- The effect of chronotherapy on depressive symptoms: Evidence-based practice
- What is Chronotherapy? – Benefits, Types & Results
- What Is Chronotherapy?
- What Is Circadian Rhythm?
- 1) Bright Light Therapy
- 2) Wake Therapy/ Sleep Deprivation Therapy
- 3) Sleep Phase Advance Therapy
- 4) Triple Chronotherapy
- 1) Helps Combat Seasonal Mood Disorder
- 2) May Help Combat Major Depression
- 3) May Help Combat Bipolar Disorder
- 4) May Help With Eating Disorders
- 5) Is Effective Against Delayed Sleep Phase Disorder
- Drug Chronotherapy (Treatment Scheduling)
- 1) It’s Drug-Free
- 2) It’s Simple to Administer
- 3) Follows a Specific Protocol
- Side Effects
- Limitations and Caveats
- User Experiences
- 5 Things to Know About Chronotherapy
- 1. Chronotherapy aims to mitigate the side effects of chemotherapy by aligning drug administration with the body's circadian rhythm.
- 4. Whether you're a morning person or night person can influence the effectiveness of chemotherapy.
- 5. You can shift the body's circadian rhythm or even disrupt a tumor's clock to make chronotherapy feasible for everyday implementation.
The effect of chronotherapy on depressive symptoms: Evidence-based practice
1. Soria V, Urretavizcaya M. Circadian rhythms and depression. Actas Españolas De Psiquiatría. 2009;37:222–232. [PubMed] [Google Scholar]
2. Kondratova A, Kondratov R. The circadian clock and pathology of the ageing brain. Nat Rev Neurosci. 2012;13:325–335. [PMC free article] [PubMed] [Google Scholar]
3. Wulff K, Gatti S, Wettstein J, Foster R. Sleep and circadian rhythm disruption in psychiatric and neurodegenerative disease. Nat Rev Neurosci. 2010;11:589–599. [PubMed] [Google Scholar]
4. World Health Organization. Depression [Internet] 2012. [[cited 4 November 2015]]. Available from: http://www.who.int/mental_health/management/depression/en/
5. American Psychiatric Association. Diagnostic and statistical manual of mental disorders. 5th ed. Arlington (VA): American Psychiatric Publishing; 2013. [Google Scholar]
6. Vos T, Flaxman A, Naghavi M, Lozano R, Michaud C, Ezzati M, et al. Years lived with disability (YLDs) for 1160 sequelae of 289 diseases and injuries 1990-2010:a systematic analysis for the Global Burden of Disease Study 2010. The Lancet. 2012;380(9859):2163–2196. [PMC free article] [PubMed] [Google Scholar]
7. Fitzpatrick J, Tusaie K. Advanced practice psychiatric nursing:Integrating psychotherapy, psychopharmacology, and complementary and alternative approaches. New York (NY): Springer Pub; 2013. [Google Scholar]
8. Lépine JP, Briley M. The increasing burden of depression. Neuropsychiatr Dis Treat. 2011;7(Suppl 1):3–7. [PMC free article] [PubMed] [Google Scholar]
9. Samuels N, Gropp C, Singer S, Oberbaum M. Acupuncture for Psychiatric Illness:A Literature Review. Behav Med. 2008;34:55–64. [PubMed] [Google Scholar]
10. Goetzel R, Pei X, Tabrizi M, Henke R, Kowlessar N, Nelson C, et al. Ten modifiable health risk factors are linked to more than one-fifth of employer-employee health care spending. Health Aff (Millwood) 2012;31:2474–2484. [PubMed] [Google Scholar]
11. American Psychiatric Association. Depression [Internet] 2010. [[cited 12 October 2015]]. Available from: http://apa.org/topics/depress/index.aspx .
