Macritchie K, Geddes JR, Scott J, Haslam D, de Lima M, Goodwin
Department of Psychiatry, University of Oxford, Warneford Hospital, Oxford,
OXON, UK, OX3 7JX. email@example.com
Valproate for acute
mood episodes in bipolar disorder.
Cochrane Database Syst
"BACKGROUND: Bipolar disorder is a common debilitating
illness, characterised by acute affective episodes with full or partial inter-episode
remission. Effective and acceptable treatment of acute episodes is required. Valproate
has become a leading adjunctive and alternative mood stabilising treatment to
lithium in bipolar disorder. OBJECTIVES: To determine the efficacy and acceptability
of valproate in the treatment of acute episodes of bipolar disorder. SEARCH STRATEGY:
The search included the Cochrane Collaboration Depression, Anxiety and Neurosis
Controlled Trials Registrar (CCDANCTR), the Cochrane Controlled Clinical Trials
Register (CCTR), reference lists of relevant papers and books, and contact with
authors of trials, experts and pharmaceutical companies. SELECTION CRITERIA: Randomised
controlled trials comparing valproate with placebo, other mood stabilisers and
antipsychotic medication in the treatment of any bipolar affective episode. Participants
were of both sexes, of all ages, with a diagnosis of bipolar affective disorder
approximating to ICD 10 Code F31 and DSM IV 296. DATA COLLECTION AND ANALYSIS:
Methodological quality was assessed independently by two reviewers blind to the
authorship and source of papers. Ten randomised controlled trials were found comparing
valproate with other interventions in mania. None was found examining its use
in depression or mixed affective episodes. Data were extracted on the main outcome
'failure to respond by the end of the study' assessed by a less than 50% reduction
in the Young Mania Rating Scale or the SADS-S mania scale. Three trials (316 participants)
compared valproate with placebo. Three trials (158 participants) compared valproate
with lithium. Two trials (363 participants) compared valproate with olanzapine.
One trial (36 participants) compared valproate with haloperidol. Two trials (59
patients) compared valproate with carbamazepine. Acceptability of treatment was
estimated using the outcome measure 'total number of subjects withdrawing from
the study'. Three trials (321 patients) contributed to the comparison between
valproate and placebo, two studies (144 patients) contributed to the comparison
with lithium. One study (30 patients) provided data on this outcome in the comparison
between valproate and carbamazepine. Pooled relative risks (with 95% confidence
intervals) were calculated using fixed effect approaches. MAIN RESULTS: Valproate
was more efficacious than placebo (RRR 38%; RR 0.62; 95% C.I. 0.51 to 0.77) in
the treatment of mania. There was no significant difference between valproate
and lithium (RRI 5%; RR 1.05; 95% C.I. 0.74-1.50) or between valproate and carbamazepine
(RRR 34%; RR 0.66; 95% C.I. 0.38 to 1.16). Valproate was less effective than olanzapine
(failure to achieve clinical response; RRI 25%; RR 1.25, 95% C.I. 1.01 to 1.54;
average of 2.8 point less change on the Mania Rating Scale (95% CI 0.83 to 4.79).
There were no significant differences in acceptability as measured by total number
of subjects withdrawing from the study. There were significant differences in
the side effect profiles of valproate and olanzapine, with more sedation and weight
gain on olanzapine. REVIEWER'S CONCLUSIONS: There is consistent, if limited, evidence
to suggest that valproate is an efficacious treatment for acute mania. Valproate
may be less effective than olanzapine but may cause less sedation and weight gain.
More well designed, randomised controlled trials investigating the relative efficacy
and acceptability of valproate in the treatment of the full range of acute affective
episodes occurring in bipolar disorder are required." [Abstract]
RM, Baker JD, Wozniak P, Tracy K, Sommerville KW.
University of Texas Medical
Branch at Galveston, Galveston, USA. firstname.lastname@example.org
and early efficacy of oral-loaded divalproex versus standard-titration divalproex,
lithium, olanzapine, and placebo in the treatment of acute mania associated with
J Clin Psychiatry. 2003 Jul;64(7):841-6.
Previous studies have examined the safety and tolerability of oral-loaded divalproex
sodium in the treatment of acute mania, but not the early efficacy of this dosing
strategy. The purpose of this study was to evaluate the early efficacy of oral-loaded
divalproex. METHOD: In this pooled analysis, 348 subjects from 3 randomized, double-blind,
parallel-group, active- or placebo-controlled studies were used to compare the
efficacy, safety, and tolerability of oral-loaded divalproex with standard-titration
divalproex, lithium, olanzapine, or placebo. Subjects were inpatients diagnosed
with acute mania associated with bipolar I disorder (DSM-III-R or -IV and SADS-Change
Version). Patients were administered oral-loaded divalproex (20 or 30 mg/kg/day
on days 1 and 2 followed by 20 mg/kg/day, and increased at physician's discretion),
standard-titration divalproex initiated at 250 mg t.i.d. and titrated to 40-150
microg/mL, lithium (300 mg t.i.d. initial dose) titrated to 0.4 to 1.5 mEq/L,
olanzapine (10 mg q.d. initial dose) up to 20 mg/day, or placebo. RESULTS: The
results demonstrate an early efficacy advantage for oral-loaded divalproex compared
to standard-titration divalproex at days 5, 7/8, and 10. Efficacy was improved
over lithium on day 7/8. There were no efficacy differences between divalproex
loading and olanzapine. Divalproex loading showed greater efficacy than placebo
at all time points. Divalproex loading was as well tolerated or better tolerated
than the other active treatments as measured by adverse events and changes in
laboratory parameters. CONCLUSION: These results suggest the oral loading of divalproex
leads to a more rapid antimanic effect when compared with standard-titration divalproex,
lithium, or placebo and is better tolerated than olanzapine and as well tolerated
as lithium or standard-titration divalproex." [Abstract]
JM, Weisler R, Sachs G, Swann AC, Wozniak P, Sommerville KW.
St. Luke's Medical Center, Chicago, Ill 60612-3824, USA. John_Zajecka@rush.edu
comparison of the efficacy, safety, and tolerability of divalproex sodium and
olanzapine in the treatment of bipolar disorder.
Psychiatry. 2002 Dec;63(12):1148-55.
