Classes of Antidepressants

Classes of Anti-Depressants Antidepressants available in the market  Tricyclics and tetracyclics (TCAs) – e.g. doxepin.  MAO inhibitors (MAOIs) – e.g. moclobemide.  Serotonin selective reuptake inhibitors (SSRIs) – e.g. fluoxetine.  Dual serotonin and noradrenaline reuptake inhibitor (SNRI) – e.g. venlafaxine.  Serotonin-2 antagonist and reuptake inhibitors (SARIs) – e.g. nefazodone.  Noradrenalin and dopamine reuptake inhibitor (NDRI) – e.g. bupropion.  Noradrenergic and specific serotonergic antidepressant (NaSSAs) – e.g. mirtazapine.  Serotonin reuptake enhancer – eg. tianeptine. Most     prescribed antidepressant classes MAO inhibitors. Tricyclics and tetracyclics. Dual serotonin and noradrenaline reuptake inhibitor (SNR). Serotonin selective reuptake inhibitors (SSRIs). MAO inhibitors  Developed for the treatment of tuberculosis (iproniazid derivates) in 1951.  These drugs are not widely used today, although a small number of patients appear to do better in MAOIs than TCAs or the newer drugs.  Effects persist even after these drugs are no longer detectable in plasma (1 – 3 weeks).  There are 2 different isoenzymes of MAO: o MAO-A: degrades NA, 5-HT and tyramine. o MAO-B: degrades dopamine.  Non-selective inhibition of MAO enzymes: o Irreversible MAO inhibitors: hydrazides – e.g. phenelzine. o Reversible MAO inhibitors: non-hydrazides – e.g. tranylcypromine. o Decrease metabolism of most biogenic amines.   Selective inhibition of MAO enzymes: o Inhibition of MAO-A used for depression – e.g. moclobemide. o Inhibition of MAO-B used for Parkinson’s disease – e.g. deprenyl. Side effects. o “Serotonin syndrome” is a serious side effect of MAO inhibitors. o Tyramine is a naturally-occurring monoamine compound derived from the amino acid tyrosine (produced by the decarboxylation of tyrosine during fermentation in foods). o Inhibition of MAO-A leads to increased tyramine in the body, causing “tyramine pressor response” (increase in systole >30mmHg). o In detail, increase release of noradrenaline from neuronal storage vesicles by tyramine ingestion causes the vasoconstriction and increased HR and BP of the pressure response. o In severe cases, can lead to intracranial bleeding and other organ damage. Tricyclic antidepressants (TCAs)  Re-uptake inhibitors: homogenous group of drugs with potency to inhibit presynaptic NA or 5-HT uptake.  The TCAs include anticholinergic, antihistaminergic, and cardiotoxic side effects which are related to their action on muscarinic (mainly M1), histamine (H1) and adrenergic (α1) receptors, and cardiac Na+ and Ca2+ channels.  Imipramine. o First tricyclic antidepressant. o NA reuptake inhibition is strong, and 5-HT reuptake inhibition is moderate to strong. o Used for major depression and enuresis (inability to control urination). o Imipramine is often considered the “gold standard” antidepressant, as its ability to lift the most severe depressive episodes is unsurpassed. o However, causes a high rate of manic reaction, especially in patients with pre-existing bipolar disease.  Amitryptyline. o Antidepressant with sedative effects. o Strong serotonin-noradrenaline reuptake inhibitor. o 5-HT2A, 5-HT2C, 5-HT6, 5-HT7, α1-adrenergic, H1 and mACh receptor antagonist, and σ1 receptor agonist.  Side effects. o Many of the side effects relate to their anticholinergic properties. o Drowsiness, anxiety, restlessness. o Dry mouth, constipation, urinary retention or difficulty with urination. o Cognitive and memory difficulties. o Weight gain, sweating, dizziness, decrease in sexual ability and desire, muscle twitches, weakness, nausea. o Increased HR and irregular heart rhythms (rare). Selective serotonin reuptake inhibitors (SSRIs)  Most widely utilised class of antidepressants in clinical practice.  Increase the amount of 5-HT in the synaptic gap by inhibiting its reuptake. o Lack some of the side effects of the more general drugs.   