Establishing non-inferiority in treatment trials in psychiatry: guidelines from an Expert Consensus Meeting.

Comparing the efficacy of different treatments in psychiatry is difficult for many reasons, even when they are investigated in "head-to-head" studies. A consensus meeting was, therefore, held to produce best practice guidelines for such studies. This article presents the conclusions of this consensus and illustrates it using published data in the field of antidepressant treatment of generalized anxiety disorder.

The Ham D(6) is more homogenous and as sensitive as the Ham D(17).

OBJECTIVE: Using the data of a positive d.b.c.t. comparing an hypericum extract (W55570) to placebo in depressed patients we explored whether the Ham D(6) was unidimentional and in case of a positive answer whether the total score was as sensitive as the total score of the Ham D(17). METHODS: The study was a 6 weeks double blind placebo controlled trial comparing 300 mg of hypericum t.i.d (n=186), to placebo (n=189), in patients with a single or recurrent depression according to DSM-IV. Superiority of hypericum versus placebo on the main outcome criterion (HDRS 17) was already published. The unidimensionality of the Hamilton depression scale 6 and 17 items were tested using a Mokken scale analysis. The effect size according to the initial severity of depression was calculated on the ITT last observation carried forward population. RESULTS: The Ham D(6), covering the core symptoms of depression was unidimensional, implying that improving this score reflects a true antidepressant effect. The Ham D(17) was not unidimensional. Hypericum was an effective antidepressant in patients with a pre-treatment score of 12 or more (n=208) on the Ham D(6), the effect size was 0.46. No difference with placebo was observed for those with a score of less than 12 (n=167). CONCLUSIONS: For the evaluation of an antidepressant effect, because of its specificity and sensitivity, the Ham D(6) should be used as a primary outcome measure rather than the Ham D(17).

[A strategy for therapy of depressive disorders and anxiety disorders by a health education intervention in medical consultations: the results of the APRAND program]. / Prévention des troubles anxieux et dépressifs par une action d'éducation pour la santé en consultation: résultats du programme APRAND.

BACKGROUND: Studies devoted to the detection and treatment of anxiety and depression in adult populations show that at least 10% meet ICD10 criteria for an anxiety or a depressive disorder, but only half are diagnosed as such and only one third of those receive appropriate treatment. The goal of the APRAND program was to explore the possibility of improving management strategies via health education during doctors' visits. METHODS: In 2001, EDF-GDF conducted an experimental program in which 21 physicians from its in-house health insurance program used the MINI mental state examination to screen for ICD10 criteria for anxiety and depressive disorders in 9743 employees on sick leave. A "here-elsewhere" epidemiologic study evaluated the program, recording the initial diagnoses and studying a year later the outcome of the persons identified with these disorders in 8 active centers (with prevention activities) and in 13 control centers (without prevention activities). The activities consisted of explanations of the disorders identified, delivery of the test results, delivery of leaflets based on the WHO guidelines, and strong recommendations to see a general practitioner, or a psychiatrist, or the occupational physician, if necessary. Logistic regressions compared the two groups, taking into account sex, age, geographic region, comorbidity, and medical care at screening. RESULTS: Preventive activities were significantly associated with the disappearance at 1 year of depressive episodes (OR=1.93; CI 95%; 1.3-2.84) and of phobic or panic disorders (OR=1.98; CI 95%; 1.14-3.44). The only other variables affecting prognosis were age and sex. The probability of recovery or remission increased by 10 to 20% at active centers, according to age, sex and disorder. Moreover, the physicians reported that they learned a great deal from the program, which thus also improved their practices. CONCLUSION: Diagnosis and prognosis of depressive episodes and phobic and panic disorders in adult populations can be improved by a preventive diagnostic and educational approach of the type used by APRAND during doctor's visits.

APRAND programme: an intervention to prevent relapses of anxiety and depressive disorders. First results of a medical health promotion intervention in a population of employees.

OBJECTIVE: The study sought to determine whether an organized health promotion intervention during medical consultations improves the outcome for patients who meet the ICD10 criteria for anxiety or depressive disorders. METHODS: In 2001, physicians used the MINI to screen 9743 employees on sick leave and consulting physicians in 21 medical centres of a large company. A health promotion intervention was implemented in eight "active" centres. It took place immediately after diagnosis and consisted of explaining the disorders, delivering the test results and leaflets based on WHO recommendations, and advising patients to consult their personal physician, psychiatrist or occupational physician, if necessary. Its effectiveness, evaluated by symptom severity and outcome over 1 year, was assessed by comparing the eight active centres to 13 control centres (without the intervention). RESULTS: Disorders were detected among 10.6% of the subjects, 29.4% of whom had no previous diagnosis of anxiety or depressive disorder. The intervention was associated with a positive effect on the 6-week and 6-month HAD scores. Total absence of disorders at 1 year was associated with age, sex, and intervention, among all identified cases (OR=1.53), among those with at least one anxiety disorder (OR=1.45), and among those with at least one depressive disorder (OR=1.40). CONCLUSION: Combining detection with organized provision of information including printed material improves patients' outcome and physicians' diagnostic abilities.

