BIOL3025 Schizophrenia Part I-IV Lectures (2024)

BIOL3025 Schizophrenia  Suicide is the number one cause of premature death among people with schizophrenia [An estimated 10 percent to 13 percent of deaths] www.schizophrenia.com  3 topics Symptoms and Causes Antipsychotics and the Dopamine Hypothesis Genetics and Beyo...

BIOL3025 Schizophrenia  Suicide is the number one cause of premature death among people with schizophrenia [An estimated 10 percent to 13 percent of deaths] www.schizophrenia.com  3 topics Symptoms and Causes Antipsychotics and the Dopamine Hypothesis Genetics and Beyond the Dopamine Hypothesis Followed by workshop on an exam question LEARNING OUTCOMES You should be able to i)Critically assess neurobiological hypotheses for schizophrenia ii)Discuss the difficulties faced in treating schizophrenia iii)Describe the main drugs used to treat schizophrenia and what is understood about their mode of action (how they work) iv)Discuss limitations of the drugs used to treat schizophrenia v)Outline different experimental approaches used to study the neurobiological basis of schizophrenia vi) Comment on how the prospects for understanding and treating the disorder might be improved in the future Schizophrenia Part 1 Symptoms and Causes  Schizophrenia Swiss psychiatrist Bleuler 1908 “fragmentation of cognitive processes and personality” CASE HISTORY....illustrates…….. onset in adolescence complex array of symptoms role of stress in precipitating illness episodic nature  Symptoms POSITIVE hallucinations- mainly auditory (*‘inner speech’) thought disorders stereotyped behaviours NEGATIVE poverty of affect cognitive impairment temporal disorientation time-course: Symptoms Neuropsychiatr Dis Treat. 2020 Feb 21;16:519–534. doi: 10.2147/NDT.S225643  Incidence of schizophrenia consistent with a genetic component  CAUSES OF SCHIZOPHRENIA 1. GENETIC supported by high concordance rate for monozygotic twins (48%) Or environment in the home? Birth mother Adoptive incidence of Scz Tienari looked at this, babies mother adopted away from ‘normal’ normal normal 1% or ‘schizophrenic’ mothers: schizophrenic normal 8%  1. GENETIC 1000’s of risk loci however, the genetic basis of schizophrenia is complex for discussion see Schizophrenia as a pathway disease, Nature Medicine 2012 PMID: 22310687  1. GENETIC 1000’s of risk loci DISC 1 (Disrupted in Schizophrenia-1 gene = PMID 28140405) This is a scaffold protein; implicated in dopamine homeostasis COMT (catechol-O-methyl transferase gene = PMID 27622935) This is enzyme that breaks down dopamine Neuregulin (= PMID 28864885) This is cell signalling protein family involved in cell proliferation and differentiation Neuregulin (= PMID 28864885) This is cell signalling protein family involved in cell proliferation and differentiation So what clues do these genes give us?  CAUSES OF SCHIZOPHRENIA 2. PSYCHOSOCIAL adolescent onset stress can precipitate illness higher rate of relapse in ‘emotionally charged’ home environment blunted cortisol response salivary cortisol Lange et al 2017, Psychoneuroendocrinology PMID: 28549268 3. STRUCTURAL BRAIN DAMAGE? some studies (CAT Scans and MRI) show ventricular enlargement decreased volume of temporal lobe (hippocampus) BUT no gliosis (therefore not neurodegenerative) is there an ‘early’ injury to the brain? obstetric complication? developmental abnormality? Cytoarchitectural abnormalities in cortex decreased numbers of small neurones in superficial layers increased numbers of large neurones in deeper layers Developing brain Luhmann et al Frontiers in Physiol. Cytoarchitectural abnormalities in cortex decreased numbers of small neurones in superficial layers increased numbers of large neurones in deeper layers Developing brain Luhmann et al Frontiers in Physiol. Cytoarchitectural abnormalities in cortex decreased numbers of small neurones in superficial layers increased numbers of large neurones in deeper layers Developing brain 4. VIRAL INFECTION ❑ higher incidence in patients born in late winter or spring ❑ hypothesis that exposure of mother to virus during second trimester increases risk of schizophrenia to the child see e.g. Pulver et al, 1992 Risk factors in schizophrenia. Season of birth, gender, and familial risk. Br J Psychiatry. 