Long-term clinical recovery and treatment resistance in first-episode psychosis: a 10-year follow-up study.

Illness trajectories in people with first-episode psychosis (FEP) vary significantly over time. Identifying early-course parameters predicting outcomes is essential, but long-term data still needs to be provided. We conducted a 10-year follow-up study of a comprehensive first-episode psychosis (FEP) cohort investigating the prevalence of clinical recovery (CR) and treatment resistance (TR) after ten years, as well as clinical, demographic, and pre-illness predictors of long-term outcomes. 102 participants with FEP DSM-IV Schizophrenia spectrum disorders were recruited within their first year of treatment. The Treatment Response and Resistance in Psychosis Working Group (TRRIP) and the Remission in Schizophrenia Working Group (RSWG) criteria were used to define TR and CR, respectively. At 10-year follow-up, 29 (29%) of the participants were classified as in CR, while 32 (31%) were classified as TR. We also identified a larger middle group (n = 41, 40%) consisting of participants in partial recovery. 7% of all participants had tried Clozapine at the 10-year follow-up. Logistic regression analyses identified insidious onset (OR = 4.16) and baseline disorganized symptoms (OR = 2.96) as significantly associated with an increased risk of developing TR. Good premorbid academic adjustment (OR = 1.60) and acute onset (OR = 3.40) were associated with an increased chance of CR. We identified three long-term outcome groups by using recent consensus definitions. We also identified the potential importance of assessing baseline disorganized symptoms and monitoring patients with insidious onset more closely. Further, the findings suggest that clinicians should pay close attention to early-course parameters and provide adequate treatment to improve long-term outcomes of FEP.

Childhood trauma and treatment resistance in first-episode psychosis: Investigating the role of premorbid adjustment and duration of untreated psychosis.

BACKGROUND: Early identification of treatment non-response in first-episode psychosis (FEP) is essential to outcome. Despite indications that exposure to childhood trauma (CT) can have adverse effects on illness severity, its impact on treatment non-response and the interplay with other pre-treatment characteristics is sparsely investigated. We use a lack of clinical recovery as an early indicator of treatment resistance to investigate the relationship between CT and treatment resistance status at one-year follow-up and the potential mediation of this effect by other pre-treatment characteristics. METHODS: This prospective one-year follow-up study involved 141 participants recruited in their first year of treatment for a schizophrenia-spectrum disorder. We investigated clinical status, childhood trauma (CT), premorbid adjustment (PA), and duration of untreated psychosis (DUP) at baseline and clinical status at one-year follow-up. Ordinal regression analyses were conducted to investigate how PA and DUP affected the relationship between CT and one-year outcome in FEP. RESULTS: 45 % of the FEP sample reported moderate to severe CT, with significantly higher levels of CT in the early treatment resistant group compared to participants with full or partial early recovery. Ordinal regression analysis showed that CT was a significant predictor of being in a more severe outcome group (OR = 4.59). There was a partial mediation effect of PA and a full mediation effect of DUP on the effect of CT on outcome group membership. DISCUSSION: Our findings indicate that reducing treatment delays may mitigate the adverse effects of CT on clinical outcomes and support the inclusion of broad trauma assessment in FEP services.

Behind the heterogeneity in the long-term course of first-episode psychosis: Different psychotic symptom trajectories are associated with different patterns of cannabis and stimulant use.

