Psychopharmacological Treatment of Obsessive-Compulsive Disorder (OCD)

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710 Current Neuropharmacology, 2019, 17, 710-736
REVIEW ARTICLE
Psychopharmacological Treatment of Obsessive-Compulsive Disorder

(OCD)
Antonio Del Casale1,*, Serena Sorice2, Alessio Padovano2, Maurizio Simmaco1, Stefano Ferracuti3,
Dorian A. Lamis4, Chiara Rapinesi1, Gabriele Sani1, Paolo Girardi1, Georgios D. Kotzalidis1 and
Maurizio Pompili1
1
Department of Neuroscience, Mental Health, and Sensory Organs (NESMOS), Faculty of Medicine and Psychology,
Sapienza University, Unit of Psychiatry, Sant’Andrea University Hospital, Rome, Italy; 2Residency School in Psychiatry,
Faculty of Medicine and Psychology, Sapienza University, Unit of Psychiatry, Sant’Andrea University Hospital, Rome,
Italy; 3Department of Human Neuroscience, Sapienza University, Rome, Italy; 4Department of Psychiatry and Behav-
ioral Sciences, Emory University School of Medicine, Atlanta, GA, USA
Abstract: Background: Obsessive-compulsive disorder (OCD) is associated with affective and

cognitive symptoms causing personal distress and reduced global functioning. These have consider-
able societal costs due to healthcare service utilization.
Objective: Our aim was to assess the efficacy of pharmacological interventions in OCD and clinical
guidelines, providing a comprehensive overview of this field.
Methods: We searched the PubMed database for papers dealing with drug treatment of OCD, with a
A R T I C L E H I S T O R Y specific focus on clinical guidelines, treatments with antidepressants, antipsychotics, mood stabiliz-
ers, off-label medications, and pharmacogenomics.
Received: March 14, 2018 Results: Prolonged administration of selective serotonin reuptake inhibitors (SSRIs) is most effec-
Revised: July 06, 2018
Accepted: August 12, 2018
tive. Better results can be obtained with a SSRI combined with cognitive behavioral therapy (CBT)
or the similarly oriented exposure and response prevention (ERP). Refractory OCD could be treated
DOI: with different strategies, including a switch to another SSRI or clomipramine, or augmentation with
10.2174/1570159X16666180813155017
an atypical antipsychotic. The addition of medications other than antipsychotics or intravenous
antidepressant administration needs further investigation, as the evidence is inconsistent. Pharma-
cogenomics and personalization of therapy could reduce treatment resistance.
Conclusions: SSRI/clomipramine in combination with CBT/ERP is associated with the optimal
response compared to each treatment alone or to other treatments. New strategies for refractory
OCD are needed. The role of pharmacogenomics could become preponderant in the coming years.
Keywords: Obsessive compulsive disorder, psychopharmacology, pharmacogenomics, selective serotonin reuptake inhibitors,
atypical antipsychotics, off-label treatments.
1. INTRODUCTION juvenile-onset OCD is more often familial and more preva-

lent in boys than in girls [5, 6]. Age at OCD onset is bi-
Obsessive-Compulsive Disorder (OCD) is a psychiatric
modal, with the first peak in late childhood or early adoles-
disorder included in the DSM-5 Obsessive-Compulsive
cence, and the second in early adulthood (i.e., 20-29 years)
Spectrum Disorders. The main symptoms include intrusive
[7, 8]. Onset is usually gradual and its clinical presentation in
thoughts (obsessions), and ritualistic behavior (compulsions) child-onset and adult-onset forms is generally similar [1].
[1]. OCD affects more than 1% of the population worldwide
However, these differ in associated comorbidities [5]. Illness
[2, 3], with lifetime prevalence of 2-3% in the general popu-
course has a chronic but fluctuating pattern, which often re-
lation [4], and no difference in gender distribution, although
lates to stressful life events [9, 10].
The life of patients with OCD is characterized by more
*Address correspondence to this author at the Department of Neuroscience, years of disability than that of patients with multiple sclero-
Mental Health, and Sensory Organs (NESMOS), Sant’Andrea Hospital, Via
di Grottarossa 1035-1039, 00189 Rome, Italy; Tel: +39-0633775951;
sis and Parkinson disease combined [11, 12]. Despite the
Fax: +39-0633775342; E-mail: antonio.delcasale@uniroma1.it illness burden, it is often unrecognized or misrecognized in
1570-159X/19 $58.00+.00 ©2019 Bentham Science Publishers

