Neuutrarjrnilter If;




PosIsynaptK raoaptof


; * * -

PrËiyr.dplir. iiuliirFŒptç-'

Figure 20.1 Schematic diagram illustrating how antidepressants increase the concentration of extraneuronal neurotransmitter (noradrenaline and/or 5-HT). In the absence of drug (b), monoamine oxidase on the outer membrane of mitochondria metabolises cytoplasmic neurotransmitter and limits its concentration. Also, transmitter released by exocytosis is sequestered from the extracellular space by the membrane-bound transporters which limit the concentration of extraneuronal transmitter. In the presence of a MAO inhibitor (a), the concentration of cytoplasmic transmitter increases, causing a secondary increase in the vesicular pool of transmitter (illustrated by the increase in the size of the vesicle core). As a consequence, exocytotic release of transmitter is increased. Blocking the inhibitory presynaptic autoreceptors would also increase transmitter release, as shown by the absence of this receptor in the figure. In the presence of a neuronal reuptake inhibitor (c), the membrane-bound transporter is inactivated and the clearance of transmitter from the synapse is diminished ffl d o

are a2-adrenceptor antagonists and the ensuing increase in monoamine release is thought to account for their antidepressant effects (e.g. mianserin). (2) A second way of increasing synaptic concentrations of noradrenaline and 5-HT is to block their neuronal reuptake. Several groups of compounds act in this way and can be classified according to their relative selectivity for the noradrenaline and 5-HT transporters.

As described in the introduction, the first generation of antidepressant drugs comprised the MAO inhibitors and the reuptake blockers (e.g. imipramine) which became known as the tricyclic antidepressants (TCAs). The following section starts with a discussion of these two groups of compounds. Subsequent research concentrated on developing drugs that prevent the reuptake of either noradrenaline or 5-HT, like imipramine, but which lack its side-effects. Some drugs even combine reuptake inhibition with actions which increase transmitter release. Examples of all these types of compounds are given in Table 20.4. Whereas the newer antidepressants are a great improvement in terms of safety and tolerability, imipramine still remains the benchmark for efficacy. Full appraisals of antidepressants that are already in the clinic and those that are currently under development, together with their likely clinical and commercial impact, are to be found in Cheetham and Heal (2000) and Heal and Cheetham (1999).


With the exception of tranylcypromine (a phenylcycloalkylamine), the first MAOIs (e.g. iproniazid, isoniazid, phenelzine, isocarboxazid) were derivatives of hydrazine (originally used as a rocket fuel) (Fig. 20.2). All are irreversible inhibitors of the enzyme and restoration of MAO activity requires the synthesis of new enzyme.

As described above, because MAO is bound to mitochondrial outer membranes, MAOIs first increase the concentration of monoamines in the neuronal cytosol, followed by a secondary increase in the vesicle-bound transmitter. The enlarged vesicular pool will increase exocytotic release of transmitter, while an increase in cytoplasmic monoamines will both reduce carrier-mediated removal of transmitter from the synapse (because the favourable concentration gradient is reduced) and could even lead to net export of transmitter by the membrane transporter. That MAOIs increase the concentration of extracellular monoamines has been confirmed using intracranial micro-dialysis (Ferrer and Artigas 1994).

The main problems with early, irreversible MAOIs were adverse interactions with other drugs (notably sympathomimetics, such as ephedrine, phenylpropanolamine and tricyclic antidepressants) and the infamous 'cheese reaction'. The cheese reaction is a consequence of accumulation of the dietary and trace amine, tyramine, in noradrenergic neurons when MAO is inhibited. Tyramine, which is found in cheese and certain other foods (particularly fermented food products and dried meats), is normally metabolised by MAO in the gut wall and liver and so little ever reaches the systemic circulation. MAOIs, by inactivating this enzymic shield, enable tyramine to reach the bloodstream and eventually to be taken up by the monoamine transporters on serotonergic and noradrenergic neurons. Like amphetamine, tyramine reduces the pH gradient across the vesicle membrane which, in turn, causes the vesicular transporter to fail. Transmitter that leaks out of the vesicles into the neuronal cytosol cannot be metabolised because

Table 20.4 Main groups of antidepressant drugs affecting monoamine uptake, release or receptors


Specific mechanism


Additional notable actions

Inhibition of momoamine uptake

Tricyclics Preferential inhibition of noradrenaline in vivo (except clomipramine)

