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- 1. Antidepressant and antimanic drugs Dr.Denis Leboso
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- 3. Classification of depression Generallyclassified as: • Major depression (unipolar depression) • Bipolar depression (manic- depressive illness);
- 4. Depression • It isa mental illnesses characterized by pathological changes in mood, loss of interest or pleasure, feelings of guilt or low self-worth, disturbed sleep or appetite, low energy and poor concentration.
- 5. Bipolar disorder • Inbipolar disorder patients go through episodes of an elevated or agitated mood known as mania alternating with episodes of depression. • Patients suffer episodes of mania, hypomania & depression , classically with period of normal mood in between.
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- 9. Symptoms of depression Depressiveepisodes are characterized by: • depressed or sad mood • pessimistic worry • diminished interest in normal activities • mental slowing and poor concentration • insomnia or increased sleep • significant weight loss or gain due to altered eating and activity patterns, • psychomotor agitation or retardation • feelings of guilt and worthlessness • decreased energy and libido • suicidal ideation, occurring most days for a period of at least 2 weeks
- 10. Etiology • The specificcause of major depressive disorder is not known. • As with most psychiatric disorders, major depressive disorder appears to be a multifactorial and heterogeneous group of disorders involving both genetic and environmental factors.
- 11. Etiology • Depressive symptomsalso can occur secondary to other illnesses such as hypothyroidism, Parkinson’s disease and inflammatory conditions.
- 12. Biogenic amine theoryof depression and mania • Proposes that depression is due to a deficiency of monoamines such as norepinephrine and serotonin, at certain sites in the brain. • Mania is caused by an overproduction of these neurotransmitters.
- 13. Biogenic amine theory •The amine theory of depression and mania is too fails to explain why the pharmacologic effects of antidepressant and anti-mania drugs on neurotransmission occur immediately, whereas therapeutic response occurs after several weeks.
- 14. Antidepressant drugs • Inmonoamine systems, reuptake of the transmitter is the main mechanism by which neurotransmission is terminated. • Inhibition of reuptake can enhance neurotransmission, presumably by slowing clearance of the transmitter from the synapse and prolonging the ‘dwelling- time’ of the transmitter in the synapse. • All drugs commonly used to treat depression share, at some level, primary effects on serotonergic or noradrenergic neurotransmitter Systems. • In general, antidepressants enhance serotonergic or noradrenergic transmission.
- 15. Antidepressant drugs • Selectiveserotonin reuptake inhibitors (SSRI) • Serotonin norepinephrine reuptake inhibitors (SNRI) • Tricyclic antidepressants (TCAs) • Monoamine oxidase inhibitors (MOAIs) • Atypical antidepressants
- 16. Other antidepressant drugs(atypical antidepressants) • Atomoxetine • Bupropion • Mirtazapine • Nefazodone • Reboxetine • Trazodone
- 18. Selective Serotonin ReuptakeInhibitors • Examples: fluoxetine, paroxetine, sertraline, escitalopram and fluvoxamine. citalopram, • MOA: Selectively inhibits the reuptake of serotonin from the synapse thus enhancing and prolonging serotonergic transmission.
- 19. SSRIs • Antidepressants, includingSSRIs, take at least 2 weeks to produce significant improvement in mood. • Maximum benefit may require ≥12 weeks. • Do not usually produce CNS stimulation or mood elevation in normal individuals.
- 20. Therapeutic uses ofSSRIs • Depression • Obsessive Compulsive Disorder • Panic disorder • Generalised Anxiety Disorder • Post-traumatic Stress Disoder • Social anxiety disorder • Premenstrual dysphoric disorder • Bulimia nervosa (only fluoxetine is approved)
- 21. PKs • All ofthe SSRIs are well absorbed after oral administration. • Peak levels are seen in ~2-8 hours. • Food has little effect on absorption except with sertraline (food increases its absorption). • T1/2 is between 16-36 hours. Fluoxetine t1/2 is about 50 hours, t1/2 of its active metabolite ~ 10 days. • Fluoxetine is also available as a sustained-release preparation allowing once-weekly dosing . • Metabolism by CYP450 enzymes and glucuronide or sulfate conjugation. • Dosages should be reduced in patients with hepatic impairment.
- 22. Adverse effects • Headache •Sweating • Anxiety and agitation • GI effects (nausea, vomiting and diarrhea) • Weakness and fatigue • Sexual dysfunction • Changes in weight • Sleep disturbances (insomnia and somnolence) • Paroxetine and fluvoxamine are more sedating • Fluoxetine or sertraline are more activating SSRIs
- 23. ADRs • Overdose: Largedoses of SSRIs do not usually cause cardiac arrhythmias (compared to the arrhythmia risk for the TCAs). An exception is citalopram, which may cause QT prolongation. • Seizures can occur in over dose. • All SSRIs have the potential to cause serotonin syndrome when used in the presence of a MAOI or other highly serotonergic drug. • Serotonin syndrome include the symptoms of hyperthermia, muscle rigidity, sweating, myoclonus, changes in mental status and vital signs.
