Circulating myeloid-derived MMP8 in stress susceptibility and depression.

Psychosocial stress has profound effects on the body, including the immune system and the brain1,2. Although a large number of pre-clinical and clinical studies have linked peripheral immune system alterations to stress-related disorders such as major depressive disorder (MDD)3, the underlying mechanisms are not well understood. Here we show that expression of a circulating myeloid cell-specific proteinase, matrix metalloproteinase 8 (MMP8), is increased in the serum of humans with MDD as well as in stress-susceptible mice following chronic social defeat stress (CSDS). In mice, we show that this increase leads to alterations in extracellular space and neurophysiological changes in the nucleus accumbens (NAc), as well as altered social behaviour. Using a combination of mass cytometry and single-cell RNA sequencing, we performed high-dimensional phenotyping of immune cells in circulation and in the brain and demonstrate that peripheral monocytes are strongly affected by stress. In stress-susceptible mice, both circulating monocytes and monocytes that traffic to the brain showed increased Mmp8 expression following chronic social defeat stress. We further demonstrate that circulating MMP8 directly infiltrates the NAc parenchyma and controls the ultrastructure of the extracellular space. Depleting MMP8 prevented stress-induced social avoidance behaviour and alterations in NAc neurophysiology and extracellular space. Collectively, these data establish a mechanism by which peripheral immune factors can affect central nervous system function and behaviour in the context of stress. Targeting specific peripheral immune cell-derived matrix metalloproteinases could constitute novel therapeutic targets for stress-related neuropsychiatric disorders.

Preliminary Evaluation of a Web-Based International Journal Club for Ketamine in Psychiatric Disorders: Cross-Sectional Survey Study.

BACKGROUND: The use of novel rapid-acting antidepressants for psychiatric disorders is expanding. The web-based Ketamine and Related Compounds International Journal Club (KIJC) was created during the COVID-19 pandemic by UK academic psychiatrists and trainees for interested global professionals to discuss papers related to the topic of ketamine for the treatment of psychiatric disorders. The KIJC aimed to facilitate bidirectional discussions, sharing of ideas, and networking among participants. OBJECTIVE: The aim of this study is a preliminary evaluation of the journal club's format for satisfaction and impact after the first year of running. METHODS: A website, email, and word of mouth were used for recruitment. The journal club was held twice per month using videoconferencing software in 3 parts: a 20-minute presentation, a 15-minute chaired question and answer session, and a 25-minute informal discussion with participants' cameras on. The first 2 parts were recorded and uploaded to the website alongside links to the corresponding papers. In total, 24 speakers presented from 8 countries, typically within 2 (SD 2) months of publication. The average attendance was 51 (SD 20) audience members, and there were 63 (SD 50) views of each subsequent recording. Two anonymous web-based cross-sectional surveys were conducted from November 2021 to February 2022, one for speakers and another for audience members, separately. Various survey statements, 14 for speakers and 12 for the audience, were categorized according to satisfaction and impact, alongside obtaining participants' primary career roles and requesting optional written feedback. Responses were compared between both groups and analyzed, including an inductive thematic analysis and a summary of lessons learned. RESULTS: A total of 30 survey responses were obtained, demonstrating overall agreement with the statements. In total, 12 (50%) out of 24 speakers and 18 (35%) out of an average of 51 (SD 20) audience members regarded the journal club's format as satisfying and impactful. The majority (26/30, 87%) of respondents identified as clinicians (9/30, 30%), researchers (9/30, 30%), and clinician-researchers (8/30, 27%). Additionally, 11 (37%) of the 30 respondents also provided optional written feedback: 3 (10%) speakers and 8 (27%) audience members. From the written feedback, 5 main themes were derived: engagement with the journal club, desire for active participation, improving the platform, positive learning experiences, and suggestions for future sessions. CONCLUSIONS: The journal club successfully reached its intended audience and developed into a web-based community. The majority of the participants were satisfied with the format and found it impactful. Overall, the journal club appears to be a valuable tool for knowledge sharing and community building in the field of ketamine use for the treatment of psychiatric disorders. A larger sample size and additional testing methods are required to support the generalizability of the journal club's format.

Ketamine for Major Depressive Disorder.

