      • Szczepanik J.E.
      • Evans J.W.
      • Zarate Jr., C.A.
      Effects of Ketamine on Brain Activity During Emotional Processing: Differential Findings in Depressed Versus Healthy Control Participants.
      ). Further, greater differences in left temporal and bilateral precuneus activation were observed between explicit and implicit conditions post-ketamine in MDD. Conversely, a separate study found a significant increase in neural response to positively-valanced faces (happy>neutral) in the right caudate that linked with improved depressive symptoms(
      • Montgomery S.A.
      • Asberg M.
      A new depression scale designed to be sensitive to change.
      ) 24 hours following single-dose ketamine(
      • Murrough J.W.
      • Collins K.A.
      • Fields J.
      • DeWilde K.E.
      • Phillips M.L.
      • Mathew S.J.
      • et al.
      Regulation of neural responses to emotion perception by ketamine in individuals with treatment-resistant major depressive disorder.
      ). Another study used an emotional N-back task with verbal stimuli found significant associations between lower baseline dorsomedial PFC activity and improvements in cognitive but not depressive symptoms(
      • Stippl A.
      • Scheidegger M.
      • Aust S.
      • Herrera A.
      • Bajbouj M.
      • Gärtner M.
      • Grimm S.
      Ketamine specifically reduces cognitive symptoms in depressed patients: An investigation of associated neural activation patterns.
      ). Only one study has investigated emotion recognition following serial ketamine treatment(
      • Loureiro J.R.A.
      • Leaver A.
      • Vasavada M.
      • Sahib A.K.
      • Kubicki A.
      • Joshi S.
      • et al.
      Modulation of amygdala reactivity following rapidly acting interventions for major depression.
      ). Here, both patients receiving ketamine or electroconvulsive therapy (ECT) showed a decrease in amygdala response while processing positive and negative face stimuli. Changes in inferior parietal activity correlated with overall symptom improvement, and BOLD change in frontal regions correlated with anxiety and anhedonia.
      Two studies have correlated change in BOLD signal during ketamine infusion with longer term clinical response. Results showed significant associations with increased BOLD response in the ACC(71) and in the right insula and left post-central gyrus(
      • McMillan R.
      • Sumner R.
      • Forsyth A.
      • Campbell D.
      • Malpas G.
      • Maxwell E.
      • et al.
      Simultaneous EEG/fMRI recorded during ketamine infusion in patients with major depressive disorder.
      ) with improved depressive outcomes.
      Summary: To date, fMRI studies of ketamine response have focused on probing functional systems of reward, emotion and cognitive control. Considering the differences in tasks and neural targets, only partial consensus exists among studies (Figure 3). However, all find that ketamine perturbs components of MDD-relevant neural circuits. Notably, regional changes in brain activation during response inhibition (PFC, parietal and cerebellum regions) associate with improved mood and rumination(
      • Sahib A.K.
      • Loureiro J.R.
      • Vasavada M.M.
      • Kubicki A.
      • Wade B.
      • Joshi S.H.
      • et al.
      Modulation of inhibitory control networks relate to clinical response following ketamine therapy in major depression.
      ,
      • Loureiro J.R.A.
      • Sahib A.K.
      • Vasavada M.
      • Leaver A.
      • Kubicki A.
      • Wade B.
      • et al.
      Ketamine’s modulation of cerebro-cerebellar circuitry during response inhibition in major depression.
      ), while regional BOLD changes (sgACC) during reward processing associate with anhedonia(
      • Morris L.S.
      • Costi S.
      • Tan A.
      • Stern E.R.
      • Charney D.S.
      • Murrough J.W.
      Ketamine normalizes subgenual cingulate cortex hyper-activity in depression.
      ). Tasks assessing emotional response show that changes in neural signal in limbic regions, the caudate, PFC, and parietal cortex relate to improved clinical response(
      • Reed J.L.
      • Nugent A.C.
      • Furey M.L.
      • Szczepanik J.E.
      • Evans J.W.
      • Zarate Jr., C.A.
      Ketamine normalizes brain activity during emotionally valenced attentional processing in depression.
      ,
      • Murrough J.W.
      • Collins K.A.
      • Fields J.
      • DeWilde K.E.
      • Phillips M.L.
      • Mathew S.J.
      • et al.
      Regulation of neural responses to emotion perception by ketamine in individuals with treatment-resistant major depressive disorder.
      ,
      • Loureiro J.R.A.
      • Leaver A.
      • Vasavada M.
      • Sahib A.K.
      • Kubicki A.
      • Joshi S.
      • et al.
      Modulation of amygdala reactivity following rapidly acting interventions for major depression.
      ), or anhedonia(
      • Loureiro J.R.A.
      • Leaver A.
      • Vasavada M.
      • Sahib A.K.
      • Kubicki A.
      • Joshi S.
      • et al.
      Modulation of amygdala reactivity following rapidly acting interventions for major depression.
      ).
      Figure thumbnail gr3
      Figure 3This illustration summarizes results from functional imaging studies using a) response inhibition, b) reward processing, c) emotional judgment, and d) emotional face recognition tasks to investigate neural changes in functional systems associated with ketamine treatment in MDD. Increases and decreases of brain activity observed are displayed by task. A table indicating corresponding references to changes in brain activity can be found in Supplemental Table 2.

      Positron Emission Tomography

      Positron emission tomography (PET) measures metabolic or biochemical neural processes using radioactive tracers(
      • Shulman R.G.
      • Rothman D.L.
      Interpreting functional imaging studies in terms of neurotransmitter cycling.
      ). All identified PET publications meeting inclusion criteria studied single-dose ketamine infusion (Table 3).
      Table 3PET studies of ketamine treatment in depressed populations.
      StudyDemographicsOther MedicationsKetamine TreatmentData CollectionDepression AssessmentSummary of Findings
      Estrelis et al., 2018(115)N: 14 Unipolar MDD, 13 HC§NO

      No psychiatric medication in month prior to study
      Single IV infusion initial bolus 0.23mg/kg over 1 min ketamine followed by constant infusion of 0.58mg/kg over 1 hr+Neuroimaging:

      •Baseline

      •During infusion

      •24 hrs post infusion

      Clinical Assessments:

      •30 mins and 24 hrs post infusion
      MADRS

      BDI-II
      Tracer: [11C]ABP688

      Widespread binding reductions from baseline for observed during ketamine and 24 hours after infusion for both HC and MDD.

      Not significantly different between diagnoses

      ↓mGluR5 in hippocampus associated with (-) depression symptoms (MADRS and BDI-II)
      Tiger et al., 2020(78)N: 30 Unipolar TRD*NO

      Ongoing medication washed out corresponding to ≥5x half-life of drug
      Four serial IV infusion 0.5mg/kg ketamine or placebo (isotonic NaCL) over 40 mins given twice a week over 2 weeks++Neuroimaging:

      •Baseline

      •24-72 hours post-infusion

      Clinical Assessments:

      •Baseline

      •During PET

      •1, 2, 3, 18, and 24 hrs post infusion
      MADRS, MINI, QIDS-SR, PHQ, CGIS, EuroQol5DTracer: [11C]AZ10419369

      No significant differences in change in BPND over time between ketamine and placebo

      16.7% ↑BPND in hippocampus in response to first ketamine infusion

      Inverse correlation between baseline BPND in VS and ΔMADRS after first treatment in ketamine group

      Baseline BPND in DBS correlated negatively with ΔMADRS with ketamine

      ΔBPND with treatment did not correlate with antidepressant effects
      Lally et al., 2014(75)N: 36 Bipolar (I or II) TRD*YES

      Continued mood stabilizers, no psychotropic medication or psychotherapy ≥2 weeks prior to treatment
      Single IV infusion 0.5mg/kg ketamine or placebo (0.9%saline solution) followed by alternative treatment two weeks later+++Neuroimaging:

      •2 hours post infusion

      Clinical Assessments:

      •Baseline

      •40, 80, 120, 230 mins post infusion

      •1, 2, 3, 7, 10, and 14 days post infusion
      MADRS, SHAPSTracer: 18-FDG

      ΔVS rCMRGlu after ketamine significantly related to %ΔSHAPS score 230 mins post infusion

      ΔMADRS significantly predicted ΔVS rCMRGlu but not SHAPS

      Whole brain analysis: Association between improved SHAPS and ↑dACC and ↑cerebellum rCMRGlu

