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Previous studies have shown the therapeutic properties of ginseng and ginsenosides on hyperactive and impulsive behaviors in several psychiatric diseases. Herein, we investigated the effect of Panax ginseng Meyer (PG) on hyperactive/impulsive behaviors in a manic-like animal model, sleep deprivation (SD) rats. Male rats were sleep-deprived for 48 h, and PG (200 mg/kg) was administered for 4 days, from 2 days prior to the start of SD to the end date of SD. The elevated plus maze (EPM) test showed that PG alleviated the increased frequency of entries into and spent time within open arms by SD. In order to investigate the molecular mechanism on this effect of PG, we assessed differentially expressed genes (DEGs) in the prefrontal cortex of PG-treated SD rats using RNA sequencing (RNA-seq) and performed gene-enrichment analysis for DEGs. The gene-enrichment analysis showed that PG most prominently affected the glutamatergic synapse pathway. Among the glutamatergic synapse pathway genes, particularly, PG enhanced the expressions of glutamate transporter Slc1a3 and Slc1a2 reduced in SD rats. Moreover, we found that PG could inhibit the SD-induced phosphorylation of the NR2A subunit of the NMDA receptor. These results suggested that PG might have a therapeutic effect against the manic-like behaviors, regulating the glutamatergic neurotransmission.

Introduction: Acute manic episodes are a psychiatric emergency related to violence and poor patient outcomes. Combination psychotropic therapy utilizing a mood stabilizer and an atypical antipsychotic has been shown to be more efficacious for treating acute mania compared to monotherapy with either mood stabilizers or antipsychotics alone. This quality improvement project implemented evidence-based interventions for treating acute mania. The mania pathway protocol was created as a comprehensive clinical guide for guiding mania treatment. The protocol was implemented on an inpatient psychiatric unit for patients with mania diagnoses including manic/mixed episodes of bipolar disorder or schizoaffective disorder. Aims: (1) to improve the treatment of mania by using evidence-based interventions for rapid mood stabilization and (2) to educate psychiatric providers on up-to-date interventions for treating acute manic states. Method: Psychiatric providers were evaluated for knowledge enhancement through a pre-/post–educational session quiz. A retrospective chart review was used for data collection for patients treated with the mania pathway protocol. The retrospective chart review spanned 8 weeks post project implementation. Young Mania Rating Scale (YMRS) scores were analyzed to measure the effect on mania severity. Results: The percentage decrease in mean Young Mania Rating Scale scores from admission to the fifth day of hospitalization was 61%. All psychiatric providers proved knowledge attainment by scoring 100% on the postintervention quiz. Conclusions: Rapid mood stabilization may be achieved by using a combination therapy–based mania protocol. Educational sessions can enhance psychiatric provider knowledge with regard to evidence-based treatments for mania.

The pathogenesis of the Bipolar Disorder(BPD) is still unclear. Some studies suggest that abnormal signal transduction in specific pathways may play an important role in the pathogenesis of BPD (Sui et al., 2015). Adenylate cyclase (ADCY) is an essential component of the adenylate signaling pathway. Previous studies have shown that some SNPs within the adenylate cyclase gene could affect the therapeutic response to mood stabilizers and antidepressants. Moreover, in 2014, one whole-genome study suggested that the ADCY-2 gene may be associated with BPD (Muhleisen et al., 2014). This study aims to investigate the association between ADCY-2 gene polymorphism and BPD in Chinese Han population.

Introduction Lithium is the gold standard in treating bipolar affective disorders. As patients become increasingly older, drug-drug interactions leading to decreased excretion of lithium represent a key issue in lithium safety. As no study considered the effect of comedications on lithium serum concentration in combination, we aimed to quantify the impact of drugs affecting renal blood flow and function and thus potentially interacting drugs (diuretics, ACE inhibitors, AT1 antagonists, and non-steroidal anti-inflammatory drugs) on lithium serum levels in addition to age, sex, and sodium and potassium serum levels as well as renal function. Methods Retrospective data of lithium serum levels were analyzed in 501 psychiatric inpatients (2008–2015) by means of linear regression modelling. Results The number of potentially interacting drugs was significantly associated with increasing serum levels of lithium in addition to the established factors of age, renal function, and sodium concentration. Additionally, absolute lithium levels were dependent on sex, with higher values in females. However, only NSAIDs were identified to increase lithium levels independently. Discussion Routine clinical practice needs to focus on drugs affecting renal blood flow and function, especially on NSAIDs as over-the-counter medication that may lead to an increase in lithium serum concentration. To prevent intoxications, clinicians should carefully monitor the comedications, and they should inform patients about possible intoxications due to NSAIDs.

Lithium is a highly effective medication for bipolar disorder, but its mechanism of action remains unknown. In this study, brain MRI scans and blood samples for gene expression (total of 110 scans and 109 blood samples) were collected from 21 bipolar subjects before and after 2 and 8 weeks of lithium monotherapy and at the same time-points from untreated 16 healthy controls. We used linear mixed-effects models to identify brain structural features and genes with expression changed after lithium treatment, with correction for multiple testing, and correlated their concurrent changes to identify molecular pathways associated with lithium effects. There are significant increases in gray matter fraction, global cortical thickness, and the frontal and parietal cortices after 8 weeks of lithium treatment (corrected p p p

Background Lithium is primarily used to treat bipolar disorder and is known to cause several acute neurological complications. Reversible splenial lesions (RSLs) may be evident in antiepileptic drug toxicity or withdrawal, infections, and other phenomena. We report two cases of RSL presenting as neuroleptic malignant syndrome-like symptoms (NMSLS) with lithium associated neurotoxicity. Case presentation A 28-year-old woman was admitted after taking increased dosages of lithium for schizophrenia. She experienced generalized tremor, rigidity, dysarthria, high fever, and tachycardia. Symptoms and brain lesion recovered 2 weeks after discontinuation of lithium. The second case involved a 59-year-old woman who was receiving treatment for bipolar disorder since 1988. When lithium was administered for impatience and aggressive behavior, her mental state deteriorated and fever developed, along with generalized tremor in the extremities. Brain magnetic resonance imaging (MRI) in both patients showed a reversible oval-shaped lesion localized to the splenium of the corpus callosum. Both patients were defined as neuroleptic malignant syndrome-like symptoms (NMSLS) based on the DSM-5 diagnostic criteria for neuroleptic malignant syndrome. The suspected etiology of our cases was lithium associated neurotoxicity according to their clinical course and medical information. Our patients fully recovered in 10–14 days after the discontinuation of lithium. Conclusions The patients experienced similar clinical courses and had similar radiological findings of RSL. Manifestations in both cases were related to lithium associated neurotoxicity and this should be considered in patients with RSL and NMSLS.

Optimal dose management of psychotropic drugs during the perinatal period reduces the risk for recurrence of mood episodes in women with Bipolar Disorder. Physiological changes during pregnancy are associated with decreases in the plasma concentrations of the majority of mood stabilizing medications. Regular symptom and drug concentration monitoring for lithium and anticonvulsants with reflexive dose adjustment improves the probability of sustained symptom remission across pregnancy. The elimination clearance trajectory across pregnancy for psychotropics dictates the frequency of laboratory monitoring and dose adjustment. The literature on the pharmacokinetics of lithium, lamotrigine, carbamazepine and atypical antipsychotics during pregnancy and postpartum are reviewed, recommendations for symptom and laboratory monitoring are proposed and recommendations for dose adjustments are presented.

