No Antidepressant Boost With Addition of Metyrapone

Liam Davenport

January 07, 2016

Augmentation of antidepressant therapy with a drug that targets the stress systems in the brain appears to be ineffective in improving response to treatment, the results of a new study show.

In a trial of more than 160 patients with treatment-resistant depression, researchers found that there was no benefit to antidepressant therapy from adding the antiglucocorticoid drug metyrapone (Metopirone, HRA Pharma).

The drug acts on the hypothalamic-pituitary-adrenal (HPA) axis. A substantial proportion of patients with mood disorders, including those with major depressive disorder, have HPA-axis abnormalities, and these abnormalities are associated with a poor prognosis.

Lead author R. Hamish McAllister-Williams, MD, Institute of Neuroscience, Newcastle University, Newcastle upon Tyne, United Kingdom, believes that the study findings raise doubts concerning the use of drugs that affect the HPA axis.

"I think that what it says is that if you look at patients who are not responding to conventional antidepressants and have been ill for some time, they are perhaps unlikely to respond to drugs targeting the HPA axis," he told Medscape Medical News.

"Certainly, our evidence suggests that's the case with regards to metyrapone. So, while there is abundant evidence that suggests that stress and HPA-axis abnormalities are an important element of the pathophysiology and etiology of mood disorders, for this particular group of patients, treatments targeting the HPA axis don't seem to be effective."

The findings were published online in the Lancet Psychiatry on December 22, 2015.

Contrasting Findings

Their results contrast with those of a previous study by Holger Jahn, MD, Department of Psychiatry and Psychotherapy, University Medical Center Hamburg-Eppendorf, Hamburg, Germany, and colleagues.

In a positive, double-blind analysis of 63 inpatients with treatment-responsive depression who were randomly assigned to receive either placebo or metyrapone along with standard serotonergic antidepressant therapy, they found that significantly more of the patients who were given metyrapone than those given placebo had a positive treatment response after 3 weeks.

Consequently, the team concluded that metyrapone "is an effective adjunct in the treatment of major depression" that accelerates the onset of antidepressant action.

In a comment that accompanies the current study, Dr Jahn pointed out that the two studies differ with respect to their patient populations and the serotonergic antidepressants used.

Calling for more research into the area, he notes: "However, the studies do have something in common: a shortage of comprehensive data regarding the activity of the so-called HPA axis."

For the current analysis, Dr McAllister-Williams and colleagues recruited 165 patients from seven National Health Service Mental Health Trusts in the United Kingdom from three areas. They were aged 18 to 65 years and had treatment-resistant depression, as defined by a score of ≥18 on the Hamilton Depression Rating Scale and a score of 2 to 10 on the Massachusetts General Hospital Treatment-Resistant Depression Staging model.

The participants, who were already taking a single agent or combination treatment that included a serotonergic drug at the time of the study, were randomly assigned to receive metyrapone 500 mg twice daily or placebo for 21 days.

The primary outcome assessment, which consisted of completing the Montgomery-Åsberg Rating Scale (MADRS) 5 weeks after randomization, was completed by 83% of metyrapone patients and 90% of those receiving placebo.

At 5 weeks, there was no significant difference in MADRS scores between patients receiving metyrapone and those receiving placebo, at 21.7 points vs 22.6 points (adjusted mean difference, -0.51 points; P = .74).

A total of 12 serious adverse events were reported in 5% of the patients receiving metyrapone and in 7% of those in the placebo group, none of which were linked to the study drug.

The team recorded 134 adverse events in 70% of patients receiving metyrapone and in 55% of those given placebo, with 8% and 4%, respectively, deemed to be probably related to the study drug.

Alternative Hypothesis

Dr McAllister-Williams said that he was surprised that metyrapone augmentation of antidepressant therapy was not effective in the current study.

"We certainly anticipated that metyrapone would help patients who had failed to respond to conventional antidepressant treatments, and there were various pieces of preclinical data, animal- based data, that supported a potential mechanism for it working," he said. "So, yes, we were surprised that it didn't have an effect.

"We know that conventional antidepressants have an effect on the HPA axis indirectly, and therefore patients who have an abnormality in their HPA axis may well respond, on the whole, not too badly to conventional antidepressants," he added.

"By selecting patients who have not responded to conventional antidepressants, we may be selecting individuals who have got less HPA-axis abnormalities, and our population would certainly be consistent with that."

