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ORIGINAL ARTICLE
Amisulpride as Add-on Treatment for Resistant Obsessive-Compulsive Disorder: Retrospective Case Series AQ1 AQ2
Chanoch Miodownik, MD,* Joseph Bergman, MD,† Paul P. Lerner,‡ Anatoly Kreinin, MD, PhD,† and Vladimir Lerner, MD, PhD* Obsessive-compulsive disorder (OCD) is one of the most common and disabling psychiatric disorders. Treatment with selective serotonin reuptake inhibitors (SSRIs) shows significant improvement; however, residual symptoms remain in most patients despite continued treatment. For partial or nonresponding patients to multiple SSRIs, augmentation strategies are usually recommended. Here we present a consecutive sample of patients with resistant OCD treated with amisulpride augmentation to SSRIs. Methods: We present 10 patients (5 males, 5 females) experiencing resistant OCD. Subjects were treated openly for 6 weeks with amisulpride 200 mg/d as add-on, excluding 1 patient who was treated with only 100 mg/d due to acute extrapyramidal adverse effect on a larger dose. Efficacy was assessed at baseline and after 6 weeks of treatment using the Yale-Brown Obsessive-Compulsive Scale, Clinical Global ImpressionSeverity, and Clinical Global Impression-Improvement. Results: The treatment was generally well tolerated without serious events. In all patients, average Yale-Brown Obsessive-Compulsive Scale scores diminished from 25.3 ± 5.96 points at baseline to 12.2 ± 5.98 at the sixth week (P < 0.0005). Of 10 patients, 7 had significant and partial improvement, and 3 patients did not demonstrate any improvement. Conclusions: Treatment-resistant OCD patients positively responded and well tolerated amisulpride add-on to their ongoing regular pharmacotherapy. This case series demonstrates that amisulpride could be a promising optional therapy for patients who have resistant OCD. Further randomized controlled studies are necessary. Key Words: obsessive-compulsive disorder, treatment, treatment-resistant OCD, antidepressants, augmentation, amisulpride (Clin Neuropharm 2014;00: 00–00)
O
bsessive-compulsive disorder (OCD) was considered a rare condition, but today it is viewed not only as one of the most common psychiatric disorders,1 but also as one of the most disabling medical disorders.2 It is the fourth most frequent psychiatric disorder, with a lifetime prevalence of 2.5%,3 characterized by recurrent distressing thoughts (obsessions) and repetitive rituals (compulsions).4 The mean age at the OCD onset ranges from 22 to 36 years. The disorder is developed in only 15% of patients older than 35 years. Men tend to have an earlier age at onset than women, but women eventually catch up, and roughly 50% of adults with OCD are women.5 Although acute episodes of OCD have been documented, the illness is generally chronic with a variable course.6
*Be'er Sheva Mental Health Center, Faculty of Health Sciences, Ben-Gurion University of the Negev, Be'er Sheva; †Mental Health Center Tirat Carmel, Bruce Rappaport Faculty of Medicine Technion, Haifa; and ‡Faculty of Medicine, Bar-Ilan University, Tsfat, Israel. Address correspondence and reprint requests to Vladimir Lerner, MD, PhD, Be'er Sheva Mental Health Center, Faculty of Health Sciences, Ben-Gurion University of the Negev, PO Box 4600, Be'er Sheva, 84170, Israel; E-mail:
[email protected] Conflicts of Interest and Source of Funding: The authors have no conflicts of interest to declare. Copyright © 2014 Wolters Kluwer Health, Inc. All rights reserved. DOI: 10.1097/WNF.0000000000000065
Clinical Neuropharmacology • Volume 00, Number 00, Month 2014
