Classification

As shown in Table 175-1, the most commonly used classification scheme divides antidepressant medications into tricyclic antidepressants, monoamine oxidase inhibitors, selective serotonin reuptake inhibitors, serotonin and norepinephrine reuptake inhibitors, and a miscellaneous group of drugs referred to as atypical antidepressants.^5–7 This classification is suboptimal from a pharmacologic standpoint because it mixes structural (TCA) and functional (e.g., SSRI, MAOI) drug characteristics. In addition, as discussed later, functional characteristics can vary markedly among the drugs in each category, and significant overlap can occur between categories. Nevertheless, this classification scheme does provide a framework for discussing the pharmacology, clinical manifestations, and management of antidepressant overdose.

TABLE 175-1 Classification of Antidepressant Medications

Pharmacology

Before describing the pharmacology of the antidepressant drugs, it is important to review the release, reuptake, and metabolism of serotonin (5-hydroxytryptamine [5-HT]) and norepinephrine (NE), two monoamine neurotransmitters that are believed to play a major role in the pathogenesis of depression. As illustrated in Figure 175-1, 5-HT and NE are each synthesized by specific neurons and packaged into vesicles in the presynaptic nerve terminal. An action potential causes these vesicles to fuse with the nerve membrane, thereby releasing 5-HT or NE into the synaptic cleft. After release, these neurotransmitters bind to specific postsynaptic receptors. Seven serotonin receptor families (designated 5-HT₁, 5-HT₂, and so forth) have been identified, and many contain more than one receptor subtype (e.g., 5-HT_1A, 5-HT_1B).⁸ Each family and each receptor subtype appears to have specific functions and distributions throughout the body, although all are present in the central nervous system (CNS). NE binds to two major families of postsynaptic receptors termed α and β, and each has two major subtypes, referred to as α₁, α₂, β₁, and β₂. After release, the actions of 5-HT and NE are terminated primarily by active reuptake into the presynaptic neuron by amine-specific transporters. There, they are either repackaged into vesicles for future release or inactivated by the mitochondrial-bound enzyme, monoamine oxidase (MAO). MAO has the important role of inactivating a wide variety of monoamines and is found in the brain, gastrointestinal (GI) tract, and liver as well as other organs and tissues. There are two enzyme subtypes. MAO-A primarily functions to inactivate 5-HT, NE, and tyramine, whereas dopamine, phenylethylamine, tyramine, and tryptamine are the major substrates of MAO-B.⁸

Figure 175-1 Serotonin (5-HT) and norepinephrine (NE) are released into the synaptic cleft and bind to specific post-synaptic receptors. Their effects are terminated by active reuptake into the pre-synaptic neuron by amine-specific transporters. There, they are either repackaged into vesicles or inactivated by monoamine oxidase (MAO).

Pharmacologic Actions

Most antidepressant medications act to increase the extraneuronal concentrations of serotonin and/or norepinephrine in the CNS. The TCAs, SSRIs, and SNRIs do this by inactivating specific transporters in the presynaptic neuron, thereby preventing the reuptake of these biogenic amines from the synaptic cleft. As shown in Table 175-2, the TCAs have a wide range of potencies and specificities for the 5-HT and NE transporters.^5,9 For example, desipramine is the most potent inhibitor of NE reuptake, whereas clomipramine is the most effective serotonin reuptake blocker. The SSRIs, although much more specific, also demonstrate variable potency for transporter blockade.^5,10–13 The SNRIs inhibit both 5-HT and NE reuptake, but with the exception of duloxetine have relatively low potency.^5,14,15 At present, it is not clear that differences in drug selectivity translate into differences in efficacy, and differences in potency are largely eliminated through dosage adjustments.

TABLE 175-2 Potencies of Antidepressants for Blocking Neurotransmitter Reuptake

Drug	Norepinephrine (NE)	Serotonin (5-HT)
Tricyclic Antidepressants
Desipramine	+++++	++
Protriptyline	++++	++
Nortriptyline	+++	+
Amoxapine	++	+
Doxepin	++	+
Clomipramine	+	+++++
Imipramine	+	++++
Amitriptyline	+	++
Selective Serotonin Reuptake Inhibitors
Paroxetine	+	+++++
Sertraline	±	++++
Escitalopram	—	++++
Citalopram	—	+++
Fluoxetine	±	+++
Fluvoxamine	—	++
Serotonin and Norepinephrine Reuptake Inhibitors
Duloxetine	+++	+++++
Venlafaxine	±	+
Desvenlafaxine	+	++
Milnacipran	+	+

Potency increases progressively from ± to +++++. —, no effect.

MAOIs prevent the breakdown of 5-HT and NE after reuptake has occurred.¹⁶ The antidepressant effect of these drugs requires the inhibition of MAO-A and is presumed to result from increased concentrations of 5-HT and NE in the brain. Most MAOIs, including isocarboxazid, phenelzine, and tranylcypromine, irreversibly inactivate both MAO-A and MAO-B. Recently, several new drugs which selectively and reversibly inactivate MAO-A have been developed. The most widely studied of these drugs, moclobemide, has been approved for use in several European countries but is not yet available in the United States.

The so-called atypical antidepressants act through a variety of different mechanisms.^6,7,17 Bupropion primarily inhibits the reuptake of dopamine by blocking specific presynaptic transporters. Mirtazapine is a potent central α-adrenergic agonist that promotes the release of both serotonin and norepinephrine. It also acts as an antagonist at 5-HT₂ and 5-HT₃ receptors. Reboxetine is a selective inhibitor of NE reuptake. Nefazodone and trazodone act primarily by blocking 5-HT_2A receptors.

In addition to their therapeutic effects, many of the antidepressant drugs also have a variety of undesirable properties. As shown in Table 175-3, many of them block α₁-adrenergic, cholinergic, and/or histamine (H₁) receptors.^5–15 The TCAs are the most potent antagonists of all three receptor types, although the atypical antidepressants, mirtazapine, nefazodone, and trazodone, also block H₁ and/or α₁-adrenergic receptors. In general, the SSRIs and SNRIs have little or no effect on these receptors. The TCAs also block fast inward sodium channels on myocardial cells, which is analogous to the effect of type I antiarrhythmic drugs.

TABLE 175-3 Potencies of Antidepressants as Receptor Antagonists

Toxicology

The symptoms and signs that accompany an overdose, the severity and duration of toxicity, and even specific therapeutic strategies can be predicted based on a knowledge of the pharmacologic actions of each of the antidepressant drugs. Because of their potent antagonistic effects at cholinergic, adrenergic, and histaminic receptors and their ability to block sodium channels in the myocardium, TCAs are the most likely class of antidepressant drugs to cause major morbidity or death when taken in overdose.¹⁹ Not surprisingly, significant morbidity and mortality are very uncommon following ingestion of the SSRIs and SNRIs, which lack these properties.¹⁹ MAOIs and the atypical antidepressants have an intermediate toxicity profile.

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