Cortical thickness following electroconvulsive therapy in patients with depression: a longitudinal MRI study.

OBJECTIVE: Several studies have found an increase in hippocampal volume following electroconvulsive therapy (ECT), but the effect on cortical thickness has been less investigated. We aimed to examine the effects of ECT on cortical thickness and their associations with clinical outcome. METHOD: Using 3 Tesla MRI scanner, we obtained T1-weighted brain images of 18 severely depressed patients at three time points: before, right after and 6 months after a series of ECT. The thickness of 68 cortical regions was extracted using Free Surfer, and Linear Mixed Model was used to analyze the longitudinal changes. RESULTS: We found significant increases in cortical thickness of 26 regions right after a series of ECT, mainly within the frontal, temporal and insular cortex. The thickness returned to the baseline values at 6-month follow-up. We detected no significant decreases in cortical thickness. The increase in the thickness of the right lateral orbitofrontal cortex was associated with a greater antidepressant effect, r = 0.75, P = 0.0005. None of the cortical regions showed any associations with cognitive side effects. CONCLUSION: The increases in cortical thickness induced by ECT are transient. Further multimodal MRI studies should examine the neural correlates of these increases and their relationship with the antidepressant effect.

Conceptualizing patient-reported outcome measures for use within two Danish psychiatric clinical registries: description of an iterative co-creation process between patients and healthcare professionals.

BACKGROUND: Denmark has national clinical indicator programs for adult patients diagnosed with depression and schizophrenia, respectively. Within each program, the responsible steering group (SG) decided to add some indicators based upon patient-reported outcome measures (PROMs). AIMS: The primary aim was to describe the process of selecting PROMs and defining a national measurement concept for use in clinical practice and for indicator monitoring and the secondary aim s to collect patient recommendations for implementation. METHODS: An interdisciplinary SG of healthcare professionals and a Patient Peer Board (PPB) representing both patient groups co-created the output in an iterative process. The work included literature search, PPB workshops, SG meetings, ratings of PROM topics and items, and a pilot. The PPB discussed the following: item relevance, mode of data collection, graphical format of the online PROMs, and display of results. Finally, requirements for PROM patient information were identified. Based upon input from the PPB, the SG selected the items and specified the measurement concept. RESULTS: The PPB prioritized 20 of 53 suitable items and suggested alternative wording and answer categories. A pilot was performed and 19 items covering well-being, lack of well-being, impairment of functioning, and overall health were selected for clinical testing. The patients recommended concrete, unambiguous, easily understandable information and procedures for data collection and display of results. CONCLUSIONS: The iterative co-creation process based upon a high degree of patient involvement resulted in a set of PROMs, a national measurement concept, and patient recommendations for implementation. The cooperation between patients and professionals was successful.

Electroconvulsive therapy increases brain volume in major depression: a systematic review and meta-analysis.

OBJECTIVE: The main purpose of this review was to synthesise evidence on ECT's effects on brain's structure. METHOD: A systematic literature review of longitudinal studies of depressed patients treated with ECT using magnetic resonance imaging (MRI) and meta-analysis of ECT's effect on hippocampal volume. RESULTS: Thirty-two studies with 467 patients and 285 controls were included. The MRI studies did not find any evidence of ECT-related brain damage. All but one of the newer MRI volumetric studies found ECT-induced volume increases in certain brain areas, most consistently in hippocampus. Meta-analysis of effect of ECT on hippocampal volume yielded pooled effect size: g = 0.39 (95% CI = 0.18-0.61) for the right hippocampus and g = 0.31 (95% CI = 0.09-0.53) for the left. The DTI studies point to an ECT-induced increase in the integrity of white matter pathways in the frontal and temporal lobes. The results of correlations between volume increases and treatment efficacy were inconsistent. CONCLUSION: The MRI studies do not support the hypothesis that ECT causes brain damage; on the contrary, the treatment induces volume increases in fronto-limbic areas. Further studies should explore the relationship between these increases and treatment effect and cognitive side effects.

Exposure to selective serotonin reuptake inhibitors in utero and early elementary school outcomes.

