Is aberrant affective cognition an endophenotype for affective disorders? - A monozygotic twin study.

BACKGROUND: Identification of endophenotypes can improve prevention, detection and development of new treatments. We therefore investigated whether aberrant affective cognition constitutes an endophenotype for affective disorders by being present in monozygotic (MZ) twins with unipolar or bipolar disorder in partial remission (i.e. affected) and their unaffected co-twins (i.e. high-risk) relative to twins with no family history of affective disorder (i.e. low-risk). METHODS: We conducted an assessor blind cross-sectional study from 2014 to 2017 of MZ twins using Danish population-based registers in recruitment. Twins attended one test session involving neurocognitive testing, clinical ratings and questionnaires. Main outcomes were attention to and recognition of emotional facial expressions, the memory of emotional self-referential words, emotion regulation and coping strategies. RESULTS: Participants were 103 affected, 44 high-risk and 36 low-risk MZ twins. Groups were demographically well-balanced and showed comparable non-affective cognitive performance. We observed no aberrant affective cognition in affected and high-risk relative to low-risk twins. However, high-risk twins displayed attentional avoidance of emotional faces (ps ⩽ 0.009) and more use of task-oriented coping strategies (p = 0.01) compared with affected twins. In contrast did affected twins show more emotion-oriented coping than high- and low-risk twins (ps ⩽ 0.004). CONCLUSIONS: Our findings provide no support of aberrant affective cognition as an endophenotype for affective disorders. High-risk twins' attentional avoidance of emotional faces and greater use of task-oriented coping strategies may reflect compensatory mechanisms.

The association between mixed symptoms, irritability and functioning measured using smartphones in bipolar disorder.

OBJECTIVE: To (i) validate patient-evaluated mixed symptoms and irritability measured using smartphones against clinical evaluations; (ii) investigate associations between mixed symptoms and irritability with stress, quality of life and functioning, respectively, in patients with bipolar disorder. METHODS: A total of 84 patients with bipolar disorder used a smartphone-based system for daily evaluation of mixed symptoms and irritability for nine months. Clinically evaluated symptoms, stress, quality of life and clinically rated functioning were collected multiple times during follow-up. RESULTS: Patients presented mild affective symptoms. Patient-reported mixed symptoms and irritability correlated with clinical evaluations. In analyses including confounding factors there was a statistically significant association between both mixed symptoms and irritability and stress (P < 0.0001) and between irritability and both quality of life and functioning (P < 0.0001) respectively. There was no association between mixed mood and both quality of life and functioning. CONCLUSION: Mixed symptoms and irritability can be validly self-reported using smartphones in patients with bipolar disorder. Mixed symptoms and irritability are associated with increased stress even during full or partial remission. Irritability is associated with decreased quality of life and functioning. The findings emphasize the clinical importance of identifying inter-episodic symptoms including irritability pointing towards smartphones as a valid tool.

New drug candidates for depression - a nationwide population-based study.

OBJECTIVE: To investigate whether continued use of non-aspirin NSAID, low-dose aspirin, high-dose aspirin, statins, allopurinol and angiotensin agents decreases the rate of incident depression using Danish nationwide population-based registers. METHODS: All persons in Denmark who purchased the exposure medications of interest between 1995 and 2015 and a random sample of 30% of the Danish population was included in the study. Two different outcome measures were included, (i) a diagnosis of depressive disorder at a psychiatric hospital as in-patient or out-patient and (ii) a combined measure of a diagnosis of depression or use of antidepressants. RESULTS: A total of 1 576 253 subjects were exposed to one of the six drugs of interest during the exposure period from 2005 to 2015. Continued use of low-dose aspirin, statins, allopurinol and angiotensin agents was associated with a decreased rate of incident depression according to both outcome measures. Continued uses of non-aspirin NSAIDs as well as high-dose aspirin were associated with an increased rate of incident depression. CONCLUSION: The findings support the potential of agents acting on inflammation and the stress response system in depression as well as the potential of population-based registers to systematically identify drugs with repurposing potential.

A multisystem composite biomarker as a preliminary diagnostic test in bipolar disorder.

