The symptomatology of Attention-Deficit/Hyperactivity Disorder and the genetic control of vitamin D levels.

OBJECTIVES: Vitamin D deficiency has been associated with psychiatric disorders and behavioral phenotypes such as Attention-Deficit/Hyperactivity Disorder (ADHD). Considering that vitamin D levels are polygenic, we aim to evaluate the overall effects of its genetic architecture on symptoms of inattention, hyperactivity, and impulsivity and on the serum levels of vitamin D in two independent samples of adults, as well as the specific effects of five relevant polymorphisms in vitamin D-related genes. METHODS: We evaluated 870 subjects from an ADHD sample (407 cases and 463 controls) and 319 subjects from an academic community (nutrigenetic sample). Vitamin D serum levels were obtained through Elisa test and genetic data by TaqMan™ allelic discrimination and Infinium PsychArray-24 BeadChip genotyping. Polygenic Scores (PGS) were calculated on PRSice2 based on the latest GWAS for Vitamin D and statistical analyses were conducted at Plink and SPSS software. RESULTS: Vitamin D PGSs were associated with inattention in the ADHD sample and with hyperactivity when inattention symptoms were included as covariates. In the nutrigenetic sample, CYP2R1 rs10741657 and DHCR7 rs12785878 were nominally associated with impulsivity and hyperactivity, respectively, and both with vitamin D levels. In the clinical sample, RXRG rs2134095 was associated with impulsivity. DISCUSSION: Our findings suggest a shared genetic architecture between vitamin D levels and ADHD symptoms, as evidenced by the associations observed with PGS and specific genes related to vitamin D levels. Interestingly, differential effects for vitamin D PGS were found in inattention and hyperactivity, which should be considered in further studies involving ADHD.

Early-life trauma, impulsivity and suicide attempt: a systematic review and meta-analysis.

INTRODUCTION: Suicide is a worldwide health concern and up to date there is no good predictor of it except a previous suicide attempt. Therefore, there are increasing efforts in the understanding of which factors, genetic or environmental, are associated with suicide behaviour. OBJECTIVE: To review evidence of the effect of childhood trauma and impulsivity on suicidal behavior through a systematic review and meta-analysis. METHODS: Searches were conducted on the 12th of June 2021 in the PubMed, Scopus, and Web of Science databases. Two reviewers evaluated each record for eligibility and discussed upon disagreement, when no consensus was reached, a third reviewer was involved to make a decision. RESULTS: A total of 11,530 records were identified through the searches. After duplicates were removed, 6,595 records remained to be screened. The full text was sought for 1,561 records. Our qualitative synthesis included 22 studies, from which 9 were included in the meta-analyses. We found a significant effect of sexual abuse, physical abuse, emotional abuse and physical neglect on suicide attempts in the prisoners, and Substance Use Diorder (SUD) subgroups. Moreover, there was a significant effect of Childhood Trauma Questionnaire (CTQ) total score and emotional neglect dimension for all the subgroups. CONCLUSION: The present study has provided an overview of the state-of-the-art research on childhood trauma and impulsivity and their association with suicidal behavior and quantified their effects on suicide attempts. Hopefully this evidence will be considered in future research and harnessed for clinical gain in detection and treatment of suicide behaviour.

Diagnosis of bipolar and major depressive disorders: The appropriateness of MINI compared to the clinical interview in a sample of patients with mood disorders in tertiary mental health care.

OBJECTIVE: The Mini International Neuropsychiatric Interview (MINI) is one of the most used instruments for the assessment of Mental Disorders, playing an essential role in psychiatric research and in clinical and hospital practice. Despite this, the accuracy of the MINI, when used by a psychiatrist, is poorly studied, particularly in relation to Bipolar Disorder (BD). The early diagnosis of BD and Major Depressive Disorder (MDD) is extremely important, as it provides an opportunity for intervention that can reduce the impact on the patient's daily life and functionality. As such, this study assesses the suitability of MINI for diagnosing BD or MDD in a sample of patients with mood disorders. METHOD: Agreement between the MINI and the clinical interview was assessed in a sample of 347 outpatients by calculating Cohen's kappa, sensitivity, specificity, positive predictive value, negative predictive value, and the area under the curve (AUC). RESULTS: The sample consisted of 347 patients with mood disorders. 279 were women (80.40%), 105 (30.3%) were diagnosed with MDD and 242 (69.7%) with BD from the assessment performed in the clinical interview. In the MINI assessment, 97 individuals (28%) were classified with a diagnosis of MDD and 250 (72%) with BD. We found a sensitivity of 87.2% and specificity of 62.8% for the MINI in the diagnosis of BD and a Cohen's kappa between the MINI and the clinical interview of 0.51. The AUC was 0.75. CONCLUSIONS: MINI has greater sensitivity (87.2%) for the diagnosis of BD and greater specificity (87.2%) for the diagnosis of MDD. In addition, the moderate Cohen kappa (0.51) and AUC (0.75) values between the MINI and the clinical interview are acceptable when considering most available psychiatric diagnostic tools.