Objectives Acute mania is a serious medical condition that impacts men and women equally. Longtime presentation of manic symptoms is sex‐dependent; however, little is known about acute symptoms of mania. The objective of this study is to track and compare acute manic symptoms for sex differences during inpatient hospitalization. Methods All patients with bipolar mania admitted to a large university hospital between January and October 2017 were invited to participate in this longitudinal naturalistic follow‐up study. Manic (YMRS), depressive (MADRS), and psychotic (PAS) symptoms were tracked daily from admission to discharge. Results The total YMRS scores decreased significantly overtime (p, The progression of certain domains of manic symptoms shows sex difference. Female manic patients had better insight into their illness compared to manic males who exhibited more sexual interest, disruptive, and aggressive behaviors, but better appearance. Both males and females received comparable doses of antipsychotics and lithium. Valproic acid (VPA) doses were significantly higher in males compared to females. However, VPA plasma concentrations were not significantly different between the two groups.

Predicting lithium response (LiR) in bipolar disorder (BD) may inform treatment planning, but phenotypic heterogeneity complicates discovery of genomic markers. We hypothesized that patients with “exemplary phenotypes”—those whose clinical features are reliably associated with LiR and non-response (LiNR)—are more genetically separable than those with less exemplary phenotypes. Using clinical data collected from people with BD (n = 1266 across 7 centers; 34.7% responders), we computed a “clinical exemplar score,” which measures the degree to which a subject’s clinical phenotype is reliably predictive of LiR/LiNR. For patients whose genotypes were available (n = 321), we evaluated whether a subgroup of responders/non-responders with the top 25% of clinical exemplar scores (the “best clinical exemplars”) were more accurately classified based on genetic data, compared to a subgroup with the lowest 25% of clinical exemplar scores (the “poor clinical exemplars”). On average, the best clinical exemplars of LiR had a later illness onset, completely episodic clinical course, absence of rapid cycling and psychosis, and few psychiatric comorbidities. The best clinical exemplars of LiR and LiNR were genetically separable with an area under the receiver operating characteristic curve of 0.88 (IQR [0.83, 0.98]), compared to 0.66 [0.61, 0.80] (p = 0.0032) among poor clinical exemplars. Variants in the Alzheimer’s amyloid–secretase pathway, along with G-protein-coupled receptor, muscarinic acetylcholine, and histamine H1R signaling pathways were informative predictors. This study must be replicated on larger samples and extended to predict response to other mood stabilizers.

Background Uric acid (UA) has been suggested as a possible biomarker of bipolar disorder (BD) in recent studies. We aimed to provide a clearer comparison of UA levels between BD and major depressive disorder (MDD). Methods We retrospectively reviewed the medical chart records of psychiatric inpatients aged 19–60 years, whose main discharge diagnoses were either MDD or BD, with an admission between January 1, 2015 and December 31, 2018 at Seoul National University Hospital. Data such as sex, age, body mass index (BMI), medication usage, and serum UA levels were extracted. Patients with medical conditions or on medications that could influence UA levels were excluded. Age, sex, BMI, and psychiatric drug usage were considered in the comparison of serum UA between MDD and BD patients. Results Our sample consisted of 142 MDD patients and 234 BD patients. The BD patients had significantly higher serum UA levels compared to the MDD patients, without accounting for other confounding variables (5.75 ± 1.56 mg/dL vs. 5.29 ± 1.59 mg/dL, P = 0.006). T-test comparisons between psychiatric medication users and non-users revealed that mood stabilizers and antipsychotics may be relevant confounding factors in our sample analysis. The likelihood of BD diagnosis was significantly correlated with higher UA levels (odds ratio, 1.410; 95% confidence interval, 1.150–1.728; P = 0.001) when accounting for sex, age, and BMI in the logistic regression analysis. Also, accounting for mood stabilizers or antipsychotics, the likelihood of BD diagnosis was still significantly correlated with higher UA levels. Conclusion Our study confirms that BD patients are significantly more likely to show higher serum UA levels than MDD patients. The high UA levels in BD point to purinergic dysfunction as an underlying mechanism that distinguishes BD from MDD. Further research is recommended to determine whether UA is a trait or a state marker and whether UA correlates with the symptoms and severity of BD., Graphical Abstract

Background Hyperammonemic encephalopathy is a rare and serious adverse reaction to valproate. Although there is documentation of this reaction in previous reports, very little is still known about the exact mechanism of action. In addition, there are no established guidelines of the next steps needed when a patient does develop this reaction. Therefore, this case report highlights what is known as well as the areas of research still needed. Case presentation Our patient was a 57-year-old Caucasian woman with a medical history of bipolar I disorder, opioid use disorder, benzodiazepine use disorder, and Crohn’s disease who was admitted to our behavioral health unit for suicidal ideation. She had been experiencing multiple panic attacks for 2.5 weeks along with poor sleep, increased energy, excessive spending, and feelings of helplessness. The patient was diagnosed with bipolar I disorder, manic episode without psychotic features, and benzodiazepine use disorder. She was started on valproic acid, citalopram, propranolol, and quetiapine. By day 6 of her hospitalization, the patient had altered mental status, varying levels of consciousness, confusion, and ataxic gait. Her ammonia levels were found to be elevated. All of her medications were discontinued, and lactulose was initiated. She returned to her baseline mentation within 48 hours and was discharged with lithium and quetiapine. The treatment team concluded that this patient had valproate-induced hyperammonemic encephalopathy, a rare but reversible reaction to valproate. Conclusion Fortunately, rapid identification of this rare condition led to a favorable outcome in our patient. This case report illustrates the course of treatment in a patient who experienced this reaction and reviews current knowledge as well as areas of needed research in regard to valproate-induced hyperammonemic encephalopathy.

Lithium activates Wnt/β-catenin signaling leading to stabilization of free cytosolic β-catenin. The aim of the present study is to evaluate the in vivo effect of acute and chronic lithium treatment on the expression of β-catenin target genes, addressing its transcripts HIG2, Bcl-xL, Cyclin D1, c-myc, in cortical and hippocampal tissue from adult mice. Lithium doses were established to yield therapeutic working concentrations. In acute treatment, mice received a 300µL of a 350 mg/kg solution of LiCl by gavage, and were euthanized after 2 h, 6 h and 12 h. To determine the effect of chronic treatment, animals were continuously fed either with chow supplemented with 2 g/kg Li2CO3, or regular chow (controls), being euthanized after 30 days. All animals had access to drinking water and 0.9% saline ad libitum. After acute and chronic treatments samples of peripheral blood were obtained from the tail vein for each animal, and serum concentrations of lithium were determined. All transcripts were up-regulated in cortical and hippocampal tissues of lithium-treated mice, both under acute and chronic treatments. There was a positive correlation between serum lithium concentrations and the increment in the expression of all transcripts. This effect was observed in all time points of the acute treatment (i.e., 2, 6 and 12 hours) and also after 30 days. We conclude that Wnt/β-catenin transcriptional response (HIG2, Bcl-xL, Cyclin D1 and c-myc) is up-regulated in the mouse brain in response to acute and chronic lithium treatment at therapeutic concentrations.

