Andrea M. Auther

Generalized and specific neurocognitive deficits in prodromal schizophrenia.

BACKGROUND Neurocognitive deficits are considered to be central to the pathophysiology of schizophrenia, and the neurodevelopmental model suggests that such deficits precede full-blown psychosis. The present study examined performance on a broad neuropsychological battery of young subjects considered to be at clinical high risk for schizophrenia, who were subsequently followed to determine clinical outcome. METHODS Subjects were 38 clinical high-risk patients (58% male patients; mean age = 16.5) and 39 sex- and age-matched healthy control subjects. At baseline, all high-risk patients had attenuated (subpsychotic) schizophrenialike positive symptoms. Clinical follow-up data of at least 6 months duration was available on 33 patients, of whom 12 developed nonaffective psychotic disorders. RESULTS At baseline, clinical high-risk patients had significantly impaired global cognitive performance relative to control subjects and to estimates of their own prior intellectual functioning. Measures of verbal memory and executive functioning/working memory showed significantly greater impairments; visuospatial functioning was relatively spared. Prodromal patients who later developed psychosis had significantly lower verbal memory scores at baseline compared with patients who remained nonpsychotic. CONCLUSIONS Verbal memory deficits may be an important risk marker for the development of schizophrenia-spectrum psychotic disorders, possibly indicating the presence of a prefrontal-hippocampal neurodevelopmental abnormality. Generalized neurocognitive impairment may be a nonspecific vulnerability marker.

Nonspecific and attenuated negative symptoms in patients at clinical high-risk for schizophrenia

BACKGROUND Retrospective studies have shown that nonspecific psychopathology and negative symptoms, including social isolation and academic dysfunction, tend to precede onset of psychosis. The present report describes the baseline psychopathology of subjects in the Hillside Recognition and Prevention (RAP) Program, and presents an operationalized classification algorithm for the prospective study of both positive and negative symptoms of clinical high-risk (CHR) for schizophrenia. METHODS Eighty-two adolescent and young adult patients were characterized using semi-structured interviews of both a parent informant and the patient. The Scale of Prodromal Symptoms (SOPS) was utilized to derive a three-part classification scheme: CHR- subjects (n=20) were defined as having at least one attenuated negative symptom with no positive symptoms; CHR+ subjects (n=42) were defined as having one or more attenuated positive symptoms without psychosis; schizophrenia-like psychosis (SLP) subjects (n=20) were defined as having a psychotic symptom, but without meeting criterion A, B, or C of DSM-IV schizophrenia. RESULTS Social isolation was the most common presenting symptom. The three RAP subgroups did not significantly differ in levels of attenuated negative and disorganized symptoms, despite the fact that these were not required for inclusion in the CHR+ and SLP groups. Common co-morbid diagnoses included major depression, attention deficit hyperactivity disorder, avoidant personality disorder, and Cluster A personality disorders. CONCLUSIONS Negative symptoms and other nonspecific behavioral abnormalities represent clinically important phenomena in prodromal patients, and may provide insight into pathophysiologic mechanisms in schizophrenia and possible preventive interventions.

Impact of Neurocognition on Social and Role Functioning in Individuals at Clinical High Risk for Psychosis

OBJECTIVE Cognitive deficits have been well documented in schizophrenia and have been shown to impair quality of life and to compromise everyday functioning. Recent studies of adolescents and young adults at high risk for developing psychosis show that neurocognitive impairments are detectable before the onset of psychotic symptoms. However, it remains unclear how cognitive impairments affect functioning before the onset of psychosis. The authors assessed cognitive impairment in adolescents at clinical high risk for psychosis and examined its impact on social and role functioning. METHOD A sample of 127 treatment-seeking patients at clinical high risk for psychosis and a group of 80 healthy comparison subjects were identified and recruited for research in the Recognition and Prevention Program. At baseline, participants were assessed with a comprehensive neurocognitive battery as well as measures of social and role functioning. RESULTS Relative to healthy comparison subjects, clinical high-risk patients showed significant impairments in the domains of processing speed, verbal memory, executive function, working memory, visuospatial processing, motor speed, sustained attention, and language. Clinical high-risk patients also displayed impaired social and role functioning at baseline. Among patients with attenuated positive symptoms, processing speed was related to social and role functioning at baseline. CONCLUSIONS These findings demonstrate that cognitive and functional impairments are detectable in patients at clinical high risk for psychosis before the onset of psychotic illness and that processing speed appears to be an important cognitive predictor of poor functioning.