160:65-71. (for Northern hemisphere) these causes/hypotheses concerning the underlying mechanisms for schizophrenia are not mutually exclusive  SUMMARY; CAUSES OF SCHIZOPHRENIA GENETICS ENVIRONMENT SCHIZOPHRENIA for recent review see Ortiz-Valladares et al. 2024. Neuroscience PMID: 39159841 Recap Symptoms- positive and negative Time course Causes- synergy between genetic susceptibility and environment Site of brain dysfunction?  Site of brain dysfunction 1. Limbic structures of brain: decreased size of temporal lobe, increased activity during auditory hallucication schizophrenia control showing enlarged ventricles & decreased size of temporal lobe Site of brain dysfunction 2. Dysfunction of dominant cerebral hemisphere Left hemisphere is specialised for verbal function In normal individuals this is shown by increased brain activity to the left side of the brain during a verbal task This lateralisation appears disrupted in schizophrenia page 647 Purves 3rd Edition – split brain patients Site of brain dysfunction 3. Hypofunctionality of dorsal-lateral prefrontal cortex “SZ was described as an orchestra without a conductor”; conductor resides in frontal lobes…..esp in dorso-lateral PFC PMID:34285373 control schizophrenia Site of brain dysfunction 4. Basal ganglia (Site of action of antipsychotics) PMID: 38110704  CURRENT UNDERSTANDING Genetic susceptibility is involved but environment can modulate expression Positive symptoms involve temporal lobe Negative symptoms involve prefrontal cortex Consider; what challenges does this present for therapy?  Schizophrenia Part II Neurochemical imbalances Regional changes Dopamine and glutamate [higher in Basal Ganglia] Dopamine, glutamate and GABA [lower in frontal cortex] PMID:38110704 Schizophrenia Part II Antipsychotics and the Dopamine Hypothesis  Neurochemical basis of schizophrenia there is indirect, circumstantial evidence to implicate dopamine 1. reserpine is antipsychotic 2. amphetamine causes toxic psychosis in susceptible individuals 3. L-DOPA can trigger psychotic episodes 4. chlorpromazine Chlorpromazine  Chlorpromazine increases DA turnover X plus chlorpromazine DA X effect inhibition of release X increased release of dopamine leads to increased appearance of metabolites in CSF- this suggest chlorpromazine is a DA receptor antagonist Does dopamine receptor blockade explain the antipsychotic action of chlorpromazine? Seeman (1998) Molecular Psychiatry 3, 123-124  The dopamine hypothesis The symptoms of schizophrenia are due to excess dopamine neurotransmission in mesolimbic and mesocortical regions of the brain Dopamine Pathways IS THE DOPAMINE HYPOTHESIS OF SCZ TRUE? is there increased dopaminergic transmission in schizophrenia? is there increased dopaminergic transmission in schizophrenia? dopamine release? no consistent evidence for increase in dopamine release dopamine receptors? measurements made in post mortem brain show an increase in D2 receptors- however, this could be due to drug treatment measurements in drug naive patients using PET do not show consistent increased levels of D2  DOPAMINE HYPOTHESIS dopamine schizophrenia BUT no evidence for increased dopamine release OR increased dopamine receptor number? or increased sensitivity? (the literature is extensive and conflicting..) Recap Dopamine receptor antagonists are antipsychotic Formulation of dopamine hypothesis But no evidence for change in dopamine signalling in schizophrenia...  Antipsychotics (neuroleptics) ‘TYPICAL’ or 1st generation anti-psychotics phenothiazines thioxanthenes butyrophenones but have limitations- not effective in all patients only effective against positive symptoms  Side effects of ‘typical’ antipsychotics weight gain ANTIHISTAMINE sedation postural hypotension ALPHA ADRENOCEPTOR atropine-like side effects hyperprolactinaemia D2 neuroleptic malignant syndrome movement disorders acute e.g. Parkinson like syndrome chronic Tardive dyskinesia  Tardive dyskinesia repetitive, purposeless movement; Hyper-facial disorders; Problems with swallowing irreversible CAUSE? Unclear; hypersensitivity to D2 R?  