ANTIDEPRESSANTS

•Tricyclic Antidepressants

•Selective Seratonin Reuptake Inhibitors

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 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 (!)

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 CNSSupported 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 sensitivityThe 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

Therapy of depression

Pharmacotherapy/Mood Elevators– 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)

• 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:– 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

I. Tricyclic Antidepressants (TCAs)I. Tricyclic Antidepressants (TCAs)

imipramine

Mode of action• Block reuptake of NE,Serotonin and

Dopamine at nerve terminal,thus increasing the NE,5HT or DA at the extracellular and more of its action on at receptor site.

• Down regulation of Beta-adregernic receptors• in most TCA, other receptors (incl. those outside the CNS) are also

affected: blockade of H1-receptor, -receptors, M-receptors

Pharmacological action

• CNS-mood elevation in depress patient,can cause ataxia,epilepsy,seizures and coma.

• CVS-orthostatic hypotension

• ANS-anticholinergic effects.Most potent anticholinergic action

Classification

• A. Tertiary Amines: Amitriptyline, Butriptyline, Clomipramine, Dosulepin, Doxepin, Imipramine, Lofepramine, Trimipramine

• B. Secondary Amines: Desipramine, Nortriptyline, Protriptyline

• C. Others/Dibenzodiazepine derivitive: Dibenzepin

ClassificationA. NA and 5HT reuptake inhibitors

Imipramine,Amitryptaline,Clomipramine

B. Predominantly NA reuptake inhibitor

Desipramine,Nortriptyline,Amoxapine

Most important TCAs

• imipramine• 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

INDICATIONS• Clinical depression• Neuropathic pain-Diabetic

neuropathy/Analgesia• ADHD • Nocturnal Enuresis (Imipramine)• Panic disorder(Imipramine)• OCD(Clomipramine)• Others like eating

disorder,narcolepsy

• Agranulocytosis

• Severe liver damage

• Glaucoma

• Prostatic hyperplasia

• Epilepsy

• lactation

Contraindication

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.

Drug interaction

• Tricyclic interaction includes additive depression of the CNS with other antidepressents include ethanol, barbiturates, benzodiazipines, and opioids.

• Tricyclic may also cause reversal of the anti-hypertensive action of guanethidine by blocking its transport into sympathetic nerve endings.

• Less commonly, tricyclics may interfere with the anti-hypertensive actions of methylnorepinephrine( the active metabolite of methyldopa) and clonidine.

• Tricyclics also share metabolic pathways with phenytoin, hence it may increase concentrations of phenytoin.

• Tricyclics also potentiate the pressor effects of adrenaline and noradrenaline, so that there is a potantial hazard when a local anaesthetic is used with a pressor amine.

Drug Dose

• It takes about 2-3 weeks before tricyclic antidepressents has any evident action on depression( although sleep and agitation may respond earlier).

• Hence, it is useless to give it as per needed only.They must be administred regularly in sufficient doses to achieve the desired effect.

• After remission of symptoms, it is essential to continue the anti-depressents for 6-12 months in the 1st episode and longer duration in subsequent episodes to prevent reccurence of symptoms.

• A drug, e.g. imipramine is given in sufficient doses(100-300 mg) for 6 weeks, can it be called as ineffective for a particular patient.

• When starting the drug start with a low dose and gradually increase it to prevent the side-effects.

• When stopping the drug, taper the dose over 2-3 weeks period. As if you were to stop it abruptly, it will cause withdrawal symptoms such as:

-Nausea -Tremor -Headache -Insomnia

Adverse EffectsPharmacological Action Adverse Effect

Muscarinic receptor Blockage/ Anticholinergic

•Dry mouth, tachycardia, blurred vision, glaucoma•Constipation, Urinary retention, Sexual dysfunction•Cognitive impairement

ᾴ1 Adrenoceptor blockade •Drowsiness, Postural Hypotension, Sexual dysfunction(loss of libido, impaired erection)•Cognitive Impairement

Histamine H1 receptor Blockade Drowsiness, Weight Gain

Membrane stabilizing properties Cardiac conduction defects, Cardiac arrythmia, Seizures

Others Rash, Oedema, Leukopenia, Elevated liver enzymes

Teratogenic effects• Have not been proved

but it should be used cautiously in the first trimester of pregnancy.