'NARI' Inhibition of noradrenaline reuptake

'SSRI' Inhibition of 5-HT reuptake

SNRIs Inhibition of noradrenaline and 5-HT reuptake

Increased monoamine release

MAOIs Irreversible, non-selective inhibition of MAO

(causes secondary increase in monoamine release)

RIMA Reversible, selective inhibition of MAOa (causes a secondary increase in noradrenaline and 5-HT release) Tetracyclic a2-adrenoceptor antagonist a2-adrenoceptor antagonist and some 5-HT uptake inhibition Mechanism unknown 'Atypical'




















Pir lindóle

Mianserin Mirtazepine Trazodone Nefazodone

Potent antagonists of: M-receptors, o^ -adrenoceptors and Hrreceptors. Some are antagonists of 5-HT2 receptors

Hr and arantagonism


Hj -antagonist, 5-HTb 5-HT2 and 5-HT3 antagonist and some «¡-antagonism (especially mianserin) 5-HT1A and 5-HT2 antagonist and some ar (especially trazodone) and Hj antagonism


Molecular Structure Imipramine
Figure 20.2 The chemical structure of some well-known MAO inhibitors. Most of these drugs irreversibly inhibit both MAOa and MAOb but reversible inhibitors (RIMAs), such as moclobemide, inhibit MAOA only

MAO has been inhibited. As a result, transmitter accumulates in the cytoplasm and is exported into the synapse via the membrane-bound transporter. The ensuing (impulse-independent) sympathetic arousal can be disastrous, culminating in a hypertensive crisis and stroke. Although this process is a pharmacological curiosity and certainly contributed to the demise of MAOIs, it is possibly overrated (Tyrer 1979): it has been estimated that the number of deaths associated with the use of the MAOI, tranylcypromine, amounts to only 1 per 14000 patient years. However, this sequence of events echoes exactly the acute actions of methylenedioxymethamphetamine (MDMA, 'Ecstasy') and undoubtedly accounts for some of the deaths attributed to this drug.

The discovery that MAO has two isoenzymes with different distributions, substrate specificity and inhibitor sensitivity has helped to rehabilitate the MAOIs to some extent. These isoenzymes are the products of different genes on the X-chromosome and share about 70% sequence homology. Whereas noradrenaline and 5-HT are metabolised preferentially by MAOA, tyramine and dopamine can be metabolised by either isoenzyme. Selective inhibitors of MAOA (e.g. moclobemide; Da Prada et al. 1989) should therefore be safe and effective antidepressants whereas the selective MAOb inhibitor, selegiline, should not have any appreciable antidepressant activity (Table 20.5).

Both these predictions are borne out by clinical experience despite the snag that only MAOB is found in serotonergic neurons (Saura et al. 1996). So far, there is no explanation for this anomaly. However, the lack of a tyramine-induced pressor effect with moclobemide probably owes more to the fact that it acts as a reversible inhibitor of MAOa (RIMA) than to its isoenzyme selectivity. Its reversible inhibition of MAOA means that, should tyramine ever accumulate in the periphery, it will displace

Table 20.5 Irreversible MAO inhibitors and RIMAs

MAOa Non-selective MAOB

Substrates Noradrenaline ß-Phenylethylamine

5-Hydroxytryptamine Benzylamine

Tyramine Dopamine


Irreversible Clorgyline Iproniazid Selegiline

Isocarboxazid Pargyline

Phenelzine Tranylcypromine

Reversible ('RIMA') Befloxaton Brofaromine Moclobemide Pirlindole Toloxatone

RIMA: Reversible Inhibitor of Monoamine Oxidase^-

moclobemide from the enzyme, thereby ensuring that it is metabolised before reaching sympathetic neurons (Benedetti et al. 1983).


The tricyclic antidepressants (TCAs) derive their name from their three-ringed molecular structure (Fig. 20.3) and emerged, in 1958, from a search for better neuroleptics than chlopromazine among the phenothiazines. The prototype, imipramine, turned out to be ineffective in treating the positive symptoms experienced by schizophrenics but it did relieve their depression (negative symptoms). In fact, imipramine is still the standard agent against which novel antidepressants are compared in clinical trials.

