Journal of Affective Disorders 184 (2015) 1317

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Journal of Affective Disorders

journal homepage: www.elsevier.com/locate/jad

Research report

Music therapy as an adjunct to standard treatment for obsessive

compulsive disorder and co-morbid anxiety and depression: A randomized
clinical trial
Shahrzad Shirani Bidabadi a,n, Amirhooshang Mehryar b
a
b

Department of Psychology, Faculty of Psychology and Education, Islamic Azad University, Marvdasht Branch, Marvdasht, Iran
Department of Behavioural Science, Institute for Research on Management and Planning, Tehran, Iran

art ic l e i nf o

a b s t r a c t

Article history:
Received 13 December 2014
Received in revised form
2 April 2015
Accepted 2 April 2015
Available online 11 April 2015

Background: Previous studies have highlighted the potential therapeutic benets of music therapy as an
adjunct to standard care, in a variety of psychiatric ailments including mood and anxiety disorders.
However, the role of music in the treatment of obsessivecompulsive disorder (OCD) have not been
investigated to date.
Methods: In a single-center, parallel-group, randomized clinical trial (NCT02314195) 30 patients with
OCD were randomly assigned to standard treatment (pharmacotherapy and cognitive-behavior therapy)
plus 12 sessions of individual music therapy (n 15) or standard treatment only (n 15) for one month.
Maudsley ObsessiveCompulsive Inventory, Beck Anxiety Inventory, and Beck Depression InventoryShort Form were administered baseline and after one month.
Results: Thirty patients completed the study. Music therapy resulted in a greater decrease in total
obsessive score (post-intervention score: music therapy standard treatment: 12.47 1.9 vs standard
treatment only: 15.1 7 1.7, po 0.001, effect size 56.7%). For subtypes, signicant between-group
differences were identied for checking (p 0.004), and slowness (p 0.019), but not for washing or
responsibility. Music therapy was signicantly more effective in reducing anxiety (post-intervention
score: music therapy standard treatment: 16.9 77.4 vs standard treatment only: 22.9 7 4.6, p o0.001,
effect size 47.0%), and depressive symptoms (post-intervention score: music therapy standard treatment: 10.8 73.8 vs standard treatment: 17.1 73.7, p o0.001, effect size 47.0%).
Limitations: Inclusion of a small sample size, lack of blinding due to the nature of the intervention, short
duration of follow-up.
Conclusion: In patients with OCD, music therapy, as an adjunct to standard care, seems to be effective in
reducing obsessions, as well as co-morbid anxiety and depressive symptoms.
& 2015 Published by Elsevier B.V.

Keywords:
Obsessive compulsive disorder
Music therapy/methods
Combined modality therapy
Anxiety disorders/therapy
Treatment outcome
Randomized clinical trial

1. Introduction
Often overlooked and under diagnosed, obsessivecompulsive
disorder (OCD) is a common psychiatric ailment and is estimated to
affect 13% of the population at some point in their lives (Grant, 2014).
In a nation-wide survey of Iranian adults aged 18 and above, a pointprevalence of 1.8% for OCD was documented (Mohammadi et al.,
2004). Obsessions are characterized by the presence of worrisome
images, ideas, or impulses that are intrusive and unwanted, and are

n
Correspondence to: Department of Psychology, Faculty of Psychology and
Education, Islamic Azad University, Marvdasht branch, Bahman-Beigi Street,
Ashoora Square, Marvdasht, Fars Province, Iran. Tel.: 98 71 43234805;
fax: 98 71 43234756.
E-mail addresses: shahrzadshirani@miau.ac.ir (S. Shirani Bidabadi),
AmirMehryar36@gmail.com (A. Mehryar).

http://dx.doi.org/10.1016/j.jad.2015.04.011
0165-0327/& 2015 Published by Elsevier B.V.

usually accompanied by compulsions: repetitive actions, mental

images, or ritualistic behaviors that the patient feels compelled to do
in order to relieve anxiety caused by obsessive thoughts (American
Psychiatric Association, 2000).
Pharmacotherapy with selective-serotonin reuptake inhibitors
(SSRI), or the tricyclic antidepressant clomipramine combined with
psychotherapy (e.g. exposure-response prevention, cognitive behavioral therapy) are the mainstay of treatment in the management
of OCD (American Psychiatric Association, 2006; Fineberg and Gale,
2005). For OCD treatment, compared with anxiety and depression,
SSRIs need to be prescribed at higher doses and usually take longer to
take effect (American Psychiatric Association, 2006). Consequently, the
patient may experience more troubling dose-related side effects, negatively impacting medication's tolerability (Bloch et al., 2010; Jenike,
2004). Additionally, a prolonged course of treatment is required in
order to achieve full resolution of symptoms and to forestall relapse

