Glutamate-Modulating Drugs As A Potential Therapeutic Strategy in Obsessive-Compulsive Disorder

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Current Neuropharmacology, 2017, 15, 000-000 1
REVIEW ARTICLE
Glutamate-Modulating Drugs as a Potential Therapeutic Strategy in

Obsessive-Compulsive Disorder
Zoya Marinovaa,*, De-Maw Chuangb and Naomi Finebergc
a
Department of Psychosomatic Medicine, Clinic Barmelweid, Barmelweid, Switzerland; bNational Institute of Mental
Health, National Institutes of Health, Bethesda, Maryland, United States; cHertfordshire Partnership University NHS
Foundation Trust and University of Hertfordshire, Welwyn Garden City, AL8 6HG, United Kingdom
Abstract: Objective: Obsessive-compulsive disorder (OCD) is a mental disease commonly

associated with severe distress and impairment of social functioning. Serotonin reuptake inhibitors
and/or cognitive behavioural therapy are the therapy of choice, however up to 40% of patients do
not respond to treatment. Glutamatergic signalling has also been implicated in OCD. The aim of the
current study was to review the clinical evidence for therapeutic utility of glutamate-modulating
drugs as an augmentation or monotherapy in OCD patients.
Methods: We conducted a search of the MEDLINE database for clinical studies evaluating the
A R T I C L E H I S T O R Y effect of glutamate-modulating drugs in OCD.
Received: August 23, 2016 Results: Memantine is the compound most consistently showing a positive effect as an augmenta-
Revised: December 27, 2016
Accepted: March 15, 2017
tion therapy in OCD. Anti-convulsant drugs (lamotrigine, topiramate) and riluzole may also provide
therapeutic benefit to some OCD patients. Finally, ketamine may be of interest due to its potential
DOI:
10.2174/1570159X15666170320104237 for a rapid onset of action.
Conclusion: Further randomized placebo-controlled trials in larger study populations are necessary
in order to draw definitive conclusions on the utility of glutamate-modulating drugs in OCD.
Furthermore, genetic and epigenetic factors, clinical symptoms and subtypes predicting treatment
response to glutamate-modulating drugs need to be investigated systematically.
Keywords: Obsessive-compulsive disorder, glutamate, glutamate-modulating drugs, treatment response, memantine, clinical
subtypes.
INTRODUCTION Brain Circuits Implicated in Obsessive-Compulsive

Disorder
Obsessive-compulsive disorder (OCD) is a neuropsy-
chiatric disease characterized by anxiety-provoking, un- Dysfunction of the cortico-striatal-thalamo-cortical
wanted and repetitive thoughts (obsessions) and repeated circuitry has been implicated in OCD, including structural
ritualistic behaviours aimed to decrease the anxiety (compul- abnormalities, altered brain activation and connectivity [5,
sions). Symptoms can cause severe distress and functional 6]. Meta-analyses of volumetric studies have implicated re-
impairment [1]. OCD affects 2-3 % of the population and is duced orbitofrontal cortex (OFC), anterior cingulate cortex
ranked within the ten leading neuropsychiatric causes of dis- (ACC) and dorsal mediofrontal/anterior cingulate volume, as
ability [2; WHO, 2008]. OCD comorbidity with depression, well as increased thalamic and lenticular nucleus extending
bipolar disorder, and substance use and impulse control dis- to the caudate nucleus volume in OCD patients [7, 8]. On the
orders has been reported, and is associated with increased other hand, meta-analyses of positron emission tomography
overall distress and suicidality rates as well as additional (PET), single-photon emission computed tomography
treatment challenges [3, 4]. (SPECT) and functional magnetic resonance imaging (fMRI)
studies implicated the head of the caudate, the orbital gyrus
and the dorsal frontoparietal network in OCD [9, 10].
*Address correspondence to this author at the Department of Psychosomatic Glutamate is the primary neurotransmitter within the
Medicine, Clinic Barmelweid, 5017 Barmelweid; Tel: + 41 62 857 22 51; implicated in OCD cortico-striatal-thalamic circuits [11].
E-mails: Zoya.Marinova@barmelweid.ch, zoya.marinova@barmelweid.ch Anatomical nodes of relevance within this circuitry include
1570-159X/17 $58.00+.00 ©2017 Bentham Science Publishers

