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Biological Psychiatry Global Open... Jul 2023Frequent cannabis use is associated with a higher risk of developing cannabis use disorder and other adverse consequences. However, rodent models studying the underlying...
Daily Δ-Tetrahydrocannabinol and Withdrawal Increase Dopamine D-D Receptor Heteromer to Mediate Anhedonia- and Anxiogenic-like Behavior Through a Dynorphin and Kappa Opioid Receptor Mechanism.
BACKGROUND
Frequent cannabis use is associated with a higher risk of developing cannabis use disorder and other adverse consequences. However, rodent models studying the underlying mechanisms of the reinforcing and withdrawal effects of the primary constituent of cannabis, Δ-tetrahydrocannabinol (THC), have been limited.
METHODS
This study investigated the effects of daily THC (1 mg/kg, intraperitoneal, 9 days) and spontaneous withdrawal (7 days) on hedonic and aversion-like behaviors in male rats. In parallel, underlying neuroadaptive changes in dopaminergic, opioidergic, and cannabinoid signaling in the nucleus accumbens were evaluated, along with a candidate peptide designed to reverse altered signaling.
RESULTS
Chronic THC administration induced anhedonic- and anxiogenic-like behaviors not attributable to altered locomotor activity. These effects persisted after drug cessation. In the nucleus accumbens, THC treatment and withdrawal catalyzed increased cannabinoid CB receptor activity without modifying receptor expression. Dopamine D-D receptor heteromer expression rose steeply with THC, accompanied by increased calcium-linked signaling, activation of BDNF/TrkB (brain-derived neurotrophic factor/tropomyosin receptor kinase B) pathway, dynorphin expression, and kappa opioid receptor signaling. Disruption of the D-D heteromer by an interfering peptide during withdrawal reversed the anxiogenic-like and anhedonic-like behaviors as well as the neurochemical changes.
CONCLUSIONS
Chronic THC increases nucleus accumbens dopamine D-D receptor heteromer expression and function, which results in increased dynorphin expression and kappa opioid receptor activation. These changes plausibly reduce dopamine release to trigger anxiogenic- and anhedonic-like behaviors after daily THC administration that persist for at least 7 days after drug cessation. These findings conceivably provide a therapeutic strategy to alleviate negative symptoms associated with cannabis use and withdrawal.
PubMed: 37519471
DOI: 10.1016/j.bpsgos.2022.07.003 -
CNS Neuroscience & Therapeutics Mar 2024Noninvasive brain stimulation (NIBS) techniques are a promising tool for treating the negative symptoms of schizophrenia. Growing evidence suggests that different... (Meta-Analysis)
Meta-Analysis
Is it more effective for anhedonia and avolition? A systematic review and meta-analysis of non-invasive brain stimulation interventions for negative symptoms in schizophrenia.
BACKGROUND
Noninvasive brain stimulation (NIBS) techniques are a promising tool for treating the negative symptoms of schizophrenia. Growing evidence suggests that different dimensions of negative symptoms have partly distinct underlying pathophysiological mechanisms. Previous randomized controlled trials (RCTs) have shown inconsistent impacts of NIBS across dimensions.
OBJECTIVE
This systematic review and meta-analysis evaluated the effects of NIBS on general negative symptoms, and on specific domains, including blunted affect, alogia, asociality, anhedonia, and avolition.
DATA SOURCES
PubMed, Web of Science, Embase, Cochrane CENTRAL, PsycINFO, OpenGrey, and Clinicaltrials.gov from the first date available to October, 2023.
RESULTS
Among 1049 studies, we identified eight high-quality RCTs. NIBS significantly affects general negative symptoms (SMD = -0.54, 95% CI [-0.88, -0.21]) and all five domains (SMD = -0.32 to -0.63). Among dimensions, better effects have been shown for improvement of avolition (SMD = -0.47, 95% CI [-0.81, -0.13]) and anhedonia (SMD = -0.63, 95% CI [-0.98, -0.28]). Subgroup analyses of studies that applied once daily stimulation or >10 sessions showed significantly reduced negative symptom severity.
CONCLUSION
NIBS exerts distinct effects across multiple dimensions of negative symptom, with treatment effects related to stimulation frequency and total sessions. These results need to be confirmed in dedicated studies.
