Lecture 12 Schizophrenia PS403 PDF

PS403 Biological Psychology Schizophrenia Lecture 12 Anne Marie Keane BA MLitt Module Coordinator (ALL QUERIES HERE): Dr Tom Burke, Senior Clinical Psychologist, School of Psychology School of Psychology (tom.bu...

PS403 Biological Psychology Schizophrenia Lecture 12 Anne Marie Keane BA MLitt Module Coordinator (ALL QUERIES HERE): Dr Tom Burke, Senior Clinical Psychologist, School of Psychology School of Psychology ([email protected]) Lecturing: Mia Casburn University of Galway [email protected] Evie Doherty  Core Textbook Current Key Chapter Reading Basic Reading: Ø Kalat, J.W. (2019). Biological Psychology, 13th edition. Boston, Massachusetts: Cengage Learning. ! Chapter 14: Module 14.3 Schizophrenia Cannabis Use  Cannabis Use Gene-Environment Interaction ! Two studies for example have reported a moderating effect of COMT valine allele on adolescent cannabis use in development of adult psychosis (Caspi et al., 2005; Henquet et al., 2006)  Caspi et al. (2005) ! COMT gene comes in two forms – ‘Met’ and ‘Val’ ! Individuals with one or two copies of the Val variant have higher risk of developing schizophrenic-type disorders if they used cannabis during adolescence (green bars) ! Those with only Met variant were unaffected by cannabis use  Caspi et al. (2005) N = 151 48 311 91 148 54  Cannabis Use Gene-Environment Interaction ! Estrada et al. (2011) replicated Caspi et al.’s (2005) finding ! Age at which cannabis was first used positively correlated with age at onset of schizophrenia-spectrum disorder (i.e., earlier use of cannabis, earlier age at onset of disorder)  Estrada et al. (2011) ! The COMT Val158Met genotype seems to modulate association between cannabis use & age at onset of schizophrenia spectrum disorders (N=77) ! Val/Val genotype carriers showed an earlier age at onset of disorder than Met carriers Estrada et al. (2011)  Estrada et al. (2011) ! According to Estrada – results suggest effects of cannabis may depend on the state of brain development and maturity at moment of first exposure ! Perhaps these young patients are more sensitive to effect of cannabis on regulation of dopaminergic systems due to their genetic background  Cannabis Use Gene-Environment Interaction ! NB Cannabis use has been shown to act together with other environmental factors e.g., childhood trauma, urbanicity – producing synergistic dopamine sensitisation effects See review on blackboard by Pelayo- Terán (2012)  Cannabis Use ! Di Forti et al. (2015) examined how frequent use of high-potency (e.g., skunk) cannabis in south London affects association between cannabis & psychotic disorders ! Calculated proportion of new cases of psychosis attributable to different types of cannabis use in south London  Di Forti et al. (2015) ! Daily use of ‘skunk-like’ cannabis conferred highest risk of psychotic disorders compared with no use of cannabis (adjusted OR 5·4, 95% CI 2·81–11·31, p=0·002) ! High prevalence of use of high-potency cannabis (218 [53%] of 410 patients) in the study Comparison of Risk Factors  Comparison of Risk Factors ! Torrey et al. (2012) conducted a comparison between risk factor Toxoplasma gondii and other identified risk factors for schizophrenia ! Risk factors were divided into those associated with ! Conception and perinatal period ! Childhood or early adulthood  Highest Risk Factors Highest Risk Factors ! Having a first-degree relative with schizophrenia i.e., mother, father, sibling (RR 6.99–9.31) ! Being the offspring of an immigrant from selected countries (RR 4.5)  Intermediate Risk Factors Intermediate Risk Factors ! Having antibodies to Toxoplasma gondii (OR 2.73) ! Being an immigrant from selected countries (RR 2.7) ! Being raised in an urban area (RR 2.75) ! Being a cannabis user (OR 2.10 – 2.93) ! Having minor physical anomalies (OR 2.23) ! A father over 55 years old (OR 2.21)  Low Risk Factors Low Risk Factors ! Head injuries in early childhood (OR 1.65) ! Obstetrical complications (OR 1.29–1.38) ! Having a father 45 or older (OR 1.38–1.66) ! Specific common genetic polymorphisms (OR 1.09–1.24) ! Birth seasonality (OR 1.07–1.95) ! Maternal exposure to influenza (RR 1.05) ! Extreme prenatal stress (RR 1.00)  Comparison of Risk Factors Torrey et al. (2012) noted that: ! Risk factors associated with childhood & early adulthood (e.g., cannabis use, infection with Toxoplasma gondii) seem more important than risk factors associated with conception & perinatal period (e.g., prenatal stress, OCs)  Comparison of Risk Factors Torrey et al. (2012) ! Torrey suggests that carefully following children prospectively in long-term longitudinal studies may be useful to better understand aetiology of schizophrenia Dopamine Hypothesis of Schizophrenia  Dopamine Hypothesis ! The dopamine hypothesis has received attention over last 50 years – as possible explanation for positive symptoms of schizophrenia ! Dopamine theory posits that positive symptoms of schizophrenia are caused by an excess of dopamine in mesolimbic pathway  Dopamine Hypothesis ! However – the precise reasons for this excess activity at dopamine synapses is still not known ! Dopamine