Prediction of 12-Week Remission by Psychopharmacological Treatment Step in Patients With Depressive Disorders

Article information

Psychiatry Investig. 2022;19(10):866-871
Publication date (electronic) : 2022 October 21
doi : https://doi.org/10.30773/pi.2022.0160
Department of Psychiatry, Chonnam National University Medical School, Gwangju, Republic of Korea
Correspondence: Jae-Mim Kim, MD, PhD Department of Psychiatry, Chonnam National University Medical School, 160 Baekseo-ro, Dong-gu, Gwangju 61469, Republic of Korea Tel: +82-62-220-6143, Fax: +82-62-225-2351, E-mail:jmkim@chonnam.ac.kr
Received 2022 June 10; Revised 2022 August 4; Accepted 2022 August 22.

Abstract

Objective

To investigate the predictors of remission by 4 treatment steps in depressive outpatients receiving 12-week psychopharmacotherapy.

Methods

Patients were consecutively recruited at a university hospital in South Korea from March 2012 to April 2017. At baseline, 1,262 patients were evaluated for sociodemographic and clinical data including assessments scales, and were received antidepressant monotherapy. For patients with an insufficient response or uncomfortable side effects, next treatment steps (1, 2, 3, and 4) with alternative strategies (switching, augmentation, combination, and mixtures of these approaches) were administered considering measurements and patient preference at every 3 weeks in the acute treatment phase (3, 6, 9, and 12 weeks). Remission was defined as a Hamilton Depression Rating Scale score of ≤7.

Results

In the multi-variate logistic regression analyses, remission was predicted by higher functional levels in patients received Step 1 and 2 treatment; by lower life stressors in Step 1; by higher social support in Step 3 and 4; and by lower suicidality in Step 1–3.

Conclusion

Differential associations were found between symptoms or functions and treatment steps, which suggested that multi-faceted evaluations at baseline could predict remission by treatment steps.

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.

Baseline characteristics by 12-week remission status according to treatment steps in 1,246 patients with depressive disorders

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.

Predictors of 12-week remission by treatment steps in 1,246 patients with depressive disorders

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.

Supplementary Materials

The online-only Data Supplement is available with this article at https://doi.org/10.30773/pi.2022.0160.

SUPPLEMENTARY MATERIAL 1
Supplementary Figure 1.

Participant flow by treatment steps and strategies for 12-week outcomes. Antidepressants initiated, switched or combined were bupropion, desvenlafaxine, duloxetine, escitaloproam, fluoxetine, mirtazapine, paroxetine, sertraline, venlafaxine, and vortioxetine. Augmented drugs were buspiron, lithium, triiodothyronine, and atypical antipsychotics including aripirprazole, risperidone, olanzapine, quetiapine, and ziprasidone.Treatment strategies were continuing initial monotherapy (M), switching antidepressants (S), augmenting with other drugs (A), combination of other antidepressants (C), S+A, S+C, A+C, and S+A+C.

Notes

Availability of Data and Material

The data that support the findings of study are available from the corresponding author (JM Kim) upon reasonable request.

Conflicts of Interest

Jae-Min Kim declares research support in the last 5 years from Janssen and Lundbeck. Sung-Wan Kim declares research support in the last 5 years from Janssen, Boehringer Ingelheim, Allergan and Otsuka. Jae-Min Kim and Sung-Wan Kim, contributing editors of the Psychiatry Investigation, were not involved in the editorial evaluation or decision to publish this article. All remaining authors have declared no conflicts of interest.

Author Contributions

Concenptualization: Jae-Min Kim. Data curation: Yun-Tae Jin, Ha-Yeon Kim, Ju-Wan Kim, Min Jhon. Funding acquisition: Jae-Min Kim. Investigation: Yun-Tae Jin, Ha-Yeon Kim, Min Jhon. Methodology: Ju-Wan Kim, Ha-Yeon Kim, Sung-Wan Kim. Project administration: Yun-Tae Jin, Ha-Yeon Kim, Hee-Ju Kang. Resources: Sung-Wan Kim, Il-Seon Shin, Jae-Min Kim. Software: Ju-Wan Kim, Ha-Yeon Kim. Supervision: Jae-Min Kim. Validation: Ju-Yeon Lee, Sung-Wan Kim, Il-Seon Shin. Visualization: Ha-Yeon Kim, Ju-Wan Kim, Min Jhon, Hee-Ju Kang. Writing—original draft: Yun-Tae Jin, Jae-Min Kim. Writing—reviewing & editing: Ha-Yeon Kim, Min Jhon, Ju-Wan Kim, Ha-Yeon Kim, Ju-Yeon Lee, Sung-Wan Kim, Il-Seon Shin, Jae-Min Kim.

Funding Statement

The study was funded by a grant of National Research Foundation of Korea Grant (NRF-2019M3C7A1031345 to Professor Jae-Min Kim.

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Article information Continued

Table 1.

