Benjamin Kelmendi

Overview of glutamatergic neurotransmission in the nervous system

This introductory article to the special edition on glutamate neurotransmission in neuropsychiatric disorders provides an overview of glutamate neurotransmitter system physiology and pharmacology. Glutamate was only relatively recently recognized as the major excitatory neurotransmitter in the mammalian brain, in part due to its ubiquitous nature and diverse metabolic roles within the CNS. The extremely high concentration of glutamate in brain tissue paired with its excitotoxic potential requires tight physiological regulation of extracellular glutamate levels and receptor signaling in order to assure optimal excitatory neurotransmission but limits excitotoxic damage. In order to achieve this high level of control, the system has developed a complex physiology with multiple regulatory processes modulating glutamate metabolism, release, receptor signaling, and uptake. The basic physiology of the various regulatory components of the system including the rich receptor pharmacology is briefly reviewed. Potential contributions from each of the systems components to the pathophysiology of neuropsychiatric illnesses are briefly discussed, as are the many new pharmacological targets for drug development provided by the system, especially as they pertain to the proceeding preclinical and clinical articles in this issue.

PTSD: from neurobiology to pharmacological treatments

Posttraumatic stress disorder (PTSD) is a chronic debilitating psychiatric disorder characterized by symptoms of re-experience, avoidance, and hyperarousal that can arise immediately or many years after exposure to a traumatic event and injury. Although extensive research has been done over the past 30 years, the etiology of PTSD remains largely unknown. Several neurobiological systems have been implicated in the pathophysiology and vulnerability for developing PTSD; however, first-line pharmacotherapies are limited. Less than 30% achieve full remission, and even then, approved pharmacological treatments often take weeks for therapeutic effect. This article aims to review the pathophysiology of PTSD within multiple neurobiological systems and how these mechanisms are used as pharmacologic targets of treatment, as well as their potential for future targets of intervention. Highlights of the article We reviewed the neurobiological abnormalities in PTSD as they relate to well-established, preliminary, and future targets for pharmacological interventions. Abnormalities across different neurotransmitter systems have been implicated in the pathophysiology of PTSD but none of these systems function uniformly among all patients with PTSD First-line pharmacotherapy for PTSD provides a suboptimal response rates. Future pharmacological targets for PTSD include the cannabinoid and oxytocin systems, as well glutamatergic modulating agents. Drug development for PTSD should specifically address various dimensions of PTSD symptomatology.

Association of polymorphisms in HCN4 with mood disorders and obsessive compulsive disorder.

Hyperpolarization activated cyclic nucleotide-gated (HCN) potassium channels are implicated in the control of neuronal excitability and are expressed widely in the brain. HCN4 is expressed in brain regions relevant to mood and anxiety disorders including specific thalamic nuclei, the basolateral amygdala, and the midbrain dopamine system. We therefore examined the association of HCN4 with a group of mood and anxiety disorders. We genotyped nine tag SNPs in the HCN4 gene using Sequenom iPLEX Gold technology in 285 Caucasian patients with DSM-IV mood disorders and/or obsessive compulsive disorder and 384 Caucasian controls. HCN4 polymorphisms were analyzed using single marker and haplotype-based association methods. Three SNPs showed nominal association in our population (rs12905211, rs3859014, rs498005). SNP rs12905211 maintained significance after Bonferroni correction, with allele T and haplotype CTC overrepresented in cases. These findings suggest HCN4 as a genetic susceptibility factor for mood and anxiety disorders; however, these results will require replication using a larger sample.

Synaptic Loss and the Pathophysiology of PTSD: Implications for Ketamine as a Prototype Novel Therapeutic

Purpose of ReviewStudies of the neurobiology and treatment of PTSD have highlighted many aspects of the pathophysiology of this disorder that might be relevant to treatment. The purpose of this review is to highlight the potential clinical importance of an often-neglected consequence of stress models in animals that may be relevant to PTSD: the stress-related loss of synaptic connectivity.Recent FindingsHere, we will briefly review evidence that PTSD might be a “synaptic disconnection syndrome” and highlight the importance of this perspective for the emerging therapeutic application of ketamine as a potential rapid-acting treatment for this disorder that may work, in part, by restoring synaptic connectivity.SummarySynaptic disconnection may contribute to the profile of PTSD symptoms that may be targeted by novel pharmacotherapeutics.

