Nearly half of all clinically depressed patients fail to respond to available antidepressant medications (1). Though antidepressants are effective for some depressed patients, this selective efficacy is still not fully understood. Professor Poul Videbech, a specialist at the Centre for Psychiatric Research at Aarhus University Hospital, has dedicated himself to researching the effects of depression to better understand the mechanism of antidepressants. (2)
In one project, Videbech scanned the brains of depressed patients to observe structural effects of the disorder. Videbech concluded, “My review shows that a depression leaves its mark on the brain as it results in a ten percent reduction of the hippocampus… In some cases this reduction continues when the depression itself is over” (2). Videbech believes that nerve reduction supports the neurogenesis theory of depression which posits that depression results in a cessation of neuron birth in the brain (3). Support for this theory lies in the fact that, with extended use, antidepressants trigger neurogenesis by initiating the birth of new nerve cells. Studies at the Centre for Psychiatric Research, where patients suffering from depression were followed for ten years using brain scans, demonstrate that shrinking of the hippocampus is reversible when depressed patients are treated.
People not suffering from depression have a balance in degradation and regeneration processes in the brain. The degradation process refers to the breaking down of nerve cells, while regeneration refers to the formation of nerve cells (1). Depressed patients show greater activity in the degradation system, which explains Videbech’s findings that brain structures are reduced in patients with depression. The location of reduction cited by Videbech is the hippocampus, the structure of the brain responsible for the storage and retrieval of memories. Hippocampal reduction explains the common symptom of memory problems in patients with depression. With antidepressant use, and hence a return of neurogenesis, memory problems and depressive symptoms are reduced. Meaning, boosting neurogenesis results in a returned balance between the degradation and regeneration processes. (2)
The most common form of antidepressants, serotonin reuptake inhibitors (SSRIs), were believed to have their effect by boosting levels of serotonin in the brain. However, scientists have proven that SSRIs take about a month to improve mood in depressed patients. This delay in treatment suggests that another process, one influenced by serotonin, is involved. The neurogenesis theory of depression explains that the delay in mood improvement is a result of the minimal effect serotonin has on neurogenesis. Researchers have turned their focus to chemicals in the brain that promote neurogenesis and suggest that new treatments targeting said chemicals could be a more logical and effective treatment for depression. (1)
The neurogenesis theory has been supported with animal studies. In one trial, researchers induced a depression-like condition in mice so they develop a depressive behavioral pattern. The mice were then given antidepressants and normal behavior returned. Then, when the mice were subjected to radiation treatment, a process known to terminate the formation of new nerve cells, the antidepressants stopped working and the mice returned to their depressed behaviors (1). Videbech cites this study as proof that antidepressants are only effective because of their influence on neurogenesis and when that influence is eliminated, antidepressants no longer improve depressive symptoms (2).
A recent article in Nature Medicine cites a promising new line of research in the ceramide system. In one study, after mice took Prozac-like antidepressants the levels of ceramide, a fat molecule in the brain, significantly decreased. In the brain, ceramide blocks brain cell growth. Meaning, Prozac affected ceramide levels which in turn increased neurogenesis. Scientists believe that further research on molecules like ceramide will continue, and eventually result in, more direct and effective antidepressant treatments. (4)
1. A. Maxmen, Psychol. Today. 64, 39-40 (2013).
2. S. Hildebrandt, Depression Can Damage the Brain (2011). Available at http://sciencenordic.com/depression-can-damage-brain (19 December 2013).
3. I. Dell, Depression: Neurogenesis and Depression (2010). Available at http://sites.lafayette.edu/neur401-sp10/applications-in-health-and-medicine/depression/ (19 December 2013).
4. E. Gulbins et al, Nat. Med. 19, 934-938 (2013).