Chronic treatment with the antipsychotic lurasidone modulates the neuroinflammatory changes associated with the vulnerability to chronic mild stress exposure in female rats.

Stress exposure is a key risk factor for the developmentof depressive-like conditions. However, despite the higher incidence of Major Depressive Disorder in the female population, classical stress-based experimental paradigms have primarily focused on males. In the present study, we used the well-established chronic mild stress (CMS) paradigm to investigate the development of anhedonia, a cardinal symptom of affective disorders, in the female animals and we also studied the potential effect of the antipsychotic drug lurasidone in normalizing the alterations brought about by stress exposure. We found that three weeks of CMS exposure produced a significant reduction of sucrose intake in 50% of the animals (vulnerable, CMS-V), whereas the others were resilient (CMS-R). The development of an anhedonic phenotype in CMS-V was associated with a significant elevation of different immune markers, such as Complement C3 and C4, and inflammatory cytokines, including INFß and Il1ß in dorsal and ventral hippocampus. Interestingly, sub-chronic treatment with the antipsychotic drug lurasidone was able to revert the anhedonic phenotype while normalizing most of the molecular alterations found in rats vulnerable to CMS exposure. This study extends the ability of lurasidone to normalize the anhedonic phenotype in CMS rats also to females. Moreover, we provide novel evidence on lurasidone's potential effectiveness in treating mental disorders characterized by immune-inflammatory dysfunction.

Relationship of prefrontal cortex activity with anhedonia and cognitive function in major depressive disorder: an fNIRS study.

Background: Major depressive disorder (MDD) is associated with deficits in cognitive function, thought to be related to underlying decreased hedonic experiences. Further research is needed to fully elucidate the role of functional brain activity in this relationship. In this study, we investigated the neurofunctional correlate of the interplay between cognitive function and hedonic experiences in medication-free MDD using functional near-infrared spectroscopy (fNIRS). Methods: We examine differences of brain activation corresponding to the verbal fluency test (VFT) between MDD patients and healthy controls (HCs). Fifty-six MDD patients and 35 HCs underwent fMRI scanning while performing the VFT. In exploratory analyses, cognitive performance, as assessed by the Cambridge Neuropsychological Test Automated Battery (CANTAB), four dimensions of hedonic processing (desire, motivation, effort, and consummatory pleasure) measured by the Dimensional Anhedonia Rating Scale (DARS), and relative changes in oxygenated hemoglobin concentration during the VFT were compared across groups. Results: Patients with MDD demonstrated impairments in sustained attention and working memory, accompanied by lower total and subscale scores on the DARS. Compared to healthy controls, MDD patients exhibited reduced activation in the prefrontal cortex (PFC) during the VFT task (t = 2.32 to 4.77, p < 0.001 to 0.02, FDR corrected). DARS motivation, desire, and total scores as well as sustained attention, were positively correlated with activation in the dorsolateral PFC and Broca's area (p < 0.05, FDR corrected). Conclusions: These findings indicate that changes in prefrontal lobe oxygenated hemoglobin levels, a region implicated in hedonic motivation and cognitive function, may serve as potential biomarkers for interventions targeting individuals with MDD. Our results corroborate the clinical consensus that the prefrontal cortex is a primary target for non-invasive neuromodulatory treatments for depression.

Systematic Review and Meta-Analysis Confirm the Moderate Efficacy of High-Frequency r-TMS in Alzheimer's Disease: Mediating Effects of Anhedonia-Apathy and Add-On Motor-Cognitive Excersizes.

