FIG. 3.12 Possible effects of receptor binding of the antidepressant medications.
FIG. 3.13 Normal release, reuptake, and destruction of the monoamine neurotransmitters.
FIG. 3.14 How the tricyclic antidepressants block the reuptake of norepinephrine.
Hypotheses of antidepressants’ mechanism of action are:
1. The monoamine hypothesis of depression suggests that there is a deficiency in one or more of the three neurotransmitters: serotonin, norepinephrine, or dopamine. The theory implies that by increasing these neurotransmitters depression is alleviated.
The monoamine receptor hypothesis of depression also suggests that low levels of neurotransmitters cause postsynaptic receptors to be up-regulated (increased in sensitivity or number). Increasing neurotransmitters by antidepressants results in down-regulation (desensitization) of key
neurotransmitter receptors. Delayed length of time for down-regulation may explain why it takes 4 to 6 weeks for antidepressants to work, especially if they rapidly increase neurotransmitters.
2. Another hypothesis for the mechanism of antidepressant drugs suggests that with prolonged use they increase production of neurotrophic factors. These factors regulate the survival of neurons and enhance the sprouting of axons to form new synaptic connections (Stahl, 2013).
Selective Serotonin Reuptake Inhibitors
As the name implies, the selective serotonin reuptake inhibitors (SSRIs), such as fluoxetine (Prozac), sertraline (Zoloft), paroxetine (Paxil), citalopram (Celexa), escitalopram (Lexapro), and fluvoxamine (Luvox), block the reuptake of serotonin thereby making more of this neurotransmitter available. However, they each have slightly different effects.
Fluoxetine (Prozac) is a serotonin (5-HT2C) antagonist, which can lead to the anorexic and antibulimic effects of fluoxetine at higher doses. Both sertraline (Zoloft) and fluvoxamine (Luvox) have sigma-1 receptor binding property. Researchers do not completely understand sigma-1 action but believe it contributes to anxiety-reducing and antipsychotic actions.
Paroxetine (Paxil) is the most anticholinergic among the SSRIs due to its muscarinic-1 antagonist property. Although it is relatively less anticholinergic than the tricyclic antidepressants, paroxetine may not be the best choice for patients with contraindications to anticholinergic agents (e.g., narrow angle glaucoma).
Citalopram (Celexa) has R- and S-enantiomers. At lower doses, the R-isomer may inhibit the increased 5-HT effects of the S-isomer leading to inconsistent efficacy. Escitalopram (Lexapro) has the S-enantiomer structure only without the R-enantiomer, which explains its more predictable efficacy at lower doses (Stahl, 2013).
As a class, SSRIs have less ability to block the muscarinic and histamine receptors than do the tricyclic antidepressants. As a result of their more selective action, they seem to show comparable efficacy without causing the anticholinergic and sedating side effects. However, SSRIs have other side effects resulting from stimulation of different serotonin receptors. Stimulation of the 5-HT2A
and 5-HT2C receptors in the spinal cord may inhibit the spinal reflexes of orgasm. Stimulation of the
5-HT2A receptors in the mesocortical area may decrease dopamine activity in this area, leading to apathy and low libido. Stimulation of the 5-HT3 receptors in the hypothalamus or brainstem may cause nausea or vomiting while gastrointestinal (GI) side effects are secondary to the 5-HT3 and/or 5-HT4 receptors in the GI tract (Stahl, 2013; Fig. 3.14).
Norepinephrine and Serotonin Specific Antidepressant
The class of drugs known as the norepinephrine and serotonin specific antidepressant (NaSSA) is represented by only one drug, mirtazapine (Remeron), which increases norepinephrine and
serotonin transmission by antagonizing (blocking) presynaptic alpha-2 adrenergic autoreceptors.
Mirtazapine offers both antianxiety and antidepressant effects with minimal sexual dysfunction and improved sleep. This antidepressant causes fewer GI symptoms. The most common side effects are sedation, appetite stimulation, and weight gain.
Norepinephrine Dopamine Reuptake Inhibitor
Bupropion (Wellbutrin) is an antidepressant also used for smoking cessation (Zyban). It seems to act as a norepinephrine-dopamine reuptake inhibitor (NDRI). With no serotonergic activities, it does not cause sexual dysfunction side effects. Side effects include insomnia, tremor, anorexia, and weight loss. It is contraindicated in patients with a seizure disorder, in patients with a current or prior diagnosis of bulimia or anorexia nervosa, and in patients undergoing abrupt discontinuation of alcohol or sedatives (including benzodiazepines) due to the potential of seizures.
