This report was reviewed for medical and scientific accuracy by Robert G. Stern, MD, Associate Professor of Psychiatry, University of Medicine and Dentistry of New Jersey (UMDNJ), Robert Wood Johnson Medical School, New Brunswick, New Jersey

Introduction

Exciting new data presented at the 42nd NCDEU illustrates the expanding use of divalproex sodium across a spectrum of psychiatric disorders whose treatment to date has been largely unmet or inadequately fulfilled. Divalproex sodium is a mood stabilizer approved by the FDA for the treatment of acute manic episodes associated with bipolar disorder.¹ In addition, published studies support a role for divalproex sodium in the treatment of behavioral dyscontrol symptoms such as irritability, impulsive aggression, and hostility in patients with a variety of personality disorders.^2,3 This report will touch upon promising data on divalproex sodium in the treatment of Cluster B Personality Disorders, schizoaffective bipolar disorder, combination with an antipsychotic in schizophrenia, and reduction of agitation in the elderly.

New Treatment Option for Cluster B Personality Disorders

Patients with Cluster B Personality Disorders may require pharmacologic treatment for impulsive aggression, yet no FDA-approved pharmacologic agent exists for these disorders. Eric Hollander, MD, Mount Sinai School of Medicine, New York, NY and colleagues evaluated the safety and efficacy of divalproex sodium (Depakote, Abbott Laboratories) in reducing the symptoms of impulsive aggression compared to placebo in a multicenter, randomized, double blind, 12-week trial of 96 patients with Cluster B Personality Disorders.⁴ The study's primary efficacy measure was the average of the last four assessments in the Aggression Scale of the Overt Aggression Scale-Modified (OAS-M Aggression Score).

In order to participate in the study, patients had to be between age 18-65 years, have a diagnosis of Cluster B Personality Disorder, a score of ≥ 15 on the OAS-M Aggression Score, express verbal or physical outbursts at least twice a week, and have demonstrated spontaneous aggression which caused marked distress or impaired occupational or interpersonal functioning. Primary Cluster B diagnosis included borderline (55%), narcissistic (13%), antisocial (10%), histrionic (1%) and non-specified (21%). Patients with a history of Bipolar I Disorder were excluded.

Patients randomized to divalproex sodium (n = 43) initiated dosing at 250 mg twice a day, increasing by 250 mg every 3-7 days based on clinical judgment up to a maximum dose of 30 mg/kg/day. The recommended target serum level was 80-120 mcg/mL by week 3. The mean modal daily dose of divalproex sodium was 1,404 mg (18 mg/kg) and the mean serum level at final evaluation was 66 mcg/mL.

Efficacy of Divalproex Sodium in the Treatment of Cluster B Personality Disorders

During the last 4 weeks of the study, divalproex sodium-treated patients had significantly lower OAS-M Aggression Scores compared to placebo patients (p = 0.047). Further, the median Aggression Score for the last 4 weeks of treatment revealed a statistically significant improvement in the divalproex sodium-treated patients (p = 0.016). Investigators noted an even greater result when the OAS-M Aggression Score excluded patients with a primary diagnosis of Antisocial Personality Disorder (see Figure 1).

Over the entire 12-week period of the study, a significant treatment difference favoring divalproex sodium was noted in the change from baseline in the OAS-M Aggression Score. Greater improvements from baseline were seen for divalproex sodium-treated patients in the OAS-M Irritability Score at weeks 2, 3, 6, 7, 8, 10, and 12 and in CGI-Severity Scores at weeks 1, 3, 6, 9, 10, 11, and 12.

Adverse events were assessed as mild to moderate. No new safety concerns were observed. Eleven patients experienced weight gain with divalproex sodium (versus 2 on placebo) and 7 patients each exhibited elevations in SGOT and SGPT. Forty-four patients discontinued from the study, of which 22 were on placebo and 22 on divalproex sodium. Reasons for discontinuation included adverse events (10%), ineffectiveness (4%), noncompliance (7%), lost to follow-up (11%), and other (13%).

These findings suggest that divalproex sodium may be an effective pharmacologic agent in the treatment of impulsive aggression and irritability in patients with Cluster B personality disorders. Further, the investigators noted due to adverse event consideration, "Future studies should consider the use of divalproex sodium extended-release in this population".

