Mood Stabilizers In Bipolar Disorder Research Articles

Lithium and the risk of fractures in patients with bipolar disorder: A population-based cohort study

Lithium is considered to be the most effective mood stabilizer for bipolar disorder. Evolving evidence suggested lithium can also regulate bone metabolism which may reduce the risk of fractures. While there are concerns about fractures for antipsychotics and mood stabilizing antiepileptics, very little is known about the overall risk of fractures associated with specific treatments. This study aimed to compare the risk of fractures in patients with bipolar disorder prescribed lithium, antipsychotics or mood stabilizing antiepileptics (valproate, lamotrigine, carbamazepine).Among 40,697 patients with bipolar disorder from 1993 to 2019 identified from a primary care electronic health record database in the UK, 13,385 were new users of mood stabilizing agents (lithium:2339; non-lithium: 11,046). Lithium was associated with a lower risk of fractures compared with non-lithium treatments (HR 0.66, 95 % CI 0.44–0.98). The results were similar when comparing lithium with prolactin raising and sparing antipsychotics, and individual antiepileptics. Lithium use may lower fracture risk, a benefit that is particularly relevant for patients with serious mental illness who are more prone to falls due to their behaviors. Our findings could help inform better treatment decisions for bipolar disorder, and lithium's potential to prevent fractures should be considered for patients at high risk of fractures.

Ratiometric detection of lithium ions in serum and living cells using DNAzyme-assisted hybridization chain reaction

Lithium, a first-line mood stabilizer for bipolar disorder (BD), presents challenges due to its narrow therapeutic window (0.6–1.2 mM) and potential side effects in overdose. Hence, it is crucial to accurately and sensitively detect lithium ions (Li+) in serum and living cells for timely monitoring of BD progression and gaining mechanistic insight into lithium-based therapy. In this study, we design a Li+-responsive DNAzyme-HCR amplifier by combining hybridization chain reaction (HCR) and the Li+-specific DNAzyme. The presence of Li+ catalytically cleaves the DNAzyme, releasing the embedded HCR DNA trigger and generating numerous DNAzyme-assisted HCR products, ultimately activating the fluorescence resonance energy transfer response. Our results demonstrate that the DNAzyme-HCR amplifier enables amplified Li+ detection in serum, which are consistent with the results obtained using the inductively coupled plasma optical emission spectroscopy (ICP-OES) method. Furthermore, the DNAzyme-HCR amplifier allows for Li+ imaging in living cells, showing promising potential in monitoring treatment effects against BD.

Mortality risk and mood stabilizers in bipolar disorder: a propensity-score-weighted population-based cohort study in 2002-2018.

Accumulating studies have assessed mortality risk associated with mood-stabilizers, the mainstay treatment for bipolar disorder (BD). However, existing data were mostly restricted to suicide risk, focused on lithium and valproate and rarely adequately adjusted for potential confounders. This study aimed to assess comparative mortality risk with all, natural and unnatural causes between lithium, valproate and three frequently prescribed second-generation antipsychotics (SGA), with adjustment for important confounders. This population-based cohort study identified 8137 patients with first-diagnosed BD, who had exposed to lithium (n = 1028), valproate (n = 3580), olanzapine (n = 797), quetiapine (n = 1975) or risperidone (n = 757) between 2002 and 2018. Data were retrieved from territory-wide medical-record database of public healthcare services in Hong Kong. Propensity-score (PS)-weighting method was applied to optimize control for potential confounders including pre-existing chronic physical diseases, substance/alcohol use disorders and other psychotropic medications. PS-weighted Cox proportional-hazards regression was conducted to assess risk of all-, natural- and unnatural-cause mortality related to each mood-stabilizer, compared to lithium. Three sets of sensitivity analyses were conducted by restricting to patients with (i) length of cumulative exposure to specified mood-stabilizer ≥90 days and its medication possession ratio (MPR) ≥90%, (ii) MPR of specified mood-stabilizer ≥80% and MPR of other studied mood-stabilizers <20% and (iii) monotherapy. Incidence rates of all-cause mortality per 1000 person-years were 5.9 (95% confidence interval [CI]: 4.5-7.6), 8.4 (7.4-9.5), 11.1 (8.3-14.9), 7.4 (6.0-9.2) and 12.0 (9.3-15.6) for lithium-, valproate-, olanzapine-, quetiapine- and risperidone-treated groups, respectively. BD patients treated with olanzapine (PS-weighted hazard ratio = 2.07 [95% CI: 1.33-3.22]) and risperidone (1.66 [1.08-2.55]) had significantly higher all-cause mortality rate than lithium-treated group. Olanzapine was associated with increased risk of natural-cause mortality (3.04 [1.54-6.00]) and risperidone was related to elevated risk of unnatural-cause mortality (3.33 [1.62-6.86]), relative to lithium. The association between olanzapine and increased natural-cause mortality rate was consistently affirmed in sensitivity analyses. Relationship between risperidone and elevated unnatural-cause mortality became non-significant in sensitivity analyses restricted to low MPR in other mood-stabilizers and monotherapy. Valproate- and lithium-treated groups did not show significant differences in all-, natural- or unnatural-cause mortality risk. Our data showed that olanzapine and risperidone were associated with higher mortality risk than lithium, and further supported the clinical guidelines recommending lithium as the first-line mood-stabilizer for BD. Future research is required to further clarify comparative mortality risk associated with individual SGA agents to facilitate risk-benefit evaluation of alternative mood-stabilizers to minimize avoidable premature mortality in BD.