12. Gertsik L, Poland R, Bresee C, Rapaport M. Omega-3 fatty acid augmentation of citalopram treatment for patients with major depressive disorder. J Clin Psychopharmacol. 2012;32:61–64. [PMC free article] [PubMed] [Google Scholar]
13. Linden M, Wurzendorf K, Ploch M, Schaefer M. Self medication with St. John’s wort in depressive disorders: An observational study in community pharmacies. J Affect Disord. 2008;107:205–210. [PubMed] [Google Scholar]
14. Sajatovic M, Levin J, Fuentes-Casiano E, Cassidy K, Tatsuoka C, Jenkins J. Illness experience and reasons for nonadherence among individuals with bipolar disorder who are poorly adherent with medication. Compr Psychiatry. 2011;52:280–287. [PMC free article] [PubMed] [Google Scholar]
15. Freeman M. Complementary and Alternative Medicine for Psychiatrists. Can J Psychiatry. 2012;57:395–396. [PubMed] [Google Scholar]
16. National Health Service. About complementary medicines – Live Well – NHS Choices [Internet] 2012. [[cited 6 November 2015]]. Available from: http://www.nhs.uk/Livewell/complementary-alternative-medicine/Pages/complementary-alternative-medicines.aspx .
17. Smith G, Wu S. Nurses’ beliefs, experiences and practice regarding complementary and alternative medicine in Taiwan. J Clin Nurs. 2012;21:2659–2667. [PubMed] [Google Scholar]
18. Ravindran A, Lam R, Filteau M, Lespérance F, Kennedy S, Parikh S, et al. Canadian Network for Mood and Anxiety Treatments (CANMAT) Clinical guidelines for the management of major depressive disorder in adults. J Affect Disord. 2009;117(Suppl1):S54–S64. [PubMed] [Google Scholar]
19. National Center for Complementary and Alternative Medicine. Complementary, Alternative, or Integrative Health: What’s In a Name? [Internet] [[Updated 2008; cited 2015 November 3]]. Available from: http://nccam.nih.gov/health/whatiscam .
20. Wirz-Justice A. Temporal organization as a therapeutic target. Dialogues Clin Neurosci. 2012;14:335–337. [PMC free article] [PubMed] [Google Scholar]
21. Ohdo S. Chronotherapeutic strategy: Rhythm monitoring, manipulation and disruption. Adv Drug Deliv Rev. 2010;62:859–875. [PubMed] [Google Scholar]
22. Dallaspezia S, Benedetti F. Chronobiological therapy for mood disorders. Expert Rev Neurother. 2011;11:961–970. [PubMed] [Google Scholar]
23. Wirz-Justice A, Terman M. Chronotherapeutics (light and wake therapy) as a class of interventions for affective disorders. Handb Clin Neurol. 2012;106:697–713. [PubMed] [Google Scholar]
24. Cagampang F, Bruce K. The role of the circadian clock system in nutrition and metabolism. Br J Nutr. 2012;108:381–392. [PubMed] [Google Scholar]
25. Valdez P, Ramírez García A. Circadian rhythms in cognitive performance: implications for neuropsychological assessment. Chrono Physiology and Therapy. 2012;2:81–92. [Google Scholar]
26. Hasler B, Buysse D, Kupfer D, Germain A. Phase relationships between core body temperature, melatonin, and sleep are associated with depression severity: Further evidence for circadian misalignment in non-seasonal depression. Psychiatry Res. 2010;178:205–207. [PMC free article] [PubMed] [Google Scholar]
27. O’Brien P, Kennedy W, Ballared k. Psychiatric Mental Health Nursing: An Introduction to theory and practice. Sudbury (MA): Jones and Bartlett Publishers; 2008. [Google Scholar]
28. Reppert S, Weaver D. Coordination of circadian timing in mammals. Nature. 2002;418:935–941. [PubMed] [Google Scholar]
29. Lambert G, Reid C, Kaye D, Jennings G, Esler M. Effect of sunlight and season on serotonin turnover in the brain. The Lancet. 2002;360(9348):1840–1842. [PubMed] [Google Scholar]
30. Benedetti F, Barbini B, Colombo C, Smeraldi E. Chronotherapeutics in a psychiatric ward. Sleep Med Rev. 2007;11:509–522. [PubMed] [Google Scholar]
31. Martiny K. Chronotherapeutics for affective disorders. A clinician’s manual for light and wake therapy. Acta Psychiatr Scand. 2013;129:160. [Google Scholar]
32. Bódizs R, Purebl G, Rihmer Z. [Mood, mood fluctuations and depression: role of the circadian rhythms] Neuropsychopharmacol Hung. 2010;12:277–287. Hungarian. [PubMed] [Google Scholar]
