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Cell Mar 2021It is unclear how binding of antidepressant drugs to their targets gives rise to the clinical antidepressant effect. We discovered that the transmembrane domain of...
It is unclear how binding of antidepressant drugs to their targets gives rise to the clinical antidepressant effect. We discovered that the transmembrane domain of tyrosine kinase receptor 2 (TRKB), the brain-derived neurotrophic factor (BDNF) receptor that promotes neuronal plasticity and antidepressant responses, has a cholesterol-sensing function that mediates synaptic effects of cholesterol. We then found that both typical and fast-acting antidepressants directly bind to TRKB, thereby facilitating synaptic localization of TRKB and its activation by BDNF. Extensive computational approaches including atomistic molecular dynamics simulations revealed a binding site at the transmembrane region of TRKB dimers. Mutation of the TRKB antidepressant-binding motif impaired cellular, behavioral, and plasticity-promoting responses to antidepressants in vitro and in vivo. We suggest that binding to TRKB and allosteric facilitation of BDNF signaling is the common mechanism for antidepressant action, which may explain why typical antidepressants act slowly and how molecular effects of antidepressants are translated into clinical mood recovery.
Topics: Animals; Antidepressive Agents; Binding Sites; Brain-Derived Neurotrophic Factor; Cell Line; Cholesterol; Embryo, Mammalian; Fluoxetine; Hippocampus; Humans; Mice; Models, Animal; Molecular Dynamics Simulation; Protein Domains; Rats; Receptor, trkB; Visual Cortex
PubMed: 33606976
DOI: 10.1016/j.cell.2021.01.034 -
Journal of Affective Disorders May 2023Antidepressant medication and running therapy are both effective treatments for patients with depressive and anxiety disorders. However, they may work through different... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Antidepressant medication and running therapy are both effective treatments for patients with depressive and anxiety disorders. However, they may work through different pathophysiological mechanisms and could differ in their impact on physical health. This study examined effects of antidepressants versus running therapy on both mental and physical health.
METHODS
According to a partially randomized patient preference design, 141 patients with depression and/or anxiety disorder were randomized or offered preferred 16-week treatment: antidepressant medication (escitalopram or sertraline) or group-based running therapy ≥2 per week. Baseline (T0) and post-treatment assessment at week 16 (T16) included mental (diagnosis status and symptom severity) and physical health indicators (metabolic and immune indicators, heart rate (variability), weight, lung function, hand grip strength, fitness).
RESULTS
Of the 141 participants (mean age 38.2 years; 58.2 % female), 45 participants received antidepressant medication and 96 underwent running therapy. Intention-to-treat analyses showed that remission rates at T16 were comparable (antidepressants: 44.8 %; running: 43.3 %; p = .881). However, the groups differed significantly on various changes in physical health: weight (d = 0.57; p = .001), waist circumference (d = 0.44; p = .011), systolic (d = 0.45; p = .011) and diastolic (d = 0.53; p = .002) blood pressure, heart rate (d = 0.36; p = .033) and heart rate variability (d = 0.48; p = .006).
LIMITATIONS
A minority of the participants was willing to be randomized; the running therapy was larger due to greater preference for this intervention.
CONCLUSIONS
While the interventions had comparable effects on mental health, running therapy outperformed antidepressants on physical health, due to both larger improvements in the running therapy group as well as larger deterioration in the antidepressant group.
TRIAL REGISTRATION
Trialregister.nl Number of identification: NTR3460.
Topics: Humans; Female; Adult; Male; Depression; Hand Strength; Antidepressive Agents; Sertraline; Anxiety Disorders
PubMed: 36828150
DOI: 10.1016/j.jad.2023.02.064 -
Molecular Psychiatry Jun 2022Major depressive disorder (MDD) was previously hypothesized to be a disease of monoamine deficiency in which low levels of monoamines in the synaptic cleft were believed... (Review)
Review
Major depressive disorder (MDD) was previously hypothesized to be a disease of monoamine deficiency in which low levels of monoamines in the synaptic cleft were believed to underlie depressive symptoms. More recently, however, there has been a paradigm shift toward a neuroplasticity hypothesis of depression in which downstream effects of antidepressants, such as increased neurogenesis, contribute to improvements in cognition and mood. This review takes a top-down approach to assess how changes in behavior and hippocampal-dependent circuits may be attributed to abnormalities at the molecular, structural, and synaptic level. We conclude with a discussion of how antidepressant treatments share a common effect in modulating neuroplasticity and consider outstanding questions and future perspectives.
