Brain Chemistry And The Medical Treatment Of Major Depression

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Information about Brain Chemistry And The Medical Treatment Of Major Depression

Published on January 19, 2008

Author: Giakas

Source: slideshare.net

Brain Chemistry and the Medical Treatment of Major Depression William J. Giakas, M.D.

What is Major Depression? Mood disorder Common condition Affects both the brain and body Multiple causes Chronic, recurring Debilitating for individual and family Treatment resistance is a challenge

Mood disorder

Common condition

Affects both the brain and body

Multiple causes

Chronic, recurring

Debilitating for individual and family

Treatment resistance is a challenge

What Are The Challenges? Correct diagnosis Proper medication selection Managing adverse effects Proper dosing and duration Compliance with treatment Achieving full remission

Correct diagnosis

Proper medication selection

Managing adverse effects

Proper dosing and duration

Compliance with treatment

Achieving full remission

General Approach Assess medical and psychiatric history Address stress and coping skills Normalize sleep Encourage exercise Healthy diet Pharmacotherapy

Assess medical and psychiatric history

Address stress and coping skills

Normalize sleep

Encourage exercise

Healthy diet

Pharmacotherapy

Chemical Messengers Acetylcholine (ACh) Norepinephrine (NE) Dopamine (DA) Serotonin (5-HT) Gamma-Aminobutyric Acid (GABA) Neuropeptides

Acetylcholine (ACh)

Norepinephrine (NE)

Dopamine (DA)

Serotonin (5-HT)

Gamma-Aminobutyric Acid (GABA)

Neuropeptides

 

Choosing an Antidepressant Clinical diagnosis and particular features Side effect profile History of prior antidepressant treatment Efficacy and rate of response Ease of dosing Drug interactions Withdrawal potential Expense

Clinical diagnosis and particular features

Side effect profile

History of prior antidepressant treatment

Efficacy and rate of response

Ease of dosing

Drug interactions

Withdrawal potential

Expense

Identifying Target Symptoms General Medical Fever Cough Sputum production Chest discomfort Weakness Headache Psychiatric Depressed mood Irritability Impaired Concentration Mental slowing Poor appetite Insomnia Nausea

General Medical

Fever

Cough

Sputum production

Chest discomfort

Weakness

Headache

Psychiatric

Depressed mood

Irritability

Impaired Concentration

Mental slowing

Poor appetite

Insomnia

Nausea

Biological Options Single action antidepressant Antidepressant with multiple action Combination antidepressants Add-on therapies Augmentation strategies Antidepressants + VNS or ECT

Single action antidepressant

Antidepressant with multiple action

Combination antidepressants

Add-on therapies

Augmentation strategies

Antidepressants + VNS or ECT

Single-Action Antidepressants Lexapro Celexa Zoloft Prozac Paxil Luvox

Lexapro

Celexa

Zoloft

Prozac

Paxil

Luvox

Serotonin and Behavior 5-HIAA LO Impulsivity HI

Serotonin Pathways

Pitfalls in SSRI Treatment Somnolence Diarrhea Anxiety EPS Tremors Diaphoresis Confusion Sexual SEs Nausea Insomnia Headaches Increased fatigue Withdrawal Hyponatremia

Somnolence

Diarrhea

Anxiety

EPS

Tremors

Diaphoresis

Confusion

Sexual SEs

Nausea

Insomnia

Headaches

Increased fatigue

Withdrawal

Hyponatremia

Multi-Action Antidepressants Effexor-XR Cymbalta Wellbutrin-XL TCAs MAOIs

Effexor-XR

Cymbalta

Wellbutrin-XL

TCAs

MAOIs

Tricyclic Antidepressants TCA Α 1,2 M1 NRI H 1,2 SRI

Monoamine Oxidase Inhibitors (MAOIs) More difficult to use Dietary compliance issues Risk of hypotension or hypertension Possible advantage, MAOI activity increases with age Proven more effective than TCAs in atypical depression

More difficult to use

Dietary compliance issues

Risk of hypotension or hypertension

Possible advantage, MAOI activity increases with age

Proven more effective than TCAs in atypical depression

Remeron (5-HT and NE) Increases serotonin and norepinephrine Less nausea and sexual side effects Mild  1 antagonist Weight gain and somnolence Anticholinergic effects Agranulocytosis Can  cholesterol and triglycerides

