Aetiology: Part 1 Mike Akroyd, 9th May 2014

Aims Illustrate how aetiology fits into MRCPsych: Paper 1 and beyond Explore aetiological factors of general adult psychiatric illness (Old age and child in part 2, in 2 weeks)

Objectives “By the end of this session I will be able to...” Describe basic aetiological concepts Apply aetiological factors to the biopsychosocial model Identify aetiological factors involved in general adult psychiatric disorder Answer some exam questions on the above

Why aetiology? We want to understand causes of mental disorder Identification of at-risk individuals Suggestion of management approaches Possibility of preventive interventions Patients (or parents...) want to know “am I to blame?” ...and it accounts for c.12/200 questions in Paper 1...

Aetiological theory Two broad categories of explanatory model Reductionist Understand causation by tracing back to simpler stages E.g. schizophrenia caused by faulty neurotransmission in specific part of brain (narrow) medical models Non-reductionist Problems relate to wider issues E.g. schizophrenia caused by patient’s family Sociological models

Aetiological factors Genetic Psychological Psychodynamic Social Political Environmental Behavioural Developmental

Biopsychosocial formulation Predisposing Genetics IQ Personality Family Social class Marital status Precipitating Illness Drugs Traumatic event Unemployment Divorce Perpetuating Chronic illness Withdrawal Hopelessness Ongoing unemployment

Basic aetiological terms Heritability “Proportion of liability to a disorder in a population that is accounted for by genetic effects” How much of the aetiology is likely to be accounted for by genetics? (As opposed to environment) Expressed in percentage term Applied to population, not individual Derived from difference in concordance between MZ and DZ twins

Heritability estimate Disorder Heritability estimate Schizophrenia 80% Major Depression 40% Bipolar Affective Disorder Generalised Anxiety Disorder 30% Panic Disorder Phobia 35% Alcohol Problem/Dependence 60%

Basic aetiological terms Not everything that runs in families is genetic... Religion, Football team Equally, not everything passed on shows itself Concept of penetrance Likelihood that having a particular genotype results in manifestation of associated characteristic. Relatively few conditions fully penetrant.

Basic statistical concepts Lifetime prevalence Risk Relative risk

Lifetime prevalence What proportion of people will develop a given illness in their lifetime? Lifetime prevalence of schizophrenia = 1% 1 in 100 will develop schizophrenia in their lifetime

Risk Risk = Chance = Probability Probability that a given event will occur In a given timeframe What is the probability that a person will develop schizophrenia across their lifetime? 1/100 develop schizophrenia Risk = 0.01

Relative risk Ratio of risk in a group exposed to a certain risk, compared to a group not exposed. i.e. Risk in exposed group Risk in unexposed group If relative risk =1, no difference between groups If relative risk >1, exposed group more likely to develop disorder If relative risk <1, exposed group less likely

Relative risk Cannabis use and schizophrenia Lifetime prevalence (risk) of schizophrenia = 1/100 Risk in cannabis users = 5/200 Relative risk of schizophrenia in cannabis users? 5/200 = 5/200 = 5 = 2.5 1/100 2/200 2

General Adult Aetiology Schizophrenia Bipolar affective disorder Depression Anxiety disorders Dependency

Schizophrenia Bio Psycho Social Predisposing 80% HERITABILITY Birth complications Maternal influenza Winter birth Paternal age Failure to negotiate P-S position Family patterns Social class Urbanicity Migration Precipitating Cannabis use Non-specific life events Perpetuating Chronic illness Withdrawal Hopelessness Ongoing unemployment

Schizophrenia – Genetics 80% heritability Complex genetic disorder Or group of disorders

Schizophrenia – Genetics Non-identical twin: 10-15% Child of 2 patients: 40% 4-5.5% 10-15% 42-50% 2% 12-16% 6%

