Mogens Unden

Repetitive transcranial magnetic stimulation (rTMS) in combination with escitalopram in patients with treatment-resistant major depression: a double-blind, randomised, sham-controlled trial.

BACKGROUND The role of high-frequency rTMS over the left cortex as an add-on strategy in the treatment of major depression is still uncertain even in patients resistant to pharmacotherapy. We had planned a large sham TMS controlled study in the acute phase with a placebo-controlled relapse-prevention phase with escitalopram. However, because a recent meta-analysis showed only a small effect size of rTMS over sham TMS in the acute treatment phase of depressed patients, we decided to make an interim analysis. METHOD In patients with medication-resistant major depression we administered in a randomised trial 15 sessions of sham-controlled rTMS over three weeks in combination with 20 mg escitalopram daily. After the last rTMS, the patients were followed for another 9 weeks on 20 mg escitalopram daily. The antidepressant effect was measured by the HAM-D(6) as primary outcome scale. RESULTS A total of 45 patients with complete data were randomised so that 23 patients received sham TMS and 22 patients received active, high-frequency rTMS over the left cortex. Over the 3 weeks, the active rTMS treatment was superior to sham TMS with effect sizes on the HAM-D(6) above 0.70, which indicates not only a statistically but also a clinically significant effect. The patients had typically been through two failed antidepressant treatment attempts with non-tricyclics before inclusion in the study. Both the rTMS and escitalopram were well-tolerated. CONCLUSION High-frequency rTMS over the left cortex is an add-on strategy of clinical significance in combination with escitalopram in patients with major depression resistant to non-tricyclic antidepressants.

Adjunctive bright light in non-seasonal major depression: results from clinician-rated depression scales

Objective:  To investigate the use of bright light therapy as an adjunct treatment to sertraline in non‐seasonal major depression.

Modafinil augmentation in depressed patients with partial response to antidepressants: A pilot study on self-reported symptoms covered by the Major Depression Inventory (MDI) and the Symptom Checklist (SCL-92)

The association between former amphetamine dependence and cognitive performance was studied in a sample of 12 individuals with former amphetamine dependence who had been abstinent for at least 1 year and in 12 age-, gender- and verbal IQ-matched controls. The groups were compared by cognitive tests on attention, memory, executive function and fluid intelligence. Individuals with former amphetamine dependence performed significantly poorer than controls in memory domain. Follow-up analysis of variance showed minor deficits in tests of delayed verbal memory. The results remained essentially the same when participants with current DSM-IV axis I diagnosis were excluded from the analysis. It is concluded that individuals with former amphetamine dependence have normal cognitive function with the possible exception of verbal memory. Thus, if widespread cognitive deficits are found in individuals with former amphetamine dependence, etiologies other than amphetamine abuse as such should be carefully investigated.Treatment-resistant depression, i.e. partial or no response to antidepressants in spite of various treatment attempts with optimized doses and combinations, is rather common. With residual symptoms such as tiredness, anhedonia and concentration disturbances, the treatment strategy has often been to use monoamino-oxidase inhibitors (MAOIs). Their use, however, is limited due to interaction problems. Modafinil is a recently developed wake-promoting drug with only minor side-effects. Pilot studies indicate that it appears to have an augmentation effect in treatment-resistant depression. This open-label study performed in the private psychiatric practice setting is the first to make a comprehensive evaluation of the target patient profile based on patient-reported symptoms. Modafinil in doses of 100–400 mg was administered as augmentation to ongoing antidepressant therapy in patients with partial response and suffering from hypersomnia. The total number of patients was 21 and 43% of these were responders (i.e. had a score reduction of >50% on the Major Depression Inventory (MDI)) as well as remitters, i.e. the remission rate was 43%. At endpoint, the responders had psychological distress scores on the Symptom Checklist (SCL-92) on the level of the general Danish population. Baseline characteristics for responders were lower scores on depression, hostility, anxiety, somatization, obsession and psychoticism. Modafinil thus appears to be an appropriate augmentation to antidepressant treatment, leading to a remission rate of 43%. However, the results from this open-label study need to be confirmed in a placebo-controlled trial.

Adjunctive bright light in non-seasonal major depression: results from patient- reported symptom and well-being scales

Objective:  In this study, we tested the efficacy of bright light therapy as an adjunct to antidepressant treatment (sertraline) in patients with non‐seasonal major depression.

