Alda Scale Research Articles

Measurement of lithium response in patients with bipolar disorder using the Retrospective Assessment of Response to Lithium Scale (Alda scale)

Lithium is the first-line medication for the treatment of bipolar disorder (BD), but its exact biological mechanisms have not been identified. One of the major obstacles in lithium-related research is the difficulty in precisely and reliably measuring the response to lithium. The Alda scale was developed to retrospectively measure lithium response in a standardized way. However, several aspects should be considered in understanding previous studies that used the Alda scale. In this narrative review, we aim to review previous studies and present the limitations of prior findings. Additionally, we suggest future strategies for applying the Alda scale in measuring lithium response. Initial studies using the Alda scale mainly included patients who were on lithium monotherapy for a long-term period. However, lithium monotherapy is relatively rare in clinical practice. More importantly, in clinical practice, if patients do not respond well to lithium, clinicians do not prescribe it for a long-term period. Thus, a modified approach to include diverse patients is necessary to identify true poor responders. Most previous studies also mainly included European populations, and ancestrally diverse populations should be included in the research. Furthermore, applying the same scale to explore the effects of other medications would also enhance our understanding of the neurobiological mechanisms of psychiatric medications in BD. Applying electronic health record data in evaluating lithium response would soon facilitate large-scale studies. Future studies that include diverse clinical populations reflecting the clinical practice are necessary to advance precision psychiatry.

Integrated proteomic and genomic analysis to identify predictive biomarkers for valproate response in bipolar disorder: a 6-month follow-up study

BackgroundSeveral genetic studies have been undertaken to elucidate the intricate interplay between genetics and drug responses in bipolar disorder (BD). However, there has been notably limited research on biomarkers specifically linked to valproate, with only a few studies investigating integrated proteomic and genomic factors in response to valproate treatment. Therefore, this study aimed to identify biological markers for the therapeutic response to valproate treatment in BD. Patients with BD in remission were assessed only at baseline, whereas those experiencing acute mood episodes were evaluated at three points (baseline, 8 ± 2 weeks, and 6 ± 1 months). The response to valproate treatment was measured using the Alda scale, with individuals scoring an Alda A score ≥ 5 categorized into the acute-valproate responder (acute-VPAR) group. We analyzed 158 peptides (92 proteins) from peripheral blood samples using multiple reaction monitoring mass spectrometry, and proteomic result-guided candidate gene association analyses, with 1,627 single nucleotide variants (SNVs), were performed using the Korean chip.ResultsThe markers of 37 peptides (27 protein) showed temporal upregulation, indicating possible association with response to valproate treatment. A total of 58 SNVs in 22 genes and 37 SNVs in 16 genes showed nominally significant associations with the Alda A continuous score and the acute-VPAR group, respectively. No SNVs reached the genome-wide significance threshold; however, three SNVs (rs115788299, rs11563197, and rs117669164) in the secreted phosphoprotein 2 gene reached a gene-based false discovery rate-corrected significance threshold with response to valproate treatment. Significant markers were associated with the pathophysiological processes of bipolar disorders, including the immune response, acute phase reaction, and coagulation cascade. These results suggest that valproate effectively suppresses mechanisms associated with disease progression.ConclusionsThe markers identified in this study could be valuable indicators of the underlying mechanisms associated with response to valproate treatment.

Immunogenetics of lithium response and psychiatric phenotypes in patients with bipolar disorder

