Quantitative Susceptibility Mapping MRI in Deep-Brain Nuclei in First-Episode Psychosis.

BACKGROUND: Psychosis is related to neurochemical changes in deep-brain nuclei, particularly suggesting dopamine dysfunctions. We used an magnetic resonance imaging-based technique called quantitative susceptibility mapping (QSM) to study these regions in psychosis. QSM quantifies magnetic susceptibility in the brain, which is associated with iron concentrations. Since iron is a cofactor in dopamine pathways and co-localizes with inhibitory neurons, differences in QSM could reflect changes in these processes. METHODS: We scanned 83 patients with first-episode psychosis and 64 healthy subjects. We reassessed 22 patients and 21 control subjects after 3 months. Mean susceptibility was measured in 6 deep-brain nuclei. Using linear mixed models, we analyzed the effect of case-control differences, region, age, gender, volume, framewise displacement (FD), treatment duration, dose, laterality, session, and psychotic symptoms on QSM. RESULTS: Patients showed a significant susceptibility reduction in the putamen and globus pallidus externa (GPe). Patients also showed a significant R2* reduction in GPe. Age, gender, FD, session, group, and region are significant predictor variables for QSM. Dose, treatment duration, and volume were not predictor variables of QSM. CONCLUSIONS: Reduction in QSM and R2* suggests a decreased iron concentration in the GPe of patients. Susceptibility reduction in putamen cannot be associated with iron changes. Since changes observed in putamen and GPe were not associated with symptoms, dose, and treatment duration, we hypothesize that susceptibility may be a trait marker rather than a state marker, but this must be verified with long-term studies.

Intra and inter-individual variability in functional connectomes of patients with First Episode of Psychosis.

Patients with Schizophrenia may show different clinical presentations, not only regarding inter-individual comparisons but also in one specific subject over time. In fMRI studies, functional connectomes have been shown to carry valuable individual level information, which can be associated with cognitive and behavioral variables. Moreover, functional connectomes have been used to identify subjects within a group, as if they were fingerprints. For the particular case of Schizophrenia, it has been shown that there is reduced connectome stability as well as higher inter-individual variability. Here, we studied inter and intra-individual heterogeneity by exploring functional connectomes' variability and related it with clinical variables (PANSS Total scores and antipsychotic's doses). Our sample consisted of 30 patients with First Episode of Psychosis and 32 Healthy Controls, with a test-retest approach of two resting-state fMRI scanning sessions. In our patients' group, we found increased deviation from healthy functional connectomes and increased intragroup inter-subject variability, which was positively correlated to symptoms' levels in six subnetworks (visual, somatomotor, dorsal attention, ventral attention, frontoparietal and DMN). Moreover, changes in symptom severity were positively related to changes in deviation from healthy functional connectomes. Regarding intra-subject variability, we were unable to replicate previous findings of reduced connectome stability (i.e., increased intra-subject variability), but we found a trend suggesting that result. Our findings highlight the relevance of variability characterization in Schizophrenia, and they can be related to evidence of Schizophrenia patients having a noisy functional connectome.

Dysconnectivity in Schizophrenia Revisited: Abnormal Temporal Organization of Dynamic Functional Connectivity in Patients With a First Episode of Psychosis.

BACKGROUND AND HYPOTHESIS: Abnormal functional connectivity between brain regions is a consistent finding in schizophrenia, including functional magnetic resonance imaging (fMRI) studies. Recent studies have highlighted that connectivity changes in time in healthy subjects. We here examined the temporal changes in functional connectivity in patients with a first episode of psychosis (FEP). Specifically, we analyzed the temporal order in which whole-brain organization states were visited. STUDY DESIGN: Two case-control studies, including in each sample a subgroup scanned a second time after treatment. Chilean sample included 79 patients with a FEP and 83 healthy controls. Mexican sample included 21 antipsychotic-naïve FEP patients and 15 healthy controls. Characteristics of the temporal trajectories between whole-brain functional connectivity meta-states were examined via resting-state functional MRI using elements of network science. We compared the cohorts of cases and controls and explored their differences as well as potential associations with symptoms, cognition, and antipsychotic medication doses. STUDY RESULTS: We found that the temporal sequence in which patients' brain dynamics visited the different states was more redundant and segregated. Patients were less flexible than controls in changing their network in time from different configurations, and explored the whole landscape of possible states in a less efficient way. These changes were related to the dose of antipsychotics the patients were receiving. We replicated the relationship with antipsychotic medication in the antipsychotic-naïve FEP sample scanned before and after treatment. CONCLUSIONS: We conclude that psychosis is related to a temporal disorganization of the brain's dynamic functional connectivity, and this is associated with antipsychotic medication use.

