ANTIPSYCHOTICS

Crash Course Lecture

July 2016 Version

ASCP Model Curriculum for

Psychopharmacology

David N. Osser, M.D.

Associate Professor of Psychiatry
Harvard Medical School
 Pre-Lecture Exam
Question 1
1. Which of the following is an antipsychotic
dose that is in excess of the optimal?
A. Aripiprazole 15 mg/day
B. Ziprasidone 80 mg bid
C. Haloperidol 20 mg qd
D. Risperidone 4 mg/day
E. Quetiapine 300 mg bid
 Question 2
2. Which of the following antipsychotics must
be taken twice daily, with 500 kcal of food
for it to be bioavailable?
A. Ziprasidone
B. Lurasidone
C. Clozapine
D. Aripiprazole
E. Risperidone
 Question 3
3. Which of the following is the
recommended starting dose for clozapine?
A. 25 mg twice a day
B. 12.5 mg
C. 25 mg
D. 50 mg
 Question 4
4. All of the following are true of a patient on
risperidone who gets parkinsonian side
effects, except:
A. D2 receptor occupancy is 75% or more
B. The patient is above the “neuroleptic
threshold”
C. Patient is at risk for secondary negative
symptoms
D. Raising the dose is likely to be helpful
 Question 5
5. All of the following are true of olanzapine,
except
A. Smoking increases clearance by 40%
B. Works most quickly when started at 15-20
mg/d
C. Elevated Hemoglobin A1C the most in
CATIE
D. Increased triglycerides the most in CATIE
E. Produces clinically significantly better
results at doses over 20 mg daily.
 Outline of Lecture
• Pre-lecture questions
• Introduction
• Algorithm for selecting antipsychotics
• How to give trials of antipsychotics
• Prescribing antipsychotics in dementia
• Cost-conscious use of antipsychotics
• Post-lecture questions and answers
 *Major Teaching Points
• Psychopharmacology algorithms help
structure the knowledge base that pertains to
decision-making
• Dosing strategies should be informed by the
pertinent evidence-base
• Antipsychotic choice should be influenced
by the patient’s likely susceptibility to the
common side effects
• Occasionally, cost considerations may be
relevant
 Recommended Book
• Taylor D et al. The Maudsley Prescribing
Guidelines in Psychiatry. 12th edition 2015.
Wiley-Blackwell. $80
Note chapters 1 and 2 on schizophrenia and use of
blood levels.
Has exceptional commitment to citing evidence to
support almost all statements and
recommendations. Has useful short algorithms.
Some meds are not available in US and vice-versa.
 *Antipsychotics: The Menu I.
First-Generation (FGAs) – generic and (old)
brand names and approx. daily dose equivalence
• Chlorpromazine 300 mg • Thorazine**
(CPZ) • Prolixin
• Fluphenazine HCl 6 mg • Haldol
• Haloperidol 6 mg • Loxitane
• Loxapine 30 mg • Serentil
• Mesoridazine 150 mg • (Moban – no longer made 2010)
• (Molindone 30 mg) • Trilafon
• Perphenazine 24 mg • Mellaril
• Thioridazine 300 mg • Navane
• Thiothixene 15 mg • Stelazine
• Trifluoperazine 15 mg
 *Antipsychotics: The Menu II.
Second-Generation (SGAs) – generic and (old)
brand names & dose equivalence with CPZ 300 mg
• Asenapine 5 mg bid SL • Saphris
• Aripiprazole 15 mg • Abilify
• Brexpiprazole 2-4 mg • Rexulti
• Cariprazine 1.5-6 mg • Vraylar
• Clozapine 400 mg • Clozaril
• Iloperidone 12-24 mg • Fanapt
• Lurasidone 40-80mg • Latuda
• Olanzapine 15 mg • Zyprexa
• Paliperidone 6-12 mg • Invega
• Quetiapine 400-600 mg • Seroquel
• Risperidone 4 mg • Risperidal
• Ziprasidone 80 mg bid • Geodon
 *Importance of Detecting,
Treating Schizophrenia
• Headline. August, 2011. US Army
private shoots Afghan detainee in his cell.
Diagnosis of soldier: Schizophrenia.
• Average age of onset: 18 for men, up to 25
for women. 2-3 years younger in
marijuana users (Large et al, 2011)
• Suicide attempts in 20-50% (Ilgen, 2010)
• Watch for odd, suspicious behavior.
Patients often deny their symptoms.
 Goals of Treatment
• Recovery and normalized activity are the
goals of adequate antipsychotic trials.
• Response short of this should be considered
unsatisfactory.
• If response is unsatisfactory, review
diagnosis, psychosocial factors, and
investigate behavioral toxicity
 *Prevention of Schizophrenia
(Amminger et al. Arch Gen Psych 2010;67(2):146-54)
(Amminger et al. Nat Commun 2015;6:7934)
• 80 very high risk young adults age 13-25
randomized to 2 grams of fish oil twice daily
or placebo for 12 weeks. Followed 9 months
• Conversion to schizophrenia:
- omega-3FA – 5%
- placebo – 28% p < 0.007, NNT 4
• No side effects
• 7 year follow-up: 10% conversion vs. 40%
• If replicated – may have great importance
PSYCHOPHARMACOLOGY
TREATMENT ALGORITHM
 *PSYCHOPHARMACOLOGY
ALGORITHM PROJECT AT THE
HARVARD SOUTH SHORE PROGRAM
at www.psychopharm.mobi
David N. Osser, M.D.
General Editor
Robert D. Patterson, M.D.
Director of Technology
 *Features of the PAPHSS Algorithm
for Schizophrenia
• Primarily addresses positive sx of schizophrenia
• Negative sx typically improve with positive sx.
• “Secondary negative symptoms” improve when
EPS and sedation are managed successfully.
• Residual primary negative and cognitive sx are
very treatment-resistant with few proven remedies
• Unlike other algorithms, assumes there are some
differences in effectiveness among the non-
clozapine options. (McCue 2006, Suzuki 2007,
Komosa 2009; full refs on this slide’s Notes Page)
 2016 Schizophrenia Algorithm of the
Harvard South Shore Algorithm Project*
F ir s t E p is o d e S c h iz o p h r e n ia

