Antidepressants

DRUGS USED IN AFFECTIVE
DISORDERS
Dr. D. K. Brahma
Associate Professor
Department of Pharmacology
NEIGRIHMS, Shillong

What are affective Disorders?
1. Mania
2. Depression
• Reactive
• Endogenous or Major Depression
• Depressive syndromes – Unipolar or Bipolar

Bipolar Disorder - imageBipolar Disorder - image

Drugs used in Mania – MoodDrugs used in Mania – Mood
StabilizersStabilizers
 Lithium CarbonateLithium Carbonate
 Alternative Drugs:Alternative Drugs:
– CarbamazepineCarbamazepine
– Sodium ValproateSodium Valproate
– LamotrigineLamotrigine
– TopiramateTopiramate
– Atypical anyipsychotics – Olanzapine, risperidoneAtypical anyipsychotics – Olanzapine, risperidone

Lithium Carbonate – PharmacologicalLithium Carbonate – Pharmacological
actionsactions
 CNS:CNS:
– No discernible psychotropic effect in normalNo discernible psychotropic effect in normal
individualsindividuals
– Similarly, no effect on Manic-depressiveSimilarly, no effect on Manic-depressive
patientspatients
– On prolonged administration – acts as moodOn prolonged administration – acts as mood
stabilizerstabilizer
– Suppresses the episodes af attackSuppresses the episodes af attack

Effect of
Lithium
Salts in
Mania:

Lithium Carbonate – Mechanism ofLithium Carbonate – Mechanism of
actionaction
1.1. Effect on Electrolyte and ion transport:Effect on Electrolyte and ion transport:
– Li is the lightest of the alkali metal atomsLi is the lightest of the alkali metal atoms
– Na+ and K+ are important in this familyNa+ and K+ are important in this family
– Li distributes evenly in extracellular and intracellular fluidsLi distributes evenly in extracellular and intracellular fluids
(contrast to Na+ and K+)(contrast to Na+ and K+)
– Build up a small concentration gradient across cellBuild up a small concentration gradient across cell
membranemembrane
– But, cannot be transported via Na+/K+ ATPaseBut, cannot be transported via Na+/K+ ATPase
– Interfere with transuducer mechanism of cell membraneInterfere with transuducer mechanism of cell membrane

Lithium Carbonate – MechanismLithium Carbonate – Mechanism
of actionof action
2.2. Effects on 2Effects on 2ndnd
MessengerMessenger
– IPIP33 and DAG are important 2and DAG are important 2ndnd
messenger for alpha andmessenger for alpha and
Muscarinic transmissionMuscarinic transmission
– Lithium inhibits several enzymes in the normal recycling ofLithium inhibits several enzymes in the normal recycling of
PhosphoinositidePhosphoinositide
– These include IPThese include IP22 to IPto IP11 and IP to Inositoland IP to Inositol
– These leads to depletion of PIPThese leads to depletion of PIP22, the membrane precursor, the membrane precursor
of IPof IP33 and DAGand DAG
– Ultimate effect may be in G-protein receptors – mayUltimate effect may be in G-protein receptors – may
uncouple receptors from G-proteinuncouple receptors from G-protein

Lithium Carbonate, Mechanism –Lithium Carbonate, Mechanism –
contd.contd.

Lithium Carbonate, Mechanism –Lithium Carbonate, Mechanism –
contd.contd.
3.3. Neurotransmitters:Neurotransmitters:
– Enhances the action of SerotoninEnhances the action of Serotonin
– Decrease the noradrenaline and dopamineDecrease the noradrenaline and dopamine
turnover – antimanic actionturnover – antimanic action
– Augment synthesis of AcetylcholineAugment synthesis of Acetylcholine

