Schizophrenia

schizophrenia

a chronic psychosis; a form of the psychiatric diseases known as schizophrenia spectrum and other psychotic disorders

Positive symptoms dominant (healthy people don’t have; schizophrenics do):

• delusions and hallucinations, disorganized speech and thinking, bizarre behavior, perception disturbances, and inappropriate emotions

  • Patients tend to be an older onset and respond well to antipsychotic medication

Negative symptoms dominant (healthy people have; schizophrenics don’t have):

reduced speech, flat affect, loss of motivation, social withdrawal, anhedonia, lack of feeling, blunted emotions

cognitive symptoms

impaired working memory and learning, executive function, etc

Bran function abnormalities:

• Reduced function of PFC (hypofrontality) – PET scans show less blood flow to the frontal cortex when performing cognitive tasks

• Some brain areas show more activation, other brain areas show less, than in controls

Genetic vulnerability may … the probability that events during perinatal brain development will contribute to risk

increase

DA imbalance hypothesis

• Symptoms are due to reduced DA function in mesocortical neurons, along with excess DA function in mesolimbic neurons

  • Negative symptoms and impaired thinking are explained by impaired PFC function (low mesocortical activity)

  • Positive symptoms improved by reducing DA function in mesolimbic neurons

The neurodevelopmental model

• This model integrates anatomical and neurochemical evidence

• Negative and cognitive symptoms are associated with reduced frontal lobe function

• Excessive mesolimbic DA activity following early mesocortical cell loss can explain the positive symptoms

• Early mesocoritcol cell loss due to genetics or environmental events that alter brain development is followed by loss of inhibitory control of mesolimbic cells and onset of positive symptoms

Hypoglutamate hypothesis of schizophrenia

• Inadequate glutamate may explain the apparent increase in mesolimbic DA and decrease in PFC.

• Glutamatergic neurons influence both mesocortical and mesolimbic DA pathways

  • Reducing glutamate reduces the DA released into the prefrontal cortex

Class (pre-90s, “typical”):

• phenothiazines and butyrophenones

  • Modeled on D2 antagonism

  • EPS/TD

Second generation (post-90s; “atypical”)

• clozapine, risperidone, and aripiprazole

  • Produce fewer side effects

  • Modeled on 5-HT/D2 antagonism

  • Weight gain, sedation, diabetes

Classic neuroleptics: effectiveness

• Antipsychotic drugs are prescribed as maintenance therapy to prevent relapse

• Unpleasant side effects cause many patients to stop treatment

• Psychotherapy and group therapy are important additions

Four DA pathways in the brain are important for understanding drug action:

• Mesolimbic pathway: affects positive symptoms

• Mesocortical pathway: cognitive and negative symptoms

• Nigrostriatal pathway: motor side effects

• Tuberohypophyseal pathway: regulates pituitary hormone secretion; neuroendocrine effects

Parkinsonian symptoms

 involve the extrapyramidal motor system (EPS)

tardive dyskinesia (TD)

a neurological disorder characterized by involuntary movements of the face and jaw

Neuroleptic malignant syndrome (NMS

• life-threatening

  • Fever, rigidity, altered consciousness, and ANS instability (including rapid heart rate and fluctuations in blood pressure).

Atypical antipsychotics are distinctive in several ways

Atypical or second-generation antipsychotics reduce positive symptoms without causing significant EPS and other side effects

Broad-spectrum antipsychotics

block other receptor types in addition to D2 receptors

block other receptor types in addition to D2 receptors

Enhancing ACh with subtype-selective nicotinic antagonists or positive allosteric modulators (PAMs)