Ethical Issues in Emerging Treatments for Neuropsychiatric Disorders

Neuropsychiatric disorders are among the most disabling and treatment-refractory illnesses. They are often severe and chronic for patients and can impose significant burdens to caregivers and society. A third of patients with major depressive disorder, for example, fail to achieve remission after four successive treatment trials with a variety of antidepressants and psychotherapy (1). Moreover, patients who respond to secondary or tertiary treatment trials have higher rates of symptom relapse. Patients who experience such treatment-resistant major depressive disorder face higher rates of social and occupational impairment, other medical illness, and mortality (2–4).

Fortunately, a number of promising “emerging therapies” are currently under investigation. Although the term has no consensus definition, an emerging therapy may be described as any intervention for which there is preliminary, but inconclusive, evidence of clinical benefit for a specific disorder. Importantly, research on the therapy in relation to the disorder in question remains incomplete. Outstanding research may be needed to determine how to best deliver the therapy (i.e., dose, route, or frequency), whether its risks have been adequately identified, and whether the risks are tolerable and offset by the therapy’s clinical benefit. Implicit in the fact that the research is ongoing is the notion that the therapy is not generally considered the current standard of care (at least for the disorder in question). After all, emerging therapies that show early substantial benefit may subsequently lose favor for any number of reasons, including initial misattribution of positive effect, identification of adverse effects not identified from earlier studies, or discovery of other therapies with greater or equal benefit with lower risk burden.

The prospect that emerging therapies may lead to significant improvement, particularly for patients who have not derived benefit from existing treatments, can lead to considerable excitement. Such enthusiasm often leads to their availability in the community, even while research on their safety, tolerability, and efficacy continues. The accessibility of emerging therapies in the clinical practice realm raises several ethical questions.

This column examines some of these questions in the context of a fictional case involving a patient with treatment-refractory major depressive disorder considering intravenous ketamine. Ketamine is an N-methyl-d-aspartate receptor antagonist that has traditionally been used as an anesthetic. Over the past decade, subanesthetic doses of ketamine have shown great promise in providing antidepressive effects in patients with severe and treatment-refractory major depressive disorder. Moreover, unlike typical antidepressant medications, which tend to require weeks to months of treatment before symptom reduction, in research studies, ketamine has been found to yield symptom relief in hours to days. In light of these findings, the use of ketamine as an off-label treatment for major depressive disorder (among other mood disorders) has rapidly increased in recent years. Notwithstanding these promising data, a recent consensus statement published by the American Psychiatric Association notes that the current evidence base for ketamine as a treatment for major depressive disorder is based on relatively small sample sizes, with a lack of adequate data on the efficacy and safety of long-term ketamine administration (5).

Case Illustration

Margaret is a 34-year-old married female with recurrent and severe treatment-refractory major depressive disorder. She has been treated by her outpatient psychiatrist for the past four years. During that time, her psychiatrist prescribed her multiple antidepressant medications with little to no benefit. Last year, she received an acute course of electroconvulsive therapy (ECT). This led to an initial, modest improvement in her symptoms and functioning. Unfortunately, her condition has worsened over the past six months, despite receiving continuation ECT and ongoing antidepressant medication. Throughout this time, she has been engaged in weekly psychotherapy. When she presents for a follow-up appointment with her psychiatrist, she asks about intravenous ketamine after a friend with depression received it and told her it was “amazing.”

The Case Continues.

As her primary psychiatrist begins to explore this option with Margaret, she recounts with excitement an article she read that reported study participants experienced a “rapid” improvement in their depressive symptoms with “minimal side effects.” Her primary psychiatrist takes great care to educate her on the known risks of ketamine and the benefits that have been identified in published research.

The Case Continues.

After a discussion with her primary psychiatrist, Margaret elects to meet with another psychiatrist who provides ketamine infusions in an outpatient clinic setting. When she presents to the office for a consultation, the psychiatrist who runs the ketamine clinic begins to explain the procedure to her.

The Case Continues.

For the next two weeks, Margaret receives weekly ketamine infusions at the clinic. She experiences a substantial improvement in her mood and functioning. Given the limited benefit she has found from other therapies, she envisions that she would like to continue to receive ketamine on an ongoing basis. However, she begins to doubt whether she can afford to pay for it out of pocket. During a follow-up visit, she informs the psychiatrist of her improvement and then shares her concern about being able to cover the cost of subsequent infusions.

The Case Continues.

Shortly after Margaret begins ketamine treatment, the psychiatrist who runs the clinic learns of a newly published clinical trial on intravenous ketamine treatment for major depressive disorder from a colleague who read the article. The psychiatrist retrieves the article and puts reading it on his “to-do” list. Several weeks pass, however, and he has yet to read the article.

