Phenomenology, psychopharmacology, counselling, hypnotics, ECT Flashcards
What are antidepressants?
Antidepressants are drugs used for the treatment of moderate to severe depressive episodes
and dysthymia.
They are also used for a range of other conditions including severe anxiety and panic attacks,
obsessive–compulsive disorder (OCD), chronic pain, eating disorders and post-traumatic stress
disorder (PTSD).
All antidepressants work on the basis of the monoamine hypothesis by enhancing the activity of the monoamine neurotransmitters, noradrenaline (NA) and
serotonin (5-HT)
How do MAO Inhibitors work?
Work at presynaptic receptor to prevent breakdown of dopamine, norepinephrine and serotonin
How do TCAs work?
Work at synaptic cleft to block the reuptake of serotonin and norepinephrine
Bupropion, mirtazapine, nefazodone, trazodone, venlafaxine
How do SSRIs work?
Work at presynaptic receptor to specifically block the reuptake of serotonin
What are the neurotransmitters that are released between presynaptic and postysynaptic receptor in the cleft?
Norepinephrine
Dopamine
Serotonin
What are the classes of antidepressants
SSRI Selective Serotonin Reuptake Inhibitor
SNRI Serotonin and Noradrenaline Reuptake Inhibitor
TCA Tricyclic Antidepressant
MAOI Monoamine Oxidase Inhibitor
NARI Noradrenaline Reuptake Inhibitor
NASSA Noradrenaline-Serotonin Specific Antidepressant
SARI Serotonin Antagonist and Reuptake Inhibitor
What is considered 1st line for depression?
Evidence suggests that SSRIs are better tolerated, work more quickly and have a lower risk of
inducing mania compared with other antidepressants. Therefore, they are generally considered
first-line for depression
Examples of SSRI’s
Citalopram, escitalopram, fluoxetine, paroxetine, sertraline,
fluvoxamine
When are SSRI’s are used?
Depression (all SSRIs), panic disorder (citalopram, escitalopram,
paroxetine), social phobia (escitalopram, paroxetine), bulimia nervosa
(fluoxetine), OCD (most SSRIs), PTSD (paroxetine, sertraline), GAD
(paroxetine)
Mechanism of action of SSRI
They work by inhibiting the reuptake of serotonin from the synaptic cleft
into pre-synaptic neurones and therefore SSRIs increase the
concentration of serotonin in the synaptic cleft.
Side effects of SSRI
GI + STRESS
Gastrointestinal: nausea, dyspepsia, bloating, flatulence, diarrhoea and
constipation.
Sweating, Tremor, Rashes, Extrapyramidal side effects
(uncommon), Sexual dysfunction, Somnolence, ‘Stopping SSRI’
Nausea, headache, GI upset (5-HT3)
Agitation, akathisia, anxiety (5-HT2)
Sexual dysfunction (5-HT2)
Insomnia (5-HT2)
Hyponatraemia (SIADH)
SE of tricyclic antidepressants?
Anticholinergic effects, Alpha-1 adrenergic antagonism, Antihistaminergic (H1)
Overdose, seizures
Contraindications of SSRI
Cautions: History of mania, epilepsy, cardiac disease (sertraline is the
safest), acute angle-closure glaucoma, diabetes mellitus (monitor
glycaemic control after initiation), concomitant use with drugs that
cause bleeding, GI bleeding (or history of GI bleeding), hepatic/renal
impairment, pregnancy and breast-feeding, young adults (possible ↑
suicide risk), suicidal ideation.
Contraindications: Mania.
Dosage and Route of SSRI’s
Sertraline (50–200 mg/day), fluoxetine (20–60 mg/day), citalopram (20–
40 mg/day), escitalopram (10–20 mg/day), paroxetine (20–50 mg/day).
Oral.
Features for the monoamine of hypothesis of depression?
All antidepressant classes increase NA and 5-HT function
Amphetamines and Cocaine elevate mood
50% of depressed patients have low CSF 5-HIAA
features agains the monoamine hypothesis of depression?
Amphetamines and Cocaine less effective in depressed people
Alpha and beta blockers have no effect on BAD
Time to therapeutic effect is long
What about other treatments of depression – Ketamine (NMDA reception antagonist), ECT, TMS?
What else have we found out about depression since the monoamine hypothesis?
Stress (via the elevation of serum cortisol) is very neurotoxic, especially in the hippocampus
- It also induces Glutamate release…
- …which decreases neuronal neuroplasticity
Depressed people have decreased levels of neuroprotective chemicals such as BDNF.