Lithium Carbonate - PharmacokineticsLithium Carbonate - Pharmacokinetics
•Initial Dose is 600 mg/day and gradually increased (600 to
1200 mg/day
 Well absorbed orally, but slowlyWell absorbed orally, but slowly
 Not metabolized and not protein boundNot metabolized and not protein bound
 Attains uniform distribution in total bodyAttains uniform distribution in total body
waterwater
 Apparent Vd – 0.8L/kg at steady stateApparent Vd – 0.8L/kg at steady state

Lithium, Pharmacokinetics –Lithium, Pharmacokinetics –
contd.contd.
 Li is actively reabsorbed from proximal tubule in theLi is actively reabsorbed from proximal tubule in the
kidney similar to Na+kidney similar to Na+
 When Na+ is restricted larger portion of Na+ isWhen Na+ is restricted larger portion of Na+ is
reabsorbed - similar is in case of Lireabsorbed - similar is in case of Li
 Initially rapid excretion, then slower in later phase.Initially rapid excretion, then slower in later phase.
 T1/2 is 16 to 30 HrsT1/2 is 16 to 30 Hrs
 Clearance is 20% of creatinineClearance is 20% of creatinine
 Steady state is attained in 5-7 daysSteady state is attained in 5-7 days
 Available as 300 and 400 mg tabletsAvailable as 300 and 400 mg tablets

Lithium – Monitoring of TreatmentLithium – Monitoring of Treatment
 Individual variation in the rate of excretionIndividual variation in the rate of excretion
 Narrow margin of safetyNarrow margin of safety
 Done 5 days after the start of treatmentDone 5 days after the start of treatment
 Measurement is done 12 Hrs after the last doseMeasurement is done 12 Hrs after the last dose
 If no therapeutic improvement, chnge the doseIf no therapeutic improvement, chnge the dose
 New dose = desired plasma level/present levelNew dose = desired plasma level/present level
 Monitor the new dose level after 5 days againMonitor the new dose level after 5 days again
 If steady state (0.5 to 0.8 mEq/L – increase theIf steady state (0.5 to 0.8 mEq/L – increase the
interval of monitoringinterval of monitoring

Lithium – Adverse EffectsLithium – Adverse Effects
1.1. CNS:CNS:
– Tremor is frequentTremor is frequent
– Coarse tremor, giddiness, ataxia, motor incoordination,Coarse tremor, giddiness, ataxia, motor incoordination,
nystagmus etc. – delirium, comanystagmus etc. – delirium, coma
– Occurs mainly when plasma level is high (2mEq/L)Occurs mainly when plasma level is high (2mEq/L)
– Treat with propranolol, atenolol etc.Treat with propranolol, atenolol etc.
– If required – Osmotic diuretics for Li excretionIf required – Osmotic diuretics for Li excretion
1.1. Renal: Polyuria and PolydipsiaRenal: Polyuria and Polydipsia
– Loss of ability of collecting tubules to conserve water by influenceLoss of ability of collecting tubules to conserve water by influence
of ADH (G protein)of ADH (G protein)
– Excessive free water clearanceExcessive free water clearance
– Nephrogenic Diabetes InsipidusNephrogenic Diabetes Insipidus

Lithium, Adverse Effects – contd.Lithium, Adverse Effects – contd.
3.3. Cardiac Effects:Cardiac Effects: Sick-sinus syndrome –Sick-sinus syndrome –
contraindicated – flattening of T wavecontraindicated – flattening of T wave
4.4. Thyroid Function:Thyroid Function: Decrease in thyroidDecrease in thyroid
Function – goitre (G protein)Function – goitre (G protein)
5.5. PregnancyPregnancy – contraindicated– contraindicated
– Foetal goitre, congenital abnormalities (cardiac)Foetal goitre, congenital abnormalities (cardiac)

