(1) Identification of neurocognitive and neuroimaging biomarkers of affective disorders
Emotional bias in monozygotic and dizygotic twins at heritable risk of depression (the UBFAL study)
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 is also present in healthy individuals with hereditary risk for depression. In this study, we therefore investigated never-depressed monozygotic twins at heritable risk of depression (indexed by depression in their co-twins) and healthy twins at low risk (no personal or co-twin history of psychiatric disorder) with neurocognitive tests and fMRI. The study was part of an ongoing high-risk study elucidating risk factors for affective disorder in a large cohort of high- and low-risk twins. The results revealed different neural response and functional connectivity within fronto-limbic and occipito-parietal regions during emotional face processing and enhanced fear vigilance in healthy high-risk twins. This adds to the growing evidence for abnormalities in the processing of emotional faces as a key endophenotype for depression. In parallel, we investigated emotional bias in dizygotic twins at heritable risk of depression and have a manuscript describing the results under review.
Neuromapping of Endophenotypes for Affective disorders: A twin study of neurocognitive, neuroimaging, cellular and epigenetic markers (the NEAD study)
Affective disorders are characterized by a high rate of misdiagnosis which results in delay in appropriate treatment and thus a high rate of recurrence and disability. The NEAD study aims to identify better diagnostic tools that can support earlier correct diagnoses. Specificaly, the study investigates neurocognitive, neuroimaging and biochemical biomarkers (endophenotypes) for affective disorders in 3 groups of monozygotic twins recruited through the Danish registers: 1) twins who both have an affective disorder, 2) twins who are at genetic risk indexed by co-twin history of affective disorder and 3) twins who are both healthy and with no psychiatric history. The results will delineate candidate neurocognitive, neuroimaging, cellular and epigenetic endophenotypes for depression and bipolar disorder and show potential correlations between these endophenotypes and biomarkers. We hope that this research will advance our understanding of key pathophysiological mechanisms in the etiology of affective disorders and, longer-term, aid earlier diagnosis and treatment.
The Bipolar Illness Onset study – work package 3 (BIO-3)
The BIO-3 study aims to identify a brain-based biomarker by comparing neurocognitive and neuroimaging measures of brain function in individuals with newly diagnosed/first-episode bipolar disorder, their unaffected first-degree relatives and healthy controls. The results will improve our understanding of the aetiology of bipolar disorder and contribute to development of better diagnostic tools. The study is part of the largest longitudinal bipolar disorder cohort study to date (Bipolar Illness Onset; BIO), which was started at the Copenhagen Affective Disorders Clinic in 2015 and is led by Professor Lars Vedel Kessing with Dr Miskowiak as work-package leader of BIO-3.
(2) Development of novel treatments targeting cognitive dysfunction
Effects of erythropoietin on depressive symptoms and neurocognitive deficits in depression and bipolar disorder (EPO trials)
There is a need for more effective treatments which aid cognitive function in depression and bipolar disorder. Erythropoietin (Epo) is involved in neuroplasticity and is a candidate for treatment of cognitive dysfunction and mood symptoms affective disorders. We therefore conducted 2 parallel randomized controlled clinical phase II trials in treatment-resistant (unipolar) depression and bipolar disorder in remission to examine the effects of 8 weeks of weekly EPO vs. saline infusions on mood and cognition in these groups. Beneficial (mood-independent) effects of EPO were found on cognitive function across both patient groups. There were no clear beneficial effect of EPO on the primary measure of mood in treatment-resistant depression (although EPO improved self-rated depression and quality of life; tertiary outcome measures in the trial). The findings highlight EPO as a promising candidate treatment to target deficits in neuroplasticity and cognition in affective disorders.
Prefrontal Target Engagement as a biomarker model for Cognitive improvement - Erythropoietin (PRETEC-EPO)
Cognitive dysfunction is a core feature of bipolar disorder, which hampers functional recovery and reduces work capacity. However, there is a lack of treatments with solid and enduring pro-cognitive efficacy. This is partially related to major methodological challenges in this relatively new field including the absence of a brain-based biomarker model to select among candidate treatments. Preclinical and clinical studies point to erythropoietin (EPO) as one of the most promising candidate cognition treatments. PRETEC-EPO therefore aims to:
- Investigate cognitive effects of weekly EPO vs. placebo (saline) treatment for 12 weeks in cognitively impaired remitted bipolar disorder patients and their first-degree relatives and
- identify patterns of early neural activity change that is predictive of subsequent cognitive improvement using functional magnetic resonance imaging (fMRI).
Effects of Short-Term Cognitive Remediation on Cognitive Dysfunction in Partially or Fully Remitted Individuals with Bipolar Disorder (the REMEDI study)
Cognitive remediation (CR) is a new psychological treatment which aims to improve cognitive function, compensational skills, coping skills and, consequently, psychosocial function. There is substantial evidence forbeneficial effects of CR in patients with schizophrenia. This first randomized, controlled trial of CR in bipolar disorder aimed to examine if 12 weeks group-based CR improves cognition in remitted patients with bipolar disoder who experienced moderate to severe cognitive difficulties. The trial revealed no beneficial effects on objectively measured cognitive function, suggesting that more a intensive, individualised intervention may be necessary.
(3) Exploring neurocognitive and neuroimaging mechanisms of established and novel treatments
The neural correlates of EPO-associated improvement of cognition
As part of the EPO studies, we conducted prospective neuroimaging assessments at baseline and after treatment completion to explore the neuronal correlates of any beneficial effects of EPO on cognition and mood. This revealed that the memory improvement in EPO-treated pateints was accompanied by structural increase in the left hippocampus and functional changes in neuronal activity in the dorsal prefrontal cortex and funtionally related regions. The EPO-associated improvement in executive function was also accompanied by increase in task-relevant activity in the dorsal prefrontal cortex. Together, these findings point to modulation of task-related prefrontal cortex activity as a key neurobiological target for treatments targeting cognition. I am therefore planning to investigate this in additional studies using other treatments to target cognition.
Effects of electroconvulsive therapy on neurocogntive and neuroimaging measures of brain function
We have investigated the effects of electroconvulsive therapy (ECT) on neuroimaging and neurocognitive measures in patients with depression. The results are currently being written up for publication.