Ida Hageman

Comparison of propofol and thiopental as anesthetic agents for electroconvulsive therapy: a randomized, blinded comparison of seizure duration, stimulus charge, clinical effect, and cognitive side effects.

Objectives: To compare propofol and thiopental as anesthetic agents for electroconvulsive therapy (ECT) with respect to seizure duration, stimulus charge, clinical effect, and cognitive side effects. Methods: Randomized, blinded study of 62 depressed patients treated with bilateral ECT. Algorithm-based charge dosing was used. Results: The mean seizure duration of the patients in the thiopental group was 36.3 seconds versus 25.7 seconds in the propofol group (P = 0.001). The charge per treatment was 79.5 mC in the thiopental group versus 109.8 mC in the propofol group (P = 0.026). Sixteen patients in the propofol group (52%) reached the highest electrical dose versus 8 patients (26%) in the thiopental group (P = 0.014). No difference in response to treatment or number of treatments was observed. The mean score on Mini-Mental State Examination (MMSE) was 28.9 in the thiopental group versus 26.8 in the propofol group (P = 0.014). However, age distribution of patients completing the study differed between the groups. Conclusions: Propofol significantly decreases seizure duration without significant difference in the clinical outcome. Using the employed treatment algorithm, patients anesthetised with propofol received higher electrical charge. Mini-Mental State Examination scores suggest that this results in more severe cognitive side effects. Results, however, might be confounded by the differences in age distribution in the groups.

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.

Electroconvulsive stimulations normalizes stress-induced changes in the glucocorticoid receptor and behaviour.

Animal models of chronic stress, such as 21 days of 6h/daily restraint stress cause changes in neuronal morphology in the hippocampus and alter behaviour. These changes are partly mediated by the glucocorticoids. The objective of this study was threefold: (1) to study how this particular chronic stress paradigm influences expression of hippocampal glucocorticoid receptor mRNA, (2) to study the effect of previous repeated restraint stress on the behaviours executed in the forced swim test (FST) (e.g. a novel inescapable stress situation) and (3) to investigate the modulating effect of electroconvulsive stimulations (ECS) on the neural and behavioural effects of the stress paradigm. The study shows that restraint stress lowered glucocorticoid receptor mRNA levels in all hippocampal regions, including the CA3 region which is the site of the characteristic dendritic reorganization seen in this model. Furthermore, stressed rats displayed higher increases in immobility and decreased latency to immobility subjected to the novel stressor of the FST than non-stressed rats. ECS abolished both the neural and behavioural effects of the restraint stress and thus protected against the deleterious effects of the stress paradigm. The clinical relevance of these findings is discussed.

The effect of MELatOnin on Depression, anxietY, cognitive function and sleep disturbances in patients with breast cancer. The MELODY trial: protocol for a randomised, placebo-controlled, double-blinded trial

Introduction Breast cancer represents about one-third of all cancer diagnoses and accounts for about 15% of cancer deaths in women. Many of these patients experience depression, anxiety, sleep disturbances and cognitive dysfunction. This may adversely affect quality of life and also contribute to morbidity and mortality. Melatonin is a regulatory circadian hormone having, among others, a hypnotic and an antidepressive effect. It has very low toxicity and very few adverse effects compared with the more commonly used antidepressants and hypnotics. Methods and analysis The objective of this double-blind, randomised, placebo-controlled trial is to investigate whether treatment with oral melatonin has a prophylactic or ameliorating effect on depressive symptoms, anxiety, sleep disturbances and cognitive dysfunction in women with breast cancer. Furthermore, the authors will examine whether a specific clock-gene, PER3, is correlated with an increased risk of depressive symptoms, sleep disturbances or cognitive dysfunction. The MELODY trial is a prospective double-blinded, randomised, placebo-controlled trial in which the authors intend to include 260 patients. The primary outcome is depressive symptoms measured by the Major Depression Inventory. The secondary outcomes are anxiety measured by a Visual Analogue Scale, total sleep time, sleep efficiency, sleep latency and periods awake measured by actigraphy and changes in cognitive function measured by a neuropsychological test battery. Tertiary outcomes are fatigue, pain, well-being and sleep quality/quantity measured by Visual Analogue Scale and sleep diary and sleepiness measured by the Karolinska Sleepiness Scale. The PER3 genotype is also to be determined in blood samples.

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.

Seasonal difference in brain serotonin transporter binding predicts symptom severity in patients with seasonal affective disorder

Cross-sectional neuroimaging studies in non-depressed individuals have demonstrated an inverse relationship between daylight minutes and cerebral serotonin transporter; this relationship is modified by serotonin-transporter-linked polymorphic region short allele carrier status. We here present data from the first longitudinal investigation of seasonal serotonin transporter fluctuations in both patients with seasonal affective disorder and in healthy individuals. Eighty (11)C-DASB positron emission tomography scans were conducted to quantify cerebral serotonin transporter binding; 23 healthy controls with low seasonality scores and 17 patients diagnosed with seasonal affective disorder were scanned in both summer and winter to investigate differences in cerebral serotonin transporter binding across groups and across seasons. The two groups had similar cerebral serotonin transporter binding in the summer but in their symptomatic phase during winter, patients with seasonal affective disorder had higher serotonin transporter than the healthy control subjects (P = 0.01). Compared to the healthy controls, patients with seasonal affective disorder changed their serotonin transporter significantly less between summer and winter (P < 0.001). Further, the change in serotonin transporter was sex- (P = 0.02) and genotype- (P = 0.04) dependent. In the patients with seasonal affective disorder, the seasonal change in serotonin transporter binding was positively associated with change in depressive symptom severity, as indexed by Hamilton Rating Scale for Depression - Seasonal Affective Disorder version scores (P = 0.01). Our findings suggest that the development of depressive symptoms in winter is associated with a failure to downregulate serotonin transporter levels appropriately during exposure to the environmental stress of winter, especially in individuals with high predisposition to affective disorders.media-1vid110.1093/brain/aww043_video_abstractaww043_video_abstract.