Schizophrenia – Genetics Susceptibility genes Neuregulin (NRG1) – strong evidence Dysbindin (DTNBP) – strong evidence D-Amino acid oxidase activator (G72) Regulator of G-protein signalling-4 (RGS-4) Disrupted in schizophrenia (DISc-1) Metabotropic glutamate receptor 3 (GRM3) Catechol-O-methyl transferase (COMT) (also implicated in velocardiofacial syndrome) D-aminoacid oxidase (DAAO) 5-HT2A receptor (HTR2A) Dopamine D3 receptor (DRD3)

Schizophrenia – Genetics 1st degree relatives of patients with schizophrenia Risk of schizophrenia Risk of schizoaffective disorder Risk of schizotypal personality disorder 1st degree relatives of patients with schizoaffective

Schizophrenia – Social Lower social class Competing hypotheses Low predisposing IQ, hardship? Social drift in prodrome/illness? Urbanicity Migration Higher risk in migrants Particularly 2nd generation UK migrants from Afro-Caribbean higher risk than indigenous UK population or non-migrating Afro-Caribbean

Schizophrenia – Environmental Obstetric complications Reported in retrospective studies Not consistently replicated in prospective studies Maternal influenza 2nd trimester influenza exposure Mixed evidence Winter birth Effect shown in N+S hemispheres Cannabis use Andreasson’s Swedish military conscripts Dose-dependent relationship Paternal age Some evidence

Schizophrenia – Organic Metachromatic leucodystrophy 35% develop schizophrenia Velocardiofacial syndrome (aka Di George) Schizophreniform and affective psychosis in 30% Huntington’s disease Associated with schizophreniform/affective psychosis Increased risk in epilepsy (birth of ECT...)

Schizophrenia – Neurological Developmental Distinguishable from peers at c.11 Hostility toward adults Language delays Poor rapport Isolation from peers Low IQ Prevalence of schizophrenia in LD = 3%

Schizophrenia – Psychological Psychodynamic Freud – Narcissism Klein – Failure to negotiate paranoid-schizoid position

Schizophrenia – Psychological Family Fromm-Reichmann - Deviant role relationships (“schizophrenogenic mother”) Lidz – Abnormal family patterns “Marital skew” – one parent yields to other’s eccentricity “Marital schism” – contrary views, divided loyalties Bateson & Wynee – Disordered communication “Double bind” – instruction contradicted by covert instruction Not routinely used Scarce data, induction of guilt

Schizophrenia – Precipitants Non-specific life events precede first onset & relapses Increased rate in preceding 3 weeks

Schizophrenia – Relative risks Factor Relative risk Cannabis use (heavy) 6 Epilepsy 2.4 (or 9...) Migrants 2.7 In 6 months post ‘Life Event’ 2 Winter birth 1.1 Urban birth 2.4 Cannabis use (overall) 2.5 Maternal influenza (Up to 7...)

Schizophrenia – Aetiological theory Neurodevelopmental Leading hypothesis Structural brain abnormalities precede symptom onset Cognitive/social impairment in childhood “Soft” neurological signs Perinatal risk factors Abberant connectivity Inadequate integration of brain regions Stress-diathesis model Vulnerability from early factors Later stressors trigger onset, determine course

BPAD Lifetime prevalence = c.1% Heritability = 80-85% First degree relatives: Risk of BPAD (7-10% vs 1%) Risk of unipolar depression (20-30% vs 10-20%) Risk of schizoaffective disorder And risk of BPAD if first degree relative has: Unipolar depression (2%) (some dispute) Schizoaffective disorder (4.8%)

BPAD Genetics Social Psychological Precipitating factors Tyrosine hydroxylase; COMT; 5HT transporter; BDNF Social Higher socioeconomic class; divorced/single Psychological Cyclothymic personality predisposes Precipitating factors Life events “Kindling effect”

Depression Lifetime prevalence = c.10-20% Heritability estimates vary (40-75%) Lower MZ concordance First degree relatives: Risk of unipolar depression (20-30%) Risk of BPAD 2%? 1%?

