Eric J. Lenze, MD

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Although not a DSM diagnosis, fear of falling is recognized as a common source of functional impairment and distress. The author presents 7 commonly prescribed medication categories that may increase fall risk in older adults.

Caution: 7 Medications That May Increase Falls in Your Older Patient

is Professor of Psychiatry, Washington University, St Louis, MO.

In the elderly, falls are a common and important problem. In the US, fall-related injuries cost approximately $30 billion per year, and about 30% of older adults fall at least once in a given year.

 One of the most feared consequences of falling is a hip fracture, which occurs in almost 400,000 older adults each year. Other consequences include other fractures, head injuries, and less serious injuries that can nonetheless impair function and quality of life.

Moreover, after a fall-related injury, many older adults can have a fear of falling, a common geriatric condition marked by anxiety and low self-confidence about walking safely. Although not a DSM diagnosis, fear of falling is recognized as a common source of functional impairment and distress (and increased risk of falls) in older adults.

Falls are highly relevant to psychiatry because they are often preventable, and one of the most highly feasible prevention strategies concerns psychotropic drugs. Simply stated: if we reduce the use of psychotropic drugs that are known to cause falls (or better yet, avoid such drugs in the first place), we will greatly improve our older patients’ quality of life by preventing falls and fall-related injuries.

Case 1: Your patient is a 74-year-old woman who was referred to you by her primary care physician for management of a complicated psychotropic medication regimen. Her family is very concerned about her gait instability. Upon meeting her, you see obvious ataxia, and at times she has to hold on to the wall for support when she walks. She has had 3 falls in the past 6 months, one of which was serious enough to require a visit to the emergency department. Her family wants to know whether her medications increase her risk of falls-and what should be done about them.

How to reduce falls in older psychiatric patients

First, review your patient’s entire list of medications (not just the “psych” drugs) to look for any drugs that are known to cause falls, in order to stop them (or better yet, not to start them in the first place). There are 2 kinds of medication-related problems: the first are individual drugs that increase fall risk; the second are drug interactions that increase fall risk. For both of these, the most common drugs are sedatives, and in particular benzodiazepines. The Table lists commonly used medications in older adults that increase fall risk.

Be aware of the following clinical points about benzodiazepines and falls in older adults:

There are no “safe benzos”: all benzodiazepines have fall risk, including short-acting medications such as alprazolam.

 There’s no therapeutic index for older adults: there is no dose at which benzodiazepines are effective for anxiety disorders yet safe from fall risk.

 Sedation equals fall risk: a patient who complains of daytime sedation or shows signs of sedation on examination is a patient whose reaction time and postural control are reduced.

 Risk is dose-related: the higher the dose, the greater the risk of falls. This can be an issue with the highly potent benzodiazepines such as clonazepam. A dosage of clonazepam 1 mg twice daily might not sound like a high dosage to many practitioners, but 1 mg of clonazepam is equal in potency to 2 mg of alprazolam or 4 mg of lorazepam.

Avoid the use of benzodiazepines, especially long-term use. Benzodiazepines initiated in a hospital or consultative setting (eg, the patient is anxious) should have an automatic stop in the order (eg, “stop prescription upon discharge”).

Do not prescribe benzodiazepines in the first place: many safer, effective treatments exist. Since the 2 main reasons for a benzodiazepine prescription are insomnia and anxiety, use behavioral methods as a first-line intervention. Cognitive behavioral therapy, brief behavioral therapy, and sleep hygiene are all good first-line choices for insomnia; cognitive behavioral therapy, relaxation training, and mindfulness training are all effective for chronic anxiety. In addition, both insomnia and anxiety disorders have effective medication regimens that are safer than benzodiazepines: trazodone, ramelteon, and melatonin for insomnia; and SSRIs, SNRIs, and mirtazapine for anxiety.

Taper and try to stop benzodiazepines in older adults, especially in those with obvious fall risk (such as recent falls or ataxia). A good rule of thumb is to go slow: a small dose reduction every 2 weeks should avoid overt withdrawal and more insidious rebound effects.

A final point about reducing and stopping benzodiazepines is to remember that these medications are habit-forming. Clearly describe their risks in ways that patients understand and remember (eg, “this medication causes hip fractures”; “it is bad for your brain, like having Alzheimer’s”). Reiterate these risks, using the same memorable language, at follow-up appointments.

