Effects of music therapy on depression: A meta-analysis of randomized controlled trials.

BACKGROUND: We aimed to determine and compare the effects of music therapy and music medicine on depression, and explore the potential factors associated with the effect.
METHODS: PubMed (MEDLINE), Ovid-Embase, the Cochrane Central Register of Controlled Trials, EMBASE, Web of Science, and Clinical Evidence were searched to identify studies evaluating the effectiveness of music-based intervention on depression from inception to May 2020. Standardized mean differences (SMDs) were estimated with random-effect model and fixed-effect model.
RESULTS: A total of 55 RCTs were included in our meta-analysis. Music therapy exhibited a significant reduction in depressive symptom (SMD = -0.66; 95% CI = -0.86 to -0.46; P<0.001) compared with the control group; while, music medicine exhibited a stronger effect in reducing depressive symptom (SMD = -1.33; 95% CI = -1.96 to -0.70; P<0.001). Among the specific music therapy methods, recreative music therapy (SMD = -1.41; 95% CI = -2.63 to -0.20; P<0.001), guided imagery and music (SMD = -1.08; 95% CI = -1.72 to -0.43; P<0.001), music-assisted relaxation (SMD = -0.81; 95% CI = -1.24 to -0.38; P<0.001), music and imagery (SMD = -0.38; 95% CI = -0.81 to 0.06; P = 0.312), improvisational music therapy (SMD = -0.27; 95% CI = -0.49 to -0.05; P = 0.001), music and discuss (SMD = -0.26; 95% CI = -1.12 to 0.60; P = 0.225) exhibited a different effect respectively. Music therapy and music medicine both exhibited a stronger effects of short and medium length compared with long intervention periods.
CONCLUSIONS: A different effect of music therapy and music medicine on depression was observed in our present meta-analysis, and the effect might be affected by the therapy process.

Introduction

Depression was reported to be a common mental disorders and affected more than 300 million people worldwide, and long-lasting depression with moderate or severe intensity may result in serious health problems [1]. Depression has become the leading causes of disability worldwide according to the recent World Health Organization (WHO) report. Even worse, depression was closely associated with suicide and became the second leading cause of death, and nearly 800 000 die of depression every year worldwide [1, 2]. Although it is known that treatments for depression, more than 3/4 of people in low and middle-income income countries receive no treatment due to a lack of medical resources and the social stigma of mental disorders [3]. Considering the continuously increased disease burden of depression, a convenient effective therapeutic measures was needed at community level.

Music-based interventions is an important nonpharmacological intervention used in the treatment of psychiatric and behavioral disorders, and the obvious curative effect on depression has been observed. Prior meta-analyses have reported an obvious effect of music therapy on improving depression [4, 5]. Today, it is widely accepted that the music-based interventions are divided into two major categories, namely music therapy and music medicine. According to the American Music Therapy Association (AMTA), “music therapy is the clinical and evidence-based use of music interventions to accomplish individualized goals within a therapeutic relationship by a credentialed professional who has completed an approved music therapy program” [6]. Therefore, music therapy is an established health profession in which music is used within a therapeutic relationship to address physical, emotional, cognitive, and social needs of individuals, and includes the triad of music, clients and qualified music therapists. While, music medicine is defined as mainly listening to prerecorded music provided by medical personnel or rarely listening to live music. In other words, music medicine aims to use music like medicines. It is often managed by a medical professional other than a music therapist, and it doesn’t need a therapeutic relationship with the patients. Therefore, the essential difference between music therapy and music medicine is about whether a therapeutic relationship is developed between a trained music therapist and the client [7-9]. In the context of the clear distinction between these two major categories, it is clear that to evaluate the effects of music therapy and other music-based intervention studies on depression can be misleading. While, the distinction was not always clear in most of prior papers, and no meta-analysis comparing the effects of music therapy and music medicine was conducted. Just a few studies made a comparison of music-based interventions on psychological outcomes between music therapy and music medicine. We aimed to (1) compare the effect between music therapy and music medicine on depression; (2) compare the effect between different specific methods used in music therapy; (3) compare the effect of music-based interventions on depression among different population [7, 8].

Materials and methods

Search strategy and selection criteria

PubMed (MEDLINE), Ovid-Embase, the Cochrane Central Register of Controlled Trials, EMBASE, Web of Science, and Clinical Evidence were searched to identify studies assessing the effectiveness of music therapy on depression from inception to May 2020. The combination of “depress*” and “music*” was used to search potential papers from these databases. Besides searching for electronic databases, we also searched potential papers from the reference lists of included papers, relevant reviews, and previous meta-analyses. The criteria for selecting the papers were as follows:(1) randomised or quasi-randomised controlled trials; (2) music therapy at a hospital or community, whereas the control group not receiving any type of music therapy; (3) depression rating scale was used. The exclusive criteria were as follows: (1) non-human studies; (2) studies with a very small sample size (n<20); (3) studies not providing usable data (including sample size, mean, standard deviation, etc.); (4) reviews, letters, protocols, etc. Two authors independently (YPJ, HZH) searched and screened the relevant papers. EndNote X7 software was utilized to delete the duplicates. The titles and abstracts of all searched papers were checked for eligibility. The relevant papers were selected, and then the full-text papers were subsequently assessed by the same two authors. In the last, a panel meeting was convened for resolving the disagreements about the inclusion of the papers.

Data extraction

We developed a data abstraction form to extract the useful data: (1) the characteristics of papers (authors, publish year, country); (2) the characteristics of participators (sample size, mean age, sex ratio, pre-treatment diagnosis, study period); (3) study design (random allocation, allocation concealment, masking, selection process of participators, loss to follow-up); (4) music therapy process (music therapy method, music therapy period, music therapy frequency, minutes per session, and the treatment measures in the control group); (5) outcome measures (depression score). Two authors independently (TQS, ZH) abstracted the data, and disagreements were resolved by discussing with the third author (YPJ).

Assessment of risk of bias in included studies

Two authors independently (TQS, ZH) assessed the risk of bias of included studies using Cochrane Collaboration’s risk of bias assessment tool, and disagreements were resolved by discussing with the third author (YPJ) [10].

Music therapy and music medicine

Music Therapy is defined as the clinical and evidence-based use of music interventions to accomplish individualized goals within a therapeutic relationship by a credentialed professional who has completed an approved music therapy program. Music medicine is defined as mainly listening to prerecorded music provided by medical personnel or rarely listening to live music. In other words, music medicine aims to use music like medicines.

Music therapy mainly divided into active music therapy and receptive music therapy. Active music therapy, including improvisational, re-creative, and compositional, is defined as playing musical instruments, singing, improvisation, and lyrics of adaptation. Receptive music therapy, including music-assisted relaxation, music and imagery, guided imagery and music, lyrics analysis, and so on, is defined as music listening, lyrics analysis, and drawing with musing. In other words, in active methods participants are making music, and in receptive music therapy participants are receiving music [6, 7, 9, 11–13].

Evaluation of depression

Depression was evaluated by the common psychological scales, including Beck Depression Inventory (BDI), Children’s Depression Inventory (CDI), Center for Epidemiologic Studies Depression (CES-D), Cornell Scale (CS), Depression Mood Self-Report Inventory for Adolescence (DMSRIA), Geriatric Depression Scale-15 (GDS-15); Geriatric Depression Scale-30 (GDS-30), Hospital Anxiety and Depression Scale (HADS), Hamilton Rating Scale for Depression (HRSD/HAMD), Montgomery-sberg Depression Rating Scale (MADRS), Patient Reported Outcomes Measurement Information System (PROMIS), Self-Rating Depression Scale (SDS), Short Version of Profile of Mood States (SV-POMS).

Statistical analysis

The pooled effect were estimated by using the standardized mean differences (SMDs) and its 95% confidence interval (95% CI) due to the different depression rate scales were used in the included papers. Heterogeneity between studies was assessed by I-square (I) and Q-statistic (P<0.10), and a high I (>50%) was recognized as heterogeneity and a random-effect model was used [14-16]. We performed subgroup analyses and meta-regression analyses to study the potential heterogeneity between studies. The subgroup variables included music intervention categories (music therapy and music medicine), music therapy methods (active music therapy, receptive music therapy), specific receptive music therapy methods (music-assisted relaxation, music and imagery, and guided imagery and music (Bonny Method), specific active music therapy methods (recreative music therapy and improvisational music therapy), music therapy mode (group therapy, individual therapy), music therapy period (weeks) (2–4, 5–12, ≥13), music therapy frequency (once weekly, twice weekly, ≥3 times weekly), total music therapy sessions (1–4, 5–8, 9–12, 13–16, >16), time per session (minutes) (15–40, 41–60, >60), inpatient settings (secure [locked] unit at a mental health facility versus outpatient settings), sample size (20–50, ≥50 and <100, ≥100), female predominance(>80%) (no, yes), mean age (years) (<50, 50–65, >65), country having music therapy profession (no, yes), pre-treatment diagnosis (mental health, depression, severe mental disease/psychiatric disorder). We also performed sensitivity analyses to test the robustness of the results by re-estimating the pooled effects using fixed effect model, using trim and fill analysis, excluding the paper without information on music therapy, excluding the papers with more high biases, excluding the papers with small sample size (20< n<30), excluding the papers using an infrequently used scale, excluding the studies focused on the people with a severe mental disease. We investigated the publication biases by a funnel plot as well as Egger’s linear regression test [17]. The analyses were performed using Stata, version 11.0. All P-values were two-sided. A P-value of less than 0.05 was considered to be statistically significant.

Results

Characteristics of the eligible studies

Fig 1 depicts the study profile, and a total of 55 RCTs were included in our meta-analysis [18-72]. Of the 55 studies, 10 studies from America, 22 studies from Europe, 22 studies from Asia, and 1 study from Australia. The mean age of the participators ranged from 12 to 86; the sample size ranged from 20 to 242. A total of 16 different scales were used to evaluate the depression level of the participators. A total of 25 studies were conducted in impatient setting and 28 studies were in outpatients setting; 32 used a certified music therapist, 15 not used a certified music therapist (for example researcher, nurse), and 10 not reported relevent information. A total of 16 different depression rating scales were used in the included studies, and HADS, GDS, and BDI were the most frequently used scales (Table 1).

Fig 1

Prisma 2009 flow diagram literature search and study selection.

PRISMA diagram showing the different steps of systematic review, starting from literature search to study selection and exclusion. At each step, the reasons for exclusion are indicated. Doi: 10.1371/journal.pone.0052562.g001.

