First-episode Psychosis Research Articles

The Role of Proximity to Coordinated Specialty Care For Early Psychosis And Program Engagement in Washington State: The Interaction of Travel Time, Race, and Ethnicity.

Proximity to mental health services is a predictor of timely access to services. The present study sought to investigate whether travel time was associated with engagement in coordinated specialty care (CSC) for early psychosis, with specific attention to whether the interaction of travel time by race and ethnicity had differential impact. Data collected between 2019 and 2022 as part of the New Journeys evaluation, the CSC model in Washington State. This cross-sectional study included a sample of 225 service users with first episode psychosis (FEP) who had received services from New Journeys. Service users' addresses, and the physical location of CSC were geocoded. Spatial proximity was calculated as travel time in minutes. Scheduled appointments, attendance and program status were captured monthly by clinicians as part of the New Journeys measurement battery. Proximity was significantly associated with the number of appointments scheduled and attended, and program status (graduation/completion and disengagement). Among Hispanic service users with spatial proximity further away from CSC (longer commutes) was associated with a lower likelihood of graduating/completing CSC compared to non-Hispanic service users (p = .04). Non-white services users had a higher risk of disengagement from CSC compared to white service users (p = .03); additionally, the effects of spatial proximity on disengagement were amplified for non-White service users (p = .03). Findings suggest that proximity is associated with program engagement and partially explains potential differences in program status among ethnoracial group.

Neurocognitive performance and cognitive biases in young adults with schizotypal traits

Recent research suggests that neurocognitive deficits in patients with schizophrenia may increase the risk of developing cognitive biases. As such, we set out to determine this predictive relationship as it pertains to the development of a first-episode psychosis. We hypothesized that poorer performance in processing speed would be associated with jumping to conclusions and an externalizing bias. Poorer performance in working memory would be associated with belief inflexibility and jumping to conclusions, and poorer performance in attention would be associated with attention to threat. We hypothesized that all cognitive biases would be associated with subsyndromal positive symptoms, and schizotypal traits would moderate these relationships. Undergraduate students (N = 130) completed the Schizotypal Personality Questionnaire, DAVOS Assessment of Cognitive Biases, Community Assessment of Psychic Experiences, and a computerized neuropsychological assessment battery. Processing speed had a small effect on externalizing bias, which in turn affected subsyndromal positive symptoms. There was no moderating effect of schizotypal traits on externalizing bias, but it was significantly associated with subsyndromal positive symptoms. Only the externalizing bias was associated with subsyndromal positive symptomatology, which might be explained by a restricted range and reduced variance in performance as a result of using a university student sample. This is one of few studies that sought to explain the mechanism responsible for the development of subsyndromal positive symptoms in a healthy sample using self-report measures.

Long-latency auditory evoked response amplitudes at first episode of psychosis predict six-month recovery in positive symptom severity

Predicting treatment response would facilitate individualized medical treatment in first-episode psychosis (FEP). We examined relationships between auditory-evoked M100 and longitudinal change in positive symptoms in FEP. M100 was measured from source-resolved magnetoencephalography and symptoms were assessed at initial contact and six months later. M100 at baseline significantly predicted symptom change. Larger M100 at baseline predicted symptom improvement, as did shorter untreated psychosis. Shorter untreated psychosis also correlated with larger M100, and M100 mediated the effect of untreated psychosis on treatment response. Thus, M100 may provide a proximal and objective index of untreated psychosis and a viable route to individualized medicine.

The liminal space of first-episode psychosis and its treatment: A qualitative study exploring the experience of young people participating in an antipsychotic dose reduction randomized controlled trial.