Any sedative can cause falls. Aside from benzodiazepines, sleeping medications (particularly the “z-drugs”-zolpidem, zaleplon, and eszopiclone), centrally acting anticholinergics and antihistamines, and some other psychotropic drugs (eg, gabapentin; some antipsychotics) can increase the risk of falls. Many of these drugs are “non-psychiatric” drugs, such as anticholinergics for the bowel or bladder, antihistamines for allergies, and over-the-counter sleep medications such as diphenhydramine. Because these drugs adversely affect the brain, identifying and stopping them is the psychiatrist’s job, as doing so reduces patients’ fall risk, helps their cognitive function, and reduces their risk of delirium and cognitive decline. The centrally acting anticholinergics can often be stopped immediately, or if they are needed, they can be switched to a less toxic alternative. Thus, many of these sedating drugs are easy to fix with a “stop or switch” approach.

This article should not be taken as a recommendation to stop or avoid all fall-risk medications. Indeed, many may be necessary for stabilizing a patient psychiatrically (eg, antipsychotics or mood stabilizers for severe mental illness) or medically (eg, antiseizure medications). This article cannot provide a one-size-fits-all recommendation in such cases; they will be classic “risk versus risk” decisions that consider the risk of a patient falling (or suffering cognitive impairment) against the risk of clinically worsening. In fact, there are scenarios in which patients must receive medications that are hazardous to them; for example, antipsychotics in dementia with behavior disturbance. In such cases, communicate with patients and their families this balance of risks and benefits, and aim for a shared decision-making process.

Two types of drug combinations are known to cause falls. The first is “cumulative” (or pharmacodynamic) interactions. For example, an older adult who takes 2 sedative drugs is at greater risk for falling than an older adult who takes one (assuming same dose). Remember that some of these hazardous combinations may include something “over the counter” (eg, alcohol plus a sedative medication).

The second drug interaction is pharmacokinetic: one drug interferes with the metabolism of another, raising its concentration and making it toxic. Some antidepressants are notorious for these interactions-namely, paroxetine (strong CYP 2D6 and 2B6 inhibitor), fluoxetine and duloxetine (moderate CYP 2D6 and 2B6 inhibitors), and bupropion (strong CYP 2D6 inhibitor). For example, a common antidepressant combination strategy is paroxetine plus bupropion. This makes sense from a pharmacodynamic perspective, as paroxetine is an SSRI while bupropion is a norepinephrine and a dopamine reuptake inhibitor. But it is a nightmare from a pharmacokinetic perspective: paroxetine inhibits 2D6 (thus, it inhibits its own metabolism, producing non-linear pharmacokinetics) and 2B6, which metabolizes bupropion. Bupropion in turn also inhibits 2D6 (further inhibiting paroxetine’s metabolism). The result can be a positive feedback loop in which the 2 drugs increase each other’s concentration and cause adverse effects, including falls.

 For this reason, it is important to be aware of the pharmacokinetic effects of common psychotropics.

Do commonly prescribed antidepressants cause falls in older adults?

Case 2: Your patient is a 60-year-old woman whom you are treating for recurrent major depression with an SSRI. She has responded well and comes for routine follow-up. However, at this visit, she wants to stop the antidepressant. She says she recently read that antidepressants cause falls in older adults, and she is afraid of falling because she has osteopenia and her mother died of complications of a hip fracture. What should you do?

Several observational studies have reported that antidepressants are associated with falls in older adults. This includes SSRIs and SNRIs. It should also be noted that a host of additional “risks” of these antidepressants have been reported in observational studies, including all-cause mortality, suicide, and bone loss. However, there is no evidence that antidepressants cause falls (or any of these other risks) in older adults, as no randomized controlled trial has demonstrated this association. In spite of the absence of conclusive evidence, some may argue observational studies are sufficient to assert that these antidepressants do cause falls and therefore that clinical practice and policy should reflect this risk. Such a viewpoint might recommend that antidepressants be less commonly used in older adults, perhaps in favor of psychotherapy, and that they be reserved for the most severe acute cases and then be tapered off.

