Antidepressant drugs .pptx (needs completion )

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1. Antidepressant Drugs Dr . Dipu Kumar Verma JR PHARMACOLOGY (MD) GGSMCH FARIDKOT

2. WHAT IS DEPRESSION ? EPIDEMIOLOGY PATHOPHYSIOLOGY (THEORIES) SIGN & SYMPTOMS DIAGNOSIS TYPES OF DEPRESSION TREATMENT :- VARIOUS GROUPS OF DRUGS (SSRI SNRI tCA MAO-I(A/B) ATYPICAL ANTIDEPRESSANTS OTHER TREATMENT ,NON PHARMACOLOGICAL ,ECT MANIA ,BIPOLAR DISORDERS & ITS TREATMENT CONTENT OF TOPICS UNDER FOLLOWING HEADING

3. What is depression ? MOOD DISORDER other name major depressive disorder/Unipolar disorder Most common psychiatric illness [ india /world wide] Anxiety Most common psychiatric illness in medical illness – depression Due to low level of mono amines Neurotransmitters SEROTONINE, NOR ADRENALINE,DOPAMINE On the other hand schizophrenia is a disease of Thought Disorder

4. EPIDEMIOLOGY Most common psychiaric illness of mood disorder Common prevalence 17% world wide Every 5 th person of world male > female (2:1) Mean age of onset 40 -50 years It affects all socio economic status Most common cause of suicide Depression in all psychiatric illness have maximum DALY DALY (Disability Adjusted Life Years

5. Symptoms of depression ICD -10 CRITERIA INCLUDED AS - LOSS OF INTREST (ANHEDONIA) - DEPRESSED MOOD - FATIGUABILITY Accessory symptoms ; Reduced attention & concentration Decreased self esteem & self confidence Ideas of guilt and unworthiness Negative view of future Disturbed sleep Diminished appetite

6. MILD - 2 MAIN - 2 ACCESSORY MODERATE – 2 MAIN - ¾ ACCESSORY SEVERE - 3 MAIN - > 4 ACCESSORY

7. DSM -5 CRITERIA Sadness of mood /depressed mood – Dysphoria Loss of intrest /Anhedonia according to DSM 5 At least one of these 2 is essential 3. Excessive guilt / feeling of worthlessness 4.Lack of energy/Fatigue 5.Poor concentration 6.Disturbed appetite (dec. appetite) 7.Psychomotor retardation or agitation 8.Sleep disturbances - early morning insomnia (classical feature) - Reduced latency of REM sleep 9.Suicidal thoughts

8. DSM 5 Major depression & At least 5 ,5/6 present At least 1 out of 2 starting Duration – 14 days (2 weeks ) For minor depression - < 5 but > 2 (2-4) for 2 weeks

9. SIGNS OF DEPRESSION OMEGA SIGN ( FORE HEAD)

10. 1. ATYPICAL DEPRESSION Increased appetite ,obesity Leaden paralysis arms appears heavy ,subjective feeling of happiness Mood Swing ,Anger Outburst OTHERS TYPES OF DEPRESSION

11. 2.POST PARTUM DEPRESSION- IN FEMALE AFTER DELIVERY OF NEW BORN 3.CATATONIC DEPRESSION PATIENT UN AWARE WITH SURROUNDING ENVIRONMENT SILENT MOOD 4.SEASONAL AFFECTIVE DISORDER 5.MELANCHOLIC DEPRESSION OLD AGE ,LACK OF REACTIVITY TO USUAL PLEASURABLE STIMULI GUILT FEELING ,SOMATIC SYMPTOM ,NIHILISTIC SYMPTOMS MARKED AGITATION OR RETARDATION

12. DRUG INDUCED DEPRESSION

13. THEORIES FOR PATHOGENESIS OF DEPRESSION PSYCHOLOGICAL THEORY COGNITIVE THEORY Aaron Beck Cognition -thinking & learning According to this negative thought responsible for depression Cognitive theory of triad Also known as becks triad Negative view about self ( WORTHLESS NESS ) Negative view about environment /other ( HELPLESSNESS ) Negative view about future ( HOPELESSNESS ) BECKS TRIAD

14. THEORIES OF LEARNED HOPELESSNESS According to this due to repetitive failure person started beliving that ,life circumstances are not under his control and losses the motivation to act

15. ETIOLOGY OF DEPRESSION NEUROTRANSMITTORS DECREASED OF MONOAMINES (NOR ADRENALINE/5HT/DOPAMINE) ENDOCRINE ABNORMALITY:- THYROID HYPO/HYPER ADRENAL :- CUSHING, ADDISONS ds. PARATHYROID HYPER /HYPO HYPO PITUITARISM RAISED GH,ACROMEGALY GENETIC CAUSES

16. Neurotransmitters: involved in depression

17. NOR EPINEPHRINE SYSTEM

18. NE System Almost all NE pathways in the brain originate from the cell bodies of neuronal cells 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.