A n y S G A e x c e p t c lo z a p in e , o la n z a p in e , q u e tia p in e
O la n , q u e t n o t f ir s t - lin e d u e t o m e t a b o lic is s u e s .
Q u e t le s s e f f e c t iv e t h a n o t h e r s f o r m a in t e n a n c e .
If p a tie n t c a n n o t t o le r a t e 4 w e e k t r ia l, tr y a n o th e r .

If y o u tr ie d r is p , o la n z , F G A : If y o u tr ie d a r ip ip r a z o le , If y o u tr ie d a r ip ip r a z o le
n o w tr y a n y S G A o r F G A Q o r z ip r a s id o n e , q u e t ia p in e o r z ip r a s id o n e :
a n d th e n a n o th e r o f th e s e : n e x t t r y r is p e r id o n e ,
n o w tr y a th ir d a n tip s y c h o tic . o la n z a p in e , F G A

C lo z a p in e
( G r a d u a lly r e m o v e
o th e r a n tip s y c h o tic s
t o c o m p le t e m o n o t h e r a p y t r ia l)

A d d r is p e r id o n e , la m o t r ig in e , o r E C T

O t h e r c o m b in a t io n s w it h c lo z a p in e
O t h e r m o n o t h e r a p ie s - e .g . a r ip ip r a z o le
F G A p lu s m ir ta z a p in e o r c e le c o x ib
O t h e r c o m b in a t io n s ( le a s t e v id e n c e )

*Osser DN, Jalali M, Manschreck T. Harvard Rev Psychiatry 2013;

21(1):18-40
*Antipsychotic Efficacy Differences?
McCue RE et al. Br J Psychiatry 2006;189:433-440
• 327 acute inpatients randomized open label to
haloperidol (mean maximum dose 16 mg), aripiprazole
22 mg, olanzapine 19 mg, quetiapine 650 mg,
risperidone 5.2 mg, ziprasidone 150 mg.
• Response was defined as being able to be discharged in 3
weeks – a “real world” outcome measure.
• No pharmaceutical firm support
• Olanzapine 92%, haloperidol 89%, risperidone 88%,
aripiprazole 64%, quetiapine 63%, ziprasidone 64%
 SGAs Not Equal? – 2
Suzuki T et al. Psychopharmacology 2007;195:285-95

• 78 patients who never had an adequate trial of a SGA

were randomized to olanzapine, risperidone, or
quetiapine for up to 8 weeks.
• If no response (30% drop in PANSS) to doses (in mg)
O=18, R=5.5, Q=560, they were randomized to one
of the other two for up to 8 more weeks. If still no
response, they were given the third. The Results:
Trial 1 – O=62%, R=54%, Q=35%. Q did less well.
Trial 2 – 60% responded to quetiapine at the 2nd trial.
Trial 3 - Only 2 patients responded to the third SGA.
 *SGAs Not Equal? – 3
• Cochrane Review (2009) of 9 randomized
trials concluded that ziprasidone appears
less effective than olanzapine, risperidone,
and amisulpride (not available in US).
(Komosa K et al. Cochrane Reviews 2009(4) Art. No.
CD006627)
• This may be due to issues related to dosage
and food intake (to be discussed later)
*Combinations: Role in Algorithm
Kane et al. J Clin Psychiatry 2009;70(10):1348-57

• 323 patients with unsatisfactory response to

risperidone (4-8 mg) or quetiapine (400-800
mg) were randomized to aripiprazole 2-15 mg
daily (mean: 10) or placebo for 16 weeks.
• About 70% completed the study
• 78% diagnosis schizophrenia
• This data (next slide) strongly suggests that
combinations should not have an early role in
the algorithm
 *Role of Plasma Levels of
Antipsychotics
• Confirm bioavailability
• Confirm compliance
• Aripiprazole has well-delineated optimal
range of 150 to 210 ng/ml (Sparshatt, 2010)
• Olanzapine 20-40 ng/ml with added toxicity
over 80 ng/ml (Bishara, 2013)
• Other possible ranges: risperidone: 20-60 (for
risp + pali), haloperidol 5-15. (see Maudsley)
 *New Atypical Antipsychotics
• No specific place for them in algorithm
• Iloperidone (Fanapt) was rejected by FDA in July
2008 due to lack of efficacy. Decision reversed in
May 2009. It was equivalent to ziprasidone in one
study. Wgt gain ~ 5 lb short term. Some QTc increase
• Asenapine (Saphris) approved in Aug. 2009.
Sublingual administration: hard to evaluate its
practicality. One negative and two positive studies.
Did not do well in unpublished studies.
• Lurasidone (Latuda) approved in 2010. Two
positive studies. Not as effective as olanzapine in 1
study.
• Paliperidone (Invega), active metabolite of
risperidone – will be discussed later
 * New SGAs, Cont.
• Brexpiprazole (Rexulti): Some differences
in receptor effect from aripiprazole but
probably clinically insignificant. Also FDA-
approved for antidepressant augmentation.
• Cariprazine (Vraylar): A partial DA agonist
like aripiprazole and brexpiprazole. Also
FDA- approved for treatment of mania and
mixed mania.
See Citrome L. Int J Clin Pract 2015, for review
of these new agents
 * New SGAs Cont.
• Brexpiprazole (Rexulti): Some differences
in receptor effect from aripiprazole but
probably clinically insignificant. Also
approved for antidepressant augmentation.
(Citrome 2015)
• Cariprazine (Vraylar): Also is a partial DA
agonist like aripiprazole and brexpiprazole.
Also is approved for treatment of mania and
antidepressant augmentation.
See Citrome L. Int J Clin Pract 2015, for review
of these new agents
 What about
High Dose Olanzapine?
Why isn’t that in the algorithm?*