BACKGROUND: Data-driven classification of long-term psychotic symptom trajectories and identification of associated risk factors could assist treatment planning and improve long-term outcomes in psychosis. However, few studies have used this approach, and knowledge about underlying mechanisms is limited. Here, we identify long-term psychotic symptom trajectories and investigate the role of illness-concurrent cannabis and stimulant use. METHODS: 192 participants with first-episode psychosis were followed up after 10 years. Psychotic symptom trajectories were estimated using growth mixture modeling and tested for associations with baseline characteristics and cannabis and stimulant use during the follow-up (FU) period. RESULTS: Four trajectories emerged: (1) Stable Psychotic Remission (54.2 %), (2) Delayed Psychotic Remission (15.6 %), (3) Psychotic Relapse (7.8 %), (4) Persistent Psychotic Symptoms (22.4 %). At baseline, all unfavorable trajectories (2-4) were characterized by more schizophrenia diagnoses, higher symptom severity, and longer duration of untreated psychosis. Compared to the Stable Psychotic Remission trajectory, unstable trajectories (2,3) showed distinct associations with cannabis/stimulant use during the FU-period, with dose-dependent effects for cannabis but not stimulants (Delayed Psychotic Remission: higher rates of frequent cannabis and stimulant use during the first 5 FU-years; Psychotic Relapse: higher rates of sporadic stimulant use throughout the entire FU-period). The Persistent Psychosis trajectory was less clearly linked to substance use during the FU-period. CONCLUSIONS: The risk for an adverse long-term course could be mitigated by treatment of substance use, where particular attention should be devoted to preventing the use of stimulants while the use reduction of cannabis may already yield positive effects.

The relationship between visual hallucinations, functioning, and suicidality over the course of illness: a 10-year follow-up study in first-episode psychosis.

Visual hallucinations in psychosis are under-researched despite associations with increased illness severity, functional impairments, and suicidality in the few existing studies. Further, there are no long-term longitudinal studies, making it impossible to conclude if these associations are state or trait phenomena. In the current prospective longitudinal study, 184 individuals with first-episode psychosis were assessed with semi-structured clinical interviews and self-report questionnaires at baseline and 10-year follow-up. Participants were grouped based on lifetime experience of visual hallucinations: before or at baseline (VH+/+), first during follow-up (VH-/+), or never (VH-/-). Associations with functioning, suicide attempts, childhood trauma and other markers of illness severity were tested using multinomial logistic regression analysis. At baseline, the VH+/+ group (37.5%), but not VH-/+ (12.5%), had poorer functioning, higher symptom severity, a lower age at onset, and included more individuals with a history of multiple suicide attempts than the VH-/- group (50%). At follow-up, the VH-/+ group, but not VH+/+, had poorer functioning and higher symptom severity than the VH-/- group. However, the number of participants who committed multiple suicide attempts during the follow-up period was again significantly higher in the VH+/+ group. There was no association with childhood trauma. Hence, visual hallucinations are associated with impaired functioning and higher symptom severity, but only in the short-term. However, visual hallucinations that arise early in the course of illness are a risk indicator for repeated suicide attempts throughout the illness course. These findings highlight the relevance of assessing visual hallucinations and monitoring their development over time.

Teleological reasoning bias is predicted by pupil dynamics: Evidence for the extensive integration account of bias in reasoning.

Teleological reasoning is the tendency for humans to see purpose and intentionality in natural phenomena when there is none. In this study, we assess three competing theories on how bias in reasoning arises by examining performance on a teleological reasoning task while measuring pupil size and response times. We replicate that humans (N = 45) are prone to accept false teleological explanations. Further, we show that errors on the teleological reasoning task are associated with slower response times, smaller baseline pupil size, and larger pupil dilations. The results are in line with the single-process extensive integration account and directly oppose predictions from dual-processing accounts. Lastly, by modeling responses with a drift-diffusion model, we find that larger baseline pupil size is associated with lower decision threshold and higher drift rate, whereas larger pupil dilations are associated with higher decision threshold and lower drift rate. The results highlight the role of neural gain and the Locus Coeruleus-Norepinephrine system in modulating evidence integration and bias in reasoning. Thus, teleological reasoning and susceptibility to bias likely arise due to extensive processing rather than through fast and effortless processing.

Aberrant uncertainty processing is linked to psychotic-like experiences, autistic traits, and is reflected in pupil dilation during probabilistic learning.

