Biological treatments for obsessive-compulsive and related disorders

Journal of Obsessive-Compulsive and Related Disorders ∎ (∎∎∎∎) ∎∎∎–∎∎∎

1 Contents lists available at ScienceDirect 2 3 4 5 6 journal homepage: www.elsevier.com/locate/jocrd 7 8 9 Review 10 11 12 13 a b c 14 Q1 Xenia Borue , Mehak Sharma , Robert Hudak 15Q15 a University of Pittsburgh, PGY-4 Child/Adolescent Psychiatry Fellow, USA b PGY-4 Adult Psychiatry, USA 16 c Q32 University of Pittsburgh, USA 17 18 19 art ic l e i nf o a b s t r a c t 20 21 Article history: The availability of evidence based treatments for OCD is a fairly recent development. While this 22 Received 9 February 2015 emerging field is an exciting time for those seeking to help individuals with OCD, some aspects of 23 Accepted 21 March 2015 treating OCD can be challenging for today's psychiatrist. Often SSRI's are used at higher dosages in OCD 24 than in the treatment of other psychiatric illnesses. This often leads to pharmacists, medical review 25 committees and insurance companies to question the therapy, requiring time to advocate for the best Keywords: 26 Obsessive compulsive disorder treatment. As with any field in which treatment options are evolving, understanding which patients may 27 SSRI benefit from emerging medication options, communicating these choices to the patients and families Pharmacotherapy 28 may consume more and more time for the effective psychiatrist. The goal of this review is to guide the 29 reader through the currently available literature for obsessive compulsive and related disorders in order 30 to provide them with the tools to appropriately tailor their pharmacotherapy and, when necessary, advocate for their patients. 31 & 2015 Published by Elsevier Inc. 32 33 34 35 36 Contents 37 38 1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2 39 2. Medication treatment with ERP vs. ERP alone . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2 40 3. First-line OCD treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2 41 4. Specific agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 42 4.1. Fluvoxamine. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 4.2. Sertraline . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 43 4.3. Fluoxetine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4 44 4.4. Paroxetine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4 45 4.5. Citalopram and escitalopram . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4 46 4.6. Clomipramine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4 47 5. Managing side effects of SSRI . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4 48 5.1. Common side effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4 49 5.2. Gastrointestinal effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4 50 5.3. Excessive sweating . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4 51 5.4. Akathesia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 52 5.5. Movement disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 53 5.6. Apathy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 5.7. Weight gain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 54 5.8. Sexual side effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 55 5.9. Hyponatremia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 56 5.10. Gastrointestinal bleeding. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 57 5.11. Serotonin Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6 58 5.12. Discontinuation syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6 59 6. Implementing and dosing of meds . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6 60 61 62 E-mail address: [email protected] (R. Hudak). 63 64 http://dx.doi.org/10.1016/j.jocrd.2015.03.003 65 2211-3649/& 2015 Published by Elsevier Inc. 66

Journal of Obsessive-Compulsive and Related Disorders

Biological treatments for obsessive-compulsive and related disorders

Please cite this article as: Borue, X., et al. Biological treatments for obsessive-compulsive and related disorders. Journal of ObsessiveCompulsive and Related Disorders (2015), http://dx.doi.org/10.1016/j.jocrd.2015.03.003i

67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99

X. Borue et al. / Journal of Obsessive-Compulsive and Related Disorders ∎ (∎∎∎∎) ∎∎∎–∎∎∎

2

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35Q16 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 66

7. 8. 9.

Discontinuation vs. maintenance of SRIs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6 Treatment resistance and augmentation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7 Augmentation with antipsychotics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8 9.1. Risperidone . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8 9.2. Aripiprazole . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8 9.3. Olanzapine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9 9.4. Quetiapine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9 9.5. Clozapine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10 9.6. Other second generation antipsychotics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10 9.7. First Generation Antipsychotics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10 9.8. Side effects, and drug–drug interactions with anti-psychotic augmentation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11 10. Glutamatergic medications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11 10.1. Riluzole . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11 10.2. Memantine. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11 10.3. D-cycloserine (DCS) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12 10.4. Additional glutamatergic agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12 11. Augmentation with mood stabilizers and anticonvulsants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12 11.1. Lamotrigine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12 11.2. Topiramate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13 11.3. Other mood stabilizers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13 12. Additional augmenting agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13 12.1. 5-HT3 receptor antagonists . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13 12.2. Mirtazapine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13 12.3. B-blockers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13 13. “Last-line” agents. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13 14. Trichotillomania (hair pulling disorder) and excoriation (skin picking disorder) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14 15. Hoarding Disorder . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14 16. Body Dysmorphic Disorder . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15 17. Special populations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15 Uncited references . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15

1. Introduction The availability of evidence based treatments for OCD is a fairly recent development. At the time of this writing, there are many psychiatrists still in practice who were trained during a time in which a diagnosis of OCD offered little hope to the effected individual. The first medication treatment studies which were able to demonstrate an improvement in OCD symptoms were conducted in 1980 (Montgomery, 2003; Marks, Stern, Mawson, Cobb, & McDonald, 1980). The first medication that was approved in the United States for the treatment of OCD was clomipramine, and was granted approval by the FDA in 1987. As a result, the use of medication treatment and other biologically based therapies is a relatively new occurrence in the field of psychiatry. Since that time, the efficacy of serotonin selective reuptake inhibitors (SSRIs) has been demonstrated as well, leading to a number of medications that are approved for the treatment of OCD with evidence based effectiveness. Along with clomipramine, SSRIs are considered to be the first line of medication treatment for OCD. Recent work has focused on additional classes of medication to expand the treatment options currently available. While this emerging field is an exciting time for those seeking to help individuals with OCD, some aspects of treating OCD can be challenging for today's psychiatrist. Often SSRI's are used at higher dosages in OCD than in the treatment of other psychiatric illnesses. This often leads to pharmacists, medical review committees and insurance companies to question the therapy, requiring time to advocate for the best treatment. As with any field in which treatment options are evolving, understanding which patients may benefit from emerging medication options, communicating these choices to the patients and families may consume more and more time for the effective psychiatrist. The goal of this review is to guide the reader through the currently available literature for

obsessive compulsive and related disorders in order to provide them with the tools to appropriately tailor their pharmacotherapy and, when necessary, advocate for their patients.

2. Medication treatment with ERP vs. ERP alone Exposure Response Prevention (ERP) is a highly effective evidence-based behavioral treatment for OCD in adult and pediatric populations. ERP, which has an exceedingly low risk to benefit ratio, should be considered a first line treatment and where available should be provided independently or concurrently with first-line pharmacotherapy prior to the exploration of any other treatment modalities. In adults, a recent head to head trial of risperidone vs. ERP augmentation of Serotonin Reuptake Inhibitors (SRI) is consistent with this recommendation, showing significant superiority of ERP over the antipsychotic (Simpson et al., 2013). In pediatric OCD, the POTS study showed the combination of SRI and ERP is significantly more effective than SRI alone, with nearly half of those receiving dual therapy experiencing remission of symptoms (Pediatric OCD Treatment Study, 2004). Unfortunately, ERP providers remain rare in many parts of the country although this is improving. In the event that the patient is unable or unwilling to participate in ERP, medications can be a reasonable alternative. Pharmacotherapy may also be necessary to augment ERP or decrease symptoms enough to allow for ERP participation in patients with moderate to severe OCD (see Fig. 1).

3. First-line OCD treatment Potential treatments for OCD are generally assessed based on their efficacy in reducing OCD symptoms rather than inducing

Please cite this article as: Borue, X., et al. Biological treatments for obsessive-compulsive and related disorders. Journal of ObsessiveCompulsive and Related Disorders (2015), http://dx.doi.org/10.1016/j.jocrd.2015.03.003i

67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108 109 110 111 112 113 114 115 116 117 118 119 120 121 122 123 124 125 126 127 128 129 130 131 132

X. Borue et al. / Journal of Obsessive-Compulsive and Related Disorders ∎ (∎∎∎∎) ∎∎∎–∎∎∎

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 66

Diagnosis of OCD

Moderate to severe OCD

Mild to moderate OCD

CBT (ERP)

SSRI

No or partial response*

CMI

No response

Partial Response*

No response

2

nd

SSRI

No or partial response*

Augment with CMI

No or partial response*

Augmentation with Memantine. Consider first - line antipsychotic (Risperidone or Aripiprazole) No or partial response* Switch to different first-line antipsychotic, or initiate Memantine. Consider Ondansetron

3

institute for Health and Clinical Excellence analysis of randomized control comparator trials failed to identify significant differences between the various SSRI's and clomipramine either for efficacy or adverse effects (Soomro, 2012; Fineberg, Reghunandanan, Brown, & Pampaloni, 2013). In pediatric patients with OCD, the list of currently FDA approved medications includes clomipramine, fluoxetine, sertraline, and fluvoxamine. Similar to adult studies of OCD, studies looking at pharmacotherapy in pediatric OCD has showed that SSRI's and clomipramine are efficacious for the treatment of OCD. In randomized controlled trials, the SSRI's fluoxetine (Geller et al., 2001), sertraline (March et al., 1998; Pediatric OCD Treatment Study Team, 2004), and fluvoxamine (Riddle et al., 2001) have demonstrated efficacy in treatment efficacy in pediatric OCD. A meta-analysis of RCT demonstrates significant effects in active treatment vs. placebo for OCD, with significant reduction in symptom severity of the medications included, which were fluoxetine, sertraline, paroxetine, fluvoxamine, and clomipramine (Geller et al., 2003). Another meta-analysis showed efficacy for SSRI's, clomipramine, and ERP in the treatment of OCD with ERP showing a slight advantage over medication treatment (Watson & Rees, 2008).

No or partial response* 2nd line agents: 2nd line antipsychotics, anticonvulsants, other glutamatergic agents, 5HT3R antagonists. Combination of augmentation

4. Specific agents

strategies. Re-trial of ERP if it has not been continued.

4.1. Fluvoxamine Treatment refractory: Has failed 2x SSRIs, CMP, 2 augmentation strategies, ERP. Experimental treatments including neurosurgery.

Fig. 1. Treatment algorithm for OCD. Due to the highly favorable risk to benefit ratio and strong evidence of efficacy we recommend ERP (when available) as the first line treatment. In individuals with moderate to severe OCD, this should be combined with an SSRI (Sertraline, Fluoxetine, Fluvoxamine preferred see SSRI section). For individuals with partial response to initial or 2nd trials of SSRI, especially those on Fluvoxamine, consider decreasing the dose and augmenting with Clomipramine (CMI). Depending on the severity and dose dependence of side effects, augmentation with CMI may also be a useful option. A trial of CMI monotherapy is generally recommended for those failing to respond to SSRIs.

remission. Treatment response in most recent clinical trials has been defined as either a 25% or 35% reduction in the Yale-Brown Obsessive-Compulsive Scale (YBOCS). A select few studies also include quality of life measures. The end-point YBOCS score has also been used to sub-stratify patients. A decline in symptoms below a threshold of 16 (the boundary between mild and moderate symptoms) is thought to represent a ‘full response’ to treatment. Treatment responders who continue to have moderate to severe symptoms are generally referred to as ‘partial responders’ (Obsessive-Compulsive Disorder: Contemporary Issues in Treatment, 2000). The YBOCS has faced criticism for its poor sensitivity in detecting subtle yet significant changes in symptoms, such as a decrease in rituals from 5 to 3 h per day (Pallanti & Quercioli, 2006). In spite of its shortcomings, the YBOCS provides a consistent yardstick for measuring treatment outcomes and is likely to remain that way for the time being. In adults, clomipramine, fluoxetine, fluvoxamine, paroxetine and sertraline are approved by the FDA for treatment of OCD. Citalopram and escitalopram are not approved by the FDA for treatment of OCD but are considered to be as efficacious as the other FDA approved serotonin selective inhibitors (SSRI's). When looked at as a group, the pooled data from several Randomized Controlled Trials (RCT) showed the following five SSRI's – Citalopram, fluoxetine, fluvoxamine, sertraline and paroxetine – to be effective for OCD symptoms vs. placebo (Soomro, Altman, Rajagopal, & Oakley Browne, 2008). Participants receiving SSRI's were almost twice as likely to achieve clinical response when compared to subjects receiving placebo. A recent UK National

Several RCT have demonstrated efficacy of fluvoxamine for OCD (Goodman, Price, & Delgado, 1989; Goodman, Kozak, & Liebowitz, 1996; Fineberg, Reghunandanan et al., 2013). In a multicenter RCT, patients receiving fluvoxamine had a 32% improvement in YBOCS scores vs. 21% on placebo. A decrease in YBOCS scores was seen in patients as early as 2 weeks into treatment (Goodman et al., 1989). One meta-analysis found that the relative risk of side effects from active treatment did not differ significantly from placebo (Soomro et al., 2008). Due to its unique status among SSRIs as being approved only for OCD and not for Major Depressive Disorder, Fluvoxamine has a tendency to be viewed as separate or different from other SSRIs. However, there is no evidence that this medication is more efficacious for OCD than other SSRI's. In clinical use, its short half-life is a consideration due to the fact that it requires twice daily dosing with the standard formulation. This can have a negative effect on compliance. The continuous release (CR) formulation may be used on a once daily dosing regimen. Fluvoxamine has a high potential for drug–drug interactions compared with other SSRI's. 4.2. Sertraline The evidence base for sertraline has been mixed, due to numerous underpowered trials, unusually high placebo response rates and low doses utilized (Fineberg, Reghunandanan et al., 2013; FIneberg & Gale, 2005). One study demonstrated that sertraline had a response rate of 41% vs. placebo at 23% with response seen as early as 3 weeks (Kronig et al., 1999; Kronig, Apter, & Asnis et al., 1999). Although the FDA approved maximum for sertraline is 200 mg per day, in our experience much higher doses are required to achieve a clinical effect. Ushijima et al. in 1997 suggested a dose response relationship for sertraline. Ninan et al. (2006) confirmed that increasing sertraline to 400 mg in people who did not respond after 16 weeks at the 200 mg dose led to an improvement in symptoms. Consequently, trial of low-dose sertraline should not be considered a treatment failure. As it is unlikely that a patient would have received high dose sertraline outside of a specialized OCD clinic, this is our agent of choice when we are unable to obtain an accurate history of past medication trials. Of note, sertraline is unique among the SSRI's in that

Please cite this article as: Borue, X., et al. Biological treatments for obsessive-compulsive and related disorders. Journal of ObsessiveCompulsive and Related Disorders (2015), http://dx.doi.org/10.1016/j.jocrd.2015.03.003i

67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108 109 110 111 112 113 114 115 116 117 118 119 120 Q17 121 122 123 124 125 126 127 128 129 130 131 132

X. Borue et al. / Journal of Obsessive-Compulsive and Related Disorders ∎ (∎∎∎∎) ∎∎∎–∎∎∎

4

1 2 3 4 5 6 7 8 9 10 Q3 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 Q4 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 66

absorption is improved when taken with food. Due to the high incidence of gastrointestinal side effects with this agent, administration with meals is preferred to reduce this potential side effect as well. 4.3. Fluoxetine As with sertraline, there appears to be a dose-response relationship for Fluoxetine and higher doses tend to be more effective (Liebowitz et al., 2002; Fineberg & Gale, 2005). Fluoxetine has the longest half life of the SSRI's of up to 2–4 days. The active metabolite, norfluoxetine, has a half life of seven to nine days. This results in fluoxetine having the least amount of discontinuation syndrome symptoms. However, this long half life can also be responsible for delayed appearance of side effects and clinical response compared with other SSRI's. 4.4. Paroxetine Although clearly effective in the treatment of OCD (Zohar & Judge, 1996; Fineberg & Gale, 2005; Fineberg, Reghunandanan et al., 2013), paroxetine has a short half-life and produces severe symptoms upon discontinuation. Discontinuation symptoms can sometimes manifest during unplanned delays in dosing. Paroxetine can also produce problematic drug–drug interactions due to it being a strong inhibitor of CYP2D6. For these reasons we recommend reserving this agent for patients not responding to other SRIs who reside in a controlled environment or are reliably compliant with treatment. Due to the severity of discontinuation symptoms, practitioners should consider cross-titrating patients wishing to discontinue paroxetine to an alternate agent before initiating the taper (Schatzberg et al., 2006). 4.5. Citalopram and escitalopram Though currently not approved by the FDA for OCD both citalopram and escitalopram are likely comparable to the other SSRI's. Again, higher doses tend to be more efficacious (Montgomery, Kasper, & Stein, 2001; Stein, Andersen, Tonnoir, & Fineberg, 2007; Dougherty et al., 2009). Unfortunately, citalopram's use is currently limited by a FDA black box warning regarding prolongation of QTc and potential risk of torsades de pointes at doses above 40 mg. In patients over the age of 60, it is not recommended to be used at doses over 20 mg. Given the lack of a black box warning, escitalopram is typically preferred to citalopram. A benefit of these agents is the decreased risk of drug–drug interactions and improved tolerability in some patients. 4.6. Clomipramine Clomipramine is a more specific serotonin reuptake inhibitor than other tricyclic antidepressants and is the only pharmaceutical from this class with a clear anti-obsessional effect (Fineberg, Reghunandanan et al., 2013). It has a very solid evidence base supporting its efficacy in adult OCD, including several Double Blind Randomized Controlled Trials (DB-RCT) (Fineberg, Reghunandanan et al., 2013). Clomipramine has also been shown to be efficacious in both presence and absence of depression (Fineberg & Gale, 2005). Likewise, Clomipramine was the first medication to be studied in pediatric OCD. Two double blind placebo-controlled crossover studies support its efficacy (Flament et al., 1985; Leonard et al., 1989). Clinical experience has shown clomipramine to have a range of fairly predictable and specific side effects resulting from its anticholinergic, antihistaminergic and antiadrenergic properties. Most notable are dry mouth, urinary retention, constipation, sedation, weight gain and orthostatic hypotension. Clomipramine also has

the potential for cardio toxicity through prolongation of the QT interval and therefore cardiac risks of patients should be taken into account. Elevated liver transaminases and increased seizure risk in doses over 250 mg are also possible side effects. Given their equal efficacy, the choice of SRI should be based on patient and family members responses to previous medication trials in combination with mild differences in the side effects profile. Some patients prefer a trial of clomipramine first before trying SSRIs, which may be perceived to have less predictable side effects than clomipramine.

5. Managing side effects of SSRI Side effects are one of the most common reasons for treatment failures stemming from noncompliance and inability to tolerate adequate doses. Commonly encountered adverse outcomes in OCD treatment include amotivation/apathy, weight gain, and decreased sexual wellbeing. Anxious patients tend to experience higher levels of side effects during pharmacotherapy and anxiety frequently accompanies obsessions. An added challenge in this patient population is the presence of somatically based obsessions, which can increase concerns about medication side effects. Given their extensive use in OCD, this section is devoted to a detailed description of adverse reactions to SSRIs ranging from time limited side effects to life threatening adverse reactions. Additional side effects from augmentation agents are addressed in subsequent sections. 5.1. Common side effects Commonly reported effects include excessive yawning, headache, dry mouth, dizziness, constipation, vivid dreams/nightmares and tremors. Tolerance frequently develops and initial management of these should be conservative but may include temporarily decreasing SRI dose. Headaches and constipation can frequently be managed with over the counter pain killers and stool softeners respectively. 5.2. Gastrointestinal effects GI side effects are frequently encountered when initiating SSRI therapy and are usually related to the serotonin receptors located in the GI tract. Common symptoms include nausea, vomiting, diarrhea, stomach pain (Murphy, Segarra, Storch, & Goodman, 2008). In many patients these are transient symptoms that are usually self remitting if patients are maintained at the same dose for a few weeks. Starting at lower doses and recommending patients to take medications with meals can also be helpful. 5.3. Excessive sweating Relatively uncommon, excessive sweating occurs in 7–11% of patients taking SSRI's (Garber and Gregory, 1997). Many people with this side effect find that the benefit of treatment far outweighs the negative effects of this. Conservative management is therefore encouraged, such as suggesting having a change of clothes handy in the middle of the night. Unlike many other adverse effects, this does not improve over time. In the small number of cases where this is severe or distressing enough to the patient, lowering the dose or switching SSRI's are options. Benztropine has been suggested as potential treatment (Garber and Gregory, 1997) as has cyproheptadine (Ashton & Weinstein, 2002) and clonidine Feder, 1995). However, these suggestions have only been published as case reports and no controlled studies are available. If conservative management is not sufficient, we

Please cite this article as: Borue, X., et al. Biological treatments for obsessive-compulsive and related disorders. Journal of ObsessiveCompulsive and Related Disorders (2015), http://dx.doi.org/10.1016/j.jocrd.2015.03.003i

67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108 109 110 111 112 113 114 115 116 117 118 119 Q5120 121 122 123 124 125 126 127 128 129 130 131 132

X. Borue et al. / Journal of Obsessive-Compulsive and Related Disorders ∎ (∎∎∎∎) ∎∎∎–∎∎∎

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 Q6 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 Q7 62 63 64 Q8 65 66

5

recommend benztropine as the first choice of medication for treatment due to its relative safety and ease of use.

it can often be managed with change in lifestyle including diet and exercise.

