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Depression associated with reactive disorders usually does not call for drug therapy and can be managed by psychotherapy and the passage of time In severe cases particularly when vegetative signs are significant and symptoms have persisted for more than a few weeks antidepressant drug therapy is often effective Drug therapy is also suggested by a family history of major depression in first-degree relatives or a past history of prior episodes The antidepressant drugs may be conveniently classified into three groups: (1) the newer antidepressants, including the SSRIs and bupropion, venlafaxine, nefazodone, and mir-
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Psychiatric Disorders
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CMDT 2008
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Select and initiate treatment
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Monitor acute treatment (every 1 2 weeks)
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Assess response (week 6)1
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Somewhat better
Not better at all
Continue treatment (adjust dosage) Continue treatment for 6 more weeks
Augment or change treatment
Monitor treatment (every 1 2 weeks)
Clearly better
Assess response (week 12)1
Not better Complete remission Yes No Relapse
Medication continued for 4 9 months Consider maintenance treatment
Refer or consult a psychiatrist or other mental health professional
Change treatment
of assessment (weeks 6 and 12) rest on very modest data It may be necessary to revise the treatment plan earlier for patients not responding at all
Figure 25 2 Overview of treatment for depression (Reproduced from Agency for Health Care Policy and Research: Depression in Primary Care Vol 2: Treatment of Major Depression United States Department of Health and Human Services, 1993)
received special scrutiny In all cases of pharmacologic management of depressed states, caution is indicated until the risk of suicide is considered minimal 1 SSRIs and atypical antidepressants The chief advantages of these agents are that they do not generally cause significant cardiovascular or anticholinergic side effects, and
they have much lower lethality in overdose compared to TCAs The SSRIs include fluoxetine, sertraline, paroxetine, fluvoxamine, citalopram and its enantiomer escitalopram The atypical antidepressants are bupropion, which appears to exert its effect through the dopamine neurotransmitter system; venlafaxine and duloxetine, both of which inhibit the reuptake of both serotonin and norepinephrine; nefazodone,
CMDT 2008
effective antidepressant treatment in patients with acute myocardial infarction or unstable angina Withdrawal syndromes have been reported for the SSRIs and venlafaxine These include dysphoric mood, agitation, and a flu-like state These medications should be discontinued gradually over a period of weeks or months to reduce the risk of withdrawal phenomena Fluoxetine, fluvoxamine, sertraline, venlafaxine, and citalopram in customary antidepressant doses do not appear to increase the risk of major fetal malformation when used during pregnancy Recent evidence, however, has suggested that paroxetine may be associated with a twofold increased risk of cardiac abnormalities Postpartum developmental effects are thought to be minimal, but this question calls for ongoing investigation Peripartum effects may be a of concern and are documented anecdotally in the literature The risk of depression to the mother and fetus needs to be part of the discussion with the patient about treatment options The decision to use SSRIs and other psychotropic agents during pregnancy and postpartum must be based on a thorough risk-benefit analysis for each individual A recent review of the literature on antidepressants levels in breast-feeding mothers and their infants suggests that nortriptyline, paroxetine, and sertraline are least likely to lead to detectable levels in infants Venlafaxine is reported to be well-tolerated without significant anticholinergic or cardiovascular side effects Nausea, nervousness, and profuse sweating appear to be the major side effects Venlafaxine appears to have few drug-drug interactions It does require monitoring of blood pressure because dose-related hypertension may develop in some individuals Duloxetine may also result in small increases in blood pressure Common side effects include dry mouth, dizziness, and fatigue Inhibitors of 1A2 and 2D6 may increase duloxetine levels with a risk of toxicity Nefazodone appears to lack the anticholinergic effects of the TCAs and the agitation sometimes induced by SSRIs Nefazodone should