Serotonin Reuptake Inhibitors and Similar Antidepressant Medications

Antidepressants encompass several drug classes and are used to treat individuals with depression, anxiety, and psychiatric conditions, as well as those with 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 symptoms of menopause Menopause Menopause is a physiologic process in women characterized by the permanent cessation of menstruation that occurs after the loss of ovarian activity. Menopause can only be diagnosed retrospectively, after 12 months without menstrual bleeding. Menopause. Antidepressants include selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), and many other drugs in a class of their own. Antidepressants are indicated as the 1st-line treatment for anxiety disorders and 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 (MDD) and are contraindicated in cases of current or recent use of monoamine oxidase inhibitors Monoamine oxidase inhibitors Monoamine oxidase inhibitors are a class of antidepressants that inhibit the activity of monoamine oxidase (MAO), thereby increasing the amount of monoamine neurotransmitters (particularly serotonin, norepinephrine, and dopamine). The increase of these neurotransmitters can help in alleviating the symptoms of depression. Monoamine Oxidase Inhibitors. Therapeutic response to antidepressants takes 2–4 weeks and complete benefit is not seen until up to 8 weeks, which is attributed to downstream cellular responses necessary for eliciting a physiologic response. In general, serotonin-affecting antidepressants are well tolerated, but caution must be taken while prescribing them in combination with other drugs that inhibit or induce the same hepatic cytochrome P450 enzymes Enzymes Enzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body's constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics of Enzymes to prevent increased levels of both drugs. An overdose can be life-threatening. It is important to recognize the signs and symptoms of SSRI/SNRI overdose to enable prompt treatment in an emergency setting.

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Editorial responsibility: Stanley Oiseth, Lindsay Jones, Evelin Maza

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Chemistry and Pharmacodynamics

Mechanisms of action

  • Selective serotonin reuptake inhibitors (SSRIs):
    • Vary considerably in their chemical structures
    • Have similar mechanisms of action, which result in increased synaptic serotonin (also known as 5-hydroxytryptamine (5-HT))
  • Serotonin-norepinephrine reuptake inhibitors (SNRIs) have a similar mechanism of action to SSRIs:
    • Chemical structures of duloxetine, milnacipran, and venlafaxine are dissimilar.
    • Desvenlafaxine and venlafaxine are bicyclic phenylethylamines with a similar structure.
    • Duloxetine is a naphthalene derivative.
  • Serotonin antagonist and reuptake inhibitors (SARIs): trazodone and nefazodone
    • Inhibit reuptake of serotonin by blocking the 5-HT2A receptor (antagonist)
    • Induce significant changes in the 5-HT presynaptic receptor adrenoreceptors
    • Block histamine (H₁) and α-1 adrenergic receptors
  • 5-HT1A receptor partial agonist: vilazodone
    • Inhibits CNS neuron serotonin uptake
    • No significant effect on the reuptake of norepinephrine (NE) or dopamine
  • Serotonin modulator and stimulator (SMS): vortioxetine
    • Inhibits serotonin reuptake
    • Has agonist activity at the 5-HT1A receptor and antagonist activity at the 5-HT3 receptor
Mechanisms antidepressants

Mechanisms of antidepressants:
The basic mechanisms of action of commonly prescribed antidepressants are listed. These medications include monoamine oxidase (MAO) inhibitors, the α-2 antagonist mirtazapine, the selective serotonin reuptake inhibitor fluoxetine, the serotonin antagonist and reuptake inhibitor trazodone, the tricyclic antidepressant desipramine, and the tetracyclic drug maprotiline.

Image by Lecturio.

Pharmacodynamics Pharmacodynamics Pharmacodynamics is the science that studies the biochemical and physiologic effects of a drug and its organ-specific mechanism of action, including effects on the cellular level. Pharmacokinetics is "what the body does to the drug," whereas pharmacodynamics is "what the drug does to the body." Pharmacokinetics and Pharmacodynamics

