Anti-Depressants Part 1
21.2 Antidepressants: Selective Serotonin Reuptake Inhibitors (SSRIs)
Introduction to SSRIs:
Fluoxetine (Prozac) was the first SSRI in the United States.
SSRIs became popular due to reported dramatic patient responses to depression treatment.
Fewer side effects compared to earlier antidepressants (TCAs and MAOIs).
Safer in overdose than previous antidepressants.
Helped reduce the stigma of depression and treatment.
Other SSRIs:
Examples: sertraline (Zoloft), paroxetine (Paxil), fluvoxamine (Luvox), citalopram (Celexa), escitalopram (Lexapro), and vilazodone (Viibryd).
Efficacy and Indications:
Generally, all SSRIs are equally effective in treating depression.
Some SSRIs are FDA-approved for multiple indications (major depression, OCD, PTSD, PMDD, panic disorder, social phobia/social anxiety disorder).
Fluvoxamine is considered an antidepressant in other countries, not FDA-approved as such in the U.S. due to a marketing decision.
Differences Among SSRIs:
Meaningful differences exist in pharmacodynamics, pharmacokinetics, and side effects.
These differences can affect clinical responses among individual patients.
Explains why some patients respond better to one SSRI than another.
Side Effects:
SSRIs have more problematic side effects than suggested in original clinical trials.
Quality-of-life adverse effects: nausea, sexual dysfunction, weight gain.
These side effects can reduce the therapeutic benefits.
Withdrawal symptoms can occur when SSRIs are stopped abruptly.
Withdrawal is especially true with paroxetine and other SSRIs with short half-lives.
Pharmacologic Actions
Pharmacokinetics:
Significant difference among SSRIs is their serum half-lives.
Ranges of half-lives:
Fluoxetine: 4-6 days; active metabolite half-life is 7-9 days.
Sertraline: 26 hours; less active metabolite half-life is 3-5 days.
Citalopram: 35 hours (no significant pharmacologic activity of metabolites).
Escitalopram: 27-32 hours (no significant pharmacologic activity of metabolites).
Paroxetine: 21 hours (no significant pharmacologic activity of metabolites).
Fluvoxamine: 15 hours (no significant pharmacologic activity of metabolites).
Absorption and Peak Effects:
SSRIs are well absorbed after oral administration.
Peak effects occur in the range of 3-8 hours.
Food slightly enhances sertraline absorption.
Plasma Protein Binding:
Differences in plasma protein binding percentages.
Highly bound: sertraline, fluoxetine, and paroxetine.
Least bound: escitalopram.
Metabolism:
All SSRIs are metabolized in the liver by CYP450 enzymes.
Due to broad therapeutic index problematic increases in SSRI concentrations from other drugs are rare.
Critical drug-drug interactions result from SSRIs inhibiting the metabolism of other medications.
Each SSRI possesses a potential for slowing or blocking the metabolism of many drugs.
Examples of clinically significant interactions:
Fluvoxamine and theophylline (Slo-Bid, Theo-Dur) via CYP1A2 interaction.
Fluvoxamine and clozapine (Clozaril) via CYP1A2 inhibition.
Fluvoxamine with alprazolam (Xanax) or clonazepam (Klonopin) via CYP3A4 inhibition.
Fluoxetine and paroxetine affect CYP2D6 isozyme, interfering with the efficacy of opiate analogs like codeine and hydrocodone by blocking their conversion to active forms.
Sertraline, citalopram, and escitalopram are least likely to complicate treatment due to interactions.
Vilazodone Pharmacokinetics:
Dose-proportional pharmacokinetics (5 to 80 mg).
Steady-state plasma levels achieved in about 3 days.
Elimination is primarily by hepatic metabolism.
Terminal half-life is approximately 25 hours.
Pharmacodynamics:
SSRIs exert therapeutic effects through serotonin reuptake inhibition.
Little effect on norepinephrine or dopamine reuptake.
Clinical activity and saturation of the 5-HT transporters are often achieved at starting dosages.
Higher dosages do not necessarily increase antidepressant efficacy but may increase the risk of adverse effects.
Citalopram and escitalopram are the most selective inhibitors of serotonin reuptake, with very little inhibition of norepinephrine or dopamine reuptake and very low affinities for histamine H1, GABA, or benzodiazepine receptors.
