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Rationale: Several lines of evidence indicate that an insertion/deletion (I/D) polymorphism in the angiotensin-converting enzyme gene (ACE) gene may be involved in the pathogenesis of schizophrenia and cognitive impairment. However, the relationship between ACE I/D polymorphism and cognitive impairment in patients with schizophrenia remains unclear., Objectives: The aim of this study was to examine whether ACE gene I/D polymorphism contributed to cognitive impairment in Chinese patients with schizophrenia, and whether the association between clinical symptoms and cognitive impairment depended on different ACE genotypes., Methods: The ACE I/D polymorphism was genotyped in 928 schizophrenia patients and 325 healthy controls using a case-control design. The severity of psychopathological symptoms was assessed using the Positive and Negative Syndrome Scale (PANSS). Cognitive functioning was assessed by the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS)., Results: There were significant differences in genotype and allele frequencies of the ACE I/D polymorphism between patients and healthy controls (both P < 0.01). After controlling for demographic characteristics, patients who are homozygous carriers of D and I performed worse on the RBANS attention index than heterozygous carriers (P = 0.009). In addition, attention index score was negatively correlated with PANSS negative symptom score in patients of all genotypes (all P < 0.05), and positively correlated with positive symptom score only in the I/I genotype (P = 0.005)., Conclusions: These findings suggest that ACE I/D gene variants play a role in susceptibility to schizophrenia, specific cognitive impairment and the association between clinical symptoms and cognitive impairment in schizophrenia patients., Competing Interests: Declarations Declarations of interest No conflict of interest was disclosed for each author., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Rationale and Objective: Schizophrenia displays sex differences in many aspects. Decreased brain-derived neurotrophic factor (BDNF) levels have been reported to be associated with high body weight or obesity as well as other psychopathological aspects in schizophrenia patients. This study aimed to explore sex differences in the relationship between serum BDNF levels and obesity in patients with chronic schizophrenia., Methods: We recruited 132 Chinese patients with chronic schizophrenia (98 males and 34 females) and compared sex differences in the body mass index (BMI), obesity, serum BDNF levels, and their associations. Psychopathology symptoms were assessed using the Positive and Negative Syndrome Scale (PANSS). A regression model with various demographic and clinical variables was applied to predict the serum levels of BDNF., Results: Female patients had a higher rate of obesity and higher BMI, but lower BDNF levels than male schizophrenia patients. A significantly negative correlation was observed between BMI and BDNF levels only in female patients but not in male patients. The multiple regression model with demographic and clinical variables significantly predicted BDNF levels only in female patients, with a medium size effect. And only in female patients, BMI made a significant contribution to this prediction., Conclusion: Our results indicate significant sex differences in the obesity, BMI, BDNF levels, and their association in chronic patients with schizophrenia, showing a significant inverse correlation between BMI and BDNF levels only in female patients. Thus, sex needs to be considered when assessing the relationship between BDNF and metabolic syndromes in schizophrenia.

Objective: Many studies have reported that long-term exposure to job-related stress can lead to burnout, which may be influenced by genetic and environmental factors. Burnout correlates with depression. This study investigated whether one tag polymorphism rs6354 in 5-HTT gene modulated the influence of job-related stress on burnout in the medical professionals in a Chinese Han population, which to our best knowledge has not been explored., Methods: Seven hundred twelve subjects were recruited from a general hospital and measured for burnout symptoms using the Maslach Burnout Inventory (MBI), the stress using the House and Rizzo's Work Stress Scale, and the stressors using the Evers, Frese, and Cooper's Sources of Pressure Scale. The 5-HTT rs6354 polymorphism was genotyped in 376 subjects., Results: The majority of correlations between the work stress score or the six stressor scores and three burnout subscores were significant (all p < 0.05). There was no significant main effect of the 5-HTT rs6354 genotype on burnout symptoms; however, there was a statistically significant interaction between 5-HTT rs6354 and work stress on burnout (F = 5.08, df = 2, 369, p = 0.007). In the low stress group, G allele carriers had significantly higher burnout level than TT homozygote (F = 11.60, df = 1, 48, p < 0.001). On the contrary, in the high stress group, G allele carriers exhibited significantly lower burnout level compared to TT homozygote (F = 3.86, df = 1, 103, p = 0.025)., Conclusions: Our findings suggest that the 5-HTT rs6354 polymorphism may modulate the influence of job-related stress on burnout by adjusting serotonin transporter function and neurotransmission, showing that individuals with TT genotype displayed a greater susceptibility to both the detrimental effects of higher stress and the beneficial effects of lower stress compared to those with G allele, which supports the differential-susceptibility hypothesis.

Objective: Few studies have examined the potential interactive effect of both smoking and drinking on cognition. Brain-derived neurotrophic factor (BDNF) plays a critical role in cognition. This is the first study to examine the neurocognitive consequences of cigarette smoking combined with chronic alcohol consumption and their relationship to serum BDNF levels in a Chinese Han population., Materials and Methods: We recruited 191 healthy male subjects, including 47 isolated smokers, 31 isolated chronic alcohol users, 58 combined smokers and chronic alcohol users, and 55 non-smokers and non-alcohol users. We then compared the repeatable battery for the assessment of neuropsychological status (RBANS) scores and serum BDNF levels in these four groups., Results: When compared to the non-smoking + non-alcohol-using group, the smoking group performed worse on immediate memory, attention, language, and RBANS total score. There were no significant differences in the RBANS scores between the alcohol-using group and non-smoking + non-alcohol-using group, or between the smoking group and smoking + alcohol-using group. We did not find an association between BDNF and smoking or drinking status or between BDNF and cognitive performance. In the smoking group, there was a significant correlation between BDNF and carbon monoxide concentration, and between BDNF and the Fagerstrom Test for Nicotine Dependence (FTND) total score., Conclusions: Our results suggest that smoking is associated with cognitive decline, but not with BDNF levels in a normal population. However, smoking severity is positively associated with BDNF levels. Concomitant alcohol use does not worsen the cognitive decline caused by smoking.

Objective: A substantial body of evidence implicates TNF-alpha (TNFα) and TNFα-related signaling pathways in the pathophysiology of schizophrenia. The current study examined the relationship between TNFα serum levels and both psychopathological as well as cognitive symptoms in schizophrenia., Materials and Methods: Serum TNFα levels were assessed in 89 patients diagnosed with schizophrenia and compared to 43 healthy control subjects matched for age and gender. Schizophrenic symptomatology was assessed with the Positive and Negative Syndrome Scale (PANSS), and serum TNFα levels were measured by sandwich enzyme-linked immunosorbent assay (ELISA)., Results: TNFα levels were significantly lower in patients with chronic schizophrenia relative to healthy control subjects (p<0.01). Correlation analysis revealed a significant negative correlation between the TNFα levels and the PANSS total score (p<0.01). Additionally, TNFα levels were significantly negatively correlated with scores on general psychopathology (p<0.01), positive (p<0.05) and cognitive subscales (p<0.05). Stepwise multiple regression analysis identified TNFα levels as a significant predictor of scores on the general psychopathology subscale of the PANSS., Conclusion: The significant relations observed in the current study between TNFα and the PANSS and its subscales suggest that immune disturbance may be involved in the psychopathology and cognitive deficits of schizophrenia.

Background: Long-term antipsychotic treatment for schizophrenia is often associated with the emergence of tardive dyskinesia (TD), which is linked to greater cognitive impairment. Brain-derived neurotrophic factor (BDNF) plays a critical role in cognitive function, and schizophrenia patients with TD have lower BDNF levels than those without TD., Objective: This study examines the BDNF levels, the cognitive function, and the association of BDNF with cognitive function in schizophrenia patients with or without TD., Methods: We recruited 83 male chronic patients with (n=35) and without TD (n=48) meeting DSM-IV criteria for schizophrenia and 52 male control subjects. We examined the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) and BDNF levels for all subjects. Positive and Negative Symptom Scale (PANSS) and the Abnormal Involuntary Movement Scale (AIMS) were assessed in patients., Results: BDNF levels were lower in patients with than those without TD (p<0.05). RBANS total score (p<0.01) and subscales of immediate memory, visuospatial/constructional performance, and attention were lower in patients with than those without TD (all p<0.05). BDNF levels were positively associated with immediate memory in patients without TD, but negatively in TD patients (both p<0.05). Multiple regression analysis confirmed that in either TD or non-TD group, BDNF was an independent contributor to immediate memory (both p<0.05)., Conclusions: BDNF may be involved in the pathophysiology of TD. While the associations between BDNF and cognition in both TD and non-TD patients suggest a close relationship between BDNF and cognition, the different directions may implicate distinct mechanisms between TD and non-TD patients.

The available literature on the use of atypical antipsychotics for the treatment of bipolar disorder was reviewed. All uncontrolled and controlled reports were identified through a comprehensive Medline search. Based on the available evidence, olanzapine was found to be the most appropriate atypical antipsychotic agent utilized for the treatment of manic bipolar patients, although there is also preliminary data suggesting the efficacy of risperidone and clozapine. The preliminary data evaluating the efficacy of quetiapine and ziprasidone in bipolar disorder are still very limited. Double-blind controlled studies with atypical antipsychotics in the long-term treatment of bipolar disorder are still largely not available, but will be critical to determine the effectiveness of these agents in the maintenance treatment of bipolar disorder. There are recent uncontrolled suggestions that olanzapine may have beneficial effects in depressed bipolar patients, which deserve further investigation in controlled studies. In conclusion, atypical antipsychotics, due to lower potential for neurotoxicity and preliminary evidence suggesting better efficacy than typical antipsychotics, are increasingly having a more prominent role in the pharmacological management of bipolar patients. Nonetheless, until there is systematic data from long-term controlled follow-up studies on the comparative efficacy of these agents with mood stabilizers, atypical antipsychotics should be cautiously utilized, and preferably in combination with a mood stabilizer for the maintenance phase of treatment.

