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Mood Disorders Neurobiological Causes and Pharmacological Intervention.

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1 Mood Disorders Neurobiological Causes and Pharmacological Intervention

2 Key issues and questions Target of antidepressant or mood-stabilizing drugs: Target of antidepressant or mood-stabilizing drugs: People with Mood Disorders! People with Mood Disorders! What constitutes a “Mood Disorder”? What constitutes a “Mood Disorder”? What is the neurochemical basis of clinically significant mood change? What is the neurochemical basis of clinically significant mood change? What is the neurochemical basis of changes produced by drugs that treat mood disorders? What is the neurochemical basis of changes produced by drugs that treat mood disorders? How well do the drugs work? How well do the drugs work?

3 Mood Disorders The structure of mood disorders Normal affective responses on a continuum-brief in duration vs. dominant and sustained  Unipolar Mood Disorder A state of depression (or mania) A state of depression (or mania) Mostly depression Mostly depression  Bipolar Mood Disorder Alternation between depression and mania Alternation between depression and mania Subtypes Subtypes Bipolar I (full manic episodes) Bipolar I (full manic episodes) Bipolar II (hypomanic episodes) Bipolar II (hypomanic episodes) Cyclothymia (“moodiness” – up and down) Cyclothymia (“moodiness” – up and down)  Anxiety Disorders

4 Nature of Unipolar Mood Disorders Depressive Disorders Depressive Disorders Melancholic depression (40-60%)-symptoms Melancholic depression (40-60%)-symptoms Atypical depression (~15%)-symptoms Atypical depression (~15%)-symptoms Dysthymia-symptoms Dysthymia-symptoms If there are different levels of depression, and different types, is the underlying neurochemical problem different in nature or degree? If 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? Therefore, are pharmacological therapies different for each subtype?

5 Facts & Statistics 7-8% lifetime prevalence 7-8% lifetime prevalence Usually recurrent Usually recurrent Major Depression or Dysthymia: Females > Males Major Depression or Dysthymia: Females > Males Mean age of onset: 25 yrs Mean age of onset: 25 yrs ~50% concordance for monozygotic twins ~50% concordance for monozygotic twins Length of episode varies Length of episode varies Remission is common Remission is common Risk of suicide Risk of suicide Bipolar Disorders: Females = Males Bipolar Disorders: Females = Males Similar in children and adults, ~80% concordance in monozygotic twins Similar in children and adults, ~80% concordance in monozygotic twins

6 Genetic influence on depression Risk of developing unipolar depression increases with multiple family members with depression

7 Behaviors addressed by antidepressant drug use DSM IV Criteria 1-4 for major depressive episode (5/9): 1. Persistence of depressed mood nearly every day (> 2 weeks) 2. Diminished interest or pleasure, eg., loss of libido (anhedonia and vegetative) 3. Weight fluctuations and loss of appetite (vegetative) 4. Insomnia or hypersomnia (vegetative)

8 Specific behavioral changes that need to be targeted by antidepressant drugs DSM IV Criteria 5-9 for Depression 5. Psychomotor agitation or retardation (feelings of restlessness or being slowed down) 6. Fatigue or loss of energy 7. Worthlessness; guilt 8. Inability to think, concentrate or act decisively 9. Preoccupation with thoughts of death or suicidal ideation

9 Anxiety Disorders Panic Attack Panic Attack 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 flashes 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 flashes Agoraphobia Agoraphobia Panic Disorder w/o agoraphobia (GAD) Panic Disorder w/o agoraphobia (GAD) Social Anxiety Disorder Social Anxiety Disorder fear in social situations fear in social situations exposure to social situations provokes anxiety exposure to social situations provokes anxiety social situations avoided social situations avoided distress interferes with normal routine distress interferes with normal routine Obsessive Compulsive Disorder Obsessive Compulsive Disorder

