Acute neural effects of the mood stabiliser lamotrigine on emotional processing in healthy volunteers: a randomised control trial.

Lamotrigine is an effective mood stabiliser, largely used for the management and prevention of depression in bipolar disorder. The neuropsychological mechanisms by which lamotrigine acts to relieve symptoms as well as its neural effects on emotional processing remain unclear. The primary objective of this current study was to investigate the impact of an acute dose of lamotrigine on the neural response to a well-characterised fMRI task probing implicit emotional processing relevant to negative bias. 31 healthy participants were administered either a single dose of lamotrigine (300 mg, n = 14) or placebo (n = 17) in a randomized, double-blind design. Inside the 3 T MRI scanner, participants completed a covert emotional faces gender discrimination task. Brain activations showing significant group differences were identified using voxel-wise general linear model (GLM) nonparametric permutation testing, with threshold free cluster enhancement (TFCE) and a family wise error (FWE)-corrected cluster significance threshold of p < 0.05. Participants receiving lamotrigine were more accurate at identifying the gender of fearful (but not happy or angry) faces. A network of regions associated with emotional processing, including amygdala, insula, and the anterior cingulate cortex (ACC), was significantly less activated in the lamotrigine group compared to the placebo group across emotional facial expressions. A single dose of lamotrigine reduced activation in limbic areas in response to faces with both positive and negative expressions, suggesting a valence-independent effect. However, at a behavioural level lamotrigine appeared to reduce the distracting effect of fear on face discrimination. Such effects may be relevant to the mood stabilisation effects of lamotrigine.

New Advances in the Pharmacology and Toxicology of Lithium: A Neurobiologically Oriented Overview.

Over the last six decades, lithium has been considered the gold standard treatment for the long-term management of bipolar disorder due to its efficacy in preventing both manic and depressive episodes as well as suicidal behaviors. Nevertheless, despite numerous observed effects on various cellular pathways and biologic systems, the precise mechanism through which lithium stabilizes mood remains elusive. Furthermore, there is recent support for the therapeutic potential of lithium in other brain diseases. This review offers a comprehensive examination of contemporary understanding and predominant theories concerning the diverse mechanisms underlying lithium's effects. These findings are based on investigations utilizing cellular and animal models of neurodegenerative and psychiatric disorders. Recent studies have provided additional support for the significance of glycogen synthase kinase-3 (GSK3) inhibition as a crucial mechanism. Furthermore, research has shed more light on the interconnections between GSK3-mediated neuroprotective, antioxidant, and neuroplasticity processes. Moreover, recent advancements in animal and human models have provided valuable insights into how lithium-induced modifications at the homeostatic synaptic plasticity level may play a pivotal role in its clinical effectiveness. We focused on findings from translational studies suggesting that lithium may interface with microRNA expression. Finally, we are exploring the repurposing potential of lithium beyond bipolar disorder. These recent findings on the therapeutic mechanisms of lithium have provided important clues toward developing predictive models of response to lithium treatment and identifying new biologic targets. SIGNIFICANCE STATEMENT: Lithium is the drug of choice for the treatment of bipolar disorder, but its mechanism of action in stabilizing mood remains elusive. This review presents the latest evidence on lithium's various mechanisms of action. Recent evidence has strengthened glycogen synthase kinase-3 (GSK3) inhibition, changes at the level of homeostatic synaptic plasticity, and regulation of microRNA expression as key mechanisms, providing an intriguing perspective that may help bridge the mechanistic gap between molecular functions and its clinical efficacy as a mood stabilizer.

In-silico functional analyses identify TMPRSS15-mediated intestinal absorption of lithium as a modulator of lithium response in bipolar disorder.

