-
Translational Psychiatry Dec 2023Activity changes within the anterior cingulate cortex (ACC) are implicated in the antidepressant effects of ketamine, but the ACC is cytoarchitectonically and... (Randomized Controlled Trial)
Randomized Controlled Trial
Activity changes within the anterior cingulate cortex (ACC) are implicated in the antidepressant effects of ketamine, but the ACC is cytoarchitectonically and functionally heterogeneous and ketamine's effects may be subregion specific. In the context of a double-blind randomized placebo-controlled crossover trial investigating the clinical and resting-state fMRI effects of intravenous ketamine vs. placebo in patients with treatment resistant depression (TRD) vs. healthy volunteers (HV), we used seed-based resting-state functional connectivity (rsFC) analyses to determine differential changes in subgenual ACC (sgACC), perigenual ACC (pgACC) and dorsal ACC (dACC) rsFC two days post-infusion. Across cingulate subregions, ketamine differentially modulated rsFC to the right insula and anterior ventromedial prefrontal cortex, compared to placebo, in TRD vs. HV; changes to pgACC-insula connectivity correlated with improvements in depression scores. Post-hoc analysis of each cingulate subregion separately revealed differential modulation of sgACC-hippocampal, sgACC-vmPFC, pgACC-posterior cingulate, and dACC-supramarginal gyrus connectivity. By comparing rsFC changes following ketamine vs. placebo in the TRD group alone, we found that sgACC rsFC was most substantially modulated by ketamine vs. placebo. Changes to sgACC-pgACC, sgACC-ventral striatal, and sgACC-dACC connectivity correlated with improvements in anhedonia symptoms. This preliminary evidence suggests that accurate segmentation of the ACC is needed to understand the precise effects of ketamine's antidepressant and anti-anhedonic action.
Topics: Humans; Ketamine; Gyrus Cinguli; Prefrontal Cortex; Antidepressive Agents; Magnetic Resonance Imaging
PubMed: 38040678
DOI: 10.1038/s41398-023-02674-1 -
Pharmacological Reports : PR Dec 2023Treatment-resistant depression (TRD) is a subgroup of major depressive disorder in which the use of classical antidepressant treatments fails to achieve satisfactory... (Review)
Review
Treatment-resistant depression (TRD) is a subgroup of major depressive disorder in which the use of classical antidepressant treatments fails to achieve satisfactory treatment results. Although there are various definitions and grading models for TRD, common criteria for assessing TRD have still not been established. However, a common feature of any TRD model is the lack of response to at least two attempts at antidepressant pharmacotherapy. The causes of TRD are not known; nevertheless, it is estimated that even 60% of TRD patients are so-called pseudo-TRD patients, in which multiple biological factors, e.g., gender, age, and hormonal disturbances are concomitant with depression and involved in antidepressant drug resistance. Whereas the phenomenon of TRD is a complex disorder difficult to diagnose and successfully treat, the search for new treatment strategies is a significant challenge of modern pharmacology. It seems that despite the complexity of the TRD phenomenon, some useful animal models of TRD meet the construct, the face, and the predictive validity criteria. Based on the literature and our own experiences, we will discuss the utility of animals exposed to the stress paradigm (chronic mild stress, CMS), and the Wistar Kyoto rat strain representing an endogenous model of TRD. In this review, we will focus on reviewing research on existing and novel therapies for TRD, including ketamine, deep brain stimulation (DBS), and psychedelic drugs in the context of preclinical studies in representative animal models of TRD.
Topics: Rats; Animals; Humans; Depression; Depressive Disorder, Major; Antidepressive Agents; Depressive Disorder, Treatment-Resistant; Rats, Inbred WKY
PubMed: 37882914
DOI: 10.1007/s43440-023-00542-9 -
Biological Psychiatry Apr 2024Understanding the interactions between the gut microbiome and psychotropic medications (psycho-pharmacomicrobiomics) could improve treatment stratification strategies in... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Understanding the interactions between the gut microbiome and psychotropic medications (psycho-pharmacomicrobiomics) could improve treatment stratification strategies in psychiatry. In this systematic review and meta-analysis, we first explored whether psychotropics modify the gut microbiome; second, we investigated whether the gut microbiome affects the efficacy and tolerability of psychotropics.
