S-Adenosyl-L-Methionine for Major Depressive Disorder

Abstract

S-Adenosyl-L-Methionine (also called SAMe) was first discovered in Italy in 1952 and soon became popular in Europe and the USA. SAMe is an important physiologic compound, widely distributed throughout the body tissues and fluids. It plays a central role as precursor molecule in several biochemical reactions involving enzymatic transmethylation. Numerous studies have shown that SAMe may affect the regulation of various critical components of monoaminergic neurotransmission involved in the pathophysiology of major depressive disorder (MDD). Some evidence has confirmed its antidepressant effect. These findings have suggested that SAMe may have therapeutic potential in treating MDD. Moreover, SAMe has a very favourable side-effect profile, comparable with that of placebos. Therefore, it may offer considerable advantages as an alternative to antidepressant drugs or as an adjunctive therapy in the treatment of MDD and/or treatment-resistant depression (TRD). A summary of the literature evidence available so far on efficacy of SAMe as monotherapy or as an adjunctive drug in the treatment of MDD and TRD was here provided.

Full text

© Springer India 2016
V. Srinivasan et al. (eds.), Melatonin, Neuroprotective Agents and Antidepressant Therapy,
DOI 10.1007/978-81-322-2803-5_49
S-Adenosyl-L-Methionine
for Major Depressive Disorder
Domenico De Berardis, Laura Orsolini,
Felice Iasevoli, Carmine Tomasetti, Monica Mazza,
Alessandro Valchera, Michele Fornaro,
Giampaolo Perna, Monica Piersanti,
Marco Di Nicola, Giovanni Martinotti,
Francisco López- Muñoz,
and Massimo Di Giannantonio
D. De Berardis (*)
NHS, Department of Mental Health, Psychiatric
Service of Diagnosis and Treatment, Hospital
“G. Mazzini”, ASL 4, Teramo, Italy
Department of Neuroscience, Imaging and Clinical
Science, University “G. D’Annunzio”,
Chieti, Italy
Polyedra Clinical Group, Teramo, Italy
e-mail: dodebera@aliceposta.it
L. Orsolini
Polyedra Clinical Group, Teramo, Italy
Academic Department of Experimental and Clinical
Medicine, United Hospitals, Polytechnic University
of Marche, Ancona, Italy
School of Life and Medical Sciences, University of
Hertfordshire, Hatfield, Herts, UK
Villa S. Giuseppe Hospital, Hermanas Hospitalarias,
Ancona, Italy
F. Iasevoli • C. Tomasetti
Polyedra Clinical Group, Teramo, Italy
Laboratory of Molecular Psychiatry and
Psychopharmacotherapeutics, Section of
Psychiatry, Department of Neuroscience,
University School of Medicine “Federico II”,
Naples, Italy
M. Mazza
Polyedra Clinical Group, Teramo, Italy
Department of Health Science, University of
L’Aquila, L’Aquila, Italy
49
A. Valchera
Polyedra Clinical Group, Teramo, Italy
Villa S. Giuseppe Hospital, Hermanas Hospitalarias,
Ancona, Italy
Laboratory of Molecular and Translational
Psychiatry, Department of Neuroscience, University
School of Medicine “Federico II”, Naples, Italy
M. Fornaro
Polyedra Clinical Group, Teramo, Italy
Department of Education Science, University of
Catania, Catania, Italy
G. Perna
Department of Clinical Neurosciences, Hermanas
Hospitalarias, FoRiPsi, Villa San Benedetto Menni,
Albese con Cassano, Como, Italy
Department of Psychiatry and Neuropsychology,
University of Maastricht, Maastricht,
The Netherlands
Department of Psychiatry and Behavioral Sciences,
Leonard Miller School of Medicine, University of
Miami, Coral Gables, FL, USA
M. Piersanti
NHS, Department of Mental Health, Psychiatric
Service of Diagnosis and Treatment, Hospital
“G. Mazzini”, ASL 4, Teramo, Italy
M. Di Nicola
Institute of Psychiatry and Psychology, Catholic
University of Sacred Heart, Rome, Italy
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49.1 Introduction
S-Adenosyl-L-Methionine (commonly known as
SAMe) is a naturally occurring molecule, located
in several body tissues and fluids. SAMe was
firstly discovered in Italy in 1952 [13]. It was
introduced and sold as a dietary supplement in
the US market in the late 1990s, even though it
has been used as a prescription drug in Italy since
1979, in Spain since 1985 and in Germany since
1989 [28, 45]. It rapidly became one of the most
widely used natural antidepressant [46, 52].
