2014 John Wiley & Sons A/S

Published by John Wiley & Sons Ltd.

Bipolar Disorders 2014: 16: 410421

BIPOLAR DISORDERS

Original Article

Melatonin attenuates antipsychotic metabolic

eects: an eight-week randomized,
double-blind, parallel-group,
placebo-controlled clinical trial
Romo-Nava F, Alvarez-Icaza Gonz

alez D, Fres

an-Orellana A, Saracco
Alvarez R, Becerra-Palars C, Moreno J, Ontiveros Uribe MP, Berlanga
C, Heinze G, Buijs RM. Melatonin attenuates antipsychotic metabolic
eects: an eight-week randomized, double-blind, parallel-group,
placebo-controlled clinical trial.
Bipolar Disord 2014: 16: 410421. 2014 John Wiley & Sons A/S.
Published by John Wiley & Sons Ltd.
Objective: Second-generation antipsychotics (SGAs) are among the rstline treatments for bipolar disorder and schizophrenia, but have a
tendency to generate metabolic disturbances. These features resemble a
metabolic syndrome for which a central autonomic imbalance has been
proposed that may originate from the hypothalamic suprachiasmatic
nuclei. In a clinical trial, we hypothesized that melatonin, a hormone
that regulates the suprachiasmatic nucleus, could attenuate SGAinduced adverse metabolic eects.
Methods: In an eight-week, double-blind, randomized, placebocontrolled, parallel-group clinical trial, we evaluated the metabolic eect
of melatonin in SGA-treated patients in terms of weight, blood pressure,
lipid, glucose, body composition, and anthropometric measures. A total
of 44 patients treated with SGAs, 20 with bipolar disorder and 24 with
schizophrenia, randomly received placebo (n = 24) or melatonin 5 mg
(n = 20).
Results: The melatonin group showed a decrease in diastolic blood
pressure (5.1 versus 1.1 mmHg for placebo, p = 0.003) and attenuated
weight gain (1.5 versus 2.2 kg for placebo, F = 4.512, p = 0.040)
compared to the placebo group. The strong benecial metabolic eects
of melatonin in comparison to placebo on fat mass (0.2 versus 2.7 kg,
respectively, p = 0.032) and diastolic blood pressure (5.7 versus 5.5
mmHg, respectively, p = 0.001) were observed in the bipolar disorder
and not in the schizophrenia group. No adverse events were reported.
Conclusions: Our results show that melatonin is eective in attenuating
SGAs adverse metabolic eects, particularly in bipolar disorder. The
clinical ndings allow us to propose that SGAs may disturb a centrally
mediated metabolic balance that causes adverse metabolic eects and
that nightly administration of melatonin helps to restore. Melatonin
could become a safe and cost-eective therapeutic option to attenuate or
prevent SGA metabolic eects.

Francisco Romo-Navaa,b,c, Den

Alvarez-Icaza Gonza
lezb,d, Ana
Fresa
n-Orellanad, Ricardo Saracco
Alvareze, Claudia Becerra-Palarsb,
Julia Morenod, Martha P Ontiveros
Uribef, Carlos Berlangad, Gerhard
Heinzea and Ruud M Buijsc
Departamento de Psiquiatr
a y Salud Mental,
Facultad de Medicina, UNAM, bCl
nica de
Trastornos Afectivos, Instituto Nacional de
Psiquiatr
a Dr. Ramo
n de la Fuente,
c
Hypothalamic Integration Mechanisms
Laboratory, Departmento de Biologia Celular y
Fisiologia, Instituto de Investigaciones
Biome
dicas, UNAM, dSubdireccio
n de
Investigaciones Cl
nicas, eCl
nica de
Esquizofrenia, fSubdireccio
n de Servicios
Cl
nicos, Instituto Nacional de Psiquiatr
a Dr.
Ramo
n de la Fuente, Mexico City, DF, Mexico
a

doi: 10.1111/bdi.12196
Key words: bipolar disorder blood pressure
fat mass melatonin metabolic
schizophrenia second-generation
antipsychotic weight
Received 8 April 2013, revised and accepted for
publication 5 November 2013
Corresponding author:
Ruud M. Buijs, Ph.D.
Hypothalamic Integration Mechanisms
Laboratory
Department de Biologia Celular y Fisiologia
Instituto de Investigaciones Biome
dicas
Ciudad Universitaria
Universidad Nacional Auto
noma de Me
xico
Sede del Tercer Circuito Exterior
Edificio B, 2 Piso
Mexico City 04510
Mexico
Fax: 52 55 56228958
E-mail: ruudbuijs@gmail.com
ClinicalTrials.gov Identifier: NCT01811160.

