The role of titration schedule of topiramate for the development of depression in patients with epilepsy
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: email@example.com
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 constructed: Model 1 examined the independent effect of rapid TPM titration after separate adjustment 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 titration 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.
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 mechanisms of action likely responsible for their antiseizure activity but also for their effects on mood and behavior. AED-related psychopathology has a complex pathophysiology 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 et al., 2003a), hippocampal sclerosis (HS) (Mula et al., 2003c), or a history of febrile seizures (FS) (Mula et al., 2003a, 2004; Gilliam & Santos, 2006; Mula et al., 2007) may be relevant factors. The identification of a specific clinical endophenotype indexing a greater risk of developing depression would have important implications in informing clinical management. In fact, a rapid titration of TPM could be adopted in patients without significant risk factors for TPM-induced depression, further simplifying TPM prescription. Therefore, the aim of the present study was to assess whether a fast titration schedule of TPM has a different effect on the occurrence of depression in the presence of other risk factors such as FS, HS, and (HxDEP).
Study sample and data collection
This is a retrospective analysis of consecutive patients with epilepsy prescribed TPM at the specialist epilepsy clinics of the National Hospital for Neurology and Neurosurgery (Chalfont and Queen Square sites). Data come from a large case registry set up in 2001 for prospective studies aimed at investigating psychiatric adverse events of AEDs (Mula et al., 2003a, 2003b, 2007). Demographic and clinical details were extracted from case records; the classification of the epilepsy type was based on clinical history, seizure description, electroencephalography (EEG), and neuroimaging investigations. Depression of any type was diagnosed according to DSM-IV criteria by experienced neuropsychiatrists through a clinical interview. Behavioral changes that did not meet DSM criteria for depression were excluded from the analyses. TPM-related depression was defined according to our operational definition for a psychiatric adverse event of AEDs (Mula et al., 2003a, 2003b, 2004, 2007), namely, a psychiatric manifestation that occurred during AED therapy unrelated to other AED changes, physical illnesses, or personal events in patients without a psychiatric disorder when the drug was started.
For the purpose of the present study, we specifically focused on four main variables, namely previous HxDEP, history of FS, presence of HS (all of them categorized as present/absent) and titration schedule of TPM (categorized as regular/rapid) with regular defined as 25 mg as starting dose with a 25-mg increase every 1 or 2 weeks and rapid defined as 50 mg as starting dose with a 50-mg increase every 1 or 2 weeks.
Previous HxDEP was defined by a previous diagnosis of any unipolar depressive disorder (i.e., major depressive episode, major depressive disorder, dysthymia, or minor depression) by a psychiatrist.
The diagnosis of HS was made visually by specialist neuroradiologists using high-resolution, thin section, magnetic resonance imaging (MRI) scans as part of the routine assessment of all patients. Diagnostic criteria for HS were the presence of hippocampal atrophy demonstrated with T1-weighted coronal inversion-recovery images and increased signal intensity within the hippocampus in T2-weighted images. These represent widely used and reproduced criteria for neuroimaging in patients with epilepsy (ILAE Commission on Neuroimaging, 1997).
Student’s t-test for independent samples was used to compare continuous clinical and demographic variables and the chi-square statistic to compare categorical variables. The Mann–Whitney test was used to compare not-normally distributed continuous variables (median time at the onset of depression and TPM dose range at the onset of depression).
Logistic regression was used with presence or absence of depression as the dependent variable. Two models were constructed. Model 1 examined the independent effect of rapid TPM titration schedule on the development of depression after separate adjustment for FS, HxDEP, and HS. Model 2 examined the effects of the cooccurrence of these pairs of risk factors on the development of depression. For example, we evaluated whether the increased risk for depression observed with rapid TPM titration differed according to the presence or absence of FS. The statistical significance of the interactions between fast TPM titration and FS, fast TPM titration and HxDEP, or fast TPM titration and HS, was tested in models with each of these pairs of risk factors entered separately along with the interaction term. Age and gender were examined as potential confounders.
All analyses were two-tailed and were carried out using the Statistical Package for Social Sciences (SSPS, version 12 for Windows; SPSS Inc., Chicago, IL, USA).
