MIAMI BEACH, FLA— Although rapid response to antidepressant therapy is desirable for any patient, the need to accelerate recovery may be particularly urgent in geriatric patients, for whom the combination of depression and acute or chronic medical problems can greatly increase mortality. While researchers have explored the potential value of several strategies for speeding antidepressant response, the most promising approaches in severely depressed elderly patients are combination therapy and electroconvulsive therapy, experts reported at the 13th annual meeting of the American Association for Geriatric Psychiatry. Both techniques appear to be faster than conventional monotherapy, although in the case of combination therapy additional controlled trials are needed. On the other hand, studies suggest that there is little to be gained from administering antidepressants intravenously, and the jury is still out on whether the presumed efficacy of transcranial magnetic stimulation is fact or fable, researchers said.

COMBINATION THERAPY: HOW MUCH FASTER?

In many cases, antidepressant response can be accelerated by treating patients with more than one agent. For example, augmenting selective serotonin reuptake inhibitors (SSRIs) with pindolol when treatment is initiated can reduce response time by five to seven days in severely depressed, hospitalized patients, reported J. Craig Nelson, MD.

The SSRI/pindolol approach does not work in patients who are resistant to SSRIs, and it must be used with caution in elderly patients who are already taking beta-blockers for cardiovascular indications. In these populations, other multiagent regimens may be effective, such as combining an SSRI with a tricyclic antidepressant, or using a stimulant such as dextroamphetamine together with a tricyclic. Unfortunately, few of these strategies have been studied in older patients, said Dr. Nelson, who is professor of psychiatry at Yale University School of Medicine in New Haven, Conn, and director of Psychiatric Inpatient Services in the Geriatric Psychiatry Programs at the Yale-New Haven Hospital.

ENHANCING SEROTONIN TRANSMISSION

Several studies have explored the potential benefits of combining low doses of pindolol with an SSRI. This is a theoretically attractive strategy, according to Dr. Nelson, because pindolol blocks the presynaptic 5-HT1A receptor. "That is partly an autoreceptor," he noted. "Normally when you give an SSRI, the autoreceptor shuts down the firing rate in response to it and decreases serotonin transmission. The idea behind adding pindolol is that blocking the autoreceptor will produce enhanced serotonin transmission more quickly."

Of the five studies examining the pindolol/SSRI approach, four demonstrated faster response times. For example, one double-blind trial of 80 patients randomized to paroxetine and either pindolol or placebo found that the placebo group required seven additional days to reach the same level of response as the pindolol patients. "This suggests that you may gain a week's time with pindolol," Dr. Nelson said. Although the difference "started to level off" by the end of the study, the earlier response with pindolol is still clinically significant, Dr. Nelson said.

Similar studies have shown a five- to six-day decrease in response time when pindolol is combined with an SSRI. In one report, the benefits were even greater: patients achieved a 50% reduction in symptoms 10 days earlier with the pindolol/SSRI combination.

Unfortunately, pindolol is ineffective in patients who are SSRI-resistant, Dr. Nelson said. A 1999 study published in the Archives of General Psychiatryfound that adding pindolol after six or more weeks of SSRI treatment produced "no clinically meaningful difference" in patients who had not responded up to that point.

DOES SSRI PLUS TRICYCLIC EQUAL FASTER RESPONSE?

SSRI/tricyclic combinations are also promising. In an open-label trial, Dr. Nelson's group found that more patients achieved clinical remission with a fluoxetine/desipramine combination than would be expected on the basis of historical results with SSRI monotherapy. Currently, he is completing a prospective, randomized trial comparing the effects of fluoxetine (20 mg/d) plus desipramine (adjusted to an optimal plasma level) to the effects of fluoxetine alone. Data are still being analyzed, but Dr. Nelson said that the group on multiagent therapy "did do a little better." He added that with this combination of medications, the benefit may not be faster onset of efficacy but greater ability to produce complete response.

Another strategy is to give patients with primary affective disorder or major depression a stimulant at the beginning of treatment along with an antidepressant. "About half of depressed patients have some response to a stimulant within two to five days," Dr. Nelson said. "As the stimulant is wearing off, the antidepressant is reaching efficacy. The net effect might be more rapid response, with continued and sustained response." In one study, inpatients with major depression were given methylphenidate and a tricyclic. "By the end of one week, 30% of the patients had a 50% improvement. By the end of two weeks, 63% had 50% improvement. There was no comparison group, but these data suggested that this might be an effective early treatment."

Dr. Nelson noted that other researchers have suggested that adding methylphenidate to sertraline or a stimulant to an SSRI might be effective. "In my experience, adding mirtazapine to an SSRI can be helpful," he reported. "Elderly patients who are depressed often have trouble maintaining weight, so the weight gain would be desirable. They almost always have insomnia, so if mirtazapine helps sleep, that is a positive effect. We have found it to be a useful combination, and we use it often in patients when we are interested in saving hospital days, especially patients who also have some resistance to the SSRI."

