March - Behavioral Health Care Services

CONTINUING
MEDICAL EDUCATION
Bipolar Disorder and ADHD
Kiki Chang MD
March 9 12:15 - 1:30
San Mateo MHS, 225 West 37th St.
San Mateo (650) 573-2530
Metabolic Complications in Schizophrenia
Mahtab Jafari, PharmD
March 10 12:00 – 1 pm
Alameda Co BHCS 2000 Embarcadero #400
Oakland (510) 567-8106
Drugs, Diet, Herbs
Talia Puzantian, PharmD, BCPP
March 12 11:45 – 1 pm
SFGH Room #7M-30, 1001 Potrero Avenue
San Francisco (415) 206-4938
Neuroimaging Of Emotion
Processes In Social Anxiety
Phillipe Goldin Ph.D.
March 23 12:15 - 1:30
San Mateo MHS, 225 West 37th St.
San Mateo (650) 573-2530
Mood and Menopause
Jeanne Leventhal-Alexander, M.D.
March 26 11:45 – 1 pm
SFGH Room #7M-30, 1001 Potrero Avenue
San Francisco (415) 206-4938
Antipsychoitc Use in Bipolar Disorder
Mark Viner, MD
March 31 12:00 – 1 pm
Alameda Co BHCS 2000 Embarcadero #400
Oakland (510) 567-8106
Psychopharmacology of PTSD
Mark Hamner, M.D.
April 9 11:45 – 1 pm
SFGH Room #7M-30, 1001 Potrero Avenue
San Francisco (415) 206-4938
THIS
Pain Management
Barry Rosen MD
April 13 12:15 - 1:30
San Mateo MHS, 225 West 37th St.
San Mateo (650) 573-2530
Diabetes and Mental Health Disease
Kenneth R. Feingold, M.D.
April 23 11:45 – 1 pm
SFGH Room #7M-30, 1001 Potrero Avenue
San Francisco (415) 206-4938
HIV And Psychiatry
Aaron Chapman, MD
April 27 12:15 - 1:30
San Mateo MHS, 225 West 37th St.
San Mateo (650) 573-2530
Long-acting Risperdal Depot
David Feifel, MD
April 28
12:00 – 1 pm
Alameda Co BHCS 2000 Embarcadero #400
Oakland (510) 567-8106
Updates on Bipolar Disorder
Terrence Ketter, M.D.
May 7
11:45 – 1 pm
SFGH Room #7M-30, 1001 Potrero Avenue
San Francisco (415) 206-4938
Cultural Issues
Amy Chagnon, MD
May 11
12:15 - 1:30
San Mateo MHS, 225 West 37th St.
San Mateo (650) 573-2530
Editor:
Douglas Del Paggio, PharmD, MPA
2000 Embarcadero Cove, Suite 400
Oakland, California 94606-5300
(510) 567-8110 FAX (510) 567-6850
email: [email protected]
Contributors:
Alameda County:
Richard P. Singer, MD
Douglas Del Paggio, PharmD, MPA
Alice Myong, PharmD
San Francisco County:
Jimmy Jones, MD
Mary Ann Sullivan, PharmD
Renée Spencer, MA, PhD
Talia Puzantian, Pharm D
San Mateo County:
Celia Moreno, MD
Barbara Liang, PharmD
Graphic Designer: Janie Chambers
Treatment Of Binge Eating
Deborah Safer, MD
May 25 12:15 - 1:30
San Mateo MHS, 225 West 37th St.
San Mateo (650) 573-2530
NEWSLETTER IS SUPPORTED BY UNRESTRICTED EDUCATIONAL GRANTS FROM:
THE BAY AREA PSYCHOPHARMACOLOGY NEWSLETTER
Douglas Del Paggio, PharmD, MPA, Editor
2000 Embarcadero Cove, Suite 400
Oakland, California 94606-5300
Psychopharmacology
BAY AREA PSYCHOPHARMACOLOGY
NEWSLETTER
NEWSLETTER
Volume 7, Issue 1
March 2004
Recent Treatment Advances in Bipolar Disorder
Joanne Okuda, UCSF PharmD candidate and Renée Spencer, MA, PhD
U
ntil recently, there were no FDA approved medications for
the treatment of bipolar depression. Symbyax (SIMMbee-ax), manufactured by Eli Lilly, is a combination drug consisting of olanzapine (Zyprexa) and fluoxetine HCl (Prozac). It is
the first agent to gain FDA approval for the treatment of bipolar
depression. In addition, there are now three agents with official
FDA indications for maintenance treatment of bipolar disorder:
lithium, olanzapine, and lamotrigine (Lamictal). (Valproic acid
or Depakote and carbamazepine or Tegretol are commonly used
for maintenance but do not have FDA indications for this use).
Lastly a number of the atypical antipsychotics have recently received indications for the treatment of acute mania including
olanzapine, risperidone (Risperdal) and quetiapine (Seroquel),
while studies have been filed with the FDA for acute mania indications for aripiprazole (Abilify) and ziprasidone (Geodon).
Conventional antipsychotics have demonstrated efficacy in acute
mania but their use in bipolar disorder has been limited due to
concerns about the risks of extrapyramidal symptoms, tardive
dyskinesia, and worsening of the depressive component of bipolar disorder.
The focus of this article is on OFC (olanzapine-fluoxetine combination or Symbyax) in bipolar depression and Lamictal in bipolar maintenance.
OFC IN BIPOLAR DEPRESSION
The results of one 8-week randomized, double-blind, controlled trial sponsored by Eli Lilly were submitted to the FDA.