Table 1

Characteristics of clinical trials included in this meta-analysis.

Studies	Country	Ample size	Mean age (SD)	Pre-intervention diagnosis	Music intervention method (total)	Intervenor or therapist	Intervention description	Control group	Outcome Measures
Biasutti et al., 2019	Italy	N = 45, Female = 29	84.6 (7.17)	Healthy or with cognitive impairment	Active music therapy (improvisational music therapy)	Certified music therapist	Twice weekly (70 min/session) for 6 weeks	45-minute gymnastic activities	GDS-15
Burrai et al., [48]	Italy	N = 159, Female = 124	73.05 (11.5)	Heart failure	Music medicine	Researchers	Once daily (30 min/session) for 36 weeks	Standard HF treatment	HADS
Burrai et al., [49]	Italy	N = 24, Female = 9	62.3(2.8)	End-stage kidney disease	Music medicine	Nurse	Once daily (15 min/session) for 2 weeks	Standard hemodialysis	HADS
Chan et al., 2009	Hong Kong China	N = 47, Female = 26	>60	No mental illness	Music medicine	Researchers	Once weekly (30 min/session) for 4 weeks	Without any intervention	GDS-30
Chan et al., 2010	Hong Kong China	N = 42, Female = 23	>60	No mental illness	Music medicine	Researchers	Once weekly (45 min/session) for 4 weeks	Without any intervention	GDS-15
Chan et al., 2012	Singapore	N = 50, Female = 32	>55	No mental illness	Music medicine	Researchers	Once weekly (30 min/session) for 8 weeks	Without any intervention	GDS-15
Chen et al., 2015	Taiwan China	N = 71, Female = 69	18.5	Depressive disorder	Music medicine	Researchers	Twice weekly (40 min/session) for 10 weeks	Without any intervention	DMSRIA
Chen et al., 2018	China	N = 52, Female = 52	-	Breast cancer	Receptive music therapy	Certified music therapist	Once weekly (60 min/session) for 8 weeks	Standard care	HADS
Chen et al., 2019	Taiwan China	N = 65, Female = 56	72.7(5.97)	No mental illness	Active music therapy (improvisational music therapy)	Not reported	Twice weekly (40 min/session) for 10 weeks	No music therapy	BDI
Cheung et al., 2019	Hong Kong, China	N = 60, Female = 25	13.2(3.27)	Pediatric brain tumor with a significant level of depression	Active music therapy (recreative music therapy)	Certified music therapist	Once weekly (45 min/session) for 52 weeks	No music therapy	CES-D
Chirico et al., 2020	Italy	N = 64, Female = 64	55.95(5.92)	Breast cancer	Receptive music therapy	Certified music therapist	20 min/session	Standard care	SV-POMS
Choi et al., 2008	Korea	N = 26, Female = 14	36.15(10.2)	Psychiatric disorder	Active music therapy (recreative music therapy)	Certified music therapist	Once-two weekly (60 min/session) for 12 weeks	Routine care	BDI
Chu et al., 2014	Taiwan, China	N = 100, Female = 53	82(6.8)	Dementia	Active music therapy (improvisational music therapy)	Certified music therapist	Twice weekly (30 min/session) for 6 weeks	Standard care	CS
Cooke et al., 2010	Australia	N = 47, Female = 33	>65	Dementia	Active music therapy (improvisational music therapy)	Musicians	Thrice weekly (40 min/session) for 8 weeks	Educational/entertainment activities	GDS
Erkkilä et al., 2011	Finland	N = 79, Female = 62	35.6(9.75)	Depression disorder	Active music therapy (improvisational music therapy)	Certified music therapist	Twice weekly (60 min/session) for 12 weeks	Standard treatment	MADRS
Fancourt et al., 2019	UK	N = 62, Female = 48	54.5 (14.5)	Cancer carers	Active music therapy (improvisational music therapy)	Certified music therapist	Once weekly (90 min/session) for 12 weeks	No music therapy	HADS
Gok Ugur et al., 2017	Turkey	N = 64, Female = 22	76.35(7.88)	No mental illness	Receptive music therapy (music and imagery)	Certified music therapist	Three days in a week for 8 weeks	No music therapy	GDS-15
Guétin et al., 2009	France	N = 30, Female = 22	86(5.6)	Moderate stages of Alzheimer’s disease	Receptive music therapy (music-assisted relaxation)	Certified music therapist	Once weekly (20 min/session) for 16 weeks	Educational/entertainment activities	GDS-30
Hanser et al., 1994	USA	N = 30, Female = 23	67.9	Depressive disorder	Receptive music therapy (guided imagery and music)	Certified music therapist	Once weekly (1 h/session; 20 min/session) for 8 weeks	No music therapy	GDS
Hars et al., 2014	Switzerland	N = 134, Female = 129	75(7)	No mental illness	Music medicine	Not reported	Once weekly (1 h/session) for 26 weeks	No music therapy	HADS
Liao et al., 2018	China	N = 107, Female = 66	71.79(7.71)	Mild to moderate depressive symptoms	Music medicine	Not reported	Once weekly (50 min/session) for 12 weeks	Routine health education	GDS-30
Low et al., 2020	USA	N = 43, Female = 33	50.07(5.48)	Chronic pain	Active+receptive music therapy	Certified music therapist	Once weekly (90 min/session) for 12 weeks	Standard care	PROMIS
Mahendran et al., 2018	Singapore	N = 68, Female = 56	71.1(5.3)	Mild cognitive impairment	Receptive music therapy (guided imagery and music)	Certified music therapist	Once weekly for 3 months, then fortnightly for 36 weeks.	No music therapy	GDS-15
Park et al., 2015	South Korea	N = 29, Female = 16	8.17(1.47)	No mental illness	Active music therapy (improvisational music therapy)	Music therapist	Once weekly (120 min/session) for 15 weeks	Educational creative movement program	CDI
Pérez-Ros et al., 2019	Spain	N = 119, Female = 61	80.52(7.44)	No mental illness	Active music therapy (improvisational music therapy)	Physiotherapists	5 times weekly (60 min/session) for 8 weeks	No music therapy	CS
Ploukou et al., 2018	Greece	N = 48, Female = 46	-	Oncology nurses without diseases	Music medicine	Not reported	Once weekly (60 min/session) for 4 weeks	No music therapy	HADS
Ribeiro et al., 2018	Brazil	N = 21, Female = 21	22.5(6.5)	Mothers of preterm	Receptive music therapy (music and discuss)	Certified music therapist	Once weekly (30–40 min/session) for 7–9 weeks	No music therapy	BDI
Sigurdardóttir et al., 2019	Denmark	N = 38, Female = 25	25.4	Mild and moderate depression	Music medicine	Not reported	Twice weekly (20 min/session) for 4 weeks	No music therapy	HRSD-6, HRSD-17
Toccafondi et al., 2018	Italy	N = 242, Female = 147	>18	Cancer	Receptive music therapy	Certified music therapist	Once weekly	Standard care	HADS
Trimmer et al., 2018	Canada	N = 28, Female = 15	43(13.8)	Depression and anxiety	Active music therapy (recreative music therapy)	Not reported	Once weekly (90 min/session) for 9 weeks	Treatment as usual	HADS
Volpe et al., 2018	Italy	N = 106, Female = 106	43.83(12.7)	Psychosis	Active music therapy (improvisational music therapy)	Certified music therapist	Twice daily (60 min/session) for 6 weeks	Standard drug treatment	HADS
Wu et al., 2019	China	N = 60, Female = 60	36.2(9.47)	Methamphetamine use disorder	Active+receptive music therapy	Certified music therapist	Once weekly (90 min/session) for 13 weeks	Standard treatment	SDS
Albornoz et al., 2011	Venezuela	N = 24, Female = 0	16–60	Depressed adults with substance abuse	Active music therapy (improvisational music therapy)	Therapist	Once weekly (120 min/session) for 12 weeks	Standard treatment	BDI, HRSD
Hendricks et al., 1999	USA	N = 20	14–15	Depression	Active+receptive music therapy	Therapist	Once weekly for 8 weeks	Individual psychotherapy	BDI
Hendricks et al., 2001	USA	N = 63	12–18	Depression	Music medicine	counsellor-researcher	Once weekly (60 min/session) for 12 weeks	Cognitive-based psychotherapy	BDI
Radulovic et al., 1996	Serbia	N = 60	21–62 (40)	Depression	Receptive music therapy	Therapist	Twice weekly (20 min/session) for 6 weeks	Treatment as usual	BDI
Zerhusen et al., 1995	USA	N = 60	70–82 (77)	Moderate to severe depression	Music medicine	Not reported	Twice weekly (30 min/session) for 10 weeks	psychological therapy or treatment as usual	BDI
Chang et al., 2008	Taiwan China	N = 236, Female = 236	22-41(30.03)	Pregnant women	Music medicine	Music faculty members	Once a day (30 min/session) for 2 weeks	General prenatal care	EPDS
Chen et al., 2020	Taiwan China	N = 100 Female = 100	30.19(9.50)	Beast cancer undergoing chemotherapy.	Receptive music therapy	Trained music therapist	Once weekly (45 min/session) for 3 weeks	Routine nursing care	HADS
Chen et al., 2016	China	N = 200, Female = 0	35.5(9.75)	Prisoners with mild depression;	Active+receptive music therapy, including music and imagery, improvisation, and song writing	Music therapist	Twice weekly (90 min/session) for 3 weeks	Standard care	BDI
Esfandiari et al., 2014	Iran	N = 30, Female = 30	Not reported	Severe depressive disorder	Music medicine	not reported	90 min/session	Standard care	BDI
Fancourt et al., 2016	UK	N = 45, Female = 37	53.54 (13.85)	Mental health service users	Music medicine	Professional drummer	Once weekly (90 min/session) for 10 weeks	Without any intervention	HADS
Giovagnoli et al., 2017	Italy	N = 39, Female = 24	73.64(7.11)	Mild to moderate Alzheimer’s disease	Active music therapy (Improvisational music therapy)	Music therapist	Twice weekly (45 min/session) for 12 weeks	Cognitive training or neuroeducation	BDI
Harmat et al., 2008	Hungary	N = 94, Female = 73	22.6(2.83)	Seep complaints	Music medicine	Investigators	Once a day (45 min/session) for 3 weeks	listening to an audiobook or no intervention	BDI
Koelsch et al., 2010	Germany	N = 154, Female = 78	24.6	No disease	Active music therapy	Music therapist	Not reported	Individual psychotherapy	POMS
Liao et al., 2018	China	N = 60, Female = 30	61.82(13.20)	Cancer	Receptive music therapy+muscle relaxation training	not reported	Once a day (40 min/session) for 8 weeks	Muscle relaxation training	HADS
Lu et al., 2013	Taiwan China	N = 80, Female = 21	52.02 (7.64)	Schizophrenia	Active music therapy+receptive music therapy	Trained research assistant	Twice weekly (60 min/session) for 5 weeks	Usual care	CDSS
Mahendran et al., 2018	Singapore	N = 68, Female = 56	71.1(5.05)	Mild cognitive impairment	Receptive music therapy	Music therapist	Weekly in the first 3 months, then fortnightly for 6 months.	Standard care without any intervention	GDS-15
Mondanaro et al., 2017	Italy	N = 60, Female = 35	48.20(4.49)	Patients after spine surgery	Active music therapy (improvisational music therapy)	Music therapist	30-minute music therapy session during an 8-hour period within 72 hours after surgery	Standard care without any intervention	HADS
Nwebube et al., 2017	UK	N = 36, Female = 36	Not reported	Pregnant women	Music medicine	Investigators	Once a day (20 min/session) for 12 weeks	Standard care without any intervention	EPDS
Porter et al., 2017	Northern Ireland	N = 184, Female = 73	12.7 (2.5)	Adolescents with behavioural and emotional problems	Active music therapy (improvisational music therapy)	Music therapist	Once weekly (30 min/session) for 13 weeks	Usual care	CES-D
Raglio et al., 2016	Italy	N = 30, Female = 17	64 (10.97)	Amyotrophic lateral sclerosis	Active music therapy	Music therapist	Three times weekly (30 min/session) for 4 weeks	Standard care	HADS
Torres, et al., 2018	Spanish	N = 70, Female = 70	35-65(51.3)	Fibromyalgia	Receptive music therapy	Music therapist	Once weekly (120 min/session) for 12 weeks	Without any additional service	ST/DEP
Wang et al., 2011	China	N = 80, Female = 21	19.35(1.68)	Student	Receptive music therapy	Not reported	Not reported	Without any additional service	SDS
Yap et al., 2017	Singapore	N = 31, Female = 29	74.65(6.4)	Elderly people	Active music therapy (improvisational music therapy)	Experienced instructors	Once weekly (60 min/session) for 11 weeks	Without any intervention	GDS

