Antidepressant News: Just the Right Amount of Opiate?

In the early 1950s, opium was considered an effective treatment for depression, but gradually it fell out of favor as its addiction risk became clear. Nonetheless, there's no denying that opioids rapidly elevate the mood of just about anybody, even the very depressed. So that's a pretty tantalizing challenge: Is it possible to harness the elating effects of opiates while avoiding the addictive "side effects," as it were.

source: amrismartsourcing.com

A recent contender is a drug made by Alkermes code named ALKS 5461. This drug is a combination of buprenorphine and samidorphan. Buprenorphine is an opioid which is often combined with naltrexone to produce drugs for opioid use disorder, such as Suboxone. Samidorphan is a derivative of naltrexone, and it doesn't antagonize opioid receptors quite as avidly as its cousin. So combining these two might just allow enough opioid receptor stimulation to squeeze through to treat depression, without it being too appealing to potential addicts.

Early phase I and phase II clinical trials with small numbers of subjects were promising. Based on these results, the company conducted larger phase III trials, called the FORWARD (Focused On Results With A Rethinking of Depression) trials. Unfortunately, the first two of the larger trials failed, showing no improvement over placebo. The third trial (FORWARD-5) was more successful. In that trial, 407 patients with depression unresponsive to a trial of standard antidepressants were randomized to receive ALKS 5461 as an adjunct, or placebo as an adjunct. The company reports that patients receiving the higher dose of 2mg of ALKS 5461 did significantly better than placebo, as measured by the MADRS rating scale. Side effects were nausea, dizziness, and fatigue.

Will this drug see the light of day? It’s unclear, but according to pharmaceutical industry news sources, Alkermes has been talking up its latest results with the FDA and hopes to get approval at some point within a year or two. It sure would be nice to have another antidepressant at our disposal.

Antidepressants Ineffective? Don't Believe It! (Part 2)

Last week, I posted part 1 of my reaction to the JAMA study showing that antidepressants don't beat placebo for mild to moderate depression. The many comments I received were intelligent and informed--reading them will give anybody an instant education in the limitations of antidepressant research.

It has been clear for years that antidepressants barely outperform sugar pills, at least in the artificial environment of the double blind, placebo controlled study. It is also clear that most psychiatrists in the trenches are perplexed by these results, because in our practices we appear to see people responding very robustly to antidepressants--including those with only mild to moderate symptoms. So what gives?

I presented a hypothetical patient who became depressed because of financial woes, who saw a psychiatrist, received a prescription for Zoloft and Klonopin, and got better. Some commenters wondered why the patient was given medication rather than therapy. My answer is simply that in modern psychiatry, such a patient is more likely to be given meds, even though therapy may be just as effective. The reasons for this are complex, but have to do with how psychiatrists are trained (primarily, they are taught how to prescribe medications), how insurance companies reimburse (they pay twice as much for an hour's worth of medication visits than for an hour of therapy), and what patients want (many prefer the quick fix of medications over multiple therapy visits). I personally believe that psychiatrists should incorporate more therapy into their practices, but the current state of the field is as outlined above.

Anyway, I then considered what would happen if the same patient got enrolled in a randomized, placebo-controlled trial of an antidepressant. Once accepted, he is told that he will be randomly assigned to either active medication or placebo.

Let's assume that our patient lucks out and gets assigned to the latest SSRI, "Newexa," and let's further assume that Newexa works as well as all other SSRIs (like Zoloft or Lexapro). One would assume that since our patient is assigned to a drug that works as well as Zoloft, he stands the same chance of improvement. But not so.

When patients are enrolled in preliminary "open label" studies, in which everybody is given the active drug, and there is no blinding, the response rates are in the 70-80% range. But when patients are given the same drug in the context of a placebo-controlled trial, the response rates plummet to the 40-50% range. The reason for this is that if you strongly believe that you are taking an effective treatment, this confidence in itself boosts the effects of the drug. On the other hand, if you know that there is a 50% chance that you are taking a sugar pill, you have less confidence in the chances of a recovery. Essentially, by not telling patients what they are taking, researchers are turning down the volume of the placebo effect. But when I see a patient in my office, I do just the opposite. I try to maximize the placebo effect. I say things like, "I've had great success with Zoloft in patients like you....I would say you have an 80-90% chance of feeling much better within the next 2 weeks....These drugs are remarkably effective...."

