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Introduction to depression and antidepressant agents

Learn about the diagnosis, symptoms, treatment, and neurobiological theories of depression and how antidepressant agents work. Explore the impact of depression on various medical conditions and the role of neurotrophic and monoamine hypotheses in depression. Discover the neuroendocrine factors associated with major depressive disorder.

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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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