OBJECTIVE: Data on special education in offspring exposed to selective serotonin reuptake inhibitors (SSRIs) in utero are lacking. We examined associations of in utero SSRI exposure with special education needs and delayed elementary school start. METHODS: A population-based case-cohort study using Danish nationwide birth and prescription registry data from 2005 to 2008. Follow-up ends during 2011-2015 to capture special education needs during and delayed entry to the first elementary school year. Cases were in utero SSRI-exposed offspring. Cohort-controls were SSRI-unexposed offspring of mothers previously on SSRIs. We reported odds ratios (ORs) and 95% confidence intervals (CIs), adjusted for relevant potential confounders. RESULTS: Of 117 475 first-incident non-multiple pregnancy births, 3314 were SSRI-exposed, and 3536 were unexposed. Among SSRI-exposed offspring, 3.2% (n = 98) had special school needs vs. 2.4% (n = 77) in unexposed offspring, P-value=0.048. Correspondingly, 12.3% (n = 383) among SSRI-exposed children had delayed school entry vs. 9.4% (n = 308) in unexposed offspring, P-value < 0.001. Adjusted OR for the association with special school needs was 1.12 (95% CI 0.82-1.55; P-value = 0.48) and 1.38 (95% CI 0.90-2.13; P-value = 0.14) for exposure in all three trimesters. The corresponding adjusted ORs for delayed school entry were 1.17 (95% CI 0.99-1.38; P-value = 0.073) and 1.40 (95% CI 1.11-1.76; P-value = 0.004). CONCLUSION: In utero SSRI exposure in all three trimesters was associated with delayed elementary school start but not special education needs.

Patients experiences of patient education on psychiatric inpatient wards; a systematic review.

OBJECTIVE: To synthesize the evidence on how patients with serious mental disorders perceived patient education on psychiatric wards and to learn more about the patient perceived benefits and limitations related to patient education and how well patient education meets the perceived needs of inpatients. METHODS: Quantitative and qualitative data were categorized and synthesized. A systematic literature search was conducted. Articles were validated using validated critical appraisal tools. Data were analyzed using inductive content analysis. RESULTS: Five articles met the inclusion criteria. The results concerned the specific population with bipolar disorder or schizophrenia. Two explanatory syntheses were aggregated: (I) Benefits and perceived barriers to receiving education and (II) Educational needs of mental health patients. Patients reported mechanical information dissemination and lack of individual and corporative discussions. Patients preferred patient education from different educational sources with respect to individual needs. CONCLUSION: Patient education were most useful when it could be tailored to an individuals specific needs and match patient preference for how to receive it. The findings did not provide evidence to support any educational methods of preference. PRACTICE IMPLICATIONS: The findings may contribute to the development of educational interventions that are perceived more helpful for in-patients suffering from serious mental disorders.

Wake and light therapy for moderate-to-severe depression - a randomized controlled trial.

OBJECTIVE: To examine the efficacy of using wake and light therapy as a supplement to standard treatment of hospitalized patients with depression. METHOD: In this randomized, controlled study, 64 patients with moderate-to-severe depression were allocated to standard treatment or to the intervention, which additionally consisted of three wake therapy sessions in one week, 30-min daily light treatment and sleep time stabilization over the entire nine-week study period. RESULTS: Patients in the wake therapy group had a significant decrease in depressive symptoms in week one as measured by HAM-D17 , 17.39 (CI 15.6-19.2) vs. 20.19 (CI 18.3-22.09) (P = 0.04), whereas no statistically significant differences were found between the groups in weeks two to nine. At week nine, the wake therapy group had a significantly larger increase in general self-efficacy (P = 0.001), and waking up during nights was a significantly less frequent problem (1.9 times vs. 3.2) (P = 0.0008). In most weeks, significantly fewer patients in the wake therapy group slept during the daytime, and if they slept, their naps were shorter (week three: 66 min vs. 117 min P = 0.02). CONCLUSION: The antidepressant effect initially achieved could not be maintained during the nine-week study period. However, sleep and general self-efficacy improved.

