Introduction
Kraepelin [Reference Kraepelin1] and Bleuler [Reference Bleuler2] outcomes in patients with psychosis have been studied extensively. Both clinical and functional outcomes are important. For everyday well-being, functional outcomes are often considered the most important factor by patients and caregivers [Reference Karambelas, Filia, Byrne, Allott, Jayasinghe and Cotton3]. Negative symptoms, poor premorbid psychosocial development, educational and occupational achievements, male sex, single marital status, and a lack of interpersonal networks have all been associated with a poor illness course and worse functional outcomes in patients with psychosis, particularly in those with schizophrenia [Reference Salokangas4–Reference Salokangas, From, Ilonen, Luutonen, Heinimaa and Armio7]. Moreover, neurocognitive deficits and childhood adversities have been associated with functional outcomes in patients with psychosis [Reference Pantelis, Yücel, Wood, McGorry and Velakoulis8–Reference Trotta, Murray and Fisher10].
The onset of psychosis is often preceded by milder-than-psychosis psychiatric disturbances, such as the prodromal stage [Reference Kraepelin1], latent schizophrenia [Reference Bleuler2], pseudo-neurotic schizophrenia [Reference Hoch and Polatin11], basic symptoms [Reference Huber12], the basic symptom criterion “cognitive disturbances” [Reference Klosterkötter, Hellmich, Steinmeyer and Schultze-Lutter13, Reference Schultze-Lutter, Klosterkötter, Picker, Steinmeyer and Ruhrmann14] and ultra-high-risk and clinical high risk of psychosis (CHR-P) [Reference Yung and McGorry15, Reference McGlashan, Miller and Woods16]. In follow-up studies, less than 30% of the patients seeking help for CHR-P have converted to psychosis [Reference Simon, Velthorst, Nieman, Linszen, Umbricht and De Haan17, Reference Fusar-Poli, De Pablo, Correll, Meyer-Lindenberg, Millan and Borgwardt18]; however, for patients meeting both ultra-high-risk and cognitive disturbance criteria, the conversion rate is higher [Reference Schultze-Lutter, Klosterkötter and Ruhrmann19]. A majority of nonconverted CHR-P patients, including those meeting cognitive criteria, experience other clinical disturbances and functional deficits in clinical settings [Reference Beck, Andreou, Studerus, Heitz, Ittig and Leanza20, Reference Michel, Ruhrmann, Schimmelmann, Klosterkötter and Schultze-Lutter21] and in community life [Reference Michel, Osman, Rinaldi, Schimmelmann, Kindler and Schultze-Lutter22].
CHR-P patients are characterized by clinical disorders, particularly affective disorders, impairments in working ability, and deficits in educational and social functioning [Reference Fusar-Poli, De Pablo, Correll, Meyer-Lindenberg, Millan and Borgwardt18]. In outcome studies of CHR-P patients, premorbid psychosocial adjustment, childhood adversities, negative and disorganised symptoms, neurocognitive deficits, depression, and poor employment/study situations have been shown to predict poor functional outcomes [Reference Salokangas, Heinimaa, From, Löyttyniemi, Ilonen and Luutonen23–Reference Koutsouleris, Kambeitz-Ilankovic, Ruhrmann, Rosen, Ruef and Dwyer26]. Lifetime affective diagnoses are very common in CHR-P patients [Reference Salokangas, Ruhrmann, Von Reventlow, Heinimaa, Svirskis and From27]. Using combined clinical and neuroimaging machine learning modelling, Koutsouleris et al. [Reference Koutsouleris, Kambeitz-Ilankovic, Ruhrmann, Rosen, Ruef and Dwyer26] reported that persistent social functioning impairments were associated with an increased risk of psychotic, depressive, and anxiety disorders at follow-up in CHR-P patients.
