Effectiveness of paroxetine in the treatment of obsessive-compulsive disorders

Clomipramine ushered in a new age of pharmacotherapy for obsessive-compulsive disorders, and it also facilitated our understanding of the biological aspects of obsessive-compulsive disorder, focusing on the serotonergic systems. The introduction of selective serotonin reuptake inhibitors has led to great progress in the pharmacological study of obsessive-compulsive disorder based on the serotonin hypothesis. Currently, selective serotonin reuptake inhibitors are positioned as a first-line drug of obsessive-compulsive disorder pharmacotherapy in the various guidelines and algorithms. Among six different selective serotonin reuptake inhibitors (paroxetine, sertraline, fluoxetine, fluvoxamine, citalopram, escitalopram) that are available worldwide, paroxetine has the broadest treatment spectrum and promises great benefits not only for obsessive-compulsive disorder patients, but also for those with comorbid depression and/or various kinds of anxiety disorders. This paper presents several clinical trials of paroxetine carried out, and discusses and reviews the therapeutic strategies for obsessive-compulsive disorder.     

Pharmacotherapy for major depression in children and adolescents

Major depression is a serious illness in children which adversely effects their social, academic, and emotional development. It is essential to identify safe and effective medication for the treatment of this disorder in youths. Only some selective serotonin reuptake inhibitors (citalopram, fluoxetine, sertraline) have demonstrated superiority to placebo on primary outcome measures in acute controlled treatment trials. This article will review acute efficacy studies as well as long-term studies of antidepressants for the treatment of childhood depression. Treatment recommendations are discussed and the issue of suicidality and antidepressants are addressed.     

Pharmacokinetics of SSRI antidepressants: half-life and clinical applicability

The selective serotonin reuptake inhibitors (SSRIs) antidepressants are at present time the most useful for the treatment of depression. SSRIs exhibit differences in potency of inhibiting serotonin reuptake, although the differences do not correlate with clinical efficacy. There are substantial pharmacokinetic differences among the five SSRIs, fluvoxamine, fluoxetine, paroxetine, sertraline and citalopram. Optimum use of these drugs requires a working knowledge of these differences. Among these pharmacokinetic parameters, half-life and metabolism pathways are the most relevant. There are substantial differences in term of their half-life between fluoxetine and others SSRIs. The half-life of fluoxetine and its active metabolite norfluoxetine is respectively 2 to 4 days and 7 to 15 days, more extended than other SSRIs (approximately 1 day). The extended half-life of fluoxetine and its active metabolite may be an advantage in the poorly compliant patient and may offer a potential safety advantage over shorter-acting SSRIs, with respect to abrupt discontinuation of therapy. Conversely, this long half-life needs a long period of wash-out (5 weeks) before introducing other drugs (MAOIs, sumatriptan) which can interact with serotonin function and can lead to the serotoninergic syndrome. SSRIs are potent inhibitors of the hepatic isoenzyme P450-2D6 and would be expected to have effects on the clearance of drugs metabolized by this enzyme. Paroxetine is the most potent inhibitor, followed by fluoxetine, sertraline, citalopram and fluvoxamine. The metabolite elimination of citalopram, paroxetine and fluvoxamine is delayed by renal disease and dosages should be lowered in elderly patients. Conversely the pharmacokinetic of fluoxetine and sertraline are not affected by either age or renal impairment and, for fluoxetine, by obesity.     

Sertraline-induced hyperglycemia: case report

Empirical studies with humans suggest that selective serotonin reuptake inhibitors (SSRIs) may, through increases in serotonergic activity, increase insulin secretion, increase insulin sensitivity, and lower serum glucose levels. Indeed, the potentially beneficial effects of SSRI treatment in diabetics are documented. However, we describe the case of a female, with diet-controlled, type 2 diabetes, whose glucose levels increased with exposure to sertraline.     

