Prescribing selective serotonin reuptake inhibitors in older age

Apart from commercial reasons, two motivations have led to the introduction of SSRIs to replace the first and second generation antidepressants already available. One was the search for a more rational treatment, based on specific mechanisms, the other the development of effective treatments with fewer side effects, particularly for older patients, who have a greater sensitivity to cardio-vascular and central nervous system effects. The first has been frustrated up to a point, in that SSRIs and other single mechanism drugs do not appear to be more effective than the earliest relatively non-specific antidepressants. The second has been fulfilled, in that SSRIs generally are better tolerated in older patients and in overdose. However, there is a spectrum of other side effects that are particularly relevant in older age and that need attention when treating depression in this particular patient group.     

Depression impairs learning,whereas the selective serotonin reuptake inhibitor,paroxetine, impairs generalization in patients with major depressive disorder

To better understand how medication status and task demands affect cognition in major depressive disorder (MDD), we evaluated medication-naïve patients with MDD, medicated patients with MDD receiving the selective serotonin reuptake inhibitors (SSRI) paroxetine, and healthy controls. All three groups were administered a computer-based cognitive task with two phases, an initial phase in which a sequence is learned through reward-based feedback (which our prior studies suggest is striatal-dependent), followed by a generalization phase that involves a change in the context where learned rules are to be applied (which our prior studies suggest is hippocampal-region dependent). Medication-naïve MDD patients were slow to learn the initial sequence but were normal on subsequent generalization of that learning. In contrast, medicated patients learned the initial sequence normally, but were impaired at the generalization phase. We argue that these data suggest (i) an MDD-related impairment in striatal-dependent sequence learning which can be remediated by SSRIs and (ii) an SSRI-induced impairment in hippocampal-dependent generalization of past learning to novel contexts, not otherwise seen in the medication-naïve MDD group. Thus, SSRIs might have a beneficial effect on striatal function required for sequence learning, but a detrimental effect on the hippocampus and other medial temporal lobe structures is critical for generalization.     

The safety of selective serotonin reuptake inhibitors: hemostasis

The literature data of the reaction of haemostatic system to antidepressants from the group of selective inhibitors of serotonin reuptake are summarized. The development of haemorrhagic complications is analyzed. The risk/benefit ratio is estimated for the treatment of depression in patients with acute myocardial infarction and stroke. A differential approach to indication of antidepressants is substantiated for the treatment of comorbid depressive disorders in different types of somatic pathology.     

Antifungal properties of 5-hydroxytryptamine (serotonin) against Aspergillus spp. in vitro

This study shows that 5-hydroxytrypatmine (5-HT, serotonin) is fungicidal towards conidia and hyphae of clinical isolates of Aspergillus (A.) fumigatus, A. flavus and A. terreus. The minimal fungicidal concentrations for Aspergillus conidia and hyphae ranged between 14.68 to 117.5 mM and 29.37 to 235 mM during 24 and 48 h of incubation. Several serotonin receptor antagonists (5-HT2, 5-HT3) studied in vitro did not influence antifungal activity.     

Analysis of COMT gene (Val 158 Met polymorphism) in the clinical response to SSRIs in depressive patients of European origin

INTRODUCTION AND OBJECTIVES: There is convincing evidence of interactions between serotonergic and dopaminergic systems and it seems that an increase of dopamine concentration in the whole brain could be a limiting factor for the antidepressant like effect of antidepressants. The COMT gene might be a good candidate for explaining some aspects of the pharmacological response to SSRIs. METHODS: The aim of our study was to analyse the Val 158 Met functional polymorphism on COMT gene and clinical response (4 weeks) and clinical remission (6/8 and 12 weeks) in two samples of depressive patients (DSM-IV) treated with SSRIs of Italian and Spanish origin. Clinical outcome was measured using 21 items Hamilton scale, weekly in the Italian sample (along 6 weeks) and monthly in the Spanish one (along 12 weeks). RESULTS: No overall effect of genotype or genotypextime interaction was detected. However, we observed a genotypextime interaction on HDRS decrease for citalopram treatment (F((4.6,317.5)) = 3.38, P = 0.007) in the Spanish sample. No clear effect was observed in the Italian sample. The three samples were pooled in order to test if carrying the Met/Met genotype confers an increased risk for non-remission at 6-8 weeks. The results showed that Met/Met carriers have an odds ratio of 2.21 (95% CI [1.20-4.12]) for non-remission (chi(2) = 7.43, df = 2, P = 0.006). The Met/Met effect was not observed in response at 4th week (for all SSRI treatments) or in remission at 12th week (citalopram treatment). CONCLUSIONS: COMT gene could have a small and indirect effect of clinical response to SSRIs by slowing-down the antidepressant action along the follow-up, basically in citalopram treatment.     

