Lumateperone-mediated effects on prefrontal glutamatergic receptor-mediated neurotransmission: A dopamine D1 receptor dependent mechanism.

Lumateperone is a novel drug approved for the treatment of schizophrenia in adults and depressive episodes associated with bipolar depression in adults, as monotherapy and as adjunctive therapy with lithium or valproate treatment in the United States. Lumateperone simultaneously modulates key neurotransmitters, such as serotonin, dopamine, and glutamate, implicated in serious mental illness. In patients with schizophrenia, lumateperone was shown to improve positive symptoms along with negative and depressive symptoms, while also enhancing prosocial behavior. Moreover, in patients with bipolar I or II disorder, lumateperone improved depressive symptoms as well. To further understand the mechanisms related to lumateperone's clinical response, the aim of this study was to investigate the effect of lumateperone on dopaminergic- and glutamatergic signaling in the rat medial prefrontal cortex (mPFC). We used the conditioned avoidance response (CAR) test to determine the antipsychotic-like effect of lumateperone, electrophysiology in vitro to study lumateperone's effects on NMDA- and AMPA-induced currents in the mPFC, and the neurochemical techniques microdialysis and amperometry to measure dopamine- and glutamate release in the rat mPFC. Our results demonstrate that lumateperone; i) significantly suppressed CAR in rats, indicating an antipsychotic-like effect, ii) facilitated NMDA and AMPA receptor-mediated currents in the mPFC, in a dopamine D1-dependent manner, and iii) significantly increased dopamine and glutamate release in the rat mPFC. To the extent that these findings can be translated to humans, the ability of lumateperone to activate these pathways may contribute to its demonstrated effectiveness in safely improving symptoms related to neuropsychiatric disorder including mood alterations.

Exposure to risperidone versus other antipsychotics and risk of osteoporosis-related fractures: a population-based study.

OBJECTIVE: Antipsychotics may increase serum prolactin, which has particularly been observed with risperidone. Further, hyperprolactinemia has been linked to osteoporosis-related fractures. Therefore, we investigated fracture risk in a nationwide cohort exposed to antipsychotics. METHODS: Swedish registers were used to identify adults with two consecutive dispensations of risperidone (n = 38 211), other atypical antipsychotics not including paliperidone (n = 60 691), or typical antipsychotics (n = 17 445) within three months between 2006 and 2013. An osteoporosis-related fracture was defined as a non-open hip/femur fracture in primary analyses. Cox regression was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). RESULTS: Risperidone users were on average older (mean age of 68, 44, and 63 years for risperidone, other atypical antipsychotics, and typical antipsychotics respectively). Compared with other atypical antipsychotics, there was no association between risperidone and osteoporosis-related fractures in the overall (HR = 1.04, CI: 0.91-1.19) or age-stratified analyses. A significantly increased risk of typical antipsychotics (HR = 1.24, CI: 1.07-1.45) compared with other atypical antipsychotics remained for ages >45 years. CONCLUSION: Risperidone does not appear to be associated with an increased risk of osteoporosis-related fracture compared with other atypical antipsychotic agents as a group. For typical antipsychotics, a moderately elevated risk of hip fractures was noted compared with other atypical antipsychotics, possibly because of residual confounding.

Age-dependent regulation of host seeking in Anopheles coluzzii.

Behavioural attraction of the malaria vector Anopheles coluzzii to human host odour increases during adult maturation. We have previously demonstrated that the onset of host seeking in An. coluzzii coincides with an increased sensitivity of the CO2-sensitive neurons and abundance of chemosensory receptor gene transcripts in the maxillary palp. In this study, we extend our analysis to the antenna. Functional characterisation of the near-complete repertoire of odorant receptors (Ors) expressed in this tissue, to fractioned human odour, reveals a subset of salient human odorants to be detected by Ors at physiological relevant concentrations. When presented as a blend in their ratio of natural emission, these odorants elicit attraction by host-seeking mosquitoes, emphasising that Ors alone can mediate this behaviour. However, the same blend inhibits attraction in teneral mosquitoes. This switch in behavioural response indicates a change in valence during adult maturation. Quantitative analysis of Or transcript abundance and in vivo electrophysiological analysis reveal that the olfactory system of female An. coluzzii undergoes concerted changes that correlate with the onset of host seeking. We conclude that changes in Or abundance modulate peripheral olfactory coding, resulting in ecologically relevant behavioural effects.

