Switching from Standard Divalproex to Extended Release in Schizophrenia
351 Leslie Citrome, MD, MPH; Fabien Tremeau, MD; Pe Shein Wynn, MD, MPH; Biman Roy, MD; Hassan Dinakar, MD
Nathan S. Kline Institute for Psychiatric Research, Orangeburg, NY; New York University School of Medicine, Department of Psychiatry, New York, NY, and Rockland Psychiatric Center, Orangeburg, NY
Abstract
Objective: To assess the safety, efficacy, and tolerability of switching from a multiple dose preparation
of divalproex sodium delayed release (DR) to once daily dosing with divalproex sodium extended
release (ER) in patients with schizophrenia already receiving the standard DR formulation.
Method: Thirty subjects with schizophrenia were switched from divalproex DR to a four-week
open-label treatment trial of the ER formulation. Baseline plasma levels of valproate were obtained
12 hours post dose. Patients were converted from divalproex DR to ER on a mg per mg basis (rounded
up to the nearest 500 mg increment) if baseline valproate plasma levels were greater than or equal to
85 mcg/mL, otherwise the conversion rate was 1.0 mg to 1.2 mg, rounded up. Measured at baseline
and end-point were the Brief Psychiatric Rating Scale (BPRS) and the UKU Side Effect Scale. Endpoint
plasma levels were obtained at both 12 hours and 24 hours post dose.
Results: Patients switched from divalproex DR to ER had a small improvement noted on the total
BPRS at endpoint (mean change -2.3±5.4; t=-2.2538; df=28; p=0.0322) and on the UKU (mean
change -2.2±4.1; t=-2.7361; df=26; p=0.0111). Baseline and endpoint trough plasma levels were
80.1±20.4 mcg/mL and 73.1±24.2 mcg/mL respectively. Patients converted on a 1.0 mg per 1.0 mg
basis had lower end-point valproate trough plasma levels than at baseline, but did not experience
deterioration on their psychopathology. For all patients, endpoint valproate peak and trough plasma
levels were statistically significantly different (t=-3.8706; df=27; p=0.0006), but these differences
were small in magnitude (mean 14.6±19.6 mcg/mL).
Conclusions: Switching to a once daily formulation of extended release divalproex can be
accomplished without a deterioration in psychopathology. The extended release formulation
of divalproex sodium appears well-tolerated.
Introduction
Although there is no FDA-approved indication for the use of valproate in patients with schizophrenia,
it is extensively prescribed in this population (see adjacent poster #350). Until recently, there have
been two commonly prescribed preparations of valproate, valproic acid and divalproex sodium delayed
release. Equivalent oral doses of either preparation deliver equivalent quantities of the valproate
molecule systemically1. Introduced in 2000 is an extended release (ER) preparation of divalproex
sodium. The FDA-approved indications are for prophylaxis of migraine headaches and for seizure
disorder. It is intended for once-a-day oral administration. However, this formulation is not bioequivalent
to the standard delayed release tablets (DR); the ER tablet produces an average bioavailability of
81 – 89% relative to DR tablets given BID2,3.
Information on switching from DR to ER is limited. Published reports include an open-label 7-day
study of 55 patients with bipolar disorder, major depression, schizophrenia, schizoaffective disorder,
Alzheimer’s disease, dementia, or intermittent explosive disorder4. Patients were successfully switched
on a mg per mg basis. In a report of 12 patients with bipolar disorder or schizoaffective disorder
switched to ER in an open-label 6-week trial, doses were adjusted to maintain steady serum valproate
concentrations5. Although the switch was well-tolerated, 21% higher doses of the ER preparation were
required. Both of the above reports4, 5 are limited by their lack of a parallel group design and diagnostic
heterogeneity.
Switching to a once daily preparation of valproate may result in improved compliance and lower risk of
relapse for those patients with schizophrenia who derive benefit from adjunctive valproate, and perhaps
greater patient satisfaction. To our knowledge, this is the first report of a systematic study examining
the feasibility of switching to ER from DR in patients with schizophrenia (and excluding patients with
schizoaffective or bipolar disorder).
Supported by funding from Abbott Laboratories
Methods
The study was conducted with inpatients and outpatients at Rockland Psychiatric Center (RPC),
a 400-bed hospital operated by New York State Office of Mental Health. The outpatients were housed
in residential facilities maintained on the hospital campus. Regardless of location, medications were
administered under the supervision of facility staff.
In this open-label study, 30 subjects were switched from the standard formulation of divalproex
sodium to a four-week treatment trial of the extended release formulation. No medication-free period
was involved. All subjects were between the ages of 18 to 65 years, with a chart diagnosis of DSM-IV
schizophrenia (supplemented by a SCID diagnosis of schizophrenia for those treated on the specialized
inpatient research unit) who have received the same daily dose of divalproex sodium within the range
of 1000 to 3000 mg/day for at least 4 weeks. Patients with a diagnosis of schizoaffective or bipolar
disorder were not eligible to participate in this study. Patients who were receiving divalproex for the
purposes of seizure or migraine headache prophylaxis were also excluded from participation.
