The therapeutic effects of cyclic antidepressants are relatively similar, but their pharmacology differs considerably. The cyclic antidepressants act as neurotransmitter postsynaptic receptor blockers for histamine, dopamine, acetylcholine, serotonin, and norepinephrine (NE). They inhibit the reuptake of neurotransmitter biogenic amines and have quinidine-like membrane-stabilizing effects [3,4,11,13,14,16,17,18,19] (Tables 123.1 through 123.3). These agents may induce atrioventricular blocks [20,21,22,23] and have a direct negative cardiac inotropic effect, demonstrated by a decrease in the rate of change in left ventricular pressure and an increase in left ventricular end-diastolic pressure [17,24,25]. CNS effects may be
related to neurotransmitter and to direct membrane effects [24,26,27]. All tricyclic antidepressants increase the density of β-adrenoreceptors.

SSRIs and SSNRIs alter serotonergic neurotransmission. The International Union of Pharmacological Societies Commission on Serotonin Nomenclature has classified at least twelve 5-hydroxytryptamine (5-HT) receptors based on operational criteria (Table 123.4). SSRIs block some serotonin receptors and inhibit the reuptake of serotonin at other receptor subtypes. Buspirone, a nonbenzodiazepine sedative-hypnotic, is a 5-HT_1A partial agonist and is inhibitory on serotonin neuronal firing. It has anxiolytic and antidepressant activity. Excessive stimulation can lead to hypotension. Antagonists at 5-HT_1C, such as ritanserin, may be anxiolytic. 5-HT_1D receptor subtype stimulation leads to inhibition of neurotransmitter release, and its agonist is sumatriptan, an antimigraine medication. 5-HT₂ stimulation can cause vasoconstriction. 5-HT₃ antagonists have antiemetic and antipsychotic activity (ondansetron) [28]. Classic tricyclic antidepressants affect serotonin neurotransmission by enhancing the sensitivity of postsynaptic 5-HT_1A postsynaptic receptors. The SSRIs alter the release of serotonin presynaptically, leading to an increase in the amount of serotonin that is available for neurotransmission without changing the sensitivity of the 5-HT_1A postsynaptic receptors [29]. In general, the SSRIs normalize the number and function of 5-HT_1A and 5-HT₂ receptors [28]. As a group, the predominant difference between SSRIs is in their effect on the hepatic cytochrome P450 system and drug–drug interactions.

Venlafaxine and duloxetine are considered selective serotonergic and NE reuptake inhibitors. Blockade of NE-α₂ receptors leads to decrease in 5-HT release. Selective serotonergic and NE reuptake inhibitors induce desensitization and downregulation of 5-HT and NE receptors, leading to disinhibition of serotonergic neurons, interruption of feedback inhibition, and increased release of synaptic 5-HT.

MAOIs inhibit the activity of MAO, a flavin-containing enzyme located in the mitochondrial membranes of most tissues [30]. MAO enzymes are divided into two families: MAO-A, which uses 5-HT as its predominant substrate, and MAO-B, whose primary substrates are 2-phenylethylamine, benzylamine, phenylethanolamine, and O-tyramine. Monoaminergic neurons contain predominantly MAO-A; serotonergic neurons have both. MAO-A metabolizes epinephrine, NE, metanephrine, and 5-HT. Both MAO-A and MAO-B metabolize tyramine, octopamine, and tryptamine [31]. MAO regulates intraneuronal catecholamine metabolism and mediates the oxidative deamination of epinephrine, NE, dopamine, and 5-HT. MAO also regulates ingested monoamine (tyramine, ethanolamine) in the gut that would normally be absorbed into the portal circulation [20,21]. The effect of MAOs is to increase the catecholamine storage pool by preventing intraneuronal degradation of catecholamines and 5-HT. These catecholamines can be released by indirectly acting sympathomimetic agents (e.g., amphetamine, tyramine, and dopamine). MAO-A is predominantly found in the intestinal mucosa, placenta, biogenic nerve terminals, liver, and brain, whereas MAO-B is found in the brain, platelets, and liver [22]. Exogenously administered catecholamines are metabolized through catechol-O-methyl transferase (COMT).

