Predictors of the effectiveness of an early medication change strategy in patients with major depressive disorder.

BACKGROUND: Patients with Major Depressive Disorder (MDD) who are non-improvers after two weeks of antidepressant treatment have a high risk of treatment failure. Recently, we did not find differences in outcomes in non-improvers randomized to an early medication change (EMC) strategy compared to treatment as usual (TAU). This secondary analysis investigated possible predictors of higher remission rates in the EMC strategy. METHODS: Of 192 non-improvers (i.e. decrease of ≤20% on the HAMD-17 depression scale) after a two-week treatment with escitalopram, n = 97 were randomized to EMC (immediate switch to high doses of venlafaxine XR) and n = 95 to TAU (continued escitalopram until day 28 with non-responders switched to venlafaxine XR). We first analyzed patient characteristics, psychopathological features and subtypes of MDD by logistic regression analyses as possible predictors of remission rates. In a second investigation, we analyzed the predictors, which showed a significant association in the first analysis before Bonferroni-Holm correction by chi-squared tests separated for treatment groups. All analyses were corrected by Bonferroni-Holm method. RESULTS: The first analyses yielded no statistically significant results after correction for multiple testing. In the second analyses, however, patients with prior medication at study entry showed higher remission rates in EMC than in TAU (24.2% versus 8.6%, p = 0.017; Bonferroni-Holm corrected significance level: p = 0.025.). Furthermore, patients with a recurrent course of MDD benefited less from treatment as usual (p = 0.009; Bonferroni-Holm corrected significance level: p = 0.025). Age, sex, age of onset, psychiatric or somatic comorbidities, and other subtypes of MDD did not predict remission rates. CONCLUSIONS: Although in our first analysis we found statistically non-significant results, the second analysis showed significant differences in remission rates between patients with or without previous medication and in patients with recurrent MDD or the first depressive episode. It would therefore be valuable to examine in larger and prospective studies whether remission rates can be increased by quick escalation of treatment in certain subgroups of patients. Promising subgroups to be tested are patients who were previously medicated, and who show a recurrent course of MDD. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00974155 . Registered at the 10th of September 2009. Retrospectively registered.

Early improvement as a resilience signal predicting later remission to antidepressant treatment in patients with Major Depressive Disorder: Systematic review and meta-analysis.

Early improvement of depressive symptoms during the first two weeks of antidepressant treatment has been discussed to be a resilience signal predicting a later positive treatment outcome in patients with Major Depressive Disorder (MDD). However, the predictive value of early improvement varies between studies, and the use of different antidepressants may explain heterogeneous results. The objective of this review was to assess the predictive value of early improvement on later response and remission and to identify antidepressants with the highest chance of early improvement. We included 17 randomized controlled trials investigating early improvement in 14,779 adult patients with MDD comparing monotherapy with an antidepressant against placebo or another antidepressant drug. 62% (range: 35-85%) of patients treated with an antidepressant and 47% (range: 21-69%) with placebo were early improver, defined as a >20%/25% symptom reduction after two weeks of treatment. Early improvement predicted response and remission after 5-12 weeks of treatment with high sensitivity (85%; 95%-CI: 84.3 to 85.7) and low to moderate specificity (54%; 95%-CI: 53.1 to 54.9). Early improver had a 8.37 fold (6.97-10.05) higher likelihood to become responder and a 6.38 fold (5.07-8.02) higher likelihood to be remitter at endpoint than non-improver. The highest early improver rates were achieved in patients treated with mirtazapine or a tricyclic antidepressant. This finding of a high predictive value of early improvement on treatment outcome may be important for treatment decisions in the early course of antidepressant treatment. Further studies should test the efficacy of such early treatment decisions.

A combined marker of early non-improvement and the occurrence of melancholic features improve the treatment prediction in patients with Major Depressive Disorders.

