This review (2017) examines ketamine's rapid antidepressant efficacy with respect to evidence that it can neurochemical/physiological disturbances, such as abnormalities in excitatory and/or inhibitory neurotransmission in association with altered brain levels of glutamate and gamma-aminobutyric acid. It highlights neuroimaging studies to support the notion that glutamatergic modulation may be a viable biomarker for investigating depression in future studies.
In patients with major depressive disorder (MDD) or bipolar disorder (BD), abnormalities in excitatory and/or inhibitory neurotransmission and neuronal plasticity may lead to aberrant functional connectivity patterns within large brain networks. Network dysfunction in association with altered brain levels of glutamate (Glu) and gamma-aminobutyric acid (GABA) have been identified in both animal and human studies of depression. In addition, evidence of an antidepressant response to subanesthetic dose ketamine has led to a collection of studies that have examined neurochemical (e.g. glutamatergic and GABA-ergic) and functional imaging correlates associated with such an effect. Results from these studies suggest that an antidepressant response in association with ketamine occurs, in part, by reversing these neurochemical/physiological disturbances. Future studies in depression will require a combination of neuroimaging approaches from which more biologically homogeneous subgroups can be identified, particularly with respect to treatment response biomarkers of glutamatergic modulation.
Earlier preclinical and clinical work has implicated abnormalities in excitatory and inhibitory neurotransmission—principally involving glutamate (Glu) and gamma-aminobutyric acid (GABA)—in the pathophysiology of major depressive disorder (MDD) and bipolar disorder (BD). Animal models using pharmacologic and stress-induction paradigms have shown cortical Glu alterations that are reversible with conventional antidepressant interventions, motivating a glutamatergic hypothesis that extends beyond monoaminergic explanations. Human neurochemical studies using proton magnetic resonance spectroscopy (1H-MRS), positron emission tomography (PET), and functional imaging (EEG, MEG, fMRI) have reported region-specific changes in Glu, Gln, Glx (combined Glu and Gln), and GABA, and concurrent evidence has linked these neurochemical alterations with aberrant large-scale network functional connectivity in depressed patients. Lener and colleagues present a narrative review that synthesises neurochemical and functional imaging literature to explore links between Glu/GABA disturbances, network-level dysfunction, and the rapid antidepressant effects of subanesthetic-dose ketamine. The review highlights ketamine as a molecular probe for glutamatergic modulation in humans because of its reproducible rapid antidepressant effects and relatively lower side-effect burden compared with other glutamatergic agents. The authors argue for combined multimodal imaging approaches to better characterise biologically homogeneous subgroups and to identify biomarkers predictive of treatment response to glutamatergic interventions such as ketamine.
Papers cited by this study that are also in Blossom
Fond, G., Loundou, A., Macgregor, A. et al. · Psychopharmacology (2014)
Newport, D. J., Carpenter, L. L., Mcdonald, W. M. et al. · American Journal of Psychiatry (2015)
Berman, R. M., Cappiello, A., Anand, A. et al. · Biological Psychiatry (2000)
Murrough, J. W., Iosifescu, D. V., Chang, L. C. et al. · American Journal of Psychiatry (2013)
The extracted text does not provide a formal Methods section describing literature search strategy, inclusion/exclusion criteria, dates, databases searched, or systematic review procedures. From the content, the paper appears to be a narrative review that integrates findings from animal studies and clinical investigations using 1H-MRS, 13C-MRS, PET, fMRI, MEG, and EEG, and also discusses interventional ketamine studies (both clinical trials and imaging/pharmacodynamic experiments). The authors organise the review by modality and topic: they summarise rodent and human neurochemical studies of Glu and GABA (including the Glu/Gln metabolic cycle and mitochondrial energetics), PET studies of Glu receptors (for example mGluR5), 1H-MRS findings across brain regions, functional connectivity abnormalities from resting-state fMRI and MEG/EEG, and imaging/pharmacologic studies examining ketamine's effects on neurochemistry and circuitry. Where available, the review reports sample sizes and study designs of highlighted studies (for example, early double-blind placebo-controlled ketamine trials and small MRS or PET investigations), but no systematic quality assessment or meta-analytic pooling methods are described in the extracted text.
