Summary of the pharmacological properties of antidepressants in general use in Europe

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Tricyclic antidepressants (TCAs)

This group of drugs was introduced during the early 1960s following the chance discovery of the antidepressant effects of imipramine. The therapeutic efficacy of the TCAs has been ascribed to their ability to inhibit the reuptake of noradrenaline and serotonin into the neuron following the release of these transmitters into the synaptic cleft. In addition, these drugs inhibit the muscarinic receptors (causing dry mouth, impaired vision, tachycardia, difficulty in micturition), histamine type-1 receptors (causing sedation) and alpha-1 adrenoceptor antagonism (causing postural hypotension). Such side effects often lead to non-compliance (estimated to be at least 40% in general practice situations) and are more frequent in the elderly.

The excellent clinical efficacy of the TCAs has been well documented and the pharmacokinetic profiles are favourable. The most serious disadvantage of the TCAs lies in their cardiotoxicity. Thus, with the exception of lofepramine, all the tricyclic antidepressants, including maprotiline, block the fast sodium channels in the heart which can lead to heart block and death. Approximately 15% of all patients with major depression die by suicide and a high proportion of these (up to 25%) do so by taking an overdose of TCAs. Such a dose can be as low as 5-10 times the recommended daily dose.

Lofepramine differs from the other TCAs in that its structure seems to preclude it from causing the anticholinergic, antihistaminergic and antiadrenergic effects evident with the other TCAs. In addition, it does not appear to be any more cardiotoxic than most of the second-generation antidepressants. The reason for this is an enigma, as the main metabolite of lofepramine is desipramine, a typical cardiotoxic TCA. There is a suggestion that, due to its high lipophilicity, it impedes the access of desipramine to the sodium fast channels in the heart without interfering with their normal function. Thus lofepramine would appear to fulfil many of the requirements of a safe and effective TCA; it has been widely used, particularly in elderly depressed patients, in the past in both the UK and Ireland.

Irreversible inhibitors of monoamine oxidase (MAOIs)

Iproniazid, an MAOI no longer available because of its hepatotoxicity, was the first effective antidepressant to be discovered; it was introduced shortly before the discovery of imipramine. All MAOIs are presumed to have a similar mode of action, namely to inhibit the intra- and interneuronal metabolism of the biogenic amine neurotransmitters (noradrenaline, dopamine and serotonin). These amines are primarily metabolized by MAO-A (noradrenaline and serotonin) or MAO-B (dopamine). The irreversible MAOIs are inhibitors of MAO-A while selegiline (deprenyl), used as an adjunctive treatment for Parkinson's disease, is a selective, irreversible inhibitor of MAO-B.

The main limitation to the clinical use of the MAOIs is due to their interaction with amine-containing foods such as cheeses, red wine, beers (including non-alcoholic beers), fermented and processed meat products, yeast products, soya and some vegetables. Some proprietary medicines such as cold cures contain phenylpropanolamine, ephedrine, etc. and will also interact with MAOIs. Such an interaction (termed the ''cheese effect''), is attributed to the dramatic rise in blood pressure due to the sudden release of noradrenaline from peripheral sympathetic terminals, an event due to the displacement of noradrenaline from its intraneuronal vesicles by the primary amine (usually tyramine). Under normal circumstances, any dietary amines would be metabolized by MAO in the wall of the gastrointestinal tract, in the liver, platelets, etc. The occurrence of hypertensive crises, and occasionally strokes, therefore limited the use of the MAOIs, despite their proven clinical efficacy, to the treatment of atypical depression and occasionally panic disorder.

The side effects of the MAOIs include, somewhat surprisingly, orthostatic hypotension. This is thought to be due to the accumulation of dopamine in the sympathetic cervical ganglia where it acts as an inhibitory transmitter, thereby reducing peripheral vascular tone. Other side effects include psychomotor restlessness and sleep disorder. The MAOIs are cardiotoxic but probably less so than the TCAs. Potentially fatal interactions can however occur when MAOIs are combined with SSRIs or any type of drug which enhances serotonergic function. The interaction can give rise to hyperexcitability, increased muscular tone, myoclonus and loss of consciousness. The analgesic pethidine is particularly dangerous in this respect (Figure 7.1).

Reversible inhibitors of monoamine oxidase (RIMAs)

Antidepressants of this class, such as moclobemide, have a high selectivity and affinity for MAO-A. However, unlike the MAOIs, the RIMAs are reversible inhibitors of the enzyme and can easily be displaced from the enzyme surface by any primary amine which may be present in the diet. This means that the dietary amines are metabolized by MAO in the wall of the gastrointestinal tract while the enzyme in the brain and elsewhere remains inhibited. Thus the RIMAs have brought the MAOIs back into use as antidepressants in general practice. It is now evident that the RIMAs are not as potent as most currently available antidepressants.

