Effects of transcranial pulsed electromagnetic field stimulation on quality of life in Parkinson's disease.

BACKGROUND AND PURPOSE: Pulsed electromagnetic fields induce a protective and anti-inflammatory effect in the nervous system primarily due to growth factor upregulation that possibly abates neurodegeneration in Parkinson's disease (PD). This study investigated treatment effects of transcranial pulsed electromagnetic fields (T-PEMFs) on quality of life in PD and the feasibility and safety of this treatment. METHODS: In this double-blinded clinical study, 97 participants with idiopathic PD (Hoehn & Yahr stage I-IV), on optimal medical anti-parkinsonian treatment, were block randomized (3:3) to either active (n = 49) or placebo treatment (n = 48). Treatment with T-PEMFs entailed one daily 30-min home treatment for eight consecutive weeks. The 39-item Parkinson's Disease Questionnaire (PDQ-39) was assessed at baseline and endpoint. A special questionnaire was used to profile adverse events by interviewing the participants over the full treatment period. Treatment compliance was accounted for by daily treatment registration. RESULTS: The active group improved with respect to clinical effect size for the two dimensions, i.e. mobility and activities of daily living, compared with the placebo group. No between-group differences were found for the remaining PDQ-39 dimensions. There were no between-group difference in adverse events. Treatment compliance was 97.9%. CONCLUSION: Treatment with T-PEMFs improved mobility and activities of daily living scores for clinical effect size only in the active group, indicating a positive treatment response for motor symptoms. No difference was found between the two groups for the remaining PDQ-39 dimensions. The treatment had no or only mild adverse events and was performed with high compliance.

The validity and sensitivity of PANSS-6 in treatment-resistant schizophrenia.

OBJECTIVE: To test the validity and sensitivity of the six-item version (PANSS-6) of the 30-item Positive and Negative Syndrome Scale (PANSS-30) in treatment-resistant schizophrenia (TRS). METHOD: Using data from the clozapine phase (2E) of the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) study, we investigated the following: (i) The scalability of PANSS-6 and PANSS-30; (ii) The correlation between PANSS-6 and PANSS-30 total scores; (iii) Whether PANSS-6 could identify cross-sectional symptom remission; and (iv) The efficacy of clozapine, olanzapine, risperidone and quetiapine in TRS using the 'speed of change' on PANSS-6 and PANSS-30 (change in total score per week) as outcome measures. RESULTS: We found that (i) only PANSS-6 and not PANSS-30 was scalable; (ii) The correlation between PANSS-6 and PANSS-30 total scores was high (Spearman coefficient: 0.85), (iii) PANSS-6 accurately identified cross-sectional symptom remission as defined by the Andreasen et al. criteria; and (iv) The only antipsychotic that caused improvement (speed of change significantly lower than 0 during the first three months of treatment) was clozapine, both when using PANSS-6 (speed of change: -0.50 points/week; 95%CI: -0.84, -0.17) and PANSS-30 (speed of change: -1.41 points/week; 95%CI: -2.80, -0.02) as outcome measures. CONCLUSION: PANSS-6 validly measures severity, remission and antipsychotic efficacy in TRS.

A pharmacopsychometric overview of major depressive episodes in positive psychiatry.

ABSTRACTBackground:The use of the pharmacopsychometric triangle to enhance patient-reported well-being as the ultimate goal of treatment has most intensively been studied in patients with a major depressive episode. METHODS: The review is structured on the pharmacopsychometric triangle in which the desired clinical effect of an antidepressive medication is balanced against the undesired side effects induced by this medication in terms of restored well-being. As a biological treatment, the antidepressive medication is compared clinically with both electroconvulsive therapy and psychological treatment. RESULTS: In the process of this review, evidence from a dose-response study in patients suffering from a major depressive episode with an adequate duration and symptom severity has demonstrated that the dose-response relationship emerged when using the patient-reported well-being outcome rather than the symptomatic reduction as outcome. CONCLUSION: The pharmacopsychometric triangle is in patients with major depressive episodes providing important information within positive psychiatry.

