Effective Treatment For Bipolar Disorder Research Articles

Enhancing Patient-Centric Approaches and Regulatory Measures in Valproate Use

Valproate is an effective treatment for bipolar disorder, migraine, and seizures. It is a flexible medication for neurological illnesses. In addition to its immediate benefits, the neuroprotective capabilities of this substance, which may be attributed to its antioxidant and anti-inflammatory properties, contribute to its complexity. Nevertheless, the presence of significant negative consequences such as pancreatitis, liver failure, teratogenicity, and an elevated risk of suicide present considerable difficulties. Significantly, its capacity to block histone deacetylase motivates investigation into possible epigenetic impacts for the treatment of AIDS and cancer. The article discusses the issue surrounding the use of valproate in neurology. It agrees with the guidelines set by the MHRA (Medicines and Healthcare products Regulatory Agency), but also emphasises the need for further considerations in patient care and regulatory enhancements. The statement emphasises the need of providing clear guidance to patients and carers, while highlighting the need for comprehensive education of neurologists worldwide, with the backing of government. The paper advocates for allocating funding to support in-depth understanding through preclinical and clinical investigations, emphasising the importance of a well-rounded approach that prioritises the needs of patients. The aim is to create a flexible framework that can respond to changing medical knowledge by incorporating risk assessment, patient education, and thorough monitoring after regulatory changes. The objective of this strategy is to achieve a balance between ensuring reproductive safety and promoting the well-being of those who are reliant on valproate. This involves taking into account both the practical and emotional aspects of patient care.

Comparing measurements of lithium treatment efficacy in people with bipolar disorder: systematic review and meta-analysis

Background Lithium has long been recognised as an effective treatment for bipolar disorder. Its relative efficacy has been measured with a diverse range of clinical outcomes, resulting in differences in efficacy reporting that have not been systematically reviewed. Aims We aimed to identify and compare the various measures of lithium efficacy employed in interventional studies for people with bipolar disorder. Method Database (PubMed, Web of Science) and hand searches were performed to identify studies that assessed a clinical response in patients with bipolar disorder who received lithium, up to the end of 2021. We included primary human interventional studies without excluding specific study designs, bipolar disorder subtypes, duration or dosage of lithium treatment. Continuous outcome effects were meta-analysed; binary outcomes were synthesised visually and narratively. The Cochrane risk-of-bias tool was used to assess study-level risk of bias. Results Seventy-one studies were included (N = 30 542). Approximately two-thirds of participants attained a clinically significant improvement in manic or depressive symptoms, and over 50% achieved remission. About a third required hospital admission (study length 2–12 years) and around 50% needed further treatment to stay well or had recurrence of symptoms; the latter two outcomes tended to be assessed over long-term maintenance periods. Conclusions An abundance of measurements have been used to assess lithium's clinical effects, across several study designs. Despite the resultant high heterogeneity, an overall picture of lithium's effects emerges that supports previous literature; between half and two-thirds of patients respond well to lithium across varying outcome measures, baseline mood states, study durations and bipolar disorder subtypes.

Components of an effective treatment for bipolar disorder; A qualitative study

Components of an effective treatment for bipolar disorder; A qualitative study

Binge Eating Disorder in Patients with Bipolar Disorder and Relationship with Clinical Features

IntroductionCurrent studies indicate a strong relationship between Eating Disorders and obesity, while studies on Bipolar Disorder (BPD) show that patients with BPD form an important risk group in terms of obesity.ObjectivesThe aim of this study is to investigate the frequency of Binge Eating Disorder (BED) in patients diagnosed with euthymic Bipolar Disorder 1 (BPD 1), and the relationship between their clinical featuresMethodsThis study included 150 patients between 18-65 years of age, diagnosed with euthymic BPD 1 according to DSM 5 criteria. Structured Clinical Interview for DSM-5 Disorders, Structured Sociodemographic Form, Young Mania Scale, Beck Depression Scale, Eating Disorders Assessment Scale (EDAS) , Eating Attitude Test (EAT) were applied to participants.ResultsA diagnosis of BED was detected in 19.3% of the patients. Body weight, highest weight and BMI values were significantly higher in those who were diagnosed with BED compared to those who were not diagnosed with BED. Most of the diagnosed with BED are women; gender was found to be determinant for BED. The total and subscale scores of EAT and EDAS of those with a diagnosis of BED were statistically significantly higher than those who did not. The rate of attacks with psychotic symptoms, rapid cycling and presence of suicide attempt were significantly higher in those with a diagnosis of BED compared to those who did not.ConclusionsBED may be frequent in BPD 1 patients. Noticing BED in BPD1 patients might help both the more effective treatment of BPD and the prevention of obesity.DisclosureNo significant relationships.

