Steven P. Roose, M.D.
Bruce G. Pollock, M.D., Ph.D.
D. P. Devanand, M.D.
Adverse events caused by medication are a significant cause of morbidity and mortality in the elderly. In a large study of ambulatory Medicare enrollees, 38% of adverse drug events were serious, life-threatening, or fatal and 28% were considered preventable (Gurwitz et al. 2003). Moreover, psychotropics are among the most common medications associated with preventable adverse drug events in elderly patients in long-term care settings (Gurwitz et al. 2000).
In general, age-associated pharmacokinetic changes result in higher and more variable drug concentrations. Nonetheless, specific information on the pharmacokinetics of most psychoactive medications is inadequate, particularly with regard to medical comorbidities and potential drug interactions. The limited information that does exist for older subjects is largely derived from classical pharmacokinetic modeling. Traditional pharmacokinetic studies require a large number of plasma drug samples obtained from a small number (i.e., 6–12) of volunteers. These single-dosage pharmacokinetic studies usually are not adequate to rule out the possibility of nonlinear kinetics. Moreover, age or illness-associated differences in pharmacodynamics are not interpretable in the absence of drug concentration data. Population pharmacokinetics provides a means for addressing heterogeneous drug exposure for elders using minimal sampling methods (Bigos et al. 2006). For example, using this approach, we have examined age and cytochrome P450 (CYP) genotype effects for citalopram, escitalopram, and paroxetine (Bies et al. 2004; Feng et al. 2006; Jin et al. 2010).
Although individuals older than 65 years account for more than one-third of prescription drug expenditures in the United States, they are often excluded from clinical and regulatory trials. In addition, the trials that do include elders rarely include the “oldest old” (i.e., 85+ years), those having multiple comorbidities, or those taking multiple medications. These exclusions raise questions about the generalizability of psychotropic data to the frail elderly.
Age-associated pharmacokinetic differences may be due to changes in absorption, distribution, metabolism, or elimination of a drug (Table 56–1). The multidimensional changes associated with aging are heterogeneous, and only generalizations can be made (Lotrich and Pollock 2005).
Organ system |
Change |
Pharmacokinetic consequence |
Gastrointestinal tract |
Decreased intestinal and splanchnic blood flow |
Decreased rate of drug absorption |
Circulatory |
Decreased concentration of plasma albumin and increased α1-acid glycoprotein |
Increased or decreased free concentration of drugs in plasma |
Kidney |
Decreased glomerular filtration rate |
Decreased renal clearance of active metabolites |
Muscle |
Decreased lean body mass and increased adipose tissue |
Altered volume of distribution of lipid-soluble drugs, leading to increased elimination half-life |
Liver |
Decreased liver size; decreased hepatic blood flow; minimal effects on cytochrome P450 enzyme activity |
Decreased hepatic clearance |
Although absorption of nutrients is often impaired in the elderly, the rate and extent of passive drug absorption are not affected by normal aging. Antacids, high-fiber supplements, and cholestyramine may significantly diminish the absorption of medications.
For most psychotropics that are lipid soluble, the loss of lean body mass with aging will lead to increases in their volumes of distribution, resulting in longer half-lives and drug accumulation. This is because a drug’s half-life is directly proportional to its apparent volume of distribution. Conversely, for water-soluble drugs such as lithium and digoxin, volumes of distribution will be diminished in older patients, reducing the margin of safety after acute increases in plasma drug concentration.
Reductions in serum albumin with age and possible increases in α1-acid glycoprotein with illness may affect the extent of drug bound to plasma proteins. However, it is now recognized that changes in plasma protein binding are of clinical significance only when therapeutic drug monitoring is used to adjust dosing, because total drug concentrations (free+protein bound) are usually reported (Benet and Hoener 2002). Total drug levels may be interpreted as too low if a drug’s free fraction is increased by diminished plasma proteins or drug displacement. The use of free drug levels in older patients has been found to be useful for lidocaine, theophylline, phenytoin, and digitoxin.
Available evidence suggests that there is no uniform age-associated decline in liver metabolism by CYP enzymes (Pollock et al. 1992b; Schmucker 2001). Nonetheless, reductions in hepatic mass and blood flow with aging place greater emphasis on interindividual differences in drug metabolic capacity. These metabolic differences may be either genetic or the result of interactions from multiple medications. Enzyme specificity suggests that inhibition or induction of a given CYP enzyme will affect all drugs metabolized by that specific enzyme. Updated information on CYP-mediated drug–drug interactions is available at the University of Indiana School of Medicine’s “Drug Interactions” Web page (see Flockhart 2007).
CYP2D6 is the enzyme responsible for metabolizing tricyclic antidepressants (TCAs) and venlafaxine as well as several older antipsychotics and risperidone. Among the white population, 5%–10% are genetically poor CYP2D6 metabolizers.
Drugs metabolized by CYP3A4, such as alprazolam, triazolam, sertraline, and mirtazapine, appear to be cleared less well in elderly patients (Greenblatt et al. 1991; Ronfeld et al. 1997; Timmer et al. 1996). However, this may be because metabolism of CYP3A4 drugs is typically perfusion limited (i.e., dependent on hepatic blood flow, which is known to decline substantially with age) (Wynne et al. 1990). CYP3A4 makes up 30% of total hepatic CYP and nearly all of drug-metabolizing enzyme in the small bowel, and therefore is substantially responsible for “first-pass” or presystemic drug disposition (Shimada et al. 1994). Serious toxicity has occurred when the 3A4-mediated clearance of terfenadine, astemizole, cisapride, cerivastatin, midazolam, and triazolam was inhibited (Dresser et al. 2000). CYP3A4 activity may be inhibited by grapefruit juice, protease inhibitors, macrolide antibiotics, and triazole antifungals. Among antidepressants, fluvoxamine is the most potent inhibitor of CYP3A4, followed by fluoxetine, through its demethylated metabolite. The very long half-life of norfluoxetine may result in interactions occurring many weeks after the initiation of fluoxetine treatment. The 3A4 enzyme is also potently induced by other drugs, such as carbamazepine, phenytoin, topiramate, modafinil, barbiturates, steroids, and St. John’s wort. CYP3A4 induction will increase the likelihood of therapeutic failure for concurrently prescribed 3A4 substrate drugs. Many CYP3A4 inhibitors (e.g., diltiazem) and inducers (e.g., St. John’s wort) also have been found to inhibit or induce the P-glycoprotein drug transporter, amplifying their effects on 3A4 (Yu 1999).
CYP1A2 metabolizes clozapine, olanzapine, fluvoxamine, and theophylline and contributes to the demethylation of some tertiary TCAs. This enzyme is induced by cigarette smoking, cruciferous vegetables, and charcoaled meats. CYP 2C9 metabolizes several drugs with a narrow therapeutic index (i.e., phenytoin, tolbutamide, ibuprofen, and warfarin). It is therefore important to recognize that this enzyme may be inhibited by fluvoxamine and fluoxetine.
Age-associated decline in renal clearance may affect excretion of psychotropic drug metabolites and lithium in older patients. The magnitude of this decline varies greatly among the aged (Pollock et al. 1992b), being exacerbated by concomitant conditions (e.g., diabetes and hypertension) and medications (e.g., nonsteroidal anti-inflammatory drugs). Accumulation of active TCA metabolites in the elderly was previously a subject of concern (Pollock et al. 1992a). Higher concentrations of bupropion and venlafaxine metabolites also have been observed in older patients and those with renal impairment, with uncertain clinical consequences.
Interindividual differences in pharmacodynamics become evident when those with similar plasma drug concentrations experience different effects. In general, older patients are more sensitive to adverse effects of psychotropics at lower concentrations. Homeostatic mechanisms, such as postural control, water balance, orthostatic circulatory responses, and thermoregulation, are frequently less robust in the aged. This factor may interfere with the ability to physiologically adapt to medication. For example, all psychotropics, including selective serotonin reuptake inhibitors (SSRIs), may increase the risk of falls and hip fractures (Liu et al. 1998). Similarly, the syndrome of inappropriate antidiuretic hormone secretion has been reported as an age-associated adverse effect of all SSRIs and of venlafaxine (Kirby and Ames 2001).
Reductions in dopamine or acetylcholine function with age may increase sensitivity to antipsychotics and SSRIs (which indirectly reduce dopamine outflow) as well as medications with antimuscarinic effects (Gerretsen and Pollock 2011; Graff-Guerrero et al. 2015). Even low serum anticholinergic levels may be associated with cognitive impairment in depressed and nondepressed elderly persons (Mulsant et al. 2003; Nebes et al. 2012). Unfortunately, anticholinergic drugs continue to be widely prescribed in older patients (Chew et al. 2008; Roe et al. 2002).
Anticoagulant–antidepressant interactions may be both pharmacokinetic and pharmacodynamic. Fluvoxamine and fluoxetine pose the greatest risk of pharmacokinetic interactions through CYP2C9 inhibition, reducing the clearance of warfarin’s active S-enantiomer. However, increased bleeding times with SSRIs alone or in combination with anticoagulants or nonsteroidal anti-inflammatory drugs also may be possible as a result of depleting platelets of serotonin and attenuating their aggregation (Pollock et al. 2000b; Shin et al. 2015).
At present, there is only limited evidence that genetic differences may influence pharmacodynamics in older patients. Depressed elderly patients with the long–long (LL) serotonin transporter promoter genotype were found to have a more rapid initial response to paroxetine (Pollock et al. 2000a). This is consistent with results obtained with other SSRIs in younger patients (Serretti et al. 2006). Another study in geriatric major depression found that carriers of the short (S) allele experienced more severe adverse events during paroxetine treatment (Murphy et al. 2004). Interestingly, findings in Koreans with late-life depression were in the opposite direction—that is, better responses among carriers of the S allele (Kim et al. 2006).
The combined prevalence of major depressive disorder and dysthymia in late life is 5%–12% in epidemiological studies; this rate is similar to the rate in the younger adult population. However, the symptom pattern and frequency of specific depressive subtypes appear to be different; older patients have more somatic symptoms, and both the melancholic and the delusional subtypes of depression increase in frequency in older populations. In addition, some degree of cognitive impairment, whether manifesting only concurrently with the depressive episode or as a function of age, is common.
As in younger patients, untreated depression in late life causes significant social, vocational, and interpersonal morbidity, and depression in late life is associated with a significant risk of mortality. Comorbid depression adversely affects the course of several disease processes; this has been best documented for ischemic heart disease. Patients with unstable angina, post–myocardial infarction, or congestive heart failure who are depressed have a higher cardiac mortality rate than do medically comparable patients who are not depressed (Musselman et al. 1998). Furthermore, the suicide rate in men (in the United States, specifically white men) increases dramatically after age 60 years and continues to rise significantly as a function of age.
Considering the physiological changes associated with aging and the differences in the phenomenology and possible etiology of depression in late life compared with earlier in life, it is expected that clinical trials of antidepressants in late life will have a unique set of patient moderators and study design mediators that may significantly affect results. Variability in results of randomized controlled trials of antidepressants in late-life depression may result from heterogeneity in the patient population. Treatment moderators that have been identified as significant for late-life depression include the following:
Subtype (e.g., melancholic or atypical)
Severity
Medical burden
Social support
Abnormalities on magnetic resonance scans indicating vascular disease
Pattern of neurocognitive abnormalities labeled “executive dysfunction”
With respect to mediators of treatment response, the standard considerations in study design—namely, randomization, placebo versus comparator control, dosage, duration, and criteria for response and remission—are all important, but specifically the value of placebo-controlled trials versus comparator trials and optimal duration of treatment have been systematically reexamined. Sneed et al. (2008) conducted a meta-analysis of all studies published in peer-reviewed journals from 1985 to 2006 that were randomized placebo-controlled or comparator (a comparison of two active conditions) trials of antidepressants for the treatment of late-life depression. The intent of the meta-analysis was to determine whether rates of response to medications in comparator trials are significantly higher than rates of response to comparable medications in placebo-controlled trials—that is, whether study design significantly affects treatment outcome. Sixteen studies (9 comparator trials and 7 placebo-controlled trials) met the rigorous inclusion criteria for the meta-analysis. As hypothesized, antidepressant response rates were significantly higher in the comparator trials compared to placebo-controlled trials; the estimated probability of antidepressant response in a placebo-controlled trial was 46% as compared with 60% in a comparator trial. One possible explanation for the higher response rate to the same medication in a comparator trial is that patient, doctor, and even research rater expectations of response are higher when it is known that the subject is receiving an active medication. Irrespective of the reason that response rates are higher in comparator trials, the results of the study suggest that when clinicians want to make evidence-based treatment decisions and communicate likelihood of response to patients, data from comparator trials may be more appropriate than results of placebo-controlled trials, since comparator trials more closely approximate the clinical situation in that both patient and doctor know that an active medication is being prescribed.
Most of the placebo-controlled trials involving TCAs were done before the use of plasma-level measurements to ensure optimal TCA treatment. Later randomized controlled trials that compared TCAs with SSRIs were invariably supported by the pharmaceutical industry, which had no desire to compare their new compound against optimal TCA treatment. Consequently, the preponderance of studies of TCA treatment in late-life depression reported inadequate dosages of the tertiary-amine TCAs amitriptyline and imipramine. Nonetheless, the results of these studies established that TCAs are an effective treatment for depression in geriatric patients.
Nortriptyline. Of the TCAs, nortriptyline has been found to induce the least orthostatic hypotension and has a documented “therapeutic window” that permits optimal dosing (Roose et al. 1981). Consequently, nortriptyline has emerged as the choice of this class of medications issued to treat late-life depression. However, there are no rigorous placebo-controlled trials of nortriptyline in late-life depression; thus, the relative effectiveness of this medication is inferred from two open trials and three randomized comparator trials.
In a study reported by Flint and Rifat (1996), 101 patients meeting DSM-III-R (American Psychiatric Association 1987) criteria for major depressive disorder were treated openly with nortriptyline. The dosing schedule was as follows: all patients achieved a daily dosage of 75 mg by the end of week 1, and then the dosage was adjusted if necessary to achieve a plasma level within the therapeutic window of 50–150 ng/mL. The treatment duration was 6 weeks, and the remission criterion was a final Hamilton Rating Scale for Depression (Ham-D; 17-item) score of 10 or less; 60% of the intent-to-treat sample and 75% of the completers met the remission criterion. To establish speed of response, the authors determined the week of treatment that the 61 patients who met the criterion for remission at the end of the study first achieved sustained remission. Not surprisingly, at the end of week 1, no patient met the criterion for remission, and thus the cumulative response rate was 0%. At week 2, 11% of the sample met the remission criterion, and at week 3, 33% met the remission criterion (thus, the cumulative rate at the end of week 3 was 11%+33%, or 44%). At weeks 4 and 5, 25% and 20%, respectively, met the remission criterion. Thus, the accumulated remission rate at the end of week 5 was 89%. Although it is widely believed that late-life depression patients should have longer treatment trials, specifically 12 weeks, this study found that 89% of the patients who eventually recovered did so by the end of week 5. A second open study of a therapeutic plasma level of nortriptyline reported on 42 inpatients (mean age: 70 years) with cardiac disease and melancholic depression who also were treated for 6 weeks (Roose et al. 1994). The remission criterion was a final Ham-D (21-item) score of 8 or less; the intent-to-treat remission rate was 67%, the completer remission rate was 82%, and the dropout rate was 19%.