Baseline characteristics by 12-week remission status according to treatment steps in 1,246 patients with depressive disorders

Step 1 (N=534)
Step 2 (N=412)
Step 3 (N=226)
Step 4 (N=74)
No remission (N=347) Remission (N=187) No remission (N=217) Remission (N=195) No remission (N=109) Remission (N=117) No remission (N=33) Remission (N=41)
Socio-demographic characteristics
Age (yr) 56.0±15.3 60.1±13.0 56.6±15.8 59.1±13.9* 53.2±17.1 56.9±14.6 50.2±16.8 51.6±14.6
Sex, female 253 (72.9) 131 (70.1) 148 (68.2) 132 (67.7) 74 (67.9) 71 (60.7) 22 (66.7) 31 (75.6)
Education (yr) 9.1±4.6 8.8±4.7 8.9±4.9 9.2±4.8 9.3±4.7 9.2±5.4 10.8±4.3 9.8±4.6
Marital status, married 234 (67.4) 133 (71.1) 141 (65.0) 146 (74.9)* 72 (66.1) 83 (70.9) 23 (69.7) 31 (75.6)
Living alone 56 (16.1) 32 (17.1) 31 (14.3) 28 (14.4) 19 (17.4) 16 (13.7) 2 (6.1) 3 (7.3)
Religious affiliation 159 (45.8) 73 (39.0) 97 (44.7) 83 (42.6) 43 (39.4) 51 (43.6) 19 (57.6) 20 (48.8)
Employed status 249 (71.8) 141 (75.4) 149 (68.7) 133 (68.2) 73 (67.0) 87 (74.4) 18 (54.5) 32 (78.0)*
Monthly income, <2,000 USD 218 (62.8) 116 (62.0) 132 (60.8) 107 (54.9) 67 (61.5) 65 (55.6) 17 (51.5) 18 (43.9)
Clinical characteristics
Major depressive disorder 286 (82.4) 156 (83.4) 193 (88.9) 160 (82.1) 96 (88.1) 105 (89.7) 29 (87.9) 38 (92.7)
Melancholic feature 44 (12.7) 26 (13.9) 37 (17.1) 24 (12.3) 20 (18.3) 18 (15.4) 9 (27.3) 8 (19.5)
Atypical feature 13 (3.7) 5 (2.7) 15 (6.9) 13 (6.7) 15 (13.8) 7 (6.0)* 4 (12.1) 10 (24.4)
Age at onset (yr) 50.9±17.5 55.1±15.4 51.7±16.9 55.3±15.5* 47.4±17.4 52.0±16.1* 45.6±18.5 46.3±15.9
Duration of illness (yr) 5.2±9.1 5.0±9.2 4.9±9.0 3.8±7.1 5.8±9.0 4.9±9.9 4.6±6.6 5.3±7.3
Recurrent depression 183 (52.7) 88 (47.1) 110 (50.7) 93 (47.7) 64 (58.7) 62 (53.0) 16 (48.5) 29 (70.7)
Number of depressive episodes 1.1±1.4 1.0±1.5 1.0±1.4 0.9±1.4 1.4±1.8 1.0±1.2* 1.9±2.6 1.4±1.3
Duration of present episode (mon) 7.8±11.0 6.3±7.6 8.1±12.8 6.5±8.1 8.5±11.5 6.3±8.1 11.2±15.7 6.6±10.4
Family history of depression 52 (15.0) 21 (11.2) 28 (12.9) 23 (11.8) 15 (13.8) 29 (24.8)* 5 (15.2) 10 (24.4)
Number of physical disorders 1.6±1.3 1.6±1.1 1.5±1.2 1.7±1.3 1.7±1.3 1.7±1.3 1.6±1.5 1.9±1.3
Assessment scales
Hamilton Depression Rating Scale 20.7±4.1 20.2±4.4 21.4±4.6 20.2±3.9 20.9±4.0 20.5±4.3 23.1±4.4 21.6±3.8
Hospital Anxiety and Depression Scale-anxiety subscale 11.6±4.1 10.6±3.9 12.3±3.8 11.3±4.0 12.5±4.1 12.2±4.2 13.9±3.6 12.5±4.2
EuroQol-5D 0.69±0.16 0.71±0.15 0.65±0.16 0.70±0.14 0.66±0.15 0.67±0.17 0.64±0.17 0.64±0.15
Social and Occupational Functional Assessment Scale 55.8±7.4 57.9±7.6 54.0±8.2 56.7±6.7 54.5±7.4 56.5±7.1* 52.9±8.2 57.2±7.6*
Life Experiences Survey 2.1±1.3 1.7±1.1 2.0±1.5 1.9±2.0 2.3±1.8 2.1±1.6 3.7±4.4 2.2±2.5
Perceived Stress Scale 26.8±6.3 25.4±6.7* 27.7±6.6 26.8±6.5 28.6±6.8 27.9±5.2 29.0±6.9 26.9±7.0
Connor-Davidson Resilience Scale 44.0±17.3 47.9±17.8* 40.0±18.2 44.5±18.3* 38.5±18.0 42.6±16.4 35.9±19.2 39.0±17.7
Multidimensional Scale of Perceived Social Support 38.6±12.2 40.2±11.9 38.5±12.3 40.6±11.7 36.3±11.5 40.4±10.7 38.3±12.3 42.8±10.6*
Brief Psychiatric Rating Scale suicidality item 2.9±1.3 2.4±1.2 3.1±1.4 2.5±1.4 3.3±1.4 2.9±1.4* 2.9±1.4 3.1±1.6

