Sovaldi , for Hepatitis C, is $483 in India and $84,000 in the USA

Sofosbuvir, sold under the brand name Sovaldi among others, is a medication used for the treatment of hepatitis C.[1] It is only recommended with some combination of ribavirinpeginterferon-alfasimeprevirledipasvirdaclatasvir, or velpatasvir.[3][4] Cure rates are 30 to 97% depending on the type of hepatitis C virus involved.[5] Safety during pregnancy is unclear; while, some of the medications used in combination may result in harm to the baby.[5] It is taken by mouth.[1]

Common side effects include feeling tired, headache, nausea, and trouble sleeping.[1] Side effects are generally more common in interferon-containing regimens.[6]:7 Sofosbuvir may reactivate hepatitis B in those who have been previously infected.[7] In combination with ledipasvir, daclatasvir or simeprevir it is not recommended with amiodarone due to the risk of an abnormally slow heartbeat.[6] Sofosbuvir is in the nucleotide analog family of medication and works by blocking the hepatitis C NS5B protein.[8]

Sofosbuvir was discovered in 2007 and approved for medical use in the United States in 2013.[3][9] It is on the World Health Organization’s List of Essential Medicines, the most effective and safe medicines needed in a health system.[10] As of 2016 a 12-week course of treatment costs about US$84,000 in the United States, US$53,000 in the United Kingdom, US$45,000 in Canada, and US$483 in India.[11] Over 60,000 people were treated with sofosbuvir in its first 30 weeks being sold in the United States.[1

Drug prescribing for older adults in the USA

Drug prescribing for older adults

Author:
Paula A Rochon, MD, MPH, FRCPC
Section Editor:
Kenneth E Schmader, MD
Deputy Editor:
Daniel J Sullivan, MD, MPH
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Dec 2017. | This topic last updated: May 26, 2017.

INTRODUCTION — Optimizing drug therapy is an essential part of caring for an older person. The process of prescribing a medication is complex and includes: deciding that a drug is indicated, choosing the best drug, determining a dose and schedule appropriate for the patient’s physiologic status, monitoring for effectiveness and toxicity, educating the patient about expected side effects, and indications for seeking consultation.

Avoidable adverse drug events (ADEs) are the serious consequences of inappropriate drug prescribing. The possibility of an ADE should always be borne in mind when evaluating an older adult individual; any new symptom should be considered drug-related until proven otherwise.

Prescribing for older patients presents unique challenges. Premarketing drug trials often exclude geriatric patients and approved doses may not be appropriate for older adults [1]. Many medications need to be used with special caution because of age-related changes in pharmacokinetics (ie, absorption, distribution, metabolism, and excretion) and pharmacodynamics (the physiologic effects of the drug).

Particular care must be taken in determining drug doses when prescribing for older adults. An increased volume of distribution may result from the proportional increase in body fat relative to skeletal muscle with aging. Decreased drug clearance may result from the natural decline in renal function with age, even in the absence of renal disease [2]. Larger drug storage reservoirs and decreased clearance prolong drug half-lives and lead to increased plasma drug concentrations in older people.

As examples, the volume of distribution for diazepam is increased, and the clearance rate for lithium is reduced, in older adults. The same dose of either medication would lead to higher plasma concentrations in an older, compared with younger, patient. Also, from the pharmacodynamic perspective, increasing age may result in an increased sensitivity to the effects of certain drugs, including benzodiazepines [3-6] and opioids [7].

Hepatic function also declines with advancing age, and age-related changes in hepatic function may account for significant variability in drug metabolism among older adults [8]. Especially when polypharmacy is a factor, decreasing hepatic function may lead to adverse drug reactions (ADRs).

A stepwise approach to optimized prescribing of drug therapy for older adults will be reviewed here. Drug treatments for specific conditions in the older population are discussed separately.

MEDICATION USE BY OLDER ADULTS — Medications (prescription, over-the-counter, and herbal preparations) are widely used by older adults.

Prescription medications — A survey in the United States of a representative sampling of 2206 community-dwelling adults (aged 62 through 85 years) was conducted by in-home interviews and use of medication logs between 2010 and 2011 [9]. At least one prescription medication was used by 87 percent. Five or more prescription medications were used by 36 percent, and 38 percent used over-the-counter medications.

In a sample of Medicare beneficiaries discharged from an acute hospitalization to a skilled nursing facility, patients were prescribed an average of 14 medications, including over one-third with side effects that could exacerbate underlying geriatric syndromes [10].

Herbal and dietary supplements — Use of herbal or dietary supplements (eg, ginseng, ginkgo biloba extract, and glucosamine) by older adults has been increasing, from 14 percent in 1998 [11] to 63 percent in 2010 [9]. One study in over 3000 ambulatory adults 75 years of age or older in four states in the United States found that almost three-quarters used at least one prescription drug and one dietary supplement [12]. Often, clinicians do not question patients about use of herbal medicines and patients do not routinely volunteer this information. In one United States survey, three-quarters of respondents aged 18 years and older reported that they did not inform their clinician that they were using unconventional medications [13].

Herbal medicines may interact with prescribed drug therapies and lead to adverse events, underscoring the importance of routinely questioning patients about the use of unconventional therapies. Examples of herbal-drug therapy interactions include ginkgo biloba extract taken with warfarin, causing an increased risk of bleeding, and St. John’s wort taken with serotonin-reuptake inhibitors, increasing the risk of serotonin syndrome in older adults [14]. A study of the use of 22 supplements in a survey of 369 patients aged 60 to 99 years found potential interactions between supplements and medications for 10 of the 22 supplements surveyed [15]. (See “Overview of herbal medicine and dietary supplements”, section on ‘Herb-drug interactions’.)

Many older adults receive their information about herbal products from the internet. Eighty percent of 338 retail web sites identified in a search of the eight most widely used herbal supplements (ginkgo biloba, St. John’s wort, echinacea, ginseng, garlic, saw palmetto, kava, and valerian root) made at least one health claim suggesting that the therapy could treat, prevent, or even cure specific conditions [16].

QUALITY MEASURES OF DRUG PRESCRIBING — Multiple factors contribute to the appropriateness and overall quality of drug prescribing. These include avoidance of inappropriate medications, appropriate use of indicated medications, monitoring for side effects and drug levels, avoidance of drug-drug interactions, and involvement of the patient and integration of patient values [17].

Measures of the quality of prescribing often focus on one or some of these factors, but rarely on all. Furthermore, the predictive value of these measures of “quality of prescribing” in determining important long-term outcomes of care have not been determined. Approaches to decrease inappropriate prescribing in older adults include educational interventions, computerized order entry and decision support, multidisciplinary team care led by physicians, clinical pharmacists, and combinations of these approaches. Available data for these interventions generally show significant improvements in inappropriate prescribing but mixed results for health outcomes or costs [17,18]. A 2016 systematic review of eight studies of different prescribing interventions in long-term care homes (medication review, case conferences, staff education, clinical decision support technology, and/or some combination of these) showed no effect of the interventions on hospital admissions, adverse drug events (ADEs), and mortality [18]. The studies that evaluated medication-related problems, appropriate prescribing, or cost of medication showed some evidence that interventions helped the recognition and solving of medication problems. A previous 2008 systematic review of 10 studies of computerized physician order entry with clinical decision support showed a mixed effect on reduction in ADEs, with five studies that showed a statistically significant reduction in ADEs, four that showed nonsignificant decrease, and one study that showed no impact on rate of ADEs [19].

POLYPHARMACY — Polypharmacy is defined simply as the use of multiple medications by a patient. The precise minimum number of medications used to define “polypharmacy” is variable, but generally ranges from 5 to 10 [20]. While polypharmacy most commonly refers to prescribed medications, it is important to also consider the number of over-the-counter and herbal/supplements used.

The issue of polypharmacy is of particular concern in older people who, compared with younger individuals, tend to have more disease conditions for which therapies are prescribed. It has been estimated that 20 percent of Medicare beneficiaries have five or more chronic conditions and 50 percent receive five or more medications [21]. Among ambulatory older adults with cancer, 84 percent were receiving five or more and 43 percent were receiving 10 or more medications, in one study [22].

The use of greater numbers of drug therapies has been independently associated with an increased risk for an adverse drug event (ADE), irrespective of age [23], and increased risk of hospital admission [24,25]. However, it is difficult to eliminate the impact of confounding factors in considering the relationship between polypharmacy and a variety of outcomes in observational studies [26].

There are multiple reasons why older adults are especially impacted by polypharmacy:

Older individuals are at greater risk for ADEs due to metabolic changes and decreased drug clearance associated with aging; this risk is compounded by increasing numbers of drugs used.

Polypharmacy increases the potential for drug-drug interactions and for prescription of potentially inappropriate medications [27].

Polypharmacy was an independent risk factor for hip fractures in older adults in one case-control study, although the number of drugs may have been an indicator of higher likelihood of exposure to specific types of drugs associated with falls (eg, central nervous system [CNS]-active drugs) [28].

Polypharmacy increases the possibility of “prescribing cascades” [29]. A prescribing cascade develops when an ADE is misinterpreted as a new medical condition and additional drug therapy is then prescribed to treat this medical condition. (See ‘Prescribing cascades’ below.)

Use of multiple medications can lead to problems with adherence in older adults, especially if compounded by visual or cognitive impairment. A 2017 systematic review of observational studies suggested that drug regimen complexity is associated with medication nonadherence [24].

A balance is required between over- and under-prescribing. Multiple medications are often required to manage clinically complex older adults. Clinicians are often challenged with the need to match the complex needs of their older patients with those of disease-specific clinical practice guidelines. For a hypothetical older female patient with chronic obstructive pulmonary disease, type 2 diabetes, osteoporosis, hypertension, and osteoarthritis, clinical practice guidelines would recommend prescribing 12 medications for this individual [30].

A more systematic approach is required to guide the tailoring of medication regimens to the needs of individuals. One important principle is to match the medication regimen to the patient’s condition and goals of care. This includes a careful consideration of the medications that should be discontinued or substituted [31] (table 1).

It is particularly important to reconsider medication appropriateness late in life. A model for appropriate prescribing for patients late in life has been proposed [32] (table 2). The process considers the patients’ remaining life expectancy and the goals of care in reviewing the need for existing medications and in making new prescribing decisions. For example, if a patient’s life expectancy is short and the goals of care are palliative, then prescribing a prophylactic medication requiring several years to realize a benefit may not be considered appropriate. This is increasingly being recognized as an important consideration when managing individuals with advanced dementia [33]. Additionally, therapeutic medications (eg, antibiotics for pneumonia) may not increase comfort or quality of life when palliative care is the objective [34].

INAPPROPRIATE MEDICATIONS — Various criteria have been developed by expert panels in Canada [35] and in the United States [36-41] to assess the quality of prescribing practices and medication use in older adult individuals. The most widely used criteria for inappropriate medications are the Beers criteria. (See ‘Beers criteria’ below.)

