Psychotropic Side Effects of Commonly Prescribed Medications in the Elderly

Abhilash K. Desai, MD

Dr. Desai is clinical instructor in the Department of Psychiatry at Saint Louis University School of Medicine in Missouri.

Disclosure: Dr. Desai is on the speaker’s bureaus of Eli Lilly, Forest, Janssen, Novartis, and Pfizer.

Please direct all correspondence to: Abhilash K. Desai, MD, Department of Geriatric Psychiatry, St Louis University School of Medicine, St Louis, MO 63104; Tel: 215-453-4273; Fax: 215-453-4488; E-mail: [email protected].

Abstract

Psychotropic side effects of commonly prescribed medications in the elderly are prevalent and, in most instances, predictable and preventable. They are also associated with considerable morbidity and mortality. Delirium, mood changes, and psychotic symptoms are the most serious categories of psychotropic side effects. Although any drug that crosses the blood-brain barrier has the potential for causing psychotropic side effects, certain commonly prescribed classes of drugs, such as anticholinergics, psychotropics, antihistaminics, and many over-the-counter medications, are particularly suspect. A variety of interventions, such as decreasing the inappropriate prescription and performing a routine evaluation of the older patient’s drug regimen, can prevent or minimize psychotropic side effects. Practitioners must be vigilant in monitoring elderly patients for psychotropic side effects of all commonly prescribed drugs.

Introduction

Psychiatric adverse effects are behavioral and psychological symptoms that are thought to be due to one or more drugs consumed by a person. Each year, adverse drug events affect millions of older patients and are responsible for considerable morbidity and mortality.¹ While some of these adverse drug events are unpredictable (eg, anaphylaxis from an unrecognized allergy), many others can be anticipated and prevented.² The prediction and prevention of psychiatric adverse events is often attainable based on a knowledge of previous research reports, clinical studies, and an understanding of pharmacologic principles.

Adverse drug effects can mimic almost any clinical syndrome in geriatrics.³ Age, sex, comorbidity, multiple-drug regimens, alcohol intake, and cognitive function have been shown to be independently associated with adverse psychiatric drug reactions.^4,5 The pharmacologic changes and physiologic decline associated with aging, the high use of prescription and over-the-counter (OTC) medications, and the increasing burden of chronic illness in the older population all make assessing and reducing the risks of all adverse drug effects (including psychiatric) of critical importance in the practice of geriatric medicine.

This article discusses various psychiatric syndromes caused by commonly prescribed medications in the elderly, as well as the potential sequelae of these psychiatric side effects (Table 1),^6,7 and examines the interventions necessary to resolve them.

Medications Linked to Delirium and Other Cognitive Disorders

Delirium is a clinical state of acute onset and is characterized by fluctuating disturbances in cognition, mood, attention, arousal, and self-awareness. In most instances, delirium is reversible when the underlying cause is identified and treated. Medications are the most common reversible cause of delirium and dementia in the elderly (Table 2).^6-8

It is estimated that medications contribute to 22% to 39% of all causes of delirium.⁹ They are often thought to be the critical element in a multifactorial etiology of delirium. It has also been estimated that >10% of patients attending memory clinics have drug-induced dementia.¹⁰ Furthermore, medication side effects may account for 5% of reversible dementias in patients ^>60 years of age.¹¹

The classes of drugs most often associated with the development of drug-induced dementia are benzodiazepines and anticholinergics.¹⁰ All drugs that are linked to delirium may also cause other less serious (but still clinically important) cognitive disorders, such as amnesia and executive dysfunction. Drug-induced cognitive dysfunction tends to be subtle in persons with preexisting dementia in the earlier stages, whereas delirium is more likely to develop in the advanced dementia population. Most drugs listed in the recently updated Beer’s list of medications¹² that are potentially inappropriate for the elderly carry a high risk of cognitive toxicity. Frail elderly persons, elderly with cognitive impairment, and elderly in whom multiple medications are added at one time are most at risk for drug-induced cognitive impairment.¹³ Although delirium is known as a transient syndrome, many studies have demonstrated that symptoms of delirium may persist over time, especially among seniors.¹⁴ Typically, among elderly patients, delirium is caused by numerous factors (eg, electrolyte imbalance, infection, adverse drug effects), which must be addressed by clinicians in order to treat the condition properly.¹⁵