SAMe is synthetized from the amino-acid
L-methionine and adenosine triphosphate (ATP)
by methionine adenosyltransferase, through the
one-carbon cycle. Its metabolic pathway depends
on the dietary intake of vitamin B12, vitamin B6
and folate [22, 23, 30, 54, 63]. SAMe is a com-
mon substrate involved in methyl group trans-
fers. The methyl group (CH3) attached to its
methionine sulphur atom is chemically reactive
and participates into several transmethylation
reactions. In fact, more than 40 metabolic reac-
tions involve the transfer of a methyl group from
SAMe to various substrates, such as nucleic
acids, proteins, lipids and secondary metabo-
lites. In particular, these synthetic reactions
include the neurotransmitter synthesis (e.g. ace-
tylcholine, serotonin, norepinephrine, melatonin
and dopamine), methylation of phospholipids,
glutathione synthesis, DNA transcription, and
myelination and synthesis of carnitine, coen-
zyme Q10 and creatinine [3]. Moreover, it is also
involved in various biological processes, includ-
ing immune system, central nervous system
(CNS) and anti- oxidative (radical scavenging,
glutathione precursor) and anti-inflammatory
processes [42].
SAMe may affect the regulation of various
critical components of monoaminergic neuro-
transmission both by an indirect modulation of
neurotransmitter synthesis (by promoting the
synthesis of BH4 enzymatic cofactor) and a
direct modulation of catabolic enzymes, mono-
amine transporters and neurotransmitter recep-
tors via methylation. In addition, SAMe has been
recognized to be one of the end-products of the
‘one-carbon cycle’, and several studies have sug-
gested that major depressive disorder (MDD) is
associated with a dysregulation in one-carbon
metabolism [31, 53]. These findings have sug-
gested that SAMe may have therapeutic potential
in treating MDD [10, 11].
Several randomized clinical trials (RCTs)
have supported that the antidepressant efficacy of
SAMe in monotherapy is superior to placebo and
tricyclic antidepressants ([53, 57]; Papakostas
et al. 2009). Recent findings have also demon-
strated its efficacy in patients nonresponsive to
selective serotonin reuptake inhibitors (SSRIs)
and serotonin-norepinephrine reuptake inhibitors
(SNRIs) [55, 65].
Pharmaceutical preparations of SAMe are
available as intravenous (IV), intramuscular (IM)
and oral (PO) forms. SAMe PO achieves peak
plasma concentrations 3–5 h after ingestion of an
enteric-coated tablet (400–1,000 mg). The plasma
half-life is about 100 min. Oral formulation
should be taken on an empty stomach. IM SAMe
owns a bioavailability of around 96 %; it reaches
peak plasma concentrations in around 45 min
after injection. It is excreted in urine and faeces
[32]. The dose range is typically 100–200 mg/day
(or 200–400 mg/day) IM or 800–1,200 mg/daily
PO, depending on severity and tolerance.
49.2 Efficacy of SAMe
in the Treatment of MDD
Several clinical trials have shown that SAMe
possesses an antidepressant activity [10, 12,
46, 56] both in monotherapy and as an adjunctive
therapy in patients who failed or were partial
responders to antidepressant drugs [2, 55]. Some
G. Martinotti • M. Di Giannantonio
Department of Neuroscience, Imaging and Clinical
Science, University “G. D’Annunzio”, Chieti, Italy
F. López-Muñoz
Faculty of Health Sciences, Camilo José Cela
University, Madrid, Spain
Department of Biomedical Sciences (Pharmacology
Area), Faculty of Medicine and Health Sciences,
University of Alcalá, Madrid, Spain
Neuropsychopharmacology Unit, “Hospital 12 de
Octubre” Research Institute (i+12), Madrid, Spain
D. De Berardis et al.
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studies focused on the evaluation of efficacy of
SAMe in the treatment of patients with stage II
treatment-resistant MDD (TRD), i.e. patients
who had failed to respond to at least 8 weeks of
treatment with two adequate and stable dose of
antidepressants of different classes (HAM-
D≥16), according to the classification of Thase
and Rush [64].
