Emotional Brain- Depression and Antidepressants Flashcards
What is primary depression?
Depressive symptoms in isolation (depression on its own)
What is secondary depression?
Depression caused by another psychological or physiological condition. Ex: thyroid problems, demntia, etc.
1st demension of depression: two types?
SEVERITY
Mild: dysthymia
Severe: major depression
2nd dimension of depression?
CYCLICITY
unipolar: depressive episodes only
Bipolar: depressive and MANIC episodes (Sometimes rapid cycling)
Other terminology for: mild unipolar mild bipolar severe unipolar severe bipolar
mild unipolar=dysthymia
mild bipolar=cyclothymia
severe unipolar=unipolar major depression
severe bipolar=bipolar disorder
How does the depressive scale go?
Depression-Melancholia-Normal-Hypomania-Mania
What was depression historically referred to as?
melancholia. Later= depressive personality disorder
What are the symptoms of major depression?
Anhedonia (cannot feel pleasure in enjoyable things) Psychomotor retardation (or agitation during manic phases, if applicable) > motor is suppressed, movement is difficult, hard time getting up -> dopamenergic system
Sleep problems (hyposomnia- sleeping less than normal) or hypersomnia Eating problems (hypophagia=eating less than normal) or hyperphagia Elevated glucocorticoids (cortisol) in 50% of major depression cases
What symptoms are prevalent in milder depression?
Hypersomnia more prevalent (as in SAD)
Hyperphagia (as in SAD-carb cravings)
-other symptoms not usually part of milder depression
Complete chart: For melancholic (mild depression) and Atypical depression: Pattern? Diurnal variation? Sleep? Eating habits? Motivation? Other characteristics? Prevalence?
Melancholic:
Phasic, Worse in the AM, Morning insomnia(early awakening), hypophagia/anorexia, ahedonia/loss of interest, psychomotor agitation and mental pain, 40-60%
Atypical: Chronic, worse in PM, hypersomnia, hyperphagia/weight gain, anxiety prominent (good response to some SSRIs and MAOIs, cheer up when good things happen, 15%
Neurotransmission + depression:
What happens with reuptake?
neurotransmitter is recycled + repackaged for future use by axon terminals
Degradation?
neurotransmitter is degraded and flushed- in cerebrospinal fluid then blood, then urine
What happens if the clearing of the neurotransmitter fails? (no reuptake or degradation?)
More NT remains in the synapse and a stronger signal is processed by the receiving neuron
What is monoamine theory?
An NE hypothesis of depression
NE- main NT involved
ex: in bipolar disorder, an actual depressive episode is depletion of NE and a manic episode is an excess of NE
serotonin (5-HT): to a lesser an extent (by the way, 5-HT is an indoleamine, as opposed to a catecholamine)
dopamine (DA): to a much lesser extent
Antidepressants supporting this theory: TCA’s, MAOI’s, heterocyclics
When does the monoamine theory apply best?
In the context of a cyclical disorder (cyclothymia or bipolar).
What is the serotonin theory?
Serotonin is the exclusive suspected neurotransmitter.
What are the antidepressants used in serotonin theory? Are they efficient? example of one.
SSRI’s
-Some very efficient: IF depression and anxiety combined (ex: Paroxetine)
What are the problems associated with SSRI’s (3 S’s)
- suicide
- SSRI withdrawal
- serotonin syndrome
What happens if NE or 5-HT levels are decreased in normal people? Study?
They are likely to become depressed.
In some treatments of hypertension, an artificial decrease of NE leads to low blood pressure but CAUSES depression.
What is norepinephrine involved in, via its affect on the ANS?
The four 4’s,Fighting, fucking, fleeing, feeding.
What is the pleasure pathway hypothesis?
- from self-stimulation studies on rats
pathway: -rich in NE and DA receptors - lack of NE or DA could cause anhedonia (inability to feel pleasure)
What is the motor pathway hypothesis?
