Management Of Bipolar Disorder Research Articles

Study of the different sleep disturbances during the prodromal phase of depression and mania in bipolar disorders.

One of the challenges in bipolar disorder (BD) lies in early detection of the illness and its recurrences, to improve prognosis. Sleep disturbances (SD) have been proposed as reliable predictive markers of conversion. While preliminary studies have explored the relationship between SD and the onset of mood episodes, the results remain heterogeneous and a few have specifically examined patients' perception of prodromal symptoms and their progression until the episode occurs. Identifying prodromes represents a crucial clinical challenge, as it enables early intervention, thereby reducing the severity of BD. Therefore, the objective of this study is to better characterize and evaluate the progressive nature of SD as prodromal symptoms of mood episodes, and patients' perception of it. Patients diagnosed with BD, either hospitalized or seeking treatment for a (hypo)manic or depressive episode benefited from standardized questionnaires, structured interviews, and self-report questionnaires to evaluate SD prior to the current episode, as well as sociodemographic and clinical information. Out of the 41 patients included, 59% spontaneously reported SD prior to the episode, appearing 90 days before depression and 35 days before mania (pre-indexed/spontaneous reports: 51.22% insomnia complaints, 4.88% hypersomnolence complaints, 7.32% parasomnias, 2.44% sleep movements). After inquiry about specific SD, the percentage of patients reporting prodromal SD increased significantly to 83%, appearing 210 days before depression and 112.5 days before mania (post-indexed reports: 75.61% presented with insomnia complaints appearing 150 days before depression and 20 days before mania, 46.34% had hypersomnolence complaints appearing 60 days before depression, 43.9% had parasomnias appearing 210 days before depression and 22.5 days before mania, 36.59% had sleep movements appearing 120 days before depression and 150 days before mania). Of note, bruxism appeared in 35% of patients before mania, and restless legs syndrome in 20% of patients before depression. This study highlights the very high prevalence of SD prior to a mood episode in patients with BD with differences between depressive and manic episodes. The more systematic screening of sleep alterations of the prodromal phase improved the recognition and characterization of different symptoms onset by patients. This underscores the need for precise questioning regarding sleep patterns in patients, to better identify the moment of transition toward a mood episode, referred to as "Chronos syndrome". The study emphasizes the importance of educating patients about the disorder and its sleep prodromal symptoms to facilitate early intervention and prevent recurrences.

Significant improvements in the olfactory sensitivity of bipolar I disorder patients during euthymia versus manic episodes: a longitudinal study.

Research has indicated that individuals diagnosed with bipolar disorder (BD) might experience alterations in their olfaction or levels of serum tumor necrosis factor-α (TNF-α), but no studies have investigated olfactory function and serum TNF-α in BD patients simultaneously. Moreover, there is a lack of existing research that compares the longitudinal olfactory function between individuals with manic and euthymic BD I. Patients with manic BD I (BDM, n=44) and healthy controls (HCs, n=32) were evaluated symptoms (measured via the Young Manic Rating Scale, YRMS), social function (measured via the Global Assessment Function, GAF), serum TNF-α, and olfactory function (via the Sniffin' Sticks test) including olfactory sensitivity (OS) and olfactory identification (OI). The BDM patients were followed up to the remission period and re-evaluated again. We compared OS, OI and serum TNF-α in manic and euthymic patients with BD I and HCs. We examined the correlation between olfactory function and symptoms, social function, and serum TNF-α in patients with BD I. The BDM patients exhibited significantly lower OS and OI compared to the HCs (Z = -2.235, P = 0.025; t = -6.005, P < 0.001), while a positive correlation was observed between OS and GAF score (r = 0.313, P = 0.039). The OS in the BD I remission group (n=25) exhibited significantly superior performance compared to the BDM group (t = -4.056, P < 0.001), and the same as that in the HCs (P = 0.503). The change in OS showed a positive correlation with the decrease in YMRS score (r = 0.445, P = 0.026), and a negative correlation with the course of disease (r = -0.594, P = 0.002). The TNF-α in BD I patients was significantly lower compared to HCs (P < 0.001), and not significantly correlated with olfactory function (all P > 0.05). The findings suggest that OS and OI are impaired in BDM patients, and the impaired OS in those patients can be recovered in the remission stage. OI may serve as a potential characteristic marker of BD. OS might be useful as an index for BDM treatment efficacy and prognosis.

