Paroxetine: current status in psychiatry

Paroxetine is a selective serotonin reuptake inhibitor (SSRI) with antidepressant and anxiolytic properties. It is commercially available in both an immediate-release (paroxetine) and a controlled-release formulation (paroxetine CR). The latter product was developed to improve gastrointestinal tolerability. Paroxetine is the most potent inhibitor of the reuptake of serotonin among the available SSRIs. It has approved indications for the treatment of major depression, obsessive-compulsive disorder, panic disorder, generalized anxiety disorder, post-traumatic stress disorder and social phobia in adults. Paroxetine CR is approved for the treatment of major depression, social anxiety disorder, panic disorder and premenstrual dysphoric disorder in adults. While the overall efficacy of paroxetine appears to be comparable with other SSRIs in the treatment of major depression, it is approved for use in a wider variety of anxiety disorders than any other antidepressant. Long-term data suggest that paroxetine is effective in preventing relapse or recurrence of depression for up to 1 year. Limited data show that paroxetine maintains a therapeutic response over 1 year in obsessive-compulsive disorder and up to 6 months in panic disorder. The side-effect profile of paroxetine is largely similar to that of the other SSRIs, although paroxetine tends to be more sedating and constipating in some patients, perhaps due to its anticholinergic activity. The potential for discontinuation syndrome and weight gain appears to be slightly higher with paroxetine than with other SSRIs. This review focuses on the immediate release and controlled-release formulations of paroxetine. It summarizes the efficacy and tolerability data for both formulations, with a particular emphasis on paroxetine CR which was introduced in 2002. It also discusses emerging evidence in other clinical areas and recent data that have led to modifications in the safety profile of paroxetine.     

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.     

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.     

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.     

Antidepressants in epilepsy

People with epilepsy (PWE) frequently suffer from comorbid mood and anxiety disorders. Depression is one of the major psychiatric comorbidities having a negative impact on the quality of life in people with epilepsy. A review of the literature indicates that the majority of antidepressant-related seizures have been associated with either ultra-high doses or overdosing and, generally, the risk of antidepressant-associated seizures is low. Correspondingly, there is some evidence indicating that antidepressants of most widely used groups may additionally lower the risk of triggering seizures. Four antidepressants are not recommended for patients with epilepsy, i.e.: amoxapine, bupropion, clomipramine and maprotiline. Clinicians applying first line of depression treatment in patients with epilepsy should consider use of SSRIs or SNRIs, particularly sertraline, citalopram, mirtazapine, reboxetine, paroxetine, fluoxetine, escitalopram, fluvoxamine, venlafaxine, duloxetine. Implementation of anticonvulsive drugs in depressed patients should include valproate, carbamazepine, lamotrigine, gabapentin, pregabalin. The paper reviews the evidence for the clinical use of antidepressants in PWE.     

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.     

A review of pharmacologic treatments for obsessive-compulsive disorder

OBJECTIVE: Obsessive-compulsive disorder is a chronic and often disabling disorder that affects 2 to 3 percent of the U.S. population. Optimal treatment involves a combination of pharmacologic and cognitive-behavioral therapies. Advances in psychopharmacology have led to safe and effective treatments for obsessive-compulsive disorder that provide clinically significant improvement in symptoms. In this article the authors review studies of pharmacologic treatments. METHODS: A MEDLINE search was conducted to identify relevant articles from 1991 to 2002. Double-blind, placebo-controlled studies as well as open-label studies and case reports were included. RESULTS AND DISCUSSION: The serotonin reuptake inhibitors (SRIs), including clomipramine, fluvoxamine, fluoxetine, sertraline, and paroxetine, have been approved by the U.S. Food and Drug Administration for the treatment of adults with obsessive-compulsive disorder; three of these (clomipramine, fluvoxamine, and sertraline) have been approved for treatment of children and adolescents. Clomipramine and the selective serotonin reuptake inhibitors (SSRIs) are first-line agents. However, 40 to 60 percent of patients with obsessive-compulsive disorder do not respond to adequate treatment trials with SRIs, and agents that alter serotonin receptors and other neurotransmitter systems, such as dopamine, norepinephrine, and second-messenger systems, may play a role in treatment. Treatment options for patients who do not respond to SRIs include switching, augmentation, or novel-agent strategies. Up to two-thirds of patients with obsessive-compulsive disorder have comorbid psychiatric disorders, which may present a challenge in pharmacologic treatment. Major depressive disorder is the most common comorbid condition. Nonpharmacologic invasive techniques may play a role in refractory cases of obsessive-compulsive disorder, but further research is warranted.     

