Several Selective Serotonin Reuptake Inhibitors Research Articles

Molecular Biomarkers Predictive of Sertraline Treatment Response in Young Children With Autism Spectrum Disorder.

Sertraline is one among several selective serotonin reuptake inhibitors (SSRIs) that exhibited improvement of language development in Autism Spectrum Disorder (ASD); however, the molecular mechanism has not been elucidated. A double blind, randomized, 6-month, placebo-controlled, clinical trial of low-dose sertraline in children ages (3–6 years) with ASD was conducted at the UC Davis MIND Institute. It aimed at evaluating the efficacy and benefit with respect to early expressive language development and global clinical improvement. This study aimed to identify molecular biomarkers that might be key players in the serotonin pathway and might be predictive of a clinical response to sertraline. Fifty eight subjects with the diagnosis of ASD were randomized to sertraline or placebo. Eight subjects from the sertraline arm and five from the placebo arm discontinued from the study. Furthermore, four subjects did not have a successful blood draw. Hence, genotypes for 41 subjects (20 on placebo and 21 on sertraline) were determined for several genes involved in the serotonin pathway including the serotonin transporter-linked polymorphic region (5-HTTLPR), the tryptophan hydroxylase 2 (TPH2), and the Brain-Derived Neurotrophic Factor (BDNF). In addition, plasma levels of BDNF, Matrix metallopeptidase 9 (MMP-9) and a selected panel of cytokines were determined at baseline and post-treatment. Intent-to-treat analysis revealed several primary significant correlations between molecular changes and the Mullen Scales of Early Learning (MSEL) and Clinical Global Impression Scale – Improvement (CGI-I) of treatment and control groups but they were not significant after adjustment for multiple testing. Thus, sertraline showed no benefit for treatment of young children with ASD in language development or changes in molecular markers in this study. These results indicate that sertraline may not be beneficial for the treatment of children with ASD; however, further investigation of larger groups as well as longer term follow-up studies are warranted.

Hippocampal Endoplasmic Reticulum Stress: Novel Target in PTSD Pharmacotherapy?

Posttraumatic stress disorder (PTSD) is an anxiety disorder that occurred in individual who had experienced severe traumatic stresses. This disorder is accompanied by functional impairments in daily activities, comorbidities (such as depression) and increased risk of suicide. Some studies also demonstrate that PTSD is linked to structural and functional impairment of hippocampus. Hippocampal defect has been found in PTSD model, especially in single-prolonged stress (SPS)-induced animal model, with excessive or prolonged endoplasmic reticulum (ER) stress-induced neuronal apoptosis as a proposed mechanism. Unfortunately, this cellular event has not been studied and validated in humans suffering from PTSD. Two chaperones known as glucose-regulated protein 78 (GRP78) and sigma-1 receptor (Sig1R) have been demonstrated to exhibit central roles in mitigating the effects of severe ER stress on cell survival. Several selective serotonin-reuptake inhibitors (SSRIs), such as fluvoxamine and sertraline, are also found to be an agonist and antagonist of sigma-1 receptor (Sig1R) in animal brain cells, respectively. There is also link between antidepressant use and risk of suicidal ideation. Therefore, the authors propose that hippocampal ER stress may be involved in PTSD pathobiology. Pharmacodynamics of currently available therapeutic agents for PTSD and its comorbidities on hippocampal ER stress should be clearly elucidated to promote therapy optimization and drug development.

Serotonergic agents act on 5-HT3 receptors in the brain to block seizure-induced respiratory arrest in the DBA/1 mouse model of SUDEP.

Drugs that enhance the action of serotonin (5-hydroxytrypamine, 5-HT), including several selective serotonin reuptake inhibitors (SSRIs), reduce susceptibility to seizure-induced respiratory arrest (S-IRA) that leads to death in the DBA/1 mouse model of sudden unexpected death in epilepsy (SUDEP). However, it is not clear if specific 5-HT receptors are important in the action of these drugs and whether the brain is the major site of action of these agents in this SUDEP model. The current study examined the actions of agents that affect the 5-HT3 receptor subtype on S-IRA and whether intracerebroventricular (ICV) microinjection of an SSRI would reduce S-IRA susceptibility in DBA/1 mice. The data indicate that systemic administration of SR 57227, a 5-HT3 agonist, was effective in blocking S-IRA in doses that did not block seizures, and the S-IRA blocking effect of the SSRI, fluoxetine, was abolished by coadministration of a 5-HT3 antagonist, ondansetron. Intracerebroventricular administration of fluoxetine in the present study was also able to block S-IRA without blocking seizures. These findings suggest that 5-HT3 receptors play an important role in the block of S-IRA by serotonergic agents, such as SSRIs, which is consistent with the abnormal expression of 5-HT3 receptors in the brainstem of DBA mice observed previously. Taken together, these data indicate that systemically administered serotonergic agents act, at least, in part, in the brain, to reduce S-IRA susceptibility in DBA/1 mice and that 5-HT3 receptors may be important to this effect.

