Human brain 7Li-MRI following low-dose lithium dietary supplementation in healthy participants.

BACKGROUND: Lithium is an effective mood stabiliser, but its mechanism of action is incompletely defined. Even at very low doses, lithium may have neuroprotective effects, but it is not clear if these relate to brain lithium concentration in vivo. We have developed magnetic resonance imaging (7Li-MRI) methods to detect lithium in the brain following supplementation at a very low dose. METHODS: Lithium orotate supplements were taken by nine healthy adult male subjects (5 mg daily) for up to 28 days, providing 2-7 % of the lithium content of a typical therapeutic lithium carbonate dose. One-dimensional 7Li-images were acquired on a 3.0 T MRI scanner. All subjects were scanned on day 14 or 28; seven were scanned on both, one at baseline and one after 7-days washout. RESULTS: 7Li-MR signal amplitude was broadly stable between days 14 and 28. Two subjects had notably higher 7Li-signal intensities (approximately 2-4×) compared to other study participants. LIMITATIONS: Lithium adherence was self-reported by all participants without formal validation. The coarse spatial resolution necessary for detection of low concentrations of 7Li exhibits imperfect spatial separation of signal from adjacent pixels. CONCLUSIONS: 7Li-MRI performed using a clinical 3T scanner demonstrated detection of lithium in the brain at very low concentration, in the range of approximately 10-60 mM. The methods are suited to studies assessing low dose lithium administration in psychiatric and neurodegenerative disorders, and permit the comparison of different lithium salt preparations at a time of emerging interest in the field.

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.

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.

New pharmacotherapies to tackle the unmet needs in bipolar disorder: a focus on acute suicidality.

INTRODUCTION: Suicidal behavior is relatively frequent in patients with bipolar disorder (BD) and constitutes their most frequent cause of death. Suicide rates remain high in patients with BD despite adherence to guidelines recommending lithium as first line, and/or antidepressants, antipsychotics, psychotherapy, psychosocial interventions, and electroconvulsive therapy. Hence the need to identify more effective and rapid anti-suicide interventions. AREAS COVERED: To tackle the unmet needs of pharmacotherapy, we investigated the PubMed database on 24-25 January 2024 using strategies like ('acute suicid*'[ti] OR 'suicide crisis syndrome' OR 'acute suicidal affective disturbance') AND (lithium[ti] OR clozapine[ti]), which obtained 3 results, and ('acute suicid*'[ti] OR 'suicide crisis syndrome' OR 'acute suicidal affective disturbance') AND (ketamine[ti] OR esketamine[ti] OR NMDA[ti] OR glutamat*[ti]), which yielded 14 results. We explored glutamatergic abnormalities in BD and suicide and found alterations in both. The noncompetitive NMDS antagonist ketamine and its S-enantiomer esketamine reportedly decrease acute suicidality. EXPERT OPINION: Intranasal esketamine or subcutaneous ketamine, single-bolus or intravenous, and possibly other glutamate receptor modulators may improve suicidal behavior in patients with unipolar and bipolar depression. This may be achieved through prompt remodulation of glutamate activity. The correct use of glutamatergic modulators could reduce acute suicidality and mortality in patients with BD.

Lithium administered to pregnant, lactating and neonatal rats: entry into developing brain.