Improving lithium dose prediction using population pharmacokinetics and pharmacogenomics: a cohort genome-wide association study in Sweden

Lithium is the most effective treatment for bipolar disorder, resulting in strong suicide prevention effects. The therapeutic range of lithium, however, is narrow and treatment initiation requires individual titration to address inter-individual variability. We aimed to improve lithium dose prediction using clinical and genomic data. We performed a population pharmacokinetic study followed by a genome-wide association study (GWAS), including two clinical Swedish cohorts. Participants in cohort 1 were from specialised outpatient clinics at Huddinge Hospital, in Stockholm, Sweden, and participants in cohort 2 were identified using the Swedish National Quality Registry for Bipolar disorder (BipoläR). Patients who received a lithium dose corresponding to at least one tablet of lithium sulphate (6 mmol) per day and had clinically relevant plasma concentrations of lithium were included in the study. Data on age, sex, bodyweight, height, creatinine concentration, estimated glomerular filtration rate (eGFR), lithium preparation, number of tablets of lithium per day, serum lithium concentration, and medications affecting kidney function (C09 antihypertensives, C03 [except C03D] sodium-retaining diuretics, and non-steroidal anti-inflammatory drugs) were obtained retrospectively for several timepoints when possible from electronic health records, BipoläR, and the Swedish prescription registry. The median time between timepoints was 1·07 years for cohort 1 and 1·09 years for cohort 2. The primary outcome of interest was the natural logarithm of total body clearance for lithium (CLLi) associated with the clinical variables. The residual effects after accounting for age and sex, representing the individual-level effects (CLLi,age/sex), were used as the dependent variable in a GWAS. 2357 patients who were administered lithium (1423 women [60·4%] and 934 men [39·6%]; mean age 53·6 years [range 17-89], mainly of European descent) were included and 5627 data points were obtained. Age (variance explained [R2]: R2cohort1=0·41 and R2cohort2=0·31; both p<0·0001), sex (R2cohort1=0·0063 [p=0·045] and R2cohort2=0·026 [p<0·0001]), eGFR (R2cohort1=0·38 and R2cohort2=0·20; both p<0·0001), comedication with diuretics (R2cohort1=0·0058 [p=0·014] and R2cohort2=0·0026 [p<0·0001]), and agents acting on the renin-aldosterone-angiotensin system (R2cohort1=0·028 and R2cohort2=0·015; both p<0·0001) were clinical predictors of CLLi. Notably, an association between CLLi and serum lithium was observed, with a lower CLLi being associated with higher serum lithium (R2cohort1=0·13 and R2cohort2=0·15; both p<0·0001). In a GWAS of CLLi,age/sex, one locus was associated with a change in CLLi (rs583503; β=-0·053 [95% CI -0·071 to -0·034]; p<0·00000005). We also found enrichment of the associations with genes expressed in the medulla (p=0·0014, corrected FDR=0·04) and cortex of the kidney (p=0·0015, corrected FDR=0·04), as well as associations with polygenic risk scores for eGFR (p value threshold: 0·05, p=0·01), body-mass index (p value threshold: 0·05, p=0·00025), and blood urea nitrogen (p value threshold: 0·001, p=0·00043). The model based on six clinical predictors explained 61·4% of the variance in CLLi in cohort 1 and 49·8% in cohort 2. Adding genetic markers did not lead to major improvement of the models: within the subsample of genotyped individuals, the variance explained only increased from 59·32% to 59·36% in cohort 1 and from 49·21% to 50·03% in cohort 2 when including rs583503 and the four first principal components. Our model predictors could be used clinically to better guide lithium dosage, shortening the time to reach therapeutic concentrations, thus improving care. Identification of the first genomic locus and PRS to be associated with CLLi introduces the opportunity of individualised medicine in lithium treatment. Stanley Medical Research Institute, Swedish Research Council, Swedish Foundation for Strategic Research, Swedish Brain Foundation, Swedish Research Council, Söderström-Königska Foundation, Bror Gadelius Minnesfond, Swedish Mental Health Fund, Karolinska Institutet and Hospital.