"BACKGROUND: This study compared
the efficacy, safety, and tolerability of divalproex and olanzapine in the treatment
of acute mania associated with bipolar disorder. METHOD: This randomized, 12-week,
double-blind, parallel-group, multicenter study included DSM-IV-defined bipolar
disorder type I patients hospitalized for acute mania and randomly assigned to
treatment with divalproex or olanzapine. After an inpatient period of up to 21
days, subjects were followed as outpatients. Dose adjustment was permitted during
the inpatient period. Efficacy was assessed using change from baseline in Mania
Rating Scale (MRS) score to day 21; other efficacy measures included the Brief
Psychiatric Rating Scale, the Hamilton Rating Scale for Depression, and the Clinical
Global Impressions-Part I, Severity of Illness scale. The primary safety endpoint
was change from baseline in weight. Other safety and tolerability endpoints included
spontaneous adverse event reporting and changes from baseline in laboratory measures
and vital signs. RESULTS: 120 subjects (N = 63 divalproex, N = 57 olanzapine)
were randomly assigned to treatment. No significant differences between groups
were found for any efficacy variable for change from baseline to day 21. Mean
MRS score changes from baseline to day 21 were -14.8 for divalproex and -17.2
for olanzapine (p =.210). A significantly (p <.05) greater proportion of olanzapine-treated
subjects experienced somnolence, weight gain, edema, rhinitis, and speech disorder
(slurred speech); no adverse events were significantly greater in the divalproex
group. A number of laboratory measures also demonstrated significant treatment
differences, but the clinical significance of many of these is uncertain. Mean
body weight changes were significantly greater in the olanzapine group (+ 8.8
lb [+ 4.0 kg]) than the divalproex group (+ 5.5 lb [+ 2.5 kg], p <.050). One
death occurred during the study (olanzapine group, diabetic ketoacidosis). CONCLUSION:
No significant difference in efficacy was found between treatment groups. Divalproex
was associated with a more favorable adverse event profile and significantly less
weight gain than olanzapine." [Abstract]
M, Ketter TA, Zarate CA, Suppes T, Frye M, Altshuler L, Zajecka J, Schuh LM, Risser
RC, Brown E, Baker RW.
Lilly Research Laboratories, IN 46285, USA. email@example.com
versus divalproex sodium for the treatment of acute mania and maintenance of remission:
a 47-week study.
Am J Psychiatry. 2003 Jul;160(7):1263-71.
Few double-blind trials have compared longer-term efficacy and safety of medications
for bipolar disorder. The authors report a 47-week comparison of olanzapine and
divalproex. METHOD: This 47-week, randomized, double-blind study compared flexibly
dosed olanzapine (5-20 mg/day) to divalproex (500-2500 mg/day) for manic or mixed
episodes of bipolar disorder (N=251). The only other psychoactive medication allowed
was lorazepam for agitation. The primary efficacy instrument was the Young Mania
Rating Scale; a priori protocol-defined threshold scores were > or =20 for
inclusion, < or =12 for remission, and > or = 15 for relapse. Analytical
techniques included mixed model repeated-measures analysis of variance for change
from baseline, Fisher's exact test (two-tailed) for categorical comparisons, and
Kaplan-Meier estimates of time to events of interest. RESULTS: Over 47 weeks,
mean improvement in Young Mania Rating Scale score was significantly greater for
the olanzapine group. Median time to symptomatic mania remission was significantly
shorter for olanzapine, 14 days, than for divalproex, 62 days. There were no significant
differences between treatments in the rates of symptomatic mania remission over
the 47 weeks (56.8% and 45.5%, respectively) and subsequent relapse into mania
or depression (42.3% and 56.5%). Treatment-emergent adverse events occurring significantly
more frequently during olanzapine treatment were somnolence, dry mouth, increased
appetite, weight gain, akathisia, and high alanine aminotransferase levels; those
for divalproex were nausea and nervousness. CONCLUSIONS: In this 47-week study
of acute bipolar mania, symptomatic remission occurred sooner and overall mania
improvement was greater for olanzapine than for divalproex, but rates of bipolar
relapse did not differ." [Abstract]
DA, Paramore LC, Sommerville KW, Swann AC, Zajecka JM; Depakote Comparator Study
Center for Outcomes Research, MEDTAP International, Bethesda, MD 20814,
Divalproex sodium versus olanzapine in the
treatment of acute mania in bipolar disorder: health-related quality of life and
medical cost outcomes.
J Clin Psychiatry. 2003 Mar;64(3):288-94.
Divalproex sodium is a mood stabilizer used in the United States for the treatment
of acute mania associated with bipolar disorder. Recently, olanzapine, an atypical
antipsychotic, was approved for the treatment of acute mania. This study compares
the clinical, health-related quality of life (HRQL), and economic outcomes of
divalproex and olanzapine in the treatment of acute mania associated with bipolar
disorder. METHOD: This 12-week, double-blind, double-dummy, randomized clinical
trial included 120 subjects with DSM-IV bipolar disorder type I hospitalized for
an acute manic episode recruited from 21 U.S. clinical centers. Subjects were
randomly assigned to treatment with either divalproex or olanzapine and were followed
in hospital for up to 21 days. If after 21 days clinical improvements (based on
the Mania Rating Scale [MRS]) were not observed, subjects were discontinued. Subjects
showing clinical improvement were treated for up to 12 weeks. HRQL was assessed
using the Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q) after
hospital discharge (baseline) and at 6 and 12 weeks. Medical resource use and
costs were collected over the 12-week study. RESULTS: A total of 120 subjects
(N = 63 divalproex, N = 57 olanzapine) were randomized, and 78 (65%) were followed
beyond 21 days. No statistically significant differences between the treatment
groups for baseline-to-endpoint MRS or Q-LES-Q scores were observed. Total 12-week
outpatient medical costs were significantly lower for the divalproex-treated group
(541 US dollars) compared with the olanzapine-treated group (1080 US dollars)
(p =.004). There was no significant difference in total medical costs between
the 2 groups (divalproex = 13,703 US dollars; olanzapine = 15,180 US dollars;
p =.88). CONCLUSION: Divalproex is associated with lower 12-week outpatient costs
compared with olanzapine. Divalproex and olanzapine have similar short-term effects
on clinical or HRQL outcomes in bipolar disorder subjects." [Abstract]
M, Baker RW, Altshuler LL, Zarate CA, Suppes T, Ketter TA, Milton DR, Risser R,
Gilmore JA, Breier A, Tollefson GA.
Lilly Research Laboratories, Indianapolis,
IN 46285, USA. firstname.lastname@example.org
Olanzapine versus divalproex in
the treatment of acute mania.
Am J Psychiatry. 2002 Jun;159(6):1011-7.
