Auditory verbal hallucination (AVH), defined as the auditory perception of speech in the absence of a real external stimulus, occurs in individuals with and without mental illness. The distribution of functional abnormalities in patients with AVH suggests aberrant brain network connectivity. However, no study has measured the global functional connectivity density (gFCD) associated with AVH in patients with major depressive disorder (MDD); gFCD is used widely to examine the density distribution of whole-brain resting-state functional connectivity and can serve as an index reflecting brain metabolism disturbance. In this study, we involved drug-naive patients with first-episode MDD with (n = 35) and without (n = 40) AVH and healthy controls (n = 50). Whole-brain resting-state functional magnetic resonance imaging data were acquired and gFCD was calculated and compared among groups. We found the following gFCD alterations that were shared by both MDD groups: (1) decreased gFCD in the bilateral postcentral gyrus, precentral gyrus, insular cortices and occipital lobe; and (2) increased gFCD in the left middle cingulate cortex. More importantly, we found AVH-specific gFCD changes in patients with MDD: increased gFCD in the left Wernicke's brain regions and bilateral hippocampus and thalamus, and decreased gFCD in the bilateral lateral prefrontal lobule. These findings reflect the disturbance of brain information communication and metabolism in patients with MDD and AVH, related mainly to the language and memory processing circuits, and to some extent provide further support for the "VOICE" model of AVH.
Background: This research was designed to investigate patient-reported and doctor-reported reasons for the discontinuation of pharmacological treatment in Chinese patients with major depressive disorder (MDD), which was part of the National Survey on Symptomatology of Depression (NSSD) from 2014 to 2015. Methods: This cross-sectional study included 649 patients who had discontinued antidepressant medications and 711 patients who had remained on them, selected from a group of 3516 candidates who have had at least one depressive episode. Differences in the two groups' sociodemographic factors, clinical characteristics, medication use, and self-reported reasons for drug discontinuation were compared via Student's t-test or chi-square test. Logistic regression analysis was then used to determine the association of all non-subjective dichotomous and ordinal categorical variables, including the additional 63 items of our physician-evaluated symptomatic assessment, with drug compliance. Results: Compared to the spontaneous drug discontinuation (SDD) group, the drug adherence (DA) group had significantly lower rates of the following: family history of mental disease (9.0% vs 13.6%), highest level of education achieved being post-graduate or above (1.6% vs 4.7%), smoking (5.8% vs 9.7%), and other health problems (33.9% vs 42.4%) (p's<0.05). On the other hand, first-episode depression (48.5% vs 21.9%) and taking of mood stabilizer(s) (8.3% vs 5.6%) were higher in the former group than in the latter (p's< 0.05). Logistic Regression Analysis showed that five symptoms, such as depressed mood, were correlated positively with SDD, while another six symptoms, such as psychomotor retardation, were correlated negatively with it. The receiver operating characteristic (ROC) curve of this model yielded an area under the curve (AUC) of 0.701 (95% CI, 0.673-0.729). Notably, there were three main reasons given by patients in the DA group as to why they discontinued their medication(s): (1) concern about long-term side effects (36.1%), (2) no perceived need for taking said medication(s) long-term (34.2%), and (3) believing oneself to have been cured completely (30.0%). Conclusions: The aforementioned factors may affect patient compliance and elicit maladaptive thinking even from patients with good educational backgrounds, increasing the risk of drug discontinuation. Compliance of pharmacological treatment might be improved by increasing clarification and elucidation of different symptom clusters to the patient and combating the main reasons for drug discontinuation.
