Factors associated with the discrepancy between objective and subjective cognitive impairment in bipolar disorder.

OBJECTIVE: The aim of this study is to evaluate the discrepancy between objective cognitive measures and cognitive subjective complaints in a sample of euthymic patients with bipolar disorder (BD). METHODS: One hundred and sixteen participants (83 euthymic patients with BD and 33 healthy controls) were enrolled for this study. Patients were assessed with a comprehensive neuropsychological battery and they also reported their subjective cognitive complaints with the Cognitive Complaints in Bipolar Disorder Rating Scale (COBRA). The discrepancy between objective and subjective data was calculated using a novel methodology proposed in a previous study (Miskowiak, 2016). Statistical analyses included Pearson correlations and multiple linear regression. RESULTS: Higher number of previous depressive episodes was identified as one variable associated with the global sensitivity composite score (Beta = 0.25; t = 2.1; p = 0.04) and with the verbal learning and memory sensitivity score (Beta = 0.26; t = 2.16; p = 0.03). That is, patients with more previous depressive episodes tend to over-report cognitive complaints. In contrast, higher number of previous hospitalizations was associated with stoicism in the global total score (Beta = -0.27; t = -2.24: p = 0.029) and in the domain of attention/processing speed (Beta = -0.34; t = -2.52; p = 0.016), indicating patients with more hospitalizations tend to report less cognitive complaints. DISCUSSION: Our study identified some factors that might help to explain the discrepancy between objective and subjective cognitive measures in BD, including number of previous depressive episodes and number of previous hospitalizations. This highlights the need of the combined use of both types of cognitive measures to make an accurate assessment of cognitive dysfunctions and their effective treatment.

An event-based adaptation of the relay feedback experiment for frequency response identification of stable processes.

An event-based modification of the classical relay feedback experiment without the inclusion of additional elements (integrator, time delay, …) for identification of the spectrum of stable processes between zero and the phase cross-over frequency is presented. By inserting an event-based sampler in the control loop, the natural behaviour of a classical relay is simulated and the system is forced to work in two modes. The event-based sampler activates the first mode by sending control actions to the process every time the error signal crosses zero; this mode is to discover the approximated value of the cross-over frequency [Formula: see text] . During the second mode, the event-based sampler sends samples to the process simulating that the error signal crosses zero at [Formula: see text] where N is the number of points to identify in the range [Formula: see text] . One advantage of this procedure is that the logic used in an already existing relay feedback experiment to fit a transfer function model or tune a controller could be maintained just replacing the relay block by the event-based sampler block presented in the paper. Simulations and experiments with different processes and in presence of noise demonstrate the effectivity of the procedure.

Factors associated with poor functional outcome in bipolar disorder: sociodemographic, clinical, and neurocognitive variables.

OBJECTIVE: The current investigation aimed at studying the sociodemographic, clinical, and neuropsychological variables related to functional outcome in a sample of euthymic patients with bipolar disorder(BD) presenting moderate-severe levels of functional impairment. METHODS: Two-hundred and thirty-nine participants with BD disorders and with Functioning Assessment Short Test(FAST) scores equal or above 18 were administered a clinical and diagnostic interview, and the administration of mood measure scales and a comprehensive neuropsychological battery. Analyses involved preliminary Pearson bivariate correlations to identify sociodemographic and clinical variables associated with the FAST total score. Regarding neuropsychological variables, a principal component analysis (PCA) was performed to group the variables in orthogonal factors. Finally, a hierarchical multiple regression was run. RESULTS: The best fitting model for the variables associated with functioning was a linear combination of gender, age, estimated IQ, Hamilton Depression Rating Scale (HAM-D), number of previous manic episodes, Factor 1 and Factor 2 extracted from the PCA. The model, including all these previous variables, explained up to 29.4% of the observed variance. CONCLUSIONS: Male gender, older age, lower premorbid IQ, subdepressive symptoms, higher number of manic episodes, and lower performance in verbal memory, working memory, verbal fluency, and processing speed were associated with lower functioning in patients with BD.

Psychometric properties of the well-being index (WHO-5) spanish version in a sample of euthymic patients with bipolar disorder.

