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Within each class or subclass drugs are listed in order of frequency of prescription in the United Kingdom ( 1997 data). Abbreviations; RIMA—reversible inhibitor of monoamine oxidase; NaRI—noradrenaline reuptake inhibitor; SNRI—serotonin and noradrenaline reuptake inhibitor; NaSSA—noradrenaline and specific serotonergic antidepressant.

* Citalopram is a racemic mixture of S and R isomers.The antidepressant activity of citalopram appears to reside in the S-isomer. Escitalopram the pure S-isomer, may offer clinical benefits over existing preparations.

f Trazodone, nefazodone and mirtazapine have been classed as 'receptor blocking' antidepressants based on their antagonism of postsynaptic serotonin receptors (trazodone, nefazodone) and presynaptic a2-receptors (trazodone, mirtazapine). Nefazodone has additional weak SSRI activity, jl Not available in the United Kingdom.

Within each class or subclass drugs are listed in order of frequency of prescription in the United Kingdom ( 1997 data). Abbreviations; RIMA—reversible inhibitor of monoamine oxidase; NaRI—noradrenaline reuptake inhibitor; SNRI—serotonin and noradrenaline reuptake inhibitor; NaSSA—noradrenaline and specific serotonergic antidepressant.

* Citalopram is a racemic mixture of S and R isomers.The antidepressant activity of citalopram appears to reside in the S-isomer. Escitalopram the pure S-isomer, may offer clinical benefits over existing preparations.

f Trazodone, nefazodone and mirtazapine have been classed as 'receptor blocking' antidepressants based on their antagonism of postsynaptic serotonin receptors (trazodone, nefazodone) and presynaptic a2-receptors (trazodone, mirtazapine). Nefazodone has additional weak SSRI activity, jl Not available in the United Kingdom.

years the TCA class enlarged to more than 10 agents with heterogeneous pharmacological profiles and further modifications of the original three ring structure gave rise to the related (but pharmacologically distinct) antidepressant trazodone.

In the 1980s an entirely new class of antidepressant arrived with the SSRIs, firstly fluvoxamine immediately followed by fluoxetine (Prozac). Within 10 years, the SSRI class accounted for half of antidepressant prescriptions in the United Kingdom. Further developments in the evolution of the antidepressants have been novel compounds such as venlafaxine, reboxetine, nefazodone and mirtazapine, and a reversible monoamine oxidase inhibitor, moclobemide.

Mechanism of action

The monoamine hypothesis proposes that, in depression, there is deficiency of the neurotransmitters noradrenaline and serotonin in the brain which can be altered by antidepressants. Drugs that affect depression can modify amine storage, release, or uptake (Fig. 19.2). Thus the concentration of amines in nerve endings and/or at postsynaptic receptors is enhanced. In support of the monoamine hypothesis are the findings that amfetamines, which release presynaptic noradrenaline and dopamine from stores and prevent their reuptake, have a weak antidepressant effect, whilst the antihypertensive agent reserpine, which prevents normal noradrenaline storage, causes depression, as does experimental depletion of the serotonin precursor tryptophan. The importance of serotonin is further illustrated by the finding that depressed patients may exhibit down-regulation of some postsynaptic serotonin receptors.

Specific serotonin reuptake inhibitors, as the class name implies, act predominantly by preventing serotonin reuptake and have more limited effects on noradrenaline reuptake. Tricyclic antidepressants in general inhibit noradrenaline reuptake, but effects on serotonin reuptake vary widely; desipra-mine and protriptyline have minimal potential for raising serotonin concentrations, whereas clomipramine possesses a greater propensity for blocking serotonin reuptake than for noradrenaline. The

1950s

1960s

1970s

1930s

1990s

Reuptake inhibitors

Tricyclics

Amitriptyline Imipramine

Predominantly noradrenergic TCAs

Desipramine

! Predominantly : seratonergic TCAs

; Clomipramine

SSRIs

Fluoxetine Paroxetine

Receptor blockers

Mianserin11 Trazodone

SNRIs

Venlafaxine

Nefazodonet

NaRls

Reboxetine

Mirtazapine ¡

Monoamine Oxidase Inhibitors

Phenelzine

Enzyme inhibitors

RIMAs

Moclobemide

Key-Drugs classes in boxed, shaded fields represent the three major antidepressants groups, tricyclics

(TCAs), selective serotonin reuptake inhibitors (SSRIs) and monoamine oxidase inhibitors.

Novel compounds are left unboxed.

NaRI-noradrenaline reuptake inhibitor

SNRI-serotonin and noradrenaline reuptake inhibitor

RIMA-reversible inhibitor of monoamine oxidase

*-Mianserin is rarely used due to associations with aplastic anaemia t-Nefazodone is both a reuptake inhibitor and receptor blocker

Fig. 19.1 Flow chart of the evolution of antidepressant drugs and classification by mechanism of action.

novel compound venlafaxine is capable of exerting powerful inhibition of reuptake of both transmitters, noradrenergic activity appearing at doses greater than 200 mg/day. Mirtazapine also achieves an increase in noradrenergic and serotonergic neurotransmission, but through antagonism of presynaptic a2-autoreceptors (receptors that mediate negative feedback for transmitter release, i.e. an autoinhibi-tory feedback system). Nefazodone has properties of weak serotonin reuptake inhibition but additionally has complex but principally antagonist effects on postsynaptic serotonin receptors, a property it shares with trazodone.

MAOIs increase the availability of noradrenaline and serotonin by preventing their destruction by the monoamine oxidase type A enzyme in the presynaptic terminal. The older MAOIs, phenelzine, tranylcypromine and isocarboxazid, bind irreversibly to monamine oxidase enzyme by forming strong (covalent) bonds. The enzyme is thus rendered permanently ineffective such that amine metabolising activity can be restored only by production of fresh enzyme, which takes weeks. These MAOI are thus called hit and run drugs as their effects greatly outlast their detectable presence in the body.

But how do changes in monoamine transmitter levels produce an eventual elevation of mood? Raised neurotransmitter concentrations produce immediate alterations in postsynaptic receptor activation, leading to changes in second messenger (intracellular) systems and to gradual modifications in cellular protein expression. Antidepressants increase a cyclic AMP response-element binding (CREB) protein which in turn is involved in

Physiological processes at the synapse:

1. When an electrical signal reaches the presynaptic terminal, presynaptic amine vesicles fuse with the neuronal membrane and release their contents into the synaptic cleft.

2. Amines in the synaptic cleft bind to postsynaptic receptors to produce a post synaptic response.

3. Amines may be removed from the synaptic cleft by reuptake into the presynaptic neuron.

4. The monoamine oxidase enzyme breaks down presynaptic amines.

Effects of antidepressants:

A. Tricyclics prevent presynaptic reuptake of the amines nonadrenaline and serotonin

B. SSRIs predominantly block reuptake of serotonin.

C. MAOIs reduce the activity of monoamine oxidase in breaking down presynaptic amines (leaving more available for release into the presynaptic cleft).

D. Some antidepressants (e.g. nefazodone) block postsynaptic receptors directly.

Fig. 19.2 Mechanism of action of antidepressant drugs at the synapse.

Synaptic cleft

Presynaptic neuron

Postsynaptic receptors i.'-'V ' - . . . ^ 1 ■ ■ ' .

Induction of postsynaptic effects

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