Purpose of Review: Chronic pain continues to be one of the leading healthcare cost burdens in the United States and is typically defined as ongoing pain, lasting longer than six months. Various treatment options exist for chronic pain, including physical therapy, medical management, pain psychology, and interventional therapies. Pain medications have been the mainstay of treatment for chronic pain conditions with an increasing use of membrane stabilizers and antidepressants to treat neuropathic pain conditions. Specifically, serotonin noradrenaline reuptake inhibitors (SNRIs) have been used to treat a range of pain conditions expanding from everyday use for depressive disorders. Recent Findings: SNRIs, including duloxetine, venlafaxine, and milnacipran, have demonstrated efficacy in reducing pain in musculoskeletal pain (chronic low back pain and osteoarthritis), fibromyalgia, and neuropathic pain conditions (peripheral diabetic neuropathy). Summary: The article describes the function, role, and use of SNRIs to treat chronic and neuropathic pain by altering the noradrenergic descending inhibitory pathways.

Background: Chronic pain affects a significant proportion of the population in the United States and poses a significant public health concern. Beyond physical discomfort, chronic pain has been increasingly linked to cognitive dysfunction, including impairments in memory, attention, executive function, and decision-making. The relationship is particularly pronounced in older adults and may contribute to the onset or progression of neurodegenerative diseases. Objective: This comprehensive review explores the relationship between chronic pain and cognitive function, emphasizing the underlying neurobiological mechanisms, structural brain changes, and associated comorbidities. Methods: A review was conducted using peer-reviewed studies that began with the earliest pain and cognition mechanisms, followed by further investigation of cognitive effects of chronic pain, neuroimaging findings, and comorbid neuropsychiatric and neurodegenerative conditions. Sources included large-scale cohort studies, functional MRI analyses, and neurobiological investigations focusing on prefrontal cortex activity, default mode network alterations, and gray matter atrophy. Results: Chronic pain is associated with cognitive deficits through multiple converging pathways. It contributes to measurable impairments in cognitive function and is linked to structural and functional brain alterations. Regions of interest include the dorsolateral prefrontal cortex, medial prefrontal cortex, and default mode network, which can be connected to the neural resource hypothesis because of their cognitive domain impairments. A better understanding of these mechanisms highlights the importance of early recognition and multidisciplinary management strategies, including neuromodulation and cognitive rehabilitation. Future research should prioritize longitudinal studies and integrated interventions targeting both pain and cognitive health.

Purpose of review: This is a comprehensive review of the literature regarding the use of ketamine as a treatment for treatment-resistant depression (TRD). It covers the epidemiology, risk factors, pathophysiology, and current treatment modalities regarding Major Depressive Disorder (MDD) and TRD. It provides background on the mechanism of action of ketamine, its history, current approved and off-label indications in the field of psychiatry, and then provides an overview of the existing evidence for the use of ketamine in the treatment of TRD. Recent findings: MDD is a mental illness that puts an enormous strain on the affected and a high socio-economic burden on society. The illness is complex and combines genetic, pathophysiologic, and environmental factors that combine to negatively affect neurotransmitter balance in the brain. Additional evidence suggests dysregulation of the hypothalamic-pituitary (HPA) axis, brain-derived neurotrophic factor (BDNF), vitamin D levels, and involvement of pro-inflammatory markers. Core symptoms include depressed mood or anhedonia, combined with neurovegetative symptoms such as sleep impairment, changes in appetite, feelings of worthlessness and guilt, and psychomotor retardation. Current first-line treatment options are antidepressants of the selective serotonin reuptake inhibitor (SSRI) and serotonin-norepinephrine reuptake inhibitor (SNRI) class. Failure to respond to two adequate trials of treatment meets the criteria for TRD. Esketamine (Spravato) is an NMDA-receptor antagonist with additional AMPA-receptor agonist properties, which the FDA approved in 2019 to treat adult TRD in conjunction with an oral antidepressant. It can be administered intranasally, providing a rapid response and proven effective and safe. Additional research suggests that oral ketamine might be effective for PTSD and anxiety disorders. Intravenous administration of ketamine has also shown benefits for acute suicidal ideation and depression and substance use to reduce relapse rates. Summary: TRD is associated with huge costs on individual and societal levels. Underlying disease processes are multifactorial and not well understood. Adjunctive therapies for TRD with proven benefits exist, but acutely depressed and suicidal patients often require prolonged inpatient stabilization. Intranasal esketamine is a new FDA-approved alternative with rapid benefit for TRD, which has also shown a rapid reduction in suicidal ideation while maintaining a favorable side-effect profile. Additional potential off-label uses for ketamine in psychiatric disorders have been studied, including PTSD, anxiety disorders, bipolar depression, and substance use disorders.