Download Psy.419.ch16

• Two principle types of affective disorder
– Major depression
• Unipolar disorder
– Bipolar disorder
• Sometimes referred to as manic-depressive
disorder
Major Depression
• We all have experienced the essential feelings
associated with depression
– Feel down and listless
– Lack energy to do things
• If the result of a life event such as death of a loved one,
loss of job, or breakup of a relationship
– Considered reactive depression
– Does not constitute mental illness unless the symptoms last
longer than normal or are abnormally intense
• However, clinical depression is different from these
normal reactions to life events.
Major Depression
• In clinical depression the mood disorder is
severe.
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A more intense emotional reaction
Lasts longer
Individual withdraws from life and social interactions
Anhedonia
• inability to experience pleasure in anything
– Often stop eating, bathing, caring for themselves
• May remain in bed for prolonged periods
– suicidal thoughts and/or attempts
• One estimate is that 7-15% of depressed individuals commit
suicide
• Compared to 1-1.5% of general population
• Most episodes of unipolar depression will
improve in 6-9 months.
• However, the episodes usually recur
throughout life
– Increasing in frequency and intensity
• Stress is often associated with the first
episode of depression
– Later episodes can occur in the absence of
significant stressors
• About 3-4% of men experience
unipolar depression
• About 5-9% of women
• Mean onset of unipolar
depression is about 27 years
• Diagnosis of depression has
been on the rise, and occurring
earlier in life
– Americans born before 1905
• 1% developed depression by
age 75
– Americans born since 1955
• 6% developed depression by
age 24
Bipolar disorder
• Depressive and manic phases alternate.
• We have already discussed depressive symptoms
• The primary symptom of mania is elation
– Sometimes they can be irritable, impatient, or belligerent
• Their thoughts are and ideas are racing
• Everyone else is so slow
• Approximately 1% of the population is diagnosed with
bipolar depression
– No gender differences
– Onset is between 20-30 years of age
– Episodes continue throughout lifetime
Mental illness and creativity
• A high proportion of creative individuals in
the arts and sciences have experienced
bipolar disorder
– Some find the manic phases to be very
productive times
• Is creativity linked to mental illness?
Box 16.1 Mood Disorders and Creativity
Biological risk factors
• Scientists agree that psychiatric disorders
develop as a result of an interaction of
genes and environmental events.
• Role of heredity
– Adoption studies
– Twin studies
– Linkage studies
Role of heredity
• Adoption studies
– Individuals diagnosed with an affective disorder who
were adopted at an early age
– If the disorder has a heritable component one would
expect that the adopted individual would have more
biological relatives with the same disorder, rather that
being like the adopted family
• Better evidence comes from twin studies
– Compare the concordance rate for monozygotic
(100% shared genes) to dizygotic (50% shared
genes).
• Dizygotic is sometimes also referred to as fraternal
Role of heredity
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•
•
Overall (any mood disorder)
concordance rate is 65% for
identical and about 20% for
fraternal.
Note that severe depression has a
higher heritability effect than less
severe depression.
Also note that the heritability effect
for Bipolar disorder is very large.
– 80% vs. 16%
•
Keep in mind that even fraternal
twins are showing heritability
effects
– General population depression =
about 5-6%  goes up to 20
some %
– General population bipolar =
about 1%  goes up to 16%
Role of heredity
• Linkage studies look for similarities in
gene location on chromosomes in families
that have a history of a disorder
• No single dominant gene for affective
disorder is known
Role of stress
• There is a lot of evidence that anxiety and
depression are closely related
• People diagnosed with depression are often
experiencing anxiety
• It has also been shown that intense
environmental stress and anxiety often precede
episodes of depression
– Especially early in the disorder
• Altered patterns of stress hormones are
frequently found in depressed patients
Stress
• Identical life stressors can be perceived very
differently by individuals
– Some cope well
– Others succumb more easily
• It is likely that genetics plays a role in how we
respond physically and behaviorally to daily
traumas and stress
• Neuroscientists have focused on the
hypothalamic-pituitary-adrenal (HPA) axis as an
important area of the nervous system involved in
stress response and etiology of depression
HPA axis
• When we are stressed the hypothalamus releases CRF
(corticotropin releasing factor).