The effects of olanzapine and divalproex for the treatment of mania were compared
in a large randomized clinical trial. METHOD: A 3-week, randomized, double-blind
trial compared flexibly dosed olanzapine (5-20 mg/day) to divalproex (500-2500
mg/day in divided doses) for the treatment of patients hospitalized for acute
bipolar manic or mixed episodes. The Young Mania Rating Scale and the Hamilton
Depression Rating Scale were used to quantify manic and depressive symptoms, respectively.
Safety was assessed with several measures. RESULTS: The protocol defined baseline-to-endpoint
improvement in the mean total score on the Young Mania Rating Scale as the primary
outcome variable. The mean Young Mania Rating Scale score decreased by 13.4 for
patients treated with olanzapine (N=125) and 10.4 for those treated with divalproex
(N=123). A priori categorizations defined response and remission rates: 54.4%
of olanzapine-treated patients responded (> or = 50% reduction in Young Mania
Rating Scale score), compared to 42.3% of divalproex-treated patients; 47.2% of
olanzapine-treated patients had remission of mania symptoms (endpoint Young Mania
Rating Scale < or = 12), compared to 34.1% of divalproex-treated patients.
The decrease in Hamilton depression scale score was similar in the two treatment
groups. Completion rates for the 3-week study were similar in both groups. The
most common treatment-emergent adverse events (incidence >10%) occurring more
frequently during treatment with olanzapine were dry mouth, increased appetite,
and somnolence. For divalproex, nausea was more frequently observed. The average
weight gain with olanzapine treatment was 2.5 kg, compared to 0.9 kg with divalproex
treatment. CONCLUSIONS: The olanzapine treatment group had significantly greater
mean improvement of mania ratings and a significantly greater proportion of patients
achieving protocol-defined remission, compared with the divalproex treatment group.
Significantly more weight gain and cases of dry mouth, increased appetite, and
somnolence were reported with olanzapine, while more cases of nausea were reported
with divalproex." [Abstract]
A, Diaz E, Baker CB, Pearsall HR, Woods SW.
Department of Psychiatry, Yale
University School of Medicine, New Haven, CT 06508, USA.
of divalproex versus lithium on length of hospital stay among patients with bipolar
Psychiatr Serv. 2000 Sep;51(9):1184-6.
medical records of all inpatients with bipolar disorder at the Connecticut Mental
Health Center in 1997 were examined to compare length of stay for patients who
began monotherapy with divalproex (27 treatment starts) and lithium (20 treatment
starts). No statistically significant difference was found in length of stay (11.
5+/-6.9 and 10.3+/-5.2 days for patients on divalproex and lithium, respectively)
or other length-of-stay variables. Demographic variables, diagnostic variables,
and dosages of neuroleptics and benzodiazepines used adjunctively were similar
as well. Dosages and blood levels for divalproex and lithium were consistent with
practice guidelines. Prospective randomized studies are needed to compare the
cost-effectiveness of divalproex and of lithium in the treatment of bipolar disorder."
SL, Keck PE, Stanton SP, Tugrul KC, Bennett JA, Strakowski SM.
Psychiatry, University of Cincinnati College of Medicine, Ohio, 45267, USA.
randomized comparison of divalproex oral loading versus haloperidol in the initial
treatment of acute psychotic mania.
J Clin Psychiatry. 1996
"BACKGROUND: Uncontrolled evidence suggests that divalproex
administered via the oral loading strategy of 20 mg/kg/day may produce clinically
significant antimanic response within 3 days of treatment in some patients. We
conducted a prospective study to compare the antimanic response of divalproex
oral loading with that of haloperidol in the initial treatment of acute psychotic
mania. METHOD: After a < or = 1-day screening period, 36 consecutive hospitalized
patients with bipolar disorder, manic or mixed phase and with psychotic features,
were randomly assigned to receive either divalproex 20 mg/kg/day or haloperidol
0.2 mg/kg/day for 6 full days, without other psychotropic agents except lorazepam
up to 4 mg/day for management of agitation. Serum valproate concentrations were
measured after 1 day of treatment. Response was measured daily by a blind rater
using the Young Mania Rating Scale and the Scale for Assessment of Positive Symptoms.
RESULTS: Divalproex oral loading and haloperidol were equally effective in acutely
reducing manic and psychotic symptoms. The greatest rate of improvement for both
drug regimens occurred over the first 3 full days of treatment. Side effects were
infrequent and minor for both treatments, except for extrapyramidal side effects
which were significantly more common with haloperidol. CONCLUSION: Divalproex
oral loading may produce rapid onset of antimanic and antipsychotic response comparable
to that of haloperidol and with minimal side effects in the initial treatment
of acute psychotic mania in a subset of bipolar patients." [Abstract]
Kowatch RA, Suppes T, Carmody TJ, Bucci JP, Hume
JH, Kromelis M, Emslie GJ, Weinberg WA, Rush AJ.
Department of Psychiatry,
University of Texas Southwestern Medical Center at Dallas 75235-9070, USA. email@example.com
size of lithium, divalproex sodium, and carbamazepine in children and adolescents
with bipolar disorder.
J Am Acad Child Adolesc Psychiatry.
"OBJECTIVE: To develop effect sizes for 3 mood
stabilizers--lithium, divalproex sodium, and carbamazepine--for the acute-phase
treatment of bipolar I or II disorder, mixed or manic episode, in children and
adolescents aged 8 to 18 years. METHOD: Forty-two outpatients with a mean age
of 11.4 years (20 with bipolar I disorder and 22 with bipolar II disorder) were
randomly assigned to 6 weeks of open treatment with either lithium, divalproex
sodium, or carbamazepine. The primary efficacy measures were the weekly Clinical
Global Impression Improvement scores and the Young Mania Rating Scale (Y-MRS).
RESULTS: Using a > or = 50% change from baseline to exit in the Y-MRS scores
to define response, the effect size was 1.63 for divalproex sodium, 1.06 for lithium,
and 1.00 for carbamazepine. Using this same response measure with the intent-to-treat
sample, the response rates were as follows: sodium divalproex, 53%; lithium, 38%;
and carbamazepine, 38% (chi 2(2) = 0.85, p = .60). All 3 mood stabilizers were
well tolerated, and no serious adverse effects were seen. CONCLUSIONS: Divalproex
sodium, lithium, and carbamazepine all showed a large effect size in the open
treatment of children and adolescents with bipolar I or II disorder in a mixed
or manic episode." [Abstract]
Bahk WM, Shin YC, Woo JM, Yoon BH, Lee JS, Jon DI, Chung SK, Choi SK, Paik IH, Pae CU
Topiramate and divalproex in combination with risperidone for acute mania: a randomized open-label study.
