The modern era in the pharmacotherapy of obsessive-compulsive disorder (OCD) began in the late 1960s with the observation that clomipramine, not other tricyclic antidepressants such as imipramine (Tofranil), was effective in treating OCD. Clomipramine is the most thoroughly studied drug for OCD and was the first to receive FDA approval for this indication.

Like other tricyclic antidepressants, side effects of dry mouth, constipation and urinary retention are common. Like other SRIs, nausea and tremor also are common with clomipramine. Impotence and delayed or failed orgasm occurs with clomipramine. Many patients complain of fatigue and weight gain. Safety concerns with clomipramine include adverse affects on heart conduction and seizures. The risk of seizures increases significantly at doses more than 250 mg daily. Intentional overdoses with clomipramine can be lethal.

The only medications that have been consistently shown effective in treating OCD are antidepressants that interact with the brain chemical serotonin.

Serotonin is one of the brain’s many chemical messengers, or neurotransmitters, that allow one nerve cell (called a neuron) to communicate with another neuron. Instead of being joined directly together, most neurons are separated from each other by a narrow fluid-filled gap called the synapse.

In order for an electrical signal to pass from one neuron to the next, a neurotransmitter is released into the synapse, where it floats freely across to the adjoining neuron. There, it comes in contact with a specialized part of the neuron called the receptor.

The receptor is like a lock and the neurotransmitter the key. With the key in the lock, an electrical signal is triggered and passes along the receiving neuron to convey information elsewhere in the brain. In addition to interacting with the adjoining neuron, released serotonin is actively taken back up into the neuron from which it was released. This serotonin reuptake pump acts to recycle serotonin, assisting in reclaiming it for later release. It also may serve to reduce the amount of “noise” that would be generated if too much serotonin lingered in the synapse after each nerve firing.

Clomipramine (Anafranil) has a number of different chemical properties, including the ability to latch on to the serotonin reuptake pump and prevent the movement of serotonin into its home neuron. Medications such as clomipramine, which block the serotonin pump, are referred to as serotonin reuptake inhibitors or SRIs.

In addition to clomipramine, several selective SRIs have been shown effective in treating OCD, including fluvoxamine (Luvox), fluoxetine (Prozac), sertraline (Zoloft) and paroxetine (Paxil). Some evidence suggests the selective SRI citalopram (Celexa) also may be effective for OCD, even though it does not have FDA approval for this indication.

In a series of different studies, researchers have shown that SRIs are more effective in treating OCD than other antidepressants that do not interact with the serotonin pump. Thus, all SRIs can treat depression, but not all antidepressants can treat OCD. For example, desipramine, which is not an SRI, is an effective antidepressant but is ineffective in treating obsessive-compulsive symptoms. This specificity of response lends weight to the widely held opinion that OCD involves a biochemical imbalance.

In recent years, trials have been conducted in OCD patients with a newer generation of antidepressant drugs that are both potent and selective blockers of serotonin reuptake, i.e., fluvoxamine, paroxetine, sertraline and fluoxetine. Unlike clomipramine, none of these medications loses its selectivity for blocking serotonin reuptake in the body. Also in contrast to clomipramine (and other tricyclics), these drugs lack significant affinity for brain receptors that are thought to be responsible for undesirable side effects. In other words, the selective SRIs are “cleaner” drugs compared to clomipramine.

All potent SRIs tested to date have proven effective in treating OCD. The effectiveness of fluvoxamine has been confirmed in children. Selective SRIs are generally well-tolerated. The most common side effects are nausea, drowsiness, insomnia, tremor and sexual dysfunction (problems with orgasm). There are few significant safety concerns and the risk with overdose is small.

SRIs take time to work. Daily treatment for eight to 12 weeks may be required before the symptoms of OCD begin to recede. Once improvement occurs, the medication usually is continued for at least another six to 12 months. Some patients can be successfully tapered off medication, but the majority seem to relapse after complete discontinuation of medication. Adding behavior therapy may reduce the rate of relapse following discontinuance of medication.

Nearly two-thirds of patients with OCD experience significant symptom relief on SRIs. Among those who do improve, the degree of change is meaningful, but it is rarely complete. A person with OCD who has had a good response to an SRI might report that the time occupied by obsessions and compulsion is cut from six to two hours a day. This may allow the individual to return to work or school and resume a relatively normal and fulfilling life.

Interestingly, how long someone has had OCD does not predict how well they will respond to SRI treatment. Marked improvement can be observed even after 35 years of continuous obsessive-compulsive symptoms.

SRIs are not without side effects. Nausea, tremors, diarrhea, insomnia and daytime drowsiness are some of the common side effects of the SRIs. Clomipramine may produce additional unpleasant symptoms, including dry mouth, constipation and weight gain. It also has risks associated with it, including possible adverse affects on heart rhythm, seizures and death with overdose. Some patients will tolerate one SRI better than another, but for the most part the selective SRIs listed above are better tolerated than clomipramine. With help from their doctor, most patients can find a dosage of medication that relieves symptoms while keeping side effects to a tolerable level.