Psychopharmacological Treatment of Obsessive-Compulsive Disorder (OCD) Current Neuropharmacology, 2019, Vol. 17, No. 8 711
both primary and psychiatric settings, since its symptoms are spectrum disorders, schizophrenia, bipolar disorders, and
often internally rather than externally expressed, and because epilepsy. We also excluded transcranial magnetic stimula-
many patients manifest self-stigma (symptoms experienced tions, surgery, neuroimaging, psychometrics, and animal
with shame, embarrassment, or guilt) [12-15]. Consequently, studies. We excluded 182 studies for not meeting our inclu-
the mean time from OCD onset to introduction of a pharma- sion- and/or meeting our exclusion-criteria. Of these, 3 were
cological treatment is nearly eight years [12, 16, 17]. Less animal studies; case reports, 9; focused on CBT or psycho-
than 40% of patients coming to clinician’s attention receive metrics, 14; neuroimaging, 13; not focused on OCD, 63;
OCD-specific therapy, and less than 10% obtain evidence- non-systematic reviews, 20; mainly focused on clinical or
based treatment [12, 18]. Epidemiological studies suggest psychopathological aspects, or non-pharmacological studies,
that over 50% of patients with OCD have at least one co- 58; 2 were focused on child/adolescent patients. Then, we
morbid psychiatric disorder, most commonly an anxiety dis- searched for studies prior to the considered period in article
order or major depressive disorder. Moreover, alcohol use references and on PubMed through the function “Similar
disorder is more frequent in OCD than in the general popula- articles”, further including 93 other studies on the basis of
tion [19]. our inclusion and exclusion criteria. Based on these criteria,
we finally included 177 papers focusing on OCD psycho-
A preponderance of evidence supports the combined
pharmacology (see PRISMA flow-chart, Fig. 1).
OCD treatment with selective serotonin reuptake inhibitors
(SSRIs) and cognitive behavioral approaches. Most patients 3. DISCUSSION
show symptom improvement with these interventions, either
alone or in combination [20]. Given this, clinical practice 3.1. Antidepressant Medications
usually consists of combining SSRI treatment with cognitive
Changes in the serotonergic transmission, including the
behavioral therapy (CBT) [21]. However, even when a theo-
enhancement of postsynaptic signals induced by serotonin,
retically appropriate treatment is established, 40-60% of
have been associated with OC symptom improvement. In
OCD patients exhibit disabling residual symptoms, indicat- physiological neurotransmission, serotonin is transported
ing the need for innovative pharmacological treatments, dif-
from the synaptic cleft back to the presynaptic neuron
ferent augmentation strategies, and novel physical treatment
through membrane transporter proteins and from there into
techniques [12, 22].
the readily releasable synaptic pool through vesicular
The aim of this article is to provide a comprehensive re- bioamine transporters. SSRIs can specifically block mem-
view of the developments in the pharmacological manage- brane transporters, resulting in an accumulation of serotonin
ment of OCD in adults within the past 10 years. We re- in the synaptic cleft [23]. SSRIs are generally first-line, with
viewed the most recent evidence of the effectiveness of anti- good response rates and positive long-term results [23-25],
depressant, antipsychotic, and mood stabilizing drugs, as despite the possible slight superiority of clomipramine in
well as off-label drug treatment. We summarized clinical efficacy studies [26].
guidelines and highlighted the possibilities of a positive im- 3.1.1. Selective Serotonin Reuptake Inhibitors (SSRIs)
pact of pharmacogenomics and of personalized mental health
approaches. Most of these drugs showed effectiveness in treating
OCD both in the acute and in the maintenance phase and
2. METHODS showed good tolerability. A Cochrane review confirmed the
efficacy for all SSRIs (including citalopram, fluoxetine, flu-
2.1. Study Selection voxamine, paroxetine, and sertraline), without significant
We performed a PubMed search to identify peer- differences [27].
reviewed studies investigating psychopharmacological The response to SSRI treatment may be more delayed in
treatments in adult patients with OCD. We used a stepwise patients with OCD than in those with major depression or
procedure to identify relevant experimental articles focusing anxiety disorders. However, a recent meta-analysis showed
on OCD psychopharmacology. First, we identified studies in that a significant benefit from SSRI treatment compared to
the last 10 years through a standard search with the title- placebo occurred already after 2 weeks from the start of
abstract specification in PubMed (http://www.pubmed.gov). treatment [28]. Long-term treatment (24-52 weeks) with an
On 25 February 2017 we performed a search including the SSRI compared to placebo was associated with significantly
terms ‘obsessive compulsive disorder’, ‘pharmacol*’, ‘anti- lower probability of relapse with SSRIs [29, 30]. SSRIs
depress*’, ‘antipsych*’, ‘lithium’, ‘stabilis(z)er’, ‘antiepi- should be maintained at the maximum effective dose for at
lept*’, and excluding the terms ‘p(a)ediatr*’, ‘child*’, ‘case least 12 months. Treatment response is dose-related, with
report’, ‘tourette’, ‘schizophr*’, ‘bipolar’, ‘epilepsy’, ‘neu- better clinical responses associated with higher dosages [29,
ropsychol*’, ‘personality disorder’, ‘dTMS’, ‘rTMS’, 30], although lower doses (e.g., in the case of escitalopram)
‘stimulation’, ‘ECT’, ‘surgery’, ‘*tomy’, ‘mice’, ‘animal’, could be effective in preventing relapses [30]. OCD family
‘rat’, ‘dysmorphic’, ‘somatic symptom disorder’, ‘hoarding’, history, aggressive, sexual, and religious obsessions, orbi-
‘skin’, ‘neuroimaging’. We retrieved 266 papers. We in- tofrontal cortex hypometabolism, and right caudate nucleus
cluded pharmacological trials, and systematic reviews and hypermetabolism correlated with high likelihood of respond-
meta-analyses. We excluded papers that included ing to SSRI treatment [31, 32]. Hoarding behavior [33], poor
child/adolescent patients, case reports, diagnoses of Tourette insight, severe concomitant depressive episode [34], and
syndrome, dysmorphic, hoarding, excoriation (skin picking), higher levels of disability [35] correlated with limited SSRI
nail biting, personality, somatic symptom and other OCD treatment response.
712 Current Neuropharmacology, 2019, Vol. 17, No. 8 Del Casale et al.
Fig. (1). PRISMA flow diagram [362] showing search and inclusion strategy.
Several studies have focused on paroxetine treatment of Escitalopram showed favorable pharmacokinetics and
OCD. Doses of 20-60 mg/day generally correlated with sig- good tolerability. It is the most 5-HT-selective among SSRIs,
nificant symptom improvement. Paroxetine showed a with little or no affinity for other transmitter transporters or
marked anxiolytic effect and may be recommended as a first- receptors [59]. Compared to other SSRIs, escitalopram may
line therapy in the treatment of OCD comorbidities [36]. It have weak or minimal interactions with the cytochrome
reduced avoidance related to phobic symptoms improving P450 system [60, 61]. In a randomized, double-blind, pla-
quality of life [37]. Its safety and long-term efficacy are sup- cebo-controlled 24-week trial in OCD, escitalopram (20
ported by the literature [38]. It has been consistently associ- mg/day) was associated with an increase in response rate
ated with treatment response (i.e., drop of at least 25% on the compared to placebo after 12 weeks. Other placebo-
Yale-Brown Obsessive-Compulsive Scale [Y-BOCS]) from controlled studies consistently showed escitalopram-related
baseline scores [25, 36, 39-42]. treatment response [25, 30]. 20 mg/day escitalopram has also
Placebo-controlled studies in OCD patients consistently been associated with better OCD symptom remission com-
associated fluvoxamine administration (dosage range 100- pared to 40 mg/day paroxetine or placebo at week 12 [30].
300 mg/day) with treatment response [43-47], although with Three different escitalopram dosages (5, 10, and 20 mg/day)
some exceptions [48-52]. Fluvoxamine’s pharmacokinetic were compared with a fixed, 20 mg/day dose of paroxetine
profile and its side effects may hinder rapid titration. The in a 12-week study, in which escitalopram showed both
drug showed efficacy in social anxiety, avoidance, and pho- greater efficacy and better tolerability [62].
bic symptoms after 6-8 weeks of treatment and subsequently Fluoxetine was shown to be safe and effective at a dose
was associated with further improvement [53]. Long-term of 40-60 mg/day [63, 64]. The effects of fluoxetine on dif-
treatment (40-weeks with a dose of 100-300 mg/day) was ferent clinical OCD subtypes have been studied, showing
associated with improvements of psychosocial skills and improvement of obsessive thoughts, washing compulsions,
obsessive symptoms [54]. psychosocial functioning, and quality of life [65]. Regarding
Citalopram proved to be effective in the treatment of the management of phobic symptoms, fluoxetine has been
OCD [55], with best results at doses of 60 mg/day [56], shown to be equally effective in both the short- and the me-
which correlated with improvements on psychosocial func- dium-term (24 weeks), both in monotherapy and in combina-
tioning, depressive symptoms, obsessive thoughts, repetitive tion with CBT [66]. Placebo-controlled studies consistently
behavior, and anxiety. It showed good tolerability [57] and associated the administration of fluoxetine with treatment
appeared to be effective in patients with refractory OCD response (drop of at least 25% on the Y-BOCS from base-
[58]. line) [63, 64, 67-69], although with some exception [70, 71].
Fluoxetine proved to be useful and safe in preventing recur- ness (study 2). Both studies demonstrated that clomipramine
rence of obsessive symptoms in patients who responded to was significantly more effective than placebo. Among the most
short-term administration. The low overall relapse rates were frequent clomipramine-related adverse effects (similar to the
evident at the maintenance dose of 40 mg/day, although 60 other tricyclic antidepressants), seizures and aminotransferase
mg/day seemed to provide more protection. augmentation were the most dangerous. However, clomi-
pramine was generally well-tolerated [84]. One more double-
Sertraline has shown efficacy and safety at doses of 50- blind placebo-controlled study conducted on 25 patients with
200 mg/day [72] in treating phobic-related states, with a OCD for 10 weeks showed that clomipramine treatment vs.
greater reduction in symptoms related to anxiety/fear, physi- placebo significantly improved symptoms. Side effects
cal symptoms and avoidance behaviors [73]. Clinical im- mainly included heart rate increase. The authors showed
provements in obsessive symptoms and phobic behavior clomipramine-related attenuation of autonomic reactivity to
have been achieved with long-term therapy, with a good tol- stressors, which they interpreted as a direct autonomic effect
erability profile. A rapid sertraline titration up to 200 mg/day of clomipramine or an increased unresponsiveness to psy-
correlated with fast response rates. A 20-week study with chological stressors [85]. Twenty-five OCD patients with
sertraline 50-200 mg/day produced significant improvements moderate to severe symptoms and at least 2 years of illness
both in functioning and social skills [74]. Stable sertraline duration were involved in a double blind, placebo-controlled,
treatment guaranteed lower recurrence rates, and a general 10-week study that showed the superiority of clomipramine
improvement in quality of life. Placebo-controlled studies over placebo. Another analysis focused on symptoms out-
consistently showed sertraline-related treatment response come and plasma drug concentrations in 33 OCD patients