Serotonin Antagonist and Reuptake Inhibitors
Nefazodone, formerly sold as Serzone, is a novel drug indicated only for depression. It is a
serotonin antagonist and reuptake inhibitor (SARI) that works by blocking serotonin receptors and weakly inhibiting the reuptake of norepinephrine and serotonin. The most common side effects are sedation, headache, fatigue, dry mouth, nausea, constipation, dizziness, and blurred vision. Weight gain and sexual dysfunction are minimal. This drug should be used with caution due to life- threatening liver failure and should never be given to people with pre-existing liver problems.
Trazodone, formerly sold under the trade name Desyrel, was not used for antidepressant treatment for many years. It was often given, along with another agent, for the treatment of insomnia as sedation is one of its common side effects. A trademarked version, Oleptro, has FDA approval as an extended-release drug indicated for the use of major depressive disorder in adults.
Its antidepressant effects are due to its action as a 5-HT reuptake inhibitor and 5-HT2A/2C antagonist.
Common side effects of trazodone are sedation, dizziness, and orthostatic hypotension. Potent alpha-1 antagonists with little anticholinergic effects, such as trazodone, can lead to priapism, a painful prolonged erection caused by the inability for detumescence (subsidence of erection).
Brexpiprazole (Rexulti) was introduced in 2015. It has FDA approval as a treatment for the depression that accompanies schizophrenia. It works as a partial agonist at serotonin 5-HT1A and dopamine D2 receptors and antagonist activity at serotonin 5-HT2A receptors. Due to dopamine effects, it may result in akathisia. Weight gain is also a side effect of this drug.
Serotonin Modulator and Stimulator
Vortioxetine (Trintellix) is a serotonin modulator and stimulator. It affects many different serotonin receptors by inhibiting serotonin reuptake like the SSRIs, agonizing the 5-HT1A receptor like
buspirone, partially agonizing the 5-HT1B receptor, and antagonizing the 5-HT3, 5-HT1D, and 5-HT7 receptors. Geriatric patients may experience an improvement of cognitive deficits independent of its antidepressant properties. Common side effects include constipation, nausea, and vomiting. More serious side effects are hyponatremia and, rarely, induction of hypomania/mania.
Serotonin Norepinephrine Reuptake Inhibitors
Serotonin norepinephrine reuptake inhibitors (SNRIs) increase both serotonin and norepinephrine.
Venlafaxine (Effexor) acts more like a serotonergic agent at lower therapeutic doses and promotes norepinephrine reuptake blockade at higher doses, leading to the dual SNRI action. Hypertension
approximately 7 to 10 mm Hg.
Desvenlafaxine (Pristiq) is the primary active metabolite of venlafaxine. When people take venlafaxine, the majority of the benefit comes from venlafaxine being metabolized into desvenlafaxine. Therefore the mechanism of action and effects of the two antidepressants are similar.
Duloxetine (Cymbalta) is an SNRI indicated for both depression and GAD, as well as diabetic peripheral neuropathy, fibromyalgia, and chronic musculoskeletal pain.
Like the tricyclic antidepressants, many of the SNRIs also have therapeutic effects on neuropathic pain. The common underlying mechanism of neuropathic pain is nerve injury or dysfunction. The mechanism by which tricyclic antidepressants and SNRIs reduce neuropathic pain is activating the descending norepinephrine and 5-HT pathways to the spinal cord, thereby limiting pain signals from reaching the brain.
The previously discussed SNRIs inhibit serotonin reuptake more than they inhibit norepinephrine reuptake. Levomilnacipran (Fetzima) is an SNRI with a greater effect on
norepinephrine reuptake than any of the other SNRIs available for treating depression. Increasing norepinephrine may be responsible for observed increases in heart rate and blood pressure in some patients.