Lithium‐associated nephrotoxicity: role of GDF15‐mediated collecting duct cells proliferation

Lithium (Li+) salts are the most effective treatment of bipolar disorder (BD), affecting 1 to 4% of the population worldwide. However, this efficacy is counterbalanced by adverse long‐term events, mostly renal effects. Lithium treatment discontinuation is usually not an option as it substantially increases suicidal risk. Understanding the sequence of events in the kidneys might thus improve therapeutic strategies while maintaining this treatment.Li+‐induced nephrogenic diabetes insipidus (NDI) is the earliest and the most frequent side effect of chronic lithium use, leading to polyuria and polydipsia. Li+ treatment decreases AQP2 expression both in vivo and in vitro. Li+ treatment also induces a microcystic tubulointerstitial nephropathy eventually leading to end‐stage kidney disease. The mechanisms of tubular toxicity and microcyst formation have been related to a proliferative effect of Li+. The time course, the site and the mechanisms of this proliferation are still a matter of debate.Previous studies from our lab have shown that acidosis‐induced collecting duct cell proliferation depended on the overexpression of GDF15 by principal cells, especially in the early phase of linear proliferation along the tubular axis.Our objective during this project is to determine the pathways leading to planar and cystic proliferation of collecting duct cells, in particular GDF15 signaling, and their role in lithium nephrotoxicity, and to identify potential biomarkers that could help to predict the course of Li‐induced nephropathy.We have established a rat and a mouse experimental model treated with therapeutic concentrations of Li+, displaying as expected polyuria and polydipsia, with microcystic tubular dilations and a global proliferation of collecting duct cells (both principal and intercalated) on kidney slices and on microdissected collecting ducts, with an increase in the intercalated/principal cells ratio (figure). We examined the effect of Li+ in GDF15‐/‐ and wild type (WT) mice and found significantly lower polyuria and polydipsia in GDF15‐/‐ mice, along with a higher urine osmolality, and decreased intercalated/principal cell ratio compared to WT mice (figure).As collecting duct cell proliferation is mediated by GDF15, we studied urinary GDF15 levels (GDF ELISA kit) in Li+‐treated patients with proven diabetes insipidus and found them significantly increased compared to control patients (p&lt;0.01) (figure).In conclusion, these results suggest a direct relationship between lithium‐induced proliferation signals, collecting duct cell dysfunction and GDF15 expression. Further investigation is needed to determine if GDF15 signaling might represent a therapeutic target in Li+‐induced nephrotoxicity.

Novel experimental and early investigational drugs for the treatment of bipolar disorder

ABSTRACT Introduction The quest toward more effective treatments for bipolar disorder (BD) solicits novel drugs and further research on the underpinning neurobiology. The present review aims to critically appraise the existing evidence about the pharmacological treatment of BD toward the development of novel treatment avenues. Areas covered The present review appraises animal and human studies concerning both the currently available psychotropic drugs, and the general medicine drugs which may represent a path toward the development of novel drugs for BD. PubMed and Scopus were last accessed on February 20th, 2021 for records indexed upon inception relevant to the pharmacological treatment of BD. Immune-modulating agents, anti-inflammatory agents, and glutamate antagonists represent the most intriguing potential targets for the development of new drugs for BD, thus receiving critical appraisal in the present text. Expert Opinion Regardless of the neurobiological pathways worthy of investigation toward the development of experimental drugs for BD, several unmet needs need to be addressed first. In particular, several biomarkers are altered in BD. However, it is the opinion herein expressed by the authors that it remains uncertain what comes first, that is peripheral changes or the disease.

