Neurodevelopmental and genetic determinants of exposure to adversity among youth at risk for mental illness.

BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) and lower cognitive ability have been linked with increased likelihood of exposure to adversity. We hypothesized that these associations may be partly due to genetic factors. METHODS: We calculated polygenic scores for ADHD and intelligence and assessed psychopathology and general cognitive ability in a sample of 297 youth aged 5-27 years enriched for offspring of parents with mood and psychotic disorders. We calculated an adversity score as a mean of 10 indicators, including socio-economic disadvantage, childhood maltreatment and bullying. We tested the effects of polygenic scores, externalizing symptoms and IQ on adversity scores using mixed-effects linear regression. RESULTS: Externalizing symptoms and general cognitive ability showed expected positive and negative relationships with adversity, respectively. Polygenic scores for intelligence were unrelated to adversity, but polygenic scores for ADHD were associated with adversity (ß = 0.23, 95% CI 0.13 to 0.34, p < .0001). ADHD polygenic scores uniquely explained 4.0% of variance in adversity score. The relationship between polygenic scores for ADHD and adversity was independently significant among individuals with (ß = 0.49, 95% CI 0.25 to 0.75, p < .0001) and without (ß = 0.14, 95% CI 0.02 to 0.26, p = .022) ADHD. CONCLUSIONS: A genetic score indexing liability to ADHD was associated with exposure to adversity in early life. Previously observed associations between externalizing symptoms, lower cognitive ability and adversity may be partially attributed to genetic liability to ADHD.

Visual memory and psychotic symptoms in youth.

BACKGROUND: Psychotic symptoms are common during childhood and adolescence and may indicate transdiagnostic risk of future psychiatric disorders. Lower visual memory ability has been suggested as a potential indicator of future risk of mental illness. The relationship between visual memory and clinician-confirmed definite psychotic symptoms in youth has not yet been explored. METHODS: We examined visual memory and psychotic symptoms among 205 participants aged 7-27 years in a cohort enriched for parental mood and psychotic disorders. We assessed visual memory using the Rey Complex Figure Test (RCFT) and psychotic symptoms using validated semi-structured interview measures. We tested the relationship between visual memory and psychotic symptoms using mixed-effects logistic regression. RESULTS: After accounting for age, sex, and family clustering, we found that psychotic symptoms were significantly associated with lower visual memory (OR = 1.80, 95% CI 1.06-3.06, p = 0.030). This result was unchanged after accounting for general cognitive ability. CONCLUSION: Lower visual memory performance is associated with psychotic symptoms among youth, regardless of general cognitive ability. This finding may inform future targeted early interventions.

Affective lability in offspring of parents with major depressive disorder, bipolar disorder and schizophrenia.

Affective lability, defined as the propensity to experience excessive and unpredictable changes in mood, has been proposed as a potential transdiagnostic predictor of major mood and psychotic disorders. A parental diagnosis of bipolar disorder has been associated with increased affective lability in offspring. However, the association between affective lability and family history of other mood and psychotic disorders has not been examined. We measured affective lability using the self- and parent-reported Children's Affective Lability Scale in a cohort of 320 youth aged 6-17 years, including 137 offspring of a parent with major depressive disorder, 68 offspring of a parent with bipolar disorder, 24 offspring of a parent with schizophrenia, and 91 offspring of control parents. We tested differences in affective lability between groups using mixed-effects linear regression. Offspring of a parent with major depressive disorder (ß = 0.46, 95% CI 0.17-0.76, p = 0.002) or bipolar disorder (ß = 0.47, 95% CI 0.12-0.81, p = 0.008) had significantly higher affective lability scores than control offspring. Affective lability did not differ significantly between offspring of a parent with schizophrenia and offspring of control parents. Our results suggest that elevated affective lability during childhood is a marker of familial risk for mood disorders.

Disruptive mood dysregulation disorder in offspring of parents with depression and bipolar disorder.

BackgroundIt has been suggested that offspring of parents with bipolar disorder are at increased risk for disruptive mood dysregulation disorder (DMDD), but the specificity of this association has not been established.AimsWe examined the specificity of DMDD to family history by comparing offspring of parents with (a) bipolar disorder, (b) major depressive disorder and (c) a control group with no mood disorders.MethodWe established lifetime diagnosis of DMDD using the Schedule for Affective Disorders and Schizophrenia for School Aged Children for DSM-5 in 180 youth aged 6-18 years, including 58 offspring of parents with bipolar disorder, 82 offspring of parents with major depressive disorder and 40 control offspring.ResultsDiagnostic criteria for DMDD were met in none of the offspring of parents with bipolar disorder, 6 of the offspring of parents with major depressive disorder and none of the control offspring. DMDD diagnosis was significantly associated with family history of major depressive disorder.ConclusionsOur results suggest that DMDD is not specifically associated with a family history of bipolar disorder and may be associated with parental depression.

