Version 1-25-13
2nd-Generation Antipsychotic Summary: Package Inserts (except where noted)
Numbers correspond to Active Drug Rate : Placebo Comparison Rate
Weight Gain (Percent with ≥ 7% body weight gain in short-term schiz trials)
PALIP 6:5 (at dose of ≤ 6 mg/d)
LUR
5.6:4
ASEN 5:2 (Potkin J Clin Psychiatry: Risp 17%: Saphris 4.3%: PL 1.9%)
ARIP 8:3
ZIP
10:4
ILOP
RISP
13:4 (Cutler JCPsychopharm: ILOP > ZIP): ILOP 21%: ZIP 7%: PL 3%)
18:9
QUET 23:6
OLZ
22:3 (long-term: 64% gain 7% wt; 32% gain 15% wt; 12% gain 25% weight)
Akathisia (% in Short-term Schiz)
QUET < PL
ILOP 2:3
PALIP 3:4 (at dose of ≤ 6 mg/d)
ZIP
8:7
ASEN 4:3
ARIP
RISP
LUR
OLZ
8:4
5:2
15:3
10-11: 1
Parkinsonsism (% in Short-term Schiz)
QUET Slightly LESS parkinsonism, EPS incidence, and use of anticholinergics WITH QUET THAN PL (and no dose
relationship).
ILOP PL=0, 10-16 mg=0.2, 20-24 mg=0.3
ARIP
Tremor: PL=2, All doses=3; Extrapyramidal syndrome “equal to or less than placebo”
PALIP EPS excluding akathisia: PL=8, 3 mg=10, 6 mg=7, 9 mg=20, 12 mg=18
ASEN
EPS excluding akathisia (PL=7, 5mg bid=9, 10 mg bid=12)
RISP
OLZ
LUR
ZIP
PL=1.2, 2 mg=0.9, 6 mg=1.8, 10 mg=2.4, 16 mg=2.6
PL=10, 5 mg=8, 10 mg=14, 15 mg=20
PL=5, All doses=10; 20 mg=6, 40 mg=9, 80 mg=8, 120 mg=17, 160 mg=11
EPS adverse events: PL=1, All doses=5. Dose-related hypertonia and tremor
Page 1 of 3
Version 1-25-13
Sedation
ARIP 11:8 = PALIP 11:7
ASEN
15:7 = ZIP 14:7 = ILOP 12:5
RISP
8:1
QUET: 18:11
LUR
22:10
OLZ
29:13
Prolactin (change from baseline in short-term schiz trials)
Package inserts are highly variable in the type (if any) human data reported for prolactin effects. Below is a
summary of PRL effects based on available evidence, including a systematic review (Byerly, 2007).
ARIP tends to lower PRL levels
CLOZ, OLZ, QUET, ZIP, ASEN, ILOP, and LUR have modest elevating effects (about 2-9ng/ml > than placebo)
PALIP increases in Prolactin (ng/ml): 27.9 males; 18.7 females; “decreased from baseline” for PL and OLZ in
same trial (large, pre-marketing trial - Kane, 2007)
RISP: Invega (PALIP) PI states PRL changes for PALIP and RISP are similar
Seizure Risk in Schizophrenia (%)
LUR
<0.1
ARIP 0.1
ILOP 0.1
ASEN 0.3 at 10 mg bid; 0 at 5 mg bid
RISP 0.3
ZIP
0.4
QUET 0.8
OLZ
0.9
CLOZ 5
Pharmacokinetics of Newer Antipsychotics:
CYP 450 Drugs with Increased Drug Strong Inhibitors
Some Inducers in Psychiatric
Enzyme Levels When Given with
prescribing
Inhibitors (Preskorn, 2012)
1A2
CLOZ, OLZ, (possibly ASEN) fluvoxamine, ciprofloxacin
Tobacco, modafinil, omeprazole
2D6
ARIP, ILOP, RISP
bupropion, fluoxetine, paroxetine,
rifampin, dexamethazone
quinidine, cinacalcet
3A4
ARIP, ILOP, LUR, QUET, ZIP ketoconazole, itraconazle, some HIV
carbamazepine, oxcarbazapine,
antivirals (indinavir, nelfinavir, ritonavir),
rifampin
clarithromycin, telithromycin, saquinavir
See Flockhart’s CYP450 Drug Interaction Table for specifics: http://medicine.iupui.edu/clinpharm/DDIs/table.aspx
ASEN increases levels of drugs that are both inhibitors of and substrates for CYP 2D6 (doubles paroxetine drug
levels).