BACKGROUND: The concept of well-being which focuses on positive emotions has received increased research attention. However, a consensus definition of this term is lacking. The Well-Being Index scale (WHO-5) is a generic, self-report scale that contains five Likert-type items to evaluate psychological well-being. This construct may provide a relevant outcome in bipolar disorder (BD) research and care beyond the rating of mood symptoms. Thus, in the current study, the psychometric properties of the WHO-5 Spanish version were assessed in a sample of euthymic patients with BD. METHODS: Patients with BD- I and BD-II and healthy controls completed the Well-Being Index (WHO-5) together with an assessment of depressive (Hamilton Depression Rating Scale-17; HAM-D) and manic symptoms (Young Mania Rating Scale; YMRS); and a measure of psychosocial functioning (Functioning Assessment Short Test; FAST). Internal consistency reliability was measured through Cronbach's alpha. Test-retest reliability was calculated comparing the WHO-5 total score at baseline and after 10 days of the first administration. To assess the structure of the scale, a principal component analysis (PCA) was carried out. Correlations between the WHO-5, HAM-D, YMRS and FAST were calculated. Finally, a t-test for independent samples was applied to compare the WHO-5 total score in the patient and control groups. RESULTS: A total of 104 patients with BD and 40 healthy controls were included in this study. A Chronbach's alpha of 0.83 indicated acceptable internal consistency. A paired sample t-test revealed no significant differences between WHO-5 total score at baseline and at follow-up (tn = - 0.72; df = 15; p = 0.48). The PCA provided a single factor solution that accounted for 59.74% of the variation in WHO-5. Test-retest reliability was high (r = 0.83; p < 0.001). Moderate negative correlations were observed between the WHO-5 total score, the FAST (r = - 0.46.; p < 0.001) and the HAM-D (r = - 0.68; p < 0.001), but not with the YMRS (r = - 0.07; p = 0.42). Finally, significant differences were found when comparing the WHO-5 total score between patient and healthy controls (t = 5.1; df = 147; p < 0.001). LIMITATIONS: some limitations include the lack of a comparator scale to test for validity construct and the small sample size in the test-retest reliability CONCLUSIONS: The WHO-5 shows an acceptable reliability index and measures a unitary construct in a Spanish population of euthymic patients with BD.

Treatment of neurocognitive symptoms in unipolar depression: A systematic review and future perspectives.

BACKGROUND: Cognitive symptoms in Major Depressive Disorder (MDD) are persistent and commonly entail neurocognitive impairment and a decline in quality of life. This systematic review gathers the current scientific evidence on therapeutic strategies for neuropsychological impairment in MDD. METHOD: A systematic search on PubMed, PsycINFO and Clinicaltrials.gov was carried out on December 2016 according to PRISMA using Boolean terms to identify interventions for the treatment of cognitive dysfunction in MDD. Only English-written articles providing original data and focusing in adults with MDD were included with no time restrictions. RESULTS: A total of 95 studies reporting data on 40 pharmacological and non-pharmacological interventions were included. Interventions were grouped into the following categories: 1) Pharmacological Therapies (antidepressants, stimulants, compounds acting on NMDA receptors, compounds acting on the cholinergic system, compounds showing anti-inflammatory or antioxidant properties, other mechanisms of action), 2) Physical Therapies and 3) Psychological Therapies, 4) Exercise. There are some promising compounds showing a positive impact on cognitive symptoms including vortioxetine, lisdexamfetamine or erythropoietin. LIMITATIONS: The studies included showed significant methodological differences in heterogeneous samples. The lack of a standardized neuropsychological battery makes comparisons between studies difficult. CONCLUSION: Current evidence is not sufficient to widely recommend the use of procognitive treatments in MDD although promising results are coming to light.

Analog isolated electronic dynamometer based on a magnetoresistive current sensor.

In this work, an electronic system is presented to measure the force applied by a solenoid. The originality of the work is focused on the use of a magnetoresistive current sensor to provide the isolation barrier needed in the actual industrial plant where the solenoids are working. The design of the electronic system is presented as well as experimental measurements as a result of a calibration process showing a negligible hysteresis with that specific sensor. The magnetoresistive current sensor is used to develop transmission functions rather than playing its usual sensing roles.

Manual motor speed dysfunction as a neurocognitive endophenotype in euthymic bipolar disorder patients and their healthy relatives. Evidence from a 5-year follow-up study.