METHODS
Following PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines, we searched (November 2022) for longitudinal and cross-sectional studies that investigated the effect of psychotropics on the gut microbiome. The primary outcome was the difference in diversity metrics (alpha and beta) before and after treatment with psychotropics (longitudinal studies) and in medicated compared with unmedicated individuals (cross-sectional studies). Secondary outcomes included the association between gut microbiome and efficacy and tolerability outcomes. Random effect meta-analyses were conducted on alpha diversity metrics, while beta diversity metrics were pooled using distance data extracted from graphs. Summary statistics included standardized mean difference and Higgins I for alpha diversity metrics and F and R values for beta diversity metrics.
RESULTS
Nineteen studies were included in our synthesis; 12 investigated antipsychotics and 7 investigated antidepressants. Results showed significant changes in alpha (4 studies; standard mean difference: 0.12; 95% CI: 0.01-0.23; p = .04; I: 14%) and beta (F = 15.59; R = 0.05; p < .001) diversity metrics following treatment with antipsychotics and antidepressants, respectively. Altered gut microbiome composition at baseline was associated with tolerability and efficacy outcomes across studies, including response to antidepressants (2 studies; alpha diversity; standard mean difference: 2.45; 95% CI: 0.50-4.40; p < .001, I: 0%).
CONCLUSIONS
Treatment with psychotropic medications is associated with altered gut microbiome composition, and the gut microbiome may in turn influence the efficacy and tolerability of these medications.
Topics: Humans; Cross-Sectional Studies; Psychotropic Drugs; Antidepressive Agents; Antipsychotic Agents; Gastrointestinal Microbiome
PubMed: 37567335
DOI: 10.1016/j.biopsych.2023.07.019 -
Proceedings of the National Academy of... Dec 2023Individuals with a history of early-life stress (ELS) tend to have an altered course of depression and lower treatment response rates. Research suggests that ELS alters...
Individuals with a history of early-life stress (ELS) tend to have an altered course of depression and lower treatment response rates. Research suggests that ELS alters brain development, but the molecular changes in the brain following ELS that may mediate altered antidepressant response have not been systematically studied. Sex and gender also impact the risk of depression and treatment response. Here, we leveraged existing RNA sequencing datasets from 1) blood samples from depressed female- and male-identifying patients treated with escitalopram or desvenlafaxine and assessed for treatment response or failure; 2) the nucleus accumbens (NAc) of female and male mice exposed to ELS and/or adult stress; and 3) the NAc of mice after adult stress, antidepressant treatment with imipramine or ketamine, and assessed for treatment response or failure. We find that transcriptomic signatures of adult stress after a history of ELS correspond with transcriptomic signatures of treatment nonresponse, across species and multiple classes of antidepressants. Transcriptomic correspondence with treatment outcome was stronger among females and weaker among males. We next pharmacologically tested these predictions in our mouse model of early-life and adult social defeat stress and treatment with either chronic escitalopram or acute ketamine. Among female mice, the strongest predictor of behavior was an interaction between ELS and ketamine treatment. Among males, however, early experience and treatment were poor predictors of behavior, mirroring our bioinformatic predictions. These studies provide neurobiological evidence for molecular adaptations in the brain related to sex and ELS that contribute to antidepressant treatment response.
Topics: Humans; Male; Female; Mice; Animals; Depression; Escitalopram; Ketamine; Adverse Childhood Experiences; Antidepressive Agents; Treatment Outcome; Stress, Psychological
PubMed: 38011563
DOI: 10.1073/pnas.2305776120 -
Australasian Psychiatry : Bulletin of... Dec 2023To review the usefulness of esketamine for treatment-resistant depression. (Review)
Review
OBJECTIVE
To review the usefulness of esketamine for treatment-resistant depression.
