Abstract
Adolescence is characterized by significant changes in several domains, including
brain structure and function, puberty, and social and environmental factors. Some
of these changes serve to increase the likelihood of psychosis onset during this period,
while others may buffer this risk. This review characterizes our current knowledge
regarding the unique aspects of adolescence that may serve as risk factors for schizophrenia
spectrum disorders. In addition, we provide potential future directions for research
into adolescent-specific developmental mechanisms that impart vulnerability to psychosis
and the possibility of interventions that capitalize on adolescents’ unique characteristics.
Specifically, we explore the ways in which gray and white matter develop throughout
adolescence in typically developing youth as well as in those with psychosis spectrum
disorders. We also discuss current views on the function that social support and demands,
as well as role expectations, play in risk for psychosis. We further highlight the
importance of considering biological factors such as puberty and hormonal changes
as areas of unique vulnerability for adolescents. Finally, we discuss cannabis use
as a factor that may have a unique impact during adolescent neurodevelopment, and
subsequently potentially impact psychosis onset. Throughout, we include discussion
of resilience factors that may provide unique opportunities for intervention during
this dynamic life stage.
Keywords
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References
- Imaging structural and functional brain development in early childhood.Nat Rev Neurosci. 2018; 19: 123-137
- Neurodevelopmental trajectories of the human cerebral cortex.J Neurosci. 2008; 28: 3586-3594
- Microstructural maturation of the human brain from childhood to adulthood.Neuroimage. 2008; 40: 1044-1055
- Peers increase adolescent risk taking by enhancing activity in the brain’s reward circuitry.Dev Sci. 2011; 14: F1-10
- Is adolescence a sensitive period for sociocultural processing?.Annu Rev Psychol. 2014; 65: 187-207
- Incidence rates and cumulative incidences of the full spectrum of diagnosed mental disorders in childhood and adolescence.JAMA Psychiatry. 2019;
- Lifetime prevalence and age-of-onset distributions of DSM-IV disorders in the National Comorbidity Survey Replication.Arch Gen Psychiatry. 2005; 62: 593-602
- Schizophrenia: Etiology and course.Annu Rev Psychol. 2004; 55: 401-430
- Early and late neurodevelopmental influences in the prodrome to schizophrenia: Contributions of genes, environment, and their interactions.Schizophr Bull. 2003; 29: 653-669
- A typological model of schizophrenia based on age at onset, sex and familial morbidity.Acta Psychiatr Scand. 1994; 89: 135-141
- Sex difference in age at onset of schizophrenia.Arch Gen Psychiatry. 1984; 41: 157-161
- An updated and conservative systematic review and meta-analysis of epidemiological evidence on psychotic experiences in children and adults: On the pathway from proneness to persistence to dimensional expression across mental disorders.Psychol Med. 2013; 43: 1133-1149
- Psychosis risk and development: What do we know from population-based studies?.Biol Psychiatry. 2019;
- Adult outcomes of child-and adolescent-onset schizophrenia: Diagnostic stability and predictive validity.Am J Psychiatry. 2000; 157: 1652-1659
- Is adolescent-onset first-episode psychosis different from adult onset?.J Am Acad Child Adolesc Psychiatry. 2005; 44: 782-789
- Comprehensive versus usual community care for first-episode psychosis: 2-year outcomes from the NIMH RAISE Early Treatment Program.Am J Psychiatry. 2016; 173: 362-372
- Developmental disruptions in neural connectivity in the pathophysiology of schizophrenia.Dev Psychopathol. 2008; 20: 1297-1327
- Clinical characteristics and predictors of outcome of schizophrenia-spectrum psychosis in children and adolescents: A systematic review.J Child Adolesc Psychopharmacol. 2016; 26: 410-427
- Age at onset and the outcomes of schizophrenia: A systematic review and meta-analysis.Early Interv Psychiatry. 2017; 11: 453-460
- Age at onset and cognition in schizophrenia: Meta-analysis.Br J Psychiatry. 2009; 195: 286-293
- The psychosocial outcome of adolescent-onset schizophrenia: A 12-year followup.Schizophr Bull. 2000; 26: 801-816
