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Journal of Psychiatric Research Jun 2024One-third of people with depression do not respond to antidepressants, and, after two adequate courses of antidepressants, are classified as having treatment-resistant... (Randomized Controlled Trial)
Randomized Controlled Trial
Evaluating the efficacy and mechanisms of a ketogenic diet as adjunctive treatment for people with treatment-resistant depression: A protocol for a randomised controlled trial.
BACKGROUND
One-third of people with depression do not respond to antidepressants, and, after two adequate courses of antidepressants, are classified as having treatment-resistant depression (TRD). Some case reports suggest that ketogenic diets (KDs) may improve some mental illnesses, and preclinical data indicate that KDs can influence brain reward signalling, anhedonia, cortisol, and gut microbiome which are associated with depression. To date, no trials have examined the clinical effect of a KD on TRD.
METHODS
This is a proof-of-concept randomised controlled trial to investigate the efficacy of a six-week programme of weekly dietitian counselling plus provision of KD meals, compared with an intervention involving similar dietetic contact time and promoting a healthy diet with increased vegetable consumption and reduction in saturated fat, plus food vouchers to purchase healthier items. At 12 weeks we will assess whether participants have continued to follow the assigned diet. The primary outcome is the difference between groups in the change in Patient Health Questionnaire-9 (PHQ-9) score from baseline to 6 weeks. PHQ-9 will be measured at weeks 2, 4, 6 and 12. The secondary outcomes are the differences between groups in the change in remission of depression, change in anxiety score, functioning ability, quality of life, cognitive performance, reward sensitivity, and anhedonia from baseline to 6 and 12 weeks. We will also assess whether changes in reward sensitivity, anhedonia, cortisol awakening response and gut microbiome may explain any changes in depression severity.
DISCUSSION
This study will test whether a ketogenic diet is an effective intervention to reduce the severity of depression, anxiety and improve quality of life and functioning ability for people with treatment-resistant depression.
Topics: Humans; Diet, Ketogenic; Depressive Disorder, Treatment-Resistant; Adult; Combined Modality Therapy; Male; Female; Proof of Concept Study; Middle Aged; Outcome Assessment, Health Care; Young Adult
PubMed: 38653031
DOI: 10.1016/j.jpsychires.2024.04.023 -
PloS One 2024Groove, or the pleasurable urge to move to music, offers unique insight into the relationship between emotion and action. The predictive coding of music model posits...
Groove, or the pleasurable urge to move to music, offers unique insight into the relationship between emotion and action. The predictive coding of music model posits that groove is linked to predictions of music formed over time, with stimuli of moderate complexity rated as most pleasurable and likely to engender movement. At the same time, listeners vary in the pleasure they derive from music listening: individuals with musical anhedonia report reduced pleasure during music listening despite no impairments in music perception and no general anhedonia. Little is known about musical anhedonics' subjective experience of groove. Here we examined the relationship between groove and music reward sensitivity. Participants (n = 287) heard drum-breaks that varied in perceived complexity, and rated each for pleasure and wanting to move. Musical anhedonics (n = 13) had significantly lower ratings compared to controls (n = 13) matched on music perception abilities and general anhedonia. However, both groups demonstrated the classic inverted-U relationship between ratings of pleasure & move and stimulus complexity, with ratings peaking for intermediately complex stimuli. Across our entire sample, pleasure ratings were most strongly related with music reward sensitivity for highly complex stimuli (i.e., there was an interaction between music reward sensitivity and stimulus complexity). Finally, the sensorimotor subscale of music reward was uniquely associated with move, but not pleasure, ratings above and beyond the five other dimensions of musical reward. Results highlight the multidimensional nature of reward sensitivity and suggest that pleasure and wanting to move are driven by overlapping but separable mechanisms.
