Sandra Jacobson, MD

Slideshows

It is important to monitor and alter psychotropic medications and dosages in older patients as needed. This slideshow serves as quick reference on the effects of pharmacokinetic and pharmacodynamic changes in the elderly.

10 Facts About Geriatric Pharmacotherapy

The consultation/liaison service provides an excellent opportunity to showcase the skills and knowledge base of psychiatrists. Clinical issues that arise at the interface of psychiatry, medicine, and surgery can prove challenging and often require a multimodal approach that involves pharmacological and nonpharmacological interventions. This article summarizes 5 cases from consultation services at several teaching hospitals. Each case includes notes on the consultation problem posed, pertinent details of the psychiatry team’s evaluation, and the outcome of the consultation.

The poisoned patient: the case of Mrs Shaw

Mrs Shaw, aged 85 years, was admitted to the hospital in a dehydrated state after several falls at home. The medical team consulted the psychiatry service to request a determination of whether she had the capacity to make her own decision about placement after discharge. Her expressed preference was to return home, but the team and her family felt that assisted living placement was indicated because of fall risk. In this case, the challenge involved a standoff between the two sides.

On first encounter, Mrs Shaw appeared mildly sedated and was irritable when awakened for the interview. She was angry that her doctors were not paying attention to her requests and held the belief that the only reason she was having problems was because she was being “poisoned” by prescription drugs. The nurse caring for Mrs Shaw reported that she had been claiming this since her admission, and she had been resistant to taking the prescribed medications.

Mrs Shaw scored 28/30 on the Mini-Mental State Exam (MMSE). She did not endorse symptoms of depression. She was questioned in detail about her current situation of independent living. Her children were contacted to confirm that except for her recent falls, she was managing well. The team concluded that Mrs Shaw did have the capacity to make her own decision about placement.

Mrs Shaw’s laboratory values were in the normal range, except for a serum creatinine level of 1.7 mg/dL (upper limit of normal, 1.2 mg/dL). Blood urea nitrogen level was 20 mg/dL. An estimate of her glomerular filtration rate (eGFR) was obtained using the Modification of Diet in Renal Disease formula, which requires the user to input the patient’s sex, ethnicity, age, and serum creatinine value.

 indicated severe reduction in renal function (

Given this degree of renal insufficiency, could medications be causing Mrs Shaw’s falls, as she claimed? Psychotropic drugs and metabolites that are primarily renally excreted would be most affected by reduced renal function.

shows several psychotropics and some commonly used nonpsychotropics in this category. Mrs Shaw’s medications included gabapentin 600 mg 3 times daily for peripheral neuropathy. This drug may cause somnolence and ataxia in older patients, particularly at toxic levels. Gabapentin is cleared exclusively through the kidneys, and for such drugs, the dose should be reduced in proportion to the reduction in eGFR. A normal eGFR is 60 mL/min/1.73 m

 or higher. Because Mrs Shaw’s eGFR was reduced by 50%, her target dose of medication should be reduced by 50%.

Was it possible that Mrs Shaw was right all along, that her dose of gabapentin was in fact excessive? It was agreed that a trial of a lower dose was indicated. The dose was reduced to 300 mg 3 times daily; this was done without any worsening of neuropathy. In addition, physical therapy was consulted to work with her on a program of falls prevention. In the end, Mrs Shaw was discharged home. In this case, a solution emerged when additional facts were brought to bear on the case, making the difference of opinion as to placement a moot issue.

Mania and the liver: the case of Mr Bertram

Mr Bertram, aged 67 years, was admitted for treatment of ulcerative colitis. Mania developed while he was receiving high-dose methylprednisolone, and the psychiatry team was consulted for help with management. A time-limited course of divalproex was recommended, to be tapered off as the corticosteroid dose was tapered and mania subsided. Two days before the patient was to be discharged, the psychiatry team was contacted and told that Mr Bertram’s liver function tests (LFTs) were elevated. Mr Bertram had a number of other medical problems, but the challenge to the psychiatry team was this: was divalproex harming this patient?