410

Melatonin attenuates antipsychotic metabolic eect

Bipolar disorder and schizophrenia are frequently
associated with an elevated risk for obesity, hypertension, diabetes mellitus, dyslipidemia, and other
metabolic disturbances (1, 2). Second-generation
antipsychotics (SGAs) have a demonstrated ecacy in acute and long-term treatment of these disorders and are considered a rst option in most
treatment guidelines (35). Unfortunately, the use
of SGAs is associated with drug-induced weight
gain, disturbed glucose and lipid regulation, and
an increase of cardiovascular risk, and these
adverse side eects become a cause for nonadherence to treatment (6). Mortality in this population
often reaches levels that are double or triple the
rates reported for the general population, and cardiovascular disease is one of the main causes of
mortality and morbidity in patients with these illnesses (79).
Metabolic disturbances induced by SGAs vary
depending on the drug. For example, the most
eective SGAs, clozapine and olanzapine, are
more frequently associated with weight gain and
increases in triglyceride and cholesterol levels than
quetiapine and risperidone (10).
There are several hypotheses attempting to
explain the complex pathways that lead to antipsychotic therapeutic eects and their accompanying adverse metabolic eects (10). Melatonin
has been shown to reduce weight gain in rats
(1113). It was also recently given to animals
receiving SGAs and prevented, to a large
extent, the body weight increase, thus indicating
a possible role for biological rhythms in SGAinduced body weight accumulation (14). Melatonin is a hormone secreted by the pineal gland
that follows a circadian rhythm with increased
secretion in the middle of the night (15). This
hormone acts, in particular, on the suprachiasmatic nucleus (SCN) and other areas in the
brain and periphery (16). Thus, melatonin has
been shown to be involved in a series of biological functions such as sleep regulation (17, 18),
blood pressure (BP) (19, 20), regulation of circadian rhythms, mood, and behavior (21), and
more recently the regulation of metabolic processes including insulin, leptin, and lipid regulation (20, 22, 23).
Given previous results in experimental animals
(14), the purpose of the present study was to
test the potential eect of melatonin in reducing
or preventing some of the metabolic disturbances associated with SGAs. The results show
that melatonin treatment indeed prevents, to a
large extent, the adverse metabolic disturbances
in SGA-treated patients, particularly in bipolar
disorder.

Methods
Study setting

The study was conducted in accordance with Good

Clinical Practices and the World Medical Association Declaration of Helsinki, and the study protocol was registered and approved (Project
Registration #144) by the Institutional Review
Boards of the Instituto Nacional de Psiquiatr
a
Ram

on de la Fuente Mu~
n
z (INPRF) in Mexico
City. Written informed consent was obtained after
the procedures had been explained in detail to the
patients.
Subjects

Patients were recruited from both the inpatient

and outpatient services of the INPRF, a highly
specialized mental health center dedicated to
research, education, and treatment of psychiatric
patients. Subjects were included in the study if they
met the following criteria: (i) men and non-pregnant, non-lactating women aged between 18 and
45 years; (ii) DSM-IV-TR criteria for schizophrenia or bipolar disorder type I; (iii) free of concomitant medical or neurological illness (as per review
of systems and general physical examination); (iv)
free of DSM-IV current substance abuse or a history of substance dependence in the last six
months; and (v) initiated on continuous treatment
with SGAs (clozapine, olanzapine, quetiapine, or
risperidone) for a period no greater than the last
three months prior to their inclusion in the present
study. Patients were excluded if they: (i) were diagnosed with hypertension, diabetes mellitus, dyslipidemia, thyroid disorders, or hepatic illness; (ii) had
a history of hypersensitivity to melatonin; (iii)
exhibited high risk for suicide or high risk for
aggressiveness; or (iv) were women who were not
practicing reliable forms of contraception. Patients
were eliminated from the study if they suspended
SGAs or two consecutive doses of the study capsule at any point during the follow-up period.
Study design and procedures

This was an eight-week, randomized, doubleblind, parallel-group, placebo-controlled clinical

trial. An initial screening interview with eligible
patients was performed to determine the fulllment of inclusion and exclusion criteria. If these
criteria were met, voluntary written informed consent was obtained and patients were scheduled for
a baseline visit (no more than seven days after the
screening evaluation). After the baseline clinical
evaluation, patients were randomly allocated by

411

Romo-Nava et al.
single randomization procedures (computerized
random numbers generated by one investigator,
AF-O) with a 1:1 allocation ratio to receive daily
either a 5-mg presentation of slow-release melatonin (Cronocaps; Productos Medix, S.A. de C.V.,
M
exico City, M
exico) or a physically identical
placebo capsule to be administered orally at
20:00 hours.
Melatonin
administration
at
20:00 hours during the duration of the study had
the purpose of favoring regular sleeping schedules.
This prolonged release presentation has a delivery
system that allows 12 hours of slow release of
melatonin with a Tmax = 2.7  0.7 hours (Tmax:
the time after administration of a drug when the
maximum plasma concentration is reached) and a
t1/2 = 1.5  0.7 hours (t1/2: the period of time
required for the concentration or amount of drug
in the body to be reduced to one-half of a given
concentration or amount) (unpublished bioavailability study, Productos Medix, S.A. de C. V.).
Therefore, a more physiological melatonin distribution is expected if it is administered two hours
before bedtime. Similar administration schedules
have been reported with positive results (20). The
dose was maintained until the end of the followup period (eight weeks). Changes in SGA types
were prohibited throughout the study, but dose
adjustments were allowed and documented. SGAs
were classied as high risk (clozapine and olanzapine) or medium risk (quetiapine and risperidone)
according to their risk for inducing metabolic disturbances. Psychotropic drug administration other
than the prescribed study medication and the
SGAs, such as antidepressants, hypnotics, or
mood stabilizers, were permissible if clinically
indicated. All concomitant medication use was
recorded.
Assessments

Patients were asked to fast 12 hours prior to

each evaluation. Programmed evaluations began
at 7:008:00 hours. First, laboratory testing of
blood was performed and, secondly, anthropometric measures including body weight, height,
body mass index (BMI), fat mass percentage, fat
mass, lean mass, and total body water measures
were obtained using a TANITA 300A Body
Composition Analyzer (Tanita Corporation of
America, Inc., Arlington Heights, IL, USA).
Also, waist and hip circumferences, waist/hip
ratio, and BP were determined. Finally, two
trained psychiatrists (FR-N and DA-I), who were
blinded to the treatment randomization at all
times, performed a clinical evaluation. This
included the application of the Positive and

