Global Benefit-risk Evaluation of Antidepressant Action: Comparison of Pooled Data for Venlafaxine,SSRIs, and Placebo

Do antidepressants have an equivalent risk-benefit ratio? Venlafaxine, a serotonin-norepinephrine reuptake inhibitor, is an effective antidepressant for treating major depression. The results of some clinical studies have suggested that venlafaxine may have more potent efficacy in sustaining remission in patients with major depression. Comparative clinical studies, however, lack suitable power to discern treatment differences in safety and also lack a quantitative basis for comparing risk and benefit. A global benefit-risk analysis of pooled data from eight randomized, double-blind, clinical trials of the safety and efficacy of venlafaxine and selective serotonin reuptake inhibitors (SSRIs) was performed. By using the ratio measure of risk-benefit, patients treated with venlafaxine (n=851) for 6-8 weeks experienced a relative gain of 1.57 compared with SSRI-treated patients (n=743) and a relative gain of 2.27 compared with placebo-treated patients (n=439). Subgroup analyses showed a relative gain of 1.35 for venlafaxine-treated patients (n=538) compared with fluoxetine-treated patients (n=549) and a relative gain of 2.53 compared with placebo-treated patients (n=357). A dose-response relationship was apparent between low (<75 mg/day), medium (75-150 mg/day), and high (>150 mg/day) dosages of venlafaxine; r values were 0.758, 0.822, and 1.181, respectively (P=.023, high dosage versus placebo; P=.030, medium dosage versus placebo). Important differences in risk and benefit exist between venlafaxine and SSRIs as a group compared with fluoxetine alone. A significant gain in benefit-risk in the treatment of major depression was observed with an increase in venlafaxine dosage from 75->150 mg/day.     

The Efficacy of Acupuncture in the Treatment of Major Depression in Women

The effectiveness of acupuncture as a treatment for major depression was examined in 38 women, randomly assigned to one of three treatment groups. Specific treatment involved acupuncture treatments for symptoms of depression; nonspecific treatment involved acupuncture for symptoms that were not clearly part of depression; a wait-list condition involved waiting without treatment for 8 weeks. The nonspecific and wait-list conditions were followed by specific treatment. Five women terminated treatment prematurely, 4 prior to the completion of the first 8 weeks. Following treatments specifically designed to address depression, 64% of the women (n = 33) experienced full remission. A comparison of the acute effect of the three 8-week treatment conditions (n = 34) showed that patients receiving specific acupuncture treatments improved significantly more than those receiving the placebo-like nonspecific acupuncture treatments, and marginally more than those in the wait-list condition. Results from this small sample suggest that acupuncture can provide significant symptom relief in depression, at rates comparable to those of psychotherapy or pharmacotherapy. Acupuncture may hold sufficient promise to warrant a larger scale clinical trial.     

Topiramate in the preventive treatment of episodic migraine: a combined analysis from pilot,double-blind,placebo-controlled trials

The safety and efficacy of medications for preventive treatment of migraine is the subject of current concern and investigation in health care. Two single-center, double-blind, placebo-controlled studies were conducted to evaluate the efficacy and safety of topiramate for migraine prophylaxis. Seventy patients with a diagnosis of migraine were randomly assigned to topiramate-treated and placebo groups. The studies consisted of a 4-week baseline phase, a 6-8 week titration, and 8-12 weeks of maintenance. Topiramate was titrated from an initial dose of 25 mg/day to a target dose of 100 mg BID. The primary efficacy measure, the mean 28-day migraine frequency, was lower in topiramate-treated patients than in the placebo group (3.2 versus 3.8, P=.001). Similarly, topiramate treatment resulted in a significantly greater mean reduction in migraine frequency than did placebo (1.55 versus 0.47, P=.001) and a significantly higher responder rate (35.3% versus 8.3%, P=.008). Paresthesia was the most common side effect reported with topiramate treatment. Other topiramate-associated adverse events included altered taste, memory impairment, diarrhea, and appetite suppression/weight loss. The rates of discontinuation were similar for the topiramate group (n=10) and the placebo group (n=8). These results suggest that topiramate is effective and well tolerated in the preventive treatment of migraine headaches.     