Prog Neuropsychopharmacol Biol Psychiatry. 2005 Jan;29(1):115-21.
Mood stabilizers and atypical antipsychotics are commonly combined for the treatment of bipolar mania. The aim of this study was to compare the effectiveness and tolerability of topiramate and divalproex in combination with risperidone for treating acute mania patients in a naturalistic treatment setting. Seventy-four patients who met the DSM-IV criteria for bipolar mania were enrolled in this study. In order to assess the efficacy and the extrapyramidal symptoms (EPS), the Young Mania Rating Scale (YMRS), Clinical Global Impression (CGI) and Simpson-Angus Rating Scale (SARS) were measured at the baseline and at weeks 1, 3 and 6. From the baseline to the endpoint, the YMRS and CGI scores were reduced by 67.9% and 56.6% in the topiramate plus risperidone group (TPMG). The YMRS and CGI scores were also reduced by 63.7% and 58.2% in the divalproex plus risperidone group (DVPG). The weight and body mass index (BMI) increased significantly by 3.6% and 3.3% from the baseline to the endpoint in the DVPG, while they decreased by 0.5% and 0.4%, respectively, with no significant difference in the TPMG. There were no serious adverse events in either group. Despite the methodological limitations, topiramate was effective and tolerable for treating acute mania and may also be a promising alternative to a weight-gain liable mood stabilizer (MS) such as divalproex. [Abstract]
Baker RW, Brown E, Akiskal HS, Calabrese JR, Ketter TA, Schuh LM, Trzepacz PT, Watkin JG, Tohen M
Efficacy of olanzapine combined with valproate or lithium in the treatment of dysphoric mania.
Br J Psychiatry. 2004 Dec;185472-8.
BACKGROUND: Few controlled studies examine the treatment of depressive features in mania. AIMS: To evaluate the efficacy of olanzapine, in combination with lithium or valproate, for treating depressive symptoms associated with mania. METHOD: Secondary analysis of a 6-week, double-blind, randomised study of olanzapine (5-20 mg/day) or placebo combined with ongoing valproate or lithium open treatment for 344 patients in mixed or manic episodes. This analysis focused on a dysphoric subgroup with baseline Hamilton Rating Scale for Depression (HRSD) total scores of 20 or over contrasted with non-dysphoric patients. RESULTS: In the dysphoric subgroup (n=85) mean HRSD total score improvement was significantly greater in olanzapine co-therapy patients than in those receiving placebo plus lithium or valproate (P<0.001). Substantial contributors to this superiority included the HRSD Maier sub-scale (P=0.013) and the suicide item (P=0.001). Total Young Mania Rating Scale improvement was also superior with olanzapine co-therapy. CONCLUSIONS: In patients with acute dysphoric mania, addition of olanzapine to ongoing lithium or valproate monotherapy significantly improved depressive symptom, mania and suicidality ratings. [Abstract]
Yatham LN, Paulsson B, Mullen J, Vågerö AM
Quetiapine versus placebo in combination with lithium or divalproex for the treatment of bipolar mania.
J Clin Psychopharmacol. 2004 Dec;24(6):599-606.
Quetiapine (QTP) combined with lithium (Li) or divalproex (DVP) for the treatment of mania was evaluated in 2 double-blind, placebo-controlled studies. Patients were randomized to 3 or 6 weeks of treatment with QTP plus Li/DVP or placebo (PBO) plus Li/DVP. Quetiapine was dosed up to 800 mg/d; Li was dosed to achieve serum concentrations of 0.7-1.0 mEq/L and DVP to 50-100 microg/mL. A total of 402 patients were randomized: 197 to QTP + Li/DVP and 205 to PBO + Li/DVP. The mean quetiapine dose in responders was 492 (+/-204) mg/d. Improvement in the Young Mania Rating Scale (YMRS) at day 21 in the QTP + Li/DVP group (-15.29) was statistically superior to the PBO + Li/DVP group (-12.19) (P < 0.05). A statistically significant difference in favor of quetiapine was observed within the first week (P < 0.05). Significantly more QTP + Li/DVP patients achieved a response (> or =50% decrease in the YMRS) at day 21 (QTP + Li/DVP, 55.7%; PBO + Li/DVP, 41.6%;P < 0.01). Improvements in Clinical Global Impression-Bipolar Severity of Illness scores by day 21 were also significantly greater in QTP + Li/DVP-treated patients (-1.59) versus PBO + Li/DVP (-1.19) (P < 0.01). Common adverse events (> or =5% and twice that in the PBO + Li/DVP group) in the QTP + Li/DVP group were somnolence, dry mouth, and asthenia. Quetiapine combined with Li/DVP was not associated with extrapyramidal symptoms (including akathisia) or emergent depression. More QTP + Li/DVP-treated patients completed the trial, and there was no difference in discontinuation rates due to adverse events between the two groups. Quetiapine, in combination with lithium or divalproex, is well tolerated and has superior efficacy to lithium or divalproex alone in the treatment of bipolar mania. [Abstract]
Swann AC, Bowden CL, Calabrese JR, Dilsaver SC,
Department of Psychiatry and Behavioral Sciences, University of
Texas Health Science Center, Houston 77030, USA.
of number of previous episodes of affective disorder on response to lithium or
divalproex in acute mania.
Am J Psychiatry. 1999 Aug;156(8):1264-6.
The authors investigated the relationship between number of lifetime episodes
of affective disorder and the antimanic response to lithium, divalproex, or placebo.
METHOD: The subjects were 154 of the 179 inpatients with acute mania who entered
a 3-week parallel group, double-blind study. The primary efficacy measure was
the manic syndrome score from the Schedule for Affective Disorders and Schizophrenia.
The relationship between improvement and number of previous episodes was investigated
by using nonlinear regression analysis. RESULTS: An apparent transition in the
relationship between number of previous episodes and response to antimanic medication
occurred at about 10 previous episodes. For patients who had experienced more
episodes, response to lithium resembled the response to placebo but was worse
than response to divalproex. For patients who had experienced fewer episodes,
however, the responses to lithium and divalproex did not differ and were better
than the response to placebo. This differential response pattern was not related
to rapid cycling or mixed states. CONCLUSIONS: A history of many previous episodes
was associated with poor response to lithium or placebo but not to divalproex."
AC, Bowden CL, Calabrese JR, Dilsaver SC, Morris DD.