BACKGROUND: Little is known about the extent of drug entry into developing brain, when administered to pregnant and lactating women. Lithium is commonly prescribed for bipolar disorder. Here we studied transfer of lithium given to dams, into blood, brain and cerebrospinal fluid (CSF) in embryonic and postnatal animals as well as adults. METHODS: Lithium chloride in a clinically relevant dose (3.2 mg/kg body weight) was injected intraperitoneally into pregnant (E15-18) and lactating dams (birth-P16/17) or directly into postnatal pups (P0-P16/17). Acute treatment involved a single injection; long-term treatment involved twice daily injections for the duration of the experiment. Following terminal anaesthesia blood plasma, CSF and brains were collected. Lithium levels and brain distribution were measured using Laser Ablation Inductively Coupled Plasma-Mass Spectrometry and total lithium levels were confirmed by Inductively Coupled Plasma-Mass Spectrometry. RESULTS: Lithium was detected in blood, CSF and brain of all fetal and postnatal pups following lithium treatment of dams. Its concentration in pups' blood was consistently below that in maternal blood (30-35%) indicating significant protection by the placenta and breast tissue. However, much of the lithium that reached the fetus entered its brain. Levels of lithium in plasma fluctuated in different treatment groups but its concentration in CSF was stable at all ages, in agreement with known stable levels of endogenous ions in CSF. There was no significant increase of lithium transfer into CSF following application of Na+/K+ ATPase inhibitor (digoxin) in vivo, indicating that lithium transfer across choroid plexus epithelium is not likely to be via the Na+/K+ ATPase mechanism, at least early in development. Comparison with passive permeability markers suggested that in acute experiments lithium permeability was less than expected for diffusion but similar in long-term experiments at P2. CONCLUSIONS: Information obtained on the distribution of lithium in developing brain provides a basis for studying possible deleterious effects on brain development and behaviour in offspring of mothers undergoing lithium therapy.

Combined treatment of myo-inositol and d-chiro-inositol (80:1) as a therapeutic approach to restore inositol eumetabolism in patients with bipolar disorder taking lithium and valproic acid.

OBJECTIVE: Patients with bipolar disorder (BD) experience a poor quality of life (QoL) and a weak adherence to the therapy due to the various side effects occurring during the pharmacological therapy. To date clinicians have no tools to intervene on such effects, considering them as an unavoidable part of the therapy. This review paves the way for a step forward in the management of patients with BD bridging the therapeutic gap in clinical practice. MATERIALS AND METHODS: We reviewed the literature, searching through different databases (MEDLINE, Scopus, Google Scholar). We used different keywords, including bipolar disorder, lithium and valproic acid, inositol role in bipolar disorder, side effects, inositol depletion, supplementation of inositols under lithium treatment, inositol role in metabolism, hypothyroidism, renal and cardiac functionality. In particular, we narrowed the search down to English literature, excluding works before 1980s. Regarding clinical studies, we included case reports and both preclinical and clinical studies, especially only those exhibiting a control group. The outcome of the database search was to highlight the threat of side effects and the relationship with inositol lower levels, paving the way for a step forward in the management of patients with BD. RESULTS: Based on the collected evidence, the combined administration of myo-inositol (myo-ins) and d-chiro-inositol (d-chiro-ins) is strongly recommended in order to restore levels and metabolism of inositols. Previous studies pointed out the beneficial effects of inositols in recovering pathological conditions, like polycystic ovary syndrome (PCOS), hypothyroidism, weight gain, cardiac functionality, being all these conditions related to the depletion of inositols. Furthermore, a controlled dosage of inositols, up to 6 grams/daily, may reduce the side effects caused by lithium therapy, without hindering its central therapeutic role on patients' mood. CONCLUSIONS: Considering the iatrogenic depletion of inositols, the tailored ratio 80:1 in favour of myo-ins, may become a safe and effective strategy to counteract side effects, by providing a large amount of myo-ins and an adequate one of d-chiro-ins. The clinical dosage of inositols used as dietary supplementation is 4 grams/daily, and it may allow the recovery of the side effects and improve patients' QoL, without reducing the central therapeutic effect of the pharmacological therapy.

Lithium carbonate: Updated reproductive and developmental toxicity assessment using scientific literature and guideline compliant studies.

