Anti -depressants ppt lecture Cology (1).pdf

Pharm D

1. Antidepressant
Dr. Kashif Iqbal

2. Introduction
The most common mood disorders are major
depression (unipolar depression) and manic-
depressive illness (bipolar disorder).
Major depression is a common disorder that
continues to result in considerable morbidity
and mortality despite major advances in
treatment.

3. Introduction
Definition:
Majordepressivedisorder(MDD),alsoknownsimplyas
depression,isamentaldisordercharacterizedbyatleast
twoweeksoflowmoodthatispresentacrossmost
situations.Itisoftenaccompaniedbylowself-esteem,loss
ofinterestinnormallyenjoyableactivities,lowenergy,and
painwithoutaclearcause.
Majordepressiongenerallypresentsasdepressedmood,
diminishedinterestinnormalactivities,anorexiawith
significantweightloss,insomnia,fatigue,andinabilityto
concentrate

4. Introduction
•By contrast, manic episodes associated with
manic-depressive illness are characterized by
expansive mood, grandiosity, inflated self
esteem, pressured speech, flight of ideas, and
poverty of sleep.

5. Treatment of major depression
•Itisoftensurprisingthatelevatingagentsdo
notactasstimulantsofthecentralnervous
system(CNS).
•Withtheexceptionofvarying
degreesofsedation,theantidepressantshave
littleeffectonbehaviorearlyintreatment.

6. Treatment
•Onlyafter2to3weeksofdosingwilla
therapeuticbenefitondepressionemerge.
•Inaddition,manyofthevegetativesignsofthe
illness(e.g.,insomnia,anorexia)abate,andthe
patientregainsaninterestindailyactivities.

7. Treatment
•Failuretocontinuethemedication,however,
willresultinanimmediaterelapseintothe
depressivestate.
•Therefore,maintenancetherapymustbe
continuedforatleast6months.

8. Classification

9. Mechanism of antidepressant drugs
•Mostclinicallyusefulantidepressantdrugs
(Figure10.1)potentiate,eitherdirectlyor
indirectly,theactionsofnorepinephrineand/or
serotonin(5-HT)inthebrain.This,alongwith
otherevidence,ledtothebiogenicaminetheory,
whichproposesthatdepressionisduetoa
deficiencyofmonoamines,suchas
norepinephrineandserotonin,atcertainkeybrain
sites

10. Mechanism
•Conversely,thetheoryproposesthatmaniais
causedbyanoverproductionofthese
neurotransmitters.
•However,thebiogenicaminetheoryof
depressionandmaniaisoverlysimplistic.

11. Selective Serotonin Reuptake
Inhibitors
•The selective serotonin reuptake inhibitors
(SSRIs) are a group of antidepressant drugs
that specifically inhibit serotonin reuptake,
having 300-to 3000-fold greater selectivity for
the serotonin transporter, as compared to the
norepinephrinetransporter.

12. SSRI
•SSRIshavelittleblockingactivityat
muscarinic,α-adrenergic,andhistaminicH1
receptors.
•SSRIshavelargelyreplacedTCAsand
monoamineoxidaseinhibitors(MAOIs)asthe
drugsofchoiceintreatingdepression.

13. SSRI
•TheSSRIsincludefluoxetine(theprototypic
drug),citalopram,escitalopram,fluvoxamine
,paroxetine,andsertraline.Escitalopramis
thepureS-enantiomerofcitalopram.

14. Actions
•TheSSRIsblockthereuptakeofserotonin,
leadingtoincreasedconcentrationsofthe
neurotransmitterinthesynapticcleft.
•Antidepressants,includingSSRIs,typically
takeatleast2weekstoproducesignificant
improvementinmood,andmaximumbenefit
mayrequireupto12weeksormore

15. Therapeutic uses
•The primary indication for SSRIs is
depression.
•Other’s are OCD, Panic disorder, GAD, PTSD,
Social anxiety disorder, and bulimia nervosa.

16. Pharmacokinetics
•All of the SSRIs are well absorbed after oral administration.
•Food has little effect on absorption (except with sertraline, for
which food increases its absorption).
•Plasma half life is between 16-36 hours.
•Metabolism by cytochrome P450 system.
•Fluoxetinediffers from the other members of the class by
having a much longer half-life (50 hours), and the half life of
its active metabolite S-norfluoxetineis quite long, averaging
10 days.
•Dosages of the SSRIs should be reduced in patients with
hepatic impairment.

