Module IV - Lecture 5 - Mood and Anxiety Disorders Flashcards
What is major depression?
-characterized by a depressed mood or loss of interest or pleasure in nearly every day it is self reported or observed
-there is diminished pleasure or interest in all activities nearly every day
AT LEAST FOUR OF THE FOLLOWING SYMPTOMS ARE PRESENT EVERY DAY FOR TWO WEEKS:
1.weight loss or weight gain
2.insomnia or hypersomnia
3.psychomotor agitation or retardation nearly every day
4. fatigue or loss of energy nearly every day
5. feeings of worthlessness are excessive guilt
6. cannot think or concentrate or decide
7.thoughts about death
What are the symptoms of mood disorders?
FOR A MANIC EPISODE:
-distinct period of elevated, expansive or irritable mood that lasts for at least 1 week or any duration if hospitilization is necessary
-during the period of mood disturbance three or more of the following symptoms have persisted four if the mood is only irritable -
1.inflated self esteem
2.less sleep
3. more talkative
4.flight of ideas or subjective experiences that thoughts are racing
5. distractibility
6. increase in goal directed activity
7. excessive involvement in pleasurable activities that have a high potential for painfukl consequences
What is the prevalence of unipolar depression?
-leading cause of disability worldwide
-lifetime risk is 16.2% in the US
-similar symptoms around the world
-6.6% of world pop has depression
-occurs in equally in males and females in childhood and after puberty more common in women 1:7
What is the prevalence of bipolar disorder?
-less common than uinpolar depression 1% of the population in most countries
-similar symptoms around the world
-risk of bipolar disorder is equivalent in males and females
What is the concordance rate of mood disorders?
in monozygotic twins they are less than 100% in both bipolar depression and unipolar depression and this means that genes go along with environmental factors in the disease
-caused by a change to many genes that a single gene is the cause for mood disorders
What are the brain centers of emotional dysfunction in patients with depression?
there are multiple centers of individuals with this
-can have issues with the PFC, lateral and medial orbital, amygdala and hippocampus, dorsolateral PFC, anterior cingulate cortex
What area of the brain has been consistently linked to both major depressive and bipolar disorders?
gyrus of the anterior cingulate cortex - has been implicated in major depressive and bipolar disorder - plays a role in cognitive processing like learning and conflict ad error monitoring
What has fMRI data shown about the role of the anterior cingulate cortex in depression?
there is an increase in activity there and this activity level seems to be relatively predictive in whether or not patient will respond to antidepressant medication
-do not know if this change in activity is causal or an adaptive response to depression
Hyperfunction in what region of the brain is also associated with mood disorders?
amygdala - it processes negative emotions like fear and the basal level of activity is elevated in these people and there is an enlargement of the amygdala too
-fear
-basal level of activity increase
-enlargement
What is the HPA axis and what does it control?
hypothalamic-pituitary- adrenal axis
-controls cortisol secretion and this is transiently increased during acute stress
and this triggers the fight or flight response and this suppresses the immune system and shifts body to catabolic state and increases energy levels and sharpens cognition
-catabolic
-high energy
-better cognition
-supress immune system
What to elevations in the amygdala in response to stress cause?
the release of CRF from the hypothalamus from the paraventricular nucleus and this CRF trigger ACTH form the pituitary gland and this triggers cortisol release from the adrenal cortex
amygdala—-Hypothalamus (paraventricular nucleus secretes CRH)—–pituitary(ACTH)—–adrenal cortex (cortisol)
How are depression and stress interrelated?
chronically high cortisol may contribute to symptoms of depression
What is cushing disease and what do these people experience?
have pituitary tumor which cause ACTH release leading to excess cortisol experience severe depression
-fatigue, headache, increased thrist and urination
What is the negative feedback mechanism of the HPA axis to prevent glucocorticoid release?
it is broken in many cases of depression as cortisol levels rise in the blood this is detected by the pituitary and the PVN and this causes the PVN to release less CRF and pituitary to release less ACTH and this leads to less cortisol
In what percent of people with depression is the negative feedback mechanism impaired?
50% - this HPA axis is even resistant suppression even by potent synthetic glucocorticoids
What did antidepressant drugs initially act on?
monoaminergic NT systems in the nervous system
What are the monoaminergic systems of the nervous system?
serotonergic system, noradrenergic system, dopaminergic system
Where do monoamine NT nuclei project to in the brain and what do their projections allow for?
send axons to all over the brain found in almost all brain structures
permits them to produce a coordinated response and thus influence functions such a arousal, attention, vigilance, motivation and other cogntive and emotional states that involve multiple brain regions
Where do the major serotonergic systems in the brain arise from?
the raphe nuclei in the brainstem which are both rostral and caudal
There are many serotonergic receptors in the brain what type of receptor are they all and why?