      ΔAnhedonia levels following ketamine not related to general changes in depressive symptoms associated with ↑dACC, pregenual cingulate/callosal region, and right dPFC, fusiform gyrus, claustrum, and putamen metabolism
      Lally et al., 2015(74)N: 20 TRD**NO

      Drug free for ≥2 prior to treatment
      Single IV infusion ketamine over 40 mins+Neuroimaging:

      •Baseline

      Clinical Assessments:

      •Baseline

      •40, 80, 120, 230 mins post-infusion

      •Daily for subsequent 28 days
      MADRS

      SHAPS
      Tracer: 18-FDG

      No association between rCMRGlu and SHAPS score at baseline

      Baseline metabolism did not correlate with change in anhedonia

      Significant negative association between ↑dACC rCMRGlu and (-) anhedonia and after ketamine

      ↑glucose metabolism in cluster in right hippocampus and entorhinal cortex associated with (-) anhedonia

      ↓rCMRGlu in right OFC and left inferior frontal gyrus associated with (-) anhedonia
      Chen et al., 2018(76)N: 24 Unipolar TRD***YES

      Stable antidepressant treatment ≥2 weeks prior to treatment
      Single IV infusion of 0.5mg/kg, 0.2mg/kg or placebo (saline) over 40 mins+++Neuroimaging:

      •Baseline

      Clinical Assessments:

      •Baseline

      •40, 80, 120, 240 mins post infusion

      •1 day post infusion
      HDRS-17Tracer: 18-FDG

      High dose ketamine treatment showed (+)SUV in supplementary motor area and dorsal anterior cingulate cortex (dACC) than low dose ketamine treatment

      ΔSUV in dACC negatively associated with HDRS-17 symptoms at day 1 ((+)ΔSUV

      (-)depressive symptoms)
      Ortiz et al. 2015(77)N: 29 Bipolar TRD*YES

      Stable mood stablizer (lithium or valproate) ≥4 weeks at therapeutic levels
      Single IV infusion 0.5mg/kg over 40 mins+++Neuroimaging:

      •Baseline

      Clinical Assessments:

      •Baseline

      •230 mins post infusion

      •1, 2, 3, 7, and 10 days post infusion
      MADRS↑Baseline Shank3 levels associated with (+)rMRGlu in hippocampus and amygdala

      ΔMADRS not significantly correlated with ΔrMRGlu
      *≥1 failed treatment

      **≥2 failed treatment

      ***≥3 failed treatment

      TRD: Treatment resistant depression

      MDD: Major Depressive Disorder

      HC: Healthy Control

      §: HC received ketamine

      +: Open Label

      ++: Randomized Placebo

      +++: Randomized Crossover

      F: Female

      M: Male

      IV: Intravenous

      Hrs: Hours

      Mins: Minutes

      MADRS: Montgomery-Åsberg Depression Rating Scale

      SHAPS: Snaith-Hamilton Pleasure Scale

      HDRS: Hamilton Depression Rating Scale

      BDI: Beck Depression Inventory
      Mini: Mini International Neuropsychiatric Interview

      PHQ: Patient Health Questionnaire

      CGIS: Clinical Global Impressions Scale (Severity and Improvement)

      BPDN: Non-displaceable binding rCMRGlu: Regional glucose metabolic rate

      mGluR5: Metabotropic glutamate receptor 5

      SUV: Standardized uptake values of glucose metabolism dACC: Dorsal anterior cingulate cortex

      dPFC: Dorsal prefrontal cortex

      VS: Ventral striatum

      DBS: Dorsal brain stem

      OFC: Orbitofrontal cortex

      ↑: Higher

      ↓: Lower (+): Increase

      (-): Decrease

      Δ: Change
      Most PET studies evaluating ketamine response at least 24 hours post treatment in MDD used [18F]-fluorodeoxyglucose (FDG) PET to measure glucose metabolism, a proxy for estimating glutamatergic neurotransmission(
      • Shulman R.G.
      • Rothman D.L.
      Interpreting functional imaging studies in terms of neurotransmitter cycling.
      ). These findings suggest increased glucose metabolism in the dACC post-ketamine are linked with improved anhedonia(
      • Snaith R.P.
      • Hamilton M.
      • Morley S.
      • Humayan A.
      • Hargreaves D.
      • Trigwell P.
      A scale for the assessment of hedonic tone the Snaith-Hamilton Pleasure Scale.
      ) in both unipolar(
      • Lally N.
      • Nugent A.C.
      • Luckenbaugh D.A.
      • Niciu M.J.
      • Roiser J.P.
      • Zarate Jr., C.A.
      Neural correlates of change in major depressive disorder anhedonia following open-label ketamine.
      ) and bipolar(
      • Lally N.
      • Nugent A.C.
      • Luckenbaugh D.A.
      • Ameli R.
      • Roiser J.P.
      • Zarate C.A.
      Anti-anhedonic effect of ketamine and its neural correlates in treatment-resistant bipolar depression.
      ) depression, and with improved depressive symptoms(
      • Hamilton M.
      A rating scale for depression.
      ) in TRD(76). The dACC functions to integrate emotional and cognitive processes and is likewise implicated is rsfMRI and task fMRI ketamine studies (see previous sections). Post-ketamine improvements in anhedonia have also been associated with increased FDG in the hippocampus(
      • Lally N.
      • Nugent A.C.
      • Luckenbaugh D.A.
      • Niciu M.J.
      • Roiser J.P.
      • Zarate Jr., C.A.
      Neural correlates of change in major depressive disorder anhedonia following open-label ketamine.
      ), SMA(76), and cerebellum(
      • Lally N.
      • Nugent A.C.
      • Luckenbaugh D.A.
      • Ameli R.
      • Roiser J.P.
      • Zarate C.A.
      Anti-anhedonic effect of ketamine and its neural correlates in treatment-resistant bipolar depression.
      ), also regions implicated in fMRI studies. Increased glucose metabolism in the hippocampus and amygdala have been specifically observed in bipolar patients with higher baseline levels of Shank3, a protein involved in glutamatergic neurotransmission, following single ketamine infusion. However, findings did not associate with changes in depressive symptoms >24 hours post-treatment(
      • Montgomery S.A.
      • Asberg M.
      A new depression scale designed to be sensitive to change.
      ,
      • Ortiz R.
      • Niciu M.J.
      • Lukkahati N.
      • Saligan L.N.
      • Nugent A.C.
      • Luckenbaugh D.A.
      • et al.
      Shank3 as a potential biomarker of antidepressant response to ketamine and its neural correlates in bipolar depression.
      ). Using a serotonin (5-HT1B) receptor selective radioligand to investigate serotonin1B receptor binding in SSRI-resistant depression, one study found a 17% increase in non-displaceable binding to the 5-HT1B receptor (BPND) in the hippocampus 1-3 days following ketamine infusion(
      • Tiger M.
      • Veldman E.R.
      • Ekman C.-J.
      • Halldin C.
      • Svenningsson P.
      • Lundberg J.
      A randomized placebo-controlled PET study of ketamine´s effect on serotonin1B receptor binding in patients with SSRI-resistant depression.
      ). Additionally, baseline BPND in the ventral striatum and the dorsal brainstem were both inversely correlated with changes in depressive symptoms(
      • Montgomery S.A.
      • Asberg M.
      A new depression scale designed to be sensitive to change.
      ), however changes in BPND were not correlated with antidepressant effects.

