Drug therapy of depression

Pharmacology of antidepressant agents

1. Drug therapy of depression Dr Htet Htet MBBS, MMedSc , PGCertHPE

2. Lesson outcomes After this session, you should be able to: Enlist the groups of antidepressants Describe their mechanism of action and adverse effects Explain cheese reaction

3. Lecture outline What is depression? Types & theories of depression Management of depression Classification of antidepressants Pharmacology of drugs

4. What is depression? most common of the affective disorders ( disorder of mood). may range from a very mild condition, to severe (psychotic) depression accompanied by hallucinations and delusions. Worldwide , depression is a major cause of disability and premature death . In addition to the significant suicide risk, depressed individuals are more likely to die from other causes , such as heart disease or cancer. often associated with other psychiatric conditions including anxiety, eating disorders and drug addiction

5. Lecture outline What is depression? Types & theories of depression Management of depression Classification of antidepressants Pharmacology of drugs

6. Types of depression Unipolar depression (Major depressive disorder) Depressed mood, loss of interest or pleasure in life, sleep disturbances, feeling of worthlessness, diminished ability to think or concentrate, recurrent thoughts of suicide. They can be irritable or anxious. Bipolar disorder (Manic-depressive disorder) Recurrent fluctuations in mood, energy, behaviour that encompass the extremes of human experience. Dysthymia low-grade depressed mood without sufficient other symptoms to count as “clinically significant” or major depression

7. Types of depression Classification based on aetiology Reactive depression (external stimuli) Endogenous depression (caused by the factors within individual independent of outside stimuli)

8. Theories of depression Monoamine hypothesis ( main biochemical theory of depression) first proposed in 1965, which states that depression is caused by a functional deficit of the monoamine transmitters, noradrenaline and 5-hydroxytryptamine (5- HT) at certain sites in the brain, deficit in function or amount of monoamines while mania results from a functional excess

9. The monoamine hypothesis of depression (Figure) suggests that depression is related to a deficiency in the amount or function of cortical and limbic serotonin (5-HT), norepinephrine (NE), and dopamine (DA ).

10. Theories of depression Neurotrophic hypothesis brain-derived neurotrophic factors (BDNF) are critical in the regulation of neural plasticity, resilience, and neurogenesis depression is associated with the loss of neurotrophic support and that effective antidepressant therapies increase neurogenesis and synaptic connectivity in cortical areas such as the hippocampus. BDNF is thought to exert its influence on neuronal survival and growth effects by activating the tyrosine kinase receptor B in both neurons and glia

11. Neurotropic hypothesis of depression

12. Lecture outline What is depression? Types & theories of depression Management of depression Classification of antidepressants Pharmacology of drugs

13. Management of depression Choice depends on Patient preference and local availability Very severe depression with psychotic symptoms, e.g. suicidal risk – ECT

14. Treatment of depression related disorders Acute anxiety with depression: e.g. benzodiazepines (Separate Lecture) mild , neurotic depression , esp. with anxiety. Short-term for acute onset, not effective for long-term treatment of psychotic depression . Antidepressants: for psychotic depression, severe neurotic depression; long- term treatment.

15. Overview of drug therapies Drugs that are used to treat depression acts by enhancing the neurotransmission at serotonergic and/or noradrenergic neurons Most of the drugs does this by inhibiting the reuptake of these neurotransmitters (5HT, NA) and hence enhancing their effects in the CNS.

16. Classification of antidepressant drugs 1. Monoamine uptake inhibitors 1.tricyclic antidepressants, (TCA) 2.selective serotonin reuptake inhibitors (SSRI) 3. N ewer inhibitors of noradrenaline and 5-HT reuptake (SNRI) 4. NA reuptake inhibitor 3. Monoamine receptor antagonists 5 . Monoamine oxidase (MAO) inhibitors

17. Drug classes used in treatment of depression and anxiety disorders Selective serotonin reuptake inhibitors (SSRI) Newer inhibitors of noradrenaline and 5-HT reuptake (SNRI) Tricyclic antidepressants Monoamine oxidase (MAO) inhibitors Atypical antidepressants Atypical antipsychotics

18. Tricyclic antidepressants (TCA) Mechanism of action: inhibits the reuptake of NA and 5HT into the presynaptic neuron, increased availability of NA and 5HT at the receptors, increasing their concentration in the synaptic cleft in the CNS and periphery  mood elevation TCAs additionally block muscarinic, alpha adrenergic, histaminergic receptors which are responsible for adverse effects Onset Therapeutic effect is noticeable in a week or two (onset of action)

