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Two phase 2B, randomized, double-blind studies assessed the efficacy and safety of fixed or flexible dose of triple monoamine uptake inhibitor BMS-820836 in patients with treatment-resistant depression to demonstrate whether switching to BMS-820836 was superior to the continuation of standard antidepressant treatment. Patients with a history of inadequate response to 1 to 3 adequate trials of antidepressant therapies were prospectively treated with duloxetine 60 mg/d for 8 weeks (CN162-006) or duloxetine 60 mg/d or escitalopram 20 mg/d for 7 weeks (CN162-007). Inadequate responders were randomized to continue their prospective phase treatment or switch to flexible-dose (0.5-2 mg/d; CN162-006) or fixed-dose (0.25, 0.5, 1, or 2 mg/d; CN162-007) BMS-820836 for 6 weeks. The primary end point in both studies was mean change in Montgomery-Åsberg Depression Rating Scale (MADRS) total score from randomization to study end point. BMS-820836 flexible (0.5-2 mg/d) or fixed dose of 1 mg/d or greater showed efficacy similar to the continuation of antidepressant treatment, with no statistically significant or clinically meaningful differences. In the CN162-006 study, the adjusted mean (SE) change in MADRS total score was -8.7 (0.661) and -8.1 (0.656) for BMS-820836 and duloxetine, respectively (P = 0.526). In the CN162-007 study, the adjusted mean (SE) change in MADRS total score was -7.3 (0.830) and -6.6 (0.842) for BMS-820836 of 1 and 2 mg, respectively, and -6.9 (0.602) for the continuation group (P = 0.910). Thus, BMS-820836 was well tolerated, with no evidence of dose-dependent discontinuations due to adverse events, but it failed to demonstrate superiority to the continuation of an existing antidepressant in patients with treatment-resistant depression.

The aim of this study was to evaluate the efficacy, tolerability, and effects on quality of life of sertraline, a selective serotonin reuptake inhibitor, in the prevention of relapse of generalized social phobia. Fifty adult outpatients with generalized social phobia who were rated much or very much improved on the Clinical Global Impression Scale of Improvement (CGI-I) after 20 weeks of sertraline treatment (50-200 mg/day) were randomly assigned in a one-to-one ratio to either continue double-blind treatment with sertraline or immediately switch to placebo for another 24 weeks. The initial 20-week study was placebo-controlled, and 15 responders to placebo also continued to receive double-blind placebo treatment in the continuation study. Eighty-eight percent of patients in the sertraline-continuation group and only 40% of patients in the placebo-switch and placebo-responder groups completed the study. In intent-to-treat endpoint analyses, 1 (4%) of 25 patients in the sertraline-continuation group and 9 (36%) of 25 patients in the placebo-switch group had relapsed at study endpoint (chi2 = 8.0, Fisher exact test, p = 0.01). The relative risk (hazards ratio) for relapse associated with placebo-switch relative to sertraline-continuation treatment was 10.2 (95% confidence interval, 1.3-80.7). Mean CGI-Severity, Marks Fear Questionnaire (MFQ) Social Phobia subscale, and Duke Brief Social Phobia Scale (BSPS) total scores were reduced by 0.07, 0.34, and 1.86 in the Sertraline-Continuation group and increased by 0.88, 4.09, and 5.99 in the Placebo-Switch group (all F > 5.3, p < 0.03), respectively. CGI-Severity, MFQ Social Phobia subscale, and BSPS scores also increased in the Placebo-Responder group. Discontinuations because of lack of efficacy were 4% in the sertraline-continuation group, 28% in the placebo-switch group (chi2 = 5.36, Fisher exact test, p = 0.049), relative to sertraline, and 27% in the placebo-responder group. Sertraline was effective in preventing relapse of generalized social phobia. Future research should assess whether improvements may be maintained or further increased by longer periods of treatment or through the addition of cognitive-behavioral techniques.

