Anti-Depressants

Types + Pathophysiology

1. Unipolar:

Exogenous / Reactive Depression

Endogenous/Major Depression

2. Bipolar : Manic – depressive illness

Monoamine Hypothesis

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

• mania caused by overproduction of NT

• 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

• Limitations:

  • antidepressant effects not seen until 2-4 wks of treatment

  • overly simplistic

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 → take 2-12 weeks to produce significant improvements in mood

• Fluoxetine, paroxetine → CYP2D6 inhibitor

• Fluvoxamine → CYP3A4 inhibitor

SSRIs MOA and Uses

• Serotonin transporter (SERT) embedded in axon terminal and cell body of serotonergic neurons → responsible for reuptake of serotonin from synaptic cleft

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

• SSRIs binds to SERT and selectively inhibit it from a site other than serotonin site

• this serotonin is then used for transcription of genes for neurotropic factors → AD effect

• 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 - generalized anxiety disorder + social anxiety disorder

• Post traumatic stress disorder

• Obsessive compulsive disorders

• Bulimia nervosa → fluoxetine

• 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

• delayed ejaculation

• anorgasmia

• assess at follow up

   

CNS:  

• Headache,

• insomnia → paroxetine, fluvoxamine → sedating (useful in pts who have difficulty sleeping)

• somnolence → fluoxetine, sertraline

• Suicidal tendency

  • patients have increased suicidal tendency

  • C/I below  25 years of age 

  • fluoxetine, sertraline, fluvoxamine approved for children for OCD

  • fluoxetine, escitalopram for childhood depression

• Serotonin syndrome with MOAI

 

CVS

• citalopram → QT prolongation → arrhythmias

• Discontinuation syndrome:

  • after abrupt withdrawal

  • chronic SSRI use → inc synaptic serotonin lvls → brain adapts by downregulating serotonin receptors (5HT1A and 5HT2A) → after abrupt withdrawal → drop in synaptic serotonin lvls → adapted brain now receives less serotonin stimulation → neurochemical imbalance → symptoms

  • caused by agents with short half lives and inactive metabolites

  • fluoxetine has lowest risk due to its longer half life and active metabolite

  • headache, malaise, flu-like symptoms, agitation, irritability, nervousness, changes in sleep

• Weight gain : Paroxetine

• Dizziness & Paraesthesia

• reduces seizure threshold → inc seizures

SSRIs DDI - SEROTONIN SYNDROME

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 → cognitive, autonomic, somatic effects

  • 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 

  • (active demethylated metabolite of venlafaxine)

  • inhibitor of serotonin reuptake and at medium/higher doses → inhibits NE

• CYP 2D6 inhibitor

• lowest PPB (27-30%)

• T1/2 →11hrs

• OD dosing 

• Duloxetine (inhibits at all doses)

  • avoid in pts with liver dysfunction

  • GI side effects common

• t1/2 →12hrs 

•  extensive oxidative metabolism via CYP2D6 & CYP1A2

    Mechanism of Action

• inhibit serotonin and norepinephrine transporters. 

• Both serotonin and norepinephrine levels increase → inc transcription of neurotropic growth factors

• depression is accompanied by chronic pain such as backache and muscle aches for which SSRIs are ineffective → this pain is modulated by serotonin and NE pathways → SNRIs effective

• 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 on presynaptic neuron→ inc lvls of serotonin and NE in cleft

• SERT - clomipramine / imipramine 

• NET - desipramine / nortriptyline

• alpha blocking (Orthostatic hypotension), anticholinergic & antihistamine (doxepin → pruritis) 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)

  • improves mood in 50-70% individuals

  • onset of mood elevation is slow (2wks+)

  • adjust dose according to response

  • tapering of agents recommended to avoid discontinuation syndrome and cholinergic effects

• Panic disorder.

• Enuresis in children - bed wetting (imipramine used as an alt to desmopressin)

• Neuropathic and other pain conditions (amitriptyline)

• Generalized Anxiety Disorder

• Obsessive Compulsive Disorder

• Attention deficit hyperkinetic Disorder.

•  Neuralgias

• Migraine (amitriptyline)

• Smoking cessation (nortryptalline)

• insomnia - low doses of TCAs including doxepin
  

TCA A/E

• NE release → hypertension, inc BP (venlafaxine → cardiotoxic)

• Anticholinergic effects (amitriptyline, imipramine)

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

  • aggravation of angle-closure glaucoma

• α  blocking property

  • Orthostatic hypotension & reflex tachycardia  

• arrythmogenic + quinidine-like property

  • 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

CI

• use with caution in pts with bipolar disorder because AD may cause a switch to manic behavior

• depressed pts who are suicidal should be given very limited quantities and monitored

• exacerbates BPH, epilepsy, arrhythmias

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

Pharmacokinetics

• Well absorbed after oral administration.

• Extensive PPB

• Extensively metabolized in liver

• Both drugs are converted into active metabolites, having potent antidepressant activity.