A pilot randomised controlled trial of an Internet-based cognitive behavioural therapy self-management programme (MS Invigor8) for multiple sclerosis fatigue

The majority of people affected by Multiple Sclerosis (paMS) experience severe and disabling fatigue. A recent randomised controlled trial (RCT) showed that cognitive behaviour therapy with a clinical psychologist was an effective treatment for MS fatigue. An Internet-based version of this intervention, MS Invigor8, was developed for the current study using agile design and input from paMS. MS Invigor8 includes eight tailored, interactive sessions. The aim was to test the feasibility and potential efficacy and cost-effectiveness of the programme in a pilot RCT. 40 patients were randomised to MS Invigor8 (n=23) or standard care (n=17). The MS Invigor8 group accessed sessions over 8-10 weeks and received up to three 30-60min telephone support sessions. Participants completed online standardised questionnaires assessing fatigue, mood, quality of life and service use at baseline and 10 weeks follow-up. Large between group treatment effects were found for the primary outcomes of fatigue severity (d=1.19) and impact (d=1.02). The MS Invigor8 group also reported significantly greater improvements in anxiety, depression and quality-adjusted life years. These data suggest that Internet-based CBT may be a clinically and cost-effective treatment for MS fatigue. A larger RCT with longer term follow-up is warranted.     

Aripiprazole-related tardive dyskinesia

The low prevalence of extrapyramidal symptoms associated with atypical antipsychotics has led to their widespread use during the past decade. Aripiprazole, the newest medication in this class, has been associated with extrapyramidal symptoms (eg, akathisia) and with improvement of tardive dyskinesia (TD), but to date it has not been associated with the development of TD. We report a case of TD associated with the use of aripiprazole 15 mg/day for 18 months for refractory depression. Symptoms of TD resolved within several weeks of discontinuation of aripiprazole.     

Optimizing treatment of schizophrenia. Enhancing affective/cognitive and depressive functioning

Recognition and treatment of schizophrenia has largely focused on positive symptoms of the disorder, such as delusions, hallucinations, and disorganization. However, other important symptoms, such as depression, cognition, and social functioning, have not received comparable attention. Fifty percent of schizophrenic patients suffer from comorbid depression, which is a major risk factor for suicide in this population, while 10% to 25% suffer from comorbid obsessive-compulsive disorder. Cognitive deficits commonly observed in patients with schizophrenia include problems with concentration, attention, and memory, as well as problem-solving and verbal skills. These deficits are observed at early stages of the illness and can predict deficits in functional capabilities, such as occupational and social skills, educational attainment, and the ability to live independently. The severity of such impairments affects all patient in this population, including up to 10% of patients working full time and up to one third of those working part time. In light of the debilitating effects of depression, cognitive impairment, and other aspects of affective functioning on the quality of life of patients with schizophrenia, physicians need to partner with their patients to address these concerns and determine an appropriate treatment regimen. This can be done with simple functional-based cognitive questioning, the use of evidence-based psychosocial practices, and psychoeducation on the many pharmacotherapeutic options. It is recommended that depressive or suicidal symptoms of schizophrenia be treated with an antidepressant or mood stabilizer only if the symptoms have not subsided after treatment of the psychosis with an atypical antipsychotic. Additionally, relative to older medications, atypicals have demonstrated benefit in improving some of the cognitive impairments.     

