ANTIDEPRESSANTS

By
J. Ndeto
 Depression
• It is a mental illness characterized by
pathological changes in mood, loss of interest
or pleasure, feelings of guilt or low self-worth,
disturbed sleep or appetite, low energy and
poor concentration
 Symptoms
• Emotional
• Biological
 Emotional symptoms
• Low mood
• Negative thoughts, misery ,apathy and
pessimism
• Low self esteem ,feeling of guilt, Inadequacy
and ugliness
• Indecisiveness , low motivation
• Anhedonia (↓pleasure ) , loss of reward
 Biological
• Retardation of thought and action
• Loss of libido
• Sleep disturbance
• Loss of appetite
 Types of depression
• Major depression
• Chronic depression (dysthymia)
• Atypical depression
• Bipolar disorder/manic depression
• Seasonal depression (SAD)
 Depression syndrome
• Unipolar - unidirectional mood changes
• Bipolar - depression alternating with mania
 Mania
• Excessive exuberance
• Enthusiasm and self confidence
• Impulsive actions
• Irritability , impatience and aggression
• Grand delusions
• Mood action inappropriate to circumstances
 Unipolar
• Reactive depression
- 75% Commonly non-familial associated with
stressful life events
- symptoms of anxiety and agitation

• Endogenous depression
- 25% Familial pattern
- unrelated to external stress
- different symptomatology
 Bipolar Depression
• Early adult life
• Mild to severe schizophreniform like psychosis
• Hereditary tendencies - no specific gene
association
 Pathology
• Prefrontal cortex, amygdala, hippocampus
 Mechanism of depression
• Depression is associated with changes in the
level of neurotransmitter in the brain that help
nerve cells to communicate e.g. serotonin,
dopamine, norepinephrine
• The level can be influenced by physical illness,
genetics, substance abuse, diet, hormonal
changes, brain injuries or social circumstances
 MAO hypothesis

Neurotransmitters Accumulation in Increased

When MAO is
are not the pre-synaptic availability of
blocked
metabolized neuron neurotransmitters
• Blocking the action of MAO leads to an increased
availability of neurotransmitter
• MAO-A oxidizes epinephrine, norepinephrine,
serotonin; MAO-B oxidizes phenylethylamine; both
oxidise dopamine non-preferentially
• This theory is based on the ability of the
monoamine oxidase A inhibiting drugs to facilitate
NE/5-HT neurotransmission and to act as effective
antidepressant drugs
 Monoamine Theory of Depression
-Deficit of monoamine neurotransmitter or 5HT

-Treatment with inhibition of reuptake

 Effects of antidepressants
• Neurochemical effects of antidepressants rapid
in minutes to hours but no direct primary effect

• Secondary adaptive changes in the brain

responsible for the (trophic effect ) improvement

• Immediate effect - electroconvulsive therapy,

electromagnetic therapy, deep brain
stimulation , vagus stimulation
 Serotonin noradrenaline and dopamine
hypothesis
• Depression is caused by a functional deficit of
NE and /or 5-HT and dopamine at
hippocampus in brain. Therefore, it was
reasoned that depressed must be associated
with a decreased NE/5-HT neurotransmission
 Neuroendocrine mechanisms