Conceptualizing patient-reported outcome measures for use within two Danish psychiatric clinical registries: description of an iterative co-creation process between patients and healthcare professionals.

BACKGROUND: Denmark has national clinical indicator programs for adult patients diagnosed with depression and schizophrenia, respectively. Within each program, the responsible steering group (SG) decided to add some indicators based upon patient-reported outcome measures (PROMs). AIMS: The primary aim was to describe the process of selecting PROMs and defining a national measurement concept for use in clinical practice and for indicator monitoring and the secondary aim s to collect patient recommendations for implementation. METHODS: An interdisciplinary SG of healthcare professionals and a Patient Peer Board (PPB) representing both patient groups co-created the output in an iterative process. The work included literature search, PPB workshops, SG meetings, ratings of PROM topics and items, and a pilot. The PPB discussed the following: item relevance, mode of data collection, graphical format of the online PROMs, and display of results. Finally, requirements for PROM patient information were identified. Based upon input from the PPB, the SG selected the items and specified the measurement concept. RESULTS: The PPB prioritized 20 of 53 suitable items and suggested alternative wording and answer categories. A pilot was performed and 19 items covering well-being, lack of well-being, impairment of functioning, and overall health were selected for clinical testing. The patients recommended concrete, unambiguous, easily understandable information and procedures for data collection and display of results. CONCLUSIONS: The iterative co-creation process based upon a high degree of patient involvement resulted in a set of PROMs, a national measurement concept, and patient recommendations for implementation. The cooperation between patients and professionals was successful.

PANSS-6: a brief rating scale for the measurement of severity in schizophrenia.

OBJECTIVE: The 30-item Positive and Negative Syndrome Scale (PANSS-30) is the most widely used rating scale in schizophrenia, but too long for clinical use. Shorter PANSS versions have been proposed, including the PANSS-14 and PANSS-8. However, none of these PANSS versions has been validated using the parametric Rasch rating scale model, which evaluates 'scalability'. Scalability means that each item in a rating scale provides unique information regarding syndrome severity and is a statistical prerequisite for using the total score as a measure of overall severity. METHOD: Based on data from two randomized placebo-controlled trials in schizophrenia, we tested the scalability of PANSS-30, PANSS-14 and PANSS-8 by means of the parametric Rasch rating scale model. Furthermore, we tested whether a scalable PANSS version could separate efficacy of haloperidol and sertindole from placebo. RESULTS: Neither PANSS-30, PANSS-14 nor PANSS-8 was scalable. However, PANSS-6, consisting of the items: P1-Delusions, P2-Conceptual disorganization, P3-Hallucinations, N1-Blunted Affect, N4-Social withdrawal, N6-Lack of spontaneity and flow of conversation, was scalable. Furthermore, PANSS-6 captured superior symptom reduction and higher remission rates during treatment with haloperidol and sertindole vs. placebo. CONCLUSION: PANSS-6 is a short schizophrenia severity rating scale that adequately separates antipsychotic efficacy from that of placebo.

Maintained superiority of chronotherapeutics vs. exercise in a 20-week randomized follow-up trial in major depression.