BACKGROUND: The therapeutic response to lithium in patients with bipolar disorder is highly variable and has a polygenic basis. Genome-wide association studies investigating lithium response have identified several relevant loci, though the precise mechanisms driving these associations are poorly understood. We aimed to prioritise the most likely effector gene and determine the mechanisms underlying an intergenic lithium response locus on chromosome 21 identified by the International Consortium on Lithium Genetics (ConLi+Gen). METHODS: We conducted in-silico functional analyses by integrating and synthesising information from several publicly available functional genetic datasets and databases including the Genotype-Tissue Expression (GTEx) project and HaploReg. RESULTS: The findings from this study highlighted TMPRSS15 as the most likely effector gene at the ConLi+Gen lithium response locus. TMPRSS15 encodes enterokinase, a gastrointestinal enzyme responsible for converting trypsinogen into trypsin and thus aiding digestion. Convergent findings from gene-based lookups in human and mouse databases as well as co-expression network analyses of small intestinal RNA-seq data (GTEx) implicated TMPRSS15 in the regulation of intestinal nutrient absorption, including ions like sodium and potassium, which may extend to lithium. LIMITATIONS: Although the findings from this study indicated that TMPRSS15 was the most likely effector gene at the ConLi+Gen lithium response locus, the evidence was circumstantial. Thus, the conclusions from this study need to be validated in appropriately designed wet-lab studies. CONCLUSIONS: The findings from this study are consistent with a model whereby TMPRSS15 impacts the efficacy of lithium treatment in patients with bipolar disorder by modulating intestinal lithium absorption.

Efficacy and Safety of Adding Lurasidone to Ongoing Therapy With Lithium or Valproate for the Treatment of an Acute Bipolar Depressive Episode: A Post Hoc Analysis of 2 Placebo-Controlled Trials.

PURPOSE: The aim of this study was to compare the efficacy and safety profile of lurasidone combined with either lithium or valproate, in the short-term treatment of patients with bipolar depression. METHODS: Data were pooled from two 6-week, double-blind, placebo-controlled trials of patients with bipolar depression on stable doses of lithium or valproate randomized to lurasidone (20-120 mg/d) or placebo. Efficacy measures included the Montgomery-Åsberg Depression Rating Scale, Clinical Global Impressions Bipolar Scale, and the Quick Inventory of Depressive Symptomatology via self-assessment and were analyzed using a mixed model for repeated measures approach. RESULTS: Notably larger week 6 effect sizes were observed when lurasidone was added to lithium, compared with when lurasidone was added to valproate, on 2 of the 3 depression outcome measures, Montgomery-Åsberg Depression Rating Scale total score (d = 0.45 vs 0.22) and Quick Inventory of Depressive Symptomatology via self-assessment (d = 0.63 vs 0.29); the efficacy advantage was smaller on the Clinical Global Impressions Bipolar Scale depression score (d = 0.34 vs 0.29). Similar adverse event profiles were observed for lurasidone treatment in combination with either lithium or valproate. The most frequently reported events (≥5%) in both groups were nausea, parkinsonism, somnolence, akathisia, and insomnia. Minimal changes in weight, lipids, and measures of glycemic control were observed during treatment with lurasidone combined with either lithium or valproate. CONCLUSIONS: Lurasidone added to either lithium or valproate was found to be an effective treatment for bipolar depression, with a larger antidepressant effect observed when lurasidone was combined with lithium. There were no clinically meaningful differences in the safety or tolerability of lurasidone when used adjunctively with lithium or valproate.

Phenotypic clustering of bipolar disorder supports stratification by lithium responsiveness over diagnostic subtypes.

