Neuropsychopharmacology Flashcards
what Is the function of dopamine
Dopamine modulates attention and salience
“Salience” refers to the motivational properties of a stimulus, which can cause it to attract attention and drive behavior
how is dopamine linked to delusions
Dopamine modulates attention and salience
“Salience” refers to the motivational properties of a stimulus, which can cause it to attract attention and drive behavior
Aberrant salience hypothesis:
Abnormal dopamine nuerotransmission
Tendency for irrelevant stimuli to be attributed motivational salience and thus to attract attention and influence behaviour inappropriately - brain thinks everything is important and then the brain gives a meaning for these things - leads to delusions
These are attended to, explored and given meaning – leads to formation of delusions - what meaning is given is dependent to personal circumstances - eg in NI they’ll relate it to paramilitary or psi or mi5 or something but in America it’ll be via or fbi or something like that
What causes schizophrenia
Genetic risk
first degree relative increases risk to 8-10%
Shared risk with bipolar disorder
Cannabis use in teenage years increases risk x2
Childhood trauma
Social isolation e.g. increased risk in immigrant groups
describe Schizophrenia symptoms
Positive symptoms:
- Delusions, hallucinations, impaired insight
- Distressing
- Respond well to antipsychotics
Negative symptoms:
- Emotional blunting, social withdrawal, apathy
- Can be very disabling and require long term support
- tend to be more disabling and difficult to treat
Cognitive impairment
- Pattern of impairments
- Drop in IQ
describe the dopamine hypothesis in Schizophrenia
There are significant abnormalities in dopamine transmission in the striatum
- Elevated pre-synaptic dopamine synthesis and storage
- Increased dopamine release from cells
- Increased density of D2 receptors in striatum
Antipsychotic effectiveness associated with blockade of D2 receptors in striatum
Cannabis – causes increased striatal dopamine release
Other genetic and environmental risk factors associated with abnormalities in dopamine transmission
what’s the difference between 1st vs 2nd generation / Typical vs Atypical drugs in Schizophrenia treatment
Originally termed ‘atypical’ as not thought to produce Extra Pyramidal Side effects (EPSE) at treatment doses
2nd generation / atypical more likely to produce metabolic side effects
No difference in efficacy
2nd generation have broader receptor profile – not limited to dopamine receptor antagonism
describe the pharmacology of antipsychotics
Antipsychotics are antagonists at dopamine D2 receptors – this mediates their clinical effect
They improve positive (psychotic) symptoms, but no impact on negative symptoms
Concordance enhanced by DEPOT preparations:
- Haloperidol, zuclopenthixol, risperidone, aripiprazole
Antipsychotics also act at a number of other receptors:
- Serotonin
- Histamine
- Muscarinic
- Alpha adrenergic
Both positive and adverse effects mediated by action at other receptors
what are the adverse effects of dopamine antagonism
- Nigrostriatal tract - Extra pyramidal side effects (EPSE) (Extrapyramidal side effects: Physical symptoms, including tremor, slurred speech, akathesia, dystonia, anxiety, distress, paranoia, and bradyphrenia, that are primarily associated with improper dosing of or unusual reactions to neuroleptic (antipsychotic) medications.)
