1 Table of content
Summary 3
Introduction 4
Beyond the boundaries of categories: nosography vs clinical evidence
for psychosis 4
The Ultra High Risk State 7
History and development of the concept of (Ultra High Risk HR) 8
Epidemiologic research 14
The “polygenic neurodevelopmental diathesis-stress model”: interaction of biological
and environmental factors 15
- Neuroendocrinology 17
- Other endocrinological factors of vulnerability 21
- Neuroimaging and possible pre-onset markers 22
- Clinical features
(schizotypal personality disorder, basic symptoms, psychiatric comorbidity) 25
- Stress 29 - Trauma 31 - Substance use 33 - Poor functioning 35 - Neurocognition 37 Outcomes 38 - Transition to psychosis 38
- Outcomes of non converters 42
Comorbid Anxiety and Depression associated with poor functional outcome in subjects at high clinical risk for psychosis
Background of the research 47
Methods 49
Sample 49
2
Referral and recruitment 51
Exclusion criteria 52
Pre-screening 52
Screening and baseline assessment 53
High-Risk Criteria according to CAARMS 54
Psychosis Threshold/Anti-psychotic Treatment Threshold 55
Study design 59 Focus treatments 59 Outcome measures 59 Follow up 60 Statistical analysis 61 Crossectional 61 Longitudinal 61 Results
Sample characteristics at baseline 62
Sample characteristics at follow up 62
Preventive interventions 64
Comorbid anxiety and depressive disorders and baseline symptoms 65
Course of comorbidity over time 65
Comorbid depression and anxiety disorders and functional outcome 66 Discussion 67 Limitations 72 Conclusion 73 Tables 75 Supplementary 79 CAARM 81 References 97
3 Summary
Background: Comorbid anxiety and depression have been shown to impact on the clinical presentation and distress of individuals at high risk for psychosis (HR). We investigated the impact of anxiety and depressive comorbidity on baseline and longitudinal HR characteristics.
Methods: The sample included 154 referrals to the OASIS clinic with an At Risk Mental State for psychosis. Baseline assessment data was collected using the CAARMS (Comprehensive Assessment of the At Risk. Mental State), PANSS (Positive and Negative Syndrome Scale), HAM-D and HAM-A (Hamilton Depression/Anxiety Rating Scale), SCID I and II as well as GAF (Global Assessment of Functioning). Follow-up data were available for 74 individuals.
Results: There were baseline differences in employment status across comorbidity groups (χ2
13.835; p=.008). The mean total scores of CAARMS, HAM-A, HAM-D and PANSS were also significantly different in the three comorbidity groups, with highest scores in the anxiety and/or depression comorbidity group (CAARMS F=3.572 p=.027; HAM-A F=10.231 p=.000; HAM-D F=8.374 p=.001; PANSS F=7.467 p=.001). We detected 22 cases of incident depression and/or anxiety disorders, 9 remissions and 17 recurrent/continuous cases (χ2
=9.480; p=.047). Baseline anxiety and depressive comorbidity did not predict global functioning at follow-up (p=.657). Conversely, there was a significant association between presence of comorbid anxiety or depressive disorders at follow-up and functional status (p=.008).
Conclusions: Anxiety and depressive comorbidities are associated with poorer functional outcomes in HR individuals.
5 Introduction
Beyond the boundaries of categories: nosography vs clinical evidence for psychosis
As a premise , it’s worth clarifying that in the text the term “schizophrenia” has been replaced by the more generic term “psychosis”. The theoretical basis for this choice lay on the evidence that schizophrenia is an unspecific container of different syndromes and it is the resultant of the categorical approach to mental illness. We will discuss about those people with an increased risk to develop a psychotic disorder disentangling it from strict diagnostic categories in favour of a trans-diagnostic vision of the psychotic dimension. Etiologic and diagnostic conceptualizations of psychoses have undergone significant changes over the past two decades. It is now generally accepted that the contemporary DSM diagnostic boundaries, distinguishing among psychotic disorders, especially between schizophrenia and other psychotic disorders, do not converge with recent advances in our understanding of genetic and environmental factors that contribute to the diathesis. For example, a huge amount of genetic research indicates that many genes contribute to increase vulnerability but in an unspecific way with overlaps between bipolar and DSM psychotic disorders[1, 2]. Similarly, familiar and bio-environmental risk factors, such as prenatal complications and substance use[3], appear to be associated with heightened vulnerability for both schizophrenia and the affective psychoses.
Another important issue is considering mental disorders and, in particular psychosis, on a phenomenologically and longitudinally continuum rather than on a dichotomous vision “presence/absence” of the illness[4]. Independently from the study of HR criteria in clinical samples, population-based studies have been examining subthreshold psychotic experiences (PEs). These studies have shown that the dichotomous disease model of psychosis can be complemented with a model of
6 psychosis as an extended phenotype across clinical and non-clinical expressions. At one end of the continuum lies full blown psychotic disorders, in the middle are psychotic mental disorders with PEs, and at the other extreme lie PEs in healthy, non-help-seeking individuals[5, 6]. Thus, psychotic symptoms may be experienced by potentially any subject with different level of perceived stress and incidental psychopathology. Despite this, much of the research on subthreshold extended phenotypes is still conducted within non communicating silos so that, for example, subthreshold depressive states are presented as specifically predicting depression, subthreshold mania as specifically predicting bipolar disorder and subthreshold psychosis as specifically predicting psychotic disorders. An attempt to overcome these limits dates back to almost 10 years ago when the research unit of the university of Pisa introduced a new approach to mental illness: the spectrum model. It emphasizes soft signs, low-grade symptoms, subthreshold syndromes, as well as temperamental and personality traits. As far as the psychotic dimension my concern, the psychotic spectrum considers a psychopathological continuum, ranging from psychotic soft signs, personality disorders (in particular Cluster A, Borderline and Avoidant) to full-blown major psychoses (Schizophrenia, Schizoaffective and Delusional Disorders, Mood Disorders with psychotic features). There’s a robust literature which describes in depth the advantages in terms of clinical flexibility and treatment orientation[7-11]. The recently published DSM-V considered to add specific risk syndromes for each disorder as for example the Attenuated Psychosis Syndrome (APS). Anyway, the main reason for not including a risk syndrome for each disorder lay in the aspecificity of the earliest expression of psychopathology: a mixture of affective dysregulation, aberrant salience, motivational alterations and anxiety that create a common ground and a concausal network for the possible future development of a full blown disease.