Preclinical and human neurochemical findings: Rodent paradigms that induce depressive-like behaviour are associated with cortical Glu alterations that can be normalised by monoaminergic antidepressants and electroconvulsive therapy. In human 1H-MRS studies, patients with MDD commonly show reduced Glu, Glx, and Gln in dorsolateral, dorsomedial, dorsoanterolateral prefrontal cortex (PFC) regions and the anterior cingulate cortex (ACC), with increased Glu/Glx reported in occipital cortex in some studies. A meta-analysis of 17 1H-MRS studies found reductions of Glx in the PFC that correlated with the number of failed antidepressant treatments, suggesting a relation with illness chronicity, but did not find isolated Glu reductions, implicating astrocytic metabolic dysfunction as a potential mechanism. One in vivo 13C-MRS plus 1H-MRS study reported a 26% reduction in mitochondrial energy production in glutamatergic neurons in patients with MDD versus healthy controls; however, no difference in measured Glu/Gln cycle rate was observed, and the reported negative association between Glu concentrations and number of depressive episodes was a post hoc, uncorrected finding. In BD, results are more heterogeneous: two meta-analyses noted increased Glx in the PFC irrespective of mood state and increased ACC Glu in depressed states, and elevated ACC Glu correlated with episode counts in one study. Medication confounding and clinical heterogeneity in BD samples complicate interpretation. GABA-related findings: 1H-MRS studies in MDD tend to report lower GABA in PFC, ACC, and occipital cortex, with some evidence of greater reductions in melancholic presentations. In BD the literature is inconsistent, with reports of decreased, increased, or unchanged GABA. Overall, the pattern supports that an excitatory/inhibitory imbalance—often manifesting as reduced excitatory neurotransmission or altered Glu/GABA ratios—may characterise a subset of depressed patients rather than a universal GABA deficit. PET receptor studies and other molecular findings: Two PET studies reported reduced mGluR5 availability in patients with MDD. The review notes the need for more specific ligands for metabotropic Glu receptors and ionotropic receptor subunits to clarify receptor-level pathology. Functional connectivity and electrophysiology: Resting-state fMRI studies identify network abnormalities in MDD, including hyperconnectivity within the default mode network (DMN) and increased coupling between subgenual ACC (sgACC) and medial PFC (mPFC), alongside reduced frontoparietal connectivity. MEG studies (including beta- and gamma-band analyses) show concordant connectivity disruptions; for example, Lener and colleagues' group reported decreased connectivity between the sgACC and a precentral motor/precuneus network and increased limbic connectivity in MDD. Combined MRS–fMRI data link regional Glu reductions with decreased functional connectivity and blunted BOLD responses to emotional stimuli, suggesting that local amino-acid neurochemistry may relate to specific network dysfunctions. Ketamine clinical and imaging findings: The initial double-blind placebo-controlled study cited administered 0.5 mg/kg intravenous ketamine over 40 minutes and observed an antidepressant response (>=50% HAMD reduction) in 4 of 8 patients (7 completers). Subsequent studies replicated rapid antidepressant effects in MDD and BD: symptom reduction begins within 2 hours, peaks around 24 hours, and can persist up to 1 week. Mechanistically, preclinical data indicate ketamine antagonises NMDA receptors on GABAergic interneurons (leading to disinhibition of glutamatergic neurons) and on postsynaptic neurons (promoting intracellular growth factor synthesis such as BDNF), with downstream activation of mTOR signalling and promotion of synaptogenesis. Neurochemical imaging during ketamine: Human studies are inconsistent. Some healthy volunteer studies observed an acute rise in Glu during ketamine infusion (a proposed "glutamate surge") with Glu returning to baseline after infusion; other double-blind studies found no change in mPFC/ACC Glx, Glu, or GABA 40 minutes after infusion. PET with an mGluR5 ligand in 10 healthy subjects detected reduced ligand binding across cortical and limbic regions after ketamine, though ligand characteristics limit interpretation. Clinical 1H-MRS studies in patients with MDD (small samples) reported mixed results: of three studies summarised, two found no specific neurochemical signature predictive of antidepressant response, while one reported that a higher pretreatment Glx/Glu ratio in dorsomedial/dorsal anterolateral PFC associated with clinical improvement. Some studies detected transient increases in Glx/water and GABA/water ratios during infusion, indicating target engagement, but these changes did not consistently predict clinical response. Ketamine and functional circuitry: Pretreatment activation in the rostral ACC has been associated with antidepressant response across modalities. Ketamine acutely alters ACC–mPFC connectivity in healthy subjects (increasing acutely, decreasing by 24 hours). PET studies link ketamine to altered glucose metabolism in dorsal ACC and PFC regions; sgACC hypermetabolism has been reported to predict ketamine response in BD. MEG studies in healthy volunteers (N=25 men) show ketamine-induced increases in anterior theta and gamma power and decreases in posterior low-frequency power, with frontoparietal connectivity changes and reduced NMDA/AMPA-mediated frontoparietal connectivity. The extent to which electrophysiological gamma-band changes directly index glutamatergic signalling in depressed patients remains unresolved, as most electrophysiological ketamine work to date has been in healthy samples.
