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\n\u2022 The goal of treatment is complete
\nremission of current symptoms as well as
\nprevention of future relapses
\n\u2022 Treatment most often reduces or even
\neliminates symptoms, but not a cure since
\nsymptoms can recur after medicine is
\nstopped
\n\u2022 Continue treatment until all symptoms are
\ngone (remission)
\n\u2022 Once symptoms gone, continue treating for
\n1 year for the first episode of depression
\n\u2022 For second and subsequent episodes of
\ndepression, treatment may need to be
\nindefinite
\nIf It Doesn\u2019t Work
\n\u2022 Many patients have only a partial response
\nwhere some symptoms are improved but
\nothers persist (especially insomnia, fatigue,
\nand problems concentrating)
\n\u2022 Other patients may be nonresponders,
\nsometimes called treatment-resistant or
\ntreatment-refractory
\n\u2022 Consider increasing dose as early as
\n2 weeks after initiating treatment if
\na response is insufficient (decision on dose
\nincrease has to be balanced with a higher
\nrisk of transaminase elevation; any dose
\nincrease should be made on an individual
\npatient benefi t\/risk basis and with strict
\nrespect of liver function tests monitoring)
\n\u2022 Consider switching to another agent or
\nadding an appropriate augmenting agent
\n\u2022 Consider psychotherapy
\n\u2022 Consider evaluation for another diagnosis
\nor for a comorbid condition (e.g., medical
\nillness, substance abuse, etc.)
\n\u2022 Some patients may experience apparent
\nlack of consistent effi cacy due to activation
\nof latent or underlying bipolar disorder, and
\nrequire antidepressant discontinuation and
\na switch to a mood stabilizer
\nBest Augmenting Combos
\nfor Partial Response or
\nTreatment Resistance
\n\u2022 SSRIs (excluding fl uvoxamine), SNRIs,
\nbupropion, reboxetine, atomoxetine
\n(use combinations of antidepressant
\nwith caution as this may activate bipolar
\ndisorder and suicidal ideation)
\n\u2022 Modafi nil, especially for fatigue, sleepiness,
\nand lack of concentration
\n\u2022 Mood stabilizers or atypical antipsychotics
\nfor bipolar depression, psychotic depression,
\nor treatment-resistant depression
\n\u2022 Benzodiazepines
\nTests
\n\u2022 Liver function tests before initiation of
\ntreatment and then after around 3 weeks,
\n6 weeks, 12 weeks, 24 weeks, and
\nthereafter when clinically indicated
\n\u2022 When increasing the dose, liver
\nfunction tests should be performed at
\nthe same frequency as when initiating
\ntreatment
\n\u2022 Liver function tests should be repeated
\nwithin 48 hours in any patient who
\ndevelops raised transaminases
\nAgomelatine.indd 1 gomelatine.indd 1 7\/11\/2017 4:05:56 PM \/11\/2017 4:05:56 PM
\n2
\nAGOMELATINE (continued)
\naugmentation strategies to treat side
\neffects
\n\u2022 Many side effects are time-dependent (i.e.,
\nthey start immediately upon dosing and upon
\neach dose increase, but go away with time)
\n\u2022 Many side effects cannot be improved with
\nan augmenting agent
\n\u2022 Therotically activation and agitation may
\nrepresent the induction of a bipolar state,
\nespecially a mixed dysphoric bipolar II
\ncondition sometimes associated with
\nsuicidal ideation, and require the addition
