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Serotonin and Norepinephrine Antidepressant Effects*

Authors: Martin L. Korn, MDFaculty and Disclosures



With the introduction of fluoxetine, the treatment of depression was revolutionized. Selective for the serotonergic reuptake mechanism, it was easy to administer and had an excellent safety profile compared with the tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors (MAOIs). This medication, as well as similar serotonin-selective agents, quickly became the treatment of choice for depression as well as a variety of other disorders.

Several new classes of antidepressants have since been introduced or are in the process of development. As we learn about the therapeutic profile of these newer agents, our understanding of the role of serotonin and norepinephrine in the psychiatric disorders is being both challenged and refined. Atomoxetine and reboxetine are specific norepinephrine reuptake inhibitors that have not yet been introduced. Venlafaxine and, more recently, duloxetine are dual reuptake inhibitors that inhibit both noradrenergic as well as serotonergic reuptake mechanisms. This symposium at the American Psychiatric Association 155th Annual Meeting focused on our new conceptual understanding of these neurotransmitters and the evolving role of these medications in treatment.


Basic Mechanisms of Antidepressant Actions

Gerard Sanacora, MD, PhD,[1] Director of the Yale University School of Medicine Depression Research Program, discussed the ways in which the antidepressants exert their clinical effect. The monoamine theory of depression evolved from several clinical observations.[2,3] Catecholamine-depleting drugs such as reserpine and tetrabenazine were known to induce depression. Alternatively, MAOIs were able to alleviate depression through the blocking of enzymes that degrade the monoamines. TCAs, by blocking reuptake sites for the monoamines, were also noted to be efficacious.

Despite evidence supporting the monoamine deficit hypothesis, there were discrepant findings as well. Only a minority of patients given reserpine or tetrabenazine became depressed. The findings on cerebrospinal fluid (CSF) metabolite findings were inconsistent as well. Furthermore, reuptake inhibition would occur within hours to days, yet the time course to therapeutic effect was several weeks. In order to accommodate these discrepant data, other mechanisms of action have been posited, including presynaptic alpha-2 supersensitivity and beta-receptor abnormalities.[4] The 5-HT-1A and 5-HT-2A serotonergic receptors may also be involved in antidepressant actions. Yet synaptic adaptation alone does not appear to explain all of the therapeutic effects, and other factors have been implicated.

One method for testing the specificity of the different antidepressants is the monoamine depletion paradigm. The essential amino acid tryptophan is the sole precursor for serotonin. Utilizing tryptophan-free drinks, 70% to 80% of plasma serotonin can be depleted within 5 hours.[5] This can also induce a 90% reduction in CSF tryptophan and 35% reduction in CSF 5-HIAA, the primary metabolite of serotonin. When tryptophan depletion was carried out in patients with depression who had responded to the selective serotonin reuptake inhibitor (SSRI) fluoxetine, increased depression scores were noted within several hours. In contrast, the depletion of tryptophan in patients who had responded to the selective noradrenergic reuptake inhibitor (SNRI) desipramine did not result in a reversal of the antidepressant effect.[6] Administration of the tyrosine hydroxylase inhibitor alpha-methylparatyrosine (AMPT) results in depletion of catecholamines. This agent reversed the antidepressant response to noradrenergic reuptake inhibitors, but had no significant effect on patients who responded to serotonergic reuptake agents.[7] If serotonergic and noradrenergic depleting agents are administered in individuals with no history of depression, no increased depressive symptoms occur.[8]

There are several possible ways of interpreting the data relevant to the role of the 2 neurotransmitters in psychiatric disorders:


  • Common actions. Both noradrenergic and serotonergic agents have been shown to be efficacious in some common disorders such as depression and panic disorder.  
  • Disease specificity. In some disorders, only one class of medications is effective. For example, serotonergic agents are only helpful with obsessive compulsive disorder (OCD), while noradrenergic agents are only effective in attention deficit hyperactivity disorder (ADHD).  
  • Different target symptoms. Although both neurotransmitters may be involved in depression or anxiety, each may target specific symptoms. For example, noradrenergic agents may be more effective in focusing attention and increasing motivation in the depressed individual. Alternatively, serotonin may be more helpful with obsessive symptoms.  
  • Converging pathways. Since both neurotransmitters have some differential effects, combining the 2 may result in additive synergistic effects.  