Three randomized controlled trials compared nortriptyline with an SSRI; two studies compared a therapeutic plasma level of nortriptyline with paroxetine, and one study compared flexible-dose nortriptyline with sertraline. Mulsant et al. (2001a) compared nortriptyline with paroxetine in 116 inpatients and outpatients (mean age: 72 years) in a 12-week trial. Patients were considered to be in remission if the final Ham-D (17-item) score was 10 or less; the intent-to-treat remission rate was 57% for the nortriptyline group and 55% for the paroxetine group. The rate of dropout due to side effects in the nortriptyline group was significantly higher than that in the paroxetine group (33% vs. 16%; P=0.04).
A second randomized controlled trial comparing nortriptyline (targeted to a therapeutic plasma level) with paroxetine is included in this chapter, although technically it should not be considered a geriatric study because the mean age of the patients was 58 years (Nelson et al. 1999). However, it is the only other study comparing a therapeutic plasma level of a TCA with an SSRI, and the results are consistent with those of the Mulsant et al. (2001a) study. In this trial, 81 outpatients with ischemic heart disease were treated with medication for 6 weeks. The remission criterion was a final Ham-D (17-item) score of 8 or less; in the intent-to-treat analysis, 63% of the nortriptyline group and 61% of the paroxetine group were remitters. The dropout rate for nortriptyline (35%) was significantly higher than the dropout rate for paroxetine (10%) (P<0.05). The rate of remission in study completers was 85% for nortriptyline and 68% for paroxetine, which was not a statistically significant difference, although the power of this comparison was limited by the small size of the completer group.
The randomized controlled trial comparing sertraline with nortriptyline included 210 patients (mean age: 68 years) randomly assigned to 12 weeks of medication treatment (Bondareff et al. 2000). This study did not report remission rates but only response rates, defined as a 50% reduction in Ham-D (24-item) score from baseline. The response rates for nortriptyline and sertraline were 41% and 52%, respectively.
TCA side effects and safety. Unfortunately, despite their robust effectiveness, the clinical utility of TCAs in the late-life population is limited by their side-effect and safety profiles. TCAs have significant anticholinergic effects that result in dry mouth, constipation, urinary retention, and confusional states.
The major safety problem with respect to the TCAs is cardiovascular effects (Glassman et al. 1993). TCAs are lethal in overdose, and as little as three times the daily dosage can result in death from heart block or arrhythmias. The TCAs have type 1A antiarrhythmic activity similar to that of moricizine and quinidine and consequently are presumed to confer an increased risk of sudden cardiovascular death if given to patients with ischemic heart disease. Given the prevalence of occult and manifest ischemic heart disease in both men and women older than 60 years, the use of TCAs in this population must reflect a careful consideration of the risk–benefit ratio.
As in younger depressed patients, the SSRIs are the most prescribed class of antidepressants for late-life depression. Within this class, the various SSRIs appear to have equivalent efficacy and side-effect profiles. There are differences in pharmacokinetics and potential for drug–drug interactions, which are of importance in the geriatric population and have been discussed earlier in this chapter.
Fluoxetine. Four large studies of fluoxetine in late-life depression have been conducted: 1) a placebo-controlled study; 2) a three-cell study comparing venlafaxine, placebo, and fluoxetine; 3) a randomized controlled trial with a comparator drug; and 4) open treatment. In the first study, fluoxetine was compared with placebo in 671 patients (Tollefson et al. 1995). The dosing schedule was fluoxetine 20 mg/day for 6 weeks, and the remission criterion was a Ham-D (17-item) score of 7 or less after 4 weeks. The intent-to-treat analysis remission rate was 23% for fluoxetine and 13% for placebo; in the completer analysis, the remission rate was 27% for fluoxetine and 16% for placebo. Although fluoxetine was significantly more effective than placebo in both the intent-to-treat and the completer analyses, this was the first large SSRI trial in a geriatric population, and in comparison to the clinical experience with therapeutic plasma levels of TCAs, the remission rates in this study were disappointingly low.
In the comparator randomized clinical trial, patients were randomly assigned to receive either fluoxetine 20–40 mg/day or sertraline 50–100 mg/day for 12 weeks (Newhouse et al. 2000). The sample of 225 patients (mean age: 68 years) was somewhat unusual because the mean duration of the current episode of major depression was 9 years. The intent-to-treat remission rate was 46% for fluoxetine and 45% for sertraline, the completer remission rate was 60% for fluoxetine and 59% for sertraline, and the dropout rate was 33% for fluoxetine and 32% for sertraline. This study also reported an intriguing analysis of the response pattern of a subsample of 75 patients (42 treated with sertraline, 33 treated with fluoxetine) with a mean age of 75 years. For both sertraline and fluoxetine, 95% of the patients who achieved a 50% reduction in baseline Ham-D score did so by the end of week 8. As with the Flint and Rifat (1996) study of a therapeutic plasma level of nortriptyline, these data challenge the clinical wisdom that antidepressant trials in late-life depression must be extended to 12 weeks.
Finally, 308 patients meeting DSM-III (American Psychiatric Association 1980) criteria for major depressive disorder (mean age: 66 years) were treated openly with 20 mg/day of fluoxetine for 8 weeks (Mesters et al. 1992). The remission criterion was a final Ham-D (24-item) score of 10 or less; the intent-to-treat remission rate was 35%, the completer remission rate was 50%, and the dropout rate was 29%.
Sertraline. In addition to the two randomized controlled comparator trials previously described, nortriptyline versus sertraline and fluoxetine versus sertraline, a large rigorous placebo-controlled trial of sertraline in late-life depression was completed (Schneider et al. 2003). In this study, 716 patients (mean age: 70 years) were randomly assigned to flexible-dosage sertraline (50–100 mg/day) or placebo in an 8-week clinical trial. The criterion for remission was a final Ham-D (17-item) score of 10 or less; the intent-to-treat remission rate was 29% in the sertraline group, compared with 23% in the placebo group (P<0.05).
Paroxetine. In addition to the two previously described trials that compared nortriptyline at a therapeutic plasma level with paroxetine, and in which the intent-to-treat remission rates (final 17-item Ham-D score ≤10) were 55% and 61%, respectively, a third trial compared mirtazapine with paroxetine (Schatzberg et al. 2002). In this study, 255 patients (mean age: 72 years) were randomly assigned to receive mirtazapine 30–45 mg/day or paroxetine 30–40 mg/day in an 8-week clinical trial. The criterion for remission was a final Ham-D (17-item) score of 7 or less; the intent-to-treat remission rates were 38% for mirtazapine and 28% for paroxetine and were not statistically different.
Citalopram and escitalopram. Many of the studies of citalopram in a geriatric population included patients with depression and dementia or significant cognitive impairment; therefore, the results of these studies are not comparable to those of other antidepressant trials in late-life depression (Gottfries 1996). However, two studies have provided information on citalopram in this population; the first was a single-blind comparison between citalopram and a therapeutic plasma level of nortriptyline, and the second was a comparison of citalopram with placebo in depressed patients older than 75 years.
In the first study, 58 patients (mean age: 71 years) were randomly assigned to treatment with a citalopram dosage of 30–40 mg/day or a therapeutic plasma level of nortriptyline in a 12-week clinical trial (Navarro et al. 2001). The criterion for remission was a final Ham-D (17-item) score of 7 or less; the intent-to-treat remission rates were 69% for citalopram and 93% for nortriptyline. The remission rates for both medications were strikingly high in comparison with those in other trials; whether this result derived from differences in patient population or in study design is not obviously apparent.
The second trial is unique in the literature because it is the only study to focus on treatment of depression in the “old-old.” In this study, 174 patients were randomly assigned to treatment with either citalopram 20–40 mg/day or placebo in an 8-week clinical trial (Roose et al. 2002). The population was 58% female, with a mean age of 80 years and a mean baseline Ham-D (24-item) score of 24. The intent-to-treat response rate (50% reduction from baseline Ham-D score) was 41% in the citalopram group and 39% in the placebo group. The sample was divided for secondary analyses into patients with “severe” and “not severe” depression, which were defined as being either above or below the mean Ham-D score, respectively. The “not severe” group had a baseline Ham-D score of 22 and included 47 patients randomly assigned to receive citalopram and 59 patients randomly assigned to receive placebo. The criterion for remission was a final Ham-D score of 10 or less. In this group, the intent-to-treat remission rate was 34% for citalopram and 41% for placebo. The “severe” patient group had a mean baseline Ham-D score of 28 and included 37 patients randomly assigned to citalopram and 31 patients randomly assigned to placebo. In this group, the intent-to-treat remission rate was 36% for citalopram and 19% for placebo (P<0.05). Thus, citalopram was significantly more effective than placebo in the “severe” patient population, but this difference resulted not from an increased efficacy of citalopram compared with “not severe” patients but rather from a decreased efficacy of placebo.
A third study—an 8-week randomized controlled trial—compared citalopram (flexible dosage of 10–20 mg/day) and venlafaxine (flexible dosage of 75–150 mg/day) in the treatment of late-life depression (Allard et al. 2004). The study included 151 patients (mean age: 73 years; 73% female) with a baseline Montgomery-Åsberg Depression Rating Scale (MADRS) score of 27±4. The response rates for venlafaxine versus citalopram were 75% and 73%, respectively, and the remission rates were 19% and 23%, respectively. The differences between the response rates and the remission rates were quite striking; it is unusual to see such a differential.
There has been one randomized controlled trial of escitalopram in the treatment of late-life depression (Kasper et al. 2005). In this study, 517 patients (mean age: 75 years; 75% female; mean baseline MADRS score: 28±4) were randomly assigned to escitalopram (10 mg/day), fluoxetine (20 mg/day), or placebo. There was no significant difference in response rates across the three treatment conditions (response rates: escitalopram 46%, fluoxetine 37%, and placebo 47%).
SSRI side effects and safety. As a group of medications, the SSRIs have the same side-effect profile in older patients as in younger patients: specifically, gastrointestinal distress, agitation, insomnia, and sexual dysfunction. Discontinuation rates for SSRIs are not statistically different from the discontinuation rates reported for a therapeutic plasma level of nortriptyline in the geriatric samples.
With respect to safety, the SSRIs offer a significant advantage over the TCAs. SSRIs are relatively benign in overdose (Barbey and Roose 1998) and do not have an effect on blood pressure, heart rate, cardiac conduction, or cardiac arrhythmias (Glassman et al. 2002; Roose et al. 1998). SSRIs block the uptake of serotonin into platelets and significantly reduce platelet function. SSRIs are associated with upper gastrointestinal bleeding, intracerebral hemorrhage, and postoperative bleeding complications (Musselman et al. 1998).
Venlafaxine. One study reported meaningful information about venlafaxine in a geriatric population (Schatzberg and Cantillon 2000). In this 8-week randomized controlled clinical trial, 204 patients (mean age: 71 years) were randomly assigned to treatment with venlafaxine (75–225 mg/day), fluoxetine (20–60 mg/day), or placebo. Remission was defined as a Ham-D (24-item) score less than 8; the intent-to-treat remission rate was 42% for venlafaxine, 29% for fluoxetine, and 38% for placebo (no statistically significant differences). Significantly more patients treated with venlafaxine (27%) and fluoxetine (19%) discontinued study participation because of side effects than did those given placebo (9%) (P<0.05). Cardiovascular measures, including heart rate and measures of cardiac conduction (including pulse rate, QRS, and QTc intervals), were assessed, and neither medication induced a significant change compared with placebo in any of these measures.
Duloxetine. There has been one randomized controlled trial of duloxetine for the treatment of late-life depression. In this study, 311 patients (mean baseline Ham-D score: 22±4) were randomly assigned in a 2-to-1 allocation favoring duloxetine (Raskin et al. 2007). The response and remission (final Ham-D score: ≤7) rates were significantly greater for duloxetine than for placebo (response rates: duloxetine 37%, placebo 27% [P< 0.001]; remission rates: duloxetine 19%, placebo 15% [P=0.002]). However, as with many other trials of antidepressant medication for the treatment of late-life depression, the remission rates are distressingly low.
Mirtazapine. As previously discussed, in one randomized controlled comparator trial of mirtazapine versus paroxetine in a geriatric population, the intent-to-treat remission rates were 38% for the mirtazapine group and 28% for the paroxetine-treated patients (Schatzberg et al. 2002). In this study, the rate of discontinuation due to adverse events was similar in both groups: 33% for mirtazapine and 29% for paroxetine.
Bupropion. One randomized controlled comparator trial of bupropion versus paroxetine in late-life depression has been published, and this represents the only data available on bupropion in this population (Weihs et al. 2000). In this 6-week clinical trial, 100 patients (mean age: 70 years), with a baseline Ham-D (24-item) score of 27, were randomly assigned to treatment with either bupropion (100–300 mg/day) or paroxetine (10–40 mg/day). Rates of response (defined as a 50% reduction from baseline Ham-D score) in the intent-to-treat analysis were 71% in the bupropion group and 77% in the paroxetine group. Remission data were not reported. Discontinuation rates were 17% in the bupropion group and 15% in the paroxetine group.
The use of atypical antipsychotics as an augmentation strategy in adults whose symptoms have not responded to antidepressants has been shown to be effective in many placebo-controlled studies. Concerns have been raised about whether the same approach would be effective and safe in the late-life population. In a recently completed study involving 181 depressed patients older than 60 years who had not responded to an open trial of venlafaxine, patients were randomly assigned to receive the addition of either aripiprazole or placebo for a 12 weeks (Lenze et al. 2015). The response rate with aripiprazole augmentation was significantly higher than that with placebo (44% vs. 29%). Aripiprazole treatment was associated with akathisia and parkinsonism, but these side effects resolved if the medication was discontinued.
No class of medication, including antipsychotics, is approved by the U.S. Food and Drug Administration (FDA) to treat psychosis or agitation in patients with dementia, although risperidone is approved in Germany and a few other countries for this purpose. Nonetheless, antipsychotics and other psychotropic medications are used widely in the management of dementia-related psychosis or agitation because there are no treatment alternatives; evidence for the effectiveness of nonpharmacological behavioral approaches is limited and may apply mainly to patients with mild behavioral symptoms (Brodaty and Arasaratnam 2012).
In the elderly, antipsychotic use in neurodegenerative disorders exceeds antipsychotic use in schizophrenia because of the difference in disease prevalence rates (Colenda et al. 2002). In this population, the prevalence of schizophrenia remains below 1%, whereas the prevalence of dementia is approximately 2%–5% for people older than 60 years, and the prevalence increases to 15%–40% for people older than 85 years (Thomas et al. 2001). Psychosis and behavioral dyscontrol occur in the majority of patients with dementia during the course of illness (Devanand et al. 1997; Lyketsos et al. 2000). Consequently, use of antipsychotics is greater in elderly patients with dementia (prescribed off-label) than in those with schizophrenia.
Older patients are more sensitive to the side effects of antipsychotics, which can include sedation, cardiac effects (e.g., tachycardia, orthostatic hypotension), anticholinergic side effects (e.g., dry mouth, blurred vision, constipation, urinary retention), neuroleptic malignant syndrome with hyperpyrexia, autonomic instability and tachycardia, pigmentary retinopathy, weight gain and associated metabolic changes, allergic reactions, and seizures (Arana 2000).
