Update on Neurodegenerative Diseases and Glutamate: A PMHNP Single Case Study Report of a Diagnostically Complex Adult Patient,Interventions,and Unexpected Outcomes

Abstract

Objective:

While dysfunction of serotonin and dopamine neurotransmitters has been studied in depth, in regard to the etiology of mental illness, the neurotransmitter glutamate and its dysfunction is now being explored as contributing to neurodegenerative psychiatric diseases, schizophrenia, autism, depression, and Alzheimer’s disease. This article explains its synthesis, neurotransmission, and metabolism within the brain and subsequent dysfunction that is responsible for neurocognitive loss associated with several psychiatric disorders.

Method:

The case study will report on the screening for pseudobulbar affective (PBA) disorder in a 29-year-old male with bipolar disorder, autism spectrum disorder, and intellectual developmental disability who was experiencing extreme, uncontrolled emotional outbursts requiring continuous family isolation (pre-COVID-19) for safety. With the positive screen for PBA, the patient was subsequently treated with a glutamatergic drug, dextromethorphan/quinidine.

Results:

The patient’s unexpected response to this treatment including the acquisition of language, increased cognition, and improved executive functioning is presented. At 2 years post the initiation of treatment, his PBA screening score is reduced, uncontrolled outbursts and aggression have subsided, and the family can spend time outside of their home.

Conclusions:

Neurodegeneration and its impact is being researched and treated with medications affecting glutamate. The addition of a glutamatergic medication to this young man’s medication regimen has improved both his and his family’s quality of life. The psychiatric diagnoses, medications, and treatments associated with glutamate are explained in depth. The importance of nurses’ understanding of glutamate, its synthesis, transmission, and dysfunction causing excitotoxicity and brain cell death and its impact on patients’ behavior and safety is explained.

Keywords

severe chronic psychiatric illness neurocognitive degeneration glutamatergic dysfunction

Introduction

A working knowledge regarding glutamate as a neurotransmitter, its impact on psychiatric illnesses, and medications that can regulate it are essential for an understanding of psychiatric illness management for nurses. Ismail et al. (2017) explain that neuroplasticity of the brain is the inherent ability of neurotransmitters to connect, coordinate, repair, and integrate with one another as an adaptation to stressors to form appropriate responses, both motor and nonmotor. This important function enables an individual to adapt to their environment through learning and memory. Stressful experiences, genetics, and maladaptive behavioral responses can greatly influence the process of neuroplasticity.

An important element of neuroplasticity is the role of the brain-derived neurotrophic factor (BDNF), which is a protein that provides neurons with signaling beginning in an individual’s childhood through adulthood and into later life, to encourage, differentiate, and maintain synaptic modifications in the brain (Sadock et al., 2015). Normally, brain glutamatergic and BDNF systems work together to support brain plasticity like arborization and brain cell growth (Ismail et al., 2017). Dysregulation of these systems with subsequent decreased brain plasticity have been linked to psychiatric conditions such as depression, schizophrenia, Alzheimer’s disease (AD), and autism spectrum disorder (ASD; Gulyaeva, 2017; Ismail et al., 2017; Muguruza et al., 2016). The effect of this dysfunction is the cognitive degeneration that is characteristic of these severe, often debilitating, psychiatric illnesses (Islam et al., 2017; Sadock et al., 2015). This article will explain this neurotransmitter, glutamate, and its activity; will describe the associated psychiatric illnesses; and explore a selection of medications that have been developed to treat this dysfunction. It will include a case study that illustrates the effect of treatment with one of the medications on a neurodegenerative disorder.

Background

Glutamate, the most important excitatory neurotransmitter of the central nervous system, is involved in all brain cell activity (Danbolt et al., 2016). It is also a precursor to gamma-aminobutyric acid or GABA, the most abundant inhibitory neurotransmitter in the brain (Karthik et al., 2020). Most brain cells have glutamate receptors and are, therefore, influenced by this excitatory neurotransmitter. Brain cells are constantly removing glutamate from the extracellular fluid; excessive concentrations of glutamate are potentially neurotoxic (Iovino et al., 2020). This extracellular buildup of excessive glutamate could be involved in diseases of neuroinflammation and neurodegeneration (Lewerenz & Mahler, 2015).