There are several possible secondary targets that may be affected by the reuptake inhibitors. Some of these include amino acid neurotransmitter systems, second messenger systems, and mediators of neuronal plasticity. Antidepressants have demonstrated effects on glutaminergic neurotransmission[9] as well as GABAergic neurotransmission.[1] Antidepressants activate secondary messenger systems, including cAMP, and this, in turn, leads to the regulation of target genes and increases in neurotrophic factors.[10] One of the neurotrophic factors expressed is the brain-derived neurotrophic factor (BDNF), especially in some areas of the hippocampus and cerebral cortex. Stress, alternatively, decreases the expression of BDNF and may lead to atrophy in some areas of the brain such as the hippocampus. Theories concerning these mechanisms may help to explain some of the more complex aspects of the psychiatric disorders that cannot be understood by simplistic synaptic transmission and receptor models.


Clinical Spectrum of Action of the Antidepressants

Although depression has often been viewed as a unified disease process, there is great diversity in clinical presentations. As more sophisticated neurotransmitter and neuroanatomic theories evolve, our clinical conceptions of affective syndromes are also evolving. Pedro Delgado, MD,[11] Chairman, Department of Psychiatry, Case Western Reserve University, Cleveland, Ohio, presented the varied presentations of depressive syndromes.

Emotional responses consist of both positive as well as negative affects. Some of the positive emotions include pleasure, happiness, enthusiasm, interest, surprise, and creativity. Negative affects include anger, irritability, sadness, guilt, and worry. In order to adequately assess depressive states, both of these affective states must be considered. The monoamines act as neuromodulators and act on different aspects of brain function. Norepinephrine is more involved in motivation, energy, interest, and concentration. Serotonin is more involved in impulsivity, sexual function, and appetite. The 2 neurotransmitters overlap in mood, sleep, stress, and pain. Treatment with SSRIs may result in emotional blunting, which is not seen with the drugs effecting norepinephrine.

Although pain complaints are increased in depression, some of the most frequent complaints in nondepressed individuals are related to pain. Kellner and colleagues[12] noted that 64% of depressed patients complained of headaches compared with 48% of controls. Muscle aches and "rheumatism" were reported in 53% of psychiatric patients and 27% of controls. Stomach and chest pain complaints were similarly high. The dual reuptake inhibitor duloxetine was effective in reversing neuropathic pain as well as pain in the formalin model of persistent pain.[13-15] Relief of pain is not restricted to this antidepressant, however, as TCAs, venlafaxine, and bupropion have also been shown to be effective. Each of these agents has dual reuptake properties. SSRIs with single neurotransmitter efficacy have not been shown to be effective in chronic pain.

Given the differing profiles of each of the neurotransmitters, it is expected that therapeutic as well as side effect profiles will differ. This has been observed with bupropion, a dual noradrenergic and dopaminergic reuptake inhibitor that has less sexual dysfunction than agents acting on the serotonergic system. The combination of several neurotransmitters may result in synergistic actions not achieved with a single neurotransmitter acting agent. For example, venlafaxine has been shown to produce greater remission rates compared with some of the SSRIs.[16]

Unfortunately, the scales currently used in depression studies do not measure the necessary psychological traits to determine if there is differential effect. For example, scales such as the Hamilton Depression Rating scales and the Beck Depression Scale measure a restricted range of symptoms directly related to the depressive syndrome. They do adequately measure traits such as motivation and impulsivity that may also be regulated by antidepressant therapy.