The antipsychotics most likely to cause orthostatic hypotension are low-potency conventional (or typical) antipsychotics such as chlorpromazine and thioridazine and the atypical antipsychotics clozapine, risperidone, olanzapine, and quetiapine (Tandon 1998). Low-potency conventional antipsychotics and clozapine have the greatest potential to cause anticholinergic effects. At comparable dosages, low-potency conventional antipsychotics are less likely than high-potency conventional antipsychotics such as haloperidol to cause extrapyramidal side effects (EPS), but up to 50% of patients 60–80 years of age receiving conventional antipsychotics develop either EPS or tardive dyskinesia (TD) (Jeste et al. 1999). Saltz et al. (1991) reported an incidence of TD of 31% after 43 weeks of conventional antipsychotic treatment in a sample of elderly patients, and antipsychotic-induced TD is five to six times more prevalent in elderly than in younger patients (Jeste 2000). The susceptibility of older patients to the side effects of typical antipsychotics, particularly the neurological side effects of EPS and TD, requires the use of dosages lower than those commonly used in young adults. Atypical antipsychotics have a lower potential for TD compared with typical antipsychotics (Jeste 2000).
To varying degrees, the metabolic syndrome with glucose dysregulation is a potential side effect of all antipsychotic medications. New-onset type 2 diabetes mellitus or diabetic ketoacidosis may be more common with clozapine and olanzapine compared with other antipsychotics, and blood glucose levels need to be monitored in elderly patients (Jin et al. 2004). Weight gain is a problematic side effect of several antipsychotics, particularly olanzapine and clozapine.
Sedation is one of the most common side effects of antipsychotic medications, with low-potency conventional antipsychotics being potent sleep inducers. In addition, low-potency antipsychotics have a greater propensity to cause anticholinergic side effects, which can lead to daytime confusion and disorientation in the elderly.
An Ontario, Canada, study that examined the medical records of 97,777 patients found an association between antipsychotic use and abnormal kidney function tests, although the mechanism underlying this effect was not clear (Hwang et al. 2014). There have been reports of an association between antipsychotic use and deep vein thrombosis in patients with dementia, which may be related to the decrease in mobility that is a common side effect of several antipsychotics (Parker et al. 2010).
Elderly patients are often taking a large number of medications, and drug interactions need to be considered when prescribing antipsychotics. Specifically, adding fluoxetine to risperidone raises risperidone levels (Bondolfi et al. 2002), and similar effects have been reported when fluoxetine is combined with typical antipsychotics (Solai et al. 2001).
The use of antipsychotics is associated with an increased risk of sudden cardiac death (Ray et al. 2001). Among the antipsychotics, thioridazine appears to carry the highest risk of sudden unexplained death that is believed to be due to cardiac causes (Reilly et al. 2002). Risperidone prolongs the QTc interval but has no effect on QT dispersion (Yerrabolu et al. 2000). Prolongation of the QTc interval, which is associated with the development of torsades de pointes and sudden death, is known to occur with several antipsychotics, including the atypical antipsychotic ziprasidone, but aripiprazole may reduce the QTc interval (Goodnick et al. 2002).
Based on a review of double-blind, placebo-controlled trials of atypical antipsychotics in patients with dementia, the FDA concluded that there was a significantly greater mortality risk (1.6–1.7 times) for patients treated with these medications compared with those treated with placebo, and that all antipsychotic medications must carry a black box warning to this effect (Jeste et al. 2008; Schneider et al. 2005). There is no clear explanation as to why the use of atypical antipsychotics is associated with an increased mortality risk in patients with dementia. There may be a small increase in the risk of stroke (Brodaty et al. 2003), but the increase in stroke risk does not by itself account for the increased mortality risk (Jeste et al. 2008). In a large-scale medical records study involving more than 75,000 nursing home patients receiving antipsychotics, haloperidol was associated with the greatest increase in mortality risk, risperidone and olanzapine with intermediate risk, and quetiapine with the lowest increase in mortality risk (Huybrechts et al. 2012). In a large U.S. Department of Veterans Affairs (VA) study, the association between antipsychotic use and mortality was highest for haloperidol, with the caveat that some patients receiving higher dosages of haloperidol were being treated for delirium, which may have artificially increased the mortality rate observed because of the known association between delirium and increased mortality (Maust et al. 2015). Another review suggested that the mortality risk associated with antipsychotics may not be as large as believed, possibly because the FDA black box warning has led to a decrease in antipsychotic prescribing for elderly patients with dementia who also have serious medical illness (Hulshof et al. 2015).
Age-related decreases in gut motility and the anticholinergic effects of antipsychotics may decrease absorption rates. Antipsychotic drugs undergo biotransformation primarily in the liver, with the gastrointestinal tract, lungs, and kidneys being secondary sites. Antipsychotics have slightly longer half-lives in the elderly than in the rest of the adult population, thereby prolonging side effects (Hicks and Davis 1980). The concomitant use of antacids may lower antipsychotic blood levels (Fann et al. 1973).
Dopamine neurons degenerate with aging, particularly after age 70 years, and decreases in the number of cholinergic receptors occur in Alzheimer’s disease (Davies and Maloney 1976; Perry et al. 1977). The decrease in the number of available dopaminergic receptors reduces the tolerance of elderly patients to antipsychotics, thus increasing the likelihood of neurological side effects, including EPS and TD.
Blockade of dopamine type 2 (D2) receptors is believed to be the primary mechanism of action of antipsychotics. Atypical antipsychotics are more potent antagonists at the serotonin type 2A (5-HT2A) receptor than at the D2 receptor, resulting in fewer EPS and less TD compared with typical antipsychotics (Jeste et al. 1999).
Patients with dementia often develop behavioral disturbances (e.g., agitation, aggression) or psychotic features (e.g., delusions, hallucinations). As used here, the term behavioral complications denotes both behavioral disturbances and psychotic features. Behavioral complications occur in most forms of dementia, lead to considerable burden for caregivers, and are common precipitants of institutionalization.
Personality changes occur early in dementia and include apathy, anhedonia, irritability, inability to pay attention, depression, and loss of emotional connection (Rubin and Kinscherf 1989). In later stages, varying degrees of agitation may occur in more than half of Alzheimer’s disease patients in outpatient clinics (Devanand et al. 1997) and nursing homes (Cohen-Mansfield et al. 1989), with aggressive behavior also becoming common (Devanand et al. 1997; Swearer et al. 1988). Other disinhibited behaviors include pacing, wandering, verbal and physical aggression, repetitive calling out and screaming, and (rarely) self-mutilating behaviors. Catastrophic reactions, including bursts of anger and even violent behavior, can occur when patients are required to perform tasks beyond their cognitive capacities (Devanand et al. 1992a). Stubbornness, or refusal to complete essential activities of daily life, can be particularly frustrating for caregivers.
The prevalence of delusions ranges from 0% to 50% in different samples of Alzheimer’s disease patients (Devanand et al. 1997; Lyketsos et al. 2000; Reisberg et al. 1989). Isolated delusional thoughts are more common than diagnosable psychotic disorders, and paranoid delusions of theft and suspicion are the most frequent types of delusions. Systematized complex delusions and grandiose delusions are relatively rare in Alzheimer’s disease and other dementias. Delusional processes in dementia can be chronic or intermittent, a feature that distinguishes them from delusions in schizophrenia. Hallucinations, which can be visual or auditory, occur in 5%–15% of patients with dementia. In Alzheimer’s disease, a typical hallucination is the conviction that someone else is in the house (i.e., phantom boarder syndrome). Diagnostic criteria for psychosis in Alzheimer’s disease have been developed (Jeste and Finkel 2000).
In a series of 235 patients with mild to moderate Alzheimer’s disease who were followed prospectively for up to 5 years, approximately half of the patients who manifested paranoid delusions or hallucinations at baseline were likely to manifest the same symptom 6 months later (Devanand et al. 1997), a finding consistent with other reports (Ballard et al. 1997; Paulsen et al. 2000). However, paranoid delusions or hallucinations were evident at three out of four consecutive visits (over a period of 2 years) in only 10%–15% of patients, which raises the question of how long patients need to continue taking antipsychotics after treatment response. Psychosis and behavioral dyscontrol often coexist in Alzheimer’s disease, and treatment with antipsychotics is often prescribed for one or both sets of symptoms.
In elderly patients, assessment and treatment of psychopathology should occur after reversible medical conditions (e.g., occult urinary tract infection, metabolic imbalance, iatrogenic or medication-induced symptoms) have been ruled out. Because of the impairment induced by Alzheimer’s disease and other dementias, most rating scales have been developed as informant-based interviews. Commonly used rating scales for measurement of neuropsychiatric symptoms of Alzheimer’s disease include the Neuropsychiatric Inventory (NPI; Cummings et al. 1994), the Neuropsychiatric Inventory—Nursing Home Version (Wood et al. 2000), the Behavioral Pathology in Alzheimer’s Disease Rating Scale (BEHAVE-AD; Reisberg et al. 1987), the Consortium to Establish a Registry for Alzheimer’s Disease (CERAD) Behavior Rating Scale (Tariot et al. 1995), the Cohen-Mansfield Agitation Inventory (CMAI; Cohen-Mansfield et al. 1989), and the Columbia University Scale for Psychopathology in Alzheimer’s Disease (CUSPAD; Devanand et al. 1992b). The NPI, which uses a quantitative time-efficient decision-tree approach, is the most widely used scale for evaluating the effects of antipsychotic treatment in patients with dementia. Recently, international consensus criteria were developed for the syndrome of agitation in dementia and other neurocognitive disorders in older adults, and these criteria are being used in treatment trials for agitation in dementia, including the most common form, Alzheimer’s disease (Cummings et al. 2015).
Alzheimer’s disease patients with psychosis have been found to have significantly more plaques and tangles in the medial temporal–prosubicular area and the middle frontal cortex (Zubenko et al. 1991) and four to five times higher levels of abnormal paired helical filament (PHF)–tau protein in the entorhinal and temporal cortices (Mukaetova-Ladinska et al. 1993). A decrease in serotonin in the prosubiculum of the cerebral cortex has been reported in patients with psychotic compared with nonpsychotic dementia (Lawlor et al. 1995; Zubenko et al. 1991). Decreases in acetylcholine have been correlated with increases in thought disorder (Sunderland et al. 1997). Cholinergic agents, including the acetylcholinesterase inhibitors (donepezil, rivastigmine, galantamine) that are used to treat cognitive impairment in Alzheimer’s disease, may also reduce behavioral symptoms (Bodick et al. 1997; Kaufer et al. 1996; Raskind 1999). Higher levels of norepinephrine in the substantia nigra (Zubenko et al. 1991) and higher levels of β-adrenergic receptors (Russo-Neustadt and Cotman 1997) in multiple brain regions have been reported in psychotic compared with nonpsychotic patients with Alzheimer’s disease. These data suggest an enhanced responsiveness of catecholamines that may be associated with increased psychosis in Alzheimer’s disease (Peskind et al. 1995). Homozygosity of the 1 and 2 alleles of the dopamine receptor DR3 gene (Holmes et al. 2001; Sweet et al. 1998) and homozygosity for the C102 allele of the 5-HT2A receptor gene (Nacmias et al. 2001) may be associated with psychosis in Alzheimer’s disease. However, the precise pathophysiology underlying psychosis in Alzheimer’s disease is still unknown.
Studies in the 1970s and early 1980s indicated that nearly half of inpatients with dementia in VA hospitals (Prien et al. 1975) and in other settings (Michel and Kolakowska 1981) received psychotropic medications, primarily antipsychotics and benzodiazepines (Ray et al. 1980). Growing awareness of the neurological side effects of typical antipsychotics, particularly in dementia patients in nursing homes, led to the promulgation of the Omnibus Budget Reconciliation Act (OBRA) of 1987 (Elon and Pawlson 1992), which became effective in 1990. OBRA required identification of target symptoms, justification for the use of antipsychotics, and mandatory attempts to decrease or stop the antipsychotic medication every 3 months. Nonetheless, antipsychotic medications have remained the treatment of choice for behavioral complications in dementia (Devanand et al. 1998; Katz et al. 1999; Schneider et al. 1990; Street et al. 2000), and drug utilization studies show that antipsychotics are used in 30%–50% of elderly institutionalized patients (Giron et al. 2001; Lantz et al. 1990), although their use may have decreased in recent years after the FDA black box warning on increased mortality in patients with dementia receiving antipsychotics.
The results of a 1990 meta-analysis of placebo-controlled treatment trials indicated that typical antipsychotic treatment in dementia was significantly more efficacious than placebo, with the magnitude of the advantage over placebo averaging 18% (Schneider et al. 1990). In later placebo-controlled clinical trials with typical or atypical antipsychotics, response rates have varied between 45% and 60% for active medication and between 20% and 45% for placebo (De Deyn et al. 1999; Devanand et al. 1998; Katz et al. 1999; Street et al. 2000), with an overall advantage for antipsychotic over placebo in the range of 18%–26% (Kindermann et al. 2002; Lanctôt et al. 1998). Clinically, a complete “cure” of the target psychotic and behavioral symptoms is uncommon.
In schizophrenia, antipsychotics are often assumed to be specific to the treatment of psychosis, and improvement in behavioral dyscontrol is believed to be secondary to improvement in psychosis. However, in patients with dementia, placebo-controlled studies consistently show comparable advantages for antipsychotics over placebo for symptoms of both psychosis and behavioral dyscontrol (Brodaty et al. 2003; De Deyn et al. 1999; Devanand et al. 1998; Katz et al. 1999; Street et al. 2000).
Typical antipsychotics. Early placebo-controlled studies of typical antipsychotics used in the management of behavioral complications of dementia showed moderate efficacy with a high placebo response rate, and considerable EPS occurred even at moderate dosages (Barnes et al. 1982; Finkel et al. 1995; Petrie et al. 1982; Rada and Kellner 1976). In a double-blind, placebo-controlled, randomized comparison of standard-dosage (2–3 mg/day) and low-dosage (0.50–0.75 mg/day) haloperidol in 71 outpatients with Alzheimer’s disease (Devanand et al. 1998), standard-dosage haloperidol was efficacious and superior to both low-dosage haloperidol and placebo for symptoms of both psychosis and agitation (Devanand et al. 1998). EPS tended to be greater for haloperidol (2–3 mg/day) than for the other two conditions. Low-dosage haloperidol did not differ from placebo on any measure of efficacy or side effects.
In another study that compared the SSRI citalopram, the typical antipsychotic perphenazine, and placebo, citalopram was comparable to perphenazine in efficacy and significantly superior to placebo, with an advantageous side-effect profile (Pollock et al. 2002).
Atypical antipsychotics. Because of their more favorable safety profile, the atypical antipsychotics have gradually replaced typical antipsychotics in the treatment of behavioral complications in dementia. Atypical antipsychotics can be safely administered with cholinesterase inhibitors (e.g., donepezil, rivastigmine, galantamine), which are used to treat the cognitive impairment of dementia (Weiser et al. 2002). The choice of atypical antipsychotic depends on the patient’s clinical profile and the medication’s side-effect profile (e.g., a patient prone to falls should receive a medication that is not likely to cause orthostatic hypotension). Clozapine, risperidone, paliperidone and iloperidone (risperidone metabolites), olanzapine, quetiapine, aripiprazole, ziprasidone, lurasidone, asenapine, and cariprazine are the atypical antipsychotics that are currently available. There are as yet no published studies examining ziprasidone, lurasidone, asenapine, or cariprazine in the treatment of psychosis or agitation in patients with dementia.