[72, 75, 76], although with one exception [77]. Treatment of taking clomipramine showed that clomipramine plasma con-
refractory OCD with high doses of sertraline (250-400 mg/day) centrations directly correlated with outcome measures. Pa-
resulted in a significant symptom improvement and a similar tients with treatment response significantly showed higher
rate of adverse events observed with a 200 mg/day dose [78]. plasma clomipramine and a trend toward lower desmethyl-
3.1.2. Clomipramine clomipramine [86].
Clomipramine, a tricyclic antidepressant (TCA) with a Clomipramine has been compared to paroxetine in a mul-
transporter blockade profile that is much similar to the pro- tinational randomised study involving 406 subjects with
files of most SSRIs as far as the serotonin/noradrenaline ra- OCD of at least six months duration received double-blind
tio is concerned [38], placing it midway between SSRIs and medication for up to 12 weeks and doses adjusted according
SNRIs and quite far from other TCAs, was the first drug to therapeutic effect and side-effects. Both treatments proved
used to treat OCD. In addition, one of the primary metabo- to be an appropriate treatment for OCD [39].
lites of clomipramine, desmethylclomipramine, is a potent Summarising, the efficacy of clomipramine in OCD is
noradrenaline uptake blocker [26]. It has a unique anti- consistently reported and appeared to be equivalent to or
obsessive effect due to its potent inhibition of serotonin re- slightly better than that of SSRIs, although its side effect
uptake, and this action has drawn attention to a possible role profile is less favorable [39, 80, 82-86].
of serotonin in the neuropathophysiology of OCD [79]. The
efficacy of clomipramine in treating OCD is well supported 3.1.3. Serotonin–Norepinephrine Reuptake Inhibitors
by the literature [26]. Among studies, a multicenter double (SNRIs)
blind, randomized, placebo-controlled trial conducted in 122
SNRIs combine the actions of SSRIs with inhibition of
OCD patients compared clomipramine vs. exposure and re-
noradrenaline reuptake. These drugs have little effect on the
sponse prevention (ERP) vs. ERP plus clomipramine combi-
activity of α1-adrenergic, muscarinic cholinergic or hista-
nation vs. placebo. The study provided ERP for four weeks,
minergic receptors, thus showing better tolerability than
with subsequent maintenance sessions for eight weeks and/or
clomipramine.
clomipramine (up to 250 mg/day) treatment for 12 weeks. At
week 12, all active treatments proved to be superior to placebo. Venlafaxine short-term treatment of OCD showed similar
ERP did not show differences from clomipramine+ERP efficacy to clomipramine, although with a more favorable
combination, which were more effective than clomipramine safety profile [87]. Most studies have shown efficacy in both
only [80]. Other data also showed that intravenous clomi- naïve and treatment-resistant OCD patients at daily dosages
pramine could be effective in treating refractory OCD [81]. between 150 mg/day and 375 mg/day with satisfactory re-
A 10-week double-blind, placebo-controlled trial conducted sponse rates (30-60%) [88-92]. OCD treatment with 300
on 27 OCD outpatients treated with oral clomipramine showed mg/day venlafaxine compared to 60 mg/day paroxetine
that the drug was significantly superior to placebo [82]. An- showed similar response rates, although paroxetine may be
other 10-week double-blind study on thirty-two OCD pa- more effective than venlafaxine in refractory patients [93].
tients without depression showed that the treatment with Duloxetine has shown some efficacy in the treatment of
clomipramine was associated with significant improvement OCD, although most evidence comes from case reports or
in OCD symptoms, although with more frequent and severe studies with small samples [94-96].
side effects than placebo [83]. Two multicentre (21 sites)
Some preliminary reports focused on OCD treatment
double-blind studies focused on the efficacy, safety, and tol-
with milnacipran, which has a recognized efficacy in fi-
erability of clomipramine (up to 300 mg/day) vs. placebo in
bromyalgia and major depression [97]. Milnacipran is used
520 OCD patients, of whom 239 with more than two years of
much in France, Canada and Japan, but its usefulness in
illness (study 1), and 281 between one and two years of ill-
OCD needs further examination.
3.1.4. Other Antidepressants press anxiety-related activation of the amygdala [112]. Based
on the hypotheses of dopaminergic hyperactivation in the
Agomelatine 5-HT2C antagonism could mediate anx-
etiology of the OCD, an important strategy is the use of an-
iolytic effects, and melatonin modulation (MT1 and MT2
tipsychotic drugs in add-ons to SSRIs.
receptors antagonism) could contribute to circadian rhythm
restoration in OCD patients [98]. It has been tested both in 4.1. Nosological Issues
substitution [99] and in addition [100] to standard SSRI
treatment, and to clomipramine [101]. Other antidepressants From a clinical viewpoint, antipsychotics should be pref-
showed little or no effects in OCD. A double-blind discon- erentially used for comorbid psychotic symptoms, which are
tinuation study showed for mirtazapine a significantly better not rare in OCD [113]. The overlap of symptoms between
effect of the drug with respect to placebo on Y-BOCS scores schizophrenia and OCD relates to difficulties in differential
[102]. Another double-blind study showed poor improve- diagnosis and therapeutic management and constitutes an
ment of obsessive-compulsive symptoms with trazodone important research line of psychopathology since the begin-
[103]. Many antidepressants were reported to be useful ning of modern psychiatry. “Folie raisonnante”, “folie lu-
mainly as add-ons on established pharmacotherapy in the cide”, “folie avec conscience" already identified in the nine-
attempt to overcome treatment-resistance in case reports, but teenth century those clinical pictures between delusions and
none showed efficacy in double-blind studies. obsessions, in which ideas are egosyntonic and reality per-
ception is preserved, and in which the diagnostic definition is
3.1.5. Antidepressants in Refractory OCD borderline between neurosis and psychosis. Over time, in-
A management strategy for treatment-resistant OCD may creasing evidence indicated the existence of dynamic rela-
consist of adding SSRIs to other drugs that further enhance tionships between obsessive and psychotic symptoms, with
serotoninergic transmission [104]. Some open studies sug- the use of several terms, such as “obsessive psychosis”,
gested that the combined treatment with clomipramine and “OCD with prevalent ideas”, “OCD with psychotic aspects”.
an SSRI is effective and well tolerated. Positive results have Recently, the definition “OCD with poor insight” distin-
been reported with the addition of citalopram to clomi- guishes an “atypical” subtype of OCD, which relates to
pramine in the long term [58]. Encouraging data were also worse outcome. It is characterized by the coexistence of
reported with the combination of clomipramine with fluoxet- compulsive obsessions and rituals with psychotic symptoms
ine or sertraline [54]. In any case, add-on treatment on or by obsessions (considered realistic and reasonable by pa-
clomipramine requires careful clinical monitoring [81]. tients) that can be comparable to delusions or hallucinations
[114, 115]. Conversely, prevalence of obsessive-compulsive
Intravenous antidepressant administration, including symptoms/OCD is high in patients with schizophrenia [116].
clomipramine and citalopram, was associated with faster According to a psychodynamic interpretation, obsessive-
response, but eventually, with continued treatment, the result compulsive rituals could protect patients with schizophrenia
is similar to oral administration [105, 106]. Intravenous vs. from psychotic breakdown. The neuropathophysiology of
oral clomipramine was more effective in two double-blind these disorders involves the dopaminergic and serotonergic
placebo-controlled studies [107, 108]. Treatment with high neurotransmitter systems, which are mutually interacting
doses of serotonin reuptake inhibitors is another strategy to [117].
consider, including 250-400 mg/day sertraline [78], and 30-
50 mg/day escitalopram [109, 110]. There is no evidence Overall, the manifestation of psychotic symptoms affects
that switching from one first-line drug to another can pro- 1-12% of patients with OCD [118-121]. This subgroup has
duce benefits. Lower response rates were reported after an earlier onset, a greater impairment of functioning at work,
switching from one SSRI to another, as compared to the shift more severe depressive symptoms and a more frequent
from an SSRI to clomipramine [76]. Summarizing the evi- chronic course. It is also correlated to specific basic symp-
dence, it appears that the last resort could be clomipramine. toms (mainly cognitive, thought and perception disorders)
and schizotypal personality disorder [122-124]. Ganesan et al.
4. ADD-ON ANTIPSYCHOTIC TREATMENTS [125] suggested that the manifestation of psychotic symp-
toms in OCD is an unfavorable prognostic factor, predicting
About 40-60% of OCD patients do not satisfactorily re- worse illness course and poor response to standard treat-
spond to monotherapy with serotonergic drugs [111], con- ments (both pharmacological and psychotherapeutic).
sidering for response a reduction of at least 25-35% of the
values of the Y-BOCS [51]. The main lines of research on 4.2. Guidelines
refractory OCD have focused on the study of psychotropic
drugs as add-ons. The cortico-striatal OCD working model A short duration of SSRI therapy could be a source of
speculates on the existence of an imbalance of the direct vs. bias because some patients may respond to these drugs more
indirect pathway, with subsequent circuitry hyperactivations slowly than others. Hence, SSRIs should be administered for
that may relate to OCD-related repetitive behaviors [112]. an adequate time before a treatment change. The American
The amygdalocentric model hypothesises malfunctioning in Psychiatric Association guidelines recommend a period of at
the physiological top-down inhibition of the amygdala in least 8-12 weeks of SSRI treatment (with at least 4-6 weeks
OCD patients, which may relate to the more intrusive at the maximum tolerable dose) before considering a change
thoughts and chronic anxiety. Dysfunctional top-down inhi- in drug strategy [126]. Accordingly, in cases of partial initial
bition of the amygdala may be affected by modifications of treatment response, the addition of antipsychotics should be
the mesolimbic dopaminergic system; increased dopamine preferred over the switch to a different SSRI, which should
adversely affects the ability of the prefrontal cortex to sup- be conducted only in case of non-response [126]. The World
Federation of Societies of Biological Psychiatry (WFSBP) The literature is not consistent regarding the usefulness
recommended a co-administration of SSRI-haloperidol, - of adding quetiapine to a SSRI for the treatment of OCD.
quetiapine, -olanzapine or -risperidone for treatment- Vulink et al. [142] examined the effect of the combination of
resistant OCD (grade 3 recommendation) [127]. quetiapine with citalopram in patients with non-refractory
OCD, showing a significantly higher efficacy of quetiapine
To date, the addition of antipsychotics to standard sero- compared to placebo. All but one [143] placebo-controlled
tonin enhancers is one of the most documented strategies for
studies of 50-500 mg/day add-on quetiapine on SSRIs
treatment-resistant OCD. The prevalence of antipsychotic
showed a greater than 20% reduction of Y-BOCS scores of
prescriptions in OCD patients is currently high and increas-
treatment-refractory OCD patients [139, 144-147]. Signifi-
