Drugs Used in Mood Disorders

Overview of Drugs Used in Mood Disorders

• Key neurotransmitters in depression include serotonin, norepinephrine, and dopamine.
• Lithium is indicated for the treatment of bipolar disorder.
• Antidepressants typically show clinical improvement in 2-4 weeks.

Depression - DSM-5 Criteria

• A diagnosis of depression requires at least 5 symptoms.
• Depressed mood is one of the two mandatory symptoms for depression diagnosis.
• Weight gain due to a medical condition should not be included when diagnosing depression.

Pathophysiology of Depression

• The monoamine hypothesis links depression to deficiencies in serotonin, norepinephrine, and dopamine.
• Glucocorticoid receptor binding is associated with decreased brain-derived neurotrophic factor (BDNF) in depression.
• Cortisol dysregulation is commonly observed in depressed patients.

Depression Symptom Mnemonic

• "I" in the mnemonic stands for interest loss.
• "S" represents sleep disturbance within the mnemonic for depression symptoms.
• Appetite changes in the mnemonic indicate potential weight fluctuations.

Normal Brain Physiology

• Serotonin regulates mood, appetite, and sleep.
• Monoamine oxidase (MAO) degrades serotonin and norepinephrine in the synaptic cleft.
• Norepinephrine is crucial for mood regulation and cognitive functions such as memory and learning.

Neurotrophic Hypothesis

• Brain-derived neurotrophic factor (BDNF) is vital for neural plasticity and resilience.
• Antidepressants are known to increase BDNF levels.
• Increased norepinephrine is not typically associated with reduced BDNF levels in depression.

Neuroendocrine Hypothesis

• Elevated cortisol levels are commonly seen in depressed patients.
• Thyroid dysregulation affects approximately 25% of patients with depression.
• Estrogen deficiency may contribute to mood symptoms in postpartum depression.

Monoamine Hypothesis

• SSRIs and SNRIs increase levels of serotonin and norepinephrine, supporting the monoamine hypothesis.
• Acetylcholine is not typically implicated in depression according to this hypothesis.
• Propranolol, a drug that blocks central monoamine activity, can potentially cause depression.

Neurotrophic Hypothesis (Continued)

• BDNF promotes neural plasticity and neurogenesis in the brain.
• Increased BDNF levels following antidepressant therapy support the neurotrophic hypothesis in depression.
• Glucocorticoid receptor binding is associated with reduced BDNF synthesis in the brain.

Mechanism of Antidepressants

• Most antidepressants alleviate depression symptoms by enhancing neurotransmitter levels in the brain (details on mechanism were not provided in the text).

Monoamine Hypothesis

• Depression is linked to a deficiency of serotonin, norepinephrine, and dopamine.
• Evidence: Reserpine, known to deplete monoamines, can induce depression in some individuals.
• Glutamate levels are elevated in the cerebrospinal fluid of depressed patients.

Neurotrophic Hypothesis

• Depression correlates with reduced levels of Brain-Derived Neurotrophic Factor (BDNF).
• Antidepressants increase BDNF levels, facilitating neurogenesis.
• Patients with depression often exhibit elevated cortisol levels, indicating hormonal dysregulation.

Antidepressant Mechanisms

• Most antidepressants work by increasing serotonin and norepinephrine concentrations in the synaptic cleft.
• Selective serotonin reuptake inhibitors (SSRIs) relieve depression symptoms by blocking serotonin reuptake into presynaptic neurons.
• Antidepressants typically require several weeks for clinical effects due to the time needed for BDNF synthesis.

FDA Warning on Antidepressants

• Patients under 25 face an increased risk of suicidality when using antidepressants.
• Antidepressant use during the third trimester of pregnancy is associated with low birth weight and premature delivery.
• In lactating mothers, weighing risks and benefits of continuing medication is recommended.

Selective Serotonin Reuptake Inhibitors (SSRIs)

• SSRIs primarily target the serotonin transporter (SERT).
• They are primarily prescribed for Major Depressive Disorder (MDD).
• Fluoxetine is notable for its long half-life and potential activating effects.

SSRI Pharmacokinetics

• Fluoxetine has the longest half-life among SSRIs, allowing for once-daily dosing.
• SSRIs are predominantly metabolized by Cytochrome P450 (CYP) enzymes.
• Their long half-lives permit less frequent dosing.

