What’s new: the roots of depression
Is SSRI therapy akin to bailing the water without plugging the leak?
by Barry Gilbert
Vol.18, No.03, March 2010

Our clinical experience with patients shows that we still lack a full understanding of the neurochemistry of depression. For example, the STAR*D trial found that only 60% of depressed patients responded to first-line treatment with the antidepressant citalopram, a serotonin reuptake inhibitor (SSRI). But if SSRIs increase serotonin at the neural synapse, and it’s a lack of available serotonin at the synapse that causes depression, how can this lack of response be explained?

Psychiatrists have long known that the evidence supporting the “monoamine theory of depression” is contradictory. This theory proposes that depression results from a lack of neuronal monoamines — mainly serotonin, norepinephrine and dopamine.

But new research out of Toronto complicates the issue (Arch Gen Psychiatry 2009; 66[12]:1304-12). Researchers used PET scans to examine the amount of monoamine oxidase A (MAO-A) in 9 brain regions. MAO-A is an enzyme concentrated on mitochondrial walls that metabolizes serotonin, norepinephrine and dopamine and that plays an important role in the chemistry of the brain. The higher the concentration of MAO-A, the more monoamines are metabolized, presumably reducing the amount available at the neural synapses.

The study looked at MAO-A levels in 3 groups: 28 non-depressed controls; 16 patients with a current depression and a history of previous depressions; and 18 patients with previous depression who were in remission for at least a year and who hadn’t taken
antidepressants for at least a year.

The patients with current depression had to have been free of antidepressants before starting the study. They were then scanned once for a baseline and a second time after being treated for 6 weeks with either citalopram to 40 mg/day or sertraline to 100 mg/day. The remission group were scanned and then followed for 6 months for possible recurrence of depression.

Monoamine theory vs MAOism

Depressed subjects had significant MAO-A elevations compared to controls in all brain areas examined. On repeat scans after 6 weeks’ SSRI treatment, MOA-A was found to remain elevated, both in non-responders and subjects in remission. Patients who had a history of depression and who were in remission at the outset of the study also showed significant elevations of brain MAO-A compared to the controls. Moreover, among these patients in remission, those who had significantly higher MAO-A levels in the prefrontal cortex and the anterior cingulated cortex went on to have a relapse in the next 6 months.

The authors conclude that persistent abnormalities in monoamine metabolism (i.e. elevated MAO-A levels) exist in depressed patients even after successful treatment with an SSRI and sustained remission. This offers a rationale, they suggest, for continuing treatment with an antidepressant long after the depression has cleared. Although the SSRI may restore levels of serotonin in the synaptic cleft, SSRIs fail to address this underlying disturbance that results in increased metabolism of serotonin and other monoamines.

Back to the future?

One of the authors has argued that these findings should encourage us to consider using monoamine oxidase inhibitor antidepressants when SSRI’s don’t work. The older MAOIs such as phenelzine are irreversible inhibitors and have complex dietary restrictions — foods and drink with too much tyramine can cause a life-threatening hypertensive reaction. The reversible MAOI moclobemide is safer and can be used with fewer dietary restrictions. It’s still more complicated to use than an SSRI, though it lacks SSRI sexual side effects. Early experience with moclobemide was often disappointing. Perhaps there is a subset of patients for whom this may be an effective antidepressant.

Finally, the investigators note that the finding of persistent MAO-A elevations in patients in sustained remission from depression suggests either a genetic trait or possibly an acquired “scar.” Future research may look for ways to intervene more directly in MAO-A function, which may address more directly the roots of depression.

Barry L. Gilbert, MD, CCFP, FRCPC is a psychiatrist, psychoanalyst and Assistant Professor of Psychiatry at the University of Toronto.

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