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  2. 2. OVERVIEW OF DEPRESSION DepressionDepression is a state of low mood andaversion to activity. Depression is asyndrome. Depressive syndromes :Depressive syndromes :- major depression(with subtypes)- dysthymic disorder(low-grade but verychronic form of depression, which lastsfor more than 2 years)- minor depression
  3. 3. CLINICAL PRESENTATION(SYMPTOMS) Emotions :Emotions : depressed mood loss of interest or pleasure in most or all activities IdeationIdeation thoughts of worthlessness or guilt recurrent thoughts about death or suicide Somatic symptomsSomatic symptoms change in appetite or weight low energy psychomotor retardation or agitation poor concentration
  4. 4. SOME DEPRESSION FEATURES Depression is an illness, not ais an illness, not achoicechoice, and is just as sociallydebilitating as coronary arterydisease and more debilitating thandiabetes mellitus or arthritis. Up to 15% of severely depressedpatients will ultimately commitsuicide. Depression can be successfullysuccessfullytreatedtreated.
  5. 5. DepressionDepression is episodic, with untreated episodescommonly lasting 6 to 24 months, followed byrecovery or remission.
  6. 6. BIOCHEMICAL BASIS OF DEPRESSIONNoradrenergicNoradrenergicsynapsesynapsestructurestructure
  8. 8. BIOCHEMICAL BASIS OF DEPRESSIONMonoamine Hypothesis:Monoamine Hypothesis: depression was due to adeficiency of monoamine neurotransmitters, notablynor-epinephrine (NE) and serotonin (5-hydroxytryptamine [5HT])
  9. 9. EVIDENCE FOR MONOAMINE HYPOTHESIS Certain drugs that depleted these neurotransmitters could inducedepression Known antidepressants at that time both had pharmacologicalactions that boosted these neurotransmitters. The idea was that the "normal" amount of monoamineneurotransmitters became somehow depleted, perhaps by anunknown disease process, by stress, or by drugs leading to thesymptoms of depression. An overly simplified notion about depression
  10. 10. BIOCHEMICAL BASIS OF DEPRESSION Neurotransmitter ReceptorNeurotransmitter ReceptorHypothesisHypothesis The neurotransmitter receptor theory posits that something is wrong withthe receptors for the key monoamine neurotransmitters.
  11. 11. In this figure, monoamine neurotransmitter isIn this figure, monoamine neurotransmitter isdepleted (see red circle).depleted (see red circle).
  12. 12. The consequences of monoamine neurotransmitterdepletion could cause the postsynaptic receptors toabnormally up-regulate (indicated in red circle). This up-regulation or other receptor dysfunction is hypotheticallylinked to the cause of depression.
  13. 13.  there is no clear and convincing evidence that monoamine deficiencyaccounts for depression there is no clear and convincing evidence that excesses or deficienciesof monoamine receptors account for depression; there is growing evidence that despite apparently normal levels ofthere is growing evidence that despite apparently normal levels ofmonoamines and their receptors, these systems do not respond normallymonoamines and their receptors, these systems do not respond normally
  14. 14. MONOAMINE HYPOTHESIS OFGENE EXPRESSIONThe monoamine hypothesis of gene expression proposes thatdepression itself is linked to abnormal functioning ofneurotransmitter-inducible gene expression, particularly neurotrophicfactors such as brain-derived neurotrophic factor (BDNF), leading toatrophy and apoptosis of critical hippocampal neurons.
  15. 15. MECHANISM OF ACTIONAll antidepressants have a common action on monoamine neurotransmitters:they increase monoamine neurotransmission, leading tochanges in gene expression in the neuronstargeted by the monoamines. This includes desensitization ofneurotransmitter receptors, leading to both therapeutic action and toleranceto side effects.
  16. 16. Effectdevelops onlyafter 10-14days.
  17. 17. ANTIDEPRESSANTS TYPES 1 Selective serotonin reuptake inhibitors (SSRIs) Citalopram,Escitalopram, Fluoxetine 2 Serotonin-norepinephrine reuptake inhibitors (SNRIs) Duloxetine,Venlafaxine 3 Norepinephrine reuptake inhibitors (NRIs)Atomoxetine, Reboxetine 4 Norepinephrine-dopamine reuptake inhibitors (NDRIs) Bupropion,Methylphenidate
  18. 18.  5 Tricyclic antidepressant (TCAs) Amitriptyline, Clomipramine, Imipramine 6 Tetracyclic antidepressants (TeCAs) Mianserin, Maprotiline 7 Monoamine oxidase inhibitors (MAOIs) – reversible and irreversiblePhenelzine, Selegiline(MAO-B),Moclobemide, Tranylcypromine
  19. 19. TRICYCLIC ANTIDEPRESSANTS(TCA)- Their organic chemical structurecontains three rings.- The majority of the TCAs act primarily asserotonin-norepinephrine reuptakeinhibitors (SNRIs).As other tricyclic drugs (antipsychotic) they haveantimuscarinic, antihistaminic and alfa-receptor blockingactivity.