BackgroundStudies have shown that rates of lithium use for bipolar disorder (BPD) in the United States declined through the 1990s as other mood stabilizing anticonvulsants and second-generation antipsychotics (SGAs) became more popular. We examined recent prescribing trends of medications for BPD over the past two decades.MethodsTwenty years of data (1996-2015) from the National Ambulatory Medical Care Survey (NAMCS) were used. Weighted percentages of prescriptions of lithium, anticonvulsants, SGAs and antidepressants were calculated over two-year intervals. Logistic regression was used to examine factors related to polytherapy.ResultsPrescriptions of lithium declined from 38.1% (95%CI: 29.8% - 46.3%) in 1996-97 to 14.3% (95%CI: 10.6% - 18.1%) in 2006-07 and has remained stable since. During this time, prescriptions of SGAs more than doubled. SGAs and/or anticonvulsants were prescribed in 78.6% (95%CI: 73.0% - 84.2%) of BPD visits in 2014-2015. Polytherapy increased by approximately 4% every two years and in 2014-15 occurred in over 35% of BPD visits. Antidepressants were prescribed in 40-50% of BPD visits, but their prescriptions without other mood stabilizers decreased from 18.2% (95%CI: 11.7% - 24.8%) in 1998-99 to 5.8% (95%CI: 3.0% - 8.6%) in 2014-15.LimitationsThe sample had limited power to study the effect of individual medications or the potential for differing effects in certain subgroups of patients.ConclusionsThis study further documents the declining prescriptions of lithium for BPD, and corresponding increase in prescriptions of anticonvulsants and SGAs, despite the fact that lithium is typically recommended as a first line therapy for BPD.

Too many patients receive incorrect treatment for bipolar disorder; prescribing seems to differ more by clinician than by patient characteristics. New treatment guidelines are available for the management of acute manic episodes and can help clinicians make treatment decisions tailored to their patients' individual symptom clusters and illness characteristics, leading to greater chances of lasting remission. However, many clinicians lack familiarity with these symptom targeting best practices. Therefore, clinicians need education on how to manage bipolar I disorder symptoms with evidence-based treatment options. In addition, as new treatment targets are identified, clinicians need education on psychopharmacologic and pharmacokinetic advances.

BackgroundResistant bipolar disorder is a major mental health problem related to significant disability and overall cost. The aim of the current study was to perform a systematic review of the literature concerning (1) the definition of treatment resistance in bipolar disorder, (2) its clinical and (3) neurobiological correlates, and (4) the evidence-based treatment options for treatment-resistant bipolar disorder and for eventually developing guidelines for the treatment of this conditionMaterials and MethodsThe PRISMA method was used to identify all published papers relevant to the definition of treatment resistance in bipolar disorder and the associated evidence-based treatment options. The MEDLINE was searched to April 22, 2018.ResultsCriteria were developed for the identification of resistance in bipolar disorder concerning all phases. The search of the literature identified all published studies concerning treatment options. The data were classified according to strength, and separate guidelines regarding resistant acute mania, acute bipolar depression, and the maintenance phase were developed.DiscussionThe definition of resistance in bipolar disorder is by itself difficult due to the complexity of the clinical picture, course, and treatment options. The current guidelines are the first, to our knowledge, developed specifically for the treatment of resistant bipolar disorder patients, and they also include an operationalized definition of treatment resistance. They were based on a thorough and deep search of the literature and utilize as much as possible an evidence-based approach.

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

Bipolar disorder is a psychiatric pathology characterized by biphasic mood episodes of mania or hypomania and depression. The pharmacotherapy of bipolar disorder has significant adverse effects impairing treatment adherence and patient quality of life. The N/OFQ-NOP receptor system has been widely implicated with mood disorders. Clinical and preclinical findings suggest antidepressants actions for NOP antagonists. More recently, the administration of NOP agonists has shown to promote depressant states. The present study aimed to investigate the effects of non-peptide NOP ligands in methylphenidate-induced manic-like behavior in mice. The NOP agonist Ro 65–6570 (0.01–1 mg/kg, ip), at the higher dose, did not affect spontaneous locomotion per se, but prevented the methylphenidate (10 mg/kg, sc)-induced hyperlocomotion. The NOP partial agonist AT-090 (0.001–0.03 mg/kg, ip) and the NOP antagonist SB-612111 (1–10 mg/kg, ip) did not significantly affect the psychostimulant-induced hyperactivity. Experiments performed with mice lacking the NOP receptor (NOP(−/−)) demonstrated that the treatment with methylphenidate induced similar hyperlocomotion in NOP(−/−) and NOP(+/+) mice. In conclusion, these findings suggest a potential role for NOP agonists in the prevention of manic states, especially by counteracting the hyperactivity symptom of bipolar patients. However, more studies are necessary in order to evaluate these compounds in other features of bipolar disorder.

Background Although mood stabilizers such as lithium (LIT), valproate (VAL), and lamotrigine (LMT) appear to be efficacious treatments for bipolar disorder (BD) in research settings, the long-term response to these mood stabilizers in clinical practice is highly variable among individuals. Thus, the present study examined the characteristics associated with good or insufficient responses to long-term treatment with LIT, VAL, or LMT for BD. Methods This study retrospectively analyzed the medical records of patients who visited an outpatient clinic with a diagnosis of BD I or II. Data from patients who were treated with one of three mood stabilizing medications (LIT, VAL, or LMT) for more than 6 months were selected, and the long-term treatment responses were evaluated using the Alda scale. For the purposes of this study, two response categories were formed: insufficient response (ISR), including non-response or poor response (Alda total score ≤ 6), and good response (GR; Alda total score ≥ 7). Results Of the 645 patients included in the present study, 172 were prescribed LIT, 320 were prescribed VAL, and 153 were prescribed LMT for at least 6 months. A binary logistic regression analysis revealed that a diagnosis of BD II (odds ratio [OR], 8.868; 95% confidence interval [CI], 1.123–70.046; p = 0.038), comorbid alcohol/substance use disorder (OR, 4.238; 95% CI, 1.154–15.566; p = 0.030), and a history of mixed episodes (OR, 4.363; 95% CI, 1.191–15.985; p = 0.026) were significant predictors of LIT-ISR. Additionally, a depressive-predominant polarity significantly predicted LMT-GR (OR, 8.586; 95% CI, 2.767–26.644; p < 0.001). Conclusion The present findings demonstrated that patients with a diagnosis of BD II, a comorbid alcohol/substance problem, or a history of mixed episodes were not likely to respond to LIT treatment. Additionally, LMT might be a better treatment choice for patients with a depressive-predominant polarity.