Serotonin Partial Agonist and Reuptake Inhibitor
Vilazodone (Viibryd) is an antidepressant approved by the FDA in 2011. It enhances the release of serotonin by inhibiting the serotonin transporter (similar to SSRIs) and by stimulating serotonin (5- HT1A) receptors through partial agonism (similar to the antianxiety medication buspirone). With this dual activity, vilazodone is considered to be a serotonin partial agonist and reuptake inhibitor (SPARI). Commonly observed adverse reactions during clinical trials include diarrhea, nausea, insomnia, and vomiting. Patients should take this antidepressant with food for better
bioavailability, and avoid nighttime doses due to insomnia.
Tricyclic Antidepressants
Tricyclic antidepressants (TCAs) were widely used before the development of SSRIs. They are no longer considered first-line medications since they have more side effects, take longer to reach an optimal therapeutic dose, and are far more lethal in overdose. The TCAs act primarily by blocking the reuptake of norepinephrine for the secondary amines (e.g., nortriptyline [Pamelor]) and both norepinephrine and serotonin for the tertiary amines (e.g., amitriptyline, imipramine [Tofranil]). As shown in Fig. 3.15, this blockade prevents norepinephrine from coming into contact with its
degrading enzyme, MAO, increasing the level of norepinephrine at the synapse. Similarly, the tertiary TCAs block the reuptake and destruction of serotonin and increase the synaptic level of this neurotransmitter.
FIG. 3.15 How the selective serotonin reuptake inhibitors work.
FIG. 3.16 Blocking of monoamine oxidase (MAO) by inhibiting agents (MAOIs), which prevents the breakdown of monoamine by MAO.
To varying degrees, many of the tricyclic drugs also block the muscarinic acetylcholine receptors.
As discussed in the previous section, this blockade leads to anticholinergic effects such as blurred vision, dry mouth, tachycardia, urinary retention, and constipation. These adverse effects can be troubling to patients and limit their adherence to the regimen.
Depending on the individual drug, these agents can also block histamine 1 (H1) receptors in the brain. Blockade of these receptors by any drug causes sedation and drowsiness, an unwelcome symptom in daily use (see Fig. 3.12). Persons taking TCAs often have adherence issues because of their adverse reactions. TCA overdose can be fatal secondary to cardiac conduction disturbances from excessive sodium channel blockade.
Monoamine Oxidase Inhibitors
Monoamine oxidase inhibitors (MAOIs) are a class of antidepressant drugs that can have a desired effect in the brain while exerting potentially dangerous effects elsewhere. To understand the action of these drugs, keep in mind the following definitions:
• Monoamines are organic compounds.
• Monoamines include the neurotransmitters norepinephrine, epinephrine, dopamine, serotonin, and many different food substances and drugs.
• MAO is an enzyme that destroys monoamines.
• MAOIs are drugs that inhibit the action of MAO to prevent the destruction of monoamines.
• MAOIs increase the synaptic level of neurotransmitters resulting in the antidepressant effects of these drugs (Fig. 3.16).
• Examples of MAOIs include isocarboxazid (Marplan), phenelzine (Nardil), selegiline (EMSAM), and tranylcypromine (Parnate).
There is a problem with inhibiting MAO. The liver uses these enzymes to degrade monoamine substances that enter the body from food. One monoamine, tyramine, is present in most protein- based foods. However, some foods are extremely rich in tyramine. They include aged cheeses, pickled or smoked fish, and wine. If the liver cannot break down the tyramine from these
substances, tyramine can produce significant vasoconstriction. This vasoconstriction results in an elevation in blood pressure and the threat of a hypertensive crisis.
In addition to food, a number of drugs, such as other antidepressants and sympathomimetic drugs, can result in serious reactions. In a patient taking drugs to inhibit MAO, the blood level of monoamine drugs can reach high levels and cause serious toxicity. Any drug that amplifies
hypertensive crisis due to an excess supply of these neurotransmitters. For example, paroxetine (Paxil) inhibits the reuptake of serotonin, making more serotonin available. At the same time, if MAO is inhibited and is not degrading the serotonin as quickly, dangerous levels of serotonin can occur. Patients should avoid using some over-the-counter products with sympathomimetic properties (e.g., oral decongestants) or serotonergic properties (e.g., dextromethorphan).
Because of the dangers that result from inhibition of hepatic and intestinal MAO, patients taking MAOIs must be given a list of foods and drugs to avoid. Chapter 14 discusses the treatment of depression and contains a list of foods to avoid and foods to be taken in moderation along with nursing measures and instructions for patient education.