RECENT ADVANCES IN SCHIZOPHRENIA AND THE ATYPICAL ANTIPSYCHOTICS or 2nd generation anti- psychotics less sedation REPORTEDLY low incidence of movement disorders REPORTEDLY more effective against negative symptoms Classes CLOZAPINE QUETIAPINE OLANZIPINE RISPERIDONE ARIPIPRAZOLE ASENAFINE PALIPERIDONE Side effects? THE RECEPTOR PROFILE OF HALOPERIDOL Plasma concentration THE RECEPTOR PROFILE OF CLOZAPINE RECAP Symptoms – positive & negative Causes- multicomponent Treatment – antipsychotics and the dopamine hypothesis Side-effects Clozapine- fewer EP side effects, pharmacology?  Schizophrenia III Integration of observations and experimental models Genetics- Beyond the Dopamine Hypothesis GENETIC BASES FOR SCHIZOPHRENIA (linkage analysis further implicates cortical dysfunction) DISC-1 NEUREGULIN CATECHOL-O-METHYL-TRANSFERASE But note- hundreds of genetic susceptibility factors have been linked to schizophrenia Insight provided by: association with chromosomal microdeletion syndrome rare familial variants of schizophrenia  Candidate Genes? catechol-O-methyl-transferase (COMT) expression pattern? metabolic enzyme for dopamine  Candidate Genes? two COMT alleles in humans valine 108 methionine 108- less stable enzyme hypothesis that met-108 gives rise to higher synaptic dopamine but val108 is the allele that shows linkage with schizophrenia and impaired cognitive function  Familial schizophrenia provides clues… Scottish family with inherited psychiatric disorders Disrupted in schizophrenia = DISC-1 Chromosomal translocation can introduce DNA breaks  Disrupted in Schizophrenia 1 (DISC1) Identified in family that has chromosomal translocation DISC-1 increased expression during neuronal development expressed in cortical neurones interacts with several proteins e.g. NuDEL, LIS1 The DISC1 interactome Ming & Song. Disc1 partners with GSK3B in schizophrenia Link between DISC1 and Mutations that cause Lissencephaly Linkage for other genes involved in neural migration in schizophrenia Neuregulin  Neuregulin Linkage analysis and fine genetic mapping identified a locus on chromosome 8 as a risk factor for schizophrenia: The region encodes neuregulin Neuregulin is a growth factor that interacts with a receptor* that regulates neuronal differentiation and migration * ErbB: epidermal growth factor like receptor tyrosine kinase Neuregulin Post mortem analysis of brain from schizophrenics has identified an increase in levels of mRNA for neuregulin Current hypothesis is that an increase in neuregulin signalling is a risk factor for schizophrenia (possibly by reducing the function of the glutamate receptor, the NMDA receptor) Remember- the glutamate-dependent control of subcortical systems Hypothesis for schizophrenia Cortex hypofunctionality inhibition Subcortical systems Excessive activity  Summary Evidence for involvement of PFC and subcortical dopamine in the negative and positive symptoms of schizophrenia PFC: 1. hypofunctionality in brain imaging 2. altered cytoarchitecture in PM brain 3. decreased D1 in PM brain 4. lesions in primates give negative symptoms 5. DISC1 and COMT highly expressed in cortex 6. DISC1 implicated in neuronal migration and interacts with proteins which are mutated in lissencephaly indicates that there may be neurodevelopmental defect that causes abnormality in organisation of cortical neurones Antipsychotics block dopamine receptors Cortex hypofunctionality antipsychotics antipsychotics inhibition Subcortical systems Excessive activity  Clozapine- an atypical antipsychotic Awakenings : Schizophrenia: A New Drug Brings Patients Back to Life They Are Tormented by demons and at times lost to reality. Now, after years of madness, some schizophrenia patients are being awakened by a costly new drug. By Claudia Wallis and James Willwerth Monday, July 06, 1992 Read more: Awakenings : Schizophrenia: A New Drug Brings Patients Back to Life - TIME http://content.time.com/time/magazine/article/0,9171,975910,00.html#ixzz2vAmTs jp3  Conclusions need to increase understanding of the genetic basis for the disorder to get insight into the underlying mechanisms inform development of new models for the disorder and facilitate improved therapies understand the complex interaction between environmental and genetic susceptibility factors that lead to expression of the disorder aim early and accurate diagnosis and the development of therapies that limit the severe impact of schizophrenia on the patient