Treatment-Resistant Obsessive-Compulsive Disorder (OCD): Focus on Antipsychotic Augmentation to SRIs

Abstract

Introduction: Obsessive-Compulsive Disorder (OCD) is a common psychiatric illness with 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 common and the evaluation of next-step treatment strategies is highly relevant. Antipsychotic augmentation is the most studied pharmacological strategy. The purpose of this review is to provide guidance regarding the choice of antipsychotic medication on the basis of current evidence.

Material and Methods: We carried out a search on MEDLINE/PUBMED database, selecting meta-analyses, systematic reviews and randomized controlled studies written in English on antipsychotic augmentation of treatment resistant OCD. We also considered open-label studies and case series, written in English. We reviewed the available evidence for antipsychotic use in treatment-resistant-OCD.

Results: Antipsychotic addition to SRI treatment is supported by a positive number of double-blind studies although differences between them seem to exist. Fourteen double blind, randomized, placebo controlled trials investigating quetiapine (N=5), risperidone (N=3), olanzapine (N=2), aripiprazole (N=2), haloperidol (N=1), paliperidone (N=1) were identified. Significant efficacy was identifiable for risperidone and aripiprazole but not for quetiapine and olanzapine. Results regarding haloperidol and paliperidone were inconsistent.

Discussion: Overall, about 50% of SRI-resistant-OCD patients benefited from augmentation strategy with antipsychotic. Risperidone and aripiprazole can be considered as the agents of first choice and should be preferred to the others antipsychotic. In our opinion, olanzapine may be a valid alternative to risperidone. Further trials are required to optimize pharmacological treatment for SRI-resistant-OCD.

Keywords: Obsessive-Compulsive Disorder (OCD); Treatment-resistant OCD; Augmentation; Antipsychotic

Introduction

Obsessive-Compulsive Disorder (OCD) is a heterogeneous disorder of unknown etiology, characterized by the presence of recurrent or persistent, upsetting, worries, images, or urges, which are experienced as intrusive and senseless (obsessions), and excessive repetitive behaviors or mental acts (compulsions), performed in response to these obsessions (DSM-5, APA, 2013).

Diagnosis

The diagnosis is made by clinical interview, with a specific and detailed focus on OCD. To warrant DSM-5 diagnosis, the patient must have obsessions, compulsions or both. Obsessions are defined by (1) and (2):

a) Recurrent and persistent thoughts, urges, or images that are experienced, at some time during the disturbance, as intrusive and unwanted, and that in most individuals cause marked anxiety or distress;

b) The individual attempts to ignore or suppress such thoughts, urges, or images, or to neutralize them with some other thought or action. Compulsions are defined by (1) and (2):

a) Repetitive behaviors or mental acts that the individual feels driven to perform in response to an obsession or according to rules that must be applied rigidly;

b) The behaviors or mental acts are aimed at preventing or reducing anxiety or distress, or preventing some dreaded event or situation; however, these behaviors or mental acts are not connected in a realistic way with what they are designed to neutralize or prevent, or are clearly excessive.

The obsessions or compulsions are time-consuming (e.g., take more than 1 hour per day) or cause clinically significant distress or impairment in social, occupations, or other important areas of functioning. The obsessive-compulsive symptoms are not attributable to the physiological effects of a substance or another medical condition. The disturbance is not better explained by the symptoms of another mental disorder (DSM-5, APA 2013). The Yale- Brown Obsessive-Compulsive Scale (Y-BOCS) is regarded as the gold standard measure of obsessive-compulsive symptom severity and is used in most treatment trials [1].

Prevalence and impact

Epidemiological studies conducted in the last 20 years have established a prevalence rate in the general population of approximately 2-3%, making it a far more common disorder than previously believed [2]. The disorder has no sex differences in distribution with the exception that in children the disorder is more common in boys than in girls [3] OCD has a significant impact on human and social functioning, quality of life, family relationships, and socio-economic status [4-7].The World Health Organization listed this disorder among the 10 most disabling illnesses [8], while the National Comorbidity Survey-Replication study indicated that OCD is the anxiety disorder with the highest percentage (50.6%) of serious cases [9]. Moreover, it has been estimated that most individuals with OCD spend an average of 17 years before receiving an appropriate diagnosis and treatment for their illness [10].

