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

Introduction

Schizophrenia is a major psychotic disorder that affects approximately 1% of the United States (U.S.) population and accounts for 2.5% ($16-$19 billion) of national healthcare costs.¹ Indirect costs from loss of productivity and family burden are estimated at $46 billion.^2,3 Unemployment rates can reach 70%-80% in severe cases,⁴ and it is estimated that schizophrenic patients constitute 10% of the totally and permanently disabled.¹ It is so devastating that as many as 10% to 25% of patients with schizophrenia will commit suicide, half will make attempts.⁵ Additionally, suicidal behavior in depressed patients with schizophrenia can be impulsive and unpredictable.⁶

Traditional Antipsychotic Agents

Antipsychotic medications have comprised the main treatment for patients with schizophrenia. First generation or "typical" antipsychotics are dopamine receptor antagonists with a higher affinity for D₂ than for D₁ receptors. First generation antipsychotics effectively treat the positive symptoms of schizophrenia but not the negative symptoms. These include chlorpromazine, mesoridazine, fluphenazine, perphenazine, trifluoperazine, haloperidol, loxapine, molindone, and thiothixene. Adverse effects limit treatment with first generation antipsychotics and include extrapyramidal symptoms (EPS), tardive dyskinesia (TD), parkinsonian syndrome, and akathisia. Other significant adverse effects include sedation, orthostatic hypotension, and elevated prolactin levels.

Second and third generation or "atypical" antipsychotic medications have a broader spectrum of efficacy in terms of treating both positive and negative symptoms of schizophrenia (as compared to first generation) while inducing fewer EPS. Chemically, they differ from the older agents in their preferential binding at one or more dopamine receptors (D₁, D₂, D₄, and D₅), selectivity for limbic dopamine receptors, and their ability to block one or more 5-hydroxytryptamine (5-HT) receptors (5-HT₂, 5-HT₆, 5-HT₇). Second generation agents include risperidone and ziprasidone. However, they may elevate prolactin levels. Third generation agents include clozapine, olanzapine, and quetiapine. These agents are prolactin sparing while resulting in fewer EPS and less TD. However, weight gain can be a problem. Clozapine may cause agranulocytosis, seizures and requires complete blood count (CBC) monitoring. This potential complication restricts clozapine to refractory patients.⁷

Despite recent pharmacotherapeutic advances in the treatment of schizophrenia, many patients continue to experience positive and negative symptoms, disturbed affect, cognitive impairment, impulsivity, hostility and aggression. Consequently, many patients need additional treatment for persistent symptoms. Because of their mood stabilizing effects in acute mania, investigators have explored whether anticonvulsants might be of clinical benefit in treatment-refractory and treatment-resistant schizophrenia; particularly for agitation and aggressive and impulsive behavior.^8,9 Particular attention has been focused on divalproex sodium.

Evaluation of Divalproex Sodium with Antipsychotics

The exact mechanism of the synergistic action of divalproex sodium with antipsychotics is unknown. However, divalproex sodium does increase concentrations of gamma-aminobutyric acid (GABA).¹⁰ Laboratory evidence has generally supported the ability of GABA to reduce dopaminergic activity and has suggested GABA may be effective in combating hypofrontality in patients resistant to treatment with antipsychotics.¹¹ Through GABA-ergic mechanisms, divalproex sodium's mechanism of action is quite distinct as compared to antipsychotics, which are not known to affect this neurotransmitter.

Wassef et al.¹² demonstrated that divalproex sodium augmentation enhanced the efficacy of antipsychotics, reduced the length of hospital stay and improved Brief Psychiatric Rating Scale (BPRS) scores. In a preliminary study of 30 subjects [n = 16 on antipsychotic monotherapy; n = 14 early-augmentation], divalproex sodium augmentation improved core psychotic symptoms, impacted emotional withdrawal and improved hallucinatory behavior. In a study among all patients with schizophrenia hospitalized in psychiatric centers operated by the New York State Office of Mental Health from 1994 to 1998, the adjunctive use of valproate nearly tripled from 12.3% to 35% of patients.¹³ Although lacking in primary efficacy outcome measurement, the study revealed the need for controlled clinical trials to further examine the adjunctive use of valproate among patients with schizophrenia.

