2. Objectives
• Provide a background on melatonin, including its uses,
pharmacokinetic profile, side effect profile, and drug-drug
interaction profile
• Compare the side effect profiles of the most commonly
used medications for insomnia in the NYCCC facility, which
include, quetiapine and trazodone, to melatonin
• Summarize studies in an effort to confirm the positive
effects of melatonin on individuals with insomnia/delayed
sleepy latency
• Address the issues associated with the use of quetiapine or
trazodone for sleep, including concerns with drug-drug
interactions, side effect profiles, and potential issues upon
discharge
3. Melatonin: Background
• Biosynthesized from tryptophan, converted to serotonin and
ultimately to melatonin.
• Primary site of melatonin production: pineal gland
• Some production occurs in the retina, bone marrow, bile and GI tract
• Secretion of melatonin from the pineal gland is highest during
pediatric years and decreases with age.
• It is believed to be responsible for regulating sleep-wake cycles by
helping adjust the patient’s circadian cycle.
• Release coincides with darkness and is suppressed by daylight; it
typically begins around 9 pm and lasts until about 4 am.
• Although the exact mechanism of action is unknown, it is thought
that synthetic melatonin copies the effects of natural melatonin in
the brain.
• Exogenous melatonin maximally advances delayed rhythms when
administered before endogenous melatonin levels begin to increase
in the evening.
• It decreases nocturnal core body temp, which helps facilitate sleep.
4. Melatonin: Pharmacokinetics
• It crosses the blood brain barrier.
• Some accumulation in fat tissue may occur with prolonged
daily administration.
• Elimination half-life of IR formulation: 45 minutes!!!
• Hepatically metabolized to minor glucuronide metabolite
in addition to 6-sulfaoxymelatonin.
• Only 0.01% of melatonin is excreted unchanged in urine.
• 6-sulfaoxymelatonin: also excreted in urine.
• Salivary melatonin and urinary 6-sulfaoxymelatonin can be
used for monitoring melatonin activity
• Predominantly CYP1A2, minor CYP2C9 and CYP2C19
• Oral 3mg dose: peak serum and salivary concentrations at
20 and 60 minute post dose respectively.
5. Medication Use
Melatonin • Insomnia
• Menopause
• Only sleep problems associated with menopause
• Benzodiazepine withdrawal
• Breast cancer
• Several studies have indicated that low melatonin levels may be associated with
breast cancer risk
• Prostate cancer
• Studies have shown that low melatonin levels may be associated with prostate
cancer risk
• Attention Deficit Hyperactivity Disorder
• Melatonin may help promote sleep in those with ADHD or autism
Quetiapine
NO LABEL OR OFF-
LABEL
INDICATION FOR
INSOMNIA
Labeled Indications
• Bipolar disorder: acute treatment of manic or mixed episodes associated with Bipolar I
disorder, bother as monotherapy and as an adjunct to lithium or divalproex; maintenance
treatment of bipolar I disorder as an adjunct to lithium or divalproex; acute treatment of
depressive episodes associated with bipolar disorder
• Major depressive disorder (ER only): adjunctive therapy to antidepressants
• Schizophrenia
Off-Label Indications
• Augmentation in treatment resistant obsessive compulsive disorder
• Delirium in the critically ill patient
• Delusional parasitosis
• Psychosis/agitation related to Alzheimer’s dementia
• Tardive dyskinesia
Trazodone Labeled Indications
• Treatment of major depressive disorder
Off-Label Indications
• Insomnia
• Potential augmenting agent for antidepressants
6. Medication Contraindications and Precautions
Melatonin • Quality control is not required and variability can occur in potency and purity of products. These impurities may cause allergic
reactions or side effects
• Some products are derived from pineal glands of beef cattle. Use with caution in patients with bovine protein hypersensitivity
• The use of animal source melatonin not recommended due to risk of viral contamination or infection so it is recommended that
facilities attempt to buy synthetic products.
• Use with caution in patients with pre-existing neurological disease since it acts on the CNS and has sedative effects.
• It is currently unknown if it worsens depressive conditions.
• Caution in patients treated for other psychiatric disease.
• Since melatonin may affect epileptic activity, use with caution in patients with seizure disorder.
• There have been no studies conducted with melatonin use in presence of renal or hepatic disease so use with caution in these
cases.
• CI in pregnancy right now – in pregnant women, endogenous melatonin crosses placenta and enters fetal circulation
• High doses inhibit ovulation and have effects on prolactin secretion.1
Quetiapine • Anticholinergic side effects (confusion, agitation, constipation, blurred vision, etc.)
