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Psychopharmacological treatment is an important component of the multimodal intervention approach to treating mental health conditions in children and adolescents. Currently, there are many unmet needs but also opportunities, alongside possible risks to consider, regarding the pharmacological treatment of mental health conditions in children and adolescents. In this Position Paper, we highlight and address these unmet needs and opportunities, including the perspectives of clinicians and researchers from the European College of Neuropsychopharmacology–Child and Adolescent Network, alongside those of experts by lived experience from national and international associations, via a survey involving 644 participants from 13 countries, and of regulators, through representation from the European Medicines Agency. We present and discuss the evidence base for medications currently used for mental disorders in children and adolescents, medications in the pipeline, opportunities in the development of novel medications, crucial priorities for the conduct of future clinical studies, challenges and opportunities in terms of the regulatory and legislative framework, and innovations in the way research is conducted, reported, and promoted.

Recent longitudinal studies in youth have reported MRI correlates of prospective anxiety symptoms during adolescence, a vulnerable period for the onset of anxiety disorders. However, their predictive value has not been established. Individual prediction through machine-learning algorithms might help bridge the gap to clinical relevance. A voting classifier with Random Forest, Support Vector Machine and Logistic Regression algorithms was used to evaluate the predictive pertinence of gray matter volumes of interest and psychometric scores in the detection of prospective clinical anxiety. Participants with clinical anxiety at age 18–23 (N= 156) were investigated at age 14 along with healthy controls (N= 424). Shapley values were extracted for in-depth interpretation of feature importance. Prospective prediction of pooled anxiety disorders relied mostly on psychometric features and achieved moderate performance (area under the receiver operating curve = 0.68), while generalized anxiety disorder (GAD) prediction achieved similar performance. MRI regional volumes did not improve the prediction performance of prospective pooled anxiety disorders with respect to psychometric features alone, but they improved the prediction performance of GAD, with the caudate and pallidum volumes being among the most contributing features. To conclude, in non-anxious 14 year old adolescents, future clinical anxiety onset 4–8 years later could be individually predicted. Psychometric features such as neuroticism, hopelessness and emotional symptoms were the main contributors to pooled anxiety disorders prediction. Neuroanatomical data, such as caudate and pallidum volume, proved valuable for GAD and should be included in prospective clinical anxiety prediction in adolescents.

In recent years, there have been extensive efforts in secondary schools to prevent, treat and raise awareness of adolescent mental health problems. For some adolescents, these efforts are essential and will lead to a reduction in clinical symptoms. However, it is also vital to assess whether, for others, the current approach might be causing iatrogenic harm. A growing body of quantitative research indicates that some aspects of school-based mental health interventions increase distress or clinical symptoms, relative to control activities, and qualitative work indicates that this may be partly due to the interventions themselves.

ABSTRACTAdolescent depression is a serious and debilitating disorder associated with lifelong negative outcomes, including heightened risk for recurrence into adulthood, psychiatric comorbidities, and suicide. Among evidence-based treatments for adolescents, psychotherapies for depression have the smallest effect sizes of all psychiatric conditions studied. Advancing care for depression in adolescents is complex due to the heterogeneity in etiology and co-occurring difficulties among youth presenting with depression symptoms. This and a companion paper (Lewandowski et al., 2022) draw on a recent multisite collaboration that focused on implementing depression treatment for adolescents within clinical and research contexts. Specifically, this paper will review our work adapting behavioral activation (BA) as a principle-based framework to improve effectiveness and efficiency of depression treatment used within clinical and research settings in academic medical centers. Piloted adaptations include the use of BA principles to address idiographic drivers of depression and in-session BA “exposures” to illustrate BA principles. Case vignettes illustrate these adaptations of BA to address adolescent depression in the context of co-occurring difficulties.