ing [128]. However, no antipsychotic agent is officially ap-
cant efficacy was not demonstrated for olanzapine and queti-
proved for the treatment of OCD. The use of add-on antipsy-
apine in a first meta-analysis [133], but subsequently shown
chotics to SSRIs in OCD with comorbid Body Dysmorphic by a second one by the same group [148]. Still another meta-
Disorder needs further study [129].
analysis [149] did not show efficacy for quetiapine or olan-
zapine compared to placebo. Other studies showed remark-
4.3. Use of Add-on Antipsychotics in OCD
able response rates in treatment-resistant OCD with add-on
Albert et al. [130, 131], comparing the efficacy of vari- antipsychotic treatment. Haloperidol [150], quetiapine [144,
ous antipsychotics in different mental disorders, found a sig- 151], olanzapine [152], and amisulpiride [153] have shown
nificant role of prolonged-release quetiapine, risperidone and efficacy in more than 40% of treated patients. After 6
aripiprazole as possible adjuvant alternatives in treatment- months of add-on to high-dose SSRIs treatment, ziprasidone
resistant OCD. was less effective than quetiapine in patients with resistant
OCD (44.4% vs. 80% clinical response) [139].
Consistent evidence of efficacy in resistant OCD is re-
lated to risperidone. Komossa et al. [132], comparing 11 Add-on aripiprazole to SSRIs has shown encouraging
RCTs that examined the efficacy of the add-on strategy with results in the treatment of resistant OCD. The efficacy of
SGA versus placebo in about 400 cases of refractory OCD, aripiprazole has been also observed for the treatment of
indicated risperidone as the most promising augmenting compulsive obsessive symptoms in patients with bipolar
agent. Quetiapine did not appear to improve the response to disorder [154], schizophrenia [155], or children with Tic
antidepressant treatment but was statistically superior to pla- disorders [156]. Its therapeutic role in refractory OCD was
cebo in reducing the mean Y-BOCS score and showed posi- initially evaluated as monotherapy. Already the first studies
tive effects on anxiety and depressive symptoms. The least showed greater efficacy of aripiprazole in augmentation to
advantageous option was the add-on with olanzapine, which antidepressant drugs rather than in monotherapy [157-163].
showed less efficacy and tolerability, especially in terms of A recent meta-analysis showed that 10 mg/day aripiprazole
weight gain, although the data were too limited to draw defi- was the most effective short-term option with an important
nite conclusions [132]. Similar conclusions emerged from overall effect size [149]. Risperidone also showed a small
another meta-analysis [133], which examined 12 other RCTs effect size in the short term in this study. Treatment with
evaluating add-on strategies with quetiapine, risperidone, aripiprazole at a dose of 5-20 mg/day added on to paroxet-
olanzapine, aripiprazole and haloperidol in 394 treatment- ine, fluvoxamine or clomipramine showed high response
resistant OCD patients. Overall, about a third of patients rates [164]. Aripiprazole was also well tolerated and the
were benefiting from the augmentation strategy with average most commonly observed adverse reactions were akathisia,
antipsychotic doses; risperidone was confirmed as a potential nausea, vomiting, and agitation [164]. Aripiprazole in addi-
first choice, both for response rates and for total Y-BOCS tion to SSRIs showed significant improvements in obsessive-
score drop. Li et al. [134] compared the treatments with add- compulsive symptoms also in the midterm (12 months fol-
on risperidone (1 mg/day) and haloperidol (2 mg/day) in a low-up) [162, 165]. Confirmations of efficacy and tolerabil-
crossover study. Both drugs were significantly effective on ity of low doses of add-on aripiprazole (10 mg/day) in se-
obsessive symptomatology, but only haloperidol signifi- vere, treatment-resistant OCD also derive from other two
cantly reduced the total Y-BOCS score. Placebo-controlled randomized double-blind placebo-controlled trials [166,
studies showed add-on risperidone to reduce more than 20% 167]. Compared to other antipsychotics, aripiprazole showed
Y-BOCS scores [104, 135, 136], while other studies con- a lower risk of weight gain, sedation, and prolactin increase
firmed reduction of Y-BOCS, although to a lesser degree [168]. Long-term follow-up studies are needed to assess the
[137, 138]. On the other hand, risperidone induced signifi- efficacy and safety of aripiprazole added on to SSRIs in
cant improvements in depressive symptoms and was signifi- treatment-resistant OCD.
cantly more tolerable than haloperidol [139]. Maina et al.
[140] compared risperidone and olanzapine as add-on to a Overall, antipsychotics as augmenting agents compared
SSRI, demonstrating a significant improvement in obsessive- to placebo showed a statistical superiority in terms of clinical
compulsive symptomatology with each strategy. Selvi et al. improvement. Haloperidol, risperidone and aripiprazole
[141] showed the superiority of add-on risperidone (3 showed more consistent positive effects on refractory OCD
mg/day) compared to aripiprazole (15 mg/day). A very low as add-ons. For other antipsychotics, like quetiapine, olan-
dose of risperidone (0.5 mg/day) added on standard SSRI zapine, and paliperidone the evidence is less compelling, and
treatment showed a greater effect size than a moderate dose some studies showed they did not significantly differ from
[137], but placebo-controlled studies showed a greater effect placebo [138, 148, 167, 169]. In summary, the most recent
of higher doses (2-3 mg/day) [104, 135, 136]. studies suggested that risperidone and aripiprazole might be
used as add-on agents to SSRIs/CBT in resistant OCD more than quetiapine. Since response rates to haloperidol
patients. and risperidone were found to be higher than those of queti-
apine and olanzapine in meta-analytical studies, it can be
4.4. Clozapine and Clozapine-related Obsessive- assumed that besides antidopaminergic activity, there must
compulsive Syndrome (OCS) be other mechanisms supporting the anti-psychotic efficacy
of the former drugs in treatment-resistant OCD. The antido-
Clozapine is not recommended for OCD due to poor evi-
paminergic hypothesis is supported by an open-label aug-
dence of efficacy [170]. In addition, several case reports and
mentation study with 200-600 mg/day amisulpiride, a selec-
clinical studies support the association of clozapine with
tive and potent blocker of the D2 and D3 receptors, which
worsening or onset of obsessive-compulsive symptoms in
showed promising results [153]. Since amisulpiride, like
patients with a psychotic disorder [171-176]. At least 20% of
other substituted benzoamides, is highly specific for dopa-
individuals treated with clozapine (and other antiserotonergic
mine receptors, this would seem to confirm the involvement
antipsychotics) would experience worsening or emergence of
of D2 antagonism in the therapeutic action in resistant OCD.
obsessive-compulsive symptoms [177], which are dose-
However, the study was not double blind, so the efficacy of
related [178] and generally reversible upon discontinuation
amisulpiride in this condition remains undetermined.
of clozapine treatment and switch to a different antipsychotic
[179]. The mechanism by which clozapine and other second- According to positron emission tomography (PET) stud-
generation antipsychotics (SGAs) can induce or worsen ob- ies, low doses of atypical antipsychotics induced high levels
sessive-compulsive symptoms is unclear and probably re- of 5-HT2A/C antagonism, while relatively higher doses are
lated to 5-HT2A receptor blockade in areas known to be in- necessary to determine significant blockade of D2 receptors
volved in the neuropathophysiology of OCD, such as the [193]. However, SGAs were effective augmentation agents
anterior cingulate cortex, the dorsal posterior prefrontal cor- in treatment-resistant OCD at medium doses, lower than
tex and the orbitofrontal cortex [180-182]. Supporting the those currently recommended for the treatment of psychotic
antiserotonergic hypothesis, there is evidence that first- disorders, similarly to what occurs in the treatment of major
generation antipsychotics (FGAs), which mainly have do- depression. Both haloperidol (strong D2 and moderate 5-
paminergic actions, are not implicated in iatrogenic OCS HT2A receptor blocker) and aripiprazole (the most peculiar
[183]. Patients exposed to a potent dopamine antagonist before among SGAs in terms of effects on D2, 5-HT1A, 5-HT2A, and
clozapine would be more susceptible to the development of 5-HT2C receptors) proved to be useful in refractory OCD.
clozapine-induced OCS, pointing to hypersensitisation. The use This could indicate that antipsychotic augmentation in OCD
of clozapine following the upregulation of striatal D2 receptors treatment mainly relies on the modulation of the interplay of
induced by chronic FGA exposure would result in a reduction serotonergic and dopaminergic transmissions [149]. Fur-
of the dopaminergic block with consequent OCS. Finally, thermore, since low doses of antipsychotics primarily an-
polymorphisms of various genes (i.e., SLC1A1, GRIN2B and tagonize the presynaptic dopamine autoreceptor, this mecha-
GRIK2) may be related to clozapine-induced OCS [184]. nism is more likely to increase or modulate rather than an-
tagonize dopaminergic transmission. The promising results
OCS induced by clozapine should not be confused with
of aripiprazole added on SSRI treatment may relate to its
worsening of psychosis; in fact, one would be prompted to
peculiar partial agonism of D2 and 5-HT1A receptors and
increase dosages to obtain proper antipsychotics that could
antagonism of 5-HT2A/2C receptors.
be associated with further symptom worsening. Clozapine-
related OCS should not lead to clozapine withdrawal when 4.6. Limitations
primary psychotic symptomatology has clearly benefitted.
Therapeutic options for clozapine-induced OCS include dos- Different studies produced inconsistent results and were
age reduction [185], introduction of a serotonin enhancer limited by small samples of treatment-resistant OCD pa-
[186], or aripiprazole [187], which could be effective due to tients, multiplicity of study designs, inconsistent definitions
its partial 5-HT1A agonism, cautiously considering potential of treatment resistance, lack of homogeneity in the adopted
pharmacokinetic interactions. The possible introduction of response criteria, and heterogeneity of the clinical pictures of
fluoxetine, paroxetine or clomipramine deserves caution due included OCD patients. Some symptom subsets may differ-
to the mild-to-moderate inhibition of clozapine metabolism ently respond to a specific treatment, even if symptoms over-
by these drugs [188, 189]. Fluvoxamine should be avoided, lap and vary in severity. To date, there is no genotype or
as it is a potent inhibitor of clozapine metabolism and may phenotype identified as a predictor of add-on antipsychotic
cause toxicity [190]. Some case reports described other clo- treatment efficacy in resistant OCD. A further limitation is
zapine-induced OCS management modalities, including the the variability of inclusion and exclusion criteria regarding
introduction of valproic acid and the use of electroconvulsive comorbidities particularly tic disorders. Tourette and tic dis-
therapy [191, 192]. orders tend to co-occur with OCD and are usually treated
with antipsychotic drugs; it should be considered that OCD
4.5. Pharmacodynamics patients with comorbid tic disorder benefit more from addi-
tional antipsychotic drugs than patients with OCD without
The mechanism of action of SGAs is the combination of
tic disorders [194].
D2 and 5-HT2A antagonism. To date, it is not clear which
receptor, in addition to the serotonin uptake inhibition re- 4.7. Future Directions
lated to SSRI treatment, is at the heart of the therapeutic ef-
