I. Emotion and Affect
A. Defining emotions
B. Ontogeny of emotion
C. Expression and measurement of components of emotion
II. Theories of Emotion
A. James-Lange
B. Cannon-Bard
C. Papez-MacLean
III. Theories of Stress
A. Cannon
B. Selye
C. Mason
D. A contemporary view
IV. Stress and Pathophysiology
A. Selye's general adaptation syndrome
B. Allostasis 241-5.0a
31:241 Behavioral and Cognitive Neuroscience31:241 Behavioral and Cognitive NeuroscienceProfessor A.K. JohnsonProfessor A.K. Johnson
Fall 2012Fall 2012OutlineOutline
Neurobiology of Mood, Emotion and Mental IllnessNeurobiology of Mood, Emotion and Mental Illness11/6; 11/13; 11/1511/6; 11/13; 11/15
V. Neural and Neurochemical Substrates of Fear and AnxietyA. The defense response and the conditioned emotional response (CER)
1. Neural pathwaysB. Neurochemistry
1. CRH2. GABA
C. Anxiety DisordersD. Somatic disease, stress and the defense response
VI. DepressionA. Mood disorders introductionB. Epidemiology and genetics of depressionC. Physiological and biochemical correlates of depression
1. Autonomic and cardiovascular changes2. Endocrine and cytokine3. Biological rhythms - Seasonal affective disorder
D. Theories of Depression1. Biogenic-amine2. Stress and the brain–pituitary-adrenal dysfunction3. Sickness behavior, inflammatory cytokines and depressive symptomatology4. Stress-Impaired neurogenesis
E. Antidepressant drugs and electroconvulsive shock 241-5.0b
Neurobiology of Mood, Emotion and Mental IllnessNeurobiology of Mood, Emotion and Mental Illness
(Continued)(Continued)
Key Terms and ConceptsKey Terms and Concepts
AnhedoniaAllostasisAllostatic loadAmygdalaArousalBasic emotionsBrain-deprived neurotrophic factor (BDNF)Cannon-Bard theory of emotionConditioned emotional response (CER)Corticotropic releasing hormone (CRH) or factor (CRF)Defense responseElectroconvulsive therapy (ECT)Emotional responseGeneral adaptation syndrome (GAS)Generalized anxiety disorderLeukocytesMacLean's visceral brain (limbic system) theory of emotion
Median forebrain bundleMonamine oxidase inhibitors (MAOI) antidepressantsNociceptorsNucleus accumbensPanic disorderPapez theory of emotionPeriaqueductal gray (PAG)Post-traumatic stress syndromeSimple phobiaSocial phobiaStressStress responseStressorSubjective feelingsTricyclic/polycyclic (TCA) antidepressantsWilliam James' theory of emotion
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Examples of Lists of Basic EmotionsExamples of Lists of Basic Emotions
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• Surprise • Fear• Interest • Disgust• Joy • Shame• Rage • Anguish
• Surprise • Fear• Happiness • Disgust• Anger • Sadness
A Scheme Proposed by BridgesA Scheme Proposed by Bridgesfor the Development of Emotionsfor the Development of Emotions
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Types of Emotional ResponsesTypes of Emotional Responses
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FeelingsFeelings
Emotional Emotional Subjective Action Expression Feelings
Darwin's Expression of theDarwin's Expression of theEmotions in Man and AnimalsEmotions in Man and Animals
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Commonality of Emotional ExpressionCommonality of Emotional Expressionin the Faces of Animals and Peoplein the Faces of Animals and People
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William James' Theory of EmotionWilliam James' Theory of Emotion
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Cannon-Bard Theory of EmotionCannon-Bard Theory of Emotion
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The Papez Circuit Theory of EmotionThe Papez Circuit Theory of Emotion
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MacLean's Visceral BrainMacLean's Visceral Brain(Limbic System) Theory of Emotion(Limbic System) Theory of Emotion
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Originators and Popularizers of the Concept of StressOriginators and Popularizers of the Concept of Stress
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Cannon (1920's) used the term "stress" to characterize the physical impact of averse stimuli on an organism much as an engineer uses the term stress and strain to characterize the effect of a load placed on steel structures.
Selye (1936) used the term stress to account for the generalized physiological response to different averse insults to the body.