Aberrant belief updating due to misestimation of uncertainty and an increased perception of the world as volatile (i.e., unstable) has been found in autism and psychotic disorders. Pupil dilation tracks events that warrant belief updating, likely reflecting the adjustment of neural gain. However, whether subclinical autistic or psychotic symptoms affect this adjustment and how they relate to learning in volatile environments remains to be unraveled. We investigated the relationship between behavioral and pupillometric markers of subjective volatility (i.e., experience of the world as unstable), autistic traits, and psychotic-like experiences in 52 neurotypical adults with a probabilistic reversal learning task. Computational modeling revealed that participants with higher psychotic-like experience scores overestimated volatility in low-volatile task periods. This was not the case for participants scoring high on autistic-like traits, who instead showed a diminished adaptation of choice-switching behavior in response to risk. Pupillometric data indicated that individuals with higher autistic- or psychotic-like trait and experience scores differentiated less between events that warrant belief updating and those that do not when volatility was high. These findings are in line with misestimation of uncertainty accounts of psychosis and autism spectrum disorders and indicate that aberrancies are already present at the subclinical level.

Spared performance but increased uncertainty in schizophrenia: Evidence from a probabilistic decision-making task.

Aberrant attribution of salience to in fact little informative events might explain the emergence of positive symptoms in schizophrenia and has been linked to belief uncertainty. Uncertainty is thought to be encoded by neuromodulators, including norepinephrine. However, norepinephrinergic encoding of uncertainty, measured as task-related pupil dilation, has rarely been explored in schizophrenia. Here, we addressed this question by comparing individuals with a disorder from the schizophrenia spectrum to a non-psychiatric control group on behavioral and pupillometric measures in a probabilistic prediction task, where different levels of uncertainty were introduced. Behaviorally, patients performed similar to controls, but their belief uncertainty was higher, particularly when instability of the task environment was high, suggesting an increased sensitivity to this instability. Furthermore, while pupil dilation scaled positively with uncertainty, this was less the case for patients, suggesting aberrant neuromodulatory regulation of neural gain, which may hinder the reduction of uncertainty in the long run. Together, the findings point to abnormal uncertainty processing and norepinephrinergic signaling in schizophrenia, potentially informing future development of both psychopharmacological therapies and psychotherapeutic approaches that deal with the processing of uncertain information.

Overestimation of volatility in schizophrenia and autism? A comparative study using a probabilistic reasoning task.

BACKGROUND AND OBJECTIVES: A plethora of studies has investigated and compared social cognition in autism and schizophrenia ever since both conditions were first described in conjunction more than a century ago. Recent computational theories have proposed similar mechanistic explanations for various symptoms beyond social cognition. They are grounded in the idea of a general misestimation of uncertainty but so far, almost no studies have directly compared both conditions regarding uncertainty processing. The current study aimed to do so with a particular focus on estimation of volatility, i.e. the probability for the environment to change. METHODS: A probabilistic decision-making task and a visual working (meta-)memory task were administered to a sample of 86 participants (19 with a diagnosis of high-functioning autism, 21 with a diagnosis of schizophrenia, and 46 neurotypically developing individuals). RESULTS: While persons with schizophrenia showed lower visual working memory accuracy than neurotypical individuals, no significant group differences were found for metamemory or any of the probabilistic decision-making task variables. Nevertheless, exploratory analyses suggest that there may be an overestimation of volatility in subgroups of participants with autism and schizophrenia. Correlations revealed relationships between different variables reflecting (mis)estimation of uncertainty, visual working memory accuracy and metamemory. LIMITATIONS: Limitations include the comparably small sample sizes of the autism and the schizophrenia group as well as the lack of cognitive ability and clinical symptom measures. CONCLUSIONS: The results of the current study provide partial support for the notion of a general uncertainty misestimation account of autism and schizophrenia.

The interplay between executive control, behavioural variability and mind wandering: Insights from a high-definition transcranial direct-current stimulation study.

