Antidepressants  other drugs used in affective disorders

1. Antidepressants  other drugs usedin affective disorders Martin Štěrba, PharmD., PhD. Associate professor Department of Pharmacology 2012

2. Definitions • Affective disorders- mental illnesses characterized by pathological changes inmood (not thought – compare with schizophrenia) • Unipolar disorders • Depression – pathologically depressed mood (life time prevalence up to 17%) • Mania – excessive elation and accelerated psychomotoric activity (rare) • Bipolar disorder(manic-depressive illness) – „cycling mood“ • = severe highs (mania, event. hypomania) and lows (major depressive episodes) • prevalence 1-5%, life-time illness, stronger genetic background

3. Depression • common mental disorder that presents with depressed mood, loss of interest or pleasure, feelings of guilt or low self-worth, disturbed sleep or appetite, low energy, and poor concentration(WHO def.) • Major Depressive Episode Criteria/Core symptoms • Five (or more) of the following symptoms have been present during the same 2-week period and represent a change from previous functioning • (1) depressed mood or (2) loss of interest or pleasure must be present • significant weight loss /gain • insomnia or hypersomnia • psychomotor agitation or retardation, fatigue or loss of energy • feelings of worthlessness or excessive or inappropriate guilt • diminished ability to think or concentrate, or indecisiveness • recurrent thoughts of death or suicidal ideation without a specific planor a suicide attempt (!)

4. What is not depression • it is not the same as a passing „blue mood“. • It is not a sign of personal weakness or a condition that can be wished away. • people with a depressive disease can not merely "pull themselves together" and get better. - no effect of encouraging to do so! • without treatment, symptoms can last for weeks, months, or years. • appropriate treatment, however, can help most people with depression.

5. Neurobiological theory of depression • Monoamine (catecholamine) theory (1965) • = underlying biological basis for depression is a deficiency of central noradrenergic and/or serotonergic transmission in the CNS Supported by: • pharmacological effects of antidepressants (TCA, MAOI) • In the past, medication of hypertension with reserpine induced depression Contradiction: • several drugs (e.g., cocaine) increase the amount of these neurotransmitters in theCNS, but are unable to treat depression • antidepressants induce rapid change in neurotransmitters, but onset of antidepressant action is significantly delayed • „Receptor theory“ • the problem is in up-regulation of post-synaptic receptors and alterations in their sensitivity • The antidepressant treatment increases the amount of monoamines in CNS and gradually normalize the density/sensitivity of their receptors • The precise pathophysiology of depression remains unsolved

6. Therapy of depression Pharmacotherapy • Tricyclic antidepressants (TCA) • Monoamine oxidase inhibitors (MAOI) • Selective Serotonin Re-uptake Inhibitors (SSRI) • Other and atypical antidepressant • Serotonin-2 Antagonists/Reuptake Inhibitors (SARI) • Serotonin and Noradrenaline Reuptake Inhibitors (SNRI) • Noradrenaline and Dopamine Reuptake Inhibitors (NDRI) • Noradrenaline Reuptake Inhibitors (NaRI) • Noradrenergic/Specific Serotonergic Antidepressants (NaSSA) Duration of treatment – 6 months after recovery (1st epizode), may be even life-long treatment in recurrent depression Non-pharmacological treatment • Psychotherapy • Light therapy • Electroconvulsive therapy (ECT)

7. Tricyclic Antidepressants (TCAs) • Chemical structure with characteristic three-ring nucleus – lipophilic nature • Originally developed as antipsychotics (1949), but were found to have no effect in this indication. • Principal mechanism of action: • blockade of re-uptake of monoamine neurotransmittersnoradrenaline(NA)and serotonin (5-HT) • by competition for binding site of the carrier protein (NET and SERT) • NET vs SERT inhibition – variable within the group • 5HT and NA neurotransmission is similarly affected but the effect on the dopamine system is much less important (compare with cocaine) • in most TCA,other receptors(incl. those outside the CNS) • blockade of H1-receptor, -receptors, M-receptors imipramine

8. Most important TCAs • imipramine(a representative) • desimipramine • demethylated form, theactive metabolite of imipramine • amitriptyline • nortriptyline • demethylated form, the active metabolite of amitriptyline) • Clinical use and efficacy is relatively similar within the group • The more significant difference is in their adverse effects

9. Pharmacokinetics • Administered orally • rapid absorption, extensive first pass effect  low and inconsistent BAV • Strong binding • to plasma proteins(90-95% bound). • in tissues + wide distribution(high lipophilicity) = large distribution volumes (ineffectiveness of dialysis in acute intoxications). • Biotransformation • in the liver (CYP450, N-demethylation and tricyclic ring hydroxylation) • most of these metabolites are active! CYP450 polymorphisms • Glucuronidation  inactive metabolites excreted in the urine. • Elimination half-lives • generally LONG(T1/2 =10-80h). • Elderly patients – even longer T1/2  risk of accumulation.