not be given with terfenadine, astemizole, or cisapride (Terfenadine and astemizole are not commercially available in the United States) Because nefazodone inhibits the liver s cytochrome P450 3A4 isoenzymes, concurrent use of these medications can lead to serious QT prolongation, ventricular tachycardia, or death Through the same mechanism of enzyme inhibition, nefazodone can elevate cyclosporine levels sixfold to tenfold Nefazodone has been given an FDA warning because it has been implicated in liver failure in rare cases Pretreatment and ongoing monitoring of liver enzymes are indicated Mirtazapine is thought to enhance central noradrenergic and serotonergic activity with minimal sexual side effects compared with the SSRIs Its action as a potent antagonist of histaminergic receptors may make it a useful agent for patients with depression and insomnia Its most common adverse side effects include somnolence, increased appetite, weight gain, lipid abnormalities, and dizziness There have been reports of agranulocytosis in 2 of 2796 patients Although it is metabolized by P450 isoenzymes, it is not an inhibitor of this system It is given in a single dose at bedtime starting at 15 mg and increasing in 15-mg increments every week or every other week up to 45 mg
which blocks the reuptake of serotonin but also inhibits the 5HT2 postsynaptic receptors; and mirtazapine, which selectively blocks presynaptic 2-adrenergic receptors and enhances both noradrenergic and serotonergic transmission All of these antidepressants are effective in the treatment of depression, both typical and atypical The SSRI drugs have been effective in the treatment of panic attacks, bulimia, generalized anxiety disorder, OCD, and PTSD They do not seem to be as clearly effective in some pain syndromes as the TCAs, although venlafaxine may have some efficacy in the treatment of neuropathic pain, and duloxetine is FDAapproved for the treatment of diabetic peripheral neuropathy Most of the drugs in this group tend to be activating and are given in the morning so as not to interfere with sleep Some patients, however, may have sedation, requiring that the drug be given at bedtime This reaction occurs most commonly with paroxetine, fluvoxamine, and mirtazapine The SSRIs can be given in once-daily dosage Nefazodone and venlafaxine are usually given twice daily Bupropion and venlafaxine are available in extendedrelease formulations and can be given once daily There is usually some delay in response; fluoxetine, for example, requires 2 6 weeks to act in depression, 4 8 weeks to be effective in panic disorder, and 6 12 weeks in treatment of OCD The starting dose (10 20 mg) is the usual daily dose for depression, while OCD may require up to 80 mg daily Some patients, particularly the elderly, may tolerate and benefit from as little as 10 mg/d or every other day The other SSRIs have shorter half-lives and a lesser effect on hepatic enzymes, which reduces their impact on the metabolism of other drugs (thus not increasing significantly the serum concentrations of other drugs as much as fluoxetine) The shorter half-lives also allow for more rapid clearing if adverse side effects appear Venlafaxine appears to be more effective with doses greater than 200 mg/d, although some individuals respond to doses as low as 75 mg/d The side effects common to all of these drugs are headache, nausea, tinnitus, insomnia, and nervousness Akathisia has been common with the SSRIs; other extrapyramidal symptoms (eg, dystonias) have occurred infrequently but particularly in withdrawal states Sexual side effects of erectile dysfunction, retrograde ejaculation, and dysorgasmia are very common with the SSRIs Antidotes to SSRI-induced sexual dysfunction are occasionally helpful Sildenafil, 25 50 mg 1 hour prior to sexual activity, can improve erectile dysfunction in some patients Cyproheptadine, 4 mg orally prior to sexual activity, may be helpful in countering drug-induced anorgasmia Adjunctive bupropion (75 150 mg daily) may also help with restoring erectile function The SSRIs are strong serotonin uptake blockers and may in high dosage or in combination with MAO inhibitors, including the antiparkinsonian drug selegiline, cause a serotonin syndrome This syndrome is manifested by rigidity, hyperthermia, autonomic instability, myoclonus, confusion, delirium, and coma This syndrome can be a particularly troublesome problem in the elderly Several cases of angina have been reported in association with SSRIs However, current research indicates that SSRIs are safer agents to use than TCAs in patients with cardiac disease A study has found that sertraline is a safe and
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