The effect of prenatal lithium exposure on the neuropsychological development of the child.

ObjectivesLithium 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.MethodsParticipants 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.ResultsLithium 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.ConclusionIn 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.

Gestational valproic acid exposure induces epigenetic modifications in murine decidua

IntroductionValproic acid (VPA), a widely prescribed antiepileptic drug and an effective treatment for bipolar disorder and neuropathic pain, results in multiple developmental defects following in utero exposure. Uterine decidua provides nutritional and physical support during implantation and early embryonic development. Perturbations in the molecular mechanisms within decidual tissue during early pregnancy might affect early embryonic growth, result in early pregnancy loss or cause complications in the later gestational stage. VPA is a known histone deacetylase inhibitor and epigenetic changes such as histone hyperacetylation and methylation have been proposed as a mechanism of VPA-induced teratogenesis. MethodsThis study investigated the effects of in utero VPA exposure on histone modifications in murine decidual tissue. Pregnant CD-1 mice were exposed to 400 mg/kg VPA or saline on GD9 via subcutaneous injection. Decidual tissue from each gestational sac was harvested at 1, 3 and 6 h following exposure. Levels of acetylated histones H3, H4 and H3K56, as well as methylated histones H3K9 and H3K27 were acid extracted and assessed by western blotting followed by acid histone extraction. ResultsVPA exposure induced a significant increase (p < 0.05) in the levels of acetylated H3 at 1, 3 h; acetylated H4 at 1, 3 and 6 h and trimethylated H3K9 at 6 h. In contrast, no significant perturbations were noted in the levels of monomethylated H3K9, trimethylated H3K27 and acetylated H3K56. DiscussionThe results from this study suggest that VPA-induced decidual histone modifications might play an important role as a mechanism of VPA-induced teratogenesis during early embryonic growth.

Discovery of suppressors of CRMP2 phosphorylation reveals compounds that mimic the behavioral effects of lithium on amphetamine-induced hyperlocomotion

The effective treatment of bipolar disorder (BD) represents a significant unmet medical need. Although lithium remains a mainstay of treatment for BD, limited knowledge regarding how it modulates affective behavior has proven an obstacle to discovering more effective mood stabilizers with fewer adverse side effects. One potential mechanism of action of lithium is through inhibition of the serine/threonine protein kinase GSK3β, however, relevant substrates whose change in phosphorylation may mediate downstream changes in neuroplasticity remain poorly understood. Here, we used human induced pluripotent stem cell (hiPSC)-derived neuronal cells and stable isotope labeling by amino acids in cell culture (SILAC) along with quantitative mass spectrometry to identify global changes in the phosphoproteome upon inhibition of GSK3α/β with the highly selective, ATP-competitive inhibitor CHIR-99021. Comparison of phosphorylation changes to those induced by therapeutically relevant doses of lithium treatment led to the identification of collapsin response mediator protein 2 (CRMP2) as being highly sensitive to both treatments as well as an extended panel of structurally distinct GSK3α/β inhibitors. On this basis, a high-content image-based assay in hiPSC-derived neurons was developed to screen diverse compounds, including FDA-approved drugs, for their ability to mimic lithium’s suppression of CRMP2 phosphorylation without directly inhibiting GSK3β kinase activity. Systemic administration of a subset of these CRMP2-phosphorylation suppressors were found to mimic lithium’s attenuation of amphetamine-induced hyperlocomotion in mice. Taken together, these studies not only provide insights into the neural substrates regulated by lithium, but also provide novel human neuronal assays for supporting the development of mechanism-based therapeutics for BD and related neuropsychiatric disorders.

