{mosimage}Nancy Byatt, DO, MBA
Harvard University Medical School
{mosimage}Rebecca Lundquist, MD
University of Massachusetts Medical School
Introduction
Late-life major depressive disorder (MDD) is a common disorder that is associated with severe symptoms and substantial functional impairment. With an estimated prevalence of 3% in people aged 60 years or more, MDD has growing health implications for the aging population. In addition, MDD is often associated with physical disability in this age group as well as a high mortality rate. Conditions leading to chronic pain, the presence of comorbid medical illnesses, social isolation, and dysphoria secondary to life-cycle issues predispose the elderly population to the development of depression. These factors also point elderly individuals with depression in the direction of more severe symptoms and a relatively poor outcome.
While it is a commonly known psychiatric disorder, depression in the geriatric population is under-recognized and under-treated, leading to unnecessary impaired social and occupational functioning.1 Studies suggest that approximately 25% of patients aged 65 years or more who have a chronic medical illness also experience symptoms of depression. Evidence supports the increased prevalence of depression in several specific chronic medical illnesses, including vascular disease, diabetes mellitus, and arthritis; the relative risk for depression is 2-3 times higher in these patients than in individuals without these comorbidities.1 Depression in the geriatric population has also been reported to be more somatic and less ideational than depression in younger adults. Elderly people who suffer from comorbid depression and medical illness have an increased morbidity and mortality.1 Authors have also noted a brittle response to antidepressant therapy and an increased risk for chronic depression in the elderly population.2 Safe, effective, well-tolerated antidepressants are needed for elderly patients with MDD, especially for those who are also struggling with chronic medical illness.1
TREATMENT OPTIONS FOR MDD IN THE ELDERLY
The evidence supports the use of selective serotonin reuptake inhibitors (SSRIs) as first-line therapy for MDD in all age groups. However, in view of their adverse effect profile and efficacy, atypical antidepressants may also be considered as a primary treatment option.3 The relatively high comorbid prevalence of conditions that lead to chronic pain and depression in the elderly population is of significance, given that a direct relationship between the intensity of pain and the degree of depression has also been established. In this subset of geriatric depression, clinicians should consider the use of serotonin-norepinephrine reuptake inhibitors (SNRIs) such as duloxetine or venlafaxine in view of the combined effect of this class of medication in treating both depression and the chronic pain condition.1
Studies also suggest that antidepressant drugs that combine the serotonergic and noradrenergic mechanisms of action are of comparable efficacy to SSRIs and may even be modestly more effective in the treatment of MDD.4 Studies also suggest that treatment with venlafaxine may be effective in geriatric patients with treatment-resistant MDD and is better tolerated than prescribing additional medication to augment antidepressant treatment.
PHARMACOLOGY AND PHARMACOKINETICS OF ATYPICAL ANTIDEPRESSANTS
SNRIs block the reuptake of both serotonin (5-HT) and norepinephrine with differing selectivity. They have been shown to be superior to placebo and have comparable efficacy to the tricyclic antidepressants (TCAs). SNRIs include venlafaxine and duloxetine and have an adverse effect profile similar to that of the SSRIs.5 A difference, however, between this class of antidepressants and other classes is the ability of SNRIs to effectively treat chronic pain irrespective of whether the pain is related to depression or unrelated.6 In addition to treating depression, duloxetine may also offer a new treatment for patients with neuropathic pain and stress urinary incontinence.7 Adverse effects specific to individual drugs have been documented; venlafaxine has been associated with hypertension and duloxetine has been associated with hepatotoxicity.
