2018-11-07 11:07:34

Today's Topics

  • Schizophrenia

Schizophrenia

Simulating the Experience

Overview

  • Lifetime prevalence ~ 0.3-0.7%
    • Broader definitions suggest 2-3 or 3-5%
  • ~1/3 chronic & severe
  • Onset post-puberty, early adulthood
  • Males earlier onset & greater severity
  • Pervasive disturbance in mood, thinking, movement, action, memory, perception
  • Increased (early) mortality

"Positive" symptoms

  • “Additions” to behavior
  • Disordered thought
  • Delusions of grandeur, persecution
  • Hallucinations (usually auditory)
  • Bizarre behavior

"Negative" symptoms

  • “Reductions” in behavior
  • Poverty of speech
  • Flat affect
  • Social withdrawal
  • Impaired executive function
  • Anhedonia (loss of pleasure)
  • Catatonia (reduced movement)

Cognitive symptoms

  • Memory
  • Attention
  • Planning, decision-making
  • Social cognition
  • Movement

Affective dysregulation

  • Depressive, manic states

Biological bases

  • Genetic predisposition
  • Brain abnormalities
  • Developmental origins

Genetic disposition

Heritability

But, no single gene…

Genes associated with schizophrenia at higher than chance levels

  • NOTCH4, TNF:
    • Part of major histocompatibility complex (MHC), cell membrane specializations involved in the immune system
  • DRD2 (dopamine D2 receptor), KCNN3 (Ca+ activated K+ channel), GRM3 (metabotropic glutamate receptor)

(Johnson et al., 2017)

Ventricles larger, esp in males

Ventricular enlargement increases across time

Enlargement precedes diagnosis?

Hip, amyg, thal, NA smaller

  • Related to ventricular enlargement
  • Early disturbance in brain development?

(Jiao et al., 2017)

  • Dentate gyrus (DG) in hippocampus
    • spatial coding, learning & memory, emotion processing
  • DG dysfunction implicated in schizophrenia
  • Gene linked to schizophrenia, Transmembrane protein 108 (Tmem108) enriched in DG granule neurons
  • Tmem108 expression increased during postnatal period critical for DG development.

(Jiao et al., 2017)

  • Tmem108-deficient neurons form fewer and smaller spines.
  • Tmem108-deficient mice display schizophrenia-relevant behavioral deficits.

Rapid gray matter loss in adolescents?

(P. M. Thompson et al., 2001)

Widespread white matter disruption

White matter loss over age

Dysconnectivity in cortical networks

Inconsistent connectivity findings (Fornito & Bullmore, 2015)

  • Structural connectivity vs.
    • Synaptic, dendritic, axonal connections b/w regions
    • Usually measured via DTI or related diffusion-based MRI technique
  • Functional connectivity
    • BOLD, EEG, or MEG covariance
    • Task-free 'resting' state or task-based
  • Global signal variations?

(Fornito & Bullmore, 2015)

Global signal alterations

Dysconnectivity b/w 'hubs' -> higher functional connectivity

Dopamine hypothesis

Evidence for DA hypothesis

  • DA (\(D_2\) receptor) antagonists (e.g. chlorpromazine)
    • improve positive symptoms
  • Typical antipsychotics are DA \(D_2\) antagonists
  • DA agonists
    • amphetamine, cocaine, L-DOPA
    • mimic or exacerbate symptoms

Evidence against…

  • New, atypical antipsychotics
    • (e.g. Clozapine) INCREASE DA in frontal cortex, affect 5-HT
  • Mixed evidence for high DA metabolite levels in CSF
  • Some DA neurons may release 5-HT, cannabinoids, glutamate (Seutin, 2005)

Glutamate/ketamine hypothesis

  • Psychomimetic drugs induce schizophrenia-like states
    • Phencyclidine (PCP), ketamine
    • NMDA receptor antagonists

Ketamine

  • dissociative (secondary) anesthetic
  • side effects include hallucinations, blurred vision, delirium, floating sensations, vivid dreams
  • binds to serotonin (\(5HT_{2a}\)) receptor, \(\kappa\) opioid receptor, and \(\sigma\) receptor "chaperone"
  • may be dopamine \(D_2\) receptor antagonist

Glutamate/ketamine hypothesis

  • Schizophrenia == underactivation of NMDA receptors?
    • NMDA receptor role in learning, plasticity
    • DG neurons in (Jiao et al., 2017) were glutamate-releasing.
  • NMDAR antagonists -> neurodegeneration, excitotoxicity, & apoptosis

Schizophrenia summed up

  • Wide-ranging disturbance of mood, thought, action, perception
  • Broad changes in brain structure, function, chemistry, development
  • Dopamine hypothesis giving way to glutamate hypothesis
  • Genetic (polygenic = multiple genes) risk + environmental factors

Early life stress increases risk

  • 2x greater odds for children in urban environments
  • Higher risk among migrant populations (Cantor-Graae & Selten, 2005)
  • Exposure to infection in utero, other birth complications
  • Exposure to cannibis
  • Paternal age > 40

(Levine, Levav, Pugachova, Yoffe, & Becher, 2016)

