Schizophrenia - MPBD 2023 Lecture Notes PDF

Schizophrenia Hylke Vervaeke  Content What is schizophrenia? (symptoms) Etiology – Dopamine hypothesis – Glutamate hypothesis – Integrated DA-GLU hypothesis – Neurodevelopmental hypothesis 2  Symptoms schizophrenia Symptoms 3 categories: Positive...

Schizophrenia Hylke Vervaeke  Content What is schizophrenia? (symptoms) Etiology – Dopamine hypothesis – Glutamate hypothesis – Integrated DA-GLU hypothesis – Neurodevelopmental hypothesis 2  Symptoms schizophrenia Symptoms 3 categories: Positive – negative – cognitive symptoms 3  Positive Symptoms schizophrenia Positive symptoms = excess of normal functions Psychosis (delusions + hallucinations) Disorganized speech Distortions / exaggerations in language + communication Disorganized behaviour (‘verward gedrag’) Agitation 4  Positive Symptoms schizophrenia Delusions = misinterpretation of perception or experience Paranoid delusions or persecutory delusions (persecution, espionage, conspiracy) Referential delusion: erroneously thinking that something refers to oneself (secret messages) Grandiose delusions (megalomania): erroneously thinking that one is a powerful person Scientific delusions 5  Positive Symptoms schizophrenia Religious delusion (thinking you are Jezus or another divine being) Delusion that you are poisoned Sexual delusion (one is convinced to be irresistible) Leaky mind: thoughts are ‘leaking out’ the brain and can be read by others or are broadcasted Thoughts are not from the person, but are transplanted into the brain (eg by aliens) 6  Positive Symptoms schizophrenia Hallucinations Most common: auditory (harsh voices giving negative comments / orders) But may occur in any sensory modality: visual, tactile, gustatory, olfactory (smell of gas, rotting meat) 7  Negative Symptoms schizophrenia Negative symptoms = reduction in normal functions Blunted affect: restrictions in range and intensity of emotional expression (feeling empty; recalls few emotional experiences; little facial expression) Dysfunction of motivation: reduced motivation persistence, passivity, reduced ability to undertake and complete everyday tasks; may have poor personal hygiene Anhedonia: dysfunction of capacity for pleasure; reduced ability to experience pleasure; decreased interest in previous hobbies 8  Negative Symptoms schizophrenia Asociality: reduced social drive and interaction; little sexual interest; few friends, little interest in spending time with friends 9  Cognitive Symptoms schizophrenia Attentional problems Executive dysfunction: problems with planning, maintaining goals, problem solving, prioritizing 10  Etiology Symptoms of schizophrenia arise because of malfunctioning brain circuits Different symptoms > different brain circuits 11  Etiology 12  Etiology Dopamine has long played prominent role in hypotheses of schizophrenia Which drugs do you know that could elicit psychosis? Cocaine (DAT reuptake inhibitor) en Amphetamine (DAT reuptake inhibitor + DA releaser: more DA in synapse) > psychosis First antipsychotics: DA receptors blockers (DA antagonists) Dopamine hypothesis of schizophrenia 13  Dopamine hypothesis a) nigrostriatal b) mesolimbic c) mesocortical d) tuberoinfundibular 14  Dopamine hypothese 15  Dopamine hypothesis ‘mesolimbic dopamine hypothesis of positive symptoms of schizophrenia’ Positive symptoms (psychosis: delusions and hallucinations) arise because of hyperactive DA neurons in mesolimbic circuit ‘too much DA in ventral striatum’ 16  Dopamine hypothese 17  Dopamine hypothesis ‘mesocortical dopamine hypothesis of cognitive and negative symptoms of schizophrenia’ Negative en cognitive symptoms arise because of hypoactive DA neurons in mesocortical circuit ‘too little DA in PFC’ 18  Dopamine hypothese 19  Dopamine hypothese 20  Dopamine hypothesis Integrated dopamine hypothesis of schizophrenia attempts to explain all symptoms of schizophrenia by: Dysregulation of mesolimbic and mesocortical dopamine pathway With relative preservation of functioning of nigrostriatal and tuberoinfundibular pathways 21 22 23  Antipsychotics D2-antagonist Classic antipsychotics (like haloperidol) are dopamine D 2-receptor antagonists Blocking hyperactive mesolimbic circuit However: extrapyramidal side-effects (parkinson-like) by blockade nigrostriatal DA pathway 24  Glutamate hypothesis Recently: glutamate attained key role in pathophysiology schizophrenia ‘NMDA receptor hypofunction hypothesis of schizophrenia’ 25  Glutamate hypothesis NMDA-antagonists like ketamine: occasionally temporary state of mind very similar to symptoms schizophrenia Ketamine (high dosage) is used in brain imaging research as ‘schizophrenia-like model’ Positive symptoms: delusions and hallucinations Negative symptoms (blunted affect, social withdrawal) and cognitive symptoms (executive dysfunction) 26  Glutamate hypothesis Important: ketamine-induced psychosis is not common Ketamine when used as recreational drugs > also euphoria Ketamine when used as antidepressant medication > increased mood (1-2 weeks) 27  Glutamaat hypothese 28  Glutamate hypothesis (a) cortical brainstem glutamate projection (b) corticostriatal glutamate pathway (c) thalamocortical glutamate pathways (d) corticothalamic glutamate pathways (e) corticocortical glutamatergic pathways 29  Glutamate hypothesis NMDA-antagonists like PCP and ketamine: temporary state of mind very similar to symptoms schizophrenia Glutamate hypothesis: NMDA-receptor hypofunction in corticobrainstem projection 30  Glutamaat hypothese 31  Glutamate hypothesis Normally: corticobrainstem projection communicates directly with DA neurons of mesocortical pathway VTA: Glu stimulates mesocortical DA neurons via AMPA-R and NMDA-R > activation (‘acceleration’ or tonic excitation) of mesocortical pathway Schizophrenia: NMDA-R hypoactive > less activation mesocortical DA neurons > less DA release in PFC > negative and cognitive symptoms schizophrenia NMDA-R hypofunction causes hypoactivation mesocortical DA pathway = coupling glutamate- and dopamine hypotheses! 