by Randy A. Sansone, MD, and Lori A. Sansone, MD
Dr. R. Sansone is a professor in the Departments of Psychiatry and Internal Medicine at Wright State University School of Medicine in Dayton, Ohio, and Director of Psychiatry Education at Kettering Medical Center in Kettering, Ohio; Dr. L. Sansone is a family medicine physician (civilian) and Medical Director, Family Health Clinic, Wright-Patterson Medical Center in WPAFB, Ohio. The views and opinions expressed in this column are those of the authors and do not reflect the official policy or position of the United States Air Force, Department of Defense, or US government.
Innov Clin Neurosci. 2011;8(6):10–14
Funding: There was no funding for the development and writing of this article.
Financial disclosures: The authors have no conflicts of interest relevant to the content of this article.
Key words: Duloxetine, milnacipran, obsessive-compulsive disorder, OCD, SNRIs, serotonin-norepinephrine reuptake inhibitors, venlafaxine
Abstract: Obsessive compulsive disorder can be a challenging psychiatric phenomenon to diagnose and treat. At the present time, recommended treatment strategies include cognitive behavioral therapy (e.g., exposure and response prevention) and pharmacotherapy (e.g., selective serotonin reuptake inhibitors and clomipramine). Unfortunately, even with adequate pharmacotherapy, only 70 percent of patients improve, indicating the clinical need for pharmacological alternatives. Such alternatives may presently exist in the group of antidepressants classified as serotonin-norepinephrine reuptake inhibitors. Although large, double-blind, placebo-controlled studies are lacking, preliminary evidence through case reports and small studies suggests potential efficacy for three currently available serotonin-norepinephrine reuptake inhibitors (e.g., venlafaxine, duloxetine, milnacipran). If genuinely efficacious, serotonin-norepinephrine reuptake inhibitors would be likely to have fewer side effects than clomipramine and might be a reasonable second-line alternative to selective serotonin reuptake inhibitors. Only further research will clarify the role of serotonin-norepinephrine reuptake inhibitors in the treatment of obsessive compulsive disorder.
According to the findings of the National Comorbidity Survey Replication, the lifetime prevalence of obsessive compulsive disorder (OCD) in the general population of the United States is 1.6 percent. While not particularly prevalent, in our experience, patients with OCD in either psychiatric or primary care settings are not typically forthright in their disclosure of OCD symptoms to clinicians, which can complicate accurate diagnosis and effective treatment. Effective treatment may include cognitive behavioral therapy (CBT) (particularly exposure and response prevention) and/or pharmacotherapy (i.e., the selective serotonin reuptake inhibitors [SSRIs] and clomipramine, which are presently first- and second-line agents, respectively). Despite available treatments, however, according to a meta-analysis of pharmacological interventions in OCD, only about two-thirds of participants who complete pharmacological trials improve. In addition, SSRIs and clomipramine may have side effects that impair long-term patient adherence with these medications (e.g., sexual dysfunction with SSRIs and weight gain with clomipramine). Are there pharmacological alternatives? In this edition of The Interface, we will explore the potential role of serotonin-norepinephrine reuptake inhibitors (SNRIs) in the treatment of OCD.
Currently Recommended Pharmacological Approaches to OCD
According to the Practice Guideline for the Treatment of Patients with Obsessive-Compulsive Disorder, recommended psychotropic drugs for first-line monotherapy in the treatment of OCD are SSRIs and clomipramine. At the present time, the majority of the SSRIs have been approved by the United States Food and Drug Administration (FDA) for the treatment of OCD. Fluoxetine and fluvoxamine were approved by the FDA in 1994, paroxetine in 1996, and sertraline in 1997. Only the SSRIs citalopram and escitalopram have not been approved by the FDA at this juncture, although they are also effective in the treatment of OCD. Clomipramine, a tricyclic antidepressant, was the very first drug to be approved by the FDA for the treatment of OCD (1991).
According to the Practice Guideline for the Treatment of Patients with Obsessive-Compulsive Disorder, when there is little or no response to the preceding monotherapy treatments, monotherapy trials with either venlafaxine, an SNRI, or mirtazapine may be considered. (Mirtazapine is not a reuptake inhibitor of either serotonin or norepinephrine—i.e., it is not an SNRI.) While no SNRI is presently approved by the FDA for the treatment of OCD, during the remainder of this article, we will discuss their potential role in the treatment of this challenging psychiatric disorder. We will begin with a review of the data on venlafaxine and then continue with findings related to duloxetine and milnacipran. (We were unable to locate any data on the use of desvenlafaxine in OCD.)