Excess extracellular glutamate may lead to excitotoxicity in acute insults like ischemic stroke, and chronic excitotoxicity has been hypothesized to play a role in numerous neurodegenerative diseases including AD and Huntington’s disease (Lewerenz & Mahler, 2015). Glutamate is hypothesized to be associated with symptom development in schizophrenia, autism, and chronic alcohol use disorder (Kashem et al., 2019); it also appears to be implicated in age-related cognitive changes in the brain (Roalf et al., 2020). Therefore, understanding those illnesses and others, implicated in the dysfunction of glutamate, requires an understanding of the synthesis, expression, transportation, uptake, and metabolism of this neurotransmitter. Medications are now being researched and approved to treat these neurotoxic diseases and to regulate this powerful neurotransmitter and its metabolic process.

Coulter and Eid (2016) report that, once used in neuronal transmission, glutamate is removed by excitatory amino acid transporters, which shift glutamate away from the synaptic cleft. It is subsequently taken up by astrocytes (specialized glial cells) and converted to glutamine by the enzyme glutamine synthetase. The glutamine is then released, taken up by neurons, and converted back to glutamate being available to be used once again for neurotransmission. This is thought to be the normal recycling process of this neurotransmitter. In brief, glutamate is chemically changed to glutamine by astrocytes, released, and then changed back to glutamate once it reenters the cell.

Glutamate transmission efficiency at the neuron depends on the correct functioning of glutaminergic receptors and transporters, located both on the neurons and on glial cells. Glutamate reuptake and removal by dedicated transporters prevents its accumulation at the synapse. Iovino et al. (2020) explain that extrasynaptic glutamate diffusion is strongly associated with prompt glial cell reaction resulting in the prevention of its accumulation, which would cause neuroinflammation if the accumulation occurred. Glutamate-induced excitotoxicity is mainly linked, therefore, to an impaired ability of glial cells to recognize, respond, and reuptake glutamate. This dysfunction of the glial cells is considered a common hallmark in many neurodegenerative diseases, including Parkinson’s disease. The function of glial cells and specifically astrocytes, a type of glial cell, therefore, is to maintain homeostasis in glutamate and prevent excitotoxicity. Therefore, glial dysfunction causes glutamate-induced excitotoxicity leading to neurodegeneration or cell death.

The NMDA (N-methyl-D-aspartate) receptor on the neuron cell membrane is responsible for the activation of the cell by glutamate (Newcomer et al., 2000). It plays an important role in creating consequent neuroplasticity. However, Newcomer et al. (2000) describe how overactivation of the receptor can cause a longer interval of opening the receptor, which allows an excessive influx of calcium-causing excitotoxicity and eventual cell death. Therefore, medications that partially block this NMDA receptor can help reduce the amount of calcium flowing into the cell and reduce the toxic effects. In all, dysfunction of the neurotransmission of the excitatory neurotransmitter glutamate can occur by overaccumulation at the synaptic site because of the failure of the transporter to remove it from the synaptic site; failure of the glutamate-converting enzyme glutamine synthetase to convert it to glutamine, release it, and then reconvert it to glutamate by the neuron; or failure of the glial cells to recognize the glutamate and respond by uptake, and thus the potential for neurotoxic accumulation. This dysfunction is also facilitated when the NMDA receptor remains open and allows excessive calcium and sodium into the cell or excessive potassium to flow out of the cell (Luscher & Malenka, 2012). Understanding the complexity of the metabolism of glutamate is necessary to understand how its dysfunction is connected to the development of psychiatric illnesses.