5.4. Akathesia

5.8. Sexual side effects

Agitation and akathesia are frequently seen early in treatment (usually in the first few weeks) and during dose increases. The symptoms can be similar to akathesia seen in anti-psychotic use; motor restlessness and physical sense of anxiety. This can be managed with lowering the dose for a short time or by switching SSRI's. In pediatric patients, agitation may manifest as behavioral activation which can be seen as an increase in impulsivity, talkativeness, and/or hyperactivity (Murphy et al., 2008). Because of the possibility of an increase in suicidal behavior the FDA issued warnings concerning anti-depressant use for pediatric patients, and for adult patients under the age of 25.

Few studies have examined the rate of sexual dysfunction in SSRI use. Many of the patients in these studies are also diagnosed with major depression which in itself can be a contributing factor to sexual dysfunction. Regardless, rates of 30–43% have been previously reported (Clayton et al., 2002). It is therefore imperative that clinicians screen for this side effect. The most common sexual side effects reported are loss of libido, anorgasmia, and loss of physical arousal: erectile dysfunction in males and lack of lubrication in females. Often anorgasmia is the reason for erectile dysfunction in men and hence a good history is crucial. There is a lack of controlled studies on treatment for SSRI induced sexual function. Reports have highlighted the use of buproprion to improve sexual function at a dose of 300 mg/day (Clayton et al., 2004), while another demonstrated no efficacy at 150 mg/day (DeBattista, Solvason, Poirier, Kendrick, & Loraas, 2005). Busprione has also been reported to helpful for SSRI induced sexual side effects (Rosen, Lane, & Menza, 1999) and clinically is a safe treatment option. The dosage recommend is between 20 and 60 mg daily. Other medications have been reported to have efficacy for sexual side effects including nefazodone, cyproheptadine, mirtazapine, amphetamines and some herbal compounds (Schweitzer et al., 2009). The potential usage of these various agents is dependent on patients' choice after informed consent and their appropriateness for these drugs. Obviously, a good sexual history is vital to recommend the best option for any individual patient. We recommend either decreasing SSRI's to the lowest effective dose or waiting to see if symptoms remit spontaneously. We have seen spontaneous remission of sexual side effects even after many months of treatment. One reasonable option with some patients is the use of a drug holiday (an exception is fluoxetine as drug holidays are ineffective here due to its long half). The method used in our OCD specialty clinic usually involves patient skipping their morning dose both prior to and on the day of planned sexual activity. After sexual intercourse, they can take the dose skipped that morning and then resume their normal dosing schedule the following day. As a result, this schedule results in only one missed dose. We do not recommend more than one drug holiday per week for our patients. We have rarely encountered SSRI discontinuation when this method is used although we generally do not recommend it to those on paroxetine.

5.5. Movement disorders Extrapyramidal symptoms can be seen in antidepressant use and are known side effects of both SSRI's and TCA's (Arya, 1994; Vandel et al., 1997). This may include myoclonus which is defined as sudden, abrupt, brief, shock-like involuntary movements caused by muscular contractions. Occasionally, patients also complain of jaw tightness or locking of the jaw particularly during sleep. These are rare side effects but something of which the clinician needs to be aware. They can be usually managed with lowering the medication or by switching the drug. Often the movements remit spontaneously (Vandel et al., 1997). 5.6. Apathy Frontal lobe amotivational syndrome is characterized by apathy, affective blunting and memory issues (Murphy et al., 2008). It can be severe enough that at times patients are not able to relate it to the clinician; instead family members will voice the complaint. Commonly seen in SSRI therapy using higher doses (Murphy et al., 2008) this is an SSRI side effect that does not appear to improve as the patient continues the medication over time. Therefore active management is a necessity. While depression should be considered in the differential diagnosis, generally a low mood is not present in this particular patient group which can help distinguish between the two phenomena. Patients with frontal lobe amotivational syndrome generally report lacking emotions and feel neither happy nor sad. Sedation can also be present with this constellation of symptoms. (Of note, excessive yawning is a possible SSRI side effect. Some patients may interpret this as fatigue and report it as such. A careful history can help distinguish between these two different phenomena.) The recommendations for intervention include lowering the offending agent or initiating a switch to another medication (Murphy et al., 2008). Clinically in our OCD specialty practice we have found modafinil to be helpful in reversing this syndrome.

5.9. Hyponatremia Hyponatremia is manifested by muscle cramps, fatigue, confusion and in severe cases seizures. Risk factors include advanced age, female gender, or concomitant use of diuretics (Moret et al., 2009). It is relatively rare with incidence reported to 0.5% per year. It usually occurs in first few weeks of treatment initiation or with a dose change.

5.7. Weight gain 5.10. Gastrointestinal bleeding All of the SSRI's may lead to weight gain over time and many patients report this weight gain in the absence of change in diet or lifestyle. While paroxetine in particular has been noted to cause weight gain (Par and Patkar, 2007) this is a potential side effect of all SSRI's. This side effect is often not seen until the patient has been given extended treatment, and therefore may not be noticed until six months after initiation (Ferguson, 2001). With paroxetine usage the weight gain may be noticed early on, as well as in the long term. While this side effect can be quite distressing to patient,

Increased risk of GI bleeding is a reported side effect of SSRI's, likely due to their effect on platelet serotonin. This risk is increased with NSAIDS or other anti-platelet agents. Patients who concomitantly use acid suppressing drugs have lower risks of bleeding in this setting, though further studies will be needed to fully examine this issue (Jiang et al., 2014). Clinicians should be aware of this potential side effect and mitigate their pharmacological choices accordingly in high risk patients.

Please cite this article as: Borue, X., et al. Biological treatments for obsessive-compulsive and related disorders. Journal of ObsessiveCompulsive and Related Disorders (2015), http://dx.doi.org/10.1016/j.jocrd.2015.03.003i

67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 Q9 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108 109 110 111 112 113 114 115 116 117 118 Q10 119 120 121 122 123 124 125 126 127 128 129 130 131 132

X. Borue et al. / Journal of Obsessive-Compulsive and Related Disorders ∎ (∎∎∎∎) ∎∎∎–∎∎∎

6

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28Q11 29 30 31 32 33 34 35 36 37 38 39 40Q12 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 66

Table 1 Dosage guidelines for SRI treatment of OCD in adults. Adapted from the APA treatment guidelines (2007). Occasionally Usual Starting and prescribed maximum incremental dosage maximum dose (mg/day) dose (mg/day) (mg/day) Citalopram Clomipraminea Escitalopram Fluoxetine Fluvoxamine Paroxetine Sertraline

20 25 10 20 50 20 50

80b 250 40 80 300 60 200

120b — 60 120 450 100 400

a Combined plasma levels of clomipramine plus desmethylclomipramine 12 h after the dose should be kept below 500 ng/ml to minimize risk of seizures and cardiac conduction delay. b Due to FDA black box warnings, doses about 40 mg are not recommended for adult patients, and doses about 20 mg are not recommended for geriatric patients.

Table 2 Dosage guidelines for SRI treatment of OCD in pediatric populations. Adapted from Gilbert (2011). Medication

Starting dose (mg/day)

Dosage range (mg/day)

Citalopram Escitalopram Fluoxetineb Fluvoxamineb Paroxetineb Sertralineb Clomipramineb

5–10 5–10 5–10 12.5–50 5–10 12.5–25 12.5–25

10–60a 10–40 10–80 50–300 10–60 50–250 50–200

a FDA currently recommends dosage no higher than 40 mg/day due to cardiac risks. b FDA approved medications for treatment of children and adolescents with OCD.

Abrupt discontinuation of SSRI's may lead to discontinuation syndrome, which can range from mild to severe in symptoms. While the symptoms can cause significant distress and discomfort, they do not require aggressive medical intervention. Symptoms include dizziness, light-headedness, insomnia, fatigue, anxiety, headache, nausea and sensory disturbance described as electric sensation in the head or limbs (Zajecka et al., 1997). Patients often refer to this last symptom colloquially as ‘brain zaps’. These are more likely to occur with medications with short half-lives such as paroxetine, and less likely to occur with fluoxetine which has a longer half-life. They are more likely to occur in female patients (Schatzberg et al., 2006). In the acute phase, symptoms can be managed by restarting the SSRI at the previous dose which most patients find quite effective. When discontinuing treatment, slow taper is generally recommended, though some patients will have difficulty with even very slow tapers and may need an extended taper tail when low doses are reached.

months. Therefore, a therapeutic trial of an anti-obsessional agent should be not considered to be complete until the patient has been on the maximum dose recommended for OCD (see below) for at least 3 months. In select individuals with a partial response to treatment, in may be prudent to prolong the initial trial beyond 12 weeks (Albert, Aguglia, Bramante, Bogetto, & Maina, 2013). Dosing of medications is based on patient and clinician preference, as well as side effect tolerability. General guidelines are provided for adults in Table 1 and adolescents in Table 2. Given dose response data, there are grounds to increase the dose to the maximum recommended amount upon initiation of medications with tolerability taken into account. Bogetto, Albert, and Maina (2002) showed that rapid dose titration of sertraline to 150 mg over 5 days was favorable compared with the 15 day titration when both were looked at 4–6 weeks, but group differences disappeared later in treatment. Slower dose titration does eliminate side effects of nausea and agitation and dose related side effects of headaches can be better managed with slower titration (Fineberg & Gale, 2005). Our practice in a specialty OCD clinic indicates that a reasonable course of action in drug naive patients is to try moderate doses initially as opposed to an immediate titration to the highest OCD recommended dosages. If there is a noticeable clinical response within the first 3–5 weeks of treatment, it is worth maintaining the patient at those moderate doses until they have achieved the full 12–16 week trial period. This can allow patients to minimize potential side effects related to dose. Further increases to higher doses may be considered after that time if adequate improvement in symptoms has not been obtained. Patients who have already had a failed medication trial of a different SSRI at a maximum recommended dose are unlikely to respond adequately to low or moderate doses of a different SSRI. Therefore, in those patients who are treatment resistant to one SSRI we recommend that titration of any subsequent SSRIs occur until the highest possible dose tolerated is achieved.

6. Implementing and dosing of meds

7. Discontinuation vs. maintenance of SRIs

In general it has been recommended to use higher doses of SSRI's in OCD treatment than in depression and anxiety (Fineberg & Gale, 2005). As opposed to mood disorders, where treatment response can be seen within a month of starting treatment in responsive patients, symptom improvements in OCD are frequently not observed until the patient has been on therapeutic SSRI doses for 12 weeks. Consistent with this, high rates of “placebo response” are observed in the placebo arms of Randomized Controlled Trials (RCT) of SRI augmentation employing initial treatment durations shorter than 12 weeks. Additionally, some individuals who appear to have poor response to treatment at 12 weeks have been found to respond when given several more

There have been a few studies conducted in which treatment responders have been followed for up to 2 years. Tollefson, Rampey, and Potvin (1994) showed that patients on fluoxetine over the full range of doses continued to improve, with greater improvement with a 60 mg dose. Another study demonstrated that patients maintained improvements as long as they remained on sertraline and even noted improvements in the second year of treatment (Greist et al., 1995). Few studies have looked at lowering the dose in long term treatment; as a result and most providers continue with maintenance treatment at the initial effective dose. Several studies have shown symptom relapse with discontinuation of medication, usually within a few weeks of stopping medication.

5.11. Serotonin Syndrome Serotonin syndrome is a rare but serious medical condition, which is usually associated with combination of drugs that can increase serotonin levels, though it may occur with a single agent. Symptoms include mental status changes, automatic instability (such as tachycardia, hypertension and hyperthermia), and neuromuscular abnormalities such as myoclonus, hyperreflexia, hypertonicity and rigidity (Boyer and Shannon, 2005). Treatment mainly involves supportive care up to and including ICU level of care depending on the severity and nature of the symptoms. 5.12. Discontinuation syndrome

Please cite this article as: Borue, X., et al. Biological treatments for obsessive-compulsive and related disorders. Journal of ObsessiveCompulsive and Related Disorders (2015), http://dx.doi.org/10.1016/j.jocrd.2015.03.003i

67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108 109 110 111 112 113 114 115 116 117 118 119 120 121 122 123 124 125 126 127 128 Q13 129 130 131 132

X. Borue et al. / Journal of Obsessive-Compulsive and Related Disorders ∎ (∎∎∎∎) ∎∎∎–∎∎∎

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17Q14 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57Q18 58 59 60 61 62 63 64 65 66

One double blind study looked at fluoxetine discontinuation after a year of treatment. Patients in the discontinuation group suffered a 38% relapse rate over 12 months, while the patients remaining on the 60 mg dose showed a 17.5% relapse, although the difference failed to reach statistical significance (Romano, Goodman, Tamura, & Gonzales, 2001). Another study examined relapse on sertraline vs. placebo, with the placebo group showing a numerical although again, not statistically significant higher rate of relapse (Koran, Hackett, & Rubin, 2002). Another study observed that treatment responders had a better outcome at 6 months if they remained on active treatment with paroxetine and had a lower relapse rate than patients on placebo (Hollander et al., 2003). When escitalopram responders were studied over a 24 week relapse prevention phase, only 23% of treatment group relapsed compared to 52% of patients in the placebo group. Adverse effects were not different in either group indicating the tolerability of the medication (Fineberg et al., 2007). In addition, it was determined that relapse was correlated with reduced function (Fineberg, Reghunandanan et al., 2013). While it can be difficult to interpret and compare these studies due to their differing definitions of relapse, and due to what is often only numerical differences in placebo vs. active maintenance groups, our recommendation is to offer patients on-going medication therapy to provide protection against relapse. This is especially emphasized with patients who are tolerating their active treatment well, as the long term risk of maintaining medications is minimal. There is minimal risk in continuous and chronic use of high dose SSRI treatment. On-going medication management should be strongly considered at the same dose at which that the person initially responded. While the recommended continuation is for 1–2 years in responders (Fineberg & Gale, 2005) continuing with active medication treatment beyond that time should be strongly considered. Any history of prior relapse strengthens the recommendation to continue active treatment. Providing patients with this information so that they may make an informed decision about whether or not to remain on medications is the responsibility of the provider. However, if a patient requests that medications be discontinued, the dosage taper should be done very slowly as to minimize the risk of relapse. Our practice is to taper medications over a period of 4–6 months. Patients should be educated to look for early signs of relapse, and at that in the event of relapse, reinstatement of pharmacotherapy may allow for symptoms remission, though the reiteration is not guaranteed at the same level (Fineberg & Gale, 2005). During any attempt to taper OCD medications, active participation in appropriate behavior therapy should be strongly encouraged.

8. Treatment resistance and augmentation OCD is typically considered to be a chronic illness with early intermittent periods of illness frequently giving way to unremitting symptoms later in life. The measured effect of modern treatment on the clinical course of OCD appears to vary widely, depending on the demographics of the population and duration of follow up. Estimates of remission in adults have varied from
20% in chronically and severely ill populations (Bloch, Panza, Grant, Pittenger, & Leckman, 2013; Bloch et al., 2013; Eisen et al., 2013) to
65% in patients with moderate OCD of shorter pre-treatment duration (Cherian, Math, Kandavel, & Reddy, 2014). Remission rates in pediatric OCD have been somewhat more consistent, with
30–50% achieving remission on long-term follow up (Wagner, Cook, Chung, & Messig, 2003; Bloch et al., 2009; Mancebo et al., 2014). Due to concerns that the clinical samples followed in most OCD studies may bias the results towards more unfavorable outcomes, a large community-based study was undertaken in

7

Zurich, Switzerland. A broad population screen of 19–20 year olds identified 394 individuals with OCD, who were followed for the 30-year duration of the study, with a 57% overall retention rate. Over the course of the study
2/3 of participants had achieved remission (Fineberg, Hengartner et al., 2013). Although recent studies suggest a more favorable long-term outcome than previously hypothesized, treatment failure remains a considerable problem. Up to 25% of adults fail to experience any improvement from the initial SRI trial and an estimated 40–50% will fail 2þ SRIs (Bloch et al., 2006; Pallanti & Quercioli, 2006). Similar rates (30–40%) are seen for pediatric patients (Storch et al., 2008b). No clear relationship between quality of OCD symptoms and prognosis has been identified. Factors more consistently associated with a poorer prognosis include longer duration and greater severity of OCD symptoms (Eisen et al., 2013), poor response to initial treatment, and the presence of a comorbid disorders such as major depressive disorder and hoarding (Marcks, Weisberg, Dyck, & Keller, 2011; Fineberg, Reghunandanan et al., 2013; Bloch et al., 2014). The terminology applied to patients failing to respond to treatment has been diverse, including treatment failure, treatment refractory, non-response, treatment resistant. There has been no consensus or standardized criteria for defining treatment resistance in OCD, in part due to a lack of consensus in defining treatment response. It has been proposed that ‘treatment resistant’ and ‘treatment refractory’ should represent two separate states with different criteria: ‘Treatment resistance’ can be defined as a lack of adequate response (o25% reduction in YBOCS) to two trials of SRIs. The term ‘treatment refractory’ should be reserved for patients who have failed clomipramine and at least two additional SRIs, augmentation with at least two first-line agents, and treatment with ERP while on a therapeutic dose of an SRI (Husted & Shapira, 2004). Here, failure would also include individuals whose YBOCS scores continued to fall into the severe range (424 total) even if they did improve from baseline. This much higher bar has appropriately been used in the selection of patients for surgical trials. Some caveats must be observed before labeling a patient as treatment resistant or refractory. First, the clinician must verify that OCD diagnosis is valid. Second, an adequate trial of a first line treatment is essential. This means at least 12 weeks at a moderate to high dose of SRI. Unlike depression, treatment response in OCD tends to be gradual and slow to build. Very high rates of symptom improvement are observed in the placebo arms of Randomized Controlled Trials (RCT) employing initial treatment durations shorter than 12 weeks. Additionally, some individuals who appear to have poor response to treatment have been found to respond when given several more months. In select individuals with a partial response to treatment, it may be prudent to prolong the initial trial beyond 12 weeks (Albert et al., 2013). Finally, accurate assessment and treatment of psychiatric comorbidities is critical, as this can dramatically alter response to OCD-specific treatments. The first most logical step in treating individuals who fail an SRI is switching to an alternate SRI, which has been discussed. What to do after an individual fails to adequately respond to their second SRI trial is somewhat less clear and depends on patient-specific variables including availability of ERP, comorbid conditions, presence of partial response to the current agent, side effects profiles (see Fig. 1: algorithm for managing treatment resistant and refractory patients). Clomipramine, once the mainstay of OCD treatment, has been underutilized since the introduction of SSRIs due to concerns about side effects and potential lethality (Arumugham and Reddy, 2014). We argue in favor of more frequent utilization of this TCA in monotherapy and perhaps more importantly as an augmenting agent. Most available treatment algorithms suggest a trial of Clomipramine after a patient

Please cite this article as: Borue, X., et al. Biological treatments for obsessive-compulsive and related disorders. Journal of ObsessiveCompulsive and Related Disorders (2015), http://dx.doi.org/10.1016/j.jocrd.2015.03.003i

67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108 109 110 111 112 113 114 115 116 117 118 119 120 121 122 123 124 125 126 127 128 129 130 131 132

