Men and Women With First Episode Psychosis Present Distinct Profiles of Social Cognition and Metacognition


 Deficits in social cognition and metacognition impact the course of psychosis. Gender differences in social cognition and metacognition could explain heterogeneity in psychosis. 174 (58 females) patients with first-episode psychosis completed a clinical, neuropsychological, social cognitive and metacognitive assessment. Subsequent latent profile analysis split by gender yielded 2 clusters common to both genders, a specific male profile characterized by presenting jumping to conclusions and a specific female profile characterized by cognitive biases. Males and females in the homogeneous profile seem to have a more benign course of illness. Males with jumping to conclusions had more clinical symptoms and more neuropsychological deficits. Females with cognitive biases were younger and had less self-esteem. These results suggest that males and females may benefit from specific targeted treatment and highlights the need to consider gender when planning interventions.


Background
Gender differences in the onset and expression of psychosis are well documented and apparent since the rst episode of psychosis (FEP) [1,2]. Gender is one of the most predictive variables of clinical features at FEP [3], although this predictive power may be related to the large disparities that exist in other risk factors between the two genders [4]. Men with psychosis have poorer premorbid adjustment, higher levels of substance abuse and dependence, and more negative symptoms [2,4]. Furthermore, men usually exhibit worse social functioning [5] and male sex is a predictor of relapse after FEP [6].
The reasons behind better prognosis in women are largely unknown. However, social cognition and metacognition seem an important variable to consider when explaining gender differences in psychosis. Patients with FEP experience signi cant de cits in social cognition [7] and metacognition [8]. Social cognition encompasses perception, interpretation, and information processing for adaptive social interactions [9], while metacognition refers to the spectrum of mental activities that involve the re ection upon one's and the other's thinking, and the synthesis of these phenomena into an integrated sense of the self and the others [10,11]. Both social cognition and metacognition are important predictors of functional outcome when assessed globally [9,[12][13][14], but even speci c subdomains of both constructs have distinct impacts in the disorder. The Jumping to Conclusions bias (JTC) has speci c associations with neurocognition [15][16][17][18], inaccurate processing of social information [19], worse outcome [20], delusion forming and severity [16, 21,22] and suicidal behavior [23]. Clinical insight has been related to treatment compliance, quality of life, depression, and symptoms among others [12,[24][25][26]] but seems to be independent of neurocognition [27]. Attributional style has a clear in uence in paranoia and persecutory delusions [28][29][30], and cognitive insight is related to depressive symptoms [31], and treatment compliance, symptoms and quality of life [12].
Research exploring gender differences in social cognition and metacognition is inconclusive, probably due to the tendency to present averaged results [32].
Although a majority of studies have failed to nd signi cant differences between genders in social cognition [33,34] or metacognition [35,36]. However, exploring gender differences in social cognition and metacognition beyond mean differences often leads to important differences. found that women with psychosis present more extreme dichotomous thinking but a richer personal identity system [38]. Likewise, Salas-Sender et al., (2019) found that men and women with FEP responded differently to metacognitive training [39].
Differences in social cognition and metacognition in psychosis may not be apparent when comparing performance, but may be rooted in discrepancies in information processing. Data driven methods permit capturing heterogeneity according to data, without testing preconceived hypothesis. Therefore, in this work, we sought to explore whether men and women with FEP present different pro les of social cognition and metacognition using latent pro le analysis (LPA). As a second objective, we tested differences in demographic, clinical and neuropsychological variables among the derived pro les.

Methods
The design of the study and data collection stems from two research sources aimed to address the effectiveness of metacognitive training in people with FEP, under the register numbers NCT04429412 and NCT02340559. Inclusion criteria contemplated: 1) a diagnosis of schizophrenia, psychotic disorder not otherwise speci ed, delusional disorder, schizoaffective disorder, brief psychotic disorder, or schizophreniform disorder (according to DSM-IV-TR); 2) <5 years from the onset of symptoms; 3) a score ≥3 in item delusions, grandiosity, or suspiciousness of PANSS in the last year; 4) clinical stability in the previous 3 months, de ned as no changes on psychopharmacological treatment or hospitalization in the previous 3 months, and 5) age between 18 and 45.

Sociodemographic questionnaire
Data on socio-demographic variables was collected on-site. Diagnosis and treatment were collected. We transformed the antipsychotic treatment to olanzapine de ned daily dose (DDD) [40].

