textbook ch.17 (pt1 - schizophrenia)

% of ppl w/ schizophrenia in the world

1%

what does the word ‘schizophrenia’ mean? what did the man who invented it mean?

‘split mind’ - but it doesn’t imply a split/multiple personality but instead a break/split from reality

3 categories of symptoms

positive, negative, cognitive

provide examples of positive symptoms

disordered thoughts - disorganized, irrational thinking

delusions - beliefs contrary to facts

• delusions of persecution - belief that others are plotting again oneself

• delusion of grandeur - false beliefs in ones power and importance

• delusion of control - person believes they’re controlled by others (via radar or something in their brain)

hallucinations - perceptions of stimuli that aren’t actually present

• 70% auditory, 25% visual, 10% other senses

provide examples of negative symptoms

flattened emotional response, poverty of speech, lack of initiative and persistence, anhedonia, social withdrawal

provide examples of cognitive symptoms

difficulty in sustaining attention, low psychomotor speed, deficits in learning and memory, poor abstract thinking, poor problem solving

how does schizophrenia typically progress in terms of symptoms?

symptoms of depression, then social withdrawal (negative), and cognitive difficulties, and then positive symptoms

does carrying the “schizophrenia genes” mean you will have schizophrenia?

no, because you may have the genes but be in an environment where the schizophrenia is never triggered

Gottesman and Bertelsen (1989) twin study suggested this

monozygotic twins, placenta/chorion and concordance rate

while monozygotic twins are genetically identical, that may not share the same prenatal environment - they may have their own placenta’s depending on when the blastocyst splits

monochorionic twins - higher concordance rate (60%)

dichorionic twins - lower concordance rate (10.7%)

mutations (DISC1)

DISC1 - disrupted in schizophrenia 1

gene involved in lots of developmental processes

increases risk of schizophrenia by factor of 50

this mutation also appears in other mental disorders (bipolar, mdd, autism)

parental age

older dads = higher chance of schizo…

errors in DNA sequence caused by increasing cell divisions

epigenetics

ig it also plays a factor?

chromosomes wrap around histones, methylation to histones = tighter = region can’t be translated

environmental factors: season of birth and viruses/infections

season of birth - birth in late winter/early spring (febraury-may) = higher chance

• why - maybe viral epidemics (pregnant women more likely to contract a viral illness the previous autumn, impacts fetuses development)

infection in 2nd trimester = higher chance

maternal infections w/ 2 other infections = higher chance

infections later in life = ligher chance

immunomodulatory drugs (like aspirin) show promise for reducing symptoms of schizophrenia??

environmental factors: vitamin d

vitamin d plays important role in brain development

a vitamin d deficiency, especially in colder parts of the world w/ less sunlight and for darker skinned people = increases chance of schizo

lowest levels of vitamin d found in babies born in fall, winter, early spring - connects with seasonality effect

environmental factors: population density

likelihood of developing schizo is 3x higher for ppl living in the middle of large cities - viruses more readily transmitted in high density areas

the longer someone lives in a city the more likely they’ll develop schizophrenia

so population density impacts pregnant women, and also just regular people who may be genetically susceptible

environmental factors: prenatal malnutrition and stress

study found increase risk for women were were pregnancy during the hunger winter (famine)

why - abrupt buildup of toxins in brain of developing fetuses when mother suddenly begins eating normal diet

underweight mothers, and low-birth-weight babies = higher risk

prenatal stress (like exposure to terrorist attack) = higher risk

environmental factors: substance abuse

maternal tobacco use (including second hand) = higher risk

excessive maternal alcohol use (over 120mL/week) = higher risk

repeated marijuana use in teenage years = higher risk

causal relationship not yet determined (individuals at risk of developing schizo are more likely to use marijuana)

THC worsens positive, negative and cognitive symptoms

what are some environmental PROTECTIVE factors?

avoiding exposure to toxins and infectious agents, nutritional stability during pregnancy, vitamin B and D supplements when needed, avoidance of prenatal and early life stressors, avoidance of early life use of cannabis, supportive social/family environments

obstetric complications and schizophrenia

evidence indicates that obstetric complications can also contribute to schizophrenia

complications like inadequate blood supply to uterus/placenta can impact brain development - contributing to enlarged ventricles (associated w/ schizophrenia)

behavioral anomalies

negative affect in facial expressions, abnormal movements, deficient psychomotor functioning

physical anomalies

minor physical anomalies: high-steepled palate, especially wide-set or narrow-set eyes, partial webbing of two middle toes, etc

brain anomalies

enlarged lateral ventricles (twice the size) caused by loss of brain tissue (especially in frontal and temporal cortex), smaller hippocampus, faster loss of cerebral cortex tissue (D1PFC region), overall loss in brain volume

is schizophrenia is neurodegenerative disease?

