Vincenzo Micale, MD, PhD, Senior Researcher Central European Institute of Technology (CEITEC) MU, Group: Experimental and Applied

Transcription

1 Antidepressant and Antimanic drugs Vincenzo Micale, MD, PhD, Senior Researcher Central European Institute of Technology (CEITEC) MU, Group: Experimental and Applied Neuropsychopharmacology

2 Affective Disorders Depression Mania Bipolar Disorder A mental disorder characterized by consistent pervasive, alterations of mood and affecting thoughts, emotions and behaviours It is not a simple change in mood state

3 Depression Major depression Chronic depression (Dysthymia) Atypical depression Bipolar disorder/manic depression Seasonal depression (SAD) Diagnostic Statistical Manual of Mental Disorders V

4 Five of the symptoms, at least may be evident daily or almost every day for 2 weeks Diagnostic Statistical Manual of Mental Disorders V

5 Depressive patients Boris Jeltzin Ernest Hemingway George S. Patton / US General Isaac Newton Jack London Jean-Claude Van Damme John Lennon Laurence Olivier Ludwig van Beethoven Marlon Brando Michaelangelo Mozart Napoleon Petr Iljič Čajkovskij Richard M. Nixon Spencer Tracy Victor Hugo Vincent van Gogh

6 Pathophysiology of depression: 1) Genetic

7 Pathophysiology of depression: 2) Neurotrophic Hypothesis

8 Pathophysiology of depression: 3) Neuroendocrine Hypothesis Upregulation of HPA axis

9 Pathophysiology of depression: 4) Dysregulation of circadian rhythm

10 Pathophysiology of depression: 5) Monoamine Hypothesis Serotonin (5-HT) Norepinephrine (NE)

11 Brain region involved in depression

12 Treatment for depression Psychotherapy/talk therapy Electroconvulsive therapy Natural alternatives (St. John`s wort) Medication Antidpressants

13 Frequency of drug classes prescription PSYCHOTROPICS diuretics antihypertenzives anti - angina pect. cardiotonic agents psychotropics antiartritic drugs analgesics... PSYCHOTROPICS IN ELDERLY in depression sleeping disorders Parkinson disease Alzheimer diseases memory disorders dementia anxiety

14 The Purpose of Antidepressant Agents..

15 Antidepressants: 1) MAO-Inhibitors (MAO-I)

16 MAO-I i. generation - nonselective and irreversible tranylcypromine, phenelzin, iproniazide II. generation - selective and reversible RIMA - reversible inhibitors of MAO A moclobemide selective inhibitors of MAO B - irreversible selegilin (deprenyl) - reversible caroxazone

17 MAO-I: History

18 MAO-I: Mechanism of action

19 MAO-I adverse event: 1) Cheese Effect

20

21 MAO-I adverse event: 2) Serotonin Syndrom A potentially fatal interaction when SSRI s or and MAOI s are combined Symptoms: autonomic instability (labile HR/BP) hyperthermia rigidity and myoclonus confusion,delirium seizures coma

22 MAO-I Adverse events: 3) Others Drowsiness/Fatigue Constipation Nausea Diarrhea Dizziness Low blood pressure Lightheadedness Decreased urine output Decreased sexual function Sleep disturbances Muscle twitching Weight gain Blurred vision Headache Increased appetite Restlessness Shakiness Weakness Increased sweating

23 Tertiary amines Amitriptyline, Doxepine Imipramine, Clomipramine Secondary amines Desipramine, Nortriptyline Protriptyline Antidepressants: 2) Tricyclic (TCAs)

24 TCAs: History

25 TCAs: Mechanism of action Block 5-HT and NE reuptake pump Block 5-HT2A and 5-HT2C DA and NE

26 TCAs: Adverse events

27 TCAs: Adverse events

28 citalopram SRI Antidepressants: 3) Selective serotonin reuptake inhibitor (SSRIs) DRI H-1 sertralina SRI M-ACh NRI paroxetina NOS SRI NRI fluoxetina SRI fluvoxamina SRI 5HT 2c

