1 in 100 people have had a schizophrenia episode. more than 2 1 in 100 people have had a schizophrenia episode... more than 2.2 million Americans. Previously- talked about 1/3 rule 1/3 take meds and get better; 1/3 take med but have ups and downs; 1/3 medication does little to help NEW MEDS PROBABLY HAVE CHANGED THESE NUMBERS!!

Slight diversion – how to study whether genetics plays a role in a disorder? twin studies look at monozygotic (1 egg) twins – 99% genes in common vs dyzgotic twins – 50% genes in common

Other ways to look at role of genetics Adoption studies allows you to look at role of environment vs genes

Adoption Studies – 2 potential scenarios biological parent (shares 50% genes) adoptive parent (shares env) child has schizophrenia normal home increased incidence of schizophrenia

Adoption Studies – 2 potential scenarios biological parent (shares 50% genes) adoptive parent (shares env) child normal home has schizophrenia increased incidence of schizophrenia

Symptoms of schizophrenia positive and negative symptoms positive symptoms – things that you can see; hallucinations, delusions, etc negative symptoms – things that are absent social withdrawal

The Way We Used to Think About Schizophrenia 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

Recent History in Pharmacotherapy of Schizophrenia First drugs to treat schizophrenia appeared in early 1950’s – major impact! called traditional neuroleptics, antipsychotics treat the positive symptoms Now – atypical neuroleptics – 1989 – 1999 treat positive and negative symptoms

Recent txt history 1950’s – chlorpromazine (Thorazine) and haloperidol (Haldol) still the most widely used and cheapest way to treat positive symptoms Other Uses for chlorpromazine nausea and vomiting, chronic hiccups, severe itching, manage psychotic component in acute mania, to treat alcohol hallucinosis

What is the main mechanism of action? 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

Evidence for the DA Theory for Schizophrenia drugs that block DA; drugs that increase DA activity l-dopa used to treat Parkinsons Disease potential side effect: amphetamine and cocaine acute psychosis

So where are the DA pathways in the brain? mesolimbic DA pathway – important for reward and probably some of the positive symptoms associated with schizophrenia nigrostriatal DA pathway – important for movement (pathway for Parkinsons Disease)

So what are some of the side effects with antipsychotic drugs? a lot of problems related to movement

Parkinson like symptoms brought on by medication ~ 20% characteristics: rigidity, tremor, difficulty initiating movement, flat affect dystonia – spastic contractions of discrete muscle groups ~ 10% occurs most commonly in neck, eyes and torso; causes great distress

akathisia- complain of an inner sensation of restlessness and an irresistible urge to move various parts of body (often seen as pacing and inability to sit still) 20 – 25% of patients show it frequent cause of noncompliance

tardive dyskinesia probably most serious of the movement disorders; involuntary movement disorder caused by sustained exposure to antipsychotic medication most commonly affects oral facial region – so tongue protrusions, lip smacking, neck jerking, etc until recently considered a permanent effect

Is it only DA that is affected by these drugs? NO! – these drugs have effects on multiple other neurotransmitters that also have significant side effects

1 in 3 patients who start an antipsychotic will either switch medications or discontinue their medication within a year. Why do they discontinue? At least 1/3 appear to discontinue because of the side effects of the medication.

Sedation- most common single side effect of antipsychotic medication Common side effects Sedation- most common single side effect of antipsychotic medication often most pronounced early in treatment variety of adverse effects, can occur in 10 – 50% of treated patients some patients experience problems with thermoregulation weight gain: up to 40% treated patients gain significant weight

atypical neuroleptics first atypical neuroleptic was clozapine people who had not been able to leave hospital for 25 years were suddenly better!

atypical neuroleptics first atypical neuroleptic was clozapine effective in proportion of patients that were unresponsive to previous medication

atypical neuroleptics first atypical neuroleptic was clozapine effective in proportion of patients that were unresponsive to previous medication reduced negative symptoms

atypical neuroleptics first atypical neuroleptic was clozapine effective in proportion of patients that were unresponsive to previous medication reduced negative symptoms reduced tardive dyskinesias

atypical neuroleptics 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)

consequence Initially, clozapine cost 36,000/year. now off patent required contract with nurses that would take weekly blood tests subsequent costs ~ 12,000/year now off patent

Since clozapine 5 new atypicals on the market – the most recent in 2002; one still in clinical trials none are as effective as clozapine for treating tardive dyskinesias all expensive

What is different about these atypicals? 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

atypical neuroleptics clozapine – Clozaril – 1989 – generic 1998 risperidone – Risperdal - 1994 olanzapine – Zyprexa - 1996 quetiapine – Seroquel - 1999 ziprasidone – Geodon - aripiprazole (Abilify)- approved 11/2002 $13.00/pill? iloperidone (Zomaril) Novartis – phase III program including those with schizoaffective and comorbid polysubstance use action on all monoaminergic receptor systems