The investigators interpret the accumulated evidence as supportive of a role for glutamatergic dysfunction in a subset of patients with MDD and BD, with GABAergic abnormalities being less consistently observed. They emphasise that altered glutamatergic metabolism and impaired mitochondrial energy production in glutamatergic neurons could contribute to an excitatory/inhibitory imbalance and to network-level connectivity perturbations evident in resting-state fMRI and electrophysiology. Ketamine is framed as a valuable translational probe: its rapid antidepressant effects and mechanistic profile (NMDA antagonism, disinhibition of glutamatergic neurons, BDNF and mTOR pathway engagement) provide a means to test how modulation of Glu/GABA systems affects functional circuitry. However, the authors note that clinical neurochemical and electrophysiological studies to date are limited by small sample sizes, heterogeneous patient populations, variable imaging platforms and field strengths, differences in voxel placement, and medication confounds—factors that contribute to inconsistent findings across studies. To address these limitations, the authors advocate for multimodal, combinatorial imaging approaches that pair MRS or PET measures of amino-acid neurochemistry with functional imaging (resting-state and pharmacodynamic fMRI, MEG/EEG) before, during, and after ketamine infusion. Specific recommendations include using higher magnetic field strengths (for example 7T) and focusing on targeted regions of interest such as the sgACC, dACC, mPFC, frontoparietal cortices, and limbic structures. They also highlight resting-state MEG—particularly beta- and gamma-band analyses—and pharmacodynamic fMRI as promising methods for identifying biomarkers predictive of ketamine response. Finally, the authors underscore the need to identify biologically homogeneous subgroups within MDD and BD to improve diagnostic specificity and to personalise glutamatergic treatments.
In rodent studies, pharmacologic-and stress-induction paradigms that lead to depressive-like behaviors have been associated with alterations in cortical glutamate (Glu) (1-3), findings that have been reversed by monoaminergic antidepressants and electroconvulsive therapy. As a result, a glutamatergic hypothesis of depression was posited that extends beyond monoaminergic dysfunction in patients with major depressive disorder (MDD) or bipolar disorder (BD). Interestingly, clinical studies of depression using magnetic resonance spectroscopy (MRS) and positron emission tomography (PET) have identified alterations in Glu and gammaaminobutyric acid (GABA) concentrations and activity, suggesting that dysfunction in excitatory and/or inhibitory neurotransmitter signaling mechanisms may play a critical role in depression. In this review, we examine studies that use electroencephalography (EEG), magnetoencephalography (MEG), and functional magnetic resonance imaging (fMRI) techniques to identify aberrant functional neural circuitry patterns in patients with MDD and BD. We then hypothesize links between neurotransmitter abnormalities and functional neurocircuitry deficits in depression, from which we encourage future work using MRS or PET techniques in conjunction with functional imaging techniques to elucidate and characterize these relations. Furthermore, a pivotal role of glutamatergic neurotransmission in the pathophysiology of and treatment response in MDD and BD has been supported by studies that demonstrate antidepressant efficacy of the N-methyl-D-aspartate (NMDA) receptor antagonist ketaminein preclinical and clinical studies. Here, we highlight ketamine as the best available molecular tool with which to probe the impact of glutamatergic modulation on excitatory/inhibitory neural circuitry dynamics in healthy and depressed subjects with MDD or BD owing to evidence supporting ketamine's efficacy and its lower burden of side effects compared with other glutamatergic modulating agents. Within this framework, we review clinical studies using MRS, PET, fMRI, and MEG to explore how glutamatergic modulation may alleviate aberrant functional neurocircuitry in depression and mediate antidepressant response to ketamine. Finally, we emphasize the importance of using a combinatorial approach to better identify and predict treatment responders to ketamine. minor contribution from GABA (known as Glx) that is often reported owing to poor signal resolution between these metabolites in weaker magnetic fields. 1 H-MRS studies examining levels of GABA, Glu, Gln, and Glx in the brain require an appreciation of Glu metabolism, particularly the Glu/Gln cycle(Figure). Briefly, Glu is produced in neurons from glucose-derived tricarboxylic acid cycle intermediates and branched-chain amino acids. Cytosolic Glu is packaged into vesicles by vesicular Glu transporters for exocytotic release. After neuronal depolarization and release into the synaptic cleft, Glu binds to one of three types of ionotropic Glu receptors-NMDA, α-amino-3-hydroxy-5-methyl-4isoxazolepropionic acid (AMPA), or kainate-all of which are embedded in the postsynaptic membrane and clustered within postsynaptic densities. Glu also binds to metabotropic receptors (mGluRs), typically found extrasynaptically and presynaptically. To prevent synaptic spillover and excitotoxicity, Glu is removed from the synapse by Glu transporters in astrocytes and metabolically converted into Gln by glutamine synthetase. Gln is released by astrocytes into presynaptic neurons