- 24. Withdrawal syndrome (discontinuationsyndrome) • All of the SSRIs have the potential to cause withdrawal syndrome after abrupt discontinuation. • Fluoxetine has the lowest risk of causing an SSRI discontinuation. • Signs and symptoms of SSRIs withdrawal syndrome include: headache, malaise, flu-like symptoms, agitation and irritability, nervousness, and changes in sleep pattern.
- 25. Serotonin- Norepinephrine ReuptakeInhibitors • Duloxetine • Venlafaxine, • Desvenlafaxine • Levomilnacipran
- 26. Mechanism of actionof SNRIs • Inhibit the reuptake of both serotonin and norepinephrine. • May be effective in treating depression in patients where SSRI are ineffective.
- 28. SNRIs • Effective againstchronic painful symptoms, such as backache and muscle aches, against which SSRIs are relatively ineffective. • This pain is modulated by serotonin and norepinephrine pathways in the CNS. • Both SNRIs and TCAs, with their dual actions of inhibiting both serotonin and norepinephrine reuptake, are sometimes effective in relieving physical symptoms of neuropathic pain such as diabetic peripheral neuropathy.
- 29. Discontinuation syndrome (withdrawal syndrome) •SNRI precipitate a discontinuation syndrome if treatment is abruptly stopped.
- 30. Venlafaxine and Desvenlafaxine Venlafaxine •A potent inhibitor of serotonin reuptake and, at medium to higher doses, is an inhibitor of norepinephrine reuptake. Desvenlafaxine • Active metabolite of the parent compound venlafaxine. • No significantly different clinical or adverse effects than venlafaxine. ADRs of venlafaxine and desvenlafaxine • Nausea, headache, sedation, dizziness, insomnia • Sexual dysfunction • Constipation
- 31. Doluxetine • Inhibits serotoninand norepinephrine reuptake at all doses. • Extensively .metabolized in the liver, should not be administered to patients with hepatic insufficiency • Metabolites are excreted in the urine and the use of duloxetine is not recommended in patients with end-stage renal disease. Adverse effects • Nausea • Dry mouth • Constipation • Insomnia • Sexual dysfunction • Risk for an increase in either blood pressure or heart rate NB: Duloxetine inhibits CYP2D6 and CYP3A4 (CYP450 inhibitor).
- 32. Tricyclic Antidepressants imipramine, clomipramine, trimipramine,amoxapine, • Examples: amitriptyline, nortriptylline, desipramine, trimipramine, maprotiline, protriptyline, doxepin. • MOA: inhibit reuptake of both noradrenaline and serotonin into the presynaptic membrane. • These drugs block both serotonin reuptake transporter (SERT) and norepinephrine transporter (NET).
- 33. TCAs • TCAs havea long record of efficacy in the treatment of depression and have the advantage of lower cost. • They are used less commonly because of the need to titrate the dose to a therapeutic level and because of their considerable toxicity in overdose. • TCAs are often prescribed for many other psychiatric disorders, such as generalized anxiety disorder and post-traumatic stress disorder. • They are also used to treat chronic pain, such as neuropathy and migraine headaches.
- 34. Actions • Elevate mood,improve mental alertness, increase physical activity and reduce morbid preoccupation in 50-70% of individuals with major depression. • The onset of the mood elevation is slow taking ≥ 2 weeks. • No CNS stimulation or mood elevation in normal individuals. • Physical and psychological dependence is rare. • Slow withdrawal to minimize discontinuation syndromes and cholinergic rebound effects. • Can be used for prolonged treatment of depression.
- 35. Other actions ofTCAs TCAs also block: • α-adrenergic receptors • Histaminic receptors • muscarinic receptors • Binding to these receptors contribute to many of adverse effects of the TCAs.
- 36. Therapeutic uses • Effectivein treating moderate to severe depression. • Some patients with panic disorder also respond to TCAs. • Imipramine has been used to control bed-wetting in children (older than age 6 years) by causing contraction of the internal sphincter of the bladder. • The TCAs, particularly amitriptyline, are used in migraine headache prophylaxis and management of chronic pain syndromes (for example, neuropathic pain) in a number of conditions for which the cause of the pain is unclear. • Low doses of TCAs, especially doxepin, can be used to treat insomnia. • Treatment of anxiety disorders.
