Incidence of depression and influence of depression on the number of treatment cycles and births in a national cohort of 42,880 women treated with ART.

STUDY QUESTION: Does prior depression in women treated with assisted reproduction technology (ART) influence the number of treatment cycles and ART live births? SUMMARY ANSWER: Women with a depression diagnosis prior to ART treatment initiated statistically significantly fewer ART treatment cycles and had a lower mean number of ART live births compared with women with no history of depression. WHAT IS KNOWN ALREADY: Previous studies have shown an increased prevalence of depressive symptoms in fertility patients than in the comparison groups. STUDY DESIGN, SIZE, DURATION: A register-based national cohort study, including all women (n = 42,915) treated with IVF, ICSI, frozen embryo transfer and oocyte recipient cycle in Denmark from 1 January 1994 to 30 September 2009 extracted from the IVF register (ART cohort). Data on births and depression diagnoses were obtained by linking to the Danish Medical Birth Register (1994-2010) and the Danish Psychiatric Central Research Register (1969-2010). PARTICIPANTS/MATERIALS, SETTING, METHODS: For each woman in the ART cohort, we included five age-matched women from the female background population not having received ART treatment. This comparison group was cross-linked with identical register data as the ART cohort. Women with incomplete ART information or a depression diagnosis before 18 years of age were excluded; remaining n = 42,880. The ART cohort was grouped into (i) women with a depression diagnosis and (ii) women never diagnosed with depression. In the ART group with depression, analyses were specified on women with their first depression prior to ART treatment. In total, 2.6% of the women in the ART cohort had a depression diagnosis. For the incidence rate ratio (IRR) 39,194 women from the ART cohort (3686 women were excluded due to migration) were compared with 206,005 women from the age-matched comparison group who did not receive ART treatment. MAIN RESULTS AND THE ROLE OF CHANCE: Of the women in the ART cohort with a depression diagnosis, 34.7% had their first depression diagnosis prior to ART treatment, 4.7% during ART treatment and 60.7% after ART treatment. The mean number of initiated ART cycles was significantly lower in the ART group of women having a depression diagnosis prior to ART treatment [2.55 (±1.78)] compared with the ART group of women without a depression diagnosis [3.22 (±2.31); P < 0.001; P < 0.001]. Women having a depression diagnosis prior to ART treatment had a lower mean number of ART live births [0.82 (±0.73)] compared with women without a depression diagnosis [1.03 (±0.81); P < 0.001]. The incidence rate of first and recurrent depression diagnoses in the ART cohort was significantly lower compared with the age-matched background population group; IRR = 0.80 (P < 0.001) and IRR = 0.77 (P < 0.001). LIMITATIONS, REASONS FOR CAUTION: Only clinical depression diagnoses treated in a psychiatric hospital setting are included. The age-matched comparison group from the background population is heterogeneous as it consists of women differing in fertility status (both mothers and childless women). WIDER IMPLICATIONS OF THE FINDINGS: Fewer women in the ART cohort developed depression over time compared with the age-matched background population, which might reflect a healthy patient effect of the women seeking ART treatment. Women with a depression diagnosis before ART treatment receive fewer ART treatments and are less likely to achieve an ART live birth. These women might be more vulnerable and we recommend that they be offered more psychiatric attention before starting, as well as during and after ART treatment. STUDY FUNDING/COMPETING INTEREST(S): Research grants are funded by the Danish Health Insurance Foundation and Merck Sharp & Dohme. The funders had no influence on the data collection, analyses or conclusions of the study. No conflict of interests to declare. TRIAL REGISTRATION NUMBER: N/A.

The association between antidepressant use and assisted reproductive technology (ART) treatment in Danish women: A national registry-based cohort study.

