Affective Recurrences in Bipolar Disorder After Switching From Lithium to Valproate or Vice Versa: A Series of 57 Cases

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To the Editors
For many years lithium was the only mood stabilizer (MS) in common use, and it is still the first choice in the preventive treatment for bipolar disorder (BD).1 However, there are many safety and tolerability concerns such as cognitive impairment, weight gain, dermatological reactions, and renal or thyroid dysfunction that can lead to the use of lithium being stopped.2 A higher risk of recurrences even after many years of clinical stability is associated with the discontinuation of lithium,3,4 and, in case of rapid discontinuation, recurrences increase sharply soon after.5
When lithium is tapered off, an alternative MS should be started. Among MSs, valproate represents a first-line treatment for BD.6 Nevertheless, evidence for its effectiveness in comparison with lithium remains sparse. In the BALANCE study, lithium was more effective than valproate in preventing recurrences. Combined therapy was also not more effective than lithium alone.7 Similar findings emerged from an observational cohort study with links to nationwide registers of patients with BD in psychiatric hospital settings who were treated with valproate or lithium.8 Taken together, these results seem to indicate that lithium is superior to valproate in the maintenance treatment of BD. However, there is a lack of data regarding the efficacy of valproate in patients who discontinue maintenance treatment with lithium, and the same applies for patients switching from valproate to lithium.
Thus, we compared the recurrence rates in patients with BD who switched from lithium to valproate and vice versa. Moreover, we analyzed any correlation between the baseline characteristics of the patients and occurrence of mood episodes after the treatment switch. We considered patients in the euthymic phase (for at least 8 weeks, based on clinical judgment), either responders to monotherapy with lithium (Li-R) or valproate (Va-R), and requiring change of MS for any reason with the exception of lack of efficacy. Patients were excluded based on having the following: main diagnosis other than BD, concomitant severe/unstable neurological or physical diseases, history of nonresponse to lithium or valproate, any safety/tolerability concerns to valproate for patients in current treatment with lithium and vice versa.
No attempt was made to influence decisions regarding the study treatments, and patients received care as per usual. The aims of the study and study procedures were thoroughly explained to potential participants who gave their oral consent before participation.
At the study entry, Li-R were prescribed valproate and Va-R were prescribed lithium. Within 4 weeks, the serum levels of both valproate and lithium were adjusted to comply with the therapeutic range (valproate, 50–100 μg/L; lithium, 0.5–0.8 mmol/L). The previous MS was gradually discontinued. Each patient was followed-up for an 18-month period. Patients were assessed monthly in the first 6 months, then every 3 months thereafter. In addition, all patients were informed to contact their psychiatrists every time they experienced a worsening of symptoms.
We compared demographic and clinical characteristics between the two patient groups by way of χ2 in the case of categorical variables and analysis of variance (F) in the case of continuous variables. A LogReg analysis was then conducted to assess any relationship between characteristics of the patients-independent variables: sex, age, type of BD, age at onset, duration of illness, previous MS (lithium or valproate), duration of treatment with previous MS, stop motivation, and reduction time of previous MS-and presence/absence of a recurrent episode of BD (dependent variable).
Fifty-seven patients participated in the study. Of those, 33 were Li-R and 24 were Va-R. Before lithium or valproate monotherapy, most of the subjects typically received varying combinations of MSs, antidepressants, antipsychotics, and benzodiazepines as indicated by changing clinical requirements.
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