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PubMedDate not supplied

Potential vascular and bleeding complications of treatment with selective serotonin reuptake inhibitors.

Selective serotonin reuptake inhibitors (SSRIs) alter peripheral handling of serotonin, leading to potential side effects. Further, the majority of the body's serotonin is found outside the central nervous system. Peripheral serotonin is important in platelet aggregation and the modulation of vascular tone. SSRIs block platelet uptake and pulmonary endothelial metabolism of serotonin, and use of these agents may conceivably result in bleeding and vasospastic complications.

Endothelium↗

PubMed1999

Metabolic interactions of central nervous system medications and selective serotonin reuptake inhibitors.

Selective serotonin reuptake inhibitors (SSRIs) are prescribed alone and in combination with other psychotropic medications in the treatment of a variety of psychiatric disorders. Such combinations create the potential for pharmacokinetic interactions by affecting the activity of the cytochromes P450 (CYP450), drug metabolizing oxidative enzymes. SSRIs are not equivalent in their potential for interactions when combined with other central nervous system (CNS) medication. Generally citalopram and sertraline are characterized by weaker inhibition of CYP450 enzymes and, therefore, hold less potential for interaction than the other SSRIs. Paroxetine potently inhibits CYP2D6, which can result in increased neuroleptic serum concentrations, accompanied by increased CNS side-effects. Similarly, as a potent inhibitor of CYP2D6, fluoxetine can increase serum concentrations of neuroleptics and antidepressants and numerous case reports have documented concomitant adverse events. Fluoxetine also inhibits CYP3A and CYP2C19, increasing serum concentrations of some benzodiazepines. Fluvoxamine is a potent inhibitor of CYP1A2, a moderate inhibitor of CYP3A and a mild inhibitor of CYP2D6. Therefore, interactions with clozapine and benzodiazepines are evident.

Animals↗

PubMed2001

Polymorphism of the serotonin transporter: implications for the use of selective serotonin reuptake inhibitors.

Selective serotonin reuptake inhibitors (SSRIs) are used to treat a number of psychiatric disorders related to mood and anxiety, and variations in the serotonin transporter (5-HTT) gene may be involved in a number of these. A polymorphic site in the promoter region is associated with differences in 5-HTT gene expression. Studies suggest that the short allele of the 5-HTT promoter (5-HTTPR) site can adversely influence the antidepressant response to SSRIs, and is associated with anxiety-related traits, depression, and impulsive disorders such as alcohol abuse. Several studies do not replicate these findings; potential confounding factors include age, gender, and population stratification. Other 5-HTT polymorphisms also exist. For example, individuals with the short allele of a variable number of tandem repeats (VNTR) polymorphism, located in the second intron, may have reduced responsiveness to SSRIs, and the STin2.12 allele at this site has been associated with bipolar disorder. Findings both supporting and inconsistent with these conclusions are reviewed. The clinical effects of the polymorphisms may be associated with effects on platelets, neural 5-HTT levels, and indices of serotonergic function.

Alzheimer Disease↗

PubMed2006

A meta-analysis of clinical trials comparing milnacipran, a serotonin--norepinephrine reuptake inhibitor, with a selective serotonin reuptake inhibitor for the treatment of major depressive disorder.

CONTEXT: Over the past few years, a number of studies have emerged suggesting that the treatment of major depressive disorder (MDD) with antidepressants which enhance both noradrenergic as well as serotonergic neurotransmission may result in higher response or remission rates than treatment with antidepressants which selectively enhance serotonergic neurotransmission. OBJECTIVE: The objective of this paper was to compare response rates among patients with MDD treated with either milnacipran, an antidepressant thought to simultaneously enhance both noradrenergic and serotonergic neurotransmission, or a selective serotonin reuptake inhibitor (SSRI). DATA SOURCES: Medline/Pubmed were searched. No year of publication or language limits were used. STUDY SELECTION: Double-blind, randomized clinical trials comparing milnacipran with an SSRI for the treatment of MDD. DATA EXTRACTION: Data were extracted with the use of a pre-coded form. DATA SYNTHESIS: Analyses were performed comparing response rates between the two antidepressant agents. Data from 6 reports involving a total of 1082 outpatients with MDD were identified and combined using a random-effects model. Patients randomized to treatment with milnacipran were as likely to experience clinical response as patients randomized to treatment with an SSRI according to the MADRS (RR = 1.04, 95% CI: 0.88-1.23, p = 0.533) or the HDRS (RR = 1.06, 95% CI: 0.90-1.24, p = 0.456) for the random effects model. Simply pooling MADRS-based response rates between the two agents revealed a 58.9% response rate for milnacipran and a 58.3% response rate for the SSRIs. Similarly, HDRS-based response rates were 59.7% and 57.5%. There was also no difference in overall discontinuation rates (RR = 0.93; 95% CI: 0.76-1.14; p = 0.506), the rate of discontinuation due to adverse events (RR = 0.77; 95% CI: 0.55-1.1; p = 0.157), or the rate of discontinuation due to inefficacy (RR = 0.98; 95% CI: 0.7-1.38; p = 0.95) between the two groups. CONCLUSIONS: These results suggest that milnacipran and the SSRIs do not differ with respect to their overall efficacy in the treatment of MDD.