An international study of psychological problems in primary care. Preliminary report from the World Health Organization Collaborative Project on 'Psychological Problems in General Health Care'.

This article describes a large longitudinal multicenter collaborative study that investigated the form, frequency, course, and outcome of psychological problems that were seen in primary health care settings in 15 different sites around the world. The research employed a two-stage sampling design in which the 12-item General Health Questionnaire was administered to 26,422 persons aged 18 to 65 years who were consulting health care services. Of these persons, 5604 were selected for detailed examinations using standardized instruments and were followed up at 3 months and 1 year to provide information on course and outcome. All assessment instruments have been translated into 13 different languages. The project has produced a database that allows for the exploration of the nature of psychological disorders experienced by patients in general medical care and their association with physical illness, illness behavior, and disability over time.

CSF 5-HIAA levels are lower in impulsive as compared to nonimpulsive violent suicide attempters and control subjects.

BACKGROUND: We studied CSF 5-HIAA and HVA concentrations in violent suicide attempters and examined their relationship with depression, anxiety, and impulsivity. METHODS: CSF 5-HIAA and HVA concentrations were determined very shortly after hospital admission and compared to those of a matched control population. Clinical evaluation was performed concomitantly; the level impulsivity was evaluated by the Impulsivity Rating Scale (IRS). RESULTS: Twenty-three patients and 23 control subjects were included. According to the IRS, 14 patients were classified as impulsive, including all patients suffering from personality disorders, and 9 as nonimpulsive, with a main DSM-IIIR diagnosis of melancholia. CSF 5-HIAA concentrations in the suicide group were significantly lower than in control subjects. This difference was entirely due to the impulsive suicide attempters. There was an inverse correlation between the IRS score and CSF 5-HIAA (r = -.47, p = .02) and only a trend for HVA (r = -.41, p = .078) levels in the suicide group. CONCLUSIONS: This study of a group of violent suicide attempters distinguished a subgroup of patients diagnosed with personality disorder with high impulsivity scores and a subgroup of patients with the main diagnosis of severe depression. CSF 5-HIAA was significantly lower in impulsive violent attempters than in nonimpulsive violent attempters, therefore desintangling violence from impulsivity and linking this biologic abnormality to impulsivity.

Effect of yohimbine on blood pressure in patients with depression and orthostatic hypotension induced by clomipramine.

Orthostatic hypotension, one of tricyclic antidepressant treatment's side effects, is also a factor in limiting adequate antidepressant dosing. We tested in a double-blind, crossover, placebo-controlled study the effect of low doses (4 mg/t.i.d.) of yohimbine in 12 patients with depression with clomipramine-induced orthostatic hypotension. Yohimbine, a selective alpha 2-adrenoceptor antagonist, had a favorable effect in orthostatic hypotension and induced a significant increase in blood pressure. A pharmacodynamic and pharmacokinetic interaction between yohimbine and clomipramine or demethylclomipramine was discussed.

A reversible monoamine oxidase A inhibitor (moclobemide) facilitates smoking cessation and abstinence in heavy, dependent smokers.

OBJECTIVE: To assess the effectiveness of moclobemide on smoking cessation and abstinence in heavy, dependent smokers. There is a strong association between smoking and depression, especially in dependent smokers. It was hypothesized that smoking is a self-medication to treat depression. Cigarette smoke has monoamine oxidase (MAO)-inhibitory properties, and smokers have lower MAO activity than non-smokers. METHODS: We used a randomized, double-blind, placebo-controlled parallel-group study. Placebo or moclobemide, 400 mg/day for 2 months and 200 mg/day during the third month, was given. Main outcome measures were self-reported and biochemically verified (plasma cotinine levels, < 20 ng/ml) abstinence rate. Secondary outcome measures were withdrawal symptoms, Montgomery-Asberg Depression Rating Scale, Hamilton anxiety rating scores, platelet MAO-B activity, and plasma dihydroxyphenylglycol as a measure of MAO-A activity. RESULTS: Eighty-eight smokers were randomized to receive moclobemide (n = 44) or placebo (n = 44). The continuous self-reported abstinence rate was higher with moclobemide than with placebo (intention-to-treat analysis until the end point, 6 months: p < 0.05; until the end of follow-up, 1 year: p = 0.09). The abstinence rate according to plasma cotinine levels showed a trend to effectiveness of moclobemide (end point: p = 0.13; follow-up: p = 0.12). Platelet MAO-B activity increased after smoking cessation but without a significant difference. Plasma dihydroxyphenylglycol levels did not change in the placebo group but decreased dose dependently in the moclobemide group. No difference occurred for withdrawal symptoms, Montgomery-Asberg Depression Rating Scale, and Hamilton anxiety scores. Cessation of moclobemide had no adverse effect. More subjects reported insomnia with moclobemide (n = 16) than with placebo (n = 3). CONCLUSION: In this preliminary study, the reversible, selective MAO inhibitor moclobemide facilitated smoking cessation in highly dependent smokers. Further studies with substantially more smokers are needed to evaluate the role of MAO inhibitors in smoking cessation and abstinence in smokers with high nicotine dependence.