All TCAs are either secondary- or tertiary-amines of a dibenzazepine nucleus (Fig. 20.3), and they all inhibit neuronal reuptake of noradrenaline and/or 5-HT but are much less potent as dopamine reuptake blockers. A common claim is that secondary amines (e.g. desipramine) are preferential inhibitors of noradrenaline uptake whereas the tertiary derivatives (e.g. imipramine, doxepin and amitryptyline) preferentially inhibit 5-HT uptake. However, when Richelson and Pfenning (1984) actually compared the effects of a wide range of antidepressants on the synaptosomal uptake of [3H]monoamines in vitro, and compared their Kis, instead of merely ranking IC50s collected from different studies, they found that tertiary- and secondary-substituted compounds were equi-potent inhibitors of [3H]noradrenaline uptake. Moreover, all the TCAs turned out to be more potent inhibitors of [3H]noradrenaline than of [3H]5-HT uptake. Tertiary amines are even less convincing inhibitors of 5-HT reuptake in vivo, because any such action is diminished by their metabolism to secondary amines (e.g. imipramine to desipramine; amitriptyline to nortriptyline). Only clomipramine retains any appreciable 5-HT uptake blocking activity in vivo with (an unimpressive) five-fold selectivity for 5-HT versus noradrenaline.

Set against this background is the finding that the inhibition of [3H]noradrenaline uptake by the neuroleptic, chlorpromazine, is even greater than that of imipramine and yet chlorpromazine has no apparent antidepressant effects. This serves as a testimony

Ssri Sar Basic Structure
Figure 20.3 The basic structure of tricyclic antidepressants with some well-known examples

to the complex pharmacology of chlorpromazine and also as a warning that studies in vitro can be poor predictors of drug effects on patients' mood and behaviour.

The major drawback of the TCAs is their adverse side-effects. These are explained by their high affinity for histamine Hj- and aj-adrenoceptors and all five of the muscarinic (M-) receptor subtypes. They consequently induce sedation (possibly through Hj-receptor antagonism), anticholinergic effects, such as dry mouth and blurred vision (M-receptor antagonism), orthostatic hypotension and dizziness (aj-adrenoceptor antagonism). In fact, the tertiary TCA, doxepin, is considerably more potent as an Hj-receptor antagonist (KB: 56pM) than the standard Hj-receptor antagonist, mepyramine (KB: 1 nM). The combination of inhibition of noradrenaline uptake and anticholinergic (antivagal) effects accounts for the pronounced cardiotoxi-city of the older TCAs. This is of particular concern when treating the elderly, especially if patients have a history of cardiac problems, and, together with hyperpyrexia and convulsions, these effects explain the toxicity of TCAs in overdose. Other side-effects include loss of libido and stimulation of appetite which leads to weight gain. Little is known about the physiological bases of these actions which, although not life-threatening, are important because they undermine patient compliance.

The adverse side-effects of the TCAs, coupled with their toxicity in overdose, provoked a search for compounds which retained their monoamine uptake blocking activity but which lacked the side-effects arising from interactions with Hj, aradreno-ceptors and muscarinic receptors. One of the first compounds to emerge from this effort was iprindole, which has an indole nucleus (Fig. 20.3). This turned out to be an interesting compound because it has no apparent effects on monoamine uptake and is not a MAO inhibitor. This, together with its relatively minor antimuscarinic effects, led to it commonly being described as an 'atypical' antidepressant. Mechanisms that could underlie its therapeutic actions have still not been identified but, in any case, this drug has now been withdrawn in the UK.


Another compound to emerge from the refinement of the TCAs is the tetracyclic agent, mianserin (Fig. 20.4). Like iprindole, this drug lacks antimuscarinic activity and, since it also has no significant effects on monoamine reuptake or MAO activity, it was regarded as another 'atypical' agent. However, it is now known to act as an a2-adrenoceptor antagonist, an action that will increase the release of noradrenaline through blockade of autoreceptors on the cell bodies and terminals of noradrenergic neurons (see Chapter 8). In the sense that this process will increase synaptic concentrations of noradrenaline, and is thought to explain (or contribute to) its therapeutic effects, mianserin is not at all 'atypical'. Of course, it is likely that this drug will also block postsynaptic a2-adrenoceptors, unless it specifically targets a different subtype of this receptor family, but this evidently does not prevent its therapeutic effects.

Mianserin will also increase 5-HT release through inhibition of a2-heteroceptors on serotonergic neurons. Whether this contributes to its antidepressant actions is uncertain because it is a potent antagonist of 5-HT2A/2B/2C receptors and because, like other antidepressants (and despite being an antagonist), its chronic administration leads to downregulation of these receptors. However, this action of mianserin might well limit or reduce any co-existing anxiety and insomnia. A recent addition to this class of




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