Background: An inverse relationship between risk of schizophrenia and premorbid IQ is a robust empirical finding. Cognitive impairment may be a core feature of schizophrenia in addition to the clinical symptoms that have historically defined the disorder. Aims: To evaluate whether risk of schizophrenia increases linearly or nonlinearly with the lowering of premorbid IQ after adjustment for a range of confounding factors. Methods: IQ data from the 1958 National Child Development Study, a prospective national birth cohort (n = 17 419), were linked with psychiatric admissions in England and Wales over a 20-year period. Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition diagnoses were derived from case notes. Results: A clear nonlinear inverse relationship between general intelligence at ages 7 and 11 and risk of adult psychosis was found even after adjustment for potential social, behavioral, or demographic confounding factors. No such relationship was found for affective disorders. Conclusions: The nonlinear relationship suggests an excess risk of schizophrenia in children with premorbid IQ in the learning disabilities range. Previous reports of a linear relationship are likely to be a result of less sensitive statistical methods for detecting nonlinearity.
risk of schizophrenia; premorbid IQ; birth cohort; epidemiology
Background: Myths and concerns about the extent and meaning of genetic risk in schizophrenia may contribute to significant stigma and burden for families. Genetic counseling has long been proposed to be a potentially informative and therapeutic intervention for schizophrenia. Surprisingly, however, available data are limited. We evaluated a contemporary genetic counseling protocol for use in a community mental health-care setting by non–genetics professionals. Methods: We used a pre-post study design with longitudinal follow-up to assess the impact of genetic counseling on family members of individuals with schizophrenia, where molecular testing had revealed no known clinically relevant genetic risk variant. We assessed the outcome using multiple measures, including standard items and scales used to evaluate genetic counseling for other complex diseases. Results: Of the 122 family members approached, 78 (63.9%) actively expressed an interest in the study. Participants (n = 52) on average overestimated the risk of familial recurrence at baseline, and demonstrated a significant improvement in this estimate postintervention (P < .0001). This change was associated with an enduring decrease in concern about recurrence (P = .0003). Significant and lasting benefits were observed in other key areas, including increased knowledge (P < .0001) and a decreased sense of stigma (P = .0047). Endorsement of the need for genetic counseling was high (96.1%). Conclusions: These results provide initial evidence of the efficacy of schizophrenia genetic counseling for families, even in the absence of individually relevant genetic test results or professional genetics services. The findings support the integration of contemporary genetic counseling for families into the general management of schizophrenia in the community.
schizophrenia; genetics; genetic counseling; genetic predisposition to disease; copy number variation; stigma
Background: Recent advances in schizophrenia genetics are shedding new light on etiopathogenesis, but issues germane to translation of findings into clinical practice are relatively understudied. We assessed the need for, and efficacy of, a contemporary genetic counseling protocol for individuals with schizophrenia. Methods: After characterizing rare copy number variation in a cohort of adults with schizophrenia, we recruited subjects from the majority of individuals who had no clinically relevant structural genetic variant. We used a pre-post study design with longitudinal follow-up to assess both the profile of need and the impact of general genetic counseling on key knowledge-based and psychological factors. Results: Thirty-nine (60.0%) of 65 patients approached actively expressed an interest in the study. At baseline, participants (n = 25) tended to overestimate the risk of familial recurrence of schizophrenia, express considerable concern related to this perceived risk, endorse myths about schizophrenia etiology, and blame themselves for their illness. Postcounseling, there was a significant improvement in understanding of the empiric recurrence risk (P = .0090), accompanied by a decrease in associated concern (P = .0020). There were also significant gains in subjective (P = .0007) and objective (P = .0103) knowledge, and reductions in internalized stigma (P = .0111) and self-blame (P = .0401). Satisfaction with genetic counseling, including endorsement of the need for such counseling (86.4%), was high. Conclusions: These results provide initial evidence of need for, and efficacy of, genetic counseling for individuals with schizophrenia. The findings may help facilitate development of a contemporary genetic counseling process that could optimize outcomes in the nascent field of evidence-based psychiatric genetic counseling.