So this is the crux of the issue. Response rates are always lower in randomized controlled trials than they are in the real world of the office, where our patients know exactly what they are taking. Thus, when I read about the measly outcome results of antidepressants in these trials, I take it with a big grain of salt. I interpret it in light of many other studies that have indeed shown antidepressants to be more effective than placebo in conditions as diverse as severe depression, anxiety disorders, and eating disorders. Rather than concluding that these meds don't work, I conclude that they do work, but that there is a large placebo component.

In the best of all worlds, we would be allowed to prescribe sugar pills to patients, and we would presumably get a robust response without many side effects. This is considered unethical by the AMA. Nonetheless, according to this recent survey of 679 U.S. physicians, about half reported prescribing a placebo on a regular basis, most of which were "active" placebos--things like vitamins and over the counter pain relievers such as Tylenol.

The bottom line is that while medicine could not survive without placebo-controlled trials, they are rarely generalizable to the real world. I view their results more as signals of efficacy rather than as definitive answers.

Antidepressants Ineffective? Don't Believe It! (Part 1)

A recent study in JAMA (the Journal of the American Medical Association) appeared to show that antidepressants do not work well in patients whose depression is mild to moderate, which is the majority of patients. The authors combined the results of six studies (three evaluated Paxil and three evaluated the old tricyclic imipramine) and found that there was little difference between active drug and placebo in patients with less severe depression. However, there was a large benefit of the active drug in patients with very severe depression.

The study made news--see, for example, this piece in the New York Times. But do the results really mean that antidepressants are ineffective? I don't think so. In order to understand the implications of the study, you have to understand how clinical trials are conducted, and how radically they differ from usual care.

First, let's look at what happens if you were to seek care through the usual treatment system. You have become increasingly morose after your 401K tanked in the current recession. For weeks, you have been unable to sleep well, you are wracked with anxiety and panic, you have no energy, nothing is enjoyable, and you have been questioning whether life is worth living. You go to a psychiatrist, who diagnoses you with major depression and anxiety and prescribes you a combination of Zoloft (an antidepressant) and Klonopin (an antianxiety medication.) She tells you that your symptoms are an understandable response to a difficult situation, and that in her experience the Zoloft/Klonopin combo is almost certain to help over the next few weeks. And indeed, you get better.

Suppose, instead, that you sought treatment through a research study that was advertised on the radio. Your ears perked up when you heard that treatment was free, and that you would be paid a small stipend to attend sessions. You go to your first appointment and you are surprised to find that this is not a university, but a private clinical research company. The majority of clinical trials now occur in such for-profit enterprises, because drug companies have found that they can exert more control over the research conducted at such companies than they can at universities.

You meet first with a research assistant, who asks you a few screening questions, then you meet with a psychiatrist. Unbeknownst to you, the psychiatrist will get paid several thousand dollars for each patient he enrolls in the study. The drug company, which designed the study, has given the psychiatrist a long list of inclusion and exclusion criteria. For example, you are ineligible if you have bipolar disorder, suicidal ideation, panic disorder, obsessive compulsive disorder, substance abuse within the last 6 months, or an unstable medical condition. There are so many exclusion criteria that only about 10% of depressed patients in a typical clinic would be eligible for such studies (see here for more background).

The screening psychiatrist will interview you with a goal of getting you into the study, and will typically try to "undiagnose" you of any conditions that might otherwise exclude you. For example, the anxieties that you have had are very similar to panic attacks, but this is a matter of clinical judgment. After asking several questions, your psychiatrist convinces himself that you do not have panic disorder, but rather, you have anxiety that often accompanies depression. You admit to drinking a little more than normal as a way of coping, but after careful questioning, your psychiatrist opines that your drinking pattern is not quite severe enough to be labeled "alcohol abuse."

And so on. After an hour or so, your psychiatrist tells you that you are eligible to enter the study....

(To be continued. Tune in next week to follow the adventures of our patient who learns about the peculiar world of the placebo-controlled clinical trial).