Metabolic syndrome in first-time hospitalized patients with depression: a 1-year follow-up study.

OBJECTIVE: Studies on metabolic syndrome (MetS) in younger patients with depression are few. We examined the prevalence and progression of MetS in first-time hospitalized patients with depression during 1 year of follow-up. Furthermore, we explored putative risk factors of MetS. METHOD: We evaluated MetS and its components in first-time hospitalized patients with depression (N = 52) and healthy controls (N = 50) (18-45 years). Physical activity, aerobic fitness, sleeping disturbances, smoking and dietary habits, and psychopharmacological treatment were recorded at baseline for all participants and after 1 year for the patients. RESULTS: Patients had significantly higher waist circumference (WC) and lower high-density lipoproteins compared with healthy controls (P < 0.05). Patients had higher prevalence of MetS, but this was not significant when adjusted for age. Patients had significant increase in WC and triglycerides and a non-significant increase in the prevalence of MetS. Antipsychotic medication (OR 10.5, 95% CI 1.18-94.14) and low aerobic fitness (OR 0.79, 95% CI 0.68-0.93) were significantly correlated with MetS (P < 0.05). CONCLUSION: Metabolic syndrome is highly prevalent in younger, severely depressed patients and the incidence increases during 1 year of follow-up. Low aerobic fitness and use of atypical antipsychotics are strongly correlated with MetS.

Use of psychotropic drugs during pregnancy and breast-feeding.

OBJECTIVE: To write clinical guidelines for the use of psychotropic drugs during pregnancy and breast-feeding for daily practice in psychiatry, obstetrics and paediatrics. METHOD: As we wanted a guideline with a high degree of consensus among health professionals treating pregnant women with a psychiatric disease, we asked the Danish Psychiatric Society, the Danish Society of Obstetrics and Gynecology, the Danish Paediatric Society and the Danish Society of Clinical Pharmacology to appoint members for the working group. A comprehensive review of the literature was hereafter conducted. RESULTS: Sertraline and citalopram are first-line treatment among selective serotonin reuptake inhibitor for depression. It is recommended to use lithium for bipolar disorders if an overall assessment finds an indication for mood-stabilizing treatment during pregnancy. Lamotrigine can be used. Valproate and carbamazepin are contraindicated. Olanzapine, risperidone, quetiapine and clozapine can be used for bipolar disorders and schizophrenia. CONCLUSION: It is important that health professionals treating fertile women with a psychiatric disease discuss whether psychotropic drugs are needed during pregnancy and how it has to be administered.

Metabolic syndrome and aerobic fitness in patients with first-episode schizophrenia, including a 1-year follow-up.

OBJECTIVE: To compare the prevalence of metabolic syndrome (MetS) and metabolic abnormalities in patients with first-episode schizophrenia (FES) with sex- and age-matched healthy controls; to investigate changes in MetS during 1year of treatment; and to investigate predictors of MetS. METHODS: Patients with FES (N=99) and healthy controls (N=50) were included in the study. MetS was defined according to IDF based on waist circumference (WC), blood pressure (BP), triglycerides (TG), high-density lipoprotein (HDL), and fasting-glucose. Data on physical activity, aerobic fitness, smoking, and dietary habits, sleeping disturbances, psychopathology and psychotropic medication were also obtained. Patients were assessed at baseline and at 1year follow-up. RESULTS: Compared with healthy controls patients with FES had a higher baseline prevalence of MetS (p=.07), and metabolic abnormalities: WC (p<.01), TG (p<.01), HDL (p=.017), and fasting glucose (p=.04). Patients with FES had significantly increased prevalence of MetS (p=.03), WC (p=.04), and TG (p=.01) during the study period. Antipsychotics and low physical activity were significantly correlated with the increase in metabolic abnormalities. In multivariate analyses low aerobic fitness was the most consistent and significant predictor of metabolic abnormalities and MetS. CONCLUSION: MetS and metabolic abnormalities are highly prevalent in patients with FES, and both increase significantly during 1year of treatment. Apart from confirming the metabolic adverse effects of antipsychotics, our study highlights that low aerobic fitness is a significant risk factor for MetS. Promoting a healthier lifestyle should be part of psychiatric treatment and rehabilitation.