OBJECTIVE: Diagnosis and management of bipolar disorder (BD) are limited by the absence of available laboratory tests. We aimed to combine data from different molecular levels and tissues into a composite diagnostic and state biomarker. METHODS: Expression levels of 19 candidate genes in peripheral blood, plasma levels of BDNF, NT-3, IL-6 and IL-18, leukocyte counts, and urinary markers of oxidative damage to DNA and RNA were measured in 37 adult rapid-cycling patients with BD in different affective states during a 6- to 12-month period and in 40 age- and gender-matched healthy individuals in a longitudinal, repeated measures design comprising a total of 211 samples. A composite biomarker was constructed using data-driven variable selection. RESULTS: The composite biomarker discriminated between patients with BD and healthy control individuals with an area under the receiver operating characteristic curve (AUC) of 0.83 and a sensitivity of 73% and specificity of 71% corresponding with a moderately accurate test. Discrimination between manic and depressive states had a moderate accuracy, with an AUC of 0.82 and a sensitivity of 92% and a specificity of 40%. CONCLUSION: Combining individual biomarkers across tissues and molecular systems could be a promising avenue for research in biomarker models in BD.

Remitted affective disorders and high familial risk of affective disorders associate with aberrant intestinal microbiota.

OBJECTIVE: Affective disorders seem associated with aberrant intestinal microbiota but whether this pattern also occurs in individuals at increased heritable risk is unknown. We investigated associations between gut microbiota profiles and affective disorders by comparing monozygotic (MZ) twins concordant (affected twins with unipolar or bipolar disorder in remission) and discordant to affective disorders (high-risk) with MZ twins without affective disorders (low-risk). METHODS: Stool samples were collected from 128 MZ twins and the microbiome was profiled using 16S rDNA sequencing of the V3-V4 region. RESULTS: Affected twins had a lower diversity and an absence of a specific operational taxonomical unit (OTU) in comparison with low-risk twins. The high-risk twins exhibited the same pattern although the lower diversity was only at a trend level. The OTU belonged to the family Christensenellaceae. The findings were not explained by lifestyle factors (smoking, alcohol consumption, body mass index, or psychotropic medication). CONCLUSION: Affected twins in remission and high-risk twins presented aberrant gut microbiota with depletion of a specific OTU. If replicated, this reduced relative sequence absence may together with the globally altered microbiota composition act as a vulnerability marker by accentuating the effect of gene-environment interactions in individuals genetically disposed for an affective disorder.

Assessing and addressing cognitive impairment in bipolar disorder: the International Society for Bipolar Disorders Targeting Cognition Task Force recommendations for clinicians.

OBJECTIVES: Cognition is a new treatment target to aid functional recovery and enhance quality of life for patients with bipolar disorder. The International Society for Bipolar Disorders (ISBD) Targeting Cognition Task Force aimed to develop consensus-based clinical recommendations on whether, when and how to assess and address cognitive impairment. METHODS: The task force, consisting of 19 international experts from nine countries, discussed the challenges and recommendations in a face-to-face meeting, telephone conference call and email exchanges. Consensus-based recommendations were achieved through these exchanges with no need for formal consensus methods. RESULTS: The identified questions were: (I) Should cognitive screening assessments be routinely conducted in clinical settings? (II) What are the most feasible screening tools? (III) What are the implications if cognitive impairment is detected? (IV) What are the treatment perspectives? Key recommendations are that clinicians: (I) formally screen cognition in partially or fully remitted patients whenever possible, (II) use brief, easy-to-administer tools such as the Screen for Cognitive Impairment in Psychiatry and Cognitive Complaints in Bipolar Disorder Rating Assessment, and (III) evaluate the impact of medication and comorbidity, refer patients for comprehensive neuropsychological evaluation when clinically indicated, and encourage patients to build cognitive reserve. Regarding question (IV), there is limited evidence for current evidence-based treatments but intense research efforts are underway to identify new pharmacological and/or psychological cognition treatments. CONCLUSIONS: This task force paper provides the first consensus-based recommendations for clinicians on whether, when, and how to assess and address cognition, which may aid patients' functional recovery and improve their quality of life.

Neural correlates of improved recognition of happy faces after erythropoietin treatment in bipolar disorder.

