Current Neuropharmacology - Volume 21, Issue 6, 2023

Pediatric bipolar disorder (PBD) is associated with significant psychosocial impairment, high use of mental health services and a high number of relapses and hospitalization. Neuroimaging techniques provide the opportunity to study the neurodevelopmental processes underlying PBD, helping to identify the endophenotypic markers of illness and early biological markers of PBD. The aim of the study is to review available studies assessing structural and functional brain correlates associated with PBD. PubMed, ISI Web of Knowledge and PsychINFO databases have been searched. Studies were included if they enrolled patients aged 0-18 years with a main diagnosis of PBD according to ICD or DSM made by a mental health professional, adopted structural and/or functional magnetic resonance as the main neuroimaging method, were written in English and included a comparison with healthy subjects. Of the 400 identified articles, 46 papers were included. Patients with PBD present functional and anatomic alterations in structures normally affecting regulations and cognition. Structural neuroimaging revealed a significant reduction in gray matter, with cortical thinning in bilateral frontal, parietal and occipital cortices. Functional neuroimaging studies reported a reduced engagement of the frontolimbic and hyperactivation of the frontostriatal circuitry. Available studies on brain connectivity in PBD patients potentially indicate less efficient connections between regions involved in cognitive and emotional functions. A greater functional definition of alteration in brain functioning of PBD patients will be useful to set up a developmentally sensitive targeted pharmacological and nonpharmacological intervention.

Background: Serum prolactin levels are influenced by sex, physical development and medications among other factors. Antipsychotics usually increase serum prolactin levels in both adults and younger patients, but no study has reviewed the potential association between sex and vulnerability for developing hyperprolactinemia among children and adolescents. Objective: Systematic review and meta-analysis of serum prolactin levels in children and adolescents on antipsychotic treatment for any psychiatric diagnosis to determine the effect of sex. Methods: A systematic search was performed in MEDLINE/PubMed/Web of Science and Cochrane databases for randomized controlled trials of antipsychotics in children and adolescents reporting serum prolactin levels by sex. Results: Of 1278 identified records, seven studies were included, comparing different single antipsychotics to placebo (risperidone N=4; lurasidone N=1; olanzapine N=1; queriapine N=1). Both male and female children and adolescents on antipsychotics presented a significant increase in prolactin levels relative to subjects receiving a placebo. (Male: 16.53 with 95% CI: 6.15-26.92; Female: 26.97 with 95% CI: 9.18-44.75). The four studies using risperidone had similar findings (Male: 26.49 with 95% CI: 17.55-35.43; Female: 37.72 with 95% CI: 9.41-66.03). In the direct comparison between sexes, females showed greater increases in prolactin, but the differences were not statistically significant. Conclusion: Serum prolactin levels are increased in children and adolescents of both sexes on antipsychotics, with females showing a slightly greater increase than males. Further research is needed to clarify the influence of sex and pubertal status on prolactin levels in children and adolescents taking antipsychotics.

Background: Lithium is the standard treatment for bipolar disorders (BD) in adults. There is a dearth of data on its use in the pediatric age. This review aimed to investigate the use of lithium in pediatric bipolar disorder (BD) and other externalizing childhood-related disorders. Methods: We applied the Preferred Reporting Items for Systematic Reviews and Meta-analyses criteria (PRISMA) to identify randomized controlled trials evaluating the use of lithium in pediatric (BD), conduct disorder (CD), attention deficit hyperactivity disorder, oppositional defiant disorder, and disruptive mood dysregulation disorder. The primary outcome of our study was to evaluate the efficacy of lithium compared to a placebo or other pharmacological agents. The secondary outcomes were acceptability and tolerability. Results: Twelve studies were eligible, 8 on BD and 4 on CD. Overall, 857 patients were treated with lithium. No studies for externalizing disorder diagnoses were identified. Regarding BD patients (n = 673), efficacy results suggested that lithium was superior to placebo in manic/mixed episodes but inferior to antipsychotics. Lithium efficacy ranged from 32% to 82.4%. Results on maintenance need to be expanded. Comorbidity rates with other externalizing disorders were extremely high, up to 98.6%. Results in CD patients (n= 184) suggested the efficacy of lithium, especially for aggressive behaviors. No severe adverse events directly related to lithium were reported in BD and CD; common side effects were similar to adults. Conclusion: This systematic review supports the use of lithium in BD and CD as an efficacious and generally well128;tolerated treatment in the pediatric age. However, evidence is limited due to the paucity of available data.

