Discuss the pharmacology of different classes of antidepressants.

Outline:

·        Clinical features of depression.

·        Mechanism of action of antidepressants.

·        Tricyclic antidepressants (TCA)

·        Selective serotonin reuptake inhibitors (SSRI)

·        Monoamine oxidase inhibitors (MAOI)

Suggested Answer:

Depression is a major psychiatric syndrome characterized by depressed mood accompanied by neuro-vegetative symptoms (e.g. loss of drive, reduced energy, disturbance in sleep, loss of appetite and libido) with or without psychotic features that affect their normal functioning.

The prevalence rate of depression in Singapore was found to be 8.6% in a study by Fones, Kua, Ng and Ko (1988). For the elderly, the rate is lower at 5.7% (Kua, 1990). The World Health Organization ranks depression as the world’s fourth greatest public health problem. Untreated depression is associated with high mortality.

Antidepressants are drugs that are used to treat depression. According to the amine hypothesis of depression, it is believed that decreased amine (serotonin and noradrenalin) neurotransmission is associated with depression. Antidepressants work chiefly by increased the amine stores present in the body.

Tricyclic antidepressants (TCAs) have a 3 interlinked-carbon ring nucleus in their molecular structure. Their antidepressant action is due to their blocking the re-uptake of serotonin and noradrenalin into the presynaptic terminals. By this blockade of uptake, they permit a prolonged action of the neurotransmitters at the receptor sites. Therapeutic effect is delayed for 7 – 14 days due to down-regulation of the receptors activated by the potentiated amines.

TCAs are well absorbed orally from the gastrointestinal tract and they generally have long half-lives ranging from 15 to 100h, with imipramine at the lower end and protriptyline at the upper. Their plasma concentrations peak after ingestion. They are highly protein bound and have a large volume of distribution. Metabolism involves demethylation, hydroxylation and conjugation. Between 25 and 75% of these drugs are metabolized first-pass through the liver after oral administration. Some of the metabolites have antidepressant action, e.g. desipramine and nortriptyline are metabolites of imipramine and amitriptyline respectively. About 50% of the drugs are excreted through the bile, but because of an active enterohepatic circulation, 2/3 are eventually excreted in the urine.

TCAs have adverse cardiovascular, anti-cholinergic and CNS effects which have to be taken note of when treating the elderly. Cardiovascular effects are related to individual sensitivities, underlying cardiac problem, and the dosage of TCAs. Postural hypotension and tachycardia occur frequently especially in elderly patients. Rarely, heart block, arrhythmias and sudden death may occur, particularly in patients with pre-existing cardiac disease. Anti-cholinergic effects vary from mild to severe. Blurring of vision, dryness of mouth, urinary retention and constipation can be serious in the elderly. Male sexual function may be impaired. Sedation is very common. Non-specific muscle weakness, fatigue and vertigo occur occasionally. Tremors, hallucinations, confusion, excitement and precipitation of mania and epilepsy can occur. TCAs do not cause addiction but rapid discontinuation can produce symptoms of GIT disturbance, insomnia, extrapyramidal symptoms and acute psychiatric disturbances. Overdose causes cardiac dysrhythmias, hypotension and convulsions. The clinical picture is dominated by marked anti-cholinergic activities such as mydriasis, ataxia and confusion. In severe cases, coma, myoclonic seizures, hyperpyrexia, hypotension and cardiac arrhythmias occur.

Catecholamines and other sympathomimetics are potentiated. Severe toxicity can occur if full doses of TCA are combined with an MAO inhibitor. Phenothiazines and TCAs may mutually compete so that plasma concentrations of both are elevated. Because TCAs are extensively metabolized in the liver, both induction of and competition for metabolizing enzymes can occur. Hazardous cardiovascular effects may occur in patients receiving local anaesthetic which contains adrenaline or noradrenaline. Effects of alcohol may be increased.

TCAs are indicated in major depressive illness. Other uses are enuresis in children, chronic headache, bulimia and obsessive-compulsive disorders. Contraindications include recent myocardial infarction or cardiac disease, past history of narrow angle glaucoma and male patients with prostatic enlargement. In the presence of cardiac of cardiac disease and old age, mianserin or trazodone may be preferred as safer than others.

Mianserin does not inhibit the amine pump; it may act via central a₂-adrenoceptors. It is a sedative, has little antimuscarinic effect and is less cardiotoxic than are TCAs. However, it can cause agranulocytosis and aplastic anaemia. Trazodone is a phenylpiperazine derivative. It is absorbed orally and is excreted as metabolites in faeces and urine. It is sedating and has very low anti-cholinergic properties. It blockers 5-HT receptor in the CNS and may decrease the sensitivity of central b-receptors. It has no cardiotoxicity, but can cause priapism resulting in permanent impotence.

