Neuroimaging in Depression: One Pathological Biomarker at a Time

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By: Jeffrey H. Meyer, MD, PhD, FRCPC, & Yekta Dowlati, BSc, MSc

According to the World Health Organization, clinical depression is currently the leading cause of death and disability in moderate- to high-income nations and will be the leading cause of death and disability worldwide by 2030.(1,2) Clearly it is imperative that we increase our ability to prevent this illness and improve its treatment to avoid this concerning prediction. One approach towards understanding this illness at a biological level is to identify its fundamental changes in order to develop better strategies for prevention and treatment, just like any other medical illness.

On the surface, this may sound overly challenging. It is sometimes said that there are no defining biological markers of clinical depression; however, the evidence accumulated suggests otherwise. There are a number of influential changes in the brain in clinical depression, such as reduced volume of the hippocampal memory structures of the brain, reduced levels of supporting type cells called glial cells, suboptimal levels of cellular signalling molecules, greater vulnerability of brain cells towards dying, and changes in chemical binding sites and enzymes reflecting deficiencies in levels of mood controlling chemicals called monoamines.(3-6) These differences each represent important pathological biomarkers, meaning they are abnormal changes implicated in either initiating or perpetuating symptoms of this disease. The complicated issue is that it is becoming increasingly evident that several changes are required to tip the balance from health to clinical depression.

Another challenging issue pertains to the idea of control: since mood is something that is controllable through personal will and effort in health, should this not also be possible in illness? Unfortunately, the “snap out of it” or “pull yourself up by the bootstraps” approaches alone are not helpful as spontaneous remissions are infrequent and they tend to occur only early in the course of clinical depression. On the other hand, therapies from psychological models have been successful. Such models can, and should, be integrated into a broad biological understanding, including key markers of pathology. Even so, most clinicians and researchers recognize that only a subset of those with clinical depression are likely to benefit from therapy; our biological understanding, therefore, remains vital.

In this article, we demonstrate the approach of investigating important biomarkers of pathology, primarily through brain imaging monoamine oxidase A (MAO-A) density in people with clinical depression and depressed mood states. MAO-A is a protein in the brain with several important functions. One of these functions is to metabolize monoamine brain chemicals such as serotonin, norepinephrine, and dopamine. Depletion of these chemicals can induce sad mood and this was originally demonstrated in the 1950s when an antihypertensive medication called reserpine was developed that depleted these monoamines. People taking reserpine would sometimes develop a side effect of clinical depression, which, upon stopping the medication, often resolved.7 Another function of MAO-A is to create oxidative stress through the creation of hydrogen peroxide. Also, brain cells can make more MAO-A at times as a tool to bring such cells towards death. While we investigate MAO-A throughout the brain, our key interest is in the regions active in generating sad mood states and psychological symptoms of pessimism (i.e. the prefrontal cortex and anterior cingulate cortex).

Are MAO-A levels different in clinical depression? In 2006, we led the first investigation of MAO-A levels in early onset clinical depression (before age of 40 years). We discovered that the concentration of MAO-A in clinically depressed patients was elevated by about 35% in comparison to healthy individuals.(7) We chose early onset clinical depression because it is the most common type of depression and it is the type of depression usually induced by chronic stress, which had been implicated in raising MAO-A levels.  Previous studies, which were negative, focused on late onset depression—which can be common to a variety of conditions such as Parkinson’s disease, Alzheimer’s disease, and strokes—while the question of an abnormal rise of MAO-A in early onset depression had been overlooked. We subsequently replicated our finding in a separate sample in 2009.(9) In 2011, an independent laboratory reported similar elevated MAO-A levels and activity in a post-mortem study of the prefrontal cortex, with a 40% difference between clinical depression and health.(10)

How do MAO-A levels relate to the state of clinical depression? Clinical depression is characterized by repeated episodes of major depression with variable levels of interepisode recovery. We have found that MAO-A levels often remain elevated even during recovery, and their elevation is associated with recurrence of a subsequent depressive episode.(9) Unfortunately, the most commonly prescribed antidepressants, such as the Prozac-like selective serotonin reuptake inhibitors (SSRIs), do not target MAO-A.(9,10) There is a partial match between this abnormality of elevated MAO-A and SSRI treatment: MAO-A breaks down serotonin, and SSRIs counter this in part by raising serotonin where brain cells communicate with each other. However, MAO-A also creates oxidative stress, participates in apoptosis (programmed cell death), and breaks down other brain chemicals. We hypothesize that this mismatch may contribute to the inadequate response to treatment seen in 40% of people treated with SSRIs.(9,10) Also, given the association of high levels of MAO-A with recurrence, we think this mismatch contributes to the high recurrence rates of 20% to 50% seen over 2 years with SSRI treatment in clinical settings. SSRIs are known to normalize some important pathological targets such as abnormal signalling in cells,(11) but they do not normalize MAO-A levels.