Tohen et al. compared the efficacy and safety of OFC, olanzapine, and placebo in 833 adults with bipolar depression. The primary measure of efficacy was change in the Montgomery-Asberg
Depression Rating Scale (MADRS) scores. Significant improvements in MADRS scores and depressive symptoms were achieved
by both the olanzapine and OFC groups compared to placebo
starting week 1 and were maintained through week 8. From week
4 continuing through week 8 the OFC group demonstrated significantly greater improvements in MADRS scores compared to
the olanzapine group (P<.002). The OFC group had a significantly greater response rate (50% or greater improvement of
MADRS score) compared to the placebo and olanzapine groups.
The remission rate (MADRS score <12) and time to reach remission were significantly higher and shorter for the OFC group than
for the placebo and olanzapine groups. Treatment-emergent mania did not differ significantly among the groups.i
Limitations of this study include a high dropout rate (placebo61.5%, olanzapine-51.6%, OFC-36%), short study duration,
INSIDE THIS ISSUE
County Insert . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .3
Risperdal Consta–Dosing Clarification . . . . . . . . . . . . . . 5
CME Calendar . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .6
small sample size for the OFC group (n=86), and possible biases
of a manufacturer-sponsored study. Presumably a treatment arm
with fluoxetine alone was not included in the study design because of the increased likelihood that antidepressant treatment
alone could induce a switch to mania.
ADVERSE EFFECTS
Common adverse effects are sedation, weight gain, dry mouth,
increased appetite, tremors, insomnia, diarrhea, sore throat, and
weakness.ii Tohen reported significant weight gain in the OFC
group compared to placebo with a mean increase of 2.79±3.23 kg.i
Orthostatic hypotension associated with syncope, dizziness, tachycardia, bradycardia were also reported. Tohen reported significant decreases of at least 30mmHg in systolic blood pressure in the OFC
group compared to placebo and olanzapine.i Cautious use in patients
with cardiovascular disease is suggested.
OFC has also been associated with an increased risk of bleeding, hyperglycemia, body temperature deregulation, hyponatremia, allergy/rash, and liver transaminase elevations (signs/symptoms of
hepatotoxicity). Neuroleptic malignant syndrome and tardive dyskinesia are potential adverse effects of olanzapine use.ii Sexual dysfunction associated with fluoxetine has been reported with OFC use.
OFC is contraindicated in concurrent use with MAO inhibitor and
thioridazine.
DRUG-DRUG INTERACTIONS
While Olanzapine is a substrate and clinically an insignificant
inhibitor of the CYP2D6 enzyme, fluoxetine is a potent inhibitor
of the CYP2D6 enzyme. Therefore, OFC may enhance the antihypertensive effects of antihypertensive medications. It may antagonize the effects of levodopa and dopamine agonists.
Phenytoin levels may elevate when used concomitantly with fluoxetine. Increased bleeding has also been reported when warfarin
and fluoxetine are coadministered.
Continued on page 2
Recent Treatment Advances in Bipolar Disorder
Risperdal Consta–Dosing Clarification
(continued)
Renée Spencer, MA, PhD
DOSAGE
Symbyax capsules are available as 6/25, 6/50, 12/25, 12/50 (mg
olanzapine/mg fluoxetine). Lilly recommends initiating therapy
with one 6/25mg capsule once daily in the evening, with or without food. Adjust dose according to efficacy and tolerability.
ISSUES
Additional studies investigating long-term use in bipolar depression (particularly related to induction of mania given the small
sample size in the Tohen study) are needed. In addition, studies
with standard of care comparator treatments such as lithium,
VPA, and lamotrigine would be informative. One advantage over
some standard treatments is that OFC does not require blood
draws for serum level monitoring. Questions about chronic use
of antipsychotics including risk of extrapyramidal symptoms and
tardive dyskinesia remain a concern, particularly in a non-psychotic population. Decreased dosing flexibility associated with
combination products may be less desirable, but compliance may
improve with the convenience of a single dosage unit. Pricing is
similar to that of olanzapine.
In summary, it is not yet clear whether OFC is as effective as
standard treatments or less toxic than standard treatments, especially related to potential risks of extrapyramidal symptoms, tardive dyskinesia, hyperglycemia, and lipid changes.
LAMOTRIGINE IN BIPOLAR MAINTENANCE
Two large, randomized, multicenter, double-blind, placebocontrolled trials of 18 months’ duration compared the efficacy and
tolerability of lamotrigine and lithium to placebo in delaying relapse or recurrence of mood episodes in patients with bipolar I disorder. Both studies were supported by GlaxoSmithKline, the
manufacturer of Lamictal.
The first study included 349 currently or recently (within 60
days) manic or hypomanic patients. In a 8-16 week open-label
phase, lamotrigine was initiated at 25mg/day, and titrated to a target dose of 100-200mg/day, while other concomitant psychotropic medications were gradually discontinued. At the end
of the open-label phase, 175 were stabilized and included in the
randomized, double-blind phase lasting up to 76 weeks. These
patients were randomized to the lamotrigine, lithium and placebo
treatment groups. The mean dose of lamotrigine was 211 mg/day.
The primary outcome measure was the time to intervention for a
mood episode (depressive, manic, hypomanic, mixed). Both
lithium and lamotrigine were superior to placebo in prolonging
the time to intervention. Lamotrigine significantly prolonged
time to a depressive episode. Lithium significantly prolonged
time to a manic, hypomanic, or mixed episode. The lamotrigine
treatment group reported a median of 141 intervention-free days
compared to 85 days for patients receiving placebo.iii
The second study is similar in design to the study described above
except 966 currently or recently (within 60 days) depressed patients with bipolar I disorder were enrolled. At the end of the 816 week lamotrigine initiation phase, 463 were stabilized and
randomized to either the lamotrigine (50, 200, 400mg/day,
n=221), lithium (n=121) or placebo (n=121) treatment group lasting for up to 76 weeks. Both lithium and lamotrigine significantly
prolonged time to intervention longer than placebo. Lamotrigine
significantly prolonged time to a depressive episode.iv There were
no significant differences between lithium & lamotrigine on
efficacy measures in either study except for delaying time to a
manic/hypomanic episode. Lamotrigine showed efficacy in
Page 2
delaying time to a manic/hypomanic episode in pooled data only
(both studies described above) and lithium was superior to lamotrigine on this measure.