↓NE , 5HT
↓
Hypothalamus
↓
CRH →behavioral (↓activity, anorexia, anxiety) endocrine
↓
ACTH
↓
Cortisol → depression
↓
Depression
 Trophic effect of neuroplasticity
• Decrease brain derived neurotrophic factors
• Glycogen synthase kinase 3↑
• Glutamine ↑
 Antidepressants
• Drugs which enhance alertness and may
result in an increased output of behavior
• Potentiate directly or indirectly the action of
– Dopamine
– Serotonin
– Noradrenaline
• The purpose of antidepressants is to increase
the neurotransmitters in the synapse
 Antidepressants
• They are used for the relief of symptoms of
moderate and severe depression
• Antidepressants are taken for at-least 4-6
months
• They can be used alone or in combination with
other medications
 Types of antidepressants
• Tricyclic antidepressants (TCAs)
• Monoamine oxidase inhibitors (MAOIs)
• Selective serotonin reuptake inhibitors (SSRIs)
• Atypical antidepressants (others)
 Classification of antidepressants
• Classic tricyclic antidepressants
– imipramine
– desipramine
– amitriptyline
– nortriptyline
– clomipramine
• Inhibitors of monoamine uptake
- SSRIs - fluoxetine, fluvoxamine, paroxetine,
sertraline ,citalopram , escitalopram
vilazodone
Classification of antidepressant 2
- Mixed 5HT and NE reuptake
Venflaxine, desvenlafaxine , duloxetine

- NE reuptake inhibition
bupropion , reboxetine , atamoxetine

- Herbal - St John’s wort (hyperforin)

 Tricyclic antidepressants
• They have been employed in drug therapy
since the late 1950s
• Largest group of drug agents used for the
treatment of depression
• Referred as “tri-cyclic” compounds – three
rings
 Properties of TCAs
• Characteristic three ring nucleus
• Are metabolized in the liver
• High protein binding
• High lipid solubility
 Classification of TCAs
A. NA + 5-HT reuptake inhibitors
 Imipramine, amitriptyline, trimipramine,
doxepin, dothiepin, clomipramine
B. Predominantly NA reuptake inhibitors
 desipramine., nortriptyline, amoxapine,
reboxetine
 MOA of TCAs
• Inhibit the re-uptake of neurotransmitters
• They inhibit serotonin, norepinephrine or dopamine
reuptake at pre-synaptic nerve terminals thus lead to
increased concentration of these transmitter in the
synaptic cleft
• Competes with the binding site of the amine transporter
• Takes up to 4 weeks for all TCA antidepressant to have
an effect
• Most inhibit NA and 5HT uptake; less effect on
dopamine
• > 5HT - improvement emotional
> NA - improvement in biological symptoms
 Other receptors affected by TCAs
• Muscarinic blockade – anticholinergic side
effects (dryness etc)
• Histamine blockade – sedation
• Alpha receptor blockade – postural
hypotension
• Dopamine blockade – antipsychotic effect
(amoxapine)
 Imipramine
• It is a prototype drug of class TCA
• Closely related to antipsychotic drug phenothiazines
• Inhibits monoamine reuptake (serotonin and
noradrenaline) thus increase the concentration of
serotonin and NA at synapse and potentiate the
action
• Used to treat a wide class of depression