412

Negative Syndrome Scale (PANSS) (30 items, 1

7 severity scale) (24), the Clinical Global ImpressionSeverity of Illness (CGI-S) scale (25), the
Hamilton Depression Rating Scale (HDRS) (26),
and the Young Mania Rating Scale (YMRS)
(27) for patients diagnosed with bipolar disorder;
and the Calgary Depression Scale (CDSS) (28)
for patients with schizophrenia. These assessments were all determined at baseline, after week
3 of treatment, and at the end of the study.
Statistical procedures

Demographic and clinical characteristics were

described using frequencies and percentages for
categorical variables and means and standard
deviations (SDs) for continuous variables. First,
to evaluate group dierences, mean changes in
anthropometric and metabolic variables from
baseline to endpoint were used as dependent
variables and analyzed using the t-test for independent samples according to treatment group
and diagnostic group comparisons. Secondly,
patients were included in four analysis of covariance (ANCOVA) models of mean change from
baseline to endpoint, with baseline values as a
covariate, and the SGA metabolic risk in ANCOVA model 1, gender in ANCOVA model 2, mood
stabilizers (lithium, valproate, lamotrigine, or carbamazepine) in ANCOVA model 3, and baseline
BMI in ANCOVA model 4 as the eect of interest. The primary outcome parameters were the
changes observed in weight, body composition,
anthropometric measures, and metabolic variables from baseline to endpoint according to
placebo or melatonin treatment allocation. Secondary parameters included changes from baseline to endpoint in the severity symptom scales
and the fulllment of metabolic syndrome criteria
during the study [according to Adult Treatment
PanelIII (ATPIII) diagnostic criteria]. All statistical tests were two-sided and performed at a 0.05
signicance level.

Results
Patients

A total of 60 patients were assessed for eligibility

from October 2008 to November 2011. Fifty
patients met the inclusion criteria, were recruited
and were randomized to receive placebo (n = 25)
or melatonin (n = 25); 29 were diagnosed with
schizophrenia and 21 with bipolar disorder. Six
patients were lost before the third week of the follow-up (placebo: n = 1, melatonin: n = 5) and

Melatonin attenuates antipsychotic metabolic eect

SGAs, while 11 (45.8%) and ve (25%) patients
received high-risk SGAs, respectively. The mean
antipsychotic dose (chlorpromazine equivalence)
at baseline was 275.1 mg/day (SD = 280 mg/day).
Prior to baseline comparison of demographic
characteristics and illness features between treatment groups, some dierences emerged between
patients with schizophrenia and bipolar disorder; a
higher percentage of patients with schizophrenia
were single when compared to patients with bipolar disorder (91.7% versus 55%, respectively;
v2 = 7.8, df = 1, p = 0.005), while patients with
bipolar disorder were more frequently employed
than those with schizophrenia (40% versus 12.5%,
respectively; v2 = 4.4, df = 1, p = 0.03). Patients
with bipolar disorder reported an earlier age at illness onset (19.5 versus 23.9 years, respectively;
t = 2.0, df = 42, p = 0.04) and a longer duration of
illness (642 versus 220.6 weeks, respectively;
t = 3.4, df = 42, p = 0.005) (Table 1).

Fig. 1. CONSORT patient ow diagram.

were excluded from the analysis, as there was no

post-baseline assessment in these patients. Fortyfour patients completed the eight-week follow-up
(placebo: n = 24, melatonin: n = 20) and were
included in the analyses (see Fig. 1).
Baseline demographic and clinical characteristics. Demographic features of the sample were as
follows. Fifty per cent of the patients were men,
and the mean age was 29.5 years (SD = 8.3 years).
Thirty-three patients (75%) were single and 33
patients (75%) were unemployed at the time of
their recruitment. The mean duration of education
was 12.1 years (SD = 3.5 years). Mean age at illness onset was 21.9 years (SD = 7.3 years) with a
mean length of illness of 412.1 weeks (SD = 505.1
weeks). There were no signicant dierences
between melatonin and placebo treatment groups
in baseline demographic characteristics, and they
were also comparable in terms of illness features at
baseline.
At baseline, 15 patients (34.1%) were receiving
quetiapine, 14 (31.8%) olanzapine, and 13 (29.5%)
risperidone, and the remaining two patients (4.5%)
were treated with clozapine. Thus, 13 patients
(54.2%) in the placebo group and 15 (75%) in the
melatonin group were treated with medium-risk

Concomitant treatment. The comparisons of concomitant medication between patients allocated to

the placebo or the melatonin group showed no signicant dierences in the use of each medication,
with the exception of mood stabilizers; a higher
percentage of patients in the melatonin group
(n = 13, 65%) when compared to the placebo
group (n = 8, 33.3%) were using this type of medication (v2 = 4.3, df = 1, p = 0.03). Most patients
in the bipolar disorder group were treated with
mood stabilizers (n = 18, 80%) during the study
and only two patients in the schizophrenia group
(8%). No dierences in concomitant treatment
with mood stabilizers, antidepressants, or benzodiazepines were observed between patients who
received placebo or melatonin in each diagnostic
group as shown in Table 1.
Baseline anthropometric, body composition, metabolic and symptom severity variables. At baseline,
melatonin-treated patients had signicantly higher
cholesterol (t = 2.2, df = 42, p = 0.02) and triglyceride (t = 2.0, df = 42, p = 0.04) levels, while at the
end of the study dierences remained in cholesterol
(t = 2.2, df = 42, p = 0.03) but not in triglyceride
(t = 0.7, df = 42, p = 0.44) levels as compared to
placebo-treated patients. Changes reported from
baseline to endpoint were signicant (<0.05) in all
variables with the exception of waist circumference
(p = 0.06) and triglyceride levels (p = 0.77).
Although patients with schizophrenia in the placebo group showed a higher score on the CDSS at
baseline when compared to the melatonin group
(t = 2.27, df = 22, p = 0.03), no statistically signicant dierences emerged between these groups at