OBJECTIVE: Bipolar disorder is associated with impairments in social cognition including the recognition of happy faces. This is accompanied by imbalanced cortico-limbic response to emotional faces. We found that EPO improved the recognition of happy faces in patients with bipolar disorder. This randomized, controlled, longitudinal fMRI study explores the neuronal underpinnings of this effect. METHOD: Forty-four patients with bipolar disorder in full or partial remission were randomized to eight weekly erythropoietin (EPO; 40 000 IU) or saline (NaCl 0.9%) infusions in a double-blind, parallel-group design. Participants underwent whole-brain fMRI at 3T, mood ratings and blood tests at baseline and week 14. During fMRI, participants viewed happy and fearful faces and performed a gender discrimination task. RESULTS: Thirty-four patients had complete pre- and post-treatment fMRI data (EPO: N = 18, saline: N = 16). Erythropoietin vs. saline increased right superior frontal response to happy vs. fearful faces. This correlated with improved happiness recognition in the EPO group. Erythropoietin also enhanced gender discrimination accuracy for happy faces. These effects were not influenced by medication, mood, red blood cells or blood pressure. CONCLUSIONS: Together with previous findings, the present observation suggests that increased dorsal prefrontal attention control is a common mechanism of EPO-associated improvements across several cognitive domains.

Differences in neural and cognitive response to emotional faces in middle-aged dizygotic twins at familial risk of depression.

BACKGROUND: Negative bias and aberrant neural processing of emotional faces are trait-marks of depression but findings in healthy high-risk groups are conflicting. METHODS: Healthy middle-aged dizygotic twins (N = 42) underwent functional magnetic resonance imaging (fMRI): 22 twins had a co-twin history of depression (high-risk) and 20 were without co-twin history of depression (low-risk). During fMRI, participants viewed fearful and happy faces while performing a gender discrimination task. After the scan, they were given a faces dot-probe task, a facial expression recognition task and questionnaires assessing mood, personality traits and coping. RESULTS: Unexpectedly, high-risk twins showed reduced fear vigilance and lower recognition of fear and happiness relative to low-risk twins. During face processing in the scanner, high-risk twins displayed distinct negative functional coupling between the amygdala and ventral prefrontal cortex and pregenual anterior cingulate. This was accompanied by greater fear-specific fronto-temporal response and reduced fronto-occipital response to all emotional faces relative to baseline. The risk groups showed no differences in mood, subjective state or coping. CONCLUSIONS: Less susceptibility to fearful faces and negative cortico-limbic coupling during emotional face processing may reflect neurocognitive compensatory mechanisms in middle-aged dizygotic twins who remain healthy despite their familial risk of depression.

Peripheral blood brain-derived neurotrophic factor in bipolar disorder: a comprehensive systematic review and meta-analysis.

Peripheral blood brain-derived neurotrophic factor (BDNF) has been proposed as a potential biomarker related to disease activity and neuroprogression in bipolar disorder, speculated to mirror alterations in brain expression of BDNF. The research area is rapidly evolving; however, recent investigations have yielded conflicting results with substantial variation in outcomes, highlighting the need to critically assess the state of current evidence. The aims of the study were to investigate differences in peripheral blood BDNF concentrations between bipolar disorder patients and healthy control subjects and between affective states in bipolar disorder patients, including assessment of the effect of treatment of acute episodes on BDNF levels. A systematic review of English language studies without considering publication status was conducted in PubMed (January 1950-November 2014), Embase (1974-November 2014) and PsycINFO (1806-November 2014), and 35 studies comprising a total of 3798 participants were included in the meta-analysis. The results indicated that crude peripheral blood BDNF levels may be lower in bipolar disorder patients overall (Hedges' g=-0.28, 95% CI: -0.51 to -0.04, P=0.02) and in serum of manic (g=-0.77, 95% CI: -1.36 to -0.18, P=0.01) and depressed (g=-0.87, 95% CI: -1.42 to -0.32, P=0.002) bipolar disorder patients compared with healthy control subjects. No differences in peripheral BDNF levels were observed between affective states overall. Longer illness duration was associated with higher BDNF levels in bipolar disorder patients. Relatively low study quality, substantial unexplained between-study heterogeneity, potential bias in individual studies and indications of publication bias, was observed and studies were overall underpowered. It could thus not be excluded that identified differences between groups were due to factors not related to bipolar disorder. In conclusion, limitations in the evidence base prompt tempered conclusions regarding the role of peripheral BDNF as a biomarker in bipolar disorder and substantially improving the quality of further research is warranted.