INTRODUCTION: The aim of this study was to determine whether the clinical profiles of bipolar disorder (BD) patients could be differentiated more clearly using the existing classification by diagnostic subtype or by lithium treatment responsiveness. METHODS: We included adult patients with BD-I or II (N = 477 across four sites) who were treated with lithium as their principal mood stabilizer for at least 1 year. Treatment responsiveness was defined using the dichotomized Alda score. We performed hierarchical clustering on phenotypes defined by 40 features, covering demographics, clinical course, family history, suicide behaviour, and comorbid conditions. We then measured the amount of information that inferred clusters carried about (A) BD subtype and (B) lithium responsiveness using adjusted mutual information (AMI) scores. Detailed phenotypic profiles across clusters were then evaluated with univariate comparisons. RESULTS: Two clusters were identified (n = 56 and n = 421), which captured significantly more information about lithium responsiveness (AMI range: 0.033 to 0.133) than BD subtype (AMI: 0.004 to 0.011). The smaller cluster had disproportionately more lithium responders (n = 47 [83.8%]) when compared to the larger cluster (103 [24.4%]; p = 0.006). CONCLUSIONS: Phenotypes derived from detailed clinical data may carry more information about lithium responsiveness than the current classification of diagnostic subtype. These findings support lithium responsiveness as a valid approach to stratification in clinical samples.

Lithium carbonate revitalizes tumor-reactive CD8+ T cells by shunting lactic acid into mitochondria.

The steady flow of lactic acid (LA) from tumor cells to the extracellular space via the monocarboxylate transporter symport system suppresses antitumor T cell immunity. However, LA is a natural energy metabolite that can be oxidized in the mitochondria and could potentially stimulate T cells. Here we show that the lactate-lowering mood stabilizer lithium carbonate (LC) can inhibit LA-mediated CD8+ T cell immunosuppression. Cytoplasmic LA increased the pumping of protons into lysosomes. LC interfered with vacuolar ATPase to block lysosomal acidification and rescue lysosomal diacylglycerol-PKCθ signaling to facilitate monocarboxylate transporter 1 localization to mitochondrial membranes, thus transporting LA into the mitochondria as an energy source for CD8+ T cells. These findings indicate that targeting LA metabolism using LC could support cancer immunotherapy.

Common changes in rat cortical gene expression after valproate or lithium treatment particularly affect pre- and post-synaptic pathways that regulate four neurotransmitters systems.

OBJECTIVES: We have postulated that common changes in gene expression after treatment with different therapeutic classes of psychotropic drugs contribute to their common therapeutic mechanisms of action. METHODS: To test this hypothesis, we measured levels of cortical coding and non-coding RNA using GeneChip® Rat Exon 1.0 ST Array after treatment with vehicle (chow only), chow containing 1.8 g lithium carbonate/kg (n = 10) or chow containing 12 g sodium valproate/kg (n = 10) for 28 days. Differences in levels of RNA were identified using JMP Genomics 13 and the Panther Gene Ontology Classification System was used to identify potential consequences of RNA. RESULTS: Compared to vehicle treatment, levels of cortical RNA for 543 and 583 coding and non-coding RNAs were different after treatment with valproate and lithium, respectively. Moreover, levels of 323 coding and non-coding RNAs were altered in a highly correlated way by treatment with valproate and lithium, changes that would impact on cholinergic, glutamatergic, serotonergic and dopaminergic neurotransmission as well as on voltage gated ion channels. CONCLUSIONS: Our study suggests that treating with mood stabilisers cause many common changes in levels of RNA which will impact on CNS function, particularly affecting post-synaptic muscarinic receptor functioning and the release of multiple neurotransmitters.

Bipolar mania and epilepsy pathophysiology and treatment may converge in purine metabolism: A new perspective on available evidence.

