Total valproate versus free valproate in therapeutic drug monitoring for bipolar disorder: A cross-sectional study.

INTRODUCTION: The debate about observing total versus free serum valproate levels for therapeutic drug monitoring (TDM) has been unresolved for decades. This study was planned to assess the agreement between the total versus free valproate levels and the advantage of one method over the other in TDM. METHODS: The present cross-sectional study was done on 93 patients with bipolar disorder. The intraclass correlation coefficient, Bland Altman analysis, and Lin's concordance analysis were done to assess the agreement between the total and free valproate concentrations. Linear and polynomial models were constructed to evaluate the relation between the two measurements. Receiver operating characteristics analysis was done to compare the accuracy for differentiating remission from non-remission on Young's mania rating scale (YMRS). RESULTS: The intraclass correlation coefficient and Lin's concordance correlation coefficient were 0.491 (p = .002) and 0.055 (95% CI:0.037, 0.073), respectively. Bland Altman's analysis showed proportional bias. A polynomial model of second order was found to be the best fit for the prediction of free valproate from the data for total valproate, and 81.4% of the variability in free valproate could be explained when adjusted for albumin levels. The area under the curve for total valproate was 0.60 when compared to free valproate 0.56 for differentiating between remission and non-remission, but the comparison between the two ROC analyses was not statistically significant. CONCLUSION: Free valproate does not provide any added advantage over the total valproate levels; hence, total valproate levels may continue to be used as the marker for drug monitoring.

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

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

Sex differences in effectiveness and adverse effects of mood stabilizers and antipsychotics: A systematic review.

BACKGROUND: Psychiatric disorders differ in their prevalence, symptom profiles, and disease courses in men and women. However, sex differences in psychiatric disorders have not received enough attention to guide treatment recommendations. This systematic review aims to summarize sex differences in the treatment responses and adverse effects of mood stabilizers and antipsychotics transdiagnostically. METHODS: We conducted a systematic review following the PRISMA 2020 statement (CRD42020212478). A literature search was conducted using MEDLINE, Embase, Cochrane Central, PsycINFO, Web of Science Core Collection, and Scopus databases. Studies comparing mood stabilizer or antipsychotic treatment outcomes in men and women were included. JBI critical appraisal checklists were used to assess bias risk. RESULTS: Out of 4866 records, 129 reports (14 on mood stabilizers, 115 on antipsychotics) with varying designs were included. Sample sizes ranged from 17 to 22,774 participants (median = 147). The most common psychiatric diagnoses were schizophrenia spectrum (n = 109, 84.5 %) and bipolar disorders (n = 38, 29.5 %). Only four studies explored sex differences in mood stabilizer treatment response. In 40 articles on antipsychotic treatment response, 18 indicated no sex difference, while 16 showed females had better outcomes. Women had more adverse effects with both mood stabilizers and antipsychotics. The risk of bias was low in 84 (65.1 %) of studies. LIMITATIONS: Substantial heterogeneity among the studies precluded performing a meta-analysis. CONCLUSION: Number of studies focusing on sex differences in treatment outcomes of mood stabilizers is limited. Women may respond better to antipsychotics than men, but also experience more side effects. The impact of pharmacokinetics on sex differences warrants more attention.

Pharmacoepidemiology and Clinical Correlates of Lithium Treatment for Bipolar Disorder in Asia.

BACKGROUND: As clinical practices with lithium salts for patients diagnosed with bipolar disorder (BD) are poorly documented in Asia, we studied the prevalence and clinical correlates of lithium use there to support international comparisons. METHODS: We conducted a cross-sectional study of use and dosing of lithium salts for BD patients across 13 Asian sites and evaluated bivariate relationships of lithium treatment with clinical correlates followed by multivariate logistic regression modeling. RESULTS: In a total of 2139 BD participants (52.3% women) of mean age 42.4 years, lithium salts were prescribed in 27.3% of cases overall, varying among regions from 3.20% to 59.5%. Associated with lithium treatment were male sex, presence of euthymia or mild depression, and a history of seasonal mood change. Other mood stabilizers usually were given with lithium, often at relatively high doses. Lithium use was associated with newly emerging and dose-dependent risk of tremors as well as risk of hypothyroidism. We found no significant differences in rates of clinical remission or of suicidal behavior if treatment included lithium or not. CONCLUSIONS: Study findings clarify current prevalence, dosing, and clinical correlates of lithium treatment for BD in Asia. This information should support clinical decision-making regarding treatment of BD patients and international comparisons of therapeutic practices.

