Illness-related outcomes of illicit substance use disorder in adolescents with early onset schizophrenia: a multicenter study.

OBJECTIVES: Lifetime co-occurring substance use disorders are common at the time of presentation for the treatment of primary psychosis. Our aim was to investigate the clinical characteristics of adolescents with early-onset schizophrenia/schizoaffective disorder (EOS), categorized as either with (EOS + SUD) or without SUD (non-SUD/EOS), in a multi-center sample. METHODS: Between 2016 and 2022, 255 patients were evaluated across three tertiary-care inpatient units. Diagnoses were confirmed by the treating physician according to the DSM-5 during the hospital stay. The severity of symptoms was measured using the Positive and Negative Syndrome Scale (PANSS). RESULTS: The EOS + SUD group exhibited a higher illness onset, fewer years of education, longer duration of untreated psychosis (DUP), a higher frequency of male gender, more frequent hospitalizations, increased use of clozapine and zuclopenthixol LAI, along with higher rates of post-traumatic stress disorder and conduct disorder. Notably, differences in DUP, clozapine use, and the number of hospitalizations did not persist in the multivariate logistic regression model. CONCLUSIONS: Our findings support the notion of SUD playing a role in modifying the course of illness in EOS. Future studies should emphasize exploring treatment responses to medications and interventions among youth with dual diagnoses.

Molecular mechanisms involved in alcohol craving, IRF3, and endoplasmic reticulum stress: a multi-omics study.

Alcohol use disorder (AUD) is the most prevalent substance use disorder worldwide. Acamprosate and naltrexone are anti-craving drugs used in AUD pharmacotherapy. However, molecular mechanisms underlying their anti-craving effect remain unclear. This study utilized a patient-derived induced pluripotent stem cell (iPSC)-based model system and anti-craving drugs that are used to treat AUD as "molecular probes" to identify possible mechanisms associated with alcohol craving. We examined the pathophysiology of craving and anti-craving drugs by performing functional genomics studies using iPSC-derived astrocytes and next-generation sequencing. Specifically, RNA sequencing performed using peripheral blood mononuclear cells from AUD patients with extreme values for alcohol craving intensity prior to treatment showed that inflammation-related pathways were highly associated with alcohol cravings. We then performed a genome-wide assessment of chromatin accessibility and gene expression profiles of induced iPSC-derived astrocytes in response to ethanol or anti-craving drugs. Those experiments identified drug-dependent epigenomic signatures, with IRF3 as the most significantly enriched motif in chromatin accessible regions. Furthermore, the activation of IRF3 was associated with ethanol-induced endoplasmic reticulum (ER) stress which could be attenuated by anti-craving drugs, suggesting that ER stress attenuation might be a target for anti-craving agents. In conclusion, we found that craving intensity was associated with alcohol consumption and treatment outcomes. Our functional genomic studies suggest possible relationships among craving, ER stress, IRF3 and the actions of anti-craving drugs.

INTERNET GAMING DISORDER AND PROBLEMATIC INTERNET USE: THE LINKS BETWEEN CYBERBULLYING, AGGRESSION, LONELINESS AND PSYCHIATRIC COMORBIDITIES.

AIMS: To compare adolescents clinically diagnosed with Internet Gaming Disorder (IGD) and problematic internet use (PIU) in terms of cyberbullying, aggression, and loneliness. METHODS: Male adolescent patients (N=124, 14.3±1.7 years) with Internet Addiction Scale (IAS) scores ≥50 were clinically interviewed for IGD in utilizing DSM-5 criteria. Patients without full IGD criteria were included as PIU comparisons. Clinical variables were assessed using the second version of the Revised Cyber Bullying Inventory, short-form of the UCLA Loneliness Scale, Buss Perry Aggression Questionnaire, Child Depression Inventory, and Screen for Child Anxiety Related Emotional Disorders. RESULTS: Compared to individuals with PIU, those with IGD were significantly more likely to have attention-deficit hyperactivity disorder, higher social phobia scores, higher cyberbullying scores, higher loneliness scores, been a cyberbully, and been a cyberbully victim. CONCLUSION: Male adolescents with IGD have higher rates of psychiatric comorbidity, perceived loneliness, cyberbullying, and being a victim of cyberbullying than those with PIU. Future studies could evaluate these predictors of transition from PIU to IGD in large cohort samples.