2 Current Neuropharmacology, 2017, Vol. 15, No. 0 Marinova et al.
areas of the frontal and cingulate cortex, caudate, putamen matergic signalling has been implicated in a number of neu-
and thalamus, comprising the direct cortico-striatal pathway, ropsychiatric illnesses, including OCD, depression, bipolar
as well as the globus pallidus and subthalamic nucleus com- disorder and schizophrenia [35, 36]. Glutamate mediates its
prising the indirect loop [2]. Dysregulation of glutamatergic effects through ionotropic (NMDA, AMPA, kainate) and
signaling within the cortico-striatal circuitry has been pro- metabotropic (mGluRs) receptors [37]. The NMDA receptor
posed in OCD, with reduced glutamatergic concentrations in requires in addition to glutamate also binding of glycine or
the anterior cingulate cortex, combined with overactivity of D-serine to its glycine cofactor site, in order to ensure its
glutamatergic signaling in the striatum and orbitofrontal cor- activation. Overall, ionotropic glutamate receptors are a
tex [12-15]. However, additional circuits, including the critical constituent of the core mechanisms of rapid neuro-
amygdalo-cortical circuitry may also be important for the transmission, while metabotropic glutamate receptors par-
pathophysiology of OCD [16]. Overall, the neuroimaging ticipate in the slower modulation of neuronal function. Both
data implicate disruptions of glutamatergic signalling in ionotropic and metabotropic glutamate receptors are local-
OCD, which suggests glutamate-modulating drugs may be ized in the candidate brain circuitry of OCD. Glutamate re-
potentially useful for the disorder. ceptors are involved in the processes of long term potentia-
tion (LTP) and long term depression (LTD) of neuronal fir-
Dysregulation of Neurotransmitter Signalling in OCD ing, which are forms of long term synaptic plasticity criti-
Serotonin reuptake inhibitors (SRIs) are considered to cally important for learning [38]. Glutamate receptors have
been implicated in virtually every form of learning in the
exert their effects by influencing the cortico-striato-thalamo-
brain, including habit learning [38-40]. The relationship be-
cortical circuit, even though the exact mechanism of action
tween activity levels at different glutamate receptor subtypes
remains elusive. For example, escitalopram treatment has
is currently not well understood in OCD. Interestingly, inter-
been associated with restoring imbalances in brain connec-
actions with serotonergic signalling for both ionotropic and
tivity in OCD patients [17]. A meta-analysis of genetic po-
lymorphisms previously implicated in OCD suggested a role metabotropic glutamate receptors have been demonstrated
[41, 42].
of serotonergic genes (the serotonin transporter SLC6A4 and
the serotonin 2A receptor HTR2A) in OCD vulnerability In addition, Na+-dependent glutamate transporters
[18]. On the other hand, recent genome-wide association (EAATs 1-5) and vesicular glutamate transporters (VGLUTs
studies (GWAS) have not identified involvement of seroton- 1-3) mediate the reuptake of glutamate into glial and neu-
ergic genes at genome-wide significant levels [19; 20]. ronal cells and thus terminate its action in the synaptic cleft
However, in a GWAS investigating genetic polymorphisms [43]. EAAT1 and EAAT2 are the primary astrocyte gluta-
influencing treatment response to SRIs in OCD, enrichment mate transporters, while EAAT3 is the primary neuronal
analysis suggested a role for serotonergic and glutamatergic glutamate transporter. Astrocytes convert glutamate into
genes polymorphisms [21]. glutamine and release it. Neurons in turn take up glutamine
and convert it into glutamate [44]. The cystine/glutamate
Pathophysiological processes involving other neuro-
antiporter on astrocytes mediates the cellular uptake of cys-
transmitter systems and signalling molecules, besides sero-
tine in exchange for simultaneous release of extrasynaptic
tonin, may also be important in OCD. Notably, dopamine
glutamate. Overactivity of the cystine/glutamate transporter
dysfunction has been found in some OCD cases [22, 23]. An
has been associated with glutamatergic excitotoxicity in sev-
autoimmune hypothesis for the development of an OCD sub-
eral pathological conditions [45].
type has also been suggested, implicating Group A Strepto-
coccal infections. Accordingly, in a subgroup of OCD pa- Glutamatergic Dysfunction in OCD
tients changes in anti-streptococcal, anti-neuronal or anti-
basal ganglia antibody titers, immune cells and circulating Glutamate is the primary neurotransmitter within the im-
cytokines have been detected [24, 25]. Additional systems plicated in OCD cortico-striatal-thalamo-cortical circuits
implicated in OCD include neuropeptide neurotransmitters [11]. Increased glutamate levels have been measured in cere-
[26] and sex steroids [27, 28]. Second messenger pathways brospinal fluid of OCD patients compared to healthy controls
alterations in OCD have also been detected and are of inter- [46, 47]. Excessive glutamate levels could lead to glutamate
est due to the potential for their specific therapeutic targeting receptor hyperactivity or even excitotoxicity in neurons.
[29-31]. Finally, a rapidly increasing number of studies Genetic studies have also implicated an association of
indicate that changes in glutamatergic neurotransmission glutamatergic genes with OCD. SLC1A1 coding for the neu-
may be involved in OCD pathophysiology, with glutamate- ronal glutamate transporter EAAT3 and GRIN2B coding for
modulating agents presenting a potential therapeutic alterna- the NR2B subunit of NMDARs have repeatedly shown asso-
tive [32] (see next section). ciation with OCD [48-50]. The 9p chromosome, in which
SLC1A1 is located, has also been implicated in OCD by
Glutamatergic Signalling linkage analysis [51].
Glutamate is the major excitatory neurotransmitter in the Several animal studies have further corroborated the pos-
brain, present in about 50% of synapses. Glutamatergic neu- sible benefit of anti-glutamatergic drugs for reducing OCD
rotransmission has a fundamental role for neuronal plasticity, resembling behaviours in animals. Thus, the uncompetitive
learning, and memory [33]. However, in pathological condi- NMDAR antagonists memantine and amantadine inhibited
tions glutamate can act as a neuronal excitotoxin, leading to marble-burying without affecting locomotor activity in mice
rapid or delayed neurotoxicity [34]. Dysregulation of gluta- [52]. Furthermore, fluoxetine and memantine had a synergis-
Glutamate-Modulating Drugs for OCD Treatment Current Neuropharmacology, 2017, Vol. 15, No. 0 3
tic effect in reducing compulsive scratching in mice, with the sure and response prevention (ERP) and serotonin reuptake
combination of both drugs exerting an effect at lower con- inhibitors (SRIs) [54]. SRIs include clomipramine and the
centrations than each of them alone [53]. It has to be noted selective serotonin reuptake inhibitors (SSRIs). In mild to
that there are significant limitations in the interpretation of moderate OCD cases monotherapy with CBT or SRIs is the
animal data in relation to clinical OCD. treatment of choice, while severe OCD commonly requires a
combination of CBT and SRIs [55, 56]. However, only about
Thus, converging evidence from preclinical and clinical
60 % of patients respond to current treatment and even
research suggests that glutamatergic signalling dysregula-
among responders symptoms often persist to some degree
tion, possibly involving the corpus striatum, is associated
[57]. SSRIs (fluoxetine, sertraline, etc) are generally well
with OCD and is potentially reversible with treatment. This
tolerated (also better in comparison to clomipramine), but
suggests possible therapeutic utility for glutamate-modulating
side effects can occur, most commonly gastrointestinal com-
drugs in OCD. plaints, sexual dysfunction, sedation, and behavioural activa-
tion. In addition, in children and adolescents rare cases of
Current Treatment Strategies for Obsessive-Compulsive suicidal ideation arising after SSRIs administration have
Disorder been described [58].
The current first-line treatment for OCD includes cogni- In treatment-resistant OCD several augmentation strate-
tive behavioural therapy (CBT) applied in the form of expo- gies are available. The most extensively studied augmenta-
Fig. (1). Mechanisms of action of glutamate-modulating drugs at the glutamatergic synapse.

tion agents are antipsychotic drugs, which provide therapeu- reversible after discontinuation transaminases elevation.
tic benefit to a subgroup of OCD patients, but are associated More serious rare potential side effects include hepatotoxic-
with significant side effects [56, 59, 60]. Therefore, a need ity and pancreatitis in children and adolescents [68, 69].
for the development of novel therapeutic agents for OCD
Results on riluzole efficacy in OCD so far have been
exists. Glutamatergic drugs constitute one of the candidates
for augmentation or monotherapy in OCD (including treat- mixed. The first encouraging data on its potential utility
came from a case report of an adult OCD patient [70]. Small
ment-resistant OCD) in light of a possible role for glutama-
open-label studies suggested therapeutic efficacy of riluzole
tergic signalling dysregulation in the disorder.
as an adjunctive therapy in treatment-resistant OCD, includ-
The Therapeutic Potential of Glutamate-Modulating ing one investigation in children and adolescents [71] and
Drugs in Other Psychiatric Disorders two in adults [72, 73]. Interestingly, 2 of the 5 responders in
the Coric et al. study [72] showed predominantly hoarding
Under the broad term of “glutamate-modulating” drugs phenotypes. However, the open-label design and small study
compounds with different mechanisms of action are included numbers require caution in the data interpretation.
(Fig. 1). They differ significantly in their toxicity and safety
profiles, as well as in the speed of onset and duration of the A double-blind, placebo-controlled trial with riluzole was
therapeutic effects. conducted in 60 treatment-resistant children and adolescents
with OCD [69]. The sample group in this study was charac-
Glutamate-modulating drugs have shown promise as po- terized by treatment resistance, high degree of comorbidity
tential therapeutic agents in other psychiatric disorders, in- with other psychiatric disorders (including 17 patients with
cluding depression, bipolar disorder, suicidality, and self- autism spectrum disorder) and additional pharmacological
injurious behaviour [61-63]. There is a high comorbidity treatment in 92% of the cases. In this 12 weeks trial riluzole
between OCD and affective disorders [64], and comorbid did not show superior effect as an add-on medication to the
OCD has been associated with increased overall distress and existing therapeutic regimen on any of the primary (CY-
suicidality rates [65]. Thus, there are strong arguments to BOCS, CGAS, CGI-I and CGI-S) or secondary outcome
investigate the effect of glutamate-modulating drugs in co- measures [69]. Most patients tolerated riluzole well; however
morbid as well as in treatment-resistant OCD. there was one case of pancreatitis.
METHOD A second randomized placebo-controlled trial of riluzole

