Letters to the Editor
Modafinil Treatment of Excessive Sedation Associated With Divalproex Sodium
Dear Editor:
Divalproex is recognized as a first-line agent in the treatment of bipolar disorders (BDs) (1). However, sedation can be an unwelcome side effect of dival- proex sodium treatment (2), and unwanted side effects can lead to patient noncompliance (3). Ultimately, noncompliance can contribute to hospitalizations (4). I present 2 cases in which patients treated with divalproex sodium for BD experienced excessive sedation that responded favourably to modafinil.
Case Report 1
Mr A is a 35 year-old man suffering from BD I diagnosed according to DSM-IV criteria (5), as well as from methamphetamine abuse. His most recent episode was depressed, and he presented in remission. He was taking bupropion sustained release (SR) 150 mg twice daily and divalproex 750 mg twice daily. Mr A complained that, since restarting divalproex 1 month prior to consultation, he was sleeping 12 to 14 hours daily and unable to work. Laboratory examination showed a divalproex level of 85 µg/mL. His complete blood count, hepatic enzymes, serum electrolytes, lipase, amylase, and ammonia were all within normal limits, and a urine drug screen was negative for illicit substances. Mr A denied the use of alcohol and was enrolled in an outpatient rehabilitative program; however, he was not as active as he wanted to be, owing to excessive sedation. To diminish the excessive sedation, he agreed to a reduced divalproex dosage, and this medication was decreased from 750 mg twice daily to 500 mg twice daily. A serum dival- proex level was maintained in the therapeutic range at 67 µg/mL. Unfortunately, he continued to experience daytime somnolence. He agreed to a trial of modafinil initiated at 100 mg daily. He did not experience any side effects and noted decreased sedation within 1 week of starting modafinil. After 1 week of modafinil at 100 mg, his dosage was increased to 200 mg daily, with marked improvement. He was sleeping 8 hours nightly and felt awake during the day. He was able to participate in family life and was able to find employment after having been unemployed for 9 months and at one time thinking of filing for permanent disability. His divalproex levels have remained within the therapeutic range while he is on modafinil. He remains stable at 1 year, with no triggering of hypomanic or manic symptoms associated with modafinil.
Case Report 2
Mr B is a 27-year-old man diagnosed with BD I and obsessive–compulsive disorder (OCD) according to DSM-IV criteria (5). His most recent episode was manic. He was taking divalproex 500 mg every morning and 750 mg at bedtime, sertraline 200 mg daily, quetiapine fumarate 75 mg at bedtime, and clona- zepam 1 mg daily. He had recently been hospitalized but had been compliant for 2 months on the medications. He complained of sleeping 14 hours daily. His serum level of divalproex was 87 µg/mL. The rest of his laboratory examination included a complete blood couont, hepatic panel, pancreatic enzymes, ammonia, serum electrolytes, and urine drug screen, all of which were unremarkable. The clonazepam and quetiapine were tapered off to determine to what extent they might have contributed to Mr B’s sedation. After discontinuing the clonazepam and quetiapine, he slept about 12 hours nightly. The divalproex was decreased by 250 mg at night with no decrease in next-day sedation. Mr B agreed to a trial of modafinil started at 200 mg daily. He experienced a mild anxious feeling. Within 1 week, his daytime sedation was markedly improved, and he was averaging 7 to 8 hours of sleep nightly. He remains stable at 1 year with no noted exacerbation of mood symptoms or worsening of his OCD. As well, while on modafinil, his subsequent divalproex serum levels have been therapeutic.
Modafinil is approved in the by the US Food and Drug Administration to treat excessive daytime somnolence associated with narcolepsy. It is chemically unrelated to the psychostimulants (6). It is thought to alter the balance of GABA and glutamate, resulting in activation of the hypothalamus (7,8). Modafinil has been used as an adjunct in the treatment of major depression, allowing patients to achieve remission as well as targeting residual tiredness (9). Makela and others recently reported the successful use of modafinil to treat sedation induced by antipsychotics in 3 patients (10). Although I reduced my patients’ medication and tapered concomitant medications that could have contributed to sedation, I felt that modafinil could alleviate their excessive sedation. Because it is structurally unrelated to traditional stimulants, I did not expect to trigger hypomania or mania. In Mr A’s case, I considered the possibility of substance abuse, although modafinil does not appear to have abuse potential (11). Modafinil also did not appear to alter serum levels of divalproex, which is another important consideration.
To my knowledge, this is the first report of using modafinil to treat excessive sedation associated with divalproex sodium. Case reports must be interepreted with caution; however, modafinil may be useful in treating excessive sedation associated with divalproex sodium. Further studies in a controlled manner are encouraged.
References
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2. McNamara JO. In: Hardman JG, Limbird EE, editors; Gilman AG, consulting editor. Drugs effective in the therapy of the epilepsies. Goodman and Gilman’s the pharmacologic basis of therapeutics. 10th ed. New York: McGraw Hill; 2001. p 521–47.
3. Sachs GS, Rush AJ. Response, remission and recovery in bipolar disorders: what are the realistic goals. J Clin Psychiatry 2003;64(Suppl 6):18–22.
4. Keck PE Jr, McElroy SL, Strakowski SM, Bourne ML, West SA. Compliance with maintenance in bipolar disorder. Psychopharmacol Bull 1997;33:87–91.
5. American Psychiatric Association. Diagnostic and statistical manual of mental disorders. 4th ed. Washington (DC): American Psychiatric Association; 1994.
6. Antonelli T, Ferraro L, Hillion J. Tomasini MC, Rambert FA, Fuxe K. Modafinil prevents glutamate cytotoxicity in cultured cortical neurons. Neuroreport 1998;9:4209–13.
7. Ferraro L, Tanganelli S, O’Connor WT, Antonelli T, Rambert FA, Fuxe K. The vigilance of promoting drug modafinil increases dopamine release in the rat nucleus accumbens via the involvement of a local GABAergic mechanism. Eur J Pharmacol 1996;306:33–9.
8. Lin JS, Hou Y, Jouvert M. Potential brain neuronal targets for amphetamine-, methylphenidate-, and modafinil-induced wakefulness evidenced by c-fos imunocytochemistry in the cat. Proc Natl Acad Sci USA 1996;93:14128–33.
9. Menza MA, Kaufman KR, Castellanos A. Modafinil augmentation of antidepressant treatment in depression. J Clin Psychiatry 2000;61:378–81.
10. Makela EH, Miller K, Cutlip WD. Three case reports of modafinil use in treating sedation induced by antipsychotic medication [letter]. J Clin Psychiatry 2003;64:485–6.
11. US Modafinil in Narcolepsy Study Group. Randomized trial of modafinil in the treatment of pathologic somnolence in narcolepsy. Ann Neurol 1998;43:88–97.
Tim Berigan, DDS, MD
Vail, Arizona
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