      Summary

      The PET literature suggest regional changes in glucose metabolism post-ketamine are associated with improvements in overall depressive symptoms (dACC)(
      • Lally N.
      • Nugent A.C.
      • Luckenbaugh D.A.
      • Niciu M.J.
      • Roiser J.P.
      • Zarate Jr., C.A.
      Neural correlates of change in major depressive disorder anhedonia following open-label ketamine.
      ,
      • Lally N.
      • Nugent A.C.
      • Luckenbaugh D.A.
      • Ameli R.
      • Roiser J.P.
      • Zarate C.A.
      Anti-anhedonic effect of ketamine and its neural correlates in treatment-resistant bipolar depression.
      ,
      • Chen M.-H.
      • Li C.-T.
      • Lin W.-C.
      • Hong C.-J.
      • Tu P.-C.
      • Bai Y.-M.
      • et al.
      Persistent antidepressant effect of low-dose ketamine and activation in the supplementary motor area and anterior cingulate cortex in treatment-resistant depression: A randomized control study.
      ) and anhedonia (dACC, hippocampus, SMA and cerebellum)(
      • Lally N.
      • Nugent A.C.
      • Luckenbaugh D.A.
      • Niciu M.J.
      • Roiser J.P.
      • Zarate Jr., C.A.
      Neural correlates of change in major depressive disorder anhedonia following open-label ketamine.
      ,
      • Lally N.
      • Nugent A.C.
      • Luckenbaugh D.A.
      • Ameli R.
      • Roiser J.P.
      • Zarate C.A.
      Anti-anhedonic effect of ketamine and its neural correlates in treatment-resistant bipolar depression.
      ,
      • Chen M.-H.
      • Li C.-T.
      • Lin W.-C.
      • Hong C.-J.
      • Tu P.-C.
      • Bai Y.-M.
      • et al.
      Persistent antidepressant effect of low-dose ketamine and activation in the supplementary motor area and anterior cingulate cortex in treatment-resistant depression: A randomized control study.
      ). These changes in neurofunction and circuitry suggest that ketamine’s therapeutic mechanism may be at least partially attributed to downstream effects on glutamatergic signaling that may be attributable to synaptic and dendritic remodeling reported in animal studies(
      • Hess E.M.
      • Riggs L.M.
      • Michaelides M.
      • Gould T.D.
      Mechanisms of ketamine and its metabolites as antidepressants.
      ). Observed increases in hippocampal BPND(78) suggest changes in 5-HT1B receptor density may contribute to ketamine’s therapeutic effects, as has been observed in conjunction with anti-depressive properties of ketamine in preclinical models(
      • du Jardin K.G.
      • Liebenberg N.
      • Cajina M.
      • Müller H.K.
      • Elfving B.
      • Sanchez C.
      • Wegener G.
      S-Ketamine Mediates Its Acute and Sustained Antidepressant-Like Activity through a 5-HT1B Receptor Dependent Mechanism in a Genetic Rat Model of Depression.
      ).

      Arterial Spin Labeling

      Arterial spin labeling (perfusion) MRI measures cerebral blood flow (CBF) using magnetically labeled arterial blood without the need for any radioactive ligand. ASL CBF measurements have been validated using O-water PET(81), and since perfusion is normally coupled with metabolism, yield information comparable to FDG-PET(82). Thus, by providing quantitative measures of brain hemodynamics, ASL provides information regarding neurofunction that is complementary to fMRI.
      Increased CBF in the thalamus has been observed 24 hours after single IV ketamine (
      • Gärtner M.
      • de Rover M.
      • Václavů L.
      • Scheidegger M.
      • van Osch M.J.P.
      • Grimm S.
      Increase in thalamic cerebral blood flow is associated with antidepressant effects of ketamine in major depressive disorder.
      ,
      • Gonzalez S.
      • Vasavada M.
      • Njau S.
      • Sahib A.K.
      • Espinoza R.
      • Narr K.L.
      • Leaver A.M.
      Acute changes in cerebral blood flow after single-infusion ketamine in major depression: a pilot study.
      ). Furthermore, change in thalamic perfusion has been associated with greater reductions in depressive symptoms, and patients with lower baseline thalamic perfusion showed larger increases in perfusion after ketamine(
      • Gärtner M.
      • de Rover M.
      • Václavů L.
      • Scheidegger M.
      • van Osch M.J.P.
      • Grimm S.
      Increase in thalamic cerebral blood flow is associated with antidepressant effects of ketamine in major depressive disorder.
      ). One study leveraged multiband pseudo-continuous ASL (pCASL) MRI to compare global and regional CBF (rCBF) in TRD patients at baseline and 24 hours after receiving single, and four serial ketamine infusions(
      • Sahib A.K.
      • Loureiro J.R.A.
      • Vasavada M.M.
      • Kubicki A.
      • Joshi S.H.
      • Wang K.
      • et al.
      Single and repeated ketamine treatment induces perfusion changes in sensory and limbic networks in major depressive disorder.
      ). In concordance with the direction of prior acute-response PET results(
      • Carlson P.J.
      • Diazgranados N.
      • Nugent A.C.
      • Ibrahim L.
      • Luckenbaugh D.A.
      • Brutsche N.
      • et al.
      Neural correlates of rapid antidepressant response to ketamine in treatment-resistant unipolar depression: a preliminary positron emission tomography study.
      ), post-single ketamine rCBF increased in the posterior cingulate and in visual association regions. Post-serial infusion therapy, rCBF decreased in the bilateral hippocampus and right insula, normalizing towards levels of healthy controls. Further, acute changes in CBF in visual areas predicted improvements in anhedonia, anxiety, and overall mood following treatment(
      • Sahib A.K.
      • Loureiro J.R.A.
      • Vasavada M.M.
      • Kubicki A.
      • Joshi S.H.
      • Wang K.
      • et al.
      Single and repeated ketamine treatment induces perfusion changes in sensory and limbic networks in major depressive disorder.
      ).

      Summary

      ASL findings suggest that neurophysiological changes occurring with ketamine treatment include initial engagement of the thalamus(
      • Gärtner M.
      • de Rover M.
      • Václavů L.
      • Scheidegger M.
      • van Osch M.J.P.
      • Grimm S.
      Increase in thalamic cerebral blood flow is associated with antidepressant effects of ketamine in major depressive disorder.
      ,
      • Gonzalez S.
      • Vasavada M.
      • Njau S.
      • Sahib A.K.
      • Espinoza R.
      • Narr K.L.
      • Leaver A.M.
      Acute changes in cerebral blood flow after single-infusion ketamine in major depression: a pilot study.
      ) posterior ACC, precuneus (DMN nodes) and primary and higher-order visual areas(
      • Carlson P.J.
      • Diazgranados N.
      • Nugent A.C.
      • Ibrahim L.
      • Luckenbaugh D.A.
      • Brutsche N.
      • et al.
      Neural correlates of rapid antidepressant response to ketamine in treatment-resistant unipolar depression: a preliminary positron emission tomography study.
      ,
      • Sahib A.K.
      • Loureiro J.R.A.
      • Vasavada M.M.
      • Kubicki A.
      • Joshi S.H.
      • Wang K.
      • et al.
      Single and repeated ketamine treatment induces perfusion changes in sensory and limbic networks in major depressive disorder.
      ), that reflect improvements in overall mood(
      • Gärtner M.
      • de Rover M.
      • Václavů L.
      • Scheidegger M.
      • van Osch M.J.P.
      • Grimm S.
      Increase in thalamic cerebral blood flow is associated with antidepressant effects of ketamine in major depressive disorder.
      ,
      • Sahib A.K.
      • Loureiro J.R.A.
      • Vasavada M.M.
      • Kubicki A.
      • Joshi S.H.
      • Wang K.
      • et al.
      Single and repeated ketamine treatment induces perfusion changes in sensory and limbic networks in major depressive disorder.
      ), as well as improved anhedonia and anxiety (Table 4). Continued ketamine treatment includes the subsequent engagement of deeper limbic structures and the insula (affective networks and SN).
      Table 4ASL studies of ketamine treatment in depressed populations.
      StudyDemographicsOther MedicationsKetamine TreatmentData CollectionDepression AssessmentSummary of Findings
      Sahib et al., 2020(85) NCT02165449N: 22 Unipolar TRD*, 18 HCYES

      Monoaminergic antidepressants allowed if stable ≥6 weeks prior to treatment

      No Benzodiazapine ≤72 hours prior to treatment
      Four serial IV infusions of 0.5mg/kg ketamine over 40min+Neuroimaging & Clinical Assessments:

      •Baseline

      •24 hours post first infusion

      •24-72 hours post fourth infusion
      HDRS

      SHAPS
      (+) mean CBF after first infusion that normalizes/decreases after fourth infusion

      (+) regional CBF after first infusion in mid and posterior cingulate and proximal association areas in paracentral lobule, cuneus, precuneus, and higher order visual association regions like fusiform

      (-) baseline CBF in fusiform associated with (+)ΔHDRS after first infusion

      ΔCBF in cuneus after first infusion positively correlated with change in overall mood, anhedonia, an apathy after serial treatment

      (-) CBF in bilateral hippocampus and right insula after serial infusion
      Gärtner et al., 2022(83)N: 21 Unipolar MDDYES

      No restrictions to permitted medication
      Single IV infusion 0.5mg/kg racemic ketamine or 0.25mg/kg S-ketamine over 45min+Neuroimaging & Clinical Assessments:

