Results of indirect and mixed treatment comparison of fracture efficacy for osteoporosis treatments: a meta-analysis.

UNLABELLED: Network meta-analysis techniques (meta-analysis, adjusted indirect comparison, and mixed treatment comparison [MTC]) allow for treatment comparisons in the absence of head-to-head trials. In this study, conditional estimates of relative treatment efficacy derived through these techniques show important differences in the fracture risk reduction profiles of marketed pharmacologic therapies for postmenopausal osteoporosis. INTRODUCTION: This study illustrates how network meta-analysis techniques (meta-analysis, adjusted indirect comparison, and MTC) can provide comparisons of the relative efficacy of postmenopausal osteoporosis therapies in the absence of comprehensive head-to-head trials. METHODS: Source articles were identified in MEDLINE; EMBASE; Cochrane Central Register of Controlled Trials (CENTRAL) via Wiley Interscience; and Cumulative Index to Nursing and Allied Health Literature (CINAHL) between April 28, 2009 and November 4, 2009. Two reviewers identified English-language articles reporting randomized controlled trials (RCTs) with on-label dosing of marketed osteoporosis agents and fracture endpoints. Trial design, population characteristics, intervention and comparator, fracture outcomes, and adverse events were abstracted for analysis. Primary analyses included data from RCTs with fracture endpoints. Sensitivity analyses also included studies with fractures reported through adverse event reports. Meta-analysis compared fracture outcomes for pharmacological therapies vs. placebo (fixed and random effects models); adjusted indirect comparisons and MTC assessed fracture risk in postmenopausal women treated with denosumab vs. other agents. RESULTS: Using data from 34 studies, random effects meta-analysis showed that all agents except etidronate significantly reduced the risk of new vertebral fractures compared with placebo; denosumab, risedronate, and zoledronic acid significantly reduced the risk for nonvertebral and hip fracture, while alendronate, strontium ranelate, and teriparatide significantly reduced the risk for nonvertebral fractures. MTC showed denosumab to be more effective than strontium ranelate, raloxifene, alendronate, and risedronate in preventing new vertebral fractures. CONCLUSIONS: The conditional estimates of relative treatment efficacy indicate that there are important differences in fracture risk reduction profiles for marketed pharmacological therapies for postmenopausal osteoporosis.

Fear of falling, fracture history, and comorbidities are associated with health-related quality of life among European and US women with osteoporosis in a large international study.

UNLABELLED: We studied 7,897 women with postmenopausal osteoporosis to assess factors that influence health-related quality of life (HRQoL). An increased number of comorbidities, fear of falling, and previous vertebral fracture were associated with significant reductions in HRQoL. Understanding the factors that affect HRQoL may improve management of these patients. INTRODUCTION: HRQoL is impaired in women treated for postmenopausal osteoporosis (PMO). The objective of this study was to examine the relationship between clinical characteristics, comorbidities, medical history, patient demographics, and HRQoL in women with PMO. METHODS: Baseline data were obtained and combined from two large and similar multinational observational studies: Prospective Observational Scientific Study Investigating Bone Loss Experience in Europe (POSSIBLE EU®) and in the US (POSSIBLE US™) including postmenopausal women in primary care settings initiating or switching bone loss treatment, or who had been on bone loss treatment for some time. HRQoL measured by health utility scores (EQ-5D™) were available for 7,897 women (94 % of study participants). The relationship between HRQoL and baseline clinical characteristics, medical history and patient demographics was assessed using parsimonious, multivariable, mixed-model analyses. RESULTS: Median health utility score was 0.80 (interquartile range 0.69-1.00). In multivariable analyses, young age, low body mass index, previous vertebral fracture, increased number of comorbidities, high fear of falling, and depression were associated with reduced HRQoL. Regression-based model estimates showed that previous vertebral fracture was associated with lower health utility scores by 0.08 (10.3 %) and demonstrated the impact of multiple comorbidities and of fear of falling on HRQoL. CONCLUSIONS: In this large observational study of women with PMO, there was substantial interindividual variability in HRQoL. An increased number of comorbidities, fear of falling, and previous vertebral fracture were associated with significant reductions in HRQoL.

Fracture hospitalizations between years 2000 and 2007 in Switzerland: a trend analysis.

