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PHL 322

PHL 322. ANTIDEPRESSANTS AND MOOD STABILIZING DRUGS Dr. Mohamed M. Sayed -Ahmed. Introduction. Depression. " Depression " is a very common psychiatric disorder that is related to the " mood " (affective disorder). Changes in mood are associated with depression and/or mania.

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PHL 322

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  1. PHL 322 ANTIDEPRESSANTS AND MOOD STABILIZING DRUGS Dr. Mohamed M. Sayed-Ahmed

  2. Introduction

  3. Depression "Depression" is a very common psychiatric disorder that is related to the "mood" (affective disorder). • Changes in mood are associated with depression and/or mania. • Disorders of mood rather than disturbance in thought or cognition. • Clinical depression: feeling sad for more than two weeks.

  4. Symptoms of Depression 1- Emotional Symptoms • Intense feelings of sadness, hopelessness and despair • Inability to experience ordinary pressure or to cope with ordinary life events • Feeling of guilt and ugliness • Indecisiveness and loss of motivation • Loss of energy and interest

  5. 2- Biological symptoms 1- Retardation of thought and action 2- Loss of libido 3- Loss of appetite and sleep disturbance *** DEPRESSION IS THE MOST COMMON CAUSE OF SUICIDE

  6. Symptoms of "mania" are exactly the opposite: •Happy, excited, euphoric , self-confidence, lack of judgment • Sudden odd decisions that are mostly of disastrous consequences •Excessive rapid talking , moving quickly from one to another (Flight of ideas) •Hyperactive & full of energy, unable or unwilling to sleep •Sudden irritability, rage or paranoia •Impatience,Aggression

  7. Classification of Depression A) According to severity of symptoms: 1. Mild depression---------self-limiting 2. Moderate depression -------difficulties at home and work 3. Severe depression --------serious, associated with suicidal thoughts

  8. B) According to type 1- Unipolar depression (major depression): • mood swings are always in the same direction • about 75% of cases non-familial • accompanied by symptoms of anxiety and agitation • Associated with stressful life events • 25% familial • unrelated to external stresses • endogenous depression 2- Bipolar depression (manic-depressive): • in which depression alternates with mania • enthusiasm and self-confidence, accompanied by impulsive actions

  9. The patient swings between "mania" and "depression“ (manic-depressive illness) - It is mainly hereditary and appears in early adult life. - Alternating depression and mania

  10. 3- Other forms of depression • Psychotic depression • Postpartum depression • Atypical depression What are the possible mechanisms of depression? • Depression is associated with insufficient central release of NA and 5-HT • Led to development of the Biogenic Amine Hypothesis

  11. The Monoamine Theory of Depression • Proposed in 1965 and states that DEPRESSIONis caused by a functional deficit of Monoamine transmitter at certain sites in the brain,while MANIA results from functional excess. • The Theory is based on the ability of known antidepressat drugs (TCAs and MAOIs) to facilitate monoaminergic transmission and of drugs as Reserpine to cause depression.

  12. Pharmacological evidence supporting The Monoamine Theory of Depression

  13. Monoamine nerves: Neurotransmission

  14. Normal synapse, no depression.

  15. Neurotransmitter deficiency lead to Depression

  16. 5-HT deficiency may cause the sleep problems, irritability and anxiety associated with depression Decreased level of NE, which regulates mood, alertness, arousal, appetite, reward & drives, may contribute to the fatigue and depressed mood of the illness However, dopamine is important for pleasure, sex & psychomotor activity

  17. Treatment of Depression 1. Psychological treatment 2. Pharmacological treatment 70 % of depressed patients respond to antidepressants 3. ECT ( electroconvulsive therapy) for very severe depression, which has not responded to other treatments or for patients who cannot take antidepressants

  18. Pharmacotherapy

  19. Sites of Action for Antidepressants 1- Monoamine (NE or/ and 5-HT) re-uptake pump inhibitors 2- Blockade of pre-synaptic a2 receptors 3- Inhibition of MAO enzyme

  20. Antidepressants • Antidepressants do not act immediately (show clinical effects after 2 weeks) indicating that secondary adaptive changes in the brain are important. • The most consistent adaptive change seen with antidepressant drugs is the downregulation of beta-, alpa-2 and 5-HT2 receptors. Alpha-1 is not affected. • Affect only people who are depressed. • Effect does not increase with increasing doses. • Antidepressants are not habit-forming. • Antidepressants differ widely in side effects.

