Clinical Trials News

Who Benefits From Antidepressants? US Health Inequities

2008-02-26T11:43:00.000-08:00

A new study published today in PLoS Medicine suggests that antidepressants only benefit some, very severely depressed patients.

"New generation" antidepressants, such as fluoxetine (Prozac) are widely prescribed for the treatment of clinical depression. However some studies have suggested that these drugs do not help the majority of depressed people get better by very much. Irving Kirsch, from the University of Hull, and his colleagues, studied this question in closer detail, looking at whether a patient's response to antidepressant therapy depends on how badly depressed they are to start out with.

Kirsch and colleagues used a technique called "meta-analysis", where they put together data on clinical benefit from all the trials submitted to the US Food and Drug Administration for four drugs: fluoxetine (Prozac), venlafaxine (Effexor), nefazodone (Serzone), and paroxetine (Seroxat / Paxil). (The researchers also wanted to include sertraline and citalopram, but couldn't find all the relevant data for those two drugs). By including data from unpublished as well as published trials, the researchers set out to avoid bias that might come from non-publication of disappointing findings.

When the data from all of these trials had been put together, the improvement in depression amongst patients receiving the trial drug, as compared to those receiving placebo (dummy tablets), was not clinically significant in mildly depressed patients or even in most patients who suffer from very severe depression. The benefit only seemed to be clinically meaningful for a small group of patients who were the most extremely depressed to start out with. This improvement seemed to come about because these patients did not respond as well as less depressed patients to placebo, rather than responding better to the drug.

Irving Kirsch, summarising the paper, says: "Although patients get better when they take antidepressants, they also get better when they take a placebo, and the difference in improvement is not very great. This means that depressed people can improve without chemical treatments."

Given these results, the researchers conclude that there is little reason to prescribe new-generation antidepressant medications to any but the most severely depressed patients unless alternative treatments have been ineffective

Antidepressants Only Benefit The Severely Depressed

2008-02-26T11:20:00.000-08:00

A new study by researchers in the UK suggests that antidepressants only benefit the very severely depressed and are no more effective than a placebo for everyone else.

The meta-analytical study (ie one that systematically pools the results of other studies) is the work of Dr Irving Kirsch, from the University of Hull, and his colleagues, and is published today, 26th February, in the open access journal PLoS Medicine.

Antidepressants are prescribed for the treatment of clinical depression, and the most widely used are the "new generation" drugs, the SSRIs such as fluoxetine (Prozac) and venlafaxine (Effexor).

Previous meta-analytical studies of antidepressants have already suggested they have only modest benefits over placebos, and the authors pointed out that when data from unpublished trials are included, the benefits are so small they fall below the criteria for clinical significance. What has not been clear in the past however, is whether within this overall result, the effectiveness of antidepressants depends on how severely depressed patients are when they start treatment.

Kirsch and colleagues pooled all the available full data sets from all clinical trials submitted to the US Food and Drug Administration (FDA) for licensing four of the new generation of antidepressants, the SSRIs fluoxetine (Prozac), venlafaxine (Effexor), nefazodone (Serzone), and paroxetine (Seroxat, Paxil). The data came from both published and unpublished trials.

The point of including data from unpublished as well as published trials, is to avoid potential bias arising from the omission of "disappointing" unpublished findings.

SSRI stands for "selective serotonin reuptake inhibitors". This new type of antidepressant, like the older ones, works by attempting to stabilize chemicals in the brain that influence mood, except that SSRIs specifically target and increase the circulating levels of a brain chemical called serotonin, a neurotransmitter that regulates mood. They do this by inhibiting the reuptake of serotonin so that more of it is available for binding to cell receptors.

Using meta-analytical techniques (a way of pooling data from a range of studies as if they were one big study with broadly the same objectives) the authors assessed the relation between the initial severity of depression and the improvements shown by drug and placebo groups, as well as the relation between initial severity and differences in drug-placebo improvement scores.

The results showed that:

* Drug-placebo differences got bigger as initial severity went up.

* This difference was hardly noticeable at moderate levels of initial depression, went up to a relatively small difference for patients with severe depression, and reached a level that would be classed as clinically significant only in those patients at the extreme end of the very depressed scale.