Pharmacotherapy in depressed children and adolescents

In children and adolescents, antidepressants are used in the treatment of depressive symptoms and several other psychiatric conditions. In the treatment of mild and moderate depressive symptoms, non-pharmacological approaches such as psychotherapy play a major role, a severe symptomatology may demand a combination with antidepressants. As first-choice medication for the treatment of juvenile depression, the selective serotonin reuptake inhibitor (SSRI) fluoxetine is recommended, due to its efficacy and approval. As second-choice antidepressants the SSRIs sertraline, escitalopram and citalopram might be used. Other antidepressants - such as tricyclic antidepressants, α(2)-adrenoceptor antagonists, selective noradrenalin reuptake inhibitors (SNRI) - may be alternatively used, but not as first- or second-choice medications. In the case of "off-label" use, patients and parents have to be carefully informed prior to the start of medication, after a thorough risk-benefit analysis. In the following overview we address a general framework, therapeutic strategies and the issues of antidepressant pharmacotherapy for the treatment of unipolar depression in childhood and adolescence.     

Pharmacological treatment of adolescent major depression

Antidepressant agents are widely prescribed for adolescents, although specific data regarding their efficacy in this age range are limited. The aims of the present article are to review research findings regarding the use of antidepressant drugs for adolescent depression and to discuss the main results in light of our clinical experience. Only 13 controlled trials on the use of antidepressant drugs for adolescent major depression are available in the literature. Six studies evaluated the efficacy of tricyclic antidepressants, yet they only included 196 adolescents altogether. Seven studies, including a total of 1,403 patients, evaluated the efficacy of three specific serotonin reuptake inhibitors: fluoxetine, paroxetine, and sertraline. Based on published data, serotonin reuptake inhibitors appear to be the first-line psychopharmacologic treatment for adolescent depression, as three compounds (fluoxetine, paroxetine, and sertraline) appeared to be effective in this indication. Conversely, all published studies failed to demonstrate that the tricyclic antidepressants were superior to placebo. Several questions remain open and are discussed: How should we use available scientific data in clinical practice? Are there nonspecific factors implicated in treatment response? Is there a serotonin hypothesis for juvenile depression? What are the priorities for future research?     

Second-generation SSRIs: human monoamine transporter binding profile of escitalopram and R-fluoxetine.

BACKGROUND: Single isomers of the selective serotonin reuptake inhibitors citalopram (escitalopram, S-citalopram) and fluoxetine (R-fluoxetine) are currently under development for the treatment of depression and other psychiatric disorders. Previous studies conducted in laboratory animals have revealed that the biological effects on serotonin reuptake for citalopram reside in the S enantiomer. In contrast, both enantiomers of fluoxetine contribute to its biological activity. METHODS: In the present study, the potency and selectivity of escitalopram, R-fluoxetine, and all of the other currently available selective serotonin reuptake inhibitors were compared for binding affinity at the human serotonin, norepinephrine, and dopamine transporters and several select neurotransmitter receptors using radioligand binding assays. RESULTS: Both escitalopram and R-fluoxetine were potent inhibitors of the serotonin transporter (K(i) = 1.1 and 1.4 nmol/L, respectively). Escitalopram was the most serotonin transporter-selective compound tested and was approximately 30-fold more potent than R-citalopram. CONCLUSIONS: As noted previously, paroxetine and sertraline possess moderate affinity (<50 nmol/L) for the human norepinephrine transporter and dopamine transporter, respectively. R-Fluoxetine, unlike the other selective serotonin reuptake inhibitors, possesses moderate affinity (K(i) = 64 nmol/L) for the serotonin 2C receptor. Potential clinical correlates of these unique attributes of escitalopram and R-fluoxetine are discussed.     

SSRI efficacy-finding the right dose

The selective serotonin reuptake inhibitors (SSRIs) are a class of effective, well-tolerated antidepressants. They have a number of benefits compared with the tricyclic antidepressants (TCAs) including improved safety in overdose, reduced side-effect burden, and uncomplicated dosing regimens. To avoid the potential for troublesome side effects with TCAs, doses should be gradually increased over several weeks. Dose titration can be associated with several drawbacks such as patients discontinuing therapy due to a prolonged time to therapeutic response, additional visits to a prescribing healthcare provider, or additional hospitalizations. In contrast, the SSRIs typically do not require dose titration since many patients find the initial dose effective. The ability to prescribe an initial optimum therapeutic dose while avoiding dose-related side effects is important in the treatment of major depression. With this in mind, the authors consider the recommended dose ranges for the five SSRIs: citalopram, fluoxetine, fluvoxamine, paroxetine, and sertraline.     