In the present naturalistic study, we focused on functioning, which encompassed psychiatric symptoms and functional disability, over an 18-month follow-up period in patients in the early stages of psychosis. Using premorbid and baseline factors and follow-up symptoms as predictors, our aim was to identify the precursors associated significantly with functional outcomes at baseline (T0), 9 months (T1), and 18 months (T2) among recent-onset psychosis (ROP) and CHR-P patients. We used univariate and multivariate general linear models for repeated measures (GLMrm) and path analyses to analyse mediating processes between precursors and functioning. We suggest that premorbid psychosocial adjustment, childhood adversities and preadmission affective disturbances, together with clinical, functional, and neurocognitive characteristics at the first clinical assessment, provide the most relevant and necessary information for clinicians. This information is essential when planning and implementing interventions aimed at supporting functional recovery. The inclusion of follow-up symptoms in predictive models is justified, as the early phase of treatment extends through the first month postadmission, when individually tailored interventions should be adapted to meet the patient’s changing needs. This strategy was used in a previous follow-up study of patients with CHR-P and patients with a recent-onset depression [Reference Koutsouleris, Kambeitz-Ilankovic, Ruhrmann, Rosen, Ruef and Dwyer26].
Material and methods
This study is part of the Personalized Prognostic Tools for Early Psychosis Management (PRONIA; https://www.pronia.eu/) study, carried out in five European countries. All procedures contributing to this work comply with the ethical standards of the relevant national and institutional committees on human experimentation and with the Helsinki Declaration of 1975, as revised in 2008. All participants (if minors, also their guardians) provided their written informed consent prior to study inclusion. The PRONIA was registered at the German Clinical Trials Register (DRKS00005042) and approved by the local research ethics committees in each location.
PRONIA recruited young help-seeking patients with ROP, CHR-P, a recent-onset depression, and healthy controls between February 2014 and May 2016. The first publication resulting from the PRONIA study [Reference Koutsouleris, Kambeitz-Ilankovic, Ruhrmann, Rosen, Ruef and Dwyer26], along with the supplementary methods, provides a detailed description of the study protocol, sampling procedures (including the criteria for ROP and CHR-P patients) [Reference Salokangas, Ruhrmann, Von Reventlow, Heinimaa, Svirskis and From27, Reference First, Spitzer, Gibbon and Williams28], assessments of the examined factors, and analytical methods used. The present study included 296 ROP patients and 262 CHR-P patients. The methods of the present study are described in detail in the Supplementary Material. Baseline and follow-up assessments are briefly described in Figure 1.
Figure 1. Study design with assessments at baseline and follow-up points.
Statistical analyses, described in detail in the Supplementary Material, are summarised as follows. First, to reduce the number of factors and heterogeneity of the scales, the Premorbid Adjustment Scale (PAS), the Structured Interview for Psychosis-Risk Syndromes (SIPS), and neurocognitive test scores were factorised. The following factor dimensions were derived and used as precursors for functional outcomes: the PAS Sociability and Scholastic performance; the SIPS mood and stress, negative, positive, and disorganised dimensions; cognitive domains of social cognition; processing speed; working memory; verbal learning (memory); attention, and the sum of these factors (global). These and other outcome precursors, sociodemographic backgrounds, lifetime nonpsychotic diagnoses, and medications are described in Table 1 and Figure 1. Differences in the distributions and mean scores of the precursors between ROP patients and CHR-P patients were tested with the χ2 test and Mann–Whitney U test, respectively.
Table 1. Distribution of background and means (SD) of PAS and neuropsychological test dimension scores, CTQ, SIPS, medication, and GAFsd scores by diagnosis (recent onset of psychosis, ROP; clinical high risk of psychosis, CHR-P)
Abbreviations: CTQ, Childhood Trauma Questionnaire; GAFsd, Global Assessment of Functioning, Symptoms and Disability; OLANZ, olanzapine; PAS, Premorbid Adjustment Scale dimension scores; SIPS, Structural Interview of Prodromal Syndromes; SSRI, Serotonin selective reuptake inhibitor.
Note: Differences between ROP/CHR-P (χ2 *and Mann–Whitney U test §: p1). Associations of each factor with follow-up functioning in a linear general model repeated measures (p2 and eta squared η2).
