Clinical high risk for psychosis: the association between momentary stress, affective and psychotic symptoms.

OBJECTIVE: The aim of this study was to assess associations between momentary stress and both affective and psychotic symptoms in everyday life of individuals at clinical high risk (CHR), compared to chronic psychotic patients and healthy controls, in search for evidence of early stress sensitization. It also assessed whether psychotic experiences were experienced as stressful. METHOD: The experience sampling method was used to measure affective and psychotic reactivity to everyday stressful activities, events and social situations in 22 CHR patients, 24 patients with a psychotic disorder and 26 healthy controls. RESULTS: Multilevel models showed significantly larger associations between negative affect (NA) and activity-related stress for CHR patients than for psychotic patients (P = 0.008) and for CHR compared to controls (P < 0.001). Similarly, the association between activity-related stress and psychotic symptoms was larger in CHR than in patients (P = 0.02). Finally, the association between NA and symptoms (P < 0.001) was larger in CHR than in patients. CONCLUSION: Stress sensitization seems to play a role particularly in the early phase of psychosis development as results suggest that CHR patients are more sensitive to daily life stressors than psychotic patients. In this early phase, psychotic experiences also contributed to the experience of stress.

Effect of illness expression and liability on familial associations of clinical and subclinical psychosis phenotypes.

OBJECTIVE: Given the familial influences on schizophrenia, it may be hypothesized that specific symptom domains also cluster within families, and that this applies to both clinical and subclinical levels of expression. This hypothesis was put to the test in a group of patients with a DSM-IV diagnosis of psychotic disorder together with their unaffected siblings, and a group of healthy sib-pairs. METHOD: Subclinical positive, negative and depressive symptoms in relatives and healthy controls were assessed with the Community Assessment of Psychic Experiences (CAPE). Positive and negative schizotypy in relatives and controls was measured with the Structured Interview for Schizotypy-Revised. Multilevel linear regression analyses were conducted to investigate clustering of symptom dimensions within patient-relative sib-pairs (N = 811 pairs), healthy sib-pairs of affected families (N = 136 pairs) and healthy control sib-pairs (N = 58 pairs). RESULTS: Familial clustering of symptoms was found in all three groups. Effect sizes were largest in healthy control sib-pairs, smallest in patient-relative sib-pairs and intermediate in healthy sib-pairs of affected families. CONCLUSION: Studies of sibling associations in genetic studies of psychometric expression of psychosis liability need to take into account the fact that the higher levels of background genetic risk and presence of diagnosed illness are inversely associated with sibling associations.

Increased stress reactivity: a mechanism specifically associated with the positive symptoms of psychotic disorder.

BACKGROUND: An increased reactivity to stress in the context of daily life is suggested to be an independent risk factor underlying the positive symptoms of psychotic disorder. The aim of this study was to investigate whether positive symptoms moderate the association between everyday stressful events and negative affect (NA), known as stress reactivity. This hypothesis was put to the test in patients with a diagnosis of psychotic disorder. Method The Comprehensive Assessment of Symptoms and History (CASH) and the Positive and Negative Syndrome Scale (PANSS) were used to assess positive and negative symptoms. The experience sampling method (ESM), a structured diary technique, was used to measure stress reactivity and psychotic symptoms in daily life. RESULTS: Higher levels of positive symptoms (CASH: B = 0.14, p = 0.005; PANSS: B = 0.05, p = 0.000; ESM: B = 0.03, p = 0.000) and lower levels of negative symptoms (PANSS: B = - 0.05, p = 0.001) significantly moderate the association between unpleasant events and NA. No significant moderating effect was found for CASH negative symptoms. Moreover, the moderating effect of lifetime and current symptoms on the stress-NA association was significantly larger for those patients with predominantly positive symptoms (CASH: B = 0.09, p = 0.000; PANSS: B = 0.08, p = 0.000; ESM: B = 0.13, p = 0.000). CONCLUSIONS: Patients with a 'psychotic syndrome' with high levels of positive symptoms and low levels of negative symptoms show increased reactivity to stress in daily life, indicating that stress reactivity is a possible risk factor underlying this syndrome.