8

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 66

X. Borue et al. / Journal of Obsessive-Compulsive and Related Disorders ∎ (∎∎∎∎) ∎∎∎–∎∎∎

has failed to respond to two SSRIs. Due to the favorable interactions between it and SSRIs, attempting low dose Clomipramine augmentation prior to a trial of Clomipramine monotherapy is recommended. Clomipramine augmentation may be especially helpful in patients who are unable to tolerate high dose SSRIs due to side effects. Low dose Clomipramine-moderate-dose SRI combinations have been shown to have similar efficacy to high dose SRI regimens but frequently with more tolerable side effects (Andrade, 2013). An additional favorable interaction exists between Clomipramine and fluvoxamine or fluoxetine due to their inhibition of clomipramine metabolism (Vandel et al., 1992, 1995; Conus, Bondolfi, Eap, Macciardi, & Baumann, 1996). This makes augmentation in individuals already on these agents an even more attractive option. The addition of clomipramine to fluvoxamine in particular will increase the clomipramine/desmethylclomipramine ratio to an optimal range of 4:1 or greater. If the total clomipramine level is maintained at 450 ng/ml or less, this strategy is well tolerated, and allows the possibility of effective treatment in treatment resistant patients (Szegedi, Wetzel, Leal, Hartter, & Hiemke, 1996). An alternative strategy, best reserved for individuals with partial response to SRI treatment is augmentation with antipsychotics. Discussed in greater detail below, this option may be particularly useful for individuals with comorbid tic or psychotic disorders. Antipsychotic augmentation may also be undertaken in the event of Clomipramine failure. Although backed by a much smaller evidence base, the significantly more favorable side effects profile of the glutamatergic agent, memantine, and the 5HT-3R antagonist, ondansetron, make these attractive alternatives in select patient populations. Further down the algorithm, we suggest agents with an even smaller evidence basis and further still, in the realm of treatment refractory individuals there is the potential for surgical interventions

9. Augmentation with antipsychotics Initially tried due to their effectiveness in Tourette's syndrome, antipsychotics are currently the most frequently employed augmentation agents in treatment resistant OCD (Bloch, Panza et al., 2013; Bloch et al., 2013; Van Ameringen et al., 2014; Van Ameringen, Patterson, & Simpson 2014). There is a growing evidence base supporting their efficacy, especially for the second-generation antipsychotics, which, as a class, appear to benefit approximately 1/3 of adults with treatment resistant OCD (Dold, Aigner, Lanzenberger, & Kasper, 2013). The number needed to treat has been estimated to be
4.5 (Bloch et al., 2006) which is slightly more favorable than that seen for SSRI treatment of major depressive disorder (Gibbons, Hur, Brown, Davis, & Mann, 2012). Data from adolescents is less robust but results have been generally consistent with trends observed in adults. The clinical utility of antipsychotics in OCD may be tied to their effects at the D2 and D3 dopaminergic receptors as agents with higher affinity for these receptors appear to be more effective (Ducasse et al., 2014). There may also be synergistic antagonism of the serotonin receptor subtypes 5-HT2a, 5-HT2c, 5-HT 1a, 5-HT 1d, and 5-HT 7. Specific agents are addressed individually in the subsections that follow. Improvement of symptoms in responders is generally seen within the first 4–6 weeks of treatment (Bloch et al., 2006) and a different treatment strategy should be considered in those failing to respond by week 8. Once initiated, augmentation with antipsychotics should probably be continued indefinitely in treatment responders, as the vast majority will relapse within 8 weeks of treatment discontinuation (Albert et al., 2013). Concerns about the long term efficacy of antipsychotic augmentation were raised after a prospective cohort study showed that patients receiving antipsychotic augmentation, who at baseline had greater YBOCS scores than those treated with SRIs only (29.3 vs.25.8), continued

to have significantly higher YBOCS scores after 1 year of treatment (19.3 vs.13.7) (Matsunaga et al., 2009). The validity of these concerns is difficult to explore due to the fact that patients receiving risperidone, olanzapine, and quetiapine were lumped together for analysis. The benefits of augmentation must be weighed against the common and significant side effects burden associated with these agents, which will be addressed in greater detail at the end of this section. It has been difficult to predict which individuals would be more likely to respond to antipsychotic augmentation. In adults, comorbid tic disorders appear be positively correlated with improved treatment response. This relationship has been more prominent in studies using antipsychotics with high D2/D3 affinity at moderate to high doses (Bloch et al., 2006; Carey et al., 2012). Adolescents with comorbid tic disorders may receive similar benefits at lower doses (Masi, Pfanner, & Brovedani, 2013). Antipsychotic augmentation in these patients would have the added benefit of improving their tics (Budman, 2014). Data on specific characteristics of OCD, neuroimaging findings, as well as other comorbid disorders have been highly mixed and mostly inconclusive (Buchsbaum et al., 2006; Karadağ et al., 2013; Arumugham & Reddy, 2014). A recent meta analysis suggests that hoarding comorbid with OCD significantly decreases treatment response rates (Bloch et al., 2014). As with SRIs, insight into symptoms and strength of initial response are associated with increased rates of sustained treatment response (Hollander, Baldini Rossi, Sood, & Pallanti, 2003a). 9.1. Risperidone Risperidone has a well-established evidence base supporting its safety and efficacy in OCD and tic disorders. It is considered by many to be the drug of choice for SRI augmentation. For adults, numerous case reports/series show favorable outcomes of 0.5– 3 mg/day risperidone augmentation (McDougle et al., 1995a, 1995b; Kawahara, Ueda, & Mitsuyama, 2000; Arias Horcajadas et al., 2006; Yoshimura, Kaneko, Shinkai, & Nakamura, 2006). After a successful open label trial (Pfanner et al., 2000) came 3 DoubleBlind Randomized Controlled Trials (DB-RCT) with mean daily doses of 2.2 mg, 2.25 mg, 0.5 mg respectively, all supporting the efficacy of risperidone (McDougle, Epperson, Pelton, Wasylink, & Price, 2000; Hollander et al., 2003a; Erzegovesi, Guglielmo, Siliprandi, & Bellodi, 2005). Taken in combination via metaanalysis, approximately 50% of the 72 total patients experienced treatment response (Dold et al., 2013; Ducasse et al., 2014). One of the DB-RCT also showed improvement in comorbid mood and anxiety symptoms as measured by the HAM-D (Li et al., 2005). Curiously, the response rate for risperidone treatment in a recent clinical trial comparing it to ERP was significantly lower than that seen in previous studies (Simpson et al., 2013). The reason for this is unclear. Studies of risperidone augmentation in adolescents remain limited to case studies and series (Fitzgerald, Stewart, Tawile, & Rosenberg, 1999; Thomsen, 2004). In a select subset of patients, risperidone can have the paradoxical effect of exacerbating obsessions. It has also been shown to induce de-novo obsessive compulsive symptoms (OCS) in individuals with schizophrenia (Diler, Yolga, Avci, & Scahill, 2003; Levy, Margolese, Sultan, & Chouinard, 2003; Mahendran, Liew, & Subramaniam, 2007). No consistent variable has helped identify patients at risk of paradoxical reaction although some hypothesize that the effect may be dose dependent, with higher doses being less likely to induce OCS (Ramasubbu, 2002). 9.2. Aripiprazole Although currently less solid than for risperidone, the evidence basis for the efficacy of aripiprazole augmentation is steadily

Please cite this article as: Borue, X., et al. Biological treatments for obsessive-compulsive and related disorders. Journal of ObsessiveCompulsive and Related Disorders (2015), http://dx.doi.org/10.1016/j.jocrd.2015.03.003i

67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 Q19 101 102 103 104 105 106 107 108 109 110 111 112 113 114 115 116 117 118 119 120 121 122 123 124 125 126 127 128 129 130 131 132

X. Borue et al. / Journal of Obsessive-Compulsive and Related Disorders ∎ (∎∎∎∎) ∎∎∎–∎∎∎

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 66

growing. Like risperidone, aripiprazole has been found to be effective in reducing tic severity and co-occurring OCS in adults and adolescents with tic disorders, both as monotherapy (Murphy et al., 2009) and as an augmentation agent (Da Rocha & Correa, 2007; Winter, Heinz, Kupsch, & Ströhle, 2008; Lai, 2009). In adults with OCD, numerous case reports and series describe successful aripiprazole augmentation of SRIs (Connor, Payne, Gadde, Zhang, & Davidson, 2005; Da Rocha & Correa, 2007; Friedman, Abdallah, Oumaya, Rouillon, & Guelfi, 2007; Fornaro, Gabrielli, Mattei, Vinciguerra, & Fornaro, 2008; Sarkar, Klein, & Krüger, 2008; Uguz, 2010; Matsunaga, Hayashida, Maebayashi, Mito, & Kiriike, 2011; Higuma et al., 2012; Hou & Lai, 2014). Similarly, in adolescents, there have been several case reports (Storch, Lehmkuhl, Geffken, Touchton, & Murphy, 2008a; Oztürk & Coskun, 2009) and a case series of 39 patients (Masi, Pfanner, Millepiedi, & Berloffa, 2010). Building on three promising open label trials (Pessina, Albert, Bogetto, & Maina, 2009; Ak, Bulut, Bozkurt, & Ozsahin, 2011; Delle Chiaie, Scarciglia, Pasquini, Caredda, & Biondi, 2011) are two recent DB-RCTs of aripiprazole augmentation in treatment resistant OCD (Muscatello et al., 2011; Sayyah, Sayyah, Boostani, Ghaffari, & Hoseini, 2012). Treatment duration for both RCT was longer than that typically seen in other RCT of antipsychotic augmentation at 16 and 12 weeks respectively. Perhaps in part due to the long duration of the studies, placebo effect was quite small. 68.7% of the 16 patients receiving 15 mg per day aripiprazole for 16 weeks responded to treatment. Response to a lower dose, 10 mg per day for 12 weeks was smaller at 53% (n ¼ 17 patients) but still quite favorable and on par with that seen with risperidone augmentation. Furthermore, there was a trend towards decreased rates of sexual dysfunction in the treatment arm. In a small single blind head to head study of 3 mg/day of risperidone vs.15 mg/day aripiprazole, significantly more patients receiving risperidone achieved treatment response ( 435% reduction in YBOCS). Response rates were high for both agents, 72% and 50% respectively and it is worth noting that the response to risperidone in this study was considerably higher than the
50% rate observed in previous DB-RCT (Selvi et al., 2011). A separate prospective cohort study of adolescents with tic disorders randomly assigned to risperidone or aripiprazole augmentation found no significant differences in response rates between the two agents (Masi et al., 2013). Although additional, larger head to head trials are necessary to better compare the two agents, both appear to be quite effective. Comorbid OCD and OCS occur in 13.6% and 30.3% of patients with schizophrenia respectively (Swets et al., 2014). The extensive use of antipsychotics in this population has provided an excellent additional resource for evaluating their efficacy. A recent yearlong longitudinal study of a large cohort of antipsychotic-treated patients suggests a protective effect of aripiprazole. The level of OCS in those receiving clozapine or olanzapine was found to be significantly higher at baseline and steadily increased over the year-long duration of the study to
12 total on the YBOCS. Conversely, the already low level of OCS in those receiving aripiprazole or amisulpride further decreased to
1, with no new onset OCS noted (Schirmbeck & Zink, 2013). Consistent with this, a 6 weeks-long open label study, 6 of the 7 patients converted to aripiprazole monotherapy showed greater than 35% reductions in YBOCS scores (Glick, Poyurovsky, Ivanova, & Koran, 2008). Aripiprazole also appears to decrease OCS when added as an adjunct to other treatments and several case series have shown reductions in OCS when aripiprazole was added to olanzapine or clozapine (Englisch et al., 2009; Schönfelder, Schirmbeck, Waltereit, Englisch, & Zink, 2011; Villari, Frieri, & Fagiolini, 2011; Eryılmaz, Hızlı Sayar, Ozten, Gögcegöz Gül, & Karamustafalıoğlu, 2013).

9

Risperidone has typically been the antipsychotic of choice for augmentation of SRIs in treatment resistant OCD, however, in light of an accruing body of evidence, aripiprazole appears to be a rational first-line alternative for both adolescents and adults. Due to its adverse effects profile, aripiprazole may be preferable in select populations (see section on side effects). 9.3. Olanzapine Numerous open-label studies support the efficacy of olanzapine augmentation of SRIs in treatment-resistant patients (Bogetto, Bellino, Vaschetto, & Ziero, 2000; Koran, Ringold, & Elliott, 2000; Francobandiera, 2001; D'Amico et al., 2003; Marazziti et al., 2005). Two DB-RCT have been conducted in patients with treatment resistant OCD. Bystritsky (Bystritsky et al., 2004) noted a treatment response (4 35% reduction in YBOCA scores) in 46% of patients receiving moderate dose (mean dose: 11 mg, max: 20 mg) olanzapine as compared to 0% of those receiving placebo. Shapira (Shapira et al., 2004) noted similar rates of response in patients receiving low dose (mean dose: 6 mg, max: 10 mg) augmentation but the group failed to separate from controls due to a fairly robust placebo response. No differences in response rates were observed during a head to head single blind study comparing low dose (mean 5 mg) olanzapine and risperidone (mean dose: 2 mg) (Maina, Pessina, Albert, & Bogetto, 2008). The potency of the placebo response in this study is unclear due to a lack of a control arm. A DB-RCT of olanzapine monotherapy (mean dose: 10.8 mg) in patients with a primary diagnosis of trichotillomania yielded significant reductions in scores for the CGI and YBOCS for trichotillomania when compared to placebo (Van Ameringen, Mancini, Patterson, Bennett, & Oakman, 2010). Like risperidone, olanzapine can have the paradoxical effect of exacerbating and inducing de-novo OCS (Alevizos, Papageorgiou, & Christodoulou, 2004; Schönfelder et al., 2011; Kulkarni, Narayanaswamy, & Math, 2012). In adults with schizophrenia, OCS were seen at a significantly higher rate in those receiving olanzapine (De Haan, Beuk, Hoogenboom, Dingemans, & Linszen, 2002). Curiously, in a DB-RCT of young patients with early psychosis, olanzapine was shown to be superior to risperidone in reducing OCS (Van Nimwegen et al., 2008). No consistent variable has helped identify patients at risk of paradoxical reaction. Olanzapine appears to be effective as an augmentation agent in a significant percentage of patients, with a minority experiencing a paradoxical increase in symptoms. However, due to its significant side effects burden (see section on side effects), it should be relegated to those failing to improve or unable to tolerate risperidone or aripiprazole. 9.4. Quetiapine Out of the 5 most commonly utilized antipsychotic medications, quetiapine has the least evidence behind its efficacy. A preliminary single-blind study comparing quetiapine to placebo in 27 treatmentrefractory patients produced significant improvement in symptoms (Atmaca, Kuloglu, Tezcan, & Gecici, 2002). Although an initial DB-RCT produced favorable results, with patients experiencing a significant reduction in YBOCS scores compared to placebo (Denys, de Geus, van Megen, & Westenberg, 2004), subsequent trials failed to replicate these findings. One of these negative trials may have been limited by an elevated placebo response, which may have resulted from the somewhat lax criteria for recruiting treatment resistant patients6 weeks at maximal SRI dose (Carey et al., 2012). Three other negative trials, however, did not have these limitations (Fineberg, Sivakumaran, Roberts, & Gale, 2005; Kordon et al., 2008; Diniz et al., 2011). In a recent meta analysis, quetiapine augmentation failed to separate from placebo (Dold et al., 2013).

Please cite this article as: Borue, X., et al. Biological treatments for obsessive-compulsive and related disorders. Journal of ObsessiveCompulsive and Related Disorders (2015), http://dx.doi.org/10.1016/j.jocrd.2015.03.003i

67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108 109 110 111 112 113 114 115 116 117 118 119 120 121 122 123 124 125 126 127 128 129 130 131 132

X. Borue et al. / Journal of Obsessive-Compulsive and Related Disorders ∎ (∎∎∎∎) ∎∎∎–∎∎∎

10

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 66

Similar to olanzapine, there have been numerous reports of quetiapine exacerbating or inducing OCS (Ozer, Arsava, Ertuğrul, & Demir, 2006; Stamouli & Lykouras, 2006). Although quetiapine appears to be well tolerated both at relatively low and moderate doses, the evidence for its efficacy in OCD is weak and conflicting. Its use should be reserved for cases where it may address comorbid disorders or in patients unable to tolerate other medications in this class.

treatment of OCD, these results are not promising. One favorable open label trial exists for amisulpride (Metin, Yazici, Tot, & Yazici, 2003). A recent RTC of paliperidone, a metabolite of risperidone, for augmentation of SRIs in treatment resistant OCD showed a trend towards improvement in YBOCs as compared to the placebo group but suffered from small sample size and significant placebo effect (Storch et al., 2013). Further work is needed to better evaluate the efficacy of paliperidone in OCD.

9.5. Clozapine 9.7. First Generation Antipsychotics Clozapine, has been found to be significantly more obsessogenic than other antipsychotics, frequently eliciting exacerbation of existing symptoms and inducing de novo OCS (Mahendran et al., 2007; Englisch et al., 2009). This effect appears to be independent of dose and may be delayed relative to the initiation of clozapine. In a recent large scale naturalistic study of 543 patients with psychotic disorders,
47% of patients who had been on clozapine for 6 months or greater reported OCS, more than double the rate for unmedicated controls. {Beduin 2012}. Consistent with these findings, an open-label trial of clozapine monotherapy in treatment-resistant OCD failed to show any improvement in symptoms (McDougle et al., 1995a, 1995b). There have been no RCT for clozapine in the treatment of OCD. Consequently, clozapine is best reserved for comorbid conditions such as schizophrenia or bipolar disorder and should used with caution in patients with OCD. 9.6. Other second generation antipsychotics There is minimal data available regarding the efficacy of ziprasidone augmentation in OCD. A single retrospective study of 25 patients receiving high dose SRI treatment augmented by quetiapine vs. ziprasidone showed higher levels of symptom improvement in those receiving quetiapine (Savas, Yumru, & Ozen, 2008). Given the questionable efficacy of quetiapine in the

There have been few studies employing first generation antipsychotics. In a DB-RCT, 11 out of 17 patients receiving haloperidol (mean daily dose 6.2 mg) augmentation of fluvoxamine were found to be treatment responders at the 4 week end point as compared to none in the placebo group (McDougle, 1994). Comorbid tic disorder appeared to be a reliable predictor of response, with all 8 patients sharing this comorbidity responding to the haloperidol augmentation. A more recent 9 week placebo controlled cross-over study of risperidone vs. haloperidol showed similar rates of OCD symptom reduction during both treatment periods with greater improvement in depressive symptoms during treatment with Risperidone. These results should be interpreted with caution, however due to the small group size, short duration of treatment, and washout effects (Li et al., 2005). Although preliminary findings suggest that haloperidol may be effective in treatment resistant OCD, its use may be associated with an increased side effects burden. It should be considered a second line agent. The evidence base for the use of other first generation antipsychotics in OCD and related disorders is limited to case reports (Delgado, Goodman, Price, Heninger, & Charney, 1990; Stein & Hollander, 1992) and one open label trial (Delgado et al., 1990). It is not sufficient enough to recommend other specific agents in this class.

Table 3 Comparison of frequently encountered antipsychotic side effects. (Adapted from James, 2010.) Adverse effect

Risperidone

Aripiprazole

Haloperidol

Olanzapine

Quetiapine

Anticholinergic Sedation Parkinsonian Akathesia Weight gain Metabolic changes Elevated prolactin

0 þ /0 þþ þ þ þ þþþ

0 0 þ /0 þþ þ /0 þ /0 0a

þ þ þþþ þþþ þ þ /0 þþþ

þ þþ þ þ þþþ þþþ 0

þ/0 þþ 0 þ þþ þ/ þ þ 0

Side effects severity: 0, none reported; þ , minor; þ þ , moderate; þ þ þ , severe. a

Aripiprazole tends to decrease prolactin levels.

Table 4 Clinically significant drug–drug interactions.