The study sample included 423 patients (51.8% females); the mean age (SD) was 35.5 (11.8) years, with mean duration of epilepsy of 22.2 (11.5) years. All patients were followed up for at least 1 year. The majority of patients had a diagnosis of cryptogenic partial epilepsy (47.3%), whereas 38.1% had symptomatic partial, 10.2% idiopathic generalized epilepsy, and 4.5% symptomatic generalized epilepsy. MRI was normal in 55.1% of patients, whereas evidence of HS was found in 72 (17.1%); 7.8% had left-sided HS, 7.6% right-sided HS, and 1.7% bilateral HS. The majority of patients (63.1%) presented a seizure rate of 1–10/month, fewer had 11–20 seizures/month (23.4%) and more than 20 seizures per month (13.5%).
When TPM was started, 27% patients were on monotherapy, whereas 48.7% were taking two AEDs, and 24.3% were taking three or more. TPM was added to the previous AED regimen in the majority of cases (70%), whereas in 30% of patients it was substituted for another AED, mainly in patients on polytherapy.
The standard TPM titration schedule of 25 mg as starting dose with a 25-mg increase every 1 or 2 weeks was adopted in 73.8% of patients, whereas in the remaining 26.2% of patients the starting dose was 50 mg with a 50-mg increase every 1 or 2 weeks. Patients with rapid TPM titration did not differ in age, gender, epilepsy syndrome, age at onset of epilepsy, history of FS, HxDEP, or duration of the follow up when compared to those with a regular titration schedule. There was, however, a difference in the seizure frequency distribution, with patients with 11–20 seizures per month being more represented in the fast titration group (34.2% vs. 19.6%; χ2 = 11.747, d.f. = 2, p = 0.003).
Depression was diagnosed in 44 patients (10.4%) after TPM treatment was started (Table 1): 41 were diagnosed a major depression, 2 patients had dysthymia, and one patient a mixed episode with psychotic features.
Table 1. Distribution of the investigated variables in the study sample (n = 423)
|Age (SD)||38.7 (13.5)||35.1 (11.6)||0.097|
| Male||23 (52.3%)||181 (47.8%)||0.634|
| Female||21 (47.7%)||198 (52.2%)|
|Partial epilepsy||40 (90.9%)||321 (84.7%)||0.369|
|Hippocampal sclerosis||12 (27.3%)||60 (15.8%)||0.087|
|Febrile seizures||18 (40.9%)||71 (18.7%)||0.001|
|Fast titration schedule||26 (59.1%)||85 (22.4%)||<0.001|
|History of depression||13 (23.5%)||36 (9.5%)||<0.001|
There was no difference in the mean TPM dose and dose range—281.4 ± 179.5 (100–700) vs. 211.0 ± 141.0 (50–800); z = 1.740; p = 0.082 between patients with rapid titration and standard titration, but depression occurred significantly earlier in the fast titration group than in the standard titration group (median days 60 vs. 95; z = 2.352; p = 0.018).
Rapid TPM titration, FS, and HxDEP were each associated with an increased risk for developing depression. HS was not associated with a statistically significant increased risk for depression (Table 1).
Adjusted analyses demonstrated that there was no confounding in models that included rapid TPM titration with FS, HxDEP, or HS (Table 2). Further adjustment for age, gender, and seizure frequency did not change these results.