Associations between the precursor factors and follow-up functional outcomes, assessed using GAFsd at T0, T1, and T2, were analysed using a general linear model for repeated measures (GLMrm). Although GAFsd at T0 represents baseline functioning, it also represents an outcome factor in relation to the preadmission stage (PAS, CTQ, and previous treatment) and was therefore included in the conceptualisation of follow-up functional outcomes. In the univariate GLMrm analyses, background, preadmission, and clinical factors were introduced as independent precursor variables to predict follow-up functioning (Table 2). In multivariate GLMrm analyses, the explanatory variables that had an indicative (p < 0.1) association with functioning (Table 1), according to univariate GLMrm analyses, were included in the model (Stage 1). The factors with nonindicative (p > 0.1) associations with functioning were subsequently omitted one by one (Stage 2). Finally, follow-up symptoms were included in the model, and all nonsignificant (p > 0.5) variables were omitted (Stage 3, Table 3). After each modelling step, the effects of omitted variables were tested and included if they did not meet the omission criterion. The analyses were carried out for all patients and for the ROP and CHR-P groups separately.
Table 2. Univariate general linear model repeated measures, main effects, for good follow-up functioning (GAFsdT0, GAFsdT1 and GAFsdT2) to each factor separately in all and in recent onset of psychosis (ROP) and clinical high risk (CHR-P) patients separately
Note: Significant associations bolded.
Abbreviations: CTQ, Childhood Trauma Questionnaire; SIPS, Structural Interview of Prodromal Syndromes; SSRI, serotonin selective retake inhibitor; GAFsd, global assessment of functioning, symptoms and disability; T0, baseline examination; T1, 9 months; T2, 18 months; η2, eta squared.
# Marital status: single/ever married; partnership: no/yes; education: no/graduation/university degree; current work: no/yes; PAS: premorbid adjustment scale dimension scores; NEUCOG: neurocognitive test dimension scores.
Table 3. Multivariate general linear model repeated measures for good follow-up functioning (GAFsdT0, GAFsdT1, and GAFsdT2) in all and diagnostic groups separately, including follow-up symptoms
Note: Significant associations only.
Abbreviations: NEUCOG, neurocognitive test dimension scores; PAS, Premorbid Adjustment Scale Dimension Scores; SIPS, Structural Interview of Prodromal Syndromes; GAFsd, Global Assessment of Functioning, symptoms and disability; η, eta squared; T1: 9 months’ follow-up; T2: 18 months’ follow-up.
# Education: no/graduation/university degree; #current work: no/yes.
To analyse mediation processes, path analyses were performed, and a PROCESS macro in SPSS (model template 4) by Hayes [Reference Hayes36] was used. In the present study, we applied a prospective model to analyse the effects of preadmission precursor PAS and CTQ domains on follow-up functioning [GAFsdT1 + GAFsdT2], with neurocognitive and SIPS domains as mediators. We also analysed the indirect effects of neurocognitive and SIPS domains on follow-up functioning, with follow-up symptoms as mediators. The data were analysed using SPSS software (28.0 for Windows). p Values less than 0.05 (two-tailed) were considered to indicate statistical significance. Effect size is indicated by eta squared (η 2).
Results
Compared with CHR-P patients, ROP patients were more often males and older and were less likely to work. They also had more neurocognitive deficits and positive SIPS symptoms, and their GAFsd scores were lower at baseline and at follow-up (Table 1). A total of 50.0% of ROP patients and 43.1% of CHR-P patients had been treated for a lifetime nonpsychotic disorder (χ2 = 2.621, p = 0.125). Lifetime affective disorders, depression, and anxiety were more prevalent among the CHR-P patients (38.9% vs. 22.9%, χ 2 = 16.647, p < 0.001) (Supplementary Table 1). CHR-P patients received antidepressant medication more often than ROP patients did, but there was no difference in the use of medication for psychosis (Table 1). Compared with females, males were more often single, lived less often in partnerships, and had lower education levels. Compared with males, females reported fewer problems with PAS scholastic performance (−0.27 vs. 0.23; p < 0.001) (Supplementary Table 2).
