Akt and AMPK activators rescue hyperexcitability in neurons from patients with bipolar disorder.

BACKGROUND: Bipolar disorder (BD) is a multifactorial psychiatric illness affecting ∼1% of the global adult population. Lithium (Li), is the most effective mood stabilizer for BD but works only for a subset of patients and its mechanism of action remains largely elusive. METHODS: In the present study, we used iPSC-derived neurons from patients with BD who are responsive (LR) or not (LNR) to lithium. Combined electrophysiology, calcium imaging, biochemistry, transcriptomics, and phosphoproteomics were employed to provide mechanistic insights into neuronal hyperactivity in BD, investigate Li's mode of action, and identify alternative treatment strategies. FINDINGS: We show a selective rescue of the neuronal hyperactivity phenotype by Li in LR neurons, correlated with changes to Na+ conductance. Whole transcriptome sequencing in BD neurons revealed altered gene expression pathways related to glutamate transmission, alterations in cell signalling and ion transport/channel activity. We found altered Akt signalling as a potential therapeutic effect of Li in LR neurons from patients with BD, and that Akt activation mimics Li effect in LR neurons. Furthermore, the increased neural network activity observed in both LR & LNR neurons from patients with BD were reversed by AMP-activated protein kinase (AMPK) activation. INTERPRETATION: These results suggest potential for new treatment strategies in BD, such as Akt activators in LR cases, and the use of AMPK activators for LNR patients with BD. FUNDING: Supported by funding from ERA PerMed, Bell Brain Canada Mental Research Program and Brain & Behavior Research Foundation.

Fourteen-year trends in prescribing patterns for patients with bipolar mania discharged from a public psychiatric hospital in Taiwan.

Bipolar disorder is a complex mental illness. Pharmacological therapy, including antipsychotics and mood stabilizers, is the primary treatment approach for manic episode. The study aimed to analyze prescribing patterns over a 14-year period for patients with bipolar mania discharged from a psychiatric hospital in Taiwan. Patients with bipolar mania discharged from the study hospital between 2006 and 2019 (n = 2956) were included in the analysis. Prescribed drugs for the treatment of manic episode, included mood stabilizers (i.e., lithium, valproate, carbamazepine) and any antipsychotics (i.e., second- and first-generation antipsychotics; SGAs & FGAs). Monotherapy, simple polypharmacy, and complex polypharmacy were also examined. Simple polypharmacy was defined as being prescribed 2 different bipolar drugs (lithium, valproate, carbamazepine, and any antipsychotics), while complex polypharmacy at least 3 bipolar drugs. Temporal trends of each prescribing pattern were analyzed using the Cochran-Armitage Trend test. The prescription rates of valproate, SGAs, and complex polypharmacy significantly increased over time, whereas the prescription rates of any mood stabilizers, FGAs, and simple polypharmacy significantly decreased. Prescription rates of lithium and monotherapy did not significantly change. The study highlights the shifts in prescribing practices for bipolar mania. SGAs were prescribed more while FGAs declined, likely due to SGAs' favorable properties. Complex polypharmacy increased, reflecting the complexity of treating bipolar disorder. Long-term outcomes of these changes require further research.

Lithium response in bipolar disorder is associated with focal adhesion and PI3K-Akt networks: a multi-omics replication study.

Lithium is the gold standard treatment for bipolar disorder (BD). However, its mechanism of action is incompletely understood, and prediction of treatment outcomes is limited. In our previous multi-omics study of the Pharmacogenomics of Bipolar Disorder (PGBD) sample combining transcriptomic and genomic data, we found that focal adhesion, the extracellular matrix (ECM), and PI3K-Akt signaling networks were associated with response to lithium. In this study, we replicated the results of our previous study using network propagation methods in a genome-wide association study of an independent sample of 2039 patients from the International Consortium on Lithium Genetics (ConLiGen) study. We identified functional enrichment in focal adhesion and PI3K-Akt pathways, but we did not find an association with the ECM pathway. Our results suggest that deficits in the neuronal growth cone and PI3K-Akt signaling, but not in ECM proteins, may influence response to lithium in BD.

Edward Trautner (1890-1978), a pioneer of psychopharmacology.

