Use of slow-release melatonin in treatment-resistant depression

Abstract

To examine antidepressant augmentation with and hypnotic effects of slow-release melatonin (SR-melatonin) in patients with treatment-resistant depression.
Open-label trial.
Tertiary care outpatient depression clinic.
Nine outpatients who had failed to respond to 2 or more 8-week trials of antidepressant medication.
Patients received SR-melatonin 5 mg per day for the first 2 weeks and 10 mg per day for the final 2 weeks, in addition to their antidepressant medication.
Structured Clinical Interview for DSM-IV, Axis 1 Disorders, Hamilton Rating Scale for Depression (HRSD), Beck Depression Inventory, Response Style Questionnaire, sleep and fatigue measures.
One patient was excluded after 1 week because of the development of a mixed affective state. In the remaining 8 patients there was a 20% mean decrease in HRSD scores after 4 weeks of treatment, with no individual achieving an improvement of 50% or more. There was a 36% decrease on the 3-item HRSD related to insomnia, with 4 of 8 patients showing at least a 50% improvement on this measure. The greatest decrease in insomnia occurred during the last 2 weeks of the study, following the increase in dosage to 10 mg per day of SR-melatonin. Patients also reported significantly lower levels of fatigue post-treatment.
SR-melatonin may be a useful adjunct for sleep, but does not substantially augment existing antidepressant therapies in some patients with treatment-resistant depression.

Full text

Use
of
slow-release
melatonin
in
treatment-resistant
depression
E.
Jane
Dalton,
BSc;
Debra
Rotondi,
BSc;
Robert
D.
Levitan,
MD;
Sidney
H.
Kennedy,
MD;
Gregory
M.
Brown,
MD,
PhD
Dalton,
Rotondi
-
Research
Assistant,
Depression
Clinic,
Centre
for
Addiction
and
Mental
Health
(CAMH-Clarke),
Toronto,
Ont.;
Levitan
-
Research
Head,
Depression
Clinic,
CAMH,
and
Department
of
Psychiatry,
University
of
Toronto;
Kennedy
-
Clinical
Director,
Mood
&
Anxiety
Disorders
Program,
CAMH,
Department
of
Psychiatry,
University
of
Toronto;
Brown
-
Head,
Neuroendocrinology
Research
Section,
CAMH,
and
Department
of
Psychiatry,
University
of
Toronto
Objective:
To
examine
antidepressant
augmentation
with
and
hypnotic
effects
of
slow-release
melatonin
(SR-melatonin)
in
patients
with
treatment-resistant
depression.
Design:
Open-label
trial.
Setting:
Tertiary
care
outpatient
depression
clinic.
Patients:
Nine
outpatients
who
had
failed
to
respond
to
2
or
more
8-week
trials
of
antidepressant
medication.
Interventions:
Patients
received
SR-melatonin
5
mg
per
day
for
the
first
2
weeks
and
10
mg
per
day
for
the
final
2
weeks,
in
addition
to
their
antidepressant
med-
ication.
Outcome
measures:
Structured
Clinical
Interview
for
DSM-IV,
Axis
Disorders,
Hamilton
Rating
Scale
for
Depression
(HRSD),
Beck
Depression
Inventory,
Response
Style
Questionnaire,
sleep
and
fatigue
measures.
Results:
One
patient
was
excluded
after
I
week
because
of
the
development
of
a
mixed
affective
state.
In
the
remaining
8
patients
there
was
a
20%
mean
decrease
in
HRSD
scores
after
4
weeks
of
treatment,
with
no
individual
achieving
an
improvement
of
50%
or
more.
There
was
a
36%
decrease
on
the
3-item
HRSD
related
to
insomnia,
with
4
of
8
patients
showing
at
least
a
50%
improvement
on
this
measure.
The
greatest
decrease
in
insomnia
occurred
during
the
last
2
weeks
of
the
study,
following
the
increase
in
dosage
to
10
mg
per
day
of
SR-melatonin.