fects in resistant OCD. Haloperidol has slightly more affinity There is a lack of studies focusing on high-dose antipsy-
for D2 receptors than olanzapine and risperidone and much chotics in refractory OCD, and we cannot exclude that this
strategy may increase the proportion of responders. Further Taking into account the chemical and pharmacodynamic
studies are needed addressing these issues to allow for the heterogeneity of the SSRIs as a class, further studies should
optimization of treatment recommendations for refractory evaluate which of them is the most suitable for antipsychotic
OCD. Considering the possibly low overall response to SSRI augmentation in refractory OCD.
monotherapy, early co-administration of antipsychotics is a
commonly recommended strategy for treatment-resistant 5. OTHER ADD-ON PHARMACOLOGICAL TREAT-
OCD. There is still no precise guideline about antipsychotic MENTS
choice, neither on optimal dosing, nor on appropriate treat-
5.1. Antiepileptics
ment duration or long-term safety of increasing antipsychotic
doses. Further investigations are needed to clarify the effi- Considering the significant proportion of drug-resistant
cacy and safety of each antipsychotic drug and establish pos- OCD patients, further treatment strategies have been at-
sible differences. There are no studies with a very long-term tempted, including augmentation with antiepileptic drugs.
follow-up investigating the outcome or adverse events of Overactivation of the cortico-striatal-thalamo-cortical circuit,
add-on antipsychotics. Although benefits have been found, in which a role could be played by glutamate, is apparently
especially for aripiprazole and risperidone, potential long- involved in OCD, justifying the assumption that antiepileptic
term risks are not known. After one year of treatment, queti- medications antagonizing glutamatergic activity could re-
apine, risperidone and olanzapine added on CBT and SSRIs duce OCD symptoms [181, 182, 201].
in non-responder patients were associated with symptom
Add-on topiramate at daily dose ranges up to 400 mg
improvement, but also with increases in body mass index
improved refractory OCD [201-204]. One study reported a
(over 10%) and fasting blood glucose levels in more than
positive effect of 225-675 mg/day pregabalin augmentation
half of treated patients [195]. The potential benefits of antip-
in 10 partial responder/resistant OCD patients to combined
sychotic medications should be carefully balanced against
SSRI/SGA treatment [205].
the risk of side effects. Should a patient with standard treat-
ment-resistance be judged to respond to a 4-week add-on Lamotrigine at 150 mg/day added on 225 mg/day clomi-
antipsychotic, he/she should be advised to regularly monitor pramine [206] in a case and at 100-200 mg/day added to the
weight, blood glucose, and blood lipid profile; the clinician same clomipramine dose or to 60 mg/day paroxetine in two
should monitor the patient for possible long-term adverse cases [207] obtained improvement; this was further con-
effects. firmed in two placebo-controlled studies, both showing effi-
Alternative strategies to antipsychotic augmentation may cacy vs. placebo of 100 mg/day lamotrigine added on SSRIs
be more efficacious and safer in the long run. For example, in refractory OCD [208, 209]. The addition of gabapentin to
CBT showed more efficacy and less side effects than risperi- fluoxetine reduced time to treatment response [210]. Deltito
done or placebo [138], which prompted the investigators to [211] (1994) reported that 8 of 10 patients who did not toler-
provide non-pharmacological treatment first, thus defining ate standard antiobsessional treatment, who were pretreated
treatment-resistant patients as those who also had evidence with valproate, responded to subsequent reintroduction of the
of a failed CBT course. However, this study is flawed by the antiobsessional with a reduction of OCD symptoms. Another
fact that there is no such a thing as a blind sham psychother- report, in which one patient has been treated similarly; clini-
apy administration, so conclusions should be avoided. Inves- cians gradually tapered-off clomipramine and continued on
tigators should be prompted to speak about drug-resistance valproate monotherapy, obtaining further reduction of obses-
when only drugs have been tried and of treatment resistance sive-compulsive symptoms [212]. These finding have not
when all possible treatments have failed, otherwise they been replicated to date.
should define resistance as SSRI-, psychotherapy
(CBT/ERP)- or somatic (TMS, DBS, ECT, or psychosur- 5.2. Ondansetron
gery)-treatment–resistance (i.e., they should be more specific Ondansetron is a 5-HT3 serotonin receptor antagonist
in their definition of a resistant/refractory patient in the titles used primarily to reduce nausea and vomiting associated
of the articles they publish). Some evidence supported the with chemotherapy, radiotherapy, post-surgery, and preg-
add-on of clomipramine to a SSRI before trying an antipsy- nancy. Since 5-HT3 blockade produces a weak inhibitory
chotic add-on treatment. The addition of clomipramine (25- effect on dopaminergic neurotransmission [213], ondanse-
75 mg/day) to fluoxetine showed more effectiveness than
tron has been tested in the treatment of schizophrenia [214],
add-on quetiapine [196]; also, the use of add-on clomi-
Tourette's disorder [215] tardive dyskinesia [216], alcoholism
pramine to citalopram was superior to citalopram alone
[217] (Johnson et al., 2011), and OCD [218]. Both uncon-
[197]. In such cases, a combination with clomipramine re-
trolled and placebo-controlled studies showed that ondanse-
quires ECG monitoring [197], but this is just one of the pre-
tron was safe and effective in treating refractory OCD, both
cautions that should be taken, as this type of practice exposes
in monotherapy and added on SSRIs. In a pilot, 8-week,
the patient to the risk of a serotonin syndrome [198, 199].
open-label trial, oral ondansetron monotherapy (3 mg/day)
To date, more data are needed to predict the response to resulted in 29-55% reduction of Y-BOCS scores from base-
SGAs in add-on to standard treatment. Further studies are line and to 45% worsening 2 weeks after suspension [219].
needed to identify subgroups of patients that could benefit Fourteen patients with refractory OCD received ondansetron
from this treatment option [200]. Further evidence showed (0.5-1 mg/day) added on SSRIs and SGAs for 12 weeks,
that reducing the dose of SSRI after the introduction of an showing decrease of at least 23% of the Y-BOCS scores and
antipsychotic does not improve response to treatment [196]. some minor adverse events [220]. Twenty-one patients who
did not respond adequately to a SSRI, received 12 weeks of dard OCD treatment may result in a clinically significant
0.5-1 mg/day add-on ondansetron, obtaining a 27.2% aver- improvement in a proportion of refractory patients, particu-
age reduction of Y-BOCS (57% response rate). Four weeks larly in people who partially responded to SSRIs. This ob-
after ondansetron discontinuation, Y-BOCS scores increased servation supports the hypothesis of a close interaction be-
by 15.5% on the average in the entire sample and 38.3% in tween opioid and serotonergic systems; however, further
the responder sub-sample. No clinically significant side ef- trials are needed to better understand the role of the opioid
fects emerged [221]. system in OCD and related disorders.
Two RCTs investigated moderate-high (4-8 mg/day) 5.4. D-cycloserine
doses ondansetron combination with SSRIs. In the first study
[222], 42 patients with refractory OCD randomly received An emerging therapeutic approach for patients with re-
ondansetron 4 mg/day or placebo in addition to fluoxetine fractory anxiety disorders, OCD, and PTSD, is the treatment
for 8 weeks, showing significant greater decrease of Y- with D-cycloserine (DCS) added on CBT. Originally de-
BOCS scores with ondansetron compared to placebo. Hei- signed as anti-tuberculosis, DCS has been tested in Alz-
dari et al. [223] randomized 46 adults with severe refractory heimer's dementia and in the treatment of negative symptoms
OCD to receive 8 mg/day ondansetron or placebo for 8 of schizophrenia [234, 235]. DCS did not show anxiolytic
weeks in addition to 100-200 mg/day fluvoxamine. After 8 properties and is not considered a first-line strategy for anxi-
weeks of treatment the mean Y-BOCS scores dropped to 15 ety disorders. However, favorable effects on anxious symp-
in the ondansetron group and to 21 in the placebo group; the tomatology could derive from DCS-related associative learn-
Y-BOCS improvements that followed ondansetron vs. pla- ing enhancement [236].
cebo were significant for obsessions, compulsions, and Animal studies showed DCS to enhance conditioned fear
global symptoms. The efficacy of ondansetron in treating extinction learning, a central mechanism in ERP [237]. Par-
refractory OCD was superior in RCTs than in uncontrolled tial agonism at the site of glycine recognition of the glutama-
studies [220, 221]. Reported adverse events were very few tergic N-methyl-D-aspartate (NMDA) glutamate receptor,
and comparable between ondansetron and placebo. However, which is linked in the amygdala to learning and memory,
patients of uncontrolled studies had history of drug resis- could be the basis of the mechanism of action of DCS.
tance, while RCTs did not report history of drug resistance NMDA antagonists, on the other hand, would block learning
and their patients were not taking medications in the six pre- of the extinction of fear. Human studies showed the potential
vious weeks, in spite of OCD severity. Moreover, ondanse- therapeutic role of DCS in anxiety disorders, although the
tron was given at higher doses in RCTs [222, 223] vs. uncon- effect size of DCS seemed to be less than animal studies
trolled studies [220, 221]. Ondansetron (1-8 mg/day) is a [238]. A meta-analysis conducted on patients with OCD,
potential augmenting agent in patients for whom SGAs are PTSD, and severe anxiety disorders showed that add-on
problematic [224]. However, further studies are necessary to DCS improved ERP, facilitating the extinction of fear [239].
confirm these acquisitions, to establish long-term efficacy and Of note, interactions of DCS with other psychotropic drugs
safety, and to identify appropriate dosing and treatment duration. require further investigation.
5.3. Buprenorphine A study conducted by Anderson et al. [240] in 128 OCD
patients who underwent 5 sessions of 12-week guided expo-
The evidence for the use of buprenorphine and other
sure and were on stable antidepressant therapy, suggested
opioids in the treatment of severe and refractory OCD is
that DCS added on CBT could be a promising strategy only
weak [225-229]. The mechanism underlying the therapeutic
in patients who were not receiving antidepressants. Long-
action of opiates in OCD is still debated. Buprenorphine,
term administration of different classes of antidepressants,
through partial agonism of the µ-opioid receptor, promotes
including imipramine and citalopram, alters NMDA receptor
the release of serotonin and dopamine in the central nervous
system [230, 231]. Conversely, naloxone, i.e. a pure opioid subunits and DCS regulation of the glycine binding site,
antagonist with affinity for all three types of opioid receptors blocking its facilitatory effect on fear extinction [241]. A
(µ, δ, κ) has been shown to rapidly worsen OCD symptoms recent meta-analysis conducted on 21 RCTs [242], which
[232, 233]. included 1047 subjects with a severe anxiety disorder or
OCD or PTSD randomized to receive DCS or placebo in
Buprenorphine 400-600 µg/day added on SSRIs (200 addition to CBT, showed add-on DCS to correlate with
mg/day fluvoxamine or 200 mg/day sertraline) or 150 symptom improvement only from pre-treatment to post-