This article examines the scientific career of Edward Trautner, who did pioneering research in the 1950s on lithium treatment for psychiatric disorders. Trautner was the first scientist to study the mechanism of action of lithium as a psychiatric medication. His research established that lithium could be used safely and rationally, and anticipated by a decade the large volume of research in the 1960s and 1970s that led to international acceptance of lithium treatment for mood disorders. Trautner was a pioneer of biological psychiatry who considered pharmacology to be a useful therapeutical tool rather than a permanent cure for putative chemical imbalances. His research involved cross-disciplinary collaborations that combined clinical and laboratory research in the disciplines of psychiatry, physiology, biochemistry, teratology, and even oncology. Trautner himself had a multidisciplinary background that included publications in literature and philosophy.

Lithium Therapy in Old Age: Recommendations from a Delphi Survey.

INTRODUCTION: While lithium (Li) has been well established for the treatment of bipolar disorder, geriatric patients require special attention when it comes to issues of drug safety. Declining renal function, amongst other medical conditions, and polypharmacy may pose increased risks. Only a few previous studies have addressed the management of Li in geriatric patients. METHODS: Twenty-four German medical experts on geriatric medicine and Li treatment participated in a Delphi survey, consisting of two rounds of questionnaires and a final formulation of treatment recommendations. Three major issues of Li therapy were outlined: initiation of treatment, monitoring of ongoing therapy, and withdrawal due to medical reasons. Final recommendations were consented to at a threshold of at least 80% expert agreement. RESULTS: Final consensus was achieved on 21 clinical recommendations. The approved recommendations covered aspects of necessary laboratory checks, concomitant medication, and target Li serum concentration in geriatric patients. Concerning the termination of Li therapy, an agreement was reached on the appropriate time span for tapering and on potential alternatives to Li. No consensus was achieved on whether concomitant dementia or frailty should be considered contraindications for Li treatment and the appropriate threshold of the estimated glomerular function rate for withdrawing Li. CONCLUSION: According to the view of German experts, Li may be used in geriatric patients, but it should be monitored carefully. However, the lack of consent in several specific treatment situations underlines the need for research on specific issues of Li therapy.

Thalidomide Attenuates Epileptogenesis and Seizures by Decreasing Brain Inflammation in Lithium Pilocarpine Rat Model.

Thalidomide (TAL) has shown potential therapeutic effects in neurological diseases like epilepsy. Both clinical and preclinical studies show that TAL may act as an antiepileptic drug and as a possible treatment against disease development. However, the evidence for these effects is limited. Therefore, the antiepileptogenic and anti-inflammatory effects of TAL were evaluated herein. Sprague Dawley male rats were randomly allocated to one of five groups (n = 18 per group): control (C); status epilepticus (SE); SE-TAL (25 mg/kg); SE-TAL (50 mg/kg); and SE-topiramate (TOP; 60mg/kg). The lithium-pilocarpine model was used, and one day after SE induction the rats received pharmacological treatment for one week. The brain was obtained, and the hippocampus was micro-dissected 8, 18, and 28 days after SE. TNF-α, IL-6, and IL-1ß concentrations were quantified. TOP and TAL (50 mg/kg) increased the latency to the first of many spontaneous recurrent seizures (SRS) and decreased SRS frequency, as well as decreasing TNF-α and IL-1ß concentrations in the hippocampus. In conclusion, the results showed that both TAL (50 mg/kg) and TOP have anti-ictogenic and antiepileptogenic effects, possibly by decreasing neuroinflammation.

Valproate and lithium: Old drugs for new pharmacological approaches in brain tumors?

Beyond its use as an antiepileptic drug, over time valproate has been increasingly used for several other therapeutic applications. Among these, the antineoplastic effects of valproate have been assessed in several in vitro and in vivo preclinical studies, suggesting that this agent significantly inhibits cancer cell proliferation by modulating multiple signaling pathways. During the last years various clinical trials have tried to find out if valproate co-administration could enhance the antineoplastic activity of chemotherapy in glioblastoma patients and in patients suffering from brain metastases, demonstrating that the inclusion of valproate in the therapeutic schedule causes an improved median overall survival in some studies, but not in others. Thus, the effects of the use of concomitant valproate in brain cancer patients are still controversial. Similarly, lithium has been tested as an anticancer drug in several preclinical studies mainly using the unregistered formulation of lithium chloride salts. Although, there are no data showing that the anticancer effects of lithium chloride are superimposable to the registered lithium carbonate, this formulation has shown preclinical activity in glioblastoma and hepatocellular cancers. However, few but interesting clinical trials have been performed with lithium carbonate on a very small number of cancer patients. Based on published data, valproate could represent a potential complementary therapeutic approach to enhance the anticancer activity of brain cancer standard chemotherapy. Same advantageous characteristics are less convincing for lithium carbonate. Therefore, the planning of specific phase III studies is necessary to validate the repositioning of these drugs in present and future oncological research.