• Also used to treat nocturnal enuresis
• Usual dose 50-150 mg daily
 Therapeutic uses
• Severe major depression
• Phobic and panic anxiety disorders
• Neuropathic pain
• Obsessive compulsive disorder (OCD)
• Nocturnal enuresis; imipramine has been used to
control bed-wetting in children (older than 6
years) by causing contraction of the internal
sphincter of the bladder
 Adverse Effects
• Sedation, confusion, motor incoordination;
Wear off in 1-2 weeks
• Anti-muscarinic - dry mouth, blurred vision ,
constipation and urine retention, mydriasis
• Postural hypotension (paradox) amitriptyline >
desipramine
• Ventricular dysrhythmias ↑QT
• Rashes and jaundice (mianserin)
 Interactions
• Metabolised by CYP 450
• Inhibited by antipsychotics and corticosteroids
• ETOH -severe respiratory depression
• Care with anaesthesia and treatment with anti
-hypertensives
 Amoxapine
• Blocks D2 + inhibition of NA reuptake
• Has mixed antidepressant and neuroleptic
effects
• Good for psychotic depression
 Reboxetine
• Selective NA reuptake blocker
• Weak action on 5-HT Mechanism
• Anticholinergic effects are minimal
 TCAs (Acute poisoning)
• Usually suicidal attempt
• Presents as
– Excitement
– Delirium
– Anticholinergic symptoms like atropine
poisoning
– Muscle spasm
– Convulsions
– Arrhythmias
– Respiratory depression
 TCAs acute toxicity treatment
• Gastric lavage
• I.V line
• Oxygen
• Maintenance of BP and temperature
• Diazepam IV
• Propranolol/lignocaine
 PK
• TCAs well and rapidly absorbed PO
• PPB 90-95 %
• Extravascular tissue binding
• Large volume of distribution
• Slow elimination rate
• Haemodialysis ineffective
• Metabolism in the liver to active metabolites
• Demethylation and hydroxylation then
inactivation by glucuronidation
• Excretion in urine
• Elimination half-life 10-20 hours , protryptyline
80 hours gradual accumulation and ADRs
• Narrow therapeutic index
 Monoamine oxidase inhibitors
• Treatment of depression began with the use of
MAOIs in 1950s
• These drugs are not widely used today, although a
small number of patients appear to do better in
MAOIs than TCAs or the newer drugs
• They are particularly effective in treating atypical
depression, panic disorders and social phobia
• Due to potentially lethal dietary and drug
interactions, MAOIs had been reserved as the last
line of treatment; used only when other classes of
 What is monoamine oxidase?
• MAO is a mitochondrial enzyme found in most
tissues
• The enzyme responsible for the degradation of
monoamine neurotransmitters
• There are 2 forms of mono-amine oxidase: MAO-A
and MAO-B
• MAO-A is responsible for NE, 5-HT and tyramine
metabolism
• MAO-B is more selective for dopamine metabolism
 Monoamine oxidase
• In neuron, MAO functions as “safety valve” –
inactivate an excess neurotransmitters
MAO- A MAO-B
-adrenergic nerve endings - brain ( basal ganglia) -
Intestinal mucosa -Human Platelets -Liver
placenta -Liver
-Deaminates Serotonin , -Deaminates dopamine
Noradrenalin and dopamine