The link between bipolar disorder (BP) and immune dysfunction remains controversial. While epidemiological studies have long suggested an association, recent research has found only limited evidence of such a relationship. To clarify this, we performed an exploratory study of the contributions of immune-relevant genetic factors to the response to lithium (Li) treatment and the clinical presentation of BP. First, we assessed the association of a large collection of immune-related genes (4925) with Li response, defined by the Retrospective Assessment of the Lithium Response Phenotype Scale (Alda scale), and clinical characteristics in patients with BP from the International Consortium on Lithium Genetics (ConLi+Gen, N = 2374). Second, we calculated here previously published polygenic scores (PGSs) for immune-related traits and evaluated their associations with Li response and clinical features. Overall, we observed relatively weak associations (p < 1 × 10−4) with BP phenotypes within immune-related genes. Network and functional enrichment analyses of the top findings from the association analyses of Li response variables showed an overrepresentation of pathways participating in cell adhesion and intercellular communication. These appeared to converge on the well-known Li-induced inhibition of GSK-3β. Association analyses of age-at-onset, number of mood episodes, and presence of psychosis, substance abuse and/or suicidal ideation suggested modest contributions of genes such as RTN4, XKR4, NRXN1, NRG1/3 and GRK5 to disease characteristics. PGS analyses returned weak associations (p < 0.05) between inflammation markers and the studied BP phenotypes. Our results suggest a modest relationship between immunity and clinical features in BP. More research is needed to assess the potential therapeutic relevance.

How effective are mood stabilizers in treating bipolar patients comorbid with cPTSD? Results from an observational study

BackgroundMultiple traumatic experiences, particularly in childhood, may predict and be a risk factor for the development of complex post-traumatic stress disorder (cPTSD). Unfortunately, individuals with bipolar disorder (BP) are more likely to have suffered traumatic events than the general population. Consequently, cPTSD could be comorbid with BD, and this may negatively affect psychopathological manifestations. To date, no one has explored whether such comorbidity also affects the response to treatment with mood stabilizers in BD patients.ResultsHere, a cross-sectional study was carried out by comparing the response to treatment, measured by the Alda scale, in a cohort of 344 patients diagnosed with BD type I and II, screened for the presence (or absence) of cPTSD using the International Trauma Questionnaire. The main result that emerged from the present study is the poorer response to mood stabilizers in BD patients with comorbid cPTSD compared with BD patients without cPTSD.ConclusionsThe results collected suggest the need for an add-on therapy focused on trauma in BD patients. This could represent an area of future interest in clinical research, capable of leading to more precise and quicker diagnoses as well as suggesting better tailored and more effective treatments.

Association of BDNF risk variant and dorsolateral cortical thickness with long-term treatment response to valproate in type I bipolar disorder: An exploratory study.

Valproate is among the most prescribed drugs for bipolar disorder; however, 87% of patients do not report full long-term treatment response (LTTR) to this medication. One of valproate's suggested mechanisms of action involves the brain-derived neurotrophic factor (BDNF), expressed in the brain areas regulating emotions, such as the prefrontal cortex. Nonetheless, data about the role of BDNF in LTTR and its implications in the structure of the dorsolateral prefrontal cortex (dlPFC) is scarce. We explore the association of BDNF variants and dorsolateral cortical thickness (CT) with LTTR to valproate in bipolar disorder type I (BDI). Twenty-eight BDI patients were genotyped for BDNF polymorphisms rs1519480, rs6265, and rs7124442, and T1-weighted 3D brain scans were acquired. LTTR to valproate was evaluated with Alda's scale. A logistic regression analysis was conducted to evaluate LTTR according to BDNF genotypes and CT. We evaluated CT differences by genotypes with analysis of covariance. LTTR was associated with BDNF rs1519480 and right dlPFC thickness. Insufficient responders with the CC genotype had thicker right dlPFC than TC and TT genotypes. Full responders reported thicker right dlPFC in TC and TT genotypes. In conclusion, different patterns of CT related to BDNF genotypes were identified, suggesting a potential biomarker of LTTR to valproate in our population.

Association of polygenic score and the involvement of cholinergic and glutamatergic pathways with lithium treatment response in patients with bipolar disorder