7 Moreover, the transition from a subthreshold state to a particular psychiatric disorders is not symptom specific. For example, it’s a well replicated evidence that subthreshold psychotic symptoms may be predictive of both psychotic spectrum disorders and, more rarely, non psychotic outcomes[5]. The other key point is that the early expressions of psychopathology dynamically interact with each other either cross-domain then within the same cross-domain. For example hallucinations may result in clinical outcomes in a higher probability when combined with delusional ideation[12], moving from subthreshold mania to bipolar disorder is favoured by the presence of earlier subthreshold psychosis[13], as well as subthreshold psychosis is strongly associated with subthreshold depression[14]; insomnia has an impact on paranoia especially if associated with mood dysregulation[15], subthreshold mania increase the risk of suicidality in patients with post-traumatic stress disorders[16]. Finally, the presence of subthreshold psychotic symptoms in those individuals with an anxiety or depressive disorder seems to impact negatively on future prognosis and outcome[17]. Fig 1, Fig 2
8 Fig.1 From aspecific symptoms of distress to clinical dimensions
Fig.2 Vulnerability to psychosis is present as a continuum in the general population as aspecific psychotic-like experiences. The clinical high risk state for psychosis is defined when distress and disability trigger help-seeking behaviours in presence of specific signs or symptoms (attenuated psychotic symptoms). The longitudinal course of the high risk state may include outcomes other than psychotic disorders such as the development of bipolar disorders, anxiety or depressive disorders, substance abuse or clinical remission.
9 The Ultra High Risk State
History and development of the concept of HR
Empirical evidences of” transient” or “attenuated” psychotic symptoms have been available since the early days of the schizophrenia research suggesting that the onset of the illness may be antedated or accompanied by characteristic qualitative changes of subjective experience. In Germany, Berze and Grhrle, contemporaries of Bleuer, provided rich descriptions of such experiential anomalies, grouping them into anomalies of perceptions and attention, bodily and movement awareness, cognition and self-awareness. Grhrle coined the characteristic self-transformation in schizophrenia as the “schizophrene Grundstimmung” emphasizing this phenomenon’s basic trait status. French psychiatry designated these phenomena as “petits automatisms” by De Clerambault. McGhie and Chapman were the first Anglo-Saxon authors to describe such experiences in 1960s. Huber continued this line of research using the term “basic symptoms” and thanks to his work the term prodromal formally appeared in PubMed literature for the first time in 1989 starting the first prospective early detection study in the 1980s[18]. In 1989, Hafner et al., for the first time, examined the prodromes on a representative population of more than 232 first admitted psychosis patients of a large catchment area in Germany in the ABC (Age, Begin and Course of schizophrenia) study[19]. It was shown that in 73% of all subjects the disorder began with a prodromal phase which lasted, on average, 5 years. The symptomatology was characterized mainly by depressive mood and the lifetime prevalence rate for at least one 2-week episode of depression was 83 %. In 1991, Jackson and McGorry started to assess first-episode patients via a semi-structured
10 interview to determine the presence or absence of prodromal symptoms[20]. The EPPIC center started in October 1992, seeking to provide a comprehensive community-based service to young individuals experiencing the first onset of a psychotic illness and to provide support and care through the critical period. The aims were early detection, preventing secondary morbidity, maintaining or restoring global functioning during the "critical period"[21].
On the basis of this work, Yung et al., in 1995 started to investigate the predictive validity of the ARMS (At Risk Mental State) criteria developing the first psychometric instrument for this purpose: the Comprehensive Assessment of At-Risk Mental States (CAARMS)[22]. It had two functions: (i) to assess psychopathology thought to indicate imminent development of a first-episode psychotic disorder; and (ii) to determine if an individual met criteria for being at ultra high-risk (HR) for onset of first psychotic disorder. Some years later, Miller and McGlashan from United States developed a similar psychometric instruments to rate quantitatively the severity of symptomatology of HR patients. They were the Structural Interview for Prodromal Syndromes (SIPS) and the Scale of Prodromal Symptoms (SOPS).
In Europe, the attention was focused on Basic Symptoms (BS) thanks to the effort of the group led by Klosterkotter[23]. The term "basic symptoms" (BS) might be confused with Bleuler's "fundamental symptoms"; however, the difference is clear: fundamental symptoms and negative symptoms, are externally observed by others on the basis of behaviour and expression, whereas BS can only be identified immediately by the person affected. To some extent a continuum between the two symptom groups seems to exist. Some BS are probably only milder and preceding degrees of the fundamental or negative symptoms. Accordingly, the correspondence in the Anglo-American symptomatology are the "early symptoms'" or "early signs". Basic
11 symptoms are subtle, subjectively experienced subclinical disturbances in drive, affect, thinking, speech, (body) perception, motor action, central vegetative functions and stress tolerance. They can occur in every stage of the illness, from the prodrome to the first episode of psychosis, in relapses and in residual states. Insight that something is wrong is present. It’s usually very difficult for the person experiencing these symptoms to explain them. The ability to cope with them often attenuates with progressive illness and emerging psychotic symptoms but it is restored with remission. Basic symptoms are the most immediate symptomatic expression of the neurobiological correlates of the illness thus the term “basic”. It’s worth saying that they are not specific for psychosis since they represent a a common groung for psychopathology rather than to psychosis itself. Klosterkotter studied the predictive capacity of the basic symptoms in a cohort of non-psychotic patients attending a tertiary referral psychiatric setting and who were suspected as being ‘susceptible to schizophrenia’ on the basis of their psychopathology. Participants were followed up on average eight years after initial assessment, and during this period over 50% of them had developed schizophrenia. Certain basic symptoms (disturbances of receptive speech, blocking of thoughts, visual perceptual disturbances, olfactory, gustatory and other sensory disturbances) were found significantly more often in the group which developed schizophrenia compared to the group which did not, suggesting that these symptoms may be predictors of schizophrenia. From this study, the authors developed a checklist of nine symptoms suggestive of a schizophrenia prodrome: inability to divide attention, thought interference, thought pressure, thought blockages, disturbance of receptive speech, disturbance of expressive speech, disturbances of abstract thinking, unstable ideas of reference and captivation of attention by details of the visual field.
12 High-risk criteria were then developed requiring the presence of at least two of these symptoms. The predictive validity of these criteria has been examined in a multi-site European study[24].
Moller and Husby[25] (2000) extracted eight dimensions of self-experienced cognitive perceptual changes during the prodromal stages of psychosis. The most commonly occurring experiences included changes in perception of the self (for example feeling unreal or changed, feeling like a spectator), preoccupation with unusual ideas (for example being absorbed in one’s own thoughts, rumination) and “neurotic like experiences”. Other frequent reported complaints are about the fear of losing control and being unable to monitor their own thoughts.
