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OBJECTIVE Valproic acid (VPA) is used for the treatment of epilepsy and bipolar disorder (BD). The aims of this study was to examine that long-term VPA use affects mortality in BD patients. METHODS Association analysis was conducted using the National Health Insurance Research Database (NHIRD) of Taiwan. The long-term VPA use group was selected as patients treated with VPA for BD who used VPA only. The control group consisted of BD patients who were not treated with VPA or lithium. The lithium use group consisted by BD patients used lithium only was also joined the analysis. The cofactors included age (>65 years), sex and the Charlson Comorbidity Index. RESULTS The hazard ratio (HR) of mortality for the VPA group was 0.83 (95% confidence interval (CI), (0.70-0.99); P = 0.04) and the result of lithium group did not reach statistical significance. Furthermore only the duration> 3 years subgroup had a significantly lower incidence of mortality than the control group, with an HR of 0.54 (95% CI, (0.42-0.70); P

BACKGROUND: A case series suggested efficacy for lithium to treat agitation in dementia, but no placebo-controlled trials have been conducted. OBJECTIVES: To evaluate low-dose lithium treatment of agitation in Alzheimer’s disease (AD). METHOD: In a four-site trial, patients with AD and agitation/aggression score ≥ 4 on the Neuropsychiatric Inventory (NPI) were randomized, double-blind, to lithium carbonate 150–600 mg daily or placebo for 12 weeks. Primary efficacy outcome was change in NPI agitation/aggression; secondary efficacy outcome was treatment response (30% reduction in NPI score for agitation/aggression plus psychosis and a Clinical Global Impression (CGI) score of much or very much improved). Safety profile of lithium was assessed. RESULTS: Fifty-eight of 77 patients (75.3%) completed the trial. In linear mixed effects model analyses, lithium was not significantly superior to placebo for agitation/aggression. Proportion of responders was 31.6% on lithium and 17.9% on placebo (χ(2)=1.26, p=0.26). Moderate or marked improvement (CGI) was greater on lithium (10/38=36.8%) than placebo (0/39=0%, Fisher’s exact test p

Objective Lithium is a drug of choice in the treatment of bipolar disorder and refractory depressive disorders. However, previous research suggests lithium has a negative cognitive impact in recovery from electroconvulsive therapy (ECT) and a higher risk of delirium, so patients are often required to stop taking lithium before ECT, despite risk of relapse. We studied the cognitive impact of serum lithium levels in patients undergoing ECT. Methods This was an observational prospective study. Serum lithium levels, thyroid and biochemical parameters were measured prior to each ECT session. Time elapsed from the anesthetic induction to the electrical stimulus and then to the patients’ reorientation was recorded, as well as the motor seizure duration and electroencephalogram (EEG) seizure duration. A statistical analysis using a linear mixed model was run while adjusting for confounding factors. Results Ten participants underwent a total of 86 ECT sessions (41% right unilateral ultrabrief pulse, and 59% bilateral brief pulse). A negative interaction between lithium levels and reorientation time was found among those doing bilateral brief pulse ECT. No association was observed in patients doing unilateral ultrabrief pulse ECT. No significant relationship was observed between lithium and both motor and EEG-assessed seizure duration. Conclusion This study suggests that low to moderate serum lithium levels (< 0.7 mmol/L) might have no harmful cognitive effects in patients under right unilateral ultrabrief pulse and bilateral brief pulse ECT.

Background Bipolar disorder (BD) is associated with marked parenchymal brain loss in a significant fraction of patients. The lack of necrosis in postmortem examination suggests an apoptotic process. Emerging evidence suggests that mood stabilizers, like lithium, have antiapoptotic actions. Glutamatergic abnormalities have been associated with BD. Methods Olfactory neuroepithelial progenitors (ONPs) harvested by biopsy from type I bipolar patients (BD-ONPs, n = 3) and non-bipolar controls (non-BD-ONPs, n = 6), were treated with glutamate at concentrations sufficient to mimic the observed doubling of intracellular sodium known to occur in both mania and bipolar depression, to investigate potential differential lithium effect on both BD-ONPs and non-BD-ONPs. Results Apoptosis was detected in BP-ONPs exposed to 0.1 M glutamate for 6 h but in non-BD-ONPs at 24 h. Moreover, after treatment with 0.1 M glutamate treated for 6 h the levels of the pro-apoptotic cleaved-caspase-3 and cleaved-PARP proteins were significantly higher in BD-ONPs compare to non-BD-ONPs. Pretreatment with a therapeutic concentration of 1 mM lithium for 3 days attenuated the glutamate induced apoptosis. Lithium pretreatment 3 days also prevented the DNA fragmentation induced by glutamate, and significantly increased the antiapoptotic phospho-B-Raf and Bcl-2 proteins in BD-ONPs compared to non-BD-ONPs. Limitations ONPs are obtained from subjects with and without bipolar illness, but outcome of their study may still not reflect the biology of the illness. Conclusions ONPs derived from BD are more susceptible to glutamate-induced apoptosis. Lithium is associated with a greater increase of anti-apoptotic B-Raf and Bcl-2 expression in BD-ONPs.

Background: We primarily aimed to explore the associations between duration of untreated illness (DUI), treatment response, and functioning in a cohort of patients with bipolar disorder (BD). Methods: 261 participants with BD were recruited. DUI was defined as months from the first affective episode to the start of a mood-stabilizer. The functioning assessment short test (FAST) scores and treatment response scores for lithium, valproate, or lamotrigine according to the Alda Scale Total Score (TS) were compared between patients with short (

Background Lithium is one of the most effective medications for bipolar disorder episode prevention, but its mechanism of action is still largely unknown. The hippocampus is a subcortical cerebral structure involved in the formation of emotional responses, cognition and various primitive functions, altered during affective episodes. Deviations in the anatomy or physiology of the hippocampus would partially explain the symptomatology of bipolar subjects, and restoration may reflect treatment response. Methods In this mini review, we summarize the studies which have investigated the effect of lithium intake on the volume of hippocampus, measured using magnetic resonance imaging (MRI). We performed a bibliographic search on PubMed, using the terms terms “hippocampus”, “lithium”, “bipolar disorder”, “volume” and “MRI”. Only original studies were considered. Results Thirteen studies met the inclusion criteria. Nine studies demonstrated increased total hippocampal volume or hippocampal subfield volumes in BD patients on lithium treatment (Li BD) compared to those not taking lithium (non-Li BD), while four failed to show significant differences between groups. When healthy controls were compared to either the Li subjects or the non-Li ones, the findings were more heterogeneous. Limitations Heterogeneity in the methodology and definition of groups limits the comparison of study results. Conclusions Lithium may be associated with increased hippocampal volume in BD, potentially due to its putative neurotrophic action, but further research is needed better define the morphological alterations of hippocampus in BD and the longitudinal effects of lithium in the short and long-term.

Supplemental Digital Content is available in the text., Lithium, a mood stabilizer used in the treatment of bipolar disorder is known for its anti-inflammatory properties with the discussion of its potential use in COVID-19 infection. The SARS-CoV-2 virus causing COVID-19 infection is known to enter the target cells through angiotensin converting enzyme-2 receptors present in abundance in the lung and renal tissue. Recent research supports the evidence for direct renal injury by viral proteins. Here we report two patients with bipolar disorder presenting with lithium toxicity in the presence of COVID-19 infection. Two patients with bipolar disorder, maintaining remission on lithium prophylaxis, presented to the psychiatric emergency with recent-onset fever and altered sensorium. Both the patient’s investigations revealed lithium toxicity, elevated serum creatinine, urea and inflammatory markers. Hypernatremia, hyperkalaemia, and hyperchloremia were seen in one patient. Lithium and other psychotropic medications were stopped immediately, and COVID-19 treatment was initiated. Patient with clinical signs of lithium toxicity, hypernatremia, hyperkalaemia, and hyperchloremia developed ventricular tachycardia. He survived and regained consciousness after 2 weeks of aggressive conservative management. However, another patient died of acute respiratory failure on day 3. Possible direct infection of the kidney by SARS-CoV-2 viral proteins can manifest with acute kidney injury and lithium toxicity among patients on long-term lithium therapy. Health professionals treating COVID-19 infection among individuals on lithium therapy should be aware of the possibility of lithium toxicity in the background of renal injury.

