Will the Proteus sensor enhance adherence to aripiprazole or other antipsychotics?

KEYWORDS:

• Adherence
• schizophrenia
• antipsychotics
• Proteus
• aripiprazole
• sensor
• compliance

Schizophrenia is a devastating illness with high direct costs and even higher indirect costs related to unemployment and disability. Even though antipsychotics are the mainstay of treatment in patients with schizophrenia and are associated with a lower risk of relapse, almost 50–75% of patients are nonadherent with their antipsychotic medications [1,2]. Clinicians overestimate adherence in schizophrenia patients by a factor of at least three [3]. Currently available measurements of nonadherence are troublesome and very limited, since clinicians mostly depend on self-assessment/report by patients and partially objective measurements by practitioners. In the field of schizophrenia, simple pill counts, information and communication technology (ICT)-based prompting methods, such as short message services and emails, refill records, and electronic Medication Event Monitoring System on medication bottle caps have been tested for improvement of adherence but they were found to be limited in enhancing adherence in the treatment of patients with schizophrenia [4,5]. This is an important issue, as nonadherence can lead to poorer outcomes [6]; however, improving adherence may not necessarily improve outcomes in all cases [7].

The reasons for nonadherence include patient or illness-related factors, treatment-related factors or physician-related factors. Patient- or illness-related factors include lack of insight, the psychopathology, and comorbid substance abuse. Treatment-related factors include side effects, dosing frequency, and lack of effectiveness. Finally, physician-related factors include inadequate attention to adverse events and adherence, lack of a therapeutic alliance and inadequate follow-up with discharge planning [8–10].

Nonadherence can either be intentional (examples include nonadherence because of adverse effects or attitude toward the illness), which accounts for 70% of nonadherence, or unintentional (examples include lack of insight or ‘forgetting’ to take the medication), which represents 30% of nonadherence. Strategies to deal with the two types of nonadherence are very different, a distinction many clinicians and pharmaceutical companies do not appreciate. Most strategies to improve adherence focus on the latter rather than the former [10,11].

Even though nonadherence is associated with every single medical illness, the field has not made much progress in increasing the rate of adherence in schizophrenia over the last 50 years (perhaps with the exception of long-acting injectable antipsychotics). Some have argued that pharmaceutical companies have not done enough, as they do not build adherence into the long-term commercialization strategies. In addition, the pharmaceutical industry is sometimes seen as putting a focus on getting the drug approved and initially prescribed by the physician.

In order to improve the rates of adherence to treatments among psychiatric patients, we need to think of the patient as a person who exists, not just in the healthcare system, but also in our wider society. We have to empower patients to become more engaged, to make their own choices, and to be an active partner in their care. Clinicians are trained to provide solutions for nonadherence without involving the patients in the solution [11]. For example rather than tell the patient at each visit that they should take the medications as prescribed, the clinicians could ask the patient about strategies that they personally find helpful to remind them to take their medications. Clinicians will be surprised to learn that individual patients have very different strategies.

Strategies to improve adherence include selecting the most effective antipsychotic and dose for the patient, with good tolerability to boot. There is a misconception among clinicians that all antipsychotics are created equal in the treatment of schizophrenia. Several meta-analysis have shown that not to be true [12]. Clinicians should follow well established guidelines like NICE or Florida Medicaid guidelines. Clozapine is also a very effective treatment that is under-utilized in the United States and many parts of the world in treatment-resistant schizophrenia. Similarly, the tolerability of the antipsychotics, including the atypicals, varies considerably. Certain side effects such as weight gain, extrapyramidal symptoms, including akathisia, sedation, and metabolic disturbances, are the most likely causes of nonadherence [13]. Therefore, the choice of atypical antipsychotic is extremely important, as the wrong choice can lead to frequent unnecessary switching and irrational polypharmacy in clinical practice [14].

Long-acting injectable antipsychotic medications can also be used to improve adherence in patients with schizophrenia even though there is considerable controversy in recent years regarding their superiority relative to oral atypical antipsychotics, particularly when you control for frequency of visits, time spent with the patient, and psychoeducation about adherence [15,16]. Addressing comorbid substance abuse is also extremely important to improve adherence. This can be done by psychosocial interventions like motivational enhancement and behavioral therapies. Finally, psychoeducational programs, including addressing negative attitudes toward the illness, assertive community treatment and intensive case management, as additions to medications, can decrease nonadherence, relapse and rehospitalization [17–21]. Innovative programs like Fountain House need to be widely disseminated and supported.

