Sunteți pe pagina 1din 12

Clinical Neuropsychiatry (2013) 10, 1, 19-30

TREATMENT-RESISTANT OBSESSIVE-COMPULSIVE DISORDER (OCD): CURRENT KNOWLEDGE


AND OPEN QUESTIONS

Umberto Albert, Andrea Aguglia, Stefano Bramante, Filippo Bogetto, Giuseppe Maina

Abstract

Objective: Obsessive-compulsive disorder (OCD) is a common psychiatric illness with a lifetime prevalence in
the general population of approximately 2-3%. Serotonin reuptake inhibitors (SRIs) and cognitive-behavioral therapy
(CBT) in the form of exposure and response prevention (ERP) both represent first-line treatments for OCD. However,
unsatisfactory response to these treatments is very common and the evaluation of next-step treatment strategies is highly
relevant. The purpose of this paper is to review available data on treatment-resistant OCD and to build a treatment
algorithm for those patients who fail to respond to a first SRI trial.
Method: We carried out a search on MEDLINE/PUBMED database, selecting meta-analyses, systematic reviews
and randomized controlled studies written in English on treatment-resistant OCD. We also considered open-label
studies and case series and/or reports, written in English. We reviewed the available evidence for different strategies
and tried to delineate an evidence-based treatment algorithm for clinicians.
Results: Antipsychotic addition to SRIs and CBT augmentation of drug treatment both are supported by a number
of double-blind studies, although differences between antipsychotics seem to exist and the effectiveness of routinely
delivered CBT as an adjunct to medication in real world OCD patients with incomplete response to medication need
to be replicated. The switch to IV administration of clomipramine may be clinically useful in some cases, although the
return to oral formulation often is associated with a relapse. Switching to other first-line agents or to other compounds
(such as venlafaxine) is supported by open-label studies or by double-blind studies without a placebo arm.
Conclusions: Several evidence-based effective strategies are available to clinicians in case of treatment-resistant
OCD. Strengths and limitations of each of the effective strategies are still under study and will be the focus of future
comparative trials. There is also a strong need for alternative therapeutic options for OCD patients.

Key words: obsessive-compulsive disorder, treatment-resistant OCD, augmentation, switch

Declaration of interest: none

Umberto Albert, Andrea Aguglia, Stefano Bramante, Filippo Bogetto, Giuseppe Maina
Mood and Anxiety Disorders Unit Department of Neuroscience University of Turin

Corresponding author:
Prof. Umberto Albert
Postal address: via Cherasco 11 10126 Turin, Italy
Telephone number: +39 011 633 5425
Fax number: +39 011 633 4341
E-mail address: umberto.albert@unito.it

1. Introduction relationships, and socio-economic status (Albert et al.


2010, Fontenelle et al. 2010, Hollander et al. 2010,
Obsessive-compulsive disorder (OCD) is a Wittchen et al. 2011). The World Health Organization
heterogeneous disorder of unknown etiology, listed this disorder among the 10 most disabling
characterized by the presence of upsetting, persistent illnesses (Nolen 2002), while the National Comorbidity
worries, images, or impulses, which are experienced as Survey-Replication study indicated that OCD is the
intrusive and senseless (obsessions), and/or excessive anxiety disorder with the highest percentage (50.6%)
repetitive behaviors or mental acts (compulsions), of serious cases (Kessler et al. 2005). Moreover, it has
performed in response to these obsessions (APA 2000). been estimated that most individuals with OCD spend
Epidemiological studies conducted in the last an average of 17 years before receiving an appropriate
20 years have established a prevalence rate in the diagnosis and treatment for their illness (Jenike 2004).
general population of approximately 2-3%, making it According to several recent treatment guidelines,
a far more common disorder than previously believed both serotonin reuptake inhibitors (SRIs) (citalopram,
(Ruscio et al. 2010). OCD has a significant impact on escitalopram, fluoxetine, fluvoxamine, paroxetine,
human and social functioning, quality of life, family sertraline, and clomipramine), and cognitive behavior

Submitted January 2012, Accepted february 2013


2013 Giovanni Fioriti Editore s.r.l. 19
Umberto Albert et al.

therapy (CBT) in the forms of exposure and response 2; partial response as greater than 25% but less 35%
prevention (ERP) and/or cognitive restructuring are Y-BOCS reduction; non response as less than 25%
considered first-line treatments for OCD (March 1997, Y-BOCS reduction and CGI 4 (Rauch and Jenike 1994,
Baldwin et al. 2005, Canadian Psychiatric Association Pallanti et al. 2002a, Pallanti and Quercioli 2006).
2006, APA 2007, Bandelow et al. 2008, Bandelow et al. Furthermore, recovery is defined as a complete and
2012). Both CBT and SRIs have been in fact recognized objective disappearance of symptoms, corresponding
more effective than wait-list, inactive psychological to Y-BOCS value of 8 or below; remission can indicate
treatments or placebo in individual randomized a response that reduces symptoms to a minimal level,
controlled trials (RCT) (Deacon and Abramowitz 2004, i.e. Y-BOCS score of 16 or less, being this value the
Eddy et al. 2004, Fisher and Wells 2005, Rodrigues minimum threshold one for a patient to be included in
et al. 2011, Marazziti et al. 2012a). Concerning the a clinical trial.
relative efficacy between different SRIs, a Cochrane Before defining a patient as resistant to a
review comprising 17 RCTs could not identify any pharmacological treatment, several issues have to be
significant difference between citalopram, fluoxetine, considered:
fluvoxamine, paroxetine and sertraline (Soomro et 1. clinicians have to be sure that the diagnosis
al. 2008). Equally, escitalopram improved obsessive- of OCD is correct and that other symptoms are not
compulsive symptoms without any significant incorrectly considered as obsessions or compulsions
difference as compared to paroxetine (Fineberg et al. (obsessive-compulsive personality disorder;
2007, Stein et al. 2007). ruminations occurring in major depressive disorder or
Given the equivalence of both psychological other anxiety disorders; repetitive stereotyped behaviors
and pharmacological approaches, the severity of the encountered in psychoses or in mental retardation,
disorder and the age of the subject might guide the organic mental disorders; obsessive concern about
physicians choice: when treating an adult affected by body shape or ritualized eating behaviors in eating
a severe OCD, clinicians should prefer drug treatment disorders; patterns of behaviors, interests or restricted
with SRIs, eventually associating CBT. Conversely, and repetitive activities in autism);
childhood OCD should be first treated with ERP or 2. has the pharmacological treatment been taken
cognitive therapy, eventually adding pharmacotherapy adequately in terms of doses and time? Clinicians
in the most severe cases. The selection might also be should evaluate the response to first-line treatment in
affected by patient preferences, and of course by the OCD patients after at least 12 weeks with moderate-
local availability of services able to offer evidence- high dosages of SRIs, as illustrated in table 1 (Bloch et
based psychological interventions. al. 2010). The pattern of response in OCD, moreover, is
Unfortunately, 40-60% of OCD patients do not quite dissimilar to that seen in Major Depression: first
respond adequately to SRIs therapy and an even greater signs of improvement do not correspond to remission
proportion of patients fail to experience complete of symptoms but they consist in a slow and progressive
remission of their symptoms after a first trial (Alacron reduction of obsessive-compulsive symptoms;
et al. 1993, Ravizza et al. 1995, Erzegovesi et al. 2001). 3. clinicians have to assess the potential presence
Even those patients who are judged to be clinical of medical or psychiatric comorbidity that could affect
responders based on stringent response criteria (i.e., treatment response; paradigmatic the case of OCD
typically a greater than 25 or 35% decline in Yale- comorbid with Bipolar Disorder, where treatment with
Brown Obsessive Compulsive Scale rating) continue to high doses of SRIs could worsen both bipolar disorder
experience significant impairment from their residual (mixed episodes, rapid cycling, switch) and OCD
obsessive-compulsive symptoms (Goodman et al. 1993). (Ghaemi et al. 2008, Salvi et al. 2008);
Because of the high number of patients withobsessive- 4. some individuals who fail to improve
compulsive disordernot responding satisfactorily to the after three months of treatment at adequate doses
initial SRIs monotherapy, the evaluation of additional may turn into treatment responders after additional
treatment options is highly relevant. months of continued treatment: this suggests that the
The purpose of this paper is to review available data first available strategy could be just waiting for the
on treatment-resistant OCD and to build a treatment treatment to produce a full response. This strategy
algorithm for those patients who fail to respond to a first should be reserved to patients who showed at least a
SRIs trial. A necessary premise to the current review is partial response during the treatment (De Haan et al.
that the vast majority of available studies investigated 1997, McDonough et al. 2002).
the efficacy of various possible strategies for patients Another issue that should be kept in mind in the
not responding to a first trial with drugs, while very assessment of treatment-resistant OCD is the potential
few examined next step strategies in the case of non- role of the family in reinforcing the disorder and
response to CBT. We will then focus our attention on reducing patient compliance. Family members tend to
literature data on next step options for patients failing become emotionally over-involved, neglecting their
to respond to a first drug treatment. own needs and at the same time perpetuating the cycle
of obsessions and compulsions. On the other hand,
family members might express criticism by voicing
2. Definition of treatment resistance expectations that the patient just snaps out of it. Both
attitudes, besides worsening relatives quality of life
Treatment-resistant OCD patients are defined as (Albert et al. 2007, Grover and Dutt 2011), contribute
those who undergo adequate trials of first-line therapies to the maintenance of patients symptoms as well
without achieving a satisfactory response, usually (van Noppen and Steketee 2003). Psychoeducational
defined by a reduction in the Yale-Brown Obsessive interventions directed to the families might help to
Compulsive Scale (Y-BOCS) score 35% or 25% establish a therapeutic alliance, to provide education
with respect to baseline (Rauch and Jenike 1994). The about the disorder and its treatment, to improve family
International Treatment Refractory OCD Consortium problem solving skills, and to ameliorate compliance to
has recently proposed stages of response to treatment; drug treatments (van Noppen et al. 1997, Albert et al.
full response is defined as 35% or greater reduction of 2006, Maina et al. 2006).
Y-BOCS and Clinical Global Impression (CGI) 1 or Once all these questions have been addressed and a