Patients
also
reported
significantly
lower
levels
of
fatigue
post-treatment.
Conclusions:
SR-melatonin
may
be
a
useful
adjunct
for
sleep,
but
does
not
sub-
stantially
augment
existing
antidepressant
therapies
in
some
patients
with
treatment-resistant
depression.
Objectif:
Etudier
1'effet
de
I'ajout
au
traitement
antidepresseur
de
la
melatonine
a
liberation
prolong'e
(melatonine
LP)
et
ses
effets
hypnotiques
chez
les
patients
aux
prises
avec
une
depression
refractaire.
Conception
:
Essai
ouvert.
Contexte
:
Clinique
de
traitement
tertiaire
de
la
depression
en
service
externe.
Patients:
Neuf
patients
en
service
externe
qui
n'avaient
pas
reagi
a
deux
essais
ou
plus
de
traite-
ment
aux
antidepresseurs
d'une
duree
de
huit
semaines.
Interventions:
Les
patients
ont
reSu
de
la
mela-
tonine
LP
a
raison
de
5
mg
par
jour
pendant
les
deux
premieres
semaines
et
de
10
mg
par
jour
pendant
les
deux
dernieres
semaines,
en
sus
de
leur
medicament
antidepresseur.
Mesures
de
resultats:
Entrevue
clinique
structuree
pour
DSM-IV,
troubles
de
l'axe
1,
echelle
de
depression
de
Hamilton
(HRSD),
inven-
taire
de
la
depression
de
Beck,
questionnaire
a
reponses,
mesures
du
sommeil
et
de
la
fatigue.
Resultats:
Correspondence
to:
Robert
D.
Levitan,
Centre
for
Addiction
and
Mental
Health,
250
College
St.,
Toronto
ON
MST
I
R8;
fax
416
979-
6821;
Robert_Levitan@camh.net
Medical
subject
headings:
depression;
fatigue;
insomnia;
melatonin;
psychiatric
status
rating
scales
J
Psychiatry
Neurosci
2000;25(1):48-52.
Submitted
Mar.
16,
1999
Revised
June
14,
1999
Accepted
June
17,
1999
i
2000
Canadian
Medical
Association
A4
fte
'':,-
..
"I
.
':
%
I
;.,A
,...
..
WC
1.4w

M.Iatonir
00
ai$
tnt.
'resisw,t#'
,
o'
On
a
exclu
un
patient
apres
une
semaine
a
cause
de
I'apparition
d'un
etat
affectif
mixte.
Chez
les
huit
patients
restants,
on
a
constate
une
baisse
moyenne
de
20
%
des
resultats
HRSD
apres
quatre
semaines
de
traitement,
et
aucun
sujet
n'a
montre
une
amelioration
de
50
%
ou
plus.
On
a
constate
une
diminution
de
36
%
des
resultats
des
trois
questions
de
1'echelle
HRSD
qui
ont
trait
a
l'insomnie,
et
quatre
des
huit
patients
ont
montre
une
amelioration
d'au
moins
50
%
de
cette
mesure.
La
reduction
la
plus
marquee
de
l'insomnie
s'est
produite
au
cours
des
deux
dernieres
semaines
de
I'etude
apres
une
augmentation
de
la
dose
a
10
mg
par
jour
de
m6latonine
LP.
Les
patients
ont
aussi
signale
des
niveaux
de
fatigue
beaucoup
moins
eleves
apres
le
traitement.
Conclusions:
La
m6latonine
LP
peut
Atre
un
traitement
d'appoint
utile
pour
faciliter
le
sommeil,
mais
elle
n'ameliore
pas
de
facon
substantielle
1'effet
du
traitement
antid6presseur
deja
administre
i
certains
patients
aux
prises
avec
une
depression
refractaire.
Introduction
Melatonin,
a
hormone
secreted
by
the
pineal
gland
pri-
marily
at
night,
plays
an
intrinsic
role
in
the
regulation
of
the
sleep-wake
cycle.