Pharmacogenomic overlap between antidepressant treatment response in major depression & antidepressant associated treatment emergent mania in bipolar disorder

There is increasing interest in individualizing treatment selection for more than 25 regulatory approved treatments for major depressive disorder (MDD). Despite an inconclusive efficacy evidence base, antidepressants (ADs) are prescribed for the depressive phase of bipolar disorder (BD) with oftentimes, an inadequate treatment response and or clinical concern for mood destabilization. This study explored the relationship between antidepressant response in MDD and antidepressant-associated treatment emergent mania (TEM) in BD. We conducted a genome-wide association study (GWAS) and polygenic score analysis of TEM and tested its association in a subset of BD-type I patients treated with SSRIs or SNRIs. Our results did not identify any genome-wide significant variants although, we found that a higher polygenic score (PGS) for antidepressant response in MDD was associated with higher odds of TEM in BD. Future studies with larger transdiagnostic depressed cohorts treated with antidepressants are encouraged to identify a neurobiological mechanism associated with a spectrum of depression improvement from response to emergent mania.

State- and trait-related dysfunctions in bipolar disorder across different mood states: a graph theory study.

The interplay between state- and trait-related disruptions in structural networks remains unclear in bipolar disorder (BD), but graph theory can offer insights into global and local network changes. We sought to use diffusion-tensor imaging (DTI) and graph theory approaches to analyze structural topological properties across distinct mood states and identify high-risk individuals by examining state- and trait-related impairments in BD. We studied changes in white matter network among patients with BD and healthy controls, exploring relationships with clinical variables. Secondary analysis involved comparing patients with BD with unaffected people at high genetic risk for BD. We included 152 patients with BD, including 52 with depressive BD (DBD), 64 with euthymic BD (EBD) and 36 with manic BD (MBD); we also included 75 healthy controls. Secondary analyses involved 27 unaffected people at high genetic risk for BD. Patients with DBD and MBD exhibited significantly lower global efficiencies than those with EBD and healthy controls, with patients with DBD showing the lowest global efficiencies. In addition, patients with DBD displayed impaired local efficiency and normalized clustering coefficient (γ). At a global level, γ correlated negatively with depression and anxiety. Compared with healthy controls, and across mood states, patients with BD showed abnormal shortest path lengths in the frontolimbic circuit, a trend mirrored among those at high genetic risk for BD. Considerations include medication effects, absence of recorded BD episode counts and the cross-sectional nature of the study. Mood-specific whole-brain network metrics could serve as potential biomarkers in BD for transitions between mood states. Moreover, these findings contribute to evidence of trait-related frontolimbic circuit irregularities, shedding light on underlying pathophysiological mechanisms in BD.

The Janus face of antipsychotics in glial cells: Focus on glioprotection.