Inhibited by moclobemide and -Inhibited by selegiline

clorgyline
 Classification of MAOIs
• According to reversibility; they can be
classified into:
1. Irreversible agents: tranylcypromine,
phenelzine
2. Reversible agents: moclobemide
 Classification of MAOIs
• According to selectivity, MAOIs can be classified
into:
1. Non-selective agents: phenelzine,
tranylcypromine: inhibit MAO-A & MAO-B
2. Selective agents:
 (MAO-A)I: moclobemide
 (MAO-B)I: selegiline
 Properties of MAOIs
• Readily absorbed from GI tract
• Widely distributed throughout the body
• May have active metabolites, inactivated by
acetylation
• Effects persist even after these drugs are no
longer detectable in plasma (1-3 weeks)
 Mechanism of action of MAOIs
• MAO is a mitochondrial enzyme found in
nerve and other tissues
• Monoamine oxidase breaks down
norepinephrine, serotonin and dopamine.
• When monoamine oxidase is inhibited,
norepinephrine, serotonin and dopamine are
not broken down, increasing the
concentration of all three neurotransmitters in
the brain
• MAOIs may reversibly or irreversibly inactivate
enzymes by making stable complexes, permitting
neurotransmitter molecules to escape
degradation and accumulate within the synaptic
cleft
• This may cause activation of norepinephrine and
serotonin receptors responsible for
antidepressant action
 Phenelzine
• White powder freely soluble in water
• Insoluble in ethanol
• It has low sedative properties
 Reversible inhibitor of MAO-A (RIMAs)
• Moclobemide
– Reversible and selective MAO-A inhibitor
– Competitive enzyme inhibition
– Tyramine is able to displace it
– Cheese reaction is less likely
– Devoid of anticholinergic, sedative, cognitive and
cardiovascular effects
– Good for elderly with heart diseases
 Therapeutic uses
• Indicated for depressed patients who are
unresponsive or allergic to TCAs
• Patients with low psychomotor activity
• Treatment of phobic states
 Adverse effects
• Drowsiness/fatigue
• Constipation
• Nausea
• Diarrhea
• Dizziness
• Low blood pressure
• Lightheadedness
• Decreased urine output
• sleep disturbances
 Interactions
• These drugs inhibit a number of other enzymes as
well and interact with many food constituents and
drugs
• Many foods containing tyramine are normally
degraded in the gut by MAO-A
• Since the enzyme is inhibited by MAOIs, tyramine
from ingested food is absorbed and then taken up
into adrenergic neurons
• It is converted into octopamine – a false transmitter
which causes massive release of norepinephrine and
may result in hypertensive
 Food Interactions
• People taking MAOIs should avoid foods rich
in tyramine e.g aged wine, aged cheese
(cheese reaction), liver, sausages, fish, some
meat and yeast extracts
 Drug interactions
• Use of MAO inhibitors with TCAs causes elevated levels
of NE and hypertensive crisis
• Concurrent use of a MAOI and fluoxetine may lead to
the serotonin syndrome
• Local anaesthetics or cold medications contain
(pseudoephedrine, ephedrine) have synergistic effects
with the increased levels of catecholamines caused by
MAOIs
• MAOIs with pethidine may lead to abnormal syndrome
characterized by hyperpyrexia, irritability, hypotension
and coma due to an abnormal pethidine metabolite
resulting from the inhibition of the normal
demethylation pathway of pethidine by MAOIs
 Selegiline patch
• Selective MAO-B Inhibitor
• Bioavailability: orally – 4%; transdermally –
74%
• Avoid first-pass GI exposure
• Much less inhibition of gut and liver MAO-A
• Using a patch may cause fewer side effects
than MAOIs taken by mouth
 Selective Serotonin Reuptake Inhibitors
• Most commonly prescribed
• Fluoxetine, sertraline, paroxetine, fluvoxamine
escitalopram , citalopram
• Selective to 5HT
• No anticholinergic effect (associated with TCA)
• Less dangerous in overdose. Safest antidepressant
for use
• No cheese reaction (associated with MAOIs)
• Anxiolytic and effective in premature ejaculation
 SSRIs