Molecular mechanisms and therapeutic potential of lithium in Alzheimer's disease: repurposing an old class of drugs.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline and memory loss. Despite advances in understanding the pathophysiological mechanisms of AD, effective treatments remain scarce. Lithium salts, recognized as mood stabilizers in bipolar disorder, have been extensively studied for their neuroprotective effects. Several studies indicate that lithium may be a disease-modifying agent in the treatment of AD. Lithium's neuroprotective properties in AD by acting on multiple neuropathological targets, such as reducing amyloid deposition and tau phosphorylation, enhancing autophagy, neurogenesis, and synaptic plasticity, regulating cholinergic and glucose metabolism, inhibiting neuroinflammation, oxidative stress, and apoptosis, while preserving mitochondrial function. Clinical trials have demonstrated that lithium therapy can improve cognitive function in patients with AD. In particular, meta-analyses have shown that lithium may be a more effective and safer treatment than the recently FDA-approved aducanumab for improving cognitive function in patients with AD. The affordability and therapeutic efficacy of lithium have prompted a reassessment of its use. However, the use of lithium may lead to potential side effects and safety issues, which may limit its clinical application. Currently, several new lithium formulations are undergoing clinical trials to improve safety and efficacy. This review focuses on lithium's mechanism of action in treating AD, highlighting the latest advances in preclinical studies and clinical trials. It also explores the side effects of lithium therapy and coping strategies, offering a potential therapeutic strategy for patients with AD.

The relationship between familial-genetic risk and pharmacological treatment in a Swedish national sample of patients with major depression, bipolar disorder, and schizophrenia.

Using Swedish registers, we examine whether the prescription of and the response to antidepressants (AD), mood stabilizers (MS), and antipsychotics (AP) in the treatment of, respectively, major depression (MD), bipolar disorder (BD), and schizophrenia (SZ), are influenced by familial-genetic risk. We examined individuals born in Sweden 1960-1995 with a first diagnosis of MD (n = 257,177), BD (n = 23,032), and SZ (n = 4248) from 2006 to 2018. Drug classes and Defined Daily Dose (DDD) were obtained from the Pharmacy register using the Anatomical Therapeutic Chemical system. We utilized the Familial Genetic Risk Scores (FGRS) calculated from morbidity risks in first- through fifth degree relatives. Treatment with antidepressants (AD) in MD, mood-stabilizers (MS) in BD, and antipsychotics (AP) in SZ were associated with significantly higher disorder-specific familial-genetic risks. Using dosage trajectory analysis of AD, MS, and AP treatment for MD, BD, and SZ, respectively, familial-genetic risk was positively associated with higher and/or increasing drug dosages over time. For MD and BD, examining cases started on the most common pharmacologic treatment class (SSRIs for MD and "other anti-epileptics" for BD), familial-genetic risks were significantly lower in those who did not versus did later receive treatment from other AD and MS classes, respectively. Higher familial-genetic risk for BD predicted switching AD medication in cases of MD. Among pharmacologically treated cases of BD, familial-genetic risk was significantly higher for those treated with lithium. In a large population-based patient cohort, we found evidence of a wide-spread association between higher familial-genetic risk and i) increased likelihood of receiving pharmacologic treatment but 2) responding more poorly to it-as indicated by a switching of medications -- and/or requiring higher doses. Further investigations into the clinical utility of genetic risk scores in the clinical managements of MD, BD, and SZ are warranted.