• Trazodone is converted to m-cpp  (m-chloro phenyl piperazine)

• Nefazodone is converted into hydroxy nefazodone and m-cpp 

• Nefazodone potent CYP3A4 inhibitor

• Trazodone cyp 3 A4 substrate

Mechanism of action

• block 5HT_2A  receptors → antianxiety, anti-psychotic and antidepressant effects

• Nefazodone: Weak inhibitor of SERT & NET → raising the amine levels

• Trazodone: weak inhibitor of SERT with little effect on NET

• alpha blocking & antihistamine effects 

Therapeutic uses of 5HT₂ antagonists

• Depression

• Anxiety disorder

• Insomnia (trazodone)

Adverse effects

• GIT upset

• Hepatotoxicity  with Nefazodone

• Sedation → Trazodone → antihistamine effect

• Orthostatic hypotension alpha blocking effect 

Tetracyclic and Unicyclic AD

Pharmacokinetics

• Well absorbed after oral administration.

• Extensive PPB.

• Extensively metabolized in liver

  Bupropion 

• has three active metabolites including 7-hydroxybupropion

• biphasic elimination 

  • 1^st phase: 1 hour; 2^nd phase: 14 hours

• inhibits reuptake of NE and dopamine by inhibiting NET and DAT

• Stimulates presynaptic release of catecholamines

• metabolized by CYP2B6

• avoid in seizure/bulimia risk

Mirtazapine 

• Blocks alpha 2 presynaptic receptors, H1 receptors

• Enhances the release of NE & serotonin (serotonergic and adrenergic)

• Antagonist of  inhibitory receptors 5-HT2A, 5-HT2C and 5-HT3 receptors--- incre. availability of serotonin

• no MOA reuptake inhibition

Amoxapine → hydroxy amoxapine → D₂ receptor blocking activity → antipsychotic effects

• also block NET, SERT and have some anticholinergic activity → caution when administered together

Clinical uses

• Depression unresponsive to other therapies

• Bupropion – obesity, smoking cessation & ADHD

  • decreases cravings and attenuating withdrawal relating to nicotine

   Adverse effects

• Sedation → mirtazapine, bupropion → antihistaminic effect

• Parkinsonism → Amoxapine → D2 antagonist

• Maprotiline → TCA like effects

• Bupropion → causes stimulation leading to agitation, insomnia, anorexia.

• Hydroxy bupropion is 2D6 inhibitor

• CI in pts taking MAOI

MAOI

Pharmacokinetics

• orally active

• Extensive hepatic first pass metabolism 

• Alternative routes like transdermal and S/L preparation of selegiline → by pass gut & liver (no FPE) → incre B.A.→ dec food interactions

• selegiline and tranylcypromine → amphetamine-like stimulant effect → agitation/insomnia

Mechanism of action:

• “safety valve” to oxidatively deaminate and inactivate excess NTs that leak out of synaptic vesicles when neuron is at rest

• MAOI form stable complexes with the enzyme → irreversible activation → inc stores of NE, serotonin, dopamine in neuron + diffusion of excess NT in synaptic space

• inhibits MAO-A and MAO-B

MAO-A 

• present in noradrenergic, dopaminergic neurons   

• degrades  NE, epinephrine, serotonin, dopamine and tryptamine. 

• found in gut, liver, placenta and brain.

MAO-B 

• present in serotonergic & histaminergic neurons 

• degrades monoamines, phenylethyl amine, tyramine, dopamine and tryptamine. 

• present mainly in brain, platelets and  liver.

Clinical uses

• used for pts who are unresponsive or intolerant to other AD (not preferred due to their DD and drug-food interactions)

• Anxiety disorder

• Selegiline –Parkinson’s disorder

Adverse effects

• Orthostatic hypotension 

• Weight gain

• Sedation (Phenelzine)

•  Amphetamine like effects → CNS stimulation, insomnia, irritability, restlessness

• Dec sexual functions

• Discontinuation syndrome 

• Psychosis, excitement, confusion, delirium

Drug interactions

Cheese reaction/tyramine pressor response

• normally tyramine is taken from food and extensively metabolized by MAO in gut → less  BA.

• Food containing tyramine given to a patient on MAOI.

• MAO is blocked → tyramine is not degraded → pass from gut to circulation + sympathetic nerve endings

• Acting as indirectly acting sympathomimetics → displace norepinephrine from nerve endings → incre. availability of NE → malignant hypertension, stroke, cerebral hemorrhage & MI (hypertensive crisis), occipital headache, arrhythmias

• Foods like cheese, beer/red wine, sausages, liver, smoked fish are avoided in pts taking MAOI.

SSRIs shoudl not be co-administered with MAOI → serotonin syndrome

• washout period of 2wks before other type administered (except fluoexetine which should be discontinued 6wks before MAOI adm)

Overdose of MAO inhibitors

• Autonomic instability

• Psychotic symptoms

• Fever

• Confusion

• Delirium

• Seizures

• Management 

  • Cardiac monitoring, vital 

  • support & lavage

NMDA receptor Antagonists

• Ketamine & esketamine NMDA receptor blocker

• These drugs have multiple other actions that can contribute to efficacy  in depression

• These include  interactions with  opioids receptors, monoamine receptors, cholinergic receptors &  ca channels.

• Ketamine enhances activity of descending setonergic pathways that may be imp for antidepressant property

GABA_A receptor Modulators

GABA_A receptors are ligand gated chloride conducting ion channels that causes inhibition of neural networks including  those associated with limbic overactivity in maj depression

Brexanolone resets the dysregulated brain function in depressive episodes through modulation of GABA_A receptors

Electroconvulsive Therapy

• For severe suicidal depression

• Electrodes r placed on head & give convulsions--- incre NT levels