In another approach, a Drug Burden Index has been modelled incorporating drugs with anticholinergic or sedative effects, total number of medications, and daily dosing [42,43]. An increased drug burden for anticholinergic and sedative medications was associated with impaired performance on mobility and cognitive testing in high-functioning community-based older adults. Zolpidem, in particular, was implicated in 21 percent of emergency department visits for adverse drug events (ADEs) related to psychiatric medication among adults 65 years and older [44].

Total number of medications was not associated with impaired performance when sedatives and anticholinergics were excluded [42,43]. A high Drug Burden Index has been correlated with increased risk for functional decline in community dwellers [43] and with increased risk of falls in residents in long-term care facilities [45].

Anticholinergic activity — Anticholinergic medications are associated with multiple adverse effects to which older individuals are particularly susceptible. Nonetheless, an analysis of United States medication expenditures between 2005 and 2009 found that 23.3 percent of community-dwelling persons >65 years with dementia were prescribed medications with clinically significant anticholinergic activity (AA) [46].

Adverse effects associated with anticholinergic use in older adults include memory impairment, confusion, hallucinations, dry mouth, blurred vision, constipation, nausea, urinary retention, impaired sweating, and tachycardia. A case-control study found an association between anticholinergic use and risk of community-acquired pneumonia [47]. Anticholinergics can precipitate an acute glaucoma episode in patients with narrow angle glaucoma and acute urinary retention in patients with benign prostatic hypertrophy. Specific studies of the relationship between dementia and anticholinergic use include the following:

In a population study of 6912 men and women 65 years and older, those taking anticholinergic drugs were at increased risk for cognitive decline and dementia and risk decreased with medication discontinuation [48].

In a population of 3434 men and women age 65 and older in one health care setting, who had no baseline dementia and who were followed for 10 years, the risk of dementia and Alzheimer’s disease increased in a dose-response relationship with use of anticholinergic drug classes (primarily first-generation antihistamines, tricyclic antidepressants, and bladder antimuscarinics) [49].

In another population of 13,004 individuals aged 65 and older, use of anticholinergic medications was also shown to be associated with greater decline in cognition as measured by the Mini-Mental State Examination [50]. In addition, anticholinergic medication use was associated with increased mortality over a two-year period after adjustment for multiple factors, including comorbid health conditions.

Multiple scales, including the Drug Burden Index [42], have been developed to identify the anticholinergic burden of medications. For nine scales evaluated in one study, a higher score was associated with increased risk for hospitalization and length of stay, falls, and medical utilization [51]. A listing of medication classes that contain significant AA is shown in a table (table 3).

A study measured the in vitro AA of 107 medications commonly used in older adults [52]. At usual doses, AA was most significantly elevated for amitriptylineatropineclozapinedicyclominedoxepin, L-hyoscyamine, thioridazine, and tolterodine. AA also was increased for chlorpromazinediphenhydraminenortriptylineolanzapineoxybutynin, and paroxetine. It should be noted, however, that higher doses of an agent with relatively low or moderate AA can produce significant AA effects. Additionally, the cumulative effects of more than one agent with low AA can produce significant AA effects.

Alternative drugs with lower AA are available in many classes represented by these drugs. However, adverse drug reactions (ADRs) other than AA should also be taken into account in weighing the clinical benefits of possible substitutions (eg, dyskinesias and sedation with haloperidol and perphenazine).

Beers criteria — The Beers criteria, initially developed by an expert consensus panel in 1991 to target nursing home residents, are the most widely cited criteria used to assess inappropriate drug prescribing [36]. The panel produced a list of medications considered inappropriate for older patients, either because of ineffectiveness or high risk for adverse events.

The original Beers criteria have been revised in 1997, 2003, 2012, and most recently in 2015 [37,38,53,54]. The 2015 revised Beers criteria are available through the American Geriatrics Society website. The criteria include over 50 medications designated in one of three categories: those that should always be avoided (eg, barbiturates, chlorpropamide); those that are potentially inappropriate in older adults with particular health conditions or syndromes; and those that should be used with caution. New additions since 2012 are a table of non-antiinfective drug interactions and a table of non-antiinfective medications to avoid or adjust for decreased renal function [54]. Some notable changes in the 2015 listings are removal of loratadine from the list of medications with strong anticholinergic properties; a more liberal renal threshold (now creatinine clearance <30 rather than <60 mL/min) for withholding nitrofurantoin; avoidance of long-term proton pump inhibitors because of risk of Clostridium difficileinfections and bone loss; and stricter guidelines to avoid antipsychotics for behavioral problems unless other options have failed and the older adult is threatening harm to self or others.

Several studies, using older versions of the Beers criteria, have identified that use of drugs identified as “inappropriate” was widespread in the United States, Canada, and Europe [55-57]. In a sample of community-dwelling older adults in the United States, 43 percent used at least one medication that would be deemed potentially inappropriate by the updated Beers criteria, with nonsteroidal antiinflammatory drugs (NSAIDs) being the most common [58]. Another study, using Medicare data and the 2012 Beers criteria, found that the point prevalence in each calendar month of potentially inappropriate medications used in adults ≥65 years was 34.2 percent in 2012 [59].

Some of the inappropriate drug therapies identified on the Beers list are available as over-the-counter products [60]. This reinforces the need to always consider over-the-counter drug therapies when reviewing a patient’s medications and to educate individuals on potential problems that can arise from the use of over-the-counter preparations.

The Beer’s criteria are increasingly being used to monitor quality of care for older adults. The validity of these consensus-derived criteria in predicting adverse outcomes therefore is becoming increasingly more important. Studies of earlier versions of the Beers criteria found that while the criteria did predict adverse outcomes, some medications that were not on the earlier criteria correlated more closely with adverse outcomes:

Data from the 1996 Medical Expenditure Panel survey showed that risks of hospitalization and death were greater for nursing home patients who had been prescribed medications defined as potentially inappropriate by the 2003 combined Beers criteria [61].

A systematic review of 18 retrospective cohort studies found that for patients >65 years old in the community setting, inappropriate medication use (defined by Beers criteria 1991, 1997, and 2003) was associated with increased hospitalization rates but not mortality; for patients in the nursing home setting, the relationship between inappropriate medications and hospitalization rates was inconclusive [62].

A study that used electronic data to survey ADEs associated with emergency department visits for patients ≥ 65 years of age found that drugs meeting Beers criteria for always potentially inappropriate accounted for 3.6 percent (95% CI 2.8-4.5 percent) of the estimated 178,000 visits [63]. Three medications not on the Beers list at the time of the study (warfarindigoxin, and insulin) accounted for 33.3 percent (95% CI 27.8-38.7 percent) of the visits, and medications in the general class of anticoagulants or antiplatelet agents, antidiabetic agents, and narrow therapeutic index agents accounted for nearly half of all visits, though were prescribed in only 9.4 percent of patients seen.

Similar methodology was used by the same group to evaluate ADEs resulting in emergency hospitalizations among older Americans [64]. Four types of medication (warfarin, insulin, oral antiplatelet agents, and oral hypoglycemics) accounted for 67.0 percent of the ADEs, while 6.6 percent of the hospitalizations were attributed to Beers-criteria potentially inappropriate medications.

Other criteria sets — The Screening Tool of Older Person’s Prescriptions (STOPP) criteria, another tool for identifying inappropriate prescribing, were introduced in 2008 [65-67]. The 2003 Beers criteria have been compared with the Screening Tool of Older Person’s Prescriptions (STOPP); STOPP and Beers criteria overlapped in several areas, but earlier versions of the Beers criteria used in this comparison contained some drugs no longer in common use, and STOPP includes consideration of drug-drug interactions and duplication of drugs within a class. In two studies, STOPP identified a significantly higher proportion of older people requiring hospitalization as a result of a medication-related adverse event than did the 2003 Beers criteria [65,67]. In a cluster randomized trial in Ireland, presenting attending physicians with potentially inappropriate medications based on the STOPP/START (Screening Tool to Alert doctors to the Right Treatment) criteria reduced the number of adverse drug events and medication costs during the index hospitalization, but did not reduce length of stay [68].

The FORTA (Fit FOR The Aged) list identifies medications rated in four categories (clear benefit; proven but limited efficacy or some safety concerns; questionable efficacy or safety profile, consider alternative; clearly avoid and find alternative) with ratings based on the individual patient’s indication for the medication [69]. The tool, developed in Germany, has undergone consensus validation with a panel of geriatricians [70], but studies of its impact on clinical outcomes are ongoing.

Health care financing administration — The Centers for Medicare and Medicaid Services drug utilization review criteria target eight prescription drug classes (digoxin, calcium channel blockers, angiotensin-converting enzyme (ACE) inhibitors, H2 receptor antagonists, NSAIDs, benzodiazepines, antipsychotics, and antidepressants) and focus on four types of prescribing problems (inappropriate dose, inappropriate duration of therapy, duplication of therapies, and potential for drug-drug interactions). In one study, 19 percent of 2508 community-dwelling older adults were using one or more medications inappropriately; NSAIDs and benzodiazepines were the drug classes with the most potential problems [40].

Assessing Care of Vulnerable Elders project — Another expert panel has identified quality indicators for appropriate medication use as part of the Assessing Care of Vulnerable Elders (ACOVE) project [71,72]. These indicators begin with practical suggestions on how to improve prescribing practices:

Document the indication for a new drug therapy

Educate patients on the benefits and risks associated with the use of a new therapy

Maintain a current medication list

Document response to therapy

Periodically review the ongoing need for a drug therapy

In addition, these indicators specify drug therapies that either should not be prescribed for older adults or that warrant careful monitoring after they have been initiated (table 4).

UNDERUTILIZATION OF APPROPRIATE MEDICATION — Much attention has been paid to over-prescribing for older adults; under-prescribing appropriate medications is also of concern. Prescribing strategies that seek to simply limit the overall number of drugs prescribed to older adults in the name of improving quality of care may be seriously misdirected.

Clinicians may be better at avoiding over-prescribing of inappropriate drug therapies than at prescribing indicated drug therapies. As an example, one study of older adults (n = 372) in two managed care organizations found that 50 percent had not been prescribed some recommended therapy, while only 3 percent were prescribed medications classified as inappropriate [73]. However, under- and overutilization of medications were equally prevalent in another study [74]. In a US Department of Veterans Affairs (VA) outpatient population, mean age 75 years (n = 196), inappropriate medications were documented for 65 percent and medication underuse for 64 percent; simultaneous under and overutilization occurred in 42 percent of patients.

START (Screening Tool to Alert doctors to the Right Treatment) is a set of 22 validated criteria, developed by a consensus process involving experts in geriatric pharmacotherapy, aimed to identify potential prescribing omissions in older hospitalized patients [75]. One or more potential prescribing omissions was identified in nearly 60 percent of patients in one study.

