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PostPosted: Tue Apr 11, 2017 2:41 am 
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https://www.nytimes.com/2016/06/05/opinion/sunday/are-opioids-the-next-antidepressant.html

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Are Opioids the Next Antidepressant?

ONE of the most painful experiences of being a psychiatrist is having a patient for whom none of the available therapies or medications work.

A while back, I was asked to do a consultation on just such a patient. This person had been a heroin addict in her early 20s. She had quit the opioid five years earlier, but her life was plagued with anxiety, apathy and self-doubt that prior treatments had not helped. At the end of the session, almost as an afterthought, she noted with irony that the only time in her adult life when she had been able to socialize easily and function at work was when she had been hooked on heroin.

We are in the midst of a devastating and often lethal opioid epidemic, one of whose victims, we learned last week, was the pop star Prince. At such a time, it is hard to remember that there are multiple opioids naturally produced in our brains and required for our well-being. The neural circuitry utilizing these substances controls some of our most fundamental feelings of pain, stress and hopelessness, as well as pleasure and even euphoria.

There is obviously a need for extreme caution, but research suggests that certain opioids may actually be useful in treating psychiatric diseases that have proved frustratingly unresponsive to current medications.

It is the potentially addictive subset of opioids, whose natural ancestors were originally derived from poppies, that we associate with the word. These substances have been with us for most, if not all, of human civilization. Poppy seeds have been found at archaeological sites of Neolithic man. The Sumerians wrote about “the joy plant”; an Egyptian papyrus from the second millennium B.C. described the use of a product of poppies to stop the crying of children. Hippocrates suggested its use for female ailments, and a ninth-century Persian physician advocated the use of opium for melancholia.

Millenniums later, during the American Civil War, the Union Army used 10 million opium pills to treat wounded soldiers. And then there were the two Opium Wars fought between China and Britain. Unquestionably, no other psychoactive substance has played such a central role in human affairs.

Beginning in the 19th century, chemists derived ever more potent forms of this class of drugs: morphine, oxycodone, heroin and codeine, to name just a few. They were a boon to the management of pain, but their addictive potential was enhanced as well.

These drugs interact primarily with only one type of opioid receptor in the brain. A second powerful family of opioids called dynorphins activate their own receptors in the central nervous system and have effects that are in many ways the opposite of those we have come to expect from opioids. Stimulation of their receptors produces feelings of depression, anxiety, memory loss and a reduced ability to enjoy rewarding experiences.

They are thought to function as part of our defensive reaction to stress and particularly chronic, inescapable stress. While blunting our sensations of mental and physical pain, dynorphins simultaneously dull or even extinguish our positive responses to pleasure. In human studies, activating these receptors creates a sensation called dysphoria — a depressive, anxious state. In experimental models, blocking these receptors seems to prevent this depressive response to stress — opening up the possibility of future treatments using this mechanism.

What might it look like if someone had an imbalance between these two opioid systems — if perhaps they had too much of one or a paucity of the other or a defective receptor? This could theoretically occur as a result of environment — trauma, for example, or chronic stress — or from a genetic problem or some combination.

One result might be a depressive syndrome that is not responsive to the antidepressants now in use. There is little doubt that the current medications are inadequate for a significant portion of the population. A large study funded by the National Institute of Mental Health found that the rate of remission after two rounds of drug treatment was about 50 percent. After four rounds, around 30 percent of patients still suffered from depression.

Essentially, all the anti-depressants now in use affect a single group of neurotransmitters called monoamines and are likely to treat only specific subtypes of depression. Clinicians and scientists alike are in agreement that other pathways in the brain that control mood need to be explored. The opioids are one such pathway.

One “natural,” nonmedicinal use of opioids for depression is already widespread. There is a generally accepted hypothesis that long distance running produces a “runners’ high” via the production of endorphins, one of the brain’s opioids. Intense exercise is often “prescribed” for the treatment of depression. I have had several patients over the years whose lives revolved around punishing exercise schedules. On days when they could not exercise, they often experienced feelings of malaise and low mood — not unlike patients who miss a day or two of their antidepressants.

A medication that modulates the opioid system, buprenorphine, already exists, but is approved for the treatment of opioid addiction. Its actions are incompletely understood, but it is thought to block the opioid receptors that cause depression and only partly activate the receptors that enhance feelings of well-being, thereby blunting the high of drugs like morphine.

Whether buprenorphine will prove to be an effective and nonaddictive treatment for depression is unclear. Small studies of patients unresponsive to regular antidepressants have been encouraging — including a recent one in which very low-dose buprenorphine given for four weeks reduced suicidal thoughts in dangerously depressed patients. Research with larger numbers of patients and longer-term follow-up is needed before such medications can be recommended for clinical use.

