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.     

A review of the efficacy of selective serotonin reuptake inhibitors in obsessive-compulsive disorder

BACKGROUND: Obsessive-compulsive disorder (OCD) is a chronic illness associated with substantial morbidity; it often requires long-term medication. The best-studied therapeutic agent in the treatment of this disorder is the tricyclic antidepressant clomipramine. Since other tricyclic antidepressants appear to lack efficacy in OCD, that of clomipramine has been linked to its potent effects on serotonin. Consequently, agents that selectively inhibit serotonin reuptake have been the focus of several large-scale, placebo-controlled studies of OCD. Their efficacy in OCD is the focus of our review. DATA SOURCES: MEDLINE search (1966 to present) of OCD treatment with clomipramine or SSRI antidepressant medication using the key words obsessive-compulsive disorder, serotonin reuptake inhibitors, clomipramine, and pharmacology. STUDY FINDINGS: The selective serotonin reuptake inhibitors fluoxetine, sertraline, fluvoxamine, and paroxetine have, in separate multicenter trials, demonstrated efficacy and tolerability in the treatment of OCD. In contrast, clomipramine, though efficacious, is often associated with substantial adverse events, particularly anticholinergic side effects. While 2 recent meta-analyses support the superior efficacy of clomipramine over selective serotonin reuptake inhibitors in the treatment of OCD, 5 of 6 head-to-head comparisons of either fluoxetine or fluvoxamine versus clomipramine have found similar efficacy but a lower incidence of side effects with the selective serotonin reuptake inhibitor. A recently completed multicenter, 12-week, double-blind trial of paroxetine versus clomipramine versus placebo showed paroxetine to be as effective as clomipramine. With significantly fewer dropouts due to adverse effects than clomipramine, paroxetine was also associated with superior tolerability. CONCLUSION: The suggestion that selective serotonin reuptake inhibitors possess efficacy similar to that of clomipramine, but have a superior side effect profile, may have important implications for patients with OCD who require long-term treatment.     

Suizidalität bei depressiven Kindern und Jugendlichen unter Behandlung mit selektiven Serotoninwiederaufnahmehemmern

Due to concerns that selective serotonin reuptake inhibitors (SSRI) might be associated with an increased risk of suicidal ideation and suicide attempts in depressive children and adolescents, treatment with these drugs is controversial. All available data from randomised controlled trials on SSRIs treating depression in these age groups were examined regarding efficacy and suicidality. Results suggest that fluoxetine and, less clearly, sertraline are effective in such treatment. A meta-analysis yielded no statistically significant difference between treatment with SSRI and placebo with regard to the occurrence of suicidal behavior. Following evidence-based criteria, the risk:benefit ratio is favourable for fluoxetine and sertraline. Their use in the pharmacotherapy of depressive children and adolescents is indicated.     

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.     

Selective serotonin reuptake inhibitor and venlafaxine use in children and adolescents with major depressive disorder: a systematic review of published randomized controlled trials.

OBJECTIVE: This review critiques published randomized placebo-controlled trials pertaining to the efficacy and safety of selective serotonin reuptake inhibitors (SSRIs) and venlafaxine in the treatment of major depressive disorder in children and adolescents. METHOD: Medline was searched for articles meeting defined inclusion criteria. The following key terms were used: depressive disorders, antidepressive agents, fluoxetine, paroxetine, sertraline, citalopram, fluvoxamine, venlafaxine, child, and adolescent. RESULTS: Six articles met inclusion criteria. Only 2 studies claim efficacy by significant results in primary outcomes; both have since been contested in further analysis. Not one study adequately examines safety, particularly with respect to whether a link exists between antidepressant use and induction of suicidal ideation or attempts. CONCLUSION: Published studies on SSRI or venlafaxine use in children and adolescents are inconclusive with respect to safety and efficacy, owing to inappropriate claims of efficacy, lack of improvement in global functioning scores, nonstandardized data collection regarding adverse effects, exclusion of suicidal subjects in the recruitment process, grouping of children and adolescents together, small sample sizes, conflict of interest posed by pharmaceutical company sponsorship, and publishing bias. Future investigators should consider these factors when developing study designs.     

