A pinboard by
Thomas Winkler

Postdoctoral Fellow, KTH Royal Institiute of Technology


Development of a BioMEMS device to assist in schizophrenia treatment planning and monitoring

Clozapine is an antipsychotic drug, and it’s the most effective one available for treating schizophrenia. An estimated 50 million people worldwide struggle with this complex and challenging mental disorder. Its defining feature is psychosis, or being out of touch with reality. Without medication, delusions and hallucinations are common symptoms. For the famous case of the late Nobel Laureate John Nash, this was memorably depicted in the Academy Award-winning movie “A Beautiful Mind”.

Unfortunately, the highly effective clozapine is only prescribed to a very small fraction of patients, largely because of the burden to both patients and doctors from the current monitoring cycle. Specifically, the doctor needs to check two things, initially on a weekly basis: First, the patient’s white blood cell counts, to prevent a rare side effect that would leave the patient at a high risk of infection. Second, how much of the drug is in the patient’s blood – that way, the doctor can adjust the dosage to the optimum level, and also ensure the patient is actually taking the drug.

The goal of my research is to greatly simplify the current monitoring cycle by developing a device for rapid testing with only a single drop of blood. The concept is somewhat akin to the glucometers used in diabetes management. Specifically, I have developed new types of sensors that can measure the drug level and count white blood cells without relying on bulky and expensive equipment. Working with my clinical team, I have tested actual patient blood samples for clozapine, and the results from my sensor match those from a certified clinical lab.

I am integrating these sensors in a small chip; put together with some electronics, pumps, and batteries, the device could be made available to patients at the pharmacy, eventually even at home. This allows for a simplified, more convenient monitoring cycle to ensure treatment efficacy, safety, and adherence. As a result of my research, many more patients could benefit from clozapine’s effectiveness, allowing them something most of us take for granted – perceiving the world as it is. And lastly, the success of this device could inspire many more researchers to finally bring medical device technology into the much neglected field of mental health management.


Blood Draw Barriers for Treatment with Clozapine and Development of Point-of-Care Monitoring Device.

Abstract: Clozapine is the most effective antipsychotic drug for schizophrenia treatment, however it is currently underused. In order to understand the barriers of frequent blood draws for white blood cell counts (WBCs) and clozapine levels, we developed a psychiatrist survey and began and integrative approach of designing a point-of-care device that could eventually have real-time monitoring with immediate results.We ascertained barriers related to clozapine management and the acceptance of possible solutions by sending an anonymous survey to physicians in psychiatric practice (N=860). In parallel we tested clozapine sensing using a prototype point-of-care monitoring device.255 responses were included in the survey results. The two barriers receiving mean scores with the highest agreement as being a significant barrier were patient nonadherence to blood work and blood work's burden on the patient (out of 28). Among nine solutions, the ability to obtain lab results in the physician's office or pharmacy was top-ranked (mean±sd Likert scale (4.0±1.0)). Physicians responded that a point-of-care device to measure blood levels and WBCs would improve care and increase clozapine use. Residents ranked point-of-care devices higher than older physicians (4.07±0.87 vs. 3.47±1.08, p<0.0001). Also, the prototype device was able to detect CLZ reliably in 1.6, 8.2, and 16.3μg/mL buffered solutions.Survey results demonstrate the physician's desire for point-of-care monitoring technology, particularly among younger prescribers. Prototype sensor results identify that clozapine can be detected and integrated for future device development. Future development will also include integration of WBCs for a complete detection device.

Pub.: 29 Jul '15, Pinned: 28 Jun '17

Reliable clinical serum analysis with reusable electrochemical sensor: Toward point-of-care measurement of the antipsychotic medication clozapine.