The psychiatry team first determined which LFTs were elevated. Levels of aspartate aminotransferase and/or alanine aminotransferase (ALT) that are up to 2 times the upper limit of normal are common when a new drug is started and are not useful predictors of liver injury. On the other hand, higher elevations, particularly when coupled with elevation of bilirubin levels, are of concern. Mr Bertram’s ALT value was 6 times the upper limit of normal and bilirubin level was 4 times the upper limit of normal.

Whether a drug is causing hepatotoxicity can be determined using Hy’s law, which includes the following 2 criteria: ALT 3 or more times the upper limit of normal and bilirubin 2 or more times the upper limit of normal.

. In making this determination, it is important to exclude other causes of hepatotoxicity, such as evidence of an obstructive pattern (eg, elevation of alkaline phosphatase levels), history of Gilbert syndrome, hepatitis, or recent marked circulatory insufficiency, and to consider the effects of other coadministered medications.

The team was able to determine that the changes in Mr Bertram’s liver function occurred only after treatment with divalproex was started. In general, the liver has a significant capacity to rid the body of bilirubin, a toxin. If the liver is injured, that capacity is reduced, and bilirubin levels in the blood increase. In Mr Bertram’s case, it was apparent that divalproex had induced significant liver injury as reflected in the increased bilirubin level. This is a cause for genuine concern; patients meeting Hy’s law may have a poor outcome, with high rates of referral for liver transplant and/or mortality. The solution was for the psychiatry team to take responsibility for the problem and to make recommendations that could be implemented quickly. Accordingly, divalproex was stopped, and lorazepam was used to manage mood symptoms. Fortunately, Mr Bertram’s liver function recovered over the ensuing weeks, and by the time he was discharged, his LFTs had normalized.

Blatant nonadherence: the case of Mrs Murdoch

Mrs Murdoch, aged 72 years, had diabetes and problems with glycemic control. She was admitted for treatment of a nonhealing foot ulcer. The psychiatry team was consulted for help with management when the treating team became frustrated because of her nonadherence to medical and wound care recommendations. Among other problems, she was frequently found eating candy and other sweets brought in by friends and family, and the team was finding it impossible to regulate her glucose levels. The challenge here was that a good medical outcome seemed more important to her treating doctors than to her.

Her mental status examination was normal, but she scored only 21/30 on the MMSE. Mrs Murdoch was questioned about what her medical team had recommended, and the only thing she remembered was that she was not supposed to remove the dressing from her wound without the wound care nurse present. Moreover, she did not seem to appreciate that her own actions were working against her recovery.

The psychiatry team noted that Mrs Murdoch was receiving clonazepam and diphenhydramine for insomnia. She lived alone and had no problems with activities of daily living. The team discussed the possibility that cognitive impairment could explain her medical nonadherence. Furthermore, the question arose whether diphenhydramine and/or the benzodiazepine might be contributing to her cognitive problems.

It was recommended that clonazepam be tapered off and that diphenhydramine be discontinued. Trazodone was recommended as an alternative hypnotic. The treating team was encouraged to write down medical recommendations and leave them at the bedside. The psychiatry team had a talk with Mrs Murdoch and her sister about the connection between glucose dysregulation and cognitive impairment, and her sister agreed to help her with dietary adherence. At the time of discharge, Mrs Murdoch’s memory had improved, and she was no longer at odds with the medical team.

Treat the disease, not the syndrome: the case of Mr Fisher

Mr Fisher, aged 80 years, was admitted from an assisted living facility because of altered mental status. He had reported symptoms of an upper respiratory tract infection within the past week. Three days before admission, he became confused and visual hallucinations, agitation, and worsening gait difficulties developed. A chest radiograph and complete blood cell count (blood drawn the morning after admission) were normal; serum sodium level was low (130 mEq/L). The psychiatry team was consulted for help in the management of delirium in a patient with presumed dementia.