Despite strong evidence supporting the efficacy of lamotrigine in
bipolar disorder treatment, there are also studies that did not show
superiority of lamotrigine over placebo. The agent does not appear
effective for the treatment of acute mania or mixed episodes.
Lamotrigine has been shown to be superior to gabapentin in the treatment of refractory mood disorders.v
ADVERSE EFFECTS
Lamotrigine has a black-box warning regarding its potential to induce serious life-threatening rashes, including Stevens-Johnson
Syndrome. There is an increased risk in the pediatric population
(0.8%) compared to adults (0.3%). Dose titration should occur
slowly. Rapid dose escalation is associated with an increased risk for
serious rashes. Although some rashes may be benign, there is no way
of distinguishing a benign rash from a serious rash. Lamotrigine
should be discontinued at the first sign of rash. Discontinuation may
not prevent a rash from becoming life-threatening, disabling, or disfiguring.vi
Common adverse effects are dizziness, headache, blurred or double
vision, lack of coordination, sedation, nausea, vomiting, insomnia,
and rash.vi Lamotrigine is not associated with significant weight gain.
Lamotrigine overdose can be fatal (>15g). High-risk suicidal patients
should be monitored closely.
DRUG-DRUG INTERACTIONS
Enzyme-inducers (carbamazepine, phenytoin, phenobarbital, primidone, rifamycins) and oral contraceptives can decrease lamotrigine levels. Valproate may increase lamotrigine levels. Lamotrigine may
increase the toxicity of carbamazepine and decrease valproate levels.vi
Adjustments to the initial and target dosages are required if co-administered with valproate or carbamazepine.
DOSAGE
The target dose for bipolar maintenance is 200 mg/day. With concomitant use with valproate, the target dose is 100 mg/day and with
carbamazepine or other enzyme-inducing drugs, the target dose can
reach 400 mg/day. Doses exceeding 200 mg/day are not recommended. Lamotrigine should be initiated at 25 mg/day and slowly
titrated to the target dose. GlaxoSmithKline recommends increasing
the dose to 50 mg/day at week 3, then to 100 mg/day at week 5, and
finally to 200 mg/day at week 6 for patients not taking concurrent
enzyme-inducing or inhibiting medications. Slower dose escalation
strategies are sometimes used, particularly in patients taking valproate
concurrently.
A
t the time that the December issue went to press, complete
dosing information was not yet available from Janssen for
Risperdal Consta (risperidone long-acting injectable). The article
in the December issue incorrectly stated that initial dosing is twotiered with patients stabilized on oral risperidone doses of 4 mg
daily or less starting at 25 mg of the long-acting injection and patients taking greater than 4 mg daily of oral risperidone starting on
37.5 mg of the long-acting injection. The current recommended
dosing strategy is to start all patients on risperidone long-acting 25
mg once every two weeks regardless of the previous oral risperidone
dose (or oral other oral antipsychotic dose) on which a patient is
stabilized. Patients receiving the higher dosage (50 mg q2 weeks) of
risperidone long-acting injectable did not have better responses
than those who received lower doses, however they experienced increased side effects, particularly extrapyramidal effects.
INITIAL DOSING AND DOSAGE INCREASES
After a single intramuscular (IM) injection of long-acting risperdone, there is a small initial release of the drug followed by a lag
time of three weeks. The main release of the drug starts from three
weeks onward, is maintained for four to six weeks, and subsides by
seven weeks following the IM injection. Steady state plasma levels
are reached after six weeks or four consecutive injections of longacting risperidone injection. Efficacy does not appear to be dependent on steady state level and occurs three weeks after the first
injection.
All patients should be started on 25 mg of risperidone long-acting injection once every two weeks. The dose of risperidone longacting should not be increased beyond the initial 25 mg dose until
at least four weeks or after three consecutive injections (it may be
more prudent to wait six to eight weeks until steady-state is
achieved). If necessary, the dose may then be increased to 37.5 mg
every two weeks. Any further dose increase to the 50 mg maximum
dose should not occur sooner than a minimum of three injections
or four weeks of treatment at the 37.5 mg dose due to the delayed
effect of risperidone long-acting (again it may be more prudent to
wait six to eight weeks until a new steady-state is achieved). Upon
discontinuation, steady state plasma levels are maintained for four
weeks after the last injection.
Oral risperidone or another antipsychotic medication should be
taken for the first 3 weeks of treatment with long-acting risperidone injection due to the delayed onset of effect of the microsphere delivery
The maximum dosage for risperidone long-acting is 50 mg every
2 weeks. If oral risperidone is required in addition to the injection,
the maximum daily dose of oral risperidone is 4 mg. Dosing recommendations are the same for otherwise healthy elderly patients and
nonelderly patients. Patients with renal and hepatic impairment
should be treated with titrated doses of oral risperidone prior to initiating treatment with risperidone long-acting. If a dose of at least 2
mg oral risperidone is well tolerated, an injection of 25 mg risperidone long-acting can be administered every 2 weeks. In children under 18 years, risperidone long-acting is not recommended as there
have been no studies done with this age group.
For patients who are on depot haloperidol or depot fluphenazine,
long-acting risperidone 25 mg can be administered instead of the
conventional depot antipsychotic at the next scheduled injection date
without oral risperidone coverage (provided they have had previous
exposure to oral risperidone and not had a hypersensitivity reaction).
