Download Psychopharmacs - antidepressants

Psychopharmacs antidepressants
prof. MUDr. Eva Češková, CSc.
Dept. of Psychiatry,
Masaryk University , Brno
Psychopharmacs - antidepressants
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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
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 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 -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
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
Relapse
Normal
Relapse
x
x
Recurrence
Severity
Response
Symptoms
x
Syndrome
Treatment phases
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
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 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 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