1. Dr salman kareem

2. 2 3. 1. Catecholamine Hypothesis2. Serotonin Hypothesis3. Adrenergic Cholinergic Balancehypothesis4. Serotonin nor epinephrine dichotomy5. Opioid Hypothesis6. Receptor down regulation hypothesis7. GABA hypothesis 4. Widely known and acknowledgedActivity of catecholamines are high inmania and diminshed levels in depression.Higher urinary methoxy hydroxy phenylglycol 5. Nor epinephrine Manic patients higher urinary MHPG levels thandepressed patients. Plasma MHPG levels are also high Plasma levels of cAMP is raised in mani and lowin depression. CSF MHPG is higher in mania. 6. Fusaric acid inhibits enzyme dopamine hydroxylase ( converts DA NE) leadingto decrease in synthesis of NEClonidine reduces NE transmission bydirect action on presynaptic receptors andthus improves manic symptom.Propranolol posses anti manic properties.action of venlafaxine noradrenergiceffect. 7. Down regulation of b adrenergic receptorsand the clinical anti depressent response.Reduction in the activity of alpha -2adrenergic recpetors leading to decreasein NE. 8. Dopamine Overactivity of dopamine plays important role inpathogenesis of mania. Drugs and disease that reduce dopamineconcentraton lead to depression. CSF homvallinic acid is elevated in mania / switchfrom depression to mania. 9. L DOPA , amphetmanine preciptates maniasymptomsDopmaine recpetor agonists likebromocriptine and piribedil precipitates mania Bupropion reduces the depression.Various anti psychotic driugs(chlorpromazine,haloperidol and pimozide )have dopamine receptor blocking actionshown to have more effectiv ein it. 10. two new theoriesMesolimbicdopaminepathway bedysfuntionalDopamine D1receptor hypoactive 11. Serotonin is the biogenic amine mostcommonly associated with depression.Pathophysiology of depression.Normal or reduced levels of 5 HIAA , aprimary metabolite of serotonin in manicpatients. 12. Balance between the twoDepression a disease of cholinergicpreponderance and mania is a disease ofadrenergic preponderanceAnti catecholamine drugs (have centraland peripheral cholinomimetic activity).Physostigmine a cholinesterase inhibitorcauses dramatic decrease in the manicand hypomanic symptoms. 13. A tri cyclic anti depressant is given only ifthe patient has nor adrenergic orserotonergic depression.Assessed by presence of CSF MHPG. 14. Hypothesis that central opiod mechanismcontrol of expression of mood.Positive evidence I V endorophinsNegative no action of methadone 15. Inhibitory neurotransmitter Postulated to contribute to the etiology ofpsychotic states.Reduction have been observed in plasma ,CSF and brain GABA levels in depression.Sodium valproate inhibits the degradation ofGABA and reported improvement in acutemania and effective in prophylaxis of bipolardisorder. 16. Hypothalamic pituitary adrenal axis(HPA)Midnight levels are increased in pts withmood disorder.50% manifest a decrease suppression ofcortisol secretion after administration ofdexamethasone. 17. Carrol Et al1mg of DXM orally at 11pmPlasma cortisol levels are determined at 8am, 4pm amd 11 am.Above 5g/dl abnormalCan be used to follow the response ofdepressed person to treatment.Normalization of DST not an indication tostop antidepressent 18. FALSE POSITIVE FALSE NEGATIVE Cushings disease Estrogen Severe weight loss Drugs phenytoinbarbiturates Uncontrolled Dm Gh grade fever A/c alcohol withdrawal Addisons disease Hypopitutarism Steroids benzodiazepines 19. Hypothalamic Pituitary Adrenal Axis (HPA)overactivity (elevated CRH and cortisol,dexamethasone resistance) is present in manypatients with severe depression. Corticosteroids reduce hippocampal 5-HT1Areceptor sites in animal studies and may explainreduced hippocampal damage in depression.20 20. Release of thyroid secreting hormone is byTRH , via anterior pituitary.Release of TRH is influenced by limbic andother brain areas. 