Major Depressive Disorder (MDD) is a leading cause of disability worldwide. Conventional antidepressant treatment is characterised by a significant time to onset of therapeutic action (approximately 2 weeks) and fails to achieve a stable remission of symptoms in one-third of subjects with MDD. In the last 20 years the discovery of antidepressant effects of the N-methyl-d-aspartate (NMDA) receptor antagonist ketamine as a rapid acting (within hours) and sustained (up to 7 days) antidepressant has represented a major paradigm shift in the field.The present chapter reviews the pharmacology, safety, and efficacy of ketamine as a novel therapeutic agent for MDD and specifically for subjects who did not respond to conventional antidepressant (treatment resistant depression). The impact of ketamine on suicidal ideation, the availability of brain biomarkers of ketamine treatment response and the association of ketamine and psychotherapy are considered.

Social stress induces autoimmune responses against the brain.

Clinical studies have revealed a high comorbidity between autoimmune diseases and psychiatric disorders, including major depressive disorder (MDD). However, the mechanisms connecting autoimmunity and depression remain unclear. Here, we aim to identify the processes by which stress impacts the adaptive immune system and the implications of such responses to depression. To examine this relationship, we analyzed antibody responses and autoimmunity in the chronic social defeat stress (CSDS) model in mice, and in clinical samples from patients with MDD. We show that socially stressed mice have elevated serum antibody concentrations. We also confirm that social stress leads to the expansion of specific T and B cell populations within the cervical lymph nodes, where brain-derived antigens are preferentially delivered. Sera from stress-susceptible (SUS) mice exhibited high reactivity against brain tissue, and brain-reactive immunoglobulin G (IgG) antibody levels positively correlated with social avoidance behavior. IgG antibody concentrations in the brain were significantly higher in SUS mice than in unstressed mice, and positively correlated with social avoidance. Similarly, in humans, increased peripheral levels of brain-reactive IgG antibodies were associated with increased anhedonia. In vivo assessment of IgG antibodies showed they largely accumulate around blood vessels in the brain only in SUS mice. B cell-depleted mice exhibited stress resilience following CSDS, confirming the contribution of antibody-producing cells to social avoidance behavior. This study provides mechanistic insights connecting stress-induced autoimmune reactions against the brain and stress susceptibility. Therapeutic strategies targeting autoimmune responses might aid in the treatment of patients with MDD featuring immune abnormalities.

A Randomized Controlled Trial of Repeated Ketamine Administration for Chronic Posttraumatic Stress Disorder.

Objective: Posttraumatic stress disorder (PTSD) is a chronic and disabling disorder, for which available pharmacotherapies have limited efficacy. The authors' previous proof-of-concept randomized controlled trial of single-dose intravenous ketamine infusion in individuals with PTSD showed significant and rapid PTSD symptom reduction 24 hours postinfusion. The present study is the first randomized controlled trial to test the efficacy and safety of repeated intravenous ketamine infusions for the treatment of chronic PTSD. Methods: Individuals with chronic PTSD (N=30) were randomly assigned (1:1) to receive six infusions of ketamine (0.5 mg/kg) or midazolam (0.045 mg/kg) (psychoactive placebo control) over 2 consecutive weeks. Clinician-rated and self-report assessments were administered 24 hours after the first infusion and at weekly visits. The primary outcome measure was change in PTSD symptom severity, as assessed with the Clinician-Administered PTSD Scale for DSM-5 (CAPS-5), from baseline to 2 weeks (after completion of all infusions). Secondary outcome measures included the Impact of Event Scale-Revised, the Montgomery-Åsberg Depression Rating Scale (MADRS), and side effect measures. Results: The ketamine group showed a significantly greater improvement in CAPS-5 and MADRS total scores than the midazolam group from baseline to week 2. At week 2, the mean CAPS-5 total score was 11.88 points (SE=3.96) lower in the ketamine group than in the midazolam group (d=1.13, 95% CI=0.36, 1.91). Sixty-seven percent of participants in the ketamine group were treatment responders, compared with 20% in the midazolam group. Among ketamine responders, the median time to loss of response was 27.5 days following the 2-week course of infusions. Ketamine infusions were well tolerated overall, without serious adverse events. Conclusions: This randomized controlled trial provides the first evidence of efficacy of repeated ketamine infusions in reducing symptom severity in individuals with chronic PTSD. Further studies are warranted to understand ketamine's full potential as a treatment for chronic PTSD.Reprinted from Am J Psychiatry 2021; 178:193-202, with permission from American Psychiatric Association Publishing. Copyright © 2021.

Ketamine versus ECT for Nonpsychotic Treatment-Resistant Major Depression.