Antipsychotics are commonly prescribed to treat several neuropsychiatric disorders, including schizophrenia, mania in bipolar disorder, autism spectrum disorder, delirium, and organic or secondary psychosis, for example, in dementias such as Alzheimer's disease. There is evidence that typical antipsychotics such as haloperidol are more effective in reducing positive symptoms than negative symptoms and/or cognitive deficits. In contrast, atypical antipsychotic agents have gained popularity over typical antipsychotics, due to fewer extrapyramidal side effects and their theoretical efficacy in controlling both positive and negative symptoms. Although these therapies focus on neuron-based therapeutic schemes, glial cells have been recognized as important regulators of the pathophysiology of neuropsychiatric disorders, as well as targets to improve the efficacy of these drugs. Glial cells (astrocytes, oligodendrocytes, and microglia) are critical for the central nervous system in both physiological and pathological conditions. Astrocytes are the most abundant glial cells and play important roles in brain homeostasis, regulating neurotransmitter systems and gliotransmission, since they express a wide variety of functional receptors for different neurotransmitters. In addition, converging lines of evidence indicate that psychiatric disorders are commonly associated with the triad neuroinflammation, oxidative stress, and excitotoxicity, and that glial cells may contribute to the gliotoxicity process. Conversely, glioprotective molecules attenuate glial damage by generating specific responses that can protect glial cells themselves and/or neurons, resulting in improved central nervous system (CNS) functioning. In this regard, resveratrol is well-recognized as a glioprotective molecule, including in clinical studies of schizophrenia and autism. This review will provide a summary of the dual role of antipsychotics on neurochemical parameters associated with glial functions and will highlight the potential activity of glioprotective molecules to improve the action of antipsychotics.

Are dysfunctional attitudes elevated and linked to mood in bipolar disorder? A systematic review and meta-analysis.

Dysfunctional attitudes (DA) are higher in depression; however, less is understood about their role in bipolar disorder (BD). This paper aimed to explore the presence of DA in BD in comparison to clinical and non-clinical groups. Also explored were the associations between DA and mood states of depression, mania or euthymia in BD. A systematic review and meta-analysis were conducted. A total of 47 articles were included in the systematic review of which 23 were included in the meta-analysis. The quality of each study was rated. The meta-analysis showed significantly higher DA in BD than healthy controls (d = .70). However, no difference was observed between BD and unipolar participants (d = -.16). When reviewing mood state within BD, a significant mean difference was found between DA scores for euthymic and depressed participants (d = -.71), with those who were depressed scoring higher. Three studies found that psychological therapies significantly reduce DA in BD (d = -.38). These findings imply not only that DA are both a characteristic of BD that is not as prevalent in healthy populations but also that a depressed mood state is associated with increased severity. This implies that DA could possibly go 'offline' when mood symptoms are not present. Psychological therapies appear to reduce DA in BD. Implications for future research as well as practice-based implications are expanded on in the discussion.

Neutrophil/high-density lipoprotein cholesterol (HDL), monocyte/HDL and platelet/HDL ratios are increased in acute mania as markers of inflammation, even after controlling for confounding factors

Objective Recent studies show that inflammation is related to the pathogenesis of acute mania of bipolar disorder. Neutrophil/high-density lipoprotein (HDL) ratio (NHR), lymphocyte/HDL ratio (LHR), monocyte/HDL ratio (MHR) and platelet/HDL ratio (PHR) have recently been investigated as novel markers of inflammation. In addition, the atherogenic index of plasma (AIP) and atherogenic coefficient (AC) are the leading atherogenic indices. The study aimed to investigate these inflammation and atherogenic index markers in acute mania of bipolar disorder. Another aim was to determine whether there is a relationship between these markers and disease severity and psychotic symptoms. Methods A total of 109 BD-M and 101 (HC) were enrolled in the study. The differences in NHR, LHR, MHR, PHR, AIP and AC and their association with illness severity and psychotic symptoms were analyzed after adjusting for age, sex, total cholesterol level, body-mass index and smoking status. Then, a receiver operating characteristic (ROC) curve and linear discriminant analysis (LDA) were used to analyze these parameters’ diagnostic potential. Moreover, the Young Mania Rating Scale (YMRS) and Clinical Global Impression Scale for use in bipolar illness-Severity subscale (CGI-BP-S) were used to assess the severity of clinical symptoms. Results We found higher levels of NHR, MHR, PHR and AIP, but not LHR and AC, after adjusting confounding factors in patients with BD-M compared to HCs. In logistic regression analysis, higher levels of MHR and NHR were associated with BD-M. MHR, NHR and PHR were predictors for differentiating the BD-M group from the HC group. However, the severity of the illness or the psychotic feature of the manic episode did not significantly affect the parameters. In the ROC curve analysis of BD-M, the indicators with an area under the curve (AUC) higher than 0.6 were the MHR, NHR, PHR and LHR. Conclusions These results provide information about the role of inflammation in the pathophysiology of BD-M. Even after controlling for confounding factors, MHR, NHR, PHR and AIP are potential biomarkers for BD-M. Moreover, the increase in AIP may explain the co-morbidity between BD and cardiovascular diseases. However, the severity of the illness or the psychotic feature of the manic episode did not significantly affect the levels of inflammation ratios used in our study. Due to the low cost and widespread use of lipid metabolism and related inflammation rates, it may be beneficial to know the MHR, NHR, PHR and AIP levels in BD-M patients.