Ketamine works as an NMDA receptor antagonist which decreases Glutamate release.
What is the neuroplasticity hypothesis?
Antidepressants cause slow increase in BDNF via GPCRs
Antidepressants also decrease glutamate release via other downstream mechanisms
Antidepressants may directly increase plasticity in hippocampal neurones
Do SSRIs actually work?
Do they actually work?
STAR*D (AJ Psych, 2006)
37% initial remission, 67% overall
How long do they take to work?
Potentially two weeks
Longer in the elderly and shorter in children
How long do I need to keep taking them?
6-9/12 if first episode + uncomplicated
2 years if recurrent depressive disorder, very severe episode, major relapse factors present
SNRIs examples and doses
Venlafaxine (75mg a day in divided doses)
Duloxetine (60-120mg a day)
SNRI indication
2nd or 3rd line for depression and anxiety
More rapid onset of action and are more effective than SSRIs
Mechanism of action of SNRI’s
Prevent reuptake of noradrenaline and serotonin
Dont block cholinergic receptors and do not have have as many anti-cholinergic side effects as TCAs
Side effects of SNRIs
Nausea, dry mouth, headache, dizziness, sexual dysfunction, HT
Cautions of SNRIs
Cardiac arrhythmias and HT
Examples and doses of Noradrenaline serotonin specific antidepressants (NASSAs)
Mirtazapine (15-45 mg a day)
Mirtazapine indication
2nd line depression - benefit of weight gain and suffer from insomnia
Mechanism of action of mirtazapine
Weak noradrenaline reuptake inhibiting effect
Anti histaminergic properties
Is an a1 and a2 blocker
Therefore Inc appetite and is a sedative
SE of mirtazapine
Inc appetite
weight gain
dry mouth
postural HT
oedema
drowsiness
fatigue
tremor
dizziness
dreams abnormal
confusion
anxiety
insomnia
arthralgia
myalgia
Cautions and contraindications of mirtazapine
Elderly
Cardiac disorders
Hypotension
urinary retention
glaucoma
diabetes
psychoses
seizures
blood disorders
Reboxetine dose
8-12 mg a day
Indication of reboxetine
2nd or 3rd line for major depression
Mechanism of action for Reboxetine
Highly specific noradrenaline reuptake inhibitor
SE of Reboxetine
Nausea
Dry mouth
constipation
Anorexia
Tachycardia
palpitations
vasodilation
Postural hypotension
headache
insomnia
dizziness
chills
Cautions/ contraindications for reboxetine use
CVD
Epilepsy
bipolar
urinary retention
prostatic hypertrophy
pregnancy
glaucoma
How do we choose the right antidepressant (Long - Maryam shorten it)
- Overall safety profile: Most national and local guidelines suggest SSRIs as first choice
because of their safety profile in overdose as well as their effectiveness.
227 - Patient preference: After discussing side effects of each antidepressant, it is appropriate and
important to involve the patient in the decision making. - Prior treatment: If a patient has had benefit from a previously used antidepressant, that same
one should be used, provided no contraindications have developed; equally if an
antidepressant has already been tried and not benefited, another one should be trialled. - Type and severity of depression: SSRIs are usually indicated for all severities of depression
and when there is mixed anxiety and depression. In SSRI-resistant cases, SNRIs should be
tried. When insomnia is present or weight gain is desired, mirtazapine can be given. - Suicidal ideation: Avoid drugs that are toxic in overdose such as TCAs and MAOIs (see Key
facts 2). SSRIs should still be used with caution and appropriate review (see DO and DO NOT
boxes). - Age and co-morbidities: SSRIs are usually the safest in elderly. Sertraline is the safest drug
post-MI. See Table 12.2.2 for all other cautions and contraindications. - Drug–drug interactions: Avoid SSRIs in those on blood-thinning agents such as warfarin,
heparin and the newer anticoagulant agents (e.g. rivaroxaban, apixaban and dabigatran), as
well as NSAIDs. See BNF if in doubt. - Pregnancy and breast feeding: All antidepressants should be used with caution and if required,
the lowest effective dose should be used. Sertraline and fluoxetine are the safest during
pregnancy along with some TCAs such as amitriptyline. The SSRIs paroxetine and sertraline
are most likely suitable first-line agents during breast feeding. - History of mania: All antidepressants have the potential to trigger a manic episode but SSRIs
are usually the safest (avoid TCAs).
What is serotonin syndrome?
The serotonin syndrome is a rare but life-threatening complication of increased serotonin
activity, usually rapidly occurring within minutes of taking the medication.
