Nearsighted Drug Development

© Antonio Gravante | Dreamstime.com

© Antonio Gravante | Dreamstime.com

I was encouraged to hear that ALKS 5461 failed in two late-stage clinical trial studies. This isn’t because I have something against Alkermes, the pharmaceutical company developing the drug. I don’t own stock in a competing company trying to bring their new fast-acting antidepressant drug to market ahead of Alkermes. I do think antidepressants are overprescribed and have potentially harmful side effects for some people, but that’s not why I was happy to hear that ALKS 5461 is in trouble. I just don’t think that putting an antidepressant drug on the market that uses a potentially addictive opioid as its active ingredient is a good idea.

Reporting for Reuters, Amrutha Penumudi said that when news of the failed clinical trails for ALKS 5461 were made public by Alkermes, the company saw its shares fall in value by 42.8%, a $3.88 billion loss for the company. ALKS 5461 is the company’s main product, so the bad news about the clinical trials was a major financial blow. William Tanner, an analyst for Guggenheim Partners was widely quoted by Reuters and others as saying that “We believe trial failures present a major setback in the evolution of the company.” Even if ALKS 5461 succeeds in a third as-yet not completed clinical trial, more studies may be required, according to Ken Cacciatore.

ALKS 5461 is a new molecular entity (NME) that has been fast tracked by the FDA for approval as a treatment of Major Depressive Disorder (MDD) with patients who didn’t respond to standard antidepressant therapies. It is a combination of buprenorphine, a Schedule IV Controlled Substance and samidorphan, a naloxone-like substance. Suboxone, which is a combination of buprenorphine and naloxone, is commonly used as an opioid substitution medication for heroin and prescription opioid addicts. The major difference between ALKS 5461 and Suboxone as far as buprenorphine is concerned is that ALKS 5461 is currently being tested in 2 mg and .5 mg doses, where standard protocols for Suboxone as an opioid substitution drug could reach 16 mg or higher. You will find more information on ALKS 5461 and my concerns about its use to treat depression in: “The Coming Depression Apocalypse,” an article I published here a few months ago.

But it doesn’t seem Alkermes is going to give up the fight. In their press release, Richard Pops, the CEO of Alkermes said:

We are steadfast in our commitment to developing new medicines for serious CNS conditions where there is a clear and compelling need for new treatment options for patients and their families. . . . Major depressive disorder is one of these conditions. We are building a large body of evidence supporting our belief in the clinical utility and the novel mechanism of action of ALKS 5461. We await the results of FORWARD-5 and will determine our next steps along the regulatory path with those results in hand.

In one of the failed trials, Alkermes did post-hoc analyses (reanalysis of the data after the fact) that indicated the 2 mg dose was more effective than a placebo. Given the results of the two failed studies, Alkermes said they plan to increase the number of patients in the ongoing trial and “update” the planned statistical analysis for FORWARD-5, the third efficacy study in the FORWARD program. The updated analysis sounds like it means they plan to use the same analysis process applied to the 2mg dose group for FORWARD-4 after the fact. This is bit like cheating if the researchers went p-hacking or data-dredging in their post-hoc analysis. See “How to Lie About Research” for more information on p-hacking.

Another factor regarding Alkermes and ALKS 5461 that concerns me is how the company describes the drug. In their above-linked press release, Alkermes said that ALKS 5461 acted “as a balanced neuromodulator in the brain;” and was “designed to rebalance brain function that is dysregulated in the state of depression.” This sounds eerily similar to the chemical imbalance theory of depression that even psychiatrists such as Ronald Pies have said was always a kind of urban legend. In an article in Psychiatric Times, he said: “To my knowledge, no professional psychiatric organization has ever publicly promoted a ‘chemical imbalance theory’ of mental illness in general.” Look at Robert Whitaker’s response to that article by Pies and the reams of additional evidence to show how Pies’ claim was clearly wrong.

But there is now another concern with the use of opioids to treat depression. A study by Scherrer et al., published in the Annals of Family Medicine, found that people who used prescription opioids for longer than a month may have an increased risk of developing depression. Scherrer was quoted by Agata Blaszczak-Boxe for Live Science as saying the researchers rigorously controlled for pain, “and we feel strongly that these results are independent of the known contribution of pain to depression.” The longer individuals were taking opioids, the greater was their risk of depression.

Citing a 2014 study by Howe and Sullivan in General Hospital Psychiatry, Scherrer et al. said that research on the efficacy of opioids in treating depression was limited by small sample sizes, short follow-up time and lack of control groups. So they do not support opioids as effective long-term treatments for depression. “This evidence, combined with the finding from the present study, supports the conclusion that opioids may cause short-term improvement in mood, but long-term use is associated with risk of new-onset depression.”

