The multidimensionality of schizotypy in nonpsychotic relatives of patients with schizophrenia and its applications in ordered subsets linkage analysis of schizophrenia.

This study aimed to examine the multidimensionality of schizotypy and validate the structure using ordered subset linkage analyses on information from both relatives' schizotypy and probands' schizophrenia symptoms. A total of 203 and 1,310 nonpsychotic first-degree relatives from simplex and multiplex schizophrenia families, respectively, were interviewed with the Diagnostic Interview for Genetic Studies, which contains a modified Structured Interview for Schizotypy. Using Mplus program with categorical factor indicators, a four-factor model (Negative Schizotypy, Positive Schizotypy, Interpersonal Sensitivity, and Social Isolation/Introversion) was extracted by exploratory factor analysis from relatives of simplex families and was confirmed in relatives of multiplex families. The validity of each factor was supported by distinct linkage findings resulting from ordered subset analysis based on different combinations of schizophrenia-schizotypy factors. Six chromosomal regions with significant increase in nonparametric linkage z score (NPL-Z) were found as follows: 15q21.1 (NPL-Z = 3.60) for Negative Schizophrenia-Negative Schizotypy, 10q22.3 (NPL-Z = 3.83) and 15q21.3 (NPL-Z = 3.36) for Negative Schizophrenia-Social Isolation/Introversion, 5q14.2 (NPL-Z = 3.20) and 11q23.3 (NPL-Z = 3.31) for Positive Schizophrenia-Positive Schizotypy, and 4q32.1 (NPL-Z = 3.31) for Positive Schizophrenia-Interpersonal Sensitivity. The greatest NPL-Z of 3.83 on 10q22.3 in the subset was significantly higher than the greatest one of 2.88 in the whole sample (empirical P-value = 0.04). We concluded that a consistent four-factor model of schizotypy could be derived in nonpsychotic relatives across families of patients with different genetic loadings in schizophrenia. Their differential relations to linkage signals have etiological implications and provide further evidence for their validity.

Impaired flush response to niacin skin patch among schizophrenia patients and their nonpsychotic relatives: the effect of genetic loading.

We previously reported familial aggregation in flush response to niacin skin patch among schizophrenia patients and their nonpsychotic relatives. However, little is known about whether this abnormal skin response is associated with genetic loading for schizophrenia. This study compared the niacin flush response in subjects from families with only one member affected with schizophrenia (simplex families) with those from families having a sib-pair with schizophrenia (multiplex families). Subjects were patients with schizophrenia and their nonpsychotic first-degree relatives from simplex families (176 probands, 260 parents, and 80 siblings) and multiplex families (311 probands, 180 parents, and 52 siblings) as well as 94 healthy controls. Niacin patches of 3 concentrations (0.001M, 0.01M, and 0.1M) were applied to forearm skin, and the flush response was rated at 5, 10, and 15 minutes, respectively, with a 4-point scale. More attenuated flush response to topical niacin was shown in schizophrenia probands and their relatives from multiplex families than in their counterparts from simplex families, and the differentiation was better revealed using 0.1M concentration of niacin than 0.01M or 0.001M. For the highest concentration of 0.1M and the longest time lag of 15 minutes, a subgroup of probands (23%), parents (27%), and siblings (19%) still exhibited nonflush response. Flush response to niacin skin patch is more impaired in schizophrenia patients and their relatives from families with higher genetic loading for schizophrenia, and this finding has implications for future genetic dissection of schizophrenia.

Familial aggregation in skin flush response to niacin patch among schizophrenic patients and their nonpsychotic relatives.

Though a reduced flush response to niacin has been found in schizophrenic patients, whether it is a vulnerability indicator to schizophrenia remains little known. We aimed to examine the familial aggregation in niacin flush response among schizophrenic patients and their nonpsychotic relatives. In a sample of 153 schizophrenia probands, 217 parents, 70 siblings, and 94 normal subjects, 3 concentrations (0.001 M, 0.01 M, and 0.1 M) of niacin were applied to the forearm skin and the flush response was rated at 5, 10, and 15 minutes, respectively, with a 4-point scale. Both the heritability for continuous flush scores and the recurrence risk ratios for binary non-flush response in the nonpsychotic relatives of schizophrenic patients were estimated, and ordinal logistic regression analyses of relatives' niacin response on probands' were further conducted to adjust for potential confounders. The greatest heritabilities ranged from 47% (0.01 M at 10 minutes) to 54% (0.1 M at 5 minutes). The risk ratios of 0.01 M at 10 minutes (ranging from 2.60 for using score 1 or less to 5.06 for using score 0 as non-flush) and 5 minutes (1.66 for using score 0 as non-flush) were significantly greater than one. Multiple ordinal logistic regression analyses further revealed that the association between probands and relatives in niacin flush response remained after adjustment for potential confounders, including age, sex, allergy, tobacco smoking, and coffee drinking. These findings provide support for the potential of niacin flush response as a vulnerability indicator to schizophrenia.

Re-examining sustained attention deficits as vulnerability indicators for schizophrenia: stability in the long term course.

