Interactions

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Antidepressant use offers considerable scope for an adverse interaction with other drugs through both pharmacodynamic and pharmakokinetic mechanisms. It is therefore prudent always to check specific sources for a possibly unwanted outcome whenever a new drug is added or removed to a prescription list that includes an antidepressant.

TCAs and SSRIs

Pharmacodynamic interactions. Many TCAs cause sedation and therefore co-prescription with other sedative agents such as opioid analgesics, antihistamines, anxiolytics, hypnotics and alcohol may lead to excessive drowsiness and daytime somnolence. The majority of TCAs can have undesirable cardiovascular effects, in particular prolongation of the QT interval. A similar risk of QT prolongation arises with many other cardiovascular drugs including amiodarone, disopyramide, procainamide, propa fenone, quinidine, terfenadine, also psychotropic agents such as pimozide, sertindole and thioridazine. Their use in combination with TCAs known to prolong QT enhances the risk of ventricular arrhythmias (for further discussion see p. 509). The combination of thioridazine with any such TCA is thought to be particularly dangerous and is formally contraindicated. TCAs potentiate the effects of catecholamines and other sympathomimetics but not P2-receptor agonists used in asthma. Even the small amounts of adrenaline or noradrenaline in dental local anaesthetics may produce a serious rise in blood pressure.

Both TCAs and SSRIs may cause central nervous system toxicity if co-prescribed with the dopaminergic drugs entacapone and selegiline (for Parkinson's disease). SSRIs increase the risk of toxicity (the serotonin syndrome) when combined with other drugs which upregulate serotonin transmission, e.g. the 5HT1 antagonist sumatriptan (antimigraine) and the anti-obesity drug sibutramine (see p. 697).

Tricyclics and SSRIs can lower the convulsion threshold making epilepsy more difficult to control by anti-epilepsy drugs and lengthening seizure time in electroconvulsive therapy. The situation is further complicated by the ability of carbamazepine to accelerate (induce) the metabolism of antidepressants and inhibition of carbamazepine metabolism by certain antidepressants (below).

Pharmacokinetic interactions. TCAs and SSRIs are metabolised extensively by cytochrome P450 enzymes and adding, changing or stopping antidepressants to a drug regimen can have important consequences.

Potential interactions through the cytochrome P450 CYP 2D6 and CYP 3A4 enzymes can be noted from Tables 19.2a and 19.2b. The combination of drugs that are substrates of the same enzyme creates potential for competitive inhibition of their metabolism with unexpected elevation of plasma concentration. Similarly, potent inhibitors, e.g. fluoxetine and paroxetine (CYP 2D6), fluoxetine and nefazodone (CYP 3A4) and fluvoxamine (CYP 1A2), may cause adverse effects by reducing metabolic breakdown of co-prescribed drugs that are used in standard doses. Antidepressants are commonly prescribed with antipsychotics in a depressive psychosis. Some combinations may have an unexpected adverse outcome unless anticipatory dose adjustment is made, e.g. paroxetine + thioridazine (CYP 2D6), fluoxetine + sertindole (CYP 3A4) and fluvoxamine + olanzapine (CYP 1A2) but others, e.g. fluoxetine + quetiapine (CYP 3A4) appear to be of less significance. An interaction of particular importance involves zuclopenthixol acetate used rapidly to tranquillise psychotic patients who are also receiving fluoxetine or paroxetine and an oral antipsychotic (see p. 363). Inhibition of zuclopenthixol metabolism (CYP 2D6) by fluoxetine or paroxetine, and exacerbated by competition from another antipsychotic CYP 2D6 substrate, can provoke serious over-sedation and respiratory depression.

Epilepsy is a common co-morbid illness in patients who have both psychiatric illness and learning disabilities. The necessary combination of the anti-epilepsy drug carbamazepine, a CYP 3A4 enzyme inducer, with a CYP 3A4 inhibiting SSRI antidepressant then calls for particularly careful increment in drug doses supported by monitoring of plasma carbamazepine concentration.

Depression and hypertension are both common conditions such that some co-morbidity is inevitable, and panic disorder is epidemiologically associated with hypertension. Co-prescription of an enzyme-inhibiting antidepressant with a P-adrenoceptor blocker (metoprolol, CYP 2D6) or with a calcium antagonist (diltiazem, amlodipine, CYP 3A4) may exaggerate antihypertensive effects.

P450 enzyme inhibition by SSRIs may also augment effects of alcohol, tramadol, methadone, terfenadine (danger of cardiac arrhythmia), -caine anaesthetics and theophylline.

Monoamine oxidase inhibitors

Hypertensive reactions. Many sympathomimetic substances can cause highly dangerous hypertensive reactions if taken by patients using MAO inhibitors. Patients taking MAOIs are vulnerable for two reasons. Firstly, since MAOIs cause an increase in catecholamine stores in adrenergic and dopaminergic nerve endings, there is potentiation of sympathomimetics that act indirectly by releasing stored noradrenaline. Secondly, patients taking a monoamine oxidase inhibitor are deprived of the protec tion of the MAO enzyme present in large quantities in the gut wall and liver. Thus orally administered sympathomimetics that would normally be inactivated by this enzyme can be absorbed in much greater quantities. Note that potentiation of administered adrenaline, noradrenaline and isoprenaline is not to be expected since these substances are chiefly destroyed by catechol-O-methyltransferase in the blood and liver.

Symptoms and treatment of hypertensive crisis. Symptoms include a severe, sudden throbbing headache with slow palpitation, flushing, visual disturbance, nausea, vomiting and severe hypertension. If headache occurs without hypertension it may be due to histamine release. The hypertension is due both to vasoconstriction from activation of a-adrenoceptors and to increased cardiac output consequent on activation of cardiac [^-adrenoceptors. The mechanism is thus similar to that of the episodic hypertension in a patient with phaeochro-mocytoma. The rational and effective treatment is an a-adrenoceptor blocker (phentolamine, 5 mg i.v.) and a fi-blocker may be later added in case of excessive tachycadia.