20 Clinical Neuropsychiatry (2013) 10, 1


Treatment-resistant OCD

condition of treatment-resistance of OCD is confirmed, had a significantly higher response rate than patients
several therapeutic options are available, that can be receiving stress management training (decrease 25%
classified in augmentation or switching strategies. in the Y-BOCS total score 74% and 22%, respectively;
p <.001) (Simpson et al. 2008). Evidence from this
randomized, controlled study strongly supports the use
3. Augmentation strategies of CBT incorporating ERP as an SRI augmentation
strategy for OCD non-responders to medication.
The first strategy given to clinicians in case of However, while randomized, controlled studies
unsatisfactory response with a SRIs is to add another have very strong internal validity (they allows the
therapeutic agent. Alternative augmentation strategies elimination of biases and confounding factors effects),
after an adequate trial of first-line medications involve the generalizability of their findings to the real world
the addiction of psychotherapy (CBT) or drugs. could be limited by several factors such as rigid
inclusion/exclusion criteria and therapy use under
3.1. Psychotherapy augmentation ideal conditions. In Simpson and colleagues study
(2008), for example, comorbid diagnoses were allowed
This strategy consists in adding to the failed SRIs if clearly secondary, mania, psychosis, prominent
treatment a cognitive-behavioral therapy in the form suicidal ideation, substance abuse or dependence in the
of exposure and response prevention, either alone or previous 6 months were exclusion criteria. Moreover,
associated with cognitive restructuring. ERP protocol, consisted in 17 twice-weekly sessions
Before considering this strategy, it is very important (each 90-120 minutes), daily homework assignments,
to consider the following essential conditions: between-session phone calls (twice per week), and
willingness of the patient to undergo a CBT trial, good included at least two sessions in the patients home
collaboration and motivation of the subject, good environment to promote generalization. Although ERP
intellectual capacity to understand the rationale of the was not really intensive, one might ask if patients in the
psychotherapy, and, possibly, a collaborative familiar real world can follow this CBT format and if therapists
milieu. in the real world can follow these rules. So, it could be
Several open-label and case report studies useful for clinicians to know if Simpson and colleagues
emphasized the efficacy of psychotherapy as an randomized, controlled study results are confirmed in
augmentation strategy for OCD patients resistant to large multicenter effectiveness studies.
drug treatment: approximately 50% of resistant patients We performed a multicenter study to investigate the
do respond to the addition of CBT (Simpson et al. effectiveness of CBT as an augmentation strategy to
1999, Kampman et al. 2002, Albert et al. 2003, Tolin medication in severe, real-world, SRIs non-responder
et al. 2004, Tundo et al. 2007, Anand et al. 2011). The OCD patients. 119 OCD subjects resistant to SRIs
efficacy of CBT addition to pharmacotherapy has been (resistance was prospectively evaluated) were offered
validated in a well-conducted 8-week, randomized, a CBT trial. Subjects were representative of a severe,
controlled trial with stress management training as the real-world sample of resistant patients, with multiple
control condition. At the endpoint, the mean Y-BOCS comorbidities and several previous ineffective trials.
total score decreased from 25.4 to 14.2 in patients CBT was delivered in a naturalistic setting. Patients were
assigned to ERP (n=54) and from 26.2 to 22.6 in the assessed at baseline, at 6 and 12 months. Responder rates
other group (n=54); moreover, patients receiving ERP at 6 and 12 months were 32.8% and 58%, respectively;

Table 1. Dosing of Serotonin Reuptake Inhibitors (SRIs) in the treatment of obsessive-compulsive disorder
(from APA. Practice guideline for the treatment of patients with obsessive-compulsive disorder. American
Psychiatric Association, Arlington, VA: 2007)
Starting dose and
Usual target dose Usual maximum dose Occasionally prescribed
SRI incremental dose (mg/
(mg/day) (mg/day) maximum dose (mg/day) (b)
day) (a)
Citalopram 20 40-60 80 120
Clomipramine 25 100-250 250 __ (c)
Escitalopram 10 20 40 60
Fluoxetine 20 40-60 80 120
Fluvoxamine 50 200 300 450
Paroxetine 20 40-60 60 100
Sertraline (d) 50 200 200 400

(a): some patients may need to start at half this dose or less to minimize undesired side effects such as nausea or to
accommodate anxiety about taking medications.
(b): these doses are sometimes used for rapid metabolizers or for patients with no or mild side effects and inadequate
therapeutic response after 8 weeks or more at the usual maximum dose.
(c): combined plasma levels of clomipramine plus desmethylclomipramine 12 hours after the dose should be kept
below 500 ng/mL to minimize risk of seizures and cardiac conduction delay
(d): sertraline, alone among the selective serotonin reuptake inhibitors, is better absorbed with food.

Clinical Neuropsychiatry (2013) 10, 1 21


Umberto Albert et al.