Invasive Dental Treatment and Risk for a First Myocardial Infarction.

Invasive dental treatment is suggested to be associated with an increased risk for the development of cardiovascular events. We tested the hypothesis that the incidence of a first myocardial infarction (MI) within 4 wk after invasive dental treatments is increased. A registry-based case-control study within nationwide health care and population registries in Sweden was performed. The case patients included 51,880 individuals with a first fatal or nonfatal MI between January 2011 and December 2013. For each case, 5 control subjects, free from prior MI and matched for age, sex, and geographic area of residence, were randomly selected from the national population registry through risk set sampling with replacement, resulting in 246,978 control subjects. Information on dental treatments was obtained from the Dental Health Register, and the procedures were categorized into invasive dental treatments or other dental treatments. Conditional logistic regression was used to estimate odds ratios (ORs) for MI with corresponding 95% confidence intervals (CIs). In addition to the matching variables, adjustments were made for the following confounders: diabetes, previous cardiovascular disease (CVD), CVD drug treatment, education, and income. The mean age for case patients and controls subjects was 72.6 ± 13.0 y and 72.3 ± 13.0 y, respectively. Case patients more often had previous CVD (49% vs. 23%; P < 0.001) and diabetes (19% vs. 11%; P < 0.001) and received more treatment with CVD drugs (68% vs. 56%; P < 0.001) than control subjects. There was no association between invasive dental treatments during the 4 wk preceding the MI index date (crude OR = 0.99; 95% CI, 0.92 to 1.06; adjusted for confounders OR = 0.98; 95% CI, 0.91 to 1.06). This study did not support the hypothesis of an increased incidence of MI after recent invasive dental treatment.

Temperature-controlled airflow ventilation in operating rooms compared with laminar airflow and turbulent mixed airflow.

AIM: To evaluate three types of ventilation systems for operating rooms with respect to air cleanliness [in colony-forming units (cfu/m3)], energy consumption and comfort of working environment (noise and draught) as reported by surgical team members. METHODS: Two commonly used ventilation systems, vertical laminar airflow (LAF) and turbulent mixed airflow (TMA), were compared with a newly developed ventilation technique, temperature-controlled airflow (TcAF). The cfu concentrations were measured at three locations in an operating room during 45 orthopaedic procedures: close to the wound (<40cm), at the instrument table and peripherally in the room. The operating team evaluated the comfort of the working environment by answering a questionnaire. FINDINGS: LAF and TcAF, but not TMA, resulted in less than 10cfu/m3 at all measurement locations in the room during surgery. Median values of cfu/m3 close to the wound (250 samples) were 0 for LAF, 1 for TcAF and 10 for TMA. Peripherally in the room, the cfu concentrations were lowest for TcAF. The cfu concentrations did not scale proportionally with airflow rates. Compared with LAF, the power consumption of TcAF was 28% lower and there was significantly less disturbance from noise and draught. CONCLUSION: TcAF and LAF remove bacteria more efficiently from the air than TMA, especially close to the wound and at the instrument table. Like LAF, the new TcAF ventilation system maintained very low levels of cfu in the air, but TcAF used substantially less energy and provided a more comfortable working environment than LAF. This enables energy savings with preserved air quality.

The continuous reaction time test for minimal hepatic encephalopathy validated by a randomized controlled multi-modal intervention-A pilot study.

