Macro-level gender equality and women's depressive symptoms in South Korea: a longitudinal study.

PURPOSE: In 2014, the Korean Government passed the Gender Equality Act, which was accompanied by policies to increase women's participation in the labour force and representation in positions of power in the public and private sectors. While Korea has witnessed modest progress in macro-level gender equality, little is known about the effects of these changes on mental health outcomes. Our study investigated the relationship between regional-level gender equality (as measured by women's economic and political power) and women's depressive symptoms from 2013-18, and whether the effects differed across women from different socioeconomic positions. METHODS: To examine how change over time in political and economic power influences the severity of depressive symptoms, we applied a fixed-effect regression, using a nationally representative sample for women aged 19-64 (n = 9,589) from the Korean Longitudinal Survey of Women and Families (2013-2018, wave 4 to 6) residing across the 16 regions of South Korea. RESULTS: Our study found that increases in women's political and economic power led to moderate reductions in depressive symptoms (-0.25 and -0.23 points in CESD respectively). Sensitivity analyses indicate that economic power is more consistently associated with subsequent reductions in CESD. The effect of economic and political power on depressive symptoms did not differ by women's socioeconomic positions. CONCLUSIONS: Our findings suggest that even modest improvements in gender equality were associated with increases in women's mental health. Further progress to ensure gender equality, such as the anti-discrimination legislation, may lead to greater improvements in public mental health.

Social Movement and Mental Health of South Korean Women Sexual Violence Survivors, 2012-2019.

Objectives. To examine whether the #MeToo movement influenced depressive symptoms among women in South Korea with a history of experiencing sexual violence. Methods. We used data from a nationally representative sample (n = 4429) of women 19 to 50 years of age who participated in the Korean Longitudinal Survey of Women and Families between 2012 and 2019. A difference-in-differences model was used to estimate within-person changes in depressive symptoms attributable to the #MeToo movement across women with and without a history of experiencing sexual violence. Depressive symptoms were measured with the Center for Epidemiologic Studies Depression Scale (CESD). Results. After adjustment for potential confounders, the #MeToo movement led to a 1.64 decrease in CESD scores among women with a history of experiencing sexual violence relative to women without such a history. Conclusions. Our findings suggest that the #MeToo movement in Korea led to reduced depressive symptoms among women with a history of experiencing sexual violence. Public Health Implications. Despite the progress of the #MeToo movement, there are still judicial and institutional problems that can revictimize sexual violence survivors. Further policy changes will likely improve the mental health of survivors. (Am J Public Health. 2022;112(9):1337-1345. https://doi.org/10.2105/AJPH.2022.306945).

What are the mental health consequences of austerity measures in public housing? A quasi-experimental study.

BACKGROUND: As governments around the world implement austerity measures to reduce national deficits, there is an urgent need to investigate potential health impacts of specific measures to avoid unintended consequences. In 2013, the UK government implemented the underoccupancy penalty (ie, the bedroom tax) to reduce the national housing benefits bill, by cutting social housing subsidies for households deemed to have excess rooms. We investigated the impact of the bedroom tax on self-reported psychological distress. METHODS: Using data from the UK Household Longitudinal Study (2010-2014), the sample included those who received housing subsidies, aged 16-60, living in England. Control and treatment groupings were identified on their household composition and housing situation. We used matching methods to create an exchangeable set of observations. Difference-in-differences analysis was performed to examine changes across the prereform and postreform psychological distress of the treatment and control groups, using the 12-item General Health Questionnaire. RESULTS: The implementation of the reform was associated with a moderate increase in psychological distress (0.88, 95% CI 0.06 to 1.71) among the treatment group, relative to the control group. However, the announcement was not associated with change in psychological distress (0.53, 95% CI 0.21 to 1.27). CONCLUSION: Our study provides evidence that the implementation of housing austerity measures can increase psychological distress among social housing tenants. As the use of austerity measures become more widespread, policy-makers should consider supplementary interventions to ameliorate potential negative health consequences.

Do social protection programmes have a causal effect on suicide mortality? A protocol for a systematic review and meta-analysis.