- from motor pathway stim in rats/levels of activity
- inability to do things (helpless/passive) : psychomotor retardation
- motor functions rely on NE and DA in motor pathways
What are problems with the NE and 5-HT hypotheses?
Timing: Antidepressants can change NE and 5-HT signalling within hours but takes weeks for subjects to feel better.
What is the dysregulation hypothesis of depression?
-Too much or too little NE or 5-HT is the problem.
Antidepressants: What are the factors of too much NE or 5-HT?
“Down-regulation” at the receiving neuron
- How much is the emitting neuron producing?
- How sensitive is the receiving neuron? (how many receptors?)
Normally, If depression is caused by a surplus of NE and 5-HT, and If TCA’s or MAOI’s are prescribed…
The consequence will be a dramatic increase in NE and 5-HT. If it is true that there is too much NE or 5-HT to start with:
Initially, the depressive symptoms following intake of TCA’s or MAOI’s should be worse (there is evidence for this with both TCA’s and MAOI’s).
After a while, down-regulation should occur… the person will eventually (and likely) feel better.
Antidepressants: The problem is too little NE or 5-HT?
Options?
The axon terminals of the sending neuron release:
autoreceptors: they will respond to
neurotransmitter molecules that “come back”. These returning neurotransmitter molecules act like a feedback signal.
This feedback is necessary for “decision making” at the pre-synaptic level.
Options:
Release more neurotransmitter? or Synthesize more neurotransmitter?
What if the autoreceptors of the sending neuron can make wrong evaluations (likely underestimating the amount of released neurotransmitters)?
What happens when antidepressants given?
The autoreceptors make wrong decisions»_space;> Strong down- regulation of the autoreceptors.
This down-regulation sends the message: “you’re releasing too little NE and/or 5-HT”.
Consequence: increase in the synthesizing and releasing of NE and 5-HT.
In depressive individuals we already have too little NE and/or 5- HT.
Antidepressants are given»_space;> increase in the signalling of NE and 5-HT.
Consequence: increase in signalling will cause down-regulation of NE / 5-HT receptors (receiving neuron).
KEY ISSUE of too little NE or 5-HT in antidepressants?
KEY ISSUE: the autoreceptors on the releasing neuron (sending, emitting) will down-regulate more than the receptors on the receiving neuron.
This will cause an even greater increase of NE / 5-HT signalling.
The individual feels better because the releasing neuron will release sufficient amounts of NE / 5-HT to overcome the lack of sensitivity of the receiving neuron.
MAO inhibition or NE reuptake blockade can act on which receptors and autoreceptors?
alpha2-autoreceptor beta-receptor alpha2-somatodendritic autoreceptor alpha1-receptor alpha2-receptor
What is the effect of antidepressants, ECT and sleep deprivation? Result?
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Reduction in autoreceptor responsiveness.
This causes a gradual increase in NE cell firing and turnover.
PET scan studies and depressive individuals results?
Less active: caudate nucleus (basal ganglia) suggesting a dopamine involvement. (ability to make decisions- very indecisive)
• More active: amygdala.
This may support the “psychomotor retardation/agitation” theory.
• More active: frontal cortex; hemispheric bias?
This may support the overactive HPA/ANS/ limbic system theory
How can thyroid hormones affect depression?
can ameliorate depressive symptoms, including the ones occurring during PMS
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TRH (thyrotropin releasing hormone; from the hypothalamus): low in depressed patients
TSH (thyroid stimulating hormone or thyrotropin; from the anterior pituitary): low in depressed patients
How can pituitary hormones affect depression?
unclear, but apparent impaired responses of the following:
GH
Prolactin
How can gonadal hormones affect depression?
Estrogens: low levels»_space;> depression (involved in, PMS, PPD, PMD/ menopause?) or at least fluctuations with progestogens
Progestogens: see above (evidence from PMS, PPD, PMD) Androgens: low levels»_space;> depression (mainly testosterone; andropause?).
