Saturday, March 5, 2016

Polypharmacy and the Deprescribing Movement

As we get older, the number of medications we take increases. According to 2013 data from the Kaiser Foundation, in California people in the 19-64 age range filled or refilled an average of 11.1 prescriptions per year, whereas those 65 and older the number of prescriptions filled or refilled was 31.4 on average. In my hospital practice, I routinely see elderly patients for changes in mental status who are taking 10 or more medications for a variety of conditions. However, younger and middle aged people with a chronic condition such as diabetes, high cholesterol, high blood pressure, or pain, as well as psychiatric conditions such as depression or anxiety, are likely to be taking multiple medications. Further, according to the Centers for Disease Control and Prevention, the number of medications per person is increasing each year, regardless of age (

Polyphamacy is the practice of simultaneously prescribing multiple medications, often to treat a single medical condition. In the elderly, polypharmacy often involves multiple medications for each of several medical conditions, which results in a truly overwhelming array of tablets, capsules, and liquids that must be ingested daily. Often the medications are prescribed at as many as 4 different times a day, making it virtually impossible to keep track of which pills have been taken at what times. As a result, dosing compliance becomes difficult, as patients inadvertently miss doses or double up on doses in a single day. Cost becomes a major concern, because insurance co-pays on multiple medications, particularly those still under patent protection, rapidly add up.

Polypharmacy not only raises compliance and medication cost concerns, but also can result in serious medical complications. In a study of over 1000 elderly patients presenting to the emergency room with falls, 63% of the fallers were taking 4 or more medications (McMahon and colleagues, Age Ageing. 2014 Jan;43(1):44-50). Among medication classes, opiate painkillers are among the most commonly prescribed, according to data from the Rochester Epidemiology Study. Benzodiazepine tranquilizers, such as diazepam (Valium), chlordiazepoxide (Librium), and lorazepam (Ativan) are also very commonly prescribed in primary care settings as well as in hospitals. In patients with chronic pain, opiates and benzodiazepines are often co-prescribed. Both opiates and benzodiazpeines affect balance, coordination, and mental awareness, markedy increasing the risk of falls and other accidents. The American Geriatrics Society (J AmGeriatr Soc. 2012;60(4):616-631) has published a list of potentially inappropriate medications for older people; the majority of the medications on this list have sedating properties. However, many of these medications continue to be prescribed, often in combination, to older people.

In patients with chronic pain, knowledgeable practitioners often prescribe modern antidepressants such as venlafaxine or duloxetine, as these have demonstrated efficacy in many chronic pain disorders, even when the patient does not complain of depression. However, contrary to popular belief, these antidepressants are not without side effects, particularly in the elderly. Antidepressants such venlafaxine and duloxetine, as well as other widely prescribed antidepressants such as fluoxetine and citalopram, result in a small but significant in increase the risk of fractures in the elderly. The increased risk is probably due to antidepressant induced dizziness, as well as a possible direct effect on bone metabolism. Modern antidepressants also frequently induce hyponatremia (low serum sodium), which has repeatedly been associated with falls. When the antidepressant is added to opiate painkillers and benzodiazepine tranquilizers in the elderly patient with chronic pain, the risks of falls and other accidents are compounded.

An important reason why polypharmacy effects on balance, coordination, and level of awareness are of particular concern in the elderly is the change in neurologic and musculoskeletal function that occurs with aging. At 80 years of age most people experience a signficant decline in muscle mass, strenth, balance, joint range of motion, cardiac output, and maximum breathing capacity. Together, these changes may result in a condition termed frailty, which has various definitions but can include weight loss, lack of endurance along with easy exhaustion, loss of grip strength, difficulty arising from a chair, and decreased overall physical activity. There is often mild cognitive impairment. When medications promoting sedation, cognitive changes, or impairment of balance and muscle strength are prescribed to the frail elderly, the risk increases for falls, hip fractures, motor vehicle accidents, and other serious injury. Further, medications impairing mobility directly promote frailty by limiting overall activity, which in turns accelerates the process of decline. There is a strong positive correlation between the number of medications prescribed, and frailty in the elderly (Cullinan and colleagues Age Ageing. 2016 Jan;45(1):115-20). Although frail elders may be prescribed more medications in an attempt to correct conditions leading to frailty, it is certain that prescribing medications that affect cognition and mobility promote frailty.