Background: Gender differences have been reported in the severity and psychopathological features of major depressive disorders among adults but are poorly reported in adolescent samples. Objective: This study aimed to examine gender differences in the psychopathology of mixed depression among adolescents. Methods: We analyzed 341 outpatients with the current major depressive episode (MDE) retrospectively to identify patients with DSM-5 MDE with mixed features. We compared examiner-rated depressive and (hypo)manic symptoms and self- and parent-reported symptoms between sexes. Results: We identified 76 patients with an MDE with mixed features (67.1% females, 32.9% with bipolar disorder). Depression severity was significantly greater in females versus males (CDRS-R total score 56.2 vs. 48.2, p = 0.014). Depressive symptoms were significantly and independently found to be more severe among females in a logistic regression model, including excessive fatigue (OR 1.68; p = 0.025), low self-esteem (OR 1.67; p = 0.04), excessive weeping (OR 1.62; p = 0.021), and CBCL AAA index (OR 1.04; p = 0.015). None of the depressive symptoms scored greater in males. Males had higher levels of motor activity (2.12 vs. 1.69; p = 0.048) and pressured speech (1.80 vs. 1.24; p = 0.004). Self-rated anxiety (69.3 vs. 56.8, p = 0.047) and CBCL AAA index (207 vs. 189; p = 0.007) were higher in females. Conclusion: Adolescent depression with mixed features is more severe in women, with a higher expression of core affective symptoms and excessive fatigue. While in males, slightly higher levels of psychomotor activation are reported, in females, emotional dysregulation and excessive weeping may subtend a difference in a broader spectrum of mixed features.

Background: There is evidence of alterations in mitochondrial energy metabolism and cerebral blood flow (CBF) in adults and youth with bipolar disorder (BD). Brain thermoregulation is based on the balance of heat-producing metabolism and heat-dissipating mechanisms, including CBF. Objective: To examine brain temperature, and its relation to CBF, in relation to BD and mood symptom severity in youth. Methods: This study included 25 youth participants (age 17.4 ± 1.7 years; 13 BD, 12 control group (CG)). Magnetic resonance spectroscopy data were acquired to obtain brain temperature in the left anterior cingulate cortex (ACC) and the left precuneus. Regional estimates of CBF were provided by arterial spin labeling imaging. Analyses used general linear regression models, covarying for age, sex, and psychiatric medications. Results: Brain temperature was significantly higher in BD compared to CG in the precuneus. A higher ratio of brain temperature to CBF was significantly associated with greater depression symptom severity in both the ACC and precuneus within BD. Analyses examining the relationship of brain temperature or CBF with depression severity score did not reveal any significant finding in the ACC or the precuneus. Conclusion: The current study provides preliminary evidence of increased brain temperature in youth with BD, in whom reduced thermoregulatory capacity is putatively associated with depression symptom severity. Evaluation of brain temperature and CBF in conjunction may provide valuable insight beyond what can be gleaned by either metric alone. Larger prospective studies are warranted to further evaluate brain temperature and its association with CBF concerning BD.

Background: Emerging evidence points towards the involvement of the cerebellum in the processing of emotions and pathophysiology of mood disorders. However, cerebellar and related cognitive alterations in youth with pediatric bipolar disorder (PBD) and those at high risk to develop the disorder, such as bipolar offspring (BD-OFF) are not clearly defined. Objective: To investigate cerebellar gray and white matter volumes, cognition, and their relationship in youth with PBD and BD-OFF. Methods: Thirty youth (7 to 17 years, inclusive) with PBD, 30 BD-OFF and 40 healthy controls (HC) were recruited. Study participants underwent a computer-based cognitive battery assessing affective processing, executive function, attention, psychomotor speed, and learning. Three-tesla MRI scan was performed to assess cerebellar white and gray matter volumes. Cerebellar segmentation was performed with FreeSurfer. Statistical analyses include between-group differences in cognitive domains, cerebellar gray, and white matter volumes. Relationships between cerebellar volumes and cognitive domains were examined. Results: Youth with PBD showed greater cerebellar gray matter volumes than both BD-OFF and HC, whereas no differences were present between BD-OFF and HC. Both youth with PBD and BD-OFF showed altered processing of negative emotions and a bias towards positive emotions. In youth with PBD and BD-OFF, greater impairment in the processing of emotions correlated with greater cerebellar gray matter volumes. Conclusion: The present findings corroborate hypotheses on cerebellar involvement in the processing of emotions and the pathophysiology of PBD. The presence of cerebellar dysfunction in BD-OFF is unclear.