augmentation was conducted in treatment-refractory adult
We systematically searched the database PubMed OCD patients, including both outpatients and inpatients [74].
(http://www.ncbi.nlm.nih.gov/pubmed) for articles investi- Riluzole or placebo was added to the existing SRI treatment
gating the effect of glutamate-modulating drugs in OCD us- regimen for 12 weeks after a 2 weeks placebo lead-on phase.
ing the search terms “obsessive-compulsive disorder” or No significance was achieved in the study sample as a whole
“OCD” AND “glutamate” or “riluzole” or “memantine” or on the primary outcome measure (Y-BOCS score), even
“ketamine” or “glycine” or “sarcosine” or “topiramate” or though Y-BOCS scores change after riluzole augmentation
“lamotrigine” or “N-acetylcysteine” or “minocycline” or “D- was nominally greater. Riluzole showed some benefit in
cycloserine”. Papers published until February 15th, 2017 outpatients, where significantly more patients achieved at
were retrieved and clinical trials or case reports were in- least partial treatment response in comparison to the placebo
cluded in the analysis. [74].
RESULTS Finally, in a double-blind, placebo-controlled trial of 50
adult OCD patients adjunctive therapy with riluzole in addi-
A growing number of clinical investigations have assessed
tion to fluvoxamine treatment for 10 weeks resulted in
the utility of glutamate-modulating drugs as an augmentation
or monotherapy in OCD, including difficult to treat OCD. greater reduction of total and compulsions subscale Y-BOCS
However, there are significant variations in between studies scores compared to the fluvoxamine group [75].
in terms of treatment-resistance, comorbidity, age and gender The results to date suggest that riluzole may have the
of the patients. Many were open-label trials with small sam- potential for efficacy in a less severe or treatment-resistant
ple sizes and no placebo controls or case reports. Recently, OCD population, however tolerability and acceptability is-
several small double-blind, placebo-controlled trials on glu- sues may impact on its further development as a treatment
tamate-modulating drugs as monotherapy or augmentation of for OCD.
an existing psychotropic regimen (summarized in Table 1) or
as augmentation of psychotherapy (summarized in Table 2) Memantine
have also been conducted and due to their theoretically supe-
rior study design have provided more reliable data on the The uncompetitive NMDAR antagonist memantine is
drugs’ efficacy. approved for the treatment of moderately severe Alzheimer’s
disease. Memantine is generally well tolerated even in the
Riluzole elderly population and has a relatively low propensity for
drug-drug interactions [76]. Side effects most commonly
Riluzole, a drug approved for the treatment of amyotro- include fatigue, headache, increase in blood pressure and
phic lateral sclerosis, inhibits synaptic glutamate release and dizziness. Memantine has been tested in treatment-resistant
stimulates glutamate uptake by astrocytes [66, 67]. Side ef- OCD. Positive results from a few case-reports [77-80]
fects reported with riluzole are usually mild: diarrhea and suggested memantine may be associated with clinical
Table 1. Placebo-controlled, randomized, double-blind clinical trials of glutamate-modulating drugs as monotherapy or augmenta-
tion of the existing psychotropic regimen in OCD
Study & Drug Duration & Adjunctive/ Subjects Treatment Endpoint Results on Side Effects Effect on Primary
Dose Monotherapy Resistance Efficacy Outcome: (Yes/no)
at Baseline
Riluzole
Grant et al., 12 weeks Adjunctive 60 pediatric Yes No significant differences in Mainly well CY-BOCS score
2014 Final dose: Initial treatment: OCD patients change of CY-BOCS, tolerated change: no
100 mg/day SRI (17 with co- CGAS, CGI-I and CGI-S 1 pancreatitis case CGI-I score change: no
morbid ASD) scores between the placebo 5 transaminases CGI-S score change: no
and riluzole groups at the elevation cases CGAS score change: no
end of the trial
Pittenger et al., 12 weeks + 2 Adjunctive 38 adult OCD Yes No significant difference in Well tolerated Y-BOCS score change:
2015 weeks lead-on Initial treatment: patients Y-BOCS scores change no
placebo SRI (27 outpatients between the placebo and
Final dose: and 11 inpa- riluzole groups at the end of
100 mg/day tients) the trial
Among OCD outpatients
only significantly more
achieved at least partial
treatment response with
adjunctive riluzole.
Emamzadehfar 10 weeks Adjunctive 50 adult OCD Significant greater reduction Well tolerated Y-BOCS score change:
d et al., 2016 Final dose: Initial treatment: patients of Y-BOCS total and com- yes
100 mg/day fluvoxamine pulsions scores between the
placebo and riluzole groups
at the end of the trial
Memantine
Ghaleiha et al., 8 weeks Adjunctive 42 adult OCD No Greater reduction of Y- Well tolerated Y-BOCS score change:
2013 Final dose: 20 Initial treatment: patients BOCS scores in the meman- yes
mg/day fluvoxamine tine group at the end of the
trial (p = 0.006)
Haghighi et al., 12 weeks Adjunctive 40 adult OCD No Greater reduction of Well tolerated Not predefined
2013 Dose: 5-10 Initial treatment: patients Y-BOCS scores in the Y-BOCS score change:
mg/day SRI memantine group at the end yes
of the trial (p = 0.005)
Ketamine
Rodriguez Ketamine & Monotherapy 15 adult OCD Part of the Greater reduction in Mild increase in Not predefined
et al., 2013 saline i.v. patients sample Y-BOCS scores for subjects blood pressure Y-BOCS score change:
infused at (2 with mild or receiving ketamine as first and pulse yes for ketamine as first
least 1 week moderate co- infusion at 7 days post Dissociation, infusion
apart in ran- morbid depres- infusion (p < 0.01) psychotic and OCD-VAS score
dom order sion) Obsession symptoms manic symptoms, change: yes
Dose: severity (OCD-VAS score) time perception
0.5  mg/kg with ketamine significantly distortion,
lower at mid-infusion, 230 dizziness, nausea,
min and 7 days post infusion vomiting,
compared to the saline headache
group
Glycine
Greenberg 12 weeks Adjunctive 24 adult OCD Not specified Reduction of Y-BOCS High drop-out Y-BOCS score change:
et al., 2009 Final dose: 60 Initial treatment: patients scores in the glycine com- rate related no (strong trend towards
g/day stable psycho- pared to the placebo group to glycine’s significance)
pharmacological at the endpoint showed a unpleasant taste
or psychothera- trend towards significance and nausea
peutic treatment (p = 0.053)
(Table 1) contd….
Study & Drug Duration & Adjunctive/ Subjects Treatment Endpoint Results on Side Effects Effect on Primary
Dose Monotherapy Resistance Efficacy Outcome: (Yes/no)
at Baseline
Topiramate
Mowla et al., 12 weeks Adjunctive 49 adult OCD Yes Y-BOCS score mean de- Y-BOCS score change:
2010 Dose: 100-200 Initial treatment: patients crease 32.0% in the topi- yes
mg/day existing treatment ramate group vs. 2.4% in the
regimen placebo group (p < 0.05)
Berlin et al., 12 weeks Adjunctive 36 adult OCD Yes No significant treatment Due to adverse Y-BOCS total score
2011 Dose: 50-400 Initial treatment: patients effect of topiramate on total effects 28% change: no
mg/day SSRI Y-BOCS scores (p = 0.11) discontinuation Y-BOCS obsessions
or obsessions subscores and 39% dose subscore change: no
(p = 0.99) reduction in the Y-BOCS compulsions
Significant treatment effect topiramate group subscore change: yes
of topiramate on Y-BOCS Weight loss,
compulsions subscores influenza-like