Buprenorphine was not one of the opioids studied, but the findings of the Scherrer et al. study does give me increased concern with the fast-track status the FDA has given ALKS 5461. Recent findings do suggest the risk of new onset of depression increases with a longer duration of opioid use. A replication attempt of Scherrer’s study with buprenorphine seems needed before approving ALKS 5461. The short-term projected improvements could lead to long-term problems with depression.  “Patients and practitioners should be aware that opioid analgesic use of longer than 30 days imposes risk of new-onset depression.”

Hopefully the FDA will have the foresight to weigh all the potential adverse effects with ALKS 5461 before approving it. There is a very real potential for physical dependency to develop with ALKS 5461 given that its active ingredient is a Schedule IV controlled substance. Heroin addicts have told me buprenorphine was more difficult for them to come off of than heroin or methadone. And to top it all off, there seems to be evidence that using opioids longer than 30 days carries a risk of new-onset depression. This is not a very promising profile for a future treatment for depression.

Additionally, the initial statistical analysis done on the first two clinical trials failed to demonstrate that it was more effective than a placebo. Only after a post hoc analysis was there evidence of any statistically significant results. And then it was only with the higher, 2mg, dose. Will that lead to even higher doses of buprenorphine to increase its effectiveness? Read more on the concerns with outcome switching in clinical trials here.

Revising the statistical analysis (outcome switching) of the remaining clinical trial may produce statistically significant results, and if it does, it seems Alkermes intends to argue with the FDA to approve ALKS 5461. On the one hand, I can see where Alkermes would attempt to salvage their “lead product.” But I’m hoping their nearsighted focus on profits and the company’s market value will not blind the FDA to the long-term consequences of using opioids like buprenorphine to treat depression.


The Coming Depression Apocalypse

© 3quarks | 123RF.com

© 3quarks | 123RF.com

According to the Motley Fool, the pharmaceutical company Alkermes has a potential blockbuster drug for treating major depression in its pipeline. Currently in Phase 3 clinical trials, ALKS-5461 is one step away from Alkermes filing for approval by the FDA. Mental Health Daily reported that ALKS-5461 was given fast track approval by the FDA and is expected to be available in 2016. Its projected use is as a supplementary treatment to current antidepressant drugs. But once approved, the “supplementary” element will likely stop because it’s new and fast acting. The problem is, the drug in ALKS-5461 that is supposed to treat depression is an opioid with addictive potential.

Before going further on this issue, we need to take a short trip into pharmacology and neurotransmitter function in order to understand what’s going on. There are proteins embedded within the membrane of a cell called receptors. These receptors receive chemical signals from outside the cell, and in turn produce a biochemical reaction inside the cell. The chemicals that bind and activate a specific receptor are called agonists. While an agonist causes a reaction, an antagonist blocks that reaction from occurring within the cell. It turns the cell off from the influence of the agonist.

Receptors are activated by either endogenous agonists (hormones or neurotransmitters), or exogenous agonists (drugs). Endogenous agonists are produced by the body. The endogenous opioid agonists include dynorphins, and the more widely known endorphins. If you want more information on biochemistry and neurotransmitter activity, try these Wikipedia pages for starters: opioid receptor, mu-opioid receptor, and agonist.

Opioids are known to have energizing and mood enhancing effects with some users. This effect seems to be associated with dynorphin, which is elevated in depression. Dynorphin is a full agonist for the kappa opioid receptor (KOR). Studies like that done by Knoll and Carlezon, “Dynorphin, Stress and Depression,” suggest that KOR antagonists may have a potential therapeutic potential in treating anxiety and depression. While this biochemical hypothesis makes sense to psychiatrist Daniel Carlat, in The Carlat Psychiatry Report, he was more reserved on the treatment potential of ALKS-5461 than Mental Health Daily and the Motley Fool.

The efficacy of ALKS-5461 for depression remains to be seen. Some trials of ALKS-33 alone have already been performed, particularly in the areas of alcohol dependence and binge-eating disorder. These have been negative.

Now let’s look at my concern with ALKS-5461. First, it is a combination of buprenorphine, and samidorphan, or ALKS-33. Buprenorphine is used in addiction treatment as a detoxification drug and in opioid maintenance therapy, where its brand names are Suboxone (buprenorphine with naloxone) and Subutex (buprenorphine without naloxone). Suboxone and Subutex are classified as Schedule III controlled substances, meaning they have a moderate to low potential for physical and psychological withdrawal. Other Schedule III drugs include ketamine and anabolic steroids.

