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PSEUDOBULBAR AFFECT: DEFINITIONS AND INTRODUCTION

Pseudobulbar affect (PBA) is a syndrome of disinhibition of emotional expression thought to occur due to a disturbance or disorganization in the limbic structures of the brain.¹ PBA was originally described centuries ago. Various terms have been used to describe the condition since its identification (Table 1),^2,3 but PBA has only recently had a widely accepted name to define it. Also only recently have effective treatments been identified and applied for PBA.

Multiple neurologic diseases have been associated with PBA symptoms with varying frequencies (Table 2).^2-5 Injury to brain pathways that control affect, regardless of specific disease etiology, are thought to be the common pathophysiology. In the 19^th and 20^th centuries, researchers attempted to identify the location of brain injury through evaluation of the brain at autopsy. These early researchers theorized that the etiology was from the presence of lesions that occurred bilaterally in descending corticobulbar pathways, thus leading to the name "pseudobulbar affect."

When computed tomography (CT) and magnetic resonance imaging (MRI) became available, evaluations of the brains of live patients with PBA were possible. Initially, these evaluations were focused on patients with stroke: in these patients, specific lesions could be identified and the nearby brain structures could be assessed for abnormality. Most of these studies identified the basis pontis in the brainstem as the location of injury. This structure relays impulses between the brainstem and the cerebellum.² When deep brain stimulation became available, reports of PBA symptoms emerged that were associated with these procedures, thereby implicating the subthalamic nucleus, anterior cingulate, and hypothalamus in the pathophysiology of the syndrome. Further advances with functional MRI, positron emission tomography (PET), and single-photon emission computed tomography (SPECT) allowed for more detailed determination of possible pathologic sites. In some cases, investigators were able to perform scans on patients during a period of emotional expression, and important information about the cause of PBA was obtained. On the basis of available information, a newer theory was developed that describes a disconnect between the cerebral cortex, which evaluates stimuli for emotional and social context, and the cerebellum, which unconsciously and automatically modulates emotional expression.²

PBA was described before the 21^st century, but it was presented primarily in case reports and a few case series, so its epidemiology was difficult to determine. Table 2 lists known disease associations and their relative frequencies identified with PBA.^2-5 Because long-term care residents are frequently afflicted with associated diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), and stroke, consultant pharmacists are likely to care for individuals with PBA, and they should be familiar with the clinical presentation, treatment approaches, and use of pharmacotherapy in its management.

DIAGNOSTIC CRITERIA FOR PBA

A key feature of PBA is that a patient's laughing or crying is not an expression of his or her mood or experience. However, this is not always evident from an observer's perspective. In most cases, the patient reports not experiencing mirth or sadness, but he is outwardly expressing these emotions and has insight that the behavior is abnormal. The exception to this rule is a patient with cognitive impairment that has reduced the ability to provide accurate reports of his mood at a past point in time, such as patients with AD or Multiple System Atrophy.^2,3 In these cases, the clinician must rely on caregiver observations to inform decision-making and diagnosis.

PBA diagnosis is based on clinical observation. Most patients have already been diagnosed with one of the associated neurologic conditions at the time of PBA diagnosis. Without one of these prior diagnoses and with abrupt onset of symptoms, a possible diagnosis of vascular disease or stroke should be considered.

Four criteria for PBA diagnosis were originally proposed⁶:

• 1) Emotional response inappropriate to the situation
• 2) Incongruence of emotions and affective response
• 3) Inability to control the duration and severity of the episode
• 4) Emotional expression does not lead to a feeling of relief for the patient

More recently, it was suggested that, in addition to these original criteria, the episodes should be judged to cause distress or lead to functional impairment. However, this may not be appropriate for a patient with AD or similar disease in which cognition or insight is lacking. Another proposed criteria is the elimination of other psychiatric or neurologic disorders or substance effects as the cause of the emotional dysregulation before a patient is given the diagnosis of PBA.⁷ The addition of these 2 criteria are particularly helpful for the purpose of research, since more severe symptoms can be targeted and are more likely to respond to treatment.

Other factors for differential diagnosis include evaluation for depression, bipolar disorder, or peculiar forms of epilepsy. It is possible for mood disorders and PBA to coexist in the same patient, further complicating diagnosis. An electroencephalogram may be helpful in distinguishing a seizure disorder from PBA. Observation of a patient's experience compared to his expression is fundamental to an accurate PBA diagnosis. In other words, a patient who is not experiencing depression but expresses uncontrollable crying spells despite the lack of sadness would be judged to be suffering from PBA. A conundrum occurs when a patient is experiencing sadness and also has uncontrollable crying spells.