Increases serotonin and norepinephrine

Less nausea and sexual side effects

Mild  1 antagonist

Weight gain and somnolence

Anticholinergic effects

Agranulocytosis

Can  cholesterol and triglycerides

Effexor-XR (5-HT, NE, +-DA) Approved for MDD and GAD Effective for severely depressed patients Use in retarded, hypersomnia, atypical, and weight gaining depressives Baseline hypertension is not exclusionary Nausea can be treated with Zofran Diaphoresis can be treated with clonidine or benztropine May be less effective for PMS-related anxiety

Approved for MDD and GAD

Effective for severely depressed patients

Use in retarded, hypersomnia, atypical, and weight gaining depressives

Baseline hypertension is not exclusionary

Nausea can be treated with Zofran

Diaphoresis can be treated with clonidine or benztropine

May be less effective for PMS-related anxiety

Effexor-XR Effects 5HT, NE, DA Potential for a more rapid onset of action Minimal inhibition of CYP 2D6 Once daily dosing Ascending dose-response curve No effect on histamine, muscarinic, or alpha-adrenergic receptors

Effects 5HT, NE, DA

Potential for a more rapid onset of action

Minimal inhibition of CYP 2D6

Once daily dosing

Ascending dose-response curve

No effect on histamine, muscarinic, or alpha-adrenergic receptors

Wellbutrin (DA and NE) Dopamine and norepinephrine enhanced Higher incidence of seizures (0.4%) No known serious drug interactions No sexual side effects Appetite-suppressing Stimulant effects ( ADHD and smoking) No benefit in PMS-related depressive exacerbations

Dopamine and norepinephrine enhanced

Higher incidence of seizures (0.4%)

No known serious drug interactions

No sexual side effects

Appetite-suppressing

Stimulant effects ( ADHD and smoking)

No benefit in PMS-related depressive exacerbations

Benefits of “Adverse” Effects Appetite suppression Weight gain Sedation Stimulation H2-blockade Constipation Diarrhea Inhibited ejaculation Antihistamine (H1) Urinary retention

Appetite suppression

Weight gain

Sedation

Stimulation

H2-blockade

Constipation

Diarrhea

Inhibited ejaculation

Antihistamine (H1)

Urinary retention

Focus of Research in Depression Neurotransmitters Surface Receptors Intracellular Signaling Cascades

Hippocampus Critical in regulation of motivation and emotion Lesions associated with severe amnesia Widespread connections to diverse brain regions involved in mood regulation

Critical in regulation of motivation and emotion

Lesions associated with severe amnesia

Widespread connections to diverse brain regions involved in mood regulation

Temporal Lobe and Hippocampus

Neuroplasticity Alterations of dentritic function Synaptic remodeling Long-term potentiation Axonal sprouting Neurite extension Synaptogenesis Neurogenesis

Alterations of dentritic function

Synaptic remodeling

Long-term potentiation

Axonal sprouting

Neurite extension

Synaptogenesis

Neurogenesis

Evidence Linking Hippocampal Function To Depression Hippocampus is 15-20% smaller Stress response causes ↑ glucocorticoids (GC) HPA axis abnormalities (DST) Primate data using implanted GC pellets Stress studies in animal models

Hippocampus is 15-20% smaller

Stress response causes ↑ glucocorticoids (GC)

HPA axis abnormalities (DST)

Primate data using implanted GC pellets

Stress studies in animal models

Potential Mechanisms of Cell Loss and Atrophy Glucocorticoids Neurotrophic Factors Glutamate

Glutamate Excitatory neurotransmitter Calcium mobilization “memory” Extrusion of Ca ++ is ATP or ionic gradient dependent Excess cytosolic calcium produces “promiscuous” overactivity of calcium-dependent enzymes Reduction in glial cells

Excitatory neurotransmitter

Calcium mobilization “memory”

Extrusion of Ca ++ is ATP or ionic gradient dependent

Excess cytosolic calcium produces “promiscuous” overactivity of

calcium-dependent enzymes

Reduction in glial cells

Glucocorticoids Decrease glucose transport Increase intracellular cytosolic calcium Inhibit transcription of calcium-ATPase pump Increases glutamate concentrations in the hippocampal synapse