mg/day clomipramine correlated with improvement of symp- treatment, but not from pre-treatment to mid-treatment or
toms in severe refractory OCD. Buprenorphine was adminis- from pre-treatment to follow-up. The CBT group also
tered at lower doses than those used to treat chronic pain, showed lower severity of symptoms at the end of treatment
i.e., started at 200 µg/day, with the dosage doubled after one and at follow-up. In this study, the concomitant use of anti-
week, and further 200 µg/day increases based on clinical depressants did not moderate the effect of DCS [242]. Other
response [229]. Opioid treatment was not associated with RCTs conducted on pure OCD samples showed that DCS
significant side effects (cyclizine was prescribed in the initial augmentation may lead to a faster response to treatment than
treatment phase in case of nausea) and improvement was placebo, although without beneficial effects at the end of the
maintained without tapering-off. Patients that did not re- treatment or at follow-up [243-247].
spond to buprenorphine augmentation were affected by se-
vere OCD, severe depression, and were resistant to SSRI To date, DCS has proven to be a promising strategy for
treatments and CBT [229]. Add-on buprenorphine to stan- strengthening CBT. It could reduce the number of CBT ses-
sions needed, reduce the exposure-related anxiety, and facili- ders. To date, the use of cannabinoids in the treatment of
tate adherence to treatment, leading to faster patient relief OCD is not recommended, also in consideration of the re-
and lower healthcare costs [248]. DCS appears to be effec- lated risk of psychosis [264]. However, the use of can-
tive when administered 1-2 hours before or after exposure nabidiol-like molecules alone should not pose such safety
(during the period of consolidation of the memory that oc- questions and may constitute a viable strategy for the future,
curs after exposure rather than during exposure itself) [238- not only in OCD, but in anxiety and psychotic disorders as
249]. The possible efficacy of a small number of DCS ad- well.
ministrations can be explained by the progressive receptor
desensitization with continued use of the substance [238]. 5.6. Other Medications
However, clinical research should be performed to indicate
Different placebo-controlled studies showed some effec-
adequate protocols, treatment time, and DCS doses for re- tiveness in refractory OCD of add-on treatments with mavo-
fractory OCD.
glurat [265], eicosapentaenoic acid [266], celecoxib [267],
Add-on DCS dosage range of 50-500 mg/day did not L-carnosine [268], inositol [269], the 5-HT3 antagonist
show significant differences in CBT enhancement [250]. For granisetron [270], the µ-opioid agonist morphine [228], and
doses lower than 500 mg/day, DCS was well tolerated and the β-adrenoceptor/5-HT1A antagonist pindolol [271].
no significant adverse effects were reported. DCS admini-
Promising results from placebo-controlled studies con-
stration infrequently correlated with nightmares the night cerning the efficacy of add-on treatments with memantine
after the CBT session and euphoric mood with hyperactiva-
[272-274] and N-acetylcysteine [275-277] (however, the
tion in a person with chronic depression [251]. Other re-
latter showed some inconsistencies [278]) need replication.
ported unwanted effects were increased anxiety, somnolence,
xerostomia [244], mild gastrointestinal disorders, dizziness, Other placebo-controlled studies showed lack of effec-
tiredness [243], and nausea during the hour following DCS tiveness of add-on buspirone [279, 280], clonazepam [281],
administration [251]. De Kleine et al. [252] did not find dif- glycine powder [282], lithium [283], naltrexone [284], and
ferences between DCS and placebo groups regarding adverse riluzole [285].
events. Stable high DCS doses (500-1000 mg/day) were re-
lated to headache, confusion, tremor, memory difficulties, 6. PERSONALIZED TREATMENT STRATEGIES
paraesthesia and seizures [253]. Furthermore, DCS in ani-
6.1. Treatment Response Prediction
mals seems to induce tolerance when administered at high
and/or chronic doses, probably due to a paradoxical antago- Given the significant rate of treatment resistance and the
nistic effect on NMDA receptor [254], with consequent fear significant disability in OCD patients, an improved knowl-
extinction reduction [255]. In summary, due to the minimal edge of the predictive factors of drug treatment response
side effects of low-dose DCS, this drug appears to be a safe could allow better improvement through the implementation
alternative for improving CBT outcomes [246]. of personalized therapeutic regimens. The identification of
homogeneous subgroups of OCD patients could help finding
Many aspects need further investigation, including char-
treatment response predictors and selecting better personal-
acteristics of patients who could potentially benefit from ized pharmacological treatment options [286].
DCS in addition to CBT, considering that this treatment
could be effective in subtypes of OCD with prevalent cleans- Autogenic obsessions (A-OCD) are generally sexual,
ing/contamination symptoms [256]. More studies are needed aggressive or immoral, intrusive, unrelated thoughts and
to evaluate treatment modalities, including the number of impulses with identifiable triggers. These are associated with
CBT sessions to perform, treatment time, DCS dosages, avoidant control, magical rituals, and superstitious behavior
methods of administration (it is not yet known if DCS can be or through thought-control strategies, and frequently associ-
effective if administered only after successful sessions), and ated with schizotypal personality and disorders of thought or
interactions of DCS with antidepressant treatments. perception. Reactive obsessions (R-OCD) concern contami-
nation, errors, accidents, symmetry and loss, and can be trig-
5.5. Cannabidiol gered by specific external stimuli. R-OCD can lead to coping
behaviors such as trying to avoid or actually avoiding any
Activation of the CB1 cannabinoid receptors is involved
in fear extinction and prevention of reconsolidation of fear negative consequences related to the meaning of thought,
and are associated with perfectionist personality traits [287,
[257], i.e., the negative feedback of the neuroendocrine
288]. A-OCD and R-OCD subtypes showed different neuro-
stress response and the protection from the adverse effects of
biological correlates [289, 290].
chronic stress [258, 259]. As a consequence, CB1 receptor
agonists, including Δ9-tetrahydrocannabinol and cannabidiol, The current literature on the different therapeutic ap-
and synthetic agents capable of enhancing CB1 activation, proaches to autogenic or reactive obsessions reports incon-
such as fatty acid amide hydrolase inhibitors, are being sistent results. Some studies suggested that A-OCD might
evaluated as new anti-anxiety treatments [260-262]. Preclini- not respond to ERP and SSRI as well as R-OCD [9, 291,
cal data showed that cannabidiol could be safe and effective 292], others showed no subtype differences [34, 55, 293].
in reducing fear- and anxiety-related behaviors in schizoaf- The augmentation with a SGA showed more clinically rele-
fective, post-traumatic stress, anxiety and obsessive- vant improvements in the A-OCD vs. R-OCD group [294].
compulsive disorders [262, 263]. Further preclinical and The increased symptom severity and frequent association
clinical studies are needed to assess the usefulness of drugs with schizotypal personality traits could explain the higher
targeting the cannabinoid system in some psychiatric disor- antipsychotic prescription rate in the A-OCD subtype [288].
However, the presence of mixed obsessions is frequent, and than those of the short allele (S) [305]. The variation of the
the OCD subtype may change over time [9]. Treatment activity of this transporter influences the availability of sero-
strategies may not be adaptable to specific OCD subtypes of tonin in the synaptic cleft, having an impact on the activity
symptoms, given that many other factors may influence of postsynaptic receptors.
clinical response and outcome, including symptom severity
[111], age of onset [294], co-occurrence of schizotypal per- The association of 5-HTTLPR polymorphisms with OCD
has been reported in the literature, although somewhat in-
sonality disorder [295], chronic tics [150], and depression
consistently, with some studies not showing any significant
[296]. The debate on the potential role of the OCD subtypes
association and others indicating an association of the L-
in pharmacological treatment strategies requires further and
allele expression with OCD [306]. Higher diencephalic ex-
more detailed studies.
pression of the transporter prior to treatment may correlate
To date, predictors of response to SSRIs include positive with increased transporter occupation and better response to
family history [34], aggressive, sexual and religious obses- antidepressants (e.g., sertraline) [307]. HTR2A gene poly-
sions [31], and OFC hypometabolism and right caudate morphisms may also influence the response to SSRI treat-
hypermetabolism [32]. On the other hand, a poorer response ment [308]. A single nucleotide polymorphism of the COMT
to SSRI has been related to prevalence of hoarding symp- gene was associated with response to citalopram, indicating
toms [33], lack of insight [34], severe concomitant depres- that the Met/Met (L/L) genotype of the COMT Val158Met
sion [292], and higher levels of basic disability [35]. polymorphism could predict a better response to antidepres-
sant treatment [309].
The most consistent predictor of add-on antipsychotic
response is a comorbid tic disorder [194]. Few studies on There is increasing evidence of the role of the glutama-
add-on benzodiazepines, which are commonly considered tergic system in the etiology of many neuropsychiatric disor-
ineffective [297], and glutamatergic agents [298, 299] cannot ders, including OCD [310]. In fact, altered glutamatergic
fully clarify specific predictors of treatment response. function is seen as one of the main biological correlates of
hyperactivity of the cortico-striatal-thalamo-cortical circuit
6.2. Pharmacokinetics Factors [311]. Drugs interfering with the glutamatergic system (such
as phenobarbital, lamotrigine, topiramate, riluzole, N-
CYP2D6 metabolizes most of the antidepressants, such
acetylcysteine, memantine, ketamine, and DCS) have been
as TCAs, SNRIs and most SSRIs. CYP2C19 metabolizes
used as potentiating agents in refractory OCD. Different
several TCAs and some SSRIs, including escitalopram and
haplotypes of the SLC1A1 gene, which encodes the neural
citalopram. Gene polymorphisms of CYP2D6 and CYP2C19
alter the metabolism of drugs, influencing their efficacy and glutamate transporter, have been associated with OCD [312].
the profile of adverse effects. Other CYP450 enzymes (such Neurodevelopmental changes in ventral prefrontal-
as CYP1A2, CYP2B6, CYP2C9 and CYP3A4) may also striatal circuitry causing developmentally-mediated network
play a role in metabolizing psychoactive drugs. CYP2D6 and dysplasias were advanced to account for the onset of OCD
CYP2C19 polymorphisms could be related to antidepressant [313]. This hypothesis received support from both neuroi-
response in OCD patients [300-302]. Reduced CYP2D6 maging [314] and genetic studies [315-317]. A study by Qin
function has been associated with lack of response, and non- et al. [318] demonstrated that the top SNP associated with
extensive CYP2D6 metabolizers, compared to extensive, the response to SSRIs was rs17162912 (i.e., an intergene
showed a significantly higher number of failed responses to variation near the DISP1 gene), which is involved in neuro-
different antidepressant drugs [302]. developmental cell-cell interaction [319].
6.3. Pharmacodynamics Factors Briefly, pharmacogenetics and personalised medicine