Clozapine. Clozapine was the first atypical antipsychotic to become available in the United States. Clozapine causes substantial serotonergic blockade and has antiadrenergic and antimuscarinic properties (Lieberman 1998). Clozapine may be more efficacious than other antipsychotics in schizophrenia, and it carries essentially no risk of TD (Kane et al. 1988). Circulating levels of clozapine rise with dosage and age and may be slightly higher in women than in men; sedation is common, and seizure potential is elevated (Centorrino et al. 1994; Kurz et al. 1998). Clozapine’s anticholinergic properties can lead to dry mouth and constipation and can adversely affect cognition in the elderly. Also, intensive monitoring is required for blood dyscrasias, particularly agranulocytosis, which is reported to occur in 0.38% of patients (Kane et al. 1988). These factors, as well as the increased risk of falls and fractures related to the side effect of orthostatic hypotension, limit the use of clozapine in the elderly. The few retrospective reviews and case reports available indicate moderate efficacy but significant adverse events, suggesting very low tolerability in elderly patients with dementia (Chengappa et al. 1995; Oberholzer et al. 1992; Pitner et al. 1995). Therefore, clozapine is rarely used in patients with dementia.
Risperidone. Risperidone has serotonin 5-HT2 and dopamine D2 blocking properties, α1- and α2-adrenergic blocking properties, minimal histaminergic (H1) blocking properties, and little affinity for cholinergic receptors (Janssen et al. 1988). Its elimination half-life is between 20 and 22 hours, allowing for once-a-day dosing (Byerly and DeVane 1996).
In young adults with schizophrenia, risperidone 6 mg/day has the best therapeutic profile compared with lower and higher dosages, with a low propensity for EPS (Chouinard et al. 1993). By contrast, the optimal risperidone dosage range is much lower for elderly patients (Katz et al. 1999). Compared with the other atypical antipsychotics, risperidone may be more likely to lead to EPS and TD, although its risk is still considerably lower than that associated with typical antipsychotics such as haloperidol; in one study, risperidone’s 1-year cumulative incidence of TD was a relatively low 2.6% in institutionalized patients with dementia (Jeste et al. 2000). Risperidone is mildly sedating and has the potential to cause orthostatic hypotension, although the latter effect is uncommon when low dosages are used in the elderly (Katz et al. 1999).
In a multicenter study, 625 nursing home patients (mean age: 83 years) with dementia (73% Alzheimer’s disease, 15% vascular dementia, 12% mixed dementia; mean 30-item Mini-Mental State Examination [MMSE] score: 6.6) who had behavioral complications were randomly assigned to receive risperidone—at 0.5 mg/day, 1.0 mg/day, or 2.0 mg/day—or placebo for 12 weeks (Katz et al. 1999). At study endpoint, response rates for risperidone 1 mg/day (45%) and 2 mg/day (50%) were significantly superior to rates for placebo and risperidone 0.5 mg/day, which showed similar response rates (33%). Patients receiving risperidone 2 mg/day were more likely than those receiving risperidone 0.5 mg/day or 1 mg/day to develop EPS and sedation, suggesting a relatively narrow therapeutic window. Therefore, a risperidone starting dosage of 0.5 mg/day, with gradual upward dosage titration to 1–2 mg/day, is recommended. A meta-analysis of four placebo-controlled trials with risperidone found that it was superior to placebo in treating psychosis and agitation, particularly in severely disturbed patients (Katz et al. 2007). Although a long-acting injectable risperidone preparation is available, that formulation has not been studied in the treatment of behavioral complications of dementia.
Paliperidone and iloperidone are chemically related to risperidone and are approved for the treatment of schizophrenia (Davidson et al. 2007; Marder et al. 2007) but have not been studied systematically in the treatment of behavioral complications in dementia.
Olanzapine. Olanzapine blocks multiple receptor sites, including serotonin 5-HT2A/2C and dopamine D4/3/2/1 (serotonin-to-dopamine receptor binding ratio of 8:1), histaminergic H1 receptors, muscarinic acetylcholine receptors, and noradrenergic α1 receptors (Bymaster et al. 1996). Olanzapine is well absorbed and, is unaffected by food, and because of its mean half-life of 30 hours, it can be used once a day (Fulton and Goa 1997).
Sedation and weight gain are prominent side effects of olanzapine, and its use has been associated with the development of metabolic syndrome. Orthostatic hypotension is not common when low dosages are used in elderly patients (Street et al. 2000). Intramuscular olanzapine is a useful alternative to intramuscular haloperidol in the treatment of acutely psychotic, agitated patients with schizophrenia (Breier et al. 2002a) and may be a useful alternative to intramuscular lorazepam in patients with dementia (Meehan et al. 2002).
In a double-blind, placebo-controlled multicenter clinical trial, 206 nursing home patients (mean age: 83 years) with Alzheimer’s disease (mean MMSE score: 6.9) and behavioral complications were randomly assigned to placebo or fixed-dosage olanzapine (5 mg/day, 10 mg/day, or 15 mg/day) for 6 weeks. Olanzapine 5 mg/day was significantly more efficacious than placebo, but the 10-mg/day and 15-mg/day dosages were not superior to placebo. The prominent side effects of sedation and weight gain were limiting factors at the higher dosages (Street et al. 2000). Clinically, a starting dosage of 2.5 mg/day with gradual upward titration is recommended.
Quetiapine. Quetiapine acts as an antagonist at multiple neurotransmitter receptors in the brain, including dopamine D1 and D2, serotonin 5-HT1A and 5-HT2, histamine H1, and α1- and α2-adrenergic receptors. D2 receptor affinity is less than 5-HT2 receptor affinity. Quetiapine has no appreciable binding affinity at cholinergic muscarinic or benzodiazepine receptors (Casey 1996). Although it has a short half-life (approximately 3–6 hours; Fulton and Goa 1997), quetiapine’s efficacy has been documented with twice-daily administration (McManus et al. 1999).
The incidence of EPS is very low with quetiapine. In a study of 284 elderly patients with dementia, quetiapine (average dosage 96.9 mg/day) and haloperidol (average dosage 1.9 mg/day) were indistinguishable from placebo on most measures of efficacy, although haloperidol led to more EPS (Tariot et al. 2006). The optimal dosage for quetiapine is undetermined because dosage comparison studies have not been conducted in patients with dementia. Wide dosage ranges (from 12.5 to 800 mg/day) are used in clinical practice. Physicians often prescribe quetiapine because of its relatively benign side-effect profile and to take advantage of its main side effect, sedation, in patients who have insomnia.
Aripiprazole. A placebo-controlled study of aripiprazole in 208 outpatients with behavioral complications of Alzheimer’s disease showed no advantage for aripiprazole on the main outcome measure (NPI score), but there was superiority on secondary outcome measures (Brief Psychiatric Rating Scale [BPRS] psychosis and BPRS Core subscale scores). The average dosage used was 10 mg/day, which was generally well tolerated (De Deyn et al. 2005). These limited data suggest that aripiprazole has a role as a second-line atypical antipsychotic treatment in Alzheimer’s disease patients with behavioral complications and that low starting dosages of 2–5 mg/day can be used.
Comparisons among antipsychotics. Head-to-head comparison studies have shown few differences between typical antipsychotics in the treatment of behavioral complications in dementia (Barnes et al. 1982; Carlyle et al. 1993; Petrie et al. 1982; Smith et al. 1974; Tsuang et al. 1971).
In a study comparing a typical with an atypical antipsychotic, patients with dementia and behavioral complications were randomly assigned to receive flexible-dose risperidone, haloperidol, or placebo (De Deyn et al. 1999). In 344 patients, risperidone (average dosage: 1.1 mg/day), haloperidol (average dosage: 1.2 mg/day), and placebo produced improvement rates of 54%, 63%, and 47%, respectively, at week 12 (P=0.25). No significant differences in improvement were seen between the groups on psychosis scores. In post hoc analyses, both haloperidol and risperidone were significantly better than placebo in reducing BEHAVE-AD total scores and CMAI aggression cluster scores (P=0.01), and risperidone was superior to haloperidol on the CMAI aggression cluster score (P=0.05). Patients taking haloperidol had significantly higher EPS scores at endpoint than did patients taking either risperidone or placebo, with no significant difference in EPS scores between patients receiving risperidone and those receiving placebo (De Deyn et al. 1999). Overall, risperidone’s efficacy was comparable to that of haloperidol, but with a superior side-effect profile. In smaller studies in patients with dementia, comparisons of haloperidol and risperidone have yielded equivocal results (Chan et al. 2001; Suh et al. 2004).
In adults with schizophrenia, the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) showed only marginal superiority in antipsychotic effectiveness for olanzapine compared with typical and other atypical antipsychotics (Lieberman et al. 2005). In England, the Cost Utility of the Latest Antipsychotic Drugs in Schizophrenia Study (CUtLASS) of 227 patients with schizophrenia did not show any differences in treatment response for atypical versus typical antipsychotics (Jones et al. 2006).
In the 421 elderly patients who participated in the Clinical Antipsychotic Trials of Intervention Effectiveness–Alzheimer’s Disease (CATIE-AD), which compared risperidone, olanzapine, quetiapine, and placebo (first randomized phase), there were no significant differences in time to discontinuation because the superior efficacy of risperidone and olanzapine was compromised by their increased propensity to side effects; quetiapine was indistinguishable from placebo (Schneider et al. 2006). These findings indicate that efficacy must be weighed against side effects when prescribing risperidone or olanzapine in a patient with dementia and that quetiapine may not be as effective.
Comparisons of antipsychotics versus benzodiazepines. The few early studies that compared antipsychotics with benzodiazepines suffered from methodological flaws, particularly in sample selection and study design (Burgio et al. 1992; Covington 1975; Kirven and Montero 1973; Stotsky 1984; Tewfik et al. 1970). The data available from these studies did not indicate superiority for benzodiazepines over antipsychotics in the treatment of behavioral complications in patients with dementia.
Benzodiazepines are known to have deleterious effects on learning and memory both in healthy younger subjects (Ghoneim et al. 1981; Jones et al. 1978; Liljequist et al. 1978) and in the elderly, even without baseline cognitive impairment (Pomara et al. 1991, 2015). Benzodiazepines can lead to tolerance and dependence, and worsening of cognition is a concern. Therefore, benzodiazepines should be used at low dosages, and use should be restricted to short-term crisis management of agitated and anxious behaviors if antipsychotics or other medications are ineffective.
Studies of anticonvulsants and other agents. A small-sample study by Tariot et al. (1998) suggested that carbamazepine was effective in the treatment of behavioral complications of Alzheimer’s disease, and there were suggestions that valproate was efficacious in a single-site study by the same research group (Porsteinsson et al. 2001). However, valproate at an average dosage of 800 mg/day did not show superiority over placebo in a larger study of 153 nursing home patients who participated in a double-blind, placebo-controlled trial (Tariot et al. 2005). Nonetheless, anticonvulsants such as valproate are routinely prescribed in nursing homes.
Studies of other medications, such as buspirone (Lawlor et al. 1994), trazodone (Sultzer et al. 1997; Teri et al. 2000), lithium (Holton and George 1985), and propranolol (Shankle et al. 1995; Weiler et al. 1988), have involved case series or small samples, usually without placebo controls. These medications can be considered as therapeutic options only after antipsychotic treatment has failed.
In a 12-week placebo-controlled trial in patients with dementia and agitation, citalopram showed a small but significant advantage over placebo in some but not all measures of efficacy (Porsteinsson et al. 2014). However, the majority of patients received citalopram 30 mg/day, which is higher than the FDA dosage limit of 20 mg/day, which was instituted because of QT prolongation on the electrocardiogram at higher dosages.
The potential side-effect profile should determine the choice of antipsychotic for individual patients (Ellingrod et al. 2002). Clozapine should be reserved for those patients who do not respond to the other available antipsychotics. Patients prone to orthostatic hypotension (e.g., patients receiving β-blockers) may develop this side effect while taking risperidone or olanzapine, although postural hypotension is uncommon at low dosages (Katz et al. 1999; Street et al. 2000). Olanzapine causes weight gain and is strongly sedating, but the latter side effect may be advantageous in patients with prominent insomnia. The metabolic syndrome can occur with all antipsychotics but is most likely to occur with olanzapine. Quetiapine is generally well tolerated, but it can be sedating. Among the atypical antipsychotics, risperidone is the most likely to cause EPS, so olanzapine or quetiapine should be preferred in elderly patients who have parkinsonian features. The incidence of TD is much lower with atypical antipsychotics than with the typical antipsychotic haloperidol (Jeste et al. 2000). In a study of 35 agitated patients with dementia who were switched from haloperidol to risperidone, the crossover was generally safe and effective (Lane et al. 2002). Overall, the decreased likelihood of neurological side effects, both short-term and long-term, makes atypical antipsychotics the treatment of choice in these patients.
The studies with haloperidol and risperidone produced similar results: very low dosages were ineffective, whereas high dosages led to side effects, suggesting a relatively narrow therapeutic window for these medications in dementia patients who develop behavioral complications. The optimal dosage for olanzapine appears to be 5 mg/day, based on the study comparing 5, 10, and 15 mg/day (Street et al. 2000). The optimal quetiapine dosage remains uncertain.
In patients with Alzheimer’s disease, risperidone should be started at 0.25–0.50 mg/day at bedtime (or twice-daily dosing), with a 0.5-mg/day increase per week to a maximum of 2 mg/day (or possibly 3 mg/day). Olanzapine should be started at 2.5 mg/day or 5.0 mg/day at bedtime and slowly increased to a target daily dosage of 5–10 mg. Quetiapine should be started at 25 mg twice daily, with dosage increases as tolerated up to 300 mg twice daily, based solely on clinical response and side effects, because the optimal dosage range for quetiapine has not been identified. If a typical antipsychotic is used, a starting dosage equivalent to haloperidol 0.5 mg/day is advisable, with subsequent individualized titration to achieve an optimal trade-off between efficacy and side effects.
Use of anticholinergic agents to treat EPS should be avoided, particularly in Alzheimer’s disease, in which a cholinergic deficit is believed to underlie much of the cognitive impairment. In some patients, concomitant use of a hypnotic (e.g., zolpidem 5–10 mg/day or zaleplon 5–10 mg/day) may be required. Trazodone at dosages of 25–200 mg/day can also be used as a hypnotic in these patients. As noted earlier, benzodiazepine use should be limited to short-term crisis management of anxiety or agitation.
A trial of 6–12 weeks usually is sufficient to determine the outcome of an antipsychotic treatment trial. If the optimal antipsychotic dosage is reached quickly, clinical response may occur within the first 1 or 2 weeks. On the other hand, the need to adjust the dosage because of side effects may require a relatively prolonged trial period.
The expected natural course of target symptoms during the course of dementia should be considered in determining the duration of antipsychotic treatment. Delusions and hallucinations are not very persistent, whereas agitation usually persists for several months to years during the course of Alzheimer’s disease (Devanand et al. 1997).
Conflicting evidence exists regarding how long antipsychotic medications should be continued in these patients. One report suggested that antipsychotics and other psychotropics can be discontinued in nursing home patients with dementia without increased risk of behavioral symptom relapse (Cohen-Mansfield et al. 1999), but other reports indicate a moderate to high rate of relapse after discontinuation (Avorn et al. 1992; Fitz and Mallya 1992; Horwitz et al. 1995). A British study suggested that antipsychotic withdrawal leads to a moderately increased risk of relapse (Ballard et al. 2004), but multiple antipsychotics were withdrawn, and the results were not clear-cut.
