Auditory steady state response in bipolar disorder: relation to clinical state, cognitive performance, medication status, and substance disorders

Rass O, Krishnan G, Brenner CA, Hetrick WP, Merrill CC, Shekhar A, O’Donnell BF. Auditory steady state response in bipolar disorder: relation to clinical state, cognitive performance, medication status, and substance disorders.
Bipolar Disord 2010: 12: 793–803. © 2010 The Authors.
Journal compilation © 2010 John Wiley & Sons A/S. Objectives: Abnormalities in auditory steady state response (ASSR) at gamma range frequencies have been found in bipolar disorder, but the relationship of these neurophysiological disturbances to clinical factors has not been well characterized. We therefore evaluated the ASSR in bipolar disorder and examined its sensitivity to clinical symptoms, cognitive function, and pharmacological treatment. Methods: A total of 68 patients with bipolar disorder and 77 control participants were evaluated. Click trains presented at 20, 30, 40, and 50 Hz evoked ASSRs. Mean trial power (MTP) and phase locking factor (PLF) measured response magnitude and phase synchronization of the ASSR at each stimulation frequency. Clinical state, pharmacological treatment, and neuropsychological performance were assessed, and their respective relationships with ASSR measures were evaluated. Results: Patients with bipolar disorder showed reduced MTP and PLF compared to control participants. Bipolar disorder patients taking psychotropic medications had decreased PLF relative to patients withdrawn from medications. Control participants performed better on neuropsychological tests than bipolar disorder patients; however, test scores did not correlate with ASSR measures. Conclusions: Deficits in the generation and maintenance of ASSR are present in bipolar disorder, implicating disturbances in auditory pathways. ASSR may be sensitive to medication status. Other clinical features, including mood state, psychotic features, cognitive performance, smoking, or history of substance use disorder, were unrelated to MTP or PLF.     

Early stage vision in schizophrenia and schizotypal personality disorder

Previous studies of visual perception have reported deficits in contrast sensitivity and dot motion discrimination in schizophrenia. We tested whether these deficits also appear in schizotypal personality disorder (SPD). SPD appears to be genetically and symptomatically related to schizophrenia, but without the marked psychosocial impairment associated with psychotic disorders. The present study investigated contrast sensitivity for moving and static gratings, form discrimination and dot motion discrimination in 24 patients with schizophrenia or schizoaffective disorder (SZ), 16 individuals with SPD, and 40 control subjects. SZ, but not SPD subjects, showed impairments on tests of contrast sensitivity for static and moving gratings, form discrimination in noise, and dot motion discrimination. Visual performance did not differ between medicated SZ patients and patients withdrawn from medication. These results confirm early stage visual deficits in schizophrenia regardless of medication status. SPD subjects, in contrast, show intact early stage visual processing despite the presence of marked schizotypal symptoms.     

Childhood-onset schizotypal disorder: a follow-up study and comparison with childhood-onset schizophrenia

OBJECTIVE: This paper presents results from the UCLA Follow-Up Study of Childhood-Onset Schizophrenia (SZ) Spectrum Disorders. METHOD: We assessed 12 children with schizotypal personality disorder (SPD) and 18 children with schizophrenia 1-7 years following initial project intake. RESULTS: There was significant continuity between SZ spectrum disorders in childhood and adolescence. Although not all children who presented initially with SZ spectrum disorders continued to meet criteria for SZ spectrum disorder as they progressed through the follow-up period, rates of SZ spectrum disorders ranged from 75% to 92% across the 3 follow-up years for children initially presenting with SPD, and from 78% to 89% for children initially presenting with SZ. CONCLUSION: The most common clinical outcome for children with SPD was continuing SPD, supporting the hypothesis of continuity between childhood and later SPD. However, 25% of the SPD sample developed more severe SZ spectrum disorders (schizophrenia or schizoaffective disorder), also supporting the hypothesis that SPD represents a risk or precursor state for more severe SZ spectrum disorders.     

