Ethical Issues in Psychopharmacology

TL is a 58-year-old woman with a history of bipolar disorder, attention-deficit hyperactivity disorder, and anxiety. After moving from another state, she presented to find a new psychiatric provider. Upon interview of the patient and review of her medications, TL’s new psychiatrist saw that she had been prescribed divalproex sodium, alprazolam, and modafinil by her previous psychiatrist. The dosing patterns appeared unconventional, and the interview revealed that at least some of the dosing variation was patient driven (e.g., dosing divalproex sodium daily with an additional dose every 3 days, dosing modafinil and alprazolam in very small doses multiple times a day, and daily variability in the doses taken of these two medications).

1.1 What is the most appropriate initial step for the psychiatrist in this case? (More than one response may be appropriate.)

TL described that, after numerous medication trials over the years, alprazolam, modafinil, and divalproex sodium are the only medications that have helped her psychiatric symptoms reach stability. In addition, she stated that she is very sensitive to medications and thus responds to very small doses of medications, especially when dosed throughout the day. She stated that she used to be on much higher doses of alprazolam and modafinil in the past but has been able to wean herself off these higher doses.

TL’s care was also complicated by having insurance that restricts medications to certain formulary-approved medications. She also must pay a large copay for her office visits.

1.2 What is the most appropriate next step for the psychiatrist?

After a patient-centered discussion, TL and the psychiatrist agreed to gradually try other medications instead of the alprazolam and modafinil, such as cross-tapering from alprazolam onto clonazepam for decreased risk for dependence and using trazodone to help with sleep. In addition, TL agreed to try to take more regular doses of medications instead of changing them as needed. Although these changes were done slowly and one at a time, the changes resulted in TL having substantially increased anxiety and mood lability. The psychiatrist then cross-tapered the medications back to her previous medications, with adjustment of alprazolam and modafinil to the lowest possible doses that helped TL’s symptoms.

1.3 What were the ethical principles involved in the agreement between the psychiatrist and TL that she use alprazolam and modafinil and use the medications in her previous unusual dosing patterns?

Mr. R was a 71-year-old married Caucasian man who was referred by his primary care physician to an outpatient geriatric psychiatry clinic for evaluation and management of agitation. The referral stated that the patient was diagnosed as having Alzheimer’s disease 6 years ago and that the patient’s agitation started approximately 2 to 3 years ago. Although his wife had received caregiver education and support through the local Alzheimer’s Association chapter with some improvement in her ability to redirect the patient, she was nonetheless experiencing additional caregiver burnout, despite additional support from their children living in the community. At the time of his initial visit to geriatric psychiatry, the patient’s cognition was obviously impaired. He was minimally responsive to questions, became irritable when asked basic questions, and was unable to tolerate a cognitive assessment. The history was obtained from the patient’s wife, Mrs. R.

At the initial geriatric psychiatry visit, Mrs. R reported that the agitation had been worsening over the past several months. The behaviors consisted of resisting care, restlessness and purposeless behaviors, screaming, and occasional physical aggressiveness. Upon detailed questioning, it became apparent that his behavioral issues were exacerbated over the past year by worsening nonfluent aphasia and increased functional limitations, including bowel and bladder incontinence requiring more invasive caregiving. Although the agitation also appeared to be associated with paranoia toward caregivers, Mrs. R—who was the primary caregiver and designated power of attorney—adamantly declined consideration of psychotropic medications, including cholinesterase inhibitors, instead querying regarding complementary or alternative interventions.

2.1 What is the most appropriate next step in the management of Mr. R’s agitation? (More than one answer may be appropriate.)

Previous alternative interventions initiated by Mrs. R, including consultation with faith healers and use of medicinal cannabis, had been of limited benefit. Aromatherapy, music therapy, and reminiscence therapy were also attempted with limited response. Although a day program was attempted several months before the initial geriatric psychiatry visit, Mr. R’s screaming and aggressive behaviors led to his being asked to leave after the first 2 weeks.

After several visits to the geriatric psychiatry clinic, during which rapport and trust were gradually established with Mrs. R, the staff discussed nonpharmacologic approaches with her at length, as well as the risks and benefits of several classes of medications. Mrs. R eventually agreed to a trial of an antidepressant medication targeting Mr. R’s agitation.

