Disruption of NMDA receptor-mediated regulation of PPI in the maternal immune activation model of schizophrenia is restored by 17ß-estradiol and raloxifene.

Maternal immune activation (MIA) during pregnancy is known to increase the risk of development of schizophrenia in the offspring. Sex steroid hormone analogues have been proposed as potential antipsychotic treatments but the mechanisms of action involved remain unclear. Estrogen has been shown to alter N-methyl-d-aspartate (NMDA) receptor binding in the brain. We therefore studied the effect of chronic treatment with 17ß-estradiol, its isomer, 17α-estradiol, and the selective estrogen receptor modulator, raloxifene, on MIA-induced psychosis-like behaviour and the effect of the NMDA receptor antagonist, MK-801. Pregnant rats were treated with saline or the viral mimetic, poly(I:C), on gestational day 15. Adult female offspring were tested for changes in baseline prepulse inhibition (PPI) and the effects of acute treatment with MK-801 on PPI and locomotor activity. Poly(I:C) offspring had significantly lower baseline PPI compared to control offspring, and this effect was prevented by 17ß-estradiol and raloxifene, but not 17α-estradiol. MK-801 reduced PPI in control offspring but had no effect in poly(I:C) offspring treated with vehicle. Chronic treatment with 17ß-estradiol and raloxifene restored the effect of MK-801 on PPI. There were no effects of MIA or estrogenic treatment on MK-801 induced locomotor hyperactivity. These results show that MIA affects baseline PPI as well as NMDA receptor-mediated regulation of PPI in female rats, and strengthen the view that estrogenic treatment may have antipsychotic effects.

Massed v. standard prolonged exposure therapy for PTSD in military personnel and veterans: 12-month follow-up of a non-inferiority randomised controlled trial.

BACKGROUND: The utilisation of massed therapy for treating posttraumatic stress disorder (PTSD) is gaining strength, especially prolonged exposure. However, it is unknown whether massed prolonged exposure (MPE) is non-inferior to standard prolonged exposure (SPE) protocols in the long term. The current study aimed to assess whether MPE was non-inferior to SPE at 12 months post-treatment, and to ascertain changes in secondary measure outcomes. METHODS: A multi-site non-inferiority randomised controlled trial (RCT) compared SPE with MPE in 12 clinics. The primary outcome was PTSD symptom severity (CAPS-5) at 12 months post-treatment commencement. Secondary outcome measures included symptoms of depression, anxiety, anger, disability, and quality of life at 12 weeks and 12 months post-treatment commencement. Outcome assessors were blinded to treatment allocation. The intention-to-treat sample included 138 Australian military members and veterans and data were analysed for 134 participants (SPE = 71, MPE = 63). RESULTS: Reductions in PTSD severity were maintained at 12 months and MPE remained non-inferior to SPE. Both treatment groups experienced a reduction in depression, anxiety, anger, and improvements in quality of life at 12 weeks and 12 months post-treatment commencement. Treatment effects for self-reported disability in the SPE group at 12 weeks were not maintained, with neither group registering significant effects at 12 months. CONCLUSIONS: The emergence of massed protocols for PTSD is an important advancement. The current study provides RCT evidence for the longevity of MPE treatment gains at 12 months post-treatment commencement and demonstrated non-inferiority to SPE. Promisingly, both treatments also significantly reduced the severity of comorbid symptoms commonly occurring alongside PTSD.

Effect of massed v. standard prolonged exposure therapy on PTSD in military personnel and veterans: a non-inferiority randomised controlled trial.

