Research report
Dopaminergic mechanism of antidepressant action in depressed patients

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Abstract

Clinical studies have not yet determined a common mechanism of action for antidepressant drugs, which have primary sites of action on a variety of different neurotransmitter systems. However, a large body of evidence from animal studies demonstrates that sensitisation of D2-like dopamine receptors in the mesolimbic dopamine system may represent a ‘final common pathway’ in antidepressant action. The present study aimed to determine whether, consistent with data from animal studies, the clinical antidepressant action of selective serotonin reuptake inhibitors (SSRIs) is reversed by acute administration of a receptor antagonist selective for D2-like receptors in the mesolimbic dopamine system. The participants were patients diagnosed with major depressive disorder (n=8) who had been treated successfully (Hamilton Depression Scale<10) with selective serotonin uptake inhibitors (fluoxetine, citalopram or paroxetine); and age-matched, non-depressed, untreated volunteers (n=10). They attended a psychiatric research ward on an out-patient basis, and received double-blind acute administration of either placebo, or a low dose of the selective dopamine D2/D3 receptor antagonist sulpiride (200 mg), in a counterbalanced order. Mood and psychomotor effects were assessed using visual analogue scales and the Fawcett–Clark Pleasure Capacity Scale. Sulpiride slightly improved subjective well-being in the control group, but in the antidepressant-treated patients, sulpiride caused a substantial reinstatement of depressed mood. These data are consistent with the hypothesis that sensitisation of D2-like receptors may be central to the clinical action of SSRIs.

Section snippets

Participants

Participants were 8 depressed patients [4 male, 4 female; mean (±SEM) age=43.5 (±4.1)], and 10 non-depressed controls [5 male, 5 female; mean (±SEM) age=42.3 (±2.6)]. They provided written informed consent.

Antidepressant treatment

During the course of antidepressant treatment, mean (±SEM) HDRS ratings in the patient group fell from 27.1 (±1.4) prior to treatment to 8.6 (±0.5: range, 6–10) at the time of testing.

FCPCS scores increased significantly over the course of antidepressant treatment [mean±SEM: before treatment, 2.35±0.14; after treatment, 3.36±0.14; t(7)=6.23, p<0.001]. Post-treatment scores in the treated group were marginally lower than control scores [3.60±0.12].

Effects of sulpiride on overall mood scores

The statistical analysis of the VAS scores is

Discussion

Consistent with an earlier study (Mehta et al., 1999), the administration of a low dose of sulpiride caused no worsening of mood in non-depressed, non-antidepressant-treated volunteers. Indeed, in the control group, sulpiride caused a slight enhancement of psychological well-being. This observation may be relevant to the efficacy of low-dose sulpiride as an antidepressant (Del Zompo et al., 1990, Ruther et al., 1999), and most likely reflects the inhibitory action of sulpiride at presynaptic

References (35)

  • C.F. Caley

    Extrapyramidal reactions from concurrent SSRI and atypical antipsychotic use

    Can. J. Psychiatry

    (1998)
  • M. Del Zompo et al.

    Clinical evidence for a role of dopaminergic system in depressive syndromes

  • H. D'haenen et al.

    Successful antidepressant treatment with SSRIs is associated with an increased D2 binding

    Int. J. Neuropsychopharmacol.

    (1999)
  • D. Ebert et al.

    Dopamine and depression: striatal dopamine D2 receptor SPECT before and after antidepressant therapy

    Psychopharmacology

    (1996)
  • J. Fawcett et al.

    Assessing anhedonia in psychiatric patients: the pleasure scale

    Arch. Gen. Psychiatry

    (1983)
  • R.M. Lane

    SSRI-induced extrapyramidal side-effects and akathisia: implications for treatment

    J. Psychopharmacol.

    (1998)
  • J. Maj

    Behavioral effects of antidepressant drugs given repeatedly on the dopaminergic system

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