W.B. Cannon Hans Selye
Evolution of the Concept of StressEvolution of the Concept of Stress
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Adaptive Effects of the Stress ResponseAdaptive Effects of the Stress Response
Immediate increase of metabolic fuel
Increased oxygen intake
Optimization of blood flow to key tissues
Inhibition of digestion, growth immune function, reproduction and pain perception
Enhancement of sensory intake and memory
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Selye's General Adaptation Syndrome (GAS) Selye's General Adaptation Syndrome (GAS) and the Consequence of Another Stressorand the Consequence of Another Stressor
241-5.13
Original Stress
Normal
New Stress
Pathological State Associated with Chronic StressPathological State Associated with Chronic Stress
Fatigue, myopathy; steroid diabetes
Hypertension
Peptic ulcers
Psychosocial dwarfism
Impotence; anovulation; loss of libido
Impaired disease resistance; cancer
Accelerated neural degeneration during aging
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Allostasis and Allostatic LoadAllostasis and Allostatic Load
Idea evolved from concepts of homeostasis and stress.
P. Sterling and J. Eyer were the originators of the concept.
Allo – prefix meaning variable.
Allostasis = maintaining stability through change; the active process of maintaining a physiological function in the face of a challenge by old control systems adjusting level of function or "new" systems being activated.
Systems involved in the stress response show dramatic responses.
Allostatic load = wear and tear on the body that results from repeated or sustained activation of processes that maintain homeostasis.
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Bruce McEwen
Popularizer of Allostasis and Allostatic Load
The Cardiovascular Defense ResponseThe Cardiovascular Defense Response
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Brain Stimulation-Induced Defense ResponseBrain Stimulation-Induced Defense Response
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Behavioral• Piloerection• Hissing• Halloween Posture
Cardiovascular• Cardiac Output ( HR)• Blood Pressure• Skeletal Muscle Blood Flow• Renal Blood Flow• Mesenteric Blood Flow
The Conditioned Emotional Response (CER):The Conditioned Emotional Response (CER):
A Rat Undergoing Fear Conditioning
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Neural Pathways Mediating theNeural Pathways Mediating theCardiovascular (A) and the BehavioralCardiovascular (A) and the Behavioral
(Freezing) (B) Components of the Defense Response(Freezing) (B) Components of the Defense Response
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The Amygdala and FearThe Amygdala and Fear
241-5.20
Stress Pathways and the Control of GlucocorticoidsStress Pathways and the Control of Glucocorticoids
241-5.21
The Physiological Effects of CRFThe Physiological Effects of CRF
241-5.22
Putative CRF Pathways and CRFPutative CRF Pathways and CRF1 1 (a) and(a) and
CRFCRF22 (b) Receptor Localization (b) Receptor Localization
241-5.23
Effects of Amygdala Lesions on the CRF Effects of Amygdala Lesions on the CRF Enhancement of the Startle ResponseEnhancement of the Startle Response
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The Projections of the Amygdala That Mediate The Projections of the Amygdala That Mediate Behavioral, Physiological and Endocrine Behavioral, Physiological and Endocrine
Responses to Fear StimuliResponses to Fear Stimuli
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There is a Key Role for GABA inThere is a Key Role for GABA inControlling Activity of the AmygdalaControlling Activity of the Amygdala
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The GABA SynapseThe GABA Synapse
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GABA SynthesisGABA Synthesis
241-5.28
COOH COOH
CH2 CH2
+ CO2
CH2 CH2
H2N CH H2N CH2
COOH Glutamic Acid GABA
Glutamic Acid
Decarboxylase
The Interplay Between NeuronsThe Interplay Between Neuronsand Glia in GABA Metabolismand Glia in GABA Metabolism
241-5.29
Schematic Model of the GABASchematic Model of the GABAAA Receptor Complex Receptor Complex
241-5.30BDZ, benzodiazepine
Anxiety DisordersAnxiety Disorders
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The Defense Response as an Inducer of The Defense Response as an Inducer of Chronic HypertensionChronic Hypertension
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About 50 years ago, Folkow hypothesized that sustained or repeated activation of the defense response predisposes towards developing chronic hypertension.
