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.