Fluoxetine weakly inhibits norepinephrine reuptake and binds to 5-HT2C receptors.
Sertraline weakly inhibits norepinephrine and dopamine reuptake.
Paroxetine has significant anticholinergic activity at higher dosages and binds to nitric oxide synthase.
Vilazodone has 5-HT1A receptor agonist properties; clinical implications are not yet evident.
Combined fluoxetine-olanzapine increases brain concentrations of norepinephrine.
Concomitant use of SSRIs and triptans (sumatriptan [Imitrex], naratriptan [Amerge], rizatriptan [Maxalt], zolmitriptan [Zomig]) may result in serotonin syndrome.
A similar reaction may occur when SSRIs are combined with tramadol (Ultram).
Therapeutic Indications
Depression:
All SSRIs except fluvoxamine are FDA-approved for depression treatment in the U.S.
Antidepressants with serotonin-norepinephrine activity (MAOIs, TCAs, venlafaxine, mirtazapine) may produce higher remission rates than SSRIs in head-to-head studies.
SSRIs are still first-line due to simplicity of use, safety and broad spectrum of action.
No individual SSRI is consistently superior to another.
$>50%$ of people who respond poorly to one SSRI will respond favorably to another.
Before shifting to non-SSRI antidepressants, it is most reasonable to try other agents in the SSRI class for persons who did not respond to the first SSRI.
Some clinicians may select an SSRI based on its adverse effect profile.
SSRIs are more effective in patients with more severe symptoms of major depression than those with milder symptoms.
Suicide:
FDA has issued a black box warning for antidepressants and suicidal thoughts and behavior in children and young adults.
More recent data has shown that suicidal thoughts and behavior decreased over time for adult and geriatric patients treated with antidepressants as compared with placebo; no differences were found for youths.
In adults, reduction in suicide ideation and attempts occurred through a reduction in depressive symptoms.
In all age groups, the severity of depression improved with medication and was significantly related to suicide ideation or behavior.
SSRIs (and SNRIs) may have a protective effect against suicide that is mediated by decreases in depressive symptoms with treatment.
For youths, no significant effects of treatment on suicidal thoughts and behavior were found, although depression responded to treatment.
No evidence of increased suicide risk was observed in youths receiving active medication.
SSRIs prevent potential suicides as a result of their primary action, the shortening and prevention of depressive episodes.
In clinical practice, a few patients become anxious and agitated when started on an SSRI, which could provoke suicidal ideation.
All depressed patients should be closely monitored during the first few days and weeks of SSRI treatment.
Depression During Pregnancy and Postpartum:
High rates of relapse during pregnancy among women who discontinue or modify antidepressant regimens (68-100%).
Many women need to continue medication during pregnancy and postpartum.
There is no significantly increased risk for major congenital malformations after exposure to SSRIs during pregnancy (with the exception of paroxetine).
The risk of relapse into depression when a newly pregnant mother is taken off SSRIs is severalfold higher than the risk to the fetus of exposure to SSRIs.
There is some evidence suggesting increased rates of special care nursery admissions after delivery for children of mothers taking SSRIs.
There is also a potential for a discontinuation syndrome with paroxetine.
Absence of clinically significant neonatal complications associated with SSRI use.
Studies that have followed children into their early school years have failed to find any perinatal complications, congenital fetal anomalies, decreases in global intelligence quotient (IQ), language delays, or specific behavioral problems attributable to the use of fluoxetine during pregnancy.
Postpartum depression affects a small percentage of mothers.
Some clinicians start administering SSRIs if the postpartum blues extend beyond a few weeks or if a woman becomes depressed during pregnancy.
Babies whose mothers are taking an SSRI in the latter part of pregnancy may be at a slight risk of developing pulmonary hypertension.
Data about the risk of this side effect are inconclusive, but it is estimated to involve 1 to 2 babies for 1,000 births.
Paroxetine should be avoided during pregnancy; FDA classified as pregnancy Category D medication.
In 2005, the FDA issued an alert that paroxetine increases the risk of congenital disabilities, particularly heart defects, when women take it during the first 3 months of pregnancy.
Women taking paroxetine plan to consult their physicians about the potential risks of taking paroxetine during pregnancy.
Studies showed that women who took paroxetine during the first 3 months of pregnancy were about one-and-a-half to two times as likely to have a baby with a heart defect as women who received other antidepressants or women in the general population.
Sometimes these septal defects resolve without treatment.
