Pharmacology Section 10. Antidepressants and mood stabilizing drugs

1. PharmacologySection 10.Antidepressants and mood stabilizing drugs Marta Jóźwiak-Bębenista martia1@tlen.pl

2. Affective disorders • psychiatric diseases 1. Major depressive disorder (MDD) monopolar depression/ unipolar affective disorder • Dysthymic disorder • Seasonal affective disorder (SAD) • Postpartum depression („baby blues”) • Premenstrual dysphoric disorder (PMDD) • Substance-iduced mood disorder 2. Bipolaraffective disorder (BAD) manic depressive disorder  alternating manic, normal and depressive episodes

3. Depression • everyone feels "blue" at certain times • transitory feelings of sadness are perfectly normal • clinical depression is a serious condition that affects a person's mind and body. • all aspects of everyday life including eating, sleeping, working, relationships, and how a person thinks about himself/herself. • cannot simply will themselves to feel better or „snap out of it” • symptoms can continue for weeks, months, or years at untreated patients

4. Statistics and Information about depression • Depression affects almost 10% of the population, or 19 million Americans, in a given year • During their lifetime, 10%-25% of women and 5%-12% of men will become clinicallydepressed • Women are affected by depression almost twice as often as men - hormonal changes brought on by puberty, menstruation, menopause, and pregnancy. - suicide isserious risk for men with depression, 4 times more likely than women • It can affect any person at any age (usually25-44)

5. Statistics and Information about depression • Two-thirds of those who are depressed never seek treatment and suffer needlessly • personal weakness or character flaw • do not recognize the signs or symptoms that something may be wrong. • 80%-90% of those who seek treatment for depression can feel better within just a few weeks - one-third of those who are depressed actually receive treatment • Depression as the "common cold" of mental illness. • The economic cost ofdepression is estimated to be over $30 billion each year

6. Symptoms of depression • Emotional usually worst in the morning • depressed mood most of the day, nearly every day • sad, anxiety or “empty” feelings • lack of pleasure in usual activities • no interest in the future. • restlessness, irritability, pessimism • feelings of guilt, worthlessness, helplessness, and hopelessness • difficulty thinking, such as concentrating or making decisions, memory impairment - recurrent thoughts of death or suicide

7. Symptoms of depression • Physical (biological) • change in sleep patterns. • usually early morning awakening • inability to sleep • sleeping too much • change in appetite and weight • decreased appetite with weight loss (most common) • sometimes increased appetite with weight gain • loss of energy or fatigue • unexplained physical problems: • headaches, stomach problems, aches and pains,…

8. People who are depressed may not experience all of these symptoms. Some will have many symptoms, others will have just a few. In order to make diagnosis of a major depressive disorder, the symptoms (five or more) must have been present without a return to normality for at least 2 weeks.

9. Causes of depression It is not fully known what exactly causes clinical depression. Numerous theories: • biological causes • genetic causes • environmental influences Clinical depression is most often caused by the influence of more than just one or two factors.

10. Biological causes of depression • monoamine theory Deficit of monoamines: NA, 5-HT, DA in the brain The drugs, that will be increasing neurotransmission, in aminergic neuron systems will be used in depression treatment.  Concentration in the synaptic cleft 2. Cortisol- hormone that the body produces in response to stress  Neurotransmission in the brain Depressed patients havea raised baseline cortisol concentration

11. Biological causes of depression inadequate neurotransmitter signalling • functional deficit of NA, DA and 5-HT (monoamine theory) • desensitization of β-adrenergic and 5-HT2A receptors • dopaminergic system • GABA • peptidergic systems (AVP, opiates)

12. Reducing the central serotonin, noradrenaline, and dopamine concentration can lead to depression Drugs that increase the central serotonin, noradrenaline, and dopamine concentration improve depression!

13. Causes of depression • genetic causes • the result of what patients inherit from parents • If one or both parents have a vulnerability to depression, then it can be transmitted to their children. • if one identical twin suffers from depression or manic-depressive disorder, the other twin has a 70% chance • environmental influences - stress, breakup of important attachments (lack of loving parents, death of a parent during childhood), physical illness (medication, substance abuse)

14. Treating depression 1.Antidepressant drugs 2.Electroconvulsive therapy (ECT) -success rate of 78% - ECT for individuals whose depression is severe or lifethreatening or is effective in cases where antidepressantmedications do not provide sufficient relief of symptoms 3.Psychotherapy - learning about their disorder, learning to identify and avoid situations that may induce another depressive episode, view themselves and their situations more realistically, and to improve their interpersonal relationship skills.

