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Aims: The remission rates for patients with major depressive disorder (MDD) during algorithm-guided treatment (AGT), which consisted of four treatment strategy steps were prospectively compared with treatment as usual (TAU).
Methods: The remission rates of patients with mild or moderate MDD during AGT (n = 83) were compared with TAU (n = 127).
Results: The remission rate in the AGT group (60.2%) was approximately 10% greater than that in the TAU group (49.7%). The median number of days to achieve remission in the AGT group (93 days) was half as long as that in the TAU group (191 days). The hazard ratio of remission was 1.5 (95% confidence interval: = 1.2–1.8). A higher rate of lithium augmentation in the AGT group (20.5%) compared to theTAU (4.7%) may have led to the greater remission rate. Most participants who did not achieve remission either during the initial or second treatment steps dropped out from AGT.
Conclusions: AGT may be superior to TAU for patients with mild or moderate MDD, based on the remission rates achieved. The later treatment steps in the AGT, however, were rarely utilized because participants who did not receive any benefit dropped out early.
PHYSICIANS SHOULD TRY to treat patients with psychiatric disorders logically or on the basis of scientific evidence. Physicians often prescribe medication, however, based on their personal experience rather than evidence-based information. As a consequence there is much individual variation among physicians, and some strategies may be ineffective and therefore prolong symptoms that otherwise might disappear if proven medications were adopted. This is especially true for the treatment of major depressive disorder (MDD) because of the complexity of the symptoms and the clinical course. A possible method for overcoming these problems may be a systematic treatment algorithm with the optimal application, sequencing, and appropriate decision making based on scientific evidence.
Treatment algorithms provide three types of guidance: (i) strategies as to what treatments to use; (ii) tactics on how to implement the treatments; and (iii) treatment steps in a prescribed order to implement the different treatments.1 The critical decision points are defined in the course of treatment, at which time the therapeutic response is to be assessed. On the basis of this assessment, specific treatment revisions are recommended according to the preset if–then rules. Treatment algorithms should determine for how long a single treatment is maintained and how rapidly the treatment plan can be revised.1 Too-frequent decision points bear the risk of not allowing enough time for a specific treatment to show therapeutic benefit. Too-infrequent decision points risk leaving patients on an ineffective treatment for too long. Therefore, the treatment algorithms should set up the optimal intervals between critical decision points based on evidence-based information. But because only a few trials compared next-step treatments in non-responders with initial antidepressant treatment,2–4 the second or third treatment steps are still to be determined. Although actual treatment algorithms remain incomplete, a previous study showed that an algorithm-guided treatment (AGT) for MDD was superior to treatment as usual (TAU).
Some previous studies on AGT of MDD have been conducted.5–7 The Texas Medication Algorithm Project (TMAP) was the first large-scale randomized controlled multicenter study to evaluate treatment algorithms in outpatients with MDD.8 TMAP included seven steps of medication algorithms for the treatment of non-psychotic MDD. Stages 1–3 were monotherapy with an antidepressant. Stages 4–6 were augmentation of an antidepressant with lithium, combination therapy with multiple antidepressants, and electroconvulsive therapy, respectively. The study compared 3-month and 12-month outcomes between AGT and TAU, and found a substantially greater benefit in terms of depressive symptoms, function, and side-effect burden for the algorithm group.