Depression Genetics Social 5HT transporter gene Risk in unemployed, divorced, separated Risk if poor social support, isolation Brown & Harris – 3 factors in women Not working outside the home Lack of confiding relationship 3+ children under 14

Depression Environmental Organic Precipitating factors Loss of parent before 11 Family discord, separation, divorce Childhood sexual abuse Organic Risk in HIV, MS, endocrine disorders Iatrogenic: L-Dopa, methyldopa, ß-blockers, steroids Precipitating factors Kindling

Depression – Psychological Relationship with parents Non-caring/overprotective Attachment problems (e.g. maternal depression) Personality High need for approval Neuroticism (Eysenck) Beck’s cognitive triad 1. Self: negative self-perception 2. World: hostile, demanding 3. Future: expectation of suffering, failure

Depression – Psychological Freud, Abraham Disturbance of oral phase predisposes Real/imagined loss of an object Object introjected (defence) Invokes love and hate Anger toward lost object directed inwards Seligman Learned helplessness

Suicide UK suicide rate c.1/10,000 Genetics Organic Men (17/100,000) > Women (5/100,000) Genetics Positive family history increases risk Organic Associated with: Epilepsy; MS; AIDS; Huntington’s Low 5-HIAA in CSF of completed suicide Presynaptic marker of 5HT function

Suicide – Social Risk in: Durkheim: 4 types of suicide Males, unemployed, Caucasian, migrants Low social class, professionals, fall in status Married, with children Wartime Durkheim: 4 types of suicide Egoistic – Not integrated Altruistic – Excessive integration Anomic – Disrupted integration Fatalistic – Escape from oppression

Suicide

Anxiety disorders OCD PTSD Prevalence = c.2-3%; 35% in 1st degree Risk in single 35% premorbidly anankastic Freud: Regression to anal phase PTSD Women > Men Risk in single/divorced/widowed; withdrawn, low SE Risk in alcohol misuse, previous childhood trauma Precipitated by Interpersonal violence (assault, rape, combat) External locus of control (natural disaster)

Anxiety disorders Phobias Panic disorder 31% of 1st degree relatives will have a phobia ‘Prepared learning’ – some evolutionary benefit E.g. snakes Conditioning Development of phobia following stressor Panic disorder Heritability = c.30-40% 1st degree relatives c.3x more likely

Alcohol Alcohol dependence Heritability = c.60% Social learning theory Biological sons adopted away retain risk Social learning theory Comorbid psychiatric disorder is common Rate of dependence mirrors rate of consumption

Drugs 4 factors contribute to drug use 1. Availability of drugs 2. Vulnerable personality School record, truancy, thrill-seekers, impulsivity 3. Social environment Condoned use, unemployment, homelessness 4. Pharmacological factors Not every user becomes an abuser Risk if create positive feeling or alleviate stress

Which of the following theories suggests that schizophrenia occurs when individuals who are vulnerable to the disease undergo a life stress which precipitates the initial episode ? Kindling effect Abberant connectivity Neurodevelopmental hypothesis Stress-diathesis model Social model

A mother wants to know what is the risk of schizophrenia in her son who smokes cannabis? Four-fold increase in risk Two-fold increase in risk Four-fold decrease in risk Two-fold decrease in risk No association between cannabis and schizophrenia

Which of the following does not increase the risk of developing bipolar disorder? Family history of depression Family history of schizoaffective disorder Family history of schizophrenia Cyclothymic personality Family history of bipolar disorder

Which of the following is not a vulnerability factor for depression as described by Brown and Harris? Lack of confiding relationship Loss of parent before age of 11 Not working outside the home Having 3 or more children under the age of 14 None of the above

A person who feels like he has lost his place is society due to being made redundant goes on to commit suicide. According to Emile Durkheim what type of suicide would that be? Anomic Altruistic Egoistic Fatalistic Holistic

Which of the following risk factor is likely to be causative in a young man diagnosed with schizophrenia? Alcoholism HLADR2 gene Being a migrant Having lost his mother before the age of 14 Living alone