• Different responses of individual patients to different
SSRIs
• Escitalopram and citalopram are both SSRIs used to
treat depression and anxiety disorders
• Escitalopram (Lexapro): The S-enantiomer of
citalopram, meaning it is a more refined version with
only the active component.
• Citalopram (Celexa): A racemic mixture, containing
both S- and R-enantiomers, but only the S-
enantiomer has therapeutic effects
• Escitalopram (S isomer) . Lacks R isomer of citalopram
thus no antihistamine effects or CYP2D6 inhibition
 SSRIS
• Escitalopram: More potent and effective at lower doses
due to its purified structure. Citalopram may require a
higher dose to achieve similar effects.
• Side Effects: Both drugs have similar side effects, including
nausea, dry mouth, drowsiness, and sexual dysfunction.
– Citalopram has a higher risk of QT prolongation, especially at
doses above 40 mg, which can lead to serious heart rhythm
issues
• Escitalopram is often preferred due to its higher potency,
fewer side effects, and lower risk of heart issues.
– Citalopram may still be a good option for patients who respond
well to it or need a more cost-effective choice
 PK of SSRIs
• Good absorption after oral administration
• Important biotransformation in the liver
• Longer half-lives of elimination
– Plasma half-life of 18-24 hours> fluoxetine 24-96 hours
• Drug mostly excreted from kidney
• Few drugs are excreted from feaces
• Paroxetine and fluoxetine inhibit CYP2D6 and ↓
metabolism of TCAs
 Mechanism of action
• Inhibition of serotonin reuptake into the
presynaptic cell, increasing the level of serotonin
leading to greater post-synaptic neuronal activity
• They do not have significant effects on
norepinephrine and dopamine
• They typically take 2 to 12 weeks to produce
improvement in mood
 Therapeutic uses
• Depression
• Generalized Anxiety
• Obsessive-compulsive disorder (the only indication
for fluvoxamine)
• Panic disorder
• Premenstrual dysphoric disorder
• Bulimia nervosa (only fluoxetine is approved)
 SSRIs
• Fluoxetine
– Prototype SSRIs
– Longest acting
– Activating SSRI
• Fluvoxamine
– Short acting
– Sedating SSRI
– Commonly used in indoor patients
 SSRIs
• Sertraline
– Activating SSRIs
– Less chances of drug interactions due to low
potency to cause cytochrome enzyme
depression
• Paroxetine
– Short acting
– Sedating SSRI
– More GI side effects
 Adverse reactions
• Nausea , anorexia, insomnia
• Loss of libido , failure of orgasm
• Enhanced stimulation of postsynaptic 5HT
receptors - wrong receptor subtype or wrong
region of the brain
• Serotonin syndrome in combination with
MAOIs
- tremors, hyperthermia, CVS collapse , death
• Fluoxetine - aggression , violence
• Children < 18 years – excitement, insomnia,
aggression , suicide
• Safer than TCA in overdose
• Can prolong cardiac QT interval leading to
ventricular arrhythmias
Seletivity
 TCA vs SSRIs
• Limitations of TCA • Benefits of SSRI
• Anticholinergic effects • More tolerability and better
• Alpha blocking action acceptability
• Cardiotoxicity • No sedation, no seizure ppt
• Sedation, seizures ppt • No alpha blocking action
• • Less chances of arrhythmia
Weight gain
• No weight gain
• Overdose poisoning
common • Used in depression as well
as in OCD, panic
• Incomplete response to
• Now 1st choice for OCD,
treatment
panic disorders, social
phobia, eating disorders,
premenstrual syndrome,
 Atypical antidepressants
• They are a mixed group of agents that have actions
at several different sites
• Atypical antidepressants ease depression by
affecting chemical messengers (neurotransmitters)
used to communicate between brain cells.
• Like other types of antidepressants, atypical
antidepressants affect neurotransmitters including
dopamine, serotonin and nor epinephrine.
• Changing the balance of these chemicals seems to
help brain cells send and receive messages, which
in turn boosts mood
 Mixed-action antidepressants
• Selective serotonin- norepinephrine reuptake