remitter rates were 15.1% and 31.1%, respectively 2004) and one aripiprazole (Muscatello et al. 2011).
(Albert et al. 2012a). Our multicenter, prospective, The authors conclude that antipsychotic augmentation,
naturalistic study indicates that the positive results of overall, significantly improved obsessive-compulsive
the controlled study concerning the efficacy of CBT symptoms refractory to SRIs monotherapy in at least
addition to medication non-responder OCD patients can one-third of cases. Due to its favorable risk-benefit
be generalized, although at a lesser degree, to routine ratio, risperidone can currently be considered as the
clinical practice. compound of first choice for such treatment strategy.
For the future, further controlled trials employing No evidence could be identified for the efficacy of
OCD patients with various patterns of symptoms are adjunctive quetiapine (no difference in response between
required to allow for a generalization of results. quetiapine and placebo in four of the five studies) and
olanzapine (one positive study Bystritsky et al. 2004
and one negative Shapira et al. 2004). However, the
3.2. Pharmacotherapy augmentation negative study with olanzapine (Shapira et al. 2004) was
biased by the fact that the Authors included patients not
When the first-line SRIs treatment provides an responding to only 8 weeks of SRIs monotherapy; thus
unsatisfactory response and CBT augmentation is not patients in both the placebo and the olanzapine arms
available or acceptable to the patient, another available showed a significant response rate. Our single-blind
and evidence-based option is pharmacotherapy study comparing olanzapine with risperidone addition
augmentation, which consists in adding to the ongoing showed similar response rates (Maina et al., 2008). We
SRIs another drug. Several augmenting agents have then think that olanzapine may be a valid alternative
been studied, some of them in open-label and other to risperidone as an augmentation strategy in resistant
in single or double blind conditions. The most studied patients. A very recent study, not included in meta-
effective strategy is antipsychotic augmentation. analysis published by Dold and colleagues, evaluated
the efficacy of aripiprazole (10 mg/day, fixed-dose) in
3.2.1. Antipsychotic augmentation 39 patients with treatment-resistant OCD: aripiprazole
augmentation was significantly more effective than
Following the hypothesis of dopaminergic placebo (Sayyah et al., 2012). This study confirmed
hyperactivation in OCD (Denys et al. 2004a, Koo et al. the efficacy of aripiprazole in treatment-resistant OCD.
2010), many research projects focused on the examination Table 2 summarizes results of studies investigating
of antipsychotic compounds in this disorder. Because antipsychotic augmentation.
the serotonergic metabolism is supposed to be centrally In positive studies, response rates were around 50%;
involved in the pathophysiology of OCD (Zohar et al. when response to antipsychotic addition occurs it is
1987, Goddard et al. 2008), most studies were aimed at evident within the first 4-6 weeks (Bloch et al. 2006).
determining whether the co-administration of SRIs and Further research is needed to clarify the relative
antipsychotics is effective in patients unresponsive to efficacy of different antipsychotics in OCD by
SRIs alone (Vulink et al. 2011). conducting RCTs that directly compare the different
Several randomized, double-blind, placebo- antipsychotics (head-to-head comparisons). Only
controlled studies exist, to date, supporting the use of two 8-weeks, single-blind RCTs exist (Maina et al.
this strategy; review and meta-analytical studies also 2008, Selvi et al. 2011). Maina and colleagues (2008)
confirm that, as a class, antipsychotics are effective compared directly risperidone and olanzapine addition
when added to SRIs in resistant patients (Sareen et to SRIs in resistant OCD patients (n=50); as previously
al. 2004, Bloch et al. 2006, Skapinakis et al. 2007, mentioned, the two compounds were equally effective
Komossa et al. 2010, Dold et al. 2012). However, not in improving obsessive-compulsive symptoms. Selvi
all antipsychotics have been studied in double-blind and coworkers (2011) compared risperidone (3 mg/day)
conditions and differences in efficacy exist between and aripiprazole (15 mg/day) augmentation; both drugs
antipsychotics. proved to be effective strategies in resistant patients,
Early studies added typical antipsychotics although a significantly higher response rate was found
(haloperidol and pimozide) to SRIs (McDougle et with risperidone (72.2%) compared to aripiprazole
al. 1990, McDougle et al. 1994); only haloperidol, (50%).
however, among the typical antipsychotics, proved to Another unresolved question is how long clinicians
be effective in a double-blind, placebo-controlled study, should maintain the antipsychotic in combination with
particularly for patients with comorbid tic disorders the serotoninergic drug, once response is achieved.
(McDougle et al. 1994). The side effect profile of Maina and colleagues showed that the discontinuation of
haloperidol, with dose-dependent extrapyramidal the antipsychotic in patients previously responsive only
symptoms, limits the potential benefit of this strategy to the augmentation strategy leads to an exacerbation
in resistant OCD patients. By comparison, the atypical of obsessive-compulsive symptoms (relapse) in the vast
antipsychotics may be better tolerated in the short-term, majority of patients (83.3% within the 24-week follow-
although concerns exist regarding long-term metabolic up); 72.2% of patients relapsed within the first 8 weeks
side effects (Marazziti et al. 2005, Fineberg et al. 2006, from discontinuation (Maina et al. 2003). Although
Matsunaga et al. 2009). retrospective, our study provides initial evidence that
Recently, Dold and colleagues published a meta- antipsychotic augmentation has to be maintained for
analysis of results of all double-blind studies on patients who respond to this strategy, because the vast
antipsychotic augmentation of SRIs in treatment- majority of subjects who discontinue the antipsychotic
resistant OCD (Dold et al. 2012). Concerning second- relapse within 2 months. On the other hand, however,
generation antipsychotics, five RCTs examined the if such treatment is carried out over the long-term,
addition of quetiapine (Denys et al. 2004b, Carey patients are exposed to the common and serious
et al. 2005, Fineberg et al. 2005, Kordon et al. 2008, adverse effects associated with long-term antipsychotic
Diniz et al. 2011), three risperidone (McDougle et al. administration, especially metabolic ones: increased
2000, Hollander et al. 2003a, Erzegovesi et al. 2005), glucose, triglycerides, abdominal circumference, blood
two olanzapine (Bystritsky et al. 2004, Shapira et al. pressure and decreased cholesterol HDL (Matsunaga et
al. 2009, Albert et al. 2012b). Antipsychotic-induced

22 Clinical Neuropsychiatry (2013) 10, 1


Treatment-resistant OCD

weight gain may influence patients adherence to compounds showed preliminary evidence of efficacy
medication, and places them at risk for a broad range as compared to placebo: caffeine and d-amphetamine
of medical problems such as cardiovascular diseases, (Koran et al. 2009), lamotrigine (Bruno et al. 2012),
type 2 diabetes, stroke, premature mortality (Khang et topiramate, which was effective only on compulsions
al. 2010, Gupta et al. 2011, Joseph et al. 2011, Tanner et and not on obsessions and Y-BOCS total score
al. 2011, Novelletto et al. 2012). (Mowla et al. 2010, Berlin et al. 2011), pindolol
Some evidence exists in favor of the combination of (beta-adrenergic antagonist with pre-synaptic 5-HT1A
SRIs and antipsychotic from beginning of treatment, in antagonist activity), ineffective in reducing the latency
non-refractory OCD patients (Vulink et al. 2009). In our of response of antiobsessive agents (Mundo et al. 1998)
opinion, given the adverse effect profile of long-term but effective in treatment-resistant patients (Dannon et
antipsychotic use, antipsychotic augmentation should al. 2000). Although potentially effective, we consider
be reserved for patients not responding adequately after these drugs as a last chance option to be reserved for
12 weeks of SRIs monotherapy. patients refractory to other evidence-based alternatives.
Further research is still required regarding the
optimal dose of several antipsychotics, the ideal
duration of add-on treatment, its long-term tolerability 3.2.3. SRIs augmentation (combination)
and the evaluation of predictors of response. Further
investigations should also assess which SRIs are This strategy is a combination therapy, and consists
the most suitable for an antipsychotic augmentation in associating two serotoninergic compounds (usually
strategy. clomipramine CMI, added to the ongoing selective
serotonin reuptake inhibitors SSRI trial). Of all
the SSRI, sertraline and citalopram, having a lower
3.2.2. Other augmentation strategies metabolic interference with the cytochrome P450,
should be considered the first-choice drugs to associate
Other less evaluated augmentation strategies to CMI in order to empower the serotonin reuptake
include the combination of two SRIs or the addition inhibition. Results from open trials support the efficacy
to the current SRIs of a compound other than the of this strategy (Simeon et al. 1990, Ravizza et al.
antipsychotic; the evidence regarding these treatment 1996, Figueroa et al. 1998, Marazziti et al. 2008, Diniz
approaches is considerably weaker. et al. 2010). In our study, for example, the addition
Several double-blind, placebo-controlled studies of sertraline 50 mg/day to clomipramine 150 mg/day
evaluated the potential efficacy of different drugs yielded a greater reduction in Y-BOCS scores than
used as augmentation strategies in treatment-resistant the increase of clomipramine dosage up to 250 mg/
OCD patients; among these, ineffective (and not day, being also associated with a more favorable side-
recommended on the basis of current knowledge) are effect profile (Ravizza et al. 1996). However, all the
lithium (McDougle et al. 1991, Pigott et al. 1991), aforementioned studies were performed in an open-
buspirone (Pigott et al. 1992, McDougle et al. 1993, label fashion and involved few patients per trial.
Grady et al. 1993), desipramine (Barr et al. 1997), Diniz and colleagues recently performed a double-
inositol (Fux et al. 1999), clonazepam (Crockett blind, placebo-controlled trial comparing the efficacy
et al. 2004), naltrexone (Amiaz et al. 2008). Some of adding quetiapine (200 mg/day) or clomipramine

Table 2. Double-blind, placebo-controlled studies on antipsychotic augmentation in treatment-resistant OCD


Length Dose range Mean Final Dose
Antipsychotic Authors N Results
(weeks) (mg/day) (mg/day)
Haloperidol McDougle et al. 1994 34 4 2-10 6.2 3.0 Haloperidol > Placebo
McDougle et al. 2000 36 6 1-6 2.2 0.7 Risperidone > Placebo

Hollander et al. 2003 16 8 0.5-3 2.25 0.86 Risperidone > Placebo


Risperidone
Erzegovesi et al. 2005 39 6 0.5 (fixed-dose) 0.5 (fixed-dose) Risperidone > Placebo
Bystritsky et al. 2004 26 6 5-20 11.2 6.5 Olanzapine > Placebo

Olanzapine Shapira et al. 2004 44 6 5-10 6.1 2.1 Olanzapine = Placebo


Atmaca et al. 2002* 27 8 50-200 91 41 Quetiapine > Placebo

Denys et al. 2004 40 8 200-300 300 Quetiapine > Placebo

Fineberg et al. 2005 21 16 50-400 215 124 Quetiapine = Placebo

Quetiapine Carey et al. 2005 42 6 25-300 168.8 120.8 Quetiapine = Placebo

Kordon et al. 2008 40 12 400-600 - Quetiapine = Placebo

Diniz et al. 2011 54 12 200 - Quetiapine = Placebo


Muscatello et al. 2011 40 16 15 (fixed-dose) 15 (fixed-dose) Aripiprazole > Placebo
Aripiprazole
Sayyah et al. 2012 39 12 10 (fixed-dose) 10 (fixed-dose) Aripiprazole > Placebo
* single-blind, placebo-controlled study

Clinical Neuropsychiatry (2013) 10, 1 23


Umberto Albert et al.

