Schizophrenia is characterized by positive and negative symptoms. Positive symptoms include hallucinations while negative symptoms involve a lack of normal behaviors. Traditional neuroleptics effectively treat positive symptoms by blocking dopamine (DA) receptors but have no effect on negative symptoms. Atypical neuroleptics like clozapine are more effective at treating both positive and negative symptoms due to their action on multiple receptor types including serotonin and acetylcholine receptors in addition to DA receptors. However, atypical neuroleptics also carry risks like significant weight gain and metabolic side effects that must be weighed against their benefits.

1. schizophrenia
• characterized by positive and negative
symptoms
– positive symptoms – those that can be
observed; ex. hallucinations
– negative symptoms – absence of normal
behaviors – lack of affect – “anhedonia”,

2. treatment options
• positive symptoms
– majority of traditional “neuroleptics” reduce positive
symptoms
• negative symptoms
– majority of traditional “neuroleptics” have no effect on
negative symptoms
– originally thought that negative symptoms were
simply an indicator of brain damage
– new thought: atypical neuroleptics also appear to
reduce negative symptoms

3. traditional neuroleptics
• traditional neuroleptics – chlorpromazine
(Thorazine), haloperidol (Haldol)
– ability to block “positive” symptoms – linked to
high well the drug binds to and blocks D2
receptors
• DA theory for schizophrenia
– too much DA activity responsible for +
symptoms
– reduce DA activity, reduce positive symptoms

4. DA pathways
• mesolimbic –
– emotion, reward, may be responsible for +
symptoms
• nigrostriatal –
– motor movement, extrapyramidal motor
system
• degeneration associated with Parkinsons disease

5. problems with traditional
neuroleptics
• parkinson like side effects
– early on; see symptoms in virtually all schizophrenics that were
similar to PD
• extrapyramidal motor side effects
– motor induced akinesias – paucity of movement
– akathesia – uncontrolled restlessness, constant compulsive
movements
– tardive dyskinesia –
• avoid it by periodically changing meds; atypical neuroleptics?
• relatively safe- therapeutic index is as high as 1000
• malignant neuroleptic syndrome
• reduces sexual interest and ability

6. atypical neuroleptics
• clozapine (Clozaril)
– works on positive and negative symptoms
– reduced motor side effects
– more selective at binding to DA R (and does
not bind as potently)
– also blocks ACh, histamine, 5HT

7. problems with clozapine
• risk of agranulocytosis (1%)
• requires weekly blood testing
• only used for treatment resistant
schizophrenia or those nontolerant to
conventional antipsychotics (ie motor side
effects)

8. some other atypicals
• risperidone (Risperdal)
• olanzapine (Zyprexa)
– potential increased risk for diabetes
• quietiapine (Seroquel)
• aripiprazole (Abilify)

9. other atypical neuroleptics
• do not produce agranulocytosis
• block 5HT2 receptors and ACh receptors
• less motor side effects than traditional neuroleptics (?)
• appear able to reduce negative symptoms;
• appear to be somewhat less sedating (?)
• at lower risk for producing tardive dyskinesia (?)
• improvement can be more rapid
• not all are generic yet
reduction in
noncompliance

10. negative side of the atypicals
• weight gain-
20 – 40 lbs average but can be much more!
• still have anticholinergic side effects
– dry mouth, memory problems, urinary
retention
• tachycardia
• direct costs can be up to 100X greater
than typical neuroleptics

12. tolerance, dependence, wd, animal
self administration?
• no (except to parkinson like symptoms
maybe), no, no and no