Differences of affective and non-affective psychoses in early intervention services from Latin America.

BACKGROUND: Psychosis presentation can be affected by genetic and environmental factors. Differentiating between affective and non-affective psychosis (A-FEP and NA-FEP, respectively) may influence treatment decisions and clinical outcomes. The objective of this paper is to examine differences between patients with A-FEP or NA-FEP in a Latin American sample. METHODS: Patients from two cohorts of patients with a FEP recruited from Brazil and Chile. Subjects included were aged between 15 and 30 years, with an A-FEP or NA-FEP (schizophrenia-spectrum disorders) according to DSM-IV-TR. Sociodemographic data, duration of untreated psychosis and psychotic/mood symptoms were assessed. Generalized estimating equation models were used to assess clinical changes between baseline-follow-up according to diagnosis status. RESULTS: A total of 265 subjects were included. Most of the subjects were male (70.9 %), mean age was 21.36 years. A-FEP and NA-FEP groups were similar in almost all sociodemographic variables, but A-FEP patients had a higher probability of being female. At baseline, the A-FEP group had more manic symptoms and a steeper reduction in manic symptoms scores during the follow- up. The NA-FEP group had more negative symptoms at baseline and a higher improvement during follow-up. All domains of The Positive and Negative Syndrome Scale improved for both groups. No difference for DUP and depression z-scores at baseline and follow-up. LIMITATIONS: The sample was recruited at tertiary hospitals, which may bias the sample towards more severe cases. CONCLUSIONS: This is the largest cohort comparing A-FEP and NA-FEP in Latin America. We found that features in FEP patients could be used to improve diagnosis and support treatment decisions.

Childhood adversity increases risk of psychotic experiences in patients with substance use disorder.

INTRODUCTION: Adverse childhood experiences (ACEs) increase the risk of psychotic experiences (PE), but little is known about heterogeneities of this association in different developmental stages, dimensions, or whether they are affected by substance use disorder (SUD). This study examines the association between different types of ACEs at various developmental stages and lifetime PE in patients with SUD in Chile. METHODS: We included 399 consenting adults in outpatient or residential SUD treatment programs. Sociodemographic data and information about PE and ACEs were obtained by trained clinical psychologists. RESULTS: Patients reporting PE experienced more ACEs compared to patients without PE (4.2 versus 3.4). They also experienced more complex adversities (41.8% versus 25.1%), had more psychiatric comorbidities (85% versus 70.4%), and reported using more substances (mean 4.5 versus 3.9). Adjusted association between ACEs and PE showed the highest OR for arrests (1.88), sexual abuse (1.81), alcohol abuse by parents (1.48), school exclusion (1.39), foster or residential care (18.3). CONCLUSION: Early exposure to ACEs is a risk factor for later PE among patients with SUD. Type of ACE and the period when they occurred is important, suggesting the existence of critical periods where the individual is more susceptible to adverse environmental stimuli.

Consent, decisional capacity and guardianship in mental health research.

Background: Research with adults who cannot give informed consent has important social value. However, enrolling adults who cannot consent in research raises significant ethical concerns.  Methods: To evaluate how researchers in low and middle-income countries (LMICs) can assess individuals' decisional capacity, and the conditions under which it is appropriate, and the conditions under which it is not appropriate to include individuals who lack decisional capacity.  Results: In LMICs, where resources may be limited, implementing protections for adults with decisional incapacity can be especially challenging. Recognition of the ethical concerns, and awareness of the circumstances and available resources, offers the means to protect these vulnerable participants. Conclusions: Researchers in low and middle-income countries should be aware of steps they can take to ensure appropriate protections for subjects with decisional impairments while conducting clinical trials on methods to improve their clinical care.

Functional Dysconnectivity in Ventral Striatocortical Systems in 22q11.2 Deletion Syndrome.