33. Moscovici L, Kotler M. A multistage chronobiologic intervention for the treatment of depression: A pilot study. J Affect Disord. 2009;116:201–207. [PubMed] [Google Scholar]
34. Hamid H. A Primary Care Study of the Correlates of Depressive Symptoms Among Jordanian Women. Transcult Psychiatry. 2004;41:487–496. [PubMed] [Google Scholar]
35. Taqui A, Itrat A, Qidwai W, Qadri Z. Depression in the elderly: Does family system play a role? A cross-sectional study. BMC Psychiatry. 2007;7:57. [PMC free article] [PubMed] [Google Scholar]
36. Corcoran K. From the scientific revolution to evidence-based practice: Teaching the short history with a long past. Research on Social Work Practice. 2007;17:548–552. [Google Scholar]
37. Cleary M. The “Buzz” About Evidence-Based Practice in Psychiatric-Mental Health Nursing. J Psychosoc Nurs Ment Health Serv. 2014;52:3–4. [PubMed] [Google Scholar]
38. Rice M. Evidence-Based Practice Principles: Using the highest level when evidence is limited. J Am Psychiatr Nurses Assoc. 2011;17:445–448. [PubMed] [Google Scholar]
39. Rycroft-Malone J, Seers K, Titchen A, Harvey G, Kitson A, McCormack B. What counts as evidence in evidence-based practice? J Adv Nurs. 2004;47:81–90. [PubMed] [Google Scholar]
40. Levin R, Chang A. Tactics for teaching evidenced-based practice: determining the level of evidence of a study. Worldviews Evid Based Nurs. 2014;11:75–78. [PubMed] [Google Scholar]
41. Peterson M, Barnason S, Donnelly B, Hill K, Miley H, Riggs L, et al. Choosing the best evidence to guide clinical practice: Application of AACN levels of evidence. Crit Care Nurse. 2014;34:58–68. [PubMed] [Google Scholar]
42. Calandra C, Luca M, Luca A. Sleep disorders and depression: brief review of the literature, case report, and nonpharmacologic interventions for depression. Clin Interv Aging. 2013;8:1033–1039. [PMC free article] [PubMed] [Google Scholar]
43. American Psychiatric Association. Practice guideline for the treatment of patients with major depressive disorder. 3rd ed. Arlington (VA): American Psychiatric Publishing; 2010. [Google Scholar]
44. Bauer M, Glenn T, Whybrow P, Grof P, Rasgon N, Alda M, et al. Changes in self-reported sleep duration predict mood changes in bipolar disorder. Psychol Med. 2008;38:1069–1071. [PubMed] [Google Scholar]
45. Bauer M, Pfennig A, Linden M, Smolka M, Neu P, Adli M. Efficacy of an algorithm-guided treatment compared with treatment as usual. J Clin Psychopharmacol. 2009;29:327–333. [PubMed] [Google Scholar]
46. Even C, Schröder C, Friedman S, Rouillon F. Efficacy of light therapy in nonseasonal depression: A systematic review. J Affect Disord. 2008;108:11–23. [PubMed] [Google Scholar]
47. American Academy of Sleep Medicine. American Academy of Sleep Medicine-Association for Sleep Clinicians and Researchers [Internet] [[Updated 2008; cited 10 November 2016]]. Available from: http://www.aasmnet.org/
48. Howland R. Somatic therapies for seasonal affective disorder. J Psychosoc Nurs Ment Health Serv. 2009;47:17–20. [PubMed] [Google Scholar]
49. Pail G, Huf W, Pjrek E, Winkler D, Willeit M, Praschak-Rieder N, et al. Bright-light therapy in the treatment of mood disorders. Neuropsychobiology. 2011;64:152–162. [PubMed] [Google Scholar]
50. Niederhofer H, von Klitzing K. Bright light treatment as mono-therapy of non-seasonal depression for 28 adolescents. Int J Psychiatry Clin Pract. 2012;16:233–237. [PubMed] [Google Scholar]
51. Lieverse R, Van Someren E, Nielen M, Uitdehaag B, Smit J, Hoogendijk W. Bright light treatment in elderly patients with nonseasonal major depressive disorder: a randomized placebo-controlled trial. Arch Gen Psychiatry. 2011;68:61–70. [PubMed] [Google Scholar]
52. Hizli Sayar G, Agargun, Tan Bulut. Comparison of effects of bright light therapy alone or combined with fluoxetine on severity of depression, circadian rhythms, mood disturbance, and sleep quality, in patients with non-seasonal depression. ChronoPhysiology and Therapy. 2013;3:53–59. [Google Scholar]
53. Chicago Psychiatry Associates. Chicago Psychiatry Associates’ Program in Psychiatric Chronotherapy [Internet] 2011. [[cited 11 November 2016]]. Available from: http://www.chicagochronotherapy.com/waketherapy.html .