Recently, dextromethorphan 20 mg/quinidine 10 mg (DM/Q), a glutamatergic drug, was approved to treat pseudobulbar affect (PBA) based on Phase 3 trials (Hammond et al., 2018). PRISM II evaluated DM/Q effectiveness, safety, and tolerability for PBA following stroke, dementia, or traumatic brain injury (TBI). DM/Q-treated participants showed significant mean (SD) reductions in Center for Neurologic Study-Lability Scale (CNS-LS; see section on PBA) from baseline (Day 30, −5.6 [5.2]; Day 90, −8.5 [5.2]; both, p < .001). Compared with baseline, PBA episodes were reduced by 61.3% and 78.5% at Days 30 and 90 (both, p < .001). At Day 90, 78% and 73% of study participants had “much improved” or “very much improved,” whereas Mini-Mental State Exam scores were unchanged (Hammond et al., 2018). This clinical trial and its outcomes suggest to providers that this is a safe and effective drug that may herald new clinical trials for classes of drugs to treat severe symptoms from glutamatergic dysfunction that effects many people with psychiatric illnesses.

Psychiatric Diagnoses Related to Glutamate

Autism

It has been hypothesized that in ASD, the glutamate-glutamine cycle is impaired and the enzymes that convert glutamate to glutamine called glutamine synthetase are dysregulated (Najat et al., 2018). Therefore, glutamine and glutamate levels are altered in individuals with ASD (Ajram et al., 2017; El-Ansary & Al-Ayadhi, 2014; Horder et al., 2013). Glutamine synthetase has been found to be decreased in postmortem brain tissues from individuals with autism suggesting some dysfunction in the glutamate-glutamine recycling process. The growing evidence suggests that this dysfunction in the excitatory/inhibitory system is the mechanism causatively linked to cognitive disability in autism (El-Ansary & Al-Ayadhi, 2014; Najat et al., 2018).

Schizophrenia

It has long been understood that the dysfunction of the neurotransmitter dopamine plays an important role in the development of this disease and that blocking this neurotransmitter (using atypical antipsychotic medication) at the receptor site reduces some positive symptoms successfully. But because other symptoms such as negative symptoms and cognitive symptoms remain and are not effectively treated by antipsychotic medication alone, it was also clear that there were other neurotransmitter systems that are implicated in this illness (Miyamoto et al., 2012). Small studies comparing cerebrospinal fluid (CSF) of people with schizophrenia with normal controls found reduced levels of glutamate in the affected individuals. Martinez-Cerdeno (2017) explains that postmortem studies investigating structural alterations of neurons have generally found reductions in dendrite arborization, spine density, and the glycoprotein synaptophysin expression across frontal and temporal regions of the brain. Synaptophysin is a protein found in the presynaptic vesicle that guides the neurotransmitter into the synaptic cleft and facilitates neurotransmission. These studies also show a decreased level of the glutamate transporter EAAT 2 (excitatory amino acid transporter) in the frontal and temporal areas of patients with schizophrenia. Without those transporters, excessive glutamate builds at the synaptic clef causing excitotoxicity. This abnormal process could account for the loss of cognitive function through the chronicity of this illness. Postmortem analysis of the brain of individuals with schizophrenia who have attempted suicide shows significantly higher levels of glutamine and glutamate when compared with healthy controls (Bernstein et al., 2013).

Depression

Major depression is one of the psychiatric illnesses that accounts for significant disability worldwide. By comparison with other mental illnesses, the fatality rate is very high, and it tends to be recurring and chronic. Treatment in the past has focused on the neurotransmitter serotonin. However, treatment is sometimes ineffective, resulting in what has been described as treatment-resistant depression. Recent studies are focusing on glutamate and its dysfunction in depression. First-episode depression patients have been found to have significantly reduced levels of glutamate when compared with healthy controls (Dragonov et al., 2020). Interestingly, when the patient showed clinical improvement after treatment with an selective serotonin reuptake inhibitors, the glutamate level did not rise, suggesting the involvement of glutamatergic pathways in the pathophysiology and progressive abnormalities associated with recurrences and refractoriness in chronic depression (Dragonov et al., 2020; Kishimoto et al., 2016). Therefore, the exact relationship of this neurotransmitter to this illness is not fully understood, but it is believed that glutamate neurotransmitter dysfunction is implicated in the development of depression, especially chronic depression or treatment-resistant depression and needs to be researched further to understand the exact relationship and effective treatment.

