Selective Serotonin Reuptake Inhibitors
SSRIs are considered first-line pharmacotherapy for late-life depression. These drugs act on the serotonergic system by blocking the presynaptic reuptake of the neurotransmitter, serotonin. In comparison with most other antidepressants, SSRIs generally have a more favorable side-effect profile and are well tolerated. They are also markedly safer than their parent drugs, TCAs, in overdose. Over 30 randomized, placebo-controlled, clinical trials with more than 5000 older patients with SSRIs have been conducted. These studies have included patients with a variety of psychiatric and medical illnesses, including mild cognitive impairment, dementia, minor depression, schizophrenia, cardiovascular and cerebrovascular disease, or other medical conditions. In the largest clinical trial studies published, SSRI response rates (defined as ≥ 50% reduction in the severity of depression) ranged from 35% to 60%, in comparison with placebo, which ranged from 26% to 40%. There is not enough evidence in the current literature, however, to conclude that SSRIs increase remission rates in depressed older persons.
SSRIs are established as the preferred pharmacologic treatment of anxiety in younger adults, however, only a single placebo-controlled trial and two open-label studies have suggested efficacy of SSRIs for anxiety in later life. There is still limited evidence supporting the efficacy of SSRIs in treating dementia-related behavioral disturbances, such as agitation, disinhibition, delusions, and hallucinations. For instance, the Citalopram for Agitation in Alzheimer Disease (CitAD) study examined patients with probable AD with significant agitation. The trial found that psychosocial intervention along with citalopram significantly reduced agitation and caregiver distress when compared with placebo. One of the challenges with citalopram, however, is the risk of arrhythmia at higher doses, which may limit its practical application.
Although there is similar efficacy between each of the SSRIs, citalopram, escitalopram, and sertraline have better pharmacokinetic profiles, are less of a risk for drug-drug interactions, and appear not to interfere with cognition. As such, these drugs are generally preferable to fluvoxamine, fluoxetine, or paroxetine. Recently, however, citalopram and escitalopram were associated with dose-dependent QT interval prolongation in those greater than 60 years, increasing the risk of fatal arrhythmia and limiting the maximum recommended dose in late life. In older adults, starting dosages are administered in one daily dose, at half the amount administered to younger adults (Table 64-1). Dosages are typically increased every 2 to 4 weeks based on response and tolerability, but can be increased more rapidly, that is after a week of use as needed. Fluvoxamine is the only SSRI that should be given according to a twice-daily dosing regimen. Of note, concomitant use with MAOIs should be avoided due to the risk of a hypertensive crisis or the development of serotonin syndrome.
TABLE 64-1ANTIDEPRESSANT ORAL DOSAGES AND SIDE EFFECTS |Favorite Table|Download (.pdf) TABLE 64-1 ANTIDEPRESSANT ORAL DOSAGES AND SIDE EFFECTS
|CLASS/MEDICATION ||INITIAL DAILY DOSE (mg) ||MAX DAILY DOSE (mg) ||RISK FOR DRUG INTERACTION ||SIDE EFFECTS |
|Selective serotonin reuptake inhibitors |
|Citalopram ||5–10/d ||20/d ||Low ||GI distress, sexual dysfunction, slight weight gain, QTc prolongation, hyponatremia, SIADH |