Topics: Humans; Music; Anhedonia; Female; Male; Adult; Pleasure; Reward; Young Adult; Auditory Perception; Emotions; Adolescent; Acoustic Stimulation
PubMed: 38652721
DOI: 10.1371/journal.pone.0301478 -
Progress in Neuro-psychopharmacology &... Jul 2024Reserpine (RES), a Vesicular Monoamine Transporter 2 (VMAT) inhibitor agent, has been used in preclinical research for many years to create animal models for depression...
BACKGROUND
Reserpine (RES), a Vesicular Monoamine Transporter 2 (VMAT) inhibitor agent, has been used in preclinical research for many years to create animal models for depression and to test experimental antidepressant strategies. Nevertheless, evidence of the potential use and validity of RES as a chronic pharmacological model for depression is lacking, and there are no comprehensive studies of the behavioral effects in conjunction with molecular outcomes.
METHODS
Experiment 1. Following baseline behavior testing sensitive to depression-like phenotype and locomotion (Phase 1), 27 Sprague-Dawley (SD) rats received i.p. either vehicle solution (0.0 mg/kg), low (0.2 mg/kg) or high (0.8 mg/kg) RES dose for 20 days using a pre-determined schedule and reassessed for behavioral phenotypes (Phase 2). After 10 days washout period, and a final behavioral assessment (Phase 3), the brains were collected 16 days after the last injection for mRNA-expression assessment. Experiment 2. In a similar timetable as in Experiment 1 but without the behavioral testing, 12 SD rats underwent repetitive dopamine D receptor PET scanning with [F]DMFP following each Phase. The binding potential (BP) of [F]DMFP was quantified by kinetic analysis as a marker of striatal DR availability. Weight and welfare were monitored throughout the study.
RESULTS
Significant, dose-dependent weight loss and behavioral deficits including both motor (hypo-locomotion) and non-motor behavior (anhedonia, mild anxiety and reduced exploration) were found for both the low and high dose groups with significant decrease in DR mRNA expression in the accumbal region for the low RES group after Phase 3. Both RES treated groups showed substantial increase in [F]DMFP BP (in line with dopamine depletion) during Phase 2 and 3 compared to baseline and Controls.
CONCLUSIONS
The longitudinal design of the study demonstrated that chronic RES administration induced striatal dopamine depletion that persisted even after the wash-out period. However, the behavior phenotype observed were transient. The data suggest that RES administration can induce a rodent model for depression with mild face validity.
Topics: Animals; Reserpine; Positron-Emission Tomography; Rats, Sprague-Dawley; Disease Models, Animal; Male; Rats; Depression; Behavior, Animal; Receptors, Dopamine; Dose-Response Relationship, Drug; Brain; Vesicular Monoamine Transport Proteins; Motor Activity
PubMed: 38636702
DOI: 10.1016/j.pnpbp.2024.111013 -
Psychiatry Research Jun 2024Approximately half of generalised anxiety disorder (GAD) patients do not recover from first-line treatments, and no validated prediction models exist to inform...
Approximately half of generalised anxiety disorder (GAD) patients do not recover from first-line treatments, and no validated prediction models exist to inform individuals or clinicians of potential treatment benefits. This study aimed to develop and validate an accurate and explainable prediction model of post-treatment GAD symptom severity. Data from adults receiving treatment for GAD in eight Improving Access to Psychological Therapies (IAPT) services (n=15,859) were separated into training, validation and holdout datasets. Thirteen machine learning algorithms were compared using 10-fold cross-validation, against two simple clinically relevant comparison models. The best-performing model was tested on the holdout dataset and model-specific explainability measures identified the most important predictors. A Bayesian Additive Regression Trees model out-performed all comparison models (MSE=16.54 [95 % CI=15.58; 17.51]; MAE=3.19; R²=0.33, including a single predictor linear regression model: MSE=20.70 [95 % CI=19.58; 21.82]; MAE=3.94; R²=0.14). The five most important predictors were: PHQ-9 anhedonia, GAD-7 annoyance/irritability, restlessness and fear items, then the referral-assessment waiting time. The best-performing model accurately predicted post-treatment GAD symptom severity using only pre-treatment data, outperforming comparison models that approximated clinical judgement and remaining within the GAD-7 error of measurement and minimal clinically important differences. This model could inform treatment decision-making and provide desired information to clinicians and patients receiving treatment for GAD.
