The relevance of chronic stress for the acute stress reaction in people at elevated risk for psychosis.

BACKGROUND: Theoretical models and empirical evidence suggest that alterations of the acute stress reaction are a vulnerability indicator of psychosis. However, more studies are needed that use laboratory stressors and a multimodal assessment of the stress reaction. Furthermore, it needs to be clarified whether alterations of the acute stress reaction result from the chronic stress level. METHODS: We recruited participants at familial (n = 32) and symptomatic risk (n = 43) for psychosis and a low-risk control group (n = 35). We assessed their chronic stress levels (self-report, hair cortisol concentrations) and self-reported (subjective, affective, paranoia) as well as physiological (heart rate, skin conductance level, cortisol) reactions to the Trier Social Stress Test. RESULTS: The groups did not differ in their acute stress reaction but both at-risk groups showed higher levels of self-reported chronic stress. Chronic stress predicted changes in negative affect, paranoia and skin conductance level in the total sample. CONCLUSIONS: We could not confirm that alterations of the acute stress reaction are an early vulnerability indicator of psychosis and conclude that they might develop at a later time-point on the trajectory to psychosis. The high chronic stress level of the at-risk groups might constitute an intermediate state that increases the likelihood of altered stress reactions in later risk stages. To test this, future work needs to investigate the temporal order between chronic stress levels, acute stress reactions and symptom development across the psychosis continuum.

Models of persecutory delusions: a mechanistic insight into the early stages of psychosis.

Identifying robust markers for predicting the onset of psychosis has been a key challenge for early detection research. Persecutory delusions are core symptoms of psychosis, and social cognition is particularly impaired in first-episode psychosis patients and individuals at risk for developing psychosis. Here, we propose new avenues for translation provided by hierarchical Bayesian models of behaviour and neuroimaging data applied in the context of social learning to target persecutory delusions. As it comprises a mechanistic model embedded in neurophysiology, the findings of this approach may shed light onto inference and neurobiological causes of transition to psychosis.

Paranoid schizophrenia and methamphetamine-induced paranoia are both characterized by a similar LINE-1 partial methylation profile, which is more pronounced in paranoid schizophrenia.

BACKGROUND: There is evidence that schizophrenia is a neuro-immune disorder. Genes linked to intragenic LINE-1 methylation show a strong association with immune-associated disorders including psychosis. The aim of this study was to examine LINE-1 methylation patterns in paranoid schizophrenia and methamphetamine-induced paranoia, a model for schizophrenia. METHODS: This study recruited 31 patients with paranoid schizophrenia, 94 with methamphetamine-induced paranoia (MIP) and 163 normal controls. LINE-1 methylation patterns were assayed in peripheral blood mononuclear cells and a combined bisulphite restriction analysis and COBRA were used to estimate LINE1 methylation (mC) and CpG dinucleotide methylation patterns, namely 2 methylated (mCmC) and 2 unmethylated (uCuC) CpGs and the partially methylated loci mCuC (5'm with 3'u) and uCmC (5'u with 3'm). RESULTS: Patients with paranoid schizophrenia show highly significant changes in LINE-1 partial methylation patterns, namely a higher percentage of mCuC and lower percentage of uCmC as compared with controls and MIP patients, while the latter show a higher percentage of mCuC but lower percentage of uCmC as compared with controls. Higher mCuC significantly predicts paranoid schizophrenia with a sensitivity of 51.6%, specificity of 97.5% and an area under the ROC curve of 0.895. CONCLUSIONS: The results indicate that a common dysfunction in LINE-1 partial methylation may underpin both paranoid schizophrenia and MIP and that this methylation pattern is significantly more expressed in paranoid schizophrenia than MIP. Reciprocal links between impairments in LINE-1 methylation and neuro-immune and neuro-oxidative pathways may underpin the pathophysiology of both MIP and paranoid schizophrenia.

Dopaminergic basis for signaling belief updates, but not surprise, and the link to paranoia.

Distinguishing between meaningful and meaningless sensory information is fundamental to forming accurate representations of the world. Dopamine is thought to play a central role in processing the meaningful information content of observations, which motivates an agent to update their beliefs about the environment. However, direct evidence for dopamine's role in human belief updating is lacking. We addressed this question in healthy volunteers who performed a model-based fMRI task designed to separate the neural processing of meaningful and meaningless sensory information. We modeled participant behavior using a normative Bayesian observer model and used the magnitude of the model-derived belief update following an observation to quantify its meaningful information content. We also acquired PET imaging measures of dopamine function in the same subjects. We show that the magnitude of belief updates about task structure (meaningful information), but not pure sensory surprise (meaningless information), are encoded in midbrain and ventral striatum activity. Using PET we show that the neural encoding of meaningful information is negatively related to dopamine-2/3 receptor availability in the midbrain and dexamphetamine-induced dopamine release capacity in the striatum. Trial-by-trial analysis of task performance indicated that subclinical paranoid ideation is negatively related to behavioral sensitivity to observations carrying meaningful information about the task structure. The findings provide direct evidence implicating dopamine in model-based belief updating in humans and have implications for understating the pathophysiology of psychotic disorders where dopamine function is disrupted.

Trust versus paranoia: abnormal response to social reward in psychotic illness.

