Depression & Antidepressants Lecture Notes PDF

Depression & Antidepressants Dr.Rania A. Abdel-Emam  DEPRESSION Types & Causes Symptoms Diagnosis Treatment DEPRESSION is a mood disorder that may be  Reactive depression: reaction to some stressors or adverse life situations like loss of...

Depression & Antidepressants Dr.Rania A. Abdel-Emam  DEPRESSION Types & Causes Symptoms Diagnosis Treatment DEPRESSION is a mood disorder that may be  Reactive depression: reaction to some stressors or adverse life situations like loss of a person by death, divorce, financial crisis or chronic major illness.  Endogenous depression (Major depressive disorder, MDD): occurs at any time of life. It may have genetic factors (neurotransmitter dysfunction), physiologic or metabolic disturbances. The patient frequently suffers from lack of interest, withdrawal from activities & feeling of guilt, inability to concentrate, feeling of worthlessness, somatic complaints (e.g. headache, disturbed sleep) thoughts of death and suicidal tendency. TYPES OF DEPRESSION Major depression (endogenous) Chronic depression (Dysthymia) Atypical depression Bipolar disorder/Manic depression Seasonal depression (SAD)  CAUSES OF DEPRESSION Genetics: managed by antidepressants + ECT Reactive: Death/Abuse Medications: reserpine, oral contraceptives Spontaneous: managed by antidepressants Neurotrophic Hypothesis Monoamines & Other Neurotransmitters  SYMPTOMS persistently sad, anxious, or empty moods loss of pleasure in usual activities (anhedonia) feelings of helplessness, guilt, or worthlessness crying, hopelessness, or persistent pessimism fatigue or decreased energy loss of memory, concentration, or decision-making capability restlessness, irritability sleep disturbances change in appetite or weight physical symptoms that do not respond to treatment (especially pain and gastrointestinal complaints) thoughts of suicide or death, or suicide attempts poor self-image or self-esteem (as illustrated, for example, by verbal self-reproach)  DIAGNOSIS Extensive patient and family history Blood test for hypothyroidism Current medication DSM-IV [Diagnostic and Statistical Manual of Mental Disorders, 4th. Edition]. Better known as the DSM-IV, the manual is published by the American Psychiatric Association and covers all mental health disorders for both children and adults. – One of the first two symptoms – Five other symptoms – DAILY occurrence – For at least 2 weeks  TREATMENT FOR DEPRESSION Psychotherapy Electroconvulsive therapy Natural alternatives Medication SSRIs SNRIs TCAs NDRIs MAOIs TeCAs  Clinical Indications Mood disorders Anxiety disorders Eating disorders Chronic pain Incontinence  NEUROTRANSMITTERS AND THE CATECHOLAMINE HYPOTHESIS Neurotransmitters pass along signal Smaller amount of neurotransmitters causes depression  THE RECEPTOR SENSITIVITY HYPOTHESIS Supersensitivity and up-regulation of post- synaptic receptors leads to depression Suicidal and depressed patients have increased pre-synaptic 5HT-1 and α2 receptors  THE RECEPTOR SENSITIVITY HYPOTHESIS [cause of LAG period] Chronic administration of antidepressants causes further biochemical changes in the sensitivity of both pre- and post-synaptic receptors. Pre-synaptic receptors: reduction in its sensitivity and down-regulation, e.g. pre-synaptic alpha 2 receptors, increase NE release. Post-synaptic receptors: down-regulation occur, e.g. post-synaptic alpha 1 and β1 receptors, increase NE action.  The therapeutic effect Time lag of 2 - 4 weeks before antidepressant effect occurs. Side effects & improved sleep occur earlier in 1st week (but Suicide risk). Follow-up your patient: 1st episode: Up to 1 year following recovery. Repeat episodes: Up to 3 years (Royal Australian and New Zealand College of Psychiatrists Clinical Practice Guidelines Team for Depression, 2004). Normal Stopping anti-depressants Mood too early can lead to RELAPSE Depression 2-4 weeks relief requiring depression treatment 1-3 weeks sex drive, self care, activity, memory 1st week anxiety sleep (but SUICIDE risk still present). Begin anti- depressant  Major and sub-classes of anti-depressants Based on 2 physiological actions: 1. Reuptake inhibition 2. Enzyme inhibition (Nash & Nutt, 2007).  