*See Bishara D et al.

J Clin
Psychopharmacology 2013;33:329-335
 *Olanzapine 10, 20, and 40 mg
Kinon BJ et al. J Clin Psychopharmacol 2008;28(4):392-400

• 599 mostly outpatients (mean PANSS

93) with schizophrenia and suboptimal
response to previous antipsychotics
were randomized double-blind to one
of 3 doses of olanzapine for 8 weeks.
• Over the first 2 weeks, previous
medications were tapered
*Olanzapine 10, 20, 40 mg: Results
• No difference in efficacy by multiple
measures at any weekly treatment point or
at end point.
• Weight gain was greater on the 40 mg dose
• However, patients in the top 10% of
severity (PANSS > 110) did somewhat
better on 40 mg. But: this group was on
higher doses of antipsychotic at study
entry.
• So, the better results at 40 mg relative to 10
and 20 mg were probably due to the fact
that 2/3 of these patients were assigned to a
lower equivalent dose of olanzapine.
 High Dose Olanzapine vs.
Clozapine
• 16 week DB crossover study comparing 50
mg of olanzapine with 450 mg of clozapine*
• 13 patients met rigorous criteria for
treatment-resistant schizophrenia
• Criteria for response was 20% improvement
on BPRS, final score <35 or CGI
improvement score greater than 1.0
*Conley RR et al J Clin Psychopharmacology 2003;23:668-71
 Results of Conley et al.
• Clozapine response was good: 30% had BPRS
drop of 20%. Similar to other clozapine
studies. Effect size 0.5
• No olanzapine patients improved.
• Six of 13 patients dropped out when in the
olanzapine phase vs. none in the clozapine
phase.
• Conclusion: Again, no support for high dose
olanzapine.
 *Speed of Response
• Speed is critical in the acute inpatient, managed-
care-driven environment.
• If the patient does not achieve a 25% reduction in
symptoms in the first 2 weeks, outcome is likely to
be poor at 4 weeks. (Leucht S: J Clin Psychiatry 2007)
• More improvement occurs in the first two weeks
than the second two weeks. (Leucht S: Biol Ps 2005)
– So, probably switch if no response in 2 weeks
• Risperidone, olanzapine, and conventional
antipsychotics may work faster than aripiprazole,
quetiapine and ziprasidone*
(*Osser & Sigadel: J Clin Psychopharmacol 2001, McCue
et al: Br J Psychiatry 2006)
 IM Treatment of Agitation in ER
Mantovani C et al. JCPsychopharmacol 2013;33:306-12
• This is the largest and best controlled study but it
confirms earlier smaller studies
• 100 patients with schizophrenia mostly, 36 with
mania, randomly assigned to haloperidol 2.5 plus
midazolam 7.5; haloperidol 2.5 plus promethazine
25; olanzapine 10; or ziprasidone 10.
• In 60 minutes, efficacy was best was H + M or O,
but OR for side effects was 1.6 greater with O and
3.64 greater with H + P.
Giving Adequate Trials of
Individual Antipsychotics
Dosing, Administration, and
Side Effect Management
 *Ziprasidone – caveats from
package insert
• Avoid ziprasidone if EKG shows QTc is >500
milliseconds
• Is patient on medications that might prolong the
QTc since EKG was done? (citalopram, haloperidol,
tricyclics, quetiapine, floxacins.) If so, repeat EKG
• Check pulse. Low pulse risks Torsades. Is the
patient on a drug that lowers pulse? (Beta-blocker –
often; SSRI – infrequently)
• Risk for electrolyte problems? (alc dependent,
purging bulimic) If so, get K+, Mg++ and follow
• History of arrhythmias? Get medical clearance.
 *Dosing of Ziprasidone - 1