In 1993, Robinson and colleagues published a tool for either patient or caregiver interview to identify patients with PBA.⁸ The Pathological Laughter and Crying Scale (PLACS) rates 18 items describing the experience, cause, duration, and patient control of either laughing or crying over the previous 2 weeks. Each item is rated as occurring rarely or not at all (score 0) to frequently (score 3). Scores above 13 correlated with diagnosis of PBA in a cohort of patients with stroke.⁸

In 1997, a simpler tool for self-report of PBA symptoms was published by Moore et al.⁹ The Center for Neurologic Study-Lability Scale (CNS-LS) includes 7 items rated on a scale of 1 to 5, with 1 indicating "never" and 5 indicating "most of the time." Four items involve control of laughter, specifically addressing the patient's ability to control his or her laughter, the association of laughter with something funny, and others' perceptions of the laughing. Three items involve control of crying, specifically addressing how easily a patient cries and how quickly he starts and stops crying. A patient without PBA and typical emotional regulation would score 7, given that the minimum score is 1 for each of the 7 items. A score of 13 or above is suggestive of PBA, and the maximum score is 35.⁹

The natural progression of PBA has not been well described. One crossover trial in patients with stroke indicated that patients were less likely to revert to the same baseline symptomatology after treatment with citalopram, whether it was during the first or second phase of the study.¹⁰ Given the diverse disease states associated with PBA, it is likely that patients with progressive cognitive diseases (e.g., PD, AD, amyotrophic lateral sclerosis [ALS]) would have increasing symptomatology until such time as the underlying disease progresses to diminish motor responses. On the other hand, diseases in which improvements in function are anticipated (e.g., cerebrovascular accident [CVA], traumatic brain injury [TBI]), PBA symptoms may improve without specific treatment or after treatment is withdrawn.¹⁰

CLINICAL PRESENTATION

Patients with PBA present with spasmodic, uncontrolled laughter or tears, indistinguishable from the affect they might have if they were filled with mirth or sadness. However, the mood, the social situation, or the stimuli are incongruent with patient affect. While most patients experience either laughter or tears, there is a subset of patients who exhibit both responses.

In studies, patients reported outburst frequencies that ranged from once daily to 20 or more times each day.¹¹ No data describe the prognosis of symptoms in terms of whether a patient presents with symptoms only a few times per day and then builds to a higher number of episodes or if the symptom frequency waxes and wanes over time. Also, it is unknown if symptoms resolve over time: as noted, this would be expected in patients with progressive neurologic disorders such as ALS or AD, given that the patient's disease progresses until the ability for neuromuscular activity eventually diminishes.¹²

While PBA has not been linked to increased mortality, for patients who are aware and interact socially, quality of life is significantly decreased due to social embarrassment, isolation, reduced employment, and increased healthcare costs. This was demonstrated in a case-control survey evaluation using the Short Form-36 and Visual Analog Scales of quality of life. All domains of physical and mental health were significantly reduced in patients with PBA compared to controls when adjusted for severity of disease.¹³ Caregiver burden may also be increased, and 15% of patients report that PBA led to the need for institutionalization in a nursing home or other supervised setting. These burdens are in addition to those occurring from the primary underlying disorder. Furthermore, caregivers that do not understand the condition may assume the patient is depressed or having hallucinations that are causing the laughter or crying and try to intervene inappropriately.

PREVALENCE AND RISK FACTORS

PBA is a symptom of various neurologic diseases, so reports of its prevalence are variable and difficult to quantify. Early data focused on patient/caregiver reports and the prevalence ranged from 10% to 18% in stroke, multiple sclerosis (MS), and AD, but it was reported in 49% of patients with ALS. This may have been due to a better system of identifying patients with ALS and including them in a registry compared to other disease states, which do not have long-standing disease registries. With improved standardization of tests and the development of a disease registry for PBA, researchers have been able to show higher rates of the syndrome for stroke, MS, and AD than previously reported; the ALS rate has remained consistent with the earlier reports.⁴ TBI (and its association with PBA) has gained increased attention in recent decades. It was not listed as an associated illness in earlier publications, but TBI is clearly associated with the rate of PBA and PBA is now reported in more than 50% of TBI cases. Table 2 summarizes the prevalence of PBA in associated conditions.^2-5

The higher prevalence of PBA shown in more recent studies led researcher to estimate the syndrome may be present in as many as 2 million patients in the United States (U.S.), although it is unknown how many of these patients have a disease severe enough to warrant treatment. Whether treatment is warranted or not, it is helpful for patients and caregivers to identify a diagnosis of PBA so that they may better cope when symptoms occur.