BACKGROUND: Minimal hepatic encephalopathy (MHE) is clinically undetectable and the diagnosis requires psychometric tests. However, a lack of clarity exists as to whether the tests are in fact able to detect changes in cognition. AIM: To examine if the continuous reaction time test (CRT) can detect changes in cognition with anti-HE intervention in patients with cirrhosis and without clinically manifest hepatic encephalopathy (HE). METHODS: Firstly, we conducted a reproducibility analysis and secondly measured change in CRT induced by anti-HE treatment in a randomized controlled pilot study: We stratified 44 patients with liver cirrhosis and without clinically manifest HE according to a normal (n = 22) or abnormal (n = 22) CRT. Each stratum was then block randomized to receive multimodal anti-HE intervention (lactulose+branched-chain amino acids+rifaximin) or triple placebos for 3 months in a double-blinded fashion. The CRT is a simple PC-based test and the test result, the CRT index (normal threshold > 1.9), describes the patient's stability of alertness during the 10-minute test. Our study outcome was the change in CRT index in each group at study exit. The portosystemic encephalopathy (PSE) test, a paper-and-pencil test battery (normal threshold above -5), was used as a comparator test according to international guidelines. RESULTS: The patients with an abnormal CRT index who were randomized to receive the active intervention normalized or improved their CRT index (mean change 0.92 ± 0.29, p = 0.01). Additionally, their PSE improved (change 3.85 ± 1.83, p = 0.03). There was no such effect in any of the other study groups. CONCLUSION: In this cohort of patients with liver cirrhosis and no manifest HE, the CRT identified a group in whom cognition improved with intensive anti-HE intervention. This finding infers that the CRT can detect a response to treatment and might help in selecting patients for treatment.

High serum total cholesterol is associated with suicide mortality in Japanese women.

OBJECTIVE: To investigate the association between serum total cholesterol (TC) and suicide using a large general population cohort with long follow-up times. METHOD: Analyses included 16 341 men and 28 905 women aged 40-69 from the Japan Public Health Center-based Prospective Study followed from 1990 to 2012. TC levels were defined per clinical guidelines: low (<4.66 mmol/l [180 mg/dl]), normal (4.66-5.70 mmol/l [180-220 mg/dl]), and high (≥5.70 mmol/l [220 mg/dl]). Cox proportional hazards regression models were used to determine hazard ratios (HR) and confidence intervals (CI) for suicide according to TC level. Mean follow-up time was 19 years for men and 20 years for women. RESULTS: There were 185 suicides (men: 107; women: 78) during follow-up. Compared to women with normal TC, women with high TC had a significantly increased risk of suicide (HR = 1.90, 95% CI, 1.13-3.19). Incremental increases (0.26 mmol/l [10 mg/dl]) of low-density lipoprotein (HR = 1.11, 95% CI, 1.02-1.21) and non-high-density lipoprotein cholesterol (HR = 1.09, 95% CI, 1.01-1.18) were also associated with increased risk of suicide in women. There was no association between TC levels, or lipid fractions, and suicide in men. CONCLUSION: High TC levels may be associated with an increased risk of suicide in women.

The influence of comorbidity on mortality in ovarian cancer patients.

BACKGROUND: Ovarian cancer is a severe disease with a peak incidence in the older age groups where concurrent morbidity is common and could potentially influence mortality rates. OBJECTIVES: The aim was to study the influence of common comorbidity diagnoses on mortality in ovarian cancer patients. METHODS: The study population was patients with ovarian cancer in Sweden 1993-2006 (n=11.139) identified in the national Cancer Register. Comorbidity data was obtained from the Patient Register and mortality from Cause of Death Register. Mortality was analyzed with Cox' proportional hazards models and subgroup analyses were performed by age and tumor histology. RESULTS: Almost all of the assessed comorbidities increased mortality in ovarian cancer patients. Thromboembolism was the most hazardous comorbidity (HR=1.95, <1 year after cancer diagnosis and HR=7.83, 1-5 years after cancer diagnosis) followed by hematologic complications (HR=1.84 and 7.11 respectively) and infectious disease (HR=1.48 and 5.28 respectively). The occurrence of diabetes mellitus and hypertension had less impact on mortality. CONCLUSION: Thromboembolism, hematologic complications and infections had a pronounced effect on mortality rates in women with ovarian cancer. The impact of comorbidity was mainly apparent among those with a more prosperous prognosis, such as longer time since cancer diagnosis, less aggressive tumors and younger age.