How can pineal hormone affect depression?
Pineal hormone: Low melatonin* production (made from serotonin)
How can adrenal hormones affect depression?
Adrenal hormones: high levels in (50%) depressed humans.
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DHEA: weak androgen in sharp decrease during aging. Corticosterone: high levels in rodent models of depression. Cortisol: see below.
• ! Glucocorticoids (or corticosteroids)
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Depression = overactive HPA axis? Limbic system? Autonomic nervous system?
High glucocorticoid production (adrenal glands [cortex]) because of high ACTH production (from the pituitary gland). Hypothalamic cells are over-excited by the limbic system.
Hypothalamus»_space;> CRH»_space;> Pituitary gland»_space;> ACTH»_space;> adrenal cortex»_space;> cortisol
What are cortisol levels linked to?
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Cortisol connection
linked to dysfunction in circadian rhythms? disinhibition of the HPA axis?
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investigation of the CRH-ACTH-cortisol patterns direction of causality:
depression»_space;> high cortisol levels ?
high cortisol levels»_space;> depression ? levels of cortisol:
very low levels»_space;> depression e.g., Addison’s disease very high levels»_space;> depression e.g., Cushing’s disease
Stress response can lead to?…
- Mobilization of energy at cost of energy storage:
- Increased cardiovascular tone
- Suppressed digestion
- Suppressed growth
- Suppressed reproduction
- Suppressed immunity/inflammatory response
- Analgesia
- Neural responses
- Fatigue, muscle wasting, steroid diabetes
- Hypertension
- Ulcers
- Bone decalcification, dwarfism
- Suppressed ovulation, impotency, lost libido
- Impaired disease resistance
- Apathy
- Accelerated neural degeneration during aging
What are the protective effects of anti-depressants?
Stress»_space;> high gluc.»_space;> low BDNF (brain-
derived neurotrophic factors)»_space;> atrophy or death of neurons (apoptosis; high in the hippocampus).
Antidepressants»_space;> increase 5-HT and NE»_space;> increase BDNF»_space;> decrease gluc.»_space;> increases survival and growth of neurons.
Animal models of depression-problems?
There are no animal models of depression that mimic all the symptoms of depression.
All current models are models of reactive depression. They typically focus on one or a few of the following
aspects of depression:
Reduction in psychomotor activity Anhedonia
Neuroendocrine responses
Cognitive changes
Eating dysfunctions
Sleeping dysfunctions
-animals tend to live in moment, planning and existentialism not very present (due to smaller frontal lobes)
What is reactive depression?
Triggered by stress (broadly defined: social or physical): Tends to involve by default the HPA axis.
(depression naturally not involving HPA axis)
Explain depressed individuals with enlarged pituitary and adrenal glands.
Many depressed individuals have higher levels of cortisol, produce more cortisol than non- depressed for the same increase in ACTH.
when stressed, adrenal glands are getting enlarged
extreme stress can cause adrenal tumours
-adrenal tumours can also cause stress because of elevated levels
-stress= problem for people with diabetes, dysregulates system and insulin control
Cortisol and depression?
Negative feedback loop:
when depression occurs= system unable to slow down, and stop producing cortisol, getting out of hand
What NT’s/hormones does stress affect?
NE, Acetylcholine, GABA
-they regulate CortisolRH from hypothalamic cells
What kind of levels of CRF do depressed individuals have compared with non depressed?
Higher CRF in their CSF and more CRF producing cells in the hypothalamus.
What reduces CRF levels?
Antidepressants and ECT
What is Dexamethasone?
Synthetic glucocorticoid
What is the challenge in Dexamethasone?
Who is more likely to relapse in depression?
It should induce a strong downregulation of CRF and ACTH (negative feedback loop)
-this does not occur in depressed individuals)
Non-responders to DEX treated successfully with anti-depressants are more likely to relapse than those that respond to DEX.
