How Neuroscience Is Informing Treatments: Ethical Issues

Psychiatry is a rapidly evolving field, the last in medicine to develop an understanding of the pathophysiology of its disorders. However, psychiatry is now more firmly embracing calls to view itself as a clinical neuroscience discipline (1, 2). In the past, it has been difficult to fully assess the etiology and pathophysiology of psychiatric disorders; thus, psychiatric treatments have been based on an empirical accumulation of outcomes data. With evolving imaging and molecular techniques, neuroscientists are developing a detailed knowledge base of psychiatric pathophysiology. As this occurs, the lines blur between neurology, neuropsychiatry, and psychiatry. The history of psychiatry provides several examples of how a deeper understanding of pathophysiology has resulted in disorders moving from the “psychiatric” realm (e.g., “general paresis of the insane” or “the sacred disease”) to the “neurologic” realm (e.g., tertiary syphilis and epilepsy, respectively). Disorders that, until recently, would often have been categorized as idiopathic psychiatric conditions are now known by such mechanistic names as anti-NMDA (N-methyl-d-aspartate) receptor (aNMDAR) encephalitis or 22q11.2 deletion syndrome.

A more thorough understanding of pathophysiology allows for the development of more precise treatments. Most psychiatric medications were found serendipitously while researchers explored antitubercular agents (monoamine oxidase inhibitors) (3) or anesthetics (chlorpromazine and its derivatives, which include antipsychotics and most antidepressant medications) (4). However, psychiatrists are now using treatments designed to intervene directly on neural circuits (e.g., repetitive transcranial magnetic stimulation, deep brain stimulation). Additionally, new neurotransmitter targets (e.g., glutamate, orexin) are being explored, and long-known effective psychiatric treatments, such as electroconvulsive therapy (ECT), are having their neurobiological mechanisms understood (5).

Historically, medical research and the practice of psychiatry has been punctuated with ethically problematic practices, many involving the lack of informed consent and respect for autonomy. Some of these include the “warehousing” of psychiatric patients in asylums and experiments conducted by Nazis during World War II (e.g., hypothermia experiments, forced sterilizations) (6). In response to these incidents, governments and human rights organizations codified a set of medical ethics for research and practice through the Nuremberg Code and Declaration of Geneva, established after World War II in 1947 and 1948, respectively; the Declaration of Helsinki in 1964; and the Belmont Report, established in 1979 (7–9). These put emphasis on informed consent and formalized the four major rules of medical ethics that physicians and scientists accept today: autonomy (including the necessity for informed consent), nonmaleficence, beneficence, and justice. Autonomy and informed consent bring up specific challenges in the practice of psychiatry and neurology, as patients often have impaired reasoning as a symptom of their illnesses (10).

In the context of expanding knowledge, psychiatrists’ identities are evolving. The need to discuss neuroscience and pathophysiology in clinical encounters is growing (11, 12). Here, we explore, through case examples, some ethical issues brought on by this new era of psychiatric practice.

Case 1

Jane Doe is a 22-year-old woman brought to the emergency department by police after having been found wandering on the streets in the winter in Chicago. She is underdressed for the weather, wearing only an oversized t-shirt and undergarments. She is internally preoccupied, mumbling to herself and laughing, and religiously preoccupied, which she expresses through her belief that the physician is an angel. Her thought process is tangential with loosening of associations. The emergency room physician has difficulty obtaining a coherent history. Jane has no identification and is unable to provide her name, date of birth, and contact phone numbers. The emergency department physician suspects schizophrenia. Objectively, she is in sinus tachycardia, with an otherwise unremarkable physical examination, basic metabolic panel, complete blood count, urinalysis, and urine toxicology screen. She is transferred to the inpatient psychiatry unit involuntarily for further management.