Alzheimer’s Disease

Glutamate is heavily implicated in AD; however, the mechanism is complex. The NMDA receptor signaling and opening at the synapse allows calcium to flow into the cell along with neurotransmission at the synapse. That activation process is the normal function of neurotransmission of glutamate. However, in AD, it appears that the NMDA receptors, which are not at the synapse, become active and open allowing calcium ions to flow into the cell excessively, causing excitotoxicity and eventual cell death. This dysfunctional signaling of the receptor cells, which are away from the synapse and erroneously allow excessive calcium to flow into the cell, accounts for excessive cell death and the gradual loss of cognitive functioning in this disorder. The level of NMDA receptor signaling must be maintained at a proper level so that it is enough to promote neuronal survival but not harmful causing neurodegeneration as occurs in AD.

Obsessive Compulsive Disorder

Obsessive compulsive disorder (OCD) is a chronic, often disabling, disorder with onset generally in young adulthood. It is characterized by the presence of obsessions; repetitive and persistent thoughts, images, impulses, or urges that are intrusive and unwanted; and often associated with anxiety and compulsions, repetitive behaviors, or mental acts that the individual feels driven to perform stereotypically in response to an obsession or to achieve a sense of “completeness” (Karthik et al., 2020). Despite the availability of treatment options with therapy and psychopharmacology, half of the patients with OCD fail to respond to this treatment. Unfortunately, about 30% are treatment refractory (Stein et al., 2019) because many individuals with this illness do not respond to serotonergic medication; therefore, it is important to consider other neurotransmission dysfunction in attempting to treat this illness and obtain at least some symptom remission. Two studies have examined glutamate concentrations in CSF of unmedicated OCD patients. One study (Chakrabarty et al., 2005) described measurements of glutamate in the CSF of 21 unmedicated adult patients and 18 controls and found statistically significantly higher glutamate levels in patients when compared with healthy controls. In a second study, both glutamate and glycine were found to be elevated in a group of 23 unmedicated adult OCD patients, compared with 23 controls (Pittinger et al., 2011).

In a review comparing 59 magnetic resonance spectroscopy studies across three related conditions, namely, ASD, attention-deficit/hyperactivity disorder (ADHD), and OCD, it was found that there is a common hyper glutamatergic state in the striatum in all three conditions (Karthik et al., 2020). Findings were divided in terms of glutamate levels in the anterior cingulate cortex, with reduced levels being reported in adults with ASD and ADHD and increased levels being reported in pediatric and adolescent patients with ASD and ADHD. Currently, magnetic resonance spectroscopy studies cannot clearly differentiate between intracellular and extracellular glutamate; nor can they differentiate between presynaptic and postsynaptic glutamate. Given this limitation, it may be difficult to confidently associate glutamate-level differences to distinct pathogenetic processes that may underlie OCD; however, it does indicate dysfunction of glutamate and implicates its modulation in treatment. Further research is required to understand the exact relationship of glutamate with this severe debilitating illness.

Pseudobulbar Affective Disorder

This condition is now understood to be a disinhibition syndrome in which specific pathways involving serotonin and glutamate are disrupted or modulated causing reduced cortical inhibition of a cerebellar/brainstem-situated “emotional” laughing or crying focal center. Reduced serotonin and dopamine transmission and elevated glutamate transmission are key components in the emotional dysregulation (Lapchak, 2015). The screening tool for PBA is called the Center for Neurologic Study–Lability Scale (CNS-LS). The CNS-LS is used to assess change in PBA episode frequency and severity (Hammond et al., 2016). It is a seven-item, self-report rating scale including four laughing and three crying items (Hammond et al., 2016). The rating scale is based on the degree to which each of the seven items applies to the patient over the past week on a scale of one (applies never) to five (applies most of the time); the range of scores is 7–35. CNS-LS score of 13 or higher may suggest a PBA (Avanir Pharmaceuticals Inc., 2018). The CNS-LS can be completed by the patient or the caregiver acting as a patient proxy on Day 1 for baseline, and it assesses change in PBA episode frequency and severity for patients treated with DM/Q as rated by a clinician or by the patient or caregiver (Hammond et al., 2016).