\nof lithium, a mood stabilizer or an atypical
\nantipsychotic, and\/or discontinuation of
\nagomelatine (class warning)
\nSIDE EFFECTS
\nHow Drug Causes Side Effects
\n\u2022 Adverse reactions usually mild to moderate
\nand occur within the fi rst 2 weeks of treatment
\n\u2022 Actions at melatonergic receptors and at
\n5HT2C receptors could contibute to the
\nside effects described below
\nNotable Side Effects
\n\u2022 Nausea and dizziness are most common
\n\u2022 Other adverse reactions are somnolence,
\nfatigue, insomnia, headache, anxiety,
\ndiarrhea, constipation, upper abdominal
\npain, vomiting, hyperhidrosis
\n\u2022 Increase of transaminase levels
\nLife-Threatening or
\nDangerous Side Effects
\n\u273d Rare hepatitis, hepatic failure
\n\u2022 Theoretically rare induction of mania (class
\nwarning)
\n\u2022 Rare activation of suicidal ideation and
\nbehavior (suicidality) (short-term studies
\ndid not show an increase in the risk of
\nsuicidality with antidepressants
\ncompared to placebo beyond age 24)
\n(class warning)
\nWeight Gain
\n\u2022 Occurs in signifi cant minority
\n\u2022 Cases of weight decrease have been
\nreported
\nSedation (Somnolence)
\n\u2022 Occurs in signifi cant minority
\n\u2022 Generally transient
\n\u2022 May be more likely to cause fatigue than
\nsedation
\nWhat to Do About Side Effects
\n\u2022 Wait
\n\u2022 Wait
\n\u2022 Stop if transaminase levels exceed 3 times
\nthe upper limit of normal
\n\u2022 Switch to another drug
\nBest Augmenting Agents for Side
\nEffects
\n\u2022 Often best to try another antidepressant
\nmonotherapy prior to resorting to
\nDOSING AND USE
\nUsual Dosage Range
\n\u2022 25\u201350 mg\/day at bedtime
\nDosage Forms
\n\u2022 Tablet 25 mg
\nHow to Dose
\n\u2022 Initial 25 mg\/day at bedtime; after
\n2 weeks can increase to 50 mg\/day
\nat bedtime
\nDosing Tips
\n\u2022 If intolerable anxiety, insomnia, agitation,
\nakathisia, or activation occur either upon
\ndosing initiation or discontinuation,
\nconsider the possibility of activated bipolar
\ndisorder and switch to a mood stabilizer or
\nan atypical antipsychotic
\nOverdose
\n\u2022 Drowsiness and epigastralgia; fatigue,
\nagitation, anxiety, tension, dizziness,
\ncyanosis, or malaise have also been
\nreported
\nLong-Term Use
\n\u2022 Treatment up to 12 months has been found
\nto decrease rate of relapse
\nHabit Forming
\n\u2022 No
\nHow to Stop
\n\u2022 No need to taper dose
\nAgomelatine.indd 2 gomelatine.indd 2 7\/11\/2017 4:05:56 PM \/11\/2017 4:05:56 PM
\n(continued) AGOMELATINE
\n3
\nPharmacokinetics
\n\u2022 Half-life 1\u20132 hours
\n\u2022 Metabolized primarily by CYP450 1A2
\nDrug Interactions
\n\u2022 Use of agomelatine with potent CYP450
\n1A2 inhibitors (e.g., fl uvoxamine) is
\ncontraindicated
\n\u2022 Tramadol increases the risk of seizures in
\npatients taking an antidepressant (class
\nwarning)
\nOther Warnings\/
\nPrecautions
\n\u2022 Use with caution in patients with hepatic
\ninjury risk factors, such as obesity\/
\noverweight\/non-alcoholic fatty liver disease,
\ndiabetes, patients who drink large quantities
\nof alcohol and\/or have alcohol use disorder,
\nor who take medication associated with risk
\nof hepatic injury. Doctors should ask their
\npatients if they have ever had liver problems.
