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Antidepressant medications have been grouped as follows: 1) TCAs, which for the purposes of this guideline also include the tetracyclic antidepressant medication maprotiline; 2) SSRIs, which include fluoxetine, sertraline, paroxetine, fluvoxamine, citalopram, and escitalopram; 3) SNRIs, which include venlafaxine, desvenlafaxine, and duloxetine; 4) other antidepressant medications, including bupropion, nefazodone, trazodone, and mirtazapine; and 5) MAOIs, which include phenelzine, tranylcypromine, isocarboxazid, and the transdermal formulation of selegiline. Although some studies have suggested superiority of one mechanism of action over another, there are no replicable or robust findings to establish a clinically meaningful difference. For most patients, the effectiveness of antidepressant medications is generally comparable between classes and within classes of medications. Response rates in clinical trials typically range from 50% to 75% of patients, with some evidence suggesting greater efficacy relative to placebo in individuals with severe depressive symptoms as compared with those with mild to moderate symptoms (71–73). Although remission rates are less robust and selective publication of positive studies could affect the apparent effectiveness of treatment (74, 75), these factors do not appear specific to particular medications or medication classes.

Nevertheless, antidepressant medications do differ in their potential to cause particular side effects such as adverse sexual effects, sedation, or weight gain. Therefore, the initial selection of an antidepressant medication will largely be based on the tolerability, safety, and cost of the medication, as well as patient preference and history of prior medication treatment (Table 3). Other factors include the medication half-life and potential for drug interactions related to properties such as plasma protein binding or metabolism through the cytochrome P450 system (Tables 4 and 5). On the basis of these considerations, the following medications are optimal for most patients: SSRIs, SNRIs, mirtazapine, and bupropion. Table 6 provides the starting and usual doses of medications that have been shown to be effective for treating major depressive disorder.

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Table 3. Factors to Consider in Choosing an Antidepressant Medication

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Table 3. Factors to Consider in Choosing an Antidepressant Medication
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Table 4. Cytochrome P450 Enzyme Metabolism of Antidepressive Agentsa

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Table 4. Cytochrome P450 Enzyme Metabolism of Antidepressive Agentsa
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Table 5. Cytochrome P450 Enzyme Inhibition by Antidepressive Agentsa

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Table 5. Cytochrome P450 Enzyme Inhibition by Antidepressive Agentsa
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Table 6. Dosing of Medications Shown To Be Effective in Treating Major Depressive Disordera

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Table 6. Dosing of Medications Shown To Be Effective in Treating Major Depressive Disordera

In choosing an antidepressant medication, many psychiatrists also consider the family history of response to particular medications; however, the impact of this factor on the likelihood of the patient's response to these medications is unclear. Nevertheless, the medication experiences of others close to the patient do influence the patient's belief about particular medications and pharmacotherapy in general.

The presence of co-occurring psychiatric or general medical conditions can be a significant factor influencing the choice of an antidepressant medication. For example, TCAs are generally not optimal in patients with cardiovascular conditions, cardiac conduction defects, closed angle glaucoma, urinary retention, significant prostatic hypertrophy, or eating disorders with significant malnutrition or purging. In older adults and others with malnutrition, autonomic disorders (e.g., diabetic neuropathy, Parkinson's disease), or low blood pressure, TCAs may exacerbate hypotension and orthostasis, resulting in syncope or falls. Selective serotonin reuptake inhibitors and SNRIs may be inappropriate for patients who are experiencing sexual dysfunction. Patients who are receiving tamoxifen for breast cancer or other indications should generally be treated with an antidepressant (e.g., citalopram, escitalopram, venlafaxine, desvenlafaxine) that has minimal effect on metabolism through the cytochrome P450 2D6 isoenzyme, because reduced metabolism of tamoxifen through CYP 2D6 is likely to be associated with lower levels of tamoxifen's active metabolite (76–79) with the possibility of poorer patient outcomes (80, 81).

Because of the need for dietary restrictions and the potential for serious side effects and drug interactions, use of MAOIs is generally limited to patients who do not respond to other treatments. MAOIs may be particularly effective for patients with major depressive disorder with atypical features, although many psychiatrists prefer to prescribe SSRIs for such patients because of SSRIs' greater safety and tolerability and more favorable adverse effect profile.

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a. Efficacy of antidepressant medications

+ 1. Selective serotonin reuptake inhibitors

Selective serotonin reuptake inhibitors currently available include fluoxetine, sertraline, paroxetine, fluvoxamine, citalopram, and escitalopram. A large body of literature supports the superiority of SSRIs compared with placebo in the treatment of major depressive disorder. In more than 10 systematic reviews and meta-analyses, the effectiveness of SSRIs has been compared with that of other antidepressant medications, mainly TCAs. The SSRIs have demonstrated comparable efficacy to the TCAs (8488), even when anxiety symptoms are considered (85, 8790).

Although a few analyses suggest small advantages of SNRIs over SSRIs in rates of remission (91), a preponderance of the data finds no significant evidence of the superiority of any other class or agents over SSRIs (84, 89, 90, 9295). One meta-analysis suggests a slight superiority of escitalopram compared with other SSRIs and venlafaxine (93), and another found significantly greater efficacy for escitalopram, sertraline, venlafaxine, and mirtazapine as compared with duloxetine, fluoxetine, fluvoxamine, and paroxetine (96), but other studies show no differences in efficacy among individual SSRIs (84, 93–95, 97, 98).

