Mood changes correlate to changes in brain serotonin precursor trapping in women with premenstrual dysphoria

Abstract

The cardinal mood symptoms of premenstrual dysphoria can be effectively treated by serotonin-augmenting drugs. The aim of the study was to test the serotonin hypothesis of this disorder, i.e. of an association between premenstrual decline in brain serotonin function and concomitant worsening of self-rated cardinal mood symptoms. Positron emission tomography was used to assess changes in brain trapping of ¹¹C-labeled 5-hydroxytryptophan, the immediate precursor of serotonin, in the follicular and premenstrual phases of the menstrual cycle in eight women with premenstrual dysphoria. Changes in mood and physical symptoms were assessed from daily visual analog scale ratings. Worsening of cardinal mood symptoms showed significant inverse associations with changes in brain serotonin precursor trapping; for the symptom “irritable”, r_s = − 0.83, and for “depressed mood” r_s = − 0.81. Positive mood variables showed positive associations, whereas physical symptoms generally displayed weak or no associations. The data indicate strong inverse associations between worsening of cardinal symptoms of premenstrual dysphoria and brain serotonin precursor (¹¹C-labeled 5-hydroxytryptophan) trapping. The results may in part support a role for serotonin in premenstrual dysphoria and may provide a clue to the effectiveness of serotonin-augmenting drugs in this disorder but should, due to small sample size and methodological shortcomings, be considered preliminary.

Introduction

Premenstrual dysphoric disorder (PMDD) is characterized by the cyclical occurrence of disabling mood symptoms in the luteal (premenstrual) phase of the menstrual cycle, with a profound impact on the afflicted woman and her near environment (American Psychiatric Association, 1994). The cardinal symptoms are irritability, depressed mood, affective lability and impaired impulse control, all of which are effectively alleviated by drugs increasing brain serotonin activity (Eriksson, 1999). Randomised trials have shown selective serotonin reuptake inhibitors (SSRIs) to be effective pharmacological treatments in about 60% of women with PMDD (Rapkin, 2003), and these drugs are considered the most effective treatment known at present (Dimmock et al., 2000). This implies that reduced serotonergic activity might be one symptom-provoking factor in premenstrual dysphoria, supporting the “serotonin hypothesis” of the pathogenesis of the disorder, namely that worsening of self-rated premenstrual mood symptoms is associated with a concomitant decline in brain serotonin activity (Steiner and Pearlstein, 2000, Parry, 2001, Eriksson et al., 2002). Positron emission tomography (PET) was used to measure brain trapping of ¹¹C-5-hydroxy-l-tryptophan (¹¹C-5-HTP), which when radiolabeled in the metabolically stable β-position is a marker of aromatic l-amino-acid decarboxylase (AAAD) activity (Bjurling et al., 1990, Hartvig et al., 1992, Hartvig et al., 1993, Lindner et al., 1997). Associations between changes in cardinal symptoms of PMDD and changes in brain ¹¹C-5-HTP trapping from early (mid-follicular) to late (premenstrual) in the menstrual cycle were investigated. Primary end-points were associations between changes in the core symptoms of premenstrual dysphoria, “irritable” and “depressed mood”, and changes in ¹¹C-5-HTP trapping in a large brain region representing the “whole brain” and in specific areas of the forebrain that are known to be involved in affective disorders (Ågren and Reibring, 1994, Brody et al., 2001, Davidson, 2002).