According to Conrad’s classic model, during the prodromal period (the “trema” or “stage fright”), the HR patients may experience an increasingly oppressive internal tension, a “feeling of nonfinality” or expectation, describing that something is “in the air” without being able to say what exactly has changed[26]. These subjective experiences can vary between patients but are usually characterized by marked change of “emotional-motivational” state, which can be expressed in anxiety and depressive symptoms. At first, the trema is associated with the most salient situations but then it diffuses to the whole favouring the structuring of delusions and aberrant interpretation of the world. Fig 3
13 Fig.3 A Model of Huber’s Concept of Basic Symptoms (BS).4,5 (1) Reversible postpsychotic basic stage; (2) prodrome of relapse; (3) irreversible postpsychotic basic (‘‘pure defect syndrome’’)
Young, McGorry and colleagues have made progress to develop operational criteria to diagnose HR state. HR subjects have been clustered in three groups: The first group is represented by those individuals with attenuated, subthreshold positive psychotic symptoms (APS) such as paranoia, ideas of reference, bizarre belief or magical ideation, perceptual disturbance, weird speech, incongruous behaviour or appearance which occur several times per week. These individuals have experienced these symptoms for more than one week but less than five years and they do not meet the criteria for schizotypal personality disorder. The second group is represented by those with transient psychotic symptoms (Brief Limited Intermittent Psychotic Symptoms, BLIP) where the psychotic symptoms are over threshold, occurred in the last year but
14 the duration is less than one week and resolve spontaneously. The third group are those with “trait plus state risk factors” that is to say individuals with a schizotypal personality disorder or a first-degree relative with a DSM-IV psychotic disorder, and had experienced a significant decline in mental state or functioning for at least one month but no longer than five years assessed by GAF.
As in all other fields of psychiatry, the boundaries between these categories are week and there appears to be considerable overlap between these three groups[27, 28]. As stated before, different interview measures have been developed to assess HR features and to determine whether individuals meet the previously mentioned criteria. The most frequently used are: the Comprehensive Assessment of At-Risk Mental State (CAARMS), the Structured Interview for Prodromal Symptoms (SIPS) (including the companion Scale of Prodromal Symptoms [SOPS]), the Early Recognition Inventory for the Retrospective Assessment of the Onset of Schizophrenia (ERIraos), and the Basel Screening Instrument for Psychosis (BSIP).
The development of the early intervention services in South London and the Maudsley (SLaM) began in 1997, when the deficiencies in existing services for young people with first episode psychosis were first identified by an internal committee report in Lambeth called ' Bridging the Gap '. The first unit, The Lambeth Early Onset (LEO) Community Team began in January 2000 as an extended service to a small clinic near the centre of Brixton. A unit of 18 beds for acute patients with first-episode psychosis has been commissioned at Lambeth Hospital in 2001, where it is still located. The team OASIS has been developed at the same time (2001) in Lambeth Borough to identify individuals at high clinical risk for psychosis. This Unit adopted the clinical classification for HR subject introduced by Yung adding, since 2008, the fourth category of Cognitive Perceptive Basic Symptoms (BS). At first they assessed BS
15 using the Bonn Scale for Basic Symptoms (BABS) subsequently substituted by the Schizophrenia Proness Instrument Adult Version (SPI-A)[29]. Fig 4
Fig 4. Clinical management (diagnosis and treatment) flowchart of the clinical high-risk state (HR) for psychosis. APS indicates attenuated psychotic symptoms subgroup; BLIP, brief limited intermittent psychotic episode subgroup; BS, basic symptoms subgroup; FEP, first-episode psychosis; GRD, genetic risk and deterioration syndrome subgroup; and UPS, unspecified prodromal symptoms subgroup.
Epidemiologic research
As all HR criteria rely on help-seeking individuals, the prevalence of the HR state in the general population is unknown[30]. The available epidemiologic research are
16 based on fully structured lay person interviews and questionnaires for the assessment of psychotic symptoms, which have been shown to generate results different from those of clinical interviews[31]. It estimates a prevalence of approximately 4% to 8% for psychotic symptoms or psychotic-like experiences: such symptoms may be associated with a degree of distress and help-seeking behaviour but do not necessarily amount to clinical psychotic disorder[32]. However, studies in children have indicated that even frank psychotic symptoms occur in nearly every 10th child but frequently possess little clinical relevance and remit without intervention. A pilot study assessing HR criteria according to the SIPS and BS criteria on the telephone by trained clinicians found much lower prevalence risks of 2% in 16- to 40-year-olds[33]. Another recent study in a general population sample of 212 adolescents who attend school (aged11-13 years) estimated that up to 8% met the APS criteria for a risk syndrome according to the SIPS criteria, whereas only 1% did so when also considering the CAARMS disability criterion. Notably, 89% of adolescents with any APS reported distress caused by them. Thus, approximately 6.9% in this adolescent population fulfilled the APS and the distress criterion necessary to diagnose the DSM-5 syndrome.
The “polygenic neurodevelopmental diathesis-stress model”: interaction of biological and environmental factors
The ‘diathesis–stress’ model has dominated conceptualizations of psychoses etiology for over four decades[34]. The basic underlying assumption is that psychotic disorders arise from interaction of pre-existing vulnerability (i.e., “diathesis) with exposure to various psychosocial and environmental stressors that have the potential to trigger its
17 expression in a cascade of increasing deviance finally culminating in psychosis. Vulnerability to psychosis is assumed to originate from genetic factors and fetal neurodevelopment abnormalities[35]. Subsequently, adolescent neuromaturational processes are supposed to play a role in the clinical expression of psychotic illness, as its clinical onset is typically in late adolescence/early adulthood[36]. It has been suggested, for example, that aberrant neural connectivity, acting in concert with dopamine (DA) circuitry abnormalities, arises during adolescence and sets the stage for the first psychotic episode[37].