+ 2. Serotonin norepinephrine reuptake inhibitors

The serotonin norepinephrine reuptake inhibitors currently available are venlafaxine, desvenlafaxine (the principal metabolite of venlafaxine), and duloxetine. An immediate-release form of venlafaxine is available, but most clinicians prefer the extended-release formulation because it is approved for once-daily dosing and may be less often associated with reported withdrawal symptoms.

Each of these medications is efficacious (i.e., superior to placebo in controlled studies and meta-analyses) (95, 99), and venlafaxine (75–150 mg/day) and duloxetine (60 mg/day) showed comparable efficacy in a pair of trials (100). For venlafaxine and perhaps desvenlafaxine, clinically significant norepinephrine reuptake inhibition may not be achieved for the average patient at lower therapeutic doses, although desvenlafaxine has a much greater bioavailability, resulting in a lower effective dose. In individual studies, venlafaxine and duloxetine are generally as effective as SSRIs (see the meta-analyses of Nemeroff et al. [101] and Thase et al. [102] for tabulated summaries of individual study results from the more than 40 relevant randomized controlled trials). Results of comparative studies of desvenlafaxine are not known at this time. Relative to SSRIs, some analyses of pooled data sets have suggested a small advantage for SNRIs (91), which might afford clinically modest benefits for patients with more severe depression (102) or for patients who have not responded to prior trials of SSRIs (103). However, other meta-analyses have shown equivalent efficacy for SSRIs and SNRIs (95), whereas some have shown superiority of individual medications but no clearcut medication class effects (96). Relative to TCAs, venlafaxine's efficacy is comparable (91, 104, 105), whereas the more recently introduced duloxetine and desvenlafaxine have not been systematically compared with TCAs.

+ 3. Other antidepressant medications

A number of other antidepressant medications differ structurally or in their pharmacological action from medications in the categories just described and are included here.

Although bupropion is classified as a norepinephrine and dopamine reuptake inhibitor, the latter effect is relatively weak, and its mechanism of action remains unclear (106). There are three formulations of bupropion: immediate release, sustained release, and extended release. Bupropion is distinct from most antidepressants in not having an indication for the treatment of any primary anxiety disorder, and it may be less well tolerated than other antidepressants among patients with significant anxiety. In addition, a meta-analysis showed that SSRIs were modestly superior to bupropion for a subset of patients with major depressive disorder and anxiety (107). For individuals with low to moderate levels of anxiety, the same meta-analysis showed that the efficacy of bupropion in treating major depressive disorder was roughly comparable to that of the SSRIs (107). Results of another meta-analysis suggested that bupropion may be more likely to improve symptoms of fatigue and sleepiness than at least some of the SSRIs (108). Bupropion may be a good choice for patients who have a goal of quitting smoking as it has U.S. Food and Drug Administration (FDA) approval for this indication, reduces desire for nicotine, and doubles rates of smoking cessation (109, 110). Patients typically experience minimal weight gain or even weight loss on bupropion (111), and for this reason it may be an appropriate antidepressant for patients who are overweight or obese.

Mirtazapine is thought to work through noradrenergic and serotonergic mechanisms, although this tetracyclic compound is not a reuptake inhibitor (112). Mirtazapine has comparable efficacy to SSRIs (113).

Trazodone is the oldest medication from this group that is still in wide use. Although trazodone is an effective antidepressant, relative to placebo (105, 114, 115), in contemporary practice it is much more likely to be used in lower doses as a sedative-hypnotic than as an antidepressant. Despite widespread use of trazodone as a hypnotic, few data support its use for this indication.

Nefazodone has an analogous structure to trazodone but somewhat different pharmacological properties. In comparative trials versus SSRIs, nefazodone showed comparable efficacy and overall tolerability (116).

+ 4. Tricyclic antidepressants

Tricyclic antidepressants (amitriptyline, nortriptyline, protriptyline, imipramine, desipramine, doxepin, and trimipramine) are effective treatments for major depressive disorder and have comparable efficacy to other classes of antidepressants, including SSRIs, SNRIs, and MAOIs (85, 105). The efficacy of subclasses of tricyclics (e.g., secondary amines or tertiary amines) appears to be comparable. TCAs may be particularly effective in certain populations, such as in hospitalized patients (117, 118). Conventional wisdom is that this advantage is explained by the superiority of TCAs (versus SSRIs) among the subset of patients with melancholia or more severe depression, because such a specific advantage has not been consistently documented in studies of less severely ill outpatients (85, 105, 118).

+ 5. Monoamine oxidase inhibitors

MAOIs currently used as antidepressants include phenelzine, tranylcypromine, isocarboxazid, moclobemide, and the transdermally delivered formulation of selegiline.

MAOIs have comparable efficacy to other antidepressants for outpatients with major depressive disorder and may be appropriate for patients with major depressive disorder who have not responded to safer and more easily used treatments (119, 120). In fact, the role of MAOIs in major depressive disorder is now almost exclusively reserved for patients who have not responded to at least several other pharmacotherapies. Studies have demonstrated the effectiveness of MAOIs in patients who have not responded to other antidepressant medications, particularly TCAs (119). However, the effectiveness of MAOIs relative to other strategies for treatment-resistant patients in contemporary practice remains unclear, particularly for patients who have not responded to multiple sequential trials with SSRIs and SNRIs (121).