19. 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 NET Antidepressant MAO Inhibitors Stimulant

20. Serotonin System As with the NE system, serotonin neurons located in the pons and midbrain (in groups known as raphe nuclei) send their projections diffusely to the cortex, hippocampus, amygdala, hypothalamus, thalamus, etc. --same areas implicated in depression. This system is also involve in: Anxiety. Sleep. Sexual behavior. Rhythms (Supra chiasmatic nucleus). Temperature regulation. CSF production.

21. Pathogenesis  :PHARMACOLOGICAL BASIS Decreased level of serotonin is responsible Low level of nor adrenaline dopamine also causes depression Hypothyroidism –Depression Hyperthyroidism –Depression + Anxiety

22. MAO - I (MONO AMINE OXIDASE INHIBITOR)

23. TYPES OF DEPRESSION Major depression Chronic depression ( Dysthymia ) Atypical depression Bipolar disorder/Manic depression Seasonal depression (SAD)

24. Major depression – recurring and disabling. Symptoms must last for at least two weeks and impair one’s ability to interfere with a person's ability to work, sleep, study, eat, and enjoy once-pleasurable activities. Chronic depression – less disabling than major depression, but symptoms can last longer, sometimes being unhappy for two years. More common in women, affects 11 million people. Atypical depression, rather than the other two, is characterized less by pervasive sadness and more by overeating, oversleeping, sensitivty to rejection

25. Bipolar/manic depression oscillates between major depression and epsidoes of mania (extreme elation), Bipolar I – episode of mania with or without depression. Bipolar II – episode of depression with episode of hypomania or mania. Seasonal depression (SAD) – often occurs where winters are short or there is a big change in the amount of sunlgiht , and often treated with light therapy.

26. 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 defy diagnosis and 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)

27. TREATMENT FOR DEPRESSION Psychotherapy Electroconvulsive therapy Natural alternatives Medication SSRIs MAOIs TCAs SNRIs NDRIs TeCAs

28. ANTI DEPRESSANT DRUGS FIRST GENERATION ; tCA TRICYCLIC ANTI DEPRESSANT DRUGS MAO –I ( MONO AMINE OXIDASE INHIBITORS) SECOND GENERATION SSRIs : SELECTIVE SEROTONIN REUPTAKE INHIBITORS SNRIs : SELECTIVE NORADRENALINE REUPTAKE INHIBITORS ATYPICAL ANTI DEPRESSANTS

29. t-CA ( TRICYCLIC ANTI DEPRESSANT tCA NEURONS BLOCK REUPTAKE OF NT BY DECREASES RECEPTOR ACTIVITY OF Α1 H1 D2 WHICH INCREASES SEROTONIN NE DA MECHANISM OF ACTION SIDE EFFECTS CONSTIPATION ,BLURRED VISION URINARY RETENTION CARDIAC ABNORMALITY PHOTO SENSITIVITY WEIGHT GAIN DRY MOUTH ,NAUSEA, SEDATION CONTRAINDICATION GLAUCOMA RECENT MI USE IN CNS /DEPRESSANTS PSYCHOSIS HISTORY OF SEIZURE DRUGS CLOMIPRAMINE Amitryptaline (50-300mg) Imipramine (30-300mg) nocturnal eneuresis DESIPRAMINE Doxepine (25-300mg) Desipramine(25-300g) NORTRYPTALINE

30. TRICYCLIC ANTIDEPRESSANTS ( tCAs ) History Imipramine Current Drugs Mechanism of Action Side Effects Imipramine

31. MECHANISM OF ACTION OR PHARMACOKINETICS OF TCA uses Absorbed orally & binds to plasma protein,highly lipophilic so get distributed through the systemic circulation metabolism takes place in liver by hepatic microsomal enzyme. Excreted through urine peak plasma concentration is 2-6 hours & estimated half life 24 hours USES : Treat major depression panic attack social phobia Anxiety disorder OCD, nocturnal eneuresis Bulimia nervosa, migraine, insomni,fibromyalgia , PTSD Chronic uses: - presynaptic downregulation of synthesis - post synaptic down regulation of receptors

32. MAOIs SIDE EFFECTS Drowsiness/Fatigue Constipation Nausea Diarrhea Dizziness Lightheadedness, Decreased urine output Decreased sexual function Sleep disturbances Muscle twitching Weight gain Blurred vision Headache Increased appetite Restlessness Shakiness Weakness Increased sweating