(75 mg/day) to a treatment regimen consisting of reported as low as 27-33% (Rasmussen et al. 1993,
fluoxetine (40 mg/day). The clomipramine-fluoxetine Ackerman et al. 1998). These response rates are even
combination resulted a safe and effective treatment lower if patients failed two previous SRIs trials: only
for fluoxetine non-responders, while the addition of 19% of patients responded to fluvoxamine after failure
quetiapine was not; results of this double-blind trial to respond to clomipramine and fluoxetine (Goodman et
support the use of this strategy, which may be reserved al. 1997). Data over the use of citalopram are conflicting:
especially for those patients who cannot tolerate high in one study, only a patient out of 7 (14%) responded
doses of fluoxetine (Diniz et al. 2011). to citalopram after two previous unsuccessful trial
There is, however, the need for additional double- with SRIs (Pallanti et al. 1999), while another open-
blind studies to support this combination strategy and label trial with a similar design showed that 14 OCD
determine which, among combination and augmentation patients out of 18 achieved a good therapeutic response
strategies, is more effective. (Marazziti et al. 2001), suggesting that non response
to a single SSRI does not necessarily imply a lack of
response to another SSRI.
4. Switching strategies Published studies have not clarified whether
clinicians should switch from a first failed SSRI to
The option to switch to another first-line drug might CMI, to another SSRI, or to a different compound.
be preferred when, after an adequate trial, there is no sign The Expert Consensus Guidelines on the Treatment
of improvement in obsessive-compulsive symptoms. of OCD (March et al. 1997) recommends switching to
This strategy involves switching to a different route of another SSRI after a non-response to a first SSRI, and
administration (from oral to intravenous formulation), switching to clomipramine only after 2 to 3 failed SSRI
when possible, to a second first-choice medication, or trials. Pigott and colleagues treated 11 OCD patients
to a different compound. with either fluoxetine or CMI during 10 weeks, and
then switched therapy to the other drug for an additional
4.1. Switch to intravenous (iv) route of period of 10 weeks. The authors found that 5 patients
responded preferentially to CMI, two to fluoxetine and
administration four to both drugs, thus indicating that individuals not
The rationale of IV clomipramine is to avoid first- responding to one drug may still respond to the other
pass metabolism, assuming that partial or no clinical (Pigott et al. 1990). In an open study presented at the
response with the oral formulation may be due to 4th IOCDC we observed that switching from CMI to an
inadequate plasma levels of clomipramine or to low SSRI or vice-versa yields higher response rates (33 to
clomipramine/desmethylclomipramine ratio, which 40%) than switching from one SSRI to another (0 to
is normally around 1:2 (Greist and Jefferson 1998, 20%) (Koran et al. 2000).
Marazziti et al. 2012b). The switch to IV clomipramine The better tolerability profile of SSRI supports
seems to be an effective option in treatment-resistant the choice of a second SSRI trial before switching to
OCD patients. In the early open-label reports, this clomipramine, which may be reserved as a third choice.
therapeutic strategy has proved good tolerability and a However, these considerations are based on open label
rapid relief of obsessional symptoms in resistant OCD trials and should be viewed as preliminary.
(Warneke 1989, Fallon et al. 1992, Koran et al. 1997,
Koran et al. 2006). In order to rule out the hypothesis 4.3. Switch to another compound in
that the efficacy of IV clomipramine was a placebo monotherapy
effect (invasive treatment), Fallon and colleagues
performed a double-blind study of IV clomipramine Given that preliminary evidence stands for a
versus IV placebo (14 infusions over a time span of potential role of venlafaxine in the treatment of OCD,
18 days) in 54 resistant patients. Therapeutic effects switching to a drug other than the approved SSRI and
were seen after the last infusion was performed: 21% clomipramine may be an option in some resistant cases.
of the patients treated with IV clomipramine responded Venlafaxine has been studied in patients with
as compared 0% of patients treated with IV placebo. OCD in one small, placebo-controlled trail versus
One month after, response rate was 58% in patients placebo (Yaryura-Tobias et al. 1996) and in two active
continuing on open-label oral CMI (Fallon et al. 1998). comparator controlled studies versus clomipramine
Citalopram is the only SSRI currently available (Albert et al. 2002) and paroxetine (Denys et al. 2003).
in the IV formulation. Pallanti and colleagues, in an In the first study venlafaxine failed to separate from
open study, examined the efficacy of IV citalopram in placebo, probably because the study lasted only 8 weeks
subjects with OCD who failed at least two adequate oral (Yaryura-Tobias et al. 1996); moreover, this study
SRIs trials, other than citalopram. The findings showed did not use the Y-BOCS as the outcome measure. We
a discrete clinical efficacy of IV citalopram after three performed a single-blind study comparing venlafaxine
weeks (59% of patients had a decrease in the Y-BOCS 225 mg/day versus clomipramine 150 mg/day in
score 25%); the IV citalopram administration may be 73 drug-nave patients through a 12-week trial. At the
viewed as a mean of accelerating OCD symptom relief endpoint, the two compounds showed similar response
and eventually predicting response to oral citalopram rates without any statistically significant difference
treatment (Pallanti et al. 2002b). Data on the efficacy (Albert et al. 2002). Another positive study is a double-
of IV citalopram in patients resistant to oral citalopram blind trial where venlafaxine (300 mg/day) was
are lacking. compared to paroxetine (60 mg/day) in a large cohort
of patients (150 patients); both treatments appeared
4.2. Switch to a second first-choice compound equally effective in reducing Y-BOCS scores, with
a response rate of almost 40% in both groups (Denys
A second option consists in switching to another et al. 2003). On the basis of such preliminary results,
serotoninergic compound, although data from published venlafaxine was used to treat resistant cases. A single-
studies are still scarce. After a previous unresponsive blind study investigated the efficacy of venlafaxine 225-
SRIs trial, response rate to a second SRIs has been 300 mg versus CMI 150-225 mg and citalopram 40-60

24 Clinical Neuropsychiatry (2013) 10, 1


Treatment-resistant OCD

mg in patients resistant to at least two SSRI: responder for the treatment of resistant patients. This strategy is not
rates at the end of the study were 42.8% for venlafaxine, supported by double-blind, placebo-controlled studies,
37.5% for CMI and 14.3% with citalopram (Maina et but results of open label studies with sertraline at a dose
al. 2001). Hollander and coworkers demonstrated the of 250-400 mg/die (Ninan et al. 2006), escitalopram
efficacy of venlafaxine (mean dose 232.2 mg/day) in up to 50 mg/day (Rabinowitz et al. 2008), citalopram
39 patients with OCD, 29 of which had previously up to 120 mg/day and fluoxetine up to 100 mg/day
completed one or more therapeutic attempts with SSRI; (Pampaloni et al. 2010) are promising.
76% of patients had a clinical benefit from the switch to
venlafaxine (Hollander et al. 2003b). These preliminary
results seem to indicate that, beside clomipramine, 5. Conclusions
after two failed SSRI trials clinicians should consider
switching OCD patients to venlafaxine. Several questions regarding the strategies to be
Other non-serotonergic drug with potential implemented in case of unsatisfactory response to drug
antiobsessive efficacy (to be used in patients refractory treatment in OCD remain unresolved and need to be
to conventional therapies) are duloxetine (DellOsso addressed by future research.
et al. 2008), mirtazapine (Koran et al. 2001, Koran et Is switching from one SSRI to a second classmate
al. 2005), and agomelatine (Fornaro 2011). All these effective? Or should we switch to clomipramine,
compounds are off-label therapies and should be given the broader neurotransmitter action of this
considered in very refractory cases, until their efficacy compound? In case of unsatisfactory response to a first
in drug-nave or resistant OCD patients is confirmed in drug, should we switch to CBT or should we switch to
methodologically sound studies. another drug? What if a patient has failed two previous
The use of mega-doses of SRIs is another alternative SSRIs? Would venlafaxine be a preferential approach

Figure 1. Algorithm for the management of treatment-resistant OCD patients

First-line treatment: SSRI

Unsatisfactory response after No response at all after 12


12 weeks at maximum dose weeks at maximum dose

Add atypical Add CBT(ERP)


antipsychotic
Switch to
another SSRI

If first-line
treatment is
citalopram or
clomipramine No response after 12 weeks
at maximum dose

Change route of
administration

Switch to another
antidepressant
(clomipramine or
Randomized, Open label
venlafaxine)
controlled studies studies

Clinical Neuropsychiatry (2013) 10, 1 25


Umberto Albert et al.