Toxic Effects• CVS: Ventricular fibrillation, Conduction disturbances,

Low BP, --- ecg shows prolong PR and QT intervals, depressed ST, flattened T waves. Heartblock occasionally

• RS: Respiratory depression -> Hypoxia, Aspiration pneumonia

• CNS: Agitation, twitching, convulsions, hallucinations, delerium, coma. Parasympathetic dry mouth, dilated pupil, blurred vision, urine retention, pyrexia

Management of toxicity

• Supportive care• Cardiac monitoring---if arrythmia, ICU• Plasma level monitoring: Shudn go above

450ng/ml or 300ng/ml if concomitant medical disorder

• TCA has delayed gastric emptyin, do gastric lavage if several hours after overdose

• Activated Charcoal 1gm/kg PO/NG

Newer Drugs

• Lofepramine-Has strong anti-cholinergic side-effect than amitriptyline and is less sedating; however, it may cause anxiety and insomnia.In overdose it is also less toxic than conventional tricyclics.

• Trazodone-Also has few anti-cholinergic side effects, but has strong sedating properties.

II. II. Selective Serotonin Re-uptake Selective Serotonin Re-uptake InhibitoInhibitorrs (SSRI)s (SSRI)

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

• Principal mechanism of action:

– selective inhibition of 5-HT (serotonin) reuptake more extracellular seratonin → More action on seratonin receptors on post synaptic → more stimulation

• Other indications of SSRI - anxiety disorders: generalized anxiety, panic disorder, social anxiety disorder, obsessive-compulsive disorder

+ bulimia nervosa, gambling

Most important SSRI

• (10-60mg/day)Fluoxetine (Prozac, Fontex, Seromex, Seronil, Sarafem, Fluctin (EUR), Fluox (NZ), Depress (UZB), Lovan (AUS)

• (50-300mg/day) Fluvoxamine (Luvox, Fevarin, Faverin, Dumyrox, Favoxil, Movox)

• (10-40mg/day) Paroxetine (Paxil, Seroxat, Sereupin, Aropax, Deroxat, Rexetin, Xetanor, Paroxat)

• (50-200mg/day) Sertraline (Zoloft, Lustral, Serlain)

• (10-40mg/day) Citalopram (Celexa, Cipramil, Cipram, Dalsan, Recital, Emocal, Sepram, Seropram, Citox)

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.

HO

HO

NH2

OH

Norepinephrine(Noradrenaline)

HO

Serotonin5-Hydroxytryptamine

(5-HT)

NH

NH2

CN

O

N

F

MeMe

Citalopram(CelexaTM)

O

Fluoxetine(ProzacTM)

NH

CF3

Me

NeurotransmittersOH groups necessary for agonist activity

NO

Fluvoxamine(LuvoxTM)

F3C

NH2

OCH3

OO

O

HN

FParoxetine(PaxilTM)

Sertraline(ZoloftTM)

Cl

Cl

HN

O

NMe Me

Dapoxetine

Commercial SSRI's

Adverse effects

• Relative improvement to other antidepressants (mostly mild)

• Less Cardiotoxic compared to TCA• Generally, much safer in overdose• Lack anticholinergic effects and are not Sedating

• GIT – nausea, vomiting, diarrhea• Neuropsychiatry – Headache, Irritability, Restless

(Akathisia)-EPS more common in SSRI than TCA, Agitation, Tremor, Insomnia and daytime somnolence, Seizures Mania

• Sexual dysfunctions – Ejaculatory delay, anorgasmia• Suicidal Behavior• Serotonin syndrome upon intoxication or drug interactions

Serotonin Syndrome• SSRIs are contraindicated with concomitant

use of MAOIs (monoamine oxidase inhibitors). This can lead to increased serotonin levels which could cause a serotonin syndrome.

• CF:-– NEURO: Myoclonus, Nystagmus, Headache,

Tremors, Rigidity, Seizures– MENTAL STATE: Irritability, Confusions, Agitations,

Hypomania, Coma– OTHERS: Hyperpyrexia, sweating, diarrhea,

cardiac arrythmia, death

SSRI discontinuation syndrome

• not as significant as benzodiazepines

• little to no abuse potential

• Withdrawal symptoms: common descriptions include dizziness, electric shock-like sensations, sweating, nausea, insomnia, tremor, confusion, and vertigo

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