OBJECTIVE: To investigate the long-term antidepressant effect of a chronotherapeutic intervention. METHOD: In this randomized controlled trial 75 patients with major depression were allocated to fixed duloxetine and either a chronotherapeutic intervention (wake group) with three initial wake therapies, daily bright light therapy, and sleep time stabilization or to a group using daily exercise. Patients were followed 29 weeks. We report the last 20 weeks, a follow-up phase, where medication could be altered. Patients were assessed every 4 weeks. Remission rates were primary outcome. RESULTS: Patients in the wake group had a statistically significant higher remission rate of 61.9% vs. 37.9% in the exercise group at week 29 (OR = 2.6, CL = 1.3-5.6, P = 0.01). This indicated continued improvement compared with the 9 weeks of treatment response (44.8% vs. 23.4%) with maintenance of the large difference between groups. HAM-D17 endpoint scores were statistically lower in the wake group with endpoint scores of 7.5 (SE = 0.9) vs. 10.1 (SE = 0.9) in the exercise group (difference 2.7, CL = 0.5-4.8, P = 0.02). CONCLUSION: In this clinical study patients continued to improve in the follow-up phase and obtained very high remission rates. This is the first study to show adjunct short-term wake therapy and long-term bright light therapy as an effective and feasible method to attain and maintain remission.

Rating scales measuring the severity of psychotic depression.

OBJECTIVE: Unipolar psychotic depression (PD) is a severe and debilitating syndrome, which requires intensive monitoring. The objective of this study was to provide an overview of the rating scales used to assess illness severity in PD. METHOD: Selective review of publications reporting results on non-self-rated, symptom-based rating scales utilized to measure symptom severity in PD. The clinical and psychometric validity of the identified rating scales was reviewed. RESULTS: A total of 14 rating scales meeting the predefined criteria were included in the review. These scales grouped into the following categories: (i) rating scales predominantly covering depressive symptoms, (ii) rating scales predominantly covering psychotic symptoms, (iii) rating scales covering delusions, and (iv) rating scales covering PD. For the vast majority of the scales, the clinical and psychometric validity had not been tested empirically. The only exception from this general tendency was the 11-item Psychotic Depression Assessment Scale (PDAS), which was developed specifically to assess the severity of PD. CONCLUSION: In PD, the PDAS represents the only empirically derived rating scale for the measurement of overall severity of illness. The PDAS should be considered in future studies of PD and in clinical practice.

Relapse Prevention in Major Depressive Disorder After Successful Acute Electroconvulsive Treatment: a 6-month Double-blind Comparison of Three Fixed Dosages of Escitalopram and a Fixed Dose of Nortriptyline - Lessons from a Failed Randomised Trial of the Danish University Antidepressant Group (DUAG-7).

INTRODUCTION: Electroconvulsive treatment (ECT) is an effective treatment for severe depression but carries a risk of relapse in the following months. METHODS: Major depressive disorder patients in a current episode attaining remission from ECT (17-item Hamilton Depression Rating Scale (HAM-D17) score≤9) received randomly escitalopram 10 mg, 20 mg, 30 mg or nortriptyline 100 mg as monotherapies and were followed for 6 months in a multicentre double-blind set-up. Primary endpoint was relapse (HAM-D17≥16). RESULTS: As inclusion rate was low the study was prematurely stopped with only 47 patients randomised (20% of the planned sample size). No statistically significant between-group differences could be detected. When all patients receiving escitalopram were compared with those receiving nortriptyline, a marginal superiority of nortriptyline was found (p=0.08). One third of patients relapsed during the study period, and one third completed. DISCUSSION: Due to small sample size, no valid efficacy inferences could be made. The outcome was poor, probably due to tapering off of non-study psychotropic drugs after randomisation; this has implications for future study designs. ClinicalTrials.gov Identifier: NCT00660062.

Measuring psychotic depression.

