US Pharm. 2017;42(11):31-35.

ABSTRACT: Pseudobulbar affect (PBA) is a type of affect lability characterized by sudden, frequent, and uncontrollable episodes of crying, and or laughing. The disease states most frequently associated with PBA are Alzheimer’s disease, amyotrophic lateral sclerosis, multiple sclerosis, Parkinson’s disease, stroke, and traumatic brain injury. Standardized rating scales can be used for PBA as screening instruments or to more objectively measure PBA. The treatments utilized for PBA target serotonin, norepinephrine, and glutamate with goals of reducing severity and episode frequency of PBA.

Pseudobulbar affect (PBA) is a type of affect lability characterized by sudden, frequent, and uncontrollable episodes of crying and/or laughing. In PBA, a person’s affect, or external manifestation of his or her internal state, is incongruent.1-3 Classic signs of PBA include uncontrolled or inappropriate crying during a happy event or laughing hysterically during a sad event. PBA affects about 1.5 million people in the United States; many cases are thought to go undiagnosed, so the actual number may be larger.4

Recognition of PBA is challenging since many physicians are unaware of the criteria for diagnosis. The patient’s emotional response may be noted by healthcare professionals as disproportionate to the situation and can be wrongly attributed to poor coping, depression, or changes to the patient’s baseline neurocognitive disease and, therefore, may not be addressed. Often, patients are misdiagnosed as having only a depressed mood.5 This is not surprising, as 30% to 35% of patients with PBA are depressed.5 Unfortunately, patients and/or caregivers do not always discuss these episodes with their healthcare providers.6 Among those who do discuss these events, only 40% are given a diagnosis of PBA and less than half receive specific treatment.6

PBA has been described in patients since the 19th century. In 1872 Charles Darwin noted, “Certain brain diseases, such as hemiplegia, brain-wasting, and senile decay, have a special tendency to induce weeping.”7 Pierre Marie described “emotional lability” in 1892 as occurring with amyotrophic lateral sclerosis (ALS).8 In 1924, Kinnier Wilson described the core features of PBA when he noted that these patients’ displayed emotions were often out of proportion to the stimuli that evoked them and inappropriate to the social context in which they occurred.9 Because PBA is generally an under-recognized, improperly diagnosed, and insufficiently treated condition, the need for improvements in both diagnostic criteria and disease awareness is imperative. This article summarizes the established knowledge on PBA, as well as recent findings related to etiology, pathophysiology, clinical manifestation, diagnosis, treatment, and prevention.

Etiology and Pathophysiology

PBA occurs secondary to many neurological disease states.6 The most common diseases associated with PBA are Alzheimer’s disease (AD), ALS, multiple sclerosis (MS), Parkinson’s disease (PD), stroke, and traumatic brain injury (TBI).5,10 The exact cause of PBA is unknown, but it is thought to be related to nerve impulse disruption from the cerebellum to the limbic and paralimbic systems.10 Dysregulation and disinhibition in the frontal cortex are also thought to be part of the process underlying PBA. The release hypothesis, gate control theory, and dysfunction of neurotransmitters theory are among the proposed mechanisms of PBA.

Release Hypothesis: The release hypothesis explains the disruption of cortical inhibition in the upper brainstem center, leading to a release of lower bulbar nuclei affecting responses to laughing and crying. A revised theory behind the release hypothesis suggests that cerebellar structures involved in laughing and crying are operating on incomplete information because of the lesions affecting this part of the brain.10

Gate Control Theory: The gate control theory proposes inhibition of the mechanism regulating emotional expression. MS and related neurological damage are thought to be involved in disrupting activity in the cortical structures related to sensory, motor, and emotional processes, along with overactive motor cortical areas.10

Dysfunctional Neurotransmitters Theory: In the dysfunctional neurotransmitters theory, serotonin, dopamine, glutamate, and sigma-1 are disrupted in various brain pathways, leading to alterations in emotional expression.10 Therefore, medications that modulate these neurotransmitters may play a role in providing therapeutic benefit.

Clinical Manifestations

PBA can be described in terms of emotional lability involving laughing and/or crying. Careful consideration to the emotional or behavioral descriptors from those close to the patient must be given to gain the proper perspective on the patient’s symptoms. As perceived by others, these episodes seem to be unprovoked, incongruent, and disconnected from the actual precipitating situation. Laughter may appear uncontrollable and out of context to what is considered the normal emotional response to an amusing situation.5 An example of this response would be a situation in which a smile or giggle would be expected, but uncontrollable laughter occurs.