Serotonin syndrome in elderly patients treated for psychotic depression with atypical antipsychotics and antidepressants: two case reports

We report two cases of serotonin syndrome in elderly patients during treatment of psychotic depression with atypical antipsychotics and antidepressants. The first case is a 69-year-old man who was admitted for depression with psychosis and treated with trazodone, risperidone, and sertraline. Subsequently, he developed myoclonus, tremor, cogwheel rigidity, and diaphoresis. The second case is a 72-year-old female initially admitted to a medical inpatient unit for a change in mental status that presented as increased confusion, lethargy, slurred speech, and a fever of 101.5 degrees. She had been on phenelzine and quetiapine. In both cases, all symptoms resolved within 24 hours of the psychotropics being stopped. In both cases, we believe that serotonin syndrome was produced by a combination of an antidepressant and an atypical antipsychotic. There have been several case reports of serotonin syndrome from similar combinations of antidepressant and atypical antipsychotic treatment. Clinicians treating elderly patients with a combination of serotonergic antidepressants and atypical antipsychotics for psychotic depression should be aware of the potential for serotonin syndrome.     

Chronic treatment with haloperidol induces deficits in working memory and feedback effects of interval timing

Normal participants (n=5) having no experience with antipsychotic drugs and medicated participants (n=5) with clinical experience with chronic low doses of haloperidol (3-10 mg/day for 2-4 months) in the treatment of neuroses were evaluated for the effects of inter-trial interval (ITI) feedback on a discrete-trials peak-interval timing procedure. Feedback was presented during the ITI in the form of a histogram showing the distribution of the responses participants made on the previous trial plotted on a relative time scale. As feedback concerning the accuracy and precision of a reproduced duration (e.g., 7- and 14-s visual signals) became more remote in time, reproduced intervals gradually lengthened in duration. This rightward horizontal shift in peak time increased as a function of the probability of feedback and was enhanced by chronic treatment with haloperidol in a manner that was proportional to the duration of the signal. Our data suggest a gradual change in the underlying representation of the signal duration as a function of the remoteness of ITI feedback that is dependent upon both changes in working memory and the speed of the internal clock used to time durations in the seconds-to-minutes range.     

Cognitive effects of hormone therapy in early postmenopausal women

Recent reports suggest that hormone therapy (HT) with estrogen may have a protective effect on the ageing brain and cognitive function. However, clinical evidence regarding the cognitive effects in menopausal women under HT has produced conflicting results. The purpose of the present study was to assess and compare the cognitive effects after 6 months of HT in 30 early postmenopausal women, who were divided into three groups as follows: group I, Therapy conjugated equine estrogen (ET) CEE 0.625 mg/day (n = 10); group II, Estrogen‐Progestin Therapy (EPT), CEE 0.625 mg/day plus, chlormadinone 1 mg/day (n = 10); and group III, the control group, who did not receive treatment (n = 10). The three groups were matched by age and years of education. Exclusion criteria were: central nervous system diseases, severe cardiac disease, and clinical history of cancer and depression. Subjects were tested using a comprehensive battery for the evaluation of attention, memory and executive functions, which was standardized and validated in Spanish‐speaking subjects. The rate of cognitive change was defined by the difference between the measurements at the sixth month minus the baseline score. Mean group differences were assessed with MANOVA, followed by one‐way ANOVA considering statistical significance when p < .05; the alpha significance level .05 was corrected using the Bonferroni procedure. The EPT group showed higher scores than the control group and ET group in the Total Attention Score and in the copy of the Rey‐Osterreith Complex Figure. The ET group showed significantly higher scores than the control group and the EPT group in the subtest of Spatial Backward Span and in the Immediate Face Codification. The short‐term positive effects observed with HT in this sample could be related to the stimulation of brain receptors and/or neurotrophic factors that are still present at this age.     

Attributional style and self-control behavior in depressed and nondepressed children and their parents

Do the reformulated model of learned helplessness and the self-control model apply to clinically depressed children? Are the related cognitive patterns specific to depression? Are the cognitive deficits associated with depression learned from one's parents? To address these questions this investigation examined three groups of children (ages 8–12) and their parents: nonclinic (n =25),nondepressed clinic (n=22),and depressed clinic (n=15).Children were diagnosed depressed on the basis of Kiddie-SADS interview data. Depressed clinic children self-reported more depression, had a more depressive attributional style, and had more self-control problems. There were more depressed mothers in the clinic than in the nonclinic sample. Depressed clinic children had more depressed mothers than did nondepressed clinic children. There were no differences among the three groups of parents in their cognitive patterns. No relationship was found between the attributional style and self-control behavior of children and their parents.     