On the basis of findings from the Citalopram for Agitation in Alzheimer’s Disease (CitAD) Study (4), the psychiatrist prescribed 10 mg citalopram and gradually titrated it upward, over several months, to 40 mg. Unfortunately, this upward titration was associated with an increase in Mr. R’s corrected QT (QTc) interval to 492, without an apparent reduction in agitation intensity or frequency. Citalopram was subsequently discontinued.

Mrs. R firmly declined consideration of any further medication trials for nearly 6 months. Ultimately, Mr. R’s daughter sustained a broken wrist when Mr. R pushed her while she was providing caregiver support.

2.2 What is the most appropriate next step in the management of Mr. R’s agitation? (More than one answer may be appropriate.)

After the episode in which her daughter was injured, Mrs. R agreed reluctantly to psychiatric hospitalization of Mr. R for further evaluation and management, with clear communication from the outpatient geriatric psychiatrist that the use of psychotropic medications would be necessary to ensure patient and staff safety. She reluctantly agreed to the emergent use of benzodiazepines, if needed, and was willing to consider mood-stabilizing medications. However, she was unwavering in her refusal to consider use of antipsychotic medications after a review of the U.S. Food and Drug Administration (FDA) black-box warning regarding the use of antipsychotic medications in dementia (5).

During the initial phase of psychiatric hospitalization, multiple emergent intramuscular injections of lorazepam were necessary to mitigate bouts of physical aggression toward staff. Mr. R also appeared suspicious toward both staff and family members, including his wife, with clear reactions to internal stimuli and apparent misidentification delusions with angry posturing at his mirror image. After further review of the treatment of psychosis, Mrs. R agreed to a trial of low-dose risperidone. However, this brief trial was aborted at her firm request because of the emergence of a resting tremor. Mrs. R also declined further trials of antipsychotic or mood-stabilizing medications, despite multiple family meetings wherein the couple’s children noted their belief that Mr. R would not have foregone treatment of his psychotic symptoms. Consequently, because of the need for routine prn doses of lorazepam, which his wife accepted, the patient was started on scheduled clonazepam. With the scheduled use of 2 mg clonazepam twice daily, the patient was ultimately calmer, although now bedbound and requiring total care. He was discharged back to his family’s care at the wife’s request, against medical advice.

2.3 Which ethical principles was the treatment team trying to balance in the care for Mr. R and in communication with Mrs. R?

Although dementia (i.e., major neurocognitive disorder) is a broad category of illnesses defined primarily by a range of cognitive deficits, some of the most challenging and distressing symptoms for patients and caregivers are the behavioral and psychological symptoms of dementia (BPSD). These symptoms (also commonly known as neuropsychiatric symptoms, or NPS) include psychosis (delusions and hallucinations), verbal or physical agitation, verbal or physical aggression, depression, anxiety, apathy, disinhibition, and wandering (6).

Mr. R’s case illustrates the numerous complex challenges faced by families who care for their loved ones with dementia who are experiencing BPSD. Clinicians who are asked to evaluate and manage these patients will inevitably face numerous ethical questions. In several ways, the treatment of BPSD represents a perfect storm of ethical dilemmas. First, patients with dementia in the moderate to advanced stages generally lack adequate capacity to provide informed consent for their own treatment. Second, because patients with diminished autonomy such as those with advanced dementia require surrogates to make medical decisions on their behalf, clinicians find themselves in the difficult position of trying to alleviate the patient’s symptoms while helping families navigate this often fraught decision-making process. Third, because BPSD can become severe to the point where patient and caregiver safety may be in jeopardy, such potential harms must be factored into the evaluation of potential harms of treating versus not treating the patient psychopharmacologically. Finally, relatively limited treatment options present challenging trade-offs of potential benefits versus risks.

Nonpharmacological interventions are universally recognized as the first-line management for BPSD (7), with those based on family caregiver interventions having the greatest evidence of benefit. These include interventions such as caregiver education and skills training in dementia care; enhancing support and self-care techniques for caregivers to mitigate burnout; and home environmental redesign to improve patient safety, minimize their confusion, and enrich their sensory stimuli, among others (8, 9).