Initially, this appeared to be a routine consultation for a delirious patient with dementia. However, early in the consultation process, the psychiatry team established that Mr Fisher was not cognitively impaired at baseline. He was independent for all activities of daily living, except that he was no longer driving. Moreover, he was not as frail at baseline as he appeared to be in the hospital; only days before admission, he had been ambulating independently. His medications included an antihypertensive, venlafaxine SR 150 mg/d, and mirtazapine 15 mg at bedtime. For the recent cough, dextromethorphan as needed had been prescribed.

On examination, Mr Fisher appeared anxious; he was tremulous and diaphoretic. His blood pressure was elevated. He was disoriented to time and place and was reaching forward in space as if having visual hallucinations. His MMSE score was 9. Generalized hyperreflexia and more than 20 beats of ankle clonus were noted. These motor findings were the clue to another, possibly critical diagnosis for Mr Fisher. What is that diagnosis?

Although it is possible that an isolated metabolic abnormality, such as hyponatremia, could cause delirium, this syndrome in elderly patients is often a function of multiple derangements. In this case, a more worrisome possibility would be serotonin syndrome.

 Mr Fisher exhibited the classic triad of abnormalities found in this condition: mental status abnormalities, autonomic signs, and neuromuscular signs. This syndrome is more common in elderly patients, often is not considered in the differential for delirium, and can be fatal if not recognized and treated in a timely manner.

Mr Fisher was treated for presumptive serotonin syndrome. Three drugs were discontinued: mirtazapine, venlafaxine, and dextromethorphan. Supportive care was instituted, including intravenous fluids and oxygen to keep saturation above 93%. Neurological checks and vital signs were taken every 4 hours. Within 24 hours, neuromuscular and autonomic symptoms abated. Mental status improved more slowly. No treatment was needed for hyponatremia, which turned out to be chronic in this patient.

When more is not better: the case of Mrs Tucci

Mrs Tucci, aged 69 years, was admitted for exacerbation of chronic obstructive pulmonary disease (COPD). The psychiatry team was consulted before discharge for recommendations regarding depression treatment. Fluoxetine had been prescribed on an outpatient basis, and because of poor response, the dose had been titrated to 60 mg/d. The patient remained depressed. The last dose increment had coincided with the development of a resting tremor. She had been seen by the neurology service for evaluation of suspected Parkinson disease, and a trial of levodopa-carbidopa had been recommended.

On examination, Mrs Tucci appeared depressed but reported no suicidal ideation or psychotic symptoms. Her score on the 15-item Geriatric Depression Scale was 9. Her score on the Montreal Cognitive Assessment was 30/30.

 Motor findings included cogwheel rigidity and a resting tremor in both upper extremities.

Although SSRIs and SNRIs are treatments of choice for patients with COPD and depression, Mrs Tucci appeared to be suffering adverse effects from the high dose of fluoxetine. It is not uncommon to see older patients for whom higher doses of an SSRI have been prescribed by primary care or other health care professionals who continue to escalate the dose of an SSRI because they are not comfortable prescribing non-SSRIs. It is also not uncommon to see a “flat” dose-response curve for the antidepressant effects of an SSRI, coupled with an increasing range and severity of adverse effects at higher doses.

The literature reflects some controversy as to whether SSRIs can cause parkinsonism, but high-dose fluoxetine has repeatedly been implicated in this syndrome.

 The challenge in this case was that both the patient and the medical team were expecting to initiate combination levodopa-carbidopa therapy, but the psychiatry team recommended waiting to see what the effects would be with a change in psychotropic. This recommendation was communicated directly to the medical and neurological teams, and supporting literature was provided.

Mrs Tucci and her other treating physicians eventually agreed with the plan. It was recommended that fluoxetine be tapered off rapidly (slow taper is not necessary because of fluoxetine’s long half-life) and that venlafaxine SR be initiated after a washout interval. She was scheduled for outpatient follow-up in psychiatry. Two months after discharge, she showed improvement in mood on a regimen of venlafaxine SR 150 mg/d. Her parkinsonism had completely resolved.

