22/24: Schizophrenia

mental disorder susceptibility genes

→ gene varients associated in with an ↑ risk of psychiatric disorders

• Often regulate brain development and neural plasticity

• Do not cause significant damage alone; usually have effects as unfortunate but significant combinations

• Do not directly cause illness;

• Rather takes a collection of compromises to the evolved interactions (fixated genes), hindering proper, normal, and robust brain function

Variants’ variation:

• Overall, patients with mental illnesses tend to have more brain peculiarities relative to an average person

  • Moreover, between other patients, brain peculiarities differ/aren’t consistent

schizophrenia susceptibility genes

Genetic pre-disposition to schizophrenia:

• < 1% in general population

  • ↑ if a person has a collection of gene variants that ↑ likelihood

• Identical twin concordance finding - if 1 twin has schizophrenia, there is a 50% chance the other twin will have it too

  • Environmental risk factors were found to be generally uninvolved

What has been driving schizophrenic genes’ survival in the human gene pool?

• Theories suggest that there could be some advantage to reproductive success since the disorder could make people more intelligent???

• No other offsetting benefits have been discovered

Schizophrenia’s genetic risk of comorbidity:

• Common gene variants associated with developing schizophrenia are also associated with vulnerability to developing mood and anxiety disorders such as depression, bipolar disorder (BD), autism spectrum disorder, obsessive-compulsive disorder (OCD), attention deficit hyperactivity disorder (ADHD), anorexia nervosa (eating disorder)

diagnostic categories

→ complexity proves that mental disorders aren’t discrete or unitary due to too much…

• Heterogeneity (diseases' criteria overlaps) within-

• Comorbidity (diseases’ prevalences overlap) across-

• Continuity with normality

• Were made out of good faith to describe clusters of symptoms, or researchers’ best attempts to reflect historical conventions while reflecting some now-known biological differences

• Somewhat helpful for treatment decisions, but not solely relied on because it is increasingly clear that symptoms’ causes are near impossible to isolate

neurodevelopmental robustness

ex.Bilateral symmetry

• Premise: The 2 sides of bilateral organisms develop independently from the same set of genomic instructions

• Question: Could this be an indicator of developmental stability? How is it possible that symmetry can withstand environmental variation and molecular noise?

• Findings:

  • Symmetrical bodies presumably reflect high-quality genetic instructions

    • Correlates with ↑ intelligence, physical attractiveness, and physical health

  • Conversely, asymmetry may suggest underlying obscurities in genetic instructions

mutation-selection balance

→ despite gene elimination caused by natural selection, new mutations arise with every generation

• This may explain the prevalence of (mental) illnesses across the human genome

• 20,000 protein-encoding genes in the human genome — inevitably, some gene mutations can transend elimination processes across generations transcend

  • Half express in the brain at some point in life

• Though recall that only significant combinations of gene mutations put a strain on brain development and function (not some genes alone)

do i need to get DNA tested?

nah.

• Identifying personal genome hasn’t been particularly helpful with regard to prevention or treatment (at least not yet)

• The issue is that aren’t really preventative measures for psychiatric diseases (I mean trauma can only be avoided so much, and these things just happen as they do)

• Generally speaking, take care of your body and brain and hopefully you’ll be fine

direction of psychiatric biomedical treatments

• Gene-editing technologies

  • For living humans

  • To use part of in vitro fertilization

• Pharmacological treatments

  • Producing drugs that directly target intracellular signaling cascades rather than ligand signalling

• Deep brain stimulation

  • Closed-loop stimulation strategies involving penetrating brain regions with metal wire conductors to manipulate neural circuitry

schizophrenia

→ psychiatric disorder characterized by social withdrawal, disorganized thinking, abnormal speech, and an inability to understand reality

Prevalence: ~1% general population

Prognosis: Symptoms usually begin gradually in young adulthood and never resolve (although 20% is said to eventually, quite well)

• 30-50% of patients don’t believe they have an illness / nor do they comply with recommended treatment

Treatment: No cure

• Mainly medication coupled with psychological and social support addresses the symptoms (especially the positive type)

schizophrenic symptomology

3 types:

1. Negative → characterized by an absence of behaviours

   • Social withdrawal, muteness, reduced emotionality and motivation, etc.