University of Texas-Houston
Medical School and Harris County Psychiatric Center, USA.
differential effects of previous depressive and manic episodes on response to
Acta Psychiatr Scand. 2000 Jun;101(6):444-51.
We compared effects of previous depressive or manic episodes on antimanic response.
METHOD: In-patients in a parallel-groups, double-blind comparison of lithium,
divalproex or placebo for manic episodes had comprehensive evaluations of illness
history. We used non-linear curve fitting of change in Manic Syndrome Score (MSS)
of the Schedule for Affective Disorders and Schizophrenia (SADS) versus previous
depressive or manic episodes to investigate their relationships to MSS improvement.
RESULTS: Response to lithium, but not to divalproex or placebo, worsened with
increased depressive or manic episodes. More than 11 manic, or four depressive,
episodes was associated with response to lithium that did not differ from placebo.
Effects of previous depressive and manic episodes appeared independent, and could
not be accounted for by increased rapid cycling or mixed states. CONCLUSION: At
least four previous depressive or 12 previous manic episodes are associated with
reduced antimanic response to lithium." [Abstract]
L, Bowden CL, McElroy SL, Calabrese JR, Petty F, Swann AC, Chou JC, Wassef A,
Risch CS, Hirschfeld RM, Nemeroff CB, Keck PE Jr, Evans DL, Wozniak PJ.
of Psychiatry, University of Pennsylvania, Philadelphia, PA 19104, USA. firstname.lastname@example.org
efficacy of divalproex in the prevention of bipolar depression.
2003 Jul;28(7):1374-82. Epub 2003 May 28.
"Breakthrough depression is
a common problem in the treatment of bipolar disorder. Only one, recently published,
double-blind, placebo-controlled trial has examined the efficacy of divalproex
in the prevention of depressive episodes in bipolar patients. This report describes,
in further detail, the findings from that trial of the effect of divalproex on
multiple dimensions of depressive morbidity in bipolar disorder. A randomized,
double-blind, parallel-group, multicenter study was conducted over a 52-week maintenance
period. Bipolar I patients, who may have been treated with open-label lithium
or divalproex and who met recovery criteria within 3 months of onset of an index
manic episode, were randomized to maintenance treatment with divalproex, lithium,
or placebo in a 2 : 1 : 1 ratio. Adjunctive paroxetine or sertraline for breakthrough
depression was allowed in maintenance phase. Outcome measures were the rate of
early discontinuation for depression, time to depressive relapse, proportion of
patients with depressive relapse, mean change in Depressive Syndrome Scale score,
proportion of patients receiving antidepressants, and time in the study. Among
patients taking an antidepressant, a higher percentage of patients on placebo
than divalproex discontinued early for depression. Patients who were previously
hospitalized for affective episodes or took divalproex in the open period relapsed
later on divalproex than on lithium during the maintenance period. Divalproex-treated
patients had less worsening of depressive symptoms than lithium-treated patients
during maintenance. Indices of severity of prestudy illness course predicted worse
outcome in all treatment groups. Divalproex improved several dimensions of depressive
morbidity and reduced the probability of depressive relapse in bipolar disorder,
particularly in patients who had responded to divalproex when manic, and among
patients with a more severe course of illness." [Abstract]
CL, Calabrese JR, McElroy SL, Gyulai L, Wassef A, Petty F, Pope HG Jr, Chou JC,
Keck PE Jr, Rhodes LJ, Swann AC, Hirschfeld RM, Wozniak PJ.
Department of Psychiatry,
University of Texas Health Science Center at San Antonio, 78284-7792, USA. email@example.com
randomized, placebo-controlled 12-month trial of divalproex and lithium in treatment
of outpatients with bipolar I disorder. Divalproex Maintenance Study Group.
Gen Psychiatry. 2000 May;57(5):481-9.
"BACKGROUND: Long-term outcomes
are often poor in patients with bipolar disorder despite treatment; more effective
treatments are needed to reduce recurrences and morbidity. This study compared
the efficacy of divalproex, lithium, and placebo as prophylactic therapy. METHODS:
A randomized, double-blind, parallel-group multicenter study of treatment outcomes
was conducted over a 52-week maintenance period. Patients who met the recovery
criteria within 3 months of the onset of an index manic episode (n = 372) were
randomized to maintenance treatment with divalproex, lithium, or placebo in a
2:1:1 ratio. Psychotropic medications were discontinued before randomization,
except for open-label divalproex or lithium, which were gradually tapered over
the first 2 weeks of maintenance treatment. The primary outcome measure was time
to recurrence of any mood episode. Secondary measures were time to a manic episode,
time to a depressive episode, average change from baseline in Schedule for Affective
Disorders and Schizophrenia-Change Version subscale scores for depression and
mania, and Global Assessment of Function scores. RESULTS: The divalproex group
did not differ significantly from the placebo group in time to any mood episode.
Divalproex was superior to placebo in terms of lower rates of discontinuation
for either a recurrent mood episode or depressive episode. Divalproex was superior
to lithium in longer duration of successful prophylaxis in the study and less
deterioration in depressive symptoms and Global Assessment Scale scores. CONCLUSIONS:
The treatments did not differ significantly on time to recurrence of any mood
episode during maintenance therapy. Patients treated with divalproex had better
outcomes than those treated with placebo or lithium on several secondary outcome
AC, Bowden CL, Morris D, Calabrese JR, Petty F, Small J, Dilsaver SC, Davis JM.
of Psychiatry, University of Texas Medical School at Houston, USA.
during mania. Treatment response to lithium or divalproex.
Gen Psychiatry. 1997 Jan;54(1):37-42.