Does waterborne citalopram affect the aggressive and sexual behaviour of rainbow trout and guppy?

Citalopram is one of several selective serotonin reuptake inhibitors (SSRIs) commonly found in treated sewage effluents. Accordingly, there are concerns about possible adverse effects of SSRIs on aquatic organisms, particularly behavioural effects similar to those associated with SSRI use in humans. Rainbow trout fry and adult male guppies were therefore exposed to waterborne citalopram, ranging from environmentally relevant to high concentrations (1, 10, 100μg/L) for 3–7 days. Under these experimental conditions citalopram does not appear to cause significant effects on aggression in rainbow trout fry or on sexual behaviour in male guppies. This may be explained by a relatively low uptake of citalopram from water to fish.

Antidepressants and youth: Healing or harmful?

A series of drug innovations that began in 1987, including the introduction of several selective serotonin reuptake inhibitors (SSRIs), has led to a tremendous growth in the use of antidepressants in the United States. This growth, however, has been accompanied by a growing concern about the risks of prescribing antidepressants, particularly to children. Indeed, research linking the use of antidepressant drugs to an increased risk of suicidal behaviors in youth motivated the US Food and Drug Administration to direct antidepressant drug manufacturers to include warning labels about the potential dangers. This paper examines the relationship between antidepressants and suicide among youth in the USA. Using state-level data on youth suicides and age-specific prescriptions for antidepressants, we find no relationships between suicides for adolescents aged 15–19 and prescriptions for SSRIs/serotonin–norepinephrine reuptake inhibitors or tricyclic and tetracyclic antidepressants. In contrast, we find that newer generation antidepressants are associated with lower numbers of suicides for this age group. For younger children aged 10–14, we find no relationship with suicides for any type of antidepressant.

Why does milnacipran produce so few discontinuation syndromes following abrupt withdrawal?