Dexamphetamine selectively increases 40 Hz auditory steady state response power to target and nontarget stimuli in healthy humans

Background: An emerging endophenotype of schizophrenia is the reduction of both power and phase locking of the 40 Hz auditory steady state response (ASSR), and there have been a number of reports linking increased γ activity with positive psychotic symptoms. Schizophrenia and, more specifically, positive psychotic symptoms have been closely linked to increased dopamine (DA) neurophysiology. Therefore, we gave dexamphetamine to healthy participants to determine the effect that increased DA transmission would have on the ASSR. Methods: We administered 0.45 mg/kg of dexamphetamine orally in a double-blind placebo-controlled crossover study. Stimuli were 20 Hz and 40 Hz click trains presented in an auditory oddball-type stimulus format (probability of stimulus presentation: 0.2 for targets, 0.8 for nontargets). Results: We included 44 healthy volunteers (18 women) in the study. Dexamphetamine significantly increased the 40 Hz power for both target and nontarget ASSR stimuli. Dexamphetamine did not significantly affect the 40 Hz phase-locking factor (PLF) or the 20 Hz power and PLF. Whereas there were significant effects of selective attention on power and PLF for 20 and 40 Hz ASSR, there were no significant interactions between dexamphetamine and selective attention. Limitations: Dexamphetamine releases both noradrenaline and DA with equal potency. Further research with selective dopaminergic and noradrenergic agents will better characterize the effects of monoamines on γ activity. Conclusion: The results demonstrate a frequency-specific effect of dexamphetamine on the ASSR. This finding is consistent with previous research that has found an association between increased γ and positive symptoms of psychosis. However, this result also raises the possibility that previous 40 Hz ASSR findings in people with schizophrenia may be confounded by effects of antipsychotic medication. Possible neural mechanisms by which dexamphetamine specifically increases 40 Hz power are also discussed. Australian and New Zealand Clinical Trials Registry number: ACTRN12608000610336.     

Schizotypal dimensions: continuity between schizophrenia and bipolar disorders

BACKGROUND: Family studies have suggested that schizophrenia and bipolar disorders share some susceptibility factors. Schizotypal personality disorder (SPD) may be an intermediate phenotype common both to schizophrenia and bipolar disorders. We explored the familiality of schizotypal dimensions by comparing the magnitude of schizotypal dimensions between schizophrenic and bipolar relatives. We also looked for intra-familial resemblance for these dimensions, and for an increased familial risk of schizophrenia and/or bipolar disorders associated with a particular schizotypal dimension. METHODS: We used the Schizotypal Personality Questionnaire (SPQ) to study the three schizotypal dimensions (disorganization, negative and positive) in a sample of unaffected first-degree relatives of schizophrenic (N=85), psychotic bipolar (N=63) and bipolar (N=32) probands. Differences between groups were tested using a two-tailed t-test or ANOVA for continuous variables and a chi-squared test for discrete variables. We used the intraclass correlation method to study the intra-familial correlation. Linear mixed models were used to measure the familial risk. RESULTS: The disorganization dimension appears to be common to relatives of both schizophrenia and psychotic bipolar disorders, but not in the relatives of non-psychotic bipolar probands. This dimension also increases the familial risk of these two disorders. The negative dimension shows intra-familial resemblance (R=0.29), we failed to observe the expected familiality for the disorganized dimension. CONCLUSIONS: The shared nature of the disorganization dimension shown by a similar familial risk for schizophrenia and psychotic bipolar disorders suggests that same genetic background may underlie psychotic disorders. Although, negative dimension is familial, it is not associated for an increased familial risk for both disorders.     

Schizotypal personality disorder in individuals with and without schizophrenic relatives: similarities and contrasts in neurocognitive and clinical functioning.

