Defining phenotypes of long-term lithium and valproate response, including combination therapy: a modified application of the Alda scale in patients with bipolar disorders

Abstract

Background When evaluating the long-term treatment response to mood stabilizers using the Alda scale, mood stabilizer combination therapy is typically considered a confounding factor, and patients receiving combination therapy are excluded from the analysis. However, this may result in bias if those under combination therapy are worse treatment responders. This study aims to explore whether the Alda scale is applicable to patients taking lithium and valproate combination therapy. We compared long-term treatment response in patients receiving monotherapy and combination therapy of the two drugs, and investigated clinical correlates of the responses to each drug. Methods The study subjects consisted of 102 patients with bipolar I (BD-I) or bipolar II (BD-II) disorder who had been undergoing maintenance treatment with lithium and/or valproate for more than 2 years at a single specialized bipolar disorder clinic. Long-term treatment response was measured using the Alda scale and compared among the lithium monotherapy group, the valproate monotherapy group, and the mood stabilizer combination group. Clinical correlates of long-term treatment response were evaluated in lithium users and valproate users separately. Results There were no significant differences in terms of baseline illness characteristics among groups. The combination group showed the worst treatment response for all the response measurements applied. This group also had the higher rate of ‘poor responder’ with a statistically significant difference compared to valproate group. Older age at onset and (hypo)manic episode at onset showed significant positive associations with total Alda score in lithium users, while comorbid anxiety disorders, obsessive–compulsive disorder and mixed episode showed significant negative associations in valproate users. Conclusions The combination group had poorer long-term treatment response but did not show distinct clinical characteristics compared to the monotherapy groups. When exploring the long-term effects of mood stabilizers, excluding patients undergoing combination treatment could result in bias because they may represent a poor response group. The long-term treatment responses of lithium and valproate had different clinical correlates.

Lithium and Valproate in Bipolar Disorder: From International Evidence-based Guidelines to Clinical Predictors

“…Lithium is the second and valproate the third choice in prevention of mixed relapses in CANMAT 2021 guidelines [ 24 ] ( Table 7 ). In a RCT (n = 117) and in 3 retrospective studies (n = 100; n = 300; n = 645), anamnesis of mixed episodes is associated to poor response to lithium [ 54 - 57 ], while in one of these studies and in a naturalistic observational study (n = 102) valproate is not related to poor response [ 57 , 58 ].…”

“…Border-line symptoms are found predictive of favorable response to valproate in a RCT (n = 30) [ 70 ]. Comorbidity between obsessive-compulsive personality disorder (OCD) and BD were related to favorable outcome to valproate in a retrospective study (n = 102) [ 58 ]. Alcohol use is found predictive of poor response to lithium in retrospective (n = 645), prospective (n = 248) studies and in a systematic review [ 57 , 64 ,71].…”

“…In a RCT (n = 59) valproate is superior to lithium on reducing alcohol assumption [ 72 ]. A trend toward lithium non responsiveness in bipolar patients with comorbid anxiety disorders is shown in 2 prospective studies (n = 81; n = 94) [ 73 , 74 ] and an association with long-term treatment response to valproate in a naturalistic study (n = 102) [ 58 ].…”

“…MDI pattern is reported as a favorable predictor of re-sponse to lithium in several studies [12,63,65]; others do not report any correlation [61]. Psychiatric comorbidities are related to poor response to lithium [12], including alcohol use [57,64,71,72], anxiety symptoms/disorders [73,74] and personality disorders [64], while valproate is related to good response with alcohol use [57], anxiety symptoms/disorders, OCD [58], borderline personality symptoms [12,70].…”

The heterogeneous early illness courses of Korean patients with bipolar disorders – replication of the stage model

“…All The long-term treatment response to mood stabilizers was evaluated using the Alda scale (Grof et al 2002). The Alda scale comprises two subscales: The Alda A score evaluates the degree of improvement during the intervention, while the Alda B score assesses confounding variables that affect the outcome leaving medication effect aside (Lee et al 2020). The total score is a composite score calculated by subtracting B from A.…”