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Antidepressants

Notes

Antidepressants

Sections



Psychopharmacology

Overview

Monoamine Oxidase Inhibitors (MAOIs)

  • (eg, phenelzine)

Tricyclic Antidepressants (TCAs)

  • (eg, amitriptyline)

Selective Serotonin Reuptake Inhibitors (SSRIs)

  • (eg, fluoxetine)

Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs)

  • (eg, venlafaxine)

Atypical Antidepressants

which can be subdivided into:

  • Heterocyclic antidepressants, (eg, buproprion)
  • Serotonin (5-HT) receptor antagonists (eg, trazodone)

Antidepressant Classes

Mechanism of Action: Overview

Serotonin & Norepinephrine

  • Draw a presynaptic serotonin (5-HT) neuron and then a presynaptic norepinephrine (NE) neuron.
  • Then, draw a postsynaptic neuronal membrane and include both 5-HT and NE receptors.

Serotinergic Neuron

  • Show neurotransmitter empty into the synaptic cleft and pass across to the 5-HT postsynaptic receptor.
  • Show neurotransmitter re-enter the presynaptic axon terminal via a reuptake transporter and show that it will then re-enter the pool of neurotransmitters destined to empty back into the synaptic cleft.
  • Now, include monoamine oxidase (MAO) and indicate that it metabolizes neurotransmitter.

Norepinephrine

  • Draw the same set-up for norepinephrine.
  • Here, however, also include an alpha-2 adrenergic presynaptic receptor, which have the capacity to inhibit norepinephrine release.

Typical Antidepressant Classes

Overview

Risk of Suicidality

  • Before we dive into the various classes, as a general rule, let's indicate that all classes of antidepressants can cause suicidality (this is an important rule to remember when counseling patients).

Monoamine Oxidase Inhibitors (MAOIs)

Examples

  • Tranylcypromine, isocarboxazid, phenelzine, and selegeline (a selective MAO-B inhibitor).
    • We discuss selegeline in detail along with medications to treat Parkinson's disease.

Mechanism

  • In our diagram, show that MAO Inhibitors block MAO metabolization of neurotransmitters (we show NE and 5-HT in our diagram), which keeps more of the neurotransmitters actively available.
  • Older MAOIs inhibit both MAO-A, which metabolizes norepinephrine (NE), serotonin (5-HT), and tyramine, and also MAO-B, which metabolizes dopamine (DA), but newer, selective MAO-B inhibitors (eg, selegeline) also exist.

Side Effects

  • Nonselective MAO inhibition results in increases in norepinephrine, serotonin, tyramine, and dopamine, which results in peripheral autonomic sympathetic overactivation.
  • This can result in a hypertensive crisis from MAO-A inhibition of tyramine and other neurotransmitters when taken in combination with tyramine-containing foods, or other sympathomimetics or SSRIs.
  • The "cheese effect," is a hypertensive response to excess dietary tyramine. Note that it is pharmacologic inhibition of monoamine oxidase type A (MAO‐A), but not MAO‐B, that creates this risk to excess dietary tyramine (a biogenic sympathomimetic amine).
  • CNS overactivation is another important potential MAOI side effect.
  • Chronic use of MAOIs results in a lowering of blood pressure, which we note, in part, because it seems counterintuitive.

Tricyclic antidepressants (TCAs)

Examples

  • The -triptyline's (amitriptyline, nortriptyline, and protriptyline); the -ipramine's (clomipramine, desipramine, imipramine, and trimipramine maleate); and doxepin.

Mechanism

  • The TCAs block NE reuptake and 5-HT reuptake and also block histamine (H1) receptors, muscarinic (acetylcholine) receptors, and alpha-adrenergic receptors, and thus they have fairly robust side effects.

Structure

  • As their name suggests, tricyclic antidepressants consist of a three-ringed structure with an attached amine, which is either secondary or tertiary.
    • Secondary amines (including desipramine, nortriptyline, and protriptyline) have a greater norepinephrine reuptake inhibition.
    • Tertiary amines (including amitriptyline, clomipramine, doxepin, imipramine, and trimipramine) have greater serotonin reuptake inhibition.
    • As a chemistry reminder, secondary amines have a nitrogen bound to two carbons whereas tertiary amines have a nitrogen bound to three carbons.

Side Effects

  • Histamine receptor inhibition results in sedation; histamine is a potent wakefulness neurotransmitter.
  • Alpha-1 receptor inhibition results in postural hypotension.
  • Anticholinergic effects are multifold, including dry mouth and, importantly, confusion.
    • As a general rule, tertiary amine TCAs (amitriptyline) produce more anticholinergic side effects than secondary amine TCAs (eg, nortriptyline).
  • Serotonin reuptake inhibition results in weight gain, sedation, and anorgasmia.
  • Norepinephrine reuptake inhibition results in sympathomimetic effects and tremor.

