The new antidepressants - mechanisms of action
Trevor R. Norman, Associate Professor, Department of Psychiatry, University of Melbourne, Austin and Repatriation Medical
Centre, Melbourne
(Aust Prescr 1999;22:106-8)
SYNOPSIS
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.
Introduction
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. This causes an initial increase in serotonin only at the cell body and the dendrites, not at axon terminals.
The immediate consequence is to inhibit the rate of firing of serotonin neurons (and the release of serotonin) by an action
at 5HT1A somatodendritic autoreceptors.
Longer-term exposure to serotonin eventually causes downregulation of
these 5HT1A autoreceptors 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 downregulate. The downregulation 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 downregulation
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.
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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 autoreceptors.
(C) Long-term administration causes downregulation of 5HT1A
autoreceptors, increasing firing rate of neuron. In the presence of blockade of reuptake, more serotonin is available to act
postsynaptically.
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Fig. 2
Downregulation
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 upregulation).
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 downregulation).
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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.
Venlafaxine
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.
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 downregulation of postsynaptic b1 receptors occurs following single and repeated doses of venlafaxine (tricyclics
cause b1 adrenoceptor downregulation 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
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 downregulation of cortical 5HT2A receptors as well as
b1 adrenoceptor downregulation. 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.
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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 |
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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. |
Overview
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 multifactorial 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.
R E F E R E N C E S
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.
FURTHER READING
Stahl SM. Essential psychopharmacology: neuroscientific basis and clinical applications.
Cambridge: Cambridge University Press; 1996.
Stahl SM. Psychopharmacology of antidepressants. London: Martin Dunitz; 1997.