Need Dose Adjustment with hepatic Impairment: ASEN, CLOZ, LUR, QUET, RISP, ZIP (ILOP not rec’d with hep impair.)
Need Dose Adjustment with renal Impairment: CLOZ, LUR, PALIP, RISP
Page 2 of 3
Version 1-25-13
Pregnancy: Class B Classification: LUR and CLOZ. Class C: other antipsychotics (worse than class B).
Some additional clinical information regarding antipsychotics:
1) Modest doses of antipsychotics have equal efficacy to high and above-label doses (essentially all data
demonstrate this), including in acutely ill hospitalized patients. Clinical use of high doses is probably driven
by benefit of sedating actions in acutely ill patients (i.e., antipsychotic effect is not greater at higher doses).
Higher doses are associated with greater side effects.
2) Dosing guidance of individual drugs: Use of PI-recommended dosing is optimal for most agents. Below are
some exceptions or often-overlooked PI data:
a. ASEN: daytime sedation is a problem with PI-rec’d bid dosing. Most experienced prescribers of this
drug use QHS dosing. Start at 5 mg HS, then increase to 10 mg HS based on clinical
response/tolerability. Dissolve in cheek and wait 2 min before eat/drink (instead of PI under tongue and
10 min) for similar bioavailability with less taste/numbness problems. For inpts with meaningful
agitation, consider starting at 10 bid to utilize sedating action (labeling is 5 bid start for schiz).
b. CLOZ plasma levels have reasonable predictive value. If remission not obtained at initial target dose
(300 mg/d women and 400 mg/d men), check level and try for clozapine plasma level (parent drug level
alone) of ≥ 400 ng/ml. Try to avoid parent and metab levels > 1,000 due to sz risk.
c. ILOP: daytime sedation is a problem with PI-rec’d bid dosing. Most experienced prescribers of this
agent use QHS dosing and decrease titration rate in half for outpts (i.e., give 2 titration packs and 2 days
at each dose at HS alone). Do NOT titrate faster than PI rec’d for inpt’s due to orthostatic effects.
d. LUR has dose-related EPS like many antipsychotics. If see akathisia, 1st try to lower dose to 40 mg/d.
e. OLZ doses above 10 mg/d were NOT more efficacious than 10 mg/d for schizophrenia (source – PI).
Since > weight gain at > dose, give 10 mg/d a very good try (or come back to this dose if possible once
stabilized).
f. QUET doses > 300-400 mg are NOT more efficacious (on average) than higher doses (source – PI and 2
RCT’s testing 1200 mg/d vs. lower doses). Since > weight at > dose, give 300-400 mg/d a very good try
(or come back to this dose if possible once stabilized).
g. PALIP side effects are lower (and quite good overall – source PI) at ≤ 6 mg/d. Side effects, including
weight and EPS increase (meaningfully) above 6 mg/d.
h. RISP PI states 8 mg/d dose more efficacious than 4 mg/d, so stopping at 4 mg/d in pts with unremitted +
symptoms is not advisable in some. Push to 6 mg or even 8 mg/d if tolerated. Unfortunately, MANY pts
will not be able to tolerate 6 or 8 mg/d due to EPS.
i. ZIP: Post-marketing analyses suggest that higher approved doses of ZIP (120-160 mg/d) are more
efficacious than lower approved does (40-80 mg/d)
j. Should take with food (source PI’s): LUR, ZIP.
k. Weight effect of almost all antipsychotics is dose-related, so this is another reason to use lowest
effective dose.
3) QT Prolongation (most to least): ZIP (21 msec - PI), ILOP (19 msec - PI)…ARIP has least (no increase on ave)
Key: (Abbreviation/generic/trade names)
ARIP aripiprazole
(Abilify)
ASEN asenapine
(Saphris)
CLOZ clozapine
(Clozaril/Fazaclo)
ILOP iloperidone
(Fanapt)
LUR
lurasidone
(Latuda)
OLZ
olanzapine
(Zyprexa)
PALIP paliperidone (Invega, Invega Sustenna)
QUET quetiapine
(Seroquel, Seroquel XR)
RISP risperidone
(Risperdal, Risperdal Consta)
ZIP
ziprasidone
(Geodon)
Page 3 of 3