Selective serotonin reuptake inhibitors (SSRIs)

Examples

  • The -oxetine's (fluoxetine and paroxetine); the -alopram's (citalopram and escitalopram); sertraline; and fluvoxamine.

Mechanism

  • The SSRIs block serotonin reuptake into the presynaptic axon terminal; specifically, they block the serotonin transporter (SERT).

Side effects

  • Key side effects include sedation (they are often administered at night); nausea (the GI effects can be very prominent); anorgasmia (inability to ejaculate or have an orgasm); and potentially hyponatremia from SIADH.
  • Serotonin syndrome results from excess 5-HT activation (we'll discuss it in more detail at the end).
  • Serotonin discontinuation syndrome, which results from an overly rapid drop in 5-HT activation. It can manifest in profound symptoms such as brain zaps (paresthesias), dizziness, hyperarousal, and potentially flu-like symptoms. Note that the timecourse for SSRI tapering is very person-dependent.

Serotonin-norepinephrine reuptake inhibitors (SNRIs)

Examples

  • The -lafaxine's (desvenlafaxine, venlafaxine); the -naciprin's (levomilnaciprin, milnacipran); and duloxetine.

Mechanisms

  • The SNRIs inhibit both NE reuptake and also 5-HT reuptake.

Side effects

  • The side effects are serotinergic and also include NE sympathomimetic effects, so there is less sedation, more potential for anxiety, increased risk of HTN, and greater risk of insomnia.

Aypical Antidepressants

Buproprion

  • First, buproprion, show that it is a norepinephrine reuptake inhibitor.
  • And also write out that it is a dopamine reuptake inhibitor (not shown in the diagram).
  • Indicate that it can commonly causes headaches, is an important iatrogenic cause of seizures, and is one of the few antidepressants that can promote weight loss.

Mirtazapine

  • Next, show that mirtazapine is a presynaptic alpha-2 blocker.
  • This receptor inhibits NE release, thus blockade of it results in NE release.
  • Show that it is also a 5-HT subreceptor antagonist; the effects of this are less intuitive but can increase serotonin levels to impact non-inhibited subreceptors.
  • Write out these mechanisms and also indicate that it is an H1 blocker, as well.
  • Indicate that mirtazapine can cause sedation and weight gain.

Trazodone

  • Now, show that trazodone blocks SERT and 5-HT receptors, which has complicated effects but overall increases serotonin levels and is a potential contributor to serotonin syndrome.
  • Indicate that it can, notably, cause priapism, a sustained erection, postural hypotension, and sedation (its used to treat insomnia).

Varenicline

  • Next, indicate varenicline, which is a nicotinic partial acetylcholine receptor agonist.
  • We can remember its mechanism by associating "nicline" is used for nicotine cravings to help in smoking cessation.

Vilazodone & Vortioxetine

  • Then, show that vilazodone and vortioxetine are serotinergic agents that block 5-HT reuptake.

Toxicity

  • Now, as a review, let's run through some of the major risks of toxicity from these medications.

Seizures

  • First, indicate that all classes of medications can result in seizures.

MAOIs

  • Then, indicate that MAOIs can result in a hypertensive crisis, especially when taken with sympathomimetic agents and tyramine-containing foods (again, the cheese effect).
  • Also, indicate that they can result in serotonin syndrome, which we'll address soon.

TCAs

  • Next, indicate that in TCA overdose, the following toxicities can occur by system:
    • Neurological abnormalities include delirium and neuromuscle excitation and problems, which can progress to coma.
    • Cardiac abnormalities include conduct defects that can progress to cardiac arrhythmias.
    • Respiratory abnormalities include respiratory depression, which can progress to respiratory failure.
    • Dysautonomia can occur, especially hyperpyrexia (fever).
      Remember the mneomonic: hot as a hare, blind as a bat, dry as a bone, red as a beet, mad as a hatter.

SSRIs and SNRIs

  • Now, for the SSRIs and SNRIs, indicate that serotonin syndrome can occur, which results in:
    • CNS and neuromuscle excitation: muscle rigidity, myoclonus, delirium, and seizures. And hyperthermia and cardiovascular instability can occur.
  • Indicate that causes of serotonin syndrome include MAOIs, TCAs, SSRIs (& SNRIs), atypical agents, as well as illicit drugs (MDMA), dextromethorphan, meperidine, tramadol, and St. John's wort.
  • Show that treatments include antiepileptic drugs, benzodiazepines, and serotonin blockers (namely, cyproheptadine, which is primarily an anti-histamine but also has serotonin receptor blocking effects).