The current guidelines recommend continuation of antipsychotic medication for a minimum of at least 1 year following a first episode of psychosis (FEP). There have been several trials investigating whether early dose reduction or cessation leads to improved functional outcomes. The aim of this study was to explore the experience of consenting to and participating in a randomized controlled trial (RCT) of antipsychotic medication cessation. Five participants in the Reduce trial-an RCT evaluating early antipsychotic medication dose reduction/cessation following FEP-aged 22-24 years completed a semistructured qualitative interview following the RCT. Interpretive phenomenological analysis was undertaken to understand the key themes. A superordinate theme was derived from interviews: the Liminal Space of FEP and treatment. Themes within the Liminal Space included: rejection versus identification with psychosis, medication as symbolic of illness versus wellness, embodiment of wellness and illness with medication, medication as symbolic of independence versus dependence, discovery of independence when autonomously choosing medication, the Reduce trial offered safety to navigate the liminal space, and self-exploration versus altruism. The experience and treatment of FEP involves young people feeling torn between multiple, competing perspectives, demands, and priorities. Participation in an RCT exploring dose reduction provided additional supports contributing to the perception of greater safety to navigate their own experiences of treatment that was appropriate for them. When treatment is experienced as collaborative, involves shared decision making and support, other than medication, young people feel more equipped to navigate the liminal space. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Computational analysis of linguistic features in speech samples of first-episode bipolar disorder and psychosis

BackgroundIn recent years, automated analyses using novel NLP methods have been used to investigate language abnormalities in schizophrenia. In contrast, only a few studies used automated language analyses in bipolar disorder. To our knowledge, no previous research compared automated language characteristics of first-episode psychosis (FEP) and bipolar disorder (FEBD) using NLP methods. MethodsOur study included 53 FEP, 40 FEBD and 50 healthy control participants who are native Turkish speakers. Speech samples of the participants in the Thematic Apperception Test (TAT) underwent automated generic and part-of-speech analyses, as well as sentence-level semantic similarity analysis based on SBERT. ResultsBoth FEBD and FEP were associated with the use of shorter sentences and increased sentence-level semantic similarity but less semantic alignment with the TAT pictures. FEP also demonstrated reduced verbosity and syntactic complexity. FEP differed from FEBD in reduced verbosity, decreased first-person singular pronouns, fewer conjunctions, increased semantic similarity as well as shorter sentence and word length. The mean classification accuracy was 82.45 % in FEP vs HC, 71.1 % in FEBD vs HC, and 73 % in FEP vs FEBD. After Bonferroni correction, the severity of negative symptoms in FEP was associated with reduced verbal output and increased 5th percentile of semantic similarity. LimitationsThe main limitation of this study was the cross-sectional nature. ConclusionOur findings demonstrate that both patient groups showed language abnormalities, which were more severe and widespread in FEP compared to FEBD. Our results suggest that NLP methods reveal transdiagnostic linguistic abnormalities in FEP and FEBD.

Association between suicidal ideation, negative symptoms and theory of mind in first episode psychosis.

Suicidal thoughts are common among patients with first episode psychosis (FEP). The impact of symptoms' severity and social cognition on suicidal risk should be a focus of attention. This study aimed at assessment of the severity of suicidal ideation in patients with FEP and its potential association with the theory of mind (ToM) impairment and symptoms' severity. Ninety-six participants were recruited consecutively and subdivided into three equal groups: FEP, schizophrenia, and healthy controls (HC). The symptoms' severity was assessed using Positive and Negative Syndrome Scale (PANSS) and Beck Depression Inventory (BDI). Suicidal ideation was evaluated using Beck Scale for Suicidal Ideation (BSSI). Reading the Mind in the Eyes revised version (RMET) was used to assess ToM. Suicidal ideation was significantly higher only in FEP compared to HC (p = 0.001). Both FEP and schizophrenia had substantially lower performance than HC on RMET (p < 0.001). Higher depression (β = 0.452, p = 0.007) and negative symptoms (β = 0.433, p = 0.027) appeared to be significantly associated with increased suicidal ideation severity in FEP while RMET did not. Patients with FEP and chronic schizophrenia have comparable deficits in theory of mind dimension of social cognition. The severity of negative and depressive symptoms potentially contributes to the increased risk of suicide in FEP.