The present study is the first to evaluate AGT in outpatients with MDD in Japan. We created the Saitama Medication Algorithm Project (SMAP) for outpatients with MDD based on the Japanese Psychopharmacology Algorithm Project.9,10 The SMAP algorithm included four treatment steps: the initial three steps were antidepressant monotherapy similar to TMAP. Augmentation therapy with lithium was performed at each step whenever a patient did not achieve remission. We adopted lithium augmentation because lithium has been rarely used in the actual clinical setting even though augmentation with lithium has the strongest research support.11
The standard initial therapy for MDD is monotherapy with an antidepressant, but only 30–50% of patients respond to the first monotherapy.12 Further treatment interventions such as antidepressant augmentation is commonly recommended when patients fail to respond to two or more trials of antidepressant monotherapy. Treatment guidelines most often mention lithium, thyroid supplements, a second ‘add-on’ antidepressant, second-generation antipsychotic medications, and buspirone as potentially helpful augmenting agents.13 Among these augmentation strategies, lithium has the strongest research support. Crossley and Bauer undertook a meta-analysis concerning 10 randomized controlled trials of lithium augmentation of tricyclic antidepressants (TCA) or selective serotonin re-uptake inhibitors (SSRI).14 The authors found that lithium augmentation compared to placebo treatment had a substantially greater response rate with a number needed to treat (NNT) of 5, suggesting that lithium augmentation is the first-choice treatment procedure for patients with MDD who fail to respond to antidepressant monotherapy. Surprisingly, however, lithium has been used rarely in clinical settings.
Recently, Valenstein et al. examined the prevalence and characteristics of antidepressant augmentation in clinical settings.11 Twenty-two percent of patients with depression received an augmentation agent. The most commonly used agents were an add-on second antidepressant (11%) and a second generation antipsychotic (7%). Only 0.5% of the patients received lithium, however, suggesting that lithium augmentation may be a vanishing practice. The treatment outcome of MDD might be more improved if AGT adopts lithium augmentation in a positive manner. To examine the effectiveness of the SMAP algorithm, we compared the clinical results for patients with MDD during AGT, which relied heavily on lithium augmentation, versus TAU.
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The present results suggest that AGT is superior to TAU for patients with mild or moderate MDD based on their respective remission rates. The remission rate in the AGT group was approximately 10% greater than that in the TAU group. The median number of days to achieve remission in the AGT group was half that in TAU group. The hazard ratio of the remission rate in the AGT group compared to the TAU group was 1.5 (95%CI: 1.2–1.8).
The superiority of AGT in treatment outcome may be explained by two reasons. The first is that AGT requires physicians to decide whether the ongoing medication should be maintained or changed every 2 weeks. Such critical decision points do not exist in TAU. These critical decision points in AGT might reduce the time it takes to achieve remission compared to that for those treated with TAU. Future studies should examine how long TAU physicians maintain the same medication if a patient has a partial response.
The second reason for the superiority of AGT is that the present AGT protocol adopted lithium augmentation in a positive and consistent manner. Lithium currently has the most research support and is well-documented as being the strongest augmentation strategy in refractory depression.16 Interestingly but perhaps expectedly, the remission rate for antidepressant monotherapy without lithium was similar in both the AGT and TAU groups. Therefore, we concluded that the higher rate of lithium augmentation in the AGT group led to their improved remission rate. The maintenance of lithium augmentation, however, is burdensome.
The reasons for the low penetration of lithium augmentation in TAU are unclear but may include concerns about safety, convenience, and tolerability.11 Unlike other augmentation strategies, lithium requires regular laboratory monitoring of medication blood levels, with therapeutic doses sometimes being close to toxicity. Several of lithium's side-effects may appear shortly after treatment initiation. Lithium may also cause renal impairment and thyroid dysfunction. Although the present results again supported the efficacy of lithium, lithium augmentation may become non-existent unless AGT become widely used.
Although the present AGT consisted of four treatment steps, only three out of 83 participants entered the treatment line 3 and no one entered line 4. Whatever further treatment steps such as lines 4 and 5 are prepared for outpatients who have not had a satisfactory response to an initial and one or more subsequent treatments, it is likely that no one will undergo the later treatment steps. We found most outpatients dropped out from AGT when they did not feel a satisfactory response to treatment lines 1 and 2. Although we did not follow up the participants who dropped out, most of them might possibly visit another medical center. Because the therapeutic focus of the present AGT was outpatients with only mild or moderate MDD, we should emphasize that AGT is not applicable for outpatients with severe MDD. Future studies should examine these issues.
The present study had some methodologic limitations: the outcome of the participants was not assessed blindly and rating scales for MDD other than CGI were not used. We believe, however, that the present results suggest the efficacy and efficiency of algorithm-guided treatment for patients with MDD.