• Only 80 mg bid was better than placebo

in All Cause Discontinuation in meta-
analysis of 4 studies.* (In CATIE they
used only 110 mg/day, and ziprasidone
underperformed)
*Citrome L et al. Schizophrenia Research 2009;111:39-45
 *Dosing of Ziprasidone - 2
• Absorption is reduced by at least 50% if not
taken with food, more at higher doses. 500
kcal needed – not even 250 is enough. Fat
content not important. (Gandelman et al. J Clin
Psychiatry. 2009 Jan;70(1):58-62)
• Citrome et al also found NO differences in
discontinuation rates due to side effects at
160 mg vs 40 mg.
 *Ziprasidone Side Effects
• Activation, especially at low doses
• Sedation
• Nausea, dry mouth
• EPS occasionally
• No QTc problems were seen in CATIE compared
to the others. Previous data found ~10 msec
greater increase compared to most others
• HOWEVER, since 2007 FDA warning about QTc
prolongation and Torsades with haloperidol,
“particular caution” is advised when combining
with ziprasidone. Prod. Info says “contraindicated”
 Aripiprazole – Dosage Issues
• 4 week multicenter DBPC compared 15 or 30
mg aripiprazole with 10 mg haloperidol
• 414 acutely ill inpatients entered the study.*
• Fixed doses
• Lorazepam and benztropine were allowed
• Dropouts: 45% on placebo; 42% on Haldol
and aripiprazole 30; 33% on aripiprazole 15.
*Kane et al. J Clin Psychiatry 2002;63:763-771
Mean Change in PANSS Positive Symptoms
CGI Outcome
*Conclusions on Dose of Aripiprazole
• 15 mg is superior to 30 mg, at all data points and
even after 1 week
• Probably better to use than risperidone for First
Episode patients (Robinson et al 2015); Dose 15 mg
• There is no advantage to a “loading dose”
• Results develop slowly compared to haloperidol 10
mg, but patience is rewarded. There is no advantage
to raising dose.
• Six-month relapse rates are somewhat higher than
other antipsychotics (27%, compared to 15-19%)*
*Pigott TA J Clin Psychiatry 2003;64:1048-1056
 *Aripiprazole Issues
• 75 hour half life
• Substrate for Cytochrome P450 3A4 and 2D6.
Paroxetine and fluoxetine will raise levels (use 50%
dose), carbamazepine will lower them 50%.
• 8% of population are poor metabolizers of 2D6 and will
get 60% higher levels. So, some patients need only 5 mg
• Advantage: aripiprazole, for patients at cardiac risk. It
had the least QTc elev. of any antipsychotic (Chung et al, 2011)
• 30 mg? Possible use in tx-resistant schizophrenia* (next
slide)
 Aripiprazole in TR Schizophrenia*
• 426 TR patients were identified.
• Patients had failed at least 2 AP trials of 6 weeks
(one had to be 3 months), then had open trial of 3
weeks of olanzapine or risperidone. If they
improved 20% on PANSS they were not eligible.
• Only 2% improved 20%. 300 patients randomized
to aripiprazole (93% at 30 mg) or perphenazine:
mean dose 39 mg (about double the CATIE dose)
• Response defined as 30% improvement in PANSS
*Kane JM et al. J Clin Psychiatry 2007;68:213-223
 Aripiprazole Side Effects-1
• Dizziness
• Insomnia
• Akathisia, agitation
• Headache
• Sedation
• Metabolic syndrome – low risk
• Hypoprolactinemia – New finding (Sogawa
2016). Decreases sperm motility/quantity
and women may not lactate post-partum.
 *Aripiprazole Side Effects-2
• Some patients develop irritability, insomnia,
excitement, and nervousness. Also (2016 FDA
warning) urges to gamble, shop, binge, have sex
• Is this a dopamine agonist effect?
• These side effects may occur more often if the
patient was recently on a strong dopamine
blocker like a FGA or risperidone.* Also, avoid
adding DA stimulants such as bupropion.
*Raja M. Int J Neuropsychopharmacol 2007;10:107-110.
Jong-Yih L. J Clin Psychopharmacol 2009;29(1):93-5
 *Risperidone: Dosing
• 4 mg to less than 6 mg daily for 3-6 weeks produces
optimal benefits and least side effects*
• A dose that produces parkinsonian side effects is
probably too high a dose
• Acute exacerbation: 1 mg bid, then 2 mg bid
• First episode/first treatment: 0.5 mg bid, then 1 mg bid
(maximum 2 to less than 4 mg daily)**
• Elderly: Similar to first episode, or less
• P450 Drug Interactions: 2D6 substrate
*Li C et al. Cochrane Reviews 2009(4):art.No. CD007474
**Robinson DG et al. Schizophrenia Bulletin 2015;41:1227-36
 Risperidone dosing and D2
receptor occupancy
• In first-episode and drug free patients, risperidone at
6 mg per day produced EPS in almost everyone and
dopamine D2 receptor occupancy averaging 82%*
• At risperidone 3 mg, EPS were usually not present
and the average D2 occupancy was 72%.*
• Previous studies have shown that the optimal D2
occupancy level for maximizing benefits and
minimizing EPS is 70-80%.
• CATIE phase 1 dose was 3.9 mg/day – slightly low
for non-neuroleptic naïve patients.
*Nyberg S et al, 1999
