Psychopharmacs antidepressants prof MUDr Eva ekov CSc Dept

Psychopharmacs antidepressants prof. MUDr. Eva Češková, CSc. Dept. of Psychiatry, Masaryk University , Brno

Psychopharmacs - antidepressants § § § § § definition and history development of antidepressants (AD) classification of ADs mechanism of action neurobiology of depression phases of treatment, efficacy doses and duration of treatment side effects indication literature

Definition and history Definition: antidepressants (AD) - psychopharmacs influencing affectivity in a positive way History- ADs were discovered empirically: § as a result of clinical observation of pts. who were receiving the drugs for other disorders: tuberculosis in the case of monoaminooxydase inhibitors (MAOI) and schizophrenia in the case of tricyclic antidepressants (TCA) § currently available ADs fit into one of three pharmacological classes: enzyme inhibitor (MAOI, RIMA), uptake blockers and receptor blockers

Developement of antidepressants 1950: MAOI 1960: TCA (I. generation) 1970: heterocyclics (II. generation) - maprotiline, mianserin, trazodone, bupropion 1980: SSRI (III. generation) 1990: receptor modulatores - nefazodone, mirtazapine dual reuptake inhibitors (IV. generation) venlafaxine, duloxetine, milnacipran selective reuptake inhibitor (NA- reboxetine) selective reuptake stimulator (tianeptine) Newer ADs are more specific, better tolerated, safer

Developement of ADs - specific ADs SSRI (selective serotonin reuptake inhibitors) SARI (serotonin antagonist/reuptake inhibitor): trazodone, nefazodone NRI (NA reuptake inhibitors) : reboxetine, atomoxetine NDRI (NA/DA reuptake inhibitor): bupropion D 2/D 3 autoreceptors antagonist: amisulpride Dual –acting ADs: SNRI (serotonin and noradrenaline reuptake inhibitors) venlafaxine, milnacipran, duloxetine Na. SSA (noradrenaline and specific serotonergic antidepresant) mirtazapine

Classification of AD TCA (I. generation): Chemistry: § TCA have a 3 ring nucleus § TCA with 2 methyl groups on the nitrogen atom of the side chain - tertiary amines (amitriptyline, clomipramine) with only one methyl group in this position -secondary amines (desipramine, nortriptyline) Tetracyclic ADs (II. generation) § mianserine, maprotiline § some others- trazodone, viloxazine

Classification of AD SSRI (III. generation) : § fluoxetine (f. o. Prozac) § fluvoxamine (f. o. Fevarin) § sertraline (f. o. Zoloft) § paroxetine (f. o. Seroxat) § citalopram (f. o. Seropram) § nowadays, SSRIs are antidepressants of the first choice § there are differences among individual SSRIs especially in pharmacokinetics, e. g. in their potential to inhibit CYP 450 enzymatic system

Classification of AD Dual acting antidepressants (IV generation): § efficacy comparable to TCA, higher than SSRI, especially in severe depression § venlafaxine - available in sustained release formulation-Effexor XR (prolonged duration of action, lower peak plasma levels and fluctuations, better tolerability - higher compliance § milnacipran § mirtazapine - available also in orally disintegrating formulation -Remeron. Sol. Tab (dissolves on the tongue, pleasant taste - increased comfort and compliance)

Classification of AD: MAOI Chemistry: § phenelzine and isocarboxazid - derivative of hydrazine, tranylcypromine and selegiline - cyclopropylamine (structurally related to amphetamine) Pharmacokinetic: § MAO - widely distributed enzyme, high concentration in the liver, GIT, CNS and the sympathetic nervous system § MAO has 2 types : A( specific substrate serotonin, noradrenaline, adrenaline) and B (phenyletylamine, benzylamine, metylhistamine), mixed substrate: dopamine, tyramine, tryptamine

Classification of AD: MAOI § the MAO in GIT - responsible for the metabolism of dietary tyramine, when MAO i s inhibited, dietary tyramine can enter the circulation and act as a presser, resulting in a hypertensive crisis -diet with low tyramine with MAOI application! Drug available: § phenelzine (f. o. Nardil) § isocarboxazid (f. o. Marplan) § tranylcypromine (f. o. Parnate) RIMA -reversible inhibitors of MAO - preferred !! § moclobemide (f. o. Aurorix)