INTRODUCTION: Recent international and national strategies to reduce suicide mortality have suggested that social protection programmes may be an effective multisectoral response given the link between material deprivation and suicides in observational studies. However, there is a lack of evidence on the causal relationship between social protection programmes and suicide, which may hinder substantial national budget reallocations necessary to implement these policies. Social protection programmes are government interventions that ensure adequate income now and in the future, through changes to earned income (eg, minimum wage increase) or social security (via cash transfers or cash equivalents). Our review aims to evaluate the existing evidence on a causal relationship between social protection programmes and suicide mortality by examining all relevant experimental and quasi-experimental studies between January 1980 and November 2021. METHODS AND ANALYSIS: The review will be conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guideline. We will search references published between 1 January 1980 and 30 November 2021 in 10 electronic databases, including MEDLINE (PubMed), PsycINFO, EMBASE and Applied Social Sciences Index Abstracts. Seven reviewers will independently participate in screening studies from titles, abstracts and full texts across all the stages. Experimental (ie, randomised controlled trials) and quasi-experimental studies (ie, non-randomised interventional studies) written in English, French, Spanish, German, Chinese, Korean and Japanese examining the impact of income security programmes on suicide mortality were included. Meta-analyses will be conducted if there are at least three studies with similar income security programmes. ETHICS AND DISSEMINATION: Our proposed review does not require ethical approval. In collaboration with our community partners, we will develop a policy brief for stakeholders to support efforts to implement social protection programmes to help prevent suicides. Our findings will be presented at conferences, published in a peer-reviewer journal and promoted on social media platforms. PROSPERO REGISTRATION NUMBER: CRD42021252235.

Does the longitudinal association between neighbourhood cohesion and mental health differ by ethnicity? Results from the UK Household Longitudinal Survey.

PURPOSE: While the association between neighbourhood cohesion and mental health has been widely studied in the general population, the effects of neighbourhood cohesion across ethnic groups are not well understood. Ethnicity is often left out of study design, many studies do not consider effect modification by ethnicity, or they rely on overly simplistic ethnic categories. METHODS: Data from the UK household longitudinal study were used to investigate whether changes in neighbourhood cohesion are independently associated with changes in mental health (measured using the GHQ) over 9 years (2009-2018), and whether the association differed across 17 ethnic groups. The study used a fixed-effect modeling approach that includes within-person estimators that allow each participant to act as their own control. RESULTS: Compared to British White, the following ethnic groups all saw a similar improvement in GHQ (- 0.76, 95% CI - 0.83 to - 0.70) for each point increase in neighbourhood cohesion: Irish, any other White, White and Asian mixed, Chinese, Caribbean, African, any other Black, Arab, and others. Some ethnic groups saw stronger improvements in mental for each point increase in neighbourhood cohesion, including White and Black Caribbean mixed, any other mixed, Indian, Pakistani, any other Asian, with the strongest effect seen in Bangladeshi participants (- 2.52. 95% CI - 3.48 to - 1.56). CONCLUSION: Our study highlights the importance of ethnocultural data in research examining neighbourhood effects on mental health. Future research should evaluate policies to improve neighbourhood cohesion for ethnic minorities to address ethnic mental health disparities.

Family support modifies the effect of changes to same-sex marriage legislation on LGB mental health: evidence from a UK cohort study.

BACKGROUND: Many lesbian, gay and bisexual (LGB) individuals continue to experience unique challenges, such as the lack of family support and access to same-sex marriage. This study examines the effect of the introduction of same-sex marriage in the UK (2013-14) on mental health functioning among sexual minorities, and investigates whether low family support may hamper the positive effects of marriage equality legislation among LGB individuals. METHODS: This analysis included LGB participants (n = 2172) from the UK household longitudinal study waves 3-7, comprising two waves before and two waves after marriage equality legislation passed in England, Wales and Scotland. Individual-level mental health functioning was measured using the mental component score (MCS-12) of the Short Form-12 survey. Fixed-effect panel linear models examined the effect of marriage equality on MCS-12 across varying family support levels. Analyses included adjustment for covariates and survey weights. RESULTS: Legalization of same-sex marriage was independently associated with an increase of 1.17 [95% confidence interval (CI): 0.28-2.05] MCS-12 in men and 1.13 (95% CI: 0.47-2.27) MCS-12 in women. For men, each additional standard deviation of family support modified the effect of legalization on mental health functioning by +0.70 (95% CI: 0.22-1.18) MCS-12 score. No interaction was found in women. CONCLUSIONS: Our findings provide evidence that same-sex marriage will likely improve LGB mental health functioning, and these effects may be generalizable to other European countries. Since male sexual minorities with low family support benefited the least, additional interventions aimed at improving family support and acceptance of this group is required to help reduce mental health disparities.

