Psychotropic Side Effects of Commonly Prescribed Medications in the Elderl
Psychotropic Side Effects
of Commonly Prescribed Medications in the Elderly
Dr. Desai is clinical
instructor in the Department of Psychiatry at Saint Louis University School of
Medicine in Missouri.
Dr. Desai is on the speaker’s bureaus of Eli Lilly, Forest, Janssen, Novartis,
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: firstname.lastname@example.org.
commonly used medications can induce psychiatric symptoms in nonpsychiatrically
ill elderly and can exacerbate preexisting psychiatric disorders.
• Anticholinergics, antihistaminics, psychotropics, and many
over-the-counter medications can cause these psychiatric effects.
psychotropic side effects of these medications, although dose-related, may
occur even at low or subtherapeutic doses in elderly patients.
• Older persons who are frail, cognitively impaired, on
multiple drugs, and have renal or hepatic insufficiency are particularly
vulnerable to psychotropic side effects.
• Avoiding inappropriate medications and performing a routine
evaluation of the drug regimen in question are some of the key interventions
for preventing psychotropic side effects of commonly prescribed medications.
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.
must be vigilant in monitoring elderly patients for psychotropic side effects
of all commonly prescribed drugs.
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
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
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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
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).
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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).
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
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.
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.
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
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
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
Pentazocine also carries
a high risk for cognitive impairment and hallucinations. Its use should be
avoided in the elderly.
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
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
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
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
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 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
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.
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
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.
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.
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
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
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
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Decreasing Psychotropic Side Effects and Drug-Induced Morbidity and
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.
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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
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.
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