Bipolar At-Risk Criteria and Risk of Bipolar Disorder Over 10 or More Years

Predicting the onset of bipolar disorder (BD) could facilitate preventive treatments. Among risk measures, bipolar at-risk (BAR) criteria have shown promise in predicting onset of bipolar disorder in the first year in clinical cohorts; however, it is not known whether BAR criteria are associated with the onset of BD in the longer term. To assess the association of BAR criteria with onset of BD over 10 to 13 years follow-up. This prospective cohort study, completed between May 1, 2020, and November 7, 2022, included consenting people seeking help for nonpsychotic major mental health difficulties, including mood, personality, and substance use disorders, who were originally recruited at ages 15 to 25 years from a tertiary youth mental health setting in metropolitan Melbourne, Victoria, Australia, from May 1, 2008, to September 30, 2010. Meeting BAR criteria at baseline. Criteria included subthreshold mania, cyclothymic features, subthreshold depression, and family history of BD. A matched clinical comparison group was recruited from the same help-seeking population. The primary outcome was expert consensus diagnosis of BD I or II based on the Mini International Neuropsychiatric Interview, self-reported information collected through online assessments, and linked data on mental health service utilization in Victoria over 10 to 13 years of follow-up. Among 69 eligible participants, follow-up data were available for 60 (88.2%). The mean (SD) age at the end of follow-up was 32.9 (2.8) years, and 49 (81.7%) were women. A total of 28 participants met BAR criteria, and 32 were in the comparison group. In the BAR group, 8 patients (28.6%) developed BD over a mean (SD) of 11.1 (0.7) years of follow-up, and no patients in the comparison group developed BD. The risk of developing BD was higher in the BAR group than in the non-BAR group (χ21 = 70.0; P < .001). The proportions of transitions to BD were equal in the first and second halves of the follow-up period. In this cohort study of participants seeking care for mental health difficulties, patients meeting the BAR criteria were significantly more likely to transition to BD over a decade after ascertainment compared with patients not meeting the BAR criteria. The findings suggest that those meeting BAR criteria may benefit from longer-term monitoring and support. Evaluation of predictive properties in longer-term studies using a risk measure will help with implementation of BAR criteria in clinical settings.

Circulating T-cell subsets discrepancy between bipolar disorderand major depressive disorder during mood episodes: A naturalistic, retrospective study of 1015 cases.

We aimed to investigate whether peripheral T-cell subsets could be a biomarker to distinguish major depressive disorder (MDD) and bipolar disorder (BD). Medical records of hospitalized patients in the Department of Psychiatry, the First Affiliated Hospital, Zhejiang University School of Medicine, from January 2015 to September 2020 with a discharge diagnosis of MDD or BD were reviewed. Patients who underwent peripheral blood examination of T-cell subtype proportions, including CD3+, CD4+, CD8+ T-cell, and natural killer (NK) cells, were enrolled. The Chi-square test, t-test, or one-way analysis of variance were used to analyze group differences. Demographic profiles and T-cell data were used to construct a random forest classifier-based diagnostic model. Totally, 98 cases of BD mania, 459 cases of BD depression (BD-D), and 458 cases of MDD were included. There were significant differences in the proportions of CD3+, CD4+, CD8+ T-cell, and NK cells among the three groups. Compared with MDD, the BD-D group showed higher CD8+ but lower CD4+ T-cell and a significantly lower ratio of CD4+ and CD8+ proportions. The random forest model achieved an area under the curve of 0.77 (95% confidence interval: 0.71-0.83) to distinguish BD-D from MDD patients. These findings imply that BD and MDD patients may harbor different T-cell inflammatory patterns, which could be a potential diagnostic biomarker for mood disorders.

