BCL-2 is dispensable for thrombopoiesis and platelet survival.

Navitoclax (ABT-263), an inhibitor of the pro-survival BCL-2 family proteins BCL-2, BCL-XL and BCL-W, has shown clinical efficacy in certain BCL-2-dependent haematological cancers, but causes dose-limiting thrombocytopaenia. The latter effect is caused by Navitoclax directly inducing the apoptotic death of platelets, which are dependent on BCL-XL for survival. Recently, ABT-199, a selective BCL-2 antagonist, was developed. It has shown promising anti-leukaemia activity in patients whilst sparing platelets, suggesting that the megakaryocyte lineage does not require BCL-2. In order to elucidate the role of BCL-2 in megakaryocyte and platelet survival, we generated mice with a lineage-specific deletion of Bcl2, alone or in combination with loss of Mcl1 or Bclx. Platelet production and platelet survival were analysed. Additionally, we made use of BH3 mimetics that selectively inhibit BCL-2 or BCL-XL. We show that the deletion of BCL-2, on its own or in concert with MCL-1, does not affect platelet production or platelet lifespan. Thrombocytopaenia in Bclx-deficient mice was not affected by additional genetic loss or pharmacological inhibition of BCL-2. Thus, BCL-2 is dispensable for thrombopoiesis and platelet survival in mice.

Sertraline treatment of generalized social phobia: a 20-week, double-blind, placebo-controlled study.

OBJECTIVE: The authors evaluated the efficacy, safety, and tolerability of sertraline, a selective serotonin reuptake inhibitor, in the treatment of generalized social phobia. METHOD: 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. RESULTS: 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. CONCLUSIONS: Sertraline is an effective treatment for patients with generalized social phobia.

Treatment of dysthymia with sertraline: a double-blind, placebo-controlled trial in dysthymic patients without major depression.

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.

A critical review of selective serotonin reuptake inhibitor-related sexual dysfunction; incidence, possible aetiology and implications for management.

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 noncompliance. The SSRIs may have advantageous effects on sexual functioning and these may also be underreported 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-HT2, alpha2 adrenergic receptor antagonists and dopamine receptor agonists.

SSRI-induced extrapyramidal side-effects and akathisia: implications for treatment.

The selective serotonin reuptake inhibitors (SSRIs) may occasionally induce extrapyramidal side-effects (EPS) and/or akathisia. This may be 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-HT2C receptor, 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.

Pharmacokinetic drug interaction potential of selective serotonin reuptake inhibitors.

Obsessive-compulsive disorder (OCD) is a chronic disorder requiring long-term treatment. The pharmacological management of the disorder, therefore, requires the use of agents which, in addition to being efficacious and well tolerated, are unlikely to cause pharmacokinetic drug-drug interactions with concomitantly administered medication which the patient is receiving or may receive in the future. The selective serotonin reuptake inhibitors (SSRIs) have similar pharmacodynamic profiles but their pharmacokinetic profiles are very different. Perhaps the most substantial pharmacokinetic difference among these drugs is in their potential for drug-drug interactions via the inhibition of cytochrome P450 (CYP) isoenzymes. This review provides comprehensive background information on these enzyme systems and discusses their significance with respect to the optimal care of patients. Fluoxetine is a substantial inhibitor of CYP2D6, has mild effects on CYP3A3/4, and may also have effects on CYP2C9/10 and CYP2C19. Effects on drugs metabolized by these enzymes can persist for many weeks after fluxoetine discontinuation due to the long half-life of fluoxetine and its active metabolite norfluoxetine. Fluvoxamine is a substantial inhibitor of CYP1A2 and CYP2C19, and a moderate inhibitor of CYP3A3/4. Paroxetine is a substantial inhibitor of CYP2D6. In contrast, sertraline and citalopram are mild inhibitors of CYP2D6 at their usually effective doses and are not known to produce clinically meaningful inhibition of any other isoenzymes. However, citalopram has not been well studied against all of these enzymes, especially in vivo. An increased risk of pharmacokinetic drug interactions is the immediate clinical consequence of the inhibitory effects of these drugs on CYP isoenzymes. However, with the emphasis on long-term treatment, particularly in chronic conditions such as OCD, it will also be important to determine the long-term clinical consequences of substantially inhibiting specific CYP isoenzymes with those SSRIs which have these effects. Thus knowledge of the substrates and inhibitors of CYP isoenzymes may help clinicians to anticipate and avoid pharmacokinetic drug interactions and may better define rational prescribing practices.