Anticholinergics

Impaired cholinergic neurotransmission has been implicated in the pathogenesis of delirium, Alzheimer’s disease, and Lewy body dementia. Moreover, anticholinergic medications are the class of drugs that have the highest risk of acute and chronic confusional states (Table 3). Nevertheless, polypharmacy with anticholinergic compounds is common, especially in nursing home residents.¹⁶ Anticholinergic effects have been identified in many drugs other than those classically thought of as having major anticholinergic effects (eg, digoxin, theophylline, thiazide diuretics, and cimetidine).

Recent studies have suggested that the total burden of anticholinergic drugs may determine the development of delirium, rather than any single agent.¹⁷ The total burden of anticholinergic medications is the sum of the anticholinergic activity of all the drugs a patient is consuming. For example, if a person is on amitriptyline for neuropathic pain, cimetidine for dyspepsia, and theophylline for asthma, the total burden of anticholinergic drugs in this person is high because each of these drugs has anticholinergic activity (amitriptyline being the most anticholinergic among these drugs). This patient is at high risk for cognitive toxicity due to this anticholinergic burden and he or she is also at high risk for developing frank delirium if another drug with significant anticholinergic activity (eg, diphenhydramine) is added to this regimen (either by self-administration or as per the instruction of his or her prescribing healthcare provider).

Antihistaminics

Antihistamines constitute one of the most widely used class of medications in the United States, among both prescription and OTC drugs.¹⁸ First generation histamine (H)₁ antihistaminics (Table 3) are highly anticholinergic and are thus associated with high risk of cognitive toxicity. Although H₂ blockers, such as cimetidine and ranitidine, have been reported to cause delirium, especially in patients with hepatic or renal insufficiency, the overall incidence is low.¹⁹

Gastrointestinal Medications

Medications used for irritable bowel syndrome (IBS), such as dicyclomine or hyoscamine, carry a high risk of cognitive toxicity due to high anticholinergic activity. Desipramine is preferable to these drugs for treatment of pain due to IBS.²⁰ Loperamide, commonly used to treat diarrhea, is also highly anticholinergic.

Psychotropics

Long-acting benzodiazepines (eg, diazepam, chlordiazepoxide, or flurazepam) are the most common medications that may cause or exacerbate dementia.¹⁶ Benzodiazepines may cause delirium during benzodiazepine intoxication, benzodiazepine withdrawal (in this case, short-acting agents more so than long-acting benzodiazepines), and in vulnerable elderly, even at low doses. Long-acting benzodiazepines should be avoided in the elderly and even short-acting benzodiazepines should not exceed the suggested daily maximums (ie, lorazepam 1.5 mg/day, oxazepam 30 mg/day, alprazolam 1 mg/day, temazepam 15 mg/day, and triazolam .25 mg/day).^12,21

Cognitive impairment is an unavoidable dose-related complication of the older tricyclic antidepressants (TCAs).²² The anticholinergic activity of this class of drugs appears to be responsible for these cognitive effects.

Although selective serotonin reuptake inhibitors (SSRIs) can be safely used in most elderly, they may occasionally cause delirium secondary to serotonin syndrome or secondary to hyponatremia caused by drug-induced syndrome of inappropriate antidiuretic hormone (SIADH).²³ Advanced age, concomitant use of diuretics, and smoking appear to increase the risk of SIADH associated with antidepressants.

