positive and negative symptoms positive symptoms – ◦ things that you can see; hallucinations, delusions, etc negative symptoms – things that are absent ◦ social withdrawal
Schizophrenia is clearly a brain disease with a genetic basis
twin studies ◦ look at monozygotic (1 egg) twins – 99% genes in common vs dyzgotic twins – 50% genes in common ◦ look at concordance rates – proportion of cases in which both twins have the disorder
family studies ◦ allows you to look at increased concordance rates (particularly in first-degree relatives)
Adoption studies ◦ allows you to look at role of environment vs genes
role of stress? ◦ stress does not cause schizophrenia BUT viral exposure?
role of stress? ◦ stress does not cause schizophrenia BUT viral exposure? fetal insult? ◦ hypoxia, etc
positive symptoms – could be treated medically negative symptoms – would not respond to drugs but rather was brain damage as a consequence of whatever schizophrenia did to the brain
1950’s - first drugs to treat schizophrenia appeared called traditional neuroleptics, antipsychotics ◦ treat the positive symptoms Now – atypical neuroleptics – 1989 – 1999 ◦ treat positive and negative symptoms
1950’s – chlorpromazine (Thorazine) and haloperidol (Haldol) ◦ cheapest way to treat positive symptoms, still widely used many other uses for chlorpromazine ◦ nausea and vomiting, chronic hiccups, severe itching, manage psychotic component in acute mania, to treat alcohol hallucinosis
Blocking DA receptors Resulted in the DA theory for schizophrenia D2 receptor subtype important ◦ how well the drug binds to D2 receptor is clearly linked to reduction in positive symptoms
drugs that block DA; drugs that increase DA activity l-dopa ◦ used to treat Parkinsons Disease ◦ potential side effect: amphetamine and cocaine ◦ acute psychosis ephedrine
mesolimbic DA pathway – emotion nigrostriatal DA pathway –movement mesocortical DA pathway – ◦ higher cognitive function tuberofundibular DA pathway – ◦ within the hypothalamus – controls the release of certain hormones
a lot of problems related to movement ◦ parkinson like symptoms ◦ spastic muscle contractions in head and neck ◦ restlessness, constant movement ◦ tardive dyskinesia
NO! – these drugs have effects on multiple other neurotransmitters that also have significant side effects block ACh as one ◦ memory deficits, dry mouth, urinary retention,
first atypical neuroleptic was clozapine ◦ effective in proportion of patients that were unresponsive to previous medication
first atypical neuroleptic was clozapine people who had not been able to leave hospital for 25 years were suddenly better!
first atypical neuroleptic was clozapine ◦ effective in proportion of patients that were unresponsive to previous medication ◦ reduced negative symptoms ◦ reduced tardive dyskinesias ◦ risky side effects – agranulocytosis (potentially lethal drop in white blood cells ~ 1% of people on drug)
Initially, clozapine cost 36,000/year. ◦ required contract with nurses that would take weekly blood tests ◦ subsequent costs ~ 12,000/year now off patent ◦ reduced requirements by the FDA
at least 7 new atypicals on the market – the most recent in 2003; one still in clinical trials none are as effective as clozapine for treating tardive dyskinesias but none associated with the potentially lethal side effect all expensive
good question – some say the drugs bind to D2 receptors but also to a certain type of 5HT receptors some say these drugs do not bind quite as well to D2 receptors as the more traditional ones; but binds to other types of DA receptors this is a huge step forward for treating schizophrenia
From the basic research phase to completion of clinical trials.