14

S. Shirani Bidabadi, A. Mehryar / Journal of Affective Disorders 184 (2015) 1317

Hospital, Isfahan, Iran) were assessed for eligibility. Patients were

found eligible if: (1) were at least 18 years or older; (2) had axis I
diagnosis of OCD according to the criteria delineated by the diagnostic
and statistical manual of mental disorders fourth edition (American
Psychiatric Association, 2000) diagnosed by an experienced psychiatrist; (3) had not received treatment previously for the disorder; and
(4) agreed to partake in the study. Initially, 96 patients were assessed
for eligibility among whom 30 met the inclusion criteria and were
randomized to treatment arms. Written informed consent was
obtained from all participants prior to enrollment. All procedures
dealing with human subjects were conducted in accordance with the
guidelines laid in the latest revision of Helsinki declaration. The
protocol of the study was approved by the ethics committee of the
Faculty of Psychology, Islamic Azad University, Marvdasht Branch.

(Ravizza et al., 1996). Even with cooperative patients where medication adherence is not a major obstacle, in at least one third of the
patients, treatment response remains insufcient. In the naturalistic
follow-up study of Brown Longitudinal Obsessive Compulsive Study
(BLOCS), 38% of patients receiving SSRIs at recommended doses
appraised their symptoms as minimally improved, unchanged, or
even worse (Mancebo et al., 2006). Use of psychotherapeutic techniques alongside pharmacotherapy augments treatment efcacy (Grant,
2014). However, in many clinical settings, psychotherapy is only offered to a fraction of patients and its use remains relatively low. The
BLOCS study demonstrated that less than one-fourth of OCD patients
participate in the recommended number of cognitive-behavioral
therapy sessions (Mancebo et al., 2006).
Given the shortcomings of medications and psychotherapy in the
management of OCD, complementary and alternative medicine (CAM)
methods have the capacity to be used as an adjunct to standard care
and help improve patient outcomes (Sarris et al., 2012). Music therapy,
a form of CAM, is a non-invasive, safe, well-tolerated, inexpensive, and
readily available technique which has been shown to provide therapeutic benets in a wide range of psychiatric disorders including but
not limited to depression, anxiety, schizophrenia, autism, and dementia
(Lin et al., 2011). Bruscia (1998) denes music therapy as a systematic
process of intervention wherein the therapist helps the client to
promote health, using music experiences and the relationships that
develop through them as dynamic forces of change (Bruscia, 1998).
Aside from its role in inducing relaxation, music in the context of
psychiatric disorders could be viewed as a medium for non-verbal
communication between the patient and the therapist, and could be
incorporated to help patient express feelings that are not articulated
otherwise (Mssler et al., 2011).
A number of studies to date have delved into the possible therapeutic implications of music therapy in relieving anxiety, anxietyrelated disorders, and depression (Elliott et al., 2011; Erkkila et al.,
2011; Goldbeck and Ellerkamp, 2012). Despite a strong theoretical
framework, and expanded knowledge regarding the mechanistic of
music on neuropsychology, clinical evidence corroborating therapeutic implications of music therapy in the treatment of OCD is only
sparsely available. The present randomized clinical trial was thus
designed and conducted to investigate the efcacy of music therapy
as an adjunct to standard treatment, on OCD. Moreover, given the
fact that a signicant proportion of patients with OCD have other
comorbid mood or anxiety disorders, the question of whether
therapeutic benets of music could be expanded to also affect
concurrent depressive and anxiety symptoms was explored.