Opioids may also hold out hope for a devastating illness formally known as borderline personality disorder. Characterized by severe emotional dysregulation, patients with this disorder have feelings of loneliness, rejection, anger and sadness that can quickly overwhelm them. They struggle to maintain relationships and are terrified of abandonment. They are often substance abusers and — in fact — opioids are frequently their drugs of choice. In one study, 44 percent of patients seeking buprenorphine treatment for their opioid addiction were found to have borderline personality disorder.

THERE are no Food and Drug Administration-approved medications for this illness. Several intense therapeutic interventions have been shown to be beneficial, but they are far from curative. Curiously, many patients actually try to induce pain by superficially cutting or burning their skin, saying this provides them with emotional relief. It is believed that the self-mutilation generates a release of opioids in the brain that soothes them and helps them regulate their feelings.

Research looking at opioid receptors in patients with borderline personality disorder in comparison to control subjects has documented abnormalities in these patients’ opioids system. It is a finding that would help explain why many opioid abusers describe the sensation they get from using drugs not as “getting high” but as “getting right,” or as “feeling normal.”

It may seem counterintuitive and even dangerous to be considering the medicinal use of substances that are currently a scourge to our society. Yet opioids have a long history of being used to treat melancholia and other psychological disorders — right up until the 1950s, when the current group of antidepressants were discovered. Is it possible we’ve come full circle? We don’t know yet. But we owe it to our patients to find out.


Correction: June 19, 2016

An Opinion article on June 5 about opioids and depression incorrectly described the approved uses of buprenorphine. It is F.D.A.-approved for the treatment of acute and chronic pain as well as opioid addiction; it is not approved only for the treatment of opioid addiction.


Personally I think it's not a good idea to go back down that road. I fear history could potentially repeat itself. Psychiatry has experimented with using opioids for depression in the past, most memorably when opium and morphine were given to institutionalised psych patients (the Opium Cure) for all kinds of ailments from psychosis to melancholia to alcoholism. Results were amazing and promising at first, however it wasn't long before patients ended up tolerant to their doses, required more and more to get any therapeutic benefit, and drug-seeking behaviour (ie addiction) surfaced. In the end it just added another crippling condition (opioid addiction) to their already list of serious health problems.

Some people claim that buprenorphine is different, that because it's a partial agonist antagonist that it somehow won't lead to people becoming tolerant and thus is an effective antidepressant. However all it means (in my experience) is that once a person's tolerance hits the ceiling effect and the antidepressant effect diminishes, increasing the dose won't help. So they'll be dependent on buprenorphine at a ceiling dose with no antidepressant effect. Back to square one, only this time they're now dependent on opioids as well! This is why I think people need to be cautious about seeing Suboxone as a potential answer to depression. Prescribing to people who are already opioid tolerant is fine, but using it on the opioid naive?

Reason I'm conscious of this at the moment is a friend of mine with quite severe type 1 bipolar, in her early 20's, has just recently found opioids while in a depressive spell. It started with Tramadol, large numbers of tylenol a day, and now she's getting her hands on low doses of Suboxone. She's claiming it's the answer to her problems, that she feels relief, wellness and happiness after she takes it. Nothing I say to her about her going down "the opioid road" seems to be getting through. But nothing I could say to myself when I started out would have gotten through either.

As someone with bipolar type 1 who experiences significant depression that's difficult to treat at times, I really think we need to put more research into brain sciences. I fear if opioids are still considered a viable answer to treat psychiatric conditions, that we are still in the dark ages.


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PostPosted: Tue Apr 11, 2017 7:20 am 
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Quote:
Personally I think it's not a good idea to go back down that road.



Thanks for this very interesting piece TeeJay,

But when you say the above, are you speaking just for yourself, or are you
recommending against opioid treatment for depression in general?

I think there's very little question that these drugs are for many people effective antidepressants. Even after
12 years of taking large amounts of opium in the form of poppy tea I continued to get a boost in mood, including feelings of social expansiveness and increased energy. I'd say that bupe does the sane sort
of thing for me, in a much more subtle way.

I notice an improvement in mood, an hour or two after taking a dose. It's temporary, but it's there, I don't get pain relief, but I do get a noticeable bump emotionally.

I've been experimenting with this lately and have found It doesn't take much...even just a fraction
of my daily dose to get this effect. . I'm open to it being some sort of placebo effect, but I don't think it is. It's my understanding that expectations play a role in the placebo effect, and I had no expectation at all of this kind of thing.

I noticed it around my writing first. An hour or two after taking my daily dose I noticed an urge to sit down and work. This was a reliable effect with the opium, but a complete surprise with the bupe.

