Most Antidepressants Miss Key Target of Clinical Depression

Way back in what now seems like the dark ages of depression medications, the most effective and widely used drugs were MAOIs, or monoamine oxidase inhibitors. The MAOIs have some serious risks for those who do not avoid certain foods in their diets:

When ingested orally, MAOIs inhibit the catabolism of dietary amines. When foods containing tyramine are consumed (so-called "cheese syndrome"), the individual may suffer from hypertensive crisis. If foods containing tryptophan are consumed, hyperserotonemia may result. The amount required to cause a reaction varies greatly from individual to individual, and depends on the degree of inhibition, which in turn depends on dosage and selectivity.

The exact mechanism by which tyramine causes a hypertensive reaction is not well understood, but it is assumed that tyramine displaces norepinephrine from the storage vesicles.^[4] This may trigger a cascade in which excessive amounts of norepinephrine can lead to a hypertensive crisis. Another theory suggests that proliferation and accumulation of catecholamines causes hypertensive crises.

Here is an explanation of how the MAOIs work, from the Mayo Clinic:

How MAOIs work

Researchers believe MAOIs relieve depression by preventing the enzyme monoamine oxidase from metabolizing the neurotransmitters norepinephrine (nor-ep-ih-NEF-rin), serotonin (ser-oh-TOE-nin) and dopamine (DOE-puh-mene) in the brain. As a result, these levels remain high in the brain, boosting mood.

Antidepressants, in general, may also work by playing a neuroprotective role in how they relieve anxiety and depression. It's thought that antidepressants may increase the effects of brain receptors that help nerve cells keep sensitivity to glutamate — an organic compound of a nonessential amino acid — in check. This increased support of nerve cells decreases glutamate sensitivity, providing protection against the glutamate overwhelming and exciting key brain areas related to anxiety and depression.

Therapeutic effects of antidepressants may vary in people, due in part to each person's genetic makeup. It's thought that people's sensitivity to antidepressant effects, especially selective serotonin reuptake inhibitor effects, can vary depending on:

• How each person's serotonin reuptake receptor function works
• His or her alleles — the parts of chromosomes that determine inherited characteristics, such as height and hair color, that combine to make each person unique

Antidepressant medications are often the first treatment choice for adults with moderate or severe depression, sometimes along with psychotherapy. Although antidepressants may not cure depression, they can help you achieve remission — the disappearance or nearly complete reduction of depression symptoms.

Because of the risks involved with these drugs, and based on the unsupported assumption that serotonin is the most important neurotransmitter in depression, the selective serotonin reuptake inhibitors (SSRI) were developed to address this element of brain chemistry. They do not work for many people, and sometimes figuring out which one might work takes several trials. They do have fewer severe risks, but as many or more overall side effects, most notably weight gain (they interfere with glucose metabolism, i.e., cause diabetes in some people) and loss of sexual desire/function.

Turns out, according to this new study, that they really are only making us stoned on serotonin, not addressing the real issues of depression in our brain chemistry.

It seems the original idea, that the MAO inhibitors address the neuro-chemistry of depression, if we can make them safer.

Most Antidepressants Miss Key Target of Clinical Depression, Study Finds

ScienceDaily (Dec. 8, 2009) — A key brain protein called monoamine oxidase A (MAO-A) -- is highly elevated during clinical depression yet is unaffected by treatment with commonly used antidepressants, according to an important study published in the Archives of General Psychiatry. The study has important implications for our understanding of 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 per cent 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 per cent 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."

Virginia Wilson knows first-hand the struggle it can be to find effective medication. After being diagnosed with depression, eight years passed before a medication was developed that worked well for her. "During this time I was on every type of antidepressant available. This process was enormously frustrating, painful -- and took a great toll on my personal life." The current research into depression gives Virginia hope for others who struggle as she did. "Understanding of the biochemical mechanisms behind depression is so important and can really improve the treatments that are available -- it can save lives."

Some early antidepressant medications did target MAO-A, but these MAO-A inhibitors fell out of favour in the 1970s due to adverse interactions with certain foods. There have been advances that overcome these problems, but the vast majority of antidepressant development and use has overlooked the MAO-A target.

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."

~ Dr. Meyer is a Canada Research Chair in the Neurochemistry of Depression and the Head of the Neurochemical Imaging Program in Mood Disorders. The study was funded by the Canadian Institutes of Health Research, the Ontario Mental Health Foundation, and the Canadian Foundation for Innovation.

Journal Reference:

1. Meyer et al. Brain Monoamine Oxidase A Binding in Major Depressive Disorder: Relationship to Selective Serotonin Reuptake Inhibitor Treatment, Recovery, and Recurrence. Archives of General Psychiatry, 2009; 66 (12): 1304 DOI: 10.1001/archgenpsychiatry.2009.156

Tags: depression, drugs, medicine, Most Antidepressants Miss Key Target of Clinical Depression, MAOI, SSRI, monoamine oxidase inhibitors, Science Daily, monoamine oxidase, serotonin, selective serotonin reuptake inhibitors