Fluvoxamine Fluoxetine Paroxetine Sertraline Citalopram/Escitalopram

Risperidone

Aripiprazole

Olanzapine

Quetiapine

Clomipramine

þ /þ þ 2 þ þ þ 3,5 þ þ3 0/ þ 3 03

þ þ1 þ1 01 n/a n/a

þ þ þ þ 3, 0/ þ 3 04 03, 4 04

þ þ þ þ3 03 n/a n/a n/a

þ þ þ þ3 þ þ þ þ3 þ þ þ þ3 n/a n/a

4

Increase in antipsychotic plasma concentration: 0, no known increase; þ, mild increase, with unclear clinical significance; þ þ , 20–50% increase in antipsychotic levels; þ þ þ, 50–99% increase in levels; þ þ þ þ, 4100% increase in levels; n/a, data not available. Notes: 1: (Urichuk, Prior, Dursun, & Baker, 2008). 2: Minimal changes in risperidone when combined with 100 mg Fluvoxamine daily, 26% increase with 200 mg daily (D'Arrigo et al., 2005). 3: (Spina & de Leon, 2007; Muscatello, Spina, Bandelow, & Baldwin, 2012) Fluoxetine and paroxetine increase clomipramine levels by 200–400%, fluvoxamine increases clomipramine by
400%. 4: (Bergemann, Frick, Parzer, & Kopitz, 2004). 5: (Spina et al., 2002).

Please cite this article as: Borue, X., et al. Biological treatments for obsessive-compulsive and related disorders. Journal of ObsessiveCompulsive and Related Disorders (2015), http://dx.doi.org/10.1016/j.jocrd.2015.03.003i

67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108 109 110 111 112 113 114 115 116 117 118 119 120 121 122 123 124 125 126 127 128 129 130 131 132

X. Borue et al. / Journal of Obsessive-Compulsive and Related Disorders ∎ (∎∎∎∎) ∎∎∎–∎∎∎

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 66

9.8. Side effects, and drug–drug interactions with anti-psychotic augmentation Medication side effects are one of the most common reasons for treatment noncompliance and discontinuation. Whenever augmentation strategies are employed, close attention should be paid to the increasing side effects burden. This is especially important with antipsychotic augmentation due to the greater number of risks associated with these agents. Although a detailed discussion of adverse effects is beyond the scope of this review, we will provide a concise overview of the most common clinically relevant ones. Problematic side effects associated with antipsychotic use include extrapyramidal symptoms (EPS) such as Parkinsonism and dystonias, metabolic and weight changes, sedation, akathesia, and sexual side effects. Development of tardive dyskinesia is an additional risk of longterm antipsychotic use. Side effects, particularly EPS, are typically more problematic in children and adolescents than adults (Correll, 2008). The adverse effects profile differs between agents (see Table 3) and should be taken into account, especially when considering agents of similar efficacy. Excessive weight gain, associated with a high degree of morbidity, is a particularly problematic side effect of OCD treatment that is frequently compounded by antipsychotics. Due to its limited impact on weight, aripiprazole may be preferable to risperidone as the first line augmentation agent in patients with obesity or elevated risk factors for metabolic syndrome. Sedation tends to be dose-dependent and is most prominent for olanzapine. Sedation tends to decrease over time as tolerance develops. Akathesia is most problematic for haloperidol and aripiprazole and may be limiting in some individuals. Several mechanisms likely underlie antipsychotic-related sexual dysfunction, although risperidone and haloperidol appear to be the worst offenders due to their significant impact on prolactin levels. Quetiapine appears to be least likely to produce sexual side effects (Baldwin, 2003) but has not been consistently shown to be efficacious. As with weight gain, aripiprazole appears to be less likely to impact sexual function (Mir et al., 2008). Although it is important to be cognizant of these potential pitfalls, it is notable that in most of the antipsychotic augmentation studies, the agents were generally fairly well tolerated with only mild and transient side effects. This is likely due to the low to moderate doses typically employed. Weight gain and metabolic changes over the long term are notable exceptions (Matsunaga et al., 2009). Another potential pitfall is drug–drug interactions, which primarily occur through the cytochrome 450 isoenzymes (CYP450). Commonly encountered interactions are presented in Table 4. SRIs can inhibit one or more of the isoenzymes, although with different potency, and this can elevate the blood levels of antipsychotics metabolized via those isoenzymes. Fluvoxamine is a potent inhibitor of CYP1A2 and CYP2C9, while Fluoxetine and Paroxetine inhibit CYP2D6. Clomipramine may inhibit CYP2C19 and CYP2D6. Sertraline, citalopram, and escitalopram are weak inhibitors and are less likely to cause problematic drug–drug interactions. CYP450 effects must be factored in when switching treatments, especially when switching to-from the potent inhibitors. In some cases, alterations of the antipsychotic doses may be advisable to avoid increased side effects and toxicity. QTc prolongation is especially concerning and may not always be associated with increased antipsychotic drug levels (Sala et al., 2005). ECGs may be advisable in patients receiving augmentation, especially those with cardiac risk factors.

10. Glutamatergic medications A growing body of evidence shows that abnormalities of glutamate neurotransmission in the cortico-striato-thalamo-cortical circuitry may contribute to the pathogenesis of OCD. As such, medications

11

modifying glutamatergic signaling seem a logical target for investigation of efficacy in OCD. Potential glutamatergic agents include riluzole, memantine, DCS, N-acetylcysteine (NAC), and other NMDA-receptor antagonists (e.g., amantadine and ketamine). Certain anticonvulsants also have glutamatergic properties (e.g., topiramate and lamotrigine) but are discussed under mood stabilizers. Given that SRIs are considered to be first line in the treatment of OCD, most studies have focused on augmentation in treatment-resistant individuals. 10.1. Riluzole Riluzole, a calcium and sodium-channel blocker currently approved in the USA for the treatment of Amyotrophic Lateral Sclerosis, was one of the first glutamatergic agents investigated. Riluzole inhibits synaptic glutamate release and enhances glutamate uptake by astrocytes (Grados, Specht, Sung, & Fortune, 2013). Favorable preliminary results were reported in a 12-week openlabel trial of 100 mg/day with riluzole added on to pre-study pharmacotherapy in adults with treatment-refractory OCD (Coric et al., 2005). In a subsequent case series of similar duration, 7 out of 13 adults receiving augmentation with 100–200 mg/day experienced a4 35% reduction in YBOCS (Pittenger, Kelmendi, Wasylink, Bloch, & Coric, 2008). Notably, 3 of these responders had prominent hoarding symptoms. Riluzole was generally well tolerated. Monitoring of liver function enzymes has been recommended, however, due to frequently occurring transient increases in liver enzymes. In children, a preliminary 12 week open label trial of 100 mg/ day riluzole augmentation also produced favorable outcomes, with 4 out of 6 children experiencing greater than 30% reductions in their Y-BOCS scores (Grant, Lougee, Hirschtritt, & Swedo, 2007). A subsequent DB-RCT failed to build on these preliminary findings. At the end of the 12 week trial of 100 mg/day augmentation in adolescents with moderate to severe OCD, no statistically significant differences in disease severity were identified between treatment and placebo groups (Grant et al., 2013). It is possible that more favorable outcomes may be seen in RCT employing higher daily doses or conducted in less treatment-resistant patients. There are currently no published placebo controlled studies in adults. At this point, there is not enough evidence to recommend routine use of this compound. 10.2. Memantine A growing body of evidence supports the use of memantine, a non-competitive NMDA receptor antagonist currently approved for the treatment of Alzheimer's disease. A case series of treatment resistant patients piqued interest in this agent after 6 of the 14 patients responded to 20 mg/day memantine augmentation of SRI therapy with a 425% reduction in their Y-BOCS scores (Aboujaoude, Barry, & Gamel, 2009). A single blind study of 22 patients receiving Intensive Residential Treatment demonstrated a significantly greater Y-BOCS improvement in patients receiving memantine as compared to patients receiving standard treatment only (Stewart et al., 2010). Two subsequent double-blind, placebo-controlled studies produced favorable results (Haghighi et al., 2013) showing significant symptom improvement in individuals with treatment refractory OCD who received 10 mg/day of memantine in addition to chronic SRI treatment. By week 12, 9 of the 14 patients experienced a 435% reduction in Y-BOCS score while an additional 4 showed a 425% reduction, as compared to only 4 partial responders in the placebo group. Even greater improvement was noted in a nontreatment resistant group of patients with OCD, who received 20 mg/day of memantine in addition to fluvoxamine (which was started at 100 mg daily and increased to 200 mg daily after 4 weeks) during an 8 week trial. By the end of the trial, 89% of

Please cite this article as: Borue, X., et al. Biological treatments for obsessive-compulsive and related disorders. Journal of ObsessiveCompulsive and Related Disorders (2015), http://dx.doi.org/10.1016/j.jocrd.2015.03.003i

67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108 109 110 111 112 113 114 115 116 117 118 119 120 121 122 123 124 125 126 127 128 129 130 131 132

X. Borue et al. / Journal of Obsessive-Compulsive and Related Disorders ∎ (∎∎∎∎) ∎∎∎–∎∎∎

12

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 66

the combined treatment group had achieved clinical remission of symptoms, as compared to 32% of the fluvoxamine only group. The dropout rate was minimal and no significant increase in side effects was noted (Ghaleiha et al., 2013). As compared to antipsychotics, memantine has a much more favorable side effect profile and was well tolerated during all of the aforementioned studies. Most studies support using 20 mg/day and there does not appear to be any advantage to using a lower dose. Although the evidence basis behind its use is smaller than for risperidone or aripiprazole, memantine appears to provide a higher benefit to risk ratio and should be considered in select patients as a first line augmentation agent. Adding memantine to SSRI's in poor responders should be attempted before moving on to antipsychotics or other agents. 10.3.

D-cycloserine

(DCS)

Extinction of fear has been linked to NMDA-r-dependent neural plasticity within the basolateral amygdala (Davis, 2002). Shown to potentiate fear extinction in animal models, DCS, a partial N-methyl-D-aspartate agonist, has subsequently been studied as an adjunct to ERP. Originally developed as an antibiotic, DCS tends to be exceedingly well tolerated. In a small DB-RCT of ERP augmented with 125 mg of DCS 2 h prior to the therapy, DCS appeared to significantly speed up symptom reduction as well as reduce treatment attrition 6-fold in comparison to placebo (down to 6%). DCS effects were greatest at the 4th session and by session 10, the placebo group had caught, up suggesting that DCS did not boost the effect size of ERP (Kushner et al., 2007). A similar trend was observed in a separate DB-RCT of ERP augmented by 100 mg DCS administered 1 h prior (Wilhelm et al., 2008). The largest separation between treatment and placebo groups was noted at the midpoint of the study. A trend towards improved Y-BOCS scores was observed at 1-month follow up and depressive symptoms were significantly better in the DCS group throughout the study. Post-hoc analysis suggests a 2-fold steeper slope of DCSaugmented improvement in OCD symptoms with subsequent ceiling effects limiting separation between control and treatment groups (Chasson et al., 2010). Conversely, despite administering a larger dose, 250 mg, Storch et al. (Storch et al., 2007) did not observe any differences in treatment response. A possible explanation was the longer delay between DCS administration and ERP (4 h vs.1–2 h). In children and adolescents with OCD, the results have been less consistent. When given 25–50 mg (0.7 mg/kg) one hour prior to ERP, children with OCD had marginally greater improvements in OCD symptoms at both the midpoint and end of the 7 sessions of ERP, although this trend did not reach statistical significance (Storch et al., 2010). A similar trend was observed in a different DB-RCT of adolescents with medication and ERP-resistant OCD (defined as minimal response to 6þ ERP sessions) who received 25–50 mg DCS 1 h prior to ERP (Farrell et al., 2013). Conversely, there were no observed differences in rate of recovery or OCD symptoms when children received 50 mg DCS immediately after ERP (Mataix-Cols et al., 2014). Although DCS appears promising, further work to elucidate the effect of timing and dosing on treatment response is necessary before DCS can be recommended for routine clinical use. 10.4. Additional glutamatergic agents Ketamine, is a non-competitive NMDAR antagonist, which has shown promise in the treatment of depression and suicidality is being increasingly explored for treatment refractory OCD. Small but clinically significant transient decreases in YBOCS scores were observed in an open-label trial of ketamine augmentation (0.5 mg/kg IV over

40 min) of SRIs in treatment-refractory OCD (Bloch et al., 2012). A subsequent double-blind, placebo-controlled crossover study focused on unmedicated adults with obsessions encompassing 8þh/day under the hypothesis that intrusive obsessions may be more responsive to ketamine infusion. Patients receiving ketamine infusion showed significant and rapid reduction in obsessions during the infusion that persisted for
1 week with 50% of patients exhibiting a greater than 35% reduction in their YBOCS scores at the 1 week mark (Rodriguez et al., 2013). Although this preliminary data suggests that ketamine may be helpful in some patients, longer-term studies are necessary to fully explore its utility. N-acetylcysteine, an amino acid compound that is thought to attenuate glutamatergic neurotransmission, was found to be effective as an adjunct for SRI treatment in a case report (Lafleur et al., 2006). Although a RCT in trichotillomania produced favorable results (Grant, Odlaug, & Kim, 2009), there have been no RCT in OCD. Augmentation with glycine, an NMDA receptor coagonist, was poorly tolerated and failed to show significant improvement in OCD symptoms over placebo (Greenberg et al., 2009). Better preliminary evidence exists for sarcosine, an endogenous antagonist of the glycine transporter, which is thought to enhance NMDA neurotransmission. In a 10 week open label trial, 8 of the 25 subjects experienced a greater than 35% reduction in YBOCS with minimal side effects (Wu, Tang, Lane, Tsai, & Tsai, 2011). There have been no controlled research studies exploring the use of amantadine in OCD. However, in one case study, an adult with treatment refractory OCD exhibited a 50% reduction in his YBOCS score within 2 weeks of starting on 200 mg/day of amantadine in addition to chronically administered clomipramine (Pasquini, Berardelli, & Biondi, 2010). At this point, the evidence for all of these additional agents is in its most preliminary stages and none are worth including as part of a standard treatment approach.

11. Augmentation with mood stabilizers and anticonvulsants 11.1. Lamotrigine The inhibitory effect of the anticonvulsant lamotrigine on glutamatergic neurotransmission has spurred interest in this agent for the treatment of OCD. A small number of case studies utilizing lamotrigine augmentation in patients with treatment resistant OCD showed significant improvements in YBOCS scores (Uzun, 2010; Arrojo-Romero, Tajes Alonso, & de Leon, 2013). One case series of lamotrigine augmentation reported a negative outcome but it was impeded by an overly-brief treatment duration
6 weeks total including upwards titration (Kumar & Khanna, 2000). A recent 16 week long DB-RCT of 100 mg/day lamotrigine augmentation of SRIs produced more favorable results. Lamotrigine was slowly titrated up to the target dose over the course of 4 weeks, with only mild and transient side effects reported. 17 out of 20 patients were treatment responders with 7/17 obtaining 435% reductions in YBOCS scores; there were no responders in the placebo only group (Bruno et al., 2012). Additional evidence supporting the efficacy of lamotrigine comes from an 8 week open label study of lamotrigine (titrated up to 100 mg by week 3 and 200 by week 5) augmentation for OCS in psychotic disorders. Nine out of 11 patients completed the study and all had a clinically significant reduction in their OCS. Those with schizoaffective disorders seemed to benefit the most, with all 5 completers experiencing greater than 35% reductions in OCS (Poyurovsky, Glick, & Koran, 2010). Additional RCT are necessary before definitive recommendations can be made regarding this agent but the preliminary results are promising. Lamotrigine may be worth

Please cite this article as: Borue, X., et al. Biological treatments for obsessive-compulsive and related disorders. Journal of ObsessiveCompulsive and Related Disorders (2015), http://dx.doi.org/10.1016/j.jocrd.2015.03.003i

67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108 109 110 111 112 113 114 115 116 117 118 119 120 121 122 123 124 125 126 127 128 129 130 131 132

X. Borue et al. / Journal of Obsessive-Compulsive and Related Disorders ∎ (∎∎∎∎) ∎∎∎–∎∎∎

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 66

preferentially employing in patients with comorbid conditions such as psychosis and mood disorders. 11.2. Topiramate The evidence for topiramate, which also has inhibitory effects on glutamatergic neurotransmission, has been less clear. Following two promising preliminary case series of topiramate augmentation in treatment resistant OCD (Rubio, Jiménez-Arriero, MartínezGras, Manzanares, & Palomo, 2006; Van Ameringen, Mancini, Patterson, & Bennett, 2006), two DB-RCT 12 week-long were conducted with disparate findings. Mowla, Khajeian, Sahraian, Chohedri, & Kashkoli (2010) administered topiramate 100– 200 mg daily (mean dose
180 mg) to 24 patients with treatment refractory OCD. 12 out of the 20 study completers were found to be treatment responders as compared to none in the placebo group. Berlin et al. targeted a higher dose, 400 mg/day and observed mild improvements in the compulsions subscale of the YBOCS in study completers but a high dropout rate may have skewed the data. 5 of the original 18 patients withdrew due to side effects and an additional 7 required a dose reduction (Berlin et al., 2011). Further work is necessary to explore the efficacy of and better delineate the optimal dose for topiramate augmentation in OCD. Current studies suggest that the benefit to side effects ratio decreases substantially for doses higher than 200 mg/day. 11.3. Other mood stabilizers A case series and a small open label trial provide promising preliminary evidence for yet another inhibitor of glutamatergic neurotransmission, pregabalin. 8 out 10 patients who participated in the open label trial (mean daily dose
400 mg added to chronic medication regimen) experienced greater than 35% YBOCS reductions by week 8 of the trial with only mild and transient side effects (Oulis, Mourikis, & Konstantakopoulos, 2011). In a 16 week case series 9 out of 12 patients receiving pregabalin augmentation (mean daily dose
290 mg) were treatment responders (Di Nicola et al., 2011). RCT are needed to further evaluate the potential efficacy of this agent. There has been no evidence to support the use of other mood stabilizers such as valproate or carbamazepine for the treatment of OCD. Although initial case studies suggested potential benefit to lithium augmentation, subsequent RCT failed to establish any efficacy (Arumugham & Reddy, 2014). The use of these agents should therefore be reserved for comorbid bipolar disorder.

13

Two DB-RCT have explored 5-HT3R antagonist augmentation of fluvoxamine treatment in non-treatment resistant populations. By week 8 of the RCT, all 20 patients receiving 2 mg/day of granisetron experienced treatment response, with 18 meeting remission criteria as compared to a 35% response rate in the placebo group (Askari et al., 2012). Similarly, by week 8 of the second trial, 14 out of 24 patients receiving 8 mg/day of ondansetron achieved remission (YBOCS o16) and an additional 7 were responders as compared to 6 in remission with 2 additional responders out of 22 in the placebo group (Heidari et al., 2014). In a different sample of non treatment-resistant patients, 4 mg/day ondansetron augmentation of low-dose fluoxetine (20 mg/day) produced significant symptom improvements as compared to fluoxetine only by week 8 of the DB-RCT (Soltani et al., 2010). More studies are necessary to identify optimal dosing, efficacy in maintenance treatment and optimal treatment duration for these agents. The evidence basis for granisetron is more preliminary than for ondansetron. Given its extremely good tolerability and low risks of use, it may be worth considering ondansetron (at a dose of 4–8 mg/day) as an alternative to antipsychotics in select populations or co-administration during the initiation of SRI therapy in patients with moderate to severe OCD. 12.2. Mirtazapine Mirtazapine is an antidepressant with specific noradrenergic and serotonergic receptor antagonistic properties. It enhances serotonin neurotransmission indirectly. There is preliminary evidence of its use as an anti-obsessional agent as a monotherapy (Koran, Gamel, Choung, Smith, & Aboujaoude, 2005). In a single blind RCT, 15–30 mg/day augmentation of Citalopram with mirtazapine was associated with earlier onset of response and reduced adverse effects (Pallanti, Quercioli, & Bruscoli, 2004). However, the final outcome did not differ between mirtazapine and placebo. At this point, there is not enough evidence to recommend this agent. 12.3. B-blockers There is conflicting evidence for pindolol, a β-adrenergic blocker with putative antagonistic action at presynaptic 5HT1A receptor. Two small DB-RCT produced disparate results and more work is needed to better evaluate this compound (Arumugham & Reddy, 2014).