The dopamine-norepinephrine reuptake inhibitor (DNRI) bupropion primarily blocks the reuptake of dopamine and norepinephrine with no direct action on the serotonin system.8 Bupropion has been shown to have efficacy comparable to both TCAs and SSRIs in the treatment of MDD.5 Bupropion has a lower risk of sexual dysfunction and weight gain than some other antidepressants and is an effective alternative or adjunctive treatment for patients whose symptoms do not respond to SSRIs.8 Compared to SSRIs, treatment with bupropion has the disadvantage of an increased adverse effect profile that includes headaches, tremors, and seizures. The risk of seizures decreases at doses less than 450 mg and with divided dosing.5
The norepinephrine-serotonin modulator mirtazapine enhances the release of norepinephrine by blocking α2-adrenergic autoreceptors as well as serotonin 5-HT2A and 5-HT3 receptors and histamine H1 receptors. Its efficacy is similar to that of TCAs and SSRIs, and it is less likely to cause sexual adverse effects. Mirtazapine has been associated with weight gain and sedation, which can be helpful for patients who are also experiencing decreased appetite and insomnia.9
Serotonin modulators, which include nefazodone and trazodone, block the 5-HT2A serotonin receptor and serotonin reuptake and have an antidepressant efficacy similar to that of SSRIs. Nefazodone and trazodone and are less commonly used to treat depression because of their adverse-effect profiles of hepatoxicity and sedation, respectively. Trazodone is mainly used in clinical practice for its sedative properties separate from the treatment of depression.5
SPECIAL CONSIDERATIONS WHEN PRESCRIBING ATYPICAL ANTIDEPRESSANTS TO ELDERLY PATIENTS
The presence of high levels of pain in elderly patients may diminish the degree of response for the comorbid symptoms of depression for any given antidepressant therapy. The detection, diagnosis, and management of chronic pain should routinely include the identification and treatment of coexisting medical conditions that may contribute to or complicate late-life depression. Both the depression and the comorbid medical condition that is contributing to the depression should be treated from the outset.3
When prescribing an antidepressant to an elderly patient, the initial dose of the agent must be determined by individual symptom response, known adverse effect profile, drug-drug interactions, and any comorbid medical and psychiatric conditions. The initial dose selected may be smaller than that prescribed to younger patients because of age-related physiological changes such as impaired hepatic and renal elimination that can result not only in higher serum concentrations of the drug for a given dose but also in a higher likelihood of adverse effects. As a general rule of thumb, clinicians should “start low and go slow” when prescribing antidepressants to elderly patients.10
While venlafaxine may be effective and be associated with fewer drug-drug interactions and a generally favorable adverse effect profile, it is associated with some undesirable cardiovascular effects, such as hypertension, orthostatic hypertension, and new-onset tachycardia or palpitations. Systematic monitoring of cardiovascular parameters is strongly recommended in elderly patients, especially those who are taking more than 150 mg of venlafaxine per day.11
Mirtazapine, like SSRIs, has been reported to uncommonly cause hyponatremia. While this adverse effect is uncommon, it should be considered in any elderly patient with altered mental status who has recently started to take mirtazapine.12
The issue of drug-drug interactions is of particular relevance for geriatric patients because of the increased likelihood of polypharmacy for comorbid illnesses. Polypharmacy may lead not only to notable adverse effects as a result of the interaction of medications but also to an increased risk of known adverse effects from the prescribed antidepressant. The antidepressants with the least potential for altering drug metabolism are some of the SSRIs, such as citalopram, and the selected atypical antidepressants, such as venlafaxine, duloxetine, and mirtazapine.13
REFERENCES
Wise TN, Wiltse CG, Iosifescu DV, et al. The safety and tolerability of duloxetine in depressed elderly outpatients with and without medical comorbidity. Int J Clin Pract. 2007:61(8);1283-93.
Meltzer CC, Price JC, Mathis CA, et al. Serotonin 1A receptor binding and treatment response in late-life depression. Neuropsychopharmacology. 2004;29(12):2258-65.
Alexopoulos GS, Katz GS, Reynolds CF, et al. The expert consensus guidelines series. Pharmacotherapy of depressive disorders in older patients. Postgrad Med. 2001;Oct:1-86.
Papakostas GI, Thase ME, Fava M, et al. Are antidepressant drugs that combine serotonergic and noradrenergic mechanisms of action more effective than the SSRIs in treating major depressive disorder? A meta-analysis of studies of newer agents. Biol Psychiatry. 2007;[Epub ahead of print].
American Psychiatric Association. Practice guideline for the treatment of patients with major depressive disorder (revision). Am J Psychiatry. 2000;157(4 Suppl):1-45.
Stahl SM, Grady MM. Moret C, Briley M. SNRIs: their pharmacology, clinical efficacy, and tolerability in comparison with other classes of antidepressants. CNS Spectr. 2005;10(9):732-47.
Westanmo AD, Gayken JM, Haight R. Duloxetine: a balanced and selective norepinephrine- and serotonin-reuptake inhibitor. Am J Health Syst Pharm. 2005:62;2481-90.
Papakostas GI. Dopaminergic-based pharmacotherapies for depression. Eur Neuropsychopharmacol. 2006:16(6);391-402.
Mann JJ. The medical management of depression. N Engl J Med. 2005;353(17):1819-34.
Antai-Otong D. Poststroke depression: psychopharmacological considerations. Perspect Psychiatr Care. 2004:40(4);167-70.
Johnson EM, Whyte E, Mulsant BH, et al. Cardiovascular changes associated with venlafaxine in the treatment of late-life depression. Am J Geriatr Psychiatry. 2006:14(9);796-802.
Ladino M, Guardiola VD, Paniagua M. Mirtazapine-induced hyponatremia in an elderly hospice patient. J Palliat Med. 2006:9(2);258-60.
Levy RH, Collins C. Risk and predictability of drug interactions in the elderly. Int Rev Neurobiol. 2007:81;235-51.
