Lecture 6: Circadian Rhythms and Disease 2

How Can the Biological Clock Be Behaviourally and Environmentally Targeted Therapeutically?

• General strategies include strengtheing entrainment ot the environment or to increase the amplitude of rhythms

• This can be achieved through e

  • Bright light therapy (BLT)

  • Melatonin (*chemical rather than behavioural intervention)

  • Cognitive Behavioural Therapy

  • Interpersonal and social rhythm therapy

  • Scheduled exercise

  • Meal patterning

How Can Restrictive Feeding Help to Re-Synchronise a Biological Clock

• Eating times are restricted to 6 hours, with fasting for the remaining 18 hours

• Weight loss and health benefits seen

• A behavioural approach that helps to synchronise the biological clock when it malfunctions

How Can Bright Light Therapy Help To Synchronise the Biological Clock?

• Behavioural/ environmental approach that typically involves high-intensity blue light exposure early in the day.

• Blue light is most effective for entraining the SCN

• Light boxes are used to emit light at a specific intensity and wavelength.

• Sit in front of the light for about 1 hour each morning.

• This can help reset circadian rhythm and improve mood, sleep efficency and increased melatonin gradeint (decreased in elderly and disase)

What Clinical Indications for Bright Light Therapy

• Accepted treatment option for:

  • Mood disorders:

    • Seasonal Affective Disorder (SAD)

    • Unipolar & bipolar depression

    • Antepartum depression

    • Premenstrual depression

  • Also used for:

    • Jet lag

    • Insomnia & circadian rhythm sleep disorders

    • Elderly patients, including Alzheimer’s disease → in care homes bright lights placed in corridors and common rooms to help adjust rhythms to day and night

What is Cognitive Behavioural Therapy (CBT) For Sleep Disturbances

• Behavioural approach originally developed for primary insomnia, but is now widely used for people with psychiatric disorders co-morbid with sleep problems.

• It includes:

  • Behavioural components (e.g., relaxation techniques, sleep restriction)

  • Cognitive components (challenging unhelpful attitudes about sleep)

  • Educational component (sleep hygiene: establishing consistent routines and behaviours that signal to the body it’s time to sleep)

• Effective in reducing depressive symptoms and lowering suicidal ideation.

What is Interpersonal And Social Rhythm Therapy (IPSRT)

• Behavioural approach that addresses interpersonal problems and disrupted social rhythms by creating daily routines and avoiding disruption

• A therapist monitors and improves the regularity of five daily activities over 20 weeks (acute intervention) or monthly (maintenance treatment)

• 5 daily activities must occur at the same time with the therapist helping to integrate them into everyday life (regimented behaviour)

  1. Time out of bed

  2. first contact with another person

  3. start of daily activity

  4. dinner

  5. time for bed

• Effective in acute bipolar depression treatment and preventing bipolar mood episodes

How Can the Biological Clock Be Targeted Pharmacologically with Agomelatine (Valdoxan)?

• Use of melatonin analogue

  • Tablets used to induce sleep and minimise jet lag

• Melatoninergic MT1 and MT2 receptor agonist and 5HT2C receptor antagonist → anti-depressive and sedative effect (dual MoA)

• Efficacious in animal models of depression and resynchronises animal models of jet lag, blindness, and delayed phase sleep

What Are the Clinical Indications for Melatonin

• Blind → helps synchronise 24-hour rhythms

• Elderly

• Depression

• Alzheimer's

• Sleep disturbances

• Jet lag

What Entrainment Therapy Is Used in Alzheimer's Disease?

• Behavioural and drug approaches combined (BLT and melatonin),

• Aim: Increase the patient’s level of physical activity and social relations, and decrease sleeping time during the day

  • Light Therapy:

    • Increases nighttime sleep

    •  Higher daytime activity

    •  Lower daytime sleep

  • Melatonin:

    • Increases sleep time

    •  Decreases nocturnal activity

    •  No change in daytime sleep

• Effect of treatments: Some of the cognitive benefits and caregiver benefits seen → increased QoL

How Could the Biological Clock Genes Be Pharmacologically?