Nurse practitioner educational preparation and confidence related to managing antipsychotic medications and associated drug-induced movement disorders.

Antipsychotic medications (APMs) have been used to treat multiple psychiatric disorders for decades. The conditions to use these medications have expanded from primarily psychotic disorders to Food and Drug Administration-approved uses as first-line mood stabilizers in bipolar disorder and adjunctive pharmacotherapy in unipolar depression. Antipsychotic medications can have serious side effects, including drug-induced movement disorders (DIMDs). Nurse practitioners (NPs) in non-psychiatric-mental health specialties are increasingly managing psychotropic medication regimes. There is a void in peer-reviewed literature capturing the scope of NPs managing APMs, such as whether they received training to prescribe and manage risks of APM, and if so, what type (e.g., continuing education, attending conferences, consulting), and their confidence assessing and managing DIMDs. To describe the scope of NP management, knowledge, and confidence related to APMs and associated risks of DIMDs. Nonexperimental, descriptive, cross-sectional survey. Participants ( n = 400) recruited through a professional association membership portal. Nearly two-thirds of participants reported managing APMs (64%) and receiving training to prescribe and manage risks of APMs (63%). More than half (54%) reported they received training to do so in their NP education program. Thirty-five percent of participants indicated they were either completely (6%) or fairly (29%) confident, whereas most (65%) endorsed being somewhat (26%), slightly (20%), or not (19%) confident in assessing and managing DIMDs. Opportunities exist to broaden NP education in managing APMs and associated risks of DIMDs.

Protocolo terapéutico de los trastornos del humor

The treatment of mood disorders includes the use of antidepressants and mood stabilizers in bipolar disorder and, in some cases, treatment-resistant depression. Treatment must be in accordance with severity, personalized for each case, comprehensive, and based on scientific evidence. Therapeutic measures also include hygiene and dietary measures, physical exercise, psychotherapy, functional rehabilitation, and, on occasion, electroconvulsive therapy. This protocol includes algorithms, tables, and figures with the aim of facilitating the decision on which pharmacological treatment to use.

Lithium Provides Broad Therapeutic Benefits in an Alzheimer's Disease Mouse Model.

Alzheimer's disease (AD) is a chronic neurodegenerative disorder with a progressive loss of cognitive function. Currently, no effective treatment regimen is available. Lithium, a mood stabilizer for bipolar disorder, exerts broad neuroprotective and neurotrophic actions and improves cognitive function. The study investigated if lithium stabilizes Ca2+ signaling abnormalities in hippocampal neurons and subsequently normalize downstream effects on AD neuropathology and synaptic plasticity in young AD mice. Four-month-old 3xTg-AD mice were treated with a LiCl diet chow for 30 days. At the end of the lithium treatment, a combination of two-photon Ca2+ imaging, electrophysiology, and immunohistochemistry assays were used to assess the effects of the LiCl treatment on inositol trisphosphate receptor (IP3R)-dependent endoplasmic reticulum (ER) Ca2+ and voltage-gated Ca2+ channel (VGCC)-mediated Ca2+ signaling in CA1 neurons, neuronal nitric oxide synthase (nNOS) and hyperphosphorylated tau (p-tau) levels and synaptic plasticity in the hippocampus and overlying cortex from 3xTg-ADmice. Thirty-day LiCl treatment reduced aberrant IP3R-dependent ER Ca2+ and VGCC-mediated Ca2+ signaling in CA1 pyramidal neurons from 3xTg-AD mice and restored neuronal nitric oxide synthase (nNOS) and hyperphosphorylated tau (p-tau) levels to control levels in the hippocampal subfields and overlying cortex. The LiCl treatment enhanced post-tetanic potentiation (PTP), a form of short-term plasticity in the hippocampus. The study found that lithium exerts therapeutic effects across several AD-associated early neuronal signaling abnormalities including aberrant Ca2+ signaling, nNOS, and p-tau formation and enhances short-term synaptic plasticity. Lithium could serve as an effective treatment or co-therapeutic for AD.

