Treatment Developments in Depression

The problem of science in silos.

Posted Mar 09, 2019

Science works best when scientists communicate with each other. That sounds obvious—and with the myriad scientific conferences occurring these days, might be supposed to not be an issue. But there are, surprisingly, a number of areas in which scientists exploring solutions to the same problem operate on completely parallel tracks. That situation has the potential to leave consumers of science confused and, in some instances, their health jeopardized.

We see this clearly demonstrated by current research into new treatments for depression. One of the most common health conditions, depression affects an estimated 16.2 million people in the U.S. There are many treatments for depression, but those backed by solid evidence fall into two very broad categories often termed “somatic” and “psychosocial.” The somatic category includes antidepressants and other medications, electroconvulsive (shock) treatment (ECT), and transcranial magnetic stimulation (TMS). Psychosocial treatments are mostly comprised of the various forms of psychotherapy, with cognitive behavioral therapy (CBT) and interpersonal psychotherapy (IPT) having the strongest evidence bases and psychoanalytic (or psychodynamic) psychotherapy being widely used as well.

Many of these treatments are clearly effective, but every one of them has both drawbacks and many non-responders. Antidepressant medications, for example, have a range of adverse side effects and can take weeks to work. Furthermore, only about 30 percent of patients with depression have a complete response to the first antidepressant they try. Psychotherapy takes many weeks to months to be effective, requires concentration and motivation from the patient, and can be expensive. It is no surprise, then, those researchers are trying to find more effective and practical treatments for depression.

Two interesting and very different groups of treatments for depression are currently emerging. On the somatic treatment front, a bevy of drugs we once considered to be mainly drugs of abuse is gaining traction. These include ketamine—an inhaled version of which was just approved by FDA—psilocybin (mushrooms), and MDMA (Ecstasy). On the psychosocial treatment side are non-drug approaches that we usually associate with lifestyle enhancement and general health and wellness: meditation, yoga, and exercise, for example.

A troubling aspect of these developments, however, is that they are occurring in silos. No one is comparing ketamine to meditation or mushrooms to yoga, for example. If you have depression, should you try MDMA or hire a trainer? Neither front-line mental health practitioners nor their patients are likely to be given any answers to such questions as things are now developing.

Better Drugs are Needed

Mental health clinicians and scientists agree that we desperately need new and better medications for depression. All of the currently available antidepressants operate on the same basic neurobiological mechanism, enhancing the action of one or both of two chemical neurotransmitters in the brain, serotonin (5-HT) and noradrenaline (NA). Back in the 1950s, scientists serendipitously discovered that drugs that interact with these neurotransmitters can be effective in treating depression and the first generation of medications, called tricyclic antidepressants (TCAs), was born.

Then, in the 1980s, the second generation of antidepressants was initiated with the introduction of Prozac, the first of a new selective serotonin reuptake inhibitor (SSRI) class of medications to be made available in the US. Although the SSRIs have some adverse side effect advantages over the TCAs, they still operate by increasing serotonin levels and they work no better than TCAs (and in some cases possibly not as well).

Through the subsequent years, more SSRIs and various other new antidepressants have been developed, all touted by their manufacturing pharmaceutical companies as breakthroughs, but all are still based on the same mechanism of action, and none actually offer any advantage in effectiveness. Psychopharmacologists now routinely express their frustration with the lack of progress in developing a better, safer, and more effective class of antidepressants.

An important reason for this stagnation is that the antidepressants we have were essentially first discovered by accident without any basic understanding of what problem they were actually addressing. In all other fields of medicine, new drugs are generally developed based on an understanding of the physiology of the disease they are designed to treat. But this kind of “rational” approach to drug development was not employed in the case of antidepressant medications. One thing we actually know for sure is that serotonin and noradrenaline levels aren’t actually reduced in the brains of people with depression. Thus, why drugs that increase their activity work in treating depression remains obscure—and repeatedly introducing variations on this theme has stifled progress.

Now, things may be developing in a better direction. The possibility that ketamine may be an effective antidepressant has generated significant excitement, for good reason. Unlike the current strategy of merely tinkering with the serotonin and norepinephrine systems, ketamine represents a new and rational approach to antidepressant drug design. There is good basic scientific evidence to suggest that excessive activity of the neurotransmitter that ketamine targets—glutamate—is involved in human depression. This means that ketamine may be addressing a fundamental abnormality in the brains of people suffering from depression. Furthermore, it also seems to work better in some situations than the antidepressant drugs we already have; whereas the current crop of antidepressants can take weeks before they become effective, a single injection of ketamine has been shown in multiple studies to provide almost immediate and substantial relief from depression.