54. Bunney B, Bunney W. Mechanisms of Rapid Antidepressant Effects of Sleep Deprivation Therapy: Clock Genes and Circadian Rhythms. Biol Psychiatry. 2013;73:1164–1171. [PubMed] [Google Scholar]
55. Casher M, Schuldt S, Haq A, Burkhead-Weiner D. Chronotherapy in Treatment-Resistant Depression. Psychiatr Ann. 2012;42:166–169. [Google Scholar]
56. Wu J, Kelsoe J, Schachat C, Bunney B, DeModena A, Golshan S, et al. Rapid and Sustained Antidepressant Response with Sleep Deprivation and Chronotherapy in Bipolar Disorder. Biol Psychiatry. 2009;66:298–301. [PubMed] [Google Scholar]
57. Hegerl U, Hensch T. The vigilance regulation model of affective disorders and ADHD. Neurosci Biobehav Rev. 2014;44:45–57. [PubMed] [Google Scholar]
58. Hegerl U, Sander C, Olbrich S, Schoenknecht P. Are Psychostimulants a Treatment Option in Mania? Pharmacopsychiatry. 2009;42:169–174. [PubMed] [Google Scholar]
59. Hegerl U, Wilk K, Olbrich S, Schoenknecht P, Sander C. Hyperstable regulation of vigilance in patients with major depressive disorder. World J Biol Psychiatry. 2012;13:436–446. [PubMed] [Google Scholar]
60. Martiny K, Refsgaard E, Lund V, Lunde M, Sørensen L, Thougaard B, et al. The Day-to-Day Acute Effect of Wake Therapy in Patients with Major Depression Using the HAM-D6 as Primary Outcome Measure: Results from a Randomised Controlled Trial. PLoS One. 2013;8:e67264. [PMC free article] [PubMed] [Google Scholar]
61. Echizenya M, Suda H, Takeshima M, Inomata Y, Shimizu T. Total sleep deprivation followed by sleep phase advance and bright light therapy in drug-resistant mood disorders. J Affect Disord. 2013;144:28–33. [PubMed] [Google Scholar]
62. Benedetti F, Riccaboni R, Locatelli C, Poletti S, Dallaspezia S, Colombo C. Rapid Treatment Response of Suicidal Symptoms to Lithium, Sleep Deprivation, and Light Therapy (Chronotherapeutics) in Drug-Resistant Bipolar Depression. J Clin Psychiatry. 2013;75:133–140. [PubMed] [Google Scholar]
63. Sahlem G, Kalivas B, Fox J, Lamb K, Roper A, Williams E, et al. Adjunctive triple chronotherapy (combined total sleep deprivation, sleep phase advance, and bright light therapy) rapidly improves mood and suicidality in suicidal depressed inpatients: An open label pilot study. J Psychiatr Res. 2014;59:101–1017. [PMC free article] [PubMed] [Google Scholar]
What is Chronotherapy? – Benefits, Types & Results
Circadian rhythm is extremely important for our overall health and wellbeing. Chronotherapy makes use of the body’s circadian rhythm to help with mood, eating, and sleep disorders. Read on to learn more about the benefits and advantages of chronotherapy, as well as its potential side effects.
What Is Chronotherapy?
Chronotherapy is a drug-free therapeutic intervention that exploits the body’s circadian rhythms through changes in sleep/wake cycles and daily light exposure .
Chrono is derived from the Greek word khrono which means time. Hence, chronotherapy aims to reset a dysregulated circadian rhythm (biological clock) of an individual to normal sleep/wake cycles.
Increasingly, chronotherapy also refers to administering medications in accordance with circadian rhythms to achieve optimal effects along with reducing unwanted side effects in the body (treatment scheduling).