Generally, people with OCD see 3 to 4 doctors and spend more than 9 years seeking treatment before they receive a correct diagnosis. It takes about 17 years from the onset of OCD to obtain appropriate treatment.7 An effective treatment may reduce the severity of symptoms; however, some symptoms still remain.5 Serotonergic antidepressants, such as selective serotonin reuptake inhibitors (SSRIs) and clomipramine, are established as the pharmacologic first-line treatment of OCD. Medium to large doses of these medications for at least 3 months are recommended until efficacy is obtained. Although many individuals with OCD show significant improvement after treatment with SSRIs, the beneficial effect is usually partial, and residual symptoms remain in most cases despite continued treatment. Failure to achieve a satisfactory remission is estimated at approximately 40% of treated patients. Even following a switch to another SSRI, the nonresponding portion remains about 30%.8,9 Although a consensus regarding the definition of “treatment-resistant” and “treatment-refractory” OCD has not been reached, treatmentresistant OCD generally refers to individuals who have failed at least 2 adequate trials of SSRIs, whereas treatment refractory refers to a greater degree of treatment failure.10 Augmentation strategies are recommended for partial responders to SSRI treatment or nonresponders to multiple SSRIs.11 Atypical antipsychotics can augment the effectiveness of SSRIs in such patients; however, the mechanism underlying this synergetic effect remains elusive.12 The treatment of resistant OCD with different psychotropic medications includes first-generation and second-generation antipsychotics as add-on, which demonstrated controversial results.12–15 Furthermore, some researchers found that antipsychotics with antiserotonergic activity could induce themselves obsessive-compulsive symptoms.16–27 There are no such data about conventional antipsychotics and amisulpride.28 At the same time, there are few publications about efficacy of amisulpride augmentation in patients with resistant OCD and obsessivecompulsive symptoms in schizophrenia patients.29,30 Amisulpride is a second-generation antipsychotic with pharmacological characteristics that differentiate it from other antipsychotic medications of this generation. It is highly selective for the dopamine D2/D3 receptors.28 Therefore, it could be hypothesized that amisulpride, in contrast to other antipsychotics, should not induce or exacerbate obsessive-compulsive symptoms because there is a lack of affinity for the 5-HT2A receptor.29 We found only 1 publication concerning amisulpride-SSRIs combination as treatment for resistant OCD.30 Here we present a consecutive sample of patients diagnosed as having resistant OCD treated with amisulpride as augmentation.
PATIENTS AND METHODS During 2 years, from August 2012 to August 2014, we collected outpatients who had OCD treated in 2 psychiatric medical centers. The total number of patients was 10 (5 men and 5 women; age range, 29-64 years; mean [SD], 49.6 [11.1] years). The clinical and demographic data are presented in Table 1. All patients www.clinicalneuropharm.com
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1
T1
Clinical Neuropharmacology • Volume 00, Number 00, Month 2014
Miodownik et al
TABLE 1. Clinicodemographic Characteristics of Patients and Their Response to Amisulpride Add-on YCGIBOCS CGI-S I
Sex
Age, y
Duration of OCD, y
1 2 3 4
F F M F
59 64 62 52
30 35 40 35
28 16 32 14 19 15 34 8
6 6 5 6
5 6 7 8
M M M F
46 29 38 53
30 17 26 38
19 4 24 23 21 6 20 16
9
M
41
27
23
10 F
52
25
BL EP BL EP
EP
Last Antidepressant(s), mg/d
3 2 3 1
2 1 3 1
5 6 5 5
2 6 1 4
1 4 1 3
6
6
2
1
33 14
6
1
1
Fluvoxamine 300 Fluoxetine 60 Fluoxetine 50 Clomipramine 300; fluoxetine 60 Fluvoxamine 300; reboxetine 8 Citalopram 60; mirtazapine 45 Escitalopram 20; mianserin 60 Clomipramine 225; mirtazapine 45 Escitalopram 20; clomipramine 150 Clomipramine 300; venlafaxine 225
Amisulpride, mg/ d Response 200 200 200 200
++ +++ + +++
200 200 200 200
+++ 0 +++ +
200
+++
100
+++
Comorbid Diagnosis MDD MDD MDD
MDD MDD
BL, baseline; EP, end point; M, male; F, female; MDD, major depressive disorder; 0, no change; +, minimal improvement; ++, partial improvement; +++, significant improvement.
