Clinical ethics committees.

This review describes the clinical ethics committees in Denmark. The clinical ethics committee is an interdisciplinary committee at a hospital intended to analyse ethically challenging situations and burdensome choices in patient care. The work in Danish KEKs takes place without formal organisation, in contrast to several other countries, where clinical ethics is regulated by law as research ethics is in Denmark.

Effect of specialised versus generalised outpatient treatment for bipolar disorder: the CAG Bipolar trial - study protocol for a randomised controlled trial.

INTRODUCTION: Despite current available treatment patients with bipolar disorder often experience relapses and decreased overall functioning. Furthermore, patients with bipolar disorder are often not treated medically or psychologically according to guidelines and recommendations. A Clinical Academic Group is a new treatment initiative bringing together clinical services, research, education and training to offer care and treatment that is based on reliable evidence backed up by research. The present Clinical Academic Group for bipolar disorder (the CAG Bipolar) randomised controlled trial (RCT) aims for the first time to investigate whether specialised outpatient treatment in CAG Bipolar versus generalised community-based treatment improves patient outcomes and clinician's satisfaction with care in patients with bipolar disorder. METHODS AND ANALYSIS: The CAG Bipolar trial is a pragmatic randomised controlled parallel-group trial undertaken in the Capital Region of Denmark covering a catchment area of 1.85 million people. Patients with bipolar disorder are invited to participate as part of their outpatient treatment in the Mental Health Services. The included patients will be randomised to (1) specialised outpatient treatment in the CAG Bipolar (intervention group) or (2) generalised community-based outpatient treatment (control group). The trial started 13 January 2020 and has currently included more than 600 patients. The outcomes are (1) psychiatric hospitalisations and cumulated number and duration of psychiatric hospitalisations (primary), and (2) self-rated depressive symptoms, self-rated manic symptoms, quality of life, perceived stress, satisfaction with care, use of medication and the clinicians' satisfaction with their care (secondary). A total of 1000 patients with bipolar disorder will be included. ETHICS AND DISSEMINATION: The CAG Bipolar RCT is funded by the Capital Region of Denmark and ethical approval has been obtained from the Regional Ethical Committee in The Capital Region of Denmark (H-19067248). Results will be published in peer-reviewed academic journals, presented at scientific meetings and disseminated to patient organisations and media outlets. TRIAL REGISTRATION NUMBER: NCT04229875.

Cerebral hemodynamics and capillary dysfunction in late-onset major depressive disorder.

In major depressive disorder (MDD), perfusion changes in cortico-limbic pathways are interpreted as altered neuronal activity, but they could also signify changes in neurovascular coupling due to altered capillary function. To examine capillary function in late-onset MDD, 22 patients and 22 age- and gender-matched controls underwent perfusion MRI. We measured normalized cerebral blood flow (nCBF), cerebral blood volume (nCBV), and relative transit-time heterogeneity (RTH). Resulting brain oxygenation was estimated in terms of oxygen tension and normalized metabolic rate of oxygen (nCMRO2). Patients revealed signs of capillary dysfunction (elevated RTH) in the anterior prefrontal cortex and ventral anterior cingulate cortex bilaterally and in the left insulate cortex compared to controls, bilateral hypometabolism (parallel reductions of nCBV, nCBF, and CMRO2) but preserved capillary function in the subthalamic nucleus and globus pallidus bilaterally, and hyperactivity with preserved capillary function (increased nCBF) in the cerebellum and brainstem. Our data support that perfusion changes in deep nuclei and cerebellum reflect abnormally low and high activity, respectively, in MDD patients, but suggest that microvascular pathology affects neurovascular coupling in ventral circuits. We speculate that microvascular pathology is important for our understanding of etiology of late-onset MDD as well as infererences about resulting brain activity changes.

Long-Term Risk of Developing Dementia After Electroconvulsive Therapy for Affective Disorders.

