Schizophrenia

• Heterogenous syndrome


  Characterised by disorganised thoughts, delusions, hallucinations, impaired psychosocial functioning
• Heritable


  • 65-80%
• Psychosis


  Detachment from reality
• Psychotic symptoms


  Disturbing and dramatic psychological phenomena where they lose touch with reality
• Psychotic episode symptoms


  1. Hallucinations - sensory perceptions, not linked to physical stimulus e.g. hearing voices

  2. Illusions - not optical problems or sensory misperception, they are distorted perceptions or misinterpretations of stimuli e.g. seeing an object pulsating or auras

  3. Delusions - false beliefs not shared by others e.g. believing you're god

  4. Ideas of reference where ordinary objections contain messages for them
• Some patients believe outside organisations has removed or added things to their brain
• 3 main symptomatic clusters to have schizophrenia

  • Positive - not good or bad just presence, delusions, hallucinations, disordered speech, erratic behaviour
  • Negative - absence of certain things, reduced expression of emotions, poverty of speech (less speech less words etc.), social withdraw (tend to become isolate)
  • Cognitive - impaired executive function like planning and organisation, working memory impaired, impaired working memory and difficult initiating goal-directed behaviour
• Schizophrenia onset


  • Mid-late teens, go through a phase of prodromal symptoms where early signs get triggered during this age, a sign that something is wrong, personality starts to change, start to have difficulty at school, socially isolated
• Age group and distribution

  • A lot more females than male
  • First sign is ab 24yrs in males, 26yrs first psychotic symptom and 28yrs seek medical help (index condition)
  • In females it is slightly later suggesting they are better at masking than males but can tend to be the same age for onset but the masking can stop, same with ADHD
• Pattern how schizophrenia presents itself across individuals lifespan

  • Slow onset of simple courses before you get full psychosis but persist after for the rest of your life at a constant level
  • Undulating courses have Period between remissions where you're not feeling any symptoms can vary
  • Atypical is unpredictable
• Impairments in cognitive dysfunction

  • Like executive function working memory and other things mediated by the PFC is an important predictor for outcome - the degree at which your showing changes in cognitive performance is a predictor for the timecourse for how the disorder will progress and respond to certain medications and treatments
• Underlying mechanisms


  • Genetic
  • Development theories - linked with environment
  • Environment
  • Dopamine theory
  • Glutamate - Changes in NMDAr function
  • GABA theory
  • Diet
  • Viruses
  • Network theories
• Genetics


  • 1% population
  • Schizophrenia is highly influenced by genes, environmental factors are poorly defined
  • 9% risk if you have sibling with it and 48% increase if identical twins how likely you are to develop a schizophrenia episode, 48 fold increase with monozygotic twin (because genetically identical basically 50% chance), the more genetically similar you are the more likely to get it
• Dysregulation in Dysbindin


  • Important protein found inside of neurons important for trafficking receptors and moving things around and synaptic organisation, can play a role in synaptic vesicle trafficking so neurotransmitter release because it interacts with SNAP-25 involved with fusion
  • May be linked to D2 receptor levels and glutamate and GABA transmission and their surface expression at synapse
  • Important in neurodevelopment - migration and synaptogenesis so disrupts critical periods of brain development leading to abnormal synaptic connections
• COMT enzyme


  Degrades dopamine once its been released from synaptic transmission and when there is a dysfunction in it, it leads to increase in dopamine. Especially in the PFC associated with cognitive dysfunction in schiz
• Neuregulin 1


  • Involved in synaptic formation, plasticity and myelination in early and adult neurodevelopment interacting with ACh receptors to regulate function and neurotransmission. NRG1 mutations = schizophrenia
  • Proliferation, migration, differentiation and synaptic formation
  • Maintains glutamatergic and GABAergic synapses
• BDNF


  • Roles in neurogenesis survival, growth, differentiation, plasticity, learning and memory
  • Reduced BDNF levels early in life may lead to impaired neurotransmission and the development of psychotic symptoms later on
• Neurexin-Neuroligin junction disruption


  • May contribute to synaptic abnormalities
  • NMDAr signalling
  • Spine structures
  • Can influence DISC1 expression
• DISC1


  • Regulated neurogenesis, synaptogenesis, neuronal migration, neurite formation and synapse development
  • Alters dopamine release in models
  • Stress interaction with DISC1 contributes to dopamine dysregulation seen in psychosis
  • May lead to reduction in PV interneurons
  • Can influence BDNF expression
• PRODHZ enzyme


  Involved in energy metabolism, mutations lead to increased risk of schizophrenia disrupting cell homeostasis, oxidative stress, mitochondrial dysfunction and neurotransmitter imbalance
• Glutamate hypothesis


  Dysfunction in glutamatergic transmission involving NMDA hypofunction leads to alterations in signalling, neurotransmission and plasticity
• NMDAR antagonists


  • Ketamine
• Dopaminergic hypothesis


  Excessive dopamine in mesolimbic pathway disrupts normal synaptic function = psychotic symptoms
• GABAergic interneurons dysfunction


  Role in E/I balance, dysfunction leads to decrease GABA synthesis or release, altered expression of GABAR or impaired GABAergic transmission = less synaptic inhibition
• Synaptic plasticity deficits


  Deficits in LTP and LTD impairs learning, memory and information processing
• Abnormal brain development in life span

  • Links to schizophrenia
  • Dysbindin and neuregulin are most linked because of synaptogenesis and trafficking
  • Others like DAOA more bipolar disorders involving plasticity and neurotransmission
• Schizophrenics have less overall grey matter
• Thinning of grey matter

  In cortical areas, activity is reduction in cortical volume in image
• Areas in frontal cortex and temporal lobe are showing less grey matter
• Changes in grey matter start at those teenage years where those prodromal symptoms come about in teenagers
• There is significant progressive loss occurring in parietal, motor, supplementary motor and superior frontal cortices
• There is not much difference between males and females with loss of grey matter, loss up to 5% per year in parietal frontal and temporal cortices
• Reduced spine volume and spine number

  Loss of brain matter is not due to neuronal death themselves or loss of glial cells but the loss of spines, dendrites, axons, synapses (neuropil basically) and changes in branch patterns and axons causing the reduction in grey matter
• Adolescence


  Involves significant synaptic punting = enhanced network efficiency but in schizophrenia there seems to be excessive loss of synapses in the prefrontal cortex possibly due to dysregulation of synaptic function
• Schizophrenia


  Have enlarged ventricles due to loss of grey matter and shrinking cortical volume
• Interactions between genes and environment


  Changes in genetic predisposition exacerbated but environmental influences in key stages of development across the lifespan
• Key developmental stages


  • Birth
  • Adolescence
  • Young adulthood
• Prodromal symptoms happens mid to late adolescence
• Interneurons increase from birth to adolescence that increases exponentially towards the end of adolescence and young adulthood
• Mesocortical dopaminergic projection to cortex and other limbic areas, occurs early childhood reaching a peak at young adulthood