These cases illustrate several points for the consultation/liaison psychiatrist to consider in caring for elderly hospitalized patients. The first is that psychotropic drugs are not benign in this population. Not infrequently, the needed intervention is to reduce the dose or discontinue a psychotropic medication rather than to start something new. Non-drug treatments may be preferred in many cases. Second, the extent to which the consultant is able to empathize with the patient will determine just how effective the consultant is in recommending and implementing needed interventions. This was exemplified best by the cases of Mrs Shaw and Mrs Murdoch. Last, there is a core medical knowledge base that must be mastered by psychiatry consultants to ensure the safety and well-being of geriatric patients. This includes not only a familiarity with important adverse effects of drugs but also the skill set to evaluate hepatic and renal function.

Dr Jacobson is Research Associate Professor at the University of Arizona College of Medicine in Phoenix and Research Physician at Banner Sun Health Research Institute. She reports no conflicts of interest concerning the subject matter of this article.

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Articles

This article summarizes 5 cases from consultation services at several teaching hospitals. These challenging cases illustrate several points for the consultation/liaison psychiatrist to consider in caring for elderly hospitalized patients. 

Consultation/Liaison Psychiatry in Geriatrics: Overcoming Challenges and Finding Solutions

CME credit for this article is now expired. It appears here for your reference.

At the end of this article, readers should be able to:

1. Appreciate and analyze the pharmacodynamic and pharmacokinetic changes that occur as patients age.

2. Develop/modify appropriate treatment strategies for older adults based on pharmacodynamic and pharmacokinetic changes.

3. Assess signs of problems associated with medication pharmacodynamics and pharmacokinetics in older patients.

Heterogeneity is a hallmark of the geriatric population, and nowhere is this as evident as it is in geriatric pharmacotherapy. Variable changes in organ and receptor function with aging make it difficult, in fact, to formulate rules that apply to all patients in the geriatric population. Comorbid disease and coadministered medications, which generally increase with age, add to the complexity.

Certain determinants of drug response in younger patients continue into old age. This is true, for example, of genetic endowment related to cytochrome P-450 (CYP450) metabolizing capacity. Other processes, such as drug absorption and glucuronidation, are little affected by aging. As a general rule, however, all other pharmacological processes change with aging.

Basic pharmacokinetic process: an orally ingested drug passes from the stomach to the proximal small intestine

, an orally ingested drug passes from the stomach to the proximal small intestine, where most absorption takes place. Absorption was once thought to be a simple, passive process, but research over the past few decades has shown that enterocytes lining the intestinal villi express a variety of specific drug transporters to take in drugs and efflux mechanisms to extrude them back into the gut lumen. The enterocytes are thus able to regulate how much drug is passed on to the liver.

Representation of the action of the P-glycoprotein pump

P-glycoproteins (Pgp) that are first encountered in the gut wall act as “pumps” to move absorbed drug back into the gut lumen, where it can be metabolized by resident CYP3A4 enzymes, reabsorbed, or passed along the gut for excretion. The action of the Pgp pump is shown schematically in 

. This pump has a general efflux function in the liver, the brain, the kidneys, and other organs. The Pgp pump has specific drug substrates, inhibitors, and inducers, similar to CYP450 enzymes. Of particular interest to psychiatrists are drugs listed in 

Selected P-glycoprotein (ABCB1) substrates, inhibitors, and inducers

As with CYP450 enzymes, genetic variations that result in expression and activity of the Pgp pump have been identified in the 

 With aging, reduced Pgp pump function at the blood-brain barrier has been demonstrated in vivo.

 This results in a “leakier” blood-brain barrier that is more porous to drugs and toxins.

How quickly a drug is absorbed determines in part how quickly it takes effect. Among the elderly, the rate of absorption may be affected by reduced gastric motility or delayed emptying due to diseases (eg, diabetes) or drugs (eg, antacids). In the absence of significant disease, however, the extent of absorption is little affected in the elderly.