Sertraline 50 mg daily: the optimal dose in the treatment of depression.

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 24 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.

Predictors of an acute antidepressant response to fluoxetine and sertraline.

Sertraline and fluoxetine have different pharmacologic and pharmacokinetic profiles which may be of clinical relevance in the determination of response in different subtypes of depression. A randomized, double-blind, 6-week study comparing sertraline (50-100 mg/day) with fluoxetine (20-40 mg/day) in 286 outpatients with major depression, who had demonstrated comparable efficacy and tolerability for the two drugs, was analysed by subgroups of patients at baseline with melancholia, severe depression, single depressive episode, multiple depressive episodes, high anxiety, low anxiety, psychomotor retardation and psychomotor agitation. Multiple logistic regression with regressors including treatment-by-subgroup variables revealed that, within certain subgroups, the efficacy might differ substantially from that of the whole treatment group. However, the only treatment-by-subgroup interaction term that was significant was anxiety (P < 0.05). There was no evidence of interaction in single or recurrent episode subgroups, and these were not included in subsequent analyses. Subsequent two-sample statistical comparison tests of response (i.e. Hamilton Depression Scale reduction > or = 50%) rates at study endpoint between treatment groups demonstrated that patients with melancholic depression and those with symptoms of psychomotor agitation yielded a significantly greater proportion of responders with sertraline compared to fluoxetine (P < 0.05). Response rates in sertraline- and fluoxetine-treated patients, respectively, were: overall study 59%, 51%; melancholia 59%, 44%; severe depression 59%, 41%; low anxiety 71%, 55%; high anxiety 47%, 48%; psychomotor retardation, 48%, 46%; and psychomotor agitation 62%, 39%. Multiple logistic regression adjusting for possible confounding factors, that included a treatment by anxiety interaction term, also led to similar findings. In particular, the analysis showed that significant differences existed in favour of sertraline in patients with low anxiety in the melancholia and severe depression subgroups (P < 0.05), indicating that these characteristics predicted a superior response to 6 weeks of treatment with sertraline relative to fluoxetine. Sertraline also demonstrated advantages over fluoxetine on parameters such as sleep and weight disturbance in severely depressed patients, and sleep disturbance, weight, cognitive disturbance and retardation in melancholic patients.

A double-blind study of the efficacy and safety of sertraline and clomipramine in outpatients with severe major depression.

This study compared the efficacy and safety of the selective serotonin reuptake inhibitor sertraline with that of the tricyclic antidepressant clomipramine in patients with severe depression, as defined by a baseline 17-item Hamilton Depression Rating Scale (HAM-D) of at least 25. The study included 166 outpatients, randomized to double-blind treatment with sertraline (50-200 mg) or clomipramine (50-150 mg) for 8 weeks. The efficacy of both treatments was similar, 74% of patients in the sertraline group and 71% of clomipramine patients being classified as responders at the end-point, as defined by a Clinical Global Impression-Improvement (CGI-I) score of 1 or 2. Mean HAM-D scores fell from 29.8 at baseline to 12.3 at endpoint in the sertraline group, and from 29.6-12.7 in the clomipramine group. There were more withdrawals due to adverse events in the clomipramine group than in the sertraline group (17% versus 12%). Dry mouth, tremor, dizziness and constipation were all substantially more common in the clomipramine group, whereas diarrhoea/loose stools was more common in the sertraline group. Overall, sertraline was as effective as clomipramine in this group of severely depressed outpatients, and showed better tolerability.

SSRIs and hyponatraemia.