The catechol-O-methyltransferase (COMT) Val158Met genotype modulates working memory-related dorsolateral prefrontal response and performance in bipolar disorder.

OBJECTIVES: Cognitive dysfunction affects a substantial proportion of patients with bipolar disorder (BD), and genetic-imaging paradigms may aid in the elucidation of mechanisms implicated in this symptomatic domain. The Val allele of the functional Val158Met polymorphism of the catechol-O-methyltransferase (COMT) gene is associated with reduced prefrontal cortex dopamine and exaggerated working memory-related prefrontal activity. This functional magnetic resonance imaging (fMRI) study investigated for the first time whether the COMT Val158Met genotype modulates prefrontal activity during spatial working memory in BD. METHODS: Sixty-four outpatients with BD in full or partial remission were stratified according to COMT Val158Met genotype (ValVal [n=13], ValMet [n=34], and MetMet [n=17]). The patients completed a spatial n-back working memory task during fMRI and the Cambridge Neuropsychological Test Automated Battery (CANTAB) Spatial Working Memory test outside the scanner. RESULTS: During high working memory load (2-back vs 1-back), Val homozygotes displayed decreased activity relative to ValMet individuals, with Met homozygotes displaying intermediate levels of activity in the right dorsolateral prefrontal cortex (dlPFC) (P=.016). Exploratory whole-brain analysis revealed a bilateral decrease in working memory-related dlPFC activity in the ValVal group vs the ValMet group which was not associated with differences in working memory performance during fMRI. Outside the MRI scanner, Val carriers performed worse in the CANTAB Spatial Working Memory task than Met homozygotes (P≤.006), with deficits being most pronounced in Val homozygotes. CONCLUSIONS: The association between Val allelic load, dlPFC activity and WM impairment points to a putative role of aberrant PFC dopamine tonus in the cognitive impairments in BD.

Methodological recommendations for cognition trials in bipolar disorder by the International Society for Bipolar Disorders Targeting Cognition Task Force.

OBJECTIVES: To aid the development of treatment for cognitive impairment in bipolar disorder, the International Society for Bipolar Disorders (ISBD) convened a task force to create a consensus-based guidance paper for the methodology and design of cognition trials in bipolar disorder. METHODS: The task force was launched in September 2016, consisting of 18 international experts from nine countries. A series of methodological issues were identified based on literature review and expert opinion. The issues were discussed and expanded upon in an initial face-to-face meeting, telephone conference call and email exchanges. Based upon these exchanges, recommendations were achieved. RESULTS: Key methodological challenges are: lack of consensus on how to screen for entry into cognitive treatment trials, define cognitive impairment, track efficacy, assess functional implications, and manage mood symptoms and concomitant medication. Task force recommendations are to: (i) enrich trials with objectively measured cognitively impaired patients; (ii) generally select a broad cognitive composite score as the primary outcome and a functional measure as a key secondary outcome; and (iii) include remitted or partly remitted patients. It is strongly encouraged that trials exclude patients with current substance or alcohol use disorders, neurological disease or unstable medical illness, and keep non-study medications stable. Additional methodological considerations include neuroimaging assessments, targeting of treatments to illness stage and using a multimodal approach. CONCLUSIONS: This ISBD task force guidance paper provides the first consensus-based recommendations for cognition trials in bipolar disorder. Adherence to these recommendations will likely improve the sensitivity in detecting treatment efficacy in future trials and increase comparability between studies.

Evidence for clinical progression of unipolar and bipolar disorders.

