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Clinical Specialist, Department of Neuroscience, Neurology Division, Annunziata Hospital, Cosenza, Italy
Specialist, Chair of Pharmacology, Department of Experimental and Clinical Medicine, Faculty of Medicine and Surgery, University Magna Graecia of Catanzaro, Clinical Pharmacology and Pharmacovigilance Unit, Mater Domini University Hospital, Via T. Campanella 115, 88100 Catanzaro, Italy, fax 39-0961-774424, luca_gallelli{at}hotmail.com
Assistant, Chair of Pharmacology, Department of Experimental and Clinical Medicine, Faculty of Medicine and Surgery, University Magna Graecia of Catanzaro, Clinical Pharmacology and Pharmacovigilance Unit, Mater Domini University Hospital
Professor, Chair of Pharmacology, Department of Experimental and Clinical Medicine, Faculty of Medicine and Surgery, University Magna Graecia of Catanzaro, Clinical Pharmacology and Pharmacovigilance Unit, Mater Domini University Hospital
Published Online, February 27, 2007. www.theannals.com, DOI 10.1345/aph.1H614
Case Report. A 48-year-old woman (168 cm, 58 kg) with a 10 year
history of complex partial seizures of unknown etiology was admitted to the
hospital on March 3, 2006, after experiencing 2-3 partial complex seizures per
month for the previous 5 months. At the time of admission, she was being
treated with sodium valproate 500 mg twice daily; she was receiving no other
drug therapy The patient had no history of alcohol or other drug abuse, and
there was no significant past medical or surgical history. Family history was
unremarkable. A standard electroencephalogram disclosed mild, generalized
background 
activity throughout the recording. Blood chemical analysis
and plasma ammonium levels were within normal limits; the sodium valproate
plasma concentration was 75.6 µg/mL (reference range 50-100 µg/mL).
On March 4, levetiracetam 500 mg twice daily was added to the sodium
valproate therapy. There was no further seizure activity and the patient
experienced no adverse drug reactions; therefore, she was discharged after 3
days. However, the seizure activity resumed, and, on March 11, the
levetiracetam dose was increased to 1500 mg/day (1000 mg in the morning, 500
mg at night). For a 10 day period, while the patient was on this regimen, no
epileptic manifestations were reported. On March 24, she was evaluated for
agitation, anxiety, and sleeplessness. Laboratory tests did not show renal or
hepatic failure (creatinine 0.8 mg/dL, aspartate aminotransferase 22 U/L,
alanine aminotransferase 16 U/L, bilirubin 0.8 mg/dL, 
-glutamyl
transpeptidase 15 U/L), and the sodium valproate plasma concentration was
stable (75.5 µg/mL).
Psychiatric evaluation revealed no history of depression or other psychiatric manifestations in either the patient or her relatives; therefore, we assumed that drug treatment might have induced these behavioral manifestations. Because of its reduced effectiveness, sodium valproate was discontinued and replaced with carbamazepine, which was titrated to a dose of 400 mg twice daily. Five days later, we noted a complete remission of psychiatric symptoms. During the 6 month follow-up period, while the patient was on levetiracetam 1500 mg/day and carbamazepine 800 mg/day, neuropsychological evaluation and blood chemical tests appeared normal. There was no residual seizure activity, and no dose adjustments or drug substitutions were required.
Discussion. The Naranjo probability scale indicated a probable relationship between the acute reversible psychic symptoms and treatment with levetiracetam plus sodium valproate.5 We considered the development of psychosis after levetiracetam treatment, the improvement in adverse reactions after sodium valproate discontinuation, the absence of alternative causes, and the presence of objective evidence.
We hypothesize that a pharmacodynamic interaction between sodium valproate
and levetiracetam may cause a behavioral abnormality through both the increase
in -aminobutyric acid levels and the modulation of calcium channel
activity in the brain.
References
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