BACKGROUND The selective serotonin reuptake inhibitor sertraline has been shown to be efficacious and well tolerated for the treatment of major depressive disorder. Relatively few trials, however, have examined the role of pharmacotherapy in dysthymia without concurrent major depression. The current investigation focuses on the use of sertraline for the treatment of dysthymia. METHOD In this 12-week, multicenter, double-blind study, 310 patients with a DSM-III-R diagnosis of dysthymic disorder without concurrent major depression were randomly assigned to receive either sertraline (N = 158) or placebo (N = 152). Sertraline was initiated at a dose of 50 mg daily, with titration permitted to a maximum of 200 mg daily. The primary evaluation criteria were the Structured Interview Guide for the Hamilton Depression Rating Scale, Seasonal Affective Disorder Version (SIGH-SAD), the Montgomery-Asberg Depression Rating Scale (MADRS), and the Clinical Global Impressions-Severity of Illness (CGI-S) and -Improvement (CGI-I) scales. RESULTS Mean percentage reductions for the intent-to-treat population in SIGH-SAD scores were 44.6% for the sertraline-treated group and 33.2% for the placebo-treated group (p = .03); MADRS scores, 43.6% and 33.0% (p = .02); and CGI-S scores, 32.8% and 22.8% (p = .02). A significantly greater proportion of the sertraline-treated group was classified as responders (defined for HAM-D and MADRS scores as a 50% score reduction and for CGI-I as a score of 1 or 2 by the final visit) and remitters (SIGH-SAD score < or = 8) relative to the placebo-treated group by the final visit. In addition, sertraline-treated patients experienced greater improvements in all 9 domains of the Battelle Quality of Life Questionnaire than placebo-treated patients did, with a significant difference observed in favor of sertraline in 8 of the 9 domains. The life satisfaction and social interaction quality of life domains showed significantly greater response in sertraline responders compared with placebo SIGH-SAD responders. Sertraline was well tolerated. Thirteen percent of the sertraline-treated group versus 8% of the placebo-treated group withdrew from therapy owing to adverse events (p = .14). CONCLUSION Sertraline is efficacious and well tolerated in the short-term treatment of dysthymia without concurrent major depression.

Sexual problems are highly prevalent in both men and women and are affected by, among other factors, mood state, interpersonal functioning, and psychotropic medications. The incidence of antidepressant-induced sexual dysfunction is difficult to estimate because of the potentially confounding effects of the illness itself, social and interpersonal comorbidities, medication effects, and design and assessment problems in most studies. Estimates of sexual dysfunction vary from a small percentage to more than 80%. This article reviews current evidence regarding sexual side effects of selective serotonin reuptake inhibitors (SSRIs). Among the sexual side effects most commonly associated with SSRIs are delayed ejaculation and absent or delayed orgasm. Sexual desire (libido) and arousal difficulties are also frequently reported, although the specific association of these disorders to SSRI use has not been consistently shown. The effects of SSRIs on sexual functioning seem strongly dose-related and may vary among the group according to serotonin and dopamine reuptake mechanisms, induction of prolactin release, anticholinergic effects, inhibition of nitric oxide synthetase, and propensity for accumulation over time. A variety of strategies have been reported in the management of SSRI-induced sexual dysfunction, including waiting for tolerance to develop, dosage reduction, drug holidays, substitution of another antidepressant drug, and various augmentation strategies with 5-hydroxytryptamine-2 (5-HT2), 5-HT3, and alpha2 adrenergic receptor antagonists, 5-HT1A and dopamine receptor agonists, and phosphodiesterase (PDE5) enzyme inhibitors. Sexual side effects of SSRIs should not be viewed as entirely negative; some studies have shown improved control of premature ejaculation in men. The impacts of sexual side effects of SSRIs on treatment compliance and on patients' quality of life are important clinical considerations.