Rationale: In vitro and in vivo animal studies suggest that the intracellular phosphatidylinositol (PI) pathway is an important target for the effects of lithium., Objectives: We conducted a preliminary study to examine the in vivo effects of lithium treatment on platelet membrane phosphoinositides in bipolar disorder subjects, in an attempt to examine further the hypothesis that lithium has significant in vivo effects on the PI pathway in these patients., Methods: We quantitated PI, phosphatidylinositol-4-phosphate (PIP), and phosphatidylinositol-4,5-bisphosphate (PIP2) in platelet membranes of seven subjects (five male, two female; mean age= 27.9+/-5.7 years), initially while they were unmedicated, and a second time after at least 21 days of lithium treatment (mean+/-SD=28.7+/-7.1 days)., Results: The mean+/-SD values for PI were 5.63+/-2.25% and 5.21+/-1.06%; for PIP 0.68+/-0.20% and 0.55+/-0.11%; and for PIP2 0.60+/-0.21% and 0.38+/-0.15%, before and after lithium treatment, respectively. The decrease in PIP2 values after lithium treatment was statistically significant (Wilcoxon signed ranks test, Z=-2.37, P=0.02)., Conclusion: This longitudinal study suggests that therapeutic doses of lithium significantly decrease platelet membrane PIP2 levels in vivo in bipolar disorder subjects, which may be related to lithium's mechanism of action in bipolar disorder.

Limited data exists on mechanisms contributing to elevated risk for alcohol use disorder (AUD) in bipolar disorder. Variation in subjective response to alcohol may relate to alcohol use and risk for AUD. This study used a randomized, placebo-controlled, cross-over, within-subjects design to investigate differences in subjective response to alcohol in 50 euthymic young adults (n = 24 with and n = 26 without bipolar disorder type I). Eighty-three percent of participants with bipolar disorder were medicated. Participants completed assessments of clinical history, alcohol expectancies, and recent alcohol use. Participants were dosed to a .08 g% breath alcohol concentration. The placebo condition occurred on a separate counter-balanced day. Subjective response to alcohol was investigated at similar time points during both conditions. Group, condition, and group-by-condition interactions were modeled, with condition and time of subjective response assessment as repeated within-subject variables, and subjective response to alcohol as the dependent variable. Greater stimulating effects and liking of alcohol were reported in people with bipolar disorder (group-by-condition interactions, p < .05) than healthy young adults. While young adults with bipolar disorder reported anticipating feeling less "mellow/relaxed" when drinking (p = .02), during both beverage conditions they reported feeling more "mellow/relaxed" (main effect of group, p = .006). Feeling more "mellow/relaxed" during the alcohol condition related to greater recent alcohol use in bipolar disorder (p = .001). Exploratory analyses suggested anticonvulsants and sedatives/antihistamines may relate to differences in subjective response to alcohol in bipolar disorder. Results suggest young adults with bipolar disorder may differ in alcohol expectancies and experience alcohol intoxication differently-with distinct relations between subjective response to alcohol and alcohol use-compared to healthy young adults., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Deep brain stimulation (DBS) delivered to the ventromedial prefrontal cortex (vmPFC) induces antidepressant- and anxiolytic-like responses in various animal models. Electrophysiology and neurochemical studies suggest that these effects may be dependent, at least in part, on the serotonergic system. In rodents, vmPFC DBS reduces raphe cell firing and increases serotonin (5-HT) release and the expression of serotonergic receptors in different brain regions., Methods: We examined whether the behavioural responses of chronic vmPFC DBS are mediated by 5-HT 1A or 5-HT 1B receptors through a series of experiments. First, we delivered stimulation to mice undergoing chronic social defeat stress (CSDS), followed by a battery of behavioural tests. Second, we measured the expression of 5-HT 1A and 5-HT 1B receptors in different brain regions with western blot. Finally, we conducted pharmacological experiments to mitigate the behavioural effects of DBS using the 5-HT 1A antagonist, WAY-100635, or the 5-HT 1B antagonist, GR-127935., Results: We found that chronic DBS delivered to stressed animals reduced the latency to feed in the novelty suppressed feeding test (NSF) and immobility in the forced swim test (FST). Though no significant changes were observed in receptor expression, 5-HT 1B levels in DBS-treated animals were found to be non-significantly increased in the vmPFC, hippocampus, and nucleus accumbens and reduced in the raphe compared to non-stimulated controls. Finally, while animals given vmPFC stimulation along with WAY-100635 still presented significant responses in the NSF and FST, these were mitigated following GR-127935 administration., Conclusions: The antidepressant- and anxiolytic-like effects of DBS in rodents may be partially mediated by 5-HT1 B receptors., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Rationale: An imbalance of the tryptophan kynurenine pathway (KP) commonly occurs in psychiatric disorders, though the neurocognitive and network-level effects of this aberration are unclear. Objectives: In this study, we examined the connection between dysfunction in the frontostriatal brain circuits, imbalances in the tryptophan kynurenine pathway (KP), and neurocognition in major psychiatric disorders. Methods: Forty first-episode medication-naive patients with schizophrenia (SCZ), fifty patients with bipolar disorder (BD), fifty patients with major depressive disorder (MDD), and forty-two healthy controls underwent resting-state functional magnetic resonance imaging. Plasma levels of KP metabolites were measured, and neurocognitive function was evaluated. Frontostriatal connectivity and KP metabolites were compared between groups while controlling for demographic and clinical characteristics. Canonical correlation analyses were conducted to explore multidimensional relationships between frontostriatal circuits-KP and KP-cognitive features. Results: Patient groups shared hypoconnectivity between bilateral ventrolateral prefrontal cortex (vlPFC) and left insula, with disorder-specific dysconnectivity in SCZ related to PFC, left dorsal striatum hypoconnectivity. The BD group had higher anthranilic acid and lower xanthurenic acid levels than the other groups. KP metabolites and ratios related to disrupted frontostriatal dysconnectivity in a transdiagnostic manner. The SCZ group and MDD group separately had high-dimensional associations between KP metabolites and cognitive measures. Conclusions: The findings suggest that KP may influence cognitive performance across psychiatric conditions via frontostriatal dysfunction. [ABSTRACT FROM AUTHOR]

Rationale: Patients with schizophrenia with second-generation antipsychotics (SGAs) treatment have shown an increased risk of bone fragility and susceptibility to fracture; however, it is still unclear whether this risk is derived from the effect of antipsychotics on balance of bone metabolism., Objectives: We investigated the changes of two bone turnover biomarkers (BTMs) concentrations in people with schizophrenia receiving SGAs: procollagen type I aminoterminal propeptide (PINP) and C-terminal telopeptide of type I collagen (CTX-1) as BTMs of osteogenesis and bone resorption, respectively, to explore how antipsychotics contribute to bone fragility., Methods: We recruited 59 Chinese male patients with schizophrenia (32 drug-naïve first-episode (DNFE) patients and 27 chronic patients) to undergo 8 weeks SGAs treatment. Fasting peripheral blood samples of pre- and posttreatment were collected, plasma levels of PINP and CTX-1 were measured., Results: The interaction effects of group and time on PINP and CTX-1 concentrations were found (P = .016 and P = .008). There was a significant decrease for both BTMs concentrations of the posttreatment compared to the pretreatment (P<.001 and P = .003). Chronic patients had significantly higher changes of BTMs concentrations compared to DNFE patients (P = .048 and P = .024). There was a positive correlation of the two BTMs of pretreatment with disease course in DNFE group (r = .37, P = .039;r = .38, P = .035) and a negative correlation of PINP of pretreatment with age in the chronic group (r=-.40, P = .039)., Conclusion: Long-term SGAs medication inhibited osteogenesis in a dose- and time-dependent manner and damaged the balance of bone formation and bone resorption., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Rationale: Job stress can lead to job burnout, and BDNF polymorphism has been found to be involved in its psychopathological mechanism. Research needs a better understanding of the important role of gene × environment (i.e., BDNF polymorphism × job stress) interaction on job burnout., Objective: This study aimed to explore how BDNF rs6265 polymorphism may moderate the relationship between job stress and job burnout., Methods: Three hundred forty-one healthy participants (187 males and 154 females) from a Chinese university were included. The present study used a standardized questionnaire including demographic characteristics, job stress assessed by the House and Rizzo's Work Stress Scale, and job burnout assessed by the Maslach Burnout Inventory-General Survey. The BDNF rs6265 polymorphism was genotyped., Results: Job stress showed a positive correlation with emotional exhaustion (p < 0.001), cynicism (p < 0.001), and reduced personal accomplishment (p < 0.01). The main effects of BDNF rs6265 polymorphism on emotional exhaustion and cynicism were significant [F (1,333)  = 5.136, p = 0.024; F (1,333)  = 4.175, p = 0.042, respectively]. The interaction between job stress and BDNF rs6265 on cynicism was significant (△ R 2  = 0.013, p = 0.014) after controlling for age, sex, education, and position, indicating that individuals with BDNF rs6265 TT genotype showed higher level of cynicism when in high job stress., Conclusions: The results provided evidence for the association of BDNF gene rs6265 polymorphism, job stress, and their interaction with job burnout. Individuals with TT genotype in BDNF rs6265 might be susceptible to stressful situations, which would lead to cynicism., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Objective: People with schizophrenia exhibit a high obesity rate. However, little is known about the prevalence of obesity and its relationship with clinical symptoms and metabolic indicators in first-episode drug-naïve (FEDN) schizophrenia., Methods: Demographic and lipid parameters were gathered from 297 FEDN schizophrenia and 325 healthy controls. The patients' symptomatology was evaluated by the Positive and Negative Syndrome Scale (PANSS)., Results: The obesity rate of FEDN patients was 10.77%, similar to that of controls (10.5%). The prevalence of overweight plus obesity of patients was 44.8%, significantly higher than that of controls (36.6%). Compared with non-obese patients, obese patients had higher levels of cholesterol (4.81 ± 0.93 vs 4.22 ± 1.00 mmol/L), triglyceride (0.27 ± 0.21 vs 0.14 ± 0.24 mg/dL), low-density lipoprotein (0.48 ± 0.12 vs 0.40 ± 0.12 mg/dL), greater ratio of triglyceride/high-density lipoprotein (2.01 ± 1.23 vs 1.44 ± 1.26), and higher PANSS positive symptom subscale score (29.81 ± 6.29 vs 27.05 ± 6.15), general psychopathology subscale score (70.75 ± 11.74 vs 66.87 ± 11.37), and total score (149.81 ± 21.08 vs 140.64 ± 21.58), but lower high-density lipoprotein level (1.09 ± 0.21 vs 1.27 ± 0.34 mg/dL) (all p < 0.05). Correlation analysis revealed that body mass index (BMI) was positively correlated with triglyceride, cholesterol, high-density lipoprotein, low-density lipoprotein, triglyceride/high-density lipoprotein ratio, PANSS positive symptoms, general psychopathology, and total scores (all p < 0.05, r = 0.124 ~ 0.335). Multiple regression analysis confirmed that PANSS positive symptoms, total score, and cholesterol level were significantly associated with BMI (all p < 0.05, β: 0.126-0.162)., Conclusion: There was no significant difference in the prevalence of obesity between FEDN patients and the control group. Moreover, BMI was positively associated with positive symptom severity in FEDN patients.