– This is in response to NTs such as NE, ACh, and GABA
• CRF causes the anterior pituitary gland to release ACTH
(adrenocorticotropic hormone) into the blood stream
• ACTH causes the adrenal glands (atop the kidneys) to
increase the release of cortisol as well as other
glucocorticoids
– These substances all play a role in the stress response
• Sympathetic reaction.
• Normally increasing cortisol levels feedback to the brain
and the HPA to shut down.
16.3 The HPA axis
HPA
• One consistent
finding in depressed
individuals is
abnormal secretion of
cortisol.
– Many depressed
patients have elevated
cortisol levels
– This is the result of
greater-than-normal
release of ACTH
HPA
• Depressed patients often have enlarged pituitary and
adrenal glands
– However, this enlargement is likely due to the increased activity
that is asked of the glands, rather than the original abnormality
– The hypersecretion is likely due to abnormal regulation of CRF
by the hypothalamus
• Studies have shown higher-than-normal CRF levels in
the CSF (cerebrospinal fluid).
– Also increased numbers of CRF-producing cells have been
found in the hypothalamus
• Postmortem
• It has also been shown that antidepressant drugs and
electroconvulsive therapy reduce CRF levels in
depressed patients
Circadian secretion of cortisol
• Another consistent finding in
depressed patients is an
abnormal circadian rhythm of
cortisol secretion
• Notice the higher than normal
levels, but also flatter release
function for depressed patients
• May reflect a general
abnormality in the biological
clock
– Disrupted sleep and
temperature patterns are also
common
Dextramethasone challenge
• Depressed individuals also
tend to fail to dextramethasone
challenge.
– Dextramethasone is a
synthetic glucocorticoid
– Should act as a negativefeedback stimulus
• Suppress hypothalamic
release of CRF
• Suppress pituitary release of
ACTH
– Which should decrease
cortisol levels
• Depressed patients that don’t
respond to dextramethasone
challenge
– more likely to relapse
Consequences of altered glucocorticoid levels
• Normal release of glucocorticoids is useful in preparing
an organism for stress
• When the levels are persistently elevated several
systems begin to show pathological changes
– Damage to immune system
– Disrupts organ function
– neuronal atrophy in hippocampus
• Leading to cognitive impairment
– imbalances in the serotonin system
• Correlated with anxiety
– hormonal changes
• Associated with depression
Altered biological rhythms
• Not just cortisol
• Altered sleep rhythms are very common in
depression
• Normal sleep cycle has 4 stages of nonREM sleep
– lasting about 70-100 minutes
• Followed by 10-15 minutes of REM sleep
• You cycle through these stages 4 or 5
times per night
• Depressed individuals have distinct abnormalities in their sleep
rhythm
• 1) long period before sleep onset
• 2) significant decrease in time spent in slow-wave sleep
• 3) onset of REM sleep occurs much earlier after onset of sleep
finally begins
• Can sometime occur immediately after falling asleep
• 4) REM sleep is significantly increased during the first third of sleep.
• 5) normally REM periods tend to increase as the night progresses,
but depressed individuals do not show this pattern
• 6) When ocular movement is measured depressed individuals show
more frequent and vigorous eye movements.
• Which suggests more intense dreaming.
16.5 Altered sleep architecture in depression (Part 1)
16.5 Altered sleep architecture in depression (Part 2)
• These alterations in sleep patterns are similar to
what happens when someone required to alter
their sleep pattern by 12 hours
• Sometimes circadian rhythms seem
desynchronized
– Sleep awake cycle
– Temp cycle
– Hormone cycle
• Has led to novel treatment
– Sleep deprivation therapy.