Compared with ROP patients, CHR-P patients had more depression at T1 and T2, and more anxiety at T2. There was no significant difference in psychotic symptoms (Supplementary Figure 2). Follow-up medication use was also not significantly different between diagnostic groups (Supplementary Figure 3a). However, patients who received preadmission treatment for nonpsychotic disorders were more likely to receive both antidepressant and antipsychotic medication at T0 and T1 than were those who did not receive such treatment (Supplementary Figure 3b).
In the univariate rmGLM, female sex, good education and work situation, PAS sociability and scholastic performance, low emotional abuse, low emotional neglect and physical neglect scores, numerous lifetime nonpsychotic diagnoses, good performance in all the NEUPSY domains, and low scores in all the SIPS dimensions were associated with good functional outcomes (Table 2). In ROP patients, a good work situation, good PAS sociability and scholastic performance, low emotional and physical neglect scores, good performance in all the NEUPSY domains, and low scores in all the SIPS dimensions were associated with good functioning (Table 2). In the CHR-P patients, female sex, a good work situation, good sociability, low scores for emotional and physical abuse and emotional neglect, a high number of lifetime nonpsychotic diagnoses, better performances in social cognition, faster processing of verbal learning tasks, and low scores in all but the positive SIPS dimension were associated with good functioning. Medication was not associated with functional outcome (Table 2). However, the SSRI and OLANZ equivalents correlated with each other in all patients (ρ = 0.196; p < 0.001) and in ROP (ρ = 0.232; p < 0.001) and CHR-P (ρ = 0.211; p = 0.001) patients, indicating a combined use of SSRIs and OLANZs.
Patients with previous affective disorders had higher GAFsd scores at baseline, at T1 and at T2 (Supplementary Table 5). Patients who were working had the best functional outcomes, whereas those who were unable to work had the poorest functional outcomes. There was no difference between unemployed patients and those who did not work for other reasons (Figure 2).
Figure 2. Functional outcome in univariate general linear model repeated measures of Global Assessment of Functioning, symptoms, and disability (GAFsdT0, GAFsdT1, and GAFsdT2) by current work situation in the whole sample (ROP and CHR-P). T0 = Baseline, T1 = 9 months follow-up, T2 = 18 months follow-up.
Significance of differences:
Not working versus Working (p = 0.026), Unemployed (p = 706), Unable to work (p = 0.003).
Working versus Unemployed (p < 0.001), Unable to work (p < 0.001).
Unemployed versus Unable to work (p = 0.001).
Multivariate rmGLM analysis revealed that good functional outcomes were associated with female sex, good education and work status, high PAS sociability, lifetime nonpsychotic disorders, and good verbal learning. Poor functioning was related to high scores in all the SIPS dimensions, as well as elevated anxiety and depression at T1 and depression and psychotic symptoms at T2 (Table 3 and Supplementary Table 6a). In ROP patients, female sex, a good work situation, and good working memory were associated with good functioning, whereas high scores in the SIPS negative and disorganisation dimensions, high scores in mood/stress, high follow-up anxiety and depression at T1, and psychotic symptoms at T2, were associated with poor functional outcomes (Table 3 and Supplementary Table 6b). In the CHR-P patients, female sex, a good work situation, high PAS sociability, high social cognition, and a high number of nonpsychotic lifetime diagnoses were associated with good functioning, whereas depression at T1 and T2 and psychotic symptoms at T1 were associated with poor functioning (Table 3 and Supplementary Table 6c). Among the SIPS dimensions, only disorganized symptom scores correlated significantly with lifetime nonaffective disorders (ρ = −0.238; p < 0.001).
In path analyses, the precursors that were omitted in multivariate rmGLM were tested as mediators. The effect of PAS scholastic performance on functioning was mediated through certain NEUPSY and SIPS dimensions and follow-up symptoms. Some CTQ and NEUPSY components were associated with functional outcomes via certain SIPS and follow-up symptoms (Supplementary Table 7a-g).
The sensitivity analysis for functional outcome (limited to GAFsdT0 and GAFsdT1) indicated that the effect of depression at T2 in CHR-P patients and of the SIPS negative dimension in ROP patients became more pronounced over a longer follow-up period (Supplementary Table 8).