What else can clinicians do to improve adherence in patients with schizophrenia? One of the most important rate limiting steps to improving adherence is the health literacy of psychiatric patients, particularly those with schizophrenia. Because of the negative symptoms and cognitive dysfunction [22], which are an integral part of illnesses like schizophrenia, patients have a wide range of health literacy in understanding even simple instructions provided by the clinician. Unfortunately, patient programs believe in a one size fits all model with undesirable consequences. Pharmaceutical companies need to do a better job educating clinicians around the issues of adherence. Moreover, it is important to wrap the medication and the adherence program together, which may also provide value-added services to the prescribing clinician.

In recent years, bioelectronic medicine has raised the prospect of using implants to treat chronic conditions like diabetes mellitus without the need for pills or injections. In psychiatric illnesses, like schizophrenia, such advances are in the distant horizon [23,24].

We need to fundamentally reframe what adherence means to our psychiatric patients. The language around adherence has had negative connotations and we need to ask ourselves the fundamental question, can we make taking medicines not a negative experience? [25] Examples of positive medication experiences include using video games to encourage diabetic children to take regular blood tests, and use of cartoons and personalization to approach cognitive behavior therapy (CBT). Can we do the same for patients with psychiatric illnesses?

Recently, the digital medicine system (DMS), a novel drug-device combination, has been studied in schizophrenia to capture medication ingestion. The DMS consists of medication embedded with an ingestible sensor, a wearable sensor (being attached on left costal area on patient’s body), and software applications (mobile computing devices). After ingestion of the medication, the sensor embedded in medication is automatically activated in stomach and then a signal containing adherence-related information is transmitted to a secure cloud-based server via communication between the wearable sensor and the mobile application. Therefore, usage of the DMS is not applicable to all patients with schizophrenia, since they present with different levels of illness insight, psychotic symptoms in terms of delusions or hallucinations, cognitive decline, and functional impairments, all of which may substantially impact such integrated and complex ICT-based methods to enhance adherence in routine practice. In a study by Peter-Strickland et al., 67 patients with schizophrenia took aripiprazole embedded with the Proteus sensor. Seventy-three percent of patients completed the 8-week study. Seventy percent of the patients found it at least somewhat satisfying [26]. However, the patients included in the study clearly failed to represent ordinary patients with schizophrenia, those who we meet in daily clinical practice since they were all a stable population with mild intensity of psychotic symptoms as measured by Clinical Global Impression-Severity scale (CGI-S). The study outcome rather begs the question – what does DMS have to offer as a tool to improve adherence in patients with schizophrenia in a routine busy clinical practice?

Patients with schizophrenia have delusions and hallucinations as an integral part of the illness. How does the clinician convince the paranoid patient that the DMS system is not monitoring his thoughts, actions, and life in general? What about privacy issues around the collection and storage of personal health data on smart devices? Is a study of 67 self-selected patients who volunteer for a clinical trial, an adequate representation of what happens in the real world?

As described earlier, given the time intensive nature of the DMS, and the fact that all it is able to do is identify nonadherent patients, it does not appear to be a good use of the busy clinicians’ time. This technology in no way provides a differential diagnosis of nonadherence that we discussed or treatment thereof. It would be far more productive for a clinician to spend a few minutes routinely inquiring about non-adherence in all their patients including doing a plasma level when indicated.

There are still many unmet needs in the treatment of schizophrenia, including lack of access to inpatient care, acute shortage of psychiatrists, particularly those who treat schizophrenia, and lack of access to proven psychotherapies and psychoeducation. Treatment today consists of 5-min medication checks with busy psychiatrists, or nurse practitioners who are replacing psychiatrists in many settings. Companies should allocate their resources to improve the quality of life in patients with schizophrenia by developing truly innovative medications rather than just a generic pill embedded with a sensor.

Declaration of interest

P. Masand has acted as a consultant for Allergan, Lundbeck, Merck, Otsuka, Pfizer, Sunovion, Takeda; has received research support from Allergan and Merck; discloses speaker’s bureau from Allergan, Lundbeck, Merck, Otsuka, Pfizer, Sunovion, and Takeda; and discloses stock ownership in Global Medical Education. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Additional information

Funding

This paper was not funded.