Class

Drugs used to treat depression are classified as TCAs, atypical heterocyclic (second- and third-generation) agents, SSRIs, and monoamine oxidase inhibitors (MAOIs). Other conditions for which certain antidepressant agents are used include panic disorder, obsessive-compulsive disease (OCD), bipolar affective disorder, chronic pain, and enuresis.

SSRIs are the most extensively prescribed antidepressant agents because, unlike tricyclic and heterocyclic agents, they produce less sedation, have fewer antimuscarinic cholinoreceptor effects, and are safer in overdose. Nevertheless, they may cause sexual disturbances, GI dysfunction, headache, and stimulation (insomnia, tremor, and anxiety). TCAs may cause sedation, tremor, insomnia, blurred vision, constipation, urinary hesitancy, weight gain, and sexual disturbances. The MAOI phenelzine may cause weight gain, sexual disturbances, and sleep disturbances. The adverse effects of heterocyclic agents vary depending on the agent. Bupropion is contraindicated in patients with seizure disorders (Table Antidepressant agents).

Table: Antidepressant agents

Drug interactions of TCAs include additive sedative effects with other sedatives, particularly alcohol. Phenelzine, by increasing catecholamine stores, sensitizes patients to indirectly acting sympathomimetic agents, including tyramine that is contained in many fermented foodstuffs (red wine or aged cheese), and which together can result in a severe and sometimes fatal hypertensive episode. MAOIs and SSRIs can interact to cause a potentially lethal “serotonin syndrome” that includes tremor, hyperthermia, muscle rigidity, and cardiovascular collapse.

All antidepressant agents now carry a “black-box warning” of an increased risk of suicidality when used in children and adolescents.

Structure

TCAs have a three-ring nucleus similar to that of the antipsychotic phenothiazine agents. The MAOIs are subclassified as hydrazides (phenelzine) or nonhydrazides (tranylcypromine).

Mechanism of Action

The therapeutic activity of most of the available therapeutic antidepressant agents is due, at least in part, to their actions on norepinephrine and serotonin. The TCAs block, to one degree or another, the prejunctional neuronal uptake transporters in the CNS that terminate norepinephrine and serotonin neurotransmission, thus allowing increased activity at their respective receptors. Amoxapine also blocks dopamine receptors.

The atypical agents have a variety of pharmacodynamic effects. Some act similar to the TCAs, whereas others act as inhibitors at certain subtypes of the serotonin receptor (trazodone, mirtazapine, nefazodone). Mirtazapine also blocks the prejunctional α₂-adrenoceptor to enhance serotonin and norepinephrine neurotransmission. Duloxetine inhibits norepinephrine and serotonin uptake.

As the name implies, SSRIs selectively block the prejunctional neuronal uptake transporters in the CNS that terminate serotonin neurotransmission thus allowing increased activity at serotonin receptors.

The MAOI hydrazide, phenelzine, and nonhydrazide, tranylcypromine, essentially irreversibly bind to and inhibit the activity of monoamine oxidase (A and B forms). New enzyme must be synthesized to restore activity. As a result of their actions, both drugs prevent prejunctional metabolism of norepinephrine and serotonin, thus allowing more to accumulate and to be released on nerve stimulation.

The neurochemical and biochemical actions described for the antidepressant agents occur soon after their administration. However, the therapeutic effect of these drugs may not be apparent for up to several weeks with continued administration. Thus, considerable attention has been devoted to discovering the long-term neurochemical and biochemical actions of the antidepressant agents that may correlate better with their clinical effectiveness. Decreased numbers of α-adrenoceptors and decreased cyclic adenosine monophosphate (cAMP) accumulation are two such long-term effects. With chronic administration, enhanced serotonin transmission is also implicated in the therapeutic action of antidepressant agents.

The antidepressant agents also produce a myriad of adverse effects that, depending on the agent, may be caused by blockade of histamine receptors, adrenoceptors, and cholinoreceptors in the peripheral and central nervous systems (see Discussion, Class, and Table Antidepressant agents).

Administration

Dosing, which may be by the oral or parenteral routes, is determined empirically in relation to the therapeutic response and the patient’s tolerance of adverse effects.

Pharmacokinetics

Monodemethylation by the liver of the tertiary amines TCAs amitriptyline and imipramine results in, respectively, the active metabolites nortripty-line and desipramine. Venlafaxine has an active metabolite, O-desmethyl-venlafaxine.

Metabolism of the SSRI fluoxetine results in an active metabolite, norfluoxetine, which has a long half-life. Fluoxetine and paroxetine inhibit a number of liver microsomal enzymes, particularly P450 2D6, that can cause clinically significant drug-drug interactions. Nefazodone inhibits cytochrome P450 3 A4, which can result in increased levels of other drugs that are dependent on this metabolic pathway for their inactivation.

Case: Antidepressant agents. Questions – Answers

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