The serotonin–dopamine interaction is critical for fast-onset action of antidepressant treatment: in vivo studies in an animal model of depression

131

In several previous biochemical, pharmacological, and genetic studies, the catechol-O-methyltransferase (COMT) has been suggested to be involved in the pathogenesis as well as the pharmacological treatment of affective disorders. In the present study, 256 patients with major depression (DSM-IV) of Caucasian descent were genotyped for the functional COMT val158met polymorphism and characterized for clinical response to antidepressive pharmacological treatment as measured by intra-individual changes of Hamilton Depression (HAM-D-21) scores over 6 weeks. The COMT 158val/val genotype conferred a significant risk of worse response after 4-6 weeks of antidepressant treatment in patients with major depression (week 4: p ¼ 0.003; week 5: po0.0001; week 6: po0.0001) after Bonferroni correction for multiple comparisons. The present results strongly point toward a negative influence of the higher activity COMT 158val/ val genotype on antidepressant treatment response during the first 6 weeks of pharmacological treatment in major depression, possibly conferred by consecutively decreased dopamine availability. This finding suggests a potentially beneficial effect of an antidepressive addon therapy with substances increasing dopamine availability individually tailored according to COMT val158met genotype.

Section: Discussionsupporting

confidence: 64%

Section: Introductionmentioning

confidence: 99%

Association of the COMT val158met Variant with Antidepressant Treatment Response in Major Depression

Baune

Hohoff

Berger³

et al. 2007

131

“…This is the first time that decreases in DHEA levels have been shown in brain regions central to manifestation of depressive behavior in an animal model (Figure 1). Furthermore, chronic treatment of FSL rats with DHEA significantly decreased their immobility in the swim test (Figure 2) to the same extent as conservative antidepressants (Dremencov et al, 2004), thus confirming an antidepressive-like action of DHEA in an animal model of depression. The dose response curve of DHEA is concordant with other reports (Urani et al, 2001) demonstrating a narrow therapeutic window.…”

Section: Discussionsupporting

confidence: 56%

DHEA Lessens Depressive-Like Behavior via GABA-ergic Modulation of the Mesolimbic System

Genud

Merenlender

Gispan-Herman

et al. 2008

Self Cite

Alterations in the levels of dehydroepiandrosterone (DHEA) in the brain can allosterically modulate g-aminobutyric-acid-type-A (GABA A R), N-methyl-D-aspartate (NMDAR), and Sigma-1 (s1R) receptors. In humans, DHEA has antidepressive effects; however, the mechanism is unknown. We examined whether alterations in DHEA also occur in an animal model of depression, the Flinders-sensitiveline (FSL) rats, with the intention of determining the brain site of DHEA action and its antidepressant mechanism. We discovered that DHEA levels were lower in some brain regions involved with depression of FSL rats compared to Sprague-Dawley (SD) controls. Moreover, DHEA (1 mg/kg IP for 14 days)-treated FSL rats were more mobile in the forced swim test than FSL controls. In the NAc and VTA, significant changes were observed in the levels of the d-subunit of GABA A , but not of s1R mRNA, in FSL rats compared to SD rats. The d-subunit controls the sensitivity of the GABA A R to the neurosteroid. Indeed, treatment (14 days) of FSL rats with the GABA A agonist muscimol (0.5 mg/kg), together with DHEA (a negative modulator of GABA A ), reversed the effect of DHEA on immobility in the swim test. Perfusion of DHEA sulfate (DHEAS) (3 nM and 30 nM for 14 days) into the VTA and NAc of FSL rats improved their performance in the swim test for at least 3 weeks post-treatment. Our results imply that alterations in DHEA are involved in the pathophysiology of depression and that the antidepressant action of DHEA is mediated via GABA A Rs in the NAc and VTA.

“…Dremencov et al (2004Dremencov et al ( , 2005 showed that the increased inhibition of dopamine release in the NAc, mediated by 5-HT 2C receptors in rats with depressive-like behavior, is normalized by antidepressants and that restoration of the 5-HT-dopamine interaction correlated directly with improvement of behavior (Dremencov et al, 2004(Dremencov et al, , 2005. Although it may be speculated that this interaction at the biological level reflects the interdependence between experience of stress-sensitivity and reward experience at the behavioral level, there are no data to support this hypothesis at present.…”

Section: Emotional Processes and Biological Systemsmentioning

confidence: 99%

Reduced Stress-Sensitivity or Increased Reward Experience: The Psychological Mechanism of Response to Antidepressant Medication

Wichers

Barge-Schaapveld

Nicolson

et al. 2008

122

126

Depression has often been associated with increased negative affect reactivity to stress (Stress-Sensitivity) and reduced capacity to experience pleasure or positive affect (Reward Experience). To date, no studies have prospectively examined changes in StressSensitivity and Reward Experience following antidepressant treatment. The sample included 83 depressed patients and 22 healthy controls. A randomized controlled trial was carried out with patients receiving either imipramine or placebo for 6 weeks. At baseline and 6 weeks, patients and controls participated in an Experience Sampling procedure, prospectively measuring ecologically valid daily life appraisals of activities and mood states. The course of depression was assessed with the Hamilton Depression Rating Scale (HDRS). Multilevel linear regression analyses showed that patients had higher negative and lower positive appraisals of activities than controls. In addition, patients showed increased Stress-Sensitivity (negative affect reactivity to negatively appraised activities). Treatment with imipramine decreased Stress-Sensitivity and increased Reward Experience (positive affect reactivity to positively appraised activities). Changes in Stress-Sensitivity and Reward Experience were in part reducible to changes in the process of activity appraisal itself. However, increase in Reward Experience, but not decrease in Stress-Sensitivity, discriminated between patients who responded and those who did not, independent of changes in the process of activity appraisal itself. Response to treatment in depression may be conditional on restoration of hedonic capacity, the cerebral substrate of which requires further study in relation to antidepressant response. A search for (synergistic) antidepressant therapies specifically targeting ability to experience reward may be warranted.