Blood and cerebrospinal fluid biomarker changes in patients with HIV-associated neurocognitive impairment treated with lithium: analysis from a randomised placebo-controlled trial.

HIV-associated neurocognitive disorders (HAND) persist in the era of antiretroviral therapy (ART). Thus, ART does not completely halt or reverse the pathological processes behind HAND. Adjuvant mitigating treatments are, therefore, prudent. Lithium treatment is known to promote neuronal brain-derived neurotrophic factors (BDNF). Lithium is also an inhibitor of glycogen synthase kinase-3 beta (GSK-3-ß). We analyzed biomarkers obtained from participants in a randomized placebo-controlled trial of lithium in ART-treated individuals with moderate or severe HAND. We assayed markers at baseline and 24 weeks across several pathways hypothesized to be affected by HIV, inflammation, or degeneration. Investigated biomarkers included dopamine, BDNF, neurofilament light chain, and CD8 + lymphocyte activation (CD38 + HLADR +). Alzheimer's Disease (AD) biomarkers included soluble amyloid precursor protein alpha and beta (sAPPα/ß), Aß38, 40, 42, and ten other biomarkers validated as predictors of mild cognitive impairment and progression in previous studies. These include apolipoprotein C3, pre-albumin, α1-acid glycoprotein, α1-antitrypsin, PEDF, CC4, ICAM-1, RANTES, clusterin, and cystatin c. We recruited 61 participants (placebo = 31; lithium = 30). The age baseline mean was 40 (± 8.35) years and the median CD4 + T-cell count was 498 (IQR: 389-651) cells/µL. Biomarker concentrations between groups did not differ at baseline. However, both groups' blood dopamine levels decreased significantly after 24 weeks (adj. p < 002). No other marker was significantly different between groups, and we concluded that lithium did not confer neuroprotection following 24 weeks of treatment. However, the study was limited in duration and sample size.

Structural and biochemical analysis of human inositol monophosphatase-1 inhibition by ebselen.

Bipolar disorder is a major psychiatric disorder associated with cognitive impairment and a high suicide rate. Frontline therapy for this condition includes lithium (Li+)-containing treatments that can exert severe side effects. One target of Li+ is inositol monophosphatase-1 (IMPase1); inhibition of IMPase1 through small-molecule compounds may provide an alternative treatment for bipolar disorder. One such compound is the anti-inflammatory drug ebselen, which is well tolerated and safe; however, ebselen's exact mechanism of action in IMPase1 inhibition is not fully understood, preventing rational design of IMPase1 inhibitors. To fill this gap, we performed crystallographic and biochemical studies to investigate how ebselen inhibits IMPase1. We obtained a structure of IMPase1 in space group P21 after treatment with ebselen that revealed three key active-site loops (residues 33-44, 70-79, and 161-165) that are either disordered or in multiple conformations, supporting a hypothesis whereby dynamic conformational changes may be important for catalysis and ebselen inhibition. Using the thermal shift assay, we confirmed that ebselen significantly destabilizes the enzyme. Molecular docking suggests that ebselen could bind in the vicinity of His217. Investigation of the role of IMPase1 residues His217 and Cys218 suggests that inhibition of IMPase1 by ebselen may not be mediated via covalent modification of the active-site cysteine (Cys218) and is not affected by the covalent modification of other cysteine residues in the structure. Our results suggest that effects previously ascribed to ebselen-dependent inhibition likely result from disruption of essential active-site architecture, preventing activation of the IMPase1-Mg2+ complex.Communicated by Ramaswamy H. Sarma.

Fourteen-year trends in the prescribing patterns of pediatric bipolar patients discharged from two public mental hospitals in Taiwan.