Venlafaxine in OCD
Venlafaxine was the first available SNRI in the United States, which may explain the more extensive existing literature with regard to its use in the treatment of OCD. There are several published case reports on the successful treatment of OCD with venlafaxine,[6–8] as well as three open-label, one single-blind, and three double-blind studies. The existing studies have been well summarized by Dell’Osso et al.
Open-label studies. In a 1996 study, Rauch et al enrolled 10 outpatients with OCD into a 12-week venlafaxine trial. With dosages between 150mg per day and 375mg per day, 30 to 40 percent of participants were judged as responders, depending on the assessment measure.
In a 2002 Turkish study, Sevincok et al enrolled 12 outpatients with OCD into an eight-week venlafaxine trial. The mean dosage of venlafaxine in this study was 210mg per day. Depending on the assessment measure, 50 to 75 percent of participants were judged as responders.
In a 2003 study, Hollander et al enrolled 39 outpatients with OCD into a multimonth investigation. According to study measures, nearly 70 percent of participants responded to venlafaxine at a mean final dose of 232mg per day. Interestingly, in this sample, 29 participants had failed prior treatment with SSRIs.
Single-blind studies. In a 2002 single-blind Italian study, Albert et al enrolled 73 outpatients with OCD into a 12-week study comparing venlafaxine to clomipramine. In this study, 26 participants were taking venlafaxine (mean dose of 265mg per day) and 47 were taking clomipramine (mean dose of 168mg per day). While there were no statistically significant differences between the two drugs according to two types of analyses (i.e., they were comparable), clomipramine exhibited a numerically higher response rate in both statistical strategies.
Double-blind studies. In a 1996 double-blind, placebo-controlled study, Yaryura-Tobias et al enrolled 30 outpatients with OCD into an eight-week investigation of venlafaxine. Sixteen patients were taking venlafaxine, with doses up to 225mg per day. Factoring in the eight patients who dropped out of the study (2 on venlafaxine), six patients improved on venlafaxine (42.9%) versus zero patients on placebo.
In a 2003 double-blind Dutch study comparing venlafaxine extended release with paroxetine, Denys et al enrolled 150 participants with OCD into a 12-week trial. In this study, 75 participants received venlafaxine extended release (final dose of 300mg per day) and 75 participants received paroxetine (final dose of 60mg per day); there was no difference in response rate (i.e., both drugs were equally effective).
Finally, using the preceding sample, Denys et al shifted nonresponders to the alternative drug and published findings in 2004. At the end of a 12-week trial, 19 percent of participants who switched to venlafaxine extended release responded whereas 56 percent of participants who switched to paroxetine responded, suggesting that paroxetine might be more efficacious than venlafaxine extended release in nonresponders.
Caveats. Note that in the preceding reports, patient samples have generally been small, some trials have only been eight weeks in length rather than the recommended 10 to 12 weeks, and dosages of venlafaxine or venlafaxine extended release have varied from study to study.
Duloxetine in OCD
To date, we were only able to locate case reports on the use of duloxetine in the treatment of patients with OCD. In a 2007 case report, Blay and Black described a 38-year-old man with an eight-year history of OCD. This patient was initially treated with clomipramine and then paroxetine, but both were discontinued due to problems with side effects. The patient was then treated with mirtazapine with some improvement, but experienced a symptom exacerbation and was eventually switched to escitalopram. Following a stable period of 12 months, the patient again became symptomatic. Escitalopram was discontinued and the patient was then treated with duloxetine at a final dose of 120mg per day. At one-year follow-up, the patient was still doing well.
In a 2008 Italian case report, Dell’Osso et al treated four patients with OCD with duloxetine. All patients had been partial or nonresponders to treatment with other anti-OCD medications. Duloxetine dosages were up to 120mg per day and patients were followed for 12 weeks. Three patients (75%) experienced improvement.
Finally, in a 2009 Taiwanese case report, Yeh et al described a 30-year-old man with OCD who was refractory to treatment with several SSRIs and venlafaxine. This patient achieved a full remission after 12 weeks of monotherapy with high-dose duloxetine (180mg per day).
