M.S. van Noorden

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.

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

van der Loos MLM, Mulder P, Hartong EGThM, Blom MBJ, Vergouwen AC, van Noorden MS, Timmermans MA, Vieta E, Nolen WA, for the LamLit Study Group. Efficacy and safety of two treatment algorithms in bipolar depression consisting of a combination of lithium, lamotrigine or placebo and paroxetine.

Catecholamine-Mediated Increases in Gain Enhance the Precision of Cortical Representations.

Neurophysiological evidence suggests that neuromodulators, such as norepinephrine and dopamine, increase neural gain in target brain areas. Computational models and prominent theoretical frameworks indicate that this should enhance the precision of neural representations, but direct empirical evidence for this hypothesis is lacking. In two functional MRI studies, we examine the effect of baseline catecholamine levels (as indexed by pupil diameter and manipulated pharmacologically) on the precision of object representations in the human ventral temporal cortex using angular dispersion, a powerful, multivariate metric of representational similarity (precision). We first report the results of computational model simulations indicating that increasing catecholaminergic gain should reduce the angular dispersion, and thus increase the precision, of object representations from the same category, as well as reduce the angular dispersion of object representations from distinct categories when distinct-category representations overlap. In Study 1 (N = 24), we show that angular dispersion covaries with pupil diameter, an index of baseline catecholamine levels. In Study 2 (N = 24), we manipulate catecholamine levels and neural gain using the norepinephrine transporter blocker atomoxetine and demonstrate consistent, causal effects on angular dispersion and brain-wide functional connectivity. Despite the use of very different methods of examining the effect of baseline catecholamine levels, our results show a striking convergence and demonstrate that catecholamines increase the precision of neural representations. SIGNIFICANCE STATEMENT Norepinephrine and dopamine are among the most widely distributed and ubiquitous neuromodulators in the mammalian brain and have a profound and pervasive impact on cognition. Baseline catecholamine levels tend to increase with increasing task engagement in tasks involving perceptual decisions, yet there is currently no direct evidence of the specific impact of these increases in catecholamine levels on perceptual encoding. Our results fill this void by showing that catecholamines enhance the precision of encoding cortical object representations, and by suggesting that this effect is mediated by increases in neural gain, thus offering a mechanistic account of our key finding.

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.

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.

Cardiorespiratory arrest in a healthy volunteer after a single oral dose of 80 mg of the beta-blocker propranolol

The oral administration of a single low-to-moderate dose ofpropranolol(30–80 mg)inyounghealthyvolunteersis widelyusedto probe the brain’s (nor)adrenergic system (for example as pub-lishedinNLM:Oei,Tollenaar,Elzinga,STollenaar,Elzinga, Spinhoven, & Everaerd, 2009; Van Stegeren et al., 2007).Propranolol, a beta-adrenergic antagonist, is an effective tool forinvestigatingtheroleofthebeta-adrenergicsysteminpsychologicalprocesses of interest. It is typically used in a placebo-controlleddesigntoparceloutthecontributionofthebeta-adrenergicsystem.The common side effects of propranolol, a drop in pulse rate andblood pressure, are well known and typically well endured. How-ever, it is less known that in rare cases the oral administration of asingle dose of propranolol may induce cardiorespiratory arrest inhealthy young volunteers.We describe a case of a young healthy volunteer without anyknown pre-existing medical condition, who participated in achallenge study and suffered a non-fatal cardiac arrest after oraladministrationofasingledoseof80 mgpropranolol.Weusedadou-ble-blind pseudo-randomized placebo-controlled crossover designof two consecutive days to investigate the effect of modulation ofthebeta-adrenergicsystemondifferentcomponentsoftheEEGpat-tern. The protocol was approved by the Medical Ethical CommitteeoftheLeidenUniversityMedicalCenterandsubjectsgavewrittenin-formed consent. A blood pressure in rest below 100/60 mmHg or apulse rate of less than 60 beats per minute (BPM) were exclusioncriteria for the study. The study was performed in the DepartmentofPsychologyofLeidenUniversity.Basedonpriorextensiveexperi-encewiththisparadigm(Oeietal.,2010;Tollenaaretal.,2009;VanStegerenetal.,2007)andadvicefrominternists,onlyaphysicianoncall with knowledge of the protocol was deemed necessary.The healthy volunteer was an eighteen-year-old male student,who was the last of the 20 subjects scheduled to participate in ourexperiment. He had no past or current history of cardiac, pulmonaryor other physical diseases. There had been no prior exposure to abeta-blocker.Thefamilyhistorymentionedthedeathofagrandfatherattheageof45,possiblyduetoacardiacarrest.Theothergrandfatherhad cardiac valve surgery at older age. The volunteer was an activesportsman.Hewasmemberofarowingcompetitionteamandtrainedfour times a week and he also played football. He was a non-smokerandusednodrugs.Heused2unitsofalcoholperday.Routinephysicalexamination showed no neurological, cardiac or pulmonary abnor-malities. The subject had a blood pressure of 120/65 mmHg with aregular pulse rate of 60 BPM while sitting, and a tension of 120/70 mmHg witha pulse rate of65 BPM while standing.The volunteer arrived in the morning of the first test day. Bloodpressure at baseline was 140/69 mmHg, with a pulse rate of 63BPM. The volunteer received an oral dose of 80 mg propranolol(blinding was broken on his test day). Thirty minutes after baselinethe blood pressure was 141/64 mmHg, with a pulse rate of 49 BPM.The volunteer felt as usual and was e-mailing. Subsequently, hewas accompanied to and placed in the EEG set-up. The volunteercomplained of being hungry and hot, and then collapsed. Hestopped breathing and there were convulsions. The researchersimmediately called an ambulance as well as the physician on call.Meanwhile the volunteer had already regained consciousness andhad a blood pressure of 110/65 with a pulse rate of 50 BPM. Afterarrival of the emergency personnel and the physician, ECG moni-toring was started and atropine administered intravenously. How-ever, the volunteer collapsed again and stopped breathing, andthere was a short asystolic period, ended by a precordial thump.He almost immediately regained consciousness again. After intra-venous administration of more atropine and physiological saltthe bradycardia disappeared and the blood pressure rose. The vol-unteer was transferred to the cardiology department for furtherobservation and evaluation. Both echography and 24-h ECG re-vealed no abnormalities. The cardiologist’s conclusion was cardio-respiratory arrest due to propranolol. The following day thevolunteer was discharged in good condition, without the need forany further follow-up.Therearemanyreportsintheliteratureoncardiorespiratoryarrestafteroraladministrationofpropranololincardiopulmonarycompro-misedpatientsorinthecaseofanoverdose. We could, however,notidentify any recent reports of cardiorespiratory arrest in healthyyoungvolunteersafteroraladministrationofasingledoseofpropran-olol. Our case report indicates that besides careful screening ofhealthy subjects in experiments involving the oral administration ofa single dose of propranolol, it is also necessary to have trained staffandequipment for resuscitation available atthe testsite.References

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.

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.

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.

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.