Exogenous
melatonin
has
been
shown
to
exert
synchronizing
effects
on
circadian
rhythms,
phase-advancing
the
sleep
of
patients
suffer-
ing
from
a
delayed
sleep-phase
syndrome,",2
facilitating
adaptation
to
jet
lag34
and
synchronizing
the
sleep-
wake
cycles
of
blind
patients
to
environmental
light/
dark
cycles.56
The
hypnotic
effects
of
melatonin
have
been
widely
reported
in
various
populations.7'8
For
example,
one
study
demonstrated
that
administration
of
75
mg
of
melatonin
over
14
days
significantly
increased
the
subjective
assessment
of
total
sleep
time
in
patients
with
chronic
insomnia.9
In
a
recent
review,
it
was
reported
that
a
5-mg
dose
of
melatonin
adminis-
tered
over
4
weeks
normalized
the
sleep
pattern
of
patients
with
delayed
sleep-phase
syndrome.'0
Similar-
ly,
it
has
been
reported
that
a
single
80-mg
dose
of
mela-
tonin
accelerated
sleep
initiation
and
sleep
efficiency
in
normal
subjects.8"10
Furthermore,
in
elderly
patients
with
insomnia,
a
2-mg
dose
of
slow-release
melatonin
(SR-
melatonin)
administered
over
a
3-week
period
normal-
ized
sleep
patterns
and
improved
sleep
maintenance."
"2
A
relation
between
biological
rhythms,
insomnia
and
melatonin
points
to
a
pathophysiologic
role
for
mela-
tonin
in
mood
disorders.
Consistent
with
this
hypothe-
sis,
numerous
studies
have
reported
a
decrease
in
noc-
turnal
melatonin
levels
in
patients
with
major
depres-
sion'3"4
and
in
patients
with
disorders
in
which
there
is
comorbid
depression.'5
To
our
knowledge,
only
a
single
study
has
examined
the
possible
therapeutic
effects
of
exogenous
SR-melatonin
in
patients
with
major
depres-
sive
disorder.'6
In
this
study,
patients
were
adminis-
tered
5
to
10
mg
of
melatonin
in
combination
with
flu-
oxetine
over
a
4-week
period.
On
average,
patients
reported
a
50%
increase
in
subjective
sleep
quality,
although
SR-melatonin
had
no
effect
on
the
rate
of
improvement
of
symptoms
of
major
depressive
disor-
der.
There
have,
however,
been
no
studies
conducted
in
patients
with
treatment-resistant
depression.
Many
patients
who
fail
to
respond
to
standard
anti-
depressant
medications
report
significant
insomnia,
establishing
a
rationale
for
a
sleep-targeted
strategy
in
these
patients.
The
goal
of
the
current
pilot
study
was
to
examine
the
hypnotic
and
antidepressant-augmenting
effects
of
SR-melatonin
in
a
group
of
patients
with
treat-
ment-resistant
depression.
SR-melatonin
has
no
demon-
strated
antidepressant
efficacy
as
a
monotherapy.'6
A
slow-release
formulation
was
used
because
it
more
closely
simulates
the
endogenous
nocturnal
profile
of
melatonin
than
does
immediate-release
melatonin."
"2
Methods
Ethics
approval
for
this
study
was
obtained
through
the
human
subjects
review
committee
at
the
University
of
Toronto.
Nine
patients
with
treatment-resistant
depres-
sion
were
included
in
this
study;
all
patients
gave
writ-
ten
informed
consent.
Patients
were
22
to
73
years
of
age
and
were
recruited
from
the
outpatient
clinic
at
the
Centre
for
Addiction
and
Mental
Health
-
Clarke
Division.
