Jill M. Harkavy-Friedman

Genome Scan Meta-Analysis of Schizophrenia and Bipolar Disorder, Part II: Schizophrenia

Schizophrenia is a common disorder with high heritability and a 10-fold increase in risk to siblings of probands. Replication has been inconsistent for reports of significant genetic linkage. To assess evidence for linkage across studies, rank-based genome scan meta-analysis (GSMA) was applied to data from 20 schizophrenia genome scans. Each marker for each scan was assigned to 1 of 120 30-cM bins, with the bins ranked by linkage scores (1 = most significant) and the ranks averaged across studies (R(avg)) and then weighted for sample size (N(sqrt)[affected casess]). A permutation test was used to compute the probability of observing, by chance, each bins average rank (P(AvgRnk)) or of observing it for a bin with the same place (first, second, etc.) in the order of average ranks in each permutation (P(ord)). The GSMA produced significant genomewide evidence for linkage on chromosome 2q (PAvgRnk<.000417). Two aggregate criteria for linkage were also met (clusters of nominally significant P values that did not occur in 1,000 replicates of the entire data set with no linkage present): 12 consecutive bins with both P(AvgRnk) and P(ord)<.05, including regions of chromosomes 5q, 3p, 11q, 6p, 1q, 22q, 8p, 20q, and 14p, and 19 consecutive bins with P(ord)<.05, additionally including regions of chromosomes 16q, 18q, 10p, 15q, 6q, and 17q. There is greater consistency of linkage results across studies than has been previously recognized. The results suggest that some or all of these regions contain loci that increase susceptibility to schizophrenia in diverse populations.

Genome scan of European-American Schizophrenia pedigrees : Results of the NIMH Genetics Initiative and Millennium Consortium

The Genetics Initiative of the National Institute of Mental Health (NIMH) was a multisite study that created a national repository of DNA from families informative for genetic linkage studies of schizophrenia, bipolar disorder, and Alzheimers disease. The schizophrenia families were collected by three sites: Washington University, Harvard University, and Columbia University. This article, one in a series that describes the data collected for linkage analysis by the schizophrenia consortium, presents the results for the European-American sample. The European-American sample comprised 43 nuclear families and 146 subjects. Ninety-six of the family members were considered affected by virtue of having received a DSM-III-R diagnosis of schizophrenia (N = 82) or schizoaffective disorder, depressed (N = 14). The families contained a total of 50 independent sib-pairs. Using the significance threshold criteria suggested by Lander and Kruglyak [(1995): Nat Genet 241-247], no region showed statistically significant evidence for linkage; two markers on chromosome 10p showed statistical evidence suggestive of linkage using the criteria of Lander and Kruglyak [(1995): Nat Genet 241-247]: D10S1423 (nonparametric linkage (NPL) Z = 3.4, P = .0004) and its neighbor, D10S582 (NPL Z = 3.2, P = .0006).

Prenatal rubella, premorbid abnormalities, and adult schizophrenia

Abstract Background: Premorbid neurocognitive, neuromotor, and behavioral function tends to be disturbed in schizophrenia. We previously demonstrated that a birth cohort clinically and serologically documented with prenatal rubella evidenced a marked increase in risk of nonaffective psychosis. In our study, we examined whether rubella-exposed subjects destined to develop schizophrenia and other schizophrenia spectrum disorders (SSD), compared with exposed control subjects, had greater impairment in several premorbid functions. Methods: Subjects were interviewed using a direct, comprehensive research assessment and diagnosed by consensus. We compared the degree of IQ decline, as well as premorbid neuromotor and behavioral dysfunction, between rubella-exposed subjects who developed schizophrenia spectrum psychosis (SSP) and exposed control subjects from the cohort. We also compared the gestational timing of rubella infection between the cases and control subjects. Results: This rubella-exposed birth cohort evidenced a markedly increased risk of SSD (20.4% or 11/53). Rubella-exposed SSP cases, compared with rubella-exposed control subjects, demonstrated a decline in IQ from childhood to adolescence, and increased premorbid neuromotor and behavioral abnormalities. Moreover, it appears that early gestational rubella exposure may represent a period of increased vulnerability for SSD. Conclusions: These findings link a known prenatal exposure, a deviant neurodevelopmental trajectory in childhood and adolescence, and SSP in adulthood within the same individuals.

Suicide risk in schizophrenia: learning from the past to change the future

Suicide is a major cause of death among patients with schizophrenia. Research indicates that at least 5–13% of schizophrenic patients die by suicide, and it is likely that the higher end of range is the most accurate estimate. There is almost total agreement that the schizophrenic patient who is more likely to commit suicide is young, male, white and never married, with good premorbid function, post-psychotic depression and a history of substance abuse and suicide attempts. Hopelessness, social isolation, hospitalization, deteriorating health after a high level of premorbid functioning, recent loss or rejection, limited external support, and family stress or instability are risk factors for suicide in patients with schizophrenia. Suicidal schizophrenics usually fear further mental deterioration, and they experience either excessive treatment dependence or loss of faith in treatment. Awareness of illness has been reported as a major issue among suicidal schizophrenic patients, yet some researchers argue that insight into the illness does not increase suicide risk. Protective factors play also an important role in assessing suicide risk and should also be carefully evaluated. The neurobiological perspective offers a new approach for understanding self-destructive behavior among patients with schizophrenia and may improve the accuracy of screening schizophrenics for suicide. Although, there is general consensus on the risk factors, accurate knowledge as well as early recognition of patients at risk is still lacking in everyday clinical practice. Better knowledge may help clinicians and caretakers to implement preventive measures.This review paper is the results of a joint effort between researchers in the field of suicide in schizophrenia. Each expert provided a brief essay on one specific aspect of the problem. This is the first attempt to present a consensus report as well as the development of a set of guidelines for reducing suicide risk among schizophenia patients.