"BACKGROUND: Little information
exists from controlled studies about clinical characteristics that predict treatment
response in mania. The presence of depressive symptoms during manic episodes may
be associated with poor response to psychopharmacological treatments. This is
an investigation of the relation between depressive symptoms and treatment response
in acute manic episodes. METHODS AND DESIGN: In a parallel-group, double-blind
study, 179 patients hospitalized for acute manic episodes were randomized to receive
divalproex sodium, lithium carbonate, or placebo (ratio, 2:1:2). The study was
carried out at 9 academic medical centers. Patients had comprehensive evaluations
of behavior and symptoms before and during 3 weeks of treatment. The primary outcome
measure, change in mania factor scores derived from the Schedule for Affective
Disorders and Schizophrenia: Change Version, was compared in patients with and
without depressive symptoms at baseline according to nurse- or physician-rated
scales. RESULTS: Depressive symptoms were associated with poor antimanic response
to lithium and with better response to divalproex. This was not due to differences
in overall severity of illness, substance abuse, gender, age, or history. CONCLUSIONS:
These data suggest that even a modest level of pretreatment depression-related
symptoms is a robust predictor of lithium nonresponse, and is associated with
better response to divalproex. Although their overall efficacy in acute mania
is similar, lithium and divalproex may be most effective in clinically and biologically
distinct groups of patients." [Abstract]
University of Texas, Houston Medical Scholl, USA.
of treatment response in acute mania: controlled clinical trials with divalproex]
"OBJECTIVE: To determine predictive factors
for response to mood stabilising treatment in manic episodes and to determine
the mood stabilising properties of divalproex. METHODS: For predictive factors,
179 subjects in 3 parallel groups (divalproex, lithium, placebo) were evaluated
over a period of 21 days by using structured interviews conducted by the clinician
(SADS-C) and by nursing staff (ADRS). For the follow-on study, 372 stabilised
patients were randomised to three groups: divalproex, lithium or placebo. RESULTS:
The presence of depressive symptoms was associated with poor response to lithium,
and patients with manic episodes with depressive symptoms or with rapid cycling
exhibited good response to divalproex, while classical manic episodes showed good
response to lithium and divalproex, and dysphoric or irritable manic episodes
responded well to divalproex but not to lithium. A high number of both manic and
depressive prior episodes is predictive of poor response to lithium and favourable
response to divalproex. The effects of depressive and manic episodes appear to
be independent and do not correlate with the duration of the illness or age at
onset. Divalproex was superior to placebo in preventing all types of episodes,
whether or not relapse was depressive or manic, and it was also superior to lithium
in preventing depressive episodes. CONCLUSION: Specific features of the disease
history and of the semiology of individual episodes help predict therapeutic response
to mood stabilisers." [Abstract]
AC, Bowden CL, Calabrese JR, Dilsaver SC, Morris DD.
University of Texas-Houston
Health Science Center, P.O. Box 20708, Houston, TX 77225, USA.
of response to divalproex, lithium, or placebo in four naturalistic subtypes of
Neuropsychopharmacology. 2002 Apr;26(4):530-6.
investigated effects of antimanic treatments on specific aspects of mania, prediction
of response, and the existence of naturalistic subgroups of patients with different
treatment response in 179 inpatients randomized to antimanic treatment with lithium,
divalproex, or placebo. Psychiatric symptom ratings were conducted by clinicians
and nurses before and during treatment. Factor analysis using physician and nurse
rating scales, followed by a cluster analysis, yielded anxious-depressive, psychotic,
classic, and irritable subtypes. We compared: (1) treatment effects on factor
scores; (2) responses to treatment across subtypes; and (3) pattern of symptom
change with each treatment. The anxious-depressed subtype did not respond to any
treatment; the psychotic and classic subtypes responded similarly to lithium and
to divalproex; and the irritable-dysphoric subtype responded better to divalproex
than to lithium. Overall, divalproex improved impulsivity and hostility significantly
more than placebo, and lithium or divalproex improved hyperactivity more than
placebo. These data suggest that there are naturalistic subtypes of manic episodes
with different responses to treatment." [Abstract]
AC, Daniel DG, Kochan LD, Wozniak PJ, Calabrese JR.
mania: specificity of its role in severity and treatment response.
Clin Psychiatry. 2004 Jun;65(6):825-9.
BACKGROUND: Psychosis is a prominent
characteristic of manic episodes. We investigated relationships between the presence
of psychotic features, the severity of the manic syndrome, and syndrome severity's
response to treatment. METHOD: 179 subjects meeting Research Diagnostic Criteria
for a manic episode of bipolar I disorder were hospitalized for acute manic episodes
and treated in a randomized trial of lithium, divalproex sodium, or placebo. Factor
and cluster analyses were carried out using the clinician-rated Schedule for Affective
Disorders and Schizophrenia, Change version (SADS-C) and the nurse-rated Affective
Disorder Rating Scale (ADRS). RESULTS: Subjects with psychotic features had significantly
(p < .005) greater overall impairment (lower Global Assessment Scale [GAS]
scores) but did not differ in severity of mania scores compared with those without
psychotic features. Psychosis factor scores correlated significantly (p < .000001)
with GAS scores but not with mania scores. Baseline psychosis factor scores did
not correlate with subsequent treatment-associated change in mania scores, but
change in mania scores during treatment correlated significantly (p < .000001)
with change in the psychosis factor. Changes in psychosis factor scores correlated
significantly with changes in mania rating scale scores regardless of treatment.
CONCLUSIONS: Psychotic features as a component of manic episodes contribute substantially
to overall impairment. Treatments that successfully treat mania also reduce psychosis
Salloum IM, Cornelius JR, Daley DC, Kirisci L, Himmelhoch JM, Thase ME
Efficacy of valproate maintenance in patients with bipolar disorder and alcoholism: a double-blind placebo-controlled study.
Arch Gen Psychiatry. 2005 Jan;62(1):37-45.
BACKGROUND: More than half of all individuals with bipolar disorder have a substance abuse problem at some point in their lifetime. Patients with comorbid substance abuse disorders often are excluded from clinical trials. Thus, treatments targeting this high-risk clinical population are lacking. OBJECTIVE: To evaluate the efficacy of divalproex sodium (hereafter referred to as valproate) in decreasing alcohol use and stabilizing mood symptoms in acutely ill patients with bipolar disorder and alcoholism. DESIGN: A 24-week, double-blind, placebo-controlled, randomized parallel-group trial. SETTING: A university hospital serving as a primary catchment-area hospital and tertiary-care facility. PARTICIPANTS: Fifty-nine subjects with diagnoses of bipolar I disorder and alcohol dependence.Intervention All study subjects received treatment as usual, including lithium carbonate and psychosocial interventions, and were randomized to receive valproate or placebo. MAIN OUTCOME MEASURES: Primary alcohol use outcomes included changes in alcohol use as indicated by changes in proportion of heavy drinking days and number of drinks per heavy drinking day. Other alcohol use outcomes included proportion of any drinking days, number of drinks per drinking day, and relapse to sustained heavy drinking. Mood outcomes included changes in depressive and manic symptoms. We used the mixed model to analyze longitudinal data. The first model used time of assessment, bipolar subtype (mixed, manic, or depressed), and treatment group (placebo or valproate) as covariates. The second nested model included the additional covariate of medication adherence. RESULTS: The valproate group had a significantly lower proportion of heavy drinking days (P = .02) and a trend toward fewer drinks per heavy drinking day (P = .055) than the placebo group. When medication adherence was added as covariate, the valproate group had significantly fewer drinks per heavy drinking day (P = .02) and fewer drinks per drinking day (P = .02). Higher valproate serum concentration significantly correlated with improved alcohol use outcomes. Manic and depressive symptoms improved equally in both groups. Level of gamma-glutamyl transpeptidase was significantly higher in the placebo group compared with the valproate group. CONCLUSIONS: Valproate therapy decreases heavy drinking in patients with comorbid bipolar disorder and alcohol dependence. The results of this study indicate the potential clinical utility of the anticonvulsant mood stabilizer, valproate, in bipolar disorder with co-occurring alcohol dependence. [Abstract]
Tohen M, Chengappa KN, Suppes T, Zarate CA Jr, Calabrese
JR, Bowden CL, Sachs GS, Kupfer DJ, Baker RW, Risser RC, Keeter EL, Feldman PD,
Tollefson GD, Breier A.
