Neuromuscular Disorders
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SSRIs …
- Updated 10.21.2021
- Released 06.12.2009
- Expires For CME 10.21.2024
SSRIs
Introduction
Overview
Selective serotonin reuptake inhibitors increase the extracellular level of the neurotransmitter serotonin by inhibiting its reuptake. SSRIs are described as “selective” because they affect only the reuptake pumps responsible for serotonin, as opposed to earlier antidepressants that affect other monoamine neurotransmitters as well. SSRIs are mainly used as antidepressants but are indicated for several other neuropsychiatric disorders. This article describes the pharmacology, uses, and neuroprotective action of some of SSRIs. Personalized use of SSRIs is also discussed for increasing safety and efficacy. Although safer than tricyclic antidepressants, SSRIs have some adverse effects associated with long-term use.
Key points
• Selective serotonin reuptake inhibitors increase the extracellular level of the neurotransmitter serotonin by inhibiting its reuptake. | |
• SSRIs are mainly used as antidepressants but are indicated for several other neuropsychiatric disorders. | |
• Several SSRIs are available, and a personalized approach is required to select an appropriate agent for safe and effective use. |
Historical note and terminology
Since its discovery in the mid-20th century, serotonin, which is also called 5-hydroxytryptamine or 5-HT, has played an increasing part in understanding human diseases, particularly those involving the nervous system. Its plays a role in management of depression and other psychiatric disorders with the demonstration of pharmacological manipulation to prevent reuptake. Its role in other neurologic disorders has also expanded. Development of SSRIs was a major pharmacological achievement. SSRIs are used for the treatment of depression, anxiety disorders, and some personality disorders. Historical landmarks in serotonin, serotonin disorders, and drugs based on manipulation of this system are shown in Table 1. The best known SSRI, fluoxetine, was introduced into medical practice in 1988.
Table 1. Historical Landmarks in Serotonin, Serotonin Disorders, and Drugs Based On Manipulation of the Serotonergic System
Year | Finding |
1911 | Ramon Y Cajal described the raphe nuclei of the brainstem but did not know that they contain serotonin. |
1928 | Start of investigation of vasoconstrictors in blood by Irvin H Page |
1948 | Isolation and characterization of serum vasoconstrictor (serotonin) from blood (34). |
1951 | Synthesis of serotonin (10). |
1952 | Enteramine, a smooth muscle-contracting substance found in the gut wall in 1952 by Erspamer, was found to be identical to serotonin (09). |
1953 | Identification of serotonin in various tissues (43). |
1954 | Discovery of the carcinoid syndrome (wherein tumors derived from chromaffin cells of the gut produce excess serotonin). This was the first disease in which serotonin was implicated (40). |
1954 | Development of urine chemical assay of 5-hydroxyindolacetic acid, a metabolite of serotonin (44). |
1954 | Identification of serotonin in the brain and proposal of its role as a neurotransmitter (01). |
1957 | Hypothesis that serotonin and epinephrine might act as opposing central neurochemical systems (03). |
1960 | Evidence for involvement of serotonin in migraine based on alleviation of symptoms of migraine by intravenous serotonin (21). |
1960s | Role of serotonin as a neurotransmitter was well recognized. |
1965 | Description of the anatomy of the serotonergic system of the brain--the wiring diagram of the neurochemical system (06). |
1969 | Development of selective serotonin reuptake inhibitors and demonstration of their efficacy as antidepressants (04). |
1974 | Discovery of fluoxetine by scientists at Eli Lilly (47). |
1975 | The possibility that some depressed patients have more of a "noradrenergic" depression and others had more of a "serotonergic depression" was suggested (24). |
1979 | Multiple 5-HT receptors were defined, ushering in the modern era of serotonin (31). |
1980s | Development of selective 5-HT receptor antagonists. |
1982 | First description of serotonin syndrome due to excess of serotonin in humans (17). |
1983 | First SSRI for depression, fluvoxamine, launched by Solvay. |
1987 | Alterations reported in serotonergic function in obsessive-compulsive states (48). |
1988 | Fluoxetine (Prozac) introduced in the medical practice by Eli Lilly & Co. |
Currently approved SSRIs include the following:
• Citalopram |
Pharmacology
Serotonin (5-HT) receptors are a group of G protein-coupled receptors and ligand-gated ion channels found in the nervous system; they mediate both excitatory and inhibitory neurotransmission and are activated by the neurotransmitter serotonin, which acts as their endogenous ligand.
