In this chapter, we focus on the use of psychotherapeutic medications in the elderly, including the antidepressant, psychostimulant, antipsychotic, mood stabilizer, and anxiolytic medications that are used to treat the psychiatric disorders of late life, including major depression, anxiety, and the psychosis and behavioral disturbances that frequently accompany Alzheimer’s disease (AD) and related disorders.

Mood and behavioral disturbances are of particular concern in the elderly. Late-life depression, including major depressive disorder and dysthymia, affects 5% to 12% of older adults. These rates are consistent with those in younger adults; however, the elderly face a disease profile that is more chronic and treatment resistant with an element of cognitive impairment. Frequently, depression in elderly, community dwelling individuals remains unidentified and untreated. Depression occurring past age 60 is likely distinct from that which occurs in younger age groups. It has been associated with significant vascular disease as evidenced in the imaging literature, and with low testosterone levels in older dysthymic men. This idiosyncratic disease profile may account for treatment resistance. For example, structural abnormalities in frontal white matter have been linked to a poorer remittance of depressive symptomatology.

Late-life depression leads to further deterioration in quality of life, as well as increasing risk for dementia and suicide. Depressed elders suffer greater rates of disability, mortality, and nursing home placement. Furthermore, when depression co-occurs with other medical or psychiatric illness, it negatively alters the disease process. For example, cardiac mortality is increased in depressed patients with unstable angina, postmyocardial infarction, or congestive heart failure, and comorbid anxiety impairs interpersonal function and leads to greater severity of physical symptoms. Consequently, the effects of depression result in greater strain on an already overburdened health care system.

Anxiety disorders are also highly prevalent in older adults, between 2% and 19% in community dwelling elders, with the most common forms being generalized anxiety disorder (GAD) and phobias. Anxious symptomatology not meeting criteria for a clinical diagnosis is experienced by a further 20% of elderly individuals. Late-life anxiety can co-occur with physical illness, depression, or side effects of medication use. Risk factors for anxiety in elders include cognitive and physical impairments, economic difficulties, and social segregation.

Older anxious individuals experience greater physical disability and cognitive impairment, as well as reduced ability to carry out activities of daily life. Quality of life is diminished and risk of mortality and coronary artery disease (particularly in men) is greater when anxiety is present in later life. Anxious elders are prone to excessive use of medical services, with anxiety disorders comprising 38% of mental health claims as compared to 21% for affective disorders.

Behavioral instability, including agitation, aggression, and psychosis, also appears frequently in late-life, especially when associated with dementia. Approximately 2% to 5% of elderly individuals 60 years of age or older suffer from dementing illnesses, while 15% to 40% of those older than 85 develop dementia. At some point in the course of dementia, most nursing home and community dwelling patients experience behavioral dysfunction and/or psychosis. For example, studies indicate that 10% to 70% of dementia patients experience psychotic symptoms. In a 4-year study, primary psychosis in patients with AD was reported to occur in 51% of patients. Across samples of AD patients, delusional symptoms, frequently related to theft or suspicion, can present in as many as 50% of patients. Hallucinations, typically related to phantom boarder syndrome (the belief that another person is in one’s home), can involve either visual or auditory stimuli, and have been reported in 5% to 15% of dementia patients.

Alterations of personality can develop early in the course of illness. Such changes include depression, apathy, irritability, emotional withdrawal, and disinhibition (e.g., wandering, aggression, repetitive calling out or screaming). More severe reactions associated with frustration can include angry or violent outbursts. Such psychopathology can be particularly troublesome for caregivers. Patients may become stubborn, combative, or neglectful of activities essential to daily life. As such, many caregivers are compelled to institutionalize their loved ones. Both in long-term care residents and community dwelling elderly, patients experiencing behavioral or psychological symptoms of dementia (BPSD) are at increased risk for mortality. Incidence of increased extrapyramidal symptoms (EPS) and greater cognitive decline has also been associated with BPSD. The use of psychotropic medications to treat these conditions is second only to the use of cardiovascular medications among older patients, including the frail and chronically ill elderly. Nearly one in five community dwelling elders and 47% of nursing home residents were found to be taking regular psychotropic medications. However, the basic pharmacokinetic and clinical evidence base underlying this use is limited. In fact, most psychiatric medications have been tested only in younger and healthier patients, prior to their release.

