Presentation on theme: "Neurobiological Causes and Pharmacological Intervention"— Presentation transcript:
1Neurobiological Causes and Pharmacological Intervention Mood DisordersNeurobiological Causes and Pharmacological Intervention
2Key issues and questions Target of antidepressant or mood-stabilizing drugs:People with Mood Disorders!What constitutes a “Mood Disorder”?What is the neurochemical basis of clinically significant mood change?What is the neurochemical basis of changes produced by drugs that treat mood disorders?How well do the drugs work?
3Mood Disorders The structure of mood disorders Normal affective responses on a continuum-brief in duration vs. dominant and sustainedUnipolar Mood DisorderA state of depression (or mania)Mostly depressionBipolar Mood DisorderAlternation between depression and maniaSubtypesBipolar I (full manic episodes)Bipolar II (hypomanic episodes)Cyclothymia (“moodiness” – up and down)Anxiety Disorders
4Nature of Unipolar Mood Disorders Depressive DisordersMelancholic depression (40-60%)-symptomsAtypical depression (~15%)-symptomsDysthymia-symptomsIf there are different levels of depression, and different types, is the underlying neurochemical problem different in nature or degree?Therefore, are pharmacological therapies different for each subtype?
5Facts & Statistics 7-8% lifetime prevalence Usually recurrent Major Depression or Dysthymia: Females > MalesMean age of onset: 25 yrs~50% concordance for monozygotic twinsLength of episode variesRemission is commonRisk of suicideBipolar Disorders: Females = MalesSimilar in children and adults, ~80% concordance in monozygotic twins
6Genetic influence on depression Risk of developing unipolar depression increases with multiple family members with depression
7Behaviors addressed by antidepressant drug use DSM IV Criteria 1-4 for major depressive episode (5/9):Persistence of depressed mood nearly every day (> 2 weeks)Diminished interest or pleasure, eg., loss of libido (anhedonia and vegetative)Weight fluctuations and loss of appetite (vegetative)Insomnia or hypersomnia (vegetative)
8Specific behavioral changes that need to be targeted by antidepressant drugs DSM IV Criteria 5-9 for DepressionPsychomotor agitation or retardation (feelings of restlessness or being slowed down)Fatigue or loss of energyWorthlessness; guiltInability to think, concentrate or act decisivelyPreoccupation with thoughts of death or suicidal ideation
9Anxiety Disorders Panic Attack Agoraphobia period of intense fear or discomfort in which the following occurs: sweating, trembling, choking, chest pain, nausea, dizziness, fear of losing control, derealization or depersonalization, chills or hot flashesAgoraphobiaPanic Disorder w/o agoraphobia (GAD)Social Anxiety Disorderfear in social situationsexposure to social situations provokes anxietysocial situations avoideddistress interferes with normal routineObsessive Compulsive Disorder
10Depression Subtypes Melancholic Atypical anxious, loss of pleasure in all activitiesdread futureinsomnia, early morning awakeningloss of appetitesymptoms worst in the morningexcessive inappropriate guiltAtypicallethargic, fatiguedincrease in appetitesymptoms best in morningextreme sensitivity to environmental stimuli (perceived or actual/positive or negative)Dysthymiasymptoms of depression chronic but less severe
11Physiological Correlates Neurochemical changesreduced or elevated norepinephrine levelsdifferences in the number of serotonin receptors - may be regulated by dysfunction in serotonin activity“biogenic amine hypothesis”Dysfunction in cortisol secretionwhat is the basis of this elevation in cortisol?
12Stress Response CRF-corticotropin releasing factor orchestrates behavioral/endocrine/immune response to stress-interaction with NEinteractions with brain areas responsible for fear reaction, transforming experiences into feeling and memory systemCRF administered to laboratory rats results in symptoms of “depression”excessive levels may explain behavioral symptoms of sleep disturbances, appetite changes, psychomotor symptomsCRF has two receptor subtypes-novel targets of antidepressant therapy?
