-
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 -
Journal of Affective Disorders Oct 2023Growing evidence indicates that anhedonia is a multifaceted construct. This study examined the possibility of identifying subgroups of people with anhedonia using...
BACKGROUND
Growing evidence indicates that anhedonia is a multifaceted construct. This study examined the possibility of identifying subgroups of people with anhedonia using multiple reward-related measures to provide greater understanding the Research Domain Criteria's Positive Valence Systems Domain and pathways for developing treatments.
METHODS
Latent profile analysis of baseline data from a study that examined the effects of a novel kappa opioid receptor (KOR) antagonist drug on measures and biomarkers associated with anhedonia was used to identify subgroups. Measures included ventral striatal activation during the Monetary Incentive Delay task, response bias in the Probabilistic Reward Task, reward valuation scores from the Effort-Expenditure for Rewards Task, and scores from reward-related self-report measures.
RESULTS
Two subgroups were identified, which differed on self-report measures of reward. Participants in the subgroup reporting more anhedonia also reported more depression and had greater illness severity and functional impairments. Graphs of change with treatment showed a trend for the less severe subgroup to demonstrate higher response to KOR antagonist treatment on the neuroimaging measure, probabilistic reward task, and ratings of functioning; the subgroup with greater severity showed a trend for higher treatment response on reward-related self-report measures.
LIMITATIONS
The main limitations include the small sample size and exploratory nature of analyses.
CONCLUSIONS
Evidence of possible dissociation between self-reported measures of anhedonia and other measures with respect to treatment response emerged. These results highlight the importance for future research to consider severity of self-reported reward-related deficits and how the relationship across measurement methods may vary with severity.
Topics: Humans; Anhedonia; Reward; Motivation; Self Report; Neuroimaging
PubMed: 37467805
DOI: 10.1016/j.jad.2023.07.081 -
Current Research in Neurobiology 2023Earlier age of cannabis usage poses higher risk of Cannabis Use Disorder and adverse consequences, such as addiction, anxiety, dysphoria, psychosis, largely attributed...
Earlier age of cannabis usage poses higher risk of Cannabis Use Disorder and adverse consequences, such as addiction, anxiety, dysphoria, psychosis, largely attributed to its principal psychoactive component, Δ9-tetrahydrocannabinol (THC) and altered dopaminergic function. As dopamine D1-D2 receptor heteromer activation causes anxiety and anhedonia, this signaling complex was postulated to contribute to THC-induced affective symptoms. To investigate this, we administered THC repeatedly to adolescent monkeys and adolescent or adult rats. Drug-naïve adolescent rat had lower striatal densities of D1-D2 heteromer compared to adult rat. Repeated administration of THC to adolescent rat or adolescent monkey did not alter D1-D2 heteromer expression in nucleus accumbens or dorsal striatum but upregulated it in adult rat. Behaviourally, THC-treated adult, but not adolescent rat manifested anxiety and anhedonia-like behaviour, with elevated composite negative emotionality scores that correlated with striatal D1-D2 density. THC modified downstream markers of D1-D2 activation in adult, but not adolescent striatum. THC administered with cannabidiol did not alter D1-D2 expression. In adult rat, co-administration of CB1 receptor (CB1R) inverse agonist with THC attenuated D1-D2 upregulation, implicating cannabinoids in the regulation of striatal D1-D2 heteromer expression. THC exposure revealed an adaptable age-specific, anxiogenic, anti-reward mechanism operant in adult striatum but deficient in adolescent rat and monkey striatum that may confer increased sensitivity to THC reward in adolescence while limiting its negative effects, thus promoting continued use and increasing vulnerability to long-term adverse cannabis effects.
PubMed: 38020805
DOI: 10.1016/j.crneur.2023.100107 -
European Neuropsychopharmacology : the... Jun 2024Ketamine, an N-methyl-D-aspartate receptor antagonist, is a racemic mixture of esketamine and arketamine used to treat unipolar and bipolar depression. Preliminary... (Review)
Review
Ketamine, an N-methyl-D-aspartate receptor antagonist, is a racemic mixture of esketamine and arketamine used to treat unipolar and bipolar depression. Preliminary reports indicate that it may be beneficial for depressed patients reporting symptoms of anhedonia. In this systematic review we aim to assess and analyze the existing body of evidence regarding the therapeutic effects of ketamine on the domain of anhedonia. Electronic databases (PubMed, APA Psycinfo and Web of Science) were searched from inception to November 2023. Protocol was registered in PROSPERO under the identifier CRD42023476603. A total of twenty-two studies, including four randomized-controlled trials and eighteen open-label trials were included. All studies reported alleviation of anhedonia symptoms following ketamine or esketamine administration, regardless of the number of infusions. Several important limitations were included, first and foremost low number of placebo-controlled randomized-controlled trials. This review indicates a potential anti-anhedonic effect of ketamine in patients with depression. Several trials used neuroimaging techniques which confirm ketamine's effect on functional connectivity correlating with the improvement in anhedonia. Despite considerable variations in methodology and the specific brain regions investigated, these studies collectively point towards ketamine's neuroplastic effects in mitigating anhedonia.