33. Imipramine was first tried as an antipsychotic drug for schizophrenia, proved to be insufficient but proved to have antidepressant qualities, in the 50s around the same time as MAOIs. Imipramine is very good for severe depression, but it’s almost too good – also causes hypomania and mania

34. TCAS ON THE MARKET Amitriptyline Desipramine Doxepin Imipramine Nortriptyline Protriptyline Trimipramine

35. Side effects have made them second line of defense to SSRIs but they are good for treatment resistant depression because they are so strong. Amitriptyline – most widely used, most effectve Desipramine – active metabolite of imipramine , used for neuropathic pain Doxepin – used for depression and insomnia Imipramine – used for major depression and enuresis Nortriptyline – same thing Protriptyline – depression UNIQUE BECAUSE IT IS ENERGIZING rather than sedating Trimipramine – depression, insomnia, and pain

36. TCAS MECHANISM OF ACTION TCAs inhibit serotonin, nore pinephrine , and dopamine transporters, slowing reuptake TCAs also allow for the down regulation of post-synaptic receptors All TCAs and SSRIs contain an essential amino group that appears to interact with Asp-98 in hSERT

37. TCAS SIDE EFFECTS Muscarinic M1 Receptor Antagonism - Anticholinergic Effects Including Dry Mouth, Blurred Vision, Constipation, Urinary Retention And Impotence Histamine H1 Receptor Antagonism - Sedation And Weight Gain Adrenergic Α Receptor Antagonism - Postural Hypotension Direct Membrane Effects - Reduced Seizure Threshold, Arrhythmia Serotonin 5-HT2 Receptor Antagonism - Weight Gain (And Reduced Anxiety)

38. TCAS SIDE EFFECTS Nonselectivity Results In Greater Side Effects tCAS Can Also Lead To Cardiotoxicity Increased LDH Leakage Slow Cardiac Conduction High Potency Can Lead To Mania Contraindicated With Persons With Bipolar Disorder Or Manic Depression

39. MONOAMINE OXIDASE (MAO) AND DEPRESSION MAO catalyze deamination of intracellular monoamines MAO-A oxidizes epinephrine, norepinephrine , serotonin MAO-B oxidizes phenylethylamine Both oxidize dopamine nonpreferentially

40. MONO AMINE OXIDASE INHIBITORS MAO-I TREATMENT of depression WITH MAO –I began in 1950s These drugs are not widely used today, although a small number Of patients appear to do better in MAO-I THAN tcas or the newer drugs Mechanism of action :- Readily absorbed from GI tract widely distributed throughout body Effect persist even after these drugs are no longer detectable in plasma (1-3 weeks)

41. CHEESE REACTION Increased NA Releases HTN Crisis Like Situation Develops DOC For Cheese Reaction PHENTOLAMIDE Antibiotic Having MAO-I Like Property Linezolid Cocaine SNRI SSRI Pethidine

42. TETRACYCLIC ANTIDEPRESSANTS (TECAS) Current Drugs Mirtazapine Mechanism of Action Same as TCAs Side Effects

43. SELECTIVE SEROTONIN REUPTAKE INHIBITORS Most commonly prescribed class Current drugs Mechanism of action Side effects Serotonin

44. Also first rationally designed drug class, up until the 70s the antidepressants were sort of found by accident Serotonin is also referred to as 5-hydroxytryptamine

45. SSRIS ON THE MARKET citalopram) dapoxetine escitalopram) fluoxetine) fluvoxamine) paroxetine sertraline zimelidine Fluoxetine 1:1 Sertraline

46. SSRI

47. More trade names once patent is over but I kept original trade names Citalopram : Major depression Dapoxetine : Premature Ejaculation Escitalopram : Major depression and various other anxiety disorders Fluxoetine : Major depression, OCD, bulimia, etc Fluvoxamine : OCD Paroxetine : Major depression or anxiety Sertraline : Major depression or anxiety Zimelidine had neurological problems like Guillan Barre Indalpine had problems with fetal low WBC

48. SSRIS SIDE EFFECTS Anhedonia Apathy Nausea/vomiting Drowsiness or somnolence Headache Bruxism (involuntarily grinding of the teeth) Extremely vivid and strange dreams Dizziness Fatigue Changes in sexual behavior Suicidal thoughts

49. SSRIS SIDE EFFECTS Many disappear within 4 weeks (adaption phase) Side effects more manageable compared to MAOIs and TCAs Sexual side effects are common SSRI cessation syndrome Brain zaps Sexual dysfunction

50. MECHANISM OF ACTION SNRIs inhibits reuptake of 5HT &NA Increased Concentration Of Substances Continuing Firing Of Postsynaptic Neuron

