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Anti-Depressant Medications Brian Ladds, M.D. Outline • Earliest meds: – MAOI – TCA • Neurotransmitter emphasized: NOR • More recent meds: – SSRI • Neurotransmitter emphasized: SE Discovery of Anti-Depressants • Historical Serendipity: – An early anti-TB medication was noted incidentally to have: • anti-depressant effects • and was found to inhibit MAO enzyme as one of its properties – Since making more monoamines available alleviated depression, perhaps the basis of depression is a deficiency of one or another monoamine in the brain Monoamines and Depression • For many decades the principal monoamine thought to be most relevant in depression was norepinephrine. • In the last decade, the role of another monoamine, serotonin, has also been emphasized. Neurotransmitters • 3 principal types of neurotransmitters – monoamine neurotransmitters (MA) – amino acid neurotransmitters – neuropeptide neurotransmitters Monoamine Neurotransmitters • Catecholamines – dopamine – norepinephrine • tyrosine hydroxylase enzyme – synthesizes l-dopa from tyrosine – rate-limiting step (usually saturated ) • Serotonin • Acetylcholine • (Histamine) Monoamine Neurotransmitters • Monoamine neurotransmitters comprise only a small percentage of neurons (vs. amino acid neurotransmitters), but: • Monoamines may regulate the balance of: – the excitatory actions of glutamate and the inhibitory actions of GABA • The receptor sites for the monoamine neurotransmitters are involved in many psychiatric disorders Monoamine Neurotransmitters • The neurons that produce monoamines originate in nuclei of the brainstem (or basal forebrain) and project widely to the cortex, where they release the neurotransmitters. Norepinephrine Pathways • Locus coeruleus in pons • -> inervation to the forebrain Life Cycle of the Monoamine Neurotransmitters • Synthesis: – from simple precursors (tyrosine, tryptophan, choline) • Storage: – stored in terminal pre-synaptic vesicles • Release: – into synaptic cleft • Site of Action: – act on post-synaptic receptors and elsewhere • Inactivation Monoamine Neurotransmitters: Inactivation • Inactivation: – primarily via re-uptake back into the presynaptic nerve terminal and then recycled – distinct “re-uptake transporters” (transmembrane proteins) for: • dopamine vs. norepinephrine vs. serotonin – and also by degradation by intra-cellular (and extra-cellular) enzymes Monoamine Oxidase Enzyme • Monoamine oxidase (MAO) enzyme – on external membrane of mitochondria – catabolizes (or degrades) monoamines in the nerve terminal cytosol (unprotected by vesicles) • MAOA breaks down serotonin and norepi • MAOB breaks down dopamine MAO Inhibitors (MAOI) • Examples: phenelzine (Nardil) or tranylcypromine (Parnate) • Irreversibly inhibit MAO enzyme – Therefore takes 2 weeks after stopping the MAOI to replenish new MAO enzyme • Increase the availability of monoamines – such as norepinephrine and serotonin, which are thought to be decreased in depression MAOI: Side Effects • Tyramine Hypertensive Crises – tyramine: contained in aged cheese, smoked meats, certain wines – is sympathomimetic and causes release of norepi from sympathetic terminals, which in the presence of MAOI can cause acute hypertensive crises and stroke MAOI: Side Effects • Medication Interactions – hypertensive crises with sympathomimetic medications (as with tyramine) – hyperthermia, e.g. with meperidine (Demerol) (as in the case of Libby Zion) • Other side effects – as with TCA’s Tri-cyclic Anti-depressants • Tri-cyclic anti-depressants (TCA): • Block re-uptake of monoamines, especially NE (and some block to a lesser extent SE) – the therapeutic mechanism of action Anti-Depressants: Efficacy • 2/3 respond • Not a euphoriant or stimulant among people who are not depressed Anti-Depressants: Time Course • Time course: 2-4 weeks delay of therapeutic effect. • Possibly due in part to: – gene expression and the synthesis of new structures & synapses – down-regulation A Theory of Down-Regulation MAOI and TCA are thought to bring about an antidepressant effect by: • making more norepinephrine available in the synaptic cleft, • thereby leading to the down-regulation of the postsynaptic adrenergic receptors • restoring them to their normal number and function. Tri-cyclic Anti-depressants: Side Effects TCA also block post-synaptic: • Histamine receptors – causing sedation, weight gain • Adrenergic receptors – causing hypotension, dizziness • Ach receptors – causing anti-cholinergic side effects Anti-cholinergic Side Effects • • • • • Blurred vision Urinary retention Constipation Dry mouth (Confusion) TCA and Risk of Overdose • Can be fatal in overdose Tri-cyclic Anti-depressants • Some TCA’s and their side effect profile: – Imipramine: one of the earliest, highly effective but many side effects – Desipramine: a metabolite of IMI, only blocks re-uptake of NE (not SE); it is the least anticholinergic TCA – Nortriptyline: least likely TCA to cause blood pressure changes – Others: amitriptyline, doxepin, amoxapine Serotonin Serotonin • 5-HT (Hydroxy-tryptamine) = Serotonin • synthesized from essential amino acid tryptophan • the rate-limiting enzyme not usually saturated – therefore increased levels of precursors cause increased synthesis of serotonin • (but dietary supplements of tryptophan not very effective AD and have had contaminants) Serotonin Pathways • Serotonin – several nuclei in the dorsal raphe in the midbrain – projects to striatum, hypothalamus, and neocortex Inactivation of Serotonin • Inactivation via pre-synaptic re-uptake • This re-uptake transport process is inhibited by some anti-depressants – TCA: imipramine (non-selective) – SSRI: fluoxetine (Prozac), paroxetine (Paxil), sertraline (Zoloft), citalopram (Celexa) SSRI • “Selective Serotonin Re-uptake Inhibitors” – probably as effective as TCA in most sub-types of depression • most are structurally unrelated to TCA’s – minimal anti-cholinergic or cardio-vascular side effects – safe in overdose Serotonin Receptors • Serotonin receptors (~ 13) – 5HT-1 – 5HT-2 – 5HT-3 SSRI: Side Effects • • • • GI upset weight loss insomnia, jitteriness sexual dysfunction (less libido, ED) Other Anti-Depressants • There are many other anti-depressants, some with different mechanism of actions, or combinations of receptor effects and side effect profiles – mirtazapine (Remeron) • alpha-2 antagonist; also with 5HT-2, 5HT-3 and histamine antagonist properties – buproprion (Wellbutrin) • NE and DA reuptake inhibitor Uses of Anti-Depressants • Depression – Dysthymia ? • Anxiety Disorders – Panic Disorder – OCD • Eating disorders • Pain • PTSD