  • SSRIs:
    • “Selective”: have affinity for the serotonin receptor and very little affinity for other receptors
    • Many types of pre- and postsynaptic serotonin receptors exist (e.g., 5-HT2A and 5-HT2C).
    • SSRIs decrease the action of the presynaptic serotonin reuptake pump by 60%–80% → increased 5-HT levels in the synaptic cleft
    • Increased levels of serotonin are not sufficient to treat depression. The beneficial effect on mood takes several weeks and occurs due to:
      • Increased production of neuroprotective proteins
      • Treatment with an SSRI for weeks modifies the serotonergic receptors.
  • SNRIs:
    • Vary in their affinity for the serotonin and NE transporters → ↑ NE and 5-HT levels in the synaptic cleft
    • The degree to which serotonin and NE reuptake is inhibited depends on the dose and drug.
  • SARIs:
    • Relatively targeted at the 5-HT2A and 5-HT2C receptors
    • 5-HT2A and 5-HT2C are G-protein-mediated receptors located in the neocortex → antidepressant action
    • Also block H₁ receptors
  • Physiologic effects:
    • Physical symptoms may improve in the 1st 1–2 weeks (energy, sleep Sleep Sleep is a reversible phase of diminished responsiveness, motor activity, and metabolism. This process is a complex and dynamic phenomenon, occurring in 4-5 cycles a night, and generally divided into non-rapid eye movement (NREM) sleep and REM sleep stages. Physiology of Sleep, appetite).
    • Affective symptoms improve after physical symptoms (mood, concentration, self-esteem).

Pharmacokinetics

Secondary serotonin reuptake inhibitors

  • 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:
    • Well-absorbed in the GI tract, not affected by food
    • Reach peak plasma levels in a few hours
  • Distribution:
    • Lipophilic
    • Widely distributed throughout the body (including the brain)
  • Metabolism:
    • Via cytochrome P450 (CYP)2D6, CYP3A4, and CYP2C19 pathways: significant for drug interactions
    • Half-lives vary from 21 hours (paroxetine) to 5 days (fluoxetine after long-term use).
    • Fluoxetine may be dosed every other day owing to its very long half-life.
    • All SSRIs except fluvoxamine produce pharmacologically active metabolites.
    • Fluoxetine is the only drug with an active metabolite that has antidepressant activity.
  • Excreted in the urine and feces

Serotonin-norepinephrine reuptake inhibitors

  • 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:
    • Food decreases the rate but not the degree of absorption.
    • Taking with meals may reduce nausea, which is generally the most common side effect of SNRIs.
  • Distribution:
    • Duloxetine is highly protein bound and primarily undergoes hepatic clearance.
    • Other SNRIs are not as highly protein bound as duloxetine. Renal excretion plays a significant role in their clearance.
  • Metabolism:
    • Significant interindividual differences in the clearance of SNRIs
    • Doses may vary substantially among individuals.
  • Excretion:
    • Partially metabolized by the kidneys Kidneys The kidneys are a pair of bean-shaped organs located retroperitoneally against the posterior wall of the abdomen on either side of the spine. As part of the urinary tract, the kidneys are responsible for blood filtration and excretion of water-soluble waste in the urine. Kidneys and excreted in the urine
    • Dosage adjustments may be required in individuals with CKD CKD Chronic kidney disease (CKD) is kidney impairment that lasts for ≥ 3 months, implying that it is irreversible. Hypertension and diabetes are the most common causes; however, there are a multitude of other etiologies. In the early to moderate stages, CKD is usually asymptomatic and is primarily diagnosed by laboratory abnormalities. Chronic Kidney Disease.

Serotonin antagonist and reuptake inhibitor = trazodone (nefazodone is not currently available in the US)

  • Short-acting drug with a half-life of 7 hours
  • Metabolized via the CYP3A4 pathway
  • Excreted in the urine

5-Hydroxytryptamine1A receptor partial agonist = vortioxetine

  • Protein binding: 98%
  • Hepatic metabolism mainly via oxidation by CYP450 isoenzymes, primarily CYP2D6, and subsequent glucuronic acid conjugation to an inactive carboxylic acid metabolite
  • Long elimination half-life: approximately 66 hours (causes fewer withdrawal symptoms if doses are missed)
  • Excreted in the urine and feces

Serotonin modulator and stimulator = vilazodone

  • Protein binding: approximately 96%–99%
  • Metabolism: extensively hepatic via CYP3A4 (major pathway) and CYP2C19 and CYP2D6 (minor pathways)
  • Elimination half-life: approximately 25 hours