Plasma brain-derived neurotrophic factor and prefrontal white matter integrity in late-onset depression and normal aging.

OBJECTIVE: To explore the relationship between brain-derived neurotrophic factor (BDNF) and vascular endothelial growth factor (VEGF), cerebral deep white matter lesions (DWMLs), and measures of white matter integrity in patients with late-onset depression, with respect to vascular risk factors. METHOD: We examined 22 patients with late-onset depression and 22 matched controls. Quantification of plasma BDNF and VEGF levels were performed with enzyme-linked immunosorbent assay (ELISA) kits. Measures of white matter integrity comprised apparent diffusion coefficient (ADC) and fractional anisotropy (FA), obtained by diffusion tensor imaging (DTI). Effects of DWMLs, FA, ADC, and vascular risk factors on BDNF and VEGF were assessed using multiple linear regression. RESULTS: The BDNF and VEGF levels did not differ significantly between groups. With pooled data for patients and controls, the BDNF level was positively associated with both number (t = 2.14, P = 0.039) and volume (t = 2.04, P = 0.048) of prefrontal DWMLs and negatively associated with FA in prefrontal normal-appearing white matter (t = -2.40, P = 0.02), adjusted for age and gender. Smoking and hypercholesterolemia was positively associated with the BDNF (t = 2.36, P = 0.023) and VEGF levels (t = 2.28, P = 0.028), respectively. CONCLUSION: Our results suggest a role for BDNF in the complex pathophysiologic mechanisms underlying DWMLs in both normal aging and late-onset depression.

Fluctuations in sedation levels may contribute to delirium in ICU patients.

BACKGROUND: Delirium in patients admitted to the intensive care unit (ICU) is a serious complication potentially increasing morbidity and mortality. The aim of this study was to investigate the impact of fluctuating sedation levels on the incidence of delirium in ICU. METHODS: A prospective cohort study of adult patients at three multidisciplinary ICUs. The Richmond Agitation and Sedation Scale (RASS) and the Confusion Assessment Method for the ICU were used at least twice a day. RESULTS: Delirium was detected at least once in 65% of the patients (n = 640). Delirious patients were significantly older, more critically ill, more often intubated, had longer ICU stays, and had higher ICU mortality than non-delirious patients. The median duration of delirium was 3 days (interquartile range: 1;10), and RASS was less than or equal to 0 (alert and calm) 91% of the time. The odds ratio (OR) for development of delirium if RASS changed more than two levels was 5.19 when adjusted for gender, age, severity of illness, and ICU site and setting. Continuous infusion of midazolam was associated with a decrease in delirium incidence (OR: 0.38; P = 0.002). CONCLUSIONS: Fluctuations in sedation levels may contribute to development of delirium in ICU patients. The risk of developing delirium might be reduced by maintaining a stable sedation level or by non-sedation.

Longitudinal MR study of brain structure and hippocampus volume in major depressive disorder.

OBJECTIVE: To determine whether long-term course of treated major depression has an effect on the structure of the brain and the hippocampal volume. METHOD: An 11-year follow-up procedure was used with data collection at baseline and again at follow-up. Tensor-based morphometry (TBM) and automatic hippocampal volume measure was performed on different datasets. The baseline dataset consisted of T1-weighted magnetic resonance images (MRIs) of 24 in-patients suffering from major depression and 33 healthy controls. The second dataset consisted of T1-weighted MRIs of 31 remitted depressive patients and 36 healthy controls. The longitudinal dataset consisted of 19 patients and 19 matched healthy controls present at both the first and the second dataset. Brain segmentation and hippocampal segmentation were fully automated and were based on a spatial normalization to the International Consortium of Brain Mapping (ICBM) non-linear model. RESULTS: Depressed patients were found to have smaller temporal lobes bilaterally, medulla and right hippocampus at baseline. However, these changes were not found at follow-up 11 years later. Moreover, these changes did not significantly correlate with the illness outcome. CONCLUSION: Brain structure changes seem to be state dependent in major depression, only occurring in acute episode of major depression and normalizing after remission.

