Treatment Resistant Obsessive-Compulsive Disorder

Treatment Resistant Obsessive-Compulsive Disorder (OCD) is defined as patients who have undergone an adequate trial of SRI (clomipramine or SSRI) and do not respond or show unsatisfactory results. This account for 40-50% of OCD patients. What other strategies can you employ in these patients?


(1) Add Pindolol: 2.5 mg TID


Mechanism: Beta-blocker and 5-HT1A presynaptic receptor antagonist –> increases serotonergic transmission through its effect on the presynaptic 5-HT1A receptor.


  • n= 14 treatmentresistant OCD patients were treated with paroxetine for 17+/-2 weeks up to 60 mg/d after they failed at least two other SSRI trials.
  • These patients who did not respond to open-label paroxetine treatment, were assigned to a double-blind, placebocontrolled Pindolol (2.5 mg three time daily) augmentation.


    1. Pindolol augmentation to paroxetine (n=8) as compared to placebo augmentation (n=6), was associated with a significant (P<0.01) improvement in Y-BOCS.


  1. Although no significant differences were found between placebo and pindolol groups on HAM-Anx and MADRS, a trend for improvement in the pindolol group was noted.


Source: Eur Neuropsychopharmacol. 2000 May;10(3):165-9.


(2) Add Haloperidol: 2-10 mg/daily


Study 1:

  • 62 patients with a primary DSM-III-R diagnosis of OCD received placebo fluvoxamine for 1 week, followed by 8 weeks of active fluvoxamine.
  • n= 34 of these patients were refractory to fluvoxamine and were randomized in a double-blind fashion to 4 weeks of treatment with either haloperidol (n = 17) or placebo (n = 17) added to ongoing fluvoxamine treatment. 
  • Haloperidol dose: initiated at 2 mg and increased to a maximum of 10 mg/day.



  1. Haloperidol addition was significantly better than placebo in reducing the severity of obsessive-compulsive symptoms as measured by the Y-BOCS.
  2. Eight of eight patients with comorbid chronic tic disorders, such as Tourette’s disorder, responded to double-blind haloperidol addition to ongoing fluvoxamine treatment.
  3. Note: Haloperidol addition was of little benefit in treating OCD patients without tics. 


Source: Arch Gen Psychiatry. 1994 Apr;51(4):302-8.

Study 2:

  • 9-week, double-blind, placebo-controlled, crossover study comparing the benefits of 2-week adjunctive treatments with risperidone, haloperidol, and placebo in patients with treatment resistant OCD 
  • n=16 patients were enrolled and 12 completed the study.
  • Dose: Haloperidol 2 mg/day; Risperidone 1 mg/day.



  1. For Obsessions: both risperidone and haloperidol significantly reduced obsession (p < .05) when compared with placebo.
  2. For Compulsions: There was a tendency that haloperidol, and to a lesser degree risperidone, also reduced the compulsion. (likely reason is lower doses of risperidone used).


Source: J Clin Psychiatry. 2005 Jun;66(6):736-43.


(3) Add Risperidone: 2 mg/daily


Study 1:

  • n=36 patients refractory to the SRI were randomized in a double-blind manner to 6 weeks of risperidone (n = 20) or placebo (n = 16) addition
  • Dose: Risperidone was initiated at 1 mg/day, and the dose was increased by 1 mg weekly. The mean final risperidone dose was only 2.2 mg/day (SD=0.7 mg/day; range=1–4).



  1. 9 (50%) of 18 risperidone treated patients were responders (mean daily dose, 2.2 +/-0.7 mg/d) compared with 0 of 15 in the placebo addition group (P<. 005).
  2. Seven (50%) of 14 patients who received open-label risperidone addition responded.
  3. Risperidone addition was superior to placebo in reducing OCD (P<.001), depressive (P<.001), and anxiety (P =.003) symptoms. 


Source: Arch Gen Psychiatry. 2000 Aug;57(8):794-801.

Study 2:

  • double-blind, placebo-controlled trial
  • n= 16 adult treatmentresistant OCD patients were randomly assigned to augmentation with 8 wk of either risperidone (n=10) (0.5-3.0 mg/d) or placebo (n=6) following at least 12 wk of SRI treatment.
  • Dose: Risperidone was started at 0.5 mg/day, and the dose was increased by 0.5 mg weekly to a maximum of 3 mg/day; the mean risperidone dose was 2.25 mg/day.



  1. Four patients on risperidone (40%) and none (0%) on placebo were responders.
  2. Risperidone was generally well tolerated.
  3. Better Y-BOCS insight score at baseline significantly correlated with a greater CGI-I score at endpoint on risperidone augmentation


Source: Int J Neuropsychopharmacol. 2003 Dec;6(4):397-401.

Study 3:

  • n= 39 obsessive-compulsive inpatients completed the study.
  • All patients received 12 weeks of a standardized open-label fluvoxamine monotherapy and then continued for 6 weeks with placebo or risperidone in a double-blind design.
  • Dose: risperidone 0.5 mg/day.