UNLABELLED: In Switzerland, the total number and incidence of hospitalizations for major osteoporotic fractures increased between years 2000 and 2007, while hospitalizations due to hip fracture decreased. The cost impact of shorter hospital stays was offset by the increasing cost per day of hospitalization. INTRODUCTION: The aim of the study was to establish the trends and epidemiological characteristics of hospitalizations for major osteoporotic fractures (MOF) between years 2000 and 2007 in Switzerland. METHODS: Sex- and age-specific trends in the number and crude and age-standardized incidences of hospitalized MOF (hip, clinical spine, distal radius, and proximal humerus) in women and men aged ≥45 years were analyzed, together with the number of hospital days and cost of hospitalization, based on data from the Swiss Federal Statistical Office hospital database and population statistics. RESULTS: Between 2000 and 2007, the absolute number of hospitalizations for MOF increased by 15.9% in women and 20.0% in men, mainly due to an increased number of non-hip fractures (+37.7% in women and +39.7% in men). Hospitalizations for hip fractures were comparatively stable (-1.8% in women and +3.3% in men). In a rapidly aging population, in which the number of individuals aged ≥45 years grew by 11.1% (women) and 14.6% (men) over the study period, the crude and age-standardized incidences of hospitalizations decreased for hip fractures and increased for non-hip MOF, both in women and men. The length of hospital stay decreased for all MOF in women and men, the cost impact of which was offset by an increase in the daily costs of hospitalization. CONCLUSIONS: Between years 2000 and 2007, hospitalizations for MOF continued to increase in Switzerland, driven by an increasing number and incidence of hospitalizations for non-hip fractures, although the incidence of hip fractures has declined.

Prevalence of osteoporosis and fractures among women prescribed osteoporosis medication in five European countries: the POSSIBLE EU study.

UNLABELLED: European observational 1-year study assessed osteoporosis and fracture patterns in 3,402 postmenopausal women prescribed osteoporosis medication. Almost 40% of patients had a previous fracture, while 25% had neither fracture nor dual energy X-ray absorptiometry (DXA) diagnosis and were prescribed medication, probably due to other risk factors. INTRODUCTION: This analysis assessed osteoporosis and fracture prevalence in postmenopausal women prescribed osteoporosis treatment in the Prospective Observational Study Investigating Bone Loss Experience in Europe(POSSIBLE EU). METHODS: Women in this observational, multicenter 1-year study were categorized by fracture history and location at baseline. Baseline characteristics were analyzed according to no DXA and DXA diagnosis (osteoporosis or osteopenia). Fractures occurring during the 1-year follow-up period were recorded. RESULTS: Of the 3,402 women enrolled, 39% had a previous fracture, of whom 30% had ≥ 2 fractures. One thousand seven hundred and eighty-four (52%) patients had a DXA diagnosis (osteoporosis 68%, osteopenia 31%, and unknown 1%). Among the osteoporosis patients, 37% had a previous fracture (hip 2.9%, vertebral 8.8%, and non-hip, non-vertebral 25%) and 35% had fractures associated with major trauma. Of the 3,402 women, 1,476 (43%) had no DXA diagnosis; of these, 57% had no fracture (25% of all women). Risk factors varied across patients with and without DXA diagnosis. During the 1-year follow-up period, the fracture incidence in patients with or without a previous fracture at baseline was 4.7% and 1.6%, respectively. CONCLUSION: Almost 40% of patients prescribed osteoporosis medication had a previous fracture, highlighting a population with advanced disease. In contrast, 25% of patients had neither a previous fracture nor DXA diagnosis and were prescribed treatment, probably due to other risk factors. There is a need for continued improvement of disease management in European women.

Autonomic abnormalities in schizophrenia. State or trait indicators?

BACKGROUND: Tonic electrodermal measures have been widely used to index autonomic abnormalities in schizophrenia, whereas phasic electrodermal nonresponsiveness has been frequently used to index attentional orienting abnormalities. The primary objective of the present study was to assess whether these electrodermal abnormalities are episode indicators or vulnerability indicators. METHODS: Twenty patients with a recent first episode of schizophrenia were tested during symptomatically remitted states and psychotic states. Twenty demographically matched normal controls were tested at two comparable intervals. Testing for stability of abnormalities across remitted and psychotic states allowed us to determine whether tonic and phasic electrodermal measures qualify as episode indicators or vulnerability indicators. RESULTS: Tonic electrodermal activity was abnormally elevated only during the psychotic state, which indicates that it is an episode indicator in schizophrenia. Phasic hyporesponsiveness relative to levels of general activation was present in both the remitted and the psychotic states, most strikingly during the psychotic state, and the proportion of patients who were electrodermally nonresponsive tended to be abnormally high during the remission test. CONCLUSION: Tonic electrodermal hyperarousal appears to be a state-sensitive episode indicator, whereas phasic electrodermal hyporesponsiveness to innocuous stimuli relative to activation level appears to be a mediating vulnerability factor.