Discussion
According to the major results, in patients with early-stage psychosis, female sex, good neurocognitive performance, and good baseline work conditions were associated with good functional outcomes, whereas baseline and follow-up clinical symptoms were associated with poor functional outcomes. In ROP patients, severe baseline negative, disorganised, and mood/stress symptoms were associated with poor functional outcomes. In CHR-P patients, good childhood sociability and preadmission occurrence of affective disorders were associated with better functional outcomes. Furthermore, poor scholastic performance in childhood and childhood adverse experiences were indirectly associated with poor functional outcomes through other precursors.
Sex and functional outcomes in early psychosis
In agreement with the findings of several previous studies [Reference Salokangas4–Reference Salokangas, From, Ilonen, Luutonen, Heinimaa and Armio7, Reference Jablensky, Sartorius, Ernberg, Anker, Korten and Cooper37, Reference Häfner, Maurer, Löffler, Van Der Heiden, Hambrecht and Schultze-Lutter38], male sex was associated with poor functioning at follow-up. Compared with female patients, male patients demonstrated poorer premorbid scholastic performance and adult education, partly explaining sex differences in functional outcomes. Thus, educational difficulties may present a special challenge for care systems aiming to rehabilitate male patients into occupational activities. Compared with females, males may prefer rehabilitative measures comprising physical (manual) and technical training and occupational or work rehabilitation supported by neurocognitive interventions [Reference Medalia and Saperstein39]. Self-esteem and overall wellbeing are more closely related to satisfaction with daily occupations for men than for women [Reference Eklund, Hansson and Bejerholm40]. To improve the functional outcomes of male patients, care services should consider their specific problems and needs, especially because psychosocial functional deficits are reported as the main driver of help-seeking males [Reference Osman, Michel, Schimmelmann, Schilbach, Meisenzahl and Schultze-Lutter41].
Effects of childhood adjustment and adversity on functional outcomes in early psychosis
In line with the findings of previous studies, patient premorbid adjustment is associated with functional outcomes [Reference Salokangas and Stengård5, Reference White, Stirling, Hopkins, Morris, Montague and Tantam6, Reference Salokangas, Heinimaa, From, Löyttyniemi, Ilonen and Luutonen23, Reference Dwyer, Buciuman, Ruef, Kambeitz, Sen Dong and Stinson42]. In the present study, childhood sociability, i.e., the ability to engage in and tolerate human social interaction, may be genetically programmed [Reference López-Tobón, Trattaro and Testa43], explaining why its effect extends from childhood to adulthood in patients in the early state of psychosis. In contrast, the effect of scholastic problems on functional outcomes was mediated through neuropsychological deficits, baseline negative and disorganised symptoms, and follow-up depression and psychotic symptoms.
Childhood sociability and scholastic deficits are associated with negative symptoms, indicating that they may have their roots in early premorbid adjustment. In alignment with these findings, negative symptoms (such as flat affect) have been associated with poor premorbid sociability and poorer social and occupational outcomes in patients with first-episode psychosis or attenuated psychotic symptoms [Reference Tarbox-Berry, Perkins, Woods and Addington44]. Clustering of difficulties in premorbid adjustment, negative symptoms, and poor functional outcomes is also detectable trans-diagnostically [Reference Dwyer, Buciuman, Ruef, Kambeitz, Sen Dong and Stinson42]. Accordingly, therapeutic and rehabilitative measures that aim to strengthen early social and educational functioning may improve the functional prospects of patients with psychosis and may also facilitate their clinical recovery from negative symptoms. This approach is important for young patients, especially young males.
Multivariate analyses revealed that CTQ or its domains, particularly emotional and physical neglect, were not associated with functional outcome because their effects on functional outcome were mediated through other precursors, such as baseline negative symptoms and follow-up symptoms. Previous studies have shown that childhood adversities are associated with mental disorders among adults, such as depression, anxiety, and psychosis [Reference McKay, Kilmartin, Meagher, Cannon, Healy and Clarke45]. Our study revealed that the negative effect of childhood adversity extends through affective and psychotic disturbances to functional outcomes. Thus, when treating patients in the early state of psychosis, it is important to scrutinise their stressful and traumatic childhood experiences and start early trauma-focused psychotherapeutic interventions to facilitate their clinical and functional recovery [Reference Coventry, Meader, Melton, Temple, Dale and Wright46].