Polypharmacy can result in both additive as well as interactive adverse events. One of the most common examples of additive effects I see is prescribing multiple sleeping medications in patients with insomnia. So for example, a patient complaining of insomnia may receive zolpidem (Ambien) for sleep, at increasing doses, but get little relief. Then a second agent, often a classic benzodiazepine such as temazepam (Restoril), may be prescribed, and then perhaps the sedating antidepressant trazodone (Desyrel), given usually at a dose lower than that used in treating depression. The end result is that during the night and the next morning the patient is quite intoxicated by this medication combination. This increases the risk for falls, transient cognitive impairment, auto accidents, impaired job performance, and when used for long periods of time may actually induce depression. Often, I am astonished to find that these patients have never had a comprehensive evaluation with a sleep specialist, nor have they been instructed in basic non-pharmacologic means for treating insomnia such as sleep hygiene, regular exercise, and decreasing alcohol intake. Even more astonishing is when I find that patients taking heavy doses of multiple sleep medications are then co-prescribed stimulants such as methylphenidate (Ritalin) or amphetamine (Adderall) to combat daytime sleepiness, which has been induced by the sedative aftereffects of the sleeping medications. These toxic sedative-stimulant combinations often result in the patient eventually being hospitalized for detoxification.

In addition to additive effects, polypharmacy can have interactive effects. A classic example would be prescribing the commonly used antibiotic erythromycin to a patient also taking digoxin for control of atrial fibrillation. The erythromycin inhibits metabolism of digoxin by the liver, resulting in sky-high digoxin levels in the body. This can lead to dangerous changs in cardiac electrical conduction as well as mental status changes such as confusion. Or, a patient taking lithium carbonate for bipolar illness is prescribed a thiazide diuretic for high blood pressure, resulting in impaired kidney clearance of lithium and a toxic reaction including confusion, gastrointestinal distress, tremors, and incoordination. There are many other examples of direct medication interactions, and the complexity of these interactions increases dramatically when the number of medications is large, because some medications may either augment or counteract interactions between other medications. It is extremely difficult to predict the nature and severity of interactions when a patient is taking 10 or more medications, as is the case with many elderly patients.

In psychiatry, polypharmacy usually starts when a patient does not respond to a single agent. There is a vast literature, including results from some excellent clinical trials, on augmentation of antidepressant effects. Unfortunately, the results have not been encouraging. Patients who fail to respond to single antidepressant rarely receive addition benefit by prescribing a second antidepressant agent. Taking more than one antidepressant with essentially the same mechanism of action in the brain is unlikely to help. Thus, simultaneous prescribing of fluoxetine, paroxetine, citalopram, escitalopram, or sertraline is irrational, since they all do about the same thing in the brain. Often the rationale is given that, for example, the patient is at the maximum dosage of say fluoxetine is being given, so therefore paroxetine, should be added to give more of a “boost”. This is wishful thinking. Even co-prescribing agents with different mechanisms of action, such as venlafaxine and bupropion has little empiral support. In fact, antidepressant non-response is one of the biggest problems in clinical psychiatry. All too often it is addressed by layering one medication on top of another with no benefit and sometimes a disabling increase in side effects, not to mention prescription costs to patients. Sadly, I often find that patients referred to me for antidepressant nonresponse are receiving a purely pharmacologic approach in which medications are added one after another without any regard for other effective modalities for treating depression such as psychotherapy, mindfulness, exercise, and others.

The only FDA-approved anti-depressant augmenting agents are secondary generation antipsychotics, such as quetiapine and aripiprazole. In recent years, use of antipsychotic medications for depression has increased dramatically, as pharmaceutical companies have gained FDA approval to broaden the indications for these medications from schizophrenia and bipolar mania to include augmentation of conventional antidepressants. In a longintudinal analysis of office visits for depressions, co-prescribing of an antipsychotic increased from 4.6% in 2000 to 12.5% in 2010 (Gerhard and colleagues, J Clin Psychiatry. 2014 May;75(5):490-7). Modern antipsychotic medications do show efficacy as augmenting agents. For example, a promising, well performed clinical trial indicates that the antipsychotic aripiprazole can augment the effects of antidepressants in geriatric depression (Lenze and colleagues, Lancet. 2015 Dec 12;386(10011):2404-12). Other similar studies exist for younger and middle aged adult populations.