• Blood dyscrasias: leukopenia, neutropenia and agranulocytosis have been reported with antipsychotic use
• CNS depression
• Extrapyramidal symptoms (EPS). Risk of dystonia (and probably other EPS) may be greater with increased doses, use of
conventional antipsychotics, males and younger patients
• Hyperglycemia
• Hyperlipidemia
• Hyperprolactinemia
• Hypersensitivity
• Hypothyroidism
• Neuroleptic malignant syndrome
• Orthostatic hypotension
• QT prolongation
• Weight gain
• May precipitate a shift to mania or hypomania in patients with bipolar disorder
• seizures
Trazodone • Bleeding risk: particularly if used concomitantly with aspirin, NSAIDs, warfarin or other anticoagulants
• Bone fractures
• Ocular effects: may cause mild pupillary dilation
• Orthostatic hypotension
• QT prolongation
• Sedation
• Serotonin syndrome
• Hyponatremia
• May worsen psychosis in some patients or precipitate shift to mania or hypomania in patients with bipolar disorder
• Seizure
7. Drug Side Effects
Melatonin Potential side effects
• Headache
• Depression
• Sinus tachycardia
• Nightmares
• Dyspepsia
• Abdominal pain
• Rash with or without pruritus
• Prolonged sleepiness or drowsiness
Quetiapine
• Many who take
quetiapine
experience weight
gain – they are at
increased risk of
developing diabetes
and
hypercholesterolemi
a which may lead to
heart disease, stroke,
and other
complications
Black Box Warning
• Antidepressants
increased the risk
compared to
placebo of suicidal
thinking and
behavior
(suicidality) in
children,
adolescents, and
young adults in
short-term studies
of major depressive
disorder (MDD) and
other psychiatric
disorders
Common but not
usually serious
• Daytime
sleepiness
• Dry mouth
• Constipatio
n
• Dizziness
• Increased
appetite
• Weight gain
Less common but
not usually serious
• Increased
restlessness or
inability to stay
still
• Shaking of
hands and
fingers
• Decreased or
slowed
movements
and decreased
facial
expressions
Less common but
potentially
serious
• Stiffness of
tongue, jaw,
neck back or
legs
• Seizure
• Increased
thirst,
frequent
urination, and
other
symptoms
associated
with diabetes
Very rare but serious side
effects
• Extreme stiffness or
lack of movement, very
high fever, mental
confusion, irregular
pulse rate or eye pain
• Sudden stiffness and
inability to swallow
• Yellowing of skin or
eyes, stomach pain, and
other symptoms that
would indicate liver
damage
Trazodone Black Box Warning
• Antidepressants increased the risk
compared to placebo of suicidal thinking
and behavior (suicidality) in children,
adolescents, and young adults in short-
term studies of major depressive
disorder (MDD) and other psychiatric
disorders
Common
• Daytime drowsiness or sleepiness
• Dry mouth
• Dizziness
• Headache
• Blurred vision
• Nausea
• Decreased appetite
• Seeing trails or shadows that aren’t
there
• Tremors (shaking)
Serotonin Syndrome
• Early signs
• Restlessness
• Confusion
• Shaking
• Skin turning
red
• Sweating
• Jerking of
muscles
8. MetabolicConsequences ofUsingLow-DoseQuetiapinefor
InsomniainPsychiatricPatients
Study Population Intervention Outcomes Comments
Metabolic
Consequences of
Using Low-Dose
Quetiapine for
Insomnia in
Psychiatric
Patients
Forty-three patients
(20 – 65 years) on low
dose quetiapine
(<200mg) at bedtime
Inclusion criteria: 19 –
65 years old, low dose
(< 200mg at bedtime)
that was initiated
between January 2005
and July 2007 for the
explicit indication of
insomnia, recorded
metabolic parameters
at baseline and
subsequent clinic visits
Patients were
monitored on
their dose of less
than 200mg/day
of quetiapine at
bedtime
Weight and BMI increased by
an average of 4.9 pounds and
0.8 points, respectively
(statistically significant)
Seventeen gained 1 – 10
pounds; four gained 11 – 20
pounds; seven gained greater
than 20 pounds
Highest increases were seen
in male Caucasians
Vast majority were already
overweight or obese but both
experienced identical mean
weight gains
• Patients gained an average
of 4.7 pounds over about 11
months which is fairly
consistent with the 3.4
pound mean weight gain
seen in patients who
received less than 200mg of
quetiapine per day for 52
weeks in an analysis of
clinical trials involving use
of quetiapine in
schizophrenia.