BACKGROUND: Few studies have examined Manual Motor Speed (MMS) in bipolar disorder (BD). The aim of this longitudinal, family study was to explore whether dysfunctional MMS represents a neurocognitive endophenotype of BD. METHODS: A sample of 291 subjects, including 131 BD patients, 77 healthy first-degree relatives (BD-Rel), and 83 genetically-unrelated healthy controls (HC), was assessed with the Finger-Tapping Test (FTT) on three occasions over a 5-year period. Dependence of FTT on participants´ age was removed by means of a lineal model of HC samples, while correcting simultaneously the time and learning effect. Differences between groups were evaluated with an ANOVA test. RESULTS: The patients' performance was significantly worse than that of HC over time (p≤0.006), and these deficits remained when non-euthymic BD patients (n=9) were excluded from analysis. Some significant differences between BD patients and BD-Rel (p≤0.037) and between BD-Rel and HC (p≤0.033) were found, but they tended to disappear as time progressed (p≥0.057). Performance of the BD-Rel group was intermediate to that of BD and HC. Most sociodemographic and clinical variables did not affect these results in patients. (p≥0.1). However, treatment with carbamazepine and benzodiazepines may exert a iatrogenic effect on MMS performance (p≤0.006). LIMITATIONS: Only right-handed subjects were included in this study. Substantial attrition over time was detected. CONCLUSIONS: There were significant differences between the patients´ MMS performance and that of healthy relatives and controls, regardless of most clinical and sociodemographic variables. Dysfunctional MMS could be considered an endophenotype of BD. Further studies are needed to rule out possible iatrogenic effects of some psychopharmacological treatments.

High cognitive reserve in bipolar disorders as a moderator of neurocognitive impairment.

BACKGROUND: Cognitive reserve (CR) reflects the capacity of the brain to endure neuropathology, minimize clinical manifestations and successfully complete cognitive tasks. The present study aims to determine whether high CR may constitute a moderator of cognitive functioning in bipolar disorder (BD). METHODS: 102 patients with BD and 32 healthy controls were enrolled. All patients met DSM-IV criteria for I or II BD and were euthymic (YMRS≤6 and HDRS≤8) during a 6-month period. All participants were tested with a comprehensive neuropsychological battery, and a Cerebral Reserve Score (CRS) was estimated. Subjects with a CRS below the group median were classified as having low CR, whereas participants with a CRS above the median value were considered to have high CR. RESULTS: Participants with BD with high CR displayed a better performance in measures of attention (digits forward: F=4.554, p=0.039); phonemic and semantic verbal fluency (FAS: F=9.328, p=0.004; and Animal Naming: F=8.532, p=0.006); and verbal memory (short cued recall of California Verbal Learning Test: F=4.236, p=0.046), after multivariable adjustment for potential confounders, including number of admissions and prior psychotic symptoms. LIMITATIONS: The cross-sectional design of the study does not allow the establishment of causal inferences. Additionally, the small size of the sample may have limited some results. CONCLUSIONS: High cognitive reserve may therefore be a valuable construct to explore for predicting neurocognitive performance in patients with BD regarding premorbid status.

The role of family interventions in bipolar disorder: A systematic review.

The reciprocal relationship between bipolar disorder (BD) and the family system highlights the importance of adjunctive family intervention. However, its implementation in clinical practice is not widespread. To update the knowledge in this field and identify areas of uncertainty this manuscript present a comprehensive overview of the bidirectional relationship between BD and family variables, and a systematic review of the evidence-based studies published up to March 2015 on the efficacy of adjunctive family intervention in BD. Findings show that not only specific family's attitudes/interactions affect the course of BD but that equally the illness itself has a strong impact on family functioning, caregivers' burden and health. Regarding family intervention, there are methodological differences between studies and variability in the sample characteristics and the intervention used. Most evidence-based studies support the efficacy of adjunctive family treatment in the illness outcomes, both in youth and adult population, as well as benefits for caregivers. The results emphasize the need to involve caregivers in the therapeutic management of BD through tailored interventions based on patients' characteristics and family needs.

The impact of repeated manic episodes and executive dysfunction on work adjustment in bipolar disorder.