10 Depression Subtypes Melancholic Melancholic anxious, loss of pleasure in all activities anxious, loss of pleasure in all activities dread future dread future insomnia, early morning awakening insomnia, early morning awakening loss of appetite loss of appetite symptoms worst in the morning symptoms worst in the morning excessive inappropriate guilt excessive inappropriate guilt Atypical lethargic, fatigued increase in appetite symptoms best in morning extreme sensitivity to environmental stimuli (perceived or actual/positive or negative) Dysthymia Dysthymia symptoms of depression chronic but less severe symptoms of depression chronic but less severe

11 Physiological Correlates Neurochemical changes Neurochemical changes reduced or elevated norepinephrine levels reduced or elevated norepinephrine levels differences in the number of serotonin receptors - may be regulated by dysfunction in serotonin activity differences in the number of serotonin receptors - may be regulated by dysfunction in serotonin activity “biogenic amine hypothesis” “biogenic amine hypothesis” Dysfunction in cortisol secretion what is the basis of this elevation in cortisol?

12 Stress Response CRF-corticotropin releasing factor CRF-corticotropin releasing factor orchestrates behavioral/endocrine/immune response to stress-interaction with NE orchestrates behavioral/endocrine/immune response to stress-interaction with NE interactions with brain areas responsible for fear reaction, transforming experiences into feeling and memory system interactions with brain areas responsible for fear reaction, transforming experiences into feeling and memory system CRF administered to laboratory rats results in symptoms of “depression” CRF administered to laboratory rats results in symptoms of “depression” excessive levels may explain behavioral symptoms of sleep disturbances, appetite changes, psychomotor symptoms excessive levels may explain behavioral symptoms of sleep disturbances, appetite changes, psychomotor symptoms CRF has two receptor subtypes-novel targets of antidepressant therapy? CRF has two receptor subtypes-novel targets of antidepressant therapy?

13 Hypothalamic-Pituitary-Adrenal Axis Hypothalamus Pituitary Adrenal cortex Hippocampus (glucocorticoid receptors) Hippocampus (glucocorticoid receptors) CRH ACTH PFC NE

14 Hypothalamic-Pituitary-Adrenal Axis Hypothalamus Pituitary Adrenal cortex Hippocampus (glucocorticoid receptors) Hippocampus (glucocorticoid receptors) CRH ACTH PFC HT

15 Dexamethasone Suppression Test- not a diagnostic tool Dexamethasone – synthetic glucocorticoid Reduces ACTH production “normal” patients show reduction (suppression) in cortisol levels in blood depressed patients do not abnormal negative feedback loop-most prominent in melancholic depression

16 Dexamethasone Suppression Test-continued Some, but not all, depressed individuals show lack of dexamethasone suppression of cortisone Some, but not all, depressed individuals show lack of dexamethasone suppression of cortisone Marginal differences between “suppressors” and “nonsuppressors” in response to pharmacotherapy Marginal differences between “suppressors” and “nonsuppressors” in response to pharmacotherapy Some depressed patients, despite elevated cortisol, show no problems with adrenal or pituitary glands Some depressed patients, despite elevated cortisol, show no problems with adrenal or pituitary glands

17 Melancholic vs. Atypical Depression Melancholic: hypercortisolism may explain symptoms of depression Melancholic: hypercortisolism may explain symptoms of depression impaired feedback loop impaired feedback loop hyperactive, anxiety, insomnia, loss of appetite hyperactive, anxiety, insomnia, loss of appetite Atypical: CRF does not stimulate cortisol response Atypical: CRF does not stimulate cortisol response impaired feedback loop impaired feedback loop lethargic, fatigued, hyperphagic, hypersomnic, lethargic, fatigued, hyperphagic, hypersomnic,

18 Animal Models of Depression Diathesis-Stress concept Antidepressant drugs screened on the following preclinical paradigms: Behavioral Despair/Learned Helplessness Behavioral Despair/Learned Helplessness HPA transgenic HPA transgenic Olfactory Bulbectomy Olfactory Bulbectomy