Selective serotonin reuptake inhibitors

Zimelidine was the first SSRI antidepressant to be launched in Europe and, despite its therapeutic success, was withdrawn in the late 1980s due to severe abdominal toxicity. Zimelidine was soon replaced by fluvoxamine which only slowly received acceptance in Europe because of the high incidence of nausea and vomiting; the recommended starting dose was initially too high. Fluoxetine was the third SSRI to be launched in Europe with the advantage of a fixed daily dose (20 mg) and relatively few side effects. Sertraline, paroxetine and citalopram followed so that by the end of the 1980s, the five SSRIs were well established throughout Europe and most of the world (Figure 7.2).

As the name implies, these drugs have a high affinity for the serotonin transporter both on neuronal and also platelet membranes. There is abundant evidence that the SSRIs inhibit the reuptake of 3H-5-HT into platelets, brain slices and synaptosomal fractions, as illustrated in Table 7.10, but it is clear that there is no direct relationship between the potency of the drug to inhibit 5-HT reuptake in vitro and the dose necessary to relieve depression in the clinic. In experimental studies, it is clear that the increased release of 5-HT from the frontal cortex only occurs following the chronic (2 weeks or longer) administration of any of the SSRIs. Thus the inhibition of 5-HT reuptake may be a necessary condition for the antidepressant activity, but it is not sufficient in itself.

Figure 7.1. Structural formulae of some monoamine oxidase inhibitors (moclobe-mide, pirlindole and toloxatone) and alpha2 adrenoceptor antagonists [S-mirtazapine and setiptiline (teciptiline)].

Despite their common ability to enhance serotonergic function in vivo, the SSRIs differ both in terms of their pharmacological profiles and their pharmacokinetics. Thus in addition to their direct inhibitory action on the serotonin transporter, they also affect other neurotransmitter systems which may have some clinical relevance. Citalopram has a modest antihistamine action which might account for its slightly sedative action. Sertraline has a

Sertraline Muscarinic

Figure 7.2. Chemical structure of some 5-HT uptake inhibitors. Zimelidine has been withdrawn due to serious adverse side effects. Norfluoxetine is an active metabolite of fluoxetine.

Figure 7.2. Chemical structure of some 5-HT uptake inhibitors. Zimelidine has been withdrawn due to serious adverse side effects. Norfluoxetine is an active metabolite of fluoxetine.

slight dopaminomimetic effect which may contribute to its alerting effect, while paroxetine is a muscarinic receptor antagonist. Both fluvoxamine and sertraline have affinity for sigma 1 receptors, the precise importance of which is uncertain but could contribute to the motor side effects which all the SSRIs are reputed to have, albeit very rarely. Fluoxetine, by activating 5-HT 2C receptors, may cause anxiety at least in some patients. Thus differences between the SSRIs are due not only to their different potencies as 5-HT reuptake inhibitors, but also because of their actions on other receptor systems. A comparison of the pharmacokinetic differences between the SSRIs is summarized in Table 7.10. These differences may be of clinical importance in terms of the special populations to whom the drugs should be administered (for example, the elderly may benefit particularly from citalopram because of its slightly sedative profile, and its lack of inhibition of cytochrome P450 enzymes in the liver, see p. 89). Sertraline could also be considered for this group and while drug interactions could be more problematic it does have a slightly alerting

Table 7.10. Classification of antidepressants available in Europe

• Antidepressants that inhibit monoamine reuptake

Tricyclic antidepressants (TCAs) - first-generation antidepressants Examples - tertiary amine type: imipramine, amitriptyline, dothiepin, clomipramine

- secondary amine type: desipramine, nortriptyline

- other effects: potent antagonists of muscarinic, histaminic and alpha-1 adrenergic receptors; cardiotoxic

Modified TCA-lofepramine - non-cardiotoxic; low affinity for muscarinic and alpha-1 adrenoceptors

• Inhibitors of noradrenaline reuptake (NARIs)

Examples - maprotiline: a "bridged" tricyclic with affinity for histamine, H1, and alpha-1 adrenoceptors. Causes seizures

- reboxetine: not cardiotoxic; does not have an affinity for any neurotransmitter receptors

• Inhibitors of serotonin reuptake (SSRIs)

Examples - citalopram (1), sertraline (2), fluoxetine (3), paroxetine (4), fluvoxamine

Slight affinity for (1) histamine, (2) dopamine, (3) serotonin, (4) muscarinic receptors (see text)

• Specific inhibitors of noradrenaline and serotonin reuptake (SNRIs)

Examples - venlafaxine (more potent inhibitor of 5-HT than noradrenaline reuptake)

- milnacipran (more potent inhibitor of noradrenaline than 5-HT reuptake)

• Antidepressants that inhibit monoamine metabolism

Irreversible monoamine oxidase inhibitors (MAOIs)