Lamotrigine is more difficult to use in that it requires gradual dose
escalation over several weeks. It is not useful in treating acute mania
where a more rapid onset of efficacy is required. The risk of serious
rash is a concern, particularly when using the agent in patients who
may not be reliable for self-monitoring and reporting dermatological
changes. The agent does appear particularly effective in bipolar depression. Compared to other available treatments, it offers the advantages of not requiring serum level monitoring and being relatively
weight neutral. Efficacy and safety of lamotrigine in bipolar treatment for children and adolescents has not been studied.
MANAGING MISSED DOSES
Before steady-state plasma levels are achieved:
If more than 2 weeks have passed since the last injection, administer
long-acting risperidone as soon as possible and provide oral coverage
for 3 weeks.
After steady-state plasma levels are achieved:
If 3-6 weeks have passed since the last injection, administer risperidone long-acting injection and monitor for symptoms.
If over six weeks have passed since the last injection, administer
risperidone long-acting injection and provide coverage with oral
antipsychotic for 3 weeks.
References available upon request
March 2004
MAXIMUM DOSES
CONVERSION FROM CONVENTIONAL DEPOT TO RISPERDAL CONSTA
ISSUES
Bay Area Psychopharmacology Newsletter
system. (Note: when increasing the dose of risperidone long-acting it
will take 3 weeks for efficacy, therefore, oral coverage may be required
for breakthrough symptoms.) In patients with no previous history of
risperidone use, oral risperidone should be used initially in order to
assess tolerability prior to commencing intramuscular treatment. In
these risperidone-naïve patients, a hypersensitivity challenge can be
given with 1-2 mg/day of oral risperidone for 2 consecutive days. In
these latter risperidone-naïve patients, conversion to risperidone longacting injection would be taking place from another oral antipsychotic
or from a depot antipsychotic.
March 2004
Bay Area Psychopharmacology Newsletter
Page 5
Bay
Alameda County
A
re
a
B E H A V I O R A L H E A LT H C A R E
W
ith the close of 2003, an abundance of information
about medication prescribing and corresponding cost
data is available for BHCS programs. Monthly, over 7,600 serious and persistently mentally ill (SMI) patients were covered
through our pharmacy services. Over 15,000 prescriptions
were dispensed last year for un-insured SMI patients. Total
medication costs were $1.1 million. Incorrect billing (primarily MediCal) were identified and reversed ($160,000), as
well as rebate collection ($43,000), which reduced our medication spending to $900,000. This figure is $200,000 greater
than our previous medication budgets for the past 6 years, and
can be directly attributed to our newest crisis program Sausal
Creek, which began seeing patients in late 2002.
The MIA Program saved $509,000 in 2003. More data will
be available about this vital program will be in our next issue
of the Bay Area Psychopharmacology Newsletter.
Alameda CO. BHCS 2003: Atypical Antipsychotic
Prescriptions n=3900
Geodon Abilify Clozapine
3%
2%
5%
Zyprexa
38%
Seroquel
23%
ATYPICAL ANTIPSYCHOTICS
Prescribing of atypical antipsychotics rose in 2003 to 85%
of all written antipsychotic prescriptions. The following graph
includes the average dose, cost (30 day supply), and MIA saving through patient assistance programs (PAPs).
Our most costly antipsychotic is Abilify @ $326 per prescription. No indigent client has yet been approved for their
PAP to help defer the cost, although 3-month vouchers have
been readily available through their drug representatives.
Although 76% of the prescription doses are for 10-15mg,
18% are for 30mg, which is much more costly. It is unclear
whether this dose has improved efficacy. Abilify is currently
NOT covered by MediCal, and TAR approval is difficult.
Risperdal
29%
Over the past year, Zyprexa’s market share has declined from
45% (2002) to currently 38%. Through their PAP, we save on
average $153 per Rx, which helps reduce the average prescription
cost to $242 per Rx for our uninsured patients. Unfortunately,
Lilly is no longer covering Zyprexa doses > 20mg through their
PAP. Currently, 11% of our prescriptions reflect these higher
doses, and result in our highest prescription costs.
Geodon prescribing continues to be low, and
represents only 5% of the atypical prescriptions.
Alameda Co. BHCS 2003: Ave Atypical Antipsychotic Rx Cost Although the average BHCS dose is 105mg, over
55% of Geodon prescriptions are for 80 mg or
& MIA Savings per 30 Day Supply
less. Our BHCS Practice Guidelines require
$450
ziprasidone should be titrated to 120-160mg
within the first two months of treatment.
MIA Savings
$400
The average Risperdal dose in our population
$153
Ave $ Rx
$350
has held steady at ~ 3.0 mg for the past several
years. In addition, 88% of all prescriptions reflect
$199
$326
$300
doses of 4mg or less.
$17
Seroquel prescribing swelled in 2003 to 29% of
$250
$115
all atypical prescriptions, growth of over 10%.
$242
$231
$200
Unfortunately, 50% of all prescribed Seroquel are
$53
for doses of under 300mg. Our BHCS Practice
$150
Guidelines require quetiapine doses to be at least
$145
$139
$126
400mg within 3 months of initiation. The
$100
AstraZeneca bulk replacement program is the
$50
best functioning PAP program, and a model for
all other programs.
$0
Abilify
17.4mg
March 2004
Zyprexa
13.9mg
Geodon
104mg
Risperdal
2.9mg
Seroquel
353mg
Clozapine
335mg
Bay Area Psychopharmacology Newsletter
Page 3
Alameda County
ANTIDEPRESSANTS
Alameda Co. BHCS 2003:
Antidepressant Prescriptions
n=4394
Non-TCA antidepressants represented 97% of all
antidepressant prescriptions written in 2003. This
includes 49% for SSRIs and 48% for other antidepressants, including bupropion, venlafaxine, mirtazapine, and nefazodone.
The most commonly prescribed antidepressant was
Paxil (23%), followed by Wellbutrin (17%) and
Prozac (16%).