The impact of changes in job security on mental health across gender and family responsibility: evidence from the UK Household Longitudinal Study.

PURPOSE: While there is strong evidence that job insecurity leads to mental distress, little is known about how gender and parental responsibilities may exacerbate this relationship. Examining their contribution as potential effect modifiers may provide insights into gender inequalities in mental health and inform gender-sensitive labour policies to ameliorate the negative effects of job insecurity. Our study addresses this gap by examining the longitudinal association between job insecurity and mental health across different configurations of gender and parental responsibilities. METHODS: Our sample includes 34,772 employed participants over the period of 2010-2018. A gender-stratified fixed-effect regression was used to model the within-person change over time in mental health associated with loss of job security, and effect modification by parent-partner status (e.g. childfree men, partnered father, etc.). RESULTS: Loss of job security was associated with a moderate decrease in mental health functioning for partnered fathers, partnered mothers, and childfree men and women ranging between a reduction in MCS-12 by 1.00 to 2.27 points (p < 0.05). Lone fathers who lose their job security experienced a higher decrease in mental health functioning at - 7.69 (95% CI - 12.69 to - 2.70), while lone mothers did not experience any change. CONCLUSION: The effects of job insecurity on mental health is consistent across gender and parent-partner status with the exception of lone fathers and lone mothers. Future studies should investigate the effects of policies that may reduce mental distress in the face of the threat of job loss such as reducing wait time for payment of unemployment benefits.

Sleep problems among sexual minorities: a longitudinal study on the influence of the family of origin and chosen family.

BACKGROUND: There is growing evidence that lesbian, gay, and bisexual (LGB) adults experience more sleep problems than the general population. As LGB individuals experience a significantly greater risk of family rejection and low family support, our study investigates the role of family support as a potential determinant of LGB sleep problems over a prolonged period, and whether friend support (i.e. chosen family) can mitigate the effect of low family support. Given the importance of sleep on mental and physical health, study results may help shed light on persistent health disparities across sexual orientations. METHODS: Our sample included 1703 LGB individuals from the UK Household Longitudinal Study (UKHLS). Mixed-effect logistic regressions were used to estimate the effect of family and friend support on the development of sleep problems after 24 months while controlling for potential confounders. A modified Pittsburgh Sleep Quality Index was used to measure 1) presence of any sleep problems, 2) short sleep duration, and 3) poor sleep quality. RESULTS: Family support at baseline was independently associated with all sleep problems in our study after 24-months: 1 SD increase in family support was associated with a 0.94 times lower risk of sleep problems (95% C.I = 0.90-0.98), a 0.88 times lower risk of short sleep duration (95% C.I = 0.81-0.95), and a 0.92 times lower risk of sleep quality (95% C.I = 0.93-0.98). Support from one's chosen family (proxied by friend support) did not mitigate the effects of low family support on sleep problems. CONCLUSIONS: Our study found a consistent effect of family support across all sleep outcomes along with evidence of a persistent effect after 24 months. Our findings point to the importance of targeting family support in designing interventions aimed at reducing LGB sleep problems.

Did the UK COVID-19 Lockdown Modify the Influence of Neighbourhood Disorder on Psychological Distress? Evidence From a Prospective Cohort Study.