21. 500 mg ofTRh is given in morning via IVover 30 seconds.Blood samples of TRH are collectedatevery 15 min intervals upto 15 minincluding baseline (pre TRH push).Maximal TRH difference is calculated frombaseline.5-7 mg/ml is considered abnormal. 22. 3. Hypothalamic pituitary growyh hormoneaxis CSF levels of somatostatin is decreased indepressed patients. Abnormal positive growth hormone response toTRh in depressed patients.4. Hypothalamic pituitary prolactin axis Inconclusive Prolactin secretion is altered in nocturnalsecretion in depressed pts 23. 5. Melatonin Stimulated by nor adrenergic recpetors Secreted at night under the influence ofcircadian rhythm. Decreased in depression.6. Insulin tolerance test 44% of bipolar and 60% of unipolar haveblunted ITT7. Vasopressin 24. Depression can interfere withimmunological competenceSeverely depressed pts have reduced invitro lymphocyte response to mitogenstimulationFewer natural killer T cell lymphocytesFewer suppressor t cells and fewcirculating lymphocytes. 25. Sleep EEG in depressed pts showsabnormalities Delayed sleep onset Shortened REM latency Incresed length of first REM sleep Abnormal delta sleepKindling - 26. Skin conductance Found to be raised inmania. 27. (a) Orbital prefrontalcortex andVentromedialprefrontal cortex(b) Dorsolateralprefrontal cortex(c) Hippocampus andAmygdala(d) Anterior cingulatecortexDavidson et al, 2002, Annu.Rev. Psychol. 28. Prefrontalcortex2Amygdala2Hippocampus5Anteriorcingulate cortex3Nucleus accumbens4Insularcortex11. Kennedy SE, et al. Arch Gen Psychiatry. 2006;63:11991208. 2. Drevets WC. Curr Opin Neurobiol. 2001;11:240249.3. Whittle S, et al. Neurosci Biobehav Rev. 2006;30:511525. 4. Schlaepfer TE, et al. Neuropsychopharmacology.2008;33:368377. 5. Gaughran F, et al. Brain Res Bull. 2006;70:221227. 29. Areas of increased activation in patients with MDD at rest (red) anddecreased activation (blue) compared with controlsIncreased activity: lateral orbital prefrontal cortex, ventromedial prefrontal cortex,amygdala, thalamus, caudateDecreased activity: dorsolateral prefrontal cortex (DLPFC), insula, pregenual and dorsalanterior cingulate cortex (dACC), superior temporal gyrusFitzgerald PB, et al. Hum Brain Mapp. 2008;29:683695. 30. Total Hippocampal Volume ( mm3)0 1000 2000 3000 4000Days of Untreated Depression60005500500045004000350030002500Sheline YI, et al. Am J Psychiatry. 2003;160(8):1516-1518.R2=0.28; p=.0006N=38 31. Atrophy of the Hippocampus in DepressionNormal DepressionBremner JD, et al. Am J Psychiatry 2000;157(1):115-118.Reprinted with permission from JD Bremner. 32. 8007006005004003002001000*P=.02 vs comparison by ANOVAComparison subjects (N=20)Major depression (N=15)Orbitofrontal cortical (gyrus rectus)volume (mm3)*MOFCImage reprinted with permission from Elsevier Patients with MDD had 32% smaller MOFC (VMPFC) than controlsANOVA=analysis of variance; MOFC=medial orbitofrontal cortices; VMPFC=ventromedial prefrontal cortex.Bremner JD, et al. Biol Psychiatry. 2002;51:273279. 33. 3-year prospective study comparing 38 patients with 30 healthy controls Significant decline in gray matter density was noted in hippocampus, amygdala,anterior cingulate cortex, and dorsomedial prefrontal cortex Threshold was set at P