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  1. Antidepressants Psychoanaleptics Mood Elevators Sanjaya Mani Dixit Assistant Prof of Pharmacology
  2. Depression • Depression is a chronic and recurrent illness that can affect at least 20% of the population at some period in their lifetime. • Associated with depletion of brain neurotransmitters: • 5-HT and • NA.
  3. Amine Hypothesis • 1950: Reserpine  Induce depression • Study: Reserpine depletes storage of amine neurotransmitters such as serotonin and norepinephrine • Break-through: MAOI and TCA • Then: Depression  Amine-dependent synaptic transmission (Antidepressants  Amine by means of reuptake and metabolism) • Conclusion: Major model for the subsequent antidepressants, except Buproprion.
  4. Biogenic Theory of Depression • The precise cause of affective disorders remains elusive. • Evidence implicates alterations in the firing patterns of a subset of biogenic amines in the CNS, • Norepinephrine (NE) and • Serotonin (5-HT).  Activity of NE and 5 -HT systems?.
  5. MAO COMT Amine neurotransmitters are either degraded (metabolized) or re-uptaken Mito
  6. Information integration cognition, thought, mood, emotion Cerebral cortex Sensory input Motor output acetylcholine norepinephrine serotonin dopamine histamine Information integration cognition, thought, mood, emotion Cerebral cortex Sensory input Motor output
  7. NE System Almost all NE pathways in the brain originate from the cell bodies of neuronal cells in the locus coereleus in the midbrain, which send their axons diffusely to the cortex, cerebellum and limbic areas (hippocampus, amygdala, hypothalamus, thalamus). • Mood: -- higher functions performed by the cortex. • Cognitive function: -- function of cortex. • Drive and motivation: -- function of brainstem • Memory and emotion: -- function of the hippocampus and amygdala. • Endocrine response: -- function of hypothalamus.  and  receptors.
  8. A synapse that uses norepinephrine (NE)
  9. Reuptake of NE Monoamine oxidase, located on outer membrane of mitochondria; deaminates catecholamines free in nerve terminal that are not protected by vesicles Selective inhibitor, reboxetine Cocaine blocks the NE Antidepressant MAO Inhibitors Stimulant
  10. Symptoms of Depression • Highly recognizable, both to those affected and to those closest to them, once they are told what to look for. • Here is a checklist of symptoms of Depressive illness: – Loss of energy and interest. – Diminished ability to enjoy oneself. – Decreased -- or increased -- sleeping or appetite. – Difficulty in concentrating; indecisiveness; slowed or fuzzy thinking. – Exaggerated feelings of sadness, hopelessness, or anxiety. – Feelings of worthlessness. – Recurring thoughts about death and suicide. – If most of these symptoms last for two weeks or more, one probably has Depressive Illness. Sometimes depression alternates with "mania" and is called Manic-Depressive Illness (Bipolar).
  11. Biochemical Theory of Affective Disorders Affective Disorders Serotonin NE NE Mania Depression Rx Drugs that decrease NE Drugs that increase NE What is the evidence to support this theory ? Amphetamine and mania while Clonidine and methyldopa produce depression.
  12. Antidepressants • Drugs which elevate mood in depressive illness • Affect mono- aminergic transmission in the brain in one way or the other.
  13. Classification of Antidepressants Based on Site of Action A ) Drugs that Block the RE-uptake of NE and 5- HT ( e.g.:Most tricyclics) B) Drugs that Selectively Block Re-Uptake of 5- HT (SSRIs) (Fluoxetine; Paroxetine; Sertraline; Citalopram) C) Drugs that Block Presynaptic α2- adrenoceptors (e.g.: Mirtazapine, Mianserin). D) Drugs that Inhibit Mono Amino Oxidase (MAOIs, Phenelzine, Tranylcypraine, Moclobemide)
  14. Mechanism of Action of Antidepressants 1) Inhibition of reuptake of NE and or 5-HT ?? or increases the release of NE or 5-HT. ??? 2) Desensitization (down-regulation) of β- adrenoceptors (decrease c-AMP). (very important and related to clinical response). How do SSRIs desensitize β-adrenoceptors? Hint: Remember Raphe nuclei!!
  15. TCAs • Very effective but potentially unacceptable side effect profile i.e. antihistaminic, anticholinergic, antiadrenergic • Lethal in overdose (even a one week supply can be lethal!) • Can cause QT lengthening even at a therapeutic serum level
  16. Tricyclics Amitryptyline • Potent sedative • Weight gain ++ • Anticholinergic ++ • Most researched • 150mg / day (Therapeutic in 95% of adults) Clomipramine • Similar side effects to amitryptyline. • Said to be best for obsessional symptoms. • 150mg / day
  17. Monoamine Oxidase Inhibitors (MAOIs) • Bind irreversibly to monoamine oxidase thereby preventing inactivation of biogenic amines such as norepinephrine, dopamine and serotonin leading to increased synaptic levels. • Are very effective for depression • Side effects include orthostatic hypotension, weight gain, dry mouth, sedation, sexual dysfunction and sleep disturbance • Hypertensive crisis can develop when MAOI’s are taken with tyramine-rich foods or sympathomimetics.
  18. SSRI • First choice in elderly. • First choice if heart disease. • First choice if suicide risk. • More expensive. Side effects • Like TCA reduce with time. • Gut problems predominate. • Flat dose response curve – so no need to titrate dose upwards. ?
  19. Selective Serotonin Reuptake Inhibitors (SSRIs) • Block the presynaptic serotonin reuptake • Treat both anxiety and depressive sx • Most common side effects include GI upset, sexual dysfunction (30%+!), anxiety, restlessness, nervousness, insomnia, fatigue or sedation, dizziness • Very little risk of cardiotoxicity in overdose • Can develop a discontinuation syndrome with agitation, nausea, disequilibrium and dysphoria
  20. Fluoxetine (Prozac) • Pros – Long half-life so decreased incidence of discontinuation syndromes. Good for pts with medication noncompliance issues – Initially activating so may provide increased energy – Secondary to long half life, can give one 20mg tab to taper someone off SSRI when trying to prevent SSRI Discontinuation Syndrome • Cons – Long half life and active metabolite may build up (e.g. not a good choice in patients with hepatic illness) – Significant P450 interactions so this may not be a good choice in pts already on a number of meds – Initial activation may increase anxiety and insomnia – More likely to induce mania than some of the other SSRIs
  21. Serotonin/Norepinephrine reuptake inhibitors (SNRIs) • Inhibit both serotonin and noradrenergic reuptake like the TCAS but without the antihistamine, antiadrenergic or anticholinergic side effects • Used for depression, anxiety and possibly neuropathic pain
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