INTRODUCTION
Depression is common and causes significant disability. Achieving remission, defined as low or absent symptom levels, has been considered as the treatment goal. However, remission rates were less than one third of cases in 8- to 12- week antidepressant trials [1,2]. Identifying subpopulations who are likely to experience better treatment responses is a practical option for increasing remission probabilities. A variety of socioeconomic and clinical factors represent the typical predictors of depression treatment outcomes [1,2]. These results have usually been drawn from trials with only a few antidepressants for the entire treatment period. However, there is accumulating evidence suggesting that antidepressant responses can be found within 2-3 weeks after treatment [3], and therefore earlier clinical decision for changing pharmacological regime may enhance treatment outcomes [4,5]. Relevant to these hypotheses, we recently reported the predictors of remission in over four step psychopharmacotherapy based on early clinical decision [6]. Determining predictors of remission would be beneficial for personalized treatment, nonetheless it has not been investigated so far. Thus, we aimed to investigate the predictors of remission in each treatment step in 12-week psychopharmacotherapy in patients with depressive disorders.
METHODS
Study outline
This was a secondary analysis, carried out as a component of the MAKE Biomarker discovery for Enhancing anTidepressant Treatment Effect and Response (MAKE BETTER) project, which intends to develop a treatment-response prediction index composed of bio-psycho-social markers for patients with depressive disorders. Study details have been published as a protocol paper7 and registered with cris.nih.go.kr (identifier: KCT0001332). To reflect real-world settings, participants enrolment and treatment interventions were conducted in a naturalistic fashion. This study was approved by the Chonnam National University Hospital Institutional Review Board (CNUH 2012-014).
Participants
Patients with depressive disorders who fulfilled the eligibility criteria (Supplementary Material 1 in the online-only Data Supplement) were consecutively recruited from March 2012 to April 2017 from those who had visited the outpatient psychiatric department of CNUH. All inclusion instances represented new treatment episodes—i.e., taking newly initiated antidepressant treatment—whether depressive symptoms were first-onset or recurrent. All participants reviewed the consent form and written informed consent was obtained.
Baseline evaluations
Socio-demographic characteristics obtained comprised age, sex, year of formal education, marital status, cohabiting status, religion, occupation, and monthly income. Clinical characteristics evaluated comprised diagnoses of major depressive disorder or others with certain specifiers based on the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria [8], age at onset and duration of illnesss, history of previous depressive episodes, number of previous depressive episodes, duration of present episode, family history of depression, and number of concurrent physical disorders (applying a questionnaire enquiring about 15 different systems or disorders). Although the DSM-5 criteria were updated in 2013 [9], the enrollment was conducted from 2012 to 2017 and then, DSM-IV version of depressive disorder instead of DSM-5 should be used as a standard. Assessment scales for investigating symptoms and function were administered. Depressive symptoms were assessed using the Hamilton Depression Rating Scale (HAMD) [10]; anxiety symptoms by the Hospital Anxiety and Depression Scale-anxiety subscale (HADS-A) [11]; quality of life by the EuroQol-5D (EQ-5D) [12]; functioning levels by the Social and Occupational Functioning Assessment Scale (SOFAS) [8]; number of stressful life events by the Life Experiences Survey (LES) [13]; subjective perception of stress by the Perceived Stress Scale (PSS) [14]; psychological resilience by the Connor-Davidson Resilience Scale (CDRS) [15]; social support deficits by the Multidimensional Scale of Perceived Social Support (MSPSS) [16]; and suicide severity was assessed with the Brief Psychiatric Rating Scale (BPRS) [17] suicidality item. Higher scores on HAMD, HADS-A, LES, PSS, and BPRS suicidality item indicate more severe symptomatology, as do lower scores on EQ-5D, SOFAS, CDRS, and MSPSS.
Stepwise pharmacotherapy
Treatment steps and strategies were published previously [5] and described in detail (Supplementary Material 1 and Supplementary Figure 1 in the online-only Data Supplement). In brief, before the treatment commencement, a comprehensive examination was conducted for patients’ clinical manifestations, illness severity, physical comorbidities and medication lists, and history of prior treatments. In the first step, patients received antidepressant medication, considering these patient data and existing treatment guidelines for 3 weeks. General effectiveness and tolerability were evaluated for going ahead with every 3 weeks next-step measurement-based treatments. In cases of inadequate improvement or intolerable adverse events, patients were directed to choose whether they would prefer to stay in the present step or get in the next step treatment with switching antidepressants (S), augmenting with other drugs (A), combination of other antidepressants (C), S+A, S+C, A+C, and S+A+C strategies. Overall, up to 4 treatment step could be possible. For settling treatment strategies, patient’s opinion was given priority.