OBJECTIVES: Alzheimer's disease (AD) presents a major global health issue of significant socio-economic impact. Pharmacological treatments for AD have limited efficacy, prompting the exploration of alternative therapies, such as repetitive transcranial magnetic stimulation (rTMS), a promising non-invasive technique to enhance cognitive function in AD patients. Our systematic review and meta-analysis aim to evaluate the efficacy of rTMS in relation to cognitive function in AD patients, identify optimal rTMS stimulation parameters, and understand the underlying neural mechanisms. METHODS: We conducted a comprehensive literature search in PubMed using predefined search terms to identify original research articles investigating the effects of rTMS on cognitive function in AD patients. We selected only randomized controlled trials (RCTs) with sufficient quantitative data for comparing active rTMS to the sham-coil treatment, and then performed a random effects meta-analysis using standardized mean differences (SMDs) to synthesize the effects across studies. RESULTS: The systematic review included 22 studies, among which 14 RCTs met our criteria for meta-analysis. High-frequency rTMS, particularly targeting the dorsolateral prefrontal cortex (DLPFC), evoked significant cognitive improvements in AD patients, with a moderate positive effect size of rTMS on cognitive function (Hedges' g=0.580, 95% CI [0.268, 0.892], p<0.001), albeit with substantial heterogeneity (I²=59%). Funnel plot asymmetry and Egger's test suggested a potential publication bias, but fail-safe N analysis indicated a robust finding. Moreover, anhedonia-apathy symptoms and motor-cognitive exercises mediated the efficacy of tTMS in ameliorating cognitive functioning across several studies. CONCLUSION: rTMS demonstrates moderate efficacy in improving cognitive function in AD-patients, most distinctly with high-frequency rTMS stimulation protocols targeting the DLPFC area. The meta-analysis support rTMS as a viable therapeutic intervention for cognitive enhancement in AD. Future promising research should focus on personalized treatment strategies targeting mediating factors, baseline connectivity patterns, and TMS-induced neuroplasticity in AD.

Anhedonia Across and Beyond the Schizophrenia Spectrum.

Anhedonia refers to the diminished ability to experience pleasure, and is a core feature of schizophrenia (SCZ). The neurocognitive and neural correlates of anhedonia remain elusive. Based on several influential theoretical models for negative symptoms, this selective review proposed four important neurocognitive domains, which may unveil the neurobiological mechanisms of anhedonia. The authors critically reviewed the current evidence regarding value representation of reward, prospection, emotion-behavior decoupling, and belief updating in the Chinese setting, covering both behavioral and neuroimaging research. We observed a limited application of the transdiagnostic approach in previous studies on the four domains, and the lack of adequate measures to tap into the expressivity deficit in SCZ. Despite many behavioral paradigms for these four domains utilized both social and non-social stimuli, previous studies seldom focused on the social-versus-non-social differentiation. We further advocated several important directions for future research.

Investigating the role of mental imagery use in the assessment of anhedonia.

Anhedonia, or a deficit in the liking, wanting, and seeking of rewards, is typically assessed via self-reported "in-the-moment" emotional and motivational responses to reward stimuli and activities. Given that mental imagery is known to evoke emotion and motivational responses, we conducted two studies to investigate the relationship between mental imagery use and self-reported anhedonia. Using a novel Reward Response Scale (adapted from the Dimensional Anhedonia Rating Scale, DARS; Rizvi et al., 2015) modified to assess deliberate and spontaneous mental imagery use, Study 1 (N = 394) compared uninstructed and instructed mental imagery use, and Study 2 (N = 586) conducted a test of replication of uninstructed mental imagery use. Results showed that greater mental imagery use was associated with higher reward response scores (Study 1 & 2), and this relationship was not moderated by whether imagery use was uninstructed or instructed (Study 1). Importantly, mental imagery use moderated the convergence between reward response and depression scale measures of anhedonia, with lower convergence for those reporting higher mental imagery use (Study 1 & 2). Results suggest that higher spontaneous mental imagery use may increase self-reported reward response and reduce the convergence between reward response scale and depression questionnaire measures of anhedonia. [199 / 200 words].

Aesthetic processing in neurodiverse populations.