MAOIs have been shown to be particularly effective in treating depressed patients with atypical features, so psychiatrists should consider using these medications for patients with symptoms such as reactive moods, reverse neurovegetative symptoms, and sensitivity to rejection (119, 120, 122). There do not appear to be any significant differences in efficacy among the older MAOIs (119), although there are important individual differences in responsiveness, and these medications are not interchangeable. There are no comparative studies of the newer transdermal (skin patch) formulation of selegiline; its efficacy has only been established relative to placebo (123–125), and clinical experience is limited.

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b. Side effects of antidepressant medications

The severity of side effects from antidepressant medications in clinical trials has been assessed both through the frequency of reported side effects and through the frequency of treatment dropout. The likelihood of different side effects varies among classes of antidepressant medications, among subclasses, and among individual agents. In addition, most newer antidepressants are better tolerated than TCAs (84–88, 97, 117, 126) and safer in overdose (127, 128).

When side effects occur during treatment with an antidepressant, an initial strategy is to lower the dose of the antidepressant or to change to an antidepressant that is not associated with that side effect. As an example, bupropion can be used if patients encounter sexual side effects with an SSRI medication. When lowering the dose or discontinuing the medication is not effective, additional strategies may be considered. These additional strategies are described in Table 7, which also lists prominent and clinically relevant side effects associated with particular medication classes.

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Table 7. Potential Treatments for Side Effects of Antidepressant Medications

Serotonin syndrome, as the name implies, is presumed to result from high levels of serotonin in the brain. Although it can occur with administration of one or more serotonergic medications, it is most severe when an MAOI is coadministered with another serotonergic medication. Consequently, great care must be taken when changing patients from another antidepressant medication to an MAOI and from an MAOI to other antidepressant medications because of the persistent effects of discontinued medications. A washout period is essential before and after using an MAOI. If the psychiatrist chooses to discontinue a monoamine-uptake-blocking antidepressant medication (e.g., SSRI, SNRI, TCA) and substitute an MAOI, toxic interactions can best be avoided by allowing at least a 2-week washout period between medication trials (Table 8). The long half-life of the SSRI fluoxetine and its metabolites necessitates a 5- to 6-week washout period or longer before the use of an MAOI. Additional information about serotonin syndrome with specific medication classes can be found in Sections II.B.2.b.1.g. and II.B.2.b.5.b.

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Table 8. Required Washout Times Between Antidepressant Trials

Because knowledge of potential drug-drug interactions is frequently changing, it is useful to consult a frequently updated drug information database before selecting an antidepressant in a patient taking other medications.

+ 1. Selective serotonin reuptake inhibitors

SSRIs have comparable tolerability overall, but the specific medications differ somewhat in their side effect profiles, which may guide selection of an agent for an individual patient. Pharmacokinetic issues, including half-life and effect on the CYP-450 enzyme system, are additional considerations in the choice of an SSRI.

+ a. Gastrointestinal

SSRIs commonly cause nausea, vomiting, and diarrhea (98). These adverse events are generally dose dependent and tend to dissipate over the first few weeks of treatment. In some patients, however, diarrhea persists.

+ b. Activation/insomnia

SSRIs sometimes precipitate or exacerbate restlessness, agitation, and sleep disturbances—side effects that often attenuate with time. Anxiety may be minimized by introducing the agent at a low dose. Akathisia has also been reported in patients taking SSRIs (129) and may contribute to reported restlessness or activation. If akathisia does occur, a beta-blocker or benzodiazepine can be tried to reduce symptoms. Insomnia can be treated by using sleep hygiene techniques or CBT as a first approach or by adding a sedative-hypnotic medication or trazodone. Some have found melatonin to be helpful in treating SSRI-induced insomnia.

+ c. Sexual side effects

Although loss of erectile or ejaculatory function in men and loss of libido and anorgasmia in both sexes may be complications of virtually any antidepressant medication, these side effects appear to be more common with SSRIs. The psychiatrist should ascertain whether the reported sexual dysfunction is a result of the antidepressant medication, the underlying major depressive disorder, a co-occurring medical disorder, a disturbance in a relationship, or a need for education about sexual functioning. If sexual dysfunction is determined to be a side effect of the antidepressant medication, a number of strategies are available, including continuing treatment to assess whether the dysfunction will disappear with time, lowering the dose, discontinuing the antidepressant, or substituting another antidepressant such as bupropion (130). Specific pharmacological treatments that can be added for arousal difficulties, erectile dysfunction, or orgasm dysfunction include buspirone (131), bupropion (132), sildenafil (133), and tadalafil (134). Other phosphodiesterase inhibitors may be also useful in treating sexual side effects, and a variety of other medications have been used with anecdotal success (135, 136).

+ d. Neurological effects

Selective serotonin reuptake inhibitors can initially exacerbate both migraine headaches and tension headaches. These effects tend to be transient and improve within the first few weeks of treatment. With continued treatment, SSRIs may actually help prevent and treat migraine headaches (137, 138). Selective serotonin reuptake inhibitors have also been associated with extrapyramidal side effects, including akathisia, dystonia, parkinsonism, and tardive dyskinesia (139, 140). The incidence of such side effects is very low with SSRIs but may be higher in older patients, especially those with Parkinson's disease.

