MD, Specialist in Psychiatry, PhD, Ass. Professor, Head of ClinicSenior researcher in clinical studies of cerebrospinal biomarkers in bipolar affective disorder
BACKGROUND The International Society for Bipolar Disorders Targeting Cognition Task Force recomme... more BACKGROUND The International Society for Bipolar Disorders Targeting Cognition Task Force recommends screening for and monitoring of cognitive impairments in patients with bipolar disorder (BD) with the Screen for Cognitive Impairment in Psychiatry (SCIP). The study aimed to provide the first demographically adjusted norms and change norms for the SCIP and to compare the cognitive trajectory over one year in remitted BD patients with normative cognitive change. METHODS Patients with fully or partially remitted BD and healthy controls (HC) were assessed with the SCIP at baseline and at a one-year follow-up. Regression-based models were used to determine demographically adjusted norms and change norms. Using the change models, predicted follow-up scores were calculated for BD and HC, and independent t-tests were used to compare deviations of the observed from the predicted follow-up scores for BD vs. HC to assess differences in cognitive trajectories. RESULTS Baseline data were collected for n=273 HC and n=218 BD, and follow-up data for n=139 HC and n=74 BD. Baseline norm models included age, sex and years of education, while change models included baseline SCIP scores and age. Patients with follow-up data showed selective impairments within verbal learning and recall at baseline. They followed the normative cognitive trajectories for all cognitive domains but verbal learning. LIMITATIONS Cognition was assessed with a screening tool. CONCLUSIONS We recommend implementing demographically adjusted norms and change norms for the SCIP in clinical and research settings. Change norms seem sensitive to subtle and selective cognitive decline over one year in remitted BD.
The mechanisms of action for selective serotonin re-uptake in-hibitors (SSRI) in depressed patien... more The mechanisms of action for selective serotonin re-uptake in-hibitors (SSRI) in depressed patients remain widely unknown. The serotonergic neurotransmitter system and the hypothalamic-pituitary-adrenal (HPA) system may interact. Further, the serotonergic neurotransmitter system seems closely linked to personality and cognition. It is not known if SSRIs have a direct effect on the HPA system, personality or cognition that is independent of their effect on depression. Thus, healthy individuals with a genetic liability for depression represent a group of particular interest when investigating if intervention with SSRIs affects these potential biomarkers. SSRIs may affect these potential biomarkers in depressed patients, but it is unclear if the effect is directly on the biomarkers or is secondary to the effect of SSRIs on depressive symptoms. It has newer been tested whether an intervention with a SSRI has a beneficial effect on these potential biomarkers in healthy individuals with a genetic liability for depression. The aim of the thesis was by an experimental medicine blinded controlled trial, to investigate if long-term intervention with SSRI versus placebo decreases cortisol response in the dexamethasone corticotropin-releasing hormone (DEX-CRH) test in healthy first-degree relatives to patients with major depressive disorder (MDD). Further, to test the hypothesis that a SSRI may reduce neuroticism in healthy first-degree relatives of patients with MDD. Finally, to test whether SSRI enhance cognitive function in healthy first-degree relatives of patients with MDD. Eighty healthy first-degree relatives to patients with MDD were randomised to receive escitalopram 10 mg versus matching pla-cebo daily for four weeks in a blinded trial. The primary outcome measure was the intervention difference in the change of the total area under the curve (CorAUCtotal) for plasma cortisol in the DEX-CRH test at entry to after four weeks of intervention. The secondary outcomes were a) change in self-reported neuroticism scores on the 240-items Revised Neuroticism-Extroversion-Openness-Personality Inventory (NEO-PI-R) and the 101-items Eysenck Personality Inventory (EPQ) at entry to after four weeks of intervention and b) the change in the general cognition score, which was the standardised mean of 13 cognitive test measures. Change in CorAUCtotal showed no statically significant difference between the escitalopram and the placebo group, p = 0.47. Fur-ther, escitalopram did not significantly affect self-reported neu-roticism compared with placebo, NEO-PI-R (p = 0.09) and EPQ (p = 0.73). Finally, mean change in the general cognition score was not significantly increased with escitalopram compared with placebo, (p = 0.37). In univariate analyses, no statistically significant correlations were found between change in the primary and secondary outcomes, respectively, and the covariates age, sex, Hamilton depression score 17-items, and plasma escitalopram levels. In conclusion, the present trial does not support an effect of escitalopram 10 mg daily compared with placebo on the HPA-axis, neuroticism and cognitive function in healthy first-degree relatives to patients with MDD.