Box 16.2 Sleep Deprivation Therapy (Part 1)
Box 16.2 Sleep Deprivation Therapy (Part 2)
• Animal models of depression
• No perfect model
– Animals don’t have feelings of worthlessness and
guilt
• Animals models can mimic certain aspects of
depression
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Reduction in motor activity
Changes in neuroendocrine response
Cognitive changes
Changes in eating and sleeping
• Reserpine induced sedation
– Reserpine blocks VMAT (vesicular monoamine
transporter)
– Causes DA and NE levels to drop to very low levels
• Remember the reserpine rabbits (ch. 5).
– Causes extreme sedation
• Clinically viable antidepressants antagonize the
effects of reserpine
– so it is effective for testing monoamine based
medications
– Not useful for novel approaches that don’t involve the
monoamine system
• Behavioral despair or forced
swim test
• Rats become immobile after
learning they cannot escape
– Immobility is thought to reflect
a lowered mood
• Resigned to fate
• Similar to learned
helplessness
– Depressed humans often
express they feel hopeless
and that nothing they do has
an effect
• Antidepressants reduce the
amount of time spent freezing
Maternal separation
• Induce stress at an early age by separating
young rats from their mothers for brief periods of
time during the first few weeks of life
• This model has shown that early stress can alter
corticotropin releasing factor function
– May predispose individuals to clinical depression later
in life
• Known as the stress-diathesis model of
depression
– Stress (early stress experiences)
– Diathesis (genetic predisposition)
Stress-diathesis model
• They propose that the genetic character of depression is expressed
by
– lowered monoamine levels in the brain
– increased reactivity of the HPA axis to stress
• These factors create a lowered threshold for depression
• Negative early life experiences may lower the threshold even further
• Nemeroff et al. showed that maternal separation rats (during first 3
weeks of life) showed elevated stress responses later in life
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Elevated ACTH and cortisol levels
Increased CRF in the brain
Increased CRF gene expression
Serotonin reuptake blockers reversed these effects
• Not yet understood how 5-HT reuptake blockade modifies CRF activity
Therapies for affective disorders
• There are several drug classes that are
effective antidepressants
• All treatment methods require chronic
administration.
– Significant change can occur in 1-3 weeks,
but maximum effectiveness may not be
achieved for 4-6 weeks
– Suggests that the clinical effect must depend
on compensatory changes that take time to
develop
MAO-Is
• Monoamine oxidase inhibitors
– MAO-Is
– Oldest antidepressants
• Iproniazid used in 1950s to treat tuberculosis
– It was noted that it had significant mood elevating effects
• Can have severe and dangerous side effects
– With appropriate dietary restrictions MAO-Is can be safe
• Tend to work well with patients that don’t respond to other treatments and
don’t want ECT
• Also effective for anxiety and eating disorders (bulimia and anorexia
nervosa).
• Common MAO-Is
– Phenelzine (Nardil)
– tranylcypromine (Parnate)
– Isocarboxazid (Marplan)
Mechanism of action for MAO-Is
• Monoamine oxidase is an enzyme that breaks
down monamines (NE, DA, and 5-HT)
• Inhibition of MAO increases the amount of
monamines for release into the synapse
• It is likely receptor density changes, or changes
in second messenger function that leads to relief
– The NT changes would occur almost immediately
– However complete effects can take weeks to develop
Side effects of MAO-Is
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Hypertension
Insomnia
Overeating
MAO-Is inhibit MAO in the liver
– MAO is responsible for deaminating tyramine
• Tyramine is a by-product of fermentation in many foods
• If these foods aren’t avoided than higher-than-normal NE levels can
occur
– Leading to dramatic increases in blood pressure
– Headache, nausea, sweating, vomiting
– Possible stroke
– MAO-Is also inhibit other liver enzymes (cytochrome P-450)
• Thus the effects of alcohol and other drugs can be intensified and
prolonged.
Tricyclic antidepressants
• Named because the
drugs all have a
characteristic three-ring
structure
• Imipramine is the
prototypical tricyclic
antidepressant
– Originally developed as an
antipsychotic it was not
very effective, but found to
have mood elevating
effects
Tricyclic antidepressants: mechanism of action
• Act by binding to the
presynaptic transporter
proteins.