Thiol-disulphide homeostasis, ischemia-modified albumin, complete blood count-derived inflammatory markers and C-reactive protein from acute mania to early remission in bipolar disorder

ObjectivesThere is much recent evidence that inflammation contributes to the pathophysiology of acute mania in bipolar disorder (BD). However, no study was evaluated in which the change in thiol-disulphide homeostasis, ischemia-modified albumin (IMA), complete blood count-derived inflammatory markers (CBC-IMs) and C-reactive protein (CRP) levels in bipolar patients was followed-up from acute mania to early remission. MethodsSeventy-seven bipolar patients in acute mania and ninety-one HC were enrolled. We measured levels of thiol-disulphide parameters, IMA, and CBC-IMs such as neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), red-cell-distribution-width (RDW)-to-platelet ratio (RPR), systemic immune-inflammatory index (SII), and systemic inflammatory response index (SIRI), CRP and platelet-to-albumin ratio (PAR), after adjusting for age, gender, body-mass index (BMI) and smoking status, during acute mania to subsequent early remission. The results were compared with HC. ResultsThe levels or ratios of all thiol-disulphide parameters except for disulphide, IMA and CRP of bipolar patients in both acute mania and early remission were significantly different from HC, after adjusting for confounders. The NLR, SII, CRP and PAR values of bipolar patients were significantly higher in only acute mania compared to HC. Significant changes in thiol-disulphide parameters and IMA levels were not found in early remission after acute mania. LimitationsShort follow-up period and lack of drug-naive patients. ConclusionsOur results suggest that thiol-disulphide parameters, IMA level and SIRI value might be a trait biomarkers of inflammation in BD. In addition, NLR, SII and PAR values and CRP level might be a state biomarker of inflammation in bipolar patients in a manic phase.

Can daily actigraphic profiles distinguish between different mood states in inpatients with bipolar disorder? An observational study.

Criterion A changes for bipolar disorder (BD) in the Diagnostic and Statistical Manual of Mental Disorders-Fifth Edition yield new difficulties in diagnosis. Actigraphy has been used to capture the activity features of patients with BD. However, it remains unclear whether long-term actigraphic data could distinguish between different mood states in hospitalized patients with BD. In this observational study, 30 hospitalized patients with BD were included. Wrist-worn actigraphs were used to monitor motor activity. The patients were divided into bipolar disorder-depression (BD-D), bipolar disorder-mania (BD-M), and bipolar disorder-mixed state (BD-MS) groups. Motor activity differences were estimated using non-parametric analyses between and within the three groups. The mean 24 h activity level differed between the groups. In the between-group analysis, the intra-individual fluctuation and minute-to-minute variability in the morning and the mean activity level and minute-to-minute variability in the evening significantly differed between the BD-M and BD-MS groups. In the within-group analysis, the BD-M group showed a disrupted rhythm and reduced activity complexity at night. Both the BD-D and BD-MS groups demonstrated significant differences between several parameters obtained in the morning and evening. The mean activity levels during the relatively long monitoring period and the intra-day variation within the groups could reflect the differences in motor activity. Sustained activity monitoring may clarify the emotional states and provide information for clinical diagnosis.