Conventional low potency antipsychotics (eg, thioridazine, mesoridazine, and chlorpromazine) and clozapine have highly anticholinergic properties and thus carry a high risk of delirium. Clinicians must also monitor for neuroleptic malignant syndrome, a rare but potentially fatal complication of antipsychotics that presents with delirium, rigidity, and hyperpyrexia. Older patients and others with neurological disease may show confusion and delirium at lithium levels that are therapeutic for younger patients.²⁴

Over-the-Counter Medications

Many OTC medications have high anticholinergic activity (eg, diphenhydramine and dextromethorphan) and thus pose a significant risk of cognitive toxicity in the elderly.⁵ Serotonin syndrome may occur if drugs with high serotonin reuptake inhibitory activity (such as SSRIs) are combined with other commonly used OTC drugs, such as detromethorphan (present in many cough medications), nonherbal supplements (eg, 5-hydroxytryptophan), or herbal remedies (eg, St. John’s wort).²⁵

Opioids

Cognitive dysfunction is a recognized complication of opioid use and opioids are among the most important causes of delirium in postoperative patients.^26,27 Elevation of opioid metabolites with renal impairment may contribute to this cognitive dysfunction.

One opioid, meperidine, is linked to psychosis and delirium in the elderly because of the anticholinergic properties of its active metabolite, normeperidine. Meperidine is also not an effective analgesic in doses commonly used and hence should be avoided in the elderly.¹²

Pentazocine also carries a high risk for cognitive impairment and hallucinations. Its use should be avoided in the elderly.

Antiepileptics

Antiepileptic drugs (AEDs) may adversely impact memory functions primarily because of their detrimental effects on attention and vigilance.²⁸ This mental status change is usually related to serum levels. AEDs are especially detrimental when used with more than one anticonvulsant and in certain patient populations, including older adults and children.

Among the AEDs, barbiturates carry the highest risk of cognitive toxicity. However, in elderly patients with low albumin, a therapeutic level of phenytoin may also be toxic. Furthermore, hyponatremia, a risk for those with advanced age and higher serum levels, is a relatively frequent side effect of carbamazepine and oxcarbazepine.²⁹ Topiramate is also known to cause memory impairment, somnolence, confusion, or psychomotor slowing, even at therapeutic dosages, especially at the onset of therapy or with rapid dose escalation.³⁰ Recently, discontinuation of levetiracetam because of behavioral side effects has been reported.³¹

Other Medications

All muscle relaxants have been linked to delirium in the elderly, even at low doses.⁵ Indomethacin, antibiotics (eg, ciprofloxacin and amphotericin), older hypnotics (eg, meprobamate and chloral hydrate), and labyrinthine sedatives (eg, meclizine and dimenhydrinate) have also been frequently linked to delirium.^5,32 Many chemotherapeutic agents (eg, methotrexate and 5-fluorouracil) are also linked to delirium, especially in patients with metastatic cancer and cancer patients undergoing radiation therapy.³³

Digoxin

Digoxin can cause delirium and other psychotropic side effects (eg, depression, visual hallucinations) even at therapeutic levels in older persons.³⁴ This could be due to digoxin’s protein-binding capacity, which, for malnourished older persons with low albumin, could result in an actual higher plasma level than that measured by serum blood levels. Also, psychotropic side effects of digoxin may be the first and only manifestation of digoxin toxicity, which, if uncorrected, can be fatal.

Medications Linked to Mood Changes

Certain medications may contribute to the etiology of depressive symptoms and depressive disorders (Table 2).^35,36 Most of the data supporting this claim is found in the form of case reports, as large, rigorous studies are usually done only with antihypertensives and interferon-a. Although initial reports suggest a high prevalence of antihypertensive drug-induced depression, the association between b-blockers and depression is uncommon (1% to 4%). Centrally-acting antihypertensives, such as methyldopa, reserpine, and clonidine, do have a high risk of inducing depressive symptoms and hence their use in the elderly should be minimized.⁵