OBJECTIVE: Psychotic depression (PD) is a highly debilitating condition, which needs intensive monitoring. However, there is no established rating scale for evaluating the severity of PD. The aim of this analysis was to assess the psychometric properties of established depression rating scales and a number of new composite rating scales, covering both depressive and psychotic symptoms, in relation to PD. METHOD: The psychometric properties of the rating scales were evaluated based on data from the Study of Pharmacotherapy of Psychotic Depression. RESULTS: A rating scale consisting of the 6-item Hamilton melancholia subscale (HAM-D6 ) plus five items from the Brief Psychiatric Rating Scale (BPRS), named the HAMD-BPRS11 , displayed clinical validity (Spearman's correlation coefficient between HAMD-BPRS11 and Clinical Global Impression - Severity (CGI-S) scores = 0.79-0.84), responsiveness (Spearman's correlation coefficient between change in HAMD-BPRS11 and Clinical Global Impression - Improvement (CGI-I) scores = -0.74--0.78) and unidimensionality (Loevinger's coefficient of homogeneity = 0.41) in the evaluation of PD. The HAM-D6 fulfilled the same criteria, whereas the full 17-item Hamilton Depression Scale failed to meet criteria for unidimensionality. CONCLUSION: Our results suggest that the HAMD-BPRS11 is a more valid measure than pure depression scales for evaluating the severity of PD.

The Diagnostic Apathia Scale predicts the ability to return to work following depression or anxiety.

OBJECTIVE: The aim of this study was to evaluate the validity of a new apathy rating scale in predicting the ability to return to work (RTW) in patients with depression or anxiety a year after discharge from a psychiatric hospital. METHODS: We evaluated 56 patients with depression or anxiety, who participated in an on-going randomised clinical trial using RTW as primary outcome. The degree of apathy was measured by the Diagnostic Apathia Scale, which contains six items covering the following neuropsychological symptoms: concentration/memory problems, difficulties in decision making, lassitude, tiredness/fatigue, insomnia, and reduced ability to work and engage in personal interests. The scale was analysed for psychometric validity (scalability) and for its ability to predict RTW. Finally, the predictive validity of the Diagnostic Apathia Scale regarding RTW was compared with scales measuring severity of depression/anxiety symptoms, disability, and psychological well-being. RESULTS: The Diagnostic Apathia Scale displayed sufficient scalability, that is, the total score was a psychometrically valid measure of apathy. Only the Diagnostic Apathia Scale, and not the scales measuring severity of symptoms, disability, or psychological well-being, had predictive validity regarding RTW. Thus, 76% with 'clinically significant apathy' at baseline were unable to RTW versus 50% of the patients without apathy (p<0.05). CONCLUSION: The Diagnostic Apathia Scale was found to have an acceptable predictive validity in terms of patients' ability to RTW 1 year after discharge from hospitalisation for depression or anxiety.

Outcomes on the pharmacopsychometric triangle in bupropion-SR vs. buspirone augmentation of citalopram in the STAR*D trial.

OBJECTIVE: To compare within the framework of a novel pharmacopsychometric triangle, augmentation treatment with bupropion vs. buspirone in the acute therapy of major depression in the STAR*D study. The triangle provides a composite view in three domains of antidepressive activity, side effects, and quality of life. METHOD: Within the pharmacopsychometric triangle, the short six-item subscales of the Hamilton Depression Scale (HAM-D(17)) and of the Inventory of Depressive Symptomatology (IDS-C(30)), referred to as HAM-D(6) and IDS-C(6), were focussed on pure antidepressive effect. Side-effects (tolerable vs. intolerable) and quality of life were measured using patient-administered questionnaires. A modified intention to treat sample was used. RESULTS: Within the pharmacopsychometric triangle, bupropion-SR (sustained release) was superior to buspirone when augmented to the current citalopram treatment. Thus, in the domain of pure antidepressive effect, bupropion-SR was superior (P = 0.05) on the HAM-D(6), IDS-C(6), and IDS-C(30), but not on the HAM-D(17). In the domain of side effects, the total scores on the Patient Rated Inventory of Side Effects (PRISE) were reduced significantly more by bupropion-SR than by buspirone (P = 0.03). In the domain of quality of life, the total scores on the Quality of Life Enjoyment and Satisfaction Questionnaire (QLES-Q) showed a trend (P = 0.10) from baseline to endpoint of a superiority for bupropion-SR compared with buspirone. CONCLUSION: In all domains of the pharmacopsychometric triangle, bupropion-SR was superior to buspirone as augmentation therapy in depressed outpatients not responding to citalopram.

