Antidepressants May Be Missing the Mark By Rick Nauert PhD

A new study suggests most antidepressants do not target a key brain protein believed to be of importance in maintaining mood.

The protein is monoamine oxidase A (MAO-A), a substance that is highly elevated during clinical depression. The new study suggests this chemical is unaffected by treatment with commonly used antidepressants.

According to experts, the study has important implications for understanding why antidepressants don’t always work.

Researchers at the Centre for Addiction and Mental Health (CAMH) used an advanced brain imaging method to measure levels of the brain protein MAO-A. MAO-A digests multiple brain chemicals, including serotonin, that help maintain healthy mood.

High MAO-A levels excessively remove these brain chemicals.

Antidepressant medications are the most commonly prescribed treatments in North America, yet 50 percent of people do not respond adequately to antidepressant treatment.

Dr. Jeffrey Meyer, the lead investigator, explains, “Mismatches between treatment and disease are important for understanding why treatments don’t always work. Rather than reversing the problem of MAO-A breaking down several chemicals, most antidepressants only raise serotonin.”

Understanding the Problem of a Persistent Illness

Depression ranks as the fourth leading cause of disability and premature death worldwide, according to the World Health Organization. Recurrent illness is a major problem. Even under the most optimal treatment circumstances, recurrence rates for clinical depression are at least 20 percent over two years.

The new study also focused upon people who had fully recovered from past episodes of clinical depression. Some people who appeared to be in recovery actually had high levels of MAO-A. Those with high levels of MAO-A then had subsequent recurrence of their depressive episodes.

This new idea of high levels of MAO-A lowering brain chemicals (called monoamines), then falling into a clinical depression is consistent with the historical finding that medications which artificially lower monoamines can lead to clinical depression as a side effect.

In the 1950’s some medications to treat high blood pressure also lowered monoamines and people began to experience depressive episodes. When the medications were removed, people recovered.

From Technology to Treatment

VP of Research Dr. Bruce Pollock highlights the study’s use of advanced brain imaging technology. “CAMH has the only positron emission tomography (PET) centre in the world that is dedicated solely to mental health and addiction treatment and research. As a consequence, we were able to develop this new technology to measure MAO-A levels.”

According to Dr. Meyer, “Since most antidepressants miss MAO-A, we are counting on the brain to heal this process of making too much MAO-A, and that doesn’t always happen. The future is to make treatments that tell the brain to make less MAO-A, even after the antidepressant treatment is over, to create better opportunities for sustained recovery.”

Monoamine oxidase inhibitors (MAOIs) are an older class of antidepressants used for the treatment of depression. While more commonly prescribed in Europe and other places, they are not commonly prescribed in the U.S. due to the potential for serious dietary and drug interactions. People who take a MAOI antidepressant must eat a restricted diet to ensure they don’t suffer from serious side effects.

The study is found in the current issue of the Archives of General Psychiatry.

Source: Centre for Addiction and Mental Health

New Grant To Study Depression Treatments

By Rick Nauert PhD Senior News Editor
Reviewed by John M. Grohol, Psy.D.

Depression affects more than 20 million people in the United States. The federal government recognizes the pervasive nature of the disease and has awarded the University of Illinois at Chicago a five-year, $4.8 million grant to develop new therapies to treat depression.

Currently, the most common treatment approach is a combination of antidepressant medication and psychotherapy.

Symptoms can include sadness, loss of interest in activities that were once enjoyed, weight change, difficulty in sleeping (or oversleeping), loss of energy, feelings of worthlessness and thoughts of death or suicide.

The illness can run in families, and it occurs more often in women than men.

What’s needed are antidepressants that work faster, have fewer side effects and that act pharmacologically in new ways, says Alan Kozikowski, UIC professor of medicinal chemistry and pharmacognosy (the study of medicines derived from natural sources) and the grant’s principal investigator.

Kozikowski and his research team had been designing and synthesizing novel nicotine-like compounds that target certain receptors in the brain, in hopes that they would improve cognition in Alzheimer’s disease. Studies in animal models revealed that some of these compounds had antidepressant activity.

“We thus chose to focus our program on depression, as this offered a very different target that might lead to something better, with a faster onset of action,” Kozikowski said.