Examples - phenelzine, pargyline, tranylcypromine, isocarboxazid. All interact with dietary monoamine to cause the "cheese effect'' (see text)

• Reversible inhibitors of monoamine oxidase A (RIMAs)

Examples - moclobemide, pirlindole. At therapeutic doses unlikely to interact with dietary amines (see text)

• Tetracyclic antidepressants

Examples - mianserin (1), mirtazepine (6-aza-mianserin) (2)

(1) The first second-generation antidepressant; an alpha-2 adrenoceptor antagonist with some affinity for 5-HT1A, 5-HT2A and 5-HT3, alpha-1 adrenoceptors and H1 receptors

(2) Known as a noradrenaline and specific serotonin antidepressant (NaSSA). More potent affinity for alpha-2 adrenoceptors and 5-HT receptors than mianserin; H1 antagonist

• Other antidepressants (sometimes called "atypical")

Examples - trazodone, nefazodone: 5-HT1A and 5-HT2 antagonists, weak SSRI activity; alpha-1 and H1 antagonism profile which could be beneficial. Fluvoxamine has also been extensively studied in the elderly, but nausea could be a problem while fluoxetine, with its very long half-life (with its active metabolite norfluoxetine, amounting to 12 days in the elderly patient) could be beneficial for the non-compliant patient. In the elderly, fluoxetine could cause some anorexia and weight loss however. Paroxetine should be administered with more care in the elderly because of its anticholinergic action.

In addition to their proven efficacy in the treatment of all types of depression, the SSRIs have been shown to be the drugs of choice in the treatment of panic disorder, obsessive-compulsive disorder, bulimia nervosa, and as an adjunct to the treatment of alcohol withdrawal and relapse prevention, premenstrual dysphoric disorder and post-traumatic stress disorder. The usefulness of these drugs in treating such a diverse group of disorders reflects the primary role of serotonin in the regulation of sleep, mood, impulsivity and food intake.

All the SSRIs have qualitatively similar side effects that largely arise from the increase in serotonergic function and the resulting activation of the different 5-HT receptor types in the brain and periphery. There are differences in the frequency of these effects however which would not be anticipated if all the SSRIs were essentially the same! These effects include nausea, vomiting, diarrhoea or constipation, insomnia, tremor, initial anxiety, dizziness, sexual dysfunction and headache. Loss in body weight may occur but this is rare. The behavioural toxicity of the SSRIs as indicated by their effects on psychomotor function, memory and learning, is low, particularly when compared to the TCAs and some of the sedative second-generation antidepressants such as mianserin, mirtazepine and trazodone. The SSRIs are not cardiotoxic and safety in overdose has been indicated for all these drugs. In general, the severity of the adverse effects is slight and seldom leads to non-compliance.

In addition to the five SSRIs currently available, many more compounds are in development which will no doubt be marketed in the near future. Of the new arrivals, escitalopram, the S-enantiomer of citalopram, has already become available in many European countries. A brief discussion of the properties of this drug has been presented on p. 98.

Noradrenaline reuptake inhibitors (NRIs)

Reboxetine is the only selective and reasonably potent noradrenaline reuptake inhibitor available clinically at the present time. Reboxetine has a chemical structure not dissimilar from viloxazine, an antidepressant which was of only limited clinical interest in the 1970s because of its weak efficacy and unacceptable side effects (nausea, vomiting and occasionally seizures). Unlike the secondary amine TCA antidepressants, such as maprotiline, desipramine, nortriptyline and protriptyline, reboxetine does not affect any other transporter or receptor system and therefore is largely devoid of TCA and SSRI-like side effects. In clinical trials, reboxetine has been shown to be as effective as the SSRIs in the treatment of depression but, unlike the SSRIs, reboxetine does not inhibit any of the cytochrome P450 enzymes in the liver.

In contrast to the widespread interest in 5-HT in depression research and in the development of antidepressants, there would appear to be little interest in developing antidepressants that selectively modulate the noradrenergic system. At the present time, there do not appear to be any drugs of this type in development.

For completeness, buproprion should be mentioned even though it is not widely registered as an antidepressant in Europe, partly because of its propensity to cause seizures in some patients. Buproprion, quite widely used in the USA as an antidepressant, appears to inhibit the reuptake of both dopamine and noradrenaline and therefore tends to have a slightly alerting action. In many European countries it has recently been introduced, at a lower than antidepressant dose, in the treatment of nicotine withdrawal in smoking cessation programmes.

Lastly, nomifensine was an interesting antidepressant that also had noradrenaline, dopamine and, due to its 4-hydroxy metabolite, serotonin reuptake properties. It was withdrawn some years ago because of the occurrence of haemolytic anaemia in a small number of patients. It was a particularly effective drug in the treatment of depression in patients with epilepsy as, unlike many antidepressants available at that time, it did not affect the seizure threshold.

