Antidepressant, Anti-anxiety Drugs

1. Antidepressant, Anti-anxiety Drugs Dr. R. K. Dixit Professor Pharmacology and Therapeutics C. S. M. Medical University Lucknow, 226003

4. Classification of Major Affective Disorders

5. Episodal (reactive) Depression • Adverse life events. • Physical illness. • Drugs. • Other psychiatric disorders.

6. Reactive (episodal) Depression • More than 60% of all depressions. • Core depressive syndrome: feelings of misery, apathy, inadequacy, pessimism, anxiety, tension, guilt.Ugliness, Low self –esteem, • Bodily complaints

7. Withdrawn. • Loss of interest in pleasurable activities. • Indecisiveness, loss of motivation. • Retardation of thought and action. • Sleep disturbance

8. In severe cases, it is accompanied by hallucinations and delusions. • Recurrent suicidal ideation, a suicide attempt or a specific suicide plan. • significant weight change (without dieting ) • Psychomotor agitation or retardation.

9. 1. Has a genetic component. 2. Depression can be drug-induced. 3. Depression can be drug-repressed. 4. Depression can be treated with drugs. 5. Depression can be treated with Electroconvulsive Therapy (ECT).

10. Mania Mania alone is rare (10%) and most frequently cycles with Major/endogenous depression (Manic-Depressive Disease, Bipolar Disorder). • Core Symptoms: • Characterized by an elevated “high” mood. • Talkative, go on-and-on about the things they will do. • Increased self-esteem. • Auditory hallucinations. • Decrease need to sleep. Expensiveness, unnecessary buying. • Lack judgment, Supermen

11. The precise cause of affective disorders remains elusive. • Evidence implicates alterations in the firing patterns of a subset of biogenic amines in the CNS, Norepinephrine (NE) and Serotonin (5-HT).  Activity of NE and 5 -HT systems?.

12. Almost all NE pathways in the brain originate from the cell bodies of neuronal cells in the locus coereleus 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.

13. 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 involved in: • Anxiety. • Sleep. • Sexual behavior. • Temperature regulation. • CSF production.

16. Blocked by antidepressants Blocked by antidepressants

17. Serotonin receptors • 5–HT1 • subtypes • 5–HT1A, 5–HT1B, 5–HT1D, 5–HT1E, 5–HT1F • primarily responsible for the therapeutic (antidepressant) effects of increased intrasynaptic serotonin • 5–HT2 • subtypes • 5–HT2A, 5–HT2B, 5–HT2C • primarily responsible for the toxic effects of increased intrasynaptic serotonin

18. Serotonin receptors • Over all 14 types divided in to 1, 2, 3, and 4-7 family • All are G-protein coupled receptors except 3 • 1- decreases cAMP while 4-7 increase • 3- ligand gated cation channel

19. Alternative Therapies No way of a priori knowing which therapy will be best for a patient. • Light Therapy • Psychological Treatment • ECT (patients with suicidal tendency and for quick action) • St. John’s Wort (Plant)

20. Antidepressants SSRIs • TCAs doxepin MAOIs TCAs MAOIs MAOIs TCAs TCAs MAOIs SSRIs isocarboxazide MAOIs TCAs MAOIs maprotiline Venflaxine Venflaxine MAOIs MAOIs SSRIs SSRIs Amoxepine SSRIs Venflaxine MAOIs Nortriptyline

21. Reversible inhibitor of MAO-A(RIMAs) Moclobemide ,Clorgyline • (Isocarboxacid, phenelzine, tranylcypromine.) • Atypical antidepressants Trazodone, Mianserine Mirtazapine, Venlafaxine Duloxetine,Tianeptine Amineptine, Bupropion • NA + 5 HT reuptake inhibitor Imipramine, Amitriptyline Trimipramine, Doxepin Dothiepin, Clomipramine • Selective serotonin reuptake inhibitors (SSRIs) Fluoxetine, Fluvoxamine Paroxetine, Sertraline Citalopram, Escitalopram • CM • RITA-Don't- Copy • Exams-For-PCS • MAD-Boy-turned-violent ANT IDEPRES SANT S • Tricyclic antideprssants (TCAs) • Predominantly NA reuptake inhibitor • Desipramine, Nortriptyline • Amoxapine, Reboxetine

