Despite decades of research, the rate of death from suicide is rising in the United States. Suicide is a complex and multifactorial phenomenon and, to date, no validated biomarkers that predict ...suicidal behavior have been identified. Only one FDA-approved drug to prevent suicide exists, and it is approved only for patients with schizophrenia. Although anti-suicide psychotherapeutic techniques exist, treatment takes time, and only preliminary data exist for rapid-acting therapies.
While more research into suicidal ideation and acute suicidal behavior is clearly needed, this research is fraught with both practical and ethical concerns. As a result, many investigators and bioethicists have called for restrictions on the types of research that individuals with suicidal behavior can participate in, despite the fact that the available empirical evidence suggests that this research can be done safely. This manuscript presents background information on the phenomenology of suicide, discusses the current state of treatment and prevention strategies, and reviews the practical and ethical issues surrounding suicide research in the context of available empirical data. Currently, the causes of suicide are poorly understood, in part due to the fact that very few studies have investigated the acute suicidal crisis. Although some biomarkers for predicting risk have been developed, none have been sufficiently validated. The most successful current interventions involve means restriction. However, while numerous hurdles face researchers, these are not insurmountable. The available evidence suggests that research into suicide can be conducted both safely and ethically.
Background Increased activity of the habenula has been implicated in the etiology of major depressive disorder (MDD), in which reductions in habenula volume are present after death. We conducted the ...first magnetic resonance imaging analysis of habenula volume in MDD and bipolar disorder (BD). Methods High-resolution images (resolution approximately .4 mm3 ) were acquired with a 3T scanner, and a pulse sequence was optimized for tissue contrast resolution. The habenula was manually segmented by one rater blind to diagnosis. Seventy-four healthy control subjects (HC) were compared with both medicated (lithium/divalproex, n = 15) and unmedicated, depressed BD ( n = 22) patients; unmedicated, depressed MDD patients ( n = 28); and unmedicated MDD patients in remission ( n = 32). Results The unmedicated BD patients displayed significantly smaller absolute ( p < .01) and normalized ( p < .05) habenula volumes than the HC subjects. In post hoc assessments analyzing men and women separately, the currently-depressed women with MDD had smaller absolute ( p < .05) habenula volumes than the HC women. None of the other psychiatric groups differed significantly from the HC group. Conclusions We provide further evidence for the involvement of the habenula in affective illness but suggest that a reduction in volume might be more pronounced in unmedicated, depressed BD subjects and female currently depressed MDD subjects. The habenula plays major roles in the long-term modification of monoamine transmission and behavioral responses to stress and in the suppression of dopamine cell activity after the absence of an expected reward. A reduction in habenula volume might thus have functional consequences that contribute to the risk for developing affective disease.
Current pharmacotherapies for major depressive disorder (MDD) have a
distinct lag of onset that can prolong distress and impairment for patients, and realworld
effectiveness trials further suggest ...that antidepressant efficacy is limited in
many patients. All currently approved antidepressant medications for MDD act
primarily through monoaminergic mechanisms, e.g., receptor/reuptake agonists or
antagonists with varying affinities for serotonin, norepinephrine, or dopamine.
Glutamate is the major excitatory neurotransmitter in the central nervous system, and
glutamate and its cognate receptors are implicated in the pathophysiology of MDD,
as well as in the development of novel therapeutics for this disorder. Since the rapid
and robust antidepressant effects of the N-methyl-D-aspartate (NMDA) antagonist
ketamine were first observed in 2000, other NMDA receptor antagonists have been studied in MDD.
These have been associated with relatively modest antidepressant effects compared to ketamine, but some
have shown more favorable characteristics with increased potential in clinical practice (for instance, oral
administration, decreased dissociative and/or psychotomimetic effects, and reduced abuse/diversion
liability). This article reviews the clinical evidence supporting the use of glutamate receptor modulators
with direct affinity for cognate receptors: 1) non-competitive NMDA receptor antagonists (ketamine,
memantine, dextromethorphan, AZD6765); 2) subunit (NR2B)-specific NMDA receptor antagonists (CP-
101,606/traxoprodil, MK-0657); 3) NMDA receptor glycine-site partial agonists (D-cycloserine, GLYX-
13); and 4) metabotropic glutamate receptor (mGluR) modulators (AZD2066, RO4917523/basimglurant).
