Psychiatric Disorders & Diversity Notes

What Causes Psychiatric Conditions?

• DNA

Heritability and Concordance Ratios

• Identical Twins (Monozygotic): 100% shared genome

• Fraternal Twins (Dizygotic): 50% shared genome

• If identical twins have a higher probability of both having a condition compared to fraternal twins, it indicates a genetic component to the condition.

DNA Structure

• Double helix structure

• Rosalind Franklin's X-ray diffraction photograph of DNA

The Double Helix

• Genome consists of sequences of four letters: A, T, C, G

• A pairs with T, C pairs with G

• Double helix unwraps, and a protein copies the strand by stringing together paired letters

The Genetic Code

• Genes instruct the cell how to make proteins using 3-letter codons

• Gene = string of codons that tells the cell how to string together amino acids to produce proteins (e.g., neurotransmitter receptors)

• Polymorphism may alter the amino acid sequence of a protein, potentially changing its function

Genetic "Polymorphisms"

• Genetic polymorphisms occur when different people have different letters at a position in the genome.

• Arise from copying "errors" = mutations

• Humans differ by an average of 3 million polymorphisms (10% of the genome)

• Most mutations are neutral, but some can change protein function for better or worse (usually worse)

Identifying Bad Polymorphisms

• Statistical association between genetic polymorphism and disorder:

  • If you have a polymorphism in a given gene, what is the probability you have the disorder?

• Across the population, probabilities for almost all genes are low.

• Many hyped findings have turned out to be false.

Heritability

• Heritability estimates from family/twin studies vs. molecular estimates

• "Missing heritability": Concordance indicates a genetic basis, but specific genes can't be found.

• Examples:

  • Schizophrenia

  • Bipolar disorder

  • ASD (Autism Spectrum Disorder)

  • PTSD (Post-Traumatic Stress Disorder)

  • Major depression

  • Anxiety disorders

Autism Spectrum Disorder

• Social and language impairment

• Narrow range of activities and interests

• More common in men than women

• Sometimes associated with special talents ("autistic savant")

Brain Size in Autism

• Early in development, the brains of autistic children are larger.

• Later in development, the brains of non-autistic children "catch up".

Autism: An Epidemic?

• ASD prevalence per 1000 8-year-old children:

  • Data from NC-ADDM (Autism and Developmental Disabilities Monitoring Network)

  • Trend shows an increase in prevalence over the years (2002-2010)

• Prevalence of Autism and Mental Retardation

  • US Department of Education (USDE) data

  • Increase in autism prevalence, decrease in mental retardation prevalence

Environmental Risk Factors for Autism

• Prenatal infection

• Prenatal nutrition (Folate, vitamin D)

• Obstetric complications

• Advanced paternal age (increased chances of mutations in sperm?)

• Migrant status

• Season of birth (6% increased risk of autism)

• Urban vs. rural environment

Caesarian Section?

• Meta-analysis of studies on the association between Caesarian section and Autistic Spectrum Disorder

• Forest plot of adjusted estimates

• Odds Ratio: $1.23$ (95% CI: $1.07, 1.40$)

• Test for overall effect: $Z = 3.02$ ($P = 0.003$)

• Heterogeneity: $Tau^2 = 0.03$, $Chi^2 = 35.37$, df = 12 ($P = 0.0004$), $I^2 = 66$

Vaccines

• Donald Trump's tweet about vaccines and autism

• Studies on the association between vaccines and ASD

  • Odds ratios and 95% confidence intervals for various studies

  • Conclusion: VACCINATE YOUR KIDS!!!!!

Sources of Genetic Mutations in Autism

• Unknown (~77%)

• Mendelian Disorders and Other Mutations (~15%)

• Rare and De Novo Mutations (~5%)

• Chromosome Abnormalities (~3%)

• Source: Guo H, Hu Z, Zhao J, et. al. Genetics of Autism Spectrum Disorders. J Cent South Univ (Med Sci). 2011, 36 (8):703-711.

Autism Genetics

• Some autism cases are caused by known mutations

• Idiopathic cases: Genetics unknown

• High-risk mutation cases: A specific gene is found to have a polymorphism that greatly increases probability of autism

Functions of Autism Risk Genes

• Cell communication

• Synaptic transmission

• Cell junction

• TGFB pathway

• Neurodegeneration

• Transcriptional regulation

How Can So Many Genes Be Involved?