The aim of this study was to study the clinical and neurocognitive variables that best explain poor work adjustment in a sample of bipolar I euthymic patients. Eighty-five euthymic patients at the Hospital Clinic of Barcelona were assessed for this study by means of a comprehensive neuropsychological battery and a work-focused interview to determine work adjustment. Clinical and sociodemographic variables were also collected. Direct logistic regression was performed to assess the impact of demographic, clinical and neuropsychological variables on the likelihood of presenting poor work adjustment. The model that best fitted contained five variables (Hamilton Depression Rating scores, number of manic episodes, number of perseverative errors in the Wisconsin Card Sorting Test (WCST), number of depressive episodes and Trail Making Test-part B). However, only two out of these variables made a unique statistically significant contribution to the model, which were number of manic episodes (OR 1.401; CI 1.05-1.86; p = 0.021) and number of perseverative errors in the WCST (OR 1.062; CI 1.00-1.12; p = 0.044). The model explained up to 36 % of the variance in work adjustment. This study highlights the role of manic relapses and neurocognitive impairment, specifically the role of executive function, in work adjustment.

Clinical implications of predominant polarity and the polarity index in bipolar disorder: a naturalistic study.

OBJECTIVE: Predominant polarity (PP) is an important variable in maintenance treatment of bipolar disorder (BD). This study aimed at determining the role of polarity index (PI), a metric indicating antimanic versus antidepressive prophylactic potential of drugs, in clinical decision-making. METHOD: Two hundred and fifty-seven of 604 (43%) of patients with BD-I or II fulfilled criteria for manic (MPP) or depressive PP (DPP). The PI, representing the ratio of number needed to treat (NNT) for depression prevention to NNT for mania prevention, was calculated for patients' current treatment. MPP and DPP groups were compared regarding sociodemographic, clinical and therapeutic characteristics. RESULTS: One hundred and forty-three patients (55.6%) fulfilled criteria for DPP and 114 (44.4%) for MPP. Total PI, Antipsychotics' PI, and mood stabilizers PI were higher, indicating a stronger antimanic action, in MPP. MPP presented higher prevalence of BD-I, male gender, younger age, age at onset and at first hospitalization, more hospitalizations, primary substance misuse, and psychotic symptoms. DP correlated with BD-II, depressive onset, primary life events, melancholia, and suicide attempts. CONCLUSION: The results confirm the usefulness of the PI. In this large sample, clinical differences among these groups justify differential treatment approach. The PI appears to be a useful operationalization of what clinicians do for maintenance therapy in BD.

The clinical implications of cognitive impairment and allostatic load in bipolar disorder.

BACKGROUND: Allostatic load (AL) relates to the neural and bodily "wear and tear" that emerge in the context of chronic stress. This paper aims to provide clinicians with a comprehensive overview of the role of AL in patophysiology of bipolar disorder (BD) and its practical implications. METHODS: PubMed searches were conducted on English-language articles published from 1970 to June 2011 using the search terms allostatic load, oxidative stress, staging, and bipolar disorder cross-referenced with cognitive impairment, comorbidity, mediators, prevention. RESULTS: Progressive neural and physical dysfunction consequent to mood episodes in BD can be construed as a cumulative state of AL. The concept of AL can help to reconcile cognitive impairment and increased rates of clinical comorbidities that occur over the course of cumulative BD episodes. CONCLUSIONS: Data on transduction of psychosocial stress into the neurobiology of mood episodes converges to the concept of AL. Mood episodes prevention would not only alleviate emotional suffering, but also arrest the cycle of AL, cognitive decline, physical morbidities and, eventually, related mortality. These objectives can be achieved by focusing on effective prophylaxis from the first stages of the disorder, providing mood-stabilizing agents and standardized psychoeducation and, potentially, addressing cognitive deficits by the means of specific medication and neuropsychological interventions.

Lower rate of depressive switch following antimanic treatment with second-generation antipsychotics versus haloperidol.