19 Biogenic Amine Hypothesis Evidence for: 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 symptoms Evidence against: response to SSRI’s is slow effect on serotonin reuptake is similar, but between-patient variability melancholic depressed patients show high NE - may be driving by high CRF levels answer: not a simple relationship

20 Action of Antidepressant Drugs on CNS Effects on the following Effects on the following Monoamine neurotransmitters Norepinephrine (noradrenaline): NE Norepinephrine (noradrenaline): NE Dopamine: DA Dopamine: DA Serotonin (5-hydroxytryptamine): 5-HT Serotonin (5-hydroxytryptamine): 5-HT

21 Treatment of Depression Pharmacotherapy Pharmacotherapy Tricyclic antidepressants (TCA) Tricyclic antidepressants (TCA) Heterocyclic or 2 nd and 3 rd generation Heterocyclic or 2 nd and 3 rd generation Monoamine oxidase inhibitors (MAOI) Monoamine oxidase inhibitors (MAOI) Selective serotonin reuptake inhibitors (SSRI) Selective serotonin reuptake inhibitors (SSRI) Non-Pharmacologic Non-Pharmacologic Electroconvulsive therapy (ECT) Electroconvulsive therapy (ECT)

22 Action of Antidepressant Drugs on CNS Increase synaptic neurotransmitter levels Increase synaptic neurotransmitter levels Impair natural mechanisms for reducing monamine actions Impair natural mechanisms for reducing monamine actions Reuptake pumps Reuptake pumps Enzymatic inactivation (MAO) Enzymatic inactivation (MAO) Autoreceptors Autoreceptors Alter receptor levels (after repeated use) Alter receptor levels (after repeated use)

23 Synaptic Effects

24 drug inactivates monoamine oxidases

25 Synaptic Transmission: the Synapse normal reuptake of NT substance from synaptic cleft to presynaptic neuron inhibition of reuptake pumps: more NT in synapse

26 Serotonin/Permissive Hypothesis: Serotonin as “inhibitory” neurotransmitter Serotonin as “inhibitory” neurotransmitter Inhibit rage – self rage (suicide?) Inhibit rage – self rage (suicide?) Mood disorders: release of inhibitory damper Mood disorders: release of inhibitory damper serotonin norepinephrine = mania Balance of 5HT and NE regulates mood Balance of 5HT and NE regulates mood

27 MAO metabolizes serotonin in the presynaptic neuron

28 Serotonergic Distribution in the Brain

29 Synthesis of Norephinephrine:

30 Noradrenergic distribution in the brain Locus coeruleus

31 Receptor Subtypes (transmembrane proteins) 5-HT 5-HT nine know receptor subtypes nine know receptor subtypes grouped into class 1, 2 and 3 grouped into class 1, 2 and 3 5-HT1a is both presynaptic (autofeedback loop) and postsynaptic 5-HT1a is both presynaptic (autofeedback loop) and postsynaptic NE NE acute use vs. chronic use acute use vs. chronic use altered sensitivity/number receptors altered sensitivity/number receptors which types? which types?

32 MAOi MAOi TCA TCA Also used for anxiety disorders and pain Also used for anxiety disorders and pain Panic and phobia (MAO) Panic and phobia (MAO) Obsessive-Compulsive Disorder (TCA) Obsessive-Compulsive Disorder (TCA) Pain (TCA) Pain (TCA) SSRI (selective serotonin reuptake inhibitors) SSRI (selective serotonin reuptake inhibitors) anxiety anxiety OCD – clomipramine, fluvoxamine, paroxetine, sertraline OCD – clomipramine, fluvoxamine, paroxetine, sertraline Classes of Antidepressant Therapy:

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35 The receptor hypothesis of antidepressant action Introduction of drug therapy RECEPTOR Clinical effect neurotransmitter High level or mood Low level or mood Alterations in receptor expression