Background: National lockdown in the UK during the COVID-19 pandemic severely restricted the mobility of residents and increased time spent in their residential neighbourhoods. This is a unique opportunity to understand how an exogenous factor that reduces mobility may influence the association between neighbourhood social environment and mental health. This study investigates whether the COVID-19 lockdown may modify the effect of neighbourhood disorder on psychological distress. Methods: We tracked changes in psychological distress, using the UK household longitudinal survey across the pre-COVID and lockdown periods in 16,535 adults. Neighbourhood disorder was measured along two subscales: social stressors and property crime. Fixed-effects regression was used to evaluate whether the widespread reduction in mobility modifies the association between the subscales of neighbourhood disorder and psychological distress. Results: The effect of neighbourhood social stressors on psychological distress was stronger in the lockdown period compared to the pre-COVID period. Compared to the pre-COVID period, the effect of being in neighbourhoods with the highest social stressors (compared to the lowest) on psychological distress increased by 20% during the lockdown. Meanwhile, the effect of neighbourhood property crime on mental health did not change during the lockdown. Conclusion: The sudden loss of mobility as a result of COVID-19 lockdown is a unique opportunity to address the endogeneity problem as it relates to mobility and locational preferences in the study of neighbourhood effects on health. Vulnerable groups who have limited mobility are likely more sensitive to neighbourhood social stressors compared to the general population.

The effect of neighbourhood cohesion on mental health across sexual orientations: A longitudinal study.

Given the persistent mental health disparities between sexual minorities and the general population, social epidemiological research should address this disparity by investigating the differential impact of neighbourhood social environments across sexual orientations. There is growing evidence that neighbourhood cohesion, conceptualized as a sense of belonging and social connection, is an important social determinant of mental health in the general population, but little is known about its impact across sexual orientations. Using data from the UK household longitudinal study (2009-2018) including waves 1, 3, 6, and 9 ( n = 52,903), this paper examined the longitudinal relationship between neighbourhood cohesion and mental health (using GHQ-12) across sexual orientations. A fixed-effect regression approach was taken to model the within-person change over time in GHQ predicted by neighbourhood cohesion with disaggregated analyses by gender and sexual orientation. Across all sexual orientations and genders, individuals who experienced an increase in neighbourhood cohesion also saw an improvement in their mental health over time. Moreover, the effect of neighbourhood cohesion on mental health over time differed by sexual orientation. Each 1-point increase in neighbourhood cohesion (on a 5-point scale) lead to mental health improvements of -0.8 GHQ score (95%CI -0.89 to -0.71) for heterosexual males at the lowest end, and up to -1.71 GHQ score (95%CI -2.31 to - 1.11) for homosexual men at the highest end. Given that the study demonstrates notable differences in the effects of neighbourhood social environment across gender and sexual orientations, this points to the need to consider sexual orientation (along with gender) as a key modifier in research involving neighbourhood effects. Future studies should evaluate the effectiveness of specific policies aimed at improving neighbourhood social environment for sexual minorities to help close mental health disparities.

Effects of acute olanzapine exposure on central insulin-mediated regulation of whole body fuel selection and feeding.

The use of antipsychotics is associated with severe disruptions in whole body glucose and lipid metabolism which may in part occur through the central nervous system and impaired insulin action at the brain. Here we investigated whether olanzapine treatment might also affect the ability of central insulin treatment to regulate food intake and fuel preference in the light and dark cycle. Male Sprague-Dawley rats were treated with olanzapine (or vehicle solution; 3 mg/kg, subcutaneous) and a simultaneous acute intracerebral ventricular (ICV) infusion of insulin (or vehicle; 3 µL at 10mU; ICV) at the beginning of the 12-h light and dark cycles. Olanzapine treatment reduced RER in the dark and light phases (most consistently in the 4-hours post-treatment), while ICV insulin reduced average RER predominantly in the dark phase, but also at the end of the light cycle. The RER lowering effect of ICV-insulin during the light cycle was absent in the group co-administered olanzapine. The reduction in RER during the dark phase was mirrored by decreased food intake with ICV insulin, but not olanzapine treated rats. The reduction in food intake by ICV-insulin was abolished in rats co-administered olanzapine suggesting rapid induction of central insulin resistance. A combination of ICV-insulin and olanzapine similarly reduced RER in the dark phase, independent of changes in food intake. Olanzapine treatment, alone or in combination with ICV-insulin, significantly reduced VCO2 at regular intervals in the dark phase (specifically 3 h post-treatment), while VO2 was not significantly altered by either treatment. Finally, heat production was increased by olanzapine treatment in the light phase, though this effect was not consistent. The findings confirm that acute olanzapine treatment directly reduces RER and suggest that treatment with this drug may also override central insulin-mediated reductions in food intake at the hypothalamus (while still independently favoring fatty acid oxidation). Acute central insulin similarly reduces RER, but in contrast to olanzapine, this may represent a physiologically appropriate response to reduction in food intake.

