Schizophrenia: Symptoms, Genetics & Diagnosis - PDF

Schizophrenia DR. SYDNEY B. MILLER LA R R Y B A ER ER IN JO H N S R A M I N IJJA R JU LI E M A R TIN G H IS LA IN E B A DA W I P S YC 340 ◼https://www.youtube.com/watch?v=AVAbNL8mrgk&t=12s OUTLINE 1. Overview of Schizophrenia 2. Positive and Negative Symptoms 3. Genetics 4. Neurological Sequalae...

Schizophrenia DR. SYDNEY B. MILLER LA R R Y B A ER ER IN JO H N S R A M I N IJJA R JU LI E M A R TIN G H IS LA IN E B A DA W I P S YC 340 ◼https://www.youtube.com/watch?v=AVAbNL8mrgk&t=12s OUTLINE 1. Overview of Schizophrenia 2. Positive and Negative Symptoms 3. Genetics 4. Neurological Sequalae 5. Dopamine SCHIZOPHRENIA Schizophrenia is characterized by a broad spectrum of disturbances in thinking (delusions), perception (hallucinations), speech, emotions, and behavior Diagnosis of schizophrenia requires that two or more positive, negative and/or disorganized symptoms be present for at least 1 month Complete recovery from schizophrenia is rare PREVALENCE OF SCHIZOPHRENIA 0.2% to 1.5% of population (equivalent for men and women) Onset in early adulthood (16-25) Very genetic disorder Family studies, twin studies, adoption studies, genetic markers SCHIZOPHRENIA Psychotic behavior Unusual behavior characterized by hallucinations, delusions and loss of contact with reality Positive symptoms Visual and auditory hallucinations and delusions Negative symptoms Deficit in normal primarily affective function (avolition, alogia, anhedonia, affective flattening) Disorganized symptoms Rambling speech, erratic behavior, inappropriate affect POSITIVE SYMPTOMS OF SCHIZOPHRENIA The presence of an abnormal response Hallucinations Delusions Hallucinations: sensory experiences not caused by actual external stimuli Delusions: idiosyncratic beliefs rigidly held despite their erroneous nature Less stable over time (Earnst & Kring, 1997) HALLUCINATIONS Most often auditory E.g., voices that comment on behaviour or give instructions E.g., voices that argue with one another Most patients find hallucinations frightening (Delespaul et al., 2002) However, can sometimes be pleasing or comforting Persistent over time DELUSIONS Common delusions: Thoughts being inserted into patient’s head Other people reading patient’s thoughts Being controlled by external forces (Gutierrez-Lobos et al., 2001) Grandiose or paranoid content Often fragmented NEGATIVE SYMPTOMS OF SCHIZOPHRENIA Deficits in behavioural responses or functions Initially more subtle or difficult to identify than positive symptoms More stable over time (Earnst & Kring, 1997) Best thought of as a continuum Major types: affective and emotional disturbances; social withdrawal; avolition; and alogia AFFECTIVE AND EMOTIONAL DISTURBANCES Blunted affect: failure to exhibit signs of emotion or feeling Faces are expressionless Voices lack typical fluctuations in volume and pitch Poor eye contact Reduced body language Lack of concern for events, themselves, or others AFFECTIVE AND EMOTIONAL DISTURBANCES Anhedonia: inability to experience pleasure Loss of interest in activities and relationships Lack of physical pleasure Early warning sign: may signal onset of prodomal phase SOCIAL WITHDRAWAL Malfunction of interpersonal relationships Seriously debilitating feature of schizophrenia Both a symptom and a strategy employed by patients Early warning sign: may develop before onset of other symptoms AVOLITION Ambivalence, loss of willpower, and indecisiveness Lack of goal-directed or independent behaviour May lack personal hygiene habits ALOGIA Impoverished thinking Literally means, “speechlessness” E.g., poverty of speech Marked reduction in amount of speech E.g., thought blocking Train