Paxil and Remeron became available as generic formulations in 2003, along with Prozac in 2002. Their
prices should continue to decrease to the level of
generic Prozac which is under $30/month.
The most costly antidepressant prescribed was,
ironically, a medication not often used for depression
alone: fluvoxamine. The average cost/Rx for a
1-month supply was $121. This represents the cost
for the generic formulation, since the brand formulation is no longer available.
Celexa will no longer be covered under the MediCal formulary, while Lexapro has been added to the
Medi-Cal formulary. Both are currently on the
BHCS formulary. The recommended starting dose
for Lexapro is 10mg/day, regardless of prior antidepressant dose. Lexapro should be dosed once daily,
without regard to meals. The maximum recommended dose of Lexapro is 20mg/day. Due to the fact
that Lexapro is flat-priced, when prescribing a total
daily dose of 20mg, it is substantially less costly to
prescribe a single 20mg tablet daily as opposed to two
(2) 10mg tablets.
Likewise, Effexor XR is also flat-priced. Prescriptions
that utilize, for example, Effexor XR 75mg doses divided twice daily or two (2) capsules are twice as costly
as prescriptions that utilize a single capsule of Effexor
XR 150mg daily. In addition, due to its extended release properties, Effexor XR may be dosed once-daily
Page 4
Prozac
16%
Serzone
1%
Effexor
15%
Paxil
22%
Wellbutrin
17%
Zoloft
13%
without any loss of efficacy. If tolerability is an issue, a gradual titration
to once-daily dosing could be beneficial.
Although Wellbutrin SR represented the highest cost savings within
the MIA program, it was not due to their difficult PAP. This year, we
expect Wellbutrin SR expenses to rise considerably due to the depletion of the PIC settlement medication.
MOOD STABILIZERS
g
28
m
et
in
e
Fl
uo
x
C
el
ex
a
15
30
m
m
g
g
g
pi
ne
Le
xa
pr
o
28
m
g
7m
irt
az
a
0m
25
el
lb
u
tr
in
13
W
fe
xo
r
Ef
Fl
uv
o
xa
m
in
e
12
0m
5m
g
g
$0
M
$20
g
$40
lo
ft
8
$60
Zo
$80
28
m
$121
$100
g
$120
in
e
$140
Fluvoxamine
1% Lexapro
1%
Depakote was the most prescribed mood stabilizer in 2003 (53%),
followed by lithium (17%). Agents which are being prescribed for
mood stabilization, but which have neither the FDA approval for
Bipolar Disorder nor any strong backing in the literature, comprised
almost a quarter of the market share of mood stabilizing agents. These
agents include Neurontin, Trileptal, and Topamax.
As previously mentioned, Neurontin, Trileptal, and Topamax are not
currently FDA-approved for the treatment of Bipolar Disorder.
Furthermore, neither Trileptal nor Topamax
are on the BHCS formulary. However,
they collectively represent almost one
Alameda Co. BHCS 2003:
quarter of the agents prescribed for mood
Antidepressant $ per 30 Day Supply
stabilization. Trileptal is the second most
costly agent being prescribed in this manner, at $164 per 1-month supply. If not
Ave PAP Savings
for the $17/Rx MIA savings, Trileptal
$119
Ave $ Rx
would cost $181/Rx, thus surpassing our
currently most expensive mood stabilizer
$7
Lamictal ($168/Rx). Lamictal is part of the
$96
$10
$13
$89
same unworkable PAP as Wellbutrin SR.
$85
$81
Neurontin is currently $92/Rx, but this
$71
$66
may decrease if/when the generic formulation
becomes available. PurePac Pharmaceuticals
received the approval in September 2003 to
$2
manufacture the generic.
$28
Topamax currently receives the highest
MIA savings ($56/Rx), but this is mostly
due to the use of drug stock ordered, again,
from the PIC settlement. Once this
Topamax supply is exhausted or expired,
relative MIA savings may decrease.
Pa
ro
xe
t
Ave
Celexa
6%
Remeron
8%
Bay Area Psychopharmacology Newsletter
March 2004
Recent Treatment Advances in Bipolar Disorder
Risperdal Consta–Dosing Clarification
(continued)
Renée Spencer, MA, PhD
DOSAGE
Symbyax capsules are available as 6/25, 6/50, 12/25, 12/50 (mg
olanzapine/mg fluoxetine). Lilly recommends initiating therapy
with one 6/25mg capsule once daily in the evening, with or without food. Adjust dose according to efficacy and tolerability.
ISSUES
Additional studies investigating long-term use in bipolar depression (particularly related to induction of mania given the small
sample size in the Tohen study) are needed. In addition, studies
with standard of care comparator treatments such as lithium,
VPA, and lamotrigine would be informative. One advantage over
some standard treatments is that OFC does not require blood
draws for serum level monitoring. Questions about chronic use
of antipsychotics including risk of extrapyramidal symptoms and
tardive dyskinesia remain a concern, particularly in a non-psychotic population. Decreased dosing flexibility associated with
combination products may be less desirable, but compliance may
improve with the convenience of a single dosage unit. Pricing is
similar to that of olanzapine.
In summary, it is not yet clear whether OFC is as effective as
standard treatments or less toxic than standard treatments, especially related to potential risks of extrapyramidal symptoms, tardive dyskinesia, hyperglycemia, and lipid changes.
LAMOTRIGINE IN BIPOLAR MAINTENANCE
Two large, randomized, multicenter, double-blind, placebocontrolled trials of 18 months’ duration compared the efficacy and
tolerability of lamotrigine and lithium to placebo in delaying relapse or recurrence of mood episodes in patients with bipolar I disorder. Both studies were supported by GlaxoSmithKline, the
manufacturer of Lamictal.
