Transition to schizophrenia and related disorders: toward a taxonomy of risk

The early detection and prevention of schizophrenia and other psychotic disorders are receiving rapidly growing attention subsequent to the suggestion that poorer outcome is associated with delayed onset of treatment among patients in their first psychotic episode. Although the first generation of so-called "prodromal" research programs has produced encouraging preliminary results, more information is necessary on the conversion rates from prodromal states to schizophrenia in specific samples. Early recognition and prevention strategies require a new taxonomy that classifies subjects by their status of risk of imminent onset of psychosis. Without additional knowledge of the mechanisms through which particular constellations of vulnerability factors, precursors, and prodromal symptoms predict the onset of schizophrenia, it is difficult to judge the effects of existing programs. In this paper, we discuss three sets of issues that will need to be resolved before these preventive programs can be implemented into routine care: (1) optimization of predicting the onset of psychotic disorders; (2) development and evaluation of alternative treatment strategies depending on the presenting risk status; and (3) evaluation of costs and benefits of identifying subjects at risk of psychosis/schizophrenia and receiving a specific preventive treatment.     

The schizophrenia prodrome: treatment and high-risk perspectives

Interest in the prodromal stage of schizophrenia-the stage directly preceding the onset of psychosis-has recently undergone a dramatic increase. To a great extent, this has resulted from the convergence of two very different research traditions. Many treatment researchers have moved from a concern with symptom control to an interest in prevention and view the prodrome as the optimal stage to begin intervention with anti-psychotics. High-risk researchers, who view the identification of accurate risk factors as necessarily preceding preventive programs, have begun to move from the premorbid to the prodromal phase as the most effective starting point. Thus, researchers in both traditions have targeted the schizophrenia prodrome as the most likely gateway to prevention. However, clashes between the two traditions in approaches, methodology and research goals have also led to considerable controversy. Such issues as how best to define the prodrome, what the actual risk for schizophrenia is among prodromal individuals, and what type of medication should be used remain largely unresolved. The Hillside Recognition and Prevention (RAP) Program has been designed to address many of these and related questions. Within a naturalistic treatment framework, the RAP program combines both high-risk and treatment research strategies. Preliminary findings from a 3-year RAP pilot study, for example, suggest that the prodrome is a developmentally complex phase of schizophrenia, that it consists of distinctly different subgroups and that novel anti-psychotics are clearly beneficial for some but not all individuals. Depending upon clinical characteristics and phase of the prodrome, anti-depressants also appear highly effective.     

Can premorbid and prodromal markers associated with psychosis be utilized for early detection and secondary prevention of schizophrenia?

The rationale for identifying markers of latent schizophrenia is the evidence that early treatment speeds remission and lessens long-term deterioration. Unfortunately hovever, although the childhood and adolescence of individual psychotics often reveal premorbid deviations from established norms, while epidemiological studies identify cognitive performance and social adjustment as potential premorbid markers, such signs vary widely and no typical prodrome has been identified. Illness-related events or behaviors are not the only factors precipitating the transition from premorbid to prodrome: educational and socioeconomic status are also involved, it follows that there is a controversy surrounding the secondary prevention of schizophrenia: because of the poor specificity of premorbid and prodromal markers, treating such patients implies thai an unacceptably high proportion of individuals who will not ultimately develop florid schizophrenia will be exposed to stigma of a provisional diagnosis of severe mental illness as well as to the adverse effects of treatment Schizophrenia, therefore, is an aggravated illustration of the dilemmas facing much preventive therapy.     

Early interventions for youths at high risk for bipolar disorder: a developmental approach

In recent decades, ongoing research programmes on primary prevention and early identification of bipolar disorder (BD) have been developed. The aim of this article is to review the principal forms of evidence that support preventive interventions for BD in children and adolescents and the main challenges associated with these programmes. We performed a literature review of the main computerised databases (MEDLINE, PUBMED) and a manual search of the literature relevant to prospective and retrospective studies of prodromal symptoms, premorbid stages, risk factors, and early intervention programmes for BD. Genetic and environmental risk factors of BD were identified. Most of the algorithms used to measure the risk of developing BD and the early interventions programmes focused on the familial risk. The prodromal signs varied greatly and were age dependent. During adolescence, depressive episodes associated with genetic or environmental risk factors predicted the onset of hypomanic/manic episodes over subsequent years. In prepubertal children, the lack of specificity of clinical markers and difficulties in mood assessment were seen as impeding preventive interventions at these ages. Despite encouraging results, biomarkers have not thus far been sufficiently validated in youth samples to serve as screening tools for prevention. Additional longitudinal studies in youths at high risk of developing BD should include repeated measures of putative biomarkers. Staging models have been developed as an integrative approach to specify the individual level of risk based on clinical (e.g. prodromal symptoms and familial history of BD) and non-clinical (e.g. biomarkers and neuroimaging) data. However, there is still a lack of empirically validated studies that measure the benefits of using these models to design preventive intervention programmes.     

