Flashcards in Chronopharmacology Deck (25):
Circadian rhythms controlled by light input from retina according to solar cycle, which travels to SCN.
SCN sustains clock via 24h transcriptional-translational feedback loop. Sets behavioural and physiological rhythms, controls rhythmic neuroendocrine secretions, syncs peripheral clocks.
Food is also zeitgeber. Rhythmic transcription of gene products in all cells of body, so drugs can work differently at different times.
Animal models show same dosage of drug can be lethal depending on timepoint. Even the case in humans e.g. oxaliplatin!
Correct timing of drug can have benefical effects on treatment in humans as it interacts with molecular target better. Individual factors also important too e.g. genetics and chronotype.
Statins best taken at night at cholesterol peaks when we sleep.
Most of us suffer from social jet lag!
Circadian dysfunction linked to many diseases.
Shift workers = high rates of GI disease
Shift workers = increased rates of breast cancer
Phase shift hypothesis for SAD
Depressed mood in winter correlated w/ winter phase shift
CT useful in psychiatric wards. Sleep deprivation & BLT.
Rapid effects, response & relapse rates similar to AD drugs.
BLT on its own found to be even more effective than fluoxetine and BLT (so superior to drugs alone).
Chronotherapy very effective as outpatient treatment for whole range of depressive disorders - 60% improve after just one night of sleep deprivation/wake therapy.
Chronotherapy effective in drug-resistant individuals and hard to treat disorders e.g. bipolar.
Case study of individual w/ bipolar.
Triple chronotherapy: wake therapy, sleep phase advance and BLT.
Caused remission for 6 months.
SAD & BLT
Especially effective for SAD.
Also benefit from scheduled mealtimes (food entrains peripheral clocks e.g. controls rhythmic liver gene transcription) and melatonin at night.
So help clock train to external environment / increase amplitude of CRs = improves symptoms in psychiatric depressive disorder.
Majority of best-selling drugs in US target clock gene products.
Differences in lethality of chlorpromazine according to time of administration.
Low dose best at activity midpoint, high best at start of night.
Haloperidol caused 48h sleep/wake cycle in Tourette's sufferer.
Reversed by risperidone at start of day and melatonin before bed.
Could then entrain to more appropriate 24h cycle, which improved QOL.
Suggests disrupted sleep/wake patterns such as those seen in Sz could be due to effects of medication? Not illness-related?
Melatonin analogues can cause sig phase shifts.
Could be useful in treating neuropsychiatric disorders characterised by circadian dysruption e.g. SAD who have winter phase advances?
Could help reset circadian rhythm to more appropriate phase.
Also agomelatine binds 5HTRs = intrinsic AD effects.
Depressive symptoms worse in people w/ late chronotype = phase delay sleep patterns.
Eveningness and insomnia (poor sleep quality) directly but independently correlated w/ severity of depressive symptoms.
So both are factors but not mutually related?
Relationship between circadian rhythms and depression is complicated!
But suggests that if we identify relationships between both late chronotype aspect and sleep disturbances aspect with depression we could identify risk factors/susceptibility to depression, change course of disease, develop better treatments.
Relationship between eveningness and depressive symptoms could be due to reduced sensitivity of Behavioural Activation System and reduced positive affect in response to reward.
Phase shifted rhythms resulting in systems not working as well?
Starting to uncover links between circadian function and factors in psychiatric disease, such as positive affect and response to reward.
Animal study found circadian rhythms in clock gene expression in dopaminergic reward system, and in behavioural responses to reward.
Drugs of abuse can entrain CRs.
Subclinical manic-like symptoms associated with eveningness.
How does this tie into dysfunction in BAS?