- Changes in brain weights during the span of human life: Relation of brain weights to body heights and body weights.Ann Neurol. 1978; 4: 345-356
- Microglia sculpt postnatal neural circuits in an activity and complement-dependent manner.Neuron. 2012; 74: 691-705
- Synaptic density in human frontal cortex-developmental changes and effects of aging.Brain Res. 1979; 163: 195-205
- Extraordinary neoteny of synaptic spines in the human prefrontal cortex.Proc Natl Acad Sci U S A. 2011; 108: 13281-13286
- Cortical gray-matter thinning is associated with age-related improvements on executive function tasks.Dev Cogn Neurosci. 2013; 6: 61-71
- Synaptic number changes in the medial prefrontal cortex across adolescence in male and female rats: A role for pubertal onset.Synapse. 2016; 70: 361-368
- Mechanisms contributing to prefrontal cortex maturation during adolescence.Neurosci Biobehav Rev. 2016; 70: 4-12
- Schizophrenia: Caused by a fault in programmed synaptic elimination during adolescence?.J Psychiatr Res. 1982; 17: 319-334
- Implications of normal brain development for the pathogenesis of schizophrenia.Arch Gen Psychiatry. 1987; 44: 660-669
- Progressive reduction in cortical thickness as psychosis develops: A multisite longitudinal neuroimaging study of youth at elevated clinical risk.Biol Psychiatry. 2015; 77: 147-157
- Reduced gray matter volume in schizophrenia.Arch Gen Psychiatry. 1999; 56: 905-911
- Decreased dendritic spine density on prefrontal cortical pyramidal neurons in schizophrenia.Arch Gen Psychiatry. 2000; 57: 65-73
- Synaptic density marker SV2A is reduced in schizophrenia patients and unaffected by antipsychotics in rats.Nat Commun. 2020; 11: 246
- Meta-analysis of gray matter anomalies in schizophrenia: Application of anatomic likelihood estimation and network analysis.Biol Psychiatry. 2008; 64: 774-781
- Two distinct neuroanatomical subtypes of schizophrenia revealed using machine learning.Brain. 2020; 143: 1027-1038
- Long-term antipsychotic treatment and brain volumes: A longitudinal study of first-episode schizophrenia.Arch Gen Psychiatry. 2011; 68: 128-137
- Common pattern of gray-matter abnormalities in drug-naive and medicated first-episode schizophrenia: A multimodal meta-analysis.Psychol Med. 2017; 47: 401-413
- Increased synapse elimination by microglia in schizophrenia patient-derived models of synaptic pruning.Nat Neurosci. 2019; 22: 374-385
- Gyrification abnormalities in childhood- and adolescent-onset schizophrenia.Biol Psychiatry. 2003; 54: 418-426
- A tension-based theory of morphogenesis and compact wiring in the central nervous system.Nature. 1997; 385: 313-318
- The myelogenetic cycles of regional maturation of the brain.in: Minkowski A. Regional Development of the Brain in Early Life. Blackwell, Oxford, UK1967: 3-70
- Age-related differences in white matter tract microstructure are associated with cognitive performance from childhood to adulthood.Biol Psychiatry. 2014; 75: 248-256
- The accumbofrontal tract: Diffusion tensor imaging characterization and developmental change from childhood to adulthood.Hum Brain Mapp. 2015; 36: 4954-4963
- Sex steroids and brain structure in pubertal boys and girls: A mini-review of neuroimaging studies.Neuroscience. 2011; 191: 28-37
- Longitudinal changes in grey and white matter during adolescence.Neuroimage. 2010; 49: 94-103
- The role of myelination in measures of white matter integrity: Combination of diffusion tensor imaging and two-photon microscopy of CLARITY intact brains.Neuroimage. 2017; 147: 253-261
- Growth of white matter in the adolescent brain: Myelin or axon?.Brain Cogn. 2010; 72: 26-35
- White matter changes of neurite density and fiber orientation dispersion during human brain maturation.PLoS One. 2015; 10e0123656
- A critical period for social experience-dependent oligodendrocyte maturation and myelination.Science. 2012; 337: 1357-1360
- Myelin remodeling through experience-dependent oligodendrogenesis in the adult somatosensory cortex.Nat Neurosci. 2018; 21: 696-706
- Training induces changes in white-matter architecture.Nat Neurosci. 2009; 12: 1370-1371
- Biology of oligodendrocyte and myelin in the mammalian central nervous system.Physiol Rev. 2001; 81: 871-927
- Diffusion imaging of white matter in schizophrenia: Progress and future directions.Biol Psychiatry Cogn Neurosci Neuroimaging. 2016; 1: 209-217
- Widespread white matter microstructural differences in schizophrenia across 4322 individuals: Results from the ENIGMA Schizophrenia DTI Working Group.Mol Psychiatry. 2018; 23: 1261-1269