OBJECTIVES: Severe depression is associated with an increased risk of developing dementia, however, whether treatment with electroconvulsive therapy (ECT) modify this risk remains unknown. METHODS: In this matched cohort study, 1089 consecutive in-patients with affective disorders, receiving ECT during the period 1982 to 2000, were matched with 3011 in-patients with affective disorders not treated with ECT (non-ECT), and 108,867 individuals randomly selected from the background population. The comparison cohorts were matched on sex, age, and the non-ECT cohort was further matched according to diagnoses and admission period and hospital. Dementia diagnoses were retrieved from the national patient health registry. Analyses were adjusted for disease severity, somatic, and psychiatric comorbidities. RESULTS: The cumulative incidence of dementia was 13.45% (10.75-16.46%) in the ECT cohort after 34 years of follow-up, 10.53% (8.5-12.81%) in the non-ECT cohort, and 8.43% (8.17-8.7%) in the background cohort. Using the ECT cohort as reference and age as the underlying time scale, the adjusted hazard ratio of developing dementia was 0.73 (0.52-1.04) in the non-ECT cohort and 0.61 (0.49-0.76) in the background cohort. The stratified analysis based on age at index (<65 years; 65-80 years; >80 years) found no age-related difference in the risk of developing dementia between the ECT cohort and non-ECT cohort. CONCLUSIONS: The ECT treatment of affective disorders was not associated with an increased long-term risk of developing dementia compared with in-patients with affective disorders not treated with ECT.

Volume of hippocampal subregions and clinical improvement following electroconvulsive therapy in patients with depression.

It is thought that the hippocampal neurogenesis is an important mediator of the antidepressant effect of electroconvulsive therapy (ECT). However, most previous studies failed to demonstrate the relationship between the increase in the hippocampal volume and the antidepressant effect. We reinvestigated this relationship by looking at distinct hippocampal subregions and applying repeated measures correlation. Using a 3 Tesla MRI-scanner, we scanned 22 severely depressed in-patients at three time points: before the ECT series, after the series, and at six-month follow-up. The depression severity was assessed by the 17-item Hamilton Rating Scale for Depression (HAMD-17). The hippocampus was segmented into subregions using Freesurfer software. The dentate gyrus (DG) was the primary region of interest (ROI), due to the role of this region in neurogenesis. The other major hippocampal subregions were the secondary ROIs (n = 20). The general linear mixed model and the repeated measures correlation were used for statistical analyses. Immediately after the ECT series, a significant volume increase was present in the right DG (Cohen's d = 1.7) and the left DG (Cohen's d = 1.5), as well as 15 out of 20 secondary ROIs. The clinical improvement, i.e., the decrease in HAMD-17 score, was correlated to the increase in the right DG volume (rrm = -0.77, df = 20, p < .001), and the left DG volume (rrm = -0.75, df = 20, p < .001). Similar correlations were observed in 14 out of 20 secondary ROIs. Thus, ECT induces an increase not only in the volume of the DG, but also in the volume of other major hippocampal subregions. The volumetric increases may reflect a neurobiological process that may be related to the ECT's antidepressant effect. Further investigation of the relationship between hippocampal subregions and the antidepressant effect is warranted. A statistical approach taking the repeated measurements into account should be preferred in the analyses.

[Catatonia].

This review summarises the knowledge of catatonia, which is a neuropsychiatric syndrome with altered psychomotor and behavioural symptoms as well as autonomic dysfunction seen in a variety of psychiatric, neurologic and medical conditions. However, catatonia frequently remains unrecognised by clinicians. The classification of catatonia differs significantly in the international classifications, reflecting the controversy regarding the concept of catatonia and its complex symptomatology. Different rating scales are developed to diagnose catatonia in clinical practice. First-choice treatment is benzodiazepines and ECT regardless of underlying condition.

Hippocampal volume and cell number in depression, schizophrenia, and suicide subjects.

