Intrauterine testosterone exposure and depression risk in opposite-sex and same-sex twins, a Danish register study.

BACKGROUND: Males have a lower prevalence of depression than females and testosterone may be a contributing factor. A comparison of opposite-sex and same-sex twins can be used indirectly to establish the role of prenatal testosterone exposure and the risk of depression. We therefore aimed to explore differences in depression risk using opposite-sex and same-sex twins. METHODS: We included 126 087 opposite-sex and same-sex twins from the Danish Twin Registry followed in nationwide Danish registers. We compared sex-specific incidences of depression diagnosis and prescriptions of antidepressants between opposite-sex and same-sex twins using Cox proportional hazard regression. RESULTS: During follow-up, 2664 (2.1%) twins were diagnosed with depression and 19 514 (15.5%) twins had purchased at least one prescription of antidepressants. First, in male twins, we found that the opposite-sex male twins had the same risk of depression compared to the same-sex male twins {hazard ratio (HR) = 1.01 [95% confidence interval (CI) 0.88-1.17)]}. Revealing the risk of use of antidepressants, the opposite-sex male twins had a slightly higher risk of 4% (HR = 1.04 (95% CI 1.00-1.11)) compared with the same-sex male twins. Second, in the female opposite-sex twins, we revealed a slightly higher, however, not statistically significant risk of depression (HR = 1.08 (95% CI 0.97-1.29)) or purchase of antidepressants (HR = 1.01 (95% CI 0.96-1.05)) when compared to the same-sex female twins. CONCLUSIONS: We found limited support for the hypothesis that prenatal exposure to testosterone was associated with the risk of depression later in life.

Hot and cold cognitive disturbances in antidepressant-free patients with major depressive disorder: a NeuroPharm study.

BACKGROUND: Cognitive disturbances are common and disabling features of major depressive disorder (MDD). Previous studies provide limited insight into the co-occurrence of hot (emotion-dependent) and cold (emotion-independent) cognitive disturbances in MDD. Therefore, we here map both hot and cold cognition in depressed patients compared to healthy individuals. METHODS: We collected neuropsychological data from 92 antidepressant-free MDD patients and 103 healthy controls. All participants completed a comprehensive neuropsychological test battery assessing hot cognition including emotion processing, affective verbal memory and social cognition as well as cold cognition including verbal and working memory and reaction time. RESULTS: The depressed patients showed small to moderate negative affective biases on emotion processing outcomes, moderate increases in ratings of guilt and shame and moderate deficits in verbal and working memory as well as moderately slowed reaction time compared to healthy controls. We observed no correlations between individual cognitive tasks and depression severity in the depressed patients. Lastly, an exploratory cluster analysis suggested the presence of three cognitive profiles in MDD: one characterised predominantly by disturbed hot cognitive functions, one characterised predominantly by disturbed cold cognitive functions and one characterised by global impairment across all cognitive domains. Notably, the three cognitive profiles differed in depression severity. CONCLUSION: We identified a pattern of small to moderate disturbances in both hot and cold cognition in MDD. While none of the individual cognitive outcomes mapped onto depression severity, cognitive profile clusters did. Overall cognition-based stratification tools may be useful in precision medicine approaches to MDD.

Familial risk and heritability of depression by age at first diagnosis in Danish twins.

OBJECTIVE: Familial and genetic factors seem to contribute to the development of depression but whether this varies with age at diagnosis remains unclear. We examined the influence of familial factors on the risk of depression by age at first diagnosis. METHODS: We included 23 498 monozygotic and 39 540 same-sex dizygotic twins from the population-based Danish Twin Registry, followed from 1977 through 2011 in nationwide registers. We used time-to-event analyses accounting for censoring and competing risk of death to estimate cumulative incidence, casewise concordance, relative recurrence risk, and heritability of first depression by age using monozygotic and same-sex dizygotic twin pairs. RESULTS: During follow-up, a total of 1545 twins were diagnosed with depression. For twins at age 35 or younger at first depression, heritability was estimated to be 24.8% (95% confidence interval [CI], 4.6-43.1%), whereas at age 90 it was 14.7% (95% CI, 3.1-26.3%). The relative recurrence risk was higher at younger ages: At age 35, the risk was 27.7-fold (95% CI, 20.0-35.5) and 6.9-fold (95% CI, 3.9-9.8) higher than the population risk for monozygotic and same-sex dizygotic twins, respectively, while the corresponding numbers were 3.0 (95% CI, 2.3-3.6) and 1.8 (95% CI, 1.3-2.2) at age 90. Heritability seemed similar for male and female twins. CONCLUSION: Familial risk of depression, caused either by genes or shared environment, seemed to slightly decrease with age at diagnosis and an elevated concordance risk for monozygotic over same-sex dizygotic pairs suggested a genetic contribution to the development of depression.