Decreased ATPergic signaling is an increasingly recognized pathophysiology in bipolar mania disease models. In parallel, adenosine deficit is increasingly recognized in epilepsy pathophysiology. Under-recognized ATP and/or adenosine-increasing mechanisms of several antimanic and antiseizure therapies including lithium, valproate, carbamazepine, and ECT suggest a fundamental pathogenic role of adenosine deficit in bipolar mania to match the established role of adenosine deficit in epilepsy. The depletion of adenosine-derivatives within the purine cycle is expected to result in a compensatory increase in oxopurines (uric acid precursors) and secondarily increased uric acid, observed in both bipolar mania and epilepsy. Cortisol-based inhibition of purine conversion to adenosine-derivatives may be reflected in observed uric acid increases and the well-established contribution of cortisol to both bipolar mania and epilepsy pathology. Cortisol-inhibited conversion from IMP to AMP as precursor of both ATP and adenosine may represent a mechanism for treatment resistance common in both bipolar mania and epilepsy. Anti-cortisol therapies may therefore augment other treatments both in bipolar mania and epilepsy. Evidence linking (i) adenosine deficit with a decreased need for sleep, (ii) IMP/cGMP excess with compulsive hypersexuality, and (iii) guanosine excess with grandiose delusions may converge to suggest a novel theory of bipolar mania as a condition characterized by disrupted purine metabolism. The potential for disease-modification and prevention related to adenosine-mediated epigenetic changes in epilepsy may be mirrored in mania. Evaluating the purinergic effects of existing agents and validating purine dysregulation may improve diagnosis and treatment in bipolar mania and epilepsy and provide specific targets for drug development.

Neuroimaging alterations associated with medication use in early-onset bipolar disorder: An updated review.

BACKGROUND: Pediatric bipolar disorder (PBD) is a severe disorder characterized by mood fluctuations starting at a young age. Several neuroimaging studies revealed a specific biological signature of PBD involving alterations in the amygdala and prefrontal regions. Considering the growing concerns regarding the effects of PBD treatments on developing brains, this review aims to provide an overview of the studies investigating the effect of mood stabilizers, antipsychotics, and anticonvulsants on neuroimaging findings in PBD. METHODS: We searched PubMed, Scopus, and Web of Science to identify all structural magnetic resonance imaging (sMRI), functional magnetic resonance imaging (fMRI), and diffusion tensor imaging (DTI) studies exploring the effects of medications on neuroimaging findings in PBD. A total of 18 studies met our inclusion criteria (fMRI n = 11, sMRI n = 6, DTI n = 1). RESULTS: Although the findings varied highly across the studies, some investigations consistently indicated that medications primarily affect the prefrontal cortex and the amygdala. Moreover, despite some exceptions, the reported medication effects predominantly lean towards structural and functional normalization. LIMITATIONS: The reviewed studies differ in methods, medications, and fMRI paradigms. Furthermore, most studies used observational approaches with small sample sizes, minimizing the statistical power. CONCLUSIONS: Evidence suggests the potential of antipsychotics and mood stabilizers to modulate the neuroimaging findings in PBD patients, mostly normalizing brain structure and function in key mood-regulating regions.

Different pharmacokinetics of lithium orotate inform why it is more potent, effective, and less toxic than lithium carbonate in a mouse model of mania.

Lithium carbonate (LiCO) is a mainstay therapeutic for the prevention of mood-episode recurrences in bipolar disorder (BD). Unfortunately, its narrow therapeutic index is associated with complications that may lead to treatment non-compliance. Intriguingly, lithium orotate (LiOr) is suggested to possess unique uptake characteristics that would allow for reduced dosing and mitigation of toxicity concerns. We hypothesized that due to differences in pharmacokinetics, LiOr is more potent with reduced adverse effects. Dose responses were established for LiOr and LiCO in male and female mice using an amphetamine-induced hyperlocomotion (AIH) model; AIH captures manic elements of BD and is sensitive to a dose-dependent lithium blockade. LiCO induced a partial block of AIH at doses of 15 mg/kg in males and 20 mg/kg in females. In contrast, LiOr elicited a near complete blockade at concentrations of just 1.5 mg/kg in both sexes, indicating improved efficacy and potency. Prior application of organic anion transport inhibitors, or inhibition of orotate uptake into the pentose pathway, completely blocked the effects of LiOr on AIH while sparing LiCO effects, confirming differences in transport and compartmentalization between the two compounds. Next, the relative toxicities of LiOr and LiCO were contrasted after 14 consecutive daily administrations. LiCO, but not LiOr, elicited polydipsia in both sexes, elevated serum creatinine levels in males, and increased serum TSH expression in females. LiOr demonstrates superior efficacy, potency, and tolerability to LiCO in both male and female mice because of select transport-mediated uptake and pentose pathway incorporation.

