Schizophrenia 2

Question 1

What is the dopamine hypothesis?

Answer 1

Proposes the schizophrenia is caused by abnormalities in DA functioning in the brain. Overactivity of DA in the mesolimbic system results in the positive symptoms of schizophrenia. Under-activity of DA in the mesocortical system results in the negative and cognitive symptoms of schizophrenia

Question 2

DA agonists indue psychosis - support for the dopamine hypothesis?

Answer 2

DA agonists produce symptoms that resemble the positive symptoms of schizophrenia. These drugs include amphetamine, cocaine, methylphenidate and L-DOPA. The symptoms that they produce can be alleviated with antipsychotic drugs
strengthens the argument that the antipsychotic drugs exert their therapeutic effects by blocking DA receptors.

Question 3

DA agonists - support for the dopamine hypothesis?

Answer 3

Henri Laborit (mid 20thce): French surgeon who discovered that a drug used to prevent surgical shock also reduced anxiety. A related compound called chlorpromazine (CPZ) was developed in 1952 which had dramatic effects on schizophrenia. CPZ is a DA antagonist – first antipsychotic.

Question 4

What are antipsychotic drugs? (support for the dopamine hypothesis)

Answer 4

Since the discovery of CPZ, many drugs have been developed for the treatment of schizophrenia – typical antipsychotics. These drugs eliminate, or at least diminish, the patients’ positive symptoms – although 20-30% do not respond. These drugs have one property in common: They block D2 receptors

Question 5

What are the different kinds of dopamine receptors?

Answer 5

D1-type family (Gs coupled): D1 & D5)

D2-type family (Gi coupled): D2, D3, D4.

Question 6

What is more evidence in support of dopamine’s involvement?

Answer 6

PET study using Iodobenzamine (IBZM), as a radio-tracer. IBZM is a D2 receptor reversible ligand which means that it will compete with DA for binding to that receptor. Measured displacement after treatment with amphetamine treatment in striatum (Abi-Dargham 1998). More displacement of IBZM means more DA activity. More DA activity in striatum correlated with positive symptoms.

Question 7

What are consequences of long-term drug treatment of schizophrenia?

Answer 7

Antipsychotic drugs cause at least some symptoms resembling those in Parkinson’s disease: slowness in movement, lack of facial expression, and general weakness. A more serious side effect occurs which affects ~1/3 of all patients who took the drugs for an extended period: tardive dyskinesia (patients with tardive dyskinesia are unable to stop moving).

Question 8

What are atypical antipsychotics?

Answer 8

Atypical antipsychotics work in treatment-resistant patients. Atypical’s do not have the extra-pyramidal side effects (EPSs) due to the fact that they have lower affinity for the D2 receptor. Improve both positive and negative symptoms of schizophrenia. Also improve the performance in neuropsychological tests which was not the case with typical antipsychotics.

Question 9

What is clozapine?

Answer 9

Clozapine, the first of the atypical antipsychotic drugs (followed by others: risperidone, olanzapine, ziprasidone, and aripiprazole). Has lower affinity for D2 and higher affinity for other DA receptors (D3, D4 and even 5HT). Although it is highly effective it is still not widely used – despite international consensus to use it when other drugs have failed. The only antipsychotic to reduce suicide rates in schizophrenics (13x higher suicide rate than in the general population). Still considered to be tricky due to its side effects: weight gain, sedation, hypersalivation, tachycardia, hypotension, neutropenia etc.

Question 10

What are problems with the dopamine hypothesis?

Answer 10

It explains only a part of schizophrenia (positive symptoms not negative symptoms). Atypical antipsychotic drugs e.g. Clozapine (with weaker anti-dopaminergic activity) are better antipsychotics. Negative symptoms are caused by under-activity inthe mesocortical dopamine pathway - so, reduced dopamine activity is the problem rather than dopamine overactivity.

Question 11

What is the glutamate system?

Answer 11

Major excitatory neurotransmitter in the CNS. Nearly 50% of neurons in the brain are believed to use glutamate as their neurotransmitter. Glutamate is balanced with GABA. Evidence implicates NMDA receptors in schizophrenia.

Question 12

What is an NMDA receptor?