Dose-response relationship of sertindole and haloperidol using the pharmacopsychometric triangle.

OBJECTIVE: Renewed insight into dose-related effects of sertindole and haloperidol was sought by re-analysing published data for antipsychotic effect, extrapyramidal effect, and patient wellbeing - i.e., the important pharmacopsychometric triangle domains. METHOD: Selected Positive and Negative Syndrome Scale (PANSS) subscales and the Simpson-Angus scale were tested for validity. Standardized effect sizes [last observation carried forward (LOCF)] at endpoint were calculated. RESULTS: The scales were found to be valid instruments. The PANSS(11) psychotic subscale showed clinically significant effect sizes for all doses of sertindole (12, 20, and 24 mg) and haloperidol (4, 8, and 16 mg). Extrapyramidal effects were evident for all doses of haloperidol, but absent for the lower doses of sertindole. The PANSS(6) depression subscale, a proxy measure of quality of life, showed a clinically significant effect for sertindole 20 mg and no effect for haloperidol. CONCLUSION: This re-analysis confirmed the antipsychotic effect and absence of extrapyramidal effects for sertindole and, in addition, showed a clinically significant antidepressant effect. A profile for bipolar states emerged.

Is the antidepressive effect of second-generation antidepressants a myth?

Two recent meta-analyses on second-generation antidepressants versus placebo in mild to moderate forms of major depression, based on data on all randomized clinical trials using the Hamilton Depression Scale (HAMD) submitted to FDA, have shown an effect size of approximately 0.30 in favour of antidepressants in the acute therapy of major depression. The clinical significance of an effect size at this level was found to be so poor that these meta-analyses have subscribed to the myth of an exclusively placebo-like effect of second-generation antidepressants. A re-allocation of HAMD items focusing on those items measuring severity of clinical depression, the HAMD6, has identified effect sizes of >or=0.40 for second-generation antidepressants in placebo-controlled trials for which even a dose-response relationship can be demonstrated. In the relapse-prevention phase during continuation therapy of patients with major depression, the advantage of second-generation antidepressants over placebo was as significant as in the acute therapy phase. To explore a myth is not to deny the facts but rather to re-allocate them.

Identifying patients with therapy-resistant depression by using factor analysis.

INTRODUCTION: Attempts to identify the factor structure in patients with treatment-resistant depression have been very limited. METHODS: Principal component analysis was performed using the baseline datasets from 3 add-on studies [2 with repetitive transcranial magnetic stimulation and one with transcranial pulsed electromagnetic fields (T-PEMF)], in which the relative effect as percentage of improvement during the treatment period was analysed. RESULTS: We identified 2 major factors, the first of which was a general factor. The second was a dual factor consisting of a depression subscale comprising the negatively loaded items (covering the pure depression items) and a treatment resistant subscale comprising the positively loaded items (covering lassitude, concentration difficulties and sleep problems). These 2 dual subscales were used as outcome measures. Improvement on the treatment resistant subscale was 40% in the active treatment group compared to 17-30% improvement in the sham treatments. DISCUSSION: It is possible to describe patients with therapy-resistant depression by a factor structure. Both rTMS and T-PEMF had a clinical effect on the factor-derived scales when compared to sham treatment.

HAM-D17 and HAM-D6 sensitivity to change in relation to desvenlafaxine dose and baseline depression severity in major depressive disorder.