(p = 0.014). symptoms, taste
perversion, pares-
thesia, memory
difficulty
Afshar et al., 12 weeks Adjunctive 38 adult OCD Yes No significant difference in 2 patients dropped Y-BOCS score change
2014 Dose range: Initial treatment: patients Y-BOCS scores between the out due to adverse at the end of the trial: no
100-200 SRI topiramate and placebo effects. (strong trend towards
mg/day group at the end of the study Paresthesia, significance)
(p = 0.058) cognitive prob- Treatment response: no
Y-BOCS scores were lems, weight loss, (strong trend)
significantly lower in the micturation fre-
topiramate vs. the placebo quency, renal
group at weeks 4 (p = 0.01) stone, decreased
and 8 (p = 0.01) of the trial. appetite
Lamotrigine
Bruno et al., 16 weeks Adjunctive 40 (final sample Yes Lamotrigine was associated Well tolerated Y-BOCS score change:
2012 Final dose: Initial treatment: 33) adult OCD with greater reduction of Sedation, fatigue, yes
100 mg/day SRI patients Y-BOCS (p < 0.0001) and headache, skin CGI-S score difference:
HDRS scores (p < 0.0001) rash yes
at endpoint. HDRS score change:
Lamotrigine was associated yes
with lower CGI-S scores
at the end of the trial
(p < 0.0001).
Khalkhali et al., 12 weeks Adjunctive 53 adult OCD Yes Lamotrigine was associated Well tolerated Y-BOCS score change:
2016 Final dose: Initial treatment: patients with greater reduction of the Headache, skin yes
100 mg/day SRI total Y-BOCS score rash
(p = 0.007), as well as the
obsessions (p = 0.01)
and compulsions subscales
(p = 0.005).
N-acetylcysteine
Afshar et al., 12 weeks Adjunctive 48 adult OCD Yes Greater reduction of Well tolerated Y-BOCS change: yes
2012 Dose: up to Initial treatment: patients Y-BOCS scores in the NAC Nausea, vomiting, Treatment response
2.4 g/day SRI compared to the placebo diarrhea rate: yes
group at the end of the trial
(p = 0.003)
Significantly more patients
in the NAC compared to
the placebo group were
responders (p = 0.013).
(Table 1) contd….
Study & Drug Duration & Adjunctive/ Subjects Treatment Endpoint Results on Efficacy Side Effects Effect on Primary
Dose Monotherapy Resistance Outcome: (Yes/no)
at Baseline
N-acetylcysteine
Sarris et al., 16 weeks Monotherapy or 44 adult Not speci- No significant difference in Well tolerated Y-BOCS change: no
2015 Dose: 3 g/day adjunctive OCD pa- fied Y-BOCS scores changes between Heartburn
Initial treatment: tients the NAC and placebo group at the
existing stable end of the study
treatment regimen
or monotherapy
Paydary et al., 10 weeks Adjunctive 44 adult Greater reduction of Y- Well tolerated Y-BOCS change: yes
2016 Dose: 2 g/d Initial treatment: OCD pa- BOCS total scores (p = 0.012)
fluvoxamine tients and obsessions subscale
(p = 0.011) in the NAC
compared to the placebo
group at the end of the trial
Costa et al., 16 weeks Adjunctive 40 adult Yes No significant difference in Well tolerated Y-BOCS change: no
2017 Dose: 3 g/d Initial treatment: OCD pa- Y-BOCS scores changes between Abdominal pain
SRI tients the NAC and placebo group at the
end of the study
Some benefit in reducing anxiety
symptoms in the NAC group
Minocycline
Esalatmanesh 10 weeks Adjunctive 102 adult No Greater reduction of Y-BOCS Well tolerated Y-BOCS change: yes
et al., 2016 Dose: 200 Initial treatment: OCD pa- total scores (p = 0.003), the
mg/d fluvoxamine tients obsession subscale (p = 0.001)
and greater response rate in the
minocycline group at the
end of the trial
Abbreviations: ADIS = Anxiety Disorders Interview Schedule, ASD = autism spectrum disorder, CBT = cognitive behavioural therapy, CSR = clinical severity rating, CY-BOCS =
Children's Yale-Brown Obsessive Compulsive Scale, CGAS = Children's Global Assessment Scale, CGI-I = Clinical Global Impression – Improvement, CGI-S = Clinical Global
Impression - Severity, GOCS = Global Obsessive-Compulsive Scale, HDRS = Hamilton Rating Scale for Depression, NAC = N-acetylcysteine, OCD-VAS = OCD visual analog
scale, SSRI = selective serotonin reuptake inhibitor, SUDS = Subjective Units of Distress Scale, Y-BOCS = Yale-Brown Obsessive Compulsive Scale.
improvement, which in one case was sustained up to 9 In the trial by Haghighi et al. [85] 40 adult OCD patients
months. Three small, open label trials of memantine, admin- were randomized to memantine or placebo as an add-on
istered either as monotherapy or adjunctive to SRI [81-83], treatment to their SRIs regimen. All OCD patients in this
were also performed. They showed promise of efficacy with study had no psychiatric comorbidities, were not defined as
approximately 45% to 60% of entrants showing some sign of treatment-resistant, and for the week before and during the
clinical response using the Y-BOCS and good tolerability. In trial were on SRI regimen. After 12 weeks significant bene-
the study by Feusner et al. [82], memantine had a preferen- ficial effect of memantine on OCD symptoms severity was
tial efficacy in OCD compared to a group of generalized observed measured by greater decrease in Y-BOCS scores (p
anxiety disorder patients. = 0.005). In addition, 9 patients from the SRI + memantine
group were full responders in comparison to 0 patients from
Recently, two double-blind, placebo-controlled trials
the SRI group. A limitation of this study was that symptoms
have also demonstrated promising results. In the study by
of depression and anxiety were not measured throughout the
Ghaleiha et al. [84] 42 OCD patients without psychiatric
study, not accounting for a possible effect of memantine on
comorbidity and without psychotropic medication use in the
them [85].
6 weeks preceding the screening, were randomized to
memantine or placebo as an add-on treatment to In a further single-blind case-control study of 44 adult
fluvoxamine. After 8 weeks patients from the memantine- patients with severe, treatment-resistant OCD 22 received
assigned group showed higher rate of remission (p < 0.001) memantine augmentation to their treatment regimen [86],
and greater improvement in both the obsession and while 22 served as controls. Mean decreases in Y-BOCS
compulsion subscales of the Y-BOCS. A limitation of the scores at discharge compared to admission were significant
study was the relatively short duration of the trial (8 weeks). in the memantine augmented group (27%) but not in the con-
Thus, it could not be definitely concluded whether the trol group (16.5%), implying beneficial therapeutic effect of
advantage over fluvoxamine treatment would have been memantine augmentation. In addition, 50% decrease in
sustained in a longer trial. Y-BOCS score was more likely in the memantine than in the
Table 2. Placebo-controlled, randomized, double-blind clinical trials of d-cycloserie as augmentation of psychotherapy in OCD
patients
Study & Duration, dose and Subjects Mode of Therapy Endpoint Results on Efficacy Side Effects Effect on Primary
Drug Temporal Relationship Outcome: (yes/no)
to CBT Sessions
Studies in adults
Storch et 12 CBT sessions with 24 adult OCD In person No significant difference be- Well tolerated Y-BOCS change:
al., 2007 DCS 4 h prior to each patients 1 session hierarchy tween the DCS and placebo no
session and education, 1 ses- groups in terms of OCD sever-
Dose: 250 mg/CBT session practice exposure ity post-treatment.
sion and 9 sessions expo-
sure and response
prevention exercises
Kushner 10 CBT sessions with 25 adult OCD In person No differences in Y-BOCS Well tolerated Y-BOCS change:
et al., DCS 2 h prior to each patients Hierarchy at baseline, scores or between the DCS and Mild gastrointes- no
2007 session 10 sessions of expo- placebo groups at the end of tinal distress,
Dose: 125 mg/CBT ses- sure/ritual prevention the trial. fatigue, anxiety
sion techniques The DCS group achieved > and dizziness
50% SUDS scores reduction
significantly faster and showed
improved compliance.
Wilhelm 10 CBT sessions with 23 adult OCD In person No significant differences in Y- Well tolerated Y-BOCS change:
et al., DCS 1 h before each patients 1 psychoeducational BOCS scores between the DCS no at post-treatment
2008 session (Including /treatment planning and placebo groups at post- or 1 mo follow up;
Dose: 100 mg/CBT ses- patients with session, 10 behavior treatment (p = 0.14) or 1 month yes at mid-treatment
sion continuing therapy sessions follow up (p = 0.12)
stable psy- Significantly lower Y-BOCS
chotropic scores in the DCS group at
treatment mid-treatment (p = 0.009)
regimen) Significantly fewer depressive
symptoms at
post-treatment (p=0.04)
Andersson DCS 1 h before 5 CBT 128 adult Therapist-supported No difference between the Well tolerated Y-BOCS change:
et al., tasks during a 12 weeks OCD outpa- internet DCS and placebo group in Y- no
2015 internet-based CBT tients 12 weeks of therapist- BOCS scores at the trial end
Dose: 50 mg/CBT task (In some supported internet- and 3 months follow up
stable antide- based CBT In the DCS group significantly
pressant more antidepressant-free pa-
regimen) tients achieved remission at the
trial’s end compared to antide-
pressant-medicated patients
(p  =  0.008).
de Leeuw 6 guided exposure ses- 39 adult OCD In person No significant difference in the Well tolerated Y-BOCS change:
et al., sions with DCS 1 h be- patients 6 weekly guided expo- Y-BOCS score change between no
2017 fore each session sure sessions the groups at the end of the
Dose: 125 mg/session trial, although decrease in DCS
group was numerically greater
(p = 0.076).
A significant effect of DCS in
the “cleaning/contamination”
subgroup (p = 0.033).
Studies in children and adolescents
Storch et 10 CBT sessions with 30 children In person No significant differences in Well tolerated CY-BOCS: no
al., 2010 DCS 1 h before each and adoles- 10 CBT sessions CY-BOCS and ADIS-CSR CGI-S: significant
session for 7 of the ses- cents with including psychoedu- scores changes at the end of the time and group, but
sions OCD cation, cognitive trial. no significant time
Dose: weight-adjusted therapy, hierarchy by group interaction
development, and ADIS-CSR: no
E/RP,
(Table 2) contd….
Study & Duration, dose and Subjects Mode of Therapy Endpoint Results on Efficacy Side Effects Effect on Primary
Drug Temporal Relationship Outcome: (yes/no)
to CBT Sessions
Studies in children and adolescents
Farrell et 9 CBT sessions with DCS 17 children In person No significant difference in Well toler- CY-BOCS scores: no at
al., 2013 1 h before each of 5 and adoles- 9 CBT sessions, in- CY-BOCS between the DCS ated post treatment or 2 mo
sessions cents with cluding 4 sessions and placebo groups at the end follow up; yes at 1 mo
Dose: weight-adjusted OCD with instruction on of the trial follow up for some of
cognitive-behavioural Greater improvement from end the measures
techniques and 5 ERP of the trial until 1 month follow CSR: no
sessions up in the DCS compared to the GOCS: yes at 1 mo
placebo group was detected for follow up; no at post
CY-BOCS obsessions subscale treatment or 3 mo
(p < 0.05), GOCS scale (p < follow up
0.05) and CGI-S (p = 0.05). CGI-S: yes at 1 mo
follow up; no at post
treatment or 3 mo
follow up
Mataix- 14 CBT sessions, 10 of 27 children In person No significant differences in Well toler- CY-BOCS change: no
Cols et them with DCS immedi- and adoles- 14-session manualised CY-BOCS scores between the ated
al., 2014 ately after each session cents with treatment, including 2 DCS and placebo group at any
Dose: 50 mg OCD sessions psychoeduca- time point
(In some tion, 10 sessions ERP
patients stable and 2 sessions relapse
psychotropic prevention.
regimen)
Storch et 10 CBT sessions with 142 children In person No significant difference in the Well toler- CY-BOCS change: no
al., 2016 DCS administered 1 h and adoles- 10 CBT sessions rate of CY-BOCS scores de- ated
prior to 7 of the sessions cents with cline between the groups.
Dose: weight-adjusted OCD No moderation effect for anti-
depressant medication ob-
served.
Abbreviations: ADIS = Anxiety Disorders Interview Schedule, ASD = autism spectrum disorder, CBT = cognitive behavioural therapy, CSR = clinical severity rating, CY-BOCS =
Children's Yale-Brown Obsessive Compulsive Scale, CGAS = Children's Global Assessment Scale, CGI-I = Clinical Global Impression – Improvement, CGI-S = Clinical Global
Impression - Severity, GOCS = Global Obsessive-Compulsive Scale, HDRS = Hamilton Rating Scale for Depression, NAC = N-acetylcysteine, OCD-VAS = OCD visual analog
scale, SSRI = selective serotonin reuptake inhibitor, SUDS = Subjective Units of Distress Scale, Y-BOCS = Yale-Brown Obsessive Compulsive Scale
placebo group (p = 0.04). A limitation of this study was the Rodriguez et al. [88] in 15 adult OCD patients with near
fact that randomization to the treatment groups was not per- constant obsession symptoms. Patients received two intrave-
formed and the decision to match cases and controls was nous infusions (one with saline and one with ketamine)
taken only after the patients’ discharge [86]. spaced at least one week apart in randomized order. After the
first infusion those receiving ketamine (n=8) showed signifi-
In summary, a beneficial therapeutic effect of memantine
cantly lower obsession symptoms severity at mid-infusion (p
in OCD patients with or without treatment resistance has
< 0.005), 230 min post infusion (p < 0.05) and 7 days post
been consistently observed in these reports. However, there
infusion (p < 0.05) compared to the saline group (n=7). In
are currently no clear indications predicting which OCD pa-
addition 50% of the OCD subjects receiving ketamine met
tients would respond beneficially to memantine treatment the treatment response criteria at one week compared to 0%
augmentation.
from the saline group. Due to the substantial carry-over ef-
fect of ketamine at one week, the cross over arm of the study
Ketamine
was not analyzed. Side effects with ketamine administration
Ketamine is a non-competitive NMDAR antagonist, were significant and included dissociation, time perception
which has been used as an anaesthetic and is currently being distortions, positive psychotic and manic symptoms, dizzi-
investigated for its rapid antidepressant effect [61; 63]. In a ness, nausea or vomiting and headache. Overall the results of
case report Rodriguez et al. [87] found that in a treatment- the study suggested a rapid effect of ketamine infusion as a
resistant patient with severe OCD a blinded ketamine intra- monotherapy in OCD, which was sustained at one week post
venous infusion caused a complete cessation of obsessions treatment. A limitation was the difficulty to blinding the pa-
with return to baseline after one week [87]. tients to the infusion due to the psychoactive effects of keta-
mine, which in turn may influence self-rating scales as OCD-
A placebo-controlled, double-blind, cross-over trial with VAS [88].
ketamine as monotherapy was subsequently conducted by
These results stand in contrast to an open-label trial car- Glycine

