Pharmacology of

Mood Stabilizers

Dr.Datten Bangun,MSc,SpFK

Dept.Farmakologi & Terapetik

Fak.Kedokteran UHN
Medan
 Definitions
• Affective disorders - mental illnesses characterized
by pathological changes in mood (not thought –
compare with schizophrenia)
I.Unipolar disorders
• Depression – pathologically depressed mood
(life time prevalence up to 17%)
• Mania – excessive elation and accelerated
psychomotoric activity (rare)
IIBipolar 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 self-worth, 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; at least one of the symptoms is either:
– (1) depressed mood or
– (2) loss of interest or pleasure.
• depressed mood most of the day…
• markedly diminished interest or pleasure
• 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) = the underlying biological or
neuroanatomical basis for depression is a deficiency of central noradrenergic
and/or serotonergic transmission in the CNS
Supported by:
• pharmacological effect 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
• the effect of antidepressants on neurotransmitter levels is relatively
quick 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
thereby gradually normalize the density/sensitivity of their receptors
• The precise pathophysiology of depression remains unsolved
ADRENERGIC SYNAPSE

Beta1-receptor
+

M2-receptor

7
 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

• Principal mechanism of action:

– blockade of re-uptake of monoamine neurotransmitters
noradrenaline (NA) and serotonin (5-HT) by competition
for binding site of the carrier protein. 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)
are also affected: 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 close within the

group the more significant difference is in their
adverse effects
 Pharmacokinetics

• Administered orally – rapid absorption, however extensive first

pass effect  low and inconsistent BAV
• Strong binding to plasma proteins (90-95% bound). They are
also 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 but 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 in the vasomotor center
(frequent in elderly)
• Sedation, drowsiness, difficulty in concentration (amitriptyline,
H1-blockade)
• Sexual dysfunction (loss of libido, impaired erection)

 Possible problems with compliance ?!!!

 Acute intoxication
• Very dangerous and relatively frequent – patients
with depression often have suicidal tendencies
• Precautions:
• taking care about 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
• Unfortunately a low therapeutic index
• Target systems – the CNS and heart
• Initially excitement, hallucinations and delirium is observed,
may be accompanied with convulsions. Coma and respiratory
depression may follow. Pronounced atropine-like effects.
• Cardiac dysrrhythmias are 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), physostgmine???
• No effect of haemodialysis and hemoperfusion is practically
ineffective
 MonoAmine Oxidase Inhibitors (MAOI)
• The first compounds (iproniazid derivatives) were 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 is attributed to MAO-A enzyme
isoform inhibition  increased cytoplasmic pool of
monoamines leading among other(s) to spontaneous
leakage of monoamines.
In contrast to other antidepressants, when given to normal non-
depressed subjects they increase a motor activity and cause
euphoria + excitements (while TCA would cause only sedation
and/or confusion).  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

treatment of Parkinson's disease.
 Adverse reactions and toxicity of MAOI

• Hypertension
• Postural hypotension (in up to 1/3 patients)
• CNS stimulation – tremor, excitement, insomnia,
convulsions in overdose.
• Weight gain (increased appetite)
• Atropine-like adverse effects – like in TCA but less
common
• Rare severe hepatotoxicity (hydrazine MAOI)
 Interaction with foods
• The most serious problem of this class of drugs
• Tyramine „cheese and wine“ reaction
– some kind of foods contain high amounts of
tyramine (natural indirect sympathomimetic
produced during fermentation), which is however
normally metabolized by MAO in the gut and liver.
– Dietary precautions: restriction in the consumption
of some maturing cheeses, wine, beer, yogurts,
bananas etc.
– This risk is minimal with modern RIMA drugs.
(Reversible inhibitors of monoamine oxidase A
(RIMAs)
 Interaction with foods
• In depressed patients treated with MAOI, these
enzymes are also inhibited  bioavailability of
tyramine is significantly higher which together with
pharmacodynamic synergism  strikingly increased
noradrenaline transmission results in hypertensive
crisis, severe headache and potentially fatal
intracranial hemorrhage or other organ damage.
 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 Inhibitos (SSRI)

• More modern (1st drug fluoxetine available in 1988) and safe

antidepressants

• Principal mechanism of action:

– selective inhibition of 5-HT (serotonin) reuptake  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
 Most important SSRI

• Fluoxetine
• Fluvoxamine
• Paroxetine
• Sertraline
• Citalopram
 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)
• 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 but also -
blockers, benzodiazepines etc.
 Adverse effects

• Relative improvement to other antidepressants (mostly mild)

• GIT – nausea, vomiting, diarrhea

• Headache
• Sexual dysfunctions
• Restlessness (akathisia)
• Insomnia and fatigue
• Few patients experience an increase in anxiety or agitation
during early treatment
• Serotonin syndrome upon intoxication or drug interactions
 Other and atypical antidepressants
• Serotonin-2 Antagonists/Reuptake Inhibitors (SARI)
– trazodone (sedative effects)
– nefazodone (newer and improved) decreased some
SSRI adverse reactions
• Serotonin and Noradrenaline Reuptake Inhibitors
(SNRI)
– venlafaxine - pharmacodynamic like in TCA however
improved profile of adverse reactions
• Noradrenaline and Dopamine Reuptake Inhibitors
(NDRI)
– bupropion – rather CNS activating effects (low
sedation), usage: severe depression + smoking
cessation treatment. Adverse reactions: insomnia, excitation,
restlessness, lowers epilepsy threshold
Other and atypical antidepressants
• Noradrenaline Reuptake Inhibitors (NaRI)
– reboxetine – also rather activating
– maprotiline
• Noradrenergic/Specific Serotonergic Antidepressants
(NaSSA)
– mirtazapine – increased NA and 5-HT neurotransmission
through blockade of their autoreceptors (low 5-HT
adverse effects – blocks also postsynaptic 5-HT receptors)
• Miscellaneous
– St John´s wort (Hypericum perforatum) – a herb
containing number of active compounds (among other
hyperforin a MAOI). It was proved to be 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)
Drugs Used to Treat
Bipolar Disorder
 Background Information
 Episodes of Mania and Depression
 Intervention when mood swings are
severe, disrupt life of the patient and/or
family
 4 % population prevalence
 At least 1 manic,hypomanic,or mixed
episode
 Types/Common Terms
• Bipolar I-
=Most severe, obscures normal
functioning, hospitalization common

