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Factors That Interact during the Development and Progression of Disease Childhood Poverty, Cumulative Risk Exposure, and Mental Health in Emerging Adults • Poverty during early development increases the rate of mental health problems for individuals as young adults • Early and sustained poverty has the most impact • Less impact on Internalizing symptoms: Depression, Anxiety • More impact on externalizing symptoms: antisocial behavior such as hyperactivity, aggression, defiance, and destructive behavior • Increased learned helplessness, the belief that one is not an effective agent in acting on one’s surroundings • Because of elevated cumulative risk exposure to • Psychosocial: violence, family turmoil, child separation from family • Physical: noise, crowding, substandard housing Diathesis-Stress Model • Diathesis is vulnerability or susceptibility – Genetic influences shown by • concordance rate in twin studies • family history of mental disorder • hypothalamic-pituitary-adrenal responsivity – Developmental • maternal stressors • childhood stressors • Interaction of Diathesis and Stress – Individuals with more vulnerability are more likely to become ill when challenged by stresssors Prevalence and Incidence Statistics • Epidemiology: is the study of the patterns, causes, and effects of health and disease conditions in defined populations. • The term 'incidence' refers to the rate at which new cases occur in a population during a specified period, usually each year. • The term 'prevalence' refers to proportion “percentage” of a population that are cases. • point prevalence, based on a single examination, at one point in time, tends to underestimate the condition's total frequency. • period prevalence is defined as the proportion of a population that are cases at any time within a stated period: • 6 months, one year or life-time • For example Table 16.1 shows prevalence data at 12 month and life-time periods. Prevalence of Serious Mental Illness among U.S. Adults Not sure what year this represents Gender http://www.nimh.nih.gov/health/statistics/prevalence/serious-mental-illness-smi-among-us-adults.shtml The Global Burden of Mental, Neurological and Substance Use Disorders: An Analysis from the Global Burden of Disease Study 2010. Whiteford 2015 PLOS ONE, DOI:10.1371/journal.pone.0116820 February 6, 2015 “Mental and substance disorders were one of the leading causes of disease burden in 2010. They were responsible for 7.4% of global DALYs and 22.9% of global YLDs, making them the fifth leading cause of DALYs and the leading cause of YLDs.” • Years Lived with Disability (YLDs) • Years lost to premature mortality (YLLs) • Disability Adjusted Life Years (DALYs) the sum of YLDs and YLLs The Global Burden of Mental, Neurological and Substance Use Disorders: An Analysis from the Global Burden of Disease Study 2010. Whiteford 2015 PLOS ONE, DOI:10.1371/journal.pone.0116820 February 6, 2015 Fig 1. Absolute DALYs Attributable to Mental, Neurological, and Substance Use Disorders, by Age, 2010. Schizophrenia Is the Major Neurobiological Challenge in Psychiatry • DSM-5 Diagnosis of Schizophrenia – Characterized by delusions, hallucinations, disorganized speech and behavior, and other symptoms that cause social or occupational dysfunction. – For a diagnosis, symptoms must have been present for six months and include at least one month of active symptoms. – DSM-5 raises the symptom threshold, requiring that an individual exhibit at least two of the specified symptoms. (In the manual’s previous editions, that threshold was one.) – The diagnostic criteria no longer identify subtypes. Prevalence of Schizophrenia •Schizophrenia affects approximately 1% of the population.(p492) • Table 16.1 has 0.70% for lifetime •Worldwide prevalence of schizophrenia. • Bhugra D (2005) The Global Prevalence of Schizophrenia. PLoS Med 2(5): e151. doi:10.1371/journal.pmed.0020151 • Lifetime prevalence is 4.00 % • Point prevalence is 0.46 % • “A total of 1,721 prevalence estimates from 188 studies were identified. These estimates were drawn from 46 countries,” • “When sites were grouped by economic status, prevalence estimates from ‘‘least developed’’ countries were significantly lower than those from both ‘‘emerging’’ and ‘‘developed’’ sites” A Model of the Interaction between Stress and Genetic Influences in Schizophrenia Living in a City Increases the Risk for Schizophrenia Heritability of Schizophrenia • The heritability of schizophrenia is a strong indicator of a biological basis for schizophrenia – Adoption studies • Adult schizophrenics that were adopted as children are