Neutrophil/lymphocyte ratio and cognitive performances in first-episode patients with schizophrenia and healthy controls

Abnormal immune and inflammatory responses are considered to contribute to schizophrenia (SZ). The neutrophil/lymphocyte ratio (NLR) is an inexpensive and reproducible marker of systemic inflammatory responses. Accumulating studies have demonstrated that NLR values are increased in SZ compared to healthy controls and closely related to clinical symptoms in antipsychotic-naïve first-episode SZ (ANFES) patients. However, to our knowledge, only one study has examined NLR in relation to neurocognition in 27 first-episode psychosis patients and 27 controls. This study aimed to examine the relationship of NLR values with cognitive performances in ANFES patients with a larger sample size. Whole blood cell counts were measured in ninety-seven ANFES patients and fifty-six control subjects. The neurocognitive functions of all subjects were measured by the repeatable battery for the assessment of neuropsychological status (RBANS). ANFES patients performed worse on cognition and had increased NLR values relative to healthy controls. In addition, increased NLR was negatively associated with cognitive functions in ANFES patients. Lymphocyte count was positively correlated with cognitive functions in patients. These findings suggest that the abnormal immune and inflammation system indicated by NLR may be involved in the cognitive functions in ANFES patients.

Emotional intelligence and neurocognition profiles in first-episode psychosis: A two-year follow-up study

Emotional intelligence (EI) and neurocognition (NC) impairments are common in first-episode psychosis (FEP), yet their evolution over time remains unclear. This study identified patient profiles in EI and NC performance in FEP. 98 adult FEP patients and 128 healthy controls (HCs) were tested on clinical, functional, EI, and NC variables at baseline and two-year follow-up (FUP). A repeated-measures ANOVA compared the effects of group (patients and HCs) and time on EI. Significant EI improvements were observed in both groups. Four groups were created based on NC and EI performance at baseline and FUP in patients: impairment in NC and EI, impairment in NC only, impairment in EI only, and no impairment. At FUP, patients impaired in NC and EI showed less cognitive reserve (CR), greater negative and positive symptoms, and poorer functional outcomes. At FUP, three group trajectories were identified: (I) maintain dual impairment (II) maintain no impairment or improve, (III) maintain sole impairment or worsen. The maintain dual impairment group had the lowest levels of CR. EI and NC impairments progress differently in FEP. Greater CR may protect against comorbid EI/NC impairment. Identifying these patient characteristics could contribute to the development of personalised interventions.

Sex differences in prolactin levels and clinical outcomes in patients with a first psychotic episode

AimTo analyze the clinical, neurocognitive, and functional impact of prolactin levels according to sex in patients with a First Episode Psychosis (FEP). MethodsWe measured prolactin levels in 221 non-affective FEP patients treated with antipsychotics (AP) and 224 healthy controls, at baseline and 2-year follow-up. We examined whether the relationships between clinical and functional variables were mediated by prolactin, controlling for antipsychotic use, according to sex. ResultsProlactin levels were higher in patients when compared to controls at both time points. Baseline factors associated with prolactin were chlorpromazine equivalents, attention, and executive functioning. In the FEP group, prolactin levels were associated with functioning and diminished expression in males, and with working memory in females. Prolactin levels (p=0.0134) played a role as a mediator between negative symptomatology (p=0.086) and functional outcome (p=0.008) only in FEP male patients at baseline. ConclusionsProlactin plays a role in the functionality and clinical symptomatology of FEP patients. Our results suggest that pharmacological counselling in patients with hyperprolactinemia at baseline and negative symptomatology might improve their functional and clinical outcomes.

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

BackgroundEarly 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. MethodsThis 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. Results45 % 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. DiscussionOur 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.