Definition of remission
Remission status was assessed at every 3 weeks (at 3, 6, 9, and 12 weeks). Patients evaluated at least once after baseline comprised the analysed sample. At each assessment point, remission was defined as a HAMD score ≤7. Achievement of 12-week remission was defined only when these were maintained up to the 12-week assessment points.
Statistical analysis
Baseline data were compared between patients achieved remission and didn’t by the four treatment steps (Step 1, 2, 3, and 4) using t-test or χ2 test, as appropriate. Variables significantly associated with remission (p<0.05) were entered into a multiple logistic regression model to identify independent predictors. Statistical analyses were carried out using the SPSS 21.0 software (IBM Co., Armonk, NY, USA).
RESULTS
Recruitment and treatment flow
Patient flow by treatment strategies and steps in Supplementary Figure 1 (in the online-only Data Supplement). Of 1,262 patients evaluated at baseline, 1,246 (98.7%) were followed at least once during the 12-week treatment period and comprised the analyzed sample. Remission was achieved in 540 (43.3%) patients.
Uni-variate associations with remission by treatment steps
At the 12-week point, 534 (42.9%) patients received Step 1 antidepressant monotherapy treatment, 412 (33.1%) received Step 2 treatment, 226 (18.1%) received Step 3 treatment, and 74 (5.9%) received Step 4 treatment. Remission rates were 35.0%, 47.3%, 51.8%, and 55.4% for treatment Step 1, 2, 3, and 4, respectively. Baseline characteristics by 12-week remission status according to treatment steps are compared in Table 1. In patients received Step 1 treatment, remission was significantly associated with higher age and age at onset, lower scores on HADS-A, LES, PSS, and BPRS suicidality item, and higher scores on SOFAS and CDRS. In Step 2, remission was significantly associated with higher age, married marital state, higher age at onset, lower scores on HAMD, HADS-A, and BPRS suicidality item, and higher scores on EQ-5D, SOFAS, and CDRS. In Step 3, remission was significantly associated with absent atypical feature, higher age at onset, lower number of depressive episodes, family history of depression, higher scores on SOFAS and MSPSS, and lower BPRS suicidality item scores. In Step 4, remission was significantly associated with employed state, lower HAMD scores, and higher scores on SOFAS and MSPSS.
Independent predictors of remission by treatment steps
Results on multi-variate analyses for identifying independent predictors of remission by treatment steps are summarized in Table 2. In Step 1, higher SOFAS scores and lower scores on LES and BPRS suicidality item; in Step 2, higher SOFAS scores and lower BPRS suicidality item scores; in Step 3, higher MSPSS scores and lower BPRS suicidality item scores; and in Step 4, only the higher MSPSS scores were determined as predictors.
DISCUSSION
In this study with depressive outpatients receiving the 12-week stepwise psychopharmacotherapy based on early clinical decision-making considering measurements and patient preference, symptoms and function evaluated by various assessment scales rather than socio-demographic and clinical characteristics at baseline were identified as predictors of remission. However, there were differences in the associations for remission between scores on assessment scales and treatment steps.
Higher functional levels and less recent life stress, assessed by SOFAS and LES, respectively, predicted remission particularly in patients receiving lower treatment steps (Step 1 or 2). Functional levels have usually been treated as correlates of depression severity or treatment outcomes [18,19]. Only a few studies evaluated the predictive value of psychosocial function on depression remission [20], although this was not a stepwise treatment. Our findings suggest that functional assessment at baseline could be useful for predicting remission particularly in short-term (up to 6 week) lower treatment steps. Associations between life stressors and depression treatment responses have been controversial in that some reported significant findings [21], while others didn’t [22]. Our findings may give a clue to this controversy in that associations between life stress and remission were significant only in very short-term (up to 3 week) monotherapy period, and then the associations lost significance with longer and higher treatment steps.
Rather, social support predicted remission in patients receiving higher treatment steps (Steps 3 and 4). This finding was in keeping with previous results reported associations between social support and treatment resistant depression and recurrence [23,24]. Suicidal severity predicted remission in most (94%) patients that received treatment Steps 1-3. Depressed patients with a higher suicidality were reportedly characterized by distinct biological characteristics [25]. Therefore, more intensive treatment with particular ongoing clinical attention would be needed in these patients.
The findings were limited by the naturalistic design and single study site evaluation, but are strengthened by large sample size and comprehensive assessments. This report suggests that multi-faceted evaluations at baseline could predict remission by treatment steps, which might serve grounds for personalized treatment of depression and future studies.
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