Subjective cognitive changes following premenopausal risk-reducing bilateral salpingo-oophorectomy.

OBJECTIVE: Women at high risk of ovarian cancer are commonly advised to undergo risk-reducing bilateral salpingo-oophorectomy (BSO) prior to natural menopause. Cognitive symptoms during natural menopause transition are frequently reported; however, very few studies have examined cognitive changes following surgical menopause. To address this gap, we explored the cognitive experiences of women within 24 months post BSO. METHODS: This observational cross-sectional sub-study is part of a larger project, the Early Menopause and Cognition Study (EM-COG). We investigated perceived cognitive experiences in Australian women (n = 16) who underwent risk-reducing BSO using qualitative interviews. Thematic analysis was undertaken to identify key themes. RESULTS: Fifteen out of 16 participants (93.75%) reported changes to cognition within 24 months post BSO. The key cognitive symptoms reported were brain fog, memory and retrieval difficulties, slower processing speed as well as attention difficulties. Five participants (31.3%) experienced negative mood symptoms post BSO. CONCLUSION: Findings from this study suggest that women experience subjective cognitive changes within 24 months post BSO. This period could be a vulnerable time for women's cognitive health. While these findings need to be confirmed by a large prospective study, our research indicates that psychoeducation and awareness will be helpful in managing cognitive symptoms after surgical menopause.

Identifying the cognitive underpinnings of voice-hearing by comparing never, past and current voice-hearers.

OBJECTIVE: The current study aimed to compare specific cognitive profiles corresponding to auditory verbal hallucinations (AVH) status and elucidate which pattern of cognitive deficits may predict voice-hearing status. METHOD: Clinical participants with schizophrenia spectrum disorders were partitioned into: (i) current voice-hearers (n = 46), (ii) past voice-hearers (n = 37) and (iii) never voice-hearers (n = 40), and compared with 319 non-clinical controls. Cognitive assessment employed the MATRICS Consensus Cognitive Battery (MCCB), supplemented by the Delis-Kaplan Executive Function System (D-KEFS) Colour-Word Interference Test (Stroop) as a robust measure of executive function. RESULTS: On the Visual Learning domain, current and past voice-hearers had significantly poorer performance relative to never voice-hearers, who in turn had significantly poorer performance than non-clinical controls. Current and never voice-hearers had significantly poorer performance on the Social Cognition domain relative to non-clinical controls. Current voice-hearers also had significantly poorer performance on the Inhibition domain relative to non-clinical controls. Binary logistic regression revealed that Visual Learning was the only significant cognitive predictor of AVH presence. CONCLUSION: Visual learning, and potentially inhibition, may be viable therapeutic targets when addressing cognitive mechanisms associated with AVHs. Future research should focus on investigating additional cognitive mechanisms, employing diverse voice-hearing populations and embarking on related longitudinal studies.

Improvement in depression with oestrogen treatment in women with schizophrenia.

Women with schizophrenia are often noted to suffer with comorbid depression. Many studies have shown associations between fluctuating oestrogen levels in the brain and mental illness. This study investigates the effect of oestradiol treatment on comorbid depressive symptoms in women with schizophrenia. This study is an 8-week, three-arm, double-blind, randomised-controlled trial. The 180 female participants were aged between 18 and 45, with schizophrenia and ongoing symptoms of psychosis Positive and Negative Syndrome Scale (PANSS) score > 60 despite a stable dose of antipsychotic medication. Depressive symptoms were assessed using Montgomery Asberg Depression Scale (MADRS) with a mean score of 73.77 at baseline. Participants received transdermal oestradiol 200 µg or transdermal oestradiol 100 µg or an identical placebo patch. The a priori outcome measure was the change in PANSS score measured at baseline and days 7, 14, 28 and 56, but in this study, we focused on the change in MADRS score at the same time points. Data were analysed by using Quade's rank analysis of covariance (ANCOVA) (Huitema 1980) with baseline MADRS score as a covariate. We found a fluctuating but overall trend towards improvement of comorbid depressive symptoms in women with schizophrenia taking transdermal oestrogen 200 mcg compared with oestrogen 100 mcg or placebo. The stronger 'antidepressant' effect of 200 mcg transdermal oestradiol was found at day 28 (p = 0.03). Our study suggests that adjunctive oestradiol treatment for depression may be a promising treatment for women with comorbid depression and schizophrenia.