– Inhibit reuptake
– Prolongs the duration of
the NTs in the synapse
– Eventually cause pre- and
postsynaptic changes
• Many tricyclics inhibit the
reuptake of NE and 5-HT
– Some are more effective
at inhibiting one or the
other
• Doesn’t seem to
influence the drugs
effectiveness
• Does determine side
effects
Tricyclic antidepressants: side effects
• Most TCAs also block choline, histamine, and α-adrenergic
receptors
– Which influences side effects
• Histamine receptor blockade can cause sedation and fatigue
• Cholinergic receptor blockade can cause drymouth, constipation,
urinary retention, dizziness, confusion, blurred vision, and impaired
memory
• α-adrenergic receptor blockade along with increased synaptic NE
can lead to hypotension, tachycardia, and arrhythmia
– Particularly problematic for elderly patients with cardiac disorders
• Low therapeutic index
– 10 times the normal dose can cause fatalities
– Particularly problematic given that these drugs are being supplied to
patients that are potentially suicidal
Second-generation antidepressants
• These drugs are an attempt to provide faster
onset of action with fewer side effects.
• They were designed to more selective in their
action.
– Avoiding anticholinergic and cardiovascular effects of
previous drugs
• Turns out that none of the drugs are more
effective nor do they have a faster onset
• The biggest difference is the nature of their side
effects
Selective serotonin reuptake inhibitors (SSRIs)
• Drugs in this class include
– Fluoxetine (Prozac)
– Sertraline (Zoloft)
– Paroxetine (Paxil)
• They are useful to treat depression but have also been
used to treat anxiety disorders, obesity, and alcoholism
• The SSRIs are safer than other antidepressants
• The SSRIs are more selective than TCAs in enhancing
serotonin function.
– Block 5-HT transporter more than noradrenergic transporter
• Takes several weeks to see full effects
Side effects of SSRIs
• Do not affect NE, ACh, or histamine
• Thus SSRIs do not produce sedation, cardiovascular toxicity, or
anticholinergic side effects
• However there are side effects related to the increased serotonin
activity
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Anxiety
Restlessness
Movement disorders
Muscle rigidity
Nausea
Headache
Insomnia
Sexual dysfunction (occurs in 40-70% of patients)
• A major reason that patients terminate treatment
– Especially young males
Side effects of SSRIs
• SSRIs are generally safer than than TCAs and MAOIs
• Can have life-threatening effects when combined with
other serotonergic agonists, or drugs that interfere with
the metabolism of SSRIs
– Referred to as serotonin syndrome
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Severe agitation
Disorientation and confusion
Ataxia
Muscle spasms
Exaggerated autonomic activity
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Fever
Shivering
Chills
Diarrhea
Hypertension
Increased heart rate
SSRIs and dependence
• Also can cause physical dependence
– About 60% of patients experience withdrawal when treatment is
terminated
– Can last for several weeks
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Dizziness
Ataxia
Nausea
Vomiting
Diarrhea
Fatigue
Chills sensory disturbances
Insomnia
Vivid dreams
Anxiety
Irritability
Third generation antidepressants
• The newer versions of antidepressants have
returned to affecting both the NE and 5-HT
system
– Mirtzapine (remeron)
• Causes increased release of NE and 5-HT at the synapse
• There are also SNRIs (serotonin norepinephrine
reuptake inhibitors)
– Duloxetine (cymbalta)
– Venlafaxine (Effexor)
• Third generation antidepressants resemble
tricyclics but with fewer side effects
Electroconvulsive therapy
• Hungarian psychiatrist (early 1900s)
– spontaneous seizures = improved mood
• Psychiatrists began inducing seizures as a treatment for depression
– Administer insulin
• In 1938 electroconvulsive therapy (ECT) was introduced
– Still used today
– Generally for patients that don’t respond to drugs
• ECT effectiveness is 80-90%
– Higher than conventional treatments
– Low incidence of side effects
• Public tends to consider it archaic which limits its use
• Must be administered several times a week for several weeks to be
effective
ECT mechanism of action
• Enhances the function of several neurotransmitter systems
– NE, 5-HT, DA, and GABA
• Repeated treatments lead to down-regulation of β2- and α2adrenergic receptors
• Has a low incidence of side effects
– Makes it very appropriate for those with cardiovascular disorders,
elderly, medically ill, and pregnant women
• Most significant side effect is confusion and memory loss.
