Pharmacological Treatments
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.