9. Drug Potential Drug Interactions
Melatonin • Fluvoxamine: Avoid! Consider other SSRI if melatonin is needed due to increased sedative effect
• Melatonin: primarily metabolized by CYP1A2, weaker CYP2C9 and CYP2C19
• Fluvoxamine: potent inhibitor of CYP1A2 and CYP2C19 and weak 2C9
• Fluvoxamine induced increase in AUC and peak of melatonin by 23 fold and 12 fold after giving a
5mg dose
• In an animal study, melatonin supplements reduced antidepressant effects of desipramine and fluoxetine.
More research is needed to determine whether or not this would occur in people. Also, fluoxetine, an SSRI,
has led to measurable depletion of melatonin in individuals
• Potential interactions with medications that inhibit serotonin reuptake such as duloxetine and
venlafaxine
• SNRIs could interact with melatonin so consider.1
• Antipsychotic medications used to treat schizophrenia: in a study of 22 people with schizophrenia and
tardive dyskinesia caused by antipsychotic medications, those who took melatonin supplements had
significantly reduced mouth movements compared to those who didn’t
• Melatonin may reduce the effectiveness of blood pressure medications such as methoxamine and
clonidine. Also, CCBs may decrease melatonin levels
• Beta blockers may reduce melatonin production in the body
• NSAIDs may reduce levels of melatonin in blood
• Caffeine may interfere with sleep and make it more difficult for melatonin to work
Quetiapine • Use caution when taking in combination with other centrally acting drugs
• Quetiapine exposure is increased by CYP3A4 inhibitors such as ketoconazole, itraconazole, ritonavir, etc.
• Quetiapine exposure is decreased by CYP3A4 inducers including phenytoin, carbamazepine, rifampin, etc.
• Because of its potential for inducing hypotension, quetiapine may enhance the effects of certain
antihypertensive agents.
Trazodone • Trazodone may enhance the response to other CNS depressants such as barbiturates
• Trazodone exposure is increased by CYP3A4 inhibitors including ketoconazole, itraconazole, ritonavir, etc.
• Trazodone exposure is decreased by CYP3A4 inducers such as carbamazepine, phenytoin, rifampin and
others
• Increased serum phenytoin levels have been reported in patients receiving trazodone
• Serotonergic drugs in combination with trazodone may increase the risk of serotonin syndrome
10. Quetiapine Cases
Case
Number
Medication List Potential Drug Interactions
1 • Clomipramine
• Quetiapine
• Quetiapine: high risk QTc prolonging agent
• Clomipramine: intermediate risk QTc
prolonging agent
• Consider therapy modification
2 • Emtricitabine,
Rilpivirine,
Tenofovir
• Lamotrigine
• Quetiapine
• Quetiapine: high risk QTc prolonging agent
• Rilpivirine: intermediate risk QTc
prolonging agent
• Consider therapy modification
• Quetiapine & Lamotrigine: both CNS
depressants. Monitor patient for
symptoms including, but not limited to,
ataxia, confusion, drowsiness, respiratory
depression, and weakness
11. Trazodone Cases
Case
Number
Medication
List
Potential Drug Interactions
3 • Haloperidol
• Olanzapine
• Trazodone
• Valproic Acid
• Haloperidol: moderate risk QTc prolonging agent
• Olanzapine: possible risk of QTc prolongation
• Trazodone: moderate risk QTc prolonging agent
• Consider therapy modification
• Trazodone: serotonin modulator
• Olanzapine: antipsychotic agent
• Serotonin modulators may enhance the adverse/toxic effect of
antipsychotic agents. Specifically, serotonin modulators may
enhance dopamine blockade, possibly increasing risk for
neuroleptic malignant syndrome.
• Antipsychotic agents may enhance serotonergic effect of serotonin
modulators, which may result in serotonin syndrome
4 • Aripiprazole
• Mirtazapine
• Trazodone
• Mirtazapine: serotonin modulator
• Trazodone: serotonin modulator
• Increased risk of serotonin syndrome
• Consider therapy modification
5 • Sertraline
• Trazodone
• Sertraline: selective serotonin reuptake inhibitor
• Trazodone: antidepressant - serotonin reuptake inhibitor/antagonist
• SSRIs may enhance serotonergic effects of antidepressants, which
may result in serotonin syndrome
• Consider therapy modification
12. Melatonin Cases
Case
Number
Medication List Potential Drug Interaction
6 • Escitalopram
• Gabapentin
• Melatonin
• Possible interaction between melatonin
and escitalopram (SSRI) – may reduce
antidepressant effect of escitalopram
7 • Aripiprazole
• Benztropine
• Melatonin
• Possible interaction between aripiprazole
and melatonin – may increase risk of
tardive dyskinesia
8 • Aripiprazole
• Fluoxetine
• Lithium
• Melatonin
• Propranolol
• Possible interaction between fluoxetine and
melatonin – may reduce antidepressant
effect of fluoxetine
13. Melatonin and Quetiapine Case
Case
Number
Medication
List
Potential drug interactions
9 • Fluoxetine
• Melatonin
• Prazosin
• Quetiapine
• Fluoxetine: high risk QTc prolonging agent
• Quetiapine: high risk QTc prolonging agents
• Category X: avoid combination
• Possible interaction between fluoxetine and
melatonin: melatonin may decrease
antidepressant effects of fluoxetine
14. MelatoninEffectiveness Studies
Study Population Intervention Outcomes
Melatonin Improves
Health Status and
Sleep in Children
with Idiopathic
Chronic Sleep-Onset
Insomnia: A
Randomized
Placebo-Controlled
Trial
• 62 patients
• 20 Caucasian males, 7
Caucasian females in melatonin
group. Mean age of 9.2 years.