In the largest study to examine relapse risk after antipsychotic discontinuation (Devanand et al. 2012), 180 Alzheimer’s disease patients with psychosis or agitation/aggression received 16 weeks of open treatment with risperidone (mean dosage 0.97 mg/day). Responders were then randomly assigned, in a double-blind manner, to one of three arms: 1) continuation risperidone for 32 weeks, 2) risperidone for 16 weeks followed by placebo for 16 weeks, or 3) placebo for 32 weeks. In the initial open-label treatment phase, psychosis and agitation improved, with mild increases in EPS; 112patients met criteria for response to treatment, and 110 of these responders entered the random-assignment portion of the study. In the first 16 weeks after randomization, patients who discontinued to placebo (Arm 3) showed greater rates of relapse than those who continued on risperidone (Arms 1 and 2) (hazard ratio=1.94, 95% confidence interval [CI]=1.09–3.45, P=0.022), for a relapse rate of 60% (24/40) for placebo versus 32.9% (23/70) for risperidone (P=0.004). During the second 16 weeks, relapse rates were again greater with discontinuation to placebo (Arm 2) compared with continuation risperidone (Arm 1) (hazard ratio=4.88, 95% CI=1.08–21.98, P=0.023), for a relapse rate of 48.1% (13/27) for placebo versus 15.4% (2/13) for risperidone (P=0.017). Postrandomization adverse events and deaths did not differ significantly, although comparisons were based on small numbers of patients, especially during the final 16 weeks. The results showed that among Alzheimer’s disease patients with psychosis or agitation who maintained response to risperidone for 4–8 months, risperidone discontinuation was associated with an increased risk of relapse (Devanand et al. 2012). The authors’ clinical recommendation, which applies to the issue of antipsychotic withdrawal in nursing homes as per federal guidelines, is that if a patient has shown a clear response to antipsychotic treatment, that patient should be continued on treatment for several months (up to 8 months based on this study) as long as side effects are not prominent. In contrast, if a patient’s symptoms do not clearly respond to antipsychotic treatment, it is advisable to withdraw the treatment in order to reduce the likelihood of persistent side effects or the development of future complications, including an increased risk of mortality.
The anticholinergic activity of antipsychotics may further compromise the already damaged central cholinergic projections in Alzheimer’s disease. The level of cognitive impairment may be increased by the use of antipsychotics with strong anticholinergic properties or by the addition of anticholinergic agents to treat drug-induced EPS. Therefore, if EPS develops following antipsychotic treatment in a patient with dementia, switching to an antipsychotic that is less likely to cause EPS is preferable to adding an anticholinergic medication to treat the EPS. At another level, the sedation produced by antipsychotics may worsen the degree of disorientation and cognitive impairment in Alzheimer’s disease.
Few studies have examined the utility of monitoring antipsychotic blood levels in patients with dementia. In a study that compared haloperidol 2–3 mg/day, haloperidol 0.5–0.75 mg/day, and placebo, plasma haloperidol levels were detectable in all patients at the 2–3 mg daily dosage, and blood levels showed stronger correlations with efficacy and EPS than did oral dosages (Pelton et al. 2003). In this series of predominantly drug-naïve Alzheimer’s disease patients, therapeutic effects occurred at haloperidol blood levels that were invariably below the postulated therapeutic window of 5–15 ng/mL in schizophrenia (Van Putten et al. 1992; Volavka et al. 1992). Also, EPS developed in some patients at these low blood levels, suggesting that the increased sensitivity to antipsychotics seen in dementia is not likely to be attributable to pharmacokinetic changes. A pharmacodynamic explanation (e.g., loss of dopamine receptors leading to greater sensitivity to even low oral dosages of antipsychotic medication) is more likely. In contrast to the associations observed with the typical antipsychotic haloperidol, clinically relevant associations between blood levels of atypical antipsychotics such as risperidone and either efficacy or side effects have not been demonstrated (Jeste 2000).
The heterogeneous nature of behavioral complications suggests that specific target symptoms should be identified before initiating antipsychotic treatment, and these target symptoms should be monitored serially during the course of treatment. A scale such as the NPI can also be used. In addition to neurological and other common antipsychotic side effects, cognition and activities of daily living need to be monitored, preferably with brief instruments such as the MMSE. In patients who are being maintained on antipsychotics for extended periods, assessment for TD using the Abnormal Involuntary Movement Scale should be conducted at regular intervals.
The relative efficacy of antipsychotics in other subtypes of dementia (e.g., vascular dementia or mixed dementia, frontotemporal dementia) has not been studied extensively. Antipsychotic treatment trials that included patients with vascular, mixed, and other forms of dementia did not reveal any differences in treatment response among the diagnostic subtypes of dementia (De Deyn et al. 1999; Katz et al. 1999). With the exceptions of diffuse Lewy body disease (DLBD) and Parkinson’s disease, in which EPS are likely to worsen with antipsychotics, the recommendations for the use of antipsychotics in Alzheimer’s disease generally apply to their use in other types of dementia.
DLBD is a subtype of dementia characterized by prominent EPS, fluctuating clinical course, hallucinations, and extreme sensitivity to the neurological side effects of antipsychotics (McKeith 2006). DLBD has features that overlap with those of Alzheimer’s disease and Parkinson’s disease, and the boundaries of DLBD as a diagnostic entity remain controversial. Sensitivity to typical antipsychotics is one of the defining criteria for DLBD (McKeith 2006), and atypical antipsychotics may be safer to use in these patients. A post hoc analysis of the olanzapine dosage comparison study in Alzheimer’s disease suggested that olanzapine was safe and effective for the subgroup of patients who met diagnostic criteria for DLBD (Cummings et al. 2002). Patients with Parkinson’s disease can develop iatrogenic psychosis caused by the levodopa–carbidopa combination (Sinemet) or dopamine agonists. Lowering the dosage of the dopaminergic agent will often lead to remission of psychotic symptoms, but the price paid may be an unacceptable increase in parkinsonian symptoms (Breier et al. 2002b). In such cases, antipsychotics with a very low propensity to cause EPS can be considered. However, two double-blind, placebo-controlled trials did not find an advantage for olanzapine over placebo in these patients (Breier et al. 2002b). Clozapine may be of some value in patients with Parkinson’s disease (J.H. Friedman and Fernandez 2002), but quetiapine may be the preferred antipsychotic in this disorder. Long-term quetiapine use is generally well tolerated in patients with Parkinson’s disease or DLBD (Fernandez et al. 2002). Pimavanserin, a selective inverse agonist at the serotonin 5-HT2A receptor, has been shown to be efficacious in treating psychosis in Parkinson’s disease (Cummings et al. 2014).
In patients with delirium, short-term administration of antipsychotics—particularly antipsychotic agents with low anticholinergic properties, such as haloperidol—is a standard treatment strategy (Tune 2002). Atypical antipsychotics are useful in the management of delirium, and olanzapine has been reported to be safe and efficacious for the treatment of symptoms of delirium in hospitalized patients (Breitbart et al. 2002).
The majority of elderly schizophrenic patients were first diagnosed as young adults, but a minority of patients are first diagnosed with schizophrenia later in life. The International Late-Onset Schizophrenia Group reached a consensus that the diagnoses of late-onset schizophrenia (onset after age 40 years) and very-late-onset schizophrenia (onset after age 60 years) have face validity and clinical utility (Howard et al. 2000). Although age at onset affects the clinical presentation to some extent (Sable and Jeste 2002), it does not appreciably influence the likelihood of response to antipsychotics or the occurrence of side effects (Sable and Jeste 2002).
Tapering and stopping antipsychotic medications in schizophrenia is associated with a high risk of relapse (Csernansky and Schuchart 2002). This risk has made it difficult to conduct placebo-controlled trials in samples of elderly schizophrenic patients (Sable and Jeste 2002). In elderly schizophrenic patients, switching from typical antipsychotics to risperidone has been reported to be effective and well tolerated (Barak et al. 2002). Atypical antipsychotics appear to be at least as efficacious as and better tolerated than typical antipsychotics in the elderly, and a study of veterans suggested that adherence to atypical antipsychotics is slightly higher than adherence to typical antipsychotics (Dolder et al. 2002).
In a 4-month comparison trial of flexible-dose risperidone (n=175) versus quetiapine (n=553) in 728 mixed-age patients with a variety of psychotic disorders, quetiapine was as effective as risperidone and was less likely to require adjustment of concomitant antiparkinsonian medication. However, quetiapine was associated with more sedation, dry mouth, and dizziness (Mullen et al. 2001). Quetiapine was evaluated in a sample of 151 elderly psychotic patients (mean age: 77 years), among whom 40% had schizophrenia, bipolar disorder, or psychotic depression; 50% had psychosis associated with Alzheimer’s disease; and 10% had psychosis associated with Parkinson’s disease. The median quetiapine dosage was 100 mg/day (range = 100–400 mg/day). Significant improvement was seen in the primary outcome measure of psychosis as measured by the BPRS (P<0.0001) and Clinical Global Impression Scale (P<0.01). The prominent side effects included somnolence in 32%, dizziness or postural hypotension in 13%, and EPS in 6% (McManus et al. 1999).
In 184 elderly patients (mean age: 76.1 years), 72% with Alzheimer’s disease and 28% with other psychoses (mainly schizophrenia), open-label quetiapine was administered over 52 weeks. Quetiapine at a median dosage of 137.5 mg/day was effective, with 49% of the patients showing a 20% or greater decline in BPRS scores. The main side effects were sedation (31%), dizziness (17%), and postural hypotension (15%) (Tariot et al. 2000). EPS-related adverse events occurred in 13% of patients, but overall ratings on an EPS scale showed a small improvement from baseline, and new-onset TD did not develop in any patient over the 1-year period. Although limited by the lack of placebo control or comparison with another antipsychotic to establish efficacy, the relatively benign side-effect profile of quetiapine is noteworthy. The CATIE studies in patients with Alzheimer’s disease suggested that quetiapine’s lack of efficacy compared with olanzapine and risperidone (quetiapine did not separate from placebo) should be an equally important consideration (Schneider et al. 2006).
In all age groups, it has been difficult to demonstrate that the atypical antipsychotics approved for use in the United States improve negative symptoms (e.g., anhedonia, apathy), even though this putative effect was one of the factors driving the development of these compounds. However, medications approved in Europe (e.g., amisulpride) have been shown to be efficacious in improving the negative symptoms of schizophrenia in controlled studies (Möller 2001).
In elderly patients with schizophrenia, a thorough evaluation followed by treatment with low dosages of atypical antipsychotics is the optimal strategy. When appropriate, antipsychotic treatment may need to be combined with psychosocial intervention (Sable and Jeste 2002).
The dosages of typical antipsychotics used in elderly patients with schizophrenia need to be lower than the dosages used in young adults (Jeste 2000). Abrupt withdrawal of atypical antipsychotics, particularly quetiapine, has not been shown to cause major adverse effects, but nonetheless, gradual withdrawal over a few days is advisable for all antipsychotics (Cutler et al. 2002). Although atypical antipsychotics can be safely combined with cholinesterase inhibitors in schizophrenia, a study in patients receiving risperidone found no cognitive benefit from adding donepezil compared with adding placebo (J.I. Friedman et al. 2002).
Late-onset delusional disorder is uncommon. As is the case in young adults, delusional disorder in elderly individuals is difficult to treat, and the delusions often do not remit even with adequate antipsychotic treatment. The diagnosis of paraphrenia overlaps considerably with current nomenclature for late-onset schizophrenia, and atypical antipsychotics are the treatment of choice for this disorder (Howard et al. 2000).
Psychotic depression is an uncommon but clinically important diagnosis in the elderly. Based on studies in mixed-age samples, antipsychotics combined with antidepressants are the pharmacological treatment of choice in psychotic depression, but electroconvulsive therapy (ECT) is still considered the most effective treatment for this disorder (Mulsant et al. 2001b; Sackeim et al. 1995; Spiker et al. 1985). Expert consensus guidelines suggest that antipsychotic medication should be continued for 6 months following treatment response in psychotic depression (Alexopoulos et al. 2001). A double-blind trial of combination pharmacotherapy for psychotic depression showed that treatment with olanzapine plus sertraline was superior to treatment with olanzapine plus placebo in both older (≥60 years) and younger adult patients, a finding that highlights the importance of combination antipsychotic and antidepressant treatment (Meyers et al. 2009).
Antipsychotics are used widely in the treatment of the manic phase of bipolar disorder across the life span (Levine et al. 2000). In bipolar disorder, there is ample evidence for the efficacy of typical and atypical antipsychotics, both individually and in combination with mood stabilizers (Sachs et al. 2002; Tohen et al. 2002). However, there is a surprising lack of data on the use of antipsychotics in geriatric patients with bipolar disorder. Lithium’s toxicity, particularly in the neurological domain, is problematic in the elderly (McDonald 2000). Hence, anticonvulsants and atypical antipsychotics are frequently used to treat mania in elderly patients. However, in the absence of controlled data, the optimal choice of antipsychotic and the optimal dosage to use in these patients are open questions that need to be answered in future research.
Although obsessive-compulsive disorder is not considered a psychotic illness, there is evidence that atypical antipsychotics are useful adjunctive medications in adults with this disorder (Denys et al. 2002). However, comparable data are lacking in geriatric patients.
Clearly, antipsychotic medications, particularly atypical antipsychotics, have an important role to play in the treatment of psychosis and behavioral dyscontrol in Alzheimer’s disease, other types of dementia, and other neurodegenerative conditions. Antipsychotics remain the first-line treatment for schizophrenia and other psychotic disorders across the life span. When antipsychotic medications are used in elderly patients, monitoring of target symptoms, somatic side effects, potential drug interactions, cognition, and activities of daily living is necessary.
