Making Ketamine Work in the Long Run

Treatments such as ketamine psychotherapy face substantial financial and regulatory obstacles to dissemination into widespread use. Newly patented medications are able to generate enough capital to pay for studies required for FDA approval, personnel to apply for coverage on insurance plans, and marketing to establish a successful launch. Ketamine is an older drug with considerable evidence of efficacy for treatment resistant depression, and almost 50 years of data concerning safety as an anesthetic agent. However, it can no longer be patented, so there is no incentive for pharmaceutical companies to help get it into widespread use. In this paper we discuss some of the complex issues surrounding use of ketamine in the outpatient setting and share information and practice pearls that have been gathered through communication with other practitioners and through direct experience with over 1000 treatments involving 120 patients in the last eight years. The safety and appropriateness of intramuscular ketamine treatment in the outpatient psychiatric office is discussed. We hope to help proponents of effective mental health interventions navigate the actual and potential challenges involved in safe application of this treatment option outside of hospital-based programs

Ketamine treatment for individuals with treatment-resistant depression: a longitudinal qualitative interview study of patient experiences

Background Ketamine has recently received considerable attention regarding its antidepressant and anti-suicidal effects. Trials have generally focused on short-term effects of single intravenous infusions. Research on patient experiences is lacking. Aims To investigate the experiences over time of individuals receiving ketamine treatment in a routine clinic, including impacts on mood and suicidality. Method Twelve fee-paying patients with treatment-resistant depression (6 females, 6 males, age 21-70 years; 11 reporting suicidality and six self-harm) who were assessed as eligible for ketamine treatment participated in up to three semi-structured interviews: before treatment started, a few weeks into treatment and two or more months later. Data were analysed thematically. Results Most participants hoped that ketamine would provide respite from their depression. All experienced improvement in mood following initial treatments, ranging from negligible to dramatic, and eight a reduction in suicidality. Improvements were transitory for most participants, although two experienced sustained consistent benefit and two had sustained but limited improvement. Some participants described hopelessness when treatment stopped working, paralleled by increased suicidal ideation for three. The transient nature and cost of treatment were problematic. Eleven participants experienced side-effects, which in two cases were significant. Suggestions for improving treatment included closer monitoring and adjunctive psychological therapy. Conclusions Ketamine treatment was generally experienced as effective in improving mood and reducing suicidal ideation in the short-term, but the lack of longer-term benefit was challenging for participants, as was treatment cost. Informed consent procedures should refer to the possibilities of relapse and of associated increased hopelessness and suicidality

Therapeutic ketogenic diet as treatment for anorexia nervosa.

Anorexia nervosa (AN) is a severe psychiatric disorder. However, we lack neurobiological models and interventions to explain and treat the core characteristics of food restriction, feeling fat, and body size overestimation. Research has made progress in understanding brain function involved in the pathophysiology of AN, but translating those results into biological therapies has been challenging. Studies have suggested that metabolic factors could contribute to developing and maintaining AN pathophysiology. Here, we describe a neurobiological model for why using a therapeutic ketogenic diet could address key alterations in brain function in AN and prevent the desire for weight loss and associated eating disorder-specific symptoms. This translational model is based on animal studies and human data and integrates behavioral traits, brain neural energy metabolism, and neurotransmitter function. Pilot data indicate that the intervention can dramatically reduce eating and body-related fears, although larger studies across illness stages still need to be conducted

Phobic memory and somatic vulnerabilities in anorexia nervosa: a necessary unity?

Anorexia nervosa is a clinically significant illness that may be associated with permanent medical complications involving almost every organ system. The paper raises a question whether some of them are associated with premorbid vulnerability such as subcellular ion channel abnormalities ('channelopathy') that determines the clinical expression of the bodily response to self-imposed malnutrition. Aberrant channels emerge as a tempting, if rather speculative alternative to the notion of cognitively-driven neurotransmitter modulation deficit in anorexia nervosa. The concept of channelopathies is in keeping with some characteristics of anorexia nervosa, such as a genetically-based predisposition to hypophagia, early onset, cardiac abnormalities, an appetite-enhancing efficacy of some antiepileptic drugs, and others. The purpose of this article is to stimulate further basic research of ion channel biophysics in relation to restrictive anorexia

Using pharmacological reconsolidation-interference strategies to attenuate maladaptive appetitive memories