The psychiatrist’s initial evaluation reveals a neurologic exam remarkable for psychomotor agitation and symmetric hyperreflexia. Cognitive testing reveals deficits in visuospatial reasoning and executive function, attention, memory, language, and abstraction. More comprehensive laboratory tests for contributory metabolic derangements do not reveal any abnormalities. Because her presentation is atypical for a primary psychotic illness (e.g., unclear acuity of onset, disorientation, and cognitive impairment), the psychiatrist decides that further workup is necessary and plans to obtain cerebrospinal fluid (CSF) to look for infectious or autoimmune etiologies, as well as magnetic resonance imaging (MRI) of the brain to look for structural abnormalities. The psychiatrist evaluates Jane’s decision-making capacity to consent to these tests and determines that she does not demonstrate adequate capacity to make these decisions. Nevertheless, the psychiatrist decides to proceed with the lumbar puncture and MRI.

• 1.1 With limited history available from the patient and no collateral information available, which principle guides the psychiatrist in proceeding with more invasive workup over accepting a diagnosis of an idiopathic psychotic disorder?

  1. Beneficence

  2. Justice

  3. Autonomy

  4. Veracity

  5. A and B

• 1.2 Which ethical principle has the psychiatrist determined is of secondary importance in this situation?

  1. Nonmaleficence

  2. Veracity

  3. Autonomy

  4. Justice

Two days later, a missing person’s report identifies the patient, and the psychiatrist contacts the family. The family provides a history of acute onset of psychotic symptoms that occurred 3 months ago while Jane was in college. Jane has had a decline in cognitive functioning and worsening psychosis over the past 3 months. She has not adhered to medications and has left her family home repeatedly without telling anyone for multiple days at a time. This was the first time that she did not return. On the unit, she continues to refuse pharmacologic intervention and does not have insight into her inability to care for herself, including the potential danger to her life from being outside for extended periods of time without proper clothing in below-freezing temperatures. The psychiatrist decides, with the support of Jane’s family, to move forward with the process of requesting court-ordered treatment.

• 1.3 Which ethical principles did the psychiatrist consider in the decision to pursue court-ordered treatment?

  1. Respect for law and beneficence

  2. Veracity and nonmaleficence

  3. Autonomy and justice

  4. Respect for law and confidentiality

Jane’s workup comes back positive for aNMDAR antibodies in the CSF. In aNMDAR encephalitis, autoantibodies develop against NMDA receptors in the brain, often because of germ cell tumors, and cause a heterogenous syndrome that includes affective, motor, behavioral, and neurologic symptoms. Diagnosis is difficult because of the possibility of various presentations that include catatonia, psychosis, amnesia, dyskinesias, and seizures. When it was first identified, it was shown to have a 75% recovery rate with immunotherapy and a 25% mortality or severe disability rate (13), underscoring the importance of accurate diagnosis.

Jane is transferred to the neurology inpatient service, with the psychiatry consult service collaborating in treatment planning. She receives immunomodulatory treatment that includes steroids, intravenous immunoglobulin therapy, and plasmapheresis. Her psychosis resolves, and her cognition improves enough for her to be discharged. With ongoing follow-up as an outpatient, she shows continued improvement and is able to return to school 6 months after initiating therapy.

Case 2

Bill, a 50-year-old man with major depressive disorder (MDD) and stable idiopathic chronic kidney disease (CKD) presents to the outpatient clinic. He has a 10-year history of MDD with nine near-lethal suicide attempts via overdose. He has had full trials of medications in every class of antidepressant and is actively engaged in psychotherapy with continued decompensations. Currently, his mood is “down,” his affect is dysphoric, and he is having thoughts of being better off dead. The psychiatrist considers the treatment options, including augmenting treatment, switching to a monoamine oxidase inhibitor, ECT, or some combination of these. Because of Bill’s history of past suicide attempts, the severity of the current depressive episode, his significant hopelessness, the availability of medications to use in overdose, his inability to identify reasons for living, poor support network, and no engagement in work, he and the psychiatrist discuss the acute risk of suicide (14). Lithium, because of evidence that it reduces suicide risk (15), and ECT, which would more likely target mood symptoms quickly, are under consideration. Bill seems wary of ECT, so the psychiatrist decides to use lithium, despite the risk of renal toxicity in the context of CKD. Bill agrees to this course of treatment, with a plan to closely monitor his kidney function.

• 2.1 Which of the following ethical principles were involved in this decision-making process?

