Thus—with some exceptions—recommended starting dosages for older patients are usually one-half those used in younger adults. For the frail older patient, the starting dosage should probably be even lower—about one-fourth the typical starting dosage in young adults.6 As in younger patients, the treatment goal is to achieve the maximal therapeutic effect with the lowest effective dosage while avoiding side effects.
More time may be required to achieve a therapeutic effect in older than in younger patients. Substantial improvement may not be seen until an older patient has been taking an antidepressant for 9 weeks or longer. In younger patients, responses are seen as early as 2 weeks after starting antidepressant therapy, and remission occurs within 6 to 8 weeks.2
SSRIs versus tricyclics
SSRIs—citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, and sertraline (Table 1)7 —are considered first-line antidepressants for late-life depression. Although SSRIs and tricyclic antidepressants (TCAs) demonstrate equivalent efficacy in older adults, SSRIs are associated with lesstroublesome side effects.2
SSRIs are less sedating than tricyclics and are not associated with adverse effects on cognition; both qualities make these agents appropriate for older patients. Risk of overdose with SSRIs also is much lower than with TCAs.2
Both types of agent have been reported to cause movement disorders such as extrapyramidal symptoms and even tardive dyskinesia, but these side effects are much more rare with SSRIs than with TCAs.2 Also—unlike the TCAs— SSRIs do not significantly effect cardiac conduction, which is an important quality in the older population with its relatively high incidence of heart disease.
Table 1
USING SSRIs TO TREAT LATE-LIFE DEPRESSION
| Drug | Half-life (hours)* | Recommended dosage after age 65 (mg/d) † |
|---|---|---|
| Citalopram | 35 | 20 to 40 |
| Escitalopram | 27 - 32 | 10 to 20 |
| Fluoxetine | 96 - 386 | 10 to 60 |
| Fluvoxamine | 16 | 25 to 300 |
| Paroxetine | 21 | 10 to 40 |
| Sertraline | 26 | 25 to 200 |
| * In the older patient, medication half-lives may be extended 1.5to 2-fold. | ||
| † The heterogeneity of aging can lead to a wide variation in antidepressant target dosages. Therefore, although starting dosages for older adults are lower, final dosages may be the same as for younger adults. | ||
| Source: Physicians’ Desk Reference (56th ed). Montvale, NJ: Medical Economics Co, 2002. | ||
Meta-analyses suggest that patients are more likely to discontinue taking tricyclics than SSRIs.8 Adherence to antidepressant medications by older patients has been associated with lower perceived stigma of mental illness, higher self-rated severity of illness, age over 60, and absence of a personality disorder.9
SSRI side effects
The most common side effect of SSRIs is nausea, which is usually mild and occurs in the first weeks of treatment.2 Dry mouth is related to noradrenergic influences on the salivary gland. Anxiety is usually transient.
Sedation can be a problem in older patients who use SSRIs. Among the six SSRIs indicated for depression, paroxetine appears to be the most sedating.10 Paroxetine exhibits the most muscarinic blockade in vitro, with a binding affinity less than that of imipramine but greater than nortriptyline.11 Studies in older patients have suggested, however, that cognitive function is not compromised with paroxetine, as is observed with other antidepressants with anticholinergic action.6
Table 2
CYTOCHROME P450 ISOZYMES INHIBITED BY SSRI ANTIDEPRESSANTS (IN VITRO)
| Drug | 1A2 | 2C9 | 2C19 | 2D6 | 3A4 |
|---|---|---|---|---|---|
| Fluoxetine | + | ++ | + | +++ | ++ |
| Sertraline | + | + | + | + | + |
| Paroxetine | + | + | + | +++ | + |
| Citalopram | + | ○ | ○ | + | ○ |
| Escitalopram | ○ | ○ | ○ | ○ | ○ |
| Fluvoxamine | +++ | ++ | +++ | + | ++ |
| Source: Adapted from Greenblatt et al. J Clin Psychiatry 1998;59(suppl 15):19-27, and von Moltke et al. Drug Metab Dispos 2001;29:1102-9. | |||||
Sexual function can be diminished by SSRIs; the most common sexual side effects are anorgasmia and delayed orgasm.12 Preserving sexual function is important to many older men and women who retain their interest in sexual activity well into later life.
Withdrawal syndrome. Abrupt discontinuation of some SSRIs can lead to withdrawal side effects, such as dizziness, fatigue, and nausea. In a study of young and older adults, withdrawal syndrome followed abrupt discontinuation at rates of 14% with fluoxetine and 60% with sertraline or paroxetine.13
Elimination half-life. Medication half-lives tend to be prolonged in older patients because of age-related pharmacokinetic changes. SSRIs with relatively shorter half-lives—such as citalopram, sertraline, paroxetine, and fluvoxamine—could be eliminated fairly rapidly should adverse events arise.
On the other hand, use of a longer-acting agent, such as fluoxetine, may be an advantage if compliance is a problem. In this case, fluoxetine’s prolonged washout rate could help protect a patient from relapse, even when doses are missed.
Potential drug-drug interactions
Individual SSRIs have different effects on the cytochrome P450 system (Table 2).14,15 For example, fluoxetine, sertraline, and paroxetine—but not fluvoxamine—are in vitro inhibitors of the 2D6 isoenzyme system,16 which metabolizes TCAs, type Ic antiarrhythmics, alpha-adrenergic blockers, dextromethorphan, chemotherapeutic agents, and some antipsychotics. Citalopram has minimal inhibitory activity and escitalopram has virtually no inhibitory action on CYP 2D6.17
Cytochrome P450 3A4 metabolizes numerous drugs, including alprazolam, triazolam, carbamazepine, calcium channel blockers, and others. The 3A4 enzymes are inhibited by fluoxetine, sertraline, and fluvoxamine.18