Paroxetine versus clomipramine in adolescents with severe major depression: a double-blind,randomized, multicenter trial

OBJECTIVE: To date, two randomized, double-blind trials of serotonin reuptake inhibitors (SRIs) have shown that antidepressant drugs are effective in treating adolescent depression. In contrast, tricyclic antidepressants (TCAs) are not superior to placebo. This has led to a serotonin hypothesis in this age group. This study explores this hypothesis and compares paroxetine, a specific SRI, with clomipramine, a TCA with SRI activity. METHOD: One hundred twenty-one adolescents (aged 12-20 years) with major depression were enrolled and randomized (stratified for age) to 20 or 40 mg of paroxetine or 75 mg or 150 mg of clomipramine for 8 weeks. Primary outcome measurements were the Clinical Global Impression (CGI) scale and the Montgomery and Asberg Depression Rating Scale (MADRS). RESULTS: Of the 121 patients, 58 received clomipramine and 63 paroxetine. Based on intent-to-treat analysis, both agents had similar efficacy, with no effect of age; 48.3% and 58.2% of the subjects receiving clomipramine and 65.1% and 59.3% of those receiving paroxetine were rated responders on the MADRS and CGI scales, respectively. Study withdrawals were frequent in both groups (41% and 31%, respectively), but side effects were significantly more frequent with clomipramine (69% versus 49.2%, respectively; p = .027). CONCLUSION: Paroxetine and clomipramine exhibit similar efficacy in adolescent depression. These data support the serotonin hypothesis but do not confirm it in the absence of a placebo arm. Given the adverse event profile of clomipramine, specific SRIs should be preferred. However, more placebo-controlled studies are needed to establish definitively the efficacy of SRIs in this age group.     

Use of Antidepressants in Treatment of Comorbid Diabetes Mellitus and Depression as Well as in Diabetic Neuropathy

After a brief review of epidemiology, the focus is on biochemistry of diabetes. Animal and human studies are reviewed in terms of the impact of alterations in catecholamines and serotonin (5-hydroxytryptamine, 5HT) on glucose utilization. Then, the implications of these experimental results for the choice of antidepressant in comorbid diabetes mellitus and depression as well as in diabetic neuropathy are discussed. Results of clinical investigations are then reviewed in terms of the above hypotheses. An Index Medicus Search for the past 10 years was supplemented by references from previous related reviews of the topic as well as by pending results, where available, not previously published. The range of prevalence of depression in diabetic patients has been 8–27%, depending on study criteria and procedures. An increase of catecholamines appears to increase glucose while both reducing insulin release and reducing sensitivity to insulin that is available. In contrast, increases in serotonergic function by increased precursor, increased release, or blocked metabolism and blocked reuptake in contrast seem to increase sensitivity to insulin and reduce plasma glucose. There have been six studies of fluoxetine, a selective serotonin reuptake inhibitor (SSRI), at a dose of 60 mg/day pursued up to 12 months that have demonstrated that medication's usefulness in diabetic patients, with reductions in weight (to 9.3 kg), in FPG (to 45 mg%), and in HbA1c (to 2.5%). In studies in comorbid diabetes mellitus and depression, nortriptyline, a norepinephrine reuptake inhibitor that produces increased synaptic catechols, has led to worsening of indices of glucose control. However, fluoxetine and sertraline, both selective serotonin reuptake inhibitors, in the same patient group, have produced results consistent with reductions in glucose levels. In diabetic neuropathy, perhaps due to the fact that catecholamines and serotonin may both be implicated in pain pathways, dual-action antidepressants appear more effective at lower doses than do specific serotonergic agents. The tricyclic antidepressants (TCA) (66.7%) have had success in double-blind studies, particularly imipramine, with a 81% response rate. Yet, there are positive reports concerning the SSRIs (paroxetine, citalopram, sertraline), as well as nefazodone, that focus on serotonin selectivity. Conclusions: In comorbid diabetes mellitus and depression, most evidence supports the use of fluoxetine in control of glucose handling. Other characteristics in terms dosing, drug interactions, cognition, and sleep make sertraline an attractive alternative agent. In diabetic neuropathy without depression, the best choices among non-TCAs may include sertraline, citalopram, and perhaps, venlafaxine, since the TCAs appear to increase cravings and increase FBG levels.     

