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Advances in Therapy Sep 2021
Topics: Anxiety Disorders; Depression; Depressive Disorder, Major; Humans
PubMed: 34417991
DOI: 10.1007/s12325-021-01859-8 -
Molecular Psychiatry Dec 2019Depression is a complex disorder that takes an enormous toll on individual health. As affected individuals display a wide variation in their clinical symptoms, the... (Review)
Review
Depression is a complex disorder that takes an enormous toll on individual health. As affected individuals display a wide variation in their clinical symptoms, the precise neural mechanisms underlying the development of depression remain elusive. Although it is impossible to phenocopy every symptom of human depression in rodents, the preclinical field has had great success in modeling some of the core affective and neurovegetative depressive symptoms, including social withdrawal, anhedonia, and weight loss. Adaptations in select cell populations may underlie these individual depressive symptoms and new tools have expanded our ability to monitor and manipulate specific cell types. This review outlines some of the most recent preclinical discoveries on the molecular and neurophysiological mechanisms in reward circuitry that underlie the expression of behavioral constructs relevant to depressive symptoms.
Topics: Anhedonia; Animals; Depression; Depressive Disorder, Major; Disease Models, Animal; Humans; Motivation; Reward; Social Behavior; Weight Loss
PubMed: 30967681
DOI: 10.1038/s41380-019-0415-3 -
British Journal of Pharmacology Mar 2022Major depressive disorder is a leading cause of disability worldwide. Because conventional therapies are ineffective in many patients, novel strategies are needed to... (Review)
Review
Major depressive disorder is a leading cause of disability worldwide. Because conventional therapies are ineffective in many patients, novel strategies are needed to overcome treatment-resistant depression (TRD). Limiting factors of successful drug development in the last decades were the lack of (1) knowledge of pathophysiology, (2) translational animal models and (3) objective diagnostic biomarkers. Here, we review novel drug targets and drug candidates currently investigated in Phase I-III clinical trials. The most promising approaches are inhibition of glutamatergic neurotransmission by NMDA and mGlu receptor antagonists, modulation of the opioidergic system by κ receptor antagonists, and hallucinogenic tryptamine derivates. The only registered drug for TRD is the NMDA receptor antagonist, S-ketamine, but add-on therapies with second-generation antipsychotics, certain nutritive, anti-inflammatory and neuroprotective agents seem to be effective. Currently, there is an intense research focus on large-scale, high-throughput omics and neuroimaging studies. These results might provide new insights into molecular mechanisms and potential novel therapeutic strategies.
Topics: Animals; Antidepressive Agents; Depression; Depressive Disorder, Major; Depressive Disorder, Treatment-Resistant; Drug Development; Humans
PubMed: 34822719
DOI: 10.1111/bph.15753 -
Psychiatrike = Psychiatriki Dec 2021Treatment resistant depression (TRD) is a serious public health problem. It is estimated that around 20- 40% of patients with a major depressive episode (whether...
Treatment resistant depression (TRD) is a serious public health problem. It is estimated that around 20- 40% of patients with a major depressive episode (whether monopolar or bipolar) do not exhibit clinical response to the current treatment with antidepressants, that is at least 50% decline in the symptoms scale. Furthermore, about half of the patients with symptom amelioration present residual symptoms which continue to negatively affect their functioning and increase the chance of relapse. Therefore, only 20-40% of patients (36.8% in STAR*D)1 who receive therapy for a major depressive episode for the first time exhibit remission (i.e., at least 70% decrease in symptom severity or HAMD score ≤7/MADRS score ≤10)2 - which is the goal of current treatments. Even when remission is achieved, though, there is often a long way to recovery and to the patient's return to the prior state of occupational and social functioning. Moreover, long-term medical treatment is needed in order to achieve and maintain the above.3 TRD is characterized by high rates of comorbidity (hypertension, diabetes mellitus, heart failure), doubles the rates of hospitalizations and lengthens the time of hospitalization by 36%, while the percentage of suicidal incidents is seven times higher in TRD compared to cases of treatment-responsive depression.4 TRD exhibits higher rates of mortality than treatment-responsive depression, with all-cause mortality rate being higher5 by 29-35% and similar to that of older by 13 years, non-depressed individuals. Despite its common occurrence and the fact that TRD constitutes an important issue in the treatment of major depression disorder (MDD), experts still disagree on the exact meaning of the term. The most widely accepted and used term of TRD refers to treatment resistance as treatment with at least two different antidepressants (of the same or different classes), administered in the right doses and for an adequate amount of time, with verified patient compliance to treatment which, however, fails to produce significant clinical results.6 Other terms have also been used as an alternative, for example Difficult to Treat Depression in order to avoid nihilism - something often seen in these cases;7 Drug Resistant Depression so as to determine the exact kind of resistance and also to underline the need for combination therapy with intervention such as psychotherapy and ECT; Multiple Therapy Resistant MDD; Pernicious Depression8 etc. Treatment of TRD is a challenge for every clinician. After excluding the possibility of pseudo-resistance due to misdiagnosis, insufficient therapeutic regimen, comorbid disorders, such as anxiety disorders, eating disorders, personality disorders, substance abuse/addiction, PTSD, non-compliance to treatment, non-identified organicity and chronic stressors, the therapeutic methods used include: optimization, watchful waiting, past response, combination treatment, add-on treatments, ECT, TMS, vagus nerve stimulation, phototherapy, psychotherapy, neurosurgery. All the above are thoroughly discussed in this Supplement issue of Psychiatriki.9.
