1. Obsessive-Compulsive Disorder: Pharmacotherapy
In this presentation I’ll summarize the pharmacotherapy of obsessive compulsive disorder.
Flavio Guzman, MD

2. Overview General concepts Using SSRIs and clomipramine for OCD
Practical considerations
Treatment resistance / Augmentation
Here is an outline for this video.
We’ll begin with general concepts on treatment response. Then we continue with the use of SSRIs and clomipramine for the treatment of OCD. After that we discuss practical considerations on the initial treatment plan. And finally, a brief introduction to treatment resistance and augmentation.

3. Use scales for rating the severity of OCD
Y-BOCS
Y-BOCS II
Florida Obsessive Compulsive Inventory (FOCI)
One of the first treatment recommendations the American Psychiatric Association makes is to use scales for rating the severity of OCD.  The Y-BOCS is a clinician-administered scale that has become the most widely used rating scale for OCD. The guideline mentions that the YBOCS in its two versions is a valid tool.
A new self report questionnaire was recently developed, the Florida Obsessive Compulsive Inventory or FOCI. Dr. Wayne Goodman has authorized its use for members of the Psychopharmacology Institute and can be downloaded from our site for personal use.
American Psychiatric Association (2013).Guideline Watch: Practice Guideline for the Treatment of Patients With Obsessive-Compulsive Disorder. Washington, DC. American Psychiatric Press

4. Defining treatment response in OCD trials
Y-BOCS score:
25-35% or greater decrease
Clinical Global Impressions-Improvement (CGI-I) score of:
1 (very much improved)
2 (much improved)
How do we define treatment response in OCD trials. The APA guideline defines response as a 25 to 35|% or greater decrease in the Y-BOCS rating scale, or a Clinical Global Impressions-Improvement (CGI-I) score of 1, which is very much improved or 2 which is much improved.
American Psychiatric Association (2013).Guideline Watch: Practice Guideline for the Treatment of Patients With Obsessive-Compulsive Disorder. Washington, DC. American Psychiatric Press

5. General concepts What percentage of patients improve?
40-60%
How much do they improve?
20-40 % reduction in their symptoms
Now that we have defined response, we can ask ourselves: What percentage of patients treated with medications improve?
In general, serotonin reuptake inhibitors lead to improvement in 40 to 60% of patients.
So, the next question is how much do they improve? Patients that receive an adequate medication trial will experience a 20 to 40% reduction in their symptoms.
Pigott, T. A., & Seay, S. M. (1999). A review of the efficacy of selective serotonin reuptake inhibitors in obsessive-compulsive disorder. Journal of Clinical Psychiatry.
Jefferson, J. W., Kobak, K. A., Katzelnick, D. J., & Serlin, R. C. (1995). Efficacy and tolerability of serotonin transport inhibitors in obsessive-compulsive disorder: a meta-analysis. Archives of General psychiatry, 52(1),

6. Medications used for OCD

7. SSRIs SRIs Clomipramine Trial of efficacy: 10-12 weeks
So let’s review now the medications used for the treatment of OCD. Pharmacotherapy is based on the use of serotonin reuptake inhibitors, this includes SSRIs and clomipramine. When treating OCD, we need to keep in mind that our trial of efficacy will last between 10 to 12 weeks.
Trial of efficacy: weeks

8. Not approved, but efficacious:
SSRIs for OCD
Generally considered equally effective
Higher doses are frequently used
FDA-approved for OCD:
Fluvoxamine
Fluoxetine
Paroxetine
Sertraline
Not approved, but efficacious:
Citalopram
Escitalopram
Let’s begin with the SSRIs. They are generally considered equally effective in the treatment of OCD. As a general rule, higher doses are frequently used. This table divides FDA approved SSRIs and non-approved SSRIs.
Fluvoxamine, fluoxetine, paroxetine and sertraline are FDA-approved for the treatment of OCD. Citalopram and escitalopram are not approved but there is evidence of their efficacy for OCD.
Hudak, R. & Dougherty, D. (2011). Clinical obsessive-compulsive disorders in adults and children. Cambridge New York: Cambridge University Press.

