Paroxetine in the treatment of post-traumatic stress disorder: pooled analysis of placebo-controlled studies

Post-traumatic stress disorder (PTSD) is increasingly understood to be a medical disorder characterised by particular psychobiological dysfunctions that respond to specific treatments. Paroxetine is a selective serotonin re-uptake inhibitor that has been found effective in the treatment of major depression as well as a range of anxiety disorders. This paper reviews data on the use of paroxetine for the treatment of adult PTSD. There have been three 12-week, placebo-controlled studies of paroxetine in PTSD. As these followed a partly similar design, a pooled analysis of the studies is possible and is reported here. Paroxetine is effective in the short-term treatment of PTSD, resulting in significantly better response and remission rates than placebo, improving sleep disturbance and reducing each of the symptom clusters of PTSD, as well as the disability associated with this condition. The medication is effective in both male and female PTSD patients and whether or not there are comorbid disorders such as depression.     

Paroxetine: safety and tolerability issues

Paroxetine is a selective serotonin re-uptake inhibitor (SSRI) available in immediate release and controlled release (CR) formulations. Paroxetine is the most potent inhibitor of serotonin re-uptake among the now available SSRIs. Paroxetine has been approved for the treatment of major depressive disorder (MDD), obsessive-compulsive disorder, panic disorder (PD), generalised anxiety disorder, post traumatic stress disorder (PTSD), and social anxiety disorder (SAD) in adults, whereas paroxetine CR is approved for the treatment of MDD, SAD, PD and premenstrual dysphoric disorder in adults. The overall efficacy of paroxetine seems to be comparable to other SSRIs in the treatment of approved indications, although paroxetine treatment induces more sedation, constipation, sexual dysfunction, discontinuation syndrome and weight gain than other SSRIs. Recent data suggest that paroxetine treatment leads to increased rates of congenital malformations, although this evidence is not conclusive. Paroxetine and paroxetine CR are not indicated for use in the paediatric population and are categorised as Pregnancy Class D. In conclusion, whether the tolerability profile of paroxetine differs substantially from other new antidepressants (including other SSRIs) needs to be determined in adequately powered well-designed randomised controlled comparative clinical trials.     

Review of sertraline and its clinical applications in psychiatric disorders

Sertraline (Zoloft^®, Pfizer) has been shown in numerous controlled studies to have similar efficacy to other selective serotonin (5-HT) re-uptake inhibitors (SSRIs) in the treatment of depression and anxiety disorders. Further research is indicating that the efficacy of sertraline extends even beyond the treatment of depression and anxiety to include utility in eating disorders, premenstrual dysphoric disorder (PMDD) and possibly substance abuse treatment. Along with other SSRIs, sertraline offers several advantages over older antidepressants, including improved patient tolerability, low risk of lethality in overdose and no dependence potential. In head-to-head comparisons, sertraline appears to be at least as well-tolerated as other SSRIs and may even have a more favourable side effect profile. Low potential for pharmacokinetic drug interactions is another advantage of sertraline. Unlike fluoxetine, fluvoxamine and paroxetine, sertraline is not a potent inhibitor of any of the cytochrome P450 isoenzyme systems. As a result of its proven efficacy, good tolerability and lack of pharmacokinetic interactions, sertraline should be considered first-line in the treatment of anxiety and depressive disorders.     

Disturbed development of the enteric nervous system after in utero exposure of selective serotonin re-uptake inhibitors and tricyclic antidepressants. Part 1: Literature review

