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Depression: HELP
Articles by Kamilla Woznica Miskowiak
Based on 30 articles published since 2008
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Between 2008 and 2019, K. W. Miskowiak wrote the following 30 articles about Depression.
 
+ Citations + Abstracts
Pages: 1 · 2
1 Review Systematic review of randomized controlled trials of candidate treatments for cognitive impairment in depression and methodological challenges in the field. 2016

Miskowiak, K W / Ott, C V / Petersen, J Z / Kessing, L V. ·Copenhagen Psychiatric Centre, Copenhagen University Hospital, Rigshospitalet, Denmark. Electronic address: kamilla@miskowiak.dk. · Copenhagen Psychiatric Centre, Copenhagen University Hospital, Rigshospitalet, Denmark. Electronic address: caroline.vintergaard.ott@regionh.dk. · Copenhagen Psychiatric Centre, Copenhagen University Hospital, Rigshospitalet, Denmark. Electronic address: jeff.zarp.petersen@regionh.dk. · Copenhagen Psychiatric Centre, Copenhagen University Hospital, Rigshospitalet, Denmark. Electronic address: lars.vedel.kessing@regionh.dk. ·Eur Neuropsychopharmacol · Pubmed #27745932.

ABSTRACT: Cognitive impairment is a core feature of Major Depressive Disorder (MDD) but treatments targeting cognition are lacking. Numerous pre-clinical and clinical studies have investigated potential cognition treatments, but overall the evidence is conflicting. We conducted a systematic search following the PRISMA guidelines on PubMed and PsychInfo to evaluate the extant evidence and methodological challenges in randomized controlled trials (RCTs) of biological, psychological and behavioural candidate treatments targeting cognition in MDD. Inclusion criteria were RCTs with a placebo control assessing potential pro-cognitive effects of candidate treatments in MDD. Two independent authors reviewed the studies and assessed their risk of bias with the Cochrane Collaboration׳s Risk of Bias tool. Twenty-eight eligible studies (24 biological and four psychological or behavioural studies) were identified. Cognition was the primary treatment target in ten (36%) trials and an additional treatment outcome together with mood symptoms in 18 (64%) trials. The risk of bias was high or unclear in 93% of trials due to potential selective outcome reporting or 'pseudospecificity' (unspecific cognitive improvement due to reduced depression severity), and/or insufficient details on how the allocation sequence was generated or how blinding was maintained. Several promising treatments were identified, including vortioxetine, erythropoietin, transcranial direct current stimulation and cognitive remediation. However, several common methodological challenges may impede advances in the field. In particular, future trials should select one cognitive composite score as primary outcome, screen for cognitive impairment before inclusion of participants and address 'pseudospecificity' issues. Together, these strategies may improve the success of future cognition trials in MDD.

2 Review Bias in Peripheral Depression Biomarkers. 2016

Carvalho, André F / Köhler, Cristiano A / Brunoni, André R / Miskowiak, Kamilla W / Herrmann, Nathan / Lanctôt, Krista L / Hyphantis, Thomas N / Quevedo, João / Fernandes, Brisa S / Berk, Michael. ·Translational Psychiatry Research Group and Department of Clinical Medicine, Faculty of Medicine, Federal University of Cearx00E1;, Fortaleza, Brazil. ·Psychother Psychosom · Pubmed #26808272.

ABSTRACT: BACKGROUND: To aid in the differentiation of individuals with major depressive disorder (MDD) from healthy controls, numerous peripheral biomarkers have been proposed. To date, no comprehensive evaluation of the existence of bias favoring the publication of significant results or inflating effect sizes has been conducted. METHODS: Here, we performed a comprehensive review of meta-analyses of peripheral nongenetic biomarkers that could discriminate individuals with MDD from nondepressed controls. PubMed/MEDLINE, EMBASE, and PsycINFO databases were searched through April 10, 2015. RESULTS: From 15 references, we obtained 31 eligible meta-analyses evaluating biomarkers in MDD (21,201 cases and 78,363 controls). Twenty meta-analyses reported statistically significant effect size estimates. Heterogeneity was high (I2 ≥ 50%) in 29 meta-analyses. We plausibly assumed that the true effect size for a meta-analysis would equal the one of its largest study. A significant summary effect size estimate was observed for 20 biomarkers. We observed an excess of statistically significant studies in 21 meta-analyses. The summary effect size of the meta-analysis was higher than the effect of its largest study in 25 meta-analyses, while 11 meta-analyses had evidence of small-study effects. CONCLUSIONS: Our findings suggest that there is an excess of studies with statistically significant results in the literature of peripheral biomarkers for MDD. The selective publication of 'positive studies' and the selective reporting of outcomes are possible mechanisms. Effect size estimates of meta-analyses may be inflated in this literature.

3 Review Cognitive remission: a novel objective for the treatment of major depression? 2016

Bortolato, Beatrice / Miskowiak, Kamilla W / Köhler, Cristiano A / Maes, Michael / Fernandes, Brisa S / Berk, Michael / Carvalho, André F. ·Department of Neurosciences, University of Padova, Padova, Italy. · Psychiatric Centre Copenhagen, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark. · Translational Psychiatry Research Group and Department of Clinical Medicine, Faculty Medicine, Federal University of Ceará, Rua Prof. Costa Mendes 1608, 4° andar, Fortaleza, CE, 60430-040, Brazil. · Deakin University, School of Medicine, IMPACT Strategic Research Centre, Geelong, Australia. · Department of Psychiatry, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand. · Laboratory of Calcium Binding Proteins in the Central Nervous System, Department of Biochemistry, Federal University of Rio Grande do Sul, UFRGS, Porto Alegre, Brazil. · Orygen, The National Centre of Excellence in Youth Mental Health, Department of Psychiatry and The Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, Australia. · Translational Psychiatry Research Group and Department of Clinical Medicine, Faculty Medicine, Federal University of Ceará, Rua Prof. Costa Mendes 1608, 4° andar, Fortaleza, CE, 60430-040, Brazil. andrefc7@terra.com.br. ·BMC Med · Pubmed #26801406.

ABSTRACT: BACKGROUND: Cognitive dysfunction in major depressive disorder (MDD) encompasses several domains, including but not limited to executive function, verbal memory, and attention. Furthermore, cognitive dysfunction is a frequent residual manifestation in depression and may persist during the remitted phase. Cognitive deficits may also impede functional recovery, including workforce performance, in patients with MDD. The overarching aims of this opinion article are to critically evaluate the effects of available antidepressants as well as novel therapeutic targets on neurocognitive dysfunction in MDD. DISCUSSION: Conventional antidepressant drugs mitigate cognitive dysfunction in some people with MDD. However, a significant proportion of MDD patients continue to experience significant cognitive impairment. Two multicenter randomized controlled trials (RCTs) reported that vortioxetine, a multimodal antidepressant, has significant precognitive effects in MDD unrelated to mood improvement. Lisdexamfetamine dimesylate was shown to alleviate executive dysfunction in an RCT of adults after full or partial remission of MDD. Preliminary evidence also indicates that erythropoietin may alleviate cognitive dysfunction in MDD. Several other novel agents may be repurposed as cognitive enhancers for MDD treatment, including minocycline, insulin, antidiabetic agents, angiotensin-converting enzyme inhibitors, S-adenosyl methionine, acetyl-L-carnitine, alpha lipoic acid, omega-3 fatty acids, melatonin, modafinil, galantamine, scopolamine, N-acetylcysteine, curcumin, statins, and coenzyme Q10. The management of cognitive dysfunction remains an unmet need in the treatment of MDD. However, it is hoped that the development of novel therapeutic targets will contribute to 'cognitive remission', which may aid functional recovery in MDD.

4 Review Erythropoietin: a candidate treatment for mood symptoms and memory dysfunction in depression. 2012

Miskowiak, Kamilla W / Vinberg, Maj / Harmer, Catherine J / Ehrenreich, Hannelore / Kessing, Lars V. ·Clinic for Affective Disorders, Psychiatric Centre Copenhagen, Copenhagen University Hospital, Rigshospitalet 6211, Blegdamsvej 9, 2100 Copenhagen, Denmark. kamilla@miskowiak.dk ·Psychopharmacology (Berl) · Pubmed #21947319.