of speech interrupted before an idea has been completed THIRD SYMPTOM DIMENSION: DISORGANIZATION Some schizophrenic symptoms do not neatly fit into positive or negative symptom categories Third category: disorganization (Grube, Bilder, & Goldman, 1998; Peralta & Cuesta, 1999) Two major symptoms: Thinking disturbances Bizarre behaviour THINKING DISTURBANCES Disorganized speech: tendency to say things that don’t make sense Loose associations Tangentiality Perseveration Incoherence or “word salad” BIZARRE BEHAVIOUR Unusual motor behaviour Catatonia: immobility and marked muscular rigidity Stuporous state: generally reduced responsiveness Inappropriate affect: affective responses obviously inconsistent with situation Incongruity Lack of adaptability in emotional expression Schizophrenia Subtypes ◼Paranoid type ◼ Delusions, hallucinations but cognitive skills and affect are relatively intact, better prognosis ◼Disorganized type ◼ Disrupted speech and behavior, delusions, hallucinations, flat or silly affect, self-absorbed ◼Catatonic type ◼ Motor disturbance predominate ◼ Major symptoms of schizophrenia (no particular type) ◼Residual type ◼ People who experienced at least one episode of schizophrenia but no longer manifest major symptoms TRADITIONAL TYPES OF GENETIC RESEARCH Family studies Does SZ ‘run’ in families? Twin studies Comparing identical twins (100% genetics) to fraternal twins (50% genetics) Adoption studies Ruling out environmental factors PREVALENCE IN FAMILIES HEREDITABILITY Gottesman & Shields (1976) 5 twin studies MZ = 35-58% compared to DZ = 9-26% Severe forms - 75-91%, milder - 17-33% Hereditability estimate = approx 85% However, twin studies assume equal environmental effects for both MZ and DZ twins ADOPTION STUDIES Children of schizophrenia parents: same risk of developing the disorder whether raised by those parents or not 13% of the biological relatives of adoptees with schizophrenia have schizophrenia Adopted children with an adoptive parent who has schizophrenia are not at an increased risk for developing schizophrenia  ADOPTION STUDIES Tienari et al (1991) 144 offspring of SZ biological mothers 178 offspring of control biological mothers 15 psychotic offspring 13/144 = 9.1% 2/178 = 1.1% 7 SZ 2 schizophreniform disorder 2 delusional disorder 2 psychotic bipolar illness  SZ AS A SPECTRUM DISORDER Schizophrenia Paranoid / Schizophreniform/ Delusional Avoidant Schizotypal/ disorders/ Personality Schizoid Psychotic bipolar Concordance rate ranges from 48% - 86% when schizophrenia-related disorders are included  SZ AS A COMPLEX INHERITANCE DISORDER Identifying susceptibility genes Multitude of genes involved in combination Genes of small to moderate effects Considerable within-group heterogeneity Different disease course and outcomes GENOME WIDE ASSOCIATION STUDIES (GWAS) GENOME WIDE LINKAGE STUDIES Inconclusive  LETTERS GENOME WIDE ASSOCIATION STUDIES L Genome-wide association study identifies a susceptibility locus for schizophrenia in Han Chinese at 11p11.2 Genome-wide association study identifies five new Wei-Hua Yue1,2,18, Hai-Feng Wang3,4, Liang-Dan Sun5,6,18, Fu-Lei Tang1,2, Zhong-Hua Liu7, Hong-Xing Zhang8,9 Wen-Qiang Li 8,9, Yan-Ling Zhang1,2, Yang Zhang1,2, Cui-Cui Ma10, Bo Du11, Li-Fang Wang1,2, Yun-Qing Ren5,6, schizophrenia loci Yong-Feng Yang8,9, Xiao-Feng Hu1,2, Yi Wang3,4, Wei Deng12, Li-Wen Tan13, Yun-Long Tan14, Qi Chen15, Guang-Ming Xu16, Gui-Gang Yang14, Xian-bo Zuo5,6, Hao Yan1,2, Yan-Yan Ruan1,2, Tian-Lan Lu11,2, Xue Han13, The Schizophrenia Psychiatric Genome-Wide Cai 1,2, Chao JinAssociation Study (GWAS) Consortium 011 Nature America, Inc. All rights reserved. Xiao-Hong Ma12, Yan Wang 1,2, Li-Wei 10, Hong-Yan