13. “Last-line” agents 12. Additional augmenting agents 12.1. 5-HT3 receptor antagonists Ondansetron and granisetron, which have well-established records for treating chemotherapy-induced emesis, have been increasingly explored as adjuncts for the treatment of OCD with very promising results. After a successful open-label pilot trial of ondansetron monotherapy (Hewlett, Schmid, & Salomon, 2003), a single-blind study of 1 mg/day ondansetron augmentation of SRI treatment in treatment resistant OCD yielded a
64% response rate (Pallanti, Bernardi, Antonini, Singh, & Hollander, 2009). A 12week single blind study of ondansetron augmentation of SRI treatment in treatment refractory individuals showed clinical response in 12 of the 21 patients receiving 1 mg/day. Relapse occurred in 8 of the 12 responders within 4 weeks of discontinuing ondansetron (Pallanti, Bernardi, Antonini, Singh, & Hollander, 2014).

It is worth briefly mentioning agents with minimal evidence of efficacy in OCD. Benzodiazepines, which have been classically used to treat anxiety symptoms, show very little promise in ameliorating obsessions or compulsions. Two DB-RCTs failed to show significant symptom improvement from monotherapy with (Hollander, Kaplan, & Stahl, 2003b) or augmentation of SRI treatment by clonazepam (Crockett, Churchill, & Davidson, 2004). An additional concern with the use of benzodiazepines, especially on a PRN basis is that they may dampen anxiety provoked during ERP, thereby decreasing the clinical utility of the treatment. Similar failure to separate from placebo was seen with buspirone, a partial agonist at the 5-HT 1A receptor, approved for the treatment of generalized anxiety disorder. Although a few patients seemed to show symptom improvement with buspirone augmentation of SRI treatment, when compared to the placebo arm of the study, these differences were not statistically significant in any of the three DB-RCT conducted (Pigott et al., 1992; Grady et al., 1993; McDougle et al., 1993). Although buspirone is generally well

Please cite this article as: Borue, X., et al. Biological treatments for obsessive-compulsive and related disorders. Journal of ObsessiveCompulsive and Related Disorders (2015), http://dx.doi.org/10.1016/j.jocrd.2015.03.003i

67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 Q20 104 105 106 107 108 109 110 111 112 113 114 115 116 117 118 119 120 121 122 123 124 125 126 127 128 129 130 131 132

14

1 2 3 4 5 6 7 8 9 10 11 12Q21 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 66

X. Borue et al. / Journal of Obsessive-Compulsive and Related Disorders ∎ (∎∎∎∎) ∎∎∎–∎∎∎

tolerated, like benzodiazepines, its use is best targeted towards comorbid disorders.

14. Trichotillomania (hair pulling disorder) and excoriation (skin picking disorder) While trichotillomania (TTM) had previously been classified as an impulse control disorder, the DSM-5 classifies this and the newly named Excoriation Disorder as Obsessive Compulsive and Related Disorders due to similar symptom presentation, course of illness and genetic vulnerabilities (Van Ameringen et al., 2014; Van Ameringen, Patterson, & Simpson, 2014). Both illnesses are grouped together because of similarities in etiological factors as well as in phenomenology (Snorrason, Belleau, & Woods, 2012) and therefore their treatment can be discussed together. There have been multiple medications that have been studied for the treatment of TTM. SSRI's are the class of medication that has been studied the most frequently. Fluoxetine has been the subject of numerous clinical trials and has generally found to be not effective for reducing symptoms of TTM (Christenson, Mackenzie, Mitchell, & Callies, 1991; Streichenwein & Thornby, 1995; van Minnen, Hoogduin, Keijsers, Hellenbrand, & Hendriks, 2003). Another SSRI, sertraline was shown to have only a minimal effect on TTM symptoms prior to the addition of behavioral therapy (Dougherty, Loh, Jenike, & Keuthen, 2006). A smaller open label trial with escitalopram (Gadde, Wagner, Connor, & Foust, 2007) which showed some efficacy for symptoms reduction would indicate that medications in the SSRI category may have some benefit. Clomipramine, a tricyclic antidepressant (TCA) with strong serotonin reuptake inhibition has been studied in the treatment of TTM and while it was found to be superior to another TCA, desipramine (Swedo et al., 1989) its effectiveness vs. placebo is minimal (Ninan, Rothbaum, Marsteller, Knight, & Eccard, 2000) so at best the data is mixed on the use of this intervention. However, the modest improvement seen would suggest that a trial of this medication is warranted in appropriate candidates. Novel medications have also been studied for the treatment of TTM. N-acetylcysteine is an amino acid that is available as an overthe-counter supplement in many drug stores and supplement shops. Its inhaled version is used to treat acetaminophen overdose. It is believed to act by causing glial cells to release of glutamate into the extra synaptic space in response to the uptake of cysteine, where it appears to stimulate inhibitory glutamate receptors on glutamatergic nerve terminals and thereby reduces the synaptic release of glutamate (Bloch, Panza et al., 2013; Bloch et al., 2013). The oral version is a glutamatergic modulator and was shown in a double blind, placebo controlled study to reduce urges to pull hair significantly compared to placebo (Grant et al., 2009) in adult patients. Patients were able to remain on other medications during the course of that study. A similarly designed study to examine N-acetylcysteine in children ages 8–17 did not show a statistical difference with placebo (Bloch, Panza et al., 2013; Bloch et al., 2013). The use of this supplement in adults may be reasonable, but lack of response in children means caution is warranted in that population. Riluzole is a glutamate modulator that is thought to be effective in the treatment of OCD. It has been reported in a cases series to be effective for TTM (Coric et al., 2007) but has not been examined in a more rigorous format at this time. Antipsychotic medication has long been used clinically for the treatment of TTM, and experience in clinical settings has shown this option to be among the most popular prescribed by general psychiatrists in community practice. However, there is little evidence for the use of these medications in routine practice. Much of the literature surrounding the use of this group of medications has involved case reports and uncontrolled trials,

and the medications have included pimozide, haloperidol, aripiprazole (White & Koran, 2011) and risperidone (Bloch, 2010). A double blind placebo controlled trial showed evidence that olanzapine was superior to placebo (Van Ameringen et al., 2010). The mean dose used in this study was just over 10 mg a day. Due to the hypothesis of some researchers that TTM bears a resemblance to substance abuse disorders, the opioid antagonist naltrexone has been studied for the treatment of TTM, and has been examined in the treatment of animals with disorders of excessive grooming (Grant, Odlaug, Schreiber, & Kim, 2014). A large, open-label trial of naltrexone in children indicated the possibility of efficacious treatment (De Sousa, 2008). However, a large, double blinded study failed to show efficacy of naltrexone at 150 mg daily vs. placebo (Grant et al., 2014) bringing the effectiveness of this potential treatment into question. Other medications have been studied for the treatment of TTM. Topiramate is an anti-convulsant approved for the treatment of epilepsy that has glutamate modulating activity. It has been shown to be successful in the treatment of binge eating and pathological gambling. It was used in a 16 week, flexible dose trial in adults with TTM, and 6 of the 14 patients were shown to have improvement, although 5 people dropped out of the study due to intolerable side effects (Lochner, Seedat, Niehaus, & Stein, 2006). Dronabinol is a canabinoid agonist that contains delta-9-tetrahydrocannabinol (THC) and is FDA-approved for the treatment of anorexia associated with weight loss in patients with AIDS and nausea and vomiting associated with cancer chemotherapy. It may reduce the exocitotoxic damage caused by glutamate release in the striatum (Grant, Odlaug, Chamberlain, & Kim, 2011). In an open label design, 9 of 14 women with TTM were considered responders to dronabinal, with the medication noted to be tolerable overall (Grant et al., 2011). In an open study of comorbid ADHD and TTM, Golubchik et al. showed that ADHD could be successfully treated with methylphenidate without increasing the severity of TTM (Golubchik, Sever, Weizman, & Zalsman, 2011). Despite the fact that medications are commonly used in the treatment of TTM, few double blind placebo controlled studies have been performed. Clinicians should view the numerous case reports and open label designs with a skeptical eye due to the fact that TTM severity often waxes and wanes during its course, and therefore many reports of response may simply be due to the natural cycle of the illness itself. Clearly, more scientifically significant studies are needed to properly evaluate biological treatments in this area. Behavioral management is preferred in most cases for treatment, although it can be difficult to obtain expert therapy in many geographical locations. While there is a role for the use of medications, use by clinicians should be cautious and preferably prescribe medication in conjunction with behavioral therapy whenever possible.

15. Hoarding Disorder Hoarding Disorder was not formally classified in the DSM-IV; it was considered by many authors to be a sub-type of OCD and was referred to as compulsive hoarding. DSM-5 now recognizes it as a separate psychiatric disorder in the category of Obsessive Compulsive and Related Disorders. Its new recognition as a separate diagnostic entity will be helpful for future treatment studies, but because of the lack of a formal category prior to this, there exists limited data for treatment of Hoarding Disorder using pharmacotherapy. Some authors had suggested that symptoms of compulsive hoarding predicted a poorer response to serotonin reuptake inhibitors (Mataix-Cols, Rauch, Manzo, Jenike, & Baer, 1999; Black et al., 1998). A trial of escitalopram (Stein et al., 2008) and citalopram (Stein et al., 2007) suggested that patients with

Please cite this article as: Borue, X., et al. Biological treatments for obsessive-compulsive and related disorders. Journal of ObsessiveCompulsive and Related Disorders (2015), http://dx.doi.org/10.1016/j.jocrd.2015.03.003i

67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108 109 110 111 112 113 114 115 116 117 118 119 120 121 122 123 124 125 126 127 128 129 130 131 132

X. Borue et al. / Journal of Obsessive-Compulsive and Related Disorders ∎ (∎∎∎∎) ∎∎∎–∎∎∎

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 66

hoarding may exhibit a poorer response to medication than people with other dimensional symptoms of OCD. However, only one study published to date has prospectively and quantitatively measured response to standardized pharmacotherapy in patients with what is now termed Hoarding Disorder, regardless of whether they or not had other OCD symptoms (Saxena, 2011). That study compared paroxetine treatment in patients with primarily hoarding symptoms to patients with OCD. They found that response rates for Hoarding and OCD were similar and no correlation was found between the severity of hoarding and treatment response (Saxena, Brody, Maidment, & Baxter, 2007). As a result of these findings, medication treatment for Hoarding Disorder using serotonin selective inhibitors should be offered to patients in addition to behavioral therapy. While many clinicians had felt that Hoarding did not respond as well to pharmacotherapy as other obsessive compulsive disorders, evidence seems to indicate that may not be the case. The use of SSRI's in Hoarding Disorder should follow the same protocol as SSRI use in OCD until evidence would indicate otherwise.

16. Body Dysmorphic Disorder There have been only a relatively small number of studies examining the pharmacotherapy of Body Dysmorphic Disorder (BDD) in spite of the severity of the illness. However, based on what has been done to this time, SSRI treatment is recommended as the first line medications for BDD. Initially, serotonin reuptake inhibitors used in the treatment of OCD- fluvoxamine and clomipramine- were shown in case reports to be helpful and improve symptoms in BDD patients (Phillips and Hollander, 2008). Eventually, larger studies were performed and two double blind placebo controlled studies were completed. In 1999, Hollander et al. took 29 patients with BDD and placed them on placebo followed by clomipramine and desipramine in a blinded, random, and crossover fashion. During the clomipramine portion of the trial, patients were noted to have significantly improved BDD symptoms. It was additionally noted that functional disability improved during the clomipramine arm of the study as well (Hollander et al., 1999). Importantly, patients who were considered to be delusional and lacking insight were the patients who responded best to clomipramine. Another study was carried out which examined the SSRI fluoxetine in a blind format compared to placebo. The active medication was significantly more likely to achieve improvement in BDD symptoms compared to placebo; interestingly, patients considered to be delusional in insight responded as well to active treatment as those who were not delusional (Phillips, Albertini, & Rasmussen, 2002). Delusional patients were less likely to respond to placebo. Fluoxetine also seems to exert a protective effect against suicidality (Phillips & Kelly, 2009). There have been no head to head studies of SSRI's performed, but based on chart reviews no significant differences in response have been noted (Phillips, Albertini, Siniscalchi, Khan, & Robinson, 2001). There has been little studied in the way of augmentation strategies for BDD. The antipsychotic medication pimozide was not found to be more efficacious than placebo in the augmentation of fluoxetine for BDD, even in patients that had a delusional level of insight. (Phillips, 2005). A small open label study showed response to buspirone augmentation of SSRIs when used at relatively high doses- averaging close to 60 mg daily (Phillips, 1996). Most of the other examinations of SSRI augmentation for BDD have involved case reports and other, non-controlled studies. Due to the general severity and treatment resistant nature of this illness combined with high rate of delusional insight, augmentation of medications may often need to be explored in

15

clinical practice. It is our recommendation to follow dosing and duration guidelines for SSRI treatment of OCD patients when treating patients with BDD. If further augmentation is needed, careful clinical consideration should be taken. Antipsychotics, especially second generation anti-psychotics, are commonly tried due to the delusional level of insight commonly seen. Clinicians should be aware that no evidence indicates that antipsychotics are preferentially useful in this population and we recommend that if a patient does not have clinically significant improvement in 2–3 months after initiation the antipsychotic should be discontinued to minimize the risk of long-term side effects. Buspirone augmentation is a strategy can be applied to most BDD patients due to the medications safety profile. Augmentation with a second SRI (most often clomipramine is used to augment an SSRI) is a treatment option that can be undertaken as well. Clearly more studies in this are needed.

17. Special populations While women are known to have an increase in the risk of psychiatric disorders in general, including OCD in the three months after delivery of a baby (Munk-Olsen, Laursen, Pedersen, Mors, & Mortensen, 2006) there has been little written about treatment recommendations in post partum women suffering from new onset or existing OCD (Hudak & Wisner, 2012). Therefore, treatment for post partum OCD should be conducted in the same manner as is recommended for other patients with OCD. In addition, little is known about the treatment of women for OCD during pregnancy. SSRI medications have not been shown to cause increases in major malformations of the fetus during development but have been shown to increase the risk of pre term birth in women with major depressive disorder. However, the risk of pre term birth from SSRI was equivalent to the risk of pre term birth from the psychiatric illness itself (Wisner et al., 2009). There have been suggestions that Persistent Pulmonary Hypertension of the Newborn (PPH) may occur when the mother has been treated with SSRIs, although the authors note that the risk is also higher in women with untreated major depression (Ornoy & Koren, 2014). Because the risk of treatment discontinuation is high in pregnant women and is outweighed by only potential and unproven risk of SSRI treatment, it is recommended that women with OCD continue to receive treatment during pregnancy (Ornoy & Koren, 2014). There is no good clinical reason to consider adjusting doses downward in pregnant women and risking relapses in illness. In fact, some data suggest that in the second half of pregnancy that medication dose requirements may actually increase (Sit, Perel, Helsel, & Wisner, 2008). Discussion of any possible benefits and risks of medication treatment for OCD during pregnancy should ideally involve not just the patient but also her partner if applicable.

Uncited references Camilla d'Angelo et al. (2014), Chamberlain, Grant, Costa, Müller, & Sahakian (2010), Koran, Hanna, & Hollander (2007), Rosenberg & Keshavan (1998), Skoog & Skoog (1999). References Aboujaoude, E., Barry, J. J., & Gamel, N. (2009). Memantine augmentation in treatment-resistant obsessive-compulsive disorder: an open-label trial. Journal of Clinical Psychopharmacology, 29, 51–55. Ak, M., Bulut, S. D., Bozkurt, A., & Ozsahin, A. (2011). Aripiprazole augmentation of serotonin reuptake inhibitors in treatment-resistant obsessive-compulsive disorder: a 10-week open-label study. Advances in Therapy, 28, 341–348.

Please cite this article as: Borue, X., et al. Biological treatments for obsessive-compulsive and related disorders. Journal of ObsessiveCompulsive and Related Disorders (2015), http://dx.doi.org/10.1016/j.jocrd.2015.03.003i

67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108 109 110 111 112 113 114 115 116 117 118 119 Q2120 121 122 123 124 125 126 127 128 129 130 131 132

16

1Q22 2 3 4 5 6 7 8 9 10 11 12 13 14Q23 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 66

X. Borue et al. / Journal of Obsessive-Compulsive and Related Disorders ∎ (∎∎∎∎) ∎∎∎–∎∎∎

Albert, U., Aguglia, A., Bramante, S., Bogetto, F., & Maina, G. (2013). Treatmentresistant obsessive-compulsive disorder (OCD): Current knowledge and open questionsClinical Neuropsychiatry. Alevizos, B., Papageorgiou, C., & Christodoulou, G. N. (2004). Obsessive-compulsive symptoms with olanzapine. The International Journal of Neuropsychopharmacology/Official Scientific Journal of the Collegium Internationale Neuropsychopharmacologicum (CINP), 7, 375–377. Andrade, C. (2013). Augmenting selective serotonin reuptake inhibitors with clomipramine in obsessive-compulsive disorder: benefits and risks. The Journal of Clinical Psychiatry, 74, e1128–e1133. Arias Horcajadas, F., Soto, J. A., García-Cantalapiedra, M. J., Rodríguez Calvin, J. L., Morales, J., & Salgado, M. (2006). Effectiveness and tolerability of addition of risperidone in obsessive-compulsive disorder with poor response to serotonin reuptake inhibitors. Actas españolas de psiquiatría, 34, 147–152. Arrojo-Romero, M., Tajes Alonso, M., & de Leon, J. (2013). Lamotrigine augmentation of serotonin reuptake inhibitors in severe and long-term treatment-resistant obsessive-compulsive disorder. Case Reports in Psychiatry, 2013, 612459. Arumugham, S. S., & Reddy, J. Y. (2014). Augmentation strategies in obsessivecompulsive disorder Ashton, A. K., & Weinstein, W. L. (2002). Cyproheptadine for drug induced sweating. American Journal of Psychiatry, 159, 874–875. Askari, N., Moin, M., Sanati, M., Tajdini, M., Hosseini, S.-M.-R., Modabbernia, A., et al. (2012). Granisetron adjunct to fluvoxamine for moderate to severe obsessivecompulsive disorder: a randomized, double-blind, placebo-controlled trial. CNS Drugs, 26, 883–892. Atmaca, M., Kuloglu, M., Tezcan, E., & Gecici, O. (2002). Quetiapine augmentation in patients with treatment resistant obsessive-compulsive disorder: a singleblind, placebo-controlled study. International Clinical Psychopharmacology, 17, 115–119. Baldwin, D. (2003). Sexual side-effects of antidepressant and antipsychotic drugs. Advances in Psychiatric Treatment, 9, 202–210. Bergemann, N., Frick, A., Parzer, P., & Kopitz, J. (2004). Olanzapine plasma concentration, average daily dose, and interaction with co-medication in schizophrenic patients. Pharmacopsychiatry, 37, 63–68. Berlin, H. A., Koran, L. M., Jenike, M. A., Shapira, N. A., Chaplin, W., Pallanti, S., et al. (2011). Double-blind, placebo-controlled trial of topiramate augmentation in treatment-resistant obsessive-compulsive disorder. The Journal of Clinical Psychiatry, 72, 716–721. Black, D. W., Monahan, P., Gable, J., Blum, N., Clancy, G., & Baker, P. (1998). Hoarding and treatment response in 38 nondepressed subjects with obsessivecompulsive disorder Aug. Journal of Clinical Psychiatry, 59(8), 420–425. Bloch, M. (2010). In R. Hudak, D.D. Dougherty (Eds.), Trichotillomaniaand impulse control disorders in clinical obsessive compulsive disorders in adults and children. Oxford University Press. Bloch, M. H., Bartley, C. A., Zipperer, L., Jakubovski, E., Landeros-Weisenberger, A., Pittenger, C., et al. (2014). Meta-analysis: hoarding symptoms associated with poor treatment outcome in obsessive-compulsive disorder. Molecular Psychiatry Bloch, M. H., Craiglow, B. G., Landeros-Weisenberger, A., Dombrowski, P. A., Panza, K. E., Peterson, B. S., et al. (2009). Predictors of early adult outcomes in pediatric-onset obsessive-compulsive disorder. Pediatrics, 124, 1085–1093. Bloch, M. H., Green, C., Kichuk, S. A., Dombrowski, P. A., Wasylink, S., Billingslea, E., et al. (2013). Long-term outcome in adults with obsessive-compulsive disorder. Depression and Anxiety, 30, 716–722. Bloch, M. H., Landeros-Weisenberger, A., Kelmendi, B., Coric, V., Bracken, M. B., & Leckman, J. F. (2006). A systematic review: antipsychotic augmentation with treatment refractory obsessive-compulsive disorder. Molecular Psychiatry, 11, 622–632. Bloch, M. H., Panza, K. E., Grant, J. E., Pittenger, C., & Leckman, J. F. (2013). Nacetylcysteine in the treatment of pediatric trichotillomania: a randomized, double-blind, placebo-controlled add-on trial. Journal of the American Academy of Child & Adolescent Psychiatry, 52(3), 231–240. Bloch, M. H., Wasylink, S., Landeros-Weisenberger, A., Panza, K. E., Billingslea, E., Leckman, J. F., et al. (2012). Effects of ketamine in treatment-refractory obsessive-compulsive disorder. Biological Psychiatry, 72, 964–970. Bogetto, F., Albert, U., & Maina, G. (2002). Sertraline treatment of obsessivecompulsive disorder: Efficacy and tolerability of a rapid titration regimen. European Neuropsychopharmacology, 12, 181–186. Bogetto, F., Bellino, S., Vaschetto, P., & Ziero, S. (2000). Olanzapine augmentation of fluvoxamine-refractory obsessive-compulsive disorder (OCD): A 12-week open trial. Psychiatry Research, 96, 91–98. Bruno, A., Micò, U., Pandolfo, G., Mallamace, D., Abenavoli, E., Di Nardo, F., et al. (2012). Lamotrigine augmentation of serotonin reuptake inhibitors in treatment-resistant obsessive-compulsive disorder: a double-blind, placebocontrolled study. Journal of Psychopharmacology (Oxford, England), 26, 1456–1462. Buchsbaum, M. S., Hollander, E., Pallanti, S., Baldini Rossi, N., Platholi, J., Newmark, R., et al. (2006). Positron emission tomography imaging of risperidone augmentation in serotonin reuptake inhibitor-refractory patients. Neuropsychobiology, 53, 157–168. Budman, C. L. (2014). The role of atypical antipsychotics for treatment of Tourette's syndrome: An overview. Drugs, 74, 1177–1193. Bystritsky, A., Ackerman, D. L., Rosen, R. M., Vapnik, T., Gorbis, E., Maidment, K. M., et al. (2004). Augmentation of serotonin reuptake inhibitors in refractory obsessive-compulsive disorder using adjunctive olanzapine: a placebocontrolled trial. The Journal of Clinical Psychiatry, 65, 565–568.