Björn Folkow Hypothalamic StimulationProducing the Defense Response
and Chronic Hypertension
Multiple EnvironmentalMultiple EnvironmentalStressor-Induced HypertensionStressor-Induced Hypertension
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Mood DisordersMood Disorders
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Major DepressionMajor Depression
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• Major depression is the leading cause of disability in the U.S. and worldwide.
• Depressive disorders affect an estimated 9.5% of adult Americans ages 18 and over in a given year, or about 18.8 million people in 1998.
Distribution of Mood Disorders in the U.S. PopulationDistribution of Mood Disorders in the U.S. Population
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Symptoms and Signs of Major Depression*Symptoms and Signs of Major Depression*
241-5.37
• Must include either pervasive depressed mood (verbal report) or pervasive loss of ability to experience pleasure or interest in other things (anhedonia).
• Must include at least five of the following:- Depressed mood (require verbal report)
- Feelings of worthlessness or guilt (require verbal report)
- Diminished concentration (require verbal report)
- Recurrent thoughts of death or suicide (require verbal report)
- Weight change - Sleep disturbance - Psychomotor agitation or retardation - Fatigue or loss of energy- Loss of pleasure (anhedonia) or interest
*Adapted form DSM-IV-RT
DSM-IV-RT Diagnostic Criteria for Dysthymic DisorderDSM-IV-RT Diagnostic Criteria for Dysthymic Disorder
241-5.38
A. Depressed mood for most of the day, for more days than not, as indicated either by subjective account or observation by others, for at least 2 years. Note: In children and adolescents, mood can be irritable and duration must be at least 1 year.
B. Presence, while depressed, of two (or more) of the following:• Poor appetite or overeating• Insomnia or hypersomnia• Low energy or fatigue• Low self-esteem• Poor concentration or difficulty making decisions• Feelings of hopelessness
C. During the 2-year period (1 year for children or adolescents) of the disturbance, the person has never been without the symptoms in Criteria A and B for more than 2 months at a time.
D. No Major Depressive Episode has been present during the first 2 years of the disturbance (1 year for children and adolescents); i.e., the disturbance is not better accounted for by chronic Major Depressive Disorder, or Major Depressive Disorder, In Partial Remission. Note: There may have been previous Major Depressive Episode provided there was a full remission (no significant signs or symptoms for 2 months) before development of the Dysthymic Disorder. In addition, after the initial 2 years (1 year in children or adolescents) of Dysthymic Disorder, there may be superimposed episodes for Major Depressive Disorder, in which case both diagnoses may be given when the criteria are met for a Major Depressive Episode.
E. There has never been a Manic Episode, a Mixed Episode, or a Hypomanic Episode, and criteria have never been met for Cyclothymic Disorder.
F. The disturbance does not occur exclusively during the course of a chronic Psychotic Disorder, such as Schizophrenia or Delusional Disorder.
G. The symptoms are not due to the direct physiological effects of a substance (e.g., a drug of abuse, a medication) or a general medical condition (e.g., hypothyroidism).
H. The symptoms cause clinically significant distress or impairment in the social, occupational, or other important areas of functioning.
Specify if:Early Onset: if onset is before age 21 yearsLate Onset: if onset is age 21 years or older
Specify (for most recent 2 years of Dysthymic Disorder):With Atypical Features
Criteria for Manic EpisodeCriteria for Manic Episode
241-5.39
A. A distinct period of abnormally and persistently elevated, expansive, or irritable mood, lasting at least 1 week (or any duration if hospitalization is necessary).
B. During the period of mood disturbance, three (or more) of the following symptoms have persisted (four if the mood is only irritable) and have been present to a significant degree:
• Inflated self-esteem or grandiosity• Decreased need for sleep (e.g., feels rested after only 3 hours of sleep)• More talkative than usual or pressure to keep talking• Flight of ideas or subject experience that thoughts are racing• Distractibility (i.e., attention too easily drawn to unimportant or irrelevant external
stimuli)• Increase in goal-directed activity (either socially at work or school, or sexually) or psychomotor agitation• Excessive involvement in pleasurable activities that have a high potential for
painful consequences (e.g., engaging in unrestrained buying sprees, sexual indiscretions,
or foolish business investments)
C. The symptoms do not meet criteria for a Mixed Episode.
D. The mood disturbance is sufficiently severe to cause marked impairment in occupational functioning or in usual social activities or relationships with others, or to necessitate hospitalization to prevent harm to self or others, or there are psychotic features.
