Cindy DeRan, RPh., FASCP,  ICP Inc. Consulting Pharmacist
In the near future, you will see two new drugs being promoted for treatment of depression.  Both Brintellix (vortioxetine) and Fetzima (levomilnacipran) were approved in 2013 by the U.S. Food and Drug Administration (FDA) for the treatment of Major Depressive Disorder (MDD) in adults.  Many of you may wonder where these new agents will fit in for treatment of depression.  In order to answer this, let’s take a brief review of depression and the antidepressants currently available.
As you may know, depression is a mood disorder that causes a persistent feeling of sadness and loss of interest.  It affects how you feel, think and behave.  Depression can lead to a variety of emotional and physical problems which can result in the inability to perform your normal day-to-day activities.  At times, depression may make you feel as if life isn’t worth living.
Depression, also called Clinical Depression or Major Depressive Disorder, is more than just a bout of the blues.  Depression isn’t a weakness, nor is it something that you can simply “snap out” of.  Treatment of depression may require long-term treatment.
The good news is that there are a number of medications available for treatment of depression.   Most work equally well to take away or reduce the symptoms of depression, so choosing the appropriate antidepressant is normally based on subtle differences including individuals particular symptoms, possible side effects, and interactions with other medications or other health conditions.
Since symptoms of depression can vary from individual to individual, the selection of an appropriate antidepressant needs to be individualized.  One antidepressant may relieve certain symptoms better than another.  For example, if your symptoms of depression include insomnia, then a more sedating agent may be the best choice.  Conversely, if your depression symptoms include low energy, then an antidepressant that’s slightly stimulating may be a good option.
Side effects of medications vary from person to person and from one medication to another.  This is important because bothersome side effects may lead to discontinuation of medication by the individual.  Sexual side effects, weight gain, or weight loss, are common reasons why people stop taking an antidepressant.
Another important consideration when selecting an appropriate antidepressant is the possibility of drug interactions with other medications or problems with other health conditions.  Some antidepressants can cause dangerous reactions when taken with other medications.  And some antidepressants may cause problems if you have certain mental or physical health conditions.  On the other hand, certain antidepressants may help treat other physical or mental health conditions along with depression.
Antidepressants relieve depression by affecting certain brain chemicals (called neurotransmitters) that are associated with depression.  The neurotransmitters affected by antidepressants are norepinephrine, serotonin, and dopamine.  The different classes of antidepressants differ in the neurotransmitters they affect.  This determines some of their side effects and potential drug interactions.  Each class of antidepressant affects these neurotransmitters in slightly different ways.
There are several classes of antidepressants available on the market today.  These include selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), monoamine oxidase inhibitors (MAOIs), tricyclic antidepressants, and miscellaneous other antidepressants.
Monoamine Oxidase Inhibitors (MAOIs) are the oldest class of medications used for treating depression.  MAO inhibitors are rarely utilized due to their potential interactions with tyramine or tryptophan-containing foods, beverages, and other medications.  Combining MAO inhibitors with foods or drinks containing tyramine can result in dangerously high blood pressure, which can lead to a stroke, heart attack, and death.  Because of this danger, MAOIs are usually used only if other medications for depression are ineffective.  Side effects can include dizziness, dry mouth, upset stomach, difficult urination, twitching muscles, sexual side effects, drowsiness, and sleep problems.  Examples of MAOIs include:
  • Isocarboxazid (Marplan)
  • Phenelzine (Nardil)
  • Tranylcypromine (Parnate)
  • Selegiline (Emsam, Eldepryl, Zelapar)

Tricyclic Antidepressants (TCAs) are another class of older antidepressants that may carry higher risks for side effects and other reactions.  While tricyclic antidepressants are effective, they are generally not a first-choice treatment for depression due to the numerous side effects such as dry mouth, constipation, difficulty urinating, sedation, weight gain, and sexual side effects.  Overdosing on a cyclic antidepressant can be deadly.  These agents are rarely the medication of choice for the elderly due to their strong anticholinergic and sedative properties.  Examples of tricyclic antidepressants include:
  • Amitriptyline (Elavil)
  • Amoxapine (Asendin)
  • Clomipramine (Anafranil)
  • Desipramine (Norpramin)
  • Doxepin (Sinequan, Silenor)
  • Imipramine (Tofranil)
  • Maprotiline (Ludiomil)
  • Nortriptyline (Pamelor)
  • Protriptyline (Vivactil)
  • Trimipramine (Surmontil)
Selective Serotonin Reuptake Inhibitors (SSRIs) are probably the most popular antidepressant type currently available.  Many doctors start depression treatment with an SSRI.  They are usually very effective at treating depression and usually do not have many serious side effects.  However, they can cause sexual side effects, e.g. failure to achieve orgasm in women and delayed ejaculation in men.  SSRIs work by increasing the level of serotonin available for cells of the brain.  Examples include:
  • Citalopram (Celexa)
  • Escitalopram (Lexapro)
  • Fluoxetine (Prozac, Sarafem, Selfemra)
  • Fluvoxamine (Luvox, Luvox CR)
  • Paroxetine (Paxil, Paxil CR, Pexeva, Brisdelle)
  • Sertraline (Zoloft)

Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs) are very similar to SSRIs, except that they also affect another chemical in the brain called norepinephrine. In general, SNRIs tend to be more stimulating than SSRIs.  This may cause more insomnia, jitteriness, or other similar side effects. SNRIs used for treatment of depression include:
  • Venlafaxine (Effexor , Effexor XR).  Venlafaxine may work for some people when other antidepressants haven’t.  It can cause side effects similar to the SSRIs, as well as cause increased blood pressure.  Overdose can be dangerous or fatal.
  • Desvenlafaxine (Pristiq).  Desvenlafaxine is similar to venlafaxine and causes similar side effects.  Studies have not proven any advantage over venlafaxine, and it usually costs more than venlafaxine, since venlafaxine is available in a generic form.
  • Duloxetine (Cymbalta).  Duloxetine is approved for physical pain in addition to depression.  It can cause a number of side effects, e.g. nausea, dry mouth, and constipation.  You shouldn’t take duloxetine if you are a heavy drinker or you have certain liver or kidney problems.
  • Levomilnacipran (Fetzima).  This antidepressant is one of the newer agents for treatment of depression.  Levomilnacipran seems to be a stronger inhibitor of norepinephrine reuptake than venlafaxine or duloxetine.  However, there are no studies to prove that it is more effective than other SNRIs. The most common side effects reported were nausea, constipation, hyperhidrosis, heart rate increased, erectile dysfunction, tachycardia, vomiting, and palpitations.

Atypical Antidepressants. There are several other antidepressants available that are collectively called Atypical Antidepressants.  They are called “atypical” because they don’t fit neatly into other categories.  Generally, these agents cause fewer sexual side effects than other antidepressants do.  Atypical antidepressants include:
  • Bupropion (Wellbutrin, Wellbutrin SR, Wellbutrin XL).  Bupropion is a Norepinephrine and Dopamine Reuptake Inhibitor (NDRI).  It is effective for depression and has few sexual side effects.  It may also suppress appetite, and it may help you stop smoking if you are trying to quit.  However, bupropion can lower seizure threshold, so people with seizure disorders should not take bupropion.  People with bulimia or anorexia shouldn’t take bupropion .
  • Trazodone (Desyrel, Oleptro) and  Nefazodone (Serzone, Nefadar) are Serotonin Antagonist and Reuptake Inhibitors (SARIs).   Trazodone is a mild antidepressant that is often prescribed as a sleep aid because it can be very sedating.  Nefazodone is effective, but isn’t commonly used because it has been linked to dangerous liver problems.
  • Mirtazapine (Remeron, Remeron SolTab).  Mirtazapine is classified as a Noradrenergic Antagonist.  It is FDA approved for treatment of depression and is best taken at bedtime due to sedation.  It is also used off-label as an appetite stimulant.
  • Vilazodone (Viibryd) and Vortioxetine (Brintellix)are Serotonin Modulator and Stimulators (SMS).  These drugs work by serving as a partial agonist at the 5-HT1a receptor and an inhibitor of the serotonin transporter.  These agents will be promoted as having a new mechanism of action, but still work by inhibiting serotonin reuptake, like an SSRI.  It also binds to some serotonin receptors, but this hasn’t been shown to increase its antidepressant effect.  In addition, vortioxetine may cause more nausea than others, as well as constipation and nausea.

So as you can see, there are a variety of antidepressants available to treat the symptoms of depression.  Each medication affects different neurotransmitters in the brain in unique ways to determine some of their side effects and potential drug interactions.  Most antidepressants work equally well to relieve the symptoms of depression so choosing the right one involves subtle differences including an individual’s particular symptoms, possible side effects, interaction with other medications or other health conditions, and cost.   
And where will these newer antidepressants fit in for the treatment of depression?  No one can say for sure.  But as many people with MDD struggle to find a treatment that works for them, these agents will provide patients and physicians with an additional option for treating this serious disease.

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