Ethical Issues in Psychopharmacology

Psychopharmacology is the scientific study of the effect of medications on the mind and behavior. Many ethical issues arise within the broader realm of psychopharmacology, including the fair allocation of resources or the weighing of risks versus benefits in the prescribing of medications. The ethical psychiatric practitioner has the responsibility to know and continue to learn the latest empirical findings on psychopharmacologic and psychosocial treatments, including their indications, adverse effects, and contraindications (1–3).

In this article, ethical principles in psychopharmacology will be addressed. Ethical principles include the following:

•  Respect for persons: regard for an individual’s worth and dignity

•  Autonomy: self-governance

•  Beneficence: the responsibility to act in a way that seeks to  provide the greatest benefit

•  Fidelity: faithfulness to the interests of the patient

•  Nonmaleficence: the commitment to do no harm

•  Veracity: the duty of truth and honesty

•  Justice: the act of fair treatment, without prejudice

•  Privacy: protection of patients’ personal information

•  Integrity: honorable conduct within the profession

All psychiatrists commonly confront ethical dilemmas when considering psychopharmacologic indications, benefits, and risks, as well as those of alternative management strategies. To the experienced clinician, balancing these factors may come to feel like second nature, particularly when the treatment context includes a solid rapport with the patient. Furthermore, patients with intact cognition, insight, and judgment are typically able to engage meaningfully in shared decision making, which then unfolds naturally over the course of treatment. However, in many other cases, psychopharmacologic management raises a host of ethical issues with no easy or optimal solutions. Three cases, presented below, illustrate a few of these challenges.

Case 1

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.)

•  A. Elicit more detail from TL about her perspectives on her medications.

•  B. Discontinue the alprazolam and modafinil.

•  C. Ask TL to describe in more detail the benefits of each medication and for what specific symptoms they are being used.

•  D. Inquire about any side effects TL has experienced.

•  E. Discuss overall goals for treating anxiety and lack of energy besides the controlled substances of alprazolam and modafinil.

•  F. Check the controlled substance monitoring database in TL’s current state and also her previous state of residence, if possible.

•  G. Contact TL’s previous outpatient psychiatrist to discuss the details of her case.

•  H. All of the above.

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?

•  A. Find alternatives that are more affordable, such as using divalproex sodium delayed release, instead of the extended-release formulation, which is more expensive.

•  B. Recommend that the patient conduct a search of prescription savings programs to find medications at a lower cost, and even do the search together.

•  C. Manage medication changes over the phone or through electronic messages to help decrease the cost and frequency of office visits.

•  D. Fill out prior authorization forms for TL’s medications.

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?

•  A. Integrity and privacy

•  B. Justice and fidelity

•  C. Respect for persons and veracity

•  D. Autonomy and beneficence

Case 2

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.)

•  A. Attempt to persuade Mrs. R to agree to a trial of risperidone.

•  B. Ask Mrs. R to carefully observe and document the patient’s behaviors to identify potential triggers and unmet physical or emotional needs.

•  C. Prescribe short-acting benzodiazepines on an as-needed (prn) basis when Mr. R starts to get agitated.

•  D. Prescribe a trial of cannabis (e.g., edibles), presuming that the patient’s behavior is anxiety related.

•  E. Prescribe a trial of citalopram for agitation.

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.)

•  A. Report Mrs. R to Adult Protective Services for neglect of an older adult.

•  B. Strongly encourage Mrs. R to consent to the patient being hospitalized to comprehensively assess and address the behaviors.

•  C. Prescribe short-acting benzodiazepines on a prn basis when Mr. R starts to get agitated.

•  D. Advise Mrs. R that the patient requires a long-acting injectable antipsychotic.

•  E. Obtain an ethics consultation.

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?

•  A. Respect for persons, beneficence, and nonmaleficence

•  B. Nonmaleficence and beneficence

•  C. Fidelity and respect for persons

•  D. Justice and beneficence

Discussion of Case 2

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.

Case 3

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?

•  A. No. If the medication is beneficial to BF, it would be devastating to him and his family to not be able to continue receiving it because of its cost.

•  B. No. There is no guarantee that the medication would be helpful, and there is a large possibility that it may even be harmful, given BF’s past responses to antipsychotics.

•  C. Yes. The medication may become more affordable in the near future.

