• 26 Jun 08
  

  harry palmer

  depression dopamine research psychiatry

  • Dopamine and Depression 

     

    The search for more effective treatments of MDD and other depressive disorders has fostered exploration of the physiologic role of dopamine in depression.^2,7 Fairly recently, dopamine was first implicated in the etiology and treatment of depression.⁸ Evidence from clinical investigations support the finding that depressed patients have reduced cerebrospinal levels of homovanillic acid (HVA), the major metabolite of dopamine in the central nervous system. Neuroimaging studies of medication-free depressed patients have found decreased ligand binding to the dopamine transporter and increased dopamine binding potential in the caudate and putamen, a finding consistent with the interpretation that depressed subjects have a functional deficiency of synaptic dopamine.⁹ 

     

    Animal behavioral models also find an association of depressive behaviors with altered dopamine functioning of the mesolimbic pathway.^2,10 Animals exhibiting “learned helplessness” behavior show dopamine depletion in the caudate nucleus and nucleus accumbens, which can be prevented by pretreatment with a dopamine agonist. In the “forced swim test,” another animal model of depression, the immobility of animals can be reversed by administration of the DNRI nomifensine as well as by tricyclic antidepressants (TCAs). Dopamine D₂/D₃ antagonists block the beneficial effects of these antidepressants in this behavioral model. Several animal models of depression have consistently found altered dopamine pathways associated with depressive behaviors. 
  • Several antidepressants possess direct dopaminergic activity as part of their pharmacologic profile. For example, MAOIs significantly increase brain concentrations of three major monoamine neurotransmitters—norepinephrine, serotonin, and dopamine. This may account for their accepted efficacy across a spectrum of depressive and anxiety disorders.¹¹ MAOIs have fallen into relative disuse due to concerns about drug-drug interactions and tyramine-associated hypertensive episodes. A transdermal formulation of the MAOI selegiline is available and offers a greater margin of safety than oral MAOIs because it spares gastrointestinal monoamine oxidase (MAO)-A and has fewer dietary restrictions.¹¹ Because selegiline exhibits relative selectivity for the MAO-B form of the enzyme, it is possible that, at antidepressant doses, the drug exerts more profound dopaminergic effects than other agents.
  • While superior to placebo treatment in well-controlled trials, SSRIs frequently fail to render depressed patients symptom free. Partial response may reflect failure of an antidepressant to pharmacologically enhance more than a single monoamine neurotransmitter system. The role of both dopamine and norepinephrine neuronal systems in depressive disorders is the focus of intense study. Several antidepressants affecting all three major monoamine neurotransmitters are currently under investigation. The question of how SSRI or SNRI drugs alter or fail to alter dopamine neuronal systems has not been answered.² Dual-acting antidepressants and use of augmentation strategies that directly enhance dopamine signaling are treatment options with potential for improving remission rates. PP

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