Depressive symptoms during the different phases of a migraine attack: A prospective diary study.

BACKGROUND: The relationship between migraine and depression has been thoroughly investigated, indicating a bidirectional comorbidity. The exact temporal relationship between acute depressive symptoms (mood changes) and the various phases of the migraine attack has not yet been examined. METHODS: We performed a prospective diary study in n = 487 participants with migraine. Participants filled out a daily diary on migraine and acute depressive symptoms during a 1-month period. We randomly selected one migraine attack per participant, consisting of six days around an attack, including the interictal, premonitory, ictal, and postdromal phases. Acute depressive symptoms covered five major items from the DSM-5 classification. Primary analysis was performed using a mixed model with post-hoc testing. We also tested whether lifetime depression influenced the presence of acute depressive symptoms. RESULTS: During a migraine headache day, patients scored higher on acute depressive symptoms than on all other days of the migraine attack (p < 0.001). There were no early warning signs for an upcoming headache attack through acute depressive symptomatology. Migraine patients with lifetime depression scored overall higher during the migraine attack than those without lifetime depression (p < 0.001). LIMITATIONS: Migraine attacks were based on self-reported migraine and one migraine attack per patient was randomly selected. CONCLUSION: We now clearly demonstrate that during the migraine headache phase, but not in the prodromal phase, patients report increased depressive symptomatology. No evidence was found for mood changes as an early warning sign for an upcoming migraine attack.

Salivary markers of stress system activation and social withdrawal in humans.

Social withdrawal is an early and common feature of psychiatric disorders. Hypothalamic-pituitary-adrenal (HPA)-axis activation through increased salivary cortisol (sC) and sympathetic activation through increased salivary alpha-amylase (sAA) may play a role. We aimed to study whether the link between increased sC and sAA on the one hand and depression on the other hand is mediated by social withdrawal. In this cross-sectional, observational study, sC and sAA measures were measured in seven saliva samples in 843 participants (231 psychiatric patients and 612 healthy controls). Social withdrawal was assessed through the Brief Symptom Inventory (BSI)-, the Short Form 36-, and the Dutch Dimensional Assessment of Personality Pathology social withdrawal subscales, and analyzed using linear regression and mediation analyses. On average, participants were 44.0 years old (SD = 12.8; 64.1% female). Basal and diurnal sAA were unrelated to any social withdrawal scale and depression. Certain sC measures were positively associated with the BSI social withdrawal subscale (i.e., area under the curve with respect to the increase, beta = 0.082, p = 0.02; evening sC value: beta = 0.110, p = 0.003; and mean sC value: beta = 0.097; p = 0.01). We found limited support for statistical mediation by social withdrawal (measured using a composite social withdrawal score) on the relationship between evening sC and depression. Thus, although we found no support for a role of basal and diurnal sAA in social withdrawal, HPA-axis activation may partly aggravate social withdrawal in depressive disorders.

Elevated salivary alpha-amylase levels at awakening in patients with depression.

BACKGROUND: Specific Major Depressive Disorder (MDD) biomarkers could help improve our understanding of MDD pathophysiology and aid in the refinement of current MDD criteria. While salivary cortisol (SC) can differentiate between healthy controls and patients with psychiatric disorders, salivary alpha amylase (sAA), may be a putative candidate biomarker for MDD specifically. METHODS: In a naturalistic cohort of consecutive out-patients and healthy controls, sAA and SC were determined in 833 participants (97 MDD patients, 142 patients with other mood, anxiety, and/or somatoform (MAS-) disorders, and 594 healthy controls). Samples were collected at 7 different time points (at awakening, after 30, 45, and 60 min, at 10:00 p.m., at 11:00 p.m., and at awakening on day 2). RESULTS: The mean age of the sample was 43.8 years (SD = 12.9; 63.9% female). Concerning sAA, MDD patients had higher sAA levels upon awakening on two consecutive days (p = 0.04, p = 0.01 respectively), as well as a higher area under the curve with respect to the increase (AUCi; p = 0.04) in comparison to both controls and the other MAS-disorders group. Regarding SC, mean levels of evening SC were elevated in MDD patients (p = 0.049) in comparison to both controls and the other MAS-disorders group. SC values on day 2 after ingestion of dexamethasone were elevated in both MDD patients and the other MAS-disorders group (p = 0.04, p = 0.047 respectively). CONCLUSIONS: sAA at awakening and not cortisol differentiates MDD from other psychiatric disorders in outpatients. This suggests that sAA may be a valuable candidate biomarker specifically for MDD.

Correcting for dependent censoring in routine outcome monitoring data by applying the inverse probability censoring weighted estimator.