Impact of mood stabilizers on creativity.

OBJECTIVE: While a DSM-5 criterion for both hypomania and mania is impaired functioning, the majority of those with a bipolar condition report improved functioning. When offered a mood stabilizer, many express concerns about any impact on their creativity. This piece seeks to address the question and attendant issues. METHOD: Reference is made to the impact of differing mood stabilizers on cognitive performance and the limited data on any specific impact on creativity, while some personal observations are offered. RESULTS: There appears to be a distinctive gradient in the cognitive impacts of differing mood stabilizers, with lithium offering the highest risk, carbamazepine and valproate providing a slight risk, and lamotrigine seemingly without cognitive side-effects. CONCLUSIONS: The question not only invites a nuanced response from the clinician but argues for close observation of any cognitive side-effects when lithium is introduced.

Common changes in rat cortical gene expression after valproate or lithium treatment particularly affect pre- and post-synaptic pathways that regulate four neurotransmitters systems.

OBJECTIVES: We have postulated that common changes in gene expression after treatment with different therapeutic classes of psychotropic drugs contribute to their common therapeutic mechanisms of action. METHODS: To test this hypothesis, we measured levels of cortical coding and non-coding RNA using GeneChip® Rat Exon 1.0 ST Array after treatment with vehicle (chow only), chow containing 1.8 g lithium carbonate/kg (n = 10) or chow containing 12 g sodium valproate/kg (n = 10) for 28 days. Differences in levels of RNA were identified using JMP Genomics 13 and the Panther Gene Ontology Classification System was used to identify potential consequences of RNA. RESULTS: Compared to vehicle treatment, levels of cortical RNA for 543 and 583 coding and non-coding RNAs were different after treatment with valproate and lithium, respectively. Moreover, levels of 323 coding and non-coding RNAs were altered in a highly correlated way by treatment with valproate and lithium, changes that would impact on cholinergic, glutamatergic, serotonergic and dopaminergic neurotransmission as well as on voltage gated ion channels. CONCLUSIONS: Our study suggests that treating with mood stabilisers cause many common changes in levels of RNA which will impact on CNS function, particularly affecting post-synaptic muscarinic receptor functioning and the release of multiple neurotransmitters.

Does the comorbidity of borderline personality disorder affect the response to treatment in bipolar patients?

Bipolar disorder (BD) is a highly prevalent condition whose response to pharmacological treatment is associated with a number of factors including psychiatric comorbidity. Borderline personality disorder (BPD) shares clinical symptoms and biological vulnerability with BD and the two conditions are frequently comorbid, thus representing a clinical challenge. The purpose of the present review is to summarize the data related to treatment response in bipolar patients with comorbid BPD. According to systematic review process, a literature search was performed on the PubMed, Embase, PsycInfo, Isi Web of Knowledge, Medscape, and Cochrane Library databases. Peer-reviewed articles until December 2022 were eligible for inclusion. Comorbidity with BPD seems to be associated with a more difficult clinical stabilization in bipolar patients, often requiring poly-therapy or a longer duration of hospitalization. However, three studies, assessing the effectiveness of mood stabilizers in bipolar patients, did not demonstrate a prominent influence of BPD comorbidity in achieving clinical response. The most frequently administered pharmacological treatments in the selected studies include mood stabilizers and atypical antipsychotics. The presence of comorbid BPD in bipolar patients may hamper treatment effectiveness. Future studies, comparing different treatments and with larger samples, are needed to confirm the results critically summarized in the present review.

Subjects suffering from bipolar disorder taking lithium are less likely to report physical pain: a FACE-BD study.

BACKGROUND: Physical pain is a common issue in people with bipolar disorder (BD). It worsens mental health and quality of life, negatively impacts treatment response, and increases the risk of suicide. Lithium, which is prescribed in BD as a mood stabilizer, has shown promising effects on pain. METHODS: This naturalistic study included 760 subjects with BD ( FACE-BD cohort) divided in two groups: with and without self-reported pain (evaluated with the EQ-5D-5L questionnaire). In this sample, 176 subjects were treated with lithium salts. The objectives of the study were to determine whether patients receiving lithium reported less pain, and whether this effect was associated with the recommended mood-stabilizing blood concentration of lithium. RESULTS: Subjects with lithium intake were less likely to report pain (odds ratio [OR] = 0.59, 95% confidence interval [CI], 0.35-0.95; p = 0.036) after controlling for sociodemographic variables, BD type, lifetime history of psychiatric disorders, suicide attempt, personality traits, current depression and anxiety levels, sleep quality, and psychomotor activity. Subjects taking lithium were even less likely to report pain when lithium concentration in blood was ≥0.5 mmol/l (OR = 0.45, 95% CI, 0.24-0.79; p = 0.008). CONCLUSIONS: This is the first naturalistic study to show lithium's promising effect on pain in subjects suffering from BD after controlling for many confounding variables. This analgesic effect seems independent of BD severity and comorbid conditions. Randomized controlled trials are needed to confirm the analgesic effect of lithium salts and to determine whether lithium decreases pain in other vulnerable populations.