Lithium carbonate is used to increase white blood cell counts as a means of counteracting leukopenia caused by the administration of antipsychotic drugs. To evaluate the effect of antipsychotics on the leukocyte‐enhancing effect of lithium, we compared white blood cell counts, serum lithium levels, and lithium dosage in patients receiving antipsychotics and lithium in combination and patients receiving lithium alone. Chlorpromazine equivalent values were used as an indicator of the antipsychotic dose. Lithium serum levels were measured in 41 hospitalized patients. The lithium dose in the combination group (median, 800 mg) was significantly higher than that in group receiving only lithium (median, 400 mg) (P = 0.03). The lithium doses in the combination group receiving ≥1000 mg chlorpromazine equivalents (overdosing; median lithium dose 800 mg) and the combination group treated with 600‐999 mg chlorpromazine equivalents (high dosing; median lithium dose 800 mg) were significantly higher than the group that was not treated with antipsychotic medication, with median lithium dose 400 mg (P, Effect of chlorpromazine equivalent dose on lithium carbonate dose, serum lithium concentration, and white blood cell count. The lithium doses in the combination group receiving ≥1000 mg chlorpromazine equivalents (overdosing; median lithium dose 800 mg) and the combination group treated with 600‐999 mg chlorpromazine equivalents (high dosing; median lithium dose 800 mg) were significantly higher than the group that was not treated with antipsychotic medication, with median lithium dose 400 mg (P

Lithium is a first-line treatment for bipolar disorder, where it acts as a mood-stabilizing agent. Although its precise mechanism remains unclear, neuroimaging studies have shown that lithium accumulates in the hippocampus and that chronic use amongst bipolar disorder patients is associated with larger hippocampal volumes. Here, we tested the chronic effects of low (0.75 mM) and high (2.25 mM) doses of lithium on human hippocampal progenitor cells and used immunocytochemistry to investigate the effects of lithium on cell parameters implicated in neurogenesis. Corresponding RNA-sequencing and gene-set enrichment analyses were used to evaluate whether genes affected by lithium in our model overlap with those regulating the volume of specific layers of the dentate gyrus. We observed that high-dose lithium treatment in human hippocampal progenitors increased the generation of neuroblasts (P ≤ 0.01), neurons (P ≤ 0.01), and glia (P ≤ 0.001), alongside the expression of genes, which regulate the volume of the molecular layer of the dentate gyrus. This study provides empirical support that adult hippocampal neurogenesis and gliogenesis are mechanisms that could contribute to the effects of lithium on human hippocampal volume.

Objectives:Bipolar disorder (BD) may be connected with accelerated aging, the marker of this can be shorter telomere length (TL). Some data suggest that lithium may exert a protective effect against telomere shortening. The study aimed to compare the TL between patients with BD and control subjects. The effect of long-term lithium treatment was also assessed.Methods:The study group comprised 41 patients with BD, including 29 patients treated longitudinally with lithium (mean 16.5 years) and 20 healthy people. TL was assessed by the quantitative polymerase chain reaction (qPCR).Results:In the control group, the TL was significantly longer in males than in females. Male bipolar patients had significantly shorter TL compared with the control male group. In bipolar patients, there was no correlation between TL and duration of treatment. The TL was negatively correlated with age in male bipolar patients.Conclusions:The study did not confirm the lithium effect on TL in bipolar patients. TL showed gender differences, being shorter in BD males, compared to control males, and longer in healthy males, compared to control females.

The diagnosis and treatment of bipolar depression (BDep) poses complex clinical challenges for psychiatry. Proton magnetic resonance spectroscopy (1H-MRS) is a useful imaging tool for investigating in vivo levels of brain neuro-metabolites, critical to understanding the process of mood dysregulation in Bipolar Disorder. Few studies have evaluated longitudinal clinical outcomes in BDep associated with 1H-MRS metabolic changes. This study aimed to longitudinally assess brain 1H-MRS metabolites in the anterior cingulate cortex (ACC) correlated with improvement in depression (from BDep to euthymia) after lithium treatment in BDep patients versus matched healthy controls (HC). Twenty-eight medication-free BDep patients and 28 HC, matched for age and gender, were included in this study. All subjects were submitted to a 3-Tesla brain 1H-MRS scan in the ACC using a single-voxel (8cm3) PRESS sequence at baseline. At follow-up (6 weeks), 14 BDep patients repeated the exam in euthymia. Patients with current BDep had higher baseline Myo-inositol/Cr (mI/Cr) and Choline/Cr (Cho/Cr) compared to HC. After six weeks, mI/Cr or Cho/Cr levels in subjects that achieved euthymia no longer differed to levels in HC, while high Cho/Cr levels persisted in non-responders . Elevated ACC mI/Cr and Cho/Cr in BDep might indicate increased abnormal membrane phospholipid metabolism and phosphatidylinositol (PI) cycle activity. Return of mI/Cr and Cho/Cr to normal levels after lithium-induced euthymia suggests a critical regulatory effect of lithium targeting the PI cycle involved in mood regulation.

Background Disorders of mental health are major risk factors for suicidal behavior and require adequate treatment. However, the effect of psychotropic medication on suicidal behavior is unclear. Methods The 120 participants in a randomized clinical trial of a brief therapy for suicide attempters (Attempted Suicide Short Intervention Program, ASSIP) reported on repeated suicide attempts, suicidal ideation, depression, and medication in the treatment as usual (TAU), at baseline, 6, 12, 18, and 24 months follow-up. The RCT had no influence on medication prescribed. Drugs prescribed were categorized as any psychotropic, antidepressants plus lithium, and antipsychotics. To assess the effect of long-term medication we identified participants with periods of continuous use of psychotropics and antidepressants plus lithium over twelve months or more, and medication-free participants for the same drug categories during the same time period. Results Reattempts and suicide ideation decreased in all drug categories. When comparing participants on medication fulfilling the definition of long-term use with participants without medication, reattempts and suicidal ideation were higher in the psychotropics and the antidepressants/lithium groups. These drug categories were associated with higher depression scores in comparison to no-medication. The survival analysis revealed a higher risk of reattempts in the long-term antidepressants/lithium group in comparison to no-medication. Treatment with the brief psychological therapy ASSIP, added to medication, was associated with a lower risk of reattempts. Limitations The study relied on the patients’ reports on treatment as usual in a randomized controlled clinical trial. Blood levels of the psychotropic compounds were not assessed. Conclusions In this observational study of the TAU condition in a clinical trial of a brief psychological therapy for patients who had recently attempted suicide, psychotropic drug use over twelve months or more was not associated with reduced suicide ideation and reattempts. Depression scores suggest that patients on psychotropic medication had more psychiatric pathology. This may be a confounding factor for the effect of medication on suicidal behavior.

Bipolar disorder often follows a set progression best described in stages where advanced stages are associated with poorer outcomes. Bipolar disorder is also often characterized by a predominance of episode polarity, where some individuals experience more depressive episodes (termed predominant depressive polarity) while others experience more hypo/manic episodes (termed predominant hypo/manic polarity). We examined the associations between staging and predominant polarity with measures of illness burden and treatment outcome utilizing data from a six-month comparative effectiveness trial of lithium and quetiapine in bipolar disorder (Bipolar CHOICE). We used number of self-reported lifetime mood (depressive and hypo/manic) episodes as a proxy for staging and ratio of depressive to manic episodes to define predominant polarity. Polarity and staging were correlated with several measures of burden of illness. Childhood abuse was correlated with more lifetime mood episodes, while more depressive episodes and depressive polarity were correlated with more anxiety disorder comorbidity. Depressive polarity was also correlated with more past trials of psychotropics, particularly antidepressants. However, neither staging nor predominant polarity moderated the randomized treatment effect of lithium vs. quetiapine. Number of depressive episodes in the past year was identified as a potential predictor of overall worse treatment outcome, regardless of medication condition. In conclusion, though staging and predominant episode polarity correlated with several measures of illness burden, they were not associated with differential treatment outcomes. This could be because many of our patients presented for treatment at advanced stages of illness and further highlights the need for early intervention in bipolar disorder.

