2. Case
40 year old man with long hx of paranoid
schizophrenia.
On perphenazine (Trilafon) 12 mg qhs,
benztropine (Cogentin) 2 mg qhs x 15 years.
PMH notable for DM II on metformin,
glyburide, accupril, last HgA1c of 7.9
Lives at B&C, smokes 2 packs per day, occ
ETOH, remote hx of methamphetamines.
3. Case
On MSE, overweight man with BMI 33, plain
dress, adequate grooming, diminished spont
movements, eye contact fixed, occ resting
tremor in R hand noted and occ grimacing.
Speech has slight delay with diminished tone but
o/w fluent. Mood is “fine” Affect is
constricted to blunted. TP generally linear, bit
concrete, sparse details. TC of:
4. Case
A) “I like what I’m taking.” Some mild paranoia
of police but without evidence of overt
delusions
B) “I know the B&C is poisoning me.”
5. Antipsychotics
First antipsychotic was a phenothiazine
(chlorpromazine) synthesized in 1950.
First Generation, also called “typical”
“Me too D2”
Second Generation, also called “atypical”
Starting in early 90’s
6. How do Typical Antipsychotics work?
Dopamine Hypothesis
Targets for D2 blockade
Mesolimbic area: antipsychotic effect
Nigrostriatal tract: EPS
Tuberinfundibular area: prolactin elevation
76-80% D2 occupancy needed for effect for
conventional antipsychotics
Problem:
Atypicals have varying occupancy requirements
7. How do Atypical Antipsychotics
work?
Leading Theories
May relate to DA receptors having subtypes D1-5 as
well as other receptors playing a part to modulate
dopamine receptors (such as 5-HT2A .)
Hypofunctional N-methyl-D-aspartate (NMDA)
receptors in VTA leads to
hyperactive mesolimibic DA activity (via GABA
interneuron)
hypoactive mesocortical DA activity
9. Acute EPS esp with high potency agents
Related to decreased DA activity in the basal ganglia
Akathisia: occurs in 2/3 of patients to some degree
Treat with beta blockers
Dystonia: occurs in 1/3 of patients
Treat with anticholinergics
Parkinsonism: occurs in 1/3 of patients treated long
term
Treat with anticholinergics
10. Neuroleptic Malignant Syndrome
Esp with high potency antipsychotics escalated
quickly to high doses
Features are hyperthermia, severe muscular
rigidity, autonomic instability, changing levels of
consciousness.
Psychiatric emergency = emergency room
11. Tardive Dyskinesia
Increased sensitivity of DA receptors in basal
ganglia.
10-20% in one year, risk increases 4-5% per year.
Higher risk: include elderly women and
schizoaffective disorder.
12. Typical Antipsychotics Bottom Line
All work by blocking D2 receptor
High potency (haloperidol) = More EPS, TD,
NMS
Low potency (chlorpromazine) = more sedation,
anticholinergic side effects
All equally efficacious
High potency preferred by patients
13. Atypical vs Typical Antipsychotics
Atypical antipsychotics advantages
greatly reduced to no propensity for EPS or TD
minimal elevation of prolactin (except risperidone)
Less impact on negative symptoms, cognition
broader spectrum of action
Typical antipsychotic advantages
depot formulations (except Consta)
cost
less severe metabolic impact
14. How do Atypical Antipsychotics
work?
Leading Theories
May relate to DA receptors having subtypes D1-5 as
well as other receptors playing a part to modulate
dopamine receptors (such as 5-HT2A .)
Hypofunctional N-methyl-D-aspartate (NMDA)
receptors in VTA leads to
hyperactive mesolimibic DA activity (via GABA
interneuron)
hypoactive mesocortical DA activity
15. Are atypicals “better?”
Efficacy and effectiveness
Maybe
Side effects
Different
Cost effectiveness
Unknown
16. Are atypicals “better?”
Improved efficacy based on short-term
structured studies, mostly industry sponsored.
Meta-analyses have shown mixed results with
risperidone and olanzapine edging typicals
slightly.
NIMH sponsored Clinical Antipsychotic Trials
of Intervention Effectiveness (CATIE) was a
randomized DB, flexible dose study with olanzapine,
risperidone, quetiapine, ziprasidone, perphenazine, 18
months
17. CATIE Points to Ponder
CATIE focused on “effectiveness” rather than
“efficacy.”
Chronic schizophrenics have a high rate (>70%) of
antipsychotic discontinuation over time.
Risperidone and especially olanzapine has
comparatively better effectiveness compared to
quetiapine and ziprasidone
Confirmed superior efficacy of clozapine
Typical antipsychotics (perphenazine) can be as
effective as atypicals (except olanzapine)
18. However…
Atypical Antipsychotics
olanzapine and clozapine: most cases of new onset
DM, DKA, death, elevated triglyceride and LDL
ziprasidone and aripiprazole: fewest cases of new
onset DM, DKA, death, elevated triglyceride and
LDL
Weight gain over 1 year (pooled data from multiple
trials)
olanzapine: > 13.2 lb, >22 lb with doses > 12.5 mg
quetiapine and risperidone: 4.4 - 6.6 lb
aripiprazole and ziprasidone: 2.2 lb
20. ADA Consensus Position on Antipsychotics and
Obesity, Diabetes, Dyslipidemia
Drug Weight Gain DM Risk Dyslipidemia
clozapine +++ + +
olanzapine +++ + +
risperidone + Discrepant Discrepant
quetiapine + Discrepant Discrepant
aripiprazole +/- No effect No effect
ziprasidone +/- No effect No effect
Diabetes Care 2004; 27:596-601
21. Monitoring
At baseline, 1 month, 3 months
weight, BP, fasting glucose, fasting lipid panel
Yearly
weight, BP, fasting glucose
Every three years
fasting lipid panel
Looking for:
> 5-7% increase from initial weight or BMI > 25
Fasting glucose > 126
BP > 140/90
Cholesterol thresholds depends on risk factors
22. clozapine (Clozaril)
Relatively low D2 blocker, significant 5-HT2A,
H1, alpha1, alpha2, muscarinic receptor blocker.