METHOD
Pivotal trials of intranasal esketamine in treatment-resistant depression were synthesized as a narrative review.
RESULTS
Esketamine is postulated to act through antagonism of N-methyl-D-aspartate (NMDA) glutamate receptors, but opioidergic effects may also be involved. Unlike intravenous ketamine, esketamine is given intranasally (under clinical observation), usually in addition to an oral antidepressant. Trials compared esketamine plus antidepressant versus placebo plus antidepressant. At 4 weeks, remission was 37% higher with esketamine/antidepressant than placebo/antidepressant. Speed of response and improvement in suicidality were comparable. In stable remitters on esketamine/antidepressant, 45% relapsed when esketamine was withdrawn over the following 6 months (whereas 25% relapsed on esketamine/antidepressant). Response appears less likely in patients with multiple antidepressant failures. Adverse effects include dissociation, dizziness, nausea, sedation, and headache but no psychosis. Hypertension affected 13%, especially older patients. Dose frequency is twice-weekly for 4 weeks, then weekly/fortnightly thereafter. No abuse has been reported. Unsubsidised cost may be beyond the reach of many Australians.
CONCLUSION
Intranasal esketamine plus antidepressant has been approved by regulators as moderately effective and acceptably tolerable for treatment-resistant depression. Cost is a drawback. Use often needs to be long-term and vigilance for abuse is essential.
Topics: Humans; Antidepressive Agents; Australia; Depression; Depressive Disorder, Treatment-Resistant; Ketamine
PubMed: 37961848
DOI: 10.1177/10398562231211171 -
European Neuropsychopharmacology : the... Nov 2023Major depressive disorder (MDD) presents different clinical features in women and men, with women being more affected and responding differently to antidepressant... (Review)
Review
Major depressive disorder (MDD) presents different clinical features in women and men, with women being more affected and responding differently to antidepressant treatment. Specific molecular mechanisms underlying these differences are not well studied and this narrative review aims at providing an overview of the neurobiological features underlying sex-differences in biological systems involved in MDD pathophysiology and response to antidepressant treatment, focusing on human studies. The majority of the reviewed studies were performed through candidate gene approaches, focusing on biological systems involved in MDD pathophysiology, including the stress response, inflammatory and immune, monoaminergic, neurotrophic, gamma-aminobutyric acid and glutamatergic, and oxytocin systems. The influence of the endocrine system and sex-specific hormone effects are also discussed. Genome, epigenome and transcriptome-wide approaches are less frequently performed and most of these studies do not focus on sex-specific alterations, revealing a paucity of omics studies directed to unravel sex-based differences in MDD. Few studies about sex-related differences in antidepressant treatment response have been conducted, mostly involving the inflammatory system, with less evidence on the monoaminergic system and sparse evidence in omics approaches. Our review covers the importance of accounting for sex-differences in research, optimizing patient stratification for a more precise diagnostic and individualized treatment for women and men.
Topics: Male; Humans; Female; Depressive Disorder, Major; Antidepressive Agents; Biomarkers
PubMed: 37595325
DOI: 10.1016/j.euroneuro.2023.07.012 -
Revista de Neurologia Jul 2023Narcolepsy type 1 is a focal degenerative disease of the hypothalamus that selectively affects orexin (hypocretin)-producing neurons. It presents multiple clinical...
INTRODUCTION
Narcolepsy type 1 is a focal degenerative disease of the hypothalamus that selectively affects orexin (hypocretin)-producing neurons. It presents multiple clinical manifestations, both in wakefulness and in sleep. The symptoms are often so disruptive that they cause enormous suffering and impair patients' quality of life. Although a non-pharmacological approach is sometimes sufficient, the vast majority of patients need medication for adequate clinical management.