 *Risperidone dosing - III
• Chinese and other East Asian ethnic
individuals (and many Africans) usually need
somewhat lower doses of antipsychotics
metabolized by 2D6, probably because 35-
50% have a less active form of the 2D6
enzyme, rendering them "Slow Metabolizers"
(SM's).
• Poor metabolizers (PM's) are comparatively
rare among Asians, being found in 1-6%
compared to 5-10% in Caucasians. They are
very prone to EPS
 Risperidone Side Effects
• Prolactin elevation, probably greater than that seen
with the typical neuroleptics. (aripiprazole can
block this effect)
• Agitation. This can look like akathisia, or it may
present as hypomania or mania. It is unclear
whether these reports represent true side effects of
the atypicals or coincidental exacerbations of the
patient's underlying condition.
• Anxiety, insomnia, headache and nausea.
• Weight gain and the metabolic syndrome – low to
medium risk
 *Paliperidone (Invega)*
• Also approved for schizoaffective disorder, July 2009
• Paliperidone is the major active metabolite of
risperidone, the result of hydroxylation mediated
primarily by CYP P450 2D6.
• 80% renally excreted.
• Slow release formulation – 1 day half-life – tablet
should not be crushed or chewed.
• Recommended dose is 6 mg in AM. Maximum is 12.
Efficacy more robust at 9-12.
*See Carlat Report: 3/07, Psychopharm Review: 7/07, Current Psychiatry 9/07
 *Paliperidone: When to Use?
Probably not too often:
• Efficacy appears the same as risperidone.
• Patients who are slow metabolizers of risperidone at
2D6, or are taking drugs that inhibit 2D6 metabolism
like paroxetine, may develop high risperidone blood
levels and more side effects. Use of paliperidone
will avoid this problem.
• However, paliperidone itself causes a lot of EPS and
other side effects, especially at 12 mg where it may
give more EPS than comparable doses of risperidone.
 Paliperidone: When to Use - 2
• No difference from risperidone in
hyperprolactinemia, weight gain, sexual side
effects, or metabolic side effects
• Avoid if patient has impaired renal clearance.
• Avoid for inpatients where rapid effect is
important and who may need crushed
medication to deal with non-compliance.
 *Asenapine (Saphris)*
*See Janicak PG, Rado JT. Asenapine: a review of the data. Psychopharm
Review 2009;44(12):89-94
• Sublingual medication. Patient must not chew or
swallow tablet. If swallowed, only 5% bioavailable
due to first-pass liver metabolism to inactive
metabolites.
• Starting and usual final dose for schizophrenia is 5
mg bid. Once daily 10 mg seems as effective and
adherence is better (Sun et al, J Clin Psychiatr 2015)
• CYP 1A2 substrate, like clozapine and olanzapine
• Side effects: 2-5 msec QTc prolongation. Oral
hypoesthesia. Somnolence. Low weight gain & EPS.
 *Haloperidol…Dosing
• With acute treatment, check for cogwheel rigidity
daily as haloperidol, started at 2 mg per day, is
increased by 2 mg every other day.
• McEvoy* found this “neuroleptic threshold” in 44 of
47 patients (94%) at a median dose of 4 mg per day. (2
mg in neuroleptic-naïve patients)
• If poor response and no parkinsonian effects, despite
dose of 10-20 mg, check plasma level to assure
absorption/compliance. (5-15 ng/ml)
*McEvoy JP, Stiller RL, Farr R. J Clin Psychopharmacol 1986; 6:133-
138.
 *Perphenazine - Dosing
• Comes in 2, 4, 8, and 16 mg tablets
• Begin with 4 mg twice daily and increase by 4
mg twice daily every other day until cogwheel
rigidity is noted.
• Average dose in CATIE was 20 mg daily
(equivalent to 6 mg haloperidol*).
• Maximum dose is 64 mg daily.
*Kane et al 2003: Expert Consensus Guideline, J Clin Psychiatry
 *Quetiapine…Dosing
• Standard recommendation is 25 mg bid, 50 mg bid on
day 2, 100 bid on day 3, 150 bid on day 4, and 200 bid
on day 5. PDR max is 800.
• Pilot randomized study showed equivalent safety and
faster results with 100 bid on day 1, 200 bid on day 2,
300 bid on day 3 and 400 bid on day 4. (Pae C-U et al: J Clin
Psychiatry 2007)
• CATIE patients received 543 mg/d
• A study comparing 600 & 1200 mg found no difference
in efficacy (Lindenmeyer et al, 2011)
 *Quetiapine side effects
• Agitation, Insomnia, Sedation, Headache, Dyspepsia
• Weight gain (not dose-related) and related metabolic
side effects; insulin resistance (Ngai et al, 2014)
• Seizures occurred 0.8% in premarketing studies,
which is similar to olanzapine 0.9% and higher than
risperidone's 0.4%.
• QTc prolongation. Avoid combining with 13 drugs.
• Postural dizziness from alpha-adrenergic blockade
will sometimes prevent rapid dosage
• Liver function tests are elevated about as often as
olanzapine and more frequently than risperidone.
 Quetiapine Sustained Release
Kahn et al. Schizophrenia Bull 2007;33:435