Alexopoulos GS, Katz IR, Reynolds CF 3rd, et al; Expert Consensus Panel for Pharmacotherapy of Depressive Disorders in Older Patients: The expert consensus guideline series. Pharmacotherapy of depressive disorders in older patients (Special Report). Postgrad Med Spec No Pharmacotherapy(October):1–86, 2001 17205639
Allard P, Gram L, Timdahl K, et al: Efficacy and tolerability of venlafaxine in geriatric outpatients with major depression: a double-blind, randomised 6-month comparative trial with citalopram. Int J Geriatr Psychiatry 19(12):1123–1130, 2004 15526307
American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, 3rd Edition. Washington, DC, American Psychiatric Association, 1980
American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, 3rd Edition, Revised. Washington, DC, American Psychiatric Association, 1987
Arana GW: An overview of side effects caused by typical antipsychotics. J Clin Psychiatry 61 (suppl 8):5–11, discussion 12–13, 2000 10811237
Avorn J, Soumerai SB, Everitt DE, et al: A randomized trial of a program to reduce the use of psychoactive drugs in nursing homes. N Engl J Med 327(3):168–173, 1992 1608408
Ballard C, O’Brien J, Coope B, et al: A prospective study of psychotic symptoms in dementia sufferers: psychosis in dementia. Int Psychogeriatr 9(1):57–64, 1997 9195279
Ballard CG, Thomas A, Fossey J, et al: A 3-month, randomized, placebo-controlled, neuroleptic discontinuation study in 100 people with dementia: the neuropsychiatric inventory median cutoff is a predictor of clinical outcome. J Clin Psychiatry 65(1):114–119, 2004 14744180
Barak Y, Shamir E, Weizman R: Would a switch from typical antipsychotics to risperidone be beneficial for elderly schizophrenic patients? A naturalistic, long-term, retrospective, comparative study. J Clin Psychopharmacol 22(2):115–120, 2002 11910255
Barbey JT, Roose SP: SSRI safety in overdose. J Clin Psychiatry 59 (suppl 15):42–48, 1998 9786310
Barnes R, Veith R, Okimoto J, et al: Efficacy of antipsychotic medications in behaviorally disturbed dementia patients. Am J Psychiatry 139(9):1170–1174, 1982 7114310
Benet LZ, Hoener BA: Changes in plasma protein binding have little clinical relevance. Clin Pharmacol Ther 71(3):115–121, 2002 11907485
Bies RR, Feng Y, Lotrich FE, et al: Utility of sparse concentration sampling for citalopram in elderly clinical trial subjects. J Clin Pharmacol 44(12):1352–1359, 2004 15545305
Bigos KL, Bies RR, Pollock BG: Population pharmacokinetics in geriatric psychiatry. Am J Geriatr Psychiatry 14(12):993–1003, 2006 17138806
Bodick NC, Offen WW, Shannon HE, et al: The selective muscarinic agonist xanomeline improves both the cognitive deficits and behavioral symptoms of Alzheimer disease. Alzheimer Dis Assoc Disord 11 (suppl 4):S16–S22, 1997 9339268
Bondareff W, Alpert M, Friedhoff AJ, et al: Comparison of sertraline and nortriptyline in the treatment of major depressive disorder in late life. Am J Psychiatry 157(5):729–736, 2000 10784465
Bondolfi G, Eap CB, Bertschy G, et al: The effect of fluoxetine on the pharmacokinetics and safety of risperidone in psychotic patients. Pharmacopsychiatry 35(2):50–56, 2002 11985287
Breier A, Meehan K, Birkett M, et al: A double-blind, placebo-controlled dose-response comparison of intramuscular olanzapine and haloperidol in the treatment of acute agitation in schizophrenia. Arch Gen Psychiatry 59(5):441–448, 2002a 11982448
Breier A, Sutton VK, Feldman PD, et al: Olanzapine in the treatment of dopamimetic-induced psychosis in patients with Parkinson’s disease. Biol Psychiatry 52(5): 438–445, 2002b 12242060
Breitbart W, Tremblay A, Gibson C: An open trial of olanzapine for the treatment of delirium in hospitalized cancer patients. Psychosomatics 43(3):175–182, 2002 12075032
Brodaty H, Arasaratnam C: Meta-analysis of nonpharmacological interventions for neuropsychiatric symptoms of dementia. Am J Psychiatry 169(9):946–953, 2012 22952073
Brodaty H, Ames D, Snowdon J, et al: A randomized placebo-controlled trial of risperidone for the treatment of aggression, agitation, and psychosis of dementia. J Clin Psychiatry 64(2):134–143, 2003 12633121
Burgio LD, Reynolds CFI, Janosky JE, et al: A behavioral microanalysis of the effects of haloperidol and oxazepam in demented psychogeriatric inpatients. Int J Geriatr Psychiatry 7:253–262, 1992
Byerly MJ, DeVane CL: Pharmacokinetics of clozapine and risperidone: a review of recent literature. J Clin Psychopharmacol 16(2):177–187, 1996 8690833
Bymaster FP, Calligaro DO, Falcone JF, et al: Radioreceptor binding profile of the atypical antipsychotic olanzapine. Neuropsychopharmacology 14(2):87–96, 1996 8822531
Carlyle W, Ancill RJ, Sheldon L: Aggression in the demented patient: a double-blind study of loxapine versus haloperidol. Int Clin Psychopharmacol 8(2):103–108, 1993 8345158
Casey DE: Extrapyramidal syndromes and new antipsychotic drugs: findings in patients and non-human primate models. Br J Psychiatry Suppl (29):32–39, 1996 8733821
Centorrino F, Baldessarini RJ, Kando JC, et al: Clozapine and metabolites: concentrations in serum and clinical findings during treatment of chronically psychotic patients. J Clin Psychopharmacol 14(2):119–125, 1994 8195452
Chan WC, Lam LC, Choy CN, et al: A double-blind randomised comparison of risperidone and haloperidol in the treatment of behavioural and psychological symptoms in Chinese dementia patients. Int J Geriatr Psychiatry 16(12):1156–1162, 2001 11748775
Chengappa KNR, Baker RW, Kreinbrook SB, Adair D: Clozapine use in female geriatric patients with psychoses. J Geriatr Psychiatry Neurol 8(1):12–15, 1995 7710640
Chew ML, Mulsant BH, Pollock BG, et al: Anticholinergic activity of 107 medications commonly used by older adults. J Am Geriatr Soc 56(7):1333–1341, 2008 18510583
Chouinard G, Jones B, Remington G, et al: A Canadian multicenter placebo-controlled study of fixed doses of risperidone and haloperidol in the treatment of chronic schizophrenic patients. J Clin Psychopharmacol 13(1):25–40, 1993 7683702
Cohen-Mansfield J, Marx MS, Rosenthal AS: A description of agitation in a nursing home. J Gerontol 44(3):M77–M84, 1989 2715584
Cohen-Mansfield J, Lipson S, Werner P, et al: Withdrawal of haloperidol, thioridazine, and lorazepam in the nursing home: a controlled, double-blind study. Arch Intern Med 159(15):1733–1740, 1999 10448776
Colenda CC, Mickus MA, Marcus SC, et al: Comparison of adult and geriatric psychiatric practice patterns: findings from the American Psychiatric Association’s Practice Research Network. Am J Geriatr Psychiatry 10(5):609–617, 2002 12213696
Covington JS: Alleviating agitation, apprehension, and related symptoms in geriatric patients: A double-blind comparison of a phenothiazine and a benzodiazepien. South Med J 68(6):719–724, 1975 1094544
Csernansky JG, Schuchart EK: Relapse and rehospitalisation rates in patients with schizophrenia: effects of second generation antipsychotics. CNS Drugs 16(7): 473–484, 2002 12056922
Cummings JL, Mega M, Gray K, et al: The Neuropsychiatric Inventory: comprehensive assessment of psychopathology in dementia. Neurology 44(12):2308–2314, 1994 7991117
Cummings JL, Street J, Masterman D, Clark WS: Efficacy of olanzapine in the treatment of psychosis in dementia with lewy bodies. Dement Geriatr Cogn Disord 13(2):67–73, 2002 11844887
Cummings J, Isaacson S, Mills R, et al: Pimavanserin for patients with Parkinson’s disease psychosis: a randomised, placebo-controlled phase 3 trial. Lancet 383(9916):533–540, 2014 24183563
Cummings J, Mintzer J, Brodaty H, et al; International Psychogeriatric Association: Agitation in cognitive disorders: International Psychogeriatric Association provisional consensus clinical and research definition. Int Psychogeriatr 27(1): 7–17, 2015 25311499
Cutler AJ, Goldstein JM, Tumas JA: Dosing and switching strategies for quetiapine fumarate. Clin Ther 24(2):209–222, 2002 11911552
Davidson M, Emsley R, Kramer M, et al: Efficacy, safety and early response of paliperidone extended-release tablets (paliperidone ER): results of a 6-week, randomized, placebo-controlled study. Schizophr Res 93(1–3):117–130, 2007 17466492
Davies P, Maloney AJF: Selective loss of central cholinergic neurons in Alzheimer’s disease. Lancet 2(8000):1403, 1976 63862
De Deyn PP, Rabheru K, Rasmussen A, et al: A randomized trial of risperidone, placebo, and haloperidol for behavioral symptoms of dementia. Neurology 53(5):946–955, 1999 10496251
De Deyn P, Jeste DV, Swanink R, et al: Aripiprazole for the treatment of psychosis in patients with Alzheimer’s disease: a randomized, placebo-controlled study. J Clin Psychopharmacol 25(5):463–467, 2005 16160622
Denys D, van Megen H, Westenberg H: Quetiapine addition to serotonin reuptake inhibitor treatment in patients with treatment-refractory obsessive-compulsive disorder: an open-label study. J Clin Psychiatry 63(8):700–703, 2002 12197450
Devanand DP, Brockington CD, Moody BJ, et al: Behavioral syndromes in Alzheimer’s disease. Int Psychogeriatr 4 (suppl 2): 161–184, 1992a 1288661
Devanand DP, Miller L, Richards M, et al: The Columbia University Scale for Psychopathology in Alzheimer’s disease. Arch Neurol 49(4):371–376, 1992b 1558517
Devanand DP, Jacobs DM, Tang M-X, et al: The course of psychopathologic features in mild to moderate Alzheimer disease. Arch Gen Psychiatry 54(3):257–263, 1997 9075466
Devanand DP, Marder K, Michaels KS, et al: A randomized, placebo-controlled dose-comparison trial of haloperidol for psychosis and disruptive behaviors in Alzheimer’s disease. Am J Psychiatry 155(11): 1512–1520, 1998 9812111
Devanand DP, Mintzer J, Schultz SK, et al: Relapse risk after discontinuation of risperidone in Alzheimer’s disease. N Engl J Med 367(16):1497–1507, 2012 23075176
Dolder CR, Lacro JP, Dunn LB, Jeste DV: Antipsychotic medication adherence: is there a difference between typical and atypical agents? Am J Psychiatry 159(1):103–108, 2002 11772697
Dresser GK, Spence JD, Bailey DG: Pharmacokinetic-pharmacodynamic consequences and clinical relevance of cytochrome P450 3A4 inhibition. Clin Pharmacokinet 38(1):41–57, 2000 10668858
Ellingrod VL, Schultz SK, Ekstam-Smith K, et al: Comparison of risperidone with olanzapine in elderly patients with dementia and psychosis. Pharmacotherapy 22(1):1–5, 2002 11794418
Elon R, Pawlson LG: The impact of OBRA on medical practice within nursing facilities. J Am Geriatr Soc 40(9):958–963, 1992 1512394
Fann WE, Davis JM, Janowsky DS, et al: Chlorpromazine: effects of antacids on its gastrointestinal absorption. J Clin Pharmacol 13(10):388–390, 1973 4355737
Feng Y, Pollock BG, Ferrell RE, et al: Paroxetine: population pharmacokinetic analysis in late-life depression using sparse concentration sampling. Br J Clin Pharmacol 61(5):558–569, 2006 16669849
Fernandez HH, Trieschmann ME, Burke MA, Friedman JH: Quetiapine for psychosis in Parkinson’s disease versus dementia with Lewy bodies. J Clin Psychiatry 63(6):513–515, 2002 12088163
Finkel SI, Lyons JS, Anderson RL, et al: A randomized, placebo-controlled trial of thiothixene in agitated, demented nursing home patients. Int J Geriatr Psychiatry 10:129–136, 1995
Fitz D, Mallya A: Discontinuation of a psychogeriatric program for nursing home residents: psychotropic medication changes and behavioral reactions. J Appl Gerontol 11(1):50–63, 1992 10116945
Flint AJ, Rifat SL: The effect of sequential antidepressant treatment on geriatric depression. J Affect Disord 36(3–4):95–105, 1996 8821312
Flockhart DA: Drug Interactions: Cytochrome P450 Drug Interaction Table. Indianapolis, Indiana University School of Medicine, 2007. Available at: http://medicine.iupui.edu/clinpharm/ddis/clinical-table/. Accessed February 28, 2016.