Folic acid does not have an anti-manic effect but protect the brain against oxidative stress in an animal model of mania induced by ouabain.

BACKGROUND: Bipolar disorder (BD) is a complex and severe mental disorder that affects 1-3 % of the world population. Studies have suggested the involvement of oxidative stress in the physiopathology of this psychiatry disorder. Folic acid (FA), a vitamin from the B complex, is a nutraceutical that has recently been researched as a possible treatment for BD since folate is reduced in patients with the disorder. The present study aimed to evaluate the effects of lithium (Li) and FA on behavioral changes and oxidative stress parameters in an animal model of mania induced by ouabain (OUA). METHODS: Wistar rats received a single intracerebroventricular (ICV) injection of OUA or artificial cerebrospinal fluid (aCSF). From the day following ICV injection, the rats were treated for seven days with gavage injections of Li (47.5 mg/kg/mL), FA (50 mg/kg/mL), or water (1 mL/kg). On the 7th day after OUA injection, locomotor activity was measured using the open-field test. In addition, the oxidative stress parameters were evaluated in rats' frontal cortex, striatum, and hippocampus. RESULTS: OUA induced mania-like behavior and oxidative stress in rats' brains, but Li could reverse these alterations. FA did not affect behavior parameters; however, it presents an antioxidant effect on the brain structures evaluated. LIMITATIONS: The study was only evaluated male rats and ICV injection is an invasive procedure. CONCLUSION: These results indicate that even though FA has an effect against the oxidative stress induced by OUA, this effect was not strong enough to interfere with behavior parameters.

Neural progenitor cells derived from lithium responsive and non-responsive bipolar disorder patients exhibit distinct sensitivity to cell death following methamphetamine.

Bipolar disorder (BD) is characterized by manic and depressive mood episodes and loss of brain gray matter. Lithium has antimanic and neuroprotective properties, but only 30% BD patients respond to lithium pharmacotherapy. Dopamine signaling has been implicated in BD and may contribute to lithium response. Methamphetamine (METH) stimulates dopamine release and models the clinical features of mania but has never been used to study cell death in BD patient neurons. We used BD patient derived neuronal progenitor cells (NPCs) to determine whether the vulnerability to cell death differed in samples from lithium responder (Li-R) and non-responder (Li-NR) BD patients and healthy controls following METH exposure in vitro. We hypothesized that NPCs from Li-R and Li-NR would differ in vulnerability to METH, dopamine signaling and neuroprotection from lithium. Following METH, NPCs from controls and Li-NR showed significantly greater cell loss compared to Li-R. Pre-treatment of NPCs with the D1 dopamine receptor antagonist SCH 23390 reversed the neurotoxic effects of METH. In Li-R NPCs, expression of phosho-ERK1/2 was significantly increased. In Li-NR NPCs, phospho-AKT, D1 and D2 dopamine receptor proteins were significantly increased. Pre-treatment of NPCs with lithium before METH reversed the neurotoxic effects of METH in control NPCs, whereas Li-NR showed less protective benefit. Li-R cells showed decreased levels of cell death after METH and comparatively high viability, and lithium treatment did not increase viability any further. This novel NPC model of mania reveals differences in cell death that could help identify mechanisms of lithium response in BD.

Use of Lithium in Pediatric Bipolar Disorders and Externalizing Childhood- related Disorders: A Systematic Review of Randomized Controlled Trials.

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 well-tolerated treatment in the pediatric age. However, evidence is limited due to the paucity of available data.

Brain morphometric features predict medication response in youth with bipolar disorder: a prospective randomized clinical trial.