Nevertheless, great caution should be taken in prescribing antipsychotics to augment the effects of conventional antidepressants. Antipsychotics increase the risk for significant side effects including weight gain, increased serum lipids, diabetes, cardiac electrical conduction changes and even irreversible neurologic syndromes. In addition, multiple studies have indicated that antipsychotic use is associated with an increase in the risk of sudden cardiac death, primarily due to lethal cardiac arrythmias. The risk of sudden death due to antipsychotics has been estimated as being 1.5 to 3 times that in the general population (Wu and colleagues, J Am Heart Assoc. 2015 Feb 23;4(2). In elderly individuals, particularly those with dementia, the risk may be particularly high (Maust and colleagues JAMA Psychiatry. 2015 May;72(5):438-45). For these reasons, it is important to use the lowest possible dose of antipsychotics, and in particular to avoid the high doses that are routinely used to treat schizophrenia and bipolar mania. For example, in the Lenze and colleagues study of aripiprazole augmentation in geriatric depression, the median dose in those achieving remission from depression was 7 mg. This is considerably less than the 20 mg dose routinely used in psychotic disorders.

Another topic of active debate in psychiatry is antipsychotic polypharmacy. Antipsychotics are routinely used to treat schizophrenia and bipolar mania. Patients with these conditions undergo periodic exacerbations of debilitating symptoms such as hallucinations and delusions. These symptoms respond to antipsychotics, but many times the positive effects can be excruciatingly slow, resulting in prolonged hospitalizations and patient suffering. When antipsychotic response is slow or incomplete, even at high dosages, many clinicians add a second antipsychotic in hopes that it will augment the effects of the first agent.

Data from the national Danish health registers indicate that antipsychotic polypharmacy peaked in 2006 at 30.8% of patients with schizophrenia, but was still highly prevalent in 2012, with 24.6% of patients receiving 2 or more antipsychotics (Sneider and colleagues Eur Neuropsychopharmacol. 2015 Oct;25(10):1669-76). Another recent study from the US showed a similar rate 23.3% polypharmacy among people with schizophrenia (Fisher and colleages, BMC Psychiatry. 2014 Nov 30;14:341). Despite widespread antipsychotic polypharmacy there is little evidence to support this practice, and increasing evidence that it is harmful. For example, a major concern with all antipsychotics is that they alter cardiac electrical conduction, which can lead to potentially lethal arrhythmias. The measure on the electrocardiogram (EKG) used to monitor this is the “QT” interval. When the QT interval lengthens, the risk of an arrhythmia increases. A recent analysis by Barbui and colleagues (PLoS One. 2016 Feb 3;11(2):e0148212) demonstrated that antipsychotic polypharmacy promotes prolonged QT interval. This finding is makes sense, in that QT prolongation by antiopsychotics is dose related, and when two are combined, the dose is effectively increased, even if the dose of the individual agents is low. As a result of widespread antipsychotic polypharmacy, researchers are starting to address the issue with clinical trials. In a carefully performed study, about 80% people with schizophrenia receiving antipsychotic polypharmacy were transitioned to monotherapy without any clinical worsening (Borlido and colleagues J Clin Psychiatry. 2016 Jan;77(1):e14-20). Similar trials are needed to assess whether antipsychotic polypharmacy has any real benefits.

In my experience, the number one clinician error leading to antipsychotic polypharmacy is not waiting long enough for the intial antipsychotic to reach full efficacy. Although there is good evidence that antipsychotics begin to have their positive effects soon after initiation, they may not reach full efficacy until 4 or more weeks. If the initial dosage is low, which is the prudent way to begin most drug treatments, the full onset may take even longer depending on how rapidly the dose is increased. Further, some patients simply appear to take longer than average to respond. In such cases, it is temping to add a second antipsychotic to try to accelerate the process, despite that lack of evidence that this practice results in improvement. Another practice I often see is simultaneous treatment with two antipsychotics each at half maximum dosage. It makes more sense, and reduces polypharmacy, to use a single agent at a dosage near the recommended maximum before considering a second agent.