Recently, chronotherapy has received increased attention because of a deeper understanding of the importance of circadian rhythms in health and diseases for humans.
The focus of the article will be on the use of chronotherapy as a behavioral intervention and its use in the treatment of mood disorders.
What Is Circadian Rhythm?
All living beings have an approximately 24-hour light/dark cycle that maintains biological processes, which is known as the circadian rhythm.
In humans, the circadian rhythm is maintained by an internal biological clock (also known as the circadian clock) in the hypothalamus region of the brain .
The circadian rhythm, whilst being produced by the internal biological clock, is also entrained by external environmental signals, such as daylight .
Reports have shown that internal body time varies by 5 – 6 hours in healthy humans and by as much as 10 – 12 hours in shift workers. These misalignments may actually contribute to various diseases and disorders, including obesity and psychiatric conditions [4, 5].
1) Bright Light Therapy
Bright light therapy involves receiving high-intensity, fluorescent illumination coming from a specially designed light box for 10 – 90 minutes each morning. People are free to engage in other activities such as reading whilst undergoing therapy.
It is relatively simple to administer but the specific light dosing and optimal treatment time of day may need adjustment on an individual basis .
Bright light therapy is the first-line treatment for seasonal mood disorders (major depressive episodes in fall/winter with a spontaneous decrease in depressive episodes in spring/summer) [7, 8, 9, 6].
It is has also been used for non-seasonal depression, with modest success .
It can be used as an adjunct treatment with antidepressants to augment the effect of the drug [11, 12, 13].
Studies suggest light exposure from this therapy may help in synchronizing the circadian rhythms of neurotransmitters that are affected in depression .
2) Wake Therapy/ Sleep Deprivation Therapy
the name of the therapy suggests, it involves completely avoiding sleep for one to three cycles (whole night and the following day) mixed with nights of recovery sleep .
The advent of wake therapy/ sleep deprivation therapy in the 1970s was a significant advancement because of the immediate beneficial effects it produced on reversing depressive symptoms (within 24 hours) .
Since then, a large number of studies have reported the efficiency of this therapy in diminishing depressive symptoms – it appears to help in 40 – 60% of patients [17, 18, 19].
A recently published meta-analysis of 66 independent studies reported a significant beneficial effect of sleep deprivation therapy on depressive symptoms. This was regardless of the way the therapy was administered, age or gender, or how depressive symptoms were measured .
3) Sleep Phase Advance Therapy
Sleep phase advance therapy involves moving bedtime and wake time forward (for instance, 5 pm to 12 am midnight) until a normal sleep/wake cycle (for instance, 11 pm to 7 am) is achieved and maintained.
This therapy has been used in conjunction with the wake/sleep deprivation therapy to alleviate depressive symptoms in both patients on and off antidepressants [21, 22].
Sleep phase advance therapy was also shown to reset the circadian clock in patients with delayed sleep phase disorder (DSPD). These patients have trouble sleeping at midnight and experience difficulties with waking up in the morning .
4) Triple Chronotherapy
Triple chronotherapy is when bright light therapy, sleep deprivation therapy, and sleep phase advance therapy are combined to help reduce depressive symptoms in a rapid and sustainable manner [23, 24].
In a study in humans, a rapid decrease in depressive symptoms was reported in 13 patients who did not respond to antidepressants, upon undergoing treatment with triple chronotherapy. These patients showed no obvious short-term side effects to the triple chronotherapy .
Triple chronotherapy also reduced suicidal and depressive symptoms in a pilot study with 10 acutely suicidal depressed patients .
While promising, these studies involve a small number of people. Larger, well-designed studies are needed to establish the benefits of triple chronotherapy.
1) Helps Combat Seasonal Mood Disorder
Bright light therapy is effective for seasonal mood disorder.
The first clinical trial that investigated bright light therapy as a treatment option for seasonal mood disorders in 1984 reported an antidepressant effect in 29 patients .
Since then, bright light therapy has become the treatment of choice for seasonal mood disorder [27, 6, 9, 8, 28].
Although most studies have been performed on adults with seasonal mood disorder, a small number of studies have also been done on children and adolescents [29, 30].
For example, in one study (DB-PCT), bright light therapy was found to be an effective treatment in 28 children (aged 7 to 17 years) who suffered from seasonal mood disorder .