Milnacipran in OCD
Milnacipran, the SNRI most recently available in the United States, has been prescribed for the treatment of fibromyalgia and major depression in France since 1996. Now available in more than 45 countries for the treatment of major depression, milnacipran was approved in 2009 by the FDA only for the treatment of fibromyalgia. In addition to milnacipran’s acknowledged efficacy in the treatment of fibromyalgia and major depression, there has been preliminary exploration of this drug for the treatment of OCD. For example, using a mouse model for OCD, Japanese researchers found that milnacipran was similar to fluvoxamine in reducing OCD behaviors.
As for case reports, we were able to locate two. In the first case, which was reported in 1990, Papart and Ansseau described a 47-year-old French woman with OCD who responded to treatment with milnacipran 300mg per day after 10 months of treatment. In a second case report in 2007, Yoshida et al described a 44-year-old Japanese patient with OCD who responded to milnacipran 200mg per day.
SNRIs: Not Created Equally
While venlafaxine, duloxetine, and milnacipran are all classified as SNRIs, and therefore may each exert a therapeutic effect on the symptoms of OCD, these drugs have differing effects on the two involved neurotransmitter systems. Specifically, both venlafaxine and duloxetine inhibit serotonin to a greater degree than norepinephrine. In laboratory animals, venlafaxine is three times more potent on serotonin than norepinephrine reuptake whereas duloxetine is five times more potent. According to Stahl et al, venlafaxine has a 30-fold selectivity for serotonin whereas duloxetine has a 10-fold selectivity for serotonin. In contrast, milnacipran exhibits a preference for the reuptake of norepinephrine. According to studies in laboratory animals, milnacipran is twice as potent on norepinephrine than serotonin reuptake. However, Stahl et al indicate that milnacipran blocks serotonin and norepinephrine with equal affinity.
While these data indicate some inconsistencies with regard to the degree of drug effect on these two neurotransmitter systems, they consistently illustrate differences among the SNRIs. Whether these differences in neurotransmitter effects will ultimately influence the treatment efficacy of the individual drugs with regard to OCD is unknown. Likewise, whether individual SNRIs might be better suited for specific patients is unknown, but suggested by studies of nonresponders.
At this juncture, some investigators are actively suggesting that SNRIs be used as second-line medications to SSRIs in the treatment of OCD. Others suggest that SNRIs may be the preferred option for patients with certain types of treatment-resistant OCD. In partial support of these perspectives, the Practice Guideline for the Treatment of Patients with Obsessive Compulsive Disorder suggests venlafaxine monotherapy for partial or nonresponders to SSRIs and clomipramine.
While SSRIs and clomipramine are well-established medications in the treatment of OCD, only 70 percent of patients respond. Therefore, efficacious monotherapy alternatives are needed. According to the existing data, SNRIs may be these alternatives. To date, venlafaxine has the most accumulated evidence, followed by duloxetine and then milnacipran. While large, double-blind, placebo-controlled studies are lacking, preliminary case reports and small studies suggest that all of the SNRIs may be efficacious in the treatment of OCD. If so, this class of drugs may offer both psychiatrists and primary care clinicians an alternative to SSRIs, which may be complicated by sexual dysfunction, and clomipramine, a side-effect-laden tricyclic antidepressant. Only further research will confirm these preliminary impressions with regard to SNRIs.
1. Kessler RC, Berglund P, Demler O, et al. Lifetime prevalence and age-of-onset distributions of DSM-IV disorders in the National Comorbidity Survey Replication. Arch Gen Psychiatry. 2005;62:593–602.
2. American Psychiatric Association. Practice Guideline for the Treatment of Patients with Obsessive Compulsive Disorder. Washington, DC: American Psychiatric Association; 2007.
3. Eddy KT, Dutra L, Bradley R, Westen D. A multidimensional meta-analysis of psychotherapy and pharmacotherapy for obsessive-compulsive disorder. Clin Psychol Rev. 2004;24:1011–1030.
4. Roseboom PH, Kalin NH. Citalopram and s-citalopram. In: Schatzberg AF, Nemeroff CB (eds). The American Psychiatric Publishing Textbook of Psychopharmacology, Fourth Edition. Arlington, VA: American Psychiatric Publishing; 2009:363–388.