413

Romo-Nava et al.
Table 1. Comparison of baseline demographic and clinical characteristics between treatment groups
Placebo
(n = 24)
Gender, n (%)
Male
12 (50)
Female
12 (50)
Marital status, n (%)
Single
18 (75)
Married
6 (25)
Employment status, n (%)
Unemployed
19 (79.2)
Employed
5 (20.8)
Antipsychotics, n (%)
High-metabolic risk SGA
Clozapine
1 (4.2)
Olanzapine
10 (41.7)
Medium-metabolic risk SGA
Risperidone
6 (25)
Quetiapine
7 (29.2)
Concomitant medications, n (%)
Bipolar disorder
Mood stabilizers
8 (80)
Lithium
2 (20)
Valproate
6 (60)
Carbamazepine

Lamotrigine

SSRIs

Benzodiazepines
1 (10)
Schizophrenia
Mood stabilizers

Lithium

Valproate

Carbamazepine

Lamotrigine

SSRIs
3 (21.4)
Benzodiazepines
4 (28.5)
Age, years, mean (SD)
28.6 (9)
Education, years, mean (SD)
12.4 (3.3)
Age of illness onset, years,
21.0 (5.6)
mean (SD)
Length of illness, weeks,
458.1 (544.7)
mean (SD)
Antipsychotic dose,
256.1 (307.9)
equivalency, mean (SD)

Melatonin
(n = 20)

10 (50)
10 (50)
15 (75)
5 (25)
14 (70)
6 (30)

1 (5)
4 (20)
7 (35)
8 (40)

10 (100)
1 (10)
7 (70)
1 (10)
1 (10)

4 (40)
1 (10)

1 (10)

2 (20)
4 (40)
30.6 (7.5)
11.8 (3.7)
23.0 (8.9)
357.0 (460.8)
297.9 (248.3)

No significant differences were observed between the placebo

and melatonin groups.
SD = standard deviation; SGA = second-generation antipsychotic; SSRI = selective serotonin reuptake inhibitor.

the end of the follow-up [2.0 (SD = 3.1) versus 1.4

(SD = 2.0), respectively; t = 0.5, df = 22, p = 0.56].
Primary outcome measures

Melatonin versus placebo. A signicant dierence

in mean diastolic BP change was observed between
the placebo and melatonin groups (1.1 versus
5.1 mmHg, respectively, p = 0.003) (Fig. 2A).
In ANCOVA model 1, when baseline values
were used as a covariate and the interaction with

414

SGA metabolic risk was considered, the dierence

in mean weight change was signicant between the
placebo and melatonin groups [2.2 (SD = 3.0) versus 1.5 (SD = 2.9) kg, respectively; F = 4.512,
p = 0.040] with a higher increase in patients who
received placebo compared to patients who
received melatonin in those treated with mediumrisk SGAs [1.9 (SD = 2.1) versus 0.6 (SD = 2.5)
kg, respectively] and a lower increase in patients
who received placebo compared to patients who
received melatonin in those treated with high-risk
SGAs [2.4 (SD = 3.9) versus 4.3 (SD = 2.4) kg,
respectively]. A signicant dierence was also
observed for waist circumference changes between
the placebo and melatonin groups [1.9 (SD = 3.8)
versus 2.2 (SD = 3.0), respectively, p = 0.05], and
trends towards signicant dierences were
observed for mean changes in BMI (0.78 versus
0.60 kg/m2, respectively; F = 3.235, p = 0.08) and
total body water (0.6 versus 0.95 kg, respectively;
F = 3.329, p = 0.076). Baseline values and changes
from baseline to endpoint for anthropometric and
metabolic variables are shown in Tables 2 and 3;
statistical analyses of the eect of treatment with
melatonin, metabolic risk of SGAs, and the combined eect of both are included in Tables 2 and 3.
In ANCOVA model 2, when baseline values
were used as a covariate and the interaction with
gender was considered, mean change in diastolic
BP showed a signicant dierence between the placebo and melatonin groups [1.1 (SD = 7.1) versus
5.1 (SD = 5.9) mmHg, respectively; F = 6.37,
p = 0.016]. A stronger eect was noted in female
patients [3.8 (SD = 6.6) versus 8.3 (SD = 6.1)
mmHg, respectively] than in male patients [ 1.5
(SD = 6.7) versus 2.0 (SD = 4.0) mmHg, respectively].
In ANCOVA model 3, when baseline values
were used as a covariate and the use of a mood stabilizer interaction was considered, a signicant difference in mean change between the placebo and
melatonin groups in fat mass was observed [1.2
(SD = 2.4) versus 0.005 (SD = 2.8) kg, respectively; p = 0.011], where a stronger eect was
noted in patients treated with mood stabilizers [2.8
(SD = 2.9) versus 0.28 (SD = 2.9) kg, respectively] than in patients without mood stabilizers
[0.48 (SD = 1.9) versus 0.5 (SD = 2.9) kg, respectively]. In this ANCOVA model, a signicant difference in mean change between the placebo and
melatonin groups in diastolic BP was observed
[1.12 (SD = 7.1) versus 5.15 (SD = 5.9) mmHg,
respectively; p = 0.005]. Patients using mood stabilizers showed a stronger eect [6.2 (SD = 5.8) versus 6.3 (SD = 6.2) mmHg, respectively] than
patients without a mood stabilizer [ 1.4

Melatonin attenuates antipsychotic metabolic eect

(B)

*p = 0.0032

DBP mean change (mmHg)

DBP mean change (mmHg)

