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Introduction to depression and antidepressant agents

Domina Petric , MD. Introduction to depression and antidepressant agents. Depression. The diagnosis of depression rests primarily on the clinical interview .

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Introduction to depression and antidepressant agents

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  1. Domina Petric, MD Introduction to depressionandantidepressantagents

  2. Depression • Thediagnosisofdepressionrestsprimarily on theclinicalinterview. • Major depressivedisorder (MDD) is characterizedbydepressedmoodmost ofthe time for at least2 weeksand/or lossofinterest or pleasurein most activities. • Depression is alsocharacterisedbydisturbancesinsleepandappetite, as well as deficitsincognitionandenergy. Katzung, Masters, Trevor. Basic and clinical pharmacology.

  3. Depression • Thoughtsofguilt, worthlessnessand suicide are common. • Coronaryarterydisease, diabetesandstrokeappear to be more commonindepressedpatients. • Depressionmayconsiderablyworsentheprognosis for patientswith a varietyofcomorbidmedicalconditions. Katzung, Masters, Trevor. Basic and clinical pharmacology.

  4. Depression • Theprimaryindication for antidepressantagents is thetreatmentof MDD. • MDD represents one ofthe most commoncausesofdisabilityinthedevelopedworld. • Major depression is commonlyassociatedwith a varietyofmedicalconditions, fromchronicpain to coronaryarterydisease. Katzung, Masters, Trevor. Basic and clinical pharmacology.

  5. Antidepressants are alsousedinthetreatmentof: • panicdisorder • generalizedanxietydisorder (GAD) • posttraumaticstressdisorder (PTSD) • obsessive-compulsivedisorder (OCD) • neuropathicpain • painassociatedwithfibromyalgia • premenstrualdysphoricdisorder (PMDD) • stressurinaryincontinence Katzung, Masters, Trevor. Basic and clinical pharmacology.

  6. Pathophysiologyof major depression Katzung, Masters, Trevor. Basic and clinical pharmacology.

  7. Neurotrophichypothesis • Nerve growthfactorssuch as brain-derivedneurotrophicfactor (BDNF) are criticalintheregulationofneuralplasticity, resilienceandneurogenesis. • Depression is associatedwiththelossofneurotrophicsupport. • Effectiveantidepressanttherapiesincreaseneurogenesisandsynapticconnectivityincorticalareassuch as hippocampus. Katzung, Masters, Trevor. Basic and clinical pharmacology.

  8. Neurotrophichypothesis • BDNF is thought to exertits influence on neuronalsurvivalandgrowtheffectsbyactivatingthetyrosinekinase receptor B inbothneuronsandglia. • Stressandpainare associatedwith a drop in BDNF levels. • Thislossofneurotrophicsupportcontributes to atrophicstructuralchangesinthehippocampusandmaybeotherareas, such as themedialfrontalcortexandanteriorcingulate. Katzung, Masters, Trevor. Basic and clinical pharmacology.

  9. Neurotrophichypothesis Katzung, Masters, Trevor. Basic and clinical pharmacology.

  10. Neurotrophichypothesis • Major depression is associatedwith a 5-10% lossofvolumeinthehippocampus. • Depressionandchronicstressstateshavealsobeenassociatedwith a substantiallossofvolumeintheanteriorcingulateandmedialorbitalfrontalcortex. • Lossofvolumeinstructures, such as thehippocampus, appears to increase as a functionofthedurationofillnessandtheamountof time thatthedepressionremainsuntreated. Katzung, Masters, Trevor. Basic and clinical pharmacology.

  11. Neurotrophichypothesis • Depressionappears to beassociatedwith a drop in BDNF levelsinthecerebrospinal fluid and serum, as wellaswith a decreaseintyrosinekinase receptor B activity. • Administrationofantidperessantsincreases BDNF levelsandmaybeassociatedwithanincreaseinhippocampusvolumein some patients. Katzung, Masters, Trevor. Basic and clinical pharmacology.