Friedman JH, Fernandez HH: Atypical antipsychotics in Parkinson-sensitive populations. J Geriatr Psychiatry Neurol 15(3): 156–170, 2002 12230086
Friedman JI, Adler DN, Howanitz E, et al: A double blind placebo controlled trial of donepezil adjunctive treatment to risperidone for the cognitive impairment of schizophrenia. Biol Psychiatry 51(5):349–357, 2002 11904128
Fulton B, Goa KL: Olanzapine. A review of its pharmacological properties and therapeutic efficacy in the management of schizophrenia and related psychoses. Drugs 53(2):281–298, 1997 9028746
Gerretsen P, Pollock BG: Drugs with anticholinergic properties: a current perspective on use and safety. Expert Opin Drug Saf 10(5):751–765, 2011 21635190
Ghoneim MM, Mewaldt SP, Berie JL, Hinrichs JV: Memory and performance effects of single and 3-week administration of diazepam. Psychopharmacology (Berl) 73(2):147–151, 1981 6785805
Giron MS, Forsell Y, Bernsten C, et al: Psychotropic drug use in elderly people with and without dementia. Int J Geriatr Psychiatry 16(9):900–906, 2001 11571771
Glassman AH, Roose SP, Bigger JT Jr: The safety of tricyclic antidepressants in cardiac patients. Risk-benefit reconsidered. JAMA 269(20):2673–2675, 1993 8487453
Glassman AH, O’Connor CM, Califf RM, et al; Sertraline Antidepressant Heart Attack Randomized Trial (SADHEART) Group: Sertraline treatment of major depression in patients with acute MI or unstable angina. JAMA 288(6):701–709, 2002 12169073
Goodnick PJ, Jerry J, Parra F: Psychotropic drugs and the ECG: focus on the QTc interval. Expert Opin Pharmacother 3(5):479–498, 2002 11996627
Gottfries CG: Scandinavian experience with citalopram in the elderly. Int Clin Psychopharmacol 11 (suppl 1):41–44, 1996 8732444
Graff-Guerrero A, Rajji TK, Mulsant BH, et al: Maintenance antipsychotic dose can be decreased in late-life schizophrenia: a prospective dopamine D2/3 receptor occupancy study with [11C]-raclopride. JAMA Psychiatry 72:927–934, 2015 26131622
Greenblatt DJ, Harmatz JS, Shader RI: Clinical pharmacokinetics of anxiolytics and hypnotics in the elderly. Therapeutic considerations (Part I). Clin Pharmacokinet 21(3):165–177, 1991 1684924
Gurwitz JH, Field TS, Avorn J, et al: Incidence and preventability of adverse drug events in nursing homes. Am J Med 109(2):87–94, 2000 10967148
Gurwitz JH, Field TS, Harrold LR, et al: Incidence and preventability of adverse drug events among older persons in the ambulatory setting. JAMA 289(9):1107–1116, 2003 12622580
Hicks R, Davis J: Pharmacokinetics in geriatric psychopharmacology, in Psychopharmacology of Aging. Edited by Eisdorfer C, Fann W. New York, Spectrum Publications, 1980, pp 169–212
Holmes C, Smith H, Ganderton R, et al: Psychosis and aggression in Alzheimer’s disease: the effect of dopamine receptor gene variation. J Neurol Neurosurg Psychiatry 71(6):777–779, 2001 11723200
Holton A, George K: The use of lithium in severely demented patients with behavioural disturbance. Br J Psychiatry 146:99–100, 1985 3978352
Horwitz GJ, Tariot PN, Mead K, et al: Discontinuation of antipsychotics in nursing home patients with dementia. Am J Geriatr Psychiatry 3:290–299, 1995
Howard R, Rabins PV, Seeman MV, Jeste DV; The International Late-Onset Schizophrenia Group: Late-onset schizophrenia and very-late-onset schizophrenia-like psychosis: an international consensus. Am J Psychiatry 157(2):172–178, 2000 10671383
Hulshof TA, Zuidema SU, Ostelo RW, Luijendijk HJ: The mortality risk of conventional antipsychotics in elderly patients: a systematic review and meta-analysis of randomized placebo-controlled trials. J Am Med Dir Assoc 16(10):817–824, 2015 25933724
Huybrechts KF, Gerhard T, Crystal S, et al: Differential risk of death in older residents in nursing homes prescribed specific antipsychotic drugs: population based cohort study. BMJ 344:e977, 2012 22362541
Hwang YJ, Dixon SN, Reiss JP, et al: Atypical antipsychotic drugs and the risk for acute kidney injury and other adverse outcomes in older adults: a population-based cohort study. Ann Intern Med 161(4):242–248, 2014 25133360
Janssen PA, Niemegeers CJ, Awouters F, et al: Pharmacology of risperidone (R 64 766), a new antipsychotic with serotonin-S2 and dopamine-D2 antagonistic properties. J Pharmacol Exp Ther 244(2):685–693, 1988 2450200
Jeste DV: Tardive dyskinesia in older patients. J Clin Psychiatry 61 (suppl 4):27–32, 2000 10739328
Jeste DV, Finkel SI: Psychosis of Alzheimer’s disease and related dementias. Diagnostic criteria for a distinct syndrome. Am J Geriatr Psychiatry 8(1):29–34, 2000 10648292
Jeste DV, Lacro JP, Palmer B, et al: Incidence of tardive dyskinesia in early stages of low-dose treatment with typical neuroleptics in older patients. Am J Psychiatry 156(2):309–311, 1999 9989570
Jeste DV, Okamoto A, Napolitano J, et al: Low incidence of persistent tardive dyskinesia in elderly patients with dementia treated with risperidone. Am J Psychiatry 157(7):1150–1155, 2000 10873925
Jeste DV, Blazer D, Casey D, et al: ACNP White Paper: update on use of antipsychotic drugs in elderly persons with dementia. Neuropsychopharmacology 33(5):957–970, 2008 17637610
Jin H, Meyer JM, Jeste DV: Atypical antipsychotics and glucose dysregulation: a systematic review. Schizophr Res 71(2–3):195–212, 2004 15474892
Jin Y, Pollock BG, Frank E, et al: Effect of age, weight, and CYP2C19 genotype on escitalopram exposure. J Clin Pharmacol 50(1):62–72, 2010 19841156
Jones DM, Lewis MJ, Spriggs TLB: The effects of low doses of diazepam on human performance in group administered tasks. Br J Clin Pharmacol 6(4):333–337, 1978 698029
Jones PB, Barnes TR, Davies L, et al: Randomized controlled trial of the effect on Quality of Life of second- vs first-generation antipsychotic drugs in schizophrenia: Cost Utility of the Latest Antipsychotic Drugs in Schizophrenia Study (CUtLASS 1). Arch Gen Psychiatry 63(10):1079–1087, 2006 17015810
Kane J, Honigfeld G, Singer J, Meltzer H: Clozapine for the treatment-resistant schizophrenic. A double-blind comparison with chlorpromazine. Arch Gen Psychiatry 45(9):789–796, 1988 3046553
Kasper S, de Swart H, Friis Andersen H: Escitalopram in the treatment of depressed elderly patients. Am J Geriatr Psychiatry 13(10):884–891, 2005 16223967
Katz IR, Jeste DV, Mintzer JE, et al; Risperidone Study Group: Comparison of risperidone and placebo for psychosis and behavioral disturbances associated with dementia: a randomized, double-blind trial. J Clin Psychiatry 60(2):107–115, 1999 10084637
Katz I, de Deyn PP, Mintzer J, et al: The efficacy and safety of risperidone in the treatment of psychosis of Alzheimer’s disease and mixed dementia: a meta-analysis of 4 placebo-controlled clinical trials. Int J Geriatr Psychiatry 22(5):475–484, 2007 17471598
Kaufer DI, Cummings JL, Christine D: Effect of tacrine on behavioral symptoms in Alzheimer’s disease: an open-label study. J Geriatr Psychiatry Neurol 9(1):1–6, 1996 8679057
Kim H, Lim SW, Kim S, et al: Monoamine transporter gene polymorphisms and antidepressant response in koreans with late-life depression. JAMA 296(13):1609–1618, 2006 17018806
Kindermann SS, Dolder CR, Bailey A, et al: Pharmacological treatment of psychosis and agitation in elderly patients with dementia: four decades of experience. Drugs Aging 19(4):257–276, 2002 12038878
Kirby D, Ames D: Hyponatraemia and selective serotonin re-uptake inhibitors in elderly patients. Int J Geriatr Psychiatry 16(5):484–493, 2001 11376464
Kirven LE, Montero EF: Comparison of thioridazine and diazepam in the control of nonpsychotic symptoms associated with senility: double-blind study. J Am Geriatr Soc 21(12):546–551, 1973 4584169
Kurz M, Hummer M, Kemmler G, et al: Long-term pharmacokinetics of clozapine. Br J Psychiatry 173:341–344, 1998 9926040
Lanctôt KL, Best TS, Mittmann N, et al: Efficacy and safety of neuroleptics in behavioral disorders associated with dementia. J Clin Psychiatry 59(10):550–561, quiz 562–563, 1998 9818639
Lane H-Y, Chang Y-C, Chiu C-C, et al: Association of risperidone treatment response with a polymorphism in the 5-HT(2A) receptor gene. Am J Psychiatry 159(9):1593–1595, 2002 12202283
Lantz MS, Louis A, Lowenstein G, Kennedy GJ: A longitudinal study of psychotropic prescriptions in a teaching nursing home. Am J Psychiatry 147(12):1637–1639, 1990 2244642
Lawlor BA, Radcliffe J, Molchan SE, et al: A pilot placebo-controlled study of trazodone and buspirone in Alzheimer’s disease. Int J Geriatr Psychiatry 9:55–59, 1994
Lawlor BA, Ryan TM, Bierer LM, et al: Lack of association between clinical symptoms and postmortem indices of brain serotonin function in Alzheimer’s disease. Biol Psychiatry 37(12):895–896, 1995 7548465
Lenze E, Mulsant B, Blumberger D, et al: Efficacy, safety, and tolerability of augmentation pharmacotherapy with aripiprazole for treatment-resistant depression in late life: a randomised, double-blind, placebo-controlled trial. Lancet 386(10011):2394, 2015 26423182
Levine J, Chengappa KN, Brar JS, et al: Psychotropic drug prescription patterns among patients with bipolar I disorder. Bipolar Disord 2(2):120–130, 2000 11252651
Lieberman JA: Maximizing clozapine therapy: managing side effects. J Clin Psychiatry 59 (suppl 3):38–43, 1998 9541337
Lieberman JA, Stroup TS, McEvoy JP, et al; Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) Investigators: Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. N Engl J Med 353(12):1209–1223, 2005 16172203
Liljequist R, Linnoila M, Mattila MJ: Effect of diazepam and chlorpromazine on memory functions in man. Eur J Clin Pharmacol 13(5):339–343, 1978 352709
Liu B, Anderson G, Mittmann N, et al: Use of selective serotonin-reuptake inhibitors or tricyclic antidepressants and risk of hip fractures in elderly people. Lancet 351(9112):1303–1307, 1998 9643791
Lotrich FE, Pollock BG: Aging and clinical pharmacology: implications for antidepressants. J Clin Pharmacol 45(10):1106–1122, 2005 16172176
Lyketsos CG, Steinberg M, Tschanz JT, et al: Mental and behavioral disturbances in dementia: findings from the Cache County Study on Memory in Aging. Am J Psychiatry 157(5):708–714, 2000 10784462
Marder SR, Kramer M, Ford L, et al: Efficacy and safety of paliperidone extended-release tablets: results of a 6-week, randomized, placebo-controlled study. Biol Psychiatry 62(12):1363–1370, 2007 17601495
Maust DT, Kim HM, Seyfried LS, et al: Antipsychotics, other psychotropics, and the risk of death in patients with dementia: number needed to harm. JAMA Psychiatry 72(5):438–445, 2015 25786075
McDonald WM: Epidemiology, etiology, and treatment of geriatric mania. J Clin Psychiatry 61 (suppl 13):3–11, 2000 11153809
McKeith IG: Consensus guidelines for the clinical and pathologic diagnosis of dementia with Lewy bodies (DLB): report of the Consortium on DLB International Workshop. J Alzheimers Dis 9 (3 suppl):417–423, 2006 16914880
McManus DQ, Arvanitis LA, Kowalcyk BB: Quetiapine, a novel antipsychotic: experience in elderly patients with psychotic disorders. Seroquel Trial 48 Study Group. J Clin Psychiatry 60(5):292–298, 1999 10362435
Meehan KM, Wang H, David SR, et al: Comparison of rapidly acting intramuscular olanzapine, lorazepam, and placebo: a double-blind, randomized study in acutely agitated patients with dementia. Neuropsychopharmacology 26(4):494–504, 2002 11927174
Mesters P, Ansseau M, Brasseur R, et al: An open multicentre study to evaluate the efficacy and tolerance of fluoxetine 20 mg in depressed ambulatory patients. Acta Psychiatr Belg 92(4):232–245, 1992 1345403
Meyers BS, Flint AJ, Rothschild AJ, et al; STOP-PD Group: A double-blind randomized controlled trial of olanzapine plus sertraline vs olanzapine plus placebo for psychotic depression: the study of pharmacotherapy of psychotic depression (STOP-PD). Arch Gen Psychiatry 66(8):838–847, 2009 19652123
Michel K, Kolakowska T: A survey of prescribing psychotropic drugs in two psychiatric hospitals. Br J Psychiatry 138:217–221, 1981 7272613
Möller HJ: Amisulpride: efficacy in the management of chronic patients with predominant negative symptoms of schizophrenia. Eur Arch Psychiatry Clin Neurosci 251(5):217–224, 2001 11829208
Mukaetova-Ladinska EB, Harrington CR, Roth M, Wischik CM: Biochemical and anatomical redistribution of tau protein in Alzheimer’s disease. Am J Pathol 143(2): 565–578, 1993 8342603
Mullen J, Jibson MD, Sweitzer D: A comparison of the relative safety, efficacy, and tolerability of quetiapine and risperidone in outpatients with schizophrenia and other psychotic disorders: the quetiapine experience with safety and tolerability (QUEST) study. Clin Ther 23(11):1839–1854, 2001 11768836
Mulsant BH, Pollock BG, Nebes R, et al: A twelve-week, double-blind, randomized comparison of nortriptyline and paroxetine in older depressed inpatients and outpatients. Am J Geriatr Psychiatry 9(4):406–414, 2001a 11739067
Mulsant BH, Sweet RA, Rosen J, et al: A double-blind randomized comparison of nortriptyline plus perphenazine versus nortriptyline plus placebo in the treatment of psychotic depression in late life. J Clin Psychiatry 62(8):597–604, 2001b 11561930
Mulsant BH, Pollock BG, Kirshner M, et al: Serum anticholinergic activity in a community-based geriatric sample: relationship with cognitive performance. Arch Gen Psychiatry 60(2):198–203, 2003 12578438
Murphy GM Jr, Hollander SB, Rodrigues HE, et al: Effects of the serotonin transporter gene promoter polymorphism on mirtazapine and paroxetine efficacy and adverse events in geriatric major depression. Arch Gen Psychiatry 61(11):1163–1169, 2004 15520364
Musselman DL, Evans DL, Nemeroff CB: The relationship of depression to cardiovascular disease: epidemiology, biology, and treatment. Arch Gen Psychiatry 55(7): 580–592, 1998 9672048
Nacmias B, Tedde A, Forleo P, et al: Association between 5-HT(2A) receptor polymorphism and psychotic symptoms in Alzheimer’s disease. Biol Psychiatry 50(6): 472–475, 2001 11566166
Navarro V, Gastó C, Torres X, et al: Citalopram versus nortriptyline in late-life depression: a 12-week randomized single-blind study. Acta Psychiatr Scand 103(6):435–440, 2001 11401657
Nebes RD, Pollock BG, Perera S, et al: The greater sensitivity of elderly APOE ε4 carriers to anticholinergic medications is independent of cerebrovascular disease risk. Am J Geriatr Pharmacother 10(3): 185–192, 2012 22534472
Nelson JC, Kennedy JS, Pollock BG, et al: Treatment of major depression with nortriptyline and paroxetine in patients with ischemic heart disease. Am J Psychiatry 156(7):1024–1028, 1999 10401446
Newhouse PA, Krishnan KRR, Doraiswamy PM, et al: A double-blind comparison of sertraline and fluoxetine in depressed elderly outpatients. J Clin Psychiatry 61(8):559–568, 2000 10982198
Oberholzer AF, Hendriksen C, Monsch AU, et al: Safety and effectiveness of low-dose clozapine in psychogeriatric patients: a preliminary study. Int Psychogeriatr 4(2):187–195, 1992 1477306
Parker C, Coupland C, Hippisley-Cox J: Antipsychotic drugs and risk of venous thromboembolism: nested case-control study. BMJ 341:c4245, 2010 20858909
Paulsen JS, Salmon DP, Thal LJ, et al: Incidence of and risk factors for hallucinations and delusions in patients with probable AD. Neurology 54(10):1965–1971, 2000 10822438
Pelton GH, Devanand DP, Bell K, et al: Usefulness of plasma haloperidol levels for monitoring clinical efficacy and side effects in Alzheimer patients with psychosis and behavioral dyscontrol. Am J Geriatr Psychiatry 11(2):186–193, 2003 12611748