The serotonin receptors modulate the release of many neurotransmitters, including glutamate, GABA, dopamine, epinephrine/norepinephrine, and acetylcholine as well as many hormones, including oxytocin, prolactin, vasopressin, cortisol, corticosterone, corticotropin, and substance P, among others.
The 5-HT3 receptor is a ligand-gated ion channel activated by serotonin. Sites of expression include several brainstem nuclei and higher cortical areas such as the amygdala, hippocampus, and cortex. Presynaptic 5-HT3 receptors are involved in mediating or modulating neurotransmitter release whereas postsynaptic 5-HT3 receptors are preferentially expressed on interneurons.
Pharmacodynamics. SSRIs increase the extracellular level of the neurotransmitter serotonin by inhibiting its reuptake into the presynaptic cell, and, thus, increase the level of serotonin available to bind to the postsynaptic receptor. However, high serotonin levels not only activate the postsynaptic receptors but also activate autoreceptors, which act as a feedback sensor for the cell and may inhibit serotonin production, leading to serotonin deficiency. Gradual adaptation to this situation occurs by downregulation of the sensitivity of the autoreceptors. SSRIs act primarily at the serotonin transporter protein, which is found in the plasma membrane of serotonergic neurons and is responsible for the reuptake of this neurotransmitter (38).
Antidepressants usually require several weeks of treatment before clinical effects are seen. A randomized study on healthy volunteers who were not depressed and who had never taken antidepressants showed that those who took a single dose of an SSRI had a marked drop of connectivity throughout the brain except enhancement in the cerebellum and thalamus as observed on brain scan 3 hours later (37). The rapid changes in brain connectivity that relinked to acute serotonin transporter blockade suggest that serotonin transporter plays a key role in the modulation of the functional connectome. However, further studies need to be done to determine the effect of antidepressants on brain connectivity long-term and the differences in response between healthy volunteers and patients suffering from depression. Distinct differences in brain connectivity between patients with depression who ultimately respond to an antidepressant and those who do not may be useful for personalizing antidepressant therapy.
SSRIs may bind to receptors other that 5-HT. SSRIs inhibit important neuronal nicotinic acetylcholine receptors with variable potencies and affinities that are clinically relevant by binding to a site that is shared with tricyclic antidepressants. A study with PET has demonstrated that oral administration of fluvoxamine, but not paroxetine, could result in its binding to sigma-1 receptors in the healthy human brain, in a dose-dependent manner, implicating these receptors in the mechanism of action of fluvoxamine (12).
Use of functional MRI to study SSRIs has shown that direct modulation of activity in neural areas involved in emotional processing may be a key mechanism by which these agents exert their clinical antidepressant effects.
There is hyperactivity of the hypothalamic-pituitary-adrenal axis in depression and flattened cortisol slopes have been seen. Results of a study suggest that SSRI escitalopram might exert its therapeutic effect in women in part through correction of a flattened diurnal cortisol rhythm (36).
In addition to action as an antidepressant, mechanisms of beneficial effects may include neuroprotective, anti-inflammatory, and immunomodulatory actions. SSRIs and SNRIs decrease the neuroinflammation through multiple mechanisms, including the reduction of blood or tissue cytokines or regulation of complex inflammatory pathways: nuclear factor kappa-light-chain-enhancer of activated B cells, inflammasomes, Toll-like receptor 4, and peroxisome proliferator-activated receptor gamma (07). The anti-neuroinflammatory role of SSRIs and SNRIs might contribute to the antidepressant effect.
Antidepressant effect. Antidepressant drug classes where serotonin is involved in the mechanism of action are listed in Table 2.