In an effort to address this need, Casey et al.¹⁴ conducted the first large, multicenter trial to assess the safety and efficacy of divalproex sodium used in combination with either risperidone or olanzapine, versus risperidone or olanzapine alone, in up to 240 patients hospitalized for psychosis associated with schizophrenia. Two hundred and forty-nine hospitalized patients (n = 249) with schizophrenia were randomized in a double blind, parallel-group 4-week trial. A schizoaffective disorder, drug-induced psychosis, manic episode, or major depressive episode excluded patients from the study.

Patients were assigned to one of four treatment groups consisting of approximately 60 patients. Treatment regimens included olanzapine, divalproex sodium and olanzapine, risperidone, or risperidone and divalproex sodium. During the first 6 days, risperidone was titrated to a fixed daily dose (bedtime) of 6 mg and olanzapine titrated to a fixed daily dose (bedtime) of 15 mg. Divalproex sodium was initiated at 15 mg/kg/day and titrated to effect over the next 12 days to a maximum dose of 30 mg/kg/day. Divalproex sodium was administered twice a day.

Adjunctive treatment with lorazepam (up to 4 mg/day) was permitted during the first week. During weeks 2 and 3, the lorazepam dose could not exceed 2 mg/day. Benztropine and propranolol could be prescribed for EPS and akathisia, respectively. Restricted use of chloral hydrate and zolpidem tartrate were also permitted during the first 3 weeks.

The primary efficacy measurement was the change from baseline to the final evaluation for the Positive and Negative Syndrome Scale (PANSS) Total score. The primary treatment comparison was combination therapy versus monotherapy. PANSS was measured on days 3, 5, 7, 10, 14, 21, and 28 with the primary measurement of day 28. Statistical analysis included a two-way ANOVA [analysis of variance] and repeated measures ANOVA. Patients on combination divalproex sodium therapy received mean daily doses of 2,363 mg (range 500-3,500 mg) divalproex sodium with olanzapine and 2,258 mg (range 1,000-3,500 mg) with risperidone. At the final visit, the preliminary mean total trough valproate concentrations were 98.2 µg/mL [31.4 Standard Deviation (SD)] for patients on olanzapine and divalproex sodium combination therapy and 100.2 µg/mL [22.1 SD] for patients on risperidone and divalproex sodium combination therapy.

Divalproex sodium significantly improved symptoms of psychosis in patients with schizophrenia as early as day 3 of the treatment period. Both the combination and monotherapy treatment groups improved on the PANSS Total scores. However, the divalproex sodium combination treatment was statistically significantly better (p < 0.05) than the monotherapy treatment at days 3, 5, 7, 10, 14, and 21 but not at day 28. Repeated measures ANOVA of the change from baseline scores demonstrated a statistically significant treatment difference between combination therapy and monotherapy over the 28 days of the study for the PANSS Total score (p = 0.020) and the PANSS Positive score (p = 0.002). Treatment differences favoring divalproex sodium combination therapy were statistically significant (p = 0.040, analysis of covariance [ANCOVA]) for the PANSS Positive score days 3, 5, 7, and 10, and the PANSS General score on days 5, 7, 10, and 14. There were no significant treatment differences in the PANSS Negative score. The following PANSS items were noted to have 4 or more time points of statistical significance favoring combination divalproex sodium treatment: delusions (p ≤ 0.05, ANCOVA), excitement (p ≤ 0.05, ANOVA), difficulty in abstract thinking (p ≤ 0.05, ANOVA) and unusual though content (p ≤ 0.05, ANOVA). In the responder analysis, the percent of patients who had at least a 20% or greater improvement in the PANSS Total score was significantly greater in the divalproex sodium combination patients compared to the monotherapy patients on days 3, 5, 7, 10, and 14.

Adverse events occurred in 48 patients (74%) of the olanzapine group, 53 patients (80%) of the olanzapine and divalproex group, 47 patients (78%) of the risperidone group, and 52 patients (90%) of the risperidone and divalproex group. These frequencies were not statistically significant. Adverse effects included somnolence, headache, dizziness, dyspepsia, weight gain, nausea, constipation, pain, increased serum glutamic pyruvic transaminase (SGPT), and rhinitis. The olanzapine and divalproex sodium combination group had a statistically lower incidence of increased SGPT compared to the olanzapine monotherapy group (0% vs. 8%, p ≤ 0.05) and the risperidone and divalproex sodium combination group had statistically lower incidences of constipation (3% vs 20%, p ≤ 0.05) and rhinitis (2% vs 13%, p ≤ 0.05) than the risperidone monotherapy group. Weight gain was slightly greater in the divalproex sodium treated patients; divalproex sodium plus olanzapine combination patients gained 8.3 pounds vs. 7.7 pounds on olanzapine monotherapy, divalproex sodium plus risperidone combination patients gained 7.5 pounds vs. 4.2 pounds on risperidone monotherapy. Most adverse events were mild to moderate in severity in all the treatment groups and no new safety concerns were observed. The percentage differences for discontinuation between monotherapy and combination treatment groups were similar with the exception of significantly fewer withdrawals of consent in the combination group (10% vs. 20%, p = 0.032).