INTRODUCTION: The management of pediatric bipolar disorder (PBD) requires pharmacotherapy to control acute symptoms, reduce relapse, prevent suicide, and improve psychosocial functioning. The purpose of this study was to investigate prescribing patterns among PBD patients discharged from two public mental hospitals in Taiwan, from 2006 to 2019. METHODS: PBD patients discharged from the two study hospitals, from 1 January 2006 to 31 December 2019 (n = 420), were included in the analysis. Prescribed drugs at discharge, including mood stabilizers (i.e., lithium, valproate, carbamazepine, and lamotrigine), antipsychotics (i.e., second- and first-generation antipsychotics, SGAs and FGAs), and antidepressants, were explored. Complex polypharmacy was defined as the use of 3 or more agents among the prescribed drugs. Time trends of each prescribing pattern were analyzed using the Cochran-Armitage Trend test. RESULTS: The most commonly prescribed psychotropic agents were SGAs (76.0%), followed by valproate (65.7%) and FGAs (24.8%). The prescription rates of SGAs, antidepressants, antidepressant plus antipsychotic, and antidepressant without mood stabilizer significantly increased over time, whereas the prescription rates of mood stabilizers, lithium, and FGAs significantly decreased. DISCUSSIONS: Prescribing patterns changed greatly for PBD patients over time. However, much more evidence supporting the effectiveness of psychotropic agents in PBD patients is required.

Prescribing changes for bipolar patients discharged from two public psychiatric hospitals in Taiwan, 2006-2019.

BACKGROUND: For bipolar disorder, a severe, recurring mental disorder, pharmacotherapy is a cornerstone of effective treatment. The purpose of this study was to investigate prescribing changes among patients with bipolar disorder discharged from two public psychiatric hospitals in Taiwan over a 14-year period. METHODS: Patients with bipolar disorder discharged from the two study hospitals between 2006 and 2019 (n = 9071) were included in the analysis. Prescribed drugs for the treatment of bipolar disorder, including mood stabilizers (i.e., lithium, valproate, carbamazepine, and lamotrigine), any antipsychotics (i.e., second- and first-generation antipsychotics; SGAs & FGAs), and any antidepressants, were examined. Complex polypharmacy was defined as the use of 3 or more agents among the prescribed drugs. Temporal trends of each prescribing pattern were analyzed using the Cochran-Armitage Trend test. RESULTS: The prescription rates of SGAs, any antidepressants, antidepressant monotherapy, antidepressants without mood stabilizers, and complex polypharmacy significantly increased over time, whereas the prescription rates of any mood stabilizers, lithium, carbamazepine, FGAs, and antidepressants plus mood stabilizers significantly decreased. LIMITATIONS: Treatment allocation is not randomized in a retrospective study. The diagnoses of bipolar disorder were based on clinical judgments. This was a hospital-based study. CONCLUSIONS: Substantial prescribing changes took place during the study period. The decreased use of lithium and the increased use of antidepressants were not in accordance with the evidence-based treatment and recommendations in treatment guidelines. Therefore, long-term outcomes of prescribing changes should be explored in the future.

Atorvastatin lowers serum calcium levels in lithium-users: results from a randomized controlled trial.

BACKGROUND: Although lithium is considered the gold-standard treatment for bipolar disorder (BD), it is associated with a variety of major endocrine and metabolic side effects, including parathyroid hormone (PTH) dependent hypercalcemia. Aside from surgery and medication discontinuation, there are limited treatments for hypercalcemia. This paper will assess data from a randomized controlled trial (RCT). METHODS: This is a secondary analysis of an RCT that explored the effects of atorvastatin (n = 27) versus placebo (n = 33) on lithium-induced nephrogenic diabetes insipidus (NDI) in patients with BD and major depressive disorder (MDD) using lithium (n = 60), over a 12-week period. This secondary analysis will explore serum calcium levels and thyroid stimulating hormone (TSH) measured at baseline, week 4, and week 12. RESULTS: At 12-weeks follow-up while adjusting results for baseline, linear regression analyses found that corrected serum calcium levels were significantly lower in the treatment group (mean (M) = 2.30 mmol/L, standard deviation (SD) = 0.07) compared to the placebo group (M = 2.33 mmol/L, SD = 0.07) (ß = - 0.03 (95% C.I.; - 0.0662, - 0.0035), p = 0.03) for lithium users. There were no significant changes in TSH. CONCLUSION: In lithium users with relatively normal calcium levels, receiving atorvastatin was associated with a decrease in serum calcium levels. Although exciting, this is a preliminary finding that needs further investigation with hypercalcemic patients. Future RCTs could examine whether atorvastatin can treat PTH dependent hypercalcemia due to lithium and other causes.

Effects of GABAB receptor positive allosteric modulator BHF177 and IRS-1 on apoptosis of hippocampal neurons in rats with refractory epilepsy via the PI3K/Akt pathway.