BACKGROUND: Electroconvulsive therapy (ECT) and subanesthetic intravenous ketamine are both currently used for treatment-resistant major depression, but the comparative effectiveness of the two treatments remains uncertain. METHODS: We conducted an open-label, randomized, noninferiority trial involving patients referred to ECT clinics for treatment-resistant major depression. Patients with treatment-resistant major depression without psychosis were recruited and assigned in a 1:1 ratio to receive ketamine or ECT. During an initial 3-week treatment phase, patients received either ECT three times per week or ketamine (0.5 mg per kilogram of body weight over 40 minutes) twice per week. The primary outcome was a response to treatment (i.e., a decrease of ≥50% from baseline in the score on the 16-item Quick Inventory of Depressive Symptomatology-Self-Report; scores range from 0 to 27, with higher scores indicating greater depression). The noninferiority margin was -10 percentage points. Secondary outcomes included scores on memory tests and patient-reported quality of life. After the initial treatment phase, the patients who had a response were followed over a 6-month period. RESULTS: A total of 403 patients underwent randomization at five clinical sites; 200 patients were assigned to the ketamine group and 203 to the ECT group. After 38 patients had withdrawn before initiation of the assigned treatment, ketamine was administered to 195 patients and ECT to 170 patients. A total of 55.4% of the patients in the ketamine group and 41.2% of those in the ECT group had a response (difference, 14.2 percentage points; 95% confidence interval, 3.9 to 24.2; P<0.001 for the noninferiority of ketamine to ECT). ECT appeared to be associated with a decrease in memory recall after 3 weeks of treatment (mean [±SE] decrease in the T-score for delayed recall on the Hopkins Verbal Learning Test-Revised, -0.9±1.1 in the ketamine group vs. -9.7±1.2 in the ECT group; scores range from -300 to 200, with higher scores indicating better function) with gradual recovery during follow-up. Improvement in patient-reported quality-of-life was similar in the two trial groups. ECT was associated with musculoskeletal adverse effects, whereas ketamine was associated with dissociation. CONCLUSIONS: Ketamine was noninferior to ECT as therapy for treatment-resistant major depression without psychosis. (Funded by the Patient-Centered Outcomes Research Institute; ELEKT-D ClinicalTrials.gov number, NCT03113968.).

Peripheral immune-derived matrix metalloproteinase promotes stress susceptibility.

Psychosocial stress has profound effects on the body, including the peripheral immune system and the brain1,2. Although a large number of pre-clinical and clinical studies have linked peripheral immune system alterations to stress-related disorders such as major depressive disorder (MDD)3,4,5, the underlying mechanisms are not well understood. Here we show that a peripheral myeloid cell-specific proteinase, matrix metalloproteinase 8 (MMP8), is elevated in serum of subjects with MDD as well as in stress-susceptible (SUS) mice following chronic social defeat stress (CSDS). In mice, we show that this increase leads to alterations in extracellular space and neurophysiological changes in the nucleus accumbens (NAc), thereby altering social behaviour. Using a combination of mass cytometry and single-cell RNA-sequencing, we performed high-dimensional phenotyping of immune cells in circulation and brain and demonstrate that peripheral monocytes are strongly affected by stress. Both peripheral and brain-infiltrating monocytes of SUS mice showed increased Mmp8 expression following CSDS. We further demonstrate that peripheral MMP8 directly infiltrates the NAc parenchyma to control the ultrastructure of the extracellular space. Depleting MMP8 prevented stress-induced social avoidance behaviour and alterations in NAc neurophysiology and extracellular space. Collectively, these data establish a novel mechanism by which peripheral immune factors can affect central nervous system function and behaviour in the context of stress. Targeting specific peripheral immune cell-derived matrix metalloproteinases could constitute novel therapeutic targets for stress-related neuropsychiatric disorders.

A randomized pilot study of the prophylactic effect of ketamine on laboratory-induced stress in healthy adults.