How does our environment influence MAO-A levels? We have identified several high risk states for depression, such as postpartum depression and heavy cigarette smoking. These are associated with elevated MAO-A levels, particularly in the brain structures that influence mood generation and pessimism. In 2009, it was discovered that estrogen decline is associated with greater MAO-A levels in cell lines and in rodents, but MAO-A had never been studied in early postpartum in any species. Estrogen levels drop over 100 fold during the first few days postpartum. In 2010, we discovered that MAO-A levels are elevated tremendously during days 4 to 6 postpartum, by an average of 43%. This is a time-point of healthy range “baby blues” (a brief mood disturbance and mild depressive state linked to child birth, occurring in nearly 84% of women during the first week after delivery) for which the degree of sad mood is predictive of the likelihood for later clinical depression.(12) Postpartum depression is the most common complication of childbearing with a 13% prevalence rate.(13) In 2011, we discovered that heavy cigarette smoking, a strong risk factor for the onset of clinical depression and depressed mood, is also associated with greater MAO-A levels in mood-controlling brain regions.(14) It is becoming clear that our environment can temporarily lead to brain changes resembling the pathologies found in clinical depression.

What can we do about elevated MAO-A levels? Our research targets three main areas for implementation. The first area that we are studying is how to reduce and/or reverse the elevation in MAO-A levels as a consequence of exposure to stress, estrogen, and toxic substances (e.g. cigarette smoke). Secondly, for situations where the elevation in MAO-A level is temporarily high (e.g. early postpartum), we are developing strategies to compensate for elevated MAO-A levels. An example of a targeted strategy includes the ingestion of dietary supplements containing the building blocks of the chemicals removed by MAO-A that might prevent the onset of postpartum depression. Thirdly, we are advancing our imaging technique to facilitate the development of antidepressants that specifically target MAO-A for depression that is resistant to traditional treatment options. We are hopeful that a step-by-step approach of preventing, compensating, and reversing key biomarkers of pathology will yield improved strategies for reducing the burden of clinical depression.

Jeffrey H. Meyer, MD, PhD, FRCPC
Canada Research Chair, Neurochemistry of Major Depressive Disorder
Centre for Addiction and Mental Health
Department of Psychiatry,
University of Toronto

Yekta Dowlati, BSc, MSc
PhD Candidate,
Institute of Medical Science

References

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  2. Murray CJL, Lopez AD. The Global Burden of Disease: A Comprehensive Assessment of Mortality and Disability from Diseases, Injuries and Risk Factors in 1990 and Projected to 2020.  Geneva, Switzerland; World Health Organization, 1996.

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  8. Meyer JH, Ginovart N, Boovariwala A, et al.: Elevated monoamine oxidase a levels in the brain: an explanation for the monoamine imbalance of major depression. Arch Gen Psychiatry 2006; 63[11]: 1209-16.

  9. Meyer JH, Wilson AA, Sagrati S, et al.: Brain monoamine oxidase A binding in major depressive disorder: relationship to selective serotonin reuptake inhibitor treatment, recovery, and recurrence. Arch Gen Psychiatry 2009; 66[12]: 1304-12.

  10. Johnson S, Stockmeier CA, Meyer JH, et al.: The reduction of R1, a novel repressor protein for monoamine oxidase A, in major depressive disorder. Neuropsychopharmacology; 36[10]: 2139-48.

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  13. O’Hara MW, Swain AM: Rates and risk of postpartum depression: a meta analysis. International review of psychiatry 1996; 8: 37-54.

  14. Bacher I, Houle S, Xu X, et al.: Monoamine oxidase A binding in the prefrontal and anterior cingulate cortices during acute withdrawal from heavy cigarette smoking. Arch Gen Psychiatry; 68[8]: 817-26.