• Can cause anterograde amnesia for several days to weeks after
treatment
• Also can cause retrograde amnesia for events preceding treatment
– Squire – t.v. programs that only ran for one year.
– Can lose memory for time during ECT and several months prior to
treatment
Transcranial magnetic stimulation
• TMS is a new brain stimulation
technique
– Place a magnet on the scalp
– Causes a localized current in
the brain
• There is evidence that this
treatment can be effective
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Noninvasive
Painless
No convulsions
Anesthesia not necessary
Drugs to treat bipolar disorder
• Lithium carbonate is the most effective treatment
• Has no effect on mood or behavior of normal individuals
• One to two weeks of lithium eliminates or reduces
symptoms in 60-80% of manic episodes.
– Does not cause depression or produce sedation
• Not as effective at terminating episodes of depression
– So it is often administered with antidepressants
• Very good at reducing future episodes of mania and
depression
– Those that continue with lithium maintenance
• Less than 2 weeks in hospital per year
– Without lithium
• 8-13 weeks in hospital per year
– See next figure
16.10 Lithium’s effectiveness for bipolar disorder (Part 1)
• Most patients require lifetime treatment
with a mood stabilizer (lithium)
• Stopping use causes symptoms to return
• Still many stop
– Don’t like side effects
• Impaired memory and confusion
• Fail to experience normal mood swings
• Object to the loss of the manic phase
– Todd
Mechanism of action of mood stabilizers
• Lithium enhances 5-HT actions
– Elevates tryptophan, 5-HT, and 5-HIAA (major metabolite)
• The increase in serotonin eventually alters synaptic function
• Reduces catecholamine activity by enhancing reuptake
and reducing release
• Despite these direct effects scientists suspect the major
action of lithium is on second messenger function
• Its ability to alter second messenger function regardless
of the NT system may be what allows it to limit extreme
swings of mood in either direction
Side effects of lithium
• Lithium is not metabolized
– Excreted by kidney
– The rate of excretion is dependent on sodium levels
– If the patient is sodium deficient lithium can build up
• Side effects at therapeutic levels are mild
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Thirst and increased urination
Impaired concentration and memory
Fatigue
Tremor
Weight gain
Side effects of lithium
• The therapeutic index is low
– Blood levels must be monitored
– If levels get too high
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Cramps
Vomiting
Diarrhea
Kidney dysfunction
Tremor
Confusion
– Very high levels can lead to seizures, coma, and
death
Other therapies for bipolar disorder
• New drugs
– Carbamazepine (tegretol)
– Valproate (depakene)
– Topiramate (topamax)
– Tiagabine (gabitrol)
• Have different toxicity profile from lithium
• Similarly effective
16.10 Lithium’s effectiveness for bipolar disorder (Part 2)
Monoamine hypothesis
• Neurochemical basis of mood disorders
• The earliest theory was the monoamine hypothesis
– Depression is the result of low monoamine levels
– Mania is the result of high monoamine levels
• Originated with the observation that reserpine (high blood pressure
med) induced depression as a side effect in many patients
– We know that reserpine blocks VMAT
• Causing depletion of monoamines
– Led to the idea that reduced levels of monoamines was responsible for
depression
• More support came when the mechanism of action for TCAs and
MAO-Is was considered
– increase the activity of NE and/or 5-HT
– Drugs in both classes reverse reserpine-induced reduction in motor
activity.