A familial risk enriched cohort as a platform for testing early interventions to prevent severe mental illness.

BACKGROUND: Severe mental illness (SMI), including schizophrenia, bipolar disorder and severe depression, is responsible for a substantial proportion of disability in the population. This article describes the aims and design of a research study that takes a novel approach to targeted prevention of SMI. It is based on the rationale that early developmental antecedents to SMI are likely to be more malleable than fully developed mood or psychotic disorders and that low-risk interventions targeting antecedents may reduce the risk of SMI. METHODS/DESIGN: Families Overcoming Risks and Building Opportunities for Well-being (FORBOW) is an accelerated cohort study that includes a large proportion of offspring of parents with SMI and embeds intervention trials in a cohort multiple randomized controlled trial (cmRCT) design. Antecedents are conditions of the individual that are distressing but not severely impairing, predict SMI with moderate-to-large effect sizes and precede the onset of SMI by at least several years. FORBOW focuses on the following antecedents: affective lability, anxiety, psychotic-like experiences, basic symptoms, sleep problems, somatic symptoms, cannabis use and cognitive delay. Enrolment of offspring over a broad age range (0 to 21 years) will allow researchers to draw conclusions on a longer developmental period from a study of shorter duration. Annual assessments cover a full range of psychopathology, cognitive abilities, eligibility criteria for interventions and outcomes. Pre-emptive early interventions (PEI) will include skill training for parents of younger children and courses in emotional well-being skills based on cognitive behavioural therapy for older children and youth. A sample enriched for familial risk of SMI will enhance statistical power for testing the efficacy of PEI. DISCUSSION: FORBOW offers a platform for efficient and unbiased testing of interventions selected according to best available evidence. Since few differences exist between familial and 'sporadic' SMI, the same interventions are likely to be effective in the general population. Comparison of short-term efficacy of PEI on antecedents and the long term efficacy for preventing the onset of SMI will provide an experimental test of the etiological role of antecedents in the development of SMI.

An integrated substance use treatment model for young adults with first-episode psychosis: A naturalistic pilot evaluation.

AIM: Approximately 50% of individuals with first-episode psychosis meet criteria for a substance use disorder and these concurrent disorders are associated with worse long-term outcomes. Psychosocial interventions, including motivational interviewing as well as cognitive and behavioural therapies, have shown some evidence for effective treatment in substance use disorders; however, there is a paucity of existing studies that have successfully examined these interventions in first-episode psychosis. METHODS: Participants (n = 64) received the concurrent disorders intervention, which included individual support alongside participation in at least one of two groups: a 4-week Motivational Engagement group utilizing motivational interviewing (n = 59) and an 8-week Relapse Prevention Training group emphasizing skill acquisition, which some participants entered directly (n = 5) and some participants entered following completion of the Motivational Engagement group (n = 16). RESULTS: Participants who completed the Motivational Engagement group (n = 59) demonstrated significantly increased motivation to change substance use (d = -.0.58; t = -3.02, p < .01) and significantly decreased substance use frequency (d = 0.65; t = 3.26, p < .01). For participants who completed the Relapse Prevention Training group (n = 21), substance use frequency significantly decreased (d = 0.92; t = 3.46, p < .01) and self-efficacy in one's ability to maintain substance use changes significantly increased (d = -0.85; t = -3.59, p < .01). CONCLUSIONS: This pilot evaluation suggests that motivational interviewing and relapse prevention skills training are acceptable and feasible interventions in the treatment of substance use disorders in young adults with first-episode psychosis.

Youth Experience Tracker Instrument: A self-report measure of developmental antecedents to severe mental illness.

AIM: We sought to examine the structure, internal consistency, convergent and criterion validity of the Youth Experience Tracker Instrument (YETI), a new brief self-report measure designed to facilitate early identification of risk for severe forms of mental illness, including major depressive disorder, bipolar disorder, and schizophrenia. METHODS: We collected 716 YETIs from 315 individuals aged 8 to 27 with and without familial risk of severe mental illness. The YETI measures six developmental antecedents that precede and predict serious forms of mental illness: affective lability, anxiety, basic symptoms, depressive symptoms, psychotic-like experiences, and sleep. A battery of concurrent questionnaires and interviews measured the same constructs. RESULTS: The best-fitting bifactor model supported the validity of both total score and antecedent-specific subscales. Internal consistency was high for the total score (ω = 0.94) and subscales (ω = 0.80-0.92; ρ = 0.72). The total score captured the majority of information from the 26 YETI items (hierarchical omega ωh = 0.74). Correlations of YETI subscales with established measures of the same constructs (r = 0.45-0.80) suggested adequate convergent validity. We propose cut-offs with high negative predictive values to facilitate efficient risk screening. CONCLUSION: The YETI, a brief self-report measure of antecedents, provides an alternative to using multiple longer instruments. Future research may examine the predictive validity of the YETI for the onset of major mood and psychotic disorders.