Rationale: Challenges in drug development for psychiatric disorders have left much room for the introduction of novel treatments with better therapeutic efficacies and indices. As a result, intense research has focused on identifying new targets for developing such pharmacotherapies. One of these targets may be the phosphodiesterase (PDE) class of enzymes, which play important roles in intracellular signaling. Due to their critical roles in cellular pathways, these enzymes affect diverse neurobiological functions from learning and memory formation to neuroinflammation. Objectives: In this paper, we reviewed studies on the use of PDE inhibitors (PDEIs) in preclinical models and clinical trials of psychiatric disorders including depression, anxiety, schizophrenia, post-traumatic stress disorder (PTSD), bipolar disorder (BP), sexual dysfunction, and feeding disorders. Results: PDEIs are able to improve symptoms of psychiatric disorders in preclinical models through activating the cAMP-PKA-CREB and cGMP-PKG pathways, attenuating neuroinflammation and oxidative stress, and stimulating neural plasticity. The most promising therapeutic candidates to emerge from these preclinical studies are PDE2 and PDE4 inhibitors for depression and anxiety and PDE1 and PDE10 inhibitors for schizophrenia. Furthermore, PDE3 and 4 inhibitors have shown promising results in clinical trials in patients with depression and schizophrenia. Conclusions: Larger and better designed clinical studies of PDEIs in schizophrenia, depression, and anxiety are warranted to facilitate their translation into the clinic. Regarding the other conditions discussed in this review (most notably PTSD and BP), better characterization of the effects of PDEIs in preclinical models is required before clinical studies. [ABSTRACT FROM AUTHOR]

Background: Rapid-eye movement (REM) sleep deprivation (SD) can induce manic-like behaviors in rodents. On the other hand, lithium, as one of the oldest drugs used in neuropsychiatric disorders, is still one of the best drugs for the treatment and control of bipolar disorder. In this study, we aimed to investigate the role of chronic short-term REM SD in the induction of manic-like behaviors in female rats., Methods: The rats were exposed to REM SD for 14 days (6 hours/day). Lithium was intraperitoneally injected at the doses of 10, 50, and 100 mg/kg., Results: REM SD induced hyperactivity and OCD-like behavior, and decreased anxiety, depressive-like behavior, and pain subthreshold. REM SD also impaired passive avoidance memory and decreased hippocampal brain-derived neurotrophic factor (BDNF) expression level. Lithium at the doses of 50 and 100 mg/kg partly and completely abolished these effects, respectively. However, lithium (100 mg/kg) increased BDNF expression level in control and sham REM SD rats with no significant changes in behavior., Conclusions: Chronic short-term REM SD may induce a mania-like model and lead to OCD-like behavior and irritability. In the present study, we demonstrated a putative rodent model of mania induced by chronic REM SD in female rats. We suggest that future studies should examine behavioral and mood changes following chronic REM SD in both sexes. Furthermore, the relationship between manic-like behaviors and chronic REM SD should be investigated., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Deep brain stimulation (DBS) delivered to the ventromedial prefrontal cortex (vmPFC) induces antidepressant- and anxiolytic-like responses in various animal models. Electrophysiology and neurochemical studies suggest that these effects may be dependent, at least in part, on the serotonergic system. In rodents, vmPFC DBS reduces raphe cell firing and increases serotonin (5-HT) release and the expression of serotonergic receptors in different brain regions. Methods: We examined whether the behavioural responses of chronic vmPFC DBS are mediated by 5-HT1A or 5-HT1B receptors through a series of experiments. First, we delivered stimulation to mice undergoing chronic social defeat stress (CSDS), followed by a battery of behavioural tests. Second, we measured the expression of 5-HT1A and 5-HT1B receptors in different brain regions with western blot. Finally, we conducted pharmacological experiments to mitigate the behavioural effects of DBS using the 5-HT1A antagonist, WAY-100635, or the 5-HT1B antagonist, GR-127935. Results: We found that chronic DBS delivered to stressed animals reduced the latency to feed in the novelty suppressed feeding test (NSF) and immobility in the forced swim test (FST). Though no significant changes were observed in receptor expression, 5-HT1B levels in DBS-treated animals were found to be non-significantly increased in the vmPFC, hippocampus, and nucleus accumbens and reduced in the raphe compared to non-stimulated controls. Finally, while animals given vmPFC stimulation along with WAY-100635 still presented significant responses in the NSF and FST, these were mitigated following GR-127935 administration. Conclusions: The antidepressant- and anxiolytic-like effects of DBS in rodents may be partially mediated by 5-HT1B receptors. [ABSTRACT FROM AUTHOR]

Rationale : Although metabolic abnormalities and metabolic syndrome (MetS) have been extensively investigated in schizophrenia, few studies have examined them in first-episode drug-naive (FEDN) patients. Objectives: This study aimed to investigate the prevalence and clinical correlates of metabolic abnormalities in FEDN schizophrenia patients. Methods: A total of 430 FEDN schizophrenia patients and 453 controls were recruited. Various parameters were measured including BMI, waist circumference, blood pressure, lipid profiles, blood glucose, glycosylated hemoglobin (HbA1c), insulin, and homeostatic model assessment for insulin resistance (HOMA-IR). Results: Patients had a higher prevalence of MetS, hypertension, hypertriglyceridemia, hypo-HDL-C, elevated HAb1c, and elevated insulin than controls (19.1% vs. 6.6%, OR = 2.52; 33.3% vs. 12.1%, OR = 3.05; 30.5% vs. 16.1%, OR = 2.25; 43.1% vs. 24.0%, OR = 2.21; 25.6% vs. 10.8%, OR = 2.62; 9.1% vs. 0.9%, OR = 10.29; all pBonferroni < 0.001). Waist circumference was associated with PANSS general psychopathology and total score (correlation coefficient r = 0.17, pBonferroni < 0.001; correlation coefficient r = 0.16, pBonferroni = 0.004). Fasting glucose was associated with PANSS negative, general psychopathology, and total score (correlation coefficient r = 0.13, pBonferroni = 0.03; correlation coefficient r = 0.19, pBonferroni < 0.001; correlation coefficient r = 0.20, pBonferroni < 0.001). BMI (OR = 1.37), smoking (OR = 3.39), and HOMA-IR (OR = 5.60) were associated with MetS in FEDN schizophrenia (all p < 0.001). Conclusions: Our results demonstrate that MetS and metabolic abnormalities co-existed in the early stages of schizophrenia without antipsychotics. Waist circumference and glucose were associated with psychopathological symptoms, while BMI, smoking, and HOMA-IR were associated with MetS in FEDN schizophrenia. [ABSTRACT FROM AUTHOR]

Rationale: Opioid use disorder is a complicated brain disease with high heritability. The underlying mechanisms of the genetic underpinnings in the susceptibility and treatment response of opioid use disorder remain elusive. Objectives: To reveal the potential associations of genotypes and gene methylations of dopaminergic system genes, as well as roles of them in opioid use disorder. In the present study, we detected the DNA methylation in the promoter regions of five representative dopaminergic system genes (DRD1, DRD2, SLC6A3, TH, and COMT) between 120 patients with heroin use disorder in methadone maintenance treatment (MMT) program and 111 healthy controls. The associations of 25 SNPs in the above genes and methylation of 237 CpG sites, known as methylation quantitative trait loci (mQTLs), were determined. Then, the correlations of the above mQTLs and traits of heroin use disorder were analyzed in a sample set of 801 patients with heroin use disorder and 930 healthy controls. Results: Our results demonstrated that several mQTLs in the DRD1 and DRD2 genes were identified both in the heroin use disorder and healthy control groups. Interestingly, rs4867798-CpG_174872884 and rs5326-CpG_174872884 in the DRD1 gene were the unique SNP-CpG pairs in the patients with heroin use disorder. Furthermore, mQTL rs5326 was associated with the susceptibility and effective dosage of MMT for heroin use disorder, and demonstrated allele-specific correlation with the expression of the DRD1 gene in the human caudate. Conclusions: Our findings suggest that some mQTLs may be associated with traits of opioid use disorder by implicating the DNA methylation and gene expression. [ABSTRACT FROM AUTHOR]