近5年儿童青少年精神科住院患者抗抑郁药临床使用情况分析

目的:调查儿童青少年患者抗抑郁药使用情况。方法:回顾性调查2010年7月至2015年6月期间住院、年龄≤18岁患者出院当日使用抗抑郁药的情况。结果:508例患者使用抗抑郁药治疗,使用频率最高的前5位抗抑郁药分别为舍曲林、艾司西酞普兰、文拉法辛、氟伏沙明、西酞普兰;在双相情感障碍、通常起病于童年和青少年的情绪和行为问题、抑郁发作、精神分裂症、精神发育迟滞伴发精神障碍5种疾病中均以使用此5种药物为主,其中舍曲林使用率最高。与儿童组(≤13岁)相比,青少年组(13岁)舍曲林(t=3.54,P0.001)、氟伏沙明(t=3.09,P=0.003)、文拉法辛(t=2.71,P=0.008)的剂量显著增加,差异有统计学意义;艾司西酞普兰(t=1.67,P=0.099)、西酞普兰(t=0.82,P=0.42)剂量两组差异无统计学意义。结论:儿童青少年精神疾病患者抗抑郁药以舍曲林为主的SSRIs类和以文拉法辛为主的SNRIs新型抗抑郁药;不同年龄段剂量有所不同。     

Second generation SSRIS: human monoamine transporter binding profile of escitalopram and R-fluoxetine

BACKGROUND: Single isomers of the selective serotonin reuptake inhibitors citalopram (escitalopram, S-citalopram) and fluoxetine (R-fluoxetine) are currently under development for the treatment of depression and other psychiatric disorders. Previous studies conducted in laboratory animals have revealed that the biological effects on serotonin reuptake for citalopram reside in the S enantiomer. In contrast, both enantiomers of fluoxetine contribute to its biological activity. METHODS: In the present study, the potency and selectivity of escitalopram, R-fluoxetine, and all of the other currently available selective serotonine reuptake ihibitors were compared for binding affinity at the human serotonin, norepinephrine, and dopamine transporters and several select neurotransmitter receptors using radioligand binding assays. RESULTS: Both escitalopram and R-fluoxetine were potent inhibitors of the serotonin transporter (Ki=1,1 and 1,4 nmol/L, respectively). escitalopram was the most serotonin transporter-selective compound tested and was approximately 30 fold more potent than R-citalopram. CONCLUSIONS: As noted previously, paroxetine and sertraline possess moderate affinity (<50 nmol/L) for the human norepinephrine transporter and dopamine transporter, respectively. R-fluoxetine, unlike the other selective serotonin reuptake inhibitors, possesses moderate affinity (Ki=64 nmol/L) for the serotonin 2C receptor. Potential clinical correlates of these unique attributes of escitalopram and R-fluoxetine are discussed. (Biol Psychiatry 2001; 50: 345-350 " 2001 Society of Biological Psychiatry).     

Inhibition of hippocampal excitability by citalopram

Purpose: Preclinical data have suggested that selective serotonin reuptake inhibitors (SSRIs) may have anticonvulsant properties, and some SSRIs are known to modulate ion channels in vitro. We screened citalopram, fluoxetine, and sertraline for anticonvulsant actions in mouse hippocampal slices, and studied the effects of citalopram on active membrane properties and repetitive action potential firing. Methods: To enable testing of antiepileptic effects and target modulation in a single experimental system, we used the simplistic low‐Ca²⁺ model, which is strongly dependent on the intrinsic excitability of CA1 pyramidal neurons. Field potentials and whole‐cell currents were recorded from brain slices, and SSRIs were bath‐applied. Key Findings: We found that citalopram, fluoxetine, and sertraline inhibited epileptiform activity recorded from area CA1. The effect of citalopram was more potent and less variable than that of fluoxetine and sertraline. The anticonvulsant action of citalopram was accompanied by marked slowing of action potential rise and decay, and robust inhibition of repetitive firing. This depression of membrane excitability appeared to be mediated in part by inhibition of a sustained potassium current. Significance: These findings confirm that SSRIs can have anticonvulsant effects in the hippocampus, and further suggest that citalopram may exert these effects at least in part by inhibition of voltage‐gated ion currents.     