CASE REPORT
A male who, at 43 years of age, began to present acutely with excessive daytime sleepiness and episodes of cataplexy. After a thorough examination, he was diagnosed with narcolepsy type 1. Throughout the course of the disease, he was prescribed antidepressants, neurostimulants and sodium oxybate, in monotherapy or in combination. The response to pharmacological treatment was insufficient and accompanied by numerous side effects. Following the introduction of pitolisant, there was a marked improvement in his symptoms and a reduction in the dose of the other drugs and their adverse effects was achieved.
CONCLUSION
A number of measures are now available to address the cardinal symptoms of the disease, although there are still cases that are resistant to anti-narcoleptic treatment. Drugs with mechanisms of action that act upon receptors in the histaminergic system can be very useful in these cases.
Topics: Humans; Male; Antidepressive Agents; Cataplexy; Central Nervous System Stimulants; Narcolepsy; Quality of Life; Sodium Oxybate; Adult; Drug Resistance, Multiple; Sleepiness
PubMed: 37477029
DOI: 10.33588/rn.77s01.2023198 -
Neuroscience and Biobehavioral Reviews Nov 2023For the past decade, ketamine, an N-methyl-D-aspartate receptor (NMDAr) antagonist, has been considered a promising treatment for major depressive disorder (MDD). Unlike... (Review)
Review
For the past decade, ketamine, an N-methyl-D-aspartate receptor (NMDAr) antagonist, has been considered a promising treatment for major depressive disorder (MDD). Unlike the delayed effect of monoaminergic treatment, ketamine may produce fast-acting antidepressant effects hours after a single administration at subanesthetic dose. Along with these antidepressant effects, it may also induce transient dissociative (disturbing of the sense of self and reality) symptoms during acute administration which resolve within hours. To understand ketamine's rapid-acting antidepressant effect, several biological hypotheses have been explored, but despite these promising avenues, there is a lack of model to understand the timeframe of antidepressant and dissociative effects of ketamine. In this article, we propose a neurocomputational account of ketamine's antidepressant and dissociative effects based on the Predictive Processing (PP) theory, a framework for cognitive and sensory processing. PP theory suggests that the brain produces top-down predictions to process incoming sensory signals, and generates bottom-up prediction errors (PEs) which are then used to update predictions. This iterative dynamic neural process would relies on N-methyl-D-aspartate (NMDAr) and α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic receptors (AMPAr), two major component of the glutamatergic signaling. Furthermore, it has been suggested that MDD is characterized by over-rigid predictions which cannot be updated by the PEs, leading to miscalibration of hierarchical inference and self-reinforcing negative feedback loops. Based on former empirical studies using behavioral paradigms, neurophysiological recordings, and computational modeling, we suggest that ketamine impairs top-down predictions by blocking NMDA receptors, and enhances presynaptic glutamate release and PEs, producing transient dissociative symptoms and fast-acting antidepressant effect in hours following acute administration. Moreover, we present data showing that ketamine may enhance a delayed neural plasticity pathways through AMPAr potentiation, triggering a prolonged antidepressant effect up to seven days for unique administration. Taken together, the two sides of antidepressant effects with distinct timeframe could constitute the keystone of antidepressant properties of ketamine. These PP disturbances may also participate to a ketamine-induced time window of mental flexibility, which can be used to improve the psychotherapeutic process. Finally, these proposals could be used as a theoretical framework for future research into fast-acting antidepressants, and combination with existing antidepressant and psychotherapy.
Topics: Humans; Ketamine; Depressive Disorder, Major; Antidepressive Agents; Brain; Signal Transduction; Receptors, N-Methyl-D-Aspartate
PubMed: 37793581
DOI: 10.1016/j.neubiorev.2023.105410 -
Cancer Causes & Control : CCC Jan 2024The use of antidepressants has increased over the years, but the relationship between antidepressant use and the risk of breast cancer is not uniform because of...