The risk of heart defects in babies whose mothers had taken paroxetine early in pregnancy was 2 percent, compared with a 1 percent risk in the whole population.
Minimal amounts of SSRIs are found in breast milk, and no harmful effects have been found in breastfed babies.
Concentrations of sertraline and escitalopram are exceptionally low in breast milk.
No decision regarding the use of an SSRI is risk-free. It is thus essential to document that communication of potential risks to the patient has taken place.
Depression in Elderly and Medically Ill Persons:
SSRIs are safe and well-tolerated in elderly and medically ill persons.
As a class, they have little or no cardiotoxic, anticholinergic, antihistaminergic, or α-adrenergic adverse effects.
Paroxetine does have some anticholinergic activity, which may lead to constipation and worsening of cognition.
SSRIs can produce subtle cognitive deficits, prolonged bleeding time, and hyponatremia, all of which may impact the health of this population.
SSRIs are effective in poststroke depression and dramatically reduce the symptom of crying.
Depression in Children:
The use of SSRI antidepressants in children and adolescents has been controversial.
Few studies have shown clear-cut benefits from the use of these drugs, and studies show that there may be an increase in suicidal or aggressive impulses; however, some children and adolescents do exhibit dramatic responses to these drugs in terms of depression and anxiety.
Fluoxetine has most consistently demonstrated effectiveness in reducing symptoms of depressive disorder in both children and adolescents.
Sertraline is effective in treating social anxiety disorder in this population, especially when combined with cognitive-behavioral therapy.
Any use of SSRIs should be undertaken only within the context of comprehensive management of the patient.
Anxiety Disorders
Obsessive-Compulsive Disorder (OCD):
Fluvoxamine, paroxetine, sertraline, and fluoxetine are indicated for OCD treatment in persons older than 18 years.
Fluvoxamine, fluoxetine, and sertraline are approved for children with OCD (ages 6-17 years).
∼50% of persons with OCD begin to show symptoms in childhood or adolescence, $>50%$ of these respond favorably to medication.
Long-term data support the model of OCD as a genetically determined, lifelong condition that is best treated continuously with drugs and cognitive-behavioral therapy from the onset of symptoms in childhood throughout the lifespan.
SSRI dosages for OCD may need to be higher than those required to treat depression.
Beneficial responses can be dramatic but take several months for maximum effects.
Patients who fail to obtain adequate relief of their OCD symptoms with an SSRI will usually benefit from the addition of a small dose of risperidone (Risperdal).
Monitor patients for increases in prolactin levels when this combination is used. Clinically, hyperprolactinemia may manifest as gynecomastia and galactorrhea (in both men and women) and loss of menses.
Several disorders are now considered to be within the OCD spectrum, such as trichotillomania, eyebrow picking, nose picking, nail-biting, compulsive picking of skin blemishes, and cutting. SSRIs treat these effectively.
Other spectrum disorders include compulsive gambling, compulsive shopping, hypochondriasis, and body dysmorphic disorder.
Panic Disorder:
Paroxetine, fluoxetine, and sertraline are indicated for the treatment of panic disorder, with or without agoraphobia.
These agents work less rapidly than do benzodiazepines but are far superior to them for the treatment of panic disorder with comorbid depression.
Citalopram and fluvoxamine also may reduce spontaneous or induced panic attacks.
Persons with panic disorder must begin taking small dosages of fluoxetine (5 mg a day) and increase the dosage slowly.
Low doses of benzodiazepines may be given to manage this side effect.
Social Anxiety Disorder:
SSRIs are effective agents in the treatment of social phobia and reduce both symptoms and disability.
The response rate is comparable to that seen with the MAOI phenelzine (Nardil), the previous standard treatment.
The SSRIs are safer to use than MAOIs or benzodiazepines.
Posttraumatic Stress Disorder (PTSD):
Pharmacotherapy for PTSD must target specific symptoms in four clusters: reexperiencing, avoidance, negative changes in mood and thinking, and arousal.
For long-term treatment, SSRIs appear to have a broader spectrum of therapeutic effects on specific PTSD symptom clusters than do TCAs and MAOIs; Benzodiazepine augmentation is useful in the acute symptomatic state.
SSRIs are associated with marked improvement of both intrusive and avoidant symptoms.