Experimental and clinical psychopharmacology, 2019
Selective serotonin reuptake inhibitors (SSRIs) are the first-line drugs in the treatment of depr... more Selective serotonin reuptake inhibitors (SSRIs) are the first-line drugs in the treatment of depression. Investigations of the effects of SSRIs in healthy individuals is a useful model to understand the mechanisms of SSRI action and potentially the underlying pathophysiology of depression. We conducted an updated systematic review of all randomized multiple-dose, placebo-controlled trials on the effect of intervention with SSRI for ≥ 7 days in healthy nonpsychiatric subjects. Tables were drawn for characteristics of the trial, quality assessment, outcome measures, and the effect of intervention with SSRI. The search strategy identified a total of 51 placebo-controlled randomized trials investigating seven different SSRIs and 249 different outcome measures. Among trials, using the same outcome measure, most associations were either contradictory or statistically nonsignificant. Replication of statistically significant findings in two or more trials showed that SSRIs compared with pla...
Background Retrospective studies conducted in psychiatric wards have indicated a shorter duration... more Background Retrospective studies conducted in psychiatric wards have indicated a shorter duration of stay for depressed inpatients in bright compared to dim daylight-exposed rooms, pointing to a possible antidepressant effect of daylight conditions. Dynamic LED lighting, aiming to mimic daylight conditions, are currently been installed in several hospitals, but their feasibility is poorly investigated. Methods To investigate the feasibility of these systems, we developed and installed a LED-lighting system in four rooms in a psychiatric inpatient ward. The system could function statically or dynamically regarding light intensity and colour temperature. The system consisted of (A) a large LED luminaire built into the window jamb mimicking sunlight reflections, (B) two LED light luminaires in the ceiling and (C) a LED reading luminaire. In the static mode, the systems provided constant light from A and B. In the dynamic mode, the system changed light intensity and colour temperature u...
Background Visible light, predominantly in the blue range, affects mood and circadian rhythm part... more Background Visible light, predominantly in the blue range, affects mood and circadian rhythm partly by activation of the melanopsin-containing intrinsically photosensitive retinal ganglion cells (ipRGCs). The light-induced responses of these ganglion cells can be evaluated by pupillometry. The study aimed to assess the blue light induced pupil constriction in patients with bipolar disorder (BD). Methods We investigated the pupillary responses to blue light by chromatic pupillometry in 31 patients with newly diagnosed bipolar disorder, 22 of their unaffected relatives and 35 healthy controls. Mood state was evaluated by interview-based ratings of depressive symptoms (Hamilton Depression Rating Scale) and (hypo-)manic symptoms (Young Mania Rating Scale). Results The ipRGC-mediated pupillary responses did not differ across the three groups, but subgroup analyses showed that patients in remission had reduced ipRGC-mediated responses compared with controls (9%, p = 0.04). Longer illness ...
Copyright: This is the peer reviewed version of the following article: Miskowiak KW, Petersen JZ,... more Copyright: This is the peer reviewed version of the following article: Miskowiak KW, Petersen JZ, Ott CV, Knorr U, Kessing LV, Gallagher P, Robinson L. Predictors of the discrepancy between objective and subjective cognition in bipolar disorder: a novel methodology. Acta Psychiatrica Scandinavica 2016, 134(6), 511-521., which has been published in final form at http://dx.doi.org/10.1111/acps.12649. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Self-Archiving.