Lithium is regarded as the first-line treatment for bipolar disorder (BD), a severe and disabling mental health disorder that affects about 1% of the population worldwide. Nevertheless, lithium is not consistently effective, with only 30% of patients showing a favorable response to treatment. To provide personalized treatment options for bipolar patients, it is essential to identify prediction biomarkers such as polygenic scores. In this study, we developed a polygenic score for lithium treatment response (Li+PGS) in patients with BD. To gain further insights into lithium’s possible molecular mechanism of action, we performed a genome-wide gene-based analysis. Using polygenic score modeling, via methods incorporating Bayesian regression and continuous shrinkage priors, Li+PGS was developed in the International Consortium of Lithium Genetics cohort (ConLi+Gen: N = 2367) and replicated in the combined PsyCourse (N = 89) and BipoLife (N = 102) studies. The associations of Li+PGS and lithium treatment response — defined in a continuous ALDA scale and a categorical outcome (good response vs. poor response) were tested using regression models, each adjusted for the covariates: age, sex, and the first four genetic principal components. Statistical significance was determined at P < 0.05. Li+PGS was positively associated with lithium treatment response in the ConLi+Gen cohort, in both the categorical (P = 9.8 × 10−12, R2 = 1.9%) and continuous (P = 6.4 × 10−9, R2 = 2.6%) outcomes. Compared to bipolar patients in the 1st decile of the risk distribution, individuals in the 10th decile had 3.47-fold (95%CI: 2.22–5.47) higher odds of responding favorably to lithium. The results were replicated in the independent cohorts for the categorical treatment outcome (P = 3.9 × 10−4, R2 = 0.9%), but not for the continuous outcome (P = 0.13). Gene-based analyses revealed 36 candidate genes that are enriched in biological pathways controlled by glutamate and acetylcholine. Li+PGS may be useful in the development of pharmacogenomic testing strategies by enabling a classification of bipolar patients according to their response to treatment.

The mediation role of impulsivity between childhood trauma and dissociative symptomatology in bipolar disorder.

We administered the Childhood Trauma Questionnaire (CTQ), Barratt Impulsivity Scale (BIS-11), Dissociative Experience Scale (DES-II), and Alda scale. Spearman correlation analysis assessed the independent variables associated with CTQ and DES-II. We performed a mediation analysis using the bootstrapping technique to verify the hypothesis that impulsivity represented an intervening variable between childhood trauma and dissociation. CTQ and DES-II scores in 100 BD patients were both significantly associated with the number of lifetime affective episodes, a clinical course of mania-depression-euthymia, suicidal ideation, a history of antidepressant-induced manic switch, poor response to mood stabilizers, mixed features, psychotic symptoms, aggressive behavior, and BIS-11 (p<0.01). At the regression analysis, CTQ was associated with DES-II (p<0.001), while DES-II was associated with the CTQ (p<0.001) and BIS-11 (p< 0.001), as well as with aggression (p=0.002). The mediation analysis showed that impulsivity significantly mediated the effect of childhood trauma on dissociative symptomatology (z=25.71; 0.930-1.084). Impulsivity might play a key role in onset and prognosis of BD patients. Our findings may help in increasing the knowledge about the possible association between impulsivity, childhood traumatic experiences and dissociative symptomatology. BD patients with dissociative symptoms might benefit from a tailored treatment which could include a training based on emotional and behavioral regulation.

Ancestry component as a major predictor of lithium response in the treatment of bipolar disorder

BackgroundBipolar Disorder (BD) represents the seventh major cause of disability life-years-adjusted. Lithium remains as a first-line treatment, but clinical improvement occurs only in 30 % of treated patients. Studies suggest that genetics plays a major role in shaping the individual response of BD patients to lithium. MethodsWe used machine-learning techniques (Advance Recursive Partitioned Analysis, ARPA) to build a personalized prediction framework of BD lithium response using biological, clinical, and demographical data. Using the Alda scale, we classified 172 BD I-II patients as responders or non-responders to lithium treatment. ARPA methods were used to build individual prediction frameworks and to define variable importance. Two predictive models were evaluated: 1) demographic and clinical data, and 2) demographic, clinical and ancestry data. Model performance was assessed using Receiver Operating Characteristic (ROC) curves. ResultsThe predictive model including ancestry yield the best performance (sensibility = 84.6 %, specificity = 93.8 % and AUC = 89.2 %) compared to the model without ancestry (sensibility = 50 %, Specificity = 94.5 %, and AUC = 72.2 %). This ancestry component best predicted lithium individual response. Clinical variables such as disease duration, the number of depressive episodes, the total number of affective episodes, and the number of manic episodes were also important predictors. ConclusionAncestry component is a major predictor and significantly improves the definition of individual Lithium response in BD patients. We provide classification trees with potential bench application in the clinical setting. While this prediction framework might be applied in specific populations, the used methodology might be of general use in precision and translational medicine.

