Antidepressant Pharmacology

• The lecture covers the pharmacology of antidepressants, their mechanisms of action, adverse effects, and clinical uses.

Major Depressive Disorder

• Major Depressive Disorder involves a persistent sad, anxious, or "empty" mood, feelings of hopelessness, guilt, worthlessness, and helplessness.
• Symptoms also include loss of interest, fatigue, difficulty concentrating, insomnia, appetite changes, thoughts of death or suicide, and chronic pain.
• Approximately 6.7% (14.8 million) of the U.S. population age 18 and older is affected each year.

Pathogenesis of Major Depression

• The Amine Hypothesis posits that depression is caused by depletion of catecholamines and 5-HT from synaptic vesicles, as demonstrated by reserpine.
• Increasing catecholamine and serotonin neurotransmission should reduce depression.
• Strategies to increase neurotransmission include blocking catecholamine/serotonin reuptake and blocking the metabolism of catecholamines/serotonin.

Delayed Therapeutic Onset

• Elevation of mood in depressed patients occurs after 2-3 weeks of antidepressant treatment.
• Compensation may be required for the initial increase in NE and 5-HT
• Chronic TCAs and MAOIs lead to a decrease in NE-stimulated cAMP and β receptors in the CNS and an increase in sensitivity to 5-HT.
• Increased neurotrophic factors can lead to increased hippocampal neurogenesis.

Neurotrophic Hypothesis of Depression

• Stress and pain reduce brain-derived neurotrophic factor (BDNF) levels.
• Loss of neurotrophic support can lead to structural atrophy in the hippocampus, medial frontal cortex, and anterior cingulate.

Ketamine

• Preclinical and clinical studies have demonstrated that ketamine can have rapid antidepressant effects after a subanesthetic, intravenous dose.
• Ketamine seems effective in treatment-resistant patients, and its antidepressant effects can persist for a week or more after a single dose.
• Its adverse effects have prevented it from being used extensively.
• Ketamine is a noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist.

Tricyclic Antidepressants

• Tricyclic antidepressants are called tricyclics because of the three rings in their chemical structure.
• They are structurally related to phenothiazines.
• Tricyclics were originally developed as antihistamines.
• They inhibit the reuptake of both norepinephrine (NE) and serotonin (5-HT).
• Examples include: amitriptyline (Elavil), imipramine (Tofranil), clomipramine (Anafranil), desipramine (Norpramin), doxepin (Sinequan), nortriptyline (Aventyl), protriptyline (Vivactil), and trimipramine (Surmontil).

Pharmacokinetic Properties of Tricyclics

• Tricyclic antidepressants are orally absorbed but have significant first-pass metabolism.
• They undergo oxidation in hepatic microsomal enzymes followed by glucuronidation.
• Imipramine is converted to the active metabolite, desipramine, and amitriptyline and doxepin also have active metabolites.
• The long half-life (10-20 hours) of tricyclics allows for a single daily dose.

Adverse Effects of Tricyclics

• Muscarinic receptor blockade can cause dry mouth, urinary retention, blurred vision, constipation, tachycardia, and confusion, especially in the elderly; amitriptyline is the worst offender.
• H1 receptor blockade can cause weight gain (increased appetite) and drowsiness.
• Sympathomimetic activity can lead to tremor (β receptor stimulation), tachycardia, and insomnia, and potentially switch a depressed patient to a manic phase.
• α1 receptor blockade can cause orthostatic hypotension, dizziness, reflex tachycardia, and impaired ejaculation.
• "Quinidine-like" cardiotoxicity can cause ventricular tachyarrhythmias (prolonged QT interval, blocked K+ channel) and conduction defects (Na+ channel blockade).

Acute Overdose of Tricyclics

• Acute overdose presents a life-threatening "3 Cs" triad with convulsions, cardiotoxicity, and coma.
• Treatment: Diazepam for seizures and Sodium bicarbonate bolus for quinidine-like cardiotoxicity (increases extracellular Na+ to counter Na+ channel blockade).

Drug Interactions with Tricyclics

• TCAs can block the antihypertensive actions of clonidine (Catapres) and guanethidine (Ismelin).
• They potentiate sedatives and alcohol.
• Heavy smoking or barbiturates may induce the metabolism of TCAs.
• Additive effects can occur with other antimuscarinic drugs and sympathomimetics.

Serotonin Syndrome with Tricyclics

• There is a risk of serotonin syndrome when TCAs are combined with MAO inhibitors or SSRIs, which can be potentially fatal.
• Serotonin Syndrome symptoms include hyperthermia, muscle rigidity, myoclonus, and fluctuating mental status.
• Excessive serotonin accumulates in the central gray nuclei and the medulla and is treated with Supportive treatment

Clinical Uses of Tricyclics

• They are used in the treatment of depression, with the choice depending on the patient and the side effects to be avoided or taken advantage of.
• For a depressed patient with insomnia or agitation, amitriptyline may be given due to its sedating effects.
• They can effectively treat panic disorder, working as well as benzodiazepines however, benzodiazepines are often preferred since less adverse effects and prompt onset of clinical benefit
• Effective treatment option for Obsessive Compulsive Disorders (OCD) Clomipramine- preferentially blocks SERT
• Can treat Enuresis (bed wetting) - Imipramine
• Be mindful that institutionalized geriatrics are sensitive when administering this treatment given it’s sensitivity to antimuscurinic confusion
• Effective treatment option for Attention deficit hyperkinetic disorder (ADHD) - Imipramine and desipramine
• Useful in treating Chronic Pain: Pain from depression or depressed from pain?