Generalized Anxiety Disorder (GAD):
SSRIs may be useful for the treatment of specific phobias, generalized anxiety disorder (GAD), and separation anxiety disorder.
A thorough, individualized evaluation is the first approach, with particular attention to identifying conditions amenable to drug therapy.
Cognitive-behavioral or other psychotherapies can be added for greater efficacy.
Bulimia Nervosa and Other Eating Disorders
Bulimia Nervosa:
Fluoxetine is indicated for the treatment of bulimia, which is best done in the context of psychotherapy.
Dosages of 60 mg a day are significantly more effective than 20 mg a day.
Fluoxetine in dosages of 60 mg a day was superior to placebo in reducing binge eating and induced vomiting.
Some experts recommend an initial course of cognitive-behavioral therapy alone-- if there is no response in 3 to 6 weeks, fluoxetine administration is added.
The appropriate duration of treatment with fluoxetine and psychotherapy has not been determined.
Fluvoxamine was not effective at a statistically significant level in one double-blind, placebo-controlled trial for inpatients with bulimia.
Anorexia Nervosa:
Fluoxetine has been used in inpatient treatment of anorexia nervosa to attempt to control comorbid mood disturbances and obsessive-compulsive symptoms.
Studies failed to find that fluoxetine affected the overall outcome and the maintenance of weight.
Effective treatments for anorexia include cognitive-behavioral, interpersonal, psychodynamic, and family therapies in addition to a trial with SSRIs.
Obesity:
Fluoxetine, in combination with a behavioral program, is only modestly beneficial for weight loss.
A significant percentage of all persons who take SSRIs, including fluoxetine, lose weight initially but later may gain weight, however, all SSRIs may cause initial weight gain.
Premenstrual Dysphoric Disorder (PMDD)
PMDD is characterized by debilitating mood and behavioral changes in the week preceding menstruation that interfere with normal functioning.
Sertraline, paroxetine, fluoxetine, and fluvoxamine have been reported to reduce PMDD symptoms.
Controlled trials of fluoxetine and sertraline administered either throughout the cycle or only during the luteal phase (the 2 weeks between ovulation and menstruation) showed both schedules to be equally effective.
Additional observation that fluoxetine was associated with changing the duration of the menstrual period by more than 4 days, either lengthening or shortening it.
The effects of SSRIs on menstrual cycle length are mostly unknown and may warrant careful monitoring in women of reproductive age.
Off-Label Uses
Premature Ejaculation:
SSRIs are useful as a treatment for men with premature ejaculation through anorgasmic effects.
The SSRIs permit intercourse for a significantly more extended period and are reported to improve sexual satisfaction in couples in which the man has premature ejaculation.
Fluoxetine and sertraline are useful for this purpose.
Paraphilias:
SSRIs may reduce obsessive-compulsive behavior in people with paraphilias.
The SSRIs diminish the average time per day spent in unconventional sexual fantasies, urges, and activities.
Evidence suggests a more significant response to sexual obsessions than for paraphilic behavior.
Autism:
Obsessive-compulsive behavior, poor social relatedness, and aggression are prominent autistic features that may respond to serotonergic agents such as SSRIs and clomipramine (Anafranil).
Sertraline and fluvoxamine have been shown in controlled and open-label trials to mitigate aggressiveness, self-injurious behavior, repetitive behaviors, some degree of language delay, and (rarely) lack of social relatedness in adults with autistic spectrum disorders.
Fluoxetine has been reported to be useful for features of autism in children, adolescents, and adults.
Precautions and Adverse Reactions
SSRI side effects need to be considered in terms of their onset, duration, and severity.
Individual drugs in this class may cause a higher rate or carry a more severe risk of specific side effects depending on the patient.
Sexual Dysfunction:
All SSRIs cause sexual dysfunction, estimated incidence is between 50 and 80 percent.
Most common complaints are anorgasmia, inhibited orgasm, and decreased libido.
Some studies suggest that sexual dysfunction is dose-related, but this has not been established.
Sexual inhibition rarely resolves in the first few weeks of use but usually continues as long as the drug is taken (improvement over time may occur in some cases).
Strategies to counteract SSRI-induced sexual dysfunction: decreasing the dosage, adding bupropion (Wellbutrin) or amphetamine, successful treatment with agents such as sildenafil (Viagra).
Switching to antidepressants that do not interfere with sexual functioning, drugs such as mirtazapine or bupropion, may be considered.