• Rev-Erb ligands

  • Reset phase of the clock, target metabolism

  • Only pre-clinical at present

• CRY activators

  • Control period, entrainment

  • Glucocorticoid actions (via GR)

  • Only pre-clinical at present

• CK1 inhibitors

  • Control period, entrainment

  • Anti-inflammatory

  • Only pre-clinical at present

• Lithium

  • Longstanding ‘mood-stabilising’ treatment

  • Targets GSK3B, modulates elements of the clock (Rev-erb, BMAL1 genes).

How do psychoactive drugs interact with biological rhythms?

• Psychoactive drugs act on the central nervous system (CNS),

• Effects can vary depending on the time of day they are taken.

• Drugs can also influence the biological clock itself, potentially disrupting or supporting circadian rhythms.

• Important to use medications that help rather than hinder the normal functioning of the biological clock.

Why is It Important to Consider the Time of Day When Administering Antidepressants

• The time of day affects the action of antidepressants → optimal time of administration

  • Lofepramine: highest antidepressant effect with a single daily dose at midnight

  • Amytriptyline: lower side effects (antimuscarinic action and sedation) in the evening vs morning → no change in therapeutic effect

  • Clomipramine: highest antidepressant effect and lowest side effects (Tremor and dry mouth) at midday

How The Dose and Time of Adminstration Affect Psychotropic Drugs Efficacy?

• Anxiolytics (e.g., Diazepam, Flunitrazepam) are more effective at the end of the night.

• Dose and time of day influence the effect of drugs:

  • Chlorpromazine:

    • Low dose is most effective mid-day.

    • Higher dose is more effective at the start of the night.

• Drug-behavioural treatment interactions seen:

  • Citalopram works best when combined with light therapy in the morning.

How Do Psychoactive Drugs Affect The Biological Clocks

• Anti-anxiolytics (Imipramine, Clorgiline, Lithium) increase and lengthen the period/ rhythm

• Tricyclic Antidepressants and SSRIs affected body temperature

  • higher body temperatures at night in depression

• Haloperidol affects sleep

  • individauls run with 48 hour rhythms → desynchronisation from the enviroment

    • when treatment halted, individual returns to 24 hour rhythm

What is Chronopharmacology

• The study of the influence of the administration time of medications on biological rhythms, as well as desired and undesired effects

• Examines how the time of day influences

  • Pharmacological effects → Chronopharmacokinetics (ADME) and Chronopharmacodynamics

  • Side effects and toxic effects → Chronotoxicology and Chronotherapy

  • Circadian effects

Where Are Biological Rhythms Present in Disease and What is the Significance of This

• Circadian rhythms are present everywhere in physiology and disease

  • Chronic pain/arthritis worsens in the evening.

  • Digestion/peptic ulcers are worse at night (avoid large meals in the evening).

  • Heart problems/angina are more common at night.

  • Asthma attacks peak early in the morning.

• Targeting drugs at the peak of these rhythms may improve treatment effectiveness.

What is Chronotoxicology

• The study of how biological timing (circadian rhythms) alters toxic responses to chemicals, poisons, pollutants, or drugs.

• It describes undesired or harmful effects from chemical, physical or other agents (poisons, pollutants and overdoses of drugs) upon biologic temporal characteristics and as a function of biologic timing

  • I.e. how the time of day can change a drug’s toxicity or efficacy.

• Example: ouabain

  • Given midday → ~74% of mice die

  • Given night → ~80% survive

• Shows that drug toxicity is gated by the circadian clock.

What is Chronopharmacokinetics?

• It describes the biological time-related changes in the absorption distribution, metabolism and elimination (ADME) of an agent

  • Rhythms in various organs will determine

  • ABSORPTION

    • (gastric acid secretion and pH, motility, gastric emptying time)

  • DISTRIBUTION

    • (gastrointestinal blood flow, drug protein binding)

  • METABOLISM

    • (liver enzyme activity, hepatic blood flow)

  • ELIMINATION

    • (urinary pH, tubular resorption)

• Example Statins:

  • Target an enzyme in cholesterol synthesis that peaks around midnight.