Effectiveness of mood stabilizers in prophylactic treatment of bipolar disorder

IntroductionProphylactic treatment during bipolar disorder aims to prevent recurrences and to improve the functional level.ObjectivesOur aim was to compare the clinical effectiveness of lithium versus sodium valproate in the prophylactic treatment of bipolar disorder type 1MethodsRetrospective, longitudinal, comparative study conducted among 162 patients followed for bipolar disorder type 1 hospitalized at the Psychiatry A department of Razi Hospital. The Alda scale and time to recurrence were used to compare the clinical effectiveness of the mood stabilizers.ResultsA difference between the two groups of patients was noted for some variables. Lithium prescription was associated with educational level, number of depressive episodes, suicide attempts, previous prescription of other thymoregulators, depressive polarity of the index episode and use of atypical antipsychotics.The prescription of Valproate was associated with educational level, unipolar mania, manic predominant polarity, manic polarity of the index episode, presence of psychotic features, prescription of long acting antipsychotics and higher doses of antipsychotics.The study of response by Alda scale showed no significant difference in the mean score of the scale nor in the rate of responders. We noted a higher rate of recurrence in patients on Valproate considering the whole duration of the study. The recurrence rate after one year was higher in patients on Lithium, the recurrence rate after two years was comparable in both groups. Survival curves showed earlier recurrences in patients on Lithium.ConclusionsThe efficacy of the two mood stabilizers was comparable. The recurrences occured earlier under Lithium.Disclosure of InterestNone Declared

Childhood maltreatment and clinical response to mood stabilizers in patients with bipolar disorder

IntroductionChildhood maltreatment (CM) is recognized to be a non-specific risk factor for the development of psychiatric disorders in adulthood. It has been consistently demonstrated that exposure to CM increases the risk of developing bipolar disorder (BD). In addition, CM has been associated with worse clinical presentation and course of BD. CM has been also linked to poorer responses to psychotropic drug treatments in different psychiatric disorders.ObjectivesThe aim of the current study was to explore retrospectively the impact of CM on the response to prophylactic treatment with lithium or anticonvulsants in a cohort of adult BD patients. Based on the reported literature, we hypothesized that BD patients with a history of CM would present a poorer response to both lithium and anticonvulsant treatments.MethodsParticipants were recruited from patients consecutively attending the outpatient facilities of the Psychiatric Unit of the University of Salerno. The following inclusion criteria were adopted: (1) diagnosis of BD type 1 or type 2 according to DSM‐5 criteria; (2) age ≥ 18 years; (3) willingness to participate in the study, expressed by written informed consent; (4) stable adequate treatments with mood stabilizers (at least 1‐year duration and, in the case of lithium, at therapeutic blood levels); (5) being clinically euthymic at the time of inclusion. Retrospective treatment response was evaluated by using the Alda scale. CM history was assessed by means of the short form of the Childhood Trauma Questionnaire (CTQ).ResultsThirty‐seven patients (24 with a history of CM and 13 without CM) were on stable lithium treatment while sixty (35 with a history of CM and 25 without CM) were on stable anticonvulsant treatment. Clinical response to drug treatment did not differ between BD with CM and those without CM in the whole sample as well as in the anticonvulsant‐treated subgroup. In the lithium‐treated subgroup, a significant negative correlation emerged between physical abuse and treatment response (ρ = −0.38; p = 0.03) and patients with CM showed a significantly reduced Alda score (p = 0.04).ConclusionsIn patients with BD, CM did not influence the clinical response of anticonvulsants, whereas it was associated with a poorer response to lithium with childhood physical abuse playing a major role in this effect.Disclosure of InterestNone Declared