BACKGROUND: A short, effective therapy for posttraumatic stress disorder (PTSD) could decrease barriers to implementation and uptake, reduce dropout, and ameliorate distressing symptoms in military personnel and veterans. This non-inferiority RCT evaluated the efficacy of 2-week massed prolonged exposure (MPE) therapy compared to standard 10-week prolonged exposure (SPE), the current gold standard treatment, in reducing PTSD severity in both active serving and veterans in a real-world health service system. METHODS: This single-blinded multi-site non-inferiority RCT took place in 12 health clinics across Australia. The primary outcome was PTSD symptom severity measured by the Clinician-Administered PTSD Scale for DSM-5 (CAPS-5) at 12 weeks. 138 military personnel and veterans with PTSD were randomised. 71 participants were allocated to SPE, with 63 allocated to MPE. RESULTS: The intention-to-treat sample included 138 participants, data were analysed for 134 participants (88.1% male, M = 46 years). The difference between the mean MPE and SPE group PTSD scores from baseline to 12 weeks-post therapy was 0.94 [95% confidence interval (CI) -4.19 to +6.07]. The upper endpoint of the 95% CI was below +7, indicating MPE was non-inferior to SPE. Significant rates of loss of PTSD diagnosis were found for both groups (MPE 53.8%, SPE 54.1%). Dropout rates were 4.8% (MPE) and 16.9% (SPE). CONCLUSIONS: MPE was non-inferior to SPE in significantly reducing symptoms of PTSD. Significant reductions in symptom severity, low dropout rates, and loss of diagnosis indicate MPE is a feasible, accessible, and effective treatment. Findings demonstrate novel methods to deliver gold-standard treatments for PTSD should be routinely considered.

Potential peripheral biomarkers associated with the emergence and presence of posttraumatic stress disorder symptomatology: A systematic review.

BACKGROUND: Evidence suggests posttraumatic stress disorder (PTSD) involves an interplay between psychological manifestations and biological systems. Biological markers of PTSD could assist in identifying individuals with underlying dysregulation and increased risk; however, accurate and reliable biomarkers are yet to be identified. METHODS: A systematic review following the PRISMA guidelines was conducted. Databases included EMBASE, MEDLINE, and Cochrane Central. Studies from a comprehensive 2015 review (Schmidt et al., 2015) and English language papers published subsequently (between 2014 and May 2022) were included. Forty-eight studies were eligible. RESULTS: Alterations in neuroendocrine and immune markers were most commonly associated with PTSD symptoms. Evidence indicates PTSD symptoms are associated with hypothalamic-pituitary-adrenal axis dysfunction as represented by low basal cortisol, a dysregulated immune system, characterized by an elevated pro-inflammatory state, and metabolic dysfunction. However, a considerable number of studies neglected to measure sex or prior trauma, which have the potential to affect the biological outcomes of posttraumatic stress symptoms. Mixed findings are indicative of the complexity and heterogeneity of PTSD and suggest the relationship between allostatic load, biological markers, and PTSD remain largely undefined. CONCLUSIONS: In addition to prospective research design and long-term follow up, it is imperative future research includes covariates sex, prior trauma, and adverse childhood experiences. Future research should include exploration of biological correlates specific to PTSD symptom domains to determine whether underlying processes differ with symptom expression, in addition to subclinical presentation of posttraumatic stress symptoms, which would allow for greater understanding of biomarkers associated with disorder risk and assist in untangling directionality.

Intimate Partner Violence (IPV) in Military and Veteran Populations: A Systematic Review of Population-Based Surveys and Population Screening Studies.

Intimate partner violence (IPV) may be a major concern in military and veteran populations, and the aims of this systematic review were to (1) provide best available estimates of overall prevalence based on studies that are most representative of relevant populations, and (2) contextualise these via examination of IPV types, impacts, and context. An electronic search of PsycINFO, CINHAL, PubMed, and the Cochrane Library databases identified studies utilising population-based designs or population screening strategies to estimate prevalence of IPV perpetration or victimisation reported by active duty (AD) military personnel or veterans. Random effects meta-analyses were used for quantitative analyses and were supplemented by narrative syntheses of heterogeneous data. Thirty-one studies involving 172,790 participants were included in meta-analyses. These indicated around 13% of all AD personnel and veterans reported any recent IPV perpetration, and around 21% reported any recent victimisation. There were higher rates of IPV perpetration in studies of veterans and health service settings, but no discernible differences were found according to gender, era of service, or country of origin. Psychological IPV was the most common form identified, while there were few studies of IPV impacts, or coercive and controlling behaviours. The findings demonstrate that IPV perpetration and victimisation occur commonly among AD personnel and veterans and highlight a strong need for responses across military and veteran-specific settings. However, there are gaps in understanding of impacts and context for IPV, including coercive and controlling behaviours, which are priority considerations for future research and policy.

