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Chapter 18: Affective Disorders — Antidepressants and Mood Stabilizers -…
Chapter 18: Affective Disorders — Antidepressants and Mood Stabilizers
Characteristics of Affective Disorders
Major depression - recurring episodes of dysphoria and negative thinking
15-20% of population experience depression at any one time
World's leading cause of disability
lifetime prevalence: 10% in men, 20% in women
estimated annual workplace losses in US: over $50 billion
Types of depression
reactive: sadness in response to situations (i.e. loss of a loved one)
not mental illness unless symptoms are disproportionate to the event or significantly prolonged
pathological: differs significantly in intensity and duration
loss of interest in almost everything and inability to experience pleasure (anhedonia)
hopelessness, sadness, worthlessness, guilt, desperation
suicidal thoughts
Bipolar disorder (manic depression)
moods cycle from depression to mania over time
symptoms in up to 2.5% of population
primary symptom of mania: elation, little need for sleep, unlimited confidence, impulsive decisions
types of bipolar
Bipolar I: manic
Bipolar II: hypomanic (less intense mania)
Extensive overlap of depression with anxiety
comorbidity 60%
comorbidity predicts more severe and persistent symptoms --> more difficult to treat
anxiety disorder (GAD or SAD) usually precedes depression
Link between anxiety and depression: stress
Intense environmental stress + anxiety often precedes episodes of depression
higher stress hormone levels in depressed patients
abnormal secretion of cortisol in response to greater-than-normal release of ACTH and CRF
stress-diathesis hypothesis: interaction between experience (i.e. neglect) + genetic predisposition (diathesis)
ex. maternal separation stimulates early life stress
young animals separated from their mothers for brief periods daily during first 2 weeks of life
as adults
high stress-induced ACTH and cortisol levels
increased CRF levels in the brain
Nature or Nurture?
Twin studies
if one monozygotic twin has a mood disorder --> likelihood of other twin to have one is 65%
dizygotic twins: 20%
genetics can increase vulnerability, many other factors too
no single dominant gene for affective disorders
Altered Biological Rhythms in Depression: either too little or too much sleep
Melatonin
resynchronizes circadian rhythms and sleep cycles
short half-life: 2hrs
limited efficacy in sleep disorders in depressed patients
long-acting melatonin agonists (agomelatine) RESETS circadian rhythms
bind to MT1 and MT2 receptors in suprachiasmatic nucleus
antidepressant-like activity due to resynchronization of circadian rhythms
Neurochemical Basis of Mood Disorders
Monoamine hypothesis: mood disorders arise from DEPLETED LEVELS of monoamines
Monoamine oxidase inhibitors --> elevations in mood
reserpine: irreversible VMAT2 inhibitor - blocks packaging of monoamines --> caused depression
evidence
manic-like activity produced by amph and cocaine is correlated with enhanced release/blocked reuptake of monamines
prolonged use causes DEPLETION of amines --> depressed mood
Criticisms
overly simple
some drugs that enhance catecholamine levels (cocaine and amph) ARE NOT effective antidepressants
cannot explain discrepancy between the rapid neurochemical action of antidepressants and DELAYED clinical efficacy (4-6wks minimum)
5HT in Affective disorders
Low 5HIAA in postmortem brains of suicide victims and in CSF of depressed patients
cause or effect?