Rationale: Proton magnetic resonance spectroscopy (1H-MRS) is a cross-species neuroimaging technique that can measure concentrations of several brain metabolites, including glutamate and GABA. This non-invasive method has promise in developing centrally acting drugs, as it can be performed repeatedly within-subjects and be used to translate findings from the preclinical to clinical laboratory using the same imaging biomarker. Objectives: This review focuses on the utility of single-voxel 1H-MRS in developing novel glutamatergic or GABAergic drugs for the treatment of psychiatric disorders and includes research performed in rodent models, healthy volunteers and patient cohorts. Results: Overall, these studies indicate that 1H-MRS is able to detect the predicted pharmacological effects of glutamatergic or GABAergic drugs on voxel glutamate or GABA concentrations, although there is a shortage of studies examining dose-related effects. Clinical studies have applied 1H-MRS to better understand drug therapeutic mechanisms, including the glutamatergic effects of ketamine in depression and of acamprosate in alcohol dependence. There is an emerging interest in identifying patient subgroups with 'high' or 'low' brain regional 1H-MRS glutamate levels for more targeted drug development, which may require ancillary biomarkers to improve the accuracy of subgroup discrimination. Conclusions: Considerations for future research include the sensitivity of single-voxel 1H-MRS in detecting drug effects, inter-site measurement reliability and the interpretation of drug-induced changes in 1H-MRS metabolites relative to the known pharmacological molecular mechanisms. On-going technological development, in single-voxel 1H-MRS and in related complementary techniques, will further support applications within CNS drug discovery. [ABSTRACT FROM AUTHOR]

Rationale: Autism spectrum disorders (ASDs) are highly prevalent neurodevelopmental disorders characterized by deficits in social communication and interaction, repetitive stereotyped behaviors, and cognitive impairments. Curcumin has been indicated to be neuroprotective against neurological and psychological disorders. However, the role of curcumin in autistic phenotypes remains unclear. Objectives: In the current study, we evaluated the effects of neonatal curcumin treatment on behavior and hippocampal neurogenesis in BTBRT+ltpr3tf/J (BTBR) mice, a model of autism. Methods: C57BL/6J (C57) and BTBR mouse pups were treated with 0.1% dimethyl sulfoxide (DMSO) or curcumin (20 mg/kg) from postnatal day 6 (P6) to P8. Neural progenitor cells (NPCs) in the hippocampal dentate gyrus (DG) were evaluated on P8, and neurogenesis was measured on P24 by immunofluorescence. A battery of behavioral tests was carried out when the mice were 8 weeks of age. Results: Neonatal curcumin treatment improved autism-related symptoms in BTBR mice, enhancing sociability, reducing repetitive behaviors, and ameliorating cognitive impairments. Furthermore, the suppression of hippocampal neurogenesis in BTBR mice was greatly rescued after neonatal curcumin treatment, leading to an increase in neurogenic processes and an increase in NPC proliferation concomitant with an expansion of the NPC pool on P8, and NPC differentiation towards the neuronal lineage was promoted in the DG of BTBR mice on P24. Conclusions: Our findings suggest that neonatal curcumin treatment elicits a therapeutic response through the restoration of hippocampal neurogenesis in BTBR mice and thus may represent a promising novel pharmacological strategy for ASD treatment. [ABSTRACT FROM AUTHOR]

Background: Previous studies have shown that patients with schizophrenia have higher smoking rates and worse cognitive function than healthy controls. However, there is no consistent conclusion about the relationship between smoking and cognitive impairment. Objectives: The main purpose of this study was to explore the effects of smoking on cognitive function by using MATRICS Cognitive Consensus Battery (MCCB) in Chinese male patients with schizophrenia. Methods: There were 164 patients with chronic schizophrenia and 82 healthy controls. All subjects were interviewed about smoking status. The cognitive function was assessed by MCCB and Stroop tests. The Positive and Negative Syndrome Scale (PANSS) was used to assess the clinical symptoms of the patients. Results: Compared with healthy controls, patients had lower MCCB scores in all of its domain scores (all p < 0.05). In the patients, the scores of spatial span test (42.3 ± 11.6), digital sequence test (42.9 ± 10.6), and Hopkins Verbal Learning Test (42.2 ± 10.1) were lower in smokers than those in nonsmokers (all p < 0.05, effect size: 0.28–0.45). Logistic regression analysis showed that the smoking status of the patients was correlated with digital sequence score (p < 0.05, OR = 1.072, 95%CI: 1.013–1.134). Multivariate regression analysis showed that the spatial span total score (β = − 0.26, t = − 2.74, p < 0.001) was associated with the duration of smoking in patients with schizophrenia. Conclusions: Our findings show that smoking patients with chronic schizophrenia exhibit more severe cognitive impairment than nonsmoking patients, especially in working memory and executive function. [ABSTRACT FROM AUTHOR]

Rationale: It remains unclear whether using N-acetylcysteine as an adjunctive treatment has any benefit for bipolar depression and major depressive disorder. Objectives: A systematic review and random-effect meta-analysis of double-blind, randomized placebo-controlled trials was conducted to explore the clinical question. Methods: Outcomes included improvement in depression scale scores (primary), Young Mania Rating Scale score, Hamilton Anxiety Rating Scale score, Clinical Global Impression-Severity Scale (CGI-S) score, Global Assessment of Functioning Scale score, Social and Occupational Functioning Assessment Scale score, Range of Impaired Functioning Tool score, Streamed Longitudinal Interval Clinical Evaluation for the Longitudinal Interview Follow-Up Evaluation score, quality of life scales scores, and the incidence of all-cause discontinuation and individual adverse events. Results: Seven studies (n = 728, 8–24 weeks, mean age = 46.81, % female = 58.45%) were included. N-acetylcysteine did not improve depressive symptoms compared with placebo (N = 7, n = 579, standardized mean difference (SMD) = − 0.12, 95% confidence interval (95% CI) = − 0.38, 0.14, p = 0.38, I2 = 52.74%). The meta-regression analysis detected an association between effect size and publication year (coefficient = 0.06, 95% CI = 0.00, 0.11, p = 0.04, I2 = 27.56%). Although N-acetylcysteine was superior to placebo in CGI-S score (N = 6, n = 563, SMD = − 0.28, 95% CI = − 0.47, − 0.10, p < 0.01, I2 = 14.88%), there was no significant difference in the other efficacy outcomes between the treatment groups. Although N-acetylcysteine was associated with a higher incidence of gastrointestinal adverse events compared with placebo (N = 4, n = 537, risk ratio = 1.79, 95% CI = 1.37, 2.32, p < 0.01, I2 = 0.00%, number needed to treat to harm = 7), there was no significant difference in all-cause discontinuation and other safety outcomes between the treatments. Conclusions: Although N-acetylcysteine decreased CGI-S score, no specific improvements in symptoms were identified. [ABSTRACT FROM AUTHOR]

Rationale: Accumulating evidence suggests that ayahuasca, a hallucinogenic beverage used in traditional Amazonian communities for ritualistic and curative purposes, has been associated with reduced rates of substance use disorders. However, the brain mechanisms underlying the therapeutic effects of ayahuasca have not yet been fully elucidated. Objectives: The aim of the present study was to investigate the effects of treatment with ayahuasca on the rewarding properties of the psychostimulant methylphenidate. Methods: The rewarding properties of ayahuasca (100 mg/kg, orally) and methylphenidate (10 mg/kg, i.p.) were investigated using the conditioned place preference (CPP) model. Furthermore, we evaluated the effects of repeated treatment with ayahuasca on the reinstatement of methylphenidate-induced CPP. Fos expression was evaluated in different limbic structures (cingulate cortex—area 1, prelimbic cortex, infralimbic cortex, orbitofrontal cortex—lateral orbital area, nucleus accumbens core and shell, ventral tegmental area, dorsal striatum, and basolateral amygdala) upon each experimental phase. Results: Both ayahuasca and methylphenidate induced CPP in mice. However, ayahuasca had limited effects on Fos expression, while methylphenidate altered Fos expression in several brain regions associated with the behavioral effects of drugs of abuse. Treatment with ayahuasca after conditioning with methylphenidate blocked the reinstatement of methylphenidate-induced CPP. Those behavioral effects were accompanied by changes in Fos expression patterns, with ayahuasca generally blocking the changes in Fos expression induced by conditioning with methylphenidate and/or reexposure to methylphenidate. Conclusions: Our findings suggest that ayahuasca restored normal brain function in areas associated with the long-term expression of drug wanting/seeking in animals conditioned to methylphenidate. [ABSTRACT FROM AUTHOR]