Under certain conditions memories can re-enter a transient, labile state in which they are susceptible to modification. ‘Reconsolidation’ thus describes the hypothetical process by which a reactivated memory is returned to a stable state. The current thesis will explore the potential of pharmacological reconsolidation-interference strategies in attenuating the maladaptive appetitive memories underlying alcohol dependence and binge eating disorder (BED). Chapter 1 presents an overview of the reconsolidation literature and its potential to treat disorders of maladaptive appetitive memory. In Chapter 2, a review and meta-analysis of the efficacy of treatments utilising behavioral and pharmacological reconsolidation strategies in clinical or sub-clinical populations is presented. In Chapter 3, the requirement for the inclusion of a prediction error (PE) at retrieval in a population of hazardous drinkers is assessed in a randomised, between subjects design (N=60). Although no effect of post-retrieval N2O (a predicted blocker of reconsolidation) was observed initially, exploratory analysis showed a memory-weakening effect only when administration occurred after cue-alcohol retrieval and PE. Chapter 4 presents a single blind, randomised, between subjects (N=90) study of the efficacy of the NMDA receptor antagonist ketamine. Relative to placebo and a no-reactivation group, ketamine produced significant reductions in drinking and putative measures of cue-alcohol memory strength. Chapter 5 explores the efficacy of rapamycin, a proven blocker of reconsolidation in pre-clinical models, to attenuate non-drug reward memory in a population with a tendency of overeat or binge on chocolate (N=75). No effect of rapamycin was observed, although this may represent the limited scope to see improvement in measures of disordered eating within this sample. Finally, Chapter 6 summaries and integrates the current findings into the existing literature. A discussion of the implications, limitations, and suggestions for future research on reconsolidation is given

Ketamine treatment for individuals with treatment-resistant depression: a longitudinal qualitative interview study of patient experiences

Background Ketamine has recently received considerable attention regarding its antidepressant and anti-suicidal effects. Trials have generally focused on short-term effects of single intravenous infusions. Research on patient experiences is lacking. Aims To investigate the experiences over time of individuals receiving ketamine treatment in a routine clinic, including impacts on mood and suicidality. Method Twelve fee-paying patients with treatment-resistant depression (6 females, 6 males, age 21-70 years; 11 reporting suicidality and six self-harm) who were assessed as eligible for ketamine treatment participated in up to three semi-structured interviews: before treatment started, a few weeks into treatment and two or more months later. Data were analysed thematically. Results Most participants hoped that ketamine would provide respite from their depression. All experienced improvement in mood following initial treatments, ranging from negligible to dramatic, and eight a reduction in suicidality. Improvements were transitory for most participants, although two experienced sustained consistent benefit and two had sustained but limited improvement. Some participants described hopelessness when treatment stopped working, paralleled by increased suicidal ideation for three. The transient nature and cost of treatment were problematic. Eleven participants experienced side-effects, which in two cases were significant. Suggestions for improving treatment included closer monitoring and adjunctive psychological therapy. Conclusions Ketamine treatment was generally experienced as effective in improving mood and reducing suicidal ideation in the short-term, but the lack of longer-term benefit was challenging for participants, as was treatment cost. Informed consent procedures should refer to the possibilities of relapse and of associated increased hopelessness and suicidality

Is this for real?:The role of advanced placebo technology when using Transcranial Magnetic Stimulation in clinical practice

This thesis offers a comprehensive exploration of repetitive Transcranial Magnetic Stimulation (rTMS) as a potential treatment avenue for neuropsychiatric disorders, encompassing depression, nicotine addiction, epilepsy, and Parkinson's disease. Through a double-blind randomized study, a retrospective study, and case reports, this research highlights rTMS' effectiveness, considering placebo effects and alternative therapies like ketamine treatment. Notably, a study on smoking cessation demonstrates aiTBS's efficacy in reducing cigarette consumption and cravings, while investigations into TRD (treatment-resistant depression) reveal comparable benefits between rTMS and IM ketamine treatments. Case reports on epilepsy and Parkinson's disease showcase positive outcomes, emphasizing potential rTMS benefits in persistent neurological conditions. Addressing safety concerns, the thesis stresses careful patient selection and monitoring during rTMS. This comprehensive work advances understanding, advocating for rTMS as a valuable neuropsychiatric treatment, though further research is required for broader applications and improved patient outcomes

Pituitary Adenylate Cyclase-Activation Polypeptide (PACAP) Regulates Feeding in the Rat Striatum and Hypothalamus