Raloxifene as a treatment for cognition in women with schizophrenia: the influence of menopause status.

Cognitive impairments cause significant functional issues for people with schizophrenia, often emerging before the onset of hallucinations, delusions and other psychosis symptoms. Current pharmacological treatments do not target cognitive dysfunction. Several lines of evidence support the beneficial effects of estrogens on cognition. Raloxifene hydrochloride, a selective estrogen receptor modulator, has been associated with cognitive improvements in healthy postmenopausal women and in schizophrenia, although findings are inconsistent. Using pooled data from two clinical trials, the aim of the current study was to compare the efficacy of 120 mg/day adjunctive raloxifene to placebo for 12 weeks on cognitive performance in women with schizophrenia who were stratified by menopause status (pre-menopausal; peri-menopausal or post-menopausal). A total of sixty-nine participants with a diagnosis of schizophrenia or schizoaffective disorder were included. Cognition was assessed at baseline and study end using the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). Results indicated that after stratifying for menopause status (strata) and adjusting for endogenous hormone levels (estrogen, progesterone, follicle stimulating hormone and luteinising hormone), semantic fluency, picture naming and list recognition change from baseline scores for the raloxifene group differed significantly from the placebo group. The findings from the current study highlight the importance of considering menopause status when interpreting the effects of hormonal treatments.

Menstrual cycle irregularity and menopause status influence cognition in women with schizophrenia.

Cognitive impairments are a core feature of schizophrenia and contribute significantly to functional complications. Current pharmacological treatments do not ameliorate cognitive dysfunction and the aetiology of cognitive impairments are poorly understood. Hormones of the hypothalamic-pituitary-gonadal (HPG) axis that regulate reproductive function have multiple effects on the development, maintenance and function of the brain and have been suggested to also influence cognition. The aim of the current study was to investigate how HPG axis hormones effect cognition, specifically exploring the influence of menopause status and menstrual cycle irregularity on cognitive performance in women with schizophrenia. The data for the present study represents pooled baseline data from three clinical trials. Two hundred and forty female participants with a diagnosis of schizophrenia or schizoaffective disorder were included in the analysis. Cognition was assessed using the Repeatable Battery for the Assessment of Neuropsychological Status. Hormone assays for serum sex steroids and pituitary hormones (including estradiol, progesterone, luteinising hormone and follicle-stimulating hormone) were conducted and women were classified as postmenopausal; perimenopausal; premenopausal/reproductive, further classified into regular and irregular menstrual cycles. To model a comparison of cognitive performance for i) perimenopausal; ii) post-menopausal women and iii) reproductive aged women with irregular cycles to reproductive aged women with regular cycles a semiparametric regression model (generalised additive mode) was fitted. The results revealed that in females with schizophrenia, menstrual cycle irregularity predicted significantly poorer cognitive performance in the areas of psychomotor speed, verbal fluency and verbal memory. Perimenopause was not associated with cognitive changes and the post-menopausal period was associated with poorer visuospatial performance. This study provides evidence to associate reproductive hormones with cognitive dysfunction in schizophrenia.

Characterizing cognitive heterogeneity on the schizophrenia-bipolar disorder spectrum.

