Symptoms of Attenuated Psychosis Syndrome in Relatives of Clinical High-Risk Youth: Preliminary Evidence

Abstract

Background and Hypothesis

Attenuated Psychosis Syndrome (APS) impacts functioning and predicts increased risk of psychosis. Risk for developing APS itself has received minimal attention. Knowledge of familial and environmental contributions to APS symptoms would advance understanding of APS and risk for psychosis. As an initial step, this report presents the first data on APS symptoms in family members of APS patients.

Study Design

This study utilized a discordant sibling-pair family study design. The Structured Interview for Psychosis-risk Syndromes (SIPS) was administered to 17 APS probands and 26 non-APS biological siblings. Probands and siblings were compared on positive, negative, disorganized, and general SIPS symptom scales and factors derived from those scales.

Study Results

There was significantly greater symptom severity in probands compared to siblings on nine of 19 SIPS scales. Negative/anxiety, functioning, and positive symptom factors were identified. Probands showed significantly greater severity than siblings on the negative/anxiety and positive factors. Elevated pathology on the negative/anxiety factor best differentiated between probands and siblings, over and above the contribution of the positive factor. No difference was found for the functioning factor.

Conclusions

Results support the importance of non-familial effects on risk for APS and suggest differences in familial contribution to APS symptoms. Understanding the relative contribution of familial and environmental effects on APS symptoms may reveal important differences among APS patients, with implications for risk characterization, symptom course, and treatment selection.

Introduction

Attenuated Psychosis Syndrome (APS) is the most common of three psychosis-risk syndromes (Brief Intermittent Psychosis Syndrome [BIPS] and Genetic Risk and Deterioration [GRD] are the other psychosis-risk syndromes) that characterize youth who are at “clinical high risk (CHR)” for psychosis,^1–4 also referred to as “ultra-high risk (UHR)” or “at-risk mental states”. Listed under “Conditions for Further Study”, DSM-5⁵ diagnostic criteria for APS include the presence of one or more attenuated “psychotic-like” symptoms, specifically delusional thinking, hallucinatory experiences, or disorganized speech. Reality testing is relatively intact, symptoms do not meet criteria for a psychotic disorder, and there is no lifetime history of psychosis. With onset between late childhood and early adulthood, APS symptoms closely resemble the schizophrenia prodrome, the period of increased psychotic-like symptoms and functional decline preceding psychosis onset.

APS is a consequential diagnosis. First, APS predicts progression to schizophrenia and other psychotic disorders. Among young people identified as CHR, approximately 20% will develop psychosis within 12 months, 30% within 2 years, and up to 40% by 3 years following APS diagnosis.^6–9 In comparison, lifetime risk for psychosis is approximately 7–13% in offspring of individuals with schizophrenia and 1.1% in the general population.^10,11

Second, APS is a clinically relevant disorder marked by significant impairment and distress, including withdrawal from friends and family, difficulty thinking and communicating clearly, suspiciousness, anxiety, hypersensitivity to stress, cognitive deficits including planning, problem solving, and sustained attention, and decline in social functioning and academic performance.^2,12 Although approximately two-thirds of young people with APS do not transition to psychosis, approximately 50% of these non-transitioned individuals continue to experience persistent, clinically significant APS symptoms and associated impairment^9,13 and up to 80% report a mental health diagnosis.³

Yet despite its clinical importance and association with psychosis, research on risk for APS is limited to a few studies. There is recent evidence that UHR (CHR) status (vs controls) is associated with polygenic risk for schizophrenia¹⁴ and evidence of elevated rates of psychotic disorders in families of UHR youth,¹⁵ suggesting importance of genetic/familial factors in characterizing risk for APS. Environmental risk factors are also indicated, including childhood trauma, obstetric complications, and younger age of exposure to cannabis.^16,17

To date, APS symptoms in relatives of APS patients have not been investigated and as such, the relative effects of familial and environmental factors on APS symptoms have not been examined. It is unknown if APS symptoms are significantly influenced by shared familial factors, including genetic effects. Alternatively, non-familial effects such as an individual’s unique environmental experiences and exposures may be most important. This is valuable information that builds on prior studies and has implications for characterization of risk for APS and early identification,¹⁸ understanding APS symptoms as phenotypic manifestations of liability to schizophrenia and other psychoses, prediction of APS outcome (ie, progression to psychosis, symptom persistence, or remission^13,19), and treatment.