Efficacy of St. John's wort extract WS 5570 in major depression: a double-blind, placebo-controlled trial.

OBJECTIVE: In a double-blind, randomized, placebo-controlled trial with 375 patients the authors investigated the antidepressant efficacy and safety of 300 mg t.i.d. of hydroalcoholic Hypericum perforatum extract WS 5570. METHOD: The study participants were male and female adult outpatients with mild to moderate major depression (single or recurrent episode, DSM-IV criteria). After a single-blind placebo run-in phase, the patients were randomly assigned, 186 to WS 5570 and 189 to placebo, after which they received double-blind treatment for 6 weeks. Follow-up visits were held after 1, 2, 4, and 6 weeks. The primary outcome measure was the change from baseline in the total score on the 17-item Hamilton Depression Rating Scale. In addition, analyses of responders (patients with at least a 50% reduction in Hamilton total score) and patients with remissions (patients with a total score of 6 or less on the Hamilton scale at treatment end) were carried out, and subscale/subgroup analyses were conducted. The design included an adaptive interim analysis performed after random assignment of 169 patients with options for group size adjustment or early termination. RESULTS: Compared to placebo, WS 5570 produced a significantly greater reduction in total score on the Hamilton depression scale and significantly more patients with treatment response or remission. It was more effective in patients with higher baseline Hamilton scores and led to global reduction of depression-related core symptoms, assessed with the melancholia subscale of the Hamilton scale. The placebo and WS 5570 groups had comparable adverse events. CONCLUSIONS: H. perforatum extract WS 5570 was found to be safe and more effective than placebo for the treatment of mild to moderate depression.

Efficacy of clonidine in 24 patients with acute mania.

The authors treated 24 newly hospitalized patients suffering from acute mania with 450-900 micrograms/day of clonidine, an alpha 2-adrenergic agonist, for 2 weeks. A marked decrease in manic symptoms was observed after 5 and 13 days of treatment in about half of the patients. Early response seemed to predict the final result. Patients with a family history of affective disorder and patients who had had a good response to neuroleptics during a previous manic episode tended not to respond to clonidine. At the doses given, the patients' tolerance to clonidine was excellent: sedation was markedly lower than it is with neuroleptic treatment.

Improvement of some schizophrenic deficit symptoms with low doses of amisulpride.

OBJECTIVE: The authors assessed the effects on primary negative symptoms of low doses of amisulpride, a substituted benzamide neuroleptic with high affinity for D2 and D3 dopamine receptors. METHOD: Young, drug-free schizophrenic patients with pure negative symptoms participated in a 6-week double-blind trial of placebo (N = 10) or low-dose amisulpride (N = 10). They were assessed with the Scale for the Assessment of Negative Symptoms. RESULTS: Amisulpride significantly improved negative symptoms. Improvement in avolition, attentional impairment, and retardation was significantly greater with amisulpride than with placebo. CONCLUSIONS: These findings suggest that some primary negative symptoms may be directly affected by low doses of benzamide neuroleptics.

The impact of comorbidity on the treatment of panic disorder.

Panic disorder comorbid with other psychiatric conditions appears to be more common than panic disorder alone. Depression is the most frequently associated disorder. This article reviews the detrimental effects of comorbidity on the severity and course of panic disorder. The presence of comorbidity results in more severe anxiety and depressive symptoms, a higher rate of suicide attempts, a higher frequency of other comorbid conditions, and a poorer response and compliance to treatment. Thus, it is important for physicians to be aware of the possibility of comorbidity in patients with panic disorder in order to select the most appropriate therapy to target all components of their condition.

Comorbidity in social anxiety disorder: impact on disease burden and management.

Social anxiety disorder is a chronic, disabling disorder in which patients suffer with considerable morbidity that, more often than not, precedes the development of other psychiatric disorders. The development of comorbidity adds to the severity of the disorder, increases the risk of suicide attempts, and increases the overall burden of the disease for both the patient (greater disability) and the health care service (greater use of medical services). Comorbidity in social anxiety disorder may result in one good thing: increased recognition and treatment, because in the absence of comorbidity the level of recognition of the disorder is very low. However, the disorder is rarely recognized correctly and, consequently, patients are often offered inappropriate treatments. Given the degree of disability caused by social anxiety disorder, whether "pure" or comorbid, there is a need for improved education of both doctors and patients regarding its status as a disorder and its treatment.

The burden of depression and anxiety in general medicine.

Psychological illness is responsible for considerable disability worldwide. The World Health Organization Global Burden of Disease Survey estimates that by the year 2020, major depression will be second only to ischemic heart disease in the amount of disability experienced by sufferers. Although different measures of disability have been used in different studies, they have consistently demonstrated that individuals with depression and anxiety disorders experience impaired physical and role functioning, more days in bed due to illness, more work days lost, increased impairment at work, and high use of health services. The disability caused by depression and anxiety is just as great as that caused by other common medical conditions, such as hypertension, diabetes, and arthritis. Comorbidity of depression with anxiety or medical illness further increases the disability experienced by sufferers. Recognition and treatment, however, relieve the burden imposed by untreated depression on the individual, society, and health services.

Prescribing patterns for depression and anxiety worldwide.

Psychiatric disorders, particularly depression and anxiety, present commonly in primary care worldwide. However, significant variation is seen between countries in the prevalence of these disorders. Differing levels of awareness and recognition due to cultural issues may be important contributing factors in this variation. Overall, roughly half of psychiatric cases presenting in primary care go unrecognized, and one third of cases recognized are misdiagnosed. Although treatment is offered in nearly 60% of recognized cases, it is seldom in the context of a specific diagnosis and is only appropriate in about 5% of cases overall. This article explores the transcultural variation in the recognition, diagnosis, and treatment of depression and anxiety disorders using data from the World Health Organization study on Psychological Problems in General Health Care. Patterns observed in Western societies are compared with those seen in the rest of the world and are discussed with a view to educational needs for primary care physicians.

Consensus statement on posttraumatic stress disorder from the International Consensus Group on Depression and Anxiety.

OBJECTIVE: To provide primary care clinicians with a better understanding of management issues in posttraumatic stress disorder (PTSD) and guide clinical practice with recommendations on the appropriate management strategy. PARTICIPANTS: The 4 members of the International Consensus Group on Depression and Anxiety were James C. Ballenger (chair), Jonathan R. T. Davidson, Yves Lecrubier, and David J. Nutt. Other faculty invited by the chair were Edna B. Foa, Ronald C. Kessler, Alexander C. McFarlane, and Arieh Y. Shalev. EVIDENCE: The consensus statement is based on the 6 review articles that are published in this supplement and the scientific literature relevant to the issues reviewed in these articles. CONSENSUS PROCESS: Group meetings were held over a 2-day period. On day 1, the group discussed the review articles and the chair identified key issues for further debate. On day 2, the group discussed these issues to arrive at a consensus view. After the group meetings, the consensus statement was drafted by the chair and approved by all attendees. CONCLUSION: PTSD is often a chronic and recurring condition associated with an increased risk of developing secondary comorbid disorders, such as depression. Selective serotonin reuptake inhibitors are generally the most appropriate choice of first-line medication for PTSD, and effective therapy should be continued for 12 months or longer. The most appropriate psychotherapy is exposure therapy, and it should be continued for 6 months, with follow-up therapy as needed.

Consensus statement on panic disorder from the International Consensus Group on Depression and Anxiety.

OBJECTIVE: To provide primary care clinicians with a better understanding of management issues in panic disorder and guide clinical practice with recommendations for appropriate pharmacotherapy. PARTICIPANTS: The 4 members of the International Consensus Group on Depression and Anxiety were James C. Ballenger (chair), Jonathan R. T. Davidson, Yves Lecrubier, and David J. Nutt. Four faculty invited by the chairman also participated: David S. Baldwin, Johan A. den Boer, Siegfried Kasper, and M. Katherine Shear. EVIDENCE: The consensus statement is based on the 6 review papers that are published in this supplement and on the scientific literature relevant to these issues. CONSENSUS PROCESS: There were group meetings held during a 2-day period. On day 1, the group discussed each review paper and the chairman and discussant (Dr. Kasper) identified key issues for further debate. On day 2, the group discussed these key issues to arrive at a consensus view. After the group meetings, the consensus statement was drafted by the chairman and approved by all attendees. CONCLUSIONS: The consensus statement provides standard definitions for response and remission and identifies appropriate strategy for the management of panic disorder in a primary care setting. Serotonin selective reuptake inhibitors are recommended as drugs of first choice with a treatment period of 12 to 24 months. Pharmacotherapy should be discontinued slowly over a period of 4 to 6 months.

Consensus statement on social anxiety disorder from the International Consensus Group on Depression and Anxiety.

OBJECTIVE: The goal of this consensus statement is to provide primary care clinicians with a better understanding of management issues in social anxiety disorder (social phobia) and guide clinical practice with recommendations for appropriate pharmacotherapy. PARTICIPANTS: The 4 members of the International Consensus Group on Depression and Anxiety were James C. Ballenger (chair), Jonathan R. T. Davidson, Yves Lecrubier, and David J. Nutt. Other faculty invited by the chair were Julio Bobes, Deborah C. Beidel, Yukata Ono, and Herman G. M. Westenberg. EVIDENCE: The consensus statement is based on the 7 review papers published in this supplement and on the scientific literature relevant to the issues reviewed in these papers. CONSENSUS PROCESS: The group met over a 2-day period. On day 1, the group discussed each review paper, and the chair identified key issues for further debate. On day 2, the group discussed these issues to arrive at a consensus view. After the group meetings, the consensus statement was drafted by the chair and approved by all attendees. CONCLUSIONS: The consensus statement underlines the importance of recognizing social anxiety disorder and provides recommendations on how it may be distinguished from other anxiety disorders. It proposes definitions for response and remission and considers appropriate management strategies. Selective serotonin reuptake inhibitors are recommended as first-line therapy, and effective treatment should be continued for at least 12 months. Long-term treatment is indicated if symptoms are unresolved, the patient has a comorbid condition or a history of relapse, or there was an early onset of the disorder.

The Mini-International Neuropsychiatric Interview (M.I.N.I.): the development and validation of a structured diagnostic psychiatric interview for DSM-IV and ICD-10.

The Mini-International Neuropsychiatric Interview (M.I.N.I.) is a short structured diagnostic interview, developed jointly by psychiatrists and clinicians in the United States and Europe, for DSM-IV and ICD-10 psychiatric disorders. With an administration time of approximately 15 minutes, it was designed to meet the need for a short but accurate structured psychiatric interview for multicenter clinical trials and epidemiology studies and to be used as a first step in outcome tracking in nonresearch clinical settings. The authors describe the development of the M.I.N.I. and its family of interviews: the M.I.N.I.-Screen, the M.I.N.I.-Plus, and the M.I.N.I.-Kid. They report on validation of the M.I.N.I. in relation to the Structured Clinical Interview for DSM-III-R, Patient Version, the Composite International Diagnostic Interview, and expert professional opinion, and they comment on potential applications for this interview.

Consensus statement on transcultural issues in depression and anxiety from the International Consensus Group on Depression and Anxiety.

OBJECTIVE: To provide primary care physicians with a better understanding of transcultural issues in depression and anxiety. PARTICIPANTS: The 4 members of the International Consensus Group on Depression and Anxiety were James C. Ballenger (chair), Jonathan R. T. Davidson, Yves Lecrubier, and David J. Nutt. Five faculty invited by the chair also participated: Laurence J. Kirmayer, Jean-Pierre Lepine, Keh-Ming Lin, Osamu Tajima, and Yutaka Ono. EVIDENCE: The consensus statement is based on the 5 review articles that are published in this supplement and the scientific literature relevant to the issues reviewed in these articles. CONSENSUS PROCESS: Group meetings were held over a 2-day period. On day 1, the group discussed the review articles, and the chair identified key issues for further debate. On day 2, the group discussed these issues to arrive at a consensus view. After the group meetings, the consensus statement was drafted by the chair and approved by all attendees. CONCLUSION: The consensus statement underlines the prevalence of depression and anxiety disorders across all cultures and nations while recognizing that cultural differences exist in symptom presentation and prevalence estimates. In all countries, the recognition of depression by clinicians in the primary care setting is low (generally less than 50%), and the consensus group recommends a 2-step process to aid the recognition and diagnosis of depression. In line with the low recognition of depression and anxiety disorders is the finding that only a small proportion of patients with depression or anxiety are receiving appropriate treatments for their condition. Biological diversity across ethnic groups may account for the differential sensitivity of some groups to psychotropic medication, but this area requires further investigation.