Psychopharmacology Research Tutorial for Practitioners - Antidepressant Drugs: Is a Dual Mechanism Better?

Donald S. Robinson, MD

Primary Psychiatry. 2004;11(8):17-18

The Monoamine Hypothesis of Depression

In the 1950s the serendipitous and nearly simultaneous discovery of the first antidepressant medications, iproniazid and imipramine, predated any understanding of the pharmacologic mechanism of action of drugs effective for the treatment of depressive disorders. Iproniazid was subsequently found to inhibit monoamine oxidase, the enzyme that degrades monoamine neurotransmitters, while imipramine was discovered to inhibit reuptake of monoamines released at nerve terminals. To a large extent, discovery of the pharmacologic actions of these antidepressants fostered promulgation of the catecholamine and monoamine hypotheses of depression. Enhancement of monoamine neurotransmitter function remains the putative mechanism of action of all antidepressants even today. Whether norepinephrine (NE) or serotonin (5-hydroxytryptamine [5-HT]) is the more critical neurotransmitter in the pathophysiology and treatment of depression is still an open question.

5-HT was an early candidate for acting as mediator of mood in the central nervous system (CNS) because of its presence in key brain regions, its structural similarity to lysergic acid diethylamide, and the fact that reserpine, an antihypertensive agent that can cause depression, depletes neuronal stores of monoamines, especially intracellular serotonin.1 The focus later shifted from 5-HT to NE as the more critical neurotransmitter in depressive disorders. This was based primarily on the seminal work of Nobel laureate Julius Axelrod, who found NE to be widely distributed in the CNS and synaptically released at adrenergic nerve endings, with its reuptake into the neuron inhibited by tricyclic antidepressants (TCAs). Arvid Carlsson, also a Nobel laureate, subsequently found that clomipramine, a TCA widely used in Europe for treating depression, inhibited 5-HT reuptake to a greater extent than NE reuptake.1

It became apparent during extensive investigation that individual TCAs varied considerably in their ability to affect either or both 5-HT and NE transporter systems. Imipramine and amitriptyline, two of the most widely prescribed TCAs, were found to inhibit reuptake of 5-HT and NE to a similar extent. The monoamine oxidase inhibitors (MAOIs), which in the 1960s gained initial clinical popularity as being broadly effective antidepressants,2 had long been known to increase neuronal stores of both 5-HT and NE in the brain by inhibiting the catabolism of monoamines.

Gradually, a large body of data accumulated showing that both MAOIs and TCAs essentially functioned as dual-mechanism antidepressants. Even though the pharmacologic mechanisms of action of these antidepressants were understood, how exactly this translated into producing antidepressant treatment response remains unclear. Depending on the specific drug, differing monoamine neurotransmitter systems might be involved, and cause an antidepressant response. Another unanswered dilemma revolves around why the onset of clinical benefit for all antidepressants is typically delayed for up to several weeks, while the pharmacologic effects of antidepressants are evident nearly immediately.

Selectivity of Reuptake Inhibition

It was not until the 1970s that the first selective inhibitor of monoamine reuptake was synthesized. Zimelidine, the first selective serotonin reuptake inhibitor (SSRI), was marketed only in Europe and was followed soon thereafter by fluoxetine, the first SSRI in the United States. These two drugs were the forerunners of a new and highly successful class of antidepressants. SSRIs proved to be broadly effective in the treatment of mood disorders, but more importantly, they were also better tolerated and safer than TCAs and MAOIs because of their highly specific affinity for the 5-HT transporter system. This pharmacology translated into a desirable therapeutic profile (of lower toxicity than earlier antidepressants) and led to the wide popularity of these drugs among general physicians as well as psychiatrists.

The clinical effectiveness of the selectively-acting 5-HT drugs for mood disorders resulted in a rethinking of the roles that 5-HT and NE played in the pathophysiology of depressive disorders and in the treatment of depression. Within the pharmaceutical industry, the search for new antidepressants shifted to highly specific receptor affinity and targeting either the 5-HT or NE system in order to discover drugs with fewer side effects and/or enhanced efficacy.

Several relatively specific norepinephrine reuptake inhibitors (NRIs) have proven to be clinically effective antidepressants and are still available, including the TCAs desipramine, nortriptyline, and protriptyline, as well as the tetracyclic drug maprotiline. The NRI reboxetine was approved recently for antidepressant use in Europe but is not available in the US. Since NRIs have been shown to be effective antidepressants, this leads to the question of whether NE might be the primary neurotransmitter in depressive disorders and a preferred target for new antidepressant development. Recent data show that increased brain NE levels may prevent neuronal atrophy in the cortex by enhancing nerve growth factors and possibly augmenting the beneficial effects of NRIs.3

