EXPERT ANALYSIS FROM the ECNP Congress

AMSTERDAM (FRONTLINE MEDICAL NEWS) – Despite persistent stigma, electroconvulsive therapy endures as an effective treatment for depression, particularly when applied with a patient-specific approach, according to several study results presented at the annual congress of the European College of Neuropsychopharmacology.

Dr. Charles Kellner, professor of psychiatry at the Icahn School of Medicine at Mount Sinai, New York, said ECT is well established as effective in elderly populations with depression and is notable for its ability to rapidly curb suicidal ideation, as shown by unpublished data from his PRIDE study (Prolonging Remission in Depressed Elderly, NCT01028508 ). That study showed an 85% drop in suicidality in patients by the end of their ECT treatment course.

“ECT would be one of the very best treatments in all of medicine” if not for several factors, Dr. Kellner said. ECT cannot prevent relapse in depression unless it is used as maintenance therapy, and varying degrees of negative cognitive impact can come with the procedure, he said. In addition, ECT has been stigmatized by the popular media and others in the profession, and by the antipsychiatry movement, he said.

Despite all this, burgeoning data indicate clinicians have a variety of effective and efficacious ECT methods from which to choose. The overall calculus for which ECT method is best in a specific case “is severity of illness,” Dr. Kellner said in an interview. “It’s usually driven by suicidality and how dysfunctional the patient has become.”

In Dr. Kellner’s PRIDE phase I study, data indicated that 40% of 240 consenting patients with a mean age of 70 years and unipolar depression, given ultrabrief pulse right unilateral ECT three times weekly until remission, and augmented by a low dose of the selective serotonin reuptake inhibitor venlafaxine (up to 225 mg per day after any previous medication washout), were successfully treated for their depression after 1 week.

The response criteria was a 50% or greater reduction from baseline in at least 21 of 24 items on the Hamilton Rating Scale for Depression ( HAM-D-24 ) after 1 week, while remission was defined as scoring 10 or less on the HAM-D-24 at two consecutive follow-up points each week. After two treatments, 8% of responders achieved remission, and nearly 18% remitted after a full week.

Meanwhile, patients who did not complete the study or meet the response and remission criteria still benefited, Dr. Kellner said. “Nonremitters [about 28% of the study] and dropouts [about 10%] get considerably better from whatever ECT they are able to have.”

ECT with a pulse width of less than 0.5 milliseconds is considered ultrabrief pulse ECT. Pulse widths of 0.5 msec or higher are considered standard ECT. Seizures induced by any pulse width are the theorized mechanism of action for reducing depression with ECT, but correlates between higher levels of energy and greater levels of negative cognitive effects are well established in the literature. Presenter Dr. Pascal Sienaert, a psychiatrist and director of the ECT program at the Catholic University of Leuven (Belgium), said that because the “ideal stimulus to depolarize a group of neurons would be 0.1 or 0.2 milliseconds,” ultrabrief pulse ECT should “theoretically” be the most effective with the least cognitive burden.

In the PRIDE study, nearly 85% of participants seized at the lowest stimulus dose during their first treatment when ultralow doses were used to determine each patient’s seizure threshold. Given the age of the cohort, this was a fortunate surprise, Dr. Kellner said, since it allowed subsequent dosing at six times the seizure threshold at low absolute stimulus charges. “This is a very efficient form of ECT for inducing a seizure,” Dr. Kellner said in his presentation.

About 10% of responders in the study experienced more than a 50% drop in their HAM-D scores after one treatment at the ultralow dose, which has created some debate over whether it was a placebo response. Dr. Kellner rejected this theory. “I think ECT is such a powerful biological treatment, it’s very hard to ascribe this to placebo.”

Rates of remission varied greatly in the PRIDE study, ranging from 20% remitting after 4 treatments, to 26% remitting after 10 treatments. “This speaks to the point that you can’t tell a patient how long their treatment will be. Some need fewer treatments; some need prolonged courses.”

But Dr. Sienaert’s own findings cast doubt on the ability of ultrabrief pulse ECT to ensure fewer cognitive burdens than standard ECT.

In a randomized comparison of ultrabrief bifrontal and unilateral ECT for patients with refractory depression, no significant differences were found in response and remission rates. However, the cohort treated with right unilateral ultrabrief pulse ECT required fewer treatments to reach response and remission (J Affect Disord. 2010 Apr;122[1-2]:60-7. doi: 10.1016/j.jad.2009.06.011 ).

Although all patients had baseline deficits across the cognitive domains, Dr. Sienaert’s study did not find any additional declines in cognition following ECT in either arm. Because the entire study group overall remained cognitively impaired, Dr. Sienaert theorized the sample was either previously cognitively scarred, putting them at risk for depression, or that the inverse was true: their depression left them vulnerable to cognitive deficits.

Taken with the results of a second study by Dr. Sienaert, there doesn’t seem to be any notable cognitive advantage to ultrabrief pulse ECT.

In the second study, a randomized, controlled comparison of right unilateral ultrabrief pulse ECT with right unilateral standard pulse ECT in 116 patients, standard pulse ECT performed significantly better than did ultrabrief pulse ECT, and had similar relapse rates at 3 and 6 months. Most of the patients in the study were women in their early 60s who were taking medication for their depression (J Affect Disord. 2015 Sep 15;184:137-44. doi: 10.1016/j.jad.2015.05.22 ).