Schizophrenia-spectrum disorders may reflect the genotype for schizophrenia. One such disorder, Schizotypal Personality Disorder (SPD), was examined as a function of family history of schizophrenia. Clinical profiles and neurocognitive functioning were evaluated in 25 schizotypal subjects (10 SPD with schizophrenic relatives and 15 SPD without schizophrenic relatives), and in 24 normal controls. The primary finding is that vigilance performance was similarly impaired in both SPD groups. An additional neurocognitive impairment, comprehension of grammatical constructions, was observed only in the SPD group with schizophrenic relatives. Of interest, the clinical profiles of the two SPD groups did not differ significantly. These results suggest that schizotypal personality disorder is associated with a continuum of neurocognitive vulnerability that increases as a function of family history of schizophrenia.     

Diagnostic approaches to schizotypal personality disorder: a historical perspective

The goal of this article is to provide a historical perspective on the DSM-III concept of schizotypal personality disorder. It is argued that two major traditions have influenced our conceptualization of this diagnostic entity. The first or familial approach emphasizes the characteristic traits found in the deviant but nonpsychotic relatives of schizophrenics. The second or clinical approach focuses on patients who appear to demonstrate the fundamental symptoms of schizophrenia without psychotic symptoms or severe personality deterioration. A review of these two traditions concludes that while similar in some regards, they also differ in important ways in their views on the characteristics of the true "schizotype." The impact of these two traditions is then traced through the Danish Adoption Studies of Kety et al. to the development of the DSM-III criteria for schizotypal personality by Spitzer, Endicott, and Gibbon. Finally, the article reviews recent studies on the validity of specific criteria for schizotypal personality disorder (SPD) and reassesses the conceptual issue about the nature of the relationship of SPD to schizophrenia on the one hand and to other personality disorders on the other.     

Schizotypal personality traits in nonpsychotic relatives are associated with positive symptoms in psychotic probands

There remains disagreement over whether increased risk of schizotypal personality disorder (SPD) is confined to the relatives of patients with a diagnosis of schizophrenia or whether it is a more general characteristic of the relatives of all psychotic patients. To examine the relationship between schizotypal dimensions in relatives and psychopathological syndromes in patients with functional psychoses, factor analysis was carried out on (1) ratings from Present State Examination (PSE) interviews with 172 consecutively admitted patients with psychosis (52% of them with schizophrenia), and (2) ratings on items from three schizotypal scales concerning 263 of their nonpsychotic first degree relatives. The factors derived from the patients' PSE interviews were correlated with the schizotypal factors and the nine DSM-IV criteria for SPD concerning the relatives and subjected to a canonical correlation analysis. In this study, no differences were observed concerning the distribution of schizotypal factors or DSM-IV schizotypal features in the relatives of patients with different psychotic diagnoses. However, a syndrome characterized by delusions, hallucinations, and thought interference (positive symptoms) in patients was correlated with high scores on the three schizotypy scales and with positive and negative schizotypal features in relatives.     

Schizotypal symptoms in the relatives of schizophrenia patients: an empirical analysis of the factor structure

This study examined the nature of schizotypal symptoms in the relatives of schizophrenia patients and investigated phenomenological differences in symptomatology manifested by a familial sample and a clinical sample of personality disorder patients. Confirmatory factor analyses were used to test models of DSM-III-R schizotypal symptoms in the first degree relatives (n = 172) of schizophrenia patients. A multisample analysis was conducted to determine whether the same model adequately described the schizotypal symptoms rated in the relatives of schizophrenia patients and in clinically selected personality disorder patients. The results indicated that a three-factor model consisting of cognitive/perceptual, interpersonal, and disorganization factors yielded the best fit to the data from the relatives of schizophrenia patients, but that this model did not adequately describe both the relatives of schizophrenia patients and personality disorder patients. These findings indicate that the structure of schizotypal symptoms in the relatives of schizophrenia patients is similar to the three-factor model of schizophrenia symptoms often reported, but not the same as the structure of schizotypal symptoms in clinically selected personality disorder patients.     

Dexamphetamine selectively increases 40 Hz auditory steady state response power to target and nontarget stimuli in healthy humans

Background

An emerging endophenotype of schizophrenia is the reduction of both power and phase locking of the 40 Hz auditory steady state response (ASSR), and there have been a number of reports linking increased γ activity with positive psychotic symptoms. Schizophrenia and, more specifically, positive psychotic symptoms have been closely linked to increased dopamine (DA) neurophysiology. Therefore, we gave dexamphetamine to healthy participants to determine the effect that increased DA transmission would have on the ASSR.