However, although nonpharmacological interventions may, over time, be effective in reducing the frequency or intensity of BPSD, the immediate benefit of such interventions is often limited in a person with dementia experiencing acute agitation or frank psychosis: When patient or caregiver safety and quality of life are in immediate jeopardy, psychotropic medications are generally necessary. Ultimately, both pharmacological and nonpharmacological interventions play a crucial role in the optimal management of BPSD, which an expert consensus panel has described using the acronym DICE for describing the symptoms and context of the behaviors; investigating the contributing factors to the behaviors; creating a treatment plan, including both nonpharmacological management and—when necessary—pharmacological interventions to ameliorate acute risk of harm to caregivers or patients or should nonpharmacological interventions be ineffective; and evaluating whether the treatment plan has been effective and modifying the plan as appropriate (7).

The central ethical tension in any treatment intervention is that between the principles of beneficence (the relief of suffering, enhancement of quality of life, and harm reduction to self or others) and nonmaleficence (avoiding harm). This tension is particularly challenging with psychotropic medications (i.e., antipsychotics, antidepressants, mood stabilizers, or sedative-hypnotics) in persons with dementia, given this population’s unique vulnerability to medication side effects and adverse events as well as their eroding decisional capacity with cognitive decline. Although all psychopharmacologic agents are associated with potential side effects—even medications as generally benign as selective serotonin reuptake inhibitors (SSRIs)—some, such as antipsychotic medications, are considered particularly risky and are labeled as such with an FDA black-box warning that notes the increased risk of stroke and mortality associated with the use of antipsychotics in persons with dementia (10). Consequently, psychotropic medications are primarily used in this population when nonpharmacological interventions are ineffective in managing BPSD or when there is imminent risk of harm to the patient or caregivers. Even so, particular efforts should be taken not only to weigh the anticipated benefits of a psychotropic medication against the potential risks but also to conduct an optimal informed-consent process with the patient or surrogate decision maker.

One must not presume that patients in the mild or early to moderate stages of dementia, or even patients with delirium, completely lack treatment decision-making capacity; nonetheless, as cognitive impairment worsens, decisional capacity invariably wanes, eventually necessitating the use of a surrogate decision maker. Ideally, this surrogate decision maker would be the person who best understands the cognitively impaired individual’s clinical situation; most appreciates their life goals and values; and is, consequently, legally recognized by the cognitively impaired person—while they maintain the capacity to make such a decision—as their health care power of attorney. Absent such a formal designation, most states designate the next of kin as decision makers, using a hierarchy of relational proximity to the person in question: typically, the person’s spouse or domestic partner, then an adult child, a parent, a sibling, then other relatives or close friends.

Although one hopes that the decisions of the legally designated decision maker or closest next of kin accurately reflect not just the patient’s life goals and values but also the consensus views of the patient’s family and friends, sadly, this is not always the case. All too often—particularly with end-of-life decisions—disagreements may arise between family members and friends regarding the patient’s goals and values. Such challenges highlight the value of early diagnosis of progressive dementing illnesses, which, in turn, allow time for the frank and timely review of the patient’s life goals and values that is at the heart of ethically appropriate clinical care. Such a discussion is a crucial step in appropriately balancing the ethical principle of beneficence against nonmaleficence in a way that best reflects the patient’s goals and values and thereby respects, as best as possible, a patient’s autonomy in an illness that all too often ends in the loss of decisional capacity.

BF is a 33-year-old man with a history of schizoaffective disorder. He is in the psychiatric hospital for psychosis complicated by medical issues as well as an unusual response to antipsychotics, including an increase in his creatine kinase. He has had neuroleptic malignant syndrome on previous trials of antipsychotics. The inpatient psychiatrist considers a newer antipsychotic that BF has not yet tried, which has a unique mechanism of action. However, even with the manufacturer’s patient assistance program, the medication costs an amount that is not feasible for BF and his family to afford.

3.1 Is it ethically justifiable to prescribe this medication if we know that the patient will not be able to afford it going forward? Does it depend on how life saving or life changing the medication potentially is?

Of note, the psychiatrist thought of this medication because of visits from a pharmaceutical representative to his clinic. The representative gave him a psychiatric textbook, meals, and office supplies to learn more about the new medication.

3.2 When is it ethically appropriate for a physician to accept “gifts” from a pharmaceutical company?