psychopharmacology Flashcards
general pharmacology strategies - indication
establish a diagnosis and identify the target symptoms that will be used to monitor therapy response
general pharmacology strategies - choice of agent and dosage
select an agent w/ an acceptable side effect profile and use the lowest effective dose
remember the delayed response for many psych meds and drug-drug interactions
general pharmacology strategies - management
adjust dosage for optumum benefit, safety and compliance
use adjunctive and combination therapies if needed however always strive for the simplest regime
indications for antidepressants
unipolar and bipolar depression
organic mood disorders
schizoaffective disorder
anxiety disorders incl OCD, panic, social phobia
PTSD
premenstrual dysphoric disorder and impulsively associated with personality disorders
how do antidepressants work
not fully understood
antidepressants increase levels of neurotransmitters (serotonin, noradrenalin) in the brain
increasing these neurotransmitters changes receptors in the brain
response rate of ~60-70% and NNT 3
takes a little while for response to occur
general guidelines for antidepressant use
antidepressant efficacy is similar (there isn’t any one that is much better than the others) so selection is based on past hx of a response, side effect profile and coexisting medical conditions
delay of ~2-4wks after a therapeutic dose is achieved before symptoms improve
if no improvement is seen after a trial of adequate length (at least 2mths) and adequate dose, either switch to another antidepressant or augment with another agent
antidepressant classifications
TCAs - tricyclics
MAOIs - monoamine oxidase inhibitors
SSRIs - selective serotonin reuptake inhibitors
SNRIs - serotonin/noradrenaline reuptake inhibitors
novel antidepressants
TCAs - how effective
very effective but potentially unacceptable side effect profile
side effect profile of TCAs and other problems
side effects: antihisatminic (weight gain, sleepy), anticholinergic (blurred vision)
lethal in overdose - even a one week supply
can cause QT lengthening, even at a therapeutic serum
how do TCAs work
increase both serotonin, dopamine and noradrenaline
hit a lot of different receptors
what are tertiary TCAs
have tertiary amine side chains
side chains are prone to cross react with other types of receptors –> more side effects
e.g. imipramine, amitriptyline, doxepin, clomipramine
have active metabolites incl desipramine and nortriptyline
what are secondary TCAs
often metabolites of 3y amines
primarily block noradrenaline
side effects are the same as 3y TCAs but generally are less severe
e.g. desipramine, nortriptyline
how to MAOIs work
bind irreversibly to monoamine oxidase thereby preventing inactivation of amines such as norepinephrine, dopamine and serotonin leading to increased synaptic levels
very effective for resistant depression
side effects of MAOIs
orthostatic hypotension
weight gain
dry mouth
sedation
sexual dysfunction
sleep disturbance
MAOIs cheese reaction
hypertensive crisis can develop when MAOIs are taken with tyramine rich foods or sympathomimetics
can be fatal
- restrict diet: cheese, red wine, some processed meats
MAOIs and serotonin syndrome
serotonin syndrome can develop if take MAOI w/ meds that increase serotonin or have sympathomimetic actions
also if using combination of antidepressants
symptoms of serotonin syndrome
abdo pain diarrhoea sweats tachycardia HT myoclonus irritability delirium
can lead to hyperpyrexia, CV shock and death
how do SSRIs work
block the presynaptic serotonin reuptake
what are SSRIs used for
treatment of anxiety and depressive sx
most common side effects of SSRIs
GI upset sexual dysfunction (30%) anxiety restlessness nervousness insomnia fatigue or sedation dizziness
other risks from SSRIs
very little risk of cardiotoxicity in overdose
can develop a discontinuation syndrome with agitation, nausea, disequilibrium and dysphoria - occurs when people stop them quickly
more common with shorter half life drugs, consider switching to fluoxetine - slowly reducing concentration and reduces problems
SSRIs and activation syndrome
caused by increased serotonin
can be distressing for patient
sx: increased anxiety, panic, agitation, nausea
typically lasts 2-10 days - warn patient
pros of sertraline
very weak P450 interactions, only slight CYP2D6 - less drug interactions
short half life with lower build up of metabolites - quick activating
less sedating when compared to paroxetine
cons of sertraline
max absorption requires a full stomach
increased number of GI adverse drug reactions
pros of fluoxetine (prozac)
long half life - decreased incidence of discontinuation syndromes, good for pts w/ medication noncompliance issues
initially activating - may provide increased energy