While the main focus of the research now is to develop medications for depression, Kozikowski said it’s likely some candidate compounds may have other clinical applications, including the treatment of schizophrenia, pain and nicotine dependence.

In fact, the UIC drug discovery group — which also includes investigators from the Barrow Neurological Institute in Phoenix and from PsychoGenics Inc. in Tarrytown, N.Y. — has already found that some of these novel agents do work for pain in animal models.

Prior research has also shown that many smokers smoke to improve their mood, supporting the notion that nicotine itself has antidepressant properties. This would explain, Kozikowski said, why cigarette smoking is much more common among depressed individuals. A recent study found that smokers are 41 percent more likely than nonsmokers to suffer from depression.

Such studies suggest that nicotinic compounds that have been modified to reduce their addictive potential while retaining the ability to balance mood could provide a new family of antidepressant drugs, he said.

This new drug class could have greater efficacy and fewer side effects than antidepressant medications currently on the market that work by inhibiting monoamine reuptake, Kozikowski said. Side effects of current antidepressants include headache, nausea, insomnia, dry mouth, constipation and agitation.

In spite of the intensive efforts that have gone into the design and study of nicotinic drugs, very few of the compounds have reached clinical trials, Kozikowski said.

The new grant is part of the National Cooperative for Drug Discovery and Development Groups and is funded by the National Institute of Mental Health, one of the National Institutes of Health.

Source: University of Illinois at Chicago

Do Antidepressants Dull Your Emotions? An Interview with Ron Pies, M.D. By Therese J. Borchard

By Therese J. Borchard

Today I have the pleasure of interviewing one of my favorite psychiatrists, Dr. Ron Pies. Dr. Pies is Professor of Psychiatry and Lecturer on Bioethics and Humanities at SUNY Upstate Medical University, Syracuse NY; and Clinical Professor of Psychiatry at Tufts University School of Medicine, Boston. He is the author of “Everything Has Two Handles: The Stoic’s Guide to the Art of Living” and has been a past contributor to the World of Psychology blog.

Question: You’ve written a lot of the topic of grief and depression. How does a person know when grief becomes depression or another mood disorder?

Dr. Pies:

I think it’s important to understand that grief is often a component of clinical depression, so the two are by no means mutually exclusive. For example, a mother may be experiencing intense grief over her recently deceased child, which would be an expectable and quite understandable reaction to such a devastating loss. As I try to explain in my essay on this topic, grief may take one of several “paths”, over longer periods of time. Through a process of mourning; receiving comfort from loved ones; and “working through” the meaning of the loss, most grieving persons are able eventually to move on with their lives. Indeed, many are able to find meaning and spiritual growth in the admittedly painful experience of grieving and mourning. Most such individuals, however, are not crippled or incapacitated by their grief, even when it is very intense.

In contrast, some inviduals who experience what I have called “corrosive” or “unproductive” grief are, in a sense, devoured by their grief, and begin to develop signs and symptoms of a major depressive episode. These individuals may be consumed by guilt or self-loathing–for example, blaming themselves for the death of a loved one, even when there is no logical basis for doing so. They may come to believe that life is not worth living any longer, and contemplate or even attempt suicide. In addition, they may develop bodily signs of a major depression, such as severe weight loss, persistent early morning awakening, and what psychiatrists call “psychomotor slowing”, in which their mental and physical processes become extremely sluggish. Some have likened this to feeling like a “zombie” or like “the living dead.”

Clearly, folks with this kind of picture are no longer in the realm of ordinary or “productive” grief–they are clinically depressed and need professional help. But I would resist the notion that there is always a “bright line” between grief and depression–Nature doesn’t usually provide us with such clear demarcations.

Question: I very much enjoyed your piece on Psych Central, “Having Problems Means Being Alive.” Early in my recovery, I was so afraid to take medication because I thought that it would numb my feelings, keep me from experiencing life’s highs and lows. What would you say to a person who is clinically depressed but afraid to take medication for that very reason?