Development and validation of Kiddie Schedule for Affective Disorders and Schizophrenia (K-SADS) for Internet Gaming Disorder (IGD) and factor analytic assessment.

OBJECTIVE: To develop and validate Kiddie Schedule for Affective Disorders and Schizophrenia, Present and Lifetime version (K-SADS-PL) for Internet Gaming Disorder (IGD) in adolescents. METHODS: Questions and threshold criteria of the K-SADS-IGD was generated based on the related section of K-SADS-PL. Then, the sample consist of IGD group and matched control group with no significant difference in psychiatric comorbidities from clinical settings were included to assess the psychometric properties of the K-SADS-IGD. Exploratory and Confirmatory Factor analysis were conducted to evaluate and compare DSM model of IGD and two different Models of IGD proposal in adolescents. RESULTS: Exploratory Factor Analysis of K-SADS-IGD revealed a single factor explaining 61.469% of the total variance. Confirmatory Factor Analysis indicates that although the K-SADS-IGD model fit indices were also acceptable, Model 1, which excluded the 7th criterion of IGD criteria of DSM-5 showed better fit in adolescent population. The Likelihood Ratio Positive and the Likelihood Ratio Negative estimates for the diagnosis of K-SADS-IGD were 31.4 and 0.12, respectively, suggesting that K-SADS-IGD was beneficial for determining the presence and the absence of IGD in adolescents. Also, K-SADS-IGD could detect disordered gamers with significantly low functionality (even after controlling the impact of comorbidities) from non-disordered gamers. CONCLUSION: K-SADS-IGD was found to be a reliable and valid instrument in adolescents. The model excluding 7th criteria of DSM-5 IGD was found to be more consistent than the current DSM-5 IGD model in the adolescent population. Therefore, the diagnostic criteria might be required to adjust according to the age group since the clinical symptomatology of IGD in adolescents may differ from that in adults. The K-SADS-IGD may meet the need for a certain and standardized tool to assess IGD in this population.

Electroconvulsive therapy or clozapine for adolescents with treatment-resistant schizophrenia: an explorative analysis on symptom dimensions.

OBJECTIVE: This study sought to compare pre-intervention patient characteristics and post-intervention outcomes in a naturalistic sample of adolescent inpatients with treatment-resistant psychotic symptoms who received either electroconvulsive therapy (ECT) or clozapine. METHODS: Data of adolescents with schizophrenia/schizoaffective disorder receiving ECT or clozapine were retrospectively collected from two tertiary-care psychiatry-teaching university hospitals. Subscale scores of the Positive and Negative Symptom Scale (PANSS) factors were calculated according to the five-factor solution. Baseline demographics, illness characteristics, and post-intervention outcomes were compared. RESULTS: There was no significant difference between patients receiving ECT (n = 13) and clozapine (n = 66) in terms of age, sex, and the duration of hospital stay. The ECT group more commonly had higher overall illness and aggression severity. Smoking was less frequent in the clozapine group. Baseline resistance/excitement symptom severity was significantly higher in the ECT group, while positive, negative, affect, disorganisation, and total symptom scores were not. Both interventions provided a significant reduction in PANSS scores with large effect sizes. CONCLUSION: Both ECT and clozapine yielded high effectiveness rates in adolescents with treatment-resistant schizophrenia/schizoaffective disorder. Youth receiving ECT were generally more activated than those who received clozapine.

Psychomotor agitation and irritability in adolescents with manic episode: Clinical data from three inpatient units.

OBJECTIVES: We aimed to investigate the characteristics of adolescents with Bipolar disorder-I with irritability and agitation (Mania+IA) compared to those without irritability and agitation (Mania-IA) in a multi-center representative sample. METHODS: Data of 145 patients from three tertiary-care inpatient units between 2016 and 2021 were obtained. Psychomotor agitation was defined as a score of ≥3 on the YMRS "Increased Motor Activity--Energy" item, irritability as a score of ≥4 on the YMRS 'irritability' item, and severity anchors of speech and thought disturbance on the YMRS '6 and 7' items. RESULTS: Previous manic episodes (p = 0.013), involuntary hospitalization (p = 0.006), psychotic features (p = 0.001), formal thought disorder (p = 0.010) and aggressive/disruptive behavior (p = 0.021) were more frequent in the Mania+IA group. Conversely, depressive episodes (p = 0.006) and family history of depression (p = 0.024) were more frequent in the Mania-IA group. The Mania+IA had poorer functioning at the time of discharge. CONCLUSIONS: Irritability and agitation were closely related to complications, psychotic symptoms and thought disorder. Assessment and monitoring of psychomotor agitation and irritability may help child and adolescent psychiatrists to predict clinical difficulties and appropriate interventions.