Several studies have reported alterations in the cerebrospinal fluid biomarkers (Abeta-42, T-tau ... more Several studies have reported alterations in the cerebrospinal fluid biomarkers (Abeta-42, T-tau and P-tau proteins), both in Alzheimer's disease (AD) and in mild cognitive impairment (MCI). To perform a meta-analysis of the diagnostic yield of this technique for the prediction of patients with MCI who are going to progress to AD. A search was conducted in PubMed and Embase of papers published between 1999 and September 2008, and as a result only prospective studies were included for the systematic review. The sensitivity and specificity for each biomarker were studied separately and also jointly. Of the 12 studies that were included, 6 quantified the Abeta-42 protein, 11 the T-tau protein and seven the P-tau protein. In three of the studies data was obtained from the three biomarkers in combination. The sensitivity of the quantification of the T-tau and P-tau proteins is 82%, with a diagnostic odds ratio of 12.09 (confidence interval 95%, CI 95% = 7.71-18.99; p = 0.1) and 16.29...
IntroductionRetrospective studies conducted in psychiatric inpatient wards have shown a relation ... more IntroductionRetrospective studies conducted in psychiatric inpatient wards have shown a relation between the intensity of daylight in patient rooms and the length of stay, pointing to an antidepressant effect of ambient lighting conditions. Light therapy has shown a promising antidepressant effect when administered from a light box. The emergence of light-emitting diode (LED) technology has made it possible to build luminaires into rooms and to dynamically mimic the spectral and temporal distribution of daylight. The objective of this study is to investigate the antidepressant efficacy of a newly developed dynamic LED-lighting system installed in an inpatient ward.Methods and analysisIn all, 150 inpatients with a major depressive episode, as part of either a major depressive disorder or as part of a bipolar disorder, will be included. The design is a two-arm 1:1 randomised study with a dynamic LED-lighting arm and a static LED-lighting arm, both as add-on to usual treatment in an in...
Although investigated for decades, surprisingly no systematic review has ever been published on m... more Although investigated for decades, surprisingly no systematic review has ever been published on monoamines concentrations in cerebrospinal fluid (CSF) in major depressive disorder (MDD) versus healthy individuals (HC). We did a systematic review and meta-analyses according to the PRISMA Statement based on comprehensive database searches for studies on CSF biomarkers of monoamines and their precursor and/or metabolites, and glutamine, glutamate and GABA in MDD versus HC. Risk of bias was systematically assessed. A total of 23 studies were included. Statistically significantly decreased levels between MDD and HC were found regarding CSF 5-HIAA (n = 2/13 (15%)), HVA (n = 2/11 (18%)), MHPG (n = 1/8 (13%)), and GABA (n = 2/4 (50%)), while increased levels were reported regarding NE (n = 1/2 (50%)), MHPG (n = 1/8 (13%)) and DOPEG (n = 1/1 (100%)). A majority of the studies found no statistically significant differences between MDD and HC regarding CSF 5-HIAA, HVA, NE, MHPG, glutamine, glu...
The brain-derive neurotrophic factor (BDNF) may play an important role in the course of depressio... more The brain-derive neurotrophic factor (BDNF) may play an important role in the course of depression. We aimed to study the associations between peripheral whole blood BDNF levels in healthy individuals with and without a family history of depression. BDNF levels were significantly increased in healthy individuals with (n = 76), compared with healthy individuals without (n = 39) a family history of depression and persisted after adjustment for age and gender differences. Higher BDNF levels were associated with increasing age and seasonality. A family history of depression may contribute to an elevation of peripheral BDNF levels in healthy individuals.
Many patients with bipolar disorder (BD) experience debilitating cognitive deficits, with risk of... more Many patients with bipolar disorder (BD) experience debilitating cognitive deficits, with risk of impaired occupational and psychosocial functioning. However, knowledge of how these deficits impact the patients' ability to perform Activities of Daily Living (ADL), tasks related to self-care and domestic life is limited. We explored the relation between impaired cognitive function and the ability to perform ADL in patients with BD. A total of 42 outpatients (mean age 36 years (range 19.0-58.0 years), 69% women) with BD in remission and with subjective cognitive complaints (≥ 13 on the Cognitive Complaints in Bipolar Disorder Rating Assessment questionnaire (COBRA)) were included. Objective neurocognitive function was evaluated with a short comprehensive cognitive test battery and ADL ability was evaluated with the performance-based Assessment of Motor and Process Skills (AMPS) in the homes of the patients. Our findings indicate that low processing speed correlated with decreased ...