Reuptake inhibitors Selective Serotonin Reuptake Inhibitors( SSRI) Selective Serotonin and Nor- Adrenaline Reuptake Inhibitors (SNRI) [venlafaxine, Desvenlafaxine, Duloxetine, Milnacipran] Tricyclic Antidepressants (TCAs) Nor-adrenaline Reuptake Inhibitor (NARI) [ Maprotiline, Amoxapine ]  Enzyme inhibitors The following antidepressant subclasses work by inhibiting the action of enzymes: Mono-Amine Oxidase Inhibitors type A (MAO-A) [Phenelzine, Tranylcypromine, Moclobemide] NE & 5-HT Mono-Amine Oxidase Inhibitors type B (MAO-B) [Seligiline] Dopamine  SSRIs 6 drugs are available Citalopram Escitalopram Fluoxetine Fluvoxamine Paroxetine Sertraline  SSRI’s Action 1.Normally serotonin, a brain neurotransmitter is released from a pre- synaptic nerve cell. 2.Serotonin is then received by the post- synaptic nerve cell. 3.Some serotonin is then re-uptaken into the pre- synaptic nerve cell via a serotonin transporter. 4.Not having enough serotonin may be associated with depression & anxiety disorders. SSRI’s block the re-uptake of serotonin into the pre-synaptic nerve cell. 5.This blocking action results in an increased amount of serotonin being available at the synapse. SSRI’s block reuptake of serotonin into presynaptic neurone (SET) Neurotransmitter Re-uptake pump Receptor MAO Dendrite Axon Synapse Presynaptic storage vesicles  Indications SSRIs Depression [1st drug of choice] Anxiety disorders [OCD, post-traumatic stress disorder, generalized anxiety disorder] Off label: Premature ejaculation Premenstrual Dysphoric Disorder Perimenopausal vasomotor symptoms Bulimia nervosa & Anorexia nervosa  Side-Effects: SSRI’s Common: 1. CNS: Nervousness & anxiety, insomnia (give dose in morning), drowsiness or fatigue. Some SSRIs can cause sedation as citalopram, fluvoxamine and paroxetine. 2. G.I.T: nausea & diarrhea, loss of appetite, weight loss [due to stimulation of 5-HT3 receptors in CNS and GIT]. 3. Sexual dysfunction: erectile dysfunction, retrograde ejaculation [due to over-stimulation of spinal 5-HT2 receptors].  Common Side Effects: SSRI Drug Daily Inso Sex Agit G.I.T Wt range mg mnia Dysf. ation gain SSRI's Citalopram 20 - 40 ++ +++ + ++ 0 Fluoxetine 20 - 40 ++ +++ ++ ++ 0 Fluvoxamine 100 - 200 ++ +++ ++ ++ 0 Paroxetine 20 - 40 ++ +++ = ++ + Sertraline 50 - 100 ++ +++ ++ ++ 0 Fluoxetine & paroxetine are potent inhibitors to CYP2D6 which mediates metabolism of TCAs, some antiarrhythmic and neuroleptics. Fluvoxamine is inhibitor CYP3A4  Less common side effects Apathy Extrapyramidal side effects (EPSEs) Increased prolactin levels Serotonin syndrome Hyponatraemia Bruising and bleeding Increased risk of gastrointestinal bleeding (Loke, Trivedi, & Singh, 2008). Clinical response SSRI’s produce a clinical response much more rapidly than tricyclic anti- depressants. True or False?  Serotonin syndrome [High doses SSRIs or combination with TCAs or MAOIs] Symptoms: rigidity, hyperthermia, confusion and autonomic instability. Prevention: do not co-administer SSRI’s and other drugs that increase serotonin. Drug free interval before changing from SSRI to other serotonin drugs.  Antidepressant Abrupt discontinuation syndrome Symptoms F = flu like symptoms I = insomnia N = nausea I = imbalance [dizziness] S = sensory disturbances [paresthesias] H = hyperarousal [anxiety, agitation, dysphoria] (Gelenberg, 1998 cited in Carson, 2000, p. 432)  Advantages SSRI’s Minimal cardiac toxicity No anticholinergic side effects Safe in overdose (wide therapeutic index) Mild side effects (better tolerated) Non sedating SSRI’s reduce overall suicide rates in depressed patients significantly more than tricyclic antidepressants. True or False? Tricyclic antidepressants:TCA’s H1 NET α1 M1 Axon Dendrite SET α1 Dendrite Tricyclics block reuptake of both noradrenaline & serotonin into presynaptic neurone (SET & NET).  TCAs Action: 4 actions 1. Block presynaptic noradrenaline reuptake pump (black lines). 2. Block presynaptic serotonin reuptake pump (red lines). 3. Block histamine H1 receptors (yellow square) = Sedative side effects. 4. Block post synaptic acetylcholine M1 receptors (grey square) = Dry mouth, confusion, memory impairments, blurred vision. 5. Block post synaptic alpha 1 receptors = orthostatic hypotension. 6. Quinidine-like actions = life-threatening arrhythmias (Torsades de points), bradycardia & hypotension. This blocking action results in an increased amount of nor-epinephrine & serotonin being available to the post synaptic neuron.  