Neurocognitive and social cognitive impairments in remission and symptomatic states of early-onset schizophrenia spectrum disorders.

Previous studies demonstrated neurocognitive impairments in early-onset schizophrenia (EOS) and other psychotic spectrum disorders (PSD). This study aimed to compare remitted and symptomatic cases in terms of neurocognition and theory of mind (ToM). 50 healthy controls (HC) and 106 patients diagnosed schizophrenia in remission (EOS-R, n = 38), symptomatic schizophrenia (EOS-S, n = 34), and other PSD (n = 34) were included in our study. The Positive and Negative Symptom Scale, Columbia-Suicide Severity Rating Scale, Reactive and Proactive Aggression Questionnaire were used to evaluate psychopathology. A cognitive battery was conducted to measure verbal learning/memory, visual learning/memory, executive functions (EF), inhibition, processing speed (PS), verbal fluency skills. Reading Mind in Eyes Test (RMET) and Faux-Pas tests were implemented to assess ToM. Principal Component Analysis was used to identify cognitive domain scores. Patient groups had poorer performance in cognitive domains than the HC group. The cognitive impairment and psychopathology levels of EOS-R and the PSD groups were comparable for all cognitive domains. The EOS-S group also had poorer scores in Rey verbal learning score (d = 0.87), RMET (d = 0.72), verbal fluency (d = 0.66), PS/EF (d = 0.82) and visual learning/memory (d = 0.83) test scores than the PSD group. Only RMET (d = 0.72) and executive function/processing speed domain (d = 0.63) were significantly impaired in the EOS-S group than the EOS-R group Cognitive impairments seen in remitted psychotic disorders were on the same continuum. Impaired EF/PS and ToM skills could be a cognitive marker for symptomatic illness in youth.

Investigating the effects of age, IQ, dosing, and anthropometric measures on the treatment persistence in long-term methylphenidate use.

OBJECTIVES: This study aimed to determine anthropometric and clinical correlates of persistence to methylphenidate (MPH) treatment in Turkish youth with attention-deficit hyperactivity disorder (ADHD). METHODS: Data from medical records of 518 children and adolescents with ADHD were recorded between March 2012 and January 2022. Clinical variables of patients persistent to MPH ≥ 2 years were compared with those of the non-persistent group. Children and adolescent age groups were compared using Kaplan-Meier estimates for treatment drop-outs. Cox regression analysis until the treatment drop-out was implemented to calculate hazard ratios (HRs) for gender, age, full-scale IQ, and anthropometric measures. Weight, height, and body mass index (BMI) z-scores were calculated per national guidelines. RESULTS: Persistent and non-persistent study groups had similar full-scale IQ, weight, height, and BMI z-scores at treatment onset. The mean MPH dose was significantly higher in the persistent group compared to the non-persistent counterparts (31.43 ± 10.70 vs. 24.28 ± 9.60 mg/d, p < 0.001, d = 0.70). Compared to children, the adolescents showed earlier treatment drop-outs in males (p < 0.001) but not in females (p = 0.110). Younger age showed a positive effect on treatment persistence. Conversely, baseline BMI and IQ scores were not associated with long-term persistence. DISCUSSION: Our study demonstrated lower daily doses and older age-onset were associated with early drop-outs in MPH treatment. These findings supported the notion that effective dosing strategies at younger ages could increase the sustainability of the treatment with MPH in the Turkish population.

Social Information Processing and Executive Functions in Male Children and Adolescents with Internet Gaming Disorder.