Medications Related to Glutamate

Lamotrigine

Lamotrigine is a glutamate, sodium channel blocker medication that blocks or inhibits release of glutamate by blocking the polarization of the sodium ion channels within the cell receptor (Stahl et al., 2018). Channels, when activated by ions to the open or closed position, regulate an action potential by allowing the action or prohibiting it; the channels are specific to sodium, calcium, or potassium (Squire et al., 2009). While the conclusive mechanism of action is not clearly defined, it is commonly thought that glutamate is reduced by lamotrigine when it blocks sodium channels and prevents excitatory neurotransmission (Stahl, 2013b). Typical uses of Lamotrigine in psychiatry are as monotherapy or adjunctive treatment in bipolar 1 disorder and as adjunctive treatment in depression in conjunction with antidepressants (Stahl et al., 2018).

Memantine

Memantine is classified as a glutamate receptor antagonist and an NMDA receptor antagonist. As an NMDA receptor antagonist, it is thought that memantine can slow or halt the constant NMDA activation that is brought about by excessive glutamate release at the postsynaptic receptor site (Stahl et al., 2018). Neuronal toxicity is present with excessive glutamate; it is hypothesized that the blockade of excessive glutamate that memantine provides slows cognitive loss in ASD and AD patients (Kulkarni et al., 2018). Memantine is approved for use in moderate to severe AD, and also used off label in mild AD and other memory and cognitive disorders (Stahl et al., 2018). Novel areas for the additional use of memantine are being researched including encouraging evidence that the affective symptoms associated with borderline personality disorder can be decreased (Kulkarni et al., 2018) with this drug.

Ketamine and Esketamine

Ketamine and esketamine are both used in clinical practice with different approval and regulations. Esketamine is an intranasal medication that is approved for use in treatment-resistant depression with or without acute suicidality, and its use requires enrollment in a risk evaluation and mitigation strategies program (Janssen Pharmaceutical Co., 2020). Risk evaluation and mitigation strategies comprise a drug safety program that the U.S. Food and Drug Administration requires for certain medications with serious safety concerns to help ensure that the benefits of the medication outweigh its risks. Ketamine is used off-label in mental health intravenously for treatment of depression (Stahl et al., 2018). Ketamine is a noncompetitive NMDA antagonist i.e., no opposing ligand can push the antagonist off the receptor (Lambert, 2004) that has two mechanisms of action (Stahl et al., 2018). It is an open-channel antagonist that binds to the NMDA receptor site and prevents glutamate from binding. Then, it stays on the receptor site after the channel is closed, thereby decreasing the amount of time the channel is open (Li & Vlisides, 2016). The patient experiences a medically managed dissociative episode that significantly reduces the intensity of their depressive and/or suicidal symptoms by providing short rapid bursts of glutamate that increase neural connections by the resultant increase in BDNF (Gulyaeva, 2017).

Ketamine was developed in the 1960s and has been in the market for both human and veterinary uses as an anesthetic since the 1970s. Since that time, it has fallen in and out of favor with the medical community as it is a Schedule III agent with abuse potential. Clinical effectiveness is seen in anesthesia, perioperative pain management, and acute agitation with medical monitoring. Ketamine has gained popularity in off-label uses for treatment of depression, posttraumatic stress disorder, bipolar disorder, OCD, and acute suicidal ideation (Kraus et al., 2019). Ketamine and esketamine are similar drugs but have different enantiomers. Enantiomers are isomers of a molecule that mimic the molecule but often have differing effects and side-effect profiles (McConathy & Owens, 2003). Ketamine is a dual enantiomer, with both s+ and r− isomers, and esketamine is exclusively the s+ enantiomer. By removing ketamine’s r− enantiomer, esketamine loses some efficacy; however, it has fewer side effects and a faster recovery time from the patient’s dissociative experience, making it a viable option in the outpatient setting (Li & Vlisides, 2016). The efficacy of outpatient treatment for acute mental illnesses and addictions is being researched and provided to make these treatments more accessible to the large numbers of people who need treatment at lower costs.

