Anti-psychotics IIBrian J. Piper, Ph.D., M.S.

piperbj@husson.edu

February 4, 2013

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

DSM5 Diagnosis of Schizophrenia• Two or more of the following, including 1, 2, or 3

1. Delusions2. Hallucinations3. Disorganized speech4. Grossly abnormal psychomotor behavior5. Negative symptoms

• Duration: 1 month during last 6• Social/occupational dysfunction• Exclusion: medical condition or drug

Atypical (Second Generation)• Mechanism of Action

– Dissociate more rapidly from the D2 receptor

Stahl, S. (2008). Essential Psychopharmacology, p. 369-370.

MOA of Atypical Antipsychotics• Dissociate more rapidly from the D2 receptor

– ↓ acute EPS, ↓ hyperprolactinemia

Stahl, S. (2008). Essential Psychopharmacology, p. 371.

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.

5-HT2A

• Hallucinogens = 5-HT2A agonists• Receptor Distribution: cortex

[11C]MDL100,907

Meyer et al. (2010). Neuroimage, 50(3), 984-993.

Brain Morphology & Schizophrenia

Some schizophrenia patients exhibit morphological changes in the brain like

enlargement of fluid-filled ventricles.

Adverse Effect of Atypicals I: Weight Gain

Weight Gain & OlanzapineWeight Gain Relative to Baseline (1.6 yrs)

% of Patients

> 7% 64%> 15% 32%> 25% 12%

Citrome et al. (2011). Journal of Clinical Investigation, 31(7), 455-482.

Risks with long-term AtypicalsMechanism: 5-HT2C

Mechanism: X

$515 Million

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.

**

Do antipsychotics cause neurostructural changes?

Repeated MRI of schizophrenicsVentricular 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.

Do antipsychotics cause neurostructural changes?

Repeated MRI of schizophrenicsWhite 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.

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

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 +6.6Change in Prolactin = = ↑ = =

Lieberman et al. (2005). New England Journal of Medicine, 353(12), 1209-1223.

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

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.

Rector & Beck (2012). J Nervous & Mental Disease, 200(10), 832-839.

1921 -

Onset Age

• Males: early 20s• Females: late 20s

Schizophrenia in Children

• More frequently recognized• Example (0 to 3 min):

http://www.youtube.com/watch?v=UTUMt05_nCI

:

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.

Receptor/Adverse EffectX: diabetesM1: sedationH1: sedation, appetiteα1: sedation5-HT2C: appetite

Stahl, S. (2008). Essential Psychopharmacology, p. 384.

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/

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?