Methods

We administered 0.45 mg/kg of dexamphetamine orally in a double-blind placebo-controlled crossover study. Stimuli were 20 Hz and 40 Hz click trains presented in an auditory oddball-type stimulus format (probability of stimulus presentation: 0.2 for targets, 0.8 for nontargets).

Results

We included 44 healthy volunteers (18 women) in the study. Dexamphetamine significantly increased the 40 Hz power for both target and nontarget ASSR stimuli. Dexamphetamine did not significantly affect the 40 Hz phase-locking factor (PLF) or the 20 Hz power and PLF. Whereas there were significant effects of selective attention on power and PLF for 20 and 40 Hz ASSR, there were no significant interactions between dexamphetamine and selective attention.

Limitations

Dexampheta-mine releases both noradrenaline and DA with equal potency. Further research with selective dopaminergic and noradrenergic agents will better characterize the effects of monoamines on γ activity.

Conclusion

The results demonstrate a frequency-specific effect of dexamphetamine on the ASSR. This finding is consistent with previous research that has found an association between increased γ and positive symptoms of psychosis. However, this result also raises the possibility that previous 40 Hz ASSR findings in people with schizophrenia may be confounded by effects of antipsychotic medication. Possible neural mechanisms by which dexamphetamine specifically increases 40 Hz power are also discussed.

Australian and New Zealand Clinical Trials Registry number

ACTRN12608000610336.     

Personality traits in schizophrenia and related personality disorders

We investigated whether schizophrenia spectrum disorders share common personality characteristics or traits. Participants with a diagnosis of schizophrenia or schizoaffective disorder (SZ) or with a schizophrenia spectrum personality disorder (schizophrenia spectrum PD: schizoid, paranoid, and schizotypal personality disorder) were compared with non-psychiatric control subjects on the five-factor model of personality and the psychosis-proneness scales. On the five-factor personality scales, SZ subjects showed higher levels of neuroticism, and lower levels of openness, agreeableness, extraversion, and conscientiousness than control subjects. Higher scores on openness and lower scores on neuroticism distinguished schizophrenia spectrum PD from SZ. On the psychosis-proneness scales, both PD and SZ participants scored high relative to non-psychiatric control participants on magical ideation and perceptual aberration, while PD participants scored intermediate between non-psychiatric control participants and SZ on social anhedonia. Discriminant analysis indicated that schizophrenia spectrum patients could be distinguished from PDs by more severe social withdrawal and maladjustment, while subjects with PDs could be best distinguished from control subjects on the basis of odd or novel ideation and decreased conscientiousness.     

Personality disorder in the families of depressed, schizophrenic, and never-ill probands

In a blind family study of 176 probands with nonpsychotic major depression, psychotic major depression, schizophrenia, or no history of DSM-III disorders, only the relatives of depressed probands with mood-incongruent psychotic features had a risk for personality disorders higher than that for the relatives of never-ill probands. The authors did not find a high rate of borderline personality in relatives of depressed probands or of schizotypal personality disorder in relatives of probands with schizophrenia or any psychosis. However, depressed probands with normal dexamethasone test results had a significantly higher familial loading for the DSM-III cluster of histrionic, antisocial, borderline, and narcissistic personality disorders.     

Increased morbid risk for schizophrenia-related disorders in relatives of schizotypal personality disordered patients

To evaluate whether probands from a clinical sample diagnosed as having DSM-III schizotypal and/or paranoid personality disorder have a familial relationship to the schizophrenia-related disorders, the morbid risk for schizophrenia-related disorders and other psychiatric disorders were evaluated in the first-degree relatives of patients with schizotypal and/or paranoid personality disorder and compared with the corresponding risk for these disorders in the first-degree relatives of patients with other non-schizophrenia-related personality disorders. The morbid risk for all schizophrenia-related disorders, and specifically for schizophrenia-related personality disorders, was significantly greater among the relatives of the probands with schizotypal and/or paranoid personality disorder than among the relatives of probands with other personality disorder. The morbid risk for other psychiatric disorders did not differ significantly between the first-degree relatives of the schizotypal/paranoid personality disorder and the other personality disorder control proband samples. These results suggest a specific familial association between schizophrenia-related disorders, particularly schizophrenia-related personality disorders, and clinically diagnosed schizotypal patients.     