19.2 THE COLLABORATIVE LITHIUM TRIALS

Lithium has been known to be a safe and effective treatment for bipolar disorder in adults. However, there was little research regarding the use of lithium in youth with bipolar disorder. The Collaborative Lithium Trials (CoLT) is a series of multisite studies examining the safety and efficacy of lithium for the treatment of bipolar disorder in youth.

Off-Label Use of Second-generation Antipsychotics in Bipolar Disorder: A Survey of Italian Psychiatrists.

Bipolar disorder (BD) is characterized by recurrent depressive and manic episodes. Lithium, valproate, lamotrigine, and some second-generation antipsychotics (SGAs) are the most typical pharmacological treatments for BD, the main goal being mood stabilization. However, despite these treatments, most patients continue to experience recurrent mood episodes and residual symptoms. Findings from several studies suggest that some SGAs may be beneficial beyond approved indications. The goal of the survey presented in this article was to examine Italian psychiatrists' attitudes concerning the off-label use of SGAs in depressive and maintenance phases of BD. A questionnaire about the off-label prescription of SGAs was e-mailed to 300 psychiatrists from Northern, Central, and Southern Italy affiliated with the Italian Society of Psychopharmacology (SINPF) to investigate the frequency of and motivation for off-label use of SGAs and evaluate the psychiatrists' attitude toward use of specific SGAs in BD; 202 questionnaires were completed. The respondents were equally distributed in terms of sex, and the mean age of respondents was 44.1 years. The majority of the sample reported use of SGAs for off-label indications either very often (16.7%), often (33.7%), or occasionally (34.7%). The main motivation for off-label use of the SGAs was the presence of published evidence (51.5%), followed by patients' nonresponse to previous treatment (37.1%). With regard to the use of specific SGAs in BD, off-label aripiprazole was considered appropriate for depressive episodes by 46% of the psychiatrists, followed by olanzapine which was considered appropriate by 33.7%. For maintenance treatment of BD, off-label asenapine was considered appropriate by 45% of the psychiatrists, followed by long-acting aripiprazole and olanzapine pamoate, which were considered appropriate by 37.1% and 23.8%, respectively. In summary, ~50% of Italian psychiatrists frequently (very often or often) prescribe SGAs for off-label indications. Given the relatively limited number of indicated effective treatments for BD, the use of some SGAs off-label may be considered appropriate when dealing with patients whose BD is resistant to medications with labeled indications for BD.

Comparison of BD Barricor™ vs. BD Rapid Serum Tube (RST) for thyroid hormones

A 70-year-old man was referred to our emergency department for shortness of breath on exertion and systemic edema. He had been taking lithium carbonate for 2 years (500 mg/day over previous 3 months) for bipolar disorder diagnosed at age 60. He was diagnosed with hypothyroidism accompanied by Hashimoto's disease 2 weeks before hospitalization. Massive pericardial effusion and bilateral pleural effusions were demonstrated by transthoracic echocardiography and computed tomography. Cardiac tamponade occurred on the 3rd day. Pericardiocentesis and thoracentesis were performed once and three times, respectively, because of the acute deterioration of hemodynamic status due to pleural and pericardial effusion. Lithium carbonate is a widely used and effective treatment for bipolar disorder. However, lithium has a narrow therapeutic range and many side effects. An important aspect of this case was the rapid development of severe hypothyroidism, although serum lithium concentration was measured regularly and was maintained within the therapeutic range. It is important to note that lithium can cause serious complications, as in this patient, even if serum lithium concentration is measured regularly and maintained within the therapeutic range. We report the first case of cardiac tamponade caused by hypothyroidism associated with administration of lithium.<Learning objective: Lithium carbonate is a widely used and effective treatment for bipolar disorder. Goiter and hypothyroidism are common clinical side effects of lithium, but the complication of cardiac tamponade has not been reported. An important aspect of this case was the rapid development of severe hypothyroidism, although serum lithium concentration was measured regularly and was maintained within the therapeutic range. Therefore, timely diagnosis and treatment of hypothyroidism by routine assessment of thyroid function should be performed.>

Predictive modeling for response to lithium and quetiapine in bipolar disorder.