22q11.2 deletion syndrome (22q11.2DS) is a genetic neurodevelopmental disorder that represents one of the greatest known risk factors for psychosis. Previous studies in psychotic subjects without the deletion have identified a dopaminergic dysfunction in striatal regions, and dysconnectivity of striatocortical systems, as an important mechanism in the emergence of psychosis. Here, we used resting-state functional MRI to examine striatocortical functional connectivity in 22q11.2DS patients. We used a 2 × 2 factorial design including 125 subjects (55 healthy controls, 28 22q11.2DS patients without a history of psychosis, 10 22q11.2DS patients with a history of psychosis, and 32 subjects with a history of psychosis without the deletion), allowing us to identify network effects related to the deletion and to the presence of psychosis. In line with previous results from psychotic patients without 22q11.2DS, we found that there was a dorsal to ventral gradient of hypo- to hyperstriatocortical connectivity related to psychosis across both patient groups. The 22q11.2DS was additionally associated with abnormal functional connectivity in ventral striatocortical networks, with no significant differences identified in the dorsal system. Abnormalities in the ventral striatocortical system observed in these individuals with high genetic risk to psychosis may thus reflect a marker of illness risk.

Effects of socioeconomic status in cognition of people with schizophrenia: results from a Latin American collaboration network with 1175 subjects.

BACKGROUND: Cognition heavily relies on social determinants and genetic background. Latin America comprises approximately 8% of the global population and faces unique challenges, many derived from specific demographic and socioeconomic variables, such as violence and inequality. While such factors have been described to influence mental health outcomes, no large-scale studies with Latin American population have been carried out. Therefore, we aim to describe the cognitive performance of a representative sample of Latin American individuals with schizophrenia and its relationship to clinical factors. Additionally, we aim to investigate how socioeconomic status (SES) relates to cognitive performance in patients and controls. METHODS: We included 1175 participants from five Latin American countries (Argentina, Brazil, Chile, Colombia, and Mexico): 864 individuals with schizophrenia and 311 unaffected subjects. All participants were part of projects that included cognitive evaluation with MATRICS Consensus Cognitive Battery and clinical assessments. RESULTS: Patients showed worse cognitive performance than controls across all domains. Age and diagnosis were independent predictors, indicating similar trajectories of cognitive aging for both patients and controls. The SES factors of education, parental education, and income were more related to cognition in patients than in controls. Cognition was also influenced by symptomatology. CONCLUSIONS: Patients did not show evidence of accelerated cognitive aging; however, they were most impacted by a lower SES suggestive of deprived environment than controls. These findings highlight the vulnerability of cognitive capacity in individuals with psychosis in face of demographic and socioeconomic factors in low- and middle-income countries.

The incidence of non-affective psychotic disorders in Chile between 2005 and 2018: results from a national register of over 30 000 cases.

BACKGROUND: Evidence suggests the incidence of non-affective psychotic disorders (NAPDs) varies across persons and places, but data from the Global South is scarce. We aimed to estimate the treated incidence of NAPD in Chile, and variance by person, place and time. METHODS: We used national register data from Chile including all people, 10-65 years, with the first episode of NAPD (International Classification of Diseases, Tenth Revision: F20-F29) between 1 January 2005 and 29 August 2018. Denominators were estimated from Chilean National Census data. Our main outcome was treated incidence of NAPD and age group, sex, calendar year and regional-level population density, multidimensional poverty and latitude were exposures of interest. RESULTS: We identified 32 358 NAPD cases [12 136 (39.5%) women; median age-at-first-contact: 24 years (interquartile range 18-39 years)] during 171.1 million person-years [crude incidence: 18.9 per 100 000 person-years; 95% confidence interval (CI) 18.7-19.1]. Multilevel Poisson regression identified a strong age-sex interaction in incidence, with rates peaking in men (57.6 per 100 000 person-years; 95% CI 56.0-59.2) and women (29.5 per 100 000 person-years; 95% CI 28.4-30.7) between 15 and 19 years old. Rates also decreased (non-linearly) over time for women, but not men. We observed a non-linear association with multidimensional poverty and latitude, with the highest rates in the poorest regions and those immediately south of Santiago; no association with regional population density was observed. CONCLUSION: Our findings inform the aetiology of NAPDs, replicating typical associations with age, sex and multidimensional poverty in a Global South context. The absence of association with population density suggests this risk may be context-dependent.

Predictors of clozapine discontinuation at 2 years in treatment-resistant schizophrenia.