Lithium – Drug InteractionsLithium – Drug Interactions
 Diuretics: Renal clearance of Lithium is reduced byDiuretics: Renal clearance of Lithium is reduced by
25% with Diuretic e.g. furosemide, Thiazides25% with Diuretic e.g. furosemide, Thiazides
 NSAIDS: Renal clearance of Lithium is reduced byNSAIDS: Renal clearance of Lithium is reduced by
25%25%
 All Neuroleptics, except clozapine – increased EPSAll Neuroleptics, except clozapine – increased EPS
 Insulin and oral hypoglycaemics: enhanceInsulin and oral hypoglycaemics: enhance
hypoglycaemiahypoglycaemia

Antimanic – Other Drugs
 Carbamazepine:
– Prolong remission
– Relapse with Li+ therapy and rapid cycling of
Mood – Li + CBZ
 Sodium Valproate:
– Ist line in acute mania
– Lithium resistance cases
– Lithium + Valproate – resistance to monotherapy

Antimanic Drugs - contd.
 Lamotrigine:
– Not for acute cases but Bipolar disorders
– Used as monotherapy as well as with Lithium
 Atypical antipsychotics:
– 1st line in acute mania in combination with BZD
except patient requiring parenteral therapy
– Olanzapine in maintenance therapy and
prophylaxis

ANTIDEPRESSANTS
ANTIDEPRESSANTS
Drugs which can Elevate Mood (Mood Elevators)

ANTIDEPRESSANTS
1. MAO inhibitors:
– Irreversible: Isocarboxazid, Iproniazid, Phenelzine and
Tranylcypromine
– Reversible: Moclobemide and Clorgyline
1. Tricyclic antidepressants (TCAs)
 NA and 5 HT reuptake inhibitors – Imipramine,
Amitryptiline, Doxepin, Dothiepin and Clomipramine
 NA reuptake inhibitors – Desimipramine, Nortryptyline,
Amoxapine
1. Selective Serotonin reuptake inhibitors:
– Fluoxetine, Fluvoxamine, Sertraline and Citalopram
1. Atypical antidepressants:
– Trazodone, Mianserin, Mirtazapine, Venlafaxine, Duloxetine,
Bupropion and Tianeptine

Causes of Depression and
Mechanism of antidepressants
 The Monoamine Theory:
 Adrenaline, Noradrenaline, Dopamine and 5-HT
are neurotransmitters (Biogenic amines)
 Called Noradrenergic, Serotonergic or
Dopaminergic etc. neurones
 Normally NA and 5 HT are in adequate numbers
at post synaptic region
 In DEPRESSION – Deficiency of NA or 5 HT or
BOTH

Mechanism of antidepressants –
contd.
 Drugs act by increasing the local availability of NA or
5 HT
 MAO Inhibitors: MAO is a Mitochondrial Enzyme
involved in Oxidative deamination of these amines
 MAO-A: Peripheral nerve endings, Intestine and
Placenta (5-HT and NA)
 MAO-B: Brain and in Platelets and Mainly
Serotonergic (Phenylalanine)
 Selective MAO-A inhibitors (RIMA) have
antidepressant property

Mechanism of antidepressants –
contd.
 TCAs:
– NA, 5 HT and Dopamine are present in Nerve endings
– Normally, there are reuptake mechanism and termination of
action
– TCAs inhibit reuptake and make more monoamines
available for action
 SSRIs:
– Serotonins also reuptaken by Nerve terminals
– SSRIs inhibit the reuptake mechanism and make more 5
HT available for action

MAO inhibitors
 Drugs: Irreversible: Isocarboxazid, Iproniazid, Phenelzine and
Tranylcypromine, Reversible: Moclobemide and Clorgyline
 Not popular now except irreversible selective MAO-A
inhibitors:
– Strict dietary restrictions
– Irreversible action
– Drug-drug interactions
– Safer drugs are available now
 Major drawbacks:
– Manic state or hypertensive crisis
– Cheese reactions
– Other drug interactions

