Clozapine, sold under a variety of brand names including Clozaril, is widely prescribed by psychiatrists as a highly effective antipsychotic medication for schizophrenia, especially cases in which the mental illness does not improve with other drugs. 

It was synthesized 65 years ago by Wander AG, a Swiss pharmaceutical company, based on the chemical structure of the tricyclic antidepressant imipramine, and the rights were later purchased by the Sandoz company. In 2002, the drug was approved in the US for reducing the risk of suicide in schizophrenic patients judged to be at chronic risk for suicidal behavior. 

Clozapine is, however, also associated with harsh side effects – some of which are serious and potentially fatal. Common side effects include constipation, bedwetting, night-time drooling, muscle stiffness, sedation, tremors, a sudden drop in blood pressure when you stand from a seated or prone (lying down) position, high blood sugar weight gain. More severe side effects include agranulocytosis (an acute condition involving a severe and dangerous lowered white blood cell count); central nervous system depression, suppression of the bone marrow and seizures.  

Both its efficacy and its side effects are strongly correlated with blood concentration levels, which can differ up to 20-fold between individuals prescribed identical doses. It can also be greatly affected by age, gender, drug interactions and other factors. 

Despite the importance of monitoring clozapine blood levels, its current monitoring scheme is burdensome and involves frequent invasive blood draws, leading to sub-optimal treatment efficacy due to the poor ability to calculate its dose for maximal therapeutic benefit while minimizing side effects. As a result, clozapine is still one of the most underused evidence-based psychiatric treatments.

Fortunately, researchers at Ben-Gurion University (BGU) of the Negev in Beersheba have developed a new method for personalizing doses of clozapine. It uses a microelectronic sensor that instantly and accurately detects concentrations of the antipsychotic drug in the blood by pricking a finger to obtain a drop of blood. This allows optimal therapeutic benefit while minimizing side effects. 

The technique was developed by Dr. Hadar Ben-Yoav of BGU’s department of biomedical engineering and Ilse Katz Institute for Nanoscale Science and Technology.

A recent study carried out in collaboration with Prof. Deanna Kelly of the Maryland Psychiatric Research Center at the University of Maryland showed good correlation between clozapine blood concentrations measured by the device compared to standard laboratory blood tests in schizophrenia patients. 

The novel sensor can be used as a platform for detecting other redox (reducing-oxidizing) chemicals in small quantities of untreated, whole blood samples. Redox molecules are involved in multiple significant chemical reactions, such as production of various substances, biochemical processes in living organisms, diagnostics and medical procedures. 

Redox agents can be monitored by specific electrodes, but currently available methods of detection require pretreatment of the blood sample to separate the desired molecules from other, interfering substances. The sensor developed by the BGU researchers can detect tiny quantities of various redox molecules in untreated blood samples, thus paving the way for developing miniaturized, point-of-care devices that will be able to monitor various targets. 

“We were excited to see the promising initial results of our novel device, that can supply people with schizophrenia and their caretakers with instantaneous, accurate results of their blood clozapine levels,” said Ben-Yoav. Clozapine plasma levels are helpful in improving response rates and minimizing unnecessary side effects. Our device can be the basis of rapid, accurate point-of-care monitoring of patients that will enable personalized medicine through close monitoring and adjustment of the dose of this important drug.”

“We hope that this innovative invention will help increase patient compliance and facilitate the use of clozapine for people living with schizophrenia,” added Josh Peleg, CEO of BGN Technologies, the university’s technology transfer company.  “The medical research field is investing considerable efforts in simplifying and miniaturizing various blood tests, making it possible for patients to receive medical results immediately and at home, and the device being developed by the BGU team is an important contribution to this trend. Importantly, the technology underlying this novel clozapine sensor can be used as a platform for the detection of additional substances. After filing for patent protection, BGN Technologies is currently seeking a strategic partner for further developing and commercializing this device.”