      •Baseline

      •24 hours post infusion
      MADRS

      HDRS
      (+) thalamic perfusion 24 hours after ketamine associated with reduced symptom severity, evident in both sites and when pooled

      patients with ↓baseline thalamus perfusion show larger ↑perfusion after ketamine

      ↓thalamic perfusion at baseline associated with more reduced depressive symptoms
      Gonzalez et al., 2020(84)N: 11 Unipolar TRD**YES

      Stable antidepressant medication ≥1mo prior to treatment
      Single IV infusion 0.5mg/kg ketamine over 40min+Neuroimaging:

      •Baseline

      •1hr, 6hrs, and 24hrs post infusion
      MADRS

      HDRS

      QIDS-SR
      (+) CBF in thalamus

      (-) CBF lateral occipital cortex

      NRs showed decrease CBF in ventral basal ganglia after ketamine
      *≥1 failed treatment

      **≥2 failed treatment

      ***≥3 failed treatment

      TRD: Treatment resistant depression

      MDD: Major Depressive Disorder

      HC: Healthy Control

      §: HC received ketamine

      +: Open Label

      ++: Randomized Placebo

      +++: Randomized Crossover

      Δ: Change

      IV: Intravenous

      Hrs: Hours
      Mins: Minutes

      MADRS: Montgomery-Åsberg Depression Rating Scale

      SHAPS: Snaith-Hamilton Pleasure Scale

      HDRS: Hamilton Depression Rating Scale

      CBF: Cerebral blood flow

      Nrs: Non-responders

      ↑: Higher

      ↓: Lower (+): Increase

      (-): Decrease

      Structural MRI

      Fewer studies have addressed how subanesthetic ketamine impacts brain structure, likely due to the expectation that structural plasticity occurs slowly, and most ketamine MRI investigations only include short follow-ups (Table 5).
      Table 5sMRI studies of ketamine treatment in depressed populations.
      StudyDemographicsOther MedicationsKetamine TreatmentData CollectionDepression AssessmentSummary of Findings
      Gallay et al., 2021(99); ACTRN12618001412224N: 30 MDD with chronic suicidalityYES

      Concurrent psychiatric medication reported in (
      • Can A.T.
      • Hermens D.F.
      • Dutton M.
      • Gallay C.C.
      • Jensen E.
      • Jones M.
      • et al.
      Low dose oral ketamine treatment in chronic suicidality: An open-label pilot study.
      )
      Once weekly dose of oral ketamine for 6-week, starting at 0.5mg/kg and titrated by 0.2-0.7mg/kg based on tolerance with maximum dose of 3.0mg/kg at 6th treatment+Neuroimaging:

      •Baseline

      •End of 5-week treatment
      -VBM:

      (+) bilateral grey matter in putamen, thalamus, caudate, nucleus accumbens, and periaqueductal grey after ketamine

      No cortical findings
      Herrera-Melendez et al., 2021(101)D NCT02099630, NCT03609190N: 33 Unipolar TRD** (23 CHB, 10 UZH)YES

      No constraints on antidepressant medication
      CHB: Single IV of 0.5mg/kg racemic ketamine over 40 mins+

      UZH: Single IV of 0.25mg/kg S-ketamine over 40 mins+
      Neuroimaging & Clinical Assessments:

      •Baseline

      •24 hours post infusion
      CHB: MADRS

      UZH: HDRS

      Rs: ΔDepressive symptoms2 >50%

      PRs: >25% ΔDepressive symptoms
      VBM:

      ↑GMV of bilateral rostral anterior cingulate at baseline associated with greater change in depressive symptoms
      Dai et al., 2020(100)N: 21 Unipolar MDD (10 with comorbid PTSD), 29 HC§NO

      No psychotropic or regular medication in past 2 months or history of psychiatric medication
      36 participants received single IV bolus infusion of 0.23mg/kg over 1 minute followed by constant infusion of 0.58mg/kg over 1 hour+

      14 participants received single IV of 0.5mg/kg over 40 mins+
      Neuroimaging:

      •Baseline

      •24 hours post infusion

      Clinical Assessments:

      •Baseline

      •24 and 48 hours post infusion.
      HDRS-24

      PTSD Checklist
      TBM:

      (-) left lateral OFC volume in MDD after ketamine

      (+) left angular gyrus, left inferior parietal gyrus, left middle cingulate and paracingulate gyri, left middle occipital gyrus, left supramarginal gyrus, left precuneus 24 hours after ketamine in full sample including comorbid PTSD

      (+) right precentral gyrus, right opercular IFG, right rolandic operculum, right insula, and right postcentral gyrus 24 hours after ketamine in unipolar MDD group

      (-) in midbrain area volume in MDD group 24 hours after ketamine
      Zhou et al., 2020(92); ChiCTR-OOC-17012239N: 44 Unipolar TRD**YES

      Stable medication for ≥4weeks prior to treatment
      Six serial IV infusions of 0.5mg/kg over 40 mins thrice-weekly for two weeks+Neuroimaging & Clinical Assessments:

      •Baseline

      •24 hours post sixth infusion
      MADRS

      Rs defined as ΔMADRS >50%
      FreeSurfer:

      (+) right hippocampal volume 24 hours after last ketamine treatment compared to baseline

      No significant associations between hippocampal volume changes and inflammatory cytokine changes
      Zhou et al., 2020(93)l; ChiCTR-OOC-17012239N: 44 Unipolar TRD**, 45 HCYES

      Stable medication for ≥4weeks prior to treatment
      Six serial IV infusions of 0.5mg/kg over 40 mins thrice-weekly for two weeks+Neuroimaging & Clinical Assessments:

      •Baseline

      •24 hours post sixth infusion
      MADRS

      Rs defined as ΔMADRS >50%
      FreeSurfer:

      Baseline Rs > NRs in left hippocampal subiculum body volume

      (+) left amygdala and right hippocampus volume after ketamine

      (+) left amygdala volume in Rs after ketamine

      (+) left hippocampal CA4 body, left GC-ML-DG body, right CA4 head and right ML head significantly increased after ketamine

      (+) left CA1 body, CA4 body, GC-ML-DG body, and right GC-ML-DG body, ML head of Rs after treatment

      (+) left subiculum body of NRs after treatment

      ↑pretreatment volumes in right thalamus and left subiculum head hippocampal subfield correlated with greater (-) in MADRS scores

      Δleft amygdala and left ΔCA4 body volume negatively correlated with (-)MADRS scores after treatment
      Abdallah et al., 2015(97); NCT00768430N: 13 Unipolar TRD***NO

      Medication free ≥1 week prior to treatment
      Single IV infusion of 0.5mg/kg of ketamine or 0.045mg/kg midazolam over 40 mins++Neuroimaging:

      •Baseline

      Clinical Assessments:

      •Baseline

      •24 hours post infusion
      MADRSPositive association between ΔMADRS and baseline left hippocampal volume
      Abdallah et al., 2017(94) NCT00768430N: 16 Unipolar TRD***NO

      Medication free ≥1 week prior to treatment
      Single IV infusion of 0.5mg/kg of ketamine over 40 mins++Neuroimaging & Clinical Assessments:

      •Baseline

      •24 hours post infusion
      MADRS

      R defined as post-treatment MADRS<10
      (-) left nucleus accumbens volume following treatment in Rs only

      (+) left hippocampal volume in Rs

      (-) bilateral nucleus accumbens volumes after treatment in participants with ↑left hippocampal volume, no change in participants with ↓total or left hippocampal volume
      Niciu et al., 2017(98)E NCT00088699N: 55 Unipolar TRD*NO

      Psychotropic medication or ECT free ≥2 weeks prior to infusion
      Single IV infusion of 0.5mg/kg ketamine over 40 mins+Neuroimaging & Clinical Assessments:

      •Baseline

      •230 mins, 24 hours and 1 week post infusion
      MADRSNo significant associations between baseline hippocampal, thalamic, or amygdalar volumes and antidepressant response
      Siegel et al., 2021(30); NCT01179009N: 23 Unipolar TRD**, 27 HCYES

      SSRI and SNRI allowed if constant for ≥6 weeks prior to infusion
      Continuous 96h IV infusion of ketamine started at 0.15mg/kg/h at 10am on day 1 and titrated to tolerance twice daily to target rate of 0.6mg/kg/h+Neuroimaging:

      •Baseline

      •2 weeks post infusion

      Clinical Assessments:

      •2, 4, 6, and 8 weeks post infusion
      MADRSSmaller Pre-treatment right hippocampal volume associated with better MADRS score
      *≥1 failed treatment

      **≥2 failed treatment

      ***≥3 failed treatment

      TRD: Treatment resistant depression

      MDD: Major Depressive Disorder

      HC: Healthy Control

      §: HC received ketamine

      +: Open Label

      ++: Randomized Placebo

      +++: Randomized Crossover

      IV: Intravenous

      HDRS: Hamilton Depression Rating Scale

      MADRS: Montgomery-Åsberg Depression Rating Scale

      PTSD: Post-traumatic stress disorder

      R: Responders

      NRs: Non-responders

      PRs: Partial responders (+): Increase

      (-): Decrease
      FA: Fractional Anisotropy

      MD: Mean diffusivity

      RD: Radial Diffusivity

      SLF: Superior longitudinal fasciculus

      ILF: Inferior longitudinal fasciculus

      UF: Uncinate fasciculus

      CC: Corpus callosum

      VBM: Voxel-based morphometry

      TBM: Tensor-based morphometry

      GMV: Gray matter volume

      OFC: Orbitofrontal cortex

      GC-ML-DG: Granule layers and molecular layers of dentate gyrus

      CA4: Cornu Ammonis 4 hippocampal subfield

      ML: Molecular layer of the hippocampus

      Δ: Change

      ↑: Higher

      ↓: Lower
      DTwo participant sites including Charité University Hospital Berlin (CHB) and University Hospital Zurich (UZH). CHB used a Siemens Tim Trio scanner, UZH used a Philips Achieva TX scanner.
      ETo pool clinical assessments from the two sites HAM-D scores were converted to MADRS scores and calculated as a percentage of change from baseline to follow up

      Subcortical regions

      Reductions of hippocampal volume are well replicated in MDD, and appear influenced by clinical state(
      • Ho T.C.
      • Gutman B.
      • Pozzi E.
      • Grabe H.J.
      • Hosten N.
      • Wittfeld K.
      • et al.
      Subcortical shape alterations in major depressive disorder: Findings from the ENIGMA major depressive disorder working group.
      ,
      • Schmaal L.
      • Veltman D.J.
      • van Erp T.G.M.
      • Sämann P.G.
      • Frodl T.
      • Jahanshad N.
      • et al.
      Subcortical brain alterations in major depressive disorder: findings from the ENIGMA Major Depressive Disorder working group.
      ,
      • Videbech P.
      • Ravnkilde B.
      Hippocampal volume and depression: a meta-analysis of MRI studies.
      ) and other antidepressant interventions(
      • Tai H.-H.
      • Cha J.
      • Vedaei F.
      • Dunlop B.W.
      • Craighead W.E.
      • Mayberg H.S.
      • Choi K.S.
      Treatment-Specific Hippocampal Subfield Volume Changes With Antidepressant Medication or Cognitive-Behavior Therapy in Treatment-Naive Depression.
      ,
      • Joshi S.H.
      • Espinoza R.T.
      • Pirnia T.
      • Shi J.
      • Wang Y.
      • Ayers B.
      • et al.
      Structural Plasticity of the Hippocampus and Amygdala Induced by Electroconvulsive Therapy in Major Depression.
      ,
      • Enneking V.
      • Leehr E.J.
      • Dannlowski U.
      • Redlich R.
      Brain structural effects of treatments for depression and biomarkers of response: a systematic review of neuroimaging studies.
      ). Initial evidence suggests that single and serial ketamine treatment may also impact hippocampal volume. Increased right gross hippocampal volumes have been observed 24 hours post-serial infusion(
      • Zhou Y.-L.
      • Wu F.-C.
      • Wang C.-Y.
      • Zheng W.
      • Lan X.-F.
      • Deng X.-R.
      • Ning Y.-P.
      Relationship between hippocampal volume and inflammatory markers following six infusions of ketamine in major depressive disorder.
      ). At the hippocampal subfields level, ketamine-induced increases in the right CA4 head/molecular layer (ML) and left CA4 body, and dentate gyrus/granule cell/molecular layer (GC-ML-DG) are reported; increases in left CA1 body, CA4 body, bilateral GC-ML-DG and right ML head occurred in responders only(
      • Zhou Y.-L.
      • Wu F.-C.
      • Liu W.-J.
      • Zheng W.
      • Wang C.-Y.
      • Zhan Y.-N.
      • et al.
      Volumetric changes in subcortical structures following repeated ketamine treatment in patients with major depressive disorder: a longitudinal analysis.
      ). An independent investigation observed increased left gross hippocampal volumes in ketamine remitters but not in non-remitters after single-dose ketamine(
      • Abdallah C.G.
      • Jackowski A.
      • Salas R.
      • Gupta S.
      • Sato J.R.
      • Mao X.
      • et al.
      The Nucleus Accumbens and Ketamine Treatment in Major Depressive Disorder.
      ).
      Previous studies suggest that pre-treatment hippocampal volume may influence subsequent response to pharmacotherapy in MDD(95,96). One study(
      • Siegel J.S.
      • Palanca B.J.A.
      • Ances B.M.
      • Kharasch E.D.
      • Schweiger J.A.
      • Yingling M.D.
      • et al.
      Prolonged ketamine infusion modulates limbic connectivity and induces sustained remission of treatment-resistant depression.
      ) found smaller pretreatment right gross hippocampal volume associated with greater reductions in depressive symptoms(
      • Montgomery S.A.
      • Asberg M.
      A new depression scale designed to be sensitive to change.
      ) following a 96-hour infusion. After standard single infusion treatments, one study reported larger left pretreatment hippocampal volume was associated greater antidepressant response(
      • Montgomery S.A.
      • Asberg M.
      A new depression scale designed to be sensitive to change.
      ,
      • Abdallah C.G.
      • Salas R.
      • Jackowski A.
      • Baldwin P.
      • Sato J.R.
      • Mathew S.J.
      Hippocampal volume and the rapid antidepressant effect of ketamine.
      ), however, another found no associations between pretreatment hippocampal volume and antidepressant response(
      • Niciu M.J.
      • Iadarola N.D.
      • Banerjee D.
      • Luckenbaugh D.A.
      • Park M.
      • Lener M.
      • et al.
      The antidepressant efficacy of subanesthetic-dose ketamine does not correlate with baseline subcortical volumes in a replication sample with major depressive disorder.
      ). Larger pretreatment left anterior subiculum volumes in serial ketamine responders have been observed(
      • Zhou Y.-L.
      • Wu F.-C.
      • Wang C.-Y.
      • Zheng W.
      • Lan X.-F.
      • Deng X.-R.
      • Ning Y.-P.
      Relationship between hippocampal volume and inflammatory markers following six infusions of ketamine in major depressive disorder.
      ). Pretreatment volumes of the right thalamus has also been associated with clinical response(
      • Montgomery S.A.
      • Asberg M.
      A new depression scale designed to be sensitive to change.
      ) following six serial ketamine infusions(
      • Zhou Y.-L.
      • Wu F.-C.
      • Liu W.-J.
      • Zheng W.
      • Wang C.-Y.
      • Zhan Y.-N.
      • et al.
      Volumetric changes in subcortical structures following repeated ketamine treatment in patients with major depressive disorder: a longitudinal analysis.
      ), however these results were not found after single ketamine treatment in an independent study(
      • Niciu M.J.
      • Iadarola N.D.
      • Banerjee D.
      • Luckenbaugh D.A.
      • Park M.
      • Lener M.
      • et al.
      The antidepressant efficacy of subanesthetic-dose ketamine does not correlate with baseline subcortical volumes in a replication sample with major depressive disorder.
      ).
      Though evidence is limited, ketamine may also affect the structure of other subcortical structures. Following serial ketamine, increased left amygdalar volume was correlated with antidepressant response(
      • Montgomery S.A.
      • Asberg M.
      A new depression scale designed to be sensitive to change.
      ,
      • Zhou Y.-L.
      • Wu F.-C.
      • Wang C.-Y.
      • Zheng W.
      • Lan X.-F.
      • Deng X.-R.
      • Ning Y.-P.
      Relationship between hippocampal volume and inflammatory markers following six infusions of ketamine in major depressive disorder.
      ). Another study observed decreased left nucleus accumbens volume following treatment in remitters only(
      • Abdallah C.G.
      • Jackowski A.
      • Salas R.
      • Gupta S.
      • Sato J.R.
      • Mao X.
      • et al.
      The Nucleus Accumbens and Ketamine Treatment in Major Depressive Disorder.
      ). However, increase nucleus accumbens, bilateral putamen, thalamus, caudate, and periaqueductal gray matter volume was detected following 6-week oral (racemic) ketamine treatment in voxel-based analyses(
      • Gallay C.C.
      • Forsyth G.
      • Can A.T.
      • Dutton M.
      • Jamieson D.
      • Jensen E.
      • et al.
      Six-week oral ketamine treatment for chronic suicidality is associated with increased grey matter volume.
      ). Finally, decreases in midbrain volumes 24 hours after single ketamine infusion have been reported(
      • Dai D.
      • Lacadie C.M.
      • Holmes S.E.
      • Cool R.
      • Anticevic A.
      • Averill C.
      • et al.
      Ketamine Normalizes the Structural Alterations of Inferior Frontal Gyrus in Depression.
      ).