Neurodiversity is a perspective on cognition which suggests a non-pathological view of individual cognitive differences. Aesthetics research on neurodivergent brains has generally been limited to neuropsychological cases. Although this research has been integral to establishing the neurological correlates of aesthetic experience, it is crucial to expand this paradigm to more psychologically complex disorders. We offer a review of research on aesthetic preference in neurodivergent brains beyond neuropsychological cases: across populations with psychotic disorder, anhedonia and depression, anxiety disorder, and autism. We identify stable patterns of aesthetic bias in these populations, relate these biases to symptoms at perceptual, emotional, and evaluative levels of cognition, review relevant neurological correlates, and connect this evidence to current neuroaesthetics theory. Critically, we synthesize the reviewed evidence and discuss its relevance for three brain networks regularly implicated in aesthetic processing: the mesocorticolimbic reward circuit, frontolimbic connections, and the default mode network. Finally, we propose that broadening the subject populations for neuroaesthetics research to include neurodiverse populations is instrumental for yielding new insights into aesthetic processing in the brain.

Insulin Resistance, Temperament and Personality Traits Are Associated with Anhedonia in a Transdiagnostic Sample.

Anhedonia constitutes a core symptom of major depressive disorder (MDD) mediating the ultimate goal of MDD treatment: functional remission. Anhedonia is also present in other clinical populations, including patients with chronic pain. Recent data links anhedonia to insulin resistance (IR). Some researchers have underlined a different dimension of anhedonia as a temperament/personality trait. The objective of this post-hoc analysis was to explore the links between anhedonia (main outcome) and (1) IR, (2) temperamental, personality, and schizotypy traits (exposures). The study population included patients with MDD, fibromyalgia, and healthy controls. Participants were split into groups: (1) insulin resistant (IR[+] n = 69, HOMA-IR ≥ 2.1) and (2) insulin sensitive (IR[-] n = 69, HOMA-IR < 2.1). Anhedonia was significantly higher in the IR[+] group than the IR[-] group. IR was a predictor of higher anhedonia levels. IR[+] vs. IR[-] participants showed higher levels of anxiety and lower levels of hyperthymic affective temperaments, as well as conscientiousness and emotional stability personality traits. Depressive, irritable, and anxious temperaments, cognitive disorganization, and introvertive anhedonia positively predicted anhedonia, while hyperthymic temperament, conscientiousness, extraversion, and emotional stability traits negatively predicted anhedonia. IR partially mediated the relationship between depressive temperament and anhedonia. In sum, IR, affective temperaments, and personality traits are predictors of anhedonia.

Inflammatory cytokines, cortisol, and anhedonia in patients with treatment-resistant depression after consecutive infusions of low-dose esketamine.

Anhedonia, defined as a significant loss of interest or pleasure, is one of the core symptoms of treatment- resistant depression (TRD) and is often associated with poor prognosis. This article primarily investigates the changes in anhedonia symptoms, inflammatory markers, and cortisol levels in TRD patients after low-dose esketamine treatments. A total of sixty patients with TRD were enrolled in the clinical study of esketamine. We primarily assessed the severity of depressive symptoms and anhedonia using the Hamilton Rating Scale for Depression (HAMD) and the Snaith-Hamilton Pleasure Scal(SHAPS), respectively, before esketamine treatment and within 24 h after each treatment. Blood specimens were collected before the first treatment and within 1 h after the sixth treatment, measuring the levels of cortisol, interleukin-6(IL-6), interleukin-4(IL-4), and tumor necrosis factor-alpha(TNF-α) in plasma. We found that after six consecutive infusions of low-dose esketamine, patients' depressive symptoms and anhedonia showed improvement. After six treatments, plasma levels of cortisol, IL-6, and TNF-α decreased in patients with TRD, while the anti-inflammatory cytokine IL-4 increased. Multiple linear regression analysis revealed that baseline cortisol levels were correlated with anhedonia, while inflammatory factors showed no significant correlation. Add-on esketamine appears to be a good choice for the treament of the anhedonia in TRD. It has also shown promising effects on altering inflammatory markers in patients with TRD. Moreover, elevated plasma cortisol levels may serve as a potential biomarker for anhedonia in patients with TRD.

Computational Modeling Differentiates Learning Rate From Reward Sensitivity Deficits Produced by Early-Life Adversity in a Rodent Touchscreen Probabilistic Reward Task.