Several other theoretical glutamate receptor targets with preclinical antidepressant-like efficacy, but that
have yet to be studied clinically, are also briefly discussed; these include ?-amino-3-hydroxyl-5-methyl-4-
isoxazoleproprionic acid (AMPA) agonists, mGluR2/3 negative allosteric modulators, and mGluR7 agonists.
Major depressive disorder (MDD) is highly prevalent and associated with considerable morbidity, yet its pathophysiology remains only partially understood. While numerous studies have investigated the ...neurobiological correlates of MDD, most have used only a single neuroimaging modality. In particular, diffusion tensor imaging (DTI) studies have failed to yield uniform results. In this context, examining key tracts and using information from multiple neuroimaging modalities may better characterize potential abnormalities in the MDD brain. This study analyzed data from 30 participants with MDD and 26 healthy participants who underwent DTI, magnetic resonance spectroscopy (MRS), resting‐state functional magnetic resonance imaging (fMRI), and magnetoencephalography (MEG). Tracts connecting the subgenual anterior cingulate cortex (sgACC) and the left and right amygdala, as well as connections to the left and right hippocampus and thalamus, were examined as target areas. Reduced fractional anisotropy (FA) was observed in the studied tracts. Significant differences in the correlation between medial prefrontal glutamate concentrations and FA were also observed between MDD and healthy participants along tracts connecting the sgACC and right amygdala; healthy participants exhibited a strong correlation but MDD participants showed no such relationship. In the same tract, a correlation was observed between FA and subsequent antidepressant response to ketamine infusion in MDD participants. Exploratory models also suggested group differences in the relationship between DTI, fMRI, and MEG measures. This study is the first to combine MRS, DTI, fMRI, and MEG data to obtain multimodal indices of MDD and antidepressant response and may lay the foundation for similar future analyses.
•Healthy and depressed subjects received tactile stimulation during MEG recording.•Subjects went on to receive infusions of 0.5mg/kg IV ketamine and placebo.•MEG recordings were repeated after both ...infusions.•Only patients who responded to ketamine demonstrated synaptic potentiation.•The study replicates earlier findings that ketamine may induce plasticity.
Preclinical and clinical evidence has demonstrated that ketamine has rapid antidepressant effects. Studies using pre-treatment with an AMPA inhibitor suggest that enhancing AMPA throughput is crucial to ketamine's effects, including increases in both basal and evoked gamma power. This study sought to replicate previous findings of increased gamma response to a somatosensory stimulus at 230 min and Day 1 in ketamine responders versus non-responders in 31 depressed subjects and 25 healthy controls. A significant difference in peak gamma power was seen in the depressed ketamine responders versus non-responders. These results implicate AMPA throughput in ketamine's mechanism of antidepressant action.
Background Multiple lines of evidence support a role for the glutamatergic system in the pathophysiology of major depressive disorder (MDD). Ketamine, an N -methyl-D-aspartate antagonist, rapidly ...improves depressive symptoms in individuals with treatment-resistant depression. The neural mechanisms underlying this effect remain unknown. Methods In this preliminary study, 20 unmedicated participants with treatment-resistant MDD underwent positron emission tomography to measure regional cerebral glucose metabolism at baseline and following ketamine infusion (single dose of .5 mg/kg intravenous over 40 minutes). Metabolic data were compared between conditions using a combination of region-of-interest and voxelwise analyses, and differences were correlated with the associated antidepressant response. Results Whole-brain metabolism did not change significantly following ketamine. Regional metabolism decreased significantly under ketamine in the habenula, insula, and ventrolateral and dorsolateral prefrontal cortices of the right hemisphere. Metabolism increased postketamine in bilateral occipital, right sensorimotor, left parahippocampal, and left inferior parietal cortices. Improvement in depression ratings correlated directly with change in metabolism in right superior and middle temporal gyri. Conversely, clinical improvement correlated inversely with metabolic changes in right parahippocampal gyrus and temporoparietal cortex. Conclusions Although preliminary, these results indicate that treatment-resistant MDD subjects showed decreased metabolism in the right habenula and the extended medial and orbital prefrontal networks in association with rapid antidepressant response to ketamine. Conversely, metabolism increased in sensory association cortices, conceivably related to the illusory phenomena sometimes experienced with ketamine. Further studies are needed to elucidate how these functional anatomical changes relate to the molecular mechanisms underlying ketamine’s rapid antidepressant effects.