While the involvement of executive processes in mind wandering is largely undebated, their exact relationship is subject to an ongoing debate and rarely studied dynamically within-subject. Several brain-stimulation studies using transcranial direct current stimulation (tDCS) have attempted to modulate mind-wandering propensity by stimulating the left dorsolateral prefrontal cortex (DLPFC) which is an important hub in the prefrontal control network. In a series of three studies testing a total of N = 100 participants, we develop a novel task that allows to study the dynamic interplay of mind wandering, behavioural varibility and the flexible recruitment of executive resources as indexed by the randomness (entropy) of movement sequences generated by our participants. We consistently find that behavioural variability is increased and randomness is decreased during periods of mind wandering. Interestingly, we also find that behavioural variability interacts with the entropy-MW effect, opening up the possibility to detect distinct states of off-focus cognition. When applying a high-definition transcranial direct-current stimulation (HD-tDCS) montage to the left DLPFC, we find that propensity to mind wander is reduced relative to a group receiving sham stimulation.

Psychosis and Psychotic-Like Symptoms Affect Cognitive Abilities but Not Motivation in a Foraging Task.

BACKGROUND AND OBJECTIVE: Goal-directed behavior is a central feature of human functioning. It requires goal appraisal and implicit cost-benefit analyses, i.e., how much effort to invest in the pursuit of a certain goal, against its value and a confidence judgment regarding the chance of attainment. Persons with severe mental illness such as psychosis often struggle with reaching goals. Cognitive deficits, positive symptoms restricting balanced judgment, and negative symptoms such as anhedonia and avolition may compromise goal attainment. The objective of this study was to investigate to what degree symptom severity is related to cognitive abilities, metacognition, and effort-based decision-making in a visual search task. METHODS: Two studies were conducted: study 1: N = 52 (healthy controls), and study 2: N = 46 (23 patients with psychosis/23 matched healthy controls). Symptoms were measured by the CAPE-42 (study 1) and the PANSS (study 2). By using a visual search task, we concomitantly measured (a) accuracy in short-term memory, (b) perceived accuracy by participants making a capture area or confidence interval, and (c) effort by measuring how long one searched for the target. Perseverance was assessed in trials in which the target was omitted and search had to be abandoned. RESULTS: Higher levels of positive symptoms, and having a diagnosis of psychosis, were associated with larger errors in memory. Participants adjusted both their capture area and their search investment to the error of their memory. Perseverance was associated with negative symptoms in study 1 but not in study 2. CONCLUSION: By simultaneously assessing error and confidence in one's memory, as well as effort in search, we found that memory was affected by positive, not negative, symptoms in healthy controls, and was reduced in patients with psychosis. However, impaired memory did not concur with overconfidence or less effort in search, i.e., goal directed behavior was unrelated to symptoms or diagnosis. Metacognition and motivation were neither affected by cognitive abilities nor by negative symptoms. Clinically, this could indicate that struggles with goal directed behavior in psychosis may not solely be dependent on primary illness factors.

Objective Versus Subjective Effort in Schizophrenia.

BACKGROUND AND OBJECTIVES: Performance on cognitive tasks is often impaired in individuals with schizophrenia (SCZ), possibly resulting from either cognitive deficits (e.g., limited working memory capacity) or diminished mental effort or both. Investment of mental effort itself can be affected by cognitive resources, task load, and motivational factors and has thus proven difficult to measure. Pupil dilation during task performance has been proposed as an objective measure, but it remains unclear to what extent this converges with self-reports of perceived task demands, motivation, and invested effort. The current study tried to elucidate this question. METHODS: A visual version of the digit span task was administered in a sample of 29 individuals with a diagnosis from the SCZ spectrum and 30 individuals without any psychiatric disorder. Pupil size was recorded during the task, whereas self-reported invested effort and task demand were measured afterward. RESULTS: No group difference was found for working memory capacity, but individuals with SCZ showed diminished trial-by-trial recall accuracy, showed reduced pupil dilation across all task load conditions, and reported higher perceived task demands. CONCLUSION: Results indicate reduced effort investment in patients with SCZ, but it remains unclear to what extent this alone could explain the lower recall performance. The lack of a direct link between objective and subjective measures of effort further suggests that both may assess different facets of effort. This has important implications for clinical and research settings that rely on the reliability of neuropsychological test results when assessing cognitive capacity in this patient group.