(A)
4
2
0
2
4
6
8

Melatonin

Placebo

10

*p = 0.0008

5
0
5
10

Melatonin

Placebo

BIPOLAR DISORDER*

Melatonin

Placebo

BIPOLAR DISORDER

Placebo

SCHIZOPHRENIA

(D)

*p = 0.0324

Melatonin

Placebo

SCHIZOPHRENIA

Triglyceride mean change (mg/dL)

Fat mass mean change (kg)

(C)

Melatonin

100

p = 0.0862

50

50

Melatonin

Placebo

BIPOLAR DISORDER*

Melatonin

Placebo

SCHIZOPHRENIA

Fig. 2. Blood pressure and metabolic eects of melatonin treatment. (A) Patients who were randomized to receive melatonin showed
a decrease in diastolic blood pressure (DBP) versus the placebo group ( 5.1 versus 1.1 mmHg, respectively; p = 0.003). Melatonin
showed a particularly benecial metabolic eect in patients with bipolar disorder in terms of mean changes in DBP (B) (5.5 mmHg
versus 5.7 mmHg for the placebo and melatonin groups, respectively; p = 0.001), fat mass (C) (2.7 versus 0.2 kg, respectively;
p = 0.032), and triglycerides (D) (50.1 versus 20 mg/dL, respectively; p = 0.08) which was not observed in the schizophrenia group.
Graphs show comparisons using Students t-test. *Statistically signicant results (p < 0.05).

(SD = 6.4) versus 2.8 (SD = 5.0) mmHg, respectively]. In ANCOVA model 4, no other signicant
dierences were observed.
Other similar ANCOVA models using baseline
BP, cholesterol, triglyceride, glucose, BMI, and
current antidepressant treatment as eects of interest were employed, and no signicant ndings were
observed.
SGA metabolic risk. Patients treated with mediumrisk SGAs showed a signicant dierence in mean
change in diastolic BP between those treated with
placebo and melatonin (1.8 versus 4.6 mmHg,
respectively; p = 0.008). Patients treated with highrisk SGAs showed signicant dierences between
the placebo and melatonin groups in mean change
in lean mass (0.8 versus 2.7 kg, respectively;
p = 0.007) and total body water (0.6 versus 2.0 kg,
respectively; p = 0.008).
Schizophrenia and bipolar disorder groups. In the
bipolar disorder group, signicant dierences
between the placebo and melatonin groups in mean
change in fat mass percentage (2.8 versus 0.03%,
respectively; p = 0.004), fat mass (2.7 versus
0.2 kg, respectively; p = 0.032), and diastolic BP
(5.5 versus 5.7 mmHg, respectively; p = 0.001)
were observed, and a trend was observed for mean

change in triglycerides (50.1 versus 20 mg/dL,

respectively; p = 0.08) (see Figs. 2BD).
In the schizophrenia group, no signicant dierences were present in anthropometric, body composition, or metabolic variables.
Secondary outcome measures

Symptom severity. Mean baseline ecacy rating

scale scores and mean changes in these scores from
baseline to endpoint in both treatment groups are
shown in Table 4. In this analysis, the placebo and
melatonin groups showed similar improvements as
measured by changes from baseline in the total
PANSS, PANSS subscales, CGI-S, and depressive
symptoms assessed by the CDSS in patients with
schizophrenia, and the HDRS and YMRS in
patients with bipolar disorder. There were no serious adverse events reported for the placebo or melatonin group.
Metabolic syndrome. At baseline, seven patients
(15.9%) met the criteria for metabolic syndrome
and at the end of week 8, these same patients met
the criteria. Nevertheless, at the end of the study,
four additional patients had metabolic syndrome.
All of them were diagnosed with bipolar disorder;
three were under treatment with quetiapine and

415

Romo-Nava et al.
Table 2. Mean change from baseline to endpoint in anthropometric variables
Placebo (n = 24)
Variable
Body weight (kg)
Baseline
Endpoint
Mean change
Body mass index
Baseline
Endpoint
Mean change
Waist circumference
Baseline
Endpoint
Mean change
Hip circumference
Baseline
Endpoint
Mean change
Fat percentage
Baseline
Endpoint
Mean change
Fat mass
Baseline
Endpoint
Mean change
Lean mass
Baseline
Endpoint
Mean change
Total body water
Baseline
Endpoint
Mean change

SGA medium risk

Mean (SD)

Melatonin (n = 20)
SGA high risk
Mean (SD)

SGA medium risk

Mean (SD)

70.0 (11.0)
72.0 (10.7)
1.9 (2.1)

66.1 (14.7)
68.6 (15.0)
2.4 (3.9)

72.2 (15.8)
72.9 (13.9)
0.6 (2.5)

75.7 (14.3)
80.1 (13.2)
4.3 (2.4)

M: F = 0.71, p = 0.40
AP: F = 5.52, p = 0.02
M 9 AP: p = 0.04

26.7 (5.4)
27.4 (5.3)
0.7 (0.8)

24.6 (6.1)
25.5 (5.9)
0.8 (1.6)

26.1 (4.2)
26.4 (3.6)
0.3 (0.8)

26.2 (5.3)
27.7 (4.7)
1.4 (0.8)

M: F = 0.18, p = 0.67
AP: F = 2.70, p = 0.10
M 9 AP: p = 0.08

96.2 (13.4)
99.0 (12.5)
2.7 (4.1)

92.1 (16.8)
93.2 (17.1)
1.1 (3.4)

95.4 (10.9)
97.0 (9.4)
1.6 (3.1)

97.6 (12.7)
101.6 (12.7)
4.0 (2.0)

M: F = 0.95, p = 0.33
AP: F = 0.06, p = 0.79
M 9 AP: p = 0.05

93.5 (12.7)
95.5 (13.6)
2.0 (4.5)