ABSTRACT: OBJECTIVE: Current pharmacological treatments for depression have a significant treatment-onset-response delay, an insufficient efficacy for many patients and fail to reverse cognitive dysfunction. Erythropoietin (EPO) has neuroprotective and neurotrophic actions and improves cognitive function in animal models of acute and chronic neurodegenerative conditions and in patients with cognitive decline. METHODS: We systematically reviewed the published findings from animal and human studies exploring the potential of EPO to treat depression-related cognitive dysfunction and depression. RESULTS: We identified five animal studies (two in male rats, two in male mice and one in male rats and mice) and seven human proof-of-concept studies (five in healthy volunteers and two in depressed patients) that investigated the above. All of the reviewed animal studies but one and all human studies demonstrated beneficial effects of EPO on hippocampus-dependent memory and antidepressant-like effects. These effects appear to be mediated through direct neurobiological actions of EPO rather than upregulation of red cell mass. CONCLUSIONS: The reviewed studies demonstrate beneficial effects of EPO on hippocampus-dependent memory function and on depression-relevant behavior, thus highlighting EPO as a candidate agent for future management of cognitive dysfunction and mood symptoms in depression. Larger-scale clinical trials of EPO as a treatment for mood and neurocognitive symptoms in patients with mood disorder are therefore warranted.

5 Clinical Trial Effects of erythropoietin on memory-relevant neurocircuitry activity and recall in mood disorders. 2016

Miskowiak, K W / Macoveanu, J / Vinberg, M / Assentoft, E / Randers, L / Harmer, C J / Ehrenreich, H / Paulson, O B / Knudsen, G M / Siebner, H R / Kessing, L V. ·Psychiatric Centre Copenhagen, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark. · Danish Research Centre for Magnetic Resonance, Centre for Functional and Diagnostic Imaging and Research, Copenhagen University Hospital Hvidovre, Hvidovre, Denmark. · Center for Integrated Molecular Brain Imaging, Rigshospitalet, Copenhagen, Denmark. · Psychiatric Centre Copenhagen, Copenhagen University Hospital Bispebjerg, Copenhagen, Denmark. · Department of Psychiatry, University of Oxford, Oxford, UK. · Clinical Neuroscience, Max Planck Institute of Experimental Medicine, Göttingen, Germany. · Neurobiology Research Unit, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark. · Department of Neurology, Copenhagen University Hospital Bispebjerg, Copenhagen, Denmark. ·Acta Psychiatr Scand · Pubmed #27259062.

ABSTRACT: 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.

6 Clinical Trial Effects of Erythropoietin on Hippocampal Volume and Memory in Mood Disorders. 2015

Miskowiak, Kamilla W / Vinberg, Maj / Macoveanu, Julian / Ehrenreich, Hannelore / Køster, Nicolai / Inkster, Becky / Paulson, Olaf B / Kessing, Lars V / Skimminge, Arnold / Siebner, Hartwig R. ·Psychiatric Centre Copenhagen, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark. Electronic address: Kamilla@miskowiak.dk. · Psychiatric Centre Copenhagen, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark. · Danish Research Centre for Magnetic Resonance, Copenhagen University Hospital Hvidovre, Hvidovre. · Clinical Neuroscience, Max Planck Institute of Experimental Medicine, Göttingen, Germany. · Department of Psychiatry, School of Clinical Medicine, University of Cambridge, Cambridge, United Kingdom. · Neurobiological Research Unit, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark. · Danish Research Centre for Magnetic Resonance, Copenhagen University Hospital Hvidovre, Hvidovre; Department of Neurology, Copenhagen University Hospital Bispebjerg, Copenhagen, Denmark. ·Biol Psychiatry · Pubmed #25641635.

ABSTRACT: BACKGROUND: Persistent cognitive dysfunction in depression and bipolar disorder (BD) impedes patients' functional recovery. Erythropoietin (EPO) increases neuroplasticity and reduces cognitive difficulties in treatment-resistant depression (TRD) and remitted BD. This magnetic resonance imaging study assessed the neuroanatomical basis for these effects. METHODS: Patients with TRD who were moderately depressed or BD in partial remission were randomized to 8 weekly EPO (40,000 IU) or saline infusions in a double-blind, parallel-group design. Patients underwent magnetic resonance imaging, memory assessment with the Rey Auditory Verbal Learning Test, and mood ratings with the Beck Depression Inventory, Hamilton Depression Rating Scale, and Young Mania Rating Scale at baseline and week 14. Hippocampus segmentation and analysis of hippocampal volume, shape, and gray matter density were conducted with FMRIB Software Library tools. Memory change was analyzed with repeated-measures analysis of covariance adjusted for depression symptoms, diagnosis, age, and gender. RESULTS: Eighty-four patients were randomized; 1 patient withdrew and data collection was incomplete for 14 patients; data were thus analyzed for 69 patients (EPO: n = 35, saline: n = 34). Compared with saline, EPO was associated with mood-independent memory improvement and reversal of brain matter loss in the left hippocampal cornu ammonis 1 to cornu ammonis 3 and subiculum. Using the entire sample, memory improvement was associated with subfield hippocampal volume increase independent of mood change. CONCLUSIONS: EPO-associated memory improvement in TRD and BD may be mediated by reversal of brain matter loss in a subfield of the left hippocampus. EPO may provide a therapeutic option for patients with mood disorders who have impaired neuroplasticity and cognition.

7 Clinical Trial Recombinant human erythropoietin for treating treatment-resistant depression: a double-blind, randomized, placebo-controlled phase 2 trial. 2014

Miskowiak, Kamilla W / Vinberg, Maj / Christensen, Ellen M / Bukh, Jens D / Harmer, Catherine J / Ehrenreich, Hannelore / Kessing, Lars V. ·Psychiatric Centre Copenhagen, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark. · Department of Psychiatry, University of Oxford, Oxford, UK. · Clinical Neuroscience, Max Planck Institute of Experimental Medicine, Göttingen, Germany. ·Neuropsychopharmacology · Pubmed #24322509.

ABSTRACT: Pharmacological treatments for depression have insufficient efficacy in 30-40% of patients and fail to reverse cognitive deficits. Erythropoietin (EPO) has neurotrophic actions and aids neurocognitive function. The aim of this exploratory study was to determine whether recombinant human EPO improves mood and memory in treatment-resistant depression. Forty treatment-resistant depressed unipolar patients with Hamilton Depression Rating Scale-17 (HDRS-17) score ≥ 17 were randomized to eight weekly EPO (Eprex; 40,000 IU) or saline infusions in a double-blind, placebo-controlled, parallel-group design. Patients were assessed at baseline and at weeks 5, 9, and 14. Primary outcome was reduction in HDRS-17 score. Global assessment of function (GAF) was reported in addition. Secondary outcome was remission rate, and tertiary outcomes were changes in Rey Auditory Verbal Learning Test (RAVLT), Beck Depression Inventory-21 (BDI-21), and World Health Organization Quality of life-BREF (WHOQOL-BREF). Exploratory outcomes were depression and cognition composite scores. HDRS-17, GAF, and remission rates showed no effects of EPO over saline at week 9 (P-value ≥ 0.09). However, EPO improved BDI (P=0.02) and WHOQOL-BREF (P=0.01), and this was maintained at follow-up week 14 (P-values ≤ 0.04). EPO enhanced verbal recall (P=0.02) and recognition (P=0.03), which was sustained at follow-up (P-values ≤ 0.04). Exploratory analysis in patients fulfilling depression severity criteria at trial start revealed ameliorated HDRS-17 in EPO (N=14) vs saline groups (N=17), which was sustained at week 14 (P-values ≤ 0.05). Exploratory analysis in the complete cohort showed that EPO reduced depression composite at weeks 9 and 14 (P-values=0.02). The findings of this exploratory study highlight EPO as an interesting compound for treatment-resistant depression, which deserves further investigation.

8 Article Clinical characteristics associated with the discrepancy between subjective and objective cognitive impairment in depression. 2019

Petersen, J Z / Porter, R J / Miskowiak, K W. ·Psychiatric Centre Copenhagen, Copenhagen University Hospital, Rigshospitalet Dep. 6233, Blegdamsvej 9, DK-2100, Copenhagen, Denmark; Department of Psychology, University of Copenhagen, Øster Farimagsgade 2A, DK-1353, Copenhagen, Denmark. Electronic address: jeff.zarp.petersen@regionh.dk. · Department of Psychological Medicine, University of Otago, Christchurch, New Zealand. Electronic address: richard.porter@otago.ac.nz. · Psychiatric Centre Copenhagen, Copenhagen University Hospital, Rigshospitalet Dep. 6233, Blegdamsvej 9, DK-2100, Copenhagen, Denmark; Department of Psychology, University of Copenhagen, Øster Farimagsgade 2A, DK-1353, Copenhagen, Denmark. Electronic address: kamilla.miskowiak@regionh.dk. ·J Affect Disord · Pubmed #30623822.