Crying episodes may present as mood-congruent or incongruent, but the emotional response is more than what has normally been produced by the individual in the past. Whether crying or laughing, the current emotional episode experienced by the patient is usually persistent and lasts a considerable amount of time. These episodes are also difficult to suppress, and symptoms can occur suddenly, lasting anywhere from a few seconds to several minutes. Between the two emotional responses, crying seems to be more prevalent than laughing. PBA may negatively impact health status, quality of life, work productivity, and social functioning, resulting in social embarrassment, anxiety, depression, and isolation.5


PBA may be suspected during the neurological evaluation. Diagnostic criteria have been established to help define PBA more objectively.5 Poeck defined four criteria for PBA: 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; and 4) emotional expression does not lead to a feeling of relief for the patient.5,11 More recently, Cummings proposed diagnostic criteria for PBA, calling it involuntary emotional expression disorder.2,3,12 These criteria include experiencing episodes of involuntary or exaggerated emotional expression (laughing, crying, or related emotional display) resulting from a brain disorder.2,3,12 These episodes are exaggerated or incongruent with the patient’s subjective state of emotion and are independent or in excess of the eliciting stimulus. These episodes also cause distress or impairment in the patient’s social functioning and cannot be attributed to another psychiatric or neurologic disorder or the effects of a substance.2,3,12

Standardized rating scales can be used for PBA as screening instruments or to better objectively measure PBA.1,5,13 One of the scales is the Center for Neurologic Study-Lability Scale (CNS-LS). The CNS-LS is a seven-item, self-administered questionnaire about the control of laughing (4 items) and crying (3 items).1,5,13,14 The scores for each question range from one to five; total scores range from seven (no excess emotional lability) to 35 (severe excess emotional lability).1,5,13,14 A score of 13 or more predicted a PBA clinical diagnosis by a neurologist in 82% of ALS patients.5,14 A score of 13 or more was less accurate in predicting a diagnosis of PBA for MS patients.5,14 Raising the score to 17 improved the specificity of a PBA diagnosis without affecting the sensitivity.5,14 The Pathological Laughter and Crying Scale) is a clinician-administered instrument that consists of 18 questions inquiring about sudden episodes of laughter and crying.1,5,15 The scores for each question range from zero (normal) to three (excessive emotional lability). A score of 13 or more predicted a clinical diagnosis of PBA in stroke patients with high sensitivity and specificity.1,5,15


The goals of pharmacotherapy are to reduce both the severity and frequency of PBA episodes. The most commonly used treatments target the primary neurotransmitters implicated in PBA, serotonin and glutamate.3,16-18 Serotonin released into the cerebellum may impact the level and type of motor activity by modulating Purkinje-cell firing, thereby affecting motor function and GABA release.17 Glutamate has a broad receptor distribution, including those networks that regulate emotional affect.19

Tricyclic antidepressants (TCAs) and selective serotonin reuptake inhibitors (SSRIs) are used in clinical practice, even though the data are limited. The serotonergic action of SSRIs and TCAs is thought to be significant in the treatment of PBA, as serotonin increases at the synapses in the corticolimbic and cerebellar pathways.3,16,17 SSRIs have a relatively narrow mechanism of action, directed toward enhancing serotonergic function, whereas TCAs alter a broader range of neurotransmitter functions. Dopaminergic medications (i.e. levodopa and amantadine) have been used as well, but with lower response rates.20

In small trials and case studies with poststroke, ALS, MS, and brain-injury patients, the SSRIs that have shown a reduction in PBA-episode frequency and severity include escitalopram, fluvoxamine, citalopram, fluoxetine, and paroxetine.21-28,31 In addition, TCAs such as amitriptyline and nortriptyline have been used in PBA.29 The observations generated by interview and/or symptomatic provocation when SSRIs including fluoxetine, citalopram, and paroxetine were used demonstrated frequency and/or severity improvement in emotional lability; this occurred as quickly as 3 days to 2 weeks in patients with traumatic brain injury and stroke.23,26,29,30 In a study of ALS, MS, and stroke patients impacted by emotional incontinence who were experiencing greater than 30 affective outbursts daily, fluvoxamine decreased emotional outbursts within 2 to 6 days, to zero to five per day.31

DHQ Efficacy Trials

The only FDA-approved product for PBA, Nuedexta, is a fixed-dose combination of dextromethorphan hydrobromide/quinidine sulfate (DHQ). Three double-blind, multicenter trials provided the efficacy data and basis for the FDA approval and use of DHQ in patients with PBA. In contrast to SSRIs and TCAs, dextromethorphan inhibits glutamatergic neurotransmission via actions at a variety of locations, including, N-methyl-d-aspartate receptors and sigma-1 receptors.32,33