BACKGROUND: Early Improvement of depressive symptoms within two weeks of antidepressant treatment is a highly sensitive but less specific predictor of later treatment outcome. The aim of this study was to identify clinical features at treatment initiation which are associated with early improvement and non-improvement as well as to identify variables predicting non-remission in patients showing an early improvement. METHODS: 889 patients with a major depressive episode according to DSM-IV who had participated in an antidepressant treatment trial served as study sample. Clinical predictors (demographic variables, psychopathology, comorbid disorders) were analysed in 698 (79%) early improver (Hamilton Depression Rating Scale reduction > 20% after 14 days of treatment) compared to 191 (21%) non-improver. Furthermore, clinical predictors for later remission and non-remission were analysed in the 698 patients showing an early improvement. RESULTS: Patients with more severe depression and suicidality were more likely to become non-improver, and also non-remitter after 8 weeks of treatment in case of early improvement. Early improver with melancholic, anxious or atypical depression as well as with comorbid social phobia or avoidant personality disorder had an increased risk for non-remission at study end. The combined marker of early non-improvement and the occurrence of melancholic features increased the specificity of treatment prediction from 30% to 90%. LIMITATIONS: Comorbid disorders were only assessed at baseline. CONCLUSIONS: Patients with early non-improvement and melancholic features at treatment initiation have a particularly high risk of later non-remission. This group of patients should be considered more attention in treatment decisions.

An overview on clinical aspects in magnetic seizure therapy.

The aim of the presented work is to provide an overview on the clinical data of the promising convulsive brain stimulation technique, the magnetic seizure therapy (MST). We review the advantages and disadvantages of MST, focusing on rationale, development and current treatment procedure. We also provide a summary of the current literature including clinical trials and case reports found in the PubMed database. Furthermore, we consider effectiveness and side effects, emphasizing on crucial issues to be addressed for a better understanding of this potential new treatment option in treatment-resistant depression (TRD).

Randomized controlled study of early medication change for non-improvers to antidepressant therapy in major depression--The EMC trial.

Patients with Major Depressive Disorder (MDD) and no improvement after two weeks of antidepressant pharmacotherapy have a high risk of treatment failure. The aim of the study was to determine whether an early medication change (EMC) strategy is superior to a guideline-based treatment in MDD patients without improvement after two weeks of antidepressant pharmacotherapy. Eight-hundred-and-eighty-nine patients with MDD were enrolled, 879 patients received the SSRI escitalopram. Of those, 192 patients had no improvement, defined as a reduction of < 20% on the Hamilton Depression Rating Scale (HAMD-17) after 14 days of treatment, and were randomly assigned to open treatment with the EMC strategy (n = 97; venlafaxine XR for study days 15-56; in case of sustained non-improvement on day 28, lithium augmentation for days 29-56) or TAU (n = 95; escitalopram continuation; non-responders on day 28 were switched to venlafaxine XR for four weeks, i.e. days 29-56). The primary outcome was remission (HAMD-17 ≤ 7) after 8 weeks of treatment as assessed by blinded raters. Remission rates were 24% for EMC and 16% for TAU, which was not significantly different (p = 0.2056). Sensitivity analyses for the primary and secondary effectiveness endpoints consistently showed favorable results for patients randomized to EMC. The results confirm data from post-hoc analyses of clinical trials showing that early non-improvement identifies patients who likely need alternate interventions. However, the herein used two-step switch/augmentation strategy for this risk group was not more effective than the control intervention. Alternate strategies and other design aspects are discussed in order to support researchers addressing the same research question.

Substances used and prevalence rates of pharmacological cognitive enhancement among healthy subjects.

Pharmacological "cognitive enhancement" (CE) is defined as the use of any psychoactive drug with the purpose of enhancing cognition, e.g. regarding attention, concentration or memory by healthy subjects. Substances commonly used as CE drugs can be categorized into three groups of drugs: (1) over-the-counter (OTC) drugs such as coffee, caffeinated drinks/energy drinks, caffeine tablets or Ginkgo biloba; (2) drugs being approved for the treatment of certain disorders and being misused for CE: drugs to treat attention-deficit/hyperactivity disorder (ADHD) such as the stimulants methylphenidate (MPH, e.g. Ritalin(®)) or amphetamines (AMPH, e.g. Attentin(®) or Adderall(®)), to treat sleep disorders such as modafinil or to treat Alzheimer's disease such as acetylcholinesterase inhibitors; (3) illicit drugs such as illicit AMPH, e.g. "speed", ecstasy, methamphetamine (crystal meth) or others. Evidence from randomized placebo-controlled trials shows that the abovementioned substances have limited pro-cognitive effects as demonstrated, e.g. regarding increased attention, increased cognitive speed or shortening of reaction times, but on the same time poses considerable safety risks on the consumers. Prevalence rates for the use of CE drugs among healthy subjects show a broad range from less than 1 % up to more than 20 %. The range in prevalence rates estimates results from several factors which are chosen differently in the available survey studies: type of subjects (students, pupils, special professions, etc.), degree of anonymity in the survey (online, face-to-face, etc.), definition of CE and substances used/misused for CE, which are assessed (OTC drugs, prescription, illicit drugs) as well as time periods of use (e.g. ever, during the past year/month/week, etc.). A clear and comprehensive picture of the drugs used for CE by healthy subjects and their adverse events and safety risks as well as comprehensive and comparable international data on the prevalence rates of CE among healthy subjects are of paramount importance for informing policy makers and healthcare professionals about CE.