Antipsychotics and mood stabilizers in bipolar disorder – associations between dosing levels and the risk of relapse and treatment safety

Antipsychotics and mood stabilizers in bipolar disorder – associations between dosing levels and the risk of relapse and treatment safety

Avis d’experts français sur la prise en charge des femmes en âge de procréer et enceintes souffrant d’un trouble bipolaire traitées par valproate

IntroductionThe perinatal period is associated with high risk of relapses in women with untreated bipolar disorder (BD) and can have significant consequences on foetal and child development. Valproate is an effective mood stabilizer in BD but it is also the anticonvulsant associated to the highest risks of neurodevelopmental disorders and congenital malformations. The National Agency for the Safety of Medicines and Health Products (ANSM) changed the conditions of use and prescription of valproate in France in 2015. Its prescription is now contraindicated (i.e., not to be prescribed) in women able to have children unless alternative treatments are ineffective or not tolerated. Moreover, valproate could only be prescribed if the protocol of a specific pregnancy prevention program is followed. MethodsA panel of experts from the French Association for Biological Psychiatry and Neuropsychopharmacology (AFPBN) provided consensus-based recommendations for switching and discontinuation of valproate in women with BD. The development of these recommendations consisted of an adaptation to French clinical practice based on a European expert opinion published in 2019. The experts discussed five real-world clinical situations in light of the scientific evidence and their clinical experience (a. Stable BD patient with valproate monotherapy who is planning pregnancy, b. Stable BD patient with valproate polytherapy who is planning pregnancy, c. Unstable BD patient with frequent relapses and valproate polytherapy who is planning pregnancy, d. Stable BD patient treated with valproate and unexpected pregnancy, e. Unstable BD patient treated with valproate and unexpected pregnancy) and developed, through several rounds of exchange drafts, a French version of clinical recommendations. ResultsFirst of all, some factors need to be considered for establishing personalized practical recommendations for a safe and effective switching or discontinuation of valproate in any clinical situations: planned pregnancy or unplanned pregnancy or current pregnancy, the existence or not of a pregnancy risk minimization program and a complete treatment history. Other factors that should be considered are the predominant polarity, the severity, the stability, the comorbidities associated with BD, the beliefs toward treatments, the family situation and the preference of the patient. The modalities for switching or discontinuation of valproate in women with BD were related to the clinical situation. First-line therapeutic alternatives such as lithium, lamotrigine, quetiapine, olanzapine or aripiprazole were preferred for patients suffering from a clinically stable BD considering pregnancy or pregnant. In patients suffering from clinically unstable BD, to reach stability was considered first. A shared decision-making should be systematically implemented and the patient must be fully informed of the risks related to an in-utero exposure to valproate, and the risks of the discontinuation/switch that is considered. ConclusionAlthough the adaptation to French practice of the recommendations from the European expert opinion highlighted some differences in the criteria taken into consideration to guide the therapeutic decision, this expert advice will guide the clinician for switching and discontinuation of valproate in BD women able to have children or pregnant.