99.3 (10.1)
99.1 (6.2)
0.1 (7.7)

99.3 (8.1)
101.3 (7.1)
2.0 (1.5)

M: F = 0.008, p = 0.93
AP: F = 0.07, p = 0.79
M 9 AP: p = 0.29

27.2 (10.5)
28.0 (10.1)
0.8 (1.8)

22.6 (13.6)
24.2 (13.3)
1.6 (3.1)

28.6 (8.8)
28.5 (7.2)
0.1 (2.2)

25.1 (14.1)
26.2 (12.5)
1.1 (2.7)

M: F = 0.50, p = 0.48
AP: F = 0.74, p = 0.39
M 9 AP: p = 0.732

19.8 (9.8)
20.7 (9.5)
0.9 (1.6)

16.1 (12.5)
17.7 (12.5)
1.6 (3.3)

21.6 (9.0)
21.1 (7.4)
0.5 (2.8)

20.4 (13.1)
22.1 (12.1)
1.6 (2.4)

M: F = 0.30, p = 0.58
AP: F = 2.29, p = 0.13
M 9 AP: p = 0.294

50.0 (6.5)
50.0 (7.4)
0.007 (4.7)

49.9 (8.6)
50.8 (9.3)
0.8 (1.2)

51.0 (10.4)
51.8 (9.8)
0.8 (1.4)

55.3 (6.5)
58.1 (6.8)
2.7 (0.9)

M: F = 2.45, p = 0.125
AP: F = 2.43, p = 0.12
M 9 AP: p = 0.486

36.9 (4.4)
37.5 (4.9)
0.6 (1.5)

36.6 (6.3)
37.2 (6.8)
0.6 (0.9)

37.3 (7.6)
37.9 (7.1)
0.6 (1.0)

40.5 (4.7)
42.5 (5.0)
2.0 (0.6)

M: F = 3.32, p = 0.07
AP: F = 3.41, p = 0.07
M 9 AP: p = 0.076

100.0 (9.1)
101.6 (7.5)
1.5 (4.5)

SGA high risk

Mean (SD)

Statistica

AP = effect according to antipsychotic metabolic risk type; SD = standard deviation; SGA = second-generation antipsychotic;
M = treatment effect (melatonin or placebo); M 9 AP = effect according to interaction of treatment (melatonin or placebo) and antipsychotic metabolic risk type.
a
Based on analysis of covariance adjusted for baseline score, treatment with melatonin or placebo (M), and antipsychotic metabolic risk
(AP) as effects of interest.

one was under treatment with olanzapine, and

three received placebo.
Discussion

In the present study, four main ndings emerged:

(i) patients receiving SGAs and melatonin showed
a decrease in diastolic BP compared to patients
allocated to the placebo group; (ii) melatonin
showed a particularly benecial metabolic eect in
patients with bipolar disorder in terms of mean fat
mass, diastolic BP, and triglycerides, changes that
were not observed in the schizophrenia group; (iii)
melatonin had varied metabolic eects depending
on the SGA metabolic risk prole; and (iv) melatonin did not aect symptom severity outcome measures in SGA-treated subjects.

416

To the best of our knowledge, this is the rst

clinical study to evaluate the metabolic eects of
melatonin in patients treated with SGAs, demonstrating that melatonin treatment is particularly
benecial in bipolar disorder. We observed that
the SGA metabolic risk prole was associated with
a dierential eect on weight gain. Melatonin
reduced weight gain in patients receiving mediumrisk SGAs, an eect that was not apparent in the
high-risk SGA- treated patients, where melatonin
seemed to be associated with greater weight gain.
This result should be examined carefully, as weight
is aected not only by fat, but also by non-fat components (lean mass and total body water). We
observed that high-risk SGA-treated patients who
received melatonin had a signicantly greater
increase in total body water compared to the

Melatonin attenuates antipsychotic metabolic eect

Table 3. Mean change from baseline to endpoint in metabolic variables
Placebo (n = 24)
Variable

SGA medium risk

Mean (SD)

Systolic blood pressure

Baseline
109.4 (10.1)
Endpoint
109.8 (10.6)
Mean change
0.3 (6.4)
Diastolic blood pressure
Baseline
71.2 (3.9)
Endpoint
73.0 (6.3)
Mean change
1.8 (5.8)
Fasting glucose
Baseline
90.2 (8.2)
Endpoint
90.3 (7.1)
Mean change
0.1 (10.7)
Triglyceride levels
Baseline
144.4 (87.4)
Endpoint
177.2 (125.9)
Mean change
32.7 (89.3)
HDL cholesterol
Baseline
43.6 (11.1)
Endpoint
41.8 (9.4)
Mean change
1.7 (5.8)
LDL cholesterol
Baseline
93.8 (26.4)
Endpoint
92.9 (24.9)
Mean change
0.9 (28.2)
Total cholesterol
Baseline
163.2 (43.4)
Endpoint
168.9 (28.8)
Mean change
5.6 (31.0)

Melatonin (n = 20)
SGA high risk
Mean (SD)

SGA medium risk

Mean (SD)

SGA high risk

Mean (SD)

Statistica

112.0 (10.5)
108.3 (8.7)
3.6 (10.3)

109.2 (9.4)
104.1 (10.5)
5.0 (14.4)

115.6 (11.2)
107.4 (18.3)
8.2 (9.6)

M: F = 1.61, p = 0.21
AP: F = 0.17, p = 0.67
M 9 AP: p = 0.68

72.3 (11.4)
72.6 (5.1)
0.2 (8.6)

73.4 (4.9)
68.8 (7.7)
4.6 (5.9)

81.6 (10.1)
74.8 (11.0)
6.8 (6.2)