Incidence of suicidal behaviour and violent crime following antidepressant medication: a Danish cohort study.

OBJECTIVE: To examine the incidence of suicidal and violent behaviour following initiation of antidepressant medication. METHOD: Cohorts of 997 911 conscripts and 95 794 patients with a first-time affective disorder were followed for purchase of antidepressant medication, suicide, suicide attempts and conviction for violent crime in Danish registries between 1997 through 2015. Incidence of outcomes was estimated for the first 28 days, 28-365 days or later after initiation of antidepressants or study entry. RESULTS: Of 16.5% of conscripts and 73.7% of patients with affective disorders initiated antidepressant medication. Incidence of suicide was 3-4 times higher during the first 28 days after initiation compared to the rates in the following year in both cohorts. A similar trend was seen among the untreated patients with affective disorders, whereas suicide incidence was stable at a low level among conscripts not treated with antidepressants. Incidence of attempted suicide was highest during the 28 days before and after initiation of antidepressants, while rates of violent crime were similar before and after initiation. These trends in incidence were independent of class of antidepressant. CONCLUSION: Higher rates of suicidal behaviour in the weeks following initiation of antidepressant medication probably reflect disease severity and a delay in mood response.

The association between depressive mood and ischemic heart disease: a twin study.

OBJECTIVE: Individuals with mood disorders have increased risk of cardiovascular disease. The aims of this study were to evaluate if the risk of cardiovascular disease in individuals with mood disorder could be explained by shared genetic and early environmental factors. METHODS: We included 6714 Danish middle and old aged twins from two large population-based studies. Cox proportional hazards regression was used to perform individual-level and intra-pair analyses of the association between self-reported depression symptomatology scores and register-based diagnoses of ischemic heart disease. RESULTS: Higher depression symptomatology scores (both total, affective, and somatic) were associated with higher incidence of ischemic heart disease after multivariable adjustment in individual-level analyses. In intra-pair analyses, this association was similar but with slightly larger confidence intervals. There was no interaction with gender and no major differences between mono- or dizygotic twins. Within twin pairs, the twin scoring highest on depressive symptoms developed ischemic heart disease more often or earlier than the lower scoring twin. A sensitivity analysis including a 2-year time lag of depression symptomatology to limit the risk of reverse causality showed similar results. CONCLUSION: Genetic factors and early life environment do not seem to explain the association between depressive mood and ischemic heart disease.

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.

Post-mortem MRI-based volumetry of the hippocampus in forensic cases of decedents with severe mental illness.

A decrease in the volume of the hippocampus is associated with severe mental illness, especially schizophrenia, and has been studied extensively in the living using magnetic resonance imaging. Autopsy cohorts also represent a valuable data source for imaging studies. However, post-mortem magnetic resonance imaging (PMMRI) is subject to unique challenges, such as the lower core temperature of scanned subjects and the influence of decomposition processes. This study aimed to determine if results from in vivo studies could be replicated on a post-mortem cohort of decedents who suffered from severe mental illness. We included 96 decedents with either schizophrenia (n = 34), depressive disorder (n = 17), or no known psychiatric diagnosis (n = 45) from April 2015 to January 2017. All cases underwent a T2-weighted cerebral MRI less than 24 h before autopsy. We used a manual segmentation algorithm to define the hippocampus on coronal images and subsequently estimate the volume of the region. The group with schizophrenia had a statistically significant 9.5% decrease in mean hippocampal volume compared with control subjects, while the group with depression trended towards a reduced volume, but this difference was not statistically significant. Thus we were able to replicate previous results from in vivo studies. PMMRI has unique potential for research in that it can be combined with procedures possible only in the research fields of clinical pathology and forensic science, e.g. histopathological sampling.

Regional brain volumes, diffusivity, and metabolite changes after electroconvulsive therapy for severe depression.