Note: BDI = Beck Depression Inventory; CDI = Children’s Depression Inventory; CDSS = depression scale for schizophrenia; CES-D = Center for Epidemiologic Studies Depression; CS = Cornell Scale; DMSRIA = Depression Mood Self-Report Inventory for Adolescence; EPDS = Edinburgh Postnatal Depression Scale; GDS-15 = Geriatric Depression Scale-15; GDS-30 = Geriatric Depression Scale-30; HADS = Hospital Anxiety and Depression Scale; HRSD (HAMD) = Hamilton Rating Scale for Depression; MADRS = Montgomery-sberg Depression Rating Scale; PROMIS = Patient Reported Outcomes Measurement Information System; SDS = Self-Rating Depression Scale; State-Trait Depression Questionnaire = ST/DEP; SV-POMS = short version of Profile of Mood States; NA = not available.

Of the 55 studies, only 2 studies had high risks of selection bias, and almost all of the included studies had high risks of performance bias (Fig 2).

Fig 2

Risk-of-bias graph and risk.

The overall effects of music therapy

Of the included 55 studies, 39 studies evaluated the music therapy, 17 evaluated the music medicine. Using a random-effects model, music therapy was associated with a significant reduction in depressive symptoms with a moderate-sized mean effect (SMD = −0.66; 95% CI = -0.86 to -0.46; P<0.001), with a high heterogeneity across studies (I = 83%, P<0.001); while, music medicine exhibited a stronger effect in reducing depressive symptom (SMD = −1.33; 95% CI = -1.96 to -0.70; P<0.001) (Fig 3).

Fig 3

Effects of music therapy and music medicine to reduce depression.

Twenty studies evaluated the active music therapy using a random-effects model, and a moderate-sized mean effect (SMD = −0.57; 95% CI = -0.90 to -0.25; P<0.001) was observed with a high heterogeneity across studies (I = 86.3%, P<0.001). Fourteen studies evaluated the receptive music therapy using a random-effects model, and a moderate-sized mean effect (SMD = −0.73; 95% CI = -1.01 to -0.44; P<0.001) was observed with a high heterogeneity across studies (I = 76.3%, P<0.001). Five studies evaluated the combined effect of active and receptive music therapy using a random-effects model, and a moderate-sized mean effect (SMD = −0.88; 95% CI = -1.32 to -0.44; P<0.001) was observed with a high heterogeneity across studies (I = 70.5%, P<0.001) (Fig 4).

Fig 4

Effects of active music therapy, receptive therapy, and music therapy+receptive therapy to reduce depression.

Among specific music therapy methods, recreative music therapy (SMD = -1.41; 95% CI = -2.63 to -0.20; P<0.001), guided imagery and music (SMD = -1.08; 95% CI = -1.72 to -0.43; P<0.001), music-assisted relaxation (SMD = -0.81; 95% CI = -1.24 to -0.38; P<0.001), music and imagery (SMD = -0.38; 95% CI = -0.81 to 0.06; P = 0.312), improvisational music therapy (SMD = -0.27; 95% CI = -0.49 to -0.05; P = 0.001), and music and discuss (SMD = -0.26; 95% CI = -1.12 to 0.60; P = 0.225) exhibited a different effect respectively (Fig 5).

Fig 5

Effects of specific music therapy method to reduce depression.

Sub-group analyses and meta-regression analyses

We performed sub-group analyses and meta-regression analyses to study the homogeneity. We found that music therapy yielded a superior effect on reducing depression in the studies with a small sample size (20–50), with a mean age of 50–65 years old, with medium intervention frequency (<3 times weekly), with more minutes per session (>60 minutes). We also found that music therapy exhibited a superior effect on reducing depression among people with severe mental disease /psychiatric disorder and depression compared with mental health people. While, whether the country have the music therapy profession, whether the study used group therapy or individual therapy, whether the study was in the outpatients setting or the inpatient setting, and whether the study used a certified music therapist all did not exhibit a remarkable different effect (Table 2). Table 2 also presents the subgroup analysis of music medicine on reducing depression.

Table 2

Subgroup analyses of music-based intervention to reduce depression.

Subgroups	Music therapy					Music medicine
	Trials number	Effects		Heterogeneity		Trials number	Effects		Heterogeneity
		SMD (95%CI)	P	I2(%)	P		SMD (95%CI)	P	I2(%)	P
Sample size
20–50	16	-1.24(-2.08, -0.39)	<0.001	143.19	<0.001	7	-1.21(-1.79, -0.62)	<0.001	26.30	<0.001
≥50, <100	17	-0.62(-0.84, -0.38)	<0.001	51.58	<0.001	5	-1.17(-2.45, 0.11)	0.073	86.86	<0.001
≥100	8	-0.36(-0.60, -0.11)	0.005	31.33	<0.001	4	-1.56(-3.10, -0.02)	0.047	206.10	<0.001
Female predominance (>80%)
Yes	13	-0.73(-1.23, -0.22)	0.005	112.85	<0.001	8	-1.71(-2.76, -0.65)	0.001	247.54	<0.001
No	24	-0.58(-0.81, -036)	<0.001	109.59	<0.001	6	-0.93(-1.32, -0.54)	<0.001	12.51	0.028
Mean age (years)
<50	20	-0.6(-0.85, -0.35)	<0.001	84.50	<0.001	5	-1.36(-2.30, -0.41)	0.005	69.99	<0.001
50–65	7	-1.43(-2.28, -0.58)	0.001	78.58	<0.001	2	-1.10(-1.66, -0.53)	<0.001	1.22	<0.001
>65	12	-0.48(-0.84, -0.13)	0.008	48.47	<0.001	6	-1.21(-2.66, 0.24)	0.102	237.19	<0.001
Pre-treatment diagnosis
Mental health	23	-0.58(-0.85, -0.32)	<0.001	141.40	<0.001	10	-1.26(-2.04, -0.47)	0.002	218.03	<0.001
Depression	9	-0.79(-1.13, -0.46)	<0.001	20.83	<0.001	6	-1.49(-2.72, -0.25)	0.018	106.87	<0.001
Severe mental disease /psychiatric disorder	9	-0.78(-1.34, -0.23)	<0.001	62.14	<0.001	0	-	-	-
Intervention frequency
Once weekly	21	-0.72 (-1.04, -0.41)	<0.001	118.78	<0.001	7	-1.11(-1.77, -0.44)	0.001	67.58	<0.001
Twice weekly	10	-0.79 (-1.13, -0.46)	<0.001	38.43	<0.001	3	-0.56(-2.49, 1.37)	0.570	53.98	<0.001
≥3 times weekly	6	-0.14 (-0.53, 0.25)	0.476	18.65	0.002	5	-1.67(-3.28, -0.06)	0.042	185.98	<0.001
Time per session (minutes)
15–40	12	-0.52(-0.86, -0.19)	0.002	59.84	<0.001	9	-1.34(-2.38, -0.29)	0.012	245.42	<0.001
41–60	10	-0.56(-0.99, -0.13)	0.012	62.25	<0.001	6	-0.96(-1.65, -0.27)	0.006	57.46	<0.001
>60	12	-0.96(-1.46, -0.47)	<0.001	81.18	<0.001	1	-4.1(-5.7, -2.50)	<0.001	0	-
Country having music therapy profession
Yes	39	-0.65(-0.86, -0.45)	<0.001	234.06	<0.001	13	-1.26(-1.99, -0.53)	0.001	309.93	<0.001
No	2	-0.83(-1.42, -0.23)	<0.001	0.03	0.864	3	-1.60(-2.86, -0.34)_	0.003	16.49	<0.001
Group therapy or individual therapy
Group therapy	30	-0.66 (-0.92, -0.41)	<0.001	177.02	<0.001	8	-1.23(-2.10, -0.36)	0.006	128.59	<0.001
Individual therapy	10	-0.67 (-1.05, -0.29)	0.001	56.14	<0.001	7	-1.57(-2.71, -0.42)	0.007	190.82	<0.001
Setting
Outpatient	16	-0.89(-1.30, -0.47)	<0.001	103.66	<0.001	12	-1.26(-1.94, -0.57)	<0.001	255.53	<0.001
Inpatient	22	-0.57(-0.83, -0.31)	<0.001	127.51	<0.001	3	-0.91(-3.10, 1.28)	0.414	54.87	<0.001
Used a certified music therapist
Yes	32	-0.69 (-0.88, -0.49)	<0.001	131.76	<0.001	-	-	-	-	-
No	5	-0.93 (-2.12, 0.25)	0.123	82.69	<0.001	10	-1.71(-2.61, -0.81)	<0.001	234.94	<0.001

In the subgroup analysis by total session, music therapy and music medicine both exhibited a stronger effects of short (1–4 sessions) and medium length (5–12 sessions) compared with long intervention periods (>13sessions) (Fig 6). Meta-regression demonstrated that total music intervention session was significantly associated with the homogeneity between studies (P = 0.004) (Table 3).

