University of South Australia Pharmacology B (Major) Depression and antidepressants PDF

(Major) Depression and antidepressant medications Pharmacology B Overview Depressive disorders Symptoms and severity of depression Treatment goals Neurotransmitters in the brain Depressive disorders Major Depression 1 in 7 Australians will experienc...

(Major) Depression and antidepressant medications Pharmacology B Overview Depressive disorders Symptoms and severity of depression Treatment goals Neurotransmitters in the brain Depressive disorders Major Depression 1 in 7 Australians will experience depression in their lifetime – (1 in 16 are already experiencing depression) Different to periods of sadness that people experience – Severity, intensity, distress and impairment – Sadness = emotion, depression = mood disorder Experienced more often by females? Diagnostic criteria for major depression Depressed mood +/- marked loss of interest or pleasure unexplained by personal circumstance and 5+ of: Symptoms according to AMH (2022) Major depression classifications: MILD MODERATE SEVERE Distress Marked symptoms Considerable symptoms Some difficulty with daily Considerable difficulty Unable to continue daily activities with daily activities activities beyond minimal extent Treatment for depression Mostly initiated by GPs Combination approach is used – Psychotherapy (usually cognitive behavioural therapy) +/- antidepressants Goal: Relieve psychological and physical symptoms ↑ functional capacity ↓ likelihood of self-harm or suicide Before starting treatment Explanation for distress? – Grief – Alcohol/illicit drug misuse – Hypothyroidism – Adverse effects of drugs (corticosteroids) Importance of neurotransmitters Involved in regulating mood: – Norepinephrine/Noradrenaline (NE/NA) – Serotonin (5-HT) Abnormal – Dopamine (DA) functioning of – GABA neurotransmitters? – Glutamate Neurotransmitter imbalances do not fully explain pathophysiology of depression; antidepressants may have unknown off target mechanisms Presynaptic regulation of noradrenaline neurotransmission MAO = monoamine oxidase enzyme VMAT = vesicular monoamine transporter Noradrenaline transporter (NET) Presynaptic regulation of serotonin neurotransmission MAO = monoamine oxidase enzyme VMAT = vesicular monoamine transporter Serotonin transporter (SERT) Antidepressants Time to clinical benefit Factors affecting drug choice Drugs: mechanisms and adverse effects Serotonin syndrome/toxicity Issues with tyramine Withdrawal effects Changing antidepressants Antidepressants Commonly used: Less frequently used: Selective Serotonin Reuptake Mono-Amine Oxidase Inhibitors Inhibitors (SSRIs) (MAOIs) Serotonin and Noradrenaline Agomelatine Reuptake Inhibitors (SNRIs) Mianserin Tricyclic antidepressants (TCAs) Reboxetine Mirtazapine Vortioxetine Most important ones to know Antidepressants take time to work Proper balance of neurotransmitters occurs quickly Clinical benefits of antidepressants: » Some symptoms improvement in 1-3 weeks » 1-2 months for full effect – No benefit starting at higher dose » Use for 6-12 months Factors affecting drug choice: Previous response Concurrent medical and psychiatric illnesses Side effects of the drug Potential for drug interactions Toxicity in overdose – TCAs greater toxicity than SSRIs, SNRIs or mirtazapine Selective Serotonin Reuptake Inhibitors (SSRIs) Drugs: – Citalopram – Escitalopram – Sertraline – Fluoxetine – Fluvoxamine – Paroxetine Mechanism: selectively inhibit the presynaptic reuptake of serotonin Serotonin = 5-hydroxytryptamine, 5HT Serotonergic neuron Selective Serotonin Reuptake Inhibitors (SSRIs) Side effects: – Nausea, vomiting, diarrhoea – Insomnia or drowsiness – Dry mouth or sweating – Sexual dysfunction Comparison: – Escitalopram, citalopram and fluoxetine more likely to ↑ QT interval – Sertraline: diarrhoea – Paroxetine: constipation SSRI: drug interactions CYP450: – Fluoxetine » potent CYP2D6 and moderate CYP2C19 inhibitor – Fluvoxamine » potent CYP1A2 and moderate CYP2C19 inhibitor – Paroxetine » potent CYP2D6 inhibitor Serotonin syndrome/serotonin toxicity  Serotonin toxicity/serotonin syndrome What is it? – ↑ ↑ serotonin in synapse – Overstimulation of serotonin receptors Occurs: – ↑ dose of single drug – > 1 serotonergic agent – Changing between antidepressants with inadequate washout Francescangeli, J.; Karamchandani, K.; Powell, M.; Bonavia, A. The Serotonin Syndrome: From Molecular Medical emergency; can be fatal Mechanisms to Clinical Practice. Int. J. Mol. Sci. 2019, 20, 2288. https://doi.org/10.3390/ijms20092288 Serotonin toxicity Class Drugs Antidepressants citalopram, clomipramine, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, imipramine, moclobemide, paroxetine, phenelzine, sertraline, St John’s wort, tranylcypromine, venlafaxine, vortioxetine Opioids dextromethorphan, fentanyl*, pethidine, tramadol* Others dapoxetine, illicit drugs (eg ‘ecstasy’ (MDMA), hallucinogenic amphetamines, LSD), linezolid, lithium, methylene