The first study included 349 currently or recently (within 60
days) manic or hypomanic patients. In a 8-16 week open-label
phase, lamotrigine was initiated at 25mg/day, and titrated to a target dose of 100-200mg/day, while other concomitant psychotropic medications were gradually discontinued. At the end
of the open-label phase, 175 were stabilized and included in the
randomized, double-blind phase lasting up to 76 weeks. These
patients were randomized to the lamotrigine, lithium and placebo
treatment groups. The mean dose of lamotrigine was 211 mg/day.
The primary outcome measure was the time to intervention for a
mood episode (depressive, manic, hypomanic, mixed). Both
lithium and lamotrigine were superior to placebo in prolonging
the time to intervention. Lamotrigine significantly prolonged
time to a depressive episode. Lithium significantly prolonged
time to a manic, hypomanic, or mixed episode. The lamotrigine
treatment group reported a median of 141 intervention-free days
compared to 85 days for patients receiving placebo.iii
The second study is similar in design to the study described above
except 966 currently or recently (within 60 days) depressed patients with bipolar I disorder were enrolled. At the end of the 816 week lamotrigine initiation phase, 463 were stabilized and
randomized to either the lamotrigine (50, 200, 400mg/day,
n=221), lithium (n=121) or placebo (n=121) treatment group lasting for up to 76 weeks. Both lithium and lamotrigine significantly
prolonged time to intervention longer than placebo. Lamotrigine
significantly prolonged time to a depressive episode.iv There were
no significant differences between lithium & lamotrigine on
efficacy measures in either study except for delaying time to a
manic/hypomanic episode. Lamotrigine showed efficacy in
Page 2
delaying time to a manic/hypomanic episode in pooled data only
(both studies described above) and lithium was superior to lamotrigine on this measure.
Despite strong evidence supporting the efficacy of lamotrigine in
bipolar disorder treatment, there are also studies that did not show
superiority of lamotrigine over placebo. The agent does not appear
effective for the treatment of acute mania or mixed episodes.
Lamotrigine has been shown to be superior to gabapentin in the treatment of refractory mood disorders.v
ADVERSE EFFECTS
Lamotrigine has a black-box warning regarding its potential to induce serious life-threatening rashes, including Stevens-Johnson
Syndrome. There is an increased risk in the pediatric population
(0.8%) compared to adults (0.3%). Dose titration should occur
slowly. Rapid dose escalation is associated with an increased risk for
serious rashes. Although some rashes may be benign, there is no way
of distinguishing a benign rash from a serious rash. Lamotrigine
should be discontinued at the first sign of rash. Discontinuation may
not prevent a rash from becoming life-threatening, disabling, or disfiguring.vi
Common adverse effects are dizziness, headache, blurred or double
vision, lack of coordination, sedation, nausea, vomiting, insomnia,
and rash.vi Lamotrigine is not associated with significant weight gain.
Lamotrigine overdose can be fatal (>15g). High-risk suicidal patients
should be monitored closely.
DRUG-DRUG INTERACTIONS
Enzyme-inducers (carbamazepine, phenytoin, phenobarbital, primidone, rifamycins) and oral contraceptives can decrease lamotrigine levels. Valproate may increase lamotrigine levels. Lamotrigine may
increase the toxicity of carbamazepine and decrease valproate levels.vi
Adjustments to the initial and target dosages are required if co-administered with valproate or carbamazepine.
DOSAGE
The target dose for bipolar maintenance is 200 mg/day. With concomitant use with valproate, the target dose is 100 mg/day and with
carbamazepine or other enzyme-inducing drugs, the target dose can
reach 400 mg/day. Doses exceeding 200 mg/day are not recommended. Lamotrigine should be initiated at 25 mg/day and slowly
titrated to the target dose. GlaxoSmithKline recommends increasing
the dose to 50 mg/day at week 3, then to 100 mg/day at week 5, and
finally to 200 mg/day at week 6 for patients not taking concurrent
enzyme-inducing or inhibiting medications. Slower dose escalation
strategies are sometimes used, particularly in patients taking valproate
concurrently.
A
t the time that the December issue went to press, complete
dosing information was not yet available from Janssen for
Risperdal Consta (risperidone long-acting injectable). The article
in the December issue incorrectly stated that initial dosing is twotiered with patients stabilized on oral risperidone doses of 4 mg
daily or less starting at 25 mg of the long-acting injection and patients taking greater than 4 mg daily of oral risperidone starting on
37.5 mg of the long-acting injection. The current recommended
dosing strategy is to start all patients on risperidone long-acting 25
mg once every two weeks regardless of the previous oral risperidone
dose (or oral other oral antipsychotic dose) on which a patient is
stabilized. Patients receiving the higher dosage (50 mg q2 weeks) of
risperidone long-acting injectable did not have better responses
than those who received lower doses, however they experienced increased side effects, particularly extrapyramidal effects.
INITIAL DOSING AND DOSAGE INCREASES
After a single intramuscular (IM) injection of long-acting risperdone, there is a small initial release of the drug followed by a lag
time of three weeks. The main release of the drug starts from three
weeks onward, is maintained for four to six weeks, and subsides by
seven weeks following the IM injection. Steady state plasma levels
are reached after six weeks or four consecutive injections of longacting risperidone injection. Efficacy does not appear to be dependent on steady state level and occurs three weeks after the first
injection.
All patients should be started on 25 mg of risperidone long-acting injection once every two weeks. The dose of risperidone longacting should not be increased beyond the initial 25 mg dose until
at least four weeks or after three consecutive injections (it may be
more prudent to wait six to eight weeks until steady-state is
achieved). If necessary, the dose may then be increased to 37.5 mg
every two weeks. Any further dose increase to the 50 mg maximum
dose should not occur sooner than a minimum of three injections
or four weeks of treatment at the 37.5 mg dose due to the delayed
effect of risperidone long-acting (again it may be more prudent to
wait six to eight weeks until a new steady-state is achieved). Upon
discontinuation, steady state plasma levels are maintained for four
weeks after the last injection.
