Affective Disorders

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Affective Disorders

• PS3010 Behavioural Pharmacology
• P.M. Moran

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Depression

• common cold of mental illness most widespread
  psychological disorder
• One in ten chance of at least one depressive
  episode of clinical proportions
• All population groups vulnerable

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Depression- Introduction

• One in 20 visits to doctor due to depression
• gt100 depressed patients per doctors list, but
  half unrecognised
• 20 develop chronic depression
• Patients may not mention depression
  embarrassment, stigma, avoid lack of sympathy

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Symptoms of Depression

• There are four sets of symptoms of in depression
• 1) mood/emotional symptoms
• 2) Thought/cognitive symptoms
• 3) Motivational symptoms
• 4)somatic/physical symtoms

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Classification of Depression

• Unipolar
• Mixed anxiety and depression
• Depressive episode (single)
• Recurrent depressive (numerous)
• Dysthymia peristant mild (depressive
  personality)

• Bipolar
• Bipolar affective disorder with manic episodes
• Cyclothymia persistant instability of mood

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Neurochemistry of Depression

• Animal models
• Metabolite measurements
• Changes in biogenic amine neurotransmitters in
  post mortem brains from suicide victims

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Monoamine Theory of depression

• Depression due to depletion of monoamines esp.
  NA, 5-HT, DA.
• Limitations of theory too simplistic, delayed
  action of antidepressant drugs
• Modified to include down regulation of NA
  receptors

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Noradrenaline Depression (I)

• Noradrenergic hypothesis- reserpine depression is
  due to reduced levels of NA(noradrenaline)
• Supported by effects of antidepressants which
  increase NA metabolism
• Problem time delay of therapeutic effect.

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Noradrenaline Depression II

• Problem with NA hypothesis- time delay of
  therapeutic effects of anti depressants
• Hypothesis expanded to include receptor
  sensitivity
• By increased exposure of the receptor to NA
  eventually the sensitivity of the receptor is
  decreased. B-receptors

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Serotonin Depression (I)

• serotonin involved in pain sensitivity,
  emotionality and response to negative
  consequences
• Metabolite 5-HIAA reduced in CSF but other
  studies refute this. Low 5-HIAA associated with
  aggressive hostile and impulsive behaviour as in
  violent suicide attempts

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Serotonin Depression II

• No concensus as to whether 5-HIAA is associated
  with depressive symptoms other than suicide
• Platelet uptake studies- Blood platelets have
  transport mechanism similar to that in the brain.
  Most studies find reduced uptake of serotonin
  with normalisation following treatment

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Monoamine oxidase inhibitors (MAOI)

• iproniazid developed in 1950s
• interaction with certain foods
• Initially non-selective, newer selective for MAO
  A or B
• used for atypical depression

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Tricyclic antidepressants

• Most often used first to treat
• Inhibit re-uptake of NA and 5-HT
• Effective, cheap, but dose related
  anticholinergic side-effects limit compliance
• Often fatal in overdose

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Selective serotonin Reuptake inhibitors (SSRI)

• Inhibit reuptake of serotonin
• Prozac widely prescribed/hypericum St. Johns Wort
• Lack sedation, free of anticholinergic side
  effects
• Seem safe in overdose
• narrow dose range

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Selective Serotonergic/ Noradrenergic Re-uptake
Inhibitors (SSNRIs)

• Newest class
• Act via inhibition of re-uptake of 5-Ht and NA
• Different from TCAs as little action on
  muscarinic and histaminergic receptors
• E.g. venlafaxine

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Animal Models of Depression

• Behavioural models
• Behavioural Despair
• Learned helplessness
• Chronic mild Stress
• Psychosocial stress

Pharmacological models Reserpine
sedation Neuronal models Olfactory bulbectomy
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Animal models of Mood Disorders

• Theory Driven - to understand the disease state
  (construct validity)
• Reproduce symptoms (face validity)
• Screen for new antidepressant drugs (predictive
  validity)
• Most based on animals response to stress