|Escitalopram ||5/d ||10/d ||Low ||GI distress, sexual dysfunction, slight weight gain, QTc prolongation, hyponatremia, SIADH |
|Fluoxetine ||10/d ||40/d ||High ||Insomnia, slight anticholinergic effects, GI distress, sexual dysfunction, slight weight gain, EPS, hyponatremia, SIADH |
|Moderate ||GI distress, sexual dysfunction, moderate weight gain, minimal sedation, withdrawal symptoms, anticholinergic effects, hyponatremia, SIADH |
|Sertraline ||12.5–25/d ||200/d ||Low ||GI distress, sexual dysfunction, slight weight gain, EPS, hyponatremia, SIADH |
|Vilazodone ||10/d ||40/d ||Moderate ||GI distress, dizziness, insomnia, sexual dysfunction, abnormal dreams (limited geriatric data) |
|Vortioxetine ||5/d ||20/d ||High ||GI distress, headache, nasopharyngitis, sexual dysfunction, hyperhidrosis, somnolence, dry mouth and dizziness, hyponatremia, SIADH (limited geriatric data) |
|Serotonin norepinephrine reuptake inhibitors |
|Duloxetine ||20/d ||60/d or 30 BID ||Low ||GI distress, dry mouth, urinary hesitancy, headaches, fatigue, drowsiness, hyponatremia, SIADH |
|High ||GI distress, minimal sedation, headaches, sexual dysfunction, serotonin syndrome, SIADH, withdrawal symptoms, adrenergic effects, dose-dependent hypertension, ECG changes, arrhythmia, acute ischemia, EPS, hyponatremia, SIADH |
|Desvenlafaxine ||50/d ||50–100/d ||Low ||Dizziness, dry mouth, insomnia, decreased appetite, GI distress, dose-dependent hypertension, QTc prolongation, elevated lipids, elevated liver enzymes, exacerbation of ischemic cardiac diseases, hyponatremia, SIADH (limited geriatric data) |
|Other second-generation antidepressants |
|Moderate ||Slight GI distress; CYP2B6 inhibitors: risk for seizure, gait disturbance, falls, psychosis, headache, agitation, dizziness, insomnia, loss of appetite, weight loss |
|Mirtazapine ||15 qhs ||45 qhs ||Low ||Mild anticholinergic effects, hypotension, high sedation, slight sexual dysfunction, serotonin syndrome, increased appetite, xerostomia |
|Preferred tricyclic antidepressants |
|Desipramine ||10–25 qhs ||50–150/d ||High ||Therapeutic window 150–300 ng/mL; mild anticholinergic effects, hypotension, slight GI distress, sedation, sexual dysfunction, slight weight gain |
|Nortriptyline ||10–25 qhs ||75–150/d ||High ||Therapeutic window 50–150 ng/mL; anticholinergic effects, hypotension, sedation, sexual dysfunction, slight weight gain |
Fluoxetine was the first SSRI to become available on the market in 1988. This drug ushered in a new era of treatment, providing an alternative to the TCAs. In geriatric patients, fluoxetine has demonstrated superiority as compared to placebo, and is as efficacious as amitriptyline, doxepin, escitalopram, paroxetine, sertraline, and trimipramine. Dosage recommendations for older adults indicate starting at 10 mg/day, which can be increased every 14 days by 10 mg to a maximum of 40 mg/day. This SSRI and its active metabolite norfluoxetine have mean half-lives of 4.6 and 9.3 days, respectively, rendering it an unfavorable choice for older adults. Fluoxetine and norfluoxetine inhibit the enzyme CYP2D6, and to a lesser extent CYP1A2 and CYP3A4. Norfluoxetine is cleared renally and subject to age-related declines in kidney function. Thus, it is crucial to consider interactions with other medications metabolized by these enzymes to avoid drug accumulation and toxicity (Table 64-2).