Cognition in offspring of parents with psychotic and non-psychotic severe mental illness.

BACKGROUND: Cognitive impairment is a feature of severe mental illness (SMI; schizophrenia, bipolar disorder, major depressive disorder). Psychotic forms of SMI may be associated with greater cognitive impairment, but it is unclear if this differential impairment pre-dates illness onset or whether it reflects a consequence of the disorder. To establish if there is a developmental impairment related to familial risk of psychotic SMI, we investigated cognition in offspring of parents with psychotic and non-psychotic SMI. METHOD: Participants included 360 children and youth (mean age 11.10, SD 4.03, range 6-24), including 68 offspring of parents with psychotic SMI, 193 offspring of parents with non-psychotic SMI, and 99 offspring of control parents. The cognitive battery assessed a range of functions using standardized tests and executive function tasks from the Cambridge Automated Neuropsychological Test Battery. RESULTS: Compared to controls, offspring of parents with psychotic SMI performed worse on overall cognition (ß = -0.32; p < 0.001) and 6 of 15 cognitive domains, including verbal intelligence, verbal working memory, processing speed, verbal learning and memory, verbal fluency, and sustained attention. Offspring of parents with non-psychotic SMI performed worse than controls on 3 of the 15 domain specific cognitive tests, including verbal intelligence, visual memory and decision-making. CONCLUSIONS: Widespread mild-to-moderate cognitive impairments are present in young offspring at familial risk for transdiagnostic psychotic SMI. Offspring at familial risk for non-psychotic SMI showed fewer and more specific impairments in the domains of verbal intelligence, visual memory and decision-making.

Visual memory in offspring of parents with mental illness.

Severe mental illness (SMI) refers to impairing and frequently chronic disorders that are difficult to treat. Lower cognitive performance early in life may be a manifestation of risk for SMI. Visual memory has been highlighted as a potential cognitive predictor of future risk of developing bipolar disorder and schizophrenia. We examined visual memory in 214 participants (mean age = 12.62, SD = 4.49) using the Rey Complex Figure Test (RCFT). Our sample included 37 offspring with no parental history of mental illness, 103 offspring with parental history of non-severe mental illness (NSMI), and 74 offspring with parental history of SMI. We tested the effects of family history of mental illness on visual memory using mixed-effects linear regression. After accounting for age, sex, and family clustering, we found that as severity of parental mental illness increases, offspring visual memory performance decreases significantly (b = -3.58, 95% CI -6.79 to -0.37, p = 0.029). We found that severity of parental mental illness predicts visual memory ability. This finding may help identify youth most at risk of developing mental illness and thus inform future interventions.

Active behaviors and screen time in offspring of parents with major depressive disorder, bipolar disorder and schizophrenia.

Activities may be modifiable factors that moderate the risk and resilience in the development of mental health and illness. Youth who spend more time using screens are more likely to have poor mental health. Conversely, time spent engaged in active behaviors (i.e., physical activity, socializing and reading) is associated with better mental health. The choice of activities may be important in offspring of parents with mental illness, who are at increased risk for developing mental disorders. Among 357 youth of the FORBOW (Families Overcoming Risks and Building Opportunities for Well-being) cohort aged 6-21, we examined whether parental diagnosis of mental illness (i.e., major depressive disorder, schizophrenia and bipolar disorder) and current levels of depression influenced the amount of time their offspring spent using screens and engaging in active behaviors. Parental history of mental illness and higher levels of current depression in mothers were associated with less time spent engaged in active behaviors and more time spent using screens. Creating opportunities and incentives for active behaviors may redress the balance between youth with and without a familial history of mental illness.

Cognitive Performance in First-Degree Relatives of Individuals With vs Without Major Depressive Disorder: A Meta-analysis.