Rationale: Evaluation of pharmacotherapies for acute stress disorder (ASD) or post-traumatic stress disorder (PTSD) is challenging due to robust heterogeneity of trauma histories and limited efficacy of any single candidate to reduce all stress-induced effects. Pursuing novel mechanisms, such as the nociceptin/orphanin FQ (NOP) system, may be a viable path for therapeutic development and of interest as it is involved in regulation of relevant behaviors and recently implicated in PTSD and ASD. Objectives: First, we evaluated NOP receptor antagonism on general behavioral performance and again following a three-species predator exposure model (Experiment 1). Then, we evaluated effects of NOP antagonism on fear memory expression (Experiment 2). Methods: Adult, male rats underwent daily administration of NOP antagonists (J-113397 or SB-612,111; 0–20 mg/kg, i.p.) and testing in acoustic startle, elevated plus maze, tail-flick, and open field tests. Effects of acute NOP antagonism on behavioral performance following predator exposure were then assessed. Separately, rats underwent fear conditioning and were later administered SB-612,111 (0–3 mg/kg, i.p.) prior to fear memory expression tests. Results: J-113397 and SB-612,111 did not significantly alter most general behavioral performance measures alone, suggesting minimal off-target behavioral effects of NOP antagonism. J-113397 and SB-612,111 restored performance in measures of exploratory behavior (basic movements on the elevated plus maze and total distance in the open field) following predator exposure. Additionally, SB-612,111 significantly reduced freezing behavior relative to control groups across repeated fear memory expression tests, suggesting NOP antagonism may be useful in dampening fear responses. Other measures of general behavioral performance were not significantly altered following predator exposure. Conclusions: NOP antagonists may be useful as pharmacotherapeutics for dampening fear responses to trauma reminders, and the present results provide supporting evidence for the implication of the NOP system in the neuropathophysiology of dysregulations in fear learning and memory processes observed in trauma- and stress-related disorders. [ABSTRACT FROM AUTHOR]

Rationale: The neuropeptide galanin has been implicated in a wide range of pathological conditions in which frontal and temporal structures are compromised. It works through three subtypes of G-protein-coupled receptors. One of these, the galanin receptor 1 (Gal-R1) subtype, is densely expressed in the ventral hippocampus (vHC) and ventral prefrontal cortex (vPFC); two brain structures that have similar actions on behavioral control. We hypothesize that Gal-R1 contributes to cognitive-control mechanisms that require hippocampal-prefrontal cortical circuitry. Objective: To examine the effect of local vHC and vPFC infusions of M617, a Gal-R1 agonist, on inhibitory mechanisms of response control. Methods: Different cohorts of rats were implanted with bilateral guide cannulae targeting the vPFC or the vHC. Following infusion of the Gal-R1 agonist, we examined the animals' behavior using a touchscreen version of the 5-choice reaction time task (5-choice task). Results: The Gal-R1 agonist produced opposing behaviors in the vPFC and vHC, leading to disruption of impulse control when infused in the vPFC but high impulse control when infused into the vHC. This contrast between areas was accentuated when we added variability to the timing of the stimulus, which led to long decision times and reduced accuracy in the vPFC group but a general improvement in performance accuracy in the vHC group. Conclusions: These results provide the first evidence of a selective mechanism of Gal-R1–mediated modulation of impulse control in prefrontal-hippocampal circuitry. [ABSTRACT FROM AUTHOR]

Rationale: The volatile anesthetic isoflurane is suggested to produce a rapid and robust antidepressive effect in preliminary clinical trials. Recently, isoflurane was found to activate the tropomyosin receptor kinase B (TrkB) signaling which is the underlying mechanism of the rapid antidepressant ketamine. Objective: Our study investigated the effect of isoflurane anesthesia on chronic unpredictable mild stressed (CUMS) model in mice and verified the role of brain-derived neurotrophic factor (BDNF)/TrkB/ the mammalian target of rapamycin (mTOR) signaling in the antidepressant effect of isoflurane. Methods: We employed the CUMS model of depression to assess the rapid antidepressant effect of isoflurane by the forced swimming test (FST), the sucrose preference test (SPT), and the novelty suppressed feeding test (NSFT). The protein expression of BDNF and TrkB/protein kinase B (PKB or Akt)/mTOR was determined through Western blot. The dendritic spine density in the hippocampus and medial prefrontal cortex (PFC) was measured by the Golgi staining. Results: A brief burst-suppressing isoflurane anesthesia rapidly reversed the behavioral deficits caused by CUMS procedure, normalized the expression of BDNF and further activated the TrkB signaling pathway in CUMS-induced stressed mice in both prefrontal cortex (PFC) and hippocampus (HC). All of those behavioral and proteomic effects were blocked by K252a, a selective receptor inhibitor of TrkB. Isoflurane significantly promoted the formation of dendritic spines in both medial prefrontal cortex (mPFC), CA1, CA3, and DG of the hippocampus. Conclusion: Our study indicates that isoflurane exerts a rapid antidepressant-like effect in CUMS depression animal model, and the activation of BDNF/TrkB signaling pathway plays an indispensable role in the biological and behavioral antidepressant effects of isoflurane. A single exposure to isoflurane could repair synaptic damage caused by chronic stimulation. [ABSTRACT FROM AUTHOR]

Rationale: Immune dysfunction has been strongly implicated in the pathophysiology of bipolar disorder (BD). As such, numerous clinical trials have investigated the effects of anti-inflammatory agents in the treatment of BD. Objectives: Review clinical studies evaluating the effects of anti-inflammatory agents in the treatment of BD during all illness phases (e.g., depression, mania, and euthymia). Methods: Relevant databases were searched from inception to August 27, 2018 for clinical studies evaluating the effects of anti-inflammatory agents in BD. Results: The majority of identified clinical trials evaluated adjunctive anti-inflammatory agents in the acute treatment of bipolar depression, demonstrating antidepressant effects with N-acetylcysteine (NAC), pioglitazone, minocycline, and coenzyme Q10, along with mixed evidence for omega-3s, and non-steroidal anti-inflammatory drugs (NSAIDs). The anti-manic effects of adjunctive anti-inflammatory agents have been minimally studied, with some promising preliminary results supporting potential anti-manic effects of adjunctive celecoxib and NAC. Maintenance studies are also limited, with inadequate evidence to support mood stabilizing effects of anti-inflammatories while euthymic. Regardless of illness phase, early results suggest that anti-inflammatory agents are likely most beneficial in the subgroup of BD with immune dysregulation. Conclusions: Several proof-of-concept clinical trials have shown promising results for anti-inflammatory agents in the treatment of bipolar depression with moderate effect sizes and good tolerability. The effects of anti-inflammatory agents during manic and euthymic periods remains uncertain. Future larger studies, using stratified samples, enriched for participants with immune dysfunction, are required to determine the role of immune modulating agents in the treatment of BD. [ABSTRACT FROM AUTHOR]

There is increasing evidence that connections formed between microbiome, the gut, and the brain play a role in health and well-being. Non-pharmaceutical targets for management of mood disorders, such as bipolar disorder, are relatively under-researched. At the same time, it is clear that there is an intimate connection between psychiatry and gastrointestinal health. Here, we have discussed various comorbid conditions associated with bipolar disorders such as inflammation, irritable bowel disease and antibiotic induced mania with importance to demonstrate possible involvement of the gut microbiota. Gut microbiota–targeted preclinical and clinical interventions have demonstrated enhancement in various psychological conditions. Further in this review, we explore links between bipolar disorder, inflammation and gut microbiome with a focus on dietary, pro- and pre-biotic interventions as potential adjuvant therapies for use in the management of mood disorders such as bipolar disorder. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is a progressive and irreversible neurodegenerative disease. The present study investigated the effects of 50 and 100 mg/kg berberine (BRB) on recognition memory, oxidative stress, and purinergic neurotransmission, in a model of sporadic dementia of the Alzheimer's type induced by intracerebroventricular (ICV) injection of streptozotocin (STZ) in rats. Rats were submitted to ICV-STZ 3 mg/kg or saline, and 3 days later, were started on a treatment of BRB or saline for 21 days. The results demonstrated that BRB was effective in protecting against memory impairment, increased reactive oxygen species, and the subsequent increase in protein and lipid oxidation in the cerebral cortex and hippocampus, as well as δ-aminolevulinate dehydratase inhibition in the cerebral cortex. Moreover, the decrease in total thiols, and the reduced glutathione and glutathione S-transferase activity in the cerebral cortex and hippocampus of ICV-STZ rats, was prevented by BRB treatment. Besides an antioxidant effect, BRB treatment was capable of preventing decreases in ecto-nucleoside triphosphate diphosphohydrolase (NTPDase), 5′-nucleotidase (EC-5'-Nt), and adenosine deaminase (ADA) activities in synaptosomes of the cerebral cortex and hippocampus. Thus, our data suggest that BRB exerts a neuroprotective effect on recognition memory, as well as on oxidative stress and oxidative stress-related damage, such as dysfunction of the purinergic system. This suggests that BRB may act as a promising multipotent agent for the treatment of AD. [ABSTRACT FROM AUTHOR]

Objective: The cerebellum plays an important role in depression. Cerebro-cerebellar circuits have been found to show aberrance in bipolar disorder (BD) and major depressive disorder (MDD). However, whether the cerebro-cerebellar connectivity contributes equally to the pathologic mechanisms of BD and MDD remains unknown.Methods: We recruited 33 patients with MDD, 32 patients with BD, and 43 healthy controls (HC). We selected six seed regions (three per hemisphere) in the cerebrum, corresponding to the affective, cognitive control, and default mode networks, to establish cerebro-cerebellar functional connectivity maps.Results: Relative to the HC, both the BD and MDD patients exhibited weaker negative connectivity between the right subgenual anterior cingulate cortex and the cerebellar vermis IV_V (pBD = 0.03, pMDD = 0.001) and weaker positive connectivity between the left precuneus and the left cerebellar lobule IX (pBD = 0.043, pMDD = 0.000). Moreover, the MDD patients showed weaker positive connectivity in the left precuneus—left cerebellar lobule IX circuit than the BD patients (p = 0.049). In addition, the BD patients showed weaker positive connectivity in the right dorsolateral prefrontal cortex—left cerebellar lobule Crus Ι circuit compared to the HC (p = 0.002) or the MDD patients (p = 0.013). Receiver operating characteristic curves analyses showed that the altered cerebro-cerebellar connectivities could be used to distinguish the patients from the HC with relatively high accuracy.Conclusions: Our findings suggested that differences in connectivity of cerebro-cerebellar circuits, which are involved in affective or cognitive functioning, significantly contributed to BD and MDD. [ABSTRACT FROM AUTHOR]