Prediction of Functional Outcome in Individuals at Clinical High Risk for Psychosis

IMPORTANCE A major public health concern associated with schizophrenia and psychotic disorders is the long-term disability that involves impaired cognition, lack of social support, and an inability to function independently in the community. A critical goal of early detection and intervention studies in psychosis is therefore to understand the factors leading to this often profound impairment. OBJECTIVE To develop a predictive model of functional (social and role) outcome in a clinical high-risk sample for psychosis. DESIGN Prospective, naturalistic, longitudinal 3- to 5-year follow-up study. SETTING The Recognition and Prevention Program in New York, a research clinic located in the Zucker Hillside Hospital in New York. PARTICIPANTS One hundred one treatment-seeking patients at clinical high risk for psychosis. Ninety-two (91%) were followed up prospectively for a mean (SD) of 3 (1.6) years. INTERVENTION Neurocognitive and clinical assessment. MAIN OUTCOMES AND MEASURES The primary outcome variables were social and role functioning at the last follow-up visit. RESULTS Poor social outcome was predicted by reduced processing speed (odds ratio [OR], 1.38; 95% CI, 1.050-1.823; P = .02), impaired social functioning at baseline (OR, 1.85; 95% CI, 1.258-2.732; P = .002), and total disorganized symptoms (OR, 5.06; 95% CI, 1.548-16.527; P = .007). Reduced performance on tests for verbal memory (OR, 1.74; 95% CI, 1.169-2.594; P = .006), role functioning at baseline (OR, 1.34; 95% CI, 1.053-1.711; P = .02), and motor disturbances (OR, 1.77; 95% CI, 1.060-2.969; P = .03) predicted role outcome. The areas under the curve for the social and role prediction models were 0.824 (95% CI, 0.736-0.913; P < .001) and 0.77 (95% CI, 0.68-0.87; P < .001), respectively, demonstrating a high discriminative ability. In addition, poor functional outcomes were not entirely dependent on the development of psychosis, because 40.3% and 45.5% of nonconverters at clinical high risk had poor social and role outcomes, respectively. CONCLUSIONS AND RELEVANCE Results from this study support the increasing emphasis on functional decline as a critically important outcome that parallels conversion to psychosis and suggest that both psychosis and long-term functional disability are equally important targets for prevention. Reduced neurocognitive performance, functional impairments, and nonpositive attenuated symptoms at baseline were associated with an increased risk of poor functional outcomes in our sample. Poor functional outcomes were not entirely dependent on positive symptoms and the development of psychosis, further highlighting the need for intervention at this early stage of development for those who do and do not convert to a full-blown psychotic disorder.

Psychosis Prevention: A Modified Clinical High Risk Perspective From the Recognition and Prevention (RAP) Program

OBJECTIVE Early intervention and prevention of psychosis remain a major challenge. Prediction would be greatly advanced with improved ability to identify individuals at true risk, which, at present, is moderate at best. The authors tested a modified strategy to improve prediction by selecting a more homogeneous high-risk sample (attenuated positive symptom criteria only, age range of mid-teens to early 20s) than is currently standard, combined with a systematic selection of neurodevelopmental deficits. METHOD A sample of 101 treatment-seeking adolescents (mean age, 15.9 years) at clinical high risk for psychosis were followed clinically for up to 5 years (mean follow-up time, 3.0 years, SD=1.6). Adolescents were included only if they exhibited one or more attenuated positive symptoms at moderate to severe, but not psychotic, severity levels. Cox regression was used to derive a risk index. RESULTS The overall conversion rate to psychosis was 28.3%. The final predictor model, with a positive predictive validity of 81.8%, consisted of four variables: disorganized communication, suspiciousness, verbal memory deficits, and decline in social functioning during follow-up. Significant effects also suggest narrowing the risk age range to 15-22 years. CONCLUSIONS Clinical high risk criteria that emphasize disorganized communication and suspiciousness while also including compromised verbal memory and declining social functioning have the potential to improve predictive accuracy compared with attenuated positive symptoms used alone. On the resulting risk index (a weighted combination of the predictors), low scores were interpreted as signifying minimal risk, with little treatment necessary, high scores as suggesting aggressive intervention, and intermediate scores, although less informative, as supporting psychosocial treatment.

HPA axis function and symptoms in adolescents at clinical high risk for schizophrenia

BACKGROUND Stress sensitivity and HPA axis activity may be relevant to the development and expression of psychotic disorders. Cortisol secretion has been associated with positive symptoms both in patients with psychotic disorders and in young people at clinical risk for psychosis. Herein, we aimed to replicate these findings, to determine which positive symptoms may be associated with cortisol levels, and to explore any associations with affective symptoms and impaired stress tolerance. METHODS Thirty-one clinical high risk patients were evaluated in cross-section for associations between salivary cortisol levels upon clinic entry at 11 am, demographic variables, and clinical symptoms. RESULTS Salivary cortisol levels were unrelated to medication exposure or demographics, except for higher levels in the ten females studied. Salivary cortisol bore no relationship to overall positive symptom severity but was associated with anxiety, as well as with suspiciousness and impaired stress tolerance, which were themselves highly intercorrelated. CONCLUSIONS Cortisol secretion in the context of a putative novel social situation (i.e. clinic entry) may be a biological correlate of suspiciousness, impaired stress tolerance and affective symptoms in individuals vulnerable to developing psychosis. These associations are consistent with findings from experience sampling studies in individuals at risk for psychosis as well as basic studies of animal models of schizophrenia.

Type and duration of subsyndromal symptoms in youth with bipolar I disorder prior to their first manic episode

The aim of the present study was to systematically evaluate the prodrome to mania in youth.