Elevated serum kynurenic acid in individuals with first-episode psychosis and insufficient response to antipsychotics

The tryptophan-metabolizing kynurenine pathway (KP) can be activated by enhanced inflammatory responses and has been implicated in the pathophysiology of schizophrenia. However, there is little evidence for KP dysregulation in the early course of psychotic illness. We aimed to investigate the potential immune-mediated hyperactivity of KP in individuals with first-episode psychosis (FEP) and the relationship with symptom severity and treatment response outcomes. Serum immunoassays were performed to measure peripheral levels of inflammatory cytokines (IL-1β, IL-10, TNF-a), KP rate-limiting enzymes (IDO/TDO), and kynurenic acid (KYNA) metabolite in 104 antipsychotic-naïve patients with FEP and 80 healthy controls (HC). The Positive and Negative Syndrome Scale (PANSS) and the Global Assessment of Functioning Scale (GAF) were administered to assess psychopathology and functioning status at admission and following 4-week treatment with antipsychotics. Cytokine and KP components levels were substantially increased in FEP patients compared to HC, before and after antipsychotic treatment. A significant positive correlation between pro-inflammatory IL-1β and KYNA levels was observed among FEP patients, but not in HC. Importantly, within-patient analysis revealed that those with higher baseline KYNA experienced more severe negative symptoms and poorer clinical improvement at follow-up. These findings suggest that KP is upregulated in early psychosis, likely through the induction of IL-1β-dependent pathways, and raised peripheral KYNA might represent a promising indicator of non-response to antipsychotic medication in patients with FEP.

Multimodal prediction of the need of clozapine in treatment resistant schizophrenia; a pilot study in first-episode psychosis

As many as one third of the patients diagnosed with schizophrenia do not respond to first-line antipsychotic medication. This group may benefit from the atypical antipsychotic medication clozapine, but initiation of treatment is often delayed, which may worsen prognosis. Predicting which patients do not respond to traditional antipsychotic medication at the onset of symptoms would provide fast-tracked treatment for this group of patients. We collected data from patient records of 38 first-episode psychosis patients, of whom seven did not respond to traditional antipsychotic medications. We used clinical data including medical records, voxel-based morphometry MRI data and inter-subject correlation fMRI data, obtained during movie viewing, to predict future treatment resistance. Using a neural network model, we correctly predicted future treatment resistance in six of the seven treatment resistance patients and 25 of 31 patients who did not require clozapine treatment. Prediction improved significantly when using imaging data in tandem with clinical data. The accuracy of the neural network model was significantly higher than the accuracy of a support vector machine algorithm. These results support the notion that treatment resistant schizophrenia could represent a separate entity of psychotic disorders, characterized by morphological and functional changes in the brain which could represent biomarkers detectable at early onset of symptoms.

A 10-Year Longitudinal Study of Brain Cortical Thickness in People with First-Episode Psychosis Using Normative Models.

Clinical forecasting models have potential to optimize treatment and improve outcomes in psychosis, but predicting long-term outcomes is challenging and long-term follow-up data are scarce. In this 10-year longitudinal study, we aimed to characterize the temporal evolution of cortical correlates of psychosis and their associations with symptoms. Structural magnetic resonance imaging (MRI) from people with first-episode psychosis and controls (n = 79 and 218) were obtained at enrollment, after 12 months (n = 67 and 197), and 10 years (n = 23 and 77), within the Thematically Organized Psychosis (TOP) study. Normative models for cortical thickness estimated on public MRI datasets (n = 42 983) were applied to TOP data to obtain deviation scores for each region and timepoint. Positive and Negative Syndrome Scale (PANSS) scores were acquired at each timepoint along with registry data. Linear mixed effects models assessed effects of diagnosis, time, and their interactions on cortical deviations plus associations with symptoms. LMEs revealed conditional main effects of diagnosis and time × diagnosis interactions in a distributed cortical network, where negative deviations in patients attenuate over time. In patients, symptoms also attenuate over time. LMEs revealed effects of anterior cingulate on PANSS total, and insular and orbitofrontal regions on PANSS negative scores. This long-term longitudinal study revealed a distributed pattern of cortical differences which attenuated over time together with a reduction in symptoms. These findings are not in line with a simple neurodegenerative account of schizophrenia, and deviations from normative models offer a promising avenue to develop biomarkers to track clinical trajectories over time.

Neural dysfunction underlying working memory processing at different stages of the illness course in schizophrenia: a comparative meta-analysis.