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Forced Swim test/Porsolt

• Most often used- high throughput
• Acute antidepressant treatments work
• False positives - increase activity
• Is it a test for anti-depressant-like activity?
  ECS activity in the model

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Learned Helplessness Theory                    
                                   Seligman
(1975) Learned Helplessness theory
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Learned Helplessness

• Learned helpless animals show biological features
  of depression- REM sleep alterations, loss of
  bodyweight, diminished sexual activity elevated
  corticosterone.
• Links cognitive function to biological function
• Controversy is it cognitive or product of stress
  induced inactivity. Recovery in Seligmans after
  48hrs.
• Extreme stress needed/ NOT legal in U.K.

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Stress and noradrenaline
reduced shortly after exposure to inescapable
shock, but recovers over the next 48 hours This
suggests that the reason Seligman's dogs did not
exhibit helplessness when tested 48 hr after
uncontrollable shock was because brain NA had
returned to normal by this time. (Weiss et al
1975)
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Chronic Mild Stress (Willner 1997)

• Involve naturalistic responses to stress
• Stressed animals are anhedonic
• Very diffficult to reproduce across laboratories

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Develop better animal models(Nestler et al, 2002)

• Human genetics studies
• Mutant mice
• Symptom focused tests
• Attention to gender
• Ethologically informed

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Behavioral, neurochemical, and electrophysiologica
l characterization of a genetic mouse model of
depressionEl Yacoubi M, Bouali S, Popa D, Naudon
L, Leroux-Nicollet I, Hamon M, Costentin J,
Adrien J, Vaugeois JMPROCEEDINGS OF THE NATIONAL
ACADEMY OF SCIENCES OF THE UNITED STATES OF
AMERICA 100 (10) 6227-6232 MAY 13 2003
selective breeding of mice with strikingly
different responses in the tail suspension
test. "helpless" mice are essentially immobile in
the tail suspension test, as well as the Porsolt
forced-swim test, and they show reduced
consumption of a palatable 2 sucrose solution.
exhibit sleep-wakefulness alterations resembling
those classically observed in depressed patients,
notably a lighter and more fragmented sleep, with
an increased rapid eye movement sleep.
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El Yacoubi et al 2003 model higher basal
corticosterone levels and lower serotonin
metabolism index in the hippocampus.
serotonin(1A) autoreceptor stimulation induces
larger hypothermia and inhibition of
serotoninergic neuronal firing in the nucleus
raphe dorsalis in helpless than in nonhelpless
mice. Thus, helpless mice exhibit a decrease in
serotoninergic tone, which evokes that associated
with endogenous depression in humans. Finally,
both the behavioral impairments and the
serotoninergic dysfunction can be improved by
chronic treatment with the antidepressant
fluoxetine. The helpless line of mice may provide
an opportunity to approach genes influencing
susceptibility to depression and to investigate
neurophysiological and neurochemical substrates
underlying antidepressant effects.
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From el-Yacoubi 2003
Differences in responses to behavioral tests
amplify between HL and NHL mouse lines when
pressure selection continues and differing
patterns of sleep-wakefulness rhythms are
revealed. Duration of NHL and HL mouse immobility
recorded for 6 min in the TST (A) and FST (B) for
the same animals (n  8-13) at S2 and S14
generations. (C) Locomotor activity of NHL and HL
mice in the open field. Horizontal (exploratory)
and vertical activities (expressed as the number
of beam crossings) were recorded for 45 min
(n  8-14) at S2 and S14 generations. (D) Amounts
of the different states of vigilance,
wakefulness, slow-wave sleep (light SWS1, or
deep SWS2), and REM sleep (REMS).
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Cortico-tropin-releasing factor

• CRF is a major neuropeptide mediator of stress
  responses in the CNS.
• It is expressed in the Paraventricular nucleus of
  the hypothalamus and co-ordinates the release of
  adrenocorticotrophin hormone (ACTH) from the
  anterior pituitary.
• CRF increased in CSF of depressed patients