Localization of white-matter lesions and effect of vascular risk factors in late-onset major depression.

BACKGROUND: Several studies suggest that patients with late-onset major depression (MD) have an increased load of cerebral white-matter lesions (WMLs) compared with age-matched controls. Vascular risk factors such as hypertension and smoking may confound such findings. Our aim was to investigate the association between the localization and load of WMLs in late-onset MD with respect to vascular risk factors. METHOD: We examined 22 consecutive patients with late-onset first-episode MD and 22 age- and gender-matched controls using whole-brain magnetic resonance imaging (MRI). The localization, number and volume of WMLs were compared between patients and controls, while testing the effect of vascular risk factors. RESULTS: Among subjects with one or more WMLs, patients displayed a significantly higher WML density in two white-matter tracts: the left superior longitudinal fasciculus and the right frontal projections of the corpus callosum. These tracts are part of circuitries essential for cognitive and emotional functions. Analyses revealed no significant difference in the total number and volume of WMLs between groups. Patients and controls showed no difference in vascular risk factors, except for smoking. Lesion load was highly correlated with smoking. CONCLUSIONS: Our results indicate that lesion localization rather than lesion load differs between patients with late-onset MD and controls. Increased lesion density in regions associated with cognitive and emotional functions may be crucial in late-onset MD, and vascular risk factors such as smoking may play an important role in the pathophysiology of late-onset MD, consistent with the vascular depression hypothesis.

The Danish PET/depression project: cognitive function and regional cerebral blood flow.

OBJECTIVE: To clarify the relationship between cognitive functions and regional cerebral blood flow (rCBF) in a large group of depressed patients compared with healthy controls. METHOD: A set of principal components was extracted from scores of a battery of neuropsychological tests of 40 patients suffering from major depression and 49 healthy controls. The components were correlated by multiple linear regression analyses to selected regions of interest in the brain obtained from positron emission tomography images. RESULTS: In contrast to findings in the healthy controls, cognitive functions in the depressed patients correlated significantly with rCBF in specified regions of interest in only a few instances. CONCLUSION: Our study indicates that disturbed cognitive functions in depression do not relate to specific areas of the brain in the same way as normal cognitive functioning, suggesting that the abnormalities of brain function in major depression may be qualitative, rather than quantitative, in nature.

The Danish PET/depression project: clinical symptoms and cerebral blood flow. A regions-of-interest analysis.

OBJECTIVE: We wanted to explore associations between clinical symptoms of depression and the blood flow to specific regions of the brain. Furthermore, we wanted to compare the regions-of-interest (ROI) method with the functions-of-interest (FOI) approach. METHOD: The resting blood flow to 42 ROI in the brain was obtained with positron emission tomography (PET) imaging in 42 representative in-patients with major depression and 47 matched healthy controls. RESULTS: The patients had increased blood flow to hippocampus, cerebellum, anterior cingulate gyrus, and the basal ganglia. A strong negative correlation was found between the degree of psychomotor retardation of the patients and the blood flow to the dorsolateral and supraorbital prefrontal cortices. The total Hamilton score was correlated with the blood flow to the hippocampus. CONCLUSION: Our findings support the notion that depressed patients have disturbances in the loops connecting the frontal lobes, limbic system, basal ganglia, and cerebellum.

The Danish PET/depression project: PET findings in patients with major depression.

BACKGROUND: It is hypothesized from previous positron emission tomography (PET) studies of patients with major depression that dysfunction of regions of the limbic system and the frontal lobes in close connection with the basal ganglia is involved in the pathophysiology of major depression. METHODS: By means of PET and 15O labelled radioactive water we determined an index of the neuronal activity by mapping the cerebral blood flow distribution of 42 unselected in-patients suffering from moderate to severe depression and 47 healthy controls controlling for age and gender. The PET maps were co-registered to magnetic resonance images of the anatomy of the brain. RESULTS: The functions-of-interest analysis revealed significant gender differences in cerebral blood flow and changes in the relative distribution of the blood with increasing age. The patients had increased activity of the hippocampus and the cerebellum compared to the healthy controls when corrected for these confounders and the influence of antidepressant medication. Furthermore, data in the Danish Psychiatric Central Register showed that the patients studied were representative of the population of depressed patients admitted to the hospital during the study period. CONCLUSION: Our main finding is increased blood flow to the hippocampus, even when controlling for a number of confounders. This is in accordance with a rapidly expanding literature suggesting an important role for this structure in major depression.

