Early detection of schizophrenia: current evidence and future perspectives

RECONSTRUCTING THE EARLY COURSE OF SCHIZOPHRENIA AND ITS CONSEQUENCES

In the ABC Schizophrenia Study (3), we studied a population- based sample of 232 patients with a first episode of schizophrenia spectrum disorder (ICD-9: 295, 297, 298.2, 298.4), aged 12 to 59 years, compared with age- and sexmatched healthy individuals from the study area. The patients were assessed using the Interview for the Retrospective Assessment of the Onset and Course of Schizophrenia and Other Psychoses (IRAOS) (17). On the basis of these data, we defined two stages in the early illness course, which have implications for risk identification and intervention: a) a prepsychotic prodromal stage, from the first sign of illness until the first psychotic symptom, with a mean duration of 4.8 years (median 2.33); b) a psychotic prephase, from the first positive symptom until first admission, with a mean duration of 1.3 years (median: 0.8 years), 1.1 years until the climax of the first episode plus 2 further months until first admission. Lower medians than means reflect a preponderance of shorter durations. Eighteen percent of the cases had an acute type of onset of four weeks or less, 15% a subacute type of four weeks to one year, and 68% a chronic type of one year or more. Only 6.5% of onsets occurred with positive symptoms alone (18).

Table 1 gives an overview of selected studies on the duration of untreated illness (DUI) and/or untreated psychosis (DUP). Results on DUI differ more markedly, because of the difficulty of precisely defining illness onset and the lack of suitable assessment instruments in a majority of studies. In about three-quarters of cases, schizophrenia onset occurs with slowly mounting depressive and negative symptoms involving increasing functional impairment and cognitive dysfunction (27).

DUP, assessed in a great number of studies, depends on the conspicuousness and velocity of symptom accumulation, help-seeking behaviour and the availability of appropriate mental health services (28-30). DUP can be shortened by improving the last two factors. An awareness programme educating and alerting both the population and health services of a region in Norway presumably helped to reduce DUP from 2.5 years to 0.5 years (31).

In a majority of studies, a prolonged DUP turned out to be a predictor of an unfavourable illness course (4,20,32-36). It was associated with a more severe course of the first episode and all the consequences associated with the latter (e.g., greater risks, more inpatient days, higher costs) (35-37). A small number of studies have also reported sustained neuropsychological deficits, higher scores on negative symptoms and disorganization, and an unfavourable functional outcome (38-40). It is still an unsettled question whether a prolonged DUP is also associated with more psychotic relapses, as reported by several authors (32,41), because long-term follow-ups are rare.

Kraepelin (7) assumed that florid bouts of illness (psychotic episodes) lead to a certain amount of irreversible consequences, which he called defects. This construct implies that schizophrenia has a deteriorating course consisting of downward steps produced by each psychotic episode (42). Reviving Kraepelin's model, Wyatt (43) and Lieberman et al (44) postulated that untreated psychosis might constitute an active morbid process toxic to the brain. That process has to be treated and suppressed early enough, in order to prevent it from becoming chronic (44,45). McGlashan and Johannessen (46) hypothesized that the plasticity of the brain can be preserved by both antipsychotic medication and social stimulation at that sensitive stage. Lieberman et al (44) interpreted the results of a 2-year controlled clinical trial as indicating that the administration of proper doses of olanzapine can halt the process of toxic brain damage.

In our sample of 232 patients with a first illness episode, we also studied the emergence of functional impairment and social deterioration (18,47). Table 2 shows the ten most frequent initial signs of schizophrenia, equally frequent in men and women, except worrying, an item which is also more frequent in women in general population studies. The early emergence of indicators of functional impairment, such as trouble with thinking and concentration or loss of energy and social withdrawal, indicates that there is an early risk of social decline.