hypothesis emerged from accidental discovery of anti-psychotic drugs  Discovery of First Anti-Schizophrenic Agents ! Henri Laborit (1950) discovered drug promethazine – used to prevent surgical shock – seemed also to reduce anxiety ! Rhone Poulenc Drug Company developed related compound chlorpromazine – was even more effective (Snyder, 1974)  Discovery of First Anti-Schizophrenic Agents ! Delay & Deniker (1952) tried out chlorpromazine on patients with variety of mental illness ! Found that chlorpromazine had dramatic effect on reducing positive symptoms (e.g. hallucinations, delusions) of patients with schizophrenia  Discovery of First Anti-Schizophrenic Agents ! Use of chlorpromazine – also frequently associated with mild motor side-effects like those of Parkinson’s disease  Discovery of First Anti-Schizophrenic Agents ! In early 1950s, Nathan Kline discovered reserpine – extract of ‘snakeroot plant’ – was effective anti- schizophrenic agent ! Also frequently associated with mild motor side effects like those of Parkinson’s disease  Parkinson’s Disease ! In 1960, Ehringer & Hornykiewicz found – at post-mortem – that normally dopamine-rich striatums of people who had died of Parkinson’s disease had little dopamine at post-mortem  Dopamine Hypothesis ! So – dopamine hypothesis was born – that is, positive symptoms of schizophrenia involve overactivity of brain dopaminergic synapses " Chlorpromazine (CPZ) identified as effective anti-psychotic agent – later found to block DA receptors  Dopamine Hypothesis ! Further evidence came from opposing effects of DA agonists ! Drugs like cocaine, amphetamine, methylphenidate (block reuptake of DA) and L-DOPA (stimulates synthesis of DA) – reproduce positive symptoms of schizophrenia  Dopamine Hypothesis ! And these positive symptoms were alleviated by antipsychotic drugs ! Suggested that positive symptoms of schizophrenia were caused by over- activity of dopaminergic synapses  Dopamine Hypothesis ! Carlsson & Lindqvist (1963) tested dopamine hypothesis – assessed effects of chlorpromazine on dopamine and its metabolites ! What they expected to find was that chlorpromazine would deplete the brain of dopamine  Dopamine Hypothesis ! But this is not what they found ! Levels of dopamine were unchanged by chlorpromazine – but level of dopamine metabolites (breakdown products) increased  Dopamine Hypothesis ! Carlsson & Lindqvist concluded that chlorpromazine produced anti- schizophrenic effects by antagonising transmission at dopamine synapses ! Chlorpromazine does so – by binding to dopamine receptors (i.e., acts as a receptor blocker)  Affinity for Dopamine Receptors ! Creese, Burt & Snyder (1976) assessed degree to which various anti-schizophrenic drugs bound to dopamine receptors " Chlorpromazine/ other effective anti- schizophrenic drugs – high affinity for dopamine receptors " Ineffective agents – low affinity for dopamine receptors  Affinity for Dopamine Receptors ! Snyder (1978) showed – potency with which these drugs bound to D2 receptors predicted their potency as anti-schizophrenic agents (see next slide) ! Potent anti-schizophrenics – drugs that are effective at low doses against schizophrenic symptoms  Affinity for Dopamine Receptors ! Potent anti-schizophrenic drugs (e.g., haloperidol) selectively bound only to D2 receptors ! Led to important revision of dopamine theory – positive symptoms of schizophrenia involve over-activity specifically at D2 receptors  Dopamine Hypothesis ! Early version of dopamine hypothesis accounted for data available then ! No link was made at this stage to genetics and neurodevelopmental deficits – little was actually known about them then  Dopamine Hypothesis ! Little clear indication of where the abnormalities were in living brain ! Required later advent and application of in-vivo imaging techniques to shed light on where they may be  Evidence of Abnormalities in DA Transmission? ! Is there any evidence that dopaminergic activity is abnormal in brains of people with schizophrenia? ! NB It is not possible to measure dopamine levels directly in humans  Evidence of Abnormalities in DA Transmission? ! Techniques have been developed that provide indirect indices of: " Dopamine release " Dopamine synthesis " Number of dopamine receptors  Increased Dopamine Release ! Is there evidence that dopaminergic neurons may release more dopamine in brains of those with schizophrenia? (Laruelle et al. 1996; Breier et al. 1997) ! Laruelle et al. used a device similar to a PET scanner  Increased Dopamine Release ! Laruelle estimated release of dopamine caused by an intravenous injection of amphetamine Remember – amphetamine stimulates the release of dopamine  Increased Dopamine Release What did Laruelle et al. find? ! Amphetamine caused greater dopamine release in striatum of those with schizophrenia vs. controls ! In addition – Ss. with greater amounts of dopamine release showed greater increases in positive symptoms  Laruelle et al. (1996) Relative amount of Relation between dopamine dopamine release in release & changes in response to amphetamine positive symptoms in persons with schizophrenia To Be Continued