Decrease glucose transport

Increase intracellular cytosolic calcium

Inhibit transcription of calcium-ATPase pump

Increases glutamate concentrations in the hippocampal synapse

Neurotrophic Factors Brain-derived neurotrophic factor (BDNF) B cell lymphoma protein-2 (bcl-2)

Brain-derived neurotrophic factor (BDNF)

B cell lymphoma protein-2 (bcl-2)

Brain-Derived Nerurotrophic Factor (BDNF) BDNF produces antidepressant effects in behavioral models of depression Antidepressants increase BDNF in animals and neuronal sprouting ↑ BDNF in postmortem brains of subjects treated with antidepressants

BDNF produces antidepressant effects in behavioral models of depression

Antidepressants increase BDNF in animals and neuronal sprouting

↑ BDNF in postmortem brains of subjects treated with antidepressants

B Cell Lymphoma Protein-2 (bcl-2) Over-expression is neuroprotective against ischemia, MPTP, β -amyloid, free radicals, excess glutamate, and ↓ BDNF Social stress worsens stroke outcome by suppressing bcl-2 expression in mice

Over-expression is neuroprotective against ischemia, MPTP, β -amyloid, free radicals, excess glutamate, and ↓ BDNF

Social stress worsens stroke outcome by suppressing bcl-2 expression in mice

Intracellular Signaling Source: Manji HK, Quiroz JA, Gould TD (2003)

How Antidepressants Effect Neuroplasticity Upregulates the CREB cascade Induce regeneration of axon terminals Increase number of new neurons in the dentate gyrus granule cell layer

Upregulates the CREB cascade

Induce regeneration of axon terminals

Increase number of new neurons in the dentate gyrus granule cell layer

 

Neurotrophic Effects of Li Markedly reduces neurological deficits and decreased brain infarct in a rat model of stroke Reduces damage due to quinolinic acid, an excitotoxin, in a rat model of Huntington’s disease Enhances hippocampal neurogenesis Increases total grey matter in bipolar patients

Markedly reduces neurological deficits and decreased brain infarct in a rat model of stroke

Reduces damage due to quinolinic acid, an excitotoxin, in a rat model of Huntington’s disease

Enhances hippocampal neurogenesis

Increases total grey matter in bipolar patients

What Does This Mean For The Treatment of Depression? Shift towards continuation treatment Lower the threshold for treatment? Possible reduced morbidity due to other complicating medical conditions Exercise also increases BDNF, so exercise Psychosocial interventions matter

Shift towards continuation treatment

Lower the threshold for treatment?

Possible reduced morbidity due to other complicating medical conditions

Exercise also increases BDNF, so exercise

Psychosocial interventions matter

Electroconvulsive Therapy

80%-90+% response rates More rapid response 50%-60% response rates in TCA failures No pharmacologic trial has ever shown superiority over ECT 20% > TCAs and 45% > MAOIs Marked superiority in psychotic depression ECT in Major Depression

80%-90+% response rates

More rapid response

50%-60% response rates in TCA failures

No pharmacologic trial has ever shown superiority over ECT

20% > TCAs and 45% > MAOIs

Marked superiority in psychotic depression

 

 

Treatment Adequacy Seizure is necessary but not sufficient Duration alone not adequate Bilateral vs. Right Unilateral Electrical dosage relative to seizure threshold Postictal seizure suppression

Seizure is necessary but not sufficient

Duration alone not adequate

Bilateral vs. Right Unilateral

Electrical dosage relative to seizure threshold

Postictal seizure suppression

High Dose vs. Low Dose Unilateral vs. Bilateral Sackeim, et al, Arch Gen Psych, June 2000

Seizure Suppression EMG EEG

AD vs. ECT + AD Gagne et al., Am J Psych, Dec 2000

Vagus Nerve Stimulation (VNS) FDA-approved for TRD Requires 4 antidepressant failures Implanted pacemaker-like device Can combine with medication No cognitive side effects

FDA-approved for TRD

Requires 4 antidepressant failures

Implanted pacemaker-like device

Can combine with medication

No cognitive side effects

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