\n\u2022 If symptoms or signs of potential liver
\ninjury (dark urine, light-colored stools,
\nyellow skin\/eyes, pain in upper right belly,
\nsustained new-onset and unexplained
\nfatigue) are present, agomelatine should be
\ndiscontinued immediately
\n\u2022 Use caution in patients with pre-treatment
\nelevated transaminases (> the upper limit
\nof the normal range and \u2264 3 times the
\nupper limit of the normal range)
\n\u2022 Discontinue treatment if serum
\ntransaminases exceed 3 times the upper
\nlimit of normal; liver function tests should
\nbe performed regularly until serum
\ntransaminases return to normal
\n\u2022 Agomelatine should be administered at
\nbedtime
\n\u2022 Use with caution in patients with bipolar
\ndisorder unless treated with concomitant
\nmood-stabilizing agent
\n\u2022 When treating children off label (an
\nunapproved use), carefully weigh the
\nrisks and benefi ts of pharmacological
\ntreatment against the risks and benefi ts
\nof nontreatment with antidepressants and
\nmake sure to document this in the patient\u2019s
\nchart
\n\u2022 Warn patients and their caregivers about
\nthe possibility of activating side effects
\nand advise them to report such symptoms
\nimmediately
\n\u2022 Monitor patients for activation of suicidal
\nideation, especially children and adolescents
\nDo Not Use
\n\u2022 If patient has hepatic impairment
\n\u2022 If patient has transaminase levels > 3 times
\nthe upper limit of normal
\n\u2022 If patient is taking a potent CYP450 1A2
\ninhibitor (e.g., fl uvoxamine, ciprofl oxacin)
\n\u2022 If patient is taking an MAO inhibitor (MAOI)
\n\u2022 If patient has galactose intolerance, Lapp
\nlactase defi ciency, or glucose-galactose
\nmalabsorption
\n\u2022 If there is a proven allergy to agomelatine
\nSPECIAL POPULATIONS
\nRenal Impairment
\n\u2022 Drug should be used with caution
\nHepatic Impairment
\n\u2022 Contraindicated
\nCardiac Impairment
\n\u2022 Dose adjustment not necessary
\nElderly
\n\u2022 Effi cacy and safety have been established
\n(< 75 years old)
\n\u2022 Dose adjustment not necessary
\n\u2022 Should not be used in patients age
\n75 years and older
\n\u2022 Should not be used in elderly patients with
\ndementia
\nChildren and Adolescents
\n\u2022 Carefully weigh the risks and benefi ts
\nof pharmacological treatment against
\nthe risks and benefi ts of nontreatment
\nwith antidepressants and make sure to
\ndocument this in the patient\u2019s chart
\n\u2022 Monitor patients face-to-face regularly,
\nparticularly during the fi rst several weeks
\nof treatment
\n\u2022 Safety and effi cacy have not been established
\nand it is not recommended
\nPregnancy
\n\u2022 Controlled studies have not been
\nconducted in pregnant women
\n\u2022 Not generally recommended for use during
\npregnancy, especially during fi rst trimester
\nAgomelatine.indd 3 gomelatine.indd 3 7\/11\/2017 4:05:58 PM \/11\/2017 4:05:58 PM
\n4
\nAGOMELATINE (continued)
\nPrimary Target Symptoms
\n\u2022 Depressed mood, anhedonia
\n\u2022 Functioning
\n\u2022 Anxiety within depression
\nPearls
\n\u2022 Agomelatine represents a novel approach to
\ndepression through a novel pharmacologic
\nprofi le, agonist at melatonergic MT1 \/
\nMT2 receptors and antagonist at 5HT2C
\nreceptors acting synergistically
\n\u2022 This synergy provides agomelatine with
\na distinctive effi cacy profi le, different
\nfrom conventional antidepressants with
\npotentially an early and continuous
\nimprovement over time
\n\u2022 Agomelatine improves anhedonia early in
\ntreatment
\n\u2022 Improves anxiety in major depressive
\ndisorder
\n\u2022 May be fewer withdrawals\/discontinuations
\nfor adverse events than with other
\nantidepressants
\n\u2022 No signifi cant effect on cardiac parameters
\nsuch as blood pressure and heart rate
\n\u2022 Some data suggest that agomelatine
\nmay be specially effi cacious in achieving
\nfunctional remission
\n\u2022 Agomelatine may improve sleep quality
\nby promoting proper maintenance of
\ncircadian rhythms underlying a normal
\nsleep-wake cycle
\n\u2022 Must weigh the risk of treatment (fi rst
\ntrimester fetal development, third trimester
\nnewborn delivery) to the child against
\nthe risk of no treatment (recurrence
\nof depression, maternal health, infant
\nbonding) to the mother and child
\n\u2022 For many patients this may mean
\ncontinuing treatment during pregnancy
\nBreast Feeding
\n\u2022 Unknown if agomelatine is secreted in
\nhuman breast milk, but all psychotropics
\nassumed to be secreted in breast milk
\n\u2022 Therefore, breast feeding or drug needs to
\nbe discontinued
\n\u2022 Immediate postpartum period is a high-risk
\ntime for depression, especially in women
\nwho have had prior depressive episodes,
\nso drug may need to be reinstituted late
\nin the third trimester or shortly after
\nchildbirth to prevent a recurrence during
\nthe postpartum period
\nTHE ART OF PSYCHOPHARMACOLOGY
\nPotential Advantages
\n\u2022 Patients with lack of energy, anhedonia,
\nanxious comorbidity, and sleep-wake
\ndisturbances
\n\u2022 Patients particularly concerned about
\nsexual side effects
\nPotential Disadvantages
\n\u2022 Patients with hepatic impairment
\nAgomelatine.indd 4 gomelatine.indd 4 7\/11\/2017 4:05:58 PM \/11\/2017 4:05:58 PM
\n(continued) AGOMELATINE
\n5
\nSuggested Reading
\nDeBodinat C , Guardiola-Lemaitre B , Mocaer
\nE , et al. Agomelatine, the fi rst melatonergic
\nantidepressant: discovery, characterization,
\nand development . Nat Rev Drug Discov
\n2010 ; 9 : 628 \u201342.