Intranasal oxytocin (OXT) has been associated with effects on diverse social-emotional domains in humans, however progress towards a therapeutic application of OXT in disorders with social-emotion impairments is currently hampered by poor replicability. Limited statistical power and individual differences in biological factors, such as oxytocin receptor (OXTR) genetics, may have contributed to these variable findings. To this end, employing a validated oxytocin-sensitive trait judgment paradigm, we present a pharmaco-genetic study aiming at (1) replicating previous findings suggesting that intranasal oxytocin (24 IU) reduces the self-referential bias in a large sample of n = 170 male subjects, (2) determining whether variations in common receptor polymorphisms (rs237887, rs2268491, rs2254298, rs53576, rs2268498) influence sensitivity to oxytocin's behavioral effects. We confirmed that in the whole sample oxytocin influenced self-other distinction in terms of reduced decision time. However, oxytocin only influenced decision time in rs53576 G carriers, whereas effects on subsequent memory performance were only found in rs2268498 TT homozygotes. In summary, the current study partially replicates our previous findings showing that oxytocin reduces the self-referential bias and suggests that sensitivity to its effects in this domain are receptor genotype dependent.
Neuroinflammation and metabolic deficits contribute to the etiology of human affective disorders, such as anxiety and depression. The zebrafish (Danio rerio) has recently emerged as a powerful new model organism in CNS disease modeling. Here, we exposed zebrafish to 2% glucose and 10% cholesterol for 19 days to experimentally induce type 2 diabetes (DM) and to assess stress responses, microglia, inflammation and apoptosis. We analyzed zebrafish anxiety-like behavior in the novel tank and light-dark box (Days 15-16) tests, as well as examined their biochemical and genomic biomarkers (Day 19). Confirming DM-like state in zebrafish, we found higher whole-body glucose, triglyceride, total cholesterol, low-density lipoprotein levels and glucagon mRNA expression, and lower high-density lipoprotein levels. DM zebrafish also showed anxiety-like behavior, elevated whole-body cortisol and cytokines IFN-gamma and IL-4, as well as higher brain mRNA expression of the glucocorticoid receptor, CD11b (a microglial biomarker), pro-inflammatory cytokines IL-6 and TNF-alpha (but not IL-1 beta or anti-inflammatory cytokines IL-4 and IL-10), GFAP (an astrocytal biomarker), neurotrophin BDNF, its receptors p75 and TrkB, as well as apoptotic Bax and Caspase-3 (but not BCl-2) genes. Collectively, this supports the overlapping nature of DM-related affective pathogenesis and emphasizes the role of peripheral and central inflammation and apoptosis in DM-related affective and neuroendocrine deficits in zebrafish.
This exploratory study aims to determine whether the change in systolic blood pressure (sBP) after acute methylphenidate (MPH) administration (.BPMPH) is associated with the neurocognitive response to MPH in the Conners Continuous Performance Test (CPT) in 513 children with ADHD (aged 6 to 12 years old). We noted that higher increases in sBP were associated with larger improvement in CPT performance with MPH. In the univariate regression model, the.BPMPH accounted for an additional 2% of the variance in the change in CPT-Overall Index (OI) after controlling for covariates (p < .001). Linear regression analysis also indicated that.BPMPH significantly contributed to predict a change in omission errors, reaction time, and reaction time variability (p < .001, p < .01, p = .001, respectively), but not in commission errors or detectability index (d`). Participants with a clinically meaningful sBP increase of at least 5 mmHg (n = 191) improved by 4.8 points on the CPT-OI score (p <.001), compared to an improvement of only 0.6 points for participants whose sBP declined by at least 5 mmHg (n = 121). In conclusion, larger sBP increases after MPH administration were associated with greater enhancement in CPT performance. These results could be useful in informing MPH dosing in clinical practice.