29 5-HT 1A Autoreceptors SSRIs: Mechanism of action

30 SSRIs: Mechanism of action

31 Indications for SSRIs Depression OCDs ( Obsesive-Compulsive Disorders ] Panic attacks Bulimia PMDD ( PreMenstrual Disphoric Disorder ) Posttraumatic stress disorders Social phobias Social anxiety disorders

32 SSRIs: Adverse events agitationtion akathisia anxiety panic atack insomnia sexual dysfunction nausea diarrhea headache stimulationtion of 5-HT 2 receptors stimulationtion of 5-HT 3 receptors Many disappear within 4 weeks (adaption phase) Side effects more manageable compared to MAOIs and TCAs

33 SSRIs: Adverse events

34 Antidepressant: 4) Selective norepinephrine reuptake inhibitor (NRIs) Reboxetine

35 NRIs: Mechanism of action NRI NRI

36 NRIs: tolerability profile

37 Multiple pharmacological mechanisms=dirty drugs

38 5) Serotonin-norepinephrine norepinephrine reuptake inhibitors (SNRIs)

39 SNRIs: Mechanism of action

40 SNRIs: Side effects Nausea/vomiting Insomnia or somnolence Headache Suicidal thoughts (5-fold increase in < 25, contraindicated in adolescents)

41 6) Norepinephrine-dopamine reuptake inhibitor (NDRI) Bupropion

42 NDRI: Mechanism of action Radafaxine (NET Inhibit>Buprop) Other active metabolites (NDRIs)

43 NDRI: tolerability profile Sexual dysfunction Weight gain Somnolence/sedation seizure threshold <TCA, SSRIs

44 7) Noradrenergic and specific Serotonergic- Antidepressants (NaSSA)

45 NaSSA: mechanism of action

46 (NaSSA): Tolerability profile H-1 Blockade: hypnotic, anxiolytic, drowsiness weight gain

47 8) Serotonin antagonist /reuptake inhibitors (SARIs) Nefazodone Trazodone

48 SARIs: mechanism of action

49 SARIs: mechanism of action

50 SARIs: Adverse Events

51 9) Melatonergic antidepressant: Agomelatine

52 Melatonin (MT) Suprachiasmatic Nuclei (SCN) = master clock Pineal gland MT 1 MT 2 Melatonin (darkness) Eye

53 Circadian activity rhythm in depression shows disturbed pattern 24-hour actigraphy in a healthy middle-aged control hour actigraphy in a patient with major depression G. Hajak 2010

54 Circadian rhythms are flattened and phase shifted in depressed patients Plasma Melatonin (pg/ml) 100 Sleep Time Healthy controls Depressive patients Souetre et al., Am J Psychiatry 1988; 145:1133-7; Psychiatry Res 1989; 28:263-78

55 Agomelatine: Mechanism of action

56 Agomelatine: Therapeutic effects

57 Agomelatine: Tolerability

58 Pharmacoresistant depression 33% of patients are nonresponders to AD Higher dose of antidepressants Combination of different antidepressants Psychotherapy Electroconvulsive therapy (ECT) Deep brain stimulation Vagus nerve stimulation (VNS)

59 a) combination of antidepressants from different subclasses serotonergic + noradrenergic antidepressants ( dual effects") serotonergic antidepressants with different mechanism of serotonergic action (e.g.: 5-HT trabsporter inhibitor + antagonist at 5-HT autoreceptors)

60 b) antidepressant + drug from other class of indication Combinations tested: lithium anticonvulsant atypic antipsychotic trijodothyronine pindolol - - dopaminergic drug glucocorticoid sex hormone buspiron psychostimulant modafinil benzodiazepine (dependence!!) glutamatergic

61 Prospective antidepressants Nonmonoaminergic mechanisms for treatment of major depression under clinical investigation with selective drugs (Millan, 2009)