The selective pharmacology of the selective serotonin reuptake inhibitors (SSRIs) results in a lower potential for pharmacodynamic drug interactions relative to other antidepressants such as the tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors (MAOIs). However, the SSRIs have been implicated in the development of the serotonin syndrome--a potentially life-threatening complication of treatment with psychotropic drugs. The syndrome is produced most often by the concurrent use of two or more drugs that enhance central nervous system serotonin activity and often goes unrecognized because of the varied and nonspecific nature of its clinical features. The serotonin syndrome is characterized by alterations in cognition (disorientation, confusion), behavior (agitation, restlessness), autonomic nervous system function (fever, shivering, diaphoresis, diarrhea), and neuromuscular (ataxia, hyperreflexia, myoclonus) activity. The difference between this syndrome and the occurrence of adverse effects caused by serotonin reuptake inhibitors alone is the clustering of the signs and symptoms, their severity, and their duration. There are important pharmacokinetic interactions between SSRIs and other serotonergic drugs due principally to their effects on the cytochrome P450(CYP) isoenzymes, the potential for which varies widely amongst the SSRI group, which may increase the likelihood of a pharmacodynamic interaction. The exceptionally long washout period required after fluoxetine discontinuation may cause additional problems and/or inconvenience. Patients with serotonin syndrome usually respond to discontinuation of drug therapy and supportive care alone, but they may also require treatment with antiserotonergic agent such as cyproheptadine, methysergide, and/or propranolol. To reduce the occurrence, morbidity, and mortality of the serotonin syndrome, it must be both prevented by prudent pharmacotherapy and given prompt recognition when it is present.

There is a high incidence of sexual dysfunction in the general population and sexual dysfunction is often an integral symptom of a depressive disorder. In addition, all antidepressants have effects on sexual functioning, as the result of side-effects of these medications and as a reflection of therapeutic success. The selective serotonin reuptake inhibitors (SSRIs) are clearly associated with delayed ejaculation, inability to ejaculate and absent or delayed orgasm. Furthermore, the incidence of sexual dysfunction obtained by patient self- report does not appear to reflect the true incidence of sexual dysfunction associated with antidepressant therapy and systematic inquiry is needed as sexual dysfunction may be an unrecognized cause of non- compliance. The SSRIs may have advantageous effects on sexual functioning and these may also be under- reported due to the same factors resulting in an under-reporting of sexual side-effects in general. In addition, studies have suggested a role for the SSRIs in the management of premature ejaculation. The effects of SSRIs on sexual functioning are clearly dose-related and may vary amongst the group due to their relative effects on the serotonin and dopamine systems and the extent to which plasma levels of these drugs accumulate in the body over time. A variety of strategies have been found useful in the management of SSRI-induced sexual dysfunction including waiting for tolerance to develop, dosage reduction, drug holidays, switching to a different antidepressant and various augmentation strategies with 5-HT 2, α2 adrenergic receptor antagonists and dopamine receptor agonists.

The highly specific mechanism of action of the selective serotonin re-uptake inhibitors (SSRIs) confers advantages on this group, relative to other classes of antidepressant, and thus represents a significant advance in the pharmacotherapy of depression. Whilst their clinical efficacy is equivalent to that of the tricyclic antidepressants (TCAs), the SSRIs have a greatly reduced risk of toxicity in overdose and have been shown to be significantly better tolerated. Specifically, the SSRIs have a low incidence of anticholinergic effects and are essentially devoid of cardiotoxicity. This tolerability advantage may be of significance in improving compliance and hence cost-effectiveness of treatment, particularly in the long term. Despite a lack of sedative effect, there is evidence that SSRIs are more effective than TCAs in the treatment of depression with anxiety. In addition, the SSRIs have been shown to be effective in obsessive-compulsive disorder, panic disorder and social phobia. Although superior efficacy has not been demonstrated for any one of the SSRIs, the structural diversity of this group is reflected in emerging qualitative and quantitative differences in side effects and drug interaction potential. Many of these differential features reflect important variations in pharmacological and pharmacokinetic profiles, including dosage flexibility, washout times, dose-plasma level proportionality and age-related changes in plasma levels. Fluoxetine, for example, has a considerably longer half-life than other SSRIs and side effects and drug interactions may thus occur for an extended period following discontinuation of treatment. Significant differences in the potential for drug interactions in this group are related to their relative potency for inhibition of important liver drug-metabolising enzymes including CYPIID6, CYPIA2 and CYPIIA4. Large comparative clinical trials of the different SSRIs have yet to be undertaken; however, the differences that have already become apparent provide important information enabling the physician to choose an SSRI appropriate to the individual patient.