Behavioral (family, twin, adoption) genetic studies yield heritability estimates of 0.65-0.70 confirmed by natural population studies[38, 39]and molecular genetic origins tested by large-scale studies confirmed the polygenic influences of either common single variants and copy number variants. The other risk domain deeply investigated as impacting the neurodevelopment process are pre and peri-natal complications. Evidence indicates higher rates of adverse prenatal events across the psychosis spectrum such as prenatal maternal viral exposure, malnutrition, stress and complications of pregnancy and delivery [40]. Since Obstetric Complications (OCs) a specific risk factor for psychosis, their incidence should be higher in patients diagnosed with first-episode psychosis (FEP) than in HR people, since only a minority of them develops full-blown psychosis[41]. Moreover, among the patients classified as HR, those who convert to psychosis should show a higher incidence of OCs than those who do not. One study compared the incidence of OCs between HR and healthy controls and found higher percentages for the HR group (OCs=46% vs 19%). However, similar proportion has been found between HR and first episode individuals (FEP= 39%)[42]. Another study investigated the role of OCs in the conversion risk and found that HR individuals with a positive history of OCs had higher risk to develop a full blown psychosis than those HR without OCs in their anamnesis [43]. A
18 recent study on 83 HR subjects and 86 individual diagnosed with first episode of psychosis (FEP)[41] found no significant difference in the incidence of OCs between these two groups. Moreover, psychosis within the spectrum of schizophrenia was related to the occurrence of OCs in FEP and, albeit not significantly, in HR patients. Twenty three percent of FEP and twenty five percent of HR subjects were positive for the occurrence of severe OCs,. OCs were more common in individuals with a family history of psychosis than in those without such a history.
.
Neuroendocrinology
Hypothalamic–pituitary–adrenal (HPA)-axis dysfunction has been deeply investigated in the development of psychotic disorders. This is supported by the finding of altered cortisol levels (plasma, salivary or urinary) and abnormal circadian cortisol rhythms in patients with psychotic disorders compared to healthy control subjects[44]. Corticotrophin releasing hormone (CRH) and arginine vasopressin (AVP) are neuropeptides seem to be involved in many psychiatric disorders such as depression and anxiety[45], and glucocorticoids seem able to trigger cognitive, affective and psychotic symptoms [46]. An imbalance in central glucocorticoid receptors (GR) and mineralocorticoid receptors (MR) has been postulated to be central to dysregulation of neuropeptides and the HPA axis in those previously mentioned mental illnesses.
The vulnerability—stress-coping model has been revisited in recent years, and some authors now hypothesise that the concept of vulnerability to psychosis should include hyperactivity of the HPA axis[47]. Several evidences, such as the increased stress sensitivity, the hippocampal volume reduction and the increased dopamine release in the striatum after stress exposure, have strengthen the hypothesis of the relationship
19 between several key elements of psychosis and alteration in the HPA axis. Nonetheless, two relevant issues are still debated. Firstly, does the enhanced stress response precede the onset of disease, and predispose to its onset (therefore, representing a marker of biological vulnerability) or is it caused by the onset of the disorder, due to the extremely stressful nature of the psychotic experience? Secondly, if it is a marker of biological vulnerability, is it part of the genetic predisposition to psychosis or is it a developmental feature, related to the environment? The available literature indicates that relatives of psychotic patients show levels of stress sensitivity that are intermediate between healthy controls and psychotic patients. HR subjects show, in general, higher levels of cortisol and positive correlations between cortisol levels and prodromal or psychotic symptoms. Corcoran et al. (2012)[48] recently found no relationship between salivary cortisol of HR subjects and overall positive symptom severity but a correlation with suspiciousness, anxiety, impaired stress tolerance and affective symptoms.
The PACE clinic investigated the HPA-axis functioning in 12 ultra-high risk participants[49]. Over a 2-year period, 3 of the 12 participants developed a psychosis and contrary to expectations, those 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 converters. This suggests that dysregulated HPA-axis functioning in HR individuals may be associated more with comorbid depression symptoms than factors specifically related to the process of emerging psychosis illness. Interestingly, Walker et al. (2010)[50], in a follow up study on HR patients, found higher salivary cortisol levels in the sub-group of patients who made the transition to psychosis compared with the group of HR patients who did not. The reason of these contrasting results may lay on the small number of subjects recruited.
20 Another indirect parameter of HPA dysregulation is the volumetric changes of the pituitary gland: increased pituitary volumes in patients with first-episode psychosis smaller volumes in individuals with chronic schizophrenia compared to controls[51]. In a longitudinal investigation of HR participants at the PACE Clinic, those who developed psychosis had larger pituitary volumes compared with ultra high risk individuals who did not develop psychosis. This increased volume is thought to reflect an increase in the size and number of corticotrophs.
The other well investigated brain area is hippocampus. Its volume (left or both sides) in HR subjects and in young individuals with Schizotypal Personality Disorder seems to be smaller in comparison with controls and larger when compared with patients[52 594]. It is hypothesised that aberrant HPA-axis responses to stress could damage and, consequently, decrease in volume the hippocampus resulting in attention, memory and other cognitive skills deficits and influencing the development of positive psychotic symptoms. However, reduced hippocampal volumes in the HR cohort at baseline does not seem to be associated with a heightened risk of transition to psychosis. In fact, those HR individuals who developed psychosis had larger hippocampi at baseline than those who did not within 1 year. The “false positive “ HR have 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 nonpsychotic psychopathology especially mood and anxiety disorders. In a subsample of HR patients who developed a full blown psychosis, the baseline and 1 year later (post-psychosis) magnetic resonance imaging (MRI) brain scans showed a significant bilateral reduction in grey matter volume in the cingulate region as well as in the left para-hippocampal gyrus,
21 left fusiform gyrus, left orbitofrontal cortex and one region of the left cerebellar cortex[53]. These findings were not present in the non-converting group. 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 unclear, it can be hypothesized the role of stress, dysregulated neurodevelopment and apoptosis and that early and effective intervention could change the prognosis of these individuals.
Those who develop a first episode of psychosis (FEP) present a peculiar HPA response: blunted cortisol awakening response, increased cortisol levels during the day and GC resistance. These abnormalities are not simply consequences of distress of comorbid disorders since the pattern is different for example from the response described in post-traumatic stress disorder (PTSD) (blunted cortisol awakening response, decreased cortisol levels during the day and GC hypersensitivity)[54], and in depression (increased cortisol awakening response, increased cortisol levels during the day and GC resistance[55]. Finally, what’s the possible role of HPA dysregulation in the transition to psychosis? We know that transition to psychosis usually occur in a period of life, adolescence and young adulthood, when HPA is developing too. Moreover, the post-pubertal increase HPA axis activity and adrenal and gonadal hormones may trigger the expression of genes involved in brain maturation such as brain-derived neurotrophic factor (BDNF)[56] and N-methyl-D-aspartate (NMDA) receptor[57], contributing to the onset of the illness. Moreover, overexposure to stress could act as an epigenetic factor determining the expression of genes or particular polymorphisms involved in psychosis. For example, the genetic polymorphisms COMT Val(158)Met and BDNF Val(66)Met are associated with feelings of paranoia in response to daily or social stress. This is reinforced by the evidence of an increased
22 prevalence of childhood trauma among HR populations and an even larger prevalence among those who later developed psychosis [46].