INTRODUCTION: This retrospective analysis compared sensitivity to change on the 17-item and 6-item Hamilton Rating Scales For Depression (HAM-D (17) and HAM-D (6), respectively) in relation to antidepressant dose and baseline depression severity. METHODS: Data were derived from 6 randomized, double-blind, placebo-controlled, 8-week trials of fixed-dose desvenlafaxine (50, 100, 200 or 400 mg/d) for major depressive disorder. HAM-D (17) and HAM-D (6) effect sizes were assessed. RESULTS: HAM-D (17) effect sizes were negative (favoured placebo) for higher desvenlafaxine doses (200-400 mg/d) at week 1, but were positive for all doses after week 2, with no clear dose-response pattern. However, HAM-D (6) effect sizes were positive for all doses at all weeks. Effect sizes were consistently greater for HAM-D (6) vs. HAM-D (17), regardless of time spent under therapy. Effect sizes were greater for HAM-D (6) vs. HAM-D (17) for all desvenlafaxine doses among patients with baseline HAM-D (17) <25, but not among patients with baseline HAM-D (17) ≥ 25. DISCUSSION: The HAM-D (6) demonstrated greater sensitivity to change and robustness than the HAM-D (17), supporting the greater homogeneity of the HAM-D (6).

Cannabis and alcohol: effects on stimulated car driving.

The effects of cannabis and alcohol on simulated car driving were studied. Cannabis resin containing 4 percent Delta(1)-tetrahydrocannabinol was administered orally in three doses equivalent to 8, 12, and 16 milligrams of that component. Alcohol was given orally in one standard dose of 70 grams. Both cannabis and alcohol increased the time required to brake and start, whereas alcohol increased while cannabis decreased the number of gear changes. An effect of dosage on response was observed with cannabis.

Fifty years with the Hamilton scales for anxiety and depression. A tribute to Max Hamilton.

From the moment Max Hamilton started his psychiatric education, he considered psychometrics to be a scientific discipline on a par with biochemistry or pharmacology in clinical research. His clinimetric skills were in operation in the 1950s when randomised clinical trials were established as the method for the evaluation of the clinical effects of psychotropic drugs. Inspired by Eysenck, Hamilton took the long route around factor analysis in order to qualify his scales for anxiety (HAM-A) and depression (HAM-D) as scientific tools. From the moment when, 50 years ago, Hamilton published his first placebo-controlled trial with an experimental anti-anxiety drug, he realized the dialectic problem in using the total score on HAM-A as a sufficient statistic for the measurement of outcome. This dialectic problem has been investigated for more than 50 years with different types of factor analyses without success. Using modern psychometric methods, the solution to this problem is a simple matter of reallocating the Hamilton scale items according to the scientific hypothesis under examination. Hamilton's original intention, to measure the global burden of the symptoms experienced by the patients with affective disorders, is in agreement with the DSM-IV and ICD-10 classification systems. Scale reliability and obtainment of valid information from patients and their relatives were the most important clinimetric innovations to be developed by Hamilton. Max Hamilton therefore belongs to the very exclusive family of eminent physicians celebrated by this journal with a tribute.

Applied psychometrics in clinical psychiatry: the pharmacopsychometric triangle.

OBJECTIVE: To consider applied psychometrics in psychiatry as a discipline focusing on pharmacopsychology rather than psychopharmacology as illustrated by the pharmacopsychometric triangle. METHOD: The pharmacopsychological dimensions of clinically valid effects of drugs (antianxiety, antidepressive, antimanic, and antipsychotic), of clinically unwanted effects of these drugs, and the patients' own subjective perception of the balance between wanted and unwanted effects are analysed using rating scales assessed by modern psychometric tests (item response theory models) RESULTS: Symptom rating scales fulfilling the item response theory models have been shown to be psychometrically valid outcome scales as their total scores are sufficient statistics for demonstrating dose-response relationship within the various classes of antianxiety, antidepressive, antimanic or antipsychotic drugs. The total scores of side-effect rating scales are, however, not sufficient statistics, implying that each symptom has to be analysed individually. Self-rating scales with very few items appear to be sufficient statistics when measuring the patients' own perception of quality of life. CONCLUSION: Applied psychometrics in psychiatry have been found to cover a pharmacopsychometric triangle illustrating the measurements of wanted and unwanted effects of pharmacotherapeutic drugs as well as health-related quality of life.