PubMed: 38917771
DOI: 10.1016/j.euroneuro.2024.04.014 -
BMC Psychiatry Jul 2023Previous neuroimaging findings have demonstrated the association between anhedonia and the hippocampus. However, few studies have focused on the structural changes in...
BACKGROUND
Previous neuroimaging findings have demonstrated the association between anhedonia and the hippocampus. However, few studies have focused on the structural changes in the hippocampus in major depressive disorder (MDD) patients with anhedonia. Meanwhile, considering that multiple and functionally specialized subfields of the hippocampus have their own signatures, the present study aimed to investigate the volumetric alterations of the hippocampus as well as its subfields in MDD patients with and without anhedonia.
METHODS
A total of 113 subjects, including 30 MDD patients with anhedonia, 40 MDD patients without anhedonia, and 43 healthy controls (HCs), were recruited in the study. All participants underwent high-resolution brain magnetic resonance imaging (MRI) scans, and the automated hippocampal substructure module in FreeSurfer 6.0 was used to evaluate the volumes of hippocampal subfields. We compared the volumetric differences in hippocampal subfields among the three groups by analysis of variance (ANOVA, post hoc Bonferroni), and partial correlation was used to explore the association between hippocampal subregion volumes and clinical characteristics.
RESULTS
ANOVA showed significant volumetric differences in the hippocampal subfields among the three groups in the left hippocampus head, mainly in the cornu ammonis (CA) 1, granule cell layer of the dentate gyrus (GC-ML-DG), and molecular layer (ML). Compared with HCs, both groups of MDD patients showed significantly smaller volumes in the whole left hippocampus head. Interestingly, further exploration revealed that only MDD patients with anhedonia had significantly reduced volumes in the left CA1, GC-ML-DG and ML when compared with HCs. No significant difference was found in the volumes of the hippocampal subfields between MDD patients without anhedonia and HCs, either the two groups of MDD patients. However, no association between hippocampal subfield volumes and clinical characteristics was found in either the subset of patients with anhedonia or in the patient group as a whole.
CONCLUSIONS
These preliminary findings suggest that MDD patients with anhedonia exhibit unique atrophy of the hippocampus and that subfield abnormalities in the left CA1 and DG might be associated with anhedonia in MDD.
Topics: Humans; Depressive Disorder, Major; Anhedonia; Organ Size; Hippocampus; Temporal Lobe; Magnetic Resonance Imaging
PubMed: 37491229
DOI: 10.1186/s12888-023-05001-6 -
Positive valence system function and anhedonia in middle-aged and older adults at high suicide risk.Biological Psychology Sep 2023Positive valence systems are disrupted in late-life depression and in individuals at risk for suicide. The reward positivity (RewP) is an event-related potential measure...
Positive valence systems are disrupted in late-life depression and in individuals at risk for suicide. The reward positivity (RewP) is an event-related potential measure of positive valence system function that relates to depression and anhedonia in children and young adults. However, it is unclear whether a reliable RewP signal can be elicited in middle-aged and older adults at high risk for suicide and, if so, whether this signal is similarly associated with clinical symptoms. In the current study, a RewP was elicited with a standard gambling task in middle-aged and older adults (N = 31) at discharge from a hospitalization for suicidal thought or behaviors. The resulting electrocortical response differed significantly for monetary wins compared to losses. Internal reliability of the RewP and the feedback negativity (FN) to monetary loss was good to excellent. Internal reliability of difference measures was lower but still largely acceptable, with residualized differences scores demonstrating stronger reliability than subtraction-based scores. A smaller residualized RewP, after accounting for the influence of the FN, was associated with greater severity of lassitude, an index of appetitive anhedonia. These findings set the groundwork for future studies of positive valence system function and depression in middle-aged and older adults at high risk for suicide.