Treatment approaches

According to several recent treatment guidelines, both Serotonin Reuptake Inhibitors (SRIs) (citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline, and clomipramine), and Cognitive Behavior Therapy (CBT) - in the forms of Exposure and Response Prevention (ERP) and/or cognitive restructuring - are considered first line treatments for OCD [11-15]. Both CBT and SRIs have been in fact recognized more effective than wait-list, inactive psychological treatments or placebo in individual randomized controlled trials (RCT) [16-19]. Concerning the relative efficacy between different SRIs, a Cochrane review comprising 17 RCTs could not identify any significant difference between citalopram, fluoxetine, fluvoxamine, paroxetine and sertraline [20] Equally, the SSRI escitalopram improved OCD symptoms without any significant difference as compared to paroxetine [19].

Given the equivalence of both psychological and pharmacological approaches, the severity of the disorder and the age of the subject might guide the physician's choice between these two approaches: when treating an adult affected by a severe OCD, clinicians should prefer drug treatment with SRIs, eventually associating CBT. Conversely, childhood OCD should be first treated with ERP or cognitive therapy, eventually adding pharmacotherapy in the most severe cases. The selection might also be affected by patient preferences, and of course by the local availability of services able to offer evidence-based psychological interventions.

Unfortunately, 40-60% of OCD patients do not respond adequately to SRI therapy and an even greater proportion of patients fail to experience complete remission of their symptoms after a first trial [21-23] Even those patients who are judged to be clinical responders based on stringent response criteria (i.e., typically a greater than 25 or 35% decline in Y-BOCS rating) continue to experience significant impairment from their residual OCD symptoms [24] Because of the high number of patients with Obsessive-Compulsive Disorder (OCD) not responding satisfactorily to the initial SRI monotherapy, the evaluation of additional treatment options is highly relevant. Augmentation of ongoing serotoninergic treatment with an antipsychotic for treatment-resistant OCD patients is one of the most studied and well documented strategies. However, differences between antipsychotics in their efficacy in treatment-resistant OCD seem to exist, reflecting the differences in pharmacodynamic characteristics of each drug.

The purpose of this paper is to review available data on antipsychotic augmentation in treatment-resistant OCD.

Definition of Treatment Resistance

Treatment-resistant OCD patients are defined as those who undergo adequate trials of first-line therapies without achieving a satisfactory response, usually defined by a reduction in the Yale- Brown Obsessive Compulsive Scale (Y-BOCS) score ≥35% or ≥25% with respect to baseline [25]. The International Treatment Refractory OCD Consortium has recently proposed stages of response to treatment; full response is defined as 35% or greater reduction of Y-BOCS and Clinical Global Impression (CGI) 1 or 2; partial response as greater than 25% but less 35% Y-BOCS reduction; non response as less than 25% Y-BOCS reduction and CGI 4. Furthermore, recovery is defined as a complete and objective disappearance of symptoms, corresponding to YBOCS value of 8 or below; remission can indicate a response that reduces symptoms to a minimal level, i.e. YBOCS score of 16 or less, being this value the minimum threshold one for a patient to be included in a clinical trial [26,27].

Before defining a patient as resistant to a pharmacological treatment, several issues have to be considered and questions have to be answered:

1. Clinicians have to be sure that the diagnosis of OCD is correct and that other symptoms are not incorrectly considered as obsessions or compulsions (obsessive-compulsive personality disorder; ruminations occurring in Major Depressive Disorder or other Anxiety Disorders; repetitive stereotyped behaviors encountered in psychoses, in mental retardation or in organic mental disorders; obsessive concerns about body shape or ritualized eating behaviors in Eating Disorders; patterns of behaviors, interests or restricted and repetitive activities in Autism);
2. Has the pharmacological treatment been taken adequately in terms of doses and time? Clinicians should evaluate the response to first-line treatment in OCD patients after at least 12 weeks with moderate-high dosages of SRIs [28] as illustrated in Table 1.



Table 1: Doses of Serotonin Reuptake Inhibitors (SRIs) in the treatment of obsessive-compulsive disorder in according to American Psychiatry Association guidelines (2007).

