An integration of schizophrenia with schizotypy: identification of schizotaxia and implications for research on treatment and prevention

The liability to schizophrenia (schizotaxia) is associated with deficits in a variety of domains, including negative symptoms and neuropsychological deficits, even in the absence of psychosis or pre-psychotic prodromal symptoms. Conceptually, this view of schizotaxia is similar to negative schizotypy (i.e., schizotypal personality disorder minus the positive symptoms). It is broader than DSM-IV schizotypal personality disorder (SPD), however, in that more relatives of patients with schizophrenia show core symptoms of schizotaxia than meet the diagnostic criteria for SPD. Three lines of evidence support the validity of schizotaxia. First, evidence of concurrent validation was obtained by showing that schizotaxic subjects were more impaired than non-schizotaxic subjects on a variety of independent clinical scales. Second, schizotaxic subjects showed higher levels of negative symptoms on the Structured Interview for Schizotypy than non-schizotaxic subjects, but did not differ on positive symptoms. Third, subjects who met predetermined criteria for schizotaxia (i.e., negative symptoms and neuropsychological deficits) showed positive effects following treatment with low doses of risperidone (0.25-2.0 mg). Thus, clinical deficits in schizotaxia may be identifiable, and to a significant extent, reversible. Implications for the conception of schizotypy and the prevention of schizophrenia will be discussed.     

Neuromotor functioning in adolescents with schizotypal personality disorder: associations with symptoms and neurocognition

Previously, Neumann and Walker (1999) used a computerized motor assessment and found that adults with schizotypal personality disorder (SPD) displayed increased and more variable motor force compared to adults with other personality disorders or healthy controls. Using the same motor assessment, the current study examined whether an independent sample of adolescents with SPD manifested a similar pattern of motor dysfunction compared to adolescents with other Axis II disorders or those without a disorder. As predicted, the SPD group showed increased and more variable force compared to the other two groups, which did not differ on these measures. These same motor variables were correlated with negative symptoms, as well as perseverative responses on a card sorting test. The significant correlations between motor functioning and perseverative responses and negative symptoms support recent research suggesting that subcortical motor regions play a role in higher order cognition and negative symptoms. Differences as well as broad similarities in the pattern of motor findings between the adult and adolescent SPD studies are discussed.     

Abnormalities of auditory event-related potentials in students with schizotypal personality disorder

Biological, phenomenological and cognitive similarities are known to exist between schizophrenia and schizotypal personality disorder (SPD). This study examined whether, and to what extent, abnormalities in event-related potentials (ERPs) already extensively reported in schizophrenia can also be observed in persons psychometrically identified with SPD. Event-related potentials were examined in nine SPD subjects and nine controls recruited from among 1693 college students, using the Schizotypal Personality Questionnaire (SPQ) and the Structured Clinical Interview for DSM-III-R (SCID I and II). Event-related potentials were recorded during an auditory oddball task. Smaller P300 amplitude and prolonged P300 latency were found in SPD subjects as compared with controls. Our findings indicate that such individuals do have deficits in information processing similar to that found in schizophrenia. We can conclude that P300 abnormalities may not be specific for SPD but that abnormalities shown in SPD are possibly a vulnerability marker for developing schizophrenia.     

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.     

Reduction of caudate nucleus volumes in neuroleptic-na?ve female subjects with schizotypal personality disorder.

BACKGROUND: The caudate nucleus might contribute to the psychopathological and cognitive deficits observed in schizotypal personality disorder (SPD), a schizophrenia spectrum disorder. Here we focused on female patients, because this group is underrepresented in studies of SPD and schizophrenia, and we might learn more about the caudate and clinical and cognitive impairments that are unique to female patients diagnosed with SPD. METHODS: Magnetic resonance imaging scans, obtained on a 1.5-T magnet with 1.5-mm contiguous slices, were used to measure the caudate in 32 neuroleptic-na?ve women with SPD and in 29 female normal comparison subjects. Subjects were group-matched for age, parental socioeconomic status, and intelligence quotient. RESULTS: We found significantly reduced left and right caudate relative volume (8.3%, 7.7%) in female SPD subjects compared with normal comparison subjects. In female SPD subjects, we found significant correlations between smaller total caudate relative volume and worse performance on the Wisconsin Card Sorting test (nonperseverative errors) and on the California Verbal Learning Test (verbal memory and learning), and significant correlations between smaller total caudate relative volume and both positive and negative symptoms on the Structured Interview for Schizotypy. CONCLUSIONS: These findings demonstrate that, for female SPD subjects, smaller caudate volume is associated with poorer cognitive performance and more schizotypal symptomatology.     

