5-HT1A changes in depression
Our literature search yielded ten published studies of 5-HT1A receptor binding in depression, comprising 218 patients with depression and 261 healthy controls. We found a mean group size of 22 patients and 26 controls per imaging study. Our meta-analysis indicated significantly decreased 5-HT1A density in MTC, and smaller reductions in 5-HT1A binding in RN, INS, HIP, CAN and OCC in patients with depression. The different PET imaging methods employed in each study to measure 5-HT1A binding in high-affinity regions (i.e., RN, INS, and OCC) may have contributed to high inter-study variability for these particular regions.
Some previous studies have reported that 5-HT1A alterations in depression are influenced by antidepressant medication, and remission and recovery status. In the 10 studies we included, patients were prescribed antidepressants prior to study enrollment, but details of drug doses and types were not reported. It was therefore difficult to investigate whether antidepressant medication affected 5-HT1A availability during treatment in our meta-analysis. We hypothesized that 5-HT1A binding would be associated with depressive symptom severity. However, no relationship was found between the severity of depressive symptoms and 5-HT1A availability in patients with depression.
Reduced 5-HT
1A binding visualized with PET may reflect changes in receptor density or affinity. Alternatively, such reductions may reflect receptor down-regulation, inter-activation, or blockage by endogenous ligands (although [11C] WAY-100635 appears to be insensitive to endogenous levels of serotonin; [
6]). In the current meta-analysis, we found significant reductions in 5-HT
1A in MTC (including amygdala). This finding is consistent with previous postmortem studies indicating lower 5-HT
1A binding and mRNA expression in MDD and bipolar disorder [
24,
26,
27]. Postsynaptic 5-HT
1A receptors exist in cortical inter-neurons and pyramidal dendrites. These receptors participate in feedback inhibition of 5-HT neuronal activity and the modulation of cortical circuits [
37]. Decreased 5-HT
1A binding may act as a compensating factor to improve postsynaptic serotonin reuptake during a depressive episode. We speculate that decreased binding in the MTC of people with depression may impair the integration of 5-HT signaling in cortico-mesiotemporal cortical circuits and disrupt limbic input back to the cortex [
2,
40]. Thus, the reduction of 5-HT
1A binding in depression found in our meta-analysis may represent mesiotemporal 5-HT
1A-mediated dysregulation of cortical and limbic structures.
We detected smaller differences in 5-HT
1A binding between depression and healthy controls in HIP, RN, CAN, and OCC. However, sensitivity analyses revealed stronger trends toward reduced 5-HT
1A binding. The HIP has previously been shown to be structurally and functionally altered during depression [
8,
29,
30]. However, the data regarding 5-HT
1A binding in OCC and RN merit special attention for several reasons. First, there is evidence that the RN contains many serotonergic cell bodies that regulate 5-HT release and uptake. Collin et al. [
10] found that the level of expression of 5-HT transporter mRNA was down-regulated in the rodent dorsal raphe nucleus in obese behaviorally depressed ob/ob mice. Decreased 5-HT
1A autoreceptor binding was also found in the dorsal raphe nucleus of people with depression who successfully committed suicide [
7]. Moreover, several studies have indicated that the OCC is involved in depression, and γ-aminobutyric acid (GABA) concentrations in this region have been shown to be functionally altered in people with depression [
5,
44]. These data support the hypothesis that depression is associated with reduced presynaptic serotonergic activity, which leads to the down-regulation of postsynaptic 5-HT
1A sites. The results of the current meta-analysis suggest that further imaging and animal studies are warranted to investigate the specific role of 5-HT
1A and serotonergic dysfunction in the OCC and RN of patients with depression.
Study heterogeneity
Study heterogeneity occurs when multiple studies investigating a particular effect are actually measuring different effects. This may be caused by differences in samples, interventions, statistical analyses, or study designs, and may cause unreliability in meta-analyses. In the current study, several factors may have caused high heterogeneity, including the severity of depressive symptoms, small sample sizes, and the chosen reference tissue for normalization in PET. Differences in PET scanning protocols were also considered to be potentially important sources of variation between measurements [
45]. Our results indicate that considerably more data are required for regions with high 5-HT
1A abundance. Moreover, we found that the regions chosen for normalization of specific binding to the radioactivity concentration in a reference region differed between studies (plasma, cerebellum gray matter, cerebellum white matter, whole cerebellum). These limitations, in combination with the measurement error and substantial biological variability in 5-HT
1A, may have caused instability in group differences, reflecting an inherently problematic aspect of data acquisition using PET. These findings highlight the ways that specific technical differences in data collection and analysis can produce conflicting or inconsistent results. The development of a gold standard for arterial blood with larger sample sizes in PET studies may provide a solution that enables definitive conclusions about 5-HT
1A density in depression.
The association between the C(-1019)G polymorphism in the promoter region of the 5-HT
1A gene and depression may be another relevant factor. There is evidence that higher expression of the G allele may increase the risk of developing depression [
19,
46,
49]. Therefore, genetic variability may contribute to heterogeneity in studies of 5-HT
1A receptors in depression. It is possible that the inter-study heterogeneity in SMD in the current results was caused by genetic variation in 5-HT
1A receptors. However, we did not consider genetic variation in our meta-analysis.
Study limitations
Several limitations should be considered in the interpretation of our findings. First, the number of published studies included was too small to exclude small study bias (i.e., smaller studies contributing to larger effect sizes). This finding indicates that future clinical molecular imaging studies should include larger sample sizes. Second, some brain regions have been associated with altered 5-HT1A binding but were not included in the current analysis because of an insufficient number of studies reporting data for these regions. Third, we suspect that heterogeneity may result from genetic variation, as well as differences in gender, depression severity, and treatment. However, we did not analyze these factors, and did not obtain sufficiently detailed data to allow such an analysis. Finally, we detected publication bias in this meta-analysis, possibly resulting from the small number of studies included.