Hippocampal volume as marker of daily life stress sensitivity in psychosis.

BACKGROUND: Reduced hippocampal size and increased stress sensitivity are associated with psychotic disorder and familial risk for psychosis. However, to what degree the hippocampus is implicated in daily life stress reactivity has not yet been examined. The current study investigated (i) whether familial risk (the contrast between controls, patients and siblings of patients) moderated the relationship between hippocampal volume (HV) and emotional daily stress reactivity and (ii) whether familial risk (the contrast between controls and siblings of patients) moderated the relationship between HV and cortisol daily stress reactivity. Method T1-weighted magnetic resonance imaging (MRI) scans were acquired from 20 patients with schizophrenia, 37 healthy siblings with familial risk for schizophrenia and 32 controls. Freesurfer 5.0.0 was used to measure HV. The experience sampling method (ESM), a structured momentary assessment technique, was used to assess emotional stress reactivity, that is the effect of momentary stress on momentary negative affect (NA). In addition, in the control and sibling groups, cortisol stress reactivity was assessed using momentary cortisol levels extracted from saliva. RESULTS: Multilevel linear regression analyses revealed a significant three-way interaction between group, HV and momentary stress in both the model of NA and the model of cortisol. Increased emotional stress reactivity was associated with smaller left HV in patients and larger total HV in controls. In line with the results in patients, siblings with small HV demonstrated increased emotional and cortisol stress reactivity compared to those with large HV. CONCLUSIONS: HV may index risk and possibly disease-related mechanisms underlying daily life stress reactivity in psychotic disorder.

Testing the hypothesis that psychotic illness begins when subthreshold hallucinations combine with delusional ideation.

OBJECTIVE: While hallucinations and delusions are often considered as a single class of 'positive symptoms', little is known about their dynamic cooccurrence in relation to clinical outcome in non-help-seeking people. METHOD: The Netherlands Mental Health and Incidence Study (NEMESIS-1) is a longitudinal study of mental disorders (n = 7075) with three measurements over a 3-year period. Risk factors, persistence of psychotic experiences, and clinical outcome were analyzed for groups with: i) no psychotic experiences, ii) only delusions, iii) only hallucinations, and iv) both delusions and hallucinations. RESULTS: Hallucinations and delusions occurred together more often (T0, 3.5%; T1, 1.0%; T2, 0.9%) than that predicted by chance (T0, 1.0%; T1, 0.1%; T2, 0.04%). The group with both symptoms showed more 'first-rank'-like delusions compared with the group with only delusions. Having both hallucinations and delusions, compared to isolated symptoms, was associated more strongly with risk factors, comorbid affective symptoms, negative symptoms, and persistence of psychotic experiences. This was not an artifact of having more symptoms in general. CONCLUSION: Experiencing both delusions and hallucinations is an indicator of greater etiological load resulting in more clinical outcome. A specific 'hallucinatory-delusional state' may represent an early phase of exacerbation of aberrant attribution of salience, increasing risk for clinical outcome.

Symptomatic remission in psychosis and real-life functioning.

BACKGROUND: In 2005 Andreasen proposed criteria for remission in schizophrenia. It is unclear whether these criteria reflect symptom reduction and improved social functioning in daily life. AIMS: To investigate whether criteria for symptomatic remission reflect symptom reduction and improved functioning in real life, comparing patients meeting remission criteria, patients not meeting these criteria and healthy controls. METHOD: The Experience Sampling Method (ESM), a structured diary technique, was used to explore real-life symptoms and functioning in 177 patients with (remitted and non-remitted) schizophrenia spectrum disorders and 148 controls. RESULTS: Of 177 patients, 70 met criteria for symptomatic remission. These patients reported significantly fewer positive and negative symptoms and better mood states compared with patients not in remission. Furthermore, patients in remission spent more time in goal-directed activities and had less preference for being alone when they were with others. However, the patient groups did not differ on time spent in social company and doing nothing, and both the remission and non-remission groups had lower scores on functional outcome measures compared with the control group. CONCLUSIONS: The study provides an ecological validation for the symptomatic remission criteria, showing that patients who met the criteria reported fewer positive symptoms, better mood states and partial recovery of reward experience compared with those not in remission. However, remission status was not related to functional recovery, suggesting that the current focus on symptomatic remission may reflect an overly restricted goal.

