PSEUDOBULBAR AFFECT (PBA) & THE BRAIN

Man and woman talking in a cafe

Pseudobulbar Affect (PBA) is a neurologic condition, not a psychiatric disorder

PBA involves the dysregulation of expression or affect and not feelings or mood. This is one way that distinguishes this condition from a psychiatric disorder. In PBA, expression refers to changes in autonomic functions and skeletal movements related to laughing and/or crying. 1 While laughing and crying presentation in PBA can look normal, many patients are unable to prevent the behavior or stop an episode voluntarily once it has happened. They may feel like they are crying for no reason or laughing out of the blue.

Laughing and crying in PBA is involuntary, sudden, and frequent and can be exaggerated in relation to the stimulus or incongruent with the patient’s underlying mood. 2

PBA occurs secondary to other neurologic conditions or brain injuries, including but not limited to stroke, dementia or Alzheimer’s disease, traumatic brain injury (TBI), Parkinson’s disease, amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS). Brain damage that results from various neurologic conditions like these may disrupt the neural networks and neurotransmitter activities that regulate emotional expression. This disruption may contribute to PBA episodes.3,4

 

PBA’s Mechanism of Disease

Molecules reacting inside a protein
See The Pathophysiology of PBA
Learn how PBA is thought to arise in a patient with a neurologic condition or brain injury.
Download a transcript of this video.
Molecular diagram of chemicals in PBA medication
See The Pharmacology of NUEDEXTA
Watch this video to learn more about the components of NUEDEXTA. The exact mechanism by which NUEDEXTA exerts its therapeutic effects in patients with PBA is unknown. 1
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PBA can be treated with NUEDEXTA, which is believed to modulate certain neurotransmitter functions. 3, 8

Learn more about NUEDEXTA pharmacology

 

 

Brain lesions can affect control over emotional expression 4

Brain diagram of normal response

 
Normal Brain Response

  • In the normal functioning of the corticopontine-cerebellar (CPC) network, a stimulus results in normal emotional expression. 4
  • The cerebellum modulates an emotional expression based on a stimulus to ensure an appropriate reaction, such as crying when something is sad.
  • Brain stem areas relay information and activate somatic and visceral motor responses. 2, 4, 5
Brain diagram of abnormal response

 
Abnormal Brain Response

  • Lesions to any part of one or more areas of the CPC network can affect emotional expression. 4
  • When neurotransmitter activities along damaged neural pathways are interrupted, it may contribute to PBA episodes of uncontrollable laughing and/or crying. 2
  • Because information may be relayed incorrectly, laughing and crying episodes can be independent or in excess of a meaningful stimulus. 2

 

Glutamate is thought to be one of the major neurotransmitters involved in PBA 2

N-methyl-D-aspartate (NMDA) is one of the main neurotransmitter receptors for glutamate. 2 Glutamate receptors, including NMDA, exist throughout the brain and are also found in the neural network where PBA is thought to arise. 2, 6

 

 

Molecules interacting with protein

 
Normal Glutamate Signaling

Glutamate receptors, such as NMDA, are responsible for facilitating many neurologic functions, including emotional expression. 4, 7 Glutamate exerts its signaling function by binding to and activating receptor proteins. 6

Molecules interacting with protein in large amounts

 
Abnormal Glutamate Signaling

In a variety of neurologic conditions and brain injuries, including stroke and various neurodegenerative disorders, too much glutamate can be released, which can cause excessive activation of glutamate receptors, leading to abnormal neurotransmission and cell dysfunction. 6, 7

 

Learn more about NUEDEXTA’s safety and efficacy profile

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References: 1. Parvizi J, Coburn K, ShillcuttS, Coffey CE, Lauterbach E, Mendez M. Neuroanatomy of pathological laughing and crying: A report of the American neuropsychiatric association committee on research. J Neuropsychiatry Clin Neurosci. 2009;21(1):75-87. 2. Ahmed A, Simmons Z. Pseudobulbar affect: prevalence and management.Ther Clin Risk Manag.2013;9(1):483-489. 3. NUEDEXTA [package insert]. Aliso Viejo, CA: Avanir Pharmaceuticals, Inc. 4. Miller A, Pratt H, Schiffer RB. Pseudobulbar affect: the spectrum of clinical presentations, etiologies and treatments.Expert Rev Neurother.2011;11(7):1077-1088. 5. Purves D. Emotions. In: Purves D, Augustine G, Fitzpatrick D, Hall WC, LaMantia AS, White LE, eds.Neuroscience. 5th ed. Sunderland, MA: Sinauer Associates; 2011:647-667. 6. Pankevich DE, DavisM, Altevogt BM; for the Institute of Medicine Forum on Neuroscience and Nervous System Disorders.Glutamate-Related Biomarkers in Drug Development for Disorders of the Nervous System: Workshop Summary.Washington, DC: The National Academies Press; 2011. 7. Nguyen L, Lucke-Wold BP, Mookerjee SA, et al. Role of sigma-1 receptors in neurodegenerative diseases.J Pharmacol Sci.2015;127(1):17-29. 8. Werling LL, Lauterbach EC, Calef U. Dextromethorphan as a potential neuroprotective agent with unique mechanismsof action. Neurologist. 2007;13(5):272-293.