TREATMENT APPROACHES

The goal of PBA treatment is to decrease the frequency and severity of emotional outbursts. A combination of dextromethorphan and quinidine (D/Q) or antidepressants are most commonly used for the treatment of PBA.

Dextromethorphan and quinidine

Currently, the only medication with a U.S. Food and Drug Administration (FDA) approval for use in PBA is the D/Q combination, which is known by the brand name Nuedexta.¹⁴ The mechanism of action in PBA is not clearly delineated, but it is believed that dextromethorphan acts as a low-affinity, noncompetitive antagonist of the N-methyl-D-aspartate (NMDA) receptor: simply, it modulates glutamate release and reduces excitatory neuronal activity. Secondarily, dextromethorphan is an agonist of sigma-1 receptors, which may be neuroprotective against glutaminergic-induced neuronal injury.^15,16 However, in the earliest use of dextromethorphan in the treatment of PBA, its pharmacokinetics required frequent dosing due to its rapid metabolism to dextrorphan by the cytochrome P450 (CYP) 2D6 enzyme during the first pass through the liver in most patients. Dextrorphan is an active metabolite, with stronger hallucinogenic effects than dextromethorphan. In rapid metabolizers, who comprise the majority of patients, dextromethorphan plasma levels are undetectable at 6 to 12 hours after a dose. These issues led researchers to attempt to block CYP2D6 activity using low doses of quinidine, which is known to be a strong inhibitor of the enzyme. The goal was for the doses of quinidine to be high enough to cause enzyme inhibition but low enough to avoid cardiac and toxic effects. Initially, doses of 75 mg of quinidine were tried; doses were subsequently lowered to 30 mg and the present formulation includes only 10 mg of quinidine.

In one study, dextromethorphan plasma levels for doses of 30 mg twice daily were reported to be 0.1 to 0.5 ng/mL when drawn 12 hours after the dose. The concentration increased to 114.7 ng/mL with the addition of 30 mg twice daily of quinidine. In that study, the quinidine plasma concentrations were 103.8 to 168.4 ng/mL, which is below the therapeutic range of 2 to 6 mcg/mL.¹⁷ In the U.S., the approved dosage of the combination is dextromethorphan 20 mg/quinidine 10 mg. Therefore, for most patients, quinidine concentrations are expected to be less than 50 ng/mL. An exception to this is individuals who are poor metabolizers, most of whom were excluded from completion of controlled studies. Generally, 10% of Caucasians and 8% of African Americans are classified as poor metabolizers, so their plasma concentrations of dextromethorphan would be therapeutic without the addition of quinidine (but not higher if quinidine was added), and their concentrations of quinidine could be slightly elevated.¹⁸ Essentially, the administration of quinidine to a patient who is a rapid metabolizer changes him to a poor metabolizer of CYP2D6 substrates. As pharmacogenomics testing expands, it could inform clinicians to guide prescribing of dextromethorphan alone in patients identified as poor CYP2D6 metabolizers or combination therapy with quinidine in patients identified as rapid metabolizers.

D/Q labeling for use in ALS and MS patients is supported by 3 moderately-sized randomized controlled studies (Table 3).^11,17,19-23 These studies support the efficacy of D/Q in ALS and MS patients, even with the relatively high placebo response rate. However, withdrawals and adverse effects tended to be high, though these occurrences are not uncommon for patients with these conditions. Open-label studies have been conducted in patients with PBA due to dementia, stroke, and/or TBI and have achieved similar results. However, these studies did not include a placebo group for comparison so establishing safety and efficacy are difficult. The mean age of patients with ALS, MS, and TBI was relatively young (45 years), but the studies of PBA in dementia included mostly older adults (mean age, 70.7 years).^24,25

Other literature examining the effects of D/Q in patients with dementia evaluated changes in agitation. As with PBA, the theory is that D/Q may improve agitation through inhibiting glutamatergic NMDA receptors or, secondarily, by inhibiting serotonin reuptake. One case report in a patient with frontotemporal dementia describes improvement in mood, eating, sexual behavior, agitation, and aggression after treatment with D/Q for 2 weeks.²⁶ A randomized clinical trial of 220 patients with AD showed statistically significant improvement in scores for the Neuropsychiatric Inventory Agitation/Aggression domains compared to placebo.²⁷ Whether or not this improvement is clinically significant is debated.²⁸ All treatment options for agitation in patients with dementia, including D/Q, are off-label uses.