We chose six social roles indicating the attainment of a basic social status in adulthood in most cultures: finished school education, finished occupational training, regular employment, own income, own accommodation and marriage or stable partnership. Table 3 shows that, at the time of illness onset, persons who will later become psychotic do not yet differ from their sex-matched healthy peers. At first admission, however, some significant differences clearly indicate a trend of social disadvantage in the early illness course. With regard to the social roles accomplished at a young age, e.g. finishing school and occupational training, patients do not differ significantly from controls, because illness onset does not occur frequently enough at that young age. A maximum of social decline occurs in the domain of marriage and stable partnership, indicating deficits in communication and mating behaviour, which were shown to be a powerful risk factor for psychosis by the Swedish (48) and the Israeli (49,50) conscript studies.

In schizophrenia spectrum disorder, the bulk of social decline occurs with the emergence of functional and social impairment in the early illness course. After the remission of the first psychotic episode, the means of the social indicators show no clear-cut trend of either deterioration or improvement in comparison with healthy controls (18,47,51). In the long-term, neuropsychological test results (52,53) tend to be characterized by a plateau rather than progressive deterioration.

Once it was established that the early course of schizophrenia is the most active stage in the overall illness course and produces the bulk of mostly permanent consequences (18,47), attempts of early intervention became to be seen as all the more important.

The first studies tentatively indicating the effectiveness of interventions administered in the early course were published by McGorry et al (54), Lewis et al (55) and Bechdolf et al (56). In the first study, one group of patients at ultra high risk (UHR) were treated with a combination of low-dose risperidone and cognitive-behavioural therapy and a control group with standard therapy over six months. In the second study (55), cognitive-behavioural therapy was compared with a standard treatment. In both studies, UHR was defined, among other criteria, by indicators of attenuated psychotic experience. Consequently, the probands were close to transition to psychosis. At oneyear follow-up, both studies showed significantly fewer transitions to full-blown psychosis in index cases compared with controls. In the third study (56), the intervention consisted of cognitive-behavioural therapy administered at the prepsychotic prodromal stage. The intervention significantly reduced prodromal symptoms and showed a trend to reducing transition to psychosis, but the results need replication, due to the shortness of the followup period and the small sample size.

EARLY RECOGNITION AND DEFINITION OF RISK

Optimal early recognition should allow as many persons at increased risk for psychosis as possible to benefit from early treatment, but that objective involves a serious dilemma: both the prediction of a psychotic episode and its diagnostic discrimination from other disorders will be the more reliable the more criteria based on DSM-IV or ICD-10 categories are fulfilled. It seems that diagnostic and predictive accuracy can only be obtained at the cost of delayed intervention. An inaccurate risk assessment at the early stages of illness would produce a large proportion of false positive cases. This issue has triggered a debate on the ethical aspects involved (57,58), because a premature treatment of schizophrenia risk would cause unnecessary distress and probably also stigma to the patients and their families, while reducing the rate of false positives could exclude a large proportion of people at risk from early treatment.

Basically, there are two solutions to this dilemma: a) enhancing the risk by assessing characteristic premonitory symptoms at a later stage of the prodrome and b) additionally considering premorbid risk factors. Such criteria were included in the definition of UHR (59): a) attenuated and brief limited intermittent psychotic symptoms (BLIPS); b) a loss of 30 points or more in the Global Assessment of Functioning (GAF) score in six weeks, plus a family history of schizophrenia or schizotypal personality. In Melbourne, the proportion of correctly predicted psychosis onsets on the basis of these criteria was about 40% over a period of one year (60). That proportion would probably have been even larger if the period considered had been longer. A psychosis risk enriched in that way, a number needed to treat (NNT) of 4 (54) and the signals of incipient psychosis used are of a magnitude that makes early intervention seem ethically and economically sensible.

Lifetime risk factors (at least one first-degree relative with schizophrenia, pre- and perinatal complications) were also included in the risk definition used in the early recognition and intervention programme of the German Research Network on Schizophrenia (61,62). Further factors indicating a slightly enhanced risk are childhood developmental delays (63), social and communication deficits in adolescence (48,50) and cannabis misuse (27,64,65).