Morbidity risk of psychiatric disorders among the first degree relatives of schizophrenia patients in Taiwan

This study aimed to assess the boundaries of the schizophrenia spectrum and whether inclusion of such phenotypes increases power for linkage analysis of schizophrenia. Participants were 234 first degree relatives (FDRs) of 94 schizophrenia probands in Northern Taiwan who completed a direct interview using the Diagnostic Interview for Genetic Studies (DIGS). Based on best estimate diagnosis, the morbidity risk in the relatives for schizophrenia was 2.5 percent (Weinberg's shorter method) or 3.9 percent (Kaplan-Meier estimate). Depending on the stringency of diagnosis, lifetime prevalence was 2.6 percent to 4.7 percent for schizotypal personality disorder, 3.4 percent to 8.6 percent for paranoid personality disorder, and 1.3 percent to 3.4 percent for schizoid personality disorder. These figures are significantly higher than the corresponding figures in the general population. However, none of the recurrence risk ratio for any spectrum that included both schizophrenia and a personality disorder (3.0 to 5.9) was greater than that of schizophrenia alone (9.3 to 14.4). Thus, including schizophrenia-related personality disorders in the spectrum did not increase power for linkage analysis of schizophrenia.     

Modulation of the startle response and startle laterality in relatives of schizophrenic patients and in subjects with schizotypal personality disorder: evidence of inhibitory deficits

OBJECTIVE: Patients with schizophrenia spectrum disorders have been shown to have deficits in sensorimotor gating as assessed by prepulse inhibition of the startle response. The authors hypothesized that nonschizophrenic relatives of patients with schizophrenia would also have prepulse inhibition deficits, thereby reflecting a genetically transmitted susceptibility to sensorimotor gating deficits. METHOD: Twenty-five comparison subjects, 23 patients with schizophrenia, 34 relatives of the schizophrenic patients, and 11 subjects with schizotypal personality disorder were assessed in an acoustic startle paradigm. The eye-blink component of the startle response was assessed bilaterally by using electromyographic recordings of orbicularis oculi. RESULTS: The patients with schizophrenia, their relatives, and subjects with schizotypal personality disorder all had reduced prepulse inhibition relative to comparison subjects, and these deficits were more evident in measures of right eye-blink prepulse inhibition. Comparison subjects demonstrated greater right versus left eye-blink prepulse inhibition, whereas the probands, their relatives, and subjects with schizotypal personality disorder showed less asymmetry of prepulse inhibition. CONCLUSIONS: These data suggest a genetically transmitted deficit in prepulse inhibition (sensorimotor gating) in patients with schizophrenia spectrum disorders, including subjects with schizotypal personality disorder and relatives of patients with schizophrenia.     

Dopamine regulation in schizotypal personality disorder and psychosis

It has recently been proposed that reduced stimulation of prefrontal cortex DI receptors secondary to hypoactivity of mesocortical dopamine (DA) projections may explain the cognitive impairments experienced by patients with schizophrenia and the schizophrenia spectrum. Findings from studies done during the past two decades suggest that schizotypal personality disorder (SPD), the prototypic disorder of the schizophrenia spectrum, is associated with cognitive deficits and social deterioration that are qualitatively similar, although less severe, to those observed in schizophrenia. It generally is acknowledged that the psychotic symptoms of schizophrenia are associated with hyperactivity of mesolimbic DA projections resulting in excessive stimulation of striatal D2 receptors. In contrast with schizophrenia, dopaminergic interventions improved cognitive function in SPD without worsening psychotic-like symptoms, raising the possibility that patients with SPD are protected against increases in subcortical dopaminergic activity associated with psychosis. However, mounting evidence suggests that alterations in other neurotransmitter systems (eg, glutamate, γ-aminobutyric acid, opioid, serotonergic) may be involved in the pathophysiology of schizophrenia. This over view focuses on common DA-related neurobiological vulnerabilities shared by schizophrenia and the schizophrenia spectrum, in addition to factors that protect SPD from the overt psychotic symptoms and more severe social and cognitive deficits experienced by patients with chronic schizophrenia.     