Background: Exposure to adversity, including unpredictable environments, during early life is associated with neuropsychiatric illness in adulthood. One common factor in this sequela is anhedonia, the loss of responsivity to previously reinforcing stimuli. To accelerate the development of new treatment strategies for anhedonic disorders induced by early-life adversity, animal models have been developed to capture critical features of early-life stress and the behavioral deficits that such stressors induce. We have previously shown that rats exposed to the limited bedding and nesting protocol exhibited blunted reward responsivity in the probabilistic reward task, a touchscreen-based task reverse translated from human studies. Methods: To test the quantitative limits of this translational platform, we examined the ability of Bayesian computational modeling and probability analyses identical to those optimized in previous human studies to quantify the putative mechanisms that underlie these deficits with precision. Specifically, 2 parameters that have been shown to independently contribute to probabilistic reward task outcomes in patient populations, reward sensitivity and learning rate, were extracted, as were trial-by-trial probability analyses of choices as a function of the preceding trial. Results: Significant deficits in reward sensitivity, but not learning rate, contributed to the anhedonic phenotypes in rats exposed to early-life adversity. Conclusions: The current findings confirm and extend the translational value of these rodent models by verifying the effectiveness of computational modeling in distinguishing independent features of reward sensitivity and learning rate that complement the probabilistic reward task's signal detection end points. Together, these metrics serve to objectively quantify reinforcement learning deficits associated with anhedonic phenotypes.

Exposure to early-life adversity can lead to psychiatric illness, including anhedonia, the loss of pleasure from previously rewarding activities. This article describes findings from rats exposed to a model of simulated poverty on a touchscreen-based assay reverse translated from a task used to characterize anhedonia in humans. We documented the ability of Bayesian computational modeling and probability analyses, identical to those used with humans, to objectively quantify reinforcement learning deficits associated with anhedonia in rats.

Abnormal hedonic process in patients with stable schizophrenia: Relationships to negative symptoms and social functioning.

Background: Anhedonia is a deficit of dynamic reward process, and a large proportion of schizophrenia patients continue to experience anhedonia even during the stable phase. However, few studies have examined the multiple aspects of performance in reward processing in patients with stable schizophrenia and evidence suggests that physical and cognitive effort may involve different neural mechanisms. Methods: Parallel measures of effort-based expenditure for reward tasks (EEfRT) and self-report questionnaires of pleasure were applied in 61 patients with stable schizophrenia (SSZ) and 46 healthy controls (HCs), and percentages of hard task choices (HTC%) were used to assess motivation in reward processing. Negative symptoms, neurocognitive and social function were evaluated in SSZ patients, and associations with performance in reward tasks were explored. Results: SSZ patients reported more severe consummatory and anticipatory anhedonia and social anhedonia. HTC% in reward tasks of SSZ patients were significantly lower than that of HCs, especially in cognitive-effort tasks. HTC% in cognitive tasks were correlated with motivation and pleasure dimension of negative symptoms, whereas HTC% in physical tasks were associated with expression dimension. Anticipatory anhedonia and negative symptoms were correlated with Personal and Social Performance Scale (PSP) scores. Conclusion: Patients with stable schizophrenia have social anhedonia, physically consummatory and anticipatory anhedonia and reduced reward motivation. They are less willing to make cognitive effort than physical effort for reward. The different associations of physical and cognitive effort with negative symptoms indicate physical and cognitive effort may represent disparate neuropsychological processes. Anticipatory anhedonia is closely related to social functioning.

Predictors of functioning in treatment-resistant schizophrenia: the role of negative symptoms and neurocognition.

