2017-11-08 12:29:21

Today's Topics

  • Schizophrenia

Schizophrenia

Simulating the Experience

Overview

  • Lifetime prevalence ~ 1/100
  • ~1/3 chronic & severe
  • Onset post-puberty, early adulthood
  • Pervasive disturbance in mood, thinking, movement, action, memory, perception

"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

Biological bases

  • Genetic disposition
  • Brain abnormalities
  • Developmental origins

Genetic disposition

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 glutatmate receptor)

(Johnson et al. 2017)

Ventricles larger, esp in males

Cause or effect?

Enlargement precedes diagnosis?

Hip and amygdala smaller

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

(Jiao et al. 2017)

  • Dentate gyrus (DG) in hippocampus critical for spatial coding, learning and memory, and 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 disruption in white matter connectivity

White matter loss over age

Dysconnectivity in cortical networks

Inconsistent connectivity findings (Fornito and 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 and 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

  • Urban vs. rural living
  • Exposure to infection in utero, other birth complications

(Levine et al. 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 of psychiatric research

The future of psychiatric research

Next time…

  • Affective disorders

References

Debost, Jean-Christophe, Liselotte Petersen, Jakob Grove, Anne Hedemand, Ali Khashan, Tine Henriksen, Ole Mors, et al. 2015. “Investigating Interactions Between Early Life Stress and Two Single Nucleotide Polymorphisms in HSD11B2 on the Risk of Schizophrenia.” Psychoneuroendocrinology 60 (October): 18–27. doi:10.1016/j.psyneuen.2015.05.013.

Erp, T G M van, D P Hibar, J M Rasmussen, D C Glahn, G D Pearlson, O A Andreassen, I Agartz, et al. 2015. “Subcortical Brain Volume Abnormalities in 2028 Individuals with Schizophrenia and 2540 Healthy Controls via the ENIGMA Consortium.” Mol. Psychiatry, June. doi:10.1038/mp.2015.63.

Fornito, Alex, and Edward T Bullmore. 2015. “Reconciling Abnormalities of Brain Network Structure and Function in Schizophrenia.” Curr. Opin. Neurobiol. 30 (February): 44–50. doi:10.1016/j.conb.2014.08.006.

Jiao, Hui-Feng, Xiang-Dong Sun, Ryan Bates, Lei Xiong, Lei Zhang, Fang Liu, Lei Li, et al. 2017. “Transmembrane Protein 108 Is Required for Glutamatergic Transmission in Dentate Gyrus.” Proceedings of the National Academy of Sciences 114 (5): 1177–82. doi:10.1073/pnas.1618213114.

Johnson, Emma C, Richard Border, Whitney E Melroy-Greif, Christiaan A de Leeuw, Marissa A Ehringer, and Matthew C Keller. 2017. “No Evidence That Schizophrenia Candidate Genes Are More Associated with Schizophrenia Than Noncandidate Genes.” Biol. Psychiatry 82 (10): 702–8. doi:10.1016/j.biopsych.2017.06.033.

Kelly, S, N Jahanshad, A Zalesky, P Kochunov, I Agartz, C Alloza, O A Andreassen, et al. 2017. “Widespread White Matter Microstructural Differences in Schizophrenia Across 4322 Individuals: Results from the ENIGMA Schizophrenia DTI Working Group.” Mol. Psychiatry, October. doi:10.1038/mp.2017.170.

Kempton, Matthew J, Daniel Stahl, Steven C R Williams, and Lynn E DeLisi. 2010. “Progressive Lateral Ventricular Enlargement in Schizophrenia: A Meta-Analysis of Longitudinal MRI Studies.” Schizophr. Res. 120 (1-3): 54–62. doi:10.1016/j.schres.2010.03.036.

Kochunov, Peter, Habib Ganjgahi, Anderson Winkler, Sinead Kelly, Dinesh K Shukla, Xiaoming Du, Neda Jahanshad, et al. 2016. “Heterochronicity of White Matter Development and Aging Explains Regional Patient Control Differences in Schizophrenia.” Hum. Brain Mapp. 37 (12): 4673–88. doi:10.1002/hbm.23336.

Levine, Stephen Z., Itzhak Levav, Inna Pugachova, Rinat Yoffe, and Yifat Becher. 2016. “Transgenerational Effects of Genocide Exposure on the Risk and Course of Schizophrenia: A Population-Based Study.” Schizophrenia Research 176 (2): 540–45. doi:10.1016/j.schres.2016.06.019.

Seutin, Vincent. 2005. “Dopaminergic Neurones: Much More Than Dopamine?” Br. J. Pharmacol. 146 (2): 167–69. doi:10.1038/sj.bjp.0706328.

Thompson, Paul M., Christine Vidal, Jay N. Giedd, Peter Gochman, Jonathan Blumenthal, Robert Nicolson, Arthur W. Toga, and Judith L. Rapoport. 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): 11650–5. doi:10.1073/pnas.201243998.

Uhlhaas, Peter J. 2013. “Dysconnectivity, Large-Scale Networks and Neuronal Dynamics in Schizophrenia.” Curr. Opin. Neurobiol. 23 (2): 283–90. doi:10.1016/j.conb.2012.11.004.

Yang, Genevieve J, John D Murray, Grega Repovs, Michael W Cole, Aleksandar Savic, Matthew F Glasser, Christopher Pittenger, et al. 2014. “Altered Global Brain Signal in Schizophrenia.” Proc. Natl. Acad. Sci. U. S. A. 111 (20): 7438–43. doi:10.1073/pnas.1405289111.