In recent years, in addition to its clinical importance, interest in the social-cognitive aspect of internet gaming disorder (IGD) has increased. This study aimed to investigate autistic traits, executive functions, and self-regulation abilities of patients with IGD. Eighty-seven male patients with IGD and eighty-three male healthy controls (HC) were included in the study. All patients were diagnosed with IGD as per the diagnostic criteria of Diagnostic and Statistical Manual of Mental Disorders-5. Healthy controls without any comorbid psychiatric diagnosis were recruited from the community. The Brief Rating Inventory of Executive Function (BRIEF) and the Social Responsiveness Scale (SRS) were implemented to evaluate autistic traits, executive functions, and self-regulation skills. The Beck Depression Inventory (BDI), Screen for Child Anxiety and Related Disorders and Internet Gaming Disorder Scale-Short-Form were used to evaluate psychopathology. The effect size of the impairments in executive functions and self-regulation skills was large (Cohen's d = 1.0-2.0). IGD groups had higher levels of autistic traits compared to healthy controls (d = 1.0-1.4). The differences in BDI and BRIEF scores remained significant in logistic regression analysis. Age at illness-onset, total severity of anxiety, and autistic traits were found as significant correlates of deficits in executive functions among patients with IGD. The results of this study supported the higher autistic traits and poorer executive function skills of patients with IGD. Deficits in executive functions were associated with autistic traits and younger age-onset of the illness.

Psychometric Properties of The Clinician Affective Reactivity Index for Assessment of Irritability in a Clinical Sample of Turkish Children and Adolescents.

Background: No clinician-oriented scale exists to assess irritability in Turkey. This pilot study aimed to evaluate the psychometric properties of the Turkish version of The Clinician Affective Reactivity Index (CL-ARI). Method: A total of 116 children and adolescents aged between 10 to 17 years (14.1 ± 2.1 years) were recruited from the psychiatric outpatient clinics. The participants completed a set of scales (Strengths and Difficulties Questionnaire [SDQ], Affective Reactivity Index [ARI], Revised Child Anxiety and Depression Scale, Swanson, Nolan, and Pelham, Version IV Scale). Diagnostic interviews were administered to confirm psychiatric diagnoses. Cronbach's alpha was calculated to assess internal consistency. Discriminant validity was further tested using independent sample t-test and Receiver Operating Characteristic curves. Interrater reliability was tested using intraclass correlation coefficients (ICC). Convergent validity was also tested using Pearson's correlation. Results: Cronbach's alpha values of CL-ARI were 0.919 total score, 0.842 for the temper outbursts score, 0.861 for the irritable mood score, and 0.840 for the impairment score. ICC values for interrater reliability were high for the temper outbursts (r = 0.993), the irritable mood (r = 0.993), the impairment (r = 0.917), and the total score (r = 0.991). In the sample, there was a high level of correlation between the self-report ARI-child/parent form and the CL-ARI total and subscale scores. Likewise, moderate-high level of correlations were found between the behavioral SDQ child/parent forms and the CL-ARI total and subscale scores. Conclusions: This is the Turkish validation of the CL-ARI, a dedicated interview and rating scale to assess irritability in the clinical sample. The results of this study suggest that the Turkish version of CL-ARI has adequate internal consistency and interrater reliability, and sufficient convergent and discriminant validity to be used in research settings.

Identifying clinical and psychological correlates of persistent negative symptoms in early-onset psychotic disorders.

Persistent negative symptoms (PNS) contribute to impairment in psychosis. The characteristics of PNS seen in youth remained under-investigated. We aimed to demonstrate clinical, treatment-related, and psychosocial characteristics of PNS in early-onset schizophrenia-spectrum disorders (EOSD). 132 patients with EOSD were assessed with Positive and Negative Symptom Scale, Brief Negative Symptom Scale, Calgary Depression Scale for Schizophrenia, and Simpson-Angus Scale. Parenting skills and resilience were evaluated using Parental Attitude Research Instrument and Child and Youth Resilience Measure-12. Longer duration of untreated psychosis (DUP) and prodromal phase were found in primary and secondary PNS groups, compared to the non-PNS group. The primary PNS group was characterized by earlier age-onset, lower smoking rates, and more common clozapine use. Resilience and egalitarian/democratic parenting were negatively correlated with symptoms related to motivation/pleasure and blunted expression. More blunted expression-related symptoms and longer DUP in the first episode significantly predicted primary/secondary PNS at follow-up. Using the data from total negative symptom scores and DUP, Receiver Operating Characteristic analyses significantly differentiated primary/secondary PNS groups from the non-PNS counterparts. PNS associated with blunted expression and low motivation/pleasure in the first episode could persist into clinical follow-up. Effective pharmacological treatment and psychosocial interventions are needed in youth.

