Psychopharmacs - antidepressants

prof. MUDr. Eva Češková, CSc.prof. MUDr. Eva Češková, CSc.

Dept. of Psychiatry, Dept. of Psychiatry,

Masaryk University , BrnoMasaryk University , Brno

Psychopharmacs - antidepressantsdefinition and historydevelopment of antidepressants (AD) classification of ADsmechanism of actionneurobiology of depressionphases 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 ADsSSRI (selective serotonin reuptake inhibitors)

SARI (serotonin antagonist/reuptake inhibitor):

trazodone, nefazodone

NRI (NA reuptake inhibitors) :reboxetine, atomoxetine

NDRI (NA/DA reuptake inhibitor): bupropion

D2/D3 autoreceptors antagonist: amisulpride

Dual –acting ADs:

SNRI (serotonin and noradrenaline reuptake

inhibitors) venlafaxine, milnacipran, duloxetine

NaSSA (noradrenaline and specific serotonergic

antidepresant) mirtazapine

Classification of AD

TCA (I. generation):

Chemistry:TCA have a 3 ring nucleusTCA 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 ADDual acting antidepressants (IV generation):efficacy comparable to TCA, higher than SSRI,

especially in severe depressionvenlafaxine - available in sustained release

formulation-Effexor XR (prolonged duration of action, lower peak plasma levels and fluctuations, better tolerability - higher compliance

milnacipranmirtazapine - available also in orally disintegrating

formulation -RemeronSolTab (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 systemMAO 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 metalscarbamazepine -structurally similar to imipraminevalproates 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 actionADs increase the synaptic availability of the main

neurotransmitterbased 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 messengerswith longer treatment certain neurotransmitter receptors

down-regulation is observed

Neurobiology of depression

Receptors

Genetics? Environment? Diet?

Serotonin and/or Noradrenaline

DepressionAnxiety

Sleep DisturbancesOther Physical Signs

Adapted according to Duman RS, et al. Arch General Psychiatry 1997;54:597-606.

transmission

Phases of treatment in depression

x

x

x

Remission Recovery

Relapse

RecurrenceRelapse

Response

Pro

gressio

n

to d

isord

er

Normal

Symptoms

Syndrome

Treatment phases

Time

Sev

erit

y

Acute(6–12 weeks)

Continuation(4–9 months)

Maintenance(1 or more years)

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 6-9 months after an acute episode of major depression, and long-term, in some cases life-long, 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

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 effectsTCA (I.generation) : sedation, autonomic effect due to alfa adrenergic blockade ,

e.g. orthostatic hypotensioncardiac effect:tachycardia, prolonged QT, depressed ST peripheral anticholinergic effect: dry moth, nose, blurred

vision, constipation, urinary retention, central anticholinergic effect:memory impairment

II. generationno 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 Milnacipran Mirtazapine

Anticholinergic - - -

Nausea/GIT ++ ++ -

Sedation - - ++

Insomnia/agitation ++ ++ -

Sexual dysfunction ++ ++ -

Ortostatic hypotension - - +

Weight gain - - ++- very low/none, + low/mild, ++ moderate/high

The absence of affinity for muscarinic, histaminic and alpha 1adrenergic receptor limits their adverse effects and allows them to be better tolerated than TCA and similar to SSRIs

Side effects - mood stabilizersLithium: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 disorderseating disorderspsychosomatic disorderspain 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