Answers

1. The answer is D. Although all of the options are ethically permissible, the ideal initial response would be to engage in a collaborative discussion that can help the patient more thoughtfully consider this treatment option. The long-standing nature of the treatment relationship suggests that she trusts that her psychiatrist will help her make a choice that is in her own best interest, consistent with the stage and severity of her illness and treatment options, and that is informed by the psychiatrist’s knowledge of a treatment about which she has limited knowledge. The process of shared decision making will allow her to voice her understanding and hopes for the treatment while providing an opportunity to educate her about the potential benefit and risks of ketamine, to clarify any misconceptions she may have, and to set realistic expectations for the outcome of this treatment. For an emerging therapy like ketamine, it is also important to share with her how much remains unknown about its long-term benefits and risks. Under a shared decision-making approach, rather than simply receiving a professional opinion about whether to try this treatment, she will be engaged in a discussion that can help her make a decision that is consistent with her own values, that is appropriate to her individual circumstances, and that is appropriate for her illness.

2. The answer is B. In the context of health care, decisional capacity has four general requirements: understanding, reasoning, appreciation, and choice. Having an understanding of the basic facts related to any treatment option (i.e., the nature of the treatment and its potential benefits, risks, and alternatives) is an essential requirement for sound decision making. Margaret’s understanding of ketamine as a treatment for major depressive disorder, however, appears to be quite limited. Therefore, the psychiatrist’s first concern should be whether she has an accurate understanding of this emerging therapy option. If not, the psychiatrist should provide psychoeducation in the areas in which she lacks information. Indeed, as part of any informed consent discussion, health care professionals have a duty to disclose such information. Reasoning, on the other hand, is demonstrated by the patient’s ability to weigh the information that has been disclosed; for example, to consider whether the potential benefits outweigh the risks of a given treatment option. Appreciation in the context of decisional capacity has to do with having insight into how the decision may personally affect someone given his or her individual symptoms and circumstances. Finally, a person must be able to express his or her own choice through some means of communication.

3. The answer is B. Margaret’s psychiatrist need not (and should not pretend to) have a comprehensive knowledge of ketamine or any other emerging therapy if it is not a treatment he offers in his practice. In other words, while all psychiatrists should engage in lifelong learning, they are not required to have expertise in emerging therapies that are not considered part of the community standard of care for treating neuropsychiatric disorders. Rather, they should maintain honesty and humility with patients regarding the extent of their knowledge and know when and how to refer a patient to someone who is better positioned to provide such information.

4. The answer is C. Much of the currently available information on the clinical use of ketamine is derived from research data, the collection of which is ongoing. As such, the generalizability of both the known benefits and risks of ketamine in patients with major depressive disorder is limited. As part of the informed consent discussion for ketamine treatment or any other emerging therapy, treatment providers must disclose that our understanding of the benefits and risks of ketamine is incomplete. Moreover, patients should also be aware that there may be other risks beyond those that have been found in early-phase research, which future research will reveal (6). Third, informed consent for the use of any emerging therapy must include disclosure that the treatment is not currently approved by the FDA. At present, there is considerable variability in both the route of administration and the dosage of ketamine being offered in clinics, and no current consensus for the route, dose, and frequency at which it should be delivered (7). For example, a recent survey of ketamine clinics found that 87.7% delivered treatment intravenously, whereas 22.8% gave oral ketamine, and 19.3% offered intranasal ketamine (8). Moreover, among clinics offering intravenous ketamine, infusion doses ranged from 0.5 mg/kg to 3.0 mg/kg (8). Having a patient selection protocol with clearly defined inclusion and exclusion parameters, although prudent for any clinic providing ketamine treatment, is not a required component of the informed consent process.

5. The answer is B. Because emerging therapies are rarely covered by health insurance, patients must typically pay for them out of pocket. Clinics that provide emerging treatments under a private-pay model should consider sliding-scale options to ensure fair access to patients.

6. The answer is A. In addition to the informed consent responsibilities described earlier, clinicians who provide such treatments assume additional requirements of staying intimately up to date on the emerging evidence regarding the treatments they offer. Although it is true that all clinicians need to keep informed of the evidence for treatments they prescribe, this task is complicated in the setting of emerging therapies where a single study could substantially change the state of knowledge regarding a particular treatment, either in favor or in opposition of its ongoing use. This means that this should alter not only the informed consent procedure for new patients but also the disclosure required for established patients. One might also consider whether there are requirements for contacting prior patients in instances when previously unknown risks are identified by new study data.