One of the great frustrations of patients and physicians alike is that the most commonly prescribed antidepressants, SSRIs, work only about half the time.

But a group of Canadian researchers has figured out why and proposed a solution for making treatment more effective - greater use of an older, cheaper form of antidepressants. Selective serotonin re-uptake inhibitors (SSRIs) work by raising levels of serotonin, a hormone that affects mood, and depression in particular.

Researchers at the Centre for Addiction and Mental Health in Toronto used sophisticated imaging techniques in the research.

They found that another protein in the brain, called monoamine oxidase A (MAO-A) can remain elevated even as patients take SSRIs and actually gobbles up serotonin.

"This helps explain why SSRIs don't always work," said Dr. Jeffrey Meyer, the Canada Research Chair in the neurochemistry of depression.

"It also helps explain why there are recurrences when patients stop their prescription," he said.

Dr. Meyer said he hopes the study will help patients and their treating physicians understand that it may take several months for SSRIs to work to keep serotonin levels high and so it is important to continue taking them, even if they start feeling better.

Dr. Meyer said that if SSRIs don't work, clinicians should consider moving quickly to prescribing a MAO-A inhibitor.

That class of drugs, popular in the 1970s and 1980s, fell out of favour because they had strange side effects and interactions with other medications. In particular, MAO-A inhibitors caused a condition called "cheese syndrome" - when patients consumed foods containing tyramine like cheese, wine and fava beans, it could provoke dangerously high blood pressure.

In his own practice, Dr. Meyer gets around that problem by prescribing a newer MAO-A inhibitor, Moclobemide, which clears the body quickly and does not have the side effects.

An added benefit of MAO-A inhibitors is that, unlike SSRIs, they do not cause sexual dysfunction and weight gain.

Last year in Canada, there were 22.6 million prescriptions for SSRIs, drugs best known under brand names like Prozac, Paxil and Zoloft (and largely sold now as generics). Total retail sales were $1.05-billion, according to IMS Health Canada, a private company that tracks prescription drug sales.

By comparison, there were only about 24,000 prescriptions for monoamine oxidase A inhibitors, with total sales of $1.3-million, according to IMS Health.

Dr. Meyer said he hopes the new findings will prompt drug companies to develop better forms of MAO-A inhibitors.

"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," he said.

The research, published in today's edition of the Archives of General Psychiatry, involved 28 patients who had recovered from clinical depression.

Their brains were examined using a positron emission tomography machine, which allowed precise measurement of levels of MAO-A. Some of the study subjects 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. Those with low levels of MAO-A did not have recurrence of depression.

Dr. Bruce Pollock, vice-president of research at CAMH, said that the centre is the only one in the world that has a PET-scanner dedicated solely to mental health and addiction treatment and research.

About one in five Canadians will suffer from clinical depression. There is a high level of recurrence.