Drugs for Depression Flashcards
What is the lifetime incidence of major clinical depression?
1 in 6 (17%)
What are the emotional symptoms of depression?
- misery, apathy, pessimism
- low self-esteem
- indecisiveness, loss of motivation
What are non-emotional symptoms of depression?
- retardation of thought and action
- loss of libido
- sleep disturbance and loss of appetite
What are the 2 major types of depression?
unipolar and bipolar
What are the 2 types of unipolar depression?
- reactive (75%) - non-familial, associated with life events and accompanied by symptoms of anxiety and agitation
- endogenous (25%) - familial and not directly related to external stress
Describe bipolar depression
strongly familial with some genetic similarities to susceptibility to schizophrenia
What is the main cause of depression?
deficits in monoamine neurotransmitters serotonin (5-HT) and noradrenaline
Where is monoamine oxidase found?
intracellularly on the mitochondrial surface of nearly all tissues
What are the 2 forms of monoamine oxidase?
MAO-A and B
What does MAO-A do?
regulate both the free and intraneuronal concentration and the releasable stores of 5-HT and noradrenaline
What does MAO-B do?
regulate both the free intraneuronal concentration and the releasable stores of dopamine
How do MAOIs work?
by increasing the biological availability of monoamines
What is the mechanism of action of inhibition of MAO-A?
- initial inhibition reduces breakdown of monoamines then enhances the release of neurotransmitters into the synapse
- elevated levels of noradrenaline and 5-HT bind to their receptors and intensify their neural activity
What is the mechanism of action of inhibition of MAO-B?
- inhibition decreases breakdown of dopamine and increases its release into the synapse
- increased levels of dopamine bind to receptors and intensify the effect
What are adverse effects of MOAIs?
the cheese reaction
What is the cheese reaction?
an interaction of the MAOI with tyramine that can lead to accumulation and a sympathomimetic effect
What are symptoms of the cheese reaction?
- severe headache
- nausea and vomiting
- sweating
- rapid heartbeat (tachycardia)
- acute hypertension
How can the cheese reaction cause acute hypertension?
tyramine is taken up into adrenergic terminals and initiates release of noradrenaline and subsequent stimulation of cardiovascular sympathetic NS activity
What are the 3 key MAOIs?
- irreversible non-selective MAOI e.g. phenelzine
- reversible MAO-A selective MAOI e.g. moclobemide
- irreversible MAO-B selective MAOI e.g. selegiline
How do TCAs work?
by blocking the uptake of 5-HT and noradrenaline which increases their concentration in the synapse and intensifies their neuronal effects
What is the source of TCA adverse effects?
binding to histamine and muscarinic ACh receptors
What are adverse effects of TCAs?
- sedation due to H1 histamine receptor antagonism
- postural hypotension due to α-adrenoreceptor sympathetic block
- dry mouth, blurred vision, constipation due to muscarinic receptor antagonism
- risk of drug induced cardiac dysrhythmias due to block of hERG potassium channel
What are the 2 key TCAs?
- non-selective e.g. amitriptyline
- selective for noradrenaline e.g. desipramine TCAs
What are SSRIs?
selective serotonin reuptake inhibitors
What is the most widely prescribed antidepressant?
fluoxetine
What are the 2 main SSRIs?
- fluoxetine (~50-fold selectivity for 5-HT)
- citalopram (~1000-fold selectivity for 5-HT)
How do SSRIs work?
by restoring the levels of 5-HT in the synaptic cleft by binding at the 5-HT reuptake transporter
How do SSRIs have less adverse effects than TCAs?
- low affinity for α-adrenoreceptors → lack of cardiovascular effects so safer in overdose
- lack of effect at histamine receptors → reduced sedation
- low affinity for muscarinic cholinergic receptors → minimal anticholinergic side effects e.g. dry mouth and constipation
What are adverse effects of SSRIs?
- 2/3 of patients get remission
- nausea
- sexual dysfunction (delayed ejaculation in men and delayed or blocked orgasm in women)
- serotonin syndrome
What is serotonin syndrome?
severe reaction resulting from drug-drug interactions with other drugs that increase serotoninergic activity e.g. MAOIs (symptoms include tremor, hyperthermia and cardiovascular collapse)
What are NARIs?
antidepressants that have have a greater noradrenaline reuptake than TCAs; they have ~1000x higher selectivity for noradrenaline than 5-HT
How do NARIs work?
by restoring the levels of noradrenaline in the synaptic cleft by binding at the reuptake transporter
What are adverse effects of NARIs?
- dry mouth and constipation due to anticholinergic effects
- insomnia due to increased noradrenergic activity in the CNS
- tachycardia due to increased availability of noradrenaline at sympathetic synapses
What are SNRIs similar to?
non-selective TCAs since they have similar dual 5-HT and noradrenaline reuptake inhibition profiles
What is the only clinical SNRI?
venlafaxine
What are advantages of SNRIs?
- different structure to and fewer adverse effects than TCA
- claimed to work slightly faster than other antidepressants
- claimed to work better in treatment-resistant patients
How do SNRIs work?
by restoring the levels of 5-HT and noradrenaline in the synaptic cleft by binding at their reuptake transporters
What are adverse effects of SNRIs?
- nausea
- insomnia
- sexual dysfunction
- serotonin syndrome
- withdrawal effects that are more common and stronger than for SSRIs and TCAs
