Selective Serotonin Reuptake Inhibitors (SSRIs)
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Mechanism of Action 300-3000 fold selectivity to block 5-HT >NE reuptake. Receptors: M, α & H (little blockade) Uses: Depression (1st line of treatment of MDD ) Anxiety disorders (GAD, OCD, Panic, …..) Eating Disorders e.g. Bulimia nervosa, Anorexia Nervosa
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Selective Serotonin Reuptake Inhibitors (SSRIs)
- 1. Selective Serotonin Reuptake Inhibitors (SSRIs) Prof. Sawsan Aboul-Fotouh Department of pharmacology, faculty of Medicine, Ain-Shams University SSRI
- 2. Selective Serotonin Reuptake Inhibitors (SSRIs)
- 3. SSRIs Mechanism of Action • 300-3000 fold selectivity to block 5-HT >NE reuptake. • Receptors: M, α & H (little blockade) Uses: 1. Depression (1st line of treatment of MDD ) 2. Anxiety disorders (GAD, OCD, Panic, …..) 3. Eating Disorders e.g. Bulimia nervosa, Anorexia Nervosa (Fluoxetine, Paroxetine, Citalopram, Escitalopram, Sertraline, Fluvoxamine) SSRI
- 4. Eating Disorders Anorexia Nervosa Distorted body image
- 5. 5. Vasomotor menopausal symptoms: “Brisdelle “paroxetine” 7.5 mg tab.” 1st Non-Hormonal Treatment (FDA 2013). Other SSRIs & SNRIs also used off-label 4. Post-traumatic stress disorder and impulse control disorder as Trichotillomania (esp. Prozac), gambling ….. 6. Premenstrual dysphoric disorder (PMDD). FDA approved fluoxetine, sertraline, and paroxetine for PMDD 7. Premature ejaculation: ALL SSRIs esp. Fluoxetine, Citalopram
- 6. Less Obesity Less Cardiotoxicity ?! (Citalopram→↑QT) Less Risk of overdose NO or Less Less Autonomic Blockade
- 7. Q: Sleep disturbance Paroxetine is sedating useful in pts with difficulty in sleeping. Fluoxetine is activating useful in pts with fatigue or excessive somnolence Adverse effects: ↑ Risk of Suicide In children and teenagers
- 8. Fluoxetine and paroxetine potent inhibitors for CYP 2D6 → Drug interactions with: TCAs, Antipsychotic drugs, Antiarrhythmic& β-Blocker. TCAs, Antipsychotics, Antiarrhythmic β-Blocker.
- 9. Paroxetine not recommended to be given with tamoxifen (estrogen receptor blocker). It inhibits CYP2D6, that converts the prodrug tamoxifen to active metabolites (endoxifen ↓58%) →↓ tamoxifen effectiveness in hormone positive cancer breast. Also, Paroxetine was found to have an estrogenic effect “weak agonist” →promote the development and growth of breast tumors in women. Bupropion active metabolites Venlafaxine has No interaction with Tamoxifen Prodrug
- 10. (Pharmacotherapy Handbook 10th ed.,2017) Venlafaxine has No Drug interaction with CYP
- 11. US Pharm. 2015;40(11):HS34-HS40. (>450 ms in males, >470 ms in females) TCAs & Citalopram
- 12. FDA issued a warning for citalopram and the risk of QT prolongation at doses higher than 40 mg/day
- 13. Q: Managing SSRI-induced sexual dysfunction?? delayed ejaculation in ♂ & ↓ sexual desire in ♀ • Reduce the dose of the drug if possible. • In erectile dysfunction sildenafil (Viagra) may improve sexual function. • Replace it with other having fewer sexual side effects: (Mirtazapine, Bupropion, Vortioxetine, Agomelatine )
- 14. With All SSRIs when used with MAOI. → Washout (2 Wks) period before administration of each other Q: SSRIs Overdoses? Hyperthermia Confusion
- 15. Akathisia and other EPS also can complicate the use of SSRIs e.g. Fluoxetine, Paroxetine. 1. SSRIs inhibit tyrosine kinase in S. Nigra → ↓ Dopamine (DA) in BG 2. Also ↑ 5-HT level and 5-HT2A activation →↓ DA in BG. 3. SSRIs inhibit CYP2D6 → ↑ risk of EPS with antipsychotics metabolized with CYP2D6 e.g. Aripiprazole, Risperidone, Fluphenazine …. Akathisia Dystonia SSRIs-induced Extrapyramidal Symptoms (EPS)
Editor's Notes