Antidepressive Agents↗

PubMed2001

[Selective serotonin reuptake inhibitor(SSRI)].

Selective serotonin reuptake inhibitors(SSRIs) are safe antidepressants and now widely used for the treatment of depression. Although there are five SSRIs(citalopram, fluoxetine, fluvoxamine, paroxetine, sertraline) available in the world, only two(fluvoxamine and paroxetine) are approved in Japan. SSRIs are also used for the treatment of obsessive-compulsive disorders, panic disorders, eating disorders and so on. Major side effects of SSRIs are gastrointestinal symptoms(especially nausea), neurological symptoms (particularly headache and tremor) and psychiatric symptoms(especially anxiety). While therapeutic effects of SSRIs seem to be related to desensitization of somatodendritic serotonin 1A autoreceptors in the raphe nuclei, other neurotransmitters and intracellular mechanisms may be also involved.

Animals↗

PubMed1992

Potential indications for the selective serotonin reuptake inhibitors.

The selective serotonin reuptake inhibitors (SSRIs) include fluoxetine, fluvoxamine, citalopram, paroxetine and sertraline. These medications may be effective for a variety of indications. The literature clearly supports their efficacy in some of these conditions in major depression. Data concerning their use in other areas is clearly preliminary but promising. These include reports of treatment of obsessive-compulsive disorder, atypical depression, panic disorder, premenstrual tension, eating disorders, substance use disorders, chronic pain, dementia, and personality disorders with aggressive or impulsive features. The variety of clinical uses for the SSRIs may compel re-examination of traditional diagnostic categories and theories of how antidepressants work.

Depressive Disorder↗

PubMed2006

Night sweats and elevated follicle-stimulating hormone levels while taking selective serotonin reuptake inhibitors.

BACKGROUND: Selective serotonin reuptake inhibitors (SSRIs) are commonly prescribed to women with depression and anxiety disorders. Although night sweats are a reported adverse effect, some women have relief of vasomotor symptoms during perimenopausal period while taking them. The relationships between SSRIs, thermoregulation, gonadotropins, and estrogen and their connection to fertility remain unclear. CASE: A reproductive-aged woman, seeking treatment for infertility, experienced night sweats and elevated follicle-stimulating hormone levels while taking SSRIs for treatment of depression. CONCLUSION: Many women of reproductive age are taking SSRIs, but the affect of SSRIs on normal reproductive function is unknown and further research in this area is needed.

Adult↗

PubMedDate not supplied

Treatment of severe depression with the selective serotonin reuptake inhibitors.

The selective serotonin reuptake inhibitors (SSRIs) are recognized as effective as and better tolerated than older antidepressant therapies and have become the drugs of choice in the treatment of mild to moderate depression. However, there is a clinical impression that the SSRIs are less effective than older therapies in the severely depressed patient. A limited number of trials have attempted to address this issue. This review assesses 16 controlled studies of SSRIs in severe depression. The findings from a majority of studies found the SSRIs to be superior to placebo and as effective as but better tolerated than the tricyclic antidepressants (TCAs) in severely depressed patients. Although future studies are needed to corroborate and elaborate on these data, studies still support the use of SSRIs in this patient population.

Antidepressive Agents, Tricyclic↗

PubMed2001

Neonatal withdrawal syndrome after in utero exposure to selective serotonin reuptake inhibitors.