Table 2. Classification of Antidepressant Drugs Where Serotonin Is Involved
Drug category | Example |
Serotonin reuptake enhancer | Tianeptine |
Serotonin and norepinephrine reuptake inhibitors | Venlafaxine |
SSRI and norepinephrine reuptake inhibitor | Duloxetine |
Noradrenergic (alpha2 antagonism) and specific (5-HT2 and 5-HT3 antagonist) serotonergic antidepressants | Mirtazapine |
Selective serotonin reuptake inhibitors | Fluoxetine |
Serotonin transporter inhibitor and modulator of other 5-HT receptors (agonist of some and antagonist of others) | Vortioxetine |
According to the monoamine hypothesis, depression is due to deficiency of at least one of three biogenic amines: serotonin, epinephrine, or dopamine. Therefore, every antidepressant drug is expected to increase neurotransmission of one or more of these amines. SSRIs accomplish this by blocking one or more of the reuptake pumps or receptors whereas other antidepressants inhibit the enzyme monoamine oxidase. SSRIs are described as “selective” because they affect only the reuptake pumps responsible for serotonin, as opposed to earlier antidepressants that affect other monoamine neurotransmitters as well. The only antidepressants that ignore the serotonin system are selective noradrenaline inhibitors and bupropion, which is a selective norepinephrine and dopamine reuptake inhibitor. The therapeutic and side effects profile of these two categories of compounds is different from other antidepressants. Viloxazine is a selective norepinephrine reuptake inhibitor that can be used as an antidepressant and does not have CNS stimulating effect.
Because of selective action, SSRIs lack some of the side effects seen with antidepressants that have a more general action. Thus, the knowledge of mechanisms of action helps to explain the differences in profiles of side effects of antidepressants. There is no significant difference in effectiveness between SSRIs and tricyclic antidepressants, which were the most used antidepressants before the development of SSRIs.
There are still a few skeptics of serotonin involvement in depression and efficacy of SSRIs as antidepressants (13). SSRIs are ineffective in mood disorders such as melancholia with raised cortisol. The glutamatergic system plays an important role in the pathophysiology and treatment of mood disorders. Ketamine, an NMDA receptor antagonist that acts on the glutamatergic system, is a more effective antidepressant than SSRIs for melancholia, leading one to question a link between serotonin and depression (02). A randomized study of patients with major depressive disorder who were resistant to SSRIs concluded that reduction of depressive symptoms after ketamine treatment is correlated inversely with baseline 5-HT1B receptor binding in ventral striatum (42). Further studies examining the role of 5-HT1B receptors in the antidepressant mechanism of action of ketamine should be conducted, focusing on the 5-HT1B receptor as a depression treatment response biomarker. The exact mechanism of antidepressant action of ketamine is not clear. In addition to glutamate receptors, ketamine may also interact with opioid receptors, either directly or indirectly.
Physical exercise has a beneficial effect on depression. The existence of both neuronal and gene expression changes common to SSRIs and exercise suggests a shared mechanism underlying their effect on depression (14). Further investigations of these changes may uncover the molecular mechanisms of depression.
Neuroprotective effect. SSRIs may protect against neurotoxicity caused by several toxic compounds. Fluoxetine suppresses kainic acid-induced neuronal loss hippocampus, and the neuroprotective effect is associated with its anti-inflammatory effects. SSRIs may promote the growth of new neural pathways or neurogenesis in experimental animals, but neuroprotective effect has not been demonstrated in humans. Repinotan, a serotonin agonist (5HT1A receptor subtype), was investigated as a neuroprotective agent in acute stroke, but further development was discontinued due to lack of efficacy.
Animal studies have shown a beneficial impact of SSRIs on pathophysiological biomarkers of Alzheimer disease, including amyloid burden, tau deposits, and neurogenesis. In humans, studies on subjects with a prior history of depression also showed a delay in the onset of Alzheimer disease in those treated with most SSRIs (26). In a study on healthy human volunteers, citalopram, a SSRI, was shown to decrease total CSF amyloid beta concentrations by 38% in the drug-treated group as compared to controls, but this effect has not been tested for prevention or treatment of Alzheimer disease (39).
Anticonvulsant effect. Experimental studies and occasional use in human patients have shown an anticonvulsant effect of SSRIs with a profile like that of conventional drugs used for epilepsy, but no clinical trials have been conducted, partly because seizures are also reported as adverse effects of SSRIs (16). There is a need for controlled clinical trials of SSRIs in epilepsy with proper selection of patients according to underlying pathology to improve efficacy and to reduce adverse effects.
