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Critical Issues 19Prodromebreakout Joint Commission National Quality Approval An Ounce of Prevention Is Worth a Pound of Cure: Identifying prodromal symptoms in mental illness to intervene early Raymond J. Kotwicki, MD, MPH, DFAPA Charles B. West Chief Medical Officer Skyland Trail Critical Issues Facing Children & Adolescents October, 2019 Learning Objectives ► Trace the mechanism of development of mental illnesses, using the stress-diathesis model ► Appreciate the complicated static/ dynamic states of genetics, including the roles of genes, epigenes, RNA, and proteins ► Define the term prodrome and understand how it relates to mental illnesses, particularly schizophrenia and bipolar illness ► Distinguish between developmental milestones, misbehavior, and prodromal illness ► Outline potential interventions that may prevent prodrome evolution to full-blown mental illness Stress / Diathesis Model • Diathesis = genetic predisposition – Suicide completions, alcoholism, MDD, BPAD, OCD, Schizophrenia – Not 100% heritable – Environmental impacts • Stressors – Major losses, life transitions – Abuse, neglect – Early substance misuse – Bullying The Stress-Diathesis Model Mental Illness known to have genetic predispositions ► Bipolar illness (heritability of 0.8) ► Schizophrenia ► Major depression ► Alcohol dependence ► OCD ► Completed suicides Genetics are not autosomal, dominant ► Approximately 99 loci for schizophrenia ► Presence of genes does not guarantee development of symptoms, illness The Dynamics of Genetics ► Time lag in “activation” of DNA and resultant human behavior ► Several points of intervention ► Resultant disabilities may exacerbate genetic instability (i.e., psychosis itself may lead to victimization which may further psychosis) Prodrome ► Prodrome synonymous with Psychosis-Risk Syndrome or Attenuated Psychosis ► Early “soft signs” harbingers for full-blown illness ► Lag between prodrome, full illness may be years ► Potential opportunities for prevention, early intervention Prodrome ► Prodrome synonymous with Psychosis-Risk Syndrome or Attenuated Psychosis ► Early “soft sign” harbingers for full-blown illness ► Lag between prodrome, full illness may be years ► Potential opportunities for prevention, early intervention Schizophrenia I. Positive Symptoms Responsive to A. Delusions pharmacology; B. Hallucinations } not predictive of recovery II. Negative Symptoms A. Amotivation B. Anhedonia Relatively unresponsive to pharmacology; C. Affective flattening better predictors of recovery D. Alogia } E. Avolition Risk Factors for Schizophrenia STATISTICALLY SIGNIFICANT RISK FACTORS Migration Winter Birth Prodrome Urbanicity First-degree Relative Advanced Paternal Age Maternal Infections Childhood Trauma Malnutrition Cannabis Abuse Obstetric Complications Schizophrenia Prodrome ► Develops weeks to years before frank psychosis ► Includes mood changes, perceptual changes, cognitive and social decline ► Depressive symptoms, “negative” symptoms emerge on average 2 – 5 years before psychosis ► “Sub threshold” positive symptoms develop on average 1 year before psychosis (Tandon et. al. Neuropsychiatry, 2012) Schizophrenia Prodrome 3 clusters of symptoms (Brietzke, 2012) 1. Attenuated Psychotic Sympotoms (APS) 2. Brief Intermittent and Limited Psychotic Symptoms (BLIPS) 3. Psychosis Around 54% conversion rate to schizophrenia Description of Prodrome Affective Cognitive Social* Perceptual • Anhedonia; • Verbal memory • Poor social cue • Childhood onset especially social impairment processing of unusual or delusional ideas • Depressed mood • Cognitive speed • Stressful events (not SIGECAPS deficits perceived more • Suspicious intensely criteria) • Increased rate of • Illusions gray matter loss in • Disorganized right superior communication frontal, middle frontal, medial orbitofrontal cortices * Early adolescence social dysfunction strongest predictor (predictive power 59%; 92% specificity) Tarbox et. al. Dev Psychopathology 2013 The Exception – 22q Syndrome ► 22q11 microdeletion autosomal dominant ► Early development of prodrome ► Accounts for 1 – 2% of all cases of schizophrenia Prodromes in Mood Disorders ► BPAD natural history fits similar model ► Anxiety disorders related more to modeling ► Social dysfunction differentiates prodrome from “normal” developmental milestones Bipolar Illness PREVALENCE Distractibility ► 5% annual American prevalence (for all types) Irritability / Insomnia Grandiosity IMPACT Flight of Ideas th ► 6 leading cause of disability worldwide Activity increase ► $38 billion in indirect costs annually Sleeplessness / Pressured Speech ► Link with heart disease Thoughtlessness / SYMPTOMS Impulsivity ► DIGFAST ► Major risk for substance abuse/ dependence Bipolar Disorder Diagnostic Complexity ► 50% patients with BPAD misdiagnosed before concluding bipolar disorder (Martin, Smith, 2014) ► 90% initial presentations of patients with BPAD were depressive episodes ► 1 in 10 people with BPAD make suicide attempt within 1 year before affective episode Bipolar Prodrome Non-specific signs ► Irritability / aggression ► Anxiety ► Mood swings not meeting diagnostic criteria More-specific “red flags” ► Sleep disturbance (differentiate from ADHD) ► Social disconnection ► Cognitive inefficiency / decline Prodromal signs / symptoms emerge 1.8−7.3 years before overt BPAD Surprising Themes 1. Early onset of depression predicts BPAD diagnosis (sensitivity 71%; specificity 68%; ppv 0.69) 2. 