MLR-NUE-US-1563-1021

INDICATION AND USAGE

NUEDEXTA® (dextromethorphan HBr and quinidine sulfate) is indicated for the treatment of pseudobulbar affect (PBA). PBA occurs secondary to a variety of otherwise unrelated neurologic conditions, and is characterized by involuntary, sudden, and frequent episodes of laughing and/or crying. PBA episodes typically occur out of proportion or incongruent to the underlying emotional state. PBA is a specific condition, distinct from other types of emotional lability that may occur in patients with neurologic disease or injury.

IMPORTANT SAFETY INFORMATION

CONTRAINDICATIONS

Quinidine and Related Drugs: NUEDEXTA contains quinidine, and should not be used concomitantly with other drugs containing quinidine, quinine, or mefloquine.

Hypersensitivity: NUEDEXTA is contraindicated in patients with a history of NUEDEXTA-, quinine-, mefloquine-, or quinidine-induced thrombocytopenia, hepatitis, bone-marrow depression, lupus-like syndrome, or known hypersensitivity to dextromethorphan (eg, rash, hives).

MAOIs: NUEDEXTA is contraindicated in patients taking monoamine oxidase inhibitors (MAOIs), or in patients who have taken MAOIs within the preceding 14 days, due to the risk of serious and possibly fatal drug interactions, including serotonin syndrome. Allow at least 14 days after stopping NUEDEXTA before starting an MAOI.

Cardiovascular: NUEDEXTA is contraindicated in patients with a prolonged QT interval, congenital long QT syndrome, history suggestive of torsades de pointes, heart failure, patients receiving drugs that both prolong QT interval and are metabolized by CYP2D6 (eg, thioridazine and pimozide), patients with complete atrioventricular (AV) block without implanted pacemaker, or at high risk of complete AV block.

WARNINGS AND PRECAUTIONS

Thrombocytopenia and Other Hypersensitivity Reactions: Quinidine can cause immune-mediated thrombocytopenia that can be severe or fatal. Non-specific symptoms, such as lightheadedness, chills, fever, nausea, and vomiting, can precede or occur with thrombocytopenia. NUEDEXTA should be discontinued immediately if thrombocytopenia occurs.

Hepatotoxicity: Hepatitis, including granulomatous hepatitis, has been reported in patients receiving quinidine, generally during the first few weeks of therapy. Discontinue immediately if this occurs.

Cardiac Effects: NUEDEXTA causes dose-dependent QTc prolongation. QT prolongation can cause torsades de pointes–type ventricular tachycardia, with the risk increasing as the degree of prolongation increases. When initiating NUEDEXTA in patients at risk for QT prolongation and torsades de pointes, electrocardiographic (ECG) evaluation of QT interval should be conducted at baseline and 3 to 4 hours after the first dose. Some risk factors include use with CYP3A4 inhibitors or drugs that prolong QT interval, electrolyte abnormalities, bradycardia, or left ventricular hypertrophy or dysfunction. If patients taking NUEDEXTA experience symptoms that could indicate the occurrence of cardiac arrhythmias (eg, syncope or palpitations), NUEDEXTA should be discontinued, and the patient further evaluated.

Concomitant Use of CYP2D6 Substrates: NUEDEXTA inhibits CYP2D6 and may interact with other drugs metabolized by CYP2D6. Adjust dose of CYP2D6 substrates as needed.

Dizziness: NUEDEXTA may cause dizziness. Take precautions to reduce the risk of falls.

Serotonin Syndrome: Use of NUEDEXTA with selective serotonin reuptake inhibitors (SSRIs) or tricyclic antidepressants increases the risk of “serotonin syndrome.”

Anticholinergic Effects of Quinidine: Monitor for worsening in myasthenia gravis.

ADVERSE REACTIONS

The most common adverse reactions (incidence of ≥3% and two-fold greater than placebo) in patients taking NUEDEXTA are diarrhea, dizziness, cough, vomiting, asthenia, peripheral edema, urinary tract infection, influenza, increased gamma-glutamyltransferase, and flatulence.

These are not all the risks for use of NUEDEXTA. Please see Full Prescribing Information.