BACKGROUND: Current group-average analysis suggests quantitative but not qualitative cognitive differences between schizophrenia (SZ) and bipolar disorder (BD). There is increasing recognition that cognitive within-group heterogeneity exists in both disorders, but it remains unclear as to whether between-group comparisons of performance in cognitive subgroups emerging from within each of these nosological categories uphold group-average findings. We addressed this by identifying cognitive subgroups in large samples of SZ and BD patients independently, and comparing their cognitive profiles. The utility of a cross-diagnostic clustering approach to understanding cognitive heterogeneity in these patients was also explored. METHOD: Hierarchical clustering analyses were conducted using cognitive data from 1541 participants (SZ n = 564, BD n = 402, healthy control n = 575). RESULTS: Three qualitatively and quantitatively similar clusters emerged within each clinical group: a severely impaired cluster, a mild-moderately impaired cluster and a relatively intact cognitive cluster. A cross-diagnostic clustering solution also resulted in three subgroups and was superior in reducing cognitive heterogeneity compared with disorder clustering independently. CONCLUSIONS: Quantitative SZ-BD cognitive differences commonly seen using group averages did not hold when cognitive heterogeneity was factored into our sample. Members of each corresponding subgroup, irrespective of diagnosis, might be manifesting the outcome of differences in shared cognitive risk factors.

Dopamine and cognitive control: sex-by-genotype interactions influence the capacity to switch attention.

Cognitive performance in healthy persons varies widely between individuals. Sex differences in cognition are well reported, and there is an emerging body of evidence suggesting that the relationship between dopaminergic neurotransmission, implicated in many cognitive functions, is modulated by sex. Here, we examine the influence of sex and genetic variations along the dopaminergic pathway on aspects of cognitive control. A total of 415 healthy individuals, selected from an international consortium linked to Brain Research and Integrative Neuroscience Network (BRAINnet), were genotyped for two common and functional genetic variations of dopamine regulating genes: the catechol-O-methyltransferase [COMT] gene (rs4680) and the dopamine receptor D2 [DRD2] gene (rs6277). Cognitive measures were selected to explore sustained attention (using a continuous performance task), switching of attention (using a Trails B adaptation) and working memory (a visual computerised adaptation of digit span). While there were no main effects for genotype across any tasks, analyses revealed significant sex by genotype interactions for the capacity to switch attention. In relation to COMT, superior performance was noted in females with the Val/Val genotype and for DRD2, superior performance was seen for TT females and CC males. These findings highlight the importance of considering genetic variation in baseline dopamine levels in addition to sex, when considering the impact of dopamine on cognition in healthy populations. These findings also have important implications for the many neuropsychiatric disorders that implicate dopamine, cognitive changes and sex differences.

Estradiol for treatment-resistant schizophrenia: a large-scale randomized-controlled trial in women of child-bearing age.

Many women with schizophrenia remain symptomatic despite optimal use of current therapies. While previous studies suggest that adjunctive oestrogen therapy might be effective, large-scale clinical trials are required before clinical applications are possible. This study is the first large-scale randomized-controlled trial in women with treatment-resistant schizophrenia. This Definitive Oestrogen Patch Trial was an 8-week, three-arm, double-blind, randomized-controlled trial conducted between 2006 and 2011. The 183 female participants were aged between 18 and 45 (mean = 35 years), with schizophrenia or schizoaffective disorder and ongoing symptoms of psychosis (Positive and Negative Syndrome Scale, PANSS score>60) despite a stable dose of antipsychotic medication for at least 4 weeks. Mean duration of illness was more than 10 years. Participants received transdermal estradiol 200 µg, transdermal estradiol 100 µg or an identical placebo patch. For the 180 women who completed the study, the a priori outcome measure was the change in PANSS score measured at baseline and days 7, 14, 28 and 56. Cognition was assessed at baseline and day 56 using the Repeatable Battery of Neuropsychological Status. Data were analysed using latent growth curve modelling. Both estradiol groups had greater decreases in PANSS positive, general and total symptoms compared with the placebo group (P<0.01), with a greater effect seen for 200 µg than 100 µg estradiol. The largest effect size was for the positive subscale of PANSS in the estradiol 200 µg treatment group (effect size 0.44, P<0.01). This study shows estradiol is an effective and clinically significant adjunctive therapy for women with treatment-resistant schizophrenia, particularly for positive symptoms.

