A 28-year-old man comes to the office due to persistent fatigue. For the past several weeks, he has been having trouble sleeping and is frequently late for work as he has difficulty getting out of bed. At work, his mind wanders, and his supervisor has commented that the quality of his work has deteriorated. The patient says, "I've been feeling down and don't feel like doing anything. My appetite is poor. I no longer go out with my friends and haven't gone to the gym in weeks." The patient has no significant medical or psychiatric history. He has 1 or 2 alcoholic drinks several days a week but does not use illicit drugs. Routine laboratory evaluation, including thyroid function tests and serum B₁₂ level, is normal. Physical examination is unremarkable. Mental status examination shows a cooperative man with sad affect. No delusions are elicited. The patient says he sometimes wishes he could "go to sleep and not wake up," but has no suicidal intent or plan. First-line pharmacotherapy for this patient most likely involves a drug with which of the following mechanisms of action?

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11ec160b_3619_45e1_9249_57be9cbd600b_MD0001_00 This patient's several-week history of depressed mood, loss of interest, fatigue, impaired sleep, poor concentration and appetite, and thoughts of death is consistent with major depressive disorder. The major neurotransmitters involved in the pathophysiology of depression are thought to be serotonin and norepinephrine (and dopamine to a lesser extent). Most available antidepressant medications affect serotonin or both serotonin and norepinephrine at the synapse. Selective serotonin reuptake inhibitors are considered first-line antidepressants that work by inhibiting the serotonin transporter (SERT) protein, which is normally responsible for transporting serotonin out of the synaptic cleft back into the presynaptic neuron. The inhibition of SERT prevents the normal reuptake of serotonin, resulting in increased availability of serotonin in the synaptic cleft. (Choices A and B) These receptor activities are the primary mechanisms of action of antipsychotics used mainly to treat schizophrenia and other psychotic disorders and to augment antidepressants in the treatment of mood disorders. Potent antagonism of dopamine 2 receptors is the mechanism of action of first-generation antipsychotics such as haloperidol. Second-generation antipsychotics have comparatively less affinity for D2 receptors and the additional property of serotonin 5-HT2 receptor antagonism, which underlies their lower risk of extrapyramidal side effects. An antipsychotic would not be appropriate monotherapy for major depression without psychotic features. (Choice C) Inhibition of sodium channels, resulting in stabilization of neuronal membranes, is the mechanism of action of some antiepileptic drugs (eg, carbamazepine). These drugs also have a role as mood stabilizers in bipolar disorder but are not a primary treatment for unipolar major depression. (Choice E) Inhibition of monoamine oxidase is the mechanism of action of monoamine oxidase inhibitors used in treatment-resistant depression. These drugs are not used as first-line therapy due to their dietary restrictions and risk of serious adverse events (eg, hypertensive crisis, serotonin syndrome). (Choice F) Benzodiazepines work to potentiate the effects of GABA, the major inhibitory neurotransmitter in the central nervous system, by facilitating the increased frequency of chloride channel opening in the GABA A receptor. They have sedative, hypnotic, anxiolytic, anticonvulsant, and muscle relaxant properties but are not a first-line treatment for depression. Educational objective: Most available antidepressants target the neurotransmission of serotonin or norepinephrine, or both. Inhibition of serotonin reuptake by blocking the serotonin transporter is the primary mechanism of action of selective serotonin reuptake inhibitors. __________ References: Neurobiology of depression and mechanism of action of depression treatments. (http://www.ncbi.nlm.nih.gov/pubmed/27046319) Regional differences in SERT occupancy after acute and prolonged SSRI intake investigated by brain PET. (http://www.ncbi.nlm.nih.gov/pubmed/24121201)

A 28-Year-Old Man Comes to the Office Due to Persistent