Minor physical anomalies, dermatoglyphic asymmetries, and cortisol levels in adolescents with schizotypal personality disorder

OBJECTIVE: A relationship between schizotypal personality disorder and schizophrenia has been documented in behavioral genetic studies, and there are similarities in the cognitive deficits and brain abnormalities associated with these disorders. Adolescents with schizotypal personality disorder are of particular interest because the postpubertal period is a critical one for the development of a DSM axis I disorder. It is likely that some schizotypal adolescents will remain stable over time, some will improve, and a subgroup will develop schizophrenia. This study tested the hypotheses that, like schizophrenic patients, schizotypal adolescents manifest an elevated rate of minor physical and dermatoglyphic anomalies, both of which suggest prenatal neurodevelopmental abnormalities. Cortisol release is also of interest because of evidence that the hypothalamic-pituitary-adrenal axis may influence the behavioral expression of vulnerability to schizophrenia. METHOD: Minor physical anomalies, dermatoglyphic asymmetries, and salivary cortisol levels were measured in three groups of adolescents: 20 with schizotypal personality disorder, 20 with other personality disorders, and 26 with no disorder. Assessments began at noon, and four saliva samples were obtained at hourly intervals. RESULTS: The schizotypal personality disorder group showed more minor physical anomalies and dermatoglyphic asymmetries than the normal comparison group and higher cortisol levels than both of the other groups. Group differences in cortisol level were most pronounced at the beginning of the evaluation. Cortisol level and age were positively correlated. CONCLUSIONS: The findings support the assumption that schizotypal personality disorder is associated with perturbations in fetal neurodevelopment and, under some circumstances, a heightened cortisol response.     

Phosphorus metabolite changes in temporal lobes of subjects with schizotypal personality disorder

Using in vivo (31)P magnetic resonance spectroscopy, phosphorus metabolite levels were measured in the temporal lobes of 11 neuroleptic-free subjects with schizotypal personality disorder (SPD) and 20 age-matched healthy subjects. SPD subjects showed smaller amounts of phosphomonoesters in the left temporal lobe than healthy subjects. Membrane phospholipid abnormalities in the left temporal lobe may be a common pathophysiologic feature in schizophrenia spectrum disorders.     

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.     

Amphetamine, psychosis, and cognition in the schizophrenia spectrum

We previously reported that subjects with a schizophrenia spectrum personality disorder (ie, an odd cluster personality disorder), of which the prototype is schizotypal personality disorder, show cognitive impairment in circumscribed areas (working memory) compared with healthy control subjects, and that amphetamine administration improves working memory in subjects with schizotypal personality disorder. In this larger series, we wanted to determine whether amphetamine treatment ameliorates working memory impairment using three groups: subjects with a schizophrenia spectrum personality disorder (ie, schizotypal, paranoid, or schizoid personality disorder), other (subjects with nonschizophrenia spectrum) personality disorder, and healthy volunteers. We hypothesized that amphetamine treatment would improve cognitive function in domains in which subjects with schizophrenia spectrum personality disorder show impairment compared with healthy volunteers and the other personality disorder group. Overall, amphetamine treatment did not improve performance in any task compared with placebo, and there was no group by drug interaction in the total sample. However, when the sample was restricted to the subjects who showed impairment at baseline, amphetamine treatment improved visuospatial working memory. In the total patient sample, amphetamine treatment reduced negative symptoms, whereas positive symptoms remained unchanged. Amphetamine treatment improves working memory in those subjects with cognitive impairment at baseline, most of whom meet criteria for a schizophrenia spectrum disorder.     