The future of selective serotonin reuptake inhibitors (SSRIs) in psychiatric treatment

Selective serotonin reuptake inhibitors (SSRIs) are widely prescribed and widely regarded as a first-line treatment for depression. Yet, a growing body of evidence indicates that these agents are only moderately more effective than placebo in treating major depressive disorder. In recent years, it has been debated whether SSRIs offer any clinically meaningful advantage over placebos. As part of this debate, it has been argued that these agents are first-line treatments for some forms of depression but not necessarily for others. The present paper examines two hypotheses that are central to these issues. The first hypothesis is that SSRIs are more effective than placebo for some types of depression but not for others. The second is that SSRIs are more effective than psychotherapies for some types of depression than others. A review of the empirical literature reveals three main classifications of depression that are relevant to the first hypothesis: (a) more vs. less severe depression, (b) melancholic vs. non-melancholic depression, and (c) depression defined according to associated genetic factors (particularly the long vs. short allele of the serotonin transporter gene promoter). There is no strong or consistent support for (a) or (b). There is, however, emerging and consistent evidence for (c), and so the first hypothesis is tentatively supported, but only for (c). Most of the empirical evidence does not support the second hypothesis. Psychotherapies (cognitive-behavioral and interpersonal therapies) and SSRIs generally have equivalent efficacy, regardless of the severity of depression. The research literature also suggests a third hypothesis that remains to be evaluated: that SSRIs are more effective for treating anxiety disorders (and possibly other disorders) than they are for treating depression. If that hypothesis is supported by subsequent research, then the future of SSRIs may lie largely in the treatment of anxiety disorders, and in the management of particular subtypes of depression.     

健康汉族人细胞色素P450 2C19基因的检测

目的：了解广东地区汉族人细胞色素（P450 2C19）基因的分布情况。方法：应用PCR技术对正常人细胞色素（P450 2C19）基因进行扩增以SmaI进行限制性酶切图谱分析。结果：广东地区汉族人P450 2C19基因中，野生型纯合子（wt/wt）频率是0.4454；CYP2C19杂合子（mt/ml）频率是0.4091；CYP2C19突变型纯合子（ml/ml）频率是0.1455。P450 2C19基因ml频率是0.3500，基因wt频率是0.6500。结论：广东地区汉族人的细胞色素CYP2C19基因频率与其它地区人群相接近。     

Lines of evidence on the risks of suicide with selective serotonin reuptake inhibitors

BACKGROUND: There has been a long-standing controversy about the possibility that selective serotonin reuptake inhibitor (SSRI) antidepressants might induce suicidality in some patients. METHODS: Starting from the clinical studies that gave rise to this issue, this paper reviews an unselected cohort of randomized clinical trials (RCTs), a series of meta-analyses undertaken to investigate aspects of the problem, studies in recurrent brief depressive disorders, epidemiological studies and healthy volunteer studies using SSRIs to shed light on this issue. RESULTS: The original clinical studies produced evidence of a dose-dependent link, present on a challenge, dechallenge and rechallenge basis, between SSRIs and both agitation and suicidality. Meta-analyses of RCTs conducted around this time indicate that SSRIs may reduce suicidal ideation in some patients. These same RCTs, however, yield an excess of suicides and suicide attempts on active treatments compared with placebos. This excess also appears in the best-controlled epidemiological studies. Finally, healthy volunteer studies give indications that SSRIs may induce agitation and suicidality in some individuals. CONCLUSIONS: The data reviewed here, which indicate a possible doubling of the relative risk of both suicides and suicide attempts on SSRIs compared with older antidepressants or non-treatment, make it difficult to sustain a null hypothesis, i.e. that SSRIs do not cause problems in some individuals to whom they are given. Further studies or further access to data are indicated to establish the magnitude of any risk and the characteristics of patients who may be most at risk.     

Inhibitory effect of selective serotonin reuptake inhibitors on the vesicular monoamine transporter 2

The neuronal vesicular monoamine transporter (VMAT2) is the target molecule of action of some psychostimulants, such as methamphetamine and 3,4-methylenedioxymethamphetamine (MDMA). The present study examined the effect of antidepressants, such as selective serotonin reuptake inhibitors (SSRIs), on VMAT2 activity by measuring adenosine triphosphate-dependent [³H]dopamine uptake into synaptic vesicles prepared from rat striatum. SSRIs, fluoxetine, paroxetine, and fluvoxamine, inhibited vesicular [³H]dopamine uptake in vitro. The rank order of potency was reserpine ? fluoxetine, paroxetine > fluvoxamine, methamphetamine > MDMA. Moreover, kinetic analysis revealed that inhibition by reserpine, a typical VMAT2 inhibitor, was uncompetitive, decreasing maximum velocity and affinity for dopamine. Inhibition by fluoxetine was noncompetitive, only decreasing maximum velocity for dopamine. These results suggest that fluoxetine inhibited the activity of VMAT2 by a mechanism different from that of reserpine and did not directly interact with the active site of VMAT2.     