Mood stabilizers (thymoprophylactics) Chemistry: § lithium - the lightest of the alkali metals § carbamazepine -structurally similar to imipramine § valproates and valpromide -converted to valproic acid (=diprophylacetic acid) Drugs available: lithium (f. o. Lithium carbonicum) anticonvulsants: § carbamazepine (f. o. Biston, Tegretol) § valproate (f. o. Everiden, Orfiril, Depakine chrono) § lamotrigine (f. o. Lamictal)

Mechanism of action § ADs increase the synaptic availability of the main neurotransmitter § based on this knowledge the first major theory about the biological aetiology of depression hypothesised that depression was due to a deficiency of monoamine neurotransmitter, notably noradrenaline (NA) and serotonin (5 -HT) § ADs reduce the reuptake of NA, 5 -HT § block some receptors § influence secondary and tertiary messengers § with longer treatment certain neurotransmitter receptors down-regulation is observed

Neurobiology of depression Genetics? Environment? Serotonin and/or Diet? Noradrenaline Receptors transmission Depression Anxiety Sleep Disturbances Other Physical Signs Adapted according to Duman RS, et al. Arch General Psychiatry 1997; 54: 597 -606.

Phases of treatment in depression Remission Recovery Normal Relapse x Recurrence ion ress Prog der isor Symptoms to d Severity Response Syndrome Treatment phases x Acute Continuation Maintenance (6– 12 weeks) (4– 9 months) (1 or more years) Time Kupfer DJ. J Clin Psychiatry 1991; 52(Suppl. 5): 28– 34

Doses and duration of treatment § current treatment guidelines recommend the continuation of antidepressant treatment for 69 months after an acute episode of major depression, and long-term, in some cases lifelong, treatment in patients with a recurrent form of the illness § in the long-term treatment the dose should be same, which was effective in the acute treatment

Efficacy for acute treatment: § circa 65% of responders § an average drug-palcebo difference circa 30% Maintenance treatment: § relapses with AD 20%, § with placebo 50%

Side effects TCA (I. generation) : § sedation, autonomic effect due to alfa adrenergic blockade , e. g. orthostatic hypotension § cardiac effect: tachycardia, prolonged QT, depressed ST § peripheral anticholinergic effect: dry moth, nose, blurred vision, constipation, urinary retention, § central anticholinergic effect: memory impairment II. generation § no anticholinergic side effects SSRI (III. generation) : § GIT (nausea, diarrhoea, anorexia, dyspepsia), CNS (headache, insomnia, nervousness), sexual dysfunction

Side effects (comparative profiles) of newer ADs Venlafaxine Anticholinergic Nausea/GIT ++ Sedation Insomnia/agitation ++ Sexual dysfunction ++ Ortostatic hypotension Weight gain - Milnacipran Mirtazapine ++ ++ - very low/none, + low/mild, ++ moderate/high The absence of affinity for muscarinic, histaminic and alpha 1 adrenergic receptor limits their adverse effects and allows them to be better tolerated than TCA and similar to SSRIs

Side effects - mood stabilizers Lithium: § renal effects (polyuria, polydipsia), thyroid effects (goitre, hypothyroidism), weight gain, tremor, cardiac effect (Twave changes) Carbamazepine: § GIT symptoms, blood dyscrasia, fatigue, vertigo, ataxia, rash, risk of drug interactions (metabolism inducer) Valproate: § fatigue, tremor, nausea, hair loss, blood dyscrasia Lamotrigine § rash, vertigo

Indications of ADs § depressive disorders (primary and secondary) § anxiety disorders § eating disorders § psychosomatic disorders § pain disorders

References : § Duman RS, Heninger GR, Nestler EJ. : A molecular and celllular theory of depression. Arch. Gen. Psychiatry, 54, 1997, pp. 597 -606. § Kupfer DJ. : Long-term treatment of depression. J. Clin. Psychiat. , 52, 1991, Suppl. 5. , s. 28 - 33 § Janicak PG. : Handbook of psychopharmacology, Baltimore: Williams and Willkins, 1999 § Kaplan HI, Sadock BJ, Grebb JA. : Kaplan and Sadock´s synopsis of psychiatry, Baltimore: Williams and Wilkins, 1997