Topics: Humans; Machine Learning; Anxiety Disorders; Adult; Male; Female; Middle Aged; Severity of Illness Index; Psychotherapy; Bayes Theorem; Young Adult
PubMed: 38608539
DOI: 10.1016/j.psychres.2024.115910 -
Spanish Journal of Psychiatry and... Sep 2023Negative symptoms (NS) include asociality, avolition, anhedonia, alogia, and blunted affect and are linked to poor prognosis. It has been suggested that they reflect two...
INTRODUCTION
Negative symptoms (NS) include asociality, avolition, anhedonia, alogia, and blunted affect and are linked to poor prognosis. It has been suggested that they reflect two different factors: diminished expression (EXP) (blunted affect and alogia) and amotivation/pleasure (MAP) (anhedonia, avolition, asociality). The aim of this article was to examine potential sex differences among first-episode schizophrenia (FES) patients and analyze sex-related predictors of two NS symptoms factors (EXP and MAP) and functional outcome.
MATERIAL AND METHODS
Two hundred and twenty-three FES (71 females and 152 males) were included and evaluated at baseline, six-months and one-year. Repeated measures ANOVA was used to examine the effects of time and sex on NS and a multiple linear regression backward elimination was performed to predict NS factors (MAP-EXP) and functioning.
RESULTS
Females showed fewer NS (p=0.031; Cohen's d=-0.312), especially those related to EXP (p=0.024; Cohen's d=-0.326) rather than MAP (p=0.086), than males. In both male and female group, worse premorbid adjustment and higher depressive symptoms made a significant contribution to the presence of higher deficits in EXP at one-year follow-up, while positive and depressive symptoms predicted alterations in MAP. Finally, in females, lower deficits in MAP and better premorbid adjustment predicted better functioning at one-year follow-up (R=0.494; p<0.001), while only higher deficits in MAP predicted worse functioning in males (R=0.088; p=0.012).
CONCLUSIONS
Slightly sex differences have been found in this study. Our results lead us to consider that early interventions of NS, especially those focusing on motivation and pleasure symptoms, could improve functional outcomes.
PubMed: 38591832
DOI: 10.1016/j.sjpmh.2023.04.001 -
Frontiers in Psychiatry 2024Individuals with depression who do not respond to two or more courses of serotonergic antidepressants tend to have greater deficits in reward processing and greater...
INTRODUCTION
Individuals with depression who do not respond to two or more courses of serotonergic antidepressants tend to have greater deficits in reward processing and greater internalizing symptoms, yet there is no validated self-report method to determine the likelihood of treatment resistance based on these symptom dimensions.
METHODS
This online case-control study leverages machine learning techniques to identify differences in self-reported anhedonia and internalizing symptom profiles of antidepressant non-responders compared to responders and healthy controls, as an initial proof-of-concept for relating these indicators to medication responsiveness. Random forest classifiers were used to identify a subset from a set of 24 reward predictors that distinguished among serotonergic medication resistant, non-resistant, and non-depressed individuals recruited online ( = 393). Feature selection was implemented to refine model prediction and improve interpretability.
RESULTS
Accuracies for full predictor models ranged from .54 to .71, while feature selected models retained 3-5 predictors and generated accuracies of .42 to .70. Several models performed significantly above chance. Sensitivity for non-responders was greatest after feature selection when compared to only responders, reaching .82 with 3 predictors. The predictors retained from feature selection were then explored using factor analysis at the item level and cluster analysis of the full data to determine empirically driven data structures.
DISCUSSION
Non-responders displayed 3 distinct symptom profiles along internalizing dimensions of anxiety, anhedonia, motivation, and cognitive function. Results should be replicated in a prospective cohort sample for predictive validity; however, this study demonstrates validity for using a limited anhedonia and internalizing self-report instrument for distinguishing between antidepressant resistant and responsive depression profiles.