When to Use Amisulpride in Adolescents: A Retrospective Chart Examination of Inpatients.

PURPOSE/BACKGROUND: Despite increasing interest in amisulpride, current knowledge about its use in the pediatric population is scarce. This chart review aimed to investigate the use of amisulpride in a naturalistic adolescent population. METHODS/PROCEDURES: Electronic medical records of a tertiary care adolescent inpatient unit were screened between January 2015 and April 2021. Sociodemographic data and all clinical information were collected via data collection forms, and targeted symptoms were obtained from patients' files. Patients with early-onset psychotic disorders (n = 58), bipolar I disorder (n = 29), major depressive disorder (n = 14), and other psychiatric diagnoses (n = 9) were included. Treatment response was defined as a Clinical Global Impression-Improvement of at least much improvement after treatment. FINDINGS/RESULTS: Median titration rate of amisulpride was 400 mg/wk, and the maximum administered daily dose ranged between 100 and 1200 mg/d. The maximum daily dose and number of previous antipsychotics were higher in the early-onset psychotic disorder group. Persistent positive symptoms and resistance to previous treatments were leading causes for amisulpride treatment. Other indications were also impulsive/disruptive behaviors, antipsychotic adverse effects, depressive symptoms, somatic complaints, and abnormalities in liver function tests. Finally, patients with lower daily treatment doses and more previous antipsychotic trials are less likely to benefit from the treatment. IMPLICATIONS/CONCLUSIONS: Persistent psychotic/mood symptoms, impulsive/disruptive behaviors, and abnormalities in liver function tests were reasons for the amisulpride treatment in adolescents. Randomized placebo-controlled trials are needed to evaluate the efficacy and safety of the treatment in adolescents.

Index depressive episode and antidepressant exposure were associated with illness characteristics of pediatric bipolar disorder.

OBJECTIVE: Pediatric bipolar disorder (PBD) is a serious, recurrent disorder leading to severe functional impairment. As a first mood episode, index episode could affect the long-term course of the illness. This study aimed to investigate the clinical characteristics of youth with PBD from our multicenter, nationwide, naturalistic follow-up samples and to identify (i) the effects of index mood episode and (ii) the effect of previous antidepressant treatments on the age at mania onset of PBD. METHOD: The study sample consisted of 271 youth with BD-I followed by the child and adolescent psychiatry clinics of seven different university hospitals and three research state hospitals, representing six geographic regions across Turkey. All diagnoses were made according to structured interviews, and all data were retrospectively obtained from clinical records by the clinicians. RESULTS: When patients with index depressive/mixed episodes (IDE, n=129) and patients with index (hypo)manic episodes (IME, n=142) were compared, the total number of mood episodes and rapid cycling feature were significantly higher in the IDE group than in the IME group. The Cox regression analysis adjusted for sociodemographic and illness characteristics revealed female adolescents in the IDE group treated with antidepressants were more likely to have an earlier onset of mania (hazard ratio=2.03, 95% confidence interval=1.31-3.12, p=0.001). CONCLUSION: This is the first large-scale nationwide follow-up study in Turkey that indicated prior antidepressant treatments were associated with an earlier onset of mania in youth, particularly in adolescent females. Larger prospective studies are needed to identify neurodevelopmental processes underlying PBD and initiate prevention approaches.

Selective serotonin reuptake inhibitors and manic switch: A pharmacovigilance and pharmacodynamical study.

BACKGROUND: There is still no approved mechanism of manic switch in bipolar disorder, yet many selective serotonin reuptake inhibitors were accused for this important adverse event. Therefore, we aimed to investigate to estimate SSRI's risk for reporting mania and elevated mood using FEARS database and investigate receptor mechanisms involved. METHODS: Mania and relevant side effects approved by FDA were screened in this dataset from the first quarter of 2004 to the third quarter of 2020. Disproportionality analysis were performed to estimate reporting odds ratio (ROR) and linear regressions were conducted to investigate relationship between ROR and Ki values. Receptor occupancy ratios were calculated from in vitro receptor binding profiles. The pharmacodynamical profile was extracted from the International Union of Basic and Clinical Pharmacology and the British Pharmacology Society dataset. Child and adolescent population was also investigated separately. RESULTS: The analysis showed that the odds of a spontaneous report of mania in the FAERS database involving an SSRI were higher than the odds that such a report involved other types of drugs (ROR: 5.324 [CI: 3.773; 7.514]). The largest effect size in this estimation was found in fluvoxamine (ROR: 13.957 [CI: 10.391; 18.747]). Significant effects were found in regression analysis for Ki values of H1 and M1 receptors on ROR. Receptor occupation was not found to have an effect on ROR. CONCLUSION: Lower degress of Ki values on M1 and H1 may be plausible pharmacological mechanism. Further pharmacological data and clinical assessments may be important to validate this safety signal.