A longitudinal study of cognition, functional outcome and quality of life in bipolar disorder and major depression.

OBJECTIVE: Cognitive impairments are known to be a frequent cause of disability in bipolar disorder (BD) and major depression (MDD). Yet there is no consensus regarding the particular cognitive functions whose impairments can lead to disability in each domain of functioning. The aim of this study was to perform a longitudinal evaluation of working memory, inhibition, cognitive flexibility and attention in BD and MDD, investigate the relationship of these cognitive functions to disability and quality of life, and evaluate the impact of variables related to cognitive reserve (education and daily cognitive stimulation) on cognitive performance. METHOD: 31 participants (MDD = 12; BD = 19) were evaluated at baseline and after an average time of 2 years. RESULTS: the BD group showed improvements in attention while patients with MDD improved on measures of attention and working memory. In BD working memory performance was associated with the cognition and mobility domains of functioning, and with physical and environmental quality of life. In MDD, cognitive flexibility was related to social relationships and environmental quality of life. CONCLUSION: working memory and cognitive flexibility may be an interesting target for interventions aiming to improve everyday functioning and quality of life in BD and MDD.

Cognitive reserve may outperform age, mood and psychiatric comorbidities as a predictor of executive functioning in bipolar disorder and healthy adults.

INTRODUCTION: Cognitive reserve plays a protective role against executive dysfunction in healthy adults and individuals with psychiatric illnesses such as bipolar disorder. However, the magnitude of the influence of cognitive reserve on specific executive functions (EFs), and its impact relative to variables such as depressive symptoms, age and psychiatric comorbidities, is unexplored. This study aimed to quantify the influence of cognitive reserve on specific EFs, and compare its impact with that of depressive symptoms, age and psychiatric comorbidities, in separate models for patients with bipolar disorder and healthy adults. METHOD: This was a cross-sectional study of 121 adults with no mood disorders and 109 with bipolar disorder, all of whom underwent a comprehensive psychiatric assessment and evaluation of the EFs. Cognitive reserve was measured using years of education, IQ and reading and writing habits. The association between EFs and predictors (cognitive reserve, depressive symptoms, age and psychiatric comorbidities) was evaluated through structural equation modeling. Four models were constructed for each group independently (bipolar disorder and control), one each for working memory, verbal fluency, inhibition and flexibility, due to group differences in age and cognitive reserve. RESULTS: Working memory, inhibition and flexibility were most significantly predicted by cognitive reserve and age. Verbal fluency was only predicted by cognitive reserve. Comorbidities and depressive symptoms were not significant in any of the models. Cognitive reserve had a positive influence on all EFs in models for patients with bipolar disorder and models for control participants. Age had a negative impact on three of the four EFs tested. CONCLUSION: Fostering cognitive reserve through continued education and cognitively stimulating leisure activities may be an effective intervention for executive dysfunction in patients and non-patients alike. In some cases, the effects of these interventions may outweigh the negative cognitive impact of aging, depressive symptoms and psychiatric conditions.

Cognitive abilities underlying performance on the modified card sorting test: novel and traditional scores.