TABLE 64-2CYP450 ISOZYME SUBSTRATES AND INHIBITORS |Favorite Table|Download (.pdf) TABLE 64-2 CYP450 ISOZYME SUBSTRATES AND INHIBITORS
|CLASS/MEDICATION ||1A2 ||2A6 ||2B6 ||2C19 ||2C8/9 ||2D6 ||2E1 ||3A4 |
|Selective serotonin reuptake inhibitors |
| Citalopram ||– ||0 ||– ||++/– ||0 ||+/– ||0 ||++ |
| Escitalopram ||0– ||0 ||0 ||++ ||0 ||– ||0 ||++ |
| Fluoxetine ||+/– – ||0 ||+/– ||+/– – ||++/– ||++/– – – ||+ ||+/– |
| Fluvoxamine ||++/– – – ||0 ||– ||– – – ||– ||++/– ||0 ||– |
| Paroxetine ||– ||0 ||– – ||– ||– ||++/– – – ||0 ||– |
| Sertraline ||– ||0 ||+/– – ||++/– – ||+/– ||++/– – ||0 ||+/– – |
| Vortioxetine ||0 ||+ ||+ ||+ ||+ ||++ ||0 ||++ |
| Vilazodone ||0 ||0 ||0 ||+/– – ||– ||+/– ||0 ||++ |
|Serotonin norepinephrine reuptake inhibitors |
| Duloxetine ||++ ||0 ||0 ||0 ||0 ||++/– – ||0 ||0 |
| Venlafaxine ||0 ||0 ||– ||+ ||+ ||++/– ||0 ||++/– |
| Desvenlafaxine ||0 ||0 ||0 ||0 ||0 ||– ||0 ||+/– – |
| Milnacipran ||0 ||0 ||0 ||+ ||+ ||+ ||0 ||++ |
|Other second-generation antidepressants |
| Bupropion ||+ ||+ ||++ ||0 ||+ ||+/– ||+ ||+ |
| Mirtazapine ||++/– ||0 ||0 ||0 ||+ ||++ ||0 ||++/– |
|Preferred tricyclic antidepressants |
| Desipramine ||+ ||– – ||– – ||0 ||0 ||++/– – ||– ||– – |
| Nortriptyline ||+ ||0 ||0 ||+ ||0 ||++/– ||– ||+ |
|Atypical antipsychotics |
| Aripiprazole ||0 ||0 ||0 ||0 ||0 ||++ ||0 ||++ |
| Clozapine ||++/– ||+ ||0 ||+/– ||+/– ||+/– ||– ||++/– |
| Olanzapine ||++/– ||0 ||0 ||– ||– ||+/– ||0 ||– |
| Quetiapine ||0 ||0 ||0 ||0 ||0 ||+ ||0 ||++ |
| Risperidone ||0 ||0 ||0 ||0 ||0 ||++/– ||0 ||+/– |
| Ziprasidone ||+ ||0 ||0 ||0 ||0 ||– ||0 ||++/– |
| Paliperidone ||0 ||0 ||0 ||0 ||0 ||0 ||0 ||0 |
| Lurasidone ||0 ||0 ||0 ||0 ||0 ||0 ||0 ||++/ – |
| Iloperidone ||0 ||0 ||0 ||0 ||0 ||++ ||0 ||+/ – |
| Asenapine ||++ ||0 ||0 ||0 ||0 ||+/– ||0 ||+ |
|Anticonvulsant mood stabilizers |
| Carbamazepine ||– – – ||0 ||– – – ||– – – ||+/– – – ||0 ||0 ||++/– – – |
| Valproic acid ||0 ||+ ||+ ||+/– ||+/– ||– ||+ ||– |
| Buspirone ||0 ||0 ||0 ||0 ||0 ||+ ||0 ||++ |
Sertraline was the second SSRI introduced, and is more specific in its effects on the inhibition of serotonin (5-hydroxytryptamine [5HT]) reuptake than fluoxetine. Its effects on the reuptake of norepinephrine and dopamine are modest. Sertraline is more effective than placebo, and is comparable to amitriptyline, fluoxetine, fluvoxamine, imipramine, nortriptyline, and venlafaxine in treating late-life depression. It is tolerated more favorably than imipramine and venlafaxine and demonstrates greater cognitive improvement than nortriptyline or fluoxetine. Dosing in older patients is typically initiated at 12.5 to 25 mg/day, with increases of 12.5 to 25 mg/day occurring every 2 to 4 weeks to a daily maximum of 200 mg. Dose may be increased more rapidly depending on tolerability. Sertraline reaches its peak plasma concentration more rapidly when it is taken with food. One study, which included frail nursing home patients, noted an average maintenance dose of 77 mg/day. Although sertraline is a mild inhibitor of CYP2D6, its minimal effects translate to lower risk for drug interactions.
