Antidepressants New
Introduction
Depressive disorders involve a persistent depressed mood, lack of interest in activities, and functional impairment.
Higher prevalence in women and in the U.S. compared to developing countries.
Biological basis: decreased serotonin (5-HT), norepinephrine (NE), dopamine, and GABA; increased glutamate.
Associated conditions: hypothyroidism, adrenal insufficiency, SLE, vitamin B12 deficiency.
Differential diagnosis includes psychiatric (bipolar disorder, schizophrenia) and medical (cancer, TB, malabsorption syndromes) causes.
Older adults often present with somatic complaints (fatigue) or cognitive issues (poor concentration).
Treatment options:
First-line: SSRIs (sertraline, paroxetine, fluoxetine).
CBT + medication: more effective than either alone.
Exercise: beneficial for depression.
Electroconvulsive Therapy (ECT): for urgent cases (suicide risk, malnutrition, refusal to eat), safe in pregnancy.
What Are Antidepressants and How Are They Used?
Indications:
Major Depressive Disorder (MDD)
Psychotic disorders (e.g., schizoaffective disorder)
Anxiety disorders (GAD, panic disorder, social anxiety)
OCD
PTSD
Eating disorders (bulimia, binge eating)
Premenstrual dysphoric disorder
Neuropathic pain and fibromyalgia
Physiology of Serotonergic & Central Adrenergic Transmission
Serotonin (5-HT) and NE roles:
Mood, reward, cognition, pain perception, neuroendocrine function.
Serotonin projections:
Spinal cord: pain modulation, visceral regulation, motor control.
Forebrain: mood, cognition, neuroendocrine regulation.
Norepinephrine system:
Modulates vigilance, stress response, neuroendocrine function, and pain.
Synthesis of Serotonin and Norepinephrine
Serotonin synthesis:
Tryptophan → 5-Hydroxytryptophan (via tryptophan hydroxylase).
5-Hydroxytryptophan → Serotonin (via aromatic L-amino acid decarboxylase).
Norepinephrine synthesis:
Tyrosine → L-DOPA (via tyrosine hydroxylase).
L-DOPA → Dopamine (via aromatic L-amino acid decarboxylase).
Dopamine → Norepinephrine (via dopamine β-hydroxylase).
Presynaptic Regulation of Serotonin and Norepinephrine
Serotonin (5-HT):
Stored in synaptic vesicles via VMAT.
Released upon action potential.
Reuptake via serotonin transporter (SERT).
Autoreceptor (5-HT1B) inhibits further release.
Degraded by MAO.
Norepinephrine (NE):
Synthesized from dopamine inside vesicles.
Recycled NE taken up via VMAT.
Reuptake via norepinephrine transporter (NET).
Autoreceptor (α2-adrenergic) inhibits release.
Degraded by MAO.
Serotonin Receptors
15 types, all GPCRs except 5-HT3 (ligand-gated ion channel).
5-HT1 (Gi-coupled) → inhibits adenylyl cyclase, opens K+ channels.
5-HT1A: presynaptic auto-receptors in raphe nuclei, postsynaptic in hippocampus.
5-HT1B: inhibits serotonin release at nerve terminals.
5-HT2 (Gq-coupled) → increases phosphatidylinositol turnover.
5-HT4, 5-HT6, 5-HT7 (Gs-coupled) → increase cAMP.
Mood Disorders: MDD & Bipolar Disorder
MDD: Single or recurrent depressive episodes.
BD: Includes manic or hypomanic episodes alongside depressive episodes.
Inhibitors of Serotonin Storage
Amphetamines, methylphenidate: Displace 5-HT, DA, and NE from storage vesicles.
Used in atypical depression, elderly depression, and ADHD.
Side effects: Increased HR/BP, tremors, addiction potential.
Inhibitors of Serotonin Degradation
MAOIs: Prevent serotonin breakdown by inhibiting monoamine oxidase (MAO).
Older non-selective MAOIs: Phenelzine, isocarboxazid (irreversible).
Newer selective MAOIs: Moclobemide, brofaromine (reversible).
Selegiline: MAO-B inhibitor (low doses), MAO-A inhibitor (high doses).
Risk: Tyramine-induced hypertensive crisis (avoid aged cheese, red wine).
Reuptake Inhibitors
1. TCAs (Tricyclic Antidepressants)
Drugs: Imipramine, amitriptyline, clomipramine (OCD first-line).
Action: Block SERT & NET.
Uses: Depression, pain syndromes, migraines.
Adverse effects:
Cardiotoxicity: Na+ channel blockade (QT prolongation, arrhythmias).
Anticholinergic: Dry mouth, constipation, urinary retention.
Antihistamine: Sedation, weight gain.
Adrenergic: Orthostatic hypotension, reflex tachycardia.
2. SSRIs (Selective Serotonin Reuptake Inhibitors)
Drugs: Fluoxetine, sertraline, paroxetine, citalopram, escitalopram.