Lithium Chloride (LiCl) toxicity, mode of action and cellular responses have been the subject of active investigations over the past decades. In yeast, LiCl treatment is reported to reduce the activity and alters the expression of PGM2, a gene that encodes a phosphoglucomutase involved in sugar metabolism. Reduced activity of phosphoglucomutase in the presence of galactose causes an accumulation of intermediate metabolites of galactose metabolism leading to a number of phenotypes including growth defect. In the current study, we identify two understudied yeast genes, YTA6 and YPR096C that when deleted, cell sensitivity to LiCl is increased when galactose is used as a carbon source. The 5'-UTR of PGM2 mRNA is structured. Using this region, we show that YTA6 and YPR096C influence the translation of PGM2 mRNA.

OBJECTIVE There is limited information available on the prescription of psychotropic agents to patients with bipolar I (BD-I) and bipolar II disorder (BD-II). The purpose of this study was to investigate the characteristics of drug therapy in BD-I and BD-II outpatients, particularly with regard to antidepressants. METHODS In 2017, the MUlticenter treatment SUrvey for BIpolar disorder in Japanese psychiatric clinics (MUSUBI) study collected data on current mental status, medications, and other factors from 2774 outpatients with BD-I or BD-II. RESULTS There were significant differences in the rates of prescriptions for mood stabilizers, antipsychotics and antidepressants. Mood stabilizers and antipsychotics were prescribed at higher rates to patients with BD-I (mood stabilizers; BD-I 86.0%, BD-II 80.8%, p

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

Abstract. Background: Suicide is often associated with depression in patients suffering from bipolar disorder (BD) and less is known about its relation to mania. Available data suggest that patients in the manic phase of BD may be at risk of suicide. Aim: We characterized suicide attempts in a cohort of patients with BD in manic and mixed phases. Method: We focused on the scope, rate, and characteristics of suicide attempts among BD patients during manic or mixed states. Associations between suicide as well as clinical and sociodemographic variables were analyzed using computerized medical chart data from 209 adult inpatients diagnosed (DSM-IV) as experiencing manic and mixed BD episodes. Results: The rate of recent suicide attempts among BD inpatients with manic and mixed episodes was 10.5%. Married patients had a decreased rate of suicide attempts. Comorbid alcohol or substance abuse were correlated with an increased risk of suicide attempts. Presence of suicidal ideation increased suicide risk while older age was linked to a decrease in the rate of suicide attempts. Limitations: The retrospective design of the study and overrepresentation of the clinical severity of BD were limitations. Conclusion: The rate of suicide attempts in the manic and mixed phases of BD is substantial and calls for raising awareness among psychiatrists.

This systematic review and meta-analysis summarized the results from nine eligible observational studies. Lithium use was significantly associated with a decrease risk of fractures. The association between lithium use and risk of fracture is uncertain. To date, there have been no meta-analyses that have studied the association between the two. We conducted a systematic review and meta-analysis to examine the effect of lithium medication on the risk of fracture. A comprehensive literature search was performed in PubMed, Embase, and MEDLINE to include eligible observational studies. Three reviewers conducted the literature search, study selection, study appraisal, and data abstraction independently. Random effects models were used to obtain the overall estimate for meta-analysis. Cochran’s Q and Higgins’ I2 were used to assess heterogeneity. A funnel plot and Egger’s regression test were employed to assess publication bias. Of the 3819 studies that were identified by our search strategy, eight were eligible for the systematic review, while seven of them qualified for the meta-analysis. In studies that reported risk ratio (RR) of fracture as an outcome (five studies [n = 1,134,722]), lithium use was associated with a 20% decrease in risk of fracture (RR = 0.80; 95% CI, 0.73–0.87; p

The aim of this study was to compare the effectiveness of lithium versus quetiapine immediate release (IR) monotherapy in patients with bipolar I, II, or subthreshold bipolar disorder at any phase.Eligible patients were randomized to lithium or quetiapine IR for 16 weeks. The difference in the time to discontinuation from study due to "all causes" between lithium and quetiapine IR groups and changes from baseline to 8 and 16 weeks in depression, mania, anxiety, quality of life (QOL), metabolic profiles, and proinflammatory markers were compared.Of the 42 patients randomized to lithium (n = 18) and quetiapine IR (n = 24), the median time to discontinuation due to "all causes" was 6 weeks (95% confidence interval, 2-12 weeks) in the lithium group and 8 weeks (95% confidence interval, 6 weeks to not calculable) in the quetiapine IR group. The mean time to discontinuation due to "all causes" was 7.7 ± 1.1 weeks for lithium versus 8.4 ± 0.8 weeks for quetiapine IR (P = 0.54). There was no significant difference between lithium and quetiapine IR in changes in the severity of depression, mania/hypomania, anxiety, and QOL as a whole or only in patients with depressive index episode. The decrease in total cholesterol was significantly larger with lithium than with quetiapine IR (P = 0.05) as a whole, but not only in patients with depression index episode. There was no other significant difference in changes in metabolic panels and inflammatory markers between the 2 groups.The difference in effectiveness between lithium and quetiapine IR monotherapy in a real-world bipolar population was minimal. Large-sample studies are needed to support or refute this finding.

Objectives To assess the efficacy and tolerability of lithium for the treatment of acute mania in children and adolescent diagnosed with bipolar disorder. Methods A systematic literature search up to August 2017 was conducted for clinical trials that included lithium in males and females up to 18 years of age with a diagnosis of bipolar disorder and experiencing a manic or mixed episode according to standardized diagnostic criteria. The protocol was registered in PROSPERO (CRD42017055675). Results Four independent studies described in seven manuscripts met the inclusion criteria. Overall, 176 patients were treated with lithium either as a monotherapy or adjunct to risperidone. Efficacy results suggest that lithium may be superior to placebo (standardized mean difference [SMD] −0.42, 95% confidence interval [CI] −0.88 to 0.04), comparable to sodium divalproex (SMD −0.07, 95% CI: −0.31 to 0.18), but significantly less effective than risperidone for treating protracted manic/mixed episodes and comorbid attention‐deficit hyperactivity disorder (ADHD) in prepubertal children (SMD 0.85, 95% CI: 0.54 to 1.15). Lithium was not associated with serious adverse events, and was generally well tolerated with common side effects similar to those reported in adults. Conclusions Limited data suggests that lithium may be an effective and tolerable treatment for some forms of paediatric mania. However, lithium is clearly inferior in efficacy to risperidone in prepubertal patients diagnosed with protracted manic/ mixed episodes and comorbid ADHD. There is a lack of data concerning the efficacy and tolerability of lithium as an acute treatment for classical mania in adolescents and important clinical issues remain unaddressed.

Lithium is the first-line treatment for bipolar affective disorder (BPAD) but two-thirds of patients respond only partially or not at all. The reasons for this high variability in lithium response are not well understood. Transcriptome-wide profiling, which tests the interface between genes and the environment, represents a viable means of exploring the molecular mechanisms underlying lithium response variability. Thus, in the present study we performed co-expression network analyses of whole-blood-derived RNA-seq data from n = 50 lithium-treated BPAD patients. Lithium response was assessed using the well-validated ALDA scale, which we used to define both a continuous and a dichotomous measure. We identified a nominally significant correlation between a co-expression module comprising 46 genes and lithium response represented as a continuous (i.e., scale ranging 0–10) phenotype (cor = −0.299, p = 0.035). Forty-three of these 46 genes had reduced mRNA expression levels in better lithium responders relative to poorer responders, and the central regulators of this module were all mitochondrially-encoded (MT-ND1, MT-ATP6, MT-CYB). Accordingly, enrichment analyses indicated that genes involved in mitochondrial functioning were heavily over-represented in this module, specifically highlighting the electron transport chain (ETC) and oxidative phosphorylation (OXPHOS) as affected processes. Disrupted ETC and OXPHOS activity have previously been implicated in the pathophysiology of BPAD. Our data adds to previous evidence suggesting that a normalisation of these processes could be central to lithium’s mode of action, and could underlie a favourable therapeutic response.