Do subthreshold psychotic experiences predict clinical outcomes in unselected non-help-seeking population-based samples? A systematic review and meta-analysis, enriched with new results.

BACKGROUND: The base rate of transition from subthreshold psychotic experiences (the exposure) to clinical psychotic disorder (the outcome) in unselected, representative and non-help-seeking population-based samples is unknown. METHOD: A systematic review and meta-analysis was conducted of representative, longitudinal population-based cohorts with baseline assessment of subthreshold psychotic experiences and follow-up assessment of psychotic and non-psychotic clinical outcomes. RESULTS: Six cohorts were identified with a 3-24-year follow-up of baseline subthreshold self-reported psychotic experiences. The yearly risk of conversion to a clinical psychotic outcome in exposed individuals (0.56%) was 3.5 times higher than for individuals without psychotic experiences (0.16%) and there was meta-analytic evidence of dose-response with severity/persistence of psychotic experiences. Individual studies also suggest a role for motivational impairment and social dysfunction. The evidence for conversion to non-psychotic outcome was weaker, although findings were similar in direction. CONCLUSIONS: Subthreshold self-reported psychotic experiences in epidemiological non-help-seeking samples index psychometric risk for psychotic disorder, with strong modifier effects of severity/persistence. These data can serve as the population reference for selected and variable samples of help-seeking individuals at ultra-high risk, for whom much higher transition rates have been indicated.

Appraisals, psychotic symptoms and affect in daily life.

BACKGROUND: Psychological models of psychosis were examined using Experience Sampling Methods (ESM) to explore relationships between dimensions and appraisals of key symptoms and affect. METHOD: Individuals were signalled to complete ESM booklets 10 times per day for six consecutive days; 534 data points were obtained from 12 out-patients with psychosis. RESULTS: Although only 3.6% of spontaneous thoughts were psychosis related, these predicted more negative and less positive affect. Delusions and hallucinations, when present, were rated at a moderate level of intensity, and intensity was associated with distress, interference and preoccupation. Symptom dimensions were related to each other, with weaker associations with delusional conviction, which, it is hypothesized, may represent a separate factor. Conviction and appraisals relating to insight and decentring ('my problems are something to do with the way my mind works') were highly variable. Decentring appraisals of delusions, but not insight, were associated with less distress. Appraisals about the power of voices were strong predictors of negative affect and symptom distress. CONCLUSIONS: This study demonstrates that ESM is a useful methodology to capture 'online' variability in psychotic phenomenology and provides evidence supporting cognitive models, which posit that psychotic symptoms are multi-dimensional phenomena, shaped by appraisals that, in turn, predict their emotional and behavioural sequelae.

Pituitary volume, stress reactivity and genetic risk for psychotic disorder.

BACKGROUND: Hypothalamic-pituitary-adrenal (HPA) axis hyperactivity, associated with increased pituitary volume, may mediate observed alterations in stress reactivity in patients with psychotic disorder. We examined the association between pituitary volume, real-life stress reactivity and genetic liability for psychotic disorder. METHOD: Pituitary volumes were derived from magnetic resonance imaging (MRI) scans of 20 patients with psychotic disorder, 37 non-psychotic siblings of these patients, and 32 controls. The Experience Sampling Method (ESM) was used to measure emotional stress reactivity [changes in negative affect (NA) associated with daily life stress] in the three groups, and biological stress reactivity (changes in cortisol associated with daily life stress) in siblings and controls. Interactions between group, stress and pituitary volume in models of NA and cortisol were examined. RESULTS: Groups did not differ in pituitary volume. Patients showed significantly higher emotional stress reactivity than siblings and controls. In addition, emotional stress reactivity increased with increasing pituitary volume to a greater degree in patients than in controls and siblings. Siblings had higher cortisol levels than controls but did not show increased cortisol reactivity to stress. There was no interaction between pituitary volume, stress and group in the model of cortisol. CONCLUSIONS: Higher pituitary volume was associated with increased emotional stress reactivity in patients with psychotic disorder, siblings and controls. The association was significantly stronger in the patient group, suggesting a process of progressive sensitization mediating clinical outcome.