Background: The impairing neurodevelopmental course of bipolar disorder (BD) suggests the importance of early intervention for youth in the beginning phases of the illness. Objective: We report the results of a 3-site randomized trial of family-focused therapy for youth at high-risk (FFT-HR) for BD, and explore psychosocial and neuroimaging variables as mediators of treatment effects. Methods: High-risk youth (<18 years) with major depressive disorder or other specified BD, active mood symptoms, and a family history of BD were randomly assigned to 4 months of FFT-HR (psychoeducation, communication and problem-solving skills training) or 4 months of enhanced care psychoeducation. Adjunctive pharmacotherapy was provided by study psychiatrists. Neuroimaging scans were conducted before and after psychosocial treatments in eligible participants. Independent evaluators interviewed participants every 4-6 months over 1-4 years regarding symptomatic outcomes. Results: Among 127 youth (mean 13.2 ± 2.6 years) over a median of 98 weeks, FFT-HR was associated with longer intervals prior to new mood episodes and lower levels of suicidal ideation than enhanced care. Reductions in perceived family conflict mediated the effects of psychosocial interventions on the course of mood symptoms. Among 34 participants with pre-/post-treatment fMRI scans, youth in FFT-HR had (a) stronger resting state connectivity between ventrolateral PFC and anterior default mode network, and (b) increased activity of dorsolateral and medial PFC in emotion processing and problem-solving tasks, compared to youth in enhanced care. Conclusion: FFT-HR may delay new mood episodes in symptomatic youth with familial liability to BD. Putative treatment mechanisms include neural adaptations suggestive of improved emotion regulation.

Background: The presence of mixed (subsyndromal hypomanic) symptoms may influence treatment outcomes in pediatric bipolar depression. This post-hoc analysis investigated “bridge” symptoms that have cross-sectional and predictive associations with depressive and manic symptom clusters in youth with bipolar depression. Methods: The moderating effects of these bridge symptoms on the response to flexibly dosed lurasidone 20-80 mg/d compared to placebo treatment was analyzed in children and adolescents with bipolar I depression in a six-week, placebo-controlled, double-blind study followed by a 2-year, openlabel extension study of lurasidone. Results: Sleep disturbances, assessed by “difficulty with sleep” (Children’s Depression Rating Scale, Revised [CDRS-R] item 4) and “decreased need for sleep” (Young Mania Rating Scale [YMRS] item 4), and “irritability” (CDRS-R item-8, YMRS item 5) were identified as “bridge” symptoms and found to have replicable causal associations with depressive (CDRS-R total) and manic symptom clusters (YMRS total) at baseline and week-6. A greater improvement in overall depression severity at week 6 with lurasidone (vs. placebo) treatment was observed in the presence (vs. absence) of decreased need for sleep at study baseline, mediated in part by significant reductions from study baseline in decreased need for sleep and manic symptom severity. The absence of sleep disturbance and irritability in patients at open-label extension study baseline was associated with higher rates of sustained recovery (symptomatic and functional remission) over 6 months compared to patients with those symptoms at baseline (68% vs. 50%, Number Needed to Treat=6). Conclusion: Our findings suggest that sleep disturbance and irritability are cardinal symptoms that “bridge” between depressive and manic symptom clusters and influence treatment outcomes in youth with bipolar depression.

Ischemic stroke includes two related pathological damage processes: brain injury caused by primary ischemia and secondary ischemia reperfusion (I/R) injury. I/R injury has become a worldwide health problem. Unfortunately, there is still a lack of satisfactory drugs for ameliorating cerebral I/R damage. Nrf2 is a vital endogenous antioxidant protein, which combines with Keap1 to maintain a dormant state under physiological conditions. When pathological changes such as I/R occurs, Nrf2 dissociates from Keap1 and activates the expression of downstream antioxidant proteins to exert a protective effect. Recent research have shown that the activated Nrf2 not only effectively inhibits oxidative stress, but also performs the ability to repair the function of compromised mitochondria, alleviate endoplasmic reticulum stress, eliminate inflammatory response, reduce blood-brain barrier permeability, inhibit neuronal apoptosis, enhance the neural network remolding, thereby exerting significant protective effects in alleviating the injuries caused by cell oxygen-glucose deprivation, or animal cerebral I/R. However, no definite clinical application report demonstrated the efficacy of Nrf2 activators in the treatment of cerebral I/R. Therefore, further efforts are needed to elaborate the role of Nrf2 activators in the treatment of cerebral I/R. Here, we reviewed the possible mechanisms underlying its potential pharmacological benefits in alleviating cerebral I/R injury, so as to provide a theoretical basis for studying its mechanism and developing Nrf2 activators.