EPA guidance on tobacco dependence and strategies for smoking cessation in people with mental illness.

Tobacco dependence is the most common substance use disorder in adults with mental illness. The prevalence rates for tobacco dependence are two to four times higher in these patients than in the general population. Smoking has a strong, negative influence on the life expectancy and quality of life of mental health patients, and remains the leading preventable cause of death in this group. Despite these statistics, in some countries smokers with mental illness are disadvantaged in receiving intervention and support for their tobacco dependence, which is often overlooked or even tolerated. This statement from the European Psychiatric Association (EPA) systematically reviews the current evidence on tobacco dependence and withdrawal in patients with mental illness and their treatment. It provides seven recommendations for the core components of diagnostics and treatment in this patient group. These recommendations concern: (1) the recording process, (2) the timing of the intervention, (3) counselling specificities, (4) proposed treatments, (5) frequency of contact after stopping, (6) follow-up visits and (7) relapse prevention. They aim to help clinicians improve the care, health and well-being of patients suffering from mental illness.

Loss of a close family member the year before or during pregnancy and the risk of placental abruption: a cohort study from Denmark and Sweden.

BACKGROUND: Maternal stress during pregnancy is associated with a modestly increased risk of fetal growth restriction and pre-eclampsia. Since placental abruption shares similar pathophysiological mechanisms and risk factors with fetal growth restriction and pre-eclampsia, we hypothesized that maternal stress may be implicated in abruption risk. We investigated the association between maternal bereavement during pregnancy and placental abruption. METHOD: We studied singleton births in Denmark (1978-2008) and Sweden (1973-2006) (n = 5,103,272). In nationwide registries, we obtained data on death of women's close family members (older children, siblings, parents, and partners), abruption and potential confounders. RESULTS: A total of 30,312 (6/1000) pregnancies in the cohort were diagnosed with placental abruption. Among normotensive women, death of a child the year before or during pregnancy was associated with a 54% increased odds of abruption [95% confidence interval (CI) 1.30-1.82]; the increased odds were restricted to women who lost a child the year before or during the first trimester in pregnancy. In the group with chronic hypertension, death of a child the year before or in the first trimester of pregnancy was associated with eight-fold increased odds of abruption (odds ratio 8.17, 95% CI 3.17-21.10). Death of other relatives was not associated with abruption risk. CONCLUSIONS: Loss of a child the year before or in the first trimester of pregnancy was associated with an increased risk of abruption, especially among women with chronic hypertension. Studies are needed to investigate the effect of less severe, but more frequent, sources of stress on placental abruption risk.

Use of serotonin reuptake inhibitors in patients with psoriasis is associated with a decreased need for systemic psoriasis treatment: a population-based cohort study.

OBJECTIVE: To investigate whether psoriasis is affected by the use of serotonin reuptake inhibitors (SSRIs). DESIGN: A population-based cohort study. SETTING: The general adult population with plaque psoriasis in Sweden between 1997 and 2006. SUBJECTS: A total of 69 830 patients with plaque psoriasis were identified in the National Patient Register. Whether study subjects were exposed to SSRIs was identified through the Swedish Prescribed Drug Register. The SSRI-exposed subjects (n = 1282) had a prescription for SSRIs dispensed twice during 6 months at a Swedish pharmacy between 1 July 2006 and 1 April 2008, with a wash-out period of 1 year or longer. The reference subjects (n = 1282), who were not exposed to SSRIs, were matched for age, county of residence, sex, psoriasis severity and seasonal variation. MAIN OUTCOME MEASURE: Change in psoriasis severity defined by switching between nonsystemic and systemic psoriasis treatments 6 months after exposure to SSRIs. RESULTS: The risk of switching from nonsystemic to systemic psoriasis treatments was significantly decreased in the SSRI-exposed group (odds ratio 0.44, 95% confidence interval 0.28-0.68). CONCLUSION: SSRI use in patients with psoriasis is associated with a decreased need for systemic psoriasis treatment.

Exploiting breakdown of the similarity relation for diffuse light transport: simultaneous retrieval of scattering anisotropy and diffusion constant.