2) May Help Combat Major Depression
Bright light therapy is possibly effective in depression.
A meta-analysis of 9 trials suggests that bright light therapy appears efficacious when administered for 2-5 weeks as monotherapy .
In a human study (RCT) of 75 adults with major depression, triple chronotherapy resulted in a better response to an antidepressant drug (duloxetine) which was also long-lasting compared to the patient group treated with exercise .
In the 20-week follow up of these patients, patients treated with triple chronotherapy showed sustained antidepressant effects with very high remission (no symptom) rates compared to the patients treated with exercise .
3) May Help Combat Bipolar Disorder
Bright light therapy is possibly effective in bipolar disorder.
Major depressive episodes that occur in patients with bipolar disorder are termed as bipolar depression .
Resistance to drugs (antidepressants) has been a major hurdle when it comes to treating patients with bipolar depression.
In a study of 60 patients with bipolar depression, a combination of bright light therapy and sleep deprivation therapy was administered along with antidepressants and lithium.
70% of patients with no history of drug resistance showed a reduction in depressive symptoms after chronotherapy treatment, and 57% of patients continued to feel better even after 9 months .
Perhaps more encouragingly, 44% of drug-resistant patients also displayed a decrease in depressive symptoms after chronotherapy intervention .
4) May Help With Eating Disorders
In eating disorders (bulimia nervosa and anorexia nervosa), the circadian rhythms associated with food intake and body temperatures are abnormal and sync.
A study reported that bright light therapy normalized body temperature circadian rhythms in 25 female patients diagnosed with eating disorders .
A recently published meta-analysis of 14 studies on the effectiveness of bright light therapy for eating disorders also highlights that bright light therapy is effective at improving both disorder-related behaviors in patients and their mood .
5) Is Effective Against Delayed Sleep Phase Disorder
In patients with delayed sleep phase disorder and insomnia, chronotherapy helped to reset their disturbed circadian clocks with a treatment schedule .
The patients also benefited from chronotherapy since they could end their dependence on hypnotic medications .
Drug Chronotherapy (Treatment Scheduling)
It is also important to note that drug chronotherapy (timing of medication in accordance with circadian rhythms) may have beneficial effects in the following diseases:
1) It’s Drug-Free
All therapies that fall under the umbrella of chronotherapy aim to tweak the body’s natural circadian rhythms. They may or may not be used in conjunction with drug treatments such as a combination of triple chronotherapy with antidepressants for the treatment of major depression.
2) It’s Simple to Administer
All forms of chronotherapy (bright light, sleep deprivation, sleep phase advance) require little use of equipment and are more of lifestyle changes for the duration of the treatment. The results from studies also highlight the sustained effect of triple chronotherapy treatments.
3) Follows a Specific Protocol
Triple chronotherapy regimes have a specific beginning, middle, and end. This makes it easier for the patient to anticipate the changes in their sleeping patterns and/or bedtimes hence, enabling them to deal with the changes psychologically.
Since chronotherapy is drug-free, there are no drug-related side effects to the body.
However, in sleep phase advance therapy, one may feel sluggish since bedtime is progressively shifted 2-3 hours each day. A dip in productivity is only natural.
In wake therapy/ sleep deprivation therapy, the most obvious side effect is daytime sleepiness and tiredness. Hence, it is advisable for patients undergoing sleep deprivation therapy to not be involved in activities that require a certain degree of concentration, such as driving a car [51, 17, 23].
In bright light therapy, certain side effects jitteriness, headaches, and nausea may occur due to exposure to high-intensity fluorescent illumination .
In addition, the following people should consult with their doctor and use caution when it comes to bright light therapy:
- People who have conditions that make their skin sensitive to light, such as lupus
- Those who take medications that increase sensitivity to sunlight, such as certain antibiotics, anti-inflammatories or the herbal supplement St. John’s Wort
- Those with an eye condition that makes eyes vulnerable to light damage
- Those with bipolar disorder. Bright light may trigger mania in some.
Limitations and Caveats
Although any form of chronotherapy is relatively simple to administer, it does require appropriate medical attention. There are factors that may need individual adjustment and monitoring of progress throughout the treatment and, hence, medical supervision is key.