• Polygenic model:

  • Particular polymorphisms in many genes must be present to increase risk

  • Caused by common polymorphisms found in many people

  • Difficult to predict who will develop the condition

  • Difficult to model in animals

• Monogenic model:

  • A polymorphism in any one of many genes increases risk

  • Caused by rare polymorphisms, each found in very few people

  • Easier to predict who will develop the condition

  • Can model in animals

Schizophrenia

• "Positive" symptoms:

  • Delusions

  • Hallucinations

• "Negative" symptoms:

  • Depression

  • Motivational impairment

  • Cognitive impairments

Enlarged Ventricles in Schizophrenia

• Enlarged lateral ventricles compared to non-schizophrenic brains

• Transgenic mice expressing the DISC1 mutation associated with schizophrenia also develop enlarged lateral ventricles

Reduction in White Matter Tracts in Schizophrenia

• Examples: Fornix, Arcuate fasciculus, Inferior occipito-frontal fasciculus, Anterior limb of the internal capsule, Superior occipito-frontal fasciculus, Parietal portion of the cingulum bundle

Schizophrenia Drug Development

Sarah Braner, September 27, 2024

• FDA approves Cobenfy, a first-in-class schizophrenia drug

• Drugs for schizophrenia have been notoriously difficult to develop

• KarXT, a drug to treat schizophrenia, consists of xanomeline and trospium.

Acetylcholine in the Brain

• Cholinergic neurons

• Act on learning, arousal, and reward

• Damaged in Alzheimer’s disease

Acetylcholine Receptors

• Postsynaptic receptors:

  • Nicotinic receptors (ionotropic)

    • Agonist = nicotine

    • Antagonist = curare (paralyzing poison)

    • 19 different subunit genes, each receptor is a combination of 5 of the subunits

  • Muscarinic receptors (metabotropic)

    • Agonist = muscarine from poison mushrooms

    • Antagonist = atropine from the belladonna lily

    • 5 subtypes

Acetylcholine Receptors and Schizophrenia Drug

• Xanomeline – Muscarinic agonist (acts in brain and brainstem)

• Trospium chloride – Muscarinic antagonist (acts in brainstem); blocks side effects

Phase 3 Clinical Trial

• Placebo – negative control, everything the same but the actual drug presence

• "Double-blind" – Clinicians and patients don’t know drug vs. placebo

• Randomized – Patients are randomly assigned to drug vs. placebo groups

Phase 3 Clinical Trial - CONSORT Flow Diagram

• Details on patient assignment, exclusion, and completion of the EMERGENT-3 Trial

• Safety and efficacy analysis included patients who received at least 1 dose of the trial drug.

Cobenfy/KarXT Clinical Trial Results

• Significantly improves positive and negative symptoms of Schizophrenia compared to placebo

Bipolar Disorder

• Symptoms:

  • Depression

  • Mania: overactivity, talkativeness, grandiosity

• Women = men

• Ventricles enlarged, as in Schizophrenia

Concordance rates: Schizophrenia vs Bipolar disorder

• Monozygotic vs Dizygotic twins concordance comparison between Schizophrenia and Bipolar disorder

Depression

• Symptoms:

  • Unhappy mood

  • Reduced energy

  • Learned helplessness (giving up)

  • Anhedonia (lack of pleasure)

• Women > Men

Anhedonia in the Brain

• Depressed brains give weaker responses to reward

• Ventral Striatum BOLD signal is reduced in depressed individuals

Genetics of Depression

• Concordance ratios indicate a strong genetic component:

  • 50% in identical twins

  • 20% in fraternal twins

• Still no genes strongly implicated!

Approaches to Genetics

• Candidate gene approach:

  • Test a hypothesis about a specific gene you think might be involved

  • Limitation: Requires prior knowledge to make an informed guess

• Genome-wide association study:

  • Test a hypothesis across the whole genome, across the population

  • Measure statistical association between a given polymorphism in a given gene and the condition

  • Requires a lot of genome sequencing

Genome-Wide Association Study (GWAS) for Major Depression

• The hypothesis-free approach

• Statistical threshold corrected for multiple comparisons (p < 10^{-6})

• Many gene variants are significantly associated with depression

• Effects are very small (Variance explained and odds ratio)

• Not predictive enough for individuals

Animal Models of Depression

• Using restraint stress to induce "depression" in mice

• Labeling neurons during female exposure

• Testing for "depression"

Understanding the Neural Code of Stress to Control Anhedonia

• Behavioral measures distinguish "susceptible" and "resilient" mice

• Fraction of selective neurons in BLA and vCA1

• Rew del (Reward delivery)

Decoding Intention Using Hidden States

• Hidden Markov Model (HMM) to infer firing rate and hidden states

• SVM switch decoding accuracy

Chemogenetic Activation of vCA1→BLA Pathway

• AAV-retroCre and AAV-DIO-hM3Dq-mCherry

• CSDS + Social interaction test (2 days post-defeat SPT + recording in susceptible mice)

Treating Depression

• Electroconvulsive therapy:

  • Very effective

  • Works right away

• SSRIs:

  • Very effective in a subset of patients

  • Takes weeks for effects to be seen

• Ketamine:

  • Works right away

  • Found that a ketamine metabolite mediates the effect

• Cognitive-behavioral therapy:

  • As effective as SSRIs

  • Most effective when combined with medicine

SSRIs

• SSRI inhibits the serotonin reuptake transporter

Ketamine Mechanism of Action

• Ketamine acts via the lateral habenula (LHb)

• Ketamine LHb excites inhibitory GABA neurons, which inhibit DA neurons, which may implement the prediction.