2y to long half life, can give one 20mg tab to taper someone off SSRI when trying to prevent discontinuation syndrome
cons of fluoxetine
long half life and active metabolite may build up - not good w/ hepatic illness
significant P450 interactions - not a good choice on pts already on a number of meds
initial activation may increase anxiety and insomnia
more likely to induce mania than some of the other SSRIs
what are SNRIs
how do they work
what are they used for
serotonin/noradrenaline reuptake inhibitors
inhibit both serotonin and noradrenergic reuptake like TCAs BUT w/o antihistamine/antiadrenergic/anticholinergic side effects
used for depression, anxiety and possibly neuropathic pain
pros of venlafaxine
minimal drug interactions and almost no P450 activity
short half life and fast renal clearance avoids build up - good for geriatrics
cons of venlafaxine
can cause a 10-15mmHg dose dependent increase in diastolic BP
may cause significant nausea, primarily w/ immediate release tabs
can cause a bad discontinuation syndrome, taper recommended after 2wks of use
QT prolongation
sexual side effects in >30%
duloxetine pros
some data to suggest efficacy for the physical symptoms of depression
far less BP increase as compared to venlafaxine - may change in time
duloxetine cons
CYP2D6 and CYP1A2 inhibitor
cannot break capsule as active ingredient not stable within stomach
higher drop out rate
what type of antidepressant is mirtazapine
novel
pros of mirtazapine
different mechanism of action may provide a good augmentation strategy to SSRIs
can be used as a hypnotic at lower doses 2y to antihitaminic effects
how does mirtazapine work
5HT2 and 5HT3 receptor antagonist
cons of mirtazapine
increases serum cholesterol by 20% in 15% of pts and triglycerides in 6% of pts
very sedating at lower doses
- at doses 30mg and above it can become activating and require change of administration time to the morning
associated w/ weight gain - esp at doses <45mg
how do we manage treatment resistant depression
combination of antidepressants e.g. SSRI/SNRI + mirtazepine
adjunctive treatment w/ lithium
adjunctive treatment w/ atypical antipsychotic e.g. quetiapine, olanzapine, aripiprazole
ECT
prophylaxis following treatment w/ antidepressants
1st episode - continue for 6-12mths
2nd episode - continue for 2yrs
3rd episode - discuss life long
american studies suggest:
- stop before 6mths - 80% relapse
- phrophylaxis >6mths - 20% relapse
management of anxiety
serotonergic anti-depressants e.g. SSRI/SNRI
tricyclic chlomipramine
adjunctive treatment: mainly antipsychotics e.g. risperidone, quetiapine
try and avoid symptomatic relief e.g. diazepam
indications for mood stabilisers
bipolar
cyclothymia
schizoaffective
classes of mood stabilisers
lithium
anticonvulsants
antipsychotics
how to choose which mood stabiliser
depends on what you are treating and the side effect profile
what is the only medication to reduce suicide rate
lithium
has been shown to reduce the rate of completed suicide in BAD by ~15%
when is lithium used as prophylaxis
effective in long term prophylaxis of both mania and depressive episodes in >70% of BAD pts
factors predicting positive response to lithium
prior long term response or family member with good response
classic pure mania
mania is follower by depression
what to do before starting lithium
baseline U+E and TSH
in women check a pregnancy test
risk of lithium use during pregnancy
during the first trimester is associated w/ Ebstein’s anomaly 1/1000
20x greater risk than in the general pop
monitoring with lithium use
steady state acheived after 5 days
check 12 hrs after last dose
once stable check level 3mths
TSH and creatinine 6mths
goal: blood level 0.6-1.2
lithium side effects
most common are GI distress incl reduced appetite, N+V, diarrhoea
thyroid abnormalities
nonsignificant leukocytosis
polyuria/polydipsia 2y to ADH antagonism
small number of pts - interstitial renal fibrosis
hair loss, acne
reduces seizure threshold, cognitive slowing, intention tremor
lithium toxicity
mild (1.5-2) - vomiting, diarrhoea, ataxia, dizziness, slurred speech, nystagmus
moderate (2-2.5) - N+V, anorexia, blurred vision, clonic limb movements, convulsions, delirium, syncope
severe (>2.5) - generalised convulsions, oliguria, renal failure
examples of anticonvulsants
valproic acid (Depakote)
carbamazepine (Tegretol)
lamotrigine (lamictal)
effectiveness of valproic acid
as effective as lithium in mania prophylaxis
not as effective in depression prophylaxis
factors predicting a +ve response to valproic acid
rapid cycling pts (F>M)
comorbid substance issues
mixed pts
pts w/ comorbid anxiety disorders
how well tolerated is valproic acid
better tolerated than lithium
what to do before starting valproic acid
baseline LFTs
pregnancy test
FBC
why can valproic acid not be used in women of childbearing age