Fig 6

Effects of music therapy and music medicine to reduce depression by total sessions.

A, evaluating the effect of music therapy; B, evaluating the effect of music medicine.

Table 3

Meta-regression analysis of the main characteristics of the 33 studies.

Characteristics	Music therapy		Music medicine
	Coef. 95%CI	P	Coef. 95%CI	P
Sample size	0(-0.01, 0.03)	0.704	0(-0.01, 0.01)	0.926
Mean age (years)	0.01(-0.03, 0.05)	0.39	-	-
Setting
Inpatient	1		1
Outpatient	0.13(-1.98, 2.23)	0.901	1.48(-0.59, 3.55)	0.139
Pre-treatment diagnosis
Mental health	1	1	1
Depression	-0.24(-1.20, 0.72)	0.622	-0.24(-2.08, 1.61)	0.789
Severe mental disease /psychiatric disorder	-0.22(-1.18, 0.75)	0.652	-
Music therapy method
Active music therapy	1
Receptive music therapy	0.13(-1.89, 2.14)	0.895	-	-
Active+receptive	0.48(-2.26, 3.21)	0.716	-	-
Total music intervention sessions	0.01(-0.05, 0.06)	0.83	-0.02(-0.03, -0.01)	0.004
Music intervention frequency	-0.08(-1.74, 1.58)	0.918	0.45(-0.66, 1.57)	0.376
Time per session (minutes)	-0.01(-0.04, 0.02)	0.482	-0.01(-0.07, 0.05)	0.778

Sensitivity analyses

We performed sensitivity analyses and found that re-estimating the pooled effects using fixed effect model, using trim and fill analysis, excluding the paper without information regarding music therapy, excluding the papers with more high biases, excluding the papers with small sample size (20< n<30), excluding the studies focused on the people with a severe mental disease, and excluding the papers using an infrequently used scale yielded the similar results, which indicated that the primary results was robust (Table 4).

Table 4

Sensitivity analyses of the main outcomes [SMD (95%CI)].

Outcomes	Trials number	Effects		Heterogeneity		Egger’s est
		SMD (95%CI)	P	I2(%)	P	a	P
Music therapy
Using fixed effect model	41	-0.50 (-0.58, -0.43)	<0.001	83	<0.001	-2.82(-4.71, -0.93)	0.005
Using trim and fill analysis	41	-0.66 (-0.86, -0.46)	<0.001	-	<0.001	-	-
Excluding the paper without information regarding music therapy (Chirico et al., 2020; Koelsch et al., 2010; Toccafondi et al., 2017; Porter et al., 2017)	37	-0.66 (-0.88, -0.43)	<0.001	82.2	<0.001	-3.03(-5.26, -0.81)	0.009
Excluding the papers with high bias (Toccafondi et al., 2017 and Fancourt et al., 2019)	39	-0.69 (-0.91, -0.47)	<0.001	83.6	<0.001	-2.95(-5.04, -0.86)	0.007
Excluding the papers with small sample size (20< n<30)	35	-0.57 (-0.77, -0.38)	<0.001	81.3	<0.001	2.22(-4.53, 0.08)	0.058
Excluding the studies focused on the people with a severe mental disease (Choi et al., 2008; Cheung et al. 2019)	32	-0.64(-0.86, -0.42)	<0.001	82.1	<0.001	‘-2.54(-4.67, -0.40)	0.022
Excluding the papers using an infrequently used scale (Erkkilä et al., 2011; Chen et al., 2015; Cheung et al., 2019; Chirico et al., 2020; Park et al., 2015; Sigurdardóttir et al., 2019; Wu et al., 2019; Low et al., 2020)	34	-0.62 (-0.84, -0.39)	<0.001	83.2	<0.001	-2.63(-4.67, -0.60)	0.013
Music medicine
Using fixed effect model	16	-0.86(-0.98, -0.73)	<0.001	95.4	<0.001	-5.78(-11.65, 0.10)	0.053
Using trim and fill analysis	16	-1.33(-1.96, -0.70)	<0.001	-	<0.001	-	-
Excluding the papers with small sample size (20< n<30) [49]	15	-1.32(-1.98, -0.66)	<0.001	95.7	<0.001	-6.09(-12.53, 0.36)	0.062
Excluding the papers using an infrequently used scale (Chen et al., 2015)	14	-1.25(-1.92, -0.57)	<0.001	95.7	<0.001	-5.71(-12.38, 0.98)	0.98

Evaluation of publication bias

We assessed publication bias using Egger’s linear regression test and funnel plot, and the results are presented in Fig 7. For the main result, the observed asymmetry indicated that either the absence of papers with negative results or publication bias.

Fig 7

Funnel plot illustrating proneness to publication bias for the included studies.

A, evaluating the publication bias of music therapy; B, evaluating the publication bias of music medicine; BDI = Beck Depression Inventory; CDI = Children’s Depression Inventory; CDSS = depression scale for schizophrenia; CES-D = Center for Epidemiologic Studies Depression; CS = Cornell Scale; DMSRIA = Depression Mood Self-Report Inventory for Adolescence; EPDS = Edinburgh Postnatal Depression Scale; GDS-15 = Geriatric Depression Scale-15; GDS-30 = Geriatric Depression Scale-30; HADS = Hospital Anxiety and Depression Scale; HRSD (HAMD) = Hamilton Rating Scale for Depression; MADRS = Montgomery-sberg Depression Rating Scale; PROMIS = Patient Reported Outcomes Measurement Information System; SDS = Self-Rating Depression Scale; State-Trait Depression Questionnaire = ST/DEP; SV-POMS = short version of Profile of Mood Stat.

Discussion

Our present meta-analysis exhibited a different effect of music therapy and music medicine on reducing depression. Different music therapy methods also exhibited a different effect, and the recreative music therapy and guided imagery and music yielded a superior effect on reducing depression compared with other music therapy methods. Furthermore, music therapy and music medicine both exhibited a stronger effects of short and medium length compared with long intervention periods. The strength of this meta-analysis was the stable and high-quality result. Firstly, the sensitivity analyses performed in this meta-analysis yielded similar results, which indicated that the primary results were robust. Secondly, considering the insufficient statistical power of small sample size, we excluded studies with a very small sample size (n<20).

Some prior reviews have evaluated the effects of music therapy for reducing depression. These reviews found a significant effectiveness of music therapy on reducing depression among older adults with depressive symptoms, people with dementia, puerpera, and people with cancers [4, 5, 73–76]. However, these reviews did not differentiate music therapy from music medicine. Another paper reviewed the effectiveness of music interventions in treating depression. The authors included 26 studies and found a signifiant reduction in depression in the music intervention group compared with the control group. The authors made a clear distinction on the definition of music therapy and music medicine; however, they did not include all relevant data from the most recent trials and did not conduct a meta-analysis [77]. A recent meta-analysis compared the effects of music therapy and music medicine for reducing depression in people with cancer with seven RCTs; the authors found a moderately strong, positive impact of music intervention on depression, but found no difference between music therapy and music medicine [78]. However, our present meta-analysis exhibited a different effect of music therapy and music medicine on reducing depression, and the music medicine yielded a superior effect on reducing depression compared with music therapy. The different effect of music therapy and music medicine might be explained by the different participators, and nine studies used music therapy to reduce the depression among people with severe mental disease /psychiatric disorder, while no study used music medicine. Furthermore, the studies evaluating music therapy used more clinical diagnostic scale for depressive symptoms.

A meta-analysis by Li et al. [74] suggested that medium-term music therapy (6–12 weeks) was significantly associated with improved depression in people with dementia, but not short-term music therapy (3 or 4 weeks). On the contrary, our present meta-analysis found a stronger effect of short-term (1–4 weeks) and medium-term (5–12 weeks) music therapy on reducing depression compared with long-term (≥13 weeks) music therapy. Consistent with the prior meta-analysis by Li et al., no significant effect on depression was observed for the follow-up of one or three months after music therapy was completed in our present meta-analysis. Only five studies analyzed the therapeutic effect for the follow-up periods after music therapy intervention therapy was completed, and the rather limited sample size may have resulted in this insignificant difference. Therefore, whether the therapeutic effect was maintained in reducing depression when music therapy was discontinued should be explored in further studies. In our present meta-analysis, meta-regression results demonstrated that no variables (including period, frequency, method, populations, and so on) were significantly associated with the effect of music therapy. Because meta-regression does not provide sufficient statistical power to detect small associations, the non-significant results do not completely exclude the potential effects of the analyzed variables. Therefore, meta-regression results should be interpreted with caution.

Our meta-analysis has limitations. First, the included studies rarely used masked methodology due to the nature of music therapy, therefore the performance bias and the detection bias was common in music intervention study. Second, a total of 13 different scales were used to evaluate the depression level of the participators, which may account for the high heterogeneity among the trials. Third, more than half of those included studies had small sample sizes (<50), therefore the result should be explicated with caution.

Conclusion

Our present meta-analysis of 55 RCTs revealed a different effect of music therapy and music medicine, and different music therapy methods also exhibited a different effect. The results of subgroup analyses revealed that the characters of music therapy were associated with the therapeutic effect, for example specific music therapy methods, short and medium-term therapy, and therapy with more time per session may yield stronger therapeutic effect. Therefore, our present meta-analysis could provide suggestion for clinicians and policymakers to design therapeutic schedule of appropriate lengths to reduce depression.

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5 Aug 2020

PONE-D-20-17706

Effects of music therapy on depression: a meta-analysis of randomized controlled trials

PLOS ONE

Dear Dr. Ye,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

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Additional Editor Comments:

Dear Author,

Thank you for your valuable submission. I think it would be appropriate to emphasize the main problem first. Various musical interventions are used in medical settings to improve the patient's well-being, and of course, there are many publications on this subject. However, it is important to properly differentiate between these interventions for some important reasons I have pointed out below.