The current publication describes most recent so far unpublished (key) guideline and GLP compliant reproductive and developmental toxicity studies of lithium carbonate in rats, including their interpretation and conclusions in terms of human hazard assessment when compared to existing literature. Particular attention was paid to the target organs and dose response of lithium ion related effects to differentiate between a primary (pharmacokinetic/pharmacodynamic) action and secondary effects as a result of systemic and target organ toxicity. In the key two-generation reproduction toxicity (OECD TG 416) study in rats, doses of 5, 15 and 45 mg/kg bw/d (0.95, 2.9 and 8.6 mg Li+/kg bw/d) were given by oral gavage, resulting in clear NOAELs of 15 mg/kg bw/d (2.9 mg Li+/kg bw/d) for systemic parental toxicity and 45 mg/kg bw/d (8.6 mg Li+/kg bw/d) for reproductive toxicity and fetal toxicity. Target organ changes were consistently observed in liver (cytoplasmic rarefaction) and kidney (dilated tubuli). In the key developmental toxicity (OECD TG 414) study in rats, doses given by oral gavage were 10, 30 and 90 mg/kg bw/d (1.9, 5.7 and 17.1 mg Li+/kg bw/d) was investigated resulting in NO(A)ELs of 30 mg/kg bw/d (5.7 mg Li+/kg bw/d) (maternal toxicity) and 90 mg/kg bw/d (17 mg Li+/kg bw/d) (fetal toxicity and teratogenicity). The highest dose of 90 mg/kg bw/day resulted in clear signs of toxicity and peak plasma concentrations at the toxic range (>1.0 mEq lithium/L). Toxic effects of lithium carbonate were not seen in the reproductive and developmental organs. No adverse effects on sperm (total motility, progressive motility and morphology of testicular and cauda epididymal sperm) were observed in the two-generation rat reproduction toxicity study. There was also no impact on fertility indices or on litter sizes in this study, nor were there any fetal effects in the two-generation reproduction toxicity and developmental toxicity study at doses causing already systemic toxicity in the dams. Secondary effects such as decreased weight (gain) and food consumption were reported in the developmental toxicity study. The absence of any reproductive/developmental findings at dose levels causing clear systemic toxicity in the test animals in these key mammalian studies, does not suggest an immediate concern for possible human reproductive or developmental toxicity effects from exposure to lithium during drug use.

Association study of BDNF Val66Met gene polymorphism with bipolar disorder and lithium treatment response in Indian population.

BACKGROUND: The association of the Val66Met (rs6265) polymorphism in the brain-derived neurotrophic factor (BDNF) gene with bipolar disorder (BD) and response to lithium treatment has been suggested, though inconsistently. The considerable diversity of allele frequency across different populations contributes to this. There is no data from South Asia till date. Hence, we examined the association of this polymorphism in BD cases from India, and its association with lithium treatment response. METHODS: BD patients (N = 301) were recruited from the clinical services of National Institute of Mental Health and Neurosciences (NIMHANS), India. Lithium treatment response for 190 BD subjects was assessed using Alda scale by NIMH life charts. Patients with total score ⩾7 were defined as lithium responders (N = 115) and patients with score <7 were defined as lithium non-responders (N = 75). Healthy controls (N = 484) with no lifetime history of neuropsychiatric illness or a family history of mental illness were recruited as control set. Genotyping was performed by TaqMan genotyping assay. RESULTS: Genotype and allele frequency of BDNF Val66Met SNP was significantly different (χ2 = 7.78, p = 0.02) in cases compared to controls, and the Val(G) allele was more frequent (χ2 = 7.08, p = 0.008) in BD patients. However, no significant difference is noted in genotype or allele frequencies of this polymorphism between the lithium responders and non-responders. CONCLUSIONS: The Val(G) allele of BDNF Val66Met polymorphism is associated with risk of BD in this sample, but it is not related to response to lithium.

A Single-Blind Randomized Comparison of Lithium and Lamotrigine as Maintenance Treatments for Managing Bipolar II Disorder.