Stress reactivity in bipolar patients and its relation to prior history of disorder.

OBJECTIVE: Two questions were posed: Does stress precipitate episodes of bipolar I disorder, and does sensitivity to stress differ in episodes later in the course of illness compared to early ones? METHOD: Fifty-two patients with bipolar I disorder were followed longitudinally for up to 2 years; clinical course was monitored, and interview assessments of life events were made every 3 months. RESULTS: The patients who had episodes of illness during follow-up had experienced significantly more severe stressors and more total stress in the preceding 6 months, and more total stress in the preceding 3 months, than those without episodes. Inconsistent with Post's stress "sensitization" hypothesis, patients with more prior episodes were more likely to have episodes following major stressors, and they relapsed more rapidly. CONCLUSIONS: Stressors may precipitate episodes of bipolar illness, especially for patients with more prior episodes. Different versions of the stress sensitization model remain to be tested.

Psychiatric syndromes linked to reproductive function in women: a review of current knowledge.

Four psychiatric syndromes related to reproductive function in women have been identified: postpartum depression, premenstrual syndrome (PMS), post-hysterectomy depression, and involutional melancholia. The authors review what is known about these syndromes and conclude, first, that postpartum depression comprises three separate syndromes, the most severe of which is most likely a variant of primary affective disorder. Second, research into the syndromal nature, biology, and treatment of PMS is still in its infancy due to a variety of methodological difficulties. Third, the rate of depression among women during the involutional period or following hysterectomy for benign pathology is not higher than it is at other times.

Correlates of stress reactivity in patients with bipolar disorder.

OBJECTIVE: The authors examined individual differences in stress reactivity as well as whether features of the illness itself or psychological characteristics differentiate between patients with bipolar disorder who are highly stress reactive and those who are not. METHOD: They assessed stressors and bipolar episodes in 58 patients with bipolar disorder followed for at least 1 year. RESULTS: Not only did stress level predict relapse, so did personality variables such as introversion and obsessionality and their interaction with stress. Number of previous episodes of bipolar illness, however, did not affect stress response. CONCLUSIONS: These results are not consistent with the view that episodes of bipolar disorder become increasingly independent of stressors after initial episodes. However, psychological traits may affect reactivity to stressors.

Life events and the course of bipolar disorder.

The authors examined the impact of life stress on the course of bipolar disorder over a 2-year period in a group of 61 outpatients. The patients were followed prospectively with ongoing assessments of stressful life events, symptoms, levels of maintenance medication, and compliance with treatment regimens. As predicted, survival analyses indicated a significant association between life events and relapse or recurrence of the disorder. These effects could not be explained by differences in levels of medication or compliance. Further research is recommended to examine which specific subgroups of bipolar patients are most susceptible to stress.

Desipramine and methylphenidate combination treatment for depression: case report.

The authors successfully treated a chronically depressed man with a combination of desipramine and methylphenidate. Methylphenidate did not change his serum desipramine level, and the authors speculate that its ability to potentiate tricyclic responsiveness may be due to its dopaminergic activity.

Relapse and impairment in bipolar disorder.

OBJECTIVE: The purpose of this study was to evaluate the outcome of bipolar disorder in the context of maintenance pharmacotherapy. METHOD: Eighty-two bipolar outpatients were followed prospectively for a mean of 4.3 years (minimum of 2 years); symptom rating and psychosocial outcome scales were used, and pharmacotherapy was rated on a 5-point scale. RESULTS: Despite continual maintenance treatment, survival analysis indicated a 5-year risk of relapse into mania or depression of 73%. Of those who relapsed, two-thirds had multiple relapses. Relapse could not be attributed to inadequate medication. Even for those who did not relapse, considerable affective morbidity was observed. A measure of cumulative affective morbidity appeared to be a more sensitive correlate of psychosocial functioning than was the number of relapses. Poor psychosocial outcome paralleled poor syndromal course. Poor psychosocial functioning, especially occupational disruption, predicted a shorter time to relapse. Depressions were most strongly related to social and family dysfunction. CONCLUSIONS: Even aggressive pharmacological maintenance treatment does not prevent relatively poor outcome in a significant number of bipolar patients.

Pharmacologic management of psychiatric illness during pregnancy: dilemmas and guidelines.