Symposium

Brief bio data of proposer: Currently working as Professor and Head of Department of Psychiatry, Kasturba Medical College, Manipal. Mostly work with adult psychiatry and addiction patients, and coordinator of Clinical Research Center for Neuromodulation in Psychiatry.Subtopics:Lithium-associated thyroid abnormalities: An overview – Dr Suma T. Udupa, Assistant Professor, Dept. of Psychiatry, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Karnataka, IndiaLithium-associated hypothyroidism: Case-based discussion – Dr Shahul Ameen,Consultant Psychiatrist, St Thomas Hospital, Chenganacherry, KeralaLithium-associated hyperthyroidism: Case-based discussion - Dr. Samir Kumar Praharaj, Professor and Head, Dept. of Psychiatry, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Karnataka, IndiaLearning objectives:1. To understand the thyroid abnormalities associated with long term lithium use.2. To understand the clinical presentations of hypo- and hyperthyroidism associated with long term lithium use and their managementBrief description of symposiumLithium is the gold standard mood stabilizer for bipolar disorder. It not only prevents mood episodes, but also has antisuicidal and neuroprotective effects. Despite its efficacy, its use is limited because of the adverse effects associated with long term use. Early identification and management of such adverse effects is the need of hour to increase acceptability among patients as well as physicians. In this symposium we focus on a less discussed topic, i.e. thyroid abnormalities associated with long term lithium use.Dr Suma T Udupa will give an overview of thyroid abnormalities associated with long term lithium use, which will include the type of abnormalities, their incidence and prevalence, and, risk factors. She will also discuss the probable mechanisms briefly. Dr Shahul Ameen and Dr Samir K. Praharaj will discuss the clinical presentations and management of lithium associated hypothyroidism and hyperthyroidism, respectively. They will use case vignettes to facilitate interactive discussion on the early presenting features, differential diagnoses and approaches to management.Protection of / prevention from violence against children: the role of educational system.The experience of violence in childhood impacts lifelong on mental health and well-being. The National Crime Records Bureau 2019 data tells us that every hour, 6 cases of child abuse occur, 57 percent of cases of sexual abuse are perpetrated by close family members. Globally, it is estimated that upto 1 billion children aged 2-7 years, have experienced physical, sexual or emotional violence or neglect (UNICEF,2020). The protection of child against violence and prevention mechanisms in our country is in very nascent stage and is currently struggling to adapt child-friendly procedure and inculcating various awareness building programes in different service sectors . There is tremendous need to inculcate new programes in educational sector to develop social and emotional skills to handle such problems at the very base level. It is the time to stop the harmful system to breed further. The study comes at a crucial time when a good number of people are showing interest to know more about the mechanisms meant for preventing and protecting children from abuse and violence. In this study some evidence based mechanisms i.e. ‘respectful relationship education’ (Australia) and ‘ happiness curriculum’(India) will be discussed. The discussion will throw some light of how social emotional learning(SEL) helps to develop skills of understanding the right communication, to identify wrong attitude, behavior, act etc and handling the signals of various situations breeding violence before it occurs.Authours : Dr. Sampa SinhaPsychiatric Social Worker, Dept. of PSW, IHBAS, DelhiDr. Deepak KumarProfessor & Head Dept. of Psychiatry, IHBAS, DelhiCorrespondence e-mail: sinhasampa25@rediffmail.com/sampa_in2000@yahoo.co.in

Therapeutic monitoring of mood stabilizers in bipolar disorder

IntroductionEfficacy of lithium is well documented in the literature, making it the gold standard treatment. However, its use declines with the advent of anticonvulsants. This raises the question about monitoring of mood stabilizers in practice.ObjectivesThe aims of this study were to determine the prophylactic lithium response in patients followed for bipolar disorder and compared to those of anticonvulsants and assess the mood stabilizers monitoring procedures in clinical practice.MethodsA retrospective study was conducted, over a period of six months, with patients followed for bipolar disorder stabilized under the same mood stabilizer (lithium or anticonvulsant) for at least one year. The participants were divided into two groups according to the mood stabilizing treatment. The two groups were compared according to socio-demographic, clinical and evolutionary profiles as well as the prophylactic response to treatment.ResultsPatients included were 64 in the study, 28 received lithium and 36 received anticonvulsants. The socio-demographic profile and clinical characteristics were similar in two groups, except for the average total number of mood episodes. Retrospective evaluation of the prophylactic response by ALDA scale showed a significantly higher mean total score in patients receiving lithium (5.9 ± 2.8 versus 2.58 ± 2.4, p = 0.025).). Ten of them were in compliance with the recommendations; while 19.44% received anticonvulsants had all the monitoring parameters within the recommended time frame.ConclusionsThymoregulators significantly modify the disease’s prognosis. Practitioners will attach particular special attention to distinguish the therapeutic efficacy of the side effects which are numerous and sometimes serious.

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

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

Hamlet's augury: how to manage discontinuation of mood stabilizers in bipolar disorder.