- Diffusion tensor imaging in the early phase of schizophrenia: What have we learned?.J Psychiatr Res. 2010; 44: 993-1004
- Disruption of white matter integrity in the inferior longitudinal fasciculus in adolescents with schizophrenia as revealed by fiber tractography.Arch Gen Psychiatry. 2007; 64: 1270-1280
- White matter abnormalities and cognitive impairment in early-onset schizophrenia-spectrum disorders.J Am Acad Child Adolesc Psychiatry. 2014; 53 (e361–362): 362-372
- White matter fractional anisotropy over two time points in early onset schizophrenia and adolescent cannabis use disorder: A naturalistic diffusion tensor imaging study.Psychiatry Res. 2015; 232: 34-41
- White matter maturation during 12 months in individuals at ultra-high-risk for psychosis.Acta Psychiatr Scand. 2018; 137: 65-78
- White matter integrity in individuals at ultra-high risk for psychosis: A systematic review and discussion of the role of polyunsaturated fatty acids.BMC Psychiatry. 2016; 16: 287
- Structural and functional brain correlates of subclinical psychotic symptoms in 11–13 year old schoolchildren.Neuroimage. 2010; 49: 1875-1885
- White matter differences among adolescents reporting psychotic experiences: A population-based diffusion magnetic resonance imaging study.JAMA Psychiatry. 2015; 72: 668-677
- Disruptions in white matter maturation and mediation of cognitive development in youths on the psychosis spectrum.Biol Psychiatry Cogn Neurosci Neuroimaging. 2019; 4: 423-433
- White matter development in the early stages of psychosis.Schizophr Res. 2015; 161: 61-69
- White matter integrity and prediction of social and role functioning in subjects at ultra-high risk for psychosis.Biol Psychiatry. 2009; 66: 562-569
- Brain white matter development is associated with a human-specific haplotype increasing the synthesis of long chain fatty acids.J Neurosci. 2014; 34: 6367-6376
- Eicosapentaenoic acid interventions in schizophrenia: Meta-analysis of randomized, placebo-controlled studies.J Clin Psychopharmacol. 2012; 32: 179-185
- Dynamic reconfiguration of structural and functional connectivity across core neurocognitive brain networks with development.J Neurosci. 2011; 31: 18578-18589
- FMRI functional connectivity applied to adolescent neurodevelopment.Annu Rev Clin Psychol. 2015; 11: 361-377
- How can studies of resting-state functional connectivity help us understand psychosis as a disorder of brain development?.Curr Opin Neurobiol. 2015; 30: 85-91
- Functional connectivity anomalies in adolescents with psychotic symptoms.PLoS One. 2017; 12e0169364
- Age-associated deviations of amygdala functional connectivity in youths with psychosis spectrum disorders: Relevance to psychotic symptoms.Am J Psychiatry. 2019; 176: 196-207
- Altered age-related trajectories of amygdala-prefrontal circuitry in adolescents at clinical high risk for psychosis: A preliminary study.Schizophr Res. 2012; 134: 1-9
- Altered relationships between age and functional brain activation in adolescents at clinical high risk for psychosis.Psychiatry Res. 2014; 221: 21-29
- Relationship between duration of untreated psychosis and outcome in first-episode schizophrenia: A critical review and meta-analysis.Am J Psychiatry. 2005; 162: 1785-1804
- The role of untreated psychosis in neurodegeneration: A review of hypothesized mechanisms of neurotoxicity in first-episode psychosis.Can J Psychiatry. 2014; 59: 513-517
- Developmental timing and critical windows for the treatment of psychiatric disorders.Nat Med. 2016; 22: 1229-1238
- Peripubertal diazepam administration prevents the emergence of dopamine system hyperresponsivity in the MAM developmental disruption model of schizophrenia.Neuropsychopharmacology. 2013; 38: 1881-1888
- Juvenile antioxidant treatment prevents adult deficits in a developmental model of schizophrenia.Neuron. 2014; 83: 1073-1084
- Perceptions of interdependence and closeness in family and peer relationships among adolescents with and without romantic partners.New Dir Child Adolesc Dev. 1997; 1997: 3-20
- Adolescent development.Annu Rev Psychol. 2001; 52: 83-110
- The emerging field of adolescent romantic relationships.Curr Dir Psychol Sci. 2002; 11: 177-180
- Social brain development and the affective consequences of ostracism in adolescence.Brain Cogn. 2010; 72: 134-145