Familial transmission of schizotypal and borderline personality disorders

The authors determined the risk for psychiatric disorders in the first-degree relatives of 36 probands with schizotypal personality disorder (13 definite, 23 probable), 17 probands with borderline personality disorder (two definite, 15 probable), and 90 normal control probands. The relatives of probands with schizotypal personality disorder without a concurrent diagnosis of borderline personality disorder had a significantly greater risk for schizotypal personality disorder than the relatives of normal control probands, borderline probands, or schizotypal probands with coexisting borderline personality disorder. The relatives of borderline probands had a significantly greater risk for definite and probable borderline personality disorder than the relatives of normal control probands.     

EEG synchronization to modulated auditory tones in schizophrenia, schizoaffective disorder, and schizotypal personality disorder

OBJECTIVE: The authors tested whether neural synchronization deficits were present in subjects with schizophrenia and schizotypal personality disorder. METHOD: Amplitude-modulated tones were used to evaluate auditory steady-state evoked potential entrainment in a combined group of 21 subjects with schizophrenia or schizoaffective disorder, 11 subjects with schizotypal personality disorder, and 22 nonpsychiatric comparison subjects. RESULTS: The schizophrenia or schizoaffective disorder group exhibited decreased power compared to the schizotypal personality disorder and nonpsychiatric comparison groups. There were no differences between groups in N100 amplitude. CONCLUSIONS: Subjects with schizophrenia but not subjects with schizotypal personality disorder have deficits in steady-state responses to periodic stimuli, despite an intact response to sensory-evoked potentials (N100). These deficits reflect aberrant neural synchronization or resolution and may contribute to disturbed perceptual and cognitive integration in schizophrenia.     

Schizotypal personality disorder. Chestnut Lodge follow-up study: VI. Long-term follow-up perspectives

This study reports the first long-term follow-up of patients with schizotypal personality disorder (SPD) as defined by DSM-III. Patients with the pure syndrome (SPD, n = 10) were compared with patients with schizophrenia (S, n = 53) and borderline personality disorder (BPD, n = 81). Three "mixed" cohorts (S/SPD, n = 61; S/SPD/BPD, n = 30; SPD/BPD, n = 18) were added to investigate the effect of schizotypal disorder on the longitudinal course of comparison groups. Schizotypal personality disorder proved to be common in the Chestnut Lodge follow-up study patients, although it was rare as a pure syndrome. From the perspective of follow-up, SPD appeared related to S but not to BPD. The mixed axis II borderline syndrome (SPD/BPD) had a long-term profile closer to BPD than to SPD, and adding SPD to S appeared (unexpectedly) to enhance outcome.     

Motor dysfunction in schizotypal personality disorder.

Past research has revealed that schizophrenia is associated with voluntary movement abnormalities, as well as higher rates of involuntary movements. On instrumental motor tasks, patients manifest reduced motor stability, excessive force and more contralateral motor overflow (movement in the non-responding hand). In the present study, an instrumental motor task (manual response forced-choice task) was administered to a group of adults with schizotypal personality disorder (SPD) in order to determine whether they show motor deficits similar to those observed in schizophrenia. As predicted, the schizotypal subjects were excessive and more variable in motor force, compared to healthy controls and other personality-disordered subjects. Additionally, the force and variability of the motor responses were positively correlated with ratings of both positive and negative SPD symptoms. Finally, motor overflow and negative symptoms were associated with higher salivary cortisol levels. The pattern of findings is consistent with previous reports linking motor abnormalities and heightened cortisol with schizotypal personality disorder.