Oral risperidone or another antipsychotic medication should be
taken for the first 3 weeks of treatment with long-acting risperidone injection due to the delayed onset of effect of the microsphere delivery
The maximum dosage for risperidone long-acting is 50 mg every
2 weeks. If oral risperidone is required in addition to the injection,
the maximum daily dose of oral risperidone is 4 mg. Dosing recommendations are the same for otherwise healthy elderly patients and
nonelderly patients. Patients with renal and hepatic impairment
should be treated with titrated doses of oral risperidone prior to initiating treatment with risperidone long-acting. If a dose of at least 2
mg oral risperidone is well tolerated, an injection of 25 mg risperidone long-acting can be administered every 2 weeks. In children under 18 years, risperidone long-acting is not recommended as there
have been no studies done with this age group.
For patients who are on depot haloperidol or depot fluphenazine,
long-acting risperidone 25 mg can be administered instead of the
conventional depot antipsychotic at the next scheduled injection date
without oral risperidone coverage (provided they have had previous
exposure to oral risperidone and not had a hypersensitivity reaction).
Lamotrigine is more difficult to use in that it requires gradual dose
escalation over several weeks. It is not useful in treating acute mania
where a more rapid onset of efficacy is required. The risk of serious
rash is a concern, particularly when using the agent in patients who
may not be reliable for self-monitoring and reporting dermatological
changes. The agent does appear particularly effective in bipolar depression. Compared to other available treatments, it offers the advantages of not requiring serum level monitoring and being relatively
weight neutral. Efficacy and safety of lamotrigine in bipolar treatment for children and adolescents has not been studied.
MANAGING MISSED DOSES
Before steady-state plasma levels are achieved:
If more than 2 weeks have passed since the last injection, administer
long-acting risperidone as soon as possible and provide oral coverage
for 3 weeks.
After steady-state plasma levels are achieved:
If 3-6 weeks have passed since the last injection, administer risperidone long-acting injection and monitor for symptoms.
If over six weeks have passed since the last injection, administer
risperidone long-acting injection and provide coverage with oral
antipsychotic for 3 weeks.
References available upon request
March 2004
MAXIMUM DOSES
CONVERSION FROM CONVENTIONAL DEPOT TO RISPERDAL CONSTA
ISSUES
Bay Area Psychopharmacology Newsletter
system. (Note: when increasing the dose of risperidone long-acting it
will take 3 weeks for efficacy, therefore, oral coverage may be required
for breakthrough symptoms.) In patients with no previous history of
risperidone use, oral risperidone should be used initially in order to
assess tolerability prior to commencing intramuscular treatment. In
these risperidone-naïve patients, a hypersensitivity challenge can be
given with 1-2 mg/day of oral risperidone for 2 consecutive days. In
these latter risperidone-naïve patients, conversion to risperidone longacting injection would be taking place from another oral antipsychotic
or from a depot antipsychotic.
March 2004
Bay Area Psychopharmacology Newsletter
Page 5
CONTINUING
MEDICAL EDUCATION
Bipolar Disorder and ADHD
Kiki Chang MD
March 9 12:15 - 1:30
San Mateo MHS, 225 West 37th St.
San Mateo (650) 573-2530
Metabolic Complications in Schizophrenia
Mahtab Jafari, PharmD
March 10 12:00 – 1 pm
Alameda Co BHCS 2000 Embarcadero #400
Oakland (510) 567-8106
Drugs, Diet, Herbs
Talia Puzantian, PharmD, BCPP
March 12 11:45 – 1 pm
SFGH Room #7M-30, 1001 Potrero Avenue
San Francisco (415) 206-4938
Neuroimaging Of Emotion
Processes In Social Anxiety
Phillipe Goldin Ph.D.
March 23 12:15 - 1:30
San Mateo MHS, 225 West 37th St.
San Mateo (650) 573-2530
Mood and Menopause
Jeanne Leventhal-Alexander, M.D.
March 26 11:45 – 1 pm
SFGH Room #7M-30, 1001 Potrero Avenue
San Francisco (415) 206-4938
Antipsychoitc Use in Bipolar Disorder
Mark Viner, MD
March 31 12:00 – 1 pm
Alameda Co BHCS 2000 Embarcadero #400
Oakland (510) 567-8106
Psychopharmacology of PTSD
Mark Hamner, M.D.
April 9 11:45 – 1 pm
SFGH Room #7M-30, 1001 Potrero Avenue
San Francisco (415) 206-4938
THIS
Pain Management
Barry Rosen MD
April 13 12:15 - 1:30
San Mateo MHS, 225 West 37th St.
San Mateo (650) 573-2530
Diabetes and Mental Health Disease
Kenneth R. Feingold, M.D.
April 23 11:45 – 1 pm
SFGH Room #7M-30, 1001 Potrero Avenue
San Francisco (415) 206-4938
HIV And Psychiatry
Aaron Chapman, MD
April 27 12:15 - 1:30
San Mateo MHS, 225 West 37th St.
San Mateo (650) 573-2530
Long-acting Risperdal Depot
David Feifel, MD
April 28
12:00 – 1 pm
Alameda Co BHCS 2000 Embarcadero #400
Oakland (510) 567-8106
Updates on Bipolar Disorder
Terrence Ketter, M.D.
May 7
11:45 – 1 pm
SFGH Room #7M-30, 1001 Potrero Avenue
San Francisco (415) 206-4938
Cultural Issues
Amy Chagnon, MD
May 11
12:15 - 1:30
San Mateo MHS, 225 West 37th St.