  20. 20. TCA SIDE EFFECTSDrowsinessDry mouthBlurred visionConstipationUrinary retentionDizzinessImpaired sexual functioningIncreased heart rateDisorientation orconfusionHeadacheLow blood pressureSensitivity to sunlightIncreased appetiteWeight gainToxocity: 3 C’s – coma, convulsions,cardiootoxicity.
  21. 21. MAO INHIBITORS Reversible or irreversible inhibition of monoaminooxydase. Monoamine oxidase exists in two subtypes, A and B. Both forms are inhibited by the original MAO inhibitors, which aretherefore nonselective The A form metabolizes the neurotransmitter monoamines most closelylinked to depression MAO A inhibition is linked both to antidepressant action and to thetroublesome hypertensive side effects of the MAO inhibitors.
  22. 22. MAO INHIBITORS CON’TNowadays we have selective inhibitors of MAO A or of MAO B andreversible inhibitors.Reversible inhibitors of MAO A called RIMAs.Exogenous amines(tyramine in cheese) can markedly elevate bloodpressure in the presence of irreversible MAO inhibitors.
  23. 23. SELECTIVE SEROTONIN REUPTAKE INHIBITORS(SSRI)Inhibition of serotonin reuptake into the presynaptic cell, increasing thelevel of serotonin available to bind to the postsynaptic receptor
  24. 24. SSRIS PHARMACOLOGY Uses:- Major depresion- Bulimia- Anxiety disorders- Premenstrual dysphoric disorderSide effects:- Anxiety- Bruxism(the habit of grinding the teeth)- Agitation- Weight loss- Sexual dysfunction(delay ejaculation)
  25. 25. 123 4Cytochrome P450 – CYP450
  27. 27. CNS STIMULANTS Stimulants are psychoactive drugs which inducetemporary improvements in either mental or physical function orboth. Common effects:Increased alertness, awareness, wakefulness, endurance,productivity, and motivation, increased arousal, locomotion, heartrate, and blood pressure, and the perception of a diminishedrequirement for food and sleep.Stimulants are widely used throughout the world(social drugs, OTCdrugs, illegal drugs).
  28. 28. CAFFEINE discovered by a German chemistin 1819 xanthine alkaloid Source : beans, leaves, and fruitof some plants, where it acts asa natural pesticide kills certaininsects feeding on the plants coffee plant, leaves of the tea,kola nut, guarana berries
  29. 29. PHARMACOLOGYHalf-life—varies widely among individuals according to age, liver function,pregnancy, some concurrent medications, and velocity of metabolism -approximately 4.9 hoursIn women taking oral contraceptives 5–10 hoursIn pregnant women - 9–11 hoursSevere liver disease - up to 96 hoursSmoking can shorten caffeines half-life
  30. 30. Caffeine is metabolized in the liver by thecytochrome P450 1A2 into:- Paraxanthine (84%): Has the effect ofincreasing lipolysis, leading to elevatedglycerol and free fatty acid levels in theblood plasma.- Theobromine (12%): Dilates blood vesselsand increases urine volume. Theobromine isalso the principal alkaloid in the cocoa bean,and therefore chocolate.- Theophylline (4%): Relaxes smooth musclesof the bronchi, and is used to treat asthma.
  31. 31. CNS EFFECTSincreased alertness and wakefulness,faster and clearer flow of thoughtincreased focus and better general body coordination
  32. 32. readily crosses the blood–brain barriercaffeine molecule is structurally similar toadenosinebinds to adenosine receptors on the surface of cellswithout activating themcaffeine acts as a competitive inhibitorcompetitive nonselective phosphodiesteraseinhibitor which raises intracellular cAMP,activates PKAMechanism of actionMechanism of action
  33. 33. AMPHETAMINE GROUPAmphetamineMethamphetamineLevoamphetamineDextroamphetamineMajor neurobiological mechanisms:-most widely studied neurotransmitter with regard toamphetamine action is dopamine-increasing dopamine release from pre-synaptic membrane-amphetamine inhibit dopamine reuptake
  34. 34. PHYSICAL EFFECTSReduced appetiteIncreased/distorted sensations,HyperactivityDilated pupilsRestlessnessTachycardiaIncreased blood pressureSweatingUncontrollable movements or shaking
  35. 35. PSYCHOLOGICAL EFFECTS Euphoria (via increased dopamine) Increased anxiety (via increasednorepinephrine) alertness concentration energy self-esteem self-confidence aggressionAlso:-Dependence-Tolerance-Withdrawalsyndrome
  36. 36. MODAFINILtreatment of narcolepsy, shift work sleep disorder and excessive daytimesleepiness associated with obstructive sleep apneaincrease the levels of various monoamines dopamine, noradrenaline andserotonin in synaptic cleftactivates glutamatergic circuits while inhibiting GABAergic neurotransmission
  37. 37. SIDE EFFECTSThe most common side effects of modafinil in clinical trialsare:headacheupper respiratory tract infectionNauseaNervousnessAnxietyinsomnia