"Second and Third Generation" Antidepressants (Heterocyclics)

• These antidepressants have varied and mixed mechanisms of action.

Amoxapine (Asendin)

• A metabolite of the antipsychotic loxapine, it retains some antipsychotic activity (dopamine receptor blockade) and adverse effects like akathisia, parkinsonism, and amenorrhea-galactorrhea.
• MOA: primarily a NE reuptake blocker
• Used to treat depression with schizophrenia
• Overdoses are difficult to control.

Bupropion (Wellbutrin)

• Bupropion has minimal effects on the reuptake of 5-HT, blocks dopamine reuptake, and increases NE levels via a presynaptic effect.
• Other Clinical Uses include smoking cessation
• Adverse effects: tachycardia, agitation, and dry mouth. It can aggravate psychosis and is one of the few antidepressants not commonly associated with sexual adverse effects. High doses can cause seizures.
• Contraindicated in patients with bulimia or anorexia due to a higher reported incidence of seizures related to electrolyte imbalances.

5-HT2 Receptor Modulators

• Trazodone (Desyrel) and Vortioxetine (Brintellix)

Trazodone (Desyrel)

• Trazodone's primary metabolite, m-chlorphenylpiperazine (m-CPP), is a potent 5-HT2A antagonist.
• It has unpredictable efficacy in treating depression but is a useful hypnotic without tolerance or dependence.
• Adverse effects: sedation, nausea, priapism (rare), and postural hypotension (blocks α1 adrenergic receptors).

Vortioxetine (Brintellix)

• It blocks 5-HT3, 5-HT7, and 5-HT1D receptors and is a partial agonist of the 5-HT1B receptor and an agonist of the 5HT1A receptor.
• Vortioxetine demonstrates efficacy in major depression and may improve some aspects of cognition in depressed patients.

Mirtazapine (Remeron)

• Blocks α2 receptors on noradrenergic and serotonergic terminals, increasing the release of NE and 5-HT.
• Also blocks some 5-HT receptors.
• Adverse effects: very sedating (H1 block), weight gain (H1 block), and one of the few antidepressants not commonly associated with sexual adverse effects.

Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs)

• Examples of include Venlafaxine (Effexor), Desvenlafaxine (Pristiq), Duloxetine (Cymbalta), Levomilnacipran (Fetzima), Milnacipran (Savella) **Labeled only for fibromyalgia.

Venlafaxine (Effexor)

• All SNRIs block 5-HT (SERT) and NE (NET) reuptake transporters.
• Unlike TCAs, SNRIs have less affinity for other receptors, so they are better tolerated.
• Other Clinical Uses: include generalized anxiety disorder, pain disorders (neuropathies, fibromyalgia), stress-induced urinary incontinence, and vasomotor symptoms of menopause.

Selective Serotonin Reuptake Inhibitors (SSRIs)

• Fluoxetine (Prozac), Paroxetine (Paxil), Sertraline (Zoloft), Fluvoxamine (Luvox), Citalpram (Celexa), and Escitalopram (Lexapro).
• SSRIs inhibit the reuptake of serotonin (5-HT).
• SSRIs have efficacy in major depression comparable to TCAs, but TCAs may be more effective.
• They lack many of the adverse effects of tricyclics and heterocyclics.
• SSRIs are less dangerous in overdose than TCAs, even though they can cause seizures in overdose, they have an extremely low probability of fatality.

SSRI Adverse Effects

• Can cause anxiety, insomnia, tremor (CNS stimulation: RAS)
• Can cause nausea and vomiting (5-HT in the chemoreceptor trigger zone).
• and cause sexual dysfunction leading to decreased libido, delayed orgasm

SSRI Pharmacokinetics

• Fluoxetine has an active metabolite, norfluoxetine, with a long half-life (7-9 days), allowing for a delayed-release formulation of Prozac Weekly.
• SSRIS have fewer compliance issues as a result of the formulation.

SSRI Drug Interactions

• Serotonin Syndrome risks increases especially with MAOIs; tryptophan (increase 5-HT synthesis);Methamphetamines (increase 5-HT release); and Dextromethorphan, cocaine and meperidine (block 5-HT reuptake)
• Fluoxetine and paroxetine are potent inhibitors of CYP 2D6 but clinically significant interactions are extremely rare

Clinical Uses of SSRIs

• SSRIs are used to treat depression
• SSRIs are used to treat Anxiety Disorders (Panic Disorder, social phobia, generalized anxiety) PTSD, Premenstrual Dysphoric Disorder, Bulimia: especially fluoxetine, Obsessive compulsive disorder, and Alcoholism.