• Once daily preparation

• Starting dose 300 at bedtime. Increase
to 600 at bedtime on second day.
• Same effectiveness as standard-release
preparation compared with placebo
 *Olanzapine: Dosing
• Works most quickly when started at 10-20 mg/d*
• Smoking increases clearance by 40%** (58-88%
of patients with schizophrenia smoke)
• Female gender decreases clearance by 30%**
• Should you exceed the PDR max. dose of 20 mg?
Generally, no. (Bishara et al, 2013)
* Osser DN, Sigadel R (2001)
**Package Insert, Weiss (2005), Carrillo (2003)
 *Metabolic Issues w. Olanzapine
• 30% of olanzapine patients gained > 7% body wgt in
CATIE. Positive relationship with serum conc.*
• Elevated triglycerides – highest with olanzapine
• HgbA1C – increased the most with olanzapine
• Triglycerides v. strongly correlated with insulin
resistance (IR)
• IR develops even after one dose!! (Hahn et al 2013)
but some other SGAs may do this as well (Teff 2015)
• Mechanisms: Fat, especially abdominal, increases
IR. Pancreas responds with increased insulin levels
to compensate. If you have bad genes, beta cells
eventually can’t keep up: Diabetes.
 Olanzapine Metabolic Issues - 2
• Consensus panels and the FDA have
concluded that olanzapine has higher risk of
weight gain, elevated lipids and diabetes.
• Several studies (non-industry sponsored)
show increased insulin secretion and
increased triglycerides within 1 to 2 weeks
of starting olanzapine, before any weight
change. This is not seen with risperidone.
J Clin Psychiatry 2004;65:267-72. Olanzapine Package Insert, PDR,
2008. J Clin Psychopharmacology 2006;26:504-7
 *Other Olanzapine Side Effects
• Liver enzyme elevation (use with caution in
hepatitis patients, and if patient on other
medications that irritate liver e.g. statins,
valproate, carbamazepine, naltrexone)
• Rare serious skin reactions (2016 FDA warning)
• EPS, prolactin elevation, & neuroleptic dysphoria
can occur at doses over 20 mg
• Pregnancy: olanzapine had the highest placental
passage of 4 antipsychotics: more low birth
weights and neonatal ICU admissions (both
31%!). Lowest rates were with quetiapine.
(Newport DJ et al Am J Psychiatry 2007;164:1214-20)
 *Monitoring Recommendations
If the patient has pre-existing diabetes, hypertension, or
obesity, consider another antipsychotic
• Baseline: FBS, HbA1C, lipids, LFTs, weight, abdominal
circumference (ac)
• Followup at 1 month: weight, ac, FBS, HbA1C
• Followup at 3 months: same, plus lipids
If metabolic problems develop, consider another antipsychotic
(Schuster J-P, 2012 found good switch results), or treat medically
• If FBS elevated, get glucose tolerance test. If abnormal,
this predicted 96% of patients who developed diabetes
(van Winkel et al JCP 2006;67:1493-1500)
 Medication Treatments for
Weight Gain from Olanzapine
• Nothing is FDA-approved
• Metformin has best evidence. Improves
metabolic parameters and, less so, weight gain.
• Can be used to prevent weight gain.
– Often, better option is switching to another AP
– Psychoeducation/diet counseling (See Correll 2013)
• Second choice: topiramate. Can also prevent
weight gain if used initially. May produce small
psychopathology benefit (Hahn 2013).
Rado et al. Psychopharm Review 2013;48:7. Mahmood S,
JCPsychopharmacol 2013. Narula PK, Sch Research 2010.
 Some Side Effect Comparisons - 1
Side typicals cloza- risperi- olanza- quetia- ziprasi- aripipra
effect pine done pine pine done -zole
Weight + - ++ 12 lbs 4 lbs 12 lbs 6 lbs 0 1.5 lbs
gain + avg/10 avg/6 avg/12 avg/6 avg/6
weeks weeks weeks weeks weeks
Sedation some - +++ + ++ ++ 0 - ++ 0 - +
+++
LFT 0 - ++ ++ 0-+ ++ ++ 0-+ 0-+
increase

CYP450 various 1A2, 2D6 1A2, 3A4 3A4 2D6,

Substrate 2D6, 2D6 3A4
for…
3A4
 Some Side Effect Comparisons - 2
Side typicals cloza- risperi- olanza- quetia- ziprasi- aripipra
effect pine done pine pine done -zole
EPS + - ++ 0 + if 0-+ 0 0-+ 0-+
+ dose < (if dose
4 mg < 10 mg)
Seizure 0.1 2–6 0.3 0.9 0.8 0.4 0.1
risk -0.3
(~ %)
Ortho- some - +++ ++ + ++ + - ++ + - ++
stasis +++