• Bipolar II-
= Hypomanic,Full manic episodes rare.
Depression often still severe
• Cyclothymia- Milder form of BP II, “Bipolar
Spectrum Disorder”
• “Rapid Cycling”- 4 or more episodes in a
12 month period,may not be permanent
 Therapy of bipolar disorder

• Main aim: to eliminate mood episodes, maximize adherence to

therapy, improve functioning of the patients and eliminate
adverse effects

„MOOD STABILIZERS“
• Lithium
• Valproate
• Carbamazepine
• Lamotrigine
• Adjunctive agents (antidepressants and benzodiazepines)
 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 is supposed.
 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
 Lithium
• 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)
 Pharmacokinetics:
• Peak blood levels reached in 3 hrs, fully
absorbed in 8 hrs
• Absorbed rapidly and completely orally
• Efficacy correlates with blood levels
• Crosses blood-brain barrier slowly and
incompletely
• Usually taken as a single daily dose
 Kinetics Cont.
• Approx. 2 wks to reach a steady state within
the body
• ½ of oral dose excreted in 18-24 hrs,rest
within 1-2 wks
• Recommended .75-1.0 mEq/L, optimum
would be .5-.7 mEq/L, with 2 mEq/L
displaying toxicity
• Metabolized b/f excretion
 Important:
• Because of its resemblance to table salt,
when Na+ intake is lowered or loss of
excessive amounts of fluid occurs, blood
levels may rise and create intoxication
 Pharmacodynamics
• No psychotropic effect on non-Bipolars
• Affects nerve membranes, multiple receptor
systems and intracellular 2nd messenger impulse
transduction systems.
• Interacts with serotonin
• Potential to regulate CNS gene expression,
stabilizing neurons w/ associated multiple gene
expression change.
How does a simple ion do all of
this?
• Even as a simple ion, it has complex
effects on multiple transmitter systems
and mood stabilizing attributes

• This is due to a latter effect reducing a

neuron’s response to synaptic input, and
therefore stabilizing the membrane
 Side Effects and Toxicity
• Relate to plasma concentration levels, so
constant monitoring is key
• Higher concentrations ( 1.0 mEq/L and up
produce bothersome effects, higher than 2
mEq/L can be serious or fatal
• Symptoms can be neurological, gastrointestinal,
enlarged thyroid, rash, weight gain, memory
difficulty, kidney disfunction, cardiovascular
• Not advised to take during pregnancy, affects
fetal heart development
 Combination Therapy
• Combination therapy with Lithium and
anti-epileptics may demonstrate better
protection against relapse, greater
therapeutic efficacy, and studies support
this as a rule vs. an exception
 If Lithium Doesn’t Work
• 40% of Bipolars are resistant to lithium or
side effects hinder its effectiveness

• Therefore, we must consider alternative

agents for treatment
 Valproic Acid (Depakote)
• An anti-epileptic, it is the most widely used
anti-manic drug
• Augments the post-synaptic action of GABA at
its receptors (increasing synthesis and
release)
• Best for rapid-cycling and acute-mania
• Therapeutic blood levels: 50-100 Mg/L
• Side effects include GI upset, sedation,
lethargy,tremor, metabolic liver changes and
possible loss of hair
• Can also be used for anxiety, mood, and
personality disorders
 Carbamazepine (Tegretol)
• Superior to lithium for rapid-cycling,
regarded as a second-line treatment for
mania
• Correlation between therapeutic and plasma
levels (estimated between 5-10 Mg/L)
• Side effects may include GI upset, sedation,
ataxia and cognitive effects
 Gabapentin
• Primarily an anti-convulsant, yet also “off label,”
or without FDA approval for treatment of Bipolar
and many other anxiety, behavioral and
substance abuse problems, possibly pain
disorders
• GABA analogue
• not bound to plasma proteins, not metabolized,
few drug interactions
• Half-Life is 5-7 hours
• Side Effects include sleepiness,dizziness,ataxia
and double vision
 Lamotrigine
• Reported effective with Bipolar, Borderline
Personality, Schizoaffective, Post-Traumatic
Stress Disorders
• 98% of administered drug reaches plasma
• Half-Life is 26 hrs.
• Inhibits neuronal excitability and modifies
synaptic plasticity
• Side Effects may include dizziness, tremor,
headache, nausea, and rash
 Topiramate and Tiagabine

• Two newer anti-convulsants that have

potential for use in the treatment of
Bipolar disorder
 Atypical Anti-psychotics
• 3 types that may be used for Bipolar
Disorders: Clozapine, Risperidone, and
Olanzapine
• Risperidone seems more anti-depressant
than anti-psychotic
• Clozapine is effective, yet not readily
used due to potential serious side effects
• Olanzapine is approved for short-term
use in acute mania
Acetylcholinesterase Inhibitors

• Potentiating the action of acetylcholine

may exert relief from mania
• This potentiation is the result of
inhibiting the enzyme acetylcholine
esterase
 Omega-3 Fatty Acids
• Obtained from plant or marine sources

• Known to dampen neuronal signaling

transduction systems in a variety of cell
systems

• Being investigated as a treatment for

Bipolar Disorder
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