The link between HPA axis impairment and psychosis could be the inability to cope with stress and the correlated increase of dopamine release in the meso-limbic areas in response to stress reported in schizophrenic patients. Fig 5
Fig 5. The stress vulnerability model and the involvement of the HPA axis
Other endocrinological factors of vulnerability
Recent developmental models of psychosis shed light on the central role of hormones as vulnerability factors to psychiatric disorders[58, 59]. Recent comprehensive reviews on estrogen[60] for example concluded that: 1) women with schizophrenia have lower levels of estrogens compared to healthy same-sex controls, 2) peak bone mass, an indicator of cumulative estrogen exposure, is significantly lower in women with first episode schizophrenia than in matched controls, 3) in adulthood, risk for psychosis is increased in postmenopausal and follicular phase of menstrual cycle when
23 are at their lowest levels, and 4) some evidences suggested that external administration of estradiol may improve psychotic symptom severity in women. The underlying mechanism is not clear, the most convincing hypothesis is the possible anti-dopaminergic and/or neuroprotective role of estrogens.
Similarly, a recent review [61] concludes that schizophrenic men, especially those with prevalent negative symptoms, showed lower level of testosterone. A similar result has been recently replicated in a sample of first episode psychosis drug naïve patients [62] as well as in HR male adolescents [63].
Neuroimaging and possible pre-onset markers
Neuroimaging applied to studies in HR samples represents a promising translational tool for detecting structural or functional markers which could predict the transition to frank psychosis or that could add specificity, with neuroanatomical and neurofunctional measures, to the heterogeneity of clinical presentation of these individuals[64].
Structural neuroimaging focus on detecting specific volume differences between HR and healthy controls especially volumetric reductions in regions known to be affected in schizophrenic patients such as hippocampus and the anterior cingulate cortex[52, 65, 66]. HR subjects present intermediate phenotype between healthy controls and patients with frank psychosis[67]. Structural MRI has evidenced several neuroanatomical differences at first clinical presentation between those who later developed psychosis (UHR-T) and those who did not (UHR-NT). Using the voxel-based morphometry (VBM) HR-T subjects showed reduced gray matter (GM) volume of the anterior cingulate cortex (ACC),inferior frontal cortex, medial and lateral
24 temporal, insular, inferior and superior frontal cortices[68], and reduced GM density of the left temporal lobe and right cerebellum[69] compared to HR-NT[53, 70]. Using the technique of ROI (Region Of Interest) the HR-T showed reduced volumes in the left parahippocampal gyrus, the bilateral insula, the left ACC and increased volume of pituitary gland and hippocampus[70-73]. Besides considering alterations in GM volume and density, other parameters such changes in regional cortical thickness (CT) and the degree of CT asymmetry have been reported[74]. Fig 6, Fig 7
Other studies have examined the same HR sample during the follow-up time with a within subject design. HR-T, compared to HR-NT, showed a progressive reduction in the GM volume of the orbitofrontal and cerebellar cortices, fusiform and parahippocampal cortices and cingulate gyrus, precuneus superior frontal, inferior temporal, superior parietal cortices[68]. Few studies investigated changes in white matter (WM) related to transition to psychosis. One showed increased WM volume in left frontal lobe and progressive decrease in the left fronto-occipital fasciculus. Other found a decrease in total WM compared to healthy controls but not to HR-NT[75].
As far as functional imaging may concern, functional magnetic resonance (fMRI) showed changes in activation in HR samples that are intermediate between those in first episode of psychosis and healthy controls[76]. This technique has been applied to study possible neurocognitive peculiar pattern which could help to predict those with a higher risk of transition as well as to study “in vivo” brain activity during specific tasks[77]. Results are encouraging even if still controversial.
Converging in vivo evidence indicates that psychotic disorders are associated with dysregulated presynaptic striatal dopaminergic function and that striatal hyperdopaminergia precedes the onset of psychosis[78]. We found that Positron emission tomography indicate that dopamine synthesis capacity is greater in those HR
25 patients that go on to a first episode of psychosis compared to healthy comparison subjects and to patients who presented with similar clinical features but did not go on to develop psychosis. This is consistent with the finding of 14% elevation in schizophrenic patients[78, 79].
Fig 6. Differences between the ultra-high-risk (HR) and control (HC) groups. The images show the medial orbital region, where the total HR sample gray matter volume relative to HCs (P_.05 after familywise error correction)[70].
Fig 7. Differences between ultra-high-risk (HR) individuals who did (HR-T) and did not (HR-NT) develop psychosis. The HR-T individuals had less gray matter volume than did the HR-NT individuals in the left parahippocampal gyrus, bordering the uncus (MNI [Montreal Neurological Institute] coordinates x, y,and z: −21, 6, and −27, respectively). For visualization purposes, effects are displayed at P_.05 uncorrected. The plot shows mean gray matter volumes for the 2 HR subgroups at each site (x-axis:1indicates London, United Kingdom; 2, Basel, Switzerland; 3, Munich, Germany; and 4, Melbourne, Australia); values on the y-axis refer to cubic millimeters per voxel. Error bars represent SD[70].
26 Clinical features
Within prodromal or ultra-high risk services, numerous clinical and psychopathological variables have now been shown to predict the onset of psychosis, including factors that are not directly related to the ultra-high risk inclusion criteria.
Schizotypal personality features
The observation that schizotypal disorders represent a direct manifestation of vulnerability to psychosis date back to more than fifty years ago since the first papers by Meehl[80]. In addition to the diagnostic criteria (ideas of reference, odd beliefs or magical thinking, unusual perceptual experiences, odd thinking and speech, suspiciousness or paranoid ideation, inappropriate or constricted affect, odd or eccentric behaviours, lack of close friends and excessive social anxiety) social anhedonia and anomalous subjective experiences are the main features of those with schizotypal traits or disorder. Clinical research in the field of prodromal psychosis has focused on those schizotypal traits which could be more predictive of a future development of a full blown psychosis. In one study, odd beliefs and magical thinking at baseline were salient predictors of psychosis at follow-up[59]. However, it’s arguable if schizotypal personality truly preceded the onset of the psychotic disorder, or if these were prodromal manifestations of the illness. In the Edinburgh High Risk study participants who developed schizophrenia spectrum psychosis over the follow-up period had a prodromal symptomatology characterized by higher levels of social withdrawal, social anxiety introversion and odd behaviour[60]. Salokangas et al.