schizophrenia; genetics; genetic counseling; genetic predisposition to disease; copy number variation; stigma
Background: While long-acting injectable antipsychotics (LAIs) are hoped to reduce high relapse rates in schizophrenia, recent randomized controlled trials (RCTs) challenged the benefits of LAIs over oral antipsychotics (OAPs). Methods: Systematic review/meta-analysis of RCTs that lasted ≥6 months comparing LAIs and OAPs. Primary outcome was study-defined relapse at the longest time point; secondary outcomes included relapse at 3, 6, 12, 18, and 24 months, all-cause discontinuation, discontinuation due to adverse events, drug inefficacy (ie, relapse + discontinuation due to inefficacy), hospitalization, and nonadherence. Results: Across 21 RCTs (n = 5176), LAIs were similar to OAPs for relapse prevention at the longest time point (studies = 21, n = 4950, relative risk [RR] = 0.93, 95% confidence interval [CI]: 0.80–1.08, P = .35). The finding was confirmed restricting the analysis to outpatient studies lasting ≥1 year (studies = 12, RR = 0.93, 95% CI:0.71–1.07, P = .31). However, studies using first-generation antipsychotic (FGA)-LAIs (studies = 10, RR = 0.82, 95% CI:0.69–0.97, P = .02) and those published ≤1991 (consisting exclusively of all 8 fluphenazine-LAI studies; RR = 0.79, 95% CI: 0.65–0.96, P = 0.02) were superior to OAPs regarding the primary outcome. Pooled LAIs also did not separate from OAPs regarding any secondary outcomes. Again, studies using FGA-LAIs and those published ≤1991 were associated with LAI superiority over OAPs, eg, hospitalization and drug inefficacy. Conclusions: In RCTs, which are less representative of real-world patients than naturalistic studies, pooled LAIs did not reduce relapse compared with OAPs in schizophrenia patients. The exceptions were FGA-LAIs, mostly consisting of fluphenazine-LAI studies, which were all conducted through 1991. Because this finding is vulnerable to a cohort bias, studies comparing FGA-LAI vs second-generation antipsychotics-LAI and LAI vs OAP RCTs in real-world patients are needed.
antipsychotics; adherence; depot; long-acting injection; meta-analysis; relapse; schizophrenia; treatment discontinuation
This study aimed to characterize the deficit syndrome in drug-naive schizophrenia patients and to examine the relationship between deficit features and primary neurological abnormalities. Drug-naive schizophrenia patients (n = 102) were examined at baseline for demographics, premorbid functioning, duration of untreated illness (DUI), psychopathology, neurological signs, and deficit symptoms, and reassessed at 1-year follow-up. Neurological abnormalities were examined before inception of antipsychotic medication and included four domains of spontaneous movement disorders (SMD) and four domains of neurological soft signs (NSS). Patients fulfilling the deficit syndrome criteria at the two assessments (n = 20) were compared with nondeficit patients (n = 82) across demographic, clinical, and neurological variables. Deficit and nondeficit groups showed similar demographic characteristics and levels of psychotic, disorganization, and depressive symptoms. Compared with nondeficit patients, deficit patients showed poorer premorbid adjustment, higher premorbid deterioration, a lengthier DUI, and much poorer functional outcome. Relative to the nondeficit patients, those with the deficit syndrome showed higher levels of SMD—excepting akathisia—and NSS. This association pattern was also evident for deficit and neurological ratings in the whole sample of schizophrenia patients. Parkinsonism, motor sequencing, and release signs were all independently related to the deficit syndrome. These findings confirm that the deficit/nondeficit categorization is replicable and reliable in first-admission patients and raise the possibility that premorbid deterioration, deficit symptoms, and neurological abnormalities represent a triad of manifestations that share common underlying neurobiological mechanisms. More specifically, the data are consistent with a neurodevelopmental model of deficit symptoms involving basal ganglia dysfunction.
deficit schizophrenia; drug-naive; neurological signs; outcome; symptom remission; basal ganglia
A comprehensive understanding of the phenomenology of auditory hallucinations (AHs) is essential for developing accurate models of their causes. Yet, only 1 detailed study of the phenomenology of AHs with a sample size of N ≥ 100 has been published. The potential for overreliance on these findings, coupled with a lack of phenomenological research into many aspects of AHs relevant to contemporary neurocognitive models and the proposed (but largely untested) existence of AH subtypes, necessitates further research in this area. We undertook the most comprehensive phenomenological study of AHs to date in a psychiatric population (N = 199; 81% people diagnosed with schizophrenia), using a structured interview schedule. Previous phenomenological findings were only partially replicated. New findings included that 39% of participants reported that their voices seemed in some way to be replays of memories of previous conversations they had experienced; 45% reported that the general theme or content of what the voices said was always the same; and 55% said new voices had the same content/theme as previous voices. Cluster analysis, by variable, suggested the existence of 4 AH subtypes. We propose that there are likely to be different neurocognitive processes underpinning these experiences, necessitating revised AH models.