Many studies suggest that the hippocampus is involved in the pathophysiology of psychiatric disorders, especially major depressive disorder (MDD) and schizophrenia. Especially, in vivo imaging studies indicate that the volume of hippocampus may be reduced in both disorders. Moreover, suicide may have a unique neurobiology. The aim of the present study is to investigate if depression, schizophrenia or suicide is associated with reduced postmortem volume of the hippocampal formation and/or changes in the numbers of neurons and/or glial cells in the different subregions of the hippocampus. We studied postmortem brain samples from 10 subjects with schizophrenia, 8 subjects with major depression, 11 suicide subjects with a history of depressive disorder, and 10 control subjects with no history of psychiatric or neurological diseases. The total volume and numbers of neurons and glial cells were estimated for the main hippocampal subregions using design-unbiased stereological techniques. We found the total volume and total numbers of neurons and glial cells similarly reduced by approximately 20% to 35% in depression and schizophrenia subjects relative to control subjects across all hippocampal regions. In suicide subjects, we only found increased neuron number in CA2/3 subregion. The volume and number of cells are reduced in depression and schizophrenia subjects relative to control subjects across all hippocampal regions. Our findings imply that the hippocampus may be a common site of pathophysiology in depression and schizophrenia. Community living suicide subjects seem to differ in hippocampal neurobiology compared to hospitalized subjects dying with MDD without suicide.

Oxygenation differs among white matter hyperintensities, intersected fiber tracts and unaffected white matter.

White matter hyperintensities of presumed vascular origin are frequently observed on magnetic resonance imaging in normal aging. They are typically found in cerebral small vessel disease and suspected culprits in the etiology of complex age- and small vessel disease-related conditions, such as late-onset depression. White matter hyperintensities may interfere with surrounding white matter metabolic demands by disrupting fiber tract integrity. Meanwhile, risk factors for small vessel disease are thought to reduce tissue oxygenation, not only by reducing regional blood supply, but also by impairing capillary function. To address white matter oxygen supply-demand balance, we estimated voxel-wise capillary density as an index of resting white matter metabolism, and combined estimates of blood supply and capillary function to calculate white matter oxygen availability. We conducted a cross-sectional study with structural, perfusion- and diffusion-weighted magnetic resonance imaging in 21 patients with late-onset depression and 21 controls. We outlined white matter hyperintensities and used tractography to identify the tracts they intersect. Perfusion data comprised cerebral blood flow, blood volume, mean transit time and relative transit time heterogeneity-the latter a marker of capillary dysfunction. Based on these, white matter oxygenation was calculated as the steady state cerebral metabolic rate of oxygen under the assumption of normal tissue oxygen tension and vice versa. The number, volume and perfusion characteristics of white matter hyperintensities did not differ significantly between groups. Hemodynamic data showed white matter hyperintensities to have lower blood flow and blood volume, but higher relative transit time heterogeneity, than normal-appearing white matter, resulting in either reduced capillary metabolic rate of oxygen or oxygen tension. Intersected tracts showed significantly lower blood flow, blood volume and capillary metabolic rate of oxygen than normal-appearing white matter. Across groups, lower lesion oxygen tension was associated with higher lesion number and volume. Compared with normal-appearing white matter, tissue oxygenation is significantly reduced in white matter hyperintensities as well as the fiber tracts they intersect, independent of parallel late-onset depression. In white matter hyperintensities, reduced microvascular blood volume and concomitant capillary dysfunction indicate a severe oxygen supply-demand imbalance with hypoxic tissue injury. In intersected fiber tracts, parallel reductions in oxygenation and microvascular blood volume are consistent with adaptations to reduced metabolic demands. We speculate, that aging and vascular risk factors impair white matter hyperintensity perfusion and capillary function to create hypoxic tissue injury, which in turn affect the function and metabolic demands of the white matter tracts they disrupt.

[Hypochondriacal paranoia is a differential diagnostic challenge].