- Anorexia and bulimia are both eating disorders. They can have similar symptoms, such as distorted body image. However, they’re characterized by different food-related behaviors. For example, people who have anorexia severely reduce their food intake to lose weight. People who have bulimia eat an excessive amount of food in a short period of time, then purge or use other methods to prevent weight gain. Although eating disorders aren’t specific to age or gender, women are disproportionally affected by them. About 1 percent of all American women will develop anorexia, and 1.5 percent will develop bulimia, according to the National Association of Anorexia Nervosa and Associated Disorders (ANAD). Overall, ANAD estimates that at least 30 million Americans are living with an eating disorder such as anorexia or bulimia. Keep reading to learn more about how these conditions present, how they’re diagnosed, available treatment options, and more. What are the signs and symptoms? Eating disorders are usually characterized by an intense preoccupation with food. Many people who have an eating disorder also express dissatisfaction with their body image. Other symptoms are often specific to the individual condition. Anorexia Anorexia often stems from a distorted body image, which may result from emotional trauma, depression, or anxiety. Some people may view extreme dieting or weight loss as a way to regain control in their lives. There are many different emotional, behavioral, and physical symptoms that can signal anorexia. The physical symptoms can be severe and life-threatening. They include: severe weight loss insomnia dehydration constipation weakness and fatigue dizziness and fainting thinning and breaking hair bluish tinge to the fingers dry, yellowish skin inability to tolerate cold amenorrhea, or absence of menstruation downy hair on the body, arms, and face arrhythmia, or irregular heartbeat Someone with anorexia may exhibit certain behavioral changes before physical symptoms are noticeable. This includes: skipping meals lying about how much food they’ve eaten eating only certain “safe” — usually low-calorie — foods adopting unusual eating habits, like sorting food on the plate or cutting food into tiny pieces talking badly about their body trying to hide their body with baggy clothes avoiding situations that could involve eating in front of other people, which can result in social withdrawal avoiding situations where their body would be revealed, like the beach extreme exercising, which may take the form of exercising for too long or too intensely, like an hour-long jog after eating a salad Emotional symptoms of anorexia may increase as the disorder progresses. They include: poor self-esteem and body image irritability, agitation, or other mood changes social isolation depression anxiety Bulimia Someone with bulimia may develop an unhealthy relationship to food over time. They may get caught up in damaging cycles of binge eating and then panic about the calories they’ve consumed. This may lead to extreme behaviors to prevent weight gain. There are two different types of bulimia. The attempts to purge are used to differentiate them. The new edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) now refers to attempts to purge as “inappropriate compensatory behaviors”: Purging bulimia. Someone with this type will regularly induce vomiting after binge eating. They may also misuse diuretics, laxatives, or enemas. Non-purging bulimia. Instead of purging, someone with this type may fast or engage in extreme exercise to prevent weight gain after a binge. Many people with bulimia will experience anxiety because their eating behavior is out of control. As with anorexia, there are many different emotional, behavioral, and physical symptoms that can signal bulimia. The physical symptoms can be severe and life-threatening. They include: weight that increases and decreases in significant amounts, between 5 and 20 pounds in a week chapped or cracked lips due to dehydration bloodshot eyes, or eyes with busted blood vessels callouses, sores, or scars on the knuckles from inducing vomiting mouth sensitivity, likely due to eroding tooth enamel and receding gums swollen lymph nodes Someone with bulimia may exhibit certain behavioral changes before physical symptoms are noticeable. This includes: constantly worrying about weight or appearance eating to the point of discomfort going to the bathroom immediately after eating