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HPA axis Hypothalamic Pituitary Adrenocortical
system
1.CRF is released in response to environmental
stressor (uncertainty arousal) 2.ACTH is then
released by the pituitary 3.Which in turn
releases cortico-steroids 4.When stressor
terminated-negative feedback occurs, shut down of
the HPA axis.
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CRF Depression (I)

• Elevated corticosteroids good index of stress
• 1) elevated in times of threat
• 2) elevated chronically at times of loss of
  control
• However transient activation does not cause
  stress, seen following drugs such as amphetamine
  and novelty
• Excessive long term activation of HPA may induce
  long term damage

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Newer targets for Antidepressants

• CRF antagonists
• NPY agonists
• 5-HT2 antagonists
• Intracellular signal transduction - cAMP
  phosphodiesterase, MAP kinase cascade, PKC
  signalling cascade
• Neurogenesis- stress decreases neurogenesis in
  HC. AD treatment, 5-HT NA ECS reverse this.
  Neurotrophic factors BDNF

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CRF Depression (II)

• Depression is associated with increased activity
  of the HPA axis (Holsboer , 1996)
• Enlargement of the adrenal gland is often seen
  and patients have elevated levels of cortisol.
• Antidepressants lower activity in the HPA axis
• Early experience can bias towards later
  protracted activity of the HPA (maternal
  separation)
• Corticosteroids are given for arthritis and cause
  depression

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CRF Depression (III)

• Re-uptake inhibitors boost the HPA system.
  Improvement in mental state associated with
  normalization of HPA activity
• Cushings Disease which involves excessive
  secretion of corticosteroids is commonly followed
  by depression.

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Monoamine Transporters

• Major mechanism controlling extracellular
  monoamine dynamics is re-uptake .
• This is achieved through presynaptic neurons via
  plasma membrane transporters.
• Dopamine (DAT)
• Serotonin (SERT)
• Noradrenaline (NET)
• These remove neurotransmitters from outside cells
  and recycle back into the releasing or
  neighbouring terminals

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Monoamine Transporters

• These transporters are targets of many
  psychostimulants and antidepressants, which
  interfere with transporter function.
• Normal function of these transporters under
  investigation using gene deletion techniques.
• Mice lacking both SERT and DAT no place
  preference for cocaine suggesting SERT
  involvement in cocaine effects on reward.(Sora et
  al 2001)

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Uptake of serotonin by adult rat corpus callosum
is partially reduced by common antidepressantsRey
es-Haro D, Garcia-Alcocer G, Miledi R,
Garcia-Colunga JJOURNAL OF NEUROSCIENCE RESEARCH
AbstractThe corpus callosum (CC) is the main
white matter tract involved in interhemispheric
brain communication. We establish that uptake of
H-35-hydroxytryptamine (5-HT) in CC is
partially inhibited by some antidepressants. The
5-HT uptake was reduced similar to60 at pH 5
compared with that at pH 7. Fluoxetine (Prozac)
inhibited only 43 of 5-HT uptake in a
concentration-dependent manner, zimelidine,
imipramine, and clomipramine inhibited 5-HT
uptake in the CC by similar to30-40. The
fluoxetine-insensitive 5-HT uptake was not
altered by high concentrations of dopamine plus
norepinephrine. The present data show that
Na-dependent 5-HT uptake occurs in the CC and
optic nerve and that this uptake is partially
sensitive to antidepressants and probably
mediated by the serotonin transporter, which may
be relevant during depression.
74 (1) 97-102 OCT 1 2003
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References

• Holsboer (2000) The corticosteroid receptor
  hypothesis of depression. Neuropsychopharmacology,
  23, 5, 477-497.
• Nestler et al. (2002) Preclinical models status
  of basic research in depression.Biological
  Psychiatry, 52 503-528.
• Gainetdinov Caron (2003) monoamine
  transporters from genes to behaviour , Ann
  Review Pharmacol. Toxicology.

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Summary

• Antidepressant treatment is taking new directions
  particularly becoming focused on monoamine
  transporters and corticosteroids.
• Animal models of depression are benefitting from
  combination of genetic technology and older
  behavioural techniques.