In our day-to-day clinical practice, most of the emphasis is placed on QTc prolongation because psychotropic drugs that we commonly prescribe are known to cause this. However, a short QTc interval is equally important to be mindful of when prescribing or monitoring patients’ ECGs. We conducted a literature search in September and October 2019, using PubMed. Studies were included if they described psychotropics effects on QTc interval. Keywords used were QTc, psychotropics ECG. Why does the QTc matter to us as psychiatrists? The short answer is that all medications at the dispense of a psychiatrist have some serious cardiotoxic side effects. This can pose as a challenge because we often see patients with significant cardiac comorbidities and polypharmacy, which can be aggravated by use of cardiotoxic medication. Antipsychotics : Antipsychotic drugs have long been known to be associated with risk of cardiac arrhythmia and cardiac arrest. These arrhythmias are often reflected as changes in the ECG, prolongation of the QT interval, ventricular tachycardias and torsades de pointes (TdP). TdP is a potentially life-threatening ventricular tachyarrhythmia that is associated with syncope and sudden death.1 Such effects could be antiarrhythmic or cardiotoxic, depending on the health (eg, post-myocardial infarct) of the myocardium. Antidepressants : The cardiovascular toxicity of older generation of tricyclic antidepressants (eg, imipramine, desipramine, amitriptyline, clomipramine) and neuroleptics (eg, haloperidol, droperidol, thioridazine, pimozide) is well established. These drugs inhibit cardiovascular Na+, Ca2+ and K+ channels often leading to life-threatening arrhythmia.1 Mood stabilisers : Lithium is a commonly used mood stabiliser, associated with cardiac side effects of ventricular irritability, sinus node dysfunction, benign, reversible T wave changes (including inversion and flattening). Carbamazepine has quinidine-like effects and can aggravate heart block.2 When talking about factors affecting the QTc, a s hort QTc syndrome is an …

The aim of this work was to clarify whether maternal lithium chloride (LiCl) exposure disrupts the neonatal neuroendocrine-cytokine axis. Pregnant Wistar rats were orally administrated 50 mg LiCl/kg b.wt. from gestational day (GD) 1 to postpartum day 28. Maternal administration of LiCl induced a hypothyroid state in both dams and their neonates compared to the control dams and neonates at lactation days (LDs) 14, 21 and 28, where the levels of serum free triiodothyronine (FT3) and free thyroxin (FT4) were decreased and the level of serum thyrotropin (TSH) level was increased. A noticeable depression in maternal body weight gain, neonatal body weight and neonatal serum growth hormone (GH) was observed on all examined postnatal days (PNDs; 14, 21 and 28). A single abortion case was recorded at GD 17, and three dead neonates were noted at birth in the LiCl-treated group. Maternal administration of LiCl disturbed the levels of neonatal serum tumor necrosis factor-alpha (TNF-α), transforming growth factor-beta (TGF-β), interleukin-1 beta (IL-1β), interferon-gamma (INF-γ), leptin, adiponectin and resistin at all tested PNDs compared to the control group. This administration produced a stimulatory action on the level of neonatal cerebral serotonin (5-HT) at PND 14 and on the level of neonatal cerebral norepinephrine (NE) at PNDs 21 and 28. However, this administration produced an inhibitory action on the level of neonatal cerebral dopamine (DA) at all examined PNDs and on the level of neonatal cerebral NE at PND 14 and the level of neonatal cerebral 5-HT at PNDs 21 and 28 compared to the corresponding control group. Thus, maternal LiCl exposure-induced hypothyroidism disrupts the neonatal neuroendocrine-cytokine system, which delay cerebral development.

Objective: Lithium and valproate are commonly used either in monotherapy or in combination with atypical antipsychotics in maintenance treatment of bipolar I disorder; however, their comparative efficacy is not well understood. This study aimed to compare the efficacy of valproate and lithium on mood stability either in monotherapy or in combination with atypical antipsychotics. Methods: We performed a post hoc analysis using data from a 52-week randomized double-blind, placebo-controlled trial, that recruited 159 patients with recently remitted mania during treatment with lithium or valproate and adjunctive atypical antipsychotic therapy. Patients were randomized to discontinue adjunctive atypical antipsychotic at 0, 24 or 52 weeks. Results: No significant differences in efficacy were observed between valproate and lithium (hazard ratio: 0.99; 95% confidence interval: [0.66, 1.48]) in time to any mood event. Valproate with 24 weeks of atypical antipsychotic was significantly superior to valproate monotherapy in preventing any mood relapse (hazard ratio: 0.46; 95% confidence interval: [0.22, 0.97]) while lithium with 24 weeks of atypical antipsychotic was superior to lithium monotherapy in preventing mania (hazard ratio: 0.27; 95% confidence interval: [0.09, 0.85]) but not depression. Conclusion: Overall, this study did not find significant differences in efficacy between the two mood-stabilizing agents when used as monotherapy or in combination with atypical antipsychotics. However, study design and small sample size might have precluded from detecting an effect if true difference in efficacy existed. Further head-to-head investigations with stratified designs are needed to evaluate maintenance therapies.

Objective The longitudinal course of neuropsychological functioning after the first manic episode in bipolar disorder is unknown. The present study evaluated cognitive change in bipolar disorder in the first 3 years after the initial manic episode. Methods Ninety-one newly diagnosed patients with bipolar disorder and 61 demographically similar healthy participants received a neuropsychological evaluation assessing multiple cognitive domains at baseline, 1-year, and 3-year time points. Patients also received clinical assessments including mood ratings at all time points. Results Patients showed deficits in all domains at baseline, but similar longitudinal trajectories across time relative to healthy participants in most cognitive domains. For processing speed, patients showed more gains than controls from baseline to 1 year, but these gains stabilized thereafter. Patients with alcohol/substance abuse showed an initial delay but subsequent recovery in executive functioning. Patients who discontinued antipsychotic treatment showed better cognitive outcomes in verbal memory. Conclusion Appropriately treated patients with bipolar disorder showed favorable cognitive outcome in the first 3 years after experiencing an initial manic episode, arguing against cognitive neuroprogression at this stage of the illness. Discontinuation of antipsychotic treatment may be associated with better cognitive outcomes, but clarification of the role of antipsychotics on cognitive functioning requires further investigation.