Users report that using bright light therapy through the fall/winter months benefited them considerably and they noticed that their irritable and anxious seasonal mood changes were less frequent. All they had to do was purchase a light box that is easy to fit in your home or office space and use it regularly, at least during the winter months.
5 Things to Know About Chronotherapy
Chronotherapy—treatment of an illness that incorporates the body's natural rhythms and cycles—has been studied since the 1980s, but has recently gained momentum due in part to the awarding of the 2017 Nobel Prize in Physiology or Medicine to Jeffrey C.
Hall, Michael Rosbash, and Michael W. Young for their work on circadian rhythms.
[1,2] Their discovery of the molecular mechanisms controlling circadian rhythm has caused chronotherapy to become a topic of paramount interest for those investigating the therapeutic implications of this circadian-cancer connection.
1. Chronotherapy aims to mitigate the side effects of chemotherapy by aligning drug administration with the body's circadian rhythm.
Also known as a sleep/wake cycle, the circadian rhythm is an internal clock that causes the brain and all biological cycles to cycle between intervals of alertness and sleepiness. Circadian rhythms comprise various elements that influence these intervals, including eating habits, body temperature, and duration of sleep, as well as external factors such as darkness and lightness.
Chronotherapy involves syncing the time at which cancer drugs are administered with a patient's natural circadian rhythm with the goal of mitigating side effects as well as maximizing the effectiveness of the drug. This involves administering drugs when healthy cells are least prone to the toxicity of these drugs or when cancer cells are most vulnerable to the effects of the drug.
A study by Davis, Mirick, and Stevens at the Fred Hutchinson Cancer Research Center in Seattle, Washington, found that exposure to light during the nighttime is associated with an increased risk of developing breast cancer. The investigators observed the sleeping habits of 813 women who worked graveyard shifts 10 years prior to diagnosis.
Compared with controls, women who worked night shifts during the decade prior to diagnosis had a 60% greater chance of developing breast cancer. There was also a direct correlation between number of hours worked during night shifts and the risk for breast cancer.
The study observed that avoiding sleep during the time in which your nocturnal melatonin levels are at their peak is a possible carcinogen.
Frequent jet lag is another possible carcinogen relating to disrupted circadian rhythms.
A study conducted by Kettner and colleagues at the Baylor College of Medicine in Houston, Texas, observed that mice that were jet lagged were more frequently diagnosed with ovarian tumors, B-cell lymphoma, pancreatic tumors, and hepatocellular carcinoma, among other cancers.
 This study observed that chronic circadian disruption was associated with increased risk for cancer, neoplastic growth, and genomic instability.
Because mice have different circadian rhythms than humans, the role of jet lag on cancer risk in humans still requires investigation; however, it is proposed that the repetitive circadian disruption associated with jet lag leads to neuroendocrine dysfunction and overall metabolic debilitation, leading to increased risk of developing cancer.
Despite the growing interest in chronotherapy following the Nobel Prize award last year, there is currently only one study being conducted in the United States on chronotherapy.
This clinical trial, titled “A Randomized Feasibility Study Evaluating Temozolomide Chronotherapy for High Grade Glioma,” is being conducted at Washington University in St. Louis, Missouri, by Jian Campian and her colleagues and is expected to be completed in 2020.
 Temozolomide was chosen as the chemotherapy drug for the trial because of its association with DNA damage. Through the use of chronotherapy, researchers hope to uncover whether the time at which temozolomide is administered influences its toxicity or effectiveness.
The 30 participants in the trial will take temozolomide at either 8 AM or 8 PM, and, while it is too early for conclusive results, Campian states that, so far, taking temozolomide at 8 PM rather than 8 AM has led to reduced side effects of the drug.
4. Whether you're a morning person or night person can influence the effectiveness of chemotherapy.
While Campian's study has been observing that the 8 PM dosage time seems to be optimal for most patients, the most effective time for a drug's administration is not universal but rather specific to a patient's individual circadian rhythm.
Your individual circadian rhythm is known as your chronotype, which, at its most basic, is whether you're a morning person or a night person. Each person has individual intervals of alertness and sleepiness, which correlate to internal molecular activity.
Thus, chronotherapy must be personalized to each specific patient even if a certain time is better for most patients on average.