Effects of acute metabolic stress on the dopaminergic and pituitary-adrenal axis activity in patients with schizotypal personality disorder

BACKGROUND: Stress has been associated with the onset of schizophrenia and exacerbation of psychotic symptoms. Patients with schizotypal personality disorder (SPD), the prototypic schizophrenia spectrum disorder, do not develop the frank psychosis of schizophrenia and appear clinically to be less reactive to stress than schizophrenic patients. Schizophrenic patients demonstrate increased dopaminergic (DA) and hypothalamic-pituitary-adrenal-axis (HPA) activation following 2-deoxyglucose (2-DG), an acute metabolic (glycopyruvic) stressor, compared to healthy volunteers (HV). We hypothesized that SPD patients would demonstrate comparable or lower DA and HPA responses after 2-DG to HV. METHODS: Fifteen SPD patients and 13 HV were administered 2-DG (40 mg/kg, i.v.) in a double-blind, placebo-controlled, randomized protocol. The area under the curve (AUC) was determined for plasma HVA, ACTH and cortisol (utilizing baseline and post infusion indices). RESULTS: 2-DG induced significant increases in ACTH, cortisol and HVA concentrations in both groups and cortisol elevations were significantly lower in patients with SPD than in HV. CONCLUSIONS: Patients with SPD have a blunted cortisol and a normal dopaminergic response to 2-DG. These results are consistent with the hypothesis that SPD patients are better buffered against DA and HPA overactivation in response to stress.     

White Matter Abnormalities in Schizophrenia and Schizotypal Personality Disorder

Prior diffusion tensor imaging (DTI) studies examining schizotypal personality disorder (SPD) and schizophrenia, separately have shown that compared with healthy controls (HCs), patients show frontotemporal white matter (WM) abnormalities. This is the first DTI study to directly compare WM tract coherence with tractography and fractional anisotropy (FA) across the schizophrenia spectrum in a large sample of demographically matched HCs (n = 55), medication-naive SPD patients (n = 49), and unmedicated/never-medicated schizophrenia patients (n = 22) to determine whether (a) frontal-striatal-temporal WM tract abnormalities in schizophrenia are similar to, or distinct from those observed in SPD; and (b) WM tract abnormalities are associated with clinical symptom severity indicating a common underlying pathology across the spectrum. Compared with both the HC and SPD groups, schizophrenia patients showed WM abnormalities, as indexed by lower FA in the temporal lobe (inferior longitudinal fasciculus) and cingulum regions. SPD patients showed lower FA in the corpus callosum genu compared with the HC group, but this regional abnormality was more widespread in schizophrenia patients. Across the schizophrenia spectrum, greater WM disruptions were associated with greater symptom severity. Overall, frontal-striatal-temporal WM dysconnectivity is attenuated in SPD compared with schizophrenia patients and may mitigate the emergence of psychosis.Key words: DTI, MRI, schizotypal personality disorder, schizophrenia, psychosis, white matter, genu, cingulum, inferior longitudinal fasciculus     

The relations among putative biorisk markers in schizotypal adolescents: minor physical anomalies, movement abnormalities, and salivary cortisol.

BACKGROUND: Evidence suggests that prenatal insult may play a role in the etiology of psychotic disorders. Minor physical anomalies (MPA) are an indicator of abnormal fetal development and are elevated in individuals at genetic and behavioral risk for psychosis. Yet, there has been little empirical research on the relationships between MPAs and other neurobiological risk indicators. We hypothesized that the frequency of MPAs (an external marker of prenatal central nervous system [CNS] disruption) would be associated with two other biomarkers suggestive of disruptions in fetal neurodevelopment: movement abnormalities (an indicator of striatal abnormalities) and heightened cortisol secretion (an indicator of hypothalamic-pituitary-adrenal [HPA]/hippocampal function). METHODS: Participants with schizotypal personality disorder (SPD; n = 39) and both normal (n = 47) and other personality disorders (n = 28) control subjects were administered structured diagnostic interviews and assessed for MPAs, movement abnormalities, and salivary cortisol. RESULTS: Schizotypal personality disorder participants showed significantly greater MPAs and movement abnormalities and higher cortisol than both the normal and other personality disorders groups. Hierarchical linear regression analyses revealed that higher rates of MPAs were linked with greater movement abnormalities and salivary cortisol. CONCLUSIONS: The findings suggest that MPAs serve as a marker of neurodevelopmental abnormalities that affect striatal and hippocampal regions.     