Clinical measures
The Positive and Negative Syndrome Scale (PANSS) [41,42] was used to measure clinical and general symptoms. We used the 7-factor solution proposed by Emsley [43]. The Spanish version of the Scale Unawareness of Mental Disorders (SUMD) [44,45] was used to measure unawareness of the mental disorder. Higher scores represent more unawareness of the mental disorder. We used the Rosenberg Self-Esteem Scale [46], where higher scores indicate better selfesteem.
Metacognition: The Beck Cognitive Insight Scale (BCIS) [47,48] was used to measure cognitive insight. The BCIS is composed of two subscales: self-certainty and self-re ectivity, which are analyzed separately. Higher scores in self-re ectivity represent more ability to questioning one's beliefs. Higher scores in selfcertainty represent more certainty in one's interpretations and misinterpretations. The Beads Task [49] was used to measure the JTC. Participants were shown a picture of two containers lled with 100 colored beads in reciprocal proportions. We used three trials with different conditions: a probabilistic trial with a 85/15 ratio, a second probabilistic trial with a 60/40 ratio, and a nal trial with an affective condition in a 60/40 ratio. Participants were told that the computer had selected a container and that the goal of the task was to determine which container. To this aim, participants were shown one bead at a time. The participant was instructed to see as many beads as they needed to guess what container the beads came from. Our outcome variable was the draws to decision in the three probabilistic conditions. Less than 3 draws to decision is considered indicative of presenting the JTC bias.
Social Cognition: The Internal, Personal and Situational Attributions Questionnaire (IPSAQ) [50] was used to assess attributional style. We used two indexes: personalizing bias and externalizing bias. The Faces Test [51,52] was used to measure emotion recognition. A reduced version of The Hinting Task [53,54] was used to measure theory of mind.

Functional outcome
The Global Assessment of Functioning (GAF) [55] was used to measure clinical and social functioning on a scale of 0-100. Higher scores represent better functioning.

Neuropsychology
The Wisconsin Sorting Card Test (WSCT) [56, 57] was used to assess exibility and inhibition. The Stroop Test (Stroop, 1935) was used to measure exibility and inhibition. The Trail Making Test (TMT-A and TMT-B) [59,60] were used as a measure of visuomotor attention, sustained attention, speed, and cognitive exibility. The Continuous Performance Test (CPT-II for Windows) [59,60] was used to assess sustained attention and impulsivity. MATRICS CPT [61, 62] was used as a measure of attention in a subsample of the participants. We created the composite variable "Attention" by adding the D-prime scores of both measures standardized into T scores. All the neuropsychological variables are presented in T scores. The Weschler Adults Intelligence Scale (WAIS) [63] subtests Vocabulary and Digits were used to measure premorbid intelligence and verbal uency, and working memory respectively. The scores are presented in their conversion to IQ.

Statistical analysis
All descriptive analyses to explore the dataset were conducted using SPSS Version 22. We explored differences between genders in all measures prior to conducting the Latent Pro le Analysis using U-Mann Whitney tests. Effect size is reported using Cohen's d.
Latent Pro le Analysis (LPA) broken down by sex was carried out using R Version 3.5.3 [64], and in particular the R package mclust [65]. This method identi es pro les of individuals, called latent pro les, based on responses to a series of continuous variables. The number of latent pro les was determined by analyzing 2-6 group models in which the variables included were: Faces Test (total score), the Hinting Task (total score), the IPSAQ (personalizing bias and externalizing bias scores), the BCIS (self-re ectivity and self-certainty scores), and the three conditions of the Beads Task (trials to decision).
Model selection to determine the optimal number of latent trajectories was performed according to the Bayesian Information Criterion (BIC) [66]. Additionally, we assessed variable importance by applying a classi cation tree via the R package rpart [67]. We used Kruskal-Wallis and Dwass-Steel-Critchlow-Fligner pairwise comparisons to calculate mean differences among the clusters. Effect size is reported using epsilon squared.

Characteristics of the sample
A total of 174 patients with FEP were included in the analysis. Females were signi cantly older than males (p=0.013) and had received signi cantly more education (p=0.028). The samples differed in diagnosis (p=0.03), depression as measured by the PANSS (p=0.033), theory of mind (p=0.047), immediate recall (p=0.019), and long-term memory (p=0.034). We did not nd any other signi cant differences between sexes.