The music therapy definition you made, as "Music therapy was defined as music therapy provided by a qualified music teacher, psychological therapist, or nurse" is not universally accepted specific definition for music therapy. Moreover, the specific methods used in receptive music therapy include music-assisted relaxation, music and imagery, and Guided Imagery and Music (Bonny Method). Each of these may have different levels of effects on depression. It is not clear that which receptive music therapy studies in your review have used which of these methods. So, the majority of studies that you accepted as the receptive music therapy seems to be music medicine studies indeed. Similar critiques may also be apply to some of the studies you describe as active music therapy. Today, it is widely accepted that these music-based interventions should be divided into two major categories, namely music therapy (MT) and music medicine (MM). MM mainly based on patients' pre-recorded or rarely listening to live music and the direct effects of the music they listen to. In other words, MM aims to use music like medicines. It often managed by a medical professional other than a music therapist, and not needed a therapeutic relationship with the patients. Conversely, music therapy is the clinical and evidence-based use of music interventions to accomplish individualized goals within a therapeutic relationship by a credentialed music therapist who has completed an approved music therapy program. So, music therapy is a relational, interaction based form of therapy within a therapeutic relationship between the therapist and the client, and includes the triad of the music, the client and the music therapist. Since music therapy interventions is an evidence-based procedure using special music therapy methods of interventions and a more pragmatic approach than other music-based interventions, their effect levels and results are also different.

In the context of the above mentioned explanations, it is clear that to evaluate the effects of music therapy and other music based intervention studies together on depression can be misleading. The subjects I have mentioned so far have never been addressed in the introduction and discussion sections of your manuscript. I think that will be perceived as a major deficiency at least by the readers who are closer to the subject. In this sense, I think that an attentive revision considering the following views will be valuable and needed:

- The universally accepted definitions of music therapy (including active and receptive music therapy) and music medicine should be taken into account.

- It should be clarified that how many studies in your review did included a certified music therapist.

- Analyses, results and discussion should be submitted to the readers in accordance with all this distinctions and definitions. (The way to this seems to be to compare the effects of music medicine and music therapy on depression in parallel with the possible differences of music interventions used, and to discuss their possible implications on the results.)

- Another important point is that you did not mention nor discuss any of important reviews on same subject (for example please see: https://www.cochranelibrary.com/cdsr/doi/10.1002/14651858.CD004517.pub3/epdf/full or https://www.frontiersin.org/articles/10.3389/fpsyg.2017.01109/full or https://www.cochranelibrary.com/cdsr/doi/10.1002/14651858.CD006911.pub3/full)

I am aware that such a major revision will, in a sense, be a challenging way that may require a new analysis of your data. However, I believe you would appreciate that a study aimed at shedding light on potential music-based interventions in an important public health problem such as depression should not be misleading.

Thank you for your effort in advance.

Annotate:

Besides, according to the statistical reviewer who only reviewed the statistical approach used in this paper, there are two caveats:

1. The authors state that they excluded studies with fewer than 20 participants in one place in the paper (page 4), but fewer than 30 participants in another place in the paper (Table 4). This needs to be corrected for consistency.

2. The authors mention stronger effects of short and medium length vs. long music therapy periods in their results but there is no accompanying figure. I think it would be beneficial to show these findings in a figure (Forest plot).

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Research in Anhui Province (SK2017A0191), Research Project of Anhui Province Social Science

Innovation Development (2018XF155), Ministry of Education Humanities and Social Sciences

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Reviewers' comments:

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Comments to the Author

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Reviewer #1: Yes

Reviewer #2: Partly

Reviewer #3: Yes

**********

2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: No

Reviewer #3: Yes

**********

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Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

**********

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Reviewer #1: Yes

Reviewer #2: No

Reviewer #3: Yes

**********

5. Review Comments to the Author

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Reviewer #1: Thank you for conducting this research and submitting it for publication consideration.

I recognize that English may not be the primary language of the authors. There are a few instances where the language could be improved, but that is mostly a copy-editing issue. There is also a lot of passive voice in the paper. I recommend making the voice active. This will enhance the readability of the paper.

I have a few comments that I hope will improve the paper.

1. Not all countries have an established music therapy profession. I recognize that this creates challenges for the authors! I'm wondering if the authors might consider including this as a factor in the analysis? For example, if a nurse provides "music therapy" in a country that does not have music therapy as a profession, is the effect equivalent as when a qualified music therapist in a country that has music therapy as a profession provides it? This might provide some incentive for occupational regulation and establishing professional music therapy associations.

2. please fix the "short title" (oxygen)

3. Music therapy with fewer minutes might yield superior effects. This may be misleading. Is there a minimum number of minutes? How many minutes might be optimal for therapeutic outcome? I believe it does make sense that longer sessions may result in less impact - quantity/duration does not always result in enhanced outcome.

4. I believe a stronger case needs to be made for the study. There are existing meta-analyses of MT for depression (Aalbers et al., 2017 Cochrane Review). What makes the current study unique and different? What are the gaps in the literature that warrant this study? Have there been a lot of recent additions to the literature that warrant a new meta-analysis?

5. A stronger discussion of the limitation of this study. Many studies did not evaluate a group with major depression/major depressive disorder (music therapy for chronic pain is important, but the variance of the populations under study does constitute a limitation). So, this study is not exclusive to adults with a major mental health condition. Might effects be different for people who are depressed versus people who are not depressed?

6. Instead of "blinding/blinded" please use "masking/masked."

7. Is there a citation that supports your classification of active versus receptive? (I would think Bruscia would be a good place to start with that...)

8. One item that I am not seeing is group therapy versus individual therapy. Did the authors screen for that? If so, is there an optimal group size? Are effects stronger when in a group format versus an individual format? This would have serious implications for clinical practice.

9. What about inpatient settings (such as a secure [locked] unit at a mental health facility) versus outpatient settings?

10. One item that I believe is missing is the dose. Not necessarily the duration (number of minutes) of each session, but the total number of sessions a participant has received. Gold has done some work in this area. Is there is a certain number of sessions that are needed to reach a therapeutic outcome? The number of sessions/week is good, but the number of total sessions is important.

11. Table 1 has the mean age. I recommend including the SD as well.

Thank you for taking the time to consider these suggestions. While receiving critical feedback can be difficult, please understand that my intentions are to improve the paper and ensure it has maximum impact. This is an important addition to the literature and I am grateful to the authors for their scholarship. I wish you the best!

Reviewer #2: This article addresses an important topic that is of interest to music therapists, psychiatrists and teachers and metal health practitioners. The statistics look promising. However, the major concern is that the definition of music therapy is theoretically and practically incorrect and misleading:

"7 Music therapy was defined as music therapy provided by a qualified music teacher, psychological

8 therapist, or nurse. " The study is missing several research studies that I am aware of and this makes its content suspicious. Also missing is a more depth-ful analysis of what active and passive music therapy is, and if it is indeed performed by those in other professions who have no training in 'musuc therapy;'-than the contents and findings are misleading and irrelevant.

Reviewer #3: I only reviewed the statistical approach used in this paper, which appeared appropriate for the research question under study. There are two caveats:

1. The authors state that they excluded studies with fewer than 20 participants in one place in the paper (page 4), but fewer than 30 participants in another place in the paper (Table 4). This needs to be corrected for consistency.

2. The authors mention stronger effects of short and medium length vs. long music therapy periods in their results but there is no accompanying figure. I think it would be beneficial to show these findings in a figure (Forest plot).

**********

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Reviewer #1: No

Reviewer #2: No

Reviewer #3: No

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29 Sep 2020

Response to Reviewers

Dear Editors and Reviewers:

Thank you for your letter and for the reviewers’ comments concerning our manuscript entitled " Effects of music therapy on depression: a meta-analysis of randomized controlled trials (PONE-D-20-17706)".

Those comments are all valuable and very helpful for revising and improving our paper, as well as the important guiding significance to our researches. We have studied comments carefully and have made revision which we hope meet with approval. All the revised portions were marked in red font in the new document. The main corrections in the paper and the responds to the reviewer’s comments are as flowing:

Additional Editor Comments:

Dear Author,

Thank you for your valuable submission. I think it would be appropriate to emphasize the main problem first. Various musical interventions are used in medical settings to improve the patient's well-being, and of course, there are many publications on this subject. However, it is important to properly differentiate between these interventions for some important reasons I have pointed out below.

The music therapy definition you made, as "Music therapy was defined as music therapy provided by a qualified music teacher, psychological therapist, or nurse" is not universally accepted specific definition for music therapy. Moreover, the specific methods used in receptive music therapy include music-assisted relaxation, music and imagery, and Guided Imagery and Music (Bonny Method). Each of these may have different levels of effects on depression. It is not clear that which receptive music therapy studies in your review have used which of these methods. So, the majority of studies that you accepted as the receptive music therapy seems to be music medicine studies indeed. Similar critiques may also be apply to some of the studies you describe as active music therapy. Today, it is widely accepted that these music-based interventions should be divided into two major categories, namely music therapy (MT) and music medicine (MM). MM mainly based on patients' pre-recorded or rarely listening to live music and the direct effects of the music they listen to. In other words, MM aims to use music like medicines. It often managed by a medical professional other than a music therapist, and not needed a therapeutic relationship with the patients. Conversely, music therapy is the clinical and evidence-based use of music interventions to accomplish individualized goals within a therapeutic relationship by a credentialed music therapist who has completed an approved music therapy program. So, music therapy is a relational, interaction based form of therapy within a therapeutic relationship between the therapist and the client, and includes the triad of the music, the client and the music therapist. Since music therapy interventions is an evidence-based procedure using special music therapy methods of interventions and a more pragmatic approach than other music-based interventions, their effect levels and results are also different.

In the context of the above mentioned explanations, it is clear that to evaluate the effects of music therapy and other music based intervention studies together on depression can be misleading. The subjects I have mentioned so far have never been addressed in the introduction and discussion sections of your manuscript. I think that will be perceived as a major deficiency at least by the readers who are closer to the subject. In this sense, I think that an attentive revision considering the following views will be valuable and needed:

Response：We have studied comments carefully and revised the manuscript extensively according to the reviewer’s comments.