The Spectrum of Serotonin Responsive Disorders

Serotonergic agents have proven efficacy for a broad range of disorders, and John Greist, MD,[17] of the University of Wisconsin, reviewed this spectrum of disorders. The SSRIs have been found to be efficacious in all of the anxiety disorders, depression, and eating disorders. There is a wide area of overlap between anxiety and depressive disorders. Two thirds of patients with depression have symptoms of anxiety. Furthermore, many of the symptoms of depressive disorders are also common to anxiety disorders. Some of these common symptoms include agitation, problems in concentration, insomnia, irritability, fatigue, and somatic symptoms, among others. Other clinical syndromes that have been responsive to the SSRIs include premenstrual dysphoric disorder,[18] bulimia,[19] and impulse disorders, as well as other syndromes.

Although medications acting on the serotonergic system are effective in many disorders, there are indications that psychotropic agents with a broader spectrum of activity may have greater therapeutic impact. In a study by Greist and colleagues[20] the serotonergic agents fluoxetine, fluvoxamine, and sertraline were equally efficacious in OCD. Alternatively, the noradrenergic reuptake inhibitor desipramine is not effective in OCD. However, Greist and associates found that the dual reuptake inhibitor clomipramine was more effective then any of the SSRIs. Furthermore, McDougle and associates[21] found that addition of the D2 receptor blocker haloperidol also resulted in significant improvement of OCD. Eleven of 17 patients responded to the combination of agents compared with 0 of 17 patients given placebo. In a second study, McDougle and colleagues[22] found that risperidone augmentation was also helpful in patients with OCD. Of the patients treated with risperidone, 7 of 14 were responders, compared with a 0 of 14 response rate for placebo.

With regard to generalized anxiety disorder (GAD), paroxetine was shown to be more efficacious than placebo.[23] The agent was not significantly better until week 7, however. When the dual reuptake agent venlafaxine was compared with placebo, efficacy began at week 1 and continued throughout the 28 weeks of the trial.[24] The dual reuptake mechanism appeared to confer some additional therapeutic benefit, although head-to-head comparison between the 2 agents would have to be carried out to test this hypothesis.


Norepinephrine Responsive Disorders

James J. Hudziak, MD,[25] Director, Behavioral Genetics, University of Vermont, discussed the emerging data concerning the role of norepinephrine in the psychiatric disorders. The use of noradrenergic medications in the treatment of ADHD has highlighted the role of this monoamine in maintaining focus, alertness, and augmenting executive functioning. The current development and testing of more specific noradrenergic agents like atomoxetine and reboxetine will further highlight and define the role of noradrenaline.

Noradrenergic and dopaminergic agents have been shown to be effective in depression and some of the anxiety disorders. However, medications acting on these monoamines also are useful in the treatment of ADHD, oppositional defiant disorder, smoking, obesity, and some addictive behaviors (Table).[25] It has been estimated that 10 million people in the United States suffer from ADHD, 45 million people in the United States smoke, and 93 million have problems with obesity.[26] Since the noradrenergic and dopaminergic systems are involved in the pathogenesis in these disorders, more attention to the role of these monoamines in psychiatry is warranted. The Table shows the specificity of the various neurotransmitters in behavioral disorders.


Table. Neurotransmitters in Various Disorders

  MDD GAD Panic OCD PMDD Phobia Smoking ADHD Obesity
Serotonin X X X X X X      
Norepinephrine X X X     X X X X
Dopamine X           X X X

Although methylphenidate and other stimulant medications have been the mainstay of treatment for ADHD, nonstimulant medications have also shown efficacy.[27] The noradrenergic TCA desipramine was shown to be efficacious by Biederman and colleagues,[28] as was the dual noradrenergic and dopaminergic reuptake inhibitor bupropion.[29] A new specific noradrenergic inhibitor, atomoxetine, improved the symptoms of ADHD in a study by Michelson and associates.[30] In addition to enhancement of attention and lessening of hyperactivity, family and social functioning also improved with this agent.