BACKGROUND The International Society for Bipolar Disorders Targeting Cognition Task Force recomme... more BACKGROUND The International Society for Bipolar Disorders Targeting Cognition Task Force recommends screening for and monitoring of cognitive impairments in patients with bipolar disorder (BD) with the Screen for Cognitive Impairment in Psychiatry (SCIP). The study aimed to provide the first demographically adjusted norms and change norms for the SCIP and to compare the cognitive trajectory over one year in remitted BD patients with normative cognitive change. METHODS Patients with fully or partially remitted BD and healthy controls (HC) were assessed with the SCIP at baseline and at a one-year follow-up. Regression-based models were used to determine demographically adjusted norms and change norms. Using the change models, predicted follow-up scores were calculated for BD and HC, and independent t-tests were used to compare deviations of the observed from the predicted follow-up scores for BD vs. HC to assess differences in cognitive trajectories. RESULTS Baseline data were collected for n=273 HC and n=218 BD, and follow-up data for n=139 HC and n=74 BD. Baseline norm models included age, sex and years of education, while change models included baseline SCIP scores and age. Patients with follow-up data showed selective impairments within verbal learning and recall at baseline. They followed the normative cognitive trajectories for all cognitive domains but verbal learning. LIMITATIONS Cognition was assessed with a screening tool. CONCLUSIONS We recommend implementing demographically adjusted norms and change norms for the SCIP in clinical and research settings. Change norms seem sensitive to subtle and selective cognitive decline over one year in remitted BD.
The mechanisms of action for selective serotonin re-uptake in-hibitors (SSRI) in depressed patien... more The mechanisms of action for selective serotonin re-uptake in-hibitors (SSRI) in depressed patients remain widely unknown. The serotonergic neurotransmitter system and the hypothalamic-pituitary-adrenal (HPA) system may interact. Further, the serotonergic neurotransmitter system seems closely linked to personality and cognition. It is not known if SSRIs have a direct effect on the HPA system, personality or cognition that is independent of their effect on depression. Thus, healthy individuals with a genetic liability for depression represent a group of particular interest when investigating if intervention with SSRIs affects these potential biomarkers. SSRIs may affect these potential biomarkers in depressed patients, but it is unclear if the effect is directly on the biomarkers or is secondary to the effect of SSRIs on depressive symptoms. It has newer been tested whether an intervention with a SSRI has a beneficial effect on these potential biomarkers in healthy individuals with a genetic liability for depression. The aim of the thesis was by an experimental medicine blinded controlled trial, to investigate if long-term intervention with SSRI versus placebo decreases cortisol response in the dexamethasone corticotropin-releasing hormone (DEX-CRH) test in healthy first-degree relatives to patients with major depressive disorder (MDD). Further, to test the hypothesis that a SSRI may reduce neuroticism in healthy first-degree relatives of patients with MDD. Finally, to test whether SSRI enhance cognitive function in healthy first-degree relatives of patients with MDD. Eighty healthy first-degree relatives to patients with MDD were randomised to receive escitalopram 10 mg versus matching pla-cebo daily for four weeks in a blinded trial. The primary outcome measure was the intervention difference in the change of the total area under the curve (CorAUCtotal) for plasma cortisol in the DEX-CRH test at entry to after four weeks of intervention. The secondary outcomes were a) change in self-reported neuroticism scores on the 240-items Revised Neuroticism-Extroversion-Openness-Personality Inventory (NEO-PI-R) and the 101-items Eysenck Personality Inventory (EPQ) at entry to after four weeks of intervention and b) the change in the general cognition score, which was the standardised mean of 13 cognitive test measures. Change in CorAUCtotal showed no statically significant difference between the escitalopram and the placebo group, p = 0.47. Fur-ther, escitalopram did not significantly affect self-reported neu-roticism compared with placebo, NEO-PI-R (p = 0.09) and EPQ (p = 0.73). Finally, mean change in the general cognition score was not significantly increased with escitalopram compared with placebo, (p = 0.37). In univariate analyses, no statistically significant correlations were found between change in the primary and secondary outcomes, respectively, and the covariates age, sex, Hamilton depression score 17-items, and plasma escitalopram levels. In conclusion, the present trial does not support an effect of escitalopram 10 mg daily compared with placebo on the HPA-axis, neuroticism and cognitive function in healthy first-degree relatives to patients with MDD.