Genetic polymorphism in the serotonin transporter gene-linked polymorphic region and response to serotonin reuptake inhibitors in patients with premature ejaculation

OBJECTIVES:

Serotonin plays a central role in ejaculation and selective serotonin reuptake inhibitors have been successfully used to treat premature ejaculation. Here, we evaluated the relationship between a polymorphism in the serotonin transporter gene-linked polymorphic region (5-HTTLPR) and the response of patients with premature ejaculation to SSRI medication.

METHODS:

Sixty-nine premature ejaculation patients were treated with 20 mg/d paroxetine for three months. The Intravaginal Ejaculatory Latency Time and International Index of Erectile Function scores were compared with baseline values. The patients were scored as having responded to therapy when a 2-fold or greater increase was observed in Intravaginal Ejaculatory Latency Time compared with baseline values after three months. Three genotypes of 5-HTTLPR were studied: LL, LS and SS. The appropriateness of the allele frequencies in 5-HTTLPR were analyzed according to Hardy-Weinberg equilibrium using the χ²-test.

RESULTS:

The short (S) allele of 5-HTTLPR was significantly more frequent in responders than in nonresponders (p<0.05). Out of the 69 total PE patients, 41 patients (59%) responded to therapy. There was no significant difference in the International Index of Erectile Function score at the end of therapy between the responder and nonresponder groups. The frequencies of the L allele and S allele were 20% and 39%, respectively, in the responder group (p<0.05).

CONCLUSION:

We conclude that premature ejaculation patients with the SS genotype respond well to selective serotonin reuptake inhibitor therapy. Further studies with large patient groups are necessary to confirm this conclusion.     

CYP2C19 genetic polymorphism in the Vietnamese population

Abstract

Background: Genetic polymorphism of CYP2C19 has been shown to affect enzyme activity and thereby contribute to inter-individual variability in drug metabolism and response. The complete genetic variation of CYP2C19 in Vietnam still remains obscure even though data of common alleles in Vietnamese Kinh have been reported.

Aim: To establish the extent of CYP2C19 polymorphism in Vietnamese.

Subjects and methods: The promoter and all nine exons of CYP2C19 in 100 healthy unrelated Vietnamese Kinh subjects were sequenced. Additionally, the CYP2C19 variants, *2, *3 and *17 were analysed by RFLP-PCR in 275 subjects of four minor ethnic groups in Vietnam (Tay, Muong, H’Mong and Nung).

Results: In 100 Kinh subjects, the percentages of CYP2C19*1, CYP2C19*2, CYP2C19*3 and CYP2C19*17 alleles were 76%, 20.5%, 2.5% and 1%, respectively. Three novel variants in introns 2, 5 and 8 had no impact on mRNA splicing according to the Human Splicing Finder. The prevalence of CYP2C19*17 in Vietnamese Kinh was significantly lower compared with figures found in Western Asia and Europe, while CYP2C19*2 frequency was statistically higher than that in Western Asia and several countries in Europe. The frequency of CYP2C19*2 in Kinh was significantly lower than in the other four ethnic minorities.

Conclusion: These results provide information on CYP2C19 polymorphism in the Vietnamese population, which could be useful for optimising drug therapies and precision medicine studies.     

Combination Analysis in Genetic Polymorphisms of Drug-Metabolizing Enzymes CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A5 in the Japanese Population

The Cytochrome P450 is the major enzyme involved in drug metabolism. CYP enzymes are responsible for the metabolism of most clinically used drugs. Individual variability in CYP activity is one important factor that contributes to drug therapy failure. We have developed a new straightforward TaqMan PCR genotyping assay to investigate the prevalence of the most common allelic variants of polymorphic CYP enzymes CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A5 in the Japanese population. Moreover, we focused on the combination of each genotype for clinical treatment. The genotype analysis identified a total of 139 out of 483 genotype combinations of five genes in the 1,003 Japanese subjects. According to our results, most of subjects seemed to require dose modification during clinical treatment. In the near future, modifications should be considered based on the individual patient genotype of each treatment.     

中国汉族人细胞色素P450 2D6Ch基因特点研究

细胞色素Ｐ４５０２Ｄ６（ＣＹＰ２Ｄ６）基因的多态性是一种药物代谢的遗传变异，其表型分为强代谢型和弱代谢型。而且表型和基因的多态性存在明显的种族差异。本文利用ＰＣＲ－ＲＦＬＰ技术对１００名正常中国人ＣＹＰ２Ｄ６基因的Ｃｈ型突变特点做了分析，结果发现，在ＣＹＰ２Ｄ６基因的第１８８位点Ｃ→Ｔ的频率为０．５７，第４２６８位点Ｇ→Ｃ的频率为０．６６，而且Ｔ１８８／Ｔ１８８、Ｔ２９８８／Ｔ２９８８及Ｃ４２６８／Ｃ４２６８纯合子的比率分别为０．３２、０．０８和０．４２。与国外报道比较，发现中国人ＣＹＰ２Ｄ６基因的这两个位点的多态性分布规律与西方人有明显的不同。