Mechanism of action

The monoamine hypothesis proposes that, in depression, there is deficiency of the neurotransmitters noradrenaline/norepinephrine and serotonin in the brain which can be restored by antidepressants. Drugs that alleviate depression also enhance monoamine availability and release (Fig. 20.2), increasing activity at postsynaptic receptors. It is relevant that (older) antihypertensive agents, e.g. reserpine, which reduced the availability of noradrenaline/norepinephrine, caused depression.

Fig. 20.2 Mechanism of action of antidepressant drugs at the synapse.

SSRIs act, as their name indicates, predominantly by preventing serotonin reuptake by blocking the cell-surface serotonin transporter; with little effect on noradrenaline/norepinephrine reuptake. Tricyclic antidepressants and reboxetine inhibit noradrenaline/norepinephrine reuptake, but tricyclic effects on serotonin reuptake vary widely; desipramine and protriptyline have no effect, whereas clomipramine is about five times more potent at blocking serotonin than noradrenaline/norepinephrine reuptake. SNRIs are capable of inhibiting reuptake of both transmitters. However, for venlafaxine a dose of at least 150 mg/day is required for noradrenaline/norepinephrine uptake blockade to be exerted. Mirtazapine also achieves an increase in noradrenergic and serotonergic neurotransmission, but through antagonism of presynaptic α₂-autoreceptors (receptors that mediate negative feedback for transmitter release, i.e. an autoinhibitory feedback system). Other novel antidepressants include trazodone, which blocks several types of serotonin receptor (including the 5HT2A and 5HT2C receptors) as well as α-adrenoceptors and histaminergic receptors and acts as a partial agonist at the 5HT1A receptor, and agomelatine which acts both as an agonist of melatonin receptors and a blocker of the serotonin 5HT2C receptor, the combined effects of these actions leading to a rise in frontal cortex dopamine availability.

MAOIs increase the availability of noradrenaline/norepinephrine and serotonin by preventing their destruction by the monoamine oxidase type A enzyme in the presynaptic terminal (see Ch. 21, Table 21.3). The older MAOIs, phenelzine, tranylcypromine and isocarboxazid, bind irreversibly to monamine oxidase 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 MAOIs are thus called ‘hit and run’ drugs as their effects greatly outlast their detectable presence in the blood.

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 regulating the transcription of genes that influence survival of other proteins, including brain-derived neurotrophic factor (BDNF), which exerts effects on neuronal growth.

Although the monoamine hypothesis of depression is conceptually straightforward, it is in reality an oversimplification of a complicated picture. Other systems that are implicated in the aetiology of depression (and which provide potential targets for drug therapy) include the hypothalamic–pituitary–thyroid axis and the hypothalamic–pituitary–adrenal (HPA) axis. The finding that 50% of depressed patients have raised plasma cortisol concentrations constitutes evidence that depression may be associated with increased HPA drive.

Drugs with similar modes of action to antidepressants find other uses in medicine. Bupropion (amfebutamone) inhibits reuptake of both dopamine and noradrenaline/norepinephrine. It was originally developed and used as an antidepressant but is now more frequently used to assist smoking cessation (see p. 321). It is also prescribed in attention deficit hyperactivity disorder (see p. 345). Sibutramine, licensed as an anorectic agent, is a serotonin and noradrenaline/norepinephrine reuptake inhibitor (SNRI).

Pharmacokinetics

The antidepressants listed in Table 20.1 are generally well absorbed after oral administration. Steady-state plasma concentrations of TCAs show great individual variation but correlate with therapeutic effect. Where there is a failure of response, measurement of plasma concentration can be useful as the failure may be attributable to low plasma levels due to ultra-rapid metabolism (though it is often not available). Antidepressants in general are metabolised principally by hepatic cytochrome P450 enzymes. Of the many isoenzymes identified, the most important in antidepressant metabolism are CYP P450 2D6 (Table 20.2A) and CYP 3A4 (Table 20.2B). Other important P450 enzymes are CYP 1A2 (inhibited by the SSRI fluvoxamine, induced by cigarette smoking; substrates include caffeine and the atypical antipsychotics clozapine and olanzapine) and the CYP 2 C group (inhibition by fluvoxamine and fluoxetine, involved in breakdown of escitalopram and moclobemide). Sometimes several CYP enzymes are capable of mediating the same metabolic step. For example, at least six isoenzymes, including CYP 2D6, 3A4 and 2 C9, can mediate the desmethylation of the SSRI sertraline to its major metabolite.