The long-term outlook for patients with unipolar depression is often poor. As few as one-fifth will remain well and a similar number will suffer chronic depression. It is now standard practice to extend acute treatment into a 4–6 month period of continuation therapy, and the value of prophylactic treatment over longer periods is becoming more widely recognised. Care must, however, be exercised in choosing suitable long-term treatment. Relatively little work on the prophylactic efficacy of the tricyclic antidepressants has been carried out, although imipramine has been shown to be effective. The selective serotonin re-uptake inhibitors (SSRIs) have been studied extensively and may be the most suitable long-term treatment for depression. Sertraline is effective in preventing both relapse and recurrence of depression and was the first agent specifically indicated for the long-term treatment of depression in the UK. In addition to clinical efficacy, many other factors favour SSRIs in the long-term management of depression. The tolerability of a drug is of major importance in long-term therapy since it affects compliance. Other important considerations include toxicity, safety in overdose, drug interaction potential, psychomotor effects and accident liability.

Retrospective data are presented to support a spectrum of early Alzheimer's disease (AD) along a continuum defined by gender and genotype. The putative neurodegenerative mechanisms driving distinct phenotypes at each end of the spectrum are glial hypoactivity associated with early failure of synaptic cholinergic neurotransmission and glial overactivation associated with loss of neural network connectivity due to accelerated age-related breakdown of myelin. In early AD, male butyrylcholinesterase K-variant carriers with one or two apolipoprotein ɛ4 alleles have prominent medial temporal atrophy, synaptic failure, cognitive decline, and accumulation of aggregated beta-amyloid peptide. Increasing synaptic acetylcholine in damaged but still functional cholinergic synapses improves cognitive symptoms, whereas increasing the ability of glia to support synapses and to clear beta-amyloid peptide might be disease-modifying. Conversely, chronic glial overactivation can also drive degenerative processes and in butyrylcholinesterase K-variant negative females generalized glial overactivation may be the main driver from mild cognitive impairment to AD. Females are more likely than males to have accelerated age-related myelin breakdown, more widespread white matter loss, loss of neural network connectivity, whole brain atrophy, and functional decline. Increasing extracellular acetylcholine levels blocks glial activation, reduces myelin loss and damage to neural network connectivity, and is disease-modifying. Between extremes characterized by gender, genotype, and age, pathophysiology may be mixed and this spectrum may explain much of the heterogeneity of amnestic mild cognitive impairment. Preservation of the functional integrity of the neural network may be an important component of strengthening cognitive reserve and significantly delaying the onset and progression of dementia, particularly in females. Prospective confirmation of these hypotheses is required. Implications for future research and therapeutic opportunities are discussed.

The authors evaluated the efficacy, safety, and tolerability of sertraline, a selective serotonin reuptake inhibitor, in the treatment of generalized social phobia.Adult outpatients with generalized social phobia (N=204) from 10 Canadian centers were randomly assigned to receive sertraline or placebo in a 2:1 ratio for a 20-week double-blind study following a 1-week, single-blind, placebo run-in. The initial dose of sertraline was 50 mg/day with increases of 50 mg/day every 3 weeks permitted after the fourth week of treatment (dosing was flexible up to a maximum of 200 mg/day). Primary efficacy assessments were the percentage of patients rated much or very much improved on the Clinical Global Impression (CGI) improvement item and the mean changes from baseline to study endpoint in total score on the social phobia subscale of the Marks Fear Questionnaire and total score on the Brief Social Phobia Scale.In intent-to-treat endpoint analyses of 203 of the patients, significantly more of the 134 patients given sertraline (N=71 [53%]) than of the 69 patients receiving placebo (N=20 [29%]) were considered responders according to their CGI improvement scores at the end of treatment. The mean reductions in the social phobia subscale of the Marks Fear Questionnaire and in the total score on the Brief Social Phobia Scale were 32.6% and 34.3% in the sertraline group and 10.8% and 18.6% in the placebo group, respectively. Analysis of covariance showed superiority of sertraline over placebo on all primary and secondary efficacy measures. Sertraline was well tolerated: 103 (76%) of the 135 sertraline-treated patients and 54 (78%) of the 69 placebo-treated patients completed the study.Sertraline is an effective treatment for patients with generalized social phobia.