where it is converted back to Glu by cytosolic glutaminase. Inhibitory GABAergic neurons also contain the enzyme glutamic acid decarboxylase, which converts Glu to GABA. In comparison with healthy subjects, aberrant amino acid neurotransmitter levels measured by 1 H-MRS have been found in individuals with MDDand BD. Specifically, in patients with MDD, Glu and Glx reductions were found in the dorsolateral prefrontal cortex (PFC)and other PFC areas such as the dorsomedial and dorsoanterolateral PFCand anterior cingulate cortex (ACC), with increased levels in the occipital cortex (OCC)to a degree that may be related to duration of illness. In a meta-analysis of 17 1 H-MRS studies of patients with MDD, reductions of Glx in the PFC were associated with number of failed antidepressant treatments, a measure of chronicity and a proxy for severity of depressive illness course. Surprisingly, this study found no isolated reductions in Glu, implicating astrocyte-mediated metabolic alterations in Glu metabolism underlying the pathophysiology of MDD. A possible explanation may be related to abnormal mitochondrial energy production in glutamatergic neurons. In an in vivo 13 C-MRS and 1 H-MRS study that examined the potential relation between the Glu/Gln cycle and mitochondrial energy production, patients with MDD showed a 26% reduction in mitochondrial energy production compared with healthy subjects, although no differences were After neuronal depolarization and release into the synaptic cleft, Glu binds to N-methyl-D-aspartate (NMDA), α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), kainate, or metabotropic receptors (mGluRs). Glu is removed from the synapse by Glu transporters in astrocytes and metabolically converted into glutamine (Gln) by glutamine synthetase. Gln is released by astrocytes into presynaptic neurons where it is converted back to Glu by cytosolic glutaminase. Inhibitory GABAergic neurons contain the enzyme glutamic acid decarboxylase (GAD), which converts Glu to GABA. (B) Ketamine-induced changes, depicted in red: Ketamine antagonizes NMDA receptors on GABAergic interneurons and on postsynaptic neurons; the former disinhibits cortical glutamatergic neurons and the latter increases synthesis of brain-derived neurotrophic factor (BDNF). By the kainate receptor, ketamine increases activity of mammalian target of rapamycin (mTOR), leading to neuroplasticity and synaptogenesis. Ketamine also increases BDNF by nitric oxide production, leading to stabilization of nitrergic Rheb and enhancement of mTOR signaling. eEF2K, eukaryotic elongation factor-2 kinase; ERK, extracellular signal-regulated kinase; SNARE, soluble N-ethylmaleimide-sensitive factory activating protein receptor; TRKB, tropomyosin receptor kinase B. found in Glu/Gln cycle rate. The investigators suggested that reductions in energy production within glutamatergic neurons resulted from reduced synaptic strength by reductions in AMPA or NMDA receptors in the postsynaptic neuron. In addition, although the study was performed post hoc without correction for multiple comparisons, the investigators found a negative association between Glu concentrations and the number of depressive episodes, suggesting that reductions in synaptic strength may reduce Glu neurotransmission over successive episodes of depression.
Neurochemical studies in patients with BD have shown mixed results. Although some studies found no differences in Glu between patients with BD and healthy subjects, two meta-analyses of 1 H-MRS studies in BD noted increased Glx in the PFC regardless of mood state, as well as in the ACC in depressed states. A recent study showed that elevated Glu in the ACC associated with patients with BD in euthymic states was related to number of depressive/manic episodes; notably, this finding may allow for differentiation of depression between BD and MDD. Impaired oxidative metabolism in glutamatergic neurons has been hypothesized to explain elevated Glx and lactate levels associated with mixed or depressed states in BDand further supports a contributory role of inflammation in the pathophysiology of depression. Wide and overlapping ranges of mood and neurocognitive states in BDincrease variation within and between study samples, contributing to challenges in interpreting neurochemical and functional imaging studies of BD. Therefore, further studies of BD may require a larger number of patients to better examine state-versus trait-related brain correlates in addition to the development of novel and sophisticated models of BD subphenotypes. Finally, in addition to known sources of heterogeneity between 1 H-MRS studies of depression, such as subject selection, field strength, MRS sequences, and anatomic placement of the voxel of interest, studies of patients with BD are further confounded by concurrent use of medications (e.g., valproate and lithium), which has been shown to alter Glu and GABA levels in the brain. Unsurprisingly, 1 H-MRS studies in MDD have consistently shown reduced levels of Glu, Gln, Glx, and GABA, whereas in BD studies, elevated levels of Glu have been observed inconsistently without differences in Gln, Glx, or GABA. Detection and quantification of neurotransmitter receptors using PET imaging, in conjunction with administration of a radioactive ligand that is displaced by the endogenous neurotransmitter of interest at its receptor, provides complementary information to MRS studies regarding neurotransmitter signaling mechanisms. For example, reduced mGluR5 (Figure) density in patients with MDD was observed in two clinical PET studies that used an mGluR5-specific radioligand. Taken together with animal studies showing antidepressantlike effects associated with the mGluR5-specific antagonists 2-methyl-6-(phenylethynyl)-pyridine and 3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine, these findings suggest that abnormal mGluR5 signaling may be involved in the pathophysiology of depression. One of the studies was of patients aged 55 to 80 yearsand may be confounded by comorbid medical conditions, their treatment, and age-related brain changes. Nevertheless, a clear need exists to develop specific Glu receptor ligands for mGluRs and ionotropic Glu receptor subunitsto better understand abnormal glutamatergic neurotransmission and plasticity in depression. Studies of inhibitory neurotransmitter systems in depression have also obtained mixed results. In 1 H-MRS studies of patients with MDD, lower GABA levels were reported in the PFC, ACC, and OCC (46) compared with healthy subjects, and these changes may be more pronounced in association with melancholia. One negative study found no group differences in GABA concentrations in patients with remitted MDD, but the investigators suggested that GABA concentrations (and activity) may be sensitive to the presence of a depressive episode. Moreover, a 1 H-MRS study of patients with MDD found no group differences in Glx concentrations within the ventromedial PFC compared with healthy subjects, but observed an increased ratio of Glx to GABA associated with lower age of depression onset, suggesting that an increased excitatory/inhibitory neurotransmitter ratio may be associated with depression vulnerability. In studies of euthymic patients with BD, decreasedand increased (49) GABA levels have been observed compared with healthy subjects, as have no differences in GABA levels. From the hypothesized excitatory/inhibitory imbalance in depression (), 1 H-MRS studies of Glu and Glu/GABA ratios suggest that a deficiency of excitatory neurotransmission or an imbalance of excitatory/inhibitory neurotransmission characterizes a subset of depressed patients. Despite the clinical efficacy of GABAergic medications (e.g., valproic acid, lamotrigine, and carbamazepine) in BD, inconsistent reports of GABA levels associated with BD does not support an isolated deficiency in GABA in depression. Abnormalities in glutamatergic neuronal metabolism may be experienced in a proximal stage of the underlying pathophysiology of MDD and BD. For example, in a study of patients with schizophrenia randomly assigned to receive pomaglumetad (a metabotropic Glu 2/3 receptor agonist) versus placebo for 6 weeks, greater improvement in symptoms was experienced earlier in the course of illness or with history of a medication targeted at the dopamine D 2 receptor. Future prospective investigations in larger clinical samples may allow identification of subgroups of depressed patients who better respond to GABA-or Glu-modulating therapies along the illness course. Moreover, innovations to current MRS techniques, such as application of novel pulse sequences at higher magnetic field strengths (e.g., 7T) that can better resolve cerebral Glu, Gln, and GABA concentrations, could facilitate identification of biologically homogeneous and enriched subgroupsto which directed clinical interventions can be addressed.
Neural circuitry describes the complex array of interconnected neurons in the brain from which simultaneous and coordinated information processing is refined and reorganized by experience-related synaptic changes. Neuroimaging methods that indirectly (e.g., fMRI blood-oxygen level dependent [BOLD] signal) or directly (e.g., EEG and MEG) examine neural activity aim to identify circuitry-level abnormalities and/or response to behavioral or neurochemical interventions. Considerations are necessary to address before links can be drawn between amino acid neurochemistry and functional imaging. First, MEG possesses greater spatial resolution than EEG; thus, we focus primarily on MEG studies. Second, although functional neuroimaging can be used in conjunction with cognitive and/or emotionally salient tasks, we focus on studies performed at resting state (taskfree) from which functional connectivity patterns are derived as EEG and MEG frequency findings are reviewed in further detail. Third, functional connectivity patterns within larger interconnected neural circuits have emerged from novel statistical techniques. Finally, we examine studies of abnormal functional connectivity networks as they may relate to neurochemical studies of Glu and GABA in depression. Abnormalities in resting-state functional connectivity patterns in patients with MDD have been found within and between large brain networks. The default mode network (DMN), which includes the medial PFC (mPFC) and posterior cingulate cortex, has been shown to deactivate during cognitive tasks and is associated with introspection or selfreferential thought when not actively recruited in task performance. The DMN and other networks involved in cognitive control of attention and emotion have been shown to differ in patients with MDD compared with healthy controls. In MDD, reduced connectivity has been shown in frontoparietal brain networks, and hyperconnectivity (increased positive or reduced negative connectivity) has been shown within the DMN and between the subgenual ACC (sgACC) and mPFC, regions that have been linked to abnormalities in GABA