Solanesol Mediated SIRT-1 Activation Prevents Neurobehavioral and Neurochemical Defects in Ouabain-Induced Experimental Model of Bipolar Disorder in Rats

Background Bipolar disorder (BD) is a chronic mental illness characterized by mood fluctuations that range from depressive lows to manic highs. Several studies have linked the downregulation of SIRT-1 (silent mating type information regulation-2 homologs) signaling to the onset of BD and other neurological dysfunctions. The purpose of this research was to look into the neuroprotective potential of Solanesol (SNL) in rats given ICV-Ouabain injections, with a focus on its effect on SIRT-1 signaling activation in the brain. Ouabain, which is found in hypothalamic and medullary neurons, is an endogenous inhibitor of brain Na+/K+ ATPase. The inhibition of brain Na+/K+ ATPase by Ouabain may also result in changes in neurotransmission within the central nervous system. SNL is a Solanaceae family active phytoconstituent produced from the plant Nicotiana tabacum. SNL is used as a precursor for the production of CoQ10 (Coenzyme Q10), a powerful antioxidant and neuroprotective compound. In the current study, lithium (Li), an important mood stabilizer drug, was used as a control. Methods This study looked at the neuroprotective potential of SNL at dosages of 40 and 80 mg/kg in ICV-OUA injections that caused BD-like neurobehavioral and neurochemical defects in Wistar rats. Wistar rats were placed into eight groups (n=6) and administered 1 mM/0.5µl ICV-OUA injections for three days. Neurochemical assessments were done in rat brain homogenates, CSF, and blood plasma samples at the end of the experiment protocol schedule. Results Long-term SNL and lithium administration have been shown to decrease the number of rearing and crossings, as well as reduce time spent in the center, locomotor activities, and immobility time. Solansesol treatment gradually raises the amount of Na+/K+ ATPase, limiting the severity of behavioural symptoms. These findings also revealed that SNL increases the levels of SIRT-1 in CSF, blood plasma, and brain homogenate samples. Furthermore, in rat brain homogenates and blood plasma samples, SNL modulates apoptotic markers such as Caspase-3, Bax (pro-apoptotic), and Bcl-2 (anti-apoptotic). Mitochondrial-ETC complex enzymes, including complex-I, II, IV, V, and CoQ10, were also restored following long-term SNL treatment. Furthermore, SNL lowered inflammatory cytokines (TNF-α, IL-1β) levels while restoring neurotransmitter levels (serotonin, dopamine, glutamate, and acetylcholine) and decreasing oxidative stress markers. Conclusion As a result, our findings suggest that SNL, as a SIRT-1 signalling activator, may be a promising therapeutic approach for BD-like neurological dysfunctions.

Managing the Unpredictable: Mechanistic Analysis and Clinical Recommendations for Lamotrigine Treatment after Bariatric Surgery

Bariatric surgery may alter the absorption and overall bioavailability of oral drugs. Lamotrigine is a major antiepileptic and mood stabilizer, that its use after bariatric surgery has not yet been studied. In this article, we provide a thorough mechanistic analysis of the effects of bariatric surgery on multiple mechanisms important for the absorption, bioavailability and overall pharmacokinetics of lamotrigine. Attributable to its pharmacokinetic properties and drug characteristics, the use of lamotrigine after bariatric surgery may be challenging. The complex situation in which some mechanisms may lead to increased drug exposure (e.g., decreased metabolism, weight loss) while others to its decrease (e.g., hampered dissolution/solubility, decreased gastric volume), may result in lowered, unchanged, or enhanced lamotrigine plasma levels after the surgery. We conclude with a set of clinical recommendations for lamotrigine treatment after bariatric surgery, aiming to allow better patient care, and emphasizing the extra caution that needs to be taken with these patients.