19. Tricyclic antidepressants (TCA) Pharmacological actions: CNS: mood elevation of depressed patients may extend to excitement, hypomania, mania with sufficient dose; agitation , seizures no mood elevation or euphoria, but causes anxiety in normal persons. lowers seizure threshold, convulsions in overdose Respiratory symptoms respiratory depression with overdose CVS: orthostatic hypotension, sinus tachycardia; arrhythmias and cardiac conduction defect with overdose Others anticholinergic action  atropine-like effects potentiates exogenous & endogenous noradrenaline, sympathomimetics

20. Severe endogenous depression Nocturnal enuresis (Imipramine) Panic Disorder Obsessive-Compulsive Disorders Chronic Neuropathic Pain (e.g., Trigeminal Neuralgia/ Diabetic Neuropathy/ Tabetic Neuropathy) Others (Eating Disorders (Bulimia)/ Narcolepsy/ School Phobia/ ADHD) Tricyclic antidepressants (TCA)

21. Adverse effects Atropine like side effects: dry mouth, blurring of vision, constipation, urinary retention α adrenergic blocking effect: postural hypotension, tachycardia, cardiac arrhythmias H1 blocking effects: sedation, confusion Others: increased appetite, weight gain, seizures Tricyclic antidepressants (TCA)

22. Drug classes used in treatment of depression and anxiety disorders Selective serotonin reuptake inhibitors (SSRI) Newer inhibitors of noradrenaline and 5-HT reuptake (SNRI) Tricyclic antidepressants Monoamine oxidase (MAO) inhibitors Atypical antidepressants Atypical antipsychotics

23. Selective serotonin reuptake inhibitors Citalopram, Escitalopram, Fluoxetine, Paroxetine, Sertraline MOA SERT mediates the reuptake of serotonin into the presynaptic terminal; neuronal uptake is the primary process by which neurotransmission via 5-HT is terminated. SSRI blocks reuptake and results in enhanced and prolonged serotonergic neurotransmission.

24. Uses Anxiety and depression disorders Impulse control disorders (OCD: impulsive buying, kleptomania) Post traumatic stress disorder (PTSD) Selective serotonin reuptake inhibitors

25. Adverse effects headache , insomnia, GI disturbances sexual dysfunction May increase risk of suicidal thoughts or  behavior Serotonin  syndrome with MAOIs ( “rare, neuromuscular hyperactivity, agitation, potential seizures, hyperthermia, delirium, death ”) Selective serotonin reuptake inhibitors

26. Selective serotonin reuptake inhibitors Advantages of SSRI Less cardiotoxic and less sedative than TCA Acute toxicity (especially cardiotoxicity) is less than that of MAOIs or TCAs, so overdose risk is reduced. SSRIs are less sedating and have fewer antimuscarinic side effects than the older TCAs. Lesser chance of food and drug interaction No food reactions, but dangerous 'serotonin reaction' (hyperthermia, muscle rigidity, cardiovascular collapse) can occur if given with MAOIs. No weight gain in general, SSRIs DO NOT: **** cause weight gain Side effect profile No postural hypotension , no sedation, do not precipitate seizures, no cardiac arrhythmias

27. SSRI Disadvantages: Mild side-effects: nervousness, restlessness, insomnia, anorexia, headache, diarrhoea Impair performance of skilled tasks, e.g. driving; sexual dysfunctions May produce withdrawal symptoms  needs tailing off -Indication : better tolerated and safer in overdose than other classes, should be considered first-line drugs for treating depression . Selective serotonin reuptake inhibitors

28. Selective serotonin reuptake inhibitors Status most commonly prescribed group of antidepressants overall antidepressant efficacy similar to TCA, less efficacious in more severe depression

29. Drug classes used in treatment of depression and anxiety disorders Selective serotonin reuptake inhibitors (SSRI) Newer inhibitors of noradrenaline and 5-HT reuptake (SNRI) Tricyclic antidepressants Monoamine oxidase (MAO) inhibitors Atypical antidepressants Atypical antipsychotics

30. What is MAO? What are MAOs? enzymes involved in deamination (degradation) of monoamines which include NA and 5-HT Two sub-types: –MAO-A, preferentially deaminates 5-HT and NA –MAO-B, preferentially deaminates phenylethylamine and dopamine. Types of MAOI 1.Non selective MAOI 2.Selective MAOI

31. Monoamine oxidase inhibitors Meclobemide inhibits MAO-A selectively and reversibly effective antidepressant, except in severe cases lacks anticholinergic, sedative, psychomotor and cardiaovascular adverse effects of typical TCAs Status: well tolerated alternative to TCAs in mild to moderate depression; especially suitable for elderly patients and those with heart disease.

