Familial Risk For Psychosis Research Articles

Response initiation in young adults at risk for psychosis in the Northern Finland 1986 Birth Cohort

IntroductionThis is one of the very few studies to investigate the specific executive function/processing speed component of response initiation in subjects at familial risk (FR) for psychosis, and the first such study in subjects at clinical risk (CR) for psychosis.MethodsParticipants (N = 177) were members of the general population-based Northern Finland 1986 Birth Cohort in the following four groups: FR for psychosis (n = 62), CR for psychosis (n = 21), psychosis (n = 25) and control subjects (n = 69). The response initiation of these groups was compared in three different tests: Semantic fluency, Stockings of Cambridge and Spatial working memory.ResultsThe two risk groups did not differ significantly from control group, but differed from, and outperformed the psychosis group in semantic fluency response initiation.ConclusionsResponse initiation deficits were not evident in a non-help seeking psychosis high-risk sample.

Familial Liability to Psychosis Is Associated With Attenuated Dopamine Stress Signaling in Ventromedial Prefrontal Cortex

Patients diagnosed with a psychotic disorder and their first-degree relatives display increased reactivity to stress. Theory predicts that experience of psychosocial stress is associated both with ventromedial prefrontal and mesolimbic dopamine neurotransmission. However, while there is evidence of aberrant striatal dopamine processing in psychotic disorder, the role of the prefrontal cortex remains under-researched. This study aimed at investigating stress-induced in vivo dopamine release in ventromedial prefrontal cortex (vmPFC) of individuals at familial risk for psychosis. Fourteen healthy first-degree relatives of patients with a diagnosis of psychotic disorder and 10 control subjects underwent a single dynamic positron emission tomography (PET) scanning session after intravenous administration of 183.2 (SD = 7.6) MBq [(18)F]fallypride. Psychosocial stress was initiated at 100 min postinjection using a computerized mental arithmetic task with social evaluative threat components. PET data were analyzed using the linearized simplified reference region model. Regression analyses were performed to compare the spatial extent of task-related ligand displacement between control subjects and relatives and to find how it related to self-rated experiences of psychosocial stress and psychosis. First-degree relatives displayed hyporeactive dopamine signaling in the vmPFC in response to stress. Increased levels of subjectively rated stress were associated with increased intensity of psychotic experiences. This effect was particularly pronounced in first-degree relatives. Although previous studies have hypothesized a role for prefrontal dopamine dysfunction in psychosis, this study, to our knowledge, is the first in vivo human imaging study showing attenuated (ie, hyporeactive) dopamine stress neuromodulation in vmPFC of individuals at familial risk for psychosis.

Verbal and visual–spatial memory impairment in youth at familial risk for schizophrenia or affective psychosis: A pilot study

BackgroundSchizophrenia and affective psychoses share several common biological origins, particularly genetic susceptibility. Kraepelin posited that differing clinical expressions in these disorders reflect different etiopathologies. We tested a neuropsychological component of this hypothesis by evaluating verbal memory and visual memory performance in nonpsychotic youth at familial risk for psychosis, taking into account contributions to memory dysfunction including executive processing and psychopathology. MethodsTeenage and young adults (ages 13–25) at familial high-risk (FHR) for schizophrenia (HR-SCZ, n=41) or affective psychosis (HR-AFF, n=24) were compared to community controls (CC, n=54) on verbal (Miller–Selfridge Context Memory) and visual (Rey–Osterrieth Complex Figure) memory tests in which the roles of strategy and contextual processing on distinct recall domains could be assessed. Effects of psychopathology, vigilance and working memory were investigated to determine their influence on memory performance. ResultsHR-AFF and HR-SCZ exhibited similarly impaired memory profiles and elevated levels of psychopathology compared to CC. HR-SCZ were significantly impaired on both verbal memory and visual–spatial memory, while HR-AFF in verbal memory only. However, effect sizes, in the medium range, were largely comparable between the two HR groups. Deficits in verbal recall and in visual memory organization remained significant after adjustment for confounders. ConclusionsYouth at FHR for psychosis present relatively common memory deficits across both visual–spatial and verbal modalities that are not explained by current psychopathology, vigilance or working memory deficits. Deficits in organizing information to be recalled represent a promising trait of psychosis vulnerability.