INTRODUCTION: Little is known about predictors of clinical response to clozapine treatment in treatment-resistant psychosis. Most published cohorts are small, providing inconsistent results. We aimed to identify baseline clinical predictors of future clinical response in patients who initiate clozapine treatment, mainly focusing on the effect of age, duration of illness, baseline clinical symptoms and homelessness. METHODOLOGY: Retrospective cohort of patients with treatment-resistant schizophrenia, aged between 15 and 60 years, that initiated clozapine between 2014 and 2017. Sociodemographic characteristics, years from illness diagnosis, and clinical presentation before the initiation of clozapine were collected and analyzed. All-cause discontinuation at two years follow-up was used as the primary measure of clozapine response. RESULTS: 261 patients were included with a median age at illness diagnosis of 23 years old (IQR 19-29) and a median age at clozapine initiation of 25 (IQR: 21-33). 72.33% (183/253) continued clozapine after two years follow-up. Being homeless was associated to higher clozapine non-adherence, with an OR of 2.78 (95%CI 1.051-7.38) (p = 0.039, controlled by gender). Older age at clozapine initiation and longer delay from first schizophrenia diagnosis to clozapine initiation were also associated with higher clozapine non-adherence, with each year increasing the odds of discontinuation by 1.043 (95%CI 1.02-1.07; p = 0.001) and OR 1.092 (95%CI 1.01-1.18;p = 0.032) respectively. CONCLUSION: Starting clozapine in younger patients or shortly after schizophrenia diagnosis were associated with better adherence.

Pharmacogenetics in Psychiatry: Perceived Value and Opinions in a Chilean Sample of Practitioners.

Use of pharmacogenetics (PGx) testing to guide clinical decisions is growing in developed countries. Published guidelines for gene-drug pair analysis are available for prescriptions in psychiatry, but information on their utilization, barriers, and health outcomes in Latin America is limited. As a result, this work aimed at exploring current use, opinions, and perceived obstacles on PGx testing among psychiatrists in Chile, via an online, anonymous survey. Among 123 respondents (5.9% of registered psychiatrists in the country), 16.3% reported ever requesting a PGx test. The vast majority (95%) of tests were ordered by clinicians practicing in the Metropolitan Region of Santiago. Having more than 20 years in practice was positively associated with prior use of PGx (p 0.02, OR 3.74 (1.19-11.80)), while working in the public health system was negatively associated (OR 0.30 (0.10-0.83)). Perceived barriers to local implementation included insufficient evidence of clinical utility, limited clinicians' knowledge on PGx and on test availability, and health systems' issues, such as costs and reimbursement. Despite the recognition of these barriers, 80% of respondents asserted that it is likely that they will incorporate PGx tests in their practice in the next five years. Given these results, we propose next steps to facilitate implementation such as further research in health outcomes and clinical utility of known and novel clinically actionable variants, growth in local sequencing capabilities, education of clinicians, incorporation of clinical decision support tools, and economic evaluations, all in local context.

Uso de cannabis en jóvenes hospitalizados por un primer episodio de psicosis: un estudio caso-control

Background: Cannabis use among young people in Chile has increased significantly in the last years. There is a consistent link between cannabis and psychosis. Aim: To compare cannabis use in patients with a first episode of psychosis and healthy controls. Material and Methods: We included 74 patients aged 20 ± 3 years (78% males) admitted to hospital with a first episode of psychosis and a group of 60 healthy controls aged 23 ± 4 years (63% males). Cannabis consumption was assessed, including age of first time use and length of regular use. Results: Patients with psychosis reported a non-significantly higher frequency of life-time cannabis use. Patients had longer periods of regular cannabis use compared with healthy subjects (Odds ratio [OR] 2.4; 95% confi-dence intervals [CI] 1.14-5.05). Patients also used cannabis for the first time at an earlier age (16 compared with 17 years, p < 0.0). The population attributable fraction for regular cannabis use associated with hospital admissions due to psychosis was 17.7% (95% CI 1.2-45.5%). Conclusions: Cannabis use is related to psychosis in this Chilean group of patients. This relationship is stronger in patients with early exposure to the drug and longer the regular use. One of every five admissions due to psychosis is associated with cannabis consumption. These data should influence cannabis legisla-tion and the public policies currently being discussed in Chile.