Table 20.2A Psychotropic (and selected other) drugs known to be CYP 2D6 substrates, inhibitors and inducers

A substrate is a substance that is acted upon and changed by an enzyme. Where two substrates of the same enzyme are prescribed together, they will compete and, if present in sufficient quantities, the metabolism of one or other, or both, drugs may also be inhibited, resulting in increased plasma concentration and possibly in enhanced therapeutic or adverse effects. An enzyme inducer accelerates the metabolism of co-prescribed drugs that are substrates of the same enzyme, reducing their effects. An enzyme inhibitor retards metabolism of co-prescribed drugs, increasing their effects.

a CYP 2D6 is involved only in the breakdown of venlafaxine to its active metabolite and therefore implications of 2D6 interactions for efficacy are of limited significance.

Table 20.2B Psychotropic (and selected other) drugs known to be CYP 3A4 substrates, inhibitors and inducers

A substrate is a substance that is acted upon and changed by an enzyme. Where two substrates of the same enzyme are prescribed together, they will compete and, if present in sufficient quantities, the metabolism of one or other, or both, drugs may also be inhibited, resulting in increased plasma concentration and possibly in enhanced therapeutic or adverse effects. An enzyme inducer accelerates the metabolism of co-prescribed drugs that are substrates of the same enzyme, reducing their effects. An enzyme inhibitor retards metabolism of co-prescribed drugs, increasing their effects.

a mCPP (meta-chlorophenylpiperazine), the active metabolite of trazodone, is a CYP 2D6 substrate; observe for unwanted effects when trazodone is co-administered with the 2D6 inhibitors fluoxetine or paroxetine.

Several of these drugs produce active metabolites that prolong their action (e.g. fluoxetine is metabolised to norfluoxetine, t_½ 200 h). The metabolic products of certain TCAs are antidepressants in their own right, e.g. nortriptyline (from amitriptyline), desipramine (from lofepramine and imipramine) and imipramine (from clomipramine). Half-lives of TCAs lie generally in a range from 15 h (imipramine) to 100 h (protriptyline), and those for SSRIs from 15 h (fluvoxamine) to 72 h (fluoxetine).

Around 7% of the Caucasian population have very limited CYP 2D6 enzyme activity. Such ‘poor metabolisers’ may find standard doses of TCAs intolerable, and it is often worth prescribing them at a very low dose. If the drug is then tolerated, plasma concentration assay may confirm the suspicion that the patient is a poor metaboliser. There is also a genetic polymorphism influencing CYP 2 C19 activity which has a clinically important effect on metabolism of escitalopram.

Therapeutic efficacy

Provided antidepressant drugs are prescribed at an adequate dose and taken regularly, 60–70% of patients with depression should respond within 3–4 weeks. Conventional meta-analyses have shown little evidence that any particular drug or class of antidepressant is more efficacious than others, but there are some possible exceptions to this general statement:

Selection

An antidepressant should be selected to match individual patients’ requirements, such as the need or otherwise for a sedative effect, or the avoidance of antimuscarinic effects (especially in the elderly). In the absence of special factors, the choice rests on the weight of evidence of efficacy, the tolerability, the safety in overdose and the likelihood of an effective dose being reached. SSRIs and other newer drugs (e.g. mirtazapine and venlafaxine) are highlighted as best meeting these needs.