Depression is a major health problem with a high prevalence and a heavy socioeconomic burden in western societies. It is associated with atrophy and impaired functioning of cortico-limbic regions involved in mood and emotion regulation. It has been suggested that alterations in neurotrophins underlie impaired neuroplasticity, which may be causally related to the development and course of depression. Accordingly, mounting evidence suggests that antidepressant treatment may exert its beneficial effects by enhancing trophic signaling on neuronal and synaptic plasticity. However, current antidepressants still show a delayed onset of action, as well as lack of efficacy. Hence, a deeper understanding of the molecular and cellular mechanisms involved in the pathophysiology of depression, as well as in the action of antidepressants, might provide further insight to drive the development of novel fast-acting and more effective therapies. Here, we summarize the current literature on the involvement of neurotrophic factors in the pathophysiology and treatment of depression. Further, we advocate that future development of antidepressants should be based on the neurotrophin theory. [ABSTRACT FROM AUTHOR]

Background: Previous studies have reported that galectin-3 is involved in inflammatory processes in the central nervous system and that neuroinflammation may play a role in the pathogenesis of schizophrenia. However, the link between schizophrenia and various galectins is unclear. Objective: The objective of the present study is to determine whether galectin, a well-known lectin protein that binds to μ-galactoside, is associated with chronic schizophrenia. Methods: Thirty-six patients with schizophrenia and 36 healthy controls participated in this study. Schizophrenia symptoms were assessed using the Brief Psychiatry Rating Scale (BPRS). Serum galectin-1 and galectin-3 levels were evaluated using ELISA and compared between the participant groups. Correlation analyses were also performed to examine the relationship between BPRS scores and each galectin level. Results: Serum galectin-3 levels were significantly higher in patients with schizophrenia than they were in controls ( p = 0.009, d = 0.640); however, serum galectin-1 levels were not significantly different between the groups ( p = 0.513). No significant correlation was identified between serum galectin-3 level and the total BPRS score; however, a significant positive correlation was found between the serum galectin-3 level and the positive symptom score of the BPRS ( ρ = 0.355; p = 0.033). Additionally, a significant negative correlation was identified between serum galectin-3 levels and the negative symptom score of the BPRS ( ρ = −0.387; p = 0.020). Conclusions: Given the high serum levels of galectin-3 found in patients with schizophrenia compared with that in controls, these findings may support the inflammation hypothesis of schizophrenia. [ABSTRACT FROM AUTHOR]

Background: Executive dysfunction is common and impairing in youth bipolar disorder (BD), and oxidative stress (OS) and brain-derived neurotrophic factor (BDNF) have been implicated in executive deficits of adult BD. This study aimed to determine the association between OS and executive dysfunction in BD adolescents and the influence of BDNF on this association. Methods: Serum levels of lipid hydroperoxides (LPH) and 4-hydroxy-2-nonenal (4-HNE) and BDNF levels were measured in 29 BD and 25 control adolescents. The intra-extra-dimensional (IED) set-shifting task assessed executive function. Lower IED scores indicated better performance. High and low BDNF subgroups were defined by median split. Results: IED Z-scores were impaired in the BD group compared to controls, whereas biomarker levels were not significantly different between groups. LPH-BDNF correlations were significantly different between BD and controls ( Z = 2.046, p = 0.041). In high BDNF BD subjects, LPH was significantly positively correlated with IED completed stage trials ( ρ = 0.755, p = 0.001) and pre-extra-dimensional shift errors ( ρ = 0.588, p = 0.017). Correlations were opposite in controls. In a linear model, LPH, BDNF, and the LPH-BDNF interaction each significantly explained variance of IED total trials (adjusted) (model r = 0.187, F = 2.811, p = 0.035). Conclusions: There is a negative association between LPH and executive function in BD adolescents, which may be modulated by BDNF. LPH and BDNF may be useful biomarkers of executive function in BD. These findings highlight the importance of examining multiple peripheral biomarkers in relation to cognitive functions in BD adolescents. Future studies should explore these factors in longitudinal designs to determine the directionality of observed associations. [ABSTRACT FROM AUTHOR]

Rationale: Cross-species quantification of physiological behavior enables a better understanding of the biological systems underlying neuropsychiatric diseases such as bipolar disorder (BD). Cardinal symptoms of manic BD include increased motor activity and goal-directed behavior, thought to be related to increased catecholamine activity, potentially selective to dopamine homeostatic dysregulation. Objectives: The objective of this study was to test whether acute administration of amphetamine, a norepinephrine/dopamine transporter inhibitor and dopamine releaser, would replicate the profile of activity and exploration observed in both humans with manic BD and mouse models of mania. Methods: Healthy volunteers with no psychiatric history were randomized to a one-time dose of placebo ( n = 25), 10 mg d-amphetamine ( n = 18), or 20 mg amphetamine ( n = 23). Eighty mice were administered one of four doses of d-amphetamine or vehicle. Humans and mice were tested in the behavioral pattern monitor (BPM), which quantifies motor activity, exploratory behavior, and spatial patterns of behavior. Results: In humans, the 20-mg dose of amphetamine increased motor activity as measured by acceleration without marked effects on exploration or spatial patterns of activity. In mice, amphetamine increased activity, decreased specific exploration, and caused straighter, one-dimensional movements in a dose-dependent manner. Conclusions: Consistent with mice, amphetamine increased motoric activity in humans without increasing exploration. Given that BD patients exhibit heightened exploration, these data further emphasize the limitation of amphetamine-induced hyperactivity as a suitable model for BD. Further, these studies highlight the utility of cross-species physiological paradigms in validating biological mechanisms of psychiatric diseases. [ABSTRACT FROM AUTHOR]

Rationale: A bidirectional relationship between alcohol use disorder (AUD) and deficits in impulse control and decision making has been suggested. However, the mechanisms by which neurocognitive impairments predispose to, or result from AUD remain incompletely understood. Objectives: The aim of this study is to gain more insight in the effects of alcohol exposure on decision making and impulse control. We used two modified versions of the rat gambling task (rGT) that differ in the net gain and the punishment magnitude associated with the different response options. Methods: In experiment 1, we assessed the effects of acute alcohol treatment (0-0.8 g/kg) on rGT performance. In experiment 2, we determined the effects of alcohol on rGT acquisition (15 sessions, 0.6 g/kg). Next, these animals were challenged with alcohol (0-1.0 g/kg) prior to rGT sessions. Results: Acute alcohol treatment suppressed baseline performance in both rGT versions but only modestly altered decision making. Treatment with alcohol during acquisition increased risky choices in the rGT version that involved larger punishment and blunted the reduction in win-shift behavior during acquisition in both rGT versions. Moreover, rats treated with alcohol during acquisition showed an increase in premature and perseverative responding upon subsequent alcohol challenges (0-1.0 g/kg) and were less sensitive to the behavioral suppressant effects of alcohol. Conclusions: Our results show that repeated alcohol exposure alters decision making during rGT acquisition and reduces the ability to adjust choice behavior on the basis of feedback. In addition, repeated alcohol exposure unmasks its behavioral disinhibitory effects in the rGT. Impaired responsiveness to choice feedback and behavioral disinhibition may contribute to the development of AUD. [ABSTRACT FROM AUTHOR]

Rationale: Bipolar disorder (BD) is a disabling and life-threatening disease characterized by states of depression and mania. New and efficacious treatments have not been forthcoming partly due to a lack of well-validated models representing both facets of BD. Objectives: We hypothesized that cholinergic- and dopaminergic-pharmacological manipulations would model depression and mania respectively, each attenuated by lithium treatment. Methods: C57BL/6 J mice received the acetylcholinesterase inhibitor physostigmine or saline before testing for 'behavioral despair' (immobility) in the tail suspension test (TST) and forced swim test (FST). Physostigmine effects on exploration and sensorimotor gating were assessed using the cross-species behavioral pattern monitor (BPM) and prepulse inhibition (PPI) paradigms. Other C57BL/6 J mice received chronic lithium drinking water (300, 600, or 1200 mg/l) before assessing their effects alone in the BPM or with physostigmine on FST performance. Another group was tested with acute GBR12909 (dopamine transporter inhibitor) and chronic lithium (1000 mg/l) in the BPM. Results: Physostigmine (0.03 mg/kg) increased immobility in the TST and FST without affecting activity, exploration, or PPI. Lithium (600 mg/l) resulted in low therapeutic serum concentrations and normalized the physostigmine-increased immobility in the FST. GBR12909 induced mania-like behavior in the BPM of which hyper-exploration was attenuated, though not reversed, after chronic lithium (1000 mg/ml). Conclusions: Increased cholinergic levels induced depression-like behavior and hyperdopaminergia induced mania-like behavior in mice, while chronic lithium treated some, but not all, facets of these effects. These data support a cholinergic-monoaminergic mechanism for modeling BD aspects and provide a way to assess novel therapeutics. [ABSTRACT FROM AUTHOR]