auditory verbal hallucinations; memory; schizophrenia
Objective: 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. Method: 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 [18F]fallypride. Psychosocial stress was initiated at 100min 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. Results: 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. Conclusion: 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.
schizophrenia; positron emission tomography; neuromodulation; relatives; mesolimbic; salience
Previous research has provided compelling support for olfactory dysfunction in schizophrenia patients, their first-degree relatives, and youth at-risk for psychosis. A previous meta-analysis revealed large effect sizes across olfactory tasks but was limited to 2 olfactory tasks and did not examine moderator variables. Thus, the current meta-analysis was undertaken to incorporate additional studies, risk cohorts, olfactory test domains, and moderator variable analyses.
A meta-analysis was conducted on 67 publications examining olfactory function in schizophrenia patients and 15 publications examining olfactory functioning in youth at-risk for psychosis, first-degree relatives of schizophrenia patients, and individuals with schizotypy.
Results revealed medium-to-large olfactory deficits in schizophrenia patients though significant heterogeneity was evident. Several variables moderated overall study effects. At-risk youths similarly demonstrated medium-to-large effect sizes, whereas first-degree relatives and individuals with schizotypy showed small effects.
Findings suggest robust olfactory deficits in schizophrenia and at-risk youths. In schizophrenia, several variables had significant impact on these deficits and warrant consideration in prospective studies. Our findings also indicate that olfactory measures may be a useful marker of schizophrenia risk status.
schizophrenia prodrome; smell; olfaction; schizotypy; psychosis
Cross-sectional studies of the signs and symptoms of psychosis yield dimensional phenotypes. However, the validity and clinical utility of such dimensions remain debated. This study investigated the structure of psychotic symptomatology, the stability of the structure over time, and the concordance between symptom dimensions and categorical diagnoses.
Sample consisted of 500 first-episode psychotic patients. A cross-sectional study (N = 500) investigated the organizational structure of symptom dimensions at the onset of psychosis and its concordance with categorical diagnoses; next, a nested longitudinal study (N = 100) examined the stability of the symptom dimensions structure after 5–10 years of follow-up.
Factor analyses identified 6 first-order factors (mania, negative, disorganization, depression, hallucinations, and delusions) and 2 high-order factors (affective and nonaffective psychoses). Cumulative variance accounted for by the first and high-order factors was 63%: 31% by the first-order factors and 32% by the high-order factors. The factorial structure of psychotic symptoms during first episode remained stable after 5–10 years of follow-up. The overall concordance between 4 categorical diagnostic groups (schizophrenia, mania with psychosis, psychotic depression and schizoaffective disorder) and dimensional symptom ranged from 62.2% to 73.1% (when the schizoaffective group was excluded).
Symptoms of psychosis assume a multidimensional hierarchical structure. This hierarchical model was stable over time and showed good concordance with categorical diagnoses. The combined use of dimensional and categorical approach to psychotic disorders would be of clinical and research utility.
symptom dimensions; diagnostic classification; psychosis; DSM-5; longitudinal study
Recent genome-wide association studies have identified many promising schizophrenia candidate genes and demonstrated that common polygenic variation contributes to schizophrenia risk. However, whether these genes represent perturbations to a common but limited set of underlying molecular processes (pathways) that modulate risk to schizophrenia remains elusive, and it is not known whether these genes converge on common biological pathways (networks) or represent different pathways. In addition, the theoretical and genetic mechanisms underlying the strong genetic heterogeneity of schizophrenia remain largely unknown. Using 4 well-defined data sets that contain top schizophrenia susceptibility genes and applying protein-protein interaction (PPI) network analysis, we investigated the interactions among proteins encoded by top schizophrenia susceptibility genes. We found proteins encoded by top schizophrenia susceptibility genes formed a highly significant interconnected network, and, compared with random networks, these PPI networks are statistically highly significant for both direct connectivity and indirect connectivity. We further validated these results using empirical functional data (transcriptome data from a clinical sample). These highly significant findings indicate that top schizophrenia susceptibility genes encode proteins that significantly directly interacted and formed a densely interconnected network, suggesting perturbations of common underlying molecular processes or pathways that modulate risk to schizophrenia. Our findings that schizophrenia susceptibility genes encode a highly interconnected protein network may also provide a novel explanation for the observed genetic heterogeneity of schizophrenia, ie, mutation in any member of this molecular network will lead to same functional consequences that eventually contribute to risk of schizophrenia.