A "clinical" approach to risk enhancement has been used by Klosterkötter et al (5). They studied patients suspected of suffering from schizophrenia who were referred to one of several German university hospitals for diagnostic clarification. From among these persons, 160 probands at risk for schizophrenia were followed up for a mean period of 9.6 years. Seventy-nine developed psychosis according to DSM-IV criteria, with a mean duration of prodromal phase of 5.6 years (5). At inclusion in the study, the authors assessed "basic symptoms" (66,67) by the Bonn Scale for the Assessment of Basic Symptoms (BSABS) (67). These symptoms close to psychosis onset are naturally of a greater discriminatory and predictive power for transition to a full-blown psychosis than unspecific prepsychotic prodromal symptoms. The percentage of correct predictions was 78%, with a negative predictive value of .96 and a positive predictive value of .70. The rate of false positives was very low (20.6%). Such a high predictive power and diagnostic specificity were possible only by studying probands at a highly specific risk during a long period. The advantage of this approach is an optimally low NNT. Its disadvantage is that only a small proportion of atrisk cases in the population, which Warner (57) estimates at 2%, will get a chance of secondary prevention.

Methods of risk enhancement limited to psychotic illness and focusing on early signs of psychosis miss the usually longer prepsychotic prodromal stage, which is frequently accompanied by cognitive and functional impairment and social decline. Many of those who increasingly suffer from serious symptoms and lose their quality of life at the prodromal stage of psychosis go untreated. Phillips et al (68) have stressed the urgent need for bringing to treatment the largest possible proportion of those people who are already suffering from illness-related prodromal symptoms bound to lead to a psychosis or possibly some other serious mental disorder. Awareness programmes can improve helpseeking behaviour and pathways to care. Screening of people at high risk can be accomplished by consecutive filters built in the health care system, as suggested by van Os and Delespaul (69) with reference to Goldberg and Thornicroft (70). The first stage of hierarchical risk enhancement relies on the self-selection of persons consulting primary health services because of mental problems. That requires a screening instrument which permits the identification of persons mainly at a moderate risk. These at-risk persons are then referred to a more detailed examination by means of an early-recognition inventory of a higher discriminatory and predictive power. This stage of risk identification should be located at specialist mental health services or early-intervention centres, which also have at their disposal a battery of neuropsychological tests and neurobiological instruments. Such a multi-stage early recognition inventory used in a consecutive system of filters is undergoing prospective validation in the German Research Network on Schizophrenia and at the same time in Italy and Israel.

THE PRODROMAL STAGE IN SCHIZOPHRENIA AND DEPRESSION

In a prospective population study of 3021 probands aged 14 to 24 years, followed up over 3 to 5 years (followup: N=2538), Wittchen et al (71) demonstrated that the risk for psychosis onset increases with an increase in depression (OR: 2.9) or anxiety (OR: 1.9) and decreases when depression (OR: 0.69) or anxiety (OR: 0.61) decreases. We postulated that there must be a consecutive-functional association between these two syndromes (27).

In order to explore what the two disorders have in common and what distinguishes them, we studied a population- based subsample of 130 first-admission cases of schizophrenia spectrum disorder aged 12 to 59 years, individually matched to 130 first-admission cases with a diagnosis of moderate (F32.10, 32.11) or severe (F32.2, 32.30, 32.31) depression and 130 healthy controls from the population of the study area.

Patients at first admission and controls were assessed retrospectively by the IRAOS and additionally by the Present State Examination (PSE) (72), the Scale for the Assessment of Negative Symptoms (SANS) (73), the Psychological Impairments Rating Schedule (PIRS) (74), and the Disability Assessment Schedule (DAS) (75,76), to gather data on positive and negative symptoms, functional impairment and social disability both at first admission and 6-month follow-up. In 81% of the patients with schizophrenia and 80% of the depressed patients, the illness course preceding first contact was more or less natural, i.e., uninfluenced by an antipsychotic or antidepressive medication. The interval from the first sign of illness to first admission was significantly longer in depression (7.3 years) than schizophrenia (5.3 years). As Table 4 shows, schizophrenia and depression share eight of the ten most frequent initial symptoms, with fairly similar ranks. Significant differences are limited to nervousness/restlessness and blunted affect, more frequent in schizophrenia, and depressed mood, more frequent in depression. A diagnostic distinction does not seem feasible at this early stage.