PubMed: 38590792
DOI: 10.3389/fpsyt.2024.1349576 -
Pharmacology & Therapeutics Jun 2024Major depression is an established risk factor for subsequent dementia, and depression in late life may also represent a prodromal state of dementia. Considering current... (Review)
Review
Major depression is an established risk factor for subsequent dementia, and depression in late life may also represent a prodromal state of dementia. Considering current challenges in the clinical development of disease modifying therapies for dementia, the focus of research is shifting towards prevention and modification of risk factors to alter the neurodegenerative disease trajectory. Understanding mechanistic commonalities underlying affective symptoms and cognitive decline may reveal biomarkers to aid early identification of those at risk of progressing to dementia during the preclinical phase of disease, thus allowing for timely intervention. Adult hippocampal neurogenesis (AHN) is a phenomenon that describes the birth of new neurons in the dentate gyrus throughout life and it is associated with spatial learning, memory and mood regulation. Microglia are innate immune system macrophages in the central nervous system that carefully regulate AHN via multiple mechanisms. Disruption in AHN is associated with both dementia and major depression and microgliosis is a hallmark of several neurodegenerative diseases. Emerging evidence suggests that psychedelics promote neuroplasticity, including neurogenesis, and may also be immunomodulatory. In this context, psilocybin, a serotonergic agonist with rapid-acting antidepressant properties has the potential to ameliorate intersecting pathophysiological processes relevant for both major depression and neurodegenerative diseases. In this narrative review, we focus on the evidence base for the effects of psilocybin on adult hippocampal neurogenesis and microglial form and function; which may suggest that psilocybin has the potential to modulate multiple mechanisms of action, and may have implications in altering the progression from major depression to dementia in those at risk.
Topics: Humans; Dementia; Animals; Neurodegenerative Diseases; Depressive Disorder, Major; Neurogenesis; Psilocybin; Hippocampus; Hallucinogens; Antidepressive Agents; Microglia
PubMed: 38583670
DOI: 10.1016/j.pharmthera.2024.108641 -
Frontiers in Psychiatry 2024Catatonia has been increasingly associated with mood disorders and is recognized as a specifier in the DSM-5 and DSM-5-TR. The DSM-5-TR recognizes melancholia as a...
BACKGROUND
Catatonia has been increasingly associated with mood disorders and is recognized as a specifier in the DSM-5 and DSM-5-TR. The DSM-5-TR recognizes melancholia as a specifier for depressive episodes in major depressive disorder and bipolar disorder. It is characterized by severe anhedonia, lack of reactivity, excessive or delusional guilt, and significant vegetative symptoms. As the conceptualization of melancholia expanded beyond its mood components to include psychomotor disturbances, its overlap with psychomotor symptoms or catatonia becomes evident. This overlap was also described in Kahlbaum's original literature, where he describes the transition between states of melancholia, mania, and catatonia.
METHOD
Case summary of six patients with major depressive disorder or depressed phase of bipolar disorder who were admitted for severe depression, anhedonia, intense anxiety, psychomotor agitation or retardation, indecisiveness, perseveration, and vegetative symptoms such as poor sleep, appetite, and significant weight loss.
RESULTS
All patients demonstrated rapid and complete resolution of their mood and psychomotor symptoms, indecisiveness, perseveration, as well as psychosis shortly after administration of lorazepam, with recurrence of the above symptoms upon lorazepam discontinuation and resolution upon resumption, in an on-and-off manner.
CONCLUSION
The present study argues for a closer relationship between melancholia and catatonia based on our case series, historical review, overlap in phenomenology, and response to treatment. We propose provisional [Mahgoub] criteria for patients with severe depression and melancholia. The role of GABA agonists, such as lorazepam, can be explored as an option for patients with treatment-resistant depression who meet these criteria for melancholia.
