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Divalproex sodium for pediatric mixed mania: a 6-month prospective trialDivalproex sodium for pediatric mixed mania:a 6-month prospective trial Pavuluri MN, Henry DB, Carbray JA, Naylor MW, Janicak PG.
Divalproex sodium for pediatric mixed mania: a 6-month prospective Bipolar Disord 2005: 7: 266–273. ª Blackwell Munksgaard, 2005 Pediatric Mood Disorders Research Program,Department of Psychiatry, University of Illinois at Objective: This prospective 6-month open trial examined the eﬀectiveness and safety of divalproex sodium (DVPX) in pediatric mixedmania.
Method: Thirty-four subjects with a mean age of 12.3 (SD ¼ 3.7)years, DSM-IV diagnosis of a current mixed episode and a baselineYoung Mania Rating Scale (YMRS) score >20 were treated with DVPXmonotherapy. The primary outcome measures were the YMRS and theChild Depression Rating Scale-Revised. Secondary measures were theClinical Global Impression Scale for Bipolar Disorder (CGI-BP) and theChildren’s Global Assessment of Functioning Scale (C-GAS). Measuresof safety and tolerability were also administered.
Results: Eﬀect size (Cohen’s d) based on change scores from baselinewas 2.9 for the YMRS and 1.23 for the CDRS-R. Response rate (‡50% Key words: adolescent – bipolar disorder – child change from baseline YMRS score and £40 score on CDRS-R at the end – clinical trial – divalproex sodium – mania – mixed of study) was 73.5%. The remission rate (‡50% change from baseline on – mood stabilizer – pediatric bipolar disorder – YMRS, £40 on CDRS-R, CGI-BP-Improvement subscale of £2, and ‡51 CGAS score) was 52.9%. Signiﬁcant improvements (p < 0.001) frombaseline were seen for mean scores on all outcome measures (i.e., YMRS, CGI-BP, CDRS-R, and C-GAS). DVPX was safe and well tolerated with accepted for publication 18 February 2005 no serious adverse events during the 6-month trial.
Corresponding author: Mani N Pavuluri, MD, Insti- Conclusion: This study provides evidence for the eﬀectiveness and tute for Juvenile Research, 912 South Wood Street safety of DVPX in the treatment of pediatric mixed mania over a (M/C 913), University of Illinois at Chicago, Chicago, 6-month period. Placebo-controlled, randomized trials involving larger samples will ultimately shed light on the eﬃcacy of this agent.
PBD, recent studies have included measures of depressive symptoms (6–9). While several of these An important observation from several studies of studies included subjects with mixed mania, they pediatric bipolar disorder (PBD) is the presence of also included subjects with pure mania (6–9) mixed episodes in 20–85% of the subjects (1–5). In hypomania and euthymia (7). The outcome of mixed episodes, features of major depression and depressive symptoms in mixed episodes needs to be manic symptoms co-exist in the same time frame.
examined in detail as opposed to the outcome of Given the increasing awareness of mixed states in subsyndromal depression in PBD. Building oneﬀorts to study the eﬀectiveness of mood stabilizersfor depressive symptoms, our study examined the MNP has received research support, acted as a consultant or served as eﬀectiveness of divalproex sodium (DVPX) for a CME speaker for Abbott, AstraZeneca, Bristol Myers Squibb, GlaxoSmithKline, Johnson & Johnson, Eli Lilly & Co., Pﬁzer and There is no agreement on the ﬁrst-line mood Shire. JAC has served as a CME speaker for Johnson & Johnson.
stabilizer for PBD. Adult studies have found that DBH, MWN and PGJ have no reported conﬂict of interest.
lithium can be eﬃcacious in bipolar depression and for suicidality (10). DVPX, however, may be diagnosis of a manic episode (n ¼ 8); or a diagno- superior to lithium for rapid cycling, mixed epi- sis of bipolar type II (n ¼ 2). A total of 35 subjects sodes or dysphoric mania (11). The latter presen- tations are more characteristic of PBD. Further,given the eﬀective response and increased use of DVPX in PBD (7–9, 12), it is important to examineits impact on mixed episodes, especially depressive All subjects underwent a standard clinical assess- symptoms. Additionally, given the chronicity and ment, which consisted of a diagnostic interview prolonged episodes in PBD (13), it is important to with the patient and his/her family. In addition, examine the eﬀect of DVPX over an extended time each child and the parent or legal guardian were period. Therefore, the purpose of our study was to interviewed using the Washington University in examine the eﬀectiveness and safety of DVPX for St Louis Kiddie Schedule for Aﬀective Disorders mixed episodes of PBD over a 6-month period.
and Schizophrenia (WASH-U-KSADS, 16). Clin-ical information from all sources contributed to aconsensus views were completed by a board-certiﬁed child This was a 6-month, single-site, prospective, open label, outpatient study of PBD. This study was assistant, or a doctoral-level nurse practitioner approved by the University of Illinois at Chicago in child psychiatry. Treatment was conducted by (UIC) Institutional Review Board. Parents gave the psychiatrist and doctoral nurse and outcome written consent and children gave assent to partic- ratings were completed by independent research clinicians. The same rater was assigned to anyone subject acquisition. All raters had at least 6 months of training prior to rating the measures toward Subjects were screened at our Pediatric Mood establishing reliability. Live diagnostic interviews Disorders Clinic to determine whether they qualiﬁed of 10 cases were coded by three researchers to for the study according to the inclusion and exclu- establish inter-rater reliability. By Cohen’s Kappa, sion criteria. Inclusion criteria included a diagnosis reliability of diagnoses was between 0.96 and of bipolar disorder I (BD type I), mixed episode as deﬁned by simultaneously meeting the DSM-IV was 0.93–0.96. Diagnostic disagreements were criteria for manic and depressed episodes at the resolved in a weekly consensus conference involv- study entry (14); 5–18 years old; and a baseline score ing the research team. All outcome measures of >20 on the Young Mania Rating Scale (YMRS; were also tested for inter-rater reliability among 15). Exclusion criteria included active substance research clinicians (masters level and above). By abuse; serious medical problems; a history of allergy Cohen’s Kappa, inter-rater reliability for the to any of the study medications; the presence of YMRS, Child Depression Rating Scale-Revised another DSM-IV Axis I diagnosis that required (CDRS-R; 17), Clinical Global Impression Scale psychopharmacologic treatment with the exception for Bipolar Disorder (CGI-BP; 18) and the of attention deﬁcit hyperactivity disorder (ADHD); Children’s Global Assessment of Functioning a history of worsening symptoms on DVPX and Scale (C-GAS; 19) were between 0.90 and 0.98.
subjects that responded poorly to DVPX in the pastand required alternative treatment. No cross titra- tion was allowed at the study entry. Stimulants werecontinued if subjects were on a stable dose. Given a The primary outcome measures were change scores study period of 6 months, severity of episodes and on the YMRS and the CDRS-R. Secondary mea- outpatient setting, the washout period consisted of sures included the CGI-BP and the C-GAS. In this tapering previous medications over 1 week prior to study, response was deﬁned as ‡50% change from study entry. At the study entry, the serum concen- baseline on YMRS, and £40 on CDRS-R. Remis- trations of lithium, DVPX or carbamazepine had to sion was deﬁned as ‡50% change from baseline on be <0.3 mEq/L, 30 mg/L, and 3 mg/L, respectively to ensure that they were adequately washed out from subscale of £2 (1 ¼ very much improved, 2 ¼ much Forty-eight potential subjects were screened; In addition, physical examination and labora- 13 did not meet the study criteria due to a history tory assessment values were obtained at baseline of worsening of symptoms with DVPX (n ¼ 3); a and at regular intervals during the 6-month follow up. These included drug levels of DVPX, calcium, suggest that they are valuable in treating comorbid phosphorus, uric acid, glucose, total protein, ADHD alongside mood stabilizers, without wors- albumin, liver function tests, cholesterol, creatinine ening the manic symptoms (26–28). Therefore, kinase, electrolytes, urinalysis with urine drug this being a 6-month long DVPX eﬃcacy trial screen, a pregnancy test for females of child- versus algorithm study that allows strategies of bearing age, a complete blood cell count, and adding other medications midway through the baseline electrocardiogram (ECG). Height, weight, clinical trial, we decided to opt for continuing the blood pressure and heart rate were also obtained subjects on stimulants when indicated. Further by the General Clinical Research Center (GCRC) dose change or stimulant formulation were not nurse. If an adequate physical examination or permitted during the trial period. If subjects were relevant laboratory tests had been conducted not beneﬁting from psychostimulants at study within the past 3 months in medication-naı¨ve entry, these drugs were discontinued. Intermittent subjects, they were not repeated. All tests were risperidone was used for breakthrough symptoms repeated on a monthly basis except for the ECG of psychosis when subjects did not respond opti- and thyroid function tests which were obtained at mally to DVPX. Risperidone was allowed for a 3-month intervals. As venous blood levels of maximum of seven consecutive days, for a total of ammonia are aﬀected by high activity and carbo- 7 days per subject throughout the trial, and on hydrate consumption regardless of valproate levels only two separate occasions. Benztropine was (20), we also obtained ammonia levels if related allowed on an as-needed basis for EPS when symptoms such as headaches, confusion and leth- risperidone was used. Low-dose trazodone was argy were observed (21). At the time of designing prescribed for acute sleep disturbance given its the study, blood testing for bioavailable androgens minimal interference with rapid eye movement (free testosterone) was considered in females if one sleep (29, 30); a maximum of three consecutive of the following features was present: menstrual irregularities, obesity or hyperandrogenism (i.e.,hirsutism and alopecia), a slightly more conserva- tive criteria than was suggested for adults onDVPX (22). EPS was assessed using the Abnormal Intent-to-treat (ITT) analyses (31) with last obser- Involuntary Movement Scale (AIMS; 23). Adverse vation carried forward were used to assess response events were also recorded monthly using Pediatric rate and eﬀect sizes. Global baseline to end point Side Eﬀects Checklist (P-SEC; 24).
eﬀect sizes were calculated on all subjects whocompleted treatment by dividing the diﬀerencebetween baseline and end point scores by the standard deviation measure, producing a widely Divalproex sodium was given at 15–20 mg/kg/day, used measure of treatment eﬀect (Cohen’s d). We with an initial dose of 250–500 mg on day 1 and also conducted random regression models of increased to full dose over 1 week. Serum levels of criterion variables (e.g., YMRS and CDRS-R) DVPX were measured 5 days after reaching a dose predicted by time and medication, controlling for that was considered tolerable and optimal, repeat- diﬀerences in gender, age, ethnicity, and the ed at day 14, then monthly. Dose increments were guided by tolerability, serum levels (50–120 lg/mL, Baseline comparisons of patient characteristics To avoid the high dropout rate prevalent inrandomized pharmacotherapy trials (25) and to One subject dropped out of the study in week 1 maximize the chance for subjects to remain in the because of worsening of symptoms and no follow- study for the entire 6 months, we allowed only up measures were completed. The ﬁnal sample that minimal use of rescue medications, a strategy completed at least one set of follow-up measures previously reported by Findling et al. (7). Subjects was 34. The mean length of treatment was 5.53 with a history of ADHD when not actively manic visits over a period of 5.05 (SD ¼ 3.36) months.
or depressed, who beneﬁted from psychostimulants Demographic and other relevant variables are at FDA-approved doses based on parent report, were continued on these medications. Stimulants 950 (±355 mg) and mean serum level was 109 lg/ were allowed in this trial as some recent reports SES ¼ socioeconomic status; ADHD ¼ Attention Deficit Hyper- activity Disorder; ODD ¼ Oppositional Defiant Disorder.
Outcome measures on intent-to-treat sample There were statistically signiﬁcant diﬀerences from baseline to end point on the YMRS [t(33) ¼ 16.85, p < 0.001] scores. These results are shown in Fig. 1. A repeated-measures, multivariate analysis of variance (MANOVA) showed that these base- line to end point diﬀerences remained signiﬁcant even when controlling for the eﬀects of age, gender, ethnicity and SES. As reported in Table 2, statis- tically signiﬁcant diﬀerences were also found between baseline and endpoint scores on various subscales of the CGI Severity Scale and on theC-GAS.
Fig. 1. (A) Young Mania Rating Scale score by month. (B)Child Depression Rating Scale-Revised score by month.
**p < 0.01 Using the criteria of ‡50% change from baselineon YMRS, and £40 on CDRS-R, the response The eﬀect size in standard deviation units (Cohen’s rate was 73.5%. Using the criteria of ‡50% d) is a standardized measure of the eﬀect of treatment. Even though the present study is not a CDRS-R, CGI-BP-Improvement subscale of £2, randomized trial, the eﬀect size is useful in that it and ‡51 CGAS score, the remission rate was allows evaluation of the magnitude of treatment 52.9%. Given the exploratory nature of the trial, eﬀect and provides a means for comparing the eﬀects we examined the variables associated with remis- found in this study with those of other studies. The sion. These results are summarized in Table 3.
overall YMRS eﬀect size calculated from the diﬀer- With the exception of variables used to deﬁne ence between baseline and end point measurements remission status, there were no signiﬁcant demo- was 2.90 by Cohen’s d, indicating a robust clinical eﬀect. A random eﬀects regression model predict- ing YMRS scores from month of treatment and Table 2. Treatment response of divalproex sodium in mixed mania (n ¼ 34) CGI-BP ¼ Clinical Global Impression Scale-Bipolar Disorder.
Table 3. Demographic information and clinical features by remission status Additional medications included risperidone (n ¼ 17, mean dose ¼ 0.76 ± 0.45 mg, mean length ¼ 7 ± 1 days), trazodone (n ¼ 5, mean dose ¼ 43.0 ± 10.4 mg, mean number of doses/days ¼ dose ¼ 15 ± 0.0 mg, held constant throughout the study period). Although it was included in the protocol, benztropine was not required.
Overall, DVPX was well tolerated and most adverse eﬀects were mild to moderate. Adverse events that were reported in more than 10% of the sample are summarized in Table 4. As mentioned before, one subject dropped out as mood symp- toms worsened within a week of starting the medication. Although 20 subjects reported weight gain on the P-SEC, all subjects gained some weight(mean increase: 5.6 ± 4.3 kg). Examination ofCDC growth charts for children aged 2–20 (33) medication, while controlling for gender, ethnicity, found that the average weight gain experienced by and SES, produced a negative eﬀect size of 0.10 children in this study represented an approximately standard deviations for each month of treatment.
1 standard deviation increase in weight, from For each month in treatment, there was an expected the 50th to the 70th percentile. Six subjects had linear decline in YMRS scores of 2.2 points with a transient, abnormally elevated alanine trans- average change from baseline to end point being 19.8 ferase level (mean ¼ 68 ± 7.2 IU/L) that nor- malized after 2 months of treatment (mean ¼ The overall CDRS-R eﬀect size calculated from 49 ± 12.1 IU/L). No signiﬁcant ECG changes the diﬀerence between baseline and end point measurements was 1.23 by Cohen’s d. Because ofthe small sample size, these eﬀects were notsigniﬁcantly diﬀerent from each other in magni- tude. A random eﬀects regression model predicting Since DVPX is used as a ﬁrst-line mood stabilizer CDRS-R scores from month of treatment and in PBD, its eﬀect on mixed symptoms needs medication, while controlling for gender, ethnicity, systematic study. To our knowledge, this is the and SES, produced a negative eﬀect size of 0.18 ﬁrst report of DVPX for the treatment of pediatric, standard deviations for each month of treatment.
mixed, manic episodes over a 6-month period. In For each month in treatment, there was an this open trial, manic symptoms improved in expected linear decline in CDRS-R scores of 3.87 3 months and depressive symptoms in 2 months.
points, with average change from baseline to end These results reﬂect our clinical experience in which initial reduction in depressive symptomsprecedes an overall response in manic symptoms.
This rapid, signiﬁcant improvement in symptoms Table 4. Adverse events reported in more than 10% of the sample during the initial phase persisted over the entire 6 months. The response rate was 73.5% and theremission rate was 52.9% in the ITT sample.
It is diﬃcult to compare our results with other relevant studies, as none of them included response or remission rates over a 6-month period in a homogenous sample of mixed mania.