      Cortical Regions

      Decreased volumes of the left lateral OFC and an increase in the right precentral gyrus, right opercular IFG, right operculum, right insula, and right postcentral gyrus have been reported 24 hours after ketamine(
      • Dai D.
      • Lacadie C.M.
      • Holmes S.E.
      • Cool R.
      • Anticevic A.
      • Averill C.
      • et al.
      Ketamine Normalizes the Structural Alterations of Inferior Frontal Gyrus in Depression.
      ). In contrast, an independent report found no significant changes in cortical volume post-ketamine(
      • Gallay C.C.
      • Forsyth G.
      • Can A.T.
      • Dutton M.
      • Jamieson D.
      • Jensen E.
      • et al.
      Six-week oral ketamine treatment for chronic suicidality is associated with increased grey matter volume.
      ). One report showed a positive association between baseline ACC volume and change in depressive symptoms(
      • Hamilton M.
      A rating scale for depression.
      ,
      • Montgomery S.A.
      • Asberg M.
      A new depression scale designed to be sensitive to change.
      ) 24 hours post-single infusion(
      • Herrera-Melendez A.
      • Stippl A.
      • Aust S.
      • Scheidegger M.
      • Seifritz E.
      • Heuser-Collier I.
      • et al.
      Gray matter volume of rostral anterior cingulate cortex predicts rapid antidepressant response to ketamine.
      ).

      Summary

      Existing data suggest that subanesthetic ketamine may lead to hippocampal structural plasticity(
      • Zhou Y.-L.
      • Wu F.-C.
      • Liu W.-J.
      • Zheng W.
      • Wang C.-Y.
      • Zhan Y.-N.
      • et al.
      Volumetric changes in subcortical structures following repeated ketamine treatment in patients with major depressive disorder: a longitudinal analysis.
      ,
      • Abdallah C.G.
      • Salas R.
      • Jackowski A.
      • Baldwin P.
      • Sato J.R.
      • Mathew S.J.
      Hippocampal volume and the rapid antidepressant effect of ketamine.
      ), despite mixed laterality of reported effects, and may also relate to antidepressant response. Notably, preclinical models have shown that ketamine induces neurotrophic processes, such as increased expression of brain derived neurotrophic factor (BDNF), and increased hippocampal spine density(
      • Zhang J.
      • Qu Y.
      • Chang L.
      • Pu Y.
      • Hashimoto K.
      R)-Ketamine Rapidly Ameliorates the Decreased Spine Density in the Medial Prefrontal Cortex and Hippocampus of Susceptible Mice After Chronic Social Defeat Stress.
      ) that may contribute to observed changes in hippocampal macrostructure(
      • Zhou Y.-L.
      • Wu F.-C.
      • Wang C.-Y.
      • Zheng W.
      • Lan X.-F.
      • Deng X.-R.
      • Ning Y.-P.
      Relationship between hippocampal volume and inflammatory markers following six infusions of ketamine in major depressive disorder.
      ,
      • Zhou Y.-L.
      • Wu F.-C.
      • Liu W.-J.
      • Zheng W.
      • Wang C.-Y.
      • Zhan Y.-N.
      • et al.
      Volumetric changes in subcortical structures following repeated ketamine treatment in patients with major depressive disorder: a longitudinal analysis.
      ,
      • Abdallah C.G.
      • Jackowski A.
      • Salas R.
      • Gupta S.
      • Sato J.R.
      • Mao X.
      • et al.
      The Nucleus Accumbens and Ketamine Treatment in Major Depressive Disorder.
      ). Other subcortical regions are also implicated in isolated studies (
      • Abdallah C.G.
      • Jackowski A.
      • Salas R.
      • Gupta S.
      • Sato J.R.
      • Mao X.
      • et al.
      The Nucleus Accumbens and Ketamine Treatment in Major Depressive Disorder.
      ,
      • Gallay C.C.
      • Forsyth G.
      • Can A.T.
      • Dutton M.
      • Jamieson D.
      • Jensen E.
      • et al.
      Six-week oral ketamine treatment for chronic suicidality is associated with increased grey matter volume.
      ) and effects may be more pronounced after serial ketamine treatment(
      • Zhou Y.-L.
      • Wu F.-C.
      • Liu W.-J.
      • Zheng W.
      • Wang C.-Y.
      • Zhan Y.-N.
      • et al.
      Volumetric changes in subcortical structures following repeated ketamine treatment in patients with major depressive disorder: a longitudinal analysis.
      ,
      • Gallay C.C.
      • Forsyth G.
      • Can A.T.
      • Dutton M.
      • Jamieson D.
      • Jensen E.
      • et al.
      Six-week oral ketamine treatment for chronic suicidality is associated with increased grey matter volume.
      ). Some data suggest that ketamine leads to changes in higher cortical areas, but studies are limited(
      • Dai D.
      • Lacadie C.M.
      • Holmes S.E.
      • Cool R.
      • Anticevic A.
      • Averill C.
      • et al.
      Ketamine Normalizes the Structural Alterations of Inferior Frontal Gyrus in Depression.
      ,
      • Herrera-Melendez A.
      • Stippl A.
      • Aust S.
      • Scheidegger M.
      • Seifritz E.
      • Heuser-Collier I.
      • et al.
      Gray matter volume of rostral anterior cingulate cortex predicts rapid antidepressant response to ketamine.
      ). Existing data also suggest that pre-treatment hippocampal (sub)structure(
      • Siegel J.S.
      • Palanca B.J.A.
      • Ances B.M.
      • Kharasch E.D.
      • Schweiger J.A.
      • Yingling M.D.
      • et al.
      Prolonged ketamine infusion modulates limbic connectivity and induces sustained remission of treatment-resistant depression.
      ,
      • Zhou Y.-L.
      • Wu F.-C.
      • Liu W.-J.
      • Zheng W.
      • Wang C.-Y.
      • Zhan Y.-N.
      • et al.
      Volumetric changes in subcortical structures following repeated ketamine treatment in patients with major depressive disorder: a longitudinal analysis.
      ,
      • Abdallah C.G.
      • Salas R.
      • Jackowski A.
      • Baldwin P.
      • Sato J.R.
      • Mathew S.J.
      Hippocampal volume and the rapid antidepressant effect of ketamine.
      ) and thalamic(
      • Zhou Y.-L.
      • Wu F.-C.
      • Liu W.-J.
      • Zheng W.
      • Wang C.-Y.
      • Zhan Y.-N.
      • et al.
      Volumetric changes in subcortical structures following repeated ketamine treatment in patients with major depressive disorder: a longitudinal analysis.
      ) volumes might associate with subsequent clinical response.