9. Fluvoxamine 250 - 300 mg/day Average dose: Earlier onset
Allows more rapid dose titration
CR formulation approved in 2008:
The average dose of fluvoxamine for OCD is between mg/day. In 2008 a controlled release formulation was approved, in clinical trials the onset of action for this formulation was earlier than for the immediate release formulation. Also, it allows more rapid dose titration than the immediate release formulation.
American Psychiatric Association (2013).Guideline Watch: Practice Guideline for the Treatment of Patients With Obsessive-Compulsive Disorder. Washington, DC. American Psychiatric Press

10. Fluvoxamine CYP1A2 inhibitor CYP3A4 inhibitor
Greater potential for DDI
The problem with fluvoxamine is that it is a CYP450 1A2 and CYP3A4 inhibitor, this is why the drug has a greater potential for drug-drug interactions.
Luvox CR (Fluvoxamine CR) [Prescribing Information]. Palo Alto, CA: Jazz Pharmaceuticals, Inc. Accessed Sep 2014

11. Fluoxetine More benefit in OCD: 40-60 mg/day Fluoxetine: 2 to 4 days
Norfluoxetine: 7 to 15 days
Fluoxetine is also approved for the treatment of OCD. Fluoxetine has shown more benefit when used in the range of 40 to 60 mg/day. As a reminder, fluoxetine has a half life of 2 to 4 days and its active metabolite, norfluoxeetine 7 to 15 days.
Hudak, R. & Dougherty, D. (2011). Clinical obsessive-compulsive disorders in adults and children. Cambridge New York: Cambridge University Press.

12. Paroxetine Advantage Studied for long-term effectiveness Disadvantages
CYP2D6 interactions
AISD
More benefit in OCD:
40-60 mg/day
Paroxetine is also used in doses between 40 and 60 mg/day. As an advantage, paroxetine has been studied for long term effectiveness over a 6-month period. As disadvantages, paroxetine is a CYP2D6 inhibitor, this may increase the possibility of drug-drug interactions. Also, paroxetine is associated with higher risk of antidepressant-induced sexual dysfunction.
Hollander, E., et al (2003). Acute and long-term treatment and prevention of relapse of obsessive-compulsive disorder with paroxetine. The Journal of clinical psychiatry, 64(9),

13. Sertraline More robust efficacy seen with doses closer to 200 mg
Doses of mg/day: additional benefit
In the case of sertraline, a more robust efficacy is seen when dosed closer to 200 mg. This image shows in dashed lines doses above the approved the FDA, for sertraline this means more than 200 mg/day. Doses of mg/day have shown additional benefit in OCD.
Ninan, P. T., et al (2006). High-dose sertraline strategy for nonresponders to acute treatment for obsessive-compulsive disorder: a multicenter double-blind trial. Journal of Clinical Psychiatry.
Hudak, R. & Dougherty, D. (2011). Clinical obsessive-compulsive disorders in adults and children. Cambridge New York: Cambridge University Press.

14. Citalopram - Escitalopram
Not FDA-approved
Evidence from several open label trials
One RCT demonstrated citalopram efficacy at all dosages (20,40, 60 mg), trend for greater efficacy at the 60 mg dosage
Citalopram and escitalopram are not approved for the treatment of OCD. However, there is evidence of efficacy from several open label trials. One randomized controlled trial conducted in 2001 demonstrated efficacy for citalopram at all dosages, with a trend for greater efficacy at the 60 mg dosage.
Montgomery, S. A., et al. "Citalopram 20 mg, 40 mg and 60 mg are all effective and well tolerated compared with placebo in obsessive-compulsive disorder."International clinical psychopharmacology 16.2 (2001):