- Tuberoinfundibular system – prolactin elevation
describe the four Extra pyramidal side effects (EPSE)
- Acute dystonia;
- Involuntary muscle spasm
- Occurs within hours of starting antipsychotics
- Torticollis / oculogyric crisis / tongue spasm
- Imbalance between nigrostriatal dopamine / acetylcholine – rapidly respond to IM anticholinergic e.g. procyclidine / benzhexol
- More common in young males / antipsychotic naïve / high potency e.g. haloperidol - Parkinsonism:
- Characteristic signs:
Tremor (“pill-rolling”)
Rigidity (cogwheel)
Bradykinesia
- Develops days to weeks after antipsychotic treatment
- Risk factors: elderly females, first generation antipsychotics
- Nigrostriatal dopamine blockade leads to relative excess of acetylcholine
- Treatment:
Add anticholinergic e.g. procyclidine
Reduce antipsychotic dose
Switch to second generation antipsychotic - Akathisia:
- A subjectively unpleasant state of inner restlessness where there is a strong desire to move:
Foot stamping when seated
Crossing/uncrossing legs
Rocking foot to foot
Pacing up and down
- Associated with increased risk of suicide and aggression
- Pathology less clear
- Occurs in 25% patients, less with 2nd generation (except risperidone and aripiprazole)
- Treatment:
Reduce dose
Switch to 2nd generation antipsychotic
Anticholinergics unhelpful
Propranolol and 5HT2 antagonists e.g. mirtazapine may help but limited evidence - Tardive Dyskinesia:
- Abnormal movements
Lip smacking and chewing
Tongue movements (‘fly catching’)
Choreiform hand movements
Pelvic thrusting
- 5% patients per year of antipsychotic exposure
- More common in elderly women and people who have had early EPSE
- Treatment:
Increasing antipsychotic may improve symptoms initially
Stop anticholinergic
Reduce dose of antipsychotic
Switch to Quetiapine or Clozapine
describe Hyperprolactinaemia
Dopamine inhibits prolactin release therefore antipsychotics can increase prolactin levels
Olanzapine, aripiprazole, clozapine and quetiapine do not increase prolactin at usual treatment doses
May be asymptomatic
Problems include: sexual dysfunction, breast growth and galactorrhoea (excessive or inappropriate production of milk), reduction in bone mineral density and menstrual disturbances
describe the metabolic side effects of antipsychotics
More common with 2nd generation antipsychotics
Include
Weight gain
Dyslipidaemia
Type 2 diabetes
Weight gain:
- Mediated by serotonin 5HT2C, 5HT1A and H1 antagonism
- Worst with clozapine and olanzapine
- Likely genetic susceptibility
Dyslipidaemia:
- Increased by lifestyle factors prevalent in individuals with schizophrenia - not eating well, not attending GP as much as they should, not exercising enough
- Also exacerbated by antipsychotics esp Clozapine, Olanzapine and Quetiapine
- Likely associated with weight gain, although precise receptor associations unclear
Type 2 Diabetes:
- Lifestyle factors
- Untreated people with schizophrenia at higher risk
- Overall approx. 13% people with schizophrenia vs 3% general pop
- Mediated by weight gain, but also likely to be direct antipsychotic effect
- Clozapine, olanzapine > Quetiapine > other 2nd gen antipsychotics
name the non-metabolic side effects of antipsychotics
Sedation (Histamine receptor antagonism)
Dry mouth, constipation (Muscarinic antagonism)
Postural hypotension (Adrenergic receptor antagonism)
Sexual dysfunction (serotonergic antagonism, plus the above)
QTc prolongation
Neuroleptic malignant syndrome
describe Neuroleptic malignant syndrome
Idiosyncratic response to antipsychotics
Caused by D2 receptor blockade
More likely with 1st generation antipsychotics
Symptom:
- Fever, confusion, muscle rigidity
- Autonomic disturbance
- Rhabdomyolysis (Raised CK) – renal failure
Treatment:
- Stop antipsychotic
- Supportive
- Restart 2nd generation cautiously
when Is clozapine used and what are its side effects
Reserved for use in treatment resistant schizophrenia
2 trials of antipsychotic, minimum 6 weeks
Side effects:
- Neutropenia→agranulocytosis (deficiency in granulocytes)
- Myocarditis (inflammation of heart)
- Hypersalivation (excessive production of saliva)
- Constipation – potentially severe