  21. Classification of Antidepressants 1) Tricyclics (TCAs) and Tetracyclics Imipramine Doxepin DesipramineAmoxapineTrimipramine Maprotiline Clomipramine Amitriptyline NortriptylineProtriptyline 2) Monoamine Oxidase Inhibitors (MAOIs) TranylcypraminePhenelzineMoclobemide 3) Selective Serotonin Reuptake Inhibitors (SSRIs) Fluoxetine Fluvoxamine Citalopram Sertraline Paroxetine Escitralopram

  22. Classification of Antidepressants 4) Serotonin and Norepinephrine Reuptake Inhibitor (SNRI) Venlafaxine Duloxetine 5) Serotonin-2 Antogonist and Reuptake Inhibitors (SARIs) NefazodoneTrazodone 6) Norepinephrine and Dopamine Reuptake Inhibitor (NDRI) Bupropion 7) Noradrenergic and Specific Serotonergic Antidepressant (NaSSAs) Mirtazapine 8) Noradrenaline Reuptake Inhibitor (NRI) Reboxetine 9) Serotonin Reuptake Enhancer Tianeptine

  23. TRICYCLIC ANTIDEPRESSANTS (TCAs) • TCAs are the oldest class of antidepressant drugs • They have characteristic three-ring nucleus • The first TCAs discovered was Imipramine Imipramine (Tofranil)

  24. TRICYCLIC ANTIDEPRESSANTS (TCAs) Imipramine Desipramine Clomipramine Amitriptyline Nortriptyline Doxepin Trimipramine TETRACYCLIC ANTIDEPRESSANTS Maprotiline Amoxapine

  25. MECHANISM OF ACTION of TCAs: • All tricyclics block reuptake pumps for both 5HT and NE in nerve terminals by competing for binding site of the transport protein • So ↑ conc. of NE & serotonin in the synaptic cleft & at the receptor site • Facilitation of NE & serotonin transmission ---- improves symptoms of depression • Some have more potency for inhibition of 5HT uptake pump; clomipramine, imipramine, amitryptyline •Others have more potency for inhibition of NE uptake pump: nortriptyline, desipramine .

  26. Blocking of receptors TCAs also block : Serotonergic receptors Alpha adrenergic receptors Histaminic receptors Muscarinic receptors Their role in therapeutic benefit is not known These actions produce the adverse effects MOA of TCAs

  27. PHARMACOLOGICAL ACTIONS 1- Elevate mood 2- Improve mental alertness 3- Increase physical activity # The antidepressant effect may develop after several weeks of continued treatment ( 2 - 3 weeks) 4- In non-depressed patients They cause sedation, confusion & motor incoordination

  28. PHARMACOLOGICAL ACTIONS The reuptake block occurs quickly but antidepressant effect develops after weeks. Amine reuptake block by tricyclics initiates a series of time-dependent changes that culminate in antidepressant effect. Certain adaptive changes occur in receptors.

  29. Receptor changes Initially presynaptic α2 & 5HT1 receptors are activated Later on desensitized / down regulated Other adaptive changes also occur Net effect is enhanced NE & serotonin transmission

  30. PHARMACOKINETICS of TCAs • Peak levels: 2-6 hours post ingestion • TCAs are "lipophilic" in nature, therefore they are well absorbed from the GIT and readily cross the blood brain barrier to penetrate the CNS. • Elimination: hepatic oxidation • TCAs are metabolized in the liver by demethylation (ImipraminetoDesipramine, AmitriptylinetoNortriptyline) and by hydroxylation into metabolites that retain the biological activity of the parent compounds.

  31. PHARMACOKINETICS of TCAs • TCAs are strongly bound to plasma proteins. • Average t1/2: 24 hours Up to 72 hours in overdose • Large T1/2 and large VD because TCA extensively bound to plasma protein (90-95 %)

  32. Therapeutic uses of TCAs Endogenous (Major) Depression -- moderate to severe. Panic attack /acute episode of anxiety. Imipramine is used for treatment of nocturnal enuresis in children and geriatric patients as it constricts internal urethral sphincter ( anti-muscarinic effect). Generalized Anxiety Disorder (GAD). Obsessive Compulsive Disorder (OCD) Attention Deficit Hyperkinetic Disorder (ADHD). Chronic neuropathic pains or Unexplained body pains.

