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Treatment Developments in Depression

The problem of science in silos
March 12, 2019 | Comments

Science works best when scientists communicate with each other. That sounds obvious and with the myriad scientific conferences occurring these days might be supposed not 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 antidepressant 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% 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 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 are 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).

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 them 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 science 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

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