Answer 12

NMDA receptor is an ionotropic receptor. When open it allows calcium influx. Activation can support learning & memory, but too much can be excitotoxic. Mutation of the receptor could cause changes in its functioning: knock-out mice exhibit signs of schizophrenia, mice lacking in GRIN2A subunit behave in a similar way to schizophrenia patients.

Question 13

What is the interaction of NMDA and schizophrenia?

Answer 13

NMDA receptors comprise a critical component of developmental processes which include development of neural pathways, neural migration, neural survival, neural plasticity, neural pruning of cortical connections, ad apoptosis.

Question 14

What is the Glutamate Hypofunctioning Hypothesis (Olney & Farber, 1995)

Answer 14

Schizophrenia is due to NMDA receptor hypofunction which may explain why there are so many treatment-resistant negative symptoms, why the onset is in early adulthood, and why the disorder is associated with structural changes and cognitive deficits.

Question 15

What is evidence for the Glutamate Hypofunctioning Hypothesis?

Answer 15

The drugs Phencyclidine (PCP, also known as “angel dust”) and ketamine (“Special K”), can cause positive, negative, and cognitive symptoms of schizophrenia. Both of them are NMDA receptor antagonists. Glutamate agonists seem to improve both positive and negative symptoms of schizophrenia.

Question 16

Positive and negative symptoms: role of the PFC (support for the glutamate hypofunctioning hypothesis).

Answer 16

The negative and cognitive symptoms produced by ketamine and PCP are apparently caused by a decrease in the metabolic activity of the frontal lobes. Jentsch et al. (1997) administered PCP to monkeys twice a day for two weeks. A week later, tested the animals on a task that involved reaching around a barrier for a piece of food, which is performed poorly by monkeys with lesions of the PFC. Control monkeys performed well, but those treated with PCP showed a severe deficit.

Question 17

What is the hypofunctioning NMDA Receptors Theory?

Answer 17

This theory is more comprehensive and it can explain the positive, negative & cognitive symptoms of schizophrenia. It accounts for the lack of effectiveness of dopamine antagonists in treating schizophrenia. Hypofunctioning NMDA receptors can account for both the excessive dopamine release in the mesolimbic dopamine system as well as the reduced release of dopamine in the prefrontal cortex.

Question 18

What is the Neuroinflammatory hypothesis of schizophrenia?

Answer 18

The brain’s immune cells are hyperactive in people at risk of developing schizophrenia. Many animal studies show a link between pro-inflammatory agents and schizophrenia symptoms. Symptoms are revered with treatment with antipsychotics or antibiotics that reduce microglial activation. Support the evidence for prenatal or perinatal infection and the increased risk for schizophrenia.

Question 19

What is the largest genome-wide analysis of schizophrenia?

Answer 19

Nature (2014) - identified more than 100 genetic regions that contribute to schizophrenia risk. The dopamine-receptor gene, DRD2, is associated with risk of schizophrenia. Most significant association is on chromosome 6, which includes a region containing genes involved in acquired immunity.

Question 20

What is the association between microglial activation and schizophrenia in animal studies?

Answer 20

Microglial activation is not instantaneous in response to infectious agents - grows steadily throughout lifespan. Therefore, a pre/perinatal infection primes microglia, and this priming may interact with cells in the developing nervous system.

Question 21

What are three main findings from animal studies?

Answer 21

1. Most replicated finding is decreased hippocampal neurogenesis in response to microglial activation.
2. Decreased reelin expression in the hippocampus – accompanied by impairments in Working Memory and motor skills (associated with neuronal migration and connectivity during development).
3. Aberrant synapse formation as a result of microglial activation as well as oligodendrocyte loss (myelin) particularly in the frontal cortex, which is reversed by atypical antipsychotics.

Question 22

What is the Estrogen Hypothesis of Schizophrenia?

Answer 22

There are gender differences in schizophrenia in regards to rate and onset of disease, severity & progression of the disease, and response to antipsychotic treatment. Support the hypothesis that sex hormones may also play a role in the aetiology & treatment of schizophrenia. Estrogen seems to play a protective role against the development of schizophrenia (buffer). Women seem to have less severe negative symptoms, later onset (which is linked to better prognosis), and a better response to antipsychotic treatment.