Treatment-resistant OCD: Pharmacotherapies in adults.

Serotonin reuptake inhibitor (SRI) medications are well established as first-line pharmacotherapeutic treatment for Obsessive-Compulsive Disorder (OCD). However, despite the excellent safety profile and demonstrated efficacy of these medications, a substantial proportion of individuals with OCD fail to attain sufficient benefit from SRIs. In this narrative review, we discuss clinical features of OCD that have been associated with poorer response to SRIs, and we present pharmacotherapeutic interventions that have been explored as augmenting or alternative treatments for treatment-resistant OCD. We additionally highlight non-SRI interventions for OCD that are currently under investigation. Pharmacotherapeutic interventions were identified via expert consensus. To assess the evidence base for individual pharmacotherapies, targeted searches for relevant English-language publications were performed on standard biomedical research databases, including MEDLINE. Information relevant to ongoing registered clinical trials in OCD was obtained by search of ClinicalTrials.gov. Pharmacotherapies are grouped for review in accordance with the general principles of Neuroscience-based Nomenclature (NbN). Clinical features of OCD that may suggest poorer response to SRI treatment include early age of onset, severity of illness, duration of untreated illness, and the presence of symmetry/ordering or hoarding-related symptoms. Based on evolving pathophysiologic models of OCD, diverse agents engaging serotonin, dopamine, norepinephrine, glutamate, and anti-inflammatory pathways have been explored as alternative or adjunctive therapies for treatment-resistant OCD and have at least preliminary evidence of efficacy. Medications with dopamine antagonist activity remain the most robustly evidence-based of augmenting interventions, yet dopamine antagonists benefit only a minority of those who try them and carry elevated risks of adverse effects. Interventions targeting glutamatergic and anti-inflammatory pathways are less well evidenced, but may offer more favorable benefit to risk profiles. Ongoing research should explore whether specific interventions may benefit individuals with particular features of treatment-resistant OCD.

Duloxetine treatment of dysthymia and double depression: an open-label trial.

BACKGROUND: Although not as common as major depressive disorder, dysthymia is not rare and is associated with substantial impairment. Antidepressants and some psychotherapies are often effective. We explored the efficacy of the antidepressant duloxetine, a serotonin and norepinephrine reuptake inhibitor. METHOD: Between February 2005 and April 2006, we recruited 24 adults with DSM-IV dysthymia or dysthymia and concurrent major depression ("double depression") who had an entry score of > or = 17 on the clinician-rated Inventory for Depressive Symptomatology (IDS-C). We excluded subjects with significant medical illnesses and those requiring other psychotropic agents or undergoing psychotherapy. Subjects received duloxetine 60 mg/day for 6 weeks, increased as tolerated to 120 mg/day for the remainder of the 12-week trial for those with an inadequate treatment response. RESULTS: The subjects' mean +/- SD IDS-C scores decreased significantly from baseline (27.3 +/- 6.3) to endpoint (7.8 +/- 7.4, Student t = 12.38, df = 23, p < or = .001). The IDS-C response rate (intent-to-treat [ITT]) was 83% (20/24); the remission rate (ITT) was 79% (19/24). Among study completers, these rates were 89% (17/19) and 84% (16/19). Five subjects (21%) discontinued for side effects. CONCLUSION: Duloxetine appears to be an effective and well-tolerated treatment for dysthymia and double depression. A double-blind, placebo-controlled study is under way. If duloxetine is found to be effective, studies powered to detect potential, clinically important differences between duloxetine and other antidepressants will be needed. CLINICAL TRIALS REGISTRATION: ClinicalTrials.gov identifier NCT00185575.

Escitalopram treatment of kleptomania: an open-label trial followed by double-blind discontinuation.

BACKGROUND: Kleptomania has no definitive treatment. Mixed reports of benefit from openly prescribed selective serotonin reuptake inhibitors led us to design a double-blind, placebo-controlled discontinuation trial of escitalopram. METHOD: Between December 2002 and March 2005, we recruited 24 subjects aged >or=20 years with DSM-IV kleptomania of >or=1 year's duration. We excluded subjects with organic mental disorders, psychoses, substance or alcohol abuse, suicidal risk, bipolar I or II disorder, anorexia nervosa, or antisocial personality disorder and subjects requiring other psychotropic medications. Our primary outcome measure was theft episodes per week. A responder was defined as a subject having a > 50% decrease in theft episodes per week and a Clinical Global Impressions-Improvement scale score of "much improved" or "very much improved." Escitalopram was started at 10 mg/day and increased as necessary and tolerated after week 4 to 20 mg/day. At the end of week 7, responders were randomly assigned to a 1-week taper followed by 16 weeks of placebo or to continuation of treatment for 17 weeks at their week 7 escitalopram dose. RESULTS: Nineteen subjects (79%) were week 7 responders and 15 were randomly assigned. Five subjects (4 responders) withdrew early: 1 for unrelated illness, 1 for protocol deviation, 2 for side effects, and 1 for withdrawn consent. Three (43%) of 7 escitalopram subjects relapsed compared with 4 (50%) of 8 placebo subjects (Fisher exact test p = .38). CONCLUSION: The high response rate during open-label escitalopram treatment was not better maintained by double-blind escitalopram than by placebo. Kleptomania may be a heterogeneous pathological behavior better treated with pharma-cotherapy in some cases and psychologically or with combined treatment in others.

Mirtazapine for obsessive-compulsive disorder: an open trial followed by double-blind discontinuation.

BACKGROUND: Many patients with obsessive-compulsive disorder (OCD) experience little response to standard treatment with serotonin reuptake inhibitors. Mirtazapine enhances serotonergic function by a mechanism distinct from reuptake inhibition. Because a pilot study suggested effectiveness of mirtazapine in OCD, we conducted a controlled trial. METHOD: We recruited 30 subjects, 15 treatmentnaive and 15 treatment-experienced, with DSM-IV OCD of > or =1 year's duration and a Yale-Brown Obsessive Compulsive Scale (YBOCS) score of > or =20. In the 12-week, open-label phase, subjects received mirtazapine starting at 30 mg/day and titrated over 2 weeks as tolerated to 60 mg/day. At week 12, responders (YBOCS score decrease > 25%) were randomly assigned, double-blind, to continue mirtazapine or switch to placebo for 8 weeks, including a 1-week, double-blind taper week for placebo subjects. RESULTS: In the open-label phase, the mean +/-SD YBOCS score fell from 28.3 +/-3.7 to 20.3 +/-8.5 (paired samples t = 4.81, p < .0001). Four subjects (13.3%) discontinued for side effects. Sixteen subjects (53.3%) (8 treatmentnaive, 8 treatment-experienced) were responders and 15 agreed to randomization. Response was independent of comorbid mood disorders. In the 8-week, double-blind, placebo-controlled discontinuation phase, the mirtazapine group's mean YBOCS score fell a mean +/-SD of 2.6 +/-8.7 points while the placebo group's mean score rose a mean +/-SD of 9.1 +/-7.5 points (Mann Whitney U = 6.5, p = .005, 1-tailed). All other outcome measures were consistent with mirtazapine's superiority versus placebo. CONCLUSION: Mirtazapine may be an effective pharmacotherapy for OCD. If our results are replicated, larger double-blind studies would be indicated.