22. Mechanism of Action 1. Inhibition of MAO enzymes. (MAOIs). • 2. Inhibition of NE and 5-HT reuptake. • (TCAs, SSRIs, Newer TCAs). 3. Prominent alpha blocking and weak 5-HT antagonists. (Nefazodone, trazodone,) 4. Serotonin and noradrenalin reuptake inhibitor (SNRIs) (venlafaxine, duloxetine) 5. Noradrenergic and specific serotonergic antidepressants (NaSSA) (Mirtazapine) 6. Inhibitor of Dopamine and Noradrenalin (Bupropion) 7. Blockade of pre-synaptic alpha 2 receptors (Mianserin) 8. Increases rather than inhibiting 5-HT uptake (Tianeptine, Amineptine) ATYPICAL

23. MAO ( monoamine oxidase) an enzymeTwo types • MAO – A -Peripheral adrenergic nerve endings -Intestinal mucosa -Human placenta -Liver -Serotonin , Noradrenalin and dopamine -Inhibited by moclobemide and clorgyline • MAO-B -brain ( basal ganglia) -Platelets -Liver -Deaminates dopamine -Inhibeted by selegiline (deprenyl) A-B C-D Isoniazide, iproniazide, phenelzine, isocarboxazide,tranylcypromine were non selective and irreversible inhibitors (Hit and run drugs) used previously but not used now due to drug drug and drug food interactions. Linezolide (new drug against MRSA) Cheese and serotonin syndrome

25. Nonselective MAOIs not favorable Cheese Reaction Cheese, beer, wine, meat, fish, yeast, (contain large amount of tyrammine and other indirectly acting amines) Due to irreversible block of MAO These escape degradation in intestinal wall and liver Hypertensive crises, CVA Medical Emergency Reach to circulation Displace large amount of noradrenalin from loaded nerves Tt. I.V. Phentolamine, Prazosin

26. Nonselective MAOIs not favorable • Cold and Cough medicines contain Ephedrine (Same result as cheese reaction) • Levodopa- excitement and hypertension • Tricyclic antidepressants- excitement, rise in BP, temperature

27. Reversible inhibitor of MAO-A(RIMAs) • Moclobemide- • Reversible and selective MAO-A inhibitor • Short duration of action • Competitive enzyme inhibition • Tyramine is able to displace it • Cheese reaction is less likely • Devoid of anticholenergic, sedative, cognitive, cardiovascular effects • Good for elderly with heart diseases

28. Tricyclic Antidepressants (TCAs) • Imipramine represents the class (Prototype) • Inhibit monoamine reuptake (serotonin and noradrenalin) • Increase the concentration of Serotonin and NA at synapse and potentiate the action (therapeutic effects) • Other receptors acted (Adverse effects) • Muscarinic- Anticholinergic side effects (dryness etc.) # • Alpha- alpha blocking actions (postural hypotension etc.) # • Histamine-Antihistaminic (sedation) # • Dopamine- antipsychotic (amoxapine, maprotiline)

29. TCAs actions (CNS) • In Normal person • Tiredness • Light-headedness • Sleepiness • Difficulty in thinking • Difficulty in concentration, • Gait disturbances • Provoke anxiety • Unpleasant • In Depressed -Sedation immediately -Elevation of mood (2-4Weeks) -Suppresses REM prolongs total sleep duration Lower seizure threshold and produce convulsions in overdose Don’t carry abuse potential, Development of dependence is less

30. TCAs uptake blockade is not directly responsible for antidepressant action? • Uptake blockade occurs quickly but antidepressant action occurs after months • Initially Pre synaptic alpha 2 and 5-HT1 auto receptors are activated by increased amount of NA and Serotonin in synaptic cleft resulting in decreased firing • But on long term desensitize and down regulation of these receptors and induce adaptive changes in the number and sensitivity of receptors and amine turnover leading to enhanced NA and Serotonin transmission required for antidepressant action.