Zhang1,2, Jun Yan 1,2, Wei-Feng Mi 1,2, Xian-Yong Yin5,6the, Wen-Bin We examined Ma10, Qigenetic role of common Liu1,2variation , Lan Kangin 1,2, Wei Sunshowed 1,2, Cheng-Ying Pan1,2in, Mei greater inflation Shuang the test 1,2,than we sa statistics Fu-De Yang14, Chuan-Yue schizophrenia Wang15association in a genome-wide , Jian-Li Yang 16, of study Ke-Qing Li 11, Xin Ma15, Ling-Jiang ers (AIMs Li13, Xin = 2.26 compared to allYu 1,2, Qi-Zhai markers Li 17A = 1.56). substantial7size: a stage 18,9discovery12sample of 21,856 3 of3,4 principal components, the distributions of the test st Nature America, Inc. All rights reserved. Xun Huang ,ofLu-Xian individuals European Lvancestry , Tao Liand, aGuo-Ping Zhao , Wei Huangdiffer, Xue-Jun stage 2 replication Zhang( 5,6=&1.18) between AIMs Daiand Zhang 1,2 all markers ( = sample of 29,839 independent subjects. The combined stage inconsistent with population stratification explainin 1 and 2 analysis yielded genome-wide significant associations deviation seen in Supplementary Figure 1. Moreover Towith identify susceptibilityforlociseven schizophrenia for schizophrenia, we performed loci, five of which are new in schizophrenia 1, 1q42.1) a meta-analysis andsummary using other genes mightgenerated results confer risk fo using Meta-analysis of GWAS: Combine independent samples to reach a two-stage genome-wide association 3,4 (1p21.3, 2q32.3, 8p23.2, 8q21.3 study (GWAS) of and 10q24.32-q24.33) andschizophrenia (SZGene, principal see URLs) components. In recent years, (Supplementary Note) GWAS were higo schizophrenia two of which in have the Han beenChinese population previously (GWAS:(6p21.32-p22.1 implicated schizophrenia havefrom with those identified several susceptibility the mega-analysis (Pearsonloci,correlation includin statistical power 746andindividuals was 18q21.2).with with Theschizophrenia rs1625579 strongest new within an andfinding 1,599 healthy intron of a putative × 10−11) ZNF804Asimilar (P = 1.6controls; primary (encoding four = 1.20; increased Supplementary zinc-finger and six decreased Fig.2q32.1) protein 804A, in 2). Of the significance, andtengene SN sugg validation: 4,027 individuals with schizophrenia and 5,603 within theextended major histocompatibility complex (MHC) regio transcript for MIR137 (microRNA 137), a known regulator most extreme values did not result from systematic infl healthy controls). We identified two susceptibility loci for (6p21), mainly in populations of European descent5–8. As a resu of neuronal development. Four other schizophrenia loci Therefore, our primary analysis used unadjusted P val schizophrenia at 6p21-p22.1significance achieving genome-wide (rs1233710 incontain an intron of predicted of the genetic targets heterogeneity less, see Table 2 forofstage schizophrenia 1 P valuesamong populations adjusted for (refo ZKSCAN4, Pcombined −11 = 4.76MIR137-mediated × 10 , odds ratio (OR) = 0.79; as adifferent ancestry, of MIR137, suggesting dysregulation In stagethe susceptibility 1 (Table loci for schizophrenia 2, Supplementary Table 4wereand no Su rs1635 in an exon previously of NKAPL, unknown Pcombined etiologic = 6.91 × 10in−12schizophrenia. mechanism , OR = 0.78; consistentlyFigs.replicated 3 and 4), across 136various studies.reached associations The current study aim genome-wid In a jointinanalysis rs2142731 an intronwith a bipolar of PGBD1, disorder Pcombined sample = 5.14 −10, × 10(16,374 (Pthe to identify × 10−8)factors < 5 genetic 7. The majority of these associations (N = underlying schizophrenia in the Ha ORaffected = 0.79) individuals and 11p11.2and 14,044 controls), (rs11038167 near the 5three UTRloci of Chinesetopopulation 5.5 Mb inbythe extended