OBJECTIVE: It is a widely held belief that affective disorders are progressive of nature; however, some recent reviews have questioned this belief. The objective of the present systematic literature review was to present evidence for associations between number of affective episodes and (i) the risk of recurrence of episodes, (ii) probability of recovery from episodes, (iii) severity of episodes, (iv) the threshold for developing episodes, and (v) progression of cognitive deficits in unipolar and bipolar disorders. METHOD: A systematic review comprising an extensive literature search conducted in Medline, Embase, and PsychInfo up to September 2016 and including cross-references from identified papers and reviews. RESULTS: Most of the five areas are superficially investigated and hampered by methodological challenges. Nevertheless, studies with the longest follow-up periods, using survival analysis methods, taking account of the individual heterogeneity all support a clinical progressive course of illness. Overall, increasing number of affective episodes seems to be associated with (i) increasing risk of recurrence, (ii) increasing duration of episodes, (iii) increasing symptomatic severity of episodes, (iv) decreasing threshold for developing episodes, and (v) increasing risk of developing dementia. CONCLUSION: Although the course of illness is heterogeneous, there is evidence for clinical progression of unipolar and bipolar disorders.

Continuation of lithium after a diagnosis of chronic kidney disease.

OBJECTIVE: To investigate whether continued lithium or anticonvulsant treatment after a first diagnosis of chronic kidney disease (CKD) was associated with progression to irreversible end-stage kidney disease. METHODS: Nationwide cohort study including all individuals in Denmark in a period from 1995 to 2012 with a diagnosis of CKD and (i) a history of lithium treatment (N = 754, among whom 238 patients had a diagnosis of bipolar disorder) or (ii) a history of anticonvulsant treatment (N = 5.004, among whom 199 patients had a diagnosis of bipolar disorder). End-stage CKD was defined as chronic dialysis or renal transplantation. RESULTS: Continuing lithium (HR = 0.58 (95% CI: 0.37-0.90) and continuing anticonvulsants (HR = 0.53 (95% CI: 0.44-0.64) were associated with decreased rates of end-stage CKD. In the subcohorts of patients with a diagnosis of bipolar disorder, continuing lithium was associated with decreased end-stage CKD (HR = 0.40 (95% CI: 0.17-0.98), whereas continuing anticonvulsants was not (HR = 0.70 (95% CI: 0.21-2.37). There were no interactions of continuing lithium and anticonvulsants. CONCLUSION: After an initial diagnosis of CKD, patients who are selected by their physicians to continue lithium treatment may not necessarily have an increased risk of developing end-stage CKD. Shifting to an anticonvulsant per se may not be associated with an advantage; however, this requires further investigation.

Rates and predictors of remission, recurrence and conversion to bipolar disorder after the first lifetime episode of depression--a prospective 5-year follow-up study.

BACKGROUND: In depression, non-remission, recurrence of depressive episodes after remission and conversion to bipolar disorder are crucial determinants of poor outcome. The present study aimed to determine the cumulative incidences and clinical predictors of these long-term outcomes after the first lifetime episode of depression. METHOD: A total of 301 in- or out-patients aged 18-70 years with a validated diagnosis of a single depressive episode were assessed from 2005 to 2007. At 5 years of follow-up, 262 patients were reassessed by means of the life chart method and diagnostic interviews from 2011 to 2013. Cumulative incidences and the influence of clinical variables on the rates of remission, recurrence and conversion to bipolar disorder, respectively, were estimated by survival analysis techniques. RESULTS: Within 5 years, 83.3% obtained remission, 31.5% experienced recurrence of depression and 8.6% converted to bipolar disorder (6.3% within the first 2 years). Non-remission increased with younger age, co-morbid anxiety and suicidal ideations. Recurrence increased with severity and treatment resistance of the first depression, and conversion to bipolar disorder with treatment resistance, a family history of affective disorder and co-morbid alcohol or drug abuse. CONCLUSIONS: The identified clinical characteristics of the first lifetime episode of depression should guide patients and clinicians for long-term individualized tailored treatment.

Neural correlates of improved executive function following erythropoietin treatment in mood disorders.