Social Adaptation Self-evaluation Scale (SASS): Psychometric analysis as outcome measure in the treatment of patients with major depression in the remission phase

INTRODUCTION: To carry out a psychometric analysis of the Social Adaptation Self-evaluation Scale (SASS), which has been found very promising during first experiences with it in the treatment of depression. METHOD: Patients in the remission phase during treatment for a major depressive episode completed the SASS over a period of 12 weeks, with monthly assessments. For comparison, the Hamilton Depression Scale with the Melancholia Scale (HAM-D/MES) was used as well as a self-reporting questionnaire, the Major Depression Inventory (MDI). In the psychometric analysis both classical tests (e.g. principal component analysis) and modern tests (Mokken analysis with the Loevinger coefficient of homogeneity) were applied. RESULTS: The SASS scale with its 21 items was found to contain at least three factors, of which the first was a general factor; this however explained less than 50% of the variance. A subscale containing the six items with the highest factor loadings was found to be a unidimensional scale. This subscale showed a much higher responsiveness than the total SASS. However, both SASS scales were found to have a lower responsiveness than the Major Depression Inventory (MDI) during the first weeks of treatment. CONCLUSION: The SASS was found to be a multidimensional scale. However, a six-items subscale (covering items with the highest loadings on the first use) was shown to be a unidimensional scale and to have a greater responsiveness than the total SASS, but still lower than the MDI. (Int J Psych Clin Pract 2002; 6: 141-146)

The lack of sustained effect of bright light, after discontinuation, in non-seasonal major depression.

BACKGROUND Recently accumulated evidence has demonstrated that bright-light therapy in combination with antidepressants is effective in patients with non-seasonal major depression. Whether bright light has a sustained effect after discontinuation is, however, poorly investigated. METHOD In this double-blind randomized study we report the results from a 4-week follow-up period in patients with major non-seasonal depression who had been treated for 5 weeks with sertraline combined with bright-light therapy or sertraline combined with dim-light therapy. At the beginning of the follow-up period the light therapy was stopped while sertraline treatment continued for 4 weeks. RESULTS Depression scores decreased substantially in both groups, resulting in high response and remission rates in both groups after 9 weeks of treatment. The difference in depression scores at week 5, favouring the bright-light-treated group, disappeared gradually in the 4-week follow-up period, resulting in similar end-point scores. CONCLUSIONS Bright light did not have a sustained effect after discontinuation. The offset of effect was complete after 4 weeks.

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.

High cortisol awakening response is associated with an impairment of the effect of bright light therapy

Objective:  We investigated the predictive validity of the cortisol awakening response (CAR) in patients with non‐seasonal major depression.

Psychometric analysis of the Melancholia Scale in trials with non-pharmacological augmentation of patients with therapy-resistant depression.

Objective The Melancholia Scale (MES) consists of the psychic core items of the Hamilton Depression Scale (HAM-D6) (depressed mood, interests, psychic anxiety, general somatic, guilt feelings, and psychomotor retardation) and the neuropsychiatric items of the Cronholm–Ottossen Depression Scale. Patients resistant to anti-depressant medication (therapy-resistant depression) have participated in our trials with non-pharmacological augmentation. On the basis of these trials, we have evaluated to what extent the neuropsychiatric subscale of the MES (concentration difficulties, fatigability, emotional introversion, sleep problems, and decreased verbal communication) is a measure of severity of apathia when compared with the HAM-D6 subscale of the MES. Methods We have focused on rating sessions at baseline (week 0) and after 2 and 4 weeks of therapy in four clinical trials on therapy-resistant depression with the following augmentations: electroconvulsive therapy, bright light therapy, transcranial magnetic stimulation or pulsed electromagnetic fields, and wake therapy. The item response theory model constructed by Mokken has been used as the psychometric validation of unidimensionality. For the numerical evaluation of transferability, we have tested item ranks across the rating weeks. Results In the Mokken analysis, the coefficient of homogeneity was above 0.40 for both the HAM-D subscale and the apathia subscale at week 4. The numerical transferability across the weeks was statistically significant (p < 0.05) for both subscales. Conclusion The apathia subscale is a unidimensional scale with acceptable transferability for the measurement of treatment-resistant symptoms, analogue to the psychic core subscale (HAM-D6).

The Diagnostic Apathia Scale predicts a dose–remission relationship of T-PEMF in treatment-resistant depression

Objective The aim of this study was to evaluate the predictive validity of the apathy subsyndrome in patients with therapy-resistant depression in the dose–remission study with transcranial pulsating electromagnetic fields (T-PEMF). Methods The apathy subsyndrome consists of the symptoms of fatigue, concentration and memory problems, lack of interests, difficulties in making decisions, and sleep problems. We evaluated 65 patients with therapy-resistant depression. In total, 34 of these patients received placebo T-PEMF in the afternoon and active T-PEMF in the morning, that is, one daily dose. The remaining 31 patients received active T-PEMF twice daily. Duration of treatment was 8 weeks in both groups. The Hamilton Depression Scale (HAM-D17) and the Bech-Rafaelsen Melancholia Scale (MES) were used to measure remission. We also focused on the Diagnostic Apathia Scale, which is based on a mixture of items from the MINI and the HAM-D17/MES. Results In patients without apathy, the remission rate after T-PEMF was 83.9% versus 58.8% in patients with apathy (p≤0.05). In patients without apathy receiving one active dose daily 94.4% remitted versus 50% for patients with apathy (p≤0.05). In patients without apathy who received two active doses 69.9% remitted versus 66.7% for patients with apathy (p≤0.05). Conclusion Taking the baseline diagnosis of the apathy syndrome into consideration, we found that in patients without apathy one daily dose of T-PEMF is sufficient, but in patients with apathy two daily doses are necessary. Including the apathy syndrome as predictor in future studies would seem to be clinically relevant.