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CHAPTER 2-13: ANTIDEPRESSANTS, GENERAL (NONCYCLIC)

Neal L. Benowitz

INTRODUCTION

Many noncyclic antidepressants are available. These can be classified as selective serotonin reuptake inhibitors (SSRIs), including fluoxetine (Prozac), sertraline (Zoloft), citalopram (Celexa), escitalopram (Lexapro), paroxetine (Paxil), and fluvoxamine (Luvox); serotonin-norepinephrine reuptake inhibitors (SNRIs), including venlafaxine (Effexor), desvenlafaxine (Pristiq) duloxetine (Cymbalta), milnacipran (Savella) and levomilnacipran (Fetzima); norepinephrine-dopamine reuptake inhibitors (NDRIs), including bupropion (Wellbutrin); and others, including trazodone (Desyrel) and mirtazapine (Remeron), the latter a tetracyclic antidepressant. Bupropion is also marketed under the brand name Zyban for smoking cessation. In overdose these drugs are generally less toxic than the tricyclic antidepressants and the monoamine oxidase (MAO) inhibitors, although serious effects, such as seizures, hypotension, cardiac arrhythmias, and serotonin syndrome, occasionally occur. Noncyclic and tricyclic antidepressants are described in Table II–8.

TABLE II–8.ANTIDEPRESSANTS
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TABLE II–8. ANTIDEPRESSANTS
  Usual Adult Daily Dose (mg) Neurotransmitter Effectsa Toxicityb
Tricyclic antidepressants
 Amitriptyline 75–200 NE, 5-HT A, H, QRS, Sz
 Amoxapine 150–300 NE, DA A, H, Sz
 Clomipramine 100–250 NE, 5-HT A, H, QRS, Sz
 Desipramine 75–200 NE A, H, Sz
 Doxepin 75–300 NE, 5-HT A, H, QRS, Sz
 Imipramine 75–200 NE, 5-HT A, H, QRS, Sz
 Maprotiline 75–300 NE A, H, QRS, Sz
 Nortriptyline 75–150 NE A, H, QRS, Sz
 Protriptyline 20–40 NE A, H, QRS, Sz
 Trimipramine 75–200 NE, 5-HT A, H, QRS, Sz
Newer, noncyclic drugs
 Bupropion 200–450 DA, NE Sz
 Citalopram 20–40 5-HT Sz, SS
 Desvenlafaxine 50 5-HT, NE Sz, SS
 Duloxetine 30–180 5-HT, NE Sz, SS
 Escitalopram 10–30 5-HT Sz, SS
 Fluoxetine 20–80 5-HT Sz, SS
 Fluvoxamine 50–300 5-HT Sz, SS
 Levomilnacipran 40–120 5-HT, NE Sz, SS
 Milnacipran 100–200 5-HT, NE Sz, SS
 Mirtazapine 15–45 Alpha2 Sz
 Nefazodone 100–600 5-HT, Alpha2 H
 Paroxetine 20–50 5-HT Sz, SS
 Sertraline 50–200 5-HT Sz, SS
 Trazodone 50–400 5-HT, Alpha2 H, Sz, SS
 Venlafaxine 30–600 5-HT, NE Sz, SS
Monoamine oxidase inhibitors See Monoamine oxidase inhibitors

aAlpha2, central alpha2-adrenergic receptor agonist; DA, dopamine reuptake inhibitor; 5-HT, serotonin reuptake inhibitor; NE, norepinephrine reuptake inhibitor.

bA, anticholinergic effects; H, hypotension; QRS, QRS prolongation; SS, serotonin syndrome; Sz, seizures.

MECHANISM OF TOXICITY

  1. SSRIs inhibit serotonin reuptake transporters resulting in increased stimulation of serotonin receptors in the brain. SNRIs inhibit both serotonin and norepinephrine reuptake transporters and also increase stimulation of CNS norepinephrine receptors. Most agents cause CNS depression. Bupropion is a stimulant that can also cause seizures, presumably related to inhibition of reuptake of dopamine and norepinephrine.

  2. Trazodone and mirtazapine produce peripheral alpha-adrenergic blockade, which can result in hypotension and priapism.

  3. Serotonin reuptake inhibitors, such as fluoxetine, citalopram, sertraline, paroxetine, fluvoxamine, venlafaxine, and trazodone, may interact with each other, with chronic use of an MAO inhibitor, or with dextromethorphan to produce the "serotonin syndrome" (see below and Hyperthermia).

  4. None of the drugs in this group has significant anticholinergic effects.

  5. Pharmacokinetics. These drugs have ...

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