BACKGROUND: Identification of treatment-specific predictors of drug therapies for bipolar disorder (BD) is important because only about half of individuals respond to any specific medication. However, medication response in pediatric BD is variable and not well predicted by clinical characteristics. METHODS: A total of 121 youth with early course BD (acute manic/mixed episode) were prospectively recruited and randomized to 6 weeks of double-blind treatment with quetiapine (n = 71) or lithium (n = 50). Participants completed structural magnetic resonance imaging (MRI) at baseline before treatment and 1 week after treatment initiation, and brain morphometric features were extracted for each individual based on MRI scans. Positive antimanic treatment response at week 6 was defined as an over 50% reduction of Young Mania Rating Scale scores from baseline. Two-stage deep learning prediction model was established to distinguish responders and non-responders based on different feature sets. RESULTS: Pre-treatment morphometry and morphometric changes occurring during the first week can both independently predict treatment outcome of quetiapine and lithium with balanced accuracy over 75% (all p < 0.05). Combining brain morphometry at baseline and week 1 allows prediction with the highest balanced accuracy (quetiapine: 83.2% and lithium: 83.5%). Predictions in the quetiapine and lithium group were found to be driven by different morphometric patterns. CONCLUSIONS: These findings demonstrate that pre-treatment morphometric measures and acute brain morphometric changes can serve as medication response predictors in pediatric BD. Brain morphometric features may provide promising biomarkers for developing biologically-informed treatment outcome prediction and patient stratification tools for BD treatment development.

Cardioprotective potential of lithium and role of fractalkine in euthymic patients with bipolar disorder.

OBJECTIVE: Over a half century, lithium has been used as the first-line medication to treat bipolar disorder. Emerging clinical and laboratory studies suggest that lithium may exhibit cardioprotective effects in addition to neuroprotective actions. Fractalkine (CX3CL1) is a unique chemokine associated with the pathogenesis of mood disorders and cardiovascular diseases. Herein we aimed to ascertain whether lithium treatment is associated with favorable cardiac structure and function in relation to the reduced CX3CL1 among patients with bipolar disorder. METHODS: We recruited 100 euthymic patients with bipolar I disorder aged over 20 years to undergo echocardiographic study and measurement of plasma CX3CL1. Associations between lithium treatment, cardiac structure and function and peripheral CX3CL1 were analyzed according to the cardiovascular risk. The high cardiovascular risk was defined as (1) age ⩾ 45 years in men or ⩾ 55 years in women or (2) presence of concurrent cardiometabolic diseases. RESULTS: In the high cardiovascular risk group (n = 61), patients who received lithium as the maintenance treatment had significantly lower mean values of left ventricular internal diameters at end-diastole (Cohen's d = 0.65, p = 0.001) and end-systole (Cohen's d = 0.60, p = 0.004), higher mean values of mitral valve E/A ratio (Cohen's d = 0.51, p = 0.019) and superior performance of global longitudinal strain (Cohen's d = 0.51, p = 0.037) than those without lithium treatment. In addition, mean plasma levels of CX3CL1 in the high cardiovascular risk group were significantly lower among patients with lithium therapy compared with those without lithium treatment (p = 0.029). Multiple regression models showed that the association between lithium treatment and mitral value E/A ratio was contributed by CX3CL1. CONCLUSION: Data from this largest sample size study of the association between lithium treatment and echocardiographic measures suggest that lithium may protect cardiac structure and function in patients with bipolar disorder. Reduction of CX3CL1 may mediate the cardioprotective effects of lithium.

Imipramine Can Be Effective on Depressive-Like Behaviors, but Not on Neurotrophic Factor Levels in an Animal Model for Bipolar Disorder Induced by Ouabain.