Maximizing Antidepressant Response

As discussed above, despite the proven efficacy of the SSRIs, numerous studies have shown greater efficacy with dual neurotransmitter antidepressants. James Nelson, MD,[31] of Yale University School of Medicine, discussed the advantages of multiple neurotransmitter treatment for affective disorders.

In review of 15 double-blind studies consisting of more than 1500 patients, the rate of response was equal for SSRIs (61.4%) and NRIs (59.5%).[32] Alternatively, in a 6-week study in treatment-resistant patients with unipolar depression, a combination of fluoxetine and desipramine was much more efficacious than either agent used alone. The dual reuptake antidepressant clomipramine was shown to be significantly better in depressed patients when compared with the SSRI paroxetine.[33] Similarly, the dual reuptake agent venlafaxine was more effective compared with fluoxetine in melancholic inpatients.[34] Thase and colleagues[16] confirmed this superiority in a meta-analysis of 8 studies including more than 1600 patients comparing venlafaxine with a variety of SSRIs. Venlafaxine was superior in producing remission compared with the SSRIs in all of the studies. The dual acting agent mirtazapine (15-45 mg), was superior compared with paroxetine (20-40 mg) in depressed patients older than aged 65 years.[35] The response rate to mirtazapine was significantly better as early as week 1.

The dual reuptake inhibitor duloxetine was found to be significantly superior to placebo at a dose of 60 mg.[36] When compared in a head-to-head study with fluoxetine,[37] duloxetine was numerically superior to the SSRI on most outcome measures. The rate of remission was 56% in duloxetine-treated patients, 30% in fluoxetine-treated patients, and 32% in patients treated with placebo. The remission rate was significantly better for duloxetine compared with placebo, but not fluoxetine, however.



Numerous studies have demonstrated that the neurotransmitters serotonin, norepinephrine, and dopamine have a different clinical spectrum of action. For example, serotonergic agents are effective in OCD, while noradrenergic medications are not. In contrast, patients with ADHD respond to noradrenergic but not serotonergic agents. In addition, emerging data indicate that there is a synergistic effect when dual neurotransmitter actions are combined. Greater remission rates have been noted in depressed patients treated with dual acting agents, and chronic pain responds best to combined noradrenergic and serotonergic medications. The introduction of more specific medications targeting the noradrenergic system as well as dual acting agents are both broadening our therapeutic reach as well as enhancing therapeutic responses.

*This section mentions off label uses for some medications. These may describe clinical uses for medications that have not been approved by the FDA.