Introduction: Predictors of functioning are well-studied in schizophrenia, but much less so in treatment-resistant schizophrenia (TRS). In this study, we aim to investigate contributions of schizophrenia symptom domains and neurocognition to predict functioning in a TRS population (n = 146). Methods: Participants were assessed on the Positive and Negative Syndrome Scale (PANSS), to calculate scores for five symptom factors (Positive, Negative, Cognitive, Depressive and Hostility) and two negative symptom constructs (Diminished Expressivity (DE), and Social Anhedonia (SA) as part of the Motivation and Pleasure-related dimension), based on a previously validated model, modified in accordance with EPA guidelines on negative symptoms assessment. Neurocognition was assessed with symbol coding and digit sequencing tasks from the Brief Assessment of Cognition in Schizophrenia (BACS). Functioning was assessed with the Social and Occupational Functioning Assessment Scale (SOFAS), employment status and World Health Organization Disability Assessment Schedule 2.0 (WHODAS 2.0). Multiple regression analyses were performed on psychopathology scores and BACS scores against all three measures of functioning, controlling for age and sex. For WHODAS, regression with PANSS scores of significant symptom factors were also performed. Results: A lower severity of negative symptoms in the SA dimension was the strongest predictor of higher functioning across all three functioning measures. Neurocognition, in particular processing speed and attention assessed on the symbol coding task, predicted employment. A lower severity of somatic concerns and depressive symptoms was associated with lesser self-reported disability on WHODAS. Discussion: This study represents a first attempt at elucidating significant predictors of functioning in TRS. We highlight negative symptoms and neurocognition as important treatment targets to improve functioning in TRS, consistent with previous studies in general schizophrenia.

Decoding visual evoked potential latency: revealing neurological connections in Parkinson's disease.

Parkinson's disease (PD) is a complex neurodegenerative disorder characterized by diverse motor and non-motor symptoms. Visual evoked potentials (VEPs) provide valuable insights into the neurological changes in PD. This study examines VEP latency to explore potential connections between visual processing and PD progression, focusing on whether inter-eye latency differences are influenced by disease severity and symptomatology. A cross-sectional observational study was conducted with 59 PD patients at the Neurology I Clinic, Cluj-Napoca County Emergency Clinical Hospital, from October 2019 to October 2021. Patients underwent neurological and psychological evaluations, including VEP testing with a reversal pattern technique. P100 wave latency was assessed for both eyes, and associations with clinical indicators like Hoehn and Yahr stages, UPDRS scores, and non-motor symptoms were analyzed. VEP latencies for the right and left eyes were 108.7 ± 10.6 ms and 108.4 ± 9.7 ms, respectively, with no significant inter-eye differences (P = 0.8). UPDRS item 4 scores correlated significantly with both latencies (P = 0.003 for the left eye and P <0.001 for the right). Latency differences between eyes were shorter in patients with symmetrical parkinsonism compared to those with unilateral predominance. Age correlated weakly with P100 latency, and a weak correlation was found between anhedonia scores and right-eye latency. VEP latency is sensitive to PD motor severity, with shorter inter-eye latency differences in symmetrical parkinsonism, suggesting balanced dopaminergic dysfunction. VEP latency differences offer insights into neurophysiological changes in PD, reflecting dopaminergic dysfunction and its impact on visual processing. These findings support the potential of VEPs as diagnostic and prognostic tools in PD assessment.

Daily Social Isolation Maps Onto Distinctive Features of Anhedonic Behavior: A Combined Ecological and Computational Investigation.

Background: Loneliness and social isolation have detrimental consequences for mental health and act as vulnerability factors for the development of depressive symptoms, such as anhedonia. The mitigation strategies used to contain COVID-19, such as social distancing and lockdowns, allowed us to investigate putative associations between daily objective and perceived social isolation and anhedonic-like behavior. Methods: Reward-related functioning was objectively assessed using the Probabilistic Reward Task. A total of 114 unselected healthy individuals (71% female) underwent both a laboratory and an ecological momentary assessment. Computational modeling was applied to performance on the Probabilistic Reward Task to disentangle reward sensitivity and learning rate. Results: Findings revealed that objective, but not subjective, daily social interactions were associated with motivational behavior. Specifically, higher social isolation (less time spent with others) was associated with higher responsivity to rewarding stimuli and a reduced influence of a given reward on successive behavioral choices. Conclusions: Overall, the current results broaden our knowledge of the potential pathways that link (COVID-19-related) social isolation to altered motivational functioning.