ried out by Bloch et al. [89] in 10 adult patients with severe
Glycine is an NMDAR (co)-agonist. The occupancy of
treatment-resistant OCD, high comorbidity rate of depres-
the glycine modulatory site by glycine, D-serine or D-
sion and high rate of concurrent psychotropic medication.
alanine is a prerequisite for the activation of the cation chan-
All participants received single intravenous infusion with
ketamine, which was associated only transiently (after 1-3 h nel by glutamate. In a double-blind, placebo-controlled trial
24 adult outpatient OCD subjects with stabilized treatment
post infusion) with substantial OCD symptoms improve-
regimen were randomized to adjunctive glycine treatment or
ment. Ketamine effect on Y-BOCS scores at days 1-3 post
placebo for 12 weeks [96]. This study was characterized by
infusion did not reach the treatment response criteria, and Y-
high non-adherence rate, mainly due to nausea and the un-
BOCS scores returned to baseline by day 7 after infusion. In
pleasant taste of glycine. From the OCD patients who com-
contrast, depression symptoms were affected significantly in
4 of the 7 ketamine treated patients with comorbid depres- pleted the study, 2 out of 5 subjects with adjunctive glycine
were responders, while 0 out of 9 subjects with add-on pla-
sion, achieving treatment response in the first 1-3 days. Ad-
cebo were responders. The decrease in Y-BOCS scores in
verse effects of ketamine included dissociative symptoms,
the glycine compared to the placebo group showed a trend
memory gaps, sensory distortions, and a transient systolic
not reaching significance (p=0.053). Limitations of the study
blood pressure increase in one subject. In two of the three
included the small sample size due to the high dropout rate
OCD subjects without comorbid depression, both of which
had trauma history, dysphoria, passive suicidal ideation and and the heterogeneity of the initial treatment regimen [96]. In
a case report of a patient comorbid for OCD and body dys-
anxiety were observed, starting within the first two days after
morphic disorder, who had failed multiple treatment trials,
treatment [89, 90]. Thus, trauma history may be an indica-
glycine treatment led to robust decrease in OCD/BDD symp-
tion for caution in ongoing investigations of ketamine in
toms and long term improved functioning [97].
OCD patients.
The results from the initial small-sized trials on ketamine Sarcosine
efficacy in OCD are contradictory – in both studies ketamine
Sarcosine is an endogenous inhibitor of the glycine
caused a rapid decrease in OCD symptoms, but the sustain-
transporter-1. By blocking the glycine transporter it increases
ability of its effect over a clinically meaningful period of
the synaptic availability of glycine. Sarcosine and glycine
time differed greatly. Two recent small, open label trials in
have shown promise also in clinical trials of schizophrenia
adult OCD patients investigated the possibility to sustain the
[98]. Sarcosine was tested in a single open-label trial in 26
therapeutic effect after a single ketamine injection using ei- OCD patients as either monotherapy or as adjunctive therapy
ther memantine treatment [91] or ERP therapy [92] and ERP
for 10 weeks. 8 OCD subjects met the criteria for responders
showed overall more promising results. Ketamine was also
in this study and sarcosine was overall well tolerated [99].
associated with serious adverse effects, including dissocia-
Limitations of the study included its open label design, and
tive symptoms, dysphoria, suicide ideation, psychotic or
small sized and heterogeneous sample. Bitopertin, another
manic symptoms and anxiety, limiting its acceptability for
inhibitor of the glycine transporter-1, has been investigated
clinical usage. However, its fast onset of action distinguishes for its efficacy as augmentation of stable SSRI regimen in
it from most other glutamate-modulating compounds and
OCD patients, but no results have been reported so far
makes it an interesting candidate for further investigations.
(NCT01674361).
It has been proposed that the rapid antidepressant effi-
cacy of ketamine involves inhibition of presynaptic NMDA Topiramate
receptors, causing increased release of glutamate from nerve Topiramate is an anticonvulsant and anti-migraine drug.
endings and activation of postsynaptic AMPA receptors. It is also an AMPA-receptor antagonist and interacts with
These events are followed by activation of voltage-sensitive voltage-gated sodium and calcium channels. Recognised
calcium channel, influx of calcium and secretion of brain- adverse effects of topiramate (including paresthesia, cogni-
derived neurotrophic factor (BDNF). The BDNF-TrkB sig- tive problems, micturation frequency, renal stones, weight
naling triggers activation of the mTOR and its down-stream loss or psychiatric adverse events) limit its tolerability and
signaling pathways, causing enhanced synthesis of synaptic acceptability. Evidence for potential benefit from topiramate
proteins and synaptogenesis [93]. Whether such a mecha- in treatment-resistant OCD was suggested by a few open-
nisms is involved in the putative efficacy of ketamine in label trials [100, 101] and case reports [102, 103]. However,
treating OCD is unknown and requires investigation. Inter- in two other case reports, topiramate treatment was associ-
estingly, the mood stabilizer lithium at subtherapeutic or low ated with the provocation of OCD symptoms in cases with-
therapeutic levels potentiates and prolongs the antidepressant out prior OCD [104; 105]. In one case, OCD improved after
effects of ketamine in a stress-induced mouse model of de- topiramate discontinuation [105].
pression, likely by augmenting the BDNF-TrkB and mTOR
signaling pathways [94]. Lithium inhibits excessive gluta- Three double-blind, placebo-controlled trials have since
mate-induced, NMDA receptor-mediated calcium influx in been conducted with topiramate in OCD, with mixed results.
neurons, presumably via reducing NR2B subunit tyrosine In the study of Mowla et al. [106], 49 treatment-resistant
phosphorylation through the Src/Fyn kinase [reviewed in OCD patients were randomized to topiramate or placebo as
95]. Together, it seems warranted to assess as to whether an add-on to their current treatment regimen. At the end of
lithium can potentiate the putative efficacy of ketamine (and the 12 weeks trial 12 from the 24 patients in the topiramate
memantine) in OCD patients. group (20 completers) were rated as responders versus no
patients from the placebo group. Significantly more im- obsessive-compulsive symptoms (OCS). Lamotrigine aug-
provement in the Y-BOCS scores was detected in the topi- mentation for 8 weeks was correlated with treatment re-
ramate compared to the placebo group (p < 0.001) [106]. In sponse concerning the OCS in 5 of the patients, all of whom
the second placebo-controlled trial, 36 treatment-resistant had schizoaffective disorder. Depressive symptoms were
adult OCD patients were randomly assigned for 12 weeks to also improved with lamotrigine treatment, while schizophre-
topiramate or placebo as an adjunctive agent to their SSRI nia symptoms were not affected [117].
treatment regimen [107]. Topiramate significantly decreased
However, accounts of OCD symptoms provocation after
compulsions subscale (p = 0.014), but not obsessions sub-
lamotrigine treatment have also emerged. Thus, Kemp et al.
scale (p = 0.99) or total Y-BOCS score (p = 0.11). Topi-
[118] described the development of obsessive symptoms in 5
ramate was not well tolerated (influenza-like symptoms,
patients suffering from bipolar II disorder after starting
paresthesia, memory difficulties, taste perversions), which
led to 28% drop-out and 39% dose reduction in the topi- lamotrigine intake. In addition, Kuloglu et al. [119] de-
scribed a case of a female bipolar disorder II patient in whom
ramate group [107]. In the third trial by Afshar et al. [108],
lamotrigine added to the treatment regimen was associated
38 adult treatment refractory OCD patients were randomly
with the appearance of disruptive obsessive symptoms.
assigned to topiramate or placebo as an adjunctive medica-
tion to their SRI treatment regimen for 12 weeks. Topiramate
N-acetylcysteine
treatment led to statistically significant improvement of Y-
BOCS scores in comparison to the control group at weeks 4 N-acetylcysteine (NAC) is an antioxidant, used as an
(p = 0.02) and 8 (p = 0.01), but not at the end point (week antidote in acetaminophen overdose and the associated hepa-
12) (p = 0.058) and was associated with a number of side totoxicity. NAC is a precursor of cysteine and modulates the
effects [108]. cystine-glutamate antiporter [120]. An early report found
benefits from NAC augmentation of fluvoxamine in an OCD
Lamotrigine case [121]. A subsequent randomized, double-blind, pla-
cebo-controlled trial was conducted in 48 adult treatment-
Lamotrigine is an anticonvulsant drug and has also anti-
resistant OCD patients, who were assigned to NAC or pla-