The Modified Card Sorting Test (MCST) is a widely used variation of the Wisconsin Card Sorting Test. It is faster to administer, less frustrating for respondents and less ambiguous in its scoring but has been criticized for its task impurity and low discriminability between control participants and clinical groups prone to executive dysfunction. This study aimed to examine the executive functions (EF) underlying traditional (number of categories completed, perseverative errors) and novel scores for the MCST, and compare their ability to differentiate between control and clinical samples. Novel and traditional MCST scores were compared between 94 control participants, 87 with bipolar disorder and 64 with major depression. The relationship between MCST scores and traditional EF tasks was examined through correlation and regression analyses. All MCST scores were associated with at least one measure of EF, the most common of which were the Trail Making or Hayling Tests. IQ predicted most scores on the MCST, save for nonperseverative errors and categorizing efficiency. Traditional and novel scores differentiated between clinical and control groups. These findings support the utility of the MCST in detecting executive dysfunction and highlight the importance of new scoring methods in increasing the specificity and interpretability of this task.

"Influence of modifiable and non-modifiable variables on functioning in bipolar disorder: a path analytical study".

OBJECTIVE: The aim of this study was to investigate the influence of modifiable (mood, cognitive reserve, cognitive performance) and non-modifiable factors (diagnosis, suicide attempts, substance use, age) on self-reported functioning in BD. METHODS: 103 adults with no mood disorders and 95 individuals with BD completed the WHODAS 2.0, in addition to a neuropsychological battery and diagnostic assessments. Path analysis was then used to analyse the relationships between modifiable and non-modifiable predictors of functioning in the sample. RESULTS: Cognitive reserve and age had an indirect influence on individual functioning, mediated by cognitive performance. The influence of diagnosis and depressive symptoms on functioning was partly direct, and partly mediated by cognition. The presence of psychiatric comorbidities in addition to BD also had a significant influence on individual functioning. CONCLUSIONS: Initiatives focussed on modifiable factors such as depressive symptoms and cognitively stimulating activities, which increase cognitive reserve, may be a useful complement to existing treatments and help patients achieve functional recovery. KEY POINTS Individual functioning was influenced by cognitive performance, cognitive reserve, age, diagnosis and depressive symptoms. Executive functioning mediated the influence of age and cognitive reserve on individual functioning. Interventions focussed on depressive symptoms and cognitive stimulation may help patients achieve functional recovery.

The effects of cognitive reserve and depressive symptoms on cognitive performance in major depression and bipolar disorder.

BACKGROUND: Significant heterogeneity is observed in the cognitive profiles of bipolar disorder (BD) and major depression (MDD), characterized in part by differences in individual and clinical variables such as cognitive reserve (CR) and depression severity. However, no other study evaluated how this variables may interact regarding neurocognitive functioning. The aim of the present exploratory study was to evaluate the interaction between different depressive symptoms severity, CR and diagnosis with neurocognitive functioning. METHOD: 202 participants (MDD=91; BD=111) classified either as euthymic, with mild depression or moderate to severe depression, and low or high CR completed a neuropsychological evaluation of verbal fluency, working memory (WM), inhibitory control (IC), cognitive flexibility (CF) and attention (Att). RESULTS: Neuroprotective effects of CR were observed in patients with BD within a major depressive episode in WM, IC, FC and Att. In MDD, CR acted as a neuroprotective factor during euthymia and moderate to severe depression in the same cognitive functions. CR and depression severity differentiated the cognitive profiles of individuals with BD and MDD. LIMITATIONS: Some variables related to neurocognitive performance like medication use, number of mood episodes, illness duration or previous hospitalizations were not controlled. CONCLUSION: CR may be protective against cognitive impairment in both BD and MDD, and these effects were observed in euthymia and during depressive episodes of varying severity. These findings highlight the importance of investigating such variables in the neuropsychological evaluation of mood disorders, which may help to understand the cognitive heterogeneity within these populations.

Diet and Neurocognition in Mood Disorders - An Overview of the Overlooked.

Bipolar disorder and major depression are associated with significant disability, morbidity, and reduced life expectancy. People with mood disorders have shown higher ratios of unhealthy lifestyle choices, including poor diet quality and suboptimal nutrition. Diet and nutrition impact on brain /mental health, but cognitive outcomes have been less researched in psychiatric disorders. Neurocognitive dysfunction is a major driver of social dysfunction and a therapeutic target in mood disorders, although effective cognitive-enhancers are currently lacking. This narrative review aimed to assess the potential cognitive benefits of dietary and nutritional interventions in subjects diagnosed with mood disorders. Eight clinical trials with nutrients were identified, whereas none involved dietary interventions. Efficacy to improve select cognitive deficits has been reported, but results are either preliminary or inconsistent. Methodological recommendations for future cognition trials in the field are advanced. Current evidence and future views are discussed from the perspectives of precision medicine, clinical staging, nutritional psychiatry, and the brain-gut-microbiota axis.