  33. Side Effects of TCAs TCAs block: - α1 adrenergic receptors - H1 histamines receptors - M1 cholinergic receptors - 5HT2 receptors

  34. Side Effects of TCAs

  35. Side Effects of TCAs

  36. Side effects of TCAs • Four major toxic effects (A, C, S, D) A = Anticholinergic C = Cardiovascular S = Seizures D = Death

  37. ANTICHOLINERGIC EFFECTS • Sedation, Delirium, coma • Tachycardia • Mydriasis • Dry mucous membranes and skin • Dry mouth • Decreased or absent bowel sounds • Constipation • Urinary retention

  38. CARDIOVSCULAR EFFECTS 1- Inhibit neuronal catecholeamines reuptake leading to Cardiac arrhythmias 2- Inhibit alpha-adrenergic receptors induces vasodilatation & PosturalHypotension 3- Membrane Depressant (quinidine like) effects cause myocardial depression and cardiac conduction disturbance due to: * Sodium channel blockade * Potassium channel blockade

  39. SEIZURES * Seizures occur as a result of inhibition of reuptake of Norepinepherine and serotonin in the brain. • TCAs lower the seizure threshold. • The muscular hyperactivity from seizures combined with decreased sweating can lead to severe HYPERTHERMIA.

  40. Death Sudden Death Occurs from: 1- Ventricular fibrillation 2- Status Epilepticus 3- Hyperthermia

  41. Interaction of TCA with other drugs • TCA are strongly bound to plasma protein, therefore their effect can be potentiated by drugs that compete for their plasma protein binding site ( Aspirin and Phenylbutazone). • TCAs are metabolized by liver microsomal enzymes, therefore their effect can be reduced by inducers of liver microsomal enzymes (Barbiturates), or potentiated by inhibitors of liver microsomal enzymes (Oral contraceptives, Antipsychotics, and SSRIs). • TCA (inhibitors of monoamine reuptake) should not be given with MAOIs (inhibitors of monoamine degradation)"hypertensive crisis".

  42. Contraindications • TCAs should not be used in patients with Glaucoma or with enlarged prostate because of their atropine-like action. • TCAs(given alone) are contraindicated in manic-depressive illness, because they tend to "switch" the depressed patient to the "manic" phase, therefore, they should be combined with "lithium salts".

  43. Monoamine Oxidase Inhibitors • Amongst the first Antidepressants • Include: - Phenelzine - Tranylcypromine - Isocarboxazid - Moclobemide - Pargyline • Onset of antidepressant effect is delayed for 2-4 weeks.

  44. Monoamine Oxidase • MAO is found in nearly all tissues and is located intracellularly associated with mitochondria. • Present in nerve terminals that release NA, DA or 5-HT. • Located on outer surface of mitochondrial membranes. • In neurons, MAOoxidativelydeaminates and inactivates any excess norepinephrine, serotonin and dopamine, that may leak out of synapsticvesicles. • MAO is not involved in the inactivation of released transmitter

  45. Monoamine Oxidase Inhibitors (MAOIs)

  46. MAO Enzyme MAO exists in tow forms coded by separate genes • MAO-A:Metabolizes norepinephrine, serotonin and tyramine. Inhibition of MAO-A produces Antidepressant effect . • MAO-B: specific for dopamine. Inhibition of MAO-B produces Anti-parkinsonianeffect.

  47. Monoamine Oxidase Inhibitors (MAOIs) 1- Irreversible and nonselective MAOIs (Classic MAOI) • Phenelzine • Tanylcypromine • Isocarboxazid • pargyline - Can not distinguish between the two isoenzymes - MAO-A and B enzyme activity can not be restored unless new enzyme is synthesized, therefore the effect of MAOIs persists for a period of 2-3 weeks after stopping treatment, where a new (fresh) enzyme has to be synthesized

  48. 2-Reversible and selective inhibitors of MAO-A: - Moclobemide (antidepressant action, Short acting) 3-Selective inhibitor of MAO-B: - Deprenyl (neurodegenerative disorder) - Selegiline (used in the treatment of Parkinsonism)

  49. Side Effects of MAOIs 1- Hypotension:After MAO inhibition, other amines such as dopamine are able to accumulate in peripheral sympathetic nerve terminals and displace vesicular NA, thus reducing NA release and sympathetic activity (sympathetic block). 2- Antimuscarinic effects (atropine-like side-effects): Dry mouth blurred vision Urinary retention

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