Major Depressive Disorder

Major Depressive Disorder

• Characterized by persistent sadness, anxiety, or an "empty" mood
• Feelings can include hopelessness, guilt, worthlessness, and helplessness
• Includes loss of interest or pleasure in activities and fatigue
• Difficulty concentrating, remembering, and making decisions is a key symptom
• Can manifest as insomnia, appetite changes, and/or weight fluctuations
• Thoughts of death or suicide, suicide attempts, restlessness, and irritability are common
• Can also involve headaches, digestive disorders, and chronic pain
• Affects about 6.7% (14.8 million) of the U.S. population age 18 and older per year

Pathogenesis of Major Depression

• The Amine Hypothesis explains that the depletion of catecholamines and 5-HT from synaptic vesicles with reserpine intake causes depression
• Increasing catecholamine and serotonin neurotransmission should reduce depression
• Blocking catecholamine/serotonin reuptake reduces depression
• Blocking metabolism of catecholamines/serotonin is considered to reduce depression

Delayed Therapeutic Onset

• Depressed patients often show elevation of mood after 2-3 weeks of treatment
• Compensation may be required for initial increase in NE and 5-HT
• Chronic TCAs and MAOIs impact NE-stimulated cAMP
• Chronic TCAs and MAOIs descrease receptors in the CNS
• Chronic TCAs and MAOIs increase sensitivity to 5-HT
• Chronic TCAs and MAOIs increase neurotrophic factors leading to increased hippocampal neurogenesis

Neurotrophic Hypothesis of Depression

• Stress and pain reduce brain-derived neurotrophic factor (BDNF) levels
• Loss of neurotrophic support leads to structural atrophy in the hippocampus and other areas like the medial frontal cortex and anterior cingulate

Ketamine

• Preclinical and clinical studies show how rapid antidepressant effects are achieved with a single subanesthetic dose of intravenous ketamine
• Seems effective in treatment-resistant patients
• Antidepressant effects persist for a week or more after a single dose
• Adverse effects can prevent it from being used as an antidepressant
• Functions as a Noncompetitive N-methyl-d-aspartate (NMDA) receptor antagonist

Tricyclic Antidepressants

• Called tricyclics because of 3 rings in their chemical structure
• Structurally related to phenothiazines
• Developed as antihistamines originally
• Inhibit reuptake of both NE and 5-HT
• Examples of tricyclic antidepressants include: Amitriptyline (Elavil), Imipramine (Tofranil), Clomipramine (Anafranil), Desipramine (Norpramin), Doxipen (Sinequan), Nortriptyline (Aventyl), Protriptyline (Vivactil), Trimipramine (Surmontil)

Pharmacokinetic Properties of Tricyclic Antidepressants

• Orally absorbed with significant first-pass metabolism
• Oxidation occurs in hepatic microsomal enzymes followed by glucuronidation
• Imipramine is converted to the active metabolite, desipramine
• Amitriptine and doxepin also have active metabolites
• Long T1/2 (10-20 hrs) allows single daily dose

Adverse Effects of TCAs

• Muscarinic receptor blockade causes dry mouth, urinary retention, blurred vision, constipation, tachycardia, and confusion (particularly in elderly), amitriptyline is worst for this
• H1 receptor blockade causes weight gain and drowsiness, increased appetite
• Sympathomimetic activity results in tremor (β receptor stimulation), tachycardia, and insomnia, may switch depressed patient to manic phase
• α1 receptor blockade causes orthostatic hypotension, dizziness, reflex tachycardia, and impaired ejaculation
• "Quinidine-like" cardiotoxicity leads to ventricular tachyarrhythmias, prolonging QT interval by blocking K+ channels, and conduction defects due to Na+ channel blockade

Acute TCA Overdose

• Acute Overdose presents a Triad known as "3 Cs" (Convulsions, Cardiotoxicity, Coma)
• Convulsions can occur due to lowered seizure threshold, probably from blocking (GIRK) K+ channels in neurons
• Cardiotoxicity
• Diazepam is used for seizures
• Sodium bicarbonate bolus for quinidine-like cardiotoxicity, increases extracellular Na+ to counter Na+ channel blockade

Drug Interactions of TCAs

• Blocks antihypertensive actions of clonidine (Catapres) and guanethidine (Ismelin)
• Potentiate sedatives and alcohol
• Heavy smoking or barbiturates may induce metabolism
• Additive with other antimuscarinic drugs and sympathomimetics

Serotonin Syndrome

• Risk when combined with MAO inhibitors or SSRIs
• Potentially fatal
• Signs include hyperthermia, muscle rigidity, myoclonus, and fluctuating mental status
• Excessive serotonin presence in central gray nuclei and the medulla
• Requires supportive treatment