Predictors of quality of life in bipolar disorder: A path analytical study.

Quality of life (QoL) is an important outcome in psychiatric illnesses like bipolar disorder (BD). However, little is known about the variables that affect it, and therefore contribute to prognosis and treatment outcomes in these populations. This study aimed to explore QoL in BD and investigate its relationship with modifiable (cognitive reserve, cognitive ability, mood symptoms) and non-modifiable factors (diagnosis, previous suicide attempts, substance misuse, age). The WHOQOL-bref was administered to 121 control participants and 109 patients with BD, who also underwent clinical and neuropsychological assessments. Factor analysis was used to identify latent constructs underlying WHOQOL-bref domains, and structural equation models were used to examine predictors of each latent construct. Two latent constructs were identified in the WHOQOL-bref, and labeled 'Personal' and 'Social' QoL. Both were directly predicted by depression symptoms and a diagnosis of BD, and indirectly predicted by (hypo)manic symptoms. Cognitive reserve was a stronger predictor of social QoL than a diagnosis of BD. Our findings suggest that the management of depression symptoms and fostering of cognitive reserve may improve QoL in BD. A diagnosis of BD and/or substance use disorders were risk factors for poor QoL, and may signal the need for preventive interventions to promote well-being.

Assessment of the psychometric properties of the 17- and 6-item Hamilton Depression Rating Scales in major depressive disorder, bipolar depression and bipolar depression with mixed features.

Assessing therapeutic response in depression requires scales that adequately measure the core symptoms of depressive symptomatology. The main goal of this study was to assess the psychometric properties of the 17-item Hamilton Depression Rating Scale (HAM-D17) and the 6-item Hamilton Depression Rating Scale (HAM-D6) in patients with Major Depressive Disorder (MDD), bipolar depression and bipolar depression with mixed features. We conducted a reanalysis of a pragmatic clinical trial in an outpatient clinic for mood disorders that included eight weeks of follow-up. A Mokken analysis was performed to evaluate the unidimensionality of the HAM-D17 and HAM-D6, and the Spearman correlation was used to assess concurrent validity between the HAM-D17, the HAM-D6 and quality of life scale (SF-36 and WHOQOL-BREF) scores. A total of 237 patients with a mean age of 40.2 years (±11.7) were included. According to the DSM-IV criteria, 58 (24.5%) were diagnosed with MDD and 73 (30.8%) were diagnosed with bipolar depression. Bipolar depression with mixed features was diagnosed in 106 (44.7%) patients according to the DSM-IV and supplemented by the Cincinnati criteria. Only the HAM-D6 scale proved to be unidimensional, showing strong homogeneity for evaluating MDD, moderate homogeneity for bipolar depression and weak homogeneity for bipolar depression with mixed features. Both the HAM-D17 and the HAM-D6 had inverse, significant correlations at baseline with SF-36 and WHOQOL-BREF scores. This is the first study to include bipolar depression patients with mixed features in an assessment of HAM-D6 unidimensionality.

Self-reported inhibition predicts history of suicide attempts in bipolar disorder and major depression.

BACKGROUND: Studies have reliably identified an association between suicide attempts and executive functions such as decision making (DM) and inhibitory control (IC) in patients with mood disorders. As such, the present study aimed to investigate the association between inhibition, DM, impulsivity and the history of suicide attempts in individuals with bipolar (BD) or major depressive disorder (MDD), identifying which assessment instruments may be most strongly associated with suicide in clinical samples. METHODS: The sample included 80 control subjects and two groups of patients with BD and MDD, matched by age and education (26 with a history of suicide attempts [MD+], and 26 with no such history [MD-]). Participants completed behavioral and self-report measures of DM and IC, which were compared between groups using ANCOVA, followed by logistic regression for patients with mood disorders only, and the presence or absence of a history of suicide as the outcome. RESULTS: Cognitive performance did not differ between groups. The MD+ group showed significantly higher motor and attentional impulsivity on the BIS-11 than the MD- and control groups. A regression analysis containing these scores showed that motor impulsivity was the only significant predictor of a history of suicide (OR = 1.14; 95%CI 1.00-1.30). CONCLUSIONS: Self-reported motor impulsivity was a significant predictor of suicide. These findings underscore the importance of self-report measures in neuropsychological assessment, and their contributions to the management and prognosis of patients with mood disorders. Lastly, they point to the role of impulsivity as a target for interventions and public policy on suicide prevention.