51. SNRIs (SELECTIVE NOR EPINEPHRINE REUPTAKE INHIBITORS THE SEROTONIN TRANSPORTER (SERT OR 5-HTT) INHIBITION NOR EPINEPHRINE TRANSPORTER(NET) INHIBITION INDICATION MAJOR DEPRESSIVE DISORDER (MDD) POST TRAUMATIC STRESS DISORDERS(PTSD) GERNERALISED ANXIETY DISORDER(GAD) SOCIAL ANXIETY DISORDER PANIC DISORDER NEUROPATHIC PAIN FIBROMYALGIA CHRONIC MUSCULOSKELETAL PAIN

52. SEROTONIN-NOREPINEPHRINE REUPTAKE INHIBITORS (SNRIS) Slightly greater efficacy than SSRIs Slightly fewer adverse effects than SSRIs Current drugs Venlafaxine (Effexor) Duloxetine (Cymbalta) Mechanism of Action Very similar to SSRIs Works on both neurotransmitters Side effects Similar to SSRIs Suicide Venlafaxine 1:1 Duloxetine

53. NOREPINEPHRINE-DOPAMINE REUPTAKE INHIBITORS (NDRIS) Current drugs Bupropion Mechanims of Action Similar to SSRIs and SNRIs More potent in inhibiting dopamine Also anα3-β4 nicotinic antagonist Adverse effects Lowers seizure threshold Suicide Does not cause weight gain or sexual dysfunction (even used to treat the two) Bupropion 1:1

54. SEROTONIN--A KEY PLAYER The overactive point of view In some depressives CSF 5-HT is elevated Approx. 30% of depressed patients do not respond to SSRIs Depletion of 5-HT by inhibition of tryptophan hydroxylase (TH) alleviates depressive symptoms in some patients Tianeptine , a 5-HT reuptake enhancer that works opposite to SSRIs, is a marketed antidepressant A selective TH inhibitor shows activity in an animal model of depression The activation of TH by stress can be blocked by Prozac

55. SYMPTOMS OF MANIA increased energy (buying, phoning, sex) increased gregariousness Pressured speech, talkativeness decreased sleep drunkenness combative,dangerous behavior distractibility racing thoughts impulsive actions and decisions elevated mood euphoria grandiosity irritability/hostility (easily angered) MANIA & BIPOLAR DISEASES

56. MANIA—too much neurotransmission? Increased production of inositol phosphate (IP-3) which increases intracellular Ca2+ signalling Increased DAG which: activates PKC which phosphorylates a number of substrates including myristoylated alanine rich C kinase (MARCK) MARCK activates nuclear transcription factors and modulates genes that increase neuromodulatory peptide hormones and alters cell signalling which: changes neurotransmitter synthesis neuronal excitabiltiy synaptic plasticity neuronal cell loss (prefrontal cortex?)

57. LITHIUM a monovalent ion that can enter neurons but is not readily removed. major mechanism is the reduction of neuronal PI second messenger resulting in reduced response of neurons to ACh and NE may actually enhance 5-HT

58. CLINICAL PHARMACOLOGY primary therapy for mania a narrow therapeutic window (0.8-1.2 meq /L; some guides say 0.6-1.4 meq /L) absolutely necessary to monitor serum level (trough level approx. 5 days after initial dose) solely eliminated by kidney, therefore assess patient’s kidney function

59. ADVERSE EFFECTS tremor decreased thyroid function polydipsia / polyuria edema ECG changes (depression of T-wave) excreted in breast milk

60. Other Medications Anticonvulsants: carbamazepine and valproic acid for rapid cyclers Olanzepine approved for treatment of mania St. John’s Wort : questionable efficacy, but high potential for drug-drug interactions

61. Factors Influencing Choice Features of illness, e.g. agitation, hypersomia Suicide risk Other therapy Other illness. Side effects Cost Special problems e.g. Age, driving, pregnancy

62. Drug Failure Non compliance. Inadequate dosage. Other drugs e.g. alcohol, caffeine. Unresolved outside problems. Up to 26% failure even if above don’t apply.

63. Adjuvants and Combinations Realm of specialists Lithium, carbamazepine Mixtures i.e. SSRI and TCA Dangerous – need expert supervision

64. FEW OTHER NON PHARMACOLOGICALLY TREATMENT FOR DEPRESSION ELECTRO CONVULSIVE THERAPY(ECT): in patients having high suicidal behaviour

65. COGNITIVE BEHAVIOUR THERAPY Donald meichenbaum

66. REPEATITIVE TRANSCRANIAL MAGNETIC STIMULATION VAGAL NERVE STIMULATION DEEP BRAIN STIMULATION

67. THANK YOU