There are only 2 postmortem investigations of 5-HTT density in subjects with recent symptoms of depressive episodes. In these 2 studies, no changes in 5-HTT density were found in either the dorsal raphe or the locus coeruleus.154,155
Other postmortem studies of 5-HTT density sampled subjects with a history of a depressive episode (not necessarily recent) and typically focused on prefrontal cortex regions. These studies tend to report either decreased 5-HTT density156–159
or no difference in 5-HTT density.160–165
In several of these studies, subjects were medication free, based on clinical history and toxicological screening.158,160,161
For many of these investigations, average postmortem delays were less than a day.154–156,158,159,162
Most of these studies were recently reviewed in detail by Stockmeier and colleagues.88
However, most postmortem studies are not representative of a depressive episode, since only 2 studies of 5-HTT density sampled subjects who recently had symptoms.154,155
Further, the postmortem studies are not completely selective for MDD because all include comorbid axis I psychiatric illnesses156–162
and some also sample bipolar disorder.158,160,165
A third key issue with sampling is that all studies include both early-and late-onset MDD.156–162
The first imaging study of 5-HTT in vivo used [123
I]β-CIT SPECT to measure specific binding of [123
I]β-CIT in the hypothalamus-midbrain region in depressed patients and healthy control subjects.166
See for a descriptive list of imaging studies of the 5-HTT. A reduction in the binding potential was found. Interestingly, subjects with major depression were subdivided based on recency of medication use, and this did not affect the results. The following methodological issue makes this finding difficult to interpret: Because [123
I]β-CIT has similar affinity for both 5-HTT and DAT transporters166
and because both the raphe and substantia nigra are within this region sampled, it is not clear whether specific binding of β-CIT reflects 5-HTT binding or DAT binding. The DAT downregulates in striatum after long-term dopamine depletion.142–145
If DAT in substantia nigra downregulate similarly and if there is a monoamine lowering process in the midbrain during depressive episodes, it would be expected that an index of specific binding (to serotonin and dopamine transporters) would be lower.
The next study of 5-HTT applied [11
C](+)McN5652 PET to measure thalamus 5-HTT BP in 7 subjects with MDD.46
The data from these subjects were added to data from 6 subjects who had bipolar disorder. Ichimiya found that, in subjects with either MDD or bipolar disorder, 5-HTT BP in the thalamus is elevated.46
A strength of the study was that subjects were medication free, and a more selective radioligand was used. A disadvantage of the study is that it may be incorrect to assume that unipolar MDEs and bipolar MDEs have a common serotonin transporter abnormality. This study did not investigate 5-HTT BP during a current MDE because only 5 subjects with a current MDE and MDD were enrolled in the study.46
The next study was the first application of [11
C]DASB PET imaging to MDD. It sampled 20 subjects with MDE and 20 healthy controls.170
This sample had a number of advantages because it was reasonably large, subjects were medication free for at least 3 months, and they had no other comorbid axis I illnesses, were nonsmoking, and had early onset depression. As a result of the technical advantages of [11
C]DASB, 5-HTT BP could be reliably measured in multiple brain regions, including cortex. There was no evidence to support a hypothesis of a difference in 5-HTT BP as no difference in regional 5-HTT BP was found between MDE and healthy subjects in any brain region.170
However, in this same study of [11
there was highly significant support for the hypothesis that greater regional 5-HTT BP would occur during MDE with severe, pessimistic dysfunctional attitudes. This hypothesis was based on the interpretation of 3 findings which argue that extracellular serotonin is lowest during MDE with severe, pessimistic, dysfunctional attitudes: The first finding is the acute shift toward optimism in humans after raising extracellular serotonin with d-fenfluramine which argues for a role of serotonin in modulating pessimism/optimism in humans.89
The second finding is that cortex 5-HT2
BP is greater during MDE with severe pessimism.89
This can occur when extracellular serotonin is low, according to the third set of findings: 5-HT2
receptor density increases when extracellular serotonin is chronically lowered92,93
(for more detail, see Key Evidence For Low Extracellular Serotonin in Untreated Major Depressive Disorder in this article). The subgroup of MDE subjects with severely pessimistic dysfunctional attitudes had significantly higher 5-HTT BP, compared with healthy subjects, in brain regions sampling serotonin nerve terminals (prefrontal cortex, anterior cingulate, thalamus, bilateral caudate, bilateral putamen) (see ). On average, 5-HTT BP was 21% greater in these regions in MDE subjects with severely pessimistic dysfunctional attitudes (see ). Moreover, within the MDE group, greater 5-HTT BP was strongly associated with more negativistic dysfunctional attitudes in the same brain regions. The interpretation was that serotonin transporters have an important role in influencing extracellular serotonin during MDEs: Greater regional 5-HTT BP can provide greater vulnerability to low extracellular 5-HT and symptoms of extremely negativistic dysfunctional attitudes.170
Fig. 2: Correlations between dysfunctional attitudes and serotonin transporter binding potential (5-HTT BP) in some of the larger regions in depression subjects. Highly significant correlations were found: prefrontal cortex (p = 0.0004), anterior cingulate (more ...)