using major histocompatibility a large two-stage GWAS. co reached genome-wide significance: −11 CACNA1C (rs4765905, 6p21.32-p22.1), a region of high linkage disequilibriu TSPAN18, P = 1.09 × 10 , OR = 1.29; rs11038172, In thefirst stageof thestudy, weconducted aGWASof 768 individua CANDIDATE GENES  CANDIDATE GENES Roles in neurotransmitter functions, nervous system development and synaptic plasticity Expressed in prefrontal cortex Believed to be implicated in “endophenotypes” rather than to the full spectrum of the disease phenotype Working memory impairment Sensorimotor integration Eye tracking or event-related potential CANDIDATE GENES Most compelling evidence comes from: Neuregulin-1 : Chromosome 8, CNS development and function PRODH: Chromosome 22, sensorimotor gating (Gogos, 1999), reduce availability of glutamate Dysbindin: Chromosome 6p, function uncertain, perhaps has role in presynaptic glutamate function COMT: Chromosome 22, encodes key dopamine catabolic enzyme Cannabis use (Caspi, 2005) Changes in expression/activity in PFC (Turnbridge, 2007) DISC-1 Identified in large Scottish family: members suffered from schizophrenia, bipolar disorder, major depression Highly expressed during brain development Role in neurogenesis and neuronal migration Regulates function, structure and expression of postsynaptic density of excitatory synapses DYSBINDIN-1 Schizophrenia and bipolar disorder Decreased levels in post-mortem schizophrenia hippocampus and PFC Involved in membrane-protein trafficking Mutations: impaired function of dopamine D2 and NMDA receptors Null mutation in mice: endophenotypes Long-term and working memory Social Interactions impairment NEUREGULIN-1 Role in NMDA, GABA and acetylcholine receptor expression Essential role in the development of nervous system Regulate development of glial cells and myelination CHROMOSOMAL ABNORMALITIES Interstitial deletion of region 22q11, called VCFS In addition to physical defects and heart problems, also associated with psychosis 50 adults with VCFS (Murphy et al.,1999) 30% had a psychotic disorder 25% DSM 1V schizophrenia LINKAGE ANALYSES SUMMARY Most replicated – 8, 13, 22, 2 Support also obtained for 5,3,11,6 & 20 Most often implicated in meta-analysis : 8 & 22 (Badner & Gershon, 2007) SUMMARY OF FINDINGS Inconsistent findings Number of putative schizophrenia susceptibility loci Weak replication evidence across studies Unlikely that all of these findings are true Candidate genes role Neurodevelopment Neurotransmission Synaptic plasticity LIMITATIONS Genes found in other psychiatric disorders Heterogeneous presentation in different patients → diagnostic uncertainty of clinical phenotype Tendency to genotype single genetic marker of the hundreds that might be available in a gene. Complex interaction between genetic and environmental etiological influences. Lack of power For 80% power, need at least 483 families! Poorly matched controls More informative markers CONCLUSIONS Strong and consistent genetic evidence from family, twin and adoption studies Multitude of genes, small effects A few susceptibility genes seem promising (3, 13, 6, 8, 22) Data confusing Most complex of human disorders: Multifactorial or polygenetic inheritance Unclear mode of inheritance Etiological heterogeneity: may need more complicated genetic models than other biomedical disorders Insufficient evidence to declare a clear-cut cause of schizophrenia  NEURAL SEQUELAE OF SCHIZOPHRENIA: IS THE EVIDENCE ANY GOOD? NO. CHANGES IN BRAIN MORPHOLOGY Lateral Ventricular Enlargement Worsens over time Some correlation with clinical outcome and antipsychotic treatment (Barondes, 1993) CHANGES IN BRAIN MORPHOLOGY Frontal lobe Some