Mode of use

Antidepressants usually require 3–4 weeks for the full therapeutic effect to be achieved. When a minimal response is seen, an antidepressant can usefully be extended to 6 weeks to see whether further benefit is achieved. By contrast, patients may experience unwanted effects, especially ‘jitteriness’ or ‘activation’ symptoms such as increased anxiety and irritability, soon after starting treatment (they should be warned about this possibility), but such symptoms usually diminish with time. Some drugs have the advantage that they can be started at a dose which would be considered adequate for the therapeutic effect (e.g. most SSRIs) but in contrast many others, including all tricylic antidepressants, need to be started at a low and generally tolerable starting dose to the therapeutic dose. For example, imipramine should be started at 25–50 mg/day, with gradual increments to a recognised ‘minimum therapeutic’ dose, around 125 mg/day (140 mg/day for lofepramine). Low starting doses are particularly important for elderly patients. Only when the drug has reached the minimum therapeutic dose and been taken for at least 4 weeks can response or non-response be adequately established. However, some patients do achieve response or remission at subtherapeutic doses, for reasons of drug kinetics and limited capacity to metabolise, the self-limiting nature of depression, or by a placebo effect (reinforced by the experience of side-effects suggesting that the drug must be having some action).

For SSRIs dose titration is often unnecessary as the minimum therapeutic dose can usually be tolerated as a starting dose. Divided doses are not usually required, and administration is by a single morning or evening dose. Evidence suggests that patients commencing treatment on SSRIs are more likely to reach an effective dose than those starting on TCAs. Of the novel compounds, trazodone usually requires titration to a minimum therapeutic dose of at least 200 mg/day. Response to reboxetine, venlafaxine and mirtazapine may occur at the starting dose, but some dose titration is commonly required. Venlafaxine is licensed for treatment-resistant depression by gradual titration from 75 to 375 mg/day. There is some need for dose titration when using MAOIs. Unlike other drug classes, reduction to a lower maintenance dose is recommended after a response is achieved if unwanted effects are problematical.

Changing and stopping antidepressants

When an antidepressant fails through lack of efficacy despite an adequate trial or due to unacceptable adverse effects, a change to a drug of a different class is generally advisable. For a patient who has not responded to an SSRI it is logical to try a novel compound such as venlafaxine, mirtazapine or reboxetine, or sometimes a tricylic antidepressant. Any of these options may offer a greater increase in synaptic noradrenaline/norepinephrine than the ineffective SSRI.

Evidence also suggests that patients failing on one SSRI may respond to a different drug within the class, an approach that is particularly useful where other antidepressant classes have been unsuccessful previously, are contraindicated, or have characteristics that the patient or doctor feels are undesirable. Awareness of biological differences between drugs within a class may also be helpful when patients cannot tolerate other drug classes. For instance, among SSRIs, paroxetine has the most affinity for the serotonin transporter and fluoxetine the least, while among TCAs, clomipramine has more important serotonergic enhancing effects than the others.

When changing between antidepressant doses, a conservative approach would be to reduce the first antidepressant progressively over 2 or more weeks before starting the new drug. The gradual reduction is particularly important with paroxetine and venlafaxine which are known to cause ‘discontinuation syndromes’ if stopped abruptly, and less important with fluoxetine due to its long half-life active metabolite which offers ‘built-in’ protection against withdrawal problems. A more proactive approach would involve ‘cross-tapering’ the second antidepressant – i.e. starting it while the first antidepressant is being reduced and gradually titrating the dose up. However, an important exception concerns changes to or from MAOIs, which must be handled with great caution due to the dangers of interactions between antidepressants (see below). Therefore MAOIs cannot safely be introduced within 2 weeks of stopping most antidepressants (3 weeks for imipramine and clomipramine; combination of the latter with tranylcypromine is particularly dangerous), and not until 5 weeks after stopping fluoxetine, due to its long half-life active metabolite. Similarly, other antidepressants should not be introduced until 2–3 weeks have elapsed from discontinuation of MAOI (as these are irreversible inhibitors; see p. 313). No washout period is required when using the reversible MAOI, moclobemide.

