2. Pharm: Antidepressants and Bipolar Disorder

Classification of depression

• Reactive: secondary in response to stimuli such as grief, illness, drugs/alcohol → 60% of all depressions

• Endogenous: genetically determined inability to experience ordinary pleasure or cope with ordinary life events

Antidepressant mechanisms for serotonin and norepinephrine

Noradrenergic receptors

1. In depression monoamine (NE, serotonin & dopamine) neurotransmission is reduced

2. As a response, its receptors on the other side of the synaptic cleft are upregulated to increase uptake of the monoamines

3. What antidepressants do is block norepinephrine transporters (NET) that reuptake leftover NE, that way they can stay in the cleft for longer

4. At first, alpha2 autoreceptors have a negative feedback that prevents NE from being released into the synaptic cleft

5. After some desensitization, NE release becomes normal again

6. Results in increased cAMP → increased krebs, Increased BDNF → increases neurogenesis → antidepressants take effect

Serotonergic receptors

1. In depression monoamine (NE, serotonin & dopamine) neurotransmission is reduced

2. As a response, its receptors on the other side of the synaptic cleft are upregulated to increase uptake of the monoamines

3. What antidepressants do is block serotonin transporters (SERT) that reuptake leftover serotonin, that way they can stay in the cleft for longer

4. At first, 5HT1A autoreceptors have a negative feedback that prevents serotonin from being released into the synaptic cleft

5. After some desensitization, serotonin release becomes normal again → antidepressants take effect

6. Results in increased cAMP → increased krebs, Increased BDNF → increases neurogenesis → antidepressants take effect

What pain drug reduces the effect of antidepressants by more than 10%?

NSAIDs

Acute poisoning by TCA is life threatening at how many grams?

At 2g, so prescribe less so they can’t use it to commit suicide

Antidepressant uses

• Major Adult depressive disorder

• Enuresis children and geriatric

• ADHD non responsive to stimulants

• Severe anxiety disorders

• PTSD

• Psychosomatic disorders

• Neuropathic pain

• COPD and apnea

• Premature ejaculation

• Migraine prophylaxis

SSRI’s

• MOA

• Pharmacokinetics

• Use

• Variations

• MOA: immediate and irreversible blockage of 5HT (SERT) which are GPCRs except 5HT₃ (causes GI effects) and 5HT_2C (causes agitation and restlessness)

• Pharmacokinetics: strongly binds plasma proteins so HL is long 7-100hrs

• Use: 1st line for depression

• Variations:

  • Fluoxetine (Prozac): prototype

    • Use: Major depressive disorder/ BPD, OCD, Bulimia, Panic/anxiety, approved for >8 for depression and >7 for OCD,

    • Adv fx: headache, induced libido, GI problems, UR infections, Myalgia (1-2%), neonates may have withdrawals, slow elimination

    • Contraindications: may prolong QT, do not combine with MAOIs (serotonin syndrome), rash/lupus-like syndrome

  • Paroxetine: antimuscarinic, weak NET inhibitor

    • Use: more calming/sedating than others

    • Adv fx: increased male sexual dysfunction, significant withdrawals

  • Sertraline (Zoloft):

    • Use: PTSD, Premenstrual dysphoric disorder and social anxiety disorder

      • Most used due to least interactions

      • Weak dopamine transporter (DAT) inhibitor so good for low energy patients

    • Adv fx: QT prolongation

  • Citalopram:

    • Use: elderly and hot flashes

    • Adv fx: racemic mixture has antihistaminic actions and can increase QT

  • Escitalopram (Lexapro): citalopram’s more potent S-enantiomer

    • Use: no antihistaminic effect, no QT, pure SERT inhibition

    • Adv fx: few observed

  Not Pure SSRI’s

  • Vortioxetine: partial agonist at 5HT1B ( slightly decreases release by pre-synaptic), agonist at 5HTA1( blocks release in presynaptic/desensitizes but increases mood in post-synaptic) and antagonist at 5HT3 + 5HT7 (reduces nausea+anx+cognitive dulling , improves, mood, sleep and cognitive flexibility)

    • Use: improves cognition independent of Major depression Disorder and cause less weight gain

  • Trazodone→ Serotonin Antagonist (weak 5HT2A and 5HT2C) and reuptake Inhibitor (SERT) → “SARI”

    • Use: Highly sedating so used as hypnotic, use higher dose for antidepressant or combine with a true SSRI or SNRI, reduces anxiety, insomnia and sexual side-effects

  • Vilazodone → Serotonin Partial Agonist (stimulates 5HT1A receptors) and Reuptake Inhibitor (blocks SERT) → “SPARI”

    • Use: improves sexual dysfunction side effects

Heterocyclics, 2nd an 3rd generation antidepressants; Atypical antidepressants

Bupropion:

• MOA: higher affinity to DAT and some NET action (acts like an amphetamine)

  • Metabolites block NET and increase NE

• Use: little to no sedation, muscarinic effects and decreases sexual dysfunction → depression, ADHD, smoking cessation

• Contraindications: seizure disorders and aggravation of psychosis

Mirtazapine

• Mirtazapine: stimulates 5HT/NE receptors to release due to antagonism of alpha 2 autoreceptors

  • MOA: Antagonizes 5HT and 2C post-synaptic receptors → sedating effects and weight gain

  • Combined with SNRI’s, it is called California rocket fuel

SNRI’s

MOA: All increase DA, NE and 5HT in prefrontal cortex and can be used to treat neuropathic pain due to adrenergic effects

Venlafaxine:

• MOA: at low doses acts like SSRI, very low histaminic, muscarinic or adrenergic effects → must increase dose for NET effect

• Use: GAD, Social anxiety, panic disorder, severe depression, Off-label for Diabetic neuropathy

Desvenlafaxine: same but higher NE activity and more side effects

Duloxetine:

• MOA: SERT>NET

• Use: pain, depression or both → diabetic neuropathy

Milnacipran:

• MOA: NET>SERT = energizing

• Use: fibromyalgia

• Adv effects: sweating and urinary incontinence

Tricyclic Antidepressants (TCA)

MOA: developed as antipsychotics, have mixed NE and SE reuptake, no DA → affects alpha 1 adrenergic (heart and BP), muscarinic, histaminic and voltage gated Na+ channels → many side effects

• Adverse effect: Sedation, sympathomimetic, antimuscarinic, cardiovascular, Psychiatric, neurologic, metabolic, overdose can be fatal

• Contraindications: do not mix with MAOI until 2 weeks after stopping (convulsions, hyperpyretic crisis, death), acute recovery period from M, heart conditions, lowers seizure threshold, withdrawals

Amitriptyline:

• Use: 2nd line for depression, off-label neuropathic pain, ADHD, enuresis, social anxiety

• One of the most sedating

Clomipramine

• Use: OCD, depression, autism and premature ejaculation

• Highly sedating

Protriptyline

• Use: Depression with apathy and withdrawal, adjunct to COPD due to stimulation of central respiratory centers

Doxepin

• Use: More effect on 5HT than NE → Major depression, anxiety, bipolar, alcoholism. eczema, migraine prophylaxis, insomnia (low dose)

• Contraindications: do not use with glaucoma or urinary retention

Monoamine Oxidase Inhibitors (MAOI)

MOA: Block MAO from deaminating and metabolizing monoamines

Two types: MAO-A (prefers NE, Epi and 5HT) and MAO-B (phenethylamine) → both metabolize DA

Pharmacokinetics: metabolized by acetylation so ½ of the population will experience slow acetylation

Drugs:

• Phenelzine → A+B → irreversible (takes 2 weeks to clear)

• Tranylcypromine → A+B → reversible

• Selegiline → Only B → irreversible

Contraindications: do not mix with sympathomimetics (causes hypertensive crisis), no vasoconstrictors, avoid Wine, cheese, pickled herring etc (tyramine? foods), serotonin syndrome, do not use with SSRI’s, SNRI’s, Bupropion, meperidine or buspirone

Tx of hypertensive crisis → Phentolamine (alpha 2 antagonist)

Uses: Atypical, non-endogenous neurotic pts, used if pts are refractive to other drugs

Newer ADMs

Esketamine (Spravato): nasal spray

• MOA: blocks NMDA receptors (antagonist)

• Use: used in tx resistant patients (have tried 2 different AD), effects are present in 24rs, drug goes away but antidepressant effects are present for a longer time (short term)

Brexanolone:

• MOA: Allopregnanolone analog, increase GABA-A

• Use: 60r infusion to prevent post partum depression, monitor for CNS depression → very expensive

Electric convulsive therapy

Most rapid and effective way to treat severe acute depression in suicidal pts

Lithium

MOA: Alters electrochemical gradients in CNS, blocks release of DA and glutamate but stimulates serotonin and GABA, downregulates NMDA receptors, increases 5HT synthesis, G-protein de-coupling → basically a bunch of things that ultimately decreases monoamine neurotransmission

Pharmacokinetics:

• Distributes in total body water, crosses BBB, 95% eliminated in urine but decreased Na+ (hyponatremia) increases its reabsorption and may cause toxicity

• HL: 20-24 hrs

• Small therapeutic index so serum levels should be monitored

Off-label tx for Bipolar

• Valproate (1st line), Carbamazepine or Lamotrigine (maintenance) → for mania

• Cariprazine → only drug approved for both manic and depressive phases

• Risperidone (antipsychotic) , Haloperidol, Lurasidone

• Valproate (antiepileptic) → Increases GABA