Utilizing a discordant sibling-pair study design, this report presents the first data on APS symptoms in family members of APS patients.

Specific Aim

1. 1) To assess APS symptoms in biological siblings of APS probands, determine the factor structure best representing APS symptoms in this sibling-pair sample, and compare symptom severity in siblings and probands.

Methods

Study protocol and informed consents were approved by the Human Subjects Research Institutional Review Board (IRB) at Yale University School of Medicine.

Participants

Seventeen unrelated APS probands and 26 of their full biological siblings not meeting APS diagnostic criteria (see below) participated in this study. All participants were identified through the PRIME prodromal research clinic (Prevention through Risk Identification, Management, and Education), located in the Connecticut Mental Health Center on the medical campus of Yale University. Participants provided written informed consent prior to study enrollment.

Recruitment

APS probands age 12–30 years old were recruited through three methods (via parent/guardian if under 18): (1) approaching current PRIME clinic research study participants, (2) contacting former PRIME study participants who provided permission to be re-contacted, and (3) through recruitment advertisements. Interested individuals contacting the PRIME clinic were given a phone screening to establish likelihood of meeting APS diagnostic criteria and otherwise verify eligibility.

Potential participants were asked to approach at least one full biological sibling aged 12–30 years old about participating in the study. Sibling(s) (or parent/guardian) initiated contact with the PRIME clinic and completed a phone screening to verify eligibility. Enrollment of at least one full biological sibling was required for APS proband participation.

Inclusion/Exclusion Criteria

All Participants.

All study participants met the following criteria: (1) age 12–30 years, (2) able to understand and sign an informed consent/assent document in English, (3) no current or lifetime diagnosis of a psychotic disorder, (4) no current treatment with antipsychotic medication, and (5) no current or lifetime history of a disorder that could confound diagnosis of APS.

APS Probands.

Proband eligibility additionally required diagnosis of APS on the Structured Interview for Psychosis-risk Syndromes and Scale Of Psychosis-risk Symptoms (SIPS/SOPS).^20–22 Diagnosis requires (1) onset or worsening in the past month of at least one SOPS positive symptom (Unusual Thought Content, Suspiciousness, Grandiosity, Perceptual Abnormalities, Disorganized Communication) rated “3” (moderate), “4” (moderately severe), or “5” (severe but not psychotic), (2) occurring with an average frequency of at least once per week, and (3) not likely due to another condition. Former research participants originally diagnosed with APS and in partial remission at the time of the current study were also eligible. Partial remission means that at least one clinically significant APS positive symptom (“3”, “4”, or “5” severity level) meets all criteria except it is more than 1 month but less than 6 months since symptom onset or worsening.

Non-APS Siblings.

Full biological siblings who did not meet diagnostic criteria for APS or another psychosis-risk syndrome were eligible to participate. Psychosis-risk symptoms were not exclusionary for siblings as long as diagnostic criteria for a psychosis-risk syndrome had never been met and symptoms were never present at a psychotic level of intensity. Non-psychotic psychiatric diagnoses also were not exclusionary. Number of enrolled siblings per proband was not restricted.

Assessment

Assessments were conducted by PhD-level clinical psychologists. Interviewers were not blind to proband/sibling status. All study procedures were conducted at the PRIME Clinic at Yale University.

APS.

