1-real-lead-image-human-brainIt comes as no surprise that the most common form of treatment for serious depressive illness is antidepressant drugs. Since the introduction of Prozac over 25 years ago many new drugs have been introduced and there is a general perception that the newer drugs are somehow different or more effective than the older ones. In reality since the first antidepressants became available in the mid 1950s, all antidepressants currently approved by the FDA are believed to work by enhancing certain chemicals in the brain, so-called neurotransmitters, that work on serotonin, norepinephrine, or dopamine. While there are differences among the drugs and some people respond better to some others, essentially the presumed mechanisms of action remain similar. One consequence of this limited spectrum of mechanisms is that a significant proportion of patients being treated for depression do not benefit from the medications, and even if they do, they may discontinue treatment because side effects are unacceptable. For example, the most popular antidepressants, the selective serotonin reuptake inhibitors, drugs like Prozac, Zoloft, or Lexapro, all can produce side effects such as loss of libido, difficulty achieving orgasm and weight gain. To put it bluntly, there have been no major changes in the basic nature of the drugs that are now available for treating major depression.

But now, change may be on the way. It has long been known that some patients who did not benefit from FDA approved antidepressant treatment reported getting significant — if not complete — relief from using medications that unfortunately have some abuse potential. Specifically, this would refer to opiates, marijuana and to some anesthetic agents, like ketamine, which has been used as a so-called club drug for getting high. Because of the abuse potential of these drugs, and the unpredictability about who might not be able to be responsible if they were prescribed therapeutically, they have not been accepted as treatments for patients with resistant depression. The change that may be coming is the result of research in which some of these agents have been modified so that they may be able to be used therapeutically with minimal risk of addiction and abuse.

One of the promising drugs in the pipeline uses an opiate-like compound called buprenorphine, which is used to treat pain and also is used in combination with another drug to keep people from relapsing into opiate abuse. By attaching a molecule buprenorphine, the researchers have been able to largely eliminate the euphoric effect of the drug. Earlier this year, based on completed studies, this drug was fast tracked by the FDA and is currently being studied in late stage studies. It’s possible that it may be available for clinical use sometime within the next 2 years.

3-scientist-in-labAs already mentioned, the anesthetic drug ketamine, when taken orally, has been used recreationally. It causes dissociation, which can be a desired effect for someone trying to get high, but is very unpleasant for someone who would just use it therapeutically. Over a decade ago it was discovered that some patients recovering from surgical procedures who were given ketamine woke up with their long-standing depression relieved. This led to research in which ketamine was used as a slowly infused intravenous treatment, and remarkably, patients with long-standing depression that had not responded to any existing treatment felt better even after the first treatment.

Typically, current antidepressants take weeks to begin to work, so this is very significant. Ketamine infusions are now used throughout the country, there are even some private practitioners who offer it as a treatment and there are many academic centers and clinical trials which are examining its effects and possible risks. An especially interesting report tells us that several new compounds have been developed that work on the same neurotransmitter system, the glutamate system, as ketamine. These may be available in the near future with the advantage of being able to be used orally and not have the same spectrum of side effects as ketamine itself. Several of these drugs also have been fast tracked by the FDA.

4-hands-and-cannibasPerhaps most intriguing of all is the fact that some of the compounds found marijuana to have been synthesized and are shown to produce antidepressant effects. Some of these so-called cannabinoidals are already being used in neurology to treat epilepsy. Clinical trials are underway studying these drugs as treatments for both anxiety and for depression.

There are several important points that research with these new drugs brings out. One is that not all depressions are the same. It probably has many different causes and because of the limitations of current treatments, segments of the depressed population don’t benefit from treatment. With these newer mechanisms of action, treatments may benefit a subgroup of patients. Psychiatric medications always provoke a certain degree of controversy and no doubt the possible availability of drugs that have a history of abuse and misuse will no doubt raise concerns. But it’s important to remember that major depression, meaning depressions that are disabling and distressing and often associated with suicidal thinking or acts, need to be treated. With these new treatments there’s hope, something that depressed patients often find difficult to feel.

Norman Sussman MD is Professor of Psychiatry and Director, Treatment Resistant Depression Program at the New York University School of Medicine in New York City, and is a frequent contributor to Z’Scoop. 

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Kaplan & Sadock’s Pocket Handbook of Psychiatric Drug Treatment (Fifth Edition)
by Benjamin J. Sadock MD, Virginia A. Sadock MD, and Norman Sussman MD
Hardcore Self Help: F*ck Anxiety (Volume 1)
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Hardcore Self Help: F*ck Depression (Volume 2)
by Robert Duff Ph.D.

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