This PPT is part 2 of 2 lectures given to second year pharmacy students in a pharmacology & toxicology class.

1. Anti-psychotics II
Brian J. Piper, Ph.D., M.S.
piperbj@husson.edu
February 4, 2013

2. Goals
• Pharmacy students should be able to:
– describe the MOA and adverse effects of second
generation antipsychotics
– evaluate the relative pros and cons (acute and
long-term) of first and second generation
antipsychotics

3. DSM5 Diagnosis of Schizophrenia
• Two or more of the following, including 1, 2, or 3
1. Delusions
2. Hallucinations
3. Disorganized speech
4. Grossly abnormal psychomotor behavior
5. Negative symptoms
• Duration: 1 month during last 6
• Social/occupational dysfunction
• Exclusion: medical condition or drug

4. Atypical (Second Generation)
• Mechanism of Action
– Dissociate more rapidly from the D2 receptor
Stahl, S. (2008). Essential Psychopharmacology, p. 369-370.

5. MOA of Atypical Antipsychotics
• Dissociate more rapidly from the D2 receptor
– ↓ acute EPS, ↓ hyperprolactinemia
Stahl, S. (2008). Essential Psychopharmacology, p. 371.

6. MOA of Atypicals
• Atypicals
– Dissociate more rapidly from the D2 receptor
– Block the 5-HT2A (and so many other!) receptors
Stahl, S. (2008). Essential Psychopharmacology, p. 384.

7. 5-HT2A
• Hallucinogens = 5-HT2A agonists
• Receptor Distribution: cortex
[11C]MDL100,907
Meyer et al. (2010). Neuroimage, 50(3), 984-993.

8. Brain Morphology & Schizophrenia
Some schizophrenia patients exhibit
morphological changes in the brain like
enlargement of fluid-filled ventricles.

9. Adverse Effect of Atypicals I: Weight Gain

10. Weight Gain & Olanzapine
Weight Gain % of Patients
Relative to Baseline (1.6 yrs)
> 7% 64%
> 15% 32%
> 25% 12%
Citrome et al. (2011). Journal of Clinical Investigation, 31(7), 455-482.

11. Risks with long-term Atypicals
Mechanism: 5-HT2C
Mechanism: X
$515 Million

12. Concern
• Adult monkeys received
FGA (haloperidol) or *
SGA (olanzapine) *
antipsychotics for 2
years at doses similar to
schizophrenics.
• Gray matter in parietal
cortex was examined.
Konopaske et al. (2007). Neuropsychopharmacology, 32, 1216-1223.

13. Do antipsychotics cause neurostructural
changes?
Repeated MRI of schizophrenics
Ventricular volume change
(slope) by antipsychotic
treatment
– most (+.39)
– intermediate (+.36)
– least (+.16)
Beng-Choon et al. (2011). Archives of General Psychiatry, 68(2), 128-137.

14. Do antipsychotics cause neurostructural
changes?
Repeated MRI of
schizophrenics
White matter change
(slope) by antipsychotic
treatment
– most (-.64)
– intermediate (-.51)
– least (+1.30)
Beng-Choon et al. (2011). Archives of General Psychiatry, 68(2), 128-137.

15. Practice Makes Perfect
• FGA:
http://www.howjsay.com/index.php?word=perphenazine&submit=Submit
• SGA:
– http://www.howjsay.com/index.php?word=ziprasidone&submit=Submit
– http://www.howjsay.com/index.php?word=quetiapine&submit=Submit
– http://www.howjsay.com/index.php?word=risperidone&submit=Submit

16. Clinical Antipsychotic Trials for
Intervention Effectiveness) CATIE
• 18-month randomized, double-blind trial of FGA & SGAs in real-world
(N=1,432) funded by non-industry (NIMH)
Perphenazine Olanzapine Risperidone Ziprasidone Quetiapine
Discontinuation
Rate
75% 64% 74% 79% 82%
Weight Change
(lbs/month)
-0.2 +2.0 +0.4 -0.3 +0.5
Change in
Cholesterol
+1.5 +9.4 -1.3 -8.2 +6.6
Change in
Prolactin
= = ↑ = =
Lieberman et al. (2005). New England Journal of Medicine, 353(12), 1209-1223.

17. CATIE Findings
• FGAs & SGAs showed similar efficacy with a
slight advantage for olanzapine.
• Olanzapine showed a higher metabolic risk
relative to both FGA and other SGAs.
Black Box For All SGAs

18. Cognitive Behavioral Therapy
• Antipsychotics show limited efficacy for negative symptoms & many
patients continue to exhibit hallucinations & delusions
• Cognitive Behavioral Therapy is a short-term, empirically based
psychotherapy developed by Aaron “Tim” Beck (left) that is used with
antipsychotics.
1921 -
Rector & Beck (2012). J Nervous & Mental Disease, 200(10), 832-839.

20. Onset Age
• Males: early 20s
• Females: late 20s

21. Schizophrenia in Children
• More frequently recognized
• Example (0 to 3 min):
http://www.youtube.com/watch?v=UTU
Mt05_nCI
:

22. Summary
• SGAs produce less acute EPS than FGA but
also cause diabetes.
• No clear consensus exists in the choice
between FGA and SGA.
• Using agents at above recommended doses or
combining drugs are common clinically but are
not well studied.

23. Receptor/Adverse Effect
X: diabetes
M1: sedation
H1: sedation, appetite
α1: sedation
5-HT2C: appetite
Stahl, S. (2008). Essential Psychopharmacology, p. 384.

24. Self-Test #1
• _________ were the top selling drugs in 2009.
– A) antipsychotics
– B) oncology agents
– C) antidiabetics
– D) respiratory agents
– E) HIV antivirals
http://www.nytimes.com/2010/10/03/business/03psych.html?_r=4&hp=&pagewanted=all&
http://survivingantidepressants.org/index.php?/topic/2963-the-top-prescription-drugs-of-2011/

25. Self-Test #2
• If a family member were diagnosed with
schizophrenia, what agent would you prefer
they receive and why? Would this differ based
on age or health?