* The improvement seemed to result from the most severely depressed patients not responding as well to placebo compared to their less depressed counterparts, than because they responded better to the active drug.

Kirsch and colleagues concluded that:

"Drug-placebo differences in antidepressant efficacy increase as a function of baseline severity, but are relatively small even for severely depressed patients."

"The relationship between initial severity and antidepressant efficacy is attributable to decreased responsiveness to placebo among very severely depressed patients, rather than to increased responsiveness to medication," they added.

In other words, the difference in effect between drug and placebo was only clinically significant in those patients who were very severely depressed at the start of their treatment and this effect was more likely due to a weaker response to the placebo than a stronger response to the drug itself in that group.

This study is important because although licensing authorities like the FDA in the US and NICE (National Institute for Health and Clinical Excellence) in the UK have approved SSRIs for treating depression, there are nagging doubts about how effective they are.

Depression, which affects about 1 in 6 people at some point in their life, is a serious medical condition characterized by imbalances in brain chemicals that regulate mood. The illness, which can last for months and sometimes years, makes a person feel unmotivated, worthless, hopeless, and sometimes even that life is so futile it would be better to be dead. Depression is often a cause of suicide.

Severity of depression is measured using a questionnaire called the Hamilton Rating Scale of Depression (HRSD) which comprises up to 21 items. If the total score comes to 18 or more, the person is classed as severely depressed.

For an antidepressant to receive a license, clinical trials have to show that it can significantly improve the HRSD score compared to a placebo.

Different countries have slightly different clinical criteria for how much the HRSD score has to improve by before the drug can be licensed to treat depression. In the UK, NICE require that the drug show an improvement in the HRSD score of 3.

A previous meta-analysis of published and unpublished trials sent to the FDA for licensing these drugs showed they only have an average benefit of 1.8 HRSD points.

The reason this study was done was to find out if underneath this 1.8 average there might be subgroups of patients for whom the improvement score was significantly higher, perhaps within the range required by NICE.

And indeed, this is what Kirsch and colleagues found: the clinical criteria were only met when the drugs were used to treat the most severely depressed patients, that is ones with an initial HRSD score of 28 or more, at the extreme end of the scale. And perhaps just as important, is the finding that this effect did not arise as a result of responding to the drug, but because of decreased responsiveness to the placebo.

This last, rather surprising finding, provides a new direction for future research.

"Initial Severity and Antidepressant Benefits: A Meta-Analysis of Data Submitted to the Food and Drug Administration."
Kirsch I, Deacon BJ, Huedo-Medina TB, Scoboria A, Moore TJ, et al.
PLoS Medicine Vol. 5, No. 2, e45
Published online: February 26, 2008.
doi:10.1371/journal.pmed.0050045

Scheduling Of Zolpidem (Stilnox), Australia

2008-02-24T13:54:00.000-08:00

The National Drugs and Poisons Schedule Committee (NDPSC) considered the scheduling of zolpidem (contained in the medicine Stilnox) at its February 2008 meeting, held this week, because of concerns relating to reports of potential abuse of this substance.

The NDPSC also considered a number of submissions describing personal accounts of adverse events, including bizarre sleep behaviours and their consequences.

While the NDPSC acknowledges the concerns that members of the public have raised regarding these adverse events, members of Committee concluded that the current Schedule 4 (Prescription Only) status of zolpidem remains appropriate.

In reaching this conclusion, the NDPSC agreed that zolpidem does not meet the criteria for a Schedule 8 (Controlled Drug) medicine. Schedule 8 medicines must demonstrate a substantial risk of abuse, dependence or misuse for illegal purposes. There was no compelling evidence presented to the NDPSC that the abuse potential of zolpidem requires it to be rescheduled.

The NDPSC noted that zolpidem is only available by prescription under the supervision of a medical practitioner and its use should be carefully monitored by the prescribing doctor. It is only indicated for short-term use and should not be used with alcohol. Zolpidem should be used with caution if taking other central nervous system medications, such as antidepressants, under close medical supervision.

The NDSPSC also noted that the TGA has taken several appropriate regulatory actions and is currently continuing its evaluation of Australian and international data on the safety of zolpidem. The NDPSC will be keeping a watching brief on this matter over the coming months.