With the exception of dissocial behaviour, the period prevalence of the ten most frequent symptoms in the early course of schizophrenia and depression (from onset to first admission) differs significantly from healthy controls in the same period of age (Table 5), but five symptoms have an almost equal prevalence in the two disorders.

Thus, the two illness groups are similar to each other, but clearly distinguishable from healthy controls, in the early course. We interpreted the core symptoms of schizophrenia and depression at the prodromal stage (depressive and negative symptoms and functional impairment) as a common prodromal core syndrome. In both disorders that core syndrome frequently persists also in the further course (77).

The early social course, as based on social behaviour and social role attainment assessed by the DAS, indicated considerable social impairment at this early stage. Two years before first admission, more than 50% of the patients in both illness groups differed significantly from controls, showing DAS scores >2 in the domains of work performance, household activities, communication and leisure activities.

In order to gain a precise picture of symptom accumulation, we depicted the onset of all 65 IRAOS symptoms on the basis of five clinical categories, on a time axis until first admission (Figure 1). In both disorders, onset is frequently marked by depressive symptoms. They are followed and in part overlapped by a large number of negative symptoms. A clear-cut difference becomes visible only after the onset of and a steep increase in psychotic symptoms in the last time window, on average one year before first admission. In severe depression, the few psychotic symptoms do not show any increase over time.

These results strongly suggest that severe depression and schizophrenic psychosis share a prepsychotic prodromal stage at which it is hardly possible to distinguish them reliably. The aim of early intervention at the prepsychotic prodromal stage is to alleviate depressive and negative symptoms, functional impairment and its social consequences by cognitive-behavioural therapy and social skills training (55,61). There is no indication for antipsychotic pharmacological treatment until psychotic symptoms occur.

ASSESSMENT INSTRUMENTS FOR DETECTING PEOPLE AT RISK

Assessment instruments for detecting people at risk for schizophrenia include screening instruments and earlyrecognition instruments (78). The aim of screening instruments is to detect in the population the largest possible proportion of persons at an increased risk. These are short interviews mostly designed for use with people seeking help because of mental problems in primary health services. Some are also designed as self-rating questionnaires. A more indepth risk assessment at specialist mental health services or early intervention centres requires detailed scales for measuring a prodromal syndrome or an incipient psychotic episode. Some instruments also assess subjective distress caused by the symptoms, symptom severity and course over time.

CONCLUSIONS

Research into the early course of schizophrenia has identified a prepsychotic prodromal stage (mean duration: 4.8 years) and a psychotic prephase (mean duration: 1.3 years). Comparisons of individually matched samples have demonstrated prodromal symptoms common to schizophrenia and moderate to severe depression. It is not until positive symptoms emerge that psychosis and mood disorders become distinguishable from each other. The onset of both disorders is marked by depressive mood. In a risk period of 3 to 5 years, an increase in depression and anxiety as prodromal symptoms is associated with a higher, their decrease with a lower risk for psychosis. Depression can be seen as an integral part of the disease process leading to psychosis. In both disorders the prodromal stage early produces functional impairment and related social consequences. Hence, early intervention is of great public health relevance and gives hope of ameliorating illness symptoms and the consequences involved.

Early intervention is targeted at manifest symptoms and not at the underlying, still unknown disease process. Cognitive- behavioural therapy at the prepsychotic prodromal stage seems to favourably influence the short-term illness course. In the psychotic prephase, a combination with low-dose antipsychotics seems to have some efficacy. Long-term effects have not yet been demonstrated.

The aim of early recognition by the instruments discussed in this paper is to permit the identification of the largest possible proportion of at-risk persons as early as possible and their referral to appropriate treatment. Early recognition centres should focus not only on the psychotic prephase and risk for schizophrenic psychosis, but also on providing early recognition and intervention in mood disorders.