Paroxetine is as effective in depressed geriatric patients as amitriptyline, bupropion, clomipramine, doxepin, fluoxetine, imipramine, and nortriptyline. Again, this SSRI demonstrates superiority to placebo; however, in a study of very old long-term care patients with minor depression, paroxetine resulted in greater cognitive impairment as compared to placebo, which may be attributable to its increased anticholinergic effects relative to other SSRIs. Mirtazapine displayed marginal efficacy over paroxetine in one double-blind, randomized trial. Paroxetine elicits fewer side effects compared to the tricyclic nortriptyline. A starting dose of 5 to 10 mg/day is recommended for geriatric patients. After 1 week, dosing can increase by 5 to 10 mg to a maximum of 40 mg/day. Dose titration from 20 to 30 mg results in median half-life changes (30 and 38 hours, respectively), as well as changes in steady-state concentrations (46 ng/mL and 80 mg). Paroxetine can be given by controlled-release tablets at an initial dose of 12.5 mg/day and titrated each week up to a maximum of 50 mg/day. This drug is another potent inhibitor of CYP2D6, and thus the metabolic activity of concomitant medications must be examined prior to administration of paroxetine to minimize the risk of drug interactions. Paroxetine has the most anticholinergic activity of the SSRIs. Of note, paroxetine is clinically well known to cause significant withdrawal symptoms if stopped abruptly. It should therefore be gradually tapered over days to weeks as clinically indicated.
Citalopram and escitalopram
The majority of published trials examining citalopram in depressed older individuals include those with concomitant dementia or cognitive impairment. Escitalopram is the S-enantiomer of racemic citalopram. Only one randomized, controlled trial has evaluated escitalopram in late-life depression. Citalopram has demonstrated greater efficacy over placebo in depressed older adults without dementia, and has similar efficacy as amitriptyline, and venlafaxine. While citalopram is associated with lower remission rates than nortriptyline, it is much better tolerated. In the single study comparing escitalopram, fluoxetine, and placebo, both active drugs were well tolerated. However, neither was more efficacious than placebo in reducing depressive symptoms. Geriatric dosage recommendations for citalopram indicate a starting dose of 10 mg, which can be titrated after 1 to 4 weeks. The United States Food and Drug Administration (FDA) issued a warning in 2011 that citalopram causes dose-dependent QT interval prolongation which can lead to the life-threatening cardiac arrhythmia, torsade de pointes. The warning recommended a maximum dose of citalopram of 20 mg/day and escitalopram of 10 mg/day among older adults (60 years or older), patients with hepatic impairment, patients who are CYP2C19 poor metabolizers, or patients taking concomitant medications that inhibit CYP2C19. It is also recommended that electrocardiograms be performed when starting citalopram or escitalopram and occasionally thereafter in order to monitor QT interval prolongation. With the aforementioned caveat in mind, for patients taking other medications, citalopram and escitalopram are often a good choice as neither is significantly affected by, nor do they affect, the CYP450 system. In older patients, however, the half-life of citalopram is increased, while availability and clearance are decreased. Those patients with mild-to-moderate renal function experience a 17% reduction in citalopram clearance.