Males
We identi ed three diagonal, variable volume, variable shape, coordinate axes orientation (VVI) pro le pro les (i.e., diagonal pro les with variable shape, volume, and orientation aligned to the coordinate axes) according to BIC (BIC=-2854.815). Additionally, the CART classi cation tree assessed that the affective condition of the beads task (40%) and the 60-40 condition of the beads task (36%) were the most important variables.
Pro le 1, JTC, (28.7%) comprised males that presented the jumping to conclusions bias. Pro le 2, Indecisive, (18.3%) presented an excessive number of trials in the three conditions of the Beads Task. Pro le 3, Homogeneous, (53%) characterized a homogeneous pro le in which all the variables examined grouped around the mean. Figure 1 shows the graphic representation of each pro le in the male group.
Kruskal-Wallis tests yielded signi cant differences in positive (p=0.03) and disorganized (p=0.03) symptoms. Signi cant differences in positive symptoms did not survive subsequent pairwise comparisons. However, we found that males in the JTC pro le had worse disorganized symptoms than males in the Homogeneous pro le. Further, males in the JTC pro le presented worse clinical insight than the other two pro les. We did not nd other clinical differences.
As for neuropsychological variables, we found that males in the JTC pro le scored worse than their counterparts in pro les Indecisive and Homogeneous in TMT-A and TMT-B, and worse than males in the Homogeneous pro le in total errors of WSCT.
Males in the JTC pro le scored better in our sustained attention measure than males in the Homogeneous pro le. The mean scores of each variable included in the LPA and mean differences among pro les are presented in Table 1. Differences among the pro les in clinical and neuropsychological variables are displayed in table 2.

Females
We identi ed three diagonal, variable volume, equal shape, coordinate axes orientation (VEI) pro le pro les for females (i.e., diagonal pro les with variable volume, equal shape, and orientation aligned to the coordinate axes) according to BIC (BIC=-1443.49). The CART classi cation tree indicated that the most important variables in de ning the pro le structure were the Personalizing Bias (32%) and Externalizing Bias (23%) subscales of the IPSAQ.
Pro le 1, Homogeneous, was the dominant group, comprising 79.3% of the sample. Subjects in this sample were characterized by a homogeneous pro le, with performance in all the variables clustered towards the mean.
Pro le 2, Indecisive, included 8.6% of the sample, characterized by an excessive number of trials to decision in the Beads Task.
Pro le 3, Cognitive Biases, was formed by 12.1% of the sample. It was de ned by high self-re ectivity, very low externalizing bias, and very high personalizing bias. Figure 2 shows the graphic representation of each pro le in the female group.
Kruskal-Wallis tests yielded signi cant age differences (p=0.04) and self-esteem (p=0.04). Subsequent pairwise comparisons indicated that females in the Homogeneous pro le were signi cantly older than females in the Cognitive Bias pro le.
The mean scores of each variable included in the LPA and mean differences among pro les are presented in Table 1. Differences among the pro les in clinical and neuropsychological variables are summarized in table 2.