Lilly Research Laboratories, Eli Lilly & Co, Indianapolis,
IN 46285, USA.
Efficacy of olanzapine in combination with valproate
or lithium in the treatment of mania in patients partially nonresponsive to valproate
or lithium monotherapy.
Arch Gen Psychiatry. 2002 Jan;59(1):62-9.
A 6-week double-blind, randomized, placebo-controlled trial was conducted to determine
the efficacy of combined therapy with olanzapine and either valproate or lithium
compared with valproate or lithium alone in treating acute manic or mixed bipolar
episodes. METHODS: The primary objective was to evaluate the efficacy of olanzapine
(5-20 mg/d) vs placebo when added to ongoing mood-stabilizer therapy as measured
by reductions in Young Mania Rating Scale (YMRS) scores. Patients with bipolar
disorder (n = 344), manic or mixed episode, who were inadequately responsive to
more than 2 weeks of lithium or valproate therapy, were randomized to receive
cotherapy (olanzapine + mood-stabilizer) or monotherapy (placebo + mood-stabilizer).
RESULTS: Olanzapine cotherapy improved patients' YMRS total scores significantly
more than monotherapy (-13.11 vs -9.10; P = .003). Clinical response rates (>
or = 50% improvement on YMRS) were significantly higher with cotherapy (67.7%
vs 44.7%; P< .001). Olanzapine cotherapy improved 21-item Hamilton Depression
Rating Scale (HAMD-21) total scores significantly more than monotherapy (4.98
vs 0.89 points; P< .001). In patients with mixed-episodes with moderate to
severe depressive symptoms (DSM-IV mixed episode; HAMD-21 score of > or = 20
at baseline), olanzapine cotherapy improved HAMD-21 scores by 10.31 points compared
with 1.57 for monotherapy (P< .001). Extrapyramidal symptoms (Simpson-Angus
Scale, Barnes Akathisia Scale, Abnormal Involuntary Movement Scale) were not significantly
changed from baseline to end point in either treatment group. Treatment-emergent
symptoms that were significantly higher for the olanzapine cotherapy group included
somnolence, dry mouth, weight gain, increased appetite, tremor, and slurred speech.
CONCLUSION: Compared with the use of valproate or lithium alone, the addition
of olanzapine provided superior efficacy in the treatment of manic and mixed bipolar
M, Chengappa KN, Suppes T, Baker RW, Zarate CA, Bowden CL, Sachs GS, Kupfer DJ,
Ghaemi SN, Feldman PD, Risser RC, Evans AR, Calabrese JR.
prevention in bipolar I disorder: 18-month comparison of olanzapine plus mood
stabiliser v. mood stabiliser alone.
Br J Psychiatry. 2004
BACKGROUND: Few controlled studies have examined the use of
atypical antipsychotic drugs for prevention of relapse in patients with bipolar
I disorder. Aims To evaluate whether olanzapine plus either lithium or valproate
reduces the rate of relapse, compared with lithium or valproate alone. METHOD:
Patients achieving syndromic remission after 6 weeks'treatment with olanzapine
plus either lithium (0.6-1.2 mmol/l) or valproate (50-125 microg/ml) received
lithium or valproate plus either olanzapine 5-20 mg/day (combination therapy)
or placebo (monotherapy), and were followed in a double-masked trial for 18 months.
RESULTS: The treatment difference in time to relapse into either mania or depression
was not significant for syndromic relapse (median time to relapse: combination
therapy 94 days, monotherapy 40.5 days; P=0.742), but was significant for symptomatic
relapse (combination therapy 163 days, monotherapy 42 days; P=0.023). CONCLUSIONS:
Patients taking olanzapine added to lithium or valproate experienced sustained
symptomatic remission, but not syndromic remission, for longer than those receiving
lithium or valproate monotherapy. [Abstract]
B, Retzow A, Henn FA, Giedke H, Walden J.
Department of Psychiatry, University
Clinic Benjamin Franklin, Berlin, Germany. firstname.lastname@example.org
as an adjunct to neuroleptic medication for the treatment of acute episodes of
mania: a prospective, randomized, double-blind, placebo-controlled, multicenter
study. European Valproate Mania Study Group.
J Clin Psychopharmacol.
"To compare the efficacy of sodium valproate administered
as adjunct to neuroleptic medication for patients with acute mania with the efficacy
of neuroleptics alone, the authors conducted a 21-day, randomized, double-blind,
parallel-group, placebo-controlled trial. The study design closely reflected a
clinical psychiatric setting in Europe where patients with acute mania commonly
receive neuroleptic medication. In this trial, 136 hospitalized patients met the
ICD-10 criteria for acute manic episodes; these patients received a fixed dose
of 20 mg/kg of body weight of sodium valproate (Orfiril, Desitin Arzneimittel
GmbH, Hamburg, Germany) orally, in addition to basic neuroleptic medication, preferably
haloperidol and/or perazine. The primary outcome measure was the mean dose of
neuroleptic medication (after conversion into haloperidol-equivalents) for the
21-day study period. Severity of symptoms was measured using the Young Mania Rating
Scale (YMRS), the Global Assessment Scale, and the Clinical Global Impression
Scale. Intent-to-treat analysis was based on 69 patients treated with valproate
and 67 patients who received placebo. Groups were comparable with regard to demographic
and clinical baseline data. Premature discontinuations occurred in only 13% of
the patients. The mean neuroleptic dose declined continuously in the valproate
group, whereas only slight variations were observed in the placebo group; the
difference was statistically significant (p = 0.0007) for study weeks 2 and 3.