Effects of work and educational situation on functional outcomes in early psychosis
Employment and work situation are among the most important factors that are repeatedly associated with functional outcome in patients with psychosis [Reference Kraepelin1, Reference Salokangas, Heinimaa, From, Löyttyniemi, Ilonen and Luutonen23, Reference Tsang, Leung, Chung, Bell and Cheung47]. Indeed, work is an essential indicator of functioning. In the present study, approximately half of all patients were employed, with fewer employed ROP patients than CHR-P patients, and the baseline work situation was strongly associated with follow-up functioning in both patient groups. Consequently, in addition to effective interventions that alleviate neurocognitive deficits and clinical symptoms, direct work-related rehabilitation may enhance the work/employment status of patients with psychosis. Supported employment, which is based on the place-and-train strategy (individual placement and support; IPS), is an effective method for improving patients’ ability to return to, or initiate, work or educational activities [Reference Modini, Tan, Brinchmann, Wang, Killackey and Glozier48, Reference Rosenheck, Mueser, Sint, Lin, Lynde and Glynn49]. In the present study, the patients who were not working or were unemployed (25%), as well as some of the patients who were on temporary sick leave, may be among those who would most benefit from IPS intervention. In addition to providing income, successful employment provides opportunities to build social support networks, engage in daily activities, and maintain the structure that is essential for individuals with severe mental illness [Reference Nicholson, Wright and Carlisle50]. The benefits of employment include increased self-esteem and self-confidence, experiences of success, greater independence, improved social integration and community participation, and reductions in negative and depressive symptoms, which all improve functioning and quality of life [Reference Marwaha and Johnson51, Reference Wallstroem, Pedersen, Christensen, Hellström, Bojesen and Stenager52].
Effects of neuropsychological performance on functional outcomes in early psychosis
In alignment with the findings of previous studies [Reference Pantelis, Yücel, Wood, McGorry and Velakoulis8, Reference Niendam, Bearden, Johnson, McKinley, Loewy and O’Brien53–Reference Squarcina, Kambeitz-Ilankovic, Bonivento, Prunas, Oldani and Wenzel55], neuropsychological deficits are associated with poor functional outcomes in both ROP patients and CHR-P patients. Multivariate analyses revealed that the effects of neuropsychological deficits on functional outcomes were mediated mainly through baseline and follow-up clinical symptoms. The direct effect of the individual neuropsychological tests varied between diagnostic groups. Verbal learning and working memory deficits have repeatedly been associated with poor functioning in patients with severe psychosis (e.g., schizophrenia) [Reference Niendam, Bearden, Johnson, McKinley, Loewy and O’Brien53], whereas deficits in social cognitive functioning are associated with poor functional outcomes in UHR patients [Reference Glenthøj, Fagerlund, Hjorthøj, Jepsen, Bak and Kristensen24]. Neurocognitive interventions, e.g., neurocognitive enhancement therapy or cognitive remediation, may essentially improve patients’ capacity to cope with the requirements of various work tasks [Reference Bell, Zito, Greig and Wexler56–Reference Lystad, Falkum, Haaland, Bull, Evensen and McGurk59], while continuous work and occupational activities may maintain the positive effects achieved by neurocognitive interventions.
In severely disturbed patients, psychoeducation reduces relapses and readmission, promotes medication compliance, and improves overall well-being [Reference Xia, Merinder and Belgamwar60]. Additionally, less demanding work activities (e.g., sheltered employment), supported housing (e.g., rehabilitation homes), strong social support (e.g., caregivers), and assistance with daily routines, personal hygiene, appearance, and even transportation to the workplace may be needed [Reference Kohn-Wood and Wilson61]. No patient who has recovered from psychosis is unsuitable for supported employment.
