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PSYC 342: Psychopharmacology

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Presentation on theme: "PSYC 342: Psychopharmacology"— Presentation transcript:

1 PSYC 342: Psychopharmacology

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

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