Lithium augmentation of ketamine increases insulin signaling and antidepressant-like active stress coping in a rodent model of treatment-resistant depression

Lithium, a mood stabilizer and common adjunctive treatment for refractory depression, shares overlapping mechanisms of action with ketamine and enhances the duration of ketamine’s antidepressant actions in rodent models at sub-therapeutic doses. Yet, in a recent clinical trial, lithium co-treatment with ketamine failed to improve antidepressant outcomes in subjects previously shown to respond to ketamine alone. The potential for lithium augmentation to improve antidepressant outcomes in ketamine nonresponders, however, has not been explored. The current study examined the behavioral, molecular and metabolic actions of lithium and ketamine co-treatment in a rodent model of antidepressant resistance. Male Wistar rats were administered adrenocorticotropic hormone (ACTH; 100 µg/day, i.p. over 14 days) and subsequently treated with ketamine (10 mg/kg; 2 days; n = 12), lithium (37 mg/kg; 2 days; n = 12), ketamine + lithium (10 mg/kg + 37 mg/kg; 2 days; n = 12), or vehicle saline (0.9%; n = 12). Rats were subjected to open field (6 min) and forced swim tests (6 min). Peripheral blood and brain prefrontal cortical (PFC) tissue was collected one hour following stress exposure. Western blotting was used to determine the effects of treatment on extracellular signal-regulated kinase (ERK); mammalian target of rapamycin (mTOR), phospho kinase B (Akt), and glycogen synthase kinase-3ß (GSK3ß) protein levels in the infralimbic (IL) and prelimbic (PL) subregions of the PFC. Prefrontal oxygen consumption rate (OCR) and extracellular acidification rates (ECAR) were also determined in anterior PFC tissue at rest and following stimulation with brain-derived neurotrophic factor (BDNF) and tumor necrosis factor α (TNFα). Blood plasma levels of mTOR and insulin were determined using enzyme-linked immunosorbent assays (ELISAs). Overall, rats receiving ketamine+lithium displayed a robust antidepressant response to the combined treatment as demonstrated through significant reductions in immobility time (p < 0.05) and latency to immobility (p < 0.01). These animals also had higher expression of plasma mTOR (p < 0.01) and insulin (p < 0.001). Tissue bioenergetics analyses revealed that combined ketamine+lithium treatment did not significantly alter the respiratory response to BDNF or TNFα. Animals receiving both ketamine and lithium had significantly higher phosphorylation (p)-to-total expression ratios of mTOR (p < 0.001) and Akt (p < 0.01), and lower ERK in the IL compared to control animals. In contrast, pmTOR/mTOR levels were reduced in the PL of ketamine+lithium treated animals, while pERK/ERK expression levels were elevated. Taken together, these data demonstrate that lithium augmentation of ketamine in antidepressant nonresponsive animals improves antidepressant-like behavioral responses under stress, together with peripheral insulin efflux and region-specific PFC insulin signaling.

Bullying, Present Romantic Relationship and Depression as Predictive Factors of Non-Suicidal Self-Injury in Adolescent Psychiatric Patients