inhibitors ( SNRIs)
• Norepinephrine reuptake inhibitors (NRIs)
• Norepinephrine-dopamine reuptake inhibitors
(NDRIs)
 Serotonin and NA uptake inhibitors
• Nonselective to 5HT and NA
• SNRIs are a newer form of anti- depressants that
work on both 5-HT (SSRI-plus) and weak NE
reuptake blockade
• They have similar side effects to the SSRIs except
increased risk of hypertension
• Examples : Venlafaxine
• Duloxetine inhibits NA and 5-HT uptake
 Venlafaxine
• Potent inhibitor of serotonin, NE reuptake
transporter (SNRIs)
• Unlike, TCAs, has little activity at adrenergic,
histaminic and muscarinic receptors (fewer side
effects than TCAs)
• It is metabolized to desvenlafaxine, which is also
antidepressant
 Reboxetine
• Na reuptake inhibitor [ NARIs ]
• No affinity for 5HT, DA, H, muscarinic receptors
• Has a positive effect on the concentration and
motivation in particular
• Safe to combine with SSRIs
• Minimal side effects only related to activation of
adrenergic system as tremor, tachycardia
 Mirtazapine
• Belongs to a newer class of antidepressants
• acts by blocking presynaptic central alpha-2
adrenergic receptors leading to increased release
of NE and serotonin
• + blocking serotonin receptors ( 5HT 3, 5HT 2
receptors)------- > lower incidence of adverse
effects such as anxiety, insomnia, and nausea
• has only minimal activity at dopaminergic and
muscarinic receptors.
 Mirtazapine
• Does not cause anti-muscarinic side effects,
less sexual dysfunction
• Side effects include sedation (antihistaminic
effect) and weight gain
 Mirtazapine
• Mirtazapine is preferred in cancer patients
because:
– Improves appetite
– ↓ nausea & vomiting ( 5-HT 3 blocking)
– ↑ body weight
– Sedation (antihistaminic)
– Less sexual dysfunction (5-HT 2 blocking)
– Has no anti-muscarinic effect
 Norepinephrine-dopamine reuptake
inhibitors (NDRIs)
• Bupropion (Wellbutrin ) is a unique drug that
has been shown to possess significant potency
as NE and dopamine reuptake inhibitor in the
brain with no direct action on the serotonin
system
• Generally similar to TCAs but lack major major
receptor blocking properties, so fewer side
effects
• Less risk of cardiac effects, so safer in overdose
than TCAs
 Norepinephrine-dopamine reuptake
inhibitors (NDRIs)
• Therapeutic uses:
– Treatment of major depression and bipolar depression
– Can be used in smoking cessation as it reduces the
severity of nicotine craving & withdrawal symptoms
• Advantages:
– No sexual dysfunction
– No weight gain (as no serotonin effect)
– No orthostatic hypotension
• Side effects:
– ppt seizures :it ↓ threshold of neuronal firing
 Uses in summary
• Venlafaxine, desvenlafaxine and duloxetine- anxiety
disorders
• Duloxetine and milnacipram – neuropathic pain and
fibromyalgia
• Bupropion – nicotine dependence
• Duloxetine - neuropathic pain , fibromyalgia and
urine incontinence
• Venlefaxine and duloxetine - metabolised by CYP2D6
• Venlefaxine metabolised to desvenlafaxine
>inhibition of NA
 Adverse Reactions
• Increased adrenoceptor activity
– headache, insomnia, sexual dysfunction , dry mouth
dizziness, sweating and anorexia
• Overdose
– CVS depression , serotonin toxicity syndrome , seizures
cardiac conduction abnormalities
• Duloxetine – hepatitis
• mianserin-bone marrow depression
 Other clinical uses of antidepressants
• Neuropathic pain-amitriptyline, nortriptyline,
duloxetine
• Anxiety disorders- SSRIs, venlafaxine, duloxetine
• Fibromyalgia – SSRIs, duloxetine, venlafaxine, TCAs
• Bipolar disorder – fluoxetine in conjunction with
olanzapine
• Smoking cessation – bupropion
• Attention deficit/hyperactivity disorder –
atomoxetine
 Brain stimulating therapies
• Bright light stimulation- seasonal affective disorders
• ECT - response rate 60-80%
- fast onset and effective in suicidal pts.
- disadvantage : confusion and memory
loss for days to weeks
• TMS
– repetitive transcranial magnetic stimulation
– no need for anaesthesia, and no cognitive impairment

