Mind Flashcards
What are the core symptoms of depression?
- depressed mood
- loss of interest of pleasure
- reduced energy
What is the differences between genders in regards to depression?
twice as many females to males get depression
lifetime prevalence of major depression: 10-25% for women, 5-12% for men
What are factor to consider when diagnosing depression?
- suicide (thoughts, ideations, attempts)
- comorbidity (other psychiatric conditions, neurological diseases)
- general medical conditions in which you often find depression (terminal illness, stroke, drug abuse, parkinson, chronic pain, thyroid dysfunction)
- anxiety disorder
What are some possible causes of depression?
- genetic predisposition
- environmental factors; loss of relative/friend, environmental stressors, social isolation
- neurobiological factors; NA and 5-HT deficiency,
What are pharmacological treatment options for depression?
- TCAs
- MAOIs
- SSRIs
- SNRIs
What are non-pharmacological treatment options for depression?
- CBT
- interpersonal therapy
How do MAOI’s work?
- catalyses breakdown of MA into dopamine and 5-HT and NA
- MAO located in nerve terminal
- vesicular MA mostly protected from MAO
- MAO also present in liver and intestine
- MAOIs cause essentially irreversible inhibition
What are the side effects of MAOIs?
- CNS stimulation; insomnia, postural hypotension, hypertensive crisis
- cheese effect; tyramine can get into circulation - hypertensive crisis, sympathomimetic so displaces NA from vesicles
- oedema in elderly
How do TCAs work?
- inhibit monoamine reuptake
- with secondary amine group show greater selectivity for inhibiting NA
- wth tertiary amine group show greater selectivity for inhibition 5-HT
What are the possible side effects of TCAs?
- anticholinergic effects
- tachycardia and cardiac arrhythmias
- tremor
- weight gain
- lower seizure threshold
- TOXIC IN OVERDOSE
How do SSRIs work?
more selective than TCAs
selective serotonin reuptake inhibitors
What are possible side effects of SSRIs?
- headache
- agitation
- nervousness
- sexual dysfunction
- GI problems
- nausea/vomiting/reduced appetite
- SAFER IN OVERDOSE
What are biological symptoms of depression?
- early morning waking
- loss of appetite
- diurnal variation in mood
- psychomotor retardation/agitation
- loss of libido
- reduced concentration and attention
What are cognitive symptoms of depression?
- reduced confidence and self worth
- worthlessness and guilt
- helplessness
- hopelessness
- self harm/suicide
What are the boundaries between mild/moderate/severe depression?
MILD: 2 core + 2 others
- none to an ‘intense degree’
- distressed and ‘some difficulty’ continuing with ordinary work and social activity
MODERATE: 2 core + 3/4 others
- considerable difficulty in continuing with social, work or domestic activity
SEVERE: 3 core + 4 others with some of ‘severe intensity’
- unlikely that they will be able to continue social, work or domestic activities
- includes psychotic depression
What is the epidemiology of depression?
- very common
- M:F 1:2
- 3rd most common GP consultation
- leading cause of disability worldwide
What are risk factors for depression?
INTERNALISING FACTORS:
- genetics
- neuroticism
- low self esteem
- early onset anxiety disorder
- past history of major depression
EXTERNALISING FACTORS:
- genetics
- substance misuse
- conduct disorder
ADVERSITY
- trauma during childhood or adulthood
- stressful lie events in past year
- parental loss
- low parental warmth
- history of divorce
- material problems
- low social support
- low education
What NTs are involved in depression?
- 5-HT, Na and DA implicated
- hypothalamus link between nervous system and endocrine system
- GABA and glutamate increasingly implicated in pathophysiology of depression: ketamine has been studied with some positive effects
- antidepressants use and possibly ECT increase BDNF, stress decreases in rats
What is cortisol’s application in depression?
- half of patients with Cushing’s suffer from depression which remits after cortisol hyper secretion is corrected
- 50% of depressed patients show non-suppression on DST
- BDNF expression decreased by cortisol
- postulated that CRH acts as NT in limbic system - response to stress
- CRH increased in CSF of depressed patients
What does thyroid function have to do with depression?