in animal models, as well as GABA reductionsand Glx/GABA imbalancesin patients with MDD. In a systematic review of eight resting-state fMRI studies of patients with BD in all mood states, abnormalities in functional connectivity were found in the mPFC and ACC with limbicstriatal regions. Compared with MDD patients, BD patients show significantly stronger functional connectivity within the dorsolateral PFC and ventrolateral PFC, as well as inferior frontal/dorsolateral PFC to ACC, suggesting that changes in functional connectivity between the ACC and PFC, as well as differences in Glu neurotransmission within the ACC, may differentiate the two disorders. This is supported by studies that compared BD and MDD patients and found differences in PFC activation during emotionally laden tasks. Similarities between functional connectivity patterns derived from resting-state fMRI studies and MEG studies across multiple frequency bands were demonstrated in healthy subjects using a model-free independent component analysis. With the use of a similar model on beta bandfiltered MEG data, our group identified decreased connectivity between the sgACC and a network within the precentral motor cortex and precuneus and increased connectivity in limbic areas (i.e., amygdala and temporal cortex) in patients with MDD compared with healthy subjects. These results support the role of the sgACC and other cortical and subcortical regionsin impaired cognitive control, psychomotor retardation, and other symptom clusters in depression. In a study using both 1 H-MRS and fMRI in patients with MDD, Glu levels in the mPFC associated with connectivity to subcortical regions, and Glx reductions in the sgACC predicted decreased functional connectivity between the sgACC and the anterior insula. Decreased Glu levels corresponded with decreased BOLD response to an emotional stimulus in patients with MDD with prominent anhedonia, suggesting that reduced glutamatergic neurotransmission and/or signaling may contribute to alterations in functional connectivityat specific electrophysiologic oscillation frequencies relating to cognitive and limbic-related symptoms in depression.
Ketamine's antidepressant effects were demonstrated over a decade ago in a double-blind, placebo-controlled clinical study of eight depressed patients randomly assigned to receive either a subanesthetic dose (0.5 mg/kg intravenously over 40 minutes) of ketamine or saline. Four of the eight patients (n 5 7 completers) had an antidepressant response to ketamine (defined as a reduction of 50% or greater on the Hamilton Depression Rating Scale). Subsequently, our group and others replicated intravenous ketamine's antidepressant effects in both MDD and BD patients across single and repeated administrations under various study designs. The time course of the antidepressant response is characterized by an initial reduction in depressive symptoms within 2 hours, a maximal reduction in depressive symptoms within 24 hours, and a sustained response for up to 1 week after administration. Ketamine's effect on glutamatergic and GABAergic neurons has emerged from preclinical studies (80-83) (Figure). Ketamine antagonizes NMDA receptors on GABAergic interneurons and on postsynaptic neurons; the former disinhibits cortical glutamatergic neuronsand the latter increases synthesis of intracellular growth factors, such as brain-derived neurotrophic factor. In addition, by the kainate receptor, ketamine increases activity of mammalian target of rapamycin and other molecules responsible for neuroplasticity and synaptogenesis. A recent study examining both signaling pathways found that ketamine increased brainderived neurotrophic factor by generating nitric oxide, leading to the stabilization of nitrergic Rheb, a small G protein that enhances mammalian target of rapamycin signaling. These findings have shifted our conceptualization of the pathophysiology and treatment of depressionand have encouraged the development of Glu-based treatments for depressive disorders.
MDD subjects N 5 14 (9 men, 5 women) Lamotrigine and risperidone resulted in widespread attenuation of the ketamine-induced increases in signal, including the frontal and thalamic regions; a contrasting effect across both pretreatments was observed only in the sgPFC, in which ketamine reduced the signal ACC, anterior cingulate cortex; BD, bipolar disorder; BOLD, blood-oxygen level dependent; CCN, cognitive control network; dACC, dorsal anterior cingulate cortex; DLPFC, dorsolateral prefrontal cortex; DM/DA-PFC, dorsomedial/dorsal anterolateral prefrontal cortex; DMN, default mode network; 18 [F]-FDG, 18 fluoro-deoxyglucose; fMRI, functional magnetic resonance; GABA, gamma-aminobutyric acid; Gln, glutamine; Glu, glutamate; Glx, combination of Glu and Gln; 1 H-MRS, proton magnetic resonance spectroscopy; IV, intravenous; MDD, major depressive disorder; MEG, magnetoencephalography; mPFC, medial prefrontal cortex; MRI, magnetic resonance imaging; NAA, N-acetylaspartate; OCC, occipital cortex; OFC, orbitofrontal cortex; PET, positron emission tomography; PFC, prefrontal cortex; pgACC, perigenual anterior cingulate cortex; phfMRI, pharmacologic functional magnetic resonance; ROI, region of interest; sgACC, subgenual anterior cingulate cortex; sgPFC, subgenual prefrontal cortex; SPM, statistical parametric mapping; STG/MTG, superior and middle temporal gyri; TRD, treatment-resistant depression; vlPFC, ventrolateral prefrontal cortex; vmPFC, ventromedial prefrontal cortex.
