Depressive Disorders and Antidepressants Flashcards
What are the risk factors for suicide?
Male sex, Age <19 or >45, Depression, Previous attempts, Ethanol use or other substances, Rational Thinking Loss, Single, Organised Plan, No social support, Sickness or other comorbidities.
(SADPERSONS)
Discuss the psychopharmacology of Mirtazapine and its uses
MOA - NaSSA - Noradrenergic and Specific Serotonergic Antidepressant.
- No monoamine reuptake inhibition
- antagonist at alpha2, H1, 5HT2A, 5HT2C, 5HT3
- blocks alpha2 autoreceptors in noradrenergic neurons. Activation of these receptors in the pre-synaptic neuron causes inhibition of NE release and therefore blocking this receptor causes loss of inhibition which in turn causes an increase in NE release
- blocks alpha2 heteroreceptors in serotonergic neurons. Serotonergic neurons are also inhibited by alpha2 receptors and therefore blocking them causes loss of inhibition and therefore more serotonin
- blocks 5HT3 receptors in the chemoreceptor trigger zone (which is linked to vomiting) and this is why mirtazapine is useful in chemotherapy patients to treat nausea and vomiting
- the blockade of 5HT2A and 5HT2C receptors has been linked to the antidepressant effects
H1 antagonist (therefore can cause sedation and weight gain)
Commonly used in elderly population
No significant drug drug interactions which makes it a popular choice for augmentation. Venlafaxine and Mirtazapine combination has been called “California Rocket Fuel”
DOSAGE: 15-45mg/day
Half-life of 20-40hrs
No active metabolites
Not a significant inhibitor of cytochrome P450 enzymes.
Metabolized in the liver by 3 different cytochrome P450 enzymes - CYP1A2, CYP2D6, CYP3A4.
No significant DDI
USES: depression, PD, GAD, SAD, add-on to SCZ for negative symptoms, emesis, insomnia
SIDE EFFECTS
Most side effects are related to the blockade of H1 receptors. Sedation, increased appetite and weight gain, dry mouth
BENEFITS OVER OTHER ADS:
- less sexual dysfunction, GI upset and insomnia
Discuss Trazodone MOA and use
MOA - weak inhibitor of serotonin reuptake. Blocks the post-synaptic 5HT2 receptors.
Also has potent H1 blocking activity and is therefore sedating.
Labeled use for MDD. Off-label use for alcohol dependence, anxiety, panic disorder, insomnia.
DOSAGE: Initial dose is 150mg/day in divided doses. Increase by 50mg/day every 3-4 days.
Maximum dose for inpatients 600mg/day in divided doses.
Outpatient 400mg/day in divided doses.
CONTRAINDICATION: Initial recovery phase following an MI. Hypersensitivity. ECT therapy.
Use with caution in cardiac disease and those with risk of suicide.
COMMON SIDE EFFECTS: dry mouth, dizziness, drowsiness, fatigue, anxiety, nausea, weight gain, increased appetite
SERIOUS SIDE EFFECTS: hypotension, orthostatic hypotension, arrythmias, priapism, leukopenia
What is the monoamine hypothesis?
Depression results from a deficiency in one of the three key monoamines (serotonin, norepinephrine and dopamine).
Monoamine depletion causes the post-synaptic receptors to upregulate which causes depression. Suspected that there is an abnormally functioning gene that causes depression.
Comment on the MOA and use of SSRIs and give some examples of SSRIs.
- The postsynaptic receptor for serotonin is 5-HT receptors (many subtypes)
- Serotonin is synthesized from amino acid called tryptophan and then stores in vesicles awaiting release
- Reabsorbed from the synapse by SERT (serotonin reuptake transporter)
- Once reabsorbed, they are partially repackaged into the presynaptic vesicles and partially broken down into inactive metabolites by MAO - monoamine oxidase
- SSRIs inhibit the reuptake of serotonin from the synapse and accomplish this by blocking the serotonin transporter - Fluoxetine, Paroxetine, Citalopram, Escitalopram, Sertraline, Fluvoxamine
ADVANTAGES
- safe in pregnancy except paroxetine (safest is sertraline)
- drug of choice in the elderly and adolescents (fluoxetine)
- safer than other antidepressants when taken in overdose
Why do SSRIs take weeks to take effect?