However, it should also be recognized that determination of “under-prescribing” is based on guidelines that address individual disease entities, while most geriatric patients have multiple conditions [21]. As an example, a patient with a myocardial infarction, history of diabetes, and elevated lipids would require a beta-blocker, angiotensin-converting enzyme (ACE) inhibitor, aspirin, statin, and a hypoglycemic medication. Accordingly, many older adults need to take six or more essential medications. In this context, clinicians may make informed decisions to “under-prescribe” to foster compliance with essential medications, limit drug interactions, and prioritize health benefits for active treatment of serious conditions over preventive therapies or conditions that have less impact on quality of life.

Factors leading to unintended underutilization include clinicians not recognizing medication benefit in the older population, affordability, and dose availability.

Medication effectiveness — Studies of drug effectiveness specifically often exclude the geriatric population due to concerns with comorbidities and side effects, causing difficulty in interpretation of study results. Therefore, the benefit of treatment for older adults, especially for preventive purposes, may not be established or may not be recognized by prescribing clinicians. As an example, in a study of statin use for secondary prevention in patients over age 66, the likelihood of being prescribed statin therapy declined 6.4 percent for every year of age; overall, only 19 percent of patients in this high-risk population had been prescribed a statin [76].

Affordability — A prescription may be written but not filled, or filled and not taken regularly, due to financial considerations. This may be a particular problem in countries where there is no universal insurance coverage for drug therapy for older adults.

Enhanced drug coverage for older adults can be a powerful incentive to improve the use of beneficial therapies. A comparison of two groups of Medicare patients, as an example, found that statin use was 4.1 percent in patients without drug coverage and 27 percent in those with drug benefits [77]. Significant utilization differences between insured and uninsured patients were seen even for the use of inexpensive medications such as beta-blockers and nitrates.

Cost-related medical noncompliance affected almost 30 percent of disabled Medicare enrollees in 2004, and noncompliance rates were significantly higher for patients with multiple comorbidities [78].

Additional information on the affordability of medications can be found elsewhere in UpToDate. (See “Patient education: Reducing the costs of medicines (Beyond the Basics)”.)

Dose availability — Older individuals often require lower than usual doses of medications, especially at initiation. If medications are not readily available in prescribed doses, the need to split tablets may make it more difficult for patients to take beneficial drug therapy [79].

ADVERSE DRUG EVENTS — A number of factors in older individuals contribute to their increased risk for developing a drug-related problem. These include frailty, coexisting medical problems, memory issues, and use of multiple prescribed and non-prescribed medications [80].

Drug-related hospitalizations account for 2.4 to 6.5 percent of all medical admissions in the general population; the proportion is much higher for older patients [81-83]. In the United States, it is estimated that annually from 2007 to 2009 there were 99,628 emergency hospitalizations for adverse drug events (ADEs) in individuals 65 years and older, with two-thirds due to unintentional overdoses [64]. A meta-analysis found a fourfold increase in the rate of hospitalization related to ADEs in older adults compared with younger adults (16.6 versus 4.1 percent); it was estimated that 88 percent of the ADE hospitalizations among older adults were preventable, compared with 24 percent among young persons [84].

Adverse drug reactions (ADRs) are noxious responses to drugs used in usual doses for treatment or prevention of disease. ADEs are any injury that occurs from a drug, including noxious responses, drug administration errors, and any other circumstances that lead to an injury.

Prescribing cascades — Prescribing cascades occur when a new drug is prescribed to treat symptoms arising from an unrecognized ADE related to an existing therapy [29]. The patient is then at risk for developing additional ADEs related to the new and potentially unnecessary treatment (table 5). Older adults with chronic disease and multiple drug therapies are at particular risk for prescribing cascades.

Drug-induced symptoms in an older person can be easily misinterpreted as indicating a new disease or attributed to the aging process itself rather than the drug therapy. This misinterpretation is particularly likely when the drug-induced symptoms are indistinguishable from illnesses that are common in older persons. Selected examples of prescribing cascades are described below.

One of the best recognized examples of a prescribing cascade relates to the initiation of anti-Parkinson therapy for symptoms arising from use of drugs such as antipsychotics [85-87] or metoclopramide [88]. The anti-Parkinson drugs can then lead to new symptoms, including orthostatic hypotension and delirium.

In a case-control study of 3512 Medicaid patients (age 65 to 99 years), patients who had received an antipsychotic medication in the preceding 90 days were 5.4 times more likely to be prescribed anti-Parkinson therapy than patients who had not received an antipsychotic (95% CI 4.8-6.1) [85].

Some prescribing cascades may be less obvious, especially for drugs whose adverse events are not as commonly recognized. As an example, cholinesterase inhibitors (eg, donepezilrivastigmine, and galantamine) are commonly used for the management of dementia symptoms in older adults. The adverse events associated with these drugs can be viewed as the reverse of those that might be expected with anticholinergic therapies. Accordingly, while anticholinergic therapies may cause constipation and urinary retention, cholinesterase inhibitors may cause diarrhea and urinary incontinence. A prescribing cascade occurs when the prescription of a cholinesterase inhibitor is followed by a prescription for an anticholinergic therapy (eg, oxybutynin) to treat incontinence.

A retrospective cohort study in older adults in Canada (n = 44,884) found that the risk of treatment with an anticholinergic medication for urinary incontinence was greater for patients who had received a cholinesterase inhibitor (adjusted hazard ratio 1.53; 95% CI 1.39-1.72) [89]. This study suggests that clinicians should consider the possible contributing role of cholinesterase inhibitors in new-onset or worsening urinary incontinence.

Drug-drug interactions — Older adults are particularly vulnerable to drug-drug interactions because they often have multiple chronic medical conditions requiring multiple drug therapies. The risk of an adverse event due to drug-drug interactions is substantially increased when multiple drugs are taken [90-94]. As an example, the risk of bleeding with warfarin therapy is increased with coadministration of selective and nonselective nonsteroidal antiinflammatory drugs (NSAIDs), selective serotonin reuptake inhibitors, omeprazole, lipid-lowering agents, amiodarone, and fluorouracil [90].

A case control study from Canada evaluated hospitalizations for drug-related toxicity in a population of older patients who had received one of three drug therapies: glyburidedigoxin, or angiotensin-converting enzyme (ACE) inhibitor [94]. Hospitalization for hypoglycemia was six times more likely in patients who had received co-trimoxazole. Digoxin toxicity was 12 times more likely for patients who had been started on clarithromycin. Hyperkalemia was 20 times more likely for patients who were treated with a potassium-sparing diuretic.

Care must be taken when prescribing any medication, especially for the older individual, to review existing medications and consider potential drug interactions.

Dose-related adverse drug events — ADEs are often dose-related. Examples include:

A case-control study from the 1980s related risk of hip fracture in a Medicaid population with use and dose of psychotropic drugs [95]. A dose-related effect was seen for use of long half-life hypnotic-anxiolytics, tricyclic antidepressants, or neuroleptic therapy, and hospitalization for hip fracture.

A study of people 65 years and older in Quebec (n >250,000) found that more than a quarter (27.6 percent) were dispensed at least one prescription for a benzodiazepine [96]. The risk of injury was dose-related for some benzodiazepines (oxazepamflurazepam, and chlordiazepoxide), though not for alprazolam.

Dose of benzodiazepine, but not elimination half-life, was related to risk for hip fracture in a case-control study of adults aged 55 years and older from the Netherlands [6].

Renal impairment — A common cause of dose-related adverse events in older adults is failure to properly adjust doses for renal insufficiency. Renal impairment becomes more common with advancing age. For patients with stable renal function, creatinine clearance can be estimated according to published formulas which factor age into the calculation (calculator 1). Because of decreased muscle mass in older adults, however, serum creatinine levels may not adequately reflect renal function; many older patients with a normal creatinine nonetheless have modestly impaired renal function. In one study, 40 percent of almost 10,000 older adults living in long-term care were found to have renal insufficiency [97]. In a community population over age 65 in France, the prevalence of renal insufficiency (estimated glomerular filtration rate [GFR] <60 mL/min/1.73 m2) was 13.7 percent using the MDRD equation and 36.9 percent using the Cockcroft-Gault formula [98]. (See “Assessment of kidney function”.)

Dosing guidelines for decreased creatinine clearance are available to calculate dose adjustments for medications that are cleared through the kidney [99]. The list of medications is long and includes many antibiotics. In a community population, 52 percent of adults over age 65 with mild renal insufficiency were taking medications that required dose adjustment for low GFR; antihypertensives, fibrates, sedative/hypnotic, and anxiolytic medications accounted for most of these drugs [98]. The drug database (Lexi-Comp) available through UpToDate includes appropriate dose adjustments for renal function and for older adults, and can be accessed by searching on any individual drug. As a general rule, the initial dose for starting medications in older adults should be significantly reduced, and titrated up as tolerated by monitoring side effects or drug levels.

Decision aids have been moderately effective in decreasing the percentage of in-hospital prescriptions written with inappropriate adjustments for renal status (46 to 33 percent) [100].

Adverse drug events in long-term care setting — Long-term care residents are at a particularly high risk for developing adverse events [101]. The average United States nursing home resident uses seven to eight different medications each month, and about one-third of residents have monthly drug regimens of nine or more medications [102].

A study of ADEs in two large academic long-term care facilities in the United States and Canada found 815 ADEs occurring during 8336 resident months [101]. The overall rate of ADEs was 9.8 per 100 resident–months; 42 percent of the ADEs were deemed preventable. Of the more serious adverse events, 61 percent were deemed preventable. The more serious the adverse event, the more likely it was to be considered potentially preventable. These rates were approximately four-times higher than had been previously reported [103] but may reflect the better documentation of ADEs at these institutions.

Preventable ADEs were most frequently associated with atypical antipsychotics and warfarin therapy (table 6). Neuropsychiatric events (confusion, oversedation, delirium), hemorrhagic events, and gastrointestinal events were the most frequent types of ADEs in the long-term care facilities studied (table 7). In a 12-month observational study of 490 long-term care residents taking warfarin in 25 nursing homes, there were 720 ADEs (625 minor, 82 serious, and 13 life-threatening); 57 percent of the serious events were considered preventable [104].

Atypical antipsychotics — Atypical antipsychotic medications, used for the management of the behavioral and psychological symptoms of dementia, are among the drugs most frequently associated with adverse events in long-term care facilities [101]. In particular, psychotropic medications are associated with an increased risk for falls. In one meta-analysis of patients age 60 or older, the odds ratio for any psychotropic use among patients who had one or more falls was 1.73 (95% CI 1.52-1.97) [105].

There is limited evidence to support the efficacy of these agents for management of behavioral and psychological symptoms in older adults. (See “Management of neuropsychiatric symptoms of dementia”, section on ‘Antipsychotic drugs’ and “Second-generation antipsychotic medications: Pharmacology, administration, and side effects”.)

Nonetheless, use of antipsychotic medications in long-term care facilities is widespread. A study of 19,780 older adults with no history of major psychosis prior to long-term care admission found that antipsychotic therapy was prescribed for 17 percent within 100 days of their long-term care admission and for 24 percent within one year [106]. A study of 485 nursing homes in Canada found that there was about a threefold variation in antipsychotic prescribing, not related to clinical factors, between high- and low-prescribing facilities [107].