Adolescence is a period of major brain reorganization shaped by biologically timed and by environmental factors. We sought to discover linked patterns of covariation between brain structural development and a wide array of these factors by leveraging data from the IMAGEN study, a longitudinal population-based cohort of adolescents. Brain structural measures and a comprehensive array of non-imaging features (relating to demographic, anthropometric, and psychosocial characteristics) were available on 1476 IMAGEN participants aged 14 years and from a subsample reassessed at age 19 years (n= 714). We applied sparse canonical correlation analyses (sCCA) to the cross-sectional and longitudinal data to extract modes with maximum covariation between neuroimaging and non-imaging measures. Separate sCCAs for cortical thickness, cortical surface area and subcortical volumes confirmed that each imaging phenotype was correlated with non-imaging features (sCCA rrange: 0.30–0.65, all PFDR< 0.001). Total intracranial volume and global measures of cortical thickness and surface area had the highest canonical cross-loadings (|ρ| = 0.31−0.61). Age, physical growth and sex had the highest association with adolescent brain structure (|ρ| = 0.24−0.62); at baseline, further significant positive associations were noted for cognitive measures while negative associations were observed at both time points for prenatal parental smoking, life events, and negative affect and substance use in youth (|ρ| = 0.10−0.23). Sex, physical growth and age are the dominant influences on adolescent brain development. We highlight the persistent negative influences of prenatal parental smoking and youth substance use as they are modifiable and of relevance for public health initiatives.

The use of SSRIs for the treatment of depression and anxiety in young people is increasing. However, the effects of SSRIs in adolescence, a time when there are substantial changes in neural, cognitive, and social functioning, are not well understood. Here, we review evidence from clinical trials about the benefits and risks of SSRIs in young people and consider their mechanisms of action, as shown through human experimental work and animal models. We emphasise key outstanding questions about the effects of SSRIs in youth, identified through gaps in the literature and in consultation with young people with lived experience. It is crucial to characterise the mechanisms underpinning risks and benefits of SSRIs in this age group to progress the field, and to narrow the chasm between the widespread use of SSRIs in youth and the science on which this use is based.

Based on its course over time, irritability is linked to depression cross-sectionally and longitudinally. Cross-sectionally, irritability takes an episodic form as a symptom in pediatric depression; yet, irritability in the absence of depressed mood or anhedonia is rare. Longitudinally, chronic irritability has been shown to predict depression rather than bipolar disorder or externalizing disorders. Evidence suggests that the link between irritability and depression is explained mostly by shared genetic risk. Both conditions are also associated with higher rates of family history of depression, childhood temperaments and personality styles, and negative parenting styles. The treatment implications are discussed.

The orbitofrontal cortex (OFC) is implicated in depression. The hypothesis investigated was whether the OFC sensitivity to reward and nonreward is related to the severity of depressive symptoms.

Irritability in pediatric samples is associated with higher rates of subsequent suicide-related outcomes. No study, to date, has evaluated the longitudinal association between irritability and suicidal ideation (SI) in adults with major depressive disorder (MDD). This report evaluated whether irritability is associated with SI at the same visit (i.e., concurrently) and whether early changes in irritability with antidepressant treatment predict subsequent levels of SI. Participants of Combining Medications to Enhance Depression Outcomes (CO-MED, n= 665), Establishing Moderators and Biosignatures of Antidepressant Response in Clinical Care (EMBARC, n= 296), and Suicide Assessment Methodology Study (SAMS, n= 266) were included. Repeated-measures mixed model analyses evaluated concurrent association throughout the trial between irritability (five-item irritability domain of Concise Associated Symptom Tracking scale) and SI (three-item suicidal thoughts factor of Concise Health Risk Tracking scale) after controlling for overall depression (excluding suicidality-related item), and predicted subsequent levels of SI (repeated observations from week-2-to-week-8) based on early (baseline-to-week-2) changes in irritability after controlling for early changes in overall depression. Higher irritability was associated with higher SI concurrently; estimates (standard error) were 0.18 (0.02, p< 0.0001), 0.64 (0.02, p< 0.0001), and 0.26 (0.04, p< 0.0001) in CO-MED, EMBARC, and SAMS respectively. Greater baseline-to-week-2 reductions in irritability predicted lower levels of subsequent SI; estimates (standard errors) were −0.08 (0.03, p= 0.023), −0.50 (0.05, p< 0.0001), and −0.12 (0.05, p= 0.024) in CO-MED, EMBARC, and SAMS, respectively. Controlling for anxiety or insomnia produced similar results. In conclusion, irritability and SI were consistently linked in adults with MDD. These findings support careful assessment of irritability in suicide risk assessment.