Classification and Indications

Antidepressant medications that affect serotonin levels in the brain to treat depression, anxiety, and other conditions are classified into several groups. The most commonly prescribed antidepressants are SSRIs. Other important classes of antidepressants include monoamine oxidase inhibitors Monoamine oxidase inhibitors Monoamine oxidase inhibitors are a class of antidepressants that inhibit the activity of monoamine oxidase (MAO), thereby increasing the amount of monoamine neurotransmitters (particularly serotonin, norepinephrine, and dopamine). The increase of these neurotransmitters can help in alleviating the symptoms of depression. Monoamine Oxidase Inhibitors (MAOIs), 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), and the NE/dopamine reuptake inhibitor (NDRI) bupropion.

Classification

The brand names of commonly used medications are listed in parentheses for further understanding.

  • SSRIs:
    • Citalopram (Celexa)
    • Escitalopram (Lexapro)
    • Fluoxetine (Prozac)
    • Fluvoxamine (Luvox)
    • Paroxetine (Paxil)
    • Sertraline (Zoloft)
  • SNRIs:
    • Duloxetine (Cymbalta)
    • Venlafaxine (Effexor)
    • Desvenlafaxine (Pristiq)
    • Milnacipran (Savella)
  • SARIs:
    • Trazodone (generic)
    • Nefazodone: not currently available in the US (August 2021), but may soon be made available
  • SMS: vortioxetine (Trintellix)

Indications

Antidepressants are used to treat several psychiatric conditions, and SSRIs/SNRIs/SARIs/SMS are most commonly used to treat 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 (MDD) such as unipolar depression and anxiety disorders, and also to treat 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.

General indications for antidepressant medications:

  • MDD:
    • SSRIs are usually the preferred 1st-line agents (except fluvoxamine).
    • Concomitant therapy with psychosocial/behavioral therapy should be considered.
  • Anxiety disorders:
    • Generalized anxiety disorder Generalized anxiety disorder Generalized anxiety disorder (GAD) is a common mental condition defined by excessive, uncontrollable worrying causing distress and occurring frequently for at least 6 months. Generalized anxiety disorder is more common in women. Clinical presentation includes fatigue, low concentration, restlessness, irritability, and sleep disturbance. Generalized Anxiety Disorder
    • Social anxiety disorder Social anxiety disorder Social anxiety disorder, or social phobia, is a psychiatric illness marked by fear and avoidance of social interactions due to concerns about embarrassment. The disorder usually occurs in more than one social situation for more than 6 months and leads to a significant decline in function. Social Anxiety Disorder
    • Panic disorder Panic disorder Panic disorder is a condition marked by recurrent and episodic panic attacks that occur abruptly and without a trigger. These episodes are time-limited and present with cardiorespiratory (palpitations, shortness of breath, choking), GI (nausea, abdominal distress), and neurologic (paresthesias, lightheadedness) symptoms. Panic Disorder
  • OCD OCD Obsessive-compulsive disorder (OCD) is a condition characterized by obsessions (recurring and intrusive thoughts, urges, or images) and/or compulsions (repetitive actions the person is compelled to perform) that are time-consuming and associated with functional impairment. Obsessive-compulsive Disorder (OCD): SSRIs and SNRIs are effective.
  • 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:
    • Neuropathic 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
    • Chronic musculoskeletal 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
    • Fibromyalgia Fibromyalgia Fibromyalgia is a chronic pain syndrome characterized by widespread body pain, chronic fatigue, mood disturbance, and cognitive disturbance. It also presents with other comorbid symptoms such as migraine headaches, depression, sleep disturbance, and irritable bowel syndrome. Fibromyalgia:
      • Duloxetine
      • Milnacipran (Savella) indicated for fibromyalgia, not depression
  • Unique uses for some medications that may be preferred over other similar drugs:
    • Premature ejaculation: sertraline
    • Vasomotor symptoms of menopause Menopause Menopause is a physiologic process in women characterized by the permanent cessation of menstruation that occurs after the loss of ovarian activity. Menopause can only be diagnosed retrospectively, after 12 months without menstrual bleeding. Menopause: paroxetine, venlafaxine, escitalopram
    • Vulvodynia may respond to SNRIs.
    • Migraine prophylaxis in individuals without depression: escitalopram, venlafaxine
    • PTSD PTSD Posttraumatic stress disorder is a psychiatric illness characterized by overwhelming stress and anxiety experienced after exposure to a life-threatening event. Symptoms last more than 1 month and involve re-experiencing the event as flashbacks or nightmares, avoiding reminders of the event, irritability, hyperarousal, and poor memory and concentration. Posttraumatic Stress Disorder (PTSD): venlafaxine, paroxetine
    • 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: fluoxetine
    • Premenstrual dysphoric disorder Premenstrual Dysphoric Disorder Premenstrual dysphoric disorder (PMDD) refers to a group of mood, somatic, and behavioral symptoms that follow a cyclical pattern experienced by some women prior to menstruation. Unlike premenstrual syndrome (PMS), PMDD is characterized by significant distress and/or functional impairment. Premenstrual Dysphoric Disorder (PMDD): fluoxetine, sertraline
    • 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: Trazodone is used more as a sleep Sleep Sleep is a reversible phase of diminished responsiveness, motor activity, and metabolism. This process is a complex and dynamic phenomenon, occurring in 4-5 cycles a night, and generally divided into non-rapid eye movement (NREM) sleep and REM sleep stages. Physiology of Sleep aid than to treat depression.
    • Atomoxetine (Strattera) is used for ADHD and narcolepsy Narcolepsy Narcolepsy is a neurological sleep disorder marked by daytime sleepiness and associated with cataplexy, hypnagogic hallucinations, and sleep paralysis. There are 2 types of narcolepsy: type 1 is associated with cataplexy and type 2 has no association with cataplexy. Narcolepsy:
      • The exact mechanism of action is unknown; however, it selectively inhibits NE reuptake.
      • Not used for depression