Rationale: Lithium is the mainstay for the treatment of bipolar disorder (BD) and inhibits glycogen synthase kinase-3β (GSK-3β). The less active GSK-3β promoter gene variants have been associated with less detrimental clinical features of BD. GSK-3β gene variants and lithium can influence brain gray and white matter structure in psychiatric conditions, so we studied their combined effect in BD. Objectives: The aim of this study is to investigate the effects of ongoing long-term lithium treatment and GSK-3β promoter rs334558 polymorphism on regional gray matter (GM) volumes of patients with BD. Materials and methods: GM volumes were estimated with 3.0 Tesla MRI in 150 patients affected by a major depressive episode in course of BD. Duration of lifetime lithium treatment was retrospectively assessed. Analyses were performed by searching for significant effects of lithium and rs334558 in the whole brain. Results: The less active GSK-3β rs334558*G gene promoter variant and the long-term administration of lithium were synergistically associated with increased GM volumes in the right frontal lobe, in a large cluster encompassing the boundaries of subgenual and orbitofrontal cortex (including Brodmann areas 25, 11, and 47). Effects of lithium on GM revealed in rs334558*G carriers only, consistent with previously reported clinical effects in these genotype groups, and were proportional to the duration of treatment. Conclusions: Lithium and rs334558 influenced GM volumes in areas critical for the generation and control of affect, which have been widely implicated in the process of BD pathophysiology. In the light of the protective effects of lithium on white matter integrity, our results suggest that the clinical effects of lithium associate with a neurotrophic effect on the whole brain, probably mediated by GSK-3β inhibition. [ABSTRACT FROM AUTHOR]

Rationale: Schizophrenia is a debilitating disorder comprising positive, negative and cognitive deficits with a poorly defined neurobiological aetiology; therefore, animal models with greater translational reliability are essential to develop improved therapies. Objectives: This study combines two developmental challenges in rats, neonatal phencyclidine (PCP) injection and subsequent rearing in social isolation from weaning, to attempt to produce more robust behavioural deficits with greater translational relevance to schizophrenia than either challenge alone. Methods: Forty-two male Lister-hooded rat pups received the N-methyl- d-aspartate (NMDA) receptor antagonist, phencyclidine (PCP, 10 mg/kg, s.c.), or vehicle on post-natal day (PND) 7, 9 and 11 and were weaned on PND 23 into group housing (saline-treated n = 11 or PCP-treated n = 10) or isolation (saline n = 10 or PCP n = 11). Six weeks post-weaning, novelty- and PCP-induced (3.2 mg/kg) locomotor activity, novel object discrimination, prepulse inhibition of acoustic startle and contextual memory in a conditioned emotion response (CER) were recorded. Results: Isolation rearing alone significantly elevated baseline locomotor activity and induced visual recognition memory impairment in novel object discrimination. Neonatal PCP treatment did not induce locomotor sensitisation to a subsequent acute PCP injection, but it impaired prepulse inhibition when combined with isolation rearing. CER freezing behaviour was significantly reduced by isolation rearing but an even greater effect occurred when combined with neonatal PCP treatment. Conclusions: Neonatal PCP and isolation rearing both produce behavioural deficits in adult rats, but combined treatment caused a wider range of more severe cognitive impairments, providing a more comprehensive preclinical model to determine the neurobiological aetiology of schizophrenia than either treatment alone. [ABSTRACT FROM AUTHOR]

Rationale: Comorbid depression is commonly observed in individuals who suffer from neuropathic pain, which necessitates improved treatment. Curcumin, a phenolic compound derived from Curcuma longa, possesses both antinociceptive and antidepressant-like activities in animal studies, suggesting its possible usefulness in treating this comorbidity. Objective: We investigated the effect of curcumin on depressive-like behaviors in mice with mononeuropathy, and explored the mechanism(s). Methods: Chronic constriction injury (CCI) was produced by loosely ligating the sciatic nerves in mice. The nociceptive behaviors were examined using Hargreaves test, and the depressive-like behaviors were determined by forced swim test (FST) and tail suspension test (TST). Results: After CCI injury, the neuropathic mice developed nociceptive and depressive-like behaviors, as shown by thermal hyperalgesia in Hargreaves test and protracted immobility time in FST and TST. Chronic treatment of neuropathic mice with curcumin (45 mg/kg, p.o., twice per day for 3 weeks) corrected their exacerbated nociceptive and depressive-like behaviors, which was abolished by chemical depletion of brain serotonin rather than noradrenaline. The paralleled antinociceptive and antidepressant-like actions of curcumin seem to be pharmacologically segregated, since intrathecal and intracerebroventricular injection of methysergide, a nonselective 5-HT receptor antagonist, separately counteracted the two actions of curcumin. Further, this antidepression was abrogated by repeated co-treatment with 5-HT receptor antagonist WAY-100635 and greatly attenuated by acute co-treatment with GABA receptor antagonist bicuculline. Conclusion: Curcumin can normalize the depressive-like behaviors of neuropathic mice, which may be independent of the concurrent analgesic action and possibly mediated via the supraspinal serotonergic system and downstream GABA receptor. [ABSTRACT FROM AUTHOR]

Rationale: Preliminary data on the efficacy of tamoxifen in reducing manic symptoms of bipolar disorder (BD) suggest that this agent may be a potential treatment for the management of this psychiatric disorder. However, the antimanic properties of tamoxifen have not been fully elucidated, hampering the development and/or use of mood-stabilising drugs that may share its same therapeutic mechanisms of action. Notably, we may gain a greater understanding of the neurobiological and therapeutic properties of tamoxifen by using suitable animal models of mania. Objectives: Here, we review the preclinical studies that have evaluated the effects of tamoxifen to provide an overview of the current progress in our understanding of its antimanic actions, highlighting the critical role of protein kinase C (PKC) as a therapeutic target for the treatment of BD. Conclusions: To date, this field has struggled to make significant progress, and the organisation of an explicit battery of tests is a valuable tool for assessing a number of prominent facets of BD, which may provide a greater understanding of the entire scope of this disease. [ABSTRACT FROM AUTHOR]

Rationale: Women are increasingly prescribed selective serotonin reuptake inhibitors (SSRIs) during pregnancy, with potential implications for neurodevelopment. Whether prenatal SSRI exposure has an effect on neurodevelopment and behavior in the offspring is an important area of investigation. Objectives: The aim of this paper was to review the existing preclinical and clinical literature of prenatal SSRI exposure on serotonin-related behaviors and markers in the offspring. The goal is to determine if there is a signal in the literature that could guide clinical care and/or inform research. Results: Preclinical studies ( n = 4) showed SSRI exposure during development enhanced depression-like behavior. Half of rodent studies examining anxiety-like behavior ( n = 13) noted adverse effects with SSRI exposure. A majority of studies of social behavior ( n = 4) noted a decrease in sociability in SSRI exposed offspring. Human studies ( n = 4) examining anxiety in the offspring showed no adverse effects of prenatal SSRI exposure. The outcome of one study suggested that children with autism were more likely to have a mother who was prescribed an SSRI during pregnancy. Conclusions: Preclinical findings in rodents exposed to SSRIs during development point to an increase in depression- and anxiety-like behavior and alteration in social behaviors in the offspring, though both the methods used and the findings were not uniform. These data are not robust enough to discourage use of SSRIs during human pregnancy, particularly given the known adverse effects of maternal mental illness on pregnancy outcomes and infant neurodevelopment. Future research should focus on consistent animal models and prospective human studies with larger samples. [ABSTRACT FROM AUTHOR]

Rationale: Ro 64-6198, the prototypical non-peptide nociceptin/orphanin FQ peptide (NOP) receptor agonist, has potent anxiolytic-like effects in several preclinical models and species. However the effects of Ro 64-6198 on distinctive anxiety-provoking conditions related to unconditioned conflict behavior as well as its role in despair-like behavior remain to be addressed. Objective: Here we examined the effects of Ro 64-6198 on unconditioned conflict anxiety using stimuli with different salience and on regulation of autonomic reactivity and compared these to the effects of benzodiazepine receptor agonists. We also addressed the potential effects of Ro 64-6198 on despair-like behavior. Materials and methods: Ro 64-6198 (0.1 to 10 mg/kg i.p.) and either diazepam or chlordiazepoxide were tested in the Vogel conflict punished drinking test (VCT) in Sprague Dawley rats, in the social approach-avoidance (SAA) test in Lewis rats, in the novelty-induced hypophagia (NIH) in C57BL/6J mice, and in stress-induced hyperthermia in NMRI mice, as well as in the forced swim test (FST) in Sprague Dawley rats and the tail suspension test (TST) in C57BL/6J mice. Results: Ro 64-6198 (0.3 to 3 mg/kg) dose-dependently produced anxiolytic-like effects in the VCT, SAA, NIH, and SIH, similar to benzodiazepine receptor agonists. Ro 64-6198 did not alter immobility time in the FST and TST. Conclusions: Ro 64-6198 produced marked anxiolytic-like effects in response to a variety of mild to strong anxiogenic stimuli, whereas it did not facilitate depression-related behaviors. This data extend previous literature suggesting that NOP receptors are a viable target for the treatment of anxiety disorders. [ABSTRACT FROM AUTHOR]