Effect on premature ejaculation. Dapoxetine, a short-acting SSRI, is approved for the treatment of premature ejaculation in some countries and is the only drug with regulatory approval for such treatment. The results of a postmarketing observational study demonstrated that dapoxetine for treatment of premature ejaculation has a good safety profile and low prevalence of treatment-related adverse effects (28). Originally developed as an antidepressant, dapoxetine, unlike other SSRIs, is absorbed and eliminated rapidly in the body. Its fast action makes it suitable for the treatment of premature ejaculation but not for the treatment of depression.
Pharmacokinetics. The metabolism and pharmacokinetics of SSRIs vary between assorted drugs. The half-life of fluoxetine is 3 days whereas its metabolite norfluoxetine has a half-life of about 1 week. This is an advantage over other SSRIs that have a half-life of about 1 day or less. Despite occasional missed doses, fluoxetine and norfluoxetine concentrations remain in the therapeutic range. Another advantage of this long half-life is that the patients are unlikely to experience withdrawal effects from sudden discontinuation of fluoxetine, an event that can occur following withdrawal of a SSRI with a short half-life. In vivo pharmacokinetic data, however, do not precisely predict clinical response or adverse effects.
Most reports of metabolic enzyme inhibition by SSRIs have focused on changes in concentration of the affected drug. For example, studies have addressed elevated desipramine concentrations with paroxetine, increases in imipramine concentrations with fluvoxamine, and increased phenytoin concentrations with sertraline. Due to interindividual variability in drug disposition, plasma concentrations of SSRIs vary significantly among individuals. Change in enzyme activity due to drug-to-drug interaction may be equally clinically relevant for heterozygous extensive metabolizers (toward poor-metabolizer status) and homozygous extensive metabolizers (toward heterozygous extensive-metabolizer status). A possible cause of significant interindividual differences in the magnitude of CYP2D6 inhibition is the pharmacokinetic variability of the inhibitor itself. Another determinant of overall interaction magnitude is unbound drug concentration in plasma and hepatocytes. A similar extent of intersubject variability in hepatocyte drug concentration is likely at the site of enzyme inhibition. Gender-related differences in pharmacokinetics of SSRIs have been shown to result in different pharmacological responses, but their clinical relevance remains unproven.
SSRIs are metabolized by and have effects on the cytochrome P450 system. Fluoxetine, paroxetine, sertraline, citalopram, and escitalopram are inhibitors of CYP2D6. Fluoxetine and fluvoxamine are inhibitors of CYP2C19. Fluvoxamine is an inhibitor of CYP1A2. Positive and significant correlations between paroxetine and fluoxetine concentrations and CYP2D6 inhibition illustrate the role of plasma concentrations and dosage on magnitude of enzyme inhibition. The potential of paroxetine, a CYP2D6 substrate, as an inhibitor may be further affected by specific genotype and basal metabolic capacity of individual subjects.
Therapeutic drug monitoring. A simple and sensitive liquid chromatography-electrospray ionization mass spectrometry method for the simultaneous quantification in human plasma of all SSRIs is now available in most clinical laboratories and is suitable for therapeutic drug monitoring as well as pharmacokinetic studies.
Pharmacogenetics. There is strong evidence from association studies that some gene polymorphisms are associated with SSRI response. Relatively good efficacy in response to SSRIs has been reported in Chinese patients with single nucleotide polymorphisms in 5-HT2A signal transduction-related genes rs5443TT and rs2230739GG (23). Approximately one third of patients with depression do not respond to an initial trial of SSRI treatment, possibly due to structural variations in the 5-HT(1A) receptor. The serotonin transporter-linked polymorphic region (5-HTTLPR) is the most widely studied polymorphism of the 5-HTT gene, SLC6A4, and is suspected of conferring vulnerability to elderly depression and resistance to treatment. 5-HTTLPR seems to influence the likelihood of adverse effects, and the promoter region may contribute to response variability during the initial stages of treatment, which is explained, in part, by a gene-concentration interaction for paroxetine. However, no randomized trials have yet tested the efficacy of genetic tests to improve outcome in those with treatment resistance or treatment intolerance to SSRIs.