Chronotype is associated with affective temperaments, clinical severity and worse treatment outcomes in bipolar disorders: results from a two-center, cross-sectional study

Objective The present study was aimed at investigating the clinical correlates of evening chronotype in a population of subjects suffering from bipolar disorders (BD). Methods We assessed chronotype using the Morningness-Eveningness Questionnaire. We administered the brief Temperament Evaluation of Memphis, Pisa, and San Diego, the Barratt Impulsiveness Scale, and the Alda Scale to evaluate affective temperaments, impulsiveness, and response to mood stabilisers. We performed bivariate analyses and ran a logistic regression model to analyse clinical variables associated with evening chronotype. Results In our sample (n = 178), subjects with an evening chronotype (n = 56, 31.5%) more often suffered from BD type I and reported higher prevalence of seasonality, antidepressant-induced mood switches, psychotic, aggressive, mixed, and anxiety features, and substance use disorders. The number of lifetime suicide attempts and mood episodes was higher in this subgroup. Depressive, cyclothymic, irritable, and anxious temperament scores were higher among evening-chronotype subjects, who also displayed greater levels of impulsiveness and worse treatment response. At the logistic regression, evening chronotype was associated with depressive and irritable temperaments. Conclusions Subjects with evening chronotype display higher clinical severity and worse BD course. Clinicians should evaluate the presence of evening chronotype in BD subjects, especially in those with irritable or depressive temperament. Key points Evening chronotype is a frequent clinical feature in subjects suffering from bipolar disorders (BD); Affective temperaments, particularly depressive and irritable, are associated with evening chronotype in BD; Evening chronotype underpins higher severity of the clinical picture in BD, as well as a worse response to mood stabiliser treatment; Circadian preferences should be systematically assessed in subjects suffering from BD, with particular attention to evening preference.

Sex Differences in Bipolar Disorders: Impact on Psychopathological Features and Treatment Response.

IntroductionSex differences were demonstrated in bipolar disorders (BD) concerning epidemiological, clinical, and psychopathological characteristics, but consensus is lacking. Moreover, data concerning the influence of sex on treatment response in BD is contrasting. The present cross-sectional study aimed to analyze sex differences in a population of BD subjects, with specific focus on psychopathological features and treatment response.Materials and MethodsSubjects diagnosed with BD according to the Diagnostic and Statistical Manual of Mental Disorders, 5th version (DSM-5) were recruited. Socio-demographic and clinical characteristics were collected. The Hamilton Rating Scale for Depression, the Mania Rating Scale (MRS), the brief version of the Temperament Evaluation of Memphis, Pisa and San Diego—Münster version (briefTEMPS-M), and the Barratt Impulsiveness Scale−11 items (BIS-11) were used for psychopathological assessment. Treatment response was appraised with the Alda Scale. We performed bivariate analyses to compare socio-demographic, clinical, and psychopathological characteristics between men and women (p < 0.05). A logistic regression was run to analyze features that were significantly associated with female sex.ResultsAmong the recruited 219 BD subjects, 119 (54.3%) were females. Women had a lower scholarity (p = 0.015) and were less frequently employed (p = 0.001). As for psychopathological features, a higher MRS total score (p < 0.001) was detected among women, as well as higher BIS-11 total score (p = 0.040), and briefTEMPS-M score for anxious temperament (p = 0.006). Men showed higher prevalence of DSM-5 mixed features (p = 0.025), particularly during a depressive episode (p = 0.014). Women reported longer duration of untreated illness (DUI) (p < 0.001). There were no sex differences in the Alda Scale total score when considering the whole sample, but this was significantly higher among men (p = 0.030) when evaluating subjects treated with anticonvulsants. At the logistic regression, female sex was positively associated with longer DUI (p < 0.001; OR 1.106, 95% CI 1.050–1.165) and higher MRS total score (p < 0.001; OR 1.085, 95% CI 1.044–1.128) and negatively associated with employment (p = 0.003; OR 0.359, 95% CI 0.185–0.698) and DSM-5 mixed features (p = 0.006; OR 0.391, 95% CI 0.200–0.762).ConclusionsThe clinical presentation of BD may differ depending on sex. The severity of BD should not be neglected among women, who may also display worse treatment response to anticonvulsants.