Health Service Interventions for Intimate Partner Violence among Military Personnel and Veterans: A Framework and Scoping Review.

IPV is a significant concern among active duty (AD) military personnel or veterans, and there is a need for initiatives to address violence perpetrated by such personnel, and IPV victimisation in military and veteran-specific contexts. The aim of this paper was to provide an overview of major IPV intervention approaches and evidence in military and veteran-specific health services. A scoping review was conducted involving a systematic search of all available published studies describing IPV interventions in military and veteran-specific health services. Findings were synthesised narratively, and in relation to a conceptual framework that distinguishes across prevention, response, and recovery-oriented strategies. The search identified 19 studies, all from the U.S., and only three comprised randomised trials. Initiatives addressed both IPV perpetration and victimisation, with varied interventions targeting the latter, including training programs, case identification and risk assessment strategies, and psychosocial interventions. Most initiatives were classified as responses to IPV, with one example of indicated prevention. The findings highlight an important role for specific health services in addressing IPV among AD personnel and veterans, and signal intervention components that should be considered. The limited amount of empirical evidence indicates that benefits of interventions remain unclear, and highlights the need for targeted research.

Massed versus standard prolonged exposure for posttraumatic stress disorder in Australian military and veteran populations (RESTORE trial): Study protocol for a non-inferiority randomized controlled trial.

Posttraumatic stress disorder (PTSD) can be a severe problem, affecting veterans and military personnel at higher rates than the general community. First-line treatment for PTSD, prolonged exposure (PE), is typically delivered weekly for 10-12 weeks, however this duration can pose a barrier to accessing and completing the treatment, particularly for current serving military. This paper presents the RESTORE trial protocol, the first randomized controlled trial of massed PE therapy outside of the United States and by an independent research group. One hundred and thirty-five Australian Defence Force members and veterans (18-80 years) who meet criteria for PTSD related to a military trauma will be randomly allocated to one of two conditions: standard PE (SPE; 10 weekly 90-min sessions) or massed PE (MPE; 10 daily 90-min sessions). Across eight sites, patients will be assessed at pre-treatment, and at 4 weeks, 12 weeks, and 12 months post-treatment commencement. The primary outcome is clinician-measured and self-reported PTSD symptom severity at the 12 week assessment. We hypothesize that MPE will be as effective as SPE in reducing PTSD severity at 12 weeks post-treatment commencement. The adaptation and testing of evidence-based interventions is critical to reduce barriers to treatment uptake among veterans and military personnel. Outcomes of this study have the potential to result in international, cross-service uptake and delivery of this rapid treatment for veterans and military members, as well as civilians, thereby improving clinical outcomes for patients and their families.

TrkB agonist 7,8-dihydroxyflavone reverses an induced prepulse inhibition deficit selectively in maternal immune activation offspring: implications for schizophrenia.

Reduced brain-derived neurotrophic factor (BDNF) signalling has been implicated in schizophrenia endophenotypes, including deficits in prepulse inhibition (PPI). Maternal immune activation (MIA) is a widely used neurodevelopmental animal model for schizophrenia but it is unclear if BDNF and its receptor, tropomyosin receptor kinase B (TrkB), are involved in PPI regulation in this model. Pregnant Long Evans rats were treated with the viral mimetic, polyinosinic-polycytidylic acid (poly I:C; 4 mg/kg i.v.), and nine male offspring from these dams were compared in adulthood to 11 male Long Evans controls. Offspring underwent PPI testing following injection with the TrkB agonist, 7,8-dihydroxyflavone (7,8-DHF) (10 mg/kg i.p.), with or without the dopamine receptor agonist, apomorphine (APO; 1 mg/kg s.c.), or the dopamine releasing drug, methamphetamine (METH; 2 mg/kg s.c.). Acute administration of APO and METH caused the expected significant reduction of PPI. Acute administration of 7,8-DHF did not alter PPI on its own; however, it significantly reversed the effect of APO on PPI in poly I:C rats, but not in controls. A similar trend was observed in combination with METH. Western blot analysis of frontal cortex revealed significantly increased levels of BDNF protein, but not TrkB or phosphorylated TrkB/TrkB levels, in poly I:C rats. These findings suggest that, selectively in MIA offspring, 7,8-DHF has the ability to reverse PPI deficits caused by dopaminergic stimulation. This effect could be associated with increased BDNF expression in the frontal cortex. These data suggest that targeting BDNF signalling may have therapeutic potential for the treatment of certain symptoms of schizophrenia.