Clinical trials
As of October 2021, 728 clinical trials relevant to SSRIs are listed including those that have been completed, terminated, or are in progress. Some of these are planned but not recruiting patients yet. Clinical trials can be tracked on the NIH’s Clinical Trials website (www.ClinicalTrials.gov). These trials include use of approved SSRIs and those in development as well as other drugs in patients that fail to respond to SSRIs. Trials for managing adverse effects of SSRIs are also included. The PRISE-MD Study, completed in 2013, evaluated "Personalized indicators for predicting response to SSRI treatment in major depression." In the observational study Factors Influencing Depression Endpoints Research (FINDER), patients who received only SSRIs between 0 and 3 months comprised the study cohort (22). Patients were categorized as remitters, partial responders, or nonresponders at 3 months and then followed up at 6 months. Partial response was common, and patients in partial response had a poorer quality of life than those who achieved remission.
A systematic review and meta-analysis of randomized, placebo-controlled clinical trials of dose-response relationship of SSRIs in major depressive disorder shows that higher doses are slightly more effective, but this is somewhat offset by decreased tolerability at high doses (18). A systematic review of controlled clinical trials shows that there is no unbiased evidence that SSRIs are superior to placebo in treating the key symptoms of fibromyalgia (46).
A systematic analysis of controlled clinical trials of SSRIs found that all were more effective than placebo in adults with major depressive disorders, but there were differences in head-to-head comparisons of antidepressants (05). Agomelatine, amitriptyline, escitalopram, mirtazapine, paroxetine, venlafaxine, and vortioxetine were more effective than other antidepressants, whereas fluoxetine, fluvoxamine, reboxetine, and trazodone were the least efficacious drugs. In another comparative study, vortioxetine was found to improve cognitive functioning in major depressive disorders and was effective for prevention of relapse (25). Based on these findings, the 2016 Canadian Network for Mood and Anxiety Treatments guidelines for major depressive disorders includes vortioxetine as a first-line treatment.
One trial (NCT04901494) is investigating if SSRI use in patients with mild cognitive impairment will lead to a lower rate of progression to dementia. This is a retrospective study of prospectively collected longitudinal data in patients followed at a Cognitive and Memory Disorders Center from 2010 to 2019.
Indications
Indications for use of SSRIs include the following conditions:
• Anxiety disorders | ||
-- Anorexia nervosa | ||
• Migraine: acute attacks | ||
Off-label uses
SSRIs are under investigation for the following conditions:
• Alcohol withdrawal |
Contraindications
A major contraindication of SSRIs is the concomitant use of monoamine oxidase inhibitors, as it is likely to cause severe serotonin syndrome.
Liver impairment is another contraindication for use of SSRIs. SSRIs are extensively metabolized in the liver, resulting in decreased clearance and increased plasma concentrations in patients with hepatic dysfunction.
Goals and duration of treatment
It may take several weeks for the drug to reach its optimal effect. Duration of treatment varies according to the condition and the SSRI selected. Individualization of the treatment is also considered.
Personalization of SSRI treatment. Despite advantages of SSRIs over other antidepressants, not all patients benefit from treatment; some do not respond adequately whereas others may react adversely. Response to the first-line antidepressant drug treatment is inadequate in approximately one third of patients and requires switching to alternative therapeutics. This necessitates a review of the initial treatment choice, often involving extended periods of illness while a more suitable therapy is sought. Such a scenario could be avoided were it possible to determine the most suitable drug prior to treatment.
The Mayo Clinic (Rochester, MN) is offering a new genetic test through Mayo Medical Laboratories to help US physicians identify patients who are likely to have side effects from drugs commonly used to treat depression. The test is based on a key genetic biomarker, 5HTT-LPR that identifies people who respond differently to antidepressants including SSRIs. The 5HTT-LPR biomarker has potential to improve management of patients with major depression and others who benefit from SSRI treatment. It provides unique information relating to drug response: side effect and compliance.
The physician can make a better choice of antidepressant medications for their patients based on their serotonin transporter genotype used in conjunction with CYP450 genotyping. Depending on genotypes, some patients should respond well to SSRIs, some may respond to SSRIs but more slowly, and some patients may respond more effectively to non-SSRI antidepressants.