Functional magnetic resonance imaging (fMRI) studies have revealed the existence of robust, interconnected brain networks exhibiting correlated low frequency fluctuations during rest, which can be ...derived by examining inherent spatio-temporal patterns in functional scans independent of any a priori model. In order to explore the electrophysiological underpinnings of these networks, analogous techniques have recently been applied to magnetoencephalography (MEG) data, revealing similar networks that exhibit correlated low frequency fluctuations in the power envelope of beta band (14–30Hz) power. However, studies to date using this technique have concentrated on healthy subjects, and no method has yet been presented for group comparisons. We extended the ICA resting state MEG method to enable group comparisons, and demonstrate the technique in a sample of subjects with major depressive disorder (MDD). We found that the intrinsic resting state networks evident in fMRI appeared to be disrupted in individuals with MDD compared to healthy participants, particularly in the subgenual cingulate, although the electrophysiological correlates of this are unknown. Networks extracted from a combined group of healthy and MDD participants were examined for differences between groups. Individuals with MDD showed reduced correlations between the subgenual anterior cingulate (sgACC) and hippocampus in a network with primary nodes in the precentral and middle frontal gyri. Individuals with MDD also showed increased correlations between insulo-temporal nodes and amygdala compared to healthy controls. To further support our methods and findings, we present test/re-test reliability on independent recordings acquired within the same session. Our results demonstrate that group analyses are possible with the resting state MEG-independent component analysis (ICA) technique, highlighting a new pathway for analysis and discovery. This study also provides the first evidence of altered sgACC connectivity with a motor network. This finding, reliable across multiple sessions, suggests that the sgACC may partially mediate the psychomotor symptoms of MDD via synchronized changes in beta-band power, and expands the idea of the sgACC as a hub region mediating cognitive and emotional symptomatic domains in MDD. Findings of increased connectivity between the amygdala and cortical nodes further support the role of amygdalar networks in mediated depressive symptomatology.
NCT00024635 (ZIA-MH002927-04)
•A model-free Independent Component Analysis was used to extract networks.•A methodology for determining group differences was formulated and applied to MDD.•MDD patients had decreased connectivity between motor cortex and subgenual cingulate.•Increased connectivity was seen between unilateral temporal ICs & bilateral amygdala.