Background: Stress exposure is a key risk factor for the development of major depressive disorder and posttraumatic stress disorder. Enhancing stress resilience in at-risk populations could potentially protect against stress-induced disorders. The administration of ketamine one week prior to an acute stressor prevents the development of stress-induced depressive-like behavior in rodents. This study aimed to test if the prophylactic effect of ketamine against stress also applies to humans. Methods: We conducted a double-blind, placebo-controlled study wherein 24 healthy subjects (n = 11 males) were randomized to receive either ketamine (0.5 mg/kg) or midazolam (0.045 mg/kg) intravenously one week prior to an acute stress [Trier Social Stress Test (TSST)]. The primary endpoint was the anxious-composed subscale of the Profile of Mood States Bipolar Scale (POMS-Bi) administered immediately after the TSST. Salivary and plasma cortisol and salivary alpha amylase were also measured at 15-min intervals for 60 min following the stressor, as proxies of hypothalamic pituitary adrenal (HPA) and sympathetic-adrenal-medullary (SAM) axis activity, respectively. Results: Compared to the midazolam group (n = 12), the ketamine group (n = 12) showed a moderate to large (Cohen's d = 0.7) reduction in levels of anxiety immediately following stress, although this was not significant (p = 0.06). There was no effect of group on change in salivary cortisol or salivary alpha amylase following stress. We conducted a secondary analysis excluding one participant who did not show an expected correlation between plasma and salivary cortisol (n = 23, ketamine n = 11). In this subgroup, we observed a significant reduction in the level of salivary alpha amylase in the ketamine group compared to midazolam (Cohen's d = 0.7, p = 0.03). No formal adjustment for multiple testing was made as this is a pilot study and all secondary analyses are considered hypothesis-generating. Conclusions: Ketamine was associated with a numeric reduction in TSST-induced anxiety, equivalent to a medium-to-large effect size. However, this did not reach statistical significance . In a subset of subjects, ketamine appeared to blunt SAM reactivity following an acute stressor. Future studies with larger sample size are required to further investigate the pro-resilient effect of ketamine.

Ketamine as a prophylactic resilience-enhancing agent.

Stress exposure is one of the greatest risk factors for psychiatric illnesses, including major depressive disorder (MDD) and posttraumatic stress disorder (PTSD). Enhancing stress resilience could potentially protect against the development of stress-induced psychiatric disorders, yet no resilience-enhancing pharmaceuticals have been developed to date. This review serves to consider the existing evidence for a potential pro-resilience effect of ketamine in rodents as well as the preliminary evidence of ketamine as a prophylactic treatment for postpartum depression (PPD) in humans. Several animal studies have demonstrated that ketamine administered 1 week prior to a stressor (e.g., chronic social defeat and learned helplessness) may protect against depressive-like behavior. A similar protective effect has been demonstrated against PTSD-like behavior following Contextual Fear Conditioning (CFC). Recent work has sought to explore if the administration of ketamine prevented the development of postpartum depression (PPD) in humans. Researchers administered ketamine immediately following caesarian-section and found a significantly reduced prevalence of PPD in the ketamine-treated groups compared to the control groups. Utilizing ketamine as a resilience-enhancing treatment may have unique applications, including leading to a deeper understanding of the neurobiological mechanism underlying resilience. Future trials aiming to translate and replicate these findings with humans are warranted.

Exaggerated amygdala response to threat and association with immune hyperactivity in depression.

BACKGROUND: Depression is characterized by altered neurobiological responses to threat and inflammation may be involved in the development and maintenance of symptoms. However, the mechanistic pathways underlying the relationship between the neural underpinnings of threat, inflammation and depressive symptoms remain unknown. METHODS: Twenty participants with major depressive disorder (MDD) and 17 healthy controls (HCs) completed this study. Peripheral blood mononuclear cells (PBMCs) were collected and stimulated ex vivo with lipopolysaccharide (LPS). We then measured a broad array of secreted proteins and performed principal component analysis to compute an aggregated immune reactivity score. Subjects completed a well-validated emotional face processing task during functional magnetic resonance imaging (fMRI). Amygdala activation was measured during perception of threat for the main contrast of interest: fear > happy face. Participants completed the Mood and Anxiety Symptom Questionnaire (MASQ) and the Perceived Stress Scale (PSS). Correlation analyses between amygdala activation, the aggregate immune score, and symptom were computed across groups. A mediation analysis was also performed across groups to further explore the relationship between these three variables. RESULTS: In line with our hypotheses and with prior work, the MDD group showed greater amygdala activation in response to threat compared to the HC group [t35 = -2.038, p = 0.049]. Internal consistency of amygdala activation to threat was found to be moderate. Response to an ex vivo immune challenge was greater in MDD than HC based on the computed immune reactivity score (PC1; t35 = 2.674, p = 0.011). Amygdala activation was positively correlated with the immune score (r = 0.331, p = 0.045). Moreover, higher amygdala activation was associated with greater anxious arousal measured by the MASQ (r = 0.390, p = 0.017). Exploring the role of stress, we found that higher perceived stress was positively associated with both inflammatory response (r = 0.367, p = 0.026) and amygdala response to threat (r = 0.325, p = 0.050). Mediation analyses showed that perceived stress predicted anxious arousal, but neither inflammation nor amygdala activation fully accounted for the effect of perceived stress on anxious arousal. CONCLUSION: These data highlight the potential importance of threat circuitry hyperactivation in MDD, consistent with prior reports. We found that higher levels of inflammatory biomarkers were associated with higher amygdala activation, which in turn was associated with anxious arousal. Future research utilizing larger sample sizes are needed to replicate these preliminary results.