- free T3 may be depolarised
- 1/4 of depressed patients have a blunted TSH response to TRH (not specific to depression)
- thyroxine treatment for resistant depressing in the Maudsley Guidelines
What is the physiological/social aetiology of depression?
PERSONALITY:
- perfectionism
- needing to be in control
- tendency to blame themselves
EARLY ENVIRONMENT:
- parental separation and discord
- parental style: lack of care and over protection
- recalled childhood abuse
VULNERABILITY AND SOCIAL FACTORS
- 3+ children under 14
- not working outside the home
- lack of confidante
LIFE EVENTS:
- life events/trauma
- physical illness
What are type of anxiety disorder?
- panic attacks
- specific phobias
- OCD
- social phobia
- PTSD
- generalised anxiety
What are the symptoms of a panic attack?
- fear
- dizzy or faint
- choking
- shortness of breath
- smothering
- fear of dying
- fear of losing control
What is involved in OCD?
Obsessions: unwanted and repeated thoughts, feelings, ideas, sensations
Compulsions: repetitive behaviour and mental acts that neutralise obsessions and reduce emotional distress.
Usually recognised by the patient
What is PTSD?
- frightening and overwhelming flashbacks
- especially if suffered abuse/neglect as a child or abuse or violence as an adult
- other symptoms involve avoidance, numbing and being on guard
What is generalised anxiety disorder?
this is an ongoing state of excessive anxiety lacking any clear reason or focus. it affects 2% of the population. difficult to control.
Symptoms include:
- restless/irritable/muscle tension/’keyed up’ a lot of the time
- tired easily
- difficulty concentrating
- mind goes blank quite often
- insomnia
Risk factors:
- low SES
- childhood maltreatment and conduct problems
What are examples of anxiety anxiolytics?
- 5-HT
- GABA
- CRF
- CCK
What is GABA’s involvement in anxiety?
- mediates postsynaptic inhibitory transmission
- receptor subtypes: GABAa GABAb GABAc
- activation of GABAa receptors increases chloride conductance
- GABA is a NT present in almost all brain areas. Mainly interneurons, some longer pathways
Ligands acting at allosteric sites on GABA receptor complex:
- barbiturates
- benzodiazepines
- neurosteroids
- alcohol
these act by modulating the effects of GABA. Alcohol and barbiturates also have many other sites of action.
What is serotonin’s involvement in anxiety?
- relationship between anxiety and 5-HT not simple
- many receptor subtypes located presynaptically
- some drugs act on reuptake mechanisms or are parietal agonists
- prolonged effects of drugs may be different from initial effects e.g. SSRIs desensitise 5-HT auto receptors, resulting in increased release of 5-HT
What is 5-HT?
- Serotonin
- there are 5-HT cell bodies in the raphe nuclei in the pons and medulla.
The rostral nuclei project to the cerebral cortex, limbic system and the hippocampus.
The caudal nuclei project to the`medulla and the spinal cord.
There are different receptor subtypes (1-7) with many subdivisions. The 5-HT receptor activation can be excitatory or inhibitory
What is 5-HT involved in?
- sleep/wakefulness
- mood
- nociception
- temperature regulation
- feeding
What is the function of 5-HT receptors?
- 5-HT1A receptors control raphe cell firing
- 5-HT1B/D receptors control 5-HT release at terminals
About corticotrophin releasing factor
- released from the hypothalamus
- controls release of ACTH
- NT in CNS, especially in amygdala
What areas of the brain are involved in anxiety?
- hippocampus
- basal ganglia
- amygdala
- bed nucleus and stria terminals
- dorsal periaqueductal grey
What are examples one treatment for anxiety?
- benzodiazepines
- SSRIs
- 5-HT1A receptor agonists
- 5HT2/3 receptor antagonists
- beta blockers
- GABApentin (neurontin)
- others e.g. MDMA, psilocybin
What are the properties of benzodiazepines?