Topics: Humans; Anhedonia; Brain; PubMed; Schizophrenia; Electric Stimulation Therapy
PubMed: 38432851
DOI: 10.1111/cns.14645 -
Biological Psychiatry May 2024Chronic low-grade inflammation is observed across mental disorders and is associated with difficult-to-treat-symptoms of anhedonia and functional brain changes -...
BACKGROUND
Chronic low-grade inflammation is observed across mental disorders and is associated with difficult-to-treat-symptoms of anhedonia and functional brain changes - reflecting a potential transdiagnostic dimension. Previous investigations have focused on distinct illness categories in those with enduring illness, with few exploring inflammatory changes. We sought to identify an inflammatory signal and associated brain function underlying anhedonia among young people with recent onset psychosis (ROP) and recent onset depression (ROD).
METHOD
Resting-state functional magnetic resonance imaging, inflammatory markers, and anhedonia symptoms were collected from N=108 (M age=26.2[SD 6.2]years; Female =50) participants with ROP (n=53) and ROD (n=55) from the EU-FP7-funded PRONIA study. Time-series were extracted using the Schaefer atlas, defining 100 cortical regions of interest. Using advanced multimodal machine learning, an inflammatory marker model and functional connectivity model were developed to classify an anhedonic group, compared to a normal hedonic group.
RESULTS
A repeated nested cross-validation model using inflammatory markers classified normal hedonic and anhedonic ROP/ROD groups with a balanced accuracy (BAC) of 63.9%, and an area under the curve (AUC) of 0.61. The functional connectivity model produced a BAC of 55.2% and an AUC of 0.57. Anhedonic group assignment was driven by higher levels of Interleukin-6, S100B, and Interleukin-1 receptor antagonist, and lower levels of Interferon gamma, in addition to connectivity within the precuneus and posterior cingulate.
CONCLUSION
We identified a potential transdiagnostic anhedonic subtype that was accounted for by an inflammatory profile and functional connectivity. Results have implications for anhedonia as an emerging transdiagnostic target across emerging mental disorders.
PubMed: 38823495
DOI: 10.1016/j.biopsych.2024.05.019 -
BJPsych Open Nov 2023There is a common perception that creativity is associated with psychopathology. Previous studies have shown that members of creative groups such as comedians, artists...
BACKGROUND
There is a common perception that creativity is associated with psychopathology. Previous studies have shown that members of creative groups such as comedians, artists and scientists scores higher than the norm on psychotic traits, and scientists in STEM (science, technology, engineering and mathematics) fields score highly on autistic traits.
AIMS
To test whether magicians, a creative group that has not been studied before, also score highly on psychopathological traits and autism, and to test the associations of creative self-efficacy and creative identity with schizotypal and autistic traits among magicians.
METHOD
A sample of 195 magicians and 233 people from the general population completed measures of schizotypal traits (Oxford-Liverpool Inventory of Feelings and Experiences) and autism (Abridged Version of the Autism-Spectrum Quotient), as well as the Short Scale of Creative Self. Magicians were also compared with other creative groups with respect to schizotypal traits, based on previously published data.
RESULTS
Magicians scored lower than the general population sample on three of the four schizophrenia measures (cognitive disorganisation, introvertive anhedonia and impulsive nonconformity) but did not differ with respect to unusual experiences or autism scores. Magicians scored higher on creative self-efficacy and creative personal identity than the general sample. Magicians' scores on schizotypal traits were largely lower than those of other creative groups. Originality of magic was positively correlated with unusual experiences ( = 0.208), creative self-efficacy ( = 0.251) and creative identity ( = 0.362).
CONCLUSIONS
This is the first study to show a creative group with lower scores than norms on psychotic traits. The results highlight the unique characteristics of magicians and the possible myriad associations between creativity and mental disorders among creative groups.
PubMed: 37964594
DOI: 10.1192/bjo.2023.609 -
Psychological Medicine Sep 2023Irremediability is a key requirement for euthanasia and assisted suicide for psychiatric disorders (psychiatric EAS). Countries like the Netherlands and Belgium ask... (Review)
Review
BACKGROUND
Irremediability is a key requirement for euthanasia and assisted suicide for psychiatric disorders (psychiatric EAS). Countries like the Netherlands and Belgium ask clinicians to assess irremediability in light of the patient's diagnosis and prognosis and 'according to current medical understanding'. Clarifying the relevance of a default objective standard for irremediability when applied to psychiatric EAS is crucial for solid policymaking. Yet so far, a thorough examination of this standard is lacking.