may radically change the clinical practice for treating OCD,
The serotonergic system is involved in the pathogenesis guiding physicians to indicate the best antidepressant treat-
of OCD; in fact, SSRIs are the first-line treatment of this ment (and perhaps also alternative augmenting strategies) for
disorder, which is widely supported by the literature [126]. each patient [303]. The continuous and rapid development of
Many genes have been found to regulate the expression and genomic testing and related studies focused on predictive
function of serotonin, including SLC6A4 and its promoter factors, association studies, and pharmacoeconomy will
HTTLPR, HTR2A, HTR2C, HTR1B and TPH [303]. prove or disprove the validity of the personalised approach
There is no evidence supporting the hypothesis that a in mental health. An important question regarding timing
single genetic variation or gene can be related to antidepres- (i.e., when a psychiatrist should indicate a pharmacogenomic
sant responses in patients with OCD. However, several sin- test) is still unclear [320].
gle-nucleotide polymorphisms (SNPs) of candidate genes Although no published studies to date examined this is-
within the neural aminergic systems and the CYP450 liver sue in OCD, pharmacogenomics in psychiatry can lead to
system might be involved with both OCD neuropathophysi- improvement in patients’ adherence to treatment, decreases
ology and treatment response [303]. The SLC6A4 gene in healthcare costs [321], and better response to antidepres-
(chromosome 17) encodes the serotonin transporter, which sants in major depression [322]. Because of the lack of
carries on the reuptake of serotonin [304]. A polymorphism pharmacogenomic studies in OCD, we hypothesise that this
in the promoter region of SLC6A4 influences gene expres- method could at least be considered when a patient is refrac-
sion, with the long allele (L) correlating with higher levels of tory to the switch to a second SSRI, clomipramine, or SSRI/
serotonin transporter expression, which is up to three times clomipramine with add-on atypical antipsychotics (Fig. 2).
6.4. OCD Treatment During Pregnancy Generally, higher antidepressant doses are used in OCD
than those used in the treatment of major depression [352].
OCD is relatively common during the perinatal period.
For this reason, the risk of pre-term birth associated with
Pregnancy and postpartum are associated with higher risk of
overdose of SSRI [101, 353] should be taken into account,
OCD onset [323] or recurrence, although some patients pre-
and the minimum effective dose should be used [335].
sent symptom improvement [324-326]. Data on the safety
and efficacy of OCD treatment during pregnancy are limited Uguz et al. recently suggested a scheme of pharmacol-
and mainly derive from retrospective studies. Furthermore, ogical interventions in refractory OCD during pregnancy
safety data of drug treatment during pregnancy mainly come [335]. If clinical response to the first-line SSRIs appears to
from studies focused on other psychiatric disorders, and it is be only partial, it is recommended to increase the dose, care-
not certain that drug safety does not vary according to the fully monitoring both the woman and future child. In cases
specific disorder. Few data exist about the effects of untreated of unresponsiveness to sertraline, citalopram or escitalopram,
OCD during pregnancy on fetal and child development. a switch to fluvoxamine vs. clomipramine should be pre-
ferred. Further refractoriness could be treated with higher
Stress and anxiety during pregnancy correlate with in-
doses of SSRIs or the combination of a SSRI with clomi-
creased resistance to placental blood flow, preterm birth, low
pramine (with all the caution that was mentioned before).
gestational age, and increased risk of placental detachment;
Clinicians should consider that the latter strategy is related to
sleep and eating disorders, ADHD and cognitive-behavioral
risk of drug interactions and/or adverse reactions, including
and emotional problems may occur in the child [327-331]. convulsions [354], and data on its effectiveness are inconsis-
Newborns of women with OCD showed significantly lower
tent. Should the addition of clomipramine be necessary, it must
birth weight compared to controls and higher levels of the
be administered at the lowest possible dosage [58, 336, 355].
proinflammatory cytokine tumor necrosis factor-alpha (TNF-α)
[332]. These findings suggest that maternal OCD can poten- Safety data about SSRI augmentation with antipsychotics
tially influence future child neurodevelopment; however, are scanty. Given that this strategy does not guarantee the
conclusions cannot be drawn due to the lack of studies in remission of treatment-resistant OCD [133, 356, 357], its use
literature on this topic. during pregnancy should be considered only if all other
pharmacological approaches and CBT fail. The dosages of
Factors to be considered in treatment strategy decisions
add-on antipsychotic drugs must be as low as possible.
are family psychiatric history, previous adverse reactions to
Among available antipsychotics, risperidone is recom-
drug treatment, risks related to untreated maternal OCD,
mended as the first choice, because it has the best safety pro-
safety and effectiveness of drugs during pregnancy, the
file for the unborn child. Haloperidol and quetiapine, which
availability of non-pharmacological treatments [333], OCD have an established safety profile, in terms of efficacy are
severity, and related reduced global functioning [334].
placed in an intermediate position between risperidone and
Pharmacological treatment should be indicated in cases of
olanzapine. Olanzapine use is related to a risk of gestational
severe depression and anxiety, elevated risk of suicide,
diabetes mellitus. Safety data about add-on aripiprazole are
OCD-related sleep and eating disorders, and unresponsive-
limited. Quetiapine and olanzapine should be preferred in
ness to CBT [335].
case of severe sleep disorders and loss of appetite. Particular
SSRIs are the first-line drugs also in OCD during preg- caution should be adopted for combinations of high doses of
nancy [333, 336], given the absence of related teratogenesis SSRIs with moderate-high doses of antipsychotics or clomi-
[333, 337-342]. Sertraline, citalopram and escitalopram ap- pramine [133, 356, 357].
pear to be the most favorable in the perinatal period [341],
In conclusion, the recent acquisitions on OCD treatment
considering their effectiveness in OCD and the association
during the perinatal period are still limited. Optimal treat-
lack with congenital malformations [333, 343, 344].
ment dosages and duration are still unknown. More informa-
Pregnancy safety data on fluvoxamine are few, and its tion is needed regarding the relationship between congenital
use during pregnancy is less frequent compared to other malformations and antidepressant doses, as well as safety
SSRIs. Therefore, caution is recommended with regard to the and efficacy of the SSRI/antipsychotic combination options.
use of fluvoxamine [345, 346]. Paroxetine and fluoxetine
correlated with an increased risk of cardiac malformations 7. CLINICAL GUIDELINES
and "poor neonatal adaptation syndrome" (PNAS) [347]. On According to the National Institute for Health and Care
this basis, these drugs should be used only in case of non- Excellence (NICE) CG31 guidelines (updated to September
response or intolerance to other SSRIs. 2013 and which in February 2014 showed no expected
Clomipramine is another first-line agent for OCD treat- changes for the next 3-5 years) for the treatment of OCD in
ment [336] but presents an unfavorable safety profile in adults [358], patients with mild functional impairment
pregnancy. During this period, the risk of cardiovascular should be directed towards low-intensity CBT/ERP (<10
defects of the future child doubles [348, 349]; this drug is the hours of therapist input for patient). If ineffective, more in-
TCA that is most associated with PNAS [350]. In addition, tensive cycles of SSRI or CBT (more than 10 hours) are con-
the risk of maternal intolerance is high. Venlafaxine does not sidered comparably effective. Adults with OCD with moder-
seem to be related to congenital malformations, but limited ate functional impairment should have the opportunity to
evidence exists about its effectiveness in OCD, and similarly choose between an intensive SSRI or CBT cycle. If func-
to SSRIs, its use involves different risks, including miscar- tional impairment is severe, combined treatment with a SSRI
riage, premature birth, and PNAS [333, 334, 340, 351]. and CBT/ERP is recommended [358].
Fig. (2). Algorithm on OCD treatment strategies.
Initial drug treatment for adults with OCD includes a are not clinically significant, and patient’s functioning is
SSRI (fluoxetine, fluvoxamine, paroxetine, sertraline or cita- good for at least 12 weeks) to prevent relapse and allow fur-
lopram). If treatment response is not adequate and no side ther improvement. A further prolongation of treatment dura-
effects have occurred, dosage increases may be considered tion should be reassessed, taking into account the severity
after 4-6 weeks of treatment. SSRI administration should be and duration of the previous symptoms, number of previous
reviewed if patient develops marked and/or prolonged episodes, presence of residual symptoms, and concomitant
akathisia, restlessness or agitation. Treatment should con- psychosocial difficulties [358].