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.

Electroconvulsive stimulations prevent chronic stress-induced increases in L-type calcium channel mRNAs in the hippocampus and basolateral amygdala.

Although affective disorders have high prevalence, morbidity and mortality, we do not fully understand disease etiopathology, nor have we determined the exact mechanisms by which treatment works. Recent research indicates that intracellular calcium ion dysfunction might be involved. Here we use the chronic restraint stress model of affective disorder (6 h restraint per day for 21 days) in combination with electroconvulsive stimulations to examine the effects of stress and an effective antidepressive treatment modality on L-type voltage gated calcium channel subunit mRNA expression patterns in the brain. We find that stress tended to upregulate Ca(v)1.2 and Ca(v)1.3 channels in a brain region specific manner, while ECS tended to normalise this effect. This was more pronounced for Ca(v)1.2 channels, where stress clearly increased expression in both the basolateral amygdala, dentate gyrus and CA3, while stress only upregulated Ca(v)1.3 channel expression significantly in the dentate gyrus. ECS effects on Ca(v)1.2 channel expression were generally specific to stressed animals. Our findings are consistent with and extent previous studies on the involvement of intracellular calcium ion dysfunction in affective disorders. Selective modulation of neuronal L-type voltage gated calcium channels appears to be a promising target for the development of novel antidepressive treatment modalities.

Antipsychotic polypharmacy in a treatment-refractory schizophrenia population receiving adjunctive treatment with electroconvulsive therapy.

Background Antipsychotic polypharmacy (APP) is frequent, but its pattern is unknown in treatment-refractory schizophrenia-spectrum patients receiving electroconvulsive therapy (ECT). Methods We performed a retrospective chart review of ECT-treated inpatients hospitalized at 2 Danish University hospitals from 2003 to 2008, focusing on APP patterns in patients with schizophrenia-spectrum disorders (n = 79, 13.2%). In addition to univariate analyses, a multivariate logistic regression analysis was performed to identify independent predictors of APP. Results Of 79 antipsychotic-treated patients (aged 48.6 ± 14.2 years; illness duration, 18.3 ± 10.6 years) ultimately treated with ECT, 86.1% received 2 or more psychotropic medications, including mood stabilizers (19.0%), antidepressants (32.9%), and APP (72.2%; 2 antipsychotics = 41.8%, 3 = 21.5%, 4–5 = 7.6%). Most patients received first-generation antipsychotic (FGA) + second-generation antipsychotic (SGA) (48.1%), followed by SGA + SGA (24.1%), SGA monotherapy (22.8%), and FGA monotherapy (5.1%). Individual antipsychotics included olanzapine (44.3%), risperidone (26.6%), clozapine (26.6%), quetiapine (22.1%), ziprasidone (13.9%), aripiprazole (10.1%), and sertindole (3.8%). Antipsychotic polypharmacy was associated with a greater number of FGAs (0.8 ± 0.7 vs 0.1 ± 0.4, P < 0.0001) and SGAs (1.7 ± 0.8 vs 0.8 ± 0.4, P < 0.0001), zuclopenthixol use (31.6% vs 0%, P = 0.0019), olanzapine use (52.6% vs 22.7%, P = 0.017), less serotonin-noradrenaline reuptake inhibitor use (3.5% vs 18.2%, P = 0.027), and a trend toward more good to excellent ECT response (86.0% vs 68.2%, P = 0.071). In the logistic regression analysis, APP was independently associated with a higher number of FGAs (P = 0.0002) and olanzapine use (P = 0.0098) (r2 = 0.314, P < 0.0001). Discussion Only 22.6% of this treatment-refractory population received clozapine, yet 72.4% received APP. Following the results from our study as well as the general level of evidence, patients with refractory schizophrenia-spectrum disorder should receive clozapine or ECT before being tried on APP.

Psychiatric disorders among women and men in assisted reproductive technology (ART) treatment. The Danish National ART-Couple (DANAC) cohort: protocol for a longitudinal, national register-based cohort study

Introduction There are complex causal associations between mental disorders, fertility treatment, fertility treatment outcome and infertility per se. Eating disorders cause endocrine disturbances, anovulation and thereby infertility, and research has shown that infertility as well as unsuccessful assisted reproductive technology (ART) treatment are potential risk factors for developing a depression on a long-term basis. Despite the fact that worldwide more than 400 000 ART treatment cycles are performed every year, the causal associations between mental disorders, use of medication for mental disorders and ART treatment in both sexes have only been sparsely explored. Method and analysis The main objective of this national register-based cohort study is to assess womens and mens mental health before, during, and after ART treatment in comparison with the mental health in an age-matched population-based cohort of couples with no history of ART treatment. Furthermore, the objective is to study the reproductive outcome of ART treatment among women who have a registered diagnosis of a mental disorder or have used medication for mental disorders prior to ART treatment compared with women in ART treatment without a mental disorder. We will establish the Danish National ART-Couple (DANAC) cohort including all women registered with ART treatment in the Danish in vitro fertilisation Register during 1994–2009 (N=42 915) and their partners. An age-matched population-based comparison cohort of women without ART treatment (n=215 290) and their partners will be established. Data will be cross-linked with data from national registers on psychiatric disorders, medical prescriptions for mental disorders, births, causes of deaths and sociodemographic data. Survival analyses and other statistical analyses will be conducted on the development of mental disorders and use of medication for mental disorders for women and men both prior to and after ART treatment.