  • Children (N=51,233) of parents who born during Nazi era (1922-1945)
  • Emigrated before (indirect exposure) or after (direct exposure) to Nazi era
  • Children exposed to direct stress of Nazi era in utero or postnatally
    • Did not differ in rates of schizophrenia, but
    • Had higher rehospitalization rates

(Debost et al., 2015)

  • Danish cohort (n=1,141,447)
  • Exposure to early life stress
    • in utero did not increase risk of schizophrenia, but
    • during 0-2 years increased risk
  • Increased risk associated with an allele of a cortisol-related gene

The future: Outcomes following hospitalization

The future of psychiatric research

The future of psychiatric research

Next time…

  • Affective disorders

References

Cantor-Graae, E., & Selten, J.-P. (2005). Schizophrenia and migration: A meta-analysis and review. The American Journal of Psychiatry, 162(1), 12–24. https://doi.org/10.1176/appi.ajp.162.1.12

Debost, J.-C., Petersen, L., Grove, J., Hedemand, A., Khashan, A., Henriksen, T., … Mortensen, P. B. (2015). Investigating interactions between early life stress and two single nucleotide polymorphisms in HSD11B2 on the risk of schizophrenia. Psychoneuroendocrinology, 60, 18–27. https://doi.org/10.1016/j.psyneuen.2015.05.013

Erp, T. G. M. van, Hibar, D. P., Rasmussen, J. M., Glahn, D. C., Pearlson, G. D., Andreassen, O. A., … Turner, J. A. (2015). Subcortical brain volume abnormalities in 2028 individuals with schizophrenia and 2540 healthy controls via the ENIGMA consortium. Mol. Psychiatry. https://doi.org/10.1038/mp.2015.63

Fornito, A., & Bullmore, E. T. (2015). Reconciling abnormalities of brain network structure and function in schizophrenia. Curr. Opin. Neurobiol., 30, 44–50. https://doi.org/10.1016/j.conb.2014.08.006

Jiao, H.-F., Sun, X.-D., Bates, R., Xiong, L., Zhang, L., Liu, F., … Mei, L. (2017). Transmembrane protein 108 is required for glutamatergic transmission in dentate gyrus. Proceedings of the National Academy of Sciences, 114(5), 1177–1182. https://doi.org/10.1073/pnas.1618213114

Johnson, E. C., Border, R., Melroy-Greif, W. E., Leeuw, C. A. de, Ehringer, M. A., & Keller, M. C. (2017). No evidence that schizophrenia candidate genes are more associated with schizophrenia than noncandidate genes. Biol. Psychiatry, 82(10), 702–708. https://doi.org/10.1016/j.biopsych.2017.06.033

Kelly, S., Jahanshad, N., Zalesky, A., Kochunov, P., Agartz, I., Alloza, C., … Donohoe, G. (2017). Widespread white matter microstructural differences in schizophrenia across 4322 individuals: Results from the ENIGMA schizophrenia DTI working group. Mol. Psychiatry. https://doi.org/10.1038/mp.2017.170

Kempton, M. J., Stahl, D., Williams, S. C. R., & DeLisi, L. E. (2010). Progressive lateral ventricular enlargement in schizophrenia: A meta-analysis of longitudinal MRI studies. Schizophr. Res., 120(1-3), 54–62. https://doi.org/10.1016/j.schres.2010.03.036

Kochunov, P., Ganjgahi, H., Winkler, A., Kelly, S., Shukla, D. K., Du, X., … Hong, L. E. (2016). Heterochronicity of white matter development and aging explains regional patient control differences in schizophrenia. Hum. Brain Mapp., 37(12), 4673–4688. https://doi.org/10.1002/hbm.23336

Levine, S. Z., Levav, I., Pugachova, I., Yoffe, R., & Becher, Y. (2016). Transgenerational effects of genocide exposure on the risk and course of schizophrenia: A population-based study. Schizophrenia Research, 176(2), 540–545. https://doi.org/10.1016/j.schres.2016.06.019

Os, J. van, & Kapur, S. (2009). Schizophrenia. The Lancet, 374(9690), 635–645. https://doi.org/10.1016/S0140-6736(09)60995-8

Seutin, V. (2005). Dopaminergic neurones: Much more than dopamine? Br. J. Pharmacol., 146(2), 167–169. https://doi.org/10.1038/sj.bjp.0706328

Thompson, P. M., Vidal, C., Giedd, J. N., Gochman, P., Blumenthal, J., Nicolson, R., … Rapoport, J. L. (2001). Mapping adolescent brain change reveals dynamic wave of accelerated gray matter loss in very early-onset schizophrenia. Proceedings of the National Academy of Sciences, 98(20), 11650–11655. https://doi.org/10.1073/pnas.201243998

Uhlhaas, P. J. (2013). Dysconnectivity, large-scale networks and neuronal dynamics in schizophrenia. Curr. Opin. Neurobiol., 23(2), 283–290. https://doi.org/10.1016/j.conb.2012.11.004

Yang, G. J., Murray, J. D., Repovs, G., Cole, M. W., Savic, A., Glasser, M. F., … Anticevic, A. (2014). Altered global brain signal in schizophrenia. Proc. Natl. Acad. Sci. U. S. A., 111(20), 7438–7443. https://doi.org/10.1073/pnas.1405289111