As noted above, D/Q is supplied in capsules containing 20 mg of dextromethorphan and 10 mg of quinidine, and the recommended dose is a single capsule daily for 7 days; the dose is then increased to 1 capsule every 12 hours for maintenance therapy.¹⁴

The most commonly reported adverse effects of D/Q are diarrhea (13%) and dizziness (10%), followed by peripheral edema, vomiting, and cough (5% each). D/Q has important contraindications: individuals currently receiving quinidine, quinine, or mefloquine or with history of hypersensitivity to these agents or to dextromethorphan should not take this drug; additionally, individuals taking monoamine oxidase (MAO) inhibitors (within 14 days), drugs that prolong the QT interval, or other CYP2D6 substrate drugs should not receive this agent. Further, individuals with a prolonged QT interval, history of torsades de pointes, heart failure, or complete atrioventricular block without a pacemaker should not receive D/Q. Rare but serious reactions include thrombocytopenia, hepatitis, and QT prolongation. Therefore, monitoring of platelet count, liver function tests, and electrocardiogram are indicated with D/Q.¹⁴

Antidepressants

Off-label uses of amitriptyline and nortriptyline have been studied in the treatment of PBA. It is postulated that tricyclic antidepressants (TCAs) work through their serotonin effects in the central nervous system. Serotonin and serotonin receptors are densely localized in the areas of the brain that are thought to be central to the development of PBA. Serotonin has broad effects on mood, anxiety, memory, learning, sleep, sex, and appetite, so it is reasonable to think it may be involved in motor functions of crying and laughing.²⁹ An alternative hypothesis is that these drugs potentiate transmission of the inhibitory substance to restore subcortical neuronal relays.³⁰

One small, double-blind, placebo-controlled crossover trial of amitriptyline in MS patients reported improvement in symptoms in 8 of 12 patients receiving a mean dose of 57.8 mg per day. The mean age of these subjects was 44.3 years and the duration of treatment was limited to 30 days.³⁰ A randomized, double-blind, placebo-controlled trial of nortriptyline was studied in 28 patients with stroke at daily doses beginning at 20 mg and titrated up to 100 mg. In these subjects, who had a mean age of 57 years, the PLACS score was significantly lower with nortriptyline treatment than with placebo over 6 weeks (1.2 vs. 9.6).⁸ Other TCAs have been mentioned as possible alternatives to amitriptyline and nortriptyline, such as desipramine and imipramine, but evidence of their efficacy is lacking in the literature.

Generally, dosing of amitriptyline or nortriptyline should begin at 25 mg or less per day and increased every 1 to 2 weeks until response is seen or a maximum of 100 mg daily is reached. Given the risk for sedation, bedtime dosing is preferred. Patients may develop tolerance to this effect, as well as other side effects including anticholinergic effects of dry mouth, blurred vision, constipation, urinary retention, orthostatic hypotension, and cardiac arrhythmias. Use of lower doses reduces the risk of adverse effects. These medications are not recommended for use in older adults, since, for these patients, the risks generally outweigh the benefits at any dose.³¹

Similar to TCAs, selective serotonin reuptake inhibitors (SSRIs) are thought to work by increasing the serotonin at brain receptors in the central nervous system.¹⁵ This theory is supported by evidence obtained in PET scans. High rates of response in the treatment of PBA, as high as 100% in some instances, have been reported in case reports and case series. Because the onset of action in PBA is usually within days, researchers postulate that a direct stimulation of serotonergic activity provides the positive effect.