Camilla d'Angelo, L. S., Eagle, D. M., Grant, J. E., Fineberg, N. A., Robbins, T. W., & Chamberlain, S. R. (2014). Animal models of obsessive-compulsive spectrum disorders. CNS Spectrums, 19(1), 28–49. Carey, P. D., Lochner, C., Kidd, M., Van Ameringen, M., Stein, D. J., & Denys, D. (2012). Quetiapine augmentation of serotonin reuptake inhibitors in treatmentrefractory obsessive-compulsive disorder: Is response to treatment predictable? International Clinical Psychopharmacology, 27, 321–325. Chamberlain, S. R., Grant, J. E., Costa, A., Müller, U., & Sahakian, B. J. (2010). Effects of acute modafinil on cognition in trichotillomania Dec. Psychopharmacology (Berl), 212(4), 597–601. Chasson, G. S., Buhlmann, U., Tolin, D. F., Rao, S. R., Reese, H. E., Rowley, T., et al. (2010). Need for speed: evaluating slopes of OCD recovery in behavior therapy enhanced with D-cycloserine. Behaviour Research and Therapy, 48, 675–679. Cherian, A. V, Math, S. B., Kandavel, T., & Reddy, Y. C. J. (2014). A 5-year prospective follow-up study of patients with obsessive-compulsive disorder treated with serotonin reuptake inhibitors. Journal of Affective Disorders, 152–154, 387–394. Christenson, G. A., Mackenzie, T. B., Mitchell, J. E., & Callies, A. L. (1991). A placebocontrolled, double-blind crossover study of fluoxetine in TrichotillomaniaAmerican Journal of Psychiatry, 148, 1566–1571. Clayton, A. H., Pradko, J. F., Croft, H. A., Montano, C. B., Leadbetter, R. A., BoldenWatson, C., et al. (2002). Prevalence of sexual dysfunction among newer antidepressants Apr. Journal of Clinical Psychiatry, 63(4), 357–366. Clayton, A. H., Warnock, J. K., Kornstein, S. G., Pinkerton, R., Sheldon-Keller, A., & McGarvey, E. L. (2004). A placebo-controlled trial of bupropion SR as an antidote for selective serotonin reuptake inhibitor-induced sexual dysfunction Jan. Journal of Clinical Psychiatry, 65(1), 62–67. Connor, K. M., Payne, V. M., Gadde, K. M., Zhang, W., & Davidson, J. R. T. (2005). The use of aripiprazole in obsessive-compulsive disorder: preliminary observations in 8 patients. The Journal of Clinical Psychiatry, 66, 49–51. Conus, P., Bondolfi, G., Eap, C. B., Macciardi, F., & Baumann, P. (1996). Pharmacokinetic fluvoxamine-clomipramine interaction with favorable therapeutic consequences in therapy-resistant depressive patient. Pharmacopsychiatry, 29, 108–110. Coric, V., Kelmendi, B., Pittenger, C., Wasylink, S., Bloch, M. H., & Green, J. (2007). Beneficial effects of the antiglutamatergic agent riluzole in a patient diagnosed with trichotillomania Jan. Journal of Clinical Psychiatry, 68(1), 170–171. Coric, V., Taskiran, S., Pittenger, C., Wasylink, S., Mathalon, D. H., Valentine, G., et al. (2005). Riluzole augmentation in treatment-resistant obsessive-compulsive disorder: an open-label trial. Biological Psychiatry, 58, 424–428. Correll, C. U. (2008). Antipsychotic use in children and adolescents: minimizing adverse effects to maximize outcomes. Journal of the American Academy of Child and Adolescent Psychiatry, 47, 9–20. Crockett, B. A., Churchill, E., & Davidson, J. R. T. (2004). A double-blind combination study of clonazepam with sertraline in obsessive-compulsive disorder. Annals of Clinical Psychiatry: Official Journal of the American Academy of Clinical Psychiatrists, 16, 127–132. D'Amico, G., Cedro, C., Muscatello, M. R., Pandolfo, G., Di Rosa, A. E., Zoccali, R., et al. (2003). Olanzapine augmentation of paroxetine-refractory obsessive-compulsive disorder. Progress in Neuro-psychopharmacology & Biological Psychiatry, 27, 619–623. D'Arrigo, C., Migliardi, G., Santoro, V., Morgante, L., Muscatello, M. R., Ancione, M., et al. (2005). Effect of fluvoxamine on plasma risperidone concentrations in patients with schizophrenia. Pharmacological Research: The Official Journal of the Italian Pharmacological Society, 52, 497–501. Da Rocha, F. F., & Correa, H. (2007). Successful augmentation with aripiprazole in clomipramine-refractory obsessive-compulsive disorder. Progress in Neuropsychopharmacology & Biological Psychiatry, 31, 1550–1551. Davis, M. (2002). Role of NMDA receptors and MAP kinase in the amygdala in extinction of fear: clinical implications for exposure therapy. The European Journal of Neuroscience, 16, 395–398. De Haan, L., Beuk, N., Hoogenboom, B., Dingemans, P., & Linszen, D. (2002). Obsessive-compulsive symptoms during treatment with olanzapine and risperidone: A prospective study of 113 patients with recent-onset schizophrenia or related disorders. The Journal of Clinical Psychiatry, 63, 104–107. DeBattista, C., Solvason, B., Poirier, J., Kendrick, E., & Loraas, E. (2005). A placebocontrolled, randomized, double-blind study of adjunctive bupropion sustained release in the treatment of SSRI-induced sexual dysfunction Jul. Journal of Clinical Psychiatry, 66(7), 844–848. Delgado, P. L., Goodman, W. K., Price, L. H., Heninger, G. R., & Charney., D. S. (1990). Fluvoxamine/pimozide treatment of concurrent Tourette's and obsessivecompulsive disorder. The British Journal of Psychiatry: The Journal of Mental Science, 157, 762–765. Delle Chiaie, R., Scarciglia, P., Pasquini, M., Caredda, M., & Biondi., M. (2011). Aripiprazole augmentation in patients with resistant obsessive compulsive disorder: A pilot study. Clinical Practice and Epidemiology in Mental Health: CP & EMH, 7, 107–111. Denys, D., de Geus, F., van Megen, H. J. G. M., & Westenberg, H. G. M. (2004). A double-blind, randomized, placebo-controlled trial of quetiapine addition in patients with obsessive-compulsive disorder refractory to serotonin reuptake inhibitors. The Journal of Clinical Psychiatry, 65, 1040–1048. De Sousa, A. (2008). An open-label pilot study of naltrexone in childhood-onset trichotillomania. Journal of Child and Adolescent Psychopharmacology, 18(1), 30–33. Di Nicola, M., Tedeschi, D., Martinotti, G., De Vita, O., Monetta, M., Pozzi, G., et al. (2011). Pregabalin augmentation in treatment-resistant obsessive-compulsive

Please cite this article as: Borue, X., et al. Biological treatments for obsessive-compulsive and related disorders. Journal of ObsessiveCompulsive and Related Disorders (2015), http://dx.doi.org/10.1016/j.jocrd.2015.03.003i

67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108 109 110 111 112 113 114 115 116 117 118 119 120 121 122 123 124 125 126 127 128 129 130 131 132

X. Borue et al. / Journal of Obsessive-Compulsive and Related Disorders ∎ (∎∎∎∎) ∎∎∎–∎∎∎

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 Q24 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 66

disorder: A 16-week case series. Journal of Clinical Psychopharmacology, 31, 675–677. Diler, R. S., Yolga, A., Avci, A., & Scahill, L. (2003). Risperidone-induced obsessivecompulsive symptoms in two children. Journal of Child and Adolescent Psychopharmacology, 13(Suppl 1), S89–S92. Diniz, J. B., Shavitt, R. G., Fossaluza, V., Koran, L., de B. Pereira, C. A., & Miguel, E. C. (2011). A double-blind, randomized, controlled trial of fluoxetine plus quetiapine or clomipramine versus fluoxetine plus placebo for obsessive-compulsive disorder. Journal of Clinical Psychopharmacology, 31, 763–768. Dold, M., Aigner, M., Lanzenberger, R., & Kasper, S. (2013). Antipsychotic augmentation of serotonin reuptake inhibitors in treatment-resistant obsessive-compulsive disorder: A meta-analysis of double-blind, randomized, placebocontrolled trials. The International Journal of Neuropsychopharmacology/Official Scientific Journal of the Collegium Internationale Neuropsychopharmacologicum (CINP), 16, 557–574. Dougherty, D. D., Loh, R., Jenike, M. A., & Keuthen, N. J. (2006). Single modality versus dual modality treatment for trichotillomania: Sertraline, behavioral therapy, or both? Journal of Clinical Psychiatry, 67, 1086–1092. Ducasse, D., Boyer, L., Michel, P., Loundou, A., Macgregor, A., Micoulaud-Franchi, J.A., et al. (2014). D2 and D3 dopamine receptor affinity predicts effectiveness of antipsychotic drugs in obsessive-compulsive disorders: A metaregression analysis. Psychopharmacology Eisen, J. L., Sibrava, N. J., Boisseau, C. L., Mancebo, M. C., Stout, R. L., Pinto, A., et al. (2013). Five-year course of obsessive-compulsive disorder: Predictors of remission and relapse. The Journal of Clinical Psychiatry, 74, 233–239. Englisch, S., Esslinger, C., Inta, D., Weinbrenner, A., Peus, V., Gutschalk, A., et al. (2009). Clozapine-induced obsessive-compulsive syndromes improve in combination with aripiprazole. Clinical Neuropharmacology, 32, 227–229. Eryılmaz, G., Hızlı Sayar, G., Ozten, E., Gögcegöz Gül, I., & Karamustafalıoğlu, O. (2013). Aripirazole augmentation in clozapine-associated obsessive-compulsive symptoms in schizophrenia. Annals of General Psychiatry, 12, 40. Erzegovesi, S., Guglielmo, E., Siliprandi, F., & Bellodi, L. (2005). Low-dose risperidone augmentation of fluvoxamine treatment in obsessive-compulsive disorder: a double-blind, placebo-controlled study. European Neuropsychopharmacology: The Journal of the European College of Neuropsychopharmacology, 15, 69–74. Farrell, L. J., Waters, A. M., Boschen, M. J., Hattingh, L., McConnell, H., Milliner, E. L., et al. (2013). Difficult-to-treat pediatric obsessive-compulsive disorder: feasibility and preliminary results of a randomized pilot trial of D-cycloserineaugmented behavior therapy. Depression and Anxiety, 30, 723–731. Feder, R. (1995). Clonodine treatment of excessive sweating. Journal of Clinical Psychiatry, 56, 35. Fineberg, N. A., Hengartner, M. P., Bergbaum, C., Gale, T., Rössler, W., & Angst, J. (2013). Remission of obsessive-compulsive disorders and syndromes; evidence from a prospective community cohort study over 30 years. International Journal of Psychiatry in Clinical Practice, 17, 179–187. Fineberg, N. A., Reghunandanan, S., Brown, A., & Pampaloni, I. (2013). Pharmacotherapy of obsessive-compulsive disorder: Evidence-based treatment and beyond Feb. Australian and New Zealand Journal of Psychiatry, 47(2), 121–141. Fineberg, N. A., & Gale, T. M. (2005). Evidence-based pharmacotherapy of obsessivecompulsive disorder. International Journal of Neuropsychopharmacology, 8(1), 107–129 (Epub 2004 Sep 28). Fineberg, N. A., Sivakumaran, T., Roberts, A., & Gale, T. (2005). Adding quetiapine to SRI in treatment-resistant obsessive-compulsive disorder: A randomized controlled treatment study. International Clinical Psychopharmacology, 20, 223–226. Fitzgerald, K. D., Stewart, C. M., Tawile, V., & Rosenberg, D. R. (1999). Risperidone augmentation of serotonin reuptake inhibitor treatment of pediatric obsessive compulsive disorder. Journal of Child and Adolescent Psychopharmacology, 9, 115–123. Flament, M. F., Rapoport, J. L., Berg, C. J., Sceery, W., Kilts, C., Mellström, B., et al. (1985). Clomipramine treatment of childhood obsessive-compulsive disorder. A double-blind controlled study. Archives of General Psychiatry, 42(10), 977–983. Fornaro, M., Gabrielli, F., Mattei, C., Vinciguerra, V., & Fornaro, P. (2008). Aripiprazole augmentation in poor insight obsessive-compulsive disorder: a case report. Annals of General Psychiatry, 7, 26. Francobandiera, G. (2001). Olanzapine augmentation of serotonin uptake inhibitors in obsessive-compulsive disorder: An open study. Canadian Journal of Psychiatry Revue canadienne de psychiatrie, 46, 356–358. Friedman, S., Abdallah, T. A., Oumaya, M., Rouillon, F., & Guelfi, J.-D. (2007). Aripiprazole augmentation of clomipramine-refractory obsessive-compulsive disorder. The Journal of Clinical Psychiatry, 68, 972–973. Gadde, K. M., Wagner, R. H., 2nd, Connor, K. M., & Foust, M. S. (2007). Escitalopram treatment of trichotillomania. International Clinical Psychopharmacology, 22(1), 39–42. Geller, D. A., Biederman, J., Stewart, S. E., Mullin, B., Martin, A., Spencer, T., et al. (2003). Which SSRI? A meta-analysis of pharmacotherapy trials in pediatric obsessive-compulsive disorder Nov. American Journal of Psychiatry, 160(11), 1919–1928. Geller, D. A., Hoog, S. L., Heiligenstein, J. H., Ricardi, R. K., Tamura, R., Kluszynski, S., et al. (2001). Fluoxetine Pediatric OCD Study Team. Fluoxetine treatment for obsessive-compulsive disorder in children and adolescents: a placebocontrolled clinical trial Jul. Journal of the American Academy of Child & Adolescent Psychiatry, 40(7), 773–779. Ghaleiha, A., Entezari, N., Modabbernia, A., Najand, B., Askari, N., Tabrizi, M., et al. (2013). Memantine add-on in moderate to severe obsessive-compulsive disorder: randomized double-blind placebo-controlled study. Journal of Psychiatric Research, 47, 175–180.