Efficacy of antidepressants in juvenile depression: meta-analysis

BACKGROUND: The safety of antidepressants in children and adolescents is being questioned and the efficacy of these drugs in juvenile depression remains uncertain. AIMS: To assess antidepressant efficacy in juvenile depression. METHOD: Systematic review and meta-analysis of randomised controlled trials (RCTs) comparing responses to antidepressants, overall and by type, v. placebo in young people with depression. RESULTS: Thirty drug-placebo contrasts in RCTs lasting 8 weeks (median) involved 3069 participants (512 person-years) of average age 13.5 years. Meta-analysis yielded a modest pooled drug/placebo response rate ratio (RR=1.22, 95% CI 1.15-1.31), with little separation between antidepressant types. Findings were similar for response rate differences and corresponding number needed to treat (NNT): overall NNT=9; tricyclic antidepressants NNT=14 > serotonin reuptake inhibitors NNT=9 > other antidepressants NNT=8. Numbers needed to treat decreased with increasing age: children (NNT=21) > mixed ages (NNT=10) > adolescents (NNT=8). CONCLUSIONS: Antidepressants of all types showed limited efficacy in juvenile depression, but fluoxetine might be more effective, especially in adolescents. Studies in children and in severely depressed, hospitalised or suicidal juvenile patients are needed, and effective, safe and readily accessible treatments for juvenile depression are urgently required.     

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-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.     

National Patterns of Medication Treatment for Depression, 1987 to 2001

BACKGROUND: We investigated trends in antidepressant use, as well as broader changes in depression treatment, following the availability of selective serotonin reuptake inhibitors (SSRIs). METHOD: Using data from the National Disease and Therapeutic Index, a nationally representative survey of U.S. office-based physicians conducted by IMS HEALTH, we analyzed trends in antidepressant prescribing patterns from 1987 through the third quarter of 2001. Annual sample sizes of physician visits by patients reported to have depression ranged from 3901 visits in 1987 to 6639 in 1998. Outcomes examined included the frequency of depression visits, the likelihood of antidepressant therapy, and the use of specific medications. RESULTS: The estimated national number of physician visits by patients with depression increased from 14.4 million visits in 1987 to 24.5 million in 2001 (annualized). The rate of antidepressant medication treatment in these patients also increased from 70% in 1987 to 89% in 2001. In 1987, tricyclic antidepressants were prescribed to 47% of patients with depression. The most common individual antidepressants were amitriptyline (14%), trazodone (12%), doxepin (8%), and desipramine (6%). In 1989, a year after its introduction, fluoxetine was prescribed to 21% of patients with depression. The introduction of other SSRIs led aggregate SSRI use to grow to 38% in 1992, 60% in 1996, and 69% in 2000. In 2001, sertraline (18%), paroxetine (16%), fluoxetine (14%), citalopram (13%), and bupropion (9%) were the leading antidepressants, while tricyclics were used in only 2% of patients. The use of benzodiazepines in depression declined from 21% of patients in 1987 to 8% in 2001. CONCLUSION: The increasing therapeutic dominance of SSRIs may have contributed to other changes in depression treatment, including declining benzodiazepine use, increased aggregate antidepressant treatment rates, and increased reporting of depression.     

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.     

抗抑郁药物治疗的依从性观察

目的　探讨抗抑郁药物临床治疗的依从性。方法　对 10 2例抑郁症患者所服用阿米替林、氯丙咪嗪、氟西汀、盐酸帕罗西汀、文拉法辛 5种抗抑郁药的开放性治疗情况进行了 6个月的随访观察。结果　 5种药物治疗后患者获得痊愈的比例和脱落情况无显著差异 (P >0 0 5 ) ,但在起效时间、不良反应、处方依从、治疗态度等方面存在着差异 (P <0 0 5 )。结论　SSRI和SNRI抗抑郁药的临床依从性显著高于传统的三环类抗抑郁药     

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.     

Treatment of depression in children and adolescents

Depression occurs in children and adolescents, although it may appear differently in younger patients. Research suggests juvenile depression may respond to psychotherapy and to pharmacologic agents, and that antidepressants remain a valuable treatment for juveniles with depression. Diagnostic considerations in juveniles with mood symptoms are discussed. A brief overview is provided of the evidence supporting psychotherapy for juveniles with depression. Controlled antidepressant trials in juveniles with depression provide some support for the use of some selective serotonin reuptake inhibitors and little support for atypical antidepressants, tricyclic antidepressants, or monoamine oxidase inhibitors. Evidence from suicide rates over time, autopsy findings among juvenile suicides, and impacts of antidepressant prescribing trends are related to the current controversy over suicidality and antidepressant use in juvenile patients. Based on this evidence, practical guidelines for treatment of juvenile depression are provided.