32. Monoamine oxidase inhibitors Status: •much less frequently used, because of ( i ) Interactions: “ cheese reaction” with food containing tyramine, dopamine etc., - cheese, beer, wines, pickled meat and fish, yeast extract  hypertensive crisis with TCAs  severe toxicity resembling atropine poisoning - with many others including: (indirect sympathomimetic drugs) cold & cough remedies, antiparkinsonian drugs, MAOI + SSRI – serotonin syndrome

33. Drug classes used in treatment of depression and anxiety disorders Selective serotonin reuptake inhibitors (SSRI) Newer inhibitors of noradrenaline and 5-HT reuptake (SNRI) Tricyclic antidepressants Monoamine oxidase (MAO) inhibitors Atypical antidepressants Atypical antipsychotics

34. Serotonin-Norepinephrine Reuptake Inhibitors Venlafaxine, duloxetine Inhibitors of SERT and NET Use in anxiety and depression, ADHD, autism, fibromyalgia, PTSD, menopause symptoms

35. Drug classes used in treatment of depression and anxiety disorders Selective serotonin reuptake inhibitors (SSRI) Newer inhibitors of noradrenaline and 5-HT reuptake (SNRI) Tricyclic antidepressants Monoamine oxidase (MAO) inhibitors Atypical antidepressants Atypical antipsychotics

36. Atypical antidepressants Mirtazapine, trazodone, and nefazodone  5HT 2  receptor antagonists (blocks 5-HT2C receptors) Mirtazapine also blocks α2 adrenoreceptors Block of α2 adrenoceptors will not only increase noradrenaline release but will also enhance 5-HT release

37. Drug classes used in treatment of depression and anxiety disorders Selective serotonin reuptake inhibitors (SSRI) Newer inhibitors of noradrenaline and 5-HT reuptake (SNRI) Tricyclic antidepressants Monoamine oxidase (MAO) inhibitors Atypical antidepressants Atypical antipsychotics

38. Atypical antipsychotics Aripiprazole, Olanzapine, Quetiapine … Use for Resistant major depression and psychotic disorders Schizophrenia Bipolar depression  

39. Treatment of depression Mild depression - non-drug measures, antidepressant drugs – used - if the response is poor. antidepressant drugs have similar efficacy but different side effects. Choice of drug is based on individual aspects including concomitant disease (TCAs in particular have several indications) and treatment (MAOIs and TCAs cause important interactions), suicide risk and previous response to treatment.

40. Treatment of depression Other things being equal, an SSRI is preferred (better tolerated, less dangerous in overdose .) take several weeks before taking effect (so decisions on dose increment or switching to another class should not be made precipitately ) In urgent situations, specialist consideration - possible use of electroconvulsive therapy. Anxiolytic (e.g. benzodiazepine), or antipsychotic drugs are useful adjuncts in some patients.

41. Treatment of depression Important points for drug therapy: reviewed every 1 – 2 weeks at start of therapy continued f or at least 4 weeks (6 weeks in elderly) before contemplating switch following remission, continue same dose for at least 6 months withdrawal symptoms if stopped suddenly after 8 weeks or more, (physical dependence);  needs tailing off (4 weeks or longer) –at least 2 weeks gap in-between, when switching drugs Both CBT and interpersonal therapy are as effective as antidepressants for mild to moderate depression . Antidepressant drugs are, however, preferred for severe depression. Drug and psychological treatments can be used in combination.

42. Other uses of antidepressants neuropathic pain (e.g. amytriptyline , nortryptyline ) anxiety disorders (e.g. SSRIs, venlafaxine, duloxetine) fibromyalgia bipolar depression smoking cessation (e.g. buproprion ) attention-deficit hyperactivity disorder Premature ejaculation

43. References Brunton , L. Chabner , B. Knollman , B. Goodman & Gilman’s Pharmacological Basis of Therapeutics. 12th Edition. United States: The McGraw-Hill Companies, Inc. Rang , HP, Dale, MM, Ritter, JM, Flower, RJ, Henderson, G (2012). Rang and Dale's Pharmacology. 7th ed. London: Elsevier Churchill Livingstone