Antipsychotics I

Brian J. Piper, Ph.D., M.S.piperbj@husson.edu

February 4, 2013

Goals• Pharmacy students

should:– be familiar with the

symptoms & health consequences of schizophrenia

– be able to describe the mechanism(s) of action and adverse effects of first-generation antipsychotics

Schizophrenia

The Greek translation is schizein “split” and phren “mind” which refers to a split from reality. A group of severe disorders characterized by atypical:

1. Cognition2. Behavior 3. Emotions NOT Multiple Personality

Disorder

Symptoms of SchizophreniaPositive symptoms: the presence of inappropriate behaviors

delusions: thoughts

hallucinations: auditory >>> visual > other

disorganized talking: “word salad”

movements

Negative symptoms: the absence of appropriate behaviors

flat affect: joy, anger, disgust

anhedonia

catatonia: waxy flexibility

Example Patient

Gerald (upto 2:30): http://www.youtube.com/watch?v=gGnl8dqEoPQ

Delusions of grandeur inappropriate beliefs about one’s self-worth or specialpowers

Epidemiology of Schizophrenia

Frequency: 0.7%Sex: Males > Females (1.4:1) in # and severityLow SES (downward drift)Rule of thirdsComorbidity with depression & smoking

Sources: Anna K. Kring

History of Antipsychotics• 1953: an antihistamine agent (cholpromazine) is found to

improve psychosis in schizophrenics• 1960-1970: identification of D2 blockade as the key mechanism,

development of these first-generation of antipsychotic agents

Dopamine System I• nigrostriatal: substania nigra (soma) to striatum (axons)

Stahl, S. (2008). Essential Psychopharmacology, p. 330.

Antipsychotics & Tardive Dyskinesia

Chronic blockade of D2 receptors leadsthem to up-regulate.

This may cause involuntary movements.

Example: 4:20 to 5:50: http://www.youtube.com/watch?v=QYYx1mZDpPw

tardive: slow or belated onsetdyskinesia: presence of involuntary movements, tongue thrusts, lip smacking, eye blinking

Potentially permanent!

TD = Extrapyramidal Symptoms (Long-Term)

Brodal (2010). The central nervous system. p. 83.

Extrapyramidal Symptoms (Short-term)• Pseudo-Parkinsonism:

– tremor– rigidity– bradykinesia

• dystonia: involuntary muscle spasms– torticollis: abnormal head or neck position

• akathisia: severe sensation of restlessness, strong desire to move

Excellent Examples (0:30- 4:50-9:15): http://www.youtube.com/watch?v=WAg2iLEWVh0

Dopamine Inhibits Acetylcholine

Stahl, S. (2008). Essential Psychopharmacology, p. 338.

D2 Inhibition & Increased ACh

Stahl, S. (2008). Essential Psychopharmacology, p. 339.

Solution: Anti-cholinergics

Stahl, S. (2008). Essential Psychopharmacology, p. 339.

Dopamine Inhibits Prolactin

Stahl, S. (2008). Essential Psychopharmacology, p. 334.

Consequencesamenorrheagalactorhea↓ sex interestgynecomastia

Dopamine & Mood

• Dopamine projections to nucleus accumbens• Increasing dopamine increases reward• anti-psychotics block this pathway

Non-Selectivity of FGA

Stahl, S. (2008). Essential Psychopharmacology, p. 338, 340.

Haloperidol

• MOA: D2 antagonist, α1 antagonist• Indications: acute psychosis/schizophrenia • Adverse Effects: extrapyramidal symptoms

(EPS), hypotension

Summary: Pros & Cons• FGAs have strong efficacy against + symptoms.• FGAs either do not help – symptoms or exacerbate them.• The primary concern with FGAs is long-term development of

tardive dyskinesia although acute EPS impair the quality of life of schizophrenics.

Stahl, S. (2008). Essential Psychopharmacology, p. 369.

Terminology

• Neuroleptic = major tranquilizer = antipsychotic

• First Generation Antipsychotic = Typical = Conventional

Reduced Lifespan (N = 5,036,662)

Male Life Expectancy

MaleYears Lost

FemaleLifeExpectancy

FemaleYears Lost

All (Psychiatric History - )

76.5 NA 80.9 NA

Schizophrenia 57.8 18.7 64.6 16.3

Bipolar 62.9 13.6 68.8 12.1

Laursen (2011). Schizophrenia Research, 131, 101-104.

Contributing Factorssuicide, accident, homicides, self-care (diet/smoking), metabolic (?)