BackgroundThe 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 correlation with lithium treatment response.MethodsBD 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 ResultsGenotype 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. Although there was trend towards significance for greater occurrence of Val(G) allele among lithium non-responders, this difference did not persist in an analysis of extreme response groups.ConclusionsThe Val(G) allele of BDNF Val66Met polymorphism is associated with risk of BD in this sample, but is not related to response to lithium.

The aim of this study was to compare treatment adherence and tolerability of different lithium formulations in 70 bipolar patients receiving lithium therapy for the first time. During the 1-year follow-up, information was collected regarding patient's clinical course, therapeutic adherence, side effects of the treatment and serum levels of lithium, creatinine and thyroid-stimulating hormone. At baseline, 30 patients (43%) were on prolonged-release lithium formulations and 40 (57%) on immediate-release formulations. At the final evaluation, 37 patients (53%) were considered lost to follow-up. Both prolonged- and immediate-release patients showed significant improvement in the Functioning Assessment Short Test and in the Clinical Global Impressions for Bipolar Disorder scores during the follow-up. At the first follow-up visit, the mean plasma lithium level of prolonged-release patients was higher than immediate-release patients (0.61 vs. 0.47, respectively; P = 0.063), as well as the therapeutic adherence (85 vs. 64%, respectively; P = 0.089). Fine tremor and gastrointestinal symptoms were more frequent in immediate-release patients than in prolonged-release patients at each follow-up visit, with the sole exception of gastrointestinal symptoms at the last evaluation. Prolonged-release lithium therapy could provide potential advantages over immediate-release formulations. Future naturalistic studies and clinical trials with a longer follow-up duration are needed.

Susac-syndrome is a rare autoimmune disease that manifests with mood alterations in up to 15% of cases and is usually treated with corticosteroids. We present the case of a 41-year-old woman with a first manic episode and history of Susac-syndrome, secondary Cushing's syndrome after receiving high doses of corticosteroids and a previous depressive episode. Differentiating between primary and secondary mania is difficult, as people with bipolar disorder are prone to multiple psychiatric and nonpsychiatric comorbidities, in this case, the differential diagnosis included secondary mania, corticoid-induced manic episode and primary bipolar disorder. Upon admission, corticosteroid treatment was suspended, and the patient was started on lithium and risperidone. Secondary causes of mania were discarded and, assessing temporal and dosage criteria, it was deemed unlikely that the present episode was corticosteroid-induced. One-year outpatient follow-up pointed towards a primary bipolar type I disorder, as a separate entity from her Susac-syndrome. Corticosteroid use or abrupt withdrawal pose an underestimated risk of inducing depressive or manic symptoms, which may unmask affective disorders in susceptible individuals. Many medical conditions share CNS involvement and/or high-dose/prolonged corticosteroid treatment. In such cases, psychiatric manifestations such as mania or depression should be regarded as secondary and studied to determine the existence of medical complications before considering primary psychiatric conditions.

In rats, lisdexamfetamine (LDX) induces manic-like behaviors such as hyperlocomotion and increases in appetitive 50-kHz ultrasonic vocalizations (USV), which are prevented by antimanic drugs, such as lithium. Inhibition of glycogen synthase kinase 3 beta (GSK3β) and antioxidant activity have been associated with antimanic effects. Thus, the aim of the present study was to evaluate the possible antimanic-like effects of andrographolide (ANDRO), a GSK3β inhibitor, on LDX-induced hyperlocomotion and 50-kHz USV increases. In addition, the effect of ANDRO was studied on LDX-induced oxidative stress. Lithium was used as positive control. Adult Wistar rats were treated with vehicle, lithium (100 mg/kg i.p., daily) or ANDRO (2 mg/kg i.p., 3 times a week) for 21 days. On the test day, either 10 mg/kg LDX or saline was administered i.p. and USV and locomotor activity were recorded. LDX administration increased the number of 50-kHz calls, as well as locomotor activity. Repeated treatment with lithium or ANDRO prevented these effects of LDX on 50-kHz USV and locomotor activity. LDX increased lipid peroxidation (LPO) levels in rat striatum and both lithium and ANDRO prevented this effect. LPO levels in rat striatum were positively correlated with increases in 50-kHz USV emission as well as hyperlocomotion. In conclusion, the present results indicate that ANDRO has antimanic-like effects, which may be mediated by its antioxidant properties.

Background Lithium is a first-line pharmacotherapy for the treatment of bipolar disorder, but long-term use is associated with nephrotoxicity. However, as dialysis effectively eliminates lithium, it remains a pharmacotherapeutic option for patients on dialysis. This systematic review seeks to evaluate the dosing, safety, efficacy, and monitoring of lithium in patients receiving dialysis. Method A PubMed database search performed May 5th, 2020, identified 535 article titles. After exclusion criteria were applied, a total of 15 articles were included in this systematic review. Results In 18 patients receiving dialysis, lithium was primarily used for the treatment of mood disorders. The majority of patients received 300–900 mg lithium carbonate thrice-weekly following dialysis, but several alternative lithium salts and dosing strategies were utilized. The pharmacokinetic properties of lithium in dialysis are not well understood and can be complicated by a serum lithium “rebound effect” following dialysis, due to a two-compartment volume of distribution. Additionally, presence of residual diuresis in some patients may be reason to administer lithium more frequently than thrice-weekly following dialysis. Lithium was shown to be an effective pharmacotherapy in all patients, with many demonstrating rapid improvement after drug initiation. Five patients experienced an adverse event on lithium, but only one patient required lithium discontinuation. Conclusion Lithium may be used in patients on dialysis, with close monitoring of pre-dialysis serum lithium concentrations for at least two weeks after treatment initiation, followed by a lower frequency after stabilization to ensure therapeutic concentrations and reduce toxicity risk.

OBJECTIVE Electroconvulsive therapy (ECT) is an effective acute treatment for severe and/or medication-resistant depression but maintaining remission following completion of a course remains a clinical challenge. METHODS EFFECT-Dep Trial (ISRCTN23577151) participants with a DSM-IV major depressive episode who met remission criteria after a randomly assigned course of twice-weekly brief-pulse bitemporal (1.5 × seizure threshold) or high-dose (6 × seizure threshold) right unilateral ECT were monitored for relapse for 12 months. In line with the pragmatic trial design, all patients received treatment-as-usual individualised pharmacotherapy during and after ECT; no remitter received continuation ECT. RESULTS Of 61 remitters, 24 (39.3%) relapsed, one (1.6%) withdrew from the study while in remission and the remaining 36 (59.0%) stayed well for a year. Most relapses occurred within the first six months, resulting in a cumulative six-month relapse rate of 31.1%. In a multivariable Cox proportional hazards regression model, older age (p = 0.039) and psychotic features at pre-ECT baseline (p = 0.037) were associated with a more favourable long-term prognosis while a greater number of previous depressive episodes (p = 0.028) and bipolar II (but not bipolar I) diagnosis (p = 0.030) were associated with a worse long-term outcome. Electrode placement and medication resistance prior to ECT had no effect on relapse. Adjusting for covariates, fewer patients treated with lithium relapsed in the overall group (p = 0.008) and in the unipolar depression subgroup (p = 0.027). CONCLUSION Long-term outcome following high-dose right unilateral ECT does not differ from bitemporal ECT. Prognosis is particularly favourable in older adults, psychotic depression and patients maintained on lithium.

Background: Recently, numerous large clinical trials have been performed to evaluate the effectiveness and tolerability of extended-release formulations of carbamazepine in bipolar disorder. Objective: In the current study, we compared lithium with a prolonged-release form of carbamazepine (Tegretol CR) to evaluate its efficiency and safety in a group of patients with a diagnosis of acute mania. Methods: Fifty patients with the diagnosis of acute mania were selected for a three-week, doubleblind study, and were randomly administered lithium carbonate or tegretol CR. The main outcome measured in the present evaluation was the Manic State Rating Scale (MSRS), which was scored at baseline and weekly intervals up to the third week. Moreover, insight and overall illness severity and improvement were assessed using the Schedule for Assessment of Insight (SAI), the Clinical Global Impressions-Global Improvement scale (CGI-I), and the Clinical Global Impressions Severity Scale (CGI-S), respectively. The statistical significance was defined with a p-value ≤0.05, and the treatment efficacy was analyzed by independent samples t-test and repeated measures analysis of variance (ANOVA). Results: Despite the fact that the mean total score of MSRS improved significantly with respect to both lithium carbonate and tegretol CR at the end of the third week, the between-group analysis showed a significant advantage of lithium, regarding both frequency and intensity of symptoms, at the end of the study. The mean total score of SAI, as well, showed significant improvement caused by both of them. Nevertheless, while the CGI-I demonstrated significant improvement in participants taking lithium and tegretol CR, the CGI-S showed significant progress only with lithium. Besides, Cohen’s effect size analysis showed a large improvement of MSRS by lithium and medium improvement by tegretol CR. Post-hoc power analysis showed an intermediate power of 0.42 on behalf of the current evaluation. Conclusion: While both lithium carbonate and tegretol CR were found to be valuable for the improvement of manic symptoms, management with lithium appears to be more helpful.