15Dexamethasone Suppression Test- not a diagnostic tool Dexamethasone – synthetic glucocorticoidReduces ACTH production“normal” patients showreduction (suppression) in cortisol levels in blooddepressed patients do notabnormal negative feedback loop-most prominent in melancholic depression
16Dexamethasone Suppression Test-continued Some, but not all, depressed individuals show lack of dexamethasone suppression of cortisoneMarginal differences between “suppressors” and “nonsuppressors” in response to pharmacotherapySome depressed patients, despite elevated cortisol, show no problems with adrenal or pituitary glands
17Melancholic vs. Atypical Depression Melancholic: hypercortisolism may explain symptoms of depressionimpaired feedback loophyperactive, anxiety, insomnia, loss of appetiteAtypical: CRF does not stimulate cortisol responselethargic, fatigued, hyperphagic, hypersomnic,
18Animal Models of Depression Diathesis-Stress conceptAntidepressant drugs screened on the following preclinical paradigms:Behavioral Despair/Learned HelplessnessHPA transgenicOlfactory Bulbectomy
19Biogenic Amine Hypothesis Evidence for:altered serotonin and norepinephrine levels in depressed and suicide victims (blood and CSF)drugs which reduce NE/5-HT result in depression/suicidal tendencies (reserpine)drugs which elevate serotonin and NE (MAOi, amphetamine) also alleviate symptomsEvidence against:response to SSRI’s is sloweffect on serotonin reuptake is similar, but between-patient variabilitymelancholic depressed patients show high NE - may be driving by high CRF levelsanswer: not a simple relationship
20Action of Antidepressant Drugs on CNS Effects on the followingMonoamine neurotransmittersNorepinephrine (noradrenaline): NEDopamine: DASerotonin (5-hydroxytryptamine): 5-HT
21Treatment of Depression PharmacotherapyTricyclic antidepressants (TCA)Heterocyclic or 2nd and 3rd generationMonoamine oxidase inhibitors (MAOI)Selective serotonin reuptake inhibitors (SSRI)Non-PharmacologicElectroconvulsive therapy (ECT)
22Action of Antidepressant Drugs on CNS Increase synaptic neurotransmitter levelsImpair natural mechanisms for reducing monamine actionsReuptake pumpsEnzymatic inactivation (MAO)AutoreceptorsAlter receptor levels (after repeated use)
25Synaptic Transmission: the Synapse normal reuptake of NT substance from synaptic cleft to presynaptic neuroninhibition of reuptake pumps: more NT in synapse
26Serotonin/Permissive Hypothesis: Serotonin as “inhibitory” neurotransmitterInhibit rage – self rage (suicide?)Mood disorders: release of inhibitory damperserotonin norepinephrine = maniaBalance of 5HT and NE regulates mood
27MAO metabolizes serotonin in the presynaptic neuron
30Noradrenergic distribution in the brain Locuscoeruleus
31Receptor Subtypes (transmembrane proteins) 5-HTnine know receptor subtypesgrouped into class 1, 2 and 35-HT1a is both presynaptic (autofeedback loop) and postsynapticNEacute use vs. chronic usealtered sensitivity/number receptorswhich types?
32Classes of Antidepressant Therapy: MAOiTCAAlso used for anxiety disorders and painPanic and phobia (MAO)Obsessive-Compulsive Disorder (TCA)Pain (TCA)SSRI (selective serotonin reuptake inhibitors)anxietyOCD – clomipramine, fluvoxamine, paroxetine, sertraline
35The receptor hypothesis of antidepressant action Alterations in receptor expressionIntroduction of drug therapyRECEPTORClinical effectneurotransmitterHigh levelor moodLow level
36Receptor Subtypes in Depressed Patients Not all studies find an associationIncreased number if 5HT1a neuronsincreased inhibition of 5HT transmissionAltered number of 5HT2 receptorsPresynaptic and postsynapticChanges match chronic stress animal model
37Therapeutic LagTheory: improved mood following SSRI treatment corresponds to augmented serotonergic transmissionthis enhanced 5-HT activity is partially due to autoreceptor blockadeNew therapy: combine SSRI with 5HT1a antagonistProblems: antidepressant efficacy correlated with postsynaptic 5HT1a receptor affinity
38The altered gene (s) hypothesis of antidepressant action Excess neurotransmitter leads to alterations in:Genes that code for receptorsreceptor expressionsensitivity of receptorsdifferences in expression in pre- and post-synaptic receptorsupregulate or sensitize 5HT1a in hippocampusdesensitize 5HT2 receptors elsewhere in the brainGenes that serve to protect and/or facilitate neuronal function (eg., brain derived neurotrophic factor)BDNF does not appear to be associated with disease
39Relationship of SSRI’s to BDNF levels and neuronal function
40Interaction of stress, corticosteriods and depression:
42Side effects Blockade of NE uptake Blockade of 5-HT uptake tachycardiatremorsBlockade of 5-HT uptakeGI disturbancesinteractions with l-tryptophanincrease/decrease in anxiety (dose dependent)sexual dysfunctionBlockade of histamine receptorspotentiation of depressant drugssedationweight gainhypotensionBlockade of Ach receptorsblurred vision,drymouthconstipation
43Efficacy of Antidepressant Therapy Use of a placebo or active control (randomized, controlled clinical trial) or any controlConsistency of study populationsEfficacy of one group over another?Treatment guidelinesdose, duration, compliancestarting dose-enduring responsepatient compliance-adverse events
44Efficacy subtypes MAOi TCA Heterocyclics atypical and refractory (fail to respond to other types of medications)TCAmelancholic depressionnot effective in reactive depressionSSRImild to moderate depressionbetter tolerated than TCAsdo not take with MAOiHeterocyclicsuse when severe insomnia is presentuseful in elderly