ABSTRACT: BACKGROUND: Patients with unipolar disorder (UD) commonly experience cognitive dysfunction during symptomatic and remitted phases. However, it is not necessarily the patients with the greatest subjective complaints, who display the largest objectively-measured deficits on neuropsychological tests. OBJECTIVE: This report investigated the demographic and clinical factors associated with the discrepancy between subjective and objective measures of cognition in two separate depressed patient populations in Denmark and New Zealand, respectively, using a new methodology. METHODS: Data from 137 depressed patients and 103 healthy controls including neuropsychological test scores, self-reported cognitive difficulties, and ratings of mood were pooled from two studies conducted in Copenhagen, Denmark, and Christchurch, New Zealand, respectively. Cognitive discrepancy scores were calculated using a novel methodology, with positive values indicating disproportionately more subjective than objective difficulties (i.e., "sensitivity") and negative values indicating more objective than subjective impairments (i.e., "stoicism"). RESULTS: In the Danish partially remitted patient sample, greater 'sensitivity' was associated with more subsyndromal depression severity (standardized Beta (std. β )= 0.4, p < 0.01)), illness duration (std. β = 0.4, p < 0.01), and younger age (std. β = 0.6, p < 0.001). This association was replicated in the New Zealand sample of more symptomatic patients (p-values ≤ 0.05). LIMITATIONS: The cross-sectional design hampered causal inferences. We had obtained different measures of objective and subjective cognition from the two studies. CONCLUSIONS: Patients with more depressive symptoms and younger age overreported cognitive impairments across all illness states. The use of an objective cognition screener thus seems particularly relevant for these patients to assess whether subjective complaints are accompanied by measurable cognitive deficits.

9 Article Effects of recombinant human erythropoietin on cognition and neural activity in remitted patients with mood disorders and first-degree relatives of patients with psychiatric disorders: a study protocol for a randomized controlled trial. 2018

Petersen, Jeff Zarp / Schmidt, Lejla Sjanic / Vinberg, Maj / Jørgensen, Martin Balslev / Hageman, Ida / Ehrenreich, Hannelore / Knudsen, Gitte Moos / Kessing, Lars Vedel / Miskowiak, Kamilla Woznica. ·Neurocognition and Emotion in Affective Disorder (NEAD) Group, Copenhagen Affective Disorder Research Centre (CADIC), Psychiatric Centre Copenhagen, Copenhagen University Hospital, Blegdamsvej 9, DK-2100, Copenhagen, Denmark. · Department of Psychology, University of Copenhagen, Øster Farimagsgade 2A, DK-1353, Copenhagen, Denmark. · Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. · Clinical Neuroscience, Max Planck Institute of Experimental Medicine, Göttingen, Germany. · DFG Center for Nanoscale Microscopy & Molecular Physiology of the Brain (CNMPB), Göttingen, Germany. · Neurobiology Research Unit and Center for Integrated Molecular Imaging, Rigshospitalet, Copenhagen, Denmark. · Neurocognition and Emotion in Affective Disorder (NEAD) Group, Copenhagen Affective Disorder Research Centre (CADIC), Psychiatric Centre Copenhagen, Copenhagen University Hospital, Blegdamsvej 9, DK-2100, Copenhagen, Denmark. kamilla.woznica.miskowiak@regionh.dk. · Department of Psychology, University of Copenhagen, Øster Farimagsgade 2A, DK-1353, Copenhagen, Denmark. kamilla.woznica.miskowiak@regionh.dk. ·Trials · Pubmed #30400939.

ABSTRACT: BACKGROUND: Bipolar disorder (BD) and unipolar disorder (UD) are associated with cognitive deficits and abnormal neural activity in a "cognitive control network." There is an increased prevalence of cognitive dysfunction in psychiatric patients' first-degree relatives, which constitutes a risk factor for psychiatric illness onset. However, there is no treatment with enduring pro-cognitive efficacy. We found preliminary evidence for beneficial effects of eight weekly doses of recombinant human erythropoietin (EPO) on cognition in BD in a recent randomized controlled trial (RCT). The present RCT consists of two sub-studies that extend our previous work by investigating important novel aspects: (1) the effects of 12 weekly doses of EPO on cognition in first-degree relatives of patients with BD, UD, or schizophrenia; and (2) the effects of extending the treatment schedule from 8 to 12 weeks in remitted patients with BD or UD; and (3) assessment of early treatment-associated neural activity changes that may predict cognitive improvement. METHODS: The trial comprises two parallel sub-studies with randomized, controlled, double-blinded, parallel group designs. First-degree relatives (sub-study 1; n = 52) and partially or fully remitted patients with BD or UD (sub-study 2; n = 52) with objectively verified cognitive dysfunction are randomized to receive weekly high-dose EPO (40,000 IU/mL) or placebo (saline) infusions for 12 weeks. Assessments of cognition and mood are conducted at baseline, after two weeks of treatment, after treatment completion, and at six-month follow-up. Functional magnetic resonance imaging (fMRI) is conducted at baseline and after two weeks of treatment. Psychosocial function is assessed at baseline, after treatment completion and six-month follow-up. The primary outcome is change in a cognitive composite score of attention, verbal memory, and executive functions. Statistical power of ≥ 80% is reached to detect a clinically relevant between-group difference by including 52 first-degree relatives and 52 patients with BD or UD, respectively. Behavioral data are analyzed with an intention-to-treat approach using mixed models. fMRI data are analyzed with the FMRIB Software Library. DISCUSSION: If this trial reveals pro-cognitive effects of EPO, this may influence future treatment of mood disorders and/or preventive strategies in at-risk populations. The fMRI analyses may unravel key neurobiological targets for pro-cognitive treatment. TRIAL REGISTRATION: ClinicalTrials.gov , NCT03315897. Registered on 20 October 2017.

10 Article Effect of electroconvulsive therapy on neural response to affective pictures: A randomized, sham-controlled fMRI study. 2018

Miskowiak, K W / Macoveanu, J / Jørgensen, M B / Ott, C V / Støttrup, M M / Jensen, H M / Jørgensen, A / Harmer, C J / Paulson, O B / Siebner, H R / Kessing, L V. ·Psychiatric Centre Copenhagen, Copenhagen University Hospital, Rigshospitalet Dep. 6233, Blegdamsvej 9, DK-2100 Copenhagen, Denmark; Department of Psychology, University of Copenhagen, Øster Farimagsgade 2A, Copenhagen, Denmark. Electronic address: kamilla@miskowiak.dk. · Psychiatric Centre Copenhagen, Copenhagen University Hospital, Rigshospitalet Dep. 6233, Blegdamsvej 9, DK-2100 Copenhagen, Denmark; Danish Research Centre for Magnetic Resonance, Centre for Functional and Diagnostic Imaging and Research, Copenhagen University Hospital Hvidovre, Kettegård Alle 30, Hvidovre, Denmark; Center for Integrated Molecular Brain Imaging, Rigshospitalet, Blegdamsvej 9, Copenhagen, Denmark. · Psychiatric Centre Copenhagen, Copenhagen University Hospital, Rigshospitalet Dep. 6233, Blegdamsvej 9, DK-2100 Copenhagen, Denmark. · Psychiatric Centre Copenhagen, Digevej 110, Amager, Denmark. · Department of Psychiatry, University of Oxford, Warneford Hospital, Oxford, UK. · Danish Research Centre for Magnetic Resonance, Centre for Functional and Diagnostic Imaging and Research, Copenhagen University Hospital Hvidovre, Kettegård Alle 30, Hvidovre, Denmark; Center for Integrated Molecular Brain Imaging, Rigshospitalet, Blegdamsvej 9, Copenhagen, Denmark; Neurobiology Research Unit, Copenhagen University Hospital, Rigshospitalet, Blegdamsvej 9, Copenhagen, Denmark. · Danish Research Centre for Magnetic Resonance, Centre for Functional and Diagnostic Imaging and Research, Copenhagen University Hospital Hvidovre, Kettegård Alle 30, Hvidovre, Denmark; Center for Integrated Molecular Brain Imaging, Rigshospitalet, Blegdamsvej 9, Copenhagen, Denmark; Department of Neurology, Copenhagen University Hospital Bispebjerg, Bispebjerg Bakke 23, Denmark. ·Eur Neuropsychopharmacol · Pubmed #29891215.