SSRI Side Effects

• The most prevalent side effect of SSRIs is sexual dysfunction due to increased serotonergic activity.
• Paroxetine is associated with a higher risk of weight gain compared to other SSRIs.
• Abrupt discontinuation can result in dizziness and paresthesias, termed discontinuation syndrome.

Serotonin Syndrome

• A common sign of serotonin syndrome includes autonomic instability, characterized by hyperthermia and hypertension.
• Cyproheptadine is used to treat serotonin syndrome by blocking serotonin receptors.
• Anticholinergics are not typical causes of serotonin syndrome, which is primarily caused by SSRIs, SNRIs, and MAO inhibitors.

SNRI Mechanism and Indications

• SNRIs inhibit the reuptake of serotonin and norepinephrine.
• In addition to depression, SNRIs are effective in treating neuropathic pain.
• Duloxetine is frequently prescribed for generalized anxiety disorder (GAD) and chronic pain conditions like fibromyalgia.

SNRI Side Effects

• Hypertension is the most common side effect associated with SNRIs, especially at high doses.
• Nausea and vomiting are common gastrointestinal side effects linked to SNRIs.
• Combining SNRIs with monoamine oxidase inhibitors (MAOIs) should be avoided due to the increased risk of serotonin syndrome.

Bupropion (Wellbutrin)

• Mechanism of action: Norepinephrine and dopamine reuptake inhibitor.
• Contraindicated in seizure disorders.
• Benefits over SSRIs include a lower risk of sexual side effects.

Dextromethorphan/Bupropion ER (Auvelity)

• Dextromethorphan acts as an NMDA receptor antagonist.
• Combined with bupropion for enhanced antidepressant effects.
• Significant risk when combined with serotonergic medications: Serotonin syndrome.

Trazodone (Desyrel)

• Low-dose mechanism of action: Alpha-1 and 5-HT2A receptor antagonist.
• Commonly used to treat insomnia.
• Rare but serious side effect: Priapism.

Mirtazapine (Remeron)

• Antagonizes alpha-2 adrenergic receptor, increasing norepinephrine and serotonin levels.
• Common side effect, especially at lower doses: Weight gain.
• Less likely to cause sexual dysfunction compared to SSRIs.

NMDA Receptor Antagonists

• Ketamine approved for treatment-resistant depression.
• Common side effect of esketamine (Spravato): Dissociation.
• Effectiveness linked to modulation of the glutamate neurotransmitter system.

Monoamine Oxidase Inhibitors (MAOIs)

• Function by inhibiting the enzyme that breaks down norepinephrine, dopamine, and serotonin.
• Foods to avoid: Cheese.
• Risk of life-threatening condition (serotonin syndrome) when combined with SSRIs.

MAOI Side Effects and Interactions

• Common side effect: Orthostatic hypotension.
• Should not be combined with SSRIs due to risk of hypertensive crisis.
• Serious interaction when combined with sympathomimetics: Hypertensive crisis.

Tricyclic Antidepressants (TCAs)

• Block reuptake of serotonin and norepinephrine.
• Serious side effect of overdose: QT prolongation and cardiac arrhythmias.
• Clomipramine is commonly prescribed for obsessive-compulsive disorder (OCD).

TCA Side Effects

• Anticholinergic properties lead to urinary retention.
• Common CNS side effect: Sedation.
• Fall risk associated with alpha-1 adrenergic receptor blockade.

TCA Overdose

• Primary cause of death: Cardiovascular toxicity (arrhythmias).
• Electrolyte imbalance commonly associated: Hyponatremia.

SNRI Overview

• SNRIs (Serotonin-Norepinephrine Reuptake Inhibitors) primarily inhibit the reuptake of serotonin and norepinephrine.
• Duloxetine (Cymbalta) is indicated for both depression and neuropathic pain.

Additional Uses

• Venlafaxine is also used for social anxiety disorder alongside its primary use for depression.

Pharmacokinetics of SNRIs

• SNRIs are metabolized by the Cytochrome P450 enzyme system.
• Dose reduction is required for patients with renal insufficiency.
• Hypertension is a common side effect of SNRIs.

SNRI Side Effects

• Hypertension is dose-dependent.
• Increased sweating is a side effect commonly associated with both SSRIs and SNRIs.
• Combining SNRIs with MAOIs poses a risk of serotonin syndrome.