The principal dependent variable was the total Brief Psychiatric Rating Scale (BPRS) score6
administered at baseline and endpoint by the same rater for each subject. The BPRS is used routinely
by RPC clinicians in the regular assessment of their patients. Facility-wide training in the use of the
BPRS, including the scoring of interviews observed on videotape, was provided by one of the authors
(LC), however inter-rater reliability measures were not calculated.
The secondary outcome measure was the UKU Side Effect Rating Scale7, which allows for the
systematic assessment of side effects in several categories: psychic, neurologic, autonomic,
and other. Spontaneously occurring adverse events were also recorded when they occurred.
Baseline valproate plasma levels were measured 12 hours post dose. Endpoint valproate plasma levels
were measured at both 12 hours and 24 hours post dose. Valproate plasma levels were not obtained
in between baseline and endpoint. Additional safety measures included baseline and endpoint blood
chemistry and CBC, including platelet count.
Patients were converted on a mg per mg basis to the ER formulation if baseline trough (12 hour)
plasma levels of valproate were greater than or equal to 85 mcg/mL. If baseline trough plasma level
of valproate was less than 85 mcg/mL, the conversion rate was 1 mg standard formulation to 1.2 mg
ER, rounded up. All conversions were rounded up to the nearest 500 mg increment (the 250 mg ER
tablet was not available at study initiation) (e.g., all possible ER doses were 1000, 1500, 2000, 2500,
3000, 3500, and 4000 mg/day – the latter two dosages could be used only if baseline plasma levels of
valproate were less than 85 mcg/mL). The rationale for the 1:1 conversion came from a report (initially
a poster when this study was designed) where a mg per mg switch was successful in a randomized
crossover study of extended-release vs. enteric-coated formulations of divalproex sodium in epileptic
patients8. The concern about the bioavailablity of the ER formulation being less than that of standard
divalproex sodium was mitigated in our study by the provision of a baseline plasma level “floor”
that minimizes the risk of decompensation should bioavailability issues reduce the plasma levels to
a subtherapeutic amount. The study medication was given daily at 8 AM. There were no changes to
divalproex dosing during the course of the study. Inasmuch as possible, other standing medications
were also held constant.
The primary analysis tested the hypothesis that conversion to ER would result in no deterioration in the
total BPRS score. The sample size was selected on the basis of logistical constraints; a power analysis
was not done. We compared baseline and endpoint total BPRS scores using the paired t-test. Secondary
analyses tested the hypotheses that conversion to ER will result in lower UKU Side Effect Scores. This
was examined by using paired t-tests (two-tailed).
Baseline and endpoint plasma valproate levels were compared using paired t-tests (two-tailed) to test
the hypothesis that conversion to the ER formulation will result in lower plasma levels if the switch is
done on a mg per mg basis.
Presented at the 157th Annual Meeting of the American Psychiatric Association, New York City, NY • May 4, 2004.
In Press in the Journal of Clinical Psychopharmacology.
Results
A total of 30 subjects with schizophrenia were recruited, with 27 completing
the entire 28-day treatment period. There were 25 (83%) males and
5 (17%) females. Most of the subjects (N=20) were inpatients, the remaining
ten were outpatients. The average age (with standard deviation) was
38.5±10.5 years and the average number of psychiatric hospitalizations was
15±13. Ethnicity of the study participants were 17 (57%) African-American,
6 (20%) White, 6 (20%) Hispanic, and 1 (3%) Other.
Mean baseline BPRS total score was 37.9±9.2 (N=30). Endpoint average
was 35.7±11.2 (N=29). Mean change and standard deviation for the total
BPRS score was thus -2.3±5.4 (N=29). Figure 1 illustrates the variability
of the changes in total BPRS scores.
Figure 1. Change in BPRS and UKU Scores
from Baseline to Endpoint
15
10
5 improvements in the UKU Side Effect Scale total score. Pharmacokinetic studies8 have established that
0 and who may have been covertly non-compliant with medication treatment.
-5
-10
-15
-20
Total BPRS Score UKU Side Effect Scale
Mean Change = -2.3±5.4 Mean Change = -2.2±4.1
(N=29) (N=27)
Using paired t-tests, a statistically significant difference (improvement)
was found between baseline and endpoint on the total BPRS score for
the entire sample (t=-2.2538; df=28; p=0.0322), and marginally for the
group that was switched on a 1.0 mg per 1.0 mg basis (N=12) (mean
change=-2.8±4.1; t=-2.1596; df=10; p=0.0561). For the group that
was switched on a 1.2 mg per 1.0 mg basis (N=18), this difference was
not statistically significant (mean change=-2.0±6.3; t=-1.2698; df=16;
p=0.2223).