15. Herbal remedies • Derived fromHypericum perforatum • Most popular remedy in the world • Appears effective for milder depression • Side effects: phototoxicity • available without prescription • 900-1800mg/day is recommended dose St. JohnsWort

16. Antidepressants

17. Antidepressants

18. Tricyclic antidepressants • Since the 1950s • Imipramine (Tofranil) • Three-ring chemical structures • Less popular choice than the new generation of antidepressants • Similar therapeutic efficacy • Choice of drug (side effects/duration of action) • Change of medicine after three weeks

19. Mode of action: • beefing up the brain`s supply of NA, 5-HT levels • Ø monoamine (NA, 5-HT) reuptakeinto presynaptic nerve from the synaptic cleft  concentration of NE, 5-HT  neurotransmission • The antidepressant effect of TCAs occur after two weeks or longer of continued treatment !!! - decreased reuptake  immediateeffect  not the antidepressant effect • long- termadaptational changes in receptors the antidepressant effect!!! - reuptake blocking potency doesn’t correspond with clinical potency • Ø receptors for ACh, HA, 5-HT, α

20. Tricyclic Antidepressants (TCAs) · amitriptyline (Elavil, Endep) · clomipramine (Anafranil) · desipramine (Norpramin, Pertofrane) · doxepin (Adapin, Sinequan) · imipramine (Imavate, Janimine, Presamine, Tofranil) · nortriptyline (Aventyl, Pamelor) · protriptyline (Vivactil) · trimipramine (Surmontil) Heterocyclic Antidepressants Second-generation amoxapine (Ascendin) maprotiline (Ludiomil) The important drugs of TCAs

21. Pharmacokinetics 1. Absorption and distribution • good absorption from GI tract upon oral administration • lipophilic properties • good BBB penetration • long half-life (for imipramine 4-18 h) • first-pass effect  inconsistent and low bioavailability • patient’s response  dose adjustment

22. Pharmacokinetics 2. Fate • TCAs are metabolized by enzymes Cyt.P450 • metabolites pharmacologically active! Amitriptylinenortriptyline* Imipramine desipramine* • Active metabolites prolong pharmacological effects • excretion  urine

23. Therapeutic uses of TCAs • severe depression - also prevents recurrence • depression with anxiety • panic and phobic disorders • bet-wetting in children(imipramine) • chronic or psychogenic pain • bipolar disorder

24. Side effects of TCAs • antimuscarinic effects: dry mouth, blurred vision, urinary retention, constipation and aggravation of glaucoma and epilepsy • postural (orthostatic) hypotension  reflex tachycardia • cardiovascular (heart failure, hypertension, hypotension, sudden death, arrhythmias, ECG changes) • sedation • hormonal effects (loss of libido, impotence) • others: gastric irritation, weight change, allergic skin reactions and jaudince

25. Contraindications to TCAs • prostate • narrow angle glaucoma • recent myocardial infarction • heart block, heart failure • arrhythmias • epilepsy

26. Drug interaction of TCAs • MAOI „serotonin syndrome” - life threatening! tachycardia, hypertension, hyperactivity,hyperpyretic crisis, convulsions, coma TCAs should not be given in conjunction with- or within at least two weeks of treatment with -a MAOI. TCA+MAOI= monitoring! • Drugs having anticholinergic actions • Central nervous system depressant (alcohol, barbiturates) • Hepatic enzyme inhibitors (cimetidine, SSRI) • Hepatic enzyme inducers (carbamazepine) • Oral coumarin anticoagulants (increase effect) • Guanetydyna (decrease effect)

27. Tolerance and withdrawal with TCA’s • Tolerance generally develops to anticholinergic and sedative side effects within a short time • An occasional withdrawal syndrome is reported with abrupt discontinuation from high dosages. • True dependence, however, does not occur • TCAs can be used for prolonged treatment without loss of effectiveness

28. Tricyclic antidepressants • (!) unmask manic behavior in BAD • (!) low TI  suicidal attempts  acute toxicity (arrhytmias, respiratory depression, convulsions,…) • monitored closely

29. Antidepressants

30. Selective serotonin-reuptake inhibitors SSRIs • Introduced in the 1980s as a new antidepressants • Replaced the TCAs • Affect the serotonin-containing nerves • safe, better tolerability, less severe side effects • Less toxic in overdose than TCAs • Do not require blood monitoring

31. Mode of action of SSRIs • Specifically inhibit 5-HT reuptake from synaptic cleft into presynaptic nerve terminals • concentration of 5-HT in the synaptic cleft long term adaptational changesserotonin neurotransmission • no effect on NE reuptake • don`t have affinity for M, HA, 5-HT and α receptors

32. SSRIs include: • -Citalopram (brand name: Celexa), • -Fluoxetine (brand name: Prozac), • - Paroxetine (brand name: Paxil) • - Sertraline (brand name: Zoloft) • - Fluvoxamine Fluoxetine is now the most widely prescribed antidepressant in the United States!

33. Pharmacokinetics of SSRIs • Absorption and distribution • oral administration • rapidly absorbed and distributed • Active metabolites! – citalopram, fluoexetine, sertraline fluoexetine  norfluoxetine* • Norfluoxetine is 3x more selective, potent than parent drug • fluvoxamine(+) no active metabolite  t0.5~ 15 h fluoexetine t0.5up to 30 days

34. The long half-life of fluoxetine and its metabolite imposes cautious management when treatment is to be changed, because the drug lingers in the blood for some time after the treatment has been discontinued, this way increasing the risk of drug interactions.

