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Schizophrenia: Clinical Lecture

Schizophrenia: Clinical Lecture. Tuesday, April 14 th Alexandra McHale. Features of Schizophrenia. Heterogeneous brain disease (Slightly) More common & severe in men than women (1.4:1) Age of onset: men = late teens/early 20 ’ s; women = late 20 ’ s/early 30 ’ s ~20 year shorter lifespan

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Schizophrenia: Clinical Lecture

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  1. Schizophrenia: Clinical Lecture Tuesday, April 14th Alexandra McHale

  2. Features of Schizophrenia • Heterogeneous brain disease • (Slightly) More common & severe in men than women (1.4:1) • Age of onset: men = late teens/early 20’s; women = late 20’s/early 30’s • ~20 year shorter lifespan • Characterized by deficits in integration of information across multiple domains • Perception • Language • Emotion • Behavior

  3. Heritability Concordance Rates Pesold, 2004

  4. Symptom Dimensions Positive (Psychosis) Cognitive Negative (Deficit) • Abnormal reward processing • Abulia/Avolition • Apathy • Anhedonia • Poverty of speech • Flat affect • Executive function dysfunction • Deficits in working memory and attention • Poor executive functioning • Abnormal salience processing • Hallucinations • Delusions • Disorganized behavior and speech • Disordered thoughts

  5. DSM-V Diagnosis of Schizophrenia A. Characteristic symptoms: > 2 of 5 of the following symptoms: • delusions • hallucinations • disorganized speech (e.g., frequent derailment or incoherence) • grossly disorganized or catatonic behavior • negative symptoms, i.e., affective flattening, alogia, or avolition Note: 1,2 OR 3 is required for diagnosis B. Causes social/occupational dysfunction • Duration: Continuous signs for at least 6 months • at least 1 month of Criterion A symptoms (or less if successfully treated) • may include periods of prodromal or residual symptoms. D.-F. – Excluding other causes

  6. Heterogeneity of Psychiatric Disorders Van Os, 2009

  7. Clinical course • Prodrome (early adolescence) • Subtle changes (e.g., acting odd, social withdrawal, strange affect/beliefs, ”paranoid” statements, etc.) • 80% correct • Acute index episode (~ first hospitalization) • late adolescence early adulthood • clear break from reality, onset of symptoms • Relapsing, remitting course • symptoms plateau ~ 5 years after diagnosis • medications improve acute and long-term outcome

  8. Onset and course of psychotic symptoms

  9. Cognitive findings: Thought Disorder/ “Word Salad” • Grandiosity (ex: “NOTHING kills me”) • Perseveration (ex: “Hell/ Hells Angel”, “CIA”) • Loose associations (ex: “See/Seen”, “Head/Mind”)

  10. Other cognitive findings • Eye tracking of swinging pendulum; other abnormal eye movements (saccades) • Pre Pulse Inhibition fails • Weaker prestimulus is supposed to inhibit reaction to a stronger stimulus that appears later • Attention deficits: selective attention and sustained attention both impaired • Increased olfactory thresholds and decreased discrimination of odors

  11. Niendam, 2003

  12. Structural Imaging Abnormalities • Global atrophy • Lateral ventricular enlargement • Decreased volume specifically in • medial temporal lobe (amygdala, hippocampus and parahippocampalgyrus) • superior temporal gyrus • parietal lobe (esp. angular and supramarginalgyrus) • cerebellum • basal ganglia • corpus callosum • thalamus Shenton, 2001

  13. Functional Imaging of Auditory Hallucinations • Broca’s area, Wernike’s Area, limbic regions • Active during normal conversations and hallucinations Jardri, 2011

  14. Is Schizophrenia a developmental disorder? Increased risk of schizophrenia with prenatal maternal exposure to stress malnutrition viruses obstetrical complications delayed development milestones subtle cognitive, emotional and motor deficits in childhood Pesole, 2004

  15. Is Schizophrenia a developmental disorder? Strong familial predisposition Shares a susceptibility gene with developmental syndrome with high rate of psychosis Velocardial-facial syndrome - microdeletion of 22q11 10-40% have psychosis Many associated SNPs, no causal gene Alterations in developmentally-relevant gene transcripts and proteins Pesole, 2004

  16. Is Schizophrenia a developmental disorder? Neuropathology absence of focal pathology migrational anomalies in prefrontal, parietal and temporal cortex diffuse loss of synapses increased neuronal density without loss of neurons reductions in axon terminal density & dendritic spines decreased expression of gene products associated with synaptic function symptom onset at conclusion of synaptic pruning