Discussion
In this study, we conducted a latent pro le analysis to obtain pro les of social cognition and metacognition in FEP according to gender. We identi ed three pro les in each gender. We found 2 pro les (Homogeneous and Indecisive) that were present in males and females, while we found 2 pro les (JTC and Cognitive Biases) that were speci c to each sex.
Males in the homogeneous pro le seemed to have a more benign course of illness than their counterparts, speci cally than males in the JTC pro le. Conversely, females in the homogeneous pro le were older, had fewer depressive symptoms and more self-esteem than females in the Cognitive Bias pro le.
These ndings may have relevant clinical consequences, as our results suggest that having homogeneous levels of social cognition and metacognition could be indicative of a more benign course of illness, although this explanation should be clari ed in future research.
We found a second pro le common to both genders (Indecisive), characterized by average scores in most variables except for draws to decision, which were a standard deviation higher than the mean. Females in this pro le only presented signi cantly better self-esteem than the other pro les. Males in this pro le had more positive symptoms than males in the homogeneous pro le but scored signi cantly better in attention than males in the JTC pro le. This pro le grouped the least proportion of participants both in males (18.3%) and females (8.6%) and seems to have a clinical state similar to the homogeneous pro le. However, the importance of its traits cannot be neglected. Although to our knowledge the role of an excessive number of DTDs in the beads task has not been studied, one interpretation could be excessive metacognitive monitoring. Participants could be constantly evaluating whether they have enough information to make a decision, which could inhibit decision making [24]. The particularities of this pro le indicate that subjects with this pro le could bene t from a different therapeutic approach.
Males in the JTC pro le had worse neuropsychological performance, more positive and disorganized symptoms, and worse clinical insight. These results are consistent with previous studies reporting the association between JTC and more positive symptoms [16] and worse neuropsychological de cits [15][16][17].
between clinical insight seems to be independent of neurocognitive abilities [27]. Notwithstanding, the three constructs have been associated with poorer outcomes [12,14,20], indicating that males in this pro le could have a more troubled course of the disease and worse functioning.
Females in the Cognitive Bias pro le had more personalizing bias and self-re ectivity, but less self-esteem than their counterparts. Further, we found a trend for signi cance in depression measured with BDI. Females in the Cognitive Bias pro le scored higher in depression than the other two pro les. This presentation seems consistent with the insight paradox [25], a phenomenon in which more self-re ectivity is positively associated with depression and selfesteem [31].
Depression, self-esteem, and personalizing bias have been found not only to be closely associated with persecutory ideation and paranoia [28, 29,50] but also with the severity of paranoia in subjects with FEP [30]. Females in this pro le have more self-re ectivity, indicating that they have a better ability to re ect upon their processes. This ability may lead to a better awareness of their symptoms and di culties, which could decrease self-esteem and increase depression. Ultimately, to preserve their self-esteem, females in this pro le could blame other persons for negative events, which could, in turn, increase paranoid symptoms and perpetuate symptoms. This explanation, however, remains speculative as this study did not explore causality.
Our work must be interpreted considering several limitations.
First, our sample was not balanced in gender, which can have hampered our statistical power. Likewise, the sample size of each pro le varied greatly. Therefore, although we used non-parametric tests to determine mean differences, some signi cant differences may not have been detected. Similarly, we did not conduct post-hoc analysis, as the comparisons presented in this work are qualitative comparisons based on the graphical representation of the clusters.
We did not have a control group. Therefore, whether these pro les appear in the general population, the extent of the impairment and cut-off scores could not be calculated. We used a cross-sectional design that did not allow testing pro le stability. These limitations notwithstanding, this is the rst work yielding evidence of sex pro les in social cognition and metacognition. Future research con rming our pro le solution, pro le membership predictors, and illness course according to pro le and gender are recommended, as well as understanding therapeutic components of interventions that are more adequate to speci c genders and pro le presentations.
There are relevant clinical implications to our work. A rst implication is that males that present JTC and females that present higher self-re ectivity in conjunction with personalizing bias may have a worse presentation of the disorder. Interestingly, the clinical symptoms related to the JTC pro le in males seem to be more associated with psychotic symptoms, while females in the cognitive bias pro le seem to have more affective symptomatology. This is of particular importance since JTC and cognitive biases are modi able [68] and identi cation and early correction of these cognitive patterns at prodromal stages or rst-episode could have a positive impact in the course of the disorder.
Patients with different pro les of social cognition and metacognition may respond differently to therapeutic approaches. A study assessing gender differences in response to metacognitive treatment in a sample with FEP [39] reported that females improved more in cognitive insight, personalizing bias and general symptoms than males. Conversely, males improved more in the salient condition of the Beads Task, but not females. Our results are consistent with them in that our pro les follow the same direction as their ndings, and further support them in that future studies should study which contents of metacognitive interventions could be more bene cial according to gender and pro le of impairment.
While all the pro les could bene t from therapies that target metacognition, males could bene t from boosting sessions aimed at correcting the JTC, while females could bene t from boosting sessions directed to modify cognitive insight and attributional biases. Moreover, males that present JTC nd optimal treatment in combining neurocognitive training with metacognitive therapy.
Finally, subjects with FEP do not receive an immediate chronic diagnosis, as the trajectories of the disease are heterogeneous. Predictors of pro le membership and possible illness trajectories emerge in our work as promising topics for future research. Longitudinal studies assessing the prognosis of each pro le and pro le stability are encouraged.

Declarations
Con icts of interest: The authors declare that they have no con ict of interest.   Figure 1 Pro les of each group in the male sample with standardized means in each of the variables included in the LPA.

Figure 2
Pro les of each group in the female sample with standardized means in each of the variables included in the LPA.