Schizophrenia, as a chronic and persistent disorder, exhibits working memory deficits across various stages of the disorder, yet the neural mechanisms underlying these deficits remain elusive with inconsistent neuroimaging findings. We aimed to compare the brain functional changes of working memory in patients at different stages: clinical high risk, first-episode psychosis, and long-term schizophrenia, using meta-analyses of functional magnetic resonance imaging studies. Following a systematic literature search, 56 whole-brain task-based functional magnetic resonance imaging studies (15 for clinical high risk, 16 for first-episode psychosis, and 25 for long-term schizophrenia) were included. The separate and pooled neurofunctional mechanisms among clinical high risk, first-episode psychosis, and long-term schizophrenia were generated by Seed-based d Mapping toolbox. The clinical high risk and first-episode psychosis groups exhibited overlapping hypoactivation in the right inferior parietal lobule, right middle frontal gyrus, and left superior parietal lobule, indicating key lesion sites in the early phase of schizophrenia. Individuals with first-episode psychosis showed lower activation in left inferior parietal lobule than those with long-term schizophrenia, reflecting a possible recovery process or more neural inefficiency. We concluded that SCZ represent as a continuum in the early stage of illness progression, while the neural bases are inversely changed with the development of illness course to long-term course.

Power spectral density-based resting-state EEG classification of first-episode psychosis

Historically, the analysis of stimulus-dependent time–frequency patterns has been the cornerstone of most electroencephalography (EEG) studies. The abnormal oscillations in high-frequency waves associated with psychotic disorders during sensory and cognitive tasks have been studied many times. However, any significant dissimilarity in the resting-state low-frequency bands is yet to be established. Spectral analysis of the alpha and delta band waves shows the effectiveness of stimulus-independent EEG in identifying the abnormal activity patterns of pathological brains. A generalized model incorporating multiple frequency bands should be more efficient in associating potential EEG biomarkers with first-episode psychosis (FEP), leading to an accurate diagnosis. We explore multiple machine-learning methods, including random-forest, support vector machine, and Gaussian process classifier (GPC), to demonstrate the practicality of resting-state power spectral density (PSD) to distinguish patients of FEP from healthy controls. A comprehensive discussion of our preprocessing methods for PSD analysis and a detailed comparison of different models are included in this paper. The GPC model outperforms the other models with a specificity of 95.78% to show that PSD can be used as an effective feature extraction technique for analyzing and classifying resting-state EEG signals of psychiatric disorders.

Brainwide Anatomical Connectivity and Prediction of Longitudinal Outcomes in Antipsychotic-Naïve First-Episode Psychosis

BackgroundDisruptions of axonal connectivity are thought to be a core pathophysiological feature of psychotic illness, but whether they are present early in the illness, prior to antipsychotic exposure, and whether they can predict clinical outcome remain unknown. MethodsWe acquired diffusion-weighted magnetic resonance images to map structural connectivity between each pair of 319 parcellated brain regions in 61 antipsychotic-naïve individuals with first-episode psychosis (15–25 years, 46% female) and a demographically matched sample of 27 control participants. Clinical follow-up data were also acquired in patients 3 and 12 months after the scan. We used connectome-wide analyses to map disruptions of inter-regional pairwise connectivity and connectome-based predictive modeling to predict longitudinal change in symptoms and functioning. ResultsIndividuals with first-episode psychosis showed disrupted connectivity in a brainwide network linking all brain regions compared with controls (familywise error–corrected p = .03). Baseline structural connectivity significantly predicted change in functioning over 12 months (r = 0.44, familywise error–corrected p = .041), such that lower connectivity within fronto-striato-thalamic systems predicted worse functional outcomes. ConclusionsBrainwide reductions of structural connectivity exist during the early stages of psychotic illness and cannot be attributed to antipsychotic medication. Moreover, baseline measures of structural connectivity can predict change in patient functional outcomes up to 1 year after engagement with treatment services.

Utilization of Head Imaging in Children and Adolescents With First-Episode Psychosis: A Retrospective Analysis.