Patients with persistent complaints about somatic symptoms, which cannot be explained by somatic disease, constitute a major healthcare problem. Hypochondriacal paranoia is an important subset of paranoid conditions, which should not be overlooked in patients with persistent hypochondriacal complaints. It is rare, in contrast to illness anxiety disorder or body dysmorphic disorder optionally with insufficient insight. Recent research indicates, that hypochondriacal complaints present a spectrum of evident psychotic conditions over delusion-like complaints to excessive illness anxiety.

[Hypochondrical paranoia].

This is a case report of hypochondrical paranoia in a young man, who was convinced of a toxic infection by fungi following mold growth exposure. The patient was admitted to a psychiatric facility, severely pained by the delusional perception of his insides being eaten by fungus. He had undergone a thorough medical examination without the discovery of any somatic irregularities and had attempted to treat himself several times. After four months of hospital-ization and the prescription of antipsychotic treatment, he was in recovery. Mild delusions persisted but were no longer pathologically painful.

A comparison of coping strategies in patients with fibromyalgia, chronic neuropathic pain, and pain-free controls.

Patients suffering from chronic pain may benefit from learning adaptive coping strategies. Consensus on efficient strategies for this group of patients is, however, lacking, and previous studies have shown inconsistent results. The present study has examined coping strategies in two distinctly different groups of chronic pain patients and a group of healthy controls. Thirty neuropathic pain (NP) patients, 28 fibromyalgia (FM) patients, and 26 pain-free healthy controls completed the Coping Strategy Questionnaire (CSQ-48/27) and rated their daily pain. The results showed that FM and NP patients did not cope differently with pain. The only difference between the groups was that FM patients felt more in control of their pain than NP patients. Both patient groups used more maladaptive/passive coping strategies, but surprisingly also more adaptive/active coping strategies than healthy controls. However, FM patients with high levels of passive strategies felt less in control than FM patients with low levels of passive strategies. This was not seen in NP patients. An important implication for clinical practice is therefore that passive coping strategies should be restructured into active ones, especially for FM patients. Otherwise, the same psychological treatment model can be applied to both groups since they use similar coping styles.

Increased fractional anisotropy in cerebellum in obsessive-compulsive disorder.

BACKGROUND: Previous morphology and diffusion-imaging studies have suggested that structural changes in white matter is an important part of the pathophysiology of obsessive-compulsive disorder (OCD). However, different methodological approaches and the heterogeneity of patient samples question the validity of the findings. Materials and methods In total, 30 patients were matched for age and sex with 30 healthy controls. All participants underwent T1-weighted magnetic resonance imaging, diffusion tensor imaging and T2 fluid-attenuated inversion recovery. Voxel-based morphometry and tract-based spatial statistics were used to compare white matter volumes and diffusion tensor imaging between groups. These data were analysed correcting for the effects of multiple comparisons, age, sex, severity and duration of illness as nuisance covariates. White matter hyperintensities were manually identified. RESULTS: Increase in fractional anisotropy in cerebellum was the most prominent result. A decrease in fractional anisotrophy in patients comparable with previous studies was located in forceps minor. There were no differences in the white matter morphology or in the white matter hyperintensities between patients and healthy controls. CONCLUSION: Decrease in fractional anisotrophy in forceps minor and increase in cerebellum were found, and they were not due to neither white matter hyperintensities nor morphology of the white matter. Cerebellar hyperconnectivity could be an important part of OCD pathophysiology.

Organic delirious states and other psychiatric disorders: lessons for the hepatologists.

Hepatic encephalopathy (HE) is characterized by a wide variety of neuropsychiatric symptoms, and from a psychiatric perspective its nosological status calls for clarification. According to the ICD-10 classification, it can be classified as delirium due to overt HE's core symptom of clouding of consciousness in increasing degrees. Minimal/covert HE with impairment of neurocognitive function is more difficult to classify and could correspond to Mild Cognitive Impairment or mild degrees of dementia. However, the advantages of current psychiatric nosology is the possibility of thorough characterization of both dispositional and premorbid psychopathology as well as psychiatric morbidity induced by liverdiseases or even treatment. A future closer collaboration between hepatologists and psychiatrists is advocated.