Rationale: Muscarinic acetylcholine receptors (mAChR) are G protein-coupled receptors, widely expressed in the CNS. Electrophysiological and molecular studies have provided evidence for overactive M1 receptor signaling in the fragile X knockout ( Fmr1 KO) mouse model, suggesting the involvement of the M1 receptors in fragile X syndrome. Overactive signaling through the M1 receptor has been hypothesized to contribute to the phenotypes seen in fragile X mice. Objective: We investigated the modulation of behavioral responses in the Fmr1 KO animals by reducing the activity through the muscarinic M1 receptor using the pharmacological agent dicyclomine, an M1 antagonist. Methods: The behavioral assays used to investigate the pharmacological effects include marble burying (perseverative behavior), open-field exploration (activity), passive avoidance (learning and memory), prepulse inhibition (sensorimotor gating), and audiogenic seizures. Results: Data from the marble-burying assay suggests that treatment with dicyclomine results in a decrease in the number of marbles buried in the wild-type and in the KO animals. To examine the possibility of drug-induced sedation, overall activity was measured in an open-field chamber. Dicyclomine only increases activity at a dose of 20 mg/kg in the wild-type mice but did not affect exploration in the KO animals. Lastly, we observed that dicyclomine causes a significant decrease in the percentage of audiogenic seizures in the Fmr1 KO animals. Conclusion: Our findings suggest that pharmacologically reducing the activity through the mAChR M1 alters select behavioral responses in the Fmr1 KO mice. [ABSTRACT FROM AUTHOR]

Rationale: Cigarette smoking has been linked to real-world risky behavior, but this association has been based largely on retrospective self-reports. Limitations of self-report data can be avoided by using laboratory, performance-based measures, such as the Balloon Analogue Risk Task (BART; Lejuez et al., J Exp Psychol Appl 8:75-84, ). Initial studies have suggested that smokers display greater risk-taking on this task than nonsmokers, but these studies did not account for drug abuse and psychiatric comorbidities, which are commonplace among smokers. Objectives: We sought to examine the performance of smokers and nonsmokers on the BART after excluding drug abuse and psychiatric comorbidities. Methods: We conducted a study of late adolescent/young adult (age 18 to 21) smokers ( n = 26) and nonsmokers ( n = 38) performing the BART and excluded individuals with positive drug or alcohol toxicology screens, substance abuse or dependence diagnoses, and/or current psychiatric conditions. Results: Contrary to previous findings, smokers did not display greater risk-taking on the BART than nonsmokers. In fact, when performance was examined trial-by-trial, the nonsmokers displayed progressively greater pumping relative to smokers over time ( p < .001), earning them a nonsignificantly greater amount of money than the smokers. Controlling for smoking status, additional analyses revealed that pumping on the BART was positively associated with years of education, nonverbal IQ, and employment. Conclusions: The results suggest that in young adults, smoking may be associated with a failure to take risks in situations where risk-taking is adaptive. [ABSTRACT FROM AUTHOR]

Rationale: Impulsivity has long been known as a risk factor for drug dependence, but the mechanisms underpinning this association are unclear. Impulsivity may confer hypersensitivity to drug reinforcement which establishes higher rates of instrumental drug-seeking and drug-taking behaviour, or may confer a propensity for automatic (non-intentional) control over drug-seeking/taking and thus intransigence to clinical intervention. Method: The current study sought to distinguish these two accounts by measuring Barratt Impulsivity and craving to smoke in 100 smokers prior to their completion of an instrumental concurrent choice task for tobacco (to measure the rate of drug-seeking) and an ad libitum smoking test (to measure the rate of drug-taking-number of puffs consumed). Results: The results showed that impulsivity was not associated with higher rates of drug-seeking/taking, but individual differences in smoking uptake and craving were. Rather, nonplanning impulsivity moderated (decreased) the relationship between craving and drug-taking, but not drug-seeking. Conclusions: These data suggest that whereas the uptake of drug use is mediated by hypervaluation of the drug as an instrumental goal, the orthogonal trait nonplanning impulsivity confers a propensity for automatic control over well-practiced drug-taking behaviour. [ABSTRACT FROM AUTHOR]

Rationale: The nonselective muscarinic antagonist scopolamine hydrobromide (SCOP) is employed as the gold standard for inducing memory impairments in healthy humans and animals. However, its use remains controversial due to the wide spectrum of behavioral effects of this drug. Objective: The present study investigated whether biperiden (BIP), a muscarinic m1 receptor antagonist, is to be preferred over SCOP as a pharmacological model for cholinergic memory deficits in rats. This was done by comparing the effects of SCOP and BIP using a battery of operant tasks: fixed ratio (FR5) and progressive ratio (PR10) schedules of reinforcement, an attention paradigm and delayed nonmatching to position task. Results: SCOP induced diffuse behavioral disruption, which included sensorimotor responding (FR5, 0.3 and 1 mg/kg), food motivation (PR10, 1 mg/kg), attention (0.3 mg/kg, independent of stimulus duration), and short-term memory (delayed nonmatching to position (DNMTP), 0.1 and 0.3 mg/kg, delay-dependent but also impairment at the zero second delay). BIP induced relatively more selective deficits, as it slowed sensorimotor responding (FR5, 10 mg/kg) and disrupted short-term memory (DNMTP, 3 mg/kg, delay-dependent but no impairment at the zero second delay). BIP had no effect on food motivation (PR10) or attention. Conclusion: Muscarinic m1 antagonists should be considered an interesting alternative for SCOP as a pharmacological model for cholinergic mnemonic deficits in animals. [ABSTRACT FROM AUTHOR]

Rationale: Performance on the Cambridge Neuropsychological Test Automated Battery touchscreen paired-associates learning (PAL) test is predictive of Alzheimer's disease and impaired in schizophrenia and chronic drug users. An automated computer touchscreen PAL task for rats has been previously established. A pharmacologically validated PAL task for mice would be a highly valuable tool, which could be useful for a number of experimental aims including drug discovery. Objectives: This study sought to investigate the effects of systemic administration of cholinergic agents on task performance in C57Bl/6 mice. Methods: Scopolamine hydrobromide (0.02, 0.2, and 2.0 mg/kg), dicyclomine hydrochloride (M receptor antagonist; 2.0, 4.0, and 8.0 mg/kg), and donepezil hydrochloride (cholinesterase inhibitor; 0.03, 0.1, and 0.3 mg/kg) were administered post-acquisition in C57Bl/6 mice performing the PAL task. Results: Scopolamine (0.2 and 2.0 mg/kg) and dicyclomine (at all administered doses) significantly impaired PAL performance. A significant facilitation in PAL was revealed in mice following donepezil administration (0.3 mg/kg). Conclusions: The present study shows that mice can acquire the rodent PAL task and that the cholinergic system is important for PAL task performance. M receptors in particular are likely implicated in normal performance of PAL. The finding that mouse PAL can detect both impairments and improvements indicates that this task could prove to be a highly valuable tool for a number of experimental aims including drug discovery. [ABSTRACT FROM AUTHOR]

Major depression is a chronic disabling disorder, often preceded by stress. Despite emerging clinical interest in mechanisms perpetuating episodes of depression and/or establishing increased vulnerability for relapse, little attention has been paid to address these aspects in experimental models. Here, we studied the long-term neuroadaptive effects of chronic mild stress (CMS) as well as the effectiveness of a course of an antidepressant treatment. CMS was applied for 6 weeks, and paroxetine was administered from the third week and continued for 2 weeks thereafter. In order to validate our CMS procedure, we first studied short-term (24 h after CMS) hippocampal cell proliferation and neurogenesis, along with anhedonic-like behaviour. Subsequently, we examined the long-term (one month after CMS) anhedonia, hippocampal neurogenesis, the regulation of c-Fos immunoreactivity and neurotransmitter levels in different areas as well as cortical spine density and hippocampal expression of synaptic proteins. CMS induced a decrease in short-term neurogenesis that was fully recovered in the long term. In addition, CMS-induced lasting anhedonia and region-specific changes in neuronal activity (c-Fos immunoreactivity) and neurotransmitter (glutamate and GABA) levels. Repeated paroxetine reverted these effects with the exception of decreased neuronal activity in the dentate gyrus (DG) and GABA levels in the ventral hippocampus. Moreover, CMS downregulated the GAD65 and VGLUT1 expressions. This study shows region-specific long-term neurobiological adaptations induced by CMS and residual hippocampal signs after paroxetine treatment. We propose the use of this model to study molecular mechanisms involved in chronic depression and vulnerability for relapse. [ABSTRACT FROM AUTHOR]

Lithium, some of the anticonvulsants, and several second-generation antipsychotic drugs are common medications widely prescribed to treat bipolar disorder. Molecular targets and cellular events that mediate their effects have been described for these drugs but are only partially unraveled. Few comparative studies have been performed. We evaluated seven mood stabilizers (MS) in the same in vitro system and found several differences and similarities in their cellular mechanisms (proliferation and cell survival). As some MS were previously shown to activate the Akt/GSK-3β axis, this pathway was explored for other drugs. The SH-SY5Y cells were cultured in RPMI-1640 medium. Effects of MS drugs on serum-induced cell proliferation and on slowing of cell death were analyzed. Phosphorylation and expression of Akt-1 and GSK-3β mRNA and protein were assessed for the seven drugs as well. Lithium, Valproate, Olanzapine, and Clozapine enhance proliferation and protect cells against serum withdrawal-induced injury. These drugs also activate Akt-1 and GSK-3β phosphorylation. Interestingly, gene expression of Akt-1 mRNA and protein, but not GSK-3β, was increased. The other drugs Lamotrigine, Haloperidol, and Carbamazepine did not affect cellular events nor activate Akt/GSK-3β axis. Valproate and atypical antipsychotics (Olanzapine and Clozapine) regulate SH-SY5Y cell proliferation and survival, activate the Akt/GSK-3β axis, and stimulate gene expression of Akt-1 mRNA and protein, as does Lithium. The other medications have no effect. The study shows the importance of the Akt/GSK-3 axis in MS actions but also pinpoints a different dependence of these drugs on this signaling axis. [ABSTRACT FROM AUTHOR]