Schizophrenia and Antipsychotic Treatment

Stacy Weinberg

3 April 2007

What is it?•It is a severe, chronic, disabling brain disease

•Considered to have biological origins but exact unknown

•1% of population affected

•“Schizophrenia” – split mind

•Multiple personality disorder is not schizophrenia

•Psychosis is more accurate

•Severe mental illness where patient loses contact with reality

•People have problems thinking and feeling but are aware of their surroundings

Types1. Catatonic Type

• Either in position or speech (imitating others)• Very rare

2. Disorganized Type• Disturbance in behavior, speech, and thought• Flat affect, eccentric

3. Paranoid Type• Delusions and auditory hallucinations• Cognitive functioning remains intact

4. Residual Type• Have been previously diagnosed but no longer

show prominent symptoms; still have other symptoms

5. Undifferentiated Type

Positive Symptoms

• Disturbances of thought processes

• Delusions

• Hallucinations

• Erratic/extreme emotions

• Very slow or fast movement, catatonia

• Behavioral changes

Negative Symptoms

• Lack of interest/enjoyment in activities

• Low energy/motivation

• Blank facial expression, less facial variability

• Inability to make or keep friends

• Difficulty initiating activities

• Social isolation

Causes - Dopamine Hypothesis

• Genetic aspect

• Most think it involves dopamine:– Elevation of D2 monomers, decrease of

dimers– Increased release of dopamine

• 2x higher• When given amphetamine, 2x more

dopamine is released than control

Other Hypotheses

• Dopamine hypothesis not agreed on by everyone

• Some think excitatory amino acids like glutamate could play a role– One type of glutamate receptor, NMDA:

NMDA antagonists (ex ketamine) can induce psychotic symptoms in non-schizophrenic patients

– Found increase of NMDA receptors in postmortem studies of schizophrenic brains

Types of Drug Treatment

1. Typical Antipsychotics• Dopamine antagonists

2. Atypical Antipsychotics• 5-hydroxytryptamine effect, also effect

dopamine

3. Combination Drugs

Typical

• Tend to produce Extrapyramidal side effects:– Parkinsonism – tremors, rigidity, slowness of

movement, temporary paralysis– Dystonia – involuntary muscle contractions– Akathisia – inability to resist urge to move– Tardive dyskinesia – involuntary movements

of the mouth, lips, and tongue • Chewing, puckering, grimacing, etc.

Typical - Phenothiazines

• Dopamine D2 receptor antagonists

• Chlorpromazine first developed from promethazine, first tricyclic antihistamine

ChlorpromazinePromethazine Trifluoperazine

Haloperidol

• Butyrophenone

• Used in 1970s almost exclusively

• No anticholinergic effects – therefore used in patients with delirium

Atypicals

• Atypicals do not induce EPSE

• Block D2 receptors and 5-HT seratonin receptors (decreases EPSE)

• As opposed to typicals, these are more loosely bound to D2 receptors– Easier dissociation– Shown that higher occupation of D2 receptors

by drug, higher incidence of EPSE

5-HT seratonin receptors

• Blocking 5-HT seratonin receptors decreases negative symptoms and EPSE– Mechanism is unknown– Seratonin inhibits dopamine release– Positive symptoms associated with

hyperdopaminergic condition in limbic lobe – more D2 receptors here, so D2 blocking prevails

– Negative symptoms associated with hypodopaminergic condition in frontal lobe – more 5-HT receptors here, so seratonin inhibits dopamine release – stabilizes dopamine level

Clozapine

• First atypical (1990)• Most dangerous atypical: risk of

agranulocytosis (severe decrease in WBC count)

• Most effective in reducing EPSE, also in reducing negative symptoms– Increases Fos-positive neurons in the

prefrontal cortex (shown to affect negative symptoms)

Risperidone

• Low doses needed

• Predominantly blocks D2, then 5-HT– Does not exhibit multireceptor action

• Lacks anticholinergic activity – makes it better for youth, elderly

• Problem – increases prolactin levels (shouldn’t give to people with breast cancer)

Olanzapine

• Zyprexa is number one antipsychotic in sales (Eli Lilly)

• Exhibits multireceptor action

• Good for controlling mood symptoms

• Available in a wafer

• Problems: Sedation and

weight gain

Combinations

• Example is Symbyax – Combination of olanzapine and fluoxetine

(Prozac)– Can also treat bipolar disorder

• Combination of ziprasidone and clozapine– Can be used to combat treatment resistance

• Combination of aripriprazole and clozapine