Exploring psychotherapeutic issues and agents in clinical practice
In March 2020, the U.S. Food and Drug Administration (FDA) approved lumateperone (Caplyta®) for patients with schizophrenia, and studies are still in progress for bipolar depression, treatment-resistant depression, and agitation with dementia (Ahmed et al., 2019; Krogmann et al., 2019). The continual search for better pharmacological treatments for schizophrenia is driven by the need to address negative and cognitive symptoms in addition to positive symptoms that traditional dopaminergic agents treat effectively. However, it is the negative and cognitive symptoms that so adversely affect quality of life and social functioning.
Second-generation serotonin dopamine antagonists (SDAs) were found to relieve the positive symptoms of schizophrenia as well as the early dopamine antagonists, and by blocking serotonin 2B receptors in the mesolimbic pathway, there is mild relief of negative symptoms. In addition, with selective binding to the dopamine 2 (D2) and dopamine 3 (D3) receptors, there is less effect in the nigrostriatal pathway to reduce the potential for tardive dyskinesia and extrapyramidal effects (Janicak et al., 2011). Targeting the nigrostriatal pathway yielded an effective antipsychotic agent with marked improvement in the side effect profile, at least in safety and efficacy studies. Post marketing, however, revealed metabolic side effects that equaled the deleterious side effects. The search for an effective medication that relieves positive, negative, and cognitive symptoms of schizophrenia with a safe side effect profile continues. The newer SDAs (e.g., aripiprazole, brexpiprazole, cariprazine) have the added benefit of serotonin partial agonism at the 1A receptor, which improves depressive features but without the desired improvement of broad psychotic symptoms (Hlavinka, 2020). By targeting the glutamatergic system as well as serotonin and dopamine, the hope is to improve cognitive functioning without adding to side effect burden. Hence, lumateperone was introduced.
Mechanism of Action
Ultimately, lumateperone is a serotonin, dopamine, and glutamate modulator. Similar to most second-generation SDAs, lumateperone has a low affinity for D2 and higher serotonin 2A (5HT2A) receptor binding, but also demonstrates partial agonist presynaptic D2 activity and activation of the N-Methyl-D-aspartic acid (NMDA) and alpha-amino-3-hydroxy-5-methyl-isoxazolepropionic acid (AMPA) glutamate receptors, which distinguishes it from other second- and third-generation SDAs (Kantrowitz, 2020; Kumar et al., 2018). Research on glutamate, specifically deficits in glutamate in the prefrontal cortex of individuals with schizophrenia, suggests this as an avenue for drug intervention in the cognitive disorganization prominent in treatment-resistant schizophrenia (Begni et al., 2019). Deficits in the NMDA receptor contribute to cognitive deficits and lack of neuroplasticity, resulting in difficulty in learning compensatory behaviors (Kantrowitz, 2019). Agonists of the NMDA and AMPA glutamate receptors may mediate cognitive and functional deficits in schizophrenia and open a new area for treatment.
Michael is a 52-year-old African American man who works at a public library shelving books on a part-time basis. He has a high school diploma and has taken many classes at the community college without attaining a degree. He is single and lives in shared housing with four other men who also have mental health problems. He has an older brother and sister who are married and have children, and they invite Michael to their homes several times per year.
Michael was diagnosed with schizophrenia when he was 18 years old and has struggled with his disorder, but he has been reasonably stable for the past 15 years. Initially, his symptoms included auditory and visual hallucinations, paranoid delusions, agitation and aggressiveness, speech and thought disorganization, and low motivation. As he moved into middle age, his symptoms were mainly continued auditory hallucinations, emotional blunting, social withdrawal, and eccentric behavior that sometimes includes argumentativeness, illogical thinking, and mild paranoid delusions. Currently, he acknowledges general distrust in authority figures, low threshold for frustration, discomfort among groups of people, and foggy thinking. He has difficulty maintaining his medication regimen due to frustration with side effects, lack of motivation, and simple disorganization at filling his prescriptions. Michael acknowledges that difficulty in thinking and becoming easily overwhelmed with frustration are his greatest problems with having schizophrenia. He is able to manage his delusions and social awkwardness but cannot tolerate what he refers to as fuzzy thinking.
An overview of his medication history is as follows.
- Initially treated with haloperidol up to 20 mg daily for many years, resulting in marked akathisia, tardive dyskinesia, and Parkinson-like tremors.
- Clozapine 300 mg twice daily for 9 months, with development of neutropenia, seizures, and hyperglycemia.
- Risperidone 6 mg daily with diminished hallucinations and delusional thinking and improved self-control. Switched to Risperdal Consta® for improved adherence, which resulted in weight gain, akathisia, elevated prolactin, and tremor.
- Iloperidone 12 mg twice daily, then paliperidone 12 mg daily, then Invega Trinza® 546 mg every 3 months, which resulted in weight gain, QT prolongation, and hyperprolactinemia.
- Other brief trials of olanzapine, quetiapine, and lurasidone, with limited improvement. Does not like these medications due to side effects and refused to take regularly.