There are indications that this limited knowledge base can compromise care in elders. In an acute geriatric medical unit, a recent study found that the prevalence of adverse drug reactions (ADRs) was 16% on admission for those patients taking appropriate medications and that 66% of admissions were preceded by at least one inappropriate medication. In the long-term care setting, psychoactive medications (antipsychotics, antidepressants, and sedative/hypnotics) and anticoagulants were the most common medications associated with ADRs, and neuropsychiatric events were the most common manifestations of preventable ADRs. There is also evidence that commonly used antidepressants may have limited efficacy and more adverse effects in the oldest old and frail elderly, and that the atypical antipsychotic agents often used for the treatment of the psychotic and aggressive symptoms in dementia may lead to cerebrovascular events and increased mortality in nursing home residents.

As with other medications, the treatment of older patients with psychotropics is also complicated by age-associated pharmacokinetic and pharmacodynamic changes, which are exacerbated by illness and their concomitant potential for drug–drug interactions and poor adherence. An additional complication for psychotropics is the lack of diagnostic precision and pathophysiologic understanding of what is being treated. Psychotropic treatment is based on treating symptoms that have a heterogeneous etiology. The strategy for drug discovery in psychiatry has relied upon the serendipitous observation of symptomatic benefit of a known drug, study of the mechanisms of that compound, and efforts to develop similar compounds with improved efficacy and tolerability. The limitations of this approach are evident in the treatment of “psychoses” in dementia, as if it were the same disorder as schizophrenia in younger patients. Similarly, depression appearing later in life may be associated with ischemic injury or associated with the development of AD. For currently available psychotropics, there have been few studies of their “real world” comparative effectiveness. One example is the recently published Clinical Antipsychotic Trials of Intervention Effectiveness-Alzheimer’s Disease (CATIE-AD), which found an unfavorable risk to benefit ratio for use of atypical antipsychotic medications in patients with AD. It is also difficult to demonstrate efficacy when there is variability in drug exposure. The recent use of population pharmacokinetic methodologies in elderly psychiatric patients treated with antidepressants or antipsychotics is beginning to demonstrate the extensive interindividual differences in drug clearance for these medications.

Selective Serotonin Reuptake Inhibitors

The selective serotonin reuptake inhibitors (SSRIs) are considered first-line pharmacotherapy for late-life depression. These drugs act on the serotonergic system by blocking the reuptake of this neurotransmitter. In comparison with other antidepressants, the SSRIs generally have a more favorable side effect profile and are well tolerated. They are also markedly safer than tricyclic antidepressants 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. SSRIs have received substantial attention in the treatment of anxiety in younger adults, however, only a single placebo-controlled trial and two open label studies have suggested efficacy in anxious elderly patients. Limited evidence supports the efficacy of SSRIs in treating dementia related behavioral disturbances, such as agitation, disinhibition, delusions, and hallucinations.

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 preferable to fluvoxamine, fluoxetine, or paroxetine. In the elderly, starting dosages are administered in one daily dose, and are half the amount administered in younger populations (Table 63-1). Dosages can be doubled after a week of use. Fluvoxamine is the only SSRI that should be given according to a twice-daily dosing regimen.

Fluoxetine

The first SSRI to become available on the market in 1988 was fluoxetine. This drug ushered in a new era of treatment, providing an alternative to the tricyclic antidepressants. 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 the elderly 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. Thus, it is crucial to consider interactions with other medications metabolized by these enzymes to avoid drug accumulation and toxicity (Table 63-2).

Sertraline

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 elderly patients is typically initiated at 25 mg or 50 mg, with increases occurring after 7 days to a daily maximum of 200 mg. This SSRI does require titration, with one study of frail nursing home patients noting 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