Hippocampal volume and serotonin transporter polymorphism in major depressive disorder.

OBJECTIVE: The main aim of the present study was to replicate a previous finding in major depressive disorder (MDD) of association between reduced hippocampal volume and the long variant of the di- and triallelic serotonin transporter polymorphism in SLC6A4 on chromosome 17q11.2. Secondarily, we also hypothesised that 5-HTTLPR may be a risk factor for MDD. METHODS: Quantitative magnetic resonance imaging (MRI) of the hippocampus was studied in 23 inpatients suffering from MDD and in 33 healthy controls. Normalised volumetric MRI data of hippocampus were assessed with adjustment for total brain volume and tensor-based morphometry was used to elucidate structural brain differences. A triallelic genetic marker resulting from two SLC6A4 promoter region polymorphisms, 5-HTTLPR and rs25531, was analysed for association with MDD and quantitative traits. RESULTS: Healthy controls had a smaller relative hippocampal volume (relative to brain size) but a larger total brain volume compared with patients with MDD. For patients compared with healthy controls, atrophy was found in the right temporal lobe and pons medulla. Allele and genotype frequencies were strikingly different from the previous study that we aimed to replicate, and no significant associations with the serotonin transporter polymorphism were found. CONCLUSIONS: The present quantitative and morphometric MRI study was not able to replicate the previous finding of association between reduced hippocampal volume in depressed patients and the serotonin transporter polymorphism.

Correlations between Stroop task performance and white matter lesion measures in late-onset major depression.

Cerebral white matter lesions (WMLs) are believed to play an important role in a subset of patients with late-onset depression by affecting the white matter connectivity in circuitries essential for mood and cognition. In this study we used diffusion tensor imaging-based (DTI-based) tractography to assess white matter fiber tracts affected by deep WMLs (DWMLs) in patients with late-onset major depression and age- and gender-matched controls. Tractography outcome, illustrated as pathways affected by DWMLs, was analyzed for associations with cognitive performance on the Stroop Test (ST). The patients (n=17) performed significantly worse on the ST than the controls (n=22). Poor performance on the ST correlated with higher lesion load. Regression analysis showed a significant correlation between poor performance on the ST and tracts affected by DWMLs in multiple brain areas in the control group, but very sparse correlation in the patient group. Our results suggest that DWMLs play an important role in the cognitive performance of controls,whereas their influence in depressed patients is overruled by additional, state-dependent factors. Future focus on the tract-specific localization of WMLs using DTI tractography may reveal important associations between neuroconnectivity and clinical measures.

[Generalized anxiety and depression should be diagnosis classified together]. / Generaliseret angst og depressi on burde klassificeres sammen.

Generalized anxiety disorder has a high prevalence in Denmark. From being an exclusion diagnosis to other anxiety disorders, the classification criteria have been made more strict in recent editions of international classifications. However, a marked comorbidity with depression questions the nosological status of generalized anxiety disorder. A review of psychiatric and psychological studies focusing on nosological aspects is presented, supporting that generalized anxiety disorder may be more appropriately classified together with depression as distress disorders.

Differential pain modulation in patients with peripheral neuropathic pain and fibromyalgia.