Gastrointestinal Adverse Effects:
GI side effects are widespread and are mediated mainly through effects on the serotonin 5-HT3 receptor.
Most frequent GI complaints are nausea, diarrhea, anorexia, vomiting, flatulence, and dyspepsia.
Sertraline and fluvoxamine produce the most intense GI symptoms.
Delayed-release paroxetine has less intense GI side effects during the first week of treatment, but paroxetine, because of its anticholinergic activity, frequently causes constipation.
Nausea and loose stools are usually dose-related and transient, usually resolving within a few weeks.
Initial anorexia may also occur and is most frequent with fluoxetine.
SSRI-induced appetite and weight loss peak at 20 weeks, after which weight often returns to baseline.
Up to one-third of persons taking SSRIs will gain weight gradually, sometimes over 20 lb, and is usually resistant to diet and exercise regimens.
Paroxetine is associated with more frequent, rapid, and pronounced weight gain than the other SSRIs, especially among young women.
Cardiovascular Effects:
All SSRIs can lengthen the QT interval in otherwise healthy people and cause drug-induced long QT syndrome, especially when taken in overdose.
The risk of QTc prolongation increases when an antidepressant and an antipsychotic are used in combination, an increasingly common practice.
Citalopram stands out as the SSRI with the most pronounced effect on QT intervals.
A QT study on adults compared with placebo , found a milliseconds for -mg citalopram and milliseconds for mg, while mg was estimated to be milliseconds.
Recommendations regarding citalopram use by the FDA:
mg a day is the maximum dose for patients with hepatic impairment, older than years of age.
Don't prescribe at doses greater than mg a day; Congenital long QT syndrome
Correct hypokalemia and hypomagnesemia before administering citalopram and monitor electrolytes.
Consider more frequent electrocardiograms in patients with congestive heart failure, bradyarrhythmias, or patients on concomitant medications that prolong the QT interval.
Patients should be advised to contact their prescriber immediately if they experience signs and symptoms of an abnormal heart rate or rhythm while taking citalopram.
The upper bound of the percent confidence interval for the largest placebo-adjusted, baseline- corrected QTc interval was below milliseconds, so below the clinical concern interval.
Physicians should consider if the benefits of androgen deprivation therapy outweigh risks, as reductions in androgen levels can cause QTc interval prolongation.
Quinidine can prolong the QT interval and is a potent inhibitor of CYP2D6 and should be used with caution with medications that can prolong the QT interval and inhibit CYP3A4, particularly in patients with cardiac disease.
Antepartum use of SSRIs is sometimes associated with QTc interval prolongation in exposed neonates.
Headaches:
The incidence of headache in SSRI trials was to percent, only one percentage point higher than the placebo rate.
Fluoxetine is the most likely to cause headaches.
All SSRIs are effective prophylaxis against migraine and tension-type headaches in many persons.
Central Nervous System Adverse Effects:
Anxiety: Fluoxetine may cause anxiety in the first few weeks of treatment but usually gives way to an overall reduction in anxiety after a few weeks.
Increased anxiety is caused considerably less frequently by paroxetine and escitalopram (better choices if sedation is desired).
Insomnia and Sedation:
SSRIs exert improved sleep from the treatment of depression and anxiety.
Many as percent, of persons taking SSRIs note trouble sleeping, excessive somnolence, or overwhelming fatigue.
Fluoxetine is the most likely to cause insomnia (often taken in the morning).
Sertraline and fluvoxamine as likely to cause insomnia as somnolence, and citalopram and especially paroxetine often cause somnolence.
Others benefit from taking dose before going to bed.
SSRI-induced insomnia can be treated with benzodiazepines, trazodone (Desyrel), or other sedating medicines.
Significant SSRI-induced somnolence often requires switching to the use of another SSRI or bupropion.
Other Sleep Effects: Many people recall extremely vivid dreams or nightmares report, report sleep is “busy”, and bruxism, restless legs, nocturnal myoclonus, and sweating.
Emotional Blunting: Largely overlooked but frequent when SSRIs are used chronically, with patients reporting an inability to cry, feeling of apathy or indifference, or a restriction in the intensity of emotional experiences.
Yawning: Is in result of SSRI effects on the hypothalamus.
Seizures: Reported in to percent of patients treated with SSRIs; incidence is comparable to that reported with other antidepressants and not significantly different from that with placebo, as well may interfere with the efficacy of opiate analogs, interfere with opiate interreaction.
