Other Antidepressants

Antidepressants encompass several classes of medications and are used to treat individuals with depression, anxiety, and other psychiatric conditions, as well as to manage chronic pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain and menopausal symptoms. Bupropion is an atypical antidepressant Antidepressant Antidepressants encompass several drug classes and are used to treat individuals with depression, anxiety, and psychiatric conditions, as well as those with chronic pain and symptoms of menopause. Antidepressants include selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), and many other drugs in a class of their own. Serotonin Reuptake Inhibitors and Similar Antidepressant Medications that acts by increasing neurotransmitter levels and alleviates the symptoms of depression. Brexanolone is a neurosteroid mainly used for the management of postpartum depression.

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Editorial responsibility: Stanley Oiseth, Lindsay Jones, Evelin Maza

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Overview

  • Depression is a unipolar mood disorder characterized by persistent low mood and loss of interest in association with somatic symptoms for a duration of at least 2 weeks.
  • Depression is managed via pharmacotherapy, psychotherapy Psychotherapy Psychotherapy is interpersonal treatment based on the understanding of psychological principles and mechanisms of mental disease. The treatment approach is often individualized, depending on the psychiatric condition(s) or circumstance. Psychotherapy, and neuromodulation.

Bupropion

Chemistry

Chemical structure of bupropion

Chemical structure of bupropion

Image: “Bupropion numbered” by Markus Prokott. License: CC BY-SA 2.5

Mechanism of action

Norepinephrine dopamine reuptake inhibitor (NDRI):

  • Heterocyclic structure
  • Inhibits norepinephrine (NE) transporter (NET) and dopamine (DA) transporter (DAT) in the presynaptic terminal → ↑ NE and DA levels in the synaptic cleft
  • Stimulates vesicular monoamine transporter (VMAT) activity → ↑ DA release into the synaptic cleft

Pharmacokinetics Pharmacokinetics Pharmacokinetics is the science that analyzes how the human body interacts with a drug. Pharmacokinetics examines how the drug is absorbed, distributed, metabolized, and excreted by the body. Pharmacokinetics and Pharmacodynamics

  • Absorption Absorption Absorption involves the uptake of nutrient molecules and their transfer from the lumen of the GI tract across the enterocytes and into the interstitial space, where they can be taken up in the venous or lymphatic circulation. Digestion and Absorption: Oral absorption is rapid.
  • Distribution:
    • Protein binding is 84%.
    • Elimination half-life is 13–30 hours.
  • Metabolism:
    • 1st-pass metabolism extensively in the liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver
    • Converted to hydroxybupropion by cytochrome P450 (CYP)2B6
  • Elimination:
    • Mainly via urine
    • Also in the feces, but to a lesser extent

Indications

  • Major depressive disorder Major depressive disorder Major depressive disorder (MDD), commonly called depression, is a unipolar mood disorder characterized by persistent low mood and loss of interest in association with somatic symptoms for a duration of ≥ 2 weeks. Major depressive disorder has the highest lifetime prevalence among all psychiatric disorders. Major Depressive Disorder
  • Smoking cessation
  • Seasonal affective disorder
  • Off-label use:
    • ADHD
    • Bipolar depression
    • Sexual dysfunction

