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Side Effects of


Description: Serotonin antagonist and reuptake inhibitors (SARIs) are a chemically distinct class of drugs used mainly as antidepressants, but also as hypnotics and anxiolytics. They act by antagonism of (blocking) serotonin receptors such as 5-HT2A and inhibition of uptake of serotonin, norepinephrine, and/or dopamine. Most of the SARIs are known as “phenylpiperizine” compounds. SARIs include etoperidone (Axiomin, Etonin); lorpiprazole (Normarex), mepiprazole (Psigodal), nefazodone (Serzone, Nefadar; removed from market for liver toxicity but some generic forms are still available), and trazodone (Desyrel). Trazodone was rediscovered after being on the market since the early 1970’s and is tested as part of the Rxight® drug panel. It is also considered part of the subclass of drugs known as serotonin modulators (European Journal of Pharmacology “Pharmacogenetics and the serotonin system: initial studies and future directions,” Oct 2000).

Indications: Depression and Related Conditions

SARIs such as trazodone are indicated for major depressive disorder, and may also be used for purposes not listed in the original indications. Trazodone’s efficacy is well documented in elderly patients and if often used to help such patients sleep. Trazadone has demonstrated comparable antidepressant activity to other drug classes in a clinical setting, including tricyclic antidepressants (TCAs), selective serotonin reuptake inhibitors (SSRIs) and serotonin-noradrenaline (norepinephrine) reuptake inhibitors (SNRIs). Furthermore, the SARI action of trazodone may overcome the tolerability issues that are often associated with second-generation antidepressants such as SSRIs (e.g., insomnia, anxiety and sexual dysfunction). (Physicians Desk Reference, 70th ed., 2016).

Off label and investigational uses include:

  • Alcohol withdrawal
  • Bulimia nervosa
  • Complex regional pain syndrome
  • Control of nightmares
  • Diabetic neuropathy
  • Erectile dysfunction
  • Fibromyalgia
  • Obsessive-compulsive disorder (OCD)
  • Panic disorder
  • Schizophrenia as an adjunct to improve negative symptoms

  • Serious Side Effects

    Idiosyncratic hepatotoxicity (liver toxicity) has been rarely observed, possibly due to the formation of reactive metabolites.
    Cardiac arrhythmias emerging in relation to trazodone treatment, both in patients with diagnosed mitral valve prolapse and in patients with negative family histories of cardiac disease have been noted. Patients with pre-existing cardiac disease should be very closely monitored, particularly for cardiac arrhythmias. Recent myocardial infarction precludes the use of trazodone and is not recommended for use in those patients. Concomitant administration of drugs that are inhibitors of CYP3A4 or that prolong the QT interval are not recommended as they may increase the risk of cardiac arrhythmia, and this effects is most likely in those who are genetically predisposed. (Current Drug Safety “QT alterations in psychopharmacology: proven candidates and suspects” Jan 2010). While rare, orthostatic hypotension poses an increased risk and may be associated with trazodone, particularly in elderly patients or those with pre-existing heart disease. This effect, due to adrenergic α1-receptor blockade, is related to plasma drug concentration and is a transient effect.

    Additionally, trazodone has been reported to cause seizures in a small number of patients who took it concurrently with medications to control seizures. (Trazodone drug label, U.S. Food and Drug Administration, Jan 2010).

    Common Side Effects

    SARIs are generally well tolerated for the treatment of major depressive disorder, with the most common adverse effects being drowsiness (somnolence/sedation), headache, dry mouth and dizziness. Some patients may not be able to tolerate the sedation effects of trazodone and other SARIs. For example, the more common side effects of trazodone are:

  • Confusion
  • Blurred vision
  • Sweating
  • Lightheadedness
  • Unusual tiredness or weakness
  • (Trazodone drug label, U.S. Food and Drug Administration, Jan 2010).

    Less Common Side Effects

    Among the less common side effects are:

  • Headache
  • Nervousness
  • Confusion about identity, place, and time
  • Shortness of breath
  • Pounding in the ears
  • Slow or fast heartbeat
  • Swelling
  • Decreased concentration
  • Fainting
  • General feeling of discomfort or illness
  • Lack of coordination
  • Muscle tremors
  • (Trazodone drug label, U.S. Food and Drug Administration, Jan 2010).

    Mechanism of Action

    The mechanism of action of SARIs is not fully understood. In general, it is believed that serotonin antagonist and reuptake inhibitors (SARIs) work on serotonin in two ways: they inhibit the reuptake of mostly – but not exclusively – serotonin and prevent them from binding to cell receptors, thus causing the molecules to accumulate in the synaptic clefts. Also, the SERT (sodium-dependent serotonin transporter) prevents serotonin particles that are released in a synapse from binding at certain undesired receptors and redirects them to other receptors that can help nerve cells within mood circuits function better. (European Journal of Pharmacology “Pharmacogenetics and the serotonin system: initial studies and future directions,” Oct 2000). Preclinical studies have shown that Trazodone selectively inhibits neuronal reuptake of serotonin and acts as an antagonist at 5-HT-2A/2C serotonin receptors. Trazodone also antagonizes alpha 1-adrenergic receptors, a property which may be associated with postural hypotension. Etoperidone is a similar SARI and interacts with the 5-HT2A and 5-HT1A serotonin receptors, in addition to antagonizing the α1-adrenergic receptor and the α2-adrenergic receptor. Lorpiprazole acts similarly. (European Journal of Pharmacology “Pharmacogenetics and the serotonin system: initial studies and future directions,” Oct 2000).

    Know Your Risks with the Rxight® Genetic Test

    SARI dosing is possibly more art than science, as small doses are recommended at the outset. A number of drugs may interact with SARIs, making it wise to have your genome tested for variations in the genetic alphabet that makes up the genes that code for SARI metabolism. The Rxight® pharmacogenetics test by MD Labs is well suited to inform you and your physician about any variations you may have in your drug metabolism genes that may affect your ability to take SARIs safely. Specifically, the Rxight® panel analyzes your unique genetically determined ability to metabolize SARIs and over 50 other pharmacological classes. With this information, you and your prescribers will know whether it is safe for you at standard doses, rather than relying on trial and error.

    Contributors to this Article:
    Michael Sapko, MD, PhD; Deborah Kallick, PhD, Medicinal Chemistry

    SARIs Tested Include:

    • Trazodone (Oleptro)

    Read more about Rxight® Genetic Testing For Depression Medication