My personal opinion on the possible use of opiates for depression is I think it's worth a try, especially with buprenorphine which has a different profile than full on agonists.More research seems absolutely warranted. I think I've seen Dr. Junig write hopefully about the likelihood of developing different, better opiate type drugs in the future. I'm almost sure I've seem him write that he thinks science will eventually figure a way around the tolerance effect that is responsible for so much suffering among addicts.

I think this is at the very least a hopeful area of inquiry.


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PostPosted: Tue Apr 11, 2017 10:07 am 
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Thanks Godfrey! I was not aware of that story, but the drug referred to in the article is being developed by Alkermes, called AlkS 5461. There is information on the Alkermes site, and some info about their problems with trials here: http://www.fiercebiotech.com/biotech/alkermes-third-time-lucky-alks-5461-but-doubts-linger

This is confusing, and the NYT article doesn't clarify it well- but it does not take advantage of the effects of buprenorphine that we are usually talking about, i.e. at the mu receptor. That receptor causes tolerance, which at this point is a fatal flaw. Instead, ALKS 5461 consists of buprenorphine plus Samidorphan, a.k.a. ALKS 33, which is a potent, long-acting mu antagonist.

The antidepressant properties of ALk come from the blocking effects of buprenorphine at the kappa receptor. Better details here: https://en.wikipedia.org/wiki/Buprenorphine/samidorphan

I agree with you, Godfrey, about starting buprenorphine alone for depression-- for the reasons you mentioned.


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PostPosted: Tue Apr 11, 2017 2:30 pm 
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Yes, if you are going to use an opioid for treatment, why not use one that limits the ill effects of tolerance?

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PostPosted: Tue Apr 11, 2017 2:43 pm 
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Good thread Teejay, always something interesting!
Always appreciate your posts Godfrey.
Thanks Dr J for your info.

Teejay,
So far has shown no dependence or abuse potential due to the 2 drugs interaction.
It may not be appropriate for bipolar as may precipitate mania.
It may not be appropriate for those also w pain issues as pain relieving opiate effects may be reduced or blocked.

Will ALKS 5461 get approved? We only know that the company says Phase 3 results are good. Results to be released in June.

Some consider Alkermes plan risky - to seek FDA approval based on two negative and one positive late-stage study. Patient advocates disagree saying they are desperate to try a different and perhaps better depression drug. Others say a separate study w different endpoints needs to be done.

It may be that the soon to be new FDA director, Scott Gottlieb, MD is key to ALKS 5461 and other drugs approval based on clinical data requiring the agency to bend, tweak or even maybe lower current standards. Dr. Gottleib is viewed as a 'disruptor' who has called for a number of questionable changes, including approving drugs based on safety, not on whether they are effective. Patient's advocates approve this thinking stating they have the right to try these drugs and determine effectiveness later. Biotech and Pharm companies also (of course) agree. Best to all today!! P

PS also check out Cerc 501. no bup in it but works on opiate receptors https://en.wikipedia.org/wiki/CERC-501

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PostPosted: Tue Apr 11, 2017 9:16 pm 
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Is the article really about ALKS though? It specifically says buprenorphine alone, not buprenorphine / samidorphan combination? Samidorphan / ALKS isn't mentioned in the article at all, only buprenorphine.

I don't think buprenorphine monotherapy is useful for depression as it can also act as an "entry level" opioid, and for me and most people I know, loses its antidepressant qualities once a person becomes tolerant to its effects. As such shouldn't it be reserved for people who already have an opioid tolerance. I've heard Dr J say this multiple times in his posts.


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PostPosted: Wed Apr 12, 2017 12:20 am 
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Teejay, No, Sorry, I was responding to the combo product. The article imo might be referring to http://ajp.psychiatryonline.org/doi/abs ... 5.15040535 Best P

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PostPosted: Wed Apr 12, 2017 8:52 pm 
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Wow. Thanks everyone-- and Teejay, thanks for starting the topic. i think I was confused in my last post...

I learn so much from you guys-- I was not aware of Cerc at all, and I had not seen the article about suicidal ideation.

It is funny how they refer to 'ultra low dose buprenorphine'.... if you look at the literature about buprenorphine in the late 1990s, when buprenorphine was used in Europe to treat addiction to opioids, people referred to HDB, i.e. 'high dose buprenorphine', vs. the regular doses used up to that point. Before Suboxone, buprenorphine was usually found in vials called 'Temgesic', in hundreds of microgram amounts. HDB referred to the use of 'supramaximal' doses of buprenorphine, far above the dose that achieved maximum effects.

Now, HDB has become just 'buprenorphine', and hundreds of micrograms is referred to as 'ultra-low-dose'. Everything, apparently, is relative!


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