APS symptom ratings and diagnosis were established using the SIPS/SOPS version 5.0,^21,22 a semi-structured interview and rating scale for evaluation of psychosis-risk symptoms and diagnosis of psychosis-risk syndromes. Psychosis-risk symptoms are rated on a 0–6 scale, with zero defined as “none” and higher ratings representing greater severity. For positive symptoms, a rating of six is defined as “psychotic”. The rating system allows for endorsement of symptoms at a “normal” threshold of severity, providing high sensitivity to detect symptoms at a low level of intensity. Symptom ratings were updated for participants previously interviewed with the SIPS/SOPS (eg, for another PRIME study). Detailed descriptions and psychometric properties of the SIPS/SOPS scales are available.^4,20,22

Comorbid Psychiatric Diagnoses.

Comorbid Axis I psychiatric diagnoses (DSM-IV-TR)²³ were established using the Structured Clinical Interview for DSM-IV (SCID-I).²⁴

Analyses

All analyses were conducted using SPSS version 29.²⁵ Threshold for significance was P ≤ .05 (two-tailed). Bonferroni correction was employed to adjust for multiple pairwise comparisons for analyses of comorbid psychiatric diagnoses [P = .008 (.05/6 diagnoses)] and individual SOPS symptom scales [P = .003 (.05/19 scales)].

Demographic Comparisons and Covariate Identification.

Probands and siblings were compared group-wise on age, sex, years of education, and ancestry using independent t-tests for continuous variables (age, education) and chi-square analysis for categorical variables (sex, ancestry). Second, associations between demographic variables and SOPS scale ratings were tested in the total sample and in the proband and sibling groups separately using Pearson r for continuous and the Kruskal–Wallis test for categorical variables.

Comorbid Diagnoses.

DSM-IV-TR diagnosis codes were grouped by diagnostic category (eg, anxiety disorders). Probands and siblings were compared group-wise on presence of any psychiatric diagnosis and diagnoses of current depression, remitted depression, anxiety, attention deficit hyperactivity disorder (ADHD), post-traumatic stress disorder (PTSD), and pervasive developmental disorder (PDD) (non-hierarchical) using chi-square analysis. No other diagnostic categories were present in the total sample. Associations between comorbid diagnostic categories and SOPS scale ratings and factor scores were tested in the proband and sibling groups using the Kruskal–Wallis test.

APS Symptom Scales.

Probands and siblings were compared group-wise on mean SOPS scale ratings and the mean rating for each symptom category using independent t-tests.

APS Symptom Factors.

Given correlations among SOPS scales both within and between symptom categories (Supplementary table 1) and to minimize multiple comparisons, APS factor scores were derived from SOPS ratings and used in subsequent analyses. Factor scores were used instead of the SOPS category total scores so as to not assume that the original SOPS categories would best characterize symptom variance in this novel sibling-pair sample. A parallel analysis was performed first on the raw data using principal axis factor Eigen values to determine the number of factors. Exploratory factor analysis (EFA) using unweighted least squares extraction and varimax rotation (orthogonal) with Kaiser normalization was performed on standardized SOPS ratings in the total sample and number of factors was selected based on parallel analysis results. Suitability of SOPS ratings for factor analysis was tested using the Kaiser-Meyer-Olkin Measure of Sampling Adequacy. Factor scores were calculated for each participant using the Bartlett method. Bartlett scores are strongly correlated with their factor while allowing correlation of scores between factors. Correlation between factors was calculated using Pearson r.

Factor Scores and APS Diagnosis.

Probands and siblings were compared group-wise on APS factor scores using separate one-way ANOVAs. Logistic regression analysis was then conducted with group as the dependent variable (proband or sibling) to test the extent to which APS factor scores could predict group membership. Comorbid diagnoses that differed between probands and siblings were entered as covariates on the first step. Next, factor scores were added to the model using forward step entry. Factor scores retained in the forward step model were tested for interaction effects.