Table 2. Model 1: Independent effect of a rapid titration schedule for the occurrence of depression during therapy with topiramate (TPM)
|Rapid TPM titration and FS|
| Rapid TPM titration||26 (59.1%)||85 (22.4%)||5.0 (2.6–9.5)||4.8 (2.5–9.3)|
| History of FS||18 (40.9%)||71 (18.7%)||3.0 (1.6–5.8)||2.8 (1.4–5.6)|
|Rapid TPM titration and history of depression|
| Rapid TPM titration||26 (59.1%)||85 (22.4%)||5.0 (2.6–9.5)||5.1 (2.6–9.9)|
| History of depression||13 (29.6%)||36 (9.5%)||4.0 (1.9–8.3)||4.1 (1.9–9.0)|
|Rapid TPM titration and HS|
| Rapid TPM titration||26 (59.1%)||85 (22.4%)||5.0 (2.6–9.5)||4.7 (2.5–9.1)|
| HS||12 (20.0%)||60 (15.8%)||1.99 (0.97–4.09)||1.6 (0.7–3.4)|
We examined the combined effects of these pairs of risk factors on the risk of depression. The risk of developing depression was increased 12.7-fold in the presence of both FS and rapid TPM titration (Table 3), greater than the 3.7-fold increased risk associated with FS alone and the 5.9-fold increased risk associated with rapid titration alone. The risk of developing depression was increased 23.3-fold in the presence of both HxDEP and rapid TPM titration (Table 3), greater than the 3.5-fold increased risk associated with a HxDEP alone and the 4.7-fold increased risk associated with rapid titration alone. The risk of developing depression was increased 7.6-fold in the presence of both HS and rapid TPM titration schedule (Table 3), greater than the 1.7-fold increase for HS alone and the 4.9-fold increased risk associated with rapid titration alone. These results were unchanged after adjustment for seizure frequency prior to starting TPM.
Table 3. Model 2: Effect of the cooccurrence of rapid titration in combination with history of febrile seizures (FS), previous history of depression (HxDEP), or presence of hippocampal sclerosis (HS) for the development of depression during therapy with topiramate (TPM)
|Rapid TPM titration and FS|
| Rapid TPM titration only||16||66||5.9 (2.5–13.5)|
| History of FS only||8||52||3.7 (1.4–9.9)|
| Both||10||19||12.7 (4.7–34.4)|
| Neither||10||242||1.0 (Referent)|
|Rapid TPM titration and history of depression|
| Rapid TPM titration only||18||78||4.7 (2.2–10.0)|
| History of depression only||5||29||3.5 (1.2–10.6)|
| Both||8||7||23.3 (7.3–74.1)|
| Neither||13||265||1.0 (Referent)|
|Rapid TPM titration and HS|
| Rapid TPM titration only||18||66||4.9 (2.3–10.4)|
| HS only||4||41||1.7 (0.5–5.6)|
| Both||8||19||7.6 (2.8–20.4)|
| Neither||14||253||1.0 (Referent)|
In separate analyses, we also investigated interactions among HS, FS, and HxDEP on the risk for TPM-induced depression (data not shown), and we observed that FS and HxDEP were independent risk factors. The cooccurrence of FS and HS was associated with a 4.4-fold increased risk (95%CI 1.9–10.2), whereas the cooccurrence of HS and HxDEP was associated with 6.6-fold increased risk (95%CI 1.5–28.0).
This study confirms the critical role of TPM titration rate on the occurrence of depression, showing a 5-fold increased risk of developing depressive symptoms when TPM is rapidly titrated, even after separate adjustment for other previously established risk factors for vulnerability to TPM-induced depression. The effect of rapid titration on the development of depression is amplified in the presence of HxDEP, FS, and HS, although none of these interactions is statistically significant. These data are of clinical relevance because they clearly suggest that a rapid titration is highly contraindicated in patients with HxDEP or FS, whereas the additional presence of HS imparts an increased risk for depression that is only slightly greater than that associated with rapid titration alone.
We previously observed that HS was a predictive factor for TPM-related depression [odds ratio (OR) 2.38; 95%CI 1.10–5.14) in temporal lobe epilepsy (Mula et al., 2003c). We speculated that HS could interact with rapid TPM titration to increase depression risk. Our present sample partly overlaps with the previous one but, at that time, we did not specifically considered the issue of FS, which became more and more apparent and worth investigating in recent years (Gilliam & Santos, 2006; Mula et al., 2007). In fact, the novelty of our current findings relates to the fact that FS seems to be a more important marker for vulnerability to TPM-related depression than HS itself, although FS and HS are closely interlinked (50% of patients with HS had a history of FS and 40.4% of patients with history of FS were diagnosed HS, χ2 = 43.808, d.f. = 1, p < 0.001). FS represent a clinical marker of the underlying epileptogenic process, the main hypothesis concerning neuronal loss and synaptic reorganization in the limbic system (French et al., 1993; Walker et al., 2002). Febrile status epilepticus, in particular, has been shown to be associated with hippocampal MRI abnormalities (Scott et al., 2003), whereas FS that are not status are not associated with hippocampal MRI abnormalities (Hesdorffer et al., 2008). History of FS has also been shown to predict a poor prognosis of epilepsy (Hitiris et al., 2007); however, such a history is rarely considered when evaluating drug safety and tolerability. Our study showed that a rapid TPM titration schedule is highly influenced by the cooccurrence of FS, with a 12.7-fold increased risk, suggesting that patients with a history of FS need to be counseled and followed regularly for psychiatric side effects of AEDs.