As manifested in the similarity relation of diffuse light transport, it is difficult to assess single scattering characteristics from multiply scattered light. We take advantage of the limited validity of the diffusion approximation of light transport and demonstrate, experimentally and numerically, that even deep into the multiple scattering regime, time-resolved detection of transmitted light allows simultaneous assessment of both single scattering anisotropy and scattering mean free path, and therefore also macroscopic parameters like the diffusion constant and the transport mean free path. This is achieved via careful assessment of early light and matching against Monte Carlo simulations of radiative transfer.

Evaluation of prevalent and incident ovarian cancer co-morbidity.

BACKGROUND: The peak in incidence of ovarian cancer occurs around 65 years and concurrent increasing risk by age for a number of diseases strongly influence treatment and prognosis. The aim was to explore prevalence and incidence of co-morbidity in ovarian cancer patients compared with the general population. METHODS: The study population was patients with ovarian cancer in Sweden 1993-2006 (n=11 139) and five controls per case (n=55 687). Co-morbidity from 1987 to 2006 was obtained from the Swedish Patient Register. Prevalent data were analysed with logistic regression and incident data with Cox proportional hazards models. RESULTS: Women developing ovarian cancer did not have higher overall morbidity than other women earlier than 3 months preceding cancer diagnosis. However, at time of diagnosis 11 of 13 prevalent diagnosis groups were more common among ovarian cancer patients compared with controls. The incidence of many common diagnoses was increased several years following the ovarian cancer and the most common diagnoses during the follow-up period were thromboembolism, haematologic and gastrointestinal complications. CONCLUSION: Women developing ovarian cancer do not have higher overall morbidity the years preceding cancer diagnosis. The incidence of many common diagnoses was increased several years following the ovarian cancer. It is crucial to consider time between co-morbidity and cancer diagnosis to understand and interpret associations.

Non-invasive diagnostics of the maxillary and frontal sinuses based on diode laser gas spectroscopy.

PROBLEM: Suspected, but objectively absent, rhinosinusitis constitutes a major cause of visits to the doctor, high health care costs, and the over-prescription of antibiotics, contributing to the serious problem of resistant bacteria. This situation is largely due to a lack of reliable and widely applicable diagnostic methods. METHOD: A novel method for the diagnosis of rhinosinusitis based on non-intrusive diode laser gas spectroscopy is presented. The technique is based on light absorption by free gas (oxygen and water vapour) inside the sinuses, and has the potential to be a complementary diagnostic tool in primary health care. The method was evaluated on 40 patients with suspected sinus problems, referred to the diagnostic radiology clinic for low-dose computed tomography (CT), which was used as the reference technique. MAIN RESULTS: The data obtained with the new laser-based method correlated well with the grading of opacification and ventilation using CT. The sensitivity and specificity were estimated to be 93% and 61%, respectively, for the maxillary sinuses, and 94% and 86%, respectively, for the frontal sinuses. Good reproducibility was shown. PRINCIPAL CONCLUSION: The laser-based technique presents real-time clinical data that correlate well to CT findings, while being non-intrusive and avoiding the use of ionizing radiation.

Incidence and time trends of brain metastases admissions among breast cancer patients in Sweden.

BACKGROUND: While treatment for breast cancer has been refined and overall survival has improved, there is concern that the incidence of brain metastases has increased. METHODS: We identified patients in Sweden with incident breast cancer 1998-2006 in the National Cancer Register, and matched these to the National Patient Register to obtain information on hospital admissions for distant metastases. Hazard ratios (HRs) and 95% confidence intervals (CIs) were computed with Cox regression as estimates of relative risk. RESULTS: Among 50 528 breast cancer patients, 696 (1.4%) were admitted with brain metastases during median 3.5 years of follow-up. Admissions for other metastases were found in 3470 (6.9%) patients. Compared with the period 1998-2000, patients diagnosed with breast cancer 2004-2006 were at a 44% increased risk of being admitted with brain metastases (HR 1.44, 95% CI 1.13-1.85). CONCLUSION: The incidence of admissions with brain metastases in breast cancer patients was increasing in the mid-2000s in Sweden. These findings support a true increase in incidence of brain metastases among breast cancer patients.