PURPOSE/BACKGROUND: No study to date has compared lithium and lamotrigine as maintenance mood stabilizers for bipolar II disorder. The aim of this study was to evaluate and compare these two medications in terms of their maintenance efficacy and side effect profile, thus evaluating their comparative cost/benefit profile. METHODS/PROCEDURES: Forty-four subjects with a newly diagnosed bipolar II disorder were randomly assigned to receive either lithium or lamotrigine treatment in a 20-week single-blinded study. Subjects received either slow-release lithium progressively up-titrated to achieve a serum level of 0.8 mEq/L, or lamotrigine increased progressively to a maintenance dose of 200 mg/d. Our primary outcome measure examined daily data on hypomanic and depressive symptoms. Secondary measures evaluated hypomanic and depressive symptom severity, global functioning, and global improvement in hypomanic and depressive symptoms. FINDINGS/RESULTS: We terminated the trial principally because of severe ongoing side effects experienced by many of those receiving lithium, and with additional concerns about initial severe side effects (including psychosis) experienced by several assigned to lamotrigine. Analyses of study completer data for 28 participants suggested comparable efficacy of both medications; however, lamotrigine had a distinctly lower rate of severe side effects across the study. We calculated that if study trends on outcome measures were valid, then an extremely large sample would be required to demonstrate superiority of either drug, thus making it unlikely that any such adequately powered study will be mounted in the future. IMPLICATIONS/CONCLUSIONS: The small sample size limits any definitive conclusions, but our data suggest that lithium and lamotrigine are likely to have equal efficacy as mood stabilizers for those with a bipolar II condition but that, as maintenance treatments, lithium has more distinctive side effects.

A reappraisal of the role of fever in the occurrence of neurological sequelae following lithium intoxication: a systematic review.

INTRODUCTION: We aimed to review cases of Syndrome of Irreversible Lithium-Effectuated Neurotoxicity (SILENT) characterized by neurological sequelae following acute lithium toxicity and to explore whether cerebellar sequelae are more frequent in cases presenting with fever and/or infection. AREAS COVERED: Case reports were identified from: (i) 6 reviews published up to 2005; (ii) MEDLINE, Web of Sciences, Cochrane Library and PsycINFO search. EXPERT OPINION: We identified 123 SILENT cases published from 1965 to 2019, in which cerebellar sequelae were observed in an overwhelming proportion (79%). SILENT may occur at any time during lithium treatment. This complication is most frequently observed during routine lithium treatment, with fewer than 10% of cases occurring after accidental or intentional overdoses. SILENT may occur even when lithium plasma levels are within the therapeutic range: 63% of cases had lithium plasma level <2.5 mEq/l (low/mild toxicity). Fever and/or infection were reported in nearly half of the patients (48%). The likelihood of presenting with cerebellar vs. other neurological sequelae was independently increased by elevated plasma lithium level (≥ 2.5 mEq/l) and by a history of fever and/or infection. Lithium users should be warned of the need to consult in case of fever to adjust their lithium dosage.

High dose lithium chloride causes colitis through activating F4/80 positive macrophages and inhibiting expression of Pigr and Claudin-15 in the colon of mice.

OBJECTIVE: Lithium chloride (LiCl) was a mood stabilizer for bipolar affective disorders and it could activate Wnt/ß-catenin signaling pathway both in vivo and in vitro. Colon is one of a very susceptible tissues to Wnt signaling pathway, and so it would be very essential to explore the toxic effect of a high dose of LiCl on colon. METHODS: C57BL/6 mice were injected intraperitoneally with 200 mg/kg LiCl one dose a day for 5 days to activate Wnt signal pathway in intestines. H&E staining was used to assess the colonic tissues of mice treated with high dose of LiCl. The expression of inflammation-associated genes and tight junction-associated genes in colons was measured using qPCR, Western blot and immunostaining methods. The gut microbiome was tested through 16S rDNA gene analysis. RESULTS: The differentiation of enteroendocrine cells in colon was inhibited by treatment of 200 mg/kg LiCl. The F4/80 positive macrophages in colon were activated by high dose of LiCl, and migrated from the submucosa to the lamina propria. The expression of pro-inflammatory genes TNFα and IL-1ß was increased in the colon of high dose of LiCl treated mice. Clostridium_sp_k4410MGS_306 and Prevotellaceae_UCG_001 were specific and predominant for the high dose of LiCl treated mice. The expression of IgA coding genes, Pigr and Claudin-15 was significantly decreased in the colon tissues of the high dose of LiCl treated mice. CONCLUSION: 200 mg/kg LiCl might cause the inflammation in colon of mice through activating F4/80 positive macrophages and inhibiting the expression of IgA coding genes in plasma cells and the expression of Pigr and Claudin-15 in colonic epithelial cells, providing evidences for the toxic effects of high dose of LiCl on colon.

