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Biological Psychiatry Jun 2024Striatal hyperdopaminergia is implicated in the pathoetiology of schizophrenia, but how this relates to dopaminergic midbrain activity is unclear. Neuromelanin-sensitive...
BACKGROUND
Striatal hyperdopaminergia is implicated in the pathoetiology of schizophrenia, but how this relates to dopaminergic midbrain activity is unclear. Neuromelanin-sensitive MRI (NM-MRI) provides a marker of long-term dopamine function. We examined if midbrain NM-MRI contrast-to-noise ratio (NM-CNR) was higher in people with schizophrenia relative to controls and if this correlated with dopamine synthesis capacity.
METHODS
N=154 participants (n=74 individuals with schizophrenia and n=80 healthy controls) underwent NM-MRI of the substantia nigra and ventral tegmental area (SN-VTA). A subset of the schizophrenia group (n=38) also received [18F]-DOPA PET to measure dopamine synthesis capacity (K) in the SN-VTA and striatum.
RESULTS
SN-VTA NM-CNR was significantly higher in patients with schizophrenia relative to controls (effect size=0.38, p=0.019). This effect was greatest for voxels in the medial and ventral SN-VTA. In patients, SN-VTA K positively correlated with SN-VTA NM-CNR (r=0.44, p=0.005) and striatal K (r=0.71, p<0.001). Voxelwise analysis demonstrated that SN-VTA NM-CNR was positively associated with striatal K (r=0.53, p=0.005) and that this relationship appeared strongest between the ventral SN-VTA and associative striatum in schizophrenia.
CONCLUSIONS
Our results suggest that neuromelanin levels are higher in patients with schizophrenia relative to controls, particularly in midbrain regions that project to parts of the striatum which receive innervation from the limbic and association cortices. The direct relationship between measures of neuromelanin and dopamine synthesis suggests that these aspects of schizophrenia pathophysiology are linked. Our findings highlight specific mesostriatal circuits as the loci of dopamine dysfunction in schizophrenia and, thus, potential therapeutic targets.
PubMed: 38942349
DOI: 10.1016/j.biopsych.2024.06.013 -
Neurobiology of Disease Jun 2024Anorexia nervosa (AN) is an eating disorder (ED) that has seen an increase in its incidence in the last thirty years. Compared to other psychosomatic disorders, ED can...
Anorexia nervosa (AN) is an eating disorder (ED) that has seen an increase in its incidence in the last thirty years. Compared to other psychosomatic disorders, ED can be responsible for many major medical complications, moreover, in addition to the various systemic impairments, patients with AN undergo morphological and physiological changes affecting the cerebral cortex. Through immunohistochemical studies on portions of postmortem human brain of people affected by AN and healthy individuals, and western blot studies on leucocytes of young patients and healthy controls, this study investigated the role in the afore-mentioned processes of altered redox state. The results showed that the brain volume reduction in AN could be due to an increase in the rate of cell death, mainly by apoptosis, in which mitochondria, main cellular organelles affected by a decreased dietary intake, and a highly compromised intracellular redox balance, may play a pivotal role.
PubMed: 38942323
DOI: 10.1016/j.nbd.2024.106580 -
Journal of Affective Disorders Jun 2024Early symptomatic improvement may predict treatment response in bipolar I disorder. Cariprazine has demonstrated early treatment effects in bipolar I depression and...
Early improvement with cariprazine as a predictor of antidepressant, anxiolytic, and antimanic response in bipolar I mania and depression: A pooled post hoc analysis of randomized cariprazine trials.
BACKGROUND
Early symptomatic improvement may predict treatment response in bipolar I disorder. Cariprazine has demonstrated early treatment effects in bipolar I depression and mania studies; therefore, we assessed whether early improvement with cariprazine predicts eventual treatment response.
METHODS
Post hoc analyses used pooled data from randomized, double-blind, placebo-controlled bipolar I depression (NCT02670538, NCT02670551) and mania (NCT00488618, NCT01058096, NCT01058668) trials. In depression studies (cariprazine 1.5 mg/d, 3 mg/d, or placebo), early improvement in Montgomery-Åsberg Depression Rating Scale (MADRS) and Hamilton Anxiety Rating Scale (HAM-A) total scores (≥25 % improvement at day 15) and subsequent depressive/anxiety symptom response status (≥50 % improvement at week 6) were assessed. In mania studies (cariprazine 3-12 mg/d or placebo), early improvement in Young Mania Rating Scale (YMRS) total scores (≥25 % improvement at day 7) and manic symptom response status (≥50 % improvement at week 3) were assessed.