BACKGROUND: Cognitive dysfunction in depression and bipolar disorder (BD) is insufficiently targeted by available treatments. Erythropoietin (EPO) increases neuroplasticity and may improve cognition in mood disorders, but the neuronal mechanisms of these effects are unknown. This functional magnetic resonance imaging (fMRI) study investigated the effects of EPO on neural circuitry activity during working memory (WM) performance. METHOD: Patients with treatment-resistant major depression, who were moderately depressed, or with BD in partial remission, were randomized to eight weekly infusions of EPO (40 000 IU) (N = 30) or saline (N = 26) in a double-blind, parallel-group design. Patients underwent fMRI, mood ratings and blood tests at baseline and week 14. During fMRI patients performed an n-back WM task. RESULTS: EPO improved WM accuracy compared with saline (p = 0.045). Whole-brain analyses revealed that EPO increased WM load-related activity in the right superior frontal gyrus (SFG) compared with saline (p = 0.01). There was also enhanced WM load-related deactivation of the left hippocampus in EPO-treated compared to saline-treated patients (p = 0.03). Across the entire sample, baseline to follow-up changes in WM performance correlated positively with changes in WM-related SFG activity and negatively with hippocampal response (r = 0.28-0.30, p < 0.05). The effects of EPO were not associated with changes in mood or red blood cells (p ⩾0.08). CONCLUSIONS: The present findings associate changes in WM-load related activity in the right SFG and left hippocampus with improved executive function in EPO-treated patients. CLINICAL TRIAL REGISTRATION: clinicaltrials.gov: NCT00916552.

Predictors of the discrepancy between objective and subjective cognition in bipolar disorder: a novel methodology.

OBJECTIVE: The poor relationship between subjective and objective cognitive impairment in bipolar disorder (BD) is well-established. However, beyond simple correlation, this has not been explored further using a methodology that quantifies the degree and direction of the discrepancy. This study aimed to develop such a methodology to explore clinical characteristics predictive of subjective-objective discrepancy in a large BD patient cohort. METHODS: Data from 109 remitted BD patients and 110 healthy controls were pooled from previous studies, including neuropsychological test scores, self-reported cognitive difficulties, and ratings of mood, stress, socio-occupational capacity, and quality of life. Cognitive symptom 'sensitivity' scores were calculated using a novel methodology, with positive scores reflecting disproportionately more subjective complaints than objective impairment and negative values reflecting disproportionately more objective than subjective impairment ('stoicism'). RESULTS: More subsyndromal depressive and manic symptoms, hospitalizations, BD type II, and being male positively predicted 'sensitivity', while higher verbal IQ predicted more 'stoicism'. 'Sensitive' patients were characterized by greater socio-occupational difficulties, more perceived stress, and lower quality of life. CONCLUSION: Objective neuropsychological assessment seems especially warranted in patients with (residual) mood symptoms, BD type II, chronic illness, and/or high IQ for correct identification of cognitive deficits before commencement of treatments targeting cognition.

Unaffected twins discordant for affective disorders show changes in anterior callosal white matter microstructure.

OBJECTIVE: The neurobiological mechanisms mediating an increased risk to develop affective disorders remain poorly understood. In a group of individuals with a family history of major depressive (MDD) or bipolar disorder (BD), we investigated the microstructural properties of white matter fiber tracts, that is, cingulum bundle, uncinate fasciculus, anterior limb of the internal capsule, and corpus callosum, that facilitate the communication between brain regions implicated in affective disorders. METHOD: Eighty-nine healthy mono- or dizygotic twins with a co-twin diagnosed with MDD or BD (high-risk) and 57 healthy twins with a co-twin with no familial history of affective disorders (low-risk) were included in a diffusion tensor imaging study. RESULT: The high-risk group showed decreased fractional anisotropy (FA), a measure of water diffusion directionality, and increased radial diffusivity in the anterior region of corpus callosum compared to the low-risk group. This abnormality was not associated with zygosity or type of depressive disorder of co-twin. CONCLUSION: The observed decreased anterior callosal fiber FA in the high-risk group may be indicative of a compromised interhemispheric communication between left and right frontal regions critically involved in mood regulation. Reduced anterior callosal FA may act as a vulnerability marker for affective disorders in individuals at familial risk.

Effects of erythropoietin on memory-relevant neurocircuitry activity and recall in mood disorders.