Chronic lithium exposure attenuates ketamine-induced mania-like behavior and c-Fos expression in the forebrain of mice.

Ketamine, a dissociative anaesthetic, has been used in the treatment of major depressive disorder (MDD) as a rapid acting antidepressant drug. Recent studies have shown that ketamine may increase the potential risk of treatment-induced mania in MDD patients. Lithium is a well-known mood stabilizer and has been widely used for the treatment of mania. It is not fully understood which forebrain regions are involved in ketamine- and lithium-induced expression of c-Fos. Therefore, our aim was to investigate the effect of chronic lithium treatment on mania-like behavior and c-Fos expression in the mouse forebrain activated by a single administration of ketamine. In the open field test, our results showed that ketamine significantly increased the total distance and total cumulative duration of movement in mice, while chronic lithium could attenuate these effects of ketamine. In addition, acute ketamine induced higher c-Fos expression in the lateral septal nucleus, hypothalamus, amygdala, and hippocampus of mice in the treatment group compared to those in the control group. However, chronic lithium inhibited the significant increase in c-Fos-immunoreactive neurons following acute ketamine administration in the dentate gyrus of the hippocampus, field CA1 of the hippocampus, dorsal subiculum, ventral subiculum, ventral subiculum, central amygdaloid nucleus and basolateral amygdaloid nucleus. In summary, our research shows that pretreatment with lithium moderates the effects of acute ketamine administration on mania-like behavior and c-Fos expression in the forebrain. These findings could be helpful in better understanding the episodes of mania related to ketamine treatment for MDD and bipolar disorder.

Tissue-specific protective properties of lithium: comparison of rat kidney, erythrocytes and brain.

Lithium (Li) represents a first choice mood stabilizer for bipolar disorder (BD). Despite extensive clinical use, questions regarding its mechanism of action and pathological mechanism of renal function impairment by Li remain open. The present study aimed to improve our knowledge in this area paying special attention to the relationship between the length of Li action, lipid peroxidation (LP), and Na+/K+-ATPase properties. The effects of therapeutic Li doses, administered daily to male Wistar rats for 1 (acute), 7 (short term) and 28 days (chronic), were studied. For this purpose, Na+/K+-ATPase activity measurements, [3H]ouabain binding and immunoblot analysis of α-Na+/K+-ATPase were performed. Li-induced LP was evaluated by determining the malondialdehyde concentration by HPLC. Sleep deprivation (SD) was used as an experimental approach to model the manic phase of BD. Results obtained from the kidney were compared to those obtained from erythrocytes and different brain regions in the same tested animals. Whereas treatment with therapeutic Li concentration did not bring any LP damage nor significant changes of Na+/K+-ATPase expression and [3H]ouabain binding in the kidney, it conferred strong protection against this type of damage in the forebrain cortex. Importantly, the observed changes in erythrocytes indicated changes in forebrain cortices. Thus, different resistance to SD-induced changes of LP and Na+/K+-ATPase was detected in the kidney, erythrocytes and the brain of Li-treated rats. Our study revealed the tissue-specific protective properties of Li against LP and Na+/K+-ATPase regulation.

Neuroprotective Effect of Intravitreal Single-Dose Lithium Chloride after Optic Nerve Injury in Rats.

