Schizophrenia Treatment: Dopamine, Antipsychotics & Side Effects, Lecture notes of Psychiatry

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Schizophrenia Block

Adapted from the American Society for

Clinical Psychopharmacology

Model Curriculum

Learning Objectives

• Identify major target symptoms of schizophrenia

treatment

• Become familiar with conventional & atypical

antipsychotic medications

• Recognize major side effects of antipsychotic

medications

• Recognize unique features of clozapine & depot

antipsychotics

Dopamine Hypothesis of

Schizophrenia

Dopamine Hypothesis

• Psychotic symptoms can be induced by dopamine

agonists*

• cocaine, amphetamines cause psychosis
• All anti-psychotics are dopamine antagonists
• Normal subjects-10% dopamine receptors occupied at

baseline**

• Schizophrenic subjects-20% dopamine receptors

occupied at baseline**

**Laruelle M, Quart J Nuc Med 1998;42:

Dopamine Receptor Subtypes

D 1 Family

• D 1 and D 5 receptors
• Poor correlation with

antipsychotic activity

• D 1 family may modulate

effects of D 2 family

D 2 Family

• D 2 , D 3 , D 4 receptors
• High correlation with

antipsychotic activity

• D 4 is prominent in limbic

structures, but absent from

extrapyramidal pathways

• Atypical antipsychotics

have high D 4 affinity

Clinical Efficacy and Dopamine D 2 Blockade

Seeman P, Synapse 1987:1:

IC 50

(M)

Average Clinical Dose (mg/d)

10 -

10 -

10 -

1 10 100 1000

Spiroperidol

Benperidol

Trifluperidol Pimozide

Fluphenazine (^) Droperidol

Haloperidol Thiothixene

Moperone

Molindone Prochlorperazine

Thioridazine

Clozapine^ Trazodone Chlorpromazine

Promazine

Trifluperazine

Dopamine and Antipsychotics

• 65% D 2 receptor occupancy is required for efficacy
• 80% D 2 receptor occupancy is correlated with EPS
• How can anti-psychotics hit this therapeutic

window?

• Typical vs. Atypical

Kapur S & Remington G, Biol Psychiatry 2001;50:

General Treatment Course

Onset of effect of Anti-psychotics

• IM: peak plasma level, ~ 30 min
• PO: peak plasma level, ~ 1-4 hrs
• bioavailability IM > PO
  • PO, incomplete GI absorption, 1st pass effect
• 90% protein bound; unbound passes through

blood brain barrier

Dopamine Hypothesis

• Psychotic symptoms can be induced by DA agonists*
  • cocaine, amphetamines cause psychosis
• All anti-psychotics are DA antagonists
• Antipsychotic’s clinical efficacy correlates w/ D 2 blockade*
• Normal subjects-10% DA receptors occupied at baseline**
• Schizophrenic subjects-20% DA receptors occupied at baseline**
• ~30% pts no sig. response to anti-psychotic treatment
• Glutamate system dysfunction also linked to schizophrenia

*Carlsson A, Am J Psychiatry 1978;135:164; Seeman P, Synapse 1987:1:

**Laruelle M, Quart J Nuc Med 1998;42:

Dopamine D 2 Effects

Dopamine pathway

1. Nigrostriatal tract
2. Mesolimbic tract
3. Mesocortical tract
4. Tuberoinfundibular tract

Effects

1.EPS:

Dystonia, parkinsonism, akathisia, Tardive dyskinesia

2. Antipsychotic effect
3. Negative type symptoms?
4. Endocrine changes: Prolactin elevation, galactorrhea, gynecomastia, menstrual changes, sexual dysfunction

Efficacy of Antipsychotics

FDA Approved Indications for

Antipsychotic Medications

Adults

• Schizophrenia (acute and maintenance)
• Bipolar disorder (acute mania, maintenance,

bipolar depression)

• Agitation associated with schizophrenia or bipolar

disorder

Children and Adolescents

• Schizophrenia
• Autism

Olanzapine for Prevention of Relapse

Days

0

20

40

60

80

100

0 20 40 60 80

Haloperidol Olanzapine

% of Patients Remaining in Study

*p=0.

Lieberman JA, et al. Am J Psychiatry 2003; 160:

Haloperidol for Long-term Prevention of Relapse

0

20

40

60

80

100

0 5 10 15 20 25

Placebo Haloperidol

Months

Percent of Patients Relapsed

Hogarty GE & Goldberg, SC, Arch Gen Psychiatry 1973;28: