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 RESEARCH ARTICLE

Efficacy of extended-release divalproex combined with “condensed” dialectical behavior therapy for individuals with borderline personality disorder

Richelle Moen, PhD

Department of Psychiatry, University of Minnesota Medical School, Minneapolis, MN, USA

Mary Freitag, PsyD

Integrative Psychological Services, St. Paul, MN, USA

Michael Miller, PsyD

Department of Psychiatry, University of Minnesota Medical School, Minneapolis, MN, USA

Susanne Lee, PhD

Department of Psychiatry, University of Minnesota Medical School, Minneapolis, MN, USA

Ann Romine, BA, RN

Department of Psychiatry, University of Minnesota Medical School, Minneapolis, MN, USA

Sue Song, MA

Department of Psychiatry, University of Minnesota Medical School, Minneapolis, MN, USA

Adit Adityanjee, MD

Department of Psychiatry, University of Minnesota Medical School, Minneapolis, MN, USA

S. Charles Schulz, MD

Department of Psychiatry, University of Minnesota Medical School, Minneapolis, MN, USA

BACKGROUND: Borderline personality disorder (BPD) is a significant psychiatric illness for which medication treatments are still being explored. The goal of this study was to assess divalproex extended release (ER) vs placebo for patients receiving dialectal behavior therapy (DBT).

METHODS: Patients with BPD received 4 weeks of “condensed DBT.” Those with Symptom Checklist-90 (SCL-90) scores >150 after this treatment were then randomly and blindly assigned to placebo or divalproex ER for 12 weeks. Repeated measures analysis of variance utilizing last observation carried forward was used to assess the results.

RESULTS: Seventeen participants completed the full assessment. Two patients had a significant decrease in SCL-90 in the first 4 weeks, leaving 15 patients for the medication phase of the trial. There were no significant differences between the participants assigned to divalproex ER compared with placebo. However, there was a significant improvement in both groups from baseline to endpoint (P = .001).

CONCLUSIONS: The response of 2 of 17 participants in the first 4 weeks prior to medication may point to a practice strategy in approaching outpatients with BPD. Although the patients had a decrease in symptoms during the study, there was no advantage observed for divalproex ER and DBT over placebo and DBT.

KEYWORDS: borderline personality disorder, divalproex ER, dialectical behavior therapy

ANNALS OF CLINICAL PSYCHIATRY 2012;24(4):255-260

  INTRODUCTION

Borderline personality disorder (BPD) is a common, chronic, and disabling disease that affects an estimated 1% to 2% of the general population1 and has an 8% to 10% mortality rate.2 The prevalence of BPD found in outpatient psychiatric clinics is 10%, although estimates suggest that as many as 20% of all psychiatric inpatient admissions meet full BPD criteria. BPD is twice as common in females vs males. Few patient groups require more mental health resources than BPD patients. BPD is known to be difficult to treat and treatment recommendations vary.3

BPD is characterized by instability in interpersonal relationships, self-image, and affect; high emotional reactivity with difficulty returning to baseline; chronic feelings of emptiness; dissociative experiences; and marked impulsivity. Patients also experience impulsive risk-taking behavior, inappropriate/intense anger, self-injurious behavior, multiple suicide attempts, and brief psychotic episodes.

Medication approaches to BPD have been tested in numerous studies over the last 25 years. Studies have examined a number of different compounds ranging from low doses of conventional4,5 and atypical antipsychotic medications6-9 to selective serotonin reuptake inhibitors.10,11 Based on observations that BPD patients frequently have symptoms of impulsivity and/or aggression or that they may be comorbid with mood disorders such as bipolar II disorder, a number of studies have investigated divalproex as a treatment for BPD.12,13

To date, Townsend et al14 reported reduction in rating scale scores, but not statistically significant differences from placebo in the first controlled trial of divalproex. Frankenburg and Zanarini12 examined divalproex in BPD patients who also met criteria for bipolar II disorder. They reported a significantly better outcome for the divalproex group on hostility scales. To refine the specificity of patients who may have the best response to divalproex, Hollander et al15 studied the outcome of cluster B (impulsive and aggressive) behaviors in BPD patients, noting the superiority of divalproex in aggressive patients. Finally, to explore the potential of a new preparation of divalproex—1 with extended release (ER)—Simeon et al16 reported reduction in symptoms following administration of divalproex ER in an open-label trial. Of note, the design of previous divalproex studies tended to focus attention on the impulsive-aggressive BPD patients.

Both divalproex and divalproex ER have shown significant potential for patients with BPD. Some of the recent review articles have critically assessed the efficacy data for both divalproex and divalproex ER.17-19 However, next steps would be informative if they addressed issues of psychosocial treatment and placebo response.20,21 For example, Schulz et al22 noted a significant reduction in scores of BPD patients assigned to risperidone that was equal to the placebo response, thus indicating the importance of understanding psychosocial circumstances of patients in medication trials.

Psychotherapeutic strategies are important for treating personality disorders. Dialectical behavior therapy (DBT) has been proven to be effective in BPD treatment in controlled studies.23,24 Medication and psychosocial combinations have only recently begun to be explored with this population. In a 12-week, combined placebo-controlled trial of fluoxetine plus DBT vs placebo plus DBT, Simpson et al25 found no significant differences in outcome measures between the 2 groups. On the other hand, Soler et al21 found significant advantages for DBT plus olanzapine compared with DBT plus placebo in decreasing both depressive symptoms and impulsivity/aggressive behaviors in BPD patients. Linehan et al20 found a more rapid reduction of irritability and aggression with DBT plus olanzapine than with DBT plus placebo, and both groups exhibited large and consistent reductions in aggression, depression, irritability, and self-injury.

Therefore, a double-blind, placebo-controlled pilot trial was designed to address the usefulness of divalproex ER in BPD patients in the context of short-term DBT treatment. In order to address the frequently observed rapid response of some patients during the initial phase of the clinical trial, all participants received “condensed” DBT for 4 weeks, and only those with significant symptoms were randomly assigned to blinded divalproex ER or placebo while continuing DBT. Therefore, the study addressed the issue of rapid response of patients at study entry as well as usefulness of divalproex ER in BPD patients undergoing DBT treatment.

  METHODS

Participants

Recruitment of women and men age 21 to 55 who were disturbed by moodiness, distrustfulness, impulsivity, and painful and difficult relationships was accomplished primarily through newspaper and radio advertisements in the Minneapolis area. Local psychiatric clinics and mental health centers also were notified of the study, although no clinical referrals were made. Participants were initially screened by telephone questionnaire using the 9 DSM-IV criteria for diagnosis of BPD.3 Potential participants were excluded if they had a current or past history of bipolar disorder, schizophrenia, or major depression with psychotic features; were currently prescribed any psychotropic medication; or were acutely suicidal (ie, had a clear-cut and pressing intent to commit suicide in the near future). Although current diagnosis of major depression was an exclusion criterion, a history of major depression was allowed provided it had been 12 weeks since the last major depressive episode. No current alcohol or illicit substance dependency; a seizure disorder and/or anticonvulsant medications; or pregnancy were allowed. Women of childbearing potential were given a pregnancy test at the beginning of the study. Women who were pregnant, breast-feeding, planning to become pregnant, or not using a reliable form of contraception also were excluded.

After the initial phone screen, patients were invited to participate in a face-to-face assessment screening interview. At that time, written informed consent, which was approved by the University of Minnesota institutional review board, was obtained. The following semi-structured diagnostic interview and symptom screening instruments were administered to each participant: 1) the Structured Clinical Interview for DSM-IV Axis I Disorders26; 2) the Structured Clinical Interview for DSM-IV Axis II Disorder (SCID-II)27 (along with past clinical records to screen for other mental illnesses); and 3) the Symptom Checklist-90 (SCL-90).28 In order to be included in the study, all patients had to have a score of >150 on the SCL-90 indicating a high severity of symptoms, and meet ≥5 criteria on the SCID-II. In order to participate in the study, each potential research patient had to be medication free for 2 to 4 weeks. A 4-week medication-free period was required for patients on long-acting depot medications.

Study design

In order to achieve the stated goals of the study, a 16-week, randomized, double-blind, placebo-controlled trial was designed. This controlled clinical trial consisted of a selection phase lasting 4 weeks and an experimental phase lasting 12 weeks. All participants were given the psychosocial intervention of “condensed-DBT” for 4 weeks and then reassessed. The SCL-90 was given for the second time on week 4. Those scoring >150 were considered nonresponders of “condensed-DBT” and were randomized to the double-blind (active drug vs placebo) phase. These nonresponders to the condensed-DBT were randomly and blindly assigned to receive continued “condensed-DBT” plus either divalproex ER or placebo on a 2:1 ratio. All participants continued 12 more weeks of the “condensed-DBT” (total 16-week program).

The DBT skills training that was done in this study was based on the model of DBT for Adolescents, a “condensed” version of the skills, as modified by Alec Miller and Jill Rathus. This version allowed the participants to receive all 4 modules of skills in a 12-week period of time rather than the usual 26 weeks for adults.29 Slight modifications of wording were needed to focus on “adult behaviors” vs adolescent and their parents’ references. Participants received the entire package of DBT, including all modes and functions of DBT, with weekly individual therapy sessions (45 to 50 minutes) incorporating the use of diary cards and behavioral chain analysis; skills training group (90 minutes); and telephone coaching calls (as-needed basis). The contract and commitment to this DBT program was the 16 weeks (not the 6 months of group or 1 year of individual therapy as prescribed by the formal DBT model of therapy). All therapists were intensively trained in DBT and participated in a mandatory weekly consultation group.

After the screening and enrollment into the study, participants were assessed on the Hamilton Depression Rating Scale,30 the Borderline Evaluation of Severity over Time (BEST),31 and the Barratt Impulsivity Scale (BIS).28,32 The BEST is a measure designed specifically to assess patients with BPD. It allows the patient to rate the degree of impairment or interference from each of the 9 BPD criteria over the past week; each item is rated on a 5-point scale, and scores can range from 12 to 72. The BIS is a 20-item self-report measure with subscales measuring trait impulsivity.

All participants received a physical examination, ECG, and laboratory testing (chemistry and hematology including comprehensive metabolic panel [renal and hepatic], complete blood count, thyroid-stimulating hormone, and urinalysis) to ascertain health status. Any medical illness thought to interfere with the study was cause for exclusion. Laboratory testing was performed at the same time as the divalproex ER blood level—at weeks 3, 6, 11, and 13 weeks after starting the study drug. The time of the last divalproex ER dose was documented, and divalproex ER levels were drawn approximately 24 hours after the last dose to assess relevant trough levels. All raters were kept blind of the serum divalproex level results. Only one study physician (A.A.), who did not participate in the ratings, was privy to the results of serum divalproex levels.

To study the possibility of medication side effects, all physical and psychiatric symptoms were recorded. Patients’ weight and height were measured at entry to double-blind study (to calculate body mass index) and at completion of the trial.

Divalproex ER dosing. Blood samples were obtained to measure blood concentration of divalproex ER at weeks 4, 8, and 16. A study physician then adjusted the dose to maintain the medication at the therapeutic range. The study physician changed the dosing the study medicine and placebo at pre-determined dose-escalation steps so as not to reveal medication assignment.

Data analysis

Statistical analysis of data was conducted using SPSS v.16 (Chicago, IL, USA). Chi-square analyses and one-way analysis of variance (ANOVA) were used to compare demographic characteristics between the 2 groups. Repeated measures ANOVA using last observation carried forward (LOCF) data was used to test group differences in rate of change over time on the SCL-90 total score, the BIS-Motor Score, and the BEST total score. Non-parametric test (Kruskal-Wallis test) was applied to explore group differences in the SCL-90 total score, the BIS-Motor Score, and the BEST total score at each timepoint. Non-parametric test was used for the exploratory analysis due to small sample size and high variability in scores. All statistical tests were 2-tailed with a significance of .05.

  RESULTS

Twenty-nine participants completed the telephone interview after volunteering to be in the study and signed informed consent for the diagnostic and symptom rating assessment for study entry. Nine were “screen failures.” Of the 20 participants who were eligible to continue in the trial, 3 withdrew during the 4-week period of DBT before randomization in the medication trial, leaving 17 patients to go forward with the trial. Two of the participants’ SCL-90 scores were too low to meet criteria for randomization, but continued DBT. Fifteen participants were randomized to either divalproex ER or placebo (TABLE 1). In the divalproex ER group, 6 out of 10 patients completed the study and 3 out of 5 assigned to placebo remained in the study until completion. Assessment of participation in the condensed DBT section of the study revealed that only 1 individual missed >2 of the 16 sessions.

TABLE 2 summarizes the means and standard deviations on the SCL-90 total score; BIS-Motor Score; and the BEST parts A+B (Negative Thoughts, Feelings, and Behaviors) score. According to the repeated measures ANOVA on the group difference in outcomes measured over time, there was no significant Time × Group interaction (slope) as assessed by the SCL-90 total score [F(8,56) = 1.09; P = .38] or BIS-Motor Score [F(6,39) = 0.21; P = .97]. Although no significant group differences were found in the slopes, there was a significant time effect on the SCL-90 overall score, which indicated that the 2 groups showed improvement over time [F(4,56) = 5.36; P < .001]. The statistically significant improvement of all the participants in the study are consistent with the current findings of BPD patients having better outcomes33 (TABLE 2).

Because of small sample size and high variability in scores, we applied nonparametric tests (Kruskal-Wallis Test) to compare the 2 groups at each timepoint. There was no significant group difference in the SCL-90 overall score (screening χ2[2] = 4.42, P = .11; randomization χ2[2] = 5.25, P = .07; week 4 χ2[2] = 4.44, P = .11; week 8 χ2[2] = 3.98, P = .14; week 12 χ2[2] 3.70, P = .16) or the BIS-Motor Score (randomization χ2[2] = 1.87, P = .39; week 4 χ2[2] = 1.72, P = .42; week 8 χ2[2] = 1.90, P = .39; week 12 χ2[2] = 2.65, P = .27).

Several side effects were reported during the study. Patients receiving divalproex ER during the study noted weight gain, sedation, confusion, increased appetite, yawning, vivid dreams, tremor, edema, and tinnitus. Patients on placebo also reported weight gain (although mean measures of weight declined), insomnia, and headache.

Reasons for early withdrawal for the 4 divalproex ER participants were: increased liver enzymes, stopped attending and did not return calls, assessed as potential risk to others, and did not like group therapy. For the placebo group, the reasons for early withdrawal were complaint of no change and a statement of stopping for personal reasons.


TABLE 1

Demographic characteristics of divalproex ER, placebo, and non-randomized groups

  Divalproex ER
(n = 10)
Placebo
(n = 5)
Age range 23 to 45 22 to 51
Mean age 34 37
Sex (F, M) 9, 1 3, 2
Race    
  White 9 3
  Black 0 1
  Hispanic 0 1
  Mixed 1 0
Mean high dose (range) 1,600
(1,000 to 2,000)
1,583
(1,500 to 2,000)
Completed 16-week trial n = 6 n = 3
Mean weight gain (lbs) 13.43 –0.2
ER: extended release.

TABLE 2

Means and standard deviations on SCL-90 total score, BIS-Motor Score, and BEST Parts A+B (Negative Thoughts, Feelings, and Behaviors) score

  Divalproex ER Placebo
  M SD M SD
SCL-90 Total Score
Baseline 156.1 33.6 193.8 41.0
Randomization 168.5 22.7 171.0 16.3
Week 4 148.6 61.5 137.2 74.5
Week 8 142.4 60.0 129.6 70.2
Week 12 137 60.9 114.2 79.8
BIS-Motor Score
Randomization 26.1 8.1 20.6 6.5
Week 4 26.1 7.6 20.8 6.5
Week 8 26.4 10.2 19.6 6.7
Week 12 23.9 10.3 18.2 6.4
BEST A+B Score
Randomization 33.7 8.9 41.3 5.1
Week 4 31.3 6.8 37.3 8.8
Week 8 31.1 7.7 31 11.2
Week 12 28.7 7.1 30 11.4
BEST: Borderline Evaluation of Severity over Time; BIS: Barratt Impulsivity Scale; ER: extended release; M: mean; SCL-90: Symptoms Checklist-90; SD: standard deviation.