Divalproex Sodium Extended-Release Maintains Effective Symptom Control in Patients Switched from Divalproex Sodium Delayed-Release

Divalproex sodium is a standard treatment for bipolar disorder. An extended-release (ER) formulation of divalproex sodium (Depakote ER, Abbott Laboratories) has been recently approved by the FDA (for migraine) and offers the advantage of once-daily dosing leading to smoother blood levels that suggests an improved adverse event profile.⁵ Centorrino et al⁶ assessed the safety, tolerability and efficacy of switching patients with bipolar and schizoaffective bipolar disorder from the standard delayed-release formulation to the ER formulation. Secondary assessment included the evaluation of dosing for the ER formulation required to maintain baseline valproic acid blood levels.

Twelve patients (mean age 45.6 years) with DSM-IV diagnoses of bipolar disorder or schizoaffective disorder, bipolar type and maintained on stable doses of divalproex sodium for at least 4 weeks were switched to the closest equivalent dose of the extended release formulation for 6 weeks. Valproic acid levels were collected at baseline, week one, week 6 and upon dose-adjustment.

The mean dose of divalproex sodium at baseline was 1189 mg/day (± 189 mg/day) vs. the final mean dose of divalproex sodium-ER of 1500 mg/day (± 369 mg/day). The baseline mean valproic acid level for divalproex sodium was 86.2 mg/L (± 22.9 mg/L) vs. the final mean valproic acid level of divalproex sodium-ER of 80.1 mg/L (± 22.1 mg/L).

Researchers noted that all weekly efficacy measures (YMRS, BPRS, HAMD, CGI-S, CGI-I, and GAF) as well as clinical status and laboratory values did not significantly change. On the side effects scale (UKU) there was a significant improvement at week one in comparison to baseline. All subjects elected to remain on the ER formulation at the end of the study.

The authors concluded, "This pilot study suggests that patients may be switched safely from standard divalproex sodium to the extended-release formulation, while maintaining effective symptom control. A higher dose of the extended-release [21% higher daily doses] is required to reach equivalent standard divalproex blood levels."

Divalproex Sodium Enhances Antipsychotic Effects in the Treatment of Schizophrenia

In an effort to augment the effect of antipsychotics in schizophrenia, researchers have looked to alternate mechanisms of action to treat this disorder. It has been speculated that divalproex sodium may modulate dopamine activity in brain areas relevant to symptoms of schizophrenia via GABA-ergic activity. Hoping to further explore that association, Daniel and colleagues assessed the safety and efficacy of divalproex sodium in combination with either risperidone or olanzapine compared to risperidone or olanzapine monotherapy in a multicenter, randomized, double blind, parallel-group, 4-week trial of 249 patients with schizophrenia hospitalized for psychosis.⁷

The Positive and Negative Syndrome Scale (PANSS) was administered on Days 3, 5, 7, 10, 14, 21 and 28 with the primary measurement on Day 28. Over the first 6 days, patients were randomized to risperidone (6 mg/day) or olanzapine (15 mg/day). Concurrently, over the first 12 days, divalproex sodium was initiated at 15 mg/kg/day and titrated to effect to a maximum dose of 30 mg/kg/day. Post hoc analyses revealed differences in treatment effect as early as Day 3 in the combination-treated patients versus the monotherapy-treated patients. The PANSS Total Score in the combination therapy group was significantly better at days 3, 5, 7, 10, 14, and 21 (p < 0.05). When the effect over time was evaluated using repeated measures of ANOVA, the combination therapy group was significantly better over the 28-day study period (p = 0.020). (see Figure 2)

A significantly greater percentage of patients in the combination groups had a ≥ 20% improvement in the PANSS total scores compared to the monotherapy groups. Furthermore, this improvement was seen earlier in at least 50% of patients in the combination groups by day 7 versus day 14 in the monotherapy groups. (see Figure 3)

Divalproex sodium had a similar effect when added to either risperidone or olanzapine. Few patients withdrew for adverse effects. In fact, discontinuation rates in the combination groups were 28% versus 38% in the monotherapy groups. Divalproex sodium appeared to enhance the effect of antipsychotics in these hospitalized patients with exacerbations of schizophrenia, with measurable differences occurring as early as day 3.