  1. Nonmaleficence

  2. Veracity

  3. Autonomy

  4. All of the above

After several months, despite augmentation with lithium dosed at a therapeutic blood level, Bill continues to decompensate. He spends most of his days in bed and thinks about suicide daily. Although he normally dresses impeccably, he starts coming to appointments disheveled. The psychiatrist reinitiates a discussion of treatment options, including ECT. Bill wonders whether anything will ever help him feel better and worries aloud whether there is “any point in trying.” In this discussion, he also brings up worries about “electroshock” therapy and whether it will be painful or make him “like a zombie.”

• 2.2 His severely depressed mood, hopelessness, and dysphoric affect cause the psychiatrist concern about the influence of Bill’s depression on his decision to agree to treatment. Which ethical principles should be considered when evaluating whether a patient in the midst of a depressive episode has the capacity to make a decision about treatment?

  1. Autonomy and beneficence

  2. Nonmaleficence and beneficence

  3. Justice and veracity

  4. Confidentiality and respect for law

Bill goes home to consider the option of ECT and discuss it with his family. He returns seeming more dejected. When he discussed ECT with his sister, she asked incredulously, “They still do that?” and went on to explain her disgust at the proposal of such “barbaric” treatment, likening it to a lobotomy and worrying about the possibility of brain damage. Bill expresses worry after his sister’s reaction and asks the psychiatrist, “Do you really want me to do this treatment?” The psychiatrist initiates a discussion about these worries, including a discussion of response rates; side effects, including physical and cognitive effects; and an understanding of what is known about the biological mechanisms of ECT’s efficacy. In particular, the psychiatrist highlights that the notion of ECT causing brain damage is a myth, with no scientific evidence to support it (16). Recent studies show the opposite: that ECT is associated with increases in brain volume in regions such as the hippocampus and with increased integrity of connections between brain region (17). The psychiatrist asks Bill what his thoughts are at this point and what questions he has. Bill explains that his concerns were addressed but that although he does not feel especially hopeful, he is willing to participate in the treatment if the psychiatrist feels that it is appropriate. The psychiatrist is somewhat concerned about this final statement and ultimately explains that, on the basis of Bill’s unresponsiveness to pharmacologic intervention, Bill’s suicide risk, and what we know about the efficacy of ECT, the potential benefits of ECT outweigh the risks. Given this, it is up to Bill to make the decision as to whether to proceed with treatment, and he should know that he could terminate treatment if he should decide that he no longer wants to participate.

• 2.3 What ethical principles guided the psychiatrist to discuss known neuroscience evidence and include a discussion of the risks and benefits?

  1. Beneficence

  2. Nonmaleficence

  3. Autonomy

  4. Veracity

  5. All of the above

• 2.4 What ethical concerns remain on the basis of the patient’s last statement about being willing if the psychiatrist thinks it’s best?

  1. Questionable voluntariness

  2. Lack of capacity to make a medical decision

  3. Lack of informed consent

  4. All of the above

• 2.5 What topics that were discussed satisfied the requirement for informed consent?

  1. Patient’s current diagnosis and risk of forgoing treatment

  2. Outcome statistics

  3. Mechanism of action of ECT

  4. Possible adverse side effects and ways to address adverse events

  5. All of the above

Bill received eight treatments of ECT, for three days a week, and showed marked improvement in mood and reduction in suicidality. He experienced postictal agitation that was treated with benzodiazepines, which resolved before discharge, and posttreatment nausea that was addressed with prophylactic ondansetron on subsequent treatments. Mild memory deficits were present for three weeks after termination of treatment and then completely resolved.

• 2.6 Given its higher efficacy over pharmacologic interventions, which ethical principles could be used to argue for using ECT earlier in treatment?

