Time Pressures Raise Stakes When First Antidepressant Fails


NEW YORK — Time is a crucial factor in depression treatment, as repeated failed trials and delay in achieving an adequate response take a cumulative toll on patient morale, ability to function, and finances, Jeffrey E. Kelsey, M.D., Ph.D., said at a meeting on psychopharmacology sponsored by New York University.

Good practice often requires the application of both evidence and clinical experience. “Proven therapies are a good place to start, but we can't get by solely on what evidence tells us,” said Dr. Kelsey, medical director of the Georgia Institute of Mood and Anxiety Disorders, Atlanta.

The choice of an initial antidepressant is “little more than an educated guess” for the most part, he said. If an adequate trial fails to achieve a response, the choice is between switching to a different agent and augmentation with polypharmacy.

“If the first drug isn't working at all, I would stop it before adding something else,” Dr. Kelsey said. An agent with a different mechanism of action would seem a better choice than one of the same class.

The switch, however, should not be too abrupt: A schedule that phases in the second drug while slowly tapering the first will minimize the possibility of the discontinuation syndrome that can occur when serotonergic drugs are withdrawn. The patient should be counseled about the possibility of such symptoms as malaise, gastrointestinal upset, anxiety, irritability, insomnia, and paresthesias so these symptoms are not ascribed to the new drug, he said.

Augmentation, when the first drug is well tolerated and has achieved some degree of response, is likely to achieve quicker results than switching, Dr. Kelsey said.

Lithium and thyroid hormone augmentation are “classic” strategies that have been shown to be more effective than placebo, he said.

Lithium, in particular, is underutilized. Dr. Kelsey advised a modest target blood level of 0.4–0.5 mEq/L, which is generally adequate and less likely to cause tolerability problems than higher blood levels.

Thyroid augmentation should be based on thyroid hormone assay. If only T3 is low, just T3 should be added; if both T3 and T4 are low, just T4. “Sometimes the improvement is amazing,” he said.

When an atypical antipsychotic is used for augmentation, the possible effect of drug-drug interactions must be kept in mind. Risperidone (Risperdal), for example, should be started at 0.5 mg/day and increased to 1 mg/day, but when it is used to augment an SSRI that may inhibit cytochrome P450 2D6, those dosages should be halved.

Dopaminergic agents are particularly apt for augmentation when apathy and low energy are prominent. With use of a dopamine agonist like pramipexole (Mirapex), a gradual escalation from a low dose will minimize nausea and improve tolerability.

Reducing, rather than increasing, the SSRI should be considered in this situation since anergic, amotivational symptoms may be related to dopaminergic downregulation in the frontal lobe, Dr. Kelsey explained.

With any long-standing or treatment-resistant depression, the chances for a good response are substantially increased if psychotherapy is added to whatever medication regimen is used.

As patients become more refractory, a longer trial is necessary before concluding that a treatment approach isn't working. “You won't get an immediate response, as in early illness,” Dr. Kelsey said. “Remember, the clock is ticking.”

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