ABSTRACT: Electroconvulsive therapy (ECT) is the most effective treatment for severe depression but its neurocognitive mechanisms are unclear. This randomized, sham-controlled functional magnetic resonance imaging (fMRI) study explored the effects of a single ECT on neural response to affective pictures. Twenty-seven patients with major depressive disorder were randomized to a single active ECT (N = 15) or sham (N = 12) session in a double-blind, parallel-group design. On the following day, patients underwent fMRI during which they viewed pleasant, unpleasant and neutral pictures and performed a free recall test after the scan. Mood symptoms were assessed before ECT/sham and at the time of fMRI. Subsequently, all patients continued active ECT as usual. Mood symptoms were reassessed after six active ECT sessions. A single ECT vs. sham session reduced neural response to unpleasant vs. pleasant pictures in the medial prefrontal cortex, a region showing greater response in the more depressed patients. This effect occurred in the absence of between-group differences in picture recall, mood symptoms or concomitant medication. In conclusion, modulation of medial prefrontal hyper-activity during encoding of negative affective information may be a common mechanism of distinct biological depression treatments.

11 Article Effects of erythropoietin on body composition and fat-glucose metabolism in patients with affective disorders. 2018

Vinberg, Maj / Højman, Pernille / Pedersen, Bente Klarlund / Kessing, Lars Vedel / Miskowiak, Kamilla W. ·1Psychiatric Centre Copenhagen,Rigshospitalet,University Hospital of Copenhagen Blegdamsvej,Copenhagen,Denmark. · 2The Centre of Inflammation and Metabolism (CIM) and the Centre for Physical Activity Research (CFAS),Rigshospitalet,University Hospital of Copenhagen,Copenhagen,Denmark. ·Acta Neuropsychiatr · Pubmed #29880069.

ABSTRACT: BACKGROUND: Erythropoietin (EPO) has been suggested to improve metabolism and also cognition, but human studies are scarce. This randomised controlled trial aimed to investigate whether EPO treatment influences body composition and fat and glycated haemoglobin (HbA1c) and fasting glucose, and whether these changes would be associated with previous observed cognitive benefits of EPO. METHOD: In total, 84 non-obese patients with treatment-resistant unipolar depression or bipolar disorder in remission were randomised to 8 weekly EPO (40,000 IU) or saline (NaCl 0.9%) infusions in a double-blind, parallel-group design. Patients underwent dual X-ray absorptiometry scans at baseline and week 14 (6 weeks after treatment completion). Cognitive measures were assessed and fasting levels of cholesterol, lipoprotein fractions, triacylglycerides, glucose and HbA1c were obtained at baseline, week 9 and follow-up week 14. RESULTS: In total, 79 patients had complete pre- and post-treatment data (EPO: N=40, saline: N=39). EPO had no cumulative effect on body composition and markers of fat metabolism. The EPO-treated group exhibited significantly lower HbA1c levels after 8 weeks treatment [F(1, 80)=8.51, p=0.005], however, 6 weeks after treatment termination a significantly higher fasting glucose levels [F(1, 79)=5.85, p=0.02] and HbA1c levels [F(1, 79)=5.85, p=0.02] were seen. The latter increase in HbA1c was further significantly correlated with a better cognitive outcome on verbal memory (r=0.25, p=0.03). CONCLUSION: Repeated EPO infusions had no cumulative effect on body composition in this cohort of patients with affective disorders, however, EPO modulated HbA1c and fasting glucose and this was associated with patients' improvement of verbal memory.

12 Article Imaging genetics paradigms in depression research: Systematic review and meta-analysis. 2018

Pereira, Lícia P / Köhler, Cristiano A / Stubbs, Brendon / Miskowiak, Kamilla W / Morris, Gerwyn / de Freitas, Bárbara P / Thompson, Trevor / Fernandes, Brisa S / Brunoni, André R / Maes, Michael / Pizzagalli, Diego A / Carvalho, André F. ·Department of Clinical Medicine, Translational Psychiatry Research Group, Faculty of Medicine, Federal University of Ceará, Fortaleza, CE, Brazil; Centre for Addiction & Mental Health (CAMH), Toronto, ON, Canada. · Department of Clinical Medicine, Translational Psychiatry Research Group, Faculty of Medicine, Federal University of Ceará, Fortaleza, CE, Brazil. · Institute for Clinical Research and Education in Medicine (IREM), Padova, Italy; South London and Maudsley NHS Foundation Trust, Denmark Hill, London SE5 8AZ, United Kingdom; Psychology and Neuroscience (IoPPN), King's College London, Institute of Psychiatry,De Crespigny Park, London SE5 8 AF, United Kingdom; Faculty of Health, Social Care and Education, Anglia Ruskin University, Chelmsford CM1 1SQ, United Kingdom. · Copenhagen Affective Disorders Research Centre, Copenhagen Psychiatric Centre, Copenhagen University Hospital, Rigshospitalet, Denmark. · IMPACT Strategic Research Centre, School of Medicine, Barwon Health, Deakin University, Geelong, Australia. · Faculty of Education and Health, University of Greenwich, London, United Kingdom. · IMPACT Strategic Research Centre, School of Medicine, Barwon Health, Deakin University, Geelong, Australia; Department of Biochemistry, Laboratory of Calcium Binding Proteins in the Central Nervous System, Federal University of Rio Grande do Sul, Porto Alegre, Brazil. · Department and Institute of Psychiatry, Service of Interdisciplinary Neuromodulation, Laboratory of Neurosciences (LIM-27), Interdisciplinary Center for Applied Neuromodulation University Hospital, University of São Paulo, São Paulo, Brazil. · IMPACT Strategic Research Centre, School of Medicine, Barwon Health, Deakin University, Geelong, Australia; Department of Psychiatry, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand; Department of Psychiatry, Medical University of Plovdiv, Plovdiv, Bulgaria. · Department of Psychiatry, Harvard Medical School, Belmont, MA 02478, USA; McLean Hospital, Belmont, MA 02478, USA. · McLean Hospital, Belmont, MA 02478, USA; Department of Psychiatry, Faculty of Medicine, University of Toronto, Toronto, ON, Canada. Electronic address: andre.carvalho@camh.ca. ·Prog Neuropsychopharmacol Biol Psychiatry · Pubmed #29778546.

ABSTRACT: Imaging genetics studies involving participants with major depressive disorder (MDD) have expanded. Nevertheless, findings have been inconsistent. Thus, we conducted a systematic review and meta-analysis of imaging genetics studies that enrolled MDD participants across major databases through June 30th, 2017. Sixty-five studies met eligibility criteria (N = 4034 MDD participants and 3293 controls), and there was substantial between-study variability in the methodological quality of included studies. However, few replicated findings emerged from this literature with only 22 studies providing data for meta-analyses (882 participants with MDD and 616 controls). Total hippocampal volumes did not significantly vary in MDD participants or controls carrying either the BDNF Val66Met 'Met' (386 participants with MDD and 376 controls) or the 5-HTTLPR short 'S' (310 participants with MDD and 230 controls) risk alleles compared to non-carriers. Heterogeneity across studies was explored through meta-regression and subgroup analyses. Gender distribution, the use of medications, segmentation methods used to measure the hippocampus, and age emerged as potential sources of heterogeneity across studies that assessed the association of 5-HTTLPR short 'S' alleles and hippocampal volumes. Our data also suggest that the methodological quality of included studies, publication year, and the inclusion of brain volume as a covariate contributed to the heterogeneity of studies that assessed the association of the BDNF Val66Met 'Met' risk allele and hippocampal volumes. In exploratory voxel-wise meta-analyses, MDD participants carrying the 5-HTTLPR short 'S' allele had white matter microstructural abnormalities predominantly in the corpus callosum, while carriers of the BDNF Val66Met 'Met' allele had larger gray matter volumes and hyperactivation of the right middle frontal gyrus compared to non-carriers. In conclusion, few replicated findings emerged from imaging genetics studies that included participants with MDD. Nevertheless, we explored and identified specific sources of heterogeneity across studies, which could provide insights to enhance the reproducibility of this emerging field.