Adverse effects

  • Cardiovascular:
    • Most common: tachycardia
    • Chest pain Chest Pain Chest pain is one of the most common and challenging complaints that may present in an inpatient and outpatient setting. The differential diagnosis of chest pain is large and includes cardiac, gastrointestinal, pulmonary, musculoskeletal, and psychiatric etiologies. Chest Pain
    • Arrhythmia
  • GI:
    • Most common: dry mouth
    • Constipation Constipation Constipation is common and may be due to a variety of causes. Constipation is generally defined as bowel movement frequency < 3 times per week. Patients who are constipated often strain to pass hard stools. The condition is classified as primary (also known as idiopathic or functional constipation) or secondary, and as acute or chronic. Constipation
    • Nausea/vomiting
  • Endocrine/metabolic:
    • Most common: weight loss
    • Weight gain
    • Menstrual irregularities
  • CNS:
    • Most common: insomnia Insomnia Insomnia is a sleep disorder characterized by difficulty in the initiation, maintenance, and consolidation of sleep, leading to impairment of function. Patients may exhibit symptoms such as difficulty falling asleep, disrupted sleep, trouble going back to sleep, early awakenings, and feeling tired upon waking. Insomnia
    • Headache
    • Agitation
  • Ophthalmic:
    • Most common: blurred vision
    • Diplopia
    • ↑ Risk of angle-closure glaucoma Glaucoma Glaucoma is an optic neuropathy characterized by typical visual field defects and optic nerve atrophy seen as optic disc cupping on examination. The acute form of glaucoma is a medical emergency. Glaucoma is often, but not always, caused by increased intraocular pressure (IOP). Glaucoma
  • Respiratory:
    • Most common: nasopharyngitis
    • Rhinitis Rhinitis Rhinitis refers to inflammation of the nasal mucosa. The condition is classified into allergic, nonallergic, and infectious rhinitis. Allergic rhinitis is due to a type I hypersensitivity reaction. Non-allergic rhinitis is due to increased blood flow to the nasal mucosa. Infectious rhinitis is caused by an upper respiratory tract infection. Rhinitis
  • Pregnancy Pregnancy Pregnancy is the time period between fertilization of an oocyte and delivery of a fetus approximately 9 months later. The 1st sign of pregnancy is typically a missed menstrual period, after which, pregnancy should be confirmed clinically based on a positive β-HCG test (typically a qualitative urine test) and pelvic ultrasound. Pregnancy: Diagnosis, Maternal Physiology, and Routine Care:
    • Category C
    • ↑ Risk of congenital heart disorders

Contraindications/warnings

  • Monoamine oxidase (MAO) inhibitors: 14-day washout period between initiation of other antidepressants and vice versa
  • Seizure disorder: Bupropion lowers the seizure threshold.
  • Eating disorder:
    • Anorexia nervosa Anorexia Nervosa Anorexia nervosa is an eating disorder marked by self-imposed starvation and inappropriate dietary habits due to a morbid fear of weight gain and disturbed perception of body shape and weight. Patients have strikingly low BMI and diverse physiological and psychological complications. Anorexia Nervosa
    • Bulimia nervosa Bulimia nervosa Bulimia nervosa is an eating disorder marked by recurrent episodes of binge eating accompanied by inappropriate compensatory behaviors (laxatives or diuretics use, self-induced vomiting, fasting, or excessive exercise) to counteract the effects of binge eating and prevent weight gain. Bulimia Nervosa
  • Abrupt discontinuation of sedatives:
    • Ethanol
    • Benzodiazepines Benzodiazepines Benzodiazepines work on the gamma-aminobutyric acid type A (GABAA) receptor to produce inhibitory effects on the CNS. Benzodiazepines do not mimic GABA, the main inhibitory neurotransmitter in humans, but instead potentiate GABA activity. Benzodiazepines
    • Barbiturates

Drug-drug interactions

  • Agents lowering seizure threshold:
    • Tricyclic antidepressants Tricyclic antidepressants Tricyclic antidepressants (TCAs) are a class of medications used in the management of mood disorders, primarily depression. These agents, named after their 3-ring chemical structure, act via reuptake inhibition of neurotransmitters (particularly norepinephrine and serotonin) in the brain. Tricyclic Antidepressants (TCAs)
    • Clozapine
    • Phenothiazines
    • Tramadol
  • Sympathomimetics: ↑ hypertensive effects
  • CYP2D6 substrates:
    • Bupropion is a strong CYP2D6 inhibitor.
    • ↑ 2D6 substrate levels
    • ↓ Active metabolite levels of 2D6 prodrugs
  • Bupropion ↓ active metabolite levels of:
    • Codeine
    • Tamoxifen
    • Tramadol

Brexanolone

Chemistry

  • Also known as allopregnanolone and is a C21 steroid
  • Naturally occurring neurosteroid biosynthesized from the hormone progesterone
Chemical structure of brexanolone

Chemical structure of brexanolone

Image: “Allopregnanolone” by Ed. License: Public Domain

Mechanism of action

  • GABAA receptor-positive modulator
  • Complete mechanism unknown
  • Brexanolone is an allopregnanolone analog that allosterically modulates synaptic (phasic inhibition of action potentials) and extrasynaptic (tonic) inhibition of GABAA receptors. 
  • Endogeneous allopregnanolone levels ↑ in the peripartum period and dramatically ↓ during the postpartum period → low levels blunt the inhibitory effects of GABA during stress. Administration of exogenous synthetic allopregnanolone (brexanolone) helps restore levels.