- Changes in adolescents’ daily interactions with their families from ages 10 to 18: Disengagement and transformation.Dev Psychol. 1996; 32: 744-754
- Four mechanistic models of peer influence on adolescent cannabis use.Curr Addict Rep. 2017; 4: 90-99
- Stress response and the adolescent transition: Performance versus peer rejection stressors.Dev Psychopathol. 2009; 21: 47-68
- Neural correlates of social exclusion across ages: A coordinate-based meta-analysis of functional MRI studies.Neuroimage. 2017; 153: 359-368
- Risk factors for loneliness: The high relative importance of age versus other factors.PLoS One. 2019; 15e0229087
- Premorbid social functioning in schizophrenia and bipolar disorder: Similarities and differences.Am J Psychiatry. 1997; 154: 1544-1550
- Risk factors for psychosis: Impaired social and role functioning.Schizophr Bull. 2012; 38: 1247-1257
- Social relationships in young adults at ultra high risk for psychosis.Psychiatry Res. 2017; 247: 345-351
- White matter abnormalities associated with subsyndromal psychotic-like symptoms predict later social competence in children and adolescents.Schizophr Bull. 2017; 43: 152-159
- Testing the neurodevelopmental, trauma and developmental risk factor models of psychosis using a naturalistic experiment.Psychol Med. 2019; : 1-10
- Early traumatic experiences in those at clinical high risk for psychosis.Early Interv Psychiatry. 2013; 7: 300-305
- The social defeat hypothesis of schizophrenia: An update.Schizophr Bull. 2013; 39: 1180-1186
- Do family interventions improve outcomes in early psychosis? A systematic review and meta-analysis.Front Psychol. 2017; 8: 371
- Interpersonal and social rhythm therapy: Managing the chaos of bipolar disorder.Biol Psychiatry. 2000; 48: 593-604
- Interpersonal and social rhythm therapy for adolescents with bipolar disorder: Treatment development and results from an open trial.Depress Anxiety. 2010; 27: 457-464
- Adolescence: An Anthropological Inquiry.Free Press, New York1991
- Variations in patterns of developmental transitions in the emerging adulthood period.Dev Psychol. 2003; 39: 657-669
- Stress in America: 2013.American Psychological Association, Washington, DC2013
- Educational attainment, positive psychological mediators, and resources for health and vitality in older adults.J Aging Health. 2003; 15: 591-615
- Psychological, social and role functioning as predictors of psychosis in an adolescent psychiatric sample.Early Interv Psychiatry. 2018; 12: 1064-1071
- School performance in Finnish children and later development of schizophrenia: A population-based longitudinal study.Arch Gen Psychiatry. 1999; 56: 457-463
- Premorbid academic and social functioning in patients with schizophrenia and its associations with negative symptoms and cognition.Acta Psychiatr Scand. 2018; 138: 253-266
- Social functioning in individuals at clinical high risk for psychosis.Schizophr Res. 2008; 99: 119-124
- The stress cascade and schizophrenia: Etiology and onset.Schizophr Bull. 2003; 29: 671-692
- Dopamine release in response to a psychological stress in humans and its relationship to early life maternal care: A positron emission tomography study using [11C]raclopride.J Neurosci. 2004; 24: 2825-2831
- Stress and the hypothalamic pituitary adrenal axis in the developmental course of schizophrenia.Annu Rev Clin Psychol. 2008; 4: 189-216
- Pubertal development: Correspondence between hormonal and physical development.Child Dev. 2009; 80: 327-337
- Variation in the timing of puberty: Clinical spectrum and genetic investigation.J Clin Endocrinol Metab. 2001; 86: 2364-2368
- Puberty and the human brain: Insights into adolescent development.Neurosci Biobehav Rev. 2018; 92: 417-436
- The rise in adrenal androgen biosynthesis: Adrenarche.Semin Reprod Med. 2004; 22: 337-347
- Measuring puberty.J Adolesc Health. 2006; 39: 625-626
- The organizational-activational hypothesis as the foundation for a unified theory of sexual differentiation of all mammalian tissues.Horm Behav. 2009; 55: 570-578
- Surging hormones: Brain-behavior interactions during puberty.Curr Dir Psychol Sci. 2013; 22: 134-139
- Affective reactivity during adolescence: Associations with age, puberty, and testosterone.Cortex. 2019; 117: 336-350
- Reference ranges for serum concentrations of lutropin (LH), follitropin (FSH), estradiol (E2), prolactin, progesterone, sex hormone-binding globulin (SHBG), dehydroepiandrosterone sulfate (DHEAS), cortisol and ferritin in neonates, children and young adults.Clin Chem Lab Med. 2002; 40: 1151-1160