13 Article Neural Response After a Single ECT Session During Retrieval of Emotional Self-Referent Words in Depression: A Randomized, Sham-Controlled fMRI Study. 2018

Miskowiak, Kamilla W / Macoveanu, Julian / Jørgensen, Martin B / Støttrup, Mette M / Ott, Caroline V / Jensen, Hans M / Jørgensen, Anders / Harmer, J / Paulson, Olaf B / Kessing, Lars V / Siebner, Hartwig R. ·Psychiatric Centre Copenhagen, Copenhagen University Hospital, Copenhagen, Denmark. · Department of Psychology, University of Copenhagen, Copenhagen, Denmark. · Danish Research Centre for Magnetic Resonance, Centre for Functional and Diagnostic Imaging and Research, Copenhagen University Hospital, Hvidovre, Denmark. · Center for Integrated Molecular Brain Imaging, Rigshospitalet, Copenhagen. · Psychiatric Centre Copenhagen, Copenhagen, Denmark. · Department of Psychiatry, University of Oxford, Oxford, United Kingdom. · Neurobiology Research Unit, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark. · Department of Neurology, Copenhagen University Hospital, Bispebjerg, Denmark. ·Int J Neuropsychopharmacol · Pubmed #29718333.

ABSTRACT: Background: Negative neurocognitive bias is a core feature of depression that is reversed by antidepressant drug treatment. However, it is unclear whether modulation of neurocognitive bias is a common mechanism of distinct biological treatments. This randomized controlled functional magnetic resonance imaging study explored the effects of a single electroconvulsive therapy session on self-referent emotional processing. Methods: Twenty-nine patients with treatment-resistant major depressive disorder were randomized to one active or sham electroconvulsive therapy session at the beginning of their electroconvulsive therapy course in a double-blind, between-groups design. The following day, patients were given a self-referential emotional word categorization test and a free recall test. This was followed by an incidental word recognition task during whole-brain functional magnetic resonance imaging at 3T. Mood was assessed at baseline, on the functional magnetic resonance imaging day, and after 6 electroconvulsive therapy sessions. Data were complete and analyzed for 25 patients (electroconvulsive therapy: n = 14, sham: n = 11). The functional magnetic resonance imaging data were analyzed using the FMRIB Software Library randomize algorithm, and the Threshold-Free Cluster Enhancement method was used to identify significant clusters (corrected at P < .05). Results: A single electroconvulsive therapy session had no effect on hippocampal activity during retrieval of emotional words. However, electroconvulsive therapy reduced the retrieval-specific neural response for positive words in the left frontopolar cortex. This effect occurred in the absence of differences between groups in behavioral performance or mood symptoms. Conclusions: The observed effect of electroconvulsive therapy on prefrontal response may reflect early facilitation of memory for positive self-referent information, which could contribute to improvements in depressive symptoms including feelings of self-worth with repeated treatments.

14 Article Erythropoietin as an add-on treatment for cognitive side effects of electroconvulsive therapy: a study protocol for a randomized controlled trial. 2018

Schmidt, Lejla Sjanic / Petersen, Jeff Zarp / Vinberg, Maj / Hageman, Ida / Olsen, Niels Vidiendal / Kessing, Lars Vedel / Jørgensen, Martin Balslev / Miskowiak, Kamilla Woznica. ·Copenhagen Affective Disorder Research Center (CADIC), Psychiatric Center Copenhagen, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark. · Neurocognition and Emotion in Affective Disorder (NEAD) Group, Copenhagen Affective Disorder Research Center, Psychiatric Center Copenhagen, Copenhagen University Hospital, Rigshospitalet, Blegdamsvej 9, DK-2100, Copenhagen, Denmark. · Department of Psychology, University of Copenhagen, Øster Farimagsgade 2A, DK-1353, Copenhagen, Denmark. · Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. · Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark. · Department of Neuroanaesthesia, The Neuroscience Centre, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark. · Copenhagen Affective Disorder Research Center (CADIC), Psychiatric Center Copenhagen, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark. kamilla.miskowiak@regionh.dk. · Department of Psychology, University of Copenhagen, Øster Farimagsgade 2A, DK-1353, Copenhagen, Denmark. kamilla.miskowiak@regionh.dk. · Neurocognition and Emotion in Affective Disorder (NEAD) Group, Copenhagen Affective Disorder Research Center, Psychiatric Center Copenhagen, Copenhagen University Hospital, Rigshospitalet, Blegdamsvej 9, DK-2100, Copenhagen, Denmark. kamilla.miskowiak@regionh.dk. ·Trials · Pubmed #29673379.

ABSTRACT: BACKGROUND: Electroconvulsive therapy (ECT) is the most effective treatment for severe depression, but its use is impeded by its cognitive side effects. Novel treatments that can counteract these side effects may therefore improve current treatment strategies for depression. The present randomized trial investigates (1) whether short-term add-on treatment with erythropoietin (EPO) can reduce the cognitive side -effects of ECT and (2) whether such effects are long-lasting. Further, structural and functional magnetic resonance imaging (MRI) will be used to explore the neural underpinnings of such beneficial effects of EPO. Finally, the trial examines whether potential protective effects of EPO on cognition are accompanied by changes in markers of oxidative stress, inflammation, and neuroplasticity. METHODS/DESIGN: The trial has a double-blind, randomized, placebo-controlled, parallel group design. Patients with unipolar or bipolar disorder with current moderate to severe depression referred to ECT (N = 52) are randomized to receive four high-dose infusions of EPO (40,000 IU/ml) or placebo (saline). The first EPO/saline infusion is administered within 24 h before the first ECT. The following three infusions are administered at weekly intervals immediately after ECT sessions 1, 4, and 7. Cognition assessments are conducted at baseline, after the final EPO/saline infusion (3 days after eight ECT sessions), and at a 3 months follow-up after ECT treatment completion. The neuronal substrates for potential cognitive benefits of EPO are investigated with structural and functional MRI after the final EPO/saline infusion. The primary outcome is change from baseline to after EPO treatment (3 days after eight ECT sessions) in a cognitive composite score spanning attention, psychomotor speed, and executive functions. With a sample size of N = 52 (n = 26 per group), we have ≥ 80% power to detect a clinically relevant between-group difference in the primary outcome measure at an alpha level of 5% (two-sided test). Behavioral, mood, and blood-biomarker data will be analyzed using repeated measures analysis of covariance. Functional MRI data will be preprocessed and analyzed using the FMRIB Software Library. DISCUSSION: If EPO is found to reduce the cognitive side effects of ECT, this could have important implications for future treatment strategies for depression and for the scientific understanding of the neurobiological etiology of cognitive dysfunction in patients treated with ECT. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03339596 . Registered on 10 November 2017.

15 Article Increased sensitivity to positive social stimuli in monozygotic twins at risk of bipolar vs. unipolar disorder. 2018

Kærsgaard, S / Meluken, I / Kessing, L V / Vinberg, M / Miskowiak, K W. ·Copenhagen Affective Disorder Research Centre (CADIC); Psychiatric Centre Copenhagen, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark; Department of Psychology, University of Copenhagen, Denmark. Electronic address: signe.kaersgaard.mortensen@regionh.dk. · Copenhagen Affective Disorder Research Centre (CADIC); Psychiatric Centre Copenhagen, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark; Institute of Clinical Medicine, University of Copenhagen, Denmark. Electronic address: iselin.meluken.01@regionh.dk. · Copenhagen Affective Disorder Research Centre (CADIC); Psychiatric Centre Copenhagen, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark; Institute of Clinical Medicine, University of Copenhagen, Denmark. Electronic address: Lars.Vedel.Kessing@regionh.dk. · Copenhagen Affective Disorder Research Centre (CADIC); Psychiatric Centre Copenhagen, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark; Institute of Clinical Medicine, University of Copenhagen, Denmark. Electronic address: maj.vinberg@regionh.dk. · Copenhagen Affective Disorder Research Centre (CADIC); Psychiatric Centre Copenhagen, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark; Department of Psychology, University of Copenhagen, Denmark. Electronic address: kamilla.miskowiak@regionh.dk. ·J Affect Disord · Pubmed #29499503.