 Drugs that pass from the GI tract to the liver travel by way of the portal circulation. In the liver, the drugs can travel unchanged into the general circulation by way of hepatic veins. Alternatively, drugs can be metabolized in the liver before entering the circulation, via first-pass metabolism. The extent of first-pass metabolism is determined by the activity of enzymes such as CYP450 and uridine 5'-diphosphate-glucu­ronosyltransferase (UGT). Any drug that is conjugated before leaving the liver for the general circulation can be excreted directly by the kidneys. A drug can also be removed by Pgp pump action in the liver, which results in the secretion of substrate drugs and toxins into bile, where they are removed as waste through the GI tract.

Pharmacokinetic processes up to this point are circumvented by intramuscular or intravenous administration of the drug. Avoiding first-pass metabolism renders drugs nearly 100% bioavailable, so that the dose required for the same effect is usually much smaller. Intravenous administration of drugs in geriatric patients should be approached with caution, because dangerous adverse effects can emerge quickly. In addition, intramuscular administration of drugs is not recommended for geriatric patients with small muscle mass, because this leads to erratic absorption and painful injection.

, drugs that pass into the general circulation are distributed to target organs, peripheral storage sites in fat or muscle, the kidneys for elimination, or the liver for metabolism. Distribution to peripheral storage sites is significantly affected by aging, because as lean body mass decreases, there is a relative increase in fat stores. This is true even for thin elderly patients. These changes create a larger volume of distribution for fat-soluble drugs (including most psychotropics) and a smaller volume of distribution for water-soluble drugs, such as lithium.

 Because the elimination half-life of a drug is directly proportional to its volume of distribution, the practical significance of these changes is that most psychotropics remain in the body longer in geriatric patients.

Another result of the relative increase in body fat with aging is that highly lipophilic drugs, such as diazepam, are rapidly taken up by fat storage sites, so that drug concentration in the blood falls quickly below a minimum effective threshold. With one-time dosing, the duration of effect is short for diazepam. The drug is removed slowly from fat stores, and significant accumulation of the drug can occur with repeated dosing. Moreover, the drug may be released erratically, which can result in changing serum levels over time. For these and other reasons, diazepam is not recommended for the elderly.

On the other hand, the smaller volume of distribution for water-soluble drugs, such as lithium, is associated with a greater amount of drug in the circulation and a correspondingly greater amount available to the brain as the target organ. This is one reason why smaller doses of lithium are used in elderly patients. Drugs that reach the blood-brain barrier gain access to the brain by passive diffusion or by transporters. Those drugs that are substrates for the Pgp pump residing in capillary endothelial cells may be extruded back into the circulation, a process that can be blocked by Pgp pump inhibitors or facilitated by inducers.

 Drug metabolism occurs by phase 1 (oxidation) and/or phase 2 (primarily glucuronidation) processes. The most important drug-metabolizing enzymes are the phase 1 CYP450 enzymes and the phase 2 UGT enzymes. In general, phase 1 oxidation processes are more affected by aging than are UGT processes. Given the choice in treating an elderly patient, a drug metabolized by glucuronidation (also known as “conjugation”) would be preferred to a drug metabolized by those CYP450 enzymes whose activity is reduced with aging. Among benzodiazepines, for example, lorazepam, oxazepam, and temazepam are preferred to other drugs because these drugs are simply conjugated and excreted. Diazepam and chlordiazepoxide-not recommended for the elderly-have several active metabolites, some with long half-lives (eg, desmethyldiazepam).

Clinically relevant CYP450 drug interactions

Three families of CYP enzymes are relevant to psychopharmacology: CYP1, CYP2, and CYP3. Current evidence suggests that within these families, 5 enzymes are primarily responsible for the metabolism of commonly used psychotropics. The activity of each CYP450 enzyme can be reduced by inhibitors or facilitated by inducers. Inhibitory effects are additive when more than one inhibitor is present. For most drugs metabolized by CYP450 enzymes, it is the parent drug that is active, and metabolism results in an inactive or less active metabolite. For certain drugs (eg, codeine, tramadol), the parent drug is a pro-drug with little activity, and metabolism to an active metabolite is necessary for drug effect. In these cases, inducers result in greater drug effect. Clinically relevant substrates, inhibitors, and inducers of CYP450 enzymes are listed in 