Gambling problems among military personnel after deployment.

Military and veteran populations may exhibit heightened vulnerability to gambling problems; however, there is scant relevant evidence outside the US, and few studies of transition periods, including return from operational deployment. The aim of this study was thus to highlight the extent, risk-factors, and implications of gambling problems among current members of the Australian Defence Force (ADF) following deployment to the Middle East Area of Operations (MEAO). It involved analyses of data from n = 1324 ADF personnel who deployed between 2010 and 2012, and completed surveys within four months of returning to Australia. The Problem Gambling Severity Index (PGSI) identified Problem Gambling (PG: PGSI ≥5) and At-Risk Gambling (ARG: PGSI 1-4), alongside measures of Depression (PHQ-9), Posttraumatic Stress Disorder (PCL-C), alcohol use problems (AUDIT), distress (K10), and post-deployment stressors. Analyses indicated that 7.7% of personnel reported at least some gambling problems post-deployment, including 2.0% that were distinguished by PG, and 5.7% indicating ARG. These figures were comparable to conditions including probable depression and alcohol dependence, while levels of any gambling problems were high relative to harmful drinking. Higher levels were observed among personnel who were aged 18-24, reported 0-4 years of military service, served in the Army, and comprised Non-Commissioned Officers/Other Ranks. There were strong associations with gambling problems and various indicators of mental health and wellbeing, and self-reported post-deployment difficulties. The findings indicate that gambling problems are salient concerns for some Australian military personnel post-deployment, and highlight the need for increased recognition and responses to these problems.

The effect of 17ß-estradiol on maternal immune activation-induced changes in prepulse inhibition and dopamine receptor and transporter binding in female rats.

Maternal immune activation (MIA) during pregnancy is associated with an increased risk of development of schizophrenia in later life. 17ß-estradiol treatment may improve schizophrenia symptoms, but little is known about its efficacy on MIA-induced psychosis-like behavioural deficits in animals. Therefore, in this study we used the poly(I:C) neurodevelopmental model of schizophrenia to examine whether MIA-induced psychosis-like behavioural and neurochemical changes can be attenuated by chronic treatment (2-6 weeks) with 17ß-estradiol. Pregnant rats were treated with saline or the viral mimetic, poly(I:C), on gestational day 15 and adult female offspring were tested for changes in prepulse inhibition (PPI) and density of dopamine D1 and D2 receptors and dopamine transporters in the forebrain compared to control offspring. Poly(I:C)-treated offspring exhibited significantly disrupted PPI, an effect which was reversed by chronic treatment with 17ß-estradiol. In control offspring, but not poly(I:C) offspring, PPI was significantly reduced by acute treatment with either the dopamine D1/D2 receptor agonist, apomorphine, or dopamine releaser, methamphetamine. 17ß-estradiol restored the effect of apomorphine, but not methamphetamine, on PPI in poly(I:C) offspring. There was a strong trend for a dopamine D2 receptor binding density increase in the nucleus accumbens core region in poly(I:C) offspring, and this was reversed by chronic 17ß-estradiol treatment. No changes were found in the nucleus accumbens shell, caudate putamen or frontal cortex or in the density of dopamine D1 receptors or transporters. These findings suggest that 17ß-estradiol may improve some symptoms of schizophrenia, an effect that may be mediated by selective changes in dopamine D2 receptor density.