studies show reduced volume. Eg Premkumar et al (2006), Molina et al (2004): Prefrontal cortical grey matter First-episode (FE) patients vs. controls: No differences FE patients vs. chronic: Shrinkage over time CHANGES IN BRAIN MORPHOLOGY Temporal Lobe Reduced temporal volume in FE’s, but no further reductions in chronic patients. A large scale study looking specifically at the hippocampus (Velakoulis et al, 2006) Reduced left hippocampal (HC) volume in FE patients Reduced bilateral HC volume in chronic patients Normal HC volume in high-risk subjects, including those who went on to develop schizophrenia CHANGES IN BRAIN MORPHOLOGY Frontal and temporal lobe changes follow different timelines. An indication of different processes at work? MRI studies of schizophrenia show sometimes conflicting results. Why? Local vs. global measures of brain change Heterogeneous patient populations Small sample sizes DIFFUSION TENSOR IMAGING Using an MR scanner, measure the diffusion of water in the brain Diffuses perpendicular to white matter tracts (anisotropy), in all directions in CSF (isotropy), and somewhere in between in grey matter. White matter anisotropy depends on myelination, fiber tract density, thickness and other properties. Results indicate degree and quality of connectivity between brain regions. DIFFUSION TENSOR IMAGING Colour coding refers to degree of anisotropy. (Kubicki et al, 2005) DIFFUSION TENSOR IMAGING Some DTI studies show abnormal anisotropy, others do not The most common abnormalities found: Reduced anisotropy in corpus callosum (may be implicated in hallucinations) and anterior cingulate cortex (the “belt” around the CC that may be linked to attentional deficits in SZ) Small sample sizes, heterogeneous SZ groups, differences in imaging protocols may be responsible for conflicting results. DTI is a promising new methodology but so far has not lived up to its potential in SZ. DIFFERENCES IN BRAIN FUNCTION Hypofrontality Reduced activation of prefrontal cortex during cognitive tasks Reproduced fairly consistently in PET and fMRI studies DIFFERENCES IN BRAIN FUNCTION A = control group B = SZ group Red = max during word gen Yellow = max during word rep C = Differences between groups Red = greater response in SZ Yellow = greater response Verbal fluency task (Curtis et al, 1998) in controls THE ANTISACCADE TASK A saccade is an abrupt and rapid movement of the eyes.  In the antisaccade task, Ss are asked to suppress normal saccadic movement towards a target and to move instead in the opposite direction.  Schizophrenics consistently make more errors and the antisaccadic movements they do correctly make are done more slowly compared to healthy controls. DIFFERENCES IN BRAIN PHYSIOLOGY ↓ [certain amino acids] in temporal lobe & prefrontal cortex ➔ neuronal cell loss ➔ ↓ volume in this area However: Lim et al (1998) showed a decoupling of ↓ [amino acid] & ↓ volume in grey and white matter: Grey: No ↓ [amino acid] but ↓ volume White: ↓ [amino acid] but no ↓ volume E PROCESS OR A NEURODEVELOPMENT AL ONE? A neurodevelopmental process: May begin prenatally, altering neurons and circuits, culminating in a first episode of disease, triggered perhaps by some environmental factor. OR A neurodegenerative process: Neuronal structure/function loss or cell death that gets progressively worse over time. E PROCESS OR A NEURODEVELOPMENT AL ONE? Morphological anomalies in SZ patients that are best explained as abnormal development Anterior cingulate gyral folding (Yucel et al, 2002) But on the other hand… MR studies show brain morphology and physiology changes starting with first episode, “consistent with a limited neurodegenerative process” (Lieberman, 1999) E