exercising too much, especially after they’ve eaten a lot in one sitting restricting calories or avoiding certain foods not wanting to eat in front of others Emotional symptoms may increase as the disorder progresses. They include: poor self-esteem and body image irritability, agitation, or other mood changes social isolation depression anxiety What causes an eating disorder like these? It isn’t clear what causes anorexia or bulimia to develop. Many medical experts believe it may be due to a combination of complex biological, psychological, and environmental factors. These include: Genetics. According to a 2011 studyTrusted Source, you may be more likely to develop an eating disorder if you have a family member who has one. This may be because of a genetic predisposition to traits associated with eating disorders, such as perfectionism. More research is needed to determine whether there’s truly a genetic link. Emotional well-being. People who have experienced trauma or have mental health conditions, such as anxiety or depression, may be more likely to develop an eating disorder. Feelings of stress and low self-esteem may also contribute to these behaviors. Societal pressures. The current Western ideal of body image, self-worth, and success equated with thinness can perpetuate the desire to achieve this body type. This may be emphasized further by pressure from the media and peers.
- Vasomotor menopausal symptoms. FDA approved 1st Non-Hormonal Treatment “Brisdelle “paroxetine” 7.5 mg tab.” in 2013 for Hot Flashes and night sweats) associated with Menopause Mechanism: decreasing blood flow to the skin to counter the vasodilation during flushing and lowering core body temperature through central vasodilation to negate the effects that occur during menopause due to the narrowed thermoregulatory zone. During menopause, there is decline in estrogen and progesterone levels triggers →changes in 5-HT and NE levels, → hypothalamic thermoregulatory dysfunction (↑core body temperatures and narrowing of the thermoregulatory zone). Topical doxepin is also approved for short-term (up to 8 days) management of moderate pruritus in adult patients with atopic dermatitis, pruritus or lichen simplex chronicus Pregabalin, which was the first drug to gain FDA approval for diabetic neuropathy, is an anticonvulsant and analgesic that works by binding to the alpha-2-delta subunit of voltage-gated calcium channels in the central nervous system.1,3 Numerous meta-analyses and clinical trials have concluded that pregabalin improved pain, fatigue, depressed mood, sleep disturbance, and health-related quality of life. The serotonin-norepinephrine reuptake inhibitors (SNRIs) duloxetine and milnacipran, which are the other two medications FDA-approved for fibromyalgia, are recommended by all clinical guidelines.1 In addition to these FDA-approved medications, a variety of drugs may be used off-label to treat the symptoms of fibromyalgia. The most notable of these is amitriptyline, a tricyclic antidepressant (TCA). Amitriptyline exerts its effect on pain modulation via serotonin and norepinephrine, and for many years it was the mainstay of therapy.5 In a systematic review evaluating the efficacy and acceptability of amitriptyline, duloxetine, and milnacipran, amitriptyline was found to improve pain, fatigue, and sleep and was concluded to be superior to duloxetine and milnacipran in those areas.1 Cyclobenzaprine, which is similar in structure to TCAs, has been shown to improve pain and sleep disturbances; however, many patients have reported adverse effects.2 Tramadol, a synthetic opioid receptor agonist with properties similar to those of SNRIs, inhibits the reuptake of biogenic amines—including serotonin and norepinephrine (similar to SNRI antidepressants)—and acts as a weak agonist at the mu-opioid receptor.4 Although some literature states that it may be used as first-line therapy, tramadol lacks FDA approval and is recommended as an alternative to duloxetine, milnacipran, or pregabalin.4 Nonsteroidal anti-inflammatory drugs have demonstrated benefits in combination