OBJECTIVE: Erythropoietin (EPO) improves verbal memory and reverses subfield hippocampal volume loss across depression and bipolar disorder (BD). This study aimed to investigate with functional magnetic resonance imaging (fMRI) whether these effects were accompanied by functional changes in memory-relevant neuro-circuits in this cohort. METHOD: Eighty-four patients with treatment-resistant unipolar depression who were moderately depressed or BD in remission were randomized to eight weekly EPO (40 000 IU) or saline infusions in a double-blind, parallel-group design. Participants underwent whole-brain fMRI at 3T, mood ratings, and blood tests at baseline and week 14. During fMRI, participants performed a picture encoding task followed by postscan recall. RESULTS: Sixty-two patients had complete data (EPO: N = 32, saline: N = 30). EPO improved picture recall and increased encoding-related activity in dorsolateral prefrontal cortex (dlPFC) and temporo-parietal regions, but not in hippocampus. Recall correlated with activity in the identified dlPFC and temporo-parietal regions at baseline, and change in recall correlated with activity change in these regions from baseline to follow-up across the entire cohort. The effects of EPO were not correlated with change in mood, red blood cells, blood pressure, or medication. CONCLUSION: The findings highlight enhanced encoding-related dlPFC and temporo-parietal activity as key neuronal underpinnings of EPO-associated memory improvement.

Daily electronic self-monitoring in bipolar disorder using smartphones - the MONARCA I trial: a randomized, placebo-controlled, single-blind, parallel group trial.

BACKGROUND: The number of studies on electronic self-monitoring in affective disorder and other psychiatric disorders is increasing and indicates high patient acceptance and adherence. Nevertheless, the effect of electronic self-monitoring in patients with bipolar disorder has never been investigated in a randomized controlled trial (RCT). The objective of this trial was to investigate in a RCT whether the use of daily electronic self-monitoring using smartphones reduces depressive and manic symptoms in patients with bipolar disorder. METHOD: A total of 78 patients with bipolar disorder according to ICD-10 criteria, aged 18-60 years, and with 17-item Hamilton Depression Rating Scale (HAMD-17) and Young Mania Rating Scale (YMRS) scores ≤17 were randomized to the use of a smartphone for daily self-monitoring including a clinical feedback loop (the intervention group) or to the use of a smartphone for normal communicative purposes (the control group) for 6 months. The primary outcomes were differences in depressive and manic symptoms measured using HAMD-17 and YMRS, respectively, between the intervention and control groups. RESULTS: Intention-to-treat analyses using linear mixed models showed no significant effects of daily self-monitoring using smartphones on depressive as well as manic symptoms. There was a tendency towards more sustained depressive symptoms in the intervention group (B = 2.02, 95% confidence interval -0.13 to 4.17, p = 0.066). Sub-group analysis among patients without mixed symptoms and patients with presence of depressive and manic symptoms showed significantly more depressive symptoms and fewer manic symptoms during the trial period in the intervention group. CONCLUSIONS: These results highlight that electronic self-monitoring, although intuitive and appealing, needs critical consideration and further clarification before it is implemented as a clinical tool.

Different neural and cognitive response to emotional faces in healthy monozygotic twins at risk of depression.

BACKGROUND: Negative cognitive bias and aberrant neural processing of emotional faces are trait-marks of depression. Yet it is unclear whether these changes constitute an endophenotype for depression and are also present in healthy individuals with hereditary risk for depression. METHOD: Thirty healthy, never-depressed monozygotic (MZ) twins with a co-twin history of depression (high risk group: n = 13) or without co-twin history of depression (low-risk group: n = 17) were enrolled in a functional magnetic resonance imaging (fMRI) study. During fMRI, participants viewed fearful and happy faces while performing a gender discrimination task. After the scan, they were given a faces dot-probe task, a facial expression recognition task and questionnaires assessing mood, personality traits and coping strategies. RESULTS: High-risk twins showed increased neural response to happy and fearful faces in dorsal anterior cingulate cortex (ACC), dorsomedial prefrontal cortex (dmPFC), pre-supplementary motor area and occipito-parietal regions compared to low-risk twins. They also displayed stronger negative coupling between amygdala and pregenual ACC, dmPFC and temporo-parietal regions during emotional face processing. These task-related changes in neural responses in high-risk twins were accompanied by impaired gender discrimination performance during face processing. They also displayed increased attention vigilance for fearful faces and were slower at recognizing facial expressions relative to low-risk controls. These effects occurred in the absence of differences between groups in mood, subjective state or coping. CONCLUSIONS: Different neural response and functional connectivity within fronto-limbic and occipito-parietal regions during emotional face processing and enhanced fear vigilance may be key endophenotypes for depression.