experienced OCD according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria4 and were assessed as treatment resistant. We adopted the criteria of Jenike and Rauch31 for defining resistant OCD. In the past, each subject was treated at least with 2 different SSRIs as monotherapy or with a combination of 2 medications. Both treatments were adequate in terms of compliance, dose, and duration for more than 12 weeks.32–34 In addition, these patients showed less than 25% reduction of the Yale-Brown Obsessive-Compulsive Scale (YBOCS)35,36 scores (this evaluation tool is usually used in our clinical practice for assessment of OCD patients). Because these subjects did not fully react to previous different kinds of antidepressive medications, we added amisulpride 200 mg to their regular treatment once a day in the evening. Medication compliance was verified by a self-report form filled by the patients. The patients' mental state was assessed by Y-BOCS, Clinical Global Impression-Severity (CGI-S), and Clinical Global Impression-Improvement (CGI-I).37 These outcome measures were collected twice: before starting therapy and after the sixth week. The clinical response was evaluated by comparing the rating scores at the beginning and at the end of the sixth week. The attitude toward the evaluation of the symptom improvement varied between different researchers. For example, Pallanti et al38 have proposed the term recovery to indicate an almost complete disappearance of symptoms, corresponding to a Y-BOCS value less than 8. We chose the range from 0 to 16 on the Y-BOCS scores as suggested by Tolin et al.39 None of the subjects were treated with cognitive and behavioral psychotherapy at least a month before amisulpride addition and also during the trial. Our response criteria were defined as follows: a reduction of 60% or more in Y-BOCS score (significant improvement), a reduction of 30% to 60% (partial improvement), and a reduction of less than 30% (no improvement). Because this report is consisted on retrospective evaluation of accumulated sporadic cases from our daily clinical work and was not as a planned study, there was no informed consent form or other regulatory approval.
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Statistical Analysis Statistical analysis was performed using Student t test. Differences at less than 0.05 were considered to be significant.
RESULTS The mean (SD) duration of OCD was 30.3 (6.9) years (range, 14-40 years). Five of 10 patients had a history of comorbid major depressive disorder. None had any personality disorder diagnoses. Before amisulpride was added, all patients were on stable therapy at least for 6 weeks. All subjects, except 1, received 200 mg/d of amisulpride during 6 weeks (Table 1). There was a significant difference in Y-BOCS scores between baseline and week 6: mean 25.3 ± 5.96 points at baseline diminished to 12.2 ± 5.98 points at week 6 (t9 = 5.2; P < 0.0005). Add-on amisulpride to ongoing antidepressive pharmacotherapy resulted as significant improvement in 6 subjects (60%). In these patients, Y-BOCS scores reduced by 67.8% (from mean 27.0 ± 6.7 on baseline to 8.7 ± 4.3). One patient showed partial improvement (reduction of Y-BOCS scores of 42.9%, from 28.0 to 16.0). Three patients (30%) demonstrated no improvement (from 21.0 ± 2.8 to 18.0 ± 4.9). The CGI-S and CGI-I scores also demonstrated similar results. Amisulpride was generally well tolerated. Only 1 patient developed acute akathisia, immediately after the addition of amisulpride 200 mg/d, but after reducing the dose to 100 mg/d, this adverse effect has been resolved, and the patient positively reacted even with the diminished dose.
DISCUSSION Second-generation antipsychotics as well as typical (haloperidol) antipsychotics can augment the effectiveness of SSRIs in OCD, particularly in nonresponders to SSRIs monotherapy. These medications are also recommended by the WFSBP guidelines. 30,40–43 AQ3 After such treatment, about one third of treatment-refractory OCD patients show a clinically meaningful amelioration.9 A comparison of different antipsychotics for treatment-resistant OCD demonstrated the efficacy of haloperidol and risperidone, whereas evidence regarding the efficacy of quetiapine and olanzapine was
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Clinical Neuropharmacology • Volume 00, Number 00, Month 2014