16.11 Effects of reserpine, the MAO-I iproniazid, and the TCA imipramine on rat locomotor activity
Monoamine hypothesis
• It was shown that depressed patients had
reduced levels of NE and 5-HT metabolites
(MHPG and 5-HIAA)
• It was shown that the manic-like activity
produced by amphetamines and cocaine was
associated with increased catecholamine
release
– With prolonged use depletion of these NTs occurred
leading to depression, lethargy, and drug craving
• If you put all of these pieces of evidence
together, it provides support for the monoamine
hypothesis.
Monoamine hypothesis
• However, the monoamine hypothesis is now
considered to be too simplistic.
– The most important problem with the theory is that it
fails to account for the time lag in effectiveness of
antidepressant treatments
– It is also unclear which NTs are most important, and
how they specifically contribute to the disorder.
• We suspect NE and 5-HT, but these systems are very
complicated and appear to be capable of interacting with
each other.
• Nevertheless, the monoamine hypothesis has
been extremely influential. Driving modern
research on mood disorders for decades.
Serotonin dysfunction
• Face validity
– Serotonin has influence on sensitivity to pain,
emotionality, and response to reward and
punishment.
– Also sleep, eating, and thermoregulation
• Rats with depleted stores of 5-HT
– Irritable and aggressive
– Overly sensitive to pain
– Altered eating patterns
Serotonin dysfunction
• 1) turnover
– Measure principle metabolite
• 5-HIAA
– High 5-HIAA are assumed to reflect increased
function of serotonin
• Lower = lower
– Low 5-HIAA found postmortem in depressed
individuals and suicide victims
– Low 5-HIAA found in CSF of depressed individuals
• Blood and urine levels have not led to conclusive results
Serotonin dysfunction
• 2) precurser levels
– Tryptophan
• Frequently low in depressed patients
• When formerly depressed patients are rapidly depleted of
tryptophan depressed symptoms returned to many of the patients
• 3) receptor binding
– Postmortem analysis showed increased density of postsynaptic
5-HT2 receptors in unmedicated individuals.
• Could be compensatory change due to low serotonergic activity
– Animal studies show chronic antidepressants lead to down
regulation of 5-HT2 receptors
– Table 16.4 shows that almost all treatments lead to down
regulation of 5-HT2
• ECT is the only exception
Serotonin dysfunction
• 4) PET scans
– Depressed patients show
increased activity in medial
orbitofrontal cortex and
amygdala
• Areas that are known to
be involved in emotion
– Activity in amygdala is
correlated with severity of
depression
• Returns to normal after
antidepressant drug
treatment
– Activity in orbitofrontal
cortex may reflect effort to
control unpleasant
thoughts and emotions
Serotonin effects in animals
• Acute versus chronic
effects of
antidepressants
• Acute
– Reuptake blocked
• 5-HT lingers in synapse
– Autoreceptors
activated
• Decreased release
• Two effects cancel
each other out
Serotonin effects in animals
• Chronic effects
– Tolerance (down
regulation) of autoreceptors
occurs
• Now there is an increase
in 5-HT release
– Reuptake blockade
remains
• 5-HT lingers
• Now both actions lead to
an increase in 5-HT
activity
Serotonin effects in animals
• This difference between acute and chronic
effects of antidepressants in animals may
explain the lag in antidepressant effectiveness.
• It has also been shown that the
electrophysiological response to serotonin
agonists is increased by long-term
antidepressant treatment
– This effect can take 15 days to fully develop
• Also follows the time course of antidepressant effectiveness
– See table 16.4 again
– This finding supports the notion that treatment has led
to receptor changes that have increased the
sensitivity of the serotonergic system
• It is not fully understand how down
regulation of serotonin receptors can lead
to increased responsiveness to 5-HT
agonists
– Perhaps it has to do with differences in
changes to presynaptic and post synaptic
receptors we discussed above
• Tolerance in presynaptic autoreceptors?
• Sensitization in postsynaptic receptors?