Party Drugs Becoming Antidepressant Medications

Although ketamine has long had an important medical use as an anesthetic, it is perhaps best known to the general public by its moniker “Special K,” a street drug used to get high. And in that category, ketamine has some interesting company. The Food and Drug Administration (FDA) recently agreed to let a clinical trial of psilocybin, the main ingredient in magic mushrooms, go forward. At the same time, MDMA, better known as Ecstasy, has been shown in at least one study to be effective in conjunction with psychotherapy for the treatment of post-traumatic stress disorder (PTSD) and has also been studied to treat depression. It is fascinating to learn that all of these “psychedelic” drugs share an effect on brain function that we now believe may be central to what is wrong in depression.

Work with drugs like ketamine, psilocybin, and MDMA feels almost titillating. We now have scientists working with cutting edge compounds that, because they can also be abused, have a daring side to them. We may also be finally breaking free from the serotonin/noradrenaline handcuffs and embarking on new and more rational strategies for antidepressant medication development. Finally, and of course most important, there are some signs—although much more research on both effectiveness and safety must be done—that these new drugs can help depressed people in some ways that currently available medications do not.

The prospect of a new medication for depression always seems to generate enthusiastic public and media attention. Not surprisingly, therefore, many stories about the crop of potential new drugs have appeared, whetting our appetite with hope for a breakthrough. There is a kind of “we told you so” theme to some of these stories: drugs that were heralded in the 1960s as the road to higher consciousness, only to be demonized and banned, are once again being looked upon as possible breakthroughs. But if the idea that drugs considered illicit may now become prescribable medicines seems strange and surprising, so perhaps do findings that strategies once associated with gurus, yogis, and fitness advocates that do not involve any drugs may also be effective antidepressants.

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Who’s Your Guru?

By now most of us have gotten the message that exercise is good for just about everything. Mood is no exception; many studies have clearly documented that exercise improves mood and may reduce the symptoms of depression. Although systematic reviews of the literature reach conflicting conclusions about just how potent an antidepressant exercise is, there is emerging evidence that exercise can be considered as part of the treatment plan for any patient with depression who can safely engage in physical activity. There is also evidence that exercise can prevent depression.

It is sometimes assumed that only medications have a biological basis for the treatment of psychiatric illnesses, but we are coming to understand that psychosocial interventions of various kinds also have demonstrable effects on brain function. There is now work, for example, showing that exercise has effects on the brain that may be relevant to its antidepressant effects, like increasing the size of the hippocampus, a structure critical for learning and memory. According to evolutionary biologist Herman Pontzer, exercise may blunt the effects of cortisol, the stress hormone known to play an important role in both depression and anxiety disorders. Pontzer argues that exercise is an evolutionary development that distinguishes humans from their nearest genetic relatives, the great apes. Exercise is uniquely essential for humans because “we evolved a faster metabolism, [requiring] fuel for increased physical activity and the other energetically costly traits that set humans apart, including bigger brains.”

Another “wellness” practice that also appears to have biologically-based antidepressant effects is mindfulness meditation. Although once again there are conflicting opinions about just how effective meditation is for treating depression, studies have shown that meditation normalizes connections between two brain areas critically involved in fear, anxiety, and depression—the amygdala and the prefrontal cortex. Preliminary evidence also indicates that yoga may play a role in treating depression.

Science in Silos

All of these new approaches to treating depression are exciting, but we also note that the medication and non-medication ones seem to be developed by scientists who operate in silos and rarely communicate with each other. So if you are a person suffering from depression, should you go to a psychiatrist who offers ketamine? Or would it be better for you to hire a trainer and begin exercising? Or perhaps both?

Of course, a lot of the answer to this question depends on an individual’s exact circumstances. Someone who is already a marathon runner might not benefit from more exercise. Ketamine seems to be helpful for the immediate treatment of severe depression, but we do not know yet if it is safe or effective for longer-term treatment of more moderate forms of depression. Hence, the most useful thing would be to see a mental health clinician who knows about all of these different approaches to treatment, understands which have the best evidence supporting them, and is prepared to offer an intervention plan that combines both somatic and psychosocial elements.

New medications are typically evaluated by comparing them to placebos, identically appearing but physiologically inert pills. This is a straightforward and rigorous way of determining if a new drug works—and in cases like ketamine for depression, the answer is almost certainly that it does. But for a person suffering from depression, knowing that a drug works better than nothing is informative. He or she might also ask, however, “Is this pill better for me than if I start meditating or doing yoga?”

Answers to a question like that will require breaking down some of the silos that often exist in science and getting scientists from very different fields to communicate with each other. How about a study comparing psilocybin to yoga? Or Ecstasy to meditation? And maybe add brain imaging to see to what extent the treatments normalize brain function in depressed people? This may seem like “science joins the psychedelic age,” but bold approaches are exactly what we need for serious and difficult to treat illnesses like depression. As daring as it may be to study psychedelics and strategies originally developed by Eastern practitioners as approaches to treating a medical condition, breaking down some walls that separate scientists working on the same problem might be even bolder. 

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