Genetic polymorphisms expressed as the absence or changed activity of certain CYP enzymes may result in marked differences in serum levels of psychotropic drugs among individuals administered the same dose. The following are CYP450 metabolizer phenotypes5:

• Poor (slow): little or no enzyme activity, leading to high levels of parent drug

• Intermediate: depending on the specific genotype, activity ranges from slightly more than the poor phenotype to slightly less than the extensive phenotype

• Extensive (average, rapid): normal enzyme activity but can be converted to a poor metabolizer by sufficient CYP enzyme inhibition

• Ultrasensitive (ultrarapid): parent drug is metabolized so rapidly that higher drug doses may be needed; in the case of a pro-drug, toxicity may be seen at usual therapeutic doses

Only 2 of the CYP enzymes important in psychotropic prescribing decline meaningfully with aging: CYP1A2 and CYP3A. Aging also brings a gradual reduction in liver mass, reduced blood flow, and reduced hepatic metabolic rate.

 Among other processes, these changes affect demethylation reactions involved in the conversion of tertiary amines (eg, amitriptyline) to secondary amines (eg, nortriptyline), which may cause the accumulation of more active and more toxic tertiary compounds.

 Most drugs and metabolites are excreted from the body by the kidneys at a rate determined by the glomerular filtration rate (GFR).

 For many individuals, this rate falls linearly with aging at a rate of about 1 mL/min/1.73 m2 of body surface area (the average for an adult), starting at around age 20 to 30. Thus, the GFR for such an individual at age 80 years is about half what it was at 30 years.

Drugs cleared solely by renal excretion-lithium and hydroxylated metabolites (eg, hydroxy-bupropion, hydroxy-venlafaxine, hydroxy-nortriptyline, and hydroxy-risperidone)-are most affected by this change in GFR. Reduced clearance of lithium has led to the recommendation that elderly patients be treated with a single nightly dose of short-acting lithium. This schedule allows the serum level to drift downward so that the kidneys have time to recover before the next dose.

Reduced GFR with aging is not a universal phenomenon; some elderly persons show no decline in renal function with aging. Nevertheless, in the elderly with reduced renal function, psychotropics should be used with great caution. The following recommendations apply:

• Beware of coadministration of nephrotoxic drugs (eg, NSAIDs)

• Evaluate renal function to determine dosage

• Do not rely on serum creatinine value to gauge renal function

• Use laboratory-generated report of the GFR or calculate GFR using the Cockroft-Gault equation

 Clearance of a drug from the circulation is a function not only of renal excretion but also of hepatic metabolism. Although oxidative metabolism may be reduced in old age, a more significant factor is decreased hepatic blood flow, which may be as much as 50% decreased.

 This is the primary reason why drug dosing is reduced for hepatically metabolized drugs in elderly patients. The correlation of blood flow reduction with hepatic clearance is a poor one, however, and existing liver function tests are not a good indicator of drug metabolizing capacity.

Clearance is the principal determinant of the plasma concentration of a drug at steady state. The two quantities are related by the following equation:

drug concentration at steady state = dosing rate/clearance

Reduced GFR and reduced hepatic blood flow result in reduced clearance in elderly patients compared with younger patients. This results in increased steady-state drug concentrations, with enhanced main effects and toxic effects. Reduced clearance can be managed with a smaller dose or a longer dosing interval, giving rise to the “start low and go slow” principle of prescribing for a geriatric patient.

Another reason to “go slow” with dosing in elderly patients is because of the time it takes a drug to reach steady state with repeated dosing. Steady state is the point at which the average drug concentration plateaus. Time to steady state is determined by the drug’s half-life:

In general, a drug’s half-life is increased in geriatric patients compared with younger patients, so that it takes longer to reach steady state. Changes in drug dosage are best made when steady state has been achieved, so that main and toxic effects can be observed before the dosage is escalated. The half-life of a drug can also be used to determine the time to washout:

The time to washout can be helpful in determining when a drug is out of the system so that a new medication can be started or withdrawal effects can be expected.