Norepinephrine dysfunction
• Face validity of NE
– Adrenergic system is involved in
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Endocrine effects
Reward
Attention and arousal
Stress response
• Animal studies
– electrical stimulation of locus coeruleus produces
• Vigilance
• Anxiety
• Inhibition of exploration
– Electrical recording in locus coeruleus shows
• Increased activity during threatening situations
• Decreased activity during sleep, grooming, and feeding
– Antidepressant drugs
• decrease firing rate of locus coerulus
• reduce NE metabolites
Norepinephrine dysfunction
• Human studies are not conclusive
• MHPG (major NE metabolite)
– Higher, lower, no change
– Generally found to be higher in patients
undergoing treatment
• Suggests an increase in NE turnover due to
antidepressant use
• Untreated unipolar and bipolar patients do not show differences in
adrenergic receptor binding
• Chronic treatment causes down regulation of both β-receptors and
α2-autoreceptors.
– Unfortunately these effects are opposite to one another
• Decrease autoreceptors = increase activity
• Decrease postsynaptic receptors = decrease activity
• It would seem that the down regulation of autoreceptors may
eventually win out.
– Like we discussed with serotonergic system
– Leading to increased noradrenergic turnover
• Down-regulation of β-receptors is a very consistent finding across
treatments for depression
– TCAs, MAO-Is, SSRIs, SNRIs, ECT, Lithium
– Takes 7-21 days
NE and 5-HT modulate one another
• Most consistent finding of antidepressants are
down-regulation of β-receptors and 5-HT2
receptors and an enhanced physiological
response to 5-HT
• Sulser (1989) proposed a “serotoninnorepinephrine” hypothesis of depression
• Comparing the noradrenergic and serotonergic
systems shows considerable structural and
functional overlap.
– See Figure 16.14
Serotonin-norepinephrine hypothesis
• Destroying 5-HT terminals prevents down
regulation of β-receptors due to chronic
antidepressant treatment
• 5-HT agonists can indirectly stimulate the
noradrenergic system
– Causing β-receptor down-regulation
• Increased noradrenergic activity can
increase activity in the raphe nuclei
Neurobiological models of depression
• Glucocorticoid hypothesis
– Focuses on the abnormalities that are seen in stress hormones
for depressed patients
• The hippocampus has receptors that when activated by
high levels of glucocorticoids help to inhibit CRF release
from the hypothalamus
• When prolonged or intense stress occurs these
hippocampal neurons are damaged and stop responding
– This causes the negative feedback system to fail
– Increasing cortisol levels then lead to further hippocampal
damage
– Could lead to the cognitive symptoms of depression
• Antidepressant drugs reverse this damage and increase
neurogenesis in the hippocampus
Glucocorticoid hypothesis
• Intracerebroventricular administration of
CRF elicits stress-responses in animals
– Enhanced cortisol levels
– Sympathetic activity
• Clinical tests of CRF antagonists are in the
works
– R121919
• Preliminary findings
– Decreases anxiety and depression scores
– Minimal side effects
Neurotrophic hypothesis
• Focuses on the mechanism of hippocampal
neuron loss that occurs following stress
• Stress causes deficits in neurotrophic factors
– Such as BDNF (brain-derived neurotrophic factor).
– Needed during neural development
– Also regulate changes in adult neurons
• This theory posits that decreases in neurotrophic
factors leads to atrophy of neurons
– And that antidepressants may protect cells by
preventing this decrease
• Been shown that
– 1) chronic stress reduces
BDNF in hippocampus of
rats
– 2) chronic antidepressant
treatment increased BDNF
in both animals and
humans
• Not acute
– 3) antidepressants prevent
stress-induced reductions
in BDNF
• There is no way to directly inject BDNF into humans as a
treatment
• BDNF is dependent on cAMP second messenger system
– Appears that with chronic treatment the down regulation of βand 5-HT receptors lead to an increase in cAMP activity
• It may be possible to increase BDNF production by
enhancing the cAMP cascade directly.
– Perhaps by inhibiting phosphodiesterase
• An enzyme that normally degrades cAMP
– Perhaps by activating CREB
• A transcription factor that induces the production of cAMP
16.16 Up-regulation of second-messenger pathway by chronic antidepressant treatment