Experimental and clinical pharmacology

The new antidepressants - mechanisms of action

Aust Prescr 1999;22:106-8 | 1 October 1999

Trevor R. Norman, Associate Professor, Department of Psychiatry, University of Melbourne, Austin and Repatriation Medical Centre, Melbourne


Citalopram, fluvoxamine, nefazodone and venlafaxine have recently been introduced into Australian clinical practice. The first two drugs are selective serotonin reuptake inhibitors, while the others have different acute pharmacological effects. The role of somatodendritic 5HT1A autoreceptors in the therapeutic effect of the SSRIs is important. For venlafaxine and nefazodone, downregulation of the postsynaptic b1 adrenoceptor and 5HT receptor appears to be important. The adverse effects of these new medications can be understood in terms of their effects on central and peripheral serotonergic and adrenergic receptors. A mechanism of action common to all antidepressants is yet to be identified, but given the complex nature of depression, perhaps should not be expected.

Key words: selective serotonin reuptake inhibitors, nefazodone, venlafaxine.

Several new antidepressant drugs have been introduced during the past decade. These drugs differ from each other and from older antidepressants (the tricyclics and monoamine oxidase inhibitors) both in terms of their chemical structure and their putative mechanism of action. Despite these significant pharmacological differences, neither efficacy nor speed of onset of action appears to have been altered substantially. Two new selective serotonin reuptake inhibitors (SSRIs), citalopram and fluvoxamine, together with nefazodone and venlafaxine, are the latest antidepressants to be marketed in Australia.

Mechanism of action of the new antidepressants
Selective serotonin reuptake inhibitors
In common with the three better known SSRIs, fluoxetine, paroxetine and sertraline, both citalopram and fluvoxamine have a selective effect on the serotonin reuptake pump.1,2 This causes an initial increase in serotonin only at the cell body and the dendrites, not at axon terminals (Fig. 1). The immediate consequence is to inhibit the rate of firing of serotonin neurons (and the release of serotonin) by an action at 5HT1A somatodendritic auto receptors.

Longer-term exposure to serotonin eventually causes down regulation (Fig. 2) of these 5HT1A auto receptors and disinhibition of serotonin release at axon terminals. The delay in producing the increase in serotonin at the terminals is usually taken as the reason for the delayed onset of action of the SSRIs. The increased release of serotonin at the axons, in the presence of an inhibited serotonin reuptake pump, increases availability of serotonin to postsynaptic serotonin receptors. These receptors may eventually down regulate. The down regulation of postsynaptic serotonin receptors also occurs during long-term treatment with tricyclic antidepressants and monoamine oxidase inhibitors.

For some SSRIs, chronic administration is also associated with a down regulation of postsynaptic b1 adrenoceptors, but this has not been observed for citalopram, fluoxetine or fluvoxamine. While this effect is common to other antidepressants, including nefazodone and venlafaxine, it may not be necessary for clinical efficacy. The effect of SSRIs on serotonin neurotransmission may be sufficient to explain their antidepressant effects.

Fig. 1

Mechanism of action of selective serotonin reuptake inhibitors

(A) Hypothetical serotonergic neuron.

(B) Short-term administration of SSRI blocks reuptake of serotonin at cell body leading to decreased firing of neuron due to the action of serotonin on 5HT1A auto receptors.

(C) Long-term administration causes down regulation of 5HT1A auto receptors, increasing firing rate of neuron. In the presence of blockade of reuptake, more serotonin is available to act post synaptically.


Fig. 2

Down regulation

The depletion of neurotransmitter acting at a postsynaptic receptor results in a compensatory increase in the number of receptor sites on the postsynaptic cell surface (so-called up regulation).


A long-lasting increase in the availability of neurotransmitter at a synaptic receptor site results in a decrease in the number of receptors on the cell surface (so-called down regulation).


The increased availability of serotonin at serotonin receptors in the central nervous system and elsewhere can explain many of the adverse effects of this class of medication. Stimulation of 5HT3 receptors is probably responsible for nausea, gastrointestinal discomfort, diarrhoea and headache, which often occur at the start of treatment. Similarly, agitation, akathisia, anxiety, panic attacks, insomnia and sexual dysfunction may be related to an action at 5HT2 receptors. Sexual dysfunction may also be due to disinhibition of the descending serotonin pathway from the brain stem through the spinal chord to neurons mediating spinal reflexes such as ejaculation and orgasm. The increased serotonin release inhibits sexual functioning.

Like the SSRIs, venlafaxine has acute pharmacological effects on the reuptake of serotonin by presynaptic nerve terminals. It has a simultaneous effect on noradrenaline reuptake and some weak effects on dopamine reuptake (Table 1). The combination of the effects on the reuptake mechanisms appears to be responsible for the antidepressant action of the drug.3

The reuptake effects of venlafaxine are dose dependent. At low doses (<150 mg/day), the drug acts like the SSRIs. At intermediate to high doses, the additional effects on noradrenaline reuptake become important. In this respect, venlafaxine can be regarded as analagous to the older tricyclic antidepressants, with the exception that down regulation of postsynaptic b1 receptors occurs following single and repeated doses of venlafaxine (tricyclics cause b1 adrenoceptor down regulation only after repeated doses). A possible clinical correlate of this pharmacological effect is a faster onset of action of venlafaxine, although this has not been systematically demonstrated in appropriately designed studies.