  

    
Compound
      
SRI
    
Starting    dose and incremental dose (mg/day) (a)
    
 
      
Usual    target dose
      
(mg/day)
    
 
      
Usual    maximum dose
      
(mg/day)
    
 
      
Occasionally    prescribed maximum dose (mg/day) (b)
  
  

    
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
  

Table 1:  Doses of Serotonin Reuptake Inhibitors (SRIs) in the treatment of obsessive-compulsive disorder in according to American Psychiatry Association guidelines (2007).

Close

Clinicians have to assess the potential presence of medical or psychiatric comorbidity that could affect treatment response (e.g., paradigmatic the case of OCD comorbid with Bipolar Disorder, where treatment with high doses of SRIs could worsen both bipolar disorder - mixed episodes, rapid cycling, switch - and OCD) [29,30].

Some individuals who fail to improve after three months of treatment at adequate doses may turn into treatment responders after additional months of continued treatment: this suggests that the first available strategy could be just waiting for the treatment to produce a full response. This strategy should be reserved to patients who showed at least a partial response during the treatment [31,32].

Finally, another issue that should be kept in mind in the assessment of treatment resistant OCD is the potential role of the family in reinforcing the disorder and reducing patient compliance. Family members tend to become emotionally over-involved, neglecting their 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 expectations that the patient "just snaps out of it". Both attitudes, besides worsening relatives' quality of life [33,34], contribute to the maintenance of patient's symptoms as well [35]. Psychoeducational interventions directed to the families might help to establish a therapeutic alliance, to provide education about the disorder and its treatment, to improve family problem solving skills, and to ameliorate compliance to drug treatments [36-38].

Once all these questions have been addressed and a condition of treatment-resistance of OCD is confirmed, several therapeutic options are available. In this review we will focus our attention on antipsychotic augmentation, as this strategy is the only one confirmed by several double-blind randomized controlled trials and by several meta-analyses. Another possibility is to add cognitive-behavior therapy; this option proved to be effective in several open-label studies [39] and at least one well-performed controlled (stress management training as the inactive/placebo psychological treatment arm) randomized trial [40].

Antipsychotic Augmentation

Following the hypothesis of dopaminergic hyper-activation in OCD [41,42], many research projects focused on the examination of antipsychotic compounds in this disorder. Because the serotonergic metabolism is supposed to be centrally involved in the pathophysiology of OCD [43] most studies were aimed at determining whether the co-administration of SRIs and antipsychotics is effective in patients unresponsive to SRIs alone [44].

Several randomized, double-blind, placebo-controlled studies exist, to date, supporting the use of this strategy; review and meta-analytical studies also confirm that, as a class, antipsychotics are effective when added to SRIs in resistant patients [45-50]. In summary, the evidence based on the meta-analytic calculations suggests an efficacy of this pharmacological strategy measured by both the response rates (criterion: Y-BOCS reduction ≥ 35%) and the changes in Y-BOCS total score; about one-third of OCD patients responded to this therapeutic option [50]. However, not all antipsychotics have been studied in double-blind conditions and differences in efficacy exist between antipsychotics.

Which antipsychotic?

First generation antipsychotics (FGAs)

Early studies added typical antipsychotics (haloperidol and pimozide) to SRIs [51,52], only haloperidol (mean dose 6.2±3.0 mg/die; maximal dose=10 mg/die), however, among the typical antipsychotics, proved to be effective in a double-blind, placebo-controlled study, particularly for patients with comorbid tic disorders [53]. The side effect profile of haloperidol, with dose-dependent extra-pyramidal symptoms, limits the potential benefit of this strategy in resistant OCD patients.

Second generation antipsychotics (SGAs)

Atypical antipsychotics may be better tolerated in the short-term, although concerns exist regarding long-term metabolic side effects [54]. Recently, Dold and colleagues published a new meta-analysis of results of all double-blind studies on antipsychotic augmentation of SRIs in treatment-resistant OCD [50]. Concerning atypical antipsychotics, this meta-analysis included five RCTs regarding the addition of quetiapine (178 patients) [19,55-58], three risperidone (72 patients) [59-61], two olanzapine (70 patients) [62,63] and one aripiprazole (40 patients) [64]. The authors conclude that antipsychotic augmentation, overall, significantly improve obsessive-compulsive symptoms. Significant efficacy was identifiable, however, only for risperidone, but not for quetiapine and olanzapine. However, the negative study with olanzapine [63] was biased by the fact that the Authors included patients not responding to only 8 weeks of SRIs monotherapy; thus patients in both the placebo and the olanzapine arms showed a significant response rate. Our single-blind study comparing olanzapine with risperidone addition showed similar response rates to both compounds, suggesting equivalent efficacy [65] We then think that olanzapine may be a valid alternative to risperidone as an augmentation strategy in resistant patients.