Censored data make survival analysis more complicated because exact event times are not observed. Statistical methodology developed to account for censored observations assumes that patients' withdrawal from a study is independent of the event of interest. However, in practice, some covariates might be associated to both lifetime and censoring mechanism, inducing dependent censoring. In this case, standard survival techniques, like Kaplan-Meier estimator, give biased results. The inverse probability censoring weighted estimator was developed to correct for bias due to dependent censoring. In this article, we explore the use of inverse probability censoring weighting methodology and describe why it is effective in removing the bias. Since implementing this method is highly time consuming and requires programming and mathematical skills, we propose a user friendly algorithm in R. Applications to a toy example and to a medical data set illustrate how the algorithm works. A simulation study was carried out to investigate the performance of the inverse probability censoring weighted estimators in situations where dependent censoring is present in the data. In the simulation process, different sample sizes, strengths of the censoring model, and percentages of censored individuals were chosen. Results show that in each scenario inverse probability censoring weighting reduces the bias induced in the traditional Kaplan-Meier approach where dependent censoring is ignored.

A cluster analysis of early onset in common anxiety disorders.

Early onset is regarded as an important characteristic of anxiety disorders, associated with higher severity. However, previous findings diverge, as definitions of early onset vary and are often unsubstantiated. We objectively defined early onset in social phobia, panic disorder, agoraphobia, and generalised anxiety disorder, using cluster analysis with data gathered in the general population. Resulting cut-off ages for early onset were ≤22 (social phobia), ≤31 (panic disorder), ≤21 (agoraphobia), and ≤27 (generalised anxiety disorder). Comparison of psychiatric comorbidity and general wellbeing between subjects with early and late onset in the general population and an outpatient cohort, demonstrated that among outpatients anxiety comorbidity was more common in early onset agoraphobia, but also that anxiety- as well as mood comorbidity were more common in late onset social phobia. A major limitation was the retrospective assessment of onset. Our results encourage future studies into correlates of early onset of psychiatric disorders.

[Successful amantadine treatment of a patient with ECT-resistant catatonia]. / Succesvolle behandeling met amantadine bij een patiënt met ECT-resistente maligne katatonie.

Catatonia is a common neuropsychiatric syndrome. There is a life-threatening subtype of this disease known as malignant catatonia. One of the hypotheses regarding the pathogenesis is an imbalance of multiple neurotransmitters (gaba, glutamate and dopamine). The first step in treatment is to administer benzodiazepines; if the response is insufficient, the treatment can be replaced by electroconvulsive therapy (ect). So far, there is no consensus with regard to the tertiary treatment step. On the basis of a case report we describe the beneficial effects of administering an nmda receptor antagonist, amantadine, as the tertiary step for treating a patient with treatment-resistant malignant catatonia.

Gender differences in outpatients with anxiety disorders: the Leiden Routine Outcome Monitoring Study.

BACKGROUND: Data from the general population show higher prevalence of different anxiety disorders in women as compared with men. We analysed gender differences in a naturalistic sample of outpatients with anxiety disorders in a mental healthcare setting. METHOD: Routine outcome monitoring data were collected from 1333 patients (age: 18-65; 63.3% women) fulfilling Diagnostic and Statistical Manual of Mental Disorders IV criteria of current anxiety disorder according to the Mini-International Neuropsychiatric Interview between 2004 through 2006. Data included Comprehensive Psychopathological Rating Scale, Brief Symptom Inventory (BSI), Short Form Health Survey (SF-36), Mood and Anxiety Symptom Questionnaire (MASQ). Chi-squared test and t-test were used to compare women with men for variables with parametric distributions, and Mann-Whitney test for non-parametric distribution. Adjustments for potential confounders (age, level of education, ethnicity and comorbidites) were made by logistic regression models (for discrete variables) or analysis of covariance. RESULTS: The female-to-male ratio (i.e., 844 women, 489 men) for any anxiety disorder was 1.73 : 1 (95% confidence interval [CI]: 1.63-1.83), with the strongest skewness for post-traumatic stress disorder (2.80 : 1) and the smallest one for social phobia (1.18 : 1). Compared with men, women reported more severe self-rating scores on the BSI (on average, the scores were 12.3% higher on 3 of 9 subscales: somatisation, interpersonal sensitivity and anxiety), SF-36 (self-reported generic health status was lower on 5 of 8 subscales: physical functioning, social functioning, physical problems, vitality and bodily pain) and MASQ (on average, the scores were 6.6% higher on 4 of 5 subscales: anxious arousal, general distress, general distress depression, general distress anxiety). On the contrary, no gender difference was found in the severity of anxiety symptoms measured by the Brief Anxiety Scale. Women were more likely to suffer from comorbid depression and bulimia nervosa, and less likely from substance abuse. CONCLUSIONS: In a treatment-seeking population the prevalence rate of anxiety disorders was 1.7 times higher in female compared with men. Female outpatients were more severely affected on self-rated but not on observer-rated scales.