Exploring Theta Burst Stimulation for Post-traumatic Stress Disorder in Australian Veterans-A Pilot Study.

INTRODUCTION: Post-traumatic stress disorder (PTSD) is a severe and debilitating condition affecting a significant proportion of the veteran community. A substantial number of veterans with PTSD fail to benefit from trauma-focused psychological therapies or pharmacotherapy or are left with residual symptoms, and therefore, investigation of new and innovative treatment is required. Theta Burst Stimulation (TBS) is a novel form of Repetitive Transcranial Magnetic Stimulation, which has been shown to improve depression symptoms and associated cognitive deficits. The current pilot study aimed to explore the acceptability, safety, and tolerability of intermittent TBS (iTBS) as a treatment for PTSD in Australian veterans. MATERIALS AND METHODS: This study employed a case series, repeated-measures design. Eight Australian Defence Force veterans with PTSD received 20 bilateral iTBS treatments (1 session per day, 5 days per week over a 4-week period) and were assessed on a range of mental health and neuropsychological measures, including the Clinician-Administered PTSD Scale for DSM-5 (CAPS-5) and Hamilton Depression Rating Scale (HAM-D), at pretreatment, post-treatment, and a 3-month follow-up. RESULTS: Treatment was generally welltolerated, with reported side-effects including mild to moderate site-specific cranial pain and headaches during stimulation, which were relieved with the use of low dose analgesics. No serious side effects or adverse events were reported. Participants exhibited reductions in both PTSD and depression symptom severity (the repeated-measures effect size [dRM] for the CAPS-5 was -1.78, and the HAM-D was -1.16 post-treatment), as well as improvements in working memory and processing speed. Although significance cannot be inferred, these preliminary estimates of effect size indicate change over time. CONCLUSIONS: Bilateral iTBS appears to be welltolerated by Australian veterans. Within this repeated-measures case series, iTBS treatment shows promise in reducing both PTSD and mood symptoms, as well as improving cognitive difficulties associated with these disorders. Large-scale randomized controlled trials of this promising treatment are warranted.

Sex differences in the effect of maternal immune activation on cognitive and psychosis-like behaviour in Long Evans rats.

Maternal immune activation during pregnancy is associated with increased risk of development of schizophrenia in later life. There are sex differences in schizophrenia, particularly in terms of age of onset, course of illness and severity of symptoms. However, there is limited and inconsistent literature on sex differences in the effects of maternal immune activation on behaviour with relevance to schizophrenia. The aim of this study was therefore to investigate sex differences in the effects of maternal immune activation by treating Long Evans rats with poly(I:C) on gestational day 15. We compared adult male and female offspring on spatial working memory in the touchscreen trial-unique nonmatching-to-location task, pairwise discrimination and reversal learning, as well as on prepulse inhibition and psychotropic drug-induced locomotor hyperactivity. Male, but not female poly(I:C) offspring displayed a deficit in spatial working memory, particularly at the longer delay. Neither pairwise discrimination nor reversal learning showed an effect of poly(I:C), but female controls outperformed male controls in the reversal learning task. Significant reduction of prepulse inhibition and enhancement of acute methamphetamine-induced locomotor hyperactivity was found similarly in male and female poly(I:C) offspring. These results show that maternal immune activation induces a range of behavioural effects in the offspring, with sex specificity in the effects of maternal immune activation on some aspects of cognition, but not psychosis-like behaviour.

The effect of estrogenic compounds on psychosis-like behaviour in female rats.

