Erik Roj Larsen

Vitamin D and Calcium Supplementation Prevents Osteoporotic Fractures in Elderly Community Dwelling Residents: A Pragmatic Population‐Based 3‐Year Intervention Study

This study of 9605 community‐dwelling residents supports that vitamin D and calcium supplementation may prevent osteoporotic fractures in elderly in a northern European region known to be deficient in vitamin D, especially during winter periods.

Genetic predictors of response to antidepressants in the GENDEP project.

The objective of the Genome-based Therapeutic Drugs for Depression study is to investigate the function of variations in genes encoding key proteins in serotonin, norepinephrine, neurotrophic and glucocorticoid signaling in determining the response to serotonin-reuptake-inhibiting and norepinephrine-reuptake-inhibiting antidepressants. A total of 116 single nucleotide polymorphisms in 10 candidate genes were genotyped in 760 adult patients with moderate-to-severe depression, treated with escitalopram (a serotonin reuptake inhibitor) or nortriptyline (a norepinephrine reuptake inhibitor) for 12 weeks in an open-label part-randomized multicenter study. The effect of genetic variants on change in depressive symptoms was evaluated using mixed linear models. Several variants in a serotonin receptor gene (HTR2A) predicted response to escitalopram with one marker (rs9316233) explaining 1.1% of variance (P=0.0016). Variants in the norepinephrine transporter gene (SLC6A2) predicted response to nortriptyline, and variants in the glucocorticoid receptor gene (NR3C1) predicted response to both antidepressants. Two HTR2A markers remained significant after hypothesis-wide correction for multiple testing. A false discovery rate of 0.106 for the three strongest associations indicated that the multiple findings are unlikely to be false positives. The pattern of associations indicated a degree of specificity with variants in genes encoding proteins in serotonin signaling influencing response to the serotonin-reuptake-inhibiting escitalopram, genes encoding proteins in norepinephrine signaling influencing response to the norepinephrine-reuptake-inhibiting nortriptyline and a common pathway gene influencing response to both antidepressants. The single marker associations explained only a small proportion of variance in response to antidepressants, indicating a need for a multivariate approach to prediction.

Interaction between serotonin transporter gene variants and life events predicts response to antidepressants in the GENDEP project

There is substantial inter-individual variation in response to antidepressants, and genetic variation may, in part, explain these differences. For example, there is evidence to suggest that variation in the serotonin transporter gene (SLC6A4) predicts response to selective serotonin reuptake inhibitors (SSRIs). Environmental factors such as the occurrence of stressful life events before treatment may also be important. One prior report suggests that both factors interact in predicting response to antidepressants. GENDEP, a prospective part-randomized pharmacogenomics trial, collected longitudinal data on the outcome of 811 patients with major depression undergoing treatment with either an SSRI (escitalopram) or a tricyclic antidepressant (nortriptyline). Life events experienced over 6 months preceding treatment were measured using a List of Threatening Experiences Questionnaire, and several polymorphisms in the serotonin transporter gene (SLC6A4) have been genotyped including the serotonin transporter-linked polymorphic region (5-HTTLPR). Stressful life events were shown to predict a significantly better response to escitalopram but had no effect on response to nortriptyline. Variation in the 5-HTTLPR and another polymorphism in the gene, STin4, significantly modified these effects. Gene–environment interactions including life events may therefore be important not only in the aetiology of depression, but also in predicting response to antidepressant medication.

Higher-order social cognition in first-episode major depression

Patients suffering from major depression experience difficulties in multiple cognitive faculties. A growing body of research has linked affective disorders to abnormalities in social cognition and specifically the processing of discrete emotional stimuli. However, little inquiry has gone into possible impairment in higher-order social cognition including theory of mind, social perception and metacognition. Forty-four medication-naïve patients with first-episode unipolar major depressive disorder and an equal number of matched controls were assessed by the Metacognitive Assessment Scale-Abbreviated (MAS-A), The Frith-Happé animations (FHA) and The Awareness of Social Inference Test (TASIT). Additionally, neurocognition was assessed utilyzing the Cambridge Neuropsychological Test Automated Battery (CANTAB). Depressed patients showed impairment in all domains of higher-order social cognitive ability. Importantly, social cognitive variables retained their inter-group significance after controlling for possible covariates including neurocognition. Results indicate that first-episode depressed patients experience difficulties in all domains of higher-order social cognition including theory of mind, social perception and metacognition.

Body weight as a predictor of antidepressant efficacy in the GENDEP project

BACKGROUND Being overweight or obese may be associated with poor response to antidepressants. The present report explores the moderation of antidepressant response by body weight to establish the specificity to antidepressant mode of action, type of depressive symptoms and gender. METHODS Height and weight were measured in 797 men and women with major depression treated with escitalopram or nortriptyline for twelve weeks as part of the Genome Based Therapeutic Drugs for Depression (GENDEP) project. Body mass index (BMI) and obesity (BMI>30) were tested as predictors of change in depressive symptoms using mixed linear models. RESULTS Higher BMI and obesity predicted poor response to nortriptyline but did not significantly influence response to escitalopram. The moderation of response by body weight was due to differential improvement in neurovegetative symptoms, including sleep and appetite. The relationship between body weight and change in neurovegetative symptoms was moderated by gender with obese men responding less to nortriptyline and obese women having poorer response to both antidepressants. LIMITATIONS As no placebo arm was included, the specificity of findings to antidepressants is relative. Lack of specific measures precluded accounting for differences in body fat distribution. CONCLUSIONS Body weight should be considered in the assessment of depression as it may inform the selection of antidepressant treatment.