15. Citalopram Advantage: Disadvantage: Less potential for DDI
FDA recommends a maximum citalopram dose of 40 mg/day
In geriatric patients the maximum should be 20 mg/day
In the case of citalopram we can think of a possible advantage: there is less potential for drug-drug interactions. However, one important disadvantage has to do with dosing. Because of safety concerns regarding QT prolongation, the FDA recommends a maximum citalopram dose of 40 mg/day. In geriatric patients, the maximum should be 20 mg.
This limits its use in high doses for OCD.
FDA safety information Citalopram – Accessed online:

16. Clomipramine
Tolerability: blockade of H1, M1, alpha 1 receptors and Na channels
Metabolized to an active metabolite by demethylation via CYP1A2
Fluvoxamine inhibits CYP1A2
Clomipramine is a tricyclic antidepressant associated with blockade of histamine 1 receptors, muscarinic 1 receptors, alpha 1 receptors and sodium channels. These features make clomipramine an option with less tolerability than SSRIs.
Clomipramine is metabolized to an active metabolite by demethylation via CYPA2. Also, fluvoxamine inhibits CYP1A2, this can cause pharmacokinetic interactions between these two drugs, resulting in increased clomipramine levels

17. Clomipramine for OCD Clomipramine dose: 200-250 mg/day
Does clomipramine perform better than SSRIs?
Meta-analyses:
Larger effect size for clomipramine than SSRIs (compared with placebo(
Not based on head-to head comparisons
Head-to-head comparison trials:
Mixed results
The recommended dose for clomipramine is between mg/day.
An important clinical question is if clomipramine performs better than the SSRIs for OCD
Meta-analysis have addressed this question, these studies have shown a larger effect size for clomipramine than the different SSRIs when each is compared with placebo. However, these studies were not based on head-to-head comparisons.
Head-to-head trials have shown mixed results.
Hudak, R. & Dougherty, D. (2011). Clinical obsessive-compulsive disorders in adults and children. Cambridge New York: Cambridge University Press.

18. Practical considerations

19. Recommendations for the acute phase
CBT (ERP) alone:
Not too depressed, anxious or severely ill to cooperate
SRI alone:
Previously responded
Not able to cooperate with the demands of CBT
CBT (ERP) + SRI
More effective than monotherapy
Not necessary for all patients
The APA guideline recommends three options for treatment in the acute phase of OCD. These are: cognitive behavioral therapy, specifically a type of CBT called Exposure and Response Prevention or ERP, the use of SRI alone and the combination of ERP and an SRI.
The use of ERP alone is recommended for patients that are not too depressed, anxious or severely ill to cooperate and engage in psychotherapy. The use of an SRI alone is recommended for patients who previously responded to pharmacological treatment and/or are not able cooperate with the demands of CBT.
The combination of CBT and SRIs is more effective than monotherapy, but it is not necessary for all patients.
American Psychiatric Association (2007). Practice Guidelines for the treatment of Patients with Obsessive Compulsive Disorder. Washington, DC. American Psychiatric Press
American Psychiatric Association (2013).Guideline Watch: Practice Guideline for the Treatment of Patients With Obsessive-Compulsive Disorder. Washington, DC. American Psychiatric Press

20. How to choose a specific medication
Choice not based on efficacy (SSRIs and clomipramine considered to be equally efficacious)
Based on:
Side effects profile
Comorbid condition
Family history of response
Potential for drug-drug interactions
A basic question is: How do we choose a specific medication?
The choice is not based on efficacy, SSRIs and clomipramine are considered to be equally efficacious. The choice is based on: side effects profile, the existence of a comorbid condition, a family history of reponse and the potential for drug drug interactions.
Hudak, R. & Dougherty, D. (2011). Clinical obsessive-compulsive disorders in adults and children. Cambridge New York: Cambridge University Press.