International guidelines for rational therapeutic drug monitoring are recognized for personalized treatment with antidepressants and antipsychotics. Genotyping of patients with depression shows a good agreement between the poor metabolism and ultrarapid metabolism genotypes, the therapeutic drug monitoring data and clinical outcome. Therapeutic drug monitoring combined with genotyping of CYP2D6 is particularly useful in verifying concentration-dependent adverse drug reactions due to poor metabolism and diagnosing pharmacokinetic reasons, eg, ultrarapid metabolism for drug failure. This is because adverse drug reactions may mimic the psychiatric illness itself, and therapeutic failure due to ultrarapid metabolism may be mistaken for poor compliance with the prescription.
Another method for selection of the appropriate SSRI for a patient is the use of biomarkers of drug response. A transcriptome-based genome-wide approach for searching antidepressant drug-response biomarkers involves use of drug-effect phenotypes in human lymphoblastoid cell lines (29).
Results of a placebo-controlled, randomized cross-over design study using fMRI to analyze functional connectivities of the pregenual anterior cingulate cortex, midbrain, and insula to the sublenticular extended amygdala showed it is possible to predict the development of SSRI-related decreased sexual functioning in susceptible individuals, which is a common reason for discontinuation of SSRI (27). This method has the potential to guide individual therapeutic decisions when using SSRIs. Induced pluripotent stem cell technique has been used to convert patients’ skin cells into neurons to study the response to SSRIs. In the presence of serotonin, some neurons derived from SSRI nonresponders show significantly higher activity on average compared to the neurons of healthy individuals or SSRI responders (45). When 5-HT2A and 5-HT7 serotonin receptors were blocked with a chemical compound, the neurons of nonresponders were no longer hyperactive in the presence of serotonin, suggesting that drugs targeting these receptors may be effective alternates to SSRIs in some patients. This study helps in understanding the effect of SSRIs in depression and personalizing therapy of depression.
Dosing
Dosing is detailed in the clinical summaries for individual SSRIs and in the Physicians’ Desk Reference.
Special considerations
Pediatric. Pediatric patients should be monitored closely for the risk of suicide with any SSRI. Only fluoxetine is approved for use in treating depression in pediatric patients. Fluoxetine, sertraline, and fluvoxamine are approved for obsessive-compulsive disorder in pediatric patients. None of the drugs is approved for other psychiatric indications in children. Pediatric patients being treated with antidepressants for any indication should be observed daily by caregivers for clinical worsening as well as for agitation, irritability, suicidality, and unusual changes in behavior, especially during the initial few months of a course of drug therapy or at times of dose changes--either increases or decreases.
Geriatric. SSRIs are generally well tolerated by the elderly. Geriatric patients are more likely to be on multiple drugs, some of which may interact with SSRIs, and this requires a careful check to avoid drug interactions. SSRIs should not be used if hepatic function is impaired in the elderly patients.
Pregnancy. SSRIs fall in the category C of the United States Food and Drug Administration classification regarding safety of use during pregnancy. Animal reproduction studies have shown an adverse effect on the fetus, and there are no adequate and well-controlled studies in humans. SSRIs are usually compatible with breastfeeding, but individual variations in infant exposure may occur.
Antidepressant use during pregnancy is associated with increased risks of miscarriage, birth defects, preterm birth, newborn behavioral syndrome, persistent pulmonary hypertension of the newborn, and possible longer-term neurobehavioral effects (08).
In pregnant women, SSRIs cross the placenta and have the potential to affect newborns. Sertraline and paroxetine have been associated with congenital malformations. SSRIs have also been associated with neonatal complications, such as neonatal abstinence syndrome and persistent pulmonary hypertension. The risk of persistent pulmonary hypertension of the newborn is usually low, but use of SSRIs in late pregnancy increases that risk more than twofold, and this seems to be a class effect (20).
A comparative study of cohorts of children of women with and without different antidepressant exposures before and during pregnancy failed to reveal an association with congenital heart anomalies (32). This study also found an increased risk of congenital heart anomalies in children of older women and in children of women with diabetes, obesity, and a history of alcohol and drug abuse independent of the prescription of antidepressants. Paroxetine is contraindicated in pregnancy and is classified as category D/X due to its teratogenic effects in causing cardiovascular defects, specifically cardiac malformations, if prescribed in the first trimester.