   • Accounts for most long-term disability and poor functional outcomes

   • Studies potentially attribute effects to abnormal prefrontal cortex activity

2. Cognitive → disorganized and irrational thinking

   • Deficits in learning and memory, poor problem-solving, etc.

3. Positive → characterized by the presence of delusions (beliefs in contradictions to reality) and hallucinations (perception of stimuli that aren’t present)

   • Related to the dopamine hypothesis

   • Some effects sought-after in recreational drugs

• The 3 types of symptoms usually present gradually in the above sequence, over the years

• Neurological symptoms may present throughout these symptoms’ phases as well

schizophrenic heritability

Baseline rate: Estimates say 80%

• Measures the fraction of phenotype (expression) variability that can be attributed to genotypical (gene variant) variability

  • “What proportion of variation in a given trait observed within a population is NOT explained by random chance or environmental factors?“

• 5% attribute to rare gene copy number variations (trisomies, monosomies), which often result in comorbid risks

Concordance rates:

• 50% if both parents have it; 13% if 1 parent has it

• 8% if 1 sibling has it

• 50% if identical twin has it

seasonality effect

→ disproportionately large number of schizophrenic patients are born within February to May — which demonstrates the effect of environmental factors on schizophrenic incidence

• May be related to how infectious diseases spread easily in dense cities and cold weather (such that people tend to spend time indoors)

Summary of environmental factors that can affect development in utero:

• Season (surrounding birth)

• Viral epidemics

• Population density

• Parental substance abuse

identical twin theory for schizophrenia

→ supports concordance finding + the importance of environmental factors (in this case, the prenatal environment)

• Monochorionic (identical) twins share 1 placenta, unlike dichorionic (fraternal) twins who each have their own

evidence for abnormal brain development

• Usually schizophrenic symptoms appear after childhood, but there is some evidence from patients’ childhoods relating it to abnormal prenatal development

Children who eventually develop schizophrenia…

• Display less sociable behaviour and are deficient in psychomotor functioning as kids

• Have minor anatomical abnormalities, like partial webbing of middle toes or a high-steepled palate

dopamine hypothesis

→ excessive dopamine D2 receptor activity, particularly in the nucleus accumbens (striatum), underlies positive symptoms (delusions, hallucinations) of schizophrenia

Relief:

• Dopamine receptor antagonists → reduce positive symptoms, but not negative symptoms (withdrawn behaviours)

  • Antipsychotics & neuroleptics → treatments that block dopamine D2 receptors to relieve positive symptoms of schizophrenia

Recreation:

• Dopamine receptor agonists → can elicit hedonic aspects of the positive symptoms of schizophrenia in non-patients

hypofrontality

→ decreased activity of the frontal lobes, particularly the dorsolateral prefrontal cortex, which may relate to the hypoactivity (↓) of local dopamine D1 receptors

• Consequence of negative symptoms of schizophrenia

• Summarized finding: Schizophrenia may be associated with too little dopamine in the prefrontal cortex and too much elsewhere

atypical antipsychotics

→ 2nd generation antipsychotics that aim to reduce both the positive AND negative symptoms of schizophrenia

• Clozapine → antagonist to dopamine D2 and serotonin 2A receptors, simultaneously ↓ dopamine levels in the striatum while ↑ levels in the prefrontal cortex

  • Found in monkeys

• Aripiprazole → partial agonist to dopamine D2/D3 and serotonin 1A receptors, also simultaneously ↓ dopamine levels in the striatum while ↑ levels in the prefrontal cortex

  • a.k.a Abilify, Aristada

partial agonist

→ drugs with a very high affinity for a receptor, but activates it less than the normal ligand does

Simultaneous balancing property:

• ↑ receptor activity in regions with ↓ [ ] of the ligand in question

• ↓ receptor activity in regions with ↑ [ ] of the ligand in question