UNLABELLED: Selective serotonin reuptake inhibitors (SSRIs) are a new group of antidepressants used in mild to moderate cases of depression. In studies evaluating the safety of SSRIs during pregnancy, no increase in major anomalies has been reported. This might have led to increasing off-label prescription of SSRIs to pregnant women. Neonatal withdrawal syndrome commonly occurs in infants exposed during the third trimester to drugs known to cause addiction. We report five cases of neonatal withdrawal syndrome after third trimester in utero SSRI exposure. In three cases the mother used paroxetine in doses from 10 to 40 mg, one mother used citalopram 30 mg, and one mother fluoxetine 20 mg. Withdrawal symptoms occurred within few days after birth and lasted up to one month after birth. Four of the infants needed treatment with chlorpromazine. Symptoms were irritability, constant crying, shivering, increased tonus, eating and sleeping difficulties and convulsions. CONCLUSION: Neonatal withdrawal syndrome can occur after third trimester in utero SSRI exposure. Further research should focus on whether it is safe to use SSRIs during the last trimester. All neonates exposed to SSRIs during the last trimester should be followed-up closely for withdrawal symptoms after birth.

Antidepressive Agents↗

PubMed2000

Is therapeutic drug monitoring a case for optimizing clinical outcome and avoiding interactions of the selective serotonin reuptake inhibitors?

The selective serotonin reuptake inhibitors (SSRIs) comprise citalopram, fluoxetine, fluvoxamine, paroxetine, and sertraline and they differ from each other in chemical structure, by pharmacokinetic properties and, most importantly, with respect to enzyme-specific metabolism and interactions. Citalopram is administered as a racemic mixture. The drug is oxidated to desmethylcitalopram in the liver, partially by CYP2C19 and partially by CYP3A4. Fluoxetine is administered as a racemate of R- and S-fluoxetine. Both R- and S-fluoxetine are metabolized by CYP2D6 to the active metabolites R- and S-norfluoxetine. Fluvoxamine is metabolized to inactive metabolites by CYP1A2 and CYP2D6. Paroxetine is metabolized to inactive metabolites partially by CYP2D6, and accordingly the metabolism of paroxetine is dependent on the genetic polymorphism of CYP2D6. Sertraline is metabolized to desmethylsertraline, probably by CYP3A4. Several analytical methods have been described for all SSRIs. Most assays are based on separation by high-performance liquid chromatography or gas chromatography. Stereoselective methods for the analysis of racemic citalopram and fluoxetine have been published. The SSRIs are generally well tolerated and their therapeutic indices are large. In several studies there has not been found a clear relationship between clinical efficacy and plasma concentration, nor any threshold that defines toxic concentrations. The available data do not suggest that any benefit be obtained from routine monitoring of SSRI plasma levels. Therefore therapeutic drug monitoring (TDM) of the SSRIs may be useful mainly in situations where poor compliance is suspected and when therapeutic failure or toxic events are experienced at clinically relevant dosages. Further, in special populations, such as in elderly patients, poor metabolizers of sparteine (CYP2D6) or mephenytoin (CYP2C19), and patients with liver impairment, the measurement of plasma concentrations may be useful.

Biotransformation↗

PubMed2000

Pediatrician and family physician prescription of selective serotonin reuptake inhibitors.