Depression in Alzheimer's disease. Pathophysiology, diagnosis, and treatment

Depression is a comorbid condition in Alzheimer's disease (AD) with negative consequences in patients and caregivers. Pathophysiology and optimal treatment are matters to be elucidated. A search of articles dealing with depression in AD was conducted in MEDLINE with special attention to epidemiology, pathophysiology, and treatment. Depression may predate dementia and tends to occur in up to 50% of AD patients with a decrease of noradrenalin and serotonin in the brain being the most plausible cause. Only 7 small double-blind randomized placebo-controlled clinical trials with antidepressants in AD patients with depression were found: 4 with sertraline, 1 with fluoxetine, 1 with imipramine, and another one with clomipramine. The total number of treated patients was 318. The weighted odds ratio (OR) was calculated with the method of Mantel-Haenszel. Both tricyclic antidepressants and selective serotonin reuptake inhibitors are better than placebo in treating depression in AD (weighted OR: 1.82, 95% CI: 1.13-2.96), with sertraline being one of the most used drugs. The differences were significant in 2 trials and not significant in four. The magnitude of effect is globally modest. Moreover, it is noteworthy mentioning the high rates of response to placebo in most studies. Depression is one of the most frequent behavioral symptoms in AD. Although antidepressants may work in AD, given the small number of patients treated, the effect is unclear. Further large randomized controlled clinical trials are warranted in order to know the best drug to begin with and the actual degree of efficacy.     

Clinical efficacy and achievement of a complete remission in depression: increasing interest in treatment with escitalopram

Such a prevalent disease as Major Depressive Disorder (MDD), associated with prominent impairment in physical and social functioning, implies as well an increased morbidity and mortality. Long-term treatments are required due to the frequent occurrence of relapses. Patient compliance is a core factor in both acute and continuation treatment, closely related to tolerability issues. We have partially reviewed the literature published on PubMed since 2004 which assess the relative antidepressant efficacy of escitalopram and comparator antidepressants in adult patients who met DSM-IV criteria for major depressive disorder (MDD). Clinically important differences exist between commonly prescribed antidepressants. These analyses are in favor of a superior efficacy and tolerability of long-term escitalopram treatment (10 to 20mg/day) compared with active controls, including selective serotonin re-uptake inhibitors (SSRIs) (paroxetine, citalopram, bupropion, fluoxetine, fluvoxamine, sertraline), serotonin/noradrenaline reuptake inhibitors (SNRIs) (venlafaxine, milnacipran and duloxetine) and noradrenergic and specific serotonergic antidepressants (NaSSAs) (mirtazapine). Cipriani et al. (2009) have performed a network meta-analysis of 12 new generation antidepressants. They have shown that clinically important differences exist between commonly prescribed antidepressants for both efficacy and acceptability in favor of escitalopram and sertraline in acute treatment, defined as 8-week treatment. Kasper et al. (2009) conducted a post-hoc pooled analysis of data from two 6-month randomized controlled trials that revealed superior efficacy and tolerability of escitalopram when compared with paroxetine. The pooled analysis of four randomized, double-blind, active comparator, 6-month trials in MDD, by Wade et al. (2009), showed that short-term outcomes may predict long-term treatment compliance and outcomes. A higher probability of achieving remission was associated with responding after 8 weeks and with completing 6 months of treatment. Furthermore, Week 24 complete remission (MADRS≤5) was significantly (P<0,01) higher for escitalopram (51.7%) than for the pooled comparators (45.6%). And after 6 months, fewer patients discontinued treatment with escitalopram (15.9%) than with the pooled comparators (23.9%) (P<0.001). This fragmentary review of the literature shows that it is necessary to adopt a stringent definition of remission in depression, especially in clinical trials; a MADRS total score less or equal to 10 to define remission, a MADRS total score less or equal to 5 to define complete remission, and moreover no MADRS single item greater than 1 to define symptom-free remission. In all these meta-analyses, the superiority of escitalopram compared with other antidepressants was confirmed for both acute and long-term treatment of MDD, especially in harshly depressed patients.     