The Potential of KCNQ Potassium Channel Openers as Novel Antidepressants.

Major depressive disorder (MDD) is a leading cause of disability worldwide and less than one-third of patients with MDD achieve stable remission of symptoms, despite currently available treatments. Although MDD represents a serious health problem, a complete understanding of the neurobiological mechanisms underlying this condition continues to be elusive. Accumulating evidence from preclinical and animal studies provides support for the antidepressant potential of modulators of KCNQ voltage-gated potassium (K+) channels. KCNQ K+ channels, through regulation of neuronal excitability and activity, contribute to neurophysiological mechanisms underlying stress resilience, and represent potential targets of drug discovery for depression. The present article focuses on the pharmacology and efficacy of KCNQ2/3 K+ channel openers as novel therapeutic agents for depressive disorders from initial studies conducted on animal models showing depressive-like behaviors to recent work in humans that examines the potential for KCNQ2/3 channel modulators as novel antidepressants. Data from preclinical work suggest that KCNQ-type K+ channels are an active mediator of stress resilience and KCNQ2/3 K+ channel openers show antidepressant efficacy. Similarly, evidence from clinical trials conducted in patients with MDD using the KCNQ2/3 channel opener ezogabine (retigabine) showed significant improvements in depressive symptoms and anhedonia. Overall, KCNQ channel openers appear a promising target for the development of novel therapeutics for the treatment of psychiatric disorders and specifically for MDD.

Whole blood transcriptional signatures associated with rapid antidepressant response to ketamine in patients with treatment resistant depression.

Ketamine has rapid and sustained antidepressant effects in patients with treatment-resistant depression (TRD). However, the underlying mechanisms of action are not well understood. There is increasing evidence that TRD is associated with a pro-inflammatory state and that ketamine may inhibit inflammatory processes. We thus investigated whole blood transcriptional profiles related to TRD and gene expression changes associated with treatment response to ketamine. Whole blood was collected at baseline (21 healthy controls [HC], 26 patients with TRD) and then again in patients with TRD 24 hours following a single intravenous infusion of ketamine (0.5 mg/kg). We performed RNA-sequencing and analyzed (a) baseline transcriptional profiles between patients with TRD and HC, (b) responders vs. non-responders before ketamine treatment, and (c) gene expression signatures associated with clinical improvement. At baseline, patients with TRD compared to HC showed a gene expression signature indicative of interferon signaling pathway activation. Prior to ketamine administration, the metabotropic glutamate receptor gene GRM2 and the ionotropic glutamate receptor gene GRIN2D were upregulated in responders compared to non-responders. Response to ketamine was associated with a distinct transcriptional signature, however, we did not observe gene expression changes indicative of an anti-inflammatory effect. Future studies are needed to determine the role of the peripheral immune system in the antidepressant effect of ketamine.

Peripheral immune cell reactivity and neural response to reward in patients with depression and anhedonia.

Increased levels of peripheral cytokines have been previously associated with depression in preclinical and clinical research. Although the precise nature of peripheral immune dysfunction in depression remains unclear, evidence from animal studies points towards a dysregulated response of peripheral leukocytes as a risk factor for stress susceptibility. This study examined dynamic release of inflammatory blood factors from peripheral blood mononuclear cells (PBMC) in depressed patients and associations with neural and behavioral measures of reward processing. Thirty unmedicated patients meeting criteria for unipolar depressive disorder and 21 healthy control volunteers were enrolled. PBMCs were isolated from whole blood and stimulated ex vivo with lipopolysaccharide (LPS). Olink multiplex assay was used to analyze a large panel of inflammatory proteins. Participants completed functional magnetic resonance imaging with an incentive flanker task to probe neural responses to reward anticipation, as well as clinical measures of anhedonia and pleasure including the Temporal Experience of Pleasure Scale (TEPS) and the Snaith-Hamilton Pleasure Scale (SHAPS). LPS stimulation revealed larger increases in immune factors in depressed compared to healthy subjects using an aggregate immune score (t49 = 2.83, p = 0.007). Higher peripheral immune score was associated with reduced neural responses to reward anticipation within the ventral striatum (VS) (r = -0.39, p = 0.01), and with reduced anticipation of pleasure as measured with the TEPS anticipatory sub-score (r = -0.318, p = 0.023). Our study provides new evidence suggesting that dynamic hyper-reactivity of peripheral leukocytes in depressed patients is associated with blunted activation of the brain reward system and lower subjective anticipation of pleasure.