Human 5-HT1A receptor C(−1019)G polymorphism and psychopathology

Dysfunction of the serotonin (5-HT1A) receptor (5-HTR1A) has been implicated in mood disorders, anxiety disorders, psychosis and the action of antidepressants. A common C(-1018)G [C(-1019)G] functional polymorphism in the promoter region of the human 5-HT1A receptor gene has been reported, which may be useful in identifying psychopathology associated with altered function of the human 5-HT1A receptor. We studied the relationship of this polymorphism to psychopathology and 5-HT1A binding in prefrontal cortex. The 5-HT1A receptor genotype for the C(-1019)G polymorphism was typed in 696 unrelated psychiatric subjects, 107 unrelated healthy volunteers, and in post-mortem brain samples from 241 cases. 5-HT1A receptor binding was assayed in post-mortem prefrontal cortex using [3H]8-OH-DPAT, and specific binding determined by 1 microM 5-HT. An association of genotype distribution and allele frequency of the 5-HTR1A C(-1019)G locus was observed in schizophrenia (chi2=9.51, d.f.=2, p=0.009; chi2=9.52, d.f.=1, p=0.002; Armitages trend test: chi2=9.07, d.f.=1, p=0.003), in substance use disorder (chi2=8.41, d.f.=2, p=0.015; chi2=8.35, d.f.=1, p=0.004; Armitages trend test: chi2=6.27, d.f.=1, p=0.0012), and in panic attack (chi2=6.31, d.f.=2, p=0.043; chi2=6.14, d.f.=1, p=0.013; Armitages trend test: chi2=6.27, d.f.=1, p=0.012). An association of the 5-HTR1A C(-1019)G locus with schizophrenia, substance use disorder, and panic attack was suggested by our results. In post-mortem brain samples, 5-HT1A receptor binding in prefrontal cortex and suicide were not associated with genotype. The relationship does not appear to be explained by binding differences, although we cannot rule out altered receptor affinity and transduction.

Resting neural activity distinguishes subgroups of schizophrenia patients

BACKGROUND Schizophrenia is etiologically heterogeneous. It is anticipated, but unproven, that subgroups will differ in neuropathology and that neuroimaging may reveal these differences. The optimal imaging condition may be at rest, where greater variability is observed than during cognitive tasks, which more consistently reveal hypofrontality. We previously demonstrated symptom and physiologic differences between familial and sporadic schizophrenia patients and hypothesized that the groups would show different resting regional cerebral blood flow (rCBF) patterns. METHODS Ten familial and sixteen sporadic schizophrenia patients and nine comparison subjects had single photon emission computed tomography imaging during passive visual fixation. Images were spatially normalized into Talairach coordinates and analyzed for group rCBF differences using SPM with a Z value threshold of 2.80, p < .001. RESULTS The subgroups had similar age, gender, illness duration, and medication treatment. Sporadic patients had hypofrontality (anterior cingulate, paracingulate cortices, left dorsolateral and inferior-orbitofrontal), whereas familial patients had left temporoparietal hypoperfusion; all of these regions show resting activity in healthy subjects. Both groups hyperperfused the cerebellum/pons and parahippocampal gyrus; additional hyperperfusion for sporadic patients was observed in the fusiform; familial patients also hyperperfused the hippocampus, dentate, uncus, amygdala, thalamus, and putamen. CONCLUSIONS Familial and sporadic schizophrenia patients had different resting rCBF profiles, supporting the hypothesis that certain subgroups have distinct neural underpinnings. Different neuropathologic processes among subgroups of schizophrenia patients may account for the prior contradictory results of resting imaging studies.

Association of serotonin 5-HT2A receptor binding and the T102C polymorphism in depressed and healthy Caucasian subjects.