OBJECTIVES: Selective serotonin reuptake inhibitor (SSRI) prescriptions for children and adolescents have increased greatly in recent years despite a paucity of demonstrated safety and efficacy data and a lack of clear guidelines for use. Our study sought to describe family physician and pediatrician SSRI prescribing patterns for children and adolescents, identify influences on SSRI prescription variations, and describe the use of SSRI within the overall management of depression and other mental disorders in primary care. DESIGN: A survey was mailed to all 596 active North Carolina general pediatricians and a random sample of 557 family physicians in primary care practice. Family physicians who did not see children in their practice were excluded. The survey instrument consisted of a 4-page questionnaire. Survey items included physician demographics, practice characteristics, general management, volume of pediatric patients with depressive symptoms, prescription of SSRIs for depression and other diagnoses, and potential influences on SSRI prescribing practices. The main outcomes were self-reported physician prescription of SSRIs for children and adolescents. Results were analyzed using chi(2) comparisons and logistic regression. RESULTS: The overall response rate was 66% (55% family physicians and 76% pediatricians). Of the physicians, 72% had prescribed an SSRI for a child or adolescent. Depression was the most common reason for prescribing an SSRI; over two thirds of respondents had prescribed an SSRI for depression in a child 18 years of age or younger. Over half of the physicians reported they had prescribed an SSRI for a diagnosis other than depression in a child 18 years of age or younger. Attention-deficit/hyperactivity disorder was the most frequent use cited other than depression, followed by obsessive-compulsive disorder, aggression, eating disorders, and enuresis. Primary care physicians prescribed SSRIs for adolescents more commonly than for younger children. Only 6% of the respondents had ever prescribed an SSRI for a child younger than 6 years of age. In terms of SSRI prescriptions written for depression in the last 6 months, 32% of the physicians had recently prescribed SSRIs for adolescent patients and 6% for patients younger than 12 years of age. Family physicians were more likely than pediatricians to have recently prescribed SSRIs for adolescent patients (41% vs 26%), but there was no difference in recent SSRI prescriptions for children <12 years of age by physician specialty (4% vs 6%). Prescription of SSRIs was not associated with decreased use of counseling for treatment of depression, but prescription of SSRIs was associated with decreased use of referrals (63% vs 74%). There was no difference in the use of counseling between family physicians and pediatricians (61% vs 59%). However, pediatricians were more likely to use referrals in their usual approach to depression (77% vs 48%) compared with family physicians. More family physicians had prescribed SSRIs for pediatric patients compared with pediatricians (91% vs 58%), and more family physicians had prescribed SSRIs in combination with other psychotropic medications (54% vs 31%). For the majority of respondents, SSRI prescriptions constituted most of the medications used to treat childhood depression (75% of family physicians vs 61% of pediatricians). Family physicians were more likely to report a belief in the safety (63% vs 48%) and effectiveness (40% vs 32%) of SSRIs. Only 8% of physicians reported adequate training in the treatment of childhood depression and just 16% were comfortable with the treatment of depression. There were no specialty differences in training for the treatment of childhood depression; however, more family physicians than pediatricians agreed that they were comfortable with the management of childhood depression (22% vs 11%). (ABSTRACT TRUNCATED)

Adolescent↗

PubMed1997

Drug interactions of clinical significance with selective serotonin reuptake inhibitors.

The selective serotonin (5-hydroxytryptamine; 5-HT) reuptake inhibitors (SSRIs) have internationally become the accepted 'benchmark' class of antidepressants. It has become clear, however, that there are a number of clinically significant interactions between SSRIs and other medications. The most frequently described interactions are pharmacokinetic, which are far more prevalent than pharmacodynamic interactions. This article details those medications that may interact significantly with the SSRIs, and provides clinical guidelines for minimising the likelihood of such complications. The most common pharmacokinetic interactions are caused by an inhibitory effect of the SSRIs on the hepatic cytochrome P450 (CYP) metabolic system. The SSRIs differ in their potency in inhibiting a number of important CYP isoenzymes (CYP1A2, CYP2C9/10, CYP2C19, CYP2D6 and CYP3A3/4). The major outcome of concern in relation to pharmacodynamic interactions is the development of the 'serotonin syndrome'. While combination of the SSRIs with the irreversible monoamine oxidase inhibitors is the most recognised cause of this syndrome, concurrent administration with moclobemide, tryptophan or selegiline (deprenyl) may also lead to a similar outcome.

Antidepressive Agents, Tricyclic↗

PubMed2006

Cutaneous effects of the most commonly used antidepressant medication, the selective serotonin reuptake inhibitors.

Selective seritonin reuptake inhibitors (SSRIs) are widely used antidepressants that are often safer than alternatives, but may produce a variety of cutaneous reactions including spontaneous bruising, pruritus, urticaria, angioedema, erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, erythema nodosum, alopecia, hypertrichosis, leukocytoclastic vasculitis, and an acneiform eruption. We review this category of medications and its side effects. Many cutaneous alterations seen in association with SSRIs can be serious, some even life threatening. Because there appears to be cross-reactions between SSRIs, even though they have different chemical structures, it is advisable to use another family of antidepressants if an SSRI is linked with a serious skin eruption.