but < efficacy

 Treatment of bipolar disorders
• Bipolar disorder is a mental health condition
characterized by extreme mood swings,
including emotional highs (mania or
hypomania) and lows (depression).
• These mood episodes significantly impact
daily functioning and quality of life
 Types of bipolar disorders
1. Bipolar I Disorder:
 At least one manic episode lasting a week or requiring
hospitalization.
 Depressive episodes are common but not necessary for diagnosis.
2. Bipolar II Disorder:
 At least one hypomanic episode (less severe than mania) and one
major depressive episode.
3. Cyclothymic Disorder:
 Periods of hypomanic symptoms and depressive symptoms that
don't meet the criteria for a full episode, lasting at least two years
(one year in children/adolescents).
4. Other Specified/Unspecified Bipolar Disorders:
 Conditions with bipolar features that don’t fit the above categories
 Symptoms
• Mania/Hypomania: • Depression:
• Increased energy, • Persistent sadness or
euphoria, or irritability. emptiness.
• Decreased need for • Fatigue or loss of energy.
sleep. • Difficulty concentrating.
• Rapid speech, racing • Feelings of worthlessness
thoughts, or or guilt.
distractibility. • Suicidal thoughts or
• Impulsive behaviors, such behaviors
as excessive spending or
risky activities
 Treatment
• Bipolar disorder treatment involves a combination
of mood stabilizers, antipsychotics,
antidepressants, and adjunctive therapies to
manage manic and depressive episodes
effectively.
Goals of Treatment
• Stabilize mood swings (mania and depression).
• Prevent relapse.
• Improve functioning and quality of life.
 Treatment
1. Mood Stabilizers
• These are the cornerstone of bipolar disorder treatment to
prevent mood swings.
• Lithium: First-line treatment for both mania and depression.
Requires monitoring of blood levels due to a narrow
therapeutic index.
• Valproate (Valproic Acid/Divalproex): Effective for acute
mania and maintenance therapy.
• Carbamazepine: Often used for acute mania and as a
maintenance therapy for patients who do not respond to
lithium.
• Lamotrigine: Primarily effective for bipolar depression and
long-term maintenance but less so for acute mania.
 Treatment
2. Atypical Antipsychotics
• Often used in combination with mood stabilizers,
particularly for managing acute manic or mixed episodes:
• Olanzapine: Effective for mania and maintenance; can be
combined with fluoxetine for depressive episodes.
• Risperidone: Useful for acute mania.
• Quetiapine: Effective for both manic and depressive
episodes.
• Aripiprazole: Used for acute mania and as maintenance
therapy.
• Lurasidone: Approved for bipolar depression.
• Asenapine: Useful for acute manic or mixed episodes
 Treatment
3. Antidepressants
• Used cautiously in bipolar disorder to avoid
triggering mania:
• Selective Serotonin Reuptake Inhibitors (SSRIs):
e.g., fluoxetine (combined with olanzapine).
• Bupropion: Considered less likely to induce mania
compared to other antidepressants.
• NOTE: Antidepressants are typically combined with
mood stabilizers or antipsychotics to reduce the
risk of manic episodes
 Treatment
4. Benzodiazepines (Short-term use only)
• Used to manage acute agitation or insomnia
during manic episodes:
• Lorazepam
• Clonazepam
 Clinical uses of mood stabilizing drugs
• Lithium (as the carbonate) is the classical drug. It is used:
– In prophylaxis and treatment of mania, and in the prophylaxis of
bipolar or unipolar disorder (manic depression or recurrent
depression)
• Points to note:
– There is a narrow therapeutic window and long duration of
action
– Acute toxic effects include cerebellar effects, nephrogenic
diabetes insipidus and renal failure
– Dose must be adjusted according to the plasma concentration
– Elimination is via kidney and is reduced by proximal tubular
reabsorption. Diuretics increase the activity of the reabsorptive
mechanism and hence can precipitate lithium toxicity
– Thyroid disorders and mild cognitive impairment occur during
 Clinical uses of mood stabilizing drugs
• Carbamazepine valproate and lamotrigine are
used for:
– The prophylaxis and treatment of manic episodes in
patients with bipolar disorder
– The treatment of bipolar disorder (valproate,
lamotrigine)
• Olanzapine, risperidone, quetiapine, aripiprazole
(atypical antipsychotic drugs ) ae used to treat
mania
 Lithium carbonate
• Monovalent cation
• Mimic roll of Na++ in excitable tissue
• Can cause renal tubular damage
• Thyroid enlargement and hypothyroidism
• Weight gain
• Hair loss
 PK
• Carbonate salt PO
• Excreted in the kidney
• Initial half over 12hours and the rest over 1-2
weeks
• Thus accumulates slowly over weeks
• TDM
 Toxicity
• Nausea, vomiting and diarrhoea
• Tremors
• Polyuria and polydipsia – inhibition of ADH
• Na++ retention due to ↑aldosterone
• The end