Vilazodone is a novel antidepressant approved by the FDA for the treatment of depression. The potency for serotonin reuptake has been found to be 30-fold increase in comparison to fluoxetine. The medication should be initiated at 10 mg daily for 1 week, increased to 20 mg daily for 1 week, and then administered at a recommended dose of 40 mg daily. The adherence to the schedule is purportedly important to minimize gastrointestinal adverse events. The time to peak plasma concentration is 4 to 5 hours after a single oral dose of 40 mg/day with food, which increases the bioavailability of vilazodone by 147% to 160%. The most commonly reported adverse effects with the treatment of vilazodone are mild to moderate in intensity and consist of diarrhea, nausea, dizziness, insomnia, vomiting, and abnormal dreams. The only clinically significant pharmacokinetic interactions documented involve the concomitant use of strong CYP3A4 inhibitors. Therefore, it is recommended that doses greater than 20 mg/day should not be administered with strong CYP3A4 inhibitors. The efficacy and safety of vilazodone treatment in older adults have yet to be established, thus it is recommended that vilazodone be used with caution in older adults.
Vortioxetine is a novel antidepressant that was approved recently by the FDA. This “multimodel” agent has affinity for 5HT1A and 5HT3A in addition to the serotonin transporter, which is hypothesized to produce a more robust antidepressant effects with fewer adverse effects as compared to other neurotransmitter reuptake inhibition. Only one published double-blind study exists involving 453 older depressed patients, showing that vortioxetine was well tolerated among older adults and may have beneficial cognitive effects. The recommended initial dose of vortioxetine is 10 mg once daily. The dose can be gradually titrated to a maximum of 20 mg/day as tolerated. The most common adverse events associated with vortioxetine are nausea, vomiting, headache, diarrhea, nasopharyngitis, hyperhidrosis, somnolence, dry mouth, and dizziness. There may be potential significant drug interactions in the form of increased vortioxetine levels when coadministered with bupropion (CYP2D6 inhibitor and CYP2B6 substrate), fluconazole (CYP450 2C9, 2C19, and 3A4 inhibitor), and ketoconazole (CYP3A4 and P-glycoprotein inhibitor) and decreased vortioxetine levels when it was coadministered with rifampicin (CYP inducer). It may be potentially inappropriate for use in older adults due to the risk of syndrome of inappropriate antidiuretic hormone secretion (SIADH) and for those at increased risk of falls.
Adverse effects and safety
Adverse effects are of particular concern in older adults, especially in the oldest old, frail, or medically ill. The most frequently reported adverse effects of SSRIs range from 1% to 17%, and include nausea, dry mouth, constipation, diarrhea anorexia, drowsiness, dizziness, lethargy, sleep disturbance, tremor, and anxiety. SSRIs have also received significant attention in the treatment of patients with ischemic heart disease, congestive heart failure, and immediately postmyocardial infarction. Evidence shows generally no increased cardiac risk, with no effects of SSRIs on blood pressure, cardiac conduction, or arrhythmias (with the notable exceptions of citalopram and escitalopram). Patients with bradycardia or those taking β-blockers may, however, experience a further reduction in heart rate. Though the SSRIs are well tolerated by older adults, caution should be exercised. Following initial treatment, some patients may experience gastrointestinal (GI) difficulties (eg, nausea), and there is slight potential for GI or postsurgical bleeding, especially when combined with nonsteroidal anti-inflammatory medications (NSAIDs) or low-dose aspirin. SSRIs may decrease platelet activation, affecting platelet aggregation, prolonging bleeding time. Proton pump inhibitors (PPIs) may lower that risk of GI bleeding when used in conjunction with an SSRI. Hyponatremia, is a possible consequence of SSRI use and should be assessed early in treatment or if there is a change in cognitive status. Concomitant use, or use within 3 to 4 weeks of cessation, of MAOIs can lead to the potentially fatal serotonin syndrome.
While Parkinson patients are able to tolerate SSRIs, SSRI use may cause EPS in some older patients. Antidepressant use is associated with risk for falls and hip fractures, and prolonged use of SSRIs may affect bone metabolism leading to an increased risk of fragility fractures. The risk of fractures was higher for new patients using SSRIs who initiated their medication in the last 30 days in comparison with continuous users. Risk for suicide in the first month of SSRI treatment may be elevated in older adults; however, there is a significant decrease in suicidal ideation in patients taking SSRIs versus placebo. This suggests that there may be a small subgroup susceptible to suicidal ideation during the first month of treatment with SSRIs.