Background Attitudes toward medication treatment are thought to significantly influence adherence in bipolar disorder (BD) and schizophrenia. However, the actual impact of patients' treatment attitudes on adherence and determinants of attitudes is still uncertain. Methods A longitudinal examination of treatment attitudes and their correlates was conducted among patients with BD and their caregivers compared with those with schizophrenia. Structured assessments of symptom severity, functioning, insight, medication side effects, knowledge of illness, medication adherence, treatment attitudes, and treatment satisfaction were performed among 176 selected patients (106 with BD and 70 with schizophrenia) and their caregivers. Participants were reassessed on these parameters at 3 and 6 months. Results Rates of nonadherence at baseline varied widely between self-reports, clinician ratings, and serum levels. Though symptoms and functioning improved with treatment, overall rates of nonadherence increased in the first 3 months because of early dropouts and remained stable thereafter. However, treatment attitudes and treatment satisfaction remained largely unchanged among patients and caregivers. Both positive and negative attitudes were commonly held and patients' attitudes did not differ between BD and schizophrenia. Patients' attitudes were significantly associated with adherence, insight, knowledge about illness, treatment satisfaction, symptom severity, social disadvantage, and side effects together with caregivers' knowledge, attitudes, and satisfaction. Caregivers of patients with schizophrenia were more knowledgeable and had more positive attitudes than patients. Conclusions Patients' attitudes to medication treatment are associated with adherence over time. They are relatively enduring and mainly associated with insight, knowledge of illness, and treatment satisfaction among patients and their caregivers. These findings could inform psychosocial interventions aiming to improve treatment attitudes and adherence in BD and schizophrenia.

BACKGROUND: psychomotor agitation (PA) or retardation (PR) during major depressive episodes (MDEs) have been associated with depression severity in terms of treatment-resistance and course of illness.OBJECTIVES: we investigated the possible association of psychomotor symptoms (PMSs) during a MDE with clinical features belonging to the bipolar spectrum.METHODS: the initial sample of 7689 MDE patients was divided into three subgroups based on the presence of PR, PA and non-psychomotor symptom (NPS). Univariate comparisons and multivariate logistic regression models were performed between subgroups.RESULTS: 3720 patients presented PR (48%), 1971 shown PA (26%) and 1998 had NPS (26%). In the PR and PA subgroups, the clinical characteristics related to bipolarity, along with the diagnosis of Bipolar Disorder (BD), were significantly more frequent than in the NPS subgroup. When comparing PA and PR patients, the former presented higher rates of bipolar spectrum features, such as family history of BD (OR=1.39, CI=1.20-1.61), manic/hypomanic switches with antidepressants (OR=1.28, CI=1.11-1.48), early onset of first MDE (OR=1.40, CI=1.26-1.57), atypical (OR=1.23, CI=1.07-1.42) and psychotic features (OR=2.08, CI=1.78-2.44), treatment with mood-stabilizers (OR=1.39, CI=1.24-1.55), as well as a BD diagnosis according to both the DSM-IV criteria and the bipolar specifier criteria. When logistic regression model was performed, the clinical features that significantly differentiated PA from PR were early onset of first MDE, atypical and psychotic features, treatment with mood-stabilizers and a BD diagnosis according to the bipolar specifier criteria.CONCLUSIONS: PMSs could be considered as markers of bipolarity, illness severity, and treatment complexity, particularly if PA is present. This article is protected by copyright. All rights reserved.

Objective To present up-to-date information and recommendations on the management of body weight changes during the use of antiepileptic mood stabilizers in bipolar disorder to help clinicians and patients make well-informed, practical decisions.Data sources Umbrella review. Systematic reviews and meta-analyses on the prevention, treatment, and monitoring of body weight changes as a side effect of the mood stabilizers valproate, lamotrigine, topiramate, and carbamazepine were identified in Embase (2010-2015, no language restrictions).Study selection The search yielded 18 relevant publications on antiepileptic mood stabilizers and weight changes in bipolar disorder.Data extraction Relevant scientific evidence was abstracted and put into a clinical perspective by a multidisciplinary expert panel of clinicians with expertise in the treatment of bipolar disorders across all age groups and a patient representative.Results Valproate has been proven to be associated with weight gain in up to 50% of its users, and can be detected 2-3 months after initiation. Carbamazepine has been proven to have a low risk of weight gain. Lamotrigine and topiramate are associated with weight loss. Other option for this sentence = Weigth gain has been proven to be associated with valproate use in up to 50% of its users, and can be detected within 2-3 months after initiation.Conclusion Each antiepileptic mood stabilizer has specific effects on body weight and accordingly requires a discrete education, prevention, monitoring, and treatment strategy. Clinicians are recommended to adopt an active, anticipatory approach, educating patients about weight change as an important side effect in order to come to informed shared decisions about the most suitable mood stabilizer.

Background:The study aimed to investigate severe hair loss related to psychotropic drugs (PDs) by using data from the drug safety programme Arzneimittelsicherheit in der Psychiatrie (AMSP).Methods:Data on PD utilization and reports of severe PD-related hair loss were collected in 83 psychiatric hospitals in Austria, Germany and Switzerland during the period 1993–2013.Results:Out of 432, 215 patients under surveillance, 404, 009 patients were treated with PDs for the main indications of depression, schizophrenic disorder, neurosis, mania, and organic psychosis. Severe hair loss related to PD treatment was reported in 43 cases (0.01%). The rates of hair loss under antipsychotic drugs were slightly lower than the mean rates of all PDs and antidepressant drugs. Valproic acid was related to the highest risk. In 6 of the 43 cases, hair loss was imputed to multiple drugs, with 4 cases imputed to double drug combinations and 2 cases to triple combinations. Rates of severe hair loss under valproic acid (VPA) and lithium salts were distinctly lower as compared with the overall rates reported in literature. Severe hair loss under PD treatment was reported significantly more often in female patients than in male patients (p < 0.01).Conclusion:The rate of severe PD-related hair loss was very low in the present survey. The large number of patients included in this multicentre study allows for assessment and comparison of hair loss rates related to different PDs and groups of PDs and provides new and supplementary information on PD-related hair loss.

Objective Compare clinical characteristics and outcomes in cases where DAT-SPECT imaging is used to distinguish Parkinson's disease from Drug-Induced Parkinsonsim. Background Clinical uncertainty in diagnosing Parkinson's disease is common when patients are on dopamine-blocking medications. DAT-SPECT imaging can improve diagnostic certainty but little data are available on clinical characteristics and outcomes associated with normal and abnormal scan results. Methods Retrospective chart review of patients seen at a movement disorders center between 2011 and 2017 where DAT-SPECT was ordered to distinguish Parkinson's disease from Drug-induced Parkinsonism. Descriptive statistics were calculated for variables of interest and compared by scan result. Chi-squared analyses was carried out for categorical variables and students' t-tests for continuous values. Results 51 patients met inclusion criteria with 36 normal scans and 15 abnormal scans. Those with greater than 2 cardinal manifestations (tremor, rigidity, akinesia, postural instability) were more likely to have an abnormal scan (63.89% vs 93.33%, p = 0.04). No other clinical characteristics assessed were associated with scan results. Atypical antipsychotics (aripiprazole 39.21%, olanzapine 31.37%) and mood stabilizers (valproic acid 33.33%, lithium 17.65%) were most commonly associated with suspected Drug-induced Parkinsonism cases. A post-scan change in management occurred in 41.18% of patients. 55.56% of patients with normal scans responded to changes in the offending medication, with 16.66% taking over 3 months to show improvement. Conclusions Many DAT-SPECT scans at our institution are ordered to distinguish Parkinson's disease from Drug-induced Parkinsonism because clinical characteristics alone are unreliable. DAT-SPECT results lead to changes in management and the outcomes of these changes are consistent with scan results.