Indications: treatment resistant schizophrenia,
severe TD (may improve)
Dosage: titrated over weeks to 250-450 mg qd.
If more than a 2-3 days of doses missed, should
restart titration.
Common side effects: sialorrhea, orthostatic
hypotension (can be severe, titration dependent),
tachycardia, constipation, weight gain, sedation.
23. clozapine (Clozaril)
Agranulocytosis
Overall risk < 1% with highest risk at week 6-18
Weekly CBC required for first 6 months then every
other week
Discontinue if WBC < 3000 or granulocyte count <
1500
Bottom Line: most effective antipsychotic
period but limited by side effects. Watch for
metabolic side effects. You won’t be starting it.
24. olanzapine (Zyprexa)
Antagonism at the 5-HT2A, DA, muscarinic, H1, alpha1
receptors
FDA approved for schizophrenia, acute bipolar mania
and bipolar disorder maintenance.
Dosing: (PO) start at 5-10 mg qhs and increase by 5
mg qweek to target dose of 10-30 mg qhs. Max dose 40
mg qd.
Common side effects: weight gain, sedation, dry
mouth, constipation,. May start seeing EPS at doses >
30 mg qd.
Bottom Line: Probably most effective (except
clozapine) but metabolic effects limits use.
25. risperidone (Risperdal)
Antagonism at 5-HT2A, D2, alpha1 and 2, H1
receptors
FDA approved for schizophrenia, acute bipolar mania
Dosing: start 1-2 mg qd, increase by 1-2 mg every 3-6
days with usual therapeutic dose of 4-6 mg qd. Max
dose16 mg qd. Available in M-Tab and IM Consta.
Precautions: orthostatic hypotension,
hyperprolactinemia
Common side effects: somnolence, dizziness,
constipation, weight gain and dose dependent EPS (> 6
mg qd).
Bottom line: Popular first line agent, watch for EPS at
> 6 mg and hyperprolactinemia in women.
26. quetiapine (Seroquel)
Antagonist at 5-HT2A, D1, D2, H1, alpha1, alpha2
receptors
FDA approved for schizophrenia, bipolar mania and
depression.
Dosing: start 25-50 mg bid, increase by 100-200 mg
every few days to at least 200 mg bid. Max dose 400
mg bid
Common side effects: somnolence, dizziness, dry
mouth, constipation, weight gain
Bottom Line: Sedating with no EPS liability at any
dose,. Initially marketed with target dose too low, need
to get to at least 200 mg bid. Don’t waste time at the
low doses
27. ziprasidone (Geodon)
Antagonist at D2, 5-HT2A, H1, agonist at 5-HT1A
Half life about 7 hours, metabolized by aldehyde
oxidase and less so by 3A4. Absorption
increased two fold in the presence of food.
FDA approved for schizophrenia and bipolar
mania
Dosage: Dose with food usually bid. Start
40-60 mg bid, target dose 60-80 mg bid.
Common side effects: mild somnolence,
dizziness, akathesia, nausea, agitation
28. ziprasidone (Geodon)
Warnings: QTc prolongation (> 500 msec significant)
No documented cases of torsade although this is the
presumed risk
Avoid with other QTc prolonging drugs, preexisting
bradycardia, hypokalemia / hypomagnesemia, screen for
congenital prolonged QTc syndrome. (hx of sudden death in
family)
Bottom Line: Relatively nonsedating, but watch for
agitation. QTc concern largely overblown but do
screen above as indicated. Dose adequately.
29. aripiprazole (Abilify)
“Modulates” DA: acts as DA2 agonist/antagonist, 5-
HT1A agonist, 5-HT2A antagonist. FDA approved for
schizophrenia and bipolar mania.
Dosing: start 10-15 mg qd. Most patients on 15-20 mg
qd. For bipolar mania 30 mg qd
Common side effects: anxiety, insomnia, mild
somnolence, akathesia, constipation, tremor.
Bottom Line: Like Geodon, not very sedating and a
generally positive side effect profile. Some patient will
complain of anxiety/akathesia initially.
30. Which Antipsychotic?
With exception of clozapine, all considered first
line.
Weight concern/DM: consider starting with
something other than olanzapine.
Insomnia: consider olanzapine, risperidone,
quetiapine.
EPS sensitivity or TD: consider quetiapine.
31. Which Antipsychotic?
If you see an atypical antipsychotic on a clinic
note.
Ask if the psychiatrist is checking lipids, glucose
periodically. If they are not, get a fasting lipid panel
and glucose. If the medication is new, check again in
three months, then the glucose yearly, lipids q3-5
years.
Don’t forget monitoring increased weight > 7%
from baseline while on antipsychotic.
Typical antipsychotic cause weight gain too although
there is no mandatory monitoring of lipids or
glucose. Do watch for TD.