MAOIs can be divided into reversible agents (moclobemide) or irreversible (selegiline, phenylzine, isocarboxazid, and tranylcypromine). They may also be selective to MAO-A (moclobemide) or MAO-B (pargyline, selegiline). The original MAOIs (e.g., phenelzine, isocarboxazid, and tranylcypromine) are nonselective irreversible MAO-A and MAO-B inhibitors., selegiline [23]. Selegiline and tranylcypromine are metabolized to desmethylselegiline, levoamphetamine, and levomethamphetamine and will give a positive amphetamine on drugs of abuse urine screening [32].

Cyclic antidepressants are well absorbed orally in therapeutic dosing; peak serum levels occur 2 to 6 hours after ingestion [33]. In overdose [33,34], gastrointestinal (GI) absorption may be delayed secondary to anticholinergic and antihistaminic properties of these drugs. Metabolism is predominately hepatic, with a small enterohepatic circulation [35,36]. Some cyclic antidepressants have active metabolites. The volume of distribution is large, with distribution occurring within the first several hours after ingestion [36]. Elimination half-life averages 8 to 30 hours but may be prolonged in overdose [37]. Elimination is hepatic, with minimal renal involvement. Fluoxetine has an active metabolite with an elimination half-life that extends into weeks. Cyclic antidepressants are extensively bound to serum proteins, particularly α₁-acid glycoprotein (AAG), and binding appears to be pH dependent [38]. MAO inhibitors are well absorbed orally with relatively short elimination half-lives [32]. Since the irreversible agents permanently inhibit the activity of MAO, their effects can last 4 to 6 weeks.

Toxicity from cyclic antidepressants results in CNS depression, seizures, hypotension, dysrhythmias, and cardiac conduction abnormalities [38]. Hyperthermia may occur as a result of increased muscle activity, seizures, and autonomic dysfunction [39]. These toxic effects are believed to have multiple etiologies, none of which has been fully elucidated.

Patients who ingest large amounts of cyclic antidepressants frequently present with hypotension. Several mechanisms have been suggested, including direct negative inotropic effects [17,25] and dysrhythmias, with subsequent decreases in filling time and cardiac output [39,40,41]. Receptor blockade produces vasodilation and autonomic dysfunction. In addition, blockade of the biogenic amine pump prevents adequate uptake and release of these neurotransmitters as active substances, thereby contributing to hypotension [11,16,40].

The CNS effects in cyclic antidepressant overdose can be quite profound. Although some of the newer cyclic antidepressants are less toxic in overdose, they can cause seizures and alteration in mental status [8,42,43]. The etiology of coma, seizures, and myoclonus is multifactorial and involves receptor blockade and direct membrane effects which all contribute to CNS derangements [42,43,44,45]. Cyclic antidepressants interact with both the GABA_A and GABA_B-chloride ion channel in the CNS and may alter chloride flow across the receptor [46,47,48].

Dysrhythmias and conduction abnormalities often provide a clue to the recognition of cyclic antidepressant overdose. Action potential propagation, particularly in ventricular myocardial cells and the conduction system, is significantly affected by these drugs [49]. Cyclic antidepressants blunt phase 0 of the action potential depolarization by blocking the fast inward flux of sodium through the sodium channel [50]. This, in turn, slows the rate of rise of phase 0 (V_max) and slows overall action potential depolarization. As ventricular conduction slows, the QRS complex widens [50,51,52]. This also contributes to unidirectional blocks and reentrant dysrhythmias [52]. Because inward sodium flux is coupled to the calcium excitation in myocardial cells, the myocardial cells are unable to contract fully and become less efficient. A less toxic effect is seen on phase 4 of the action potential (spontaneous diastolic depolarization), leading to decreased automaticity [49]. Delayed repolarization occurs and may contribute to QTc interval prolongation,
which has been associated with torsades de pointes [53,54,55,56]. Because cyclic antidepressants have their tightest myocardial binding during diastole, toxicity appears to be directly related to heart rate; in amitriptyline-poisoned dogs, increasing heart rate caused a decrease in V_max and widened the QRS complex [50,51,52,57,58]. Interventions that slowed the heart rate, such as beta-blockers, improved conduction but led to irreversible hypotension [53,57].