Fig. 3: Comparison of regional 5-HTT BP between 8 subjects with depression with severely negativistic dysfunctional attitudes (greater than 190) and 20 healthy subjects. For regions primarily sampling serotonergic nerve terminals (prefrontal cortex, anterior (more ...)
It is premature to conclude upon the etiology of an elevation in 5-HTT BP in the subset of MDE subjects with more severe dysfunctional attitudes, because one could consider both genetic171
and environmental influences.172
The simplest explanation is that the subgroup with greater pessimism happened to inherit a greater 5-HTT density. Under this explanation, it would be expected that inheriting a greater 5-HTT could increase the risk of acquiring a MDD with more severe pessimism during MDEs.
The relation between genotypes such as the 5-HTTLPR and/or 5-HTT LPR (LA
) and brain 5-HTT density or binding potential is an area of ongoing study.59,158,173–178
Some investigators interpret the genotype associated with greater 5-HTT synthesis in cell lines as being reflective of 5-HTT density in the brain. The genotype associated with greater 5-HTT synthesis is sometimes associated with greater clinical response179–182
and better long-term outcome.183
It is well known that better antidepressant responsiveness predicts long-term outcome.184–187
This body of literature does not need to be inconsistent with the finding of greater 5-HTT BP in depression subjects with more severe dysfunctional attitudes.170
From a theoretical perspective, it could certainly be that subjects with depression with the highest 5-HTT binding potential and the lowest levels of extracellular serotonin could have more severe pessimism, yet they could be more responsive to SSRI treatment and have better long-term outcomes as a result of being more responsive to SSRI treatment.
The other [11
C]DASB PET imaging study in mood disorder sampled depression subjects with bipolar disorder.188
Since the idea of increased 5-HTT BP being associated with illness or severity of symptoms is still new, it is interesting that 5-HTT BP was significantly greater at the uncorrected level in 5 of 8 predefined regions of interest (with a similar trend in a sixth region). On a voxel level analysis, medial prefrontal cortex, thalamus, caudate and insula had significantly greater 5-HTT BP after accounting for multiple comparisons. No region had a significant decrease in 5-HTT BP after correcting for multiple comparisons.
A fourth study of brain 5-HTT in depression applied [123
I]ADAM SPECT to study 7 subjects with MDEs and 6 healthy control subjects.167
Thalamus, striatum and midbrain regions were assessed. No difference in 5-HTT BP was found in the thalamus and striatum; however, a reduction in midbrain 5-HTT BP was reported. Limitations of the study were that 2 subjects had selective serotonin reuptake inhibitors as recently as 3 weeks previously and the small sample size.
A fifth study applied [11
C](+)McN5652 PET to study depressed and healthy subjects.168
A strength of the study was that the sample size was reasonable and a subdivision of antidepressant naive subjects was gathered. The authors employed an approach of adding constants to data and applying the natural logarithm to 5-HTT binding potential values. It was reported that the 5-HTT binding potential was lower in the midbrain and amygdala, but it is unclear that this would have been the case had untransformed 5-HTT BP values been presented.
The sixth study applied [123
in subjects with depression and in healthy subjects and found a trend toward increased midbrain 5-HTT BP. The main strengths of the study related to the sample of depression subjects selected: A reasonable number of medication-free subjects who had no comorbid illnesses were enrolled (n
= 21) .