OBJECTIVE: To investigate (1) if antidepressant use among women in assisted reproductive technology (ART) treatment and among women without ART treatment influences cumulative live birth rates (CLBR) and number of initiated treatment cycles per woman, (2) whether women undergoing ART treatment are at higher risk of initiating use of antidepressants compared to women not having undergone ART, (3) if mothers after ART treatment have higher risk for postpartum use of antidepressants after ART treatment compared to mothers not having used ART treatment. STUDY DESIGN: A Danish nation-wide register-based cohort study including all women in ART treatment between 1995 through 2009 and an age-matched comparison group of women not having initiated ART treatment. In both groups, women had no previous children before study entry. The women were followed from time of initiating first ART treatment until time of permanent emigration (> 6 months), date of death, or end of follow-up by 31st of December 2009. Chi-square test was used to assess whether observed differences in CLBR between groups were significant. Adjusted incidence rates (IR) and incidence rate ratio (IRR) with 95 % confidence interval (CI) were calculated using Poisson regression analysis. The main outcome measures were: CLBR, number of initiated ART treatment cycles and IRR of initiating antidepressant use. RESULTS: Women using antidepressants before, during or after ART treatment were significantly older, had a lower CLBR and a lower mean number of initiated ART treatment cycles compared to women in ART treatment with no use of antidepressants. No significant difference was found in the incidence of initiating antidepressant use between women in ART treatment and the comparison group. However, when comparing only women with a live birth, significantly more women in ART treatment initiated antidepressant use in the postpartum period (adjusted incidence rate ratio (IRR) = 2.56 (95 % CI 1.98-3.30; p < 0.001)). CONCLUSION: Generally, women undergoing ART treatment are not at higher risk of initiating use of antidepressants compared with an age-matched comparison group not treated with ART. However, women with antidepressant medication use prior to ART initiate fewer ART treatments and have lower CLBR. Even though it has not been possible to adjust for all relevant confounders and our follow-up period only runs until the end of 2009, we still believe the results of this study to be highly relevant. According to our study, clinicians should be aware that women conceiving after ART treatment might experience an increased level of psychological strain during the postpartum period compared to mothers who conceived without ART.

Depression among men in ART treatment: a register-based national cohort study.

STUDY QUESTION: Are male factor infertility or remaining childless risk factors for unipolar depression among men in assisted reproductive technology (ART) treatment? SUMMARY ANSWER: Male factor infertility was not associated with a significantly increased risk of unipolar depression and men remaining childless did not have a significantly increased risk of developing unipolar depression compared to men in ART treatment who became fathers. WHAT IS KNOWN ALREADY: Men in medically assisted reproduction due to male factor infertility are more distressed and have more negative emotions such as feelings of loss, stigma and low self-esteem compared to men in fertility treatment due to other infertility diagnosis. Stress is in general a risk factor for depression. However, previous studies show conflicting results whether male factor infertility is a risk factor for depression. STUDY DESIGN SIZE DURATION: This national, register-based cohort study consisted of 37 913 cohabitant male partners of women in ART treatment recorded in the Danish IVF register (1994-2009). Via a national register, the men's personal identification number data were linked to the Danish Psychiatric Central Research Register (PCRR) (1969-2009) which records psychiatric diagnoses including unipolar depression, based on the ICD-8 and ICD-10 classification system. PARTICIPANTS/MATERIALS SETTING METHODS: The full cohort of male partners (n = 37 913) was included in the initial analysis on prevalence of unipolar depression before or after ART treatment initiation. The association between male factor infertility and unipolar depression diagnosis after initiating ART treatment was analysed with Cox regression analysis in a sub-study population of men with the exclusion of men having a depression prior to ART treatment or not having full data on educational level and infertility diagnosis (n = 34 817). MAIN RESULTS AND THE ROLE OF CHANCE: Overall, 1.2% (n = 446) of the men were diagnosed with unipolar depression either before initiating ART treatment (n = 146) or during follow-up (n = 300). In all, 76.0% of men with depression prior to or after ART treatment achieved fatherhood compared to 82.3% of men without depression (P < 0.001). In the sub-study population (n = 34 817, which included 266 men with a unipolar depression diagnosis), male factor infertility was not associated a significantly increased risk of depression (adjusted hazard ratio (aHR) = 1.04, 95% CI: 0.79-1.36, P = 0.804), and ART-treated men who remained childless did not have a significantly increased risk of developing depression compared to ART treated men who became fathers (aHR = 1.13, 95% CI: 0.87-1.48, P = 0.355). LIMITATIONS REASONS FOR CAUTIONS: Only severe cases of depression are recorded and included in this national register-based study given that only men with clinically diagnosed unipolar depression recorded in a psychiatric hospital (in-patient and out-patient) are included in the Danish PCRR. It is difficult to completely rule out an association between the exposures and depression as this outcome is so rare, and therefore the results are still statistically uncertain despite a large cohort. Furthermore, only men in ART treatment were included in this study, and caution should be taken in generalising findings to the total population of men in all areas of medically assisted reproduction or infertile men who have not sought treatment. WIDER IMPLICATIONS OT THE FINDINGS: This large national cohort study suggests that despite evidence showing that male factor infertility is a potential severe stressor for men, which can increase psychological distress and negative emotions, infertile men in ART treatment and men remaining childless after ART are not at a significantly increased risk of developing clinically diagnosed unipolar depression. STUDY FUNDING/COMPETING INTERESTS: C.S.S. was funded by unrestricted research grants received by Lone Schmidt from The Danish Health Insurance Foundation (J.nr. 2008B105) and Merck Sharp & Dohme (MSD). The sponsors had no influence on how data were retrieved and analysed or on the conclusions of the study. C.S.S. and L.S. have declared conflicts of interests; the remaining co-authors have no conflicts of interests to declare. TRIAL REGISTRATION NUMBER: Not applicable.