neural tube defects
increased risk 1-2% vs 0.14-0.2% in general population
2y to reduction in folic acid
monitoring during valproic acid use
steady state achieved after 4-5days
check 12hrs after last dose and repeat CBC and LFTs
goal - target level 50-125
valproic acid side effects
thrombocytopaenia and platelet dysfunction
N+V, weight gain
sedation, tremor
hair loss
when is carbamazepine (Tegretol) indicated
1st line for acute mania and mania prophylaxis
indicated for rapid cyclers and mixed pts
what to do before starting carbamazepine
baseline LFT, FBC, ECG
monitoring during carbamazepine use
steady state acheived after 5 days
check 12hrs after last dose
repeat CBC and LFTs
goal - target levels 4-12mcg/ml
need to check level and adjust dosing ~1mth - induces own metabolism
carbamazepine side effects
rash - most common SE
N+V, diarrhoea
sedation, dizziness, ataxia, confusion
AV conduction delays
aplastic anaemia and agranulocytosis (<0.002%)
water retention - vasopressin like effect –> hyponatraemia
drug-drug interactions
indications for lamotrigine (lamictal)
indications similar to other anticonvulsants
also used for neuropathic/chronic pain
used more commonly as it doesn’t cause as many problems in women of childbearing age
SJS not as serious an issue
what to do before starting lamotrigine
baseline LFTs
initiation/titration of lamotrigine
start w/ 25mg daily for 2wks
then increase to 50mg for 2wks
then increase to 100mg
faster titration has a higher incidence of SJS
if the patient stops the med for ≥5 days, have to start at 25mg again
lamotrigine side effects
N+V
sedation, dizziness, ataxia, confusion
stevens Johnson’s syndrome and toxic epidemal necrolysis
blood dyscrasias - rare
severity of rash and severity of reaction w/ lamotrigine
severity/character of rash isn’t a good predictor of reaction severity
if any rash develops, immediately stop use
what drugs increase lamotrigine levels and what do we do in these cases
VPA - doubles concentration, use slower dose titration
sertraline
approved indications in bipolar disorder
aripiprazole (abilify) - manic, mixed, maintenance
risperidone (risperdal) - manic, mixed
quetiapine (seroquel) - manic, mainenance*
quetiapine modified release (XR) (seroquel XR) - manic, maintenance*, depressed
olanzapine (zyprexa) - manic, mixed, maintenance
when are antipsychotics useful
acutely unwell pts when they are manic
also have a sedative effect
not as good for maintenance
prophylaxis for bipolar disorder
generally lifelong
relapse is almost inevitable but impossible to predict when (could be mths or yrs)
indications for antipsychotic use
schizophrenia
schizoaffective disorder
bipolar disorder for mood stabilisation and/or when psychotic features are present
psychotic depression
augmenting agent in treatment resistant depressive and anxiety disorders
what is the mesocortical pathway
projects from the ventral tegmentum (brain stem) to the cerebral cortex
is felt to be where the -ve symptoms and cognitive disorders arise
problem in psychotic patients is too little dopamine
what is the mesolimbic pathway
projects from the dopaminergic cell bodies in the ventral tegmentum to the limbic system
this is where the +ve symptoms come from (hallucinations, delusions, thought disorders)
problem in psychotic patients is there is too much dopamine
what is the nigrostriatal pathway
projects from the dopaminergic cell bodies in the substantia nigra to the basal ganglia
involved in movement regulation
effect of dopamine on acetylcholine activity
dopamine suppresses acetylcholine activity
what is the result of dopamine hypoactivity in the nigrostriatal pathway
parkinsonian movements e.g. rigidity, bradykinesia, tremors
akathisia
dystonia
what is the tuberoinfundibular pathway
what does blocking dopamine lead to
projects from the hypothalamus to the anterior pituitary
blocking dopamine in this pathway will predispose your patient to hyperprolactinaemia
effect of dopamine on prolactin
dopamine release inhibits/regulates prolactin release
result of hyperprolactinaemia
gynaecomastia
galactorrhea
decreased libido
menstrual dysfunction
how do typical antipsychotics work
examples
D2 dopamine receptor antagonists
high potency typical antipsychotics bind to the D2 receptor w/ high affinity
- higher risk of extrapyramidal side effects
fluphenazine, haloperidol, pimozide
low potency typical antipsychotics
example
less affinity for D2 receptors but tend to interact with nondopaminergic receptors resulting in more cardiotoxic and anticholinergic adverse effects e.g. sedation, hypotension
chlorpromazine
how do atypical antipsychotics work
serotonin-dopamine 2 antagonists (SDAs)
considered atypical in the way they affect dopamine and serotonin neurotransmission in the 4 key dopamine pathways in the brain