Investigation of insulin resistance in narcoleptic patients: dependent or independent of body mass index?

BACKGROUND: Narcolepsy is a severe sleep-wake cycle disorder resulting in most cases from a lack of orexin, the energy balance-regulating hormone. Narcoleptic patients have been reported to suffer from an excess morbidity of Type 2 diabetes, even after correction for their often elevated body mass index. METHODS: To explore whether narcolepsy is specifically associated with a propensity to develop insulin resistance, we measured fasting glucose, insulin, and intact proinsulin levels in 43 narcoleptic patients and 47 controls matched for body mass index and age. The proinsulin-to-insulin ratio was calculated. Insulin resistance was determined using the homeostatic model assessment method. RESULTS: Narcoleptic patients did not show elevated insulin resistance parameters. CONCLUSION: In contrast with earlier reports, we found no evidence that narcolepsy specifically elevates the risk of insulin resistance (and consequently of type 2 diabetes) independently of body mass index.

Heavy metal exposure in patients suffering from electromagnetic hypersensitivity.

BACKGROUND: Risks from electromagnetic devices are of considerable concern. Electrohypersensitive (EHS) persons attribute a variety of rather unspecific symptoms to the exposure to electromagnetic fields. The pathophysiology of EHS is unknown and therapy remains a challenge. OBJECTIVES: Heavy metal load has been discussed as a potential factor in the symptomatology of EHS patients. The main objective of the study was to test the hypothesis of a link between EHS and heavy metal exposure. METHODS: We measured lead, mercury and cadmium concentrations in the blood of 132 patients (n=42 males and n=90 females) and 101 controls (n=34 males and n=67 females). RESULTS: Our results show that heavy metal load is of no concern in most cases of EHS but might play a role in exceptional cases. CONCLUSIONS: The data do not support the general advice to heavy metal detoxification in EHS.

Basal metabolic rate in narcoleptic patients.

STUDY OBJECTIVES: We investigated basal metabolic rate (BMR) and energy expenditure (EE) in narcoleptic patients and in BMI- and age-matched controls in order to explore the hypothesis that a reduced BMR or EE plays a role in narcolepsy-associated obesity. DESIGN: Control group design with comparison of EE and BMR. EE was determined by indirect calorimetry using the Deltatrac Metabolic Monitor system. BMR was calculated from the oxygen consumption (VO2) and the carbon dioxide consumption (VCO2) measurements after 12 hours of fasting in the morning. PARTICIPANTS: 13 narcoleptic patients and 30 controls. RESULTS: BMR and EE were not significantly reduced when all subjects were included into the analysis. Subgroup analysis revealed that only non-obese narcoleptics, but not obese narcoleptics had reduced BMRs in comparison to the BMI matched controls. CONCLUSION: Our study suggests that EE plays a role in narcolepsy associated obesity. We propose that narcolepsy may lead to a shift of individual BMI set points.

Blood laboratory findings in patients suffering from self-perceived electromagnetic hypersensitivity (EHS).

Risks from electromagnetic devices are of considerable concern. Electrohypersensitive (EHS) persons attribute a variety of rather unspecific symptoms to exposure to electromagnetic fields. The pathophysiology of EHS is unknown and therapy remains a challenge. We hypothesized that some electrosensitive individuals are suffering from common somatic health problems. Toward this end we analysed clinical laboratory parameters including thyroid-stimulating hormone (TSH), alanine transaminase (ALT), aspartate transaminase (AST), creatinine, hemoglobine, hematocrit and c-reactive protein (CRP) in subjects suffering from EHS and in controls that are routinely used in clinical medicine to identify or screen for common somatic disorders. One hundred thirty-two patients (n = 42 males and n = 90 females) and 101 controls (n = 34 males and n = 67 females) were recruited. Our results identified laboratory signs of thyroid dysfunction, liver dysfunction and chronic inflammatory processes in small but remarkable fractions of EHS sufferers as potential sources of symptoms that merit further investigation in future studies. In the cases of TSH and ALT/AST there were significant differences between cases and controls. The hypotheses of anaemia or kidney dysfunction playing a major role in EHS could be unambiguously refuted. Clinically it is recommended to check for signs of treatable somatic conditions when caring for individuals suffering from self-proclaimed EHS.