MAO inhibitors (Drawbacks) – contd.
 Drug Interactions:
– Ephedrine (drugs of cold and cough): hypertensive reaction
– Reserpine, guanethidine: excitement and rise in BP
– Levodopa: excitement and rise in BP (delayed degradation
of NA and DA)
– Antiparkinsonian anticholinergics: Hallucinations and
symptoms of atropine poisoning
– MAOI and SSRI: Serotonin Syndrome (Mental confusion,
hallucinations, sweating, hyperthermia, twitching of muscle,
clonus and convulsion)

MAO inhibitors – contd.
 Moclobomide: Advantages
– Reversible action (1-2 days after stoppage)
– Potentiation of pressor response to dietary
amines is weak
– Dietary restriction not required
– Lack of anticholinergic, sedative,, cognitive and
CVS adverse effects
– Used in elderly patients and with heart diseases
– Mild to moderate depression - alternative to TCAs

Tricyclic Antidepressants - Imipramine
 NA and 5 HT reuptake inhibitors –
Imipramine, Amitryptiline, Doxepin, Dothiepin and
Clomipramine; NA reuptake inhibitors –
Desimipramine, Nortryptyline, Amoxapine
 Analogue of CPZ
 Inhibit NET and SERT
 Interacts with variety of receptors – alpha, H1,
5HT1, 5HT2 and D2

Imipramine – contd.
 Early effects – sedation, no other CNS effect
 After 2-4 wks:
– Elevation of mood, more communicative
– REM sleep suppressed and no night awakening
– More sedative ones are for agitated and anxiety
patients (amitriptyline, doxepin)
– Withdrawn patients – less sedative Imipramine,
Nortriptyline
– Induce seizure (Clomipramine, bupropion)

Imipramine - Mechanism of action
 Inhibit uptake of Biogenic amines – NA and 5-HT
 No inhibition of DA uptake except Bupropion
 Cocaine and amphetamines are inhibitors of DA
uptake – strong CNS stimulant
 May facilitate DA transmission in forebrain –
elevation of MOOD
 Reuptake inhibition causes – increase amines in
synaptic cleft
 Inhibition of DA – stimulant action
 Inhibition of NA and 5-HT – antidepressant action

Imipramine - Mechanism of action –
contd.
 But, antidepressant action starts after few weeks, whereas
blockade starts immediately
 Inhibition of uptake is an early step but cascade of events that
follow are important
 Initially, auto receptors - α2 and 5-HT1 are activated by excess
of NA/5HT – negative feed back
 Limiting of synaptic availability of NA - homeostasis
 On repeated exposure – α2 receptor response diminishes -
desensitization of these pre-synaptic receptors
 Adaptive changes – in number and sensitivity of pre and
postsynaptic pre-synaptic production and release of NA -
normal or more
 No reuptake and no negative feed back

Imipramine – Pharmacological actions
 ANS: Dry mouth, blurring of vision,
constipation and urinary hesitancy
 CVS: Tachycardia –
– NA and anticholinergic action
– Postural hypotension
– ECG – T wave suppression
– Arrhythmia

Effect of
Antidepressants
Deficient Drive of
MOOD to -
Normal Rhythmic
Drive on
Prolonged
Treatment

Imipramine - Pharmacokinetics
 Good oral absorption but undergo 1st pass effect –
variable bioavailablity
 Highly bound to plasma protein and high Vd
 Metabolized in Liver: Active metaboites: Imipramine
– desipramine and amitriptyline – nortriptyline
 Excreted via urine, t1/2 – 16 to 24 Hrs
 One daily dose – because of active metabolites
 Therapeutic window phenomenon: Optimal effect at
50-200 ng/ml
 Doses to be individualized and titrated

Imipramine – Adverse effects
1. Anticholinergic effects: Dry mouth, bad taste,
constipaton, urinary retention etc.
2. Dysphoric state or mania - suicide
3. CVS:
 Postural hypotension – older patient and overdose
 Arrhythmia – with IHD
1. Weight gain – not with bupropion and SSRI
2. Seizure – in children
3. Sedation, mental confusion etc. – more with
amitriptyline
4. Sweating and fine tremor