Loneliness and social isolation negatively impact mental health and contribute to depressive symptoms like anhedonia. With COVID-19 restrictions such as social distancing, we examined how daily social isolation, measured ecologically, is related to anhedonic behavior. We tested 114 healthy adults using a task that measured their responses to rewards. Greater isolation was linked to an increased response to rewards but also to a reduced ability to learn from them, which lessened the influence of rewards on future behavior. These findings highlight potential mechanisms that link social isolation to changes in motivation, ultimately leading to depressive symptoms.

Approach and withdrawal from cognitively effortful activities: Development, validation, and transdiagnostic clinical utility of a cognitive motivation scale.

BACKGROUND: Deficits in cognition and motivation predict functioning in depressive and psychotic disorders. However, experimental tasks of cognitive motivation are inconsistently correlated with functioning, time-intensive, and not intuitive in clinical practice. We aimed to develop and validate a self-report instrument to assess motivation processes pertinent to engagement with cognitive activities in daily life. METHOD: Following item generation, scale dimensionality, reliability, and validity were evaluated iteratively over Studies 1-3 with online general adult participants (n1 = 205; n2 = 235; n3 = 181). The 20-item Cognitive Motivation scale was also validated in a Study 3 sub-sample reporting high levels of depressive symptoms (n = 74) and Study 4 early psychosis outpatients (n = 25). RESULTS: Two-factor model of cognitive approach and cognitive withdrawal, each with good internal consistency, convergent validity, discriminant validity was supported. Cognitive withdrawal showed stronger associations with cognitive difficulties, depressive symptoms, and functional impairments than traditional motivation scale. Participants reporting high depression levels showed more severe difficulties with cognitive motivation than participants reporting low depression levels. In early psychosis outpatients, correlations with functioning and cognitive effort expenditure provided support for scale validity. LIMITATIONS: Cross-sectional data collection restricted evaluation of repeated administration psychometric properties. Scale validation was mostly established in online community samples and a small patient sample during the COVID-19 pandemic, thereby limiting generalizability of clinical applications. CONCLUSIONS: Cognitive Motivation scale is a promising tool for future intervention trials seeking to target motivational processes associated with functioning in the general population and potentially across patient groups with amotivation symptoms.

Impact of Coffee Intake on Measures of Wellbeing in Mice.

Coffee intake is increasingly recognized as a life-style factor associated with the preservation of health, but there is still a debate on the relative effects of caffeinated and decaffeinated coffee. We now tested how the regular drinking of caffeinated and decaffeinated coffee for 3 weeks impacted on the behavior of male and female adult mice. Males drinking caffeinated coffee displayed statistically significant lower weight gain, increased sensorimotor coordination, greater motivation in the splash test, more struggling in the forced swimming test, faster onset of nest building, more marble burying and greater sociability. Females drinking caffeinated coffee displayed statistically significant increased hierarchy fighting, greater self-care and motivation in the splash test and faster onset of nest building. A post-hoc two-way ANOVA revealed sex-differences in the effects of caffeinated coffee (p values for interaction between the effect of caffeinated coffee and sex) on the hierarchy in the tube test (p = 0.044; dominance), in the time socializing (p = 0.044) and in the latency to grooming (p = 0.048; selfcare), but not in the marble burying test (p = 0.089). Intake of decaffeinated coffee was devoid of effects in males and females. Since caffeine targets adenosine receptors, we verified that caffeinated but not decaffeinated coffee intake increased the density of adenosine A1 receptors (A1R) and increased A1R-mediated tonic inhibition of synaptic transmission in the dorsolateral striatum and ventral but not dorsal hippocampus, the effects being more evident in the ventral hippocampus of females and striatum of males. In contrast, caffeinated and decaffeinated coffee both ameliorated the antioxidant status in the frontal cortex. It is concluded that caffeinated coffee increases A1R-mediated inhibition in mood-related areas bolstering wellbeing of both males and females, with increased sociability in males and hierarchy struggling and self-care in females.