The increase in selective serotonin re-uptake inhibitor (SSRI) use during pregnancy, questions concerning abnormal development of the enteric nervous system (ENS), increase in laxative use in children and the association of fluoxetine with infantile hypertrophic pyloric stenosis (IHPS) gave rise to this pharmacological literature review. The role of 5-HT and the NE uptake in ontogeny of the ENS and the effects SSRIs and TCAs might have on the development of the ENS were investigated. The literature study showed that SSRIs may influence the development of the ENS in two ways. Blockage of the serotonin re-uptake transporter (SERT) during foetal development could influence migration, differentiation and survival of cells. This could lead to abnormal development in the first trimester of pregnancy. The other way is that 5-HT seems to be a growth factor in the primitive ENS. This growth factor like action is mediated through the 5-HT(2B) receptor and stimulation of this receptor by SSRIs influences the fate of late-developing enteric neurons. This could lead to abnormal development in the second and third trimester. TCAs could influence the development of the ENS, besides through inhibition of the SERT, through inhibition of the norepinephrine transporter (NET). Expression of the NET seems to be essential for a full development of enteric neurons and especially for serotonergic neurons. In addition the NET was detected early in ontogeny and precedes neuronal differentiation, which suggests that TCAs might influence development of the ENS when exposed early in pregnancy. The insights of this study gave rise to hypotheses which will be tested in an epidemiological cohort study.     

Atorvastatin: safety and tolerability

Importance of the field: Atorvastatin is the most widely used statin administered in a variety of settings, including primary and secondary prevention of cardiovascular events, in the elderly, in patients with chronic kidney disease and in diabetic patients. Therefore, the safety and tolerability of atorvastatin is of paramount importance.

Areas covered in this review: We searched MEDLINE for literature published between 1997 and 2010 on the safety and tolerability of atorvastatin. We retrieved data from randomized controlled trials, meta-analyses, post-marketing studies, reports to regulatory bodies and case reports of rare adverse events.

What the reader will gain: The reader will gain insight into the incidence, severity, prevention and management of the major adverse effects of atorvastatin (i.e., liver function abnormalities and muscle-related side effects) overall and in special populations.

Take home message: The existing data suggest that atorvastatin is generally well tolerated across the range of its therapeutic dosage (10 – 80 mg/day).     

Citalopram: a comprehensive review

Citalopram is a selective serotonin re-uptake inhibitor that has demonstrated antidepressant efficacy in numerous controlled clinical trials. Additional studies have shown that the drug benefits patients with other illnesses that are related in some way to serotonergic dysfunction, including anxiety, panic disorder, obsessive-compulsive disorder, premenstrual dysphoria, alcohol dependence and the behavioural disturbances of dementia. This paper reviews the full spectrum of citalopram’s clinical efficacy, as well as its safety and tolerability, in a range of patients.     

帕罗西汀与其他选择性5-HT再摄取抑制药疗效及安全性的meta分析

目的 评价帕罗西汀与其他选择性5-HT再摄取抑制药的疗效及安全性。方法 计算机检索Cochrane图书馆、ISI数据库、中国知网（CNKI）、维普（VIP）、万方数字化期刊数据库,纳入帕罗西汀与其他选择性5-HT再摄取抑制药疗效及安全性随机对照试验（randomized controlled trial,RCT）、系统评价和meta分析文献,对纳入文献的RCTs进行方法学质量评价和meta分析,参考纳入文献的系统评价和meta分析结论。结果 帕罗西汀与其他选择性5-HT再摄取抑制药疗效及安全性对比分析共纳入15个RCTs。2组抗抑郁总有效率差异有统计学意义（OR=1.45,95%CI=1.01~2.09,P=0.04）;治疗2周和6周后HAMD评分差异有统计学意义（MD=-2.04,95%CI=-2.59~-1.49,P<0.000 01;MD=-0.69,95%CI=-1.18~-0.21,P=0.005）;治疗6周后药物不良反应发生率差异有统计学意义（OR=0.88,95%CI=0.78~0.99,P=0.04）。结论 与其他选择性5-HT再摄取抑制药相比较,帕罗西汀的总有效率及起效速度较低,不良反应发生率较高,其不再推荐为一线抗抑郁药。     