Telephone-administered cognitive behavior therapy for obsessive-compulsive disorder

Exposure with response prevention and cognitive behavior therapy are widely recognized as effective treatments for obsessive-compulsive disorder. Unfortunately, many people with obsessive-compulsive disorder--particularly those living in rural areas--do not have access to therapists providing these treatments. Accordingly, we investigated the efficacy of telephone-administered cognitive behavior therapy for obsessive-compulsive disorder. Two open trials are reported, for a total of 33 people with obsessive-compulsive disorder (without major depression). The first trial consisted of 12 weeks on a waiting list followed by 12 weeks of treatment (delayed treatment). The second trial consisted of 12 weeks of immediate treatment. Obsessive-compulsive symptoms did not change during the waiting period. Symptoms declined from pre- to post-treatment, with gains maintained at 12-week follow-up. For the pooled sample our pre-to-post-treatment effect size was as large or larger than those obtained in other studies of reduced contact treatment, and similar to those of face-to-face exposure with response prevention. Our proportion of treatment dropouts tended to be lower than those of other reduced contact interventions. The results suggest that telephone-administered cognitive behavior therapy is effective and well-tolerated, at least for people with obsessive-compulsive disorder without major depression. It remains to be seen whether this treatment is safe and effective when comorbid major depression is present.     

Efficacy of Guided iCBT for Depression and Mediation of Change by Cognitive Skill Acquisition

Guided internet CBT (iCBT) is a promising treatment for depression; however, it is less well known through what mechanisms iCBT works. Two possible mediators of change are the acquisition of cognitive skills and increases in behavioral activation. We report results of an 8-week waitlist controlled trial of guided iCBT, and test whether early change in cognitive skills or behavioral activation mediated subsequent change in depression. The sample was 89 individuals randomized to guided iCBT (n = 59) or waitlist (n = 30). Participants were 75% female, 72% Caucasian, and 33 years old on average. The PHQ9 was the primary outcome measure. Mediators were the Competencies of Cognitive Therapy Scale–Self Report and the Behavioral Activation Scale for Depression–Short Form. Treatment was Beating the Blues plus manualized coaching. Outcomes were analyzed using linear mixed models, and mediation with a bootstrap resampling approach. The iCBT group was superior to waitlist, with large effect sizes at posttreatment (Hedges’ g = 1.45). Dropout of iCBT was 29% versus 10% for waitlist. In the mediation analyses, the acquisition of cognitive skills mediated subsequent depression change (indirect effect = -.61, 95% bootstrapped biased corrected CI: -1.47, -0.09), but increases in behavioral activation did not. iCBT is an effective treatment for depression, but dropout rates remain high. Change in iCBT appears to be mediated by improvements in the use of cognitive skills, such as critically evaluating and restructuring negative thoughts.     

Nature against nurture: calcification in the right thalamus in a young man with anorexia nervosa and obsessive-compulsive personality disorder

This report describes the case of a young man with a large calcification in the right thalamus that was first diagnosed at 9 years of age. Case history reveals specific eating rituals and other obsessive-compulsive personality traits during the patient's childhood and adolescence, fulfilling diagnostic criteria of obsessive-compulsive personality disorder. After a critical life event the patient develops anorexia nervosa. We suggest that our case and further literature provide evidence for an involvement of specific thalamic structures, such as the dorsomedial nucleus, in the development of anorexia nervosa. Furthermore, the treatment of the patient by a combined psychotherapeutic and pharmacotherapeutic approach is described. We focus on the beneficial effect of the atypical antipsychotic olanzapine, which can induce weight gain by an increase of leptin levels.     

