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Chapter: Basic & Clinical Pharmacology : Antidepressant Agents

Antidepressant Agents

The diagnosis of depression still rests primarily on the clinical interview. Major depressive disorder (MDD) is characterized by depressed mood most of the time for at least 2 weeks and/ or loss of interest or pleasure in most activities.

Antidepressant Agents


The diagnosis of depression still rests primarily on the clinical interview. Major depressive disorder (MDD) is characterized by depressed mood most of the time for at least 2 weeks and/ or loss of interest or pleasure in most activities. In addition, depression is characterized by disturbances in sleep and appe-tite as well as deficits in cognition and energy. Thoughts of guilt, worthlessness, and suicide are common. Coronary artery disease, diabetes, and stroke appear to be more common in depressed patients, and depression may considerably worsen the prognosis for patients with a variety of comorbid medical conditions.

According to a 2007 report by the Centers for Disease Control and Prevention, antidepressant drugs were the most commonly prescribed medications in the USA at the time of the survey. The wisdom of such widespread use of antidepressants is debated. However, it is clear that American physicians have been increasingly inclined to use antidepressants to treat a host of conditions and that patients have been increasingly receptive to their use.

The primary indication for antidepressant agents is the treat-ment of MDD. Major depression, with a lifetime prevalence of around 17% in the USA and a point prevalence of 5%, is associ-ated with substantial morbidity and mortality. MDD represents one of the most common causes of disability in the developed world. In addition, major depression is commonly associated with a variety of medical conditions—from chronic pain to coronary artery disease. When depression coexists with other medical con-ditions, the patient’s disease burden increases, and the quality of life—and often the prognosis for effective treatment—decreases significantly.

Some of the growth in antidepressant use may be related to the broad application of these agents for conditions other than major depression. For example, antidepressants have received Food and Drug Administration (FDA) approvals for the treatment of panic disorder, generalized anxiety disorder (GAD), post-traumatic stress disorder (PTSD), and obsessive-compulsive dis-order (OCD). In addition, antidepressants are commonly used to treat pain disorders such as neuropathic pain and the pain associ-ated with fibromyalgia. Some antidepressants are used for treat-ing premenstrual dysphoric disorder (PMDD), mitigating the vasomotor symptoms of menopause, and treating stress urinary incontinence. Thus, antidepressants have a broad spectrum of use in medical practice. However, their primary use remains the treat-ment for MDD.


A 47-year-old woman presents to her primary care physician with a chief complaint of fatigue. She indicates that she was promoted to senior manager in her company approximately 11 months earlier. Although her promotion was welcome and came with a sizable raise in pay, it resulted in her having to move away from an office and group of colleagues she very much enjoyed. In addition, her level of responsibility increased dramatically. The patient reports that for the last 7 weeks, she has been waking up at 3 AM every night and been unable to go back to sleep. She dreads the day and the stresses of the workplace. As a consequence, she is not eating as well as she might and has dropped 7% of her body weight in the last 3 months. She also reports being so stressed that she breaks down crying in the office occasionally and has been calling in sick frequently. When she comes home, she finds she is less motivated to attend to chores around the house and has no motivation, interest, or energy to pursue recreational activities that she once enjoyed such as hiking. She describes herself as “chronically miserable and worried all the time.” Her medical history is notable for chronic neck pain from a motor vehicle accident for which she is being treated with tramadol and meperidine. In addition, she is on hydrochlorothiazide and propranolol for hypertension. The patient has a history of one depressive episode after a divorce that was treated successfully with fluoxetine. Medical workup including complete blood cell count, thyroid function tests, and a chemistry panel reveals no abnormalities. She is started on fluoxetine for a presumed major depressive episode and referred for cognitive behavioral psychotherapy. What CYP450 and pharmacodynamic interactions might be associ-ated with fluoxetine use in this patient? Which class of anti-depressants would be contraindicated in this patient?


Fluoxetine, the prototype SSRI, has a number of pharmacoki-netic and pharmacodynamic interactions. Fluoxetine is a CYP450 2D6 inhibitor and thus can inhibit the metabolism of 2D6 substrates such as propranolol and other β blockers, tricyclic antidepressants, tramadol, opioids such as metha-done, codeine, and oxycodone, antipsychotics such as halo-peridol and thioridazine, and many other drugs. This inhibition of metabolism can result in significantly higher plasma levels of the concurrent drug, and this may lead to an increase in adverse reactions associated with that drug. As a potent inhibitor of the serotonin transporter, fluox-etine is associated with a number of pharmacodynamic inter-actions involving serotonergic neurotransmission. The combination of tramadol with fluoxetine has occasionally been associated with a serotonin syndrome, characterized by dia-phoreses, autonomic instability, myoclonus, seizures, and coma. The combination of fluoxetine with an MAOI is con-traindicated because of the risk of a fatal serotonin syndrome. In addition, meperidine is specifically contraindicated in com-bination with an MAOI.

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