ADHD and Drug Holidays: Effects on Anthropometric Changes during Methylpenidate Treatment.

Objectives: The current study evaluated the long-term effects of methylphenidate (MPH) discontinuation on growth parameters in Turkish children and adolescents with attention-deficit/hyperactivity disorder (ADHD). Experimental design: 432 children and adolescents (aged 6-18 years) with ADHD receiving MPH for at least 1 year between March 2012 and January 2019 were included in a retrospective cohort study. We analyzed weight, height, and body mass index (BMI) standard deviation z scores (SDS) of groups that either did (ADHD-C) or did not (ADHD-DC) discontinue MPH. Growth parameters were converted to z scores as normative values for the Turkish population to compare the measurements at baseline and the last follow-up visit by using the paired sample t-test. Principal observations: In patients from the ADHD-C group, statistically significant negative correlations were found between age at starting MPH and differences in weight and height SDS between baseline and follow-up. Children had a greater reduction in weight and height compared to adolescents. When we evaluated the differences in pre-and post-treatment growth factors, we found no significant differences between the groups in terms of growth parameters. Conclusions: Our data showed that chronic use of MPH was likely responsible for changes in height and weight parameters.

Impaired theory of mind and emotion recognition in pediatric bipolar disorder: A systematic review and meta-analysis.

BACKGROUND: Social cognition is impaired in patients with severe mental disorders. We aimed to investigate impairments in social cognition in youth with pediatric bipolar disorder (PBD) through a systematic review of the literature and the meta-analysis. METHOD: Following the PRISMA guidelines, we searched in PubMed, Scopus, and Cochrane CENTRAL for studies reporting on the theory of mind (ToM) and emotion recognition (ER) abilities of patients with PBD compared to healthy controls (HC). We conducted a random-effects model meta-analysis for the contrast between PBD and HC. Subgroup and meta-regression analyses were conducted for demographic and clinical variables as appropriate. RESULTS: A total of thirteen studies involving 429 patients with PBD and 394 HC were included. Patients with PBD had significantly poorer social cognitive abilities (Hedges' g for ER, g = -0.74, CI = -0.91, -0.57; and for ToM, g = -0.98, CI = -1.41 to -0.55). Subgroup analysis also revealed significant impairment in ER for patients in a euthymic state (g = -0.75). Age, gender, sample size, the severity of mood symptoms, estimated IQ, the frequencies of bipolar-I disorder, attention-deficit hyperactivity disorder, medications, study quality and euthymia did not moderate the difference in meta-regression. Heterogeneity was low in all analyses and there was no evidence for publication bias. CONCLUSION: The results of this meta-analysis supported the notion that PBD is associated with a deficit in social cognitive abilities at a medium to a large level. Impairments in social cognition could be an illness-related trait of PBD. Meta-regression results did not find a moderator of the deficits in social cognition.

ADHD and Risk of Childhood Adiposity: a Review of Recent Research.

PURPOSE OF REVIEW: Attention deficit/hyperactivity disorder (ADHD) is considered as a risk factor for childhood adiposity and obesity. Studies on ADHD have provided limited data concerning the connections between eating habits, body mass index, and obesity. The purpose of this review was to examine the current literature regarding recent cohort and cross-sectional studies to determine the links between ADHD and childhood adiposity. RECENT FINDINGS: Studies in this review were classified into dietary features, nutritional status, neuroimaging findings, genetic overlapping, behavioral, cognitive, and neurocognitive aspects that play a role in mediating and moderating the relationship between ADHD and obesity. While ADHD, childhood adiposity, and overweight/obesity co-occur in children and adolescents, this relationship is largely explained by a variety of multidirectional factors.