Lithium (Li), valproate (VPA) and lamotrigine (LTG) are commonly used to treat bipolar disorder (BD). While their clinical efficacy is well established, the mechanisms of action at the molecular level are still incompletely understood. Here we investigated the molecular effects of Li, LTG and VPA treatment in induced pluripotent stem cell (iPSC)-derived neural precursor cells (NPCs) generated from 3 healthy controls (CTRL), 3 affective disorder Li responsive patients (Li-R) and 3 Li non-treated patients (Li-N) after 6 h and 1 week of exposure. Differential expression (DE) analysis after 6 h of treatment revealed a transcriptional signature that was associated with all three drugs and most significantly enriched for ribosome and oxidative phosphorylation (OXPHOS) pathways. In addition to the shared DE genes, we found that Li exposure was associated with 554 genes uniquely regulated in Li-R NPCs and enriched for spliceosome, OXPHOS and thermogenesis pathways. In-depth analysis of the treatment-associated transcripts uncovered a significant decrease in intron retention rate, suggesting that the beneficial influence of these drugs might partly be related to splicing. We examined the mitochondrial respiratory function of the NPCs by exploring the drugs’ effects on oxygen consumption rate (OCR) and glycolytic rate (ECAR). Li improved OCR levels only in Li-R NPCs by enhancing maximal respiration and reserve capacity, while VPA enhanced maximal respiration and reserve capacity in Li-N NPCs. Overall, our findings further support the involvement of mitochondrial functions in the molecular mechanisms of mood stabilizers and suggest novel mechanisms related to the spliceosome, which warrant further investigation.

© 2020, The Author(s), under exclusive licence to Springer Nature Limited.Lithium is a first-line medication for bipolar disorder (BD), but only one in three patients respond optimally to the drug. Since evidence shows a strong clinical and genetic overlap between depression and bipolar disorder, we investigated whether a polygenic susceptibility to major depression is associated with response to lithium treatment in patients with BD. Weighted polygenic scores (PGSs) were computed for major depression (MD) at different GWAS p value thresholds using genetic data obtained from 2586 bipolar patients who received lithium treatment and took part in the Consortium on Lithium Genetics (ConLi+Gen) study. Summary statistics from genome-wide association studies in MD (135,458 cases and 344,901 controls) from the Psychiatric Genomics Consortium (PGC) were used for PGS weighting. Response to lithium treatment was defined by continuous scores and categorical outcome (responders versus non-responders) using measurements on the Alda scale. Associations between PGSs of MD and lithium treatment response were assessed using a linear and binary logistic regression modeling for the continuous and categorical outcomes, respectively. The analysis was performed for the entire cohort, and for European and Asian sub-samples. The PGSs for MD were significantly associated with lithium treatment response in multi-ethnic, European or Asian populations, at various p value thresholds. Bipolar patients with a low polygenic load for MD were more likely to respond well to lithium, compared to those patients with high polygenic load [lowest vs highest PGS quartiles, multi-ethnic sample: OR = 1.54 (95% CI: 1.18–2.01) and European sample: OR = 1.75 (95% CI: 1.30–2.36)]. While our analysis in the Asian sample found equivalent effect size in the same direction: OR = 1.71 (95% CI: 0.61–4.90), this was not statistically significant. Using PGS decile comparison, we found a similar trend of association between a high genetic loading for MD and lower response to lithium. Our findings underscore the genetic contribution to lithium response in BD and support the emerging concept of a lithium-responsive biotype in BD.

Lithium is an effective treatment option for bipolar disorder in children and adolescents; however, the therapeutic window is narrow, and psychiatric, neurological, renal, gastrointestinal, dermatological, and endocrine side effects have been observed during lithium therapy.1 Iatrogenic dysphagia has been reported with psychotropic drugs, benzodiazepines, anti-inflammatory drugs, and some vasoactive drugs.2 However, oropharyngeal dysphagia due to lithium toxicity has not been reported in the literature.

ObjectiveThe objective of this study is to observe the effect of combination of lithium and lamotrigine in treatment of rapid-cycling bipolar disorder (RCBD).MethodWe searched MEDLINE, EMBASE, Cochrane Library in English and CBM, CNKI, WANFANG, and CSSCI in Chinese to find literature from 1 January 2000 to 31 December 2020 related to the combination of lithium carbonate and lamotrigine for treatment of RCBD.ResultsFive comparison studies with 265 subjects of 131 cases in a study group and 134 cases in a control group met the inclusion criteria and were included for the final meta-analysis. The comprehensive analysis shows that the study group had a significant lower score in mental symptoms than the control group (Z = 2.34, P = 0.02) with a random model (X2 = 33.02, df = 7, P < 0.01). However, the differences were only shown in PANSS (Z = 5.18, P < 0.01) and BPRS (Z = 3.08, P < 0.01). There was no difference in response rate (54.9 vs. 45.7%; OR = 1.47; 95% CI: 0.79~2.73; Z = 1.21, P > 0.05,) and remission rate (47.9 vs. 45.9%; OR = 1.05; 95% CI: 0.49~2.25; Z = 0.13, P > 0.05,) found between the two groups. The response rate of lamotrigine and lithium combination was significantly higher compare to that of monotherapy of lithium in patients with no treatment resistant (82 vs. 54%; OR = 4.26; 95% CI: 1.65~10.99; Z = 3.99, P < 0.01) with the fixed effect model (X2 = 0.89, df = 1, P > 0.05, I2 = 0%).ConclusionThe combination of lithium and lamotrigine resulted in better improvement of psychotic symptoms and higher response rate in patients with RCBP with no treatment resistant.

Objectives Polypharmacy is common in maintenance treatment of bipolar illness, but proof of greater efficacy compared to monotherapy is assumed rather than well known. We systematically reviewed the evidence from the literature to provide recommendations for clinical management and future research. Method A systematic review was conducted on the use of polypharmacy in bipolar prophylaxis. Relevant papers published in English through 31 December 2019 were identified searching the electronic databases MEDLINE, Embase, PsycINFO, and the Cochrane Library. Results Twelve studies matched inclusion criteria, including 10 randomized controlled trials (RCTs). The best drug combination in prevention is represented by lithium + valproic acid which showed a significant effect on time to mood relapses (HR = 0.57) compared to valproic acid monotherapy, especially for manic episodes (HR = 0.51). The effect was significant in terms of time to new drug treatment (HR = 0.51) and time to hospitalization (HR = 0.57). A significant reduction in the frequency of mood relapses was also reported for lithium + valproic acid vs. lithium monotherapy (RR=0.12); however, the trial had a small sample size. Lamotrigine + valproic acid reported significant efficacy in prevention of depressive episodes compared to lamotrigine alone. Conclusions The literature to support a generally greater efficacy with polypharmacy in bipolar illness is scant and heterogeneous. Within that limited evidence base, the best drug combination in bipolar prevention is represented by lithium + valproic acid for manic, but not depressive episodes. Clinical practice should focus more on adequate monotherapy before considering polypharmacy.