Elevated peripheral visfatin levels in narcoleptic patients.

OBJECTIVE: Narcolepsy is a severe sleep disorder that is characterized by excessive daytime sleepiness, cataplexies and a tendency towards obesity. Recent discoveries indicate that the major pathophysiology is a loss of hypocretin (orexin) producing neurons due to immunologically mediated degeneration. Visfatin is a recently described proinflammatory adipokine. It is identical to the immune modulating pre-B-cell colony enhancing factor (PBEF). Our study examines the hypothesis that visfatin levels are altered in narcoleptic patients. METHODS: For the analysis, a total of n = 54 patients (n = 18 males and n = 36 females) with the diagnosis of narcolepsy according to DSM-IV and the International Classification of Sleep Disorders were examined (BMI mean 30.3+/-5.5, age mean 52.5+/-16.1 years). As a control group 39 unrelated (n = 12 males and n = 27 females) healthy volunteers with no sleep disorder according to DSM-IV were included (BMI mean 28.5+/-4.6, age mean 51.1+/-13.6 years). Peripheral visfatin levels were measured using a commercial enzyme immunoassay kit with a measurement range from 0.1-1000 ng/ml. Narcolepsy symptoms, severity and frequency of symptoms as well as the total duration of various aspects of the symptomatology were assessed by unstructured and structured clinical interviews in including the Stanford Center for Narcolepsy Sleep Inventory. RESULTS: Circulating visfatin was found to be significantly increased in HLA DR2 positive narcoleptic patients compared to controls. CONCLUSION: Taken together, our results add to the evidence of disturbed immunological regulation in patients with narcolepsy.

Prevalence of eating disorders and eating attacks in narcolepsy.

Narcoleptic patients suffer frequently from obesity and type II diabetes. Most patients show a deficit in the energy balance regulating orexinergic system. Nevertheless, it is not known, why narcoleptic patients tend to be obese. We examined 116 narcoleptic patients and 80 controls with the structured interview for anorectic and bulimic eating disorders (SIAB) to test the hypothesis that typical or atypical eating attacks or eating disorders may be more frequent in narcoleptic patients. No difference in the current prevalence of eating disorders bulimia nervosa, binge eating disorder, or anorexia nervosa was found, nor was the frequency of eating attacks higher in the narcolepsy group. We conclude that present eating disorders and eating attacks as defined in DSM IV are not the reason for the observed differences in body composition. Additional factors, such as basal metabolic rates and lifestyle factors need to be considered.

Peripheral leptin levels in narcoleptic patients.

BACKGROUND: Narcolepsy is a severe sleep disorder that in most patients is characterized by the deficiency of central orexin. Clinically, narcolepsy is associated with obesity. Currently, there is a literature controversy about the potential alteration of leptin levels in narcoleptic patients. Theoretically, diminished leptin levels could partially contribute to the observed overweight of patients. Two studies have reported decreased leptin levels, whereas a larger, recent study failed to detect differences between patients and controls. METHODS: To help settle the controversy, we have measured peripheral leptin levels in 42 narcoleptic patients and in 31 body mass index-matched controls. RESULTS: No significant differences in leptin levels between the groups were observed. Mean leptin levels were 16.0 +/- 14.9 ng/mL in the narcoleptic men and 30.4 +/- 17.8 ng/mL in the narcoleptic women. The corresponding values for the controls were 21.2 +/- 17.0 ng/mL (P = 0.49, men) and 33.9 +/- 16.9 ng/mL (P = 0.31, women). In addition, no correlation was found between leptin levels and clinical symptomatology in the narcoleptic patients. CONCLUSIONS: Taken together, the data argue against a major deterioration of leptin secretion in narcoleptic patients.