Background Children and adolescents with conduct disorder (CD) show repetitive and persistent patterns of aggressive behaviour and the more severe forms are often associated with callous-unemotional (CU) traits. Objectives To systematically review and, where data are adequate, conduct meta-analyses on the efficacy of medication on aggression in children and adolescent with CD considering the impact of CU traits. Results Few studies have investigated patients with CD as primary diagnosis, and few of these have discriminated between different types of aggression or reported measures of CU traits. Methylphenidate and risperidone showed the largest effects on aggression in randomized controlled trials; other antipsychotics showed clinical efficacy on CD but this evidence is mainly revealed by open label trials. There is some low quality evidence to support a small effect of mood stabilizers and other agents. There were only two papers describing the effects of CU traits thus providing inconclusive results. Conclusion Considering heterogeneity of the disorder, more proof-of-concept clinical studies are needed to define effects of medication and role of CU traits.

For more than 40 years, lithium has been the gold standard in the long-term treatment of bipolar disorders. In the course of the last 15 years, other drugs have been approved in this indication and are widely used in clinical practice at the expense of lithium. New research from the last few years, however, indicates that lithium is still the first-line treatment in this indication. Against this background and lithium’s proven acute antimanic efficacy, we should perhaps be using lithium more regularly (in combination with an atypical antipsychotic, if necessary) right from the start for the acute treatment of a manic episode and, once remission has been achieved and euthymia maintained during continuation treatment, to regularly taper off the atypical antipsychotic, if possible, and continue with lithium as monotherapy for prophylactic treatment. This might lead to lithium being used more consistently with the scientific evidence in the long-term treatment of bipolar disorders. It remains uncertain, however, to predict who will respond to and tolerate lithium prophylactically, and more research is needed to deliver the best possible individualized care to our patients.

Background: Lithium has been used for more than 50 years and guidelines for treatment monitoring have been documented in Sweden since the beginning of the 1980s. Aims: The aim of this study was to describe compliance over time with the Swedish guidelines for long-term lithium treatment. Methods: The study material was obtained from Sahlgrenska University Hospital’s laboratory database. We analysed data (serum lithium and serum creatinine) of adult patients treated with lithium between 1981 and 2010, and determined compliance with guidelines and serum lithium levels over time. Results: Our study material included 2841 patients and 25,300 treatment-years. The compliance with guidelines’ recommendations regarding lithium and creatinine monitoring increased from 36% in 1981 to 68% in 2010. Women were on average 2% more compliant than men ( p < 0.01). Most lithium samples (87–94%) were within recommended intervals throughout the study period. The average lithium level decreased from 0.70 mmol/L in 1981 to 0.58 mmol/L in 2001, and remained stable thereafter. Conclusions: Compliance with lithium monitoring guidelines improved slowly but steadily over time. It took three decades to reach a compliance rate of just below 70%. Gender differences were small, but with a significantly better compliance rate for women. Serum lithium was kept within the recommended target interval to a large extent, throughout the study period.

Objective To assess differences between subjects with vs. without mixed features in major affective disorders. Methods In 3099 out-patient subjects with DSM-5 major depressive disorder (MDD, n = 1921) or bipolar disorders (BD, n = 1178), we compared those with (Mx) vs. without (Non-Mx) mixed features (agitated-irritable depression or dysphoric [hypo]mania) in an index episode. Results Prevalence of Mx averaged 21.9% [CI: 20.5-23.4] overall, ranking: BD-II > BD-I > MDD, and in BD depression ≥ [hypo]mania > MDD. Mx subjects were significantly more likely than Non-Mx cases to (i) have other mixed episodes, (ii) have higher irritable and agitated ratings, (iii) have more substance abuse, (iv) switch into mixed episodes, (v) have more suicide attempts and higher suicidal ratings, (vi) change diagnosis from depression to BD, (vii) have higher hypomania scores when depressed or depression scores when [hypo]manic, (viii) be unmarried or separated with fewer children and siblings, (ix) be diagnosed more with BD than MDD, (x) be unemployed, (xi) have BD, suicide and divorce among first-degree relatives, (xii) be female, (xiii) be younger at illness-onset. Both BD and MDD Mx subjects also received antidepressants less, but antipsychotics and mood-stabilizers more, alone and in combination with antidepressants. Conclusions Mood disorder subjects with agitated-irritable depression or dysphoric [hypo]mania differed from those without such mixed features, including having a less favorable clinical course and repeated mixed episodes. They may represent a distinct and prevalent, syndromal clinical subtype with prognostic and therapeutic significance.

Objectives This study compared 29 drugs for risk of psychiatric hospitalization in bipolar disorders, addressing the evidence gap on the >50 drugs used by US patients for treatment. Methods The Truven Health Analytics MarketScan® database was used to identify 190 894 individuals with bipolar or schizoaffective disorder who filled a prescription for one of 29 drugs of interest: lithium, first- or second-generation antipsychotics, mood-stabilizing anticonvulsants, and antidepressants. Competing risks regression survival analysis was used to compare drugs for risk of psychiatric hospitalization, adjusting for patient age, sex, comorbidities, and pretreatment medications. Other competing risks were ending monotherapy and non-psychiatric hospitalization. Results Three drugs were associated with significantly lower risk of psychiatric hospitalization than lithium: valproate (relative risk [RR] = 0.80, P = 3.20 × 10-4 ), aripiprazole (RR = 0.80, P = 3.50 × 10-4 ), and bupropion (RR = 0.80, P = 2.80 × 10-4 ). Eight drugs were associated with significantly higher risk of psychiatric hospitalization: haloperidol (RR = 1.57, P = 9.40 × 10-4 ), clozapine (RR = 1.52, P = .017), fluoxetine (RR = 1.17, P = 3.70 × 10-3 ), sertraline (RR = 1.17, P = 3.20 × 10-3 ), citalopram (RR = 1.14, P = .013), duloxetine (RR = 1.24, P = 5.10 × 10-4 ), venlafaxine (RR = 1.33; P = 1.00 × 10-6 ), and ziprasidone (RR = 1.25; P = 6.20 × 10-3 ). Conclusions This largest reported retrospective observational study on bipolar disorders pharmacotherapy to date demonstrates that the majority of patients end monotherapy within 2 months after treatment start. The risk of psychiatric hospitalization varied almost two-fold across individual medications. The data add to the evidence favoring lithium and mood stabilizer use in short-term bipolar disorder management. The findings that the dopaminergic drugs aripiprazole and bupropion had better outcomes than other members of their respective classes and that antidepressant outcomes may vary by baseline mood polarity merit further investigation.