Default mode network in young people with familial risk for psychosis — The Oulu Brain and Mind Study

ObjectiveThe default mode network (DMN) is active in the brain at rest and de-activated during cognitive tasks. Abnormal function in the DMN has been reported in people with schizophrenia but it is not known whether this applies also to people with a familial risk for psychosis (FR). We compared the activity of the DMN between FR participants and controls. MethodsWe conducted a resting state functional MRI (R-fMRI) in 72 young adults without psychosis and with a history of psychosis in one or both parents (FR group) and 72 age matched controls without parental psychosis, and without current psychosis or a current prodromal syndrome. Both groups were drawn from the Northern Finland Birth Cohort 1986 (Oulu Brain and Mind study). Parental psychosis was established using the Finnish hospital discharge register. We pre-processed R-fMRI data using independent component analysis followed by a dual regression approach to assess differences between the groups. The FR vs. Control group differences were assessed using non-parametric permutation tests utilizing threshold-free cluster enhancement and correcting for multiple comparisons (p<0.05). ResultsFR participants demonstrated significantly lower activity compared with controls in the posterior cingulate cortex, the central node of the DMN. The size of the region was 41mm3. ConclusionThe activity of the DMN differed between FR and control groups. This suggests that familial risk for psychotic disorders may be mediated through genetic effects on connectivity in the posterior cingulate cortex.

Hippocampal volume as marker of daily life stress sensitivity in psychosis

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. 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. HV may index risk and possibly disease-related mechanisms underlying daily life stress reactivity in psychotic disorder.

Genetic Variation Underlying Psychosis-inducing Effects of Cannabis: Critical Review and Future Directions

Cannabis use is associated with an increased risk for psychotic disorder, yet most cannabis users do not develop psychosis, suggesting that other factors are also involved. This paper reviews the available evidence suggesting that differential sensitivity to the psychosis-inducing effects of cannabis may be related to underlying genetic liability. There is robust evidence that persons at psychometric risk for psychosis are most vulnerable to display psychotic symptoms subsequent to the use of cannabis. Multiple studies have also found that persons at familial risk for psychosis have an increased sensitivity to the effects of cannabis. Together, these findings support the concept of a biological interaction between cannabis use and one's underlying genetic vulnerability. At the molecular-genetic level, however, few (if any) interactions have been consistently replicated, although a reported interaction with variation in AKT1 is promising and deserves further follow-up. The apparent lack of consistent replication can be ascribed to problems of initial gene selection, statistical power, a bias towards positive results and insufficient attempts at true replication, leading to the conclusion that increased sample sizes, greater density of genetic markers and a stronger focus on true replication are necessary. The major challenge for molecular-genetic gene-environment interaction research will be to combine the agnostic detection of disorder-associated genetic variants from genome-wide studies with the hypothesis-based approach from epidemiological and neurobiological studies. Possible strategies for future cannabis interaction studies are discussed.

Different vulnerability indicators for psychosis and their neuropsychological characteristics in the Northern Finland 1986 Birth Cohort

This study is one of very few that has investigated the neuropsychological functioning of both familial and clinical high risk subjects for psychosis. Participants (N = 164) were members of the Northern Finland 1986 Birth Cohort in the following four groups: familial risk for psychosis (n = 62), clinical risk for psychosis (n = 20), psychosis (n = 13), and control subjects (n = 69). The neurocognitive performance of these groups was compared across 19 cognitive variables. The two risk groups did not differ significantly from controls, but differed from the psychosis group in fine motor function. Neuropsychological impairments were not evident in a non-help-seeking high-risk sample.