Vitamin D and calcium supplementation prevents severe falls in elderly community-dwelling women: a pragmatic population-based 3-year intervention study

Background and aims: We evaluated the effect of two programs for the prevention of falls leading to acute hospital admission in a population of elderly community-dwelling Danish residents. Methods: This was a factorial, pragmatic, intervention study. We included 9605 community-dwelling city residents aged 66+ years. We offered a prevention program consisting of a daily supplement of 1000 mg of elemental calcium as calcium carbonate and 400 IU (10 μg) of vitamin-D3 to a total of 4957 participants. The remaining 5063 participants were offered home safety inspection with dietary and health advice, or no intervention. Results: The Calcium and Vitamin D program was followed by 50.3% and the Environmental and Health Program by 46.4%. According to a multivariate analysis including age, marital status and intervention program, female residents who followed the Calcium and Vitamin D Program had a 12% risk reduction in severe falls (RR 0.88; 95% CI 0.79–0.98; p<0.05; NNT 9). Conclusions: The present study supports the hypothesis that vitamin D and calcium supplementation prevent falls leading to acute hospitalization in community-dwelling elderly females in a northern European region known to be deficient in vitamin D.

Variation in GNB3 predicts response and adverse reactions to antidepressants

There is substantial inter-individual variation in response and adverse reactions to antidepressants, and genetic variation may, in part, explain these differences. GNB3 encodes the β3 subunit of the G protein complex, which is involved in the downstream signalling cascade following monoamine receptor activation. A functional polymorphism in this gene (C825T) has been associated with response to antidepressants. Several lines of evidence suggest that GNB3 moderates improvement in the neurovegetative symptoms of depression (such as sleep and appetite) and related adverse reactions independently of change in core mood symptoms. We here report analysis of data from GENDEP, a part-randomized pharmacogenomic trial, on the outcome of 811 subjects with major depression undergoing treatment with either escitalopram or nortriptyline in which the C825T SNP and three further SNPs in GNB3 were genotyped. The TT genotype was significantly associated with a superior response to nortriptyline and these effects were specific to improvements in neurovegetative symptoms. In addition, the same genotype predicted fewer incidents of treatment-emergent insomnia and greater weight gain on the same drug. Our results are consistent with previous associations with GNB3 and emphasize the importance of signalling genes in antidepressant response.

Sauvé-Kapandji operation for disorders of the distal radioulnar joint after Colles' fracture : Good results in 12 patients followed for 1.5-4 years

A series of 13 patients is reported in which a Sauvè-Kapandji procedure consisting of arthrodesis of the articulation between the radius and ulna combined with resection of the collum ulnae was used to treat posttraumatic caput ulnae syndrome. Among the nine female and four male patients whose median age was 42 years (range: 23 to 77 years), nine sustained a distal fracture that had healed with shortening of the radius or with subluxation of the caput ulnae. Median postoperative observation time was 16 months (range: six to 27 months). Preoperatively, all patients had persistent medial wrist pain and restricted pronation-supination. At follow-up, ten patients were without symptoms and three others had improved significantly. No patient suffered from pain from the site of the resection. A significant improvement in pronation-supination of 45 degrees and flexion-extension of 25 degrees were found. Hand grip strength improved significantly during rehabilitation. At follow-up, the average hand grip strength on the operated wrists was 69% compared to the uninjured side.

Use of psychotropic drugs during pregnancy and breast-feeding

To write clinical guidelines for the use of psychotropic drugs during pregnancy and breast‐feeding for daily practice in psychiatry, obstetrics and paediatrics.

Changes in body weight during pharmacological treatment of depression

The risk of weight gain is an important determinant of the acceptability and tolerability of antidepressant medication. To compare changes in body weight during treatment with different antidepressants, body weight and height were measured at baseline and after 6, 8, 12 and 26 wk treatment with escitalopram or nortriptyline in 630 adults with moderate-to-severe unipolar depression participating in GENDEP, a part-randomized open-label study. Weight increased significantly more during treatment with nortriptyline compared to escitalopram. The weight gain commenced during the first 6 wk of nortriptyline treatment, reached on average 1.2 kg at 12 wk (0.44-point BMI increase), and continued throughout the 6-month follow-up period. Participants who were underweight at baseline gained most weight. Participants who were obese at baseline did not gain more weight during treatment. Weight gain occurred irrespective of whether weight loss was a symptom of current depressive episode and was identified as an undesired effect of the antidepressant by most participants who gained weight. There was little weight change during treatment with escitalopram, with an average increase of 0.14 kg (0.05-point BMI increase) over 12 wk of treatment. In conclusion, treatment with the tricyclic antidepressant nortriptyline was associated with moderate weight gain, which cannot be explained as a reversal of symptomatic weight loss and is usually perceived as an undesired adverse effect. While treatment with nortriptyline may be recommended in underweight subjects with typical neurovegetative symptoms, escitalopram is a suitable alternative for subjects at risk of weight gain.