Table 1.

Biological and Psychosocial Factors That May Contribute to Psychosis Risk in Adolescence

Example Risk/Resilience Factors	Potential Mechanism(s) in Adolescence	Impact on Psychosis Risk	Areas for Future Study
Biological Factors
Accelerated Pruning	Alters cortical thickness, particularly in prefrontal regions believed to support development of higher order cognitive function, which in turn may contribute to cognitive deficits Disrupts excitatory–inhibitory balance in brain via impact on glutamatergic neuron functioning	↑	Validation of presynaptic protein marker findings in adolescent psychosis samples Identification of moderators of GM decreases Evaluation of interaction of antipsychotic medication use and GM developmental processes
Blunted Myelination	Alters maturation of long-range tracts associated with higher order cognitive function	↑	Evaluation of efficacy of WM treatments such as fatty acid administration during the adolescent developmental period Characterization of relationship between structural and functional connectivity specifically in adolescent psychosis samples
Pubertal Sex Hormones	Testosteronea Affects organizational and activational processes in the brain, which may make the brain more sensitive to environmental input Moderates dopaminergic signaling, associated with changes in thalamo-cortico-striatal networks	–	Validation of accurate puberty measures and evaluation of hormone effects using multimodal measures Investigation of hormonal correlates in adolescent psychosis samples Evaluation of interaction of HPG and HPA axes
	Estrogena Buffers loss of excitatory synapses and changes in dendritic spine density	↓
Cannabis Use: THC	Promotes downregulation of CB1 receptors on neurons, which alters maturation of PFC GABAergic neurons Promotes upregulation of CB2 receptors on microglia, which alters synaptic pruning	↑	Continued investigation of the longevity and intensity of THC-induced brain alteration Evaluation of moderators of THC-related brain change, including age at first use and frequency of use
Cannabis Use: CBD	Acts as antagonist for CB1 and CB2 receptorsa Acts as a D2 antagonist, similar to atypical antipsychotic medicationsa	–	Evaluation of mixed THC/CBD use Investigation of longevity and intensity of CBD-related symptom relief and brain change
Psychosocial Factors
Prophylactic Intervention in At-Risk Individuals	Reduces potential neurotoxicity due to dopaminergic hypersensitivitya Decreases oxidative stress, which in turn may limit reductions in PFC interneuron activitya Decreases stress responsivity/anxiety response, which in turn may reduce hippocampal damage believed to partially drive dopamine dysfunctiona	↓	Validation of animal models of psychosis risk states Continued research on biological changes associated with early intervention in humans Mapping of interventions onto biological mechanisms in human studies
Social Stressors (e.g., Defeat, Isolation)	Alters dopamine signaling following defeat Alters oligodendrocyte maturation, subsequently alters myelination in prefrontal regions following isolation	↑	Evaluation of interaction of diathesis and adolescent stressors on psychosis emergence Exploration of mechanisms linking social functioning and neural change (e.g., myelination) in humans
Role Stressors (e.g., Increased Academic Demands)	Alters cortisol release, which in turn modulates dopamine response Changes hippocampal morphology due to cortisol response	↑	Identification of developmental effects of stress in adolescent psychosis samples

CBD, cannabidiol; GABA, gamma-aminobutyric acid; GM, gray matter; HPA, hypothalamic-pituitary-adrenal; HPG, hypothalamic-pituitary-gonadal; PFC, prefrontal cortex; THC, tetrahydrocannabinol; WM, white matter.

^aAreas of limited research support.