Acute pancreatitis during valproic acid administration in a patient with vascular dementia, epileptic seizures, and psychiatric symptoms: a case report

BackgroundValproic acid (VPA) is a relatively safe drug widely used for the treatment of epileptic seizures and mania in bipolar disorder, as well as the prevention of migraine headaches. Here, we present a case of VPA-induced pancreatitis in a patient with vascular dementia, epileptic seizures, and psychiatric symptoms. He had no distinctive abdominal symptoms.Case presentationA 66-year-old Japanese man was treated with VPA for agitation and violent behavior due to vascular dementia, epileptic seizures, and psychiatric symptoms. During admission, he experienced a sudden decrease in consciousness and blood pressure. Abdominal findings were unremarkable; however, blood tests showed an inflammatory response and elevated amylase levels. Contrast-enhanced abdominal computed tomography showed diffuse pancreatic enlargement and inflammation extending to the subrenal pole. VPA-induced acute pancreatitis was diagnosed, VPA was discontinued, and high-dose infusions were administered. Acute pancreatitis resolved after treatment initiation.ConclusionsClinicians should be aware of this relatively rare side effect of VPA. Diagnosis may be challenging in elderly people and patients with dementia as they may present with non-specific symptoms. Clinicians should consider the risk of acute pancreatitis when using VPA in patients who cannot report spontaneous symptoms. Blood amylase and other parameters should be measured accordingly.

Efficacy and Safety of Clonidine in the Treatment of Acute Mania in Bipolar Disorder: A Systematic Review.

Clonidine, an alpha-2 adrenergic agonist, has been proposed as an antimanic agent that acts by reducing noradrenergic transmission. We conducted a systematic review to examine the efficacy and safety of clonidine for acute mania/hypomania. A comprehensive literature search was performed to identify randomized controlled trials (RCT) and non-randomized studies investigating the efficacy and safety of monotherapy/adjuvant treatment with clonidine for acute mania/hypomania in patients with bipolar disorder (BD). Nine studies (n = 222) met our inclusion criteria, including five RCTs (n = 159) and four non-randomized studies (n = 63). Non-randomized studies showed clonidine to help reduce symptoms of mania. However, data from placebo controlled RCTs were inconsistent. One RCT showed adjuvant clonidine as superior to placebo, whereas another RCT reported that clonidine was not better than placebo. In individual RCTs, lithium and valproate offered better antimanic effects compared to clonidine. Studies reported hypotension, depression, and somnolence as common adverse effects. Significant differences in study design and sample size contributed to high heterogeneity. This systematic review suggests low-grade evidence for clonidine as an adjuvant treatment for acute mania with mood stabilizers and inconclusive efficacy as monotherapy, warranting further well-designed RCTs.

Variations in olfactory function among bipolar disorder patients with different episodes and subtypes.

Most studies on olfactory function in individuals with bipolar disorder (BD) have not distinguished between the different subtypes or between the acute phase (mania or depression) and euthymic state. In this study, we compared olfactory function among BD patients with different subtypes and episodes to explore the potential use of olfactory function as a biomarker for the early identification of BD. The study sample consisted of 117 BD patients who were hospitalized between April 2019 and June 2019, and 47 healthy volunteers as controls. The BD patients were divided into a bipolar I disorder (BD I) (n = 86) and bipolar II disorder (BD II) group (n = 31) according to the different subtypes, and divided into depressive BD (n = 36), manic BD (n = 44), or euthymic BD (n = 37) groups according to the types of episodes they experienced. We assessed olfactory sensitivity (OS) and olfactory identification (OI) via the Sniffin' Sticks test and used the Hamilton Depression Rating Scale (HAMD) and Young Manic Rating Scale (YMRS) to evaluate BD characteristics among all subjects. Compared with controls, the participants with BD showed decreased OS and OI. We found statistically significant differences in OS and OI between the BD I group and controls, as well as differences in OS between the BD I and BD II group. Least-significant difference multiple comparisons revealed statistically significant differences in OS between the depressive BD group, manic BD group and controls and also between the manic BD and euthymic BD group. OI was positively correlated with the YMRS score in the BD I group and OS was negatively correlated with the HAMD score in the BD II group. This may be the first study to compare olfactory function in patients with BD I vs. BD II via pairwise comparisons. Our findings suggest that OS may have potential as a biomarker for distinguishing the different subtypes of BD and as a state-related biomarker for differentiating the acute phase from the euthymic state of BD. However, further prospective research is warranted.