Genetic variations in dopamine and inhibitory control: lack of influence on action restraint.

Failures of inhibitory control can severely affect everyday life in healthy individuals and represent a common feature of many neuropsychiatric conditions, particularly disorders with dopaminergic disturbances implicated. This study's aim was to examine the interacting influences of three common and functional gene variants that influence dopaminergic pathways on an aspect of inhibitory control (action restraint). Three hundred and twenty two healthy adults were selected from an international consortium linked to Brain Research and Integrative Neuroscience (BRAINnet). DNA was extracted from cheek swab samples and participants were genotyped for the Val158Met single nucleotide polymorphism on COMT (rs 4680), C957T on DRD2 (rs 6277) and the 40bp variable number of tandem repeat on the DAT1 (SLC6A3, 10/10 vs 9+). Response inhibition was measured using a computerised Go/No-Go task. Main effects and interactions between genotypes were explored. We did not observe a genotype effect on fundamental measures of response inhibition, i.e. reaction time (RT) and commission errors. RT variability was significantly increased in DRD2 C957T heterozygotes. In conclusion, this large, non-clinical study reveals that the selected genetic polymorphisms regulating dopamine (COMT, DRD2 and DAT1) do not influence one aspect of response inhibition, action restraint, as measured by the Go/No-Go task, reinforcing the neuropharmacological dissociation between stop-signal and Go/No-Go tasks. Genetic variation in striatal dopamine may, however, contribute to intraindividual RT variability.

Antipsychotics in pregnancy.

Women who are pregnant and who have a history of psychosis are commonly managed with antipsychotic medications. The evidence regarding the use of antipsychotics in pregnancy has been insufficient to provide adequate support for this practice and is a concern for clinicians and women alike. This review presents literature surrounding the use of antipsychotic medications in pregnancy, providing an overview of the historical and contemporary perspectives which influence clinicians prescribing practices. Data were sourced from Medline, CINAHL, PsycINFo, using the terms antipsychotics with pregnancy and psychosis or schizophrenia. This was expanded to include the most common atypical antipsychotics: olanzapine, risperidone, clozapine, quetiapine, ziprasidone and aripiprazole. Literature was found reporting the use of antipsychotic medications in pregnancy since the introduction of antipsychotics in the 1950s, comprising mainly of authors' reviews of the literature, case studies, retrospective reports, drug company registries and more recently a prospective comparative study. This review identifies that the literature provides no clear answer for clinicians as to the risk associated with the use of antipsychotics in pregnancy. To this effect, recently in Australia, the National Register of Antipsychotic Medications in Pregnancy was established to prospectively collect information regarding outcomes for mother and baby, when antipsychotic medications have been used during pregnancy.

Negative symptoms: A review of schizophrenia, melancholic depression and Parkinson's disease.

Negative symptoms generally refer to a reduction in normal functioning. In schizophrenia they encompass apathy, anhedonia, flat affect, avolition, social withdrawal and, on some accounts, psychomotor retardation. Negative symptoms have been identified in other psychiatric disorders, including melancholic depression, and also in neurological disorders, such Parkinson's disease. Achieving a better understanding of negative symptoms constitutes a priority in mental health. Primarily, negative symptoms represent an unrelenting, intractable and disabling feature for patients, often amounting to a severe burden on families, carers and the patients themselves. Identifying and understanding subgroups within disorders may also contribute to the clinical care and scientific understanding of the pathophysiology of these disorders. The purpose of this paper is to review the current literature on negative symptoms in schizophrenia and explore the idea that negative symptoms may play an important role not only in other psychiatric disorders such as melancholic depression, but also in neurological disorders, such as Parkinson's disease. In each disorder negative symptoms manifest with similar motor and cognitive impairments and are associated with comparable neuropathological and biochemical findings, possibly reflecting analogous impairments in the functioning of frontostriatal-limbic circuits.

Self-paced saccades and saccades to oddball targets in Parkinson's disease.