examples of atypical antipsychotics
risperidone (risperdal)
olanzaprine (zyprexa)
quetiapine (seroquel)
aripiprazole (abilify)
risperidone
formation
effects
available in regular tablets, IM depot forms and rapidly dissolving tablet
functions more like a typical antipsychotic at doses >6mg
side effects of risperidone
increased extrapyramidal side effects (dose dependent)
most likely atypical to induce hyperprolactinaemia
weight gain and sedation (dose dependent)
olanzapine formation
regular tablets
immediate release IM
rapidly dissolving tablet
depot form
olanzapine side effects
weight gain (up to 30-50lbs even with short term use)
may cause: hypertriglyceridaemia, hypercholesterolaemia, hyperglycaemia (even w/o weight gain)
may cause hyperprolactinaemia (< risperidone)
may cause abnormal LFTs (2%)
quetiapine formation
regular tablet only
quetiapine side effects
abnormal LFTs (6%)
weight gain (less than olanzapine)
hypertriglyceridaemia, hypercholesterolaemia, hyperglycaemia (even w/o weight gain) - less than olanzapine
most likely to cause orthostatic hypotension
aripiprazole formation
regular tablets
immediate release IM
depot formation
how does aripiprazole work
unique mechanism of action as a D2 partial agonist
apiprazole side effects
low extrapyramidal side effects, no QT prolongation, low sedation
not associated w/ weight gain
could cause potential intolerability due to akathisia/activation
aripiprazole interactions
CYP2D6 (fluoxetine and paroxetine) and 3A4 (carbamazepine and ketoconazole) interactions
- adjust dosing
antipsychotic efficacy
no evidence to suggest difference between 1st line agents
choice based on side effect or preparation
general rule of 1/3 good response, 1/3 some response, 1/3 poor response
what antipsychotic is used for treatment resistant patients
clozapine (clozaril)
what classifies someone as treatment resistant on antipsychotics
they have tried one antipsychotic for at least 8 weeks and then a 2nd for the same period of time of treatment and neither have worked
what formation is clozapine available in
regular tablet only
why is clozapine reserved for treatment resistant patients
due to its side effect profile
but it is very effective
clozapine side effects
associated w/ agranulocytosis (0.5-2%) - wkly bloods for 6mths then 2wkly tests for 6mths then monthly
increased risk of seizures (esp if also using lithium)
associated w/ the most sedation, weight gain and abnormal LFTs
increased risk of hypertriglyceridaemia, hypercholesterolaemia, hyperglycaemia, including nonketoic hyperosmolar coma and death, w/ or w/o weight gain
efficacy of clozapine
general rule of 1/3s
antipsychotic adverse effects
tardive dyskinesia
neuroleptic malignant syndrome
extrapyramidal side effects
what is tardive dyskinesia
involuntary muscle movements that may not resolve w/ drug discontinuation e.g. tongue protruding, lip smacking, neck movements
risk ~5% per yr
esp w/ typical antipsychotics
what is neuroleptic malignant syndrome
severe muscle rigidity
fever
altered mental status
autonomic instability
elevated WBC, CPK and LFTs
- potentially fatal
what are extrapyramidal side effects
acute dystonia
parkinson syndrome
akathisia
agents for extrapyramidal side effects
anticholinergics e.g. benztropine, trihexyphenidyl, diphenhydramine
- need to watch for anticholinergic SE esp if taken w/ other meds w/ anticholinergic activity i.e. TCAs
dopamine facilitators e.g. amantadine
beta blockers e.g. propranalol
anti-psychotic prophylaxis
life long relapse inevitable
commonest psychotic symptoms is lack of insight
people w/ psychotic illnesses relapse most commonly due to non-compliance
only 30% of pts take medication as prescribed
level of functioning after schizophrenic episode
after 3rd episode of sz - clear link to reduced functioning, lower IQ and -ve symptoms
consider long acting IM
what are anxiolytics used for
used to treat many diagnoses including panic disorder, GAD, substance related disorders and their withdrawal, insomnias and parasomnias
in anxiety disorders often use anxiolytics in combination w/ SSRIs or SNRIs for treatment
what are benzodiazpines used for
used to treat insomnia, parasomnias and anxiety disorders
often used for CNS depressant withdrawal protocols e.g. alcohol withdrawal
side effects of benzodiazepines
somnolence cognitive deficits amnesia disinhibition tolerance dependence
examples of benzodiazepines and dosage
diazepam
chlordiazepoxide
doses of ~20mg, 4x/day OR 10mg PRN up to 8x/day
different types of benzodiazepines
important points about benzodiazapines
remember dependence develops
increased tolerance - people need more and more; also becomes less effective
try and reserve for short term use only e.g. emergency sedation and withdrawal states
for psychiatric disorder use meds which treat the underlying cause