  1. Justice

  2. Veracity

  3. Autonomy

  4. Beneficence

  5. B and D

Answers

1.1. The answer is E. Both beneficence and justice take precedence here. Beneficence refers to the ethical principle of acting in the patient’s best interest (18). When a patient is in an altered mental state, an accurate diagnosis takes precedence, as general medical and neurologic etiologies in the differential diagnosis lead to very different treatment plans and outcomes. For Jane, a premature diagnosis of an idiopathic psychotic disorder would likely trigger a set of pharmacologic interventions that have serious long-term side effects, and such a label may decrease the likelihood of her receiving a workup on subsequent presentations. Additionally, there is evidence to suggest that antipsychotic medications are particularly poorly tolerated in the aNMDAR syndrome, with a high likelihood of precipitating the neuroleptic malignant syndrome/malignant catatonia (19). As described earlier, aNMDAR encephalitis has a 75% recovery rate when treated with immunotherapy (13). In pursuing a workup targeted toward the differential diagnostic possibilities, the psychiatrist served Jane’s best interest, and Jane had a complete recovery.

Justice refers to fairness in the distribution of benefits and burdens of treatment. If the psychiatrist decides to terminate workup and accept an idiopathic psychiatric diagnosis, he or she is arguably acting in a discriminatory way against patients whose neurologic disorders are presenting with psychotic and behavioral symptoms rather than purely cognitive ones (e.g., decreased level of consciousness or coma). All patients deserve a reasonable workup, and as the experts in abnormal behavior, psychiatrists must be aware of medical and neurologic syndromes that present behaviorally.

1.2. The answer is C. Physicians respect autonomy by taking into consideration their patients’ values in decision making. When patients are too ill to communicate, understand, or reason through a given decision, physicians work under the premise that the patient needs and wants help (20). In this case, the psychiatrist determined that Jane does not demonstrate the capacity to make a decision regarding her workup, and her autonomy is considered secondary to the principles of beneficence and justice, discussed earlier.

1.3. The answer is A. The psychiatrist worked within the principles of respect for law and beneficence. As discussed earlier, the principle of beneficence guides the psychiatrist in pursuing emergent workup and determining proper diagnosis. The psychiatrist determines that it is in the best interest of the patient to initiate treatment; however, the patient’s refusal complicates matters. Legally, the psychiatrist is bound by laws founded in the principles of autonomy that mandate consent for the administration of psychiatric medications outside situations that bring about imminent concern for safety. To satisfy the respect for law and the principle of beneficence, the psychiatrist must proceed with obtaining court-ordered treatment. Once testing clarifies the diagnosis of aNMDAR encephalitis, and the patient is transferred to inpatient neurology, the strict nature of laws governing patient consent loosens, and the family can act as a surrogate decision maker to consent to her immunomodulating treatment. This case highlights the tension between laws governing medical versus psychiatric encounters. As neuroscience progresses and the understanding of mental illness becomes rooted in neuropathophysiology, the difference in the inability to consent because of severe depression (currently the subject of mental health codes) and the inability to consent because of seizures or coma (currently the subject of medical surrogacy acts) becomes increasingly artificial and arbitrary. Further legal commentary is beyond the scope of this article but has been discussed elsewhere (21, 22).

2.1. The answer is D. The principle of veracity is used in the discussion of both the patient’s risk factors (i.e., his high risk of suicide) and the risks and benefits of the various treatment options (e.g., evidence that lithium reduces suicide risk [15] and potential for renal toxicity with its use). The psychiatrist respects Bill’s autonomy in pursuing lithium as a course of treatment. The principles of nonmaleficence and beneficence are in tension as the psychiatrist weighs and advises on the risks and benefits of using lithium when Bill has CKD. The psychiatrist determines that the potential benefit from using lithium in mitigating suicide risk and improving affective symptoms outweighs the potential harm of renal toxicity. In the spirit of nonmaleficence, the psychiatrist will closely monitor kidney function and serum lithium levels and adjust treatment accordingly.