Down-regulation of the rat serotonin transporter upon exposure to a selective serotonin reuptake inhibitor.

The serotonin transporter (SERT) terminates serotonergic neurotransmission by rapid reuptake of 5-hydroxytryptamine (5-HT) into the nerve terminal or axonal varicosities. SERT represents the target of various antidepressants which inhibit 5-HT transport and are widely used for the pharmacotherapy of depression. Here, we have analyzed the function of SERT stably expressed in HEK 293 cells upon exposure to citalopram, a selective serotonin reuptake inhibitor (SSRI), with respect to 5-HT transport activity and protein expression as estimated by ligand binding experiments. Our results show that long-term exposure to an SSRI causes a down-regulation of transport activity as revealed by a reduction of the maximal transport rate, without affecting substrate affinity, accompanied by a decrease in ligand binding sites.     

Sertraline-induced galactorrhea: case report and review of cases reported with other SSRIs

There is limited literature reporting galactorrhea with antidepressants including selective serotonin reuptake inhibitors (SSRIs). In this case report, I present a case of a young female who developed galactorrhea with sertraline, which improved on discontinuation of sertraline. Computer-assisted searches on galactorrhea with SSRIs yielded 23 cases, mostly with escitalopram and paroxetine and rarely with fluoxetine, fluvoxamine and sertraline, and it may be much more frequent than recognized.     

北京地区30家社区医院2010-2012年选择性5-羟色胺再摄取抑制剂使用情况分析

目的 研究北京地区30家社区医院2010-2012年选择性5-羟色胺再摄取抑制剂使用情况。 方法 对参与“北京社区医院药物利用与评价研究课题”的30家社区医院2010-2012年选择性5-羟 色胺再摄取抑制剂的使用情况进行统计。 结果 参与研究的30家社区医院2010-2012年选择性5-羟色胺再摄取抑制剂每年用量和金额逐年 增大。按用量及百分比排序分别为：帕罗西汀（44.84%）、西酞普兰（32.4%）、氟西汀（11.60%）、舍曲 林（10.9%）及氟伏沙明（0.1%）。共涉及生产厂家29家,其中中美史克制药有限公司和西安杨森制药 有限公司所占全部市场消费金额最大,分别为42.40%和14.25%。 结论 本研究中北京社区医院选择性5-羟色胺再摄取抑制剂每年用量和花费金额逐年增大。使用 药品以帕罗西汀、西酞普兰为主,外资药品生产企业占据主要的市场份额。     

Paroxetine for somatic pain associated with physical illness: a review

Objective: The purpose of this article is to review the prevalence of somatic pain with and without depression or anxiety and the pharmacologic effects of the selective serotonin reuptake inhibitor paroxetine on pain in physical conditions with and without comorbid depression or anxiety. Data Sources: MEDLINE and PsychLIT/PsycINFO database. Keywords included depression, anxiety, pain, somatic, antidepressants, and paroxetine. Only English-language publications and abstracts were considered. Study Selection: More than 100 articles that reflected the prevalence of somatic pain in patients with physical illness with and without comorbid depression or anxiety and that evaluated the efficacy of antidepressants in this population were identified and reviewed. Data Synthesis: Nearly two thirds of patients with major depressive disorder suffer from a physical illness, and about one fifth of patients with chronic physical illness are depressed. Both of these comorbidities pose diagnostic and therapeutic challenges. Therapeutic effects of antidepressants on pain improvement in patients with chronic physical illnesses and comorbid depression/anxiety have been attributed to the antidepressant or anxiolytic properties of these drugs. However, tricyclic antidepressants have demonstrated analgesic properties in patients with physical illness both with and without depression. The review looks at evidence for the efficacy of the selective serotonin reuptake inhibitor paroxetine on pain in physical illness with and without depression and the mechanisms for the relief of pain and depression. Conclusions: The efficacy of paroxetine for depression and anxiety comorbid with physical illness looks promising. Studies also allude to evidence linking the analgesic properties of paroxetine with its serotonergic and noradrenergic activity. Large randomized controlled trials within specific antidepressant classes and also comparing dualaction antidepressants are warranted that could shed some light on the unique advantage of paroxetine over other antidepressants.     