OBJECTIVE: Given concerns about use of psychotropic medication during pregnancy, the authors reviewed the literature regarding the effects of prenatal exposure to psychotropic medications on fetal outcome. METHOD: A MEDLINE search of all articles written in English from 1966 to 1995 was performed to review information on the effects of psychotropic drug use during pregnancy on fetal outcome. Where sufficient data were available and when methodologically appropriate, meta-analyses were performed to assess risk of fetal exposure by psychotropic medication class. RESULTS: Three primary effects are associated with medication use during pregnancy: 1) teratogenicity, 2) perinatal syndromes (neonatal toxicity), and 3) postnatal behavioral sequelae. For many drug classes there are substantial data regarding risk for teratogenicity. Tricyclic antidepressants do not seem to confer increased risk for organ dysgenesis. The available data indicate that first-trimester exposure to low-potency phenothiazines, lithium, certain anticonvulsants, and benzodiazepines may increase the relative risk for congenital anomalies. However, the absolute risk of congenital malformations following prenatal exposure to most psychotropics is low. CONCLUSION: Exposure to certain psychotropic drugs in utero may increase the risk for some specific congenital anomalies, but the rate of occurrence of these anomalies even with the increased risk remains low. Use of psychotropic medications during pregnancy is appropriate in many clinical situations and should include thoughtful weighing of risk of prenatal exposure versus risk of relapse following drug discontinuation. The authors present disorder-based guidelines for psychotropic drug use during pregnancy and for psychiatrically ill women who wish to conceive.

Clinical outcome following neuroleptic discontinuation in patients with remitted recent-onset schizophrenia.

OBJECTIVE: The goal of this report was to examine the clinical course following neuroleptic discontinuation of patients with recent-onset schizophrenia who had been receiving maintenance antipsychotic treatment for at least 1 year. METHOD: Fifty-three volunteer patients with recent-onset schizophrenia who had been clinically stabilized on a maintenance regimen of fluphenazine decanoate for a mean of 16.7 months had their antipsychotic medications withdrawn under clinical supervision. Participants initially entered a 24-week, double-blind crossover trial in which fluphenazine and placebo were administered for 12 weeks each. For those who did not experience symptom exacerbation or relapse during this period, fluphenazine was openly withdrawn; participants were then followed for up to 18 additional months. RESULTS: When a low threshold for defining symptom reemergence was used, 78% (N=39 of 50) of the patients experienced an exacerbation or relapse within 1 year; 96% (N=48 of 50) did so within 2 years. Mean time to exacerbation or relapse was 235 days. When hospitalization was used as a relapse criterion, only six of 45 of individuals (13%) experiencing an exacerbation or relapse who continued in treatment in the clinic were hospitalized, demonstrating the sensitivity of the psychotic exacerbation criterion. CONCLUSIONS: The vast majority of clinically stable individuals with recent-onset schizophrenia will experience an exacerbation or relapse after antipsychotic discontinuation, even after more than a year of maintenance medication. However, clinical monitoring and a low threshold for reinstating medications can prevent hospitalization for the majority of these patients.

Does thyroid supplementation accelerate tricyclic antidepressant response? A review and meta-analysis of the literature.

OBJECTIVE: The delayed onset of therapeutic response to antidepressants remains a major problem in the treatment of depression. Among the strategies to accelerate response to treatment, the early addition of thyroid hormone to antidepressants has been suggested as a viable method. The authors performed a meta-analysis of the literature on the use of thyroid hormone supplementation to accelerate the treatment of depression to determine whether there is sufficient evidence to support the clinical efficacy of this strategy. METHOD: Both a computer-aided search of the National Library of Medicine MEDLINE and an intensive search by hand were conducted to identify all double-blind, placebo-controlled studies assessing the concomitant administration of thyroid hormone and antidepressant to accelerate clinical response in patients with nonrefractory depression. RESULTS: Six studies were identified. All were conducted with triiodothyronine (T(3)) and a tricyclic antidepressant. Five of the six studies found T(3) to be significantly more effective than placebo in accelerating clinical response. The pooled, weighted effect size index was 0.58, and the average effect was highly significant. Further, the effects of T(3) acceleration were greater as the percentage of women participating in the study increased. CONCLUSIONS: This meta-analysis supports the efficacy of T(3) in accelerating clinical response to tricyclic antidepressants in patients with nonrefractory depression. Furthermore, women may be more likely than men to benefit from this intervention.

Antidepressant medications, mood and male fertility.