Citalopram in the treatment of obsessive-compulsive disorder: an open pilot study

Obsessive-compulsive disorder (OCD) is a common anxiety disorder, which often causes significant impairment of the affected individual's social, occupational or interpersonal functioning. Previous reports suggest that the disorder may be treated with the tricyclic antidepressant clomipramine, and also with the more recently introduced selective serotonin reuptake inhibitors (SSRIs), such as fluoxetine, fluvoxamine, sertraline and paroxetine. The present 24-week open pilot study was designed to examine the efficacy, appropriate dose range, side-effects and clinical usefulness of citalopram in OCD. A total of 29 OCD patients were included in the study, of whom 76% showed alleviation of symptoms as evaluated by various self-and observer-rated scales, such as the Yale-Brown Obsessive Compulsive Scale. In most cases the citalopram doses used were in most cases 40 or 60 mg daily, and the treatment was well tolerated. The most commonly experienced adverse events during the study were nausea, vomiting, increased dreaming and decreased sleep. Diminished sexual desire and orgasmic dysfunction were also reported. Despite having the limitations of an open study, our results suggest that citalopram may be effective in the treatment of obsessive-compulsive disorder.     

Selective serotonin reuptake inhibitors in autism: a review of efficacy and tolerability

BACKGROUND: Awareness of the impact and prevalence of autism spectrum disorders has significantly increased in recent years. Given the dearth of reliable interventions, there is great interest in demonstrating efficacy of the various treatment options. A growing body of evidence links autism spectrum disorders to abnormalities in serotonin function, and the selective serotonin reuptake inhibitors (SSRIs) have been utilized to target various symptoms of the disorders. This article reviews the available data on the efficacy and tolerability of SSRIs in individuals with autism spectrum disorders. Objectives for future research in this area will also be suggested. DATA SOURCES AND STUDY SELECTION: The entire PubMed database including MEDLINE (1966-July 2005) was searched for English-language biomedical articles. Search terms included autism, autism spectrum disorder, citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, pervasive developmental disorder, selective serotonin reuptake inhibitors, and sertraline. All clinical trials evaluating treatment outcomes associated with the use of SSRIs in managing symptoms of autism that were identified in the search were reviewed. All randomized controlled trials and open-label trials were included in this review. Case reports and case series were excluded. DATA SYNTHESIS: We identified 3 randomized controlled trials and 10 open-label trials or retrospective chart reviews on the use of SSRIs in autism and autism spectrum disorders. The SSRIs that have been studied in autism spectrum disorders are citalopram, escitalopram, fluoxetine, fluvoxamine, and sertraline. Most studies demonstrate significant improvement in global functioning and in symptoms associated with anxiety and repetitive behaviors. While side effects were generally considered to be mild, increased activation and agitation occurred in some subjects. CONCLUSIONS: Although SSRIs may demonstrate therapeutic benefit in autism spectrum disorders, methodological weaknesses of many of the clinical trials suggest the need for additional randomized controlled trials. Furthermore, given the increased awareness of the dangers associated with SSRI-induced activation and agitation, the presence of these side effects in the autistic population warrants closer attention to dosage, titration, and subject selection issues.     

The clinical nature and formal diagnosis of premenstrual,postpartum, and perimenopausal affective disorders

Various mood and anxiety disorders are more prevalent in reproductive-aged women, and appear to be linked to hormonal and reproductive events. Premenstrual affective disorders consist of premenstrual syndrome, premenstrual dysphoric disorder, and premenstrual exacerbation of mood or anxiety disorders. Postpartum affective disorders can range from postpartum “blues” to postpartum depression with or without psychosis, and also include anxiety disorders, such as panic disorder, generalized anxiety disorder, social phobia, and obsessive-compulsive disorder. In perimenopausal women, the vulnerability to mood and anxiety disorders is increased. All of these disorders share risk factors, and have etiologic features in common, such as exposure to the rise and fall of ovarian sex steroids. The following is a review of these syndromes and their etiology, diagnosis, and treatment.     