Neuroimaging correlates and predictors of response to repeated-dose intravenous ketamine in PTSD: preliminary evidence.

Promising initial data indicate that the glutamate N-methyl-D-aspartate (NMDA) receptor antagonist ketamine may be beneficial in post-traumatic stress disorder (PTSD). Here, we explore the neural correlates of ketamine-related changes in PTSD symptoms, using a rich battery of functional imaging data (two emotion-processing tasks and one task-free scan), collected from a subset of participants of a randomized clinical trial of repeated-dose intravenous ketamine vs midazolam (total N = 21). In a pre-registered analysis, we tested whether changes in an a priori set of imaging measures from a target neural circuit were predictive of improvement in PTSD symptoms, using leave-one-out cross-validated elastic-net regression models (regions of interest in the target circuit consisted of the dorsal and rostral anterior cingulate cortex, ventromedial prefrontal cortex, anterior hippocampus, anterior insula, and amygdala). Improvements in PTSD severity were associated with increased functional connectivity between the ventromedial prefrontal cortex (vmPFC) and amygdala during emotional face-viewing (change score retained in model with minimum predictive error in left-out subjects, standardized regression coefficient [ß] = 2.90). This effect was stronger in participants who received ketamine compared to midazolam (interaction ß = 0.86), and persisted following inclusion of concomitant change in depressive symptoms in the analysis model (ß = 0.69). Improvement following ketamine was also predicted by decreased dorsal anterior cingulate activity during emotional conflict regulation, and increased task-free connectivity between the vmPFC and anterior insula (ßs = -2.82, 0.60). Exploratory follow-up analysis via dynamic causal modelling revealed that whilst improvement in PTSD symptoms following either drug was associated with decreased excitatory modulation of amygdala→vmPFC connectivity during emotional face-viewing, increased top-down inhibition of the amygdala by the vmPFC was only observed in participants who improved under ketamine. Individuals with low prefrontal inhibition of amygdala responses to faces at baseline also showed greater improvements following ketamine treatment. These preliminary findings suggest that, specifically under ketamine, improvements in PTSD symptoms are accompanied by normalization of hypofrontal control over amygdala responses to social signals of threat.

Impact of the KCNQ2/3 Channel Opener Ezogabine on Reward Circuit Activity and Clinical Symptoms in Depression: Results From a Randomized Controlled Trial.

OBJECTIVE: Preclinical studies point to the KCNQ2/3 potassium channel as a novel target for the treatment of depression and anhedonia, a reduced ability to experience pleasure. The authors conducted the first randomized placebo-controlled trial testing the effect of the KCNQ2/3 positive modulator ezogabine on reward circuit activity and clinical outcomes in patients with depression. METHODS: Depressed individuals (N=45) with elevated levels of anhedonia were assigned to a 5-week treatment period with ezogabine (900 mg/day; N=21) or placebo (N=24). Participants underwent functional MRI during a reward flanker task at baseline and following treatment. Clinical measures of depression and anhedonia were collected at weekly visits. The primary endpoint was the change from baseline to week 5 in ventral striatum activation during reward anticipation. Secondary endpoints included depression and anhedonia severity as measured using the Montgomery-Åsberg Depression Rating Scale (MADRS) and the Snaith-Hamilton Pleasure Scale (SHAPS), respectively. RESULTS: The study did not meet its primary neuroimaging endpoint. Participants in the ezogabine group showed a numerical increase in ventral striatum response to reward anticipation following treatment compared with participants in the placebo group from baseline to week 5. Compared with placebo, ezogabine was associated with a significantly larger improvement in MADRS and SHAPS scores and other clinical endpoints. Ezogabine was well tolerated, and no serious adverse events occurred. CONCLUSIONS: The study did not meet its primary neuroimaging endpoint, although the effect of treatment was significant on several secondary clinical endpoints. In aggregate, the findings may suggest that future studies of the KCNQ2/3 channel as a novel treatment target for depression and anhedonia are warranted.