genome-wide association study; schizophrenia susceptibility genes; protein-protein interaction; common molecular networks; genetic heterogeneity; enrichment
Depression and negative symptoms can be difficult to distinguish in schizophrenia. Assessments for negative symptoms usually account for the longitudinal nature of these symptoms, whereas instruments available to measure depression mainly assess current or recent symptoms. This construct difference may confound comparison of depressive and negative symptoms in schizophrenia because both domains may have trait-like aspects. We developed an instrument to measure both longitudinal “trait” as well as recent “state” symptoms of depression and tested this instrument (Maryland Trait and State Depression [MTSD] scale) in a sample of 98 individuals with schizophrenia or schizoaffective disorder and 115 community participants without psychotic illness. Exploratory factor analysis of the MTSD revealed 2 factors accounting for 73.4% of the variance; these 2 factors corresponded with “trait” and “state” depression inventory items. Neither MTSD-state nor MTSD-trait was correlated with negative symptoms as measured with the Brief Negative Symptom Scale (r = .07 and −.06, respectively) in schizophrenia patients. MTSD state and trait scores were significantly correlated with the Brief Psychiatric Rating Scale depression subscale (r = .58 and .53, respectively) as well as the Profile of Mood States depression subscale (r = .57 and .44). Persons with schizophrenia had significantly greater trait depressive symptoms than controls (P = .031). Individuals with schizoaffective disorder had significantly higher trait depression (P = .001), but not state depression (P = .146), compared with schizophrenia patients. Trait depressive symptoms are prominent in schizophrenia and are distinct from negative symptoms.
BNSS; schizoaffective disorder; symptom domain
Background: Impairments in social cognition have been described in schizophrenia and relate to core symptoms of the disorder. Social cognition is subserved by a network of brain regions, many of which have been implicated in schizophrenia. We hypothesized that deficits in connectivity between components of this social brain network may underlie the social cognition impairments seen in the disorder. Methods: We investigated brain activation and connectivity in a group of individuals with schizophrenia making social judgments of approachability from faces (n = 20), compared with a group of matched healthy volunteers (n = 24), using functional magnetic resonance imaging. Effective connectivity from the amygdala was estimated using the psychophysiological interaction approach. Results: While making approachability judgments, healthy participants recruited a network of social brain regions including amygdala, fusiform gyrus, cerebellum, and inferior frontal gyrus bilaterally and left medial prefrontal cortex. During the approachability task, healthy participants showed increased connectivity from the amygdala to the fusiform gyri, cerebellum, and left superior frontal cortex. In comparison to controls, individuals with schizophrenia overactivated the right middle frontal gyrus, superior frontal gyrus, and precuneus and had reduced connectivity between the amygdala and the insula cortex. Discussion: We report increased activation of frontal and medial parietal regions during social judgment in patients with schizophrenia, accompanied by decreased connectivity between the amygdala and insula. We suggest that the increased activation of frontal control systems and association cortex may reflect a compensatory mechanism for impaired connectivity of the amygdala with other parts of the social brain networks in schizophrenia.
fMRI; social cognition; approachability; psychosis; neural; psychophysiological interaction
Background: Schizophrenia and bipolar disorder share aspects of phenomenology and neurobiology and thus may represent a continuum of disease. Few studies have compared connectivity across the brain in these disorders or investigated their functional correlates. Methods: We used resting-state functional magnetic resonance imaging to evaluate global and regional connectivity in 32 healthy controls, 19 patients with bipolar disorder, and 18 schizophrenia patients. Patients also received comprehensive neuropsychological and clinical assessments. We computed correlation matrices among 266 regions of interest within the brain, with the primary dependent measure being overall global connectivity strength of each region with every other region. Results: Patients with schizophrenia had significantly lower global connectivity compared with healthy controls, whereas patients with bipolar disorder had global connectivity intermediate to and significantly different from those of patients with schizophrenia and healthy controls. Post hoc analyses revealed that compared with healthy controls, both patient groups had significantly lower connectivity in the paracingulate gyrus and right thalamus. Patients with schizophrenia also had significantly lower connectivity in the temporal occipital fusiform cortex, left caudate nucleus, and left thalamus compared with healthy controls. There were no significant differences among the patient groups in any of these regions. Lower global connectivity among all patients was associated with worse neuropsychological and clinical functioning, but these effects were not specific to any patient group. Conclusions: These findings are consistent with the hypothesis that schizophrenia and bipolar disorder may represent a continuum of global disconnectivity in the brain but that regional functional specificity may not be evident.
