The monoamine hypothesis is extremely persistent, possibly partly due to the fact that monoamines are extremely profitable for pharmaceutical companies. However, numerous studies suggest that the lack of secondary messenger substances such as serotonin might not after all be the biological basis of depression. Research carried out by Dr. Claus Normann and his team at the Freiburg University Medical Centre add to the increasing evidence relating to what is misregulated in the brains of people suffering from depression. Dr. Normann and his team found that the plasticity of the brain is the major cause of depression. This finding is in line with clinical findings and also has a molecular basis, which could potentially be manipulated to help sufferers, although not in the foreseeable future.
Cautious estimates hold that about ten per cent of all women and five per cent of all men suffer from depression during their lifetime. Every year, around eleven thousand people in Germany take their lives as a result of depression; this is a far higher number than the deaths occuring as a result of AIDs, traffic accidents and murder taken together. Experts believe that the disease and its myriad consequences including the inability to work and the high cost of treatment lead to greater economic problems than cancer or cardiac diseases. However, depression is difficult to treat, and antidepressants only lead to a complete remission in about 30 per cent of all patients. There is a huge need to optimise the drugs. But in order to do so, scientists must find out how the drugs work.
The beneficial effect of antidepressants was discovered quite by accident. “Research carried out following this discovery found that antidepressants raise the level of the monoamine serotonin in the brain,” said Dr. Claus Normann of the Department of Psychiatry and Psychotherapy at the Freiburg University Medical Centre. “Many people still believe that a deficiency in this neurotransmitter is the cause of depression. But this is most likely not the case.” The researchers found that when they induce an artificial serotonin deficiency, it does not result in depression. And even if the lack of serotonin did play a role, its effect on the molecular level still remains unclear. This is why a growing number of researchers are looking for alternative approaches.Normann and his team are working on one such alternative. The basic idea is that the synaptic plasticity is disturbed in depressive people – stimuli that would normally lead to permanent changes in the behaviour of synapses and entire circuits are not longer sufficiently effective. The result: the brain can no longer learn. According to this theory, antidepressants are able to at least partially reverse the damage. According to clinical studies, such major stimuli may be losing one’s job, divorce or the death of a child. The depressive brain is then no longer able to adapt correctly.
Neurobiological investigations suggest that this hypothesis could be correct. A permanent reduction in the ability of synapses to transmit stimuli was observed in rats that had been exposed to mild stress stimuli over a period of several weeks - a phenomenon referred to as long-term depression (LTD). LTD is assumed to be due to the fact that certain calcium ion channels alter their conductibility under stress, resulting in a reduction of the electric current at the synapses.
"Permanently stressed animals are excellent models of human depression," said Normann. "They reveal many identical symptoms: they move around less, are less sexually active and eat less." Normann and his team took their experiments even further: they administered the animals antidepressants and found that LTD decreased. "This supports the hypothesis that depression is a disorder of the functional plasticity of the neural circuits and that antidepressants are able to restore this plasticity," said the researcher.
The Freiburg researchers also used brain sections to investigate the correlation between the effect of antidepressants and the restoration of brain plasticity. Electrodes were used to stimulate neurons with physiologically plausible stimuli which normally (during learning for example) trigger plastic processes. Such stimuli, which should normally lead to an attenuation of synaptic transmission, became ineffective when the experimental animals were given antidepressants. The reason for this was that the antidepressant had an effect on the calcium channels. A disorder in these channels might therefore be one of several molecular bases of depression.
At present, Normann and his colleagues are investigating the plasticity hypothesis on humans. Working with the team at Prof. Dr. Michael Bach's laboratory at the Freiburg University Medical Centre, they are currently investigating so-called visually evoked potentials (VEPs) in healthy and depressive patients.
VEPs are electrical signals of the brain's visual centre that are generated when the volunteers perceive optical patterns. The researchers from Freiburg presented the volunteers rapidly changing checker-board patterns. This type of eye and optic nerve stimulation corresponds to experimental stimuli series which can lead to long-term alterations on synapses and hence plasticity in brain sections. "The VEPs of our healthy volunteers revealed complex plastic alterations," said Normann. "These changes were largely found to be the opposite in depressive patients." Where a permanent increase in electrical transmission occurred in healthy volunteers, exactly the opposite was true for sick people, and vice versa.
In the future, Norman and his colleagues have plans to investigate these relationships on the behavioural level as well. They want to find out whether there is a correlation between the defective plasticity in depressed people and their ability to learn, such as has been suggested by clinical observations of people suffering from depressive pseudodementia. The researchers will use special learning tests that will require volunteers to remember word pairs or focus on simple conditioning. Since brain plasticity has a molecular basis, experiments carried out by Normann and his team will also sometime in the distant future contribute to the medical treatment of synapses of those suffering from depression. The plasticity hypothesis is currently no more than a hypothesis, and further research is necessary to confirm or refute it.
Further information:Dr. Claus NormannChief PhysicianFreiburg University Medical CentreDept. of Psychiatry and Psychotherapy79104 FreiburgTel.: +49 (0)761/270-6634Fax: +49 (0)761/270-6619E-mail: claus.normann(at)uniklinik-freiburg.de