Importance: Findings of cognitive impairment in major depressive disorder (MDD), including remitted MDD, raise the question whether impaired cognition is part of preexisting vulnerability rather than a consequence of MDD or its treatment. To our knowledge, no meta-analyses have been published on cognitive impairment in first-degree relatives of individuals with MDD. Objective: To compare cognitive performance between individuals with and without family history of MDD. Data Sources: Medline/PubMed, PsycINFO, and Embase using combinations of search terms for depression, first-degree relatives, and cognition from January 1, 1980, to July 15, 2018. Study Selection: Original articles that reported data on cognition in first-degree relatives of individuals with MDD compared with controls with no family history of major mental illness. Data Extraction and Synthesis: Means and SDs were extracted, and standardized mean differences (SMD) between relatives and controls were calculated for each measure of cognitive performance. The relative-control differences in overall cognition and in specific cognitive domains were synthesized in random-effects meta-analyses with robust variance estimation that allows including multiple correlated measures of cognition within each study. Heterogeneity was quantified with τ2. Publication bias was assessed with funnel plots and Egger intercept. Main Outcomes and Measures: Performance on cognitive tests. Results: Across 284 measures of cognition in 54 nonoverlapping samples including 3246 relatives of people with MDD (mean age 15.38 years, 57.68% females) and 5222 controls (mean age 14.70 years, 55.93% females), relatives of people with MDD performed worse than controls across all measures of cognition (SMD = -0.19; 95% CI, -0.27 to -0.11; P < .001). Domain-specific meta-analyses showed similar size of relative-control difference in most domains of cognition, including Full-Scale IQ (SMD = -0.19), verbal intelligence (SMD = -0.29), perceptual intelligence (SMD = -0.23), memory (SMD = -0.20), academic performance (SMD = -0.40), and language (SMD = -0.29). Study characteristics were not significantly associated with observed between-group differences. There was no evidence of publication bias. Conclusions and Relevance: A general impairment in cognition is a feature of familial disposition for MDD. Cognition may contribute to early identification of risk for depression and may be examined as potential target for early intervention.

Basic symptoms in offspring of parents with mood and psychotic disorders.

BACKGROUND: Basic symptoms, defined as subjectively perceived disturbances in thought, perception and other essential mental processes, have been established as a predictor of psychotic disorders. However, the relationship between basic symptoms and family history of a transdiagnostic range of severe mental illness, including major depressive disorder, bipolar disorder and schizophrenia, has not been examined. AIMS: We sought to test whether non-severe mood disorders and severe mood and psychotic disorders in parents is associated with increased basic symptoms in their biological offspring. METHOD: We measured basic symptoms using the Schizophrenia Proneness Instrument - Child and Youth Version in 332 youth aged 8-26 years, including 93 offspring of control parents, 92 offspring of a parent with non-severe mood disorders, and 147 offspring of a parent with severe mood and psychotic disorders. We tested the relationships between parent mental illness and offspring basic symptoms in mixed-effects linear regression models. RESULTS: Offspring of a parent with severe mood and psychotic disorders (B = 0.69, 95% CI 0.22-1.16, P = 0.004) or illness with psychotic features (B = 0.68, 95% CI 0.09-1.27, P = 0.023) had significantly higher basic symptom scores than control offspring. Offspring of a parent with non-severe mood disorders reported intermediate levels of basic symptoms, that did not significantly differ from control offspring. CONCLUSIONS: Basic symptoms during childhood are a marker of familial risk of psychopathology that is related to severity and is not specific to psychotic illness. DECLARATION OF INTEREST: None.

Stimulant Medication and Psychotic Symptoms in Offspring of Parents With Mental Illness.

BACKGROUND: Stimulants, such as methylphenidate, are among the most commonly used medications in children and adolescents. Psychotic symptoms have been reported as rare adverse reactions to stimulants but have not been systematically inquired about in most previous studies. Family history of mental illness may increase the vulnerability to drug-induced psychotic symptoms. We examined the association between stimulant use and psychotic symptoms in sons and daughters of parents with major mood and psychotic disorders. METHODS: We assessed psychotic symptoms, psychotic-like experiences, and basic symptoms in 141 children and youth (mean ± SD age: 11.8 ± 4.0 years; range: 6-21 years), who had 1 or both parents with major depressive disorder, bipolar disorder, or schizophrenia, and of whom 24 (17.0%) had taken stimulant medication. RESULTS: Psychotic symptoms were present in 62.5% of youth who had taken stimulants compared with 27.4% of participants who had never taken stimulants. The association between stimulant use and psychotic experiences remained significant after adjustment for potential confounders (odds ratio: 4.41; 95% confidence interval: 1.82-10.69; P = .001) and was driven by hallucinations occurring during the use of stimulant medication. A temporal relationship between use of stimulants and psychotic symptoms was supported by an association between current stimulant use and current psychotic symptoms and co-occurrence in cases that were assessed on and off stimulants. CONCLUSIONS: Psychotic symptoms should be monitored during the use of stimulants in children and adolescents. Family history of mood and psychotic disorders may need to be taken into account when considering the prescription of stimulants.