Adverse Effects and Contraindications

None of the SSRIs significantly affect the α-adrenergic, histaminic, or cholinergic receptors, except for paroxetine, which has a weak antagonistic effect on the cholinergic receptors. The side effects of all SSRIs are due to their effects on the serotonin receptors.

Adverse effects

SSRIs:

  • GI:
    • Nausea
    • 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 (most common with sertraline)
    • Xerostomia (dry mouth)
  • Diaphoresis
  • Sexual dysfunction:
    • Anorgasmia in women or delayed orgasm in men (sertraline may be used as a treatment for premature ejaculation)
    • Decreased libido
    • Erectile dysfunction Erectile Dysfunction Erectile dysfunction (ED) is defined as the inability to achieve or maintain a penile erection, resulting in difficulty to perform penetrative sexual intercourse. Local penile factors and systemic diseases, including diabetes, cardiac disease, and neurological disorders, can cause ED. Erectile Dysfunction
  • Weight changes: also may be due to depression itself
    • Weight gain may be seen with paroxetine.
    • Weight loss may be seen with fluoxetine.
  • Neurologic:
    • Dizziness
    • Headache
    • CNS depression
  • 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
  • Increased risk of bleeding due to inhibition of platelet serotonin uptake (and drug interaction with clopidogrel)
  • Hypoglycemic effects (and drug interactions with sulfonylureas)
  • Hyponatremia Hyponatremia Hyponatremia is defined as a decreased serum sodium (sNa+) concentration less than 135 mmol/L. Serum sodium is the greatest contributor to plasma osmolality, which is very tightly controlled via antidiuretic hormone (ADH) release from the hypothalamus and by the thirst mechanism. Hyponatremia
  • Cardiovascular: Citalopram may cause QT prolongation.

SNRIs, vilazodone, and vortioxetine:

  • Similar side effects as SSRIs
  • SNRIs may cause a slight increase in blood pressure.

