Elsevier

Biological Psychiatry

Volume 59, Issue 2, 15 January 2006, Pages 106-113
Biological Psychiatry

Original article
Altered Serotonin 1A Binding in Major Depression: A [carbonyl-C-11]WAY100635 Positron Emission Tomography Study

https://doi.org/10.1016/j.biopsych.2005.06.016Get rights and content

Background

Serotonin 1A receptors (5-HT1A) are implicated in the pathophysiology of major depressive disorder (MDD) and in the action of selective serotonin reuptake inhibitors (SSRI). SSRI desensitize 5-HT1A and down-regulate 5-HT transporters (5-HTT) with the latter persisting for weeks after discontinuation of SSRI. MDD subjects are more likely to be homozygous for the functional 5-HT1A G(-1019) allele of the promoter polymorphism and are postulated to have higher 5-HT1A than healthy volunteers (controls). We measure 5-HT1A in MDD, assess the effects of antidepressant exposure (AE), and examine the role of the C(-1019)G polymorphism.

Methods

Genotyped and determined 5-HT1A binding potential (BP) by positron emission tomography (PET) using [carbonyl-C-11]-WAY-100635 in 28 medication-free MDD subjects during a current major depressive episode and 43 controls.

Results

No difference in BP between controls and MDD subjects (p = .235). There was a difference in BP comparing the controls, antidepressant naive (AN) MDD subjects, and subjects with AE across all regions (p = .013). Post hoc testing reveals higher BP in AN compared to controls (p = .008) and to AE (p = .007). The GG genotype is overrepresented in MDD subjects (p = .059), and BP appears higher with the G allele.

Conclusions

AN have higher 5-HT1A than controls and AE suggesting a model of depression characterized by an over expression of autoinhibitory somatodendritic 5-HT1A receptors, perhaps due to the higher expressing G allele, that may result in reduced terminal field 5-HT release. AE appears to have long-term effects on 5-HT1A.

Section snippets

Subjects

Twenty eight subjects who met DSM-IV(American Psychiatric Association 1994) criteria for a current major depressive episode and 43 control subjects were included in this study. Inclusion criteria were assessed through history, chart review, Structured Clinical Interview for DSM IV (SCID I) (First et al 1995), review of systems, physical examination, routine blood tests, pregnancy test, urine toxicology and EKG. The Beck Depression Inventory (BDI) (Beck et al 1961), Hamilton Depression Rating

Comparison of Depressed Subjects with Controls

Across all regions there was no difference in BP between controls and MDD subjects using a test for mean within the mixed effects model (F = 1.028, df = 1, 68, p = .235; Figure 1).

Effects of Previous Exposure to Antidepressants

Dividing the MDD group into antidepressant naive (AN) and subjects with antidepressants exposure (AE), and including the controls, there is a significant group effect within the mixed effects model (F = 4.60, df = 2, 67, p = .013, Figure 2). Post-hoc analysis applying a one-way model to each region reveals a

Discussion

We report no differences in BP in MDD subjects compared to controls but significantly higher BP in never medicated MDD subjects during a MDE compared with controls and MDD subjects previously treated with antidepressants. We find a trend for the higher expressing GG (-1019) promoter genotype to be more common in MDD and to correlate with higher BP.

Limitations

While this is the largest sample size of MDD subjects (n = 28) and controls (n = 43) ever reported, when broken down in to AN (n = 13) and AE (n = 15), our sample sizes are still comparable to a publication with a mixed unipolar (n = 8) and bipolar population (n = 4, Drevets et al 1999) and a second with 15 unmedicated subjects (Sargent et al 2000). The subjects were treated naturalistically in the community with a variety of classes of antidepressants. Future prospective studies can be

Conclusions

We found increased 5-HT1A BP in all brain regions of antidepressant naive depressed subjects compared to controls and to previously treated depressed subjects. This may be due to greater gene expression. More autoreceptor binding may result in less serotonin neuron firing and hypofunction consistent with the indoleamine hypothesis of major depression. Reversal of that effect by antidepressant medications may exert an antidepressant effect in some subjects but perhaps not in treatment resistant

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