Effectiveness evaluation of mood disorder treatment algorithms in Brazilian public healthcare patients

Objective: To assess the effectiveness of three mood disorder treatment algorithms in a sample of patients seeking care in the Brazilian public healthcare system. Methods: A randomized pragmatic trial was conducted with an algorithm developed for treating episodes of major depressive disorder (MDD), bipolar depressive episodes and mixed episodes of bipolar disorder (BD). Results: The sample consisted of 259 subjects diagnosed with BD or MDD (DSM-IV-TR). After the onset of symptoms, the first treatment occurred ∼6 years and the use of mood stabilizers began ∼12 years. All proposed algorithms were effective, with response rates around 80%. The majority of the subjects took 20 weeks to obtain a therapeutic response. Conclusions: The algorithms were effective with the medications available through the Brazilian Unified Health System. Because therapeutic response was achieved in most subjects by 20 weeks, a follow-up period longer than 12 weeks may be required to confirm adequate response to treatment. Remission of symptoms is still the main desired outcome. Subjects who achieved remission recovered more rapidly and remained more stable over time. Clinical trial registration: NCT02901249, NCT02870283, NCT02918097

Effectiveness evaluation of mood disorder treatment algorithms in Brazilian public healthcare patients.

OBJECTIVE: To assess the effectiveness of three mood disorder treatment algorithms in a sample of patients seeking care in the Brazilian public healthcare system. METHODS: A randomized pragmatic trial was conducted with an algorithm developed for treating episodes of major depressive disorder (MDD), bipolar depressive episodes and mixed episodes of bipolar disorder (BD). RESULTS: The sample consisted of 259 subjects diagnosed with BD or MDD (DSM-IV-TR). After the onset of symptoms, the first treatment occurred ∼6 years and the use of mood stabilizers began ∼12 years. All proposed algorithms were effective, with response rates around 80%. The majority of the subjects took 20 weeks to obtain a therapeutic response. CONCLUSIONS: The algorithms were effective with the medications available through the Brazilian Unified Health System. Because therapeutic response was achieved in most subjects by 20 weeks, a follow-up period longer than 12 weeks may be required to confirm adequate response to treatment. Remission of symptoms is still the main desired outcome. Subjects who achieved remission recovered more rapidly and remained more stable over time. CLINICAL TRIAL REGISTRATION: NCT02901249, NCT02870283, NCT02918097.

Neuropsychological Clustering in Bipolar and Major Depressive Disorder.

OBJECTIVES: Cognitive dysfunction is a key feature of major depressive (MDD) and bipolar (BD) disorders. However, rather than a single cognitive profile corresponding to each diagnostic categories, recent studies have identified significant intra- and cross-diagnostic variability in patterns of cognitive impairment. The goal of this study was to contribute to the literature on cognitive heterogeneity in mood disorders by identifying cognitive subprofiles in a population of patients with MDD, BD type I, BD type II, and healthy adults. METHODS: Participants completed a neuropsychological battery; scores were converted into Z-scores using normative data and submitted to hierarchical cluster analysis. RESULTS: Three distinct neuropsychological clusters were identified: (1) a large cluster containing mostly control participants, as well as some patients with BD and MDD, who performed at above-average levels on all neuropsychological domains; (2) a cluster containing some patients from all diagnostic groups, as well as healthy controls, who performed worse than cluster 1 on most tasks, and showed impairments in motor inhibition and verbal fluency; (3) a cluster containing mostly patients with mood disorders with severe impairments in verbal inhibition and cognitive flexibility. CONCLUSIONS: These findings revealed multiple cognitive profiles within diagnostic categories, as well as significant cross-diagnostic overlap, highlighting the importance of developing more specific treatment approaches which consider patients' demographic and cognitive profiles in addition to their diagnosis. (JINS, 2017, 23, 584-593).

The predictive role of daily cognitive stimulation on executive functions in bipolar disorder.