no but some argue it is; saying the progressive nature of the disorder can be linked with brain loss overtime

others argues that it’s a sudden, rapid loss of brain volume; that disease progression begins prenatally, lies dormant for a few years until puberty, then something triggers degeneration and thats when symptoms begin to show

what’s the first drug to effectively treat schizophrenia? dopamine agonist or antagonist?

chlorpromazine - changed patient’s attitude, make hallucinations and delusions go away or become less severe (relieving positive symptoms)

chlorpromazine and other similar drugs are D2/D3 dopamine receptor blockers - dopamine antagonist

what drugs produce positive symptoms of schizophrenia? are they dopamine agonists or antagonists?

dopamine agonists - amphetamine, cocaine, methylphenidate, L-DOPA

what pathway do researchers believe is most likely involved in the positive symptoms? what does this pathway do and how does that relate to schizophrenia?

mesolimbic pathway; involved in reinforcing behavior

if reinforcement mechanisms were activated at inappropriate times, then inappropriate behaviors (like delusional thoughts) might be reinforced

what about the amygdala? how does it connect to schizophrenia?

amygdala (processes threat and emotional salience) is often hyperactive/dysregulated in schizophrenia - can cause lead to paranoia and misidentifying emotions of others

abnormalities in dopamine transmission - is the more dopamine synthesis or more dopamine receptors

more dopamine synthesis and release in the striatum; leading to positive symptoms

ppl with schizophrenia may have some more dopamine receptors but its likely that isn’t the cause of the disorder

side effects of long-term drug treatment of schizophrenia

many side effects are similar to symptoms of Parkinson’s - slowness in movement, lack of facial expression, general weakness (mostly temporary)

1/3 of patients developed tardive dyskinesia which appears opposite of Parkinson’s - repeated jitters and movements - caused by supersensitivity of the D2 receptors (when they’re inhibited for too long, they overcompensate for the effects of the drugs) ,

what is hypofrontality? how does it relate to the negative and positive symptoms?

hypofrontality - decreased activity of the frontal lobe (D1PFC region in particular)

believed to cause the negative symptoms and may also relate to the positive symptoms; D1PFC exerts inhibitory control over the mesolimbic pathways, but in hypofrontality, this control is diminished - contributing to increased activity of this pathway and positive symptoms

how does glutamate dysfunction contribute to schizophrenia? (NMDA receptor, hypofrontality, etc.)

NMDA receptor (where glutamate binds) hypofunction → ↓ glutamate signaling in d1PFC → hypofrontality (cognitive deficits, and negative symptoms; also indirectly disinhibits striatal dopamine → positive symptoms)

coke and amphetamines trigger positive symptoms, what symptoms do PCP and ketamine trigger?

positive, negative and cognitive symptoms

why do PCP and ketamine produce schizophrenia-like symptoms? what’s their connection to glutamate?

they’re glutamate antagonists!

they block NMDA receptors, reducing glutamate signaling in the PFC → hypofrontality and disrupted D1 dopamine signaling, causing cognitive, negative, and positive symptom

why is clozapine effective when other antipsychotics fail?

it decreases release of dopamine by the mesolimbic pathway- reduced positive symptoms

also increases release of dopamine in the prefrontal cortex (mesocortical pathway) - reduced negative and cognitive symptoms

why is ketamine used as an anesthetic in children but not adults? what about PCP as an anesthetic?

because it causes episodes of psychosis in adults when they wake up after surgery - why? - we don’t know…

PCP is too toxic to be used on humans, but can be used as an anesthetic in rats and similarly it causes psychosis only after rat reaches puberty…

connection between ketamine/PCP as an anesthetic and onset of schizophrenia symptoms

schizophrenia symptoms also emerge after puberty so whatever developmental change occurs after puberty makes the brain susceptible to the psychotic effects of NMDA antagonists and may also relate to the emergence of symptoms of schizophrenia

what are the two main hypotheses for the primary cause of schizophrenia?

• Pyramidal neuron (prefrontal cortex) hypothesis:

  • DISC1 suppression in PFC pyramidal neurons → normal pre-puberty, post-puberty dendritic & mesocortical dopamine abnormalities → hypofrontality & behavioral deficits → suggests PFC pyramidal neuron abnormalities drive schizophrenia.

• Striatal dopamine hypothesis:

  • ↑ D2 receptors in striatum → disrupts inhibitory GABAergic signaling in D1-PFC → hypofrontality & schizophrenia-like behaviors → suggests striatal dopamine dysfunction drives schizophrenia.

atypical antipsychotics - aripiprazole how does it work?

acts as a partial agonist at dopamine receptors; serves as an antagonist in the mesolimbic system where tm dopamine is present and serves as an agonist in regions like the prefrontal cortex where too little dopamine is present

accounts for all three categories of symptoms