  1. Sanacora G. Serotonin and norepinephrine mechanisms of action. Program and abstracts of the American Psychiatric Association 155th Annual Meeting; May 18-23, 2002; Philadelphia, Pennsylvania. ISS 36.
  2. Bunney WE Jr, Davis JM. Norepinephrine in depressive reactions. A review. Arch Gen Psychiatry. 1965;13:483-494.
  3. Schildkraut JJ. The catecholamine hypothesis of affective disorders: a review of supporting evidence. Am J Psychiatry. 1965;122:509-522.
  4. Charney DS, Heninger GR, Sternberg DE, et al. Presynaptic adrenergic receptor sensitivity in depression. The effect of long-term desipramine treatment. Arch Gen Psychiatry. 1981;38:1334-1340.
  5. Delgado PL, Charney DS, Price LH, Landis H, Heninger GR. Neuroendocrine and behavioral effects of dietary tryptophan restriction in healthy subjects. Life Sci. 1989;45:2323-2332.
  6. Delgado PL, Miller HL, Salomon RM, Licinio J, Krystal JH, Moreno FA, Heninger GR, Charney DS. Tryptophan-depletion challenge in depressed patients treated with desipramine or fluoxetine: implications for the role of serotonin in the mechanism of antidepressant action. Biol Psychiatry. 1999;46:212-220.
  7. Miller HL, Delgado PL, Salomon RM, et al. Clinical and biochemical effects of catecholamine depletion on antidepressant-induced remission of depression. Arch Gen Psychiatry. 1996;53:117-128.
  8. Heninger GR, Delgado PL, Charney DS. The revised monoamine theory of depression: a modulatory role for monoamines, based on new findings from monoamine depletion experiments in humans. Pharmacopsychiatry. 1996;29:2-11.
  9. Paul IA, Nowak G, Layer RT, Popik P, Skolnick P. Adaptation of the N-methyl-D-aspartate receptor complex following chronic antidepressant treatments. J Pharmacol Exp Ther. 1994;269:95-102.
  10. Duman RS, Heninger GR, Nestler EJ. A molecular and cellular theory of depression. Arch Gen Psychiatry. 1997;54:597-606.
  11. Delgado PL. Clinical outcome of serotonin and norepinephrine agents in depression. Program and abstracts of the American Psychiatric Association 155th Annual Meeting; May 18-23, 2002; Philadelphia, Pennsylvania. ISS 36.
  12. Kellner R, Sheffield BF. The one-week prevalence of symptoms in neurotic patients and normals. Am J Psychiatry. 1973;130:102-105.
  13. Simmons RM, Li DL, Hoo KH, Deverill M, Ornstein PL, Iyengar S. Kainate GluR5 receptor subtype mediates the nociceptive response to formalin in the rat. Neuropharmacology. 1998;37:25-36.
  14. Detke M, Goldstein D, Mallinckrodt C, Lu Y, Wiltse C, Demitrack M. Duloxetine: a potential new treatment for depressed patients with physical symptoms. Program and abstracts of the US Psychiatric & Mental Health Congress 2001; November 15-18, 2001; Boston, Massachusetts.
  15. Detke MJ, Lu Y, Goldstein DJ, Hayes JR, Demitrack MA. Duloxetine, 60 mg once daily, for major depressive disorder: a randomized double-blind placebo-controlled trial. J Clin Psychiatry. 2002;63:308-315.
  16. Thase ME, Entsuah AR, Rudolph RL. Remission rates during treatment with venlafaxine or selective serotonin reuptake inhibitors. Br J Psychiatry. 2001;178:234-241.
  17. Greist JH. The spectrum of serotonin-responsive disorders. Program and abstracts of the American Psychiatric Association 155th Annual Meeting; May 18-23, 2002; Philadelphia, Pennsylvania. ISS 36.
  18. Steiner M, Steinberg S, Stewart D, et al. Fluoxetine in the treatment of premenstrual dysphoria. Canadian Fluoxetine/Premenstrual Dysphoria Collaborative Study Group. N Engl J Med. 1995;332:1529-1534.
  19. Fluoxetine Bulimia Nervosa Collaborative Study Group. Fluoxetine in the treatment of bulimia nervosa. A multicenter, placebo-controlled, double-blind trial. Fluoxetine Bulimia Nervosa Collaborative Study Group. Arch Gen Psychiatry. 1992;49:139-147.
  20. Greist JH, Jefferson JW, Kobak KA, Katzelnick DJ, Serlin RC. Efficacy and tolerability of serotonin transport inhibitors in obsessive-compulsive disorder. A meta-analysis. Arch Gen Psychiatry. 1995;52:53-60.
