Antidepressants other

drugs
used in affective disorders

Martin trba, PharmD., PhD.

Associate professor
Department of Pharmacology
2012

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

Depression
common mental disorder that presents with depressed mood,
loss of interest or pleasure, feelings of guilt or low selfworth, 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 (!)

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.

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

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)

Duration of treatment 6 months after recovery (1st epizode),

may be even life-long treatment in recurrent depression

Non-pharmacological treatment

Psychotherapy
Light therapy
Electroconvulsive therapy (ECT)

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:

imipramine

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

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

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.

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 - H1-blockade
drowsiness, difficulty in concentration (amitriptyline,)

Sexual dysfunction (loss of libido, impaired erection)

Possible problems with compliance ?!!!

Acute intoxication with TCA

Very dangerous and relatively frequent
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

Acute intoxication
TCA - low therapeutic index
Target systems the CNS and heart
CNS - pronounced atropine-like effects.
Excitement, hallucinations, delirium, convulsions.
Coma and respiratory depression may follow.

Cardiac dysrrhythmias
very common
tachycardia (antimuscarine action)
atrial or ventricular extrasystoles, QRS complex widening,
QT interval elongation.
ventricular fibrillation and sudden death may occur.

Hypotension
Treatment- diazepam (seizures), physostigmine???
No effect of haemodialysis and hemoperfusion is
practically ineffective

MonoAminoOxidase Inhibitors
(MAOI)
The first compounds (iproniazide derivatives) - originally
developed as antimycobacterial drugs by chemical
modification of isoniazid molecule (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!

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

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)

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.

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)

Selective Serotonin Re-uptake

Inhibitors (SSRI)
More modern (1st 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-HT1A) and postsynaptic receptors
(important subtype 5-HT2A )
Other indications of SSRI
anxiety disorders
generalized anxiety, panic disorder, social anxiety disorder,
obsessive-compulsive disorder

bulimia nervosa, gambling, drug withdrawal

Most important SSRI

Fluoxetine
Fluvoxamine
Paroxetine
Sertraline
Citalopram

Enantioselective forms e.g.

escitalopram (S-enantiomer)

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!
Fluoxetine, fluvoxamine -1A2, 2C19, 2D6, 3A4
Paroxetine and duloxetine 2D6
Possible Interactions TCA, clozapine, venlafaxine,
haloperidol, warfarine, b-blockers, Ca2+ channel blockers.

Long half-lives of elimination(s)

fluoxetine (T1/2=50h) + active metabolite (T1/2 =240h)

Drug interaction

based on plasma protein binding and CYP blockade

increased effect of co-administered TCA, -blockers,
benzodiazepines etc.

Adverse effects
Relative improvement to other antidepressants (mostly mild)
GIT
nausea, vomiting, abdominal cramps, diarrhea
relatively frequent, higher doses?

Headache
Sexual dysfunctions (loss of libido, erectile
dysfunction)
Restlessness (akathisia)
Anxiety - an increase in anxiety or agitation during early
treatment
Insomnia and fatigue
Serotonin syndrome upon intoxication or drug
interactions

Other and atypical

antidepressants

Serotonin and Noradrenaline Reuptake

Inhibitors (SNRI)
venlafaxine

pharmacodynamics like in TCA

improved profile of adverse reactions
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
Liver metabolism and active metabolite

Noradrenaline and Dopamine Reuptake

Inhibitors (NDRI)

Bupropion

rather 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

severe depression prophylaxis and treatment
Adverse reactions: dry mouth, headache, dysuria, sweating

Other and atypical

antidepressants
Serotonin (5HT2A) 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 (newer and improved)

Miscellaneous
St Johns 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)

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

Therapy of bipolar disorder

Main aim:
to eliminate mood episodes
maximize adherence to therapy
improve functioning of the patients
eliminate adverse effects

MOOD STABILIZERS

Lithium
Valproate
Carbamazepine
Lamotrigine

Adjunctive agents

(antidepressants and

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 (T1/2= 20-24h; when the
treatment is abruptly stopped - slow 2nd phase of excretion /
1-2 weeks/ representing Li+ taken up by cells occurs)
only 20% of Li+ filtered by GF is excreted (80%

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)