Objective: Low levels of vitamin D were found to be associated with different mental disorders. However, the role of vitamin D in the pathogenesis of PTSD is unclear. In this study, we aimed at investigating whether PTSD is linked to reduced vitamin D levels and vitamin D deficiency. Moreover, we sought to investigate the role of the vitamin D-binding protein (also group-specific component or Gc) by testing if two functional polymorphisms (rs4588 and rs7041) were associated with vitamin D levels and PTSD. Methods: Serum levels of total 25(OH)D were measured in a general-population sample of the Study of Health in Pomerania (SHIP-1). The number of traumatic events and status of PTSD were assessed using the PTSD module of the Structured Clinical Interview for the DSM-IV. Study participants were genotyped for rs4588 and rs7041. Associations of 25(OH)D levels and the genotypes with PTSD were tested in subjects with at least one traumatic event (n=1653). Results: 25(OH)D levels were inversely (OR: 0.96; p=0.044) and vitamin D deficiency was positively (OR=2.02; p=0.028) associated with PTSD. Both polymorphisms of the Gc were associated with 25(OH)D levels and PTSD: Carriers of the CC-genotype of rs4588 showed significantly higher 25(OH)D levels (beta=0.179, p < 0.001) and lower odds for PTSD (OR=0.35; p=0.023) compared to the AA-genotype. Likewise, carriers of the TT-allele of rs7041 showed lower 25(OH)D levels (-0.122; p < 0.001) and increased odds for PTSD (OR=2.80; p=0.015) compared to the GG-genotype. Conclusions: Our results suggest that an altered vitamin D metabolism may be involved in the pathophysiology of PTSD. Also, genotypes of the Gc and thus Gc serum levels may impact on PTSD development over and above the effects of 25(OH)D. Our findings contribute to explain the associations of PTSD with different mental and physical disorders.
Patients with schizophrenia have a higher incidence of coronary artery disease. This meta-analysis was performed to evaluate the influence of a prior diagnosis of schizophrenia on mortality following acute coronary syndrome (ACS). Relevant longitudinal follow-up studies were obtained via systematic search of PubMed and Embase databases. A random effect model was used to perform the meta-analysis. This meta-analysis included 3,611,343 hospitalized patients with ACS from nine follow-up studies. The results show that, in patients with schizophrenia, ACS was associated with a significantly higher risk of mortality (multivariate adjusted risk ratio [RR]: 1.66, p < .001) with significant heterogeneity (I2 = 93%) compared to the results of mentally healthy patients. Subgroup analyses demonstrated that patients with schizophrenia were associated with higher ACS mortality within one month (RR: 1.68, p < .001) and during a follow-up period of >= one year (RR: 1.71, p = .01), in studies with (RR: 1.65, p = .06) and without the adjustment of revascularization treatments (RR: 1.68, p = .004), as compared with the results of mentally healthy patients. These results indicate that patients with schizophrenia have a higher than expected mortality risk in the case of acute coronary events.
Administration in adulthood of subanaesthetic doses of ketamine, an NMDA receptor (NMDA-R) antagonist, is commonly used to induce psychotic-like alterations in rodents. The NADPH oxidase (NOX) derived-oxidative stress has been shown to be implicated in ketamine-induced neurochemical dysfunctions and in the loss of parvalbumin (PV)-positive interneurons associated to the administration of this NMDA receptor antagonist in adult mice. However, very few data are available on the effects of early ketamine administration and its contribution to the development of long-term dysfunctions leading to psychosis. Here, by administering a subanaesthetic dose of ketamine (30 mg/kg i.p.) to mice at postnatal days (PNDs) 7, 9 and 11, we aimed at investigating early neurochemical and oxidative stress-related alterations induced by this NMDA-R antagonist in specific brain regions of mice pups, i.e. prefrontal cortex (PFC) and nucleus accumbens (NAcc) and to assess whether these alterations lasted until the adult period. To this purpose, we evaluated glutamatergic, glutamine and GABAergic tissue levels, as well as PV amount in the PFC, both two hours after the last ketamine injection (PND 11) and at 10 weeks of age. Dopamine (DA) tissue levels and DA turnover were also evaluated in the NAcc at the same time points. Levels of 8-hydroxy-2'-deoxyguanosine (8-OHdG), a reliable biomarker of oxidative stress, as well as of the free radical producers NOX1 and NOX2 enzymes, were also assessed in both PFC and NAcc of ketamine-treated pups and adult mice. Ketamine-treated pups showed increased cortical levels of glutamate (GLU) and glutamine, as well as similar GABA amount compared to controls, together with an early reduction of cortical PV levels. In the adult period, the same was observed for GLU and PV, whereas GABA levels were increased and no changes in glutamine amount were detected. Ketamine administration in early life induced a decrease in DA tissue levels and an increase of DA turnover which were also detectable at 10 weeks of age. These alterations were accompanied by 8-OHdG elevations in both PFC and NAcc at the two considered life stages. The expression of NOX1 was significantly reduced in these brain regions following ketamine administration at early life stages, while, in the adult period, significant elevation of this enzyme was observed. Levels of NOX2 were found increased at both time points. Our results suggest that an early increase of NOX2-derived oxidative stress may contribute to the development of neurochemical imbalance in PFC and NAcc, induced by ketamine administration. Modifications of NOX1 expression might represent, instead, an early response of the developing brain to a neurotoxic insult, followed by a later attempt to counterbalance ketamine-related detrimental effects.