INTRODUCTION: Despite possible risks of mania switching with the long-term use of antidepressants in patients with bipolar disorder (BD), these drugs may help in depressive episodes. Alterations in neurotrophic factor levels seem to be involved in the pathophysiology of BD. The present study aimed to evaluate the effect of acute treatment of imipramine on behavior and neurotrophic levels in rats submitted to the animal model for BD induced by ouabain. METHODS: Wistar rats received a single intracerebroventricular (ICV) injection of artificial cerebrospinal fluid or ouabain (10-3 M). Following the ICV administration, the rats were treated for 14 days with saline (NaCl 0.9%, i.p.), lithium (47.5 mg/kg, i.p.), or valproate (200 mg/kg, i.p.). On the 13th and 14th days of treatment, the animals received an additional injection of saline or imipramine (10 mg/kg, i.p.). Behavior tests were evaluated 7 and 14 days after ICV injection. Adrenal gland weight and concentrations of ACTH were evaluated. Levels of neurotrophins BDNF, NGF, NT-3, and GDNF were measured in the frontal cortex and hippocampus by ELISA test. RESULTS: The administration of ouabain induced mania- and depressive-like behavior in the animals 7 and 14 days after ICV, respectively. The treatment with lithium and valproate reversed the mania-like behavior. All treatments were able to reverse most of the depressive-like behaviors induced by ouabain. Moreover, ouabain increased HPA-axis parameters in serum and decreased the neurotrophin levels in the frontal cortex and hippocampus. All treatments, except imipramine, reversed these alterations. CONCLUSION: It can be suggested that acute administration of imipramine alone can be effective on depressive-like symptoms but not on neurotrophic factor alterations present in BD.

Bipolar disorder, mood stabilizers and cognitive flexibility: Translationally dissecting illness from drug effects.

Bipolar disorder (BD) effects on cognition are confounded by the putative cognitive impact of its major pharmacological treatments, given the neurotrophic potential of mood stabilizers, particularly lithium. We examined the area of cognitive flexibility (CF), aiming to disentangle BD from medication effects, using translational methodology. CF was assessed by CANTAB-IED (intra- extra-dimensional shift; Study 1, euthymic BD participants) and its animal analog (Study 2, rats). Both studies included groups (1) control, (2) lithium, chronic, current treatment (LI-CHRON-C, A: > 2 years, N = 32; B: 2 months, N = 11); (3) valproate, chronic, current treatment (VPA-CHRON-C, A: > 2 years, N = 30; B: 2 months, N = 12). Study 2 included 2 additional groups; Group 4: LI-CHRON-PAST (2 months, stopped 1 month pretest, N = 13); Group 5: LI-ACUTE (LI on test days only, N = 13). In Study 1, neither total nor stage (discrimination: D; reversal R; intra- extra-dimensional shifts: IED) IED errors differed between groups [Kruskal-Wallis: H(2, N = 94) 0.95 > p > 0.65]. Similarly in Study 2, errors did not differentiate the 5 pharmacological groups. Differences emerged only between LI-ACUTE and Controls in response latencies (D, R, IED ANOVAS: 0.002 > p > 0.0003; contrasts D, R: p = 0.002, 0.0001). In conclusion, LI and VPA BD patients were indistinguishable from Controls in IED errors, as were animals treated with LI-CHRON, current or past, or VPA-CHRON-C vs Controls. LI-ACUTE treatment produced significant latency deficits vs Controls. Within the limitations of translational comparisons, our results suggest that the normal CF noted in euthymic BDs is not attributable to mood stabilizer effects.

Measuring mania-like elevated mood through amphetamine-induced 50-kHz ultrasonic vocalizations in rats.

Rats emit 50-kHz ultrasonic vocalizations (USV) in appetitive situations, reflecting a positive affective state. Particularly high rates of 50-kHz USV are elicited by the psychostimulant d-amphetamine. Exaggerated 50-kHz USV emission evoked by d-amphetamine is modulated by dopamine, noradrenaline and 5-hydroxytyrptamine receptor ligands and inhibited by the mood stabilizer lithium, the gold standard anti-manic drug for treating bipolar disorder. This indicates that exaggerated 50-kHz USV emission can serve as a reliable and valid measure for assessing mania-like elevated mood in rats with sufficient translational power for gaining a better understanding of relevant pathophysiological mechanisms and the identification of new therapeutic targets. The improved capacity to study the effects of anti-manic pharmacological interventions on a broader range of behaviours by including exaggerated 50-kHz USV emission as preclinical outcome measure complementary to locomotor hyperactivity will refine rodent models for mania. LINKED ARTICLES: This article is part of a themed issue on New discoveries and perspectives in mental and pain disorders. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.17/issuetoc.