Trazodone (SARI):

  • GI:
    • 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
  • Xerostomia (dry mouth)
  • Neurologic/psychiatric:
    • Dizziness
    • Headache
    • Sedation
  • Blurred vision

Discontinuation syndrome:

  • Occurs more often in individuals taking higher doses
  • Commonly observed in drugs with shorter half-lives
  • Least risk with fluoxetine
  • Greatest risk with paroxetine and venlafaxine
  • Risk can be reduced by slowly tapering over several weeks.
  • Abruptly stopping SSRIs or SNRIs may cause:
    • Dizziness
    • Fatigue
    • Headache
    • Nausea
    • 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
    • Irritability
    • Paresthesias: including a feeling of “electric-like” shocks

Serotonin syndrome Serotonin syndrome Serotonin syndrome is a life-threatening condition caused by large increases in serotonergic activity. This condition can be triggered by taking excessive doses of certain serotonergic medications or taking these medications in combination with other drugs that increase their activity. Serotonin Syndrome (a potentially life-threatening side effect):

  • Usually caused by > 1 medication affecting the serotonin receptor
  • Was 1st described as a reaction between SSRIs and MAOIs
  • Drug combinations with SSRIs/SNRIs/other serotonergic antidepressants:
    • To treat migraine Migraine Migraine headache is a primary headache disorder and is among the most prevalent disorders in the world. Migraine is characterized by episodic, moderate to severe headaches that may be associated with increased sensitivity to light and sound, as well as nausea and/or vomiting. Migraine Headache: triptans Triptans Triptans and ergot alkaloids are agents used mainly for the management of acute migraines. The therapeutic effect is induced by binding to serotonin receptors, which causes reduced vasoactive neuropeptide release, pain conduction, and intracranial vasoconstriction. Triptans and Ergot Alkaloids and ergots
    • Antidepressants: TCAs, MAOIs, antipsychotics
    • Anticonvulsants: carbamazepine, valproic acid
    • Antianxiety drug: buspirone
    • Opioid analgesics Opioid analgesics 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: tramadol, methadone, codeine
    • Over-the-counter cough medication: dextromethorphan
    • Herbal supplements for depression: St. John’s Wort, 5-HTP
    • Antibiotic: linezolid
    • Muscle relaxant: cyclobenzaprine
    • Street drugs: cocaine, methamphetamine
  • Symptoms include CNS stimulation, cardiovascular stimulation, and GI stimulation:
    • Severe muscle rigidity
    • Mydriasis
    • Myoclonus
    • Hyperreflexia
    • Hyperthermia
    • 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
    • Tachycardia
    • Unstable blood pressure
    • 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

Mnemonic to recall serotonin syndrome manifestations: “Madam’s tips”

  • M = mental status changes
  • A = agitation
  • D = diarrhea
  • A = ataxia
  • M = myoclonus
  • S = shivering
  • T = tachycardia
  • I = increased reflexes
  • P = pyrexia
  • S = sweating