blue, milnacipran, phentermine, tryptophan Serotonin-Noradrenaline Reuptake Inhibitor (SNRI) Drugs: – Venlafaxine – Desvenlafaxine – Duloxetine  Serotonin-Noradrenaline Reuptake Inhibitor (SNRI) Mechanism: – Inhibit serotonin and noradrenaline reuptake – ↑ both 5HT and NA at the synapse Serotonergic neuron Adrenergic neuron  Serotonin-Noradrenaline Reuptake Inhibitor (SNRI) Side effects: – Nausea – Constipation, dry mouth – Sweating – Cardiovascular: » ↑ BP, tachycardia, orthostatic hypotension – Hyponatremia Comparison: – Duloxetine: moderately potent CYP2D6 inhibitor – All associated with serotonin syndrome Tricyclic antidepressants (TCAs) Drugs: – Amitriptyline – Imipramine – Nortriptyline – Dosulepin – Clomipramine – Doxepin Tricyclic antidepressants (TCAs) Mechanism: – Inhibit reuptake of 5-HT and NA – Also block: cholinergic, histaminergic and alpha-1 adrenergic receptors Serotonergic neuron Noradrenergic neuron Cholinergic neuron Other uses because of broad actions: Pain Migraine Bed-wetting TCA: structural differences *Desipramine is an active metabolite of imipramine *Nortriptyline is an active Dosulepin metabolite of amitriptyline TCAs adverse effects H1 histamine muscarinic M1 alpha-1 adrenergic Orthostatic Drug Sedation Anticholinergic hypotension amitriptyline +++ ++++ +++ clomipramine ++ ++ ++ dosulepin ++ ++ ++ doxepin ++++ +++ +++ imipramine ++ ++ ++ nortriptyline ++ + + All can also prolong QT interval and ↓seizure threshold AMH 2021  Non-selective MAOIs Drugs: – Tranylcypromine Irreversible MAO inhibitors – Phenelzine Mechanism: – Inhibit monoamine oxidases A and B » MAO-A metabolises DA, NA, 5-HT » MAO-B metabolises DA – ↑ synaptic concentration of: » NA, DA and 5-HT MAO = mono amine oxidase  Non-selective MAOIs Side effects: – Insomnia or fatigue – Dry mouth + constipation – Orthostatic hypotension Interactions with tyramine – Sympathomimetic amino acid – Also metabolised by MAO – Preventing degradation → » Release of NA from nerves; » Hypertensive crisis Tyramine containing food + drink Avoid tyramine if prescribed non-selective irreversible MAO inhibitor  Moclobemide Class: reversible MAO-A inhibitor Mechanism: – Competitively and reversibly inhibits MAO-A – ↑ synaptic concentrations of serotonin, NA and DA Serotonergic neuron Noradrenergic neuron  Moclobemide Side effects: – Nausea – Diarrhoea or constipation – Dry mouth – Insomnia Can cause serotonin syndrome No dietary restrictions – Inhibition is reversible; low affinity for MAO; easily displaced  Agomelatine Mechanism: – Melatonin receptor (MT1 and MT2) agonist and 5HT2c receptor antagonists » Beneficial for insomnia Side effects: – Dizziness – Blurred vision – Paraesthesias Contraindicated: combo with CYP1A2 inhibitors Cambridge  Mianserin Mechanism: – Tetracyclic antidepressant: many effects » Antagonist at H1 histamine receptors and some serotonin receptors » Antagonist at α1 and α2 adrenergic receptors » NA reuptake inhibitor – No anticholinergic properties Side effects: – Sedation Precautions: may ↑ risk of seizures  Mirtazapine Mechanism: – Tetracyclic antidepressant: many effects mirtazapine » Blocks postsynaptic serotonin receptors » Blocks presynaptic α2 adrenergic inhibitory autoreceptors – ↑ amount of NA + 5-HT » Potent H1 antagonist: sedative effect Side effects: – ↑ appetite, weight – Sedation – Peripheral oedema  Reboxetine Mechanism: – Selectively blocks NA reuptake – ↑ NA at the synapse – No great effect on DA; weakly inhibits serotonin reuptake NET transporter Side effects: – Orthostatic hypotension – ↑ diastolic BP – Tachycardia – Urinary retention, dry mouth, constipation Vortioxetine Mechanism: – Inhibits SERT – Acts as agonist or antagonist at 5-HT receptors » ↑ 5-HT activity in brain vortioxetine Side effects: – Nausea/vomiting – Constipation, dry mouth – Itch … relatively new medication; mechanism poorly understood Withdrawal effects Drugs Withdrawal effects Comments MAOIs nausea, vomiting, nightmares, panic, restlessness, delirium may also occur with hallucinations tranylcypromine (particularly if there was dependence) SSRIs dizziness, nausea, paraesthesia, anxiety, agitation, more common with paroxetine and tremor, sweating, confusion, electric shock-like least likely with fluoxetine sensations TCAs cholinergic rebound: hypersalivation, runny nose, more common with amitriptyline, abdominal cramping, diarrhoea, sleep disturbance doxepin SNRIs effects similar to those seen with SSRIs more common with venlafaxine mirtazapine, mirtazapine: anxiety, headache, dizziness, nausea more likely with mirtazapine; moclobemide rare/not observed with moclobemide AMH 2022 Changing antidepressants Considerations: – Need for anti-depressant free period to minimise interactions? » “Wash out period” – Avoid withdrawal symptoms? – Clinical urgency of treating symptoms? – What is the preceding drugs elimination half-life? – Possibility of serotonin toxicity? https://www.nps.org.au/australian-prescriber/articles/switching-and-stopping- antidepressants