E. The symptoms are not due to the direct physiological effects of a substance (e.g., a drug of abuse, a medication, or other treatment) or a general medical condition (e.g., hyperthyroidism). Note: Manic-like episodes that are clearly caused by somatic antidepressant treatment (e.g., medication, electroconvulsive therapy, light therapy) should not count toward a diagnosis of Bipolar 1 Disorder.
Male/Female Prevalence of Affective DisordersMale/Female Prevalence of Affective Disorders
241-5.40
Genetic Component of Behavioral/Mental DisordersGenetic Component of Behavioral/Mental Disorders
241-5.41
Confirmed Linkages in Bipolar DisorderConfirmed Linkages in Bipolar Disorder
241-5.42
Genomic Principle IndependentLocation Report Confirmations
18p11.2 Berrettini et al., 1994 (38) Stine et al., 1995 (40); Nothen et al., 1999 (41);and 1997 (39) Turecki et al., 1999 (42)
21q22 Straub et al., 1994 (44) Detera-Wadleigh et al., 1996 (45); Smythe etal., 1996 (46); Kwok et al., 1999 (47);Morissette et al., 1999 (48)
22q11-13 Kelsoe et al., 2001 (49) Detera-Wadleigh et al., 1997 (50) and 1999 (51)
18q22 Stine et al., 1995 (40) Mcinnes et al., 1996 (52); McMahon et al., 1997 (53); De Bruyn et al., 1996 (54)
12q24 Morissette et al., 1999 (48) Ewald et al., 1998 (56); Detera-Wadleigh et al.,1999 (51)
4p15 Blackwood et al., 1996 (57) Ewald et al., 1998 (58); Nothen et al., 1997(59); Detera-Wadleigh et al., 1999 (51)
Physiological and Biochemical Signs in DepressionPhysiological and Biochemical Signs in Depression
241-5.43
Vegetative• Increased heart rate
• Decreased heart rate variability
• Increased cardiovascular reactivity to psychosocial stressors
• Increased susceptibility to heart disease
Endocrine• Increased plasma norepinephrine
• Increased cerebrospinal fluid CRF
• Increased plasma corticosterone
• Altered cytokines in depressed mood
Circadian• Altered sleep cycles
• Increased REM
• Decreased REM onset latency
• Sleep deprivation and depression
• Altered CRF cycle
• Seasonal affective disorder
Average Plasma Cortisol ConcentrationsAverage Plasma Cortisol Concentrations
241-5.44
Patterns of the Stages of Sleep of a Normal Patterns of the Stages of Sleep of a Normal Subject and of a Patient with Major DepressionSubject and of a Patient with Major Depression
241-5.45
Changes in the Depression Rating of a Depressed Patient Changes in the Depression Rating of a Depressed Patient Produced by a Single Night's Total Sleep DeprivationProduced by a Single Night's Total Sleep Deprivation
241-5.46
Mean Mood Rating of Responding and Non-Responding Patients Mean Mood Rating of Responding and Non-Responding Patients Deprived of One Night's Sleep as a Function of the Time of DayDeprived of One Night's Sleep as a Function of the Time of Day
Seasonal Affective Disorder (SAD)Seasonal Affective Disorder (SAD)
241-5.47
• Distinctive constellation of symptoms including
- Overeating- Oversleeping- Carbohydrate craving
• Triggered by light deficiency• Responds to phototherapy• Theories accounting for the antidepressant
effects of phototherapy- Melatonin hypothesis- Circadian phase shift- Circadian rhythm amplitude
Light Box Therapy May AmeliorateLight Box Therapy May AmeliorateSeasonal Affective Disorder (SAD)Seasonal Affective Disorder (SAD)
241-5.48
Biological Theories of DepressionBiological Theories of Depression
I. Monoamine Theory of Depression
241-5.49
• The monoamine theory, proposed in 1965, suggests thatdepression results from functionally deficient
monoaminergic(norepinephrine and/or 5-HT) transmission in the CNS.