  21. McDougle CJ, Goodman WK, Leckman JF, Lee NC, Heninger GR, Price LH. Haloperidol addition in fluvoxamine-refractory obsessive-compulsive disorder. A double-blind, placebo-controlled study in patients with and without tics. Arch Gen Psychiatry. 1994;51:302-308.
  22. McDougle CJ, Epperson CN, Pelton GH, Wasylink S, Price LH. A double-blind, placebo-controlled study of risperidone addition in serotonin reuptake inhibitor-refractory obsessive-compulsive disorder.
  23. Pollack MH, Zaninelli R, Goddard A, et al. Paroxetine in the treatment of generalized anxiety disorder: results of a placebo-controlled, flexible-dosage trial. J Clin Psychiatry. 2001;62:350-357.
  24. Gelenberg AJ, Lydiard RB, Rudolph RL, Aguiar L, Haskins JT, Salinas E. Efficacy of venlafaxine extended-release capsules in nondepressed outpatients with generalized anxiety disorder: a 6-month randomized controlled trial. JAMA. 2000;283:3082-3088.
  25. Hudziak JJ. The spectrum of norepinephrine-responsive disorders. Program and abstracts of the American Psychiatric Association 155th Annual Meeting; May 18-23, 2002; Philadelphia, Pennsylvania. ISS 36.
  26. Wittchen HU, Robins LN, Cottler LB, Sartorius N, Burke JD, Regier D. Cross-cultural feasibility, reliability and sources of variance of the Composite International Diagnostic Interview (CIDI). The Multicentre WHO/ADAMHA Field Trials. Br J Psychiatry. 1991;159:645-653, 658.
  27. Spencer T, Biederman J, Wilens T, Harding M, O'Donnell D, Griffin S. Pharmacotherapy of attention-deficit hyperactivity disorder across the life cycle. J Am Acad Child Adolesc Psychiatry. 1996;35:409-432.
  28. Biederman J, Baldessarini RJ, Wright V, Keenan K, Faraone S. A double-blind placebo controlled study of desipramine in the treatment of ADD: III. Lack of impact of comorbidity and family history factors on clinical response. J Am Acad Child Adolesc Psychiatry. 1993;32:199-204.
  29. Silver LB. Alternative (nonstimulant) medications in the treatment of attention-deficit/hyperactivity disorder in children. Pediatr Clin North Am. 1999;46:965-975. Review.
  30. Michelson D, Faries D, Wernicke J, et al; Atomoxetine ADHD Study Group. Atomoxetine in the treatment of children and adolescents with attention-deficit/hyperactivity disorder: a randomized, placebo-controlled, dose-response study. Pediatrics. 2001;108:E83.
  31. Nelson JC. Combining serotonin and norepinephrine mechanisms in depression. Program and abstracts of the American Psychiatric Association 155th Annual Meeting; May 18-23, 2002; Philadelphia, Pennsylvania. ISS 36.
  32. Nelson JC. A review of the efficacy of serotonergic and noradrenergic reuptake inhibitors for treatment of major depression. Biol Psychiatry. 1999;46:1301-1308.
  33. Danish University Antidepressant Group. Paroxetine: a selective serotonin reuptake inhibitor showing better tolerance, but weaker antidepressant effect than clomipramine in a controlled multicenter study. Danish University Antidepressant Group. J Affect Disord. 1990;18:289-299.
  34. Clerc GE, Ruimy P, Verdeau-Palles J. A double-blind comparison of venlafaxine and fluoxetine in patients hospitalized for major depression and melancholia. The Venlafaxine French Inpatient Study Group. Int Clin Psychopharmacol. 1994;9:139-143.
  35. Schatzberg AF. Benefits of different classes of antidepressants for geriatric depression. Program and abstracts of the American Psychiatric Association 154th Annual Meeting; May 5-10, 2002; New Orleans, Louisana. ISS 18.
  36. Detke MJ, Lu Y, Goldstein DJ, Hayes JR, Demitrack MA. Duloxetine, 60 mg once daily, for major depressive disorder: a randomized double-blind placebo-controlled trial. J Clin Psychiatry. 2002;63:308-315.
  37. Goldstein DJ, Mallinckrodt C, Lu Y, Demitrack MA. Duloxetine in the treatment of major depressive disorder: a double-blind clinical trial. J Clin Psychiatry. 2002;63:225-231.