Lithium Treatment Induces Cardiac Dysfunction in Mice.

Lithium (Li) salts are commonly used as medications for bipolar disorders. In addition to its therapeutic value, Li is also being increasingly used as a battery component in modern electronic devices. Concerns about its toxicity and negative impact on the heart have recently been raised. We investigated the effects of long-term Li treatment on the heart, liver, and kidney in mice. Sixteen C57BL/6J mice were randomly assigned to receive oral administration of Li carbonate (n = 8) or act as a control group (n = 8) for 12 weeks. We evaluated the cardiac electrical activity, morphology and function, and pathways contributing to remodelling. We assessed the multi-organ toxicity using histopathology techniques in the heart, liver, and kidney. Our findings suggest that mice receiving Li had impaired systolic function and ventricular repolarisation and were more susceptible to arrhythmias under adrenergic stimulation. The Li treatment caused an increase in the cardiomyocytes' size, the modulation of the extracellular signal-regulated kinase (ERK) pathway, along with some minor tissue damage. Our findings revealed a cardiotoxic effect of Li at therapeutic dosage, along with some histopathological alterations in the liver and kidney. In addition, our study suggests that our model could be used to test potential treatments for Li-induced cardiotoxicity.

[Fortification of drinking water with lithium to reduce suicide in the population].

Antimanic and phase-prophylactic features of lithium (Li) in subjects with affective disorders has been known for a long while. Furthermore, it has also been proven for decades that - partially due to its aforementioned effects - Li has marked antisuicide properties in subjects with mood disorders. Intriguingly, consistent findings from several studies conducted in the last 15 years suggest that the antisuicide effect of Li can also be detected in those members of the population who consume drinking water with high Li contents (in connection with this, we must note that the level of Li in tap water is several orders of magnitude less than the therapeutic dose of Li). Based on these results, and also taking into the consideration the long-known anti-goiter effect of iodized table salt, some experts suggest considering the enrichment of tap water with microdose Li. This paper paper briefly summarizes our current knowledge on this topic as well as the related clinical and ethical dilemmas.

Lithium, a Treatment Option for Alzheimer's Disease? A Review of Existing Evidence and Discussion on Future Perspectives.

After over 50 years of use, lithium-salts remain the first-line therapy for the management of bipolar disorder. Throughout this period, the potential for lithium salts has been extensively studied and numerous data favor its use in the treatment of neurodegenerative disorders such as Alzheimer's disease (AD). We reviewed existing evidence gathered from clinical case reports and studies on the effect of lithium on neuropsychological symptoms of AD and as a disease-modifying treatment acting on cognitive symptoms. The review summarizes the molecular pathways, involving GSK-3ß inhibition and neuroprotection, through which lithium is proposed to exert its effect. Limitations to its current use in AD are discussed and future perspectives as a potential treatment option for AD are considered in regard to ongoing clinical trials using different forms of lithium.

Bipolar mania and epilepsy pathophysiology and treatment may converge in purine metabolism: A new perspective on available evidence.