Treatment of affective disorders may improve functional outcomes in the early state of psychosis
In ROP patients, the effect of the mood/stress dimension and follow-up anxiety and depression symptoms on functioning extended over the first nine follow-up months (T1), indicating that depression is intrinsic to the early stages of psychotic disorders [Reference Upthegrove, Lalousis, Mallikarjun, Chisholm, Griffiths and Iqbal62]. Depressive symptoms during first-episode psychosis have been associated with poorer long-term global functioning [Reference McGinty and Upthegrove63], even across diagnostic categories [Reference Dwyer, Buciuman, Ruef, Kambeitz, Sen Dong and Stinson42]. Häfner et al. [Reference Häfner, Maurer, Löffler, Van Der Heiden, Hambrecht and Schultze-Lutter38] suggested that affective disorders (depression) and schizophrenic psychoses may represent different stages of psychopathology rather than discrete illnesses. With respect to CHR-P patients, Van Oss and Guloksuz [Reference Van Os and Guloksuz64] suggested that the occurrence of subclinical psychotic or psychotic-like symptoms in clinical presentations mainly indicates the severity of affective symptomatology. Schultze-Lutter et al. [Reference Schultze-Lutter, Klosterkötter, Gaebel and Schmidt65] have criticised this conclusion for methodological reasons.
In line with previous studies [Reference Salokangas, Ruhrmann, Von Reventlow, Heinimaa, Svirskis and From27, Reference Fusar-Poli, Nelson, Valmaggia, Yung and McGuire66, Reference Falkenberg, Valmaggia, Byrnes, Frascarelli, Jones and Rocchetti67], CHR-P patients were emblematically characterised by affective disturbances, particularly depression. There was a continuum of depression from baseline over the first nine follow-up months. Interestingly, CHR-P patients with preadmission treatment for nonpsychotic (90% affective) disorders formed a clinically less disturbed group with relatively good functional outcomes. They had received more antidepressants and antipsychotics than untreated patients, both at the time of admission and during the postadmission period. Most likely, CHR-P patients with a history of previous treatment had already developed a good treatment relationship that guaranteed more intensive care, including medication during follow-up, and supported functional outcomes. After admission, functioning improved much more in ROP patients than in CHR-P patients. It is possible that improving functioning in ROP patients was associated with the recovery, either spontaneous or due to antipsychotic treatment, of positive psychotic symptoms. In CHR-P patients, the effect of a reduction in psychotic-like symptoms on functioning was weaker, and because affective symptoms remained at a higher level during follow-up (Supplementary Figure 2), improvements in functioning were delayed. Overall, affective disorders, particularly depression, constitute a key target for the treatment of early-stage psychoses.
In ROP patients, positive symptoms can be successfully treated with antipsychotic drugs [Reference Leucht, Leucht, Huhn, Chaimani, Mavridis and Helfer68], which explains why baseline SIPS positive symptoms were not significantly associated with functional outcomes. However, at T2, psychotic symptoms were associated with decreased functioning, indicating that long-term treatment of psychotic symptoms and prevention of relapses are needed. In addition to antipsychotic drugs, family interventions, family psychoeducation, and cognitive behavioural therapy are effective at reducing the risk of relapse or psychoses [Reference Bighelli, Rodolico, García-Mieres, Pitschel-Walz, Hansen and Schneider-Thoma69]. In CHR patients, attenuated psychotic symptoms were not directly associated with functioning at follow-up. However, SIPS positive, negative, and mood/stress symptoms were indirectly associated with functional outcomes through follow-up depression, emphasizing the need for treating depression both at admission and during the postadmission period.
In ROP patients, negative symptoms are strongly associated with interpersonal problems from childhood to adulthood. Interventions designed to improve social interaction skills and confidence may gradually reduce negative symptoms and, consequently, improve the overall functioning of patients recovering from psychosis. Antipsychotic drugs (e.g., aripiprazole), cognitive-behavioural therapy, skills-based training, and antidepressants, preferably combined with music and exercise therapy, as well as supported employment, may be effective in alleviating negative symptoms [Reference Lystad, Falkum, Haaland, Bull, Evensen and McGurk59, Reference Veerman, Schulte and De Haan70, Reference Lutgens, Gariepy and Malla71]. Disorganised symptoms are more narrowly associated with poor childhood sociability and impaired neurocognitive performance, indicating that interventions that improve cognitive performance, e.g., neurocognitive remediation, may accelerate the recovery of disorganised symptoms and create a foundation for improving functioning. Combining neurocognitive training programmes with psychosocial rehabilitative measures (e.g., IPS intervention) may reduce the detrimental effects of disorganised and negative symptoms on functioning and maintain positive results during neurocognitive training [Reference Mucci, Galderisi, Gibertoni, Rossi, Rocca and Bertolino72].