Biological Psychiatry May 15, 2017; 81:886-897 www.sobp.org/journal minutes after infusion that did not correlate with psychotomimetic symptoms. A third double-blind, placebo-controlled, parallel group design study of 17 men (ketamine: n 5 8; placebo: n 5 9) found that ketamine administration was not associated with changes in Glx, Glu, or GABA levels in the mPFC/ACC 40 minutes after infusion. Inconsistent results in small samples make it challenging to draw definitive conclusions about ketamine-induced amino acid neurotransmitter changes in healthy volunteers. In addition, one studydid not measure Glu directly, and scan quality was too poor in another studyto measure Gln levels. Nevertheless, consistent with the "glutamate surge" hypothesis, Glu levels increased during ketamine infusion, leading to psychotomimetic effects, with a subsequent decrease of Glu to baseline levels after infusion ceased. In support of this hypothesis, DeLorenzo et al.examined PET scans before and after infusion with an mGluR5 ligand to measure the degree of ketamine binding to the mGluR5 receptor in 10 healthy control subjects who received intravenous ketamine. Reduced mGluR5 ligand (or increased ketamine) binding was found in the ACC, mPFC, orbital PFC, ventral striatum, parietal lobe, dorsal putamen, dorsal caudate, amygdala, and hippocampus. The ligand used in this study (ABP-688) is an allosteric modulator; therefore, it may not be a valid method of measuring Glu release. Although basimglurant (RO4917523, RG7090), a negative allosteric modulator at mGLuR5, has shown promise as an adjuvant medication to traditional antidepressant medicationsin one study, a significant reduction in the Montgomery-Åsberg Depression Rating Scale was found in the self-reported rather than clinician-administered Montgomery Asberg Depression Rating Scale; therefore, replication is necessary to support its antidepressant efficacy. Three 1 H-MRS studies examined ketamine-related changes in Glu, Glx, and/or GABA in patients with MDD (92-94) (Table); two uncovered no neurochemical signature associated with antidepressant response to ketamine. The third study observed improved depressive symptoms in 14 unmedicated, treatment-resistant patients with MDD in association with increased pretreatment Glx/Glu ratio in the dorsomedial PFC/dorsal anterolateral PFC. Pretreatment measures of GABA or Glu did not correlate with reduction in depressive symptoms in either of these two regions of interest (p . .1). In another study of 11 unmedicated patients with MDD, no association was observed between antidepressant response to ketamine and Glx or GABA levels in the mPFC before, during, or after ketamine infusion. Interestingly, in this study, ketamine was associated with increased Glx/water and GABA/water ratios, indicating target engagement and suggesting that ketamine transiently increases excitatory and inhibitory neurotransmission. Finally, in a single-blind study of 10 patients with MDD, ketamine was associated with reduced depressive symptoms at 1 hour to 7 days after infusion; however, antidepressant efficacy was not associated with baseline levels or change in any amino acid neurotransmitter within the OCC. Therefore, it is unclear whether amino acid neurometabolite levels or their ratios can help predict antidepressant response to ketamine owing to inconsistent results in small samples across different imaging platforms.
Increased pretreatment neural activity in the rostral ACC associates with antidepressant response across different pharmacologic, electrophysiological, and behavioral interventions, suggesting that a common neurobiological signature may be associated with antidepressant response to treatment. In healthy subjects, functional connectivity between the rostral ACC and mPFC increased acutely (95) and decreased 24 hours after ketamine infusion. Furthermore, with the use of PET imaging methods, ketamine associated with increased glucose metabolism in the dorsal ACC (dACC), altered glucose metabolism in PFC regionsin MDD, and increased glucose metabolism in the dACC and putamen in patients with BD (100). Our group has shown that sgACC hypermetabolism predicted response to ketamine in patients with BD (101). Taken together, the evidence suggests that specific activation patterns in the sgACC and dACC lead to disrupted functional engagement of PFC regions that is partly modifiable in patients with depression through glutamatergic interventions. This adds to the substantial and mounting evidence not only that the ACC is a key hub connecting limbic dysfunction with clinical symptoms in MDD, but also that its functional response may correlate with ketamine's antidepressant efficacy. Excitatory/inhibitory neurotransmitter imbalances may be inferred through specific electrophysiological measures. For example, interactions between superficial excitatory pyramidal cells and inhibitory GABAergic interneurons are attributed to oscillations in the gamma-frequency band as measured by MEG. Increases in gamma-band power (104,105), reduced coupling of spike-rate and local field potential power within the gamma band (105), and disruptions in neuronal plasticity within prefrontal-hippocampal circuits (106) have been associated with NMDA receptor blockade