  17. ‘Synapses’ ‘Neurons’ ‘Working Memory’

  18. Decreasing neuron number does not change accuracy Sequential Input Sequence Cop – chase – old – man - ___ - ___ - ___ - ___ - Jane - kiss – girl Model Output – 81% accurate Cop – chase – __ – dog - ___ - ___ - ___ - ___ - Jane - kiss - boy Output Classification Green = correct Blue = omission error Orange = substitution error

  19. Decreasing synapse number yields hallucinations Sequential Input Sequence Cop – chase – old – man - ___ - ___ - ___ - ___ - Jane - kiss – girl Model Output – 81% accurate Cop– chase –___– man - ___ -___ -fear-___ - Jane-kiss- girl Output Classification Green = correct Blue = omission errors Red = sensory experience in absence of external stimulus = ????

  20. ‘Working Memory’

  21. ‘Working Memory’

  22. Specificity of Synaptic Reduction on Incidence of Hallucinations Synaptic reduction drives the production of hallucinations and having fewer synapses (with same number of neurons) can put one at risk for hallucinations

  23. Model of excitation-inhibition imbalance

  24. Synaptic Pruning

  25. GWAS identifies C4/C3 regulation as risk factor for schizophrenia MHC: important for acquired immunity & olfaction

  26. Allele specific effects on complement component 4 (C4) expression • Different structural forms of C4 (found in MHC) • AL copy increases risk Sekar et al, Nature 2016

  27. Loss of C4 leads to reduced pruning • Increased C4 expression in MHC locus in schizophrenia • C4 activates C3 (C3 important for pruning by microglia) • Increased C4/MHC levels may explain increased synaptic pruning in schizophrenia Sekar et al, Nature 2016

  28. How does peri-natal hypoxia predispose one to schizophrenia? Jason Hamilton, Ph.D. Thesis 2008

  29. Tangential migration of cortical interneurons

  30. Hypoxia exposed slices no longer repel migrating GABAergic interneurons from the striatum

  31. Hypoxic progenitors transplanted into host to develop and migrate in vivo also fail to avoid the striatum

  32. Molecular cues for tangential migration Sema 3F:repulsive cue in striatum Neuregulin (Nrg-1): attractive cue in cortex ErbB4:attractive cue in cortex Flames et al 2004

  33. Dopamine hypothesis • Psychosis reflects hyperactvity of D2 receptors (predominant in striatum) • Drugs that increase DA (e.g., amphetamine, PCP) can cause psychotic behavior • Anti-psychotic drugs tend to bind dopamine receptors (D2R) • Cognitive deficits reflect hypoactivity of D1 receptors (predominant in cortex) • D1 activity in DLPFC reduced in schizophrenics • D1 receptor levels inversely correlated with working memory, reflecting receptor up-regulation in response to DA deficiency

  34. Dopamine is not the Whole StoryCircuit Involved in Producing Schizophrenic Symptoms * * * * DA Glut GABA * structual & functional imaging abnormalities

  35. Glutamate hypothesis • Evidence that NMDA receptor function is reduced/lacking in schizophrenia • Pyramidal neuron architecture—decreased spines • Increased excitatory amino acid transporter (EAAT) levels (removes Glu from synaptic cleft) • Alterations in scaffolding proteins that hold NMDAR in place, like PSD-95

  36. GABA hypothesis/cellular risk factors • Neuregulin (NRG-1) polymorphisms • ErbB4 polymorphisms • NRG-1 receptor, on migrating interneurons • Hypoxia reduces sema3F signaling • Any/all of these could result in loss of GABAergic interneurons in the cortex and increased numbers in the striatum • This imbalance could affect pruning directly or indirectly

  37. Environmental Risk Factors • Prenatal and perinatal events • Pregnancy complications • Early-life adversity • Assault, maltreatment, bullying • Living/growing up in an urban environment • Migration as a minority • African-Caribbean migration to UK (AESOP study) • Early, chronic cannabis use

  38. Treatment Options in conjunction with Pharmacologicaltreatments • Social Skills training • Cognitive behavioral therapy • Vocational intervention/supported employment • Community-based management • Assertive community treatment • Assisted living situations

  39. Treatment Options (Pharmacological)

  40. Any Questions?

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