32  Glutamaat hypothese 33  Glutamate hypothesis Normally, corticobrainstem projection acts as brake (tonic inhibition) on mesolimbic DA pathway via GABA interneuron VTA: Glu stimulates GABA-neuron > more GABA release > GABA inhibits DA neurons > less DA release in ventral striatum (nucleus accumbens) Schizophrenia: NMDA-R hypoactive > less GABA release > less inhibition of DA neurons > more DA release in ventral striatum > positive symptoms schizophrenia NMDA-R hypofunction causes hyperactivation mesolimbic DA pathway = coupling glutamate- and dopamine hypotheses! 34  Glutamate hypothesis Next, hypofunction NMDA-R causes ‘sensory filter’ of thalamus dysfunction Thalamus ‘decides’ which part of sensory information is sent to the cortex and can be perceived consciously In schizophrenia efficacy of sensory filter reduced > more sensory input relayed to cortex = sensory overload > psychosis 35  Glutamate hypothesis How does sensory filter of thalamus function in healthy people? 36 37 38  Glutamate hypothesis Why does sensory filter in schizophreniacs dysfunction? 39  midbrain See slide 33 to repeat details 40  midbrain 41  Glutamate hypothesis Why does sensory filter in schizophreniacs dysfunction? TOO LITTLE GABA IN THALAMUS! Why? Two important causes: 1. Excess DA (from mesolimbic pathway) INHIBITS GABA-neuron via inhibitory dopamine receptors on GABA cellbody and dendrites 2. NMDA-R hypofunction > Glu of corticostriatal pathway less effect on excitatory NMDA (and AMPA) receptors receptors on GABA cellbody and dendrites [NMDA and AMPA receptors are both excitatory glutamate receptors) Less GABA in thalamus > less filtering sensory signals > sensory overload cortex 42  Schizophrenia Schizophrenia > malfunctioning brain circuits Errors in neuronal networks Dysconnectivity How can abnormal neuronal connectivity be triggered? Genes? Environmental factors? 43  Etiology Prevalence schizophrenia general population 1%, onset in adolescence (from age 15-25) Concordance rate dizygotic twins: 17% Concordance rate monozygotic twins: 48% 44  Etiology Heritability = proportion of phenotypic variation caused by genetic variation = estimate of relative contribution genetic factors Heritability schizophrenia = 80 % 45  Etiology Underlying genes Difficult to identify Why? Multiple genes: each risk gene increases risk by very small part Gene-environment interactions Changes in gene expression Epigenetic modifications 46  Neurodevelopmental hypothesis of schizophrenia Underlying genes Genes implicated in neuronal development, synaptogenesis, glutamate neurotransmission and LTP 47 48 49 50  Neurodevelopmental hypothesis of schizophrenia Risk genes for schizophrenia > Genes implicated in neuronal development, synaptogenesis, glutamate neurotransmission and LTP > dysfunctional brain circuits and hypofunction NMDA-R Problems arise during neurodevelopment > why disease manifests only during adolescence? 51 52  Neurodevelopmental hypothesis of schizophrenia During synaptogenesis > NO LTP > synapses stay ‘weak’ During adolescence aberrant elimination weakened synapses 53  Neurodevelopmental hypothesis of schizophrenia Presence risk genes NOT sufficient for development schizophrenia!!! Multifactorial: genes, environmental factors (stress) and personality 54  Neurodevelopmental hypothesis of schizophrenia Environmental risk factors: – Stress, infection, malnutrition during pregnancy (hungerwinter WWII) – Hypoxia during birth – Born in winter / spring (northern hemisphere) – Living in urbanised environment (OR = 2) – Ethnic minorities – Trauma/abuse – Use of cannabis Some environmental factors (such as abuse) > influence via epigenetic modifications DNA 55 56  Neurodevelopmental hypothesis of schizophrenia stress, life events Combination of risk genes schizophrenia personality 57  Learning outcomes lecture schizophrenia You can describe the symptoms of schizophrenia and categorize them (positive, negative, cognitive symptoms) You can describe the etiology of complex multifactorial disorders like schizophrenia You can estimate the heritability of schizophrenia (in %) You can explain the dopamine hypothesis and glutamate hypothesis 58  Learning outcomes lecture schizophrenia You can explain how the dopamine hypothesis is coupled to the glutamate hypothesis You can explain the dysfunctioning of the thalamic filter in schizophrenia You can explain the neurodevelopmental hypothesis of schizophrenia and elaborate on the role of dopamine, glutamate, genetic and environmental risk factors You can explain the mechanism of action of classic antipsychotics and explain the motor side effects of these drugs 59