This single-center, parallel-group, randomized clinical trial was

designed and conducted to investigate the effects of music therapy
as an adjunct treatment to pharmacotherapy and cognitive behavioral therapy in patients with OCD. The trial protocol is registered
with the clinicaltrials.gov (Identier no.: NCT02314195).
Using a simple randomization module in Microsofts Excels,
eligible patients were randomly assigned to music therapystandard
treatment, or standard treatment only arms of the trial. Patients in
the standard treatment only arm received a medication of SSRI family,
and also received cognitive behavioral therapy by a psychologist.
Patients in the music therapy arm received standard treatment as described plus sessions of receptive music therapy scheduled three days a
week, over four weeks. Baseline assessment of the patients was
conducted before randomization to prevent allocation bias. However,
given the nature of the intervention, no blinding for either the assessor
or the patients was done. Over a span of four weeks, each individual
took part in 12 sessions of individual music therapy conducted by an
experienced psychiatrist. In Iran, the concept of music therapy is
relatively new, and at present no ofcial training, registration, and
oversight for music therapists exist in the country. The receptive music
therapy scheme used herein was therefore developed by the principal
investigator working in collaboration with an experienced musician,
specialized in composition and production of Iranian classical music.
The intervention was carried out in the form of receptive music
therapy (listening to selected tracks of Iranian classical music composed by well-known musicians) followed by discussions. The protocol
and arrangement of music therapy sessions are delineated in Table 1.

2. Methods

2.3. Assessment and outcome measures

2.1. Patients

The primary outcome measure was change in the obsessional

symptoms. Corollary measures included change in co-morbid
anxiety and depressive symptoms. At baseline and before randomization, patients were surveyed using the following battery of

Between April and June 2014, consecutive patients visited in

the outpatient psychiatry clinic of a not-for-prot hospital (Shariati

2.2. Trial design and interventions

Table 1
Protocol of the music therapy sessions for patients with obsessivecompulsive disorder.
First 10 min

Music
presented

Activity

30 min First
10 min
Second
10 min
Third
10 min
Epilogue

Piano soloa

The patient is asked to recall obsessional thoughts he or she tries to generally avoid that cause great anxiety for him/her. At this
stage, the patient is asked to reect on these thoughts, images, or impulses and freely express the feelings that they provoke.
The patient is asked to focus on the music lyrics, reect on them, and to express, in a few words, how the lyrics of the song relate to
his or her feelings/experiences.
The patient is asked to close his or her eyes, relax, and focus on pleasant thoughts, images, and how to achieve them.

a
b
c

Ballad

Santur soloc

The patient is asked to discuss his or her feelings during the session. The three tracks played is given to the patient. As a homework
assignment, the patient is asked to listen to the tracks following the same protocol and write down his or her feelings.

by Morteza Mahjubi or Javad Maru.

by Mohamadreza Shajarian or Gholamhosein Banan.
by Faramarz Payvar; Santur is a Persian string instrument.

S. Shirani Bidabadi, A. Mehryar / Journal of Affective Disorders 184 (2015) 1317

Table 2
Baseline scores for obsessivecompulsive, anxiety, and depression scales of patients
with obsessivecompulsive disorder enrolled in the randomized clinical trial.
Standard treatmentmusic
therapy (n15)
Obsessions
Checking
5.9 7 1.0
Washing
5.6 7 2.0
Slowness
4.3 7 1.0
Responsibility 5.4 7 1.3
Total score
17.6 7 2.4
Anxiety
26.7 7 9.9
Depression
16.3 7 5.6

Standard treatment
only (n 15)

p
value

6.3 7 1.1
6.0 7 1.4
3.9 7 1.0
5.17 1.1
18.17 1.7
27.2 7 3.9
21.2 7 5.4

0.235
0.541
0.368
0.365
0.489
0.866
0.022

Table 3
Comparison of the effects of music therapy added to standard treatment versus
standard treatment alone on obsessivecompulsive, anxiety, and depression scores
of patients with obsessivecompulsive disorder.
a

Follow-up score

Standard
treatmentmusic
therapy (n15)
Obsessions
Checking
3.9 7 1.0
Washing
3.5 7 2.0
Slowness
2.7 7 1.2
Responsibility 4.2 7 1.5
Total score
12.4 7 1.9
Anxiety
16.9 7 7.4
Depression
10.8 7 3.8

F
statistic

p value

Effect
size

10.06
2.73
6.24
0.62
35.36
24.18
24.02

0.004
0.110
0.019
0.430
o0.001
o0.001
o0.001

26.0%
8.0%
18.0%
2.0%
56.7%
47.0%
47.0%

Standard
treatment only
(n 15)