Patients with Parkinson's disease (PD) manifest difficulty in initiation and execution of movements, particularly when movements are sequential, simultaneous or repetitive. Eye movements are particularly effective in evaluating motor impairments. We utilized a series of saccadic eye movement paradigms to explore the ability of 13 patients with mild-moderate PD and 13 age-matched healthy controls to self-pace saccades between two continuously illuminated targets, before and after an externally cued tracking period, and respond to unexpected changes in task demand. The latter was explored by measuring saccadic responses to unexpected "oddball" targets that appeared during a well-learned reciprocating sequence of saccades, in either the opposite direction to that expected or at twice the anticipated extent. Results indicated that all participants demonstrated a marked increase in saccade amplitudes from the externally cued saccade tracking to the self-paced saccades. Unexpectedly, this difference was magnified in PD patients. Self-paced saccades before externally cueing were also more frequent than requested in the PD group, but timing improved following external cueing. The second key finding was that while patients were able to respond to unexpected changes in target amplitude, performance was more variable (in terms of latency and accuracy) when responding to unexpected changes in target direction. Hence, beneficial effects of external cueing on the timing of self-paced saccades may be mediated through cortical regions, placing less emphasis on striatal regions known to be compromised in PD. Additionally, responding to changes in saccade direction (but not amplitude) may rely on basal ganglia circuitry.

Ocular motor differences between melancholic and non-melancholic depression.

BACKGROUND: Major depressive disorder may be a heterogeneous disorder, yet melancholic depression is the most consistently described subtype, regarded as qualitatively different to non-melancholic depression in terms of cognitive and motor impairments. Eye movement studies in depression are infrequent and findings are inconclusive. METHODS: This study employed a battery of saccadic eye movement tasks to explore reflexive saccades, as well as higher order cognitive aspects of saccades including inhibitory control and spatial working memory. Nineteen patients with major depressive disorder (9 melancholic; 10 non-melancholic) and 15 healthy controls participated. RESULTS: Differences were revealed between melancholic and non-melancholic patients. Melancholia was associated with longer latencies, difficulty increasing peak velocities as target amplitudes increased, and hypometric primary saccades during the predictable protocol. In contrast, the non-melancholic depression group performed similarly to controls on most tasks, but saccadic peak velocity was increased for reflexive saccades at larger amplitudes. LIMITATIONS: Most patients were taking antidepressant medication. CONCLUSIONS: The latency increases, reduced peak velocity and primary saccade hypometria with more severe melancholia may be explained by functional changes in the fronto-striatal-collicular networks, related to dopamine dysfunction. In contrast, the serotonergic system plays a greater role in non-melancholic symptoms and this may underpin the observed increases in saccadic peak velocity. These findings provide neurophysiological support for functional differences between depression subgroups that are consistent with previous motor and cognitive findings.

Hypometric primary saccades and increased variability in visually-guided saccades in Huntington's disease.

Eye movement abnormalities can be distinctive and suggestive of a specific pathophysiology. To further investigate the deficits in the control of saccades in patients with Huntington's disease (HD), we investigated the ability of 11 HD patients and 11 matched controls to perform visually-guided saccades. We adopted reflexive saccade tasks involving predictable and unpredictable sequences, at different amplitudes of target step (10 degrees, 20 degrees, 30 degrees, 40 degrees ), as well as voluntary self-paced saccades. Prolongation of initiation was observed in the HD group as the target amplitude of predictable saccades increased. During the self-paced saccade task, the HD patients had increased intersaccadic intervals, performed fewer saccades in the allocated time and displayed an increased temporal variability in comparison to the controls. Furthermore, hypometric primary saccades, and an increased number of corrective saccades, were observed during both reflexive and voluntary saccades in the HD group. The delayed initiation of large saccades, deficits in voluntary, self-paced saccades, impaired saccadic accuracy and increased corrective saccades in HD, were interpreted in light of other ocular motor and limb studies, and appear to be due to damage to the fronto-striatal loop, including the supplementary eye fields, as well as possible brainstem and cerebellar involvement.