Telephone-Administered Cognitive Behavior Therapy for Obsessive-Compulsive Disorder

Exposure with response prevention and cognitive behavior therapy are widely recognized as effective treatments for obsessive-compulsive disorder. Unfortunately, many people with obsessive-compulsive disorder - particularly those living in rural areas - do not have access to therapists providing these treatments. Accordingly, we investigated the efficacy of telephone-administered cognitive behavior therapy for obsessive-compulsive disorder. Two open trials are reported, for a total of 33 people with obsessive-compulsive disorder (without major depression). The first trial consisted of 12 weeks on a waiting list followed by 12 weeks of treatment (delayed treatment). The second trial consisted of 12 weeks of immediate treatment. Obsessive-compulsive symptoms did not change during the waiting period. Symptoms declined from pre- to post-treatment, with gains maintained at 12-week follow-up. For the pooled sample our pre-to-post-treatment effect size was as large or larger than those obtained in other studies of reduced contact treatment, and similar to those of face-to-face exposure with response prevention. Our proportion of treatment dropouts tended to be lower than those of other reduced contact interventions. The results suggest that telephone-administered cognitive behavior therapy is effective and well-tolerated, at least for people with obsessive-compulsive disorder without major depression. It remains to be seen whether this treatment is safe and effective when comorbid major depression is present.     

早期剥夺所致大鼠抑郁样行为与海马BDNF mRNA表达变化

为探讨早期剥夺对大鼠行为与海马脑源性神经营养因子(BDNF)mRNA表达的影响,将新生的SD大鼠随机分为正常对照组与早期剥夺组,早期剥夺组在出生后1～14d每天孤养4h。监测体重,在出生后36?64天进行液体消耗试验,每周一次。12w龄时,进行穿梭箱试验,酶联免疫法检测海马BDNF含量,原位杂交法观察海马BDNF mRNA的表达。早期剥夺组大鼠体重显著低于正常对照组(p0.01),糖水摄入量与糖水偏爱显著低于正常对照组(p0.05或p0.01)。穿梭箱试验中,早期剥夺组大鼠在训练时的穿梭反应次数显著少于正常对照组(p0.05),在测试时,两组大鼠的被动逃避行为、主动逃避行为与逃避错误次数无显著差异。早期剥夺组大鼠海马BDNF含量、CA1区和CA3区BDNF mRNA表达显著低于正常对照组(p=0.05或p0.05)。提示早期剥夺可导致大鼠生长减慢,表现出快感缺失的抑郁样行为,但未诱导成年大鼠表现出明显的习得性无助倾向,早期剥夺能下调成年大鼠海马BDNFmRNA的表达。     

Efficacy of Cognitive Therapy for Body Dysmorphic Disorder: A Randomized Controlled Pilot Trial

Dysfunctional cognitive processes and maladaptive interpersonal patterns have been postulated to maintain body dysmorphic disorder (BDD). The present trial evaluated CT for BDD (CT-BDD), which includes modules targeting maladaptive cognitive processing in BDD, as well as elements of schema therapy related to interpersonal problems. We investigated whether (a) CT-BDD is effective, as compared with a wait-list (WL) group at Week 12; (b) outcome of CT-BDD is maintained at posttreatment and 3- and 6-months follow-up; and (c) whether changes in shame and insight mediate changes in BDD symptom severity. Forty adults with BDD were randomized to 36 weeks immediate CT-BDD (n = 21), or to 12-week WL (n = 19). At Week 12, immediate CT-BDD was significantly superior to WL in clinician-rated BDD symptom severity, insight, self-reported BDD symptoms, shame, depression, general symptomatology, and life satisfaction. Changes in outcomes were associated with moderate to large effect sizes at Week 12. Reductions in shame and increase in insight separately mediated changes in BDD symptom severity during treatment at Week 12. From baseline to posttreatment, significant improvements occurred within CT-BDD in clinician-rated symptom severity, insight, depression, global functioning, self-reported BDD symptoms, shame, depression, general symptomatology, and life satisfaction. At posttreatment, improvements were associated with large effect sizes and were maintained at 3- and 6-month follow-up. Preliminary results support the efficacy of CT-BDD. Addressing interpersonal problems in addition to cognitive dysfunctions may increase the benefit of CBT for BDD patients.     