21. How to dose Starting dose: Titrate to highest tolerated dose
Typically not different than for other indications
Start lower if comorbid PD or GAD
Titrate to highest tolerated dose
Usually titrated weekly
Adequate trial of efficacy
10-12 weeks on highest tolerated dose
Now that we have chosen a medication, how do we dose it?
The starting dose is typically not different than the dose used for other indications. However, we need to start lower if the patient has comorbid panic disorder or generalized anxiety disorder.
We titrate to the highest tolerated dose, and this is usually done weekly. As we said before, an adequate trial of efficacy consists of a trial of weeks on the highest tolerated dose.
Hudak, R. & Dougherty, D. (2011). Clinical obsessive-compulsive disorders in adults and children. Cambridge New York: Cambridge University Press.

22. Treatment resistance / Augmentation

23. Treatment resistance What percentage do not show adequate response ?
40-60%
No standard definition of treatment resistance
Let’s see now treatment resistance
What percentage of patients do not show adequate response in clinical trials? 40 to 60% of patients fail to respond. There is no standard definition of treatment resistance.
Arumugham, S. S., & Reddy, J. Y. (2013). Augmentation strategies in obsessive compulsive disorder. Expert Review of Neurotherapeutics, 13(2),

24. Treatment resistance, according to most studies:
Y-BOCS score:
Less than 25-35% reduction
Failure to respond
Trial of 12 weeks
Not having a (CGI-I) score of:
1 (very much improved)
2 (much improved)
Even though there is no consensus of treatment resistance, most trials studying treatment options have used similar criteria. Having less than 25% or sometimes 35% reduction in the Y-BOCS scale, not having much or very much improved in the CGI scale, and a period of 12 weeks of adequate treatment with an SRI.
Arumugham, S. S., & Reddy, J. Y. (2013). Augmentation strategies in obsessive compulsive disorder. Expert Review of Neurotherapeutics, 13(2),

25. Strategies for non-responding patients
If no response to initial trial of SSRI
Switching to a different SSRI
If no response to two SSRIs
Switching to clomipramine
Partial response to treatment with an SSRI
Poor response to multiple SSRIs
Augmentation
Here we have strategies for the management of non-responding patients. As an general idea there are three strategies: switching to a different SSRI, switching to clomipramine, and augmenting.
We switch to a different SSRI if there was no response to an initial trial of an SSRI. We can switch to clomipramine if there was no response to two SSRIs.
We can try augmentation if there is partial response to treatment with an SSRI or if there was a poor response to multiple SSRIs.
Arumugham, S. S., & Reddy, J. Y. (2013). Augmentation strategies in obsessive compulsive disorder. Expert Review of Neurotherapeutics, 13(2),

26. Augmentation options Augmentation Pharmacological treatments
Psychotherapy
Other somatic treatments
Therapeutically we can augment using pharmacological treatments, psychotherapy or other somatic treatments.

27. Antipsychotic augmentation
First choice
Risperidone
Next options
Aripiprazole
Haloperidol
Use at moderate doses
Risperidone 2 mg/day
The most studied drugs for augmentation in OCD are antipsychotics. Based on current evidence, risperidone is the antipsychotic of choice for augmentation. Aripiprazole and haloperidol are the next options.
Antipsychotics should be used at moderate doses, such as 2 mg/day of risperidone.
Arumugham, S. S., & Reddy, J. Y. (2013). Augmentation strategies in obsessive compulsive disorder. Expert Review of Neurotherapeutics, 13(2),

28. Other options More evidence required: Not effective 5HT3 antagonists
Glutamatergic drugs
Topiramate
Not effective
Buspirone
Lithium
Clonazepam
Other options that need more evidence are 5HT3 antagonists, glutamatergic drugs and topiramate. Buspirone, lithium and clonazepam are currently considered not effective as augmenting drugs for OCD.
Arumugham, S. S., & Reddy, J. Y. (2013). Augmentation strategies in obsessive compulsive disorder. Expert Review of Neurotherapeutics, 13(2),

29. End of presentation