The present study was conducted to determine the effects of the γ-aminobutyric acid B (GABAB ) receptor positive allosteric modulator BHF177 on refractory epilepsy (RE). An RE rat model was initially established via treatment with lithium-pilocarpine. The RE rats were then treated with BHF177 or the GABAB receptor antagonist CGP46381, followed by recording of their seizure rate and assessment of their spatial learning in the Morris water maze test. Treatment of BHF177 reduced the seizure intensity, whereas this effect was revered upoj treatment with CGP46381. Immunohistochemistry revealed that BHF177 treatment diminished P-glycoprotein (P-gp) expression in the hippocampal tissues of RE rats. Next, we found that BHF177 activated GABAB receptor, resulting in upregulated expression of insulin receptor substrate 1 (IRS-1) and PI3K, as well as antiapoptotic factors (Bcl-2 and mTOR), along with suppression of the apoptosis factors Bax and cleaved caspase-3 in the hippocampal tissues. Further, activation of GABAB receptors by BHF177 alleviated the inflammatory response in hippocampal tissues of RE rats, as evidenced by reduced VCAM-1, ICAM-1, and tumor necrosis factor-α levels. Next, we treated primary cultured rat hippocampal neurons with BHF177 and the IRS-1 selective inhibitor NT157. BHF177 inhibited hippocampal apoptosis in rat hippocampal neurons by regulating the IRS-1/PI3K/Akt axis through crosstalk between GABAB and insulin-like growth factor-1 receptors. Collectively, our findings indicate that the BHF177 inhibited neuron apoptosis, thus protecting against RE through the IRS-1/PI3K/Akt axis, which may present a new therapeutic channel for RE.

Decreased miR-15b-5p/miR-155-5p levels and increased miR-134-5p/miR-652-3p levels among BD patients under lithium treatment.

BACKGROUND: There is an increasing interest about the role of miRNAs in the pathogenesis of bipolar disorder (BD). In this study, we aimed to examine the role of miRNAs as potential diagnostic and clinical biomarkers in BD. METHODS: Fifteen miRNAs in plasmas obtained from BD patients (n = 66) and from the healthy control group (n = 66) were analyzed by a qPCR test. Clinical variables including lithium treatment response were assessed with various test batteries. The correlation of the miRNA levels with the clinical variables and scale scores was examined. The Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were performed using the DIANA-miRPath v.3.0 software to identify the possible target genes. RESULTS: The miR-132, miR-134, miR-152, miR-607, miR-633, and miR-652 levels were significantly increased, whereas the miR-15b and miR-155 levels were found to be significantly decreased in the patient group compared to the controls. The miR-15b-5p and miR-155-5p levels and increases in the miR-134-5p and miR-652-3p levels were calculated to have 83.3 % sensitivity and 78.8 % specificity in determining the risk of BD. miR-155-5p was associated with the disease burden and severity. Fatty acid biosynthesis and metabolism, viral carcinogenesis, the EBV infection, and extracellular matrix and adhesion pathways were highlighted as target pathways. CONCLUSION: We can conclude that miRNAs may play a role in the pathophysiology of BD through various biological pathways and that miRNAs may be used as a screening test to distinguish bipolar patients from healthy controls. Our findings will provide a basis for long-term follow-up studies with larger samples.

Insulin signaling as a therapeutic mechanism of lithium in bipolar disorder.

In this paper, we propose that lithium may exert its therapeutic effect in bipolar disorder by acting on insulin signaling pathways. Specifically, we assess the importance of the phosphatidylinositol 3-kinase/Protein Kinase B (PI3K/Akt) insulin signaling pathway and we assess how the action of lithium on both glycogen synthase kinase-3 (GSK3) and the phosphatidylinositol cycle may lead to mood stabilization mediated by PI3K/Akt insulin signaling. We also highlight evidence that several other actions of lithium (including effects on Akt, Protein kinase C (PKC), and sodium myo-inositol transporters) are putative mediators of insulin signaling. This novel mode of action of lithium is consistent with an emerging consensus that energy dysregulation represents a core deficit in bipolar disorder. It may also provide context for the significant co-morbidity between bipolar disorder, type 2 diabetes, and other forms of metabolic illness characterized by impaired glucose metabolism. It is suggested that developments in assessing neuronal insulin signaling using extracellular vesicles would allow for this hypothesis to be tested in bipolar disorder patients.