A public health advisory warning issued from the US Food and Drug Administration (FDA) warns of fatal adverse events in demented patients treated with atypical antipsychotic therapy [108-110]. Data from 17 trials of older adult patients with dementia have shown that those treated with atypical antipsychotic therapy were 1.6 to 1.7 times more likely to die than those given placebo therapy. Similar concerns have been raised for haloperidol and other conventional antipsychotics [111,112]. A retrospective comparison of patients with dementia who were newly treated with atypical antipsychotics, compared with no antipsychotics, found an increased risk of death at 30 and 180 days for the treated group (at 30 days, adjusted hazard ratio [HR] 1.55, 95% CI 1.15-2.07) [113]. Mortality was further increased, again by a factor of 1.55, for patients receiving conventional antipsychotics compared with atypical antipsychotics. These data point to the need to rethink the role of these therapies in clinical practice. (See “Management of neuropsychiatric symptoms of dementia”, section on ‘Severe or refractory symptoms’.)

Predicting adverse drug reactions

A tool has been developed to identify older adult patients at increased risk for an adverse drug reaction (ADR) in hospital [114]. The tool, based on logistic regression analysis from a group of Italian patients mean age 78, and validated in a separate European cohort, found that the number of drugs prescribed and prior history of an ADR were the strongest predictors for a subsequent ADR. Compared with those receiving five or fewer medications, the risk of ADR was approximately doubled (odds ratio [OR] 1.9, 95% CI 1.35-2.68) for those prescribed five to seven medications, and was fourfold (OR 4.07, CI 2.93-5.65) for those receiving eight or more medications. Other variables incorporated in this tool are the presence of four or more comorbid conditions, heart failure, liver disease, or renal failure.

Preventing adverse drug events — The occurrence of preventable ADEs is a significant concern. Inappropriate ordering and inadequate monitoring are the most common errors in preventable adverse drug events. Errors in transcription, dispensing, and administration are less commonly identified [101].

Medications that are commonly implicated in preventable ADEs are not generally those identified by widely utilized “bad drug” lists. “Good drugs” prescribed in an inappropriate manner may be far more problematic. When drugs do cause problems, it is often because they are prescribed, dosed, or monitored inappropriately.

Prevention of ADEs in the hospital setting is discussed separately. (See “Prevention of adverse drug events in hospitals”.)

Long-term care — Enhanced surveillance and reporting systems for ADEs occurring in the nursing home setting are needed. Computerized order entry in the hospital setting has been shown to reduce serious medication errors [115]. A computer-based decision aid reduced in-hospital inappropriate dosing of psychotropic medications for geriatric inpatients [116]. However, a randomized trial of computerized order entry with clinical decision support in 29 resident care units at two long-term care facilities in Canada did not affect the rate of ADEs [117].

Community care — Patient errors in medication adherence are a significant contributor to ADEs for older patients living in the community, accounting for 21 percent of preventable ADEs in a large ambulatory Medicare population [118]. Patient errors occurred more frequently in patients who were regularly taking three or more medications, compared with those taking two or fewer [119].

Practical recommendations to reduce medical errors in the community have been proposed [120-125]:

Maintain an accurate list of all medications that a patient is currently using. This list should include the drug name (generic and brand), dose, frequency, route, and indication.

Advise periodic “brown-bag check-ups.” Instruct patients to bring all pill bottles to each medical visit; bottles should be checked against the medication list.

Patients should be made aware of potential drug confusions: sound-alike names, look-alike pills, and combination medications.

Patients should be informed of both generic and brand names, including spelling, as well as the reasons for taking their medications. This may prevent unnecessary confusion when drugs are inconsistently labeled. As an example, a patient may be unaware that digoxin (generic) and Lanoxin (brand) are the same therapy.

Medication organizers that are filled by the patient, family member, or caregiver can facilitate compliance with drug regimens. Blister packs for individual drugs, prepared by the pharmacist, can also be helpful in ensuring that patients take their medications correctly [124].

Community pharmacists are an important resource and can play a key role in working with older adults to reduce medication errors.

Transitions in care settings — Transitions in care, between hospital and nursing home or institutional setting and home, are a common source of medication errors and confusions:

One Canadian multisite study found that 23 percent of 328 older adults experienced an ADE after discharge home from the hospital; half of these ADEs were considered preventable [120].

Changes in medication (different dose, discontinued therapies, additional therapies) were identified in 45 of 50 patients discharged from a geriatric ward in the United Kingdom within 6 to 14 days of discharge [121]. Of particular concern is discharge of older patients with new prescriptions for benzodiazepines that were initiated in the hospital, leading to unplanned chronic benzodiazepine use [126].

Attending clinicians from an academic medical center reported that they believed 89 percent of their discharged patients (n = 99) understood potential side effects of their medications; 58 percent of those discharged patients reported that they understood this information [127].

ADEs attributed to medication changes occurred in 20 percent of patients on transfer from hospital to a nursing home, occurring most commonly for patients being readmitted to the nursing home (12 of 14 events) [128].

Frail older people are often found to be on unnecessary drug regimens at the time of hospital discharge. Among 384 older veterans, 44 percent were found to have at least one unnecessary drug therapy at the time of discharge [129]. Factors contributing to this include multiple prescribers, “routine” medications for hospitalization such as antacids or stool softeners, and being on nine or more drug therapies.

Effort must be made to improve communication in “hand-offs” of patient care during transitions in care setting. This is particularly true when the physician responsible for the patient in the hospital is not the same as the physician providing the patient’s longitudinal care. Accurate medication lists, direct communications between providers, and a thorough review of all medications at the time of care transition for appropriateness and intended duration of treatment, are steps that should be taken to avoid ADEs. Whenever possible, the number of prescribing physicians for an individual patient should be limited, as the number of prescribing physicians is an independent risk factor for ADEs [130]. Safe and effective hospital discharge principles are discussed separately. (See “Hospital discharge and readmission”.)

A STEPWISE APPROACH TO PRESCRIBING — Presented below is one systematic approach to improving prescribing practices when managing older adults. Other systematic approaches have been described incorporating similar elements [131]. Regardless of the sequence of steps, what is essential in prescribing is to continually reappraise the patient’s medication regimen in light of his or her current clinical status, goals of care, and the potential risks/benefits of each medication.

A concept of “time to benefit” (TTB) in relation to drug prescribing for older patients with multiple morbidities can be applied to therapeutic decisions [132]. TTB, defined as the time to significant benefit observed in trials of people treated with a drug compared with controls, can be estimated from data from randomized controlled trials. Such information, not routinely available, may in the future help guide decision-making for specific drug prescribing in individual patients.

Review current drug therapy — Periodic evaluation of a patient’s drug regimen is an essential component of medical care for an older person. Such a review may indicate the need for changes to prescribed drug therapy. These changes may include discontinuing a therapy prescribed for an indication that no longer exists, substituting a therapy with a potentially safer agent, changing a drug dose, or adding a new medication (table 8). A medication review should consider whether a change in patient status (eg, renal or liver function) might necessitate dosing adjustment, the potential for drug-drug interaction, whether patient symptoms might reflect a drug side effect, or whether the regimen could be simplified [133]. Medication reviews are often not done in a systematic manner. A reasonable approach could be having a patient meet with a pharmacist within a few weeks of starting a new medication.

In addition to routine review of therapy, review of drug therapy is indicated when patients present with an injury or illness that might have been an adverse result of a prescribed medication. As an example, one study reviewed data for a sample of 168,000 Medicare patients seen for medical care with a fracture of a hip, shoulder, or wrist [134]. In the four months prior to presentation, three-quarters of the patients had been taking a nonopioid drug associated with increased fracture risk (eg, sedative, atypical antipsychotic, or antihypertensive). In the four months after the fracture, such drugs were discontinued for 7 percent but were newly prescribed for another 7 percent.

In a survey of Medicare beneficiaries, more than 30 percent of patients reported they had not talked with their doctor about their different medications in the previous 12 months [135]. Ideally, the clinician should ask the patient to bring to the visit all of the bottles of pills that they are using. Patients may not consider over-the-counter products, ointments, vitamins, ophthalmic preparations, or herbal medicines to be drug therapies and need to be specifically told to bring these to the visit.

Unintended medication discrepancies, particularly likely to occur at the time of hospital admissions, are a common source for medication errors. As an example, one study evaluated 151 patients (average age 77 years) admitted to general internal medicine clinical teaching units and found discrepancies in more than half between admission medication orders and the patient’s usual drug therapies as identified by a medication history interview [136]. Most discrepancies involved unintentional omission of a maintenance medication and more than a third of these discrepancies had the potential to cause moderate harm.

Discontinue unnecessary therapy — Clinicians are often reluctant to stop medications, especially if they did not initiate the treatment and the patient seems to be tolerating the therapy. Sometimes, this exposes the patient to the risks for an adverse event with limited therapeutic benefit. A common example is the use of digoxin in older adults, often prescribed for indications that have not been well-documented. Renal impairment or temporary dehydration may predispose older adults to digoxin toxicity [137]. Although digoxin therapy can be safely discontinued in selected nursing home residents, it is important to recognize that discontinuation in patients with impaired systolic function can have a detrimental effect [138]. (See “Overview of the therapy of heart failure with reduced ejection fraction”.)

The decision to discontinue medication is determined in part by the goals of care for that patient and the risks of adverse effects for that patient. Targets for treatment, based on outcomes evidence from studies in younger patients, may not be appropriate for older adults [30]; thus clinical guidelines not targeted to older patients may foster overly aggressive goals for management of hypertension or diabetes in the older adult population.

One approach to assessing whether a drug is truly necessary for a given patient is presented in an algorithm (algorithm 1) [139]. In a feasibility study performed in a cohort of 70 community-dwelling patients seen for geriatric assessment, implementation of this algorithm led to recommendations to discontinue 58 percent of the medications they had been taking. Eighty-one percent of these medications were discontinued, 2 percent were restarted, and no significant adverse events were attributable to discontinuation over 13-month follow-up.

Some preventive and other therapies may no longer be beneficial to patients with short life expectancies [32]. The appropriateness of these therapies should be reconsidered when other medical conditions develop that impact a patient’s long-term prognosis, unless the therapies are thought to increase comfort.

There are limited studies about how best to withdraw medications [31]. It is reasonable to gradually taper off most medications to minimize withdrawal reactions and to allow symptom monitoring, unless dangerous signs or symptoms indicate a need for abrupt medication withdrawal. Certain common drugs require tapering, including beta blockers, opioids, barbiturates, clonidinegabapentin, and antidepressants.

Consider adverse drug events for any new symptom — Before adding a new therapy to the patient’s drug regimen, clinicians should carefully consider whether the development of a new medical condition could be the presentation of an atypical ADE to an existing drug therapy. Many prescribing cascade scenarios have been identified (table 5). (See ‘Prescribing cascades’ above.)