SSRIs do not worsen Parkinson's disease: evidence from an open-label, prospective study

Selective serotonin reuptake inhibitors (SSRIs) have been reported to be useful in the treatment of depression in patients with Parkinson's disease (PD). However, a few reports have suggested that SSRIs may worsen parkinsonian motor symptomatology and extrapyramidal side effects have been reported in depressed patients treated with SSRIs. So far, no prospective trial comparing the effects of different SSRIs in depressed patients with PD has been performed. The aim of the present study was to assess the effects of four SSRIs (citalopram, fluoxetine, fluvoxamine, and sertraline) on motor performance and their efficacy on depression in a group of patients with PD. Sixty-two consecutive nondemented, nonfluctuating, depressed patients with PD were included in four treatment groups (15 patiens received citalopram, 16 fluoxetine, 16 fluvoxamine, and 15 sertraline). The evaluation of extrapyramidal and depressive symptomatology was performed with use of the Unified Parkinson's Disease Rating Scale (UPDRS), Beck Depression Inventory, and Hamilton Depression Rating Scale at baseline and after 1, 3, and 6 months. Fifty-two patients completed the study. UPDRS scores were not significantly modified by the add-on therapy with each of the SSRIs studied. A significant improvement in depressive symptoms from baseline to the end of the trial was obtained with all SSRIs (Beck and Hamilton scores improving; p < 0.05 according to an analysis of variance). Our findings suggest that SSRIs do not significantly worsen extrapyramidal symptomatology and may ameliorate depression in patients with PD.     

Trends in Prescribing of Selective Serotonin Reuptake Inhibitors and Other Newer Antidepressant Agents in Adult Primary Care

BACKGROUND: The introduction of selective serotonin reuptake inhibitors (SSRIs) represented a breakthrough in depression treatment due to their safety and ease of use. The purpose of this study was to extend previous work on trends in antidepressant use to include recent data and to provide more detailed analysis of prescribing trends for SSRIs and newer non-SSRI antidepressants, specifically in adult primary care practice. METHOD: Adult primary care visits from the National Ambulatory Medical Care Survey (NAMCS) between 1989 and 2000 were analyzed. Chi-square tests for trend and multivariable logistic regression models were utilized to examine patterns of antidepressant use over time. SSRIs (citalopram, fluoxetine, fluvoxamine, paroxetine, sertraline) and newer non-SSRI antidepressants (bupropion, mirtazapine, nefazodone, venlafaxine) were classified as newer agents. RESULTS: 89,424 adult primary care visits were recorded in the NAMCS during the period studied. Antidepressant use increased in primary care from 2.6% ( approximately 6 million visits) in 1989 to 7.1% ( approximately 20.5 million) in 2000 (p <.001). SSRI and newer non-SSRI use increased linearly from 1989 to 2000 (p <.001), with an adjusted odds ratio for use of 1.27 per year (95% confidence interval = 1.25 to 1.29). The increase in antidepressant use was due to these newer agents (13.5% of all antidepressant use in 1989 to 82.3% in 2000) with each new agent adding to a stable base of previously introduced newer antidepressant agents. CONCLUSIONS: The prevalence of antidepressant use in adult primary care has risen dramatically since 1989, largely reflecting use of newer agents. The detailed pattern of increased use of these medications is striking, with each new agent adding to aggregate use without concomitant decrease in previously introduced newer agents. Such trends reflect more widespread pharmacologic treatment of depressed primary care patients.     