17. Adverse effects
•Headache,sweating,anxietyandagitation,
gastrointestinal(GI)effects(nausea,vomiting,
diarrhea),weaknessandfatigue,sexual
dysfunction,changesinweight,sleep
disturbances(insomniaandsomnolence)

18. Adverse effects
•Sleep disturbances:
•Paroxetineandfluvoxaminearegenerallymore
sedatingthanactivating,andtheymaybe
usefulinpatientswhohavedifficultyin
sleeping.Conversely,patientswhoarefatigued
orcomplainingofexcessivesomnolencemay
benefitfromoneofthemoreactivatingSSRIs,
suchasfluoxetineorsertraline

19. Adverse effects
•Sexual dysfunction:
Sexualdysfunction,whichmayincludelossof
libido,delayedejaculation,andanorgasmia,is
commonwiththeSSRIs.Oneoptionfor
managingSSRI-inducedsexualdysfunctionis
tochangetheantidepressanttoonewithfewer
sexualsideeffects,suchasbupropionor
mirtazapine.

20. Adverse effects
•Use in children and teenagers:
•Antidepressants should be used cautiously in children and
teenagers, because about 1 out of 50 children report
suicidal ideation as a result of SSRI treatment.
•Pediatric patients should be observed for worsening
depression and suicidal thinking with initiation or dosage
change of any antidepressant.
•Fluoxetine, sertraline, andfluvoxamineare approved for
use in children to treat obsessive–compulsive disorder,
and fluoxetineand escitalopramare approved to treat
childhood depression

21. Adverse effects
•Overdose:
•Citalopram, may cause QT prolongation. [Note: The
TCAs have a significant risk for arrhythmias in
overdose.] Seizures are a possibility because all
antidepressants may lower the seizure threshold.
•All SSRIs have the potential to cause serotonin syndrome,
especially when used in the presence of a MAOI or other
highly serotonergicdrug.
•Serotonin syndrome may include the symptoms of
hyperthermia, muscle rigidity, sweating, myoclonus
(clonicmuscle twitching), and changes in mental status
and vital signs.

22. Adverse effects
•Discontinuation syndrome:
•All of the SSRIs have the potential to cause a
discontinuation syndrome after their abrupt withdrawal.
•Fluoxetinehas the lowest risk of causing an SSRI
discontinuation syndrome due to its longer half-life and
active metabolite.
•Possible signs and symptoms of SSRI discontinuation
syndrome include headache, malaise, and flu-like
symptoms, agitation and irritability, nervousness, and
changes in sleep pattern.

23. Serotonin/Noreinephrinereuptake
inhibitors
•Venlafaxine,desvenlafaxine , levomilnacipran
and duloxetineinhibit the reuptake of both
serotonin and norepinephrine(Figure 10.5).
•These agents, termed SNRIs, may be effective
in treating depression in patients in whom
SSRIs are ineffective.

24. Diagram

25. Detail
•Depressionisoftenaccompaniedbychronicpainful
symptoms,suchasbackacheandmuscleaches,againstwhich
SSRIsarealsorelativelyineffective.
•Painis,inpart,modulatedbyserotoninandnorepinephrine
pathwaysinthecentralnervoussystem(CNS).BothSNRIs
andtheTCAs,withtheirdualinhibitionofbothserotoninand
norepinephrinereuptake,aresometimeseffectiveinrelieving
painassociatedwithdiabeticperipheralneuropathy,
postherpeticneuralgia,fibromyalgia,andlowbackpain

26. Detail
•TheSNRIs,unliketheTCAs,havelittle
activityatα-adrenergic,muscarinic,or
histaminereceptorsand,thus,havefewerof
thesereceptor-mediatedadverseeffectsthan
theTCAs.
•The SNRIs may precipitate a discontinuation
syndrome if treatment is abruptly stopped.

27. Venlafaxine and desvenlafaxine
•Venlafaxine is a potent inhibitor of serotonin reuptake and,
at medium to higher doses, is an inhibitor of norepinephrine
reuptake.
•Venlafaxine has minimal inhibition of the CYP450
isoenzymesand is a substrate of the CYP2D6 isoenzyme.
•Desvenlafaxine is the active, demethylatedmetabolite of
venlafaxine.
•The most common side effects of venlafaxineare nausea,
headache, sexual dysfunction, dizziness, insomnia, sedation,
and constipation. At high doses, there may be an increase in
blood pressure and heart rate.

28. Duloxetine
•Duloxetine inhibits serotonin and norepinephrinereuptake
at all doses. It is extensively metabolized in the liver to
inactive metabolites and should be avoided in patients with
liver dysfunction.
•GI side effects are common with duloxetine, including
nausea, dry mouth, and constipation. Insomnia, dizziness,
somnolence, sweating, and sexual dysfunction are also seen.
•Duloxetine may increase blood pressure or heart rate.
•Duloxetine is a moderate inhibitor of CYP2D6 isoenzymes
and may increase concentrations of drugs metabolized by
this pathway, such as antipsychotics.

29. Levomilnacipran
•Levomilnacipranisanenantiomerof
milnacipran(anolderSNRIusedforthe
treatmentofdepressionandfibromyalgia).
•The adverse effect profile of levomilnacipran
is similar to other SNRIs. It is primarily
metabolized by CYP3A4, and, thus, activity
may be altered by inducers or inhibitors of this
enzyme system.

30. Reference
•Lippincott Illustrated Reviews: Pharmacology