Tricyclics available Amitriptyline Clomipramine Doxepin Imipramine/Desimipramine Nortriptyline  Indications Depression [moderate to severe endogenous depression] Panic disorder Neuralgia (nerve pain) - best available evidence is for amitriptyline (Saarto & Wiffen, 2007) Nocturnal enuresis ---- imipramine ADHD ---- imipramine  Side Effects: TCA’s Common Sedation (give dose at night) Dry mouth Blurred vision Weight gain Constipation Urinary retention. Palpitation & tachycardia  TCA Serious & life-threatening side effects Postural hypotension & bradycardia Life-threatening arrhythmias Sexual dysfunction Raised intra-ocular pressure and aggravation of narrow-angle glaucoma. Lower threshold for seizures. Physical dependence Low therapeutic index ---- can be used to commit suicide by depressed patients.  Selective Serotonin and Nor- Adrenaline Reuptake Inhibitors (SNRI) Venlafaxine Low doses inhibits serotonin (- SET) Medium dose inhibits nor-adrenaline (- NET) High dose inhibits dopamine Don’t block multi-receptors, so they have better side effect profile than TCAs. Wide therapeutic index – tolerability similar to SSRIs Immediate release formulations of venlafaxine can cause elevation in systolic B.P. > 90mmHg. Monitor for elevated blood pressure & cardiotoxicity on high doses ADRs: SAME as SSRIs GIT CNS Sexual  Tetracyclics and Unicyclics: Mirtazapine, Mianserin, Bupropione, maprotiline, amoxapine, vilazodone, quetiapine Act by inhibiting NE and serotonin reuptake. Additional mechanism Also they enhance the pre-synaptic release of neurotransmitters through antagonizing their pre-synaptic inhibitory autoreceptors alpha 2 and 5HT-1 The best alternative to treat depression after SSRIs and SNRIs. Miancerin and Mirtazapine have potent H1 antagonistic action (used for depression with insomnia ---- sedative action).  New antidepressants Bupropion A non-selective inhibitor of DAT & NET. A more significant effect of bupropion is presynaptic release of catecholamines. In animal studies, bupropion appears to substantially increase the presynaptic availability of norepinephrine, and dopamine to a lesser extent. Bupropion has no direct effects on the serotonin system. Also is antagonist to neuronal nicotinic Ach receptors. Effective in treatment of depression & tobacco use cessation agent [attenuates the expression of nicotine withdrawal symptoms in animals and humans]. Still in clinical trials to be used in ADHD & obesity.  Nor-adrenaline Reuptake Inhibitor (NARI) Reboxetine, Maprotiline, Amoxapine Have anticholinergic side effects Reasonable tolerability – side effects similar to TCAs rarely, seizures. Amoxapine is associated with a parkinsonian syndrome and anti-psychotic actions due to D2-blocking action.  Enzyme inhibitors Mono-Amine Oxidase Inhibitors (MAOI) – The first antidepressants discovered Alternative mechanism for increasing synaptic availability of monoamines. MAOI prevent intracellular destruction of monoamines by MAO. MAOI’s available: Phenelzine Tranylcypromine Moclobemide  Reversibility in MAO inhibition Drug MAO inhibition Uses Phenelzine Irreversible MAO-A + MAO-B Used as antidepressant, Hepatotoxicity, Needs dietary control for restriction of tyramine intake Tranylcypromine Irreversible MAO-A + MAO-B Used as antidepressant with dietary control Selegiline Irreversible MAO-B selective. Used as antiparkinsonian. In Selectivity is dose dependent in high doses as antidepressant vivo Moclobemide Reversible highly MAO-A Moderately effective selective antidepressant drug MAOIs prevent intracellular destruction of monoamines by MAO Neurotransmitter Re-uptake pump Receptor MAO Dendrite Axon Synapse Presynaptic storage vesicles  Side Effects: MAOI’s Common: as for TCA’s, plus agitation/excess stimulation. Rare but serious: Hypertensive crisis caused by ingesting tryramine containing foods or a drug interaction (cough & cold remedies, nasal drops & sprays). Treated by I.V. phentolamine or nitroprusside.  MAOI: Diet Avoid tyramine containing foods (often in foods requiring aging): matured cheeses, aged meats, smoked or pickled fish, liver, banana.  MAOI: Diet Limited quantity: raspberries, avocado, soy sauce, commercial soups, coffee substitutes, wine, port, beer, chocolate.  Reversible Inhibitors of Mono- Amine Oxidase type A RIMAs more selective than older MAOIs Do not cause serious dietary and drug interactions (except at high doses). Have greater safety & tolerability compared to other MAOIs but are not as effective in treatment resistant depression. RIMA available Moclobemide - Not effective for OCD