BACKGROUND: Treatment of acute mania with second-generation antipsychotics has been claimed to involve a lower risk of switch to depression than haloperidol. However, clinical guidelines clearly state that this is not a proven fact. METHODS: Meta-analysis of double-blind randomized controlled trials in acute mania, comparing rates of switch to depression with atypical antipsychotics and with haloperidol. Search was conducted in MEDLINE and CENTRAL databases (last search: September 2011). RESULTS: 8 randomized clinical trials fulfilled inclusion criteria. 2 of them were excluded because of low methodological quality or lack of data. 5 second-generation antipsychotics (aripiprazole, olanzapine, quetiapine, risperidone, and ziprasidone) were compared to haloperidol. In the mixed effects model the Risk Ratio for depressive switch was 0.71 (0.52, 0.96) favouring atypical antipsychotics. In the random effects model the difference did not reach statistical significance. In the heterogeneity analysis, exclusion of an outlying aripiprazole trial yielded a Risk Ratio of 0.58 (0.42, 0.82) with a non-significant heterogeneity test. Although no atypical antipsychotic was individually significantly superior to haloperidol, a trend could be seen favouring olanzapine (RR=0.56 [0.29, 1.08]), quetiapine (RR=0.36 [0.10, 1.33]), and ziprasidone (RR=0.51 [0.22, 1.18]). LIMITATIONS: All trials were industry supported, with some variability in dosage of haloperidol. Switch to depression was not the primary outcome of the trials. Heterogeneity could be explained as a lack of class-effect for atypicals. CONCLUSIONS: Treating acute mania with atypicals is associated to 42% less risk of switch to depression than with haloperidol. Nevertheless, caution should be taken when considering this a class effect, as only olanzapine, quetiapine, and ziprasidone may show a better profile.

Subthreshold symptoms in bipolar disorder: impact on neurocognition, quality of life and disability.

OBJECTIVE: To provide empirical evidence of the effect of subthreshold symptomatology (both depressive and manic) on psychosocial functioning, neurocognition and quality of life in bipolar disorder. METHODS: A total of 133 participants were enrolled for this study (bipolar patients, n=103; healthy controls, n=30). Patients were divided into two groups according to their levels of subthreshold symptomatology: the subsyndromic group was constituted by those patients with upper levels of subthreshold symptomatology (HDRS≥4 and YMRS≥3) and the asymptomatic group represented the patients with lower scores (HDRS≤3 and YMRS≤2). All participants were administered a comprehensive neuropsychological battery. Moreover the patients answered the SF-36 (Quality of Life, QoL) and were interviewed with the WHODAS-2 (Psychosocial functioning and disability). One-way ANOVA were used in order to compare the differences between the three groups. RESULTS: The analyses revealed that both patients groups, albeit free of acute symptoms of mania or depression, differed in terms of functioning and disability assessed with the WHODAS-2. Specifically, the total global score of disability was higher for the subsyndromic group indicating more impairment (p=0.008). The same pattern of impairment was found for three of its domains: "understanding and communicating" (p=0.013); "self-care" (p=0.035) and "getting along with others" (p=0.024). The subsyndromic group also scored lower when compared to their counterparts in the Mental Component of QoL of the SF-36 (p=0.045). Finally, in the neuropsychological performance verbal learning and memory was found to be impaired regardless the levels of subthreshold symptomatology, suggesting that this variable is a robust indicator of neuropsychological impairment in BD patients. CONCLUSIONS: This report presents empirical data suggesting a moderate impact of subthreshold symptoms on functioning/disability and QoL and a discrete impact on neuropsychological impairment.

Are bipolar II patients cognitively impaired? A systematic review.

BACKGROUND: There is evidence that bipolar disorder (BD) is associated with significant neurocognitive deficits and this occurs in individuals with BD type I (BD I) and with BD type II (BD II). Only a few studies have focused on cognitive impairment in BD II. The aim of this study was to describe the pattern of cognitive impairment in patients with BD II, in order to identify specific cognitive deficits that distinguish BD II from BD I patients as well as from healthy subjects. METHOD: We performed a systematic review of the literature of neuropsychological studies of BD II published between 1980 and July 2009. Fourteen articles fulfilled the inclusion criteria and were included in this review. RESULTS: Main cognitive deficits found in BD II include working memory and some measures of executive functions (inhibitory control) and approximately half of the studies also detected verbal memory impairment. CONCLUSIONS: There are subtle differences between the two subtypes regarding cognition. This may suggest neurobiological differences between the two subgroups which will be helpful in order to determine cognitive endophenotypes in BD subtypes.

Factors associated with initial treatment response with antidepressants in bipolar disorder.