31. TCAs on other systems • ANS • Potent anticholinergic (dry mouth, blurring of vision,, constipation, urinary hesitancy) • Weak alpha 1 blocking (postural hypotension, impairment of ejaculation,) • H1 antihistaminic (sedation) • CVS • Tachycardia • Postural hypotension • Cardiac arrhythmias (T wave suppression or inversion) due to intra ventricular conduction interference due to NA and Anti cholinergic actions Tolerance to Anticholinergic and hypotensive actions develop latter on

32. TCAs (Pharmacokinetics) • Good oral absorption • Highly bound to Proteins (plasma and tissue) • Metabolized in liver (oxidation, glucuronide conjugation and CYP2D6, CYP3A4, CYP1A2 • Many active metabolites may be produced • Mostly can be given once a day (at bed) • Have Therapeutic Window phenomenon (50-200ng/ml of imipramin)

33. TCAs Adverse effects • Anticholinergic- dry moth, bad taste, constipation, epigastric fullness, urinary retention (more common in elderly male), blurred vision, palpitation • Sedation, mental confusion, weakness • Increased appetite and weight • Sweating, fine tremors • Precipitation of seizures • Postural hypotension • Cardiac arrhythmias • Rashes and jaundice

34. TCAs (Acute Poisoning) • Usually suicidal attempt • Presents as • Excitement • delirium, • Anticholinergic symptoms like atropine poisoning • Muscle spasm • Convulsions • Respiratory depression • Coma • Treatment • Gastric lavage • I.V. line • Oxygen • Maintenance of BP and Temperature • Diazepam iv • Propranolol / lignocain

35. TCAs (Interactions) • Potentiation of sympathomimetics (direct acting) • Reduce action of sympathomimetics (indirect acting) • Reduce antihypertensive action of guanethidine and clonidine ( by preventing their transport in to neurons) • Potentiate other CNS sedatives • SSRIs inhibit metabolism of TCAs • With MAO inhibitors dangerous hypertensive crisis with excitement and hallucinations • Retard the absorption of other drugs • Phenytoin, phenylbutazone, chlorpromazine, aspirin, displace TCAs and produce toxicity • Phenobarbitone induce metabolism and inhibit the effect of the drug

36. Miscellaneous • Amoxapine • Tetra cyclic compound • Blocks D2 reuptake also • Has mixed antidepressant and neuroleptic effects • Good for psychotic depression • Reboxetine • Selective NA reuptake blocker • Weak action on 5-HT mechanism • Anticholinergic effects are minimal

37. Selective Serotonin Reuptake Inhibitors (SSRIs) • Limitations of TCAs • Anticholinergic effects • Alpha blocking action • Cardio toxicity • Sedation, seizures ppt • Low safety margin • Weight gain • Therapeutic window • Overdose poisoning common • Lag of 1 month period • Incomplete response to Tt • Answers may be given by SSRIs • Selectively inhibit membrane associated SERT (serotonin transporter) • More tolerability and better acceptability • Used in depression as well as in OCD, phobias • No sedation, No seizure ppt • No alpha blocking action • Less chances of arrhythmia • No weight gain • Now 1st choice for OCD, Panic disorders, Social Phobia, Eating disorders, Premenstrual syndrome, Post traumatic stress

38. Important points • TCAs have slightly more efficacy • Some patients not responding to TCAs may respond to SSRIs, • SSRIs preferred in prophylaxis of recurrent depression • In severe depression TCAs appear to be more efficacious

39. Individual compounds • Fluoxetine • Prototype of SSRIs • Longest acting • Fluvoxamine • Short acting • Commonly used in indoor patients • Paroxetine • Short acting • More GI side effects • Sertraline • Less chances of drug interactions due to low potency to cause cytochrome enzyme depression • Escitalopram • Active enantiomer of citalopram side effects are less • Citalopram • Similar to sertraline but should be avoided in patients attempting suicide