There was no overall difference in the use of lorazepam for anxiety/agitation or benztropine/propranolol for EPS and akathisia between the monotherapy and combination treatment groups.

Conclusion

Divalproex sodium, when added to risperidone or olanzapine, significantly improved symptoms of psychosis in patients with schizophrenia as measured by PANSS as early as day 3 of treatment. The addition of divalproex sodium to risperidone or olanzapine was well tolerated and did not significantly increase the incidence of adverse events compared to antipsychotic monotherapy. Divalproex sodium may offer clinical advantages as adjunctive therapy for the psychosis of schizophrenia.

Additional Reading Materials

Citrome et al. Changes in use of valproate and other mood stabilizers for patients with schizophrenia from 1994 to 1998. Psychiatric Services 2000;51:634-8.

Wassef AA et al. Divalproex Sodium Augmentation of Haloperidol in Hospitalized Patients with Schizophrenia: Clinical and Economic Implications. J Clin Psychopharmacol 2001;21:21-6.

References

1. Williams R, Dickson RA. Economics of Schizophrenia. Can J Psychiatry 1995;40(7 Suppl 2):S60-S67.
2. Rupp A, Keith SJ: The Costs of Schizophrenia: Assessing the Burden. Psychiatr Clin North Am 1993;16:413-423.
3. Wyatt et al. An Economic Evaluation of Schizophrenia-1991. Soc Psychiatry Psychiatr Epidemiol 1995;30:196-205.
4. Attkisson et al. Clinical Services Research. Schizophr Bull 1992;18:561-626.
5. Roy A. Depression, Attempted Suicide, and Suicide in Patients with Chronic Schizophrenia. Psychiatr Clin North Am 1986;9:193-206.
6. Haugland et al. Mortality in the Era of Deinstitutionalization. Am J Psychiatry 1983;140:848-852.
7. Miller DD. Review and Management of Clozapine Side Effects. J Clin Psychiatry 2000;61(suppl 8):14-17.
8. Citrome L. The Use of Lithium, Carbamazepine, and Valproic Acid in a State-Operated Psychiatric Hospital. J Pharm Technol 1995;11(2):55-59.
9. Citrome L, Volavka J. Psychopharmacology of Violence: II. Beyond the Acute Episode. Psychiatric Ann 1997;27:696-703.
10. Depakote Prescribing Information. Abbott Labs.
11. Wassef AA et al. Critical Review of GABA-ergic Drugs in the Treatment of Schizophrenia. J Clin Psychopharmacol 1999;19:222-232.
12. Wassef AA et al. Divalproex Sodium Augmentation of Haloperidol in Hospitalized Patients with Schizophrenia: Clinical and Economic Implications. J Clin Psychopharmacol 2001;21:21-6.
13. Citrome et al. Changes in Use of Valproate and Other Mood Stabilizers for Patients with Schizophrenia from 1994 to 1998. Psychiatric Services 2000;51:634-8.
14. Casey et al. Divalproex Sodium Enhances Antipsychotic Induced Improvement in Schizophrenia. American College of Neuropsychopharmacology, Waikoloa, Hawaii, December 9-13, 2001. Poster Presentation 133.

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

David C. Howard
Has no significant relationships to disclose.

This report contains information on commercial products that are unlabeled for use or investigational uses of products not yet approved. Divalproex Sodium is not included in the labeling approved by the US FDA for the treatment of schizophrenia or psychosis associated with schizophrenia.

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

Medical Writer
David C. Howard, BS Pharmacy, Director of Research, Millennium Medical Communications, Inc., Hampton, NH

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 Neuropsych Express Report includes discussion of treatment and indications outside of current approved labeling. This Neuropsych Express Report was made possible through an unrestricted educational grant from Abbott Laboratories.

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