When a patient achieves remission, the antidepressant should be continued for at least 9 months at the dose that returned mood to normal. Premature dose reduction or withdrawal is associated with increased risk of relapse. In cases where three or more depressive episodes have occurred, evidence suggests that long-term continuation of an antidepressant offers protection, as further relapse is almost inevitable in the next 3 years.

When ceasing use of an antidepressant, the dose should be reduced gradually to avoid discontinuation syndromes (symptoms include anxiety, agitation, nausea and mood swings). Discontinuation of SSRIs and venlafaxine are associated additionally with dizziness, electric shock-like sensations and paraesthesia. Short t_½ drugs that do not produce active metabolites (e.g. paroxetine, venlafaxine) and TCAs are most likely to cause such problems.

Augmentation

The development of many new antidepressants in recent years has reduced the need to use augmentation strategies. Nevertheless augmentation, i.e. the addition of a second drug to an existing antidepressant, can be used when two or more standard antidepressants have successively failed to alleviate depressive symptoms despite treatment at an adequate dose for an adequate time. Some of the augmentations discussed may even be used earlier than this if there is an indication or justification for the augmenting drug specific to the individual patient.

One strategy which has come to prominence is to augment (or combine) an SSRI or SNRI antidepressant with the novel antidepressant mirtazapine. The initial justification for this combination stems from mirtazapine’s unorthodox mechanism of action – the idea being that the presynaptic adjustments effected by mirtazapine could act additively or even synergistically with the monoamine reuptake inhibition of SSRIs and SNRIs. A second justification is more practical – mirtazapine is known to improve the quality of sleep and serotonin reuptake inhibitors may initially disrupt this, thus mirtazapine can be added both to boost the antidepressant effect and to address an unresolved problem with sleep. An evidence base does exist both for mirtazapine–venlafaxine and mirtazapine–fluoxetine co-prescription in depression, with both combinations reported as providing significantly higher remission rates than fluoxetine alone. Ease of initiation of these combinations, along with the evidence of enhanced effectiveness, means that these are currently the most commonly used augmentation strategies for treatment of depression in psychiatry inpatients in the UK.

Another important augmentation strategy employs the mood stabiliser lithium carbonate. Controlled trials suggest that up to 50% of patients who have not responded to standard antidepressants can respond after lithium augmentation but the evidence is stronger for augmenting tricyclics than for augmenting SSRIs. Addition of lithium requires careful titration of the plasma concentration up to the therapeutic range, with periodic checks thereafter and monitoring for toxicity (see p. 331).

More recently, augmentation of SSRIs with atypical antipsychotics has been effective in clinical trials. Trial evidence is strongest using olanzapine, and also exists for quetiapine, risperidone and aripiprazole. Antipsychotics also have important potential for side-effects which must be taken into account before their introduction (see p. 322).

Tri-iodothyronine (T3) also aids antidepressant action, and most evidence points to added benefit with TCAs. When co-prescribing TCAs with thyroid hormone derivatives, be aware that the combination of lofepramine with the levo isomer of thyroxine is contraindicated. The amino acid L-tryptophan and the β-adrenoceptor blocker pindolol may also be used to augment. Tryptophan increases 5-hydroxytryptamine (5HT) production, and pindolol may act by blocking negative feedback of 5HT on to 5HT_1A-autoreceptors.

Other indications for antidepressants

Antidepressants may benefit most forms of anxiety disorder, including panic disorder, generalised anxiety disorder, post-traumatic stress disorder, obsessive–compulsive disorder and social phobia (see p. 331). SSRIs are recognised as first-line drug treatment for all five of these anxiety disorders.

Fluoxetine is effective in milder cases of the eating disorder bulimia nervosa, in higher doses (60 mg/day) than are required for depression. This effect is independent of that on depression (which may coexist), and may therefore involve a different mode of action. Antidepressants appear to be ineffective in anorexia nervosa. Antidepressants also have a role in pain control. The SNRI drug duloxetine is licensed for diabetic neuropathy while considerable trial evidence exists for use of the original tricyclic antidepressants imipramine and amitriptyline for the control of chronic pain.