Lithium and quetiapine are known to be effective treatments for bipolar disorder. However, little information is available to inform prediction of response to these medications. Machine-learning methods can identify predictors of response by examining variables simultaneously. Further evaluation of models on a test sample can estimate how well these models would generalize to other samples. Data (N=482) were drawn from a randomized clinical trial of outpatients with bipolar I or II disorder who received adjunctive personalized treatment plus either lithium or quetiapine. Elastic net regularization (ENR) was used to generate models for lithium and quetiapine; these models were evaluated on a test set. Predictions from the lithium model explained 17.4% of the variance in actual observed scores of patients who received lithium in the test set, while predictions from the quetiapine model explained 32.1% of the variance of patients that received quetiapine. Of the baseline variables selected, those with the largest parameter estimates were: severity of mania; attention-deficit/hyperactivity disorder (ADHD) comorbidity; nonsuicidal self-injurious behavior; employment; and comorbidity with each of two anxiety disorders (social phobia/society anxiety and agoraphobia). Predictive accuracy of the ENR model outperformed the simple and basic theoretical models. ENR is an effective approach for building optimal and generalizable models. Variables identified through this methodology can inform future research on predictors of response to lithium and quetiapine, as well as future modeling efforts of treatment choice in bipolar disorder.

Ronald Fieve: lithium researcher and psychiatrist to Hollywood moguls and Wall Street tycoons

During the 1980s, Ronald Fieve’s psychiatric practice in New York City was thriving. At the time, Fieve was arguably the most famous of the psychiatrists in the US who were...

Neuroprotection after a first episode of mania: a randomized controlled maintenance trial comparing the effects of lithium and quetiapine on grey and white matter volume

Lithium and quetiapine are effective treatments for bipolar disorder, but their potential neuroprotective effects in humans remain unclear. A single blinded equivalence randomized controlled maintenance trial was conducted in a prospective cohort of first-episode mania (FEM) patients (n=26) to longitudinally compare the putative protective effects of lithium and quetapine on grey and white matter volume. A healthy control sample was also collected (n=20). Using structural MRI scans, voxel-wise grey and white matter volumes at baseline and changes over time in response to treatment were investigated. Patients were assessed at three time points (baseline, 3 and 12-month follow-up), whereas healthy controls were assessed at two time points (baseline and 12-month follow-up). Patients were randomized to lithium (serum level 0.6 mmol l−1, n=20) or quetiapine (flexibly dosed up to 800 mg per day, n=19) monotherapy. At baseline, compared with healthy control subjects, patients with FEM showed reduced grey matter in the orbitofrontal cortex, anterior cingulate, inferior frontal gyrus and cerebellum. In addition, patients had reduced internal capsule white matter volume bilaterally (t1,66>3.20, P<0.01). Longitudinally, there was a significant treatment × time effect only in the white matter of the left internal capsule (F2,112=8.54, P<0.01). Post hoc testing showed that, compared with baseline, lithium was more effective than quetiapine in slowing the progression of white matter volume reduction after 12 months (t1,24=3.76, P<0.01). Our data support the role of lithium but not quetiapine therapy in limiting white matter reduction early in the illness course after FEM.

Effects of the potential lithium-mimetic, ebselen, on impulsivity and emotional processing.

RationaleLithium remains the most effective treatment for bipolar disorder and also has important effects to lower suicidal behaviour, a property that may be linked to its ability to diminish impulsive, aggressive behaviour. The antioxidant drug, ebselen, has been proposed as a possible lithium-mimetic based on its ability in animals to inhibit inositol monophosphatase (IMPase), an action which it shares with lithium.ObjectivesThe aim of the study was to determine whether treatment with ebselen altered emotional processing and diminished measures of risk-taking behaviour.MethodsWe studied 20 healthy participants who were tested on two occasions receiving either ebselen (3600 mg over 24 h) or identical placebo in a double-blind, randomized, cross-over design. Three hours after the final dose of ebselen/placebo, participants completed the Cambridge Gambling Task (CGT) and a task that required the detection of emotional facial expressions (facial emotion recognition task (FERT)).ResultsOn the CGT, relative to placebo, ebselen reduced delay aversion while on the FERT, it increased the recognition of positive vs negative facial expressions.ConclusionsThe study suggests that at the dosage used, ebselen can decrease impulsivity and produce a positive bias in emotional processing. These findings have implications for the possible use of ebselen in the disorders characterized by impulsive behaviour and dysphoric mood.Electronic supplementary materialThe online version of this article (doi:10.1007/s00213-016-4319-5) contains supplementary material, which is available to authorized users.