likely to have schizophrenic biological relatives. – Twin studies • Concordance rates for schizophrenia are higher for identical than for fraternal twins: – No single gene has been identified for schizophrenia • Genes may pass on a susceptibility to develop schizophrenia The Heritability of Schizophrenia The Heritability of Schizophrenia • Genetic influences on Schizophrenia • Many different genes could be responsible • A few critical genes have been identified • • • • Neuregulin1 for regulation of receptors for NMDA, ACh, GABA Dysbindin involved in synaptic plasticity COMT for the metabolism of dopamine G72 involved in glutamate activity • One gene appearing abnormal in one schizophrenic family is DISC1. • Transgenic mice with a mutated version of this gene developed enlarged lateral ventricles. Brain Damage and Schizophrenia • The negative symptoms of schizophrenia are related to brain damage – The neurological signs evident in schizophrenia include • • • Eye tracking problems Catatonia Problems with blinking, eye focusing, and visual pursuit – Schizophrenics exhibit enlarged brain ventricles, which suggests loss of brain cells – Regions of schizophrenic brain that are abnormal include • • • Prefrontal cortex Medial temporal lobes Medial diencephalon Eye Tracking in Patients with Schizophrenia versus Control A Simple Scan for Schizophrenia? Brain Damage and Schizophrenia The entorhinal cortex, cingulate cortex, parahippocampus, hippocampus and amygdala are smaller in schizophrenics than in most people. In schizophrenics, pyramidal cells of the hippocampus have a disorganized arrangement. Abnormal cellular arrangement also found in the entorhinal cortex, cingulate cortex and parahippocampus. This probably occurs during early cell development. Ventricular Enlargement in Schizophrenia Identical Genes, Different Fates Cellular Disarray of the Hippocampus in Chronic Schizophrenia Accelerated Loss of Gray Matter in Adolescents with Schizophrenia Adolescents with schizophrenia Hypofrontality in Schizophrenia Cortical abnormalities include a thicker corpus callosum and altered function in this structure. Some studies show a loss of gray matter in the frontal lobes, and PET shows less metabolic activity. The hypofrontality hypothesis suggests that schizophrenia may be caused by underactivation of the frontal lobes. Potential Causes of Brain Damage in Schizophrenia • The neurological symptoms of schizophrenia may be caused by – Genetic mutations – Birth trauma (obstetrical issues) – Viral infections that impair neural development during the second trimester • Seasonality effects (schizophrenia is more likely for winter births) – Nutritional issues (Hunger Winter: female offspring were more likely to exhibit schizophrenia than male offspring) – Maternal stress may compromise the immune system of the mother and lead to a greater chance of contracting a viral infection Positive Schizophrenia Symptoms: Dopamine • The “dopamine hypothesis” is that the positive symptoms of schizophrenia involve over-activity of brain dopaminergic synapses • Dopamine hypothesis is based on – antipsychotic drugs such as chlorpromazine (CPZ) block DA receptors – amphetamine release DA can reproduce the positive symptoms of schizophrenia – PET studies indicate greater release of dopamine in the striatum of schizophrenics to a test dose of amphetamine • Amount of dopamine released was related to the increase in positive schizophrenia symptoms Typical Antipsychotic Drugs Affect Dopamine Receptors Antipsychotic Drugs That Affect Dopamine Receptors Typical neuroleptic drugs are all antagonists at dopamine D2 receptors Cognitive Symptoms • 15 IQ points below the population mean • Cognitive decline several years before the onset of other schizophrenia symptoms • Lower cognitive functions is stable through out the course of the illness • Cognitive decline should be considered an important part of the etiological hypotheses. Glutamate Hypothesis • PCP and ketamine induce positive, negative and cognitive elements of schizophrenia in humans – PCP and ketamine are antagonists at the NMDA glutamergic receptor – Glutamate functions as an excitatory amino acid • NMDA receptor (ionotropic): activation allows Na+ and Ca++ ions to enter membrane (EPSP) • PCP binding site: PCP binding blocks Ca++ ion entry (antagonist) The Effects of PCP on the NMDA Receptor Glutamate and Dopamine • Schizophrenia may reflect a deficit in glutamate transmission (DA effects are secondary to NMDA) • Ketamine-induced symptoms are not reversed by DA receptor blockade (e.g. haloperidol) • Ketamine infusion increases the DA-releasing activity of amphetamine in humans