To our knowledge, this is the longest outcome study that addresses the long-term use of CBZ in bipolar patients. We collected data from 129 patients exhibiting good compliance and attendance, which implies a reasonable quality of data. We used chart review to minimize the effect of recall bias, and all patients were evaluated by experienced clinicians. It is also worth noting that the long follow-up period (mean duration of 10
years) in this study could provide information that other studies lack. Mean plasma level of patients was 7.8
μg/mL, which was within suggested therapeutic range for maintenance therapy.
We found that the frequency of mood episodes and hospitalization decreased significantly after CBZ treatment. We were also surprised to find that almost half of the patients (48.8%) had no more mood episodes after CBZ treatment, showing the efficacy of CBZ, either as monotherapy or combined with other mood stabilizers or antipsychotics, in the prophylactic treatment of bipolar disorder. It is difficult to compare our findings with other studies since there has been no other 10-year naturalistic follow-up of bipolar disorder patients treated with CBZ. The response rates for CBZ in previous studies varied. Kleindienst and Greil [24
] found that classical bipolar patients treated with CBZ had a hospitalization rate of about 62% versus 26% in those treated with lithium in a randomized clinical trial with an observation period of 2.5
years. The better remission rate in our study might be related to the naturalistic design of the study, which allowed for a combination of other medications during the study period.
A second aim of our study was to determine the correlates of the CBZ prophylactic response. In previous studies, CBZ response was related to “non-classical disease”, and patients with suicidal behavior, lithium-refractory disease, and mixed episodes. However, in our study, no specific factors were correlated with the response to CBZ treatment with the exception that males had a better response rate. Since it was impossible to attain some of the clinical variables in this retrospective review, the response may be correlated with other factors that were not considered in this study.
The adverse events reported by the patients were also reviewed. The most common side effects coded were dizziness, fatigue and somnolence (24%). Most patients in our study were able to tolerate the side effects of long-term use of CBZ. Patients who did not receive concomitant lithium or valproic acid had significantly less body weight increment. This result confirms previous reports [14
] suggesting that one benefit of CBZ include the low propensity toward weight gain and evidence of good tolerability with long-term treatment.
It is worth noting that about 40% of patients were treated concomitantly with lithium or valproic acid. Most patients needed benzodiazepines (74.4%) and antipsychotics (68.2%) in maintenance therapy. Given the naturalistic study design, we were unable to control the adjuvant medication. However, adjuvant medication usage did not differ between our CR and non-CR groups. In a review article by Keck and McElroy [25
], the authors suggested that combination therapy may provide better long-term prevention of illness relapse and recurrence in many patients with bipolar disorder.
The main limitation of this study was the potential for a confounding bias due to its observational design. Since this study was designed as a retrospective chart review, it did not include patients who were initially treated with CBZ but discontinued use later for any reason. It was difficult to estimate the percentage of patients who dropped out of initial CBZ treatment, so the results should be interpreted with caution, and may only reflect the prophylactic effect in those who initially responded to acute treatment with CBZ. It is likely that patients who did not respond well to CBZ or who did not tolerate CBZ were more likely to drop out. In a 6-month, multicenter, open-label evaluation of beaded, extended-release CBZ capsule monotherapy in bipolar disorder patients with manic or mixed episodes [26
], 68.8% of patients discontinued treatment early due to the lack of efficacy or side effects. This result reflects the fact that only a portion of patients adhere to CBZ according to perceived efficacy or tolerability of side effects. Our study merely showed that if a patient had a fair response to CBZ, they were likely to respond well in the continuing follow-up period. As mentioned earlier, due to the naturalistic setting, medications were not controlled during relapse. In addition, some variables were not reviewed (e.g., rapid cycling, or type of mood episode), which limited further analysis of clinical outcomes. Patients who were prescribed with CBZ during their first episode were coded as ‘zero episode prior to CBZ treatment’, which included 42 of the subjects. It is possible that patients with bipolar disorder who had just one episode over a long period of time may have a milder bipolar illness. However, after excluding these 42 subjects from analysis, the results remained the same (data not shown).