with ketamine in the rodent neocortex. Similarly, in humans, subanesthetic-dose ketamine infusion associates with increased gamma-band amplitudes in motor and visual cortices (102) and decreased peak gamma frequency in the visual cortex (107). Given the correlation between gammaband oscillations and BOLD connectivity in both rodents (108) and humans (109), ketamine may be associated with abnormalities in functional connectivity and disruptions in neuronal plasticity, particularly in circuits interconnecting the hippocampus and PFC (108,110). Glu levels in the posterior cingulate cortex strongly correlate with connectivity in the DMN (111), suggesting that Glu alterations by ketamine administration may give rise to alterations in brain function at rest (i.e., non-task) as well as during a task. Finally, a MEG study in healthy volunteers (N 5 25 men) found that subanesthetic-dose ketamine increased anterior theta and gamma power but decreased posterior theta, delta, and alpha power; these changes were sustained for up to 50 minutes after ketamine infusion (i.e., after the resolution of perceptual distortions) (112). The investigators reported frontoparietal connectivity changes, with ketamine reducing NMDA-and AMPA-mediated frontoparietal connectivity. If replicated, the antidepressant effects of ketamine may depend on acute and prolonged changes in MEG spectral power, as well as in electrophysiological synchrony in frontoparietal circuitry. The extent to which gamma-band changes measured by MEG reflect altered glutamatergic neurotransmission and/or signaling in association with ketamine administration is unclear. Furthermore, given that current studies are limited to healthy subjects (Table), it is not known whether ketamine-related electrophysiological changes are similar in depressed patients.
In depressed patients, evidence from neurochemical studies of MDD and BD suggests that alterations in Glu-related excitatory neurotransmission exist in a subset of patients. Although evidence of isolated abnormalities in GABA-related inhibitory neurotransmission in depression has been less clear, a reduction in efficient energy metabolism in glutamatergic neurons may lead to an imbalance of Glu over GABA neurotransmission that manifests as network connectivity perturbations in BD and MDD. Moreover, given the small number of existing clinical studies with low-powered samples of patients with MDD, it is unclear how ketamine's antidepressant efficacy is associated with specific Glu and/or GABA levels. Further studies are needed at higher magnetic field strength with attention to specific regions of interest such as the sgACC, dACC, frontoparietal cortices, mPFC, and limbic areas (Figure). In addition, resting-state MEG studies-particularly those focused on beta-and gamma-band activity-may reveal connectivity changes that correlate with and/or predict ketamine's antidepressant response. Evidence of large variations in Glu levels during and after ketamine infusion in healthy and depressed subjects warrants examination of changes in Glu/GABA neurochemistry in conjunction with functional neuroimaging before, during, and after ketamine infusion. Pharmacodynamic fMRI is a functional imaging technique that measures brain response during infusion of pharmacologic agents, thus providing early and longitudinal measures of drug action in the brain (113). Pharmacodynamic fMRI studies conducted in healthy volunteers have established test-retest reliability (114) and specificity (115) in association with ketamine infusions (Table), further supporting that such an approach in future ketamine studies may help predict those who may experience an antidepressant response. Finally, identifying reliable diagnostic and treatment response biomarkers in MDD has been a challenge, given the clinical heterogeneity of this disorder and the wide variability of treatment response. Neuroendocrine, neurochemical, and neurophysiological assays in the search for MDD biomarkers have been replicated in some, but not all, translational studies (117-120). Moreover, the consensus within the field has been that neuroimaging techniques, in conjunction with other illness biomarkers, may be required to diagnose and treat psychiatric disorders (119-121). A combinatorial approach of diverse techniques and methods (122) will be required to identify underlying neural system abnormalities that are unique to subgroups of patients with MDD and/or correlate with antidepressant response.
Create a free account to open full-text PDFs.
Grimm, O., Gass, N., Weber-Fahr, W. et al. · Psychopharmacology (2015)
Nutt, D. J. · Journal of Psychopharmacology (2015)
Li, C. T., Chen, M. H., Lin, W. C. et al. · Human Brain Mapping (2016)
Lally, N., Nugent, A. C., Luckenbaugh, D. A. et al. · Translational Psychiatry (2014)
Papers in Blossom that reference this study
Rodrigues, L. S., Rossi, G. N., Guerra, L. T. L. et al. · Journal of Clinical Psychopharmacology (2024)
Ragnhildstveit, A., Slayton, M., Jackson, L. K. et al. · Brain Sciences (2022)
Jelen, L. A., Young, A. H., Stone, J. M. · Journal of Psychopharmacology (2020)
Ionescu, D. F., Felicione, J. M., Gosai, A. et al. · Harvard Review of Psychiatry (2018)
Huang, Y. J., Lane, H. Y., Lin, C. H. · Neural Plasticity (2017)