Lithium Enhances Hippocampal Glucose Metabolism in an In Vitro Mice Model of Alzheimer's Disease.

Impaired cerebral glucose metabolism is an early event that contributes to the pathogenesis of Alzheimer's disease (AD). Importantly, restoring glucose availability by pharmacological agents or genetic manipulation has been shown to protect against Aß toxicity, ameliorate AD pathology, and increase lifespan. Lithium, a therapeutic agent widely used as a treatment for mood disorders, has been shown to attenuate AD pathology and promote glucose metabolism in skeletal muscle. However, despite its widespread use in neuropsychiatric disorders, lithium's effects on the brain have been poorly characterized. Here we evaluated the effect of lithium on glucose metabolism in hippocampal neurons from wild-type (WT) and APPSwe/PS1ΔE9 (APP/PS1) mice. Our results showed that lithium significantly stimulates glucose uptake and replenishes ATP levels by preferential oxidation of glucose through glycolysis in neurons from WT mice. This increase was also accompanied by a strong increase in glucose transporter 3 (Glut3), the major carrier responsible for glucose uptake in neurons. Similarly, using hippocampal slices from APP-PS1 mice, we demonstrate that lithium increases glucose uptake, glycolytic rate, and the ATP:ADP ratio in a process that also involves the activation of AMPK. Together, our findings indicate that lithium stimulates glucose metabolism and can act as a potential therapeutic agent in AD.

The CHAMP-study: the CHemopreventive effect of lithium in familial AdenoMatous Polyposis; study protocol of a phase II trial.

BACKGROUND: Familial adenomatous polyposis (FAP) is a rare autosomal dominant disease characterized by germline mutations in the Adenomatous Polyposis Coli (APC) gene, resulting in the development of numerous colorectal adenomas. As these patients have a high risk of developing colorectal cancer (CRC), guidelines suggest prophylactic colectomy during early adulthood, however, adenoma development is still observed in the remaining intestinal tract. Therefore, FAP patients would benefit from chemoprevention strategies reducing the development of adenomas. Recent work in mice reveals a chemopreventive effect of lithium on the development of adenomas by inhibiting the expansion of Apc mutated intestinal stem cells (ISCs) within the crypts of normal intestinal mucosa. Here, we aim to investigate the effect of lithium on the spread of APC mutant cells within the human intestinal epithelium. METHODS: This prospective phase II single arm trial has a duration of 18 months. FAP patients (18-35 years) with a genetically confirmed APC mutation who did not undergo colectomy will be treated with lithium carbonate orally achieving a serum level of 0.2-0.4 mmol/l between month 6 and 12. Colonoscopy with biopsies of normal intestinal mucosa will be performed at baseline and every six months. The primary endpoint is the effect of lithium on the spread of APC mutant cells within intestinal crypts over time by using APC specific marker NOTUM in situ hybridization. Secondary endpoints include change in adenoma burden, patient reported side effects and safety-outcomes. Total sample size is 12 patients and recruitment will take place in the Amsterdam UMC, location AMC in the Netherlands. DISCUSSION: The outcome of this study will function as a proof-of-concept for the development of novel chemoprevention approaches that interfere with the competition between normal and mutant ISCs. TRIAL REGISTRATION: ClinicalTrials.gov ( https://clinicaltrials.gov/ ): NCT05402891 (June 1, 2022) and the EU Clinical Trials Register: EuraCT 2022-000240-30 (January 1, 2022).

Mitochondrial modulators for obsessive-compulsive and related disorders: a systematic review and meta-analysis.

It remains unclear whether mitochondrial modulators (MMs) are beneficial in the treatment of obsessive-compulsive and related disorders. Thus, in an attempt to answer this clinical question, we performed a systematic review and a random-effects meta-analysis of double-blind, randomized, placebo-controlled trials. The primary outcome was change in overall symptoms as measured using standardized rating scales. Other outcomes were response to treatment; improvement in anxiety-related scales scores, depression-related scale scores, Clinical Global Impression Severity Scale (CGI-S) scores, and Sheehan Disability Scale (SDS) scores; all-cause discontinuation; and individual adverse events. We calculated the standardized mean differences for continuous outcomes and risk ratios for dichotomous outcomes with 95% confidence intervals. We reviewed 17 studies (n = 629, 72.62% female; duration = 2-20 weeks; mean age = 30.47 years) of MMs: eicosapentaenoic acid (K = 1), folic acid (K = 1), lithium (K = 1), N-acetylcysteine (K = 10), inositol (K = 3), and silymarin (K = 1). MMs outperformed placebo in overall improvement in symptoms (p < 0.01) and in improving anxiety-related scale scores (p = 0.05). Subgroup analysis of individual MMs revealed that although overall symptoms were better improved by N-acetylcysteine (p < 0.01) and lithium (p = 0.04), no MMs outperformed placebo in terms of improving anxiety-related scale scores. Neither pooled nor individual MMs outperformed placebo in improving response to treatment, depression-related scale scores, CGI-S scores, SDS scores, or all-cause discontinuation. N-acetylcysteine was no more associated with a higher incidence of individual adverse events including gastrointestinal symptoms, than placebo. In conclusion, N-acetylcysteine was beneficial in the treatment of obsessive-compulsive and related disorders. However, further study with larger samples is necessary to confirm this finding.