Drug interactions

  • Both drug factors and patient factors can contribute to the toxicity of SSRIs/SNRIs in some individuals.
    • Drug factors: Some SSRIs and SNRIs are moderate-to-potent inhibitors of hepatic cytochrome P450 → drug-drug interactions by altering blood levels of other medications that depend on these enzymes Enzymes Enzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body's constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics of Enzymes for clearance or activation
    • Patient factors: Enzyme may function differently in individuals with significant variations in the CYP2D6 gene.
      •  “Slow metabolizers”
      •  “Extensive metabolizers”
  • CYPs are hepatic enzymes Enzymes Enzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body's constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics of Enzymes that metabolize several drugs:
    • Render the drug either more or less active
    • Combinations of drugs using the same metabolic pathway can cause serious adverse effects.
    • Examples of the CYP450 family of proteins used by antidepressants:
      • CYP2D6
      • CYP3A4 
      • CYP2C9
      • CYP1A2
  • SSRI drug interactions with other drugs that are metabolized by CYP450 enzymes Enzymes Enzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body's constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics of Enzymes:
    • Citalopram and escitalopram inhibit 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 enzymes Enzymes Enzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body's constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics of Enzymes much less than other SSRIs.
    • Fluoxetine and paroxetine are potent inhibitors of CYP2D6 causing ↑ 2D6 substrate levels
    • Other CYP2D6 inhibitors that can interact with SSRIs and should be used with caution:
      • Antiarrhythmic agents: amiodarone, quinidine
      • H₂ histamine receptor antagonist: ranitidine
      • Bupropion (an antidepressant in its own class)
      • Cinacalcet (used for hyperparathyroidism Hyperparathyroidism Hyperparathyroidism is a condition associated with elevated blood levels of parathyroid hormone (PTH). Depending on the pathogenesis of this condition, hyperparathyroidism can be defined as primary, secondary or tertiary. Hyperparathyroidism)
    • Other CYP2D6 substrates (SSRIs can interact with other drugs and lead to increased drug levels and adverse effects):
      • β-blockers:
        • Used for hypertension Hypertension Hypertension, or high blood pressure, is a common disease that manifests as elevated systemic arterial pressures. Hypertension is most often asymptomatic and is found incidentally as part of a routine physical examination or during triage for an unrelated medical encounter. Hypertension or cardiac conditions: propranolol, metoprolol, atenolol, bisoprolol 
        • Combination with SSRIs can ↑ drug levels and cause hypotension Hypotension Hypotension is defined as low blood pressure, specifically < 90/60 mm Hg, and is most commonly a physiologic response. Hypotension may be mild, serious, or life threatening, depending on the cause. Hypotension
      • Tamoxifen: used to treat breast cancer Breast cancer Breast cancer is a disease characterized by malignant transformation of the epithelial cells of the breast. Breast cancer is the most common form of cancer and 2nd most common cause of cancer-related death among women. Breast Cancer
      • Antinausea medications: ondansetron, metoclopramide
      • Other antidepressants 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 and menopausal symptoms. Other Antidepressants:
        • Tricyclic (amitriptyline, imipramine, nortriptyline)
        • Combination with SSRIs can ↑ drug levels and lead to serotonin syndrome
      • Antipsychotics:
        • Aripiprazole, haloperidol, olanzapine, quetiapine, risperidone
        • Combination with SSRIs can ↑ drug levels and lead to serotonin syndrome
      • 1st-generation antihistamines Antihistamines Antihistamines are drugs that target histamine receptors, particularly H1 and H2 receptors. H1 antagonists are competitive and reversible inhibitors of H1 receptors. First-generation antihistamines cross the blood-brain barrier and can cause sedation. Antihistamines/H₁-receptor antagonists: chlorpheniramine, diphenhydramine
      • Muscle relaxants: cyclobenzaprine
      • Pain medications/opioid analgesics: codeine or tramadol
  • CYP3A4 substrates: SSRIs can interact with:
    • Some calcium channel blockers Calcium Channel Blockers Calcium channel blockers (CCBs) are a class of medications that inhibit voltage-dependent L-type calcium channels of cardiac and vascular smooth muscle cells. The inhibition of these channels produces vasodilation and myocardial depression. There are 2 major classes of CCBs: dihydropyridines and non-dihydropyridines. Class 4 Antiarrhythmic Drugs (Calcium Channel Blockers)
    • Statins Statins Statins are competitive inhibitors of HMG-CoA reductase in the liver. HMG-CoA reductase is the rate-limiting step in cholesterol synthesis. Inhibition results in lowered intrahepatocytic cholesterol formation, resulting in up-regulation of LDL receptors and, ultimately, lowering levels of serum LDL and triglycerides. Statins
    • 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
    • Hypnotics: zopiclone and zolpidem
    • Macrolide antibiotics: clarithromycin and azithromycin
    • Psychiatric medications: haloperidol, mirtazapine
    • Antivirals used in the management of HIV
  • CYP3A4 inhibitors and inducers: SSRIs can also interact with:
    • Antifungals: ketoconazole
    • Calcium channel blockers: specifically diltiazem and verapamil
    • Grapefruit juice
    • Antivirals used in the management of HIV (note that they are also CYP34 substrates, as listed above)
    • Anticonvulsants: carbamazepine, phenytoin, barbiturates
    • Rifampin
    • St. John’s wort
  • CYP2C9 pathway: fluoxetine can also interact with:
    • Antifungals: voriconazole
    • Some TCAs
    • 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
    • Proton pump inhibitors: omeprazole
    • Sulfonylureas: glipizide or glimepiride
  • Fluvoxamine (a different SSRI) is a potent CYP2C9 inhibitor:
    • ↑ Levels of the antipsychotics clozapine, thioridazine, and olanzapine
    • Contraindicated with the hypnotic drug ramelteon (Rozerem), melatonin, and the muscle relaxant tizanidine (Zanaflex) due to the risk of causing increased drug levels and CNS depression
  • SNRI drug interactions:
    • Duloxetine is a moderately potent inhibitor of CYP2D6 and may interact with other drugs:
      • ↑ Metoprolol levels
      • ↑ Thioridazine levels and risk of QT prolongation
    • Other SNRIs (venlafaxine, desvenlafaxine, and milnacipran) do not have significant effects on CYP enzymes Enzymes Enzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body's constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics of Enzymes.
  • SARI (trazodone) drug interactions:
    • Some sedatives or CNS depressants can cause increased sedation:
      • 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 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
      • Ethanol
    • Potent CYP2D6 inhibitors (paroxetine, tamsulosin): ↑ trazodone levels
  • 5-HT1A receptor partial agonist (vilazodone) drug interactions:
    • Similar adverse effects and contraindications as with SSRIs
    • Drug interactions: potent CYP3A4 inhibitors ↑ vilazodone levels
      • Antibiotics: clarithromycin, azithromycin
      • Antifungals: itraconazole, ketoconazole
      • Antivirals: indinavir, nelfinavir, ritonavir, saquinavir used in the management of HIV infection
      • Not all drugs within a class of medications inhibit CYP3A4.
  • Vortioxetine drug interactions: Use with other CYP2D6 inhibitors can ↑ vortioxetine levels