with respect to clomipramine or another SSRI in this Wittchen HU; British Association for Psychopharmacology
highly resistant patient sample? What is the role of (2005). Evidence-based guidelines for the pharmacological
non-serotonergic drugs in the treatment of OCD? What treatment of anxiety disorders: recommendations from the
about antipsychotics in terms of duration of treatment, British Association for Psychopharmacology. Journal of
doses, better choice of the compound? Psychopharmacology 19, 567-596.
However, based on this review of published Bandelow B, Zohar J, Hollander E, Kasper S, Mller HJ, WFSBP
papers on treatment-resistant OCD, we suggest the Task Force on Treatment Guidelines for Anxiety, Obsessive-
following algorithm for the management of subjects not Compulsive and Post-Traumatic Stress Disoders, Zohar J,
adequately responding to a first trial with a SSRI given Hollander E, Kasper S, Mller HJ, Bandelow B, Allgulander
at correct dosage and for at least 12 weeks (figure 1). C, Ayuso-Gutierrez J, Baldwin DS, Buenvicius R, Cassano
G, Fineberg N, Gabriels L, Hindmarch I, Kaiya H, Klein DF,
Lader M, Lecrubier Y, Lpine JP, Liebowitz MR, Lopez-Ibor
References JJ, Marazziti D, Miguel EC, Oh KS, Preter M, Rupprecht
R, Sato M, Starcevic V, Stein DJ, van Ameringen M, Vega J
Ackerman DL, Greenland S, Bystritsky A (1998). Clinical (2008). World Federation of Societies of Biological Psychiatry
characteristics of response to fluoxetine treatment of obsessive- (WFSBP) Guidelines for the pharmacological treatment
compulsive disorder. Journal of Clinical Psychopharmacology of anxiety, obsessive-compulsive and post-traumatic stress
18, 3, 185-192. disorders-first revision. World Journal of Biological Psychiatry
Alacron RD, Libb JW, Spitler D (1993). A predictive study of 9, 4, 248-312.
obsessive compulsive response to clomipramine. Journal of Bandelow B, Sher L, Bunevicius R, Hollander E, Kasper S,
Clinical Psychopharmacology 13, 210-213. Zohar J, Mller HJ; WFSBP Task Force on Mental Disorders
Albert U, Aguglia E, Maina G, Bogetto F (2002). Venlafaxine in Primary Care; WFSBP Task Force on Anxiety Disorders,
versus clomipramine in the treatment of obsessive-compulsive OCD and PTSD (2012). Guidelines for the pharmacological
disorder: a preliminary single-blind, 12-week, controlled study. treatment of anxiety disorders, obsessive-compulsive disorder
Journal of Clinical Psychiatry 63, 11, 1004-1009. and post-traumatic stress disorder in primary care. International
Albert U, Maina G, Forner F, Bogetto F (2003). Cognitive- Journal of Psychiatry in Clinical Practice 16, 77-84.
behavioral therapy in obsessive-compulsive disorder Barr LC, Goodman WK, Anand A, McDougle CJ, Price LH (1997).
patients partially unresponsive to SRIs. European Addition of desipramine to serotonin reuptake inhibitors in
Neuropsychopharmacology 13, suppl 4, S357. treatment-resistant obsessive-compulsive disorder. American
Albert U, Maina G, Saracco P, Bogetto F (2006). Multifamily Journal of Psychiatry 154, 9, 1293-1295.
psychoeducational Intervention (MPI) for obsessive- Berlin HA, Koran LM, Jenike MA, Shapira NA, Chaplin W,
compulsive study: a pilot study. Epidemiologia e Psichiatria Pallanti S, Hollander E (2011). Double-blind, placebo-
Sociale 15, 1, 70-75. controlled trial of topiramate augmentation in treatment-
Albert U, Salvi V, Saracco P, Bogetto F, Maina G (2007). Health- resistant obsessive-compulsive disorder. Journal of Clinical
related quality of life among first degree relatives of patients Psychiatry 72, 5, 716-721.
with obsessive-compulsive disorder in Italy. Psychiatry Bloch MH, Landeros-Weisenberger A, Kelmedi B, Coric V,
Service 58, 7, 970-976. Bracken MB, Leckman JF (2006). A systematic review:
AlbertU, Maina G, Bogetto F, Chiarle A, Mataix-Cols D antipsychotic augmentation with treatment-refractory
(2010). Clinical predictors of health-relatedquality of lifein obsessive-compulsive disorder. Molecular Psychiatry 11, 622-
obsessive-compulsive disorder. Comprehensive Psychiatry 51, 632.
2, 193-200. Bloch MH, McGuire J, Landeros-Weisenberger A, Leckman
AlbertU,AgugliaA, Bogetto F, Cieri L, Daniele M, Maina G, JF, Pittenger C (2010). Meta-analysis of the dose-response
Necci R, Parena A, Salvati L, Tundo A (2012a). Effectiveness relationship of SSRI in obsessive-compulsive disorder.
of cognitive-behavioral therapy addition to pharmacotherapy Molecular Psychiatry 15, 8, 850-855.
in resistant obsessive-compulsive disorder: a multicenter Bruno A, Mic U, Pandolfo G, Mallamace D, Abenavoli E, Di
study. Psychotherapy and Psychosomatics 81, 6, 383-385. Nardo F, DArrigo C, Spina E, Zoccali RA, Muscatello MR
Albert U, Aguglia A, Chiarle A, Bogetto F, Maina G (2012b). (2012). Lamotrigine augmentation of serotonin reuptake
Metabolic syndrome and obsessive-compulsive disorder: a inhibitors in treatment-resistantobsessive-compulsive
naturalistic Italian study. General Hospital Psychiatry, in disorder: a double-blind, placebo-controlled study. Journal of
press. Psychopharmacology 26, 11, 1456-1462.
American Psychiatric Association (2000). Diagnostic and Bystritsky A, Ackerman DL, Rosen RM, Vapnik T, Gorbis E,
Statistical Manual of Mental Disorders, 4th ed., text revision. Maidment KM, Saxena S (2004). Augmentation of serotonin
American Psychiatric Press, Washington, DC. reuptake inhibitors in refractory obsessive-compulsive
American Psychiatric Association (2007). Practice Guideline for disorder using adjunctive olanzapine: a placebo-controlled
the treatment of patients with obsessive-compulsive disorder. trial. Journal of Clinical Psychiatry 65, 4, 565-568.
American Psychiatric Association, Arlington, VA. Canadian Psychiatric Association (2006). Clinical practice
Amiaz R, Fostick L, Gershon A, Zohar J (2008). Naltrexone guidelines. Management of anxiety disorders. Canadian
augmentation in OCD: a double-blind placebo-controlled Journal of Psychiatry 51, 9S-91S.
cross-over study. European Neuropsychopharmacology 18, 6, Carey PD, Vythilingum B, Seedat S, Muller JE, van Ameringen
455-461. M, Stein DJ (2005). Quetiapine augmentation of SRIs in
Anand N, Sudhir PM, Bada Math S, Thennarasu K, Reddy treatment refractory obsessive-compulsive disorder: a double-
YCJ (2011). Cognitive behaviour therapy in medication non- blind, randomised, placebo-controlled study. BMC Psychiatry
responders with obsessive-compulsive disorder: a prospective 5, 5.
1-year follow-up study. Journal of Anxiety Disorders 25, 7, Crockett BA, Churchill E, Davidson JR (2004). A double-blind
939-945. combination study of clonazepam with sertraline in obsessive-
Atmaca M, Kuloglu M, Tezcan E, Gecici O (2002). Quetiapine compulsive disorder. Annals of Clinical Psychiatry 16, 3, 127-
augmentation in patients with treatment resistant obsessive- 132.
compulsive disorder: a single-blind, placebo-controlled study. Dannon PN, Sasson Y, Hirschmann S, Iancu I, Grunhaus LJ,
Int Clin Psychopharmacol 24, 10, 1439-1445. Zohar J (2000). Pindolol augmentation in treatment-resistant
Baldwin DS, Anderson IM, Nutt DJ, Bandelow B, Bond A, obsessive compulsive disorder: a double-blind placebo
Davidson JR, den Boer JA, Fineberg NA, Knapp M, Scott J, controlled trial. European Neuropsychopharmacology 10, 3,

