AT THE ASCP ANNUAL MEETING
SCOTTSDALE, ARIZ. (FRONTLINE MEDICAL NEWS) – A small proof-of-concept study of low-field magnetic stimulation to augment medical treatment for 85 individuals with treatment-resistant major depressive disorder failed to meet its primary endpoint of significant improvement in core depression symptoms at 48 hours after treatment, though some nonsignificant improvement in mood was seen, compared with sham treatment.
The study’s design did succeed, however, in reducing the substantial placebo response that plagues many clinical trials of treatments for psychiatric illness.
During a meeting of the American Society of Clinical Psychopharmacology, formerly known as the New Clinical Drug Evaluation Unit meeting, Dr. Maurizio Fava shared the results of a double-blind, proof-of-concept trial of low-field magnetic stimulation (LFMS) augmentation of antidepressant therapy for patients with treatment-resistant depression.
Overall, patients receiving LFMS saw no significant improvement on an abbreviated 6-item Hamilton Rating Scale for Depression (HAMD-6), compared with those receiving sham treatment (P = .61). Since the study looked at changes in depression scores just 24 hours after treatment, Dr. Fava said, “We used the HAMD-6, because it’s a more sensitive measure for rapid changes than the HAMD-17.
“Unfortunately, the LFMS did not separate out after 48 hours,” he said.
Nonsignificant differences also were seen for two other rating scales, the Montgomery-Åsberg Depression Scale (MADRS) and the Strengths and Difficulties Questionnaire ( SDQ ). The use of a visual analog scale to detect mood changes 120 minutes after treatment did not yield significant differences between those receiving LFMS and those receiving sham.
Many avenues in addition to medication are being explored to provide rapid relief for individuals with treatment-resistant depression (TRD), said Dr. Fava, the study’s lead investigator, associate dean for clinical and translational research, and Slater Family Professor of Psychiatry at Harvard Medical School, Boston.
The six-site Rapidly-Acting Treatments for Treatment-Resistant Depression trial was sham controlled and used a prerandomized sequential parallel comparison design (SPCD). The intervention of LFMS or sham was delivered for 20 minutes daily on 2 consecutive days, and then again for 2 more days after an interim assessment.
“In the second stage of the study, only the patients who had not responded to sham are included,” Dr. Fava said. This is the aspect of an SPCD study that can help to reduce the negative effect on results that can be seen with high placebo response rates, a common phenomenon in psychiatric clinical trials.
“This was a complicated study, involving all kind of methodologic approaches,” said Dr. Fava, noting that each enrollee had the diagnosis of moderate to severe depression (MADRS score equal to or greater than 20) confirmed by two interviewers, including one remote interviewer who was not involved in the study.
Patients who were on a stable dose of antidepressant were included “if they failed to achieve a treatment response after no more than one, but not more than three, treatment courses of antidepressant therapy of at least 8 weeks’ duration,” Dr. Fava said. “We wanted to avoid ‘super-resistance,’ which can reduce the ability to detect a signal” for efficacy, he said.
Dr. Fava also made the point that this study was of very short design, compared with other SPCD trials. “People were skeptical that you would see a reduction in placebo with only 4 days of treatment in two stages,” he said. However, “The design worked,” he said, since the reduction in depression scores was the equivalent of just 1.6 points on the HAMD-17 in the second stage of the study after the placebo responders had been eliminated. “That’s a very low placebo rate,” Dr. Fava said.
Many experimental building blocks support the use of LFMS to treat depression. Investigations began after a serendipitous 2004 discovery that patients with bipolar disorder who underwent diagnostic echo-planar magnetic resonance spectroscopic imaging (EP-MRSI) experienced relief from depressive symptoms after the scan (Am J Psychiatry. 2004 Jan;161[1]:93-8). Since then, LFMS has been shown to reduce helpless behavior in mice during a forced swim test.
In humans, FDG-PET imaging studies also have shown perceptible physiological changes when individuals with depression receive LFMS, consistent with those seen in reduced depression. Patients in two earlier proof-of-concept studies who had either bipolar or unipolar depression and who received LFMS experienced significantly greater symptom relief than did those receiving sham treatment.
Study design limitations included the relatively small sample size and potential recruitment biases for those seeking this form of augmentation for depression treatment. The study included only patients with unipolar depression, although “two previous positive studies included 81 bipolar patients and 22 unipolar patients,” Dr. Fava said.
Potential technical limitations included the low dosing of LFMS, with just 20 minutes of exposure two times; however, Dr. Fava said, the duration was chosen to parallel the previous studies done in patients with bipolar disorder. Also, seeing a detectable change in depression scoring at 48-72 hours after LFMS might not be an entirely realistic expectation.
The National Institutes of Health and the Department of Health and Human Services funded the study. Dr. Fava reported having a patent for Sequential Parallel Comparison Design (SPCD), which is licensed by Massachusetts General Hospital to RCT Logic, LLC. He also reported multiple financial relationships with pharmaceutical and medical device companies.
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