Walder DJ, Walker EF, Lewine RJ. Cognitive functioning, cortisol release, and symptom severity in patients with schizophrenia. Biol Psychiatry 48: 1121-1132

Department of Psychology (DJW, EFW), Emory University, Atlanta, Georgia 30322, USA.
Biological Psychiatry (Impact Factor: 10.26). 01/2001; 48(12):1121-32. DOI: 10.1016/S0006-3223(00)01052-0
Source: PubMed


There is substantial evidence of dysregulation of cortisol secretion, hippocampal abnormalities, and memory deficits in schizophrenia and other psychotic disorders. Research also suggests that cortisol secretion augments dopaminergic activity, which may result in increased symptom expression in this clinical population.
We examined the relations among cortisol release, cognitive performance, and psychotic symptomatology. Subjects were 18 adults with schizophrenia or schizoaffective disorder, seven with a nonpsychotic psychiatric disorder, and 15 normal control subjects. Tests of memory and executive function were administered. Cortisol was assayed from multiple saliva samples.
Findings indicated the following: 1) patients with psychotic disorders scored below the comparison groups on the cognitive measures; 2) for the entire sample, cortisol levels were inversely correlated with performance on memory and frontal tasks; and 3) among patients, cortisol levels were positively correlated with ratings of positive, disorganized, and overall symptom severity, but not with negative symptoms.
The present results suggest that abnormalities in the hypothalamic-pituitary-adrenal axis and hippocampal systems play a role in observed cognitive deficits across populations. Among psychotic patients, elevated cortisol secretion is linked with greater symptom severity.

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    • "Among different biological factors, hormones may play an important role in the pathogenesis of cognitive impairment in psychotic disorders. Most studies have focused on cortisol (Walder et al., 2000), although others, such as thyroid hormones, are also important . Thyroid hormones play an important role in the differentiation and growth of a healthy human brain and consequently in cognition. "
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    ABSTRACT: Subjects with a psychotic disorder show mild to moderate cognitive impairment, which is an important determinant of functional outcome. The underlying biological process of cognitive impairment in psychosis is unclear. We aimed to explore whether hypothalamic-pituitary-thyroid axis hormones or thyroid autoimmunity modulate cognitive functioning in subjects with early psychosis. We studied 70 patients with a psychotic disorder (<3years of illness) and a control group of 37 healthy subjects (HS). Plasma levels of thyroid-stimulating hormone (TSH), free thyroxine (FT4) and thyroid-peroxidase (TPO-Abs) and thyroglobulin antibodies (TG-Abs) were determined. Cognitive assessment was performed with the MATRICS Cognitive Consensus Cognitive Battery. We also explored the relationship between thyroid variables and cognition in three subgroups of psychotic patients: psychosis not otherwise specified, affective psychosis (bipolar disorder or schizoaffective disorder) and non-affective psychosis (schizophrenia or schizophreniphorm disorder). In patients with early psychosis, higher FT4 levels (but not TSH or thyroid antibodies) were associated with better cognitive performance in attention/vigilance and overall cognition. The relationship between FT4 levels and the attention/vigilance domain remained significant in a multivariate analysis after adjusting for education level, age, gender, substance use, and benzodiazepine and antipsychotic treatments. We did not find a significant association between FT4 and cognitive performance in HS. In the exploratory analysis by psychotic subtypes, subjects with affective psychosis had increased FT4 levels and better cognitive profile than those with non-affective psychosis. Our study suggests that FT4 levels are associated with cognitive abilities (attention/vigilance and overall cognition) in individuals with early psychosis. Copyright © 2015 Elsevier B.V. All rights reserved.
    Schizophrenia Research 05/2015; 166(1-3). DOI:10.1016/j.schres.2015.04.030 · 3.92 Impact Factor
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    • "This study found a strong negative correlation between dexamethasone abnormalities (dexamethasone non-suppressors) and cognitive performance in type II schizophrenics, implying a relationship between HPA axis hyperactivity and cognitive impairment. Furthermore, Walder et al. (61), evaluating 18 patients with chronic psychosis, 7 patients without psychosis, and 19 healthy controls, found that, in the entire sample, cortisol levels were negatively correlated with performance on memory and executive tasks. "
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    ABSTRACT: Objective: To carry out a systematic review of the literature addressing cognitive functions in first-episode psychosis (FEP), divided into domains. Although this is not a full “cognitive-genetics-in-schizophrenia review,” we will also include putative ideas of mechanism(s) behind these impairments, focusing on how early stress, and genetic vulnerability may moderate cognitive function in psychosis. Method: Relevant studies were identified via computer literature searches for research published up to and including January 2013, only case-control studies were included for the neurocognitive meta-analysis. Results: Patients with FEP present global cognitive impairment compared to healthy controls. The largest effect size was observed for verbal memory (Cohen’s d effect size = 2.10), followed by executive function (effect size = 1.86), and general IQ (effect size = 1.71). However, effect sizes varied between studies. Conclusion: Cognitive impairment across domains, up to severe level based on Cohen’s effect size, is present already in FEP studies. However, differences in levels of impairment are observed between studies, as well as within domains, indicating that further consolidation of cognitive impairment over the course of illness may be present. Cognitive abnormalities may be linked to a neurodevelopmental model including increased sensitivity to the negative effect of stress, as well as genetic vulnerability. More research on this field is needed.
    Frontiers in Psychiatry 01/2014; 4:182. DOI:10.3389/fpsyt.2013.00182
    • "Cortisol excess has neurotoxic effects on the hippocampus (Wolkowitz et al., 2009), an effect that is particularly important during developmental periods including pregnancy and early infancy. As both perinatal stress and childhood trauma have been associated with HPA axis abnormalities in adulthood (Heim et al., 2000; Newport et al., 2004; Phillips et al., 1998; van der Vegt et al., 2009), and the HPA axis is associated with cognitive impairments in subjects with psychoses (Walder et al., 2000; Aas et al., 2011;) as well as non-psychiatric populations (Lupien et al., 1994; Reynolds et al., 2010), the HPA axis is a plausible mechanism linking the association between early life stress and psychosis. In accord with this, a recent preliminary study has dissected the potential relationship between early life stressful experiences, HPA axis and cognitive abilities in subjects with early psychoses (Labad, 2012). "
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    ABSTRACT: The developing foetus makes adaptations to an adverse in utero environment which may lead to permanent changes in structure and physiology, thus 'programming' the foetus to risk of ill health in later life. Epidemiological studies have shown associations between low birth weight, a surrogate marker of an adverse intrauterine environment, and a range of diseases in adult life including cardiometabolic and psychiatric disease. These associations do not apply exclusively to low birth weight babies but also to newborns within the normal birth weight range. Early life stress, including stressors in the prenatal and early postnatal period, is a key factor that can have long-term effects on offspring health. Animal studies show this is mediated through changes in the maternal and foetal hypothalamic-pituitary-adrenal axes resulting in foetal exposure to excess glucocorticoids. Data in humans are more limited but support that the biological effects of stress in utero may be transmitted through changes in glucocorticoid action or metabolism. Common contemporary physical and social stressors of maternal obesity and socio-economic deprivation impact on the maternal response to pregnancy and the prevailing hormonal milieu that the developing foetus will be exposed to. Prenatal stress may also be compounded by early postnatal stresses such as childhood maltreatment with resultant adverse effects for the offspring. Understanding of the mechanisms whereby these stressors are transmitted from mother to foetus will not only improve our knowledge of normal foetal development but will also help identify novel pathways for early intervention either in the periconceptional, pregnancy or the early postpartum period.
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