Familial Mediterranean Fever (FMF): a single centre retrospective study in Amsterdam.

BACKGROUND: Familial Mediterranean Fever (FMF) is the earliest described and most prevalent hereditary auto-inflammatory disease. Its clinical presentation is diverse, leading to possible delay in diagnosis and treatment. Due to immigration, FMF became common in non-Mediterranean European regions. In the present single centre retrospective study, the clinical, demographic, and genetic characteristics of patients with FMF of different ancestry in Amsterdam are described. METHODS: Case records of patients with FMF, who met the Tel-Hashomer diagnostic criteria, were retrospectively analysed. The international disease severity score was used. RESULTS: Between 1990-2012, 53 patients were identified, 28 were female. Main country of origin was Turkey. The mean age at the time of analysis was 29.1 years; 13.8 years at onset of symptoms; and at time of diagnosis, 22.0 years. Most frequent symptoms were peritonitis (91%) and fever (81%). The mean C-reactive protein and erythrocyte sedimentation rate during acute attacks were 133 mg/l and 37 mm/first hour, respectively. One patient developed amyloidosis as a complication. Seventeen patients underwent abdominal surgery before diagnosis. Most patients (92%) received colchicine treatment and were responsive (81%). Most patients classified their disease as a mild disease (42%). MEFV gene mutation analysis was performed in 46 patients; most patients were compound heterozygotes (n = 17), and the most frequent mutation was M694V (n = 18). CONCLUSION: FMF in Amsterdam is diagnosed in relatively young patients and the delay to diagnosis is 8.2 years. Disease manifestations and genetic distribution of our FMF patients are comparable to those in Mediterranean regions, suggesting that ancestry is more important than environment.

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.

Complaints of stress in young soldiers strongly predispose to psychiatric morbidity and mortality: Danish national cohort study with 10-year follow-up.