ABSTRACT: BACKGROUND: Abnormalities in affective cognition are putative endophenotypes for bipolar and unipolar disorders but it is unclear whether some abnormalities are disorder-specific. We therefore investigated affective cognition in monozygotic twins at familial risk of bipolar disorder relative to those at risk of unipolar disorder and to low-risk twins. METHODS: Seventy monozygotic twins with a co-twin history of bipolar disorder (n = 11), of unipolar disorder (n = 38) or without co-twin history of affective disorder (n = 21) were included. Variables of interest were recognition of and vigilance to emotional faces, emotional reactivity and -regulation in social scenarios and non-affective cognition. RESULTS: Twins at familial risk of bipolar disorder showed increased recognition of low to moderate intensity of happy facial expressions relative to both unipolar disorder high-risk twins and low-risk twins. Bipolar disorder high-risk twins also displayed supraliminal attentional avoidance of happy faces compared with unipolar disorder high-risk twins and greater emotional reactivity in positive and neutral social scenarios and less reactivity in negative social scenarios than low-risk twins. In contrast with our hypothesis, there was no negative bias in unipolar disorder high-risk twins. There were no differences between the groups in demographic characteristics or non-affective cognition. LIMITATIONS: The modest sample size limited the statistical power of the study. CONCLUSIONS: Increased sensitivity and reactivity to positive social stimuli may be a neurocognitive endophenotype that is specific for bipolar disorder. If replicated in larger samples, this 'positive endophenotype' could potentially aid future diagnostic differentiation between unipolar and bipolar disorder.

16 Article Is negative self-referent bias an endophenotype for depression? An fMRI study of emotional self-referent words in twins at high vs. low risk of depression. 2018

Miskowiak, K W / Larsen, J E / Harmer, C J / Siebner, H R / Kessing, L V / Macoveanu, J / Vinberg, M. ·Mental Health Services - Capital Region of Denmark, Psychiatric Centre Copenhagen, Copenhagen University Hospital, Rigshospitalet, Denmark; Department of Psychology, University of Copenhagen, Denmark. Electronic address: Kamilla@miskowiak.dk. · Mental Health Services - Capital Region of Denmark, Psychiatric Centre Copenhagen, Copenhagen University Hospital, Rigshospitalet, Denmark. Electronic address: julia-evelyn@live.dk. · Department of Psychiatry, University of Oxford, United Kingdom. Electronic address: Catherine.harmer@psych.ox.ac.uk. · Danish Research Centre for Magnetic Resonance, Centre for Functional and Diagnostic Imaging and Research, Copenhagen University Hospital Hvidovre, Hvidovre, Denmark; Department of Neurology, Copenhagen University Hospital Bispebjerg, Denmark. Electronic address: hartwig.siebner@drcmr.dk. · Mental Health Services - Capital Region of Denmark, Psychiatric Centre Copenhagen, Copenhagen University Hospital, Rigshospitalet, Denmark. Electronic address: lars.vedel.kessing@regionh.dk. · Mental Health Services - Capital Region of Denmark, Psychiatric Centre Copenhagen, Copenhagen University Hospital, Rigshospitalet, Denmark. Electronic address: Julian.macoveanu@regionh.dk. · Mental Health Services - Capital Region of Denmark, Psychiatric Centre Copenhagen, Copenhagen University Hospital, Rigshospitalet, Denmark. Electronic address: maj.vinberg@regionh.dk. ·J Affect Disord · Pubmed #29020651.

ABSTRACT: BACKGROUND: Negative cognitive bias and aberrant neural processing of self-referent emotional words seem to be trait-marks of depression. However, it is unclear whether these neurocognitive changes are present in unaffected first-degree relatives and constitute an illness endophenotype. METHODS: Fifty-three healthy, never-depressed monozygotic or dizygotic twins with a co-twin history of depression (high-risk group: n = 26) or no first-degree family history of depression (low-risk group: n = 27) underwent neurocognitive testing and functional magnetic imaging (fMRI) as part of a follow-up cohort study. Participants performed a self-referent emotional word categorisation task and free word recall task followed by a recognition task during fMRI. Participants also completed questionnaires assessing mood, personality traits and coping strategies. RESULTS: High-risk and low-risk twins (age, mean ± SD: 40 ± 11) were well-balanced for demographic variables, mood, coping and neuroticism. High-risk twins showed lower accuracy during self-referent categorisation of emotional words independent of valence and more false recollections of negative words than low-risk twins during free recall. Functional MRI yielded no differences between high-risk and low-risk twins in retrieval-specific neural activity for positive or negative words or during the recognition of negative versus positive words within the hippocampus or prefrontal cortex. CONCLUSIONS: The subtle display of negative recall bias is consistent with the hypothesis that self-referent negative memory bias is an endophenotype for depression. High-risk twins' lower categorisation accuracy adds to the evidence for valence-independent cognitive deficits in individuals at familial risk for depression.

17 Article The Bipolar Illness Onset study: research protocol for the BIO cohort study. 2017

Kessing, Lars Vedel / Munkholm, Klaus / Faurholt-Jepsen, Maria / Miskowiak, Kamilla Woznica / Nielsen, Lars Bo / Frikke-Schmidt, Ruth / Ekstrøm, Claus / Winther, Ole / Pedersen, Bente Klarlund / Poulsen, Henrik Enghusen / McIntyre, Roger S / Kapczinski, Flavio / Gattaz, Wagner F / Bardram, Jakob / Frost, Mads / Mayora, Oscar / Knudsen, Gitte Moos / Phillips, Mary / Vinberg, Maj. ·Department of Psychiatry, Psychiatric Center Copenhagen, Copenhagen, Denmark. · Institute of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark. · Department of Clinical Biochemistry, Rigshospitalet, Copenhagen, Denmark. · Department of Biostatistics, University of Copenhagen, Copenhagen, Denmark. · Department of Applied Mathematics and Computer Science, Technical University of Denmark, Kongens Lyngby, Denmark. · Gene Regulation Bioinformatics at the Bioinformatics Centre, Department of Biology/BRIC, University of Copenhagen, Copenhagen, Denmark. · The Centre of Inflammation and Metabolism at Department of Infectious Diseases, Rigshospitalet, Copenhagen, Denmark. · Laboratory of Clinical Pharmacology, Rigshospitalet, Copenhagen, Denmark. · Department of Psychiatry and Pharmacology, University of Toronto, Brain and Cognition Discovery Foundation, Toronto, Ontario, Canada. · McMaster University, Hamilton, Ontario, Canada. · Department and Institute of Psychiatry, and Laboratory of Neuroscience (LIM27), University of São Paulo Medical School, São Paulo, Brazil. · IT University Copenhagen, Copenhagen, Denmark. · Create-Net: Center for Research and Telecommunications Experimentation for Networked Communities, Trento, Italy. · Neurobiology Research Unit and Center for Integrated Molecular Brain Imaging, Rigshospitalet, Copenhagen, Denmark. · Department of Psychiatry, University of Pittsburgh, Western Psychiatric Institute and Clinic, Pittsburgh, Pennsylvania, USA. ·BMJ Open · Pubmed #28645967.

ABSTRACT: INTRODUCTION: Bipolar disorder is an often disabling mental illness with a lifetime prevalence of 1%-2%, a high risk of recurrence of manic and depressive episodes, a lifelong elevated risk of suicide and a substantial heritability. The course of illness is frequently characterised by progressive shortening of interepisode intervals with each recurrence and increasing cognitive dysfunction in a subset of individuals with this condition. Clinically, diagnostic boundaries between bipolar disorder and other psychiatric disorders such as unipolar depression are unclear although pharmacological and psychological treatment strategies differ substantially. Patients with bipolar disorder are often misdiagnosed and the mean delay between onset and diagnosis is 5-10 years. Although the risk of relapse of depression and mania is high it is for most patients impossible to predict and consequently prevent upcoming episodes in an individual tailored way. The identification of objective biomarkers can both inform bipolar disorder diagnosis and provide biological targets for the development of new and personalised treatments. Accurate diagnosis of bipolar disorder in its early stages could help prevent the long-term detrimental effects of the illness.The present Bipolar Illness Onset study aims to identify (1) a composite blood-based biomarker, (2) a composite electronic smartphone-based biomarker and (3) a neurocognitive and neuroimaging-based signature for bipolar disorder. METHODS AND ANALYSIS: The study will include 300 patients with newly diagnosed/first-episode bipolar disorder, 200 of their healthy siblings or offspring and 100 healthy individuals without a family history of affective disorder. All participants will be followed longitudinally with repeated blood samples and other biological tissues, self-monitored and automatically generated smartphone data, neuropsychological tests and a subset of the cohort with neuroimaging during a 5 to 10-year study period. ETHICS AND DISSEMINATION: The study has been approved by the Local Ethical Committee (H-7-2014-007) and the data agency, Capital Region of Copenhagen (RHP-2015-023), and the findings will be widely disseminated at international conferences and meetings including conferences for the International Society for Bipolar Disorders and the World Federation of Societies for Biological Psychiatry and in scientific peer-reviewed papers. TRIAL REGISTRATION NUMBER: NCT02888262.