Results

Participants

Seventeen families, 17 APS probands and 26 non-APS siblings, met study inclusion criteria. Fifty-nine percent of probands had one sibling enrolled. Thirty-five percent had two siblings enrolled and the remaining family had four.

Demographic Characteristics

The proband and sibling groups did not differ on age, sex, years of education, or ancestry (table 1). As such, subsequent analyses did not control for these variables. Demographic variables were not associated with SOPS symptom scale ratings in either the total sample or in the proband and sibling groups separately.

Table 1.

Demographic variables and comorbid diagnoses in APS probands and siblings

	Probands	Siblings	P value
Demographics
Age, mean years (sd)	19.5 (4.4)	18.2 (4.8)	.397
Sex, % male	65	50	.342
Education, mean years (sd)	11.4 (2.9)	10.8 (3.2)	.522
Ancestry, % EA	76	81	.735
Comorbid diagnosesa
Any, % (n)	94.1 (16)	34.6 (9)	<.001
Depression, current, % (n)b	35.3 (6)	11.5 (3)	.061
Depression, in remission, % (n)	41.2 (7)	7.7 (2)	.008
Anxiety, % (n)	58.8 (10)	23.1 (6)	.018
PTSD, % (n)	5.9 (1)	3.8 (1)	.757
ADHD, % (n)	23.5 (4)	7.7 (2)	.143
PDD, % (n)	0.0 (0)	3.8 (1)	.413

Note: APS n = 17, siblings n = 26. sd, standard deviation; EA, European American; PTSD, post-traumatic stress disorder; ADHD, attention deficit hyperactivity disorder; PDD, pervasive developmental disorder.

^aDiagnoses are non-hierarchical.

^bDiagnoses % of total sample n (probands = 17, siblings = 26). Bolded P-values indicate significance of pairwise comorbid diagnosis comparison after Bonferroni correction (P ≤ .008).

Comorbid Diagnoses

A significantly higher percentage of probands were diagnosed with at least one comorbid diagnosis compared to siblings. Analysis of individual diagnostic categories (non-hierarchical) indicated that a greater proportion of probands were diagnosed with depression in remission compared to siblings. Frequencies of other psychiatric diagnoses, including current depression, did not differ between groups (table 1). Comorbid diagnoses were not associated with any SOPS scales or SOPS factor scores in probands. In siblings, remitted depression was associated with higher scores on disorganized communication (P = .003), decreased expression of emotion (P < .001), and odd behavior or appearance (P < .001) and a higher score on the negative/anxiety factor (P = .032). Anxiety was associated with deterioration in personal hygiene (P = .003). ADHD and PDD were associated with decreased expression of emotion (P < .001) and odd behavior or appearance (P < .001 and P = .003, respectively). However, frequencies of comorbid psychiatric diagnoses were low among siblings overall. Anxiety was diagnosed in only six siblings and only three or fewer siblings were represented in the remaining diagnostic categories, including remitted depression (n = 2).

APS Symptom Scales

Table 2 presents the mean unstandardized SOPS symptom scores for probands and siblings and results of t-tests. Results indicated significantly greater severity in probands compared to siblings on nine of 19 SOPS symptom scales: four positive, two negative, one disorganized, and two general symptom scales, and on the mean ratings for each category.

Table 2.