Firstly, We have amended the music therapy definition mainly based on the World Federation of Music Therapy (WFMT) and The American Music Therapy Association (AMTA), WFMT defines music therapy as “the professional use of music and its elements as an intervention inmedical, educational, and everyday environments with individuals, groups, families, or communities who seek to optimize their quality of life and improve their physical, social,communicative, emotional, intellectual, and spiritual health and wellbeing”. AMTA defines music therapy as “Music Therapy is the clinical and evidence-based use of music interventions to accomplish individualized goals within a therapeutic relationship by a credentialed professional who has completed an approved music therapy program”. [American Music Therapy Association (2020). Definition and Quotes about Music Therapy. Available online at: https://www.musictherapy.org/about/quotes/ (Accessed Sep 13, 2020).][van der Steen, J. T., et al. (2017). "Music-based therapeutic interventions for people with dementia." Cochrane Database Syst Rev 5: CD003477.]

Secondly, we have re-studed all included papers carefully and added the specific intervention methods of each paper in table 1 (Table 1. Characteristics of clinical trials included in this meta-analysis). Two main types of music therapy were distinguished in our present study - receptive (or passive) and active music therapy. The specific methods used in receptive music therapy in our included papers including music-assisted relaxation, music and imagery, and guided imagery and music (Bonny Method), while the specific methods used in active music therapy included recreative music therapy, improvisational music therapy, song writing, and so on.

Thirdly, we have added some contents regarding the distinction between music therapy and music medicine in introduction and discussion sections of our manuscript.

The following contents are added in introduction section, “Today, it is widely accepted that the music-based interventions should be divided into two major categories, namely music therapy and music medicine. According to the American Music Therapy Association (AMTA), “music therapy is the clinical and evidence-based use of music interventions to accomplish individualized goals within a therapeutic relationship by a credentialed professional who has completed an approved music therapy program”. Therefore, music therapy is an established health profession in which music is used within a therapeutic relationship to address physical, emotional, cognitive, and social needs of individualst, and includes the triad of the music, the client and the qualified music therapist. [American Music Therapy Association (2020). Definition and Quotes about Music Therapy. Available online at: https://www.musictherapy.org/about/quotes/ (Accessed Sep 13, 2020).] While, music medicine is defined as mainly listening to prerecorded music provided by medical personnel or rarely listening to live music. In other words, music medicine aims to use music like medicines. It often managed by a medical professional other than a music therapist, and not needed a therapeutic relationship with the patients. Therefore, the essential difference of music therapy and music medicine is whether a therapeutic relationship is developed between a trained music therapist and the client.

[Bradt, J., et al. (2015). "The impact of music therapy versus music medicine on psychological outcomes and pain in cancer patients: a mixed methods study." Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer 23(5): 1261-1271.

[Yinger, O. S. and L. Gooding (2014). "Music therapy and music medicine for children and adolescents." Child and adolescent psychiatric clinics of North America 23(3): 535-553.]

【Tony Wigram．Inge Nyggard Pedersen＆Lars Ole Bonde，A Compmhensire Guide to Music Therapy．London and Philadelphia：Jessica Kingsley Publishen．2002：143．】

In the context of the clear distinction between these two major cagerories, it is clear that to evaluate the effects of music therapy and other music based intervention studies together on depression can be misleading. While, the distinction was not always clear in most of prior papers, and we found that no meta-analysis comparing the effects of music therapy and music medicine was conducted. Just a few studies made a comparison of music-based interventions on psychological outcomes between music therapy and music medicine. We aimed to (1) compare the effect between music therapy and music medicine on depression; (2) compare the effect between different specific methods used inmusic therapy on depression; (3) compare the effect of music-based interventions on depression among different population.

[Bradt, J., et al. (2015). "The impact of music therapy versus music medicine on psychological outcomes and pain in cancer patients: a mixed methods study." Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer 23(5): 1261-1271.[Yinger, O. S. and L. Gooding (2014). "Music therapy and music medicine for children and adolescents." Child and adolescent psychiatric clinics of North America 23(3): 535-553.]

The last, we have made a new analysis of our data. 1) including three new papers and re-analying of our data, 2) adding the comparison of music therapy and music medicine, 3) adding the comparison of impatient setting and outpatients setting, 4) adding the comparison of depressed people and not depressed people, 5）adding the comparison of countries have having music therapy profession and not, 6) adding the comparison of group therapy and individual therapy, 7) added the comparison of different intervention dose, and so on.

- The universally accepted definitions of music therapy (including active and receptive music therapy) and music medicine should be taken into account.

Response: (1)We have amended the of definitions of music therapy. The revised difinitons of music therapy was “Music Therapy is the clinical and evidence-based use of music interventions to accomplish individualized goals within a therapeutic relationship by a credentialed professional who has completed an approved music therapy program”. [American Music Therapy Association (2020). Definition and Quotes about Music Therapy. Available online at: https://www.musictherapy.org/about/quotes/ (Accessed Sep 13, 2020).]

We have added some contents on the distinction between music therapy (MT) and music medicine (MM) in introduction and discussion sections of our manuscript.

We have added the analysis of the comparion of music therapy (MT) and music medicine (MM) in Methord and Results sections

- It should be clarified that how many studies in your review did included a certified music therapist.

Response: we have re-studed all included papers carefully and added a new varible (Intervenor or therapist) into table 1, and the corresponding description was addded in the results section. Of 55 studies, 32 used a certified music therapist, 15 not used a certified music therapist (for example researcher, nurse), and 10 not reported relevent information.

- Analyses, results and discussion should be submitted to the readers in accordance with all this distinctions and definitions. (The way to this seems to be to compare the effects of music medicine and music therapy on depression in parallel with the possible differences of music interventions used, and to discuss their possible implications on the results.)

Response: We have divided music-based interventions into two major categories, namely music therapy and music medicine according to the difinition. With respect to specific methods used in music therapy, we also have divided music therapy into receptive (or passive) and active music therapy. The specific methods used in receptive music therapy in our included papers including music-assisted relaxation, music and imagery, and guided imagery and music (Bonny Method), and the specific methods used in active music therapy included recreative music therapy and improvisational music therapy.

We have added some sub-group analyses by different music intervention categories, different music therapy categories, and specific music therapy methords.

The the above mentioned content have been added to Intruduction Analyses, results and discussion section.

- Another important point is that you did not mention nor discuss any of important reviews on same subject (for example please see: https://www.cochranelibrary.com/cdsr/doi/10.1002/14651858.CD004517.pub3/epdf/full or https://www.frontiersin.org/articles/10.3389/fpsyg.2017.01109/full or https://www.cochranelibrary.com/cdsr/doi/10.1002/14651858.CD006911.pub3/full)

Response: we are very sorry for not mentioning these important reviews. We have studied these reviews carefully and discussed these reviews in Discussion sections.

Some prior reviews have evaluated the effects of music therapy for reducing depression. Aalbers and colleagues included nine studies in their review; they concluded that music therapy provides short-term benefificial effects for people with depression, and suggested that high-quality trials with large sample size were needed. However, this review was limited to studies of individuals with a diagnosis of depression, and did not differentiate music therapy from music medicine. Another paper reviewed the effectiveness of music interventions in treating depression. The authors included 26 studies and found a signifiant reduction in depression in the music intervention group compared with the controp group. The authors made a clear distincition on the definition of music therapy and music medicine; however, they did not include all relevant data from the most recent trials and did not conduct a meta-analysis. A recent meta-analysis compared the effects of music therapy and music medicine for reducing depression in people with cancer with seven RCTs; the authors found a moderately strong, positive impact of music intervention on depression , but found no difference between music therapy and music medicine.

【Aalbers, S., et al. (2017). "Music therapy for depression." Cochrane Database Syst Rev 11: CD004517.】

【Leubner, D. and T. Hinterberger (2017). "Reviewing the Effectiveness of Music Interventions in Treating Depression." Front Psychol 8: 1109.】

【Bradt, J., et al. (2016). "Music interventions for improving psychological and physical outcomes in cancer patients." Cochrane Database Syst Rev(8): CD006911.】

To date, many new trials focued on music therapy and depression in differnt poupulation (such as people with cancer, people with dementia, people with chronic disease, and so on ) have been performed, but they have not yet been systematically reviewed.

I am aware that such a major revision will, in a sense, be a challenging way that may require a new analysis of your data. However, I believe you would appreciate that a study aimed at shedding light on potential music-based interventions in an important public health problem such as depression should not be misleading.

Thank you for your effort in advance.

Response: Those comments are all valuable and very helpful for revising and improving our paper, as well as the important guiding significance to our researches. We have studied comments carefully and have made revision according to the comments.

Annotate:

Besides, according to the statistical reviewer who only reviewed the statistical approach used in this paper, there are two caveats:

1. The authors state that they excluded studies with fewer than 20 participants in one place in the paper (page 4), but fewer than 30 participants in another place in the paper (Table 4). This needs to be corrected for consistency.

Response: We are sorry for making this mistake. In the Methord section, we defined exclusive criteria as studies with a very small sample size (n<20),while in table 4 we performed the sensitivity analyses by excluding the papers with smale sample size ( 20< n<30). We have amended the table 4.

2. The authors mention stronger effects of short and medium length vs. long music therapy periods in their results but there is no accompanying figure. I think it would be beneficial to show these findings in a figure (Forest plot).

Response: We have added these findings with a forest plot (figure 6) according to the comment.

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Response: We have adjusted these content according to the comment.

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Response: we are sorry for making this mistake, we have amended our list of authors on the manuscript accordingly.

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Response: We have checked the refer to Figure 5 and found that the refer to figure 5 was a mistake, and we have amended it.

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Response: we only have a Supporting Information files (PRISMA-2009-Checklist), and we have added the captions for this Supporting Information files accordingly. We also have updated in-text citations to match accordingly.

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Reviewer #2: Partly

Reviewer #3: Yes

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Reviewer #2: No

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Reviewer #1: Thank you for conducting this research and submitting it for publication consideration.

Response: Thinks very much for your comment.

I recognize that English may not be the primary language of the authors. There are a few instances where the language could be improved, but that is mostly a copy-editing issue. There is also a lot of passive voice in the paper. I recommend making the voice active. This will enhance the readability of the paper.

Response: Thinks very much for your comment. Our manuscript have been edited for proper English language, grammar, punctuation, spelling, and overall style by one qualified native English speaking editors.

I have a few comments that I hope will improve the paper.

1. Not all countries have an established music therapy profession. I recognize that this creates challenges for the authors! I'm wondering if the authors might consider including this as a factor in the analysis? For example, if a nurse provides "music therapy" in a country that does not have music therapy as a profession, is the effect equivalent as when a qualified music therapist in a country that has music therapy as a profession provides it? This might provide some incentive for occupational regulation and establishing professional music therapy associations.