Topics: Child; Young Adult; Middle Aged; Humans; Aged; Electroencephalography; Anhedonia; Reproducibility of Results; Evoked Potentials; Reward; Suicide
PubMed: 37499781
DOI: 10.1016/j.biopsycho.2023.108647 -
Translational Psychiatry Aug 2023Mood instability, a subjective emotional state defined as rapid mood oscillations of up and down, is a symptom that occurs in several psychiatric disorders, particularly...
Mood instability, a subjective emotional state defined as rapid mood oscillations of up and down, is a symptom that occurs in several psychiatric disorders, particularly major depressive disorder and bipolar disorder. Heat shock protein A12A (HSPA12A) shows decreased expression in the brains of schizophrenia patients. However, the causal effects of HSPA12A in any psychiatric disorders are completely unknown. To investigate whether HSPA12A affects mood stability, Hspa12a-knockout mice (Hspa12a) and wild-type (WT) littermates were subjected to tests of open field, forced swimming, elevated plus maze, and sucrose preference. Cerebral lactate levels were measured in cerebrospinal fluid (CSF). Adult hippocampal neurogenesis (AHN) was assessed by BrdU labeling. We found that acute mood stress increased hippocampal HSPA12A expression and CSF lactate levels in mice. However, Hspa12a mice exhibited behaviors of mood instability (anhedonia, lower locomotor activity, antidepression, and anxiety), which were accompanied by impaired AHN, decreased CSF lactate levels, and downregulated hippocampal glycolytic enzyme expression. By contrast, HSPA12A overexpression increased lactate production and glycolytic enzyme expression of primary hippocampal neurons. Intriguingly, lactate administration alleviated the mood instability and AHN impairment in Hspa12a mice. Further analyses revealed that HSPA12A was necessary for sustaining cerebral lactate homeostasis, which could be mediated by inhibiting GSK3β in hippocampal neurons, to maintain AHN and mood stabilization. Taken together, HSPA12A is defined as a novel regulator of mood stability and exerts therapeutic potential for mood disorder. Our findings establish a framework for determining mood disorder and AHN relevance of cerebral lactate homeostasis. HSPA12A is a novel mood stabilizer through inhibiting GSK3β in hippocampal neurons, thereby sustaining glycolysis-generated lactate to maintain cerebral lactate homeostasis, which ultimately leading to maintenance of hippocampal neurogenesis and mood stabilization.
Topics: Animals; Mice; Depressive Disorder, Major; Glycogen Synthase Kinase 3 beta; Hippocampus; Lactic Acid; Mice, Knockout; Neurogenesis; HSP70 Heat-Shock Proteins; Affect
PubMed: 37580315
DOI: 10.1038/s41398-023-02573-5 -
Journal of Affective Disorders Jan 2024Childhood trauma is a risk factor for developing multiple forms of psychopathology, including depression, posttraumatic stress disorder (PTSD), and social anxiety. Yet,...
BACKGROUND
Childhood trauma is a risk factor for developing multiple forms of psychopathology, including depression, posttraumatic stress disorder (PTSD), and social anxiety. Yet, the mechanisms linking childhood trauma and these psychopathologies remain less clear.
OBJECTIVE
Here we examined whether anhedonia, a reduced ability to experience pleasure, may mediate the relationship between childhood trauma and symptom severity of depression, PTSD, and social anxiety.
METHODS
A total of 230 trauma-exposed participants aged 18-75 were assessed for lifetime trauma exposure, including general and childhood traumatic events, anhedonia, and symptoms of depression, PTSD, and social anxiety.
RESULTS
Controlling for age, gender, and general lifetime trauma exposure, mediation analyses revealed a significant mediation effect of anhedonia for the relationship between childhood trauma and symptom severity of depression and PTSD, but not social anxiety. To better understand these significant mediation effects, we repeated the analyses separately for childhood abuse and neglect, and then for the various subtypes of each type of childhood trauma. Results showed a significant mediation effect of anhedonia on symptoms of both depression and PTSD in individuals who reported high emotional and sexual abuse levels. F Anhedonia was also found to mediate the relationship between both emotional and physical neglect and symptoms of depression and PTSD.
CONCLUSION
These findings refine our understanding of the ways in which childhood traumatic experiences may be associated with different mental health problems by increasing anhedonia. Anhedonia may be an important treatment target in survivors of childhood abuse and neglect.
Topics: Humans; Child; Stress Disorders, Post-Traumatic; Anhedonia; Depression; Adverse Childhood Experiences; Anxiety
PubMed: 37863363
DOI: 10.1016/j.jad.2023.10.107 -
Nutrients Jun 2024: Emerging evidence suggests that essential trace elements, including iodine, play a vital role in depressive disorders. This study investigated whether prenatal dietary...
