Frodl, T., Koutsouleris, N., Bottlender, R., Born, C., Jager, M, Morgenthaler, M., et al. (2008). "Reduced gray matter brain volumes are associated wtih variants of the serotonin transporter gene in major depression." Molecular Psychiatry, 1, 1093-1101.
Introduction
Major depression is suspected to be caused by an imbalance in neuronal serotonin level, and many studies have demonstrated this relationship. The serotonergic system and brian derived neurotrophic factor (BDNF) have been seen to reciprocally regulate one another, and together are responsible for early CNS development, as well as hippocampal neurogenesis in adults. Evidence of low serotonin levels in patients suffering from major depression have led Frodl et al. to suspect that dysfunctional neuronal plasticity is a major contributor to the psychopathology of mood disorders like depression. Recent studies have shown patients suffering from major depression to have generally reduced hypocampus volumes, but the manual measuring techniques used in those studies give inconsistent results for brain regions without an obvious morphologically defined border.
In addition, there have been three allelic polymorphisms (triallelic polymorphism) of the 5-HTTLPR gene responsible for encoding components of the serotonergic system; S-allele (normal), and L-allele (subtypes La and Lg) showing increased 5-HHT expression and increased 5-HT reuptake. Lg subtypes have been seen to have the same 5-HT reuptake efficiency as S-allelic individuals, therefore they have been grouped in this experiment as ‘equal’ to the S-allele. Therefore, this triallelic polymorphism is expressed as homozygous = SS/LgLg/LgS and heterozygous = LaS or LaLg.
In this experiment, Frodl et al. use Voxel-based morphology (VBM) to clearly measure the gray matter volumes from magnetic resonance images in mulitple brain regions of patients with different genotypes in the 5-HTTLPR gene, to see if patients suffering from major depression and who are homozygous for the L-allele have reduced brain gray matter in the regions explored.
Methods
Population:
N=77
middle aged inpatients suffering from major depression, diagnosed using criteria outlined in the DSM-IV. During this experiment, patients taking antidepressants (Selective serotonin reuptake inhibitors [SSRIs], tricyclic antidepressants, and others) continued taking their antidepressants as suggested by their physician.
77 healthy individuals were also analyzed, and served as a control comparison group.
Gray matter volume data was obtained using magnetic resonance imaging.
Brain regions analyzed:
- Hippocampus
- Amygdale
- Anterior gyrus cinguli (ACC)
- Dorsolateral prefrontal cortex (DLPFC)
- Dorsomedial prefrontal cortex (DMPFC)
Comparison of whole-brain gray matter volumes between control and experimental groups were tested for significant difference at a tolerance for Type 1 error of 5%. Voxel-based morphology data comparisons between the control and experimental group for each brain region of interest was tested for significant difference, at tolerance for Type 1 error of 10%.
Results & Conclusions:
In the healthy control group, there was a strong association between 5-HTTLPR polymorphism and GMVs in all investigated brain regions
5-HTTLPR contributes to brain structure development
Smallest gray matter volumes found in healthy group were of those individuals homozygous for S allele. This difference in gray matter volume was observed in all brain regions analyzed.
Reduction in gray matter volumes of S homozygous individuals of the patient group were only seen in the subregions of the hippocampus.
La homozygous patients, relative to La homozygous healthy controls show the largest volume reduction in cortical brain regions, as well as the amygdale and interior hippocampus.
Figure 1: Magnetic Resonance Images of gray matter in patients in relation to control groups, measured on a scale of density. See colour legend at bottom left of figure for density reduction scores.
Overall, the greatest gray matter volume alteration (difference between control and depressed patient) was seen in individuals homozygous for La.
Homozygous La individuals have higher expression of serotonin transporter (5-HTT) and therefore lower synapse serotonin levels. Since the serotonergic system upregulates the expression of BDNF (through upregulation of cAMP), patients with lower serotonin levels may be more vulnerable to abnormal hippocampal neurogenesis.
It is therefore likely that decrease in serotonin levels, induced by those factors contributing to depression, may cause serotonin levels to drop so severely that structural changes result in the brain. These individuals could therefore be more at risk for development of major depression.
Problems with this experiment:
The sample sizes were relatively small; larger sample sizes would have allowed Frodl et al to draw more specific conclusions.
There is too much variation with the experimental group (patients suffering from depression). Patients are on different medications, and have grown up in different environments.
Antidepressants inhibit serotonin reuptake, therefore increasing overall serotonin in the neuronal synapses. Since increasing serotonin levels in the brain helps stimulate cell growth and propogation in brain regions like the hypothalamus, patients taking antidepressants may not represent the morphological phenotype (ie: gray matter volume) that is true to the genotype. . Frodl et al, however do recognize these additional variables and suggest that further studies should be designed to explore the interactions of these variables.
Comments/Critique:
This paper was commendable because it focused on the interaction between biological factors and psychological factors in order to explain their results. Frodl’s hypothesis was of interest, because if his hypothesis holds true, it could help define a biological marker for the diagnosis of depression, or the risk in an individual to develop depression. Many researchers have attempted to explain depression through biological causal agents and therefore have designed their statistical models to include only biologically based explanatory variables. Since depression is an illness affecting the human mind, designing experiments while ignoring the complex nature of depression due to the interaction of biological agents with psychological factors renders these experiments weak.
In terms of the paper’s presentation of the results, the figures gave a good, comprehensive presentation of the MRI images taken. They underwent very thorough analysis of the data, and presented the key aspects of their statistical analysis in ANOVA tables, which allows for the public to confirm the validity of their conclusions. The positioning of the tables in the article is slightly awkward, because a few of them are located in the discussion section.
Hopefully Frodl et al. will conduct further experiments of similar nature with the addition that patients be selected to have similar life histories (if possible) or at least be taking the same type of antidepressant (or none at all, if possible).
To access this journal article through NCBI (PubMed), please visit the following link:
Full text pdf or HTML files are also available through the Journal of Molecular Psychiatry:
http://www.nature.com/mp/journal/v13/n12/abs/mp200862a.html
Thanks for visiting :)