Decreased ATPergic signaling is an increasingly recognized pathophysiology in bipolar mania disease models. In parallel, adenosine deficit is increasingly recognized in epilepsy pathophysiology. Under-recognized ATP and/or adenosine-increasing mechanisms of several antimanic and antiseizure therapies including lithium, valproate, carbamazepine, and ECT suggest a fundamental pathogenic role of adenosine deficit in bipolar mania to match the established role of adenosine deficit in epilepsy. The depletion of adenosine-derivatives within the purine cycle is expected to result in a compensatory increase in oxopurines (uric acid precursors) and secondarily increased uric acid, observed in both bipolar mania and epilepsy. Cortisol-based inhibition of purine conversion to adenosine-derivatives may be reflected in observed uric acid increases and the well-established contribution of cortisol to both bipolar mania and epilepsy pathology. Cortisol-inhibited conversion from IMP to AMP as precursor of both ATP and adenosine may represent a mechanism for treatment resistance common in both bipolar mania and epilepsy. Anti-cortisol therapies may therefore augment other treatments both in bipolar mania and epilepsy. Evidence linking (i) adenosine deficit with a decreased need for sleep, (ii) IMP/cGMP excess with compulsive hypersexuality, and (iii) guanosine excess with grandiose delusions may converge to suggest a novel theory of bipolar mania as a condition characterized by disrupted purine metabolism. The potential for disease-modification and prevention related to adenosine-mediated epigenetic changes in epilepsy may be mirrored in mania. Evaluating the purinergic effects of existing agents and validating purine dysregulation may improve diagnosis and treatment in bipolar mania and epilepsy and provide specific targets for drug development.

Diagnosis and Treatment of Bipolar Disorder: A Review.

Importance: Bipolar disorder affects approximately 8 million adults in the US and approximately 40 million individuals worldwide. Observations: Bipolar disorder is characterized by recurrent episodes of depression and mania or hypomania. Bipolar depressive episodes are similar to major depressive episodes. Manic and hypomanic episodes are characterized by a distinct change in mood and behavior during discrete time periods. The age of onset is usually between 15 and 25 years, and depression is the most frequent initial presentation. Approximately 75% of symptomatic time consists of depressive episodes or symptoms. Early diagnosis and treatment are associated with a more favorable prognosis. Diagnosis and optimal treatment are often delayed by a mean of approximately 9 years following an initial depressive episode. Long-term treatment consists of mood stabilizers, such as lithium, valproate, and lamotrigine. Antipsychotic agents, such as quetiapine, aripiprazole, asenapine, lurasidone, and cariprazine, are recommended, but some are associated with weight gain. Antidepressants are not recommended as monotherapy. More than 50% of patients with bipolar disorder are not adherent to treatment. Life expectancy is reduced by approximately 12 to 14 years in people with bipolar disorder, with a 1.6-fold to 2-fold increase in cardiovascular mortality occurring a mean of 17 years earlier compared with the general population. Prevalence rates of metabolic syndrome (37%), obesity (21%), cigarette smoking (45%), and type 2 diabetes (14%) are higher among people with bipolar disorder, contributing to the risk of early mortality. The annual suicide rate is approximately 0.9% among individuals with bipolar disorder, compared with 0.014% in the general population. Approximately 15% to 20% of people with bipolar disorder die by suicide. Conclusions and Relevance: Bipolar disorder affects approximately 8 million adults in the US. First-line therapy includes mood stabilizers, such as lithium, anticonvulsants, such as valproate and lamotrigine, and atypical antipsychotic drugs, such as quetiapine, aripiprazole, asenapine, lurasidone, and cariprazine.

Real-world use of pharmacological treatments for incident bipolar disorder: A Finnish nationwide cohort study.

BACKGROUND: Pharmacotherapy remains crucial for treating bipolar disorder (BD), but knowledge on the treatments actually used by newly diagnosed patients in real-world settings is sparse. METHODS: Individuals newly diagnosed with BD during 1996-2018, aged 15-65 years, were identified from national Finnish registers. The patients' use of different drug classes (mood stabilizers, antipsychotics and antidepressants) or combinations of these drug classes were followed from initial pharmacotherapy (first line) after BD diagnosis until the fifth line of treatment or until the two-year follow-up time ended. Clinical and sociodemographic factors associated with antidepressants-only as the first treatment line were assessed with logistic regression. RESULTS: 82.6 % of all patients used BD medication during the follow-up. 33.9 % had antidepressants-only as the first, 22.9 % as the second and 19.7 % as the third treatment line. Use of combinations of mood stabilizers, antipsychotics and antidepressants increased by successive treatment lines. Factors associated with antidepressants-only as the first treatment line included older age (>45 years aOR 2.20, 95% CI: 2.01-2.40, 25-45 years: 1.55, 1.42-1.68, compared with those aged <25), diabetes (1.35, 1.17-1.55) and female sex (1.29, 1.21-1.37). BD diagnosis registered in 2016-2018 (0.48, 0.42-0.55) and substance abuse (0.77, 0.71-0.83) were associated with decreased odds. LIMITATIONS: Due to the register-based nature of this study, not all potentially important clinical factors influencing medication use could be controlled for. CONCLUSIONS: A large proportion of patients with bipolar disorder are not treated according to treatment guidelines, as use of antidepressants alone is common. Reasons for not following evidence-based recommendations need to be further researched.