Posttraumatic Stress Disorder: An Integrated Overview of the Neurobiological Rationale for Pharmacology

Thirty years of research on the biology of posttraumatic stress disorder now provides a foundation for hypotheses related to the mechanisms underlying the pharmacotherapy of this disorder. Only two medications, sertraline and paroxetine, are approved by the U.S. Food and Drug Administration for the treatment of PTSD. While these medications are somewhat effective, other treatment mechanisms must be explored to address the unmet need for effective treatment. This article provides a concise summary of advances in our understanding of the neurobiology of PTSD that suggest novel approaches to pharmacotherapy.

Toward understanding the heterogeneity in obsessive-compulsive disorder: Evidence from narratives in adult patients

Background: Current attempts at understanding the heterogeneity in obsessive-compulsive disorder have relied on quantitative methods. The results of such work point toward a dimensional structure for obsessive-compulsive disorder. Existing qualitative work in obsessive-compulsive disorder has focused on understanding specific aspects of the obsessive-compulsive disorder experience in greater depth. However, qualitative methods are also of potential value in furthering our understanding of obsessive-compulsive disorder heterogeneity by allowing for open-ended exploration of the obsessive-compulsive disorder experience and correlating identified subtypes with patient narratives. Objective: We explored variations in patients’ experience prior to, during and immediately after performing their compulsions. Method: Semi-structured interviews were conducted with 20 adults with obsessive-compulsive disorder, followed by inductive thematic analysis. Participant responses were not analyzed within the context of an existing theoretical framework, and themes were labeled descriptively. Results: The previous dichotomy of ‘anxiety’ vs ‘incompleteness’ emerged organically during narrative analysis. In addition, we found that some individuals with obsessive-compulsive disorder utilized their behaviors as a way to cope with stress and anxiety more generally. Other participants did not share this experience and denied finding any comfort in their obsessive-compulsive behaviors. The consequences of attentional difficulties were highlighted, with some participants describing how difficulty focusing on a task could influence the need for it to be repeated multiple times. Conclusions: The extent to which patients use obsessive-compulsive disorder as a coping mechanism is a relevant distinction with potential implications for treatment engagement. Patients may experience ambivalence about suppressing behaviors that they have come to rely upon for management of stress and anxiety, even if these behaviors represent symptoms of a psychiatric illness.