26 Clinical Neuropsychiatry (2013) 10, 1


Treatment-resistant OCD

165-169. Adding quetiapine to SSRI in treatment-resistant obsessive-


Deacon BJ, Abramowitz JS (2004). Cognitive and behavioural compulsive disorder: a randomized controlled treatment study.
treatments for anxiety disorders: a review of meta-analytic International Clinical Psychopharmacology 20, 223-226.
findings. Journal of Clinical Psychology 60, 4, 429-441. Fineberg NA, Gale TM, Sivakumaran T (2006). A review of
De Haan E, van Oppen P, van Balkom AJ, Spinhoven P, Hoogduin antipsychotics in the treatment of obsessive compulsive
KA, Van Dick R (1997). Prediction of outcome and early vs late disorder. Journal of Psychopharmacology 21, 1, 97-103.
improvement in OCD patients treated with cognitive behavior Fineberg NA, Tonnoir B, Lemming O, Stein DJ (2007).
therapy and pharmacotherapy. Acta Psychiatrica Scandinavica Escitalopram prevents relapse of obsessive-compulsive
96, 354-361. disorder. European Neuropsychopharmacology 17, 430-437.
DellOsso B, Mundo E, Marazziti D, Altamura AC (2008). Fisher PL, Wells A (2005). How effective are cognitive and
Switching from serotonin reuptake inhibitors to duloxetine in behavioural treatments for obsessive-compulsive disorder?
patients with resistant obsessive compulsive disorder: a case A clinical significance analysis. Behaviour Research and
series. Journal of Psychopharmacology 22, 2, 210-213. Therapy 43, 12, 1543-1558.
Denys D, van der Wee N, van Megen HJ, Westenberg HG (2003). Fontenelle IS, Fontenelle LF, Borges MC, Prazeres AM, Rang
A double blind comparison of venlafaxine and paroxetine BP, Mendlowicz MV, Versiani M (2010). Quality of lifeand
in obsessive-compulsive disorder. Journal of Clinical symptom dimensions of patients with obsessive-compulsive
Psychopharmacology 23, 6, 568-575. disorder. Psychiatry Research 179, 2, 198-203.
Denys D, Zohar J, Westenberg HG (2004a). The role of dopamine Fornaro M (2011). Switching from serotonin reuptake inhibitors
in Obsessive-compulsive disorder: preclinical and clinical to agomelatine in patients with refractory obsessive-compulsive
evidence. Journal of Clinical Psychiatry 65, suppl 14, 11-17. disorder: a 3 month follow-up case series. Annals of General
Denys D, De Geus F, Van Megen HJ, Westenberg HG (2004b). Psychiatry 10, 1, 5.
A double-blind, randomized, placebo-controlled trial of Fux M, Benjamin J, Belmaker RH (1999). Inositol versus placebo
quetiapine addition in patients with obsessive-compulsive augmentation of serotonin reuptake inhibitors in the treatment
disorder refractory to serotonin reuptake inhibitors. Journal of of obsessive-compulsive disorder: a double-blind cross-over
Clinical Psychiatry 65, 1040-1048. study. International Journal of Neuropsychopharmacology 2,
Diniz JB, Shavitt RG, Pereira CA, Hounie AG, Pimentel I, 3, 193-195.
Koran LM, Dainesi SM, Miguel EC (2010). Quetiapine Ghaemi SN, Wingo AP, Filkowski MA, Baldessarini RJ (2008).
versus clomipramine in the augmentation of selective Long-term antidepressant treatment in bipolar disorder: meta-
serotonin reuptake inhibitors for the treatment of obsessive- analyses of benefits and risks. Acta Psychiatrica Scandinavica
compulsive disorder: a randomized, open-label trial. Journal 118, 5, 347-356.
of Psychopharmacology 24, 3, 297-307. Goddard AW, Shekhar A, Whiteman AF, McDougle CJ (2008).
DinizJB, Shavitt RG,FossaluzaV, Koran L, Pereira CA, Miguel Serotoninergic mechanisms in the treatment of obsessive-
EC (2011). A double-blind, randomized, controlled trial of compulsive disorder. Drug Discovery Today 13, 325-332.
fluoxetine plus quetiapine or clomipramine versus fluoxetine Goodman WK, McDougle CJ, Barr LC, Aronson SC, Price LH
plus placebo for obsessive-compulsive disorder. Journal of (1993). Biological approaches to treatment-resistant obsessive
Clinical Psychopharmacology 31, 6, 763-768. compulsive disorder. Journal of Clinical Psychiatry 54, suppl
Dold M,Aigner M,Lanzenberger R,Kasper S (2012). 6, 16-26.
Antipsychotic augmentation of serotonin reuptake inhibitors Goodman WK, Ward H, Kablinger A, Murphy T (1997).
in treatment-resistantobsessive-compulsive disorder: a meta- Fluvoxamine in the treatment of obsessive-compulsive
analysis of double-blind, randomized, placebo-controlled disorder and related conditions. Journal of Clinical Psychiatry
trials. International Journal of Neuropsychopharmacology 58, 5, 32-49.
1-18. Grady TA, Pigott TA, LHeureux F, Hill JL, Bernstein SE,
Eddy KT, Dutra L, Bradley R, Westen D (2004). A Murphy DL (1993). Double-blind study of adjuvant buspirone
multidimensional meta-analysis of psychotherapy and for fluoxetine-treated patients with obsessive-compulsive
pharmacotherapy for obsessive-compulsive disorder. Clinical disorder. American Journal of Psychiatry 150, 5, 819-821.
Psychology Review 24, 8, 1011-1030. Greist JH, Jefferson JW (1998). Pharmacotherapy for obsessive-
Erzegovesi S, Cavellini MC, Cavedini P, Diaferia G, Locatelli compulsive disorder. British Journal of Psychiatry 173, 64-70.
M, Bellodi L (2001). Clinical predictors of drug response Grover S, Dutt A (2011). Perceived burden andquality of lifeof
in obsessive-compulsive disorder. Journal of Clinical caregivers in obsessive-compulsive disorder. Psychiatry and
Psychopharmacology 21, 272-275. Clinical Neurosciences 65, 5, 416-422.
Erzegovesi S, Guglielmo E, Siliprandi F, Bellodi L (2005). Low- Gupta AK, Prieto-Merino D, Dahlf B, Sever PS, Poulter NR;
dose risperidone augmentation of fluvoxamine treatment ASCOT Investigators (2011). Metabolic syndrome, impaired
in obsessive-compulsive disorder: a double-blind, placebo- fasting glucose and obesity, as predictors of incident diabetes
controlled study. European Neuropsychopharmacology 15, 1, in 14.120 hypertensive patients of ASCOT-BPLA: comparison
69-74. of their relative predictability using a novel approach. Diabetic
Fallon BA, Campeas R, Schneier FR, Hollander E, Feerick J, Medicine 28, 8, 941-947.
Hatterer J, Goetz D, Davies S, Liebowitz MR (1992). Open Hollander E, Baldini Rossi N, Sood E, Pallanti S (2003a).
trial of Intravenous clomipramine in five treatment-refractory Risperidone augmentation in treatment-resistant obsessive-
patients with obsessive-compulsive disorder. The Journal of compulsive disorder: a double-blind, placebo-controlled study.
Neuropsychiatry and Clinical Neurosciences 4, 1, 70-75. International Journal of Neuropsychopharmacology 6, 4, 397-
Fallon BA, Liebowitz MR, Campeas R, Schneier FR, Marshall 401.
R, Davies S, Goetz D, Klein DF (1998). Intravenous Hollander E, Friedberg J, Wasserman S, Allen A, Birnbaum
clomipramine for obsessive-compulsive disorder refractory to M, Koran LM (2003b). Venlafaxine in treatment-resistant
oral clomipramine. Archives of General Psychiatry 55, 918- obsessive-compulsive disorder. Journal of Clinical Psychiatry
924. 64, 5, 546-550.
Figueroa Y, Rosenberg DR, Birmaher B, Keshavan MS (1998). Hollander E, Stein DJ, Fineberg NA, Marteau F, Legault M
Combination treatment with clomipramine and selective (2010). Quality of lifeoutcomes in patients with obsessive-
serotonin reuptake inhibitors for obsessive-compulsive compulsive disorder: relationship to treatment response and
disorder in children and adolescents. Journal of Child and symptom relapse. Journal of Clinical Psychiatry 71, 6, 784-
Adolescent of Psychopharmacology 8, 1, 61-67. 792.
Fineberg NA, Sivakumaran T, Roberts A, Gale T (2005). Kampman M, Keijsers GP, Hoogduin CA, Verbraak MJ (2002).

Clinical Neuropsychiatry (2013) 10, 1 27


Umberto Albert et al.