resting-state fMRI; schizophrenia; bipolar disorder; connectivity
Objective: Offspring of parents with severe mental illness (SMI; schizophrenia, bipolar disorder, major depressive disorder) are at an increased risk of developing mental illness. We aimed to quantify the risk of mental disorders in offspring and determine whether increased risk extends beyond the disorder present in the parent. Method: Meta-analyses of absolute and relative rates of mental disorders in offspring of parents with schizophrenia, bipolar disorder, or depression in family high-risk studies published by December 2012. Results: We included 33 studies with 3863 offspring of parents with SMI and 3158 control offspring. Offspring of parents with SMI had a 32% probability of developing SMI (95% CI: 24%–42%) by adulthood (age >20). This risk was more than twice that of control offspring (risk ratio [RR] 2.52; 95% CI 2.08–3.06, P < .001). High-risk offspring had a significantly increased rate of the disorder present in the parent (RR = 3.59; 95% CI: 2.57–5.02, P < .001) and of other types of SMI (RR = 1.92; 95% CI: 1.48–2.49, P < .001). The risk of mood disorders was significantly increased among offspring of parents with schizophrenia (RR = 1.62; 95% CI: 1.02–2.58; P = .042). The risk of schizophrenia was significantly increased in offspring of parents with bipolar disorder (RR = 6.42; 95% CI: 2.20–18.78, P < .001) but not among offspring of parents with depression (RR = 1.71; 95% CI: 0.19–15.16, P = .631). Conclusions: Offspring of parents with SMI are at increased risk for a range of psychiatric disorders and one third of them may develop a SMI by early adulthood.
schizophrenia; bipolar disorder; depression; offspring; meta-analysis
Sense of self (SOS)—understood as the foundation upon which individuals experience their daily lives—has been increasingly investigated in schizophrenia. A disrupted SOS is thought to represent a platform for the experience of psychiatric symptoms, social cognitive deficits, and other abnormalities of consciousness. Few studies, however, have investigated the specificity of disrupted SOS to schizophrenia. The primary objective of the present study was to test the hypothesis that SOS is deficient in schizophrenia patients compared to both nonpsychiatric controls and patients with psychotic bipolar disorder. Using select scales from the Assessment of Self Descriptions, the present study assessed SOS from spontaneous narratives provided by schizophrenia patients (N = 50), bipolar patients with psychotic features (N = 17), and nonpsychiatric controls (N = 24). Our findings indicate that facets of SOS—in particular, certain aspects of agency and relatedness to others—are deficient in schizophrenia compared to nonpsychiatric controls and bipolar patients with psychotic features, even when overall level of functioning and psychiatric symptoms are accounted for. Implications of these results are discussed.
self; phenomenology; language; narrative
Background: Early descriptive work and controlled family and adoption studies support the hypothesis that a range of personality and nonschizophrenic psychotic disorders aggregate in families of schizophrenic probands. Can we validate, using molecular polygene scores from genome-wide association studies (GWAS), this schizophrenia spectrum? Methods: The predictive value of polygenic findings reported by the Psychiatric GWAS Consortium (PGC) was applied to 4 groups of relatives from the Irish Study of High-Density Schizophrenia Families (ISHDSF; N = 836) differing on their assignment within the schizophrenia spectrum. Genome-wide single nucleotide polymorphism data for affected and unaffected relatives were used to construct per-individual polygene risk scores based on the PGC stage-I results. We compared mean polygene scores in the ISHDSF with mean scores in ethnically matched population controls (N = 929). Results: The schizophrenia polygene score differed significantly across diagnostic categories and was highest in those with narrow schizophrenia spectrum, lowest in those with no psychiatric illness, and in-between in those classified in the intermediate, broad, and very broad schizophrenia spectrum. Relatives of all of these groups of affected subjects, including those with no diagnosis, had schizophrenia polygene scores significantly higher than the control sample. Conclusions: In the relatives of high-density families, the observed pattern of enrichment of molecular indices of schizophrenia risk suggests an underlying, continuous liability distribution and validates, using aggregate common risk alleles, a genetic basis for the schizophrenia spectrum disorders. In addition, as predicted by genetic theory, nonpsychotic members of multiply-affected schizophrenia families are significantly enriched for replicated, polygenic risk variants compared with the general population.
schizophrenia; schizophrenia spectrum; polygene score; GWAS