The role of psychedelics in palliative care reconsidered: A case for psilocybin

Psychiatric research with classic hallucinogens has enjoyed a resurgence of late. While studies performed in the late 1960s and early 1970s with lysergic acid diethylamide (LSD) and psilocybin demonstrated therapeutic promise by producing a rapid and sustained reduction in anxiety, improvement in mood, and enhanced quality of life in patients with terminal cancer (Grof, 1973), a fuller exploration of their use in palliative medicine was curtailed by the establishment of a strict federal regulatory environment. Now, after decades of research inactivity, the potential of psychedelics to alleviate the distress associated with a terminal illness has been significantly advanced by the results of two recent studies investigating the efficacy of psilocybin in the treatment of anxiety and depression in patients with life-threatening cancer. Using double-blind, placebo-controlled, crossover designs, the studies conducted at Johns Hopkins University (JHU) and New York University (NYU) were methodologically rigorous and broad in the scope of their outcome variables. Both studies demonstrated that a single-dose of psilocybin can produce both an acute and enduring reduction in depression symptoms, anxiety, and existential distress in patients with lifethreatening cancer. That the studies replicated one another is a source of confidence in their findings. However, there were also informative differences between the studies. The group at JHU led by Griffiths et al. investigated the effects of a very low dose (1–3 mg/70 kg, placebo-like) versus high dose (22 mg/70 kg) of psilocybin administered five weeks apart in 51 patients diagnosed with lifethreatening cancer and suffering with symptoms of depression and/or anxiety (Griffiths et al., 2016). The group at NYU led by Ross et al. compared the effect of high-dose psilocybin (0.3 mg/ kg, ~21 mg/ 70 kg) with niacin (used as an “active” control) in 29 patients, and both groups received targeted psychotherapy (Ross et al., 2016). All patients were screened and prepared for the study intervention through several meetings with staff who established rapport and provided an understanding of the range of altered states of consciousness that might be encountered during their treatment sessions. The psilocybin experience was well tolerated by all patients, and there were no serious medical or psychological adverse events. Both studies evaluated a broad range of outcome measures, including the common measures of anxiety and depression, as well as quality of life, spirituality, and mystical experiences. In the Griffiths et al. trial, high-dose psilocybin produced large and sustained decreases in clinicianand patient-rated measures of depressed mood and anxiety, along with increases in quality of life, life meaning and optimism, and decreases in anxiety related to death. In the NYU trial, psilocybin produced rapid, substantial, and enduring reductions in cancer-related anxiety and depression, improved quality of life, increased spiritual well-being, and improved measures of existential distress, and was associated with improved attitudes toward death. At follow-up at six-and-ahalf months, the initial robust clinical effects observed after the administration of a single dose of psilocybin endured in 60–80% of the patients, and when patients were asked (six-and-a-half months post drug administration) to reflect on what they thought of their psilocybin session, 52% and 70% rated the psilocybin experience as the singular or top 5 most spiritually significant, or the singular or top 5 most personally meaningful experience of their entire lives, respectively, while 87% reported increased lifesatisfaction or well-being attributed to the experience (Ross et al., 2016). The findings that single-dose psilocybin can produce acute and sustained improvements in cancer-related anxiety and depression is perhaps the most important and novel finding of the two studies, and add to and extend the findings of a similarly designed trial in patients with terminal cancer where a single low dose (0.2 mg/kg) of psilocybin showed non-significant trends for benefit compared with placebo (Grob et al., 2011). In both studies, mediation analysis indicates that the mystical experience was a significant mediator of the effects of psilocybin dose on therapeutic outcomes. Mystical experience is defined as encountering a profound sense of unity, transcendence of time and space, deeply felt positive mood, noetic quality (sense of understanding), ineffability, transiency, and paradoxicality infused with a renewed sense of purpose and meaning (Griffiths, 2006, 2008, 2011; Grob et al., 2013). Further evidence for the The role of psychedelics in palliative care reconsidered: A case for psilocybin

Stress Response Modulation Underlying the Psychobiology of Resilience

Purpose of ReviewThis review focuses on the relationship between resilience and the ability to effectively modulate the stress response. Neurobiological and behavioral responses to stress are highly variable. Exposure to a similar stressor can lead to heterogeneous outcomes—manifesting psychopathology in one individual, but having minimal effect, or even enhancing resilience, in another. We highlight aspects of stress response modulation related to early life development and epigenetics, selected neurobiological and neurochemical systems, and a number of emotional, cognitive, psychosocial, and behavioral factors important in resilience. We also briefly discuss interventions with potential to build and promote resilience.Recent FindingsThroughout this review, we include evidence from recent preclinical and clinical studies relevant to the psychobiology of resilient stress response modulation.SummaryEffective modulation of the stress response is an essential component of resilience and is dependent on a complex interplay of neurobiological and behavioral factors.

The Role of Stress in the Pathogenesis and Maintenance of Obsessive-Compulsive Disorder:

Individuals with obsessive-compulsive disorder often identify psychosocial stress as a factor that exacerbates their symptoms, and many trace the onset of symptoms to a stressful period of life or a discrete traumatic incident. However, the pathophysiological relationship between stress and obsessive-compulsive disorder remains poorly characterized: it is unclear whether trauma or stress is an independent cause of obsessive-compulsive disorder symptoms, a triggering factor that interacts with a preexisting diathesis, or simply a nonspecific factor that can exacerbate obsessive-compulsive disorder along with other aspects of psychiatric symptomatology. Nonetheless, preclinical research has demonstrated that stress has conspicuous effects on corticostriatal and limbic circuitry. Specifically, stress can lead to neuronal atrophy in frontal cortices (particularly the medial prefrontal cortex), the dorsomedial striatum (caudate), and the hippocampus. Stress can also result in neuronal hypertrophy in the dorsolateral striatum (putamen) and amygdala. These neurobiological effects mirror reported neural abnormalities in obsessive-compulsive disorder and may contribute to an imbalance between goal-directed and habitual behavior, an imbalance that is implicated in the pathogenesis and expression of obsessive-compulsive disorder symptomatology. The modulation of corticostriatal and limbic circuits by stress and the resultant imbalance between habit and goal-directed learning and behavior offers a framework for investigating how stress may exacerbate or trigger obsessive-compulsive disorder symptomatology.