Stress, the Hippocampus and the Hypothalamic-Pituitary-Adrenal Axis: Implications for the Development of Psychotic Disorders

Phillips, Lisa; McGorry, Patrick; Garner, Belinda; Thompson, Katherine; Pantelis, Christos; Wood, Stephen J.; Berger, Gregor

doi:10.1080/j.1440-1614.2006.01877.x

Cited by 190 publications

(86 citation statements)

References 217 publications

(230 reference statements)

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“…Our finding of a positive correlation between baseline positive symptoms and progressive hippocampal loss could therefore suggest that the hippocampus is particularly sensitive to positive symptoms around and right after transition to psychosis. We speculate that this hippocampal sensitivity might reflect a higher level of stress accompanying a psychotic state possibly related to disturbances in the hypothalamic-pituitary-adrenal (HPA) axis (Phillips et al 2006). Although we did not find ventricular enlargement over time a significant correlation between ventricular increase and less negative symptom improvement was observed.…”

Section: Discussionmentioning

confidence: 99%

Progressive striatal and hippocampal volume loss in initially antipsychotic-naive, first-episode schizophrenia patients treated with quetiapine: relationship to dose and symptoms

Ebdrup

Skimminge

Rasmussen

et al. 2010

Int. J. Neuropsychopharm.

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First-generation antipsychotics have been associated with striatal volume increases. The effects of secondgeneration antipsychotics (SGAs) on the striatum are unclear. Moreover, SGAs may have neuroprotective effects on the hippocampus. Dose-dependent volumetric effects of individual SGAs have scarcely been investigated. Here we investigated structural brain changes in antipsychotic-naive, first-episode schizophrenia patients after 6 months treatment with the SGA, quetiapine. We have recently reported on baseline volume reductions in the caudate nucleus and hippocampus. Baseline and follow-up T1-weighted images (3 T) from 22 patients and 28 matched healthy controls were analysed using tensor-based morphometry. Non-parametric voxel-wise group comparisons were performed. Small volume correction was employed for striatum, hippocampus and ventricles. Dose-dependent medication effects and associations with psychopathology were assessed. Patients had significant bilateral striatal and hippocampal loss over the 6-month treatment period. When compared to controls the striatal volume loss was most pronounced with low quetiapine doses and less apparent with high doses. Post-hoc analyses revealed that the striatal volume loss was most pronounced in the caudate and putamen, but not in accumbens. Conversely, hippocampal volume loss appeared more pronounced with high quetiapine doses than with low doses. Clinically, higher baseline positive symptoms were associated with more striatal and hippocampal loss over time. Although patients' ventricles did not change significantly, ventricular increases correlated with less improvement of negative symptoms. Progressive regional volume loss in quetiapine-treated, first-episode schizophrenia patients may be dose-dependent and clinically relevant. The mechanisms underlying progressive brain changes, specific antipsychotic compounds and clinical symptoms warrant further research.

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Section: Discussionmentioning

confidence: 99%

Progressive striatal and hippocampal volume loss in initially antipsychotic-naive, first-episode schizophrenia patients treated with quetiapine: relationship to dose and symptoms

Ebdrup

Skimminge

Rasmussen

et al. 2010

Int. J. Neuropsychopharm.

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“…This further implies that subcortical dopaminergic systems come under more extensive control as intracortical neural circuitries mature, so that dysfunctions of this circuitry will have a greater influence on dopaminergic activity after it has reached the critical developmental stage after puberty (Weinberger 1987;Weinberger and Lipska 2005;Keshavan and Hogarty 1999). Taken together, enhanced mesolimbic (especially striatal) dopaminergic activity as seen in schizophrenic patients may be induced by early developmental defects of (non-dopaminergic) prefrontal-temporolimbic cortical pathways and may thus emerge secondarily to disturbances in other brain regions, particularly in prefrontal (Feinberg 1982;Weinberger 1987;Deutsch 1992;Weinberger and Lipska 2005;Laruelle et al 2003;Grace 2004) and/or hippocampal (Weiner 1990;Gray et al 1991, Gray 1998Grace 2000;Velakoulis et al 2000;Phillips et al 2006) structures (see Fig. 1a).…”