SOPS scale ratings in APS probands and siblings

	Probands, m (sd)	Siblings, m (sd)	P value
APS symptoms (SOPS Scale)
Unusual thought content (P1)	2.53 (1.13)	0.73 (0.96)	<.001
Suspiciousness (P2)	2.71 (1.11)	0.69 (0.88)	<.001
Grandiose ideas (P3)	0.82 (1.13)	0.27 (0.53)	.073
Perceptual abnormalities (P4)	2.24 (1.30)	0.62 (0.80)	<.001
Disorganized communication (P5)	1.24 (0.97)	0.35 (0.69)	.003
Mean positive scale rating	1.91 (0.82)	0.53 (0.61)	<.001
Social Anhedonia (N1)	2.76 (1.75)	0.62 (1.17)	<.001
Avolition (N2)	2.12 (1.62)	0.85 (1.19)	.005
Decreased expression of emotion (N3)	1.35 (1.22)	0.08 (0.39)	<.001
Decreased experience of emotions and self (N4)	1.53 (1.46)	0.54 (0.95)	.021
Decreased ideational richness (N5)	1.00 (0.87)	0.46 (0.81)	.045
Decreased occupational functioning (N6)	2.29 (1.90)	1.08 (1.90)	.046
Mean negative scale rating	1.84 (0.94)	0.60 (0.77)	<.001
Odd behaviour or appearance (D1)	1.24 (0.90)	0.15 (0.46)	<.001
Bizarre thinking (D2)	0.53 (0.80)	0.00 (0.00)	.015
Trouble with focus and attention (D3)	2.76 (1.56)	1.62 (1.20)	.010
Deterioration in personal hygiene (D4)	0.71 (0.69)	0.42 (0.81)	.242.
Mean disorganized scale rating	1.31 (0.65)	0.55 (0.55)	<.001
Sleep disturbance (G1)	2.06 (1.03)	1.15 (1.05)	.008
Dysphoric mood (G2)	2.94 (1.20)	1.38 (1.53)	<.001
Motor disturbances (G3)	0.53 (0.87)	0.15 (0.54)	.127
Impaired tolerance to normal stress (G4)	3.88 (2.03)	1.15 (1.78)	<.001
Mean general scale rating	2.35 (0.98)	0.96 (0.90)	<.001

Note: APS n = 17, siblings n = 26. Bolded P-values indicate significance of pairwise SOPS scale comparisons after Bonferroni correction (P ≤ .003). m, mean; sd, standard deviation; EA, European American.

APS Factors

Parallel analyses indicated that a three-factor solution provided the best fit for the data. EFA of the positive, negative, disorganized, and general SOPS symptom scales identified a three-factor solution with 64.7% of total variance explained (table 3). Sampling adequacy was confirmed (Kaiser-Meyer-Olkin Measure of Sampling Adequacy = 0.80). Factors were uncorrelated (see table 2 notes).

Table 3.

SOPS scale factor loadings

	APS factor
	Negative/anxiety	Functioning	Positive
APS symptom (SOPS Scale)
Impaired tolerance to normal stress (G4)	0.670
Decreased expression of emotion (N3)	0.580
Decreased experience of emotions and self (N4)	0.550
Suspiciousness (P2)	0.546		0.510
Decreased ideational richness (N5)	0.542
Sleep disturbance (G1)	0.541
Motor disturbances (G3)	0.520
Decreased occupational functioning (N6)		0.713
Deterioration in personal hygiene (D4)		0.709
Dysphoric mood (g2)	0.605	0.662
Avolition (N2)		0.651
Trouble with focus and attention (D3)		0.639
Odd behaviour or appearance (D1)	0.500	0.508
Bizarre thinking (D2)			0.808
Grandiose ideas (P3)			0.764
Unusual thought content (P1)			0.676
Perceptual abnormalities (P4)	0.546		0.581
Social anhedonia (N1)			0.567
Disorganized communication (P5)			0.548
Variance explained	47.56	10.11	7.03

Note: Total variance explained = 64.69; factor extraction method = unweighted least squares; rotation method = Varimax with Kaiser Normalization; Kaiser-Meyer-Olkin Sampling Adequacy = 0.80; Bartlett’s Test of Sphericity <0.001; Pearson correlations between factors as follows: negative/anxiety and functioning = −0.14, Negative/Anxiety and Positive = −0.016, and Functioning and Positive = −0.07. Factor loadings under .500 not shown to improve table readability. SOPS scale numbers are in parentheses.