The phytochemicals have antioxidant properties to counter the deleterious effects of oxidative stress in the central nervous system and can be a promising drug candidate for neurodegenerative diseases. Among various phytochemicals, constituents of spice origin have recently received special attention for neurodegenerative diseases owing to their health benefits, therapeutic potential, edible nature, and dietary accessibility and availability. Carvacrol, a phenolic monoterpenoid, has garnered attention in treating and managing various human diseases. It possesses diverse pharmacological effects, including antioxidant, anti-inflammatory, antimicrobial and anticancer. Alzheimer's disease (AD) and Parkinson's disease (PD) are major public health concerns that place a significant financial burden on healthcare systems worldwide. The global burden of these diseases is expected to increase in the next few decades owing to increasing life expectancies. Currently, there is no cure for neurodegenerative diseases, such as AD and PD, and the available drugs only give symptomatic relief. For a long time, oxidative stress has been recognized as a primary contributor to neurodegeneration. Carvacrol enhances memory and cognition by modulating the effects of oxidative stress, inflammation, and Aβ25-35- induced neurotoxicity in AD. Moreover, it also reduces the production of reactive oxygen species and proinflammatory cytokine levels in PD, which further prevents the loss of dopaminergic neurons in the substantia nigra and improves motor functions. This review highlights carvacrol's potential antioxidant and anti-inflammatory properties in managing and treating AD and PD.

Mitochondria regulate multiple aspects of neuronal development, physiology, plasticity, and pathology through their regulatory roles in bioenergetic, calcium, redox, and cell survival/death signalling. While several reviews have addressed these different aspects, a comprehensive discussion focussing on the relevance of isolated brain mitochondria and their utilities in neuroscience research has been lacking. This is relevant because the employment of isolated mitochondria rather than their in situ functional evaluation, offers definitive evidence of organelle-specificity, negating the interference from extra mitochondrial cellular factors/signals. This mini-review was designed primarily to explore the commonly employed in organello analytical assays for the assessment of mitochondrial physiology and its dysfunction, with a particular focus on neuroscience research. The authors briefly discuss the methodologies for biochemical isolation of mitochondria, their quality assessment, and cryopreservation. Further, the review attempts to accumulate the key biochemical protocols for in organello assessment of a multitude of mitochondrial functions critical for neurophysiology, including assays for bioenergetic activity, calcium and redox homeostasis, and mitochondrial protein translation. The purpose of this review is not to examine each and every method or study related to the functional assessment of isolated brain mitochondria, but rather to assemble the commonly used protocols of in organello mitochondrial research in a single publication. The hope is that this review will provide a suitable platform aiding neuroscientists to choose and apply the required protocols and tools to address their particular mechanistic, diagnostic, or therapeutic question dealing within the confines of the research area of mitochondrial patho-physiology in the neuronal perspective.

Neuronal injury during acute hypoxia, ischemia, and following reperfusion are partially attributable to oxidative damage caused by deleterious fluctuations of reactive oxygen species (ROS). In particular, mitochondrial superoxide (O2•-) production is believed to upsurge during lowoxygen conditions and also following reperfusion, before being dismutated to H2O2 and released into the cell. However, disruptions of redox homeostasis may be beneficially attenuated in the brain of hypoxia-tolerant species, such as the naked mole-rat (NMR, Heterocephalus glaber). As such, we hypothesized that ROS homeostasis is better maintained in the brain of NMRs during severe hypoxic/ ischemic insults and following reperfusion. We predicted that NMR brain would not exhibit substantial fluctuations in ROS during hypoxia or reoxygenation, unlike previous reports from hypoxiaintolerant mouse brain. To test this hypothesis, we measured cortical ROS flux using corrected total cell fluorescence measurements from live brain slices loaded with the MitoSOX red superoxide (O2•-) indicator or chloromethyl 2’,7’-dichlorodihydrofluorescein diacetate (CM-H2-DCFDA; which fluoresces with whole-cell hydrogen peroxide (H2O2) production) during various low-oxygen treatments, exogenous oxidative stress, and reperfusion. We found that NMR cortex maintained ROS homeostasis during low-oxygen conditions, while mouse cortex exhibited a ~40% increase and a ~30% decrease in mitochondrial O2•- and cellular H2O2 production, respectively. Mitochondrial ROS homeostasis in NMRs was only disrupted following sodium cyanide application, which was similarly observed in mice. Our results suggest that NMRs have evolved strategies to maintain ROS homeostasis during acute bouts of hypoxia and reoxygenation, potentially as an adaptation to life in an intermittently hypoxic environment.