Background: Schizophrenia (SCZ) is a severe mental disorder. Both environmental and genetic factors contribute to the development of SCZ. The estimated heritability of SCZ is about 80%. Previous genetic studies of SCZ mainly focused on the genetic variations associated the risk of SCZ. Limited efforts are paid to explore the roles and biological mechanism of nuclear acid methylation implicated in the pathogenesis of SCZ. Methods: A two-stage integrative analysis of SCZ GWAS and nuclear acid methylation functional annotation data (including meQTLs and m6A) was performed in this study. First, the discovery GWAS of SCZ was aligned with genomic meQTLs and m6A annotation data to identify the candidate genes associated with SCZ. Second, another independent replication GWAS dataset of SCZ was applied to validate the discovery results. Furthermore, the functional relevance of identified candidate genes with SCZ were validated by the mRNA expression profiling of SCZ brain tissues. Gene ontology (GO) and pathway enrichment analysis of identified candidate genes was performed by the DAVID tool. Results: The two-stage integrative analysis detected 106 meQTLs related candidate genes for SCZ. After comparing with the differentially expressed genes in SCZ brain tissues, 49 overlapped genes were identified for meQTLs, such as ZSCAN12, BTN3A2 and HLA-DQA1. Besides, for meQTLs, 29 SCZ associated pathways and 56 SCZ associated GO terms were detected, such as cell adhesion molecules and asthma. For m6A, 25 candidate genes were detected by the two-stage integrative analysis for SCZ, such as ZSCAN12, HLA-DQA1 and SNX19. Furthermore, 17 of the 25 genes were detected in the mRNA expression profiling of SCZ brain tissues. Conclusion: This study identified multiple SCZ associated genes and pathways, supporting the implication of nuclear acid methylation in the pathogenesis of SCZ.
Adolescent neurodevelopment confer vulnerability to the actions of treatments that produce adaptations in neurocircuitry underlying motivation, impulsivity and reward. Considering wide usage of a sedative-hypnotic agent propofol in clinical practice, we examined whether propofol is a challenging treatment for peripubertal brain. Motivation/hedonic behavior (sucrose preference test), approach/avoidance behavior (elevated plus maze test) and response to dissociative drug phencyclidine (PCP) were studied in peripubertal rats (the rodent model of periadolescence) after propofol anesthesia exposure (PAE). Neurodegeneration (Fluoro-Jade staining) and the expression of proteins (Western blot) involved in excitatory synaptic transmission and activity-dependent synaptic stabilization in the medial prefrontal cortex (mPFC) and striatum (components of motivation/reward circuitry; process both appetitive and aversive events) were examined as well. In peripubertal rats PAE produced 1) transient brain-region specific changes in the expression of N-methyl-D-aspartate (NMDA) receptor subunits NR2A and NR2B, PSD-95 and N-cadherin, without neurotoxicity, 2) hyperlocomotor response to PCP, 3) no changes in preference for palatable 1% sucrose solution and a decrease in food eaten, 4) preference for 20% sucrose solution without changes in food eaten, 5) stretch-attended postures and open arms entries in the elevated plus maze test. Overall, these novel findings show that PAE leaves transient synaptic trace recognized as early form of synaptic plasticity related to passive drug exposure in the brain systems implicated in motivation/reward, increases drug-responsiveness, favors risk-taking and preference of novel/intense stimuli repairing otherwise present motivational deficiency. These findings accentuate multifaceted response to propofol in peripuberty and the importance of environmental stability for the most favorable neurobehavioral recovery.