The SSRIs are fluoxetine, paroxetine, fluvoxamine, citalopram and sertralin. Fluoxetine (Prozac) was the first SSRI to reach general clinical use. Paroxetine and sertraline differ mainly in having shorter half-lives. While they have not been shown to be more effective overall than prior drugs, they lack many of the toxicities of the tricyclics and other antidepressants. They are therefore more acceptable and safer for use in the elderly.

Fluoxetine hydrochloride appears to be well absorbed from the GI tract following oral administration. The onset of antidepressant activity following oral administration of fluoxetine hydrochloride usually occurs within the first 1—3 weeks of therapy, but optimum therapeutic effect usually requires 4 weeks or more of therapy with the drug. Fluoxetine and norfluoxetine, the principal metabolite, are eliminated slowly. Following a single oral dose of fluoxetine in healthy adults, the elimination half-life of fluoxetine reportedly averages approximately 2—3 days (range: 1—9 days) and that of norfluoxetine averages about 7—9 days.

SSRIs are used in the clinical management of major depressive disorder, obsessive-compulsive disorder, panic disorder, social phobia, bulimia nervosa, premature ejaculation, alcohol dependence and depression associated with bipolar disorder.

Headache, nervousness, anxiety, insomnia, drowsiness and fatigue are the most common side effects of SSRIs. The common GI effects are nausea, vomiting and diarrhea. Maculopapular rashes, urticaria and purpura have been reported. Weight loss frequently occurs during therapy with SSRIs and is reversible after discontinuation of the drug. Sexual dysfunction occurs in a small percentage of patients on SSRIs, the most common of which is ejaculatory delay.

The concurrent administration of tramadol and a selective serotonin reuptake inhibitor (SSRI) may result in an additive blockage of serotonin reuptake, resulting in central serotonergic hyperstimulation and serotonin syndrome. The SSRIs may inhibit the metabolism of tramadol at the cytochrome P450-2D6 isoenzyme and may lower the seizure threshold.  Symptoms of serotonin syndrome may include irritability, altered consciousness, double vision, nausea, confusion, anxiety, hyperthermia, increased muscle tone, rigidity, myoclonus, rapid fluctuations in vital signs, and coma. Serotonin syndrome may result in death. The concurrent administration of tramadol with a SSRI may also increase the risk of seizures. SSRIs may displace warfarin from its plasma protein binding sites or inhibit its hepatic metabolism leading to an increase in the clinical effects and toxicities of warfarin. It also inhibit the metabolism of benzodiazepines, TCAs and clozapine resulting in an increase in their clinical effects.

The MAO inhibitors inhibit monoamine oxidases, a group of enzymes present inside cells of the brain, in peripheral adrenergic and dopaminergic nerve endings, and in the liver and gut wall, and which is concerned in the breakdown of serotonin and catecholamines. The irreversible MAO inhibitors are phenelzine, isocarboxazid and tranylcypromine. The reversible inhibitor of MAO-A (RIMA) are toloxaone and moclobemide. MAO inhibitors are used in atypical affective disorders and certain anxiety states and when patients fail to respond to TCAs.

MAOIs are rapidly and fully absorbed from the GIT. They are inactivated primarily by acetylation by hepatic acetyltransferase and are excreted very quickly through the intestinal tract and to a lesser extent, via the kidneys. Their half-life in the body is very short. However the irreversible MAOIs have long-lasting pharmacological effects, and the body must resynthesize the enzyme before normal metabolism of body amines resumes, a process taking 1 to 2 weeks to complete.

Non-selective irreversible MAOIs inhibit the various subtypes of MAO throughout the body (gut, liver, brain, platelets and blood vessels). By inhibiting these degradative enzymes, they lead to an accumulation of monoamines such as NA, 5-HT and DA presynpatically and more to be released. Some MAOIs have direct sympathomimetic activity by releasing stored NA. MAOIs also inhibit other enzymes and they interfere with the metabolism of many drugs.

MAOIs prevent the break down of food containing tyramine and drugs containing sympathomimetics, leading to hypertensive reaction. The foods are cheese, pickled herring, broad bean pods, wines, over-ripe bananas, avocados, figs, fermented bean curds and sausage. When the enzymes in the intestinal tract are inhibited, tyramine and other monoamines in food or produced by bacteria in the gut are not broken down and these may be absorbed in sufficient amounts to produce a hypertensive reaction. Severe hypertension can occur if L-dopa is given with an MAOI. Excitement with TCAs and SSRIs can precipitate a life-threatening ‘serotonin syndrome’ consisting of hyperthermia, tremor and convulsions. MAOI inhibits the hepatic enzyme that demethylates pethidine. If pethidine is given to a patient taking MAOI, there is liable to be respiratory depression and even coma. Insulin and oral hypoglycaemics are potentiated.