Venlafaxine has little `in vitro' affinity for muscarinic cholinergic, histamine H1 and adrenergic receptors, suggesting a more favourable adverse effect profile when compared to tricyclic antidepressants. Nausea, agitation, sexual dysfunction and insomnia at low doses of venlafaxine are probably mediated by effects on postsynaptic serotonergic receptors. At intermediate to high doses, additional adverse effects such as raised blood pressure and headache are observed in some patients. These effects are probably due to an action on adrenergic receptors.

Nefazodone has a unique pharmacological effect. It acts as a potent and selective antagonist of postsynaptic 5HT2A receptors. In addition, there is a moderate effect on presynaptic reuptake of both serotonin and noradrenaline. Both actions of the drug appear to be necessary for its clinical effect, but 5HT2A antagonism is probably the main action.4 Chronic administration of nefazodone results in a down regulation of cortical 5HT2A receptors as well as b1 adrenoceptor down regulation. Together, these actions of the drug are thought to increase serotonergic neurotransmission particularly at postsynaptic 5HT1A receptors.

In vitro receptor binding studies show that nefazodone has little or no affinity for a range of other receptors including muscarinic cholinergic, histamine H1, GABA-A and dopamine D1 and D2 receptors. These data suggest that the drug is likely to lack some of the adverse effects common to tricyclic antidepressants. Blockade of 5HT2 receptors probably accounts for some of the adverse effects of nefazodone including somnolence, asthenia and the rare event of visual streaking (palinopsia).

Formation of a metabolite, m-chlorophenylpiperazine (mCPP), which acts as a non-selective agonist at 5HT2A, 2C and 5HT3 receptors, accounts for a number of adverse effects of nefazodone. Systemic exposure to mCPP is low (=<8%) under most circumstances, but it may be substantially increased in patients with a genetic deficiency of cytochrome P450 2D6 or when prior SSRI administration has inhibited this isoenzyme.

Table 1

Relative selectivity of new antidepressants for serotonin over noradrenaline and dopamine uptake

Drug Selectivity 5HT vs. noradrenaline Selectivity 5HT vs. dopamine
Citalopram 1500 3900
Paroxetine 320 1800
Sertraline 190 32
Fluvoxamine 180 >1600
Fluoxetine 20 170
Venlafaxine 3.1 13
Nefazodone 1.1 -
Clomipramine 13 1200
Imipramine 0.65 85
Amitriptyline 0.91 54

Citalopram is 1500 times more selective for serotonin reuptake than for noradrenaline. The data do not refer to the potency of an individual drug for serotonin reuptake. Thus, while citalopram is the most selective SSRI, it is a less potent reuptake inhibitor than either paroxetine or sertraline. Despite the variability, the selectivity does not significantly influence the choice of drug.

While the introduction of these new drugs has not revolutionised the treatment of major depression, they do have more favourable adverse effect profiles than either the tricyclic antidepressants or older non-selective monoamine oxidase inhibitors. The new drugs have diverse mechanisms of action based on their acute pharmacological effects; however, one drug does not appear to have any advantages over another in terms of efficacy or speed of onset of action. Neuroadaptive changes appear to be necessary before a therapeutic benefit is evident.

A common mechanism of action of antidepressant drugs has not been found. This stems partly from the failure to recognise the underlying cause(s) of depression and elaborate the biological substrate of the illness. The multi factorial nature of depression also suggests that it has more than a single cause. Furthermore, antidepressants tend to be broad spectrum drugs effective in anxiety states as well as depression, suggesting that many neuroreceptors are involved. Given the complex inter-relationship of neuronal systems, it is unlikely that changes in one would account for all of the manifestations of depression and anxiety.

Until better models of depression are devised, establishing the mode of action of antidepressants will be difficult. The current focus has been on alterations to simple neuronal models based around serotonin and noradrenaline. Clearly, these models are not sufficient to completely explain the clinical effects of antidepressants. More complex models, taking into account other transmitters or indeed adaptive changes at the level of the gene, may be necessary.


1 . Noble S, Benfield P. Citalopram: a review of its pharmacology, clinical efficacy and tolerability in the treatment of depression. CNS Drugs 1997;8:410-31.

2 . Wilde MI, Plosker GL, Benfield P. Fluvoxamine. An updated review of its pharmacology, and therapeutic use in depressive illness. Drugs 1993;46:895-924.

3 . Holliday SM, Benfield P. Venlafaxine. A review of its pharmacology and therapeutic potential in depression. Drugs 1995;49:280-94.

4 . Davis R, Whittington R, Bryson HM. Nefazodone. A review of its pharmacology and clinical efficacy in the management of major depression. Drugs 1997;53:608-36.


Stahl SM. Essential psychopharmacology: neuroscientific basis and clinical applications. Cambridge: Cambridge University Press; 1996.

Stahl SM. Psychopharmacology of antidepressants. London: Martin Dunitz; 1997.

Self-test questions

The following statements are either true or false.
Click anywhere on the panel for the answers.

1. The gastrointestinal adverse effects of selective serotonin reuptake inhibitors are probably caused by blockade of 5HT3 receptors.

2. The mechanism of action of the new antidepressants produces a clinical response much more rapidly than the tricyclic antidepressants.

First published online 1 October 1999
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