Concerning aripiprazole, Dold et al. [50] conclude that results are preliminary on the basis of the only placebo-controlled study available, which was in favor of aripiprazole. Since then, aripiprazole proved to be effective in another study, which compared aripiprazole (10 mg/day fixed-dose for 12 weeks) and placebo in 39 treatment resistant patients with OCD: a significant difference emerged, in favor of aripiprazole, in the mean reduction of the Y-BOCS total score [66]. The evidence supporting the use of aripiprazole in the treatment of resistant OCD is increasing and, in our opinion, this compound could be considered a valid augmentation strategy.

A very recent study compared paliperidone addition (3-9 mg/die, mean final dose=4.94 mg/die) to placebo addition in 39 patients [67]; treatment resistance, however, was defined as an entry YBOCS total score of 19 or greater despite at least two adequate SRI monotherapy trials, one of which included the SRI currently being taken by the patient provided that the duration of treatment was only 8 weeks at a medium-to-high dose. This study was a negative one, as paliperidone did not differentiate from placebo: paliperidone administration resulted in significant baseline to post-treatment reductions in obsessive-compulsive symptoms (-7.98 points in YBOCS score), although placebo administration also resulted in medium size, trend-level significant YBOCS changes (-4.02 points). Paliperidone may have a potential efficacy in treating OCD patients resistant to SRIs, although further studies are needed. Future studies might benefit from including patients whose resistance to treatments is prospectively evaluated in a trial lasting a minimum of 12 weeks at the maximum dose.

Table 2 summarizes results of controlled studies investigating antipsychotic augmentation.

  

    
Compound
    
Authors
    
 
      
Patients included
    
 
      
Duration treatment (weeks)
    
 
      
Dose
      
(mg/day)
    
 
      
Medium dose
      
(mg/day)
    
 
      
Results
  
  

    
Haloperidol
    
McDougle et al [52]
    
34
    
4
    
2-10
    
6.2 ± 3.0
    
Haloperidol > Placebo
  
  

    
 
      
Risperidone
    
McDougle et al [59]
      
Hollander et al. [60]
      
Erzegovesi et al.[61]
    
36
      
16
      
39
    
6
      
8
      
6
    
1-6
      
0.5-3
      
0.5 (fixed-dose)
    
2.2 ± 0.7
      
2.25 ± 0.86
      
0.5 (fixed-dose)
    
Risperidone > Placebo
      
Risperidone > Placebo
      
Risperidone > Placebo
  
  

    
 
      
Olanzapine
    
Bystritsky et al.[62]
      
Shapira et al.[63]
    
26
      
44
    
6
      
6
    
5-20
      
5-10
    
11.2 ± 6.5
      
6.1 ± 2.1
    
Olanzapine > Placebo
      
Olanzapine = Placebo
  
  

    
 
      
Quetiapine
    
Atmaca et al.[79]
      
Denys et al. [41]
      
Fineberg et al.[19]
      
Carey et al. [56]
      
Kordon et al. [57]
      
Diniz et al. [58]
    
27
      
40
      
21
      
42
      
40
      
54
    
8
      
8
      
16
      
6
      
12
      
12
    
50-200
      
200-300
      
50-400
      
25-300
      
400-600
      
=200
    
91 ± 41
      
300
      
215 ± 124
      
168.8 ± 120.8
      
-
      
-
    
Quetiapine > Placebo
      
Quetiapine > Placebo
      
Quetiapine = Placebo
      
Quetiapine = Placebo
      
Quetiapine = Placebo
      
Quetiapine < Placebo
  
  

    
Aripiprazole
    
Muscatello et al. [64]
      
Sayyah et al. [66]
    
40
      
39
    
16
      
12
    
15 (fixed-dose)
      
10 (fixed-dose)
    
15 (fixed-dose)
      
10 (fixed-dose)
    
Aripiprazole > Placebo
      
Aripiprazole > Placebo
  
  

    
Paliperidone
    
Storch et al.[67]
    
34
    
8
    
3-9
    
4.94
    
Paliperidone = Placebo
  

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