BACKGROUND
The use of antidepressants has increased over the years, but the relationship between antidepressant use and the risk of breast cancer is not uniform because of confounding factors. We aimed to assess the effect of antidepressants on breast cancer risk using a two-sample Mendelian randomization (MR) approach.stet METHODS: Secondary data analysis was performed on pooled data from genome-wide association studies based on single-nucleotide polymorphisms that were highly correlated with antidepressants, SSRI drugs, and serotonin and prolactin levels were selected as instrumental variables to evaluate the association between antidepressants and SSRI drugs and prolactin levels with breast cancer and ER+/ER- breast cancer. We then performed a test of the hypothesis that SSRI drugs elevate prolactin concentrations. We performed two-sample Mendelian randomization analyses using inverse variance weighting, MR-Egger regression, and weighted median methods, respectively.
RESULTS
There was no significant risk association between antidepressant and SSRI use and the development of breast cancer, ER-positive or ER-negative breast cancer (P > 0.05), and serotonin concentration was not associated with breast cancer risk (P > 0.05). There was a positive causal relationship between prolactin levels and breast cancer (IVW, P = 0.02, OR = 1.058) and ER-positive breast cancer (Weighted median, P = 0.043, OR = 1.141; IVW, P = 0.009, OR = 1.125). Results in SSRI medication and prolactin levels showed no association between SSRI analogs and prolactin levels (P > 0.05).
CONCLUSION
Large MR analysis showed that antidepressants as well as SSRI drugs were not associated with breast cancer risk and the SSRI-prolactin-breast cancer hypothesis did not hold in our analysis.
Topics: Humans; Female; Breast Neoplasms; Mendelian Randomization Analysis; Genome-Wide Association Study; Prolactin; Serotonin; Polymorphism, Single Nucleotide; Antidepressive Agents
PubMed: 37540479
DOI: 10.1007/s10552-023-01766-z -
International Journal of Nanomedicine 2023The early stage of this study verified that a turmeric extract (TUR) including 59% curcumin (CU), 22% demethoxycurcumin (DMC), and 18% bisdemethoxycurcumin (BDMC), could...
PURPOSE
The early stage of this study verified that a turmeric extract (TUR) including 59% curcumin (CU), 22% demethoxycurcumin (DMC), and 18% bisdemethoxycurcumin (BDMC), could enhance the stability of CU and had greater antidepressant potential in vitro. The objective of the study was to develop a nano-delivery system containing TUR (TUR-NE) to improve the pharmacokinetic behavior of TUR and enhance its antidepressant effect.
METHODS
The antidepressant potential of TUR was explored using ABTS, oxidative stress-induced cell injury, and a high-throughput screening model. TUR-NE was fabricated, optimized and characterized. The pharmacokinetic behaviors of TUR-NE were evaluated following oral administration to normal rats. The antidepressant effect of TUR-NE was assessed within chronic unpredictable mild stress model (CUMS) mice. The behavioral and biochemical indexes of mice were conducted.
RESULTS
The results depicted that TUR had 3.18 and 1.62 times higher antioxidant capacity than ascorbic acid and CU, respectively. The inhibition effect of TUR on ASP+ transport was significantly enhanced compared with fluoxetine and CU. TUR-NE displayed a particle size of 116.0 ± 0.31 nm, polydispersity index value of 0.121 ± 0.007, an encapsulation rate of 98.45%, and good release and stability in cold storage. The results of pharmacokinetics indicated the AUC of TUR-NE was 8.436 and 4.495 times higher than that of CU and TUR, while the C was 9.012 and 5.452 times higher than that of CU and TUR, respectively. The pharmacodynamic study confirmed that the superior antidepressant effect of TUR-NE by significantly improving the depressant-like behaviors and elevating the content of 5-hydroxytryptamine in plasma and brain in CUMS mice. TUR-NE showed good safety with repeated administration.
CONCLUSION
TUR-NE, which had small and uniform particle size, enhanced the bioavailability and antidepressant effect of TUR. It could be a promising novel oral preparation against depression.
Topics: Rats; Mice; Animals; Curcumin; Antidepressive Agents; Plant Extracts; Curcuma
PubMed: 38162571
DOI: 10.2147/IJN.S430769