Six patients used
methylphenidate (10 – 25mg)
• 29 Caucasian males, 6
Caucasian females. Mean age of
10.6 years. Nineteen patients
used methylphenidate 10 –
25mg)
Melatonin group was
placed on 5mg PO at
7pm
Placebo group was
placed on the same
regimen but, instead,
was on an identical
looking placebo
tablet
Melatonin advanced
sleep onset by 57
minutes
Melatonin decreased
sleep latency by 17
minutes
The Efficacy of
Melatonin for Sleep
Problems in
Children with
Autism, Fragile X
Syndrome, or
Autism and Fragile X
Syndrome
• 18 subjects (2 – 15 years old) with
ASD or fragile X syndrome or both
• 3mg nightly for two
weeks with a one
week washout period
before switching to
alternative
• Improvements in total
sleep duration:
increased by 21
minutes
• Improvements in sleep
onset time: 42 minutes
earlier
Melatonin: An
Option for Managing
Sleep Disorders in
Children with
Autism Spectrum
Disorder
• 20 patients (4 – 16 years old) with
ASD who had sleep problems but did
not respond to behavioral
management
• Randomly assigned to
placebo or melatonin
2mg for three months
(dose escalated in
2mg increments every
3 days as needed to a
max dose of 10mg)
• Decreased sleep
latency by 46.7 minutes
• Increased total sleep
duration by average of
52.3 minutes
15. Topics to Consider
• Trazodone
• If a patient on 12.5mg dose, which one in the facility is, the pharmacy must cut
25mg tablet in half for the dose to be administered
• Unequal halves
• Forgetting to split
• Crumbling and breakage
• Discharge
• Dose when patient goes home. If the patient goes home on a 12.5mg dose, will they
remember to cut it or will they just take the full tablet. If they do cut it, how evenly is
it cut?
• Difficulty in monitoring
• QTc prolongation
• Serotonin syndrome
• Seroquel
• No indication for sleep: on label or off label
• Side effect profile
• Weight gain, which may contribute to potential future cardiovascular disease
• Discharge
• Monitoring
• QTc prolongation
• Weight gain and disease states associated with weight gain (ex. diabetes)
• Tardive dyskinesia
16. Works Cited
1. Melatonin. Clinical Pharmacology. Tampa, Florida: Gold Standard, Inc. http://www.clinicalpharmacology-
ip.com/Forms/Monograph/monograph.aspx?cpnum=2220&sec=moninte&t=0. Accessed December 05, 2014.
2. http://psychiatryonline.org/doi/pdf/10.1176/appi.books.9781585623686.ch38
3. Dennehy CE, Tsourounis C. Dennehy C.E., Tsourounis C Dennehy, Cathi E., and Candy Tsourounis.Chapter 64. Dietary Supplements &
Herbal Medications*. In: Katzung BG, Masters SB, Trevor AJ. Katzung B.G., Masters S.B., Trevor A.J. Eds. Bertram G. Katzung, et al.eds.
Basic & Clinical Pharmacology, 12e. New York, NY: McGraw-Hill; 2012.
http://accesspharmacy.mhmedical.com.jerome.stjohns.edu:81/content.aspx?bookid=388&Sectionid=45764292. Accessed December 05,
2014.
4. Melatonin: An option for managing sleep disorders in children with autism spectrum disorder
5. Trazodone drug interactions: http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=324d2543-477d-4c0b-bfa0-d76cb4e5cd48
6. http://link.springer.com/article/10.1007%2Fs10597-009-9200-0
7. http://connection.ebscohost.com/c/articles/93416551/melatonin-option-managing-sleep-disorders-children-autism-spectrum-disorder
8. http://www.ncbi.nlm.nih.gov/pubmed/19968048