• Dopamine = actual reward – expected reward

• Ketamine affects signaling in the LHb, may be the reason for therapeutic effectiveness!

• At the molecular level, ketamine is thought to act through NMDA receptors

BDNF and TrkB

• BDNF: Brain-Derived Neurotrophic Factor

• TrkB: Tyrosine receptor kinase B

• Mainly thought to be important for development

• A lot of evidence implicates this system in depression, but has been thought to play a secondary role to serotonin (SSRIs) and NMDA receptors (ketamine)

TrkB as Target for Antidepressants

• Prozac, ketamine, and other antidepressants all bind to a particular part of TrkB

• Mice engineered to have a mutation in this part of the receptor (the protein still works, just doesn’t bind to the drugs anymore) don’t respond to Prozac or Ketamine treatment

• Mice with no serotonin transporter gene (SERT KO) still respond!!!!!!!!!

• Conclusion: SERT KO TrkB mutant

Neurodegenerative Disorders

• Conditions that cause visualizable brain damage

  • Alzheimer’s disease (AD):

    • Memory

    • Cognitive problems

  • Parkinson’s:

    • Movement

    • Perceptual learning

  • Frontotemporal dementia:

    • Cognitive, emotional problems

Alzheimer's Disease

• Alzheimer's is a neurodegenerative disorder often attributed to amyloid plaques

Amyloid Plaques

• Amyloid plaques are accumulations of a fragment of a protein called APP

• APP fragments accumulate and form amyloid plaques

• These are thought to be neurotoxic

Inflations in Alzheimer’s Research

• First publication on amyloid pathology based on 1 case

• National Institute on Aging broadened the definition

• Diagnostic criteria modified to include amyloid

Mouse Models of AD

• Aẞ plaque deposition

• Aẞ40: Normal life span, not aggressive

• Aẞ42: Neuroinflammation, AB/astrocyte/microglia, memory impairment

• Immunological therapies can clear plaques and rescue memory in mice, BUT…

Failed Clinical Trials

• Failed clinical trials cost $1 billion</p></li><li><p>table detailing compounds, companies, targets, therapies and status</p></li></ul><h3 id="601205ca-2dda-4649-a109-38777198d56f" data-toc-id="601205ca-2dda-4649-a109-38777198d56f" collapsed="false" seolevelmigrated="true">Approaches to Genetics</h3><ul><li><p>Candidate gene approach:</p><ul><li><p>Test a hypothesis about a specific gene you think might be involved</p></li><li><p>Limitation: Requires prior knowledge to make an informed guess</p></li></ul></li><li><p>Genome-wide association study:</p><ul><li><p>Test a hypothesis across the whole genome, across the population</p></li><li><p>Measure statistical association between a given polymorphism in a given gene and the condition</p></li><li><p>Requires a lot of genome sequencing</p></li></ul></li></ul><h3 id="9f024eaf-a48a-4a30-aa5e-3dd09f708919" data-toc-id="9f024eaf-a48a-4a30-aa5e-3dd09f708919" collapsed="false" seolevelmigrated="true">GWAS of AD</h3><ul><li><p>APOE has p-values less than$10^{-100}!!

• Amyloid-related genes are not significantly associated

APOE GWAS of AD

• Odds ratios >10 in most of these populations

• APOE Odds ratio relative to ε3/ε3$genotype</p></li></ul><h3 id="797ad249-d542-4954-be1e-2fa2c730841b" data-toc-id="797ad249-d542-4954-be1e-2fa2c730841b" collapsed="false" seolevelmigrated="true">Apolipoprotein E</h3><ul><li><p>APOE transports free fatty acids from astrocytes to neurons</p></li><li><p>Also involved in microglial function</p></li><li><p>Lipid metabolism is implicated by other evidence in AD</p></li></ul><h3 id="ec54d6f8-5054-4866-b358-5d3034dbc54d" data-toc-id="ec54d6f8-5054-4866-b358-5d3034dbc54d" collapsed="false" seolevelmigrated="true">Skepticism</h3><ul><li><p>Neuroscience has learned a lot, but it seems like there is vastly more we don’t know, and too many examples where we delude ourselves to think that we do.</p></li><li><p>Learning that we are wrong about things is not bad, it’s progress!</p></li></ul><h3 id="e9214912-4216-4d8e-b9f1-920744e82786" data-toc-id="e9214912-4216-4d8e-b9f1-920744e82786" collapsed="false" seolevelmigrated="true">Advertisement</h3><ul><li><p>Senses in motion - PSY 407/507 WINTER ($25!!)