The following dissertation focuses on preclinical rodent feeding paradigms that were designed to examine the mechanisms by which the brain regulates caloric (homeostatic) and palatability (hedonic)-driven feeding. Taken together, my findings suggest differentially motivated feeding can, in part, signal through isolated non-overlapping mechanisms in the brain. Furthermore, some of these mechanisms occur in similar neurocircuits that have been implicated in other compulsive behaviors, such as drug abuse. In an effort to support the argument that binge eating disorder (BED) and substance abuse share similar behavioral and molecular targets, we first demonstrate that the development of BED in rodents is attenuated by both systemic and central administration of a cysteine pro-drug (N-acetylcysteine or NAC) which is a compound that targets the understudied glutamate system and is currently used to treat other disorders that have aspects of compulsion, such as trichotillomania or drug addiction (chapter II). Interestingly, NAC-induced hypophagia is specific to feeding stimulated by palatability as NAC did not produce any suppression of feeding in animals not maintained under a feeding paradigm that would produce binge behavior. In addition to studying differentially motivated feeding, a large component of this dissertation examines the mechanisms by which the neuropeptide pituitary adenylate cyclase-activating polypeptide (PACAP) regulates feeding in the ventromedial nucleus of the hypothalamus (VMN) as well as the nucleus accumbens (NAc). Our results indicate that PACAP microinjected into the VMN suppresses feeding elicited specifically by food deprivation, as PACAP did not effecting feeding elicited by palatability. Interestingly, in the nucleus accumbens, a brain region important for reward related activity, PACAP suppresses palatably-driven feeding in satiated rats, while not effecting feeding driven by food deprivation (chapter III). The opposing behavioral effects of PACAP on feeding propelled the lab to further investigate the mechanism by which PACAP was working in these two regions. In the VMN, we demonstrate that PACAP interacts with leptin signaling as acute blockade of PACAP receptors (PAC1R) in the VMN inhibits the behavioral and molecular actions of leptin (chapter IV). In the nucleus accumbens, PACAP attenuates hedonic drive in a site-specific manner and we identified PACAP mRNA expressing striatal afferents originating in the prefrontal cortex (chapter V), which is significant as obese individuals display hypoactive medial prefrontal cortex and stimulation of this area decreases calories consumed and body weight. Taken together, the opposing behavioral effects of PACAP emphasize an important point that a signaling mechanism in one brain region can be significantly different in another

Addictions

Addiction, increasingly perceived as a heterogeneous brain disorder, is one of the most peculiar psychiatric pathologies in that its management involves various, often non-overlapping, resources from the biological, psychological, medical, economical, social, and legal realms. Despite extensive efforts from the players of these various fields, to date there are no reliably effective treatments of addiction. This may stem from a lack of understanding of the etiology and pathophysiology of this disorder as well as from the lack of interest into the potential differences among patients in the way they interact compulsively with their drug. This book offers an overview of the psychobiology of addiction and its current management strategies from pharmacological, social, behavioural, and psychiatric points of view

Primate Ventromedial Prefrontal Cortex and the Physiological and Behavioural Dysfunction Characteristic of Mood and Anxiety Disorders

The heterogeneity intrinsic to the ventromedial prefrontal cortex (vmPFC) is evidenced in both its anatomy and implicated function: vmPFC subregions have roles in positive affect, negative affect and autonomic/endocrine regulation. Whether different subregions serve fundamentally different functions, or whether they perform similar computations on different inputs, remains unclear. Nevertheless, the role of the vmPFC in psychopathology is widely appreciated – in mood and anxiety disorders, over-activity within constituent regions of the vmPFC is consistently implicated in symptomatology, together with its normalisation following successful treatment. However, the precise locus of change varies between studies. The work presented in this thesis investigates the causal contributions of over-activity within two key subregions of the vmPFC – the subgenual anterior cingulate cortex (sgACC, area 25) and perigenual anterior cingulate cortex (pgACC, area 32) – in discrete dimensions of behaviour and physiology affected in psychiatric disorders. Specifically, the impact of over-activity is assessed on (i) baseline physiological function; (ii) the regulation of anticipatory, motivational and consummatory aspects of reward-related behaviour; and (iii) negative affect including fear learning, stress recovery and the intolerance of uncertainty. To provide further insight into the mechanism of action of antidepressants, the efficacy of selected treatments is tested on changes induced by over-activity of these regions. Beyond the direct relevance of the results presented here to psychiatric disorders and their treatment, the thesis aims to emphasise the importance of broader themes associated with the measurement and quantification of emotion in preclinical animal studies. First, a multi-faceted approach is utilised enabling quantification of both the autonomic and behavioural aspects of emotion. In so doing, the experiments maintain relevance to studies which assess these correlates in isolation, both in humans (which typically measure subjective responses and physiology) and in rodents (which frequently assess behaviour in isolation). The assessment of more than one dimension of emotion confers these studies with improved power to detect maladaptive changes. Second, the experiments described were conducted in the marmoset, a new-world primate. The extensive anatomical homology between marmoset and human prefrontal cortex facilitates the forward-translation of functional results. In combination with the appropriate assays, this renders marmosets as an invaluable species to study the causal contributions of vmPFC subregions to symptoms of psychiatric disorders. I believe that the results of these experiments provide important insights into the causal role primate vmPFC has in relation to the behavioural and physiological aspects of psychiatric symptomatology. Most importantly, I hope that they serve as the foundation for future work to further elucidate the neuropathological processes underlying mental disorders.MRC DTP Studentshi