5.1 7 1.1
4.5 7 1.5
3.7 7 1.1
4.6 7 1.3
15.1 7 1.7
22.9 7 4.6
17.1 7 3.7

a
Adjusted Follow-up score for outcome variables calculated controlling for the
between-group differences at baseline.

self-administered tests: (1) Maudsley ObsessiveCompulsive

Inventory (MOCI); (2) Beck Anxiety Inventory (BAI); and (3) Beck
Depression Inventory Short Form (BDISF). In a follow-up visit
scheduled at the completion of music therapy, the same battery of
tests were completed by the patients. A brief description of the
tests and their psychometric properties are presented below.
2.3.1. Maudsley obsessivecompulsive inventory (MOCI)
Developed by Hodgson and Rachman (1977), MOCI is a 30item, binary (true/false), self-administered questionnaire devised
to evaluate the extent of obsessivecompulsive complaints and
to distinguish patients from nonclinical samples. The inventory
reports scores on four obsessivecompulsive subtypes that include
checking (9 items), washing (11 items), slowness (7 items), and
doubting (7 items). The scores on individual subtypes can then be
summed up to provide a nal score ranging from zero (no symptoms) to 30 (maximum presence of symptoms). Of note, since
four items in the inventory are repeated in two subtypes, they are
only counted once to create the total obsessionality score. MOCI
has been widely used in research and clinical settings and has
been shown to be particularly sensitive to therapeutic changes,
making it a practical tool for tracking treatment response in
patient populations (Meca et al., 2011). In the present study, the
translated version of the inventory was used (Ghassemzadeh et al.,
2002).
2.3.2. Beck anxiety inventory (BAI)
Developed by Beck and Steer (1990), BAI is a 21-item selfadministered questionnaire to assess anxiety and to delineate
patients from nonclinical samples. Each item is answered on a

15

four-point Likert-type scale ranging from not at all (0 point), to

mildly (1 point), moderately (2 points), and to severely (3
points). The individual items are them summed to calculate a
nal score of 063 (Beck and Steer, 1990). In the current study,
the translated version of the inventory was used (Kaviani and
Mousavi, 2008).
2.3.3. Beck depression inventory short form (BDISF)
Originally developed by Beck et al. (1961), BDI is a 21-item selfadministered questionnaire devised to measure depression in
cognitive-affective and somatic-performance domains. In the
BDISF, only the rst 13 items of cognitive-affective domain are
retained (Beck and Steer, 1987). A score of 03 is assigned to each
item and a nal score ranging from 0 to 39 is then calculated (Beck
and Steer, 1987). In the current study, the translated version of the
inventory was used (Hojat et al., 1986).
2.4. Statistical analysis
All statistical tests were done using the Statistical Package for the
Social Sciences (SPSSs) version 17.0 (SPSS Inc., Chicago, IL). Continuous variables are presented as mean7standard deviation.
Baseline scores between the two groups were compared using
independent t-test. One-way analysis of covariance (ANCOVA)
models were conducted to compare the effectiveness of two interventions designed to reduce obsessivecompulsive complaints
score in patients with OCD. Reducing anxiety and depressive symptoms were also considered as corollary outcomes. The type of
intervention (music therapystandard treatment or standard treatment only) entered the model as independent variable. The dependent variables consisted of follow-up or post-intervention scores
on outcome variables. Baseline or pre-intervention scores were also
included in the model as covariates, thereby adjusting for the
possible baseline between-group differences. Before conducting
each analysis, preliminary checks of ANCOVA assumptions including normality, linearity, homoscedasticity, and homogeneity of regression slopes were performed and the nal model was deemed
acceptable if no violation of assumptions was identied. In each
ANCOVA model, the effect size was calculated from the partial eta
squared and is presented as percentages. Partial eta squared represents the amount of variance of the dependent variable (outcome)
explained by the independent variable (intervention). Based on
Cohen's recommendations, a partial eta squared of 13.8% or greater
indicates a large effect size. In all tests, po0.05 was consideed necessary to reject the null hypothesis of no between-group
difference.