M: F = 4.11, p = 0.04
AP: F = 0.009, p = 0.92
M 9 AP: p = 0.53

84.1 (5.7)
86.9 (3.8)
2.7 (5.5)

88.8 (8.4)
88.5 (6.7)
0.2 (8.1)

87.4 (13.1)
87.8 (3.9)
0.4 (15.6)

M: F = 0.08, p = 0.76
AP: F = 0.65, p = 0.42
M 9 AP: p = 0.59

114.7 (62.8)
140.3 (113.2)
25.6 (72.4)

174.2 (88.6)
180.1 (111.4)
5.9 (89.2)

197.2 (41.6)
204.2 (43.0)
7.0 (62.8)

M: F = 0.47, p = 0.49
AP: F = 0.01, p = 0.90
M 9 AP: p = 0.84

48.3 (12.3)
48.3 (11.2)
0.01 (8.5)

45.2 (12.9)
43.6 (11.5)
1.6 (9.2)

39.2 (5.4)
41.8 (2.5)
2.6 (4.6)

M: F = 0.003, p = 0.95
AP: F = 1.52, p = 0.22
M 9 AP: p = 0.80

95.2 (23.5)
96.8 (22.5)
1.6 (21.4)

113.0 (25.7)
112.0 (30.5)
0.9 (25.8)

97.1 (42.6)
115.7 (41.2)
18.6 (19.5)

M: F = 2.60, p = 0.11
AP: F = 1.18, p = 0.28
M 9 AP: p = 0.50

166.3 (29.1)
173.1 (27.0)
6.8 (22.8)

193.1 (35.1)
198.4 (57.1)
5.3 (44.9)

181.0 (43.8)
198.4 (36.8)
17.4 (20.2)

M: F = 1.13, p = 0.29
AP: F = 0.23, p = 0.63
M 9 AP: p = 0.77

AP = effect according to antipsychotic metabolic risk type; HDL = high-density lipoprotein; LDL = low-density lipoprotein; M = treatment effect (melatonin or placebo); M 9 AP = effect according to interaction of treatment (melatonin or placebo) and antipsychotic metabolic risk type; SD = standard deviation; SGA = second-generation antipsychotic.
a
Based on analysis of covariance adjusted for baseline score, treatment with melatonin or placebo (M) and antipsychotic metabolic risk
(AP) as effects of interest.

placebo group, an eect that was not observed in

the medium metabolic risk SGA-treated groups
and could account for the apparent weight and
waist increases in high metabolic risk SGA-treated
subjects who received melatonin. The potential
interaction of melatonin with high metabolic risk
SGAs in the modulation of the balance between
corporal water and lean mass warrants further
study.
It is known that patients with bipolar disorder
or schizophrenia have a disrupted circadian cycle
(2931) and several metabolic disturbances (2, 32)
that could precede the onset of this mental disorders (33) and the initiation of treatment (34). For
example, a recent study showed that melatonin
receptor type 1 and vasopressin and/or vasoactive
intestinal peptide positive cells were increased in
the hypothalamic SCN and paraventricular
nucleus (PVN) of patients with mood disorders,
further indicating a disturbance in mood
disorders (35) that can be linked to melatonin. A

baseline circadian rhythm disturbance and metabolic vulnerability associated with these disorders
could be exacerbated by SGA treatment. We propose that the SGA-induced metabolic adverse
eects are generated at least in part by alteration
of the functioning of hypothalamic structures
which disturbs the central regulation of metabolism, while SGAs also modulate other neurotransmitter systems and achieve therapeutic eects.
The observation that melatonin attenuates fat
mass increase, decreases diastolic BP, and possibly reduces mean changes in triglycerides in
patients with bipolar disorder but not schizophrenia suggests that melatonin may help to re-establish a damaged circadian rhythm in bipolar
disorder, but may be less eective in restoring the
function of the biological clock in schizophrenia.
Knowledge is scarce regarding the central eect
of SGAs and their relationship to adverse metabolic eects. It has been reported that antipsychotics have dierential eects in hypothalamic

417

Romo-Nava et al.
Table 4. Mean change from baseline to endpoint in clinical rating
scales

Measure

Placebo
(n = 24)
Mean (SD)

Melatonin
(n = 20)
Mean (SD)

Table 4. (Continued)

Measure

Endpoint

17.3 (8.2)

13.5 (7.4)

12.5 (6.4)

Mean
6.1 (7.2)
change
Negative PANSS
Baseline
17.9 (9.6)

4.7 (6.3)

Endpoint

15.7 (8.6)

16.0 (8.5)

13.6 (7.4)

Mean
1.9 (5.0)
change
Cognitive PANSS
Baseline
17.1 (8.3)

2.0 (2.9)

Endpoint

16.1 (7.1)

14.5 (6.6)

13.1 (6.1)

Mean
2.5 (4.6)
change
Excitement PANSS
Baseline
7.9 (4.6)

3.0 (4.5)

Endpoint

5.9 (2.5)

7.2 (3.4)
5.1 (1.2)

Mean
2.0 (3.0)
2.0 (3.1)
change
Depression and Anxiety PANSS
Baseline
9.5 (3.9)
10.3 (9.5)
Endpoint
Mean
change
Total PANSS
Baseline
Endpoint

7.0 (3.2)

6.9 (3.1)

2.5 (4.0)

3.4 (9.9)

72.3 (33.3)

64.6 (25.7)

57.0 (25.8)

50.9 (21.2)

Mean
15.3 (18.6)
13.7 (14.5)
change
Clinical Global ImpressionSeverity
Baseline
3.5 (1.5)
3.4 (1.1)
Endpoint

2.9 (1.3)

Mean
0.5 (1.1)
change
Calgary Depression Scaleb
Baseline
4.0 (3.6)
Endpoint

2.0 (3.1)