Elevated platelet serotonin levels found in approximately one third of children with autism has led to the belief that dysfunctional serotonin signaling may be a causal mechanism for the disorder and has raised concern about developmental effects of prenatal exposure to SSRIs (11). A cohort study of all singleton live births in Denmark from 1996 through 2005 with follow-up to 2009 failed to detect a significant association between maternal use of SSRIs during pregnancy and autism spectrum disorder in the offspring (15). According to one review, the absolute risks of SSRIs use in pregnancy are low and may be outweighed by the risks of untreated depression, particularly in the perinatal period (41).
Anesthesia. Adjustment of dose of local anesthetic may be necessary as SSRIs inhibit the cytochrome P450 and affect local anesthetic metabolism.
Because there are no specific interactions between SSRIs and anesthetic agents, SSRIs are generally considered safe to use during the perioperative period. However, discontinuation of SSRIs during the perioperative period may lead to the development of withdrawal symptoms. Moreover, reinstituting the drugs at patients' previous dosage, which may be the maximum dosage for some patients, may lead to the development of serotonin syndrome.
Interactions
SSRIs may interact with the following drugs and increase their blood levels to produce toxic effects:
• Antiarrhythmic agents |
SSRI toxicity may increase by interaction with the following drugs:
• CNS depressants |
Adverse effects
General side effects include apathy, nausea or vomiting, drowsiness or somnolence, headache, sleep disturbances, dizziness, urinary retention, tremors, autonomic dysfunction such as orthostatic hypotension, increased or reduced sweating, and photosensitivity. These usually occur early during therapy and subside after a few weeks of use. Hyponatremia may occur in elderly patients on long-term SSRI therapy and presents with vague nonspecific symptoms commonly associated with old age. Dizziness is the most common symptom of abrupt discontinuation of SSRIs, and exacerbation by head movement indicates that it is vestibular in origin. Dizziness is likely due to dysfunction resulting from sudden decrease in serotonin in the vestibular nucleus complex, which has an abundance of serotonin receptors.
Sexual side effects. SSRIs can cause various types of sexual dysfunction, such as loss of orgasm, erectile dysfunction, and diminished libido. The underlying mechanisms of post-SSRI sexual-dysfunction syndrome are not clear. Symptoms include genital anesthesia, erectile dysfunction, and premature ejaculation, which should be differentiated from depression-related sexual dysfunction (30). Some sexual symptoms persist or begin after the discontinuation of SSRIs. The effect of SSRIs to slow down sexual stimulation may be used as treatment for premature ejaculation.
SSRI discontinuation syndrome. SSRIs may produce some dependence, resulting in withdrawal effects. However, SSRIs have little to no abuse potential. SSRI withdrawal syndrome is defined as the onset of a cluster of symptoms following the discontinuation of a SSRI that is not attributable to other causes including somatic symptoms such as dizziness, lethargy, and sleep disturbances, as well as to psychological symptoms such as anxiety/agitation, irritability, and poor concentration. Occurrence of discontinuation syndrome depends on the SSRI half-life, with more reports of symptoms in patients treated with paroxetine compared to other SSRIs, but the role of polymorphisms of serotonin genes remains to be determined (35).
Suicidal ideation. There is a black box warning on SSRIs and other antidepressant medications regarding the increased risk of suicidality in patients younger than 24 years of age. Various studies on SSRIs and suicide among adolescents are equivocal. There are also studies showing that higher rates of SSRI prescriptions are associated with lower rates of suicide in children, although the true nature of the relationship is unclear. In adults, SSRIs overall reduce the incidence of suicide; however, paradoxical adverse effects can still occur in susceptible patients, which may precipitate suicide. Based on data from observational studies, use of SSRIs may be associated with a reduced risk of suicide in adults with depression, and among adolescents, use of SSRIs may increase suicidality.
Management
Most of the general side effects are in the early adaption phase and disappear later. If the side effects persist, SSRIs should be discontinued and replaced with another medication. Patients on long-term SSRIs should be monitored carefully. One of the serious side effects is serotonin syndrome, and its management is described in a separate article.
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Contributors
All contributors' financial relationships have been reviewed and mitigated to ensure that this and every other article is free from commercial bias.
Author
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K K Jain MD†
Dr. Jain was a consultant in neurology and had no relevant financial relationships to disclose.
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