NOT FOR THE ANXIOUS

Although there have been few controlled studies of stimulant/antidepressant combinations in the elderly, Dr. Nelson said he has seen stimulants have impressive effects in this population and that these medications are generally well tolerated. "The limitations are not cardiovascular, they are psychological," he noted. "The main side effects of stimulants are central nervous system side effects, so they might not be a good choice in very anxious, agitated, or near-delusional patients. In the patient who has been sort of shut down, the addition of a stimulant sometimes can be dramatically effective."

Although lithium has been the most widely studied augmentation agent, Dr. Nelson warned that it is difficult to use lithium in elderly patients because renal clearance declines with increasing age; this results in higher serum lithium levels, to which some patients become more sensitive. Moreover, "elderly patients may be on a number of other agents, such as hydrochlorothiazide or nonsteroidal anti-inflammatory drugs, that affect renal clearance and make the use of lithium even more complicated," he said.

INTRAVENOUS FORMULATIONS: WORTH THE TROUBLE?

Another potential strategy for accelerating recovery is to use intravenous antidepressants, which may provide higher initial plasma levels of the drug. Unfortunately, most evidence indicates that intravenous formulations offer little advantage over currently available oral antidepressants for the majority of patients, according to Bruce G. Pollock, MD, PhD, professor of psychiatry, pharmacology and nursing at the University of Pittsburgh and director of its Geriatric Psychopharmacology Program.

One obvious drawback to using intravenous therapy is that it is only feasible for inpatients. "Some of you may remember back to the good old days when you could have the luxury of hospitalizing severely depressed patients who weren't suicidal but nonetheless significantly depressed, and you had up to a month in the hospital to treat them," Dr. Pollock said. That option has nearly vanished in the United States, although intravenous therapy remains widely used in Europe.

Reviewing the literature comparing intravenous and oral dosing of a number of antidepressants, Dr. Pollock noted that intravenous administration of SSRIs is of relatively little benefit because the bioavailability of these agents is generally 80% to 90% and most reach steady state within a few days. Indeed, European studies of intravenous citalopram and viloxazine have demonstrated that the parenteral formulations are no more than marginally faster-acting than their oral equivalents.

Thus, intravenous antidepressants are best used not for accelerating response, but for patients who are unable to absorb or tolerate oral medications. Intravenous administration also assures patient compliance.

Dr. Pollock suggested that the preference for intravenous medications in Europe may have to do with the placebo effect. "If we put on white coats and do a procedure, it is a lot more powerful than just sending the patient off to get a tablet from the pharmacy. Placebo effects are, if anything, even greater in older patients; increased attention certainly does have a benefit for these patients."

ECT: IMPROVEMENT WITHIN A DAY?

Although the apparatus used for electroconvulsive therapy (ECT) may also invoke powerful placebo effects, in this case there is clear evidence of efficacy, and patients generally respond quite rapidly. "Without doubt, ECT is our most effective antidepressant," stated Harold A. Sackeim, PhD. "There are essentially no trials where another antidepressant treatment was more effective than ECT." Older patients, he continued, actually have better response rates with ECT than younger patients, "probably because the older patients are less likely to come to ECT with established medication resistance." Dr. Sackeim is chief of biological psychiatry at the New York State Psychiatric Institute and professor of clinical psychology at Columbia University's College of Physicians and Surgeons in New York.

Dr. Sackeim reported data showing that the time to achieve a 50% improvement with ECT averages about nine days (four treatments), compared with the 20 days often seen with medications. "Onset of action, defined as a 25% improvement, often occurs in one day," he said. Recent studies have shown that ECT efficacy is a function of how the treatment is given: higher dosage unilateral right ECT is as effective as bilateral ECT at more moderate doses. "The reason this is important," Dr. Sackeim said, "is that the cognitive side effects of these treatments are very distinct. The extent of retrograde amnesia is considerably more pronounced with the moderate-dosage bilateral ECT at 2.5 times seizure threshold than with unilateral ECT at six times threshold. This difference persists for months after the end of ECT."

ECT is less effective in medication-resistant patients. Dr. Sackeim said that the response rate is about 63% in these patients, compared to 91% in patients who are not medication resistant. Patients who have not responded to treatment with lithium plus a tricyclic antidepressant are the least likely to respond to ECT, with response rates of 23%.

Transcranial magnetic stimulation (TMS) is currently available only as an experimental therapy, and although promising reports have been published, the procedure may be of limited use in the elderly. Questions still remain about whether TMS works at all in depression, Dr. Sackeim stated, and it has rarely been reported to be effective in patients over age 55. He added that TMS, like ECT, is likely to have limited efficacy in medication-resistant patients.

—Janis Kelly

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