Evidence that interactive effects of COMT and MTHFR moderate psychotic response to environmental stress.

OBJECTIVE: A functional interaction between Catechol-O-Methyltransferase (COMT) Val158Met and methylenetetrahydrofolate reductase (MTHFR) C677T has been shown to differentially affect cognition in patients with schizophrenia and healthy controls; the effect of COMT Val158Met × MTHFR interaction on resilience to stress in patients and controls remains to be examined. METHOD: A total of 98 patients with non-affective psychotic disorder and 118 controls were genotyped for MTHFR C677T, MTHFR A1298C, and COMTVal158Met. Daily life reactivity to stress, modelled as the effect of daily life stress on psychotic experiences, was measured using the experience sampling method (ESM). RESULTS: The MTHFR C677T genotype moderated the interaction between COMT Val158Met genotype and stress in patients (P < 0.0001), but not in controls (P = 0.68). Further examination of this interaction revealed that in patients with the MTHFR 677 T-allele, COMT Met/Met individuals displayed the largest increases in psychotic symptoms in reaction to ESM stress [χ(2)(2) = 29.51; P < 0.0001], whereas in patients with the MTHFR 677 C/C genotype no significant COMT Val158Met × ESM stress interaction was apparent [χ(2)(2) = 3.65; P = 0.16]. No moderating effect of MTHFR A1298C was found. CONCLUSION: Stress reactivity associated with COMT Val158Met in patients with psychosis may crucially depend on MTHFR C677T genotype.

Daily cortisol, stress reactivity and psychotic experiences in individuals at above average genetic risk for psychosis.

BACKGROUND: Hypothalamic-pituitary-adrenocortical (HPA) axis abnormalities have been found in patients with a psychotic disorder and first-degree relatives of patients with a psychotic disorder react with subtle increases in non-clinical psychotic experiences and negative emotions in the face of everyday stress. The current study investigated whether HPA axis functioning is altered in individuals at above average genetic risk for psychotic disorder, examining diurnal cortisol profiles, cortisol reactivity to daily stressors and the association between HPA axis activity and subclinical psychotic experiences. METHOD: Participants included siblings of patients with a psychotic disorder (n=60) and a healthy comparison group (n=63). The Experience Sampling Method (a structured diary technique) was employed to assess stress, psychotic experiences, negative affect and salivary cortisol repeatedly in the flow of daily life. RESULTS: Multi-level analyses revealed higher diurnal cortisol levels and heightened cortisol reactivity to negative daily events in siblings compared with controls. Diurnal cortisol slope did not differ between the two groups, but momentary increases in psychotic experiences and negative affect were associated with increased cortisol in the sibling group. CONCLUSIONS: Findings support altered HPA axis activity in individuals at above average genetic risk for psychotic disorder, as evidenced by higher diurnal cortisol levels and increased cortisol reactivity to daily stress. Results also suggest a dynamic association between cortisol secretion and the intensity of psychotic-like experiences and negative emotions in daily life, although the direction of this association remains to be elucidated.

Childhood trauma and increased stress sensitivity in psychosis.