Mean baseline UKU total score was 8.8±6.7 (N=29). Endpoint average
was 7.5±5.8 (N=28). Usable baseline and endpoint UKU ratings were
available for 27 subjects, resulting in mean change and standard deviation
for the total UKU score to be -2.2±4.1. Using paired t-tests, a statistically
significant difference was found between baseline and endpoint on the total
UKU score for the entire sample (t=-2.7361; df=26; p=0.0111).
Figure 2. Valproate Plasma Levels:
Trough-Trough and Peak-Trough Differences (mcg/mL)
60
40
20
0 baseline) are clinically significant.
-20
-40
-60
-80
Trough-Trough Trough-Trough Endpoint
1:1.2 Conversion 1:1 Conversion Peak-Trough
Mean=3.3±34.9 Mean=-21.3±25.0 Mean=14.6±19.6
(N=17) (N=10)* (N=28)
* Excluding subject with unusually low endpoint plasma levels (trough 10 mcg/mL)
Figure 2 illustrates the changes in plasma levels of valproate. Trough levels
were obtained 12 hours post dose for the standard formulation and 24 hours
post dose for the ER formulation. Endpoint peak levels were obtained
12 hours post dose for the ER formulation.
Mean and standard deviation of divalproex daily dose at study entry was
1592±498 mg. This resulted in an average and standard deviation baseline
trough plasma level of 80.1±20.4 mcg/mL (N=30). Endpoint mean and
standard deviation of divalproex dose was 1950±592 mg per day. This
resulted in an average and standard deviation endpoint trough plasma level
of 73.1±24.2 mcg/mL (N=27). The average and standard deviation of the
plasma valproate trough-trough differences between baseline and endpoint
for the 1:1.2 conversion group was 3.3±34.9 mcg/mL. That for the 1:1
conversion group was -21.3±25.0 mcg/mL. The plasma valproate trough-
trough differences between baseline and endpoint for the 1 mg per 1 mg
switch group were statistically significant (t=-2.5560; df=9; p=0.0309),
but this was not the case for the subjects whose dose was increased
on a 1.2 mg per mg basis (t=0.3782; df=16; p=0.7102). The average and
standard deviation of the plasma valproate peak-trough differences at
endpoint was 14.6±19.6 mcg/mL, and was statistically significant
(t=-3.8706; df=27; p=0.0006).
Discussion/Conclusions
Although the two formulations of valproate, divalproex sodium extended release (ER) and the traditional
divalproex sodium delayed release (DR) formulations, are not bioequivalent, switching was successful
(i.e., no deterioration in psychopathology) even when conversion was done on a 1.0 mg per 1.0 mg
basis. This was also seen in prior studies of patients with seizure disorder8 and in a group of 55 patients
with a wide range of psychiatric disorders4. For our subjects whose baseline plasma levels were less
than 85 mcg/mL, the switch was also well-tolerated, even though the daily dose was increased using
a conversion rate of 1 mg to 1.2 mg, rounded up. The statistically significant improvement in total
BPRS scores, observed in the total sample and marginally among the subjects converted on a 1.0 mg
per 1.0 mg basis, is small. It may represent the effect of additional time that the subjects are receiving
treatment. It is doubtful that these small changes in the BPRS (approximately a 6% improvement from
As expected, plasma levels of valproate were lower with the ER preparation when converting on
a 1.0 mg per 1.0 mg basis. Converting on 1.2 mg per 1.0 mg basis resulted in equivalent trough levels
for the two preparations. These differences in plasma levels may not be clinically meaningful and may
not result in any perceived improvement or worsening of psychopathology.
Tolerability and side effects may be related to fluctuations in plasma levels. We have demonstrated
peak-trough differences (mean ± standard deviation 14.6±19.6) that were statistically significant,
but substantially less than comparable work done with the standard formulation of divalproex. This
may explain our observation that the ER formulation was associated with statistically significant
ER achieves a lower Cmax central value and a higher Cmin mean than the corresponding values for the
DR formulation, even after the daily dose of divalproex was increased by 14 – 20% when converting to
the ER preparation. In that study mean peak-to-trough fluctuations of valproate plasma concentrations
were 42 – 48% lower for the ER formulation compared with the DR (i.e., for 1500 mg ER, the peak-
trough difference was 33.8 mcg/mL, but for 1250 mg DR the difference was 60.6 mcg/ml). Reducing
fluctuations may reduce side effects associated with peak plasma values. On the other hand,
fluctuations may not be relevant with regard to side effects such as local gastrointestinal irritation.
The effect of once daily dosing on medication adherence could not be assessed in our study because
all subjects were administered medications under supervised conditions. However, we speculate that
the convenience of once daily dosing, combined with a favorable tolerability profile, may enhance
compliance with valproate in this challenging treatment population.
References
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Montvale, NJ: Thomson PDR, 2003:416-441.
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This poster contains information that has not been
approved by the U.S. Food and Drug Administration.
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