62 Prospective antidepressants Is ketamine the next antidepressant?

63 Antimanic or mood stabilizer Mania: 1 wk of Elevated, Expansive, Irritable Mood +3 (4): inflated self-esteem esteem or Grandiosity need for sleep (rested with <3hrs) talkative Flight of ideas, racing thoughts Distractibility goal-directed activity / psychomotor agit. pleasurable activ. w painful consequence (spending, sex, investments)

64 Mood Stabilizers Lithium Anticonvulsants Valproic Acid [Depakote] Carbamazepine [Tegretol] New Anticonvulsants (?): Lamotrigine [Lamictal] Topiramate [Topamax] Gabapentin [Neurontin] Antipsychotics Classic (Haloperidol) Novel (Clozapine, Olanzapine)

65 Lithium: mechanism of action 1) EFFECTS ON ELECTROLYTES AND ION TRANSPORT (It is a positively charged ion) 2) EFFECTS ON NEUROTRANSMITTERS (5-HT?,NE, DA, Ach ) 3) EFFECTS ON SECOND MESSENGERS (inositol phosphates)

66 Lithium: History Used since mid-xix: gout, diabetes... For BP since 1960 s, FDA 74 Effective Antimanic, mood stab, BP depr. If Discontinued relapse near 100% 2 yr Therapeutic Levels: meq/ml in elderly Same levels for prophylaxis Narrow therapeutic index

67 Lithium: Common Side Effects GI distress Polyuria / polydipsia Sedation-lethargy Cognitive (memory, concentr, slow) Wt. Gain Poor coordination, tremor Skin (worse acne)

68 Lithium: Serious SE Renal nephrogenic diabetes insipidus tubular interstitial nephritis Hypothyroidism Psoriasis (onset or worsening) Cardiac: EKG flat T, SA dysfx, tachicardia Li Tox. N/V/D, delirium, ataxia, stupor Tx dyalisis if >3.0, correct fluid-electrolites

69 Valproate FDA Sz 78, BP 96 Effective antimanic, BP depression Therapeutic effect 2 d. level mg/l oral loading mg/kg/day Elderly & hypomania responde to lower? Mixed, rapid cycling, schizoaffective Closed had injury, EEG abnormality

70 VPA: Common Side Effects GI distress Sedation Liver transaminase elevation Tremor Hair loss Weight gain-increased increased appetite Thrombocitopenia (elders) Teratogenic: neural tube, cranio-facial

71 VPA: Less Common SE Neutropenia Coagulopathies, platelet Function endocrine abnormalities Amenorrhea, policystic ovary? Hypothyroidism Hypocortisolemia

72 VPA: Rare Dangerous SE Idiosincratic Hepatic Failure lethargy, anorexia, N/V, jaund, bleed, edema Risk: <2 y.o.,., many anticonvuls, Dev. Delay Remote risk in >10yo psychiatric patients Acute Hemorrhagic Pancreatitis Bone Marrow Supression

73 Carbamazepine [Tegretol] FDA Trig Neuralg 68, TLE 74 Effective antimanic, Tx-refract Depr Onset 2 wks, antidepr 4-6 wk Ther. Levels: 4-12 or 15 mg/l Half life decreases to hrs p450 liver induction

74 CBZ: Side Effects Less cognitive probl than Li Less Wt gain, hair loss, tremor than VPA Neuro: Diplopia,blurr vision, fatigue/sed GI: Naus/diarr, Dry mouth Leukopenia, thrombocitopenia, rash LFT Agranulocytosis (Liver fail, pancreatitis, Stevens-Johnson (exfol skin), neuroteratogenic

75 Future Mood Stabilizers? Novel Antipsychotics Olanzapine: effective (2 DBPC trials) Quetiapine? New Anticonvulsants Lamotrigine:?Effective BP & depr, 10%rash, levels by CBZ, by VPA Topiramate: wt loss, 1.5% renal stones Gabapentin: effective?? (open reports, add-on) Tiagabine, Vigabatril Ca Others: Ca-channel blockers Tamoxifen Prot Kinase-C inhibitor