36 Receptor Subtypes in Depressed Patients Not all studies find an association Not all studies find an association Increased number if 5HT1a neurons Increased number if 5HT1a neurons increased inhibition of 5HT transmission increased inhibition of 5HT transmission Altered number of 5HT2 receptors Altered number of 5HT2 receptors Presynaptic and postsynaptic Presynaptic and postsynaptic Changes match chronic stress animal model Changes match chronic stress animal model

37 Therapeutic Lag Theory: improved mood following SSRI treatment corresponds to augmented serotonergic transmission Theory: improved mood following SSRI treatment corresponds to augmented serotonergic transmission this enhanced 5-HT activity is partially due to autoreceptor blockade this enhanced 5-HT activity is partially due to autoreceptor blockade New therapy: combine SSRI with 5HT1a antagonist New therapy: combine SSRI with 5HT1a antagonist Problems: antidepressant efficacy correlated with postsynaptic 5HT1a receptor affinity Problems: antidepressant efficacy correlated with postsynaptic 5HT1a receptor affinity

38 The altered gene (s) hypothesis of antidepressant action Excess neurotransmitter leads to alterations in: Excess neurotransmitter leads to alterations in: Genes that code for receptors Genes that code for receptors receptor expression receptor expression sensitivity of receptors sensitivity of receptors differences in expression in pre- and post-synaptic receptors differences in expression in pre- and post-synaptic receptors upregulate or sensitize 5HT1a in hippocampus upregulate or sensitize 5HT1a in hippocampus desensitize 5HT2 receptors elsewhere in the brain desensitize 5HT2 receptors elsewhere in the brain Genes that serve to protect and/or facilitate neuronal function (eg., brain derived neurotrophic factor) Genes that serve to protect and/or facilitate neuronal function (eg., brain derived neurotrophic factor) BDNF does not appear to be associated with disease BDNF does not appear to be associated with disease

39 Relationship of SSRI’s to BDNF levels and neuronal function

40 Interaction of stress, corticosteriods and depression:

41 Side effects MAO inhibitors MAO inhibitors dietary restrictions – dietary restrictions – serotonin syndrome- serotonin syndrome- Tricyclic Antidepressants Tricyclic Antidepressants cardiac arrhythmias, respiratory depression cardiac arrhythmias, respiratory depression serotonin syndrome serotonin syndrome severe sedation severe sedation

42 Side effects Blockade of NE uptake Blockade of NE uptake tachycardia tachycardia tremors tremors Blockade of 5-HT uptake Blockade of 5-HT uptake GI disturbances GI disturbances interactions with l-tryptophan interactions with l-tryptophan increase/decrease in anxiety (dose dependent) increase/decrease in anxiety (dose dependent) sexual dysfunction sexual dysfunction Blockade of histamine receptors Blockade of histamine receptors potentiation of depressant drugs potentiation of depressant drugs sedation sedation weight gain weight gain hypotension hypotension Blockade of Ach receptors Blockade of Ach receptors blurred vision, blurred vision, drymouth drymouth constipation constipation

43 Efficacy of Antidepressant Therapy Use of a placebo or active control (randomized, controlled clinical trial) or any control Use of a placebo or active control (randomized, controlled clinical trial) or any control Consistency of study populations Consistency of study populations Efficacy of one group over another? Efficacy of one group over another? Treatment guidelines Treatment guidelines dose, duration, compliance dose, duration, compliance starting dose-enduring response starting dose-enduring response patient compliance-adverse events patient compliance-adverse events

44 Efficacy subtypes MAOi MAOi atypical and refractory (fail to respond to other types of medications) atypical and refractory (fail to respond to other types of medications) TCA melancholic depression not effective in reactive depression SSRI SSRI mild to moderate depression mild to moderate depression better tolerated than TCAs better tolerated than TCAs do not take with MAOi do not take with MAOi Heterocyclics Heterocyclics use when severe insomnia is present use when severe insomnia is present useful in elderly useful in elderly


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