METHODS
Using treatment-resistant depression (TRD) as a test case, through a scoping review in PubMed, we analyzed the state-of-the-art evidence for whether clinicians can accurately predict individual long-term outcome and single out irremediable cases, by examining the following questions: (1) What is the definition of TRD; (2) What are group-level long-term outcomes of TRD; and (3) Can clinicians make accurate individual outcome predictions in TRD?
RESULTS
A uniform definition of TRD is lacking, with over 150 existing definitions, mostly focused on psychopharmacological research. Available yet limited studies about long-term outcomes indicate that a majority of patients with long-term TRD show significant improvement over time. Finally, evidence about individual predictions in TRD using precision medicine is growing, but methodological shortcomings and varying predictive accuracies pose important challenges for its implementation in clinical practice.
CONCLUSION
Our findings support the claim that, as per available evidence, clinicians cannot accurately predict long-term chances of recovery in a particular patient with TRD. This means that the objective standard for irremediability cannot be met, with implications for policy and practice of psychiatric EAS.
Topics: Humans; Euthanasia; Suicide, Assisted; Netherlands; Depressive Disorder, Treatment-Resistant; Belgium
PubMed: 36305567
DOI: 10.1017/S0033291722002951 -
The Patient's Perspective on the Effects of Intranasal Esketamine in Treatment-Resistant Depression.Brain Sciences Oct 2023The effectiveness of the esketamine nasal spray (ESK-NS) for treatment-resistant depression (TRD) has been confirmed by real-world studies. Available evidence derived...
The effectiveness of the esketamine nasal spray (ESK-NS) for treatment-resistant depression (TRD) has been confirmed by real-world studies. Available evidence derived from clinician-rated assessments might differ from patients' perceptions about the helpfulness of treatments. We aimed to verify the effect of ESK-NS from patients' view in 25 TRD patients (56% males, 55.1 ± 10.9 years) treated with ESK-NS (mean dose: 78.4 ± 11.43 mg) for three months and evaluated at different time-points through clinician-rated and self-administered scales, assessing changes in depression, anhedonia, sleep, cognition, suicidality, and anxiety. We observed an overall early improvement that lasted over time (endpoint total score reduction in Montgomery-Åsberg Depression Rating Scale, < 0.001, Beck Depression Inventory, = 0.003). Patients reported a significant self-rated decrease in anhedonia at two months (Snaith-Hamilton Pleasure Scale, = 0.04) and in suicide ideation at endpoint (BDI subitem 9, = 0.039) vs. earlier improvements detected by clinicians (one-month reduction in MADRS subitem 8, = 0.005, and subitem 10, = 0.007). These findings confirm the effectiveness of a three-month treatment with ESK-NS in TRD patients, highlighting an overall overlapping response from patients' and clinicians' perspectives, although with some differential effects on specific symptoms at given time-points. Including patients' viewpoints in routine assessments could inform clinical practice, ensuring a better characterization of clinical phenotypes to deliver personalized interventions.
PubMed: 37891860
DOI: 10.3390/brainsci13101494 -
JMIR Public Health and Surveillance Nov 2023Bullying victimization is highly prevalent among sexual minority youths, particularly in educational settings, negatively affecting their mental health. However,...
BACKGROUND
Bullying victimization is highly prevalent among sexual minority youths, particularly in educational settings, negatively affecting their mental health. However, previous studies have scarcely explored the symptomatic relationships among anxiety, depression, and posttraumatic stress disorder (PTSD) among sexual minority youths who experienced bullying on college campuses.
OBJECTIVE
The objectives of our study were to (1) characterize the anxiety-depression-PTSD network structures of gay or lesbian, bisexuals, and other sexual minority youths previously bullied on college campuses; and (2) compare symptomatic associations in the anxiety-depression-PTSD networks among bullied sexual minority youths and heterosexual youths' groups.