17ß-estradiol treatment has shown benefit against schizophrenia symptoms, however long-term use may be associated with negative side-effects. Selective estrogen receptor modulators, such as raloxifene and tamoxifen, have been proposed as suitable alternatives to 17ß-estradiol. An isomer of 17ß-estradiol, 17α-estradiol, is considered less carcinogenic, and non-feminising in males, however little is known about its potential as a treatment for schizophrenia. Moreover, the mechanism underlying the therapeutic action of estrogens remains unclear. We aimed to investigate the ability of these estrogenic compounds to attenuate psychosis-like behaviour in rats. We used two acute pharmacologically-induced assays of psychosis-like behaviour: psychotomimetic drug-induced hyperlocomotion and disruption of prepulse inhibition (PPI). Female Long Evans rats were either intact, ovariectomised (OVX), or OVX and chronically treated with 17ß-estradiol, 17α-estradiol, raloxifene or tamoxifen. Only 17ß-estradiol treatment attenuated locomotor hyperactivity induced by the indirect dopamine receptor agonist, methamphetamine. 17ß-estradiol- and tamoxifen-treated rats showed attenuated methamphetamine- and apomorphine (dopamine D1/D2 receptor agonist)-induced disruption of PPI. Raloxifene-treated rats showed attenuated apomorphine-induced PPI disruption only. Baseline PPI was significantly reduced following OVX, and this deficit was reversed by all estrogenic compounds. Further, PPI in OVX rats was increased following administration of apomorphine. This study confirms a protective effect of 17ß-estradiol in two established animal models of psychosis, while tamoxifen showed beneficial effects against PPI disruption. In contrast, 17α-estradiol and raloxifene showed little effect on dopamine receptor-mediated psychosis-like behaviours. This study highlights the utility of some estrogenic compounds to attenuate psychosis-like behaviour in rats, supporting the notion that estrogens have therapeutic potential for psychotic disorders.

Spatial working memory in the touchscreen operant platform is disrupted in female rats by ovariectomy but not estrous cycle.

Learning and memory deficits have been described in rats and mice after ovariectomy (OVX) and across the estrous cycle. Preclinical researchers therefore often avoid using female animals and, consequently, a large male bias exists in the preclinical cognitive literature. In the present study we examined the role of sex hormones in the touchscreen operant platform using the spatial working memory trial unique nonmatching-to-location (TUNL) task. Twenty-nine Long Evans rats were trained to acquire the TUNL task including three incremental spatial separations (S0, S1, S2). Following 20 consecutive days of training, subjects in experiment 1 (n=15) remained intact and immediately progressed to TUNL testing, while subjects in experiment 2 were OVX (n=6) or sham-operated (n=8) prior to testing. Subjects were tested on 4 spatial separations (S0-3) with a 1s or 6s delay between the sample and nonmatching stimuli. The estrous cycle of intact rats was monitored during the 4weeks of testing. The estrous cycle phase did not significantly affect performance. In contrast, compared to intact rats, OVX impaired performance at larger spatial separations (S2-3) during the 1s delay condition. Further, during the 6s delay, OVX impaired S2 performance, however not S3. Our results suggest a probable shift in cognitive strategy following OVX, when tested with a large and novel spatial separation. Our findings suggest that ovarian hormone deprivation following OVX, but not estrous cycle, impairs spatial working memory as measured by the TUNL task. This research is relevant for future studies utilising the touchscreen TUNL task and for cognitive testing of female rats.

A Role for Estrogen in Schizophrenia: Clinical and Preclinical Findings.

Gender differences in schizophrenia have been extensively researched and it is being increasingly accepted that gonadal steroids are strongly attributed to this phenomenon. Of the various hormones implicated, the estrogen hypothesis has been the most widely researched one and it postulates that estrogen exerts a protective effect by buffering females against the development and severity of the illness. In this review, we comprehensively analyse studies that have investigated the effects of estrogen, in particular 17ß-estradiol, in clinical, animal, and molecular research with relevance to schizophrenia. Specifically, we discuss the current evidence on estrogen dysfunction in schizophrenia patients and review the clinical findings on the use of estradiol as an adjunctive treatment in schizophrenia patients. Preclinical research that has used animal models and molecular probes to investigate estradiol's underlying protective mechanisms is also substantially discussed, with particular focus on estradiol's impact on the major neurotransmitter systems implicated in schizophrenia, namely, the dopamine, serotonin, and glutamate systems.