- Developmental changes in hypothalamus-pituitary-adrenal activity over the transition to adolescence: Normative changes and associations with puberty.Dev Psychopathol. 2009; 21: 69-85
- Adolescence: A central event in shaping stress reactivity.Dev Psychobiol. 2010; 52: 244-253
- Considering the role of adolescent sex steroids in schizophrenia.J Neuroendocrinol. 2018; 30: 453-460
- Testosterone, DHEA and DHEA-S in patients with schizophrenia: A systematic review and meta-analysis.Psychoneuroendocrinology. 2018; 89: 92-102
- The development of psychotic disorders in adolescence: A potential role for hormones.Horm Behav. 2013; 64: 411-419
- Ovarian hormones, genes, and the brain: The case of estradiol and the brain-derived neurotrophic factor (BDNF) gene.Neuropsychopharmacology. 2019; 44: 223-224
- A role for estrogen in schizophrenia: Clinical and preclinical findings.Int J Endocrinol. 2015; 2015: 615356
- Estradiol reverses excitatory synapse loss in a cellular model of neuropsychiatric disorders.Transl Psychiatry. 2020; 10: 16
- Gonadal steroids regulate dendritic spine density in hippocampal pyramidal cells in adulthood.J Neurosci. 1990; 10: 1286-1291
- Adolescents and androgens, receptors and rewards.Horm Behav. 2008; 53: 647-658
- White matter development in adolescence: A DTI study.Cereb Cortex. 2010; 20: 2122-2131
- Stress and neurodevelopmental processes in the emergence of psychosis.Neuroscience. 2013; 249: 172-191
- Much ado about much: Stress, dynamic biomarkers and HPA axis dysregulation along the trajectory to psychosis.Schizophr Res. 2015; 162: 253-260
- A dual-axis approach to understanding neuroendocrine development.Dev Psychobiol. 2015; 57: 643-653
- Puberty and the onset of psychosis.Schizophr Res. 1993; 10: 7-14
- Age at puberty and mental illness. Towards a neurodevelopmental aetiology of Kraepelin’s endogenous psychoses.Br J Psychiatry. 1989; 155: 536-544
- Pre-treatment, baseline, and outcome differences between early-onset and adult-onset psychosis in an epidemiological cohort of 636 first-episode patients.Schizophr Res. 2007; 95: 1-8
- Outcome in early-onset schizophrenia revisited: Findings from the Early Psychosis Prevention and Intervention Centre long-term follow-up study.Schizophr Res. 2011; 131: 112-119
- Adolescents’ reported reasons for alcohol and marijuana use as predictors of substance use and problems in adulthood.J Stud Alcohol Drugs. 2011; 72: 106-116
- Substance use in adolescence and psychosis: Clarifying the relationship.Annu Rev Clin Psychol. 2010; 6: 365-389
- Cortical neuroinflammation contributes to long-term cognitive dysfunctions following adolescent delta-9-tetrahydrocannabinol treatment in female rats.Eur Neuropsychopharmacol. 2015; 25: 2404-2415
- Adolescent exposure to THC in female rats disrupts developmental changes in the prefrontal cortex.Neurobiol Dis. 2015; 73: 60-69
- Effects of adolescent THC exposure on the prefrontal GABAergic system: Implications for schizophrenia-related psychopathology.Front Psychiatry. 2018; 9: 281
- Association of cannabis with cognitive functioning in adolescents and young adults: A systematic review and meta-analysis.JAMA Psychiatry. 2018; 75: 585-595
- Opposite effects of Δ-9-tetrahydrocannabinol and cannabidiol on human brain function and psychopathology.Neuropsychopharmacology. 2010; 35: 764-774
- Cannabidiol enhances anandamide signaling and alleviates psychotic symptoms of schizophrenia.Transl Psychiatry. 2012; 2: e94
- Cannabidiol is a partial agonist at dopamine D2High receptors, predicting its antipsychotic clinical dose.Transl Psychiatry. 2016; 6: e920
- Peripubertal cannabidiol treatment rescues behavioral and neurochemical abnormalities in the MAM model of schizophrenia.Neuropharmacology. 2019; 146: 212-221
- Cannabis use and age at onset of psychosis: Further evidence of interaction with COMT Val158Met polymorphism.Acta Psychiatr Scand. 2011; 123: 485-492
- The status of adolescent medicine: Building a global adolescent workforce.Int J Adolesc Med Health. 2016; 28: 233-243
Article info
Publication history
Published online: July 10, 2020
Accepted:
June 25,
2020
Received in revised form:
June 23,
2020
Received:
March 4,
2020
Identification
Copyright
© 2020 Society of Biological Psychiatry.