27 investigated whether self-reported schizotypal traits assessed by The Schizotypal Personality Questionnaire (SPQ) in a sample of HR patients could be predictors of transition to psychosis[81]. They found that self-rated ideas of reference and lack of close friends significantly predict transition to psychosis and those who presented both of them had a more increased risk. Indeed, difficulties in social relationships and isolation as well as social anhedonia have been associated with the onset of psychosis in several studies[82].
Basic symptoms
According to the Bonn school, basic symptoms show high sensitivity but poor specificity to detect those individuals who will develop a full blown psychosis. The Bonn Scale for the Assessment of Basic Symptoms (BABS) has been included in the 2 early detection instruments: CAARMS and SOPS. The Cologne Early Recognition (CER) project examined the predictive validity of clusters of basic symptoms in a sample of patients referred to outpatients departments of German psychiatric departments. 77 of the 79 patients who developed full blown psychosis had reported at least 1 of the 66 BSABS feature at first examination unlike those who did not transit to psychosis among which 33 of 81 had at least 1 items. The cluster of thought, language, perception and motor disturbances was found to have good predictive ability in a receiver operator analysis (ROC) analysis[27], 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
28 more symptoms of thought, language, perception or motor disturbances at baseline went on to develop full blown psychosis. Moreover, the absence of BSABS prodromal symptoms excluded the development of psychosis with a probability of 96%. However, that participants in this study were all suspected of having emerging schizophrenia limits the generalizability of the results to community samples or even cohorts of help-seekers who are not suspected of being prodromal[24, 83].
Comorbidity and HR
The issue of comorbidity in mental health has been established in many large scale studies[73] confirming its impact on functional outcome, duration of illness, severity of symptoms, response to treatment and type of onset. Depression, anxiety disorders, as well as substance use disorders, have been reported as being the most common comorbid disorders not only in general population, but also in young people[74]. The prevalence of depressive states in young population has been estimated between 2 and 6%[75] while between 15% and 30% have been diagnosed with an anxiety disorder at some point of their life. Unlike what it would be expected, the prevalence seems to remain almost the same in the last decades[76]. Although it is rare for psychotic symptoms to be experienced independently from a range of comorbid disorders, when psychosis is suspected the focus of assessment is usually on positive symptoms. Especially in the early stages of psychosis other distressing symptoms are frequently neglected as well as the wide spectrum of negative symptomatology. In these last years negative symptoms are at the centre of an alight debate about their diagnostic
29 burden for the HR since they are a well-documented source of distress and poor functioning even in the prodromal phase of the disease.
Depressive and anxiety symptoms have been historically suggested to frequently mark the onset of the prodrome of psychosis. The current high-risk criteria allow concurrent comorbid diagnosis of anxiety and depressive disorders but their association with prodromal signs and symptoms is not well established. Anxiety and depressive symptoms are more often of concern to the high-risk patients than their attenuated psychotic symptoms[1]. Impairment in global functioning together with depressive and anxiety symptoms are the core presenting complaints of HR help-seeking individuals. Moreover, psychological interventions offered by the service are often tailored to improve anxiety and depression rather than reducing the attenuated psychotic symptoms. These comorbid diagnosis are also very influent on the prognosis of HR subjects: a recent study found that depressive disorders can predict later transition to psychosis in HR patients[77]while other studies did not replicate this finding[6]. The largest high-risk study (n = 377) published to date showed about 69% of participants had one or more mood/anxiety diagnoses at entry to the service[78]. Another study (n=245) indicated even higher comorbid rates with up to 78% of the sample presenting with non psychotic diagnosis at baseline[4]. A multicentre study (n=509) reported that over 73% of the sample had an Axis I comorbid diagnosis in addition to the HR signs and symptoms; about 40% of them had a comorbid depressive disorder alone (26%) or in association with anxiety disorders (14%); anxiety disorder alone was less frequent (8%) and the other Axis I disorder were substance use (8%) and obsessive-compulsive disorder (2%). These percentage are similar to those presented in a meta-analysis conducted in 1683 HR subjects (baseline prevalence of depressive and anxiety disorders respectively 41% and 15%). As far as
30 the psychopathological field may concern, the depressive and anxiety comorbidity were associated with higher suicidality and self-harm behaviours, disorganized/odd/stigmatizing behaviour, avolition/apathy and with impaired global functioning. Thus, a proportion of individuals meeting criteria.
for the HR state could be those from the general population with affective psychopathology and (poor outcome) the co-presence of psychotic experiences (PEs). In other words, some ‘ transitions ’ to psychotic disorder in HR studies may represent the poor outcome of the general population subgroup of individuals with affective disorder and the co-presence of psychotic symptoms. Depending at which point along the extended psychosis phenotype help-seeking individuals are selected (e.g. from individuals with mild PEs but without co-morbid affective disorder, to individuals with PEs and co-morbid affective disorder to individuals with severe and multiple persistent PEs), subsequent transition risks may be higher or lower.
Even if most of the studies about Axis I comorbidity and HR state consider depression as the most salient mood dysregulation it’s doubtless that mania and bipolar disorders share a common ground with psychosis. There is substantial overlap between dimensions of mania and psychosis in clinical samples, which may be due to the sharing of genetic and non-genetic aetiological influences. Familial co-aggregation suggests that psychosis shares common genetic risk factors with mania[79] and recent studies have indeed implied shared susceptibility genes[80, 81]. Although there are quantitative differences in effect size, risk factors such as life events, ethnic group, prenatal famine and urban birth also tend to overlap to a degree between psychotic and mood disorders as do cognitive impairments and high levels of neuroticism prior to the onset of disorder[82].
31 Stress
As the vulnerability—stress-coping model suggests, the inability to cope with stressful situations represents one of the key features of psychosis.
As described before, HR subjects as well as those with a full blown psychosis, present anomalies at the HPA level with increase basal cortisol levels and blunted cortisol response. It’s not clear if these features are the predisposing groung for reduced tolerance to life avents or stressors or, on the contrary, if they are the consequence of high levels of perceived stress. Evidences, anyway, confirm that stressful life events frequently precede onset of psychotic illnesses and psychotic relapses; 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 also minor life events or ‘‘daily hassles’’ (e.g. rushing to meet a deadline, transportation problems, etc.) may cause severe stress and not only major, events such as deaths or separations[84]. It is also likely that it is the subjective experiences of stress, rather than stressful events per se, that may be relevant to outcome. In a study by Horan et al. (2005) [85]schizophrenia patients reported lower rates of life events than healthy controls and they appraised both positive and negative life events as less controllable and more poorly managed, and rated positive life events as less desirable. 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. Ratings of self-reported daily stressors are positively correlated with depressive and anxious symptom severity[86] in a vicious cycle: higher levels of anxiety worsen the ability to cope with stress increasing anxiety and distress. Among prodromal and ultra-high risk cohorts, an association at baseline between
psychotic-32 like symptoms and lifetime experience of major stressors has been reported[87], and a significant association was found between ‘impaired tolerance of normal stress’ and psychosis onset in the PACE cohort[88]. Cognitive behavioural therapy seems to be one of the most efficacious tools to develop new coping strategies and to correct those cognitive and metacognitive biases which can led to psychosis.