Conceptualization of the liability for schizophrenia: clinical implications

Historically, the Diagnostic and Statistical Manual of Mental Disorders (DSM) diagnostic criteria for schizophrenia have emphasized several features, including symptoms of psychosis, a dissociation of symptoms from their etiology, a reliance on clinical symptoms, and a categorical approach to classifying the disorder. Although these emphases are quite useful, they have limitations. We review these here, and stress the importance of incorporating recent data on the genetic /biological and neurodevelopmental origins of schizophrenia into current conceptions of the disorder. We also review "schizotaxia, " which is a concept thai embodies this point of view, occurs before the onset of psychosis, and is hypothesized to represent the liability for schizophrenia. If our hypothesis on this point is correct, the identification of schizotaxic individuals will eventually facilitate the development of prevention strategies by identifying a premorbid (but clinically significant) condition for schizophrenia. Moreover, the identification of biological or neuropsychological components of schizotaxia will provide more specific bases for developing novel treatment interventions. Our initial attempts to develop protocols for the assessment and treatment of schizotaxia are encouraging, and will be reviewed.     

Prevention and early intervention in schizophrenia: facts and visions.

There are large-scale preventive programmes to reduce the risk of death and disability caused by several frequent physical diseases. The primary and secondary prevention of schizophrenia, a disorder entailing many years of life in disability, is still being neglected. Prevention is aimed at reducing the incidence, severity or consequences of the disorder. To find ways of preventive intervention in schizophrenia, the aetiological risk factors must be identified, then eliminated or modified. As possible targets pre-, peri- and postnatal complications, urbanicity and early behavioural risk indicators are discussed. As examples of successful early prevention targeted at risk indicators attempts to prevent depression and violence are considered. The most promising approach at present is secondary prevention focused on early illness course. Based on a controlled retrospective assessment of 232 first illness episodes the course of prodromi, impairments and psychotic symptoms prior to the climax of the first episode is shown. Most of the social consequences occur before the first treatment contact, thus making plain the urgent need for preventive action. Tools sufficiently validated are not yet available for early diagnosis and prediction of psychosis onset at the prepsychotic stage. So intervention has to be based on high-risk inclusion criteria, which exclude large proportions of at-risk persons. Appropriate early intervention at the prepsychotic, prodromal and the early psychotic stage as well as relevant ethical considerations are discussed. The frequency of and distress associated with single psychotic symptoms in the general population are potent predictors of a psychosis. The vision of treating this early illness dimension with third-generation, side-effect-free antipsychotics or of preventing its onset by oestrogen-like substances is discussed.     

Treating early psychosis: who,what, and when?

Early intervention and prevention in schizophrenia is just over 10 years old. The assumption guiding this field is that intervention is likely to be most effective if it begins before psychosis sets in, ie, during the prodromal phase. Although a substantial number of prodromal treatment programs have been initiated around the world, three early programs have generated most of the intervention findings to date: Personal Assessment and Crisis Evaluation (PACE) in Australia, and the Prevention through Risk Identification, Management, and Education (PRIME) and Recognition and Prevention (RAP) programs in the USA. The data suggest that early intervention leads to a reduction in prodromal symptoms and clinical distress. However, prevention of psychosis remains an unresolved question. Other issues include defining who should be treated, with what, and when. In addition, treatment targets associated with functional disability, such as early prodromal negative symptoms and risk factors, continue to emerge. Newly identified targets, in turn, suggest the need for a variety of novel interventions and treatment strategies.     

Early recognition and intervention for schizophrenia

Studies dealing with the prodromal stage of schizophrenia point to the possibility of early detection and early intervention. Major socioeconomic and social consequences are associated with this disorder. The duration of untreated psychosis seems to play an important role in the course of the disease; i.e. a prolonged duration until adequate treatment is obtained correlates to poorer prognosis. Social, cognitive, affective, and structural brain variations appear in the early prodromal stage. Recent early intervention studies show the possibility of reducing transition rates by preventive treatment of patients at a higher risk of psychosis and already manifesting impaired function. In this review, prodromal signs and possibilities for early detection and intervention in schizophrenia are presented.     

Treatment of the schizophrenia prodrome: is it presently ethical?