OBJECTIVE: To investigate the role of hippocampal plasticity in the antidepressant effect of electroconvulsive therapy (ECT). METHOD: We used magnetic resonance (MR) imaging including diffusion tensor imaging (DTI) and proton MR spectroscopy (1 H-MRS) to investigate hippocampal volume, diffusivity, and metabolite changes in 19 patients receiving ECT for severe depression. Other regions of interest included the amygdala, dorsolateral prefrontal cortex (DLPFC), orbitofrontal cortex, and hypothalamus. Patients received a 3T MR scan before ECT (TP1), 1 week (TP2), and 4 weeks (TP3) after ECT. RESULTS: Hippocampal and amygdala volume increased significantly at TP2 and continued to be increased at TP3. DLPFC exhibited a transient volume reduction at TP2. DTI revealed a reduced anisotropy and diffusivity of the hippocampus at TP2. We found no significant post-ECT changes in brain metabolite concentrations, and we were unable to identify a spectral signature at ≈1.30 ppm previously suggested to reflect neurogenesis induced by ECT. None of the brain imaging measures correlated to the clinical response. CONCLUSION: Our findings show that ECT causes a remodeling of brain structures involved in affective regulation, but due to their lack of correlation with the antidepressant effect, this remodeling does not appear to be directly underlying the antidepressant action of ECT.

Properties of the Tampa Scale for Kinesiophobia across Workers with Different Pain Experiences and Cultural Backgrounds: A Rasch Analysis.

The main aim of this study was to evaluate whether the construct validity of the Tampa Scale for Kinesiophobia (TSK) is consistent with respect to its scaling properties, unidimensionality and targeting among workers with different levels of pain. The 311 participating Danish workers reported kinesiophobia by TSK (13 statement version) and number of days with pain during the past year (less than 8 days, less than 90 days and greater than 90 days). A Rasch analysis was used to evaluate the measurement properties of the TSK in the workers across pain levels, ages, genders and ethnicities. The TSK did not fit the Rasch model, but removing one item solved the poorness of fit. Invariance was found across the pain levels, ages and genders. Thus, with a few modifications, the TSK was shown to capture a unidimensional construct of fear of movement in workers with different pain levels, ages, and genders.

Sex-specifics of ECT outcome.

OBJECTIVE: Electroconvulsive therapy (ECT) is the most effective treatment for patients with severe major depressive disorder (MDD). Given the known sex differences in MDD, improved knowledge may provide more sex-specific recommendations in clinical guidelines and improve outcome. In the present study we examine sex differences in ECT outcome and its predictors. METHODS: Clinical data from 20 independent sites participating in the Global ECT-MRI Research Collaboration (GEMRIC) were obtained for analysis, totaling 500 patients with MDD (58.6 % women) with a mean age of 54.8 years. Severity of depression before and after ECT was assessed with validated depression scales. Remission was defined as a HAM-D score of 7 points or below after ECT. Variables associated with remission were selected based on literature (i.e. depression severity at baseline, age, duration of index episode, and presence of psychotic symptoms). RESULTS: Remission rates of ECT were independent of sex, 48.0 % in women and 45.7 % in men (X2(1) = 0.2, p = 0.70). In the logistic regression analyses, a shorter index duration was identified as a sex-specific predictor for ECT outcome in women (X2(1) = 7.05, p = 0.01). The corresponding predictive margins did show overlapping confidence intervals for men and women. CONCLUSION: The evidence provided by our study suggests that ECT as a biological treatment for MDD is equally effective in women and men. A shorter duration of index episode was an additional sex- specific predictor for remission in women. Future research should establish whether the confidence intervals for the corresponding predictive margins are overlapping, as we find, or not.

Overdiagnosis of dementia in young patients - a nationwide register-based study.

BACKGROUND: Little is known about the quality of the diagnostic evaluation and the validity of dementia diagnoses in young patients established in routine clinical practice. The aim of this study was to investigate the validity of the diagnosis of dementia registered in the Danish nationwide hospital registers in young patients. METHODS: Two hundred patients were randomly selected from 891 patients <65 years registered with a dementia diagnosis for the first time in 2008. The patients' medical records were reviewed to evaluate if they fulfilled ICD-10 and/or DSM-IV criteria for dementia and current clinical criteria for specific dementia subtypes. RESULTS: A registered diagnosis was found to be correct in only 59%. A misdiagnosis of dementia occurred primarily in patients with depression or alcohol abuse. CONCLUSION: Our results suggest that dementia is overregistered and overdiagnosed in young patients. This may be due to a different symptom profile of dementia in young patients, lack of knowledge among clinical physicians and the wide range of conditions which may be misinterpreted as dementia.