: Emerging evidence suggests that essential trace elements, including iodine, play a vital role in depressive disorders. This study investigated whether prenatal dietary iodine intake alone and in combination with supplemental iodine intake during pregnancy were associated with antepartum and postpartum depressive and anhedonia symptoms. : The study population included 837 mothers in the PRogramming of Intergenerational Stress Mechanisms (PRISM) study. The modified BLOCK food frequency questionnaire was used to estimate prenatal dietary and supplemental iodine intake, while the 10-item Edinburg Postpartum Depression Scale (EPDS) ascertained depressive symptoms. Analyses considered the global EPDS score and the anhedonia and depressive symptom subscale scores using dichotomized cutoffs. Logistic regression estimating odds ratios and 95% confidence intervals (CIs) assessed associations of iodine intake in the second trimester of pregnancy and 6-month postpartum depressive and anhedonia symptoms considering dietary intake alone and combined dietary and supplementary intake in separate models. : Most women were Black/Hispanic Black (43%) and non-Black Hispanics (35%), with 39% reporting a high school education or less. The median (interquartile range, IQR) dietary and supplemental iodine intake among Black/Hispanic Black (198 (115, 337) µg/day) and non-Black Hispanic women (195 (126, 323) µg/day) was higher than the overall median intake level of 187 (116, 315) µg/day. Relative to the Institute of Medicine recommended iodine intake level of 160-220 µg/day, women with intake levels < 100 µg/day, 100-<160 µg/day, >220-<400 µg/day and ≥400 µg/day had increased adjusted odds of 6-month postpartum anhedonia symptoms (aOR = 1.74 (95% CI: 1.08, 2.79), 1.25 (95% CI: 0.80, 1.99), 1.31 (95% CI: 0.82, 2.10), and 1.47 (95% CI: 0.86, 2.51), respectively). The corresponding estimates for postpartum global depressive symptoms were similar but of smaller magnitude. Prenatal iodine intake, whether below or above the recommended levels for pregnant women, was most strongly associated with greater anhedonia symptoms, particularly in the 6-month postpartum period. Further studies are warranted to corroborate these findings, as dietary and supplemental iodine intake are amenable to intervention.
Topics: Humans; Female; Pregnancy; Adult; Anhedonia; Depression, Postpartum; Iodine; United States; Cohort Studies; Dietary Supplements; Young Adult; Diet; Hispanic or Latino; Maternal Nutritional Physiological Phenomena; Black or African American; Prenatal Nutritional Physiological Phenomena
PubMed: 38892704
DOI: 10.3390/nu16111771 -
Translational Psychiatry Nov 2023Exposure to stress can lead to long lasting behavioral and neurobiological consequences, which may enhance the susceptibility for the onset of mental disorders. However,...
Exposure to stress can lead to long lasting behavioral and neurobiological consequences, which may enhance the susceptibility for the onset of mental disorders. However, there are significant individual differences in the outcome of stress exposure since only a percentage of exposed individuals may show pathological consequences, whereas others appear to be resilient. In this study, we aimed to characterize the effects of prenatal stress (PNS) exposure in rats at adolescence and to identify subgroup of animals with a differential response to the gestational manipulation. PNS adolescent offspring (regardless of sex) showed impaired emotionality in different pathological domains, such as anhedonia, anxiety, and sociability. However, using cluster analysis of the behavioral data we could identify 70% of PNS-exposed animals as vulnerable (PNS-vul), whereas the remaining 30% were considered resilient (PNS-res). At the molecular level, we found that PNS-res males show a reduced basal activation of the ventral hippocampus whereas other regions, such as amygdala and dorsal hippocampus, show significant PNS-induced changes regardless from vulnerability or resilience. Taken together, our results provide evidence of the variability in the behavioral and neurobiological effects of PNS-exposed offspring at adolescence. While these data may advance our understanding of the association between exposure to stress during gestation and the risk for psychopathology, the investigation of the mechanisms associated to stress vulnerability or resilience may be instrumental to develop novel strategies for therapeutic intervention.
Topics: Humans; Male; Pregnancy; Female; Rats; Animals; Adolescent; Stress, Psychological; Anxiety; Anxiety Disorders; Individuality; Anhedonia; Prenatal Exposure Delayed Effects
PubMed: 37993429
DOI: 10.1038/s41398-023-02653-6