Contraindications

  • All SSRIs are contraindicated in individuals currently taking MAOIs to treat depression.
    • The combination may increase the risk of serotonin syndrome.
    • Additive risks of CNS depression and psychomotor impairment
  • SSRIs/SNRIs/SARIs/SMS are not recommended for individuals with bipolar depression as these drugs may induce mania (except for fluoxetine).
  • SNRIs:
    • Contraindicated with MAOIs
    • Duloxetine is contraindicated in individuals with narrow-angle 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.

Overdose

Generally, an overdose of SSRI/SNRI/similar drugs can cause signs and symptoms of neuromuscular excitation and autonomic stimulation.

  • Signs:
    • Clonus
    • Agitation
    • Diaphoresis
    • Tremors
    • Hyperreflexia
    • Hyperthermia
  • Treatment:
    • Supportive care:
      • Discontinue serotonergic therapies.
      • 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 be needed for severe agitation.
      • Intubation may be required if there is a concern to protect the airway.
    • Cooling for individuals with hyperthermia
    • Individuals exhibiting refractory symptoms can be treated with cyproheptadine.

References

  1. O’Donnell, J.M., Bies, R.R., Shelton, R.C. (2018). Drug Therapy of Depression and Anxiety Disorders. In: Brunton LL, Hilal-Dandan R, Knollmann BC.(Eds.) Goodman & Gilman’s: The Pharmacological Basis of Therapeutics [Internet], 13th ed. New York, NY: McGraw-Hill. 
  2. Schatzberg, A.F., Nemeroff, C.B. (Eds.) (2017). The American Psychiatric Association Publishing Textbook of Psychopharmacology [Internet], 5e. Arlington, VA: American Psychiatric Association Publishing. https://doi.org/10.1176/appi.books.9781615371624 
  3. Stahl, S.M. (2013). Stahl’s Essential Psychopharmacology: Neuroscientific Basis and Practical Applications [Internet], 4th de. Cambridge University Press.
  4. Neurotransmitters and Neuromodulators. (2019). In: Nelson, L.S., et al. Goldfrank’s Toxicologic Emergencies [Internet], 11th ed. New York, NY: McGraw-Hill.
  5. Smink, F.R., van Hoeken, D., Hoek, H.W. (2013). Epidemiology, course, and outcome of eating disorders. Curr Opin Psychiatry. 26(6):543-8. https://doi.org/10.1097/yco.0b013e328365a24f
  6. American Geriatrics Society. (2019). 2019 Updated AGS Beers Criteria® for potentially inappropriate medication use in older adults. J Am Geriatr Soc. https://doi.org/10.1111/jgs.15767
  7. Hirsch, M., Birnbaum, R.J. (2021). Selective serotonin reuptake inhibitors: Pharmacology, administration, and side effects. UpToDate. Retrieved August 11, 2021, from https://www.uptodate.com/contents/selective-serotonin-reuptake-inhibitors-pharmacology-Administration-and-side-effects

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