The decrease in V_max during phase 0 appears to be pH sensitive [51,53,58]. Alkalinization with molar sodium lactate, sodium bicarbonate, or hyperventilation, or increasing extracellular sodium concentration, produces an increase in the rate of rise of the action potential (V_max), narrows the QRS complex, decreases the incidence of ventricular tachycardia, and improves blood pressure [53,58,59,60,61,62,63,64,65]. These studies also show that decreasing pH worsens conduction abnormalities, produces hypotension, and increases the incidence of dysrhythmias. A combination of increased extracellular sodium and alkalosis (or hyperventilation plus sodium bicarbonate) in vitro has been shown to be equally and possibly more effective than either alone [52,58]. The use of lidocaine in animal studies decreased automaticity and ectopy and improved conduction. However, it did not have the same salutary effect on the blood pressure as alkalinization and may have worsened inotropy [58]. Although binding of cyclic antidepressants to AAG is increased at an alkalotic pH, infusion of AAG in animals to increase serum protein binding has not been shown to be beneficial [38].

SSRI toxicity results from exaggeration of its pharmacologic activity and is manifest as the serotonin syndrome. The pathophysiology is not fully understood but is believed to result from excessive 5-HT_1A stimulation, although dopamine and other neurotransmitters may be involved. The serotonin syndrome is associated with SSRI use alone, change in dose, overdose, or in combination with other agents [e.g., serotonin precursor or agonists, lithium, tricyclic antidepressants, 5-HT analogs, other SSRIs, meperidine, pentazocine, tramadol, cocaine, 3,4-methylenedioxy-N-methylamphetamine (Ecstasy), MAOIs, and herbal remedies such as St. John’s Wart].

Two forms of toxicity are caused by MAOI: acute overdose and drug and food interactions. Toxicity from acute MAOI overdose results from the exaggerated pharmacologic effects of MAOI and may be associated with secondary complications [66]. The primary drug-drug interaction occurs when MAOI is taken with an indirectly acting sympathomimetic agent (e.g., ephedrine, phenylephrine, phenylpropanolamine, and amphetamine), which causes an NE surge in the peripheral sympathetic nerve terminals. MAOI and food interaction primarily involve the small amounts of tyramine or tryptophan that are normally present in certain foods (e.g., aged cheeses, smoked or pickled meats, yeast and meat extracts, red wines, Italian broad beans, pasteurized light and pale beers, and ripe avocados) and are often termed the cheese reaction. These indirectly acting agents are usually metabolized by MAO-A in the gut. When MAO-A is inhibited, tyramine absorption is unregulated, enters into the portal circulation, and causes release of stored catecholamines with resultant hypertensive response [67,68].

The onset of symptoms from cyclic antidepressant overdose is rapid. Most patients who die from overdose do so before arriving at the hospital and after having ingested large (> 1 g) amounts of drug [66]. Signs and symptoms usually occur within the first 6 hours after ingestion. Patients who survive the first 24 hours without hypoxic insult generally do well [66]. The progression of toxicity is rapid and unpredictable, with patients capable of deteriorating from an awake, alert state to seizures, hypotension, and dysrhythmias within 30 to 60 minutes and with minimal warning signs [6,69,70,71,72,73,74,75]. Cardiac arrest due to cyclic antidepressant poisoning may sometimes respond to prolonged resuscitative efforts. One case reports a patient who survived after a resuscitation of approximately 70 minutes [76].

Vital signs on presentation usually include tachycardia, although patients taking beta-blockers or those with underlying conduction blocks, or those in a premorbid state may present with bradycardia. Cyclic antidepressants without major antimuscarinic effects, such as trazodone, nefazodone, and the SSRIs, may not cause significant tachycardia. Bupropion-toxic patients almost always have vital signs reflecting a hyperadrenergic state [77,78,79]. Initial blood pressure may be elevated but can rapidly change to hypotension. The respiratory rate and body temperature may be elevated. If marked myoclonus or seizures develop, severe hyperthermia may result [39,43,71]. Cyclic antidepressants with prominent antimuscarinic effects may cause mydriasis, urinary retention, ileus, and cutaneous vasodilation (Table 123.2). Absence of these signs does not rule out cyclic antidepressant ingestion.