- Sedation and weight gain
more effective than any other antipsychotic
but use restricted because it has some severe side effects
most people tolerate it v well
when Is aripipazole used and what are its side effects
NOT A DOPAMINE ANTAGONIST! – a partial agonist at dopamine D2 receptors
Functionally acts as antagonist in presence of increased dopamine transmission in mesolimbic area
Acts as agonist in mesocortical area
Side effects include akathisia and agitation but no other EPSE, weight gain, sedation or hyperprolactinaemia - not a lot of side effects - no metabolic side effects - not sedative
no evidence that it treats negative symptoms
IF it works - can be very effective because of its side effects profile - difficulty is it doesn’t work for everybody
what are the indications for antipsychotics
Schizophrenia
Other psychotic disorders:
- Delusional disorder
- Severe depression with psychotic symptoms
- Mania with psychotic symptoms
Non-psychotic disorders:
- Maintenance in bipolar affective disorder
- Adjunctive treatment in depression
- Evidence in OCD, PTSD, ASD
what needs to be monitored when you have prescribed antipsychotics
Weight Prolactin Blood glucose ECG U&E Blood pressure
what is the difference between psychosis and neurosis
PSYCHOSIS:
- Characterized by delusions (Fixed false belief out of keeping with a person’s religion and culture), hallucinations (A perception in the absence of a stimulus) and impaired insight (The individual is not aware of the problem – although apparent to others) eg schizophrenia
- E.g:
> Schizophrenia
> Schizoaffective disorder
> Delusional disorder
> Severe depressive disorder and mania may also exhibit psychotic symptoms
NEUROSIS:
- “disorders of sense and emotion”
- No delusions or hallucinations.
- Insight intact
- Eg mood and anxiety disorders
describe mania/hypomania
A pathological mood state lasting >= 4 days characterized by:
- Elated or irritiable mood
- Overactivity
- Increased energy
- Grandiosity
- Disinhibition
- Increased libido
- Note mania may be associated with grandiose delusions
what is the difference between nicotinic and muscarinic acetylcholine receptors
Nicotinic:
- Ionotropic (fast)
- Predominant in PNS
Muscarinic:
- Metabotropic (slow)
- Predominant in CNS
Describe in outline how antidepressants are used in the treatment of depression
Chronic stress alters neuronal circuits in brain
Antidepressants increase BDNF and stimulate neurogenesis – enhance synaptic plasticity
Moderates limbic system to reduce negative cognitive bias
Increased serotinergic neurotransmission modulates other neurotransmitter systems eg GABA, dopamine
describe the mode of action of SSRIs
Selective serotonin reuptake inhibitors
Prevents re-uptake and subsequent degradation of the monoamine neurotransmitter serotonin from the synaptic cleft
Overall effect: Prolonged presence of serotonin in the synaptic cleft leads to prolonged neuronal activity – in mood disorders such as depression there are low levels of this neurotransmitter in the brain. SSRIs therefore restore the concentration of serotonin to normal levels.
describe some SSRI side effects
- Well tolerated
- Relatively safe in overdose
- First line treatment (NICE)
- GI – nausea, vomiting, dyspepsia
- Headache
- Agitation, anxiety
- Sexual dysfunction
- Hyponatraemia
- Increased risk of bleeding
- +/- Insomnia
- NO weight gain
what are some interactions of SSRIs
Dangerous in combination with other antidepressants and St John’s Wort
CYP enzyme inhibitors – increase levels of antipsychotics, benzodiazepines
Citalopram / Escitalopram – QT prolongation
describe the mode of action of SNRIs (Serotonin and Noradrenaline reuptake inhibitors)
Effect: Prevents re-uptake and subsequent degradation of the monoamine neurotransmitters
serotonin and noradrenaline from the synaptic cleft
Overall effect: Prolonged presence of serotonin and noradrenaline in the synaptic cleft leads to prolonged neuronal activity – in mood disorders such as depression there are low levels of these neurotransmitters in the brain. Serotonin/noradrenaline reuptake inhibitors therefore restore the concentration to normal levels.