Addition of cognitive-behaviour therapy for obsessive- S, Nasso ED, Pfanner C, Cassano GB (2001). Citalopram in
compulsive disorder patients non-responding to fluoxetine. refractory obsessive-compulsive disorder: an open study.
Acta Psychiatrica Scandinavica 106, 4, 314-319. International Clinical Psychopharmacology 16, 215-219.
Kessler RC, Chiu WT, Demler O, Merikangas KR, Walters EE Marazziti D, Pfanner C, DellOsso B, Ciapparelli A, Presta
(2005) Prevalence, severity, and comorbidity of 12-month S, Corretti G, Di Nasso E, Mungai F, DellOsso L (2005).
DSM-IV disorders in the National Comorbidity Survey Augmentation strategy with olanzapine in resistano obsessive-
Replication. Archives of General Psychiatry 62, 617-627. compulsive disorder: an Italian long-term open-label study.
Khang YH, Cho SI, Kim HR (2010). Risks for cardiovascular Journal of Psychopharmacology 19, 4, 392-394.
disease, stroke, ischaemic heart disease, and diabetes mellitus MarazzitiD,Golia F,Consoli G,Presta S,Pfanner C,Carlini
associated with the metabolic syndrome using the new M,Mungai F,Catena Dellosso M (2008). Effectiveness of
harmonised definition: findings from nationally representative long-term augmentation with citalopram to clomipramine in
longitudinal data from an Asian population. Atherosclerosis treatment-resistant OCDpatients. CNS Spectrum 13, 11, 971-
213, 2, 579-585. 976.
Komossa K, Depping AM, Meyer M, Kissling W, Leucht S Marazziti D, Carlini M, DellOsso L (2012a). Treatment
(2010). Second-generation antipsychotics for obsessive- srategies of obsessive-compulsive disorder and panic disorder/
compulsive disorder. Cochrane Database of Systematic agoraphobia. Current Topics in Medicinal Chemistry 12, 4,
Reviews 8, CD 008141. 238-253.
Koo MS, Kim EJ, Roh D, Kim CH (2010). Role of dopamine Marazziti D, Baroni S, Faravelli L, Giannaccini G, Massimetti G,
in the pathophysiology and treatment of obsessive-compulsive Palego L, Catena-Dell-Osso M (2012b). Plasma clomipramine
disorder. Expert Review of Neurotherapeutics 10, 2, 275-290. levels in adult patients with obsessive-compulsive disorder.
Koran LM, Sallee FR, Pallanti S (1997). Intravenous pulse International Clinical Psychopharmacology 27, 1, 55-60.
loading of clomipramine produce rapid benefit in obsessive- March J, Frances A, Carpenter D, Kahn D, eds. (1997). The
compulsive disorder. American Journal of Psychiatry 154, Expert Consensus Guidelines Series. Treatment of obsessive-
396-401. compulsive disorder. Journal of Clinical Psychiatry 58, suppl
Koran LM, Saxena S (2000). Issues and strategies in treating 4, 2-72.
refractory obsessive-compulsive disorder. CNS Spectrum 5, 6, Matsunaga H, Nagata T, Hayashida K, Ohya K, Kiriike N, Stein
suppl 4, 24-31. DJ (2009). A long-term trial of the effectiveness and safety of
Koran LM, Quirk T, Lorberbaum JP, Elliott M (2001). Mirtazapine atypical antipsychotic agents in augmenting SSRI-refractory
treatment of obsessive-compulsive disorder. Journal of obsessive-compulsive disorder. Journal of Clinical Psychiatry
Clinical Psychopharmacology 21, 5, 537-539. 70, 6, 863-868.
Koran LM, Gamel NN, Choung HW, Smith EH, Aboujaoude EN McDonough M, Kennedy N (2002). Pharmacological
(2005). Mirtazapine for obsessive-compulsive disorder: an management of obsessive-compulsive disorder: a review for
open trial followed by double-blind discontinuation. Journal clinicians. Harvard Review of Psychiatry 10, 3, 127-137.
of Clinical Psychiatry 66, 4, 515-520. McDougle CJ, Goodman WK, Price LH, Delgado PL, Krystal
Koran LM, Aboujauode E, Ward H, Shapira NA,Sallee FR, Gamel JH, Charney DS, Heninger GR (1990). Neuroleptic addition
N, Elliott M (2006). Pulse-loaded intravenous clomipramine in in fluvoxamine-refractory obsessive-compulsive disorder.
treatment-resistant obsessive compulsive disorder. Journal of American Journal of Psychiatry 147, 652-654.
Clinical Psychopharmacology 26, 79-83. McDougle CJ, Price LH, Goodman WK, Charney DS, Heninger
Koran LM, Aboujaoude E, Gamel N (2009). Double-blind study GR (1991). A controlled trial of lithium augmentation in
of dextroamphetamine versus caffeine augmentation for fluvoxamine-refractory obsessive-compulsive disorder: lack of
treatment-resistant obsessive-compulsive disorder. Journal of efficacy. Journal of Clinical Psychopharmacology 11, 3, 175-
Clinical Psychiatry 70, 11, 1530-1535. 184.
Kordon A, Wahl K, Koch N, Zurowski B, Anlauf M, Vielhaber McDougle CJ, Goodman WK, Leckman JF, Holzer JC, Barr LC,
K, Kahl KG, Broocks A, Voderholzer U, Hohagen F (2008). McCance-Katz E, Heninger GR, Price LH (1993). Limited
Quetiapine addition to serotonin reuptake inhibitors in patients therapeutic effect of addition of buspirone in fluvoxamine-
with severe obsessive-compulsive disorder: a double-blind, refractory obsessive-compulsive disorder. American Journal
randomized, placebo-controlled study. Journal of Clinical of Psychiatry 150, 4, 647-649.
Psychopharmacology 28, 5, 550-554. McDougle CJ, Goodman WK, Leckman JF, Lee NC, Heninger
Jenike MA (2004). Clinical practice. Obsessive-compulsive GR, Price LH (1994). Haloperidol addition in fluvoxamine-
disorder. New England Journal of Medicine 350, 259-265. refractory obsessive-compulsive disorder. A double-blind,
Joseph J, Svartberg J, Njlstad I, Schirmer H (2011). Risk factors placebo-controlled study in patients with and without tics.
for type 2 diabetes in groups stratified according to metabolic Archives of General Psychiatry 51, 4, 302-308.
syndrome: a 10-year follow-up of the Troms Study. European McDougle CJ, Epperson CN, Pelton GH, Wasylink S, Price LH
Journal of Epidemiology 26, 2, 117-124. (2000). A double-blind, placebo-controlled study of risperidone
Maina G, Albert U, Bogetto (2001). Venlafaxine in treatment addition in serotonin reuptake inhibitor-refractory obsessive-
resistant OCD patients: a single-blind, randomised, controlled compulsive disorder. Archives of General Psychiatry 57, 8,
study versus clomipramine and citalopram. European 794-801.
Neuropsychopharmacology 11, suppl 2, S66. Mowla A, Khajeian AM, Sahraian A, Chohedri AH, Kashkoli
Maina G, Albert U, Ziero S, Bogetto F (2003). Antipsychotic F (2010). TopiramateAugmentationin Resistant OCD:
augmentation for the treatment-resistant obsessive-compulsive ADouble-BlindPlacebo-ControlledClinicalTrial. CNS
disorder: what if antipsychotic is discontinued? International Spectrum, [Epub ahead of print].
Clinical Psychopharmachology 18, 23-28. Mundo E, Guglielmo E, Bellodi L (1998). Effect of adjuvant
Maina G, Saracco P, Albert U (2006). Family-focused treatments pindolol on the antiobsessional response to fluvoxamine: a
for obsessive-compulsive disorder. Clinical Neuropsychiatry double-blind, placebo-controlled study. International Clinical
3, 6, 382-390. Psychopharmacology 13, 5, 219-224.
Maina G, Pessina E, Albert U, Bogetto F (2008). 8-week, Muscatello MR, Bruno A, Pandolfo G, Mic U, Scimeca G, Romeo
single-blind, randomized trial comparing risperidone versus VM, Santoro V, Settineri S, Spina E, Zoccali RA (2011). Effect
olanzapine augmentation of serotonin reuptake inhibitors in of aripiprazole augmentation of serotonin reuptake inhibitors
treatment-resistant obsessive-compulsive disorder. European or clomipramine in treatment-resistant obsessive-compulsive
Neuropsychopharmacology 18, 5, 364-372. disorder: a double-blind, placebo-controlled study. Journal of
Marazziti D, DellOsso L, Gemignani A, Ciapparelli A, Presta Clinical Psychopharmacology 31, 2, 174-179.