Prolactin ++ - + transient +++ +, if > 0 0-+ 0

increase ++ 20 mg
 *QTc prolongation with
antipsychotics
• Least: Aripiprazole, ? lurasidone
• Moderate: Haloperidol, risperidone
• Most: Ziprasidone, quetiapine
(Chung et al, J Psychopharmacology.
2011 plus package insert information)
 *Depot Antipsychotics (AKA
Long Acting Injectables – LAIs)
• Fluphenazine Decanoate: 12.5 mg (0.5 cc test dose) to
50 mg (2 cc) every 2-3 weeks.
• Haloperidol Decanoate 25 mg (0.5 cc test dose) to 200
mg every 4 weeks.
• Risperidone Consta. 25-50 mg IM every 2 weeks
• Olanzapine pamoate (Relprevv): similar to oral in
efficacy, but post-injection delirium/sedation (incidence
is 0.27%) precautions may make it impractical. ? No
longer being advertised
 * Newer LAIs
• Paliperidone palmitate: does not require oral
supplementation. 50-100 mg q4weeks. Also,
3-month formulation (Invega Trinza – use
after 4 months of PP)
• Aripiprazole (Abilify Maintena) 400 mg
q4weeks and aripiprazole lauroxil (Aristada –
441 or 882 mg q4weeks): These require 2
weeks initial oral treatment, then oral
supplementation for 3 weeks.P4502D6 & 3A4
• Barriers to LAIs: Stigma. Cost of new ones >
$1,000/month 22
*Risperidone “Consta” - Efficacy
• 12-week randomized trial of IM risperidone
25, 50, 75 mg, or placebo. (Kane et al ’03)
• 461 patients entered the study.
• Patients’ CGI at start averaged 3, “mildly ill”
• Switched to oral risperidone for 1 week
before the IM: 2 mg per day, then 4 mg per
day after three days. Oral continued for 3
more weeks after the IM.
• 15% dropped out in the first week
Kane et al. Am J Psychiatry 2003:160:1125-1132
Mannaert E et al. Poster 530. CINP. Paris, June 20-24, 2004
 *Comments on this efficacy study
• These mildly-ill, cooperative patients are not
the usual population treated with depot, and yet
2/3 of them did not “survive” the transition to
risperidone long-acting injectable.
• For those who did “survive,” the results were
fair vs placebo by 12 weeks, with 25 mg.
• 50 mg was no better than 25 mg* (See Turner, 2004)
• Probably should continue oral for 6-8 weeks
• For more severely ill people, benefits unknown
*Real World Comparison of Depot
Neuroleptics and R. Consta®**
• Observational study of California Medicaid patients
with schizophrenia initiated on one of the three
depots in 2003-4. N=2,695 patients
• Most were taking < 80% of their oral medication in
the 6 months prior to depot. (mean: 60%)
• 2/3 were on more than one oral antipsychotic and
about half were on concomitant mood stabilizers,
antidepressants, and anxiolytics.
**Olfson M et al. Schizophrenia Bull 2007;33(6):1379-87
 *Results of Comparison of Depots
• Very few of these treatment-resistant, partly-
compliant Medicaid patients stayed on their
Depot for six months:
– Haloperidol Dec: 9.7%
– Fluphenazine Dec: 5.4%
– Risperidone Consta: 2.6% (p<0.0001)
• Speculate: Depots more helpful in more routine,
less treatment-resistant patients – as is more
common in Europe. Or, maybe it is the structure
that helps: e.g. “Prolixin Clinics”
 *A More Recent Comparison of
These Depots
• Suzuki H et al 2016 reported an observational
study in Japan comparing discontinuation rates
of the same 3 LAIs over 5 years (400 patients)
• One and Three year continuation rates were
remarkably high (80% and 60%), clearly
different from the California Medicaid patients
• Discontinuation rates favored risperidone LAI
over both FGA LAIs – 0.37 hazard ratio (HR).
• Aside from cultural differences in the
populations, side effects (not evaluated) could
have been higher with the FGAs due to high
rates of P450 2D6 slow metabolism.
 *Paliperidone Palmitate**
• Reaches steady state more rapidly than r.
Consta: After second weekly injections of 50
or 100 mg, plasma concentrations are robust.
• Then, injections are every 4 weeks.
• 7 days of oral paliperidone 6 or 12 mg were
given prior to the first injection.
• Strong separation from placebo in acutely ill
patients. Side effects: prolactin, injection pain
**Kramer M et al. Int J Neuropsychopharmacol 2010;13:635-47
 *RCT comparing Paliperidone
Palmitate and Haloperidol Dec.*
• 311 patients at 22 sites received ~144 mg PP or
~75 mg HD IM monthly for up to 24 months
• Efficacy failure = hospitalization or “crisis”
stabilization, big increase in outpatient visits, or
inability to stop oral medication in 8 weeks.
• Results: no difference in efficacy failure-HR 0.98
• Side effects: More weight gain and prolactin
increase with PP, more akathisia with HD
*McEvoy JP et al. JAMA 2014;311(19):1978-86. Editorial 1973-4
*Recent Studies of Effectiveness
of Depots
• Rosenheck et al (NEJM, 2011) in a non-blinded trial
in 369 veterans with unstable schizophrenia found
non-significant advantage to depot risperidone vs.
oral (HR 0.87 for rehospitalization)
• However, a study from Finland (Tiihonon et et al,
2011) and a meta-analysis (Leucht et al, 2011) found
that depots reduce relapse.
• Depots probably underutilized in the US, especially
early in the illness. Many patients are not very
adherant and may do better with a depot.
 *Aripiprazole LAI
See Kane J et al. J Clin Psychiatry 2012; 73(5):617-24
• Patients first stabilized on oral (10-30 mg daily).
• Patients were given 400 mg IM monthly or switched
to IM placebo. Dose could be decreased to 300 mg
for tolerability
• Oral is continued for 2 weeks.
• Followup for 1 year
• Efficacy: More relapses on placebo (P<0.0001)
• Side Effects: More akathisia on aripiprazole LAI
• Drug interactions: Patients on CYP 2D6 or 3A4
inhibitors (or slow metabolizers) may require lower
doses. 3A4 inducers (carbamazepine: higher doses)
 *Clozapine – a brief introduction
• Our most powerful treatment. Should not be left as a
last resort. (Marder S. Am J Psychiatry 2016)
• A full lecture on when and how to use clozapine is
available in the Model Curriculum
• Pre-treatment workup similar to olanzapine plus
WBC and ANC levels, EKG. Avoid combining with
other drugs that can cause granulocytopenia like
carbamazepine. (lesser risk: gabapentin, mirtazapine)
• Avoid combining with benzodiazepines if possible
(possible respiratory depression risk)
 *Clozapine Dosing
• 12.5 mg for first dose. Thereafter, divided doses
• Increase by 25-50 mg per day as tolerated, to
300-400 mg per day. Maximum is 900 mg/d
• If response unsatisfactory, check plasma level.
Best results are with levels of parent compound
greater than 400 ng/ml
• For outpatients go at half this pace
• No single dose should exceed 450 mg
 New CBC Monitoring with Clozapine
(see clozapineFEMS.com for full rules)
• Weekly CBC for six months, then biweekly for 6 months, then q4wks
• If ANC (absolute neutrophil count) 1.5-2.0, get repeat CBC and
biweekly CBC until levels rise.
• If ANC 1.0-1.5, hold clozapine, get daily CBC until levels rise.
Rechallenge possible. Repeat in 24 hours, then 3X weekly until > 1.5.
• If ANC <1.0, stop clozapine (unless you think benefits outweigh
risks). Monitor daily. Rechallenge not advised, though some have
done so with prophylactic Neutrophil Stimulating Factor.
• If ANC 0.5 – 0.999 and the patient has Benign Ethnic Neutropenia
(BEN), cont. clozapine & get heme consult
• One study of rechallenges (Prokopez 2016: N=19) found 70%
success, and the others had faster but less serious neutropenia.
 *Clozapine Side Effects – in
brief
Though the rewards are great, the side effects
are many and challenging. Besides wgt gain:
• Seizures (2-10%)
• Respiratory depression (If interrupt therapy by
48 hours, restart at 12.5 mg for first dose)
• Myocarditis (fatal in 1/500,000)
• Hypersalivation (try glycopyrrolate or
metoclopramide (Kreinin A 2016)
• Neuroleptic Malignant Syndrome
• Pulmonary embolus, anticholinergic toxicity,
temperature elevations, eosinophilia
 Clozapine Side Effects –
A Promising Strategy
• 68 Han Chinese received clozapine or clozapine plus 50
mg fluvoxamine to inhibit metabolism to norclozapine.
Study was open label.
• Norclozapine may be more responsible for
myelotoxicity, weight gain, and seizures.
• Only needed dose of 130 to get blood level of 500 ng/ml.