- 37. Adverse effects ofTCAs • Blockade of muscarinic receptors leads to: blurred vision, xerostomia (dry mouth), urinary retention, sinus tachycardia and constipation. • Affect cardiac conduction which may precipitate life-threatening arrhythmias in overdose. • Block α-adrenergic receptors, causing orthostatic hypotension, dizziness, and reflex tachycardia (Imipramine is the most likely, and nortriptyline the least likely, to cause orthostatic hypotension) • Sedation, especially during the first weeks of treatment due to blockade of histamine H1 receptors. • Weight gain • Sexual dysfunction
- 38. Precautions • TCAs andall antidepressants should be used with caution in bipolar disorder because antidepressants may cause a switch to manic behavior. • The TCAs have a narrow therapeutic index, suicidal patients should be given only limited quantities of these drugs and be monitored closely. • The TCAs may exacerbate certain medical conditions, such as unstable angina, benign prostatic hyperplasia, epilepsy and preexisting arrhythmias.
- 39. Monoamine Oxidase Inhibitors •Were the first class of drugs with antidepressant effects. • Examples: phenelzine, isocarboxazid, tranylcypromine and moclobemide, Selegiline. • Selegiline inhibit MAO-A at higher doses, allowing to be used for the treatment of depression. • Inhibit monoamine oxidase enzyme from metabolizing endogenous monamines (serotonin, noradrenaline and dopamine). • The drugs above are both MAO-A and MAO-B inhibitors except moclobemide, which is selective for MAO-A.
- 40. MAOIs • MAO breaksdown serotonin and norepinephrine and dopamine. • MAO-A shows noradrenaline tyramine. hydroxylated amines greater affinity for (NA), serotonin (5-hydroxytryptamine, 5-HT) such as and • MAO-B shows greater affinity for non-hydroxylated amines such as benzylamine and beta-phenylethylamine (PEA). • The amine dopamine (DA) show affinity for both enzyme forms.
- 41. Mechanism of action •Most MAOIs form stable complexes with MAO causing irreversible inactivation. • This results in increased stores of norepinephrine, serotonin and dopamine within the neuron and diffusion of excess neurotransmitter into the synaptic space.
- 42. MAOIs • These drugsalso inhibit MAO in the liver and gut that catalyze oxidative deamination of drugs and potentially toxic substances, such as tyramine, which is found in certain foods causing a high incidence of drug-drug and drug-food interactions. • Selegiline may produce less inhibition of gut and hepatic MAO.
- 43. Actions of MAOIs •The antidepressant action of the MAOIs, like that of the SSRIs and TCAs, is delayed for several weeks. • Selegiline and tranylcypromine have an amphetamine- like stimulant effect that may produce agitation or insomnia .
- 44. Therapeutic uses • Indicatedfor depressed patients who are unresponsive or allergic to TCAs or who experience strong anxiety. • Treatment of phobic states • Treatment of atypical depression (labile mood, rejection sensitivity and appetite disorders).
- 45. NOTE • MAOIs areconsidered to be last-line agents in treatment because of their risk for drug-drug and drug-food interactions. • Enzyme regeneration when irreversibly inactivated occurs several weeks after termination of the drug, when switching antidepressant agents. • A minimum of 2 weeks of delay must be allowed after termination of MAOI therapy and the initiation of another antidepressant.
- 46. ADRs • MOAIs arenot considered first-line treatment for depression because of the side effects, drug-drug interactions and dietary restrictions. • Common adverse effects include hypotension, dizziness, dry mouth, gastrointestinal upset, urinary hesitancy, headache and myoclonic jerks. • Because of the risk of hypertensive crisis with drugs that specifically inhibit MAO- A in the gastrointestinal tract, patients on these medications must follow a low-tyramine diet.
- 47. Drug interactions • Severeside effects, due to drug-food and drug-drug interactions. • Tyramine found in aged cheeses, meats, chicken liver, pickled or smoked fish, red wines, is inactivated by MAO in the gut. • Individuals receiving a MAOI are unable to degrade tyramine causing the release of large amounts of stored catecholamines from nerve terminals, resulting in “hypertensive crisis,” (headache, stiff neck, tachycardia, nausea, hypertension, cardiac arrhythmias, seizures, stroke)…..read about ‘cheese reaction.’ - Patients must be educated to avoid tyramine-containing foods - Phentolamine and prazosin are helpful in the management of tyramine-induced hypertension
- 48. Drug Interactions • MAOIsand SSRIs should not be coadministered due to the risk of the life- threatening “serotonin syndrome.” -Both types of drugs require washout periods of at least 2 weeks before the other type is administered. -Fluoxetine should be discontinued at least 6 weeks before a MAOI is initiated. • Combination of MAOIs and bupropion can produce seizures.
