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Background Nonadherence to medication compromises the effectiveness of psychiatric treatments in patients with serious mental illness (SMI). A newly developed digital medicine system (DMS) offers an opportunity to objectively assess and report patient medication adherence. DMS includes a wearable sensor that receives a data signal from a medication tablet with an embedded ingestible sensor after ingestion of the medication and transmits that data to the patient's mobile device to display health care information for the patient and treatment team. Methods/results Development of a DMS requires a program that investigates safety, tolerability, and usability of the system in patients with SMI. It necessitates rapid design adaptation of the individual components and the integrated system and human factors studies with the intended users. This article describes the program's methodology and shows results from 3 early studies, conducted in 2013 and 2014, to illustrate diversity of the programs' methodology. First, a standard 28-day study showed minimal skin irritation and demonstrated acceptable wearability of the wearable sensor. Second, a 16-week study provided usability feedback from patients with SMI and caregivers to improve the mobile application. Third, end-to-end bench-level integrated system testing led to multiple substudies of a master protocol (ClinicalTrials.gov identifier: NCT02091882) to investigate various aspects of the system (eg, ingestible sensor detection and latency). Conclusions To develop a DMS in psychiatry, the system's multiple components must be considered simultaneously using various methodologies. A focus on usability, along with agile evaluation and feedback across studies, provides an optimal strategy for ensuring patient acceptance and successful regulatory review.

BACKGROUND A digital medicine system (DMS) has been developed to measure and report adherence to an atypical antipsychotic, aripiprazole, in psychiatric patients. The DMS consists of 3 components: ingestible sensor embedded in a medication tablet, wearable sensor, and secure mobile and cloud-based applications. An umbrella study protocol was designed to rapidly assess the technical performance and safety of the DMS in multiple substudies to guide the technology development. METHODS Two sequential substudies enrolled 30 and 29 healthy volunteers between March-April 2014 and February-March 2015, respectively, to assess detection accuracy of the ingestible sensor by the DMS and the latency period between ingestion and detection of the ingestion by the wearable sensor or the cloud-based server. RESULTS The first substudy identified areas for improvement using early versions of the wearable sensor and the mobile application. The second substudy tested updated versions of the components and showed an overall ingestion detection rate of 96.6%. Mean latency times for the signal transmission were 1.1-1.3 minutes (from ingestion to the wearable sensor detection) and 6.2-10.3 minutes (from the wearable sensor detection to the server detection). Half of transmissions were completed in < 2 minutes, and ~90% of ingestions were registered by the smartphone within 30 minutes of ingestion. No serious adverse events, discontinuations, or clinically significant laboratory/vital signs findings were reported. CONCLUSIONS The DMS implementing modified versions of the smartphone application and the wearable sensor has the technical capability to detect and report tablet ingestion with high accuracy and acceptable latency time. TRIAL REGISTRATION ClinicalTrials.gov identifier: NCT02091882.

To evaluate aripiprazole once-monthly (AOM), a long-acting injectable suspension of aripiprazole, as acute treatment in patients with schizophrenia (DSM-IV-TR).Adults experiencing an acute psychotic episode were randomized to 12 weeks of double-blind treatment with AOM 400 mg or placebo (October 2012-August 2013). The primary efficacy outcome was change from baseline to endpoint (week 10) in Positive and Negative Syndrome Scale (PANSS) total score. The key secondary efficacy outcome was change from baseline in Clinical Global Impressions-Severity of Illness scale (CGI-S) score. Secondary efficacy outcomes included change from baseline in PANSS positive and negative subscale and Personal and Social Performance Scale (PSP) scores. The study took place from October 2012 through August 2013.Patients (N = 340; 79% male, 66% black) were randomized to AOM (n = 168) or placebo (n = 172). Least squares (LS) mean change from baseline to endpoint (week 10) favored AOM versus placebo in PANSS total (treatment difference, -15.1 [95% CI, -19.4 to -10.8]; P.0001) and CGI-S (treatment difference, -0.8 [95% CI, -1.1 to -0.6]; P.0001) scores, as it did at all other timepoints through 12 weeks (all P ≤ .0005). LS mean change from baseline in PANSS positive and negative subscale and PSP scores favored AOM versus placebo (P.0001). Common (10%) treatment-emergent adverse events (AOM vs. placebo) were increased weight (16.8% vs 7.0%), headache (14.4% vs. 16.3%), and akathisia (11.4% vs 3.5%).Symptoms and functioning improved with AOM 400 mg versus placebo in patients with acute schizophrenia, with acceptable safety and tolerability. These data suggest that AOM 400 mg is a viable treatment option for patients experiencing an acute schizophrenia episode.ClinicalTrials.gov identifier: NCT01663532.