Dextromethorphan/Quinidine

Dextromethorphan is a noncompetitive NMDA antagonist, receptor agonist, and has strong reuptake at both serotonin and norepinephrine sites via its effect on transporters (Stahl et al., 2018). Methorphan is an opioid derivative with the r− enantiomer and is therefore nonaddictive and does not typically have CNS effects when given in low doses (Nguyen et al., 2016). However, in high doses, it can have NMDA-antagonistic dissociative effects similar to ketamine (Nguyen et al., 2016; Stahl, 2013a; Taylor et al., 2016). Sigma-1 receptors (a subset of glutamate receptors) modulate certain ion channels including NMDA, and it is theorized that cognition can be enhanced in patients with ASD or other neuropsychiatric conditions (Nguyen et al., 2016; Stahl, 2013a) by blocking these receptors. Dextromethorphan is a CYP2D6 substrate and metabolizes rapidly; therefore, quinidine, a CYP2D6 metabolic inhibitor, is added to prolong the half-life of the dextromethorphan (Avanir Pharmaceuticals Inc., 2019; Stahl, 2013a; Stahl et al., 2018).

DM/Q is approved for use in PBA and is used off-label in unstable posttraumatic stress disorder, mild TBI, and treatment-resistant depression (Stahl et al., 2018). It has shown clinical promise in depression, Parkinson’s disease, stroke, TBI, seizures, autism (National Institutes of Health, National Library of Medicine, 2017), and multiple types of pain control (Nguyen et al., 2016). In a study by Chez et al. (2020), MD/Q was effective in improving maladaptive behavior including irritability and aggression in adults with ASD.

Case Study

This case study was conducted with the consent of the patient’s conservator. All pertinent details and identifying information has been omitted to maintain confidentially. The institutional review board ruled that review was unnecessary.

History of Present Illness

A 29-year-old obese mixed-race (Caucasian/Cuban American) male living in the rural south presented to a PMHNP (psychiatric-mental health nurse practitioner) for a routine medication check accompanied by his stepfather in September 2018. While he was previously known to the practice, this was his first visit with this PMHNP provider. He was in obvious distress: pacing, crying, and, at times, laughing. The chart revealed a history of bipolar 1 disorder with severe mood instability, profound intellectual developmental disability (IDD), and severe ASD. His stepfather reported that the family was concerned about the continued increase in frequency and severity of his symptoms over the past 2 years. He stated that despite the family’s commitment to keep their son at home and the numerous interventions that had been tried, his status was decompensating, and they were concerned about his overall mental/physical well-being as well as their ability to care for him. Consistent with his diagnoses, the patient displayed profound communication deficits; he was able to follow one- or two-step directions and his vocabulary was limited to single words that were rarely used in context. He had little ability to regulate his moods, experienced rapid cycling despite treatment, and had frequent inconsolable outbursts with increasingly severe episodes of physical aggression occurring multiple times per day. The physical aggression had become worrisome as he was stomping holes in the floor of their mobile home, and there was a concern for physical safety with pushing episodes. As is characteristic in adults with severe ASD and profound IDD, he was rigid and limited in his food and activity choices, unable to adapt to change, eating only five to six different foods, and insisting on spending his days repeatedly watching a limited number of Barney and Bob the Builder videos. However, over the past 2 years, he was becoming increasingly rigid as his mood escalations increased, and the family felt his quality of life had significantly decreased. Previously the family had enjoyed outings in the community, but due to the increase in severity of his escalations, they had been escorted out of multiple public places by public safety officers so that they were now isolated at home. The family’s goals for the patient were unchanged and included the sustained opportunity for him to remain living with the family, with increased mood stability and increased quality of life.