Adverse effects

As most antidepressants have similar therapeutic efficacy, the decision regarding which drug to select often rests on adverse effect profiles and potential to cause toxicity.

Interactions

Antidepressant use offers considerable scope for adverse interaction with other drugs and it is prudent always to check specific sources for unwanted outcomes whenever a new drug is added or removed to a prescription list that includes an antidepressant.

St John’s wort

The herbal remedy St John’s wort (Hypericum perforatum) has found favour in some patients with mild to moderate depression. The active ingredients in the hypericum extract have yet to be identified, and their mode of action is unclear. Several of the known mechanisms of action of existing antidepressants are postulated, including inhibition of monoamine reuptake and the MAO enzyme, as well as a stimulation of GABA receptors. Much of the original research into the efficacy of St John’s wort was performed in Germany, where its use is well established. Several direct comparisons with tricyclic antidepressants have shown equivalent rates of response, but the interpretation of these studies is complicated by the fact that many failed to use standardised ratings for depressive symptoms, patients tended to receive TCAs below the minimum therapeutic dose, and sometimes received St John’s wort in doses above the maximum recommended in commercially available preparations. Use of St John’s wort is further complicated by the lack of standardisation of the ingredients. A large multi-centre trial found only limited evidence of benefit for St John’s wort over placebo in significant major depression.²

Despite these reservations, there is certainly a small proportion of patients who, when presented with all the available facts, express a strong desire to take only St John’s wort, perhaps from a preference for herbally derived compounds over conventional medicine. For patients with mild depression, it seems reasonable on existing evidence to accede to this preference rather than impair the therapeutic alliance and risk prescribing a conventional antidepressant that will not be taken.

Electroconvulsive therapy

ECT involves the passage of a small electrical charge across the brain by electrodes applied to the frontotemporal aspects of the scalp with the aim of inducing a tonic–clonic seizure. Reference to it is made here principally to indicate its place in therapy.

ECT requires the patient to be under a general anaesthetic, so carrying the small risks associated with general anaesthesia in minor surgical operations. It may cause memory problems, although these are generally transient. For these reasons, as well as the relative ease of use of antidepressant drugs, ECT is usually reserved for psychiatric illness where pharmacological treatments have been unsuccessful or where the potential for rapid improvement characteristic of ECT treatment is important. This may arise where patients are in acute danger from their mental state, for instance the severely depressed patient who has stopped eating or drinking, or those with florid psychotic symptoms. Modern-day ECT is a safe and effective alternative to antidepressant treatment and remains a first-line option in clinical circumstances where a rapid response is desired, when it can be life saving.

Classification

Originally tested as an antihistamine, chlorpromazine serendipitously emerged as an effective treatment for psychotic illness in the 1950s. Chlorpromazine-like drugs were originally termed ‘neuroleptics’ or ‘major tranquillisers’, but the preferred usage now is ‘antipsychotics’. Classification is by chemical structure, e.g. phenothiazines, butyrophenones. Within the large phenothiazine group, compounds are divided into three types on the basis of the side-chain, as this tends to predict adverse effect profiles (Table 20.3). The continuing search for greater efficacy and better tolerability led researchers and clinicians to reinvestigate clozapine, a drug that was originally licensed in the 1960s but subsequently withdrawn because of toxic haematological effects. Clozapine appeared to offer greater effectiveness in treatment-resistant schizophrenia, to have efficacy against ‘negative’ in addition to ‘positive’ psychiatric symptoms (see Table 20.4), and to be less likely to cause extrapyramidal motor symptoms. It regained its licence in the early 1990s with strict requirements on dose titration and haematological monitoring. The renewed interest in clozapine and its unusual efficacy and tolerability stimulated researchers to examine other ‘atypical’ antipsychotic drugs.

Table 20.3 Antipsychotic drugs