depressant/mood-stabilizing properties utilized in the treat-
cebo adjunctive to SRI treatment for 12 weeks. At the end of
ment of bipolar disorder. It blocks voltage-gated sodium
the study significantly greater improvement of Y-BOCS
channels, thus inhibiting glutamate release, inhibits AMPA
scores in the NAC augmented group was detected (p =
receptors, is an indirect inhibitor of histone deacetylases
(HDACs) and robustly induces the prominent neuroprotec- 0.003) and the response rate in the NAC group was higher.
NAC was overall well tolerated with adverse effects includ-
tive protein Bcl-2 [109]. Positive results from case reports
ing nausea, vomiting and diarrhoea [122]. A recent random-
[110-112], and a retrospective open-label case series of 22
ized, double-blind, placebo-controlled trial was carried out in
adult treatment-resistant OCD patients [113] suggested a
44 adult OCD patients who were randomized to NAC or
possible therapeutic role for lamotrigine in OCD. On the
placebo for 16 weeks [123]. Continuation of previously sta-
other hand, in another case series of 8 treatment-resistant
OCD patients, adjunctive lamotrigine resulted in significant ble psychotropic regimen was allowed during the course of
the trial. No difference in Y-BOCS scores was detected be-
improvement in only one patient [114].
tween the NAC and placebo groups at the end of the trial. At
Bruno et al. [115] conducted a 16 weeks double blind, week 12 significant NAC was found to be significantly more
placebo controlled study of adjunctive lamotrigine in 40 effective in reducing the compulsions Y-BOCS subscale,
SRI-resistant OCD patients. At the end of the study the de- however this difference dissipated by the end of the trial
crease in Y-BOCS scores was significantly more pronounced [123]. In addition, in a double-blind, randomized, placebo-
in the lamotgrine augmented group (p = 0.003). Furthermore, controlled trial augmentation of fluvoxamine with NAC for
35% of the patients assigned to the lamotrigine group 10 weeks led to greater reduction of total (p = 0.012) and
showed a full and 50% - partial treatment response, while obsessions (p = 0.011) subscale Y-BOCS scores compared to
none of the patients in the placebo group reached the treat- the fluvoxamine and placebo group [124]. Finally, Costa et
ment response criteria. Lamotrigine was overall well toler- al. conducted a double-blind, randomized, placebo-
ated with side effects including sedation, fatigue, headache, controlled trial in 40 treatment-resistant adult OCD patients,
and in one patient skin rash [115]. Recently another 12 in whom augmentation of the existing SRI treatment regimen
weeks double blind, placebo controlled trial with adjunctive with NAC for 16 weeks did not lead to difference in the Y-
lamotrigine in addition to stable SRI treatment regimen was BOCS score change in comparison to placebo, although
conducted in 53 treatment-resistant adult OCD patients. At some benefit in reducing anxiety symptoms was observed
the end of the trial significantly greater reduction in total Y- [125].
BOCS scores (p = 0.007) was observed in the lamotrigine
group [116]. Lamotrigine was overall well tolerated with Minocycline
skin rash and headache emerging as side effects.
Minocycline is an antibiotic (a tetracycline derivative),
An open-label trial by Poyurovsky et al. [117] provided which has been shown to inhibit Na+- and Ca2+-ionic cur-
information about the possible utility of lamotrigine in rents and block glutamate release in vitro [126]. A prospec-
schizoaffective patients with obsessive-compulsive symp- tive, open-label trial examined the efficacy of minocycline as
toms. Lamotrigine was added to the ongoing psychotropic an augmenting agent to the existing treatment regimen in-
treatment regimen of patients with schizophrenia (n = 5) and cluding SRI in 9 adult treatment-resistant OCD subjects for
schizoaffective disorder (n = 6) and with clinically relevant 12 weeks. While no treatment response was observed for the
group as a whole, two patients (both with early-onset OCD) definitively clarified and may be involved in the observed
were responders [127]. In a double blind, placebo controlled findings [135]. Finally, in a double-blind, placebo-controlled
trial in 102 adult OCD patients minocycline or placebo were trial of 39 adult OCD patients DCS or placebo were adminis-
added to fluvoxamine treatment for 10 weeks. Greater reduc- tered 1 h before each of 6 weekly guided exposure sessions.
tion of Y-BOCS total scores (p = 0.003), the obsession sub- There was no significant difference in the Y-BOCS score
scale (p = 0.001) and greater response rate were observed in decrease at the end of the trial (p = 0.076), although the de-
the minocycline group at the end of the trial [128]. Mino- crease in the DCS augmented group was numerically greater
cycline’s relatively low cost and approved use in both chil- [136].
dren and adults suggests its further investigation in OCD
Storch et al. [137] conducted a double-blind, randomized
could be warranted.
trial of DCS administered 1 hour prior to 7 out of 10 CBT
D-Cycloserine sessions in 30 children and adolescents with OCD. There
was no significant effect of DCS on OCD severity at post-
D-cycloserine (DCS) is a partial NMDAR co-agonist that treatment, even though DCS patients experienced numeri-
has been hypothesized to facilitate fear extinction [129]. cally greater reduction in CY-BOCS scores. In a further
DCS at varying doses has been tested for its effect in aug- double-blind, placebo-controlled, randomized trial, 17 paedi-
menting the treatment response to CBT (ERP) in several atric patients with ‘difficult to treat’ OCD received 9 ses-
double-blind studies in adult OCD patients and younger peo- sions CBT, 5 of which were augmented with DCS or placebo
ple, with unimpressive results. 1 hour before the session. A greater improvement in CY-
BOCS scores in the DCS group compared to the placebo was
The first double-blind, placebo-controlled trial was con-
detected at 1 month follow up post-treatment [138]. On the
ducted by Storch et al. [130] in 24 adult OCD patients, to
other hand, no therapeutic benefit was present when DCS (n
whom DCS or placebo were administered 4 hours prior to
= 12) in comparison to placebo (n = 12) was administered
each of 12 CBT sessions. No significant differences were
found in this study between the two groups in terms of OCD immediately after 10 CBT sessions in a double-blind, pla-
cebo-controlled trial of early-onset OCD patients [139]. A
severity or responder rate at post-treatment. In a second dou-
recent double-blind, placebo-controlled study in 30 early-
ble-blind, placebo-controlled trial of 25 adult OCD patients,
onset OCD patients suggested that DCS augmentation of
DCS or placebo was administered 2 hours prior to each of 10
CBT was not associated with increased homework compli-
CBT sessions [131]. There were no between-group differ-
ance, even though homework compliance by itself was asso-
ences in Y-BOCS scores or subjective units of distress scale
(SUDS) scores at the last CBT session or at 3 months fol- ciated with better outcome [140]. Finally, in a double-blind,
placebo-controlled trial of 142 children and adolescents with
low-up. However, the DCS group achieved > 50% reduction
OCD DCS was administered 1 h prior to 7 out of 10 CBT
in SUDS scores significantly earlier than the placebo group.
sessions. No difference on the CY-BOCS score change was
A third double blind, placebo-controlled trial by Wilhelm et
observed between the groups [141].
al. [132] investigated 23 adult OCD patients. Participants
received DCS or placebo one hour prior to each of 10 CBT
DISUSSION
sessions. No significant differences were detected in Y-
BOCS scores at post-treatment or one month follow up. Summary
However, Y-BOCS scores in the DCS group were signifi-
cantly lower at mid-treatment. On the other hand comorbid A number of glutamate-modulating drugs are being in-
depression symptoms were significantly lower at post- vestigated for their potential therapeutic effect in OCD,
treatment, but not at mid-treatment or 1 month follow up. however definitive conclusions are precluded by small sam-
The data from the Wilhelm et al. [132] study were re- ple sizes in the trials conducted so far (see Tables 1 and 2).
analyzed to elucidate the time-course of DCS effect and it To date, memantine is the compound most consistently
was found to precipitate faster treatment-response to CBT showing a positive effect as an augmentation therapy to SRIs
[133]. Thus, DCS may accelerate the therapeutic effect of in OCD. Even though further randomized control trials are
CBT in OCD patients and appears well tolerated, though its needed to better characterize memantine’s effect, its use in
benefits are not sustained in terms of improved outcomes. A OCD patients in whom other therapeutic agents have proven
larger randomized, double blind, placebo controlled trial was ineffective may be justified. Anti-convulsant drugs (lamo-