§ G-proteins tend to cluster in parts of the brain cell membranes rich in cholesterol called lipid rafts
§ While clustered in these rafts, the G-proteins do not have access to CAMP which is needed for them to function and use serotonin.
§ Found that SSRIs also build up in these lipid rafts and gradually displace the G-proteins to other areas of the brain cell membrane where they are able to function better.
What are some side effects of SSRIs and withdrawal of SSRIs?
- SHORT TERM SIDE EFFECTS
§ Insomnia (brain)
§ Anxiety and agitation (brain)
§ Irritability (brain)
Headache (brain)
§ Sexual dysfunction (spinal)
§ N and V (GIT)
§ Diarrhoea (GIT)
Abdominal pain (GIT
- Abrupt withdrawal leads to a temporary deficiency in serotonin in the synapse which can cause headache, N and V, sleep disturbances
What are some drug interactions for SSRIs and the black box warning?
- MAOIs (high risk of serotonin syndrome)
- NSAIDs and Aspirin - increased risk of bleeding
- diuretics - increased risk of hyponatremia
BLACK BOX
Increased suicidal thinking and behavior in the short term.
Comment on the MOA and use of SNRIs
- Postsynaptic receptor for norepinephrine are Beta and alpha 1 receptors
- Norepinephrine is synthesized from an amino acid called tyrosine and then stored in vesicles to await release
- Reuptake is by transporter called NET (norepinephrine transporter)
- Once reabsorbed, they are partially repackaged into the presynaptic vesicles and partially broken down into inactive metabolites by MOA - monoamine oxidase
- Works in the same way as SSRIs but also inhibit the NET transporter. Venlafaxine is the common RSA option.
Shown to be effective in the same conditions as SSRIs but also in reducing the pain associated with fibromyalgia and pain caused by neuropathy. This is due to the increase in noradrenergic activity in the CNS.
INDICATIONS:
- 2nd line treatment for MDD or for treatment augmentation, treatment resistance or prominent pain symptoms
- SAD, PD, persistent depressive disorder, diabetic neuropathic pain
INTERACTIONS
- MAOIs - serotonin syndrome
EXAMPLES
- Venlafaxine, duloxetine, milnacipran, desvenlafaxin, levomilnacipran
What are some side effects of SNRIs?
GIT - nausea, anorexia
ANTICHOLINERGIC - constipation, blurred vision, dry mouth
CNS - sedation, dizziness, anxiety
OTHER - sweating, hypertension, erectile dysfunction, increased BP, increased PR
Comment on the MOA and use of TCAs and Tetracyclic ADs
- Core chemical structure is 3 rings connected together
- Not a straightforward MOA
- Inhibits reuptake of both serotonin and norepinephrine by blocking both of the transporters
- Different TCA agents do this with different levels of selectivity
- Also block many other receptors such as alpha receptors, histamine receptors and muscarinic receptors - this causes the side effects rather than the antidepressant activity
- Mainly used for depression but also treats pain and migraine prevention, insomnia, childhood enuresis, OCD, narcolepsy and cataplexy, agoraphobia and panic attacks
INTERACTIONS:
- MAOIs (serotonin syndrome)
- Clonidine (hypertensive crisis)
- CNS depressants (over sedation)
CONTRAINDICATED:
- pregnancy
- recent MI
- cardiac arrythmias
EXAMPLES:
- amytriptyline
- clomipramine
- imipramine
- trimipramine
- lofepramine
Tetracyclic:
- maprotiline
- Amoxapine
What are some of the side effects of TCAs and what receptor blockade are they associated with?
- SIDE EFFECTS
§ Inhibition of alpha receptors leads to orthostatic hypotension and dizziness.