Several selective serotonin reuptake inhibitors (SSRI), especially paroxetine, have been reported to produce a number of post-treatment emergent adverse events following abrupt withdrawal (Coupland et al 1996; Haddad 1997). More recently a SSRI-induced neonatal withdrawal syndrome has been described (Sanz et al 2005) in infants born of mothers treated with SSRI during pregnancy. In both of these situations, paroxetine has been associated with the greatest incidence (Warner et al 2006; Sanz et al 2005). Other SSRIs and the selective serotonin and noradrenaline reuptake inhibitor (SNRI) venlafaxine can, however also cause a withdrawal syndrome in patients (Trenque et al 2002). In contrast, milnacipran, another SNRI, has been reported to present a lower risk of withdrawal-induced adverse events (Vandel et al 2004). Furthermore the spectrum of the symptoms was different from that produced by paroxetine. In our clinic, a discontinuation syndrome is sometimes seen when SSRIs or SNRIs are discontinued suddenly, or when doses are missed or forgotten. In a total cohort of 2675 depressed patients, we identified 124 cases of antidepressant withdrawal syndrome. Sixty-three of the cases resulted from withdrawal from fluvoxamine (from a total of 1306 treated patients), 55 were withdrawn from paroxetine (from a total of 453 treated patients), while 6 were withdrawn from milnacipran (from a total of 916 treated patients). With paroxetine and fluvoxamine, respectively, the incidence of discontinuation syndrome was 18.4 times greater and 7.3 times greater than that found with milnacipran (Table 1). These differences were highly significant as determined by the χ2 test. These results are qualitatively similar to those obtained in a double-blind comparative study of milnacipran and paroxetine by Vandel et al (2004), who found an incidence of discontinuation syndrome of 13% with milnacipran and 32% with paroxetine following withdrawal after 6 weeks of treatment. Table1 Number and ratios of discontinuation syndrome with SSRIs and SNRI in our clinic Paroxetine has systematically been found to have the highest incidence of discontinuation syndrome (Warner et al 2006) while fluvoxamine has an incidence 10-fold lower and fluoxetine 100-fold lower (Westenberg and Sandner 2006). Paroxetine is the most potent inhibitor of the serotonin transporter (Sanchez and Hyttel 1999) and this potency may be a significant factor in the frequency of discontinuation syndromes for paroxetine in comparison with fluvoxamine (Westenberg and Sandner 2006) and milnacipran (Moret et al 1985). Furthermore, paroxetine is unique among the SSRI because its relatively high affinity for muscarinic receptors is similar to that of imipramine (Schatzberg et al 1997; Sanchez and Hyttel 1999). A cholinergic rebound, as observed on withdrawal of tricyclic antidepressants (Dilsaver et al 1987), could also partly explain the discontinuation syndrome paroxetine. Neither fluvoxamine nor milnacipran have any significant affinity for the muscarinic receptor (Moret et al 1985; Sanchez and Hyttel 1999). Pharmacokinetics are thought to play an important role in the incidence of withdrawal effect, with compounds with shorter half-lives having the greatest incidence of withdrawal effects. The apparent correlation between the occurrence of SSRI discontinuation syndrome and shorter drug half-lives has been highlighted (Schatzberg et al 1997). The half-life of paroxetine (21 h) may explain the relatively high incidence of discontinuation syndromes compared with fluoxetine which has a long half-life (parent compound 1–6 days, active metabolite 7–9 days). Pharmacokinetic factors, however, do not explain the low incidence of withdrawal effects with milnacipran, since the half-life of the SNRI (8 h) is shorter than that of paroxetine (Puozzo et al 1998). It is possible that low incidence of withdrawal effects with milnacipran may be related to its dual action on the reuptake of noradrenaline and serotonin compared with the selective effect of SSRI such as paroxetine on the reuptake of serotonin. It seems unlikely, however, that a simple action on the noradrenaline transporter is sufficient to explain the situation. Firstly, paroxetine is the SSRI with the highest affinity for the noradrenaline transporter (Sanchez and Hyttel 1999) and, secondly, the SNRI venlafaxine has an incidence almost as high as paroxetine (Trenque et al 2002). Although venlafaxine is considered to be a SNRI, it is, in fact, a preferential serotonin reuptake inhibitor and produces clinically relevant inhibition of noradrenaline reuptake only at high doses where serotonin reuptake is very extensively inhibited (Harvey et al 2000). A unique property of milnacipran which may be relevant is the fact that it inhibits both noradrenaline and serotonin reuptake with similar potency (Moret and Briley 1997). A recent study of changes in long-term potentiation following repeated treatment with milnacipran (Tachibana et al 2006) has shown that interactions between noradrenergic and serotonergic mechanisms play an important role in the modulation of synaptic plasticity. It is thus possible that the balance between serotonergic and noradrenergic neurotransmission may be essential in determining the nature and extent of withdrawal-related symptoms. Further preclinical and clinical studies are required to test this hypothesis.

Relative Antidepressant Efficacy of Venlafaxine and SSRIs: Sex-Age Interactions

To investigate whether differences in antidepressant efficacy are moderated by an interaction of age and gender. A pooled dataset from eight randomized, controlled trials of patients with major depressive disorder (MDD) was reanalyzed to compare remission rates following therapy with venlafaxine (n = 851), one of several selective serotonin reuptake inhibitors (SSRIs) (n = 748), or placebo (n = 446). Remission was defined as a final Hamilton Rating Scale for Depression (HAM-D) score < or =7. Pairwise comparisons were conducted using stepwise multiple logistic regression models with main effect and interaction terms for treatment, sex, and age (younger: <50; older: > or =50). Among older women, the impact of hormone replacement therapy (HRT) on remission rates also was examined. Remission rates on venlafaxine therapy were not affected by age, sex, or HRT use. Among women, but not men, there was a significant interaction reflecting poorer SSRI response in the older age group (Wald chi-square = 4.21, df = 1, p = 0.04); HRT appeared to eliminate this difference. Whereas the advantage in remission rates favoring venlafaxine was modest for men and younger women (6%-9%), the difference among older women not taking HRT was 23%. These findings provide further evidence that age, gender, and HRT moderate response to antidepressant medications.

