affective disorder/depression Flashcards
what is the monoamine hypothesis of depression and what is it based on
monoamine hypothesis: suggests depression is caused by functional defecit of noradrenaline, 5-HT and possibly dopamine in brain
therapeutic effects of antidepressant drugs attributed to augmentation or prolongation of actions of monoaminergic transmission in brain
based on:
reserpine; monoamine depletory used to treat schizo and hypertension, causes severe depression in 15% of patients
iproniazid; MAO-inhibitor, used to treat tuberculosis, sometimes induces euphoria
how is monoamine transmission modulated in antidepressant treatment
either;
increasing amount of transmitter released from nerve terminal (MAO inhibitors or mianserin)
preventing reuptake of released transmitter from synapse( tricyclics and selective uptake blockers)
what is mechanism for MAOs in depression
NA metabolised within nerve after reuptake from synapse by MAO; inhibition of the intraneuronal enzyme MAO leads to accumulation of monoamines primarily NA and 5HT
MAO inhibitors increase amount of treatment available for release, thereby increasing monoamine transmission
2 MAO isoenzymes; MAO-A and MAO-B
5HT and NA mainly; metabolised by MAO-A
dopamine metabolised by MAO-B (dopamine (and tyramine) non selective for MAO isotypes however are usually still metabolised by MAO B)
how are MAO inhibitors used to treat depression
MAO inhibitors: phenelzine and maclobemide
maclobemide is MAO-A inhibitor
phenelzine is non selective MAO inhibitor
MAO-B inhibitors have little treatment in depression, are used as adjunct in parkinsons
what are negative side ffects of MAO inhibitors
hepatotoxicity (rare but can be severe)
CNS side effects such as insomnia and agitation
postural hypotension due to potentiating effects of dopamine at autonomic ganglia (reduction in NA effects)
sympathetic effects; dry mouth, sweating, lack of appetitep
what type of uptake inhibitors are used in treatment of depression
uptake inhibitors include tricyclics and 2nd generation antidepressants
how are tricyclic antidepressants used
they block reuptake of monoamines
these compounds are related to phenothiazines and share many of their side effects such as dry mouth
in vitro tricyclics block neuronal uptake of both noradrenaline and 5HT
in vivo the metabolites of most of these compounds only inhibit uptake of NA
only clomipramine has selectivity against 5HT uptake in vivo
what are adverse effects of tricyclics
most negative effects due to antagonism of alpha 1 receptors, muscarinic and H1 receptors
adverse effects:
antimuscarinic activity: sedation, dry mouth, blurred vision
postural hypotension due to central action
cardiac dysrhythmias including ventricular fibrillation
convulsions mimicking epilepsy
confusion
how are selective uptake blockers used to treat depression
they are 2nd gen antidepressants:
developed to produce fewer side effects than tricyclics especially antimuscarinic and cardiotoxic effects
2nd gen antidepressants include:
selective NA reuptake blockers such as maprotilline
selective 5HT reuptake inhibitors (SSRIs) such as fluoxetine
how are SNRIs used in depression
serotonin noradrenaline reuptake inhibitors
most recent agents to be developed
non selective inhibitors of noradrenaline and 5HT reuptake
they have no significant antimuscarinic activity
inhibition of 5HT is maintained in vivo unlike most tricyclics
e.g venlafaxine
how are atypical antidepressants used
e.g iprindole and mianserin
neither drugs has any effect on monoamine reuptake
mechanisms underlying therapeutic effects of iprindole are unknown
mianserin is an alpha 2 adrenoceptor antagonist, preventing negative feedback inhibition of noradrenaline release, by presynaptic terminal alpha 2 autoreceptors
mianserin an antagonist for 5HT receptors (1d, 2a and 2c subtypes), which can explain its therapeutic effects
what are adverse effects of atypical antidepressants
negative side effects resemble tricyclics, particular problems include:
epileptogenesis
extrapyramidal and skin reactions
hepato and renal toxicity (especially mianserin)
postural hypotension (especially mianserin)
blood dyscrasias (especially mianserin)
what are other antidepressant used (other than MAO inhibitors, 2nd gen and atypical antidepressants)
benzos: e.g alprazolam and adinazolam
normally used to treat anxiety and are normally ineffective in depression, however triazolo and pyrazolo derivatives have both anxiolytic and antidepressant actions
main adverse effect is sedation
mirtazepine: a NA reuptake inhibitor and alpha 2 antagonist also used to treat depression
trazodone: 5HT reuptake inhibitor, 5HT2 receptor antagonist
^these 2 combine monoamine receptor uptake inhibition with receptor actions
what are problems with monoamine hypothesis of depression
iprindole used to treat depression, no known effects on monoamine turnover
pharmacological actions of antidepressants are apparent shortly after administration, however clinically there is a therapeutic lag of 2-3 weeks
many uptake blockers are not antidepressants e.g cocaine
what is the cheese reaction
tyramine normally metabolised by MAO in the gut
when MAO is inhibited tyramine diffuses into circulation and is taken up by sympathetic neurones
tyramine is an indirect sympathomimetic (see adrenergic notes), acts as “false transmitter”
release of noradrenaline into synapse is independent of neuronal activity and culiminates in exaggerated sympathetic drive
because of this potentially dangerous side effect early MAO inhibitors were reserved mainly for treatment of agititated depression (depression w anxiety) but a tyramine free diet was mandatory
tyramine is found in cheese, red wine and marmite