do 5HIAA levels accurately reflect the function of 5HT neurons? Metabolite is not the NT itself
tryptophan depletion challenge
unmedicated patients in remission --> relapse of depression symptoms
Receptor binding studies
brains from unmedicated individuals with mood disorders --> increased density of postsynaptic 5HT2 receptors
compensatory response to low serotenergic activity
chronic antidepressant treatment --> downregulation in 5HT2 receptors
Antidepressants and 5HT
antidepressants INCREASE 5HT by blocking reuptake (SSRIs and TCAs) or inhibiting MAO (MAOi)
Acute: increase in synaptic 5HT activates autoreceptors to SLOW cell firing and reduce 5HT levels
Chronic: downregulation of autoreceptors
synaptic 5HT gradually increases
increased synaptic 5HT downregulates postsynaptic 5HT2A receptors
Acute vs. chronic effects explain the delay in the therapeutic effects of antidepressants
Neurobiological models of depression
Glucocorticoid hypothesis
stress-related neuroendocrine abnormalities of depression
depressed patients have abnormally high CRF secretion
hypothalamic CRF neurons are normally controlled (feedback control) by other areas
amygdala stimulates
hippocampus inhibits
when stress is prolonged and intense, glucocorticoid levels remain high
hippocampal neurons are damaged (no longer provide negative feedback)
decreased dendritic branches and spines in the PFC and hippocampus (neurogenesis is inhibited)
Neurotrophic Hypothesis
low BDNF --> loss of dendritic branches and spines in hippocampus and PFC
low BDNF reduces neurogenesis in hippocampus
chronic stress --> reduced hippocampal BDNF
Chronic (not acute) antidepressants --> increases BDNF
ADs prevent stress-induced reductions in BDNF and neuronal atrophy
BDNF production: dependent on cAMP
chronic antidepressant treatment upregulates cAMP system in hippocampus and frontal cortex
Novel therapeutic strategy: enhancing any part of the cAMP pathway to enhance BDNF production and relieve depression
inhibition of phosphodiesterase (PDE), enzyme that degrades cAMP
Rolipram (PDEi): reduced symptoms, lots of side effects
Therapies for MDD
Challenges of treating depression
there is no one specific drug that's more effective than any other
no way to predict which patient will respond to a particular drug
meta-analysis: placebo is AS EFFECTIVE as SSRIs for mild and moderate depression
each patient must undergo trials to find a drug that optimally balances effectiveness and side effects
all require chronic administration (4-6wks to obtain max response) --> clinical effects depend on compensatory changes in function that require time to develop
Antidepressant meds: MAOis, TCAs, SSRIs, SNRIs, atypicals
differences between ADM classes
tolerability: nature and severity of side effects
suicide risk, Black Box warning
all antidepressants require period of several weeks before reaching full eficacy
modify geneexpression
altered biochemical state takes a long time to become stabilized
neurogenesis
MAO inhibitors: inhibition of MAO increases amount of NT available for release
biochem changes occur within hours
antidepressant effects require 2+ weeks of treatment
change in receptor density: downregulation of NT receptors
upregulation of cAMP
Side effects
changes in blood pressure, sleep disturbances, overeating
elevated NE levels
inhibition of liver MAO --> dietary restrictions "Wine and cheese syndrome" (hypertension)
inhibition of other CYP450 enzymes: intensifies and prolongs effects of barbs, alc, opioids, aspirin
tricyclic antidepressants (TCAs)
bind to presynaptic transporters (SERT and NET)
also block ACh, histamine, alpha1 NE receptors
different TCAs have different NE and 5HT reuptake blocking potencies
neuronal adaptation is necessary for clinical effects (many wks)
many other target sites outside of the monoamines
side effects
sedation and fatigue (histamine receptor blockade)
ACh effects: dry mouth, constipation, urine retention, dizzy, confusion, impaired memory, blurred vision
cardiovascualar effects (alpha1 receptor blockade)
low therapeutic index: fatalities occur at approximately 10x the normal dose
SSRIs
fewer side effects
anxiety, restlessness, movement disorders, muscle rigidity, nausea, headache, insomnia, sexual dysfunction
serotonin syndrome (never give with MAOi
causes physical dependence: taper withdraw, not cold turkey
Third-generation antidepressants
Goals: speed onset of effectiveness and reduce side effects
CRF receptor antagonists
enhance cAMP system
deep brain stimulation
ketamine
Therapies for Bipolar Disorder
lithium carbonate: most effective med
no effect on healthy individuals
1-2wks of use eliminates/reduces 60-80% of manic episodes
effective in 40-50% of patients
DOES NOT cause depression or produce sedation
Mech of action
Lithium enhances 5HT actions
elevates brain tryptophan, 5HT, 5HIAA levels, increases 5HT release
reduces catecholamine activity by ENHANCING reuptake and reducing release
flattens the extremes of emotion in both directions
Side effects
Mild at therapeutic doses: GI symptoms, acne, tremor, impaired cognition, incoordination
not metabolized: excreted intact
sodium depletion --> toxic levels of lithium
therapeutic index is very low: blood lithium levels must be monitored regularly
Alternatives to lithium: anti-epilepsy drugs
Valproate for acute mania
similar in efficacy to lithium (more tolerable GI effects),
teratogenic
increases GABA levels
stimulates GAD (enzyme for GABA synthesis), inhibits GABA-T (enzyme for GABA degradation)
Carbamazepine: resembles TCAs
stabilizes inactivated state of v gated Na+ channels
GABA receptor agonist
Lamotrigine