Trauma
Individuals who are at risk of developing psychosis tend to have experienced problematic early social environments or potentially traumatic events. These events may operate to undermine optimal social, emotional and cognitive development of the person through the violation of important attachment and bonding experiences undermining the ability to reflect on their own cognitive processes, regulate affect and mentalize the beliefs and intentions of others.
Adolescents who report experiencing psychotic symptoms are six times more likely to have experienced physical abuse, ten times more likely to have witnessed domestic violence, and more likely to be both a victim and perpetrator of bullying[89]. The results of these retrospective studies remained significant when controlling for possible confounds such as urbanicity, gender, family history of mental illness, and cannabis or other drug use. There is also an association between childhood trauma and the severity of the symptom and course of schizophrenia. Furthermore, trauma exposure is related to mood symptom severity, such as depression and anxiety, in patients diagnosed with non-affective psychoses. [90]. Several studies examined the impact of trauma among a sample of HR individuals. One of them reported that in a
33 small sample of 30, 97% endorsed at least one general trauma experience, 83% reported physical abuse, 67% emotional abuse, and 27% sexual abuse and that total trauma was positively associated with severity of attenuated positive symptoms (in particular grandiosity)[91, 92]. A second study from Melbourne found that approximately 70% of their sample of 92 HR individuals had experienced at least one type of trauma, and that the rates of conversion to psychosis significantly increased when the type of trauma was sexual abuse[93]. A recent study involved 360 HR subjects and 180 controls. Within the HR group, there were gender differences as females had been more often exposed trauma but not bullying, relative to males. Moreover, those who had experienced trauma had higher levels of anxiety and depression as well as a negative sense of self and others. Finally, bullying was generally associated to poorer functioning[92]. Another group investigated the relationship between childhood trauma and psychotic experiences examining the critical issue of factors that may explain this association studying the mediating role of social defeat (intended as feelings of deceased value and outsider status) and affective dysregulation (mostly depressive symptoms). They hypothesized that in general population, trauma predicted the experience of social defeat which further depressive and psychotic symptoms, while in those with a psychotic disorder, social defeat but not depressive symptoms accounted for the association between trauma and psychosis[94]. Selten et al. argued that social defeat can be considered cause (humiliation triggers pathogenic mechanisms) and consequence of psychosis (social drift)[95]. Some author raised the problem about the subjectivity of what can be considered as “traumatic”. What has been observed, anyway, is that intentional harm has a greater pathogenic effect than unspecific distress (e.g. interpersonal trauma vs accidents/bereavement; social inequality vs poverty). This stresses again the point that the psychological attitude and the personal attribution of significance to life negative
34 events pays the major role in the development of the disorder. Anyway the eziopathogenetical mechanism of early trauma in psychosis onset is probably related to the hyperresponsivity of the hypothalamic-pituitary-adrenal (HPA) axis (as described above). An alternative explanation could be that An alternative is that the subtle social and motor abnormalities of premorbid schizophrenia may increase the likelihood that a child will experience trauma, such as being victimized or abused.[91].
Substance abuse
Drug abuse is increasingly becoming very common in many countries. A lot of research effort has gone into investigating its association with psychiatric illness. It is estimated that schizophrenic population has one of the highest rates of nicotine dependence. Prospective studies suggest that substance use can contribute to the onset of psychosis in individuals, irrespective of an identified risk for illness [96]. The evidence to date is most consistent for cannabis use[97]. The principal constituents of cannabis are Δ9-tetrahydrocannabinol (Δ9-THC) and cannabidiol. The former is the main psychoactive ingredient and in experimental studies it produces transient psychotic symptoms and impaired memory in a dose-dependent manner. In contrast, cannabidiol does not induce hallucinations or delusions, and it seems to antagonise the cognitive impairment and psychotogenic effects caused by Δ9-THC.[98, 99]. The higher the concentration of THC in cannabis the higher the risk to develop psychotic symptoms. In a recent study it has been demonstrated that patients with a first episode of psychosis preferentially used high-potency cannabis preparations of the sinsemilla (skunk) variety. This is not surprising since an experimental study in normal humans
35 tested the acute effects of intravenous administration of Δ9-THC and found that the resulting psychotic symptoms were dose-dependent[100].
It is estimated that cannabis use in psychiatric population is double that found in the general population and continued use of cannabis is associated with poor outcome and more frequent and earlier relapses[101]. Moreover, there is an association between cannabis use and increased levels of psychotic experiences in non-clinical general population surveys[102]. Very often, people report they take cannabis to overcome negative feeling or to feel happier. This is consistent with the self-medication hypothesis by Howes et al.[103]. He stated that 1. Psychotic patients are more likely to consume cannabis for the self-medication; 2. Cannabis could cause psychosis; Cannabis could contribute to the risk of psychosis by precipitating a chain of events; 4. Cannabis could prolong psychotic illness in people already affected.
After these premises it seems clear the importance of investigating the role of cannabis use in HR subjects. The longitudinal studies in this area report contrasting findings. For example, a history of substance misuse was present in higher percentage in those individuals who later developed psychosis [104] although, in the PACE cohort, neither cannabis use nor dependence in the year prior to contact with services was associated with a higher risk of developing psychosis during the following year [105]. The PACE sample, however, assessed help-seeking individuals, who are not perfectly representative of the whole population of people at risk of psychosis. Furthermore, individuals with high levels of cannabis use may be less motivated to seek treatment. The Edinburgh High Risk study found out that those who used cannabis or other illicit drugs were more likely to have psychotic-like symptoms at baseline[106],but no longitudinal data examining substance use as a risk factor for transition to psychosis were available.
36 Poor functioning
Social functioning deficits, including maintaining employment and an own accommodation, and generally functioning adequately and satisfactorily in the community, are one of the defining features of psychosis. Social and functional deterioration is also a marked feature of the early phases of the illness. Since the onset of psychosis usually occurs in the late adolescence, disruptions of social functioning at this phase of development can have a detrimental impact on the long-term the duration of untreated psychosis[107] and long-term clinical outcomes. For example, there is evidence that difficulties in maintaining social networks among individuals with first episode psychosis predate first hospitalization. In addition, most clinical and psychosocial deterioration occurs within the first 5 years of the onset of the illness, suggesting that this is a critical period for treatment initiation. Pharmacological and psychosocial treatments delivered during at this stage can have a stronger impact than comparable treatments provided later in the illness. These findings taken altogether suggest that interventions should be initiated as early as possible, optimally prior to the onset of illness, when social, academic, and occupational skills are acquired and solidified.