Research has generated good quality evidence about the treatment and management of bipolar disorder in acute and, to some degree, sub-acute/continuation phases. This has informed various guidelines about the treatment and management of bipolar disorder (BD). However, for the long-term or maintenance phase of illness, most guidelines peter out and, in the absence of sufficiently high-quality research evidence, remain vague. This is particularly evident for the important clinical question of discontinuing mood stabilizing pharmacological agents after a period of remission has been achieved. The aim of this review is to put together current existing evidence about discontinuing mood stabilizers after a period of remission in order to come up with a structured and coherent strategy for managing such discontinuation and to make recommendations for future research. To this end, we reviewed the main relevant treatment guidelines and subsequent evidence following the publication of these guidelines. The current recommended long-term treatment of BD is usually considered within the same principles applicable to any chronic health condition (e.g. hypertension or diabetes) where the focus is on continuing treatment at minimum effective medication dose often life-long, switching to alternative choice of medication due to side-effects and very few, if any, indications for complete cessation. However, in the absence of strong evidence on long-term treatment and the high rate of non-concordance in BD, medication discontinuation is a very important aspect of the treatment that should be given due consideration at every aspect of the treatment.

Exposure to Valproate in Utero May Increase Risk of Autism, ADHD

Back to table of contents Previous article Next article Clinical & ResearchFull AccessExposure to Valproate in Utero May Increase Risk of Autism, ADHDNick ZagorskiNick ZagorskiSearch for more papers by this authorPublished Online:8 Jan 2021https://doi.org/10.1176/appi.pn.2021.12b14AbstractThe anticonvulsant medications carbamazepine and lamotrigine do not appear to be associated with risks of these two developmental disorders, according to an analysis of Swedish registry data.iStock/Mohammed Haneefa NizamudeenUsing the treasure trove that is national Swedish health data, researchers have found more evidence that the anticonvulsant valproate poses risks if taken during pregnancy.Valproate, which is used to treat epilepsy, migraines, and bipolar disorder, has previously been linked to neural tube birth defects. This new analysis found that children exposed to valproate in the womb had an elevated risk of autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD) compared with those who were not exposed to the medication in the womb.The research, conducted by a team at Indiana University along with colleagues at Sweden’s Karolinska Institutet, used Swedish birth and medical registers to identify 14,614 children born between 1996 and 2011 to mothers with epilepsy. About 23% of the mothers used an anticonvulsant during the first trimester of pregnancy, with carbamazepine (9.7%), lamotrigine (6.8%), and valproate (4.8%) being the three most commonly prescribed medications.After factoring in numerous variables that also contribute to ASD or ADHD risk—including demographic characteristics, other medications used by the mothers, parental psychiatric history, and seizure severity—the investigators found that children who were exposed to valproate in the womb were 2.3 times as likely to be diagnosed with ASD and 1.74 times as likely to be diagnosed with ADHD as children who were not exposed to anticonvulsants. They also identified a small risk of ASD for carbamazepine exposure, but only in mothers who took this medication in combination with another anticonvulsant. There were no observable ASD or ADHD risks to children exposed to lamotrigine in the womb.Lead author Kelsey Wiggs, a Ph.D. student at Indiana University’s Developmental Psychopathology Lab, told Psychiatric News that these findings provide some of the strongest evidence to date that valproate may cause neurodevelopmental problems, given the large sample size and robust efforts to adjust for external variables. “[W]e cannot be definite about causality, because we could not adjust for every possible influence,” such as genetic factors, she said.“While it’s important to identify evidence of risk, we should not overlook when we find evidence of relative safety,” Wiggs continued. “And our data add to a growing body of evidence that lamotrigine is a good option for women with epilepsy who may become pregnant.”Veerle Bergink, M.D., the director of Mount Sinai Hospital’s Women’s Mental Health Program, noted that these latest findings in women with epilepsy align with other research on the effects of exposure to the anticonvulsants in the womb. “In terms of teratogenicity [potential damage to embryos], we know that valproate and to a lesser extent carbamazepine are risky agents, while lamotrigine is a safer alternative,” she said. Bergink was not involved with the current study.Though safer than other anticonvulsants, lamotrigine may not always be the answer for women of reproductive age who have bipolar disorder, Bergink cautioned. “The clinical problem with lamotrigine is that it is effective for depressive symptoms, but not so much for mania,” she said.“Bipolar is complicated, and we don’t have that single, frontline choice for women who are or may become pregnant,” Bergink continued. Lithium is a highly effective mood stabilizer for bipolar disorder, but this medication also comes with risks of neurological problems in offspring, if taken during the first trimester.“The best guidance [for psychiatrists] we can give is to try and aim for monotherapy in pregnant women ... and keep them on the lowest dose possible during pregnancy,” Bergink said. “Importantly, ramp the dose back up after delivery, since the first few weeks after childbirth pose the greatest risk of symptom relapse in women with bipolar disorder.”The study by Wiggs and colleagues was published in Neurology. It was supported by multiple grants from the National Institutes of Health, along with the Swedish Initiative for Research on Microdata in the Social and Medical Sciences and the Swedish Research Council. ■“Anti-seizure Medication Use During Pregnancy and Risk of ASD and ADHD in Children”. ISSUES NewArchived