•  D. Yes. It is up to BF to decide whether he and his family want to pay for it or find another means in which to pay for it.

•  E. Any of the aforementioned responses may be justified.

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?

•  A. It is never appropriate for a physician to receive “gifts” (pens, meals, etc.) from pharmaceutical companies, as it will bias the treatment provided.

•  B. It is sometimes appropriate, as even though bias may be introduced (11), the physician may learn about the new treatments that could potentially be helpful to patients.

•  C. It is always appropriate, as this will help patients obtain the best medicine available by teaching physicians the most up-to-date pharmacotherapies.

Answers

• 1.1. A, C, D, E, F, and G are all appropriate responses. It would be inappropriate to discontinue the alprazolam and modafinil (choice B) without further information.

• 1.2. The most appropriate responses are A, B, and D. Choice C is incorrect, because it may be inappropriate to make medication changes via phone or messages because the patient may not be able to fully portray their symptoms or side effects through these modalities. For the most comprehensive care, it is best to see the patient in person, or at least through telemedicine, to be able to observe the patient’s grooming and hygiene, appearance, behavior, and affect and to assess the patient’s insight and judgment.

• 1.3. The best response is D. Autonomy (self-governance) and beneficence (the responsibility to act in a way that provides the greatest benefit) best describe the ethical principles involved. The other responses contain at least one principle that does not apply.

• 2.1. The best responses are B and E. Optimal management of a patient with behavioral and psychological symptoms of dementia (BPSD) has been described using the acronym DICE. This entails a comprehensive description of the behavioral changes associated with dementia; a careful investigation into the various factors that may be triggering a patient’s behavioral decline from their former baseline; creation of a treatment plan initially involving primarily nonpharmacological interventions but also potentially pharmacological treatment when clinically indicated; and, finally, evaluation and modification of the treatment plan based on its effectiveness. As depression is a common—but not always easily identified—driver of behavioral issues in dementia, and SSRIs are generally a low-risk and effective intervention in these cases (as found in the CITAD Study), an early trial of citalopram for BPSD is often indicated.

• 2.2. The best response is B. A comprehensive evaluation of the behavioral changes and identification of potential triggers is often best achieved during a psychiatric hospitalization, particularly when the behavioral issues are unmanageable in the home environment or potentially jeopardize the patient’s or caregiver’s safety. Although Mrs. R declined the initial treatment recommendations of providers, she did not demonstrate decisional incapacity in this decision and otherwise was meeting the basic needs of the patient and taking steps to ensure his safety; consequently, an Adult Protective Services report for neglect is unwarranted. Although prn use of benzodiazepines may be necessary at times for emergent management of behaviors that threaten the safety of the patient or care providers, they are best used in a structured, supervised setting, as the risks associated with these medications may outweigh benefits. Similarly, although antipsychotic medications may be necessary and effective as both prn and scheduled medications, they are best used in acute management of behaviors that jeopardize safety or limit necessary care, and attempts should be made to limit or discontinue medications once the crisis has resolved. Therefore use of long-acting injectable antipsychotic medications is rarely warranted.

• 2.3. The best response is A. The central ethical tensions in managing the behavioral and psychological symptoms of dementia are those arising among the principles of beneficence (improving patient quality of life, including advancing goals of safety and security in one’s surroundings), nonmaleficence (avoiding or minimizing actions that might cause harm to the patient or others), and respect for the patient’s autonomy, including in instances such as this one, protecting patients with diminished autonomy. Frank discussions with patients, families, and others involved in the patient’s care about this delicate, often difficult, ethical balancing act—including the acknowledgment that there are inherent risks and trade-offs in any decision—are best done as early as possible, while decisional capacity is still largely maintained. Despite the best efforts of clinicians, these discussions often are necessary later in the course of illness and, as this case illustrates, may be particularly challenging and complex at these later stages.

• 3.1. The best response is E. Any of the responses listed may be justifiable responses; there is no “correct” answer. This plays into the art of ethics itself, as one must weigh the risks and benefits of all possibilities for each case while simultaneously holding several potentially opposing solutions.

• 3.2. The best response is B. Although there are long-standing concerns about the potential effect of financial interests on medical decision making (12), the physician may also learn about new treatments and mechanisms of action that could be very helpful to patients.