Different research strategies have been developed to address social functioning in the pre-psychotic phases. HR subjects ,especially those who are at genetic risk for psychosis, frequently show a pattern of social dysfunction characterized by general social withdrawal, hostility and aggression, poor engagement with peers, immaturity, academic deficits and social adjustment deficits[108]. Despite some preliminary studies suggesting that poor functioning was predictive of psychosis in the following twelve months[109], very little empirical evidence is available to address the
37 longitudinal impact of social dysfunction on the long-term outcomes in people at ultra-high clinical risk for psychosis. Previous investigations comparing a number of baseline measures between subjects who converted versus those who did not convert to psychosis found that only social functioning showed a significant between-group difference[110]. These results were confirmed by a recent multicentre study which found that social impairment in association with other risk factors contributed to the 30 months prediction of transition in subjects at clinical risk of psychosis[111]. A recent paper confirmed that HR subjects tend to be more functionally impaired than healthy controls (i.e. living in communal establishments vs living at home with their parents; higher rates of unemployment) and unemployment seemed to be a risk factor for the development of a frank psychotic disorder[112].
The evidence that poor functioning at intake predicted onset of psychosis has been replicated in several separate ultra-high risk cohorts[28]. 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 lower 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. Finally, the experience of HR symptoms per se is associated with decline in global functioning and quality of life.
One of the factors that seems to impact heavily on global pre-onset functioning, is neuro and social cognition.
38 Neurocognition
Cognitive deficits are recognised as one of the core features of psychotic spectrum disorders and have been associated with functional outcome[113]. Recent research has attempted to detect the presence of cognitive deficits prior to illness onset, as they may represent neurocognitive trait markers for the disease. Widespread mild cognitive deficits are present in HR individuals, falling at a level that is intermediate between that of healthy individuals and those diagnosed as having schizophrenia[114] and comparable with those at familial (“genetic”) risk and with follow-back premorbid data[115]. One promising marker is working memory, which is consistently impaired throughout the course of the illness[116]. It has been 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[117]. The 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[118]. Two recent meta-analyses of more than 1000 HR individuals matched with control subjects yielded small-to-medium impairments across most neurocognitive domains[119]. Either neuro than social cognition are strictly related to global functioning in HR subjects. However, despite this, the predictive value of neurocognitive variables has proved to be disappointingly poor.
39
Outcomes
Possible outcomes in HR population
Transition to psychosis
There is a common acceptance within the field that the definition of “ transition to psychosis” is somewhat arbitrary. According to DSM a Brief Psychotic Disorder is an illness that lasts from 1 day to 1 months after which the patient eventually return to the premorbid level of functioning. In the HR literature, the threshold is higher and a variety of criteria have been used to define the transition to psychosis[120]. The most used criteria are based on the CAARMS criteria by Yung et al.[83]. They require the occurrence of at least 1 fully positive psychotic symptom several times a week for more than 1 week. The SIPS criteria, instead, require the presence of at least 1 fully positive psychotic symptom several times per week for at least 1 month or at least 1
40 fully psychotic symptom for at least 1 day if this symptom is seriously disorganizing or dangerous[121].
The lifetime prevalence of psychosis in general population range from 0,7% for schizophrenia[122] to higher percentages for the other disorders belonging to the psychotic spectrum[123].
It’s a well replicated evidence that people seeking help for prodromal symptoms have higher risk to develop a frank psychotic disorder than general population. In a recent meta-analysis of about 2500 HR individuals the transition risk was 18% at 6 months, 22% at 1 year and 32% at 3 years[124]. Anyway, two third of those individuals do not “transit” to psychosis in the medium-term. These individuals are the so called “false positive”. This issue has sparked a heated discussion. One hand the “high number” of non-converters raised scepticism because of the risk of stigmatizing young adults which are introduced into a path of care potentially not necessary. These concerns, anyway, tend to be overestimated since the predictive value of HR criteria is much higher than other “at risk conditions” in different medical fields world-widely accepted such as Mild Cognitive Impairment or Dementia ( 12% per year) or pre-diabetes for pre-diabetes (11% per year) [29].
HR state is indubitably a pleiotropic condition related to several potential outcomes including non-psychotic disorders. It could be considered analogous of chest pain (a condition requiring diagnosis and treatment and possibly indicating myocardial infarction but also panic attack, pulmonary embolism, gastroesophageal reflux etc) and detecting early signs and symptoms, even if with low specificity, may allow preventive interventions and a better outcome[125]. The general consideration is that the HR clinics recruits only help-seeking individuals so, independently on the event “transition”, they manifest psychological distress and need for care.
41 Another important issue is that in recent years there seems to be a decrease in the transition rate. One possible explanation could be that HR individuals present only transient subthresold symptoms that are not actually indicative of impending psychotic illness. Moreover, the attention in detecting subthreshold psychopathology has recently increased heightening the percentage of individuals with low severe symptomatology. It’s worth to remember that subclinical psychotic experiences can occur in general population or in the context of other psychopathological disturbances such as depression, anxiety or substance use disorders and are not specific markers of an impending psychotic disorder [32, 123, 126, 127].
Another possible explanation for the decrease of transition rate can be the effect of pharmacological and psychological treatment that can delay or prevent the psychosis onset (the so called “false false positive”). That is to say, those individuals who would have developed a psychotic disorder have undertaken a care path which prevented the transition. The third hypothesis is a led time bias that is earlier detection resulting in transitions seemingly occurring later [128, 129].
Besides, some authors tested if transition rates could vary according with the diagnostic instrument used, namely CAARM or SIPS, but percentages within 2 years seem to be overlapping: 27,4% and 28,1% respectively[124].
Another source of concern by many researchers derives from the CAARMS and the SIPS criteria for the event “transition” since it focuses only on positive symptomatology. This was originally done to link the transition point when antipsychotic treatment was thought to be indicated. Since the psychopathological heterogeneity of the HR sample these vision of transition seems clearly too narrow. Those HR subjects who develop a full blown psychosis may transit to a schizophrenic spectrum disorder or to an affective psychosis. A recent meta-analysis included a total of 2182 HR, 26% of which developed a psychotic disorder over the follow-up time.