Perry EK, Gibson PH, Blessed G, et al: Neurotransmitter enzyme abnormalities in senile dementia. Choline acetyltransferase and glutamic acid decarboxylase activities in necropsy brain tissue. J Neurol Sci 34(2):247–265, 1977 144789
Peskind ER, Raskind MA, Wingerson D, et al: Enhanced hypothalamic-pituitary-adrenocortical axis responses to physostigmine in normal aging. J Gerontol A Biol Sci Med Sci 50(2):M114–M120, 1995 7874590
Petrie WM, Ban TA, Berney S, et al: Loxapine in psychogeriatrics: a placebo- and standard-controlled clinical investigation. J Clin Psychopharmacol 2(2):122–126, 1982 7042770
Pitner JK, Mintzer JE, Pennypacker LC, Jackson CW: Efficacy and adverse effects of clozapine in four elderly psychotic patients. J Clin Psychiatry 56(5):180–185, 1995 7737956
Pollock BG, Everett G, Perel JM: Comparative cardiotoxicity of nortriptyline and its isomeric 10-hydroxymetabolites. Neuropsychopharmacology 6(1):1–10, 1992a 1571065
Pollock BG, Perel JM, Altieri LP, et al: Debrisoquine hydroxylation phenotyping in geriatric psychopharmacology. Psychopharmacol Bull 28(2):163–168, 1992b 1513919
Pollock BG, Ferrell RE, Mulsant BH, et al: Allelic variation in the serotonin transporter promoter affects onset of paroxetine treatment response in late-life depression. Neuropsychopharmacology 23(5):587–590, 2000a 11027924
Pollock BG, Laghrissi-Thode F, Wagner WR: Evaluation of platelet activation in depressed patients with ischemic heart disease after paroxetine or nortriptyline treatment. J Clin Psychopharmacol 20(2): 137–140, 2000b 10770450
Pollock BG, Mulsant BH, Rosen J, et al: Comparison of citalopram, perphenazine, and placebo for the acute treatment of psychosis and behavioral disturbances in hospitalized, demented patients. Am J Psychiatry 159(3):460–465, 2002 11870012
Pomara N, Deptula D, Singh R, et al: Cognitive toxicity of benzodiazepines in the elderly, in Anxiety in the Elderly: Treatment and Research. Edited by Salzman C, Lebowitz BD. New York, Springer, 1991, pp 175–196
Pomara N, Lee SH, Bruno D, et al: Adverse performance effects of acute lorazepam administration in elderly long-term users: pharmacokinetic and clinical predictors. Prog Neuropsychopharmacol Biol Psychiatry 56:129–135, 2015 25195839
Porsteinsson AP, Tariot PN, Erb R, et al: Placebo-controlled study of divalproex sodium for agitation in dementia. Am J Geriatr Psychiatry 9(1):58–66, 2001 11156753
Porsteinsson AP, Drye LT, Pollock BG, et al; CitAD Research Group: Effect of citalopram on agitation in Alzheimer disease: the CitAD randomized clinical trial. JAMA 311(7):682–691, 2014 24549548
Prien RF, Haber PA, Caffey EMJ Jr: The use of psychoactive drugs in elderly patients with psychiatric disorders: survey conducted in twelve s Administration hospitals. J Am Geriatr Soc 23(3):104–112, 1975 234489
Rada RT, Kellner R: Thiothixene in the treatment of geriatric patients with chronic organic brain syndrome. J Am Geriatr Soc 24(3):105–107, 1976 765388
Raskin J, Wiltse CG, Siegal A, et al: Efficacy of duloxetine on cognition, depression, and pain in elderly patients with major depressive disorder: an 8-week, double-blind, placebo-controlled trial. Am J Psychiatry 164(6):900–909, 2007 17541049
Raskind MA: Evaluation and management of aggressive behavior in the elderly demented patient. J Clin Psychiatry 60 (suppl 15):45–49, 1999 10418815
Ray WA, Federspiel CF, Schaffner W: A study of antipsychotic drug use in nursing homes: epidemiologic evidence suggesting misuse. Am J Public Health 70(5):485–491, 1980 6103676
Ray WA, Meredith S, Thapa PB, et al: Antipsychotics and the risk of sudden cardiac death. Arch Gen Psychiatry 58(12):1161–1167, 2001 11735845
Reilly JG, Ayis SA, Ferrier IN, et al: Thioridazine and sudden unexplained death in psychiatric in-patients. Br J Psychiatry 180:515–522, 2002 12042230
Reisberg B, Borenstein J, Salob SP, et al: Behavioral symptoms in Alzheimer’s disease: phenomenology and treatment. J Clin Psychiatry 48 (suppl):9–15, 1987 3553166
Reisberg B, Franssen E, Sclan S, et al: Stage specific incidence of potentially remediable behavioral symptoms in aging and Alzheimer’s disease: a study of 120 patients using the BEHAVE-AD. Bull Clin Neurosci 54:95–112, 1989
Roe CM, Anderson MJ, Spivack B: Use of anticholinergic medications by older adults with dementia. J Am Geriatr Soc 50(5):836–842, 2002 12028169
Ronfeld RA, Tremaine LM, Wilner KD: Pharmacokinetics of sertraline and its N-demethyl metabolite in elderly and young male and female volunteers. Clin Pharmacokinet 32 (suppl 1):22–30, 1997 9068932
Roose SP, Glassman AH, Siris SG, et al: Comparison of imipramine- and nortriptyline-induced orthostatic hypotension: a meaningful difference. J Clin Psychopharmacol 1(5):316–319, 1981 6277997
Roose SP, Glassman AH, Attia E, Woodring S: Comparative efficacy of selective serotonin reuptake inhibitors and tricyclics in the treatment of melancholia. Am J Psychiatry 151(12):1735–1739, 1994 7977878
Roose SP, Laghrissi-Thode F, Kennedy JS, et al: Comparison of paroxetine and nortriptyline in depressed patients with ischemic heart disease. JAMA 279(4):287–291, 1998 9450712
Roose S, Alexopoulos G, Burke W, et al: Treatment of depression in the “old-old”: a randomized, double-blind, placebo-controlled trial of citalopram in patients at least 75 years of age, in New Research, American Association of Geriatric Psychiatry, Orlando, FL, March 2002
Rubin EH, Kinscherf DA: Psychopathology of very mild dementia of the Alzheimer type. Am J Psychiatry 146(8):1017–1021, 1989 2750973
Russo-Neustadt A, Cotman CW: Adrenergic receptors in Alzheimer’s disease brain: selective increases in the cerebella of aggressive patients. J Neurosci 17(14):5573–5580, 1997 9204938
Sable JA, Jeste DV: Antipsychotic treatment for late-life schizophrenia. Curr Psychiatry Rep 4(4):299–306, 2002 12126599
Sachs GS, Grossman F, Ghaemi SN, et al: Combination of a mood stabilizer with risperidone or haloperidol for treatment of acute mania: a double-blind, placebo-controlled comparison of efficacy and safety. Am J Psychiatry 159(7):1146–1154, 2002 12091192
Sackeim HA, Devanand DP, Nobler MS: Electroconvulsive therapy, in Psychopharmacology: The Fourth Generation of Progress. Edited by Bloom F, Kupfer D. New York, Raven, 1995, pp 1123–1141
Saltz BL, Woerner MG, Kane JM, et al: Prospective study of tardive dyskinesia incidence in the elderly. JAMA 266(17):2402–2406, 1991 1681122
Schatzberg AF, Cantillon M: Antidepressant early response and remission with venlafaxine or fluoxetine in depressed geriatric outpatients (poster presentation [S225–S226]), in Abstracts from 13th Congress of the European College of Neuropsychopharmacology. Munich, Germany, September 9–13, 2000. Eur Neuropsychopharmacol 10 (suppl 3):S107–S424, 2000 11039098
Schatzberg AF, Kremer C, Rodrigues HE, Murphy GM Jr; Mirtazapine vs. Paroxetine Study Group: Double-blind, randomized comparison of mirtazapine and paroxetine in elderly depressed patients. Am J Geriatr Psychiatry 10(5):541–550, 2002 12213688
Schmucker DL: Liver function and phase I drug metabolism in the elderly: a paradox. Drugs Aging 18(11):837–851, 2001 11772124
Schneider LS, Pollock VE, Lyness SA: A metaanalysis of controlled trials of neuroleptic treatment in dementia. J Am Geriatr Soc 38(5):553–563, 1990 1970586
Schneider LS, Nelson JC, Clary CM, et al; Sertraline Elderly Depression Study Group: An 8-week multicenter, parallel-group, double-blind, placebo-controlled study of sertraline in elderly outpatients with major depression. Am J Psychiatry 160(7): 1277–1285, 2003 12832242
Schneider LS, Dagerman KS, Insel P: Risk of death with atypical antipsychotic drug treatment for dementia: meta-analysis of randomized placebo-controlled trials. JAMA 294(15):1934–1943, 2005 16234500
Schneider LS, Tariot PN, Dagerman KS, et al; CATIE-AD Study Group: Effectiveness of atypical antipsychotic drugs in patients with Alzheimer’s disease. N Engl J Med 355(15):1525–1538, 2006 17035647
Serretti A, Cusin C, Rausch JL, et al: Pooling pharmacogenetic studies on the serotonin transporter: a mega-analysis. Psychiatry Res 145(1):61–65, 2006 17069894
Shankle WR, Nielson KA, Cotman CW: Low-dose propranolol reduces aggression and agitation resembling that associated with orbitofrontal dysfunction in elderly demented patients. Alzheimer Dis Assoc Disord 9(4):233–237, 1995 8749613
Shimada T, Yamazaki H, Mimura M, et al: Interindividual variations in human liver cytochrome P-450 enzymes involved in the oxidation of drugs, carcinogens and toxic chemicals: studies with liver microsomes of 30 Japanese and 30 Caucasians. J Pharmacol Exp Ther 270(1):414–423, 1994 8035341
Shin JY, Park MJ, Lee SH, et al: Risk of intracranial haemorrhage in antidepressant users with concurrent use of non-steroidal anti-inflammatory drugs: nationwide propensity score matched study. BMJ 351:h3517, 2015 26173947
Smith GR, Taylor CW, Linkous P: Haloperidol versus thioridazine for the treatment of psychogeriatric patients: a double-blind clinical trial. Psychosomatics 15:134–138, 1974
Sneed JR, Rutherford BR, Rindskopf D, et al: Design makes a difference: a meta-analysis of antidepressant response rates in placebo-controlled versus comparator trials in late-life depression. Am J Geriatr Psychiatry 16(1):65–73, 2008 17998306
Solai LK, Mulsant BH, Pollock BG: Selective serotonin reuptake inhibitors for late-life depression: a comparative review. Drugs Aging 18(5):355–368, 2001 11392444
Spiker DG, Weiss JC, Dealy RS, et al: The pharmacological treatment of delusional depression. Am J Psychiatry 142(4):430–436, 1985 3883815
Stotsky B: Multicenter study comparing thioridazine with diazepam and placebo in elderly, nonpsychotic patients with emotional and behavioral disorders. Clin Ther 6(4):546–559, 1984 6380725
Street JS, Clark WS, Gannon KS, et al; The HGEU Study Group: Olanzapine treatment of psychotic and behavioral symptoms in patients with Alzheimer disease in nursing care facilities: a double-blind, randomized, placebo-controlled trial. Arch Gen Psychiatry 57(10):968–976, 2000 11015815
Suh GH, Son HG, Ju YS, et al: A randomized, double-blind, crossover comparison of risperidone and haloperidol in Korean dementia patients with behavioral disturbances. Am J Geriatr Psychiatry 12(5): 509–516, 2004 15353389
Sultzer DL, Gray KF, Gunay I, et al: A double-blind comparison of trazodone and haloperidol for treatment of agitation in patients with dementia. Am J Geriatr Psychiatry 5(1):60–69, 1997 9169246
Sunderland T, Molchan SE, Little JT, et al: Pharmacologic challenges in Alzheimer disease and normal controls: cognitive modeling in humans. Alzheimer Dis Assoc Disord 11 (suppl 4):S23–S26, 1997 9339269
Swearer JM, Drachman DA, O’Donnell BF, Mitchell AL: Troublesome and disruptive behaviors in dementia. Relationships to diagnosis and disease severity. J Am Geriatr Soc 36(9):784–790, 1988 3411060
Sweet RA, Nimgaonkar VL, Kamboh MI, et al: Dopamine receptor genetic variation, psychosis, and aggression in Alzheimer disease. Arch Neurol 55(10):1335–1340, 1998 9779662
Tandon R: Impact of antipsychotic treatment on long-term course of schizophrenic illness: an introduction. J Psychiatr Res 32(3–4):119–120, 1998 9793864
Tariot PN, Mack JL, Patterson MB, et al: The CERAD Behavior Rating Scale for Dementia (BRSD). Am J Psychiatry 152:1349–1357, 1995 7653692
Tariot PN, Erb R, Podgorski CA, et al: Efficacy and tolerability of carbamazepine for agitation and aggression in dementia. Am J Psychiatry 155(1):54–61, 1998 9433339
Tariot PN, Salzman C, Yeung PP, et al: Long-Term use of quetiapine in elderly patients with psychotic disorders. Clin Ther 22(9): 1068–1084, 2000 11048905
Tariot PN, Raman R, Jakimovich L, et al; Alzheimer’s Disease Cooperative Study; Valproate Nursing Home Study Group: Divalproex sodium in nursing home residents with possible or probable Alzheimer Disease complicated by agitation: a randomized, controlled trial. Am J Geriatr Psychiatry 13(11):942–949, 2005 16286437
Tariot PN, Schneider L, Katz IR, et al: Quetiapine treatment of psychosis associated with dementia: a double-blind, randomized, placebo-controlled clinical trial. Am J Geriatr Psychiatry 14(9):767–776, 2006 16905684
Teri L, Logsdon RG, Peskind E, et al; Alzheimer’s Disease Cooperative Study: Treatment of agitation in AD: a randomized, placebo-controlled clinical trial. Neurology 55(9):1271–1278, 2000 11087767
Tewfik GI, Jain VK, Harcup M, Magowan S: Effectiveness of various tranquilisers in the management of senile restlessness. Gerontol Clin (Basel) 12(6):351–359, 1970 4926614
Thomas VS, Darvesh S, MacKnight C, Rockwood K: Estimating the prevalence of dementia in elderly people: a comparison of the Canadian Study of Health and Aging and National Population Health Survey approaches. Int Psychogeriatr 13 (suppl 1):169–175, 2001 11892964
Timmer CJ, Paanakker JE, Van Hal HJM: Pharmacokinetics of mirtazapine from orally administered tablets: influence of gender, age and treatment regimen. Hum Psychopharmacol 11:497–509, 1996
Tohen M, Baker RW, Altshuler LL, et al: Olanzapine versus divalproex in the treatment of acute mania. Am J Psychiatry 159(6):1011–1017, 2002 12042191
Tollefson GD, Bosomworth JC, Heiligenstein JH, et al; The Fluoxetine Collaborative Study Group: A double-blind, placebo-controlled clinical trial of fluoxetine in geriatric patients with major depression. Int Psychogeriatr 7(1):89–104, 1995 7579025
Tsuang MM, Lu LM, Stotsky BA, Cole JO: Haloperidol versus thioridazine for hospitalized psychogeriatric patients: double-blind study. J Am Geriatr Soc 19(7):593–600, 1971 4937658
Tune L: The role of antipsychotics in treating delirium. Curr Psychiatry Rep 4(3):209–212, 2002 12003684
Van Putten T, Marder SR, Mintz J, Poland RE: Haloperidol plasma levels and clinical response: a therapeutic window relationship. Am J Psychiatry 149(4):500–505, 1992 1554036
Volavka J, Cooper T, Czobor P, et al: Haloperidol blood levels and clinical effects. Arch Gen Psychiatry 49(5):354–361, 1992 1586270
Weihs KL, Settle EC Jr, Batey SR, et al: Bupropion sustained release versus paroxetine for the treatment of depression in the elderly. J Clin Psychiatry 61(3):196–202, 2000 10817105
Weiler PG, Mungas D, Bernick C: Propranolol for the control of disruptive behavior in senile dementia. J Geriatr Psychiatry Neurol 1(4):226–230, 1988 3252890
Weiser M, Rotmensch HH, Korczyn AD, et al; Rivastigmine-Risperidone Study Group: A pilot, randomized, open-label trial assessing safety and pharmakokinetic parameters of co-administration of rivastigmine with risperidone in dementia patients with behavioral disturbances. Int J Geriatr Psychiatry 17(4):343–346, 2002 11994888
Wood S, Cummings JL, Hsu MA, et al: The use of the neuropsychiatric inventory in nursing home residents. Characterization and measurement. Am J Geriatr Psychiatry 8(1):75–83, 2000 10648298
Wynne HA, Goudevenos J, Rawlins MD, et al: Hepatic drug clearance: the effect of age using indocyanine green as a model compound. Br J Clin Pharmacol 30(4):634–637, 1990 2291878
Yerrabolu M, Prabhudesai S, Tawam M, et al: Effect of risperidone on QT interval and QT dispersion in the elderly. Heart Dis 2(1):10–12, 2000 11728238
Yu DK: The contribution of P-glycoprotein to pharmacokinetic drug-drug interactions. J Clin Pharmacol 39(12):1203–1211, 1999 10586385
Zubenko GS, Moossy J, Martinez AJ, et al: Neuropathologic and neurochemical correlates of psychosis in primary dementia. Arch Neurol 48(6):619–624, 1991 1710105