  • Best taken at bedtime to match peak enzyme levels.

  • Taken in the morning → reduced effect because enzyme levels are lower.

How is the blood-brain barrier (BBB) regulated by circadian rhythms during the day in mammals?

• BBB prevents the entry of external agents entering the brain

• Circadian rhythms influence BBB regulation.

• BMAL1 & clock genes are highly active.

  • Increased expression of TRPM7 magnesium transporter → more Mg²⁺ enters the brain.

  • Higher intracellular Mg²⁺ levels.

  • Activation of xenobiotic transporters → reduced brain levels of xenobiotics.

How is the blood-brain barrier (BBB) regulated by circadian rhythms during the night in mammals?

• BBB prevents the entry of external agents entering the brain

• Circadian rhythms influence BBB regulation.

• BMAL1 & clock genes have low activity

  • Decreased expression of TRPM7 magnesium transporter → lower intracellular Mg²⁺

  • Decreased activity of xenobiotic transporters → increased brain levels of xenobiotics.

• BMAL1/CLOCK Absence

What is Chronopharmacodynamics

• It describes rhythmic  differences in the susceptibility or sensitivity of a biological target to an agent”

  • Receptors: number, conformation

  • Membrane permeability -> can change in 24 hours

  • Second messengers, metabolic pathways

  • Free-to-bound fraction of medications

  • Cell, tissue, organ rhythms

What is Chronotherapy?

• Treating or preventing disease while accounting for the patient’s circadian rhythms.

  • Conisders termporal characteristics

• Therapy is timed to maximise efficacy and minimise toxicity.

• Example: Cancer chronotherapy

  • Anti-cancer drugs are delivered in a circadian-modulated schedule rather than a constant infusion rate.

  • Aligns drug delivery with times when cancer cells are most vulnerable and healthy cells are least sensitive.

What evidence supports chronotherapy in cancer treatment

• Anti-cancer drugs vary in efficacy and toxicity depending on the time of day.

• Oxaliplatin: the first anti-cancer drug developed for chronotherapy (colon cancer).

• Preclinical testing showed ~30% difference in toxicity depending on time of day.

• Human trial (n=12):

  • Compared constant infusion vs circadian-modulated delivery (higher dose at optimal time, lower at less effective times).

  • Constant infusion: 10× higher incidence of neutropenia & distal paresthesias, 55% more vomiting.

• Chronomodulated dosing was better tolerated and more efficacious, allowing a 15% dose increase with fewer side effects.

• Time of best tolerability coincides with best efficacy

How can cancer chronotherapy affect patient's lifespan?

• Giving anti-cancer drugs at the optimal circadian time can significantly extend lifespan.

• Combination therapies also show circadian dependence.

• Example: Docetaxel + doxorubicin given at the best circadian time → 3× increase in lifespan in experimental models → implications for surivial

• Highlights the importance of timing chemotherapy to maximise efficacy and reduce toxicity.

What are the 3 Main Forms of Cancer Chronotherapy:

• Chrono-chemotherapy:  It aims to give the anti-cancer drugs at the right time of day

  • Decrease drug toxicity

  • Increase drug efficacy

  • Increase tumour response – tumours get smaller

• Chrono-immunotherapy:

  • Decrease drug toxicity

  • Increase drug efficacy

  • Increase tumour response – tumours get smaller

• Chrono radiotherapy:

  • Minimise treatment-related symptoms

What Are The Overall Effects of Cancer Chronotherapy

• Minimise tumour progression

• Improve patients’ quality of life

• Improve patients’ survival

What is the Objective in Chronotherapy

• To deliver drugs to targeted sites in higher concentrations when they are needed more and lower concentrations when not needed

  • This often coincides with when the drugs are most toxic

What are the Ideal Characteristics for Chronotheraputics

• Deliver drug after time interval.

• Deliver drug when it’s more needed.

• Reduce drug release when not needed