The search for new off-label indications for antidepressant, antianxiety, antipsychotic and anticonvulsant drugs

Most drugs are prescribed for several illnesses, but it took several years for psychotropic drugs to have multiple clinical indications. Our search for serotonergic drugs in affective illnesses and related disorders led to new off-label indications for fluoxetine, sertraline, tryptophan, clonazepam, alprazolam, tomoxetine, buproprion, duloxetine, risperidone and gabapentin. Various clinical trial designs were used for these proof-of-concept studies. Novel therapeutic uses of benzodiazepines, such as in panic disorder and mania, were found with the introduction of 2 high-potency benzodiazepines, clonazepam and alprazolam, which were thought to have serotonergic properties. Our initial clinical trials of fluoxetine and sertraline led to their approved indications in the treatment of obsessive-compulsive disorder, and our trials of gabapentin led to new indications in anxiety disorders (generalized anxiety, panic attack and social phobia) and sleep disorders (insomnia).     

Antidepressants in social anxiety disorder

Social anxiety disorder (SAD) is a marked and persistent fear of doing almost everything in front of people due to concerns about being judge by others. An up-to-date review is needed in order to reach a practical judgement of all psychopharmacological data. Case reports, open and double-blind trials with SAD were described and commented upon from a clinical point of view. The MEDLINE system was searched from 1975 to 2001. The references from the selected papers were also used as a source. MAOIs (fenelzine, tranylcypromine), reversible monoamino oxidase-A inhibitors (moclobemide, brofaromine), SSRIs (paroxetine, sertraline, fluoxetine, fluvoxamine) and some other antidepressants (venlafaxine, nefazodone) have proven effective in several studies with various methodologies. The MAOIs have more serious adverse effects and the SSRIs have the best tolerance. SSRIs are efficacious and the first choice of treatment.     

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.     

SSRIs and SNRIs: broad spectrum of efficacy beyond major depression

Originally studied and introduced for the treatment of depression, the selective serotonin reuptake inhibitors (SSRIs) and serotonin/norepinephrine reuptake inhibitors (SNRIs) have proven effective for a broad range of psychiatric illnesses, including several anxiety disorders, bulimia, and dysthymia. These drugs have in common important effects on the serotonergic (5-HT) neurotransmission system, which is involved in mediating a substantial number of important functions, including mood, aggression, sexual behavior, and pain. In addition, some of the new antidepressants, like venlafaxine/venlafaxine XR, also have effects on the noradrenergic neurotransmission system, which also appears important in mood and anxiety disorders. These new drugs, because of their specificity for the serotonin and norepinephrine reuptake proteins, lack most of the adverse side effects of tricyclic antidepressants and monoamine oxidase inhibitors. Consequently, in addition to being the usual first-line treatments for major depression, they are also first-line for panic disorder, obsessive-compulsive disorder, social phobia, posttraumatic stress disorder, and bulimia. They may also be the best medication treatments for dysthymia and generalized anxiety disorder. Further advances in psychopharmacology will be driven by discoveries from brain imaging and molecular biological research.     

文拉法辛缓释剂替换治疗门诊抑郁症患者观察

目的:了解文拉法辛缓释剂替换选择性5-羟色胺再摄取抑制剂类(SSRIs)疗效欠佳的门诊抑郁症患者的有效性和安全性. 方法:将符合抑郁症诊断标准并经氟西汀,舍曲林,氟伏沙明和西酞普兰4种SSRIs抗抑郁剂之一治疗量治疗6周而疗效不佳的抑郁症患者72例随机分为两组.文拉法辛组34例换用文拉法辛缓释剂,帕罗西汀组38例换用帕罗西汀,疗程6周.换药前均停原用SSRIs药物.以汉密尔顿抑郁量表(HAMD)、汉密尔顿焦虑量表(HAMA)、临床疗效总评量表病情严重程度(CGI-SI)分别于入组时、治疗2周末、4周末、6周末评定疾病的严重程度及好转情况;以治疗中出现的症状量表(TESS)评定药物的不良反应. 结果:两组在治疗4周末及6周末时其HAMD、CGI-SI评分差异有显著性,HAMA评分则从治疗2周末起即表现出显著性差异.文拉法辛组疗效优于帕罗西汀组,两组显效率分别为70.6%和52.6%,不良反应发生率无明显差异. 结论:文拉法辛缓释剂替换经SSRIs抗抑郁剂治疗效差的门诊抑郁症患者可取得好的疗效,且安全性好.