1. Jena Ivey Burkhart, PharmD, BCPS, CPP
Antipsychotic Review
Jena Ivey Burkhart, PharmD, BCPS, CPP

2. Objectives
Review different antipsychotic agents with regard to efficacy and safety
Discuss adverse effect profiles of antipsychotic agents and learn how to pick the “best” one for your patient if indicated

3. Pop Quiz!
Which antipsychotics carry a BBW for increased mortality in dementia-related psychosis?
Which antipsychotics have been studied the most in treating the neuropsychiatric symptoms in dementia?
Which antipsychotic would be the “safest” option for a patient with a movement disorder?
Which antipsychotic has a risk for QT prolongation?

4. Antipsychotic Choice Choice of traditional vs. new generation drugs
Side effect profiles often direct selection
EPS, TD, NMS less likely with newer agents
Efficacy against negative symptoms (when relevant) is higher with the new drugs (probably related to 5HT-2 antagonism)
22% of Nursing home patients

5. Traditional Antipsychotics
All have tendency to produce EPS/TD
Low potency drugs are usually highly sedating, highly anticholinergic and promote orthostasis
Orthostatic hypotension is related to alpha-1 blocking effects and correlates highly with hip FX
Low cost is an advantage

6. Typical Antipsychotics
Chlorpromazine
Prototype typical antipsychotic
Only able to substantially improve positive symptoms, little effect on negative symptoms and many adverse effects
Equivalent doses of other typical antipsychotics based on 100 mg of chlorpromazine
AE: movement disorders, sedation, orthostasis, inc. prolactin concentrations

7. Typical Antipsychotics
Low potency
Chlorpromazine
Thioridazine
Mesoridazine
Mid potency
Molindone
Loxapine
Perphenazine
High potency
Haloperidol
Fluphenazine
Thiothixene
Trifluoperazine

8. Pharmacological Profile for Haloperidol
Affects alpha, dopamine-2 receptors
Oral, depot formulations
Oral
Start 0.5 mg daily, increase to 30 mg maximum per day in divided doses
Depot (haloperidol decanoate)
Given usually once monthly
Must been stable on oral dose first

9. Traditional Antipschotics
Type
Sedation
EPS
Anticholinergic
Cardiovascular
Low Potency
Chlorpromazine
High
Mod
Mid Potency
Perphenazine
Mod-High
Low
High Potency
Haloperidol
Very Low
Very High

10. Efficacy of Typical Antipsychotics
Most benefit seen with positive symptoms
Limited benefit with negative symptoms
May worsen negative or cognitive symptoms, especially in high doses
Have fallen out of favor as first-line agents

11. Atypical Antipsychotics
Improve psychotic symptoms
Improve (or at least not worsen) negative symptoms
May improve cognition with improvement in psychotic sx
Cause less or no EPS
Cause less or no tardive dyskinesia
Effective in refractory patients
involuntary movements of the tongue, lips, face, trunk, and extremities

12. Efficacy of Antipsychotics in Patients with Dementia
Most reviews of efficacy to-date have found these agents are not particularly effective for the NP symptoms of dementia
Risperidone/olanzapine have best evidence for benefit
Effects are modest and further complicated by ADEs
In more recent review, for global behavioral symptom scores associated with dementia in elderly patients, small but statistically significant benefits were observed for aripiprazole, olanzapine, and risperidone
JAMA. 2011;306(12):
JAMA. 2005;293:

13. Discontinuation of Antipsychotic
Recent Cochrane Review (2013) suggests that many older people with Alzheimer’s dementia and NPS can be withdrawn from chronic antipsychotic medication without detrimental effects on their behavior
Declercq T, Petrovic M, Azermai M, Vander Stichele R, De Sutter AIM, van Driel ML, Christiaens T. Withdrawal versus continuation of chronic antipsychotic drugs for behavioural and psychological symptoms in older people with dementia. Cochrane Database of Systematic Reviews 2013, Issue 3.

14. Decision of Antipsychotic
Atypical agents are now accepted to be first-line treatment
Considered ‘first-line’ now, but anticholinergic effects, orthostasis, FDA warnings, and COST are important factors in older adults
Treatment choice based on:
Past response or past side effects to individual agents and number of treatment failures
Patient or practitioner preference
Problems with EPS or tardive dyskinesia
Other concomitant disease states/medications
Compliance issues
Side effect profiles
Cost

15. Available Atypical Antipsychotics
Clozapine
Risperidone
Paliperidone
Olanzapine
Quetiapine
Ziprasidone
Aripiprazole
Newer: Asenapine, Iloperidone, lurasidone

16. Clozapine Not a first-line agent
Must have failed at least two other trials of antipsychotics
Difficult to tolerate due to adverse drug effects
Baseline work-up
CBC with diff (WBC, ANC)
Cardiac history
EKG
FLP
Weight/BMI
FPG and/or HgbA1c