Fluoxetine (Prozac). o First selective SSRI. o Initially approved for treatment of depression in Belgium in 1986. o Racemic mixture of R-fluoxetine and S-fluoxetine enantiomers, where both enantiomers are potent serotonin uptake inhibitors with essentially equivalent pharmacologic activity. o Because metabolism involves the P450D26 system, concomitant therapy with drugs also metabolised by this enzyme system (e.g. TCAs) may lead to drug interactions. o Fluoxetine has a wide range of published interactions, notably with MOAIs. o Common side-effects include anxiety, restlessness, trembling, weakness, skin rash anorgasmia, itching, and a decrease in sexual drive. Sertraline (Zoloft). o No significant affinity for adrenergic (α1, α2, β), cholinergic, GABA, dopaminergic, histaminergic, serotonergic (5HT1A, 5HT1B, 5HT2), or benzodiazepine receptors. o Side effects include insomnia, asthenia, GIT complaints, tremours, confusion and dizziness. o In about 0.5% of patients, it can induce mania or hypomania. Serotonin and noradrenaline reuptake inhibitors (SNRIs)  They act upon both 5-HT and NA.  Clinical efficacy is better than the SSRIs, owing to their compound effect.  These new drugs lack most of the adverse side effects of TCAs and MOAIs.  Venlafaxine (Effexor). o Exists as a racemic mixture of R- and S- enantiomers. o Used for the treatment of depression, generalised anxiety disorder, and social anxiety disorder in adults. o Approximately 3 – 5-fold more potent at inhibiting 5-HT than NA reuptake. o Low affinity for muscarinic, cholinergic, histamine (H1) and adrenergic receptors. o Metabolised by cytochrome P450 (CYP2D6) isoenzyme. o Drug only modestly inhibits CYP2D6, and is metabolite has no effect on this isozyme. o Side effect include nausea, dizziness, sleepiness, abnormal ejaculation, sweating, dry mouth, gas or stomach pain,   abnormal vision, nervousness, insomnia, loss of appetite, constipation, confusion/agitation, tremors and drowsiness. o Some patients stopping venlafaxine use experience SSRI discontinuation syndrome, characterised by extreme depression. Desvenlafaxine (Pristiq). o Synthetic form of the major active metabolite of venlafaxine. o Not approved in EU because it seems to be less effective, with no advantages in terms of safety and tolerability. Duloxetine (Cymbalta, Yentreve). o Serotonin-noradrenaline reuptake inhibitor by Eli Lilly. o Effective for major depressive disorder, and generalised anxiety disorder. o Also approved for painful peripheral neuropathy and fibromyalgia. o Head-to-head comparison of duloxetine with SSRI escitalopram found duloxetine to be both less tolerable and less effective. o It was also less efficacious than mirtazapine, escitalopram, venlafaxine and sertraline. o Duloxetine was similar to fluoxetine, fluvoxamine and paroxetine. o The tolerability of duloxetine was significantly worse than the tolerability of escitalopram and sertraline. Inhibition of uptake ratio Mechanism of antidepressants  Paradoxical slow onset of action. o Most typical antidepressants have a delayed onset of action (2 – 6 weeks). o However, pharmacokinetic data suggests that they should act much faster.  The standard answer is that antidepressants act by changing the concentrations of key neurotransmitters like 5-HT and NA.  There are two new hypotheses: o Network-growth factor hypothesis. o Inflammation hypothesis. Network-growth factor hypothesis  Proposes that problems in neuronal communication might underlie depression.  Antidepressants might work by improving information processing in the affected neural networks.  They initiate a ‘self-repair’ process, whereby changes in plasticity in neural networks and chemical neurotransmission gradually bring about mood elevation.  Antidepressants stimulate the growth of new neurons, and brainderived neurotrophic factor (BDNF), might be the player here. Inflammation hypothesis  Pro-inflammatory cytokine processes take place during clinical depression, mania and bipolar disorder.  Symptoms of these conditions are attenuated by the pharmacological effect of antidepressants on the immune system. o SSRIs, SNRIs and TCAs downregulate IFN-γ and IL-10, as well as TNF-α and IL-6. o Anti-depressants have also been shown to suppress TH1 upregulation.  Sickness behaviour. o Injecting rats with parts of bacterial cell walls, called lipopolysaccharides, causes their temperature to rise, their sleep patterns to change, they become less sociable and stop eating. o An injection of IL-1 makes the animal behave in exactly the same way. o Therefore, inflammatory cytokines directly influence behaviour. o Sickness behaviour is like fear – it is a state that makes the animal recognise its priorities.  Fluoxetine and citalopram are used for peripheral inflammatory diseases. o Significantly inhibited disease progression of collagen-induced arthritis in mice. o Has also been looked at in the use of inflammation in the heart.