MAO Inhibitors

• Examples include Tranylcypromine (Parnate) and Phenelzine (Nardil).
• MAO Inhibitors function through Nonselective irreversible block of monoamine oxidase (MAO-A and MAO-B) increases monoamines including DA, NE, and 5-HT
• The Anti-depressant mechanism may be related to alterations in receptor function (eg. down regulation of receptors)
• MAOA metabolizes NE, 5-HT, and tyramine and MAOB metabolizes Dopamine

MAO Inhibitors Clinical Uses

• Treats “Atypical” depression, which includes, considerable anxiety. Phobic features and Hypochondriasis

MAO Inhibitors Pharmacokinetic Parameters

• Onset of action is slow 2-3 weeks, presents with oral absorption that is good, is metabolised in theliver and Irreversible or very prolonged inhibition of MAO
• After discontinuation effects last
• Tranylcypromine – 7 days
• Phenelzine – 2 to 3 weeks

Preventing Serotonin Syndrome with MAO inhibitors

• At least 14 days should elapse between discontinuation of an MAOI and initiation of treatment with fluoxetine or paroxetine.
• At least 5 weeks for fluoxetine (but only 2 weeks for paroxetine) should elapse between discontinuation of SSRI and initiation of therapy with an ΜΑΟΙ.

MAO Inhibitors Adverse Effects

• orthostatic hypotension: Tyramine metabolized to octopamine, stored in neurotransmitter vesicles an released as false neurotransmitter; less vasoconstriction than NE
• Antimuscarinic: Dry mouth and constipation is Less than TCAs and Overdose = atropine-like poisoning
• Can lead to Sexual Dysfunction and Anorgasmia
• Can lead to Weight gain and Hepatotoxicity/ Phenelzine
• Can lead To CNS Stimulation and Insomnia/ Tranylcypromine/ Amphetamine-like structure

MAO Inhibitors Drug Interactions

• causes Hypertensive Crisis : Accumulation of tyramine due to loss of first pass metabolism by liver/MAO with Potentiation of sympathomimetics (Direct or indirect α1 agonists) and Amphetamines, Nasal Decongestants, Ephedrine can all increase the risk
• causes Serotonin Syndrome with SSRIs and TCAs
• Can intensify the effects of Tricyclics, Central depressants, Analgesics and Antimuscarinc agents

Noncompetitive NMDA Receptor Antagonists

• demonstrates Rapid antidepressant effects within hours: effective in treatment-resistant cases like Ketamine: Anesthesia (off-label for depression)
• ketamine can be delivered intravenously and Adverse effects: Sedation, dissociation, hypertension, nausea, tachycardia, and cognitive impairment alongside High potential for abuse
• Esketamine (Spravato, Ketanest): Treatment resistant depression. S-enantiomer of racemic ketamine - (delievered through)Nasal inhalation, has Potentially fewer dissociative effects than ketamine
• Reduces suicidal thoughts Administered in clinical setting due to potential hallucinations and dissociative effects with side effects listed as Nausea, Drowsiness, Hypertension, Headache
• • all used with conventional antidepressant

Bupropion + Dextromethorphan (Auvelity)

• A combination of two drug treatments that includes Dextromethorphan: NMDA receptor antagonist and sigma-1 receptor agonist: improves depressive symptoms and Bupropion: norepinephrine and dopamine reuptake inhibitor (NDRI) and a CYP2D6 inhibitor reduces dextromethorphan metabolism
• extended-release tablet for treating major depression, Rapid onset of antidepressant effects often noticeable within one week, Effective in patients not responding to traditional antidepressants
• can have the following Adverse effects: Dizziness, diarrhea, dry mouth, excessive sweating, headache, drowsiness, and sexual dysfunction

Brexanolone (Zulresso)

• can be used during Pregnancy, through these factors Placental progesterone increases allopregnanolone levels which is a Positive allosteric modulator of 8-containing GABAA receptors which reduces expression of 8-containing GABAA receptors during pregnancy
• can be used Postpartum: the sudden loss of placenta drops allopregnanolone causing “withdrawal”
• The drug enables the Treatment of postpartum depression through IV infusion of soluble formulation of allopregnanolone over 60 hours and enhances inhibition via both synaptic and extrasynaptic GABAA receptors through restoring dysfunctional GABAA inhibition by mimicking allopregnanolone
• Side effects such as Adverse effects: Excessive sedation, possible loss of consciousness, headaches, dizziness, and somnolence needs to be considered
• Antidepressant effects within 60 hours and lasts a month

Duration of Antidepressant Therapy

• Expect Remission in about 30–40% of patients within a single monotherapy trial of 8–12 weeks
• If response is inadequate, therapy is often switched to another agent or augmented by addition of another drug
• 70-80% of patients achieve remission with sequenced augmentation or switching strategies.
• Therapy continued for a minimum of 6–12 months to reduce the substantial risk of relapse.