This change in thinking was originally quite revolutionary. The conventional wisdom was that a drug needed to generate EPS (pseudo-Parkinson’s, dystonia, akathisia) in order to produce a clinical (anti-psychotic) effect. The reduced prolactin effect is overall as some SGA’s (risperidone) still have pronounced effects.
X: receptor involved with insulin resistance.
LSD, psilocin (found in mushrooms), and mescaline (found in cacti) activate 5-HT2A.
Mean weight gain during this period was 5.6 kg in this meta-analysis.
http://www.nytimes.com/2010/10/03/business/03psych.html?_r=4&hp=&pagewanted=all&“Lilly paid a $515 million criminal fine as part of a broader, $1.4 billion settlement with the government” in 2009. This was the largest fine paid by a corporation to date.
There was a smaller relationship between SCZ severity and structural changes. This structural changes were not due to extent of alcohol/drug use.
Quetiapine is also a 5-HT1A partial agonist.
The dose range of olanzapine was above that in the package insert! A metabolite of Perphenazine has some 5-HT2A affinity making it an odd choice of FGA.Patients in the olanzapine group gained more weight than patients in any other group, with an average weight gain of 2 lb (0.9 kg) per month!Ziprasidone (ziprasi doe n): http://www.howjsay.com/index.php?word=ziprasidone&submit=SubmitPerphenazine (per fen a zEne): http://www.howjsay.com/index.php?word=perphenazine&submit=Submit
There is no psychiatric disorder with aggression as the key feature but antipsychotics are often used off label for this.
#1 in terms of profits. This has slipped to #5 in 2011 (18.2 Billion versus 23 Billion for oncology).
Antipsychotics Part II
Anti-psychotics IIBrian J. Piper, Ph.D., M.S. firstname.lastname@example.org 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. 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
Atypical (Second Generation) • Mechanism of Action – Dissociate more rapidly from the D2 receptorStahl, S. (2008). Essential Psychopharmacology, p. 369-370.
MOA of Atypical Antipsychotics • Dissociate more rapidly from the D2 receptor – ↓ acute EPS, ↓ hyperprolactinemiaStahl, 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!) receptorsStahl, S. (2008). Essential Psychopharmacology, p. 384.
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.
Risks with long-term Atypicals Mechanism: 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 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.
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.
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 +6.6 Change 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. 1921 -Rector & Beck (2012). J Nervous & Mental Disease, 200(10), 832-839.
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=UTU Mt05_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 Effect X: diabetes M1: sedation H1: sedation, appetite α1: sedation 5-HT2C: appetiteStahl, 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 antiviralshttp://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?