Visuospatial working memory in schizotypal personality disorder patients

BACKGROUND: Cognitive processing deficits have been identified as an abnormality that schizotypal personality disorder (SPD) individuals share with schizophrenic patients. It has been hypothesized that impaired working memory may be a critical component of several of the more complex cognitive deficits found in schizophrenia spectrum patients. METHOD: 18 DSM-III-R SPD patients, and 17 normal comparison subjects were compared on a pen and paper visuospatial working memory task. Moreover, we identified a second psychiatric comparison group comprised of nine patients with other, non-odd cluster personality disorder diagnoses who met no more than one of the SPD criteria and were also tested on the same task. Each person was given 14 immediate recall trials and 10 trials using a 10 s delay. RESULTS: SPD patients performed significantly worse than normal control subjects on the working memory task. SPD patients also performed significantly worse compared to the non-schizophrenia-related personality disorder psychiatric comparison group. CONCLUSIONS: Like schizophrenic patients, SPD patients demonstrate working memory impairment compared to normal controls. This impairment may be specific to the schizophrenia-related personality 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.     

Visual perception and working memory in schizotypal personality disorder

OBJECTIVE: Patients affected by schizophrenia show deficits in both visual perception and working memory. The authors tested early-stage vision and working memory in subjects with schizotypal personality disorder, which has been biologically associated with schizophrenia. METHOD: Eleven subjects who met DSM-III-R criteria for schizotypal personality disorder and 12 normal comparison subjects were evaluated. Performance thresholds were obtained for tests of visual discrimination and working memory. Both form and trajectory processing were evaluated for each task. RESULTS: Subjects with schizotypal personality disorder showed intact discrimination of form and trajectory but were impaired on working memory tasks. CONCLUSIONS: These data suggest that subjects with schizotypal personality disorder, unlike patients affected by schizophrenia, have relatively intact visual perception. Subjects with schizotypal personality disorder do show specific deficits on tasks of comparable difficulty when working memory demands are imposed. Schizotypal personality disorder may be associated with a more specific visual processing deficit than schizophrenia, possibly reflecting disruption of frontal lobe systems subserving visual working memory operations.     

The pathophysiology of schizophrenia disorders: perspectives from the spectrum

OBJECTIVE: This overview focuses on neurobiological abnormalities found in subjects with schizotypal personality disorder, the prototype of the schizophrenia spectrum disorders, and chronic schizophrenia in the context of common vulnerabilities shared by schizotypal personality disorder and schizophrenia, as well as the factors that protect against the severe cognitive/social deficits and frank psychosis of chronic schizophrenia. A pathophysiological model of the relationship between schizotypal personality disorder and schizophrenia was developed based on this data. METHOD: The authors provide a selective review of major findings regarding the pathophysiology of schizotypal personality disorder and integrate these results in conjunction with preclinical studies into a model of the pathophysiology of the spectrum. RESULTS: People with schizotypal personality disorder share phenomenological, genetic, and cognitive abnormalities with people with chronic schizophrenia. While temporal volume reductions appear to be common to both groups, there may be preservation of frontal lobe volume in schizotypal personality disorder compared to schizophrenia. Findings to date regarding striatal volume, metabolic rate, and dopamine release in subjects with schizotypal personality disorder compared to subjects with chronic schizophrenia are consistent with hypotheses of reduced striatal dopaminergic activity in schizotypal personality disorder compared to schizophrenia. CONCLUSIONS: Genetic or environmental factors that promote greater frontal capacity and reduced striatal dopaminergic reactivity might contribute to sparing people with schizotypal personality disorder from the psychosis and severe social and cognitive deterioration of chronic schizophrenia. Further research is required to test these hypotheses more definitively.     