Experimental and clinical psychopharmacology, 2019
Selective serotonin reuptake inhibitors (SSRIs) are the first-line drugs in the treatment of depr... more Selective serotonin reuptake inhibitors (SSRIs) are the first-line drugs in the treatment of depression. Investigations of the effects of SSRIs in healthy individuals is a useful model to understand the mechanisms of SSRI action and potentially the underlying pathophysiology of depression. We conducted an updated systematic review of all randomized multiple-dose, placebo-controlled trials on the effect of intervention with SSRI for ≥ 7 days in healthy nonpsychiatric subjects. Tables were drawn for characteristics of the trial, quality assessment, outcome measures, and the effect of intervention with SSRI. The search strategy identified a total of 51 placebo-controlled randomized trials investigating seven different SSRIs and 249 different outcome measures. Among trials, using the same outcome measure, most associations were either contradictory or statistically nonsignificant. Replication of statistically significant findings in two or more trials showed that SSRIs compared with pla...
Background Retrospective studies conducted in psychiatric wards have indicated a shorter duration... more Background Retrospective studies conducted in psychiatric wards have indicated a shorter duration of stay for depressed inpatients in bright compared to dim daylight-exposed rooms, pointing to a possible antidepressant effect of daylight conditions. Dynamic LED lighting, aiming to mimic daylight conditions, are currently been installed in several hospitals, but their feasibility is poorly investigated. Methods To investigate the feasibility of these systems, we developed and installed a LED-lighting system in four rooms in a psychiatric inpatient ward. The system could function statically or dynamically regarding light intensity and colour temperature. The system consisted of (A) a large LED luminaire built into the window jamb mimicking sunlight reflections, (B) two LED light luminaires in the ceiling and (C) a LED reading luminaire. In the static mode, the systems provided constant light from A and B. In the dynamic mode, the system changed light intensity and colour temperature u...
Background Visible light, predominantly in the blue range, affects mood and circadian rhythm part... more Background Visible light, predominantly in the blue range, affects mood and circadian rhythm partly by activation of the melanopsin-containing intrinsically photosensitive retinal ganglion cells (ipRGCs). The light-induced responses of these ganglion cells can be evaluated by pupillometry. The study aimed to assess the blue light induced pupil constriction in patients with bipolar disorder (BD). Methods We investigated the pupillary responses to blue light by chromatic pupillometry in 31 patients with newly diagnosed bipolar disorder, 22 of their unaffected relatives and 35 healthy controls. Mood state was evaluated by interview-based ratings of depressive symptoms (Hamilton Depression Rating Scale) and (hypo-)manic symptoms (Young Mania Rating Scale). Results The ipRGC-mediated pupillary responses did not differ across the three groups, but subgroup analyses showed that patients in remission had reduced ipRGC-mediated responses compared with controls (9%, p = 0.04). Longer illness ...
Copyright: This is the peer reviewed version of the following article: Miskowiak KW, Petersen JZ,... more Copyright: This is the peer reviewed version of the following article: Miskowiak KW, Petersen JZ, Ott CV, Knorr U, Kessing LV, Gallagher P, Robinson L. Predictors of the discrepancy between objective and subjective cognition in bipolar disorder: a novel methodology. Acta Psychiatrica Scandinavica 2016, 134(6), 511-521., which has been published in final form at http://dx.doi.org/10.1111/acps.12649. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Self-Archiving.