recently conducted in 128 adult OCD outpatients [134] to trigine, topiramate) have been associated with therapeutic
whom placebo or DCS was administered 1 h before 5 CBT effect in a subset of OCD patients. Riluzole may also pro-
tasks during a 12 weeks course of internet-based CBT train- vide some therapeutic benefit in less severe or treatment-
ing. There was no difference on the Y-BOCS scores between resistant OCD patients. Ketamine remains an experimental
the DCS and placebo groups at the end of the trial. Patients treatment in OCD, in view of its adverse effect profile. Initial
were allowed to continue their stable regimen of concurrent data on its effects in OCD are contradictory with one out of
psychotropic medication and within the DCS group a signifi- two studies showing clinical benefit for OCD symptoms.
cantly greater proportion of antidepressant-free patients However, ketamine is of interest due to its potential for a
achieved remission at the end of the study in comparison to rapid onset of action in specific clinical situations (see next
antidepressant-treated patients, suggesting any possible section). N-acetylcysteine has shown contradictory results in
benefit from DCS may be limited to otherwise unmedicated four double-blind placebo-controlled trials up to date [re-
cases. There is a potential for pharmacological interaction viewed in 142]. However, it has a particularly benign side
between SSRIs and glutamatergic drugs, which is still not effects profile, which provides motivation for its clinical use
in individual cases, despite the weakness of the data support- with hoarding symptoms were more likely to respond to mi-
ing it. nocycline augmentation. These findings are only preliminary
and derived from very small sample investigations. Future
Data on glycine are limited with a trend towards a posi-
studies with larger cohorts need to systematically address
tive effect in a pilot randomized control trial, however prob-
this issue. A recent review article and meta-analysis of eight
lems with compliance due to its adverse effects profile make randomized, double-blind, placebo-controlled trials sug-
it a less likely candidate for further investigation. No ran-
gested benefit of add-on glutamate-modulating drugs in
domized controlled trials are available for sarcosine and only
OCD, including treatment-resistant OCD [145]. Investiga-
a single double-blind, placebo-controlled trial is available for
tions with different glutamate-modulating compounds in
minocycline, but further studies are warranted due to their
clinically more homogenous study populations may advance
approved use for other indications and relatively low cost.
the understanding of their potential therapeutic utility.
Finally, DCS may accelerate the effect of CBT in some OCD
patients, but the results supporting a clinically relevant effect The Potential Role of Genetic and Epigenetic Factors for
for this compound are not convincing. the Treatment Response to Glutamate-Modulating Drugs
An important caveat to the current literature remains the Predisposition to OCD is determined by a combination of
commonly inconsistent results from different study sites. For polygenic factors and environmental risk factors [14]. Epi-
example, it has been noted that studies performed at Iranian genetic modifications, including DNA methylation, histone
sites tended to produce positive outcomes [75, 85]. A clear modifications and microRNAs, have not been specifically
explanation for this inconsistency is currently not available
studied in OCD. However, they present a potential mecha-
and may include differences in study design, method of as-
nism, through which environmental factors can lead to al-
sessment or study population. Independent replication of the
terations in biological functions. Polymorphisms in glutama-
data from more sites or a clear explanation for this heteroge-
tergic genes or differences in their DNA methylation levels
neity would be needed to draw more conclusive conclusions.
may affect the response of OCD patients to glutamate-
OCD Comorbidity and the Potential Therapeutic Role of modulating drugs. A recent study by Real et al. [146] sug-
Glutamate-Modulating Drugs gested that a single nucleotide polymorphism in the SLC1A1
gene and life stress at the time of OCD disease onset can
The effect of glutamate-modulating drugs in comorbid interact to influence treatment resistance to SRIs in OCD
OCD is of interest due to the high prevalence of comorbidity patients. The potential effect of genetic polymorphisms and
in the disorder. Available data up to date are very limited and epigenetic modifications in glutamatergic genes on treatment
not allowing to draw clear conclusions. Lamotrigine has response to glutamate-modulating drugs in OCD patients
been shown to improve both obsessive-compulsive symp- needs to be systematically evaluated.
toms and depressive symptoms in OCD patients [115] and
thus warrants further investigation in patients with comorbid CONCLUSIONS
OCD and depression. So far no studies have been carried out
in comorbid OCD and bipolar disorder. However, lamo- Glutamatergic signalling has been implicated in the
trigine may be an interesting candidate to investigate in such pathophysiology of OCD by genetic, imaging, biochemical
cases, since it is approved for the prophylaxis and treatment and animal studies. Clinical investigations on the therapeutic
of bipolar depression [143]. The first trials on the effect of utility of glutamate-modulating drugs in OCD (including
ketamine in OCD patients, some of which with comorbid treatment-resistant) patients are still limited in number and
depression, showed contradictory results [88; 89]. However, precluding definitive conclusions. Research progress has
due to its the rapid onset of action, ketamine may be interest- been delayed by the relatively few studies with double-blind
ing to investigate in specific clinical situations (for example design and by the small sample sizes. So far most data on
in OCD patients with strong suicidal ideation). potential utility in subsets of OCD patients have been col-
lected for memantine, lamotrigine and riluzole. The effect of
Factors Predicting Treatment Response to Glutamate- clinical symptoms and OCD subtypes (for example early-
Modulating Drugs in OCD Patients onset or comorbid for affective disorders OCD patients), as
well as of genetic and epigenetic factors (modifications in
OCD is a clinically heterogenous disorder and some sub-
glutamatergic genes) on treatment response to glutamate-
sets of patients might respond more favourably to certain
modulating drugs needs to be further characterized. Analyz-
drugs. Identification of factors predicting treatment response
ing larger and/or more clinically or neurobiologically ho-
to glutamate-modulating drugs in OCD patients would facili-
mogenous study populations and using double-blind design
tate the decision on their use as a therapeutic alternative. So
far no studies have systematically assessed the correlation of would be informative. A combination of these approaches
response to glutamate-modulating drugs with symptom di- may help to identify a subgroup of OCD patients who would
mensions or clinical subtypes of OCD. However, we may get more effectively respond to glutamate-modulating drugs
some clues from the existing limited study data [reviewed augmentation or monotherapy.
also in 144]. For example, in an open-label trial with riluzole
CONFLICT OF INTEREST
(a drug so far not overall found to be effective in OCD) OCD
patients with prominent hoarding symptoms were noted to be The authors confirm that this article content has no con-
particularly good responders [72]. In the study of Rodriguez flict of interest.
et al. [127], OCD patients with early-onset of the disease or
ACKNOWLEDGEMENTS Nestadt, G. Genome-wide association study in obsessive-

compulsive disorder: results from the OCGAS. Mol. Psychiatry,
Declared none. 2015, 20, 337-344.
[20] Stewart, S.E.; Yu, D.; Scharf, J.M.; Neale, B.M.; Fagerness, J.A.;
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Glutamate-Modulating Drugs As A Potential Therapeutic Strategy in Obsessive-Compulsive Disorder

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Glutamate-Modulating Drugs as a Potential Therapeutic Strategy in

Zoya Marinovaa,*, De-Maw Chuangb and Naomi Finebergc

Abstract: Objective: Obsessive-compulsive disorder (OCD) is a mental disease commonly

INTRODUCTION Brain Circuits Implicated in Obsessive-Compulsive

1570-159X/17 $58.00+.00 ©2017 Bentham Science Publishers

Fig. (1). Mechanisms of action of glutamate-modulating drugs at the glutamatergic synapse.

METHOD A second randomized placebo-controlled trial of riluzole

Studies in children and adolescents

Studies in children and adolescents

These results stand in contrast to an open-label trial car- Glycine

ACKNOWLEDGEMENTS Nestadt, G. Genome-wide association study in obsessive-

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