Among the more popular antipsychotic polypharmacy practices is to combine clozapine with another antipsychotic, there being some evidence for the efficacy of “clozapine augmentation”. Not all studies support clozapine augmentation, and more quality clinical trials are required. Clozapine itself is an emotionally charged topic for patients, families, and clinicians, with some maintaining that it is a “wonder drug” that works when other medications fail. Meta-analyses of antipsychotic efficacy do sometimes show a slight advantage for clozapine compared to other modern antipsychotics. But those findings are largely based on comparisons of clozapine with older antipsychotics, and there are few data comparing clozapine head to head with other modern antipsychotics. In fact, a very recent meta-analysis that considered only the highest quality studies found no advantage for clozapine over other modern antipsychotics (Samara and colleagues, JAMA Psychiatry. 2016 Mar 1;73(3):199-210). Given that clozapine has a particularly unfavorable side effect profile, particularly in the elderly, considerable caution is required when combining this agent with others, especially if high dosages are involved

In the current environment of widespread polypharmacy, the concept of deprescribing has arisen (for a recent review, see Scott and colleagues, JAMA Intern Med. 2015 May;175(5):827-34). Deprescribing is the thoughtful, carefully considered elimination of medications in patients suffering from polypharmacy. The goal is to remove unnecessary or redundant medications, to minimize drug interactions, and to identify if possible non-pharmacologic treatments so as to reduce the number of prescriptions. Clinical pharmacists, especially those specializing in geriatric pharmacy, have played an important role in promoting deprescribing, but the movement is gaining momentum among physicians, too.

Although there is ample evidence for the negative effects of polypharmacy, clinical trials of deprescribing are in an early stage. However, results thus far are encouraging. For example, Potter and colleagues (PLoS One. 2016 Mar 4;11(3):e0149984) recently studied frail nursing home residents taking a mean of 9.5 medications, who underwent deprescribing, on average, of 2 medications. There were no adverse effects of the deprescribing protocol, and no clinical worsening. A number of clinical trials have shown that deprescribing benzodiazepines while simultaneously prescribing cognitive-behavioral psychotherapy for insomnia results in fewer medications and improved sleep. The are several criteria for deprescribing available (for example, the “STARTT/STOP” criteria; Mahony and colleagues, Age Ageing. 2015 Mar;44(2):213-8), that have been successfully applied in clinical deprescribing trials. One of the challenges at present is to devise deprescribing protocols that minimize potential withdrawal symptoms, re-emergence of symptoms, and provide sufficient patient support to ensure compliance.

The deprescribing movement dovetails nicely with the principles of conservative prescribing (Schiff and colleagues, Arch Intern Med. 2011 Sep 12;171(16):1433-40), which include starting with only 1 drug at a time, thinking beyond drugs for treatment, practicing strategic and limited prescribing, and being vigilant for medication side effects. Physicians who follow these and other conservative prescribing guidelines will be much less likely to subject their patients to toxic polypharmacy.

In summary, polypharmacy is rampant in modern medicine, particularly among those with chronic conditions, the elderly, and those with intractable psychiatric conditions. The potential for adverse medication interactions and side effects, not to mention the cost in wasted health care dollars, is high. Evidence-based prescribing, proactive deprescribing when appropriate, and emphasis on non-pharmacologic treatments when possible can be of great benefit in reducing polypharmacy.

Oddly, I’ve found that in promoting deprescribing, I sometimes run into resistance from psychiatric colleagues who view this approach as “anti-medication”. Nothing could be farther from the truth. Deprescribing seeks to achieve more elegant, parsimonious, and patient-centered prescribing to maximize efficacy and minimize side effects. There is great emphasis today on finding genetic, brain imaging and other biomarkers to “personalize” prescribing in psychiatry and other fields of medicine. For patients experiencing polypharmacy, a careful deprescribing approach can result in a considerably closer match between medications and the patient, and is easily implemented by any thoughtful physician.