-metabotropic - they allow the system to influence the brain in a diverse way and the effect it has on postsynaptic neurons can be extremely different depending on what region of the brain you are talking abut and what receptors are expressed by those postsynaptic receptors
-Galpha i coupled - inhibit cAMP production -5HT1s
-Galpha q - 5HT2s
-ligand gated - 5HT3
-Galpha s -4HT4,5,6,7
-ligan gated
Where does the major noradrenergic projection in the forebrain arise?
in the locus ceruleus
What type of receptor is the noradrenergic alpha1s?
Gq
What type of receptor is the noradrenergic alpha2s?
Gi
What type of receptor is the noradrenergic beta 1,2,3?
Gs
What compound which was used to treat hypertension produced depression in 15% taking it and why?
reserpine because it depletes the brain of norpeinephrine and serotonin and dopamine by preventing reuptake of these NT by presynaptic vesicles by inhibitng the pump that pumps them into presynaptic vesicles
What are MAO inhibiters?
prevent monoaminoxidase from breaking down norepinephrine, serotonin, or dopamine in presynaptic terminals making extra NT available for packaging and release
What are tricyclic antidepressants?
inhibits norpepinephrine or serotonin transporters or both
What drug is the prototype for the MAO inhibitor that is no longer in use and was discovered for tuberculosis?
iproniazid
What is an example of a tricyclic antidepressant?
floxetine or prozac
What can depression arise from the deficiency of?
monoaminergic synaptic transmission and therapeutics increase monoamines at synapses
When you start an MAO or tricyclic antidepressant when do the effects take place but when do you start to see a clinical change and why do you observe this discrepancy?
the effects are rapid but do not see a clinical change for a few weeks and this can be due to the fact that this can actuavte downstream signaling and change gene expression and protein synthesis which can alter neuron responsiveness and synaptic connections
How can antidepressants regulate gene expression?
covalent modification of histone proteins and change the availability of the DNA to be transcribed
Where can antidpressant change or increase the rate of neurogenesis in the brain?
in the dentate gyrus of the hippocampus
How does ketamine treat major depression?
NMDA receptor antagonist and has this ability to inhibit NMDA on GABAergic neurons and suppress inhibition causing more firing wiring and strengthening of glutamatergic synapses
How is bipolar depression treated and why?
lithium because lithium blocks the ability of cells to make PIP2 and lithium prevents IP3 from being recycled into PIP2 and IP3 becomes IP2 and buildup of IP2 because lithoum inhibits IP2 from being broke up into IP1 and inositol
What metabotropic signaling might be pathologically unregulated in people with bipolar disorder?
G alpha q
What is WNT signaling involved in?
cell proliferation and neuronal differentiation
What does lithium inhibit?
GSK-3B degradation of beta catenin which mimicks the frizzled signaling meaning that lithium ultimately promotes beta catenin mediated increase in gene expression
What does lithium inhibition if GSK-3B mimick?
when wnt binds to frizzled ad causes disheveled to inhibit GSK-3B too so get increase in gene expression
What is a panic disorder?
panic attacks with discrete period of intense fear and somatic symptoms like palpitations, short breath, sweating, dizzy, losing control or dying fears, parethesias
-people avoid crowds, bridge, or outside
What is PTSD?
emotional numbness to ordinary stimulus and painful reliving of traumatic episodes
What is generalized anxiety disorder?
chronic worrying or vigilance
What are simple phobias?
excessive fear of specific stimuli
What is social anxiety disorder?
social situations cause anxiety
What is OCD?
intrusive unwanted thoughts and compulsions and germophobic
Do anxiety disorders have a a genetic component?
yes but more so environment
Hyperfunction in what area of the brain is associated with anxiety disorders?
amygdala
How can the effects of anxiety reducing drugs be tested on rodents in the elevated plus maze?
if you have two enclosed arms and two opens arms the rodents spend more time in the enclosed but if you give them diazepam anxiety drug which is a GABA receptor agonost they they do not prefer closed arm
What is diazepam?
GABA agonist - reduces anxiety
How are anxiety disorders treated?
antidepressants such as SSRIs (tricyclines) are used
-benzodiazepines bind to GABA and make them work better and are used prior to when antidepressants go into effect
What has been used recently for anxiety disorders such as PTSD and why?
Psilocybin and MDMA
-psilocybin targets the serotonergic system by being an agonist for the receptor
-MDMA inhibits the VMAT2 transporter in the serotonergic system and prevents serotonin from being packaged into vesicles and activates this TAR1 protein which causes 5HT transporters to reverse their flow they dribble serotonin all the time and are constantly active
