1. PSYC 342: Psychopharmacology
ANTIPSYCHOTIC MEDICATIONS

2. Primary Indication for Use: Schizophrenia
Positive symptoms * Delusions Hallucinations
Negative symptoms * Anhedonia
Affective flattening Avolition Social withdrawal
Alogia
Functional Impairments Work/school Interpersonal relationships Self-care
Cognitive deficits * Attention Memory
Verbal fluency Executive function (eg, abstraction)
Mood symptoms Depression/Anxiety Aggression/Hostility
Suicidality
Disorganization
Speech
Behavior

3. DSM IV-TR Diagnostic Criteria
2 or more of the following for most of 1 month:
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

4. 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

5. 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

6. 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

7. 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)

8. A “Typical” (1st Gen) Timeline
FDA approval Generic Name Brand Name 1953 chlorpromazine (Thorazine) 1958 trifluoperazine (Stelazine) 1958 perphenazine (Trilafon) 1959 fluphenazine (Prolixin) 1959 thioridazine (Mellaril) 1967 haloperidol (Haldol) 1967 thiothixene (Navane) 1970 mesoridazine (Serentil) 1975 loxapine (Loxitane) 1977 molidone (Moban) 1984 pimozide (Orap)

9. Efficacy of Typical Antipsychotics

10. Mechanism of Action: Dopamine D2 receptor antagonist

11. 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)

13. Dopamine related side effects profile
Extrapyramidal side effects (EPS)
Extrapyramidal movement system/basal ganglia
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

14. Other Mechanism of Action
Table 4: Clinical Potency and Receptor Affinity for Typical Antipsychotic Agents
Receptor type              r with Potency
      Dopamine  D1                 .41
      Dopamine D2                  .94 
    Norephinephrine             (hypotension, sedation)
      Acetylcholine                 (anticholinergic effects)
      Serotonin                         .32
      Histamine                       -.44  (sedation)
From Baldesarrini, 1985

15. Anticholinergic effects
Memory deficits, clouded cognition
Urinary retention, constipation
Dry mouth
Blurred vision
Tachycardia

16. Limitations of D2 Blockers
“The Law of Thirds”
Treatment resistant cases
Lack of improvement of negative symptoms
EPS side effects

18. 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)

19. What’s Atypical about Clozapine?
NOT a strong D2 blocker (relatively speaking)
Antagonizes other dopamine receptors
Antagonizes 5-HT receptors
Antagonizes histimine, muscarinic Ach, adrenergic NE

20. The Atypical Boom
FDA approval Generic Name Brand Name 1990 clozapine (Clozaril) 1994 risperidone (Risperdal) 1996 olanzapine (Zyprexa) 1997 quetiapine (Seroquel) 2001 ziprasidone (Geodon) 2002 aripiprazole (Abilify) 2009 iloperidone (Fanapt) 2009 asenapine (Saphris)

21. 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
Olanzapine (Zyprexa)
Sertindole (Serlect)
Quetiapine (Seroquel)
Ziprasidone (Geodon)

22. 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

23. 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

24. 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)

25. 3rd Gens Aripiprazole (Abilify) Amisulpride (Solian) 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)

26. Next: Theories of Schizophrenia
Neurochemical Models
Dopamine Hypothesis
Glutamate Hypothesis
Etiology
Structural anomalies
Heredity
Development
Experimental Research Models