A critical examination of the sensitivity of unidimensional subscales derived from the Hamilton Depression Rating Scale to antidepressant drug effects

Unidimensional subscales for assessment of major depression may be more sensitive to antidepressant drug effects than the Hamilton Depression Rating Scale (HAM-D). To further examine this possibility, we analyzed pooled data from eight comparable, well-controlled clinical trials of venlafaxine and compared such subscales and the 17-item HAM-D (HAM-D 17) based on effect size and number of patients required for 80% power. Symptoms of depression were assessed using the HAM-D among intent-to-treat patients (2045) randomly assigned to receive venlafaxine (immediate release, n=474; extended release, n=377), one of several selective serotonin reuptake inhibitors (SSRIs) ( n=748), or placebo ( n=446) for up to 8 weeks. With SSRIs or venlafaxine vs. placebo, subscales yielded effect sizes (0.328–0.528) 16 to 76% larger than the HAM-D 17 did (0.237 and 0.396, respectively), and required 31 to 64% fewer patients for 80% power. With venlafaxine vs. SSRIs, the subscales showed no advantage over the HAM-D 17; all devices yielded comparable, positive effect sizes (0.183–0.195). Final subscale scores significantly predicted (all P<0.05) whether patients met criteria for remission (eg, HAM-D 17 score of ⩽7). These findings suggest that unidimensional subscales are more sensitive to antidepressant drug effects than the HAM-D 17 is, but only in active agent/placebo comparisons. Our data further suggest the subscales can predict the presence of remission. Given these findings, prudent use of these subscales may be appropriate, cost-effective, and informative.

Three SSRIs Are Equally Effective

Primary care physicians must choose among several selective serotonin reuptake inhibitors (SSRIs) as first-line therapy for depression. In this

Maternal sertraline treatment and serotonin transport in breast-feeding mother-infant pairs.

Pharmacological treatment of postpartum depression is frequently complicated by the mother's desire to breast-feed. Although breast milk levels of several selective serotonin reuptake inhibitors (SSRIs) have been reported to be relatively low, a critical question is whether SSRI exposure during nursing results in clinically significant blockade of serotonin (5-HT) reuptake in infants. This study determined the degree of transporter blockade in infants exposed to sertraline through maternal breast milk. The extent of maternal and infant transporter blockade was assessed by measurement of platelet levels of 5-HT in 14 breast-feeding mother-infant pairs before and after 6-16 weeks of maternal treatment with sertraline for major depression with postpartum onset. Plasma sertraline and desmethylsertraline levels were obtained in 13 of these mothers and 11 of their infants. Marked declines in platelet 5-HT levels of 70%-96% were observed in mothers after sertraline treatment, 25-200 mg/day. In contrast, infants showed little or no change in platelet 5-HT levels after exposure through breast-feeding. Mean levels of maternal plasma sertraline and its major metabolite, desmethylsertraline, were 30.7 ng/ml and 45.3 ng/ml, respectively. Drug and drug metabolite concentrations in the infants were at or below the lower limit of quantitation. The data indicate that while mothers receiving clinical doses of sertraline experience substantial blockade of the platelet 5-HT transporter, platelet 5-HT uptake in nursing infants of treated mothers is unaltered. The observations suggest that mothers taking sertraline can breast-feed without appreciably affecting peripheral or central 5-HT transport in their infants.

O- and N-demethylation of Venlafaxine In Vitro by Human Liver Microsomes and by Microsomes from cDNA-Transfected Cells: Effect of Metabolic Inhibitors and SSRI Antidepressants