  DISCUSSION

Our primary goal with this study was to examine the safety and efficacy of divalproex ER while addressing the impact of the “placebo” effect and controlled psychosocial intervention. One of the most interesting findings within this study was the effectiveness of the 4-week “run-in” of condensed DBT, which allowed us to separate out potential placebo, and/or “early responders” who benefited from treatment without medications. Almost 12% (2 of 17) of our study patients improved with therapy alone. Our research design is unique in how it mirrors psychology practice (therapists and psychologists) in that the patient’s response to therapy determines the need for a referral for medication.

All patients improved over time, even though there were no significant differences between the 2 randomized groups. These findings were consistent with earlier findings by Simpson et al,25 who reported that combined DBT plus fluoxetine did not have an advantage over DBT plus placebo. On the other hand, our results are unlike recent studies by Linehan et al20 and Soler et al,21 in which DBT plus olanzapine was found to be significantly superior to DBT plus placebo for improving mood/anxiety symptoms and impulsive behavior.

Although the patients assigned to divalproex ER had a reduction in symptoms over the course of the study, similar to results seen in earlier studies, the change was not greater than that observed in the placebo group.

Limitations of the study

This study has several methodologic limitations. First, although intended as a pilot study of a new medication, the small sample size limited our statistical power to investigate significant treatment group differences as well as our ability to generalize from our sample. Regarding the issue of whether a larger sample could have led to a significant difference between groups, it is of note that the placebo group had numerically greater response. In addition, only 6 patients in the divalproex ER- and 3 patients in the placebo-treated group completed the entire 12-week medication trial (a 60% completion rate). Because of the LOCF analysis, data of all participants were included in the report of the statistical outcome.

Because BPD is not a homogeneous population, studies are needed to increase our understanding of subcategories of BPD patients, such as those who may benefit from briefer vs longer interventions or those with symptoms that may be more responsive to divalproex ER.15 For example, a recent meta-analysis by Ingenhoven et al34 showed a targeted effect of divalproex for aggression and agitation. This patient group was not selected for specific subtypes of behaviors. It should be noted that there was no difference between divalproex ER and placebo on the BIS.

Moreover, no life-event measure or scale was used to ascertain presence or absence and putative severity of a recent life crisis in the lives of study patients. The self-referred research volunteers may have sought clinical help through the study participation following a life crisis leading to their recruitment in the study. Also, there may be some concern about the mean age of the research participants (mid-30s) and the need to study less persistently ill patients.

Lastly, it should be noted that the psychosocial treatment “condensed” DBT was chosen to match the length of time of the trial. However, this treatment has not been validated for adult patients with DBT. Therefore, a replication of this approach is warranted.

  CONCLUSIONS

In summary, divalproex has shown efficacy in some studies12-15 and the ER formulation was tested in this pilot trial. In addition, other issues of concern in BPD trials were incorporated into the study, including the treatment with “condensed” DBT during the medication trial and the exclusion of the rapidly responding patients prior to randomization.

DISCLOSURES: Dr. Schulz receives grant or research support from AstraZeneca, Myriad RBM, and Otsuka and is a consultant to Eli Lilly and Company and Genetech. Drs. Moen, Freitag, Miller, Lee, and Adityanjee and Ms. Romine and Ms. Song report no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products.

ACKNOWLEDGEMENTS: This study was sponsored by a research grant from Abbott Pharmaceuticals to the principal investigator, S. Charles Schulz, MD.

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CORRESPONDENCE: S. Charles Schulz, MD Department of Psychiatry, University of Minnesota Medical School F282/2A West, 2450 Riverside Avenue, Minneapolis, MN 55454 USA E-MAIL: scs@umn.edu