describe some side effects for SNRIs
GI – nausea, vomiting, dyspepsia Headache Agitation, anxiety, Sexual dysfunction Hyponatraemia Sweating \+/- Insomnia Elevation of blood pressure at higher doses NO weight gain,
what are the interactions of SNRIs
Dangerous in combination with other antidepressants and St John’s Wort
Metabolized by CYP2D6/34A
give some examples of SSRIs
Sertraline (Lustral): 50-200mg
Fluoxetine (Prozac): 20-60mg
Citalopram (Cipramil): 20-40mg
Escitalopram (Cipralex): 10-20mg
Paroxetine (Seroxat): 20-50mg
give 2 examples of SNRIs
Venlafaxine (Efexor, Vensir): 75 – 375mg
Duloxetine (Cymbalta): 60-120mg
name the NASSA (Noradrenergic and Specific Serotonergic antagonists) drug
Mirtazapine (Zispin): 15-45mg
describe the mode of action of NASSAs (Noradrenergic and Specific Serotonergic antagonists)
blocks the noradrenaline a2 autoreceptor
this blocks the negative feedback
and causes an increase in release of serotonin and adrenaline in the synaptic cleft
describe the mode of action of NASSAs (Noradrenergic and Specific Serotonergic antagonists)
blocks the noradrenaline a2 autoreceptor
this blocks the negative feedback
and causes an increase in release of serotonin and adrenaline in the synaptic cleft
Post synapticly:
- antagonist at 5-HT 1 and 5-HT3 receptors
- enhances 5-HT1 neurotransmission
describe the side effects of Mirtazapine
- Drowsiness, sedation
- Increased appetite and weight gain
- Dizziness
- Potential for blood dyscrasia
- Sexual dysfunction uncommon
- Few interactions
- CAN be used in combination with SSRI/SNRI with caution
list some Tricycic Antidepressants
Amitriptyline: 50-200mg/day
Clomipramine: 30-250mg/day
Lofepramine: 140-210mg/day
Dosulepin: 75-225mg/day
describe the mode of action of Tricycic Antidepressants
Target: Noradrenaline and serotonin reuptake transporters on the pre-synaptic neuronal membrane Action: Inhibitor
Effect: Prevent re-uptake and subsequent degradation of the monoamine neurotransmitters serotonin and noradrenaline from the synaptic cleft
Overall effect: Prolonged presence of serotonin and noradrenaline in the synaptic cleft leads to prolonged neuronal activity – in mood disorders such as depression there are low levels of these neurotransmitters in the brain. TCAs therefore restore the concentration to normal levels.
what are some side effects of tricyclics
Not recommended first line
Less well tolerated than other antidepressants
Potentially fatal in overdose
Dangerous in combination with other antidepressants and St John’s Wort
Other indications – eg amitriptyline and pain
- General:
Nausea, vomiting, headache - Histamine receptor:
Sedation, hangover - Alpha 1 receptor antagonism:
Postural hypotension, tachycardia, arrhythmia - Anticholinergic:
Dry mouth, blurred vision, constipation, urinary retention
list some MAOIs (Monoamine oxidase inhibitors)
Reversible: Moclobemide
Irreversible: Phenylzine, Tranylcypromine
list some MAOIs (Monoamine oxidase inhibitors)
Reversible: Moclobemide
Irreversible: Phenylzine, Tranylcypromine
describe the mode of action of MAOIs (Monoamine oxidase inhibitors)
An enzyme called monoamine oxidase is involved in removing the neurotransmitters noradrenaline, serotonin and dopamine from the brain. MAOIs prevent this from happening, which makes more of these brain chemicals available to effect changes in both cells and circuits that have been impacted by depression.
list some side effects of MAOIs
Rarely used in clinical practice
Possible role in treatment resistant depression
Dangerous in combination with other antidepressants and St John’s Wort
CHEESE REACTION:
Tyramine is contained in certain foods: aged cheeses, chicken liver, soy products, pickled fish and red wine
Tyramine normally inactivated by MAO in GIT
Patients on MAOIs cannot metabolize tyramine
Tyramine causes release of catecholamines resulting in tachycardia, hypertension, arrhythmias, seizures and stroke
