DRUGS USED IN AFFECTIVE DISORDERS

Department of Pharmacology NEIGRIHMS, Shillong

Introduction

What are affective Disorders?

1. Mania

2. Depression • Reactive• Endogenous or Major Depression• Depressive syndromes – Unipolar or Bipolar

Bipolar Disorder - imageBipolar Disorder - image

Bipolar Disorder - image

Drugs used in Mania – Mood Drugs 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 – Pharmacological Lithium Carbonate – Pharmacological actions actions

CNS:CNS:– No discernible psychotropic effect in normal No discernible psychotropic effect in normal

individualsindividuals– Similarly, no effect on Manic-depressive Similarly, no effect on Manic-depressive

patientspatients– On prolonged administration – acts as mood On prolonged administration – acts as mood

stabilizerstabilizer– Suppresses the episodes af attackSuppresses the episodes af attack

Effect of Lithium Salts in Mania:

Lithium Carbonate – Mechanism of Lithium 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 fluids Li distributes evenly in extracellular and intracellular fluids

(contrast to Na+ and K+)(contrast to Na+ and K+)– Build up a small concentration gradient across cell Build up a small concentration gradient across cell

membranemembrane– But, cannot be transported via Na+/K+ ATPase But, cannot be transported via Na+/K+ ATPase – Interfere with transuducer mechanism of cell membraneInterfere with transuducer mechanism of cell membrane

Lithium Carbonate – Mechanism Lithium Carbonate – Mechanism of actionof action

2.2. Effects on 2Effects on 2ndnd Messenger Messenger– IPIP33 and DAG are important 2 and DAG are important 2ndnd messenger for alpha and messenger for alpha and

Muscarinic transmissionMuscarinic transmission– Lithium inhibits several enzymes in the normal recycling of Lithium inhibits several enzymes in the normal recycling of

PhosphoinositidePhosphoinositide– These include IPThese include IP22 to IP to IP11 and IP to Inositol and IP to Inositol– These leads to depletion of PIPThese leads to depletion of PIP22, the membrane precursor , the membrane precursor

of IPof IP33 and DAG and DAG– Ultimate effect may be in G-protein receptors – may Ultimate effect may be in G-protein receptors – may

uncouple receptors from G-protein uncouple 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 dopamine Decrease 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 body Attains uniform distribution in total body

waterwater Apparent Vd – 0.8L/kg at steady state Apparent Vd – 0.8L/kg at steady state

Lithium, Pharmacokinetics – Lithium, Pharmacokinetics – contd.contd.

Li is actively reabsorbed from proximal tubule in the Li is actively reabsorbed from proximal tubule in the kidney similar to Na+kidney similar to Na+

When Na+ is restricted larger portion of Na+ is When 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 the If 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, nystagmus Coarse tremor, giddiness, ataxia, motor incoordination, nystagmus

etc. – delirium, comaetc. – 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

2.2. Renal: Polyuria and PolydipsiaRenal: Polyuria and Polydipsia– Loss of ability of collecting tubules to conserve water by influence Loss 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 thyroid Decrease in thyroid Function – goitre (G protein)Function – goitre (G protein)

5.5. Pregnancy Pregnancy – contraindicated– contraindicated– Foetal goitre, congenital abnormalities (cardiac) Foetal goitre, congenital abnormalities (cardiac)

Lithium – Drug InteractionsLithium – Drug Interactions

Diuretics: Renal clearance of Lithium is reduced Diuretics: Renal clearance of Lithium is reduced by 25% with Diuretic e.g. furosemide, Thiazidesby 25% with Diuretic e.g. furosemide, Thiazides

NSAIDS: Renal clearance of Lithium is reduced NSAIDS: Renal clearance of Lithium is reduced by 25%by 25%

All Neuroleptics, except clozapine – increased All Neuroleptics, except clozapine – increased EPSEPS

Insulin and oral hypoglycaemics: enhance Insulin 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

ANTIDEPRESSANTSANTID

EPRESSANTS

Drugs which can Elevate Mood (Mood Elevators)

ANTIDEPRESSANTS

1. MAO inhibitors:– Irreversible: Isocarboxazid, Iproniazid, Phenelzine and Tranylcypromine– Reversible: Moclobemide and Clorgyline

2. Tricyclic antidepressants (TCAs) NA and 5 HT reuptake inhibitors – Imipramine, Amitryptiline, Doxepin,

Dothiepin and Clomipramine NA reuptake inhibitors – Desimipramine, Nortryptyline, Amoxapine

3. Selective Serotonin reuptake inhibitors: – Fluoxetine, Fluvoxamine, Sertraline and Citalopram

4. 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

Mechanism of Antidepressants

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 - suicide3. CVS:

Postural hypotension – older patient and overdose Arrhythmia – with IHD

4. Weight gain – not with bupropion and SSRI5. Seizure – in children6. Sedation, mental confusion etc. – more with

amitriptyline7. 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

SELECTIVE SEROTONIN REUPTAKE 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.

SELECTIVE SEROTONIN REUPTAKE 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

Typical 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: BZD4. Neuropathic pain: Imipramine, Amitriptyline – post herpetic neuralgia5. Attention Deficit Hyperactivity Disorder: TCAs6. Enuresis 7. Migraine: Amitryptiline as prophylactic

Antianxiety Drugs

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.

Antianxiety Drugs – contd.

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

Thank you / Khublei