Serotonin Norepinephrine Reuptake Inhibitors
The serotonin norepinephrine reuptake inhibitors (SNRIs) are a relatively recent class of antidepressants that are considered second-line therapy for late-life depression. The three drugs that are currently available are duloxetine, venlafaxine, and desvenlafaxine. These drugs are known to involve a dual action on both major monoamines involved in depression, which are noradrenaline and serotonin. The dual reuptake ensures efficacy that is comparable to TCAs and may be higher than SSRI, particularly in the treatment of severe depression. The use of SNRIs is associated with an increased rate of response as well as remission, decreasing the risk of relapse and recurrence of depression in late life. The absence of affinity for muscarinic, histaminic, α1-adrenergic, opioid of GABAergic receptors, and the absence of action on monoamine oxidase limits the adverse effects, which allows for greater tolerability than TCAs. In randomized clinical trials involving older adults with late-life depression, however, there were no significant differences between the benefits in treatment with SSRIs and SNRIs, though adverse effects have been observed to be more frequent with the use of SNRIs.
Efficacy and tolerability of duloxetine in young adults are supported by several randomized, controlled trials in patients with major depression, pain associated with diabetic neuropathy, and stress urinary incontinence. In older adults, duloxetine is efficacious for the treatment of depression and associated pain symptoms (headaches, backaches, and arthralgias) as compared to placebo. Duloxetine was also found to improve cognitive performance and quality of life as compared to placebo among depressed older patients with medical comorbidity. Duloxetine inhibits both serotonin and norepinephrine reuptake, and aging does not seem to affect its pharmacokinetic profile. Initial doses in older adults should be started at 20 mg/day. Increases can be made to a maximum of 60 mg/day as a single or divided dose. Duloxetine is immediately absorbed following oral administration and the presence of food tends to reduce the rates of absorption by about 10%.Duloxetine moderately inhibits CYP2D6 and CYP3A4. Although it is reported to have minimal effects on heart rate and blood pressure in healthy young adults, duloxetine’s action on norepinephrine may have greater implications for older patients with heart disease. In the absence of further evidence of the safety of this antidepressant in the treatment of older adults, duloxetine should be used cautiously as it has been reported that there is a possibility of increased risk of falls.
Venlafaxine is a serotonin-norepinephrine reuptake inhibitor that can be used as a first-line alternative to SSRIs for the treatment of depression among older adults and as a preferred agent in those who do not respond to SSRIs. Venlafaxine appears to be less well tolerated than sertraline, but as tolerable as citalopram. Meta-analytic data indicate that venlafaxine is as efficacious as SSRIs in the treatment of depression in younger adults with possibly greater rates of remission rates. Such benefits may be further enhanced in women of 50 years or older. Geriatric trials of this antidepressant have included patients with atypical depression, dysthymia, and poststroke depression. Venlafaxine is also effective for late-life GAD and chronic pain. Venlafaxine’s effects on the serotonergic system tend to occur at lower doses. Typically, the extended-release formulation of the drug is prescribed. The initial starting dose for venlafaxine extended-release is 37.5 mg/day to a maximum daily dose of 225 mg/day. Dose adjustments are required for those with renal failure. Patients may experience a similar side effect profile as with SSRI use, including GI distress, headaches, sexual dysfunction, serotonin syndrome, the syndrome of inappropriate antidiuretic hormone secretion, and hyponatremia. Symptoms associated with the discontinuation of venlafaxine may also occur, regardless of drug preparation type. In addition, side effects associated with the adrenergic system can occur, such as dry mouth, constipation, increased ocular pressure, cardiovascular difficulties, and agitation. Hypertension results in a dose-dependent fashion, with hypotension, electrocardiographic changes, arrhythmia, and acute ischemia also possible when taking venlafaxine. Experts discourage the use of venlafaxine in patients with heart disease, and recommend close cardiac monitoring for patients on higher dosages. While venlafaxine has minimal effect on the CYP450 system, it is metabolized by CYP2D6. Thus, poor 2D6 metabolizers or patients taking other drugs inhibiting this isozyme may have higher concentrations of venlafaxine. Of note, venlafaxine is clinically well known to cause significant withdrawal symptoms if stopped abruptly. It should therefore be gradually tapered over days to weeks as clinically indicated.