Consider nonpharmacologic approaches — Some conditions in older adults may be amenable to lifestyle modification in lieu of pharmacotherapy. The Trial of Nonpharmacologic Interventions in the Elderly (TONE) demonstrated that weight loss and reduced sodium intake could allow discontinuation of antihypertensive medication in about 40 percent of the intervention group [140,141]. (See “Treatment of hypertension in older adults, particularly isolated systolic hypertension”, section on ‘Lifestyle modifications’.)

Care in the use of common drugs — Some commonly prescribed drugs may result in increased toxicity in older adults. As an example, numerous studies have documented adverse events associated with nonsteroidal antiinflammatory drug (NSAID) use, including gastrointestinal bleeding [142], renal impairment [143], and heart failure in this population [144]. NSAIDs should be used cautiously in older adults and generally for a limited duration. (See “Nonselective NSAIDs: Overview of adverse effects”.)

Reduce the dose — Many ADEs are dose-related. When prescribing drug therapies, it is important to use the minimal dose required to obtain clinical benefit. As an example, one study evaluated the relationship between prescribing of the newer atypical antipsychotic therapies (eg, olanzapinerisperidone, and quetiapine) and the development of parkinsonism in older adults [86]. Relative to those dispensed a low dose, those dispensed a high dose were more than twice as likely to develop parkinsonism (HR 2.07, 95% CI 1.42-3.02). As another example, one case-control study in patients over age 70 who received thyroid supplementation identified a correlation between risk of fracture and dose of levothyroxine, indicating the importance of testing for thyroid levels in this population and adjusting the dose accordingly [145].

Simplify the dosing schedule — When multiple medications are required, greater regimen complexity will increase the likelihood of poor compliance or confusion with dosing. Older adults, and particularly those with low health literacy, are not able to efficiently consolidate prescription regimens to optimize a dosing schedule [146]. The Institute of Medicine has proposed a standardized schedule for specifying medication dosing (morning, noon, evening, bedtime), recognizing that 90 percent of prescriptions are taken four or fewer times daily [147].

Simplifying the medication dosing schedule, when possible, is also important in the long-term care setting where nursing staff and time requirements for medication administration are substantial. A study illustrated that within a seven-hour shift, on a 20-bed unit, with two scheduled periods of medication administration, the process of administering medications to the residents accounted for a third of the nursing time [148]. This makes the nurse less available for other important patient care tasks.

Prescribe beneficial therapy — The fewer-the-better approach to drug therapy in older adults is often not the best response to optimizing drug regimens. Avoiding medications with known benefits to minimize the number of drugs prescribed is inappropriate. Patients must be informed about the reason to initiate a new medication and what the expected benefits are.

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, “The Basics” and “Beyond the Basics.” The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on “patient info” and the keyword(s) of interest.)

Basics topics (see “Patient education: Taking medicines when you’re older (The Basics)” and “Patient education: Side effects from medicines (The Basics)”)

SUMMARY AND RECOMMENDATIONS

The possibility of an adverse drug event (ADE) should always be borne in mind when evaluating an older adult; any new symptom should be considered drug-related until proven otherwise. Pharmacokinetic changes lead to increased plasma drug concentrations and pharmacodynamic changes lead to increased drug sensitivity in older adults. (See ‘Introduction’ above.)

Clinicians must be alert to the use of herbal and dietary supplements by older patients, who may not volunteer this information and are prone to drug-drug interactions related to these supplements. (See ‘Herbal and dietary supplements’ above.)

Various criteria sets exist identifying medications that should not be prescribed, or should be prescribed with caution, in older adults. Compliance with these lists of medications to be avoided is suboptimal. (See ‘Inappropriate medications’ above.)

Clinicians also under-prescribe medications, such as statins, that could provide benefit for older adults. Clinicians may be better at avoiding overprescribing of inappropriate drug therapies than at prescribing indicated drug therapies. Patient financial constraints and unavailability of prescribed doses may contribute to medication underutilization. (See ‘Underutilization of appropriate medication’ above.)

ADEs result in four times as many hospitalizations in older, compared with younger, adults. Prescribing cascades, drug-drug interactions, and inappropriate drug doses are causes of preventable ADEs. (See ‘Adverse drug events’ above.)

ADEs are a particular problem for nursing home residents; atypical antipsychotic medications and warfarin are the most common drugs involved in ADEs in this population. (See ‘Adverse drug events in long-term care setting’ above.)

A stepwise approach to prescribing for older adults should include: periodic review of current drug therapy; discontinuing unnecessary medications; considering nonpharmacologic alternative strategies; considering safer alternative medications; using the lowest possible effective dose; including all necessary beneficial medications. (See ‘A stepwise approach to prescribing’ above.)

Drug-Induced Urinary Incontinence

Pharmacologic agents including oral estrogens,alpha-blockerssedative-hypnotics,antidepressantsantipsychoticsACE inhibitors,loop diureticsnonsteroidal anti-inflammatory drugs, and calcium channel blockers have been implicated to some degree in the onset or exacerbation of urinary incontinence.

Drug-Induced Urinary Incontinence

Kiran Panesar, BPharmS (Hons), MRPharmS, RPh, CPh
Consultant Pharmacist and Freelance Medical Writer
Orlando, Florida

US Pharm. 2014;39(8):24-29.

ABSTRACT: Urinary incontinence affects both men and women, and especially the elderly. The Agency for Health Care Policy and Research identified four types of urinary incontinence: stress, urge, mixed, and overflow. Pharmacologic agents including oral estrogens, alpha-blockers, sedative-hypnotics, antidepressants, antipsychotics, ACE inhibitors, loop diuretics, nonsteroidal anti-inflammatory drugs, and calcium channel blockers have been implicated to some degree in the onset or exacerbation of urinary incontinence. The pharmacist should consider urinary incontinence–inducing drugs when reviewing patient profiles.

In healthy humans, voiding occurs at intervals several times a day, even though the kidneys produce urine continuously. This means that the bladder must store urine for several hours, a feature that requires the musculature of the bladder-outflow tract to contract to generate resistance. Disturbances of this storage function of the bladder lead to urinary incontinence. A number of factors may be responsible, including disease and adverse effects of medical treatment.1

A number of medications have been proposed as possible causes of drug-induced urinary incontinence, including alpha1-adrenoceptor antagonists, antipsychotics, benzodiazepines, antidepressants, and drugs used for hormone replacement therapy.1 Since drugs are frequently metabolized and excreted in the urine, the lower urinary tract is particularly vulnerable to adverse effects. Furthermore, carcinogens or inflammatory agents in the urine are in close proximity to the epithelium for prolonged periods when they are stored in the bladder. The drugs may cause stress incontinence, urge incontinence, or overflow incontinence.2

This article discusses the different types of incontinence, their causes, and the possible mechanisms underlying incontinence resulting from medications.

Epidemiology

The prevalence of urinary incontinence increases with age, with an overall prevalence of 38% in women and 17% in men. In women, the prevalence is about 12.5% in those aged 60 to 64 years and rises to about 20.9% in those aged ≥85 years. Furthermore, a higher prevalence has been noted in non-Hispanic white women (41%) compared with non-Hispanic black (20%) and Mexican-American women (36%).3 In a similar study, the prevalence of weekly incontinence was highest among Hispanic women, followed by white, black, and Asian-American women.4

In men, the prevalence increases with age, from 11% in those aged 60 to 64 years to 31% in those aged ≥85 years. The rate of incontinence in black men is similar to that for black women, but in white and Mexican-American men, the rate is 2.5 times lower than in women of the same ethnicity.3

Urinary incontinence may be underreported, owing to the embarrassing nature of the condition.

Types of Incontinence

According to the clinical practice guidelines issued by the Agency for Health Care Policy and Research (now called Agency for Healthcare Research and Quality), there are four types of incontinence: stress, urge, mixed, and overflow. Other guidelines identify functional incontinence as a fifth type.5-8 TABLE 1 describes the various types of incontinence in more detail, along with the usual approaches used in the management of each.5-10

Mechanisms of Urinary Continence

In healthy individuals, the urinary bladder senses the volume of urine by means of distention. Distention of the bladder excites afferent A-delta fibers (and C fibers, in a pathologic condition) that relay information to the pontine storage center in the brain. The brain, in turn, triggers efferent impulses to enhance urine storage through activation of the sympathetic innervation of the lower urinary tract (hypogastric nerve). These impulses also activate the somatic, pudendal, and sacral nerves.1

The hypogastric nerves release norepinephrine to stimulate beta3-adrenoceptors in the detrusor and alpha1-adrenoceptors in the bladder neck and proximal urethra. The role of beta3-adrenoceptors is to mediate smooth-muscle relaxation and increase bladder compliance, whereas that of alpha1-adrenoceptors is to mediate smooth-muscle contraction and increase bladder outlet resistance.1 The somatic, pudendal, and sacral nerves release acetylcholine to act on nicotinic receptors in the striated muscle in the distal urethra and pelvic floor, which contract to increase bladder outlet resistance.1

Efferent sympathetic outflow and somatic outflow are stopped when afferent signaling to the brain exceeds a certain threshold. At this point, the parasympathetic outflow is activated via pelvic nerves. These nerves release acetylcholine, which then acts on muscarinic receptors in detrusor smooth-muscle cells to cause contraction. A number of transmitters, including dopamine and serotonin, and endorphins are involved in this process.1

Pharmacologic Agents That Cause Urinary Incontinence

A variety of drugs have been implicated in urinary incontinence, and attempts have been made to determine the mechanism responsible based upon current understanding of the processes involved in continence and the transmitters that play a role. Each of the processes described previously can be manipulated by pharmacologic agents to cause one or more types of incontinence.