inconclusive.40 In most studies, response occurred within 1 month of augmentation. Although various atypical antipsychotics, including clozapine, risperidone, olanzapine, quetiapine, and aripiprazole, have been reported to induce or exacerbate OCD,22–27 some of these have been used as adjunct therapy for treatmentresistant OCD.29 The role of the serotonergic system in the etiology of OCD is well known, and the lack of affinity for the 5-HT2A receptor in amisulpride28 makes it an appropriate candidate for its management. Our results demonstrate that amisulpride augmentation may be efficacious and well tolerated in patients with resistant OCD. More than two thirds of our patients showed a beneficial effect after its addition to treatment. Our findings correspond with the trial by Metin et al.30 The authors have evaluated the efficacy and safety of amisulpride as an augmentation in the treatment of 20 patients with OCD with a history of resistance to treatment with SSRIs. In an open trial, amisulpride 200 mg/d was added to ongoing SSRI treatment and titrated up to 600 mg/d in flexible doses. The mean amisulpride dose was 325 mg/d. Thirty-five percent of patients showed significant improvement, 60% patients showed partial improvement, and 5% patients showed no improvement. The authors concluded that amisulpride may be a promising option as an augmentation strategy in treatment of resistant OCD.30 The hypothesis, which could explain the positive effect of amisulpride on resistant OCD patients to SSRIs therapy, consists on the assumption that these patients have insufficient serotonindopamine coupling. The combination of SSRIs with antipsychotics, especially with such selective D2/D3 antagonist as amisulpride, may be necessary to decrease dopamine neurotransmission sufficiently and thereby bring about symptoms relief.44 Ersche et al44 reported about the appearance of acute akathisia in response to a single amisulpride dose of 400 mg in 8 of 20 patients with OCD (40%), which were successfully treated with conventional doses of SSRIs. It is interesting that the authors found an inverse ration between the intensity of akathisia symptoms and the severity obsessive-compulsive symptoms on the Y-BOCS (mean [SD] total score, 17.1 [6.8]), compared with the OCD patients without akathisia (mean [SD], 24.8 [6.8]).44 According to their assumption, patients with less severe OCD symptoms have greater serotonin transporters levels, and thus experience greater potentiation of serotonin transmission by SSRI treatment in comparison to those with more severe OCD symptoms. Moreover, up-regulation of dopamine transporters may possibly be mediated by serotonin, and patients with milder OCD symptoms would then have experienced a greater attenuation of dopamine neurotransmission.44 Among our subjects, acute akathisia appeared only in 1 patient with a dose of 200 mg/d. This finding is consistent with the results of Ersche et al44 because all our patients experienced severe OCD symptoms (mean [SD] score on the Y-BOCS, 24.4 [6.0]). As mentioned previously, 1 subject reacted with akathisia, and the dose was reduced to 100 mg of amisulpride, yet even this reduced dose was enough to be effective. Although this was a single patient, nevertheless it merges the question whether even 100 mg is enough for augmentation in such patients. Except a single patient with akathisia, we did not encounter any other adverse effects in contrast to the study by Metin and colleagues,30 who reported weight gain in 70%, mild sedation in 65%, and asthenia in 35% of subjects. A possible explanation is that our patients received only a small dose of amisulpride (200 mg/d), whereas in the study by Metin et al,30 the doses were higher (the mean dose was 325 mg/d). This report has some limitations. It is a retrospective consecutive case series with an open design and contains a small number of patients. Further studies in a double-blind mode and larger
Amisulpride as Add-on for Resistant OCD AQ4
sample are needed to validate these preliminary results. Due to the specific pharmacological profile of amisulpride, it has an advantage over other second-generation antipsychotics and could be an optional therapy as an augmentation strategy for OCD patients with a history of poor or incomplete response to antidepressants. ACKNOWLEDGMENTS The authors would like to thank Professor Yuly Bersudsky for helping in preparing the study. REFERENCES 1. Weissman MM, Bland RC, Canino GJ, et al. The cross national epidemiology of obsessive compulsive disorder. The Cross National Collaborative Group. J Clin Psychiatry. 1994;55:5–10. 2. Murray CJL, Lopez AD. Global Burden of Disease: A Comprehensive Assessment of Mortality and Morbidity From Diseases, Injuries and Risk Factors in 1990 and Projected to 2020. Harvard: WHO; 1996. 