Dr. Pies: People who are told by a physician that they would benefit from antidepressant medication, or a mood stabilizer, are understandably anxious about possible side effects from these medications. Before addressing the question you raise, though, I think it is important to note–as you may know from your own experience–that depression itself often leads to a blunting of emotional reactivity and an inability to feel the ordinary pleasures and sorrows of life. Many people with severe depression tell their doctors that they feel “nothing”, that they feel “dead” inside, etc. Probably the best description I’ve seen of severe depression is William Styron’s account of his own depression, in his book, “Darkness Visible”:

Death was now a daily presence, blowing over me in cold gusts. Mysteriously and in ways that are totally remote from normal experience, the gray drizzle of horror induced by depression takes on the quality of physical pain…. [the] despair, owing to some evil trick played upon the sick brain by the inhabiting psyche, comes to resemble the diabolical discomfort of being imprisoned in a fiercely overheated room. And because no breeze stirs this caldron, because there is no escape from the smothering confinement, it is entirely natural that the victim begins to think ceaselessly of oblivion… In depression the faith in deliverance, in ultimate restoration, is absent…

I present this description to place the question of antidepressant side effects in perspective: how bad could the side effects be, in comparison with severe depression itself?

Nevertheless, you raise a good question. There is, in fact, some clinical evidence that a number of antidepressants that boost the brain chemical serotonin (sometimes referred to as “SSRIs”) may leave some individuals feeling somewhat “flat” emotionally. They may also complain that their sexual energy or drive is reduced, or that their thinking seems a little “fuzzy” or slowed down. These are probably side effects of too much serotonin–perhaps overshooting what would be optimal in the brain. (By the way, in pointing this out, I am not taking the position–sometimes promoted by pharmaceutical companies–that depression is simply a “chemical imbalance”, that can be treated merely by taking a pill! Depression is, of course, much more complicated than that, and has psychological, social, and spiritual dimensions to it).

The sort of emotional “flattening” I have described with SSRIs may occur, in my experience, in perhaps 10-20% of patients who take these medications. Often, they will say something like, “Doctor, I no longer feel that deep, dark gloom I used to feel–but I just feel kind of ‘blah’…like I’m not really reacting much to anything.” When I see this picture, I will sometimes reduce the dose of the SSRI, or change to a different type of antidepressant that affects different brain chemicals–for example, the antidepressant bupropion rarely causes this side effect (though it has other side effects). Occasionally, I may add a medication to compensate for the SSRI’s “blunting” effect.

Incidentally, for individuals with bipolar disorder, antidepressants may sometimes do more harm than good, and a “mood stabilizer” such as lithium is the preferred treatment. Careful diagnosis is needed to make the correct “call”, as my colleague Dr. Nassir Ghaemi has shown [see, for example, Ghaemi et al, J Psychiatr Pract. 2001 Sep;7(5):287-97].

Studies of patients with bipolar disorder who have taken lithium generally suggest that it does not interfere with normal, everyday “ups and downs”, nor does it appear to reduce artistic creativity. On the contrary, many such individuals will affirm that they were able to become more productive and creative after their severe mood swings were brought under control.

I do want to emphasize that most patients who take antidepressant medication under careful medical supervision do not wind up feeling “flat” or unable to experience life’s normal ups and downs. Rather, they find that–in contrast to their periods of severe depression–they are able to enjoy life again, with all its joys and sorrows. (Some good descriptions of this may be found in my colleague, Dr. Richard Berlin’s book, “Poets on Prozac”).

Of course, we have not dealt with the importance of having a strong “therapeutic alliance” with a mental health professional, or the benefits of “talk therapy”, pastoral counseling, and other non-pharmacological approaches. I virtually never recommend that a depressed patient simply take an antidepressant–that is often a recipe for disaster, since it assumes that the person will not require counseling, support, guidance, and wisdom, all of which ought to be part of the recovery process. As I often say, “Medication is just a bridge between feeling awful and feeling better. You still need to move your legs and walk across that bridge!”

Therese J. Borchard writes the daily Beliefnet.com blog Beyond Blue (voted by Psych Central as one of the Top 10 Depression Blogs) and moderates Group Beyond Blue, the Beliefnet Community online support group for depression. Her memoir “Beyond Blue: Surviving Depression & Anxiety and Making the Most of Bad Genes” will be released in January of 2010. Subscribe to Beyond Blue here or visit her at www.ThereseBorchard.com.