By modulating the activity of central neurotransmitters, psychotropic agents may affect reproductive functioning in men and women. Many neurotransmitters influence the hypothalamic-pituitary-gonadal (HPG) axis and can consequently affect menstrual cycling in women and spermatogenesis in men. Emotional state similarly may disrupt reproductive functioning through the effects of stress hormones on the HPG axis. While some data exist on the relationship between stress and menstrual cyclicity in women of reproductive age, little is known regarding the potential effect of emotional state on reproductive function in men. This paper will review: (1) aspects of male reproductive function that may be vulnerable to medication-induced influences; (2) the impact of emotional state on male reproductive function; and (3) the literature on the possible effects of antidepressant medications on male fertility.

Psychotropic medications and their effects on sexual function: diagnosis, biology, and treatment approaches.

BACKGROUND: The recognition and treatment of sexual side effects caused by psychotropic agents have become topics of increasing clinical concern. Gaps in our understanding of the biology of sex and in our knowledge of the effect of Axis I disorders on sexual functioning have made both recognition of sexual side effects and a coherent treatment approach to these side effects difficult. METHOD: The author reviews case reports, case series, and animal studies derived from a MEDLINE search for English language articles on the topics of the effects of psychiatric disorders on sexual functioning, the biology of sex, rates of sexual dysfunction associated with each medication class, and treatment approaches when these side effects occur. RESULTS: In evaluating sexual function in patients taking psychotropic medications, clinicians should first consider other potential causes of sexual dysfunction. In general, dopamine increases sexual behavior, serotonin inhibits it, while norepinephrine has conflicting effects. Sexual side effects have been described in association with all the major classes of psychotropic medications. Neuroleptics are often associated with sexual side effects. Priapism, seen with neuroleptics and trazodone, should be treated as a urological emergency. Anxiolytics cause mild, nonspecific sexual side effects as do the mood stabilizers. Among the antidepressants, the more powerful serotonergic medications--e.g., the serotonin selective reuptake inhibitors (SSRIs), clomipramine, and MAO inhibitors--may cause more sexual side effects than the tricyclics. Potential strategies to treat antidepressant-induced sexual side effects include lowering the dose, waiting, and switching to another agent. A number of specific antidotes, such as cyproheptadine and yohimbine, have been reported to reverse these side effects in a limited number of cases. CONCLUSION: Clinicians must be aware of and specifically ask about medication-induced sexual side effects. More effective treatments of these side effects must await much needed double-blind studies of various approaches, especially those to treat SSRI-induced sexual dysfunction.

The dexamethasone suppression test and response to somatic treatment: a review.

The dexamethasone suppression test (DST) has been primarily investigated as an aid in diagnosing endogenous depression; yet, its major clinical use has been as a predictor of treatment response. It is commonly held that 1) an abnormal DST predicts response to somatic (and not psychologic) therapies, 2) an abnormal DST predicts response to noradrenergic antidepressants, and 3) a normal DST predicts response to serotonergic agents. The DST predicted response to somatic therapies in only 6 of 16 published studies. No single methodologic factor, such as population variables, DST technique, or study design, can explain the marked discrepancy in study results. Only two of seven studies examining the DST and response to neurotransmitter-specific antidepressant groups found a positive relationship. The evidence that the DST predicts response to noradrenergic agents is weak. The DST does not predict acute response to somatic treatment in general or response to specific antidepressants. The selection of the appropriate treatment for depressed patients is still best made using clinical criteria.

Maintenance lithium treatment: side effects and compliance.

Fifty-one bipolar patients receiving maintenance lithium treatment were evaluated for the presence of side effects, their degree of distress, and the association of these side effects with compliance. Cognitive side effects and weight gain were the most disturbing to patients, whereas thirst and polyuria were the most common. Self-reported noncompliance correlated most highly with coordination (r = .38, p less than .01) and cognition (r = .30, p less than .05) side effects. Current depressed mood also showed a strong correlation with side effect scores, especially those for cognitive disturbances. However, the correlations between noncompliance and coordination and cognitive side effects were just as strong when the effects of depressed mood were partialled out. These findings indicate the link between noncompliance and lithium-induced central nervous side effects and suggest that related treatment issues must be addressed to ensure maximum clinical response.

Dexamethasone suppression test and treatment response.

The dexamethasone suppression test (DST) is frequently used to predict response to antidepressant therapy or to noradrenergic vs. serotonergic antidepressants. In a study of 173 inpatients and outpatients, the DST was not found to be predictive of response to antidepressant treatment for all depressed patients or of treatment response in a subgroup of melancholic patients (N = 86). Response of DST suppressors and nonsuppressors to antidepressants stratified by neurotransmitter specificity was not found to differ.