Background: Non-suicidal self-injury (NSSI), as a major public health issue of high complexity, multifactorial causes and great socioeconomic and family impact, affects China now especially after COVID-19. The aim of this study was to explore the clinical and psychological characteristic in adolescent psychiatric patients with or without NSSI.Methods: Adolescent psychiatric patients were recruited from psychiatric outpatient and inpatient unit in Guangdong mental Health Center between October and December 2020. NSSI was evaluated by the modified version of Adolescents Self-Harm Scale. Childhood trauma was assessed by the Childhood Trauma Questionnaire-Short Form (CTQ-SF). Peer bullying experience was evaluated by The Revised Olweus Bully/Victim Questionnaire（BVQ-R). Depression was assessed by the Montgomery–Asberg Depression Rating Scale (MADRS). Clinical data were collected from electronic medical record system.Results: The sample included 157 adolescent psychiatric patients (72.6% female), aged 13-18 years (M=15.39, SD=0.145). NSSI group experienced more peer bullying (t=4.08,P＜0.001), more likely to get into romantic relationship currently(χ2=5.38, P=0.02), more times of hospitalization (t=0.36, P<0.001), receiving more antipsychotic treatment (t=3.58, P<0.001), benzodiazepine treatment (t=3.46, P＜0.001), and mood-stabilizer treatment (χ2 =8.53, P<0.001). The significant predictor of NSSI for the last one year included being in romantic relationship currently (OR =4.27, 95% CI=[1.53,11.93]), outpatient (OR=0.38, 95%CI=[0.16,0.88]), BVQ-R total (OR=1.10, 95% CI=[1.02,1.18])，MARDS total (OR= 1.05, 95% CI=[1.01,1.09]), and benzodiazepine PDD/DDD (OR=5.79, 95% CI=[0.99,33.72]).Conclusions: Adolescent psychiatric patients with NSSI have significantly higher incidences of life event such as peer bulling, childhood trauma experience, and they were more likely to get into a romantic relationship. Meanwhile, patients with NSSI had significantly severe level of depression, being more on benzodiazepine and mood-stabilizer use. This provides a valuable basis for our clinical treatment of adolescent mental patients with NSSI.

Mood stabilizer: a concept analysis and operationalization of a model

Background. The term 'mood stabilizer' is controversial in literature. As there is no consensual meaning, its retirement has been suggested to avoid confusion and misuse. On the other hand, it remains largely employed, and some advocate it carries an important meaning. This issue has not been previously approached using a validated qualitative inquiry. Methods. We employed document analysis for reviewing proposed definitions for mood stabilizer. Then, we used concept analysis as a qualitative methodology to clarify meanings associated with the term. Based on its results, we built a theoretical model for mood stabilizer, matching it with evidence for drugs used in the treatment of bipolar disorder. Results. Concept analysis of documents defining the term unearthed four attributes of a mood stabilizer that could be usefully nested into the following ascending hierarchy: 'not worsening', 'acute effects', 'prophylactic effects', and 'advanced effects'. To be considered a mood stabilizer, a drug had to reach the 'prophylactic effects' tier, as this was discussed by authors as the core aspect of the class. After arranging drugs according to this scheme, lithium and quetiapine received the label, but only the former fulfilled all four attributes, as evidence indicates it has neuroprotective action. Conclusion. The proposed model uses a hierarchy of attributes that take into account the complexity of the term and help to determine whether a drug is a mood stabilizer. Prophylaxis is pivotal to the concept, whose utility lies in implying a drug able to truly treat bipolar disorder, as opposed to merely targeting symptoms. This could modify long-term outcomes and illness trajectory.

Effects of Radix Polygalae on Cognitive Decline and Depression in Estradiol Depletion Mouse Model of Menopause

Postmenopausal syndrome refers to symptoms caused by the gradual decrease in female hormones after mid-40 years. As a target organ of estrogen, decrease in estrogen causes various changes in brain function such as a decrease in choline acetyltransferase and brain-derived neurotrophic factor; thus, postmenopausal women experience cognitive decline and more depressive symptoms than age-matched men. Radix Polygalae has been used for memory boosting and as a mood stabilizer and its components have shown neuroprotective, antidepressant, and stress relief properties. In a mouse model of estrogen depletion induced by 4-vinylcyclohexene diepoxide, Radix Polygalae was orally administered for 3 weeks. In these animals, cognitive and depression-related behaviors and molecular changes related to these behaviors were measured in the prefrontal cortex and hippocampus. Radix Polygalae improved working memory and contextual memory and despair-related behaviors in 4-vinylcyclohexene diepoxide-treated mice without increasing serum estradiol levels in this model. In relation to these behaviors, choline acetyltransferase and brain-derived neurotrophic factor in the prefrontal cortex and hippocampus and bcl-2-associated athanogene expression increased in the hippocampus. These results implicate the possible benefit of Radix Polygalae in use as a supplement of estrogen to prevent conditions such as postmenopausal depression and cognitive decline.