Buprenorphine is a partial mu opioid agonist, meaning it displaces morphine, methadone, and other full opioid agonists from activating the mu opioid receptor (MOR). But it does not provide the same degree of receptor activation as the full agonists (It doesn’t get you as high), resulting in a net decrease of agonist effect and the onset of withdrawal if it used soon after a full agonist like heroin. Patients planning to begin Suboxone maintenance therapy are told to abstain from opioids for twenty-four hours before their first dose of Suboxone.

At lower doses and with individuals who are not dependent on opioids, both full agonists like heroin and partial agonists like buprenorphine will produce identical euphoric effects. Partial agonists like buprenorphine also have a ceiling effect, meaning that past a certain point, typically 12 to 16 mg, no difference in analgesia, euphoria and respiratory depression will be felt.

Buprenorphine does produce physical dependence. Reportedly, this is to a lesser degree than full opioid agonists; and it is supposed to be easier to discontinue at the end of medication treatment. While this is the received wisdom on websites like NAABT, The National Alliance of Advocates for Buprenorphine Treatment, that has not been the case for what I’ve observed clinically with individuals who have tried buprenorphine. Generally I’ve heard that buprenorphine is harder to kick than heroin. So ALKS-5461 will be treating depression with a drug that may be harder to kick than heroin.

Buprenorphine is also a full antagonist of the kappa opioid receptor (KOR), which underlies its use in ALKS-5461 as an antidepressant. If the production of dynorphine by KOR receptors increases with depression, theoretically then buprenorphine would block these receptors and limit the release of dynorphine—elevating the individual’s mood. Peter Tenore, in “Psychotherapeutic Benefits of Opioid Agonist Therapy,” said that opioids like buprenorphine could be “effective, durable and rapid therapeutic agents for anxiety and depression.”  The problem is with the partial agonist effect that buprenorphine has on mu opioid receptors (MOR) you can still use buprenorphine to get high.

That was the rationale for combining naloxone with buprenorphine in Suboxone. Naloxone is an opioid antagonist that counters the effects of opioids at the mu receptor, but doesn’t trigger a euphoric effect. Marketed under the brand name of Narcan, naloxone is used to counter the effects of opioids in overdose situations. The death of Phillip Seymour Hoffman led to calls for greater availability of naloxone (see “The Opioid-Heroin Cycle”) for individuals to use in overdose situations.

While naloxone is still the standard medication for emergency reversal of opioid overdose, its clinical use in long-term opioid addiction treatment is being superseded by naltrexone. Naltrexone (C20H23NO4) is structurally similar to naloxone (C19H21NO4), and samidorphan (C21H26N2O4). But it has a slightly increased affinity for κ-opioid receptors (KOR) and has a longer duration of action than naloxone. Naltrexone is used as a preventative medication for opioid use disorder in Vivitrol, whose marketing rights are owned by Askemet.

Samidorphan (ALKS-33) is also a full opioid antagonist, acting on the MOR receptor with mixed agonist-antagonist activity at the KOR receptor. Combining samidorphan with buprenorphine is supposed to block the agonist effect of buprenorphine on the MOR receptor, while not inhibiting the buprenorphine antagonist effect on the KOR receptor.  A study by Shram et al. comparing samidorphan to naltrexone was published online ahead of the June 2015 issue of the Journal of Clinical Psychopharmacology. Samidorphin was found to have greater binding affinity than naltrexone to mu receptors and a longer half-life. This was suggestive of prolonged opioid receptor antagonism at lower doses of samidorphin. The study, though, was funded by Askemet.

Suboxone (buprenorphine and naloxone) and ALKS-5461 (buprenorphine and samidorphin) appear to be biochemical twins. And it does not seem to me that the addictive potential of buprenorphine has been entirely neutralized by its combination with samidorphin as claimed. The history of abuse and diversion with Suboxone supports this concern. If my fear is true, then in the name of treating depression, ALKS-5461 will create a huge population of individuals who become dependent upon buprenorphine.

Coming off of buprenorphine is not fun. Here is a personal testimony of someone tapering off of buprenorphine. Oh, and mood swings with bouts of anxiety or depression are common side effects with buprenorphine withdrawal.