• All side effect parameters much improved on the

combination
• Strategy needs longer-term study, monitoring
Lu et al. J Clin Psychiatry 2004;65:766-771
 *Antipsychotics for Acute
Psychosis or Agitation in Dementia
• 15 placebo-controlled studies of atypicals were reviewed*
• Most found no benefit, and most were never published.
• Meta-analysis showed modest efficacy, NNT = 10
• Death from stroke and related disorders was greater than
placebo. Number Needed to Harm (NNH) = 100.
• Thus, for every 10 patients with good effect, 1 may die
• Typicals are not safer (NEJM Dec. 1, 2005)
• More recent CATIE-AD study had very similar results.
(NEJM 2006, Oct 12;355(15):1525-38.)
• What to do? Milieu management; AP’s very briefly
*Schneider LS et al. JAMA Oct. 19, 2005;1934-43, Maust JAMA Psychiatry 2015
 *Cost-Conscious Prescribing
• Be aware of costs of different pill sizes
• Better to diagnose cause of anxiety, depression,
insomnia, somnolence, agitation and treat cause.
(may result in < rather than > # of medications)
• It’s usually not cost-effective to combine two
second-generation antipsychotics.
• Risperidone became generic in mid-2008 and
costs ~1% of the brand products. Quetiapine and
olanzapine will follow soon.
*Antipsychotic Procurement Costs
in the VA System – 1
Monthly costs as of July, 2016

• Haloperidol 5 mg $ 2
• Fluphenazine 5 mg 6
• Perphenazine 16 mg bid 45
• Risperidone 2 mg bid 2
• Paliperidone 12 mg NF 900
• Quetiapine 50 mg 1
• Quetiapine 300 mg bid 6
*Antipsychotic Monthly Procurement
Costs in the VA System – 2
• Olanzapine 10 mg $ 3
• Ziprasidone 20 mg bid 7
• Ziprasidone 80 mg bid 83
• Aripiprazole 2.5, 5, or 7.5 30
• Aripiprazole 10 or 15 mg 39
• Aripiprazole 20 or more 78
• Asenapine 5 mg bid 189
• Lurasidone 40 mg 84
• Clozapine 300 mg 40
*LAI Antipsychotics Costs in VA
for 4 weeks of treatment (July, 2013)

• Fluphenazine Decanoate 25 mg $ 1.
• Haloperidol Decanoate 100 mg 9.
• Risperidone Consta 50 mg 693.
• Paliperidone Palmitate (PP) 156 mg 685.
– PP for first 5 weeks 2055.
 Post-Lecture Exam
Question 1
1. Which of the following is an antipsychotic
dose that is in excess of the optimal?
A. Aripiprazole 15 mg/day
B. Ziprasidone 80 mg bid
C. Haloperidol 20 mg qd
D. Risperidone 4 mg/day
E. Quetiapine 300 mg bid
 Question 2
2. Which of the following antipsychotics must
be taken with food in order to prevent
significant loss of absorption?
A. Ziprasidone
B. Olanzapine
C. Clozapine
D. Aripiprazole
E. Risperidone
 Question 3
3. Which of the following is the
recommended starting dose for clozapine?
A. 25 mg twice a day
B. 12.5 mg
C. 25 mg
D. 50 mg
 Question 4
4. All of the following are true of a patient on
risperidone who gets parkinsonian side
effects, except:
A. D2 receptor occupancy is 75% or more
B. The patient is above the “neuroleptic
threshold”
C. Patient is at risk for secondary negative
symptoms
D. Raising the dose is likely to be helpful
 Question 5
5. All of the following are true of olanzapine,
except
A. Smoking increases clearance by 40%
B. Works most quickly when started at 15-20
mg/d
C. Elevated Hemoglobin A1C the most in
CATIE
D. Increased triglycerides the most in CATIE
E. Produces clinically significantly better
results at doses over 20 mg daily.
 Answers to Pre & Post
Competency Exam
1. C
2. A
3. B
4. D
5. E