Desvenlafaxine is the major active metabolite of venlafaxine. Similar to its parent drug, desvenlafaxine is a serotonin and norepinephrine reuptake inhibitor. It is reported to have 10 times greater activity for neurotransmitter uptake compared with the norepinephrine monoamine. Desvenlafaxine was shown to reduce anxiety and improve overall functional quality-of-life outcomes. The effective doses of desvenlafaxine were found to range from 50 to 400 mg/day; however, doses greater than 50 mg/day were associated with increased adverse effects in a dose-dependent fashion with little-to-no added clinical benefit. The time to peak plasma concentration is 7.5 hours after administration and steady-state plasma concentrations are achieved after 4 days. In older patients with concurrent hepatic dysfunction or renal impairment, doses of greater than 50 mg/day should be prescribed with caution due to the limited evidence of added benefit greater than 50 mg/day. Desvenlafaxine is associated with several mild adverse effects such as dizziness, dry mouth, insomnia, decreased appetite, and with the most common side effect being nausea. The less common, but more serious adverse effects reported are hypertension, QTc interval prolongation, elevated lipids, elevated liver enzymes, and exacerbation of ischemic cardiac diseases.
Other Commonly Used Antidepressants
For older patients who are unresponsive to, or are unable to tolerate the use of SSRIs or SNRIs, antidepressants with novel mechanisms such as bupropion and mirtazapine may be used alternatively. Open-label, and small controlled clinical trials support the use of bupropion (response rate, 71%) and mirtazapine (response rate, 47%) in patients with late-life depression; however, data from rigorous placebo-controlled trials are lacking. These medications therefore should be prescribed as single agents to limit adverse effects and drug interactions; however, they are often effective adjuncts in those who partially respond to SSRIs or SNRIs.
Nonresponders to SSRIs, or those older depressed patients who cannot tolerate SSRIs, may benefit from bupropion on its own or augmented another antidepressant. For example, bupropion is favored in patients experiencing nausea, diarrhea, severe fatigue, or sexual dysfunction with SSRI use. This antidepressant is well tolerated in medically ill patients, including those with heart disease, those that smoke, and patients with neuropathic pain. Bupropion was shown to have similar efficacy to imipramine and paroxetine in depressed older patients. Typically, the sustained or extended-release formulations are prescribed. Starting-dose recommendations for older patients are 100 mg daily of the sustained-release tablets, or 150 mg/day of the extended-release formulation. Increases consistent with initial dosages can be made every 3 to 7 days up to a maximum of 300 mg/day. Bupropion is rapidly absorbed following oral administration with nearly 100% bioavailability. Patients with renal impairment should be initiated at a reduced dose because bupropion metabolites may accumulate in these patients. Bupropion should be avoided in patients at risk for seizures or psychotic symptoms. Although seizures are infrequent at therapeutic doses, those with an established seizure disorder or electrolyte disturbances, such as eating disorder patients, are at an elevated risk. Case reports have shown an association between the emergence of psychosis and the initiation of bupropion possibly owing to its action on the dopaminergic system. Bupropion is a moderate inhibiter of CYP2D6. As a substrate of CYP2B6, medications inhibiting this isozyme (eg, fluoxetine, paroxetine) may increase bupropion’s plasma concentration.