Based on enhanced efficacy and earlier treatment effect, these findings may also yield economic benefits as well because atypical antipsychotics can be expensive medications. Stephen M. Stahl MD, PhD, of the Neuroscience Education Institute, Department of Psychiatry, University of California, San Diego, California assessed the utilization patterns of atypical antipsychotics including single-agent therapy, differential dosing, polypharmacy and concomitant therapies from May 1999 through August 2000 within Medi-Cal (California Medicaid Program).⁸ In another presentation at NCDEU, Dr. Stahl noted that high dosing and polypharmacy are frequent uses of atypical antipsychotics with Medi-Cal and that divalproex augmentation is generally not as expensive as high dosing or polypharmacy with atypical antipsychotics.

Divalproex Sodium as a Replacement for Neuroleptics in Reducing Agitation in the Elderly

John M. de Figueiredo, MD, ScD, assessed the effects of divalproex sodium on the Clinical Global Impression of Change Improvement Scale (CGI-I) after 6 weeks of treatment in a retrospective chart review of 30 patients in a university-affiliated nursing home.⁹ Patients had a mean age of 81.3 years. Twenty-four patients had vascular dementia, one had mental retardation and bipolar disorder, two had probable Alzheimer's disease, one had possible Alzheimer's disease, and two had bipolar disorder.

Patients were divided into 3 groups: patients who had never received any neuroleptic (n = 10), patients on whom neuroleptics were started and discontinued and replaced by divalproex sodium (n = 9) and the remaining patients in which neuroleptics were continued and divalproex sodium constituted adjunct therapy. After 6 weeks of treatment with divalproex sodium for agitation, 63% of patients (n = 19) were rated as "very much improved" (n = 5) or "much improved" (n = 14) on the CGI-I. Of the remaining patients, 6 were rated "minimally improved" and 5 were rated "no change". No patient was rated "worse". The mean CGI-I score was 1.74. Of the patients stabilized on neuroleptics (33%), the change to divalproex sodium was uneventful and side effects minimal.

Dr. de Figueiredo commented, "The results suggest, but do not prove, that divalproex can be used in some patients with relatively few side effects as a substitute for neuroleptics, even in those cases in which neuroleptics are at least partially successful at reversing agitation."

Additional Investigations of Anticonvulsants

The use of anticonvulsants in psychiatric disorders has been investigated for some time. Carbamazepine may be a useful adjunct to antipsychotic therapy¹⁰ and may lower aggression in a broad spectrum of disorders.¹¹ More specifically, a recent meta-analysis by Leucht and colleagues¹² examined 10 studies (n = 283) that have investigated carbamazepine augmentation in schizophrenia. Results indicated that carbamazepine monotherapy tended to be less effective than carbamazepine/perphenazine adjunct therapy. Although there was a trend indicating benefit from carbamazepine as an adjunct to antipsychotics, the trend did not reach statistical significance.

Dursun and Deakin recently published a case-series outcome study evaluating the augmentation of antipsychotic treatment with lamotrigine or topiramate in patients with treatment-resistant schizophrenia.¹³ Patients receiving lamotrigine augmentation (n = 17) of clozapine had a significant decrease in Brief Psychiatric Rating Scale score after 2 weeks of treatment. There was no significant improvement when lamotrigine was added to risperidone, haloperidol, olanzapine or fluphenthixol. Similarly, there was no significant improvement observed with topiramate augmentation (n = 9) of clozapine, olanzapine, haloperidol or fluphenthixol. Conversely, in a single-patient observation published by Drapalski et al¹⁴, the addition of topiramate to antipsychotic medication produced a dramatic attenuation in the severity of negative symptoms as assessed by the Negative Scale of the Positive and Negative Syndrome Scale. Many of the studies investigating anticonvulsant use in psychiatric disorders are limited in their design and by patient population size. Clearly, more intensively structured clinical trials are needed to explore more fully their potential use in the disorders highlighted in this report.