+ e. Falls

Selective serotonin reuptake inhibitors, like other antidepressive agents, have been associated with an increased risk of falls. In studies of nursing home residents, SSRI use has been associated with an approximately twofold increase in the risk of a fall (141, 142). An even greater risk of falls in patients who were taking SSRIs was noted in a community-based cohort study (143). Meta-analyses have also documented an increased risk of falls in patients treated with antidepressive agents, in general (144, 145). The implications of this increase in fall risk are complicated by the decrease in bone density that has been noted in depressed patients (146) and in patients treated with SSRIs (147, 148). An increase in the risk of hip fractures has also been noted (149). Rarely, SSRI use has been associated with bradycardia, which could also contribute to syncope and falls (150). In all patients, including those treated with SSRIs, fall risk may be increased in individuals receiving benzodiazepines or other hypnotic agents (144, 145, 151) and in those receiving multiple medications (144, 145). Systematically reviewing patients' medication regimens may help to eliminate medications that may no longer be needed, although such interventions have not been found to alter fall risk, per se (152). Inquiring about a history of falls in the past year and assessing for abnormalities in gait and balance can also help in identifying patients at particular risk for falling (153).

+ f. Effects on weight

Weight gain, at times substantial, occurs in some patients taking SSRIs (154). Patients who take paroxetine have a higher incidence of weight gain than those who take other SSRIs (98, 155). Fluoxetine causes an initial reduction in weight, which tends to normalize with continued treatment (156).

+ g. Serotonin syndrome

Use of SSRIs has been associated with the rare development of a syndrome caused by an excess of central nervous system serotonergic activity. Features of serotonin syndrome include abdominal pain, diarrhea, flushing, sweating, hyperthermia, lethargy, mental status changes, tremor and myoclonus, rhabdomyolysis, renal failure, cardiovascular shock, and possibly death (157). Although serotonin syndrome can occur rarely with the use of SSRIs alone, it is usually associated with the simultaneous use of multiple serotonergic agents and is most severe when SSRIs are given together with MAOIs. Consequently, when an SSRI is being changed to an MAOI or vice versa, particular attention must be give to the duration of time between treatments (Section II.B.2.b) to avoid precipitating a potentially lethal serotonin syndrome. Serotonin syndrome has also been reported when SSRIs are used in combination with tramadol, high-dose triptans, or the antibiotic linezolid, which also has some ability to inhibit MAO (158, 159).

+ h. Drug interactions

The potential for drug-drug interactions differs significantly across the SSRIs. Selective serotonin reuptake inhibitors have variable effects on hepatic microsomal enzymes and therefore cause both increases and decreases in the blood levels of other medications. For example, when SSRIs that strongly inhibit the CYP 2D6 isoenzyme (e.g., paroxetine, fluoxetine) are administered concomitantly with tamoxifen, the metabolism of tamoxifen to its active metabolite is reduced (76–79), resulting in a potential decrease in its efficacy in preventing breast cancer relapse (80, 81). Interaction with other drugs was higher for fluoxetine, fluvoxamine, and paroxetine than for sertraline, citalopram, and escitalopram (98, 160, 161).

As described above, there can be a potentially lethal interaction between SSRIs and MAOIs: the serotonin syndrome. At least five half-lives should elapse between the time an SSRI is stopped and an MAOI is started; for fluoxetine discontinuation, this means waiting approximately 5–6 weeks before starting an MAOI; for discontinuation of other SSRIs, approximately 2 weeks should pass before starting an MAOI (162). A 2-week waiting period has been suggested after discontinuing an MAOI before starting an SSRI or another MAOI (Table 8).

+ i. Discontinuation syndrome

Selective serotonin reuptake inhibitors generally should not be abruptly discontinued after extended therapy and, whenever possible, should be tapered over several weeks to minimize discontinuation-emergent symptoms. Clinical experience and a few controlled studies suggest that among the SSRIs, discontinuation-emergent symptoms are more likely with paroxetine than sertraline, citalopram, or escitalopram and least likely to occur with fluoxetine (due to the long elimination half-life of its primary metabolite, norfluoxetine) (163, 164). Discontinuation-emergent symptoms include both flu-like experiences such as nausea, headache, light-headedness, chills, and body aches, and neurological symptoms such as paresthesias, insomnia, and "electric shock-like" phenomena. These symptoms typically resolve without specific treatment over 1–2 weeks. However, some patients do experience more protracted discontinuation syndromes, particularly those treated with paroxetine, and may require a slower downward titration regimen. Another strategy is to change to a brief course of fluoxetine, e.g., 10 mg for 1–2 weeks, and then taper and discontinue the fluoxetine (165).

+ 2. Serotonin norepinephrine reuptake inhibitors

The most common side effects of the SNRIs (venlafaxine, desvenlafaxine, and duloxetine) are similar to those seen with SSRIs, including nausea and vomiting, sexual dysfunction, and activation; like the side effects seen with SSRIs, those with SNRIs can attenuate with continued use. The SNRIs also are more likely to be associated with side effects that reflect noradrenergic activity, including increased pulse rate, dilated pupils, dry mouth, excessive sweating, and constipation. Although all three SNRIs carry the warning of increased blood pressure, this risk is greater during therapy with venlafaxine at doses above 150 mg/day (166) than with duloxetine at doses of 60–120 mg/day (167) or desvenlafaxine at doses of 50–100 mg/day (168). Because this blood pressure increase is dose-related, SNRI-induced hypertension may respond to dose reduction. In the absence of a reduction in hypertension, a different antidepressant medication may be considered. Alternatively, in a patient with well-controlled depressive symptoms, it may be preferable to add an antihypertensive agent rather than risk a depressive relapse or recurrence with medication tapering. As with the SSRIs, abrupt discontinuation of SNRIs should be avoided whenever possible. Discontinuation symptoms, which are sometimes protracted, are more likely to occur with venlafaxine (and, by implication, desvenlafaxine) than duloxetine (100) and may necessitate a slower downward titration regimen or change to fluoxetine. As described above (Section II.B.2.b), there can be a potentially lethal interaction between SNRIs and MAOIs: the serotonin syndrome.