[The Leiden Routine Outcome Monitoring Study: mood, anxiety and somatoform disorders in patients attending a day clinic]. / De Leiden Routine Outcome Monitoring Studie: beloop van stemmings-, angst- en somatoforme stoornissen in de poliklinische praktijk.

BACKGROUND: Routine outcome monitoring (rom) is a method for the systematic monitoring of treatment-progression. Because rom data are collected regularly and systematically, we believe it should be possible to use these data in clinical epidemiological research. AIM: To describe, on the basis of publications of the Leiden Routine Outcome Monitoring Study, a number of potential research topics in which rom data can play a role. METHOD: We used rom data of patients referred, between 2004 and 2009, to secondary or tertiary care for treatment of a mood, anxiety or somatoform disorder. RESULTS: We describe three cross-sectional studies and one prospective study in which we aimed to identify predictors of outcome. CONCLUSION: These studies demonstrate clearly that it is feasible to use rom data to supplement clinical epidemiological research done on patients. Together these findings can be a useful addition to data derived from randomised clinical trials.

Predictors of outcome in outpatients with anxiety disorders: the Leiden routine outcome monitoring study.

Little is known about the predictors of outcome in anxiety disorders in naturalistic outpatient settings. We analyzed 2-year follow-up data collected through Routine Outcome Monitoring (ROM) in a naturalistic sample of 917 outpatients in psychiatric specialty care in order to identify factors predicting outcome. We included patients with panic disorder with or without agoraphobia, agoraphobia without panic, social phobia, or generalized anxiety disorder. Main findings from Cox regression analyses demonstrated that several socio-demographic variables (having a non-Dutch ethnicity [HR = 0.71)], not having a daily occupation [HR = 0.76]) and clinical factors (having a diagnosis of agoraphobia [HR = 0.67], high affective lability [HR = 0.80] and behavior problems [HR = 0.84]) decreased chances of response (defined as 50% reduction of anxiety severity) over the period of two years. Living with family had a protective predictive value [HR = 1.41]. These results may imply that factors that could be thought to limit societal participation, are associated with elevated risk of poor outcome. A comprehensive ROM screening process at intake may aid clinicians in the identification of patients at risk of chronicity.

[Cognitive impairment due to intensive use and overdoses of gammahydroxybutyric acid (GHB)]. / Cognitieve schade door intensief gebruik en overdoses van GHB.

BACKGROUND: In several countries, including the Netherlands, the use of GHB seems to be increasing. Many recreational users of GHB consider the drug to be harmless and to have no serious side effects. In recent years the number of patients with GHB addition has been increasing steadily. AIM: To draw attention to the possible development of neurotoxicity due to chronic and intensive use of GBH. METHOD: We reviewed the literature using PubMed. RESULTS: Several studies point to an increase in the number of incidents arising from the risky use of GHB or from a GHB overdose. Other drugs, such as ketamine and alcohol, are known to cause neurotoxicity, leading to cognitive impairment. As outlined in this review article, GHB , alcohol and ketamine show clear similarities in their mechanism of action. This suggests that GHB might have almost the same neurotoxic effects as ketamine and alcohol. An overdose of GHB, just like binge-drinking and a high dose of ketamine, may lead to a coma that probably harms the brain, particularly if comas occur repeatedly. CONCLUSION: The risk of neurotoxicity is likely to increase with chronic, intensive use of GHB, which is a feature of GHB-addition. We therefore advocate research into the possible toxic effects of GHB in the long term, involving, for instance, the study of lasting effects on the cognitive functions of GHB users and former users.

Routine outcome monitoring in the Netherlands: practical experiences with a web-based strategy for the assessment of treatment outcome in clinical practice.

Routine outcome monitoring (ROM) is a method devised to systematically collect data on the effectiveness of treatments in everyday clinical practice. ROM involves documenting the outcome of treatments through repeated assessments. Assistants are employed who perform a baseline assessment comprising a standardized diagnostic interview, administration of rating scales and completion of several self-report measures by the patient. At fixed time intervals, assessments are repeated. Dedicated Web-based software has been developed to assist in this task. ROM informs therapists and patients on the severity of the complaints at intake, and the waxing and waning of symptoms over the course of treatment. Researchers can use ROM for effectiveness research, and managers can use it for benchmarking. The use of ROM for research is illustrated by presenting data on the diagnostic status of patients participating in ROM and data on treatment outcome of a subgroup of patients (with panic disorder) in our database. The results show that implementation of ROM is feasible, and after some initial reservations, most therapists now consider ROM to be a necessary and important adjunct to the clinical treatment. In addition, ROM furthers research as the data can be used to study the phenomenology of psychiatric disorders and the outcome of treatments delivered in everyday practice.