Clinical uses of TCAs

• Depression choice depends on patient and which side effects are to be avoided or taken advantage of
• A patient with insomnia or agitation may be given amitriptyline due to the sedation it causes
• Can be as effective for Panic Disorder as benzodiazepines, but benzodiazepines often have less adverse effects and more clinical benefit quickly
• Clomipramine is a TCA that is preferentially prescribed for Obsessive Compulsive Disorders (OCD) as it blocks SERT
• Can treat enuresis with imipramine
• Used for institutionalized geriatrics because they are sensitive to antimuscurinic confusion
• Attention deficit hyperkinetic disorder (ADHD) can be treated with imipramine and desipramine
• Can treat chronic pain whether pain stems from depression or depression stems from pain

Second and Third Generation Antidepressants (Heterocyclics)

• Varied and mixed mechanisms of action

Amoxapine (Asendin)

• Metabolite of antipsychotic, loxapine, and retains some antipsychotic activity like dopamine receptor blockade, and adverse effects like akathisia, parkinsonism, amenorrhea-galactorrhea
• Primarily blocks NE reuptake as MOA
• Used for depression with schizophrenia
• Overdoses are difficult to control

Bupropion (Wellbutrin)

• Consists of Minimal effects on reuptake of 5-HT
• Blocks dopamine reuptake
• Increases NE levels via presynaptic effect
• Used for Other Clinical Uses: Smoking cessation
• Tachycardia, agitation and dry mouth are adverse effects
• Can aggravate psychosis
• One of the few antidepressants not commonly associated with adverse sexual effects
• High doses can causes seizures
• Contraindicated in patients with a bulimia or anorexia because they have a higher reported incidence of seizures due to electrolyte imbalances in these patients

5-HT2 Receptor Modulators

• Examples include Trazodone (Desyrel) and Vortioxetine (Brintellix)

Trazodone (Desyrel)

• Primary metabolite, m-chlorphenylpiperazine (m-CPP), is a potent 5-HT2A antagonist
• Unpredictable efficacy in depression
• Useful as a hypnotic without tolerance or dependence
• Adverse effects: Sedation, nausea and sedation
• Priapism is rare
• Postural hypotension: blocks α1 adrenergic receptors

Vortioxetine (Brintellix)

• Blocks 5-HT3, 5-HT7, and 5-HT1D receptors
• Partial agonist of the 5-HT1B receptor
• Agonist of the 5HT1A receptor
• Showed efficacy in major depression
• May improve some aspects of cognition in depressed patients

Mirtazapine (Remeron)

• Blocks α2 receptors on noradrenergic and serotonergic terminals causing increased release of NE and 5-HT
• Also blocks some 5-HT receptors
• Results in very sedating (H1 block, weight gain (H1 block)
• Is among the few antidepressants not commonly associated with adverse sexual effects

Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs)

• Examples 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 the TCAs, SNRIs do not have much affinity for other receptors so they are better tolerated.
• Used for Generalized anxiety disorder
• Used for Pain disorders including neuropathies and fibromyalgia
• Used for Stress-induced urinary incontinence
• Used for Vasomotor symptoms of menopause

Selective Serotonin Reuptake Inhibitors (SSRIs)

• Examples include Fluoxetine (Prozac), Paroxetine (Paxil), Sertraline (Zoloft), Fluvoxamine (Luvox), Citalpram (Celexa), and Escitalopram (Lexapro)

SSRIs

• Inhibit reuptake of 5-HT
• Efficacy in major depression is equal to TCAs, although TCAs may be more effective
• Lacks many of the adverse effects of tricyclics and heterocyclics
• Less dangerous in overdose than TCAs
• Can cause seizures in overdose but have an extremely low probability of fatality

SSRIs Adverse Effects

• Anxiety, Insomnia, Tremor: (CNS stimulation: RAS)
• Nausea, vomiting (5-HT in chemoreceptor trigger zone)
• Sexual Dysfunction, decreased libido, delayed orgasm

SSRI Pharmacokinetics

• Fluoxetine has active metabolite, norfluoxetine which as a very long t1/2 (7-9 days) has allowed delayed-release formulation of Prozac Weekly
• Characterized by Less compliance issues

SSRI Drug Interactions

• Serotonin Syndrome can occur in conjunction with MAOIs, Tryptophan (increase 5-HT synthesis) , Methamphetamines (increase 5-HT release), Dextromethorphan, cocaine and meperidine (block 5-HT reuptake)
• Fluoxetine and paroxetine are potent inhibitors of CYP 2D6, but Clinically significant interactions extremely rare

Clinical Uses of SSRIs

• Can be used to treat Depression
• Can be used to treat Anxiety Disorders (Panic Disorder, social phobia, generalized anxiety)
• Used to treat PTSD, Premenstrual Dysphoric Disorder, Bulimia with fluoxetine, Obsessive compulsive disorder and Alcoholism