Use of Lithium in Hyperthyroidism Secondary to Graves' Disease: A Case Report.

BACKGROUND The therapeutic approach to Graves' disease (GD) comprises thionamides, radioiodine ablation, or surgery as first-line therapy, and cholestyramine and oral iodine as second-line therapies. The role of lithium (Li) in GD as a primary or adjunctive therapy remains contentious. We present a case of GD managed by Li therapy with oral iodine solution. CASE REPORT A 26-year-old man, admitted with acute blast crisis secondary to chronic myeloid leukemia (CML), reported palpitations, 40-lb weight loss, heat intolerance, and fatigue. An examination revealed sinus tachycardia, elevated body temperature, and thyromegaly. Laboratory evaluation confirmed hyperthyroidism (TSH <0.005 mcIU/l, FT4 5.57 ng/dl, TT3 629 ng/dl) secondary to GD (TRAb >40 IU/l, TSIg 178%). Thionamides and surgery were contraindicated due to pancytopenia from a blast crisis. Inability to maintain post-radiation precautions precluded use of RAI. Cholestyramine was attempted and discontinued due to nausea. We introduced oral Li carbonate with oral iodine, which the patient tolerated. Thyroid functions improved with therapy (TSH 0.007 mcIU/l, FT4 0.82 ng/dl, TT3 122 ng/dl) with stable Li level (0.5-0.8 mmol/l). CONCLUSIONS Li inhibits iodine uptake through interference with sodium-iodide symporter and tyrosine iodination, thyroglobulin structure changes, peripheral deiodinase blockage, and preventing TSH and TSIg stimulation. Our case shows that a low therapeutic level of Li, in combination with oral iodine, can suppress thyroid overactivity without adverse effects. We suggest that low-dose Li carbonate is a safe and effective adjunctive antithyroid medication to be considered if primary therapies for hyperthyroidism are unavailable.

MRI-based kidney radiomic analysis during chronic lithium treatment.

BACKGROUND: Lithium therapy during bipolar disorder is associated with an increased risk of chronic kidney disease (CKD) that is slowly progressive and undetectable at early stages. We aimed at identifying kidney image texture features as possible imaging biomarkers of decreased measured glomerular filtration rate (mGFR) using radiomics of T2-weighted magnetic resonance imaging (MRI). METHODS: One hundred and eight patients treated with lithium were evaluated including mGFR and kidney MRI, with T2-weighted sequence single-shot fast spin-echo. Computed radiomic analysis was performed after kidney segmentation. Significant features were selected to build a radiomic signature using multivariable Cox analysis to detect an mGFR <60 ml/min/1.73 m². The texture index was validated using a training and a validation cohort. RESULTS: Texture analysis index was able to detect an mGFR decrease, with an AUC of 0.85 in the training cohort and 0.71 in the validation cohort. Patients with a texture index below the median were older (59 [42-66] vs. 46 [34-54] years, p = .001), with longer treatment duration (10 [3-22] vs. 6 [2-10] years, p = .02) and a lower mGFR (66 [46-84] vs. 83 [71-94] ml/min/1.73m², p < .001). Texture analysis index was independently and negatively associated with age (ß = -.004 ± 0.001, p < .001), serum vasopressin (-0.005 ± 0.002, p = .02) and lithium treatment duration (-0.01 ± 0.003, p = .001), with a significant interaction between lithium treatment duration and mGFR (p = .02). CONCLUSIONS: A renal texture index was developed among patients treated with lithium associated with a decreased mGFR. This index might be relevant in the diagnosis of lithium-induced renal toxicity.