Zusammenfassung Hintergrund Für Lithium ist die Evidenzlage zu Absetzsyndromen nicht ausreichend systematisch erfasst. Ziel Systematische Übersicht zum Auftreten von Entzugssyndromen nach dem Absetzen von Lithium. Methodik Systematische Literatursuche in PubMed und den Literaturverzeichnissen von relevanten Artikeln. Eingeschlossen wurden Studien und Fallberichte mit dem Thema Entzugssyndrom nach Absetzen von Lithium. Ergebnisse Es wurden insgesamt 249 Treffer einbezogen von denen 6 Artikel die Einschlusskriterien erfüllten. Die 6 Artikel umfassen 6 Studien und 1 Fallserie mit 4 Fallberichten. Vier Studien und 3 Fallberichte geben einen Hinweis auf das Bestehen eines Entzugssyndroms, unabhängig von der Grunderkrankung. Häufig berichtet werden allgemeine Irritabilität, Unruhe und somatische Symptome wie Schwindel und Benommenheit. Die Symptome treten rasch nach Absetzen von Lithium auf und zeigen sich als eher mild und selbstlimitierend. Schlussfolgerung Bei schwacher Evidenzlage legen die vorhandenen Daten nahe, dass Entzugssyndrome nach dem Absetzen von Lithium grundsätzlich vorkommen können. Zur weiteren Bestimmung von Charakteristika, Prädiktoren und Behandlungs- oder Präventionsstrategien sind methodisch hochwertige, kontrollierte Studien erforderlich.

International audience; Background: Bipolar disorder is characterized by cyclical alternation between mania and depression, often comorbid with psychosis and suicide. Compared with other medications, the mood stabilizer lithium is the most effective treatment for the prevention of manic and depressive episodes. However, the pathophysiology of bipolar disorder and lithium’s mode of action are yet to be fully understood. Evidence suggests a change in the balance of excitatory and inhibitory activity, favouring excitation in bipolar disorder. In the present study, we sought to establish a holistic understanding of the neuronal consequences of lithium exposure in mouse cortical neurons, and to identify underlying mechanisms of action.Methods: We used a range of technical approaches to determine the effects of acute and chronic lithium treatment on mature mouse cortical neurons. We combined RNA screening and biochemical and electrophysiological approaches with confocal immunofluorescence and live-cell calcium imaging.Results: We found that only chronic lithium treatment significantly reduced intracellular calcium flux, specifically by activating metabotropic glutamatergic receptor 5. This was associated with altered phosphorylation of protein kinase C and glycogen synthase kinase 3, reduced neuronal excitability and several alterations to synapse function. Consequently, lithium treatment shifts the excitatory–inhibitory balance toward inhibition.Limitations: The mechanisms we identified should be validated in future by similar experiments in whole animals and human neurons.Conclusion: Together, the results revealed how lithium dampens neuronal excitability and the activity of the glutamatergic network, both of which are predicted to be overactive in the manic phase of bipolar disorder. Our working model of lithium action enables the development of targeted strategies to restore the balance of overactive networks, mimicking the therapeutic benefits of lithium but with reduced toxicity.

Background Despite thorough and validated clinical guidelines based on bipolar disorders subtypes, large pharmacological treatment heterogeneity remains in these patients. There is limited knowledge about the different treatment combinations used and their influence on patient outcomes. We attempted to determine profiles of patients based on their treatments and to understand the clinical characteristics associated with these treatment profiles. Methods This multicentre longitudinal study was performed on a French nationwide bipolar cohort database. We performed hierarchical agglomerative clustering to search for clusters of individuals based on their treatments during the first year following inclusion. We then compared patient clinical characteristics according to these clusters. Results Four groups were identified among the 1795 included patients: group 1 (“heterogeneous” n = 1099), group 2 (“lithium” n = 265), group 3 (“valproate” n = 268), and group 4 (“lamotrigine” n = 163). Proportion of bipolar 1 disorder, in groups 1 to 4 were: 48.2%, 57.0%, 48.9% and 32.5%. Groups 1 and 4 had greater functional impact at baseline and a less favorable clinical and functioning evolution at one-year follow-up, especially on GAF and FAST scales. Limitations The one-year period used for the analysis of mood stabilizing treatments remains short in the evolution of bipolar disorder. Conclusions Treatment profiles are associated with functional evolution of patients and were not clearly determined by bipolar subtypes. These profiles seem to group together common patient phenotypes. These findings do not seem to be influenced by the duration of disease prior to inclusion and neither by the number of treatments used during the follow-up period.

Background: Lithium is well described in managing certain mental illnesses including in people with intellectual disabilities (ID). It requires regular monitoring particularly of serum levels and r...

Purpose:rapid cycle bipolar disorder may be more resistant to treatment than other bipolar disorders. However, the effect of the synergistic use of carbamazepine and lithium in the treatment of outpatients with rapid cycle bipolar disorder without psychiatric comorbidity has not been studied in a double-blind, placebo-controlled design.Patients and methods: participants in a double-blind, placebo-controlled study met DSM-5 criteria for bipolar disorder with a rapid cycle between the ages of 18 and 65 years. The response and side effects of carbamazepine, lithium, and placebo were compared using analysis of variance (ANOVA) and chi-square tests. The respondent underwent F2, demonstrating superiority with respect to carbamazepine and lithium than in the case of placebo. Carbamazepine and lithium were generally well tolerated by the study patients, although a larger number of patients receiving carbamazepine and lithium (n = 2) early discontinued the study due to side effects.Results:twenty-seven of the 36 participants taking the combined carbamazepine and lithium regimen responded at 12 weeks, compared with six of 38 participants who received a placebo (p < 0.001). Two common side effects that led to discontinuation of carbamazepine and the lithium group were allergic reaction and drowsiness. Frequent complaints of sweating and headache during placebo treatment occurred in two out of 38 men. There were no unexpected or serious adverse events.Conclusions: the combined use of carbamazepine and lithium in the treatment of outpatients with rapid cycle bipolar disorder has demonstrated superior use of carbamazepine and lithium than placebo.

The goals of the current study were to determine whether topological organization of brain structural networks is altered in youth with bipolar disorder, whether such alterations predict treatment outcomes, and whether they are normalized by treatment. Youth with bipolar disorder were randomized to double-blind treatment with quetiapine or lithium and assessed weekly. High-resolution MRI images were collected from children and adolescents with bipolar disorder who were experiencing a mixed or manic episode (n = 100) and healthy youth (n = 63). Brain networks were constructed based on the similarity of morphological features across regions and analyzed using graph theory approaches. We tested for pretreatment anatomical differences between bipolar and healthy youth and for changes in neuroanatomic network metrics following treatment in the youth with bipolar disorder. Youth with bipolar disorder showed significantly increased clustering coefficient (Cp) (p = 0.009) and characteristic path length (Lp) (p = 0.04) at baseline, and altered nodal centralities in insula, inferior frontal gyrus, and supplementary motor area. Cp, Lp, and nodal centrality of the insula exhibited normalization in patients following treatment. Changes in these neuroanatomic parameters were correlated with improvement in manic symptoms but did not differ between the two drug therapies. Baseline structural network matrices significantly differentiated medication responders and non-responders with 80% accuracy. These findings demonstrate that both global and nodal structural network features are altered in early course bipolar disorder, and that pretreatment alterations in neuroanatomic features predicted treatment outcome and were reduced by treatment. Similar connectome normalization with lithium and quetiapine suggests that the connectome changes are a downstream effect of both therapies that is related to their clinical efficacy.

AIMS Long-term lithium therapy (LTLT) has been associated with kidney insufficiency in bipolar disorder (BD). We aimed to investigate the risk factors of chronic kidney disease (CKD) development and progression among BD patients receiving LTLT. METHODS We included adult patients with BD on LTLT (≥1 year) who were enrolled in the Mayo Clinic Bipolar Biobank, Rochester, Minnesota. We reviewed electronic medical records to extract information related to lithium therapy and kidney-related data to assess changes in the estimated glomerular filtration rate (eGFR). CKD severity was assessed based on eGFR. RESULTS Among 154 patients who received LTLT, 41 patients (27%) developed CKD, of whom 20 (49%) patients continued lithium (continuers) and 19 (46%) discontinued it (discontinuers). The median time to stage 3 CKD development was 21.7 years from the start of Li treatment. Type-2 diabetes mellitus and benzodiazepine use were independent predictors for CKD development in the survival analysis, after controlling for age. The subsequent CKD progression rate did not differ between continuers and discontinuers (mean GFR 48.6 vs. 44.1, p = 0.13) at the end of follow-up duration (mean duration: 3.5 ± 4.4 years for continuers and 4.9 ± 5.3 years for discontinuers). CONCLUSION CKD was observed in one fourth of patients with BD receiving LTLT. There was no significant difference in the progression of CKD among Li continuers versus discontinuers, at the mean follow-up duration of 4.2 years, after the CKD diagnosis. Progression of CKD could be influenced by existing comorbidities and may not necessarily be due to lithium alone.