The genetic influence on diverticular disease--a twin study.

BACKGROUND: The contribution of hereditary factors to the development of diverticular disease (DD) of the colon is unknown. Prevalence and location of diverticula differ in Western world compared to in Asia and several case reports describing families with DD have been published. AIM: To assess the heritability of DD in a large population-based sample of twins. METHODS: The Swedish Twin Registry was cross-linked to the Swedish Inpatient Registry. All twins, born between 1886 and 1980 and not dead before 1969, with a discharge diagnosis of DD were identified. Twins with diagnoses of colon cancer, coeliac disease or non-infectious colitis were excluded to decrease bias. Co-twin odds ratio (OR), concordance rates and tetrachoric correlations were calculated for monozygotic (MZ) and same gender-dizygotic (SS-DZ) twins. Mx-analyses were used to estimate the relative contributions of genetic effects and environmental factors to susceptibility for DD. Calculations were based on both primary and secondary discharge diagnoses to provide estimates reflecting impact of severity of the disease. RESULTS: A total of 104,452 twins met the inclusion criteria. Of these, 2296 had a diagnosis of DD. The OR of developing the disease given one's co-twin was affected was 7.15 (95% CI: 4.82-10.61) for MZ and 3.20 (95% CI: 2.21-4.63) for SS-DZ twins. Similarly, concordance rates and tetrachoric correlations were higher in MZ than those in SS-DZ twins. The heritability was estimated to 40% and the non shared environmental effects to 60%. CONCLUSION: Genetic susceptibility is an important component, along with individual specific environmental factors, for the development of diverticular disease of the colon.

Diverticular disease and the risk of colon cancer - a population-based case-control study.

BACKGROUND: Colon cancer and diverticular disease are most common in the Western world and their incidences tend to increase with advancing age. The association between the diseases remains unclear. AIM: To analyse the risk of colon cancer after hospitalisation for diverticular disease. METHODS: Nationwide case-control study. A total of 41,037 patients with colon cancer during 1992-2006, identified from the Swedish Cancer Register were included. Each case was matched with two control subjects. From the Swedish Inpatient Register, cases and control subjects hospitalised for diverticular disease were identified. Odds ratios (OR) and confidence intervals for receiving a diagnosis of colon cancer after hospital discharge for diverticular disease were calculated. Colon cancer mortality was compared between patients with or without diverticular disease. RESULTS: Within 6months after an admission due to diverticular disease, OR of having a colon cancer diagnosis were up to 31.49 (19.00-52.21). After 12 months, there was no increased risk. The number of discharges for diverticular disease did not affect the risk. Colon cancer mortality did not differ between patients with and without diverticular disease. CONCLUSIONS: Diverticular disease does not increase the risk of colon cancer in the long term, and a history of diverticular disease does not affect colon cancer mortality. The increased risk of colon cancer within the first 12months after diagnosing diverticular disease is most likely due to surveillance and misclassification. Examination of the colon should be recommended after a primary episode of symptomatic diverticular disease.

Nitric oxide is involved in nicotine-induced burst firing of rat ventral tegmental area dopamine neurons.

In the present study, using single cell recordings in vivo and intracellular recordings in vitro from midbrain slices, the role of N-methyl-d-aspartate (NMDA) receptor signaling on firing activity in ventral tegmental area dopamine neurons elicited by nicotine was investigated in the rat. In accordance with previous studies, systemic nicotine (0.5 mg/kg s.c.) increased both firing rate and burst firing of dopamine neurons in vivo, and bath-applied nicotine (10 microM) increased firing rate in vitro. The competitive NMDA receptor antagonist CGP39551 (2.5 mg/kg i.p.) inhibited nicotine's effects on burst firing and also attenuated the nicotine-induced increase in firing rate. Moreover, although the nitric oxide (NO)-synthase inhibitor N-nitro-l-arginine-methyl-ester (l-NAME; 5.0 mg/kg i.p.) had no effect on cell firing by itself, it prevented the response to nicotine in vivo. In contrast, l-NAME (100 microM) did not influence nicotine's effect on dopamine cell firing in vitro, suggesting that the effect of l-NAME seen in vivo is dependent on presynaptic afferent input. The present study confirms previous results suggesting that the effect of systemically administered nicotine is in part presynaptic and mediated via NMDA receptors. The data also indicate that NO plays an important role in the previously demonstrated, indirect, glutamate-mediated excitation of these neurons by nicotine. By inference, our results provide additional support for the involvement of NO in nicotine dependence.