All
patients
were
diagnosed
with
major
depressive
disorder
according
to
the
Diagnostic
and
Statistical
Manual
of
Mental
Disorders,
4th
edition
(DSM-
IV),
using
the
Structured
Clinical
Interview
for
DSM-IV,
Axis
I
Disorders
(SCID).'7
Patients
were
required
to
score
18
or
greater
on
the
17-item
Hamilton
Rating
Scale
for
Depression
(HRSD).'8
All
patients
also
met
the
crite-
ria
for
treatment-resistant
depression,
which
was
defined
as
the
failure
to
respond
to
2
or
more
trials
of
antidepressant
medication
from
different
drug
classes,
each
at
adequate
therapeutic
doses,
for
at
least
8
weeks.
........

Exclusion
criteria
included
bipolar
disorder,
eating
dis-
orders,
primary
sleep
disorders,
major
medical
illness-
es,
endocrine
disorders,
psychotic
symptoms,
active
alcohol
or
substance
abuse
and
active
suicidal
ideation.
At
the
time
of
recruitment,
all
patients
had
been
receiving
treatment
with
an
antidepressant
medication
for
at
least
8
weeks,
but
continued
to
meet
criteria
for
major
depression.
Patients
continued
taking
the
antide-
pressant
medication,
at
the
same
dosage,
throughout
the
study.
At
the
first
visit,
patients
received
SR-melatonin
in
5-mg
capsules
and
were
instructed
to
take
this
half
an
hour
before
bedtime.
The
daily
dose
was
increased
to
10
mg
if
the
patient's
HRSD
score
had
not
decreased
by
50%
at
Week
2.
Patients
were
assessed
at
baseline
using
the
SCID,
the
HRSD,
the
Beck
Depression
Inventory
(BDI),19
and
the
Response
Style
Questionnaire
(RSQ;
unpublished
scale).
The
RSQ
is
a
self-report
scale
designed
to
measure
response
style
to
depression,
which
yields
scores
on
2
factors:
distraction
and
rumina-
tion.
All
ratings
were
repeated
after
2
and
4
weeks,
except
the
RSQ,
which
was
repeated
only
after
Week
4.
Patients
also
completed
daily
ratings
of
sleep
length,
interruptions,
naps
and
sleep
quality.
Sleep
quality
was
assessed
using
a
7-item
self-report
fatigue
scale
and
the
Stanford
Sleepiness
Scale
(SSS).20
The
7-item
fatigue
scale
measures
present
level
of
energy,
and
the
SSS
measures
present
level
of
sleepiness.
Weekly
averages
for
each
of
the
2
sleep
scales,
sleep
length,
naps
and
interruptions,
were
calculated
using
pro-rated
values
for
missing
days.
Changes
in
clinical
measures
of
mood
and
sleep
were
assessed
using
a
repeated
measures
ANOVA.
Post
hoc
comparisons
were
performed
using
paired
t-tests,
applying
the
Bonferroni
correction
procedure
for
multi-
ple
t-tests.
The
SSS
and
the
fatigue
scale,
which
are
nar-
rowly
scored
categorical
variables,
were
analyzed
using
nonparametric
statistics
(Friedman
2-way
ANOVA).
Results
Of
the
9
patients,
1
was
excluded
after
1
week
because
of
the
development
of
a
mixed
affective
state,
charac-
terized
by
ongoing
depression,
agitation,
and
decreased
need
for
sleep.
By
the
end
of
Week
2,
none
of
the
patients
showed
a
50%
decrease
on
the
HRSD;
there-
fore,
the
dosage
of
SR-melatonin
was
increased
for
all
patients
to
10
mg
per
day
for
the
final
2
weeks
of
the
study.
Table
1
summarizes
demographics,
antidepres-
sant
regimens,
and
HRSD
scores
before
and
after
treat-
ment
for
each
of
the
8
patients
who
completed
the
study.
Table
2
summarizes
the
mean
depression
scores
over
the
4
weeks
of
study
for
the
8
patients.
