Dopamine and Depression

Consultant, Worldwide Drug Development

Following the clinical popularity of SSRIs, neuropharmacologic research has focused predominately on serotoninergic pathways in depressive disorders. While SSRIs are now regarded as first-line pharmacotherapy for MDD and other mood disorders, growing concerns about their effectiveness has led to re-examination of norepinephrine and dopamine systems in affective disorders. Dual-acting antidepressants, such as serotonin norepinephrine reuptake inhibitors (SNRIs) and dopamine norepinephrine reuptake inhibitors, are attracting interest. By directly affecting >1 transmitter system, these agents could represent preferred therapies for reducing residual symptoms and achieving clinical remission.

Antidepressants with Norepinephrine Selectivity

Antidepressants with marked norepinephrine-selectivity have undergone extensive investigation. The noradrenergically selective TCA desipramine has demonstrated efficacy in depressive disorders but has particular affinity for cholinergic, histaminergic, and adrenergic receptors with resulting side effects, as do all TCAs. Compared to SSRIs, desipramine has less favorable tolerability and a more complicated dosing regimen, which has limited its use.

Antidepressants with Direct Dopaminergic Effects

Several antidepressants possess direct dopaminergic activity as part of their pharmacologic profile. For example MAOIs significantly increase brain concentrations of major monoamine neurotransmitters norepinephrine, serotonin (5-HT), and dopamine. This may account for their accepted efficacy across a spectrum of depressive and anxiety disorders. MAOIs have fallen into relative disuse due to concerns about DDIs 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 GI monoamine oxidase (MAO)-A and has fewer dietary restrictions. Because selegiline exhibits relative selectivity for the MAO-B form of the enzyme, it is possible that the drug exerts more profound dopaminergic effects than other agents at antidepressant doses.

Some other antidepressants are known to have pharmacologic effects on dopaminergic systems. The dual SNRI venlafaxine at therapeutic doses modestly inhibits dopamine reuptake. At high doses, the SSRI sertraline can also inhibit dopamine reuptake, which may play a role in its therapeutic profile. Bupropion is purported to have overall efficacy similar to SSRIs and TCAs and may target specific symptoms of MDD that could offer therapeutic advantage over other antidepressants.

Antidepressant Target Symptoms

It is possible that pharmacotherapy directed at a single neurotransmitter system results in suboptimal response, reduced likelihood to induce remission, and minimized residual symptoms. The majority of antidepressants lack direct pharmacologic effects on dopamine neurotransmission, which may contribute to the propensity for low remission rates and persisting residual symptoms. Researchers have proposed a therapeutic strategy of targeting specific presenting symptoms in antidepressants in order to enhance remission and employ augmentation therapy.

A suggested strategy appropriate for many depressed patients is to utilize a dual-acting antidepressant as initial therapy and augment when necessary with an agent with direct effects on dopamine or norepinephrine pathways.

Disclosure: Dr. Robinson has served as a consultant to Bristol-Myers Squibb, CeNeRx, Genaissance, Organon, Predix, Somerset, Takeda, and Zars.