Developmental History

Patient was born to a 20-year old primigravida at 39 weeks and 5 days, weighing 5 pounds 2.5 ounces via spontaneous vaginal birth after a 7.5-hour labor where intravenous meperidine was given for analgesia. His mother had a complicated prenatal course including persistent hyperemesis, which resulted in a 2-pound maternal weight gain. The infant’s position in utero placed pressure on her left kidney, which resulted in a marked decrease in output from that kidney, resulting in a hospitalization with a kidney infection treated with intravenous antibiotic therapy. The patient’s father was deployed to Iraq for Desert Storm during the pregnancy. He sustained an injury in Iraq and was transferred back to the United States for ongoing hospitalization and multiple surgeries prior to the birth of his son, this patient.

At 3 weeks of age, the patient was found to have pyloric stenosis, which was surgically corrected; additionally, he was found to have a ventricular septal heart defect that was monitored and spontaneously corrected by 18 months of age. His mother stated that she noticed differences between him and his peers within his first few months. He walked at 15 months and began talking along with his peers, but aphasia soon developed as he was not able to put words into sentences. He developed grand mal seizure activity by the age of 8 months. By 11 months, he was having at least two grand mal seizures per month and would have repeated seizures with illnesses common to childhood, becoming cyanotic. By age 2 years he began to have cognitive regression. When he was 7 years old, he reportedly had an extended episode of status epilepticus while he was hospitalized in a small rural hospital, and after 36 hours was referred to a children’s referral hospital. He has been maintained on the antiepileptic drug carbamazepine without any additional seizure activity since that time. When he was enrolled in kindergarten, he was moved to special education the first day where he stayed until he graduated at 21 years of age. His parents divorced early in his life, and his mother stated that she struggled to maintain consistent relationships due to the severity of his illness. She has been married to his stepfather for the past 10 years. The family has maintained a residence next door to the patient’s maternal grandmother for more than 10 years, whose support has allowed his mother and stepfather to work outside of the home.

Initial Medications

Buspirone 15 mg TID

Carbamazepine 200 mg BID

Quetiapine 600 mg QHS

Risperidone 3 mg TID

Screen for PBA

Center for Neurologic Study–Lability Scale (CNS-LS): Result 20 which indicates a positive screen.

Initial Plan

After discussion with the family and his screening positive for PBA, it was decided DM/Q 20/10 mg daily would be added to his medication regimen.

One-Month Follow-up

After 1 month of this medication regimen the patient showed mild improvement in mood regulation and lability as well as a reduction in quantity and severity of outbursts. DM/Q was increased to twice daily, and he was appointed to return for follow-up in 1 month.

Follow-up Appointments Over the Next Year

He displayed increased attention and mood stability with a significant decrease in lability. Mom reported that within 3 months the outbursts had decreased to less than one per month and that he was able to go places in public and be around other people without incident. He was eating new foods, trying new activities, and his vocabulary was increasing. He was able to follow multiple step directions, and he was putting words together in sentences using appropriate context. He was beginning to self-soothe and could connect his emotions to the context of the situation (“I don’t want to go to the movies because it makes me upset”). He was able to tolerate some reduction in antipsychotic medications.

CNS-LS

Six months post introduction of DM/Q resulted in a score of 11.5, which indicated that the PBA was being effectively treated.

Additional Follow-up Appointments

He continued to improve and develop both emotionally and cognitively. With the improvements, the family was able to leave their home for activities pre-COVID-19, and since COVID-19 he has been able to adapt and remains almost free of all outbursts. When he does have outbursts, his mother reports they are not severe, are short in duration, and that she can identify the trigger.

CNS-LS

Two years into treatment resulted in a CNS-LS score of 4, which indicated ongoing effective treatment for PBA.