Serotonin 5-HT2A receptor (5-HT2A) binding is reported to be altered in individuals with suicidal behavior, mood disorders, and aggressive–impulsive traits. Genetic association with major depression, suicidal behavior, and aggressive–impulsive traits has not been established. This study examines the possible association of the 5-HT2A gene C102T polymorphism with the receptor binding kinetics, and clinical overt phenotypes. The study population included 63 healthy volunteers and 152 subjects with mood disorders, 56 of whom had a history of suicide attempts. All were Caucasian. Platelet 5-HT2A binding kinetics (Bmax and KD) were assayed and adjusted for seasonal variation. All subjects were genotyped for the T102C polymorphism. Clinical phenotype was determined by structured clinical interview. The TT genotype was associated with higher Bmax in all subjects (F=3.53, df=2,211; p=0.03), controlling for diagnosis. Bonferroni-adjusted post hoc testing showed higher binding in the TT compared with TC genotype in the control group (F=7.56, df=2,60, p=0.001), but not in the mood-disordered subjects. No difference was found in genotype and allele distribution between the mood-disordered subjects, with and without suicide attempt history, and controls. Bmax was not related to a diagnosis of mood disorders. The TT genotype appears associated with higher platelet 5-HT2A Bmax in the healthy population, but this genotypic effect appears absent in mood disorders and unrelated to psychopathology.

Protective factors against suicidal behavior in latinos

Latinos appear to be relatively protected against suicidal behavior, but the factors that mediate this effect are not known. Some protective factors may be related to cultural constructs that provide a buffer against suicidal behavior in the face of psychiatric illness. We sought to determine whether the Reasons for Living Inventory (RFLI) might capture protective factors against suicidal behavior in Latinos and non-Latinos. Patients with major depression, bipolar disorder, or schizophrenia were interviewed regarding their depressive symptomatology and lifetime history of suicidal behavior. The RFLI, which measures protective factors against suicidal acts, was also administered. Multivariate analyses were used to assess the relationship between suicide measures, ethnicity, and selected clinical and demographic variables. Although Latinos and non-Latinos did not differ significantly in attempter status (attempter/nonattempter), number of attempts, or suicide intent, Latinos reported significantly less suicidal ideation and made less lethal attempts. On the RFLI, Latinos scored significantly higher on subscales regarding survival and coping beliefs, responsibility to family, and moral objections to suicide, possibly reflective of cultural norms endorsed by Latino groups. Multivariate analyses suggested that although being Latino was independently associated with less suicidal ideation, other suicidal behaviors held a stronger relationship to moral objections to suicide and survival and coping skills than to ethnicity. Self-identification as Latino may be associated with espousing cultural constructs that mediate protective effects against suicidal behavior. Constructs identified in the RFLI may protect Latinos from acting on suicidal thoughts, affecting moral objections to suicide and survival and coping beliefs. Further studies to elucidate the impact of these factors on suicidal behavior and their relationship to specific cultural constructs would be of interest.

Visual backward-masking deficits in schizophrenia: relationship to visual pathway function and symptomatology

Patients with schizophrenia have information processing deficits which can be measured using visual backward-masking (VBM) tasks. There are two types of visual pathways: transient and sustained. The former is more sensitive to low spatial frequency (LSF) and the latter to high spatial frequency (HSF) stimuli. It has been hypothesized that the VBM deficit in schizophrenia is due to an overactive transient channel response to the mask. To examine this hypothesis, patients with schizophrenia and comparison volunteers were tested on a traditional backward-masking task as well as on tasks that altered the mask to bias stimulation toward transient (LSF) or sustained (HSF) channels. Medication effects and relationship to symptomatology were also examined. Patients with schizophrenia showed a significant deficit on the traditional backward-masking task and were also significantly impaired on the LSF- and HSF-masking tasks, though a differential deficit was not found on the latter two tasks. A U-shaped function, indicative of masking by interruption, was found on the LSF- and HSF-masking tasks. Masking performance was not altered when the same patients were tested on and off medication, and performance was related to positive and negative symptoms. In conclusion, the finding of a deficit in patients with schizophrenia on tasks producing a U-shaped function suggests that an aberrant transient response to the mask is producing increased interruption of the sustained response to the target.

Treatment of suicide attempters with bipolar disorder: a randomized clinical trial comparing lithium and valproate in the prevention of suicidal behavior.

OBJECTIVE Bipolar disorder is associated with high risk for suicidal acts. Observational studies suggest a protective effect of lithium against suicidal behavior. However, testing this effect in randomized clinical trials is logistically and ethically challenging. The authors tested the hypothesis that lithium offers bipolar patients with a history of suicide attempt greater protection against suicidal behavior compared to valproate. METHOD Patients with bipolar disorder and past suicide attempts (N=98) were randomly assigned to treatment with lithium or valproate, plus adjunctive medications as indicated, in a double-blind 2.5-year trial. An intent-to-treat analysis was performed using the log-rank test for survival data. Two models were fitted: time to suicide attempt and time to suicide event (attempt or hospitalization or change in medication in response to suicide plans). RESULTS There were 45 suicide events in 35 participants, including 18 suicide attempts made by 14 participants, six from the lithium group and eight from the valproate group. There were no suicides. Intent-to-treat analysis using the log-rank test showed no differences between treatment groups in time to suicide attempt or to suicide event. Post hoc power calculations revealed that the modest sample size, reflective of challenges in recruitment, only permits detection of a relative risk of 5 or greater. CONCLUSIONS Despite the high frequency of suicide events during the study, this randomized controlled trial detected no difference between lithium and valproate in time to suicide attempt or suicide event in a sample of suicide attempters with bipolar disorder. However, smaller clinically significant differences between the two drugs were not ruled out.