A 56-year-old man with a history of severe depression seeks a new physician after immigrating to the United States. His depression has been treated with phenelzine since diagnosis, and his new physician decides to switch him to sertraline. The patient is informed that he must wait at least 2 weeks after discontinuing phenelzine before starting the new drug. Which of the following processes occurs during this washout interval to allow sertraline therapy to be initiated safely?

Question

A 56-year-old man with a history of severe depression seeks a new physician after immigrating to the United States.  His depression has been treated with phenelzine since diagnosis, and his new physician decides to switch him to sertraline.  The patient is informed that he must wait at least 2 weeks after discontinuing phenelzine before starting the new drug.  Which of the following processes occurs during this washout interval to allow sertraline therapy to be initiated safely?

Quizplus · Accepted Answer

11ec160b_3c58_b3c6_9249_03e7de722b82_MD0001_00 The pathophysiologic basis of depression is hypothesized to involve the dysregulation of monoamine (eg, serotonin, norepinephrine, dopamine) neurotransmission. Most antidepressant medications act by various mechanisms to increase synaptic concentrations of these neurotransmitters, particularly serotonin. Monoamine oxidase (MAO) is an enzyme located in presynaptic nerve terminals that is responsible for the breakdown of monoamine neurotransmitters. Phenelzine, a monoamine oxidase inhibitor, works by irreversibly binding and inhibiting both types of MAO: A and B. This results in increased presynaptic availability of monoamine neurotransmitters, thereby increasing their release into the synaptic cleft. Because phenelzine irreversibly inhibits MAO, it may take up to 2 weeks following discontinuation of the drug before MAO is resynthesized to a level adequate for normal monoamine degradation. Sertraline is a selective serotonin reuptake inhibitor (SSRI) that specifically increases synaptic serotonin levels. Coadministration of an SSRI and an MAO inhibitor is contraindicated due to the risk of serotonin syndrome, a potentially fatal condition characterized by altered mental status, neuromuscular excitation (eg, hyperreflexia, clonus), and autonomic hyperactivity (eg, hyperthermia, tachycardia, diaphoresis). To avoid serotonin syndrome, patients must wait at least 2 weeks after MAO inhibitor discontinuation before initiating SSRI therapy, thereby allowing sufficient time for regeneration of the MAO enzyme. (Choice A) Monoamine (eg, serotonin) receptors are G protein-coupled receptors. Internalization of activated G protein-coupled receptors plays a role in downregulating postsynaptic signal transduction when synaptic monoamine levels are chronically increased. However, this is not the reason for the 2-week washout period from phenelzine, which is required to resynthesize the irreversibly inhibited MAO enzyme. (Choice B) Inositol monophosphatase inhibition is hypothesized to be one of the mechanisms by which lithium exerts its antidepressant and antimanic effects. Inositol monophosphatase is not affected by MAO inhibitors. (Choice C) MAO inhibition arrests the breakdown of monoamines, thereby increasing their release into the synaptic cleft. Overall MAO functioning gradually increases after discontinuation of irreversible MAO inhibitors (eg, tranylcypromine, phenelzine) as new MAO is synthesized. (Choice D) Increased monoamine neurotransmission due to antidepressant treatment causes downregulation of postsynaptic monoamine (eg, serotonin) receptors, decreasing their density within the synaptic cleft. This (along with other chronic, downstream neuromodulatory changes) is responsible for the delayed clinical effects of antidepressants. (Choice E) Presynaptic monoaminergic neurons actively take up norepinephrine, dopamine, and serotonin through reuptake transporters and repackage them into synaptic vesicles for future neurotransmission. Monoamine reuptake inhibitors, such as tricyclic antidepressants and SSRIs, work by blocking this reuptake. Educational objective: Coadministration of selective serotonin reuptake inhibitors (SSRIs) and monoamine oxidase (MAO) inhibitors can produce excessive synaptic serotonin levels secondary to decreased reuptake and decreased degradation of serotonin, potentially causing serotonin syndrome. To avoid this risk, a 2-week washout period after discontinuing an MAO inhibitor and before initiating SSRI therapy is required to allow sufficient time for MAO regeneration. __________ References: Switching and stopping antidepressants. (http://www.ncbi.nlm.nih.gov/pubmed/27346915) Overview of serotonin syndrome. (http://www.ncbi.nlm.nih.gov/pubmed/23145389)

A 56-Year-Old Man with a History of Severe Depression Seeks