Yet, in medicine, observational studies are typically insufficient to argue causality (with some notable exceptions, such as smoking and lung cancer). Observational studies are insufficient because they cannot rule out alternative explanations for the association. Other explanations for the antidepressant-falls association are that falls cause people to be placed on antidepressants, and that older adults who are prescribed antidepressants in the real world tend to be people who are more fall-prone in the first place-because they are medically ill and functionally impaired (and depressed!). No observational study can completely control for confounding variables.

Given the unresolved controversy, psychotropics in the elderly are an example of the typical “risk versus risk” consideration that we commonly grapple with in psychiatry; namely, does the risk of treatment outweigh the risk of non-treatment? In older adults, the known risks of untreated major depression and anxiety disorders usually outweigh the unknown risk of falls with antidepressants. This does not mean that antidepressants are completely benign in older adults. Evidence is needed-in the form of large randomized controlled trials-to determine whether antidepressants do or do not cause falls.

One study, Optimizing Outcomes of Treatment-Resistant Depression in Older Adults (OPTIMUM), may provide some answers. OPTIMUM is a large randomized controlled trial of commonly used augmentation and switch options (such as aripiprazole augmentation, or switch to bupropion) for older adults with treatment-resistant depression. OPTIMUM is ongoing, and results will not be available for several years.

What should clinicians do now? As psychiatrists, it is our job to inform patients of known risks of medications (such as tardive dyskinesia with long-term antipsychotic use), not unknown and unproven ones such as falls with antidepressants. At the same time, we can take the following measures to reduce falls in our patients:

• Ask about recent falls: “Have you fallen in the past 6 months?”

• Assess gait stability at in-person visits

• For those with unsteady gait or multiple recent falls, assess for possible causes, particularly those amenable to psychiatric management

As the 2 cases depict, concern about falls is common in geriatric psychiatry, and understanding and mitigating this risk is a core competency for any psychiatrist who sees older adults. We can do much to prevent falls by reducing risky medications, but there is not sufficient evidence to attribute falls to antidepressants as a class.

Dr. Lenze has received research support from National Institutes of Health, FDA, McKnight Brain Research Foundation, Taylor Family Institute for Innovative Psychiatric Research, Center for Brain Research in Mood Disorders, Barnes Jewish Foundation, Takeda, Lundbeck, Janssen, and Alkermes.

-This article was supported by funding from the National Institutes of Health and the Taylor Family Institute for Innovative Psychiatric Research and Center for Brain Research in Mood Disorders (at Washington University). The funding source(s) had no role in the preparation, review, or approval of the manuscript.

 Centers for Disease Control and Prevention. Costs of Falls Among Older Adults. August 2016. 

https://www.cdc.gov/homeandrecreationalsafety/falls/fallcost.html

 Iaboni A, Flint AJ. The complex interplay of depression and falls in older adults: a clinical review. 

 Joo JH, Lenze EJ, Mulsant BH, et al. Risk factors for falls during treatment of late-life depression. 

 Gebara MA, Lipsey KL, Karp JF, et al. Cause or effect? Selective serotonin reuptake inhibitors and falls in older adults: a systematic review. 

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Psychotropic Drugs and Falls in Older Adults

Despite high prevalence and negative consequences of anxiety disorders in later life, this area has received little research attention. A relatively small number of outcome investigations on late-life anxiety have focused on the impact of pharmacological and psychotherapeutic treatments.

Community prevalence rates for anxiety disorders in older adults range from 3.5% to 10.2%, suggesting a higher prevalence than for late-life depression (Beekman et al., 1998; Bland et al., 1988). Anxiety disorders are even more common among older adults with medical illness and in senior housing facilities (Junginger et al., 1993; Tolin et al., 2005). Generalized anxiety disorder (GAD) is one of the most common anxiety disorders, with community prevalence rates ranging from 1.9% to 7.3% (Beekman et al., 1998; Blazer et al., 1991). Anxiety symptoms that do not meet DSM criteria are even more prevalent, with rates from 15% to 20% in community samples and even higher in medically ill populations (Himmelfarb and Murrell, 1984; Mehta et al., 2003; Wittchen et al., 2002). For example, panic attacks, but not necessarily DSM-diagnosable panic disorder, are common in chronic obstructive pulmonary disease (COPD). Anxiety symptoms and disorders are associated with many negative consequences such as decreased physical activity and functional status, poorer self-perceptions of health, decreased life satisfaction, increased loneliness, increased physical disability, decreased quality of life, and increased service utilization (Brenes et al., 2005a, 2005b; Lenze et al., 2001; Stanley et al., 2001; van Balkom et al., 2000).