10. Adverse effects • TCA areeffectiveantidepressants • their use is complicated by numerous troublesome adverse effects • Anticholinergic (atropine-like) due toM-blockade • Dry mouth, blurred vision • Constipation, urinary retention (more in amitriptyline, less in imipramine) • Palpitations, tachycardia • Postural (orthostatic) hypotension+ reflex tachycardia • -blockadeof adrenergic transmission (frequent in elderly) • Sedation- H1-blockade • drowsiness, difficulty in concentration (amitriptyline,) • Sexual dysfunction(loss of libido, impaired erection) Possible problems with compliance ?!!!

11. Acute intoxicationwith TCA • Very dangerousand relatively frequent • patients with depression often have suicidal tendencies • Precautions • patient education - remind him/her that 2-4 week delay in the effect is anticipated and that it is NOT a failure of medication) • therapy of concomitant anxiety/agitation • prescription of limited quantities of TCA • high risk patientshould be treated under supervision of specialists or treated as inpatients

12. Acute intoxication • TCA - low therapeutic index • Target systems – the CNS and heart • CNS - pronouncedatropine-like effects. • Excitement, hallucinations,delirium, convulsions. • Coma and respiratory depression may follow. • Cardiac dysrrhythmias • very common • tachycardia (antimuscarine action) • atrial or ventricular extrasystoles, QRS complex widening, QT interval elongation. • ventricularfibrillation and sudden death may occur. • Hypotension • Treatment- diazepam (seizures), physostigmine??? • No effect of haemodialysis and hemoperfusion is practically ineffective

13. MonoAminoOxidaseInhibitors (MAOI) The first compounds (iproniazidederivatives) - originally developed as antimycobacterialdrugs by chemical modification of isoniazid molecule (1950s). Principal mechanism of action: Inhibition of intracellular enzyme MAO in CNS neurons (= decrease in degradation of catecholamines and serotonin). antidepressant action - MAO-A enzymeisoform inhibition  increased cytoplasmic pool of monoamines leading among other(s) to spontaneous leakage of monoamines. when given to normal non-depressed subjects they increase a motor activity and cause euphoria + excitementsrisk of abuse!

14. MAOI drugs • Irreversible non-selective inhibitors(hydrazides) long lasting inhibition (up to 1-2 weeks) despite of the elimination rate of adrug • phenelzine • tranylcypromine • Reversible Inhibitors of MAO-A (RIMA) • moclobemide Great difference in adverse reactions between these groups Note: Reversible inhibitors of MAO-B (e.g. selegiline) are used in the treatment of Parkinson's disease.

15. Adverse reactions and toxicity • Hypertension • Postural hypotension(in up to 1/3 patients) • CNS stimulation– tremor, excitement, insomnia, convulsions in overdose. • Weight gain(increased appetite) • Rare severe hepatotoxicity(hydrazine MAOI)

16. Interaction with food • The most serious problem of this class of drugs • Much less important in novel RIMA drugslike moclobemide • Tyramine „cheese and wine“ reaction • tyramine • a natural indirect sympathomimetic produced by fermentation • some food contain high amounts • normally metabolized by MAO in the gut and liver. • After MAOI treatment bioavailability of tyramine is significantly higher • pharmacodynamic synergism • hypertensive crisis, severe headache and potentially fatal intracranial hemorrhage or other organ damage. • Dietary restrictions: maturing cheeses, wine, beer, yogurts, bananasetc. • This risk is minimal with modern RIMA drugs.

17. Interactionwithdrugs • Hypertension & hypertensive crisis • TCAwash-out period (2 weeks) when switching these antidepressants! Lower risk in RIMA. • levodopa(catecholamine precursor), sympathomimetics • Serotonin syndrome(SSRI, TCA, opioids e.g. pethidin) • confusion, agitation and excitation, tremor, fever, sweating, nausea, diarrhea, sleep disruption • prolongs and profoundsthe effect of: • benzodiazepines, antihistamines, alcohol (inhibition of liver enzymes –low specificity)

18. Selective Serotonin Re-uptakeInhibitors(SSRI) • More modern (1st drug fluoxetine available in 1988) and safe antidepressants • Principal mechanism of action: • selective inhibition of 5-HT (serotonin) reuptake (SERT) •  gradual complex changes in the density and/or sensitivity • both autoreceptors (5-HT1A) and postsynaptic receptors (important subtype 5-HT2A ) • Other indications of SSRI • anxiety disorders • generalized anxiety, panic disorder, social anxiety disorder, obsessive-compulsive disorder • bulimia nervosa, gambling, drug withdrawal

19. Most important SSRI • Fluoxetine • Fluvoxamine • Paroxetine • Sertraline • Citalopram Enantioselective forms e.g. escitalopram (S-enantiomer)

20. Pharmacokinetics • Good absorptionafter oral administration • Important biotransformationin the liver • CYP450 - 2D6 and 2C19 isoforms polymorphism  interindividual variability in the clinical effect) and active metabolites (e.g., fluoxetine) • CYP450 inhibitors! • Fluoxetine, fluvoxamine -1A2, 2C19, 2D6, 3A4 • Paroxetine and duloxetine – 2D6 • PossibleInteractions – TCA, clozapine, venlafaxine, haloperidol, warfarine, b-blockers, Ca2+ channelblockers…. • Long half-lives of elimination(s) • fluoxetine (T1/2=50h) + active metabolite (T1/2 =240h) • Drug interaction • based on plasma protein binding and CYP blockade • increased effect of co-administered TCA, -blockers, benzodiazepines etc.