\nGoodwin GM , Emsley R , Rembry S , Rouillon F.
\nAgomelatine prevents relapse in patients with
\nmajor depressive disorder without evidence
\nof a discontinuation syndrome: a 24-week
\nrandomized, double-blind, placebo-controlled
\ntrial . J Clin Psychiatry 2009 ; 70 : 1128 \u201337.
\nKennedy SH , Avedisova A , Bela\u00efdi C ,
\nPicarel-Blanchot F , de Bodinat C . Sustained
\neffi cacy of agomelatine 10 mg, 25 mg, and
\n25\u201350 mg on depressive symptoms and
\nfunctional outcomes in patients with major
\ndepressive disorder. A placebo-controlled
\nstudy over 6 months . Neuropsychopharmacol
\n2016 ; 26 (2): 378 \u201389.
\nKhoo AL, Zhou HJ, Teng M, et al. Network
\nmeta-analysis and cost-effectiveness analysis
\nof new generation antidepressants. CNS Drugs
\n2015;29(8):695\u2013712 .
\nMartinotti G , Sepede G , Gambi F , et al.
\nAgomelatine versus venlafaxine XR in the
\ntreatment of anhedonia in major depressive
\ndisorder: a pilot study . J Clin Psychopharmacol
\n2012 ; 32 (4): 487 \u201391.
\nRacagni G , Riva MA , Molteni R , et al. Mode
\nof action of agomelatine: synergy between
\nmelatonergic and 5-HT2C receptors . World J
\nBiol Psychiatry 2011 ; 12 (8): 574 \u201387.
\nStahl SM , Fava M , Trivedi M , et al. Agomelatine
\nin the treatment of major depressive disorder.
\nAn 8 week, multicenter, randomized,
\nplacebo-controlled trial . J Clin Psychiatry
\n2010 ; 71 (5): 616 \u201326.
\nStahl SM . Mechanism of action of
\nagomelatine: a novel antidepressant exploiting
\nsynergy between monoaminergic and
\nmelatonergic properties . CNS Spectrums
\n2014 ; 19: 207 \u201312.
\nStein DJ , Picarel-Blanchot F , Kennedy
\nSH. Effi cacy of the novel antidepressant
\nagomelatine on anxiety symptoms in
\nmajor depression . Hum Psychopharmacol
\n2013 ; 28 (2): 151 \u20139.
\nTaylor D , Sparshatt A , Varma S , Olofi njana O .
\nAntidepressant effi cacy of agomelatine: metaanalysis
\nof published and unpublished studies .
\nBMJ 2014 ; 348 : g2496.
\nAgomelatine.indd 5 gomelatine.indd 5 7\/11\/2017 4:05:58 PM \/11\/2017 4:05:58 PM
\nAgomelatine.indd 6 gomelatine.indd 6 7\/11\/2017 4:05:58 PM \/11\/2017 4:05:58 PM<\/p>\n","protected":false},"excerpt":{"rendered":"