Novel Antidepressant in the Pipeline: NMDA Receptor Antagonists

Author: Brian Gabriel

In a given year, approximately 26.2% of Americans (or roughly 1 in 4 adults) will suffer from a mental disorder. The most prevalent mental disorder, major depressive disorder, strikes anywhere from 6.7% to 9.5% of U.S. adults each year. 15% of these individuals will commit suicide, making depression the second-largest cause of adult mortality in the U.S. following coronary artery disease (furthermore, studies are beginning to illuminate the positive correlation between these two diseases).

Historically, psychopharmaceuticals have putatively targeted the “monoamines” of the brain; namely serotonin, norepinephrine, and dopamine. The first widespread class of antidepressants, monoamine oxidase inhibitors (MAOIs), was serendipitously discovered to benefit those suffering from depression after patients treated with these antihypertensive medications reported elevated moods. MAOIs are fraught with side-effects, however, including the potentially fatal hypertensive crisis. Because of side-effects, MAOIs are less frequently prescribed today. Similarily, tricyclic antidepressants are also characterized by numerous burdensome side effects including fatal cardiotoxicity in overdose. Finally, while safer than MAOIs and tricyclic antidepressants, selective serotonin reuptake inhibitors (SSRIs) present additional difficulties including a delayed onset of action. While subtle variations on SSRIs have developed (including selective serotonin and norepinephrine reuptake inhibitors-SNRIs), truly novel antidepressants outside the paradigm of monoamines are currently lacking. Below is a brief discussion of one such novel class of antidepressant currently in development.

Autism: searching for a cure

We currently have drug therapies for a wide variety of conditions. We have ways to treat diabetes and reduce the risk for heart attacks. We have medications for depression and anxiety. We even have medications for schizophrenia and bipolar disorder.

When will we find a drug treatment for autism?

If you visit ClinicalTrials.gov, you'll find almost 200 trials if you type the word "autism" into the search box. Roughly half of those studies are recruiting volunteers, but the problem is that many parents do not wish to subject their children to clinical studies. So, how will researchers conduct their research? How will the medical community find a cure or treatment for autism unless we have enough clinical studies evaluating various treatment options?

Speaking of treatments, there's a startup company based in Cambridge, MA called Seaside Therapeutics and this company is testing a compound that dampens synaptic activity by mimicking GABA (an inhibitory chemical messenger in the brain). The company is evaluating this compound in patients who have fragile X and also in those who have autism.

A depressing study about depression meds on JAMA

There's a JAMA (Journal of the American Medical Association) review article that was published on January 6 titled, "Antidepressant Drug Effects and Depression Severity." The authors performed a patient-level meta-analysis and looked at quite a few different clinical studies to explore the effects of antidepressant medications in patients who have clinical depression. Here's what they found:

Conclusions: The magnitude of benefit of antidepressant medication compared with placebo increases with severity of depression symptoms and may be minimal or nonexistent, on average, in patients with mild or moderate symptoms. For patients with very severe depression, the benefit of medications over placebo is substantial.

So what does this really mean? Does it mean that those patients who have mild or moderate depression are mainly experiencing a clinical benefit derived from the placebo effect? Could this review article be flawed? Maybe the authors missed a critical factor among patients who have mild or moderate depression.

In any case, this is certainly a depressing study for pharmaceutical companies who are sell antidepressant medications. I'm sure this article will stir some considerable controversy among those who are considered "high volume" prescribers of antidepressant medications like SSRIs and SNRIs. We're talking about drugs like: bupropion, citalopram, duloxetine, escitalopram, fluoxetine, fluvoxamine, mirtazapine, nefazodone, paroxetine, sertraline, trazodone, and venlafaxine.

To read the abstract on JAMA, click here.

Grand Rounds is at Invisible Illness Week

Grand Rounds Vol 5.47 is over at Invisible Illness Week. What's an invisible illness? It's when you have a medical condition that isn't "visible" to most people. If you can hide your illness from others, then it may be an "invisible" illness because most people can't see that you're visibly "ill." That sounds like most chronic conditions, doesn't it? Depression, diabetes, cancer, cardiovascular disease, etc. The bottom line is that many people suffer silently as they hide in their illness. However, there are various support groups out there for people who go through their "silent" and "invisible" illness, so they should not be alone.

To read this week's grand rounds, head over to Invisible Illness Week.

National Invisible Chronic Illness Awareness Week is an official annual campaign sponsored by Rest Ministries in collaboration with other sponsors.

Having a family history of depression

According to a recent study published in the Archives of General Psychiatry, if you have a strong family history of depression, then you may be at higher risk for depression. CNN highlights that:

"It turns out that the more family members you have who have been found to have major depression, anxiety disorders, or drug or alcohol dependence, the greater the chances that you will too, according to Terrie E. Moffitt, Ph.D., a professor of psychology and neuroscience at Duke University's Institute for Genome Sciences & Policy."

So, the more relatives you have with major depression, anxiety disorder, or alcohol or drug dependence, the more likely you may be to have that condition too. Read the CNN story here.

Depression can be treated and we've seen some very effective medications emerge over the past few decades. We've also seen a persistent decline in depression therapy after the FDA warnings. On that topic, here's another interesting bit on the history of these warnings from the Archives of General Psychiatry:

"In October 2003 the Food and Drug Administration (FDA) issued a Public Health Advisory about the risk of suicidality for pediatric patients taking antidepressants; a boxed warning, package insert, and medication guide were implemented in February 2005. The warning was extended to young adults aged 18 to 24 years in May 2007. Immediately following the 2003 advisory, unintended declines in case finding and non–selective serotonin reuptake inhibitor substitute treatment were shown for pediatric patients, and spillover effects were seen in adult patients, who were not targeted by the warnings."

As expected, "Primary care providers continued significant reductions in new diagnoses of depression (44% lower for pediatric, 37% lower for young adults, 29% for adults)." So, now that we have all these warnings attached to drugs, what can we do to ensure that patients are appropriately diagnosed and treated?

Prescription Drug Rehab

Do you know of any good California Drug Rehab programs? When I was in medical school, I used to work in a Veterans Affairs (VA) hospital. I saw many patients who had drug and alcohol addictions. They were essentially using drugs and alcohol to cope with depression, stress, anxiety, and even PTSD (Posttraumatic Stress Disorder). Drug abuse is a common problem, even among non-military veterans. The statistics can be quite staggering. Many adults struggle with anxiety and they become dependent on benzos (like Ativan, Valium, and others) to help them relax. In the United States, benzodiazepines are Schedule IV drugs under the Federal Controlled Substances Act.

There is a strong need for better Prescription Drug Rehab programs in this country. Because of the addictive potential associated with opioids, many patients now need Vicodin Rehab (I'm not picking on a single opioid, I'm just using an example). Other commonly abused opioids include: Percocet, Dilaudid, Demerol, and Fentanyl (yes, even this drug gets misused). Opioid withdrawal symptoms can include severe dysphoria, sweating, nausea, rhinorrea, depression, severe fatigue, vomiting and pain. You've seen it in the movies. Don't let your loved ones go through withdrawal alone. Make sure to find a good rehab program for them.