Danielle McLaughlin

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.

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.

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.

Predictors of remission, schizophrenia, and bipolar disorder in adolescents with brief psychotic disorder or psychotic disorder not otherwise specified considered at very high risk for schizophrenia.

OBJECTIVE The aim of this study was to examine predictors of diagnostic and symptomatic outcome in adolescents with either psychotic disorder not otherwise specified (PsyNOS) or brief psychotic disorder (BrPsy) followed in a schizophrenia prodromal program. METHODS As part of a naturalistic study of adolescents considered at clinical high risk for schizophrenia, 26 youths (mean age, 15.9 +/- 2.6 years, 65.4% male) with psychosis not fulfilling criteria for schizophrenia/schizoaffective disorder and diagnosed with PsyNOS or BrPsy were evaluated for predictors of diagnostic and symptomatic outcome after at least 6 (mean, 22.8 +/- 19.4) months follow up. RESULTS Progression to schizophrenia, schizoaffective disorder, or psychotic bipolar disorder (n = 10, 38.5%) was predicted by fulfilling criteria for schizotypal personality disorder at baseline (p = 0.046). Development of schizophrenia/schizoaffective disorder (n = 7, 27.0%) was associated with worse executive functioning (p = 0.029) and absence of anxiety disorders (p = 0.027). Conversely, progression to bipolar disorder (n = 4, 15.4%), with (n = 3, 11.5%) or without (n = 1, 3.8%) psychosis, was associated with the presence of anxiety disorders (p = 0.014). Remission of all psychotic as well as attenuated positive or negative symptoms (n = 5, 19.4%) was predicted by Hispanic ethnicity (p = 0.0047), an initial diagnosis of BrPsy (p = 0.014), longer duration of antidepressant treatment (p = 0.035), and better attention at baseline (p = 0.042). CONCLUSIONS Results from this preliminary study suggest that patients with PsyNOS, BrPsy, or schizotypal personality disorder features in adolescence should be followed as separate risk groups in prodromal studies of schizophrenia and bipolar disorder. Executive function deficits and absence of anxiety disorders may be risk markers for schizophrenia, while presence of anxiety disorders may be linked to bipolar disorder risk. After achieving full remission, patients with sudden onset of psychosis and brief episodes could once be given the option of careful, supervised treatment discontinuation. The potential salutary effect of antidepressants during the psychotic prodrome and presence of characteristics differentiating patients at risk for schizophrenia or bipolar disorder should be investigated further.

Contributions of early cortical processing and reading ability to functional status in individuals at clinical high risk for psychosis

BACKGROUND There is a growing recognition that individuals at clinical high risk need intervention for functional impairments, along with emerging psychosis, as the majority of clinical high risk (CHR) individuals show persistent deficits in social and role functioning regardless of transition to psychosis. Recent studies have demonstrated reduced reading ability as a potential cause of functional disability in schizophrenia, related to underlying deficits in generation of mismatch negativity (MMN). The present study extends these findings to subjects at CHR. METHODS The sample consisted of 34 CHR individuals and 33 healthy comparison subjects (CNTLs) from the Recognition and Prevention (RAP) Program at the Zucker Hillside Hospital in New York. At baseline, reading measures were collected, along with MMN to pitch, duration, and intensity deviants, and measures of neurocognition, and social and role (academic/work) functioning. RESULTS CHR subjects showed impairments in reading ability, neurocognition, and MMN generation, relative to CNTLs. Lower-amplitude MMN responses were correlated with worse reading ability, slower processing speed, and poorer social and role functioning. However, when entered into a simultaneous regression, only reduced responses to deviance in sound duration and volume predicted poor social and role functioning, respectively. CONCLUSIONS Deficits in reading ability exist even prior to illness onset in schizophrenia and may represent a decline in performance from prior abilities. As in schizophrenia, deficits are related to impaired MMN generation, suggesting specific contributions of sensory-level impairment to neurocognitive processes related to social and role function.

Cognitive changes following antidepressant or antipsychotic treatment in adolescents at clinical risk for psychosis

BACKGROUND Improving neurocognitive abilities is a treatment priority in schizophrenia, however, pharmacological efforts to enhance deficits after illness onset have resulted in quite modest results that are of questionable clinical meaningfulness. Individuals at clinical risk for psychosis demonstrate neurocognitive impairments intermediate to the level of deficits observed in schizophrenia and normative performance, suggesting that a similar magnitude of improvement might result in more clinically meaningful change. In this study, we examined neurocognitive changes after six months of treatment in adolescents with clinical signs of risk for psychosis. METHODS Adolescents who were referred to the Recognition and Prevention program, which is focused on treatment and research for individuals at a clinical high risk for psychosis, were followed in a naturalistic treatment design. At study entry and approximately six months after starting treatment, we examined neuropsychological functioning and clinical symptoms for patients who remained off medications (OFF; N=27), started selective serotonin reuptake inhibitor antidepressant medication (AD; N=15), or started a second-generation antipsychotic medication (AP; N=11) within three months of study entry. We also included a locally recruited healthy comparison group (HC; N=17). RESULTS The clinical groups were not significantly different on baseline demographic, neurocognitive, or clinical symptom measures. Linear mixed models were used to examine cognitive changes, with time between assessments, depressive symptom severity, and attenuated positive symptom severity as random effects. Group by time effects were observed in sustained attention and verbal learning, with the AD group showing a more favorable response than the AP group. The AD groups improvements were not significantly different from the HC or OFF group. CONCLUSION Early intervention for those at clinical high risk for psychosis may result in neurocognitive improvements. These improvements were observed for those prescribed antidepressant, but not antipsychotic medications even though the groups did not differ in clinical symptom severity or treatment response.

Functional Capacity Assessed by the Map Task in Individuals at Clinical High-Risk for Psychosis

OBJECTIVES Recent studies have recognized that signs of functional disability in schizophrenia are evident in early phases of the disorder, and, as a result, can potentially serve as vulnerability markers of future illness. However, functional measures in the psychosis prodrome have focused exclusively on real-world achievements, rather than on the skills required to carry-out a particular real-world function (ie, capacity). Despite growing evidence that diminished capacity is critical to the etiology of the established disorder, virtually no attention has been directed towards assessing functional capacity in the pre-illness stages. In the present study, we introduce the Map task, a measure to assess functional capacity in adolescent and young-adult high-risk populations. METHODS The Map task was administered to 609 subjects at Clinical High-Risk (CHR) for psychosis and 242 Healthy Controls (HCs) participating in the North American Prodrome Longitudinal Study (NAPLS2). Subjects were required to efficiently complete a set of specified errands in a fictional town. RESULTS CHR participants showed large impairments across major indices of the Map task, relative to the HCs. Most importantly, poor performance on the Map task significantly predicted conversion to psychosis, even after adjusting for age, IQ, clinical state, and other potential confounders. CONCLUSIONS To the best of our knowledge, the Map task is one of the first laboratory-based measures to assess functional capacity in high-risk populations. Functional capacity deficits prior to the onset of psychosis may reflect a basic mechanism that underlies risk for psychosis. Early intervention targeting this domain may help to offset risk and independently improve long-term outcome.