Topics: Adult; Antidepressive Agents; Depression; Depressive Disorder, Major; Hippocampus; Humans; Neuronal Plasticity
PubMed: 35354926
DOI: 10.1038/s41380-022-01520-y -
Annual Review of Pharmacology and... Jan 2019New approaches to the neurobiology of posttraumatic stress disorder (PTSD) are needed to address the reported crisis in PTSD drug development. These new approaches may... (Review)
Review
New approaches to the neurobiology of posttraumatic stress disorder (PTSD) are needed to address the reported crisis in PTSD drug development. These new approaches may require the field to move beyond a narrow fear-based perspective, as fear-based medications have not yet demonstrated compelling efficacy. Antidepressants, particularly recent rapid-acting antidepressants, exert complex effects on brain function and structure that build on novel aspects of the biology of PTSD, including a role for stress-related synaptic dysconnectivity in the neurobiology and treatment of PTSD. Here, we integrate this perspective within a broader framework-in other words, a dual pathology model of ( a) stress-related synaptic loss arising from amino acid-based pathology and ( b) stress-related synaptic gain related to monoamine-based pathology. Then, we summarize the standard and experimental (e.g., ketamine) pharmacotherapeutic options for PTSD and discuss their putative mechanism of action and clinical efficacy.
Topics: Animals; Antidepressive Agents; Brain; Humans; Stress Disorders, Post-Traumatic
PubMed: 30216745
DOI: 10.1146/annurev-pharmtox-010818-021701 -
Nature May 2016Major depressive disorder affects around 16 per cent of the world population at some point in their lives. Despite the availability of numerous monoaminergic-based...
Major depressive disorder affects around 16 per cent of the world population at some point in their lives. Despite the availability of numerous monoaminergic-based antidepressants, most patients require several weeks, if not months, to respond to these treatments, and many patients never attain sustained remission of their symptoms. The non-competitive, glutamatergic NMDAR (N-methyl-d-aspartate receptor) antagonist (R,S)-ketamine exerts rapid and sustained antidepressant effects after a single dose in patients with depression, but its use is associated with undesirable side effects. Here we show that the metabolism of (R,S)-ketamine to (2S,6S;2R,6R)-hydroxynorketamine (HNK) is essential for its antidepressant effects, and that the (2R,6R)-HNK enantiomer exerts behavioural, electroencephalographic, electrophysiological and cellular antidepressant-related actions in mice. These antidepressant actions are independent of NMDAR inhibition but involve early and sustained activation of AMPARs (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors). We also establish that (2R,6R)-HNK lacks ketamine-related side effects. Our data implicate a novel mechanism underlying the antidepressant properties of (R,S)-ketamine and have relevance for the development of next-generation, rapid-acting antidepressants.
Topics: Animals; Antidepressive Agents; Female; Ketamine; Male; Mice; Receptors, AMPA; Receptors, N-Methyl-D-Aspartate; Time Factors
PubMed: 27144355
DOI: 10.1038/nature17998 -
Advances in Pharmacology (San Diego,... 2021Depression is one of the leading causes of disability worldwide and a major contributor to the global burden of disease, yet the cellular and molecular etiology of...
Depression is one of the leading causes of disability worldwide and a major contributor to the global burden of disease, yet the cellular and molecular etiology of depression remain largely unknown. Major Depressive Disorder (MDD) is associated with a variety of chronic physical inflammatory and autoimmune disorders, and mood disorders may act synergistically with other medical disorders to worsen patient outcomes. Here, we outline the neuroimmune complement, explore the evidence for altered immune system function in MDD, and present some of the potential mechanisms by which immune cells and molecules may drive the onset and course of MDD. These include pro-inflammatory signaling, alterations in the hypothalamic-pituitary-adrenal axis, dysregulation of the serotonergic and noradrenergic neurotransmitter systems, neuroinflammation, and meningeal immune dysfunction. Finally, we discuss the interactions between current antidepressants and the immune system and propose the possibility of immunomodulatory drugs as potential novel antidepressant treatments.
Topics: Antidepressive Agents; Depression; Depressive Disorder, Major; Humans; Hypothalamo-Hypophyseal System; Pituitary-Adrenal System
PubMed: 34099111
DOI: 10.1016/bs.apha.2021.03.004 -
International Journal of Molecular... Mar 2023Depression is a mental health disorder that develops as a result of complex psycho-neuro-immuno-endocrinological disturbances. This disease presents with mood... (Review)
Review
Depression is a mental health disorder that develops as a result of complex psycho-neuro-immuno-endocrinological disturbances. This disease presents with mood disturbances, persistent sadness, loss of interest and impaired cognition, which causes distress to the patient and significantly affects the ability to function and have a satisfying family, social and professional life. Depression requires comprehensive management, including pharmacological treatment. Because pharmacotherapy of depression is a long-term process associated with the risk of numerous adverse drug effects, much attention is paid to alternative therapy methods, including phytopharmacotherapy, especially in treating mild or moderate depression. Preclinical studies and previous clinical studies confirm the antidepressant activity of active compounds in plants, such as St. John's wort, saffron crocus, lemon balm and lavender, or less known in European ethnopharmacology, roseroot, ginkgo, Korean ginseng, borage, brahmi, mimosa tree and magnolia bark. The active compounds in these plants exert antidepressive effects in similar mechanisms to those found in synthetic antidepressants. The description of phytopharmacodynamics includes inhibiting monoamine reuptake and monoamine oxidase activity and complex, agonistic or antagonistic effects on multiple central nervous system (CNS) receptors. Moreover, it is noteworthy that the anti-inflammatory effect is also important to the antidepressant activity of the plants mentioned above in light of the hypothesis that immunological disorders of the CNS are a significant pathogenetic factor of depression. This narrative review results from a traditional, non-systematic literature review. It briefly discusses the pathophysiology, symptomatology and treatment of depression, with a particular focus on the role of phytopharmacology in its treatment. It provides the mechanisms of action revealed in experimental studies of active ingredients isolated from herbal antidepressants and presents the results of selected clinical studies confirming their antidepressant effectiveness.
