psychopharmacs - antidepressants prof. mudr. eva Češková, csc. dept. of psychiatry, dept. of...
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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