LIMITATIONS
Absence of a standardized, systematic assessment tool and a small sample size.
PubMed: 38571997
DOI: 10.3389/fpsyt.2024.1372136 -
Scientific Reports Apr 2024The health crisis caused by COVID-19 in the United Kingdom and the confinement measures that were subsequently implemented had unprecedented effects on the mental health...
The health crisis caused by COVID-19 in the United Kingdom and the confinement measures that were subsequently implemented had unprecedented effects on the mental health of older adults, leading to the emergence and exacerbation of different comorbid symptoms including depression and anxiety. This study examined and compared depression and anxiety symptom networks in two specific quarantine periods (June-July and November-December) in the older adult population in the United Kingdom. We used the database of the English Longitudinal Study of Aging COVID-19 Substudy, consisting of 5797 participants in the first stage (54% women) and 6512 participants in the second stage (56% women), all over 50 years of age. The symptoms with the highest centrality in both times were: "Nervousness (A1)" and "Inability to relax (A4)" in expected influence and predictability, and "depressed mood (D1"; bridging expected influence). The latter measure along with "Irritability (A6)" overlapped in both depression and anxiety clusters in both networks. In addition, a the cross-lagged panel network model was examined in which a more significant influence on the direction of the symptom "Nervousness (A1)" by the depressive symptoms of "Anhedonia (D6)", "Hopelessness (D7)", and "Sleep problems (D3)" was observed; the latter measure has the highest predictive capability of the network. The results report which symptoms had a higher degree of centrality and transdiagnostic overlap in the cross-sectional networks (invariants) and the cross-lagged panel network model of anxious and depressive symptomatology.
Topics: Female; Humans; Middle Aged; Aged; Male; Depression; Cross-Sectional Studies; Longitudinal Studies; Pandemics; COVID-19; Anxiety; United Kingdom
PubMed: 38565592
DOI: 10.1038/s41598-024-58256-8 -
Biochemical Pharmacology May 2024Treatment of major depressive disorder remains a major unmet clinical need. Given the advantages of intranasal administration for targeted brain delivery, the present...
Treatment of major depressive disorder remains a major unmet clinical need. Given the advantages of intranasal administration for targeted brain delivery, the present study aimed at investigating the pharmacokinetics of paroxetine, after its intranasal instillation and assessing its potential therapeutic effect on female and male mice subjected to unpredictable chronic mild stress (UCMS) protocol. IN administration revealed direct nose-to-brain paroxetine delivery but dose- and sex-dependent differences. Pharmacokinetics was nonlinear and paroxetine concentrations were consistently higher in plasma and brain of male mice. Additionally, UCMS decreased animal preference for sucrose in both male and female mice following acute (p < 0.01) and chronic stress (p < 0.05), suggesting anhedonia. Both male and female mice exhibited depressive-like behavior in the forced swimming test. UCMS females displayed a significantly longer immobility time and shorter climbing time than the control group (p < 0.05), while no differences were found between male mice. Two weeks of paroxetine intranasal administration reduced immobility time and lengthened climbing and swimming time, approaching values similar to those observed in the healthy control group. The therapeutic effect was stronger on female mice. Importantly, melatonin plasma levels were significantly decreased in female mice following UCMS (p < 0.05), while males exhibited heightened corticosterone levels. On the other hand, treatment with IN paroxetine significantly increased corticosterone and melatonin levels in both sexes compared to healthy mice (p < 0.05). Intranasal paroxetine delivery undoubtedly ameliorated the behavioral despair, characteristic of depressive-like animals. Despite its efficiency in male and female mice subjected to UCMS, females were more prone to this novel therapeutic strategy.
Topics: Female; Mice; Male; Animals; Paroxetine; Depressive Disorder, Major; Administration, Intranasal; Sex Characteristics; Corticosterone; Melatonin; Depression; Disease Models, Animal; Stress, Psychological
PubMed: 38556027
DOI: 10.1016/j.bcp.2024.116184