- anxiolytic
- anticonvulsant
- centrally acting muscle relaxants
- sedative
- amnesic
tolerance develops
have a higher therapeutic index than barbiturates
What can benzodiazepines be used for?
anxiety insomnia alcohol withdrawal status epilepticus spasticity premedication prior to general anaesthesia
What are the side effects of benzodiazepines?
- drowsiness
- ataxia
- increased appetite
- decreased stage 4 REM sleep
- occasional hostility
- can cause confusion in the elderly
Why should benzodiazepines not be used long term?
They are very addictive and dependence develops. Withdrawal syndrome is seen on cessation from long-term intake. Compulsive use can develop after a long duration of administration. They are recommended for short term prescription only because of these reasons, not more than 6 weeks.
How do you treat benzodiazepine overdose?
benzodiazepine antagonists
flumazenil
binds to benzodiazepine receptors but doesn’t alter the actions of GABA
has a short half life
How do beta-blockers work in treating anxiety?
- block B-adrenergic receptor
- decrease heart rate and blood pressure
- useful in decreasing autonomic symptoms of anxiety
- eg propranolol
What is the involvement of CRF in anxiety?
- experimentally CRF found to be involved in behaviour associated with anxiety
- CSF concentrations in CRF raised during anxiety, post traumatic stress and alcohol withdrawal
- activation of CRF receptors found to cause anxiety-related behaviour
CRF antagonists
- experimentally, antagonists at CRF receptors appear to be anxiolytic
- most available at present do not enter the brain well after systemic administration
- synthesis of new compounds may provide an important breakthrough
What is the involvement of CCK in anxiety?
- hormone released from the intestine - signals satiety at the end of a meal
- now known to be a NT in the CNS
- most abundant peptide transmitter in the CNS
- co-released with other transmitters e.g. monoamines
Infusion of CCK causes feelings of anxiety in a proportion of normal volunteers. CCK precipitates panic attacks in susceptible people. There is some evidence that these effects are due to peripheral actions of CCK.
CCK antagonists may be useful in anxiety, there are ongoing pre-clinical studies.
When is anxiety abnormal?
- out of proportion with the stressful situation
- persistent when stressful stimuli has gone
- appears for no apparent reason when there are no stressors
How is stress involved in anxiety?
- HPA axis - cortisol
- when hyperactive affects most MH conditions
- increase blood sugar, suppress immune system
direct sympathetic (parasympathetic) system
- pro-inflammatory
- reduced neurotrophic (BDNF): small hippocampus, reduced near-genesis
What examinations/investigations may be done into anxiety in patients?
- physical examination
- TFTs
- glucose
- FBC
- U&Es
- LFTs
- ESR
- B12/Folate
- Ca
What are specific phobias?
- excessive unreasonable fear, by prince or anticipation of a specific object or situation
- exposure provokes anxiety response, with to without panic attacks
- avoidance
- inside present
- interferes with life!
- exclude other mental disorder, medical conditions, primary drugs and alcohol misuse
What is social anxiety disorder (SAD)?
- social phobia
- fear of scrutiny or criticism, by others
- avoidance of social situations
- may present with blushing, hand tremor, nausea, urgency of micturition
- low self-esteem
- sometimes convinced non-psychological
- many progress to panic attacks
What are co-morbidity agents to anxiety?
- coffee
- tobacco
- OTC
What are the sedative drugs for anxiety?
- promethazine
- Z-drugs (ZZoplicone)
- benzodiazepines
- melatonin (insomnia)]
- propranolol
- pregablin
What is systemic desensitisation?
- challenge reactions to anxiety-provoking safety seeking behaviours
- proof that dysfunctional thought processes are unrealistic
What are other non-pharmacological treatments for anxiety disorders?
- CBT
- systemic desensitisation
- sustained exposure
What are typical feature son alzheimers disease?
- neurofibrillary tangles within neurone
- extra-cellular senile plaques
- neuronal depletion in cerebral cortex and hippocampus
- shrunken brain
- swollen ventricles
- thickened and deep sulci
- grey matter ribbon is thinner
What is familial AD?