Lithium Treatment in the Prevention of Repeat Suicide-Related Outcomes in Veterans With Major Depression or Bipolar Disorder: A Randomized Clinical Trial.

Importance: Suicide and suicide attempts are persistent and increasing public health problems. Observational studies and meta-analyses of randomized clinical trials have suggested that lithium may prevent suicide in patients with bipolar disorder or depression. Objective: To assess whether lithium augmentation of usual care reduces the rate of repeated episodes of suicide-related events (repeated suicide attempts, interrupted attempts, hospitalizations to prevent suicide, and deaths from suicide) in participants with bipolar disorder or depression who have survived a recent event. Design, Setting, and Participants: This double-blind, placebo-controlled randomized clinical trial assessed lithium vs placebo augmentation of usual care in veterans with bipolar disorder or depression who had survived a recent suicide-related event. Veterans at 29 VA medical centers who had an episode of suicidal behavior or an inpatient admission to prevent suicide within 6 months were screened between July 1, 2015, and March 31, 2019. Interventions: Participants were randomized to receive extended-release lithium carbonate beginning at 600 mg/d or placebo. Main Outcomes and Measures: Time to the first repeated suicide-related event, including suicide attempts, interrupted attempts, hospitalizations specifically to prevent suicide, and deaths from suicide. Results: The trial was stopped for futility after 519 veterans (mean [SD] age, 42.8 [12.4] years; 437 [84.2%] male) were randomized: 255 to lithium and 264 to placebo. Mean lithium concentrations at 3 months were 0.54 mEq/L for patients with bipolar disorder and 0.46 mEq/L for patients with major depressive disorder. No overall difference in repeated suicide-related events between treatments was found (hazard ratio, 1.10; 95% CI, 0.77-1.55). No unanticipated safety concerns were observed. A total of 127 participants (24.5%) had suicide-related outcomes: 65 in the lithium group and 62 in the placebo group. One death occurred in the lithium group and 3 in the placebo group. Conclusions and Relevance: In this randomized clinical trial, the addition of lithium to usual Veterans Affairs mental health care did not reduce the incidence of suicide-related events in veterans with major depression or bipolar disorders who experienced a recent suicide event. Therefore, simply adding lithium to existing medication regimens is unlikely to be effective for preventing a broad range of suicide-related events in patients who are actively being treated for mood disorders and substantial comorbidities. Trial Registration: ClinicalTrials.gov Identifier: NCT01928446.

Effect of repeated sodium valproate and topiramate administration on mania­like behaviors induced by methylphenidate in mice.

Novel and effective treatments for mania are needed, and well­validated animal models are important to reach this goal. The psychostimulant­induced hyperactivity is the most frequently animal model of mania used. Although this model is validated pharmacologically using mood stabilizers, data about its predictive validity with negative controls (i.e., drugs that are clinically ineffective in treating mania) are lacking. The present study evaluated the effects of the repeated administration of a clinically effective drug (sodium valproate) and clinically ineffective drug (topiramate) on methylphenidate (MPH)­induced manic­like behaviors in Swiss mice in the behavioral pattern monitor (BPM). Methylphenidate increased locomotor activity and center activity in the BPM. Valproate attenuated the effect of MPH on locomotor and general activity, with no effect on center activity. Topiramate did not affect any MPH­induced manic­like behaviors. Methylphenidate did not change exploratory activity (rearing or nose poking). These results support the predictive validity of MPH­induced hyperactivity for screening antimanic­like drugs.