Response: This suggestion is valuable and we have tried to judge if the countries in our inluded papers have an established music therapy profession by checking the author's work address, literature review, visiting the important website about music therapy, and consulting to some famous music therapist via emails. The following table showed that four countries may be not have a music therapy profession. We have added the comparison of the country having music therapy profession and not.

https://erikdalton.com/find-a-certified-therapist/

https://www.musictherapy.org/about/listserv/

Table 1. The information on the music therapy profession in the inluded papers

Country Country having music therapy profession

Korea Korean Music Therapy Association

South Korea Korean Music Therapy Association

UK British Association for Music Therapy

Australia Australian Music Therapy Association

Canada Canadian Association of Music Therapists

China Chinese Professional Music Therapist Association

Taiwan China Chinese Professional Music Therapist Association

Denmark Dansk forbund for musikterapie

Finland Finnish Society for Music Therapy

Hong Kong China Hong Kong Music Therapy and Counseling Association

Serbia Music Therapists of Serbia organize workshops

Switzerland Swiss Association of Music Therapy

USA The American Music Therapy Association

Singapore The Association for Music Therapy (Singapore)

Brazil Uniao Braileira Das Associacoes De Musicoterapia

France YES

Germany YES

Italy YES

Northern Ireland YES

Spain YES

Spanish YES

Turkey YES

Greece No

Hungary No

Iran No

Venezuela No

2.please fix the "short title" (oxygen)

Response: We’re sorry for making this mistake, and we have corrected this mistake.

Music therapy with fewer minutes might yield superior effects. This may be misleading. Is there a minimum number of minutes? How many minutes might be optimal for therapeutic outcome? I believe it does make sense that longer sessions may result in less impact - quantity/duration does not always result in enhanced outcome.

Response: In 33 included trials, intervention time each session was different, the mimimum time was 15 minutes in only one study (Burrai et al., 2019b), followed by 20 minuters in four studies (Chirico et al., 2020; Guétin et al., 2009; Hanser et al., 1994; Sigurdardóttir et al., 2019). In our subgroup analysis by time per session (minutes), we divided time per session into three groups, namely 15-40, 41-60, >60, and this presentation might be unclear.

In order to respond this comment, we have re-divided the time per session into four groups, namely 15-40, 41-60, 61-120, to explore the optimal minuter per session for therapeutic outcome.

I believe a stronger case needs to be made for the study. There are existing meta-analyses of MT for depression (Aalbers et al., 2017 Cochrane Review). What makes the current study unique and different? What are the gaps in the literature that warrant this study? Have there been a lot of recent additions to the literature that warrant a new meta-analysis?

Response: Some prior reviews have evaluated the effects of music therapy for reducing depression. Aalbers and colleagues (Aalbers et al., 2017）included nine studies in their review; they concluded that music therapy provides short-term benefificial effects for people with depression, and suggested that high-quality trials with large sample size were needed. However, this review was limited to studies of individuals with a diagnosis of depression, and did not differentiate music therapy from music medicine.

Another paper reviewed the effectiveness of music interventions in treating depression. The authors (Leubner D., 2017) included 26 studies and found a signifiant reduction in depression in the music intervention group compared with the controp group. The authors made a clear distincition on the definition of music therapy and music medicine; however, they did not include all relevant data from the most recent trials and did not conduct a meta-analysis. A recent meta-analysis (Bradt et al., 2016) compared the effects of music therapy and music medicine for reducing depression with seven RCTs; the authors found a moderately strong, positive impact of music intervention on depression , but found no difference between music therapy and music medicine. However, this review was limited to studies of individuals with a diagnosis of cancer.

【Aalbers, S., et al. (2017). "Music therapy for depression." Cochrane Database Syst Rev 11: CD004517.】

【Leubner, D. and T. Hinterberger (2017). "Reviewing the Effectiveness of Music Interventions in Treating Depression." Front Psychol 8: 1109.】

【Bradt, J., et al. (2016). "Music interventions for improving psychological and physical outcomes in cancer patients." Cochrane Database Syst Rev(8): CD006911.】

Figure 1 presents the number of published paper ( search from Pubmed) focued on music therapy and depression from 1983 to 2020, the published paper was in the rapidly growing stage during the past five years. While, the above mentioned reviews all included papers published before 2017. To date, many new trials focued on music therapy and depression in differnt poupulation (such as people with cancer, people with dementia, people with chronic disease, and so on ) have been performed, but they have not yet been systematically reviewed.

While, no meta-analysis compared the the difference of music therapy on depression in differnt poupulation (such as people with depression, people with dementia, people with chronic disease, health people, and so on ) have been performed.

Figure 1 The pubished papers from 1983 to 2020 focused on music therapy and depression (searched from Pubmed)

In our persent meta-analysis, we aimed to (1) compare the effect between music therapy and music medicine on depression; (2) compare the effect between different specific methods used inmusic therapy on depression; (3) compare the effect of music-based interventions on depression among different population.

We have added the above content to Intruduction and Dissussion sections.

5.A stronger discussion of the limitation of this study. Many studies did not evaluate a group with major depression/major depressive disorder (music therapy for chronic pain is important, but the variance of the populations under study does constitute a limitation). So, this study is not exclusive to adults with a major mental health condition. Might effects be different for people who are depressed versus people who are not depressed?

Response: This is a very important comment. According to this comment, we have made some revision.

Firstly, we have added a sensitivity analysis by excluding the studes focused on the people with a major mental health condition.

Secondly, we have re-grouped the populations into three groups, namely mental health, severe mental disease /psychiatric disorder, and depression and we have added the subgroup analysis (table 2 in revised manuscript)..

Thirdly, we have added the analysis of the difference between people who are depressed versus people who are not depressed accordingly (table 2 in revised manuscript).

6.Instead of "blinding/blinded" please use "masking/masked."

Response: We have replaced "blinding/blinded" with "masking/masked" according to this comment.

7. Is there a citation that supports your classification of active versus receptive? (I would think Bruscia would be a good place to start with that...)

Response: In active methods (improvisational, re-creative, compositional), participants are ‘making music’ , and in receptive music therapy (music-assisted relaxation, music and imagery, guided imagery and music, lyrics analysis ), participants are ‘receiving’ (e.g. listening to) music (Bruscia 2014; Wheeler 2015).

We have amended the difinition and added the citation to the Result section according to this commment.

[Bruscia KE. Defining Music Therapy. 3rd Edition.University Park, Illinois, USA: Barcelona Publishers, 2014.]

[Wheeler BL. Music Therapy Handbook. New York, New York, USA: Guilford Publications, 2015.]

8. One item that I am not seeing is group therapy versus individual therapy. Did the authors screen for that? If so, is there an optimal group size? Are effects stronger when in a group format versus an individual format? This would have serious implications for clinical practice.

Response: Of the 55 studies, 38 used group therapy, 17 used individual therapy, and 2 not reported. We have added the comparison of group therapy versus individual therapy according to this comment (table 2 in revised manuscript).

9. What about inpatient settings (such as a secure [locked] unit at a mental health facility) versus outpatient settings?

Response: Of 55 studies, a total of 25 studies were conducted in impatient setting,28 studies were in outpatients setting setting, and 2 studies not repoted the setting. We have added the subgroup analysis by inpatient settings (secure [locked] unit at a mental health facility versus outpatient settings) according to this comment (table 2 in revised manuscript).

10. One item that I believe is missing is the dose. Not necessarily the duration (number of minutes) of each session, but the total number of sessions a participant has received. Gold has done some work in this area. Is there is a certain number of sessions that are needed to reach a therapeutic outcome? The number of sessions/week is good, but the number of total sessions is important.

Response: We have added the subgroup analysis by total sessions a participant has received according to this comment.

11. Table 1 has the mean age. I recommend including the SD as well.

Response: We have added the SD in table 1

Thank you for taking the time to consider these suggestions. While receiving critical feedback can be difficult, please understand that my intentions are to improve the paper and ensure it has maximum impact. This is an important addition to the literature and I am grateful to the authors for their scholarship. I wish you the best!

Response: Thanks very much for your important comments, these comments are all valuable and very helpful for revising and improving our paper, as well as the important guiding significance to our researches.

Reviewer #2: This article addresses an important topic that is of interest to music therapists, psychiatrists and teachers and metal health practitioners. The statistics look promising. However, the major concern is that the definition of music therapy is theoretically and practically incorrect and misleading:

"7 Music therapy was defined as music therapy provided by a qualified music teacher, psychological

8 therapist, or nurse. " The study is missing several research studies that I am aware of and this makes its content suspicious. Also missing is a more depth-ful analysis of what active and passive music therapy is, and if it is indeed performed by those in other professions who have no training in 'musuc therapy;'-than the contents and findings are misleading and irrelevant.

Response: (1) We have amendded the difinition of music therapy. According to the American Music Therapy Association (AMTA), “music therapy is the clinical and evidence-based use of music interventions to accomplish individualized goals within a therapeutic relationship by a credentialed professional who has completed an approved music therapy program”.. [American Music Therapy Association (2020). Definition and Quotes about Music Therapy. Available online at: https://www.musictherapy.org/about/quotes/ (Accessed Sep 13, 2020).]

(2)We are very sorry for missing several research studies in our present meta-analysis. According to this comment, we have performed more extensive electronic search using the following terms: depression or mood disorders or affective disorders and music. We also performed manual search for the reference of all relevent reviews. In order to ensure the study quality of included papers, we excluded the studies with a very small sample size (n<20), we also excluded the non-english papers due to our language barrier. We included 23 new papers and deleted 1 old paper, in the last a total of 55 paper were included in our present analysis. The following are the new included papers and some excluded papers:

New-included papers

1)Albornoz Y. The effects of group improvisational music therapy on depression in adolescents and adults with substance abuse: a randomised controlled trial. Nordic Journal of Music Therapy 2011;20(3):208–24.

2)Hendricks CB, Robinson B, Bradley B, Davis K. Using music techniques to treat adolescent depression. Journal of Humanistic Counseling, Education and Development 1999; 38:39–46. （unavaliable）

3)Hendricks CB. A study of the use of music therapy techniques in a group for the treatment of adolescent depression. Dissertation Abstracts International 2001;62(2-A):472.

4)Radulovic R. The using of music therapy in treatment of depressive disorders. Summary of Master Thesis. Belgrade: Faculty of Medicine University of Belgrade, 1996.

