Treatment-resistant and multi-therapy-resistant criteria for bipolar depression: consensus definition.

BACKGROUND: Most people with bipolar disorder spend a significant percentage of their lifetime experiencing either subsyndromal depressive symptoms or major depressive episodes, which contribute greatly to the high levels of disability and mortality associated with the disorder. Despite the importance of bipolar depression, there are only a small number of recognised treatment options available. Consecutive treatment failures can quickly exhaust these options leading to treatment-resistant bipolar depression (TRBD). Remarkably few studies have evaluated TRBD and those available lack a comprehensive definition of multi-therapy-resistant bipolar depression (MTRBD).AimsTo reach consensus regarding threshold definitions criteria for TRBD and MTRBD. METHOD: Based on the evidence of standard treatments available in the latest bipolar disorder treatment guidelines, TRBD and MTRBD criteria were agreed by a representative panel of bipolar disorder experts using a modified Delphi method. RESULTS: TRBD criteria in bipolar depression was defined as failure to reach sustained symptomatic remission for 8 consecutive weeks after two different treatment trials, at adequate therapeutic doses, with at least two recommended monotherapy treatments or at least one monotherapy treatment and another combination treatment. MTRBD included the same initial definition as TRBD, with the addition of failure of at least one trial with an antidepressant, a psychological treatment and a course of electroconvulsive therapy. CONCLUSIONS: The proposed TRBD and MTRBD criteria may provide an important signpost to help clinicians, researchers and stakeholders in judging how and when to consider new non-standard treatments. However, some challenging diagnostic and therapeutic issues were identified in the consensus process that need further evaluation and research.Declaration of interestIn the past 3 years, M.B. has received grant/research support from the NIH, Cooperative Research Centre, Simons Autism Foundation, Cancer Council of Victoria, Stanley Medical Research Foundation, MBF, NHMRC, Beyond Blue, Rotary Health, Geelong Medical Research Foundation, Bristol Myers Squibb, Eli Lilly, Glaxo SmithKline, Meat and Livestock Board, Organon, Novartis, Mayne Pharma, Servier, Woolworths, Avant and the Harry Windsor Foundation, has been a speaker for Astra Zeneca, Bristol Myers Squibb, Eli Lilly, Glaxo SmithKline, Janssen Cilag, Lundbeck, Merck, Pfizer, Sanofi Synthelabo, Servier, Solvay and Wyeth and served as a consultant to Allergan, Astra Zeneca, Bioadvantex, Bionomics, Collaborative Medicinal Development, Eli Lilly, Grunbiotics, Glaxo SmithKline, Janssen Cilag, LivaNova, Lundbeck, Merck, Mylan, Otsuka, Pfizer and Servier. A.C. has received fees for lecturing from pharmaceutical companies namely Lundbeck and Sunovion. A.J.C. has in the past 3 years received honoraria for speaking from Astra Zeneca and Lundbeck, honoraria for consulting from Allergan, Janssen, Lundbeck and LivaNova and research grant support from Lundbeck. G.M.G. holds shares in P1Vital and has served as consultant, advisor or CME speaker for Allergan, Angelini, Compass pathways, MSD, Lundbeck, Otsuka, Takeda, Medscape, Minervra, P1Vital, Pfizer, Servier, Shire and Sun Pharma. J.G. has received research funding from National Institute for Health Research, Medical Research Council, Stanley Medical Research Institute and Wellcome. H.G. received grants/research support, consulting fees or honoraria from Gedeon Richter, Genericon, Janssen Cilag, Lundbeck, Otsuka, Pfizer and Servier. R.H.M.-W. has received support for research, expenses to attend conferences and fees for lecturing and consultancy work (including attending advisory boards) from various pharmaceutical companies including Astra Zeneca, Cyberonics, Eli Lilly, Janssen, Liva Nova, Lundbeck, MyTomorrows, Otsuka, Pfizer, Roche, Servier, SPIMACO and Sunovion. R.M. has received research support from Big White Wall, Electromedical Products, Johnson and Johnson, Magstim and P1Vital. S.N. received honoraria from Lundbeck, Jensen and Otsuka. J.C.S. has received funds for research from Alkermes, Pfizer, Allergan, J&J, BMS and been a speaker or consultant for Astellas, Abbott, Sunovion, Sanofi. S.W has, within the past 3 years, attended advisory boards for Sunovion and LivaNova and has undertaken paid lectures for Lundbeck. D.J.S. has received honoraria from Lundbeck. T.S. has reported grants from Pathway Genomics, Stanley Medical Research Institute and Palo Alto Health Sciences; consulting fees from Sunovion Pharamaceuticals Inc.; honoraria from Medscape Education, Global Medical Education and CMEology; and royalties from Jones and Bartlett, UpToDate and Hogrefe Publishing. S.P. has served as a consultant or speaker for Janssen, and Sunovion. P.T. has received consultancy fees as an advisory board member from the following companies: Galen Limited, Sunovion Pharmaceuticals Europe Ltd, myTomorrows and LivaNova. E.V. received grants/ research support, consulting fees or honoraria from Abbott, AB-Biotics, Allergan, Angelini, Dainippon Sumitomo, Ferrer, Gedeon Richter, Janssen, Lundbeck, Otsuka and Sunovion. L.N.Y. has received grants/research support, consulting fees or honoraria from Allergan, Alkermes, Dainippon Sumitomo, Janssen, Lundbeck, Otsuka, Sanofi, Servier, Sunovion, Teva and Valeant. A.H.Y. has undertaken paid lectures and advisory boards for all major pharmaceutical companies with drugs used in affective and related disorders and LivaNova. He has also previously received funding for investigator-initiated studies from AstraZeneca, Eli Lilly, Lundbeck and Wyeth. P.R.A.S. has received research funding support from Corcept Therapeutics Inc. Corcept Therapeutics Inc fully funded attendance at their internal conference in California USA and all related expenses. He has received grant funding from the Medical Research Council UK for a collaborative study with Janssen Research and Development LLC. Janssen Research and Development LLC are providing non-financial contributions to support this study. P.R.A.S. has received a presentation fee from Indivior and an advisory board fee from LivaNova.

Integrative medicine approaches to chronic depression: case studies of the recovery process with a three-step path to recovery and significant cure.

OBJECTIVES: The support provided by conventional treatments centered on the administration of medication for chronic or other types of depression is limited. Integrative medicine, which is based on both modern Western medicine and a range of complementary and alternative medicine practices, is patient-centered and promotes natural healing in patients to achieve significant cure. This report focuses on the indications of recovery from depression using integrative medicine, especially homeopathy. METHODS: Thirty-one patients (9 males and 22 females) with depression underwent homeopathic treatment using various strategies over 3 months, in addition to antidepressants. All patients were diagnosed with Major Depressive Disorders, except bipolar disorders. Three steps were used to model indications of their recovery from depression: reducing difficulties in everyday life, reducing and stopping antidepressants, and reducing and stopping the homeopathic remedies. Patients were considered to have recovered when antidepressants had been stopped for 6 months or more and 3 or more months had passed since homeopathic medicines were stopped. RESULTS: Of the 31 patients with depression, 13 recovered within 2 years of starting homeopathic treatment, and 11 completely recovered from chronic depression. CONCLUSIONS: This study suggests that integrative medicine can be a useful strategy for depression, including the use of a three-step strategy for reducing all dependence on clinical treatment. As most patients, especially chronic patients, significantly recovered from depression through homeopathy over 2 years, this model can help understand recovery from depression through integrative medicine.

The placebo effect and homeopathy.

BACKGROUND: Like other forms of medicine, including Complementary and Alternative Medicine (CAM), homeopathy elicits expectations in patients. The physician-patient relationship, personal and comprehensive treatment and lack of adverse effects are elements in creating positive expectations. Other elements may be associated with negative expectations. METHODS: We conducted a systematic literature review on placebo and nocebo effects in acupuncture and homeopathy using Medline. RESULTS: Findings on the psychophysiological and neuromediating mechanisms of the placebo-nocebo phenomenon are reviewed. Studies of these effects reveal how expectations and unconscious conditioning can be measured by imaging and EEG methods. They result in significant, non-specific therapeutic effects, which may confuse the evaluation of the specific therapeutic effects treatment, hampering selection of the simillimum. CONCLUSIONS: Directions for future research on non-specific therapeutic effects of homeopathy to improve clinical practice and clinical research are discussed.

[Prevalence of psychiatric disorders in French general practice using the patient health questionnaire: comparison with GP case-recognition and psychotropic medication prescription]. / Prévalence des troubles psychiatriques en médecine générale selon le patient health questionnaire: adéquation avec la détection par le médecin et le traitement prescrit.

INTRODUCTION: Psychiatric disorders, mainly depression and anxiety, are frequently encountered in primary care and are a major cause of distress and disability. Nearly half of cases go unnoticed and among those that are recognised, many do not receive adequate treatment. In France, there is limited research concerning the prevalence, detection and management of these conditions in primary care. OBJECTIVES: To estimate the prevalence of psychiatric disorders, overall and for the main psychiatric diagnostic categories, encountered in primary care; to describe general practitioners' (GPs') case identification rate; to examine psychotropic medication prescription according to diagnosis, in a regionally representative sample of GP attenders. METHODS: GP practicing standard general practice in an urban area of the city of Montpellier and a nearby semi-rural region were recruited to participate. The response rate was 32.8% (n=41). Five additional GP almost exclusively offering homeopathy and acupuncture were recruited nonrandomly for convenience purposes. In each GP surgery, consecutive patients entering the waiting room were invited by a research assistant to participate until 25 patients per GP were recruited. Each participant completed self-report questionnaires in the waiting time, including the patient health questionnaire (PHQ), which yields provisional DSM-IV diagnoses. The GP completed a brief questionnaire during the consultation, giving his/her rating of the severity of any psychiatric disorder present and action taken. RESULTS: The patient response rate was 89.8%. In all, 14.9% of patients reached DSM-IV criteria for major depression or anxiety disorder on the PHQ (9.1% for major depression, 7.5% for panic disorder; 6% for other anxiety disorders). For the subthreshold categories, 7.4% met criteria for other depressive disorders, 11.8% for somatoform disorders and 10.9% for probable alcohol abuse or dependence. 66.3% of patients with DSM-IV diagnoses of major depression or anxiety disorder were identified by the GP as having a psychiatric disorder. The identification rate was 51% for all depressive disorders, anxiety and somatoform disorders. Of patients receiving a prescription for anxiolytic or antidepressant medication on the survey day, 80% were classified as cases of psychiatric disorder by the GP. Only 48.8% met criteria for major depression or anxiety disorder on the PHQ. CONCLUSION: This study highlights the frequency of psychiatric disorders in a regional study of French general practice. Overall, prevalence rates were similar to those found elsewhere, except for probable alcohol abuse and dependence, which was considerably higher than in the USA PHQ validation study. As in other countries, GP identified roughly half of psychiatric cases. Furthermore, half of patients treated by anxiolytic or antidepressant medication did not meet the diagnostic criteria on the survey day for which these medications have mainly shown their efficacy. This confirms the French paradox of one of the highest psychotropic medication consumption rates in Europe despite many cases of depression remaining untreated. The PHQ could be a rapid and acceptable diagnostic aid tool for French general practice but first needs to be validated against the diagnosis of mental health professionals in this setting.

Individualized homeopathic treatment and fluoxetine for moderate to severe depression in peri- and postmenopausal women (HOMDEP-MENOP study): a randomized, double-dummy, double-blind, placebo-controlled trial.

BACKGROUND: Perimenopausal period refers to the interval when women's menstrual cycles become irregular and is characterized by an increased risk of depression. Use of homeopathy to treat depression is widespread but there is a lack of clinical trials about its efficacy in depression in peri- and postmenopausal women. The aim of this study was to assess efficacy and safety of individualized homeopathic treatment versus placebo and fluoxetine versus placebo in peri- and postmenopausal women with moderate to severe depression. METHODS/DESIGN: A randomized, placebo-controlled, double-blind, double-dummy, superiority, three-arm trial with a 6 week follow-up study was conducted. The study was performed in a public research hospital in Mexico City in the outpatient service of homeopathy. One hundred thirty-three peri- and postmenopausal women diagnosed with major depression according to DSM-IV (moderate to severe intensity) were included. The outcomes were: change in the mean total score among groups on the 17-item Hamilton Rating Scale for Depression, Beck Depression Inventory and Greene Scale, after 6 weeks of treatment, response and remission rates, and safety. Efficacy data were analyzed in the intention-to-treat population (ANOVA with Bonferroni post-hoc test). RESULTS: After a 6-week treatment, homeopathic group was more effective than placebo by 5 points in Hamilton Scale. Response rate was 54.5% and remission rate, 15.9%. There was a significant difference among groups in response rate definition only, but not in remission rate. Fluoxetine-placebo difference was 3.2 points. No differences were observed among groups in the Beck Depression Inventory. Homeopathic group was superior to placebo in Greene Climacteric Scale (8.6 points). Fluoxetine was not different from placebo in Greene Climacteric Scale. CONCLUSION: Homeopathy and fluoxetine are effective and safe antidepressants for climacteric women. Homeopathy and fluoxetine were significantly different from placebo in response definition only. Homeopathy, but not fluoxetine, improves menopausal symptoms scored by Greene Climacteric Scale. TRIAL REGISTRATION: ClinicalTrials.gov NCT01635218. PROTOCOL PUBLICATION: https://clinicaltrials.gov/ct2/show/NCT01635218 [corrected].

Pharmacologic approaches for the treatment of chronic insomnia.

Insomnia is a common problem that for many sufferers persists chronically and may result from a wide range of causes. Specific treatments address particular underlying medical disorders. General therapeutic approaches, including pharmacologic and behavioral strategies, may have broad applicability to insomnia patients. Many different medications and substances have been used in an attempt to improve sleep. This article reviews the advantages and disadvantages of medications and other substances employed to promote improved sleep. Special emphasis is given to the use of the newer-generation benzodiazepine receptor agonist hypnotics.

Early improvement in the first 2 weeks as a predictor of treatment outcome in patients with major depressive disorder: a meta-analysis including 6562 patients.

OBJECTIVE: New evidence indicates that treatment response can be predicted with high sensitivity after 2 weeks of treatment. Here, we assess whether early improvement with antidepressant treatment predicts treatment outcome in patients with major depressive disorder (MDD). DATA SOURCES: Forty-one clinical trials comparing mirtazapine with active comparators or placebo in inpatients and outpatients (all-treated population, N = 6907; intent-to-treat population, N = 6562) with MDD (DSM-III-R or DSM-IV Criteria) were examined for early improvement (>or= 20% score reduction from baseline on the 17-item Hamilton Rating Scale for Depression [HAM-D-17] within 2 weeks of treatment) and its relationship to treatment outcome. STUDY SELECTION: Data were obtained from a systematic search of single- or double-blind clinical trials (clinical trials database, Organon, a part of Schering-Plough Corporation, Oss, The Netherlands). All included trials (a total of 41) employed antidepressant treatment for more than 4 weeks and a maximum of 8 weeks. The studies ranged from March 1982 to December 2003. Trials were excluded if there were no HAM-D-17 ratings available, no diagnosis of MDD, or if the study was not blinded. Trials were also excluded if HAM-D-17 assessments were not available at week 2, week 4, and at least once beyond week 4. DATA SYNTHESIS: Early improvement predicted stable response and stable remission with high sensitivity (>or= 81% and >or= 87%, respectively). Studies utilizing rapid titration vs. slow titration of mirtazapine demonstrated improved sensitivity for stable responders (98%, [95% CI = 93% to 100%] vs. 91% [95% CI = 89% to 93%]) and stable remitters (100%, [95% CI = 92% to 100%] vs. 93% [95% CI = 91% to 95%]). Negative predictive values for stable responders and stable remitters were much higher (range = 82%-100%) than positive predictive values (range = 19%-60%). CONCLUSIONS: These results indicate that early improvement with antidepressant medication can predict subsequent treatment outcome with high sensitivity in patients with major depressive disorder. The high negative predictive values indicate little chance of stable response or stable remission in the absence of improvement within 2 weeks. A lack of improvement during the first 2 weeks of therapy may indicate that changes in depression management should be considered earlier than conventionally thought.

Pharmacotherapy of depression: a historical analysis.

Iproniazid and imipramine, the prototypes of monoamine oxidase inhibitor (MAOI) and monoamine (re)uptake inhibitor (MAUI) antidepressants, were introduced in 1957. The relationship between iproniazid's antidepressant effect and its MAO inhibiting property was tenuous. Because of the potential drug-drug interactions and the need for dietary restrictions, the use of MAOIs became restricted to atypical depression. The confounding of reserpine reversal with antidepressant effect led to the theory that MAU inhibition is responsible for imipramine's antidepressant effect. Driven by neuropharmacological theory, non-selective reuptake inhibitors were replaced first by selective norepinephrine reuptake inhibitors, then by selective serotonin reuptake inhibitors, and more recently, by a series of new antidepressants to relieve the stimulation of serotonin-5HT2A receptors and the compensatory decline of dopamine in the brain. Each antidepressant has its own identity, but meta-analyses indicate a widening of the antidepressant response range from 65-70% to 45-79%, and a lowering of the antidepressant threshold from 65% to 45%. Although one can no longer expect that 2 of 3 depressed patients will respond to treatment, the newer antidepressants are better tolerated, because they produce less anticholinergic side effects.

Estudio clínico y nosológico de veinte casos de parafrenia / Nosologic and clinical study of 20 cases of paraphrenia

Se analizaron las historias clínicas de 20 pacientes diagnosticados como parafrenia. Los casos fueron rediagnosticados según el DSM-III-R y el borrador de la CIE-10. Hubo un predominio de mujeres con una edad promedio de 37.3 años. El perfil clínico fue de un apsicosis delirante-alucinatoria de curso crónico sin deterioro de la voluntad y de la actividad pragmática. Los casos analizados se distribuyeron en varias categorías de la CIE-10 y delDSM-III-R; hubo casos que no pudieron ser diagnosticados según el DSM-III-R. Se discute la utilidad de mantener la independencia nosológica de la parafrenia