The SSRIs found in case reports and small studies are fluoxetine, citalopram, sertraline, and paroxetine. Similar to studies of TCAs, bias is prevalent in these trials. For example, methods of discerning PBA apart from depression were not standardized, so it is possible that patients had depression and not PBA or had both depression and PBA. Most studies indicated rapid improvement in symptoms for those that responded, usually within a few days. (The expected response time when treating depression is 6 to 8 weeks.) Dosing of sertraline has remained at the low end of the therapeutic range (50 mg daily), but citalopram and fluoxetine doses tended to reach typical antidepressant doses (20 mg daily), probably due to their narrower dosing ranges. Evidence from studies of SSRIs in PBA is listed in Table 4.^10,23,32-36

THE ROLE OF THE CONSULTANT PHARMACIST IN PBA

PBA is an enigma for most consultant pharmacists, which is not surprising, given the confusion surrounding the nomenclature of PBA, the wide range of reported prevalences in the multiple disease states associated with PBA, and the frequent use of non-approved agents for the treatment of PBA. One study found that 51% of nursing home residents had a predisposing condition for PBA and, upon screening by a geropsychologist, 17.5% of the predisposed group met criteria for diagnosis of PBA.³⁷ Providers need to maintain a high index of suspicion for the presence of symptoms so that appropriate therapy can be instituted to help improve patient quality of life.^38,39 Knowledge of the symptoms and their associations with ALS, MS, TBI, stroke, dementia, and other neurologic diseases is the first step. Familiarity with screening tools such as the CNS-LS aids in referral of patients for diagnosis, as well as in assessing effectiveness of therapy once implemented.

A case-control evaluation of nursing home resident electronic health records was performed to identify descriptive information that could help in screening residents who are at high risk for PBA.⁴⁰ The most commonly associated characteristics were the diagnosis of dementia or stroke, transient ischemic attack, or CVA, although the rates were similar in the matched controls. Severe cognitive impairment was identified in 64.3% of cases and in 52.9% of controls. A consistent finding was that documentation of inappropriate laughing or crying was infrequent in the electronic health record. While the model had a poor positive predictive value, consultant pharmacists can use the findings to promote awareness and suspicion of PBA.

Once a patient is diagnosed with PBA, medication management becomes particularly important. Many providers will likely begin with an SSRI, given their long history of safety in the treatment of depression and the difficulty in separating the diagnosis of depression from PBA in patients with severe cognitive impairment. Furthermore, SSRIs are a relatively inexpensive addition to the drug therapy regimen. However, the pharmacist must be aware that SSRIs do not have an approved indication for use in PBA. Among the antidepressants with supporting data, albeit of low quality, sertraline and citalopram pose the least risk for most older adults owing to their pharmacokinetic and drug-drug interaction profiles. In addition, pharmacies can provide these agents in generic form for less than $50 per month. Once initiated, it is imperative that patients be monitored for response, preferably with a validated tool such as the CNS-LS. If no response is seen or adverse effects occur, the medication should be tapered and discontinued. Given that the onset of action is typically within a few days to 1 week, this assessment should be done in 7 to 14 days rather than 6 to 8 weeks, which is indicated when SSRIs are used to treat depression.

D/Q is a drug with a larger base of evidence in the treatment of PBA and should be considered as an alternative to SSRIs. However, many providers are unfamiliar with the agent, and it is not yet available as a generic product. Many Medicare Part D insurers cover the agent, but it may require prior authorization and strict quantity limits are imposed in order to manage costs. Costs can be well over $1000 per month, making it difficult for patients to afford.⁴¹ The manufacturer offers support for individuals that have problems paying for the medication, although important restrictions apply. Specifically, reimbursement is not provided for individuals covered by insurance or federal or state health programs, which includes most of the long-term care population.⁴² Similar to the SSRIs, if no response is seen or adverse effects occur, D/Q should be discontinued.

Apart from the use of D/Q in PBA, consultant pharmacists may see patients with agitation and consider D/Q for treatment as an off-label indication. D/Q may be safer than antipsychotics, but clear evidence of clinically significant effectiveness is not yet available.²⁸ As with most dementia-related symptoms, individualized risks and benefits must be assessed for drug therapy. Periodic assessment for perceived benefits is vital.

Nursing home residents have additional challenges when using medications, even when the agent is indicated and monitored appropriately. In some cases, patients cannot swallow capsules or tablets. For sertraline and citalopram, the tablets may be crushed and dissolved in a small amount of water or mixed in a thicker substance such as jelly or applesauce for administration. Use of a compounded suspension of D/Q has been reported in palliative care patients.⁴³

Other concerns in the older adult population are the risks associated with adding a new agent to the pharmacotherapy regimen and the risk for drug-drug interactions. Adverse effects of SSRIs and D/Q that are frequently potentiated by other medications with similar effects include serotonin syndrome and QT prolongation associated with torsades de pointes.