5. Gold Standard, Inc. Clinical Pharmacology [database online]. http://www.clinicalpharmacology.com. Accessed on 7/7/10.
6. Grossman R, Hollander E. Treatment of obsessive-compulsive disorder with venlafaxine. Am J Psychiatry. 1996;153:576–577.
7. Marazziti D. Venlafaxine treatment of obsessive-compulsive disorder: case reports. CNS Spectr. 2003;8:421–422.
8. Potoczek A. Severe social phobia with obsessive-compulsive symptoms—a case study. Psychiatr Pol. 2005;39:641–657.
9. Dell’Osso B, Nestadt G, Allen A, Hollander E. Serotonin-norepinephrine reuptake inhibitors in the treatment of obsessive-compulsive disorder: a critical review. J Clin Psychiatry. 2006;67:600–610.
10. Rauch SL, O’Sullivan RL, Jenike MA. Open treatment of obsessive-compulsive disorder with venlafaxine: a series of 10 cases. J Clin Psychopharmacol. 1996;16:81–84.
11. Sevincok L, Uygur B. Venlafaxine open-label treatment of patients with obsessive-compulsive disorder. Aust N Z J Psychiatry. 2002;36:817.
12. Hollander E, Friedberg J, Wasserman S, et al. Venlafaxine in treatment-resistant obsessive-compulsive disorder. J Clin Psychiatry. 2003;64:546–550.
13. Albert U, Aguglia E, Maina G, Bogetto F. Venlafaxine versus clomipramine in the treatment of obsessive-compulsive disorder: a preliminary single-blind, 12-week, controlled study. J Clin Psychiatry. 2002;63:1004–1009.
14. Yaryura-Tobias JA, Neziroglu FA. Venlafaxine in obsessive-compulsive disorder. Arch Gen Psychiatry. 1996;53:653–654.
15. Denys D, van der Wee N, van Megen HJ, Westenberg HG. A double blind comparison of venlafaxine and paroxetine in obsessive-compulsive disorder. J Clin Psychopharmacol. 2003;23:568–575.
16. Denys D, van Megen HJGM, van der Wee N, Westenberg HGM. A double-blind switch study of paroxetine and venlafaxine in obsessive-compulsive disorder. J Clin Psychiatry. 2004;65:37–43.
17. Blay SL, Black DW. A case of obsessive-compulsive disorder responding to duloxetine. Prim Care Comparion J Clin Psychiatry. 2007;9:234–235.
18. Dell’Osso B, Mundo E, Marazziti D, Altamura AC. Switching from serotonin reuptake inhibitors to duloxetine in patients with resistant obsessive-compulsive disorder: a case series. J Psychopharmacol. 2008;22:210–213.
19. Yeh Y-W, Chen C-H, Kuo S-C, et al. High-dose duloxetine for treatment-resistant obsessive-compulsive disorder: a case report with sustained full remission. Clin Neuropharmacol. 2009;32:174–176.
20. Milnacipran. http://en.wikipedia.org/wiki/Milnacipran. Accessed on 7/7/10.
21. Sugimoto Y, Tagawa N, Kobayashi Y, et al. Effects of the serotonin and noradrenaline reuptake inhibitor (SNRI) milnacipran on marble burying behavior in mice. Biol Pharm Bull. 2007;30:2399–2401.
22. Papart P, Ansseau M. Milnacipran in obsessive-compulsive disorder: study in one case. Psychiatrie & Psychobiologie. 1990;5:325–327.
23. Yoshida K, Higuchi H, Ozaki N. Successful treatment of severe antidepressant-induced nausea with a combination of milnacipran and olanzapine. Pharmacopsychiatry. 2007;40:84–85.
24. Blier P. Dual serotonin and noradrenaline reuptake inhibitors: focus on their differences. Int J Psychiatry Clin Pract. 2006;10:22–32.
25. Stahl SM, Grady MM, Moret C, Briley M. SNRIs: the pharmacology, clinical efficacy, and tolerability in comparison with other classes of antidepressants. CNS Spectr. 2005;10:732–747.
26. Van Ingen Schenau WJB, Wisman PW. Is it time for revision of the section on OCD in the guideline on anxiety disorders? Tijdschr Psychiatr. 2007;49:315–325.