[Cannabis use among hospitalized young people experiencing a first episode of psychosis: a case control study]. / Uso de cannabis en jóvenes hospitalizados por un primer episodio de psicosis: un estudio caso-control.

BACKGROUND: Cannabis use among young people in Chile has increased significantly in the last years. There is a consistent link between cannabis and psychosis. AIM: To compare cannabis use in patients with a first episode of psychosis and healthy controls. MATERIAL AND METHODS: We included 74 patients aged 20 ± 3 years (78% males) admitted to hospital with a first episode of psychosis and a group of 60 healthy controls aged 23 ± 4 years (63% males). Cannabis consumption was assessed, including age of first time use and length of regular use. RESULTS: Patients with psychosis reported a non-significantly higher frequency of life-time cannabis use. Patients had longer periods of regular cannabis use compared with healthy subjects (Odds ratio [OR] 2.4; 95% confi-dence intervals [CI] 1.14-5.05). Patients also used cannabis for the first time at an earlier age (16 compared with 17 years, p < 0.0). The population attributable fraction for regular cannabis use associated with hospital admissions due to psychosis was 17.7% (95% CI 1.2-45.5%). CONCLUSIONS: Cannabis use is related to psychosis in this Chilean group of patients. This relationship is stronger in patients with early exposure to the drug and longer the regular use. One of every five admissions due to psychosis is associated with cannabis consumption. These data should influence cannabis legisla-tion and the public policies currently being discussed in Chile.

High prevalence of metabolic alterations in Latin American patients at initial stages of psychosis.

AIM: Studies conducted in the United States have highlighted a higher prevalence of metabolic alterations (MA) in Latino population and Latino psychotic patients. Metabolic risk in psychosis is known to be present from initial stages of the disease. To better characterize this population, we explored the prevalence of MA and metabolic syndrome (MS) in early psychosis patients in a Latin American country. METHODS: Transversal, observational study comparing the prevalence of MA and MS in patients with early psychosis from an outpatient program in Chile (n = 148) with a community representative sample from the 2009-2010 National Health Survey (n = 568). ANOVA and regression analysis were performed obtaining odds ratio for MA and MS. RESULTS: The prevalence of MS was 44.7% in patients compared to 11.4% in the community sample (odds ratio [OR] 5.28, confidence interval [CI] 95% 3.07-9.08; P-value <0.001). There was no effect of gender. Subgroup analyses showed no significant association of MS with clozapine/olanzapine use, treatment duration or tobacco use. There was an association between treatment duration and hypertriglyceridemia (P = 0.024; OR 1.02, CI 95% 1.00-1.04) and obesity (P = 0.007; OR 5.93, CI 95% 1.82-20.22). Clozapine/olanzapine use was associated with hyperglycaemia (P = 0.007; OR 6.04, CI 95% 1.63-22.38) and high low density lipoprotein (P = 0.033 ANOVA; OR 5.28, CI 95% 1.14-24.37). CONCLUSION: Latino psychotic patients have a high risk of MA and MS at initial stages of the disease which is not entirely explained by the higher risk in the whole Latino population, is irrespective of gender, and does not seem to be entirely a response to atypical antipsychotic use.

Depressive symptoms are associated with higher morning plasma cortisol in primary care subjects.

BACKGROUND: Cortisol dysregulation has a potential role in depression. AIM AND METHODS: We evaluated depressive symptoms using the Hamilton Rating Scale for Depression in 48 primary care subjects without history of previous or current depression and its association with cortisol dysregulation (morning plasma cortisol, 24-hour urinary free cortisol and cortisol metabolites). Presence of metabolic syndrome and inflammatory parameters were also assessed. RESULTS: Hamilton Rating Scale for Depression correlated significantly with morning cortisol, but not with urinary free cortisol or metabolites. A significant increase in morning cortisol by Hamilton groups (asymptomatic ≤8; mild to moderate: 9-18; moderate to severe: ≥19) was observed even when adjusted by age/gender. We observed no association of depressive symptoms with metabolic or inflammatory parameters. CONCLUSION: Depressive symptoms in primary care subjects not consulting for their mood are associated with higher morning plasma cortisol, but not urinary cortisol or its metabolites. These observations suggest that systemic hypercortisolism and related metabolic disorders are not observed in mild/initial states of depressive disorders.