In CHR-P patients, early pharmacological and psychological interventions [Reference McGorry, Yung, Phillips, Yuen, Francey and Cosgrave73–Reference Schmidt, Schultze-Lutter, Schimmelmann, Maric, Salokangas and Riecher-Rössler77] reduce the conversion to psychosis, but fail to improve functional outcomes compared with those associated with comparative conditions [Reference Schmidt, Schultze-Lutter, Schimmelmann, Maric, Salokangas and Riecher-Rössler77]. In a review, CHR-P participants who received antidepressant treatment at baseline had a lower risk of transition than those who were not exposed to antidepressants [Reference Raballo, Poletti and Preti78]. However, compared with a psychosocial intervention (cognitive–behavioural case management) alone, fluoxetine medication did not improve young CHR-P patients’ functioning [Reference McGorry, Mei, Amminger, Yuen, Kerr and Spark79]. Given that CHR-P patients are predisposed to both affective and psychotic disturbances, combined antidepressant and antipsychotic treatment may be necessary, particularly to improve functioning. If the clinical recovery of CHR-P patients is delayed, active treatment of psychosis is needed.
Advantages and limitations
The main advantage of this study is that it was conducted across five European countries, each with distinct psychiatric care systems. Thus, the results obtained can be considered practically generalizable to various European treatment systems. However, differences between countries were not analysed. The prospective study design with an 18-month follow-up encompassed an important treatment period for patients with early-stage psychosis. One limitation of the study was the lack of a comprehensive assessment of treatments received prior to baseline and during the follow-up period. Such information may have served as a moderator or mediator. Antidepressant and antipsychotic medications were administered at baseline and at the 9-month follow-up.
An important limitation is the moderately high drop-out rate (35%). Compared with psychotic patients in general, follow-up participants represent help-seeking patients in the early state of psychosis who have higher levels of education, better neurocognitive performance, better work situations, and better baseline functioning. Among the follow-up patients, differences between diagnostic groups remained similar to those observed at baseline. Because GAFsdT2 scores (at 18 months) were available for only 33% of the patients, the results of the GLMrms emphasize stage T1. In fact, the greatest clinical and functional changes occurred between baseline and T1; thereafter, the changes were smaller [Reference Bonivento, Kambeitz-Ilankovic, Maggioni, Borgwardt, Lencer and Meisenzahl34]. The significance of baseline negative symptoms and T2 depression symptoms was highlighted during the longer follow-up. In this study, we did not consider basic symptoms, and in the analyses, interactions were not considered. Retrospective preadmission data, such as childhood adversities, sociability, and scholastic success, are not as reliable as if they were obtained prospectively. However, they represent the real-world scenario when a clinician first evaluates a patient.
Conclusions
To improve functioning in patients in the early stages of psychosis, several factors should be considered. These include the patients’ sex, childhood adversities, social adjustment, scholastic performance, baseline neurocognitive deficits, clinical presentation, and work/education status, as well as clinical symptomatology during the first follow-up months. Personalized, integrated interventions and rehabilitation measures should be actively continued after the first admission period, paying special attention to the treatment of affective disturbances. Additionally, longer monitoring of psychotic symptoms is necessary.
Supplementary material
The supplementary material for this article can be found at http://doi.org/10.1192/j.eurpsy.2025.10113.
Data availability statement
Requests for sharing the anonymized database should be addressed to the lead authors.
Acknowledgements
In addition to the description of the PRONIA consortium group at the end of Supplementary material, we have no acknowledgements.
Financial support
PRONIA is a Collaborative Project funded by the European Union under the 7th Framework Programme (grant 602152). The TEPS study was funded by Turku University Central Hospital (EVO funding).
Competing interest
The authors declare none.
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