Single Versus Dual Mechanisms of Uptake Inhibition

Although the advent of the SSRIs unquestionably altered antidepressant prescribing patterns—with the additional effect that significantly more depressed patients now receive drug treatment than a decade ago—SSRIs have also acquired a reputation, perhaps undeserved, as being less effective than the older antidepressants that involve dual mechanisms of action. Two recent drugs, venlafaxine and duloxetine, which act by inhibiting both the 5-HT and the NE transporters with high specificity, have been touted as “dual mechanism antidepressants,” with the inference that they potentially have superior efficacy compared with single mechanism antidepressants.4 The claim of superior therapeutic benefits of these dual mechanism drugs remains controversial because of a paucity of data from well-controlled comparative studies (ie, prospective trials specifically designed for comparing efficacy with a standard antidepressant). Moreover, there continues to be lack of understanding as to the precise roles that 5-HT and NE may play in depressive disorders and in response to treatment. Studies seem to indicate that both 5-HT and NE systems play pivotal roles in antidepressant response through neuronal interplay and reciprocal interactions on cell bodies of these two monoamines.5

Findings of Comparative Antidepressant Trials

For a comprehensive review of basic science and clinical data relating to dual-mechanism antidepressants, the reader is directed to an article by Schatzberg6 summarizing existing data from comparative clinical trials. The largest number of comparative trials are studies involving SSRIs and TCAs. A pattern of better tolerability of SSRIs compared to TCAs is clearly evident in these trials, as would be expected because the latter interact with multiple receptors, including muscarinic, histaminic, and a-adrenergic receptors, producing many unwanted side effects. These comparative trials all suffer from the significant study design limitation that they were not prospectively designed to specifically assess relative efficacy of an SSRI with a TCA. Many of the comparative trials also were not placebo-controlled. Because the studies were not powered statistically to differentiate efficacy of an SSRI and TCA, for most studies the degree of improvement was found not to differ significantly for the comparative antidepressants.

Attempts to overcome these shortcomings in the data have involved various statistical approaches, including the method of meta-analysis (limitations of this statistical methodology were discussed in a previous tutorial). Some meta-analyses of comparative studies were confined to only placebo-controlled trials, others to severely depressed subjects, inpatients, etc. These various meta-analyses have found only trivial differences in efficacy between SSRIs and TCAs.7 There are even fewer trials that allow comparison of the more recent SSRI/NRI drugs (eg, venlafaxine or duloxetine) with an SSRI.

A meta-analysis of venlafaxine studies involved eight clinical trials; only four of these were placebo-controlled.7 Three different comparative SSRIs were studied in these trials. It appears that suboptimal dosage of the SSRI comparator was employed in some of the studies. Although a higher remission rate was claimed for venlafaxine, the data do not conclusively show the overall therapeutic advantage of venlafaxine. Subsequent re-analyses, adjusted for some of the shortcomings of the initial meta-analysis, also fail to demonstate the clear-cut therapeutic advantage of venlafaxine over SSRIs.7

In the case of the dual-mechanism drug duloxetine, there have been even fewer published placebo-controlled comparative studies with an SSRI. Similar to the findings with venlafaxine, the data from comparative trials fail to show the statistical superiority of the efficacy of duloxetine compared with that of an SSRI.8


Despite extensive research efforts over a span of several decades, the precise mechanism of action of antidepressants remains unclear. While both 5-HT and NE are deemed important mediators of antidepressant drug response, uncertainty remains as to which neurotransmitter may be the more critical in the pathophysiology of mood disorders and for treatment of depression. Based on the fact that current evidence from clinical trials is insufficient to allow valid conclusions about relative efficacy, caution should be exercized in accepting claims that multiple mechanism (two or more) drugs are superior in efficacy to single mechanism antidepressants. More data from prospective well-controlled comparative trials are warranted. PP


1. Owens MJ. Selectivity of antidepressants: from the monoamine hypothesis of depression to the SSRI revolution and beyond. J Clin Psychiatry. 2004;65(suppl 4):5-10.

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

3. Anand A, Charney DS. Norepinephrine dysfunction in depression. J Clin Psychiatry. 2000;61(suppl 10):16-24.

4. Thase ME, Entsuah AR, Rudolph RL. Remission rates during treatment with venlafaxine or selective serotonin reuptake inhibitors. Br J Psychiatry. 2001;178:234-241.

5. Blier P. Possible neurobiological mechanisms underlying faster onset of antidepressant action. J Clin Psychiatry. 2001;62(suppl 4):7-11. Discussion in: J Clin Psychiatry. 2001;62(suppl 4):37-40.

6. Schatzberg AF. Pharmacologic treatments of major depression: are two mechanisms really better than one? J Clin Psychiatry. 2004;65(suppl 4):3-4.

7. Burke WJ. Selective versus multi-transmitter antidepressants: are two mechanisms better than one? J Clin Psychiatry. 2004;65(suppl 4):37-45.

8. Hirschfeld RM, Vornik LA. Newer antidepressants: review of efficacy and safety of escitalopram and duloxetine. J Clin Psychiatry. 2004;65(suppl 4):46-52.

Dr. Robinson is a consultant with Worldwide Drug Development in Melbourne, Florida.

Disclosure: Dr. Robinson is a consultant to Bristol-Myers Squibb, Genaissance, Organon, Somerset, and Takeda.