• The theory was based on the ability of known antidepressant
drugs (TCA and MAOI) to facilitate monoaminergictransmission, and of drugs such as reserpine to causedepression.
• Other pharmacological evidence fails to support themonoamine hypothesis.
• Biochemical studies on depressed patients do not, in general,
support the monoamine hypothesis, except that consistently
low concentrations of 5-HIAA in the CSF are found.
• Though the monoamine hypothesis in its simple form is no
longer tenable as an explanation of depression,pharmacological manipulation of monoamine
transmissionremains the most successful therapeutic approach.
Pharmacological Evidence Relating to the Pharmacological Evidence Relating to the Monoamine Hypothesis of DepressionMonoamine Hypothesis of Depression
241-5.50
Effect in Drug Principal Action Depressed Patients
Effects consistent with the hypothesis
Reserpine Inhibits NE and 5-HT storage Mood
Tricyclic Block NE and 5-HT re-uptake Mood antidepressants
MAO inhibitors Increase stores of NE and 5-HT Mood
-methyltyrosine Inhibits NE synthesis Mood ; calming of manic patients
Methyldopa Inhibits NE synthesis Mood
Electroconvulsive Increases CNS response to Mood therapy NE and 5-HT
Pharmacological Evidence That Does Not SupportPharmacological Evidence That Does Not Supportthe Monoamine Hypothesis of Depressionthe Monoamine Hypothesis of Depression
241-5.51
Effect in Drug Principal Action Depressed Patients
Amphetamine Releases NE and blocks None. Euphoria in normal subjects re-uptake
Cocaine Inhibits NE re-uptake None. Euphoria in normal subjects
Tryptophan Increases 5-HT synthesis Mood? but only in some studies (5-hydroxytryptophan)
- and -adrenoceptor Blocks actions of NE Mood slightly ↓ with -adrenoceptor antagonists antagonists; No effect on manic
patients
Methysergide 5-HT receptor antagonist None
L-dopa Increases NE synthesis None
Iprindole No effect on amine Mood metabolism
Stahl's Hypothesis for Specific Syndromes Associated Stahl's Hypothesis for Specific Syndromes Associated with Different Kinds of Monoamine Deficiencieswith Different Kinds of Monoamine Deficiencies
241-5.52
Norepinephrine Deficiency Syndrome• Depressed mood
• Impaired attention
• Problems concentrating
• Deficiencies in working memory
• Slowness of information processing
• Psychomotor retardation
• Fatigue
Serotonin Deficiency Syndrome• Depressed mood
• Anxiety
• Panic
• Phobia
• Obsessions and compulsions
• Food craving; bulimia
Biological Theories of DepressionBiological Theories of Depression
II. Evidence for a CRF-HPA Theory of Depression
241-5.53
Corticotropin-releasing factor (CRF) in cerebrospinal fluida,b
Blunted adrenocorticotropic hormone (ACTH) -endorphin to CRF stimulationa
Density of CRF receptors in frontal cortex of patients who commit suicide
Pituitary gland enlargement in depressed patientsb
Adrenal gland enlargement in depressed patients and patients who commit suicideb
Cortisol production during depressiona
Plasma glucocorticoid, ACTH, and -endorphin non-suppression after dexamethasone administrationa
Urinary free cortisol concentrations
aState-dependent
bSignificantly correlated to post-dexamethasone cortisol concentrations
Biological Theories of DepressionBiological Theories of Depression
III. Macrophage Theory of Depression
-- R.S. Smith Medical Hypotheses 35:298-306, 1991
241-5.54
Seven Lines of Support1. Volunteers given monokines (IL-1; INF-; TNF) develop symptoms of a major depressive episode.