Sertraline and citalopram have antiplatelet effects and may increase bleeding in patients already at risk for bleeding due to other antiplatelet medications. Also, there is a risk for hyponatremia, especially in older Caucasian women, necessitating periodic monitoring of serum sodium levels. SSRIs are contraindicated for use within 14 days of stopping an MAO inhibitor.

D/Q is also contraindicated for use within 14 days of stopping an MAO inhibitor. In addition, patients with a history of quinidine, quinine, or mefloquine hypersensitivity should not receive the drug. Other drugs that are metabolized by CYP2D6 will interact with D/Q, so caution in combining these agents is warranted.⁴⁴

Consultant pharmacists should provide education regarding drug therapy for PBA. Given the similar adverse effect profiles of the SSRIs and D/Q, recommendations should include assessment of baseline electrocardiogram to check the patient's QT interval, liver function tests, and electrolyte levels to assess sodium, potassium, and magnesium; periodic evaluation of these parameters should be conducted at least annually. Use of the CNS-LS tool at baseline and after initiation of therapy will provide objective information regarding response to the medication. If no or limited response is seen within a month, consideration should be given for deprescribing.

ALS, MS, and dementia are progressive diseases, but, in other diseases associated with PBA, such as TBI, patients will show improvement over time. Therefore, patients should be periodically reassessed for the continued need for PBA treatment. Tapering of the dose would be the initial step, if it is not at the lowest dose, with discontinuation after 1 to 2 weeks. If symptoms recur, the medication can be re- initiated and titrated to the lowest effective dose. Deprescribing has become as important as prescribing in many patients, particularly as they near the end of life. Still, practitioners must always balance the benefits of therapy with providing the patient with the best quality of life possible.⁴⁵

While PBA has been described for over a century in the medical literature, most healthcare providers are not familiar with its etiology, prevalence, or treatment. Pharmacists are well-positioned to educate providers, patients and caregivers, and long-term care facility staff about this syndrome and can assure that patients receive optimal treatment, which has been shown to improve quality of life.

PATIENT CASE

TW is an 89-year-old woman with a past medical history of moderate-severe AD, hypertension, depression, osteoarthritis, stage IV chronic kidney disease, and vitamin B12 deficiency. Recently, she was found at her apartment confused and stuporous. Her son brought her to the hospital where she was treated for aspiration pneumonia and discharged to a skilled nursing facility (SNF) for rehabilitation.

Her medications prior to admission to the hospital were amlodipine 5 mg daily, vitamin B12 injection monthly, and sertraline 25 mg daily.

While in the hospital, she was noted to have several crying outbursts and she was inconsolable for about 20 minutes. After one episode, she was asked why she was so sad and tearful to which she replied, "I'm feeling fine. When is lunch going to be served?" The inpatient physician, thinking he needed to optimize her treatment for depression, increased her sertraline dose to 50 mg daily and continued all other medications.

At the SNF, she was observed to have continued crying outbursts 3 to 4 times a day, sometimes interrupting her therapy sessions, requiring them to be shortened on several occasions. Her physician at the SNF identified the symptoms as PBA and prescribed D/Q 20 mg/10 mg daily for 7 days, then increase to D/Q 20 mg/10 mg every 12 hours. After 3 days of treatment, TW had fewer crying episodes and was better able to participate in therapy and interact with other residents. However, on day 12 of therapy (after her dosage increase), she developed vomiting, diarrhea, increased confusion, and tachycardia. The D/Q was discontinued with resolution of her symptoms.

One week later, TW's crying episodes began to recur. Her physician ordered D/Q 20 mg/10 mg daily, which again resolved her crying outbursts, allowing her to fully participate in therapy. After 4 weeks, she had regained her strength and was at her mental baseline. She was discharged to her apartment with daily visits by a home health aide.

This case illustrates the onset of PBA symptoms after possible progression of dementia. In addition, it demonstrates therapeutic benefit, as well as adverse effects, of PBA treatment. Initially, TW responded well to treatment with D/Q, but, when it was increased to the typical maintenance dose, in this older adult with stage IV chronic kidney disease and concomitant treatment with an SSRI, regular maintenance doses led to serotonin syndrome symptoms, which were intolerable. The risk/benefit balance was managed successfully with the lower dose, allowing TW to maintain her functional status.

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