Schizophrenia in the Offspring of Antenatally Depressed Mothers in the Northern Finland 1966 Birth Cohort: Relationship to Family History of Psychosis

Maternal depression is relatively common during pregnancy. The authors examined whether maternal antenatal depressed mood increased the risk of schizophrenia and other psychoses among offspring with and without a familial history of psychosis. In the Northern Finland 1966 birth cohort, mothers of 12,058 children were asked at mid-gestation at the antenatal clinic if they felt depressed. The offspring were followed for over 30 years, and subsequent schizophrenia and other psychoses were detected using the Finnish Hospital Discharge Register, which was also used for identifying psychosis in the parents. Familial risk for psychosis was considered as a genetic risk factor and mothers' depressed mood as an environmental or genetic risk factor. The risk for schizophrenia was higher in the offspring with both maternal depressed mood during pregnancy and parental psychosis (OR=9.4, 95% CI=4.2-20.9 adjusted for sex and perinatal complications) than in those with a depressed mother but without parental psychosis (OR=1.0, 95% CI=0.6-1.8) or those without maternal depression and with a psychotic parent (OR=2.6, 95% CI=1.2-5.4). The reference group was birth cohort members without maternal antenatal depression and without parental psychosis. Maternal depressed mood during pregnancy per se is unlikely to increase the risk for schizophrenia in the offspring but may affect subjects with a family history for psychosis. This finding could be an example of a gene-environment or possibly a gene-gene interaction in the development of schizophrenia. Mothers' antenatal depression may act as additive factor for subjects vulnerable to schizophrenia.

Perceived negative attitude of others as an early sign of psychosis

Aim Risk of psychosis is defined by the presence of positive psychotic-like symptoms, by subtle self-perceived cognitive and perceptual deficiencies, or by decreased functioning with familial risk of psychosis. We studied the associations of psychiatric outpatients' self-reported functioning and interpersonal relationships with vulnerability to and risk of psychosis. Methods A total of 790 young patients attending psychiatric outpatient care completed the PROD screen [Heinimaa M, Salokangas RKR, Ristkari T, Plathin M, Huttunen J, Ilonen T, et al. PROD-screen – a screen for prodromal symptoms of psychosis. Int J Meth Psychiatr Res 2003;12:92–04.], including questions on functioning, interpersonal relationships and subtle specific (psychotic-like) and non-specific symptoms. Vulnerability to psychosis was assessed employing the patient's written descriptions of specific symptoms. Of the patients vulnerable to psychosis, those at current risk of psychosis were assessed using the Bonn Scale for Assessment of Basic Symptoms [Schultze-Lutter F, Klosterkötter J. Bonn scale for assessment of basic symptoms – prediction list, BSABS-P. Cologne: University of Cologne; 2002] and the Structured Interview for Positive symptoms [Miller TJ, McGlashan TH, Rosen JL, Somjee L, Markovich PJ, Stein K, et al. Prospective diagnosis of the initial prodrome for schizophrenia based on the structured interview for prodromal syndromes: preliminary evidence of interrater reliability and predictive validity. Am J Psychiatry 2002;159:863–65.]. Results In all, 219 patients vulnerable to and 55 patients at current risk of psychosis were identified. Vulnerability to psychosis was associated with all items of functioning and interpersonal relationships. Current risk of psychosis, however, was associated only with the subjectively reported negative attitude of others. Negative attitude of others was also associated with feelings of reference at both vulnerability and risk levels. Conclusion The subjective experience of negative attitude of others towards oneself may be an early indicator of psychotic development.

FC03-02 Schizophrenia in the offspring of antenatally depressed mothers and with familial risk - the northern Finland 1966 birth cohort