This study examined the longitudinal patterns in the sustained attention deficits detected by the Continuous Performance Test (CPT) and the factors influencing such changes in consecutively admitted schizophrenia patients (n=224) followed up for 4-7 year. Exploratory growth mixture modeling analyses of subjects' CPT performances over successive follow-ups revealed that three major (accounting for 92.8%) plus one minor subgroups could be delineated. Subgrouping was then performed on a subsample of 104 subjects who had at least 3 times of CPT data. Based on subjects' adjusted z score of the test sensitivity index d' derived from comparing with a community sample, patients were divided into three subgroups: no impairment (-1), moderate impairment (-2.5 to -1), and severe impairment (< -2.5). The trajectory taken by individual patient was analyzed according to the initial subgroup status and subsequent changes, controlling for relevant basic and clinical characteristics. Both growth mixture modeling and subgroup status analyses found that around one third of those with severe impairment at baseline showed persistent severe impairment. Those with no impairment were stable and exhibited least tendency for further performance deterioration. Those with moderate impairment tended to fluctuate markedly, mainly towards the better rather than the worse. Previous subgrouping status and concurrent task-taking strategy predicted the performance subgroup status at follow-ups, while clinical symptoms and disease course factors did not. We concluded that there is substantial heterogeneity in schizophrenia patients' long term pattern in sustained attention deficits and those with severe impairment might represent a subgroup with stable vulnerability to schizophrenia.

More severe sustained attention deficits in nonpsychotic siblings of multiplex schizophrenia families than in those of simplex ones.

Sustained attention deficits measured by the Continuous Performance Test (CPT) have been proposed as an endophenotype of schizophrenia. However, little is known about whether sustained attention deficits in first-degree relatives of schizophrenic patients are associated with familial loading for schizophrenia. We examined 107 parents and 84 siblings of simplex schizophrenia families as well as 72 parents and 56 siblings of multiplex schizophrenia families, all nonpsychotic, using the Diagnostic Interview for Genetic Studies and two sessions of the CPT (undegraded and degraded). The effect of perceptual load was assessed using the residual of the regression of the degraded score on the undegraded one. Statistical models that can adjust for familial correlations were used to compare the CPT performance of relatives between the two types of families. Siblings from multiplex families exhibited worse performance on the degraded CPT and less proficiency in processing the perceptual load than those from simplex families. No such difference was observed for the parents on either CPT version. We concluded that sustained attention along with perceptual load processing is more impaired in the siblings of schizophrenic patients with high familial loading and that this finding might be useful for future genetic dissection of schizophrenia.

Sustained attention deficits in nonpsychotic relatives of schizophrenic patients: a recurrence risk ratio analysis.

BACKGROUND: In nonpsychotic parents and siblings of schizophrenic patients, the recurrence risk ratios of sustained attention deficits, as measured by the continuous performance test (CPT), were examined with a series of cut-off points. METHODS: Among 116 parents and 95 siblings of 91 schizophrenic probands in northern Taiwan, both undegraded and degraded sessions of the CPT were administered. Subjects' signal detection sensitivity of CPT performance (d') was standardized against a community sample without (unadjusted z score) or with (adjusted z score) adjustment for age, gender, and educational level. RESULTS: Differences in the risk ratios between the parents and siblings that were based on the unadjusted z scores of CPT d' diminished markedly if the adjusted z scores were used. As the cut-off point in the adjusted z score decreased from -2.5 to -3.0, the risk ratio increased continually for both the undegraded (10.1-18.8 for parents, 10.0-16.7 for siblings) and degraded (12.4-102.7 for parents, 8.6-72.0 for siblings) test. CONCLUSIONS: Stringent cut-off criteria of CPT deficits with adjustment for demographic features leads to recurrence risk ratios greater than those based on schizophrenia alone in both parents and siblings of schizophrenic patients.

Deficits in sustained attention in schizophrenia and affective disorders: stable versus state-dependent markers.

OBJECTIVE: The authors compared sustained attention deficits measured by the Continuous Performance Test in patients with various affective disorders and patients with schizophrenia and examined whether Continuous Performance Test deficits in patients with affective disorders improve with remission of affective disorder symptoms. METHOD: Patients with schizophrenia (N=41), major depression without psychotic features (N=22), bipolar disorder without psychotic features (N=22), and bipolar disorder with psychotic features (N=46) completed Continuous Performance Test sessions with an undegraded version of the test and a 25% degraded version in which the stimulus images were visually distorted. Subjects were also interviewed with the Chinese version of the Diagnostic Interview for Genetic Studies. All inpatients with schizophrenia (N=41) and bipolar disorder (N=15) were assessed both at admission and discharge. Subjects' Continuous Performance Test scores were standardized in comparison with scores for a community sample of 345 subjects, with adjustment for age, sex, and level of education. RESULTS: Compared with the general population, all patient groups except the group with nonpsychotic major depression were significantly impaired in their ability to discriminate target stimuli from nontarget stimuli on the Continuous Performance Test. Patients with schizophrenia had the severest impairment, followed by patients with bipolar disorder with psychotic features and those with bipolar disorder without psychotic features. From admission to discharge, Continuous Performance Test deficits in schizophrenia remained unchanged, but inpatients with bipolar disorder showed significant improvement on the degraded Continuous Performance Test. All patients adopted a similar response criterion (the amount of perceptual evidence the person requires to decide that a stimulus is a target) to that in the general population, except that the patients with schizophrenia had a less stringent response criterion during the degraded Continuous Performance Test. CONCLUSIONS: Continuous Performance Test deficits are stable vulnerability indicators for schizophrenia, mediating indicators for bipolar disorder, and state-dependent indicators for major depression.

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.