The combination of neuroleptic and valproate proved superior to neuroleptics in
attempts to alleviate manic symptoms. The proportion of responders (a 50% improvement
rate shown on the YMRS) was higher for the combination with valproate than for
the group receiving only neuroleptics (70% vs. 46%; p = 0.005). Adverse events
consisted of those known for valproate or neuroleptics; the only adverse event
was asthenia, which occurred more frequently with the combination therapy. Valproate
represents a useful adjunct medication for the treatment of acute manic symptoms.
Valproate is beneficial because it allows the administration of fewer neuroleptic
medications and produces improved and quicker remission of manic symptoms."
HG Jr, McElroy SL, Keck PE Jr, Hudson JI.
Biological Psychiatry Laboratory,
McLean Hospital, Belmont, Mass 02178.
Valproate in the treatment
of acute mania. A placebo-controlled study.
Arch Gen Psychiatry.
"We conducted a placebo-controlled, double-blind
study of valproate, a drug originally developed as an antiepileptic, in 36 patients
with acute manic episodes who had previously failed to respond to or to tolerate
lithium carbonate. Treatment duration was 7 to 21 days, with no other psychotropic
medications permitted except lorazepam up to 4 mg/d during the first 10 days of
treatment. Serum valproate concentrations were measured three times weekly; an
unblinded investigator then adjusted dosage to produce serum concentrations between
50 and 100 mg/L. Valproate proved superior to placebo in alleviating manic symptoms.
The 17 patients randomized to active drug demonstrated a median 54% decrease in
scores on the Young Mania Rating Scale as compared with a median 5.0% decrease
among the 19 patients receiving placebo. On the 100-point Global Assessment Scale
of overall psychiatric functioning, patients receiving valproate improved by a
median of 20 points as compared with a zero-point change with placebo. Significant
differences also emerged on the Brief Psychiatric Rating Scale and in the number
of supplemental doses of lorazepam required by the patients in each group. Substantial
antimanic effects appeared within 1 to 4 days of achieving therapeutic serum valproate
concentrations. Adverse effects were infrequent, with no adverse effect appearing
significantly more frequently with valproate than with placebo. We conclude that
valproate represents a useful new drug for the treatment of manic patients."
CL, Brugger AM, Swann AC, Calabrese JR, Janicak PG, Petty F, Dilsaver SC, Davis
JM, Rush AJ, Small JG, et al.
Department of Psychiatry, University of Texas
Health Science Center, San Antonio.
Efficacy of divalproex vs lithium
and placebo in the treatment of mania. The Depakote Mania Study Group.
1994 Mar 23-30;271(12):918-24.
"OBJECTIVE--To compare the effectiveness
of divalproex sodium with that of lithium and placebo in patients with acute mania.
DESIGN--Randomized, double-blind, parallel-group study of treatment outcomes in
patients with manic-depressive illness. PATIENTS--A total of 179 hospitalized,
acutely manic patients meeting the Research Diagnostic Criteria for manic disorder,
approximately half of whom had been nonresponsive to lithium previously, were
studied at nine university-affiliated hospitals. INTERVENTIONS--After a minimum
3-day washout period, random assignment for 21 days to divalproex, lithium, or
placebo in a 2:1:2 ratio. Dosage of divalproex and lithium was increased if tolerated
to a target concentration of 1041 mumol/L (150 micrograms/mL) or 1.5 mmol/L (conventionally
expressed as milliequivalents per liter), respectively. MAIN OUTCOME MEASURES--Primary
outcome measures were changes in the Mania Rating scale derived from the Schedule
for Affective Disorders and Schizophrenia. RESULTS--Intent-to-treat analysis for
efficacy was based on data from 68, 35, and 73 patients in the divalproex, lithium,
and placebo groups, respectively. Groups were initially comparable except that
all eight patients with four or more manic episodes in the previous year were
in the divalproex group. In 30%, 33%, and 51% of the above groups, treatment was
prematurely terminated due to lack of efficacy, with fewer premature terminations
from divalproex than placebo (P = .017). The proportions of patients improving
at least 50% were higher for divalproex and lithium groups than for the placebo
group: 48% for divalproex (P = .004) and 49% for lithium (P = .025) vs 25% for
placebo. Divalproex was as effective in rapid-cycling manic patients as in other
patients. CONCLUSIONS--Both divalproex and lithium were significantly more effective
than placebo in reducing the symptoms of acute mania. The efficacy of divalproex
appears to be independent of prior responsiveness to lithium." [Abstract]
Bowden CL, Davis J, Morris D, Swann A, Calabrese
J, Lambert M, Goodnick P.
Psychiatric Institute, Chicago, Illinois, USA.
size of efficacy measures comparing divalproex, lithium and placebo in acute mania.
"Effect size (ES) is a statistical concept that
can be used to improve the interpretation of results from psychopharmacological
studies. ES may aid interpretation of results when sample size is unbalanced or
small or when units or levels of baseline measures differ across items. Usually,
an investigator can define a threshold value for a clinically meaningful ES based
on published data and clinical judgment or by resorting to conventions, e.g.,
a medium ES = 0.5 S.D., which can usually be discerned by the trained clinician.
In the present study, we apply ES analysis to results from a study comparing the
effectiveness of divalproex (DIVAL), lithium (LI), and placebo (PLA) in hospitalized,
acutely manic patients. One hundred seventy-six patients were randomly assigned
to DIVAL, LI, or PLA in a 2:1:2 ratio, with drug administered in a double-blind,
parallel group design for 21 days. The primary efficacy measure was the Mania
Rating Scale from the Schedule for Affective Disorders and Schizophrenia, composed
of the Manic Syndrome Score (MSS) from items that are relatively specific to the
manic state, and the Behavior and Ideation Score (BIS), which reflects severe
but nonspecific psychopathology. Improvement of the MSS after 5 days of treatment
was difficult to interpret based on percentage change (DIVAL = 19%, LI = 13.5%,
PLA = 8.5%). However, the corresponding effect sizes of 0.79, 0.55, and 0.35 indicated
a medium to marked ES for DIVAL, a medium ES for LI, and a small ES for PLA at
this early point in treatment. Similarly, the ES for change on the MSS at the
end of treatment indicated a large, readily observable improvement with both DIVAL
(ES = 1.01) and LI (ES = 0.79) vs. an ES of 0.37 for PLA. ES analysis also indicated
that the BIS is a less robust indicator of change to either drug. The ES at the
end of treatment for the BIS was 0.67 for DIVAL-, 0.62 for LI-, and 0.25 for PLA-treated