RESULTS
Patients with bipolar I depression and early MADRS improvement were approximately 4- to 6-times as likely to achieve MADRS or HAM-A response than those without early improvement; patients with early HAM-A improvement were approximately 3- to 4-times as likely to achieve MADRS or HAM-A response. A subset of patients without early improvement with cariprazine 1.5 mg/d (20-31 %) subsequently responded following up-titration. Patients with mania and early YMRS improvement were approximately 5 times more likely to have manic symptom response than those without early improvement.
LIMITATIONS
Post hoc analysis; relatively short study durations; flexible-dosing (mania studies).
CONCLUSIONS
Early symptom improvement with cariprazine may inform therapeutic decisions for patients with bipolar I disorder.
PubMed: 38942209
DOI: 10.1016/j.jad.2024.06.100 -
Journal of Affective Disorders Jun 2024Cariprazine has emerged as a promising augmenting treatment agent for unipolar depression and as a monotherapy option for bipolar depression. We evaluated cariprazine's...
BACKGROUND
Cariprazine has emerged as a promising augmenting treatment agent for unipolar depression and as a monotherapy option for bipolar depression. We evaluated cariprazine's efficacy in treating acute major depressive episodes in individuals with major depressive disorder (MDD) or bipolar disorder.
METHODS
A systematic review was conducted on MEDLINE, Embase, PyscInfo, Scopus and Web of Science, ClinicalTrials.gov and ScanMedicine. Study quality was assessed using the RoB 2 tool. Pairwise and dose-response meta-analyses were conducted with RStudio. Evidence quality was assessed with GRADE.
RESULTS
Nine RCTs meeting inclusion criteria encompassed 4877 participants. Cariprazine, compared to placebo, significantly reduced the MADRS score (MD = -1.49, 95 % CI: -2.22 to -0.76) and demonstrated significantly higher response (RR = 1.21, 95 % CI: 1.12 to 1.30) and remission (RR = 1.19, 95 % CI: 1.06 to 1.34) rates. Subgroup analysis unveiled statistically significant reductions in MADRS score in MDD (MD = -1.15, 95 % CI: -2.04 to -0.26) and bipolar I disorder (BDI) (MD = -2.53, 95 % CI: -3.61 to -1.45), higher response rates for both MDD (RR = 1.19, 95 % CI: 1.08 to 1.31) and BDI (RR = 1.27, 95 % CI: 1.10 to 1.46), and higher remission rates only for BDI (RR = 1.41, 95 % CI: 1.24 to 1.60). A higher rate of treatment discontinuation due to adverse events was observed.
LIMITATIONS
Reliance solely on RCTs limits generalisability; strict criteria might not reflect real-world diversity.
CONCLUSIONS
Cariprazine demonstrates efficacy in treating major depressive episodes, although variations exist between MDD and BDI and tolerability may be an issue.
PubMed: 38942207
DOI: 10.1016/j.jad.2024.06.099 -
Journal of Clinical Epidemiology Jun 2024To use individual participant data meta-analysis (IPDMA) to estimate the minimal detectable change (MDC) of the Geriatric Depression Scale-15 (GDS-15) and to examine...
OBJECTIVE
To use individual participant data meta-analysis (IPDMA) to estimate the minimal detectable change (MDC) of the Geriatric Depression Scale-15 (GDS-15) and to examine whether MDC may differ based on participant characteristics and study-level variables.
STUDY DESIGN AND SETTING
This was a secondary analysis of data from an IPDMA on the depression screening accuracy of the GDS. Datasets from studies published in any language were eligible for the present study if they included GDS-15 scores for participants aged 60 or older. MDC of the GDS-15 was estimated via random-effects meta-analysis using 2.77 (MDC95) and 1.41 (MDC67) standard errors of measurement (SEM). Subgroup analyses were used to evaluate differences in MDC by participant age and sex. Meta-regression was conducted to assess for differences based on study-level variables, including mean age, proportion male, proportion with major depression, and recruitment setting.