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- 50. Mania • Mania ischaracterized by enthusiasm, rapid thought and speech pattern, extreme self confidence and impaired judgment. • It is characterized by excessive desire & too much of euphoria. • Majority of the patients of mania also experience cyclic episodes of mania followed by depression (Bipolar manic depressive psychosis).
- 51. Drugs used inMania and bipolar disorder – Mood Stabilizers • Lithium Carbonate Alternative Drugs: • Carbamazepine • Sodium Valproate • Lamotrigine • Topiramate • Atypical anyipsychotics – Olanzapine, risperidone, aripiprazole and Quetiapine
- 52. Lithium • Used assalt: lithium carbonate • Lithium salts are used prophylactically for treating manic-depressive patients (bipolar disorder) and in the treatment of acute manic episodes. • Considered “mood stabilizer” • Effective in patients with mania and hypomania. • Safety factor and therapeutic index are extremely low. • Li has no effects on persons without mania.
- 53. Li and otherelectrolytes • Li is the lightest of the alkali metal atoms. • Na+ and K+ are important in this family. • Li partly replaces Na+ and distributes evenly in extracellular and intracellular fluids (contrast to Na+ and K+). • Affects ionic fluxes across brain cells or modify property of cell membranes. • However, conc. of Li in comparison to Na+ and K+ is very low.
- 54. MOA • Reduces theformation of inositol triphosphate (IP3) by inhibiting inositol monophospahatase, an enzyme in the inositol phosphate pathway. • IP3 is an important second messenger involved in neurotransmitter signal transduction.
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- 56. MAO • Li hasalso been reported to decrease the presynaptic NA and DA release in the brain (animal studies) – no affect on 5-HT release.
- 57. PKs • Well absorbedorally. • Not metabolized and not protein bound. • Lithium enters cells about as readily as sodium but does not leave as readily(mechanism uncertain). • Li is actively reabsorbed from proximal tubule in the kidney similar to Na+ • When Na+ is restricted larger portion of Na+ is reabsorbed - similar is in case of Li • Steady state is attained in 5-7 days in patients with normal renal function. • Only kidney eliminate lithium. • Half life – 15-30 hrs.
- 58. Li and monitoring •Individual variation in the rate of excretion. • Narrow margin of safety – monitoring • Monitoring serum Li concentration is essential for optimal therapy & measured 12 hr after last dose to reflect steady concentration. • Salivary concentration is propionate to serum concentration may be used to non invasive monitoring. • Excreted in sweat, saliva, breast milk etc. • Available as 300 and 400 mg tablets.
- 59. Lithium • Measurement isdone 12 Hrs after the last dose - steady state (0.5 to 0.8 mEq/L for maintenance) - 0.8 to 1.1 mEq/L for acute attack • Toxicity above 1.5 mEq/L • Dosing is usually in divided doses 2 -3 times of a tablet
- 60. Adverse effects • Headache,dry mouth • Polydipsia (excessive thirst), polyuria, polyphagia(excessive eating) • GI distress e.g. N, V, D (give lithium with food) • Tremor • Dizziness • Fatigue • Dermatologic reactions • Sedation • Convulsions (At higher doses) • Diabetes insipidus that results from taking lithium can be treated with amiloride. • Thyroid function may be decreased and should be monitored. • Lithium causes no noticeable effect on normal individuals.
- 61. Contraindications • Pregnancy, mayproduce foetal goiter & other cardiac abnormality • Renal or cardiovascular disease • Sodium depletion • Dehydration • Patients on diuretics • Lactation
- 62. Drug interactions • Diuretics(osmotic diuretics and carbonynic anhydrases) increases Li clearance. • Li tends to enhance insulin / sulfonylurea induced hypoglycemia. • Neuroleptics, Phenothiazines & Butyrophenone combination, produces marked tremor & rigidity. • Aspirin and other NSAID’S reduces renal clearance of Li+. • Li+ paradoxically potentiates succinylcholine or d-tubocurarine induced muscle relaxation
- 63. Other drugs formania and bipolar disorder • Several antiepileptic drugs like carbamazepine, valproic acid, and lamotrigine, have been approved as mood stabilizers and are used in the treatment of bipolar disorder. • Valproic acid is also indicated in the treatment and prevention of acute mania. • The atypical antipsychotics (risperidone, olanzapine, aripiprazole, and quetiapine)- bipolar disorder. • Benzodiazepines are also frequently used as adjunctive treatments for the acute stabilization of patients with mania.