The glutamatergic modulator ketamine rapidly reduces depressive symptoms in individuals with treatment-resistant major depressive disorder (TRD) and bipolar disorder. While its underlying mechanism ...of antidepressant action is not fully understood, modulating glutamatergically-mediated connectivity appears to be a critical component moderating antidepressant response. This double-blind, crossover, placebo-controlled study analyzed data from 19 drug-free individuals with TRD and 15 healthy volunteers who received a single intravenous infusion of ketamine hydrochloride (0.5 mg/kg) as well as an intravenous infusion of saline placebo. Magnetoencephalographic recordings were collected prior to the first infusion and 6-9 h after both drug and placebo infusions. During scanning, participants completed an attentional dot probe task that included emotional faces. Antidepressant response was measured across time points using the Montgomery-Asberg Depression Rating Scale (MADRS). Dynamic causal modeling (DCM) was used to measure changes in parameter estimates of connectivity
a biophysical model that included realistic local neuronal architecture and receptor channel signaling, modeling connectivity between the early visual cortex, fusiform cortex, amygdala, and inferior frontal gyrus. Clinically, ketamine administration significantly reduced depressive symptoms in TRD participants. Within the model, ketamine administration led to faster gamma aminobutyric acid (GABA) and N-methyl-D-aspartate (NMDA) transmission in the early visual cortex, faster NMDA transmission in the fusiform cortex, and slower NMDA transmission in the amygdala. Ketamine administration also led to direct and indirect changes in local inhibition in the early visual cortex and inferior frontal gyrus and to indirect increases in cortical excitability within the amygdala. Finally, reductions in depressive symptoms in TRD participants post-ketamine were associated with faster α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) transmission and increases in gain control of spiny stellate cells in the early visual cortex. These findings provide additional support for the GABA and NMDA inhibition and disinhibition hypotheses of depression and support the role of AMPA throughput in ketamine's antidepressant effects.
https://clinicaltrials.gov/ct2/show/NCT00088699?term=NCT00088699&draw=2&rank=1, identifier NCT00088699.
This study examined magnetoencephalographic (MEG) correlates of suicidal ideation (SI) and suicide attempt history in patients with treatment-resistant major depression (TRD) at baseline and ...following subanesthetic-dose ketamine infusion.
Twenty-nine drug-free TRD patients (12 suicide attempters/17 non-attempters) participated in a crossover randomized trial of ketamine. MEG data were collected during an attentional dot probe task with emotional face stimuli at baseline and several hours post-ketamine infusion. Synthetic aperture magnetometry was used to project source power in the theta, alpha, beta, and gamma frequencies for angry-neutral, happy-neutral, and neutral-neutral face pairings during a one-second peristimulus period. Mixed models were used to test for clinical, behavioral, and electrophysiological effects of group, emotion, session, and SI score.
Ketamine significantly reduced SI and depression across the sample. Post-ketamine, attempters had improved accuracy and non-attempters had reduced accuracy on the task. SI was positively associated with gamma power in regions of the frontal and parietal cortices across groups. In an extended amygdala-hippocampal region, attempters differed significantly in their emotional reactivity to angry versus happy faces as indexed by theta power differences, irrespective of drug. Ketamine significantly reduced the association between alpha power and SI for angry compared with happy faces in a fronto-insular/anterior cingulate region important for regulating sensory attentiveness.
Limitations include a small sample size of attempters.
The findings highlight key differences in band-limited power between attempters and non-attempters and reinforce previous findings that ketamine has distinct response properties in patients with a suicide history.
•Ketamine improved dot probe performance for patients with suicide attempt history.•Theta power differences were found in amygdala-hippocampal network for attempters.•Ketamine altered alpha power-ideation score associations in insula and cingulate.•Findings highlight changes in band-limited power between attempters/non-attempers.
Music and ketamine are both known to affect therapeutic outcomes, but few studies have investigated their co-administration. This scoping review describes the existing literature on the joint use of ...music and ketamine—or esketamine (the S(+) enantiomer of ketamine)—in humans. The review considers that extant studies have explored the intersection of ketamine/esketamine and music in healthy volunteers and in patients of various age groups, at different dosages, through different treatment processes, and have varied the sequence of playing music relative to ketamine/esketamine administration. Studies investigating the use of music during ketamine anesthesia are also included in the review because anesthesia and sedation were the early drivers of ketamine use. Studies pertaining to recreational ketamine use were omitted. The review was limited to articles published in the English language but not restricted by publication year. To the best of our knowledge, this scoping review is the first comprehensive exploration of the interplay between music and ketamine/esketamine and offers valuable insights to researchers interested in designing future studies.
•The co-administration of music and ketamine has rarely been explored.•With ketamine alone, music reduces dissociation and anxiety and boosts tolerability.•In combination drug studies, music promotes relaxation and reduces sedative load.•Patient-specific factors influence how music impacts response to ketamine.
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