OBJECTIVE: The notion that traumatic experiences in childhood may predict later psychotic outcomes would be strengthened if a plausible mechanism could be demonstrated. Because increased stress sensitivity is part of the behavioural expression of psychosis liability, the possible mediating role of childhood trauma was investigated. METHOD: Fifty patients with psychosis were studied with the experience sampling method to assess stress reactivity in daily life, defined as emotional and psychotic reactivity to stress. Traumatic experiences in childhood were assessed with the Childhood Trauma Questionnaire. RESULTS: A significant interaction was found between stress and CT on both negative affect (event stress: ß = 0.04, P < 0.04; activity stress: ß = 0.12, P < 0.001) and psychotic intensity (event stress: ß = 0.06, P < 0.001; activity stress: ß = 0.11, P < 0.001), showing that a history of CT is associated with increased sensitivity to stress. CONCLUSION: A history of childhood trauma in patients with psychosis is associated with increased stress reactivity later in life, suggestive for an underlying process of behavioural sensitization.

Evidence for a familial correlation between increased reactivity to stress and positive psychotic symptoms.

OBJECTIVE: This study tested the hypothesis that stress-reactivity may represent an intermediary phenotype underlying positive psychotic symptoms. It was examined whether: (i) stress-reactivity clusters within families of psychotic patients and (ii) stress-reactivity in relatives cosegregates with positive symptoms in patients. METHOD: The sample consisted of 40 patients and 47 siblings of these patients. The Experience Sampling Method (ESM - a structured diary technique) was used to measure stress-reactivity. Positive symptoms in patients were measured with the Comprehensive Assessment of Symptoms and History. RESULTS: Within-trait, cross-sib associations showed a significant association between stress-reactivity in the patient and stress-reactivity in their siblings. Significant cross-trait, cross-sib associations were established showing a significant association between positive psychotic symptoms in the patient and stress-reactivity in the sibling. CONCLUSION: The findings show familial clustering of increased stress-reactivity, suggesting common aetiological influences, probably both genetic and environmental, underlying stress-reactivity in the siblings and patients. In addition, the results underscore the hypothesis that increased stress-reactivity is an unconfounded mechanism of risk underlying the positive symptoms of psychotic disorders.

Does reactivity to stress cosegregate with subclinical psychosis? A general population twin study.

OBJECTIVE: This study assessed the relationship between stress reactivity (trait 1) and psychosis (trait 2) across genetically related persons (cross-twin, cross-trait design) to examine whether stress reactivity is an uncontaminated and unconfounded familial marker of psychosis risk. METHOD: Reactivity to stress and subclinical psychotic experiences were assessed in 289 female, general population twin-pairs. Cross-trait, within-twin associations investigating the association between stress reactivity and subclinical psychotic experiences in each person, were calculated. In addition, cross-trait, cross-twin associations were calculated to assess whether stress reactivity in one twin was moderated by subclinical psychotic experiences in the co-twin. RESULTS: Cross-trait, within-twin analyses showed significant associations between stress reactivity and subclinical psychotic experiences in each person. In addition, the cross-trait cross-twin analyses showed that stress reactivity in twin 1 was significantly moderated by subclinical experiences in the co-twin. CONCLUSION: The results suggest that the psychosis phenotype cosegregates with increased emotional reactivity to stress in daily life.

Emotion recognition in psychosis: no evidence for an association with real world social functioning.

BACKGROUND: Patients with psychotic disorders show impairments in the recognition of emotions in other people. These impairments have been associated with poor social functioning as measured by self-report questionnaires, clinical interviews and laboratory-based tests of social skills. The ecological validity of these tests, however, is low. Associations were examined between emotion recognition and daily life social interactions in 50 patients diagnosed with a non-affective psychotic disorder and 67 healthy controls. METHODS: All participants were assessed with the Degraded Facial Affect Recognition Task (DFAR), a computer test measuring the recognition of emotional facial expressions. Social functioning in daily life was assessed using the Experience Sampling Method (a random time sampling technique) with focus on measures of social context and appraisal of the social situation. RESULTS: Groups differed significantly in the recognition of angry faces, whereas no differences existed for other emotions. There were no associations between emotion recognition and social functioning in daily life and there was no evidence for differential associations in patients as compared to controls. DISCUSSION: Social functioning, when assessed in an ecologically valid fashion, is not sensitive to variation in the traditional experimental assessment of emotion recognition. Real life measures of functioning should guide research linking the handicaps associated with psychosis to underlying cognitive and emotional dysregulation.