One hundred and ninety-seven outpatients with atypical depression [Atypical Depression Diagnostic Scale (ADDS) score=4] were randomized to 12 weeks of double-blind treatment with sertraline or moclobemide in a multicentre, parallel-group clinical trial. Patients were started on either 50 mg/day sertraline or 300 mg/day moclobemide. If the therapeutic response was not satisfactoryafter 4 weeks, the dose could be increased to either 100 mg/day sertraline or 450 mg/day moclobemide. Primary effcacy evaluations were the 29-item Hamilton Psychiatric Rating Scale for Depression (HAM-D) and the Clinical Global Impression of Improvement (CGI I) response rate (much or very much improved) at study endpoint. Secondary effcacy evaluations included the ADDS, the Hamilton Anxiety Scale (HAMA), the Leeds Sleep Scale, and the Battelle Quality of Life Battery (BQOLB). In the analysis of the 172 patient effcacy-evaluable population, there was significant baseline to endpoint improvement in all primary and secondary effcacy assessments after treatment with either sertraline or moclobemide. At the endpoint, the proportion of responders on CGI-I, was 77.5% in the sertraline group and 67.5% in the moclobemide group (p=0.052). The baseline to endpoint mean 29-item HAM-D score decreased from 35.9 to 14.5 in the sertraline group and from 36.3 to 16.1 in the moclobemide group. Sertraline also resulted in a significantly (p50.05) greater degree of improvement at the endpoint, compared with moclobemide, in the proportion of remitters on the HAMA (total score47), ADDS Category IID (Rejection Sensitivity), Leeds Sleep Factor 4 (Integrity of Behaviour Following Awakening), and on three dimensions of the BQOLB (Energy/Vitality, Social Interaction and Life Satisfaction). There were no other significant differences between treatment groups. Overall, both medications were well tolerated. In this study, both sertraline and moclobemide improved the symptoms of atypical depression.

The selective serotonin reuptake inhibitors (SSRIs) may occasionally induce extrapyramidal side-effects (EPS) and/or akathisia.This maybe a consequence of serotonergically-mediated inhibition of the dopaminergic system. Manifestations of these effects in patients may depend on predisposing factors such as the presence of psychomotor disturbance, a previous history of drug-induced akathisia and/or EPS, concurrent antidopaminergic and/or serotonergic therapy, recent monoamine oxidase inhibitor discontinuation, comorbid Parkinson's disease and possibly deficient cytochrome P450 (CYP) isoenzyme status. There is increasing awareness that there may be a distinct form of melancholic or endogenous depression with neurobiological underpinnings similar to those of disorders of the basal ganglia such as Parkinson's disease. Thus, it is not surprising that some individuals with depressive disorders appear to be susceptible to developing drug-induced EPS and/or akathisia. In addition, the propensity for the SSRIs to induce these effects in individual patients may vary within the drug class depending, for example, on their selectivity for serotonin relative to other monoamines, affinity for the 5-HT2Creceptor, pharmacokinetic drug interaction potential with concomitantly administered neuroleptics and potential for accumulation due to a long half-life. The relative risk of EPS and akathisia associated with SSRIs have yet to be clearly established. The potential risks may be reduced by avoiding rapid and unnecessary dose titration. Furthermore, early recognition and appropriate management of EPS and/or akathisia is required to prevent the impact of these effects on patient compliance and subjective well-being. It is important that the rare occurrence of EPS in patients receiving SSRIs does not preclude their use in Parkinson's disease where their potentially significant role requires more systematic evaluation.

The dose regimen for sertraline in the treatment of depression has been well established. The starting dose, 50 mg/day, is the usually effective therapeutic dose, and the optimal dose when considering both efficacy and tolerability for most patients. For patients who do not show an adequate therapeutic response within 2-4 weeks, the dose of sertraline can be increased in 50 mg/day increments at no less than weekly intervals to a maximum of 200 mg/day. Sertraline is generally given as a single daily dose and may be administered at any time of the day. In contrast to other selective serotonin reuptake inhibitors, there is no need for altered dose recommendations in the elderly.