Major depressive disorder (MDD) has been associated with changes in the biological stress systems, including the locus coeruleus-noradrenergic system. Accumulated evidence suggests an upregulation of central alpha2-receptors, leading to decreased noradrenergic activity on a central level in MDD patients. Adverse childhood experiences (ACE) such as physical or sexual abuse might contribute to those changes. Furthermore, noradrenaline can affect cognitive processes, e.g. learning and memory. Cognitive dysfunctions constitute an important symptom of MDD. We aimed to investigate the relationship of alpha2-receptor dysregulation with learning processes in MDD by conducting a differential fear conditioning paradigm after double-blind administration of the alpha2-receptor antagonist yohimbine versus placebo. To investigate the role of ACE systematically, we included four groups of healthy participants and MDD patients with and without ACE (MDD-/ACE-: N=44, MDD-/ACE+: N=26, MDD+/ACE-:N=24, MDD+/ACE+: N=24; without antidepressant medication). We found increased noradrenergic activity after yohimbine administration across groups as measured by alpha-amylase and blood pressure. Overall, fear responses were higher after yohimbine as indicated by skin conductance responses and fear-potentiated startle responses. While we found no significant MDD effect, ACE had significant impact on the ability to discriminate between both conditioned stimuli (CS+ predicting an aversive stimulus, CS-predicting none), depending on drug condition. After yohimbine, CS discrimination decreased in individuals without ACE, but not in individuals with ACE. Differences in the response to yohimbine might be explained by aberrant alpha2-receptor regulation in individuals with ACE. Impaired discrimination of threat and safety signals might contribute to enhanced vulnerability following ACE.
Objective: This systematic review aimed to elucidate the relationship between polydipsia and antipsychotics. Methods: We systematically searched MEDLINE, Embase, and PsycINFO, and included clinical studies and case reports on polydipsia induced or improved by antipsychotics. Results: We identified 61 articles: 1 double-blind randomized controlled trial (RCT), 4 single-arm trials, 1 cross-sectional study, 3 case series, and 52 case reports. The double-blind RCT demonstrated no significant difference in improvement in polydipsia between olanzapine and haloperidol. Two single-arm trials showed that polydipsia improved during clozapine treatment, whereas the other 2 showed that risperidone did not improve polydipsia. The cross-sectional study showed the prevalence of hyponatremia with first-generation antipsychotics (FGAs: 26.1%) and second-generation antipsychotics (SGAs: 4.9%). Two case series reported that clozapine improved polydipsia; the other one indicated that patients with polydipsia who were treated with FGAs had schizophrenia (70.4%) and mental retardation (25.9%). Of 90 cases in the case reports, 67 (75.3%) were diagnosed with schizophrenia. Of 83 cases in which antipsychotic treatment started before the onset of polydipsia, 75 (90.3%) received FGAs, particularly haloperidol (n= 24, 28.9%), and 11 (13.3%) received risperidone. Among 40 cases in which polydipsia was improved following antipsychotic treatment, 36 (90.0%) received SGAs, primarily clozapine (n=14, 35.0%). Conclusions: Although the causal relationship between polydipsia and antipsychotics remains unclear because of the paucity of high-quality studies, antipsychotics with high affinity to dopamine D-2 receptors may be associated with an increased risk of polydipsia while clozapine may be effective for treating polydipsia.