Bipolar disorder (BD) is a neuropsychiatric illness defined by recurrent episodes of mania/hypomania, depression and circadian rhythm abnormalities. Lithium is an effective drug for BD, but 30-40% of patients fail to respond adequately to treatment. Previous work has demonstrated that lithium affects the expression of "clock genes" and that lithium responders (Li-R) can be distinguished from non-responders (Li-NR) by differences in circadian rhythms. However, circadian rhythms have not been evaluated in BD patient neurons from Li-R and Li-NR. We used induced pluripotent stem cells (iPSCs) to culture neuronal precursor cells (NPC) and glutamatergic neurons from BD patients characterized for lithium responsiveness and matched controls. We identified strong circadian rhythms in Per2-luc expression in NPCs and neurons from controls and Li-R, but NPC rhythms in Li-R had a shorter circadian period. Li-NR rhythms were low amplitude and profoundly weakened. In NPCs and neurons, expression of PER2 was higher in both BD groups compared to controls. In neurons, PER2 protein levels were higher in BD than controls, especially in Li-NR samples. In single cells, NPC and neuron rhythms in both BD groups were desynchronized compared to controls. Lithium lengthened period in Li-R and control neurons but failed to alter rhythms in Li-NR. In contrast, temperature entrainment increased amplitude across all groups, and partly restored rhythms in Li-NR neurons. We conclude that neuronal circadian rhythm abnormalities are present in BD and most pronounced in Li-NR. Rhythm deficits in BD may be partly reversible through stimulation of entrainment pathways.

Background Bipolar disorder (BD) is highly heritable and often severe, particularly when illness onset occurs early in life. There is limited knowledge regarding the clinical and neurostructural correlates of family history of BD among youth with BD. Methods Clinical characteristics were evaluated in 197 youth with BD, ages 13-20 years, including 87 with familial BD and 110 with non-familial BD. Structural neuroimaging was examined in a subsample of familial BD (n=39), non-familial BD (n=42), and healthy control (HC, n=58) youth. Region of interest (ROI) analyses of anterior cingulate cortex (ACC), inferior frontal gyrus (IFG), and amygdala were complemented by whole-brain vertex-wise analyses. Results Youth with familial BD had more family history of other psychiatric disorders, less severe worst manic episode, and less treatment with lithium, selective serotonin reuptake inhibitor (SSRI) antidepressants, and any lifetime psychiatric medications. None of these findings survived after correction for multiple comparisons. There were no significant between-group differences in ROI analyses. In whole-brain analyses, significant differences in cortical thickness were as follows: familial and non-familial BD Limitations Relatives did not complete full diagnostic interviews. Conclusions There were relatively few differences in clinical and neurostructural correlates related to family history of BD in youth with BD. Current findings suggest that family history of BD is not a strong contributor to the clinical or neuroimaging phenotypes in youth with BD.

Background Catatonia is a psychomotor syndrome that presents various symptoms ranging from stupor to agitation, with prominent disturbances of volition. Its pathogenesis is poorly understood. Benzodiazepines and electroconvulsive therapy (ECT) are safe and effective standard treatments for catatonia; however, alternative treatment strategies have not been established in cases where these treatments are either ineffective or unavailable. Here, we report a case of catatonia associated with late-life psychosis, which was successfully treated with lithium. Case presentation A 66-year-old single man with hearing impairment developed hallucination and delusions and presented with catatonic stupor after a fall. He initially responded to benzodiazepine therapy; however, his psychotic symptoms became clinically evident and benzodiazepine provided limited efficacy. Blonanserin was ineffective, and ECT was unavailable. His catatonic and psychotic symptoms were finally relieved by lithium monotherapy. Conclusions Catatonic symptoms are common in patients with mood disorders, suggesting that lithium may be effective in these cases. Moreover, lithium may be effective for both catatonic and psychotic symptoms, as it normalizes imbalances of excitatory and inhibitory systems in the brain, which underlies major psychosis. Cumulative evidence from further cases is needed to validate our findings.

Introduction : Altered levels of acute-phase proteins are often described in different conditions in BD. Nevertheless, data on the association between lithium treatment and inflammatory markers in the long-term course of BD are still missing. The aim of the study was to examine the long-term course of BD concerning long-term lithium treatment, chronic inflammatory processes and symptom progression. Furthermore, the association between duration of lithium treatment and levels of hsCRP was explored. Methods : 267 individuals (males= 139, females= 128) with BD were included. Duration of lithium treatment as well as symptom progression, defined as the increase in severity of symptoms, number of episodes a year and duration of episodes within a period of 1.5 years in the past and hsCRP were evaluated. Results : Male individuals with symptom progression over time had significantly lower duration of lithium treatment compared to individuals without symptoms progression (U= 47.4, p=.037). There were significantly higher levels of hsCRP in male individuals with symptom progression compared to males without symptom progression (U= 47.5, p=.027). Further, there was a significant negative correlation between the duration of lithium treatment and hsCRP levels in the whole sample (r= -.276, p Conclusion : Our results show that an altered inflammatory state may be associated with a more severe illness course in BD. Further, a longer duration of lithium treatment may be associated with lower symptom progression. The shown association between hsCRP-levels and lithium treatment duration suggests a potential anti-inflammatory effect of lithium as a mediator of its significant positive outcome effect in BD.

Objective Due to the global spread of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), guidance for the use of psychotropic drugs in this context is necessary. We aimed to review clinical evidence regarding the potential toxicity of psychiatric medications in the context of SARS-CoV-2 infection. Methods A systematic search for all types of empirical studies and reviews in a broad set of electronic databases and trial registries was conducted up to the 15th of August 2020. Results We identified 3 case series and 4 single-case reports on the occurrence of toxicity induced by various psychotropic drugs (lithium, n = 2; clozapine, n = 5; risperidone n = 2; haloperidol n = 1; duloxetine, n = 1). In addition, we provide a new case report on the possible precipitation of valproic acid-induced hyperammonemic encephalopathy. In most cases, SARS-CoV-2 infection may have precipitated drug toxicity/side effects. The management of toxicity did not diverge from the usually applied principles in the absence of infection. Conclusions Due to the limited available evidence and the recent genomic diversity and evolution of the SARS-CoV-2, it is currently not possible to derive evidence-based recommendations for the use of psychotropic drugs in the context of SARS-CoV-2 infection. Nevertheless, we provide some guidance based on the reviewed literature. At the current state of knowledge, there is no contraindication for any psychotropic drug. Caution is warranted regarding the dosing and, in particular, the monitoring of clozapine, lithium and valproate.

Introduction The aim of this study was to compare the outcomes of monotherapy in individuals with bipolar disorder who are prescribed lithium, valproate, quetiapine, olanzapine, venlafaxine, or citalopram in private psychiatric practices in Germany. Methods This retrospective study included bipolar disorder patients who had initially started on a monotherapy with lithium, valproate, quetiapine, olanzapine, venlafaxine, or citalopram in 93 private neuropsychiatric practices in Germany between January 2006 and December 2017. Treatment failure was defined as time to discontinuation of medication or addition of another mood stabilizer, antipsychotic, antidepressant, or benzodiazepine. Results A total of 4990 bipolar patients was examined for the period between 2006 and 2019. Initially, monotherapy with lithium (n=1.098), valproate (n=502), quetiapine (n=927), olanzapine (n=927), venlafaxine (n=574), or citalopram (n=962) was prescribed. Within 24 months, treatment failure had occurred in 76.3% (lithium), 85.1% (valproate), 84.6% (quetiapine), 85.2% (venlafaxine), 92.1% (olanzapine), and 86.6% (citalopram) of patients, respectively. The hazard ratio for treatment failure compared to lithium as reference was highest for olanzapine at 1.66 (1.46–1.88), followed by citalopram 1.27 (1.15–1.39), quetiapine 1.18 (1.07–1.29), valproate 1.18 (1.06–1.33), and venlafaxine 1.14 (1.02–1.27). Conclusions Our results underline the importance of lithium in the maintenance treatment of bipolar disorders.

