The mechanism of action of the drugs effective in treating OCD (clomipramine, a non-selective serotonin reuptake inhibitor, and the selective serotonin reuptake inhibitors [SSRIs]: citalopram, fluoxetine, fluvoxamine, sertraline and paroxetine) has given rise to the hypothesis that deficient serotonin function is a key element in the pathophysiology of OCD. These drugs block serotonin reuptake by the pre-synaptic neuron, thereby increasing serotonin availability at post-synaptic receptors. The serotonin hypothesis is also supported by the observation that m-CPP (a metabolite of trazodone), which is a partial agonist at serotonin receptor types 1A, 1D and 2C, exacerbates OCD.
About 40% to 60% of patients will respond to clomipramine or to any particular SSRI, and one cannot predict which patient will respond to which drug. A trial of 10-12 weeks at the maximum comfortably tolerated dose is necessary to determine whether a given drug is producing a clinically meaningful response. Direct, controlled comparison studies have found fluvoxamine, paroxetine and sertraline equal in efficacy to clomipramine, the first drug that was demonstrated to be effective in treating OCD.
Dr. Koran's clinical practice is to push the patient in weekly increments to the maximum easily tolerated SSRI (or clomipramine) dose, since it is not possible to predict the dose that will prove effective for an individual patient. For fluvoxamine, he starts the patient at 50 mg/day (25 mg/day for patients who are "sensitive to drugs"), and increases the dose every 5 to 7 days by 50 mg/day to a maximum daily dose of 300 mg/day if possible.
Over 10-12 weeks, symptoms decrease by about 40% to 50% or more in about 60% of patients. Disappearance of all symptoms rarely occurs. Benefit is usually noticeable after 6 weeks, but may take 8 weeks to begin. Non-responders to one SSRI may respond to another or to behavior therapy. Partial responders may benefit further from potentiating (augmenting) drugs or from adding behavior therapy (exposure and response prevention, or cognitive approaches). In addition, reports exist of cases successfully treated with buspirone (60 mg), clonazepam (6.5 mg), trazodone (plus tranylcypromine) and venlafaxine, but these drugs should not be used as single-agent therapy until other, better supported medications have been tried. Clozapine, carbamazepine, lithium, clonidine, stimulants, ECT, sleep deprivation, and bright light therapy are not effective.
Drug therapy should be continued indefinitely, since the available data suggest that patients' symptoms will return within one to two months after medications are stopped, even after two years of successful pharmacotherapy. A recent study suggests that 20% of patients who discontinue a successful drug will not respond when the drug is restarted. Available data suggest, but do not prove, that providing behavior therapy while the patient is taking medication may delay or prevent relapse when medication is discontinued. A number of drugs appear to act as potentiators or augmentors of SSRIs, although the data are limited, but controlled trials of potentiating strategies are sorely needed. OCD patients who have comorbid tics or schizotypal personality are unlikely respond to clomipramine or an SSRI alone, but usually will respond to combining one of these drugs with a modest dose of a neuroleptic such as haloperidol, pimozide or risperidone.
In patients who have not responded to an anti-OCD medication or whose response has been inadequate (about 40% of any large series of patients), the clinician can consider adding one of the following drugs: risperidone 0.5-6.0 mg/day; buspirone 60-90 mg/day; olanzapine 2.5-20 mg/day (weight gain is a problem); trazodone 150-600 mg/day; or, L-tryptophan 2 gm twice daily, plus pindolol 2.5 mg three times daily, plus niacinamide 500 mg daily. One starts with a small dose and increases the dose weekly to the likely therapeutic range, as necessary and as tolerated. Response should be evident within two weeks at a given dose, except for trazodone and the L-tryptophan combination, which may take four to six weeks to produce a substantial effect.
For severely anxious OCD patients, gabapentin 300-3600 mg/day or clonazepam 1-4 mg/day or lorazepam 1-4 mg/day are often helpful. No data support the practice of combining two SSRIs. However, European clinicians are combining clomipramine 50-150 mg with fluvoxamine (50-150 mg), fluoxetine (20-40 mg), sertraline (50-100 mg) or citalopram 40 mg/day and claiming success in many patients unresponsive to either drug alone. When clomipramine is combined with any SSRI other than citalopram, one must monitor blood levels of clomipramine and desmethylclomipramine to avoid cardiac and CNS toxicity. Aim for clomipramine levels of 225-350 ng/ml and combined clomipramine and desmethylclomipramine levels of < or = to 500 ng/ml in blood samples drawn about 12 hours after a dose; steady state takes two to three weeks to achieve. Note that Asian patients may require smaller doses of clomipramine than Caucasians. Unpleasant side effects such as sedation, sexual dysfunction, and weight gain (20-30 lbs.) can lead patients to discontinue clomipramine or SSRIs. Rare reports of akathisia, bleeding, easy bruising and dyskinesias exist. A variety of management strategies can be implemented. Anorgasmia or reduced libido may respond to bupropion 75-150 mg/day, buspirone 15-60 mg, amantadine 100-400 mg/day, methylphenidate 10-20 mg/day, dexedrine 5-10 mg/day or yohimbine 5.4-16.2 mg; additional drugs that may help anorgasmia include sildenafil, mirtazapine and nefazodone. Queasiness is usually transient (weeks) and can be minimized by lowering the dose and titrating up slowly. Diarrhea may respond to taking lactobacillus acidophilus capsules once or twice daily.