Selective noradrenaline reuptake inhibition enhances serotonergic neuronal activity and transmitter release in the rat forebrain.

Present pharmacotherapy of major depression is, in principle, based on enhancement of central monoaminergic neurotransmission. Clinical studies utilizing depletion experiments indicate that antidepressants which primarily enhance serotonergic or noradrenergic central activity, i.e. serotonin or nor-adrenaline reuptake inhibitors, largely work by two separate neuronal pathways. However, experimental studies have shown that noradrenaline may regulate serotonergic neurotransmission both at the serotonin cell body and nerve-terminal level. We therefore investigated the effects of the selective NRI reboxetine on serotonergic neuronal activity and extracellular levels of transmitter in the nerve-terminal area. In vivo electrophysiological experiments showed that low doses of reboxetine significantly enhance the firing rate of serotonergic neurons in the dorsal raphe nucleus of anaesthetized rats. Also, in the medial prefrontal cortex reboxetine (3 mg/kg s.c.) enhanced, whereas citalopram (3 mg/kg s.c.) reduced, extracellular concentrations of serotonin measured by means of microdialysis in awake rats, using a low dose of citalopram (0,5 micro M) in the perfusion solution. Local administration of reboxetine only induced an increase in cortical serotonin levels at very high concentrations (1000 micro M). Hence, NRIs may cause a secondary enhancement of central serotonergic activity by a mechanism separate from 5-HT reuptake inhibition; an effect that may contribute to their clinical antidepressant efficacy.

The gender differences in growth hormone-binding protein and leptin persist in 80-year-old men and women and is not caused by sex hormones.

OBJECTIVE: Leptin and growth hormone-binding protein (GHBP) both show gender differences that might be explained by sex hormones. To study the potential relevance of oestradiol and testosterone, we have examined 80-year-old subjects in whom oestradiol is higher in men than in women. The interrelationships between leptin, insulin, GHBP and fat mass in this age group were also investigated. DESIGN AND SUBJECTS: Ninety-four subjects (55 females and 39 males), all 80 years old, were investigated in a community-based study. None of the investigated subjects was being treated for diabetes mellitus and none of the women had oestrogen replacement. METHODS: Levels of testosterone, oestradiol, SHBG, IGF-I, GHBP, glucose, insulin and leptin were analysed. Body composition was measured with bioimpedance analysis (BIA). RESULTS: As in younger age groups, serum leptin, the ratio leptin/kilogram fat mass and serum GHBP were higher in the women (all, P< or =0.007), although serum oestradiol was higher in the men (P<0.001). There were no significant associations between sex hormones and leptin or GHBP either in women or in men (all, r<0.13, P>0.1). Leptin correlated to kilogram fat mass in both women (r=0.55, P<0.001) and men (r=0.47, P=0.003), but in contrast, there were no significant correlations between GHBP and fat mass and GHBP and IGF-I, either in women or in men (all, r<0.24, P>0.2). Insulin and leptin were significantly associated with GHBP, both in women (r=0.48, P<0.001 and r=0.43, P=0.001, respectively) and in men (r=0.40, P=0.01 and r=0.34, P=0.03, respectively). CONCLUSIONS: Although the 80-year-old men had higher oestradiol levels than the women, the women had higher levels of leptin and GHBP. There were no correlations between sex hormones and leptin and GHBP, which indicates that the gender differences are not caused by sex hormones in old age. In contrast to studies in younger subjects, GHBP did not correlate to fat mass in the investigated 80-year-old men and women. In the older subjects investigated, as in younger subjects, GHBP was significantly correlated with leptin and insulin.