Background Psychotic disorders are commonly diagnosed in the mid-20s but symptoms often emerge earlier during late teenage years to mid-20s. Notably, studies have shownthat psychotic symptoms can also affect younger individuals, with a higher prevalence among preteens than teens. Head imaging via computed tomography (CT) or magnetic resonance imaging (MRI) can be performed to rule out non-psychiatric causes of psychotic symptoms in this population but may pose additional risks and financial burdens. Practice patterns vary regarding when to utilize head imaging in pediatric patients with first-episode psychosis (FEP). The purpose of this study is to better understand the use of head imaging in pediatric FEP and associated patient characteristics. Methods A retrospective cohort study was performed. Eligible patients were <18 years of age with an encounter documented between 2013 and 2023 where a diagnosis code for psychosis was first applied. Medical records were manually reviewed if head imaging was performed during the index encounter or within one month. Descriptive statistics were used to report the study population demographics. Independent t-testing was used to compare characteristics between patients who did and did not receive head imaging. Results A total of 113 patients met the inclusion criteria for the study, of which 12 (10.6%) received head imaging within the specified timeframe. All received CTcriteria head scans, and a significantly higher proportion were African American or Black when compared tothose who did not receive head imaging (10/12 (83.3%) vs. 53/101 (52.5%) p=0.023). None of the imaging tests performed yielded significant neurological findings that suggested an underlying pathology for psychosis. Conclusions Head imaging was rarely utilized for the initial assessment of pediatric FEP in this study. When it was used, CT head scans were the modality of choice but did not yield any remarkable findings to suggest a non-psychiatric cause of psychotic symptoms. This adds to the body of evidence supporting a conservative approach when considering head imaging in pediatric FEP.

Art and mentalizing in early intervention psychosis: rationale and therapist insights on a new psychoeducational course.

In this paper, we explore the rationale for a combined art therapy and mentalization-based treatment (MBT) group course for those experiencing a first episode of psychosis (FEP). We discuss the theoretical background for how art and MBT theory can help us better understand and work with groups of individuals experiencing FEP, particularly focusing on avoidance and insecure attachment styles. We outline the delivery of a ten-week psychoeducational Art MBT course within an Early Intervention in Psychosis (EIP) Service and discuss our experiential insights into this new modality as co-therapists. We conclude by proposing that art therapy and mentalizing practice together offer an accessible, useful and practical group structure for EIP services, which could improve individuals' mentalizing capacity and overall social functioning.

Look for Hope and You Will Find It: Outlook for First-Episode Psychosis Has Never Been Better

Look for Hope and You Will Find It: Outlook for First-Episode Psychosis Has Never Been Better

Diagnostic shift in adolescents with first episode psychosis: findings from the 2-year follow-up of the "Parma Early Psychosis" program.

Diagnostic stability for people with First Episode Psychosis (FEP) is essential for treatment, but it remains poorly investigated, especially in adolescents and within a prospective design. The aims of this research were: (a) to examine diagnostic change in Italian adolescents with FEP treated within an "Early Intervention in Psychosis" program during a 2-year follow-up period and (b) to investigate any sociodemographic and clinical predictors at baseline. At baseline, 66 adolescents with FEP was recruited. Their primary diagnosis was formulated both at baseline and at the end of follow-up. At presentation, FEP adolescents completed the Health of the Nation Outcome Scales for Children and Adolescents (HoNOSCA). As for diagnostic stability, the Kappa statistic was calculated. The associations of diagnostic change with baseline clinical and sociodemographic features were analyzed using a logistic model with the diagnostic shift as dependent variable. A propensity score was finally calculated based on logistic analysis results. 38 (57.6%) FEP adolescents changed their opening diagnosis. The highest prospective diagnostic stability was for initial diagnosis of schizophrenia (95.4%) and affective spectrum psychoses (75%). Diagnostic instability was high for opening diagnosis of psychosis not otherwise specified, brief psychosis and schizophreniform disorder (100%). The best predictors of diagnostic change were fewer years of education, shorter duration of untreated psychosis and higher baseline levels of psychiatric symptoms. Diagnostic stability is crucial for treatment and clinical decision making. Addressing instability in FEP diagnoses is an important challenge for future diagnostic development in early psychosis, especially in adolescence.