Extrapyramidal Symptoms: May rarely cause akathisia, dystonia, tremor, cogwheel rigidity, torticollis, opisthotonos, gait disorders, and bradykinesia; Rare cases of tardive dyskinesia and acute worsening of motor symptoms when some with well-controlled disease taking SSRIs.
Anticholinergic Effects:
Paroxetine has a mild anticholinergic activity that causes dry mouth, constipation, and sedation in a dose-dependent fashion and are not mediated muscarinic activity.
Hematologic Adverse Effects:
SSRIs can cause functional impairment of platelet aggregation but not a reduction in platelet number; May manifest through easy bruising and excessive or prolonged bleeding.
Special monitoring is suggested when patients use SSRIs in conjunction with anticoagulants or aspirin.
Concurrent use of SSRIs and NSAIDs is associated with a significantly increased risk of gastric bleeding.
In cases where this combination is necessary, proton pump inhibitors should be used instead.
Electrolyte and Glucose Disturbances:
SSRIs may acutely decrease glucose concentrations, so diabetic patients should be monitored carefully-- long-term can increase glucose, but if that is the result of pharmacologic effect needs to be determined.
Antidepressant users may have other characteristics that raise their odds of developing diabetes, or may be more likely to be diagnosed with diabetes or other medical conditions as a result of being in treatment for depression.
Cases of SSRI-associated hyponatremia and the syndrome of inappropriate antidiuretic hormone have been seen in some patients, especially those who are older or treated with diuretics.
Endocrine and Allergic Reactions:
SSRIs can increase prolactin levels and cause mammoplasia and galactorrhea in both men and women-- breast changes are reversible upon discontinuation of the drug, but this may take several months to occur.
Various types of rashes appear in percent of all patients.
Allergic reaction may generalize and involve the pulmonary system, rarely resulting in fibrotic damage and dyspnea; the SSRI treatment may have to be discontinued in patients with drug-related rashes.
Serotonin Syndrome:
Concurrent administration of an SSRI with an MAOI, L-tryptophan, or lithium can raise plasma serotonin concentrations to toxic levels, producing a constellation of symptoms called serotonin syndrome.
Is a severe and possibly fatal syndrome of serotonin overstimulation that comprises (1) diarrhea; (2) restlessness; (3) extreme agitation, hyperreflexia, and autonomic instability with possible rapid fluctuations in vital signs; (4) myoclonus, seizures, hyperthermia, uncontrollable shivering, and rigidity; and (5) delirium, coma, status epilepticus, cardiovascular collapse, and death.
Treatment of serotonin syndrome consists of removing the offending agents and promptly instituting comprehensive supportive care (Nitroglycerine, Periactin, cooling blankets, chlorpromazine, dantrolene, benzodiazepines, anticonvulsants, mechanical ventilation, and paralyzing agents.).
Sweating:
Some patients experience is independent of temperature and Terazosine is dramatically effective here.
Overdose:
to mg vilazodone has had serotonin syndrome and disorientation involved.
Selective Serotonin Reuptake Inhibitor Withdrawal:
Abrupt discontinuance of SSRI use, especially one with a shorter half-life, has been associated with a withdrawal syndrome that may include dizziness, weak, nausea, headache, insomnia, poor concentration, upper respiratory symptoms, paresthesias, and migraine-like symptoms, usually until -weeks into treatment,
It usually resolves spontaneously in 3 weeks; Fluoxetine is least likely to be associated with this syndrome because the half-life of its metabolite is more than week, and it effectively tapers itself.
Drug Interactions
SSRIs do not interfere with most other drugs, and a serotonin syndrome can develop with the concurrent administration of MAOIs, L- tryptophan, lithium, or other antidepressants that inhibit the reuptake of serotonin.
Fluoxetine, sertraline, and paroxetine can raise plasma concentrations of TCAs, which can cause clinical toxicity.
Potential pharmacokinetic interactions have been described, but clinically relevant interactions are rare.
SSRIs that inhibit CYP2D6 may interfere with the analgesic effects of hydrocodone and oxycodone and can also reduce the effectiveness of tamoxifen.
The combined use of SSRIs and NSAIDs increases the risk of gastric bleeding.