3. Results
Thirty adult patients with the diagnosis of OCD were randomly
assigned to trial arms. All enrolled participants in both arms
completed the trial course and no patient was lost to follow up.
Age of the enrolled patients ranged from 18 to 50 years and was
comparable between the two groups. Also, the female-to-male
ratio in both groups were identical and males comprised 25% of
the studied sample (n 6).
Baseline scores for the MOCI, Beck anxiety, and Beck depression
inventories for trial arms are presented in Table 2. The overall
obsessional score, as well as scores for its four constituent
subtypes were comparable across the two groups (p 40.05 in all
tests). Additionally, baseline scores for BAI were similar between
the two groups. On the other hand, patients in the standard
treatment only arm had signicantly higher BDISF scores compared with their counterparts in the standard treatment music
therapy arm (21.2 versus 16.3, p 0.022).

16

S. Shirani Bidabadi, A. Mehryar / Journal of Affective Disorders 184 (2015) 1317

The effects of music therapy versus no music therapy on

primary and corollary outcome variables were compared using
ANCOVA models and the ndings are outlined in Table 3. With
respect to the primary outcome, music therapy, as an adjunct to
the standard treatment protocol, resulted in a greater decrease in
total obsessive score than standard treatment alone (p o0.001,
effect size56.7%). For subtypes, signicant between-group differences were identied for checking, and slowness, but not for
washing or responsibility (Table 3). Music therapy added as an
adjunct therapy was also signicantly more effective in relieving
self-reported anxiety (p o0.001), and also reducing self-reported
depressive symptoms (p o0.001). For both anxiety and depression,
music therapy plus standard treatment was approximately 47%
more effective than standard treatment alone, indicating a large
effect size.

4. Discussion
Despite a rm theoretical rationale for its medicinal use (Lin
et al., 2011; Silverman, 2008), clinical application of music for the
treatment of psychiatric illnesses have only been sparsely ticed in
the literature. In the present randomized clinical trial, we provided
preliminary evidence that receptive music therapy, incorporated
as an adjunct to the standard therapeutic module, could enhance
treatment response in adults diagnosed with OCD.
In our study of patients with the primary axis I diagnosis of
OCD, music therapy yielded signicant reductions in concurrent
anxiety and depression scores. Compared with standard treatment, music therapy was 47% more effective in reducing anxiety
and depressive scores. Previous studies have clearly shown that
OCD is often accompanied by other axis I and II disorders. In the
Brown Longitudinal Obsessive Compulsive Study (BLOCS), 293
adult patients with a primary diagnosis of OCD were followed
(Pinto et al., 2006). Indeed, it was shown that OCD is seldom an
isolated neuropsychological disorder; 91.8% of patients with OCD
were diagnosed with another axis I disorder sometime in their
lives (Pinto et al., 2006). The most common psychiatric comorbidities were mood disorders (lifetime prevalence: 74.1%), followed by
anxiety disorders (lifetime prevalence: 52.6%) (Pinto et al., 2006).
The usefulness of music therapy in the treatment of anxiety and
depression have been demonstrated. In a randomized trial of 36
children between the ages of 8 and 12 who were diagnosed with
separation anxiety disorder, generalized anxiety disorder, or specic phobias, Goldbeck and Ellerkamp (2012) showed that multimodal music therapy (including both active and receptive techniques) combined with cognitive-behavioral therapy is superior to
the usual treatment offered by the psychiatrist in terms of achieving remission; patients receiving active music therapy were two
times more likely to achieve remission (67% versus 33%). In
another randomized trial of adult patients, Erkkila et al. (2011)
looked into the potential therapeutic benets of a free improvisation and reective discussion model of music therapy in depressed
patients. Their work concluded that individual music therapy
sessions scheduled twice a week for three months results in a
greater improvement in depressive symptoms when compared
with standard care (Erkkila et al., 2011). Of note, co-morbid
anxiety was also signicantly decreased in the music intervention
arm, and improvements in the levels of general functioning were
noted (Erkkila et al., 2011). The observed effect size for depression
and anxiety were 65.0% and 49.0% (Erkkila et al., 2011), respectively which are comparable to the rates of 47.0% and 47.0% observed herein. A 2008 meta-analysis of randomized clinical trials also
provided support for the role of music therapy in the treatment of
depression. In four out of ve studies included, music therapy