21. Adverse effects • Relative improvement to other antidepressants (mostly mild) • GIT • nausea, vomiting, abdominalcramps, diarrhea • relativelyfrequent, higherdoses? • Headache • Sexual dysfunctions(lossof libido, erectiledysfunction…) • Restlessness (akathisia) • Anxiety - an increase in anxiety or agitation during early treatment • Insomniaand fatigue • Serotonin syndromeupon intoxication or drug interactions

22. Other and atypical antidepressants • Serotonin and Noradrenaline Reuptake Inhibitors (SNRI) • venlafaxine • pharmacodynamics like in TCA • improved profile of adverse reactions • Very effective, better remission rate than SSRI • Adverse reactions: nauzea, vertigo (both frequent and may improve), hypertension, manic reactions • Used in: depression and depression with anxiety, generalized anxiety disorders, social fobias, neuropathic pain • Liver metabolism and active metabolite • Noradrenaline and Dopamine Reuptake Inhibitors (NDRI) • Bupropion • rather CNSactivating effects (low sedation), • use: severe depression + smoking cessation treatment. • adverse reactions: insomnia, excitation, restless, siezures • Noradrenaline Reuptake Inhibitors (NaRI) • Reboxetine • also rather activating • severe depression prophylaxis and treatment • Adverse reactions: dry mouth, headache, dysuria, sweating

23. Other and atypical antidepressants • Serotonin (5HT2A) Antagonists/Reuptake Inhibitors (SARI) • In depression with significant anxiety and sleep disturbances • Inhibits select. SERT, antagonist on H1 and 1 and 2- receptors • Trazodone • nefazodone(newer and improved) • Miscellaneous • St John´s wort (Hypericum perforatum) • a herb containing number of active compounds (among other hyperforin a MAOI) • clinically effective and well tolerated • but it induces CYP450 • risk of drug interactions! E.g. it decreases the effect of ciclosporin which may result even in transplant rejection in transplanted patients)

24. Serotonin syndrome • upon intoxication or drug interactions • SSRI, IMAO, TCA, venlafaxine, nefazodone, pethidine, tramadol • Drugs inhibiting SSRI metabolism (erytromycine…) • Serotonine system overstimulation • Symptoms • Psychiatrical: anxiety, confusion, hypomania, agitation • Neurological: tremor, myoclonus, hyperreflexia, ataxia • GIT: nauzea, vomiting • Cardiovascular: hypertension tachycardia • Fever, sweating! • Managment – benzodiazepines (lorazepam), supportive care, • 5-HT blockers, such as methysergid, cyproheptadine, and propranolol may be given

25. Therapy of bipolar disorder • Main aim: • to eliminate mood episodes • maximizeadherence to therapy • improve functioning of the patients • eliminate adverse effects „MOOD STABILIZERS“ • Lithium • Valproate • Carbamazepine • Lamotrigine • Adjunctive agents (antidepressants and benzodiazepines)

26. Lithium • Since 1949 - indication as a prophylactic treatment in bipolar disorder. Effective also in 60-80% patients with mania or hypomania. • Principle mechanism of action • remains elusive though profound effects on second messenger systems (mainly IP3) is supposed. • Pharmacokinetics • administered orally (readily and almost completely absorbed) • distribution - extracellular, then gradually accumulates in various tissues • elimination – 95% in urine(T1/2= 20-24h; when the treatment is abruptly stopped - slow 2nd phase of excretion /1-2 weeks/ representing Li+ taken up by cells occurs) • only 20% of Li+ filtered by GF is excreted (80% reabsorbed)

27. Lithium – toxicity and adverse reactions • Acute intoxication,symptoms: • GIT: vomiting, profuse diarrhea • CNS: confusion, tremor, ataxia, convulsions, coma. • Heart:arrhythmias, hypotension Unfortunately there is no specific antidote supportive treatment • Toxicity of long-term therapy • Renal toxicity – the kidney's ability to concentrate theurine is decreased • Adverse reactions: polyuria and polydipsia, weight gain, GIT disturbances (vomiting, nausea, dyspepsia), alopecia • Drug interactions: thiazides – increased Li reabsorption  intoxication Critical importance of TDMto reach desirable effectswithout risk of toxicity! The effects as well as toxicity correlates much more better with plasma concentrations than with dose. The range of plasma concentrations is narrow: 0.5-1.0 mmol/L (above 1.5 mmol/L toxic effects appear)