- Episodic treatment with fluoxetine and sertraline for intermittent depressive symptoms that resolved.
- Currently taking Risperdal Consta 50 mg intramuscularly every 2 weeks.
Medical problems include hypertension, type 2 diabetes, hyperlipidemia, obesity, and chronic obstructive pulmonary disease. Michael has been smoking an average of two packs of cigarettes per day for 22 years and drinks one six pack of beer per week. He has been arrested for public intoxication several times without extensive incarceration. He has tried to stop smoking on many occasions due to family and health care provider pressure but admits this is not something he wants to do. He smokes marijuana occasionally but does not like it as much as tobacco and beer.
In collaboration with his primary care provider, Michael's advanced practice RN (APRN) would like him to try lumateperone to maintain improved symptom relief with less extrapyramidal and metabolic side effects. Decision making issues include preference for a long-acting injectable (LAI) to help with adherence; however, he has had complications with Consta and Invega Trinza in the past. He also continues to have metabolic issues, even when treated with diet, exercise, metformin and meglitinides, and antihypertensives.
Below are questions the APRN will need to answer in continuing care for Michael.
- What advantages might lumateperone afford Michael in his treatment?He has difficulty adjusting to the usual treatment regimen because of his unwillingness to adhere to the routine and because the side effects worsen his quality of life. Clinical studies indicate much lower likelihood of metabolic and extrapyramidal side effects with lumateperone (Correll et al., 2020), which are major complications for Michael. There are no significant differences in placebo and lumateperone related to glucose, insulin, or prolactin levels and no extrapyramidal symptoms in Phase II and III trials. With evidence of marked improvement in Positive and Negative Syndrome Scale and Clinical Global Impression Severity of Illness scores, lumateperone will benefit Michael and help with stabilization (Correll et al., 2020). Although still not evident in clinical studies, there is a possibility of improved cognitive functioning with the glutamatergic activity (Ahmed et al., 2019; Blair, 2020), which would be a major benefit to Michael. The most common side effect reported for this drug is somnolence and sedation, which will benefit Michael if he takes the once daily dosage at night to help him sleep. Most importantly, if lumateperone will improve Michael's thinking and ability to reason through his frustration, his quality of life will improve.
- What disadvantages might lumateperone contribute even if cost was not an issue?Although lumateperone has undergone extensive testing and has FDA approval, post marketing clinical experience with the drug is limited. A concern is effect on cardiac rhythm; however, Phase II trials did not indicate QT changes with lumateperone (Brown University, 2020; Citrome, 2016). Another disadvantage may be lack of a LAI formulation; however, if Michael can tolerate the medication, there may be a LAI in the future.
- How might lumateperone be introduced in Michael's treatment without jeopardizing his current level of stability?This introduction will take time and diplomacy, as Michael is likely to not tolerate change readily. It would be especially important to do a cross taper with his medications to not lose any clinical gain from what he is currently taking. There are two dosages of lumateperone available: 28 mg and 42 mg; however, the 28-mg daily dose was not clinically effective in Phase III trials, and >42 mg daily afforded no greater improvement. Therefore, Michael could be titrated down to 25 mg of Risperdal Consta at his next injection and 28 mg of lumateperone added orally and monitored for the next 2 weeks for breakthrough psychotic symptoms and side effects. If he can tolerate that dose of lumateperone, and there seems to be improvement, lumateperone can be increased to 42 mg in 2 weeks and Risperdal Consta can be discontinued. Michael's weight, glucose, lipids, white blood count, and prolactin should be monitored for 1 month, and his weight and glucose should continue to be monitored on a monthly basis for evidence of improvement in metabolic state. Now would also be a good time to encourage a gradual exercise plan to improve his cardiometabolic state.
- What are the ethical and professional implications of advocating for Michael?Cost of new medications is the greatest conflict, especially because pharmaceutical representatives are likely to offer samples for 1 year to counterbalance the excessive cost. After 1 year, free samples may no longer be available. Michael would not be able to afford the co-pay, and his insurance might not cover this medication. The APRN would need to write letters for prior authorization and advocate for Michael with his insurance company if the medication is effective and Michael is agreeable to take the medication regularly as prescribed. In addition, at issue is whether the theoretical promise of improved cognitive functioning will be actualized in clinical practice. Can the APRN offer this with sufficient certainty to help Michael?
As nurses, we always try to offer the best for our patients. In mental health, new medications tend to be infrequent, and when they are approved, they tend to be too expensive for patients. Offering a new medication is risky in that there is little post marketing clinical experience and literature to guide the clinician. The APRN relies on clinical trials and industry-sponsored studies; however, it is first-hand clinical experience with patients and their responses that best serve clinicians in decision making. Yet, newer medications with innovative mechanisms of action to target difficult symptoms offer hope in treating patients in safer ways. Our health care system can be cumbersome for patients to maneuver, and nurses need to advocate for them in getting the best care, which sometimes includes writing to pharmaceutical companies, civil services providers, insurance companies, and congressional representatives. That is what we do and how we serve our patients.
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