By blocking α2-autoreceptors, mirtazapine enhances noradrenergic and specific serotonergic transmission. Patients who do not tolerate SSRIs because of sexual dysfunction, tremor, or severe nausea may respond well to mirtazapine. This drug has also shown success in the treatment of depressed oncology patients receiving chemotherapy. Mirtazapine is as effective in the treatment of late-life depression as low-dose amitriptyline and marginally superior to paroxetine, yet no placebo-controlled trials have been published. The recommended starting dose of mirtazapine in older patients should be 15 mg at bedtime to a maximum dose of 45 mg. Its concurrent use with other SSRIs raises concerns of increased risk for serotonin syndrome in older adults, however, its coadministration with SSRIs is generally well tolerated. Cognitive impairment and excess sedation in older patients are of concern, likely as a result of its antihistaminergic properties. For similar reasons, the drug is associated with driving impairment. Drug-drug interactions are of minimal concern when taking mirtazapine, as it has little effect on the CYP450 system.
Tricyclic antidepressants and monoamine oxidase inhibitors
Once widely prescribed for the treatment of depression, TCAs have largely been supplanted by SSRIs as the treatment of choice. TCAs have been studied in numerous randomized, placebo-controlled, and comparator trials. They have similar efficacy to that of SSRIs in the treatment of late-life depression. Though these studies demonstrate the efficacy of TCAs in treating late-life depression, most do not account for optimal dosing strategies using serum level monitoring. MAOIs have also shown antidepressant effects similar to TCAs. Both of these drug classes require significant efforts to prevent associated adverse events, many of which can be severe and toxic. As such, TCAs and MAOIs are considered third- and fourth-line treatments of geriatric depression, when SSRIs, SNRIs, or safer alternatives are ineffective.
Common side effects of the TCAs include sedation, orthostatic hypotension (leading to dizziness, falls, and fractures), and anticholinergic effects, such as dry mouth, blurred vision, constipation, confusion, and delirium. Nortriptyline, a secondary amine TCA, is better tolerated in older adults and has a lower tendency to result in orthostasis, falls, and anticholinergic effects. The optimal serum level for therapeutic response is 50 to 150 ng/mL. Toxicity tends to occur at serum levels greater than or equal to 300 ng/mL, but can occur at lower doses in older adults. The ability to attain meaningful serum levels allows for more accurate and effective dosing. Two open trials of nortriptyline found this medication to be effective in treating depression in older adults. Three randomized, comparator trials found that nortriptyline was as efficacious as paroxetine and sertraline in alleviating geriatric depression; however, paroxetine was better tolerated than the TCA, and sertraline was associated with better cognitive improvement. Starting doses are usually 10 to 25 mg before bedtime. Serum levels are taken within 5 to 7 days, and linear dosage adjustments can be made up to target serum levels of 50 to 150 ng/mL. Though nortriptyline is preferred to the tertiary TCAs (ie, amitriptyline, clomipramine, doxepin, imipramine), it is still associated with anticholinergic effects. Cardiovascular events are also a significant concern with tricyclics as even slight overdoses can result in lethal heart block or arrhythmia. Patients with ischemic heart disease should not be given TCAs due to the increased risk of sudden cardiovascular death.
MAOI use in older populations is infrequent. While these medications are associated with fewer cardiac and anticholinergic side effects, serious hypo- and hypertension or serotonin syndrome may result from the concurrent intake of other serotonergic medications or foods containing tyramine. Thus, it is crucial for patients taking MAOIs to adhere to strict dietary restrictions, inform all health care providers of MAOI use, and have their blood pressure monitored. Any signs of headache, stiff neck, nausea, or vomiting require an evaluation of blood pressure. If blood pressure is elevated, immediate medical attention is required. Though very rarely used in older adults owing to adverse events and dietary restrictions, phenelzine is the preferred MAOI as it is the most studied in older patients and is shown to be effective for the treatment of late-life depression. A transdermal patch form of selegiline is approved by the FDA to treat major depression. However, there is very limited geriatric experience with this medication and dietary restrictions are still recommended for higher dosages.