Mood disorders are associated to functional unbalance in mesolimbic and frontal cortical circuits. As a commonly used mood stabilizer, lithium acts through multiple biochemical pathways, including those activated by muscarinic cholinergic receptors crucial for hippocampal-prefrontal communication. Therefore, here we investigated the effects of lithium on prefrontal cortex responses under cholinergic drive. Lithium-treated rats were anesthetized with urethane and implanted with a ventricular cannula for muscarinic activation, a recording electrode in the medial prefrontal cortex (mPFC), and a stimulating electrode in the intermediate hippocampal CA1. Either of two forms of synaptic plasticity, long-term potentiation (LTP) or depression (LTD), were induced during pilocarpine effects, which were monitored in real time through local field potentials. We found that lithium attenuates the muscarinic potentiation of cortical LTP (80 min). Moreover, lithium treatment promoted significant cross-frequency coupling between CA1 theta (3-5 Hz) and mPFC low-gamma (30-55 Hz) oscillations. Interestingly, lithium by itself did not affect any of these measures. Thus, lithium pretreatment and muscarinic activation synergistically modulate the hippocampal-prefrontal connectivity. Because these alterations varied with time, oscillatory parameters, and type of synaptic plasticity, our study suggests that lithium influences prefrontal-related circuits through intricate dynamics, informing future experiments on mood disorders.

Introduction Lithium is a medication used to treat bipolar disorder and may also prevent cognitive decline and suicide. Lithium is also found naturally, in levels well below clinical doses, in drinking water worldwide, and levels have been inversely associated with rates of psychiatric disorders. Lead (Pb) is another element in the environment but is a toxin of public health concern. Negative effects of chronic lead exposure and possible benefits of environmental lithium exposure appear complementary. Hypothesis Exposure to environmental lithium has associated benefits, which may be due to the mitigation of lead toxicity by lithium. Methods A series of reviews tested each element of the hypothesis. A systematic review clarified the psychiatric and medical correlates of lithium in drinking water. Non-systematic reviews clarified the harms of environmental lead, summarized experimental studies of lithium used to prevent lead toxicity, and explored overlapping biological mechanisms in lithium and lead exposure. Results Higher levels of lithium in drinking water were associated with lower suicide rates in 13 of 15 identified studies. While fewer studies were available for other outcomes, lithium was associated with lower rates of homicide, crime, dementia, and mortality. Lead was reported to be ubiquitous in the environment, and chronic low-level exposure has been associated with adverse effects, including effects opposite to the outcomes associated with lithium. Animal studies demonstrated that lithium pre-treatment mitigates lead toxicity. Neurophysiological correlates of lead and lithium exposure overlap. Conclusions Microdose lithium is associated with better psychiatric and medical outcomes, which are complementary to harms of environmental lead exposure. Experimental animal evidence is supportive, and lead and lithium impact overlapping neurophysiologic pathways. Therefore, several lines of circumstantial evidence suggest that lithium protects against the neurotoxic effects of lead. Further studies are required to clarify the benefits and mechanisms of low-dose lithium. There are significant public health implications if this paper's hypothesis is true.

Valproic acid and clozapine are drugs commonly used in the treatment of schizophrenic and schizoaffective disorders. Pharmacokinetic interactions of valproic acid with several drugs are well known, yet results concerning the interaction with clozapine are inconsistent.Steady-state dose-corrected serum concentrations of clozapine and its main metabolite norclozapine were retrospectively analyzed in 45 patients receiving both clozapine and valproic acid. Controls were matched for sex, age, smoking, comedication, and inflammatory response.The group receiving comedication with valproic acid showed significantly lower median dose-corrected serum concentrations of norclozapine (0.44 [0.27-0.58] (ng/mL)/(mg/d) vs 0.78 [0.60-1.07] (ng/mL)/(mg/d)) as well as metabolite to parent compound ratios (0.40 [0.36-0.47] vs 0.71 [0.58-0.84]) by approximately 44%. Dose-corrected serum concentrations of clozapine were not significantly lower. The effect of valproic acid was independent of sex and smoking.Comedication with valproic acid accelerated metabolism of clozapine with predominant effects on the degradation of norclozapine. Therapeutic drug monitoring should be applied to guide individual patient responses upon initiation of comedication.

This study evaluated risk factors for utilization of acute care services (ACS) (hospitalization or emergency department or urgent care visit) for lithium toxicity and the prevalence of lithium toxicity in a large, ambulatory population.A nested case-control study compared lithium users with ACS utilization for lithium toxicity (case group) to lithium users without toxicity (control group) by using data from Kaiser Permanente Colorado for patients with at least one lithium prescription purchase. Patients in the case group were matched 1:5 with patients in the control group who had purchased lithium within 39 days of the ACS encounter. Possible lithium toxicity, identified by lithium level or diagnosis, was confirmed by chart review. Multivariable, conditional logistic regression analysis was used to identify patient and prescription characteristics associated with ACS utilization for lithium toxicity. The prevalence of lithium toxicity was determined.Of 3,115 individuals who took lithium, 70 experienced lithium toxicity, with or without ACS utilization, for a prevalence of 2.2%. Identified risk factors for ACS utilization for lithium toxicity included a newly initiated potentially interacting medication (odds ratio [OR]=30.30, 95% confidence interval [CI]=2.32-394.95), a higher number of treated chronic diseases (OR=1.28, CI=1.12-1.45), older age (OR=1.05, CI=1.02-1.09), and higher total daily lithium dose (OR=1.00, CI=1.00-1.00).Newly initiated, potentially interacting medications are a major preventable driver of ACS use for lithium toxicity, whereas age, chronic disease, and total daily lithium dose are small but significant factors. Clinicians should use extra caution when initiating a potentially interacting medication.

Background Several currently available animal models reproduce select behavioral facets of human mania as well as the abnormal glutamatergic neurotransmission and dysregulation of glycogen synthase kinase 3β that accompanies this disease. Methods In this study, we addressed the therapeutic potential of ligands of sigma receptor type 1 (σ1R) in 2 putative models of mania: the “manic” Black Swiss outbred mice from Taconic farms (BStac) and mice with the 129 genetic background and histidine triad nucleotide-binding protein 1 (HINT1) deletion (HINT1-/- mice) that exhibit bipolar-like behaviors. Results The activity of control mice, which do not exhibit manic-like behaviors in the forced swim test, was significantly enhanced by MK801, an inhibitor of glutamate N-methyl-D-aspartate receptor activity, an effect that was not or barely observed in manic-like mice. Typical mood stabilizers, such as glycogen synthase kinase 3β inhibitors, but not σ1R ligands, reduced the N-methyl-D-aspartate receptor-mediated behaviors in control mice. Notably, σ1R antagonists S1RA, PD144418, BD1047, and BD1063, but not σ1R agonists PRE084 and PPCC, attenuated the manic-like behaviors of BStac and HINT1-/- mice by increasing antiactivity behaviors. The antimanic effects of a single administration of σ1R antagonists persisted for at least 24 hours, and these drugs did not alter the behavior of the “bipolar” HINT1−/− mice during pro-depressive episodes. Conclusions σ1R antagonists exhibit a selective normalizing effect on specific behavioral domains of mania without altering control (normal) or depressive-like behaviors.