The Relationship between Mood Symptom Severity and Perfectionism Subtypes in Mood Disorders: A Systematic Review and Meta-Analysis.

Previous research suggests that there is a link between perfectionism and symptoms of depression. This study aimed to see if different types of perfectionism are linked differently to symptoms of depression in mood disorders and if there is a relationship between perfectionism and symptoms of mania in bipolar disorder. A systematic search was conducted in the databases PsycINFO, EMBASE, Web of Science, and PubMed to find papers which examined the relationship in clinical depression and bipolar disorder. A meta-analysis pooled the correlation effect sizes for mood symptoms severity and the severity of the perfectionism subtype. Twelve papers were included in the review, with five of these being included in the meta-analysis. The meta-analysis found statistically significant positive correlations between greater severity of depression symptoms and more severe perfectionism for the following subtypes: concern over mistakes, doubts about actions, other-oriented perfectionism, parental criticism, self-oriented perfectionism, and socially prescribed perfectionism. There was no significant relationship between depression symptoms and perfectionism subtypes of organisation and personal standards. There were not enough studies reporting data for manic symptoms for the meta-analysis or for any firm conclusions to be drawn. The relationship between depression and perfectionism differs depending on the particular type of perfectionism examined. Most studies were cross-sectional and correlational, so causation cannot be inferred, and future longitudinal studies are needed.

Phase-and disorder-specific differences in peripheral metabolites of the kynurenine pathway in major depression, bipolar affective disorder and schizophrenia

Objectives Kynurenine, kynurenic and quinolinic acid are important metabolites in tryptophan metabolism. Due to an involvement in glutamatergic neurotransmission and immune response, previous studies have investigated this pathway in mental disorders such as major depressive disorder (MDD), bipolar disorder (BD) or schizophrenia (SCZ). Tryptophan and kynurenine have been shown to be decreased across disorders, hinting at the missing link how inflammation causes neurotoxicity and psychiatric symptoms. The main aim of our study was to investigate if individual catabolites could serve as diagnostic biomarkers for MDD, BD and SCZ. Methods We measured plasma levels of tryptophan, kynurenine, kynurenic acid, quinolinic acid and ratio of quinolinic acid/kynurenic acid using mass spectrometry in n = 175 participants with acute episodes and after remission, compared with controls. Results Decreased levels of all tryptophan catabolites were found in the whole patient group, driven by the difference between BD and HC. Manic and mixed phase BD individuals displayed significantly lower kynurenine and kynurenic acid levels. We could not find significant differences between disorders. Upon reaching remission, changes in catabolite levels partially normalised. Conclusions Our data suggests an involvement of the kynurenine pathway in mental disorders, especially BD but disqualifying those metabolites as biomarkers for differential diagnosis.

Treatment effect variability in the response to pharmacological treatments for mania in bipolar disorder: a new methodological approach

Treatment effect variability in the response to pharmacological treatments for mania in bipolar disorder: a new methodological approach

Effect of CYP2C19 polymorphisms on antidepressant prescription patterns and treatment emergent mania in bipolar disorder

