L10 Anxiolytics and Anti-depressants

hypothalamic pituitary axis (HPA) function in controlling cortisone

stress

monoamine neurotranmission

control of 5-HT (serotonin)

what is eustress

acute stress

what is physiological stress

the body’s response to an external pressure

define anxiety

psychological response to a perceived threat

• closely linked to fear (psychological response to real threat)

what is the fight or flight response

normal stress response to acute pressure

what is distress

chronic stress

• unrelenting pressure for long periods

• usually psychological but can be physical e.g. arthritis

• stress pivots from physiological to pathological and induces severe consequences such as sleep, anxiety and depression

in chronic stress (distress), anxiety does not subside/out of proportion to threat, in contrast to…

anxiety in acute stress

• normal anxiety response becomes pathological (chronic stress)

what are the biological mechanisms of stress

neuronal, autonomic and endocrine circuits mediating a stress response

• CNS → Autonomic NS(e.g. sympathetic NA) → HPA axis (e.g. cortisol)

give examples of stress (physiology)

• trauma

• illness

• hypoglycaemia

• exercise

• haemorrhage

• psychological

describe the physiology of the hypothalamopituitary adrenal (HPA) axis response to release cortisol

• hypothalamus releases CRH and AVP which go to the anterior pituitary

• anterior pituitary releases ACTH to the adrenals

• adrenals (glands) release cortisol

• cortisol acts on the stress response

what does the hypothalamopituitary adrenal (HPA) axis consolidate information from/ what are the cortisol levels regulated by

• stress

• circadian rhythm

core symptoms of depressive episodes

• depressed mood

• fatigue

• anhedonia

heterogenous in terms of presentation

what is anhedonia

losing interest in things one would normally find engaging

identical twins where one has depression, there is a … biological chance the other one will also have depression

50-70%

• much higher than non identical twins (Not effected by nurture)

early life adversity feeds forward into… (as well as genetic predisposition)

biological vulnerability

• e.g. psychological stress or physical illness in adulthood with biological alterations (pathophysiology) to manifest as a change emotion or behaviour.

• e.g. the HPA becoming dysfunctional (as a biological alteration within the brain) of depression

give an example of a biological alteration within the brain as a potential cause of depression

Hypothalamopituitary Axis (HPA) becomes dysfunctional

patients with Cushing’s disease (excess production of cortisol) have high incidence of…

mood disorders

patients treated with glucocorticoids (e.g. rheumatoid arthritis) have a…

high incidence of mood disorders

cortisol levels in depressed patients are often…

raised

anxiety is prevalent at… with 2:1 female to male ratio and is often comorbid with other mental health disorders (depression, substance misuse)

21%

describe generalised anxiety disorder

• excessive and persistent anxiety/ worry for more than 6 months

• fear of future events (personal safety)

• often present with somatic complaints e.g. headache, stomach ache

describe obsessive compulsive disorder (OCD)

obsessive repetitive thoughts which are often negative

• counteracted by compulsive behaviours (rituals) providing temporary relief

describe panic disorder with or without agoraphobia

• sudden unexpected panic attacks

• intense, recurrent fear might die/be ill

• palpitations, tremor dizzy chest pains

• last minutes

• fear of a certain place can result in phobic avoidance = agoraphobia

describe phobia disorders

• excessive fear disproportionate to the specific situation - generally predictable (phobic avoidance)

• social phobia - excessive fear of social situations, fear of being negatively scrutinised, humiliated

describe PTSD

• onset delayed weeks to months following an intense traumatic experience

• reexperience of trauma; fear will die (flashbacks)

• can be triggered by sensory cues so develop avoidance symptoms

• hyperarousal with hypervigilance

anxiety disorders can be characterised by…

having fear or avoidance behaviours

• avoidance behaviours allow fears to continue unchallenged

• i.e. prevents a person from observing external info that might disconfirm fears

combat related PTSD have elevated levels of…

CRF (hormone) in cerebral spinal fluid

functional magnetic resonance images show increased activation of the… in PTSD subjects exposed to fearful images

left amygdala

• overactivation/increased sensitivity

how does stimulation of the amygdala stimulate release of NA

amygdala releases CRF hormone which signals to the hypothalamus to release more CRF into the SNS to secrete NA

• hypothalamus also feeds into the HPA to release cortisol

what is the amygdala

the centre for processing fear responses in the brain

describe phobic disorders as a symptom of noradrenergic dysfunction

exposure to phobic stimuli

• increases heart rate and blood pressure

describe panic disorder as a symptom of noradrenergic dysfunction

panic attacks

• increase heart rate, blood pressure, tremor, dizziness and chest pains

describe PTSD as a symptom of noradrenergic dysfunction

exposure to traumatic reminders

• increased heart rate, blood pressure and hypervigilance

what do symptoms of noradrenergic dysfunction increase

increase sympathetic NS activation

chronic cortisol reduces dendritic…

complexity and number of spines

• loses branching

• reduces spine density

• direct effect on neuroplasticity and neurotransmission

raised cortisol (long term) loss of dendritic complexity within the cortex is linked to…

long term grey matter volume

how does chronic high cortisol affect Tryptophan hydroxylase2 mRNA and TPH2 activity