First-line for depression & anxiety disorders.
Better safety profile than TCAs (no cardiotoxicity).
Side effects:
Sexual dysfunction (low libido, delayed ejaculation).
Serotonin syndrome (hyperthermia, rigidity, confusion).
GI: Diarrhea (sertraline), constipation (paroxetine).
3. SNRIs (Serotonin-Norepinephrine Reuptake Inhibitors)
Drugs: Venlafaxine, duloxetine, milnacipran.
Used for: Depression, neuropathic pain, fibromyalgia.
4. NSRIs (Norepinephrine Selective Reuptake Inhibitors)
Drug: Atomoxetine (for ADHD).
Lower abuse potential than amphetamines.
Atypical Antidepressants
Bupropion: Dopamine reuptake inhibitor, low risk of sexual dysfunction, contraindicated in seizures.
Mirtazapine: α2 antagonist → ↑ NE/5-HT release; weight gain, sedation (good for elderly).
Trazodone: 5-HT2 antagonist, used for insomnia, risk of priapism.
Agomelatine: Melatonin receptor agonist, no sexual side effects.
Ketamine: NMDA antagonist, rapid antidepressant effects (used in resistant depression).
Serotonin Receptor Agonists
Buspirone: Partial 5-HT1A agonist (used in anxiety, non-sedating).
Triptans: 5-HT1D agonists (vasoconstrictors for migraines).
Adverse Effects of Antidepressants
Common: Drowsiness, nausea, weight gain, headache, sleep disturbances.
Sexual dysfunction: SSRIs, TCAs, MAOIs (dopamine inhibition).
Priapism (trazodone): Requires emergency intervention if prolonged.
Red Flags in Antidepressant Use
1. Serotonin Syndrome (SSRIs, SNRIs, MAOIs, MDMA, Triptans)
Symptoms: Hyperthermia, autonomic instability (sweating, tachycardia, hypertension), neuromuscular excitation (clonus, rigidity, tremor), altered mental status (confusion, agitation).
Risk Factors: Polypharmacy (SSRI + MAOI, SSRI + Triptan, SSRI + MDMA), overdose.
Management: Stop serotonergic drugs, supportive care, benzodiazepines, cyproheptadine (serotonin antagonist).
2. Hypertensive Crisis (MAOIs + Tyramine-Rich Foods or Sympathomimetics)
Symptoms: Sudden headache, severe hypertension, palpitations, chest pain, sweating, stroke.
Cause: Tyramine (found in aged cheese, wine, fermented meats) acts as an indirect sympathomimetic, causing massive norepinephrine release.
Management: Discontinue MAOI, administer phentolamine (α-blocker), avoid β-blockers initially (unopposed α-vasoconstriction).
3. Suicide Risk (Especially in Young Adults & Adolescents)
Symptoms: Increased suicidal ideation, self-harm thoughts.
Mechanism: Early improvement in energy before mood lifts can allow for suicide attempt.
Monitoring: Frequent follow-ups in the first few weeks of treatment, especially in young adults.
4. Cardiotoxicity (TCA Overdose)
Symptoms: Arrhythmias, widened QRS, seizures, hypotension, coma.
Mechanism: Na+ channel blockade → prolonged QT → torsades de pointes.
Management: Activated charcoal (if early), sodium bicarbonate (for QRS widening), supportive care.
5. Priapism (Trazodone)
Symptoms: Erection >4 hours, pain, risk of penile ischemia.
Management: Urgent urologic consultation, intracavernosal sympathomimetics (phenylephrine).
6. Discontinuation Syndrome (SSRIs, SNRIs, TCAs, MAOIs)
Symptoms: Anxiety, flu-like symptoms, insomnia, dizziness, electric shock sensations.
Risk Factors: Short half-life SSRIs (paroxetine, venlafaxine) or abrupt discontinuation.
Management: Taper slowly over weeks to months.
7. Seizures (Bupropion Overdose or in High-Risk Patients)
Risk Factors: History of seizures, eating disorders, electrolyte imbalances.
Management: Avoid in at-risk populations, supportive seizure care.
8. QT Prolongation (Citalopram, TCAs, Some Antipsychotics)
Risk: Ventricular arrhythmias (torsades de pointes).
Monitoring: Avoid high doses (>40 mg/day of citalopram), check ECG in high-risk patients.
9. Mania Induction (SSRIs, SNRIs, TCAs, MAOIs in Bipolar Disorder)
Symptoms: Agitation, racing thoughts, impulsivity, sleeplessness.
Prevention: Screen for bipolar disorder before prescribing antidepressants, combine with mood stabilizer if necessary.
10. Liver Toxicity (Nefazodone, MAOIs)
Symptoms: Jaundice, fatigue, hepatomegaly, elevated LFTs.
Prevention: Monitor liver enzymes periodically.
Comprehensive Summary Table of Antidepressants