Tricyclic Antidepressants (TCAs) Overview

• TCAs also inhibit serotonin and norepinephrine reuptake.
• Clomipramine is the TCA commonly used to treat obsessive-compulsive disorder (OCD).
• QT prolongation is a notable adverse effect of TCAs.

TCA Pharmacokinetics

• TCAs are also metabolized by the Cytochrome P450 system.
• They induce sedation, which is why they are typically administered at night.
• Elderly patients are particularly at risk due to slow metabolism.

TCA Overdose

• Cardiotoxicity (arrhythmias) is the primary cause of death in TCA overdose.
• Hyponatremia is a common electrolyte abnormality seen in overdose situations.
• Class I antiarrhythmic drugs are contraindicated in treating TCA-induced arrhythmias.

Monoamine Oxidase Inhibitors (MAOIs) Overview

• MAOIs work by inhibiting monoamine oxidase, thus preventing neurotransmitter breakdown.
• MAO-A primarily degrades serotonin and norepinephrine.
• Foods high in tyramine, like cheese, should be avoided due to hypertension risk.

MAOI Drug Interactions

• Combining MAOIs with SSRIs can lead to serotonin syndrome.
• Pseudoephedrine should be avoided with MAOIs because of the risk of hypertensive crisis.

MAOI Side Effects

• Weight gain is one of the common side effects of MAOIs.
• Sudden discontinuation can lead to a complicating condition characterized by psychosis and confusion.
• High risk of drug and food interactions makes MAOIs less common as first-line therapy for depression.

Bupropion (Wellbutrin) Overview

• Bupropion primarily inhibits the reuptake of norepinephrine and dopamine.
• It is contraindicated in patients with a seizure disorder.
• Patients often prefer bupropion due to its lower risk of sexual side effects compared to SSRIs.

Monoamine Oxidase Inhibitors (MAOIs)

• MAOIs function by inhibiting the monoamine oxidase enzyme, preventing the breakdown of neurotransmitters.
• Patients on MAOIs must avoid tyramine-rich foods, such as cheese and red wine, to prevent hypertensive crises.
• MAO-A isoform is responsible for degrading serotonin, norepinephrine, and dopamine.

MAOI Side Effects

• The most commonly associated side effect of MAOIs is orthostatic hypotension.
• MAOIs have the highest rate of sexual dysfunction as a side effect.
• Discontinuation syndrome may occur with symptoms like psychosis, excitement, and confusion following sudden cessation of MAOIs.

Bupropion (Wellbutrin)

• Bupropion acts primarily as a norepinephrine and dopamine reuptake inhibitor.
• It should be avoided in patients with a history of seizure disorder due to an increased risk of seizures.
• An advantage of bupropion compared to SSRIs is its lower risk of sexual side effects.

Dextromethorphan/Bupropion ER (Auvelity)

• Dextromethorphan acts as an NMDA receptor antagonist in Auvelity.
• Bupropion is combined with dextromethorphan to enhance antidepressant effects.
• Combining dextromethorphan with other serotonergic medications can lead to serotonin syndrome.

Trazodone (Desyrel)

• Trazodone is primarily used for insomnia treatment at low doses (25-150 mg).
• Its sedative effects are attributed to the blockade of the histamine H1 receptor.
• A rare but serious side effect of trazodone is priapism.

Nefazodone

• Nefazodone blocks the 5-HT2A receptor, contributing to its antidepressant effects.
• It is chemically related to trazodone.
• Nefazodone is less commonly prescribed due to risks of hepatotoxicity.

Mirtazapine (Remeron)

• Mirtazapine functions as an alpha-2 receptor antagonist.
• A common side effect of mirtazapine is weight gain.
• Compared to SSRIs, mirtazapine is less likely to cause sexual dysfunction.

Vortioxetine (Trintellix)

• Vortioxetine partially agonizes the 5-HT1A receptor.
• A common side effect associated with vortioxetine use is headache.
• Vortioxetine primarily inhibits the serotonin transporter (SERT) in treating depression.

Bupropion Pharmacokinetics

• Primary enzyme for bupropion metabolism is CYP2D6.
• Contraindicated in patients with a history of seizure disorder.
• Approved for smoking cessation in addition to depression treatment.

Dextromethorphan/Bupropion ER (Auvelity)

• Dextromethorphan acts as an NMDA receptor antagonist.
• Combining dextromethorphan with serotonergic medications can cause serotonin syndrome.
• Symptom improvement can start as early as 1 week after beginning Auvelity for depression.