Background The definition of neuropathic pain has recently been changed by the International Association for the Study of Pain. This means that conditions such as fibromyalgia cannot, as sometimes discussed, be included in the neuropathic pain conditions. However, fibromyalgia and peripheral neuropathic pain share common clinical features such as spontaneous pain and hypersensitivity to external stimuli. Therefore, it is of interest to directly compare the conditions. Material and methods In this study we directly compared the pain modulation in neuropathic pain versus fibromyalgia by recording responses to a cold pressor test in 30 patients with peripheral neuropathic pain, 28 patients with fibromyalgia, and 26 pain-free age-and gender-matched healthy controls. Patients were asked to rate their spontaneous pain on a visual analog scale (VAS (0-100 mm) immediately before and immediately after the cold pressor test. Furthermore the duration (s) of extremity immersion in cold water was used as a measure of the pain tolerance threshold, and the perceived pain intensity at pain tolerance on the VAS was recorded on the extremity in the water after the cold pressor test. In addition, thermal (thermo tester) and mechanical stimuli (pressure algometer) were used to determine sensory detection, pain detection, and pain tolerance thresholds in different body parts. All sensory tests were done by the same examiner, in the same room, and with each subject in a supine position. The sequence of examinations was the following: (1) reaction time, (2) pressure thresholds, (3) thermal thresholds, and (4) cold pressor test. Reaction time was measured to ensure that psychomotoric inhibitions did not influence pain thresholds. Results Pain modulation induced by a cold pressor test reduced spontaneous pain by 40% on average in neuropathic pain patients, but increased spontaneous pain by 2.6% in fibromyalgia patients. This difference between fibromyalgia and neuropathic pain patients was significant (P < 0.002). Fibromyalgia patients withdrew their extremity from the cold water significantly earlier than neuropathic pain patients and healthy controls; however, they had a higher perceived pain intensity on the VAS than neuropathic pain patients and control subjects. Furthermore, neuropathic pain patients had a localized hypersensitivity to mechanical and thermal stimuli in the affected area of the body. In contrast, fibromyalgia patients displayed a general hypersensitivity to mechanical and thermal stimuli when the stimuli were rated by the VAS, and hypersensitivity to some of the sensory stimuli. Conclusions These findings are the first to suggest that a conditioning stimulus evoked by a cold pressor test reduced spontaneous ongoing pain in patients with peripheral neuropathic pain, but not in fibromyalgia patients when directly compared. The current study supports the notion that fibromyalgia and neuropathic pain are distinct pain conditions with separate sensory patterns and dysfunctions in pain-modulating networks. Fibromyalgia should therefore not, as sometimes discussed, be included in NP conditions. Implications On the basis of the findings, it is of interest to speculate on the underlying mechanisms. The results are consistent with the idea that peripheral neuropathic pain is primarily driven from damaged nerve endings in the periphery, while chronic fibromyalgia pain may be a central disorder with increased activity in pain-facilitating systems.

Low-frequency repetitive transcranial magnetic stimulation inferior to electroconvulsive therapy in treating depression.

OBJECTIVES: Repetitive transcranial magnetic stimulation (rTMS) is a potential new antidepressant method and alternative to electroconvulsive therapy (ECT). The efficacy of right prefrontal low-frequency rTMS was shown in a previous placebo-controlled, randomized study but has never been compared with ECT. The aim of this study was to compare the antidepressant efficacy and adverse effects of right prefrontal low-frequency rTMS with that of ECT. METHODS: Sixty inpatients with major depression were randomized to 15 days of 1-Hz right prefrontal rTMS or 9 unilateral ECTs. Depressive symptoms and adverse effects were recorded using the Hamilton Scale for Depression and the Udvalg for Kliniske Undersøgelser side effect scale, supplied by neuropsychological assessment of cognitive functions. RESULTS: Repetitive transcranial magnetic stimulation was significantly less effective than ECT. The intention-to-treat analysis revealed a 26% (confidence interval, 3%-51%) higher rate of partial remission (P = 0.035) by the end of week 3. There was no difference found between the 2 methods on the Udvalg for Kliniske Undersøgelser rating scale. However, psychological examination revealed ECT to have more adverse effects on cognitive functions, whereas the rTMS group improved particularly with respect to visual memory. CONCLUSIONS: Repetitive transcranial magnetic stimulation was significantly less effective than ECT, but ECT had more adverse effects on cognitive function. The outcome does not point to right frontal low-frequency rTMS using the present stimulus design as a first-line substitute for ECT, but rather as a treatment option for patients with depression who are intolerant to other types of treatment or not accepting ECT.