Pubdate: Sun, 05 Jun 2016
Source: New York Times (NY)
Copyright: 2016 The New York Times Company
Contact: http://www.nytimes.com/ref/membercenter/help/lettertoeditor.html
Website: http://www.nytimes.com/
Details: http://www.mapinc.org/media/298
Author: Anna Fels
Note: Anna Fels is a psychiatrist and faculty member at Weill Cornell 
Medical College.

CAN OPIOIDS TREAT DEPRESSION

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 only 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.
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MAP posted-by: Jay Bergstrom