Interferon-a

Interferon-a is capable of inducing depressive symptoms and syndromes.³⁷ Reported rates of depressive symptoms (including hopelessness, tearfulness, and suicidal ideation) range from 4% to 40%. Fatigue occurs in ≤90% of patients receiving interferon-a; insomnia occurs in 40% of patients and can be another dose-limiting symptom. Lability of affect, apathy, and cognitive and behavioral changes commonly develop after a few weeks of interferon-a treatment.³⁸ Delirium and aphasia have also been reported. Moreover, elderly patients are at greater risk for psychotropic side effects with interferon-a and duration of therapy and number of courses are directly proportional to the risk of psychotropic side effects. Psychiatric symptoms are the most frequent reason for discontinuing therapy. Suicidal ideation and suicidal attempt have been reported, and completed suicide has occurred during the course of interferon-a therapy,³⁹ so depressive symptoms must be taken seriously. Presence of depressive symptoms immediately before treatment with interferon-a may be more important than a history of psychiatric illness or treatment in predicting the intensity of depression that develops during therapy.³⁸ Prophylactic antidepressants may prevent interferon-a–induced depression.⁴⁰

Corticosteroids

The overall incidence of psychotropic side effects with corticosteroids is approximately 3%, although these side effects occur in approximately 18% of patients on high doses of corticosteroids.⁴¹ The nature of side effects can appear as a variety of mental status changes. For example, depressive, manic, and mixed symptoms; affective symptoms accompanied by paranoid-hallucinatory features; only psychotic symptoms; and delirium may all occur. Predisposing factors are high dosages, female sex, and coexisting brain disease. Withdrawal of corticosteroids may also precipitate delirium.

Selective Serotonin Reuptake Inhibitors

Apathy syndrome due to SSRI use has been described and can occur months or years after effective treatment with an SSRI.²² Furthermore, all antidepressants can precipitate mania or hypomania.²⁹ Psychostimulant withdrawal is also associated with prominent depressive symptoms.

Medications Linked to Psychosis

Psychosis is a clinical state characterized by delusions and/or prominent hallucinations, with the hallucinations occurring in the absence of insight into their pathological nature. When medication-induced psychosis occurs in the elderly, the most common offenders are anti-Parkinson’s drugs, anticholinergic drugs (eg, diphenhydramine), cimetidine, digoxin, antiarrhythmic drugs (eg, lidocaine, quinidine, procainamide), and corticosteroids (Table 2).⁴² Tactile hallucinations occur most commonly in toxic and metabolic disturbances or drug withdrawal states.

Anti-Parkinson’s Medications

Anti-Parkinson’s drugs, including bromocriptine, amantadine, selegiline, anticholinergics (eg, trihexyphenidyl, benztropine, benzhexol), and levodopa, have the highest risk of drug-induced psychosis of all the classes of drugs.^42,43 The mental status changes caused by these agents include hallucinosis on a background of a clear sensorium, delusional disorders that are frequently paranoid, and frank delirium. These problems happen more often in Parkinson’s disease patients who are older and who have dementia. Abnormal dreaming and sleep disruption often precede these other, more disabling symptoms by weeks to months. Anti-Parkinson’s drugs, besides causing psychotic symptoms, have also been linked to mood symptoms, even at therapeutic doses.

Other Medications

All drugs with highly anticholinergic properties can cause hallucinations (especially visual). There have been several reports of hallucinations caused by methyldopa, and also several reports of benzodiazepine-induced hallucinations and encephalopathy.⁴⁴ Sympathetomimetics (eg, pseudoephedrine, phenylpropanolamine), which are found in most cold and cough remedies, and phenylephrine, which is found in OTC nasal sprays, have been linked to psychotic symptoms even at usual dosages.⁵

Medications Linked to Anxiety

Table 2 lists some commonly used medications that are linked to anxiety symptoms. Oral decongestant (eg, pseudoephedrine available OTC) and topical decongestant (eg, oxymetazoline, phenylephrine, and naphazoline available OTC) use is frequently associated with tremor, palpitations, anxiety, and nervousness. Akathisia (motor restlessness) can mimic anxiety disorder and can be caused by all drugs with antidopaminergic properties (eg, metoclopramide and all antipsychotics). Anxiety, restlessness, numbness, tingling in hands and face, and headache may accompany SSRI discontinuation syndrome.⁴⁵ SSRI use has been associated with tension headaches, tremors, increased anxiety, and motor restlessness.²² Flouxetine use should be avoided in the elderly because of its long half-life and risk of producing excessive central nervous system stimulation, sleep disturbances, and increasing agitation.¹²