A Randomized Controlled Trial of Repeated Ketamine Administration for Chronic Posttraumatic Stress Disorder.

OBJECTIVE: Posttraumatic stress disorder (PTSD) is a chronic and disabling disorder, for which available pharmacotherapies have limited efficacy. The authors' previous proof-of-concept randomized controlled trial of single-dose intravenous ketamine infusion in individuals with PTSD showed significant and rapid PTSD symptom reduction 24 hours postinfusion. The present study is the first randomized controlled trial to test the efficacy and safety of repeated intravenous ketamine infusions for the treatment of chronic PTSD. METHODS: Individuals with chronic PTSD (N=30) were randomly assigned (1:1) to receive six infusions of ketamine (0.5 mg/kg) or midazolam (0.045 mg/kg) (psychoactive placebo control) over 2 consecutive weeks. Clinician-rated and self-report assessments were administered 24 hours after the first infusion and at weekly visits. The primary outcome measure was change in PTSD symptom severity, as assessed with the Clinician-Administered PTSD Scale for DSM-5 (CAPS-5), from baseline to 2 weeks (after completion of all infusions). Secondary outcome measures included the Impact of Event Scale-Revised, the Montgomery-Åsberg Depression Rating Scale (MADRS), and side effect measures. RESULTS: The ketamine group showed a significantly greater improvement in CAPS-5 and MADRS total scores than the midazolam group from baseline to week 2. At week 2, the mean CAPS-5 total score was 11.88 points (SE=3.96) lower in the ketamine group than in the midazolam group (d=1.13, 95% CI=0.36, 1.91). Sixty-seven percent of participants in the ketamine group were treatment responders, compared with 20% in the midazolam group. Among ketamine responders, the median time to loss of response was 27.5 days following the 2-week course of infusions. Ketamine infusions were well tolerated overall, without serious adverse events. CONCLUSIONS: This randomized controlled trial provides the first evidence of efficacy of repeated ketamine infusions in reducing symptom severity in individuals with chronic PTSD. Further studies are warranted to understand ketamine's full potential as a treatment for chronic PTSD.

Ketamine normalizes subgenual cingulate cortex hyper-activity in depression.

Mounting evidence supports the rapid antidepressant efficacy of the N-methyl-D-aspartate receptor antagonist, ketamine, for treating major depressive disorder (MDD); however, its neural mechanism of action remains poorly understood. Subgenual anterior cingulate cortex (sgACC) hyper-activity during rest has been consistently implicated in the pathophysiology of MDD, potentially driven in part by excessive hippocampal gluatmatergic efferents to sgACC. Reduction of sgACC activity has been associated with successful antidepressant treatment. This study aimed to examine whether task-based sgACC activity was higher in patients with MDD compared to controls and to determine whether this activity was altered by single-dose ketamine. In Study 1, patients with MDD (N = 28) and healthy controls (N = 20) completed task-based functional magnetic resonance imaging using an established incentive-processing task. In Study 2, a second cohort of patients with MDD (N = 14) completed the same scanning protocol at baseline and following a 40 min infusion of ketamine (0.5 mg/kg). Task-based activation of sgACC was examined with a seed-driven analysis assessing group differences and changes from pre to post treatment. Patients with MDD showed higher sgACC activation to positive and negative monetary incentives compared to controls, associated with anhedonia and anxiety, respectively. In addition, patients with MDD had higher resting-state functional connectivity between hippocampus and sgACC, associated with sgACC hyper-activation to positive incentives, but not negative incentives. Finally, ketamine reduced sgACC hyper-activation to positive incentives, but not negative incentives. These findings suggest a neural mechanism by which ketamine exerts its antidepressant efficacy, via rapid blunting of aberrant sgACC hyper-reactivity to positive incentives.

Effects of the KCNQ channel opener ezogabine on functional connectivity of the ventral striatum and clinical symptoms in patients with major depressive disorder.

