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Early Antecedents and Detection of Schizophrenia

Early Antecedents and Detection of Schizophrenia

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Figure 2

Given the often irreversible deconstruction of a life that psychosis can bring to individuals and their families, strategies for early detection and intervention have become a focus of increasing interest. These strategies aim to prevent disorder by identifying, tracking, and treating the clinical antecedents to psychosis. In this article, we review the underlying rationale for this direction, the evidence that prevention of psychosis is possible, what psychosis-risk states look like clinically, what treatment studies show to date, and the risks and benefits of early intervention. We also outline what psychiatrists can do clinically, given what we currently know.

Early stages of psychosis

Figure 1 illustrates the typical emergence of the early stages of psychosis as it unfolds during adolescence/early adulthood. As clinicians, we usually encounter and treat patients well after the first episode, when chronic deficits in functioning are already in place and positive symptoms wax and wane with the vicissitudes of treatment adherence. However, the emphasis needs to shift to the earliest stages of this process and on how antecedent genetic vulnerability and developmental liability are initially expressed as psychopathology during the final major stage of neurodevelopment in adolescence/young adulthood.

As schematized, premorbid normality gives way to declines in school, work, and social functioning. Soon thereafter, psychological symptoms emerge that are precursors to the positive symptoms that later become the basis of a DSM diagnosis of psychosis. At this earliest stage, however, these symptoms are not as prominent or disabling as they are in full-blown psychosis, and typically they are labeled “prodromal” or “psychosis-risk” symptoms and functional deficits.

At some point, these symptoms and deficits become prominent enough to meet standard diagnostic criteria, but medical recognition and treatment usually do not occur until weeks, months, or even years later. This interval is known as the duration of untreated psychosis (DUP), which has become a major target of early intervention strategies.1

The neurobiological processes underlying this emerging clinical picture are more hypothetical. One model is illustrated in Figure 2.2 This model postulates that psychosis is the product of inadequate cortical synaptic connectivity that typically emerges or is “expressed” in the final adolescent/young adult stage of neurodevelopment, when cortical synapses are normally pruned.

Two paths to this connection deficit are schematized in Figure 2. In the first path, synaptic density is already attenuated in childhood from genetic liabilities or perinatal insults such that the normal pruning of adolescence drives connectivity below the psychosis threshold density. The second path starts with normal childhood cortical volume, but then pathologically aggressive synaptic pruning in adolescence leads to psychosis. The details and the mechanisms of this process are not the focus of this article. However, Figure 2 is presented to illustrate the hypothesis that psychosis is a product of aberrant neurodevelopment and that for any intervention to be truly preventive, it must somehow slow down, halt, or reverse this trajectory—a daunting task indeed!

Reducing DUP

Initial efforts toward secondary prevention have focused on the first psychotic episode and reducing the DUP—the period between onset and first treatment. Dozens of studies have demonstrated a robust correlation between delayed first treatment (longer DUP) and poorer outcomes.3,4 However, it was not until the Early Treatment and Intervention in First-Episode Psychosis (TIPS) series of studies over the past 12 years that any effort had been made to actually change the DUP and measure its effect on outcome. The hypothesis is that a shorter DUP in first-episode psychosis would be associated with better outcomes.4

The TIPS study is complex and ongoing, but the core findings are that the DUP can be significantly reduced through educational campaigns about psychosis aimed at practitioners, schools, and the general public.5 In the study, such an effort was engineered in a single Scandinavian health care sector. The outcomes for a 4-year sample of first-episode psychotic patients from this sector were compared with the outcomes for 4-year first-episode samples from 2 control health care sectors that made no effort to reduce the DUP.

The target sector achieved a significantly shorter DUP than the control sectors. Baseline and 1-, 2-, and 5-year outcomes have been significantly better in the experimental sector sample, especially with regard to negative symptoms and functional deficits (the core chronic symptoms of schizophrenia).6-9 All of the study sites in the TIPS series used a standard treatment battery of antipsychotic medication, individual therapy, and family therapy. Therefore, sector outcome differences were most likely related to the different timing of the same treatments, ie, earlier treatment resulted in a genuinely healthier cohort of patients.

We regard this as preliminary but compelling evidence that earlier diagnosis and earlier administration of standard treatments in the course of first-episode psychosis may actually truncate the neurobiological process(es) that generates chronicity (eg, excessive pruning). The result requires replication, but we and our Scandinavian colleagues are excited that the data strongly endorse the validity and preventive potential of early detection and treatment of psychosis.

Moving backward

If treatment earlier in a first episode can improve prognosis, could treatment before onset in the prodromal phase of the disorder actually delay or prevent onset? That question, raised by TIPS, has attracted increasing attention in early-psychosis treatment centers for more than a decade. More recently, the prevention field has been moving further backward, or earlier, in the temporal course of disorder development to the psychosis-risk or the prodromal phase of psychosis.

The study of the preventive potential of pre-onset or psychosis-risk intervention requires a common and reliable diagnosis of a risk syndrome with which to construct samples that we can track and treat and that can be replicated by independent clinical investigators. Yung and McGorry10 created the Comprehensive Assessment of At-Risk Mental States (CAARMS), a structured interview for diagnosing the psychosis-risk syndrome. Our team at Yale developed the Structured Interview for Psychosis-Risk Syndromes (SIPS); this tool is used to rate the severity/frequency of key prodromal symptoms and can be used to determine the presence or absence of several psychosis-risk syndromes. It can also be used to estimate the severity of these symptoms and syndromes, including the boundary of transition from the prodrome to psychosis, called “conversion.”11

The interrater reliability of the SIPS is satisfactory.12 Moreover, the SIPS has proved to be a valid predictor of psychosis insofar as psychosis developed over the next 2.5 years in approximately 33% of a large sample of treatment-seeking persons meeting SIPS criteria.12,13 In essence, approximately 1 of 3 persons who met an SIPS prodromal diagnosis became psychotic, which amounts to a risk for psychosis that is more than 400 times the risk for the average individual. Some of the remaining two-thirds of the sample who met an SIPS prodromal diagnosis and in whom psychosis did not develop remained prodromally symptomatic and eventually met criteria for schizotypal personality disorder; in others, Axis I disorders, such as depression, developed; and in many, prodromal symptoms remitted with time without sequelae (J. Addington et al, unpublished data, 2010).


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