Current Medications

Buspirone 15 mg TID

Carbamazepine 200 mg BID

Quetiapine 200 mg QHS

Risperidone 3 mg BID

DM/Q 20/10 mg BID

Discussion

While dysfunction of serotonin and dopamine neurotransmitters has been studied regarding the etiology of mental illness, the neurotransmitter glutamate and its dysfunction is currently being explored as contributing to neurodegenerative psychiatric diseases, schizophrenia, autism, depression, and AD. It appears that the behavioral impact of impaired glutamate expression can vary from mild to severe, can include emotional outbursts, or can create impaired cognitive responses from people who have a variety of mental health diagnoses. These consequences have the potential to become debilitating.

In their article “Treatment of Pseudobulbar Affect in a Patient with a History of Brain Injury, Partial Brain Resection and Brainstem Stroke: A Case Report,” the authors reported complete remission of symptoms of severe PBA with no side effects or any otherwise negative effects. The patient was a 62-year-old man who experienced a severe brain injury in a work accident after being hit with a falling cinderblock. Following brain resection surgery, he subsequently recovered but began to have intractable headaches and eventually a stroke. For years he was homeless and began to experience spontaneous laughing and crying spells. He found these symptoms very disturbing and avoided public places. After years of unsuccessful treatment with serotonergic medications, he was treated with DM/Q and had a full remission of his symptoms. They report he subsequently married and was living happily. Surprisingly, he had fully regained most of his speech fluency. As in the case reported in this article, the results were both very effective and unexpected. The authors (Young & Nguyen, 2020) of this case study encourage practitioners to consider this type of treatment and point out that the types of presenting symptoms from PBA or other emotional outburst symptoms may vary widely.

Mosti and Coccaro (2018) describe the frequency of mild TBI (mTBI) as being as high as 15% in veterans returning from Operation Enduring Freedom. Of those with mTBI, up to 31% had ongoing symptoms including mood changes. In their study, the results indicated a strong correlation between aggression and history of mTBI. The case study outlined in this article is of a patient with a complex history of neurological, psychiatric, and neurodevelopmental events and concerns. These multiple events during his intrauterine development could be interpreted as mTBI. Case studies such as this can open a window for the development of further research for a wide range of patient populations.

Psychiatric symptoms of emotional excess can be difficult to manage in the severely mentally ill as well in the IDD population. Nurses must address safety issues in treatment planning for chronic mentally ill patients and can therefore benefit from understanding the effect of the neurotransmitter glutamate as they assess their patients’ symptoms and acuity. With this increased knowledge, behavioral interventions can be further individualized to patients and their families. Education about the role of glutamate to patient’s families can be an integral factor in long-term management. Utilization of glutamatergic medications can be one component in an overall behavioral modification plan that helps target behavior management, cognitive function, and/or overall safety.

Glutamate has often taken a secondary role to the monoamines in recent care but can have a powerful impact on quality of life. This patient’s improvement began once glutamate became a target of treatment. While it is only observational and speculative as to what led to these results, it is evident that his increased neuroplasticity—gaining verbal skills, for instance—is likely based on glutamate management. He has stabilized and subsequently demonstrated improved cognitive development. Could his development of new language skills represent increased arborization forming new synapses and capabilities? Could his improved executive functioning with less mood instability indicate lower excitotoxicity? Could the pervasive nature of his improvement represent improved glutamatergic functioning in several areas of his brain? While these questions cannot be answered with today’s imaging techniques, recognizing and treating the glutamatergic system can affect quality of life, which was the primary goal for the family at the center of this case study. In providing holistic care to complex cases, it is critical to keep the goals of the patient and their family as the highest priority for your nursing interventions.

Footnotes

Author Roles

All authors contributed to the conception or design of the study or to the acquisition, analysis, or interpretation of the data. All authors drafted the manuscript, or critically revised the manuscript, and gave final approval of the version that was submitted for publication. All authors agree to be accountable for all aspects of the work, ensuring integrity and accuracy.

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

ORCID iD

Carole Frances Bennett

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