OBJECTIVE: Serving military can be regarded as exposure to a moderate enforced stressor independent of other vulnerability factors. The aims of this study were i) to explore psychiatric morbidity and mortality during 10 years of follow-up in a cohort of healthy adolescent Danish conscripts and ii) to investigate whether stress-related disorders precede other psychiatric disorders. METHOD: Controlled national cohort study on all psychiatric hospital contacts in young men referred to the Military Psychiatric Department (MPD) with 10 years of follow-up. RESULTS: During the follow-up period, 24% of conscripts seen at the MPD were diagnosed with a psychiatric disorder compared with 4% in the control cohort. Almost all diagnostic categories were over-represented but especially psychotic disorders. Mortality was substantially increased. Of subjects initially diagnosed with stress-related disorders at the MPD, 20% later on developed psychopathology. CONCLUSION: Young healthy men complaining of mental distress following a stressor are strongly disposed to psychiatric morbidity and mortality. The study suggests that stress-related disorders often precede more severe psychopathology.

Anti-diabetogenic effect of fusidic acid in diabetes prone BB rats.

Fusidic acid and its sodium salt (fusidin) are anti-staphylococcal drugs. In vitro studies have shown that they prevent the lymphocyte co-stimulatory activities of the cytokines IL-1 and IL-6 in a manner similar to that of cyclosporin A, and prevent the inhibitory effect of IL-1 on glucose-induced insulin production. As IL-1 and IL-6 are thought to play a role in the pathogenesis of Type 1 diabetes, the aim of this study was to investigate whether fusidin could influence the disease incidence of the spontaneously diabetic BB rat model. Accordingly, a group of 50 BB rats receiving fusidin dissolved in their drinking water were compared to a control group of 55 rats over a period of 200 days. The incidence of diabetes was found to be 52% in the experimental group and 71% in the control group (P < 0.05). The degree of insulitis and the number of islets at histological examination were similar among the non-diabetic animals whereas the diabetic fusidin-treated animals showed a higher degree of islet preservation than the diabetic control rats. The results are highly indicative of an anti-diabetogenic effect of fusidin.

Neonatal treatment of BB rats with sulphatide delays development of diabetes but does not change incidence.

Sulphatide is a newly described autoantigen in insulin-dependent diabetes mellitus; it is present in the islets of Langerhans, and anti-sulphatide antibodies are found in diabetic patients and in spontaneously diabetic BB rats. The aim of the study was to treat neonatal BB rats with sulphatide in order to induce tolerance and thereby possibly influence later diabetes development. One hundred and twelve newborn BB rats, divided into three groups, were treated once daily during the first 6 days of life with intrathymic injections of sulphatide, galactosyl-ceramide (which is similar to sulphatide but without sulphate) or phosphate buffer alone. Although the results showed no difference in diabetes incidence among the three groups, there was a delayed onset of diabetes in the sulphatide-treated group, which developed diabetes on average at 77 +/- 1 days of age, compared to 70 +/- 2 days (p < 0.02) for the galactosyl-ceramide-treated group and 70 +/- 1 days (p < 0.01) for the buffer-treated group. The degree of insulitis and the size of islets of Langerhans were studied histologically for the diabetic animals in all three groups; there were no significant differences although the sulphatide-treated group tended to have a more normal histology. The blood glucose levels for the diabetic BB rats were similar in all three groups. Thus, neonatal treatment with the diabetic autoantigen sulphatide at the chosen dosage does not influence the incidence of diabetes, but delays the onset of disease.

The therapeutic or prophylactic effect of exogenous melatonin against depression and depressive symptoms: a systematic review and meta-analysis.

Circadian- and sleep disturbances may be central for understanding the pathophysiology and treatment of depression. The effect of melatonin on depression/depressive symptoms has been investigated previously. This systematic review assesses the current evidence of a therapeutic- and prophylactic effect of melatonin in adult patients against depression or depressive symptoms. A search was performed in The Cochrane Library, PubMed, EMBASE and PsycINFO for published trials on November 14th 2013. Inclusion criteria were English language, RCTs or crossover trials. Our outcome was measurement of depression/depressive symptoms with a validated clinician-administered or self-rating questionnaire. PRISMA recommendations were followed and the Cochrane risk-of-bias tool used. Ten studies in 486 patients were included in the final qualitative synthesis and four studies, 148 patients, were included in two meta-analyses. Melatonin doses varied from 0.5-6 mg daily and the length of follow-up varied from 2 weeks to 3.5 years. Three studies were done on patients without depression at inclusion, two studies in patients with depression and five studies included a mixture. Six studies showed an improvement in depression scores in both the melatonin and placebo groups but there was no significant difference. One study showed a significant prophylactic effect and another found a significant treatment effect on depression with melatonin compared to placebo. The two meta-analyses did not show any significant effect of melatonin. No serious adverse events were reported. Although some studies were positive, there was no clear evidence of a therapeutic- or prophylactic effect of melatonin against depression or depressive symptoms.