References

1. Depakote Delayed-Release Tablets Professional Prescribing Information. Abbott Laboratories. Available at: http://www.rxabbott.com. Accessed June 14, 2002.
2. Hollander E, Allen A, Lopez RP, et al. A Preliminary Double Blind, Placebo-Controlled Trial of Divalproex Sodium in Borderline Personality Disorder. J Clin Psychiatry 2001; 62(3):199-203.
3. Kavoussi RJ, Coccaro EF. Divalproex Sodium for Impulsive Aggressive Behavior in Patients with Personality Disorder. J Clin Psychiatry 1998;59(12):676-680.
4. Hollander E, Swann A, Coccaro EF, et al. Divalproex Sodium is Superior to Placebo for Impulsive Aggression in Cluster B Personality Disorders. 42nd Annual New Clinical Drug Evaluation Unit (NCDEU) Meeting, June 10-13, 2002, Boca Raton, Florida. Abstract NR 224.
5. Depakote ER (Extended-Release) Tablets Professional Prescribing Information. Abbott Laboratories. Available at: http://www.rxabbott.com. Accessed June 14, 2002.
6. Centorrino F, Kelleher JP, Berry JM, et al. A Pilot Study of Extended Release Divalproex Sodium Switch from Standard Formulation of Divalproex Sodium in Maintenance Treatment of Bipolar Disorder and Schizoaffective Disorder, Bipolar Type. 42nd Annual New Clinical Drug Evaluation Unit (NCDEU) Meeting, June 10-13, 2002, Boca Raton, Florida.
7. Daniel DG, Wassef AA, Tracy K, Jiang P, Sommerville KW, Casey DE. Divalproex Enhances Antipsychotic Treatment of Recently Hospitalized Schizophrenia Patients. 42nd Annual New Clinical Drug Evaluation Unit (NCDEU) Meeting, June 10-13, 2002, Boca Raton, Florida.
8. Stahl SM, Simon-Leack J, Walker V. Frequency of High Cost Utilization of Atypical Antipsychotics with Medi-Cal. The California Medicaid Program: Polypharmacy, High Dosing, and Augmentation. 42nd Annual New Clinical Drug Evaluation Unit (NCDEU) Meeting, June 10-13, 2002, Boca Raton, Florida.
9. de Figueiredo JM. Replacement of Neuroleptics by Divalproex Sodium in Geriatric Neuropsychiatric Disorders. 42nd Annual New Clinical Drug Evaluation Unit (NCDEU) Meeting, June 10-13, 2002, Boca Raton, Florida.
10. Simhandl C, Meszaros K. The use of Carbamazepine in the Treatment of Schizophrenic and Schizoaffective Psychoses: A Review. J Psychiatr Neurosci 1992;17:1-14.
11. Young JL, Hillbrand M. Carbamazepine Lowers Aggression: A Review. Bull Am Acad Psychiatry Law 1994;22:53-61.
12. Leucht S, McGrath J, White P, Kissling W. Carbamazepine Augmentation for Schizophrenia: How Good is the Evidence? J Clin Psychiatry 2002;63(3):218-224.
13. Dursun SM, Deakin JF. Augmenting Antipsychotic Treatment with Lamotrigine or Topiramate in Patients with Treatment-Resistant Schizophrenia: A Naturalistic Case-Series Outcome Study. J Psychopharmacol 2001;15(4):297-301.
14. Drapalski AL, Rosse RB, Peebles RR, Schwartz BL, Marvel CL, Deutsch SI. Topiramate Improves Deficit Symptoms in a Patient with Schizophrenia when Added to a Stable Regimen of Antipsychotic Medication. Clin Neuropharmacol 2001;24(5):290-294.

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Disclosure Robert G. Stern, MD
Has no significant relationships to disclose.

This report contains information on commercial products that is outside of current approved labeling or information on the investigational use of products not yet approved by the United States Food and Drug Administration. Approved labeling should be consulted prior to treating patients with products discussed herein.

This report is supported by an educational grant from Abbott Laboratories.

The opinions expressed in this publication are those of the participating faculty and do not necessarily reflect the opinions or the recommendations of their affiliated institutions: University of Medicine & Dentistry of New Jersey; MMC, Inc.; or any other persons. Any procedures, medications, or other courses of diagnosis or treatment discussed or suggested in this publication should not be used by clinicians without evaluation of their patients' conditions, assessment of possible contraindications or dangers in use, review of any applicable manufacturer's product information, and comparison with the recommendation of other authorities. This Psychiatry Express Report(tm) includes discussion of treatment and indications outside of current approved labeling. This Psychiatry Express Report(tm) was made possible through an educational grant from Abbott Laboratories.

© 2002 Millennium Medical Communications, Inc. and UMDNJ-Center for Continuing and Outreach Education