Is Poor Lithium Response in Individuals with Bipolar Disorder Associated with Increased Degradation of Tryptophan along the Kynurenine Pathway? Results of an Exploratory Study.

Bipolar disorder is associated with an inflammation-triggered elevated catabolism of tryptophan to the kynurenine pathway, which impacts psychiatric symptoms and outcomes. The data indicate that lithium exerts anti-inflammatory effects by inhibiting indoleamine-2,3-dioxygenase (IDO)-1 activity. This exploratory study aimed to investigate the tryptophan catabolism in individuals with bipolar disorder (n = 48) compared to healthy controls (n = 48), and the associations with the response to mood stabilizers such as lithium, valproate, or lamotrigine rated with the Retrospective Assessment of the Lithium Response Phenotype Scale (or the Alda scale). The results demonstrate an association of a poorer response to lithium with higher levels of kynurenine, kynurenine/tryptophan ratio as a proxy for IDO-1 activity, as well as quinolinic acid, which, overall, indicates a pro-inflammatory state with a higher degradation of tryptophan towards the neurotoxic branch. The treatment response to valproate and lamotrigine was not associated with the levels of the tryptophan metabolites. These findings support the anti-inflammatory properties of lithium. Furthermore, since quinolinic acid has neurotoxic features via the glutamatergic pathway, they also strengthen the assumption that the clinical drug response might be associated with biochemical processes. The relationship between the lithium response and the measurements of the tryptophan to the kynurenine pathway is of clinical relevance and may potentially bring advantages towards a personalized medicine approach to bipolar disorder that allows for the selection of the most effective mood-stabilizing drug.

Genetic polymorphisms influencing response to lithium in early-onset Bipolar disorder from south India.

Early-onset Bipolar disorder (EOBD), has a more malignant course with high recurrence risk and there is a need for population-specific pharmaco-genomic study. This study is a prospective and retrospective observational study. Both newly diagnosed patients and those on follow-up with a diagnosis of bipolar I disorder with onset before 18 years of age and on lithium prophylaxis as part of treatment-as-usual were recruited for the study. Response to treatment was assessed at the end of two years follow up using ALDA scale. Ten single nucleotide polymorphisms associated with treatment response based on previous studies were chosen for analysis. Of 162 who had EOBD, sixty-four fulfilled inclusion criteria and fifty-seven completed the study. TT and TG genotypes of rs75222709 on AL157359.3 gene were found to be significantly different between non-responders(N = 43) and healthy controls (N=220). The frequency of the GA genotype of the single nucleotide polymorphism rs17204573 of the RORA (Retinoic Acid related orphan receptor alpha) gene was significantly lower among subjects (27.3%, N = 54) as compared to controls (42.9%, OR:0.5, CI: 0.26-0.96, p value 0.035). However, the significance of both disappeared after Bonferroni correction. Among clinical factors female gender was significantly associated with lithium non-response. Although conducting pharmaco-genomic studies with large sample size is a challenge for low and middle-income countries, future studies can help improve the long-term outcome of youth with EOBD.

Substance use disorders in bipolar disorders: Clinical correlates and treatment response to mood stabilizers