A review of the safety and tolerability of aripiprazole

It seems that the efficacy of aripiprazole for treating schizophrenia is mediated through a combination of partial agonism at dopamine D2 and serotonin 5-HT1A receptors and antagonism at serotonin 5-HT2A receptors. Aripiprazole has also received approval for the treatment of bipolar disorder as adjunctive therapy or monotherapy (manic or mixed episodes) as well as an augmentation therapy of major depressive disorder (MDD) by the US FDA. The overall safety and tolerability of aripiprazole is favorable compared to other atypical antipsychotics across the approved indications. Aripiprazole showed a minimal propensity for clinically significant weight gain and metabolic disruption. However, extrapyramidal side effects, such as akathisia, are reported and may limit its clinical use in some cases, particularly in patients with bipolar disorder and MDD. This review focuses on the tolerability and safety of aripiprazole across a broad spectrum of psychiatric disorders while taking into consideration results from registrational studies as well as findings from studies in the naturalistic setting. In conclusion, whereas the comparative safety and tolerability of aripiprazole has not been systematically evaluated in comparator studies, tolerability and safety issues commonly associated with atypical antipsychotics such as weight gain and metabolic syndrome are less prominent with aripiprazole.     

Review of sertraline in post-traumatic stress disorder

Sertraline (Zoloft?, Pfizer) is a selective serotonin re-uptake inhibitor (SSRI) with proven efficacy in the treatment of post-traumatic stress disorder (PTSD). PTSD is a serious, complex and often chronic mental illness that may follow exposure to a traumatic event. The high prevalence of traumatic events and PTSD in the general population and the resulting distress and dysfunction present a need for the systematic study of the efficacy and effectiveness of treatments for PTSD. Sertraline offers advantages over the older antidepressants, including demonstrated efficacy in PTSD, improved tolerability and low risk of lethality in overdose. Sertraline’s efficacy, favourable tolerability profile and relatively weak effect on the cytochrome P450 system are factors that contribute to make it a first-line agent of choice in the treatment of PTSD.     

Drug safety and tolerability in prophylactic migraine treatment

Introduction: Migraine is a frequent, disabling primary headache disorder, whose pathomechanism is not yet fully understood. Prophylactic treatment is advisable for migraineurs with severe or highly frequent attacks, which impair the quality of life.

Areas covered: The different types of prophylactic migraine drugs are discussed, with particular regard to potential adverse effects and safety issues. β-Adrenergic blockers, antiepileptic drugs and calcium-channel blockers are drugs widely used for migraine prevention, whereas complementary medicine and onabotulinumtoxin A can be used in selected cases.

Expert opinion: The background of the recurrence and chronification of migraine attacks has not been fully clarified, and causative preventive therapy is therefore not currently available. The tolerability and adverse effects of the currently used medications often limit their use. β-Adrenergic receptor blockers may induce adverse cardiovascular events, whereas flunarizine is frequently associated with a weight gain and depression. As most migraine sufferers are young women of child-bearing age, the use of valproate is limited. Topiramate is associated with central nervous system-related side effects. There is a need for future development of pathomechanism-based preventive drugs, and personalized therapy tailored to the patient.     

The Safety Profile of Fluvoxamine in Elderly Patients

The safety profile of fluvoxamine was assessed in 4843 elderly, mainly depressed patients (65 years or older; range 65 to 97 years) enrolled in worldwide post-marketing studies. This cohort of elderly patients was extracted from a population of 34 587 patients in whom the safety profile of fluvoxamine has been extensively assessed (Wagneret al., 1994). The daily dose of fluvoxamine ranged from less than 50 to 300 mg and the studies were conducted over periods of up to 1 year. The most conservative category was chosen throughout the analysis in situations where more than one category was applicable. Overall, 3250 patients (67·1 per cent) completed the full study period. At least one adverse event was reported by 2228 patients (46·0 per cent), the most frequently affected body systems being the ‘gastrointestinal’ and ‘nervous’ systems, followed by the ‘body as a whole’. Nausea was the most common adverse event. At least one serious adverse event was experienced by 135 patients (2·8 per cent), hospitalization being the most widespread classification (113 patients; 2·3 per cent). The incidence of overall suicidality with fluvoxamine was low. Thus, these findings indicate that fluvoxamine is a well tolerated drug in elderly patients.     