Major depressive disorder (MDD) is a leading cause of disability worldwide, yet current treatment strategies remain limited in their mechanistic diversity. Recent evidence has highlighted a promising novel pharmaceutical target-the KCNQ-type potassium channel-for the treatment of depressive disorders, which may exert a therapeutic effect via functional changes within the brain reward system, including the ventral striatum. The current study assessed the effects of the KCNQ channel opener ezogabine (also known as retigabine) on reward circuitry and clinical symptoms in patients with MDD. Eighteen medication-free individuals with MDD currently in a major depressive episode were enrolled in an open-label study and received ezogabine up to 900 mg/day orally over the course of 10 weeks. Resting-state functional magnetic resonance imaging data were collected at baseline and posttreatment to examine brain reward circuitry. Reward learning was measured using a computerized probabilistic reward task. After treatment with ezogabine, subjects exhibited a significant reduction of depressive symptoms (Montgomery-Asberg Depression Rating Scale score change: -13.7 ± 9.7, p < 0.001, d = 2.08) and anhedonic symptoms (Snaith-Hamilton Pleasure Scale score change: -6.1 ± 5.3, p < 0.001, d = 1.00), which remained significant even after controlling for overall depression severity. Improvement in depression was associated with decreased functional connectivity between the ventral caudate and clusters within the mid-cingulate cortex and posterior cingulate cortex (n = 14, voxel-wise p < 0.005). In addition, a subgroup of patients tested with a probabilistic reward task (n = 9) showed increased reward learning following treatment. These findings highlight the KCNQ-type potassium channel as a promising target for future drug discovery efforts in mood disorders.

Lithium continuation therapy following ketamine in patients with treatment resistant unipolar depression: a randomized controlled trial.

The N-methyl-D-aspartate (NMDA) receptor antagonist ketamine is associated with rapid but transient antidepressant effects in patients with treatment resistant unipolar depression (TRD). Based on work suggesting that ketamine and lithium may share overlapping mechanisms of action, we tested lithium compared to placebo as a continuation strategy following ketamine in subjects with TRD. Participants who met all eligibility criteria and showed at least an initial partial response to a single intravenous infusion of ketamine 0.5 mg/kg were randomized under double-blind conditions to lithium or matching placebo before receiving an additional three infusions of ketamine. Subsequent to the ketamine treatments, participants remained on lithium or placebo during a double-blind continuation phase. The primary study outcome was depression severity as measured by the Montgomery-Åsberg Depression Rating Scale compared between the two groups at Study Day 28, which occurred ~2 weeks following the final ketamine of four infusions. Forty-seven participants with TRD were enrolled in the study and underwent an initial ketamine infusion, of whom 34 participants were deemed to have at least a partial antidepressant response and were eligible for randomization. Comparison between treatment with daily oral lithium (n = 18) or matching placebo (n = 16) at the primary outcome showed no difference in depression severity between groups (t32 = 0.11, p = 0.91, 95% CI [-7.87, 8.76]). There was no difference between lithium and placebo in continuing the acute antidepressant response to ketamine. The identification of a safe and effective strategy for preventing depression relapse following an acute course of ketamine treatment remains an important goal for future studies.

Ultra-high field MRI reveals mood-related circuit disturbances in depression: a comparison between 3-Tesla and 7-Tesla.

Ultra-high field 7-Tesla (7 T) MRI has the potential to advance our understanding of neuropsychiatric disorders, including major depressive disorder (MDD). To date, few studies have quantified the advantage of resting state functional MRI (fMRI) at 7 T compared to 3-Tesla (3 T). We conducted a series of experiments that demonstrate the improvement in temporal signal-to-noise ratio (TSNR) of a multi-echo multi-band fMRI protocol with ultra-high field 7 T MRI, compared to a similar protocol using 3 T MRI in healthy controls (HC). We also directly tested the enhancement in ultra-high field 7 T fMRI signal power by examining the ventral tegmental area (VTA), a small midbrain structure that is critical to the expected neuropathology of MDD but difficult to discern with standard 3 T MRI. We demonstrate up to 300% improvement in TSNR and resting state functional connectivity coefficients provided by ultra-high field 7 T fMRI compared to 3 T, indicating enhanced power for detection of functional neural architecture. A multi-echo based acquisition protocol and signal denoising pipeline afforded greater gain in signal power compared to classic acquisition and denoising pipelines. Furthermore, ultra-high field fMRI revealed mood-related neurocircuit disturbances in patients with MDD compared to HC, which were not detectable with 3 T fMRI. Ultra-high field 7 T fMRI may provide an effective tool for studying functional neural architecture relevant to MDD and other neuropsychiatric disorders.