Mood-Stabilizing Antiepileptic Treatment Response in Bipolar Disorder: A Genome-Wide Association Study.

Several antiepileptic drugs (AEDs) have US Food and Drug Administration (FDA) approval for use as mood stabilizers in bipolar disorder (BD), but not all BD patients respond to these AED mood stabilizers (AED‐MSs). To identify genetic polymorphisms that contribute to the variability in AED‐MS response, we performed a discovery genome‐wide association study (GWAS) of 199 BD patients from the Mayo Clinic Bipolar Disorder Biobank. Most of these patients had been treated with the AED‐MS valproate/divalproex and/or lamotrigine. AED‐MS response was assessed using the Alda scale, which quantifies clinical improvement while accounting for potential confounding factors. We identified two genome‐wide significant single‐nucleotide polymorphism (SNP) signals that mapped to the THSD7A (rs78835388, P = 7.1E‐09) and SLC35F3 (rs114872993, P = 3.2E‐08) genes. We also identified two genes with statistically significant gene‐level associations: ABCC1 (P = 6.7E‐07; top SNP rs875740, P = 2.0E‐6), and DISP1 (P = 8.9E‐07; top SNP rs34701716, P = 8.9E‐07). THSD7A SNPs were previously found to be associated with risk for several psychiatric disorders, including BD. Both THSD7A and SLC35F3 are expressed in excitatory/glutamatergic and inhibitory/γ‐aminobutyric acidergic (GABAergic) neurons, which are targets of AED‐MSs. ABCC1 is involved in the transport of valproate and lamotrigine metabolites, and the SNPs in ABCC1 and DISP1 with the strongest evidence of association in our GWAS are strong splicing quantitative trait loci in the human gut, suggesting a possible influence on drug absorption. In conclusion, our pharmacogenomic study identified novel genetic loci that appear to contribute to AED‐MS treatment response, and may facilitate precision medicine in BD.

Considering a Potential Role of Linalool as a Mood Stabilizer for Bipolar Disorder.

Epidemiologic studies suggest that the lifetime prevalence of bipolar spectrum disorders ranges from 2.8 to 6.5 percent of the population. To decrease morbidity and mortality associated with disease progression, pharmacologic intervention is indicated for the majority of these patients. While a number of effective treatment regimens exist, many conventional medications have significant side effect profiles that adversely impact patients' short and long-term well-being. It is thus important to continue advancing and improving therapeutic options available to patients. This paper reviews the limitations of current treatments and examines the chemical compound Linalool, an alcohol found in many plant species, that may serve as an effective mood stabilizer. While relatively little is known about Linalool and bipolar disorder, the compound has been shown to have antiepileptic, anti-inflammatory, anxiolytic, anti-depressive, and neurotrophic effects, with mechanisms that are comparable to current bipolar disorder treatment options.

&lt;p&gt;Medication Profile and Treatment Cost Estimation Among Outpatients with Schizophrenia, Bipolar Disorder, Depression, and Anxiety Disorders in Indonesia&lt;/p&gt;