Increasing age, certain medications such as diuretics, disease processes such as malignant neoplasm and schizophrenia, and a history of hyponatraemia or polydipsia may predispose patients to the development of hyponatraemia. In addition, certain psychotropic medications, including TCAs, MAOIs, carbamazepine, trazodone and neuroleptics, may predispose to hyponatraemia, yet a causative role for most has not been firmly established and the effect is most likely to be more idiosyncratic. The SSRIs have been associated with hyponatraemia in a small number of case reports. The mean age and sex of patients in reported cases is over 70 years and predominantly female, and patients were often receiving concomitant diuretic therapy. The frequency of hyponatraemia in elderly female patients receiving fluoxetine has been estimated to be as high as eight per 1000. The risk of developing hyponatraemia appears to be highest during the first few weeks of treatment. Because of the potential seriousness of hyponatraemia, if an elderly patient receiving an SSRI develops unexplained symptoms during the first few weeks of therapy, it is necessary to measure the serum sodium level.

Chirality and drugs used in psychiatry: nice to know or need to know?

1. Many drugs used to treat psychiatric disorders contain a chiral center or a center of unsaturation and are marketed as a mixture of the resultant enantiomers or geometric isomers, respectively. These enantiomers or geometric isomers may differ markedly with regard to their pharmacodynamic and/or pharmacokinetic properties. 2. Examples of the effects of chiral centers or geometric centers on such properties are given for drugs from the following classes: antidepressants (tricyclics, selective serotonin reuptake inhibitors, monoamine oxidase inhibitors, viloxazine, bupropion, trazodone, mianserin, venlaflaxine); benzodiazepines, zoplicone, and antipsychotics. 3. As described in this review, there are several notable examples of psychiatric drugs currently available where the individual enantiomers or geometric isomers differ considerably with regard to factors such as effects on amine transport systems, interactions with receptors and metabolizing enzymes, and clearance rates from the body. Indeed, relatively recent developments in analytical and preparative resolution of racemic and geometric drug mixtures and increased interest in developing new drugs which interact with specific targets, which have been described in detail at the molecular level, have resulted in increased emphasis on stereochemistry in drug development.

Pharmacotherapy of the depressed patient with cardiovascular and/or cerebrovascular illness.

Cardiovascular and cerebrovascular disease are associated with a high incidence of depressive disorder. Despite this high level of co-morbidity, depressive disorders appear to go largely unrecognised and remain untreated. This may have serious consequences, as concomitant depression worsens the prognosis in patients with cardiovascular or cerebrovascular disease, increases medical costs, and delays return to work. Treatment with traditional tricyclic antidepressants is difficult in these patients because of the known cardiac effects. The favourable side-effect profiles of the 5-HT reuptake inhibitors suggest that they may offer therapeutic advantages, as they have little or no effect on cardiac conduction, do not cause orthostatic hypotension, and lack serious sequelae in overdose. The pharmacological profiles and the reduced potential of these newer antidepressant drugs to cause drug interaction show important differences that may be of clinical relevance in this patient population.

Effects of SSRIs on sexual function: a critical review.

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 effects of a dentifrice containing a zinc salt and a non-cationic antimicrobial agent on plaque and gingivitis.

The antiplaque potential of metal salts in mouthwashes or dentifrices has been previously demonstrated. The purpose of the present investigation was to establish the effects on plaque and gingival health of a dentifrice which contained a combination of the metal salt, zinc citrate, and the anti-microbial agent, Triclosan. Plaque growth was reduced by a dentifrice which contained either zinc citrate or triclosan, but greater inhibition was achieved with dentifrices which contained both agents. A 4-day non-brushing study in which slurries of the dentifrice were used, confirmed that the test dentifrice which contained 1% zinc citrate and 0.5% Triclosan reduced the accumulation of plaque by 50%. In a double-blind crossover study of 28 days duration, a significant reduction in plaque accumulation and an improvement in gingival health was demonstrated for the test dentifrice compared to the placebo. Further analysis of the data indicated that the dentifrice was most efficacious for participants who brushed ineffectively. Also, the greatest benefit was obtained by subjects that used the largest amount of dentifrice.

Prevention of relapse in generalized social phobia: results of a 24-week study in responders to 20 weeks of sertraline treatment.

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.