49.2.1 Studies of SAMe
as Monotherapy in Patients
with MDD
Parenteral SAMe. Some studies showed that par-
enteral preparation of SAMe, compared with a
number of standard tricyclic antidepressants such
as clomipramine, imipramine and amitriptyline,
was generally equally effective in MDD [37, 39,
44, 48]. Bell et al. [6] compared antidepressant
effects after 400 mg/day of intravenous (IV)
SAMe with those after oral doses of imipramine
following 2 weeks of treatment among 22 outpa-
tients with MDD. SAMe determined a clinically
significant improvement in depressive symptom-
atology, compared to imipramine. Other RCTs
compared MDD patients treated with IM SAMe
with placebo controls, reporting a marked
improvement of depression compared to place-
bos [1, 49]. Several open studies [4, 5, 14, 25, 37,
40, 43, 60] showed that treatment with parenteral
SAMe was followed by mood improvement in a
substantial proportion of patients. In a double-
blind placebo-controlled study carried out among
patients with MDD, Carney et al. [15] demon-
strated that 200 mg/day of IV SAMe (n = 16) was
equivalent to placebo group (n = 16) in antide-
pressant efficacy. An Italian double-blind multi-
centre study demonstrated that 200 mg/day of IV
SAMe was superior to placebo as a treatment for
outpatients with MDD and co-morbid rheuma-
toid arthritis [18]. In an open and multicentre
study conducted on 195 patients with MDD, Fava
et al. [29] reported a clinically significant remis-
sion in depressive symptoms after both 7 and
15 days of treatment with 400 mg/day IM SAMe
compared to placebo and no serious adverse
events. A multicentre, double-blind, randomized
parallel-group study, carried out to confirm both
efficacy and safety of SAMe in the treatment of
MDD, has demonstrated that there is no differ-
ence in efficacy between the group of patients
treated with IM SAMe (n = 146) at a dose of
400 mg/day and those treated with 150 mg/day of
oral imipramine (n = 147). Adverse events were
significantly less reported in patients treated with
SAMe compared to those treated with imipra-
mine [51]. Two multicentre, double-blind studies
have evaluated the efficacy and tolerability of
oral and IM SAMe in patients with a diagnosis of
MDD [26]. In one study, antidepressant effects
after taking 400 mg/day of IM SAMe (n = 147)
were compared with those of 150 mg/day orally
imipramine (n = 148), for 4 weeks. The clinical
effects of SAMe and imipramine treatment did
not differ significantly for any efficacy measure.
Oral SAMe. Kagan et al. [38] carried out a
randomized, double-blind, placebo-controlled
trial in 15 inpatients affected with MDD. The
results suggest that treatment with 1,600 mg/day
of oral SAMe for 3 weeks is a safe and more
effective antidepressant with a rapid onset of
action, compared to placebo group. A double-
blind, placebo-controlled study of SAMe in
depressed postmenopausal women showed a sig-
nificantly greater improvement in depressive
symptomatology in the group treated with
1,600 mg/day oral SAMe compared to the pla-
cebo group after 1 month [59]. A double-blind
randomized protocol compared oral SAMe with
oral desipramine treatment for 4 weeks. A sig-
nificant improvement in clinical response was
observed in patients treated with SAMe com-
pared with those treated with desipramine [7]. In
the same multicentre, double-blind study by
Delle Chiaie et al. [26], a second study was con-
ducted in a sample of outpatients who orally took
1,600 mg/day SAMe (n = 143) compared to those
who took oral 150 mg/day of imipramine
(n = 138), for 6 weeks. The antidepressant effi-
cacy of SAMe is comparable with that of imipra-
mine, but SAMe is significantly better tolerated.
An 8-week open-label study was conducted on
20 HIV-seropositive subjects diagnosed with
MDD. Patients were treated with 200–800 mg of
SAMe twice a day, adjusted according to the
severity of symptoms and clinical treatment
response, and a daily supplementation of
[AU1]
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1,000 mcg vitamin B12 and 800 mcg folic acid.