Clinical characterization of rapid cycling bipolar disorder: Association with attention deficit hyperactivity disorder.

BACKGROUND: Rapid cycling (RC) bipolar disorder (BD) is associated with more disability and worse global functioning than non-rapid cycling BD (NRC) and is understudied. This study aims to investigate clinical characteristics associated to RC in a Latin-American sample and secondarily, to generate a clinical model to test the likelihood of RC in BD. METHODS: 250 BD patients were enrolled between 2007 and 2015. All patients met DSM-IV criteria for BD type I, II or NOS. The sample was dichotomized into RC and NRC subgroups, and compared in terms of sociodemographic and clinical variables by bivariate analyses. A binary logistic regression was performed to generate a model and explain variance associated with the likelihood of presenting RC. RESULTS: Final sample included 235 patients, of which forty-four (18.7%) met RC criteria. When compared to NRC, a significantly higher proportion of RC patients were female (81.4% vs. 58.9% p = 0.006), BD type II (58.1% vs. 29.7% p = 0.002), presented more manic/hypomanic episodes (43.6 ±â€¯35.8 vs. 12.8 ±â€¯58.9, p = 0.001), and had less psychotic symptoms (20.9% vs. 42.2%, p = 0.010). Attention deficit hyperactivity disorder (ADHD) was a significant comorbidity in RC (23.7% vs. 8.3%, p = 0.007). No differences were found in suicidality, mixed symptoms, and seasonal pattern. After logistic regression, variables significantly associated with RC were presence of ADHD (OR 4.6 [95% CI 1.54-13.93] p = 0.006) and female gender (OR 3.55 [95% CI, 1.32-9.56] p = 0.012). LIMITATIONS: It is a cross-sectional study. CONCLUSIONS: Findings suggest that ADHD comorbidity, and female gender are risk factors for RC in BD.

Early treatment resistance in a Latin-American cohort of patients with schizophrenia.

BACKGROUND: Failure to respond to antipsychotic medication in schizophrenia is a common clinical scenario with significant morbidity. Recent studies have highlighted that many patients present treatment-resistance from disease onset. We here present an analysis of clozapine prescription patterns, used as a real-world proxy marker for treatment-resistance, in a cohort of 1195 patients with schizophrenia from a Latin-American cohort, to explore the timing of emergence of treatment resistance and possible subgroup differences. METHODS: Survival analysis from national databases of clozapine monitoring system, national disease notification registers, and discharges from an early intervention ward. RESULTS: Echoing previous studies, we found that around 1 in 5 patients diagnosed with schizophrenia were eventually prescribed clozapine, with an over-representation of males and those with a younger onset of psychosis. The annual probability of being prescribed clozapine was highest within the first year (probability of 0.11, 95% confidence interval of 0.093-0.13), compared to 0.018 (0.012-0.024) between years 1 and 5, and 0.006 (0-0.019) after 5years. Age at psychosis onset, gender, dose of clozapine used, and compliance with hematological monitoring at 12months, was not related to the onset of treatment resistance. A similar pattern was observed in a subgroup of 230 patients discharged from an early intervention ward with a diagnosis of non-affective first episode of psychosis. CONCLUSIONS: Our results highlight that treatment resistance is frequently present from the onset of psychosis. Future studies will shed light on the possible different clinical and neurobiological characteristics of this subtype of psychosis.

Duration of untreated psychosis and acute remission of negative symptoms in a South American first-episode psychosis cohort.

AIM: To determine the association between duration of untreated psychosis (DUP) and symptoms remission in a hospitalized first-episode psychosis cohort. METHODS: Inpatients with a first-episode non-affective psychosis were recruited. Subjects were divided into two groups of long and short DUP using a 3-month cut-off point, and this was related to remission at 10 weeks of treatment. Multivariate analyses were performed. RESULTS: Fifty-five inpatients were included. There were no differences in remission rates of positive symptoms. Up to 76.5% of the patients with a short DUP (<3 months) achieved remission of negative symptoms versus 31.6% in the DUP ≥ 3 months group (P = 0.003). After controlling for relevant factors, patients with a shorter DUP were still three times more likely to achieve negative symptoms remission (HR: 3.04, 95% CI 1.2-7.5). CONCLUSIONS: DUP is a prognostic factor that should be considered at an early stage to identify a 'high risk' subgroup of persistent negative symptoms.