In male rats, the ability of central insulin to suppress glucose production is impaired by olanzapine, whereas glucose uptake is left intact.

BACKGROUND: Insulin receptors are widely expressed in the brain and may represent a crossroad between metabolic and cognitive disorders. Although antipsychotics, such as olanzapine, are the cornerstone treatment for schizophrenia, they are associated with high rates of type 2 diabetes and lack efficacy for illness-related cognitive deficits. Historically, this risk of diabetes was attributed to the weight gain propensity of antipsychotics, but recent work suggests antipsychotics can have weight-independent diabetogenic effects involving unknown brain-mediated mechanisms. Here, we examined whether antipsychotics disrupt central insulin action, hypothesizing that olanzapine would impair the well-established ability of central insulin to supress hepatic glucose production. METHODS: Pancreatic euglycemic clamps were used to measure glucose kinetics alongside a central infusion of insulin or vehicle into the third ventricle. Male rats were pretreated with olanzapine or vehicle per our established model of acute olanzapine-induced peripheral insulin resistance. Groups included (central-peripheral) vehicle-vehicle (n = 11), insulin-vehicle (n = 10), insulin-olanzapine (n = 10) and vehicle-olanzapine (n = 8). RESULTS: There were no differences in peripheral glucose or insulin levels. Unexpectedly, we showed that central insulin increased glucose uptake, and this effect was not perturbed by olanzapine. We replicated suppression of glucose production by insulin (clamp relative to basal: 77.9% ± 13.1%, all p < 0.05), an effect abolished by olanzapine (insulin-olanzapine: 7.7% ± 14%). LIMITATIONS: This study used only male rats and an acute dose of olanzapine. CONCLUSION: To our knowledge, this is the first study suggesting olanzapine may impair central insulin sensing, elucidating a potential mechanism of antipsychotic-induced diabetes and opening avenues of investigation related to domains of schizophrenia psychopathology.

Lipoic acid and haloperidol-induced vacuous chewing movements: Implications for prophylactic antioxidant use in tardive dyskinesia.

Tardive dyskinesia (TD), a potentially irreversible antipsychotic (AP)-related movement disorder, is a risk with all currently available antipsychotics. AP-induced vacuous chewing movements (VCMs) in rats, a preclinical model of TD, can be attenuated by antioxidant-based treatments although there is a shortage of well-designed studies. Lipoic acid (LA) represents a candidate antioxidant for the treatment of oxidative stress-related nervous system disorders; accordingly, its effects on AP-induced VCMs and striatal oxidative stress were examined. Rats treated with haloperidol decanoate (HAL; 21mg/kg every 3weeks, IM) for 12weeks were concurrently treated with LA (10 or 20mg/kg, PO). VCMs were assessed weekly by a blinded rater, and locomotor activity was evaluated as were striatal lipid peroxidation markers and serum HAL levels. VCMs were decreased by the lower dose (nonsignificant), whereas a significant increase was recorded with the higher dose of LA. HAL decreased locomotor activity and this was unaffected by LA. Striatal malondialdehyde (MDA) levels in HAL-treated rats were reduced by both LA doses, while 4-hydroxynonenal (4-HNE) levels were predictive of final VCM scores (averaged across weeks 10-12). Study limitations include differences between antipsychotics in terms of oxidative stress, LA dosing, choice of biomarkers for lipid peroxidation, and generalizability to TD in humans. Collectively, current preclinical evidence does not support a "protective" role for antioxidants in preventing TD or its progression, although clinical evidence offers limited evidence supporting such an approach.

Atypical antipsychotics and effects on feeding: from mice to men.