Hemoglobin A1c-levels and subsequent risk of depression in individuals with and without diabetes.

BACKGROUND: It has been suggested that long-term glycemic load as reflected in plasma levels of Glycosylated Hemoglobin, Type A1C (HbA1c) is associated with higher risk of depression, however results have been conflicting. We examined the potential association between HbA1c and risk of depression in a large population-based cohort without baseline diabetes (the Glostrup cohort) defined by either self-reported diabetes, registry diagnosis of diabetes or use of antidiabetic medication at baseline and in a national diabetes cohort (the Danish Adult Diabetes Database). METHODS: A total of 16,124 middle-aged individuals from the Glostrup cohort and 93,544 patients registered in the Danish Adult Diabetes Database were followed from the first registered HbA1c measurement (1999-2014) for subsequent diagnosis of depression or use of antidepressant medication in nation-wide Danish registers. The association was analyzed using a Cox proportional hazards regression model with HbA1c on both a continuous scale using restricted cubic splines and categorized based on the groups found in the spline model. We adjusted for relevant sociodemographic and clinical variables including previous depression and tested for interaction of both gender, insulin use and diabetes type. RESULTS: During follow-up, 2694 (17%) in the Glostrup cohort and 29,234 (31%) in the diabetes cohort developed depression. In the Glostrup cohort, we found an indication of a positive linear association between HbA1c and depression in women, while no clear association was found in men. In patients with diabetes, we found a U-shaped association between HbA1c and depression in both men and women with the lowest risk estimates for HbA1c levels of 58 mmol/mol (7.5%) in men and of 60 mmol/mol (7.6%) in women. When HbA1c was categorized, men with the highest HbA1c-levels had significantly elevated risk of depression (HRHbA1c>9.4 1.16 (95%CI 1.10-1.23)) after multifactorial adjustment compared to the reference group with HbA1c of 42.1-56.2 mmol/mol (6.0-7.3%). Women in the lowest and highest category of HbA1c had significantly higher risk of depression HRHbA1c<6.0 1.15 (95% CI 1.09-1.22) and HRHbA1c>9.3 1.10 (95% CI 1.04-1.16), respectively, compared to the reference group with HbA1c 42.1-55.0 mmol/mol (7.2-9.3%). There was a significant interaction with gender, but no interaction for insulin use or diabetes type. CONCLUSIONS: In a population without baseline diabetes, higher HbA1c levels seemed associated with higher depression risk in women, whereas a U-shaped association was found in patients with known diabetes.

Risk of dementia and cognitive dysfunction in individuals with diabetes or elevated blood glucose.

AIMS: To determine the risk of dementia in patients with type 1 or type 2 diabetes and in individuals with glycosylated haemoglobin, type A1C (HbA1c) of ⩾48 mmol/mol, which is the diagnostic limit for diabetes. METHODS: We included the following cohorts: all incident diabetes cases aged 15 or above registered in the National Diabetes Registry (NDR) from January 2000 through December 2012 (n = 148 036) and a reference population, adult participants from the Glostrup cohort (n = 16 801), the ADDITION Study (n = 26 586) and Copenhagen Aging and Midlife Biobank (CAMB) (n = 5408). Using these cohorts, we analysed if a diagnosis of type 1 or type 2 diabetes in the NDR or HbA1c level of ⩾ 6.5% (48 mmol/mol) in the cohorts increased risk of dementia in the Danish National Patient Registry or cognitive performance assessed by the Intelligenz-Struktur-Test 2000R (IST2000R). RESULTS: A diagnosis of type 1 or type 2 diabetes in the NDR was associated with increased risk of dementia diagnosed both before or after age 65 as well as across different subtypes of dementia. Self-reported diabetes or high HbA1c levels were associated with lower cognitive performance (p = 0.004), while high HbA1c was associated with increased risk of dementia (HR 1.94 (1.10-3.44) in the Glostrup cohort but not in the ADDITION Study (HR 0.96 (0.57-1.61)). CONCLUSIONS: Both type 1 and type 2 diabetes are associated with an increased risk of dementia, while the importance of screening-detected elevated HbA1c remains less clear.