40. SSRIs • Side effects • Gastric upset • Nausea • Interfere with ejaculation • Nervousness • Restlessness • Insomnia • Anorexia • Headache • Diarrhea • Epistaxis • Ecchymosis • Others • Inhibit cytochrome enzymes and elevate the plasma level of other drugs • Other serotonergic drug ( MAOIs) is taken may precipitate Serotonin Syndrome manifesting as agitation, restlessness, sweating, twitching, convulsions

41. Atypical Antidepressants • Mianserin • Unique not inhibit NA and 5-HT uptake • Blocks pre-synaptic alpha 2 receptors increases release and turnover of NA • Antagonist at serotonin 2, 1c, and H1 receptors • Has sedative effect • Damages liver and bone marrow (Reserve drug) • Trazodone • Blocks 5-HT uptake • Has prominenent alpha blocking • Weak 5-HT2 antagonistic • No anticholinergic effect • Bradycardia • Has anxiolytic action also • Prolonged and painful penile erection (priaprism)

42. Atypical Antidepressants • Tianeptine / and Amineptine • Increases rather inhibiting 5-HT uptake • Neither sedative nor stimulant • Effective in anxiodepressive states • Venlafaxine / Duloxetine • SNRI selective in action • Faster onset of action • Increases BP • Duloxetine increases uretheral tone used in urinary incontinence ( over active bladder) • Mirtazapine (NaSSA) • Noradrenergic and specific serotonergic antidepressant • Blocks alpha 2 auto receptor (on NA neuron) and hetero- (on 5-HT neuron) receptors increasing both NA and serotonin release. • Bupropion • Inhibits DA and NA uptake has excitant effect • Used to reduce smoking

43. Antidepressant uses • Depression (ECT may be needed in severely depressed and patients having suicidal tendency) • Bipolar affective disorders TCAs and lithium or SSRIs with lithium or valporate/ lamotrigine • SSRIs with atypical antipsychotic in psychotic depression • Obsessive compulsive disorders (SSRI and Clomipramine) • Eating disorders

44. Anxiety disorders • Neuropathic pain • Attention deficit hyperactivity disorder in children • Enuresis- (Imipramine 25mg at night) • Overactive bladder (stress incontinence) • Migraine prophylaxis • Pruritus (Topical doxepin)

45. Antianxiety Drugs • Anxiety - emotional state • Unpleasant • Associated with uneasiness • Discomfort • Fear • Undefined threat • Fear about future Some amount of anxiety is must for progress When it becomes excessive, disproportionate, hampers performance then only needs treatment

46. Antianxiety Drugs • Drugs producing restful state of mind without interfering with normal mental or physical functions. • Have no effect on thought control • Don’t produce extra pyramidal side effects • Can Produce physical dependence • May Have abuse potential • Don’t selectively block conditioned avoidance response in animals • Have anticonvulsant activity

47. Antianxiety Drugs • Benzodiazepine • Diazepam • Chlordiazepoxide • Oxazepam • Lorazepam • Alprazolam • Azapirones • Buspirone • Gepirone • Ispapirone • Others • Beta blocker- Propranolol • Antihistaminics- Hydroxyzine • SSRIs and other antidepressant drugs PHO/BIG/DOCLA

48. Benzodiazepines • Relieve anxiety at low dose ( higher dose induce sleep and impair performance ) • Selective taming effect • More selective to limbic system • Have low side effects in Antianxiety dose • Lorazapam and clonazepam IM for psychotic and manic patients • Act by facilitating GABAergic transmission

49. Benzodiazepine MOA Cl Diazepam + DMCM – Flumazenil- 0 α subunit Extra-tracellular Others δεθπ Facilitator γ subunit Barbiturates Mimetic Intracellular Facilitator GABA β subunit GABA- A Receptor More Cl- intracellular more polarized more refractory Cl

50. Benzodiazepines • Adverse effects • Sedation • Light headedness • Psychomotor impairment • Cognitive impairment • Vertigo • Confusional state • Increased weight • Impaired sexual functions • Potential to produce dependence • All are almost similar selection is empirical