It is most commonly caused by SSRIs but can be caused by other drugs such as TCAs and
lithium.
Clinical features include:
1. Cognitive effects → headache, agitation, hypomania, confusion, hallucinations, and
coma.
2. Autonomic effects → shivering, sweating, hyperthermia, hypertension and tachycardia.
3. Somatic effects → myoclonus (muscle twitching), hyperreflexia, and tremor.
Management involves stopping the offending drug and supportive measures
Features of serotonin syndrome
Classic triad
- Neuromuscular abnormalities
- Altered mental state
- Autonomic dysfunction
Beware co-administration of antidepressants
Treatment
Depends on presentation, ranges from supportive to use of Cyproheptadine (5-HT2 antagonist)
What can you do on SSRIs?
Prescribe SSRIs first-line
for moderate to severe
Co-prescribe NSAIDs and SSRIs, but if you have to,
prescribe a proton pump inhibitor too.
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depression unless
contraindicated.
Be cautious when
prescribing to children and
adolescents – fluoxetine is
the drug of choice in this
age group.
Prescribe sertraline post
myocardial infarction as
there is more evidence for
its safe use in this
situation over other
antidepressants.
Review patients after 2
weeks of prescribing
SSRIs – patients <30
years of age or at ↑ risk of
suicide should be
reviewed after 1 week.
Warn patients about side
effects – GI being the
most common.
Counsel patients to be
vigilant for ↑ anxiety and
agitation after starting an
SSRI.
What cant you do on SSRIs?
Co-prescribe NSAIDs and SSRIs, but if you have to,
prescribe a proton pump inhibitor too.
Co-prescribe SSRIs and heparin/warfarin.
Stop SSRIs suddenly – if stopping an SSRI, the dose
should be gradually reduced over a 4 week period (this
is not necessary with fluoxetine).
Prescribe citalopram or escitalopram in congenital long
QT syndrome, known pre-existing QT interval
prolongation, or in conjunction with other medicines that
prolong the QT interval, as they are associated with
dose-dependent QT interval prolongation
Examples of TCA’s
Amitriptyline, clomipramine, dosulepin, doxepin, imipramine, lofepramine,
nortriptyline, trimipramine.
Indications of TCAs
Depressive illness, nocturnal enuresis in children, neuropathic pain
(unlicensed), migraine prophylaxis (unlicensed).
Mechanism of action of TCAs
TCAs work by inhibiting the reuptake of adrenaline and serotonin in the
synaptic cleft. They also have affinity for cholinergic receptors and 5HT2
receptors and these contribute to side effects.
Features of 5HT2A receptors?
Complicated, but down stream effect is to reduce dopamine release
Therefore, antagonism cuts the brake and increases dopamine release in both striatum and nucleus accumbens.
This is one of many mechanisms.
SE of TCAs
Anticholinergic: dry mouth, constipation, urinary retention, blurred vision,
confusion. Cardiovascular: arrhythmias, postural hypotension, tachycardia,
syncope, sweating. Hypersensitivity reactions: urticarial, photosensitivity.
Psychiatric: hypomania/mania, confusion or delirium (especially in elderly).
Metabolic: ↑ appetite and weight gain, changes in blood glucose levels.
Endocrine: testicular enlargement, gynaecomastia, galactorrhoea.
Neurological: convulsions, movement disorders and dyskinesias, dysarthria,
paraesthesia, taste disturbances, tinnitus. Others: headache, sexual
dysfunction and tremor.
Contraindications and cautions of TCAs
Cautions → cardiac disease, history of epilepsy, pregnancy, breast-feeding,
elderly, hepatic impairment, thyroid disease, phaeochromocytoma, history of
mania, psychoses (may aggravate psychotic symptoms), susceptibility to
angle-closure glaucoma, history of urinary retention, concurrent
electroconvulsive therapy; drowsiness may affect performance of skilled
tasks (e.g. driving); effects of alcohol enhanced. Contraindications → recent
myocardial infarction, arrhythmias (particularly heart block), mania, severe
liver disease, agranulocytosis.
Dosage of TCAs
Amitriptyline (50–200 mg/day), doxepin (30–300 mg/day, up to 100 mg as
single dose), dosulepin (75–225 mg/day), imipramine (50–200mg/day, up to
100 mg as single dose), clomipramine (30–250 mg/day in divided doses or
as a single dose at bedtime), lofepramine (140–210 mg/day)
Examples of MAOs
Irreversible: Phenelzine, isocarboxide.
Reversible: Moclobemide.
Indications of MAOs
Third-line for depression: atypical or treatment-resistant depression.