The drugs commonly pinpointed in urinary incontinence include anticholinergics, alpha-adrenergic agonists, alpha-antagonists, diuretics, calcium channel blockers, sedative-hypnotics, ACE inhibitors, and antiparkinsonian medications. Depending upon the mode of action, the effect may be direct or indirect and can lead to any of the types of incontinence. Taking these factors into account, it is important to consider a patient’s drug therapy as a cause of incontinence, particularly in new-onset incontinence patients and in elderly patients, in whom polypharmacy is common.11,12

On the other hand, a pharmacologic agent or any other factor that results in chronic urinary retention can lead to a rise in intravesical pressure and a resultant trickling loss of urine. In this way, drugs that cause urinary retention can indirectly lead to overflow incontinence.2

Alpha-Adrenergic Antagonists: As described earlier, the stimulation of alpha1-adrenoceptors by norepinephrine leads to increased bladder outlet resistance. It has been shown that alpha1-adrenoceptors influence lower urinary tract function not only through a direct effect on smooth muscle, but also at the level of the spinal cord ganglia and nerve terminals. In this way, they mediate sympathetic, parasympathetic, and somatic outflows to the bladder, bladder neck, prostate, and external urethral sphincter.13 Blocking these receptors with such agents as prazosin, doxazosin, and terazosin would therefore lead to reduced bladder outlet resistance and, accordingly, to incontinence.2 One study found that the use of alpha-blockers increased the risk of urinary incontinence in older African American and white women nearly fivefold.14 Another study showed that almost half of female subjects taking an alpha-blocker reported urinary incontinence.15Phenoxybenzamine, a nonselective, irreversible alpha-adrenoceptor antagonist, has been associated with stress urinary incontinence.1

It is useful to note that many antidepressants and antipsychotics exhibit considerable alpha1-adrenoceptor antagonist activity.1

Alpha-Adrenergic Agonists: Alpha-adrenergic agonists such as clonidine and methyldopa mimic the action of norepinephrine at receptors. In this way they may contract the bladder neck, causing urinary retention and thus overflow urinary incontinence.2,16-18

Antipsychotics: A number of antipsychotics have been associated with urinary incontinence, including chlorpromazine, thioridazine, chlorprothixene, thiothixene, trifluoperazine, fluphenazine (including enanthate and decanoate), haloperidol, and pimozide.19-24 Incontinence occurs over a broad range of antipsychotic dosages. Additionally, whereas some patients experience urinary incontinence within hours of initiating antipsychotic therapy, others do not experience incontinence for weeks after initiation. In most cases, the incontinence remits spontaneously upon discontinuation of the antipsychotic. Typical antipsychotics are primarily dopamine antagonists and lead to stress urinary incontinence, whereas atypical antipsychotics are antagonists at serotonin receptors.24 Antipsychotics also cause incontinence by one or more of the following mechanisms: alpha-adrenergic blockade, dopamine blockade, and cholinergic actions on the bladder.25 Owing to these complex drug-receptor interactions, a generalized description of how antipsychotics cause urinary incontinence cannot be given.1

If it is not possible to discontinue the antipsychotic, urinary incontinence caused by antipsychotics can be managed with a variety of pharmacologic agents. Desmopressin is perhaps the most effective, but also the most expensive, therapeutic agent available for this use. Other agents include pseudoephedrine, oxybutynin, benztropine, trihexyphenidyl, and dopamine agonists.25

Antidepressants: There are a number of classes of antidepressants, all with varying pharmacologic properties. This makes it difficult to generalize the underlying mechanisms that lead to urinary incontinence as a result of antidepressant use. However, all antidepressants result in urinary retention and, eventually, in overflow incontinence. Most antidepressants are inhibitors of norepinephrine and/or serotonin uptake. Some also act as antagonists at adrenergic, cholinergic, or histaminergic receptors at therapeutic doses.1

Diuretics: The purpose of a diuretic is to increase the formation of urine by the kidneys. As a result, diuretics increase urinary frequency and may cause urinary urgency and incontinence by overwhelming the patient’s bladder capacity. One study reported a link between diuretics and/or conditions associated with their use and urinary incontinence in community-dwelling women.26 In another study, the use of a loop diuretic with an alpha-blocker almost doubled the risk of urinary incontinence versus alpha-blockers alone, but no increased risk was noted when thiazide diuretics or potassium-sparing diuretics were added to the alpha-blockers.27

Calcium Channel Blockers: Calcium channel blockers decrease smooth-muscle contractility in the bladder. This causes urinary retention and, accordingly, leads to overflow incontinence.10

Sedative-Hypnotics: Sedative-hypnotics result in immobility secondary to sedation that leads to functional incontinence.10 Furthermore, benzodiazepines can cause relaxation of striated muscle because of their effects on gamma-aminobutyric acid type A receptors in the central nervous system.1,28

ACE Inhibitors and Angiotensin Receptor Blockers: The renin-angiotensin system exists specifically in the bladder and the urethra. Blocking angiotensin receptors with ACE inhibitors or angiotensin receptor blockers decreases both detrusor overactivity and urethral sphincter tone, leading to reduced urge incontinence and increased stress urinary incontinence.29 Furthermore, ACE inhibitors can result in a chronic dry cough that can cause stress incontinence. This was demonstrated in a female patient with cystocele who was receiving enalapril. The patient developed a dry cough and stress incontinence, which ceased within 3 weeks of discontinuing the ACE inhibitor.

Estrogens: One study showed that oral and transdermal estrogen, with or without progestin, increased the risk of urinary incontinence by 45% to 60% in community-dwelling elderly women.14 A summary of randomized, controlled trials also showed that the use of oral estrogen increased the risk of urinary incontinence by 50% to 80%.30

Hydroxychloroquine: Hydroxychloroquine has recently been identified as an agent that can induce urinary incontinence. There is currently only one report supporting this finding. In this report, a 71-year-old female patient developed urinary incontinence as an adverse reaction to hydroxychloroquine administered at therapeutic doses to treat rheumatoid arthritis. Urinary incontinence remitted with drug withdrawal and reappeared when the drug was readministered.31

Conclusion

A variety of drugs have been associated with urinary incontinence. This may be due to direct incontinence or overflow incontinence secondary to urinary retention. When reviewing patient profiles, pharmacists should take into consideration the use of oral estrogens, alpha-blockers, sedative-hypnotics, antidepressants, antipsychotics, ACE inhibitors, loop diuretics, nonsteroidal anti-inflammatory drugs, and calcium channel blockers that may lead to urinary incontinence. It is important to keep in mind that some incontinence patients taking these medications may be too embarrassed to discuss their condition voluntarily.

Inflammation Linked to Chemo Brain

Inflammation Linked to Chemo Brain

Summary: A new study reports inflammation in the blood may play a role in cognitive problems following chemotherapy. Researchers report identifying the inflammatory biomarkers and reducing inflammation may prevent some of the symptoms of chemo brain.

Source: University of Rochester.

Inflammation in the blood plays a key role in “chemo-brain,” according to a published pilot study that provides evidence for what scientists have long believed.

The research is important because it could lead to a new practice of identifying inflammatory biomarkers in cancer patients and then treating the inflammation with medications or exercise to improve cognition and other symptoms, said senior author Michelle C. Janelsins, Ph.D., associate professor of Surgery in the Cancer Control and Survivorship program at the Wilmot Cancer Institute.

Published in the Journal of Neuroimmunology, the preliminary research is believed to be among the first studies to look at cancer patients in active treatment and whether inflammation is involved in their chemo-brain symptoms.

Results showed that among 22 breast cancer patients taking chemotherapy, those with higher levels of inflammatory biomarkers in their blood did worse on neuropsychological tests for visual memory and concentration.

Chemo-brain, or cancer-related cognitive impairment, is estimated to impact 80 percent of people in treatment. Patients report fogginess, forgetfulness, and difficulty with multitasking and other problem-solving skills.

Researchers discovered that one particular biomarker for acute inflammation—tumor necrosis factor-alpha—was the strongest indicator of cognitive problems. Generally, higher levels of inflammation can be caused by cancer, its treatment, or other health problems; but until lately little had been known about the interplay of inflammation, cancer, and quality of life.

a brain is shown

Last year another study led by Janelsins —one of the largest to date for this problem—showed that women with breast cancer continued to report cognitive deficits for as long as six months after finishing treatment. That study not only validated that chemo-brain was pervasive, but Janelsins and her team also began parsing the data to understand the biological mechanisms, such as inflammation, that may put some patients at greater risk for chemo-brain.

“I’m happy that my team’s research is starting to shed light on what might be causing cognitive problems in patients with cancer,” Janelsins said, “and I’m hopeful that we’ll be able to come up with treatments in the future.”

ABOUT THIS NEUROSCIENCE RESEARCH ARTICLE

Funding: The current study’s first author was AnnaLynn Williams, M.S., a doctoral student in UR’s Division of Epidemiology and a researcher in Janelsins’ lab. Williams recently received a $372,000 National Cancer Institute F99/K00 Award supporting six years of pre-doctoral and postdoctoral research and career development. She is studying cognitive impairment in people with chronic lymphocytic leukemia under the guidance of Janelsins and Edwin van Wijngaarden, Ph.D., chief of the Division of Epidemiology in the Department of Public Health Sciences.

Source: Leslie Orr – University of Rochester
Publisher: Organized by NeuroscienceNews.com.
Image Source: NeuroscienceNews.com image is in the public domain.
Original Research: Abstract for “Associations between inflammatory markers and cognitive function in breast cancer patients receiving chemotherapy” by AnnaLynn M. Williams, Raven Shah, Michelle Shayne, Alissa J. Huston, Marcia Krebs, Nicole Murray, Bryan D. Thompson, Kassandra Doyle, Jenna Korotkin, Edwinvan Wijngaarden, Sharon Hyland, Jan A. Moynihan, Deborah A. Cory-Slechta, and Michelle C. Janelsins in Journal of Neuroimmunology. Published online October 18 2017 doi:10.1016/j.jneuroim.2017.10.005

Grow your nerves to prevent depression – medications – drugs causes it

What causes depression?

Onset of depression more complex than a brain chemical imbalance

what causes depression

It’s often said that depression results from a chemical imbalance, but that figure of speech doesn’t capture how complex the disease is. Research suggests that depression doesn’t spring from simply having too much or too little of certain brain chemicals. Rather, there are many possible causes of depression, including faulty mood regulation by the brain, genetic vulnerability, stressful life events, medications, and medical problems. It’s believed that several of these forces interact to bring on depression.

To be sure, chemicals are involved in this process, but it is not a simple matter of one chemical being too low and another too high. Rather, many chemicals are involved, working both inside and outside nerve cells. There are millions, even billions, of chemical reactions that make up the dynamic system that is responsible for your mood, perceptions, and how you experience life.

With this level of complexity, you can see how two people might have similar symptoms of depression, but the problem on the inside, and therefore what treatments will work best, may be entirely different.

Researchers have learned much about the biology of depression. They’ve identified genes that make individuals more vulnerable to low moods and influence how an individual responds to drug therapy. One day, these discoveries should lead to better, more individualized treatment (see “From the lab to your medicine cabinet”), but that is likely to be years away. And while researchers know more now than ever before about how the brain regulates mood, their understanding of the biology of depression is far from complete.

What follows is an overview of the current understanding of the major factors believed to play a role in depression.

The brain’s impact on depression

Popular lore has it that emotions reside in the heart. Science, though, tracks the seat of your emotions to the brain. Certain areas of the brain help regulate mood. Researchers believe that — more important than levels of specific brain chemicals — nerve cell connections, nerve cell growth, and the functioning of nerve circuits have a major impact on depression. Still, their understanding of the neurological underpinnings of mood is incomplete.

Regions that affect mood

Increasingly sophisticated forms of brain imaging — such as positron emission tomography (PET), single-photon emission computed tomography (SPECT), and functional magnetic resonance imaging (fMRI) — permit a much closer look at the working brain than was possible in the past. An fMRI scan, for example, can track changes that take place when a region of the brain responds during various tasks. A PET or SPECT scan can map the brain by measuring the distribution and density of neurotransmitter receptors in certain areas.

Use of this technology has led to a better understanding of which brain regions regulate mood and how other functions, such as memory, may be affected by depression. Areas that play a significant role in depression are the amygdala, the thalamus, and the hippocampus (see Figure 1).