The
HRSD
scores
were
found
to
drop
significantly
over
time;
however,
none
of
the
patients
had
a
score
below
10
at
Week
4,
and
the
mean
improvement
in
these
scores
was
modest
at
20%
(standard
deviation
[SD]
13.9%;
range
0%
to
45%).
None
of
the
patients
showed
a
50%
improvement
at
Week
4.
The
ruminative
scale
of
the
RSQ
also
showed
a
significant
decline
over
time
from
baseline
to
Week
4,
with
the
percentage
change
scores
indicating
a
modest
mean
improvement
of
16%
(SD
18.2%;
range
3%
to
47%).
With
respect
to
sleep
variables,
the
3
insomnia
items
(early,
middle
and
late)
from
the
HRSD
(i.e.,
"HRSD-3")
were
extracted
to
examine
the
effects
of
treatment
on
sleep
alone
(Tables
1
and
2).
Insomnia
was
found
to
decrease
significantly
over
time
in
all
subjects.
Applying
a
Bonferroni
correction
procedure,
a
significant
difference
..
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MeIaor~n
ad
treatentreiat
was
found
between
baseline
and
Week
4.
Percentage
change
scores
indicated
a
mean
improvement
of
36%
(SD
27.4%).
Four
of
the
8
subjects
experienced
a
50%
or
greater
improvement
on
this
measure
at
Week
4.
Scores
on
the
fatigue
scale
were
also
significantly
lower
post-treatment
(X2
7.62,
df
3,
p
=
0.05).
No
signifi-
cant
effects
over
time
were
observed
for
the
other
sleep
measures.
Discussion
In
a
small
group
of
patients
with
treatment-resistant
depression,
we
found
that
a
5-
to
10-mg
per
day
dosage
of
SR-melatonin
decreased
insomnia
(in
6
of
8
patients),
but
had
a
minimal
effect
on
mood,
overall.
The
improvement
in
sleep
appeared
to
be
greatest
following
the
increase
in
dosage
to
10
mg
per
day
(i.e.,
between
Week
2
and
Week
4).
Considering
the
morbidity
associated
with
refractory
depression,
the
effect
of
SR-melatonin
on
insomnia
may
be
clinically
relevant.
Consistent
with
this,
a
previous
study
demonstrated
that
SR-melatonin
had
an
effect
on
subjective
sleep
quality,
but
not
on
mood,
in
patients
with
uncomplicated
depression.16
The
similar
pattern
of
the
current
findings
with
the
previous
study
supports
the
sleep-inducing
qualities
of
SR-melatonin
in
depressed
populations,
and
suggests
that
SR-melatonin
may
be
of
some
benefit
in
both
uncomplicated
and
treatment-resistant
depression.
Other
than
the
excluded
patient
who
developed
a
mixed
affective
state,
no
significant
side
effects
were
noted
in
the
patients
over
the
course
of
the
study.
One
patient
did
report
a
mild
increase
in
somnolence,
and
another
reported
a
small
increase
in
agitation
at
the
higher
dose
of
SR-melatonin.
The
general
lack
of
side
effects
is
consistent
with
the
previous
study
in
patients
with
uncomplicated
depression."6
The
patient
who
developed
a
mixed
affective
state
was
a
24-year-old
woman
with
no
history
of
hypoma-
nia;
she
was
not
aware
of
any
family
history
of
bipolar
illness.
Although
the
mechanism
of
her
mixed
state
is
unknown,
a
previous
case
report
describes
an
associa-
tion
between
melatonin
levels
and
affective
switches
in
a
drug-free
patient
with
bipolar
disorder.2'
In
summary,
although
the
open-label
design
and
small
sample
size
of
this
pilot
study
limit
interpretation
of
the
findings,
it
appears
that
SR-melatonin
may
be
a
useful
adjunct
for
sleep,
but
does
not
substantially
aug-
ment
existing
antidepressant
therapies
in
treatment-
resistant
depression.
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PSlgnllcmne
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Procedure
jp
-c0.0
I
e1p
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2
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f.
.
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