Christopher W. Smith

Generalized and specific neurocognitive deficits in prodromal schizophrenia.

BACKGROUNDnNeurocognitive 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.nnnMETHODSnSubjects 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.nnnRESULTSnAt 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.nnnCONCLUSIONSnVerbal 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

BACKGROUNDnRetrospective 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.nnnMETHODSnEighty-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.nnnRESULTSnSocial 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.nnnCONCLUSIONSnNegative 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.

Spatial working memory deficits in adolescents at clinical high risk for schizophrenia

Identifying endophenotypic markers is crucial to schizophrenia research for finding appropriate preventive strategies. Working memory (WM) deficit has been suggested as a marker for schizophrenia but its presence in adolescents at high risk is understudied. We piloted a test of spatial WM function in adolescents at clinical high risk (CHR) for schizophrenia and in age- and IQ-matched low-risk control subjects. CHR adolescents showed deficits in spatial WM compared with controls but showed intact performance on a non-WM-demanding spatial control task. Although based on a small pilot study, the results strongly suggest that WM deficit may be a risk factor for psychosis.

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

BACKGROUNDnStress 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.nnnMETHODSnThirty-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.nnnRESULTSnSalivary 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.nnnCONCLUSIONSnCortisol 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.

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.

OBJECTIVEnThe 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.nnnMETHODSnAs 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.nnnRESULTSnProgression 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).nnnCONCLUSIONSnResults 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.

Treatment of the Schizophrenia Prodrome

A series of rapidly emerging research events has generated both optimism and concern about the administration of antipsychotic medication prior to the onset of psychosis: hope that early intervention will lead to the prevention of fullblown schizophrenia, but concern that this belief may be premature. Although the supporting research is encouraging, it is still in its infancy. The handful of early findings (1–3) are encouraging, but are in no way conclusive, and the possibility of prevention remains open. In this chapter, we discuss both the promise and the problems characterizing this area of research. We begin by addressing two very preliminary questions: (1) Why is schizophrenia, arguably the most severe and difficult to treat of the mental illnesses, considered preventable? and (2) Why does pharmacological intervention during the prodromal phase of schizophrenia appear justified or even acceptable as a starting point in prevention programs? We discuss the evidence that supports the use of early pharmacotherapy as well as some of the controversies that have emerged in response to the early clinical interventions. We conclude by reporting the early treatment findings emerging from the Hillside Recognition and Prevention (RAP) program, which has attempted to integrate a highrisk research methodology within a treatment framework and has, as a result, adopted a somewhat different strategy than most of the other prodromal studies now under way.

Attention deficits in the development of schizophrenia: Recent evidence from genetic high-risk and prodromal studies

Schizophrenia is a complex, heterogeneous disorder marked by a range of psychopathologic features, from positive and negative symptoms to deficits in social and occupational functioning. Impaired cognition also is a core component of schizophrenia. Understanding the role of cognitive deficits in the developmental processes leading to the full illness will clarify its causes and possible prevention. Attention, especially as measured by continuous performance tests, is a well-studied cognitive domain associated with schizophrenia. In this review, the most recent findings about attention dysfunctions measured in affected patients, their relatives (including genetically at-risk offspring and young siblings) and more recently, in young adults in the prodromal (or prepsychotic stage) of illness, are summarized and evaluated.