Although the devastating consequences of schizophrenia have long been known, interest in preventive intervention has only recently emerged. The shift in focus toward early treatment has been encouraged by findings suggesting that the longer psychosis remains untreated, the poorer the prognosis, and by the recent introduction of novel antipsychotic medications with a more benign side effect profile than conventional neuroleptics. In this paper, we argue that interest in prevention has outpaced the necessary scientific and ethical underpinnings for clinical trials involving the schizophrenia prodrome. Specifically, we maintain that the prodromal phase of schizophrenia is, at present, essentially a retrospective construct and that, as a result, the defining signs and symptoms currently in use must be validated in naturalistic, longitudinal studies. In particular, it is essential to establish solid base rates for schizophrenia in prodromal individuals before early treatment can be effectively evaluated. Additional ethical/scientific issues discussed include: (1) the need for an exit strategy (i.e. the determination of when to discontinue treatment in an individual who does not develop schizophrenia), (2) the advisability of pharmacological interventions that specifically target neurocognitive deficits, and (3) the possibility that antidepressant medications may be as effective or more effective, with fewer side effects, than antipsychotic medication for prodromal individuals.     

Predicting outcome in child and adolescent (early onset) schizophrenia and bipolar disorder.

Fifty-nine patients with DSM-III-R early onset (mean, 13.9 years) psychoses of schizophrenia (N = 30) or bipolar disorder (N = 23) were seen at follow-up (mean interval, 5 years; mean age, 19 years). About 50% of the variance in outcome was predictable using stepwise multiple correlation, which has the advantage of eliminating redundancy among variables and giving a quantitative estimate for each predictor. Abnormal premorbid adjustment/personality and degree of recovery after initial hospitalization were the substantial predictors in schizophrenia, whereas in bipolar disorder, they were premorbid adjustment and IQ. Other items such as diagnosis (bipolar or schizophrenia), symptoms, and gender predicted at too low a level to be useful clinically. Though psychosis is necessary for diagnosis, premorbid personality abnormality may be an indicator of an early onset, developmental type schizophrenia with poor prognosis.     

First-episode psychosis: psychopathology, quality of life, and functional outcome

The burgeoning interest in investigating the first episode of schizophrenia and related disorders provides an opportunity to examine how this approach has assisted our understanding of the heterogeneity of psychopathology of this disorder and the trajectories of its outcome. We present a review of relevant literature on categorical versus dimensional perspectives on psychopathology, with special reference to early signs, its relationship with other patient- and system-related characteristics, and the status and determinants of functional outcome and quality of life. The findings from longitudinal studies of the dimensional psychopathology of first-episode psychosis suggest continuity of some psychopathological dimensions from premorbid through prodromal to post-onset phases of psychosis and some aspects of longer-term course. Short-term functional outcome improves after treatment of the first episode, but longer-term outcome remains relatively poor for a substantial proportion of patients and is associated with preadolescent onset, poor premorbid adjustment, poor cognitive functioning, cerebral asymmetry, and negative symptoms during prodromal and post-onset phases. Poor quality of life is related to residual psychopathology, long delays in treatment, and poor premorbid adjustment. The potential effects of improved treatment and/or early intervention on functional outcome and quality of life have not been adequately examined, nor have the interrelationships between predictors and the underlying processes involved in determining variations in outcome. Studies of functional outcome still lack the rigor of operational definitions, choice of specific instruments for measurement, and use of large enough samples to generate meaningful results.     

Phase prodromale du trouble bipolaire

The prodromal phase is generally described as a subsyndromal stage preceding the disease onset. The characterization of such phase founds its main purpose in secondary prevention. Up to now, clinical research relating to this topic in mental health has primarily focus on schizophrenic disorders. Over the last years, some studies have applied similar methods in order to characterize a preclinical phase in bipolar disorders. In spite of the fact that this strategy appears less adequate in bipolar disorders, these studies have demonstrated the existence of prodromal signs in a majority of patients. However, these features appear for the moment neither sufficiently characteristic, nor sufficiently specific to allow the construction of suitable assessment instruments, or to suggest precise guidelines in the management of these subjects. Also, these prodromal features show considerable overlap with other psychiatric disorders, especially attention-deficit hyperactivity disorder (ADHD) and schizophrenia Interestingly, a limited number of studies have looked at the number of patients considered in a prodromal phase of schizophrenia which later developed a bipolar disorder and reported substantial proportions of subjects in this case, further highlighting the obvious bias in favor of schizophrenia in the actual prevention politics. In order to identify potential candidates at a prodromal phase of bipolar disorders that could benefit from early intervention, studies have relied on both high genetic risk and symptoms at the boundary of the actual classification. However, even within such approach, pharmacological treatments have not proven obvious advantage in terms of prevention. It is suggested that adopting a more longitudinal vision of the disease and, given the mean age of onset of bipolar disorder and a fortiori of its prodromal phase, a more developmental perspective of individuals, could help lowering the confusion in this field ; Also, given the considerable overlap in prodromal features between different psychiatric disorders, early detection programs could benefit from implementing approach open to multiple diseases assessment, rather than hyper-specialization in a specific disorder.     