Antidepressant medication is used extensively to treat bipolar depression despite uncertain efficacy. The cytochrome P450 (CYP) 2C19 enzyme metabolize several antidepressants, and polymorphisms in the corresponding gene CYP2C19 influence plasma concentration and hence treatment outcomes in major depressive disorder. Here, we investigate if CYP2C19 polymorphisms are associated with antidepressant treatment patterns and the risk of mania when antidepressants are used in bipolar disorder. Two single nucleotide polymorphisms (rs4244285 and rs12248560) were used to classify 5019 bipolar disorder patients into CYP2C19 metabolic phenotypes ranging from poor to ultra-rapid metabolizers. We used Swedish national registry data 2005–2017 on dispensed medications and inpatient care to estimate risks for early-treatment persistence, treatment discontinuation, switching to a new antidepressant medication, and mania within 3 months of treatment initiation in patients treated with citalopram, escitalopram, sertraline, amitriptyline, and clomipramine. Metabolic phenotypes of CYP2C19 were not robustly associated with the investigated treatment outcomes based on dispense patterns. Slower metabolism was associated with an increased risk of treatment emergent mania for sertraline (hazard ratio [HR] = 1.3, 95% CI = 1.04–1.62, p = 0.02) and the tricyclic antidepressants amitriptyline and clomipramine (HR = 1.46, 95% CI = 1.05–2.02, p = 0.024). In a large study of the impact of CYP2C19 metabolic phenotypes on antidepressant treatment of bipolar depression, we found an association between slower CYP2C19 metabolism and higher risk of treatment emergent mania, which is a step towards personalized risk assessments. There were, however, no clear associations with early treatment persistence, treatment discontinuation, and switching to a new antidepressant.

Phenothiazines and their Evolving Roles in Clinical Practice: A Narrative Review.

Phenothiazines, a diverse class of drugs, can be used to treat multiple mental health and physical conditions. Phenothiazines have been used for decades to treat mental illnesses, including schizophrenia, mania in bipolar disorder, and psychosis. Additionally, these drugs offer relief for physical illnesses, including migraines, hiccups, nausea, and vomiting in both adults and children. Further research is needed to prove the efficacy of phenothiazines in treating physical symptoms. Phenothiazines are dopaminergic antagonists that inhibit D2 receptors with varying potency. High potency phenothiazines such as perphenazine are used to treat various psychiatric conditions such as the positive symptoms of schizophrenia, the symptoms of psychosis, and mania that can occur with bipolar disorder. Low/mid potency phenothiazines such as chlorpromazine antipsychotic drugs that have been used to treat schizophrenia and schizophrenia-like disorders since the 1950s and are utilized in numerous disease states. The present investigation aims to elucidate the effects of phenothiazines in clinical practice.

Block of Voltage-Gated Sodium Channels by Aripiprazole in a State-Dependent Manner.

Aripiprazole is an atypical antipsychotic drug, which is prescribed for many psychiatric diseases such as schizophrenia and mania in bipolar disorder. It primarily acts as an agonist of dopaminergic and other G-protein coupled receptors. So far, an interaction with ligand- or voltage-gated ion channels has been classified as weak. Meanwhile, we identified aripiprazole in a preliminary test as a potent blocker of voltage-gated sodium channels. Here, we present a detailed analysis about the interaction of aripiprazole with the dominant voltage-gated sodium channel of heart muscle (hNav1.5). Electrophysiological experiments were performed by means of the patch clamp technique at human heart muscle sodium channels (hNav1.5), heterologously expressed in human TsA cells. Aripiprazole inhibits the hNav1.5 channel in a state- but not use-dependent manner. The affinity for the resting state is weak with an extrapolated Kr of about 55 µM. By contrast, the interaction with the inactivated state is strong. The affinities for the fast and slow inactivated state are in the low micromolar range (0.5-1 µM). Kinetic studies indicate that block development for the inactivated state must be described with a fast (ms) and a slow (s) time constant. Even though the time constants differ by a factor of about 50, the resulting affinity constants were nearly identical (in the range of 0.5 µM). Besides this, aripirazole also interacts with the open state of the channel. Using an inactivation deficit mutant, an affinity of about 1 µM was estimated. In summary, aripiprazole inhibits voltage-gated sodium channels at low micromolar concentrations. This property might add to its possible anticancer and neuroprotective properties.