2. IL-1 can account for hormonal abnormalities (e.g., ACTH; GH).
3. Diseases and cohorts characterized by macrophage activation are associated with high rates of depression.
4. Brain macrophages (microglia) secrete monokines.
5. Estrogen increases IL-1 secretion by macrophages.
6. Eicosapentaenoic acid suppresses macrophages, whereas linoleic acid activates them.
7. Substantial epidemiology is consistent with this hypothesis.
Biological Theories of DepressionBiological Theories of Depression
IV. Stress-Induced Neurodegeneration
241-5.55
Drugs Used in Affective Disorders: AntidepressantsDrugs Used in Affective Disorders: Antidepressants
241-5.56
Reuptake Inhibition Drug Name Sedative Anticholinergic EliminationGeneric (Trade) Activity Activitya Half-Life (hr) NE Serotonin Dopamine
Tricyclic CompoundsImipramine (Tofranil) Moderate Moderate 10-20 ++ ++ 0Desipramine (Norpramin) Low Low 12-75 +++ + 0Trimipramine (Surmontil) High Moderate 8-20 + + 0Protriptyline (Vivactil) Low Moderate 55-125 +++ + 0Nortriptyline (Pamelor, Aventil) Moderate Low 15-35 ++ ++ 0Amitriptyline (Elavil) High High 20-35 ++ ++ 0Doxepin (Adapin, Sinequan) High High 8-24 ++ ++ 0Clomipramine (Anaframil) Low Low 19-37 ++ ++++ 0Second-Generation (Atypical) CompoundsAmoxapine (Asendin)b Low Moderate 8-10 ++ + 0Maprotiline (Ludiomil) Moderate Moderate 27-58 +++ 0 0Trazodone (Desyrel) Moderate Low 6-13 0 ++ 0Bupropion (Wellbutrin) Low Low 8-14 0/+ 0/+ ++Venlafaxine (Effexor) None None 3-11 ++ ++++ 0Serotonin-Specific Reuptake InhibitorsFluoxetine (Prozac) None None 24-96 0 ++++ 0Sertraline (Zoloft) None None 26 0 ++++ 0Paroxetine (Paxil) None None 24 + ++++ 0Citalopram (Celexa) None None 33 0 ++++ 0Fluvoramine (Luvox) None None 15 0 ++++ 0Dual-Action AntidepressantMirtazapine (Remeron) High Low 20-40 ++ ++++ 0MAO Inhibitors: IrreversiblePhenelzine (Nardil) Low None 2-4c 0 0 0Isocarboxazid (Marplan) None None 1-3c 0 0 0Tranylcypromine (Parnate) None None 1-3c 0 0 0MAO Inhibitor: ReversibleMoclobemide (Aurorix)d None Low 1-3c 0 0 0Norepinephrine-Specific Reuptake InhibitorReboxetine (Edronax) None Low 13 ++++ 0 0
aAnticholinergic side effects include dry mouth, blurred vision, tachycardia, urinary retention, and constipation. bAlso has antipsychotic effects due to blockage of dopamine receptors. cHalf-life does not correlate with clinical effects. dNot available for use in the US. 0=no effect; +=mild effect; ++=moderate effect; +++= strong effect; ++++=maximal effect.
Changes in Adrenergic Receptors and in Changes in Adrenergic Receptors and in Norepinephrine Synthesis and Release with Chronic Norepinephrine Synthesis and Release with Chronic
Antidepressant Treatment (Reuptake Inhibitors)Antidepressant Treatment (Reuptake Inhibitors)
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Selective Serotonin Reuptake InhibitorsSelective Serotonin Reuptake Inhibitors
241-5.58
Drugs
• Fluoxetine
• Sertraline
Advantages
• Fewer anticholinergic and cardiovascular side effects
• However relatively new and long-term effects need to be evaluated
Changes Induced with Chronic Treatment withChanges Induced with Chronic Treatment withSelective Serotonin Reuptake InhibitorsSelective Serotonin Reuptake Inhibitors
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Long-Term Adaptations to Antidepressant TreatmentLong-Term Adaptations to Antidepressant Treatment
241-5.60
Progression of Changes in the Pharmacological Progression of Changes in the Pharmacological Treatment of Major Depressive DisorderTreatment of Major Depressive Disorder
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Electroconvulsive Therapy (ECT)Electroconvulsive Therapy (ECT)
241-7.62
• 1900's observed that spontaneous seizures improved psychiatric state
• Early seizures induced with camphor and oil
• 1938 ECT
• ECT generally used on depressed patients unresponsive to pharmacotherapy
• Its efficacy is 80% to 90% which is higher than conventional therapies
• Technically difficult and expensive
• Must be administered several times a week for several weeks
• Mood changes are due to cortical seizures and not to peripheral results
• Mechanisms are not known