Morphological effects of sodium fusidate (fusidin) on pancreatic islet cells: an electron microscopic study.

Fusidic acid has been shown to prevent the lymphocyte co-stimulatory activities of cytokines and seems--in preliminary trials--clinically effective as an immunoregulatory drug e.g. in insulin-dependent diabetes mellitus. A toxic effect of fusidic acid may however be suspected since a previous study showed a significant dilatation of rough endoplasmic reticulum in cultured pancreatic islet cells from normal rats. In this study we examined the ultrastructural effects of the sodium salt of fusidic acid (fusidin) on cultured rat islet cells (treatment period 3-5 days), and of islet cells from rats receiving fusidin for 6 days. Electron microscopically, fusidin treatment in vitro (3 to 30 micrograms/ml) showed a significant dilatation of the rough endoplasmic reticulum of islet cells. No dose dependent changes were found. In the in vivo model no changes were demonstrated in concentrations of fusidin up to 9.64 micrograms/ml of homogenated pancreatic tissue. It is concluded that treatment with fusidin gives no detectable ultrastructural changes in vivo.

Post-traumatic stress disorder: a review of psychobiology and pharmacotherapy.

OBJECTIVE: To review the literature on the psychobiology and pharmacotherapy of PTSD. METHODS: Relevant studies were identified by literature searches (Pub-med, Web of Science) and through reference lists. The search was ended by May 2001. RESULTS: There is evidence of involvement of opioid, glutamatergic, GABAergic, noradrenergic, serotonergic and neuroendocrine pathways in the pathophysiology of PTSD. Medications shown to be effective in double-blind placebo-controlled trials includes selective serotonin reuptake inhibitors, reversible and irreversible MAO-inhibitors, tricyclic antidepressants and the anticonvulsant lamotrigine. Still more agents appear promising in open-label trials. CONCLUSION: The complexity of the psychobiology is reflected by the difficulties in treating the disorder. According to the present knowledge, suggestions for drug treatment of PTSD are made.

Neonatal treatment with beta-cell stimulatory agents reduces the incidence of diabetes in BB rats.

The aim of the study was to investigate whether various beta-cell stimulatory drugs, given neonatally, influence the incidence of diabetes in BB rats. Newborn BB rats were treated twice daily for 6 days and diabetes development was observed during the following 200-day study period. Compared to a diabetes incidence of 63.8% in 163 control BB rats which received saline or were untreated, the percentage of experimental BB rats that developed diabetes was as follows in the different subgroups: arginine-glucose: 47% (n = 73, p < 0.02); glucagon: 37% (n = 93, p < 0.0001); tolbutamide-glucose: 36% (n = 58, p < 0.0005); and theophylline-glucose: 39% (n = 41, p < 0.005). A long-term arginine-glucose treatment was not superior to the shorter neonatal treatment. Histological examination revealed a higher degree of insulitis in diabetic than in non-diabetic animals but no difference according to the kind of treatment was observed. Finally, we found that the diabetes incidence in BB rats was higher in the first litter compared to subsequent litters (p = 0.04). Thus, neonatal treatment with various beta-cell stimulatory agents reduces diabetes incidence in BB rats. The theory behind the study, that the treatment accelerates beta-cell maturation leading to increased immunological tolerance towards beta cells, is discussed.