Trazodone (Desyrel)

• Antagonizes the histamine H1 receptor, contributing to its sedative effects.
• Commonly used at low doses to treat insomnia.
• Rare but serious side effect includes priapism.

Nefazodone

• Chemically related to trazodone.
• Serious risk of hepatotoxicity limits nefazodone's use.
• Inhibits CYP3A4 enzyme, leading to significant drug interactions.

Mirtazapine (Remeron)

• Mechanism of action involves alpha-2 adrenergic receptor antagonism.
• Common side effect is weight gain.
• Less likely to cause sexual dysfunction compared to SSRIs.

Vortioxetine (Trintellix)

• Primary mechanism of action is inhibition of the serotonin transporter (SERT).
• Partially agonizes the 5-HT1A receptor.
• Common side effect includes nausea.

Vilazodone (Viibryd)

• Acts as a partial agonist at the 5-HT1A receptor.
• Significant adverse effect requiring monitoring is long QT syndrome.
• Enhances serotonergic activity by inhibiting the serotonin transporter (SERT).

NMDA Receptor Antagonists

• NMDA receptor antagonists, such as ketamine, primarily function by blocking NMDA receptors.
• Esketamine (Spravato) is specifically indicated for treatment-resistant depression and acute suicidal ideation.
• A significant concern with ketamine treatment is the risk of dissociative symptoms and potential for abuse.

How to Choose an Antidepressant

• Bupropion is an antidepressant least likely to cause sexual side effects.
• Key considerations for selecting an antidepressant include indication, cost, availability, adverse effects, drug interactions, and patient history of response.
• Selective serotonin reuptake inhibitors (SSRIs) are the most commonly prescribed for major depressive disorder (MDD) and anxiety disorders.

Clinical Indications for Antidepressants

• The main goal of acute antidepressant treatment is to achieve full remission of depressive symptoms.
• A trial of antidepressant therapy should last 8-12 weeks to accurately determine efficacy.
• For patients with two or more serious episodes of MDD in the past five years, long-term antidepressant therapy is recommended.

Antidepressant Side Effects and Discontinuation

• Tricyclic antidepressants (TCAs) carry the highest risk of fatal overdose among antidepressant classes.
• Common symptoms of antidepressant discontinuation syndrome include dizziness and paresthesias.
• Short half-life SSRIs, like paroxetine and sertraline, are most likely to cause severe withdrawal symptoms if stopped abruptly.

Antidepressant Drug Interactions

• Paroxetine and fluoxetine are potent inhibitors of the CYP2D6 enzyme, impacting drug metabolism.
• Citalopram and sertraline are relatively free from significant drug interactions compared to others.
• MAOIs are contraindicated with SSRIs due to the risk of serotonin syndrome, a potentially life-threatening condition.

Serotonin Syndrome

• Key signs of serotonin syndrome include altered mental status, autonomic instability, and neuromuscular abnormalities.

Antidepressant Selection and Considerations

• Selecting an antidepressant involves multiple factors: indication, cost, availability, side effects, drug interactions, and prior response history.
• Bupropion, mirtazapine, and nefazodone are associated with the lowest sexual side effects.
• Selective serotonin reuptake inhibitors (SSRIs) are the most commonly prescribed for major depressive disorder (MDD) and anxiety disorders.

Clinical Indications for Antidepressants

• The primary goal of acute treatment is to achieve full remission of depressive symptoms.
• Maximum benefits from antidepressants can typically be observed in 1-2 months.
• Patients with multiple severe depressive episodes within 5 years should consider long-term antidepressant therapy.

Antidepressant Drug Interactions

• Paroxetine and fluoxetine are potent inhibitors of CYP2D6, contributing to significant drug interactions.
• Citalopram and sertraline generally have fewer notable drug interactions.
• Concurrent use of SSRIs and monoamine oxidase inhibitors (MAOIs) can lead to serious contraindications due to the risk of serotonin syndrome.

Serotonin Syndrome

• Hallmark signs of serotonin syndrome include hyperthermia, autonomic instability, and neuromuscular abnormalities.
• Cyproheptadine is commonly used to treat serotonin syndrome by blocking serotonin receptors.
• Antidepressants, particularly SSRIs and SNRIs, are the drug class most often linked to causing serotonin syndrome.