Aims:Schizophrenia is considered to be a neurodevelopmental disorder arising as a result of interactions between genetic vulnerability and environmental risk factors. We studied the association between mothers" antenatal depressed mood and schizophrenia in their adult offspring with special consideration to Familial Risk for psychosis.Method:In the Northern Finland 1966 Birth Cohort mothers of 12,058 children were asked at mid-gestation at the antenatal clinic if they felt depressed. This general population birth cohort of the children was followed up for over 30 years, being record-linked with the Finnish Hospital Discharge Register (FHDR) for detecting psychosis in the subjects. The FHDR was also used for identifying psychosis in the parents. Familial Risk for psychosis was considered as a genetic risk factor and mothers’ depression as an environmental risk factor.Results:Offspring with both Familial Risk of psychosis and depressed mother had the highest cumulative incidence of schizophrenia, 7.4% (adjusted OR 10.3; 4.6-23.0). Of the offspring with only psychotic parent without antenatal depression, 2.3% got schizophrenia (OR 2.6; 1.2-5.4). In the offspring without Familial Risk of psychosis and with maternal depression the risk of developing schizophrenia was not elevated.Conclusion:Mothers’ depressed mood during pregnancy per se is unlikely to increase the risk for schizophrenia in the offspring, but may effect in subjects at risk for psychosis. This finding is an example of a gene x environment interaction in the development of schizophrenia.Acknowledgements:This work was supported by grants from the Signe and Ane Gyllenberg Foundation and the Academy of Finland.

Insulin resistance and lipid levels in adolescents with familial risk for psychosis

Type 2 diabetes and dyslipidemias co-occur frequently with schizophrenia. It is not known how common they are in adolescents with a familial risk for psychosis. The Northern Finland 1986 Birth Cohort consists of 9432 children born alive in the two Northernmost provinces in Finland. At the age of 15/16 they participated in clinical examination including measurements of glucose, lipids and IR, and a questionnaire including items about their diet and physical activity. The Finnish Hospital Discharge Register was used to find out non-organic psychoses in parents during 1972-2000. This familial risk was found out in 54 boys and 68 girls. Their results were compared with other cohort members. No differences were observed in the cardiometabolic risk factors between the study groups. Our results suggest that familial risk for psychosis is not directly associated with disturbances of glucose and lipid metabolism among adolescents.

CONCEPTUAL PROBLEMS WITH EARLY DETECTION OF PRODROMAL PSYCHOSIS

Risk of psychosis is defined by the presence of positive psychotic-like symptoms, by subtle self-perceived cognitive and perceptual deficiencies, or by decreased functioning with familial risk of psychosis. We studied the associations of psychiatric outpatients' self-reported functioning and interpersonal relationships with vulnerability to and risk of psychosis.A total of 790 young patients attending psychiatric outpatient care completed the PROD screen [Heinimaa M, Salokangas RKR, Ristkari T, Plathin M, Huttunen J, Ilonen T, et al. PROD-screen – a screen for prodromal symptoms of psychosis. Int J Meth Psychiatr Res 2003;12:92–04.], including questions on functioning, interpersonal relationships and subtle specific (psychotic-like) and non-specific symptoms. Vulnerability to psychosis was assessed employing the patient's written descriptions of specific symptoms. Of the patients vulnerable to psychosis, those at current risk of psychosis were assessed using the Bonn Scale for Assessment of Basic Symptoms [Schultze-Lutter F, Klosterkötter J. Bonn scale for assessment of basic symptoms – prediction list, BSABS-P. Cologne: University of Cologne; 2002] and the Structured Interview for Positive symptoms [Miller TJ, McGlashan TH, Rosen JL, Somjee L, Markovich PJ, Stein K, et al. Prospective diagnosis of the initial prodrome for schizophrenia based on the structured interview for prodromal syndromes: preliminary evidence of interrater reliability and predictive validity. Am J Psychiatry 2002;159:863–65.].In all, 219 patients vulnerable to and 55 patients at current risk of psychosis were identified. Vulnerability to psychosis was associated with all items of functioning and interpersonal relationships. Current risk of psychosis, however, was associated only with the subjectively reported negative attitude of others. Negative attitude of others was also associated with feelings of reference at both vulnerability and risk levels.The subjective experience of negative attitude of others towards oneself may be an early indicator of psychotic development.