NOTE: Its use is substantially limited by toxicity, interaction with food
and inferior efficacy compared to SSRIs and TCAs (see Key facts 2).
Social phobia.
Mechanism of action for MAOs
MAOIs inactivate monoamine oxidase enzymes that oxidize the
monoamine neurotransmitters dopamine, noradrenaline, serotonin (5-
HT), and tyramine.
There are two main forms of MAO enzymes: MAO-A and MAO-B.
Moclobemide is comparatively recent compared with the other MAOIs
and binds selectively to MAO-A, therefore nullifying the need for dietary
restrictions.
SEs of MAOs
Cardiovascular (postural hypotension, arrhythmias), neuropsychiatric
(drowsiness/insomnia, headache), GI (↑ appetite, weight gain), sexual
(anorgasmia), hepatic (↑ LFTs), hypertensive reactions with tyramine
containing foods
Cheese effect: inhibitor of MAO in the gut and the effect of tyramine rich foods
Drug interactions
Contraindications and cautions of MAOs
Cautions → Avoid in agitated or excited patients (or give with sedative for up
to 2–3 weeks), thyrotoxicosis, hepatic impairment, in bipolar disorders (may
provoke manic episodes), pregnancy and breast-feeding.
Contraindications → acute confusional states, phaeochromocytoma.
Why should we limit the use of MAOS
MAOIs also metabolize tyramine; therefore, eating tyramine-rich foods such as cheese, pickled
herring, liver (of beef or chicken), Bovril, Oxo, Marmite and some red wine can cause
hypertensive crisis. These foods should be avoided when taking MAOIs.
Clinical features of the hypertensive crisis: headache, palpitations, fever, convulsions and
coma.
MAOIs also interact with other drugs including insulin, opiates, SSRIs, and TCAs as well as
anti-epileptics.
What are the positive symptoms of psychosis?
Hallucinations
Delusions
What are the negative symptoms of psychosis?
Flattened affect
Cognitive difficulties
Poor motivation
Social withdrawal
What tracts of the dopaminergic system are involved in psychosis?
Mesolimbic tract
Nigrostriatal tract
Mesocortical tract
Tuberoinfundibular tract
What is the neurobiology of psychosis
The dopamine hypothesis”
All known antipsychotics are dopamine antagonists
A relative underactivity in the meso-cortical pathway and a relative overactivity in the mesolimbic.
What is the Meso-limbic pathway
VTA -> Nucleus accumbens
Associated with reward.
The so-called “pleasure centre”.
Activated by drugs of abuse.
What is “reward”.
Blocking this pathway reduces the positive symptoms of psychosis.
BUT, might also reduces the ability to feel pleasure!
There’s evidence that drug abusers need more/seek more drugs after starting antipsychotics.
What is the aberrant salience hypothesis?
The function of ascending dopamine signalling may be the attribution of salience to a stimuli.
Psychosis is the misattribution of salience.
Think of the dinner party effect.
Now imagine that any stimulus could trigger salience…
Features of the mesocortical pathway
Arises from VTA
Fibres spread throughout neocortex
Required for executive function and cognitive control of emotions.
A relative deficiency thought to cause negative symptoms of schizophrenia
Can anybody see the problem with giving a dopamine antagonist…?
“Neuroleptic dysphoria”
Features of the nigrostriatal pathway
Fibres from the substantia nigra which innervate the striatum in basal ganglia.
Dopamine signal favours the direct pathway. (causes movement).
Therefore D2
antagonists….?
What are some Motor side effects?
Acute dystonia
- Procyclidine
Akathisia
Tardive dyskinesia
Features of the Tuberinfundibular pathway
Links hypothalamus to pituitary
DA inhibits prolactin release
Symptoms of
hyperprolactinaemia?
What is neuroleptic malignant syndrome?
Neuroleptic malignant syndrome
Tremor, muscle cramps, fever, autonomic instability, delirium
Raised Ck. Can progress to rhabdomyolysis
Slower onset. Idiosyncratic (increased risk in dementia with lewy body)
Treated with DA agonists (eg. Bromocriptine)
Difference between typical (1st generation) and atypical (2nd generation) antipsychotics
The difference between these groups is primarily the extent to
which they cause extrapyramidal side effects (EPSE).
Examples of typical 1st generation antipsychotics
Haloperidol
Chlorpromazine
Flupentixol
Fluphenazine
Sulpiride
Zuclopenthixol
Examples of atypical 2nd generation antipsychotics
Olanzapine
Risperidone
Quetiapine
Amisulpride
Aripiprazole
Clozapine