MRI abnormalities of the hippocampus and cavum septi pellucidi in females with schizotypal personality disorder

OBJECTIVE: This study examined MRI hippocampal volume and cavum septi pellucidi (CSP) in female subjects with schizotypal personality disorder (SPD) and comparison subjects. METHOD: MRI was performed on 20 SPD and 29 comparison subjects with delineation of left and right hippocampi. Number of slices containing the CSP was counted. Subjects were given a working memory task, the Delayed Alternation task and other measures of working memory including the Wechsler Memory Test-Revised and the California Verbal Learning Test. Clinical measures were derived from the SCID-II. RESULTS: SPD females evinced bilaterally smaller hippocampal volumes compared with non-psychiatric female subjects (15.1% on left, 15.7% on right). Additionally, SPD subjects showed statistically significantly more slices containing CSP, and a trend level difference when large CSP was defined as four or more slices (20% vs. 6.9%). SPD subjects demonstrated more errors, more perseverations, and a trend toward more failure to maintain set on the Delayed Alternating task, which were associated with smaller left hippocampal volumes. There was no difference between groups in logical memory, verbal learning or semantic clustering nor a significant correlation between these measures and hippocampal volumes. Clinically, in SPD subjects, right hippocampal volumes correlated negatively with odd appearance/behavior and positively with suspiciousness/paranoia, and odd speech was positively correlated with the number of slices containing a CSP in exploratory analyses. CONCLUSIONS: Female SPD subjects showed bilaterally smaller hippocampal volumes and larger CSP than comparison subjects, similar to what has been shown in schizophrenia. Moreover, these abnormalities have clinically significant associations which may help to explain some of the manifestations of the disorder.     

The brain in schizotypal personality disorder: a review of structural MRI and CT findings.

Studies of schizotypal personality disorder (SPD) are important because the condition is genetically related to schizophrenia and because data accumulating to confirm its biological underpinnings are challenging some traditional views about the nature of per-sonality disorders. This review of 17 structural imaging studies in SPD indicates that individuals with this disorder show brain abnormalities in the superior temporal gyrus, parahippocampus, temporal horn region of the lateral ventricles, corpus callosum, thalamus, and septum pellucidum, as well as in total cerebrospinal fluid volume, similar to those seen in persons with schizophrenia. Differences between SPD and schizophrenia include lack of abnormalities in the medial temporal lobes and lateral ventricles in SPD. Whether the normal volume, and possibly normal functioning, of the medial temporal lobes in individuals with SPD may help to suppress psychosis in this disorder remains an intriguing but still unresolved question. Such speculation must be tempered due to a paucity of studies, and additional work is needed to confirm these preliminary findings. The imaging findings do suggest, however, that SPD probably represents a milder form of disease along the schizophrenia continuum. With further clarification of the neuroanatomy of SPD, researchers may be able to identify which neuroanatomical abnormalities are associated with the frank psychosis seen in schizophrenia.     

Large CSF volume not attributable to ventricular volume in schizotypal personality disorder

OBJECTIVE: The purpose of this study was to determine whether schizotypal personality disorder, which has the same genetic diathesis as schizophrenia, manifests abnormalities in whole-brain and CSF volumes. METHOD: Sixteen right-handed and neuroleptic-naive men with schizotypal personality disorder were recruited from the community and were age-matched to 14 healthy comparison subjects. Magnetic resonance images were obtained from the subjects and automatically parcellated into CSF, gray matter, and white matter. Subsequent manual editing separated cortical from noncortical gray matter. Lateral ventricles and temporal horns were also delineated. RESULTS: The men with schizotypal personality disorder had larger CSF volumes than the comparison subjects; the difference was not attributable to larger lateral ventricles. The cortical gray matter was somewhat smaller in the men with schizotypal personality disorder, but the difference was not statistically significant. CONCLUSIONS: Consistent with many studies of schizophrenia, this examination of schizotypal personality disorder indicated abnormalities in brain CSF volumes.     

Executive functions in adolescents with schizotypal personality disorder

Adolescents meeting diagnostic criteria for schizotypal personality disorder (SPD) are presumed to be at risk for developing schizophrenia in adulthood, making them an important group for exploring the developmental trajectory of the disease. Deficits in executive functioning have been documented in schizophrenia patients and adults with SPD. The present study examined executive functions in adolescents with SPD. It was predicted that the SPD group would score below comparison groups (normals and adolescents with other disorders) on measures of executive function, and that those with greater 'negative' signs of SPD would show more pronounced performance deficits. Analyses revealed that the performance of the SPD subjects was impaired relative to the other groups on the modified Wisconsin Card Sorting Test (MCST), but not on the Tower of London or the Controlled Oral Word Association Test. Consistent with prediction, regression analyses indicated that MCST deficits were associated with greater negative signs of SPD, but not positive signs.