tinue for at least 12 months after OCD remission (symptoms
Initial OCD treatment should not include other classes of tions consisted of SSRIs (58%), TCAs (18%), mainly includ-
antidepressants such as TCAs, SNRIs and monoamine oxi- ing clomipramine, SGAs (38%), and FGAs (14%). Several
dase inhibitors (MAOIs) (unless comorbid disorders for patients received a tranquilizer (20%). The authors showed
which these drugs are needed), anxiolytics (except for cau- an increase over time of SSRI, SGA and tranquilizer pre-
tious, short-period use to treat possible activation/agitation scriptions, and a decrease of clomipramine. FGA use re-
induced by SSRIs during treatment introduction), combina- mained stable. The high rate of SSRI use, preference for
tions of antidepressants, and antipsychotic monotherapy or clomipramine and SGA augmentation were consistent with
augmentation. Patient’s adherence to treatment, and alcohol recommendations of international guidelines. The admini-
or substance use should be assessed in case of failed re- stration of tranquilizers and FGAs and the choice of individ-
sponse to a complete treatment cycle with a SSRI, before ual strategies were not in line with the expert recommenda-
making changes to the pharmacological strategy [358]. tions [359].
If patient shows a partial response to 12 weeks of SSRI Other guidelines confirm the above approaches. For the
treatment, NICE CG31 recommends the combination with World Federation of Biological Psychiatry (WFSBP), first-
CBT/ERP. If this combination fails, or SSRI response lacks, line treatments are SSRIs and clomipramine [360]. The use
or the patient does not endorse CBT, switching to a different of medium-to-upper doses is recommended despite lack of
SSRI or to clomipramine should be evaluated. Clomipramine evidence of a dose-response relationship for both in OCD.
should be considered in three circumstances, i.e., failure (in- These recommendations are made to general practitioners
efficacy or intolerance) of an adequate trial of at least one and in case of non-response, psychiatric consultation in rec-
SSRI, if he/she favors clomipramine, or if he/she showed ommended. In still-resistant severe OCD cases and after all
previous response to this drug. If effective, treatment with options have been attempted unsuccessfully, deep brain
clomipramine should be continued for at least 12 months, as stimulation should be considered. The updated American
there may be further improvements. Before starting clomi- Psychiatric Association guidelines [361] endorse similar
pramine, both adults and children should perform an electro- approaches, but also stress the need for identifying response
cardiogram to rule out cardiac conduction abnormalities. predictors, for assessing the long-term effectiveness and
TCAs other than clomipramine, MAOIs, SNRIs, and antip- safety of augmentation strategies in refractory OCD, and for
sychotics should not be used for treating OCD in children establishing adequate time points for intervention. Combin-
and young adults. However, these can be considered in re- ing this, the way is paved for sequential treatment and
fractory OCD [358]. for personalized medicine approaches, including genetic/
pharmacogenomic/metabolomic assessment. We propose in
If there is a lack of response after a complete trial with at our treatment algorithm (Fig. 2) to adopt such assessment in
least one SSRI, another with a SSRI and CBT/ERP, and a totally refractory OCD patients, specifically in those who did
further trial with clomipramine alone, NICE CG31 recom- not respond to augmentation with SGAs or to switch to
mends considering strategies such as additional CBT/ERP, clomipramine or to various SSRI trials.
addition of an antipsychotic to a SSRI or clomipramine, or
the combination of clomipramine with citalopram (with all Drug prescriptions in OCD patients significantly vary in
the precautions we stressed above). The optimal selection different countries. Brakoulias et al. [297] compared the pre-
sequence is not specified because there is no current evi- scription rates in Brazil, Italy, South Africa, Japan, Australia,
dence supporting the superiority of one strategy over another India, and Spain. Of 3139 OCD patients, almost 78% re-
[358]. We summarize clinical guidelines in the algorithm ceived a psychotropic drug, being in 73.5% of the cases of a
shown in Fig. 2. SSRI, which was in line with international guidelines. The
use of SSRIs varied from 59% in Australia to 96% in Japan,
People with severe, chronic, and treatment-resistant OCD clomipramine ranged from 5% in Japan and South Africa to
should have constant access to specific specialist and 26% in India and Italy, atypical antipsychotics from 12% in
multidisciplinary teams of health professionals with specific South Africa to 50% in Japan. Further prospective studies
skills in OCD treatment. Hospital services should carefully should be conducted to identifying cultural factors, pharma-
assess suicide risk, extreme discomfort or functional im- coeconomics, and pharmacogenomics, which may play a role
pairment, ineffectiveness of appropriate trials of pharmacol- in improving prescriptions and treatment outcomes.
ogical/psychological/combined treatments for long periods,
severe comorbid depression, anorexia nervosa, or schizo- CONCLUSION
phrenia, inversion of the waking cycle, severe or habitual
To date, the most effective pharmacological treatment is
compulsive and avoidance behaviors interfering with normal
the combination of an SSRI agent with CBT. Refractory
activities and daily life.
OCD symptoms can improve with high SSRI dosages or
In clinical practice, treatment strategies do not always augmentation with an atypical antipsychotic drug, mainly
follow evidence-based guidelines. Poppe et al. [359] col- risperidone and aripiprazole. Due to inconsistent evidence,
lected prescription data of 842 OCD patients from 1994 to the addition of medications other than antipsychotics and
2012 to analyze models and changes in prescription strate- intravenous antidepressant administration needs further in-
gies. Nine/tenths of patients received at least one drug and vestigation. Intervention strategies based on personalized
about 68% a combination of at least two drugs. The most medicine are of promise but require further investigation.
prescribed drugs were antidepressants (78%): the prescrip-
CONSENT FOR PUBLICATION [11] World Health Organization (WHO). The Global Burden of Dis-
ease: 2004 Update; World Health Organization: Geneva, Switzer-
Not applicable. land, 2008.
[12] Hirschtritt, M.E.; Bloch, M.H.; Mathews, C.A. Obsessive-compulsive
disorder: Advances in diagnosis and treatment. JAMA, 2017,
FUNDING 317(13), 1358-1367. [http://dx.doi.org/10.1001/jama.2017.2200]
None. [PMID: 28384832]
[13] Leon, A.C.; Olfson, M.; Broadhead, W.E.; Barrett, J.E.; Blacklow,
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from Angelini, Janssen, Lundbeck, and Otsuka. All other [14] Veldhuis, J.; Dieleman, J.P.; Wohlfarth, T.; Storosum, J.G.; van
authors of this paper have no relevant conflicts with the sub- Den Brink, W.; Sturkenboom, M.C.; Denys, D. Incidence and
prevalence of “diagnosed OCD” in a primary care, treatment seeking,
ject matter or materials discussed in the manuscript. population. Int. J. Psychiatry Clin. Pract., 2012, 16(2), 85-92. [http://
dx.doi.org/10.3109/13651501.2011.617454] [PMID: 22122660]
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OCD symptom misidentification by mental health professionals.
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Librarians of the School of Medicine and Psychology of [16] Dell’Osso, B.; Camuri, G.; Benatti, B.; Buoli, M.; Altamura, A.C.
Sapienza University, Ms. Mimma Ariano, Ms. Felicia Differences in latency to first pharmacological treatment (duration
of untreated illness) in anxiety disorders: a study on patients with
Proietti, Ms. Ales Casciaro, Ms. Teresa Prioreschi, and Ms. panic disorder, generalized anxiety disorder and obsessive-
Susanna Rospo for rendering precious bibliographical compulsive disorder. Early Interv. Psychiatry, 2013, 7(4), 374-380.
material accessible, as well as our Secretary Lucilla Martinelli [http://dx.doi.org/10.1111/eip.12016] [PMID: 23347385]
for her assistance during the writing of this manuscript. [17] Altamura, A.C.; Buoli, M.; Albano, A.; Dell’Osso, B. Age at onset
and latency to treatment (duration of untreated illness) in patients
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Psychopharmacological Treatment of Obsessive-Compulsive Disorder (OCD)

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Psychopharmacological Treatment of Obsessive-Compulsive Disorder

Abstract: Background: Obsessive-compulsive disorder (OCD) is associated with affective and

1. INTRODUCTION juvenile-onset OCD is more often familial and more preva-

1570-159X/19 $58.00+.00 ©2019 Bentham Science Publishers

6.3. Pharmacodynamics Factors Briefly, pharmacogenetics and personalised medicine

Fig. (2). Algorithm on OCD treatment strategies.

placebo-controlled trial of clomipramine in 27 patients. Am. J. Psy- 26(2), 299-304. [http://dx.doi.org/10.1177/039463201302600203]

21-27. [http://dx.doi.org/10.1001/archpsyc.56.1.21] [PMID: augmentation of cognitive-behavioral therapy in pediatric obses-

1), S104-S110. [http://dx.doi.org/10.1016/S1516-4446(12)70057-0] 16-week, double-blind, randomised, placebo-controlled study. CNS

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