Several studies have reported alterations in the cerebrospinal fluid biomarkers (Abeta-42, T-tau ... more Several studies have reported alterations in the cerebrospinal fluid biomarkers (Abeta-42, T-tau and P-tau proteins), both in Alzheimer's disease (AD) and in mild cognitive impairment (MCI). To perform a meta-analysis of the diagnostic yield of this technique for the prediction of patients with MCI who are going to progress to AD. A search was conducted in PubMed and Embase of papers published between 1999 and September 2008, and as a result only prospective studies were included for the systematic review. The sensitivity and specificity for each biomarker were studied separately and also jointly. Of the 12 studies that were included, 6 quantified the Abeta-42 protein, 11 the T-tau protein and seven the P-tau protein. In three of the studies data was obtained from the three biomarkers in combination. The sensitivity of the quantification of the T-tau and P-tau proteins is 82%, with a diagnostic odds ratio of 12.09 (confidence interval 95%, CI 95% = 7.71-18.99; p = 0.1) and 16.29...
IntroductionRetrospective studies conducted in psychiatric inpatient wards have shown a relation ... more IntroductionRetrospective studies conducted in psychiatric inpatient wards have shown a relation between the intensity of daylight in patient rooms and the length of stay, pointing to an antidepressant effect of ambient lighting conditions. Light therapy has shown a promising antidepressant effect when administered from a light box. The emergence of light-emitting diode (LED) technology has made it possible to build luminaires into rooms and to dynamically mimic the spectral and temporal distribution of daylight. The objective of this study is to investigate the antidepressant efficacy of a newly developed dynamic LED-lighting system installed in an inpatient ward.Methods and analysisIn all, 150 inpatients with a major depressive episode, as part of either a major depressive disorder or as part of a bipolar disorder, will be included. The design is a two-arm 1:1 randomised study with a dynamic LED-lighting arm and a static LED-lighting arm, both as add-on to usual treatment in an in...
Although investigated for decades, surprisingly no systematic review has ever been published on m... more Although investigated for decades, surprisingly no systematic review has ever been published on monoamines concentrations in cerebrospinal fluid (CSF) in major depressive disorder (MDD) versus healthy individuals (HC). We did a systematic review and meta-analyses according to the PRISMA Statement based on comprehensive database searches for studies on CSF biomarkers of monoamines and their precursor and/or metabolites, and glutamine, glutamate and GABA in MDD versus HC. Risk of bias was systematically assessed. A total of 23 studies were included. Statistically significantly decreased levels between MDD and HC were found regarding CSF 5-HIAA (n = 2/13 (15%)), HVA (n = 2/11 (18%)), MHPG (n = 1/8 (13%)), and GABA (n = 2/4 (50%)), while increased levels were reported regarding NE (n = 1/2 (50%)), MHPG (n = 1/8 (13%)) and DOPEG (n = 1/1 (100%)). A majority of the studies found no statistically significant differences between MDD and HC regarding CSF 5-HIAA, HVA, NE, MHPG, glutamine, glu...
The brain-derive neurotrophic factor (BDNF) may play an important role in the course of depressio... more The brain-derive neurotrophic factor (BDNF) may play an important role in the course of depression. We aimed to study the associations between peripheral whole blood BDNF levels in healthy individuals with and without a family history of depression. BDNF levels were significantly increased in healthy individuals with (n = 76), compared with healthy individuals without (n = 39) a family history of depression and persisted after adjustment for age and gender differences. Higher BDNF levels were associated with increasing age and seasonality. A family history of depression may contribute to an elevation of peripheral BDNF levels in healthy individuals.
Many patients with bipolar disorder (BD) experience debilitating cognitive deficits, with risk of... more Many patients with bipolar disorder (BD) experience debilitating cognitive deficits, with risk of impaired occupational and psychosocial functioning. However, knowledge of how these deficits impact the patients' ability to perform Activities of Daily Living (ADL), tasks related to self-care and domestic life is limited. We explored the relation between impaired cognitive function and the ability to perform ADL in patients with BD. A total of 42 outpatients (mean age 36 years (range 19.0-58.0 years), 69% women) with BD in remission and with subjective cognitive complaints (≥ 13 on the Cognitive Complaints in Bipolar Disorder Rating Assessment questionnaire (COBRA)) were included. Objective neurocognitive function was evaluated with a short comprehensive cognitive test battery and ADL ability was evaluated with the performance-based Assessment of Motor and Process Skills (AMPS) in the homes of the patients. Our findings indicate that low processing speed correlated with decreased ...
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Papers by Ulla Knorr