Transcript PSYC 342: Psychopharmacology

PSYC 342: Psychopharmacology
ANTIPSYCHOTIC MEDICATIONS
Primary Indication for Use:
Schizophrenia
Positive symptoms *
Delusions
Hallucinations
Functional Impairments
Work/school
Interpersonal relationships
Self-care
Cognitive deficits *
Attention
Memory
Verbal fluency
Executive function
(eg, abstraction)
Disorganization
Speech
Behavior
Negative symptoms *
Anhedonia
Affective flattening
Avolition
Social withdrawal
Alogia
Mood symptoms
Depression/Anxiety
Aggression/Hostility
Suicidality
DSM IV-TR Diagnostic Criteria
2 or more of the following for most of 1 month:
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Delusions
Hallucinations
Disorganized speech
Grossly disorganized or catatonic behavior
Negative symptoms
• Social/occupational dysfunction
• Duration of at least 6 months
• Not schizoaffective disorder or a mood disorder with
psychotic features
• Not due to substance abuse or a general medical
disorder
What, then, is PSYCHOSIS?
• Generally equated with positive symptoms
and disorganized or bizarre speech/behavior
• Impaired “reality testing”
• A syndrome present in many illnesses
– remove known cause or treat underlying illness
– treat symptomatically with antipsychotic
medications
Other Uses for Antipsychotics
• Schizoaffective disorder, bipolar disorder,
delusional disorder
• Off-label use for Tourette’s, autism spectrum
disorders, to augment treatment in depression
and OCD, dementia, aggression in children
• Medical treatment of nausea, hiccups
A bit more terminology…..
….before we blast off.
Many names….
Not all the same thing…..
Antipsychotics
- neuroleptic
- typical and atypical
- first gen, second gen, third gen
- phenothiazine, thioxanthene, butyrophenone
- low, med, and hi potency (1st gens)
- chemical and trade names
- chlorpromazine/thorazine; olanzapine/zyprexa
An Historical Timeline
• The state of affairs prior to the 1950s
- available treatments very ineffective
• Early 1950s experimental use of
chlorpromazine (thorazine)
• Once broadly introduced, institutions
emptied out (* but a couple of caveats)
• First generation (typical) antipsychotics
developed.
• Second generation begins with clozapine (1989)
A “Typical” (1st Gen) Timeline
FDA approval
1953
1958
1958
1959
1959
1967
1967
1970
1975
1977
1984
Generic Name
chlorpromazine
trifluoperazine
perphenazine
fluphenazine
thioridazine
haloperidol
thiothixene
mesoridazine
loxapine
molidone
pimozide
Brand Name
(Thorazine)
(Stelazine)
(Trilafon)
(Prolixin)
(Mellaril)
(Haldol)
(Navane)
(Serentil)
(Loxitane)
(Moban)
(Orap)
Efficacy of Typical Antipsychotics
Mechanism of Action:
Dopamine D2 receptor antagonist
Regions affected by D2 blockade
• Mesolimbic (midbrain – limbic) and
mesocortical (midbrain – forebrain) pathways
– Emotional, cognitive regulation and integration
• Nigrostriatal Pathway
– Basal ganglia – movement
• Hypothalamus-pituitary
– Hormones, motivation, regulatory processes
• Brain stem
– Chemoreceptor trigger zone (compazine)
– Descending RAS (reticular activating system)
Dopamine related side effects profile
• Extrapyramidal side effects (EPS)
– Extrapyramidal movement system/basal ganglia
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Drug induced Parkinson’s (aka “Thorazine shuffle”)
Acute dystonias
Akathesia
Tardive dyskinesia (sensitization, upregulation?)
– Hypothalamic pituitary
– Neuroleptic malignant syndrome (high fever, sweating, unstable
blood pressure, stupor, muscular rigidity, and autonomic
dysfunction). Aggressive medical care needed.
– Heat regulation and susceptibility to heat stroke
– Increased prolactin
– Sexual side effects
Other Mechanism of Action
Table 4: Clinical Potency and Receptor Affinity for
Typical Antipsychotic Agents
Receptor type
Dopamine D1
Dopamine D2
Norephinephrine
Acetylcholine
Serotonin
Histamine
From Baldesarrini, 1985
r with Potency
.41
.94
.24 (hypotension, sedation)
- .74 (anticholinergic effects)
.32
-.44 (sedation)
Anticholinergic effects
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Memory deficits, clouded cognition
Urinary retention, constipation
Dry mouth
Blurred vision
Tachycardia
Limitations of D2 Blockers
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“The Law of Thirds”
Treatment resistant cases
Lack of improvement of negative symptoms
EPS side effects
Next Gen #1 - Clozapine
• Introduction and withdrawal in 1970s Europe
– Agranulocytosis
• Reintroduction in US
– Works in some (30-60%) of treatment resistant
patients
– Does not produce EPS
– Improve affect, reduce suicidality
– Agranulocyctosis reversible if detected and drug
discontinued (testing protocol – weekly, monthly)
What’s Atypical about Clozapine?
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NOT a strong D2 blocker (relatively speaking)
Antagonizes other dopamine receptors
Antagonizes 5-HT receptors
Antagonizes histimine, muscarinic Ach,
adrenergic NE
The Atypical Boom
FDA approval
1990
1994
1996
1997
2001
2002
2009
2009
Generic Name
clozapine
risperidone
olanzapine
quetiapine
ziprasidone
aripiprazole
iloperidone
asenapine
Brand Name
(Clozaril)
(Risperdal)
(Zyprexa)
(Seroquel)
(Geodon)
(Abilify)
(Fanapt)
(Saphris)
A small sample of Next Gens
• Search to produce clozapine-like drug without
agranulocytosis
• Prototype: Risperidone (Risperdal)
– Dual action – block D2 and 5-HT2 receptors
– Other 5-HT/D2 combos
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Olanzapine (Zyprexa)
Sertindole (Serlect)
Quetiapine (Seroquel)
Ziprasidone (Geodon)
Strengths and Weaknesses of 2nd Gens
• Able to dissociate clinical effects from EPS side
effects
– But for some, this is dose dependent
• Able to dissociate clinical effects from
agranylocytosis
– No need for WBC monitoring
• Have become wildly popular. Off label use,
especially in young and old, has expanded.
– Raises serious concerns
Strengths and Weaknesses of 2nd Gens
• Expansion to vulnerable populations REAL
concern.
• Initial promise not entirely fulfilled
– Note CATIE and Cutlass studies reported in text
• Claims for superior efficacy over 1st gens (for increased
tolerability, superior performance with negative
symptoms and in treatment refractory) not entirely
supported.
• Tolerability - similarly lousy compliance rates
• Trade-off in side effects profiles
2nd Gen Side Effects
• Metabolic syndrome
– Weight gain
– Blood sugar dysregulation
• Increase risk of developing type 2 diabetes
• Rapid and independent of weight gain
• Increased risk of cardiac problems
– Stroke risk in dementia patients
– Electrical activity of the heart (sudden cardiac
death)
3rd Gens
• Aripiprazole (Abilify)
– 5-HT2 antagonist
– Partial agonist at D2 and 5-HT1a
• D2 effects at low and high intrinsic dopamine levels
• Antidepressant effects, especially when combined with true
antidepressants
• Amisulpride (Solian)
– D2 and D3 blocker, but selectively in limbic regions
(not basal ganglia)
– Blocks dopamine autoreceptors (increase DA release)
Next: Theories of Schizophrenia
• Neurochemical Models
– Dopamine Hypothesis
– Glutamate Hypothesis
• Etiology
– Structural anomalies
– Heredity
– Development
• Experimental Research Models