- early onset, rare
- most common gene on Chr21 and is APP
- can have a little bit cut off it at 40aa which can form Abeta and then form the plaques
- prenesilins
- swedish families
- mirror of downs syndrome?: extra version of Chr21 and an extra APP
What are prenesilins?
mutations associated with familial, early onset AD
What is sporadic AD?
- late onset (LOAD)
- much more common
- > 65 years
- > 5% over 65, >40% over 80
- global phenomenon, not to do with where you live etc - just about living long enough for it to surface
- nothing to do with genetics
- ApoE gene is a risk factor but not DETERMINING factor; these are plasma cholesterol transport proteins and are three different alleles of this (E2, E3, E4) - 1 is increase, 2 even more, 3 even more
Why is AD referred to as the 21st century plague?
- as death form other diseases go down, deaths with Ad increase
- this may be because people are living longer so more are getting it
- drain on budgets and time
- as we get older pathology accumulates in our brain, eventually taking us over the threshold of being able to be diagnosed with dementia
What is ADAS-cog?
a test that goes on for a while
patient given a list of words to remember and they are tested after 2 minutes
hard to make a global test - difficult to fairly translate between languages
What is the molecular pathology of AD?
- APP, Abeta, secretases
- tau, GSK3b, etc
What are senile plaques in AD?
extracellular deposito of Abeta fibrils
What are endogenous membrane proteins?
amyloid precursor protein APP
What are amyloid plaques?
Abeta is cleaved form APP by secretase enzymes; alpha, beta and gamma. They have an intracellular C-terminus and an N-terminus sticking out.
In healthy patients alpha secretase cleaves APP forming fragments and no harm is one. The problem is if it gets excessively chopped by beta secretase and then gamma so we end up with tiny fragments which form plaques from the Abeta. these can be 40 or 42 aa in length
What are PIB scans?
- used increasingly with Abeta in diagnostics
- smal molecules have been developed which can cross the BBB and bin selectively to amyloid plaques (can see loads in AD patients)
- this is a way of visualising amyloid load in live patients
- if we had a way of getting rid of them this would be very useful, but at the minute we don’t
What is tau?
- tau is part of the neuronal cytoskeleton
- it is essential as a type of scaffolding for neurone and we all have it
- it is bad if the tau is hyperphosphorylated
- if there is too much phosphorylation the filamentous tau protein crinkles up into a tangle
- there are filaments inside neurone and the cerebral cortex
What is the neuropathology of tau tangle?
- tangled tau clumps into little balls
- healthy tau looks like neat parallel railway tracks
About tau hyperphosphorylation..
- filaments ar ein the neve cell processes
- it wants to keep it in tact and going to where it should with connections
- if the filaments become defective and tangles, the axon with become pathological and may die
- the neurone might live but the circuit won’t work
- some phosphorylation is normal but too much is not
What is cerebral amyloid angiopathy about?
- the amyloid is not only found in plaques, can also be found around blood vessels
- Abeta40 is clustered around the vessel
- Abeta-42 forms a messy corona around that
- they are very distinct
- in someone who has it, they tend to have both 40 and 42.
- vascular is also pathological and damaging but not as bad as in plaques
What are AD treatment options?
CHOLINESTERASE INHIBITORS
- donezepil
- rivastigmine
- galantine
- memantamine (NMDA receptor antagonist)
- immunotherapy
What is the rationale behind cholinesterase inhibitors being used in AD?
- the cholinergic system is involved in memory
- Ach major transmitter in circuit son memory
- many people with MCI will see an improvement with cholinesterase inhibitors, but not all
What is the basis for using immunotherapy in AD?
- we know that Abeta is the problem and it is a protein
- if we can make an antibody to it then it’ll find the Abeta in the plaques and prevent them forming and could event rid of them
- did a trial but some people died so it was terminated (Elan vaccine trial)
- as the surviving patients died over the years their brains were examined and although some of them had completely got rid of their plaques, their MMSE scores were still at 0 (the lowest! highest/normal is 31)
- this shows that one the damage is done it is too late to sort it - closing the stable door but the horse has already left. it is too late when the AD has become symptomatic.