Along with FS, the role of a HxDEP is particularly intriguing because it further supports the view that a limbic system vulnerability predisposes to psychiatric side effects of AEDs (Gilliam & Santos, 2006; Mula et al., 2007), and could suggest that a gamma-aminobutyric acid (GABA)ergic potentiation, as occurs when TPM is rapidly titrated (Martin et al., 1999), may lead to depression in the presence of such a vulnerability (Mula & Sander, 2007). These results need to be considered in the context of the current debate about epilepsy and depression. Previous studies have shown that major depression may increase the risk of developing unprovoked seizures (Hesdorffer et al., 2000, 2006) and that a history of depression at epilepsy onset is associated with a worse seizure prognosis (Hitiris et al., 2007), supporting the hypothesis of common neurochemical and neurobiologic underpinnings. An important issue relates to the onset of depression in relation to the onset of the epilepsy. In our study, we did not specifically examine whether the prior history of depression predated the onset of the epilepsy, but it is evident that future studies of AED-related depression should examine whether a history of depression that predates the onset of epilepsy is a more important marker for vulnerability to mood effects of AEDs than depression that may first occur after epilepsy onset. In that case, it is tempting to speculate that subjects who developed depression with TPM may have a more complex neuropsychiatric disorder, wherein a particular vulnerability to mood effects of AEDs represents a clinical marker.
Our findings need to be considered with concern for the following limitations. First, our results may not be representative for epilepsy patients in general because our population represents a highly selected sample coming from a tertiary referral center. Moreover, in all cases, TPM was introduced as add-on therapy. It is, therefore, possible that the use of TPM in monotherapy in patients with newly diagnosed epilepsy may be associated with a lower prevalence of depression. Moreover, we do not have information about patients who converted from lamotrigine to TPM, which may represent a possible bias considering the protective role of lamotrigine on the onset of AED-related depression (Mula et al., 2003a,b). Second, we obtained information on a history of FS, but were unable to determine the type of febrile seizure, which may be an important indicator of vulnerability to depression during rapid titration with TPM. Third, neuropsychiatrists evaluating patients were not blinded to the titration schedule of TPM. It is, therefore, evident that further studies with a controlled design replicating our findings are needed. Finally, rapid titration was used more often in patients with more frequent seizures, which are themselves associated with a poor prognosis. In our sample, however, seizure frequency was not a confounder in our models. This is possibly because of the high proportion of patients with drug-refractory epilepsy (less than one-third of these patients were on monotherapy and one-fourth was receiving polytherapy with three or more drugs). It is, therefore, possible that other differences may become noticeable in unselected samples of patients with epilepsy.
In conclusion, a rapid titration schedule of TPM is associated with a 5-fold increased risk of developing depression. FS and HxDEP are each independently associated with depression after TPM. HxDEP and FS further augment the risk for depression when rapid titration is performed and should, therefore, be considered as contraindications to the use of a rapid titration schedule of TPM.
We confirm that we have read the Journal’s position on issues involved in ethical publication and affirm that this report is consistent with those guidelines. The authors have received no funding for the present paper and do not have any commercial association that might pose a conflict of interest in connection with this manuscript. MM and JWAS have received travel grants or consultancy fees, from various pharmaceutical companies including Novartis, Pfizer, UCB Pharma, Eisai, Schwarz-Pharma, Janssen-Cilag, Sanofi-Aventis, and GSK – involved in the manufacture of antiepileptic drugs.