Defining high risk populations

Schizotypal personality features

Schizotypal features within some high-risk samples have been found to predict the onset of schizophrenia. In one study, odd beliefs and magical thinking at baseline were salient predictors of psychosis at follow-up (Reference Mason, Startup and HalpinMason et al, 2004). However, it is not clear in this research whether schizotypal personality truly preceded the onset of the psychotic disorder, or if in retrospect these were prodromal manifestations of the illness. In another study, (the Edinburgh High Risk study) participants who developed schizophrenia over the follow-up period had initially higher levels of social withdrawal, social anxiety introversion and odd behaviour (Reference Johnstone, Ebmeier and MillerJohnstone et al, 2005). This is of note as these participants were not presenting to a clinical service, but rather were identified through relatives affected by psychotic disorders. However, the concept and measurement of schizotypy requires further examination, as items consist of a mixture of positive psychotic-like experiences, magical thinking, and negative symptoms, which make these findings difficult to interpret.

Positive psychotic phenomena

Attenuated or sub-threshold psychotic symptoms form the basis of most ultra-high risk and prodromal intake criteria in centres throughout the world. Several individual psychotic-like symptoms have also been found to be predictive of transition to full-blown psychotic disorder, including unstable ideas of reference and visual and auditory perceptual disturbances (Reference Klosterkotter, Hellmich and SteinmeyerKlosterkotter et al, 2001; Reference Mason, Startup and HalpinMason et al, 2004). Elevated scores on measures of unusual thought content, suspiciousness, perceptual disturbance and conceptual disorganisation (for example the Brief Psychiatric Rating Scale (BPRS) positive symptoms scale) have similarly been found to be significant predictors of psychosis at 12-month follow-up (Reference Yung, Phillips and YuenYung et al, 2003; Reference Haroun, Dunn and HarounHaroun et al, 2006). This is not surprising as the onset of psychosis is not a qualitative change from the sub-threshold state, instead requiring the worsening and persistence of these symptoms rather than any acquisition of new phenomena or other changes. However, it may be that some sub-threshold psychotic symptoms or psychotic-like experiences are more likely to progress than others, and some may be more likely to be associated with functional decline and poor outcome (Reference Yung, Buckby and CottonYung et al, 2006, Reference Yung, Stanford and CosgraveYung et al, 2006).

Negative symptoms

High levels of baseline negative symptoms have been observed in several ultra-high risk or prodromal samples (Reference Lencz, Smith and AutherLencz et al, 2004; Yung et al, Reference Yung, Phillips and Yuen2003, Reference Yung, Phillips and Yuen2004), despite not being part of the standard inclusion criteria. Symptoms which have been found to be predictive of psychosis include impaired concentration and attention, subjectively abnormal emotional experiences, impaired energy and impaired tolerance to stress (Reference Yung, Yuen and McGorryYung et al, 2005), marked impairment in role functioning, anhedonia and asociality (Reference Mason, Startup and HalpinMason et al, 2004), blunted affect (Reference Mason, Startup and HalpinMason et al, 2004; Reference Yung, Yuen and McGorryYung et al, 2005) and social withdrawal (Reference Johnstone, Ebmeier and MillerJohnstone et al, 2005; Reference Haroun, Dunn and HarounHaroun et al, 2006). These are of interest as they may reflect an underlying abnormality, particularly in schizophrenia and may be associated with cognitive changes.

Basic symptoms

Basic symptoms overlap with negative symptoms and are regarded by some as the subjective manifestation of negative symptoms (Reference Klosterkotter, Schultze-Lutter and GrossKlosterkotter et al, 1997). Thus many of the subjectively defined negative symptoms above could also be seen as basic symptoms. The Cologne Early Recognition (CER) project examined the predictive validity of clusters of basic symptoms in a sample of patients referred to five German psychiatric out-patient services for diagnostic clarification, on the basis of suspected incipient schizophrenia. The cluster of thought, language, perception and motor disturbances was found to have good predictive ability in a receiver operator analysis (ROC) analysis (Reference Klosterkotter, Hellmich and SteinmeyerKlosterkotter et al, 2001), such that having any five of the 35 items pertaining to these symptoms at baseline predicted onset of schizophrenia after a mean follow up of 9.6 years (specificity=0.84, sensitivity=0.56, positive predictive value=0.77 and negative predictive value=0.66). Therefore, 77% of those with five or more symptoms of thought, language, perception or motor disturbances at baseline went on to develop schizophrenia. However, that participants in this study were all suspected of having emerging schizophrenia limits the generalisability of the results to community samples or even cohorts of help-seekers who are not suspected of being prodromal. Again these basic symptoms are of interest as they may reflect a fundamental brain abnormality in schizophrenia.