METHODS
This cross-sectional study recruited college participants from Jilin Province, China. Data were analyzed using a subset of the data extracted after screening for sexual orientation and history of bullying victimization. Sexual minority youths were then divided into 3 subgroups: gay or lesbian (homosexual), bisexual, and other. Mental health symptom severity was assessed using scales: the 7-item Generalized Anxiety Disorder Scale measuring anxiety, the 9-item Patient Health Questionnaire measuring depression, and the 10-item Trauma Screening Questionnaire measuring PTSD symptoms. Combining the undirected and Bayesian network analyses, the anxiety-depression-PTSD networks were compared among sexual minority youths subgroups, and the difference between heterosexual youths and sexual minority youths was investigated. Chi-square tests were used to compare the difference in categorical variables, while independent-sample t tests were run on continuous variables.
RESULTS
In this large-scale sample of 89,342 participants, 12,249 identified as sexual minority youths, of which 1603 (13.1%, 95% CI 12.5%-13.7%) reported being bullied on college campuses in the past year. According to the expected influence (EI) and bridge expected influence (bEI) index, in the global network structure of anxiety, depression, and PTSD, sad mood (EI=1.078, bEI=0.635) and irritability (EI=1.077, bEI=0.954) were identified as central and bridge symptoms; emotional cue reactivity (EI=1.015) was a central symptom of PTSD in this global network. In the anxiety-depression-PTSD Bayesian network, anhedonia had the highest prediction priority for activating other symptoms; and feeling afraid linked symptoms from anxiety to the PTSD community. Compared to their heterosexual counterparts, sexual minority youths exhibited a stronger association between difficulty concentrating and appetite. The "sad mood-appetite" edge was strongest in the gay or lesbian network; the "irritability-exaggerated startle response" edge was strongest in the bisexual network.
CONCLUSIONS
For the first time, this study identified the most central and bridge symptoms (sad mood and irritability) within the depression-anxiety-PTSD network of sexual minority youths with past bullying-victim experiences on college campuses. Emotional cue reactivity, anhedonia, and feeling afraid were other vital symptoms in the comorbid network. Symptomatic relationships existed showing heterogeneity in bullied heterosexual youths and sexual minority youth networks, which also was present within the sexual minority youth subgroups. Consequently, refined targeted interventions are required to relieve anxiety, depression, and PTSD symptoms.
Topics: Adolescent; Female; Humans; Male; Stress Disorders, Post-Traumatic; Anhedonia; Bayes Theorem; Cross-Sectional Studies; Depression; Anxiety; Sexual and Gender Minorities; Bullying
PubMed: 37910159
DOI: 10.2196/47233 -
Neuropsychopharmacology : Official... Nov 2023Early-life stress (ELS) leaves signatures upon the brain that persist throughout the lifespan and increase the risk of psychiatric illnesses including mood and anxiety...
Early-life stress (ELS) leaves signatures upon the brain that persist throughout the lifespan and increase the risk of psychiatric illnesses including mood and anxiety disorders. In humans, myriad forms of ELS-including childhood abuse, bullying, poverty, and trauma-are increasingly prevalent. Understanding the signs of ELS, including those associated with psychiatric illness, will enable improved treatment and prevention. Here, we developed a novel procedure to model human ELS in mice and identify translationally-relevant biomarkers of mood and anxiety disorders. We exposed male mice (C57BL/6 J) to an early-life (juvenile) chronic social defeat stress (jCSDS) and examined social interaction and responsivity to reward during adulthood. As expected, jCSDS-exposed mice showed a socially avoidant phenotype in open-field social interaction tests. However, sucrose preference tests failed to demonstrate ELS-induced reductions in choice for the sweetened solution, suggesting no effect on reward function. To explore whether other tasks might be more sensitive to changes in motivation, we tested the mice in the Probabilistic Reward Task (PRT), a procedure often used in humans to study reward learning deficits associated with depressive illness. In a touchscreen PRT variant that was reverse-translated to maximize alignment with the version used in human subjects, mice exposed to jCSDS displayed significant reductions in the tendency to develop response biases for the more richly-rewarded stimulus, a hallmark sign of anhedonia when observed in humans. Our findings suggest that translationally-relevant procedures that utilize the same endpoints across species may enable the development of improved model systems that more accurately predict outcomes in humans.