Remission rates in both those who dropped out (58%) of the standard group and those who completed the standard ECT treatments (68.4%) were higher, compared with the ultrabrief intention-to-treat (41.4%) and completion (49%) groups. The standard ECT group also needed, on average, two fewer treatments to reach remission (7 vs. 9). Cognitive burdens in the two therapies were comparable.

However, a recently published meta-analysis of both standard and ultrabrief pulse ECT found that while ultrabrief pulse ECT has lower remission rates than standard ECT, it is associated with having less of a cognitive impact ( J Clin Psychiatry. 2015 Jul 21 ).

Even though, according to Dr. Sienaert, many clinicians have changed their practice, adopting ultrabrief pulse ECT for all patients, he told the audience: “I don’t think it should be the standard of care. There is not one single technique that should be … the data give us possibilities to tailor treatment to our patients.”

Having a range of treatments also helps to persuade patients who might be put off by near sadistic depictions of “shock therapy” in popular culture such as in the movie “ One Flew Over the Cuckoo’s Nest ” based on the novel by Ken Kesey and released in 1975. “It’s still responsible for the vast majority of stigma surrounding ECT,” Dr. Kellner said.

In an interview, Dr. Sienaert said having more options means, “You can choose treatments with less cognitive side effects for patients who are either afraid of [experiencing cognitive deficits] or who already have cognitive issues, such as might be in the elderly.”

Data presented by Dr. Declan McLoughlin, a research professor of psychiatry at Trinity College Dublin, considered the question of whether a specific ECT treatment’s efficacy might be outweighed by a lack of efficacy.

Previous trials have tested whether standard bitemporal ECT has better efficacy than that of high-dose unilateral ECT, but whether a cognitive impact was too great proved unclear.

In a currently unpublished study, Dr. McLoughlin and his associates showed that both forms of treatment were efficacious and effective. The upshot was that high-dose ECT was not inferior and offered some cognitive advantages, “Particularly if cognitive side effects are an issue to begin with,” he said.

The study randomly assigned 138 patients with severe depression, two-thirds of whom were women primarily in their late 50s, to receive standard bitemporal ECT at 1.5 times the patient’s established seizure threshold twice weekly, or high-dose right unilateral ECT at 6.0 times the patient’s seizure threshold twice weekly. Patients received up to 12 sessions depending upon the treatment recommended by the individual clinician. All participants, except for the clinicians administering the treatments, were blinded. Patients were rated for their response and remission rates after every second ECT treatment and were followed for 12 months after their last treatment.

Nearly 51% of patients in the low-dose group met the primary clinical outcome with a 60% or greater change from baseline on their HAM-D-24, scoring 16 or less. Just under 61% of patients met the response criteria in the high-dose group.

Forty-two percent of patients in the low-dose group met remission criteria of at least a 60% decrease in their baseline HAM-D with a score of 10 or less on two consecutive rating sessions, while just over 46% did in the high-dose group.

“Over time, the unilateral group did slightly better, including at 6 months’ follow-up,” Dr. McLoughlin said.

The higher dose group outperformed the lower-dose group by just over 1 point on the HAM-D scores, within the noninferiority threshold.

At 6 months, nearly a third of remitters in each group had relapsed with a 10-point or higher increase from their HAM-D taken at the end of their treatment.

The high-dose patients also experienced less impairment to their autobiographical memory (details they told the clinician before receiving ECT) directly after treatment and at 6-month follow-up. The low-dose patients overall recalled about 60% of their autobiographical memory, compared with the high dose group’s 70%. However, Dr. McLoughlin noted that this is normal in the general population, “but it’s probably a bit worse in depressed patients.”

An as yet unpublished meta-analysis Dr. McLoughlin and his colleagues conducted of the six previous trials comparing the efficacy of these two forms of ECT also found no significant difference between the two regarding response or remission, and that higher doses of ECT offered better reorientation times, and better retrograde autobiographical memory, with no differences in global cognition, complex figure tests, or verbal learning.

While cognitive data from the PRIDE phase I and efficacy data from the study’s phase II are forthcoming, according to Dr. Kellner, he agreed with Dr. McLoughlin that overall, bilateral treatments were better, although the unilateral treatments approach the same efficacy levels. Ultimately, however, group data are irrelevant if they fail to jibe with what is happening in front of a clinician treating a patient.

“For an individual patient who doesn’t respond to right unilateral ECT, it’s imperative they be switched over to a different form of ECT,” said Dr. Kellner, since many right unilateral nonresponders will do well with bilateral ECT. “Particularly if patients are urgently ill, one should consider using bilateral ECT from the outset. I still believe that is a true clinical dictum.”

The lineup of international ECT experts drew roughly 200 audience members, the largest such ECT audiences Dr. Kellner and Dr. Sienaert said they’d ever seen.

“The biggest problem is ECT remains stigmatized,” Dr. Kellner said. “It needs to be said at any ECT gathering.”

Dr. Kellner is a consultant to Luitpold Pharmaceuticals. Dr. Sienaert noted he had received travel expenses in the past year from MECTA, and Dr. McLoughlin had no relevant disclosures.

wmcknight@frontlinemedcom.com

On Twitter @whitneymcknight

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