18 Article Differences in neural and cognitive response to emotional faces in middle-aged dizygotic twins at familial risk of depression. 2017

Miskowiak, K W / Svendsen, A M B / Harmer, C J / Elliott, R / Macoveanu, J / Siebner, H R / Kessing, L V / Vinberg, M. ·Copenhagen Affective Disorders Research Centre,Copenhagen Psychiatric Centre, Copenhagen University Hospital,Rigshospitalet,Denmark. · Department of Psychiatry,University of Oxford,UK. · Institute of Brain, Behaviour and Mental Health, University of Manchester,UK. · Danish Research Centre for Magnetic Resonance, Centre for Functional and Diagnostic Imaging and Research, Copenhagen University Hospital Hvidovre,Denmark. ·Psychol Med · Pubmed #28397623.

ABSTRACT: 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.

19 Article Does a single session of electroconvulsive therapy alter the neural response to emotional faces in depression? A randomised sham-controlled functional magnetic resonance imaging study. 2017

Miskowiak, Kamilla W / Kessing, Lars V / Ott, Caroline V / Macoveanu, Julian / Harmer, Catherine J / Jørgensen, Anders / Revsbech, Rasmus / Jensen, Hans M / Paulson, Olaf B / Siebner, Hartwig R / Jørgensen, Martin B. ·1 Psychiatric Centre Copenhagen, Copenhagen University Hospital, Copenhagen, Denmark. · 2 Danish Research Centre for Magnetic Resonance, Copenhagen University Hospital Hvidovre, Hvidovre, Denmark. · 3 Center for Integrated Molecular Brain Imaging, Rigshospitalet, Copenhagen, Denmark. · 4 Department of Psychiatry, University of Oxford, Oxford, UK. · 5 Psychiatric Centre Copenhagen, Gentofte Hospital, Denmark. · 6 Neurobiology Research Unit, Copenhagen University Hospital, Denmark. · 7 Department of Neurology, Copenhagen University Hospital Bispebjerg, Copenhagen, Denmark. ·J Psychopharmacol · Pubmed #28351201.

ABSTRACT: Negative neurocognitive bias is a core feature of major depressive disorder that is reversed by pharmacological and psychological treatments. This double-blind functional magnetic resonance imaging study investigated for the first time whether electroconvulsive therapy modulates negative neurocognitive bias in major depressive disorder. Patients with major depressive disorder were randomised to one active ( n=15) or sham electroconvulsive therapy ( n=12). The following day they underwent whole-brain functional magnetic resonance imaging at 3T while viewing emotional faces and performed facial expression recognition and dot-probe tasks. A single electroconvulsive therapy session had no effect on amygdala response to emotional faces. Whole-brain analysis revealed no effects of electroconvulsive therapy versus sham therapy after family-wise error correction at the cluster level, using a cluster-forming threshold of Z>3.1 ( p<0.001) to secure family-wise error <5%. Groups showed no differences in behavioural measures, mood and medication. Exploratory cluster-corrected whole-brain analysis ( Z>2.3; p<0.01) revealed electroconvulsive therapy-induced changes in parahippocampal and superior frontal responses to fearful versus happy faces as well as in fear-specific functional connectivity between amygdala and occipito-temporal regions. Across all patients, greater fear-specific amygdala - occipital coupling correlated with lower fear vigilance. Despite no statistically significant shift in neural response to faces after a single electroconvulsive therapy session, the observed trend changes after a single electroconvulsive therapy session point to an early shift in emotional processing that may contribute to antidepressant effects of electroconvulsive therapy.

20 Article The effect of erythropoietin on cognition in affective disorders - Associations with baseline deficits and change in subjective cognitive complaints. 2016

Ott, Caroline Vintergaard / Vinberg, Maj / Kessing, Lars V / Miskowiak, Kamilla W. ·Psychiatric Centre Copenhagen, Copenhagen University Hospital, Rigshospitalet Dep. 6233, Blegdamsvej 9, DK-2100 Copenhagen, Denmark. Electronic address: caroline.vintergaard.ott@regionh.dk. · Psychiatric Centre Copenhagen, Copenhagen University Hospital, Rigshospitalet Dep. 6233, Blegdamsvej 9, DK-2100 Copenhagen, Denmark. Electronic address: maj.vinberg@regionh.dk. · Psychiatric Centre Copenhagen, Copenhagen University Hospital, Rigshospitalet Dep. 6233, Blegdamsvej 9, DK-2100 Copenhagen, Denmark. Electronic address: lars.vedel.kessing@regionh.dk. · Psychiatric Centre Copenhagen, Copenhagen University Hospital, Rigshospitalet Dep. 6233, Blegdamsvej 9, DK-2100 Copenhagen, Denmark. Electronic address: kamilla@miskowiak.dk. ·Eur Neuropsychopharmacol · Pubmed #27349944.

ABSTRACT: This is a secondary data analysis from our erythropoietin (EPO) trials. We examine (I) whether EPO improves speed of complex cognitive processing across bipolar and unipolar disorder, (II) if objective and subjective baseline cognitive impairment increases patients׳ chances of treatment-efficacy and (III) if cognitive improvement correlates with better subjective cognitive function, quality of life and socio-occupational capacity. Patients with unipolar or bipolar disorder were randomized to eight weekly EPO (N=40) or saline (N=39) infusions. Cognition, mood, quality of life and socio-occupational capacity were assessed at baseline (week 1), after treatment completion (week 9) and at follow-up (week 14). We used repeated measures analysis of covariance to investigate the effect of EPO on speed of complex cognitive processing. With logistic regression, we examined whether baseline cognitive impairment predicted treatment-efficacy. Pearson correlations were used to assess associations between objective and subjective cognition, quality of life and socio-occupational capacity. EPO improved speed of complex cognitive processing across affective disorders at weeks 9 and 14 (p≤0.05). In EPO-treated patients, baseline cognitive impairment increased the odds of treatment-efficacy on cognition at weeks 9 and 14 by a factor 9.7 (95% CI:1.2-81.1) and 9.9 (95% CI:1.1-88.4), respectively (p≤0.04). Subjective cognitive complaints did not affect chances of treatment-efficacy (p≥0.45). EPO-associated cognitive improvement correlated with reduced cognitive complaints but not with quality of life or socio-occupational function. As the analyses were performed post-hoc, findings are only hypothesis-generating. In conclusion, pro-cognitive effects of EPO occurred across affective disorders. Neuropsychological screening for cognitive dysfunction may be warranted in future cognition trials.

21 Article Neural correlates of improved executive function following erythropoietin treatment in mood disorders. 2016

Miskowiak, K W / Vinberg, M / Glerup, L / Paulson, O B / Knudsen, G M / Ehrenreich, H / Harmer, C J / Kessing, L V / Siebner, H R / Macoveanu, J. ·Psychiatric Centre Copenhagen,Copenhagen University Hospital,Rigshospitalet,Copenhagen,Denmark. · Danish Research Centre for Magnetic Resonance (DRCMR),Centre for Functional and Diagnostic Imaging and Research,Hvidovre Hospital, University of Copenhagen,Copenhagen,Denmark. · Center for Integrated Molecular Brain Imaging,Rigshospitalet,Copenhagen,Denmark. · Division of Clinical Neuroscience,Max Planck Institute of Experimental Medicine,Göttingen,Germany. · Department of Psychiatry,University of Oxford,Oxford,UK. ·Psychol Med · Pubmed #26996196.

ABSTRACT: 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.