Early and late neurodevelopmental influences in the prodrome to schizophrenia: contributions of genes, environment, and their interactions

Both early (i.e., pre- and perinatal periods) and late (i.e., adolescent period) neurodevelopmental processes are thought to participate in the etiology and pathophysiology of schizophrenia. However, whether markers of these processes would be expected to predict an imminent onset of psychosis, as is hoped in the current generation of prodromal research programs, depends on whether their disruptions result from genetic factors shared by patients and some of their unaffected relatives, nongenetic factors specific to those who manifest the illness phenotype, or combinations of these sets of influences. Here we present recent work deriving primarily from high-risk and family-study (i.e., "genetic high-risk") designs, which provide a framework for investigating the neural changes that may occur proximally to the initial onset of psychosis. This work indicates that some of the alterations in brain function and structure in schizophrenia are primarily genetically mediated and also appear in some of patients' unaffected first degree relatives, while other alterations are present in individuals who manifest the illness phenotype but not in relatives at genetic risk (Cannon et al. 2002a, 2002c; Van Erp et al. 2002). Whereas the primarily genetically mediated deficits shared by at-risk but nonsymptomatic relatives are not likely to show differential change in the premorbid period and may be necessary but clearly not sufficient for the development of psychotic symptoms, the deficits specific to patients who manifest the illness phenotype are good candidates for marking the neurobiological processes associated with the emergence of psychotic symptoms at the time of schizophrenia onset. Preliminary results from longitudinal studies of individuals ascertained initially in a prodromal (i.e., "clinical high-risk") state appear to be interpretable within this framework. A number of questions arising from this line of inquiry need to be addressed in the current generation of prodromal research programs: To what extent do the neural systems affected by early and late neurodevelopmental influences overlap? Is there likely to be a schizophrenia-related disturbance in the processes associated with adolescent brain maturation, or are these maturational processes themselves intact, participating in psychosis onset only indirectly, by promoting a neurobiological context in which the early neurodevelopmental disturbances can be expressed in psychotic symptoms? What pattern of changes observable from in vivo imaging studies is consistent with a reduction in neuropil volume? We develop a framework for addressing these questions and evaluating their implications for understanding the roles of early and late neurodevelopmental influences in the etiology and pathophysiology of schizophrenia.     

How does studying schizotypal personality disorder inform us about the prodrome of schizophrenia?

An increasing emphasis in the schizophrenia literature has been on the prodromal phase of the illness. The study of schizophrenia spectrum illness, including schizotypal personality disorder, has added important insight into the etiology, neuropathology, and treatment of schizophrenia, which can facilitate early identification, intervention, and perhaps prevention of the illness. The heterogeneity of the schizophrenia spectrum makes its definition elusive at best. The primary aim of the Cognitive Assessment and Risk Evaluation Program at the authors’ institution is to combine the current knowledge of clinical and demographic risk factors for schizophrenia with the rapidly emerging data on vulnerability markers, or endophenotypes, that are associated with schizophrenia. The use of brain-based vulnerability markers may help to identify neurobiologically and clinically meaningful subgroups within this heterogeneous population of individuals in the early stages of schizophrenia. Another important aim of the Cognitive Assessment and Risk Evaluation program is to thoroughly assess those individuals who have not converted to psychosis to understand potential protective factors, reduce the rate of false positives, and decrease disability. The current review details a strategy for researching the schizophrenia prodrome by using information gained from research in schizotypal personality disorder.     