  1. Significant effect of risperidone addition seen at the end of the double-blind phase (18th week) but only for fluvoxamine-refractory patients.
  2. Five patients on risperidone (50%) and two (20%) on placebo became responders.
  3. This preliminary study suggests that even very low (0.5 mg) risperidone doses are effective in OC patients who were nonresponders to a standardized treatment with fluvoxamine.


Source: Eur Neuropsychopharmacol. 2005 Jan;15(1):69-74.


(4) Add Olanzapine (date not consistent): 


Study 1:

  • n=26 with treatment resistance OCD were treated for 6 weeks in a double-blind, placebo-controlled augmentation study with either olanzapine (up to 20 mg/day) or placebo.
  • Mean olanzapine dose was 11.2 mg/day (SD=6.5; range: 5–20 mg/day)



  1. Six (46%) of 13 subjects in the olanzapine group showed a 25% or greater improvement in Y-BOCS score compared with none in the placebo group. 


Source: J Clin Psychiatry. 2004 Apr;65(4):565-8

Study 2:

  • 6-week, placebocontrolled addition of olanzapine 5-10 mg (6.1 +/- 2.1 mg, mean +/- SD) to fluoxetine in OCD subjects who were partial or nonresponders to an 8-week, open-label fluoxetine trial (40 mg in 43 subjects, 20 mg in 1 subject).



  1. Both the fluoxetine-plus-olanzapine (n = 22) and fluoxetine-plus-placebo (n = 22) groups improved significantly over 6 weeks [F(3,113) = 11.64, p <.0001] a
  2. However, the treatment x time interaction was not significant for olanzapine versus placebo addition to fluoxetine.
  3. These findings indicate no additional advantage of adding olanzapine for 6 weeks in OCD patients who have not had a satisfactory response to fluoxetine for 8 weeks, compared with extending the monotherapy trial.


Source: Biol Psychiatry. 2004 Mar 1;55(5):553-5.


(5) Inositol (will benefit minority of OCD patients) 


Inositol is a precursor in the phosphatidylinositol cycle. Inositol is reported to reverse desensitization of serotonin receptors hence is hypothesized to benefit OCD symptoms. 

Study 1:

  • n= 13 patients with OCD completed a double-blind controlled crossover trial of 18 gm inositol or placebo for six weeks each.



  1. Inositol significantly reduced scores of OCD symptoms compared with placebo.


Source: Eur Neuropsychopharmacol. 1997 May;7(2):147-55.

Study 2:

  • n= 10 treatment resistant OCD patients participated in open-label trial of inositol (18 gm/day) augmentation for 6 weeks.



  1. The majority of patients (n = 7) did not respond to treatment with inositol augmentation on the CGI improvement item.
  2. Mean Y-BOCS scores fell significantly from 23.6 (±4.4) to 17.6 (±4.6).
  3. However, a small number of patients (n = 3) did report a clinically significant response on the CGI improvement item.
  4. Unfortunately, inositol augmentation of a SRI did not lead to significant improvement in the majority of such cases.


Source: Int Clin Psychopharmacol. 1999 Nov;14(6):353-6.


(6) Morphine Sulphate (30-45 mg once weekly)


Mechanism of Action is unknown.

Study 1:

  • n= 23 patients with treatment resistant OCD were randomly assigned to random-order, 2-week blocks of once-weekly morphine, lorazepam, and placebo. Week 2 dosage was increased, decreased, or maintained depending on response and side effects.
  • Dose: 30-45 mg weekly



  1. The median Y-BOCS score after morphine (highest dose) was 25 (median decrease = 13%): 7 subjects (30%) were responders.
  2. The median Y-BOCS score after lorazepam (highest dose) was 27 (median decrease = 6%): 4 subjects (17%) responded to lorazepam;
  3. The median Y-BOCS score after placebo (highest dose) was 27 (median decrease = 7%), and no subject responded.
  4. This results support the hypothesis that once-weekly oral morphine can reduce symptoms in some treatment-resistant OCD patients.


Source: J Clin Psychiatry. 2005 Mar;66(3):353-9.


(7) Buspirone (60 mg daily- not as augmentation agent)


Study 1:

  • n= 18 outpatients with obsessive-compulsive disorder were treated with either buspirone 60mg daily or clomipramine 250 mg daily in a double-blind, random-assignment study.



  1. Both drugs led to statistically significant and similar improvements in scores on the Yale-Brown Obsessive-Compulsive Rating Scale and other obsessive-compulsive and depression scales.
  2. This preliminary result warrants further exploration with a larger sample and other serotonergic agents.


Source: Am J Psychiatry. 1991 Jan;148(1):127-9.

Note: other studies did not showed improvement in YBOCS with Buspirone augmentation. 


  1. J Clin Psychopharmacol 1992; 12:11–18
  2. Am J Psychiatry 1993; 150:647–649

Source: APA Practice Guidelines.

Please do post your questions or comments below. 

Dr. Harvinder Singh, M.D. (Admin)

Enroll in our online course to have access to all important clinically relevant psychiatry topics in one place.

Related Articles