Pharmacokinetics Pharmacokinetics Pharmacokinetics is the science that analyzes how the human body interacts with a drug. Pharmacokinetics examines how the drug is absorbed, distributed, metabolized, and excreted by the body. Pharmacokinetics and Pharmacodynamics

  • Absorption Absorption Absorption involves the uptake of nutrient molecules and their transfer from the lumen of the GI tract across the enterocytes and into the interstitial space, where they can be taken up in the venous or lymphatic circulation. Digestion and Absorption:
    • Oral bioavailability is poor.
    • Given as an IV formulation
  • Distribution:
    • Volume of distribution is 3 L/kg.
    • Protein binding is 99%.
  • Metabolism:
    • Not mediated by CYP
    • Ketoreduction via aldo-keto reductases
    • Glucuronidation
    • Sulfation
    • Elimination half-life is 9 hours.
  • Excretion:
    • Feces
    • Urine

Indications

Brexanolone is indicated in postpartum depression.

Adverse effects

  • Cardiovascular:
    • Most common: presyncope
    • Flushing
    • Tachycardia
  • CNS:
    • Most common: drowsiness/sedation
    • Dizziness
    • Vertigo Vertigo Vertigo is defined as the perceived sensation of rotational motion while remaining still. A very common complaint in primary care and the ER, vertigo is more frequently experienced by women and its prevalence increases with age. Vertigo is classified into peripheral or central based on its etiology. Vertigo
  • GI:
    • Most common: xerostomia
    • Diarrhea Diarrhea Diarrhea is defined as ≥ 3 watery or loose stools in a 24-hour period. There are a multitude of etiologies, which can be classified based on the underlying mechanism of disease. The duration of symptoms (acute or chronic) and characteristics of the stools (e.g., watery, bloody, steatorrheic, mucoid) can help guide further diagnostic evaluation. Diarrhea
    • Dyspepsia
  • BLACK BOX WARNING: excessive sedation and sudden loss of consciousness

Drug interactions

  • Other CNS depressants
  • Sedatives (e.g., opioids Opioids Opiates are drugs that are derived from the sap of the opium poppy. Opiates have been used since antiquity for the relief of acute severe pain. Opioids are synthetic opiates with properties that are substantially similar to those of opiates. Opioid Analgesics, benzodiazepines, barbiturates, ethanol, esketamine)

Ketamine

Chemistry

  • Arylcyclohexylamine derivative
  • Chiral compound
  • Pharmacologically related to phencyclidine
Chemical structure of ketamine

Chemical structure of ketamine

Image: “Ketamine2DCSD” by Brenton. License: Public Domain

Mechanism of action

  • Mechanism of antidepressant Antidepressant Antidepressants encompass several drug classes and are used to treat individuals with depression, anxiety, and psychiatric conditions, as well as those with chronic pain and symptoms of menopause. Antidepressants include selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), and many other drugs in a class of their own. Serotonin Reuptake Inhibitors and Similar Antidepressant Medications action is unclear.
  • N-methyl-D-aspartate (NMDA) receptor antagonist
  • Acts directly on the cortex and limbic system Limbic system The limbic system is a neuronal network that mediates emotion and motivation, while also playing a role in learning and memory. The extended neural network is vital to numerous basic psychological functions and plays an invaluable role in processing and responding to environmental stimuli. Limbic System
  • Increases the activation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor, which modulates a few signaling pathways to influence neurotransmission Neurotransmission The junction between 2 neurons is called a synapse. The synapse allows a neuron to pass an electrical or chemical signal to another neuron or target effector cell. The plasma membranes of the 2 neurons are placed very close together, and the space between the 2 neurons is called the synaptic cleft. The molecules that mediate the interaction are called neurotransmitters. Synapses and Neurotransmission in the limbic system Limbic system The limbic system is a neuronal network that mediates emotion and motivation, while also playing a role in learning and memory. The extended neural network is vital to numerous basic psychological functions and plays an invaluable role in processing and responding to environmental stimuli. Limbic System:
    • Upregulation of brain-derived neurotrophic factor (BDNF)
    • Activation of tropomyosin receptor kinase B
    • Activation of mammalian target of rapamycin (mTOR) pathway
    • Deactivation of glycogen synthase kinase 3
    • Inhibits phosphorylation of eukaryotic Eukaryotic Eukaryotes can be single-celled or multicellular organisms and include plants, animals, fungi, and protozoa. Eukaryotic cells contain a well-organized nucleus contained by a membrane, along with other membrane-bound organelles. Cell Types: Eukaryotic versus Prokaryotic elongation factor 2 (eEF2)