The first trial demonstrating efficacy for this combination therapy was a multicenter, randomized, parallel-group, double-blind, controlled, three-arm study to test a defined combination of dextromethorphan hydrobromide (DH) and quinidine sulfate (Q) (AVP-923) for the treatment of pseudobulbar affect in ALS. The combination of dextromethorphan 30 mg plus quinidine 30 mg (AVP-923 = DHQ 30/30) was compared with dextromethorphan monotherapy and quinidine monotherapy.  Each drug was taken individually at the same dose for 28 days. This trial used the CNS-LS questionnaire to screen for symptoms of emotional lability. The primary efficacy measure—improvement in CNS-LS score (average of Day 15 and 29)—was significantly greater in the DHQ 30/30 group than in either comparator arm.32

A second double-blind, placebo-controlled trial of DHQ compared the combination with placebo, taken twice daily, for the treatment of PBA over a 12-week period in MS patients. This trial demonstrated that clinically diagnosed PBA patients had significant improvement in mean CNS-LS scores (averaged across Weeks 2, 4, 8, and 12) in the DHQ 30/30 group versus placebo.33

The third trial, the STAR trial, was a 12-week randomized, double-blind trial in ALS and MS patients with clinically significant PBA in a parallel-group design that consisted of three treatment groups: placebo, DHQ 30/10, and DHQ 20/10. In this trial, DHQ markedly reduced the PBA-episode daily rate to 49% lower than placebo.33

Treatment Determinations

When determining the appropriate PBA treatment, the treating clinician must consider drug-drug interactions, adverse effects, impact on neurological condition/co-morbidities, and benefit to the PBA symptoms. TCAs and SSRIs are used in clinical practice even though efficacy data in PBA are limited to small trials and case studies.5 TCAs impact norepinephrine, serotonergic, cholinergic, and histaminergic neurotransmission at varying levels. Depending on the agent, the severity of key adverse effects—including weight gain, hypotension, dry mouth, constipation, confusion, sedation, sleep disturbances, and potential cardiotoxicity—may vary. Although not free from adverse effects, SSRIs’ limited neurotransmission modulation leads to a cleaner side-effect profile compared with TCAs. Common side effects associated with SSRIs are insomnia, drowsiness, anxiety, headache, and diarrhea. It is important to remember that treatment effects with TCAs and SSRIs used for PBA have quicker onset of action and lower dosages compared with treatment of depression. In addition, their effects are dependent on the patient having comorbid depression.5 See TABLE 1 for more details on commonly prescribed treatment options and dosages.

TCAs may offer a therapeutic benefit via their anticholinergic adverse effects for patients with ALS and Parkinson’s with sialorrhea, drooling, or excess salivation via the blockade of parasympathetic stimulation to salivary glands.5 However, TCAs’ clinical utility may be limited by drug-drug interactions, toxicity risks, and side-effect profile. Since SSRIs’ mechanism of action is primarily directed to serotonergic neurotransmission, the side-effect profile may be less problematic than that of TCAs. However, drug-drug interactions need to be evaluated closely prior to their initiation.

The FDA-approved dosing of Nuedexta for PBA consists of a titration of one capsule of dextromethorphan 20 mg/quinidine 10 mg taken by mouth once daily for 7 days, then increased to the maintenance dose of one capsule of dextromethorphan 20 mg/quinidine 10 mg every 12 hours, not to exceed dextromethorphan 40 mg/quinidine 20 mg in a 24-hour period.34 Dextromethorphan is considered to be the therapeutic active moiety in this combination product; however, it is rapidly converted by CYP2D6 to dextrorphan, a metabolite not considered to have therapeutic impact. Quinidine sulfate is added to the combination to inhibit CYP2D6, thereby blocking the metabolism of dextromethorphan to dextrorphan and resulting in increased and prolonged plasma concentrations of dextromethorphan.5,34 There are several contraindications to be aware of when it comes to Nuedexta. See TABLE 2 for more details.


In a review of the available evidence-based guidelines, two treatment guidelines are available on the management of PBA: the American Academy of Neurology guideline for Amyotrophic Lateral Sclerosis and the American Academy of Neurology guidelines for Psychiatric Disorders in Multiple Sclerosis. The American Academy of Neurology guideline for Amyotrophic Lateral Sclerosis provides a Level B recommendation for DHQ stating “if side effects are acceptable, DHQ should be considered for symptoms of pseudobulbar affect in patients with ALS and is probably effective for pseudobulbar affect in ALS.”35 The American Academy of Neurology guidelines for Psychiatric Disorders in Multiple Sclerosis provides a Level C recommendation, describing DHQ “as possibly effective and safe and may be considered for treating individuals with MS with PBA.”20 Recognizing the limited options for management of complex patient pharmacotherapy is important in evaluating benefits and risks of treatment.