3. Karno M, Golding JM, Sorenson SB, et al. The epidemiology of obsessive-compulsive disorder in five US communities. Arch Gen Psychiatry. 1988;45:1094–1099. 4. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Fourth Text Revision. Washington, DC: American Psychiatric Association; 2000. 5. Maj M, Sartorius N, Okasha A, et al., eds. Obsessive-Compulsive Disorder. 2nd ed. Chichester, United Kingdom: John Wiley; 2002. 6. Skoog G, Skoog I. A 40-year follow-up of patients with obsessive-compulsive disorder [see comments]. Arch Gen Psychiatry. 1999;56:121–127. 7. Jenike MA. Clinical practice. Obsessive-compulsive disorder. N Engl J Med. 2004;350:259–265. 8. March JS, Frances A, Kahn DA, et al. The Expert Consensus Guideline Series: treatment of obsessive-compulsive disorder. J Clin Psychiatry 1997; 58:1–72. 9. Kellner M. Drug treatment of obsessive-compulsive disorder. Dialogues Clin Neurosci. 2010;12:187–197. 10. Husted DS, Shapira NA. A review of the treatment for refractory obsessive-compulsive disorder: from medicine to deep brain stimulation. CNS Spectr. 2004;9:833–847. 11. Arumugham SS, Reddy JY. Augmentation strategies in obsessive-compulsive disorder. Expert Rev Neurother. 2013;13:187–202; quiz 203. 12. Fineberg NA, Gale TM, Sivakumaran T. A review of antipsychotics in the treatment of obsessive compulsive disorder. J Psychopharmacol. 2006;20: 97–103. 13. Gao K, Muzina D, Gajwani P, et al. Efficacy of typical and atypical antipsychotics for primary and comorbid anxiety symptoms or disorders: a review. J Clin Psychiatry. 2006;67:1327–1340. 14. McDougle CJ, Goodman WK, Leckman JF, et al. Limited therapeutic effect of addition of buspirone in fluvoxamine-refractory obsessive-compulsive disorder. Am J Psychiatry. 1993;150:647–649. 15. McDougle CJ, Price LH, Goodman WK, et al. A controlled trial of lithium augmentation in fluvoxamine-refractory obsessive-compulsive disorder: lack of efficacy. J Clin Psychopharmacol. 1991;11:175–184. 16. Kim JH, Ryu S, Nam HJ, et al. Symptom structure of antipsychotic-induced obsessive compulsive symptoms in schizophrenia patients. Prog Neuropsychopharmacol Biol Psychiatry. 2012;39:75–79. 17. Kulkarni G, Narayanaswamy JC, Math SB. Olanzapine induced de-novo obsessive compulsive disorder in a patient with schizophrenia. Indian J Pharmacol. 2012;44:649–650. 18. Lemke NT, Bustillo JR. Clozapine-induced obsessive-compulsive symptoms in bipolar disorder. Am J Psychiatry. 2013;170:930.
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33. Papp LA. Anxiety disorders: somatic treatment. In: Sadock BJ, Sadock VJ, eds. Comprehensive Textbook of Psychiatry. Philadelphia, PA: Lippincott Williams & Wilkins; 2000: 1490–1498. 34. Iancu I, Dannon PN, Dolberg OT, et al. Treatment of obsessive-compulsive disorder: from theory to practice. In: Halbreich U, Montgomery SA, eds. Pharmacotherapy for Mood, Anxiety and Cognitive Disorders. Washington, DC: American Psychiatric Press; 2000:465–478. 35. Goodman WK, Price LH, Rasmussen SA, et al. The Yale-Brown Obsessive Compulsive Scale. II. Validity. Arch Gen Psychiatry. 1989;46:1012–1016. 36. Goodman WK, Price LH, Rasmussen SA, et al. The Yale-Brown Obsessive Compulsive Scale. I. Development, use, and reliability. Arch Gen Psychiatry. 1989;46:1006–1011. 37. Guy W. ECDEU Assessment Manual for Psychopharmacology, Revised. US Department of Health, Education and Welfare: Washington, DC; 1976. 38. Pallanti S, Hollander E, Bienstock C, et al. Treatment non-response in OCD: methodological issues and operational definitions. Int J Neuropsychopharmacol. 2002;5:181–191. 39. Tolin DF, Abramowitz JS, Diefenbach GJ. Defining response in clinical trials for obsessive-compulsive disorder: a signal detection analysis of the Yale-Brown obsessive compulsive scale. J Clin Psychiatry. 2005;66:1549–1557. 40. Bloch MH, Landeros-Weisenberger A, Kelmendi B, et al. A systematic review: antipsychotic augmentation with treatment refractory obsessive-compulsive disorder. Mol Psychiatry. 2006;11:622–632. 41. Denys D, de Geus F, van Megen HJ, et al. A double-blind, randomized, placebo-controlled trial of quetiapine addition in patients with obsessive-compulsive disorder refractory to serotonin reuptake inhibitors. J Clin Psychiatry. 2004;65:1040–1048. 42. McDougle CJ, Goodman WK, Leckman JF, et al. Haloperidol addition in fluvoxamine-refractory obsessive-compulsive disorder. A double-blind, placebo-controlled study in patients with and without tics. Arch Gen Psychiatry. 1994;51:302–308.
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