One-way ANOVA results indicated that probands scored significantly higher (greater pathology) than siblings on the negative/anxiety factor (P < .001) and the positive factor (P < .001). Probands and siblings did not differ on the functioning factor (figure 1). The regression model that best predicted proband versus sibling group membership (controlling for remitted depression), with classification accuracy of 88.4%, consisted of the negative/anxiety and positive factors excluding the functioning factor. The negative/anxiety factor was the strongest predictor of group membership (table 4, step 1) and predicted group membership over and above the contribution of the positive factor (table 4, step 2). There was no significant interaction effect between the negative/anxiety and positive factors.

Fig. 1.

Mean APS factor scores in probands and siblings. Values are t-scores transformed from standardized factor scores (z-scores) to improve figure readability. Factor z-scores (95% CI) are as follows: negative/anxiety: probands = 0.75 (0.09–1.41), siblings = −0.49 (−0.74 to −0.24); Functioning: probands = 0.10 (−0.55 to 0.75), siblings = −0.07 (−0.49 to 0.36); Positive: probands = 0.63 (−0.11 to 1.38), siblings = −0.42 (−0.56 to −0.27).

Table 4.

APS factors and prediction of probands vs siblings final model

Factors entered at each step	β	S.E.	Wald	P	Exp(β)	95% C.I. Exp(β)
						Lower	Upper
Step 1
Depression in remission	−1.67	0.99	2.86	.091	0.19	0.03	1.31
APS negative/anxious factor	1.25	0.48	6.80	.009	3.48	1.36	8.86
Constant	0.87	0.88	0.99	.320	2.39
Step 2
Depression in remission	0.35	1.37	0.07	.798	1.42	0.10	20.88
APS negative/anxious factor	2.34	0.85	7.63	.006	10.41	1.97	54.91
APS positive factor	2.77	1.13	5.98	.014	15.94	1.73	146.53
Constant	−0.65	1.05	0.38	.540	0.52

Note: Logistic Regression Forward Step Entry: APS negative/anxiety, APS functioning, and APS positive factors. df = 1. Overall classification accuracy = 64.7%.

Discussion

This study compared APS symptom severity in APS patients and non-APS biological siblings. To our knowledge, this is the first study of APS symptoms in relatives of APS patients.

APS Symptoms in Siblings

Mean APS symptom ratings were higher (more severe) in APS probands compared to siblings on four of five positive symptoms: unusual thought content, suspiciousness, perceptual abnormalities, and disorganized communication. This was expected given that probands and siblings were selected for APS diagnosis discordance, which is determined based on positive symptom ratings. In contrast, when corrected for multiple comparisons, probands showed greater severity than siblings on only two of six negative APS symptoms, social anhedonia and decreased expression of emotion, one of four disorganized symptoms, odd behavior or appearance, and two of four general symptoms, dysphoric mood and impaired tolerance to normal stress.

Although no other data on APS siblings are available, there are published data on SOPS ratings in healthy controls. Woods et al⁴ identified 21 studies that reported SOPS positive subscale scores in healthy controls. The median score ranged from 0.1 to 1.6.^20,26–47 Mean positive scores available from a subset of these and more recent studies (n = 23) ranged from 0.06 to 4.24.^{20,26–42,47–51} A non-exhaustive review identified 22 studies that reported mean SOPS negative subscale scores in healthy controls: range 0.03–4.35,^{20,26–39,41,42,48–51} 17 studies that reported mean disorganized subscale scores in healthy controls: range 0.10–0.83,^{20,26,28–30,32–34,36–39,42,47–50} and 15 studies that reported mean general subscale scores in healthy controls: range 0.03–1.84.^{20,26,28–30,33,34,36,38,39,42,47–50} These findings suggest that severity of positive, negative, disorganized, and general symptoms in the current sibling sample may be similar to that of healthy controls. However, ranges for controls are quite large, heterogeneity across samples is likely, and comparability to the current sibling sample is unknown; as such, firm conclusions cannot be drawn.