Neuroimaging alterations associated with medication use in early-onset bipolar disorder: An updated review.

BACKGROUND: Pediatric bipolar disorder (PBD) is a severe disorder characterized by mood fluctuations starting at a young age. Several neuroimaging studies revealed a specific biological signature of PBD involving alterations in the amygdala and prefrontal regions. Considering the growing concerns regarding the effects of PBD treatments on developing brains, this review aims to provide an overview of the studies investigating the effect of mood stabilizers, antipsychotics, and anticonvulsants on neuroimaging findings in PBD. METHODS: We searched PubMed, Scopus, and Web of Science to identify all structural magnetic resonance imaging (sMRI), functional magnetic resonance imaging (fMRI), and diffusion tensor imaging (DTI) studies exploring the effects of medications on neuroimaging findings in PBD. A total of 18 studies met our inclusion criteria (fMRI n = 11, sMRI n = 6, DTI n = 1). RESULTS: Although the findings varied highly across the studies, some investigations consistently indicated that medications primarily affect the prefrontal cortex and the amygdala. Moreover, despite some exceptions, the reported medication effects predominantly lean towards structural and functional normalization. LIMITATIONS: The reviewed studies differ in methods, medications, and fMRI paradigms. Furthermore, most studies used observational approaches with small sample sizes, minimizing the statistical power. CONCLUSIONS: Evidence suggests the potential of antipsychotics and mood stabilizers to modulate the neuroimaging findings in PBD patients, mostly normalizing brain structure and function in key mood-regulating regions.

RNA Biomarkers in Bipolar Disorder and Response to Mood Stabilizers.

Bipolar disorder (BD) is a severe chronic disorder that represents one of the main causes of disability among young people. To date, no reliable biomarkers are available to inform the diagnosis of BD or clinical response to pharmacological treatment. Studies focused on coding and noncoding transcripts may provide information complementary to genome-wide association studies, allowing to correlate the dynamic evolution of different types of RNAs based on specific cell types and developmental stage with disease development or clinical course. In this narrative review, we summarize findings from human studies that evaluated the potential utility of messenger RNAs and noncoding transcripts, such as microRNAs, circular RNAs and long noncoding RNAs, as peripheral markers of BD and/or response to lithium and other mood stabilizers. The majority of available studies investigated specific targets or pathways, with large heterogeneity in the included type of cells or biofluids. However, a growing number of studies are using hypothesis-free designs, with some studies also integrating data on coding and noncoding RNAs measured in the same participants. Finally, studies conducted in neurons derived from induced-pluripotent stem cells or in brain organoids provide promising preliminary findings supporting the power and utility of these cellular models to investigate the molecular determinants of BD and clinical response.

Folic acid does not have an anti-manic effect but protect the brain against oxidative stress in an animal model of mania induced by ouabain.

BACKGROUND: Bipolar disorder (BD) is a complex and severe mental disorder that affects 1-3 % of the world population. Studies have suggested the involvement of oxidative stress in the physiopathology of this psychiatry disorder. Folic acid (FA), a vitamin from the B complex, is a nutraceutical that has recently been researched as a possible treatment for BD since folate is reduced in patients with the disorder. The present study aimed to evaluate the effects of lithium (Li) and FA on behavioral changes and oxidative stress parameters in an animal model of mania induced by ouabain (OUA). METHODS: Wistar rats received a single intracerebroventricular (ICV) injection of OUA or artificial cerebrospinal fluid (aCSF). From the day following ICV injection, the rats were treated for seven days with gavage injections of Li (47.5 mg/kg/mL), FA (50 mg/kg/mL), or water (1 mL/kg). On the 7th day after OUA injection, locomotor activity was measured using the open-field test. In addition, the oxidative stress parameters were evaluated in rats' frontal cortex, striatum, and hippocampus. RESULTS: OUA induced mania-like behavior and oxidative stress in rats' brains, but Li could reverse these alterations. FA did not affect behavior parameters; however, it presents an antioxidant effect on the brain structures evaluated. LIMITATIONS: The study was only evaluated male rats and ICV injection is an invasive procedure. CONCLUSION: These results indicate that even though FA has an effect against the oxidative stress induced by OUA, this effect was not strong enough to interfere with behavior parameters.