Pre-adult versus adult onset major depressive disorder in a naturalistic patient sample: the Leiden Routine Outcome Monitoring Study.

BACKGROUND: Pre-adult onset of major depressive disorder (MDD) may predict a more severe phenotype of depression. As data from naturalistic psychiatric specialty care settings are scarce, we examined phenotypic differences between pre-adult and adult onset MDD in a large sample of consecutive out-patients. METHOD: Altogether, 1552 out-patients, mean age 39.2 ± 11.6 years, were diagnosed with current MDD on the Mini-International Neuropsychiatric Interview Plus diagnostic interview as part of the usual diagnostic procedure. A total of 1105 patients (71.2%) had complete data on all variables of interest. Pre-adult onset of MDD was defined as having experienced the signs and symptoms of a first major depressive episode before the age of 18 years. Patients were stratified according to the age at interview (20-40/40-65 years). Correlates of pre-adult onset were analysed using logistic regression models adjusted for age, age squared and gender. RESULTS: Univariate analyses showed that pre-adult onset of MDD had a distinct set of demographic (e.g. less frequently living alone) and clinical correlates (more co-morbid DSM-IV - Text Revision diagnoses, more social phobia, more suicidality). In the multivariate model, we found an independent association only for a history of suicide attempts [odds ratio (OR) 3.15, 95% confidence intervals (CI) 1.97-5.05] and current suicidal thoughts (OR 1.81, 95% CI 1.26-2.60) in patients with pre-adult versus adult onset MDD. CONCLUSIONS: Pre-adult onset of MDD is associated with more suicidality than adult onset MDD. Age of onset of depression is an easy to ascertain characteristic that may help clinicians in weighing suicide risk.

Efficacy and safety of two treatment algorithms in bipolar depression consisting of a combination of lithium, lamotrigine or placebo and paroxetine.

OBJECTIVE: In a previous paper, we reported about the efficacy of the addition of lamotrigine to lithium in patients with bipolar depression. In the second phase of this study paroxetine was added to ongoing treatment in non-responders. METHOD: Bipolar depressed patients (n = 124) treated with lithium were randomized to addition of lamotrigine or placebo. In non-responders after 8 weeks, paroxetine 20 mg was added for another 8 weeks to ongoing treatment. RESULTS: After 8 weeks the improvement in patients treated with lamotrigine vs. patients treated with placebo was significant. After addition of paroxetine this difference disappeared as a result of greater further improvement in the non-responders to placebo. CONCLUSION: Addition of lamotrigine to lithium was found effective in bipolar depressed patients. Further addition of paroxetine in non-responders to lithium plus lamotrigine did not appear to provide additional benefit, while it appeared to do so in non-responders to lithium plus placebo.

[Genetic neuroimaging]. / Genetische neuroimaging.

BACKGROUND: Both genetics and neuroimaging have developed rapidly in the past few years. Recently the two methods have been combined in a new technique called genetic neuroimaging. AIM: To provide an overview of the backgrounds and the possibilities of genetic neuroimaging. METHOD: In this review we first discuss genetic and neuroimaging research methods that are currently in use and then discuss their synergistic combination. Finally we analyse two recent cases in which genetic neuroimaging was used to study an individual's vulnerability to affective and psychotic symptoms. results Results are very promising, particularly with regard to research into vulnerability to psychiatric disorders. It is expected that the use of genetic neuroimaging procedures will increase. Genetic and neuroimaging methods are often exceedingly complex, which means they cannot be easily accessed by the general public. CONCLUSION: Genetic neuroimaging is an important method to study the relation between candidate genes and variations in cognitive and emotional functioning and the vulnerability to psychiatric disorders.

[Delirium during withdrawal of venlafaxine]. / Delirium bij afbouw van venlafaxine.

A 35-year-old man with anxiety and depression who was treated with venlafaxine, 300 mg a day, developed severe withdrawal symptoms in the form of a delirium during gradual tapering of the dosage. The symptoms resolved when the dosage was kept constant and did not recur when the dosage was reduced more gradually. Withdrawal symptoms are common during discontinuation of antidepressants, particularly after prolonged use of agents with a short half-life. The symptoms are usually mild and transient, especially in the case of selective serotonin reuptake inhibitors and venlafaxine. The occurrence of delirium as a result of the withdrawal of venlafaxine has not been reported previously. Even when antidepressants are being withdrawn with care, one should remain alert to the possible development of severe withdrawal symptoms.