5)Zerhusen JD, Boyle K, Wilson W. Out of the darkness: group cognitive therapy for depressed elderly. Journal of Military Nursing Research 1995;1:28–32. PUBMED: 1941727]

6)Chen SC, Yeh ML, Chang HJ, Lin MF. Music, heart rate variability, and symptom clusters: a comparative study. Support Care Cancer. 2020;28(1):351-360. doi:10.1007/s00520-019-04817-x

7)Chang, M. Y., Chen, C. H., and Huang, K. F. (2008). Effects of music therapy on psychological health of women during pregnancy. J. Clin. Nurs. 17, 2580–2587. doi: 10.1111/j.1365-2702.2007.02064.x

8)Chen XJ, Hannibal N, Gold C. Randomized Trial of Group Music Therapy With Chinese Prisoners: Impact on Anxiety, Depression, and Self-Esteem. Int J Offender Ther Comp Criminol. 2016;60(9):1064-1081. doi:10.1177/0306624X15572795

9)Esfandiari, N., and Mansouri, S. (2014). The effect of listening to light and heavy music on reducing the symptoms of depression among female students. Arts Psychother. 41, 211–213. doi: 0.1016/j.aip.2014.02.001

10)Fancourt, D., Perkins, R., Ascenso, S., Carvalho, L. A., Steptoe, A., and Williamon, A. (2016). Effects of group drumming interventions on anxiety, depression, social resilience and inflammatory immune response among mental health service users. PLoS ONE 11:e0151136. doi: 10.1371/journal.pone.0151136

11)Giovagnoli AR, Manfredi V, Parente A, Schifano L, Oliveri S, Avanzini G. Cognitive training in Alzheimer's disease: a controlled randomized study. Neurol Sci. 2017;38(8):1485-1493. doi:10.1007/s10072-017-3003-9

12)Harmat, L., Takács, J., and Bodizs, R. (2008). Music improves sleep quality in students. J. Adv. Nurs. 62, 327–335. doi: 10.1111/j.1365-2648.2008.04602.x

13)Liao J, Wu Y, Zhao Y, et al. Progressive Muscle Relaxation Combined with Chinese Medicine Five-Element Music on Depression for Cancer Patients: A Randomized Controlled Trial. Chin J Integr Med. 2018;24(5):343-347. doi:10.1007/s11655-017-2956-0

14)Lu, S. F., Lo, C. H. K., Sung, H. C., Hsieh, T. C., Yu, S. C., and Chang, S. C. (2013). Effects of group music intervention on psychiatric symptoms and depression in patient with schizophrenia. Complement. Ther. Med. 21, 682–688. doi: 10.1016/j.ctim.2013.09.002

15)Mahendran R, Gandhi M, Moorakonda RB, et al. Art therapy is associated with sustained improvement in cognitive function in the elderly with mild neurocognitive disorder: findings from a pilot randomized controlled trial for art therapy and music reminiscence activity versus usual care. Trials. 2018;19(1):615. Published 2018 Nov 9. doi:10.1186/s13063-018-2988-6

16)Nwebube C, Glover V, Stewart L. Prenatal listening to songs composed for pregnancy and symptoms of anxiety and depression: a pilot study. BMC Complement Altern Med. 2017;17(1):256. Published 2017 May 8. doi:10.1186/s12906-017-1759-3

17)Porter S, McConnell T, McLaughlin K, et al. Music therapy for children and adolescents with behavioural and emotional problems: a randomised controlled trial. J Child Psychol Psychiatry. 2017;58(5):586-594. doi:10.1111/jcpp.12656

18)Raglio A, Giovanazzi E, Pain D, et al. Active music therapy approach in amyotrophic lateral sclerosis: a randomized-controlled trial. Int J Rehabil Res. 2016;39(4):365-367. doi:10.1097/MRR.0000000000000187

19)Torres E, Pedersen IN, Pérez-Fernández JI. Randomized Trial of a Group Music and Imagery Method (GrpMI) for Women with Fibromyalgia. J Music Ther. 2018;55(2):186-220. doi:10.1093/jmt/thy005

20)Verrusio, W., Andreozzi, P., Marigliano, B., Renzi, A., Gianturco, V., Pecci, M. T., et al. (2014). Exercise training and music therapy in elderly with depressive syndrome: a pilot study. Complement. Ther. Med. 22, 614–620. doi: 10.1016/j.ctim.2014.05.012

21)Wang, J. , Wang, H. and Zhang, D. (2011) Impact of group music therapy on the depression mood of college students. Health, 3, 151-155

22)Yap AF, Kwan YH, Tan CS, Ibrahim S, Ang SB. Rhythm-centred music making in community living elderly: a randomized pilot study. BMC Complement Altern Med. 2017 Jun 14;17(1):311. doi: 10.1186/s12906-017-1825-x. PMID: 28615007; PMCID: PMC5470187.

23)Koelsch, S., Offermanns, K., and Franzke, P. (2010). Music in the treatment of affective disorders: an exploratory investigation of a new method for music-therapeutic research. Music Percept. Interdisc. J. 27, 307–316. doi: 10.1525/mp.2010.27.4.307

Excluded papers：

24)Bally, K., Campbell, D., Chesnick, K., and Tranmer, J. E. (2003). Effects of patient controlled music therapy during coronary angiography on procedural pain and anxiety distress syndrome. Crit. Care Nurse 23, 50–58. （not provide useable data）

25)Atiwannapat P, Thaipisuttikul P, Poopityastaporn P, Katekaew W. Active versus receptive group music therapy for major depressive disorder - a pilot study. Complementary Therapies in Medicine 2016;26:141–5. (sample size<20)

26)Garrido S, Stevens CJ, Chang E, Dunne L, Perz J. Music and Dementia: Individual Differences in Response to Personalized Playlists. J Alzheimers Dis. 2018;64(3):933-941. doi:10.3233/JAD-180084 （not randomised or quasi-randomised controlled trials）

27)Sánchez A, Maseda A, Marante-Moar MP, de Labra C, Lorenzo-López L, Millán-Calenti JC. Comparing the Effects of Multisensory Stimulation and Individualized Music Sessions on Elderly People with Severe Dementia: A Randomized Controlled Trial. J Alzheimers Dis. 2016;52(1):303-315. doi:10.3233/JAD-151150 （the control group also received music intervention）

28)Mondanaro JF, Homel P, Lonner B, Shepp J, Lichtensztein M, Loewy JV. Music Therapy Increases Comfort and Reduces Pain in Patients Recovering From Spine Surgery. Am J Orthop (Belle Mead NJ). 2017;46(1):E13-E22. (No full text available)

29)Castillo-Pérez, S., Gómez-Pérez, V., Velasco, M. C., Pérez-Campos, E., and Mayoral, M. A. (2010). Effects of music therapy on depression compared with psychotherapy. Arts Psychother. 37, 387–390. doi: 0.1016/j.aip.2010.07.001 （not provide useable data)

30)Alcântara-Silva TR, de Freitas-Junior R, Freitas NMA, et al. Music Therapy Reduces Radiotherapy-Induced Fatigue in Patients With Breast or Gynecological Cancer: A Randomized Trial. Integr Cancer Ther. 2018;17(3):628-635. doi:10.1177/1534735418757349（not provide useable data)

31)Cheung CWC, Yee AWW, Chan PS, et al. The impact of music therapy on pain and stress reduction during oocyte retrieval - a randomized controlled trial. Reprod Biomed Online. 2018;37(2):145-152. doi:10.1016/j.rbmo.2018.04.049（not provide useable data)

32)Pezzin LE, Larson ER, Lorber W, McGinley EL, Dillingham TR. Music-instruction intervention for treatment of post-traumatic stress disorder: a randomized pilot study. BMC Psychol. 2018;6(1):60. Published 2018 Dec 19. doi:10.1186/s40359-018-0274-8 (the control group also received music intervention)

33)Silverman, M. J. (2011). Effects of music therapy on change and depression on clients in detoxification. J. Addict. Nurs. 22, 185–192. doi: 10.3109/10884602.2011.616606 （the control group also received music intervention）

34)Särkämö T, Laitinen S, Numminen A, Kurki M, Johnson JK, Rantanen P. Clinical and Demographic Factors Associated with the Cognitive and Emotional Efficacy of Regular Musical Activities in Dementia. J Alzheimers Dis. 2016;49(3):767-81. doi: 10.3233/JAD-150453. PMID: 26519435.

35)Tuinmann G, Preissler P, Böhmer H, Suling A, Bokemeyer C. The effects of music therapy in patients with high-dose chemotherapy and stem cell support: a randomized pilot study. Psychooncology. 2017 Mar;26(3):377-384. doi: 10.1002/pon.4142. Epub 2016 May 5. PMID: 27146798.（not provide useable data)

36)Hsu, W. C., and Lai, H. L. (2004). Effects of music on major depression in psychiatric inpatients. Arch. Psychiat. Nurs. 18, 193–199. doi: 10.1016/j.apnu.2004.07.007（not provide useable data)

（3）We have added some new analyses of our data. 1) including three new papers and re-analying of our data, 2) adding the comparison of music therapy and music medicine (figure 3 in revised manuscript) , 3) adding some subgroup analyses by country having music therapy profession, intervention settings, therapy mode, specific music therapy methord, intervenor /therapist, and total intervention session (table 2 in revised manuscript) .

Reviewer #3: I only reviewed the statistical approach used in this paper, which appeared appropriate for the research question under study. There are two caveats:

1. The authors state that they excluded studies with fewer than 20 participants in one place in the paper (page 4), but fewer than 30 participants in another place in the paper (Table 4). This needs to be corrected for consistency.

Response: We are sorry for making this mistake. In the Methord section, we defined exclusive criteria as studies with a very small sample size (n<20),while in table4 we performed the sensitivity analyses by excluding the papers with smale sample size ( 20< n<30). We have amended the table 4.

2. The authors mention stronger effects of short and medium length vs. long music therapy periods in their results but there is no accompanying figure. I think it would be beneficial to show these findings in a figure (Forest plot).

Response: We have added these findings with a forest plot (figure 6 in revised manuscript) according to the comment.

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Reviewer #1: No

Reviewer #2: No

Reviewer #3: No

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Submitted filename: Response to Reviewers.docx

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5 Oct 2020

Effects of music therapy on depression: a meta-analysis of randomized controlled trials

PONE-D-20-17706R1

Dear Dr. Ye,

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Thank you for your satisfactory effort to correct the many important issues highlighted in my and our reviewers' comments, and to make necessary adjustments that meet our recommendations to improve the quality of your article.

Reviewers' comments:

30 Oct 2020

PONE-D-20-17706R1

Effects of music therapy on depression: a meta-analysis of randomized controlled trials

Dear Dr. Ye:

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