Topics: Antidepressive Agents; Depression; Depressive Disorder, Major; Depressive Disorder, Treatment-Resistant; Humans; Psychotherapy
PubMed: 34990376
DOI: 10.22365/jpsych.2021.046 -
Psychiatria Polska Jun 2020Cognitive dysfunctions are part of the symptomatology of depressive disorders but they may persist even after the patient reaches symptomatic remission. As persistent... (Review)
Review
Cognitive dysfunctions are part of the symptomatology of depressive disorders but they may persist even after the patient reaches symptomatic remission. As persistent symptoms of depression, cognitive dysfunctions may inhibit and restrict the patient's functioning in many spheres and significantly impair its quality. In addition, they increase the risk of somatic diseases and contribute to the increase of benefits disbursed from state aid. Furthermore, it is a factor negatively affecting the prognosis of depressive disorders because it increases the risk of recurrence of depression and reduces the susceptibility to pharmacotherapy. Neural network dysfunctions and changes in morphometry in particular areas of the brain are responsible for the persistence of cognitive deficits after MDD treatment. Most of currently used thymoleptics facilitate remission of depressive disorders but do not lead to reversal of cognitive deficits. There is growing evidence that antidepressants used in clinical practice can improve cognitive functions regardless of their impact on the affective component. The aim of the present study is to discuss the neurobiological mechanisms of cognitive dysfunctions and their clinical symptoms, and to present therapeutic prospects for patients with persistent cognitive dysfunctions in depressive disorders.
Topics: Antidepressive Agents; Cognition; Cognitive Dysfunction; Depression; Depressive Disorder, Major; Female; Humans; Male
PubMed: 33038880
DOI: 10.12740/PP/OnlineFirst/105415 -
The European Journal of Neuroscience Jan 2021Major depressive disorder (MDD) is a chronic and recurrent psychiatric condition characterized by depressed mood, social isolation and anhedonia. It will affect 20% of... (Review)
Review
Major depressive disorder (MDD) is a chronic and recurrent psychiatric condition characterized by depressed mood, social isolation and anhedonia. It will affect 20% of individuals with considerable economic impacts. Unfortunately, 30-50% of depressed individuals are resistant to current antidepressant treatments. MDD is twice as prevalent in women and associated symptoms are different. Depression's main environmental risk factor is chronic stress, and women report higher levels of stress in daily life. However, not every stressed individual becomes depressed, highlighting the need to identify biological determinants of stress vulnerability but also resilience. Based on a reverse translational approach, rodent models of depression were developed to study the mechanisms underlying susceptibility vs resilience. Indeed, a subpopulation of animals can display coping mechanisms and a set of biological alterations leading to stress resilience. The aetiology of MDD is multifactorial and involves several physiological systems. Exacerbation of endocrine and immune responses from both innate and adaptive systems are observed in depressed individuals and mice exhibiting depression-like behaviours. Increasing attention has been given to neurovascular health since higher prevalence of cardiovascular diseases is found in MDD patients and inflammatory conditions are associated with depression, treatment resistance and relapse. Here, we provide an overview of endocrine, immune and vascular changes associated with stress vulnerability vs. resilience in rodents and when available, in humans. Lack of treatment efficacy suggests that neuron-centric treatments do not address important causal biological factors and better understanding of stress-induced adaptations, including sex differences, could contribute to develop novel therapeutic strategies including personalized medicine approaches.