PS54. Effects of the potential lithium-mimetic, ebselen, on brain neurochemistry: A magnetic resonance spectroscopy study at 7 Tesla

Rationale Lithium is an effective treatment for bipolar disorder, but safety issues complicate its clinical use. The antioxidant drug, ebselen, may be a possible lithium-mimetic based on its ability to inhibit inositol monophosphatase (IMPase), an action which it shares with lithium.

Effects of the potential lithium-mimetic, ebselen, on brain neurochemistry: a magnetic resonance spectroscopy study at 7 tesla.

RationaleLithium is an effective treatment for bipolar disorder, but safety issues complicate its clinical use. The antioxidant drug, ebselen, may be a possible lithium-mimetic based on its ability to inhibit inositol monophosphatase (IMPase), an action which it shares with lithium.ObjectivesOur primary aim was to determine whether ebselen lowered levels of inositol in the human brain. We also assessed the effect of ebselen on other brain neurometabolites, including glutathione, glutamate, glutamine, and glutamate + glutamine (Glx)MethodsTwenty healthy volunteers were tested on two occasions receiving either ebselen (3600 mg over 24 h) or identical placebo in a double-blind, random-order, crossover design. Two hours after the final dose of ebselen/placebo, participants underwent proton magnetic resonance spectroscopy (1H MRS) at 7 tesla (T) with voxels placed in the anterior cingulate and occipital cortex. Neurometabolite levels were calculated using an unsuppressed water signal as a reference and corrected for individual cerebrospinal fluid content in the voxel.ResultsEbselen produced no effect on neurometabolite levels in the occipital cortex. In the anterior cingulate cortex, ebselen lowered concentrations of inositol (p = 0.028, Cohen’s d = 0.60) as well as those of glutathione (p = 0.033, d = 0.58), glutamine (p = 0.024, d = 0.62), glutamate (p = 0.01, d = 0.73), and Glx (p = 0.001, d = 1.0).ConclusionsThe study suggests that ebselen produces a functional inhibition of IMPase in the human brain. The effect of ebselen to lower glutamate is consistent with its reported ability to inhibit the enzyme, glutaminase. Ebselen may have potential as a repurposed treatment for bipolar disorder.

A systematic review of cognitive rehabilitation for bipolar disorder.

It has been shown that bipolar disorder (BD) has a direct impact on neurocognitive functioning and behavior. This finding has prompted studies to investigate cognitive enhancement programs as potential treatments for BD, primarily focusing on cognitive reinforcement and daily functioning and not restricted to psychoeducation and coping strategies, unlike traditional psychosocial treatments. This study presents a systematic review of controlled trials of cognitive rehabilitation (CR) for BD. Our main objective is to describe the results of studies of rehabilitation programs for BD and related methodological issues. Electronic database searches (MEDLINE, Web of Science, and Embase) were conducted to identify articles using terms related to BD and CR. The methodological quality of each article was measured using the 5-item Jadad scale. A total of 239 articles were initially identified, but after application of exclusion criteria, only four were retained for this review. An average of 17 hours of intervention sessions were conducted, distributed as 0.95 hours per week and three of the four studies reported better executive function performance after CR interventions. We did not find robust evidence to support cognitive rehabilitation as an effective treatment for BD, because of: 1) the variety of intervention designs; 2) the methodological limitations of the studies; and 3) the lack of studies in the field.