• 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.– 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

• 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 negative-

feedback 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 non-

REM 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– 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– 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

• 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– 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

• Severe agitation• Disorientation and confusion• Ataxia• Muscle spasms• Exaggerated autonomic activity

– 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

• 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 α2-adrenergic 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– 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– 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

• 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

• 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 “serotonin-norepinephrine” 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 β-

and 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