22 Article Screening for cognitive dysfunction in unipolar depression: Validation and evaluation of objective and subjective tools. 2016

Ott, Caroline Vintergaard / Bjertrup, Anne Juul / Jensen, Johan Høy / Ullum, Henrik / Sjælland, René / Purdon, Scot E / Vieta, Eduard / Kessing, Lars V / Miskowiak, Kamilla W. ·Psychiatric Centre Copenhagen, Copenhagen University Hospital, Rigshospitalet Dep. 6233, Blegdamsvej 9, DK-2100 Copenhagen, Denmark. Electronic address: caroline.vintergaard.ott@regionh.dk. · Psychiatric Centre Copenhagen, Copenhagen University Hospital, Rigshospitalet Dep. 6233, Blegdamsvej 9, DK-2100 Copenhagen, Denmark. Electronic address: anne.juul.bjertrup@regionh.dk. · Psychiatric Centre Copenhagen, Copenhagen University Hospital, Rigshospitalet Dep. 6233, Blegdamsvej 9, DK-2100 Copenhagen, Denmark. Electronic address: johan.hoey.jensen@regionh.dk. · Department of Clinical Immunology, Copenhagen University Hospital, Rigshospitalet Dep. 2031, Blegdamsvej 9, DK-2100 Copenhagen, Denmark. · Psychiatric Center Hvidovre, Dep. 803A, Brøndbyøstervej 160, DK-2605 Brøndby, Denmark. Electronic address: rene.sjaelland@regionh.dk. · Alberta Hospital Edmonton Neuropsychology, and the University of Alberta Faculty of Medicine and Dentistry, Box 307 (17480 Fort Road), Edmonton, Alberta, Canada T5J 2J7. Electronic address: spurdon@ualberta.ca. · Clinical Institute of Neuroscience, Hospital Clinic, University of Barcelona, IDIBAPS, CIBERSAM, Villarroel 170, Barcelona 08036, Catalonia, Spain. Electronic address: evieta@clinic.ub.es. · Psychiatric Centre Copenhagen, Copenhagen University Hospital, Rigshospitalet Dep. 6233, Blegdamsvej 9, DK-2100 Copenhagen, Denmark. Electronic address: lars.vedel.kessing@regionh.dk. · Psychiatric Centre Copenhagen, Copenhagen University Hospital, Rigshospitalet Dep. 6233, Blegdamsvej 9, DK-2100 Copenhagen, Denmark. Electronic address: Kamilla@miskowiak.dk. ·J Affect Disord · Pubmed #26583350.

ABSTRACT: BACKGROUND: Persistent cognitive dysfunction in unipolar depression (UD) contributes to socio-occupational impairment, but there are no feasible methods to screen for and monitor cognitive dysfunction in this patient group. The present study investigated the validity of two new instruments to screen for cognitive dysfunction in UD, and their associations with socio-occupational capacity. METHOD: Participants (n=53) with UD in partial or full remission and healthy control persons (n=103) were assessed with two new screening instruments, the Danish translations of the Screen for Cognitive Impairment in Psychiatry (SCIP-D) and Cognitive Complaints in Bipolar Disorder Rating Assessment (COBRA) and with established neuropsychological and self-assessment measures. Depression symptoms and socio-occupational function were rated with the Hamilton Depression Rating Scale and Functional Assessment Short Test respectively. RESULTS: The SCIP-D and COBRA were valid for detection of objective and subjective cognitive impairment, respectively. The three parallel SCIP-D forms were equivalent. A combined SCIP-D-COBRA measure showed high sensitivity and good specificity for objective cognitive impairment (91% and 70%, respectively). There was no correlation between subjective and objective measures of cognition. Subjective cognitive difficulties correlated more with socio-occupational impairment (r=0.7, p<0.01) than did objective cognitive difficulties, for which there was a weak correlation with the executive skills domain only (r =-0.3, p=0.05). LIMITATIONS: A modest sample size. CONCLUSIONS: The SCIP-D and COBRA are valid measures of objective and subjective cognitive impairment, respectively, and should ideally be implemented together in the screening for cognitive dysfunction in UD.

23 Article Fewer study participants needed to demonstrate superior antidepressant efficacy when using the Hamilton melancholia subscale (HAM-D₆) as outcome measure. 2016

Østergaard, Søren Dinesen / Bech, Per / Miskowiak, Kamilla Woznica. ·Research Department P, Aarhus University Hospital, Risskov, Denmark; The Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH), Aarhus and Copenhagen, Denmark. · Psychiatric Research Unit, Psychiatric Center North Zealand, Copenhagen University Hospital, Hillerød, Denmark. Electronic address: Per.bech@regionh.dk. · Psychiatric Centre Copenhagen, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark. ·J Affect Disord · Pubmed #25487682.

ABSTRACT: BACKGROUND: In the development of new antidepressant treatments, the failed study has unfortunately become a prevalent problem. The number of failed studies could probably be reduced significantly by applying more informative outcome measures. Previous studies have indicated that the 6-item melancholia subscale (HAM-D6) of the 17-item Hamilton Depression Rating Scale (HAM-D17) may be more informative than other scales, due to its superior psychometric properties. In the present study we investigated whether the HAM-D6 had higher informativeness than the HAM-D17 based on data from a randomized placebo-controlled trial (RCT) testing the effect of erythropoietin (EPO) as augmentation therapy in patients with treatment-resistant depression. METHODS: We assessed the scalability (Mokken analysis of unidimensionality), responsiveness (item responsiveness analysis) and ability to show drug-placebo separation (estimation of sample size needed to detect statistically significant difference between EPO and placebo) of the HAM-D6 and the HAM-D17. RESULTS: The HAM-D6 demonstrated higher scalability, higher responsiveness, and better drug-placebo separation compared to the HAM-D17. As a consequence, only 39 participants per group would be required to detect a statistically significant difference between EPO and placebo when using the HAM-D6 as outcome measure, whereas the required group size for HAM-D17 would be 146 participants. LIMITATIONS: The EPO RCT was not originally designed to investigate the research questions addressed in this study. CONCLUSIONS: Both for ethical and financial reasons it is of interest to minimize the number of participants in clinical trials. Therefore, we suggest employing the HAM-D6 as outcome measure in clinical trials of depression.

24 Article Assessment of subjective and objective cognitive function in bipolar disorder: Correlations, predictors and the relation to psychosocial function. 2015

Demant, Kirsa M / Vinberg, Maj / Kessing, Lars V / Miskowiak, Kamilla W. ·Clinic for Affective Disorders, Psychiatric Centre Copenhagen, Copenhagen University Hospital, Rigshospitalet, Blegdamsvej 9, DK-2100 Copenhagen, Denmark. Electronic address: kirsa.moerkeberg.demant@regionh.dk. · Clinic for Affective Disorders, Psychiatric Centre Copenhagen, Copenhagen University Hospital, Rigshospitalet, Blegdamsvej 9, DK-2100 Copenhagen, Denmark. Electronic address: maj.vinberg@regionh.dk. · Clinic for Affective Disorders, Psychiatric Centre Copenhagen, Copenhagen University Hospital, Rigshospitalet, Blegdamsvej 9, DK-2100 Copenhagen, Denmark. Electronic address: lars.vedel.kessing@regionh.dk. · Clinic for Affective Disorders, Psychiatric Centre Copenhagen, Copenhagen University Hospital, Rigshospitalet, Blegdamsvej 9, DK-2100 Copenhagen, Denmark. Electronic address: kamilla.woznica.miskowiak@regionh.dk. ·Psychiatry Res · Pubmed #26073281.

ABSTRACT: Cognitive dysfunction is prevalent in bipolar disorder (BD). However, the evidence regarding the association between subjective cognitive complaints, objective cognitive performance and psychosocial function is sparse and inconsistent. Seventy seven patients with bipolar disorder who presented cognitive complaints underwent assessment of objective and subjective cognitive function and psychosocial functioning as part of their participation in two clinical trials. We investigated the association between global and domain-specific objective and subjective cognitive function and between global cognitive function and psychosocial function. We also identified clinical variables that predicted objective and subjective cognitive function and psychosocial functioning. There was a correlation between global subjective and objective measures of cognitive dysfunction but not within the individual cognitive domains. However, the correlation was weak, suggesting that cognitive complaints are not an assay of cognition per se. Self-rated psychosocial difficulties were associated with subjective (but not objective) cognitive impairment and both subjective cognitive and psychosocial difficulties were predicted by depressive symptoms. Our findings indicate that adequate assessment of cognition in the clinical treatment of BD and in drug trials targeting cognition requires implementation of not only subjective measures but also of objective neuropsychological tests.

25 Article Different neural and cognitive response to emotional faces in healthy monozygotic twins at risk of depression. 2015

Miskowiak, K W / Glerup, L / Vestbo, C / Harmer, C J / Reinecke, A / Macoveanu, J / Siebner, H R / Kessing, L V / Vinberg, M. ·Psychiatric Centre Copenhagen,Copenhagen University Hospital,Rigshospitalet,Denmark. · Department of Psychiatry,University of Oxford,Oxford,UK. · Danish Research Centre for Magnetic Resonance,Copenhagen University Hospital Hvidovre,Denmark. ·Psychol Med · Pubmed #25382193.

ABSTRACT: 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.

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