Biological/physical treatments of depression offer the magical promise of a quick fix, but here, too, evolution has followed an experimental and sometimes cruel path. In the 1930s, electro-convulsive therapy was introduced as a treatment for severe depression. Crude methods and abuses produced bone fractures, memory loss, and severe brain damage in some patients. In 1936 Dr. Egas Moniz, a Portuguese neurosurgeon, invented the frontal lobotomy, a procedure in which he used a special wire knife to sever white fibres connecting the frontal lobes to the rest of the brain. An American neurologist modified this into a quicker, cruder, and more gruesome procedure, known as the “ice-pick” lobotomy. Frontal lobotomies resulted in zombie-like patients. In the 1940s and 1950s more than 50,000 Americans with mental illness were subjected to lobotomies, with no solid evidence of any benefits.
The 1950s saw a revolution in the biological treatment of depression with the introduction of the first effective antidepressant drugs. A drug called Imipramine was tried as a treatment for hay fever, Parkinson’s disease, andthen schizophrenia. Imipramine didn’t control schizophrenia, but it brightened the mood of patients and became the first of the tricyclic class of antidepressants that are still used today. Similarly, Iproniazid, developed to treat tuberculosis, became the first of a second class of antidepressants known as monoamine oxidase inhibitors. As our understanding of depression advanced, a third generation of antidepressants, the most famous of which is Prozac, was developed more purposefully. The first SSRI (Selective Serotonin Re-Uptake Inhibitor) was a compound that boosted the brain chemical serotonin. The big advantage of Prozac, launched in 1987, was that it had fewer side effects than other antidepressants. The commercial success of Prozac spawned newer SSRIs like Paxil, Zoloft, and Celexa, and now there are dozens of antidepressants to choose from in a variety of categories.
But we still don’t know why antidepressants work for some people and not for others. Studies show that cognitive behaviour therapy and antidepressants are about equally effective, helping only about fifty percent of depressed patients. But no one knows for sure who should get drugs or talk therapy, or what drug to try first. For a depressed person seeking the best remedy, there is no clear, objective yardstick to guide the choice of treatment. “The big bugaboo of psychiatry is that there is no reliable, measurable, objective way to accurately predict how someone will do on a particular treatment,” says Mayberg. “In psychiatry, and in depression, there are those who think everyone should get drugs and in another camp there are those that think no one should get drugs. We don’t do this in any other field of medicine. With a heart attack we don’t flip a coin to see whether you are treated with bed rest or a bypass. We have evidence-based rules based on tests like an angiogram. My hope is that in the future we will diagnose and make treatment plans for depression based on the organ that’s injured – the brain.”
Dr. Helen Mayberg did not plan to devote her scientific career to the study of depression. Although she majored in psychobiology as a UCLA undergrad and was fascinated by her encounters with psychiatric patients as a medical student at the University of Southern California in the late 1970s, she chose to pursue a career in neurology. “The problem of mental illness fascinated me,” she says, “but the process of diagnosing and treating mental-health problems was fuzzy. I felt that something important was missing. Neurology is very unfuzzy; I liked the order and objectivity of it. There were rules you could apply. In psychiatry, certain rules might seem to apply, but there wasn’t a known map of the brain to guide you. Psychiatry didn’t have an evidence-based playbook.”
In 1982, Mayberg moved from her native southern California to train at the Neurological Institute of New York at Columbia University. There, she began to notice that a significant number of neurological patients, particularly stroke victims and those with Parkinson’s disease, experienced severe depression as secondary symptoms, though not all of them were depressed. Was there a neurological explanation, a pattern of damage to specific areas of the brain – a problem with the wiring – that could explain why some patients were depressed and others were not? Neither the research literature, nor New York’s top neurologists, could provide an answer.
One notable exception was a 1984study of post-stroke depression by a psychiatrist, Bob Robinson, at Johns Hopkins University. From CT brain scans, Robinson observed that depression was more common in patients with damage to the left frontal lobe. His finding piqued Mayberg’s interest because it suggested that the location of the lesion — the break in the wiring — was somehow implicated in neurological depression. “It was clear that depression involved more than just the lesion. The question was how did the lesion affect the rest of the brain to cause depression?”
Classical neurologists had to make inferences about how neurological diseases affect brain function by observing a patient’s behaviour and symptoms, and interpreting those clues based on their textbook knowledge and clinical experience. They couldn’t open up a living person’s brain to see how a disease changed the way the whole brain worked. The development of PET-scan technology in the 1970s changed that. It allowed neurologists and brain researchers to observe directly how neurological disorders, like stroke, epilepsy, and Parkinson’s disease, affect brain function and behaviour. (Other imaging technologies, such as X-rays, CT, and MRI scans, show how disease affects the structure of the brain but not how the brain works.)
Mayberg was so excited by the promise of this new scanning technology that in 1985 she took a research position at the Johns Hopkins University School of Medicine PET facility in Baltimore, where she learned how to use PET as a research tool. She used her newfound expertise to help Bob Robinson use PET scans on depressed stroke patients in search of a pattern of abnormal brain activity in stroke patients that would, neurologically speaking, distinguish depressed from non-depressed patients. But stroke patients weren’t ideal subjects because stroke damages different parts of the brain in different people and symptoms vary greatly, making it hard to find enough well-matched patients to do meaning comparisons.
Mayberg thought that Parkinson’s disease would serve as a better research model because all patients share a common pattern of disease affecting the basal ganglia (structures deep in the brain associated with feelings and movement). Sergio Starkstein, an Argentine neurologist at Hopkins, provided her with a large group of depressed and non-depressed Parkinson’s patients to study. In depressed patients the PET scans showed a striking pattern of reduced brain activity in the paralimbic regions of the frontal lobe that was not seen in the non-depressed patients.
(The paralimbic regions are in a lower portion of the cerebral cortex that surrounds the limbic system. The cortex is the outer layer of the brain associated with thinking; the limbic system is the emotional centre located deep inside the brain.) The pattern of reduced paralimbic activity suggested a disruption of the circuit connecting the basal ganglia and lower regions of the frontal lobe, a break in the wiring affecting regulation of mood.