A significant acute reduction in depressive symp-
tomatology was observed, evident as soon as
week 1 [62]. A randomized double-blind cross-
over placebo-controlled trial evaluated the effec-
tiveness and safety of using SAMe (800 mg
daily) to treat depressive disorder, attention defi-
cit/hyperactivity disorder (ADHD) and cognitive
deficits in individuals with 22q11.2 deletion syn-
drome. No significant differences in the safety
were reported between SAMe and placebo.
Individuals affected with 22q11.2 deletion syn-
drome with co-morbid depressive disorder (with/
without psychotic symptoms) reported a good
improvement on relevant clinical scales com-
pared to placebo [33]. A double-blind, random-
ized, placebo-controlled clinical trial of SAMe
versus escitalopram was conducted on a sample
of 189 outpatients with MDD. Eligible patients
were randomized for 12 weeks to SAMe (1,600–
3,200 mg/ daily), escitalopram (10–20 mg/daily)
or placebo. No significant differences in response
rates were observed in SAMe (36 %) vs. escitalo-
pram (34 %) vs. placebo (30 %) groups. Remission
rates were 28 % for SAMe, 28 % for escitalopram
and 17 % for placebo. Significant differences
were only found in the side-effect pattern between
the escitalopram and SAMe group [47]. A recent
RCT (Sarris et al. 2014) assessed the antidepres-
sant efficacy of SAMe versus escitalopram and a
placebo control. Eligible patients were random-
ized to SAMe (1,600–3,200 mg/daily), escitalo-
pram (10–20 mg/daily) or placebo group for
12 weeks of double-blind treatment. Response
rates at endpoint were superior for escitalopram
(45 %) vs. SAMe (31 %) vs. placebo (26 %),
whilst remission rates were reported significant
superior for SAMe (24 %; p = 0.003) vs. escitalo-
pram (23 %, p = 0.023) vs. placebo (6 %).
49.2.2 Studies on SAMe as an Adjunct
to Antidepressant Drugs
for MDD
Studies assessing adjunctive SAMe with antide-
pressant drugs have evaluated an improvement
in depressive symptomatology and cognitive
functions in depressed patients [17]. A double-
blind clinical trial reported an accelerated symp-
tom improvement when SAMe (200 mg IM vs.
placebo) is given in combination with a fixed dose
of 150 mg/day oral imipramine [8]. Chinchilla
et al. [20] reported that the supplementation with
SAMe (100 mg IM vs. placebo) shortened the
latency of response to fluoxetine (20 mg/day).
A double-blind and randomized RCT [55]
reported the results of an adjunctive trial of SAMe
in 73 patients with MDD who had failed a prior
SSRI/SNRI trial at an adequate dose for at least
6 weeks. Patients were randomized to SAMe
(800 mg/twice daily) or placebo, both added to
the ongoing antidepressant therapy and continued
for 6 weeks. Group with adjunctive SAMe showed
a significant improvement, compared to placebo
group, both in response rate (36.1 % vs. 17.6 %)
and in remission rates (25.8 % vs. 11.7 %). A sec-
ondary analysis of a single-centre, 6-week, ran-
domized, double-blind clinical trial involving the
use of adjunctive SAMe to SSRIs/SNRIs non-
responders affected with MDD reported greater
response and remission rates as well as an
improvement in memory-related cognitive symp-
toms compared to placebo [41].
49.2.3 Studies on SAMe as an Adjunct
for Treatment- Resistant
Depression (TRD)
Rosenbaum et al. [58] conducted an open trial in
20 outpatients with MDD after oral intake of
SAMe. A significant improvement was observed
both in non-treatment-resistant and treatment-
resistant group. A 6-week open trial was con-
ducted on 30 antidepressant-treated adult
outpatients with persisting MDD (i.e. partial or
non-responders). Subjects were treated with
800–1,600 mg daily of SAMe. Following aug-
mentation with SAMe to ongoing SSRI or venla-
faxine, a response rate of 50 % and a remission
rate of 43 % were observed on the HAM-D [2].