Patient education. It is essential to warn patients taking MAOIs not to use over-the-counter medication, as many simple remedies sold direct to the public, such as those for nasal congestion, coughs and colds, will contain sympathomimetics (ephedrine, phenylpropanolamine). Patients must receive detailed instructions about their diet and be made aware of the need to avoid the many foods containing substantial amounts of sympathomimetics, most commonly tyramine, which acts by releasing tissue-stored noradrenaline. For example, degradation of the protein 'casein' by resident bacteria in well matured cheese can produce tyramine from the amino acid tyrosine, hence use of the term 'cheese reaction' to describe provocation of a hypertensive crisis by orally administered sympathomimetics. Stale foods also present a danger, since any food subjected to autolysis or microbial decomposition during preparation or storage may contain pressor amines resulting from decarboxylation of amino acids.

Moclobemide offers the dual advantages of selective MAO-A inhibition which theoretically

The following foods are capable of producing dangerous hypertensive effects:

• cheese, especially if well matured

red wines (especially Chianti) and some white wines; and some beer (nori- or low-alcohol varieties contain variable but generally low amounts of ryramine)

• yeast extracts (Marmite. Oxo, Bovril)

• some pickled herrings

• broad bean pods (contain dopa.a precursor of adrenaline)

• over-ripe bananas, avocados, figs

• fermented bean curds including soy sauce

• fermented sausage (e.g. salami), shrimp paste

• flavoured textured vegetable protein (Vegemite).

This list may be incomplete and any partially decomposed food may cause a reaction. Milk and yoghurt appear safe.

should avoid the 'cheese' reaction by sparing the intestinal MAO, which is mainly MAO-B, and by being a competitive, reversible inhibitor. Whereas the irreversible inhibitors inactivate the MAO enzyme and can therefore continue to cause dangerous interactions in the 2-5 weeks after withdrawal, until more enzyme can be synthesised, reversible MAO inhibition is incomplete except during peak plasma concentrations. Since the inhibition is competitive, tyramine can then displace the inhibitor from the active site of the MAO enzyme. Consequently there are less dietary restrictions for patients using moclobemide but hypertensive reactions have been reported.

Interactions with other drugs. The mechanisms of many of the following interactions are obscure and some are probably due to inhibition of drug metabolising enzymes other than MAO as MAOIs are not entirely selective in their action. Effects last for weeks after stopping a MAOI. Reactions can be very severe and even fatal.

Antidepressants: Combination with tricyclic antidepressants has the potential to precipiate hypertensive crisis complicated by hyperreflexia, rigidity and hyperpyrexia. MAOI-SSRI combinations may provoke the life-threatening 'serotonin syndrome' (p. 376). Strict rules apply regarding washout periods when switching between MAOIs and other drugs (see 'Changing antidepressants', above). Very occasionally, MAOIs are co-prescribed with other antidepressants but since many combinations are highly dangerous, such practice should be reserved for specialists only and then as a last resort.

Narcotic analgesics: with co-prescribed pethidine respiratory depression, restlessness, even coma, and hypo- or hypertension may result (probably due to inhibition of its hepatic demethylation). Interaction with other opioids occurs but is milder. Other drugs which cause minor interactions with MAOIs include antiepileptics (convulsion threshold lowered), dopaminergic drugs (e.g. selegeline [MAO B inhibitor] may cause dyskinesias), antihypertensives and antidiabetes drugs (metformin and sulponylureas potentiated). Concomitant use with amfebutanone/ bupropion (smoking cessation), sibutramine (weight reduction), and 5HT1-agonists (migraine) should be avoided. Because of the use of numerous drugs during and around surgery, an MAOI is best withdrawn 2 weeks before, if practicable.

Overdose with MAOIs can cause hypomania, coma and hypotension or hypertension. General measures are used as appropriate with minimal administration of drugs: chlorpromazine for restlessness and excitement; phentolamine for hypertension, no vasopressor drugs for hypotension, because of risk of hypertension (use posture and plasma volume expansion).

ST JOHN'S WORT

Many patients with mild to moderate depression are aware of the potential benefits of the herbal remedy St. John's Wort (Hypericum perforatum). The active ingredients in the hypericum extract have yet to be identified and their mode of action is unclear, although it has been postulated that several of the known mechanisms of existing antidepressants are incorporated (inhibition of monoamine reuptake and the monoamine oxidase 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 these studies should be interpreted with caution since many trials failed to use standardised ratings for depressive symptoms, patients tended to receive tricyclic regimes below the minimum therapeutic dose and sometimes received hypericum in doses above the maximum recommended in commercially available preparations. A large multicentre trial found only limited evidence of benefit for St. John's Wort over placebo in significant major depression.1

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 is reasonable on existing evidence to go along with this preference rather than to destroy the therapeutic alliance and risk prescribing a standard antidepressant which will not be taken.

Use of St. John's Wort is complicated by the lack of standardisation of the ingredients. Those who wish to take St. John's Wort should be made aware that it may cause dry mouth, dizziness, sedation, gastrointestinal disturbance and confusion. Importantly also, it induces hepatic P450 enzymes (CYP 1A2 and CYP 3A4) with the result that the plasma concentration and therapeutic efficacy of warfarin, oral contraceptives, some anticonvulsants, antipsychotics and HTV protease/reverse transcriptase inhibitors are reduced. Concomitant use of tryptophan and St John's Wort may cause serotonergic effects including nausea and agitation.

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