The underlying brain mechanisms of ketamine in treating chronic suicidality and the characteristics of patients who will benefit from ketamine treatment remain unclear. To address these gaps, we investigated temporal variations of brain functional synchronisation in patients with suicidality treated with ketamine in a 6-week open-label oral ketamine trial. The trial’s primary endpoint was the Beck Scale for Suicide Ideation (BSS). Patients who experienced greater than 50

Oral ketamine has shown to be a rapid-acting antidepressant and a potential treatment option for suicidality, however, repeated doses are often required. Objective markers of prolonged treatment response are needed to help individuals and clinicians make informed treatment decisions. This secondary analysis sought to identify objective electrophysiological predictors of both prolonged response and dose sensitivity to low-dose oral ketamine in people with chronic suicidality. Individuals with a Beck Scale for Suicide Ideation total score (BSS) >= 6 (N = 29) completed a six-week ketamine treatment, pre-treatment electroencephalography and follow-up assessment of suicidality (four weeks from the final ketamine dose). Prolonged response was observed in 52% of participants (follow-up BSS reduced by 50% or <= 6); nearly half were prolonged non-responders. There was decisive evidence for a predictive Bayesian linear regression model with follow-up BSS score as the response variable and pre-treatment auditory evoked power bands as predictors (theta, alpha and beta frequencies, BF10 = 17,948, R2 = 0.70). A Bayesian one-way ANOVA indicated strong evidence for a model of positive association between auditory evoked power and ketamine dose sensitivity (theta-alpha BF+0 = 108, effect size delta = 1.3, 95% CI 0.5-2.1; high-beta BF+0 = 7.4, delta = 0.8, 95% CI 0.1-1.6). Given auditory evoked power may index serotonin neurotransmission, these results suggest that a prolonged response to ketamine may, in part, be mediated by pretreatment serotonergic functioning. In addition, the observed beta power differences may arise from GABAergic functioning. These suicidality phenotypes, identifiable by pre-treatment electrophysiology, may aid diagnosis, treatment selection and prediction of prolonged treatment outcome.

Suicidality is a prevalent mental health condition, and managing suicidal patients is one of the most challenging tasks for health care professionals due to the lack of rapid-acting, effective psychopharmacological treatment options. According to the literature, suicide has neurobiological underpinnings that are not fully understood, and current treatments for suicidal tendencies have considerable limitations. To treat suicidality and prevent suicide, new treatments are required; to achieve this, the neurobiological processes underlying suicidal behavior must be thoroughly investigated. Although multiple neurotransmitter systems, particularly serotonergic systems, have been studied in the past, less has been reported in relation to disruptions in glutamatergic neurotransmission, neuronal plasticity, and neurogenesis that result from stress-related abnormalities of the hypothalamic-pituitary-adrenal system. Informed by the literature, which reports robust antisuicidal and antidepressive properties of subanaesthetic doses of ketamine, this review aims to provide an examination of the neurobiology of suicidality (and relevant mood disorders) with implications of pertinent animal, clinical, and postmortem studies. We discuss dysfunctions in the glutamatergic system, which may play a role in the neuropathology of suicidality and the role of ketamine in restoring synaptic connectivity at the molecular levels.

Anorexia nervosa is a disorder associated with serious adverse health outcomes, for which there is currently considerable treatment ineffectiveness. Characterised by restrictive eating behaviours, distorted body image perceptions and excessive physical activity, there is growing recognition anorexia nervosa is associated with underlying dysfunction in excitatory and inhibitory neurometabolite metabolism and signalling. This narrative review critically explores the role of N-methyl-d-aspartate receptor-mediated excitatory and inhibitory neurometabolite dysfunction in anorexia nervosa and its associated biomarkers. The existing magnetic resonance spectroscopy literature in anorexia nervosa is reviewed and we outline the brain region-specific neurometabolite changes that have been reported and their connection to anorexia nervosa psychopathology. Considering the proposed role of dysfunctional neurotransmission in anorexia nervosa, the potential utility of zinc supplementation and sub-anaesthetic doses of ketamine in normalising this is discussed with reference to previous research in anorexia nervosa and other neuropsychiatric conditions. The rationale for future research to investigate the combined use of low-dose ketamine and zinc supplementation to potentially extend the therapeutic benefits in anorexia nervosa is subsequently explored and promising biological markers for assessing and potentially predicting treatment response are outlined.

Chronic suicidality has been associated with neuronal atrophy in cortico-striato-limbic regions and is thought to be mediated via a glutamatergic imbalance. Ketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist, has been posited to exert anti-suicidal effects by promoting neurogenesis via modulation of glutamatergic transmission. This voxel-based morphometry study examined the effect of ketamine on whole brain grey matter in adults with chronic suicidality. Grey matter in the periaqueductal grey, nucleus accumbens, putamen, caudate, and thalamus was significantly increased following 6 weeks of low dose oral ketamine treatment. These results support the notion that ketamine rapidly enhances synaptic plasticity within striato-limbic regions.

The blood oxygen level-dependent (BOLD) functional magnetic resonance imaging signal arises as a consequence of changes in blood flow and oxygen usage that in turn are modulated by changes in neural activity. Much attention has been given to both theoretical and experimental aspects of the energetics but not to the neural activity. Here we identify the best energetic theory for the steady-state BOLD signal on the basis of correct predictions of experimental observations. This theory is then used, together with the recently determined relationship between energetics and neural activity, to predict how the BOLD signal changes with activity. Unlike existing treatments, this new theory incorporates a nonzero baseline activity in a completely consistent way and is thus able to account for both sustained positive and negative BOLD signals. We also show that the increase in BOLD signal for a given increase in activity is significantly smaller the larger the baseline activity, as is experimentally observed. Furthermore, the decline of the positive BOLD signal arising from deeper cortical laminae in response to an increase in neural firing is shown to arise as a consequence of the larger baseline activity in deeper laminae. Finally, we provide quantitative relations integrating BOLD responses, energetics, and impulse firing, which among other predictions give the same results as existing theories when the baseline activity is zero. NEW & NOTEWORTHY We use a recently established relation between energetics and neural activity to give a quantitative account of BOLD dependence on neural activity. The incorporation of a nonzero baseline neural activity accounts for positive and negative BOLD signals, shows that changes in neural activity give BOLD changes that are smaller the larger the baseline, and provides a basis for the observed inverse relation between BOLD responses and the depth of cortical laminae giving rise to them.