Imipramine – Drug Interactions
1. TCAs and Sympathomimetics (Cough and
cold)
2. TCAs and MAO inhibitors – Hypertensive
crisis
3. TCAs and SSRIs – SSRIs inhibit
metabolism of TCAs
4. Anticholinergic property – delay absorption
of other drugs

Imipramine - Drawbacks
 Low safety margin
 Anticholinergic, CVS and neurological side
effects
 Therapeutic lag (2-4 wks)
 Variable patient response

SELECTIVE SEROTONIN REUPTAKE
INHIBITORS
 Drugs: Fluoxetine, Fluvoxamine, Sertraline and
Citalopram
 Similar antidepressant action
 Relatively safe and better patient acceptability
 Some patients not responding to TCAs may respond
with SSRIs
 Because of absence of psychomotor and cognitive
impairment - Preferred in prophylaxis of recurrent
depression

INHIBITORS
 Relative advantages:
– No sedation, so no
cognitive or psychomotor
function interference
– No anicholinergic effects
– No alpha-blocking action,
so no postural hypotension
and suits for elderly
– No seizure induction
– No arrhythmia
 Drawbacks:
– Nausea is common
– Interfere with ejaculation
– Insomnia, dyskinesia,
headache and diarrhoea
– Impairment of platelet
function – epistaxis
– Serotonin Syndrome:
Mental confusion,
hallucinations, sweating,
hyperthermia, twitching of
muscle, clonus and
convulsion.

INHIBITORS
 Fluoxetine:
– Prototype of SSRIs
– Slow action and not used for rapid effects
– Longest acting – 2 days, t1/2 = 2 days
– Used in depression and OCDs in adult and
children

SSRIs – Pharmacokinetic comparison
Dose
mg/day
Drug
interaction
Half life Steady
state
(Days)
Fluoxetine 5-20 high 2-4 days 30-60
Sertraline 50 low 26 Hrs 7-14
Paroxetime 20 high 20 Hrs 10-14
Citalopram 20-40 low 35 Hrs 7

Atypical Antidepressants
1. Trazodone:
 Weak 5-HT uptake block, α – block, 5-HT2 antagonist
 No anticholinergic action
 No arrhythmia
 No seizure
 ADRs: Priapism, Postural Hypotension
2. Venlafaxine:
 SNRI (Serotonin and NA uptake inhibitor)
 Fast in action
 No cholinergic, adrenergic and histaminic interference
 Raising of BP

Atypical Antidepressants – contd.
3. Mirtazapine:
 NaSSA action (Noradrenaergic and specific serotonergic
antidepressant) – enhancement of NA release and specific 5-
HT1 receptor action
 Blockade of 5-HT2 and 5-HT3
 No anticholinergic or antidopaminergic action
4. Bupropion:
 Inhibitor of DA and NA uptake (NDRI)
 Non-sedative but excitant property
 Used in depression and cessation of smoking
 Seizure may precipitated

Antidepressants - Uses
1. Endogenous Major Depression:
 Aim: Relieve symptoms of depression and restore Normal
social Behavior
 1st
choice – SSRI (atypical ones also may be considered)
 TCAs – in non-responsive cases
(TCAs have to be used in severe depression in adults)
 MAO –A inhibitors in mild and moderate cases
 Maintenance – by TCAs (Imipramine 100 mg)
 Combined with Lithium in Bipolar disorder
 Newer ones are not recommended in children – suicide
chance

Antidepressants (Uses) – contd.
2. Obsessive Compulsive Disorder (OCD) and Phobic states:
(SSRIs are useful)
– Compulsive eating in Bulimia
– Body dysmorphic disorder
– Compulsive buying
– Kleptomania
3. Anxiety Disorders: BZD
4. Neuropathic pain: Imipramine, Amitriptyline – post herpetic neuralgia
4. Attention Deficit Hyperactivity Disorder: TCAs
5. Enuresis
6. Migraine: Amitryptiline as prophylactic