With this caveat in mind, Kowatch et al. (12) studied a sample of pediatric bipolar spectrum disorders (types I and II) and reported a response continued on the antipsychotic as is often the case rate of 53% with DVPX monotherapy. Findling in pharmacotherapy algorithm (35). Its role in et al. (7) reported a remission rate similar to that ameliorating psychotic features cannot be discount- found in the present study. With a combination ed in interpreting the study results. Trazodone was of DVPX and lithium, 47% showed substantial used as a rescue medication for sleep in low doses in only ﬁve subjects over a limited period (5/184 improvement in functioning levels for four con- nights). Thus, it is unlikely that the study outcome secutive weeks. Those with mixed episodes also demonstrated signiﬁcant improvement in depres-sive symptoms. The issue of the discrepancy between response rates and remission rates is alsonoted by Wagner et al. (9), who found ﬁnal These results must be interpreted in light of the average CGI Severity Scale scores of 3.2 despite a study’s limitations. First and the most important 61% response rate. This disparity is critical in limitation is the design of the study. Without a control group, it is impossible to determine conclu- overall improvement in core symptoms may be sively the reason for the subjectsÕ improvement.
seen alongside residual associated symptoms.
Subjects may have responded because of the study’s Although DVPX is eﬀective in treating depressive length, or because of the additional support provid- and manic symptoms, the overall recovery or ed by a university-based specialty clinic. However, the length of this study was longer than the 6– Adverse events were mild to moderate in sever- 8 week average length of acute clinical trials in ity, but in general, DVPX was well tolerated. The which initial placebo responses are observed. The most common side eﬀects were weight gain, seda- open trial design may also have presented oppor- tion, increased appetite and cognitive dulling. The tunities for bias. To minimize this risk, we used higher incidence of side eﬀects reported in this three trained diagnostic interviewers and outcome study may be a genuine reﬂection of subjectsÕ ratings were independently rated by research clini- experience, as we encouraged active collaboration cians other than those who were treating the with families to elicit such eﬀects using the P-SEC.
subjects. The ratings were also checked for relia- Kowatch et al. (12) noted a pattern of worsening bility by a board-certiﬁed child psychiatrist blinded of symptoms after 3 weeks of treatment that to the timeline (baseline, interim follow-up point or resolved within a week. While the subjects were end point). The second limitation is that although not seen at week 3 in the current trial, we did not DVPX was the predominant mood stabilizer used observe a pattern of symptoms worsening over a in this trial, 38% of the subjects were also on 6-month follow up despite regular examinations stimulants. The subjects who were on stimulants (average of 4.3 week intervals). During this study, may not have belonged to the subtype who would indication did not arise to test for hyperammonia potentially have developed treatment-emergent or testosterone levels. Future studies may yield mania as described by Faedda et al. (3). Parents useful information by conducting these tests in in this study, however, reported stable response to asymptomatic subjects to uncover problems such stimulants and reluctance to discontinue them. The as encephalopathy or polycystic ovarian syndrome.
strategy of allowing stimulants on stable doses during a clinical eﬃcacy trial needs to be explored Wagner et al. (9), the DVPX plus lithium trial by in future studies. Finally, although every attempt Findling et al. (7), and the olanzapine monotherapy was made to minimize the use of rescue medica- by Frazier et al. (6) also included several subjects tions, the design did not permit us to determine the continued on methylphenidate for ADHD. It is extent to which these ﬁndings may be interpreted as likely that the outcome in pediatric mixed mania depends on combined use of DVPX and a stimu- Placebo-controlled trials would be ideal for lant, in such a sub-population. A second-generation establishing the eﬃcacy and safety of DVPX in antipsychotic was used for psychotic breakthrough pediatric mixed mania. Such a study design, symptoms similar to Findling et al. (7). This may be however, makes it diﬃcult to retain severely-ill necessary to improve response rates in those subjects with PBD in the study (9) and will be a patients with psychotic features (34) or more severe challenge to conduct. Therefore, the third limitation symptoms (8, 35) or to achieve a more rapid was the inevitable use of rescue medication. The response than with DVPX monotherapy. It is large retention rate in our study, however, may have critical to note that risperidone was given for short, been due to their utilization given the length of the time-limited periods (7/184 days); subjects were not trial. Fourthly, response rates may be higher in our study than in general practice because of exclusion of subjects with a prior history of non-response to et al. Combination lithium and divalproex sodium in pediatric bipolarity. J Am Acad Child Adolesc Psychiatry2003; 42: 895–901.
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