Identifying Poor Adherence in Outpatients with Bipolar Disorder: A Comparison of Different Measures

Objective Unlike schizophrenia, comparisons of different methods of estimating inadequate adherence in bipolar disorder (BD) are scarce. This study compared four methods of identifying inadequate adherence among outpatients with BD. Materials and Methods Two self-reports, the Morisky Medication Adherence Questionnaire (MAQ) and the Drug Attitude Inventory (DAI-10), clinician ratings employing the Compliance Rating Scale (CRS), mood-stabilizer levels, and clinic-based pill counts were compared at intake in 106 outpatients with BD and after 6 months of follow-up (n = 75). Statistical Analysis Rates of nonadherence were determined for each method. The ability to detect inadequate adherence was based on sensitivity, specificity, positive and negative predictive values (PPV and NPV), and positive and negative likelihood ratios (LR positive and LR negative). Correlation coefficients and Cohen's kappa values were used to determine the agreement between measures. Correlation coefficients were also used to evaluate the determinants of inadequate adherence Results The MAQ and the DAI-10 (cut-off score of two) yielded higher rates of nonadherence (35–47%) than the other methods. They were better at detecting adherence (specificity, 34–42%; PPV, 40–44%; and LR negative, 0.70–0.96) than other measures and had moderate ability to identify nonadherence compared with them (sensitivity, 63–73%; NPV, 54–70%; and LR positive, 1.02–1.16). They were associated with several established predictors of nonadherence. The MAQ and DAI-10 scores and the MAQ and CRS scores were modestly correlated. Multivariate analysis showed that 20% of the variance in the DAI-10 scores was explained by the MAQ scores. Despite their low yield, serum levels had a high sensitivity (88%) and higher accuracy (55%) in identifying inadequate adherence. CRS ratings and pill counts had high sensitivity but low specificity to detect inadequate adherence. Conclusion Self-reports appeared to be the most efficient method of ascertaining inadequate adherence among outpatients with BD. However, since none of the measures were adequate by themselves, a combination of different measures is more likely to maximize the chances of identifying inadequate adherence among these patients.

Genetics and antiepileptic-mood stabilizer treatment response in bipolar disorder: what do we know?

Antiepileptic-mood stabilizers (AED-MS) are often used to treat bipolar disorder (BD). Similar to other mood disorder medications, AED-MS treatment response varies between patients. Identification of biomarkers associated with treatment response may ultimately help with the delivery of individualized treatment and lead to improved treatment efficacy. Here, we conducted a narrative review of the current knowledge of the pharmacogenomics of AED-MS (valproic acid, lamotrigine and carbamazepine) treatment response in BD, including genetic contributions to AED-MS pharmacokinetics. Genes involved in neurotransmitter systems and drug transport have been shown to be associated with AED-MS treatment response. As more studies are conducted, and experimental and analytical methods advance, knowledge of AED-MS pharmacogenomics is expected to grow and contribute to precision medicine in BD.

A Review on Analytical Method for Determination of Lamotrigine in Bulk and Pharmaceutical Dosage Form

Lamotrigine is an anticonvulsant drug used in the treatment of epilepsy & bipolar disorder/major affective disorder (manic depression). Lamotrigine is and antiepileptic drug of phenyltriazine class. For epilepsy it is used to treat the partial seizures, primary and secondary tonic-clonic seizures, and seizures associated with the Lennox-Gastuat syndrome and are chemically unrelated to the other anticonvulsants. Lamotrigine is a phenyltriazine that has comparatively few side-effects and it does not requires blood monitoring/observance in monotherapy. It additionally acts as a mood stabilizer. Common side-effects of lamotrigine include, nausea, sleepiness, headache, vomiting, trouble/bother with co-ordination and rash. Serious side-effects include in, lack of red blood cells, accumulated in risk of suicide, Stevens-Johnson syndrome and allergy. It issues that use of lamotrigine throughout pregnancy or breastfeeding it’s going to lead/result in harm/damage.