Structural brain abnormalities in unselected in-patients with major depression.

OBJECTIVE: Several studies have indicated an increased frequency of cerebral atrophy and white matter lesions in patients with major depression, especially in older age groups. METHOD: Forty-four representative in-patients with major depression in which neurological disorders were clinically excluded, and 49 age- and gender-matched controls were MR scanned. RESULTS: Unexpectedly, two of the patients had severe brain pathology which could account for their psychiatric symptoms. Analysis of the remaining patients (mean age 42 years) did not reveal an increased frequency of cerebral atrophy. The number of white matter lesions increased with age to an odds ratio greater than 3 for patients aged 50, but this was not statistically significant. CONCLUSION: Brain atrophy and white matter lesions did not occur with significantly increased frequency in these relatively young unselected depressives, but the finding of severe brain pathology stresses the importance of brain imaging in late-onset psychiatric disorders.

[Depression, stress and brain function]. / Depression, stress og hjernefunktion.

Many patients with major depression have elevated serum cortisol, which cannot be suppressed with dexamethasone. This points to a disturbance in the hypothalamus-pituitary-adrenal (HPA) axis, which might have pathogenetic importance. Recent investigations with MRI have shown an increased frequency of generalised, as well as localised atrophy in the brains of depressed patients. The reduced volume of the hippocampus is particularly interesting, because of the participation of this structure in the regulation of the individual's stress response. Furthermore, the hippocampus is of major importance for cognitive processes. There is evidence that the increased cortisol concentration is neurotoxic and may cause atrophy, as is known from Cushing's disease. This is supported by studies of the accumulated duration of depressive episodes, and also by the fact that drugs that dampen the HPA axis have proved to have antidepressant properties in clinical controlled, double-blind studies. This points to new principles in the treatment of major depression and underlines the importance of early intervention in order to prevent cerebral atrophy, which is probably reversible at the beginning of the disease process.

Postpartum depression: identification of women at risk.

OBJECTIVE: To identify and test the predictive power of demographic, obstetric, and psychosocial risk factors of postpartum depression. DESIGN: Community-based, prospective follow up study based on questionnaires on past history of psychiatric disease, psychological distress and social support during pregnancy and depression at four months after delivery. Obstetric files were collected at time of birth. SETTING: Antenatal care clinic and delivery ward, Aarhus University Hospital, Denmark. POPULATION: 6,790 women giving birth between 1 January 1994 and 31 December 1995, who attended the antenatal clinic during pregnancy; 5,252 (78%) completed all questionnaires. The validation population comprised 528 women enrolled immediately prior to and after the study period. MAIN OUTCOME MEASURE: Postpartum depression four months after giving birth assessed by the Edinburgh Postnatal Depression Scale. RESULTS: 5.5% of the women suffered from postpartum depression, corresponding to a score of 13 or higher on the Edinburgh Postnatal Depression Scale. Risk factors identified by multivariate logistic regression analysis included psychological distress in late pregnancy (OR 6.3 [95% CI 4.4-9.1]), perceived social isolation during pregnancy (OR 3.6 [95% CI 1.9-7.0]); high parity (OR 3.8 [95% CI 1.8-8.0]); and a positive history of prepregnant psychiatric disease (OR 2.1 [95% CI 1.4-3.2]). No association was found between pregnancy or delivery complications, and postpartum depression. The maximum predictive power of the identified risk factors was 0.3. According to these results, one out of three women who suffers from psychological distress in late pregnancy with perceived social isolation will develop postpartum depression. CONCLUSION: Antenatal focus on psychosocial wellbeing may help to identify women at risk of postpartum depression.