Crossing the Blood-Brain Barrier: Integrating Scientific Innovation With Socio-Ethical Reflection in Predictive Medicine

As Littman and colleagues²⁷ have shown, the complexity of translational research in human subjects is overwhelming: production and validation of products of consistent safety, potency, and quality; the necessity to keep elaborate documentation of treatments to safeguard patient safety while protecting the right to privacy; the ancillary needs associated with the care of patients with severe conditions; and the cost of validating translatable biomarkers renders this discipline uniquely expensive. Therefore, advancing translational research requires new sources of funding and education. This could be achieved through public and congressional education by a joint coalition of patients' advocacy groups, academia, drug regulatory agencies, and industry.

Discoveries in biological psychiatry, and biosciences in general, occur in response to their social, economic, political, and cultural contexts.^28-33 Recognition of technical and biological complexities is crucial but not sufficient for efficient translation of scientific advances to clinically relevant and equitable treatment guidelines.

An anticipated difference of the future diagnostic tests from routine clinical chemistry (eg, complete blood counts) is that they will have to characterize several biological mechanisms and pathways in order to achieve a clinically acceptable level of predictive accuracy. These predictive tests in pharmacotherapy will comprise a battery of diagnostics (eg, looking at drug metabolism, transporters, receptors, and so forth) and will create several plausible drug response and toxicity trajectories for each patient. In this regard, a particular ethical concern is the anticipated proliferation in diagnostic patents and its impact on equitable access to new technologies and diagnostic tests. If each segment of this expanding sphere of patentable biological pathways is held by different individuals, researchers, or commercial firms, scientific advances in therapeutics can be impeded while creating hypercompetition and excessive fragmentation of the knowledge space.

Furthermore, most physicians currently receive little training in genetics, genetic counseling, or predictive medicine. The advent of predictive tests in pharmacotherapy will require physicians to familiarize themselves with genetic or proteomic influences on drug response, understand the use of genetic tests, and incorporate the results of predictive tests into their clinical decisions. Physicians will also need to obtain informed consent for such testing from patients and provide necessary counseling about their results.

Another ethical concern relates to the disclosure of undesirable or adverse effects of the drug to patients. It has been recommended that disclosing adverse events to patients be required when the adverse event has a perceptible effect on the patient but was not discussed in advance as a known risk; when it necessitates a change in the patient's care; potentially poses an important risk to the patient's future health, even if that risk is extremely small; or involves providing a treatment or procedure without the patient's consent.³⁴

From an ethical perspective, disclosure is required and should not be limited to cases in which the injury is obvious or severe. Disclosure of near misses is also discretionary but is advisable at times. In general, disclosure by a clinician involved in the patient's care is appropriate. Organizations should develop clear policies supporting disclosure and should create supportive environments that enable clinicians to meet their ethical obligations to disclose anticipated adverse drug-related events to patients and families. In fact, patients who do not respond well or suffer adverse reactions to drugs may not be adherent or their treatment outcome may be poor. This concern may be particularly important in relation to psychiatric disorders; patients may be confronted not only with the burden of stigma but also by being told that they cannot be effectively treated for it.

A major ethical issue is the extent to which individuals with severe psychiatric disorders are capable of providing informed consent, specifically whether they are able to understand the context and implications for new predictive tests or personalized treatments, what is exactly required of them, and why. A generally accepted model of practice is one that recognizes, caters to, and protects the individual's special needs and minimizes or eliminates any potential harm associated with the test or the treatment. Moreover, an ethical requirement is that the proposed test or treatment benefits the individual. In the interest of protecting patients, it has been suggested that a patient's guardian or substitute decision maker should not be approached out of convenience if the patient is likely to be competent to give consent once symptoms of their condition have been treated.³⁵ In the event that substituted consent is necessary, the patient's preference should be adhered to in selecting a proxy decision maker.

Patient privacy is another issue raised by the application of predictive testing for treatment response to psychotropic drugs. If appropriate safeguards are not in place to ensure patient privacy and confidentiality, patients may be subjected to stigma and discrimination, and may not accept the use of predictive testing in routine clinical practice. In some cases, a genetic variant that determines an individual's likelihood to respond to a drug may also indicate susceptibility to a disease that the drug is used to treat.³⁶ Under such circumstances, predictive testing for drug efficacy and safety should be treated with the same level of confidentiality and privacy as disease susceptibility testing or carrier testing results.

Finally, despite the projected clinical benefits of using genetic or other predictive tests for analyzing the response to psychotropic drugs, the results of such tests could determine eligibility criteria for insurance policies. Some patients may be viewed as large liabilities by insurance companies because their genotype indicates they will require the most expensive treatments for certain conditions, rather than because they have a high likelihood of falling ill. These concerns may not be as important if the tests indicate only the risk of an individual suffering an adverse reaction or of experiencing no therapeutic benefit. Hence, we suggest that awareness of biological complexities concerning the drug transporters as well as recognition of the socio-ethical context in which science, society, and clinical practice interact are essential to develop equitable diagnostic predictive tests for people who do not respond to conventional psychiatric therapy.