Decoding personal chronotype can help uncover the optimal time to go to bed in order to get the best night's sleep, or in this case the optimal time to take antineoplastic drugs for their toxicity to be at their lowest and their effectiveness to be at its greatest.
Not only do humans have optimal times for drug administration, but the drugs themselves have specific times in which they will be most effective.
Because each class of chemotherapy has an individualized method of killing cells, each drug also has a window of time in which it is most productive.
For example, fluorouracil, a chemotherapy given to treat a number of cancers, has been observed to work best at nighttime, while oxaliplatin, a drug most frequently used to treat advanced colorectal cancer,[9,10] has been observed to work best during the afternoon.
Francis Lévi, MD, PhD, a chronotherapy researcher at the University of Warwick in Coventry, United Kingdom, has researched the role of these drugs in metastatic colorectal cancer and observed that chronotherapy resulted in significantly lower toxicities.
5. You can shift the body's circadian rhythm or even disrupt a tumor's clock to make chronotherapy feasible for everyday implementation.
While the subject of chronotherapy has gained popularity recently, there are many pitfalls in researching chronotherapy that have been a roadblock to clinical results. One main factor has been the invasive nature of acquiring tumor biopsies, as well as the expense and time involved.
For this reason, many researchers are looking at biomarkers rather than tumor samples to investigate the effects of chronotherapy. For example, wrist actigraphy, skin temperature, and blood and saliva samples have been identified as relatively effective ways of identifying if a patient's body is alert or at rest.
However, more accurate and comprehensive biomarkers are necessary to research individualized chronotherapy.
In an attempt to circumvent the pitfalls that have made chronotherapy less feasible for everyday implementation, researchers have investigated ways to manipulate circadian rhythms to make chronotherapy more practical for patient use. This can involve ambient lighting, gradually shifting sleeping schedules, taking melatonin supplements, or altering dietary or exercise habits.
In addition to shifting a patient's circadian rhythm, the circadian clock of the tumor itself can be manipulated. Kiessling and colleagues at the Douglas Mental Health University Institute in Montreal, Canada, discovered that injecting tumors with steroids can restore clock function in cancer cells and consequently reduce tumor growth.
 The injection of the glucocorticoid dexamethasone was found to restore clock gene expression in B16 melanoma cells, which resulted in a 33% reduction in tumor size in just over a week.
The use of steroids was observed to inhibit the proliferation of cancer cells, which suggests that patients can reap the benefits of chronotherapy without disrupting their daily schedules.
While chronotherapy has been primarily associated with cancer treatments, there are benefits to its use in other medical fields as well. Chronotherapy was observed to be effective in the treatment of hypertension in a study conducted by Hermida and colleagues at the University of Vigo in Pontevedra, Spain.
 Hermida used wrist actigraphy as a biomarker to identify the circadian rhythms of patients while also monitoring their blood pressure through 48-hour sessions.
Administering antihypertensive drugs before going to sleep resulted in 37% of patients having controlled blood pressure after 3 months, as opposed to only one of the 125 patients who received antihypertensive drugs in the morning. Chronotherapy may also be useful in psychiatric conditions bipolar disorder.
Wu and colleagues at the University of California, Irvine, found significant benefits in taking antidepressants at three specific intervals in patients' circadian rhythms to achieve sustained responses to the drugs. Studies these contribute to the wide applicability of chronotherapy and its potential across a spectrum of drug therapies.
The relatively low number of chronotherapy clinical trials has been a barrier to advancements in the field.
Advocates for chronotherapy, Chi Van Dang, MD, PhD, a cancer researcher from The Wistar Institute in Philadelphia, Pennsylvania, hope that recent research on circadian rhythms will propel chronotherapy toward becoming a widely researched field with a plethora of controlled trials to prove its effectiveness. In his keynote presentation last September at the National Institutes of Health's National Cancer Institute in Bethesda, Maryland, Dang called upon oncologists to encourage chronotherapy research and implementation: “I would argue that the evidence shows there is a benefit and we can't ignore it. We just need to be more clever on how to approach the challenges.”
Medscape Oncology © 2018 WebMD, LLC
Any views expressed above are the author's own and do not necessarily reflect the views of WebMD or Medscape.
Cite this: 5 Things to Know About Chronotherapy – Medscape – Aug 17, 2018.