Double Blinded, Placebo-Controlled Trial of Paliperidone Addition in SRI-Resistant Obsessive-Compulsive Disorder

Obsessive-compulsive disorder (OCD) is a common, chronic, and oftentimes disabling disorder.
The only established first-line treatments for OCD are a specific form of Cognitive
Behavioral Therapy (CBT) and the Serotonin Reuptake Inhibitors (SRIs). Few patients with OCD
experience complete symptom resolution with either modality. Even after two consecutive
adequate SRI trials, as many as 30%-40% of patients fail to derive a satisfactory response.
Pharmacological options for these SRI-resistant cases include switching to a different
antidepressant, increasing the dose of SRI, or augmentation with another agent.

Among the pharmacological augmentation strategies, adjunctive antipsychotic medications
enjoy the most empirical support as well as wide-scale use in clinical practice. Utilizing
IMS Health's National Disease and Therapeutic Index (NDTI) for 12 months ending in November
2004, 4.2% of antipsychotic medication use is for anxiety and 1.3% specifically for OCD.
Conversely, for OCD patients, antipsychotic medications account for 8.6% of drug use (IMS
Health NDTI MAT, 2004). Among pediatric patients, prescriptions of antipsychotics increased
from 8.6 out of 1,000 U.S. children in 1995-1996 to 39.4 out of 1,000 children in 2001-2002
(Cooper et al., 2006). Similarly, Medco, a private insurance company, noted that the rate of
children 19 years and under covered by private insurance with at least one atypical
prescription jumped 80% from 2001 to 2005 — from 3.6 per 1,000 to 6.5 per 1,000 (USA Today,
extracted 5/2/2006). These rates parallel our own research, in which approximately 35% of
adult patients on psychotropics were taking an antipsychotic in addition to their SRI. Thus,
clearly there is a large sample of OCD patients that are being prescribed atypical
antipsychotics to augment other treatments.

Previous studies showed that approximately 33-50% of OCD patients who have not had an
adequate response to SRI medication had a positive response when an atypical antipsychotic
medication was added (Bloch et al., 2006). Risperidone has been the most studied agent and
has the most consistently positive findings (e.g., McDougle et al., 2000). However, the
problematic acute and long-term side effects of risperidone (and other atypicals) are of
concern and, at times, limit their use. Paliperidone, a metabolite of risperidone that
utilizes OROS osmotic drug-release technology, has a number of advantages over risperidone
including a lack of drug x drug interactions and a predictable pharmacokinetic profile that
is associated with better tolerability. Thus, paliperidone has the potential to be a safer
alternative for augmentation in OCD patients pending supporting efficacy data. Given the
need to examine the efficacy of paliperidone, this protocol is designed to determine whether
paliperidone augmentation of an SRI is effective relative to a placebo-control, and
safe/tolerable in patients with OCD who have not adequately responded to past adequate SRI
treatment.

Inclusion Criteria:

1. Meets DSM-IV-TR criteria for a principal current diagnosis of OCD which is confirmed
by both clinical evaluation and by structured interviews. OCD subjects with other
comorbidities will be included provided OCD is judged to be the chief complaint.

2. Subjects must continue to experience clinically significant symptoms of OCD (Y-BOCS
score ≥19 and a rating of "moderate" or greater on the Clinical Global Impressions
(CGI) scale) despite at least two adequate SRI monotherapy trials. One unsatisfactory
trial can include the SRI currently being taken by the patient provided that the
duration of treatment is 12 weeks or more and that the dose has been adequate.
Subjects must be taking a clinically effective dose of a SRI (i.e., clomipramine,
citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine and sertraline) for at
least 12 weeks. Subjects must be on their current dose for at least 12 weeks and
must maintain their current dose throughout the study.

3. Between the ages of 18-70 years of age.

4. Only subjects with OC symptoms of at least one-year duration will be included.

5. Eligible subjects must be in good physical health. Screening procedures will include
detailed medical history, complete physical and neurological exams, routine blood
studies (CBC, liver function tests, electrolytes), ECG, urine toxicology screen, and
serum pregnancy test in women of child-bearing potential.

Exclusion Criteria:

1. Primary depression, schizophrenia or other psychotic disorders.

2. Active bipolar disorder.

3. Non-responder in the past to atypical antipsychotic augmentation. This criterion was
chosen to prevent recruiting a sample of chronically refractory OCD cases that would
otherwise be suited for more extreme interventions such as deep brain stimulation.

4. Non-responder in the past to an adequate trial (> 20 hours) of cognitive-behavioral
therapy that will be assessed by records review.

5. Current clinically significant suicidality or individuals who have engaged in
suicidal behaviors within 6 months will be excluded and referred for appropriate
clinical intervention.

6. Alcohol or other significant substance abuse within the last 6 months.

7. History of neurosurgery, encephalitis or significant head trauma or a significant
medical condition such as heart, liver, or renal disease.

8. Nursing mothers or women of childbearing potential who do not use adequate
contraception will be excluded.

9. Subjects at an increased risk for seizures will also be excluded from this study
(e.g., subjects with a history of seizures [other than childhood febrile seizures],
subjects taking concomitant medications known to lower the seizure threshold).

10. Estimated IQ < 80, mental retardation, dementia, brain damage, or other cognitive
impairment that would interfere with the capacity to participate in the study and
complete measures. If needed, the WASI will be used to assess this at screening.

11. Concurrent use of benzodiazepines, other than for treatment of insomnia, will be
prohibited during the trial. No other psychotropic medications will be permitted.