Depression, anxiety and distress

Depression has been found to be a significant predictor of psychosis in ultra-high risk groups (Reference Yung, Phillips and YuenYung et al, 2003; Reference Johnstone, Ebmeier and MillerJohnstone et al, 2005). Indeed in community samples, individuals who experience distress or depression related to their psychotic-like experiences are more likely to seek help compared to their counterparts without such accompanying symptoms (Reference Hanssen, Krabbendam and de GraafHanssen et al, 2005; Reference Krabbendam, Myin-Germeys and HanssenKrabbendam et al, 2005). Distress and depression in relation to psychotic experiences have also been found to be associated with poor psychosocial functioning (Reference Yung, Buckby and CottonYung et al, 2006, Reference Yung, Stanford and CosgraveYung et al, 2006). These findings have prompted researchers to propose that distress, anxiety, depression and other forms of affective disturbance may play a major role in determining whether young people with psychotic symptoms progress to develop psychotic disorder (Reference Escher, Romme and BuiksEscher et al, 2002; Reference Freeman and GaretyFreeman & Garety, 2003; Reference Broome, Woolley and TabrahamBroome et al, 2005).

Poor functioning

Poor functioning at intake predicted onset of psychosis in several separate ultra-high risk cohorts (Yung et al, Reference Yung, Phillips and Yuen2003, Reference Yung, Buckby and Cotton2006, Reference Yung, Stanford and Cosgrave2006; Mason et al, Reference Mason, Startup and Halpin2004, 2006). This may indicate that a deterioration process, and actual onset of psychotic disorder, has already begun in those ultra-high risk subjects with poor functioning. However, the process may be more dynamic than this; young people with more functioning may be less able to cope with psychotic experiences, more susceptible to depression and distress, more likely to use substances and have fewer social supports than their better functioning counterparts. Hence a vicious cycle may develop in which psychotic experiences worsen in response to these factors until eventually the threshold is crossed and disorder is deemed to have begun.

Substance use

Prospective studies suggest that substance use can contribute to the onset of schizophrenia in individuals, irrespective of an identified risk for illness (e.g. Reference ThornicroftThornicroft, 1990). The evidence to date is most consistent for cannabis use (Reference ZammitZammit, 2002). An association between cannabis use and increased likelihood of psychotic relapse has also been described (Reference Linszen, Dingemans and LeniorLinszen et al, 1994), as has an association between cannabis use and increased levels of psychotic experiences in non-clinical general population surveys (Reference Johns, Cannon and SingletonJohns et al, 2004).

The role of cannabis in the onset of psychosis in ultra-high risk or prodromal groups is therefore important to investigate. The longitudinal studies in this area report contrasting findings. For example, a history of substance misuse was present in significantly more subjects who developed psychosis in the Haroun et al (Reference Haroun, Dunn and Haroun2006) sample, although, contrary to expectations, neither cannabis use nor dependence in the year prior to contact with services was associated with a higher risk of developing psychosis over the following year in the PACE cohort (Reference Phillips, Curry and YungPhillips et al, 2002a ). The PACE sample, however, included mainly help-seeking individuals, who may not be typical of the population of people at risk of psychosis. Furthermore, individuals with high levels of cannabis use may be less motivated to seek treatment than our subjects. In the Edinburgh High Risk study, those who used cannabis or other illicit drugs were more likely to have psychotic-like symptoms at baseline (Reference Miller, Lawrie and HodgesMiller et al, 2001), although no longitudinal data examining substance use as a risk factor for transition to psychosis in this cohort is available. Given the contrasting results to date, further research is required within prodromal and ultra high risk samples to clarify the role of cannabis as a risk factor for the onset of psychosis.

Stress

Stressful life events may precede onset of psychotic illnesses (Reference Bebbington, Wilkins and JonesBebbington et al, 1993) and psychotic relapses in established disorders (Reference Hirsch, Bowen and EmaniHirsch et al, 1996); this has led to the hypothesis that adverse life experiences may actually precipitate onset of psychotic episodes in vulnerable individuals. Furthermore, it has been suggested that minor life events or day-to-day hassles may cause more stress than major, although infrequent, events such as deaths or separations (Reference Malla and NormanMalla & Norman, 1992). It is also likely that it is the subjective experiences of stress, rather than stressful events per se, that may be relevant to outcome. For example, Myin-Germeys et al (Reference Myin-Germeys, van Os and Schwartz2001) found that individuals with psychotic illnesses reacted with more intense negative affect to subjective appraisals of stress in their daily life than healthy controls, suggesting a difference in tolerance to stress between the groups. Thus the experience of stressful or distressing events and the inability to adequately cope with them may affect the worsening of psychotic symptoms and the development of psychotic disorder. Among prodromal and ultra-high risk cohorts, an association at baseline between psychotic-like symptoms and lifetime experience of major stressors has been reported (Reference Miller, Lawrie and HodgesMiller et al, 2001), and a significant association was found between ‘impaired tolerance of normal stress’ and psychosis onset in the PACE cohort (Reference Yung, Yuen and McGorryYung et al, 2005). A longitudinal study in the PACE sample examining subjectively assessed stress to objective measures including cortisol levels is discussed below.