RATIONALE: So-called atypical antipsychotics (AAPs) are associated with varying levels of weight gain and associated metabolic disturbances, which in patients with serious mental illness (SMI) have been linked to non-compliance and poor functional outcomes. Mechanisms underlying AAP-induced metabolic abnormalities are only partially understood. Antipsychotic-induced weight gain may occur as a result of increases in food intake and/or changes in feeding. OBJECTIVE: In this review, we examine the available human and preclinical literature addressing AAP-related changes in feeding behavior, to determine whether changes in appetite and perturbations in regulation of food intake could be contributing factors to antipsychotic-induced weight gain. RESULTS: In general, human studies point to disruption by AAPs of feeding behaviors and food consumption. In rodents, increases in cumulative food intake are mainly observed in females; however, changes in feeding microstructure or motivational aspects of food intake appear to occur independent of sex. CONCLUSIONS: The findings from this review indicate that the varying levels of AAP-related weight gain reflect changes in both appetite and feeding behaviors, which differ by type of AAP. However, inconsistencies exist among the studies (both human and rodent) that may reflect considerable differences in study design and methodology. Future studies examining underlying mechanisms of antipsychotic-induced weight gain are recommended in order to develop strategies addressing the serious metabolic side effect of AAPs.

Metformin attenuates olanzapine-induced hepatic, but not peripheral insulin resistance.

Antipsychotics (APs) are linked to diabetes, even without weight gain. Whether anti-diabetic drugs are efficacious in reversing the direct effects of APs on glucose pathways is largely undetermined. We tested two metformin (Met) doses to prevent impairments seen following a dose of olanzapine (Ola) (3 mg/kg); glucokinetics were measured using the hyperinsulinemic-euglycemic clamp (HIEC). Met (150 mg/kg; n=13, or 400 mg/kg; n=11) or vehicle (Veh) (n=11) was administered through gavage preceding an overnight fast, followed by a second dose prior to the HIEC. Eleven additional animals were gavaged with Veh and received a Veh injection during the HIEC (Veh/Veh); all others received Ola. Basal glucose was similar across treatment groups. The Met 400 group had significantly greater glucose appearance (Ra) in the basal period (i.e., before Ola, or hyperinsulinemia) vs other groups. During hyperinsulinemia, glucose infusion rate (GINF) to maintain euglycemia (reflective of whole-body insulin sensitivity) was higher in Veh/Veh vs other groups. Met 150/Ola animals demonstrated increased GINF relative to Veh/Ola during early time points of the HIEC. Glucose utilization during hyperinsulinemia, relative to basal conditions, was significantly higher in Veh/Veh vs other groups. The change in hepatic glucose production (HGP) from basal to hyperinsulinemia demonstrated significantly greater decreases in Veh/Veh and Met 150/Ola groups vs Veh/Ola. Given the increase in basal Ra with Met 400, we measured serum lactate (substrate for HGP), finding increased levels in Met 400 vs Veh and Met 150. In conclusion, Met attenuates hepatic insulin resistance observed with acute Ola administration, but fails to improve peripheral insulin resistance. Use of supra-therapeutic doses of Met may mask metabolic benefits by increasing lactate.

The VAGUS insight into psychosis scale--self-report and clinician-rated versions.

The aim of this study was to develop self-report and clinician-rated versions of an insight scale that would be easy to administer, sensitive to small changes, and inclusive of the core dimensions of clinical insight into psychosis. Ten-item self-report (VAGUS-SR) and five-item clinician-rated (VAGUS-CR) scales were designed to measure the dimensions of insight into psychosis and evaluated in 215 and 140 participants, respectively (www.vagusonline.com). Tests of reliability and validity were performed. Both the VAGUS-SR and VAGUS-CR showed good internal consistency and reliability. They demonstrated good convergent and discriminant validity. Both versions were strongly correlated with one another and with the Schedule for the Assessment of Insight and Birchwood Insight Scale. Exploratory factor analyses identified three possible latent components of insight. The VAGUS-CR and VAGUS-SR are valid, reliable and easy to administer. They are build on previous insight scales with separate clinician-rated and self-report versions. The VAGUS-SR exhibited a multidimensional factor structure. Using a 10-point Likert scale for each item, the VAGUS has the capacity to detect small, temporally sensitive changes in insight, which is essential for intervention studies with neurostimulation or rapidly acting medications.

Effects of intracerebroventricular (ICV) olanzapine on insulin sensitivity and secretion in vivo: an animal model.