+ 3. Other antidepressant medications
+ a. Bupropion

Bupropion differs from other modern antidepressants by its lack of direct effects on serotonergic neurotransmission and, as a consequence, a virtual lack of sexual side effects (169). Neurologic side effects with bupropion include headaches, tremors, and seizures (106). The risk of seizures is minimized by avoiding high doses (e.g., using no more than 450 mg/day), avoiding rapid titration, using divided dosing schedules for the immediate-release and sustained-release formulations, and avoiding use of bupropion in patients with risk factors for seizures. Bupropion should also not be used in patients who have had anorexia nervosa or bulimia nervosa because of elevated risk of seizures (170). The risk of seizures may also be increased by the concomitant use of inhibitors of CYP 2B6 (e.g., desipramine, sertraline, paroxetine, fluoxetine) due to the resulting increase in bupropion blood levels. Bupropion has been associated with a low risk of psychotic symptoms, including delusions and hallucinations. It should therefore be used cautiously in patients with psychotic disorders. Other side effects with bupropion include agitation, jitteriness, mild cognitive dysfunction, insomnia, and gastrointestinal upset.

+ b. Mirtazapine

The most common side effects of mirtazapine include dry mouth, sedation, and weight gain. For this reason, mirtazapine is often given at night and may be chosen for depressed patients with initial insomnia and weight loss. Although these side effects tend to occur early in the treatment course and may attenuate with continued use, the weight gain associated with mirtazapine is greater than that with other non-TCA, non-MAOI antidepressants (95) and may make it a less attractive choice for some patients. Mirtazapine increases serum cholesterol levels in some patients (171). Although several patients treated with mirtazapine were observed to have agranulocytosis in early studies, subsequent clinical experience has not confirmed an elevated risk (172).

+ c. Trazodone

The most common side effect with trazodone is sedation. Because the sedation associated with trazodone is greater than that with other non-TCA, non-MAOI antidepressants (95), this can be an advantage in patients with initial insomnia (173). Trazodone can also cause cardiovascular side effects, including orthostasis, particularly among elderly patients or those with preexisting heart disease. Use of trazodone has also been associated with life-threatening ventricular arrhythmias in several case reports (173). Trazodone also can cause sexual side effects, including erectile dysfunction in men; in rare instances, priapism occurs, which might require surgical correction (174, 175).

+ d. Nefazodone

Side effects with nefazodone include dry mouth, nausea, constipation, orthostasis, and visual alterations (176). Sedation is also common and may necessitate a gradual titration of nefazodone. However, in patients with insomnia, the sedating properties of nefazodone can be helpful in improving sleep (177). There appears to be a low incidence of treatment-emergent sexual dysfunction (178, 179) with nefazodone and, unlike trazodone, it has not been associated with priapism. Nefazodone has also been associated with rare but potentially fatal liver failure (180, 181), which has limited its use in recent years. Drug-drug interactions can also be problematic as nefazodone inhibits hepatic microsomal enzymes and can raise levels of concurrently administered medications such as certain antihistamines, benzodiazepines, and digoxin.

+ 4. Tricyclic antidepressants
+ a. Cardiovascular effects

Cardiovascular effects, including arrhythmias, can be problematic with TCA treatment. Consequently, a pretreatment ECG is indicated for patients with significant cardiac risk factors and patients older than age 50 years. Follow-up ECGs may also be indicated to identify the development of conduction changes, typically during the early phase of TCA use (182). Tricyclic antidepressants act similarly to class Ia antiarrhythmic agents such as quinidine, disopyramide, and procainamide, which increase the threshold for excitation by depressing fast sodium channels, prolong cardiac cell action potentials through actions on potassium channels, and prolong cardiac refractoriness through actions on both types of channels (183). As a result, combinations of TCAs with other class I antiarrhythmic agents can exert additive toxic effects on cardiac conduction; patients with ventricular arrhythmias taking another class I antiarrhythmic agent who require TCA therapy should be under careful medical supervision. Individuals with prolonged QT intervals, whether preexistent or medication induced, are predisposed to develop ventricular tachycardia (184). Even patients with normal pretreatment ECG results may develop atrioventricular block with TCAs that reverts to normal after discontinuation of antidepressant medication treatment (185). Because of these effects on cardiac conduction, TCAs (like other class Ia antiarrhythmic agents) may carry an increased risk of serious cardiac adverse effects, including mortality (186–189). In addition, fatal arrhythmias can occur in the context of TCA overdose (190, 191).