Neurocognitive

Cognitive deficits are recognised as one of the core features of schizophrenia and have been associated with functional outcome (Reference GreenGreen, 1996). Recent research has attempted to detect the presence of cognitive deficits prior to illness onset, as they may represent neurocognitive trait markers for schizophrenia. One promising marker is working memory, which is consistently impaired throughout the course of the illness (Reference Goldman-RakicGoldman-Rakic, 1994). We recently demonstrated that working memory is impaired prior to the onset of psychotic illness in a group of young people at ultra high risk for psychosis (Reference Brewer, Francey and WoodBrewer et al, 2005). This research has also identified immediate verbal recall deficits prior to illness onset, where rapid registration and efficient recall may be the cognitive processes that indicate compromised prefrontal functioning. Olfactory identification deficits have also been found to occur prior to psychosis onset, and have been shown to be worse in patients later diagnosed with schizophrenia (Reference Brewer, Pantelis and AndersonBrewer et al, 2001). However, despite this, the predictive value of neurocognitive variables has proved to be disappointingly poor.

Neurobiological

Hypothalamic–pituitary–adrenal (HPA)-axis dysfunction may play a role in the development of psychotic disorders. This is supported by the finding of higher cortisol levels (plasma, salivary or urinary) and abnormal circadian cortisol rhythms in patients with psychotic disorders compared to healthy control subjects (Reference Kaneko, Yokoyama and HoshinoKaneko et al, 1992).

We recently investigated HPA-axis functioning in 12 ultra-high risk participants at the PACE clinic using the combined dexamethasone corticotrophin releasing hormone (DEX/CRH) test (Reference Thompson, Berger and PhillipsThompson et al, 2007). Over a 2-year period, 3 of the 12 participants developed a psychosis. Analysis indicated that contrary to expectations participants who did not make the transition to psychosis had on average higher cortisol levels, as well as a greater severity of depression and anxiety symptoms, than participants who subsequently developed psychosis. These preliminary results suggest that dysregulated HPA-axis functioning in individuals at ultra high risk for psychosis may be associated more with comorbid depression symptoms than factors specifically related to the process of emerging psychosis illness.

The pituitary gland contains corticotrophs, the cells that produce and secrete adrenocorticotrophic hormone (ACTH), which in turn activates the secretion of cortisol. A recent study found increased pituitary volumes in patients with first-episode psychosis, while individuals with established schizophrenia of at least 5-years' duration had smaller pituitary volumes than controls (Reference Pariante, Vassilopoulou and VelakoulisPariante et al, 2004). In a longitudinal investigation of ultra high risk participants at the PACE Clinic, those who developed psychosis had larger pituitary volumes compared with ultra high risk individuals who did not develop psychosis (Reference Garner, Pariante and WoodGarner et al, 2005). This increased volume is thought to reflect an increase in the size and number of corticotrophs.

Studies of brain structure may also be relevant to the HPA dysfunction model of psychotic disorders. It is hypothesised that abnormal HPA-axis responses to stress might result in hippocampal damage, which may then compromise attention, memory and other cognitive skills and ultimately influence the development of positive psychotic symptoms. Reduced hippocampal volume (Reference Velakoulis, Pantelis and McGorryVelakoulis et al, 1999), has been reported in association with psychotic illnesses.

Hippocampal volumes of PACE ultra-high risk patients at intake lie midway between those of normal controls and patients with chronic schizophrenia or first-episode psychosis (Reference Phillips, Velakoulis and PantelisPhillips et al, 2002b ). However, reduced hippocampal volumes in the ultra-high risk cohort at baseline have not been shown to be associated with a heightened risk of later developing psychosis. In fact, ultra-high risk individuals who developed psychosis had larger hippocampi at baseline than those who did not develop psychosis within a 12-month period (Reference Phillips, Velakoulis and PantelisPhillips et al, 2002b ). This was due to the ultra-high risk individuals who did not develop psychosis (the false-positives) having smaller than average hippocampal volumes. It must be remembered that these false positives are not analogous to normal healthy controls. They are help-seeking and symptomatic with a range of symptoms and psychiatric syndromes. The reduced hippocampal volume in this subsample of patients may therefore reflect this non-psychotic psychopathology.