35. Side effects of SSRIs SSRIs have fewer side effects than TCAs (fewer anticholinergic effects and lower cardiotoxicity) • gastrointenstinal disturbances: nausea,vomiting,diarrhoea • headache, insomnia, • anxiety, agitation • sexual dysfunction (loss of libido, impotence) • allergic skin reactions • weight loss • tremors, seizures • serotonin syndrome!

36. Efficacy similar to that of TCAs Major depression Clinical advantages: - no anticholinergic effects - no orthostatic hypotension - no weight gain - no toxic in overdose - lower cardiotoxicity Therapeutic uses of SSRIs:  acceptability

37. Therapeutic uses of SSRIs: • depression in early stages • minor depressive illness • anxiety disorders: - panic attacks - obsessive-compulsive disorder • eating disorders (bulimia nervosa, anorexia nervosa) • chronic pain (e.g. pain associated with diabetic neuropathy) • menstrual syndrome

38. Drug interactions of SSRIs -MAOI„serotonin syndrome” It should wait at least two weeks between stopping MAOIsand starting an SSRI, or at least five weeks after stopping an SSRI and starting an MAOI. - TCAs monitoring! -tryptophan (headache, nausea, sweating anddizziness) -warfarin (excess bleeding)

39. Drug interactions of SSRIs SSRIs are inhibitors of hepatic cytochrome P450 isoenzyme! metabolizes: -  neuroleptics, - TCAs, - some antiarrhythmics - beta blockers paroxetine> fluoxetine> sertraline> citalopram>fluvoxamine - Hepatic enzyme inhibitors (cimetidine, SSRI) -Hepatic enzyme inducers (carbamazepine)

40. Antidepressants

41. MAOIs • Adverse reactions associated with MAOIs are generally more frequent and severe than with other antidepressants. - reducing the dosage - monitoring the patients • Use of MAO inhibitors is now limited, because of the complicated dietary restrictions required of patients taking MAOIs!

42. Mechanism of action of MAOIs Inhibit the action of monoamine oxidase- MAO 5-HT, NA MAO-A Tyramine Dopamine, phenylethylamine MAO-B 1. irreversibly or reversibleinactivation MAO 2. nonselective or selective - MAOI-A and MAOI-B selective + reversible:moclobemide  less ADEs, INTs

43. Mechanism of action of MAOIs Inactivation of monoamine oxidase •  concentration ofNA, 5-HT, DA in thepresynaptic neuron •  leakage ofmonoamines intosynaptic space •  monoaminetransmission

44. MAOIs: 1. Non-reversible/non-selective monoamine oxidase inhibitors (MAOIs) • phenelzine - the hydrazine derivative, amphetamine-like activity. • isocarboxazid - the hydrazine derivative • tranylcypromine- non-hydrazine derivatives, amphetamine-like activity. 2.Non-reversible/ selective monoamine oxidase inhibitors • Selegilina MAO-B 3. Reversible/ selective monoamine oxidase inhibitors • Moclobemid

45. Actions and Pharmacokinetics of MAOIs Actions: • antidepressant action after 2-4 weeks • amphetamine-like stimulatory Pharmacokinetics: • oral administration • long duration after discontinuation of treatment (~ 2 weeks) irreversibly inactivated

46. Washout period • The irreversibility of the binding of the enzyme by IMAO is a serious problem • Effects of MAOIs continue until enough new, unbound MAO is synthesized ! • Enzyme regeneration occurs several weeks after the ending of treatment • wash-out period of at least 2 weeks should be allowed between stopping a MAOI and starting a TCA or a SSRI • During this 2 weeks the patients should continue dietary and other restrictions until this time has elapsed.

47. Therapeutic uses of MAOIs • atypical depression (e.g appetite disorders) • depression • if unresponsive to TCAs • if associated with strong anxiety • if associated low psychomotor activity • resistant depression • facial pain • phobic states

48. Adverse effects/interactions of MAOIs • tyramine rich food (cheese, red wine, beer, chicken liver)  „cheese reaction” • tyramine not inactivated by MAO   catecholamine release  tachycardia, headache, nausea, hypertension, cardiac arrhytmias, stroke • develops within 30 minutes to 1 hour after ingestion of the food • antidote  phentolamine, prazosin • Sympathomimetic agents(dopamine, ephedrine), opioid analgesics, narcotics • TCAs or SSRIs „serotonin syndrome” • washout period of ~2 weeks when therapy change

49. MAO blockade has the potential of serious and indeed lifethreatening consequences if the subject is exposed to certain agents, which would normally be metabolized by this sameenzyme. The patients treatment MAOI must therefore be educated to avoid tyramine containing foods and some drugs. For these reasons, theMAOIs are no longer considered as first-choice antidepressants and are usually only prescribed after other options have failed.

50. Foodstuffs (high in tyramine) to avoid with MAOIs • Drugs to avoid with MAOIs: 1. sympathomimetic agents, suchas: -dopamine -ephedrine -levodopa -pseudoephedrine 2. opioid analgesics 3. amphetamine 4. dextromethorphan 5. CNS depressant (e.g alcohol, narcotics) 6. SSRIs, TCAs