resulted in greater improvements than standard care (Maratos

et al., 2008).
In the present randomized clinical trial, the effects of music
therapy on different OCD subtypes was not symmetrical; music
therapy tended to yield a better therapeutic response in checking and
slowness, but not washing or responsibility. Several previous reports
have highlighted the fact that OCD is in fact a heterogeneous entity
with distinct subtypes that respond differently to intervention
(McKay et al., 2004). McLean et al. (2001) pointed out that there is
an identiable association between treatment response and type of
obsessional symptoms. According to their observations, upon receiving cognitive or behavioral therapy, patients with washing obsessions
were signicantly less likely to achieve recovery compared with
checkers, or obsessionals (McLean et al., 2001). On the other hand, in
a sample of OCD patients being treated with clomipramine, Baolu
et al. (1988) showed that checking rituals are associated with poorer
response to pharmacological therapy. It could therefore be hypothesized that music therapy might yield differential therapeutic
responses in distinct OCD subtypes, and be more effective for
alleviating some symptom groups. It should be noted however that
given the relatively small number of included patients in the current
trial and the short duration of follow up, credible inferences in this
regard are not to be made from our ndings and future studies
specically designed to delve into the issue are required. Moreover, in
the present study, not all OCD symptom types were investigated. The
MOCI scale was developed using a principal component analysis
approach; the authors decided to retain the rst four major complaint types which accounted for only 43% of the variance.
In the present study, receptive as opposed to active music
therapy was used as the intervention. Active music therapy
involves playing various musical instruments by the patient
improvisationally, usually with the oversight of a professional
music therapist (Chan et al., 2011). Compared with receptive
music therapy, active music therapy has the advantage of diligently involving the patient in the therapeutic process and thereby
potentially yielding outcomes superior to that of listening to music
alone. However, conduct of active music therapy requires certain
equipment and settings and also necessitates stewardship of
trained musicians who work in concert with the psychiatrist incharge. In clinical settings, such as the one that the present study
was carried out in, these prerequisites are often not available.
Additionally, in Iran, where the current study was carried out, at
present, no academic training, ofcial qualication process, and
organizational oversight for allied health professionals who practice music therapy is available. Consequently, receptive music
therapy could be considered as an alternative method is these
settings, since it can be carried out with the available resources at
hand. Further, with receptive music therapy, the patient can be
instructed to easily incorporate music listening into his or her
everyday life and continue to receive the therapeutic benets of
music indenitely, after the scheduled therapy sessions are concluded. Future randomized trials focused on comparing various
music therapy techniques (for instance receptive versus improvisation versus active) with standard care are needed in order to
investigate the comparative efcacy of different music therapy
interventions as adjunct to standard care for treatment of patients
with OCD.
A number of limitations in the present study deserve mentions.
First, in the current study, a relatively small sample of participants
were included, thereby increasing the possibility of type II error.
Although statistically signicant changes for the main outcome
measures were noted, mostly owing to the large effect size produced
by the intervention, our study might have been underpowered to
detect more subtle improvements observed for OCD subtypes.
Second, given the nature of music therapy, in the current study, no
blinding procedure was applicable. This raises the possibility of the

S. Shirani Bidabadi, A. Mehryar / Journal of Affective Disorders 184 (2015) 1317

observed effect for music therapy being confounded by other factors

such as improved attendance rate of the patient to therapy sessions,
enhanced interpersonal communication between the patient and the
therapist, and better adherence to non-music therapy interventions.
In the study by Erkkila et al. (2011), depressed patients in the music
therapy arm were less likely to drop out and discontinue care
compared with those receiving standard care only (9.1% versus
19.6%), albeit the difference not reaching statistical signicance. This
observation corroborates the notion that music therapy might be
benecial in improving patient's adherence to therapy. Therefore,
therapeutic benets of music therapy to some extent can be explained by this boosting effect.
In spite of these limitations, the present randomized trial provides preliminary evidence that receptive music therapy could
serve as an adjunct to standard treatment in patients with OCD
and is benecial in alleviating obsessivecompulsive, as well as,
co-morbid anxiety and depressive symptoms. Whether these
short-term benets sustain over longer periods remains to be
elucidated.
Role of funding source
This study was nancially supported by the Islamic Azad University, Marvdasht
branch.

Conict of interest
None to declare.

Acknowledgments
We would like to thank Dr. Shahla Akoochekian, MD, head of department of
psychiatry, Isfahan University of Medical Sciences, Isfahan, Iran for providing
clinical expertise throughout this project.

Appendix A. Supporting information

Supplementary data associated with this article can be found in
the online version at http://dx.doi.org/10.1016/j.jad.2015.04.011.
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