San Mateo (650) 573-2530
Editor:
Douglas Del Paggio, PharmD, MPA
2000 Embarcadero Cove, Suite 400
Oakland, California 94606-5300
(510) 567-8110 FAX (510) 567-6850
email: [email protected]
Contributors:
Alameda County:
Richard P. Singer, MD
Douglas Del Paggio, PharmD, MPA
Alice Myong, PharmD
San Francisco County:
Jimmy Jones, MD
Mary Ann Sullivan, PharmD
Renée Spencer, MA, PhD
Talia Puzantian, Pharm D
San Mateo County:
Celia Moreno, MD
Barbara Liang, PharmD
Graphic Designer: Janie Chambers
Treatment Of Binge Eating
Deborah Safer, MD
May 25 12:15 - 1:30
San Mateo MHS, 225 West 37th St.
San Mateo (650) 573-2530
NEWSLETTER IS SUPPORTED BY UNRESTRICTED EDUCATIONAL GRANTS FROM:
THE BAY AREA PSYCHOPHARMACOLOGY NEWSLETTER
Douglas Del Paggio, PharmD, MPA, Editor
2000 Embarcadero Cove, Suite 400
Oakland, California 94606-5300
Psychopharmacology
BAY AREA PSYCHOPHARMACOLOGY
NEWSLETTER
NEWSLETTER
Volume 7, Issue 1
March 2004
Recent Treatment Advances in Bipolar Disorder
Joanne Okuda, UCSF PharmD candidate and Renée Spencer, MA, PhD
U
ntil recently, there were no FDA approved medications for
the treatment of bipolar depression. Symbyax (SIMMbee-ax), manufactured by Eli Lilly, is a combination drug consisting of olanzapine (Zyprexa) and fluoxetine HCl (Prozac). It is
the first agent to gain FDA approval for the treatment of bipolar
depression. In addition, there are now three agents with official
FDA indications for maintenance treatment of bipolar disorder:
lithium, olanzapine, and lamotrigine (Lamictal). (Valproic acid
or Depakote and carbamazepine or Tegretol are commonly used
for maintenance but do not have FDA indications for this use).
Lastly a number of the atypical antipsychotics have recently received indications for the treatment of acute mania including
olanzapine, risperidone (Risperdal) and quetiapine (Seroquel),
while studies have been filed with the FDA for acute mania indications for aripiprazole (Abilify) and ziprasidone (Geodon).
Conventional antipsychotics have demonstrated efficacy in acute
mania but their use in bipolar disorder has been limited due to
concerns about the risks of extrapyramidal symptoms, tardive
dyskinesia, and worsening of the depressive component of bipolar disorder.
The focus of this article is on OFC (olanzapine-fluoxetine combination or Symbyax) in bipolar depression and Lamictal in bipolar maintenance.
OFC IN BIPOLAR DEPRESSION
The results of one 8-week randomized, double-blind, controlled trial sponsored by Eli Lilly were submitted to the FDA.
Tohen et al. compared the efficacy and safety of OFC, olanzapine, and placebo in 833 adults with bipolar depression. The primary measure of efficacy was change in the Montgomery-Asberg
Depression Rating Scale (MADRS) scores. Significant improvements in MADRS scores and depressive symptoms were achieved
by both the olanzapine and OFC groups compared to placebo
starting week 1 and were maintained through week 8. From week
4 continuing through week 8 the OFC group demonstrated significantly greater improvements in MADRS scores compared to
the olanzapine group (P<.002). The OFC group had a significantly greater response rate (50% or greater improvement of
MADRS score) compared to the placebo and olanzapine groups.
The remission rate (MADRS score <12) and time to reach remission were significantly higher and shorter for the OFC group than
for the placebo and olanzapine groups. Treatment-emergent mania did not differ significantly among the groups.i
Limitations of this study include a high dropout rate (placebo61.5%, olanzapine-51.6%, OFC-36%), short study duration,
INSIDE THIS ISSUE
County Insert . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .3
Risperdal Consta–Dosing Clarification . . . . . . . . . . . . . . 5
CME Calendar . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .6
small sample size for the OFC group (n=86), and possible biases
of a manufacturer-sponsored study. Presumably a treatment arm
with fluoxetine alone was not included in the study design because of the increased likelihood that antidepressant treatment
alone could induce a switch to mania.
ADVERSE EFFECTS
Common adverse effects are sedation, weight gain, dry mouth,
increased appetite, tremors, insomnia, diarrhea, sore throat, and
weakness.ii Tohen reported significant weight gain in the OFC
group compared to placebo with a mean increase of 2.79±3.23 kg.i
Orthostatic hypotension associated with syncope, dizziness, tachycardia, bradycardia were also reported. Tohen reported significant decreases of at least 30mmHg in systolic blood pressure in the OFC
group compared to placebo and olanzapine.i Cautious use in patients
with cardiovascular disease is suggested.
OFC has also been associated with an increased risk of bleeding, hyperglycemia, body temperature deregulation, hyponatremia, allergy/rash, and liver transaminase elevations (signs/symptoms of
hepatotoxicity). Neuroleptic malignant syndrome and tardive dyskinesia are potential adverse effects of olanzapine use.ii Sexual dysfunction associated with fluoxetine has been reported with OFC use.
OFC is contraindicated in concurrent use with MAO inhibitor and
thioridazine.
DRUG-DRUG INTERACTIONS
While Olanzapine is a substrate and clinically an insignificant
inhibitor of the CYP2D6 enzyme, fluoxetine is a potent inhibitor
of the CYP2D6 enzyme. Therefore, OFC may enhance the antihypertensive effects of antihypertensive medications. It may antagonize the effects of levodopa and dopamine agonists.
Phenytoin levels may elevate when used concomitantly with fluoxetine. Increased bleeding has also been reported when warfarin
and fluoxetine are coadministered.
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