decreases

how does chronic high cortisol affect somatodendritic 5-HT_1A function

decreases

how does chronic high cortisol affect postsynaptic 5-HT_1A receptor number

decreases

long term cortisol causes a …

net decrease in 5-HT_1A receptor-mediated transmission

Give examples of monoamine neurotransmitters

• 5-HT

• NA

• DA

• HA

give some numerous functions of monoamine neurotransmitters

• mood

• anxiety

• sleep

• cognition

• reward

what is reserpine used for

hypertension

• also lowers mood

what is iproniazid used for

TB

• also improves mood in depressed patients

what is imipramine used for

antipsychotic effect -analogue of chlorpromazine

• improved mood in depressed patients

other drugs effective against depression are found to have affinity for…

Monoamine transporters

define the monoamine theory of depression

due to the relative deficit in monoamine neurotransmission in the brain

define the 5-HT theory of depression

due to a decrease in the function of 5-HT in the brain

describe 5-HT neuropharmacology

• cell bodies in DRN and MRN

• long, branching axons

• terminals innervate neurones in the forebrain

what are the 5-HT pathways in the brain

• dorsal rafal nucleus -prefrontal cortex (regulates emotion/mood)

• hypothalamus (HPA axis)

5-HT binds to the 5-HT receptor on the…

post synaptic density

5-HT can act on autoreceptors to give…

negative feedback mechanisms controlling 5-HT release

what is 5-HT coupled to

GPCRs

• open K+ channels to decrease cAMP

• inhibitory of adenylate cyclase (from creating cAMP)

• hyperpolarising K+

what is the 5-HT1A receptor hypothermic response attenuated in

depressed patients

what does tryptophan depletion (dietary restriction) cause in depressed patients

relapse

• removing the key amino acid used to synthesise 5-HT

what is PET binding for SERT and 5-HT1A receptors attenuated in

depressed patients

drugs acting on the 5-HT system are…

effective antidepressants (SSRIs)

cortisol or CRH (endocrine responses) can be modified by…

drugs that target 5-HT

what is the most compelling evidence for mood disorders

targeting 5-HT and NA are effective antidepressants

• e.g. tricyclic antidepressants, SSRIs, psilocybin on 5-HT2A

give examples of tricyclic antidepressants

• amitriptyline

• imipramine

• lofepramine

how do tricyclic antidepressants work

inhibit 5-HT and NA reuptake

what are the side effects of tricyclic antidepressants

• block AChM1 receptors

• block H1 receptors

• block alpha 1 receptors

what are effects of tricyclic antidepressants blocking AChM1 receptors

dry mouth, blurred vision, constipation, urinary retention

what are the effects of tricyclic antidepressants on blocking H1 receptors

sedation, weight gain

what are the effects of tricyclic antidepressants on blocking alpha 1 receptors

postural hypotension

SSRI

selective serotonin reuptake inhibitor

what are SSRIs

selective for 5-HT transporter and do not have affinity for post-synaptic receptors (fewer side effects)

give examples of 2nd generation antidepressants (SSRIs)

• sertraline

• paroxetene

• fluoxetene

what are the 1st generation antidepressants

tricyclic antidepressants

what are the 2nd generation antidepressants

SSRIs

SSRIs and SNRIs have great efficacy of…

2nd generation antidepressants

SSRIs and TCAs exhibit …

equivalent antidepressant efficacy

• but TCAs have more side effects/much lower specificity

~70% of patients taking a TCA will…

experience side effects

side effects of SSRIs

disrupting 5-HT (particularly in the GI as 5-HT is expressed lots in the enteric nervous system)

• Gi disturbance

• can induce anxiety-like symptoms early on

what are other uses of SSRIs

• anxiety/panic disorder

• OCD

• eating disorders

describe serotonergic dysfunction in anxiety disorders

decreased inhibitory 5-HT1A receptor binding

chronic stress/glucocorticoid administration in animals drives…

downregulation of 5-HT1A receptor

how can the downregulation of 5-HT1A receptor be reversed in animal models

adrenalectomy

• removal of adrenal glands increases 5-HT1A receptor expression

traditional hypnotics and anxiolytics

GABA receptors

• alcohol- non specific CNS depressant, high solubility

• barbiturates- effective but small therapeutic window (should not be used for anxiety)

• benzodiazepines

discuss the use of SSRIs to treat anxiety

• first line treatment

• risk of initial symptoms of increased anxiety, agitation

• effective after weeks

• onset of anxiolytic effect may be more rapid than the antidepressant effect

what are used to treat anxiety if SSRIs are ineffective

TCAs and MAOIs

what anxiety disorders are SSRIs used in

• most

• well tolerated

• usually used if anxiety co-exists with depression

what anxiety disorders are SNRIs used in

general anxiety disorder (GAD)

what anxiety disorders are TCAs used in

panic disorder and GAD

what anxiety disorders are MAOIs used in

panic, agoraphobia, social phobia

what anxiety disorders are 5-HT1A agonists used in

only GAD

give an example of SSRIs

• escitalopram

• fluoxetine

give an example of SNRIs

venlafaxine

give an example of TCAs

imipramine

give an example of MAOIs

phenelzine

give an example of 5-HT1A agonists

buspirone

why do patients taking SSRIs have an initial enhanced anxiety response

initial, faster, side effects occur before the brain adapts to the new drug

buspirone causes 5-HT1A receptor expression to decrease in

human anxiety disorders

buspirone agonises 5-HT1A receptor expression in animals which…

decreases anxiety

anxiolytics acute use increases 5-HT transmission except for…

buspirone

buspirone is effective in

animal models

stress increases CRF mRNA but…

chronic SSRIs decrease this increase

taking a long term antidepressant that boosts serotonin neurotransmission, causes…

chronic SSRIs to decrease this increase

• affects the HPA axis → less cortisol

stress causes ..

increase in CRF(CRH) mRNA (activation of HPA)