17. Clozapine – Adverse Effects
Black Box Warnings
Hypotension
Seizure
Agranulocytosis
Myocarditis
Risk of death in elderly demented patients with psychosis
Significant potential for metabolic dysregulations
Others: sedation, constipation, tachycardia

18. Clozapine Agranulocytosis
1% incidence
More frequently occurs early in therapy
Monitor CBC weekly for first 6 months, every two weeks for next 6 months, then every 4 weeks thereafter
Must be registered to receive clozapine
Do not rechallenge if patient has experienced agranulocytosis to clozapine in the past
ANC<1000

19. Risperidone (Risperdal)
Mixed serotonin-dopamine antagonist activity
Also antagonizes alpha-2, histamine receptors
Forms: PO, IM
Baseline work-up
Cardiac history
EKG
FLP
Weight/BMI
FPG and/or HgbA1c
Black Box
risk of death in elderly demented patients with psychosis

20. Risperidone – Adverse Effects
Lower EPS than with typical antipsychotics like haloperidol
Risk of EPS higher with doses greater than 6 mg/day
Prolactin elevation
Orthostasis
Tachycardia

21. Paliperidone (Invega)
Major metabolite (9-OH) of risperidone
Innovative delivery system
Delivers smooth plasma levels over 24 hrs
Form: PO
Baseline work-up
Similar to Risperidone
Black Box
risk of death in elderly demented patients with psychosis

22. Paliperidone Comparison to risperidone
Less peak/trough fluctuations, possibly less side effects due to fluctuations
“Once-daily” dosing
No CYP 2D6 interactions (e.g. paroxetine, fluoxetine, poor metabolizers)
Better choice for patients w/liver dysfunction
Phase II metabolism

23. Olanzapine (Zyprexa)
Potent antagonist of several serotonin receptors, dopaminergic, muscarinic, histaminergic, and alpha
Forms: PO, IM
Baseline work-up
Similar to risperidone PLUS
LFTS
Black Box
risk of death in elderly demented patients with psychosis

24. Olanzapine – Adverse Effects
Significant potential for metabolic dysregulations
Sedation
Anticholinergic effects
Tachycardia
EPS less than with risperidone
monitor for akathisia at higher doses (>15mg)

25. Quetiapine (Seroquel)
Antagonist of serotonin, dopamine receptors, some effect on histamine/alpha receptors
Form: PO
Baseline work-up
Similar to risperidone PLUS:
CBC in pre-existing low WBC or h/o drug-induced neutropenia
Black Box
Risk of death in elderly demented patients with psychosis

26. Quetiapine – Adverse Effects
EPS appears to be less due to less effect on dopamine (loose and transient binding to dopamine receptors)
Sedation/fatigue
Orthostasis
Anticholinergic effects at doses > mg
Tachycardia
Increased LFTs (transient)

27. Ziprasidone (Geodon)
High affinity for serotonin receptors, moderate dopamine/histamine, no affinity for alpha/beta
Form: PO
Baseline work-up
Similar to risperidone PLUS
Electrolytes
Black Box
Risk of death in elderly demented patients with psychosis
Contraindicated
H/O arrhythmias or QTc prolongation
Uncompensated heart failure
Acute or recent myocardial infarction

28. Ziprasidone – Adverse Effects
Minimal effects on metabolic profile
EKG changes
QTc prolongation

29. Aripiprazole (Abilify)
Dopamine-2 partial agonist, partial serotonin-1A agonist
Forms: PO, IM
Baseline work-up
Similar to risperidone
Black Box
Risk of death in elderly demented patients with psychosis
Risk of increased suicidal behavior similar to antidepressants labeling
FDA approval for adjunct therapy in MDD

30. Aripiprazole – Adverse Effects
EPS initially presumed minimal
Akathisia versus anxiety, restlessness
Minimal effects on metabolic profile
Nausea
Headache

31. Antipsychotic Adverse Effects

32. Orthostatic Hypotension
Vulnerability in older adults is increased because of decreased sensitivity of baroreceptors in the carotid and BP regulatory centers in the hypothalamus PLUS decreased alpha-1 adrenergic receptors
30+% of institutionalized older adults display symptomatic orthostatic hypotension
Drugs cause this primarily by blocking alpha-1 receptors
TCAs, MAOIs, antipsychotics (including many of the new generation drugs) and lithium are all offenders
Benzodiazepines can cause falls by producing dysequilibrium rather than orthostasis

33. Tardive Dyskinesia Risk much higher in older adults
Incidence may be as high as 25% per year (versus 5% per year in younger patients)
Older adults have increased severity and lower spontaneous remission rates
Risk factors: AGE, F>M, early-onset EPS, length of neuroleptic exposure
TX:

34. Antipsychotic Comparison

36. Atypical Antipsychotics: Hyperglycemia
Hyperglycemia has been seen with olanzapine & clozapine
Good prospective studies are lacking; DM in schizophrenics increased dramatically after neuroleptics introduced in 1950s
Schizophrenics may have impaired glucose tolerance
Insulin resistance may be the mechanism
Monitor Hgb A1c every 3 months; Chol & TGs every 6 months, if indicated

37. Monitoring Protocolab
Variable
Baseline
4 weeks
8 weeks
12 weeks
Quarterly
Annually
Weight
(BMI) x
Waist circumfer.
Blood Pressure
Fasting Glucose
Fasting Lipids
aBased on American Diabetes Association Consensus statetment
bMore frequent assessments may be necessary based on clinical status

38. Managing Side Effects Anticholinergic Effects
fluids, sugarless gum, bowel regimen
EPS
lower dose of drug (esp. risperidone)
drug holiday
Hypotension
rise slowly from bed, divide doses, increase salt intake, TED hose, fludrocortisone in refractory cases
Sedation: lower dose, move to HS dosing if possible

39. QTc Prolongation In Antipsychotics
2+ Pimozide, Mesoridazine, Thioridazine, Droperidol
1+ Ziprasidone, Clozapine, Loxapine, Thiothixene, …...Chlorpromazine, Trifluoperazine, Risperidone,
…...Quetiapine
+/- Olanzapine, Haloperidol, Fluphenazine
RISK FACTORS:
Female sex
Congenital Long QT
Ischemic heart disease

40. Stroke Risk - Antipsychotics
Some evidence to suggest increased risk of cerebrovascular events and death seen in older patients treated with antipsychotics for behavioral and psychological symptoms of dementia
Risperidone, olanzapine studied the most
Similar risk noted with atypical and typical agents
Studies are retrospective and the groups receiving and not receiving antipsychotics may not be comparable for the question being asked
In the case of recent studies in Canada looking at death rates in those with dementia receiving antipsychotics vs those not receiving them, by retrospective review of prescription records, there is NO consideration given to whether there is something different between these two groups of people - i.e. could it be that those individuals being prescribed antipsychotics are sicker or that agitation may be an indication of medical decompensation in and of itself.  Only a placebo controlled prospective study would answer this question.

41. Stroke Risk - Antipsychotics
Try non-drug modalities first
Educate family/patient on risks associated with use
Must weigh benefits of use with potential harms on case-by-case basis
Pharmacologic choices are limited in this population and there is no evidence one way or the other whether other pharmacologic agents used for these same purposes are any safer or more effective

42. Selecting Atypical Antipsychotics
Specific Side Effect
Best Medication Choices to Avoid Specific Side Effects
Sedation
ziprasidone, aripiprazole, risperidone/paliperidone
Weight gain/metabolic side effects
aripiprazole, ziprasidone
EPS/tardive dyskinesia
clozapine>quetiapine>ziprasidone/aripiprazole> olanzapine
Sexual/reproductive
All except risperidone/paliperidone
Anticholinergic effects
risperidone>ziprasidone>aripiprazole, quetiapine (at low to medium doses)
Aripiprazole- limited data; ziprasidone- risk of QT prolongation. Aripiprazole and ziprasidone are newer drugs with limited long term data
J Clinical Psychiatry 1999;60:3-80

43. Pearls for Use Try nonpharm methods first
Discuss risk/benefit ration with family
Joint decision
Use lowest dose possible for therapeutic effect
Start out with HS dosing, use PRN throughout day to assess dosage need
Try to reduce dose or attempt to stop if possible after acute event or after a short treatment course
Combine with non-drug modalities if possible

44. CASES

45. Case 1
Ms. S is an 82 yof presenting to the GSC for initial evaluation. She has a diagnosis of moderate dementia and lives with her daughter in the community. Her daughter is noting that she is growing more suspicious lately that people are going to come in her house. She has started barricading her bedroom door closed with chairs, etc so that no one can get in her room, even her daughter. She stays in the room for hours at a time and her daughter is unsure of what she is doing in there. Her paranoia over this has also caused her to call 911 several times during the day while she is home alone, and the rescue has had to come over to check on her.
Her daughter wonders what can be done for these behaviors?

46. Case 2
Mr. K is a 91 yom residing in a dementia unit for the past 6 months. He had a difficult time adjusting and tried to escape from the locked unit on several occasions. He is starting to get extremely agitated every day prior to supper time (around 5:30pm) and begins demanding food be delivered to his room. When the food is delivered, he complains about it and has started knocking over his food tray onto the floor. When the staff tries to console him, he does not respond well and begins to yell at them and has hit 2 staff members in the past month. The facility is not sure that he is safe to remain there. His other PMH is significant for HTN, depression, GERD, OA, and prior hip fracture.
What are thoughts on management strategies and/or meds?