The role of titration schedule of topiramate for the development of depression in patients with epilepsy *Marco Mula, yDale C. Hesdorffer, zMichael Trimble, and zxJosemir W. Sander *Section of Neurology, Department of Clinical & Experimental Medicine, Amedeo Avogadro University, Novara, Italy; yGertrude H. Sergievsky Center and Department of Epidemiology, Columbia University, New York, New York City, U.S.A.; zDepartment of Clinical and Experimental Epilepsy, UCL Institute of Neurology, London, United Kingdom; and xSEIN – Epilepsy Institute of the Netherlands Foundation, SW Heemstede, The Netherlands SUMMARY Purpose: To determine whether a fast titration schedule of topiramate (TPM) has different effects on the occurrence of depression, in relation to other risk factors for TPM-induced depression, including history of depression (HxDEP), febrile seizures (FS), and hippocampal sclerosis (HS). Methods: Using data from a large case registry of patients prescribed TPM, two models were con- structed: Model 1 examined the independent effect of rapid TPM titration after separate adjust- ment for FS, HxDEP, and HS. Model 2 examined effect of the cooccurrence of rapid titration on the development of depression with each of these risk factors. Results: A total of 423 patients were included (51.8% females), mean age (SD) 35.5 (11.8) years, mean duration of epilepsy of 22.2 (11.5) years. Forty-four patients (10.4%) developed depression during TPM therapy. A rapid TPM titration was associated with 5-fold increased risk of depression that increased to 12.7-fold in the presence of both FS and rapid TPM titration, 23.3-fold in the presence of both HxDEP and rapid TPM titration, and 7.6-fold in the presence of both HS and rapid TPM titration schedule. Conclusions: Our study suggests that a rapid titra- tion schedule is associated with an increased risk of developing depression during TPM therapy. HxDEP and FS are major contraindications to the use of a rapid titration, with a 23.3-fold and 12.7 fold increased risk, respectively. KEY WORDS: Topiramate, Depression, Adverse effects, Febrile seizures, Hippocampal sclerosis. In the last 20 years, several new antiepileptic drugs (AEDs) have been introduced into clinical practice, and renewed attention has been paid to treatment-emergent adverse effects, including negative effects on mood (Besag, 2001; Ettinger, 2006; Gilliam & Santos, 2006; Mula & Sander, 2007). AEDs have a number of mecha- nisms of action likely responsible for their antiseizure activity but also for their effects on mood and behavior. AED-related psychopathology has a complex patho- physiology that can be only partly explained by specific psychotropic properties of the drug; the interplay between the drug and the underlying epileptic process needs to be carefully considered (Mula & Sander, 2007). Notably, some behavioral side effects of AEDs do not seem to be as prominently recognized in psychiatric populations, where they are also widely used (Ovsiew, 2004). Topiramate (TPM) is one of the new AEDs recently introduced. It is an effective compound without life- threatening adverse events. The use of TPM, however, can be complicated by a number of side effects on cognition (Thompson et al., 2000; Aldenkamp et al., 2003) and mood (Mula & Sander, 2007), with depression occurring in up to about one in five patients (Besag, 2001; Mula et al., 2003a; Ettinger, 2006; Gilliam & Santos, 2006; Mula & Sander, 2007). Rates for depressive symptoms are clearly dose-dependent, and rapid titration schemes have been shown to play a relevant role (Mula et al., 2003a). However, growing evidence suggests that a previous history of depression (HxDEP) (Kanner et al. 2003; Mula Accepted July 25, 2008; Early View publication October 24, 2008. Address correspondence to Dr. Marco Mula, M.D., Ph.D., Department of Neurology, Amedeo Avogadro University, C.so Mazzini, 18-28100 Novara, Italy. E-mail: marcomula@yahoo.it Wiley Periodicals, Inc. ª 2008 International League Against Epilepsy Epilepsia, 50(5):1072–1076, 2009 doi: 10.1111/j.1528-1167.2008.01799.x FULL-LENGTH ORIGINAL RESEARCH 1072