by Benyapa Khowpinitchai
figures with Carlos Morales

When your medication becomes less effective, the first thought you may have is to increase the dosage. But what if there was a way to increase the efficacy of the drug without needing to increase the amount? What if you could simply change when you took the drug? Indeed, the answer may lie in your biological clock.

Biological clock and health

When your doctor prescribes you medication, they also tell you how much to take and how many times a day you should take it. However, research has shown that when you take it may be just as important.  
Why does the timing of drug intake matter? Upon ingestion, the drug gets absorbed, distributed, metabolized, and eliminated by biochemical processes in the body that are regulated by your biological or molecular clock. This clock, also referred to as your circadian rhythm, has been described across species from plants and bacteria to animals, including humans. This clock serves as an internal temporal regulator of biological processes that runs through a daily cycle of approximately 24 hours. It helps to orchestrate cellular activities, behaviors, physiology, and metabolism in response to external factors like sunlight, temperature, and nutrient availability in order to maintain homeostasis, or a relatively stable equilibrium. As a result, it plays an important role in shaping daily physiological functions, such as blood pressure and body temperature that impact drug metabolism (Figure 1).

Timing your medicine right

Early research has demonstrated that the amount and distribution of proteins like albumin and α-1-glycoprotein in the blood fluctuate with time. These proteins are generally important for drug uptake into the tissues and are known to be highly expressed in the afternoon. Thus, the timing of drug administration is critical to allow its optimal functions and ensure safe treatments. Most of the best-selling drugs today work more efficiently when taken at specific times of the day. 

For example, statins are a class of medication that helps lower the level of bad cholesterol by targeting an enzyme whose expression peaks at night, so it works best when taken in the evening. Another example is antihypertensive drugs for high blood pressure that target angiotensin 2 receptors, which play an important role in blood pressure regulation. These receptors show a clear pattern of circadian oscillation, with the highest levels of expression observed around the early afternoon and the lowest around 2 AM in the morning. Therefore, these drugs are most effective when taken at night compared to the morning. 

Targeting the clock as a treatment

As we discussed, one approach to chronotherapy aims at syncing medications with patients’ body clocks. Another practice of chronotherapy focuses on directly manipulating the clock to treat diseases. Many diseases show symptoms associated with a malfunctioning clock or have temporal manifestations, ranging from general symptoms and pathology to neurological diseases, nutritional and metabolic diseases, and many others. Over 25% of diseases that involve disrupted circadian rhythm are mental and behavioral disorders. Depression, for instance, clinically manifests with symptoms of disrupted chronobiology, including changes in the sleep/wake cycle, abnormal secretion of hormones, mood fluctuation, and altered food intake. Chronotherapy for depression thus aims to control environmental factors that directly impact the patient’s biological clock and restore its function. Some of these treatments include sleep deprivation or wake therapy, sleep phase advance, and light and dark therapy, which can yield rapid results, usually within hours or days. In fact, a 2017 meta-analysis of multiple studies on the effect of sleep deprivation on depression found rapid recovery in half of the patients within the first 24 hours. 

Despite its promises, the application of chronotherapy is still in its infancy. According to the US National Institute of Health, the number of clinical trials involving the treatment of circadian rhythm or accounting for time-of-day in study designs makes up less than 0.5% of all registered studies worldwide, with North America and Europe leading most of the effort. 

The state of chronotherapy today

So, chronotherapy makes a lot of sense – it’s intuitive and supported by evidence. However, many technical and practical challenges prevent its widespread application. One of the main barriers to chronotherapy is the variability of the natural rhythm from individual to individual. The uniqueness of one’s body clock depends on many factors, including age, medical conditions, and disruption of the sleep-wake cycle, especially by the modern lifestyle; it is also subject to change over time. For example, the clock can differ by 5-6 hours given regular sleep hygiene and up to 10-12 hrs in shift workers. Thus, determining and optimizing the exact time at which treatment should be administered to sync with the patient’s unique clock has been challenging. 

Practical challenges also exist for both healthcare providers and patients, limiting the translatability of chronotherapy to the clinics. Providers may be required to closely monitor medication or treatment administration, which can limit the number of patients able to receive their care simultaneously. On the other hand, only about half of chronic disease patients stick to their prescribed medication schedule according to the World Health Organization, and adding specific time-of-day instructions may only overcomplicate the existing problem. 

Measuring your circadian rhythm

One of the first steps to applying chronotherapy is the ability to accurately measure a patient’s unique body clock (Figure 2). The fluctuating flow rates and compositions (e.g., proteins, calcium, sodium levels) of saliva were first used to estimate the cycle of the body clock. A more standard practice of estimating the circadian phase relies on dim-light melatonin analysis, whereby the maximum and minimum melatonin levels mark the start and end of a circadian night, respectively. Using this method, blood samples are collected from patients and analyzed for their plasma melatonin content or to identify other biomarkers associated with the circadian cycle, including metabolites and RNA molecules. 

Another approach considers the core body temperature (CBT) of the patient, which is consistently maintained at 37°C in vital organs, like the heart, liver, brain, and kidneys, as a proxy for the circadian phase. CBT is known to fluctuate by up to 1°C during the day due to circadian regulation, and both invasive and non-invasive methods have been developed to measure CBT to estimate the timing of the body clock. Because many factors could be influenced by circadian regulation, researchers have also developed a method to take into account multiple circadian markers, like blood pressure, body temperature, light exposure, food intake, sleep-wake cycle, and gene and protein expression, to more precisely calculate a unique circadian rhythm for individuals. If you are interested in tracking your sleep-wake cycle, many sleep trackers are also now available on the market, including Apple Watch and Fitbit, which automatically log your daily rhythms.

No time to track your medication? Science has you covered

To further facilitate the translatability of chronotherapy, a group of MIT researchers developed an implantable device that allows precise control of timing to administer medication in response to external stimuli. This device, dubbed WCBIS for Wirelessly Controlled Battery-free Implantable System, enables programmable delivery of specific amounts of drug at precise times when coupled to a mobile app. It is small, compact, and refillable and requires no battery, and most importantly, it can deliver medications at specific times to sync with the patient’s circadian rhythm. The device has been used to deliver antihypertension drugs and bromocriptine to control blood sugar levels in animal models. Emerging technologies such as WCBIS may help pave the way for chronotherapy to be more broadly applied. 

The concept of time is critical yet under-appreciated in the practice of medicine. In recent years, we have just begun the practice of personalized medicine, an approach to individualize medical treatments by taking into account the patient’s unique genetic background and biomarkers. Circadian rhythm may be another important consideration unique to each patient that can improve overall treatment outcomes. Therefore, advancements in estimating one’s circadian cycle and novel approaches to administering medication under precise temporal control may widen the applications of chronotherapy to treat diseases. 

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Benyapa (Ben/Benya) Khowpinitchai is a first-year Ph.D. student in Biological and Biomedical Sciences at Harvard Medical School. You can find her/them on Twitter as @3xon5kip.

Carlos Morales is a first-year Ph.D. student in Systems, Synthetic & Quantitative Biology. He previously researched genomic translocations in inflammatory breast cancer as potential biomarkers for this complex disease at the University of Puerto Rico-Rio, Piedras.

Cover image by geralt from pixabay

For More Information:

• This recent article is an excellent and well-rounded summary of chronotherapy.
• Check this out to read an interview with lead investigators of chronotherapy studies.
• To find out more about chronotherapy clinical trials, visit Clinicaltrials.gov.