Clinical and Functional Outcomes After 2 Years in the Early Detection and Intervention for the Prevention of Psychosis Multisite Effectiveness Trial

Objective: To test effectiveness of the Early Detection, Intervention, and Prevention of Psychosis Program in preventing the onset of severe psychosis and improving functioning in a national sample of at-risk youth. Methods: In a risk-based allocation study design, 337 youth (age 12–25) at risk of psychosis were assigned to treatment groups based on severity of positive symptoms. Those at clinically higher risk (CHR) or having an early first episode of psychosis (EFEP) were assigned to receive Family-aided Assertive Community Treatment (FACT); those at clinically lower risk (CLR) were assigned to receive community care. Between-groups differences on outcome variables were adjusted statistically according to regression-discontinuity procedures and evaluated using the Global Test Procedure that combined all symptom and functional measures. Results: A total of 337 young people (mean age: 16.6) were assigned to the treatment group (CHR + EFEP, n = 250) or comparison group (CLR, n = 87). On the primary variable, positive symptoms, after 2 years FACT, were superior to community care (2 df, p < .0001) for both CHR (p = .0034) and EFEP (p < .0001) subgroups. Rates of conversion (6.3% CHR vs 2.3% CLR) and first negative event (25% CHR vs 22% CLR) were low but did not differ. FACT was superior in the Global Test (p = .0007; p = .024 for CHR and p = .0002 for EFEP, vs CLR) and in improvement in participation in work and school (p = .025). Conclusion: FACT is effective in improving positive, negative, disorganized and general symptoms, Global Assessment of Functioning, work and school participation and global outcome in youth at risk for, or experiencing very early, psychosis.

Prospective Study of Cannabis Use in Adolescents at Clinical High-Risk for Psychosis: Impact on Conversion to Psychosis and Functional Outcome

BACKGROUND Clinical and epidemiological studies suggest an association between cannabis use and psychosis but this relationship remains controversial. METHOD Clinical high-risk (CHR) subjects (age 12-22 years) with attenuated positive symptoms of psychosis (CHR+, n=101) were compared to healthy controls (HC, n=59) on rates of substance use, including cannabis. CHR+ subjects with and without lifetime cannabis use (and abuse) were compared on prodromal symptoms and social/role functioning at baseline. Participants were followed an average of 2.97 years to determine psychosis conversion status and functional outcome. RESULTS At baseline, CHR+ subjects had significantly higher rates of lifetime cannabis use than HC. CHR+ lifetime cannabis users (n=35) were older (p=0.015, trend), more likely to be Caucasian (p=0.002), less socially anhedonic (p<0.001) and had higher Global Functioning: Social (GF:Social) scores (p<0.001) than non-users (n=61). CHR+ cannabis users continued to have higher social functioning than non-users at follow-up (p<0.001) but showed no differences in role functioning. A small sample of CHR+ cannabis abusers (n=10) showed similar results in that abusers were older (p=0.008), less socially anhedonic (p=0.017, trend) and had higher baseline GF:Social scores (p=0.006) than non-abusers. Logistic regression analyses revealed that conversion to psychosis in CHR+ subjects (n=15) was not related to lifetime cannabis use or abuse. CONCLUSIONS The current data do not indicate that low to moderate lifetime cannabis use is a major contributor to psychosis or poor social and role functioning in clinical high-risk youth with attenuated positive symptoms of psychosis.

Comparing clinical and neurocognitive features of the schizophrenia prodrome to the bipolar prodrome.

BACKGROUND There is an increased interest in early intervention strategies for severe mental disorders with hopes of mitigating the emergence and impact of the illness. Individuals at clinical high-risk (CHR) for schizophrenia have been primarily identified by the presence of attenuated positive symptoms. Although bipolar disorder and schizophrenia may have overlapping etiologies, few studies have investigated the potential prodrome in bipolar disorder. We sought to determine if there is a prodrome to bipolar disorder and if clinical or neurocognitive measures could distinguish between the bipolar and schizophrenia prodromes. METHODS We examined subjects who were initially identified as CHR for schizophrenia during the prodromal phase of the illness and followed them prospectively. Unexpectedly, eight subjects developed bipolar disorder. Baseline data from subjects who eventually developed bipolar disorder (pre-BP; N=8), schizophrenia or a psychotic disorder (pre-SZ; N=24) and a non-converter comparison group (NCC; N=115) were compared. RESULTS The pre-BP and pre-SZ groups did not differ on attenuated positive symptom severity, global measures of functioning or on the global neurocognitive score. Compared to NCC individuals, both pre-BP and pre-SZ patients reported more severe attenuated positive symptoms and were more likely to be on antipsychotic medication at baseline. The pre-SZ group had a significantly lower current IQ and was significantly more impaired than the NCC group on the overall neurocognitive score. CONCLUSIONS This study provides preliminary support for a bipolar prodrome, which may be indistinguishable from the schizophrenia prodrome based on clinical and neurocognitive measures currently used in high-risk schizophrenia programs.