1. Antidepressants  other drugs used in affective disorders Martin Štěrba, PharmD., PhD. Associate professor Department of Pharmacology 2014

2. Definitions Affective disorders - mental illnesses characterized by pathological changes in mood (not thought – compare with schizophrenia) 1.Unipolar disorders Depression – pathologically depressed mood (life time prevalence up to 17%) Mania – excessive elation and accelerated psychomotoric activity (rare) 2.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 plan or 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 the CNS, 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) Non-pharmacological treatment Psychotherapy Light therapy Electroconvulsive therapy (ECT)

7. General notes to pharmacotherapy of depression Pharmacotherapy – key approach in serous forms of depression One of the alternatives in mild forms of depression Duration of treatment ( acute phase and prophylactic treatment ) Long duration – prevention of relapses which are otherwise frequent 6-9 months (optimum 1 year) after remission of the 1st episode Even life-long treatment after multiple complicated relapses Important to keep compliance (may be difficult!) Typical chances for 1 st antidepressant (AD) response Up to 66% - positive clinical response Up to 40% - complete remission achievement (in  6 weeks) Treatment evaluation after 3-4 weeks Change of antidepressant after 4-6 weeks Combination od ADs after related failure of monotherapy Dose response need not be perfect Augmentation of therapy + atypical antipsychotics, Li + or buspiron

8. Withdrawal syndrome Vertigo, headache, nightmares, inability to concentrate, irritability, ataxia, paresthesia, tremor, nausea, diarrhea, flu-like symptoms Mostly to moderate intensity, may be unpleasant though After long treatment with higher doses Onset 1-7days after drug withdrawal, disappears after 24 hours upon AD re-administration Concerns TCA, SSRI, venlafaxine, IMAO, … T 1/2 makes the difference (longer T 1/2 and active metabolites and – lower risks!) Prevention of the syndrome – gradual decrease of doses (during weeks), prolongation of dosing interval (skipping a day) It is not a drug dependence (no reward effect - no craving) !

9. 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 neurotransmitters noradrenaline (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

10. Most important TCAs imipramine (a representative) desimipramine demethylated form, the active 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

11. 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.

12. Adverse effects TCA are effective antidepressants their use is complicated by numerous troublesome adverse effects Anticholinergic (atropine-like) due to M-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 (frequent in elderly) Sedation - H 1 -blockade drowsiness, difficulty in concentration (amitriptyline,) Sexual dysfunction (10-20% of patients, loss of libido, impaired erection) Weight gain – most significant among all ADs Withdrawal syndrome  Possible problems with compliance ?!!!

13. Acute intoxication with TCA Very dangerous - 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 patient should be treated under supervision of specialists or treated as inpatients TCA - low therapeutic index (6 individual doses may cause toxicity) Target systems – the CNS and heart CNS - pronounced atropine-like effects. Excitement, hallucinations, delirium, convulsions. Coma and respiratory depression may follow. Cardiac dysrhythmias very common tachycardia (antimuscarine action) atrial or ventricular extrasystoles, QRS complex widening, QT interval elongation. Therapy – symptomatic: (diazepam in convulsions), bicarbonate Hemodialysis ineffective – large Vd

14. MonoAminoOxidase Inhibitors (MAOI) The first compounds (iproniazide derivatives) - originally developed as antimycobacterial drugs by chemical modification of isoniazid (1950s). Principal mechanism of action: Inhibition of intracellular enzyme MAO in CNS neurons (= decrease in degradation of catecholamines and serotonin). antidepressant action - MAO-A enzyme isoform 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!

15. MAOI drugs Irreversible non-selective inhibitors (hydrazides) long lasting inhibition (up to 1-2 weeks) despite of the elimination rate of a drug 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.

16. 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)

17. Interaction with food The most serious problem of this class of drugs Much less important in novel RIMA drugs like 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, bananas etc. This risk is minimal with modern RIMA drugs.

18. Interaction with drugs Hypertension & hypertensive crisis TCA wash-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 profounds the effect of: benzodiazepines, antihistamines, alcohol (inhibition of liver enzymes – low specificity)

19. Selective Serotonin Re-uptake Inhibitors (SSRI) More modern (1 st 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-HT 1A ) and postsynaptic receptors (important subtype 5-HT 2A ) Other indications of SSRI anxiety disorders generalized anxiety, panic disorder, social anxiety disorder, obsessive- compulsive disorder bulimia nervosa, gambling, drug withdrawal

20. Most important SSRI Fluoxetine Sertraline Citalopram Fluvoxamine Paroxetine Escitalopram- enantioselective forms e.g. (S-enantiomer)

21. 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) CYP450 inhibitors! (mainly 2D6, 3A4) More in fluoxetine, fluvoxamine – less in citalopram Possible Clinical Interactions (increased effect of): TCA, venlafaxine, benzodiazepines, clozapine,haloperidol, codeine warfarine, aspirin, b-blockers, Ca2+ channel blockers…. Long half-lives of elimination(s) fluoxetine (T 1/2 =50h) + active metabolite (T 1/2 =240h) short in paroxetine

22. Adverse effects Relative improvement to other antidepressants (mostly mild) GIT nausea, vomiting, abdominal cramps, diarrhea relatively frequent, higher doses? At the begging – may be transient Anxiety - an increase in anxiety or agitation during early treatment Headache Sexual dysfunctions ( up to 50% patient, loss of libido, erectile dysfunction…) Restlessness (akathisia) Hyponatremia – syndrome of Inapropriate ADH release Insomnia and fatigue Serotonin syndrome upon intoxication or drug interactions

23. Other and atypical antidepressants Serotonin and Noradrenaline Reuptake Inhibitors (SNRI) venlafaxine pharmacodynamics like in TCA improved profile of adverse reactions (no other receptors affected) 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 Noradrenaline and Dopamine Reuptake Inhibitors (NDRI) Bupropion CNS activating effects (low sedation), use: severe depression + smoking cessation treatment. adverse reactions: insomnia, excitation, restless, siezures Noradrenaline Reuptake Inhibitors (NaRI) Reboxetine also rather activating

24. Other and atypical antidepressants Serotonin (5HT 2A ) 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 ( discontinued due to the rare severe hepatotoxicity) 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)

25. Serotonin syndrome upon intoxication or drug interactions SSRI, IMAO, TCA, venlafaxine, 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

26. Therapy of bipolar disorder Aims: To eliminate mood episodes using mood stabilizers maximize adherence to therapy improve functioning of the patients eliminate adverse effects To manage acute episodes Manic phase – atypical neuroleptics (e.g. olanzapine) may be used Depression – role of antidepressants may be tricky – may cause switch to mania and/or accelerate cycling „MOOD STABILIZERS“ Lithium Valproate Carbamazepine Lamotrigine Adjunctive drugs (antidepressants and benzodiazepines )

27. 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 (T 1/2 = 20-24h; when the treatment is abruptly stopped - slow 2 nd phase of excretion /1-2 weeks/ representing Li + taken up by cells occurs) only 20% of Li + filtered by GF is excreted (80% reabsorbed)

28. 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 the urine 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 TDM to reach desirable effects without 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)