SSRIs, particularly fluvoxamine, should not be used with clozapine because it raises clozapine concentrations, increasing the risk of seizure; and the SSRIs, such as fluoxetine, may increase the duration and severity of zolpidem (Ambien)-induced side effects, including hallucinations.
The Clinician should use low dosages of tricyclic drug, since Fluoxetine, sertraline, and paroxetine inhibit hepatic enzyme CYP2D6 metabolizing it.
Has drug interactions that may affect the plasma levels of benzodiazepines, antipsychotics, and lithium; sertraline interacts to those of fluoxetine, displacing warfarin from plasma proteins and may increase the prothrombin time.
Paroxetine has a higher risk for drug interactions than does fluoxetine or sertraline because it is a more potent inhibitor of the CYP2D6 enzyme as cimetidine raises level and phenobarbital can decrease; may precipitate serotonin syndrome in elderly when used with Tramadol.
Among the SSRIs, fluvoxamine appears to present the most risk for drug-drug interactions to alpha and diazepam raising theophylline and warfarin levels. There aren't significant intersections with lorazepam though
Citalopram Concurrent administration of cimetidine increases concentrations about , affects metoprolol with double the plasma too
Escitalopram Moderate inhibitor of CYP2D6 raise desipramine and metoprolol levels
Vilazodone Concomitant use can cause inadequate drug concentrations from inducers needing decrease dosage to 20 but has not been evaluated fully.
Laboratory Interferences
SSRIs do not interfere with any laboratory tests.
False-positive urine toxicology for benzodiazepines in patients taking sertraline; if this is suspected, additional confirmation can be sought via gas chromatography-mass spectrometry.
Dosage and Clinical Guidelines
Fluoxetine: (10-20mg capsules
20mg/5 mL oral concentrate).
Treatment: use food to minimize nausea by first minimizing starting doses.
mg is often more effective for high dosesSertraline: (25-, 50-, and 100-mg tablets). Start with to not cause GI effect. Then increase to in a week. mL oral concentration contains Alcohol.
Paroxetine: Immediate-release is available in scored -mg tablets unscored, in flavored -mg/-ml oral suspension in evening.
Increase dosage every - weeks mg with maximum of may be helpful. Use paroxetine CR by lowering dosage every - from discontinuations, though decreases plasma quickly in absences, in 12.5-, 25-, and 37.5-mg tabletsFluvoxamine: (25,50,100 tablets. With usual of -mg) First week start dosage every beginning week, decrease titration and dosage if nausea. Not FDA approved and can have interdose withdrawal. All forms must be taken wholly.
Citalopram: (20,40mg tablets that have 10 mg/5 mL). usual starting dosage is but do not for Elderly persons or persons with hepatic impairment
Escitalopram: (scored - and -mg and as mg/ mL oral solution). Recommended is a day in trials
Vilazodone: (10-, 20-, and 40-mg tablets taken during meals). Recommended for therapeutic is , with titrated initial of 10 increased the week after. is not approved for child use.
Pregnancy and Breastfeeding: Is safe apart form proxetine, transient QTc prolongation happens in babies of mothers with SSRI use
Loss of Efficacy:
Some stop responding and may increase dosage to taper drug useVortioxetine (Trintellix):
May work mostly though inhibitors, though has more pharmacologic profiles than others. Sideeffects are nausea while dosaging is between - orally with or without meals
SSRI:
The Currently there are 4 venlafaxine Succinate (DVS; Pristiq), duloxetine (Cymbalta), levomilnacipran (Fetzima),while milnacipran (Savella) Treats general illness instead though only is available outside the united states. Their goal is to conjoin the uptake though broader in treatment.
Venlafaxine and Desvenlafaxine:
MDD, GAD, social anxiety disorder and panic disorder through direct modulation of serotonin and norepinephrine, may convey more significant antidepressant effects than are exerted by medications that selectively enhance only noradrenergic or serotoninergic neurotransmission
with trials of clomipramine, amitriptyline, and imipramine and metananlysis giving the benefits
Venalaaxfine and general axiety is with extended relief for months but not so for comparison
Precaution and Adverse Reactions:
therapy associates with nauesea and sexual dysfunctions for dry mouth, and even increased hypertension through antagonizing norepinephrine reuptake, which can be concerning for patients with pre-existing hypertension or cardiovascular issues. Additionally, patients should be monitored for weight gain and potential sedation, as these side effects can impact adherence to treatment and overall quality of life.