Monoamine Oxidase Inhibitors

• Examples include Tranylcypromine (Parnate) and Phenelzine (Nardil)

MAO Inhibitors

• Nonselective irreversible block of monoamine oxidase (MAO-A and MAO-B) increases monoamines including DA, NE and 5-HT
• Antidepressant mechanism may be related to alterations in receptor function (eg. down regulation of receptors)
• MAOA metabolizes: NE, 5-HT, and tyramine
• MAOB metabolizes Dopamine

Clinical Uses of MAO Inhibitors

• "Atypical" depression characterized by considerable anxiety, phobic features, hypochondriasis (fear or idea of having a serious disease)

Pharmacokinetic Parameters for MAO Inhibitors

• The Onset of action is slow lasting 2-3 weeks
• Show good oral absorption
• Get metabolized in the liver
• Results in Irreversible or very prolonged inhibition of MAO
• After discontinuation effects last with Tranylcypromine having the action continue 7 days after discontinuation and Phenelzine at 2-3 weeks

To Avoid Serotonin Syndrome

• At least 14 days should be allowed to 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 MAOI

Adverse Effects of MAO Inhibitors

• Orthostatic hypotension caused when Tyramine is metabolized to octopamine, stored in neurotransmitter vesicles and released as false neurotransmitter resulting in less vasoconstriction than NE
• Causes Antimuscarinic effects like: Dry mouth and constipation which are Less than TCAs, also Overdose can = atropine-like poisoning
• Sexual Dysfunction like Anorgasmia
• Weight gain and Hepatotoxicity with Phenelzine
• CNS Stimulation and Insomnia
• Tranylcypromine and Amphetamine-like structure

Drug Interactions for MAO Inhibitors

• Hypertensive Crisis caused by the Accumulation of tyramine due to loss of first pass metabolism by liver MAO
• Potentiation of sympathomimetics can also occur from Direct or indirect α1 agonists like Amphetamines, Nasal, Decongestants and Ephedrine
• Serotonin Syndrome can occur in conjunction with SSRIs and TCAS
• Intensify the effects of Tricyclics, Central depressants, Analgesics and Antimuscarinc agents

Noncompetitive NMDA Receptor Antagonists

• Rapid antidepressant effects occur within hours: effective in treatment-resistant cases
• Ketamine is an Anesthesia (off-label for depression) that is Intravenous
• This drug has adverse effects: Sedation, dissociation, hypertension, nausea, tachycardia, cognitive impairment, but has a high potential for abuse

Esketamine

• (Spravato, Ketanest) is a treatment for resistant depression
• Is an (S)-enantiomer of racemic ketamine
• Consists of Nasal inhalation
• Potentially fewer dissociative effects than ketamine
• Reduces suicidal thoughts
• Administered in clinical setting due to potential hallucinations and dissociative effects
• Adverse events include: Nausea, Drowsiness, Hypertension and Headache
• Drug can be Used with conventional antidepressant

Bupropion + Dextromethorphan (Auvelity)

• Dextromethorphan acts an NMDA receptor antagonist and sigma-1 receptor agonist that improves depressive symptoms
• Bupropion: norepinephrine and dopamine reuptake inhibitor (NDRI) and a CYP2D6 inhibitor (reduces dextromethorphan metabolism)
• Functions as Extended-release tablet for treating major depression
• Results in Rapid onset of antidepressant effects, often noticeable within one week
• Is Effective in patients not responding to traditional antidepressants

The Adverse Events from Taking Bupropion + Dextromethorphan include:

• Dizziness
• Diarrhea
• Dry mouth
• Excessive sweating, headache and drowsiness and sexual dysfunction

Brexanolone (Zulresso)

• Pregnancy increases Placental progesterone and allopregnanolone levels
• Positive allosteric modulator of δ-containing GABAA receptors
• Reduces expression of δ-containing GABAA receptors during pregnancy Postpartum: the sudden loss of placenta drops allopregnanolone causing “withdrawal” Used to treat postpartum depression
• IV infusion of soluble formulation of allopregnanolone is administered over 60 hours
• Enhances inhibition via both synaptic and extrasynaptic GABAA receptors
• Restores dysfunctional GABAA inhibition by mimicking allopregnanolone Adverse effects occur as excessive sedation, possible loss of consciousness, headaches, dizziness and somnolence Antidepressant effects occur within 60 hours and lasts a month

Duration of Antidepressant Therapy

• Remission should occur 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
• With treatment, 70-80% of patients achieve remission with sequenced augmentation or switching strategies Therapy is continued for a minimum of 6-12 months to reduce the substantial risk of relapse