§ Inhibition of histamine receptors leads to sedation and weight gain
§ Inhibition of muscarinic receptors leads to anticholinergic side effects such as blurred vision, dry mouth, constipation and urinary retention.
TCAs block cardiac sodium channels - produce effects similar to antiarrhythmic agents. Palpitations, orthostatic hypotension and reflex tachycardia
Sexual dysfunction
Comment on the MOA and use of MAOIs
- Monoamine oxidase is the enzyme that degrades both serotonin and norepinephrine
- Exists in two subtypes, namely A and B with different distribution in the different tissues such as the brain, gut and liver
- MAO subtype A preferentially metabolises serotonin - blocking is responsible in the primary antidepressant effect of the MAOIs
- MAO subtype B preferentially metabolises dopamine
- Irreversible inhibitors and selective inhibitors.
- Some of the agents will block both subtype A and B
- Selegiline is a selective inhibitor of just MAO subtype B - this means that it is effective in Parkinson’s symptoms which are the result of dopamine depletion
- Are a last choice for antidepressants as they not only have a LOT of drug drug interactions but also drug food interactions as they are also present in the GUT and are responsible for the breakdown of monoamines that we ingest. This means that it can’t metabolise tyramine which is in aged and fermented foods. This Tyramine is then taken up into the synaptic nerve terminals where it acts as a catecholamine releasing agent. The release of large amounts of catecholamine due to Tyramine leads to hypertensive crisis and potentially a stroke.
BLACK BOX WARNING: Tyramine-induced hypertension
- concomitant ingestion of MAOI and substance containing tyramine can lead to severe hypertension, death or stroke. This is found in fermented foods. This is why those taking MAOIs need to wear a medic alert bracelet.
INTERACTIONS:
- most antidepressants
- CNS depressants
- anti-asthmatics
- antihypertensives
SIDE EFFECTS:
- orthostatic hypotension
- insomina
- weight gain
- oedema
- sexual dysfunction
EXAMPLES:
- Tranylcipromine, phenelzine, isocardoxazid, selegiline
Remeber selegiline as it preferentially inhibits MAO subtype B which is mostly responsible for the degradation of dopamine which makes it useful in the treatment of Parkinson’s disease which is due to dopamine depletion.
What are some examples of atypical antidepressants?
Bupropion
Mirtazapine
Trazadone
Nefazodone
Vilazodone
Vortioxetine
Briefly comment on the MOA and use of bupropion
- BUPROPION - weak norepinephrine and dopamine reuptake inhibitor. Can also use in nicotine cravings and withdrawal symptoms.
- 2nd line treatment for depression
- treatment augmentation
- used in cases that have prominent hypersomnia and fatigue as symptoms of depression
- used in those patients who have sexual dysfunction with other antidepressants
- can also be used in tobacco-use disorder, ADHD and persistent depressive disorder
ADVANTAGES: minimal effect on weight gain, cardiac conduction and sexual desire
INTERACTIONS:
MAOIs - hypertensive crisis
Drugs that decrease the seizure threshold
SIDE EFFECTS:
Headache, insomnia, dry mouth, tremor, nausea, increased sweating
Briefly comment on the MOA and use of mirtazapine
Serotonergic and Noradrenergic antidepressants
- MIRTAZEPINE - alpha 2 receptor antagonist. Blocks the presynaptic alpha 2 receptors. This increases noradrenergic and serotonergic neurotransmission. Also has some post-synaptic serotonin receptor blocking activity as well as antihistaminic activity which explains the sedating effects.
The 5HT2 and 5HT3 blocking increases the release of norepinephrine and 5HT1A mediated serotonergic transmission.
INDICATIONS: can be first or second line depending, treatment augmentation, in depression with prominent insomnia. GAD, PD, SAD, SD
ADVANTAGES:
- Limited sexual side effects
- limited interactions so can be used in cardiac patients
INTERACTIONS: MAOIs - hypertensive crisis
SIDE EFFECTS:
Increased appetite, weight gain, dry mouth, constipation, dizziness, headache, sedation, oedema