28 Clinical Neuropsychiatry (2013) 10, 1


Treatment-resistant OCD

Ninan PT, Koran LM, Kiev A, Davidson JR,Rasmussen SA, T,Ventura P (2011). CBT for pharmacotherapy non-remitters-
Zajecka JM, Robinson DG, Crits-Christoph P, Mandel -a systematicreviewof a next-step strategy. Journal of
FS, Austin C (2006). High-dose sertraline strategy for Affective Disorders129, 1-3, 219-228.
nonresponders to acute treatment for obsessive-compulsive Ruscio AM, Stein DJ, Chiu WT, Kessler RC (2010). The
disorder: a multicenter double-blind trial. Journal of Clinical epidemiology of obsessive-compulsive disorder in the National
Psychiatry 67, 1, 15-22. Comorbidity Survey Replication. Molecular Psychiatry 15, 1,
Nolen WA (2002). World Health Organization places psychiatry 53-63.
high on the agenda, also consequences for the Netherlands. Salvi V, Fagiolini A, Swartz HA, Maina G, Frank E (2008). The
Nederlands Tijdschrift voor Geneeskunde 146, 297-299. use of antidepressants in bipolar disorder. Journal of Clinical
Novelletto BF, Guzzinati S, Avogaro A (2012). Prevalence Psychiatry 69, 8, 1307-1318.
of metabolic syndrome and its relationship with clinically Sareen J,Kirshner A,Lander M,Kjernisted KD,Eleff MK,Reiss
prevalent cardiovascular disease in the Veneto region, JP (2004). Do antipsychotics ameliorate or exacerbate
northeastern Italy. Metabolic Syndrome and Related Disorders Obsessive Compulsive Disorder symptoms? A systematic
10, 1, 56-62. review. Journal of Affective Disorders 82, 2, 167-174.
Pallanti S, Quercioli L, Paiva RS, Koran LM (1999). Citalopram Sayyah M, Sayyah M, Boostani H, Ghaffari SM, Hoseini A
for treatment-resistant obsessive-compulsive disorder. (2012). Effects of aripiprazole augmentation in treatment-
European Psychiatry 14, 2, 101-106. resistant obsessive-compulsive disorder (a double blind
Pallanti S, Hollander E, Bienstock C, Koran L, Leckman J, clinical trial). Depression Anxiety 29, 10, 850-854.
Marazziti D, Pato M, Stein D, Zohar J; International Treatment SelviY,AtliA, Aydin A, Besiroglu L, Ozdemir P, Ozdemir
Refractory OCD Consortium (2002a). Treatment non response O (2011). The comparison ofaripiprazoleand risperidone
in OCD: methodological issues and operational definitions. augmentation in selective serotonin reuptake inhibitor-
International Journal of Neuropsychopharmacology 5, 2, 181- refractory obsessive-compulsive disorder: a single-blind,
191. randomised study. Human Psychopharmacology 26, 1, 51-57.
Pallanti S, Quercioli L, Koran LM (2002b). Citalopram Shapira NA, Ward HE, Mandoki M, Murphy TK, Yang MC, Blier
intravenous infusion in resistant obsessive-compulsive P, Goodman WK (2004). A double-blind, placebo-controlled
disorder: an open trial. Journal of Clinical Psychiary 63, 9, trial of olanzapine addition in fluoxetine-refractory obsessive-
796-801. compulsive disorder. Biological Psychiatry 55, 5, 553-555.
Pallanti S, Quercioli L (2006). Treatment refractory obessive- Skapinakis S, Papatheodorou T, Mavreas V (2007).
compulsive disorder: methodological issues, operational Antipsychotic augmentation of serotoninergic antidepressants
definitions and therapeuthic lines. Progress in Neuro- in treatment-resistant obsessive-compulsive disorder: a
psychopharmacology and Biological Psychiatry 30, 400-412. meta-analysis of the randomized controlled trials. European
Pampaloni I, Sivakumaran T, Hawley CJ,Al Allaq A,Farrow J, Neuropsychopharmacology 17, 79-93.
Nelson S, Fineberg NA (2010). High-dose selective serotonin Simeon JG, Thatte S, Wiggins D (1990). Treatment of adolescent
reuptake inhibitors in OCD: a systematic retrospective case obsessive-compulsive disorder with a clomipramine-fluoxetine
notes survey. Journal of Psychopharmacology 24, 10, 1439- combination. Psychopharmacology Bulletin 26, 3, 285-290.
1445. Simpson HB, Gorfinkle KS, Liebowitz MR (1999). Cognitive-
Pigott TA, Pato MT, Bernstein SE, Grover GN, Hill JL, behavioral therapy as an adjunct to serotonin reuptake
Tolliver TJ, Murphy DL (1990). Controlled comparisons of inhibitors in obsessive-compulsive disorder: an open trial.
clomipramine and fluoxetine in the treatment of obsessive- Journal of Clinical Psychiatry 60, 9, 584-590.
compulsive disorder. Behavioral and biological results. Simpson HB, Foa EB, Liebowitz MR, Ledley DR, Huppert
Archives of General Psychiatry 47, 926-932. JD, Cahill S, Vermes D, Schmidt AB, Hembree E, Franklin
Pigott TA, Pato MT, LHeureux F, Hill JL, Grover GN, Murphy M, Campeas R, Hahn CG, Petkova E (2008). A randomized,
DL (1991). A controlled comparison of adjuvant lithium controlled trial of cognitive-behavioral therapy for augmenting
carbonate or thyroid hormone in clomipramine-treated patients pharmachoterapy in obsessive-compulsive disorder. American
with obsessive-compulsive disorder. Journal of Clinical Journal of Psychiatry 165, 5, 621-630.
Psychopharmacology 11, 4, 242-248. Soomro GM, Altman D, Rajagopal S, Oakley-Browne M
Pigott TA, LHeureux F, Hill JL, Bihari K, Bernstein SE, Murphy (2008). Selective serotonin re-uptake inhibitors vs placebo for
DL (1992). A double-blind study of adjuvant buspirone obsessive-compulsive disorder (OCD). Cochrane Database of
hydrochloride in clomipramine-treated patients with obsessive- Systematic Reviews 23, CD001765.
compulsive disorder. Journal of Clinical Psychopharmacology Stein DJ, Andersen EW, Tonnoir B, Fineberg N (2007).
12, 1, 11-18. Escitalopram in obsessive-compulsive disorder: a randomized,
Rabinowitz I, Baruch Y, Barak Y (2008). High-dose escitalopram placebo-controlled, paroxetine-referenced, fixed-dose, 24-
for the treatment of obsessive-compulsive disorder. week study. Current Medical Research and Opinion 23, 701-
International Clinical Psychopharmacology 23, 1, 49-53. 711.
Rasmussen SA, Eisen LJ, Pato MT (1993). Current issues in the Tanner RM, Baber U, Carson AP, Voeks J, Brown TM, Soliman
pharmacologic management of obsessive-compulsive disorder. EZ, Howard VJ, Muntner P (2011) Association of the metabolic
Journal of Clinical Psychiatry 54, 4-9. syndrome with atrial fibrillation among United States adults
Rauch SL, Jenike MA (1994). Management of treatment-resistant (from the REasons for Geographic and Racial Differences in
obsessive-compulsive disorder: concepts and strategies. In Stroke [REGARDS] Study). American Journal of Cardiology
Hollander E, Zohar J, Marazziti D, Olivieri B (eds) Current 108, 2, 227-232.
insights in obsessive-compulsive disorder. John Wiley & Sons Tolin DF, Maltby N, Diefenbach DJ, Hannan SE, Worhunsky
Ltd, Chichester. P (2004). Cognitive-behavioral therapy for medication
Ravizza L, Barzega G, Bellino S, Bogetto F, Maina G (1995). nonresponders with obsessive-compulsive disorder: a wait-
Predictors of drug treatment response in obsessive-compulsive list-controlled open trial. Journal of Clinical Psychiatry 65, 7,
disorder. Journal of Clinical Psychiatry 56, 368-373. 922-931.
Ravizza L, Barzega G, Bellino S, Bogetto F, Maina G (1996). Tundo A, Salvati L, Busto G, Di Spigno D, Falcini R (2007).
Drug treatment of obsessive-compulsive disorder (OCD): Addition of cognitive-behavioral therapy for nonresponder to
long-term trial with clomipramine and selective serotonin medication for obsessive-compulsive disorder: a naturalistic
reuptake inhibitors (SSRIs). Psychopharmacology Bulletin 32, study. Journal of Clinical Psychiatry 68, 10, 1552-1556.
1, 167-173. van Noppen B, Steketee G (2003). Family response and
Rodrigues H,Figueira I,Gonalves R,Mendlowicz M,Macedo multifamily behavioral treatment for obsessive-compulsive

Clinical Neuropsychiatry (2013) 10, 1 29


Umberto Albert et al.

disorder. Brief Treatment and Crisis Intervention 3, 231-247. Psychiatry 34, 853-859.
van Noppen B, Steketee G, Pato M (1997). Group and multifamily Wittchen HU, Jacobi F, Rehm J, Gustavsson A, Svensson M,
behavioral treatments for OCD. In Hollander E, Stein D (Eds) Jnsson B, Olesen J, Allgulander C, Alonso J, Faravelli C,
Obsessive-compulsive disorder: diagnosis, etiology, treatment, Fratiglioni L, Jennum P, Lieb R, Maercker A, van Os J, Preisig
331-366. Marcel Dekker, New York. M, Salvador-Carulla L, Simon R, Steinhausen HC (2011). The
Vulink NC, Denys D, Fluitman SB, Meinardi JC, Westenberg size and the burden of mental disorders and other disorders
HG (2009). Quetiapine augments the effect of citalopram in in Europe 2010. European Neuropsychopharmacology 21, 9,
non-refractory obsessive-compulsive disorder: a randomized, 655-679.
double-blind, placebo-controlled study of 76 patients. Journal Yaryura-Tobias JA, Neziroglu FA (1996). Venlafaxine in
of Clinical Psychiatry 70, 7, 1001-1008. obsessive-compulsive disorder. Archives of General Psychiatry
Vulink NC, Figee M, Denys D (2011). Review of atypical 53, 7, 653-654.
antipsyhotic in anxiety. European Neuropsychopharmacology Zohar J, Mueller EA, Insel TR, Zohar-Kadouch RC, Murphy DL
21, 429-449. (1987). Serotoninergic responsitivity in obsessive-compulsive
Warneke LB (1989). Intravenous Chlorimipramine therapy disorder. Comparison of patients and healthy controls. Archives
in obsessive-compulsive disorder. Canadian Journal of of General Psychiatry 44, 946-951.

30 Clinical Neuropsychiatry (2013) 10, 1

S-ar putea să vă placă și