Psychosis is characterized by an elementary lack of trust in others. Trust is an inherently rewarding aspect of successful social interactions and can be examined using neuroeconomic paradigms. This study was aimed at investigating the underlying neural basis of diminished trust in psychosis. Functional magnetic resonance imaging data were acquired from 20 patients with psychosis and 20 healthy control subjects during two multiple-round trust games; one with a cooperative and the other with a deceptive counterpart. An a priori region of interest analysis of the right caudate nucleus, right temporo-parietal junction and medial prefrontal cortex was performed focusing on the repayment phase of the games. For regions with group differences, correlations were calculated between the haemodynamic signal change, behavioural outcomes and patients' symptoms. Patients demonstrated reduced levels of baseline trust, indicated by smaller initial investments. For the caudate nucleus, there was a significant game × group interaction, with controls showing stronger activation for the cooperative game than patients, and no differences for the deceptive game. The temporo-parietal junction was significantly more activated in control subjects than in patients during cooperative and deceptive repayments. There were no significant group differences for the medial prefrontal cortex. Patients' reduced activation within the caudate nucleus correlated negatively with paranoia scores. The temporo-parietal junction signal was positively correlated with positive symptom scores during deceptive repayments. Reduced sensitivity to social reward may explain the basic loss of trust in psychosis, mediated by aberrant activation of the caudate nucleus and the temporo-parietal junction.

Conditioned blocking in patients with paranoid, non-paranoid psychosis or obsessive compulsive disorder: associations with symptoms, personality and monoamine metabolism.

Conditioned blocking (CB) refers to a delay in learning that a new stimulus, added during learning, has the same consequences as the conditioned stimulus already present. In animals such "learned inattention" depends on monoaminergic and limbic function and, thus, CB performance should be informative on selective information processing impairments found in subgroups of psychotic patients. Attenuated CB in acute schizophrenia has been reported to normalize rapidly. This study examines in young patients the specificity of CB performance to illness, and its associations with symptoms, personality traits and monoaminergic metabolic status. CB was attenuated in psychotic patients with non-paranoid symptoms (NP: n = 12, mean age 17 years) with respect to obsessive-compulsive (OCD: n = 13, mean age 16 years) and healthy subjects (CON, n = 29, mean age 18 years), but only a transient attenuation was observed in paranoid hallucinatory patients (PH: n = 14, mean age 19 years). Outgoing personality traits in CON and OCD subjects correlated with CB. In NP patients attenuated CB was associated with increasing neurotic lability. In PH patients CB correlated positively with "manic" but negatively with psychotic or neurotic scores. The severity of negative symptoms in psychosis and specific negative/positive symptoms in the NP/PH groups was associated with reduced CB. Increased dopamine activity (24-h urine samples) correlated positively with CB, but relative increases of noradrenaline metabolism in NP and serotonin metabolism in OCD patients interfered. In summary, marked psychotic or neurotic traits and some symptom-states were associated with reduced CB. The particular selective processing problems of NP patients may reflect inappropriate NA activity.

Platelet serotonin in subtypes of schizophrenia and unipolar depression.

In subtypes of schizophrenia and unipolar depression, both increased and decreased levels of platelet serotonin were found. Hyperserotonemia was usually observed in patients with psychotic features (i.e., in paranoid schizophrenia and psychotic depression). Hyposerotonemia, although less common than hyperserotonemia, was present in nonparanoid schizophrenia and nonpsychotic depression (i.e., in patients without psychotic symptoms). A sex difference in platelet monoamine oxidase activity was observed among healthy subjects, but not among schizophrenic patients. The activity of platelet monoamine oxidase in paranoid and nonparanoid schizophrenic patients did not differ from that in healthy subjects. The findings in this study suggest that biological differences between subtypes of unipolar depression or schizophrenia might depend upon the presence of psychotic symptoms.

Thyroid hormone elevations during acute psychiatric illness: relationship to severity and distinction from hyperthyroidism.

Acute psychiatric illness may be accompanied by transient hyperthyroxinemia. The mechanism of this phenomenon was examined by determining the role of thyrotropin (TSH) in the genesis of this state. Serial measurements of TSH, thyroxine (T4), free T4 index (FT4I), triiodothyronine (T3), and free T3 index (FT3I) were performed in 45 acutely hospitalized patients with major psychiatric disorders. Twenty-two (49%) patients exhibited significant elevations (greater than or equal to 2 SD above mean value of controls) of one or more thyroid hormone (or index) levels. Among depressed patients with elevated FT4I, TSH was higher (p less than .05) on the day of the peak FT4I than on the day of the FT4I nadir. There were significant positive correlations between psychiatric symptom severity and levels of FT4I among both depressed (p less than .01) and schizophrenic (p less than .025) patients. These data show that elevations of T4, FT4I, T3, and FT3I are common among psychiatric inpatients, especially early in their hospitalization, and that levels of thyroid hormones are correlated with severity of psychiatric symptomatology. TSH is higher early in the acute phase of illness and is not suppressed in the face of elevated thyroid hormone levels, a finding that distinguishes this phenomenon from ordinary hyperthyroidism. Elevations of peripheral thyroid hormone levels, particularly among depressed patients, may result from a centrally-mediated hypersecretion of TSH.

Impairment of the blood-brain barrier as an aetiological factor in paranoid psychosis.

Possible psychiatric implications of impairment of the blood-brain barrier were studied in 25 patients with paranoid psychosis. Determination of the ratio between the albumin concentrations in cerebrospinal fluid and serum showed increased, indicating impairment of the blood-brain barrier, in seven patients and normal values in 18. The two groups were compared for clinical, pharmacokinetic, neurophysiological and anamnestic variables. The highly significant finding that onset of psychosis had occurred, on average, 20 years earlier in the patients with impairment of the blood-brain barrier than in those without suggests that such impairment might influence the development of psychosis in predisposed individuals.

Food selection in the aged.

Old people's eating habits are often idiosyncratic and unhealthy; their feeding can reflect such brain disease are dementia, depression, paranoia; poor nutrition can contribute to degenerative brain disease. The modification of nutritional requirements of the aged by genetic factors is discussed.