Depression and Suicide _ ______________________________________________________________________
the agents fluoxetine (Prozac), paroxetine (Paxil), sertraline (Zoloft), fluvoxamine (Luvox) (off-label for MDD), citalopram (Celexa), escitalopram (Lexapro), and vortioxetine (Brintellix). Escitalopram may have fewer drug-drug interactions than other SSRIs, and fluoxetine may be a better choice in patients with poorer adherence due to its long half-life [21; 22; 122]. Common Side Effects The most common side effects with SSRIs are gastrointes- tinal (nausea, vomiting, and diarrhea), activation/insomnia (restlessness, agitation, anxiety, akathisia, and sleep distur- bances), sexual, headache, fatigue, and weight gain [21; 22; 122]. Many of these side effects dissipate over time. Sertraline is particularly associated with diarrhea, and paroxetine with weight gain [22; 122]. Multimodal Antidepressants Vilazodone and vortioxetine are multimodal antidepressants that combine SSRI properties with other pharmacologic actions affecting monoamine and non-monoaminergic targets. Evidence does not suggest greater efficacy than SSRI/SNRIs, but these agents may improve tolerability or efficacy on specific clinical domains [161]. Vilazodone, approved in 2011, primarily acts as a SERT inhibi- tor and 5-HT1A receptor partial agonist, and modestly inhibits dopamine and norepinephrine transporters. This antidepres- sant may be most helpful in patients lacking response to initial SSRIs. Vilazodone must be taken with food, which increases its absorption and bioavailability by 72% [162; 163]. Vortioxetine, approved in 2013, acts through various serotonin receptors as an antagonist (5-HT3/7/1D), partial agonist (5-HT1B), or agonist (5-HT1A), and inhibits SERT. It also acti- vates the glutamate system in the frontal cortex. Vortioxetine displays a specific clinical efficacy in the treatment of cognitive deficits associated with MDD. The most common side effects are nausea, vomiting, and constipation [161]. Serotonin-Norepinephrine Reuptake Inhibitors SNRIs act by inhibiting the reuptake of the neurotransmitters serotonin and norepinephrine. This results in an increase in the extracellular concentrations of serotonin and norepineph- rine and therefore an increase in neurotransmission [21; 22; 122]. Most SNRIs, including venlafaxine (Effexor), desvenla- faxine (Pristiq), levomilnacipran (Fetzima), and duloxetine (Cymbalta), are several-fold more selective for serotonin than norepinephrine. Safety, tolerability, and side effect profiles of SNRIs resemble SSRIs, with the exception that the SNRIs have been associated (rarely) with sustained elevated blood pressure. SNRIs can be used as first-line agents, particularly in patients with significant fatigue or comorbid chronic pain, and have an important role as second-line agents in patients who have not responded to SSRIs [21; 22; 122].
Venlafaxine is especially beneficial in treating anxiety and panic attacks in patients with depression, and acts like an SSRI at lower doses (75 mg/day) but more like an SNRI at doses ≥150
mg/day [21; 22; 122]. Common Side Effects
SNRIs are associated with greater likelihood of increased pulse rate, dilated pupils, dry mouth, excessive sweating, and consti- pation [21]. Venlafaxine has a greater incidence of nausea and vomiting than SSRIs and may be associated with an increased risk for cardiovascular events [22; 122]. Tricyclic Antidepressants TCAs are predominantly serotonin and/or norepinephrine reuptake inhibitors that act by blocking the serotonin trans- porter and the norepinephrine transporter, respectively, which results in an elevation of the extracellular concentrations of these neurotransmitters, and therefore an enhancement of neurotransmission. TCAs also have varying but typically high affinity for the H1 and H2 histamine receptors and muscarinic acetylcholine receptors. As a result, they also act as potent antihistamines and anticholinergics. These properties are generally undesirable in antidepressants, however, and likely contribute to their large side effect profiles [164]. TCAs are classified by the nature of the final amine group on the side chain, with the tertiary amines amitriptyline (Elavil), clomipramine (Anafranil), doxepin (Sinequan), trimipra- mine (Surmontil), imipramine (Tofranil), and lofepramine (Lomont); the secondary amines nortriptyline (Pamelor), desipramine (Norpramin), and protriptyline (Vivactil); and the tetracyclic antidepressants amoxapine (Asendin) and maprotiline (Ludiomil). TCAs are comparable in efficacy to SSRIs/SNRIs, but their side effect profile makes them seldom used as first-line therapy [21; 22; 122]. TCAs may initially worsen anxiety or panic symptoms. Due to side effect potential of cardiac arrhythmia, TCAs should be used very cautiously, if at all, in patients with heart problems. Secondary amine TCAs cause less orthostatic hypotension and sedation than tertiary amines, which should be avoided in elderly patients due to the risk for orthostatic hypotension, sedation, cognitive problems, and cardiac effects. The secondary amine nortriptyline is especially effective for elderly patients with moderate-to-severe depression. Clomip- ramine is particularly effective in patients with obsessive- compulsive symptoms [21; 22; 122]. Common Side Effects Anticholinergic and antihistamine activity accounts for many side effects, including dry mouth, blurred vision, reduced gastrointestinal motility or constipation, urinary retention, cognitive and/or memory impairment, and increased body temperature [21; 22; 122]. Other side effects may include drowsiness, anxiety, emotional blunting (apathy/anhedonia), confusion, restlessness, dizziness, akathisia, hypersensitivity,
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