17

67 Gibbons, R. D., Hur, K., Brown, C. H., Davis, J. M., & Mann, J. J. (2012). Benefits from antidepressants: synthesis of 6-week patient-level outcomes from double68 blind placebo-controlled randomized trials of fluoxetine and venlafaxine. 69 Archives of General Psychiatry, 69, 572–579. 70 Gilbert A. R.. (2011). In Hudak, Dougherty (Ed.), Medication management of Q25 obsessive-compulsive disorder in children and adolescents in clinical obsessive 71 and compulsive disorders in adults and children. Cambridge University Press. 72 Glick, I. D., Poyurovsky, M., Ivanova, O., & Koran, L. M. (2008). Aripiprazole in 73 schizophrenia patients with comorbid obsessive-compulsive symptoms: An open-label study of 15 patients. The Journal of Clinical Psychiatry, 69, 1856–1859. 74 Goodman, W. K., Kozak, M. J., Liebowitz, M., et al. (1996). Treatment of obsessive- Q26 75 compulsive disorder with fluvoxamine: A multicentre, double-blind, placebo76 controlled trial. International Clinical Psychopharmacology, 11, 21–29. 77 Goodman, W. K., Price, L. H., Delgado, P. L., et al. (1989). Specificity of serotonin reuptake inhibitors in the treatment of obsessive-compulsive disorder: Com78 parison of fluvoxamine and desipramine. Archives of General Psychiatry, 47, 79 577–585. 80 Golubchik, P., Sever, J., Weizman, A., & Zalsman, G. (2011). Methylphenidate treatment in pediatric patients with attention-deficit/hyperactivity disorder 81 and comorbid trichotillomania: a preliminary report. Clinical Neuropharmacol82 ogy, 34(3), 108–110. 83 Grados, M. A., Specht, M. W., Sung, H.-M., & Fortune, D. (2013). Glutamate drugs and 84 pharmacogenetics of OCD:A pathway-based exploratory approach. Expert Opinion on Drug Discovery, 8, 1515–1527. 85 Grady, T. A., Pigott, T. A., L'Heureux, F., Hill, J. L., Bernstein, S. E., & Murphy, D. L. 86 (1993). Double-blind study of adjuvant buspirone for fluoxetine-treated 87 patients with obsessive-compulsive disorder. The American Journal of Psychiatry, 150, 819–821. 88 Grant, J. E., Odlaug, B. L., Chamberlain, S. R., & Kim, S. W. (2011). Dronabinol, a 89 cannabinoid agonist, reduces hair pulling in trichotillomania: A pilot study Dec. 90 Psychopharmacology (Berl), 218(3), 493–502. Grant, J. E., Odlaug, B. L., & Kim, S. W. (2009). N-acetylcysteine, a glutamate 91 modulator, in the treatment of trichotillomania: A double-blind, placebo92 controlled study. Archives of General Psychiatry, 66, 756–763. 93 Grant, J. E., Odlaug, B. L., Schreiber, L. R., & Kim, S. W. (2014). The opiate antagonist, 94 naltrexone, in the treatment of trichotillomania: results of a double-blind, placebo-controlled study. Journal of Clinical Psychopharmacology, 34(1), 95 134–138. 96 Grant, P. J., Joseph, L. A., Farmer, C. A., Luckenbaugh, D. A., Lougee, L. C., Zarate, C. A., et al. 97 (2013). 12-week, placebo-controlled trial of add-on riluzole in the treatment of childhood-onset obsessive-compulsive disorder. Neuropsychopharmacology: Official 98 Publication of the American College of Neuropsychopharmacology 99 Grant, P., Lougee, L., Hirschtritt, M., & Swedo, S. E. (2007). An open-label trial of 100 riluzole, a glutamate antagonist, in children with treatment-resistant obses101 sive-compulsive disorder. Journal of Child and Adolescent Psychopharmacology, 17, 761–767. 102 Greenberg, W. M., Benedict, M. M., Doerfer, J., Perrin, M., Panek, L., Cleveland, W. L., 103 et al. (2009). Adjunctive glycine in the treatment of obsessive-compulsive 104 disorder in adults. Journal of Psychiatric Research, 43, 664–670. Haghighi, M., Jahangard, L., Mohammad-Beigi, H., Bajoghli, H., Hafezian, H., Rahimi, A., 105 et al. (2013). In a double-blind, randomized and placebo-controlled trial, adjuvant 106 memantine improved symptoms in inpatients suffering from refractory obsessive107 compulsive disorders (OCD). Psychopharmacology, 228, 633–640. Heidari, M., Zarei, M., Hosseini, S. M. R., Taghvaei, R., Maleki, H., Tabrizi, M., et al. 108 (2014). Ondansetron or placebo in the augmentation of fluvoxamine response Q27 109 over 8 weeks in obsessive-compulsive disorder. International Clinical 110 Psychopharmacology 111 Hewlett, W. A., Schmid, S. P., & Salomon, R. M. (2003). Pilot trial of ondansetron in the treatment of 8 patients with obsessive-compulsive disorder. The Journal of 112 Clinical Psychiatry, 64, 1025–1030. 113 Higuma, H., Kanehisa, M., Maruyama, Y., Ishitobi, Y., Tanaka, Y., Tsuru, J., et al. 114 (2012). Aripiprazole augmentation in 13 patients with refractory obsessivecompulsive disorder: a case series. The World Journal of Biological Psychiatry: 115 The Official Journal of the World Federation of Societies of Biological Psychiatry, 13, 116 14–21. 117 Hollander, E., Allen, A., Kwon, J., Aronowitz, B., Schmeidler, J., Wong, C., et al. (1999). 118 Clomipramine vs desipramine crossover trial in body dysmorphic disorder: Selective efficacy of a serotonin reuptake inhibitor in imagined ugliness Nov. 119 Archives of General Psychiatry, 56(11), 1033–1039. 120 Hollander, E., Baldini Rossi, N., Sood, E., & Pallanti, S. (2003a). Risperidone augmentation 121 in treatment-resistant obsessive-compulsive disorder: A double-blind, placebocontrolled study. The International Journal of Neuropsychopharmacology/Official 122 Scientific Journal of the Collegium Internationale Neuropsychopharmacologicum (CINP), 123 6, 397–401. 124 Hollander, E., Kaplan, A., & Stahl, S. M. (2003b). A double-blind, placebo-controlled 125 trial of clonazepam in obsessive-compulsive disorder. The World Journal of Biological Psychiatry: The Official Journal of the World Federation of Societies of 126 Biological Psychiatry, 4, 30–34. 127 Hou, Y.-C., & Lai, C.-H. (2014). Rapid responses of high-dose combined therapy of 128 escitalopram and aripiprazole in a case of severe obsessive compulsive disorder with delusion. The Journal of Neuropsychiatry and Clinical Neurosciences, 26, 129 E44–E45. 130 Hudak, R., & Wisner, K. L. (2012). Diagnosis and treatment of postpartum 131 obsessions and compulsions that involve infant harm Apr. American Journal of 132 Psychiatry, 169(4), 360–363.

Please cite this article as: Borue, X., et al. Biological treatments for obsessive-compulsive and related disorders. Journal of ObsessiveCompulsive and Related Disorders (2015), http://dx.doi.org/10.1016/j.jocrd.2015.03.003i

18

1 2 3 4 5Q28 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 66

X. Borue et al. / Journal of Obsessive-Compulsive and Related Disorders ∎ (∎∎∎∎) ∎∎∎–∎∎∎

Husted, D. S., & Shapira, N. A. (2004). A review of the treatment for refractory obsessive-compulsive disorder: from medicine to deep brain stimulation. CNS Spectrums, 9, 833–847. James, A. C. (2010). Prescribing antipsychotics for children and adolescents. Advances in Psychiatric Treatment, 16, 63–75. Jiang, H. Y., Chen, H. Z., Hu, X. J., Yang, W., Deng, M., Zhang, Y. H., et al. (2014). Use of selective serotonin reuptake inhibitors and risk of upper gastrointestinal bleeding: A systematic review and meta-analysis. Clinical Gastroenterology and Hepatology (June 30) Karadağ, F., Kalkan Oğuzhanoğlu, N., Yüksel, D., Kıraç, S., Cura, C., Ozdel, O., et al. (2013). The comparison of pre- and post-treatment (99m)Tc HMPAO brain SPECT images in patients with obsessive-compulsive disorder. Psychiatry Research, 213, 169–177. Kawahara, T., Ueda, Y., & Mitsuyama, Y. (2000). A case report of refractory obsessive-compulsive disorder improved by risperidone augmentation of clomipramine treatment. Psychiatry and Clinical Neurosciences, 54, 599–601. Koran, L. M., Hackett, E., Rubin, A., et al. (2002). Efficacy of sertraline in the longterm treatment of obsessive-compulsive disorder. American Journal of Psychiatry, 159, 89–95. Koran, L. M., Hanna, G. L., Hollander, E., et al. (2007). Practice Guideline for the Treatment of Patients with Obsessive-Compulsive Disorder. Arlington, VA: American Psychiatric Association. Koran, L. M., Gamel, N. N., Choung, H. W., Smith, E. H., & Aboujaoude, E. N. (2005). Mirtazapine for obsessive-compulsive disorder: An open trial followed by double-blind discontinuation. The Journal of Clinical Psychiatry, 66, 515–520. Koran, L. M., Ringold, A. L., & Elliott, M. A. (2000). Olanzapine augmentation for treatment-resistant obsessive-compulsive disorder. The Journal of Clinical Psychiatry, 61, 514–517. Kordon, A., Wahl, K., Koch, N., Zurowski, B., Anlauf, M., Vielhaber, K., et al. (2008). Quetiapine addition to serotonin reuptake inhibitors in patients with severe obsessive-compulsive disorder: a double-blind, randomized, placebocontrolled study. Journal of Clinical Psychopharmacology, 28, 550–554. Kronig, M. H., Apter, J., Asnis, G., Bystritsky, A., Curtis, G., Ferguson, J., et al. (1999). Placebo-controlled, multicenter study of sertraline treatment for obsessivecompulsive disorder. Journal of Clinical Psychopharmacology, 19(2), 172–176. Kronig, M. H., Apter, J., Asnis, G., et al. (1999). Placebo-controlled, multicenter study of sertraline treatment for obsessive-compulsive disorder. Journal of Clinical Psychopharmacology, 19, 172–176. Kulkarni, G., Narayanaswamy, J. C., & Math, S. B. (2012). Olanzapine induced denovo obsessive compulsive disorder in a patient with schizophrenia. Indian Journal of Pharmacology, 44, 649–650. Kumar, T. C., & Khanna, S. (2000). Lamotrigine augmentation of serotonin re-uptake inhibitors in obsessive-compulsive disorder. The Australian and New Zealand Journal of Psychiatry, 34, 527–528. Kushner, M. G., Kim, S. W., Donahue, C., Thuras, P., Adson, D., Kotlyar, M., et al. (2007). D-cycloserine augmented exposure therapy for obsessive-compulsive disorder. Biological Psychiatry, 62, 835–838. Lafleur, D. L., Pittenger, C., Kelmendi, B., Gardner, T., Wasylink, S., Malison, R. T., et al. (2006). N-acetylcysteine augmentation in serotonin reuptake inhibitor refractory obsessive-compulsive disorder. Psychopharmacology, 184, 254–256. Lai, C.-H. (2009). Aripiprazole treatment in an adolescent patient with chronic motor tic disorder and treatment-resistant obsessive-compulsive disorder. The International Journal of Neuropsychopharmacology/Official Scientific Journal of the Collegium Internationale Neuropsychopharmacologicum (CINP), 12, 1291–1293. Leonard, H. L., Swedo, S. E., Rapoport, J. L., Koby, E. V., Lenane, M. C., Cheslow, D. L., et al. (1989). Treatment of obsessive-compulsive disorder with clomipramine and desipramine in children and adolescents. A double-blind crossover comparison. Archives of General Psychiatry, 46(12), 1088–1092. Levy, E., Margolese, H. C., Sultan, S., & Chouinard, G. (2003). Obsessive-compulsive symptoms in schizophrenia induced by risperidone and responding to fluoxetine. Canadian Journal of Psychiatry. Revue canadienne de psychiatrie, 48, 709–710. Li, X., May, R. S., Tolbert, L. C., Jackson, W. T., Flournoy, J. M., & Baxter, L. R. (2005). Risperidone and haloperidol augmentation of serotonin reuptake inhibitors in refractory obsessive-compulsive disorder: A crossover study. The Journal of Clinical Psychiatry, 66, 736–743. Lochner, C., Seedat, S., Niehaus, D. J., & Stein, D. J. (2006). Topiramate in the treatment of trichotillomania: an open-label pilot study. International Clinical Psychopharmacology, 21(5), 255–259. Mahendran, R., Liew, E., & Subramaniam, M. (2007). De novo emergence of obsessive-compulsive symptoms with atypical antipsychotics in asian patients with schizophrenia or schizoaffective disorder: a retrospective, cross-sectional study. The Journal of Clinical Psychiatry, 68, 542–545. Maina, G., Pessina, E., Albert, U., & Bogetto, F. (2008). 8-week, single-blind, randomized trial comparing risperidone versus olanzapine augmentation of serotonin reuptake inhibitors in treatment-resistant obsessive-compulsive disorder. European Neuropsychopharmacology: The Journal of the European College of Neuropsychopharmacology, 18, 364–372. Mancebo, M. C., Boisseau, C. L., Garnaat, S. L., Eisen, J. L., Greenberg, B. D., Sibrava, N. J., et al. (2014). Long-term course of pediatric obsessive-compulsive disorder: 3 years of prospective follow-up. Comprehensive Psychiatry Marazziti, D., Pfanner, C., Dell'Osso, B., Ciapparelli, A., Presta, S., Corretti, G., et al. (2005). Augmentation strategy with olanzapine in resistant obsessive compulsive disorder: an Italian long-term open-label study. Journal of Psychopharmacology (Oxford, England), 19, 392–394.

March, J. S., Biederman, J., Wolkow, R., Safferman, A., Mardekian, J., Cook, E. H., et al. (1998). Sertraline in children and adolescents with obsessive-compulsive disorder: a multicenter randomized controlled trial. JAMA, 280(20), 1752–1756. Marcks, B. A., Weisberg, R. B., Dyck, I., & Keller, M. B. (2011). Longitudinal course of obsessive-compulsive disorder in patients with anxiety disorders: A 15-year prospective follow-up study. Comprehensive Psychiatry, 52, 670–677. Marks, I. M., Stern, R. S., Mawson, D., Cobb, J., & McDonald, R. (1980). Clomipramine and exposure for obsessive compulsive rituals. British Journal of Psychiatry, 136, 1–25. Masi, G., Pfanner, C., & Brovedani, P. (2013). Antipsychotic augmentation of selective serotonin reuptake inhibitors in resistant tic-related obsessive-compulsive disorder in children and adolescents: A naturalistic comparative study. Journal of Psychiatric Research, 47, 1007–1012. Masi, G., Pfanner, C., Millepiedi, S., & Berloffa, S. (2010). Aripiprazole augmentation in 39 adolescents with medication-resistant obsessive-compulsive disorder. Journal of clinical psychopharmacology, 30, 688–693. Mataix-Cols, D., Rauch, S. L., Manzo, P. A., Jenike, M. A., & Baer, L. (1999). Use of factor-analyzed symptom dimensions to predict outcome with serotonin reuptake inhibitors and placebo in the treatment of obsessive-compulsive disorder Sep. American Journal of Psychiatry, 156(9), 1409–1416. Mataix-Cols, D., Turner, C., Monzani, B., Isomura, K., Murphy, C., Krebs, G., et al. (2014). Cognitive-behavioural therapy with post-session D-cycloserine augmentation for paediatric obsessive-compulsive disorder: pilot randomised controlled trial. The British Journal of Psychiatry: The Journal of Mental Science, 204, 77–78. Matsunaga, H., Hayashida, K., Maebayashi, K., Mito, H., & Kiriike, N. (2011). A case series of aripiprazole augmentation of selective serotonin reuptake inhibitors in treatment-refractory obsessive compulsive disorder. International Journal of Psychiatry in Clinical Practice, 15, 263–269. Matsunaga, H., Nagata, T., Hayashida, K., Ohya, K., Kiriike, N., & Stein, D. J. (2009). A long-term trial of the effectiveness and safety of atypical antipsychotic agents in augmenting SSRI-refractory obsessive-compulsive disorder. The Journal of Clinical Psychiatry, 70, 863–868. McDougle, C. J. (1994). Haloperidol addition in fluvoxamine-refractory obsessivecompulsive disorder. Archives of General Psychiatry, 51, 302. McDougle, C. J., Barr, L. C., Goodman, W. K., Pelton, G. H., Aronson, S. C., Anand, A., et al. (1995a). Lack of efficacy of clozapine monotherapy in refractory obsessivecompulsive disorder. The American Journal of Psychiatry, 152, 1812–1814. McDougle, C. J., Epperson, C. N., Pelton, G. H., Wasylink, S., & Price, L. H. (2000). A double-blind, placebo-controlled study of risperidone addition in serotonin reuptake inhibitor-refractory obsessive-compulsive disorder. Archives of general psychiatry, 57, 794–801. McDougle, C. J., Fleischmann, R. L., Epperson, C. N., Wasylink, S., Leckman, J. F., & Price, L. H. (1995b). Risperidone addition in fluvoxamine-refractory obsessivecompulsive disorder: Three cases. The Journal of Clinical Psychiatry, 56, 526–528. McDougle, C. J., Goodman, W. K., Leckman, J. F., Holzer, J. C., Barr, L. C., McCanceKatz, E., et al. (1993). Limited therapeutic effect of addition of buspirone in fluvoxamine-refractory obsessive-compulsive disorder. The American Journal of Psychiatry, 150, 647–649. Metin, O., Yazici, K., Tot, S., & Yazici, A. E. (2003). Amisulpiride augmentation in treatment resistant obsessive-compulsive disorder: An open trial. Human Psychopharmacology, 18, 463–467. Mir, A., Shivakumar, K., Williamson, R. J., McAllister, V., O'Keane, V., & Aitchison, K. J. (2008). Change in sexual dysfunction with aripiprazole: a switching or add-on study. Journal of Psychopharmacology (Oxford, England), 22, 244–253. Montgomery, S. A., Kasper, S., Stein, D. J., et al. (2001). Citalopram 20 mg, 40 mg, and 60 mg are all effective and well tolerated compared with placebo in obsessive-compulsive disorder. International Clinical Psychopharmacology, 16, 75–86. Montgomery, S. A. (2003). Clomipramine in Obsessional Neurosis: A placebo controlled trial. Pharmaceutical Medicine, 1, 189–192. Mowla, A., Khajeian, A. M., Sahraian, A., Chohedri, A. H., & Kashkoli, F. (2010). Topiramate augmentation in resistant OCD: A double-blind placebo-controlled clinical trial. CNS Spectrums Munk-Olsen, T., Laursen, T. M., Pedersen, C. B., Mors, O., & Mortensen, P. B. (2006). New parents and mental disorders: A population-based register study. JAMA, 296, 2582–2589. Murphy, T. K., Mutch, P. J., Reid, J. M., Edge, P. J., Storch, E. A., Bengtson, M., et al. (2009). Open label aripiprazole in the treatment of youth with tic disorders. Journal of Child and Adolescent Psychopharmacology, 19, 441–447. Murphy, T. K., Segarra, A., Storch, E. A., & Goodman, W. K. (2008). SSRI adverse events: how to monitor and manage. International Review of Psychiatry, 20(2), 203–208. http://dx.doi.org/10.1080/09540260801889211. Muscatello, M. R. A., Bruno, A., Pandolfo, G., Micò, U., Scimeca, G., Romeo, V. M., et al. (2011). Effect of aripiprazole augmentation of serotonin reuptake inhibitors or clomipramine in treatment-resistant obsessive-compulsive disorder: A doubleblind, placebo-controlled study. Journal of Clinical Psychopharmacology, 31, 174–179. Muscatello, M. R., Spina, E., Bandelow, B., & Baldwin, D. S. (2012). Clinically relevant drug interactions in anxiety disorders. Human Psychopharmacology, 27, 239–253. Ninan, P. T., Koran, L. M., Kiev, A., Davidson, J. R., Rasmussen, S. A., Zajecka, J. M., et al. (2006). High-dose sertraline strategy for nonresponders to acute treatment for obsessive-compulsive disorder: A multicenter double-blind trial Jan. Journal of Clinical Psychiatry, 67(1), 15–22.

Please cite this article as: Borue, X., et al. Biological treatments for obsessive-compulsive and related disorders. Journal of ObsessiveCompulsive and Related Disorders (2015), http://dx.doi.org/10.1016/j.jocrd.2015.03.003i

67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108 109 110 111 112 113 114 115 116 117 118 119 120 121 122 123 124 125 126 127 128 129 130 131 132