Patterns of psychiatric hospitalizations in schizophrenic psychoses within the Northern Finland 1966 Birth Cohort

We report patterns of hospitalization in schizophrenic psychoses by age 34 in a longitudinal population-based cohort. We test the predictive ability of various demographic and illness-related variables on patterns of hospitalization, with a special focus on the length of the first psychiatric hospitalization. All living subjects of the Northern Finland 1966 Birth Cohort with DSM-III-R schizophrenia (n=88) and other schizophrenia spectrum cases (n=27) by the year 1997 in the Finnish Hospital Discharge Register were followed for an average of 10.5 years. Measures of psychiatric hospitalization included time to re-hospitalization (as continuous and as re-hospitalization within 2 years) and the number of hospital episodes. Length of the first hospitalization, other illness-related and various socio-demographic predictors were used to predict hospitalization patterns. After adjusting for gender, age at first admission and number of hospital days a short (1–14 days) first hospitalization (reference >30 days; adjusted odds ratio 6.39; 95% CI 2.00–20.41) and familial risk of psychosis (OR 3.36; 1.09–10.39) predicted re-hospitalization within 2 years. A short first hospitalization also predicted frequent psychiatric admissions defined as the first three admissions within 3 years (OR 13.77; 3.92–48.36). A short first hospitalization was linked to increased risk of re-hospitalizations. Although short hospitalization is recommended by several guidelines, there may be a group of patients with schizophrenic psychoses in which too short a hospitalization may lead to inadequate treatment response.

Predictors of schizophrenia—a review

Schizophrenia is an aetiologically heterogeneous syndrome that usually becomes overtly manifest in adolescence and early adulthood, but in many cases subtle impairments in neurointegrative function are present from birth; hence it is considered to be a disorder with a neurodevelopmental component. The strongest risk factor that has been identified is familial risk with genetic loading. Other risk factors include pregnancy and delivery complications, infections during pregnancy, disturbances of early neuromotor and cognitive development and heavy cannabis use in adolescence. Unfortunately, to date it has not been possible to utilize the predictors of the disorder that have been identified in primary preventative interventions in a general population. However, some authors have claimed that in future it might be possible to reduce the risk for developing schizophrenia through general health policy. In clinical settings, it is helpful to map out possible early risk factors, at least familial risk for psychosis, especially in child, adolescent and young adult mental patients. Furthermore, in the future we may have predictive models combining data from genetic factors for schizophrenia, antenatal risk factors, childhood and adolescent development and clinical symptomatology, as well as brain structural and functional abnormalities.

Familial risk of psychosis as a function of putative organic etiology in psychotic probands: evaluation of a population-based sample.

It is unresolved what, if any, characteristics should be used as a basis for assigning psychotic probands to different liability classes in high density family studies seeking to detect possible genetic linkage. Justification for any such assignments should ideally ensue from empirical evaluation of unselected samples. It has been suggested that the genetic liability of probands with an "organic" psychosis is lower than that found in "primary" cases. Should such cases be assigned differential liabilities in linkage analyses as one way of modeling etiologic heterogeneity? Utilizing data from a population-based family study conducted in County Roscommon in Western Ireland, we examined risk in the relatives of psychotic probands as a function of clinician ratings reflecting the probability that the proband's illness was organic. Contrary to expectation, risk was not significantly lower in relatives of probands whose illness was rated as organic by experienced clinicians. Attempts to identify possible phenocopies of psychosis with a lower familial liability in this treated epidemiologic sample were unsuccessful.

Familial risk of psychosis as a function of putative organic etiology in psychotic probands: Evaluation of a population‐based sample

It is unresolved what, if any, characteristics should be used as a basis for assigning psychotic probands to different liability classes in high density family studies seeking to detect possible genetic linkage. Justification for any such assignments should ideally ensue from empirical evaluation of unselected samples. It has been suggested that the genetic liability of probands with an “organic” psychosis is lower than that found in “primary” cases. Should such cases be assigned differential liabilities in linkage analyses as one way of modeling etiologic heterogeneity? Utilizing data from a population-based family study conducted in County Roscommon in Western Ireland, we examined risk in the relatives of psychotic probands as a function of clinician ratings reflecting the probability that the probandandand's illness was organic. Contrary to expectation, risk was not significantly lower in relatives of probands whose illness was rated as organic by experienced clinicians. Attempts to identify possible phenocopies of psychosis with a lower familial liability in this treated epidemiologic sample were unsuccessful. © 1996 Wiley-Liss, Inc.