Attention-Deficit/Hyperactivity Disorder (ADHD) and conduct disorder (CD) exemplify top-down dysregulation conditions that show a large comorbidity and shared genetics. At the same time, they entail two different types of symptomology involving mainly non-emotional or emotional dysregulation. Few studies have tried to separate the specific biology underlying these two dimensions. It has also been suggested that both types of conditions consist of extreme cases in the general population where the symptoms are widely distributed. Here we test whether brain structure is specifically associated to ADHD or CD symptoms in a general population of adolescents (n?=?1093) being part of the IMAGEN project. Both ADHD symptoms and CD symptoms were related to similar and overlapping MRI findings of a smaller structure in prefrontal and anterior cingulate cortex. However, our regions of interest (ROI) approach indicated that gray matter volume (GMV) and surface area (SA) in dorsolateral/dorsomedial prefrontal cortex and caudal anterior cingulate cortex were negatively associated to ADHD symptoms when controlling for CD symptoms while rostral anterior cingulate cortex GMV was negatively associated to CD symptoms when controlling for ADHD symptoms. The structural findings were mirrored in performance of neuropsychological tests dependent on prefrontal and anterior cingulate regions, showing that while performance on the Stop Signal test was specifically related to the ADHD trait, delayed discounting and working memory were related to both ADHD and CD traits. These results point towards a partially domain specific and dimensional capacity in different top-down regulatory systems associated with ADHD and CD symptoms.

Aberrations in both neural reward processing and stress reactivity are associated with increased risk for mental illness; yet, how these two factors relate to each other remains unclear. Several studies suggest that stress exposure impacts reward function, thus increasing risk for psychopathology. However, the alternative hypothesis, in which reward dysfunction impacts stress reactivity, has been rarely examined. The current study aimed to test both hypotheses using a longitudinal design.

Studying the neural consequences of tobacco smoking during adolescence, including those associated with early light use, may help expose the mechanisms that underlie the transition from initial use to nicotine dependence in adulthood. However, only a few studies in adolescents exist, and they include small samples. In addition, the neural mechanism, if one exists, that links nicotinic receptor genes to smoking behavior in adolescents is still unknown.

The test-retest reliability of functional magnetic resonance imaging functional connectivity is critical to identifying reproducible biomarkers for psychiatric illness. Recent work has shown how reliability limits the observable effect size of brain-behavior associations, hindering detection of these effects. However, while a fast-growing literature has explored both univariate and multivariate reliability in healthy individuals, relatively few studies have explored reliability in populations with psychiatric illnesses or how this interacts with age.

Oppositional defiant disorder (ODD) is a frequent psychiatric disorder seen in children and adolescents with attention‐deficit‐hyperactivity disorder (ADHD). ODD is also a common antecedent to both affective disorders and aggressive behaviors. Although the heritability of ODD has been estimated to be around 0.60, there has been little research into the molecular genetics of ODD. The present study examined the association of irritable and defiant/vindictive dimensions and categorical subtypes of ODD (based on latent class analyses) with previously described specific polymorphisms (DRD4exon3 VNTR, 5‐HTTLPR, and seven OXTRSNPs) as well as with dopamine, serotonin, and oxytocin genes and pathways in a clinical sample of children and adolescents with ADHD. In addition, we performed a multivariate genome‐wide association study (GWAS) of the aforementioned ODD dimensions and subtypes. Apart from adjusting the analyses for age and sex, we controlled for “parental ability to cope with disruptive behavior.” None of the hypothesis‐driven analyses revealed a significant association with ODD dimensions and subtypes. Inadequate parenting behavior was significantly associated with all ODD dimensions and subtypes, most strongly with defiant/vindictive behaviors. In addition, the GWAS did not result in genome‐wide significant findings but bioinformatics and literature analyses revealed that the proteins encoded by 28 of the 53 top‐ranked genes functionally interact in a molecular landscape centered around Beta‐catenin signaling and involved in the regulation of neurite outgrowth. Our findings provide new insights into the molecular basis of ODD and inform future genetic studies of oppositional behavior. © 2015 The Authors. American Journal of Medical Genetics Part B: Neuropsychiatric GeneticsPublished by Wiley Periodicals, Inc.