      Diffusion MRI

      Diffusion-weighted MRI (dMRI) tracks and quantifies water diffusion in brain tissue to evaluate white matter microstructure and other tissue properties(
      • Basser P.J.
      • Mattiello J.
      • LeBihan D.
      MR diffusion tensor spectroscopy and imaging.
      ). In a preliminary study, patients who responded to single IV ketamine had significantly higher fractional anisotropy (FA) and lower radial diffusivity (RD) in the cingulum and forceps minor at baseline compared to non-responders, suggesting an individual’s predisposition for ketamine response may be influenced by regional white matter microstructure(
      • Vasavada M.M.
      • Leaver A.M.
      • Espinoza R.T.
      • Joshi S.H.
      • Njau S.N.
      • Woods R.P.
      • Narr K.L.
      Structural connectivity and response to ketamine therapy in major depression: A preliminary study.
      ). When investigating changes in diffusion metrics four hours after single ketamine infusion, increases in FA in the forceps minor and bilateral unicate fasciculus negatively correlated with symptom improvement(
      • Hamilton M.
      A rating scale for depression.
      ) 24 hours post-infusion(
      • Sydnor V.J.
      • Lyall A.E.
      • Cetin-Karayumak S.
      • Cheung J.C.
      • Felicione J.M.
      • Akeju O.
      • et al.
      Studying pre-treatment and ketamine-induced changes in white matter microstructure in the context of ketamine’s antidepressant effects.
      ). Further, greater pre-single infusion FA in the cingulum (hippocampal portion) and left superior longitudinal fasciculus associated with improved depressive symptoms(
      • Hamilton M.
      A rating scale for depression.
      ) 24 hours post-treatment(
      • Sydnor V.J.
      • Lyall A.E.
      • Cetin-Karayumak S.
      • Cheung J.C.
      • Felicione J.M.
      • Akeju O.
      • et al.
      Studying pre-treatment and ketamine-induced changes in white matter microstructure in the context of ketamine’s antidepressant effects.
      ). In supplementary analysis, lower baseline FA in tracts connecting the right amygdala and sgACC were associated with improved clinical response(
      • Montgomery S.A.
      • Asberg M.
      A new depression scale designed to be sensitive to change.
      ,
      • Nugent A.C.
      • Farmer C.
      • Evans J.W.
      • Snider S.L.
      • Banerjee D.
      • Zarate Jr., C.A.
      Multimodal imaging reveals a complex pattern of dysfunction in corticolimbic pathways in major depressive disorder.
      ).

      Summary

      Together dMRI studies in MDD, though few, suggest ketamine may have a unique effect on white matter microstructure and connectivity (Table 6). However, higher resolution models of diffusion(
      • Zhang H.
      • Schneider T.
      • Wheeler-Kingshott C.A.
      • Alexander D.C.
      NODDI: practical in vivo neurite orientation dispersion and density imaging of the human brain.
      ,
      • Arab A.
      • Wojna-Pelczar A.
      • Khairnar A.
      • Szabó N.
      • Ruda-Kucerova J.
      Principles of diffusion kurtosis imaging and its role in early diagnosis of neurodegenerative disorders.
      ) have not yet been investigated within the context of ketamine treatment that may reveal other measurable changes in regional white matter tissue properties.
      Table 6dMRI studies of ketamine treatment in depressed populations.
      StudyDemographicsOther MedicationsKetamine TreatmentData CollectionDepression AssessmentSummary of Findings
      Sydnor et al., 2020(105); NCT02544607N: 13 Unipolar TRD*YES

      Stable antidepressants and psychotherapy for ≥28 days prior, ketamine naïve
      Single 0.5mg/kg IV infusion over 40 mins+Neuroimaging:

      •Baseline

      •4 hours post infusion

      Clinical Assessments:

      •24 hours post infusion
      HDRS↑pre-infusion FA in left CB-hippocampal portion and left SLF associated with improvements in HDRS

      (+) FA in bilateral ILF, left SLF, and right UF between pre and post infusion

      ↑FA in CC-forceps minor and bilateral UF negatively correlated with improvement in HDRS
      Vasavada et al., 2016(104); NCT021654491N: 10 Unipolar MDD, 15 HCYES

      9 participants receiving concurrent antidepressant therapy
      Single 0.5mg/kg IV infusion over 40 mins+Neuroimaging:

      •Baseline

      Clinical Assessments:

      •Baseline

      •24 hours post infusion
      MADRS

      NRs defined as ΔMADRS <50%
      Rs FA > NRs FA in cingulum and forceps minor (-) in RD in forceps



      Only NRs showed significantly ↓FA and ↓MD in forceps minor and ↑RD in cingulum compared to HC
      Nugent et al., 2019(106) 2; NCT00088699N: 30 Unipolar TRD*, 26 HC§NO

      Psychotropic medication free for ≥2 weeks
      Single 0.5mg/kg IV infusion or saline placebo+++Neuroimaging:

      •Baseline

      •Follow up

      Clinical Assessments:

      •Baseline

      •40, 80, 120, and 230 minutes post infusion

      •1, 2, 3, 7, 10, and 11 days post infusion
      MADRS(-) FA in tracts connecting right amygdala and sgACC associated with better clinical response

      (-) FC between left amygdala and sgACC associated with better response to ketamine
      *≥1 failed treatment

      TRD: Treatment resistant depression

      MDD: Major Depressive Disorder

      HC: Healthy Control

      §: HC received ketamine

      +: Open Label

      ++: Randomized Placebo

      +++: Randomized Crossover

      F: female

      M: male

      IV: Intravenous

      HDRS: Hamilton Depression Rating Scale

      MADRS: Montgomery-Åsberg Depression Rating Scale

      Rs: Responders

      NRs: Non-responders
      FA: Fractional Anisotropy

      MD: Mean diffusivity

      RD: Radial Diffusivity

      SLF: Superior longitudinal fasciculus

      ILF: Inferior longitudinal fasciculus

      UF: Uncinate fasciculus

      CC: Corpus callosum sgACC: Subgenual anterior cingulate cortex

      ↑: Higher

      ↓: Lower (+): Increase

      (-): Decrease
      1Different cohort from the other NCT02165449 studies
      2Ketamine treatment results presented in supplemental material

      Magnetic Resonance Spectroscopy

      Magnetic resonance spectroscopy (MRS) may reveal changes in glutamate signaling or other aspects of cellular integrity and metabolism linked with or predictive of ketamine’s antidepressant effects. However, none of the four published studies using single voxel proton (1H) MRS to investigate downstream changes in brain metabolites ≥1-day post-single IV ketamine detected significant changes in brain metabolites or associations with ketamine response in MDD(109–112)(Table 7).
      Table 7MRS studies of ketamine treatment in depressed populations.
      StudyDemographicsOther MedicationsKetamine TreatmentData CollectionDepression AssessmentSummary of Findings
      Valentine et al., 2011(109)N: 10 Unipolar MDDNO

      Psychotropic medication free ≥2weeks prior to study
      Single IV infusion of saline over 40 mins followed by single IV infusion 0.5mg/kg ketamine over 40 mins one week later+++Neuroimaging:

      •Baseline

      •3 hours after infusion start

      •2 days post infusion

      Clinical Assessments:

      •Baseline

      •60 mins, 180 mins, 24 hours, 48 hours, 72 hours, 5 days, and 7 days post-infusion
      HDRS-25

      BDI

      HARS

      BPRS
      No change in AANt content following ketamine

      No correlation with clinical response

      No cortical AANT
      Milak et al. 2016(110)N: 11 Unipolar MDDNO

      Psychotropic medication free ≥2weeks prior to study
      Single intravenous infusion 0.5mg/kg over 40 mins+Neuroimaging:

      •Baseline

      •4 during infusion

      •1 immediately post infusion

      Clinical Assessments:

      •Baseline

      •230 mins and 24 hours post infusion
      HDRS-24Higher glutamate and GABA compared to baseline but not correlated with clinical response

      Norketamine levels at 90 mins post infusion correlated with improvement in depressive symptoms
      Milak et al. 2020(111)N: 38 Unipolar MDDNO

      No psychotropic medication or medication likely to interact with GABA or glutamate ≥2weeks, no neuroleptics ≥2month, no fluoxetine ≥6 weeks prior to study
      Single intravenous infusion of 0.1, 0.2, 0.3, 0.4, or 0.5mg/kg ketamine over 40 min+Neuroimaging:

      •Baseline

      •4 during infusion

      •1 immediately post infusion

      Clinical Assessments:

      •Baseline

      •24 hours post infusion
      HDRS-22Glutamate correlated with clinical improvement when ketamine blood level not included in model

      GABA not correlated with clinical improvement
      Evans et al., 2018(112); NCT00088699N: 20 Unipolar TRD*, 17 HC§NO

      Medication free ≥2weeks prior to study
      Single IV infusion 0.5mg/kg ketamine or saline placebo with alternative treatment 2 weeks later+++Neuroimaging:

      •Baseline

      •24 hours post infusion.