X. Borue et al. / Journal of Obsessive-Compulsive and Related Disorders ∎ (∎∎∎∎) ∎∎∎–∎∎∎

1 2 3 4Q29 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 66

Ninan, P. T., Rothbaum, B. O., Marsteller, F. A., Knight, B. T., & Eccard, M. B. (2000). A placebo-controlled trial of cognitive-behavioral therapy and clomipramine in Trichotillomania. Journal of Clinical Psychiatry, 61, 47–50. Obsessive-compulsive Disorder: Contemporary Issues in Treatment. (2000). (661). L. Erlbaum Associates, Publishers. Ornoy, A., & Koren, G. (2014). Selective serotonin reuptake inhibitors in human pregnancy: On the way to resolving the controversy. Seminars in Fetal and Neonatal Medicine, 19(3), 188–194. Oulis, P., Mourikis, I., & Konstantakopoulos, G. (2011). Pregabalin augmentation in treatment-resistant obsessive-compulsive disorder. International Clinical Psychopharmacology, 26, 221–224. Ozer, S., Arsava, M., Ertuğrul, A., & Demir, B. (2006). Obsessive compulsive symptoms associated with quetiapine treatment in a schizophrenic patient: A case report. Progress in Neuro-Psychopharmacology & Biological Psychiatry, 30, 724–727. Oztürk, M., & Coskun, M. (2009). Successful aripiprazole augmentation in a child with drug-resistant obsessive-compulsive disorder. Journal of Clinical Psychopharmacology, 29, 607–609. Pallanti, S., Bernardi, S., Antonini, S., Singh, N., & Hollander, E. (2009). Ondansetron augmentation in treatment-resistant obsessive-compulsive disorder: A preliminary, single-blind, prospective study. CNS Drugs, 23, 1047–1055. Pallanti, S., Bernardi, S., Antonini, S., Singh, N., & Hollander, E. (2014). Ondansetron augmentation in patients with obsessive-compulsive disorder who are inadequate responders to serotonin reuptake inhibitors: improvement with treatment and worsening following discontinuation. European Neuropsychopharmacology: The Journal of the European College of Neuropsychopharmacology, 24, 375–380. Pallanti, S., & Quercioli, L. (2006). Treatment-refractory obsessive-compulsive disorder: Methodological issues, operational definitions and therapeutic lines. Progress in Neuro-Psychopharmacology & Biological Psychiatry, 30, 400–412. Pallanti, S., Quercioli, L., & Bruscoli, M. (2004). Response acceleration with mirtazapine augmentation of citalopram in obsessive-compulsive disorder patients without comorbid depression: A pilot study. The Journal of Clinical Psychiatry, 65, 1394–1399. Pasquini, M., Berardelli, I., & Biondi, M. (2010). Amantadine augmentation for refractory obsessive-compulsive disorder: A case report. Journal of Clinical Psychopharmacology, 30, 85–86. Pediatric OCD Treatment Study, T. (2004). Cognitive-behavior therapy, sertraline, and their combination for children and adolescents with obsessive-compulsive disorder: The Pediatric OCD Treatment Study (POTS) randomized controlled trial. JAMA: The Journal of the American Medical Association, 292, 1969–1976. Pessina, E., Albert, U., Bogetto, F., & Maina, G. (2009). Aripiprazole augmentation of serotonin reuptake inhibitors in treatment-resistant obsessive-compulsive disorder: A 12-week open-label preliminary study. International Clinical Psychopharmacology, 24, 265–269. Pfanner, C., Marazziti, D., Dell'Osso, L., Presta, S., Gemignani, A., Milanfranchi, A., et al. (2000). Risperidone augmentation in refractory obsessive-compulsive disorder: An open-label study. International Clinical Psychopharmacology, 15, 297–301. Phillips, K. A., Albertini, R. S., & Rasmussen, S. A. (2002). A randomized placebocontrolled trial of fluoxetine in body dysmorphic disorder. Archives of General Psychiatry, 59(4), 381–388. Phillips, K. A., Albertini, R. S., Siniscalchi, J. M., Khan, A., & Robinson, M. (2001). Effectiveness of pharmacotherapy for body dysmorphic disorder: A chartreview study Sep. J Clin Psychiatry, 62(9), 721–727. Phillips, K. A., & Hollander, E. (2008). Treating body dysmorphic disorder with medication: evidence, misconceptions, and a suggested approach. Body Image, 5(1), 13–27. Phillips, K. A., & Kelly, M. M. (2009). Suicidality in a placebo-controlled fluoxetine study of body dysmorphic disorder. International Clinical Psychopharmacology, 24(1), 26–28. Phillips, K. A. (1996). An open study of buspirone augmentation of serotoninreuptake inhibitors in body dysmorphic disorder. Psychopharmacology Bulletin, 32(1), 175–180. Phillips, K. A. (2005). Placebo-controlled study of pimozide augmentation of fluoxetine in body dysmorphic disorder. American Journal of Psychiatry, 162 (2), 377–379. Pigott, T. A., L'Heureux, F., Hill, J. L., Bihari, K., Bernstein, S. E., & Murphy, D. L. (1992). A double-blind study of adjuvant buspirone hydrochloride in clomipraminetreated patients with obsessive-compulsive disorder. Journal of Clinical Psychopharmacology, 12, 11–18. Pittenger, C., Kelmendi, B., Wasylink, S., Bloch, M. H., & Coric, V. (2008). Riluzole augmentation in treatment-refractory obsessive-compulsive disorder: A series of 13 cases, with long-term follow-up. Journal of Clinical Psychopharmacology, 28, 363–367. Poyurovsky, M., Glick, I., & Koran, L. M. (2010). Lamotrigine augmentation in schizophrenia and schizoaffective patients with obsessive-compulsive symptoms. Journal of Psychopharmacology (Oxford, England), 24, 861–866. Ramasubbu, R. (2002). Antiobsessional effect of risperidone add-on treatment in serotonin reuptake inhibitor–refractory obsessive-compulsive disorder may be dose-dependent. Archives of General Psychiatry, 59, 472. Riddle, M. A., Reeve, E. A., Yaryura-Tobias, J. A., Yang, H. M., Claghorn, J. L., Gaffney, G., et al. (2001). Fluvoxamine for children and adolescents with obsessivecompulsive disorder: a randomized, controlled, multicenter trial. Journal of the American Academy of Child & Adolescent Psychiatry, 40(2), 222–229. Rodriguez, C. I., Kegeles, L. S., Levinson, A., Feng, T., Marcus, S. M., Vermes, D., et al. (2013). Randomized controlled crossover trial of ketamine in obsessive-

19

67 compulsive disorder: Proof-of-concept. Neuropsychopharmacology: Official Publication of the American College of Neuropsychopharmacology, 38, 2475–2483. 68 Romano, S., Goodman, W., Tamura, R., & Gonzales, J. (2001). Long-term treatment of 69 obsessive-compulsive disorder after an acute response: a comparison of 70 fluoxetine versus placebo. Journal of Clinical Psychopharmacology, 21(1), 46–52. Rosen, R. C., Lane, R. M., & Menza, M. (1999). Effects of SSRIs on sexual function: A 71 critical review. Journal of Clinical Psychopharmacology, 19(1), 67–85. 72 Rosenberg, D. R., & Keshavan, M. S. (1998). A.E. Bennett Research Award. Toward a 73 neurodevelopmental model of of obsessive–compulsive disorder. Biological Psychiatry, 43(9), 623–640. 74 Rubio, G., Jiménez-Arriero, M. A., Martínez-Gras, I., Manzanares, J., & Palomo, T. 75 (2006). The effects of topiramate adjunctive treatment added to antidepres76 sants in patients with resistant obsessive-compulsive disorder. Journal of Clinical Psychopharmacology, 26, 341–344. 77 Sala, M., Vicentini, A., Brambilla, P., Montomoli, C., Jogia, J. R., Caverzasi, E., et al. 78 (2005). QT interval prolongation related to psychoactive drug treatment: A 79 comparison of monotherapy versus polytherapy. Annals of General Psychiatry, 4, 80 1. Sarkar, R., Klein, J., & Krüger, S. (2008). Aripiprazole augmentation in treatment81 refractory obsessive-compulsive disorder. Psychopharmacology, 197, 687–688. 82 Savas, H. A., Yumru, M., & Ozen, M. E. (2008). Quetiapine and ziprasidone as 83 adjuncts in treatment-resistant obsessive-compulsive disorder: a retrospective comparative study. Clinical Drug Investigation, 28, 439–442. 84 Saxena, S., Brody, A. L., Maidment, K. M., & Baxter, L. R., Jr. (2007). Paroxetine 85 treatment of compulsive hoarding. Journal of Psychiatric Research, 41(6), 86 481–487. Saxena, S. (2011). Pharmacotherapy of compulsive hoarding. Journal of Clinical Q30 87 Psychology, 67(5), 477–484 doi: 10.1002. 88 Sayyah, M., Sayyah, M., Boostani, H., Ghaffari, S. M., & Hoseini, A. (2012). Effects of 89 aripiprazole augmentation in treatment-resistant obsessive-compulsive disorder (a double blind clinical trial). Depression and Anxiety, 29, 850–854. 90 Schirmbeck, F., & Zink, M. (2013). Comorbid obsessive-compulsive symptoms in 91 schizophrenia: contributions of pharmacological and genetic factors. Frontiers 92 in Pharmacology, 4, 99. Schönfelder, S., Schirmbeck, F., Waltereit, R., Englisch, S., & Zink, M. (2011). 93 Aripiprazole improves olanzapine-associated obsessive compulsive symptoms 94 in schizophrenia. Clinical Neuropharmacology, 34, 256–257. 95 Selvi, Y., Atli, A., Aydin, A., Besiroglu, L., Ozdemir, P., & Ozdemir, O. (2011). The 96 comparison of aripiprazole and risperidone augmentation in selective serotonin reuptake inhibitor-refractory obsessive-compulsive disorder: a single-blind, 97 randomised study. Human Psychopharmacology, 26, 51–57. 98 Shapira, N. A., Ward, H. E., Mandoki, M., Murphy, T. K., Yang, M. C. K., Blier, P., et al. 99 (2004). A double-blind, placebo-controlled trial of olanzapine addition in fluoxetine-refractory obsessive-compulsive disorder. Biological Psychiatry, 55, 100 553–555. 101 Simpson, H. B., Foa, E. B., Liebowitz, M. R., Huppert, J. D., Cahill, S., Maher, M. J., et al. 102 (2013). Cognitive-behavioral therapy vs risperidone for augmenting serotonin reuptake inhibitors in obsessive-compulsive disorder: A randomized clinical 103 trial. JAMA Psychiatry, 70, 1190–1199. 104 Sit, D. K., Perel, J. M., Helsel, J. C., & Wisner, K. L. (2008). Changes in antidepressant 105 metabolism and dosing across pregnancy and early postpartum. Journal of Clinical Psychiatry, 69(4), 652–658. 106 Skoog, G., & Skoog, I. (1999). A 40-year follow-up of patients with obsessive107 compulsive disorder [see commetns]. Archives of General Psychiatry, 56, 108 121–127. 109 Snorrason, I., Belleau, E., & Woods, W. (2012). How related are hair pulling disorder (trichotillomania) and skin pulling disorder? A review of evidence for cormor110 bidity, similarities and shared etiology. Clinical Psychology Review, 32, 618–629. 111 Soltani, F., Sayyah, M., Feizy, F., Malayeri, A., Siahpoosh, A., & Motlagh, I. (2010). A 112 double-blind, placebo-controlled pilot study of ondansetron for patients with obsessive-compulsive disorder. Human Psychopharmacology, 25, 509–513. 113 Soomro, G. M., Altman, D. G., Rajagopal, S., & Oakley Browne, M. (2008). Selective 114 serotonin Re-uptake inshibitors (SSRI) versus placebo for obsessive compulsive 115 disorder (OCD). The Cochrane Collaboration, The Chochrane Library(1). Soomro, G. M. (2012). Obsessive compulsive disorder. Clinical Evidence (Online), 116 2012, 1004. 117 Spina, E., Avenoso, A., Scordo, M. G., Ancione, M., Madia, A., Gatti, G., et al. (2002). 118 Inhibition of risperidone metabolism by fluoxetine in patients with schizo119 phrenia: A clinically relevant pharmacokinetic drug interaction. Journal of Clinical Psychopharmacology, 22, 419–423. 120 Spina, E., & de Leon, J. (2007). Metabolic drug interactions with newer antipsycho121 tics: A comparative review. Basic & Clinical Pharmacology & Toxicology, 100, 122 4–22. Stamouli, S., & Lykouras, L. (2006). Quetiapine-induced obsessive-compulsive 123 symptoms: A series of five cases. Journal of Clinical Psychopharmacology, 26, 124 396–400. 125 Stein, D. J., Andersen, E. W., Tonnoir, B., & Fineberg, N. (2007). Escitalopram in obsessive-compulsive disorder: A randomized, placebo-controlled, paroxetine126 referenced, fixed-dose, 24-week study Apr. Current Medical Research and 127 Opinion, 23(4), 701–711. 128 Stein, D. J., Carey, P. D., Lochner, C., Seedat, S., Fineberg, N., & Andersen, E. W. (2008). Escitalopram in obsessive-compulsive disorder: Response of symptom dimen129 sions to pharmacotherapy. CNS Spectrums, 13(6), 492–498. 130 Stein, D. J., & Hollander, E. (1992). Low-dose pimozide augmentation of serotonin 131 reuptake blockers in the treatment of trichotillomania. The Journal of Clinical 132 Psychiatry, 53, 123–126.

Please cite this article as: Borue, X., et al. Biological treatments for obsessive-compulsive and related disorders. Journal of ObsessiveCompulsive and Related Disorders (2015), http://dx.doi.org/10.1016/j.jocrd.2015.03.003i

20

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45

X. Borue et al. / Journal of Obsessive-Compulsive and Related Disorders ∎ (∎∎∎∎) ∎∎∎–∎∎∎

Stewart, S. E., Jenike, E. A., Hezel, D. M., Stack, D. E., Dodman, N. H., Shuster, L., et al. (2010). A single-blinded case-control study of memantine in severe obsessivecompulsive disorder. Journal of Clinical Psychopharmacology, 30, 34–39. Storch, E. A., Goddard, A. W., Grant, J. E., De Nadai, A. S., Goodman, W. K., Mutch, P. J., et al. (2013). Double-blind, placebo-controlled, pilot trial of paliperidone augmentation in serotonin reuptake inhibitor-resistant obsessive-compulsive disorder. The Journal of Clinical Psychiatry, 74, e527–e532. Storch, E. A., Lehmkuhl, H., Geffken, G. R., Touchton, A., & Murphy, T. K. (2008a). Aripiprazole augmentation of incomplete treatment response in an adolescent male with obsessive-compulsive disorder. Depression and Anxiety, 25, 172–174. Storch, E. A., Merlo, L. J., Bengtson, M., Murphy, T. K., Lewis, M. H., Yang, M. C., et al. (2007). D-cycloserine does not enhance exposure-response prevention therapy in obsessive-compulsive disorder. International Clinical Psychopharmacology, 22, 230–237. Storch, E. A., Merlo, L. J., Larson, M. J., Marien, W. E., Geffken, G. R., Jacob, M. L., et al. (2008b). Clinical features associated with treatment-resistant pediatric obsessive-compulsive disorder. Comprehensive Psychiatry, 49, 35–42. Storch, E. A., Murphy, T. K., Goodman, W. K., Geffken, G. R., Lewin, A. B., Henin, A., et al. (2010). A preliminary study of D-cycloserine augmentation of cognitivebehavioral therapy in pediatric obsessive-compulsive disorder. Biological Psychiatry, 68, 1073–1076. Streichenwein, S. M., & Thornby, J. I. (1995). A long-term, double-blind, placebocontrolled crossover trial of the efficacy of fluoxetine for Trichotillomania. American Journal of Psychiatry, 152, 1192–1196. Swets, M., Dekker, J., van Emmerik-van Oortmerssen, K., Smid, G. E., Smit, F., de Haan, L., et al. (2014). The obsessive compulsive spectrum in schizophrenia, a meta-analysis and meta-regression exploring prevalence rates. Schizophrenia Research, 152, 458–468. Swedo, S. E., Leonard, H. L., Rapoport, J. L., Lenane, M. C., Goldberger, E. L, & Cheslow, D. L. (1989). A double-blind comparison of clomipramine and desipramine in the treatment of trichotillomania (hair pulling). New England Journal of Medicine, 321, 497–501. Szegedi, A, Wetzel, H, Leal, M, Hartter, S, & Hiemke, C. (1996). Combination treatment with clomipramine and fluvoxamine: drug monitoring, safety, and tolerability data. Journal of Clinical Psychiatry, 57, 257–264. Thomsen, P. H. (2004). Risperidone augmentation in the treatment of severe adolescent OCD in SSRI-refractory cases: a case-series. Annals of Clinical Psychiatry: Official Journal of the American Academy of Clinical Psychiatrists, 16, 201–207. Tollefson, G., Rampey, A., Potvin, J., et al. (1994). A multicenter investigation of fixed-dose fluoxetine in the treatment of obsessive-compulsive disorder. Archives of General Psychiatry, 51, 559–567. Uguz, F. (2010). Successful treatment of comorbid obsessive-compulsive disorder with aripiprazole in three patients with bipolar disorder. General Hospital Psychiatry, 32, 556–558. Urichuk, L., Prior, T., Dursun, S., & Baker, G. (2008). Metabolism of atypical antipsychotics: Involvement of cytochrome P450 enzymes and relevance for drug–drug interactions. Current Drug Metabolism, 9, 410–418. Uzun, O. (2010). Lamotrigine as an augmentation agent in treatment-resistant obsessive-compulsive disorder: A case report. Journal of Psychopharmacology (Oxford, England), 24, 425–427. Van Ameringen, M., Mancini, C., Patterson, B., & Bennett, M. (2006). Topiramate augmentation in treatment-resistant obsessive-compulsive disorder: A retrospective, open-label case series. Depression and Anxiety, 23, 1–5. Van Ameringen, M., Mancini, C., Patterson, B., Bennett, M., & Oakman, J. (2010). A randomized, double-blind, placebo-controlled trial of olanzapine in the treatment of trichotillomania. The Journal of Clinical Psychiatry, 71, 1336–1343.

46 Van Ameringen, M., Patterson, B., & Simpson, W. (2014). DSM-5 obsessive Q31 compulsive and related disorders: Clinical implications of new crieria. Depres47 sion and Anxiety (Mar 10) 48 Van Ameringen, M., Simpson, W., Patterson, B., Dell'osso, B., Fineberg, N., Hollander, 49 E., et al. (2014). Pharmacological treatment strategies in obsessive compulsive 50 disorder: A cross-sectional view in nine international OCD centers. Journal of Psychopharmacology (Oxford, England) 0269881113517955– 51 van Minnen, A., Hoogduin, K. A., Keijsers, G. P., Hellenbrand, I., & Hendriks, G. J. 52 (2003). Treatment of trichotillomania with behavioral therapy or fluoxetine: A 53 randomized, waiting-list controlled study. Archives of General Psychiatry, 60, 54 517–522. Van Nimwegen, L., de Haan, L., van Beveren, N., Laan, W., van den Brink, W., & 55 Linszen, D. (2008). Obsessive-compulsive symptoms in a randomized, double56 blind study with olanzapine or risperidone in young patients with early 57 psychosis. Journal of clinical Psychopharmacology, 28, 214–218. Vandel, S., Bertschy, G., Baumann, P., Bouquet, S., Bonin, B., Francois, T., et al. (1995). 58 Fluvoxamine and fluoxetine: interaction studies with amitriptyline, clomipra59 mine and neuroleptics in phenotyped patients. Pharmacological Research: The 60 Official Journal of the Italian Pharmacological Society, 31, 347–353. 61 Vandel, S., Bertschy, G., Bonin, B., Nezelof, S., François, T. H., Vandel, B., et al. (1992). Tricyclic antidepressant plasma levels after fluoxetine addition. Neuropsycho62 biology, 25, 202–207. 63 Villari, V., Frieri, T., & Fagiolini, A. (2011). Aripiprazole augmentation in clozapine64 associated obsessive-compulsive symptoms. Journal of Clinical Psychopharma65 cology, 31, 375–376. Wagner, K. D., Cook, E. H., Chung, H., & Messig, M. (2003). Remission status after 66 long-term sertraline treatment of pediatric obsessive-compulsive disorder. 67 Journal of Child and Adolescent Psychopharmacology, 13(Suppl 1), S53–S60. 68 Watson, H. J., & Rees, C. S. (2008). Meta-analysis of randomized, controlled 69 treatment trials for pediatric obsessive-compulsive disorder. Journal of Child Psychology and Psychiatry, 49(5), 489–498. 70 White, M. P., & Koran, L. M. (2011). Open-label trial of aripiprazole in the treatment 71 of Trichotillomania. Journal of Clinical Psychopharmacology, 31(4), 503–506. 72 Wilhelm, S., Buhlmann, U., Tolin, D. F., Meunier, S. A., Pearlson, G. D., Reese, H. E., 73 et al. (2008). Augmentation of behavior therapy with D-cycloserine for obsessive-compulsive disorder. The American Journal of Psychiatry, 165, 74 335–341 (quiz 409). 75 Winter, C., Heinz, A., Kupsch, A., & Ströhle, A. (2008). Aripiprazole in a case 76 presenting with tourette syndrome and obsessive-compulsive disorder. Journal 77 of Clinical Psychopharmacology, 28, 452–454. Wisner, K. L., Sit, D. K., Hanusa, B. H., Moses-Kolko, E. L., Bogen, D. L., Hunker, D. F., 78 et al. (2009). Major depression and antidepressant treatment: impact on 79 pregnancy and neonatal outcomes May. American Journal of Psychiatry, 166 80 (5), 557–566. 81 Wu, P.-L., Tang, H.-S., Lane, H.-Y., Tsai, C.-A., & Tsai, G. E. (2011). Sarcosine therapy for obsessive compulsive disorder: a prospective, open-label study. Journal of 82 Clinical Psychopharmacology, 31, 369–374. 83 Yoshimura, R., Kaneko, S., Shinkai, K., & Nakamura, J. (2006). Successful treatment 84 for obsessive-compulsive disorder with addition of low-dose risperidone to 85 fluvoxamine: implications for plasma levels of catecholamine metabolites and serum brain-derived neurotrophic factor levels. Psychiatry and Clinical Neuros86 ciences, 60, 389–393. 87 Zohar, J., & Judge, R. (1996). Paroxetine versus clomipramine in the treatment of 88 obsessive compulsive disorder. British Journal of Psychiatry, 169, 468–474.

Please cite this article as: Borue, X., et al. Biological treatments for obsessive-compulsive and related disorders. Journal of ObsessiveCompulsive and Related Disorders (2015), http://dx.doi.org/10.1016/j.jocrd.2015.03.003i

89