100% people with schizophrenia report prodromal symptoms, often called something else 3. “Magical thinking” and perceptual abnormalities more common in BPAD prodrome than schizophrenia Early Intervention is Key! Patients identified before development of overt psychosis had milder deficits, better functionality compared to control groups in 10-year follow-up studies (Hegelstad et.al. Am Jrnl Psychiatry, 2012) Identification of Prodromal Symptoms in Young Adults Syndrome 1. *Social disability best predictor; not academic performance 2. *Sleep disturbances without tiredness 3. Disparities in cognitive processing speeds 4. Structured Interview for Prodromal Syndromes (SIPS) – High rates of false positives – Use in family members with genetic diathesis 5. Smelling tests, eye movements, blinking rate, startle responses under rigorous investigation Interventions ► Antipsychotic initiation before symptoms develop is controversial ► Treat underlying anxiety / mood / substance misuse problems to mitigate disabilities ► Omega-3 fatty acids ► Glycine ► Cognitive Behavioral Therapy ► Family therapy ► Close monitoring ► Social skills / monitoring training Summary ► Mental illnesses develop from a multifactorial model, including genetic, social, environmental, secular variables. ► Cognitive and social disabilities precede overt symptoms and are extremely disabling. ► Genetics are hard! ► Prodromal signs / symptoms emerge quite early in life and confer an opportunity to prevent frank illness. ► Teachers, counselors, coaches, parents, caregivers, have unique opportunities to initiate early interventions. References ► Corigliano V, De Carolis A, Trovini G, Dehning j, Di Pietro S, Curto M, Donato N, De Pisa E, Girardi P, Comparelli A. Neurocognition in schizophrenia: from prodrome to multi-episode illness. Psychiatry Research 2014; (14)00646- 5. ► Faedda G, Marangoni C, Serra G, Salvatore P, Sani G, Vazquez G, Tondo L, Girardi P, Baldessarini R, Koukopoulos A. Precursors of Bipolar Disorders: A Systematic Literature Review of Prospective Studies. Journal of Clinical Psychiatry 2015; 76(5);614-624 ► Olvet D, Stearns W, McLaughlin D, Auther A, Correll C, Cornblatt B. Comparing clinical and neurocognitive features of the schizophrenia prodrome to the bipolar prodrome. Schizophrenia Research 2010; 59-63. ► Dawson M, Schell A, Rissling A, Venturea j, Subotnik K, Nuechterlein K. Psychophysiological prodromal signs of schizophrenic relapse. A pilot study. Schizophrenia Research 2010; 64-67. ► Maziade M. At Risk for Serious Mental Illness – Screening Children of Patients with Mood Disorders or Schizophrenia. The New England Journal of Medicine 2017. 376;10. ► Brietzke E, Mansur R, Soczynska j, Kapczinski F, Bressan R, McIntyre R. Towards a multifactorial approach for prediction of bipolar disorder in at risk populations. Journal of Affective Disorders 2012. 140; 82-91. ► Correll C, Olvet D, Auther A, Hauser M, Kishimoto, T, Carrion R, Snyder S, Cornblatt B. the Bipolar Prodrome Symptom Interview and Scale-Prospective (BPSS-P): description and validation in a psychiatric sample and healthy controls. Bipolar Disorders 2014. 16(5); 505-522. References ► Corigliano V, De Carolis A, Trovini G, Dehning J, Di Pietro S, Curto M, Donato N, De Pisa E, Girardi P, Comparelli A. Neurocognition in schizophrenia: from prodrome to multi-episode illness. Psychiatry Research 2014; (14)00646-5. ► Cannon TD, Chung Y, He G, Sun D, Jacobson A, van Erp TG, McEwen S, Addington J, Bearden CE, Cadenhead K, Cornblatt B, Mathalon DH, McGlashan T, Perkins D, Jeffries C, Seidman LJ, Tsuang M, Walker E, Woods SW, Heinssen R, North American Prodrome Longitudinal Study Consortium. Progressive reduction in cortical thickness as psycosis develops: a multisite longitudinal neuroimaging study of youth at elevated clinical risk. Biologic Psychiatry 2014; (14)00414-4. ► Woodberry KA, Serur RA, Hallinan SB, Mesholam-Gately RI, Giuliano AJ, Wojcik JD, Keshavan MS, Frazier JA, Goldstein JM, Shenton ME, McCarley RW, Seidman LJ. Frequency and pattern of childhood symptom onset reported by first episode schizophrenia and clinical high risk youth.
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