Role of the Pharmacist

Neurologic conditions compounded with PBA are complex to manage due to multiple factors, including the heterogeneity of neurologic conditions, comorbidities, care management by multiple prescribers, and consequential polypharmacy issues. The ability of pharmacists to provide their drug expertise and leverage effective communication is essential to the care of a PBA patient, as pharmacists are able to identify polyprescriber-driven treatment risks, support health/medication literacy, and address key polypharmacy issues to optimize pharmacotherapy. As some neurologic diseases require drug treatment dispensed from a specialty pharmacy, specialty pharmacists are ideal clinicians for assisting with the management of those with complex specialty medication treatment(s) and ensuring proper education of patients and/or caregivers on the importance of communicating with all their providers on changes or additions to their treatment plan.

Pharmacotherapy of PBA may include the use of TCAs, SSRIs, or Nuedexta. Polypharmacy is a significant issue for patients with PBA, which is why pharmacists’ thorough review of medication history, treatment plan, and nonprescription supplements is paramount to safeguarding care. Additionally, the pharmacist has access to the multiple medications being prescribed and can provide support for pharmacotherapy management of the neurological conditions and existing comorbidities.

Recognizing that Nuedexta is the only FDA-approved PBA treatment, pharmacists will need to be familiar with this product. A key consideration for pharmacists in supporting patients prescribed Neudexta is being able to understand the therapeutic moiety, dextromethorphan, and the requirement of CYP2D6 inhibition from quinidine sulfate in order to maintain therapeutic levels. With this pharmacokinetic necessity, assessing current medications with CYP2D6 metabolism needs and/or impact on CYP2D6 metabolic function will be key to the efficacy and safety of both Nuedexta and concomitant medications. Also, because quinidine is a substrate for CYP3A4, other medications that may be inhibitors or inducers of CYP3A4 may need to be used cautiously to prevent any alterations in quinidine’s metabolism. Additionally, the pharmacokinetic assessment of a treatment regimen is equally important for PBA management consisting of TCAs or SSRIs.

Currently, 25% of drugs are metabolized by CYP2D6. These include medications such as antipsychotic/dopamine antagonists, antiarrhythmics, beta-blockers, neuroleptics, TCAs, and SSRIs. Pharmacogenomic research has shown a large variation in the enzyme activity of CYP2D6. This variation ranges from poor metabolizer to ultra-rapid metabolizer, making pharmacokinetic and pharmacogenomic considerations an important factor when selecting treatment.36

According to the Nuedexta package insert “approximately 7% to 10% of Caucasians and 3% to 8% of African-Americans lack the capacity to metabolize CYP2D6 substrates and are classified as poor metabolizers (PMs). The quinidine component of Nuedexta is not expected to contribute to the effectiveness of Nuedexta in PMs, but adverse events with the quinidine are still possible. In those patients who may be at risk of significant toxicity due to quinidine, genotyping to determine if they are PMs should be considered prior to making the decision to treat with Nuedexta.”34 Pharmacists should leverage results of genetic testing as part of their assessment and recommendations due to pharmacogenomic variability and potential drug-drug interactions.

Depending on the selected PBA treatment agent, there may be a need for additional vigilance on potential pharmacodynamic issues such as risks for cardiotoxicity, serotonin syndrome, and potential negative effects on the neurological condition or comorbidities, especially when treating with certain antidepressants. Pharmacists can provide their pharmacotherapy expertise and support to prescribing healthcare providers who may be unaware of potential drug-drug and/or drug-disease interactions. Pharmacists play an important role in educating patients and their caregivers on treatment, including its impact on the condition, dose titrations, potential abrupt cessation/discontinuation syndrome, and potential drug interactions and side effects, as well as encouraging open communication for concerns or questions. Pharmacists may also provide their expertise on drug-food/herbal/OTC interactions, and drive literacy supporting the appropriate use of medication for treatment goals. Pharmacists are able to address the gaps in care that may contribute to patient-safety risks in a treatment plan when multiple prescribers are involved in the care of a single patient.


PBA is a type of affect lability characterized by sudden, frequent, and uncontrollable episodes of crying and/or laughing, often associated with AD, ALS, MS, PD, stroke, and TBI. Treatments for PBA target serotonin, norepinephrine, and glutamate to reduce severity and episode frequency. Neurologic conditions compounded with PBA are complex to manage. Pharmacists can provide their expertise by making providers and patients aware of potential drug-drug and/or drug-disease interactions, dose titrations, and tapering strategies, and expectations on how long it may take to see relief in symptoms.


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