Values are presented as mean±standard deviation or number (%). The treatment steps were administered from antidepressant monotherapy (Step 1) to Step 4, every 3 weeks during 12 weeks considering overall effectiveness and tolerability. At the next step, Step 1 monotherapy continuation including dose adjustment or enter into Step 2, 3, and 4 composed of adding strategies of previous step with switching, augmentation, combination treatment. Antidepressants initiated, switched or combined were bupropion, desvenlafaxine, duloxetine, escitaloproam, fluoxetine, mirtazapine, paroxetine, sertraline, venlafaxine, and vortioxetine. Augmented drugs were buspiron, lithium, triiodothyronine, and atypical antipsychotics including aripirprazole, risperidone, olanzapine, quetiapine, and ziprasidone. Treatment strategies were continuing initial monotherapy (M), switching antidepressants (S), augmenting with other drugs (A), combination of other antidepressants (C), S+A, S+C, A+C, and S+A+C.

*

p<0.05;

p<0.01;

p<0.001

Table 2.

Predictors of 12-week remission by treatment steps in 1,246 patients with depressive disorders

Step 1 (N=534)
Step 2 (N=412)
Step 3 (N=226)
Step 4 (N=74)
OR (95% CI) p-value OR (95% CI) p-value OR (95% CI) p-value OR (95% CI) p-value
Age, higher 1.02 (0.99–1.04) 0.182 1.00 (0.97–1.02) 0.740 - - - -
Married marital state - - 1.33 (0.95–1.57) 0.083 - - - -
Employed state - - - - - - 1.17 (0.73–1.85) 0.127
Atypical feature - - - - 0.51 (0.17–1.44) 0.196 - -
Age at onset, higher 1.00 (0.98–1.02) 0.969 1.02 (0.99–1.04) 0.234 1.01 (0.99–1.03) 0.430 - -
Number of depressive episodes, lower - - - - 1.09 (0.89–1.35) 0.341 - -
Family history of depression - - - - 1.80 (0.87–3.74) 0.115 - -
Hamilton Depression Rating Scale, lower - - 1.01 (0.94–1.08) 0.864 - - - -
Hospital Anxiety & Depression Scale-anxiety subscale, lower 1.01 (0.94–1.08) 0.862 1.01 (0.93–1.11) 0.848 - - - -
EuroQol-5D, higher - - 1.07 (0.91–1.26) 0.374 - - - -
Social and Occupational Functional Assessment Scale, higher 1.03 (1.00–1.06) 0.048 1.04 (1.00–1.08) 0.041 1.02 (0.98–1.06) 0.333 1.03 (0.96–1.11) 0.446
Life Experiences Survey, lower 1.08 (1.02–1.20) 0.028 - - - - - -
Perceived Stress Scale, lower 1.01 (0.98–1.05) 0.547 - - - - - -
Connor-Davidson Resilience Scale, higher 1.01 (0.99–1.02) 0.155 1.01 (0.99–1.02) 0.375 - - - -
Multidimensional Scale of Perceived Social Support, higher - - - - 1.03 (1.00–1.06) 0.027 1.05 (1.00–1.11) 0.036
Brief Psychiatric Rating Scale suicidality item, lower 1.09 (1.02–1.20) 0.011 1.11 (1.05–1.31) 0.008 1.10 (1.00–1.37) 0.049 - -

The treatment steps were administered from antidepressant monotherapy (Step 1) to Step 4, every 3 weeks during 12 weeks considering overall effectiveness and tolerability. At the next step, Step 1 monotherapy continuation including dose adjustment or enter into Step 2, 3, and 4 composed of adding strategies of previous step with switching, augmentation, combination treatment. Antidepressants initiated, switched or combined were bupropion, desvenlafaxine, duloxetine, escitaloproam, fluoxetine, mirtazapine, paroxetine, sertraline, venlafaxine, and vortioxetine. Augmented drugs were buspiron, lithium, triiodothyronine, and atypical antipsychotics including aripirprazole, risperidone, olanzapine, quetiapine, and ziprasidone. Treatment strategies were continuing initial monotherapy (M), switching antidepressants (S), augmenting with other drugs (A), combination of other antidepressants (C), S+A, S+C, A+C, and S+A+C. OR, odds ratio; CI, confidence interval