What is anxiety?
 Anxiety is a normal reaction to stress
 It helps one deal with a tense situation in the
office, study harder for an exam, keep
focused on an important speech
 In general, it helps one cope
 But when anxiety becomes an excessive,
irrational dread of everyday situations, it has
become a disabling disorder

Antianxiety Drugs – contd.
 Five major types of anxiety disorders are:
– Generalized Anxiety Disorder (GAD)
– Obsessive-Compulsive Disorder (OCD)
– Panic Disorder
– Post-Traumatic Stress Disorder (PTSD)
– Social Phobia (or Social Anxiety Disorder)
 GAD:
– Excessive, exaggerated anxiety and worry about everyday life
events with no obvious reasons for worry
– always expect disaster and can't stop worrying about health,
money, family, work, or school
– interferes with daily functioning, including work, school, social
activities, and relationships.

What are the Drugs?
 Benzodiazepines: Alprazolam, Diazepam,
Chlordiazepoxide, Oxazepam and Lorazepam
 Older Drugs: Barbiturates, Chloral hydrate and
Meprobamate
 Azapirones: Buspirone, Gepirone and Isapirone
 Others: Propranolol, Imipramine Fluoxetine and
Zolpidem etc.

Antianxiety Drugs – BZDs
 High potency BZDs are useful
 Slow and Long duration of action
 Relieve anxiety at low doses – no generalized CNS depression
 Prescribed for short period – especially for alcohol and drug
abuse persons
 Less cognitive impairment
 At low dose – CVS and Respiratory side effects are less
 Withdrawal syndrome – tapering of Doses
 Clonazepam - social phobia and GAD
 Lorazepam - panic disorder
 Alprazolam - panic disorder and GAD
 Diazepam – acute panic state and organic disease anxiety

Antianxiety Drugs – Buspirone
 No marked sedation and euphoria
 No direct effect on GABA or BZD receptors
 No physical dependence or tolerance
 No muscle relaxant, no anticonvulsant or no
extra pyramidal effects
 No functional and cognitive impairment
 No cross tolerance to other anxiolytics and
little abuse potential

Buspirone – contd.
 Partial agonist action on presynaptic auto receptor 5-
HT1A – reduces serotonergic activity in dorsal raphe
 Antagonist of certain 5-HT1A post synaptic receptors
 Weak D2 action but no antipsychotic effect
 Adaptive changes after chronic treatment – reduction
in 5-HT2 receptors in cortex
 Given orally, absorbed rapidly – high 1st
pass
metabolism, active metabolite – urine and faeces
 Dose: 5-15 mg dose

Antianxiety Drugs - Propranolol
 Reduces symptoms of anxiety
 Symptoms: Sympathetic overactivity –
palpitation, tachycardia, rise in BP, sweating,
tremor, GIT hurrying etc
 No action on psychological symptoms – fear,
tension etc.
 Useful in examination fear, public
appearance etc.

Pharmacotherapy of Anxiety
 Anxiety is a Physiological phenomenon
 Start medication only when marked impairment of performance
 Start with a BZD according to the type of disorder at smallest
dose possible
 Doses are found out by titrating with the symptoms
 Usually start with ½ or 2/3rd
of the normal dose at bed time
 If required the rest of the doses be given at day time
 Simultaneously treat the primary cause – hypertension, Peptic
ulcer etc.
 SSRIs and Buspirone may be used in severe cases but not in
acute cases

Pharmacotherapy of Anxiety – contd.
 Beta-blockers may be given as adjuncts
 Withdraw anxiolytics, if required in tapering doses
 Lifelong therapy may be required for some patients
but avoid short acting drugs for long therapy
 Monitor for Drug interactions
 In GAD – counseling, mental relaxations and
Behavioural therapy
 Avoid:
– Excess of Cola or Coffee (stimulants)
– Combination of alcohol, antihistamines, anticholinergics

Antidepressants

In this document