Electroconvulsive stimulations prevent stress-induced morphological changes in the hippocampus.

Stress can precipitate major depression and other disorders linked to hippocampal shrinkage. It is hypothesized but not established that treatment of these disorders reverses and prevents the hippocampal changes. Dendritic retraction of individual neurons might in concert with other pathophysiological events contribute to the shrinkage phenomenon. Animal studies have shown that various stress paradigms can induce dendritic retraction in the CA3 pyramidal neurons of the hippocampus. Since electroconvulsive treatment is the most effective treatment in humans with major depression, we investigated whether repeated electroconvulsive stimulations (ECSs) could influence such changes in stressed rats. Furthermore, we investigated whether ECSs per se could influence neuronal branching and total length of the CA3 hippocampal neuronal dendritic tree in normal rats. Rats were stressed using the 21-day 6 h daily restraint stress paradigm. The study shows that stress caused remodelling of the pyramidal neurons by significantly reducing the number of dendritic branch points and total length of the apical dendritic tree. Concomitant administration of ECSs prevented these effects. ECSs had no effect on pyramidal neuron dendrites in normal rats.

The influence of the anesthesia-to-stimulation time interval on seizure quality parameters in electroconvulsive therapy.

BACKGROUND: Electroconvulsive therapy (ECT) continues to be the most efficacious treatment for severe depression and other life-threatening acute psychiatric conditions. Treatment efficacy is dependent upon the induced seizure quality, which may be influenced by a range of treatment related factors. Recently, the time interval from anesthesia to the electrical stimulation (ASTI) has been suggested to be an important determinant of seizure quality. METHODS: We measured ASTI in 73 ECT sessions given to 22 individual patients, and analyzed its influence on five seizure quality parameters (EEG seizure time, power, coherence, postictal suppression, and peak heart rate). RESULTS: Longer ASTI was significantly associated with higher peak heart rate during the seizure (p = .003). After adjustment for confounders, the association continued to be significant, even after Bonferroni correction for multiple comparisons (p = .005). ASTI was not significantly associated with other seizure parameters. LIMITATIONS: The relatively low number of sessions may lead to false negative findings. The study did not include clinical outcomes. CONCLUSIONS: Longer ASTI is associated with higher peak heart rate; a phenomenon which is thought to reflect better seizure propagation to subcortical areas of the brain. The finding indicates that delay of stimulation after anesthesia could be a simple way of improving seizure quality and thereby the clinical effect of ECT.

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

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

Spontaneous regression of restenosis: an angiographic study.

OBJECTIVES: This study was designed to examine the possibility that spontaneous regression in stenosis severity occurs over time in patients with restenosis after percutaneous transluminal coronary angioplasty. BACKGROUND: The underlying mechanisms of restenosis are intimal hyperplasia and smooth muscle cell proliferation in response to vascular injury. We hypothesized that the initial hyperplastic response is followed by dynamic remodeling and eventual spontaneous regression, leading to stabilization or a reduction in stenosis severity. METHODS: A total of 136 patients participated in a trial to evaluate the efficacy of fish oil versus placebo in preventing restenosis after angioplasty. One hundred thirteen patients completed this study with angiographic follow-up, of whom 56 had restenosis. Of these, 19 were asymptomatic and did not undergo repeat revascularization; 15 consented in a separate study to undergo repeat angiography, which was performed 6 to 25 months later to assess the possibility of regression. RESULTS: There was a significant mean (+/- SD) decrease in lesion severity from 66.9 +/- 8.7% to 47.5 +/- 9.0% (p < 0.0001) and a significant mean increase in minimal lumen diameter from 0.91 +/- 0.31 mm to 1.44 +/- 0.35 mm (p < 0.0001). No patient showed progression of stenosis, but regression of restenosis, defined as a decrease in minimal lumen diameter > or = 0.2 mm, was noted in 12 of the patients. CONCLUSIONS: Although all 15 study patients were asymptomatic, similar changes may occur in symptomatic patients. A trial of medical therapy may be appropriate in asymptomatic or mildly symptomatic patients before further interventions. This strategy would avoid unnecessary invasive procedures, prevent a "restenosis cycle" and result in significant cost savings.