A randomized and double-blind, placebo-
controlled adjunctive trial of SAMe (400 mg
twice daily) vs. placebo added to an SSRI was
conducted on a sample of patients with TRD. An
D. De Berardis et al.
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improvement in depressive symptomatology was
reported for adjunctive SAMe (36.1 % of
response and 25.8 % of remission) vs. placebo
(25.8 % of response and 11.7 % of remission).
SAMe also showed a good tolerability/safety as
augmentation strategy in SSRIs non-responder
patients with MDD [55]. An open-label, fixed-
dose (800 mg/day), single-blind study was con-
ducted on 25 outpatients with stage II TRD in
order to evaluate the efficacy of SAMe as aug-
mentation strategy to existent antidepressant (e.g.
venlafaxine, agomelatine, sertraline, mirtazap-
ine, escitalopram, duloxetine or bupropion). At
8 weeks, a significant decrease in Hamilton
Rating Scale for Depression (HAM-D) score was
observed (60 % of response; 36 % of remission)
as well as in Snaith-Hamilton Pleasure Scale
(SHAPS) and Sheehan Disability Scale (SDS)
scores [24].
49.3 Side Effects
and Pharmacological
Interactions
Studies published to date suggest that SAMe is
generally well tolerated and its side-effect profile
is extremely favourable. The most frequently
reported intolerable effects include mild gastro-
intestinal symptoms (e.g. nausea, stomach dis-
comfort and diarrhoea), sweating, vertigo,
dizziness, irritability, insomnia, tachycardia, rest-
lessness and anxiety. Other side effects reported
include anorgasmia, diminished mental acuity
and hot flashes (Mischoulon et al. 2012). An
increased risk of serotonin syndrome has been
reported if combined with dextromethorphan,
meperidine, tramadol and antidepressants with
serotonergic activity. A case report reported the
onset of altered mentation, fever, hyperreflexia
and elevated creatine phosphokinase when SAMe
(100 mg IM) was combined with clomipramine
(75 mg) in a 71-year-old woman [36].
A study reported an increases risk of manic
induction in vulnerable patients [16, 50]. A case
report described a 61-year-old-woman with no
previous history of suicidal ideations who self-
prescribed SAMe for her depressive symptoms
and attempted suicide 4 days later by burning
herself [21].
49.4 Pregnancy
and Breastfeeding
To date, there are no studies that have specifically
evaluated the efficacy of SAMe in antenatal
depression [27]. However, some studies evaluat-
ing efficacy of SAMe in the treatment of cho-
lestasis during the pregnancy were conducted on
a sample of pregnant women. These studies have
not reported any adverse events for either mother
or infant [35].
A placebo-controlled study reported a signifi-
cant decrease in depressive symptomatology
(75 % of reduction in 30 days) compared to pla-
cebo, in a sample of postnatal depressed women
treated with doses of SAMe up to 1,600 mg daily
[19]. There have been no reports of side effects or
adverse events in infants who are breastfed dur-
ing maternal use of SAMe.
However, limited evidence recommends a
careful evaluation of its use during the perinatal
period.
49.5 Concluding Considerations
These findings suggest interesting perspectives
for the use of SAMe in MDD. Most clinical stud-
ies involve parenteral or IM injections of SAMe,
rather than oral preparations. Mode of adminis-
tration should be considered when interpreting
findings of clinical studies (different pharmaco-
kinetic profiles).
Several placebo-controlled RCTs and meta-
analyses have demonstrated that SAMe (200–
1,600 mg/daily) is more efficacious than placebo
and superior or equivalent to tricyclic antidepres-
sants, in the treatment of MDD. However, few
studies were conducted on patients affected with
TRD, especially as adjunctive strategy in stage II
TRD patients [2, 34]. However, limited data have
shown that SAMe augmentation at 800 mg/day
may be an option for the treatment of stage II
TRD patients, especially due to its few side
[AU2]
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effects (i.e. constipation, nausea with decreased
appetite) [24]. In addition, SAMe may be an
effective complementary therapy in paediatric
depressive disorders [9, 61].
However, SAMe should be used with caution
in patients with a history of hypomania/mania,
due to concerns over potential switching from
unipolar depression to mania.
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