Pharmacodynamic processes are set in motion when the drug reaches the target tissue. Effects can be presynaptic or postsynaptic, or involve enzyme inhibition. Reuptake inhibitors, such as SSRI antidepressants, are examples of drugs that act at presynaptic sites. Acetylcholinesterase inhibitors (donep­ezil, galantamine, and rivastigmine) are examples of enzyme inhibitors.

Most psychotropic drugs act at postsynaptic sites; some also interact with autoreceptors on the presynaptic neuron. In general, the mechanism for these drugs includes drug-receptor binding, signal transduction, and cellular response. Effects are mediated by variables such as receptor density, concentration of the drug at the receptor site, affinity of the drug for the receptor, allosteric modulation of drug binding, intrinsic activity of the drug (the degree to which it influences the receptor to generate a cellular response), the function of second messenger systems, and homeostatic processes that tend to counter drug effects. Different drugs have different effects at the receptor.

Another variable in drug binding that is particularly relevant to drugs such as antidepressants is that of time: acute effects may be different from chronic effects. This occurs because initial pharmacological effects at the receptor induce small changes that over time result in receptor adaptation.

In general, receptors for dopamine, norepinephrine, and serotonin are coupled to G-proteins as second messengers. The mechanisms by which drug-receptor binding ultimately triggers brain effects are complex. Signaling molecules other than G-proteins-Akt, glycogen synthase kinase-3, and Î²-arrestin 2-have been shown in recent years to be involved in the mechanism of action of antidepressants, lithium, and antipsychotics.

Although elderly patients experience greater drug effects than younger patients, the reason is not always clear. The differences in drug responses can be attributed either to different baselines or to different sensitivities.

 Baseline differences in postural sway (the elderly have more sway than younger patients), for example, might account for the increased risk of falling with benzodiazepine use in the elderly. It may be that for those with a “normal” amount of postural sway (old or young) at baseline, these drugs are safe.

Another factor in differing drug responses among the elderly for certain psychotropic drugs is the reduced function of the Pgp pump with aging. The EC50 of a drug is the (effective) concentration of that drug that yields a half-maximal response. The value of EC50 for any drug is determined systemically, not in the CNS. When the elderly are found to have a lower EC50 than younger patients for a particular psychotropic drug, is that because of increased brain “sensitivity” to the drug or because of a relatively higher concentration of the drug in the CNS?

When increased sensitivity is actually demonstrated, it may be attributed to the fact that the elderly use an ever-greater proportion of reserves (eg, cognitive, motor) as they age, so that fewer reserves are available to offset a perturbation. For example, the elderly are at increased risk for orthostasis as an adverse drug effect.

Drug interactions are more frequent in elderly patients because more medications are taken. In addition, drug interactions may be more serious because of insufficient physiological reserves. When new medications are started or stopped in elderly patients, it is very important to take note of potential interactions with other drugs or foods.

Drug interactions may be pharmacokinetic or pharmacodynamic. Pharmacokinetic interactions may involve any of the phases of drug processing, although the most important and numerous relate to drug metabolism. An example of a drug interaction influencing drug absorption is the effect of an oral antacid on absorption of an antipsychotic or a benzodiazepine. The combination results in a slowing of the rate of absorption, and adverse effects are not seen as quickly. Interactions relating to drug metabolism are mediated largely by CYP450 and UGT enzyme systems. The various actions of the Pgp pump can interact with drug distribution. Introducing a low-sodium diet to a patient receiving lithium results in competition for excretion and may cause lithium levels to rise.

Pharmacodynamic interactions are numerous and involve both receptor binding effects (eg, antipsychotics given with dopamine agonists), complex remote effects (eg, SSRIs inhibiting platelet function when given with warfarin, causing significant bleeding), and additive effects (eg, MAOIs and SSRIs causing serotonin syndrome).

Note: This article was originally published as a CME in the January 2013 issue of 

Portions of it may have since been updated.