The biotransformation of venlafaxine (VF) into its two major metabolites, O-desmethylvenlafaxine (ODV) and N-desmethylvenlafaxine (NDV) was studied in vitro with human liver microsomes and with microsomes containing individual human cytochromes from cDNA-transfected human lymphoblastoid cells. VF was coincubated with selective cytochrome P450 (CYP) inhibitors and several selective serotonin reuptake inhibitors (SSRIs) to assess their inhibitory effect on VF metabolism. Formation rates for ODV incubated with human microsomes were consistent with Michaelis-Menten kinetics for a single-enzyme mediated reaction with substrate inhibition. Mean parameters determined by non-linear regression were: Vmax = 0.36 nmol/min/mg protein, Km = 41 μM, and Ks 22901 μM (Ks represents a constant which reflects the degree of substrate inhibition). Quinidine (QUI) was a potent inhibitor of ODV formation with a Ki of 0.04 μM, and paroxetine (PX) was the most potent SSRI at inhibiting ODV formation with a mean Ki value of 0.17 μM. Studies using expressed cytochromes showed that ODV was formed by CYP2C9, −2C19, and −2D6. CYP2D6 was dominant with the lowest Km, 23.2 μM, and highest intrinsic clearance (Vmax/Km ratio). No unique model was applicable to the formation of NDV for all four livers tested. Parameters determined by applying a single-enzyme model were Vmax = 2.14 nmol/min/mg protein, and Km = 2504 μM. Ketoconazole was a potent inhibitor of NDV production, although its inhibitory activity was not as great as observed with pure 3A substrates. NDV formation was also reduced by 42% by a polyclonal rabbit antibody against rat liver CYP3A1. Studies using expressed cytochromes showed that NDV was formed by CYP2C9, −2C19, and −3A4. The highest intrinsic clearance was attributable to CYP2C19 and the lowest to CYP3A4. However the high in vivo abundance of 3A isoforms will magnify the importance of this cytochrome. Fluvoxamine (FX), at a concentration of 20 μM, decreased NDV production by 46% consistent with the capacity of FX to inhibit CYP3A, 2C9, and 2C19. These results are consistent with previous studies that show CYP2D6 and −3A4 play important roles in the formation of ODV and NDV, respectively. In addition we have shown that several other CYPs have important roles in the biotransformation of VF.

Comparative behavioural toxicity of the selective serotonin reuptake inhibitors.

The psychopharmacological profiles of several selective serotonin reuptake inhibitors (SSRIs) were compared and their behavioural toxicity contrasted both to placebo and the tricyclic antidepressants dothiepin and amitriptyline. On measures of central nervous system arousal (critical flicker fusion), psychomotor speed (choice reaction time), skilled performance (compensatory tracking) and subjective ratings of sedation (line analogue rating scales), the tricyclic compounds clearly impaired performance and led to higher ratings of sedation. While the SSRIs were generally clear of these gross effects, there were quantifiable differences between the compounds, seen mainly as an increase in central nervous system arousal. It remains to be established whether these minor differences have any clinical relevance.

P16 Compression medullaire par un hematome revelant un deficit profond en facteur XI

The biotransformation of venlafaxine (VF) into its two major metabolites, O-desmethylvenlafaxine (ODV) and N-desmethylvenlafaxine (NDV) was studied in vitro with human liver microsomes and with microsomes containing individual human cytochromes from cDNA-transfected human lymphoblastoid cells. VF was coincubated with selective cytochrome P450 (CYP) inhibitors and several selective serotonin reuptake inhibitors (SSRIs) to assess their inhibitory effect on VF metabolism. Formation rates for ODV incubated with human microsomes were consistent with Michaelis-Menten kinetics for a single-enzyme mediated reaction with substrate inhibition. Mean parameters determined by non-linear regression were: Vmax = 0.36 nmol/min/mg protein, Km = 41 μM, and Ks 22901 μM (Ks represents a constant which reflects the degree of substrate inhibition). Quinidine (QUI) was a potent inhibitor of ODV formation with a Ki of 0.04 μM, and paroxetine (PX) was the most potent SSRI at inhibiting ODV formation with a mean Ki value of 0.17 μM. Studies using expressed cytochromes showed that ODV was formed by CYP2C9, −2C19, and −2D6. CYP2D6 was dominant with the lowest Km, 23.2 μM, and highest intrinsic clearance (Vmax/Km ratio). No unique model was applicable to the formation of NDV for all four livers tested. Parameters determined by applying a single-enzyme model were Vmax = 2.14 nmol/min/mg protein, and Km = 2504 μM. Ketoconazole was a potent inhibitor of NDV production, although its inhibitory activity was not as great as observed with pure 3A substrates. NDV formation was also reduced by 42% by a polyclonal rabbit antibody against rat liver CYP3A1. Studies using expressed cytochromes showed that NDV was formed by CYP2C9, −2C19, and −3A4. The highest intrinsic clearance was attributable to CYP2C19 and the lowest to CYP3A4. However the high in vivo abundance of 3A isoforms will magnify the importance of this cytochrome. Fluvoxamine (FX), at a concentration of 20 μM, decreased NDV production by 46% consistent with the capacity of FX to inhibit CYP3A, 2C9, and 2C19. These results are consistent with previous studies that show CYP2D6 and −3A4 play important roles in the formation of ODV and NDV, respectively. In addition we have shown that several other CYPs have important roles in the biotransformation of VF.