Dr. Grossi's Blog
Where are we going in terms of understanding the causes and treatment of depression? It may be instructive to start by looking at where we have been. Literary references abound. The Iliad written almost 3000 years ago describes Achilles grief reaction to the death of Patroceles which, had it continued, would have been a depression. Shakespeare's portrayal of Hamlet, the depressed Dane, in words such "How weary, stale, flat, and unprofitable seem to me all the uses of this world" is a good example. (Shakespeare had words for everything, often the best words.) In the mid 1980s William Styron produced a beautiful description of depression in the short book, Darkness Visible.
Emil Kraepelin, the father of modern psychiatry, divided psychotic disorders into those whose core disturbance was either one of cognition or one of mood. In modern terminology those disturbances of cognition are the schizophrenias and those of mood are bipolar disorders or recurrent major depressive disorders. The schizophrenias are found in about 1% of all populations around the world and the mood disorders have a prevalence of about 5%. These are both causes of major disability in the age group 15 to 45 years of age.
In 1928 Mary Hare (later Mary Bernheim), a young biochemistry graduate student at Cambridge, discovered an enzyme in liver cells which she named tyramine hydroxylase. About ten years later Ernst Zeller renamed the enzyme monoamine oxidase after demonstrating its activity on other monoamines. In 1952 two drugs, isoniazid and iproniazid, made their way to the United States to be used in treatment trials for tuberculosis. During those trials the investigators noticed that the patients became "energized", "inappropriately happy", and even "discipline problems". After several years of investigation, it was discovered that these drugs worked by inhibiting monoamine oxidase.
These findings led to the monoamine hypothesis of depresssion as described in a 1965 paper by Joseph Schildkraut. He contended that low levels of neurotransmitters were associated with depression. This also led to more investigations of the serotonin and norepinephrine pathways in the brain. They were found to arise in the brain stem and branch out or arborize up to the cortex, the most developed part of the brain. The focus was mostly on the modulating influence of these neurotransmitters and the focus was largely on the synapse. This theory and the following research underpinned the research by pharmaceutical companies that eventuated in the development and marketing of SSRIs, SNRIs, and NDRI antidepressants in the late 1980s and early 1990s.
In the early 1990s a new tool emerged to study neural activity. This was the fMRI, which measures and locates brain activity by changes in blood flow. Investigations of depressed people using this tool revealed that dysfunction in depression was not localized in one brain area but many areas dysfunctionally working, some overactive, others under-active. In turn this led to the idea that depression is a disorder of circuits. Helen Mayberg and her group discovered that a small area deep in the frontal lobe called the subcallosal cingulate (or area 25) was the negative mood regulator. This area was tightly connected to the amygdala, an almond-shaped brain structure which is involved in the processing of emotional, stressful, or novel stimuli. Also in this circuit is the hypothalmus, hippocampus, insula, and the prefrontal cortex. The hypothalmus regulates drives such as libido, appetite, and sleep; the hippocampus, which houses memory, provides a context for the area 25 presentation. The insula makes us internally aware, and finally the prefrontal cortex systhesizes and plans what action to take, if any. The point is that there is a complex set of interactions between all these areas and that depression influences those interactions by influencing many parts of the circuit.
Some recent work built on the above findings was done by Jeffrey Meyer and colleagues using a different technique. They used harmine labeled with carbon 11 selective for MAO-A and a PET scan was used to measure the MAO-A specific distribution volume which is an indication of MAO-A density in different brain regions. In their 2006 paper they found that depressed individuals had higher MAO-A density in the prefrontal cortex, temoral cortex, anterior cingulate cortex, posterior cingulate cortex, thalmus, caudate, hippocampus and midbrain. This led to the conclusion that elevated MAO-A density is the primary monoamine lowering process during major depression. in their 2009 paper they wanted to determine whether MAO-A levels in the brain are elevated in patients who have recovered and go on to have a recurrence. They found that subjects with major depressive disorder in recovery but with subsequent recurrence had significantly higher regional MAO-A density in all brain regions than healthy participants.
The most important point to be made is that the circuits of mood disorders are being revealed and many clues are present to unravel this problem in some reasonable time frame. The same cannot be said for the primarily cognitive disorders such as schizophrenia. Dealing with that problem will be a very long slog indeed.