Sertraline in Diabetic Neuropathy: Preliminary Results

Previous research has shown that antidepressants have been useful in the treatment of pain, particularly diabetic neuropathy. This study was an initial open investigation into the use of sertraline in diabetic neuropathy. Eight patients with diabetic neuropathy but not depression were treated with increasing doses of sertraline to a maximum of 150 mg/day for 8 weeks. Sertraline treatment led to significant reductions in mean visual analog scale (VAS) ratings, e.g., pain from 71.2 to 23.1 (t = 3.74, p < .01) and paresthesias from 53.8 to 15.0 (t = 4.15, p < .01). Baseline platelet serotonin (5HT) content also correlated significantly with improvement in pain (r = 0.70, p = 05). Plasma sertraline (SRT) correlated with improvement in paresthesias (r = 0.70). Conclusion: This preliminary result indicates the potential application of sertraline to treatment of diabetic neuropathy. A replication is now underway.     

Placental passage of antidepressant medications

OBJECTIVE: This study determined the placental transfer of antidepressants and their metabolites. METHOD: A total of 38 pregnant women taking citalopram, fluoxetine, paroxetine, or sertraline participated. Maternal and umbilical cord blood samples were obtained to determine antidepressant and metabolite concentrations. RESULTS: Antidepressant and metabolite concentrations were detectable in 86.8% of umbilical cord samples. The mean ratios of umbilical cord to maternal serum concentrations ranged from 0.29 to 0.89. The lowest ratios were for sertraline and paroxetine; the highest were for citalopram and fluoxetine. Maternal doses of sertraline and fluoxetine correlated with umbilical cord concentrations of these medications. CONCLUSIONS: Umbilical cord concentrations of antidepressants and their metabolites were almost invariably lower than corresponding maternal concentrations. Maternal doses predicted umbilical concentrations of fluoxetine and sertraline. Mean umbilical cord to maternal serum ratios were significantly lower for sertraline than fluoxetine, suggesting that sertraline may produce less fetal medication exposure than fluoxetine near delivery.     

Selective serotonin-reuptake inhibitors: an update.

Selective serotonin-reuptake inhibitors (SSRIs), including fluoxetine, sertraline, paroxetine, fluvoxamine, and citalopram, represent an important advance in the pharmacotherapy of mood and other disorders. They are chemically unrelated to tricyclic, heterocyclic, and other first-generation antidepressants. SSRIs are the treatment of choice for many indications, including major depression, dysthymia, panic disorder, obsessive-compulsive disorder, eating disorders, and premenstrual dysphoric disorder, because of their efficacy, good side-effect profile, tolerability, and safety in overdose, as well as patient compliance. A review of the literature was conducted using Medline and the terms "SSRIs," "fluoxetine," "sertraline," "paroxetine," "fluvoxamine," and "citalopram." Articles were limited to those published in English within the last 15 years. The search revealed that indications for antidepressants include unipolar depression, dysthymia, bipolar depression, treatment-resistant depression, depression in the medically ill, panic disorder, obsessive-compulsive disorder, eating disorders, social phobia, and premenstrual dysphoric disorder. One SSRI, fluoxetine, has demonstrated safety in pregnancy. Side effects of SSRIs include gastrointestinal disturbances, headache, sedation, insomnia, activation, weight gain, impaired memory, excessive perspiration, paresthesia, and sexual dysfunction.