Dr McAllister-Williams suggested that an alternative hypothesis is that, over time, the degree of HPA-axis abnormality decreases in patients with depression, and using treatments that target the HPA axis later on may therefore be much less effective.

"I think where it leaves things is that if these drugs have any role to play, we need to be able to identify in which patients to use them, and I would hypothesize that that's more likely to be early on in treatment, and maybe a subpopulation of patients early on in treatment," he added.

Dr McAllister-Williams believes that the next stage of research is to identify ways of stratifying patients into groups that would respond well to different types of treatments.

"I think that that is the potential place for treatments like metyrapone," he said. "The research from Dr Jahn's study suggests that at least some patients do seem to respond.

"You could argue that his study was small, and therefore it could be a false positive finding, but if not, it suggests that some patients may respond, but the sort of patients that we studied, on average, don't."

He suggested, though, that it may prove quite difficult to get independent grant bodies to fund significant studies in this area in light of these new negative findings. "I think they will use that as evidence that, well, maybe this is a complete dead end for therapy," he said. "As I say, I don't think it is, because I think there is enough evidence to demonstrate a role for HPA-axis abnormalities in at least a proportion of patients with depression, and I therefore think that research needs to be in more targeted populations.

"I think what this study has demonstrated is that if you take patients who have not responded to conventional antidepressants and you try and address...an abnormality of the stress system, it doesn't work," he concluded.

"There are potentially a number of different explanations for that. One of them is that conventional antidepressants are actually perfectly good enough to rectify those abnormalities, and therefore the patients who don't respond to conventional antidepressants are not going to respond to treatments targeting the HPA axis."

Placebo Response

Speaking to Medscape Medical News, Dr Jahn said that the differences in the trial design and patient population between his and the current study could have had a substantial impact on the findings.

Furthermore, the response rate with placebo seen in the current investigation raises questions about the patients who were included. "We have to imagine that the people were treated for 5 weeks with an antidepressant, not responding, and then they were adding some placebo," he said.

"They have some patients who are reacting on that, so they have a comparatively high placebo response in this group of very, very therapy-refractory patients...and this could point to the inclusion of patients in this trial that are actually not good patients for such a trial."

Dr Jahn believes that this could be because the researchers did not perform tests such as the dexamethasone suppression test so that they could recruit only those patients with a disturbed stress axis.

Dr McAllister-Williams disagreed with this assessment of the placebo response seen in the study, saying: "I don't think that the placebo response level is particularly high or particularly surprising. It is not that dissimilar to the placebo response seen in many other studies in similar sorts of populations."

Noting that the placebo response rate in first-line studies can be as high as 40%, he said, "We had a response rate that was down nearer 20%, and what is driving that?

"All of the things that drive placebo responses ordinarily: expectation that something may improve, the nonspecific effects of speaking to the researchers during the course of a study, the regression to the mean.... There are a number of different factors that can be associated."

Dr Jahn and Dr McAllister-Williams agreed about the need for better ways of stratifying patients with depression. Dr Jahn described patients with depression as currently "really badly characterized," adding: "The categorization systems like DSM-5 and DSM-IV are very unspecific over who to label with the diagnosis of depression."

Dr Jahn pointed out that it is known that some people have a high familial risk for depression, and that they tend to be more responsive to medication. Furthermore, there are some common genetic mutations that cause selective serotonin reuptake inhibitors (SSRIs) to be less efficacious. However, typing is currently performed for neither.

"We already know that there is definitely much more genetic difference in the population that would make it possible to say that this patient is reacting better on SSRIs, this patient is probably better reacting on a monoamine oxidase inhibitor, or something like that," Dr Jahn said.

"I am quite sure that in the next years, we will try to understand much more why some medications are acting in some forms of depression and others do not.

"But the current diagnostic procedure is just collecting symptoms, and if you have enough, you are depressed, although it's probably a bunch of different diseases below the syndrome level."

The research was supported by the Efficacy and Mechanism Evaluation Programme and the Medical Research Council (MRC) and was managed by the National Institute for Health Research (NIHR) on behalf of the MRC-NIHR partnership. Further support was obtained from Northumberland, Tyne and Wear National Health Service Foundation Trust. Several of the authors have or have had financial relationships with pharmaceutical companies within the past 3 years, which are listed in the article. Dr Jahn has disclosed no relevant financial relationships.

Lancet Psychiatry. Published online December 22, 2015. Abstract, Comment

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