Abstract: Clozapine is one of the most promising medications for managing schizophrenia but it is under-utilized because of the challenges of maintaining serum levels in a safe therapeutic range (1-3μM). Timely measurement of serum clozapine levels has been identified as a barrier to the broader use of clozapine, which is however challenging due to the complexity of serum samples. We demonstrate a robust and reusable electrochemical sensor with graphene-chitosan composite for rapidly measuring serum levels of clozapine. Our electrochemical measurements in clinical serum from clozapine-treated and clozapine-untreated schizophrenia groups are well correlated to centralized laboratory analysis for the readily detected uric acid and for the clozapine which is present at 100-fold lower concentration. The benefits of our electrochemical measurement approach for serum clozapine monitoring are: (i) rapid measurement (≈20min) without serum pretreatment; (ii) appropriate selectivity and sensitivity (limit of detection 0.7μM); (iii) reusability of an electrode over several weeks; and (iv) rapid reliability testing to detect common error-causing problems. This simple and rapid electrochemical approach for serum clozapine measurements should provide clinicians with the timely point-of-care information required to adjust dosages and personalize the management of schizophrenia.

Pub.: 17 Apr '17, Pinned: 28 Jun '17

Outcomes of medicaid beneficiaries with schizophrenia receiving clozapine only or antipsychotic combinations.

Abstract: Patients with treatment-resistant schizophrenia commonly receive nonrecommended drug regimens, including antipsychotic polypharmacy, sometimes in lieu of clozapine. This analysis compared utilization and cost outcomes for cohorts of Medicaid beneficiaries treated with clozapine monotherapy and with antipsychotic polypharmacy.Data were from the Medicaid MarketScan database. Patients (age 18-64) initiated second-generation antipsychotic polypharmacy or clozapine monotherapy between July 2006 and January 2009, had continuous Medicaid coverage from six months before (preperiod) through 12 months after (postperiod) treatment initiation, and had a diagnosis of schizophrenic disorder (ICD-9-CM code 295.XX). Study outcomes included disease-specific and all-cause hospitalization, emergency department use, and Medicaid payments. Logistic regression analyses and generalized linear models controlled for demographic factors, preperiod utilization, and comorbidities.Characteristics associated with use of clozapine monotherapy (N=479) instead of antipsychotic polypharmacy (N=2,440) included younger age, fewer comorbidities, lower preperiod utilization rates, nonwhite race, and male sex. When the analysis controlled for baseline differences, clozapine monotherapy was associated with lower odds of mental disorder-related (odds ratio [OR]=.75, 95% confidence interval [CI]=.60-.95) or schizophrenia-related (OR=.70, CI=.54-.90) emergency department use but not with hospitalization or all-cause emergency department use. Total Medicaid payments were significantly lower for the clozapine group than for the polypharmacy group: reductions of $21,315 for all-cause, $17,457 for mental disorder-related, and $10,582 for schizophrenia-related payments.Among nonelderly adult Medicaid beneficiaries with schizophrenia, treatment with clozapine instead of antipsychotic polypharmacy was associated with reduced disease-specific emergency department use and with reduced disease-specific and all-cause health care costs.

Pub.: 17 Oct '14, Pinned: 30 Jun '17

On the Slow Diffusion of Point-of-Care Systems in Therapeutic Drug Monitoring.

Abstract: Recent advancements in point-of-care (PoC) technologies show great transformative promises for personalized preventative and predictive medicine. However, fields like therapeutic drug monitoring (TDM), that first allowed for personalized treatment of patients' disease, still lag behind in the widespread application of PoC devices for monitoring of patients. Surprisingly, very few applications in commonly monitored drugs, such as anti-epileptics, are paving the way for a PoC approach to patient therapy monitoring compared to other fields like intensive care cardiac markers monitoring, glycemic controls in diabetes, or bench-top hematological parameters analysis at the local drug store. Such delay in the development of portable fast clinically effective drug monitoring devices is in our opinion due more to an inertial drag on the pervasiveness of these new devices into the clinical field than a lack of technical capability. At the same time, some very promising technologies failed in the clinical practice for inadequate understanding of the outcome parameters necessary for a relevant technological breakthrough that has superior clinical performance. We hope, by over-viewing both TDM practice and its yet unmet needs and latest advancement in micro- and nanotechnology applications to PoC clinical devices, to help bridging the two communities, the one exploiting analytical technologies and the one mastering the most advanced techniques, into translating existing and forthcoming technologies in effective devices.

Pub.: 15 Mar '15, Pinned: 30 Jun '17