  12. Monoaminehypothesis • Themonoaminehypothesisofdepressionsuggeststhatdepression is related to a deficiencyintheamountoffunctionofcorticalandlimbic serotonin (5-HT), norepinephrine (NE) anddopamine (DA). • Reserpinedepletesmonoamines: treatmentwithreserpine is associatedwithdepressionin a subsetofpatients. Katzung, Masters, Trevor. Basic and clinical pharmacology.

  13. Monoaminehypothesis • A functionalpolymorphismexists for thepromoterregionofthe serotonin transporter gene. • This gene regulates how muchofthe transporter protein is available. • Subjectswho are homozygous for theshortallelemaybemore vulnerable to developing major depressionandsuicidalbehaviorinresponse to stress. Katzung, Masters, Trevor. Basic and clinical pharmacology.

  14. Monoaminehypothesis Katzung, Masters, Trevor. Basic and clinical pharmacology.

  15. Neuroendocrinefactors • Depression is associatedwith a numberofhormonalabnormalities. MDD is associatedwith: • elevatedcortisollevels • nonsuppressionofadrenocorticotropic hormone (ACTH) releaseinthedexamethasonesuppression test • chronicallyelevatedlevelsofcorticotropin-releasing hormone Katzung, Masters, Trevor. Basic and clinical pharmacology.

  16. Neuroendocrinefactors • More severetypesofdepression, such as psychoticdepression, tend to beassociatedwith HPA abnormalities more commonlythanmilderformsof major depression. • Bothexogenousglucocorticoidsandendogenouselevationofcortisolare associatedwithmoodsymptomsandcognitivedeficitssimilar to thoseseenin MDD. Katzung, Masters, Trevor. Basic and clinical pharmacology.

  17. Neuroendocrinefactors • Up to 25% ofdepressedpatients are reported to haveabnormalthyroidfunction. • Theseinclude a bluntingofresponseofthyrotropin to thyrotropin-releasing hormone andelevationsincirculatingthyroxineduringdepressedstates. • Clinicalhypothyroidismoftenpresentswithdepressivesymptoms, whichresolvewiththyroid hormone supplementation. Katzung, Masters, Trevor. Basic and clinical pharmacology.

  18. Neuroendocrinefactors • Thyroidhormonesare alsocommonlyusedinconjunctionwith standard antidepressants to augmenttherapeuticeffectsofantidepressants. • Estrogen deficiencystates, whichoccurinthepostpartumandpostmenopausalperiods, mayplay a role intheetiologyofdepressionin some women. • Severe testosterone deficiencyinmen is sometimesassociatedwithdepressivesymtpoms. Katzung, Masters, Trevor. Basic and clinical pharmacology.

  19. Neuroendocrinefactors Katzung, Masters, Trevor. Basic and clinical pharmacology.

  20. Integrationofhypotheses • Monoamine, neuroendocrineandneurotrophicsystems are interrelatedinimportantways. • HPA and steroid abnormalitiesmaycontribute to suppressionoftranscriptionofthe BDNF gene. • Glucocorticoidreceptors are foundinhighdensityinthehippocampus. • Bindingofthesehippocampalreceptorsbycortisolduringchronicstressstatesmaydecrease BDNF synthesisandmayresultinvolumelossinstress-sensitiveregions (for example, hippocampus). Katzung, Masters, Trevor. Basic and clinical pharmacology.

  21. Integrationofhypotheses • Thechronicactivationofmonoaminereceptorsbyantidepressantsappears to havetheoppositeeffectofstress: increasein BDNF transcription. • Activationofmonoaminereceptorsappears to down-regulatethe HPA axisandmaynormalizeHPAfunction. • Amine levelsincreaseimmediatelywithantidepressant use. • Protein synthesisof BDNF typicallytakes 2 weeks or longer. Katzung, Masters, Trevor. Basic and clinical pharmacology.

  22. Literature • Katzung, Masters, Trevor. Basicandclinicalpharmacology. Katzung, Masters, Trevor. Basic and clinical pharmacology.

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