In addition to causing arrhythmias, TCAs can cause a number of other cardiovascular side effects, including tachycardia (through muscarinic cholinergic blockade and -adrenergic blockade) or orthostatic hypotension (through -adrenergic blockade). Side effects such as orthostatic hypotension may in turn lead to events such as dizziness, falls, or fractures, which are of particular concern in elderly patients (192). Of the TCAs, nortriptyline may be less likely to contribute to orthostatic blood pressure changes (185). Preexisting orthostasis, antihypertensive treatment, dehydration, and salt depletion, whether voluntary or a result of diuretic treatment, may contribute to symptomatic orthostatic hypotension with TCAs. If there is no medical contraindication, patients with symptomatic orthostatic hypotension should maintain adequate fluid intake and be cautioned against extreme dietary salt restriction.

+ b. Anticholinergic side effects

All TCAs have antimuscarinic effects; tertiary amine tricyclic antidepressants produce the most anticholinergic side effects, whereas the secondary amines desipramine and nortriptyline have less antimuscarinic activity (193). The most common consequences of muscarinic blockade are dry mouth, impaired ability to focus vision at close range, constipation, urinary hesitation, tachycardia, and sexual dysfunction. Although patients can develop some degree of tolerance to anticholinergic side effects, these symptoms may require treatment if they cause substantial dysfunction or interfere with adherence. Impaired visual accommodation may be counteracted through the use of pilocarpine eye drops. Dry mouth may be counteracted by advising the patient to use sugarless gum or candy and ensuring adequate hydration. Constipation can be managed by adequate hydration and the use of bulk laxatives. Antidepressant medications with anticholinergic side effects should be avoided in patients with cognitive impairment, narrow-angle glaucoma, or prostatic hypertrophy. Tricyclic antidepressants can impair memory and concentration and even precipitate anticholinergic delirium, particularly in patients who are elderly, medically compromised, or taking other anticholinergic medicines. Such toxic confusional states may signal the presence of high TCA blood levels and can improve with lowering of the dose (194).

+ c. Sedation

Tricyclic antidepressants also have affinity for histaminergic receptors and produce varying degrees of sedation. In general, tertiary amines cause greater sedation, while secondary amines cause less (193). Sedation often attenuates in the first weeks of treatment, and patients experiencing only minor difficulty from this side effect should be encouraged to allow some time to pass before changing antidepressant medications. Patients with major depressive disorder with insomnia may benefit from sedation when their medication is given as a single dose before bedtime.

+ d. Weight gain

Tricyclic antidepressants can cause weight gain, possibly through their histaminergic properties and/or blockade of 5-HT2 receptors (195). The degree of weight gain appears to vary by agent (e.g., greater weight gain with amitriptyline and less with desipramine), is often dose dependent, and is potentially reversible with cessation of TCA therapy. Regular monitoring of weight permits early detection of weight gain and can allow the treating clinician and patient to determine whether a management plan to minimize or forestall further weight gain is clinically indicated.

+ e. Neurological effects

Tricyclic antidepressants can cause myoclonus (196). Since this may be a sign of toxicity, the clinician may wish to check the blood level (if available) to ensure that it is not excessive. If the level is nontoxic and myoclonus is not bothersome to the patient, the agent may be continued without a change in dose. If the myoclonus is problematic and the blood level is within the recommended range, the patient may be treated with clonazepam at a dose of 0.25 mg t.i.d. Alternatively, the antidepressant medication may be changed. In overdoses, TCAs can cause seizures. Some vulnerable patients may experience seizures even on therapeutic doses of a TCA—especially clomipramine and maprotiline (197). Amoxapine, a dibenzoxazepine-derivative tricyclic antidepressant, also produces seizures in overdose and has active metabolites that block dopamine receptors, conferring a risk of extrapyramidal side effects and tardive dyskinesia (198).

+ f. Falls

Use of TCAs has been associated with an increased risk of falls in a number of studies and meta-analyses, and the relative risk of falling appears comparable to that with SSRI treatment (141, 144, 145). Although systematic reviews show a relatively minor effect of orthostatic hypotension on fall risk, TCAs may contribute to orthostasis and falls in individual patients (153). If orthostatic hypotension is prominent or associated with gait or balance problems, it may require further evaluation and treatment to minimize the likelihood of falls (199). Other aspects of fall risk with TCAs are similar to those that have already been described for patients treated with SSRIs (Section II.B.2.b.1.e). Other causes of falls include bradycardia, cardiac arrhythmia, a seizure, or ataxia.

+ g. Medication interactions

A number of medications that inhibit, induce, or are metabolized by hepatic microsomal enzymes can interact with TCAs (200). For example, medications that induce CYP 3A4 such as carbamazepine or barbiturates will cause a decrease in serum levels of TCAs. Drugs such as the antipsychotic medication perphenazine or SSRIs such as fluoxetine or paroxetine can inhibit metabolism via CYP 2D6, resulting in a reduced clearance and increased levels of TCAs. Tricyclic antidepressants can also alter the pharmacokinetics or pharmacodynamics of other medications; for example, TCAs can cause a lowering of valproate levels and reduce the activity of clonidine. Therefore, adjustments in medication doses may be necessary when TCAs are administered concomitantly with other drugs for which there is an interaction. The ability to obtain meaningful antidepressant blood levels to guide dosing is an advantage with several of the TCAs (e.g., nortriptyline, amitriptyline, desipramine, imipramine) (201). Potentially dangerous interactions, including hypertensive crises and serotonin syndrome, can develop when TCAs are administered with MAOIs (see Sections II.B.2.b and II.B.2.b.5.b), norepinephrine, or epinephrine.