Parkinson's disease (PD) is a neurodegenerative disease and its characteristic is the progressive degeneration of dopaminergic neurons within the substantia nigra (SN) of the midbrain. There is hardly any clinically proven efficient therapeutics for its cure in several recent preclinical advances proposed to treat PD. Recent studies have found that the endocannabinoid signaling system in particular the comprised two receptors, CB1 and CB2 receptors, has a significant regulatory function in basal ganglia and is involved in the pathogenesis of PD. Therefore, adding new insights into the biochemical interactions between cannabinoids and other signaling pathways may help develop new pharmacological strategies. Factors of the endocannabinoid system (ECS) are abundantly expressed in the neural circuits of basal ganglia, where they interact interactively with glutamatergic,gamma-aminobutyric acid-ergic (GABAergic), and dopaminergic signaling systems. Although preclinical studies on PD are promising, the use of cannabinoids at the clinical level has not been thoroughly studied. In this review, we evaluated the available evidence and reviewed the involvement of ECS in etiologies, symptoms and treatments related to PD. Since CB1 and CB2 receptors are the two main receptors of endocannabinoids, we primarily put the focus on the therapeutic role of CB1 and CB2 receptors in PD. We will try to determine future research clues that will help understand the potential therapeutic benefits of the ECS in the treatment of PD, aiming to open up new strategies and ideas for the treatment of PD.
Growing evidence has suggested that ascorbic acid may exhibit rapid anxiolytic and antidepressant-like effects. In this study the effects of a single administration of ascorbic acid (1 mg/kg, p.o.), ketamine (1 mg/kg, i.p., a fast-acting antidepressant) and fluoxetine (10 mg/kg, p.o., conventional antidepressant) were investigated on: a) behavioral performance in the novelty suppressed feeding (NSF) test; b) hippocampal synaptic protein immunocontent; c) dendritic spine density and morphology in the dorsal and ventral dentate gyrus (DG) of the hippocampus and d) hippocampal dendritic arborization. Ascorbic acid or ketamine, but not fluoxetine, decreased the latency to feed in the NSF test in mice. This effect was accompanied by increased p70S6K (Thr389) phosphorylation 1 h after ascorbic acid or ketamine treatment, although only ascorbic acid increased synapsin I immunocontent. Ketamine administration increased the dendritic spine density in the dorsal DG, but none of the treatments affected the maturation of dendritic spines in this region. In addition, both ascorbic acid and ketamine increased the dendritic spine density in the ventral DG, particularly the mature spines. Sholl analysis demonstrated no effect of any treatment on hippocampal dendritic arborization. Altogether, the results provide evidence that the behavioral and synaptic responses observed following ascorbic acid administration might occur via the upregulation of synaptic proteins, dendritic spine density, and maturation in the ventral DG, similar to ketamine. These findings contribute to understand the cellular targets implicated in its antidepressant/anxiolytic behavioral responses and support the notion that ascorbic acid may share with ketamine the ability to increase synaptic function.
Depressive brooding following a stressful event predicts negative affect and neuroendocrine responses related to psychological stress. The dorsolateral prefrontal cortex (DLPFC) has been associated with the top-down regulation of thoughts and emotions, and abnormal neural activity within this region has been associated with increased psychological stress and ruminative thinking. The aim of this study was to investigate whether the modulation of the DLPFC could have beneficial effects on ruminative thoughts and the endocrine response following a self-relevant stressor. Using a sham-controlled within-subjects crossover-design, two sessions of intermittent theta-burst stimulation (iTBS) were administered over the left DLPFC to thirty-eight healthy-volunteers after they were confronted with a social-evaluative stressor, the Trier Social Stress Test. To assess stress recovery, momentary rumination was measured before and after a resting period subsequent to the encounter with the stressor. In addition, cortisol levels were measured between and after the two iTBS sessions that were applied during the stress recovery phase. Overall, iTBS did not significantly influence ruminative thinking and cortisol secretion during the stress recovery phase. However, taking into account participants ruminative tendencies, our results revealed that for participants with higher levels of brooding ruminative thinking remained stable after iTBS, whereas in the sham condition there was a marginal significant increase in ruminative thinking. Moreover, only after iTBS, there was a significant reduction in cortisol secretion (i.e. a faster return to baseline as compared to sham) for high brooders during the recovery from the stressor. These results show that the prefrontal cortex plays a role in stress recovery mechanisms in individuals who are more vulnerable for psychopathology.