Safety of benzodiazepines in the geriatric population

Generalised anxiety disorder (GAD) significantly impacts upon quality of life and has a chronic and persistent nature. GAD requires pharmacological therapies that are well-tolerated, lessen the mitigating effects of common comorbidities and do not pose a high risk for dependency or abuse. Selective serotonin and serotonin–noradrenaline re-uptake inhibitors have become more viable treatments for GAD than the traditionally used benzodiazepines due to greater efficacy and a more tolerable adverse event profile. Among these newer-generation antidepressants, only paroxetine and venlafaxine are currently FDA-approved for the treatment of GAD. Paroxetine was approved after three double-blind, placebo-controlled studies demonstrated its superior efficacy compared to placebo for short-term treatment of GAD. Venlafaxine was approved for both short- and long-term treatment of GAD after demonstrating efficacy in 8-week and 6-month double-blind, placebo-controlled trials. For both paroxetine and venlafaxine, the safety and tolerability profiles during treatment of GAD are consistent with those demonstrated during the short- and long-term treatment of patients with major depressive disorder.     

Selective serotonin re-uptake inhibitors and the risk of bleeding

Despite their safety, selective serotonin re-uptake inhibitors (SSRIs) are associated with bleeding. The authors critically reviewed the medical literature on SSRIs to identify subgroups of patients at risk of bleeding complications. The authors performed a literature search using MEDLINE from 1966 to 1st September 2004 using; ‘haemorrhage, serotonin uptake inhibitors and antidepressive agents’ as search terms and followed up on citations in each paper that was relevant to SSRI associated bleeding. The authors reviewed 7 retrospective analytical studies and 24 case reports of bleeding in 43 different people. Analytical studies support an association between SSRI consumption and upper gastrointestinal (GI) bleeding and perioperative bleeding. Little evidence links SSRI use with intracerebral haemorrhage. The risk of GI bleeding appeared to be highest among patients consuming SSRIs with NSAIDs. Combining aspirin or NSAIDs with SSRIs may further increase the risk of bleeding. Clinicians should caution patients about combining SSRIs with aspirin or NSAIDs. Pharmacotherapy to reduce the risk of GI bleeding should be consid-ered in high risk patients.     

Combined treatments for major depression

Major depression is a chronic disorder with a high morbidity and mortality. Approved treatment for major depression at present includes monotherapy with antidepressants of different pharmacologic classes. There is increasingly widespread use of two other options: augmentation, the addition to an antidepressant of a second compound that is not an antidepressant when used alone; and combination, which is the use of two antidepressants concurrently to enhance or accelerate response. This review focuses on the data available to support these various augmentation and combination treatments.     

Long-acting atypical injectable antipsychotics in the treatment of schizophrenia: safety and tolerability review

Importance of the field: Although atypical antipsychotics have beneficial efficacy and tolerance, non-adherence and partial adherence remain in patients treated for schizophrenia. Long-acting injectable or depot atypical antipsychotics offer better medication adherence and tolerability advantages. Currently, two drugs are available for the treatment of schizophrenia, risperidone long-acting injectable (RLAI) and olanzapine pamoate (OP).

Areas covered in this review: Short- and long-term safety and tolerability data on RLAI and OP from January 2006 through September 2009 were reviewed by performing Medline and PubMed searches, reviewing abstracts and poster presentations, and viewing available material from the FDA and European Medicines Agency.

What the reader will gain: RLAI and OP show good short- and long-term safety when treating patients with schizophrenia, with uncommon discontinuation due to adverse effects. RLAI and OP data show rare problems with injection site reactions and patients exposed to injectable treatments prefer to continue injections. Infrequent but serious post-injection delirium sedation syndrome occurred after 1% of OP injections. Weight gain was generally higher among patients treated with OP versus RLAI.

Take home message: Healthcare providers, patients and family members should be made aware of the safety and benefits of long-acting injectable atypical antipsychotics in order to diminish the unnecessary restrictions of these therapies for patients with schizophrenia.