The first line of treatment for anxiety in later life is typically pharmacological. Benzodiazepines are the most commonly used anxiety management medication, followed by serotonergic antidepressants, buspirone (BuSpar), and venlafaxine (Effexor) (Mamdani et al., 2005). Recent research has also examined the impact of psychotherapy, typically cognitive-behavioral therapy (CBT), for late-life anxiety.

Approximately half of older patients diagnosed with an anxiety disorder in primary care are prescribed an anxiolytic or antidepressant medication (Stanley et al., 2001). All pharmacological interventions reviewed are approved treatment options for anxiety disorders. Benzodiazepines are the most frequently prescribed medications for anxiety in later life, with usage rates of 10% to as high as 43% for individuals with persistent anxiety (Gleason et al., 1998; Gray et al., 2003; Mamdani et al., 2005; Schuurmans et al., 2005). However, benzodiazepines can lead to an increased risk of falls, and possibly increased cognitive decline, in older people (Paterniti et al., 2002).

 Only three randomized controlled trials have investigated the efficacy of benzodiazepines for anxiety disorders in later life. Two of these focused on GAD (Bresolin et al., 1988; Frattola et al., 1992) and one on an earlier, comparable category of anxiety neurosis (Koepke et al., 1982). The data from these trials suggest the utility of benzodiazepines for anxiety disorders in older adults. Despite the results demonstrating efficacy, limited and short-term use of benzodiazepines is recommended given the possible negative consequences (Sheikh and Cassidy, 2000).

. Five pharmacotherapy studies of late-life anxiety disorders have tested antidepressant medications. Two of these studies included patients with panic disorder (PD), one included a mixed group of patients with GAD, PD or obsessive-compulsive disorder (OCD), and two included patients with GAD. Sheikh and Swales (1999) found promising results when comparing the efficacy of imipramine (Janimine, Tofranil), alprazolam (Xanax) and placebo in patients with PD. A follow-up investigation demonstrated improvement in anxiety symptoms in patients with PD using sertraline (Zoloft) (Sheikh et al., 2004). A sample with mixed anxiety disorders showed high response rates to fluvoxamine (Luvox) (Wylie et al., 2000). Interestingly, none of the three patients with PD responded to treatment. Katz and colleagues (2002) conducted a secondary analysis of data from patients age 60 years and older who participated in five randomized clinical trials of venlafaxine for GAD. Venlafaxine demonstrated superiority to placebo in this investigation. In the only prospective, randomized trial to date of a serotonergic antidepressant, Lenze and colleagues (2005), found citalopram (Celexa) superior to placebo, and these gains were maintained at 32-week follow-up for patients who continued taking the medication (Blank et al., in press).

Most psychotherapy studies of late-life anxiety have used CBT with patients with GAD. We found evidence for the efficacy of CBT for GAD in seven studies. The CBT protocols in these investigations typically consisted of education about anxiety, relaxation training, cognitive therapy and systematic desensitization to worry-provoking thoughts and situations, most commonly administered in a group format. Control conditions included waiting list, minimal contact control, usual care, supportive therapy and a discussion group attention placebo. Data suggest that at follow-up, gains are maintained, particularly when booster sessions are given.

One study found that supportive therapy (which emphasized empathic listening) and CBT were equally effective in reducing anxiety and depressive symptoms (Stanley et al., 1996). Another investigation compared CBT to a minimal contact control condition and demonstrated superiority of CBT, even at 12-month follow-up (Stanley et al., 2003a). Wetherell and colleagues (2003), compared active (CBT and discussion group attention placebo ) and inactive (waiting list) conditions and demonstrated roughly equal efficacy in active conditions compared to waiting list. Interestingly, CBT was only superior to discussion group placebo on one measure of anxiety, and this finding was no longer significant at six-month follow-up. A small study of primary care patients demonstrated the effectiveness of individually administered CBT compared to usual care (Stanley et al., 2003b). This investigation was an important initial effort to disseminate anxiety treatment options into a primary care setting, where the majority of older adults with GAD present for treatment.