2.8 (1.1)

1.4 (2.0)

Mean
2.0 (3.1)
0.2 (2.2)
change
Hamilton Depression Rating Scalec
Baseline
10.7 (9.8)
7.8 (3.8)

418

Change F = 33.8,
p < 0.001
Group F = 0.03,
p = 0.86

Change F = 11.9,
p = 0.001
Group F = 0.2,
p = 0.61

Change F = 19.6,
p < 0.001
Group F = 0.4,
p = 0.50

Change F = 128.7,
p < 0.001
Group F = 1.3,
p = 0.25

Change F = 174.7,
p < 0.001
Group F = 0.05,
p = 0.81

Change F = 24.8,
p < 0.001
Group F = 0.06,
p = 0.80

Change F = 10.3,
p = 0.003
Group F = 0.03,
p = 0.86

0.6 (0.9)

1.8 (1.5)

Melatonin
(n = 20)
Mean (SD)

4.4 (4.8)

4.2 (3.6)

Statistica
Endpoint

Positive PANSS
Baseline
19.6 (10.3)

Placebo
(n = 24)
Mean (SD)

Change F = 8.4,
p = 0.008
Group F = 0.2,
p = 0.62

Change F = 34.7,
p < 0.001

Mean
4.7 (8.1)
change
Young Mania Rating Scaled
Baseline
5.0 (5.9)

Statistica
Group F = 0.1,
p = 0.75

3.1 (5.3)

6.2 (8.2)

Endpoint

1.3 (1.9)

1.7 (3.0)

Mean
change

3.7 (5.7)

4.5 (8.1)

Change F = 121.1,
p < 0.001
Group F = 0.06,
p = 0.79

SD = standard deviation; PANSS = Positive and Negative Syndrome Scale.

a
Based on analysis of covariance (ANCOVA) adjusted for baseline score. Change F refers to ANCOVA F-statistic for change in
time, while Group F refers to between-group differences.
b
n = 24.
c
n = 20.
d
n = 20.

structures (36). An immunohistochemistry study,

for example, showed that clozapine and olanzapine
induced a greater activation than risperidone in the
PVN, a fundamental structure in the execution of
hypothalamic signals to the body by hormones and
the autonomic nervous system (ANS), through
which it regulates metabolic functions (37). These
functions of the PVN are strongly under the inuence of the SCN, giving a circadian rhythm to
autonomic and hormonal output (38).
Since the SCN is one of the main targets of
melatonin in the brain and melatonin inhibits the
neuronal ring of SCN neurons (3941), these
results suggest that, through the diminished activity of SCN neurons, those in the PVN are also
inhibited. Based on our clinical results, we propose that an SCN-mediated mechanism could
contribute to explaining the SGA-induced adverse
metabolic eect, and the attenuating eects of
melatonin (42).
The administration of exogenous melatonin has
shown benecial eects in essential hypertension
(43), the metabolic syndrome (20, 44), and diabetes
mellitus (45), all diseases with evidence for disturbed circadian pacemaker function. The eects
of melatonin in lowering BP have been attributed
to the enhancement of the functioning of the biological clock through repeated melatonin administration (19). The BP-lowering eect of melatonin
found in this study is consistent with previous clinical studies (19, 20, 43, 46) and is a desired, possibly
prophylactic eect in subjects treated with SGAs
(4749).

Melatonin attenuates antipsychotic metabolic eect

The benecial metabolic eects of melatonin
were rst described in rats in a study in which it
was observed that the chronic exogenous administration of melatonin suppressed increases in visceral fat, insulin, and leptin associated with aging
(11). Later, it was also reported in animal experiments that melatonin reduced weight gain independently of food intake and total body fat (12, 13)
and that melatonin increased locomotor activity
during the activity period (13). This eect has also
been observed under various obesity-generating
conditions such as a high fat diet (50) or a prolonged photoperiod (51).
In humans, evidence regarding the eect of melatonin on weight is still lacking and basic research
theories still need to be tested in clinical trials. We
provide clinical data that support these theories.
Limitations of this study include the small sample, the inclusion of four dierent SGAs with different metabolic risk proles, and the concomitant
use of other psychotropic drugs that can generate
metabolic disturbances or modify circadian
rhythm by themselves (i.e., valproate and lithium)
as a possible source of bias (5256).
SGA-induced weight gain and other metabolic
disturbances are very frequently unavoidable
landmarks in the pharmacologic treatment of
chronic mental disorders, for which SGAs currently represent the best therapeutic option. This
study shows that the administration of exogenous
melatonin could become a benign, relatively
innocuous, inexpensive and eective alternative
strategy for the attenuation of SGA-induced
adverse metabolic eects, particularly in bipolar
disorder, without aecting the benecial therapeutic eect.
Acknowledgements
This study was supported by Instituto Nacional de Psiquiatra
Dr. Ramon de la Fuente (INPRF, Project Registry #144) and
by Conacyt 79797 and PAPIIT IN-209711. This article is part
of the Ph.D. thesis of FR-N (Ph.D. program in Biomedical Sciences at the Universidad Nacional Aut

onoma de M
exico). Productos Medix, S.A. de C.V. (M
exico City, M
exico) donated
slow-release melatonin and placebo capsules and a body composition analyzer to the INPRF, and partially funded the laboratory analyses. The funders had no role in the study design,
data collection and analysis, decision to publish, or preparation of the manuscript. We also acknowledge Mar
a del Carmen Basualdo, Guadalupe L

opez- Bello, and Arturo Juana for
laboratory and experimental logistic support.

Disclosures
The authors of this paper do not have any commercial associations that might pose a conict of interest in connection with
this manuscript.

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