Immune-inflammatory mechanisms are involved in the pathophysiology of bipolar disorder. Tetracyclines present neuroprotective actions based on their anti-inflammatory and microglia suppressant effects. Doxycycline (DOXY) is a tetracycline that demonstrates a better usage profile with protective actions against inflammation and CNS injury. Here, we investigated the effects of DOXY against behavioral, neuroinflammatory, and pro-oxidative changes induced by the d-amphetamine mania model. Adult mice were given d-amphetamine 2.0 mg/kg or saline for 14 days. Between days 8 and 14, received lithium, DOXY (25 or 50 mg/kg), or their combination (lithium+DOXY) on both doses. We collected the brain areas prefrontal cortex (PFC), hippocampus, and amygdala to evaluate inflammatory and oxidative alterations. D-amphetamine induced hyperlocomotion and impairment in recognition and working memory. Lithium reversed hyperlocomotion but could not restore cognitive alterations. DOXY alone (at both doses) or combined with lithium reversed d-amphetamine-induced cognitive changes. DOXY, better than lithium, reversed the d-amphetamine-induced rise in TNFα, MPO, and lipid peroxidation. DOXY reduced the hippocampal expression of Iba1 (a marker of microglial activation), inducible nitric oxide synthase (iNOS), and nitrite. Combined with lithium, DOXY increased the phosphorylated (inactivated) form of GSK3β (Ser9). Therefore, DOXY alone or combined with lithium reversed cognitive impairment and neuroinflammation induced by the mice's d-amphetamine model. This study points to DOXY as a promising adjunctive tool for bipolar disorder treatment focused on cognition and neuroimmune changes. Our data provide the first rationale for clinical trials investigating DOXY therapeutic actions in bipolar disorder mania.

Background Bipolar disorder is the fourth most common mental health condition, affecting ~ 1% of UK adults. Lithium is an effective treatment for prevention of relapse and hospital admission, and is widely recommended as a first-line treatment. We previously showed in other areas that laboratory testing patterns are variable with sub-optimal conformity to guidance. We therefore examined lithium results and requesting patterns relative to monitoring recommendations. Methods Data on serum lithium levels and intervals between requests were extracted from Clinical Biochemistry laboratory information systems at the University Hospitals of North Midlands, Salford Royal Foundation Trust and Pennine Acute Hospitals from 2012 to 2018 (46,555 requests; 3371 individuals). Data were examined with respect to region/source of request, age and sex. Results Across all sites, lithium levels on many requests were outside the recommended UK therapeutic range (0.4–0.99 mmol/L); 19.2% below the range and 6.1% above the range (median [Li]: 0.60 mmol/L). A small percentage were found at the extremes (3.2% at Conclusions Our data showed: (a) lithium levels are often maintained at the lower end of the recommended therapeutic range, (b) patterns of lithium results and testing frequency were comparable across three UK sites with differing models of care and, (c) re-test intervals demonstrate a noticeable peak at the recommended 3-monthly, but not at 6-monthly intervals. Many tests were repeated outside expected frequencies, indicating the need for measures to minimise inappropriate testing.

Introduction: Lithium is one of the first therapeutic options for bipolar disorder, which is characterized by recurrent mood swings that strongly reduce quality of life. Our purpose was to achieve professional consensus criteria to define the contents of an information sheet for patients with bipolar disorder that are starting treatment with lithium. Material and methods: A modified Delphi method in two rounds was used. The Scientific Committee—made up by nine psychiatrists—created a 20-item questionnaire about the information that must be given to the patient treated with lithium and selected a panel of ambulatory and hospital psychiatric experts to agree on this information. Panelists scored each item based on a Likert scale of 9 points and could add comments in a confidential manner. It was considered consensus in agreement when median scores were within the range of [7-9] and in disagreement within the range of [1-3]. Results: A high level of consensus was reached. In the first round, there was agreement on 17 out of 20 items and, after the second round, there was disagreement on just one item containing information about the discovery of lithium. Finally, said item was modified in the Patient's Information Sheet based on the comments suggested by the panelists. Conclusions: This study allowed to create an information sheet for patients with bipolar disorder under treatment with lithium, with information agreed upon by a group of experts from different health care settings.

Background Lithium-induced nephropathy is a known long-term complication, sometimes limiting the use of lithium as mood stabilizer. The aim of this study is to establish the incidence of chronic kidney disease and the rate of decline of renal function in patients using lithium and to identify risk factors. Methods We selected 1012 patients treated with lithium from the laboratory database of the Antes Centre for Mental Health Care spanning a period from 2000 to 2015. Serum lithium and creatinine concentrations were retrieved and eGFR was calculated using the 4-variable CKD-EPI formula. We calculated the incidence of renal insufficiency and the rate of decline. We compared patients with and without chronic kidney disease (CKD) stage 3 regarding duration of lithium exposure. Results Incidence of chronic kidney disease was 0.012 cases per exposed patient-year. Average decline of eGFR was 1.8 ml/min/year in patients who developed chronic kidney disease stage 3. Incidence of chronic kidney disease stage 4 was only 0.0004 per patient year. No cases of end stage renal disease were found in this cohort. Odds of reaching chronic kidney disease stage 3 were increased with longer duration of lithium exposure. Conclusions The use of lithium seems to be related to a higher incidence of chronic kidney disease. Longer duration of lithium exposure significantly increased the risk of renal failure.

BackgroundThe prevalence of mental health conditions and national suicide rates are increasing in many countries. Lithium is widely and effectively used in pharmacological doses for the treatment and prevention of manic/depressive episodes, stabilising mood and reducing the risk of suicide. Since the 1990s, several ecological studies have tested the hypothesis that trace doses of naturally occurring lithium in drinking water may have a protective effect against suicide in the general population.AimsTo synthesise the global evidence on the association between lithium levels in drinking water and suicide mortality rates.MethodThe MEDLINE, Embase, Web of Science and PsycINFO databases were searched to identify eligible ecological studies published between 1 January 1946 and 10 September 2018. Standardised regression coefficients for total (i.e. both genders combined), male and female suicide mortality rates were extracted and pooled using random-effects meta-analysis. The study was registered with PROSPERO (CRD42016041375).ResultsThe literature search identified 415 articles; of these, 15 ecological studies were included in the synthesis. The random-effects meta-analysis showed a consistent protective (or inverse) association between lithium levels/concentration in publicly available drinking water and total (pooled β = −0.27, 95% CI −0.47 to −0.08; P = 0.006, I2 = 83.3%), male (pooled β = −0.26, 95% CI −0.56 to 0.03; P = 0.08, I2 = 91.9%) and female (pooled β = −0.13, 95% CI −0.24 to −0.02; P = 0.03, I2 = 28.5%) suicide mortality rates. A similar protective association was observed in the six studies included in the narrative synthesis, and subgroup meta-analyses based on the higher/lower suicide mortality rates and lithium levels/concentration.ConclusionsThis synthesis of ecological studies, which are subject to the ecological fallacy/bias, supports the hypothesis that there is a protective (or inverse) association between lithium intakes from public drinking water and suicide mortality at the population level. Naturally occurring lithium in drinking water may have the potential to reduce the risk of suicide and may possibly help in mood stabilisation, particularly in populations with relatively high suicide rates and geographical areas with a greater range of lithium concentration in the drinking water. All the available evidence suggests that randomised community trials of lithium supplementation of the water supply might be a means of testing the hypothesis, particularly in communities (or settings) with demonstrated high prevalence of mental health conditions, violent criminal behaviour, chronic substance misuse and risk of suicide.

OBJECTIVES: Lithium is an effective treatment for bipolar disorder, also during pregnancy to prevent the recurrence of episodes in the perinatal period. Little is known about the neuropsychological development of lithium-exposed offspring. The current study was designed to investigate neuropsychological functioning in lithium-exposed children with the aim to provide further knowledge on the long-term effects of lithium use during pregnancy.METHODS: Participants were offspring of women with a diagnosis of bipolar spectrum disorder, aged 6-14 years. In total, 99 children participated in the study, 56 were exposed to lithium in utero and 43 were not exposed to lithium. Neuropsychological tests were administered, including the Snijders-Oomen Nonverbal Intelligence Test and the NEPSY-II-NL assessment. Linear and negative binomial regression models were used to investigate the association between prenatal lithium exposure and neuropsychological functioning. In secondary analyses, the association between lithium blood level during pregnancy and neuropsychological functioning was assessed. Additionally, norm scores and percentiles for task outcomes were calculated.RESULTS: Lithium use during pregnancy was associated with the total number of mistakes made on the Auditory Attention task, but not statistically significant after full adjustment for potential confounding factors. No association between prenatal lithium exposure and IQ was found. Also, no relationship between lithium blood level during pregnancy and neuropsychological functioning was found after adjustment for potential confounders. Task outcomes in both groups were comparable to the general population.CONCLUSION: In this study, we found no evidence for significantly altered neuropsychological functioning of lithium-exposed children at the age of 6-14 years, when compared to non-lithium-exposed controls.