PROCESS OR A NEURODEVELOPMENT AL ONE? Gliosis growth of glial cells in areas of neuron damage. not seen in schizophrenia, a key piece of evidence against the neurodegenerative hypothesis. Perhaps apoptosis, programmed cell death, is responsible for volume loss, indicating a neurodevelopmental disorder. CONCLUSIONS Current techniques for detecting brain changes may not be sophisticated enough Do we even know where to look? Evidence for multiple processes working concurrently in different brain areas DOPAMINE REFRESHER Motor control and emotion (reward) Stored in nerve terminals, released in response to action potential Binds to receptors in the postsynaptic cell Action terminated by metabolism and reuptake into the cell DOPAMINE RECEPTORS D1-Like D1, D5 Increases cAMP, excitatory D2-Like D2, D3, D4 Decreases cAMP, inhibitory D1 and D2 most common Nucleus accumbens, striatum DOPAMINE PATHWAYS Nigrostriatal Subtantia nigra to striatum Tuberoinfundibular Hypothalamus to Mesolimbic pituitary gland Ventral tegmental area to nucleus accumbens, amygdala, hippocampus Mesocortical Ventral tegmental area to prefrontal cortex FORMULATING A DOPAMINE HYPOTHESIS OF SCHIZOPHRENIA 1960s DA hyperactivity → positive symptoms of schizophrenia 1970s Correlation between effects of antipsychotics and their ability to block D2 receptors Stimulants affecting DA system → psychotic effects TOO MUCH DOPAMINE (MESOLIMBIC) DA / VTA Mesolimbic Limbic Positive Symptoms FORMULATING A DOPAMINE HYPOTHESIS OF SCHIZOPHRENIA 1990s Negative symptoms not responsive to classical antipsychotics Brain imaging → Negative symptoms may be related to reduced DA transmission to the prefrontal cortex via D1 receptors DOPAMINE IMBALANCE (MESOLIMBIC, MESOCORTICAL) DA / VTA Mesolimbic Mesocortical Limbic Prefrontal Cortex Positive Symptoms Negative Symptoms CURRENT EVIDENCE POS SYMPTOMS: INCREASE OF DA AT D2 RECEPTOR Higher baseline levels of DA at D2 receptors (Abi-Dargham et al., 2000) Amphetamine-induced increase in DA release (Laruelle et al., 1996) Amphetamine increases psychotic symptoms, but does not create new symptoms CURRENT EVIDENCE NEG SYMPTOMS: DECREASE IN DA IN PREFRONTAL CORTEX Decrease in DA innervation to DLPC Postmortem study (Akil et al., 1999) Deficit in prefrontal DA activity at D1 receptors Evidence mixed Gating theory:DA during relevant info; DA during irrelevant info (Braver et al., 1997) Heterogeneous sample? BEYOND DOPAMINE Patients vary in the extent to which they demonstrate increased DA levels Not all patients with positive symptoms demonstrate high DA levels Positive symptoms must involve both dopaminergic and non-dopaminergic components CONCLUSIONS Dopamine clearly plays a role in schizophrenia It is not simply too much dopamine, but a dysregulation of the dopaminergic system There are complex interactions with other neurotransmitters, such as glutamate CONCLUSIONS The dopamine hypothesis does not explain the cause of schizophrenia Genetic differences may cause disturbances in the dopamine and glutamate systems The dopamine hypothesis does suggest targets for treatment Typical and atypical antipsychotics target DA receptors New treatments can be developed that target NMDA receptors Other Psychotic Disorders Schizophreniform disorder Experience symptoms of schizophrenia for a few months only (up to 6 months) Schizoaffective disorder Symptoms of schizophrenia and also major mood disorder Delusional disorder Persistent belief contrary to reality (delusion) without other symptoms of schizophrenia (onset between 40 and 49) Brief psychotic disorder involves delusions, hallucinations, disorganized speech or behavior that lasts less than 1 month (often reaction to stressor)