RESULTS
5,876 participants (mean age 76 years, 40% male, 11% with major depression) from 21 studies were included. The MDC95 was 3.81 points (95% confidence interval [CI] 3.59, 4.04), and MDC67 was 1.95 (95% CI 1.83, 2.03). The difference in MDC95 was 0.26 points (95% CI 0.04, 0.48) between ≥ 80-year-olds and < 80-year-olds; MDC95 was similar for females and males (0.05, 95% CI -0.12, 0.22). The MDC95 increased by 0.29 points (95% CI 0.17, 0.41) per 10% increase in proportion of participants with major depression; mean age had a small association (0.04 points, 95% CI 0.00 to 0.09) with MDC95, but sex and recruitment setting were not significantly associated.
CONCLUSIONS
The MDC95 was 3.81 points and MDC67 was 1.95 points. MDC95 increased with the proportion of participants with major depression. Results can be used to evaluate individual changes in depression symptoms and as a threshold for assessing minimal clinical important difference estimates.
PubMed: 38942179
DOI: 10.1016/j.jclinepi.2024.111443 -
European Neuropsychopharmacology : the... Jun 2024Evidence suggests a remarkable shared genetic susceptibility between psychiatric disorders. However, sex-dependent differences have been less studied. We explored the...
Evidence suggests a remarkable shared genetic susceptibility between psychiatric disorders. However, sex-dependent differences have been less studied. We explored the contribution of schizophrenia (SCZ), bipolar disorder (BD) and major depressive disorder (MDD) polygenic scores (PGSs) on the risk for psychotic disorders and whether sex-dependent differences exist (CIBERSAM sample: 1826 patients and 1372 controls). All PGSs were significantly associated with psychosis. Sex-stratified analyses showed that the variance explained in psychotic disorders risk was significantly higher in males than in females for all PGSs. Our results confirm the shared genetic architecture across psychotic disorders and demonstrate sex-dependent differences in the vulnerability to psychotic disorders.
PubMed: 38941950
DOI: 10.1016/j.euroneuro.2024.04.017 -
Comprehensive Psychiatry Jun 2024Provisional Tic Disorder (PTD) is common in childhood. The received wisdom among clinicians is that PTD is short-lived and mild, with at most a few tics, and rarely...
BACKGROUND
Provisional Tic Disorder (PTD) is common in childhood. The received wisdom among clinicians is that PTD is short-lived and mild, with at most a few tics, and rarely includes complex tics, premonitory phenomena or comorbid illnesses. However, such conclusions come from clinical experience, with biased ascertainment and limited follow-up.
METHODS
Prospective study of 89 children with tics starting 0-9 months ago (median 4 months), fewer than half from clinical sources. Follow-up at 12 (± 24, 36, 48) months after the first tic.
RESULTS
At study entry, many children had ADHD (39), an anxiety disorder (27), OCD (9) or enuresis (17). All had at least two current tics, with a mean total since onset of 6.9 motor and 2.0 phonic tics. Forty-one had experienced a complex tic, and 69 could suppress some tics. Tics were clinically meaningful: 64 had tics severe enough for a clinical trial, and 76 families sought medical attention for the tics. At 12 months, 79 returned, and 78 still had tics. Of these, 29 manifested no tics during history and extended examination, but only via audio-visual monitoring when the child was seated alone. Only 12/70 now had plans to see a doctor for tics. Most who returned at 2-4 years still had tics known to the child and family, but medical impact was low.
CONCLUSIONS
Our results do not contradict previous data, but overturn clinical lore. The data strongly argue against the longstanding but arbitrary tradition of separating tic disorders into recent-onset versus chronic.
PubMed: 38941871
DOI: 10.1016/j.comppsych.2024.152510 -
Psychiatry Research Jun 2024This study examined the association of clinical factors, independent of sex and high psychosocial adversity (HPAd), with the presence of ADHD or other mental disorders,...
This study examined the association of clinical factors, independent of sex and high psychosocial adversity (HPAd), with the presence of ADHD or other mental disorders, specifically within a middle-income country with a non-Caucasian population. A multi-centric cross-sectional study was conducted in three sites in Colombia. Our study recruited trios of an ADHD proband, one sibling, and one parent. We used valid instruments for assessing parents and siblings. The sample included 223 siblings, an average age of 12.3 (SD 3.9), and 51.1% Females. The ADHD recurrence risk ratio (λ) was 12. The clinical factors mainly associated with the presence of ADHD, independent of sex and HPAd, were 1) Pregnancy and childbirth complications, 2) Delayed psychomotor development, 3) Temperament, and 4) Sleep disturbances. Our research showed that, independently of HPAd and the male sex, there were other clinical factors associated with ADHD and other psychiatric disorders in this population. These findings need to be replicated in similar populations globally.