Chemosensory anhedonia facilitates depressive symptoms and cognitive impairment in late-life depression.

AIM: Chemosensory anhedonia refers to the lack of hedonic ability to experience pleasure through the senses of smell and taste, which reduces the pleasure and comfort of food, and increases the risk of nutritional and immune deficiencies. However, there is no direct scientific evidence regarding chemosensory anhedonia in patients with late-life depression (LLD). The aim of this study was to investigate chemosensory anhedonia in patients with LLD, and its potential association with depressive symptoms and cognitive function. METHODS: A total of 114 patients with LLD and 92 normal controls were included in this study. They experienced clinical assessment, Chemosensory Pleasure Scale assessment, 17-item Hamilton Depression Rating Scale assessment and cognitive assessments, which contain the Verbal Fluency Test. The associations between chemosensory pleasure and depressive symptoms or cognitive function in patients with LLD were explored using partial correlation analysis and mediation analysis. RESULTS: The Chemosensory Pleasure Scale scores were lower in the LLD group than in the normal control group, and were negatively correlated with the total scores and factors' scores (retardation, cognitive bias and anxiety/somatization) of the 17-item Hamilton Depression Rating Scale, and positively correlated with the Verbal Fluency Test scores. The scores for the Food and Imagination dimensions of the Chemosensory Pleasure Scale showed partial mediating effects on the differences in Cognitive bias (a factor of the 17-item Hamilton Depression Rating Scale) between patients with LLD and normal controls. CONCLUSIONS: Patients with LLD showed significant chemosensory anhedonia, and both depressive symptoms and cognitive impairment were associated with the severity of chemosensory anhedonia. Enhancing chemosensory pleasure in patients with LLD could potentially ameliorate their depressive symptoms. Geriatr Gerontol Int 2024; 24: 1022-1029.

Comparison of the Antianhedonic Effects of Repeated-dose Intravenous Ketamine in Older and Younger Adults with Major Depressive Episode.

OBJECTIVES: Growing evidence suggests that repeated-dose intravenous ketamine in patients with depression had rapid antianhedonic effects. However, a comparison of the antianhedonic effects of repeated-dose intravenous ketamine between younger adults and older depressed patients has not been examined. METHODS: To the best of my knowledge, this study with a total of 135 patients with major depressive episodes (MDE) is the first to compare the antianhedonic effects between younger adult (n = 116) and older (n = 19) depressed patients receiving six ketamine infusions (0.5 mg/kg over 40 min). Montgomery- Åsberg Depression Rating Scale (MADRS) was applied in this study to evaluate the clinical symptoms, and MADRS anhedonia item scoring was used to evaluate anhedonia symptoms. RESULTS: Patients received six open-label intravenous infusions of ketamine for 12 days. MADRS anhedonia subscale scores decreased in both younger (3.3, 95% CI = 2.5-4.1, p < 0.05) and older (2.8, 95% CI = 1.1-4.6, p < 0.05) MDE patients at 4h after the first infusion compared to baseline scores and the reduction was maintained over the subsequent infusion period in both groups (all Ps < 0.05). Younger MDE patients had lower MADRS anhedonia subscale scores on day 26 compared with older patients (P = 0.02). Compared with younger adult MDE patients, older patients had a lower antianhedonic response (51.7% [95% CI = 42.5%-61.0%] versus 31.6% [95% CI = 8.6%-54.6%)] and remission (24.1% [95% CI = 16.2%-32.0%] versus 0%). CONCLUSION: This study indicates that repeated-dose intravenous ketamine administration induces rapid and robust antianhedonic effects in older MDE patients. However, older MDE patients displayed less response to ketamine than younger adult MDE patients.

Meaning in life mediates the effects of sense of self and prosocial behaviours on anhedonia: A path analysis.