2.2. The answer is A. The psychiatrist’s beneficent intent is potentially at odds with Bill’s autonomy. This issue of autonomy versus beneficence in psychiatry is especially poignant given the disruption in cognition and sense of self due to illnesses involving the central nervous system. Capacity is a fluid ability that changes based on the question, the circumstances, and the ability of the patient to understand and manipulate necessary information (23). Disruption in cognition and mood can affect these abilities. The question of informed consent in patients with mental illness has been empirically evaluated in numerous studies. Overall, these studies have shown that, although patients with mental illness tend to have more difficulty with decision making for treatment, the majority maintain the capacity to make treatment decisions (7, 24–27). Alternatively, some have questioned the ideal of truly informed consent, on the basis of numerous situational, psychological, and neuropsychiatric factors that can influence rational decision making (28). Bill’s depression and associated distorted negative thoughts and hopelessness are likely influencing his treatment decisions, causing the psychiatrist to question capacity and, therefore, autonomy. At this point, it becomes the psychiatrist’s ethical duty to adequately address the concerns about influence in decision making and to adequately convey information to establish informed consent (7, 28).

2.3. The answer is E. Bill’s hopelessness is compounded by his stigmatized beliefs surrounding ECT and influence from his family. The principle of veracity guides the psychiatrist in addressing his beliefs with available evidence. Subjective beliefs can be a powerful driving force in terms of medical decision making and may supersede objective information provided during the process of informed consent (7). This underscores the importance addressing these beliefs in a respectful and objective way. Bill’s adequate understanding of available treatments, outcomes, and risks is paramount to his autonomy to make an informed decision. On the basis of the available evidence and risk–benefit analysis of this case, ECT is the treatment choice that the psychiatrist believes will provide the most benefit and mitigate the most risk, satisfying the psychiatrist’s duty of beneficence and nonmaleficence.

2.4. The answer is D. The psychiatrist worries that the question, “Do you really want me to do this treatment?” reflects Bill’s hopelessness and that he is not fully participating in the decision-making process, again calling into question his capacity to make this treatment decision and, therefore, his ability to provide informed consent. An important component of informed consent is the concept of voluntariness, or an individual’s ability to act in accordance with an authentic sense of self and freedom from undue influence (29, 30). Bill is asking the psychiatrist to make the treatment decision. His question also implies a desire to satisfy the provider and potentially reflects feelings of obligation to the psychiatrist. These subtleties in communication represent a form of professional influence from the psychiatrist. In physician–patient communication, there can be hidden, sometimes unintended, messages from providers to patients that influence what information they share; what questions they ask (31); and, ultimately, what decisions they make. Bill may interpret the way the psychiatrist discusses the efficacy of ECT and the act of promoting it as a primary treatment choice as the psychiatrist’s personal preference. In doing so, Bill may feel that he has to agree or risk disappointing the psychiatrist. This presents a complication in the ethical obligation to satisfy the principle of veracity and provide information and evidence. It may not be possible to completely separate the physician’s beliefs about a treatment from objective evidence. Nevertheless, the psychiatrist should be aware of this complication in the process of gathering informed consent. Additionally, steps to counteract this potential bias—e.g., involving another party, such as a nurse—could reduce the risk of unintended influence from a physician who may be invested in the intervention (32).

2.5. The answer is E. All of the aforementioned topics are important factors in making an informed decision. As outlined by the generally accepted standards of assessing capacity, the patient should be able to make a choice voluntarily; express reasons for that choice; and understand the relevant information, including potential outcomes and consequences of each option (23). Bill should understand his diagnosis of depression, the potential risk of suicide, and the treatment options available, as well as expected outcomes both without treatment and with the proposed treatments. There is some debate about the role for explanations of mechanisms of action in the process of obtaining informed consent; however, in this case, incorrect, stigmatizing notions about brain damage may interfere with the patient’s ability to make a fully informed, rational decision and may need to be addressed for an informed decision to be possible.

2.6. The answer is E. In this case, it may actually be a violation of the principle of beneficence that the psychiatrist opted to proceed with another medication trial when medications have been ineffective to date and there is a more effective treatment option available. As discussed earlier, the psychiatrist was respecting the patient’s preference and autonomy. The psychiatrist partially fulfilled the ethical obligation to the principle of veracity at the initial encounter by presenting ECT as an option. However, the extent of Bill’s stigmatized beliefs and hopelessness was not initially apparent, and it later became clear that Bill was working with erroneous information about ECT. The psychiatrist could have been more direct in asking about these potential barriers in the informed consent process to ensure that Bill had the appropriate information to make an informed decision earlier and, thus, fulfill the duty of beneficence and veracity.