+ 5. Monoamine oxidase inhibitors
+ a. Hypertensive crises

A hypertensive crisis can occur when a patient taking an MAOI ingests large amounts of tyramine or other vasoactive amines in foods or medications (202). This reaction is characterized by the acute onset of severe headache, nausea, neck stiffness, palpitations, profuse perspiration, and confusion and can possibly lead to stroke and death (119). Dietary restrictions include avoiding foods such as aged cheeses or meats, fermented products, yeast extracts, fava or broad beans, red wine, draft beers, and overripe or spoiled foods (202, 203). A number of medications including norepinephrine reuptake blocking drugs (e.g., SNRIs, TCAs), sympathomimetic vasoconstrictive agents, and over-the-counter decongestants can also produce a hypertensive crisis when used in combination with MAOIs (202, 204). Individuals with asthma who receive MAOIs should be cautioned regarding interactions with sympathomimetic bronchodilators, although other antiasthma agents appear to be safe. Stimulants may be added to MAOIs, but only with caution and in selected individuals with treatment-resistant symptoms (205, 206).

At low doses (6 mg/24 hours), selegiline differs from the older MAOIs in selectively blocking MAO B. In addition, the transdermal delivery of selegiline bypasses enzyme inhibition in the gut and first-pass metabolism in the liver. As a result, a low-tyramine diet is not needed when selegiline is prescribed at the minimum therapeutic dose. However, few safety data are available at higher doses at which selegiline becomes nonselective and inhibits both MAO A and MAO B. Consequently, a low-tyramine diet is needed when doses of 9 mg/24 hours and higher are prescribed as with other MAOIs (207, 208). Moclobemide, which is available in Canada but not the United States, differs from the above MAOIs in binding reversibly to MAO and makes dietary restrictions unnecessary with moclobemide. The potential for drug-drug interactions with selegiline and moclobemide has not been fully studied, but caution suggests that the same drug interactions should be considered as when prescribing the older, nonselective, irreversible MAOIs.

Although some clinicians continue to recommend that patients carry nifedipine as a self-administered antidote (e.g., 10 mg by mouth at the first sign of a hypertensive crisis [209]), this practice has not been approved by the FDA, and there are concerns about both the safety and efficacy of this strategy, which can produce dangerous hypotension (210). Definitive treatment of hypertensive crises usually involves intravenous administration of an antihypertensive agent (e.g., labetalol, sodium nitroprusside) in an emergency department setting.

+ b. Serotonin syndrome

As discussed previously in Section II.B.2.b.1.g, serotonin syndrome is caused by excess CNS serotonergic activity and is characterized by abdominal pain, diarrhea, flushing, sweating, hyperthermia, lethargy, mental status changes, tremor and myoclonus, rhabdomyolysis, renal failure, cardiovascular shock, and possibly death. Serotonin syndrome most commonly occurs when MAOIs (including reversible inhibitors of monoamine oxidase and selegiline) are taken in close proximity to other serotonergic agents, such as buspirone or antidepressants (157, 204, 211). Consequently, when patients are being changed from an SSRI other than fluoxetine or an SNRI to an MAOI, a waiting period of at least 2 weeks is needed between the discontinuation of one medication and the initiation of the other. When changing from fluoxetine to an MAOI, a waiting period of at least 5 weeks is needed before the MAOI is started (Table 8). Other medications that have been reported to produce serotonin syndrome when used in conjunction with MAOIs include synthetic opioids (e.g., dextromethorphan, meperidine, tramadol, propoxyphene, methadone), nonantidepressant tricyclic compounds (e.g., carbamazepine, cyclobenzaprine), sibutramine, and over-the-counter cold products such as chlorpheniramine (204).

+ c. Cardiovascular effects

Orthostatic hypotension is commonly seen during MAOI treatment. Possible treatments for this side effect include adding dietary salt to increase intravascular volume, or use of the mineralocorticoid fludrocortisone. Use of MAOIs can also be associated with the development of peripheral edema, which may be helped by the use of support stockings.

+ d. Weight gain

Weight gain is also commonly seen in patients treated with nonselective MAOIs. Although clinical experience is limited, results of one 52-week study suggested that treatment with transdermal selegiline may not be associated with an increased risk of weight gain (212).

+ e. Sexual side effects

Sexual side effects seen with MAOI therapy include anorgasmia, decreased libido, and erectile or ejaculatory dysfunction. Sexual side effects may diminish over time or with reductions in MAOI doses. The transdermal formulation of selegiline appears to have a relatively low risk of sexual side effects (213).

+ f. Neurological effects

Treatment with MAOIs can also be accompanied by headaches and insomnia; these side effects may diminish over time with continued use. Other neurological effects seen with MAOIs include sedation, myoclonic jerks, paresthesias, intense daytime drowsiness, and, rarely, peripheral neuropathy.

+

c. Implementation of pharmacotherapy

Improvement with pharmacotherapy can be observed as early as the first 1–2 weeks of treatment, and improvement continues up to 12 weeks. Many patients may show partial improvement as early as the end of the first week (214–216). Others achieve improvement within the first 2–4 weeks (217–220). In short-term efficacy trials, all antidepressant medications appear to require at least 4–6 weeks to achieve maximum therapeutic effects (221, 222). There is also evidence for continued accrual of benefit for an additional 4–6 weeks (223). Furthermore, longer time to therapeutic effect has been seen with studies conducted in "real world" settings (224), as well as in studies of patients with more chronic illness (225, 226) or patients with major depressive disorder complicated with co-occurring medical and/or Axis I disorders (224, 227).