Topics: Adaptation, Psychological; Animals; Antidepressive Agents; Depression; Depressive Disorder, Major; Female; Humans; Male; Mice; Neurobiology; Stress, Psychological
PubMed: 31421056
DOI: 10.1111/ejn.14547 -
Zeitschrift Fur Kinder- Und... Nov 2019Depressive symptoms have long been associated with abnormalities in neural processing of reward. However, no review has yet consolidated evidence of such deficits in... (Review)
Review
Depressive symptoms have long been associated with abnormalities in neural processing of reward. However, no review has yet consolidated evidence of such deficits in adolescent depression, integrating findings across neuroimaging modalities, such as functional magnetic resonance imaging (fMRI) and electroencephalography (EEG). The current review found consistent evidence of reduced striatal responses in anticipation and upon receipt of rewards, and blunted feedback-related negativity (FRN) potentials associated with depression in adolescence, consistent with the adult literature. Furthermore, while these occurred in currently depressed adolescents, they were also found to be predictive of the onset of depressive symptoms in longitudinal studies with community-based adolescent samples. This paper makes recommendations for future work to continue to elucidate this relationship, a greater understanding of which may lead to more targeted and efficacious treatments for depression in adolescence.
Topics: Adolescent; Depression; Depressive Disorder; Electroencephalography; Humans; Magnetic Resonance Imaging; Neuroimaging; Reward
PubMed: 30957688
DOI: 10.1024/1422-4917/a000663 -
Canadian Journal of Psychiatry. Revue... Oct 2022To determine the efficacy and safety of blue-light therapy in seasonal and non-seasonal major depressive disorder (MDD), by comparison to active and inactive control... (Meta-Analysis)
Meta-Analysis Review
OBJECTIVES
To determine the efficacy and safety of blue-light therapy in seasonal and non-seasonal major depressive disorder (MDD), by comparison to active and inactive control conditions.
METHODS
We searched Web of Science, EMBASE, Medline, PsycInfo, and Clinicaltrials.gov through January 17, 2022, for randomized controlled trials (RCTs) using search terms for blue/blue-enhanced, light therapy, and depression/seasonal affective disorder. Two independent reviewers extracted data. The primary outcome was the difference in endpoint scores on the Structured Interview Guide for the Hamilton Depression Rating Scale - Seasonal Affective Disorder (SIGH-SAD) or the Structured Interview Guide for the Hamilton Depression Rating Scale with Atypical Depression Supplement (SIGH-ADS) between blue light and comparison conditions. Secondary outcomes were response (≥ 50% improvement from baseline to endpoint on a depression scale) and remission rates (endpoint score in the remission range).
RESULTS
Of 582 articles retrieved, we included nine RCTs ( = 347 participants) assessing blue-light therapy. Seven studies had participants with seasonal MDD and two studies included participants with non-seasonal MDD. Four studies compared blue light to an inactive light condition (efficacy studies), and five studies compared it to an active condition (comparison studies). For the primary outcome, a meta-analysis with random-effects models found no evidence for the efficacy of blue-light conditions compared to inactive conditions (mean difference [MD] = 2.43; 95% confidence interval [CI], -1.28 to 6.14, = 0.20); however, blue-light also showed no differences compared to active conditions (MD = -0.11; 95% CI, -2.38 to 2.16, = 0.93). There were no significant differences in response and remission rates between blue-light conditions and inactive or active light conditions. Blue-light therapy was overall well-tolerated.
CONCLUSIONS
The efficacy of blue-light therapy in the treatment of seasonal and non-seasonal MDD remains unproven. Future trials should be of longer duration, include larger sample sizes, and attempt to better standardize the parameters of light therapy.