APS Symptom Factor Structure

Three APS symptom factors, “Negative/Anxiety”, “Functioning”, and “Positive”, were identified as best representing the 19 SOPS scales in this sample. The factor structure differed somewhat from the symptom categories used in the SIPS/SOPS. The first factor, “Negative/Anxiety”, primarily reflected negative and general symptoms, including impaired tolerance to normal stress, which loaded most strongly on this factor, followed by decreased expression of emotion and decreased experience of emotions and self. Suspiciousness and perceptual abnormalities (SOPS positive symptoms) also loaded on this factor. The second APS factor, “Functioning”, primarily reflected a combination of SOPS negative and disorganized symptoms, including decreased occupational functioning and deterioration in personal hygiene. On the third factor, “Positive”, bizarre thinking (a SOPS disorganized symptom) loaded most strongly along with four of five positive symptoms. Social anhedonia (a SOPS negative symptom) also loaded on this factor.

This three-factor model is similar to SOPS factor structures reported in the literature. We are aware of two studies published in English that conducted factor analysis on the SOPS in CHR samples. Tso et al⁵² reported a four-factor model in a large sample of unrelated clinical high-risk, clinical low risk, and early first episode patients. The composition of their positive symptom factor is nearly identical to the positive factor of our model. Our negative/anxiety factor appears to be a combination of their negative symptom and distress factors. The remaining factor in their model (“deteriorated thought process”) shows only modest overlap with our functioning factor, however. Zhang et al⁵³ identified a six-factor solution from a factor analysis of SOPS ratings in a CHR sample, although a different criterion was used to determine number of factors (eigenvalue > 1.00) with some factors barely reaching this threshold. Additionally, two GAF scores were included in the factor analysis along with the SOPS ratings.

We are aware of four studies published in English that examined SOPS symptom dimensions in CHR using principal component analysis (PCA) (Note that although PCA and factor analysis are both data-reduction methods, components and factors are not interchangeable and may not necessarily show the same solution). Hawkins et al⁵⁴ and Comparelli et al⁵⁵ each identified three components: positive, negative, and general. Tonyali et al⁵⁶ also identified a three-component solution: positive, negative, and disorganized. Klaassen et al⁵⁷ identified a four-component solution: negative, depression, disorganized, and positive. The negative and positive components in these studies resembled our negative/anxiety and positive factors, respectively. Functioning/disorganized scale loadings were less consistent among the PCA studies. Overall, the factor structure identified in the current study appears fairly consistent with models identified in other CHR samples, with positive and negative factors being most stable.

Negative/Anxiety Factor

The negative/anxiety symptom factor showed significantly higher pathology in probands versus siblings. The negative/anxiety factor was the strongest predictor of group membership in regression modeling. Furthermore, the negative/anxiety factor retained significance when controlling for the positive factor. This finding was unexpected as probands and siblings differed on only two negative symptoms and two general symptoms. Additionally, sibling-pairs were discordant for the APS diagnosis, which is determined based on positive symptoms. However, the positive symptoms “suspiciousness” and “perceptual abnormalities” contributed to the negative/anxiety factor and may in part account for the findings.

Although there are no other studies of siblings of APS patients, the literature provides substantial evidence of an association between negative symptoms and familial risk for schizophrenia. A large literature supports significant elevation of “sub-clinical” negative symptoms (eg, negative schizotypy) in non-psychotic adult first-degree relatives of schizophrenia patients compared to healthy controls and compared to relatives of affective disorder patients.^58–60 Results of the individual SOPS scale group comparisons in the current study are consistent with these findings in that that siblings did not differ from probands on the majority of SOPS negative symptoms.