BackgroundDespite its pivotal role in prophylaxis for bipolar-I-disorders (BD-I), variability in lithium (Li) response is poorly understood and only a third of patients show a good outcome. Converging research strands indicate that rest–activity rhythms can help characterize BD-I and might differentiate good responders (GR) and non-responders (NR).MethodsSeventy outpatients with BD-I receiving Li prophylaxis were categorized as GR or NR according to the ratings on the retrospective assessment of response to lithium scale (Alda scale). Participants undertook 21 consecutive days of actigraphy monitoring of sleep quantity (SQ), sleep variability (SV) and circadian rhythmicity (CR).ResultsTwenty-five individuals were categorized as GR (36%). After correcting statistical analysis to minimize false discoveries, four variables (intra-daily variability; median activity level; amplitude; and relative amplitude of activity) significantly differentiated GR from NR. The odds of being classified as a GR case were greatest for individuals showing more regular/stable CR (1.41; 95% confidence interval (CI) 1.08, 2.05; p < 0.04). Also, there was a trend for lower SV to be associated with GR (odds ratio: 0.56; 95% CI 0.31, 1.01; p < 0.06).ConclusionsTo our knowledge, this is the largest actigraphy study of rest–activity rhythms and Li response. Circadian markers associated with fragmentation, variability, amount and/or amplitude of day and night-time activity best-identified GR. However, associations were modest and future research must determine whether these objectively measured parameters, singly or together, represent robust treatment response biomarkers. Actigraphy may offer an adjunct to multi-platform approaches aimed at developing personalized treatments or stratification of individuals with BD-I into treatment-relevant subgroups.

Background When evaluating the long-term treatment response to mood stabilizers using the Alda scale, mood stabilizer combination therapy is typically considered a confounding factor, and patients receiving combination therapy are excluded from the analysis. However, this may result in bias if those under combination therapy are worse treatment responders. This study aims to explore whether the Alda scale is applicable to patients taking lithium and valproate combination therapy. We compared long-term treatment response in patients receiving monotherapy and combination therapy of the two drugs, and investigated clinical correlates of the responses to each drug. Methods The study subjects consisted of 102 patients with bipolar I (BD-I) or bipolar II (BD-II) disorder who had been undergoing maintenance treatment with lithium and/or valproate for more than 2 years at a single specialized bipolar disorder clinic. Long-term treatment response was measured using the Alda scale and compared among the lithium monotherapy group, the valproate monotherapy group, and the mood stabilizer combination group. Clinical correlates of long-term treatment response were evaluated in lithium users and valproate users separately. Results There were no significant differences in terms of baseline illness characteristics among groups. The combination group showed the worst treatment response for all the response measurements applied. This group also had the higher rate of ‘poor responder’ with a statistically significant difference compared to valproate group. Older age at onset and (hypo)manic episode at onset showed significant positive associations with total Alda score in lithium users, while comorbid anxiety disorders, obsessive–compulsive disorder and mixed episode showed significant negative associations in valproate users. Conclusions The combination group had poorer long-term treatment response but did not show distinct clinical characteristics compared to the monotherapy groups. When exploring the long-term effects of mood stabilizers, excluding patients undergoing combination treatment could result in bias because they may represent a poor response group. The long-term treatment responses of lithium and valproate had different clinical correlates.

Objective : Several evidence-based practice guidelines have been developed to better treat bipolar disorder. However, the articles cited in these guidelines were based on clinical or basic studies with specific conditional settings and were not sufficiently based on real-world clinical practice. In particular, there was little information on the doses of mood stabilizers. Methods The MUlticenter treatment SUrvey on BIpolar disorder in Japanese psychiatric clinics (MUSUBI) is a study conducted to accumulate evidence on the real-world practical treatment of bipolar disorder. The questionnaire included patient characteristics such as comorbidities, mental status, treatment period, Global Assessment of Functioning (GAF) score, and details of pharmacological treatment. Results Most patients received mood stabilizers such as lithium (n = 1,317), valproic acid (n = 808), carbamazepine (n = 136), and lamotrigine (n = 665). The dose of lithium was correlated with age, body weight, number of episodes, depression and GAF. The dose of valproic acid was correlated with body weight, number of episodes, presence of a rapid cycle and GAF. The dose of carbamazepine was correlated with age, mania, and the presence of a rapid cycle. The dose of lamotrigine was correlated with the number of episodes, depression, mania, psychotic features, and the presence of a rapid cycle. Doses of coadministered mood stabilizers were significantly correlated, except for the combination of valproic acid and lamotrigine. Conclusion The dose of mood stabilizers was selectively administered based on several factors, such as age, body composition, current mood status and functioning. Further prospective studies are required to confirm these findings.

Background Bipolar Disorder (BD) is associated with a decrease in cellular resilience. Despite the half a century old discovery of lithium's efficacy for the treatment of BD, its exact mechanisms remain elusive. Accumulating data suggest that lithium's cytoprotective properties involve the modulation of several UPR proteins, such as GRP78. Mesencephalic astrocyte-derived neurotrophic factor (MANF) is an endoplasmic reticulum resident protein that regulates proteostasis through directly interacting with GRP78. The purpose of this study was to determine whether lithium increases MANF expression using cellular and rodent models and, if so, to elucidate the cellular mechanisms of action. Procedure Mouse striatal neuroblasts were treated with PBS, lithium, or lithium + Activator Protein-1 (AP-1) inhibitor for 24-72 hours. Once cells were harvested, mRNA was extracted. In vivo experiments included, intraperitoneal injections of lithium or saline to male Sprague Dawley rats twice daily for 14 consecutive days. Following drug treatment, brain tissue was isolated, and mRNA was extracted from various regions. MANF gene expression was measured using RT-qPCR. Results In vitro studies showed lithium-treated cells displayed a significant increase in MANF mRNA expression compared to controls. In contrast, cells treated with lithium and AP-1 inhibitor showed no increase in expression. Similarly, in vivo studies revealed that lithium-treated rats compared to controls had a significant increase in MANF expression in the PFC and striatum. Conclusion Taken together, these data suggest that lithium's therapeutic mechanism involves the maintenance of ER homeostasis via increased MANF gene expression mediated by the AP-1 transcription factor.

Background: Lithium in drinking water may have significant mental health benefits. We investigated the evidence on the association between lithium concentrations in drinking water and their neuropsychiatric outcomes. Methods: We conducted a systematic review and meta-analysis and searched Pubmed, Embase, Web of Science, PsycINFO and CINAHL up to 19 January 2020, for peer-reviewed research examining the association between lithium concentrations in drinking water and neuropsychiatric outcomes. We used a pairwise analysis and a random effects model to meta-analyse suicide rates and psychiatric hospital admissions. We assessed for publication bias using Egger’s test and Duval and Tweedie’s Trim and Fill analysis. Results: Twenty-seven studies including 113 million subjects were included in this systematic review. Meta-analysis of 14 studies including 94 million people found higher lithium concentrations were associated with reduced suicide rates ( r = −0.191, 95% confidence interval = [−0.287, −0.090], p 2 = 80.7%) and the presence of publication bias (Egger’s test; t value = 2.90, p = 0.013). Other included studies did not provide sufficient data to analyse other neuropsychiatric outcomes quantitatively. Conclusion: Higher lithium concentrations in drinking water may be associated with reduced suicide rates and inpatient psychiatric admissions. The relationship with other neuropsychiatric outcomes and complications remains unclear. Further research is required before any public health recommendations can be made. Trial registration number: The study was registered with PROSPERO, number CRD42018090145.