Depression and Suicide _ ______________________________________________________________________
Atypical Antidepressants The atypical antidepressants are diverse in monoamine activ- ity and do not fit the profile of other classes. They include bupropion (Wellbutrin), nefazodone (Serzone), mirtazapine (Remeron), and trazodone (Desyrel). Nefazodone and trazo- done block postsynaptic serotonin type-2 receptors and inhibit presynaptic serotonin reuptake. Bupropion inhibits activity of norepinephrine and dopamine transporters, and the active metabolite hydroxybupropion contributes to the drug’s effects. Mirtazapine is a potent antagonist at 5-HT2, 5-HT3, alpha2, and H1 histamine receptors. As a group, these agents show low toxicity in overdose and may have an advantage over the SSRIs by causing less sexual dysfunction and gastrointestinal distress [21; 22; 122]. Each agent has apparent benefits and drawbacks, with some better suited for specific patient populations. Bupropion is associated with a risk of seizure at higher doses, especially in patients with a history of seizure or eating disorders, and should be used cautiously in anxious patients [21; 22; 122]. It may be more effective for atypical MDD than other antide- pressants. Mirtazapine can be very sedating and promotes appetite and weight increase, which in some patients may be desirable. It has a faster onset of action than fluoxetine, paroxetine, or sertraline, and may be superior to SSRIs in depression associ- ated with severe insomnia and anxiety. Trazodone is also very sedating and is usually used as a sleep aid rather than as an antidepressant [21; 22; 122]. Common Side Effects The side effects of atypical antidepressants vary considerably. With bupropion, the most common side effects are agitation, jitteriness, mild cognitive dysfunction, insomnia, gastrointesti- nal upset, and possible increased risk for seizures [122]. Patients taking mirtazapine may experience dry mouth, sedation, weight gain, and increased serum cholesterol [22]. Sedation is the most common side effect associated with trazodone, fol- lowed by cardiovascular side effects (such as orthostasis) and sexual side effects [22]. Finally, nefazodone is associated with sedation, dry mouth, nausea, constipation, orthostasis, visual alterations, and possible increased risk of hepatotoxicity have led to nefazodone being seldom prescribed [122]. CNS Stimulants Although the role of psychostimulants for antidepressant monotherapy is very limited, they may have a role in the treatment of apathetic major depression in which apathy imperils adherence to treatment and self-care, in patients who cannot tolerate the side effects of standard antidepressants, in terminally ill and medically ill patients with depression, and in elderly patients with complicating medical conditions [10; 172; 173; 174].
This medication class includes amphetamine derivatives such as dextroamphetamine (Dexedrine, Adderal), methylphenidate (Ritalin), and modafinil (Provigil). Methylphenidate inhibits dopamine reuptake by its transporter and, to a lesser degree, norepinephrine reuptake. Dextroamphetamine increases cytosolic dopamine and norepinephrine by blocking vesicu- lar sequestration of dopamine and norepinephrine through inhibition of vesicular monoamine transporter-2 activity [21; 22; 122]. Common Side Effects In general, CNS stimulants are associated with side effects related to hyperarousal (e.g., agitation, aggression, tachycardia, restlessness, insomnia). Other potential side effects include headache, anorexia, nausea, and irritability [175]. Modafinil is associated with markedly lower subjective stimulation. CNS stimulants are contraindicated in patients with a his- tory of substance use disorder, with agitated states, and with moderate-to-severe hypertension [175]. In addition, patients who have initiated MAOIs within the last 14 days should not begin therapy with a dopamine agonist. Pharmacotherapy to Improve Cognitive Dysfunction Full functional recovery is the overarching therapeutic goal of MDD treatment. Cognitive symptoms of depression criti- cally impact social, occupational, and physical functioning; often persist after mood symptoms have lessened or remitted; and elevate recurrence risk in remitted patients. Functional outcomes modestly correlate with mood symptom outcomes but are strongly influenced by persistent cognitive impair- ment [176; 177; 178]. Mood symptoms are a primary focus of depression assessment and treatment, and standard depres- sion pharmacotherapies have minimal benefit on improving cognitive dysfunction. Vortioxetine has demonstrated efficacy in improving multiple domains of cognitive function, including executive function, processing speed, attention, and learning/memory, indepen- dent of its effect on core mood symptoms [45; 179; 180]. Duloxetine can improve learning and memory in patients with MDD [181]. Lisdexamfetamine has some benefit in improving executive function, while single-dose modafinil (200 mg) sig- nificantly improved performance on tests of episodic memory and working memory in remitted MDD subjects without side effects [159; 182]. Potential Complications with All Antidepressants Sexual Dysfunction All commercially available antidepressants are associated with sexual side effects. SSRI/SNRIs show the highest rates of sexual dysfunction, including impaired sexual motivation, desire, arousal, and orgasm affecting men and women. Prescribing physicians greatly underestimate the prevalence and patient
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