      Clinical Assessments:

      •Baseline

      •Same day as infusion
      HDRS

      SHAPS
      Non-significant increase in glutamate and tNAA post-ketamine compared to baseline and placebo
      *≥1 failed treatment

      TRD: Treatment resistant depression

      MDD: Major Depressive Disorder

      HC: Healthy Control

      §: HC received ketamine

      +: Open Label

      ++: Randomized Placebo

      +++: Randomized Crossover

      F: female

      M: male

      IV: Intravenous

      HDRS: Hamilton Depression Rating Scale

      MADRS: Montgomery-Åsberg Depression Rating Scale

      SHAPS: Snaith-Hamilton Pleasure Scale

      HARS: Hamilton Anxiety Rating Scale

      BPRS: Brief Psychiatric Rating Scale

      AANt: Amino acid neurotransmitter tNAA: N-acetyl aspartate summed with N-acetylaspartylglutamate

      Conclusion

      A growing number of neuroimaging studies have investigated brain-systems level effects of subanesthetic ketamine treatment in MDD. Although results are difficult to reconcile given differing study design and analyses, recurring patterns of neurofunctional plasticity are evident. The fMRI literature consistently suggests ketamine impacts depression-relevant functional brain networks and brain activity, most frequently implicating networks encompassing prefrontal, limbic and striatal regions. Several studies reported increased fronto-striatal connectivity(
      • Mkrtchian A.
      • Evans J.W.
      • Kraus C.
      • Yuan P.
      • Kadriu B.
      • Nugent A.C.
      • et al.
      Ketamine modulates fronto-striatal circuitry in depressed and healthy individuals.
      ,
      • Abdallah C.G.
      • Averill L.A.
      • Collins K.A.
      • Geha P.
      • Schwartz J.
      • Averill C.
      • et al.
      Ketamine Treatment and Global Brain Connectivity in Major Depression.
      ,
      • Zhuo C.
      • Ji F.
      • Tian H.
      • Wang L.
      • Jia F.
      • Jiang D.
      • et al.
      Transient effects of multi-infusion ketamine augmentation on treatment-resistant depressive symptoms in patients with treatment-resistant bipolar depression - An open-label three-week pilot study.
      ) and decreased inter-limbic connectivity(
      • Siegel J.S.
      • Palanca B.J.A.
      • Ances B.M.
      • Kharasch E.D.
      • Schweiger J.A.
      • Yingling M.D.
      • et al.
      Prolonged ketamine infusion modulates limbic connectivity and induces sustained remission of treatment-resistant depression.
      ,
      • Nakamura T.
      • Tomita M.
      • Horikawa N.
      • Ishibashi M.
      • Uematsu K.
      • Hiraki T.
      • et al.
      Functional connectivity between the amygdala and subgenual cingulate gyrus predicts the antidepressant effects of ketamine in patients with treatment-resistant depression.
      ), often associated with improved depressive symptoms and normalizing towards values in healthy controls. This suggests part of ketamine’s therapeutic mechanism may be driven by its ability to regain cognitive control over emotional activity. PET and perfusion ASL studies have also identified networks and regions that may serve as biomarkers of ketamine response, including the ACC(74–76), striatal(
      • Tiger M.
      • Veldman E.R.
      • Ekman C.-J.
      • Halldin C.
      • Svenningsson P.
      • Lundberg J.
      A randomized placebo-controlled PET study of ketamine´s effect on serotonin1B receptor binding in patients with SSRI-resistant depression.
      ) and cerebellar circuitry(
      • Lally N.
      • Nugent A.C.
      • Luckenbaugh D.A.
      • Ameli R.
      • Roiser J.P.
      • Zarate C.A.
      Anti-anhedonic effect of ketamine and its neural correlates in treatment-resistant bipolar depression.
      ), as well visual regions(
      • Carlson P.J.
      • Diazgranados N.
      • Nugent A.C.
      • Ibrahim L.
      • Luckenbaugh D.A.
      • Brutsche N.
      • et al.
      Neural correlates of rapid antidepressant response to ketamine in treatment-resistant unipolar depression: a preliminary positron emission tomography study.
      ,
      • Sahib A.K.
      • Loureiro J.R.A.
      • Vasavada M.M.
      • Kubicki A.
      • Joshi S.H.
      • Wang K.
      • et al.
      Single and repeated ketamine treatment induces perfusion changes in sensory and limbic networks in major depressive disorder.
      ). These summarized changes in functional brain circuitry may be driven by rapidly occurring synapto- and dendrogenesis observed in signaling pathways downstream to NMDAR or AMPA mediated actions in preclinical models of ketamine treatment(
      • Pham T.H.
      • Gardier A.M.
      Fast-acting antidepressant activity of ketamine: highlights on brain serotonin, glutamate, and GABA neurotransmission in preclinical studies.
      ,
      • Hashimoto K.
      Molecular mechanisms of the rapid-acting and long-lasting antidepressant actions of (R)-ketamine.
      ).
      Given the small sample sizes, heterogeneity of depression and variability in imaging analysis methods, there is a need for systematic replication of prior results, which should be a goal of future studies. Though participants serve as their own controls in longitudinal studies, differences concerning whether concurrent antidepressant medication is allowed and stable could potentially influence results. Thus, more refined investigation of the effects of simultaneous antidepressant treatment may assist in deciphering underlying response mechanisms to benefit treatment approaches. While considering the limitations of the current literature (Table 8), sample demographics and neuroimaging parameters (Supplemental Tables 3-16), and study design (Table 1, Table 2, Table 3, Table 4, Table 5, Table 6, Table 7) are made available for readers to evaluate the potential impact of each study, contextualize findings, and inform the design of future studies.
      Table 8Here, we outline the are several limitations in the field to consider, particularly when trying to summarize findings and for designing future studies of ketamine antidepressant treatment.
      Limitations in the FieldNotes
      Small Sample SizesMajority of current studies consist of small sample sizes, with the largest study included in this review included 61 participants with MDD. Testing the generalizability of these findings in larger samples is crucial improving our understanding of ketamine’s therapeutic mechanisms.
      Lack of Consensus regarding TRD DefinitionThere is a lack of consensus regarding the number of failed treatments that the defining TRD, therefore the severity of treatment resistance within the population of each study is variable.
      Heterogeneous Medication Inclusion/Exclusion CriteriaThere were frequently differences in criteria for permitted concurrent antidepressant and antipsychotic medication, with some studies requiring participants to be medication free while others only requiring stable medications. It is possible that interactions between ketamine and concurrent antidepressant medication may determine treatment response(
      • Veraart J.K.E.
      • Smith-Apeldoorn S.Y.
      • Bakker I.M.
      • Visser B.A.E.
      • Kamphuis J.
      • Schoevers R.A.
      • Touw D.J.
      Pharmacodynamic Interactions Between Ketamine and Psychiatric Medications Used in the Treatment of Depression: A Systematic Review.
      ) and should be investigated further.
      Differences in Ketamine TreatmentAlthough majority of the studies generally administered ketamine intravenously at 0.5mg/kg over 40 minutes, there were varying treatment doses and administrative methods and studies investigating serial ketamine treatment varied greatly in the number of treatments administered, which likely influences treatment response.
      Observations Made During Differing Windows Post-KetamineThere was significant variability regarding when neuroimaging and clinical assessments were collected following ketamine treatment, many of which may miss the window of ketamine’s therapeutic effects.
      Inconsistent Network NomenclatureThe still maturing field of network neuroscience lacks consistent nomenclature across studies, and is further complicated by fact that particular brain regions are also shared across specific networks(
      • Seitzman B.A.
      • Snyder A.Z.
      • Leuthardt E.C.
      • Shimony J.S.
      The State of Resting State Networks.
      ,
      • Uddin L.Q.
      • Yeo B.T.T.
      • Spreng R.N.
      Towards a Universal Taxonomy of Macro-scale Functional Human Brain Networks.
      ).
      These reviewed studies have provided important leads regarding how ketamine modulates structural and functional brain systems to elicit antidepressant effects and have pointed to neurobiological features that appear to influence subsequent ketamine response in MDD. However, lack of replication, and data-driven cross-validation that more directly link macrostructural properties or changes to ketamine’s underlying antidepressant mechanisms are required before this work can meaningfully impact clinical decision making and patient outcomes.

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      Acknowledgments

      Research reported in this publication was supported by the National Institute of Mental Health Grant No. U01MH110008 and the National Institute of Neurological Disorders And Stroke of the National Institutes of Health under Award Number T32NS048004. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Mental Health or the National Institutes of Health.

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