Section: Developmental Perspective Of Abnormal Da Functions Followingmentioning

confidence: 99%

Prenatal exposure to infection: a primary mechanism for abnormal dopaminergic development in schizophrenia

Meyer

Feldon

2009

Psychopharmacology

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Dopaminergic mal-development in general, and following prenatal immune activation in particular, may represent a primary etiopathological mechanism in the development of schizophrenia and related disorders. This hypothesis differs from the view that dopaminergic abnormalities in schizophrenia may be secondary to abnormalities in other brain structures and/or neurotransmitter systems. The existence of primary dopaminergic mechanisms may have important implications for the identification and early treatment of individuals prodromally symptomatic for schizophrenia.

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“…Indeed, evidence suggests that multiple mood disorders, including anxiety conditions and major depression, are associated with chronic alterations in the circulating levels and circadian rhythm of adrenal glucocorticoids in the control of emotional reactivity (de Kloet 2003;Akil 2005;de Kloet et al 2007;Rozeboom et al 2007). Furthermore, HPA axis dysfunction may be a major biological factor underlying the relationships between psychological experience of stress and the development of psychosis, particularly in the early phase of schizophrenia (Phillips et al 2006). Similarly, immunological abnormalities have long been described in diverse psychiatric disorders, including schizophrenia (Muller et al 2000;Schwarz et al 2001;Strous and Shoenfeld 2006).…”

Section: Relevance Of Animal Models For Biological Psychiatrymentioning

confidence: 99%

Critical Age Windows for Neurodevelopmental Psychiatric Disorders: Evidence from Animal Models

2010

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A disruption in normal brain development has been hypothesized to contribute to the aetiology of major psychiatric disorders. According to the 'double-hit' hypothesis, mutant genes-based deviations, associated with specific environmental insults during brain development, may result in neurobehavioural disturbances. The existence of age windows of vulnerability to environmental conditions during brain maturation will be discussed, using as examples a series of studies we have performed during the last years. Major deviations from normative neurobehavioural trajectories have been reported in animal models following exposure to severe stress (either episodes of maternal separation, deprivation or corticosterone supplementation) early in infancy. Rodent models of difficult and/or stressful pregnancies, including obstetric complications (e.g. prenatal restrain stress or neonatal hypoxia) and gestational exposure to infection (e.g prenatal immune challenge), have been associated with profound long-lasting deficits in the offspring's emotional and social behaviour, and with immune and endocrine changes. More recently, adolescence, characterized by elevated rates of brain plasticity, has emerged as an additional period during which sensitivity to environmental influence (either adverse or stimulatory) is maximal. We have reported that both pharmacological (methylphenidate) and environmental (physical or social enrichment) interventions can be used to counteract the detrimental effects of earlier-origin developmental insults. Present findings indicate that these age periods (i.e. prenatal stage, early infancy and adolescence) do represent critical windows open to plastic changes and might be susceptible to both adverse and supportive shaping environmental forces. Taken together, age-related neuroplasticity might be considered not only as a risk factor for psychopathology but also as a potent mechanism for compensation. A better understanding of these critical periods of brain development is a concern for public health and may provide new insights into prevention strategies and into novel therapeutic approaches in neuropsychiatry.

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Stress, the Hippocampus and the Hypothalamic-Pituitary-Adrenal Axis: Implications for the Development of Psychotic Disorders

Cited by 190 publications

References 217 publications

Progressive striatal and hippocampal volume loss in initially antipsychotic-naive, first-episode schizophrenia patients treated with quetiapine: relationship to dose and symptoms

Progressive striatal and hippocampal volume loss in initially antipsychotic-naive, first-episode schizophrenia patients treated with quetiapine: relationship to dose and symptoms

Prenatal exposure to infection: a primary mechanism for abnormal dopaminergic development in schizophrenia

Critical Age Windows for Neurodevelopmental Psychiatric Disorders: Evidence from Animal Models

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