In a subsample of ultra-high risk patients who developed psychosis, we obtained magnetic resonance imaging (MRI) brain scans at baseline (i.e. prior to onset of frank psychosis) and 1 year later (post-psychosis). Scans showed a significant bilateral reduction in grey matter volume in the cingulate region as well as in the left para-hippocampal gyrus, left fusiform gyrus, left orbitofrontal cortex and one region of the left cerebellar cortex (Reference Pantelis, Velakoulis and McGorryPantelis et al, 2003). These findings were not present in a group of ultra high risk patients scanned at baseline and follow-up but who did not develop psychosis. Progressive hippocampal volume loss across the early course of illness is also strongly suggested by a much larger cross-sectional study recently reported by our group (Reference Velakoulis, Wood and WongVelakoulis et al, 2006). These findings suggest that brain changes occur during the period of transition to and early course of psychosis, and, while the basis of this remains uncertain, it opens up the possibility that stress, dysregulated neurodevelopment and apoptosis may be involved, and that with sufficiently early and effective treatment such changes could be minimised or prevented.

Intervention

Three published studies suggest that intervention may be able to delay or even prevent onset of psychosis in the ultra-high risk or prodromal group. The first randomised controlled trial was conducted at the PACE clinic from 1996 to 1999 (Reference McGorry, Yung and PhillipsMcGorry et al, 2002). This study compared the effect of intensive cognitive–behaviourally oriented psychotherapy plus low-dose neuroleptic (risperidone) with supportive therapy alone on the development of psychotic disorder. There was a significantly higher rate of transition to psychosis in the control (supportive therapy) group compared to the intervention group at the end of the 6-month treatment phase, although this difference was no longer significant at 12-month follow-up. This result is thought to indicate a delay in the onset of psychosis in the intervention group. Both groups experienced a reduction in global psychopathology and functioning over the treatment phase. Because psychological treatment and medication were combined in this trial it was not possible to determine which was the active intervention, or whether they were synergistic with each other. A trial of cognitive therapy versus monitoring only conducted by the Early Detection and Intervention (EDIE) group in Manchester showed a significant effect of the treatment (Reference Morrison, French and WalfordMorrison et al, 2004). A double masked randomised controlled trial of olanzapine versus supportive therapy and monitoring showed a trend for the intervention in effectively preventing or delaying psychosis (Reference McGlashan, Zipursky and PerkinsMcGlashan et al, 2006). Additionally, the prodromal (ultra high risk) patients who received olanzapine reported lower levels of ‘prodromal’ symptomatology compared to the UHR patients who received placebo. The results of this study highlighted the fine line between benefit and risk in this early stage, since side-effects were of more concern in this study than in the PACE trial, yet the clinical benefit, at least in terms of transition rates, was more equivocal. In all, results of these first treatment trials suggest that both antipsychotic medication and psychological interventions might have a role in treating the difficulties and problems young people at ultra-high risk experience as well as delaying or preventing the onset of psychosis. There is scope for the investigation of a wide range of other approaches, including neuroprotective agents in the treatment of the ultra-high risk population. The sequence of treatment strategies is also clearly in need of further research and the risk/benefit ratio, made explicit as the key consideration in the staging model, should be the guiding principle. In the meantime, for such patients, clear explanation of the best available evidence (incomplete though it may be, as elsewhere in psychiatry), truly informed consent and patient and family involvement in decision-making is crucial. A conservative approach in relation to antipsychotic use is strongly suggested, with psychosocial and other benign treatment interventions advised as first-line (Reference McGorry, Killackey and LambertMcGorry et al, 2005). Treatment should be offered in a non-stigmatised primary care, youth-friendly or office setting and engagement and therapeutic alliance are key initial objectives to secure. Careful follow-up and reassurance is vital. Although this area of research has been controversial in some settings, provided these guidelines are followed, we have seen no evidence of harm to patients and much benefit in our youth-friendly service setting over a 12-year period. Ethical issues have been discussed in detail elsewhere (Reference McGorry, Yung and PhillipsMcGorry et al, 2001).

Limitations

To date sample sizes in the ultra high risk (prodromal) field of research are small. Findings are inconsistent, particularly in relation to cannabis use and neuroanatomical changes. Another limitation is the onset of psychotic disorder is arbitrarily defined and does not differ qualitatively from sub-threshold psychosis.

Commonly described prodromal features of schizophrenia (modified from Reference Yung, Morrison, Addington and Francey Yung, 2006 )