Antidepressive Agents↗

PubMed1999

Selective serotonin reuptake inhibitors for migraine prophylaxis.

The objective of this study was to assess the efficacy of sertraline in migraine prophylaxis. Other selective serotonin reuptake inhibitors have been studied for migraine prophylaxis, but this is the first report with sertraline. Twenty-seven subjects were enrolled and baseline assessment of migraine frequency and severity were measured over a 4-week period. Subjects were then randomized to receive placebo or sertraline in a double-blind fashion with headache frequency and severity measured over an 8-week period. Subjects completed a daily diary reporting the occurrence, severity, and degree of impairment associated with migraine. The headache index, a composite measure of migraine frequency and severity, scores did not significantly improve between assessments at baseline (20.8 +/- 14.88), 8 weeks (17.6 +/- 12.27), and 12 weeks (16.7 +/- 6.38) in the treatment group (n=6) (P=0.956). This finding is compared to other studies with the serotonin selective reuptake inhibitors, fluoxetine, fluvoxamine, and paroxetine. The authors believe that the selective serotonin reuptake inhibitors are not as effective as conventional migraine prophylaxis medications such as beta-blockers, tricyclic antidepressants, or divalproex sodium, but that in patients with comorbid depression who have failed conventional therapy selective serotonin reuptake inhibitors may be effective.

Adult↗

PubMed2001

[Behavioral and neurochemical study on the mechanism of the anxiolytic effect of a selective serotonin reuptake inhibitor, a selective serotonin1A agonist and lithium carbonate].

The authors investigated the effects of citalopram [selective serotonin (5-HT) reuptake inhibitor; SSRI] and MKC-242 (a selective 5-HT1A agonist) following treatment with subchronic lithium (p.o., 1 week) on the expression of conditioned freezing, an index of anxiety, and on extracellular 5-HT concentrations in the medial prefrontal cortex (mPFC). In conditioned fear stress experiments, acute administration of citalopram (s.c.) reduced freezing significantly at a high dose (30 mg/kg), while showing no effect at lower doses (3 and 10 mg/kg). Acute administration of MKC-242 (s.c.; 0.1-10 mg/kg) dose-dependently reduced freezing. Subchronic lithium treatment (1 week; 0.05 or 0.2% lithium carbonate in diet; p.o.) showed no effect on freezing behavior. Acute treatment with both citalopram (3 and 30 mg/kg) and MKC-242 (1 mg/kg) after subchronic treatment with high, but not low, concentrations of lithium (1 week) reduced freezing markedly and significantly, as compared with either drug alone. In brain microdialysis experiments, acute treatment with citalopram showed significant increases in the extracellular 5-HT concentrations in a dose-dependent manner. Subchronic lithium group showed significantly higher basal levels of extracellular 5-HT, compared with normal diet controls. Acute citalopram (3 and 30 mg/kg) treatment with subchronic lithium treatment showed significant increases in the extracellular 5-HT concentrations, compared with citalopram treatment alone. Subchronic lithium did not cause decreases in extracellular 5-HT after presynaptic stimulation of 5-HT1A receptors by MKC-242. These results suggest that subchronic lithium treatment enhanced the anxiolytic-like effects of these serotonergic drugs by facilitating central 5-HT neurotransmission at clinically therapeutic plasma lithium levels. It is hypothesized that subchronic lithium treatment gives an additive effect to the treatment with citalopram (3 and 30 mg/kg) by increasing the extracellular 5-HT concentrations in the mPFC, and that subchronic lithium treatment enhances the anxiolytic effect of MKC-242 by increasing sensitivity of postsynaptic 5-HT1A receptors.

Animals↗

PubMed1998

Tricyclic antidepressant and selective serotonin reuptake inhibitors antidepressant selection and health care costs in the naturalistic setting: a multivariate analysis.