Pharmacokinetics Pharmacokinetics Pharmacokinetics is the science that analyzes how the human body interacts with a drug. Pharmacokinetics examines how the drug is absorbed, distributed, metabolized, and excreted by the body. Pharmacokinetics and Pharmacodynamics

  • Absorption Absorption Absorption involves the uptake of nutrient molecules and their transfer from the lumen of the GI tract across the enterocytes and into the interstitial space, where they can be taken up in the venous or lymphatic circulation. Digestion and Absorption:
    • Good absorption, as it is both water and lipid soluble
    • Low oral bioavailability due to 1st-pass metabolism
    • IV bioavailability is 100%.
  • Distribution:
    • Rapidly distributed to the brain and other tissues
    • Plasma protein binding is approximately 27%.
  • Metabolism:
    • Extensive metabolism via CYP3A4 and CYP2B6
    • Elimination half-life is around 2.5–3 hours.
  • Excretion:
    • Urine (90%)
    • Feces (3%)

Indications

  • Ketamine is the anesthetic of choice for short day procedures.
  • Management of treatment-resistant depression
  • Maintenance therapy for depression

Adverse effects

  • Cardiovascular:
    • Blood pressure changes
    • Tachycardia
    • Bradycardia
  • CNS:
    • Drug dependence
    • Hypertonia/tonic-clonic movements
    • Increased intracranial pressure Increased Intracranial Pressure Normal intracranial pressure (ICP) is defined as < 15 mm Hg, whereas pathologically increased ICP is any pressure ≥ 20 mm Hg. Increased ICP may result from several etiologies, including trauma, intracranial hemorrhage, mass lesions, cerebral edema, increased CSF production, and decreased CSF absorption. Increased Intracranial Pressure (ICP)
  • GI:
    • Anorexia
    • Sialorrhea
    • Nausea/vomiting
  • Ophthalmic:
    • Diplopia
    • Nystagmus
    • Increased intraocular pressure

Drug interactions

  • Potentiates the action of:
    • Opiates
    • Barbiturates
    • Alcohol
  • Benzodiazepines Benzodiazepines Benzodiazepines work on the gamma-aminobutyric acid type A (GABAA) receptor to produce inhibitory effects on the CNS. Benzodiazepines do not mimic GABA, the main inhibitory neurotransmitter in humans, but instead potentiate GABA activity. Benzodiazepines may diminish the antidepressant Antidepressant Antidepressants encompass several drug classes and are used to treat individuals with depression, anxiety, and psychiatric conditions, as well as those with chronic pain and symptoms of menopause. Antidepressants include selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), and many other drugs in a class of their own. Serotonin Reuptake Inhibitors and Similar Antidepressant Medications effect.
  • May cause seizures Seizures A seizure is abnormal electrical activity of the neurons in the cerebral cortex that can manifest in numerous ways depending on the region of the brain affected. Seizures consist of a sudden imbalance that occurs between the excitatory and inhibitory signals in cortical neurons, creating a net excitation. The 2 major classes of seizures are focal and generalized. Seizures with theophylline

References

  1. UpToDate drug information:
  2. WebMD. Bupropion HCl Oral: Uses, Side Effects, Interactions, Pictures, Warnings & Dosing. Retrieved July 10, 2021, from https://www.webmd.com/drugs/2/drug-13507-155/bupropion-hcl-oral/bupropion-oral/details
  3. Medscape drug information. Ketalar (Ketamine) Dosing, Indications, Interactions, Adverse Effects, and More. Retrieved July 10, 2021, from https://reference.medscape.com/drug/ketalar-ketamine-343099
  4. Goodman, L.S., et al. (Eds.). (2011). Goodman & Gilman’s Pharmacological Basis of Therapeutics. 12th ed, McGraw-Hill.

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