Functioning Factor

Probands and siblings did not differ in severity on the functioning factor. This was due to lower dysfunction in probands and higher dysfunction in siblings (relative to negative/anxiety and positive factor scores). Longitudinal studies in CHR youth suggest that youth who transition to psychosis show worse social functioning at baseline compared to those who do not.^61,62 It may be that level of functional impairment in the current proband sample reflects low likelihood of transition to psychosis or alternatively, increased risk could not be detected as dysfunction was non-specific in this study. Without longitudinal data, this remains speculative. Risk of transition to psychosis in APS relatives, and association with functional impairment, is also unknown.

Differences in the extent to which APS probands and siblings differ on APS symptom severity (eg, negative/anxiety vs functioning) suggest the possibility of important differences between APS patients primarily showing symptoms with low familial association and those elevated on symptoms possibly influenced by familial factors. Such patients may show different symptom trajectories, vulnerability to psychosis, and have different treatment needs.

Positive Factor

Analyses of the positive factor showed a significant difference between probands and siblings in this sample. This was expected given that groups were selected for discordance on APS diagnosis which is defined by positive symptoms. This is also consistent with the schizophrenia family study literature demonstrating that positive symptoms (eg, positive schizotypy) are not substantially elevated in relatives of schizophrenia patients.⁵⁸

Comorbid Psychiatric Diagnoses

There was high frequency of comorbid psychiatric disorders among probands (94%). Frequency in siblings was modest (35%). Diagnosis of depression in remission was elevated in probands compared to siblings. No other diagnostic categories differed between groups. Anxiety was the most common diagnosis in both groups. Evidence suggests that anxiety is associated with, and may contribute to, APS symptoms.⁶³ Although anxiety was not associated with any SOPS scales in probands and only one in siblings (deterioration in personal hygiene), sensitivity to detect association may have been low. Trauma has also been shown to be elevated in CHR patients versus controls⁶⁴ and associated with greater severity of symptoms.⁶⁵ Diagnosis of PTSD was rare in both groups and not associated with SOPS scales. A detailed trauma history assessment was not performed, however. Finally, although remitted depression, ADHD, and PDD were associated with some SOPS scale ratings in siblings and remitted depression with the negative/anxiety factor in siblings, it unclear if these are meaningful results given very limited frequency in the sibling sample (eg, remitted depression n = 2). Replication in larger samples is required.

Limitations

First, sample size limits sensitivity to detect small phenotypic effects and can contribute to factor instability. In addition, in a larger sibling sample, stratification by housing status could perhaps offer insight into effect of shared environment. Second, healthy controls were not included in this study, and therefore symptom severity in siblings versus healthy controls could not be examined. Third, siblings in this study were selected for discordance on APS diagnosis. Use of an unselected sibling sample would increase symptom variance in siblings and could provide further information on APS symptoms in family members. Fourth, over- or under-estimation of group differences is possible with unblinded assessment. Finally, data were not collected longitudinally, and therefore it is unknown if any siblings will be diagnosed with APS (or psychosis) in the future or if any APS probands will transition to full psychosis.

Summary

Positive, negative, disorganized, and general APS symptoms and three APS factors, “negative/anxiety”, “functioning”, and “positive”, were examined in APS probands and their non-APS biological siblings. The negative/anxiety factor was the strongest predictor of proband-sibling group membership and predicted group membership over and above the positive factor. Probands and siblings did not differ on the functioning factor.

Study results support the importance of non-familial effects on risk for APS and efforts to integrate environmental and genetic risk factors to improve early identification (eg, Psychosis Polyrisk Score¹⁸). Furthermore, understanding the relative contribution of familial and environmental effects on APS symptoms may reveal important differences among APS patients (eg, high versus low elevation on negative symptoms), with implications for risk characterization, symptom course, and treatment selection. Finally, this study takes a new approach to clinical high-risk research through investigation of APS symptoms using a family study design.

Funding

This work was supported by the Brain and Behavior Research Foundation (NARSAD Young Investigator Award to S.I.T.).