In accordance with the NDPSC's practice and statutory requirements, a record of reasons for this and other scheduling decisions made at the February 2008 meeting will be publicly available on the NDPSC website on 4 April 2008.

The National Drugs and Poisons Schedule Committee

The NDPSC is a statutory committee established under the Therapeutic Goods Act 1989. It is responsible for determining the classification and scheduling of substances for inclusion in the Standard for the Uniform Scheduling of Drugs and Poisons (SUSDP), together with other related functions. The NDPSC has a wide range of expert and professional members, with jurisdictional memberships from the Commonwealth, States and Territories and New Zealand.

The NDPSC is required to publish a notice in the Gazette before and after each meeting, which includes an invitation to the public to make submissions.

Scheduling and voting procedures, and the issues the NDPSC must take into account in reaching a decision, are set out in the Act and its associated regulations.

Decisions of the NDPSC are made by a majority of the members present and voting at a NDPSC meeting and must include a majority of the jurisdictional members present and voting. There are eleven jurisdictional members comprising of the Commonwealth (1), states and territories (8) and New Zealand (2). However, only one New Zealand representative is counted as a jurisdictional member for the purposes of voting.

As part of its statutory obligations, the NDPSC publishes records of reasons for its scheduling decisions. This record is published on the NDPSC website approximately six weeks after each meeting. The record of reasons for the February 2008 NDPSC Meeting will be released around 4 April 2008 and can be found here.

http://www.tga.gov.au

Antidepressants Can Help With Obsessive Compulsive Disorder

2008-02-20T17:30:00.000-08:00

Common antidepressant drugs such as Prozac and Zoloft can be effective treatment options for obsessive compulsive disorder (OCD), according to a new review of studies.

Patients who take selective serotonin reuptake inhibitors, or SSRIs, are twice as likely to get some relief from their OCD symptoms as those who take placebo pills are.

However, the drugs have a "modest" effect at best, said Dr. Ghulam Mustafa Soomro, lead review author and honorary research fellow at St. George's Hospital Medical School in London.

"Although SSRIs should be considered potentially effective treatments for OCD patients, treatment decisions need to take account of the potential adverse effects of these drugs," including nausea, insomnia and sexual dysfunction, he warned.

The review of studies appears in the latest issue of The Cochrane Library, a publication of The Cochrane Collaboration, an international organization that evaluates medical research. Systematic reviews like this one draw evidence-based conclusions about medical practice after considering both the content and quality of existing medical trials on a topic.

Many people with OCD seek out therapy that teaches them to confront, tolerate and gradually wean themselves from obsessive and compulsive behaviors.

"This is the primary kind of therapy used for OCD. It teaches patients to pay attention to their internal experiences and tolerate scary thoughts without having to act on them," said Sanjaya Saxena, M.D., director of the Obsessive-Compulsive Disorders Program at the University of California, San Diego School of Medicine. "They learn that nothing terrible happens if they refrain from their usual compulsive behaviors."

Nevertheless the success rates for this type of therapy vary, and "unfortunately, about 25 percent of patients offered this form of treatment refuse it," Soomro said, adding that SSRIs "may offer help to some of these patients."

After reviewing 17 studies that included 3,097 patients, the reviewers concluded that SSRIs were more effective than a placebo in reducing OCD symptoms six to 13 weeks after starting treatment.

None of the drugs stood out above the rest; they all appeared equally effective. However, in most cases, side effects such as nausea and headache were noticeably worse with the SSRIs than with the placebo pills.

The Cochrane Collaboration is an international nonprofit, independent organization that produces and disseminates systematic reviews of health care interventions and promotes the search for evidence in the form of clinical trials and other studies of interventions. Visit http://www.cochrane.org for more information.

Soomro GM, et al. Selective serotonin re-uptake inhibitors (SSRIs) versus placebo for obsessive compulsive disorder (OCD) (Review). The Cochrane Database of Systematic Reviews 2008, Issue 1.

Health Behavior News Service
Center for the Advancement of Health 2000 Florida Ave. NW, Ste 210
Washington, DC 20009
United States
http://www.hbns.org