Anti-Depressants

Types + Pathophysiology

1. Unipolar:

Exogenous / Reactive Depression

Endogenous/Major Depression

2. Bipolar : Manic – depressive illness

Monoamine Hypothesis

• Depression is caused by  decreased levels of monoamines, serotonin, norepinephrine, dopamine at neuronal synapses. 

• Supporting evidences

  • Use of reserpine (Depletes monoamine stores) → depression

  • Administration of synthesis inhibitor of NE → depression

  • All antidepressant drugs enhances the synaptic availability of serotonin and NE → however, antidepressant effects not seen until 2-4 wks of treatment

Neurotropic Hypothesis

• neurotropic growth factors like brain derived neurotropic factors (BDNF) critical for neurogenesis and plasticity → enhance neurogenic transmission.

• tyrosine kinase receptor B → activates enzymes → transcription of certain genes responsible for enhanced synaptic plasticity and connectivity.

• Pain/stress/depression → dec BDNF → atrophic changes in hippocampus & cortex.

• Evidences in favour of neurotrophic hypothesis

  • Direct infusion of BDNF in hippocampus → enhanced neurogenesis + antidepressant action

  • Electroconvulsive therapy increases BDNF

  • Antidepressants increases BDNF
    

Neuroendocrine factors

HPA axis abnormalities

•  cortisol & GC → depression.

Thyroid dysregulation

• Hypothyroidism → depression 

• thyroxine is given along with antidepressant to augment its effect 

Deficiency of sex hormones – 

• Estrogen deficiency (fem) and testosterone deficiency (males) → depression

SSRIs PK

• Orally active

• Well absorbed after oral administration

• PPB – 80-90%

• Fluoxetine → Norfluoxetine → t1/2 7 to 9 days 

• once weekly dose

• Fluoxetine, paroxetine → CYP2D6 inhibitor

• Fluvoxamine → CYP3A4 inhibitor

SSRIs MOA and Uses

• Serotonin transporter (SERT) is embedded in axon terminal and cell body of serotonergic neurons

• EC serotonin binds to SERT, conformational change occurs, Na+ and Cl^-  moves into the cell and serotonin is released inside the cell.

• SSRIs binds to SERT and inhibit it.

• AT therapeutic doses 80 % activity of transporter is inhibited.

• Negligible affinity for NET, β , histamine, muscarinic and other receptors.

Clinical Uses of SSRI

• Depression

• Anxiety/panic disorder

• Post traumatic stress disorder

• Obsessive compulsive disorders

• Bulimia nervosa

• Pre-menstrual dysphoric disorder

SSRIs A/E

GIT 

•  nausea

•  gastrointestinal upset

•  diarrhea

• GI s/s improves after first wk of treatment

• take with food

Sexual dysfunction

• Decreased sexual functions

• Decreased libido, both males and females

• assess at follow up

   

CNS:  

• Headache, insomnia

• Suicidal tendency

  • patients have increased suicidal tendency

  • C/I below  25 years of age 

 

• Weight gain : Paroxetine

• Discontinuation  syndrome

• Dizziness & Paraesthesia

SSRIs DDI

  Pharmacokinetic interaction

     Paroxetine & fluoxetine → CYP 2D6 inhibitor

Pharmacodynamic – MAOIs

• MAOI inhibit monoamine enzyme (responsible for degradation of NE & serotonin) → increased serotonin occurs at neuronal endings → toxic levels

Pharmacodynamic  interaction - Serotonin syndrome

• Combination of SSRIS with MAOI may result in serotonin syndrome

• Overstimulation of 5-HT receptors in medulla

• S/S include: SHIVERS

  • shivering

  • hyperreflexia + myoclonus + tremors

  • inc temperature (>41C)

  • vital signs instability → hypertension and tachycardia

  • encephalopathy (cognitive effect → delirium, coma)

  • restlessness

  • sweating

• To avoid this → gap of 2 weeks given between administration of SSRI and MAO inhibitors.

SNRIs

Pharmacokinetics

• Well absorbed after oral administration.

• Desvenlafaxine 

• CYP 2D6 

• lowest PPB (27-30%)

• T1/2 →11hrs

• OD dosing 

• Duloxetine 

• t1/2 →12hrs 

•  extensive oxidative metabolism via CYP2D6 & CYP1A2

    Mechanism of Action

•  inhibit serotonin and norepinephrine transporters. 

• Both serotonin and norepinephrine levels increase. 

• They lack potent antihistamine, alpha blocking  & anticholinergic effects

Therapeutic uses

• Major depression

• Panic disorders

• Diabetic neuropathies & fibromyalgia

• Stress urinary incontinence

• Vasomotor symptoms of menopause

 A/E

• Incre. BP

• Incre HR

• CNS activation: anxiety, agitation & insomnia

• Cardiac toxicity with venlafaxine

• Hepatic toxicity  with Duloxitine

• Discontinuation syndrome

• Dizziness, paresthesia

TCA

Pharmacokinetics

• well absorbed after oral administration

• Long t1/2---OD dosing

• Metabolized by CYP2D6 (DDI)

• Undergo extensive metabolism Demethylation / hydroxylation / conjugation

Mechanism of Action

• bind and Inhibit SERT & NET

• SERT  clomipramine / imipramine 

• NET  desipramine / nortriptyline

• alpha blocking, anticholinergic & antihistamine effects

• Affinity of TCA for receptors

• Moderate affinity for alpha 1 and alpha 2

  • Alpha 1 blocking property

  • Alpha 2 agonistic property

Therapeutic Uses

• Endogenous Depression (Refractory to SSRIs).

• Panic disorder.

• Enuresis in children 

• Neuropathic  and other pain conditions

• Generalized Anxiety Disorder

• Obsessive Compulsive Disorder

• Attention deficit hyperkinetic Disorder.

•  Neuralgias

• Migraine

• Smoking cessation (nor tryptalline)
  

TCA A/E

• Anticholinergic effects 

  • Dry mouth, constipation, urinary retention, blurred vision & confusion

• α  blocking property

  • Orthostatic hypotension & reflex tachycardia  

• arrythmogenic

  • antiarrhythmic effect but at higher doses → arrhythmias

• H1 antagonism

  • Sedation & wt gain

• Discontinuation syndrome

  • Flu like syndrome

  • Cholinergic rebound

• Overdose/ toxicity with TCA

  • Vent Tachycardia, fibrillation & arrythmias

  • BP changes

  • Anticholinergic effects

  • Seizures

• Management

  • Airway support, cardiac monitoring, gastric lavage

  • Sodium bicarbonate to uncouple the TCA from sodium channels

Dis/Advantages of SSRI over TCA

ADVTANTAGES

• Easily available

• greater safety margin/safe in overdosage

• inexpensive

• Less frequent anticholinergic & CV  A/E

• Free of sedation

• Also useful in eating disorders

DISADVANTAGES

• Frequent nausea at the start of treatment

• Sexual dysfunction

• Risk of serotonin syndrome

• Incre. Potential for D/D interactions

• Icreased suicidal tendency

5HT2 Antagonists