PubMed: 38941862
DOI: 10.1016/j.psychres.2024.115997 -
Phytomedicine : International Journal... Jun 2024Neuropathic pain (NP) due to nerve injury, disrupts neural plasticity by triggering the release of inflammatory mediators. Alongside the hypothesis that...
BACKGROUND
Neuropathic pain (NP) due to nerve injury, disrupts neural plasticity by triggering the release of inflammatory mediators. Alongside the hypothesis that neuro-inflammation contributes to this disruption, Andrographolide (Andro), a traditional bioactive compound derived from Andrographis paniculata, has garnered attention for its potent anti-inflammatory properties. However, whether Andro could ameliorate NP by regulating neuroinflammation remains unknown.
PURPOSE
This study aimed to investigate whether and how Andro regulates neuroinflammation and alleviates NP.
METHODS
The analgesic effects of Andro on NP were evaluated using both the spinal nerve ligation (SNL) and formalin rat models. A combination of network pharmacology, RNA sequencing, and experimental validation was employed to elucidate the underlying mechanism behind Andro's analgesic effects. Additionally, various techniques such as functional ultrasound, immunohistochemistry, quantitative real-time polymerase chain reaction (qPCR), patch clamp, and electron microscopy were employed to investigate the specific neural cell types, neural functions, and changes in neural plasticity influenced by Andro.
RESULTS
Network pharmacology analysis unveiled the crucial roles played by shared targets of Andro and pain in regulating pain-related inflammation, including microglia activation, neuroinflammation, immune modulation, and synaptic transmission. Furthermore, we confirmed Andro's superior efficacy in pain relief compared to the traditional analgesic drug, Gabapentin. In these models, Andro was observed to modulate the haemodynamic response triggered by SNL. Transcriptome analysis and molecular docking studies indicated the involvement of major histocompatibility complex class II (MHCII) genes (Db1, Da, and Bb). Electron microscopy revealed improvements in synaptic ultrastructure, and electrophysiological investigations showed a selective reduction in glutamatergic transmission in neuropathic rats after following Andro treatment. The integration of systems pharmacology analysis and biological validation collectively demonstrated that the mechanism of pain relief involves immune modulation, enhancement of synaptic plasticity, and precise regulation of excitatory neurotransmission.
CONCLUSION
In conclusion, this study has demonstrated that Andro, by targeting MHCII genes, may serve as a promising therapeutic candidate for neuropathic pain.
PubMed: 38941815
DOI: 10.1016/j.phymed.2024.155823 -
NeuroImage. Clinical Jun 2024Advanced age is the most important risk factor for Alzheimer's disease (AD), and carrier-status of the Apolipoprotein E4 (APOE4) allele is the strongest known genetic...
Advanced age is the most important risk factor for Alzheimer's disease (AD), and carrier-status of the Apolipoprotein E4 (APOE4) allele is the strongest known genetic risk factor. Many studies have consistently shown a link between APOE4 and synaptic dysfunction, possibly reflecting pathologically accelerated biological aging in persons at risk for AD. To test the hypothesis that distinct functional connectivity patterns characterize APOE4 carriers across the clinical spectrum of AD, we investigated 128 resting state functional Magnetic Resonance Imaging (fMRI) datasets from the Alzheimer's Disease Neuroimaging Initiative database (ADNI), representing all disease stages from cognitive normal to clinical dementia. Brain region centralities within functional networks, computed as eigenvector centrality, were tested for multivariate associations with chronological age, APOE4 carrier status and clinical stage (as well as their interactions) by partial least square analysis (PLSC). By PLSC analysis two distinct brain activity patterns could be identified, which reflected interactive effects of age, APOE4 and clinical disease stage. A first component including sensorimotor regions and parietal regions correlated with age and AD clinical stage (p < 0.001). A second component focused on medial-frontal regions and was specifically related to the interaction between age and APOE4 (p = 0.032). Our findings are consistent with earlier reports on altered network connectivity in APOE4 carriers. Results of our study highlight promise of graph-theory based network centrality to identify brain connectivity linked to genetic risk, clinical stage and age. Our data suggest the existence of brain network activity patterns that characterize APOE4 carriers across clinical stages of AD.
PubMed: 38941766
DOI: 10.1016/j.nicl.2024.103635