Nonpsychotic postpartum depression among adolescent mothers

This study examined the extent to which childbearing increases vulnerability to clinical depression and depressive symptomatology among primiparous adolescent girls (ages 14 to 18). Childbearing Ss (n = 128) were assessed during pregnancy, 6 weeks postpartum, and 1 year postpartum. Matched nonchildbearing Ss (n = 114) were assessed at corresponding time points. Six weeks postpartum, 6% of the childbearing adolescents met Research Diagnostic Criteria for major depression and 20% for minor depression. These rates were not significantly different from those found for nonchildbearing Ss (4% major depression, 10% minor depression). However, higher rates of somatic symptoms of depression were found among the childbearing Ss than among the nonchildbearing Ss.     

Methylphenidate Does Not Modify the Impact of Response Frequency or Stimulus Sequence on Performance and Event-Related Potentials of Children with Attention Deficit Hyperactivity Disorder

Twenty-six children with attention deficit/hyperactivity disorder (ADHD) participated in a double-blind trial consisting of 2 consecutive weeks each of placebo and methylphenidate (M = 26.92 mg/day = 0.78 mg/kg/day). As expected, stimulant therapy resulted in moderate weight loss, increased somatic complaints, and teacher and parent reports of reduced inattentiveness, aggression, and oppositionality. In both phases of the trial, patients were tested in a choice reaction time task assessing two aspects of the task that presumably affect response selection: response frequency (ratio of targets/nontargets = 25/75 vs. 50/50) and stimulus sequence (alternations vs. repetitions). Both manipulations yielded expected results on performance and event-related potentials (ERPs). Stimulant treatment increased accuracy and speed among younger children and curtailed variability of reaction time for the sample as a whole. However, methylphenidate did not affect ERPs. In combination, the results imply that the enhancement of performance by methylphenidate does not involve the demands of response selection examined in this study.     

Cognitive behaviour therapy for panic disorder: long-term follow-up

This paper describes a long-term follow-up of patients with panic disorder who received cognitive behaviour therapy within a randomized controlled trial. Of 89 patients eligible for follow-up, 28 (31.5%) were reassessed 6-8 years after commencement of treatment in the trial. No differences were found between those who were followed up and those lost to follow-up on most baseline measures including measures of panic-related psychopathology, or depression. Outcomes at long-term follow-up were significantly better than baseline measures of panic, avoidance and depression. In this sub-sample the effect of cognitive behaviour therapy for panic disorder appears to maintain over the long-term.     

Evaluation of a psychological treatment for inflammatory bowel disease

Inflammatory bowel disease (IBD) encompasses two related gastrointestinal-tract diseases, ulcerative colitis (UC) and Crohn's Disease (CD). This study, a randomized controlled trial, compared the effectiveness of a multi-component behavioral treatment package (n = 11), which included IBD education, progressive muscle relaxation, thermal biofeedback, and training in use of cognitive coping strategies, to the effectiveness of symptom-monitoring (n = 10) as a control condition; 8 controls subsequently completed treatment. At posttreatment, the treatment group showed mean reductions on 5 symptoms, while the symptom monitoring controls showed mean reductions on all 8 symptoms. On a measure of Total Symptomatic change, the controls showed more improvement than the treated group; the treated controls at posttreatment, showed increases on all 8 symptoms. However, treated subjects perceived themselves as coping better with IBD, as feeling less IBD-related stress, and as experiencing less depression and anxiety. It is hypothesized that inherent differences may have existed between CD and UC subjects which could have led to the differences seen in treatment responses.