Neurobiology and phenotypic expression in early onset schizophrenia

Aim: Early‐onset schizophrenia (onset before adulthood) is a rare and severe form of the disorder that shows phenotypic and neurobiological continuity with adult‐onset schizophrenia. Here, we provide a synthesis of keynote findings in this enriched population to understand better the neurobiology and pathophysiology of early‐onset schizophrenia. Methods: A synthetic and integrative approach is applied to review studies stemming from epidemiology, phenomenology, cognition, genetics and neuroimaging data. We provide conclusions and future directions of research on early‐onset schizophrenia. Results: Childhood and adolescent‐onset schizophrenia is associated with severe clinical course, greater rates of premorbid abnormalities, poor psychosocial functioning and increased severity of brain abnormalities. Early‐onset cases show similar neurobiological correlates and phenotypic deficits to adult‐onset schizophrenia, but show worse long‐term psychopathological outcome. Emerging technological advances have provided important insights into the genomic architecture of early‐onset schizophrenia, suggesting that some genetic variations may occur more frequently and at a higher rate in young‐onset than adult‐onset cases. Conclusions: Clinical, cognitive, genetic and imaging data suggest increased severity in early‐onset schizophrenia. Studying younger‐onset cases can provide useful insights into the neurobiological mechanisms of schizophrenia and the complexity of gene‐environment interactions leading to the emergence of this debilitating disorder.     

Neurobiology and the natural history of schizophrenia

Schizophrenia follows a fairly consistent natural history and longitudinal course of illness, and it can be described in the context of four specific clinical stages-the premorbid, prodromal, deterioration, and chronic/residual stages. Many patients treated in their first episode of schizophrenia respond well to treatment and achieve some symptom remission and level of recovery, but recurrent episodes, often brought on by treatment nonadherence or insufficient treatment, lead to more substantial and lasting neurologic deterioration. This presentation describes the clinical stages of schizophrenia and discusses the possibility for prevention of clinical deterioration with early detection and treatment of the illness and sustained maintenance treatment after episodic remission.     

Characteristics of early psychosis

There is little research on characteristics related to course and prognosis of early-onset psychosis. The present article aims to advance our knowledge of this disorder for the purpose of proper diagnosis and treatment. It focuses on premorbid and prodromal characteristics, treatment history, symptoms and classifications, and differences between subgroups with affective and schizophrenic psychosis. A chart review was constructed to study a group of 129 subjects (12-18 years) with psychotic symptoms referred to the University Medical Center in Utrecht. The group was characterized by early-but nonspecific-treatment, developmental problems (mostly social), and clear prodromal symptoms. Drug abuse, depressive symptoms, and suicidal behavior were also frequent. Male sex, a relatively long prodromal phase, school problems, and drug abuse were more indicative of the schizophrenic subgroup. Introversion was characteristic for boys with schizophrenia. Classifications, however, were not stable. These findings suggest that early recognition of psychosis can be enhanced in health and youth care facilities. Careful examination of the prodromal phase seems helpful to differentiate between schizophrenic and affective psychosis.     

Precursors of schizophrenia

Several likely precursors of schizophrenia have been identified. These range from possibly causative features, such as exposure to perinatal insults, to features that are the effects of an underlying vulnerability, such as abnormal childhood behaviors. Unfortunately none of these precursors is specific enough to be used in identifying individuals for targeted preventive treatment. A more useful strategy is to combine risk factors for psychotic disorders in a population seeking help for psychiatric problems. Thus, individuals who are possibly prodromal are identified. Research into this group has found high rates of onset of psychotic disorders, particularly schizophrenia, within a short time frame. Preliminary treatment trials suggest that symptoms can be reduced and psychosis onset possibly delayed or averted.     

Childhood-onset schizophrenia: premorbid and prodromal diagnostic and treatment histories

OBJECTIVE: There is increasing interest in the possible relationship between the early diagnosis and treatment of schizophrenia during adolescence and improved long-term outcome. This study reviews the premorbid and prodromal diagnostic and treatment histories for childhood-onset schizophrenia, to assess whether early identification and treatment is possible in this school-age group. METHOD: Parents of 17 children with childhood-onset schizophrenia or schizoaffective disorder were questioned retrospectively regarding symptoms, exposure to mental health professionals, diagnoses, and treatments. RESULTS: Initial presenting symptoms clustered around violent aggression and school problems. Age of first recognized psychotic symptoms ranged from 2 to 11 years, followed 2.0+/-2.0 years later by a diagnosis of schizophrenia. Prior to a schizophrenia diagnosis, these children were exposed to stimulants, antidepressants, lower-dose typical neuroleptics, mood stabilizers, alternative treatments, and individual and family therapy. CONCLUSION: Early diagnosis of childhood-onset schizophrenia is met with caution in the psychological and medical community. These children received many diagnoses before schizophrenia or schizoaffective disorder was diagnosed. A diagnosis of schizophrenia or schizoaffective disorder and utilization of effective atypical neuroleptic treatment was delayed until evaluation by a child and adolescent psychiatrist. Obstacles to early identification and treatment are discussed.