INTRODUCTION: Controversy in antidepressant (AD) use in bipolar depression relies in its potential induction of mood switches and ineffectiveness. Responders to acute AD add-on treatment maintain response with continued treatment, whilst partial/non-responders fail to reach remission despite continuation treatment. We aimed to identify response predictors to acute AD addition in bipolar depression in order to optimize treatment choice in bipolar depression and avoid unnecessary AD exposure of people unlikely to respond. METHODS: Two hundred and twenty-one DSM-IV-TR depressed bipolar - type I and II - patients were treated with AD on an observational study. AD response was defined as an at least 50% drop from baseline of their HDRS17 score after 8weeks of treatment. One hundred and thirty-eight patients (138, 62.4%) fulfilled response criteria (RI) whilst 83 patients (37.6%) did not (NRI). In all cases AD therapy was on top of previously prescribed stabilizers and/or atypical antipsychotics. RESULTS: RI patients were more likely to have had previous response to ADs, whereas NRI had a higher number of previous mood switches with ADs during past depressive episodes. Psychotic symptoms were more frequent amongst RI, whilst lifetime history of atypical depression was more frequent amongst NRI. NRI had more total, depressive, and hypomanic, but not manic or mixed, episodes in the past than RI. Analyzed through a logistic regression, higher previous response to ADs and lower rate of past hypomanic episodes in RI were the variables explaining intergroups (RI vs. NRI) differences. DISCUSSION: Taking into account the proper caution in the use of Ads in bipolar disorder, there is a subgroup of bipolar patients who might benefit from adjunctive Ads. Looking at specific clinical factors during the course of the illness could help physicians in deciding whether to use an antidepressant in a bipolar depressed patient already treated with mood stabilizers.

[Bipolar disorder, cognitive functioning and hypothalamic-pituitary-thyroid axis]. / Trastorno bipolar, funciones cognitivas y eje hipotalámico-pituitario-tiroideo.

In psychoneuroendocrinology there's a scarcity of knowledge of hypothalamic-pituitary-thyroid axis (HPT) in relation to bipolar disorder (BD) and neuropsychological functions. The aim of this study is to review the current state of the following issues: (1) neuropsychological dysfunctions in BD, as well as their hypothetic aetiology; (2) response of HPT in each phase of BD, and, finally, (3) connection between alterations in HPT and neuropsychological deficits.

Functional impairment in bipolar II disorder: is it as disabling as bipolar I?

INTRODUCTION: It is well established that patients with bipolar disorder experience functional impairment even in remission. Nevertheless, bipolar II disorder remains understudied because most investigations to date include only bipolar I patients or just a small sample of bipolar II patients, without explicitly comparing both subtypes of disorder. The main objective of the current report is to evaluate overall and multiple domains of functioning, specifically in bipolar II disorder compared to patients with bipolar I disorder and healthy subjects. METHODS: 233 subjects from 3 groups were compared: bipolar I patients (n=106), bipolar II patients (n=66) and healthy controls (n=61). Bipolar patients meeting criteria of remission were recruited at the Hospital Clinic of Barcelona and at different study sites in Argentina. All participants were assessed with 17-item Hamilton Depression Rating Scale (HAM-D), Young Mania Rating Scale (YMRS) and the Functioning Assessment Short Test (FAST). Clinical and sociodemographic data were also recorded. RESULTS: Both subgroups of patients, bipolar I and bipolar II, showed lower overall functioning (p<0.001) and in each domain of the FAST scale (all, p<0.001) when compared to the healthy control group. Tukey post hoc test revealed that bipolar II patients scored worse in the cognitive domain compared to bipolar I patients. However, after controlling for potential confounding variables, this difference disappeared and only older age (p<0.005) and HAM-D scores (p<0.001) remained significant. CONCLUSIONS: Our results suggest that bipolar II patients are as disabled as bipolar I patients. This may be explained, in part, because bipolar II patients experience greater lifetime residual depressive symptoms than the bipolar I subgroup, which may have particular impact on cognitive domains of functioning.

Note: Direct sensor resistance-to-frequency conversion with generalized impedance converter.

In this note a squared output signal is generated from an astable circuit. Its frequency has a linear dependence on the resistance value of a resistive temperature sensor. The main circuit to obtain this direct relationship is the generalized impedance converter configured as a capacitor controlled by a sensor resistance. The proposed measurement method allows a direct analog-to-digital interface of information involved in resistive sensors. The converter finds applications in portable low voltage and low power design of instrumentation electronic systems.