Sandra Jacobson, MD, has no disclosures to report.

James M. Ellison, MD, (peer/content reviewer) has disclosed that he received research support from Eli Lilly and Company.

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 Bartels AL, Kortekaas R, Bart J, et al. Blood-brain barrier P-glycoprotein function decreases in specific brain regions with aging: a possible role in progressive neurodegeneration. 

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Clinical Manual of Drug Interaction Principles for Medical Practice.

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Clinical Manual of Geriatric Psychopharmacology.

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http://medicine.iupui.edu/clinpharm/ddis/ClinicalTable.aspx

Effects of Pharmacokinetic and Pharmacodynamic Changes in the Elderly

Edited by Martha Sajatovic and Frederic C. Blow
Baltimore: Johns Hopkins University Press; 2007
280 pages • $50.00 (hardcover)

Among clinicians and researchers in geriatric psychiatry, interest in late-life bipolar disorder is growing, fueled not only by the increasing size of this clinical population but also by the recent discovery that mood stabilizers such as lithium (Eskalith, Lithobid) may influence the pathogenesis of Alzheimer disease. Until now, the literature on bipolar disorder in the elderly has been fairly scant. Old myths persist, such as the idea that bipolar disorder "burns out" in old age. Moreover, even today, it is not uncommon to see older persons with bipolar disorder treated with antidepressant monotherapy who are simply resigned to chronic symptoms and rapid cycling. Clearly, there is room for improvement in clinical care for this population.

 provides a welcome starting point for review of what is known about late-life bipolar disorder. The editors-Martha Sajatovic and Frederic Blow-are well known for their work in the field of major psychiatric disorders in the elderly, and particularly bipolar disorder and its comorbid conditions. Twenty-three contributing authors lend their expertise to 1 of 4 sections of the book: Epidemiology and Assessment; Treatment; Complexity and Comorbidity; and Specialized Care Delivery and Research.

The chapters are well-researched and well-referenced and cover all the important issues of late-life bipolar disorder. The first section includes a discussion of the differences between early- and late-onset bipolar disorder in terms of etiology and symptom presentation, it examines mood rating scales and their application in geriatrics, and it makes a case for the use of data from the current Resident Assessment Instrument to address a number of research questions on bipolar disorder in the long-term care setting.

In the Treatment section, the first chapter includes a discussion of secondary mania and its causes and outlines a diagnostic workup to distinguish secondary mania from idiopathic disease. Subsequent chapters review the use of mood stabilizers, antipsychotics, antidepressants, and electroconvulsive therapy. The chapter covering psychosocial interventions gives an overview of the Life Goals Program, a structured, manual-based, group intervention to improve illness management skills. The last chapter of this section deals with treatment adherence in the elderly with bipolar disorder and suggests several strategies to improve adherence.

The Complexity and Comorbidity section includes chapters that are devoted to substance abuse and medical comorbidity-issues that are known to complicate diagnosis and treatment of late-life bipolar disorder. A chapter on cultural issues provides some thought-provoking examples of how the clinical presentation of bipolar disorder differs between cultures (eg, predom-inance of manic episodes among Israelis and depressive episodes among Europeans). The role of the Internet as a source of information (and misinformation) about bipolar disorder is discussed briefly.

In the last section, a convincing case is made that the quality of care for elderly patients with bipolar disorder is generally suboptimal. Performance-based quality measures are encouraged, as are guideline-based treatment models. The book concludes with chapters that cover evidence-based medicine and legal and ethical issues in bipolar disorder research involving older patients.

 represents a solid contribution to the knowledge base in geriatric psychiatry. It is well indexed and includes numerous illustrative cases. Careful reading of the text yields many useful clinical pearls and will likely stimulate new areas of research inquiry.

Among clinicians and researchers in geriatric psychiatry, interest in late-life bipolar disorder is growing, fueled not only by the increasing size of this clinical population but also by the recent discovery that mood stabilizers such as lithium may influence the pathogenesis of Alzheimer disease.

Sandra Jacobson, MD

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