Research shows that the hippocampus is smaller in some depressed people. For example, in one fMRI study published in The Journal of Neuroscience, investigators studied 24 women who had a history of depression. On average, the hippocampus was 9% to 13% smaller in depressed women compared with those who were not depressed. The more bouts of depression a woman had, the smaller the hippocampus. Stress, which plays a role in depression, may be a key factor here, since experts believe stress can suppress the production of new neurons (nerve cells) in the hippocampus.

Researchers are exploring possible links between sluggish production of new neurons in the hippocampus and low moods. An interesting fact about antidepressants supports this theory. These medications immediately boost the concentration of chemical messengers in the brain (neurotransmitters). Yet people typically don’t begin to feel better for several weeks or longer. Experts have long wondered why, if depression were primarily the result of low levels of neurotransmitters, people don’t feel better as soon as levels of neurotransmitters increase.

The answer may be that mood only improves as nerves grow and form new connections, a process that takes weeks. In fact, animal studies have shown that antidepressants do spur the growth and enhanced branching of nerve cells in the hippocampus. So, the theory holds, the real value of these medications may be in generating new neurons (a process called neurogenesis), strengthening nerve cell connections, and improving the exchange of information between nerve circuits. If that’s the case, medications could be developed that specifically promote neurogenesis, with the hope that patients would see quicker results than with current treatments.

Figure 1: Areas of the brain affected by depression

Areas of the brain affected by depression

Amygdala: The amygdala is part of the limbic system, a group of structures deep in the brain that’s associated with emotions such as anger, pleasure, sorrow, fear, and sexual arousal. The amygdala is activated when a person recalls emotionally charged memories, such as a frightening situation. Activity in the amygdala is higher when a person is sad or clinically depressed. This increased activity continues even after recovery from depression.

Thalamus: The thalamus receives most sensory information and relays it to the appropriate part of the cerebral cortex, which directs high-level functions such as speech, behavioral reactions, movement, thinking, and learning. Some research suggests that bipolar disorder may result from problems in the thalamus, which helps link sensory input to pleasant and unpleasant feelings.

Hippocampus: The hippocampus is part of the limbic system and has a central role in processing long-term memory and recollection. Interplay between the hippocampus and the amygdala might account for the adage “once bitten, twice shy.” It is this part of the brain that registers fear when you are confronted by a barking, aggressive dog, and the memory of such an experience may make you wary of dogs you come across later in life. The hippocampus is smaller in some depressed people, and research suggests that ongoing exposure to stress hormone impairs the growth of nerve cells in this part of the brain.

Nerve cell communication

The ultimate goal in treating the biology of depression is to improve the brain’s ability to regulate mood. We now know that neurotransmitters are not the only important part of the machinery. But let’s not diminish their importance either. They are deeply involved in how nerve cells communicate with one another. And they are a component of brain function that we can often influence to good ends.

Neurotransmitters are chemicals that relay messages from neuron to neuron. An antidepressant medication tends to increase the concentration of these substances in the spaces between neurons (the synapses). In many cases, this shift appears to give the system enough of a nudge so that the brain can do its job better.

How the system works. If you trained a high-powered microscope on a slice of brain tissue, you might be able to see a loosely braided network of neurons that send and receive messages. While every cell in the body has the capacity to send and receive signals, neurons are specially designed for this function. Each neuron has a cell body containing the structures that any cell needs to thrive. Stretching out from the cell body are short, branchlike fibers called dendrites and one longer, more prominent fiber called the axon.

A combination of electrical and chemical signals allows communication within and between neurons. When a neuron becomes activated, it passes an electrical signal from the cell body down the axon to its end (known as the axon terminal), where chemical messengers called neurotransmitters are stored. The signal releases certain neurotransmitters into the space between that neuron and the dendrite of a neighboring neuron. That space is called a synapse. As the concentration of a neurotransmitter rises in the synapse, neurotransmitter molecules begin to bind with receptors embedded in the membranes of the two neurons (see Figure 2).

The release of a neurotransmitter from one neuron can activate or inhibit a second neuron. If the signal is activating, or excitatory, the message continues to pass farther along that particular neural pathway. If it is inhibitory, the signal will be suppressed. The neurotransmitter also affects the neuron that released it. Once the first neuron has released a certain amount of the chemical, a feedback mechanism (controlled by that neuron’s receptors) instructs the neuron to stop pumping out the neurotransmitter and start bringing it back into the cell. This process is called reabsorption or reuptake. Enzymes break down the remaining neurotransmitter molecules into smaller particles.

When the system falters. Brain cells usually produce levels of neurotransmitters that keep senses, learning, movements, and moods perking along. But in some people who are severely depressed or manic, the complex systems that accomplish this go awry. For example, receptors may be oversensitive or insensitive to a specific neurotransmitter, causing their response to its release to be excessive or inadequate. Or a message might be weakened if the originating cell pumps out too little of a neurotransmitter or if an overly efficient reuptake mops up too much before the molecules have the chance to bind to the receptors on other neurons. Any of these system faults could significantly affect mood.

Kinds of neurotransmitters. Scientists have identified many different neurotransmitters. Here is a description of a few believed to play a role in depression:

  • Acetylcholine enhances memory and is involved in learning and recall.
  • Serotonin helps regulate sleep, appetite, and mood and inhibits pain. Research supports the idea that some depressed people have reduced serotonin transmission. Low levels of a serotonin byproduct have been linked to a higher risk for suicide.
  • Norepinephrine constricts blood vessels, raising blood pressure. It may trigger anxiety and be involved in some types of depression. It also seems to help determine motivation and reward.
  • Dopamine is essential to movement. It also influences motivation and plays a role in how a person perceives reality. Problems in dopamine transmission have been associated with psychosis, a severe form of distorted thinking characterized by hallucinations or delusions. It’s also involved in the brain’s reward system, so it is thought to play a role in substance abuse.
  • Glutamate is a small molecule believed to act as an excitatory neurotransmitter and to play a role in bipolar disorder and schizophrenia. Lithium carbonate, a well-known mood stabilizer used to treat bipolar disorder, helps prevent damage to neurons in the brains of rats exposed to high levels of glutamate. Other animal research suggests that lithium might stabilize glutamate reuptake, a mechanism that may explain how the drug smooths out the highs of mania and the lows of depression in the long term.
  • Gamma-aminobutyric acid (GABA) is an amino acid that researchers believe acts as an inhibitory neurotransmitter. It is thought to help quell anxiety.

Figure 2: How neurons communicate

How neurons communicate

  1. An electrical signal travels down the axon.
  2. Chemical neurotransmitter molecules are released.
  3. The neurotransmitter molecules bind to receptor sites.
  4. The signal is picked up by the second neuron and is either passed along or halted.
  5. The signal is also picked up by the first neuron, causing reuptake, the process by which the cell that released the neurotransmitter takes back some of the remaining molecules.

Genes’ effect on mood

Every part of your body, including your brain, is controlled by genes. Genes make proteins that are involved in biological processes. Throughout life, different genes turn on and off, so that — in the best case — they make the right proteins at the right time. But if the genes get it wrong, they can alter your biology in a way that results in your mood becoming unstable. In a genetically vulnerable person, any stress (a missed deadline at work or a medical illness, for example) can then push this system off balance.

Mood is affected by dozens of genes, and as our genetic endowments differ, so do our depressions. The hope is that as researchers pinpoint the genes involved in mood disorders and better understand their functions, treatment can become more individualized and more successful. Patients would receive the best medication for their type of depression.

Another goal of gene research, of course, is to understand how, exactly, biology makes certain people vulnerable to depression. For example, several genes influence the stress response, leaving us more or less likely to become depressed in response to trouble.

Perhaps the easiest way to grasp the power of genetics is to look at families. It is well known that depression and bipolar disorder run in families. The strongest evidence for this comes from the research on bipolar disorder. Half of those with bipolar disorder have a relative with a similar pattern of mood fluctuations. Studies of identical twins, who share a genetic blueprint, show that if one twin has bipolar disorder, the other has a 60% to 80% chance of developing it, too. These numbers don’t apply to fraternal twins, who — like other biological siblings — share only about half of their genes. If one fraternal twin has bipolar disorder, the other has a 20% chance of developing it.

The evidence for other types of depression is more subtle, but it is real. A person who has a first-degree relative who suffered major depression has an increase in risk for the condition of 1.5% to 3% over normal.

One important goal of genetics research — and this is true throughout medicine — is to learn the specific function of each gene. This kind of information will help us figure out how the interaction of biology and environment leads to depression in some people but not others.

Temperament shapes behavior

Genetics provides one perspective on how resilient you are in the face of difficult life events. But you don’t need to be a geneticist to understand yourself. Perhaps a more intuitive way to look at resilience is by understanding your temperament. Temperament — for example, how excitable you are or whether you tend to withdraw from or engage in social situations — is determined by your genetic inheritance and by the experiences you’ve had during the course of your life. Some people are able to make better choices in life once they appreciate their habitual reactions to people and to life events.

Cognitive psychologists point out that your view of the world and, in particular, your unacknowledged assumptions about how the world works also influence how you feel. You develop your viewpoint early on and learn to automatically fall back on it when loss, disappointment, or rejection occurs. For example, you may come to see yourself as unworthy of love, so you avoid getting involved with people rather than risk losing a relationship. Or you may be so self-critical that you can’t bear the slightest criticism from others, which can slow or block your career progress.

Yet while temperament or world view may have a hand in depression, neither is unchangeable. Therapy and medications can shift thoughts and attitudes that have developed over time.

Stressful life events

At some point, nearly everyone encounters stressful life events: the death of a loved one, the loss of a job, an illness, or a relationship spiraling downward. Some must cope with the early loss of a parent, violence, or sexual abuse. While not everyone who faces these stresses develops a mood disorder — in fact, most do not — stress plays an important role in depression.

As the previous section explained, your genetic makeup influences how sensitive you are to stressful life events. When genetics, biology, and stressful life situations come together, depression can result.

Stress has its own physiological consequences. It triggers a chain of chemical reactions and responses in the body. If the stress is short-lived, the body usually returns to normal. But when stress is chronic or the system gets stuck in overdrive, changes in the body and brain can be long-lasting.

How stress affects the body

Stress can be defined as an automatic physical response to any stimulus that requires you to adjust to change. Every real or perceived threat to your body triggers a cascade of stress hormones that produces physiological changes. We all know the sensations: your heart pounds, muscles tense, breathing quickens, and beads of sweat appear. This is known as the stress response.

The stress response starts with a signal from the part of your brain known as the hypothalamus. The hypothalamus joins the pituitary gland and the adrenal glands to form a trio known as the hypothalamic-pituitary-adrenal (HPA) axis, which governs a multitude of hormonal activities in the body and may play a role in depression as well.

When a physical or emotional threat looms, the hypothalamus secretes corticotropin-releasing hormone (CRH), which has the job of rousing your body. Hormones are complex chemicals that carry messages to organs or groups of cells throughout the body and trigger certain responses. CRH follows a pathway to your pituitary gland, where it stimulates the secretion of adrenocorticotropic hormone (ACTH), which pulses into your bloodstream. When ACTH reaches your adrenal glands, it prompts the release of cortisol.