with antidepressants or anticonvulsants, but they decrease the antidepressant action of selective serotonin reuptake inhibitors (SSRIs) and therefore are not used often.3 he FDA-approved agents indicated for PMDD include fluoxetine, sertraline, and paroxetine. Citalopram, escitalopram, and fluvoxamine have also been effective at treating PMS/PMDD in various trialsPremenstrual dysphoric disorder (PMDD) is a health problem that is similar to premenstrual syndrome (PMS) but is more serious. PMDD causes severe irritability, depression, or anxiety in the week or two before your period starts. Symptoms usually go away two to three days after your period starts
- Sertraline, escitalopram, followed by mirtazapine & venlafaxine have better risk benefit profiles than other antidepressants. Paroxetine is sedating useful in pts with difficulty in sleeping while Fluoxetine is activating useful in pts with fatigue or excessive somnolence
- Fluvoxamine is a potent CYP1A2 inhibitor →↓ clearance of theophylline and clozapine→↑their levels → need to lower their doses
- Psychiatric Medications of Concern The antidepressants and antipsychotics that are correlated with a higher risk of QT prolongation are listed in TABLE 2. TABLE 3 includes medications that have been determined to have a lower risk. This determination was based on a review of literature and data from the comprehensive QT prolongation database, CredibleMeds, previously known as the University of Arizona Center for Education and Research on Therapeutics.8 A long QT interval due to prolonged repolarization may be associated with a polymorphic ventricular tachycardia known as torsades de pointes. During marked prolongation of the action potential (long QT) early after depolarizations may occur, which when propagated may trigger an arrhythmia. The QTc is considered prolonged if the values are greater than 450 milliseconds in males and greater than 470 milliseconds in females. The risk of cardiac events correlates with the extent of QT prolongation. However, no QTc value has been established for cardiac arrhythmia
- In August 2011, FDA issued a Drug Safety Communication (DSC) stating that citalopram should no longer be used at doses greater than 40 mg per day because it could cause potentially dangerous abnormalities in the electrical activity of the heart.
- Akathisia and other EPS also can complicate the use of SSRIs e.g. Fluoxetine, paroxetine. The propensity for SSRIs to induce EPS vary within the drug class depending, for example, on their selectivity for serotonin relative to other monoamines, affinity for the 5-HT2C & 2A receptor, pharmacokinetic drug interaction with neuroleptics and accumulation due to a long half-life. - SSRIs inhibit tyrosine kinase in Substantia Nigra reducing synthesis of Dopamine in basal ganglia (BG) also increase 5-HT level and 5-HT2A activation decrease Dopamine in BG. In addition, SSRIs with CYP2D6 inhibition increase risk of EPS with antipsychotics metabolized with CYP2D6 e.g. Aripiprazole, Risperidone, Fluphenazine , …. - EPS have been reported with different classes of antidepressants (SSRIs, SNRIs, NDRIs), are not dose related, and can develop with both short-term and long-term use.
- Akathisia and other EPS also can complicate the use of SSRIs e.g. Fluoxetine, paroxetine. The propensity for SSRIs to induce EPS vary within the drug class depending, for example, on their selectivity for serotonin relative to other monoamines, affinity for the 5-HT2C & 2A receptor, pharmacokinetic drug interaction with neuroleptics and accumulation due to a long half-life. - SSRIs inhibit tyrosine kinase in Substantia Nigra reducing synthesis of Dopamine in basal ganglia (BG) also increase 5-HT level and 5-HT2A activation decrease Dopamine in BG. In addition, SSRIs with CYP2D6 inhibition increase risk of EPS with antipsychotics metabolized with CYP2D6 e.g. Aripiprazole, Risperidone, Fluphenazine , …. - EPS have been reported with different classes of antidepressants (SSRIs, SNRIs, NDRIs), are not dose related, and can develop with both short-term and long-term use.