# The Role of Dopamine and Norepinephrine in Depression



## David Baxter PhD (May 5, 2007)

The Role of Dopamine and Norepinephrine in Depression
Donald S. Robinson, MD
_Primary Psychiatry_. 2007;14(5):21-23

The function of the neurotransmitters dopamine and norepinephrine in the etiology and treatment of depressive disorders is currently an area of intense research. A substantial body of evidence accrued from animal and human studies indicates that these two monoamine neurotransmitter systems play important roles in both the pathophysiology of depression and the therapeutic effects of antidepressants.1,2

Following the advent and clinical popularity of selective serotonin reuptake inhibitors (SSRIs), neuropharmacologic research has focused predominantly on serotoninergic pathways in depressive disorders. While the SSRIs are now regarded as first-line pharmacotherapy for major depressive disorder (MDD) and other mood disorders, growing concerns about their effectiveness has led to re-examination of norepinephrine and dopamine systems in affective disorders. Efficacy findings of SSRI depression trials consistently show that the majority of patients either fail to respond, have incomplete response, or continue to experience residual symptoms.3 As a result of these concerns, dual-acting antidepressants, such as serotonin norepinephrine reuptake inhibitors (SNRIs) and dopamine norepinephrine reuptake inhibitors (DNRIs), are attracting interest because of their broader pharmacologic spectrum of action. By having direct effects on more than a single monoamine transmitter system, dual-acting monoaminergic agents could represent preferred therapies for reducing residual symptoms and achieving clinical remission.4-6 Significant research is being directed toward discovery and development of new antidepressant agents that modulate multiple monoaminergic pathways.

*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. 

*Differential Therapeutic Response to Antidepressants*
In general, TCAs are thought to possess superior antidepressant efficacy, but TCAs have been largely replaced by the SSRIs due to the latter?s better tolerability and ease of dosing.5 Both monoamine oxidase inhibitors (MAOIs) and TCAs have direct pharmacologic effects on more than a single monoamine neurotransmitter system, and both classes of antidepressants have reputations for superior clinical efficacy.11,12 The established efficacy of these first-generation agents has fostered development of newer dual-acting antidepressants with greater receptor specificity (eg, SNRIs venlafaxine and duloxetine). In comparative clinical trials, these agents have shown equal, if not superior, efficacy to SSRIs.4-6 

*Antidepressants with Norepinephrine Selectivity*
Antidepressants with marked norepinephrine selectivity have undergone extensive investigation. The noradrenergically selective TCA desipramine has documented efficacy in the treatment of depressive disorders but shares drawbacks of other TCAs, particularly high affinity for cholinergic, histaminergic, and adrenergic receptors with resulting side effects. Compared to SSRIs, desipramine has less favorable tolerability and a more complicated dosing regimen, which has limited its use. The highly selective norepinephrine reuptake inhibitor reboxetine has been studied in clinical trials as a putative antidepressant, but is not available in the United States due to lingering efficacy questions.

*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 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.

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.2 Bupropion, a dual-acting DNRI, is purported to have overall efficacy similar to SSRIs and TCAs in controlled trials. It has been suggested that bupropion targets specific MDD symptoms, which, in some instances, may offer therapeutic advantage over other antidepressants (e.g., loss of pleasure).2,10 

*Antidepressant Target Symptoms* 
It is possible that pharmacotherapy directed at a single neurotransmitter system results in suboptimal response as well as reduced likelihood to induce remission and minimize residual symptoms. The majority of antidepressant drugs lack direct pharmacologic effects on dopamine neurotransmission, which may contribute to the propensity for low remission rates and persisting residual symptoms. Despite significant improvement of depressed mood, responding patients may continue to complain of impaired motivation, concentration difficulty, and loss of pleasure. The hypothalamus, which receives input from noradrenergic and serotonergic pathways modulating appetite and vegetative functions, and the mesolimbic dopamine pathway, which acts as a key regulator of pleasure, both represent potential pharmacologic targets in the treatment of depressive disorders. Some researchers propose a therapeutic strategy of targeting specific presenting symptoms in choice of antidepressants in order to enhance rate of remission, and if indicated, employ augmentation therapy.13 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.2,13 

*Conclusion*
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. 

*References*
1. Nutt DJ. The role of dopamine and norepinephrine in depression and antidepressant treatment. J Clin Psychiatry. 2006;67(suppl 6):3-8.

2. Dunlop BW, Nemeroff CB. The role of dopamine in the pathophysiology of depression. Arch Gen Psychiatry. 2007;64(3):327-337.

3. Nierenberg AA, DeCocco LM. Definitions of antidepressant treatment response, remission, nonresponse, partial response, and other relevant outcomes: a focus on treatment-resistant depression. J Clin Psychiatry. 2001;62(suppl 16):5-9.

4. Smith D, Dempster C, Glanville J, Freemantle N, Anderson I. Efficacy and tolerability of venlafaxine compared with selective serotonin reuptake inhibitors and other antidepressants: a meta-analysis. Br J Psychiatry. 2002;180:396-404.

5. Thase ME. Effectiveness of antidepressants: comparative remission rates. J Clin Psychiatry. 2003;64(suppl 2):3-7.

6. Nemeroff CB, Schatsberg AF, Goldstein DJ, et al. Duloxetine for the treatment of major depressive disorder. Psychopharmacol Bull. 2002;36(4):106-132.

7. Nutt DJ, Demyttenaere K, Janka Z, et al. The other face of depression, reduced positive affect: the role of catecholamines in causation and cure. J Psychopharmacol. In press. 

8. Randrup A, Munkvad I, Pog R, et al. Mania, depression, and brain dopamine. In: Essman W, Valzelli L, eds. Current Developments in Psychopharmacology, Volume 2. New York, NY: Spectrum Publications; 1975:206-248.

9. Meyer JH, McNeely HE, Sagrati S, et al. Elevated putamen D(2) receptor binding potential in major depression with motor retardation: an [11C]raclopride positron emission study. Am J Psychiatry. 2006:163(9):1594-1602. 

10. Willner P. The mesolimbic dopamine system as a target for rapid antidepressant action. Int J Psychopharmacol. 1997;12(suppl 3):S7-S14. 

11. Robinson DS. Monoamine oxidase inhibitors: a new generation. Psychopharmacol Bull. 2002;36(3):124-138.

12. Thase ME, Trivedi MH, Rush AJ. MAOIs in the contemporary treatment of depression. Neuropsychopharmacology. 1995;12(3):185-219.

13. Stahl SM, Zhang L, Damatarca C, Grady M. Brain circuits determine destiny in depression: a novel approach to the pharmacology of wakefulness, fatigue, and executive function in major depressive disorder. J Clin Psychiatry. 2003;64(suppl 14):6-17.


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## Retired (May 5, 2007)

A very interesting report.  When SSRI's were first introduced, their effectiveness was demonstrated to be similar to the gold standard at the time,  Tri Cyclic's,  but their targeted selectivity resulted in better compliance because people tolerated them better than the TCA's as the article alludes to:



> drawbacks of other TCAs, particularly high affinity for cholinergic, histaminergic, and adrenergic receptors with resulting side effects



It would seem that state of the art pharmacological technology can allow for added selectivity by expanding the target to include the effect of dopamine in the role of depression.

It will be interesting to learn about any correlation, if any,  between neurological disorders such as Parkinson's and Tourette which are dopamine based and the outcomes of these studies.


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