Mood regulation problems, such as severe chronic irritability or short episodes of mania-like symptoms, are common, impairing and a topic of intense recent interest to clinicians, researchers and the Diagnostic and Statistical Manual (DSM)-5 process. Here, we review the most recent findings about these two presentations and discuss the approaches to their treatment.

Abstract: Glutamine synthetase (GS), glial fibrillary acidic protein (GFAP) immunohistochemistry and neuronal apoptotic cell death were evaluated in a rabbit model of pneumococcal meningitis. Meningitis caused an increase of GS immunoreactivity in the cerebral cortex, but not in the hippocampal formation. GFAP immunoreactivity remained unchanged. This may represent a protective mechanism for cortical neurons. The inability of hippocampal GS to counteract the detrimental effects of glutamate may be the cause of neuronal apoptosis observed in the dentate gyrus during meningitis.

Adolescent onset of depression is associated with long-lasting negative consequences. Identifying adolescents at risk for developing depression would enable the monitoring of risk factors and the development of early intervention strategies. Using machine learning to combine several risk factors from multiple modalities might allow prediction of depression onset at the individual level.

Ketamine as an antidepressant improves anhedonia as early as 2 hours after infusion. These drug effects are thought to be exerted via actions on reward-related brain areas—yet these actions remain largely unknown. Our study investigates ketamine’s effects during the anticipation and receipt of an expected reward, after the psychotomimetic effects of ketamine have passed, when early antidepressant effects are reported.

ABSTRACTBackground: Adolescents are at high risk of sexual assault compared to any other age group. The pattern of post-traumatic stress symptoms plus life-impairing disturbances in self-organization (emotion dysregulation, negative self-concept and interpersonal problems) is termed Complex Post-Traumatic Stress Disorder (CPTSD). Research about CPTSD after sexual assault in adolescents is limited owing to the challenges associated with assessing this group. This study aims to determine the frequency and structure of CPTSD, and the relationship of emotion dysregulation with impairment and additional trauma exposure among adolescents who have been sexually assaulted.Method: Prospective cohort study of adolescents attending the Sexual Assault Referral Centres serving London over a 2-year period. We conducted cross-sectional analyses (n = 99) on data collected 4–5 months after sexual assault, and Confirmatory Factor Analyses (CFA) and Latent Class Analyses (LCA) to determine the CPTSD profile. CTPSD was defined according to the ICD-11, selecting symptom indicators from the following measures: Strengths and Difficulties Questionnaire (SDQ), Children’s Revised Impact of Event Scale (CRIES-13), Short version of the Mood and Feelings Questionnaire (S-MFQ), The Development and Well-Being Assessment (DAWBA). We analysed the association of CPTSD symptom domains with impairment (measured with the SDQ, and the Children’s Global Assessment Scale; C-GAS) and with additional trauma exposure.Results: The frequency of ICD-11 PTSD was 59%, and of ICD-11 CPTSD was 40%. CPTSD symptoms showed a strong fit for a correlated 4-factor model, and LCA distinguished a class of participants with high levels of CPTSD symptoms. Emotion dysregulation was associated with impairment in functioning and exposure to trauma beyond other self-organization disturbances and core PTSD symptoms.Conclusions: Disturbances in self-organization are frequent in sexually assaulted adolescents, and emotion dysregulation is associated with impairment and further exposure to trauma. Emotion dysregulation should be considered in preventive and treatment strategies for these vulnerable youth.