Topics: Depression; Depressive Disorder, Major; Humans; Phototherapy; Randomized Controlled Trials as Topic; Seasonal Affective Disorder
PubMed: 35522196
DOI: 10.1177/07067437221097903 -
Journal of Integrative Neuroscience Jul 2022Depression is a major public health issue in numerous countries, with around 300 million people worldwide suffering from it. Typically, depressed patients are treated... (Review)
Review
Depression is a major public health issue in numerous countries, with around 300 million people worldwide suffering from it. Typically, depressed patients are treated with antidepressants or psychological therapy or a combination of both. However, there are some limitations associated with these therapies and as a result, over the past decades a number of alternative or complementary therapies have been developed. Exercise is one such option that is supported by published extensive basic and clinical research data. The aim of this review was to examine the beneficial effects of exercise in depression. Physical activity and exercise have been shown to be effective in treating mild-to-moderate depression and in reducing mortality and symptoms of major depression. However, physical activity and exercise are still underused in clinical practice. This review attempts to propose a framework to help clinicians in their decision-making process, how to incorporate physical activity in their toolkit of potential therapeutic responses for depressed patients. We first summarize the interactions between depression and physical activities, with a particular focus on the potential antidepressant physiological effects of physical activity. We then identify some of the barriers blocking physical activity from being used to fight depression. Finally, we present several perspectives and ideas that can help in optimizing mitigation strategies to challenge these barriers, including actions on physical activity representations, ways to increase the accessibility of physical activity, and the potential of technology to help both clinicians and patients.
Topics: Antidepressive Agents; Anxiety; Depression; Depressive Disorder, Major; Exercise; Humans
PubMed: 36137954
DOI: 10.31083/j.jin2105132 -
BMC Medicine Sep 2023Major depressive disorder (MDD) has a significant impact on global burden of disease. Complications in clinical management can occur when response to pharmacological...
BACKGROUND
Major depressive disorder (MDD) has a significant impact on global burden of disease. Complications in clinical management can occur when response to pharmacological modalities is considered inadequate and symptoms persist (treatment-resistant depression (TRD)). We aim to investigate inflammation, proxied by C-reactive protein (CRP) levels, and body mass index (BMI) as putative causal risk factors for depression and subsequent treatment resistance, leveraging genetic information to avoid confounding via Mendelian randomisation (MR).
METHODS
We used the European UK Biobank subcohort ([Formula: see text]), the mental health questionnaire (MHQ) and clinical records. For treatment resistance, a previously curated phenotype based on general practitioner (GP) records and prescription data was employed. We applied univariable and multivariable MR models to genetically predict the exposures and assess their causal contribution to a range of depression outcomes. We used a range of univariable, multivariable and mediation MR models techniques to address our research question with maximum rigour. In addition, we developed a novel statistical procedure to apply pleiotropy-robust multivariable MR to one sample data and employed a Bayesian bootstrap procedure to accurately quantify estimate uncertainty in mediation analysis which outperforms standard approaches in sparse binary outcomes. Given the flexibility of the one-sample design, we evaluated age and sex as moderators of the effects.
RESULTS
In univariable MR models, genetically predicted BMI was positively associated with depression outcomes, including MDD ([Formula: see text] ([Formula: see text] CI): 0.133(0.072, 0.205)) and TRD (0.347(0.002, 0.682)), with a larger magnitude in females and with age acting as a moderator of the effect of BMI on severity of depression (0.22(0.050, 0.389)). Multivariable MR analyses suggested an independent causal effect of BMI on TRD not through CRP (0.395(0.004, 0.732)). Our mediation analyses suggested that the effect of CRP on severity of depression was partly mediated by BMI. Individuals with TRD ([Formula: see text]) observationally had higher CRP and BMI compared with individuals with MDD alone and healthy controls.
DISCUSSION
Our work supports the assertion that BMI exerts a causal effect on a range of clinical and questionnaire-based depression phenotypes, with the effect being stronger in females and in younger individuals. We show that this effect is independent of inflammation proxied by CRP levels as the effects of CRP do not persist when jointly estimated with BMI. This is consistent with previous evidence suggesting that overweight contributed to depression even in the absence of any metabolic consequences. It appears that BMI exerts an effect on TRD that persists when we account for BMI influencing MDD.
Topics: Female; Humans; Body Mass Index; Depressive Disorder, Major; Bayes Theorem; Depression; Inflammation
PubMed: 37710313
DOI: 10.1186/s12916-023-03001-7