Once an antidepressant medication has been selected, it can be started at doses suggested in Table 6. Initial doses should be incrementally raised as tolerated until a therapeutic dose is reached or the patient achieves remission, provided there has been at least some improvement in symptoms in the initial weeks of treatment (217–220). For patients who exhibit a partial response to treatment, doses of antidepressant medications should be maximized, side effects permitting, before changing to a different antidepressant medication. In some instances, due to factors such as rapid metabolism of medication (228, 229), patients may require doses above those noted in FDA labeling. Patients who have achieved some improvement during the initial weeks of treatment should be encouraged to continue taking antidepressant medication for a total of at least 4–8 weeks. If at least moderate improvement is not observed with maximally tolerated doses after 4–8 weeks of treatment, reappraisal and adjustment of the pharmacotherapy should be considered. Patients with no improvement in the initial weeks of treatment generally need an earlier adjustment of treatment. For these patients, the psychiatrist should consider changing to another antidepressant rather than increasing the dose of the medication. For some antidepressant medications, the exact relationships between doses and major depressive disorder symptom response have not been rigorously investigated with fixed-dose studies, and minimum effective doses have not been clearly established; moreover, for other antidepressant medications, some studies have failed to show dose-response relationships (230, 231). Therefore, the initial doses and usual adult doses in Table 6 are intended to serve as general guidelines, and actual doses may vary from individual to individual.

Titration of the dose to full therapeutic doses generally can be accomplished over the initial week(s) of treatment but may vary depending on the development of side effects, the patient's age, and the presence of co-occurring medical and psychiatric conditions. In general, patients who are older, are medically compromised, or have decreased ability to metabolize and clear antidepressant medications will require lower doses. In such patients, reduction of initial and therapeutic doses to 50% of usual adult doses is often recommended, and dose escalations should be made at a slower rate than for younger and healthier adults. Doses will also be affected by the side effect profile of medications and the patient's ability to tolerate these side effects. Medication doses should also be tailored to individual patients depending on the potential for pharmacokinetic alterations and drug-drug interactions.

Patients who have started taking an antidepressant medication should be carefully and systematically monitored to assess their response to treatment, the emergence of side effects, their clinical condition, safety, and adherence to treatment. Use of clinician- and patient-rated scales can facilitate such assessments (see Section II.A.8). Factors to consider when determining the frequency of treatment visits include the severity of illness, the patient's cooperation with treatment, the availability of social supports, the presence of co-occurring general medical illnesses, and the progression of symptom change. Visits should also be frequent enough to monitor and address suicide risk and to actively promote treatment adherence, since attrition from treatment continues to be a major hurdle in maximizing outcomes. Patients in clinical trials appear to benefit from monitoring once a week or more. This frequency of monitoring enhances adherence rates and likely helps patients avoid the demoralization that may occur before the onset of beneficial effects (216). In the recently completed STAR*D ("Sequenced Treatment Alternatives to Relieve Depression") trial, up to six visits were recommended during the first 12 weeks (acute phase) of measurement-based treatment at each of the four treatment steps (40). In clinical practice, the frequency of monitoring during the acute phase of pharmacotherapy may vary and can be as often as multiple times per week in more complex circumstances. The method of monitoring (e.g., face-to-face visits, telephone contact, or contact with another clinician knowledgeable about the patient) may vary depending on the clinical context and the treatment modality.

Although for most patients, monitoring of antidepressant blood levels is not necessary, it may be useful for those taking TCAs. For some medications, particularly nortriptyline, amitriptyline, desipramine, and imipramine, blood drug levels correlate with both efficacy and side effects (201, 232, 233). When such medications are given, obtaining blood drug levels can be particularly informative when patients have not responded to treatment with an adequate dose of antidepressant medication for an adequate duration; when patients are particularly vulnerable to the toxic effects of a medication and require the lowest possible effective dose; when there are concerns about patient adherence; and when there is concern that drug-drug interactions are adversely affecting antidepressant medication levels. In time, genetic testing may help guide selection or dosing of antidepressants, but data are currently insufficient to justify the cost of such tests (229).

Some antidepressant medications, especially TCAs, can cause significant morbidity and mortality in overdose (190, 191). Ingestion of a 10-day supply of a tricyclic agent administered at a dose of 200 mg/day is often lethal. Early on in treatment, it is prudent to dispense only small quantities of such antidepressant medications and keep in mind the possibility that patients can hoard medications over time. Alternatively, in patients who are suicidal, it may be preferable to employ agents that are safer in overdose such as the SSRIs, bupropion, or mirtazapine.

Table Reference Number
Table 3. Factors to Consider in Choosing an Antidepressant Medication
Table Reference Number
Table 4. Cytochrome P450 Enzyme Metabolism of Antidepressive Agentsa
Table Reference Number
Table 5. Cytochrome P450 Enzyme Inhibition by Antidepressive Agentsa
Table Reference Number
Table 6. Dosing of Medications Shown To Be Effective in Treating Major Depressive Disordera
Table Reference Number
Table 7. Potential Treatments for Side Effects of Antidepressant Medications
Table Reference Number
Table 8. Required Washout Times Between Antidepressant Trials

References

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