Antidepressants  other drugs used in affective disorders

1. Antidepressants  other drugs usedin affective disorders Martin Sterba, MSc. Department of Pharmacology

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; at least one of the symptoms is either (1) depressed mood or (2) loss of interest or pleasure. • depressed mood most of the day… • markedly diminished interest or pleasure • 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) = the underlying biological or neuroanatomical basis for depression is a deficiency of central noradrenergic and/or serotonergic transmission in the CNS Supported by: • pharmacological effect 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 • the effect of antidepressants on neurotransmitter levels is relatively quick 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 thereby 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.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) are also affected: 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 close within the group the more significant difference is in their adverse effects

9. Pharmacokinetics • Administered orally – rapid absorption, however extensive first pass effect  low and inconsistent BAV • Strong binding to plasma proteins (90-95% bound). They are also 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 are effective antidepressants but 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 - -blockade of adrenergic transmission in thevasomotor center (frequent in elderly) • Sedation, drowsiness, difficulty in concentration (amitriptyline, H1-blockade) • Sexual dysfunction(loss of libido, impaired erection) Possible problems with compliance ?!!!

11. Acute intoxication • Very dangerous and relatively frequent – patients with depression often have suicidal tendencies • Precautions: • taking care about 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 patient should be treated under supervision of specialists or treated as inpatients

12. Acute intoxication • Unfortunately alow therapeutic index • Target systems – the CNS and heart • Initially excitement, hallucinations and deliriumis observed, may be accompanied with convulsions. Coma and respiratory depression may follow. Pronounced atropine-like effects. • Cardiac dysrrhythmias are very common – tachycardia (antimuscarine action), atrial or ventricular extrasystoles, QRS complex widening, QT interval elongation. Ventricular fibrillation and sudden death may occur. • Hypotension • Treatment- diazepam (seizures), physostgmine??? • No effect of haemodialysis and hemoperfusion is practically ineffective

13. MonoAmine Oxidase Inhibitors (MAOI) The first compounds (iproniazid derivatives) were 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 is attributed to MAO-A enzyme isoform inhibition increased cytoplasmic pool of monoamines leading among other(s) to spontaneous leakage of monoamines. In contrast to other antidepressants, when given to normal non-depressed subjects they increase a motor activity and cause euphoria + excitements (whileTCA would cause only sedation and/or confusion).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) • Atropine-like adverse effects – like in TCA but less common • Rare severe hepatotoxicity (hydrazine MAOI)

16. Interaction with foods • The most serious problem of this class of drugs • Much less important in novel RIMA drugs like moclobemide • Tyramine „cheese and wine“ reaction • some kind of foods contain high amounts of tyramine (natural indirect sympathomimetic produced during fermentation), which is however normally metabolized by MAO in the gut and liver. • In depressed patients treated with MAOI, these enzymes are also inhibited  bioavailability of tyramine is significantly higher which together with pharmacodynamic synergism  strikingly increased noradrenaline transmission results in hypertensive crisis, severe headache and potentially fatal intracranial hemorrhage or other organ damage. • Dietary precautions: restriction in the consumption of some maturing cheeses, wine, beer, yogurts, bananas etc. • This risk is minimal with modern RIMA drugs.

17. Interaction with drugs • 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-uptake Inhibitos (SSRI) • More modern (1st drug fluoxetine available in 1988) and safe antidepressants • Principal mechanism of action: • selective inhibition of 5-HT (serotonin) reuptake 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

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

20. Pharmacokinetics • Good absorption after oral administration • Important biotransformation in the liver • CYP450 - 2D6 and 2C19 isoforms (polymorphism  interindividual variability in the clinical effect) and active metabolites (e.g. fluoxetine) • 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 but also -blockers, benzodiazepines etc.

21. Adverse effects • Relative improvement to other antidepressants (mostly mild) • GIT– nausea, vomiting, diarrhea • Headache • Sexual dysfunctions • Restlessness (akathisia) • Insomnia and fatigue • Few patients experience an increase in anxiety or agitation during early treatment • Serotonin syndrome upon intoxication or drug interactions

22. Other and atypical antidepressants • Serotonin-2 Antagonists/Reuptake Inhibitors (SARI) • trazodone (sedative effects) • nefazodone(newer and improved) decreased some SSRI adverse reactions • Serotonin and Noradrenaline Reuptake Inhibitors (SNRI) • venlafaxine- pharmacodynamic like in TCA however improved profile of adverse reactions • Noradrenaline and Dopamine Reuptake Inhibitors (NDRI) • bupropion – rather CNSactivating effects (low sedation), usage: severe depression + smoking cessation treatment. Adverse reactions: insomnia, excitation, restlessness, lowers epilepsy threshold • Noradrenaline Reuptake Inhibitors (NaRI) • reboxetine – also rather activating • maprotiline • Noradrenergic/Specific Serotonergic Antidepressants (NaSSA) • mirtazapine – increased NA and 5-HT neurotransmission through blockade of their autoreceptors (low 5-HT adverse effects – blocks also postsynaptic 5-HT receptors) • Miscellaneous • St John´s wort (Hypericum perforatum)–a herb containing number of active compounds (among other hyperforin a MAOI). It was proved to be 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)

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

24. 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)

25. 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)