PurposeThe present retrospective study aimed to determine the medication profile and estimate the treatment costs from medical records of new outpatients with schizophrenia, bipolar disorder, depression, and anxiety disorders from a healthcare perspective at a national referral hospital in Indonesia from 2016 to 2018.MethodsMedical records (including medical and administrative data) of 357 new outpatients with schizophrenia, bipolar disorder, depression, or anxiety disorders were collected from the hospital information system. The records of new outpatients with schizophrenia, bipolar disorder, depression, or anxiety disorders aged >18 years and had only received drugs for treatment were included. The medication profile was descriptively assessed, and estimated costs were calculated based on direct costs from a healthcare perspective.ResultsOverall, 173 medical records were further analyzed. The main drugs administered to the new outpatients were atypical and typical antipsychotics for schizophrenia, atypical antipsychotics and mood stabilizers for bipolar disorder, antidepressants and atypical antipsychotics for depression, and antidepressants and benzodiazepines for anxiety disorders. The average annual treatment costs per patient were IDR 3,307,931 (USD 236) for schizophrenia, IDR 17,978,865 (USD 1,284) for bipolar disorder, IDR 1,601,850 (USD 114) for depression, and IDR 1,190,563 (USD 85) for anxiety disorders.ConclusionThe most commonly prescribed drugs for schizophrenia were haloperidol and risperidone; for bipolar disorders, sodium divalproex and risperidone; for depression, fluoxetine and sertraline; and for anxiety disorders, sertraline and lorazepam. Considering the high prevalence and estimated treatment costs for mental disorders, special attention is required to prevent an increase in their prevalence in Indonesia.

Nrf2 activation protects against lithium-induced nephrogenic diabetes insipidus.

Lithium (Li) is the mainstay pharmacotherapeutic mood stabilizer in bipolar disorder. Its efficacious use is complicated by acute and chronic renal side effects, including nephrogenic diabetes insipidus (NDI) and progression to chronic kidney disease (CKD). The nuclear factor erythroid-derived 2-related factor 2 (Nrf2) pathway senses and coordinates cellular responses to oxidative and electrophilic stress. Here, we identify that graded genetic activation of Nrf2 protects against Li-induced NDI (Li-NDI) and volume wasting via an aquaporin 2-independent mechanism. Renal Nrf2 activity is differentially expressed on functional segments of the nephron, and its activation along the distal tubule and collecting duct directly modulates ion transporter expression, mimicking paradoxical effects of diuretics in mitigating Li-NDI. In addition, Nrf2 reduces cyclooxygenase expression and vasoactive prostaglandin biosynthesis. Pharmacologic activation of Nrf2 confers protective effects, confirming this pathway as a potentially novel druggable target for the prevention of acute and chronic renal sequelae of Li therapy.

A pyruvate dehydrogenase complex disorder hypothesis for bipolar disorder

Ketosis is a metabolic state in which the body uses ketones derived from breakdown of fatty acids as the primary mitochondrial fuel source instead of glucose. In recent years an accumulation of evidence for the beneficial effects of the ketotic state on the brain have heightened interest in its potential for use in neurological conditions. The ketogenic diet (KD) induces ketosis and is an effective treatment for medically resistant epilepsy. There is significant comorbidity between epilepsy and bipolar disorder (BD) and both conditions are treated by anti-convulsant drugs. In addition, reports on bipolar disease online fora have highlighted subjective mood stabilization effects associated with the KD. These KD reported effects could be explained if there was a disorder in the conversion of pyruvate into Acetyl-CoA (and subsequent impairment of oxidative phosphorylation) which was bypassed by ketones providing an alternative substrate for oxidative phosphorylation. This is consistent with growing evidence that mitochondrial dysfunction plays a causal role in BD and explains the reported TCA cycle dysfunction and elevated pyruvate levels in BD. Reduced levels of ATP affects the normal operation of the Na, K-ATPase in the brain with differing levels of reduction either leading to reduced neuronal action potential and inhibition of neurotransmitter release (consistent with the depressed state in BD) or increased neuronal resting potential and hyper-excitability (consistent with a [hypo]manic mood state). We hypothesize that the mitochondrial dysfunction is due to a disorder of the Pyruvate Dehydrogenase Complex (PDC) and/or Mitochondrial Carrier Protein (MCP) shuttle which moves intracellular pyruvate into mitochondria. The resultant reduction in ATP generation could explain mood instability and cycling in BD (through mechanisms such as those delineated by Mallakh and Peters). This proposed novel causal pathway could explain mood de-stabilization in BD and the reported positive effects of KD. If true, this hypothesis would suggest that there should be increased research attention to PDC (and in particular the E1 alpha subunit) as potential therapeutic targets and further study of a possible role of KD in BD to improve mood stability. Experimental approaches, such as through a clinical trial of KD on mood stabilization in BD, are required to further investigate this hypothesis.