BACKGROUND: Providers and payers have an interest in the total health care costs following the initiation of antidepressant treatment in the real world of clinical practice. Analyses of these costs can help evaluate the economic consequences of patient management decisions associated with initial antidepressant selection. OBJECTIVE: The purpose of this study was to assess the 1-year total direct health care costs for patients initiating therapy with one of the available tricyclic antidepressants (TCAs) or one of the three most often prescribed selective serotonin reuptake inhibitors (SSRIs) - paroxetine, sertraline, or fluoxetine. METHOD: A two-stage multivariate econometric model and data from fee-for-service private insurance claims between 1990 and 1994 were used to estimate the total direct health care costs following initial antidepressant drug selection for 2693 patients with a 'new' episode of antidepressant treatment. After controlling for both observed and unobserved characteristics, the 1-year total direct health care costs were found to be (1) statistically significantly lower for patients initiating therapy on fluoxetine than for patients initiating therapy on a TCA; (2) statistically significantly lower for patients who initiated therapy on fluoxetine than for patients initiating therapy on sertraline. CONCLUSIONS: Broadly considered, the findings in this study suggest that total direct health care costs differ across initial antidepressant selection after controlling for both observed and unobserved characteristics.

1-Naphthylamine↗

PubMed1998

Mechanism of action of serotonin selective reuptake inhibitors. Serotonin receptors and pathways mediate therapeutic effects and side effects.

Serotonin selective reuptake inhibitors (SSRIs) are currently among the most frequently prescribed therapeutic agents in all of medicine. Their therapeutic actions are diverse, ranging from efficacy in depression to obsessive-compulsive disorder, panic disorder, bulimia and other conditions as well. The plethora of biological substrates, receptors and pathways for serotonin are candidates to mediate not only the therapeutic actions of SSRIs, but also their side effects. Specifically, the immediate actions of SSRIs are mostly side effects, and may be mediated by the initiating actions of SSRIs, namely negative allosteric modulation of the serotonin transporter. A leading hypothesis to explain these immediate side effects is that serotonin is increased at specific serotonin receptor subtypes in discrete regions of the body where the relevant physiologic processes are regulated. Desensitization of post-synaptic receptors in these same discrete brain regions may explain the development of tolerance to these same side effects. The explanation for therapeutic effects characteristic of SSRIs may be found in delayed neurochemical adaptations. A leading hypothesis for this action is desensitization of somatodendritic serotonin 1A autoreceptors in the midbrain raphe. The hypothesis to explain why SSRIs have such diverse therapeutic actions is that somatodendritic 5HT1A autoreceptor desensitization increases serotonin in those critical brain regions and at those key serotonin receptor subtype(s) which may mediate the pathophysiologies of the various disorders. Understanding the topography of serotonin receptor subtypes in discrete anatomical pathways may enhance our understanding of both the therapeutic actions and side effects of these important pharmaceutical agents.

Autoreceptors↗

PubMed2004

Time course of the effects of the serotonin-selective reuptake inhibitor sertraline on central and peripheral serotonin neurochemistry in the rhesus monkey.

RATIONALE: Fundamental questions remain regarding the actions of the selective serotonin reuptake inhibitors (SSRIs). OBJECTIVES: To examine the time course of central and peripheral neurochemical effects of sertraline (SER) in non-human primates. METHODS: SER (20 mg/kg, p.o.) or placebo were administered daily for 4 weeks to two groups of six young adult male rhesus monkeys. Both groups received placebo during a 3-week baseline lead-in period and for 6 weeks after discontinuation. Blood and cisternal cerebrospinal fluid (cCSF) samples were obtained on days -21, -14, -7, 0, +3, +7, +14, +21, +28, +35 and +70. RESULTS: In animals receiving SER, mean (+/-SD) levels of cCSF serotonin (5-HT) increased from 38.6+/-9.0 pg/ml at baseline to 128+/-46.4 pg/ml during treatment (paired t=4.17, P=0.014). Concentrations of cCSF 5-HT were 290% of baseline on day 0 (+3 h), ranged from 260% to 436% of baseline during treatment, and returned to baseline 7 days after discontinuation. Levels of cCSF 5-hydroxyindoleacetic acid declined to 51+/-2.0% of baseline by day +3 and remained at similarly reduced levels during treatment. Plasma drug levels and decrements in platelet 5-HT were similar to those seen in patients. CONCLUSIONS: SER rapidly and substantially increases cCSF levels of 5-HT in primates, the extent of elevation is relatively constant during prolonged administration, and values return to baseline shortly after discontinuation. The results suggest that response latency for SSRIs in depression is not due to gradually increasing brain extracellular fluid 5-HT levels and tend not to support theories that posit SSRI response latency as being due to autoreceptor desensitization, transporter downregulation, or drug accumulation.

Animals↗