BackgroundSubstance use disorders (SUD) in bipolar disorders (BD) present relevant impact on psychopathological features and illness course. The present study was aimed at analyzing the clinical correlates of this comorbidity. MethodsIn- and outpatients suffering from BD were recruited. Socio-demographic and clinical characteristics were collected. Subjects underwent a psychopathological assessment evaluating affective temperaments and impulsiveness. The appraisal of treatment response to mood stabilizers was conducted with the Alda Scale. Bivariate analyses were used to compare subjects suffering from BD with (SUD-BD) or without comorbid SUD (nSUD-BD) (p<0.05). A logistic regression model was performed to identify specific correlates of SUD in BD. ResultsAmong the 161 included subjects, 63 (39.1%) were diagnosed with comorbid SUD. SUD-BD subjects showed younger age at onset (p = 0.003) and higher prevalence of BD type I diagnosis (BDI) (p<0.001). Furthermore, lifetime mixed features (p<0.001), psychotic symptoms (p<0.001), suicide attempts (p = 0.002), aggression (p = 0.003), antidepressant-induced manic switch (p = 0.003), and poor treatment response (p<0.001) were more frequent in the SUD-BD subgroup. At the logistic regression, SUD revealed a positive association with BD type I diagnosis (Odds Ratio (OR) 4.77, 95% CI 1.66–13.71, p = 0.004) and mixed features (OR 2.54, 95% CI 1.17–5.53, p = 0.019). LimitationsThe cross-sectional study design and the relatively small sample size may limit the generalizability of the findings. The retrospective evaluation of comorbid SUD could have biased the outcome assessment. ConclusionsSubjects with BD and SUD are characterized by higher clinical severity and require careful assessment of treatment response.

Dissociative Symptoms in Bipolar Disorder: Impact on Clinical Course and Treatment Response.

Background: Dissociative symptoms are under recognized and scarcely studied by clinicians and researchers in patients with bipolar disorder (BD). We examined the relationship between dissociative symptoms and the psychotic features in patients with BD and assessed clinical and socio-demographic characteristics more frequently associated with dissociative symptoms and treatment response.Methods: Participants were 100 adult outpatients with BD. They were screened with semi-structured interview to collect socio-demographic and clinical characteristics; the Dissociative Experiences Scale-II (DES-II) and the ALDA scale were used to assess dissociative psychopathologies and response to treatment with mood stabilizers, respectively.Results: DES score (mean 31.7 ± 21.7) correlated with clinical variables, BD features, and course of illness. Psychotic symptoms, mixed features, and previous suicide attempts significantly predicted DES score [F(3, 47) = 39.880, p < 0.001, R2 corrected = 0.713]. Dissociative symptoms were inversely correlated with poor response to treatment (r = −0.593; p < 0.001).Limitations: Cross-sectional design with a small sample and backward clinical assessment of psychotic symptoms.Conclusions: Dissociative phenomena are closely related to the presence of psychotic symptoms, mixed features, and previous suicide attempts in BD, especially in BD-I. Given the close association between dissociative and psychotic symptoms, this association could represent a diagnostic indicator of BD-I that may guide the clinician to plan the most appropriate treatment.

A Comparison of Different Approaches to Clinical Phenotyping of Lithium Response: A Proof of Principle Study Employing Genetic Variants of Three Candidate Circadian Genes.

Optimal classification of the response to lithium (Li) is crucial in genetic and biomarker research. This proof of concept study aims at exploring whether different approaches to phenotyping the response to Li may influence the likelihood of detecting associations between the response and genetic markers. We operationalized Li response phenotypes using the Retrospective Assessment of Response to Lithium Scale (i.e., the Alda scale) in a sample of 164 cases with bipolar disorder (BD). Three phenotypes were defined using the established approaches, whilst two phenotypes were generated by machine learning algorithms. We examined whether these five different Li response phenotypes showed different levels of statistically significant associations with polymorphisms of three candidate circadian genes (RORA, TIMELESS and PPARGC1A), which were selected for this study because they were plausibly linked with the response to Li. The three original and two revised Alda ratings showed low levels of discordance (misclassification rates: 8–12%). However, the significance of associations with circadian genes differed when examining previously recommended categorical and continuous phenotypes versus machine-learning derived phenotypes. Findings using machine learning approaches identified more putative signals of the Li response. Established approaches to Li response phenotyping are easy to use but may lead to a significant loss of data (excluding partial responders) due to recent attempts to improve the reliability of the original rating system. While machine learning approaches require additional modeling to generate Li response phenotypes, they may offer a more nuanced approach, which, in turn, would enhance the probability of identifying significant signals in genetic studies.