The boost in cortisol readies your body to fight or flee. Your heart beats faster — up to five times as quickly as normal — and your blood pressure rises. Your breath quickens as your body takes in extra oxygen. Sharpened senses, such as sight and hearing, make you more alert.

CRH also affects the cerebral cortex, part of the amygdala, and the brainstem. It is thought to play a major role in coordinating your thoughts and behaviors, emotional reactions, and involuntary responses. Working along a variety of neural pathways, it influences the concentration of neurotransmitters throughout the brain. Disturbances in hormonal systems, therefore, may well affect neurotransmitters, and vice versa.

Normally, a feedback loop allows the body to turn off “fight-or-flight” defenses when the threat passes. In some cases, though, the floodgates never close properly, and cortisol levels rise too often or simply stay high. This can contribute to problems such as high blood pressure, immune suppression, asthma, and possibly depression.

Studies have shown that people who are depressed or have dysthymia typically have increased levels of CRH. Antidepressants and electroconvulsive therapy are both known to reduce these high CRH levels. As CRH levels return to normal, depressive symptoms recede. Research also suggests that trauma during childhood can negatively affect the functioning of CRH and the HPA axis throughout life.

Early losses and trauma

Certain events can have lasting physical, as well as emotional, consequences. Researchers have found that early losses and emotional trauma may leave individuals more vulnerable to depression later in life.

Childhood losses. Profound early losses, such as the death of a parent or the withdrawal of a loved one’s affection, may resonate throughout life, eventually expressing themselves as depression. When an individual is unaware of the wellspring of his or her illness, he or she can’t easily move past the depression. Moreover, unless the person gains a conscious understanding of the source of the condition, later losses or disappointments may trigger its return.

The British psychiatrist John Bowlby focused on early losses in a number of landmark studies of monkeys. When he separated young monkeys from their mothers, the monkeys passed through predictable stages of a separation response. Their furious outbursts trailed off into despair, followed by apathetic detachment. Meanwhile, the levels of their stress hormones rose. Later investigators extended this research. One study found that the CRH system and HPA axis got stuck in overdrive in adult rodents that had been separated from their mothers too early in life. This held true whether or not the rats were purposely put under stress. Interestingly, antidepressants and electroconvulsive therapy relieve the symptoms of animals distressed by such separations.

The role of trauma. Traumas may also be indelibly etched on the psyche. A small but intriguing study in the Journal of the American Medical Association showed that women who were abused physically or sexually as children had more extreme stress responses than women who had not been abused. The women had higher levels of the stress hormones ACTH and cortisol, and their hearts beat faster when they performed stressful tasks, such as working out mathematical equations or speaking in front of an audience.

Many researchers believe that early trauma causes subtle changes in brain function that account for symptoms of depression and anxiety. The key brain regions involved in the stress response may be altered at the chemical or cellular level. Changes might include fluctuations in the concentration of neurotransmitters or damage to nerve cells. However, further investigation is needed to clarify the relationship between the brain, psychological trauma, and depression.

Seasonal affective disorder: When winter brings the blues

Many people feel sad when summer wanes, but some actually develop depression with the season’s change. Known as seasonal affective disorder (SAD), this form of depression affects about 1% to 2% of the population, particularly women and young people.

SAD seems to be triggered by more limited exposure to daylight; typically it comes on during the fall or winter months and subsides in the spring. Symptoms are similar to general depression and include lethargy, loss of interest in once-pleasurable activities, irritability, inability to concentrate, and a change in sleeping patterns, appetite, or both.

To combat SAD, doctors suggest exercise, particularly outdoor activities during daylight hours. Exposing yourself to bright artificial light may also help. Light therapy, also called phototherapy, usually involves sitting close to a special light source that is far more intense than normal indoor light for 30 minutes every morning. The light must enter through your eyes to be effective; skin exposure has not been proven to work. Some people feel better after only one light treatment, but most people require at least a few days of treatment, and some need several weeks. You can buy boxes that emit the proper light intensity (10,000 lux) with a minimal amount of ultraviolet light without a prescription, but it is best to work with a professional who can monitor your response.

There are few side effects to light therapy, but you should be aware of the following potential problems:

  • Mild anxiety, jitteriness, headaches, early awakening, or eyestrain can occur.
  • There is evidence that light therapy can trigger a manic episode in people who are vulnerable.
  • While there is no proof that light therapy can aggravate an eye problem, you should still discuss any eye disease with your doctor before starting light therapy. Likewise, since rashes can result, let your doctor know about any skin conditions.
  • Some drugs or herbs (for example, St. John’s wort) can make you sensitive to light.
  • If light therapy isn’t helpful, antidepressants may offer relief.

Medical problems

Certain medical problems are linked to lasting, significant mood disturbances. In fact, medical illnesses or medications may be at the root of up to 10% to 15% of all depressions.

Among the best-known culprits are two thyroid hormone imbalances. An excess of thyroid hormone (hyperthyroidism) can trigger manic symptoms. On the other hand, hypothyroidism, a condition in which your body produces too little thyroid hormone, often leads to exhaustion and depression.

Heart disease has also been linked to depression, with up to half of heart attack survivors reporting feeling blue and many having significant depression. Depression can spell trouble for heart patients: it’s been linked with slower recovery, future cardiovascular trouble, and a higher risk of dying within about six months. Although doctors have hesitated to give heart patients older depression medications called tricyclic antidepressants because of their impact on heart rhythms, selective serotonin reuptake inhibitors seem safe for people with heart conditions.

The following medical conditions have also been associated with mood disorders:

  • degenerative neurological conditions, such as multiple sclerosis, Parkinson’s disease, Alzheimer’s disease, and Huntington’s disease
  • stroke
  • some nutritional deficiencies, such as a lack of vitamin B12
  • other endocrine disorders, such as problems with the parathyroid or adrenal glands that cause them to produce too little or too much of particular hormones
  • certain immune system diseases, such as lupus
  • some viruses and other infections, such as mononucleosis, hepatitis, and HIV
  • cancer
  • erectile dysfunction in men.

When considering the connection between health problems and depression, an important question to address is which came first, the medical condition or the mood changes. There is no doubt that the stress of having certain illnesses can trigger depression. In other cases, depression precedes the medical illness and may even contribute to it. To find out whether the mood changes occurred on their own or as a result of the medical illness, a doctor carefully considers a person’s medical history and the results of a physical exam.

If depression or mania springs from an underlying medical problem, the mood changes should disappear after the medical condition is treated. If you have hypothyroidism, for example, lethargy and depression often lift once treatment regulates the level of thyroid hormone in your blood. In many cases, however, the depression is an independent problem, which means that in order to be successful, treatment must address depression directly.

An out-of-sync body clock may underlie SAD and other mood disorders

Research into one form of depression — seasonal affective disorder (SAD) — has uncovered another potential factor in mood disorders: an internal body clock that has gone awry.

Experts don’t fully understand the cause of SAD, but a leading theory has been that the hormone melatonin plays a role. The brain secretes melatonin at night, so longer periods of darkness in the winter months may spur greater production of this hormone. Some researchers believe light therapy has been helpful in treating SAD because exposure to light artificially lengthens daytime and decreases melatonin production.

But another theory has emerged: that SAD stems, at least partly, from an out-of-sync body clock. The researchers who propose this idea suggest that light therapy works because it resets the body’s internal clock.

Each of us has a biological clock that regulates the circadian (meaning “about a day”) rhythm of sleeping and waking. This internal clock — which is located in a small bundle of brain cells called the suprachiasmatic nucleus and gradually becomes established during the first months of life — controls the daily ups and downs of biological patterns, including body temperature, blood pressure, and the release of hormones. Although the clock is largely self-regulating, it responds to several cues to keep it set properly, including light and melatonin production.

When researchers expose people to light at intervals that are at odds with the outside world, this resets the subjects’ biological clocks to match the new light input. Likewise, melatonin affects the body clock. It’s produced in a predictable daily rhythm by the pineal gland, with levels climbing after dark and ebbing after dawn. Scientists believe this daily light-sensitive pattern helps keep the sleep/wake cycle on track.

Beyond SAD

A case is being made that circadian rhythms influence other mood disorders as well. Studies have uncovered out-of-sync circadian rhythms among people with bipolar disorder, schizophrenia, borderline personality disorder, or night eating disorder.

Figure 3: Getting back in sync

Getting back in sync

Medications

Sometimes, symptoms of depression or mania are a side effect of certain drugs, such as steroids or blood pressure medication. Be sure to tell your doctor or therapist what medications you take and when your symptoms began. A professional can help sort out whether a new medication, a change in dosage, or interactions with other drugs or substances might be affecting your mood.

Table 1 lists drugs that may affect mood. However, keep in mind the following:

  • Researchers disagree about whether a few of these drugs — such as birth control pills or propranolol — affect mood enough to be a significant factor.
  • Most people who take the medications listed will not experience mood changes, although having a family or personal history of depression may make you more vulnerable to such a change.
  • Some of the drugs cause symptoms like malaise (a general feeling of being ill or uncomfortable) or appetite loss that may be mistaken for depression.
  • Even if you are taking one of these drugs, your depression may spring from other sources.

Table 1: Medications that may cause depression

Antimicrobials, antibiotics, antifungals, and antivirals
acyclovir (Zovirax); alpha-interferons; cycloserine (Seromycin); ethambutol (Myambutol); levofloxacin (Levaquin); metronidazole (Flagyl); streptomycin; sulfonamides (AVC, Sultrin, Trysul); tetracycline
Heart and blood pressure drugs
beta blockers such as propranolol (Inderal), metoprolol (Lopressor, Toprol XL), atenolol (Tenormin); calcium-channel blockers such as verapamil (Calan, Isoptin, Verelan) and nifedipine (Adalat CC, Procardia XL); digoxin (Digitek, Lanoxicaps, Lanoxin); disopyramide (Norpace); methyldopa (Aldomet)
Hormones
anabolic steroids; danazol (Danocrine); glucocorticoids such as prednisone and adrenocorticotropic hormone; estrogens (e.g., Premarin, Prempro); oral contraceptives (birth control pills)
Tranquilizers, insomnia aids, and sedatives
barbiturates such as phenobarbital (Solfoton) and secobarbital (Seconal); benzodiazepines such as diazepam (Valium) and clonazepam (Klonopin)
Miscellaneous
acetazolamide (Diamox); antacids such as cimetidine (Tagamet) and ranitidine (Zantac); antiseizure drugs; baclofen (Lioresal); cancer drugs such as asparaginase (Elspar); cyclosporine (Neoral, Sandimmune); disulfiram (Antabuse); isotretinoin (Accutane); levodopa or L-dopa (Larodopa); metoclopramide (Octamide, Reglan); narcotic pain medications (e.g., codeine, Percodan, Demerol, morphine); withdrawal from cocaine or amphetamines
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