Topics: Humans; Mice; Male; Child; Animals; Adult; Adverse Childhood Experiences; Stress, Psychological; Mice, Inbred C57BL; Brain; Reward
PubMed: 37258714
DOI: 10.1038/s41386-023-01610-7 -
BMC Psychiatry Feb 2024Mood disorders are strongly associated with melatonin disturbances. However, it is unclear whether there is a difference in melatonin concentrations and melatonin...
BACKGROUND
Mood disorders are strongly associated with melatonin disturbances. However, it is unclear whether there is a difference in melatonin concentrations and melatonin circadian rhythm profiles between depression and bipolar disorder. In addition, the relationship between anhedonia, a common symptom of affective disorders, and its melatonin circadian rhythm remains under-investigated.
METHODS
Thirty-four patients with depression disorder, 20 patients diagnosed with bipolar disorder and 21 healthy controls participated in this study. The Revised Physical Anhedonia Scale (RPAS) was performed to assess anhedonia. Saliva samples were collected from all subjects at fixed time points (a total of 14 points) in two consecutive days for measuring the melatonin concentrations to fit circadian rhythms of subjects. Melatonin circadian rhythms were compared between the three groups using ANOVA. Partial correlation analysis and linear regression analysis were used to explore the correlation between melatonin rhythm variables and anhedonia.
RESULTS
We found that the peak phase of melatonin in the depression group was significantly advanced compared to the control group (P < 0.001) and the bipolar disorder group (P = 0.004). The peak phase of melatonin and RPAS showed a negative correlation (P = 0.003) in depression patients, which was also demonstrated in the multiple linear regression model (B=-2.47, P = 0.006).
CONCLUSIONS
These results suggest that circadian rhythms of melatonin are differentiated in depression and bipolar disorder and correlate with anhedonia in depression. Future research needs to explore the neurobiological mechanisms linking anhedonia and melatonin circadian rhythms in depressed patients.
Topics: Humans; Mood Disorders; Anhedonia; Melatonin; Cross-Sectional Studies; Circadian Rhythm
PubMed: 38413912
DOI: 10.1186/s12888-024-05606-5 -
BMJ Open Nov 2023Many depressed patients do not achieve remission with available treatments. Anhedonia is a common residual symptom associated with treatment resistance as well as low...
INTRODUCTION
Many depressed patients do not achieve remission with available treatments. Anhedonia is a common residual symptom associated with treatment resistance as well as low function and quality of life. There are currently no specific and effective treatments for anhedonia. Some trials have shown that dopamine agonist pramipexole is efficacious for treating depression, but more data is needed before it could become ready for clinical prime time. Given its mechanism of action, pramipexole might be a useful treatment for a depression subtype characterised by significant anhedonia and lack of motivation-symptoms associated with dopaminergic hypofunction. We recently showed, in an open-label pilot study, that add-on pramipexole is a feasible treatment for depression with significant anhedonia, and that pramipexole increases reward-related activity in the ventral striatum. We will now confirm or refute these preliminary results in a randomised controlled trial (RCT) and an open-label follow-up study.
METHODS AND ANALYSIS
Eighty patients with major depression (bipolar or unipolar) or dysthymia and significant anhedonia according to the Snaith Hamilton Pleasure Scale (SHAPS) are randomised to either add-on pramipexole or placebo for 9 weeks. Change in anhedonia symptoms per the SHAPS is the primary outcome, and secondary outcomes include change in core depressive symptoms, apathy, sleep problems, life quality, anxiety and side effects. Accelerometers are used to assess treatment-associated changes in physical activity and sleep patterns. Blood and brain biomarkers are investigated as treatment predictors and to establish target engagement. After the RCT phase, patients continue with open-label treatment in a 6-month follow-up study aiming to assess long-term efficacy and tolerability of pramipexole.
ETHICS AND DISSEMINATION
The study has been approved by the Swedish Ethical Review Authority and the Swedish Medical Products Agency. The study is externally monitored according to Good Clinical Practice guidelines. Results will be disseminated via conference presentations and peer-reviewed publications.
TRIAL REGISTRATION NUMBER
NCT05355337 and NCT05825235.
Topics: Humans; Pramipexole; Sweden; Depression; Anhedonia; Follow-Up Studies; Randomized Controlled Trials as Topic
PubMed: 38035737
DOI: 10.1136/bmjopen-2023-076900