OBJECTIVE: Lithium is an old drug to control bipolar disorder. Moreover, it presents neuroprotective effects and supports neuronal plasticity. The aim of this study was to evaluate neuroprotective effect of intravitreal lithium after optic nerve injury. METHODS: Three dosages of lithium chloride, including 2 pmol, 200 pmol, and 2 nmol, were injected intravitreally after rat optic nerve injury. Proteins expression were assessed by western blot. Nitric oxide (NO) metabolites were measured by Griess test. Visual evoked potential (VEP) and optical coherence tomography (OCT) measurement were performed after trauma induction, in addition to H & E and TUJ1 staining of ganglion cells. RESULTS: Western blot depicted lithium can significantly increase antiapoptotic Bcl-2 protein level and reduce p-ERK, Toll-like receptor 4 (TLR4) and proapoptotic proteins such as Bax level in retinal tissue and Griess test reflected that NO metabolites level decreased in lithium treated eyes (P < .05). While, OCT showed no significant changes (P = .36 and P = .43 comparing treated group with trauma) in retinal ganglion cell layer thickness after lithium injection, VEP P2 wave amplitude increased significantly (P < .01) in lithium-treated eyes and its latency reduced (P < .05 for N1 wave and P < .01 for P2 wave). Tuj1 antibody-labeled retinal ganglion cells analyzing showed that the number of retinal ganglion cells were significantly higher in lithium treated eyes compared to untreated eyes with optic nerve injury. CONCLUSION: It seems intravitreally lithium has optic nerve neuroprotective effects by various mechanisms like overexpression of antiapoptotic proteins, suppressing proinflammatory molecules and proapoptotic factors, and decreasing nitric oxide.

Psychotic disorders and electrocardiogram abnormalities in the acute psychiatric setting: more than the metabolic syndrome alone.

Medical comorbidity in severe mental illness (SMI) is high and often severe, accounting for reduced life expectancy in this group. We assessed the rate and degree of electrocardiogram (ECG) abnormalities in acutely unwell SMI male patients by reviewing the case notes of 50 consecutive admissions to an inpatient psychiatric unit. 82% were admitted with a psychotic disorder with a median age of 35 (range 19 - 72 years). Of the 29 patients who had an ECG during admission or recently (<90 days) prior to admission, 21% had a clinically relevant abnormality. 42% of patients did not have an ECG during admission or recently. Results indicate that SMI patients requiring acute care, in addition to metabolic disorders, may also have significant ECG abnormalities from a young age. Comprehensive medical monitoring, including regular ECGs and use of preventive strategies, should be an integral part of management of SMI from the outset.KEY POINTSThis small study found that out of 50 patients admitted to an acute psychiatric unit, 29 (58%) had a recent (<90 days) electrocardiogram (ECG); 6 of them (21%) had clinically relevant ECG abnormalities.ECG abnormalities were found in 24% (n = 10) of patients who had at least 1 documented ECG ever performed (n = 41, 82%).42% of patients did not have an ECG performed in the 90 days prior to or during admission.Results indicate that patients with Severe Mental Illness (SMI) requiring acute care are at risk of metabolic disorders and ECG abnormalities from a young age.Comprehensive medical monitoring including regular ECGs and early preventive strategies should be part of SMI patients' management plans from the outset. Larger scale studies are needed to assess the impact of early intervention on cardiovascular risk in SMI.

Novel therapeutic targets in mood disorders: Pentoxifylline (PTX) as a candidate treatment.

Numerous pharmacological treatments for mood disorders are currently available; however, rates of treatment resistance, relapse and recurrence remain high. Therefore, novel treatments acting outside of the conventionally targeted monoamine system are urgently needed to improve patient outcomes. Emerging and converging evidence suggests that immune dysfunction, oxidative stress, impaired cerebral blood flow (CBF) and decreased neurotrophic factors all contribute to mood disorder pathophysiology and are therefore treatment targets of interest. Pentoxifylline (PTX) is a phosphodiesterase inhibitor with potent anti-inflammatory and antioxidant effects, with additional pleiotropic effects that lead to improved CBF and increases in brain derived neurotrophic factor (BDNF) levels. The direct effect of non-specific phosphodiesterase inhibition may also improve alertness and cognitive function through enhancing second messenger systems. Replicated preclinical studies have demonstrated antidepressant-like effects in animal models. Small preliminary clinical trials have demonstrated promising results for antidepressant and procognitive effects, however, have yet to be replicated in larger mood disorder samples. Only one randomized clinical trial (RCT) specifically assessed the effects of adjunctive PTX in major depressive disorder (MDD), showing clinically and statistically significant antidepressant effects compared to placebo. No studies have assessed PTX in bipolar disorder (BD), where inflammation and altered CBF have also been strongly implicated. Taken together, PTX presents as a promising pleiotropic agent with several potential novel mechanisms of action meriting further evaluation in clinical trials to evaluate target engagement, antidepressant, procognitive and mood stabilizing effects.