Other approaches to the treatment of late-life anxiety have added techniques to the standard CBT protocol. One approach used an enhanced form of individually administered CBT (Mohlman et al., 2003). Enhanced CBT included the standard CBT elements as well as additional memory aids (e.g., reminder phone calls, weekly review of concepts and techniques). Overall, results suggest that CBT enhancements improved treatment outcome compared to waiting list. A follow-up investigation compared enhanced CBT to a waiting list among patients with varying levels of executive functioning (Mohlman and Gorman, 2005). Results suggested that individuals with impaired executive functioning did not respond to CBT whereas those with intact and improved executive functioning were more likely to respond. Another approach used a CBT protocol based on the concept of intolerance of uncertainty as the key feature of GAD (Ladouceur et al., 2004). The majority of patients in this study no longer met criteria for GAD upon completion of treatment.

Much less research has been conducted in older adult populations with anxiety disorders other than GAD. Some research suggests the effectiveness of CBT for PD, agoraphobia, OCD, specific phobia and social phobia. There have been no randomized, controlled psychosocial interventions conducted exclusively with older adults with PD. However, a non-controlled study produced promising results demonstrating the effectiveness of CBT in older PD patients (Swales et al., 1996). A retrospective chart review of older inpatients treated for OCD using exposure and response prevention, along with other elements (e.g., pharmacotherapy, milieu therapy) showed that staff and self-report improvement ratings were high (Carmin et al., 1998).

Several studies have demonstrated the effectiveness of CBT in samples with mixed anxiety disorder diagnoses. Radley and colleagues (1997), found efficacy for CBT in a multiple baseline design in a small sample of patients with a variety of anxiety disorders.

A small case series of patients with various anxiety disorder diagnoses also found improvement in anxiety symptoms following CBT (King and Barrowclough, 1991). Another study used a home-based individual format, which demonstrated significant effects for CBT relative to supportive therapy (Barrowclough et al., 2001). Gains were maintained at 12-month follow-up. Gorenstein and colleagues (2005) found equivalent effects for CBT plus medication management relative to medication management alone.

Overall, available data suggest the potential utility of both pharmacological and psychotherapeutic treatments for late-life anxiety disorders, especially GAD. The CBT literature has demonstrated the effectiveness of CBT compared to no treatment, but evidence does not consistently support the benefits of CBT relative to other psychosocial treatment options (e.g., supportive therapy). Pharmacological treatment is more effective than placebo in the treatment of late-life anxiety, and some evidence suggests that it is more effective than CBT (Wetherell et al., 2005).

Limitations of this literature include homogeneous and unrepresentative samples in terms of age, functional status, ethnicity, education, or medical health; neglect of anxiety disorders other than GAD; and a relative dearth of research on treatment in settings more typically used by anxious older adults (e.g., primary care). Another concern is the failure to investigate long-term maintenance. In most CBT studies, follow-up is limited to 12 months or less. Pharmacological trials have typically not examined the nature and efficacy of various maintenance options.

Psychotherapy attrition rates are higher among older adults (21% to 39%) than among younger adults (approximately 10%) (Gould et al., 2004). Attrition from pharmacotherapy trials is somewhat lower (15% to 23%) and is consistent with attrition rates in younger adults with anxiety disorders (Katz et al., 2002; Lenze et al., 2005). Psychotherapy trials typically analyze data only from completers, whereas pharmacological trials more often analyze on an intent-to-treat basis. Furthermore, psychotherapy studies typically use multiple outcome measures, which complicate the interpretation of inconsistent results across measures. Finally, there is no psychotherapy comparison condition equivalent to a pill placebo.

Although initial results point to the efficacy of pharmacological and psychotherapeutic treatment for geriatric anxiety disorders, more research is needed on other intervention techniques, patient samples, and anxiety disorder diagnoses. More research is also needed to determine whether medication is an acceptable and effective long-term management tool for these chronic disorders. Long-term follow-up of patients and creative methods for the dissemination of these treatments remain important goals for future research, as do combinations of pharmacological and psychotherapeutic treatment and stepped care approaches.

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Author | Eric J. Lenze, MD

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