Topics: Humans; Depression; Phytotherapy; Antidepressive Agents; Depressive Disorder; Hypericum
PubMed: 36902200
DOI: 10.3390/ijms24054772 -
Current Psychiatry Reports Aug 2017The aim of this review article was to summarize recent publications on effects of antidepressants on sleep and to show that these effects not only depend on the kind of... (Review)
Review
PURPOSE OF REVIEW
The aim of this review article was to summarize recent publications on effects of antidepressants on sleep and to show that these effects not only depend on the kind of antidepressant drugs but are also related to the dose, the time of drug administration, and the duration of the treatment.
RECENT FINDINGS
Complaints of disrupted sleep are very common in patients suffering from depression, and they are listed among diagnostic criteria for this disorder. Moreover, midnocturnal insomnia is the most frequent residual symptom of depression. Thus, all antidepressants should normalize sleep. However, at least in short-term treatment, many antidepressants with so-called activating effects (e.g. fluoxetine, venlafaxine) may disrupt sleep, while others with sedative properties (e.g., doxepin, mirtazapine, trazodone) rapidly improve sleep, but may cause problems in long-term treatment due to oversedation.For sleep-promoting action, the best effects can frequently be achieved with a very low dose, administered early enough before bedtime and importantly, always as a part of more complex interventions based on the cognitive-behavioral protocol to treat insomnia (CBT-I). For successful treatment of depression, it is necessary to understand the effects of antidepressants on sleep. Each physician should also be aware that some antidepressants may worsen or induce primary sleep disorders like restless legs syndrome, sleep bruxism, REM sleep behavior disorder, nightmares, and sleep apnea, which may result from an antidepressant-induced weight gain.
Topics: Antidepressive Agents; Depressive Disorder; Dose-Response Relationship, Drug; Drug Administration Schedule; Humans; Sleep; Sleep Wake Disorders; Time Factors
PubMed: 28791566
DOI: 10.1007/s11920-017-0816-4 -
Dialogues in Clinical Neuroscience Dec 2016Although a number of studies have observed that females respond better to serotonergic antidepressants than males and that postmenopausal females have a diminished... (Review)
Review
Although a number of studies have observed that females respond better to serotonergic antidepressants than males and that postmenopausal females have a diminished response to antidepressants compared with younger females, there are also studies that conflict with both of these findings, making any generalizations regarding sex differences difficult to make. Sex variance in antidepressant efficacy and pharmacokinetics profiles have been attributed to sex-based physiological differences, behavioral differences, related disorders, and sex-specific conditions, including pregnancy and menopause. This paper will review the history and current research on sex effects of antidepressant treatment.
Topics: Antidepressive Agents; Cognitive Behavioral Therapy; Depression; Depressive Disorder, Major; Estrogen Replacement Therapy; Female; Humans; Male; Medication Adherence; Sex Characteristics
PubMed: 28179816
DOI: 10.31887/DCNS.2016.18.4/ncutler -
International Journal of Molecular... Jan 2019Impaired sleep is both a risk factor and a symptom of depression. Objective sleep is assessed using the sleep electroencephalogram (EEG). Characteristic sleep-EEG... (Review)
Review
Impaired sleep is both a risk factor and a symptom of depression. Objective sleep is assessed using the sleep electroencephalogram (EEG). Characteristic sleep-EEG changes in patients with depression include disinhibition of rapid eye movement (REM) sleep, changes of sleep continuity, and impaired non-REM sleep. Most antidepressants suppress REM sleep both in healthy volunteers and depressed patients. Various sleep-EEG variables may be suitable as biomarkers for diagnosis, prognosis, and prediction of therapy response in depression. In family studies of depression, enhanced REM density, a measure for frequency of rapid eye movements, is characteristic for an endophenotype. Cordance is an EEG measure distinctly correlated with regional brain perfusion. Prefrontal theta cordance, derived from REM sleep, appears to be a biomarker of antidepressant treatment response. Some predictive sleep-EEG markers of depression appear to be related to hypothalamo-pituitary-adrenocortical system activity.
Topics: Antidepressive Agents; Depression; Electroencephalography; Female; Genetic Predisposition to Disease; Humans; Male; Sleep Wake Disorders; Sleep, REM
PubMed: 30708948
DOI: 10.3390/ijms20030607