The atypical antipsychotics (AAPs) have been associated with an increased risk of type 2 diabetes. While weight gain associated with AAPs is a risk factor for diabetes, preclinical work suggests that among these medications, olanzapine, when given peripherally in a single dose, causes pronounced effects on insulin sensitivity and secretion. Given a critical role of the hypothalamus in control of glucose metabolism, we examined the effect of central administration of olanzapine. Sprague-Dawley rats were treated with a single 75 µg intracerebroventricular (ICV) dose of olanzapine and tested using separate hyperinsulinemic-euglycemic and hyperglycemic clamps. Dosing of olanzapine was established based on inhibition of amphetamine-induced locomotion. In contrast to the single dosing peripheral paradigm, there was no effect of central olanzapine on insulin sensitivity, either with respect to hepatic glucose production or peripheral glucose uptake. Analogous to the peripheral model, a single ICV dose of olanzapine followed by the hyperglycemic clamp decreased insulin (p=0.0041) and C-peptide response (p=0.0039) to glucose challenge as compared to vehicle, mirrored also by a decrease in the steady state glucose infusion rate required to maintain hyperglycemia (p=0.002). In conclusion, we demonstrate novel findings that at least part of the effect of olanzapine on beta-cell function in vivo is central.

Acute effects of single-dose olanzapine on metabolic, endocrine, and inflammatory markers in healthy controls.

Atypical antipsychotics may "directly" influence glucose homeostasis, increasing risk of type 2 diabetes independently of changes in adiposity. Animal models suggest direct effects after even a single dose of certain atypical antipsychotics on glucose dysregulation. Here, we investigated effects of a single-dose olanzapine (OLA) on glucose metabolism in healthy volunteers, thereby minimizing confounding effects of the illness of schizophrenia and adiposity. In a randomized double-blind crossover design, 15 subjects were administered 10 mg of OLA or placebo at 7:00 A.M. on separate study dates. A frequently sampled intravenous glucose tolerance test was initiated 4.25 hours later to assess changes in glucose homeostasis, including an index of insulin sensitivity, disposition index, glucose effectiveness, and acute insulin response to glucose. We also examined effects on cortisol, prolactin, fasting free fatty acids (FFAs), insulin-mediated suppression of FFAs, and adipocytokines (leptin, adiponectin, C-reactive protein, interleukin 6, and tumor necrosis factor α). Complete data for both visits were analyzed for 12 subjects. Olanzapine treatment significantly decreased glucose effectiveness (P = 0.041) and raised fasting glucose over 4.25 hours (P = 0.03) as compared to placebo. Olanzapine was associated with lower serum cortisol (P = 0.003), lower fasting FFA (P = 0.042), and increased prolactin levels (P < 0.0001). We therefore suggest that a single dose of OLA may invoke early changes in some parameters of glucose and lipid metabolism, as well as endocrine indices.

Atypical antipsychotics and effects of adrenergic and serotonergic receptor binding on insulin secretion in-vivo: an animal model.

Atypical antipsychotics (AAPs) are associated with several metabolic sequelae including increased risk of type 2 diabetes. Growing evidence points to a direct drug effect of these compounds on glucose homeostasis, independent of weight gain. While the responsible mechanisms have yet to be elucidated, the heterogeneous binding profiles of AAPs likely include receptors involved in glucose metabolism. This study aimed to clarify weight-gain independent mechanisms of AAP-induced alterations in insulin secretion. Deconstruction of the receptor binding profiles of these agents was done using representative antagonists. Healthy rats were pre-treated with a single subcutaneous dose of prazosin 0.25mg/kg (n = 16), a selective α1 antagonist; idazoxan 0.5mg/kg (n = 10), a selective α2 antagonist; SB242084 0.5mg/kg (n = 10), a selective 5HT2C antagonist; WAY100635 0.1mg/kg (n = 10), a selective 5HT1A antagonist; MDL100907 0.5mg/kg (n = 8), a selective 5HT2A antagonist; or vehicle: 0.9% NaCl saline (n = 8), DMSO (n = 8), or cyclodextrin (n = 5). Hyperglycemic clamps were employed following injection, providing an index of secretory capacity of pancreatic ß-cells. Treatment with prazosin and MDL100907 resulted in significant decreases in both insulin and C-peptide secretion compared to their respective controls, DMSO and saline. These findings were corroborated with decreased glucose infusion rate and disposition index in the prazosin group. Results suggest that α1 and 5HT2A receptor antagonism may be involved in glucose dysregulation with AAP treatment, however, the exact mechanisms involved remain unknown.