BACKGROUND: Anhedonia, the loss of interest and pleasure, is a core symptom of depression that is resistant to treatment. Anhedonic young people describe a weakened sense of self and reduced meaning in life. Knowing if these experiences predict anhedonia could reveal novel targets for intervention development. METHODS: We recruited young people (N = 429, mean age: 20 years) with a range of depression scores. Using path analysis, we examined anhedonia, sense of self, meaning in life, and prosocial behaviours cross-sectionally and longitudinally at ∼5-month follow-up (N = 160). RESULTS: Cross-sectionally, sense of self (ß =. 81, p < .001) and prosocial behaviours (ß = 0.37, p < .001) had direct effects on meaning in life, and meaning in life had a direct effect on anhedonia (ß = -0.11, p < .001). Sense of self (ß = -0.09, p < .001) and prosocial behaviours (ß = -0.04, p < .001) had indirect effects on anhedonia, mediated by meaning in life. In the longitudinal analysis, sense of self at T1 had a direct effect on meaning in life at T2 (ß = 0.36, p < .01) and an indirect effect on anhedonia at T2 (ß = -0.05, p < .01), mediated by meaning in life. LIMITATIONS: Approximately 70 % of the participants were female. Future studies should include equal numbers of males and females. CONCLUSION: We provide novel evidence that targeting meaning in life, sense of self, or prosocial behaviours in psychotherapeutic interventions could be effective in alleviating anhedonia.

Prediction of anhedonia in patients with first-episode schizophrenia using a Wavelet-ALFF-based Support vector regression model.

Anhedonia is one of the core features of the negative symptoms of schizophrenia and can be extremely burdensome. Our study applied resting-state functional magnetic resonance imaging (fMRI)-based support vector regression (SVR) to predict anhedonia in patients with first-episode schizophrenia (FES) and analysed the correlation between the wavelet-based amplitude low-frequency fluctuation (wavelet-ALFF) of the main brain region and anhedonia. We recruited 31 patients with FES and 33 healthy controls (HCs) from the Affiliated Brain Hospital of Guangzhou Medical University. All subjects completed the Temporal Experience of Pleasure Scale (TEPS) and received resting-state fMRI (rs-fMRI). We used the wavelet-ALFF method and SVR to analyse the data. Patients with FES had lower consummatory pleasure scores than healthy subjects (t = -2.71, P<0.01). FES displays variable wavelet-ALFF in a wide range of cerebral cortices (P<0.05, GFR corrected). The SVR analysis showed that wavelet-ALFF, based primarily on the right putamen (r = 0.40, P<0.05) and right superior occipital gyrus (r = -0.39, P<0.05), was effective in predicting consummatory pleasure scores with an accuracy of 56.43 %. Our study shows that abnormal spontaneous neural activity in FES may be related to the state of consummatory anhedonia in FES. Wavelet-ALFF changes in the right putamen and superior occipital gyrus may be a biological feature of FES with anhedonia and could serve as a potential biological marker of FES with anhedonia.

Major Depression in Comorbidity with Substance use Disorders: Patients' Features and Clinical-Neurobiological Rationale of Antidepressant Treatments.

The frequent co-occurrence of major depressive disorder (MDD) and substance use disorders (SUDs) entails significant clinical challenges. Compared to patients with MDD alone, patients with MDD and SUD often show increased anhedonia, emotional blunting, and impaired cognitive function. These symptoms lead to an inability to control cravings, more substance use, increased relapse rates, and poor adherence to the treatment. This fosters a detrimental cycle leading to more severe depressive symptoms, functional impairment, and chronicity, culminating in heightened morbidity, mortality, and healthcare resource utilization. Data on antidepressant treatment of MDD-SUD patients are inconclusive and often conflicting because of a number of confounding factors in clinical trials or difficulty in dissecting the specific contributions of pharmacological versus psychological interventions in real-world studies. The patient's unique clinical features and specific SUD and MDD subtypes must be considered when choosing treatments. Ideally, drug treatment for MDD-SUD should act on both conditions and address core symptoms such as anhedonia, craving, and cognitive dysfunction while ensuring minimal emotional blunting, absence of drug interactions, and no addictive potential. This approach aims to address unmet needs and optimize the outcomes in a clinical population often underrepresented in treatment paradigms.