Medications Linked to Other Psychiatric Adverse Reactions

Subsyndromal psychotropic side effects (eg, sleep disturbances, sexual dysfunction, fatigue, dysphoria, impaired concentration, decreased alertness, deficits in verbal memory, and mental slowing) are probably more prevalent than the psychiatric syndromes described above, though they have not been well studied. Many medications (such as olanzapine) cause significant weight gain. Their use among obese older persons should be minimized because of considerable emotional distress associated with additional weight gain in patients with obesity.¹²

Causes of Psychotropic Side Effects and Drug-Induced Morbidity and Mortality

Psychotropic side effects of commonly prescribed medications are due to a variety of causes. The most common among these are drug monitoring and drug prescribing errors (Table 4).² This is because physicians receive little or no formal teaching about OTC medicines at the undergraduate or postgraduate level.⁴⁶ Furthermore, the diagnosis of drug-induced psychiatric illness in elderly patients is complicated by lack of awareness of the physiology of normal aging and the tendency by patients, families, and even physicians to mislabel many symptoms as signs of “just growing old.” In fact, physicians do not refrain from prescribing highly anticholinergic agents to older patients despite their potential adverse drug reactions in this age group.⁴⁷

Interventions for Decreasing Psychotropic Side Effects and Drug-Induced Morbidity and Mortality

Decreasing drug-induced psychiatric reactions is difficult, as the mechanism of psychotropic side effects of commonly used drugs is clear in some instances, such as cholinergic deficiency in drug-induced delirium, and poorly understood in many other instances, such as interferon-a–induced depression. The accompanying Algorithm provides a sample approach to effectively treating a patient suspected of having psychotropic side effects. Resolving drug-induced morbidity and mortality can be done through the use of psychopharmacology (Tables 5 and 6), but nonpharmacologic interventions (such as cognitive-behavioral therapy to treat drug-induced depression or behavioral and psychological therapy for drug-induced insomnia) should also be tried as first-line strategies.^48-51 The use of complementary and alternative treatment may be appropriate in the treatment of drug-induced psychiatric symptoms in certain situations as well.²⁵ Reducing anticholinergic load by just 25% has been found to improve delirium.¹⁷ The treating physician should keep in mind that serious adverse psychotropic effects (eg, delirium, psychosis, and suicide) are more likely to be preventable than less-severe events (eg, fatigue, sleep disturbances, difficulty concentrating, sexual difficulties, and irritability).²

An approach that includes regular inquiry into the psychotropic side effects of prescribed and OTC medications and vigilance in assessing the contribution of drugs in their development is recommended. Pharmacogenetics can also be helpful in identifying at-risk elderly. For example, older persons who are poor metabolizers of cytochrome P450 (CYP) 2C19 are more at risk of cognitive toxicity due to diazepam, while elderly who are poor metabolizers of CYP 2D6 are at higher risk of cognitive toxicity due to TCAs compared to the general population.⁵²

The evidence regarding much of the current information on psychotropic side effects of commonly prescribed drugs in the elderly, including the above, is in the form of case reports. Large rigorous studies are only recently being performed to clarify drug-induced psychiatric morbidity.

Conclusion

The importance of psychotropic side effects of commonly prescribed and OTC drugs is often underestimated. Side effects are common and can be life threatening and unnecessarily expensive. A high index of suspicion is crucial to early detection and resolution of symptoms. Preventive strategies directed at avoiding high-risk medications (when possible), using safer alternatives, appropriately adjusting doses based on age-related changes and medical comorbidity, and close follow-up may prevent drug-induced psychiatric morbidity. Vigilance by clinicians in detecting, diagnosing, and reporting psychotropic side effects of prescribed and over-the-counter medications is recommended. PP

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