Buprenorphine withdrawal symptoms last longer for those who use buprenorphine for longer periods of time or at higher doses. Additionally, those who use buprenorphine other than prescribed (snort, inject, chew) may experience more severe symptoms than someone taking buprenorphine as prescribed. In these cases, physical buprenorphine withdrawal symptoms can last weeks after stopping.However, psychological withdrawal symptoms can last for many months after cessation. It is recommended that you join a support group or see a psychologist who can help see you through the protracted or post acute withdrawal symptoms (PAWS). Many heavy buprenorphine users experience PAWS. With continued use of buprenorphine, there comes a point where the brain produces in an inadequate amount of neurotransmitters in the body. People going through buprenorphine PAWS manifest long lasting changes in the brain as a result of long term use.

The Substance Abuse and Mental Health Services Administration (SAMHSA) estimated that in 2013, 1.8 million people had an opioid use disorder; 517,000 of which had one related to heroin use. SAMHSA also estimated that each year, 9.1% of the adult population experience symptoms consistent with major depression. One 2012 study suggested that 10% to 30% of individuals with major depression suffer from treatment resistant depression. Using a U.S. population estimate of 320.94 million, with a median 20% for individuals with treatment resistant depression, that leaves a target population of over 5.84 million Americans with treatment resistant depression. God help us.

I don’t think it is too strong rhetorically to speak of a pending depression apocalypse. I hope I’m wrong. But widespread use of ALKS-5461 could instigate a huge population of individuals dependent upon buprenorphine. And the problems coming off of ALKS-5461 would eclipse what we now know happens with SSRI withdrawal. Within the biochemical worldview, these symptoms will be reinterpreted as evidence of the underlying depression and proof the individual needs to remain on ALKS-5461. Sound familiar?


Thor’s Psychiatric Hammer: Antidepressants

60 Minutes broadcast a segment on treating depression in February of 2012 that is still causing ripples of controversy. Two of the individuals interviewed, Irving Kirsch, a Harvard psychologist and Walter Brown, a psychiatrist with Brown University, challenged the two accepted pillars of current depression treatment. Kirsch said: “The difference between the effect of a placebo and the effect of an antidepressant is minimal for most people.” According to Brown, “The causes of depression remain a mystery.”

The chemical imbalance theory, which has guided the pharmaceutical industry in developing new drugs since the 1960s, is “probably incorrect.” Brown added that the experts in the field, the academic people who do research on drugs, now believe that the chemical imbalance theory is “a gross oversimplification.” If the neurotransmitters serotonin, norepinephrine, dopamine have anything to do with depression, “it’s of a minor role and probably sets the stage for depression. But they’re not the cause of depression. I think we know that now.”

Yet the chemical imbalance theory is still widely taught in medical schools. Many psychiatrists and mental health professionals still believe it. “The problem in psychiatry is that we don’t have a lot of tools. And if the only tool you have is a hammer, you treat everything as if it is a nail.”

Irving Kirsh has been doing research into the placebo effect for over 35 years. His original research intent with antidepressants was to evaluate the size of the placebo effect with antidepressants. He was a believer in the efficacy of antidepressants and he used to refer people to get antidepressant prescriptions. “I didn’t change the focus of my work onto looking at the drug effect until I saw the data from our first analysis.”

In a 1998 study, Kirsch found that 75% of the response to antidepressants was duplicated by placebo. He did a follow up study in 2002, where he analyzed the data submitted to the FDA for the six most widely prescribed antidepressants approved between 1989 and 1999: Prozac (fluoxetine), Paxil (paroxetine), Zoloft (sertraline), Effexor (venlafaxine), Serzone (nefazodone), and Celexa (citalopram).  He found a small but significant difference between the antidepressant drugs and inert placebo. “If the drug effect is as small as it appears … then there may be little justification for the clinical use of these medications.”

Leslie Stahl challenged Kirsch, saying that people are getting better by taking antidepressants. He agreed. “People get better when they take the drug. But it’s not the chemical ingredients of the drug that are making them better. It’s largely the placebo effect. . . . The only place where you get a clinically meaningful difference [with an antidepressant] is at these very extreme levels of depression.” The placebo effect is stronger with mild depression.

Both Kirsch and Stahl cautioned that antidepressants should not be stopped cold turkey. Leslie Stahl said that individuals who take antidepressants, and feel better as a result, will likely continue to take them. But she worried about the side effects. For some people there are serious side effects. “And if a sugar pill is just as good, how can we keep prescribing these pills?”

For more information on antidepressants, see: “Antidepressant Withdrawal or Discontinuation Syndrome?” and “Antidepressants: Their Ineffectiveness and Risks” under the Resources: Counseling Issues menu.

Do you think evidence about the placebo effect with antidepressants effectively challenges the chemical imbalance theory of depression?