A phase 2a randomised, double-blind, placebo-controlled, parallel-group, add-on clinical trial of ebselen (SPI-1005) as a novel treatment for mania or hypomania.

RATIONALE: Lithium is an effective prophylactic and anti-manic treatment in bipolar disorder; however, its use is declining through perceived poor tolerance and toxicity. Lithium inhibits inositol monophosphatase (IMPase), a probable key therapeutic mechanism. The anti-inflammatory drug, ebselen, also inhibits IMPase and appears well-tolerated and safe. OBJECTIVES: To assess the efficacy of adjunctive ebselen in mania using the Young Mania Rating Scale (YMRS) (primary outcome) and the Altman Self-Rating Mania (ASRM) Scale and Clinical Global Impression-Severity Scale (CGI-S) among the secondary outcomes. METHODS: Randomised, double-blind, placebo-controlled, parallel-group trial conducted between October 2017 and June 2019, at Oxford Health NHS Foundation Trust. Pharmacy-controlled randomisation was computer-generated, with full allocation concealment. In/outpatients (n = 68) aged 18-70, experiencing mania or hypomania, were assigned to 3 weeks ebselen (600 mg bd) (n = 33) or placebo (n = 35). Participants received usual clinical care and psychotropic medication. RESULTS: Ebselen was numerically, but not statistically, superior to placebo in lowering scores on the YMRS (adjusted mean difference and 95% confidence interval, - 1.71 (- 5.34 to 1.91), p = 0.35) and ASRM (- 1.36 (- 3.75 to 1.17), p = 0.29). However, scores on the CGI-S were significantly lower at week 3 in ebselen-treated participants (adjusted mean difference, - 0.58 (- 1.14 to - 0.03), p = 0.04). A post hoc analysis excluding patients taking concomitant valproate treatment magnified the difference between ebselen and placebo on the YMRS. Adverse events were comparable between groups, and mild. CONCLUSIONS: Ebselen merits further investigation where concomitant psychotropic medication is better controlled and participants taking valproate are excluded. If effective, ebselen's superior tolerance and safety could make it a useful alternative to lithium. TRIAL REGISTRATION: Trial Registry: www.clinicaltrials.gov , Identifier: NCT03013400.

The 'collateral side' of mood stabilizers: safety and evidence-based strategies for managing side effects.

INTRODUCTION: Adverse events (AEs) monitoring of mood stabilizers (MS) is essential during the treatment of mood disorders as safety and tolerability profiles of MS may greatly influence treatment adherence, patient's compliance, and discontinuation rate. Therefore, clinicians should be aware of their AEs profile and tapering a variety of strategies to manage them, according to an evidence-based approach. AREAS COVERED: We aimed at critically summarizing the tolerability and safety profile for each nonantipsychotic MS, providing evidence-based strategies able to manage these AEs, in order to increase clinically useful strategies which may allow clinicians enhancing adherence and therapeutic compliance, the impact on quality of life and treatment efficacy in psychiatric conditions. EXPERT OPINION: The management of the safety and tolerability profile of each MS comprises an initial assessment of the symptoms/signs to be observed/measured during the therapy, including a psychoeducational activity, a periodical monitoring with a specific timing depending on clinical parameters and each prescribed MS, but also an evaluation if a treatment modification (in terms of dose adjustment, discontinuation or additional medication to be prescribed) is required as well as which combination therapy is allowed and which caution should be posed by clinicians in some special conditions, including pregnancy and breastfeeding.