This study aimed to estimate the predictive role of clinical and demographic variables on the three core executive functions (EF) - working memory (WM), inhibitory control (IC) and cognitive flexibility (CF) - in bipolar disorder (BD). The sample consisted of 38 patients with BD type I, 39 with BD type II, and 106 control participants with no mood disorders. Subjects completed the Hayling Test, Trail Making Test, Digit Span Backwards, Sentence Word Span Test, and Stroop Color-Word Test. Composite scores for WM, IC and CF were calculated, and their correlations with clinical and demographic variables were analyzed. Stepwise hierarchical regression models including all significant correlates, gender, and diagnosis, revealed that the frequency of reading and writing habits (FRWH), IQ and diagnosis predicted 38.1% of the variance in IC. Diagnosis and IQ predicted 24.9% of the variance in WM scores. CF was predicted by the FRWH only, which accounted for 7.6% of the variance in this construct. These results suggest that daily cognitive stimulation through reading and writing make a significant positive contribution to executive functioning in BD, even in the absence of continued education. These and other forms of routine cognitive stimulation should be further emphasized in intervention programs for BD.

Quality of life, functioning and cognition in bipolar disorder and major depression: A latent profile analysis.

This study aimed to identify profiles of functioning and quality of life (QOL) in depression (MDD), bipolar disorder (BD) and healthy adults, as well as the clinical, demographic and cognitive variables associated with each of these profiles. Participants completed the WHODAS 2.0 and WHOQOL-BREF, which were submitted to latent profile analysis. The four cluster solution provided the best fit for our data. Cluster 1 consisted mostly of healthy adults, and had the highest functioning and QOL. Clusters 2 contained older patients with subclinical depressive symptoms and psychiatric comorbidities, whose impairments in QOL and functioning were associated with mood symptoms and several cognitive abilities. Patients with MDD, BDI or BDII with mild to moderate depression, such as those in cluster 3, may benefit more significantly from interventions in cognitive flexibility, inhibition, planning, and sustained attention. Lastly, patients with mood disorders and clinically significant levels of depression, as well as a history of suicide attempts, like those in cluster 4, may benefit from interventions aimed at working memory, inhibitory control, and cognitive flexibility; that is, the three core executive functions. These findings should be further investigated, and used to guide treatments for patients with mood disorders and different patterns of functional impairment.

Evaluating response to mood stabilizers in patients with mixed depression: A study of agreement between three different mania rating scales and a depression rating scale.

BACKGROUND: The aim of the present study was to evaluate agreement between three pairs formed by one of three mania scales (Young Mania Rating Scale [YMRS], Bech-Rafaelsen Mania Scale [BRMS], or the Clinician-Administered Rating Scale for Mania [CARS-M]) and a single depression scale (21-item Hamilton Depression Rating Scale [21-HAM-D]) for evaluation of response to mood stabilizers in patients with mixed bipolar disorder. METHODS: Between 2010 and 2014, 68 consecutive bipolar type I and II outpatients with mixed depression as per DSM-IV-TR and Cincinnati criteria were included in this 8-week open-label trial to randomly receive carbamazepine, lithium carbonate, or valproic acid as monotherapy. RESULTS: Patterns of response (defined as a reduction of at least 50% in one of the mania scales and on the 21-HAM-D) were strikingly similar: 21-HAM-D+YMRS=22.1%, 21-HAM-D+BRMS=20.6%, and 21-HAM-D+CARS-M=23.5% (p<0.368). Assessment of agreement revealed very high kappa coefficients: 21-HAM-D+YMRS vs. 21-HAM-D+CARS-M, kappa=0.87; 21-HAM-D+YMRS vs. 21-HAM-D+BRMS, kappa=0.78; 21-HAM-D+CARS-M vs. 21-HAM-D+BRMS, kappa=0.91 (p<0.001). LIMITATIONS: The decision to combine a depression rating scale with any one mania rating scale to assess treatment response in patients with mixed depression is questionable. CONCLUSIONS: The present study suggests that any one of the three tested mania rating scales (YMRS, BRMS, and CARS-M) can be combined with the 21-HAM-D to assess treatment response in patients with mixed bipolar disorder. This should give clinicians an added measure of confidence in using this strategy until valid, and specific instruments are developed for assessment of mixed states.