Schizophrenia Symptoms

-- Symptoms most often begin during the late teenage years and early twenties, but there are sex
differences—after age 36, more women than men experience their first episode <-- hormonal contribution
-- testosterone levels massively increase at around the age of 16 and stay elevated until around 35 that may
lead to symptoms, as opposed to females that have a decrease in estrogen during onset of menopause
that may lead to the symptoms
-- Positive symptoms: Hallucinations, holding unrealistic ideas and beliefs, delusions of persecution,
delusions that thoughts are broadcast or imposed from an outside source, communication is
confused/illogical, speech vague/repetitive or shift from one subject to another, exhibit involuntary
movements (decrease in activity in the indirect pathway of BG circuit) <-- respond well to conventional
antipsychotics that block D2 receptors (neuroleptics like haloperidol)
-- Negative symptoms: decline in normal function; reduced speech, flattened affect, loss of motivation,
social withdrawal, anhedonia, apathy (treating positive symptoms exacerbate the negative symptoms)
-- Cognitive symptoms: impaired working memory, executive functioning, and attention (based on PFC
circuit dysfunction)
-- Negative and cognitive symptoms are the most resistant to antipsychotic drugs

Etiology of Schizophrenia
-- Cerebral atrophy and enlargement of fluid-filled ventricles following cell loss
-- Hippocampal cells of patients with schizophrenia are more disorganized than those of healthy subjects
-- Selected cortical layers are atrophied, particularly the pyramidal neurons in the PFC (similar to
depression) that leads to the cognitive symptoms
-- Many brain areas show shrinking of dendritic trees that would lead to connectivity failures
-- In control, there’s higher levels of BDNF mRNA compared to schizophrenia where there’s lower levels
-- In patients with schizophrenia, there’s also lower levels of the TrkB receptor (metabotropic) that BDNF
binds to
-- Wisconsin Card Sorting Test (WCST): organize cards based on what the researcher says (shape, colour,
etc) --> rules will change so the person has to change strategies (requires PFC flexibility)
-- Imaging studies show less blood flow to the frontal cortex when people with schizophrenia are
performing these cognitive tasks
-- In controls, there is also higher levels of PFC activity at rest as opposed to schizophrenia

Neurochemical Model of Schizophrenia

-- Dopamine hypothesis: excess DA function results in positive symptoms of schizophrenia
-- Suggested by the fact that amphetamine can produce a psychotic reaction in healthy individuals that can
be reversed by D2 receptor antagonists (haloperidol)
-- Strong correlation between strength of D2 receptor blockade and reduction of schizophrenic symptoms;
post-mortem analysis shows increase in D2 receptor density in patients diagnosed with schizophrenia
-- Cortical pyramidal cells have descending glutamatergic projections onto the GABA interneurons of the
VTA, LC, dorsal raphe, which keeps these DA/5-HT neurons under inhibitory control and prevent NT release
-- Also have descending glutamatergic projections directly on the VTA (DA), LC (NE), dorsal raphe (5-HT),
which directly activate them to increase action potentials and release their NT
-- Atrophy in the cortical pyramidal neurons results in dysfunction of the brake system, losing the ability to
activate the GABA interneurons and inhibitory influence so the only thing active is the accelerating system
resulting in an increased release of DA, 5-HT, NE
-- Higher D2 receptor occupancy rate --> more extrapyramidal side effects (EPS) similar to PD, like tardive
dyskinesia --> part of the EPS is the BG circuit
-- Indirect pathway works to inhibit movement, and in SCZ there's reduced activity resulting in involuntary
movement; DA binidng to D2 receptors in striatum turns of indirect pathway so D2 receptor blockade will
prevent dopamine from turning off indirect pathway, meaning it is on and inhibiting movement --> PD
-- Clozapine (atypical antipsychotic) has low D2 receptor occupancy but high 5-HT2A receptor occupancy,
and does not produce clinically relevant EPS

Hallucinations and Serotonin Function

-- 5-HT2A receptors (Gq) --> increases internal concentration of Ca+ by releasing Ca+ from SER (IP3)
-- Atypical antipsychotics are antagonists of the 2A receptor, decreasing hallucinations, while hallucinogens
are agonists of the 2A receptor, producing hallucinations
-- The RTN neurons have 5-HT2A receptors, so 5-HT binding causes increase in EPSPs thus increasing GABA
output and hyperpolarizing the thalamic relay circuits resulting in burst firing <-- thalamic relay circuits are
meant to match the signals from the afferent sensory projections, but burst firing causes them to not
produce the approperiately matched signals
-- Glutamatergic pyramidal neurons atrophied in the PFC --> less activation of the GABAergic interneurons so
more activation of neurons in the dorsal raphe resulting in more 5-HT release on the RTN
-- There are 5-HT2A receptors in the cortex and hippocampus; 5-HT binding to 5-HT2A receptor leads to
increase in BDNF that will nourish neurons
-- 5-HT2A blocking (atypical antipsychotic) is counterproductive to reversing the cortical atrophy --> not
allowing the cortex to regenerate and rebuild the circuits so not allowing the “brake” to come back naturally
since it is just treating the outcome (not treating the source of the issue)