Prefrontal cortical thickness and clinical characteristics of long-term treatment response to valproate in bipolar disorder

Valproate compositions are frequently used to treat bipolar disorder (BD); however, 87% of patients do not report full response in the long-term. There is scarce information about the clinical features and brain structural characteristics of long-term treatment response (LTTR) to this medication. In this study, we aim to evaluate the clinical characteristics and prefrontal cortical thickness (CT) of LTTR to valproate in BD. We evaluated 30 BD outpatients on valproate treatment, and 20 controls with a 3T T1-weighted 3D brain scan and Alda's scale for LTTR. An analysis of covariance was used to evaluate CT measures and a logistic regression was conducted to predict the full response (FR) using clinical features and CT measures. Patients with an insufficient response (IR) reported thinner right frontal eye fields, anterior and dorsolateral prefrontal cortexes compared with controls. FR patients presented thicker right dorsolateral prefrontal cortex than IR and no differences with controls. Patients with mixed features presented increased odds of achieving FR, while CT measures reported non-significant results. This is the first study to report mixed features as a clinical predictor of valproate LTTR. Our findings also suggest better preservation of the right prefrontal cortex of subjects with FR to valproate.

Association study of BDNF Val66Met gene polymorphism with bipolar disorder and lithium treatment response in Indian population.

The association of the Val66Met (rs6265) polymorphism in the brain-derived neurotrophic factor (BDNF) gene with bipolar disorder (BD) and response to lithium treatment has been suggested, though inconsistently. The considerable diversity of allele frequency across different populations contributes to this. There is no data from South Asia till date. Hence, we examined the association of this polymorphism in BD cases from India, and its association with lithium treatment response. BD patients (N = 301) were recruited from the clinical services of National Institute of Mental Health and Neurosciences (NIMHANS), India. Lithium treatment response for 190 BD subjects was assessed using Alda scale by NIMH life charts. Patients with total score ⩾7 were defined as lithium responders (N = 115) and patients with score <7 were defined as lithium non-responders (N = 75). Healthy controls (N = 484) with no lifetime history of neuropsychiatric illness or a family history of mental illness were recruited as control set. Genotyping was performed by TaqMan genotyping assay. Genotype and allele frequency of BDNF Val66Met SNP was significantly different (χ2 = 7.78, p = 0.02) in cases compared to controls, and the Val(G) allele was more frequent (χ2 = 7.08, p = 0.008) in BD patients. However, no significant difference is noted in genotype or allele frequencies of this polymorphism between the lithium responders and non-responders. The Val(G) allele of BDNF Val66Met polymorphism is associated with risk of BD in this sample, but it is not related to response to lithium.

Duration of untreated illness and bipolar disorder: time for a new definition? Results from a cross-sectional study

BackgroundWe primarily aimed to explore the associations between duration of untreated illness (DUI), treatment response, and functioning in a cohort of patients with bipolar disorder (BD). Methods261 participants with BD were recruited. DUI was defined as months from the first affective episode to the start of a mood-stabilizer. The functioning assessment short test (FAST) scores and treatment response scores for lithium, valproate, or lamotrigine according to the Alda Scale Total Score (TS) were compared between patients with short (<24 months) or long DUI. Differences in FAST scores among good (GR; TS≥7), poor (PR; TS=2-6), or non-responders (NR; TS<2) to each mood-stabilizer were analyzed. Linear regression was computed using the FAST global score as the dependent variable. ResultsDUI and FAST scores showed no statistically significant correlation. Patients with a longer DUI showed poorer response to lithium (Z=-3.196; p<0.001), but not to valproate or lamotrigine. Response to lithium (β=-1.814; p<0.001), number of hospitalizations (β=0.237; p<0.001), and illness duration (β=0.160; p=0.028) were associated with FAST total scores. GR to lithium was associated with better global functioning compared to PR or NR [H=27.631; p<0.001]. LimitationsThe retrospective design could expose our data to a recall bias. Also, only few patients were on valproate or lamotrigine treatment. ConclusionsPoor functioning in BD could be the result of multiple affective relapses, rather than a direct effect of DUI. A timely diagnosis with subsequent effective prophylactic treatment, such as lithium, may prevent poor functional outcomes in real-world patients with BD.