Selective serotonin and noradrenaline reuptake inhibitors (SNRIs)

In an attempt to combine the clinical efficacy of the TCAs with the tolerability and safety of the SSRIs and NRIs, drugs showing selectivity in inhibiting the reuptake of both noradrenaline and serotonin were developed. Being structurally unrelated to the TCAs however, they lacked their side effects including their cardiotoxicity.

To date, venlafaxine is the most widely available of the SNRIs. Although it is known to enhance both serotonergic and noradrenergic function, at the lower clinical dose range it primarily enhances serotonergic function and therefore has the characteristic side effects of an SSRI. At higher therapeutic doses, venlafaxine also inhibits noradrenaline reuptake and therefore resembles a TCA antidepressant. While there is no evidence that venlafaxine is as cardiotoxic as the TCAs, recent studies have indicated that it is at least threefold more likely than the SSRIs to result in death if taken in overdose. Hypertension may occur in some patients when given a high therapeutic dose of venlafaxine.

A more potent, but qualitatively similar antidepressant to venlafaxine, duloxetine, is currently in advanced clinical development.

Milnacipran is also a dual-action antidepressant which, like venlafaxine, has been shown to be more effective than the SSRIs in the treatment of severe, hospitalized and suicidally depressed patients. At lower therapeutic doses, milnacipran blocks the noradrenaline transporters and therefore resembles the NRI antidepressants. Higher doses result in the serotonergic component becoming apparent (i.e. an SSRI-like action). The main problem with milnacipram appears to be its lack of linear kinetics with some evidence that it has a U-shaped dose-response curve (Figure 7.3).

Tetracyclic antidepressants

Mianserin was the first of the second-generation antidepressants to be developed. It lacked the amine reuptake inhibitory and MAOI actions of the first-generation drugs and also lacked the cardiotoxicity and anticholinergic activity of the TCAs. However, it was sedative (antihistaminic), caused postural hypotension (alpha-1 blockade) and also caused blood dyscrasias and agranulocytosis in a small number of patients. This has limited the use of mianserin in recent years.

Mirtazepine (called a Noradrenaline and Selective Serotonin Anti-depressant; NaSSA) is the 6-aza derivative of mianserin and shares several important pharmacological properties with its predecessor, namely its antihistaminic and alpha-1 adrenoceptor antagonistic actions. Like mianserin, mirtazepine also causes weight gain. Nevertheless, mirtazepine is better tolerated and there is no evidence of blood dyscrasias associated with its clinical use.

Regarding the mode of action of these tetracyclic compounds, both are potent alpha-2 adrenoceptor antagonists which cause an enhanced release of noradrenaline. The action of mirtazepine on serotonin receptors (5-HT1A, 5-HT2A, 5-HT3) is both direct (5-HT2A and 5-HT3) and indirect (5-HT1A). The complexity of the interaction of the drug with both adrenoceptors and serotonin receptors helps to emphasize the importance of the ''cross talk'' between these two neurotransmitter systems. Thus the antidepressant effects of both mirtazepine and mianserin are related to the enhancement of noradrenaline release (alpha-2 blockade) and 5-HT2A receptor antagonism. In addition, mirtazepine (and to a lesser extent mianserin) blocks 5-HT3 receptors therefore reducing the anxiety and nausea normally associated with drugs that enhance serotonergic function. The anti-anxiety effect of mirtazepine is ascribed to its indirect activation of the 5-HT1A receptors, an effect also seen following the administration of an SSRI. The probable sites of action of mirtazepine are shown in Figure 7.4.

Amfebutamone (bupropion)

Amfebutamone (bupropion)


Figure 7.3. Structural formulae of the noradrenaline (norepinephrine)/dopamine reuptake inhibitor amfebutamone (bupropion) and some nonselective noradrenaline and serotonin (5-hydroxytryptamine; 5-HT) reuptake inhibitors (venlafaxine, and milnacipran).


Figure 7.3. Structural formulae of the noradrenaline (norepinephrine)/dopamine reuptake inhibitor amfebutamone (bupropion) and some nonselective noradrenaline and serotonin (5-hydroxytryptamine; 5-HT) reuptake inhibitors (venlafaxine, and milnacipran).

Other, or atypical, antidepressants

These include trazodone and a derivative of its metabolite nefazodone, both of which are strongly sedative, an effect which has been attributed to their potent alpha-1 receptor antagonism rather than to any antihistaminic effects. A main advantage of these drugs in the treatment of depression is that they appear to improve the sleep profile of the depressed patient. Their antidepressant activity is associated with their weak 5-HT reuptake inhibition and also a weak alpha-2 antagonism. However, unlike most of the second-generation antidepressants, neither drug is effective in the treatment of severely depressed patients. Furthermore, there is some evidence that trazodone can cause arrythmias, and priapism, in elderly patients.

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