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. METHOD: Patients were treated with sertraline in combination with bright or dim light therapy for a 5-week period. Saliva cortisol levels were measured in 63 patients, as an awakening profile, before medication and light therapy started. The CAR was calculated by using three time-points: awakening and 20 and 60 min after awakening. RESULTS: Patients with low CAR had a very substantial effect of bright light therapy compared with dim light therapy, whereas patients with a high CAR had no effect of bright light therapy compared with dim light therapy. CONCLUSION: High CAR was associated with an impairment of the effect of bright light therapy. This result raises the question of whether bright light acts through a mechanism different from that of antidepressants.

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.

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).

Treatment-resistant depression, i.e. partial or non 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 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 ot be confirmed in a placebo-controlled trial.

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. METHOD: In a randomised double-blind trial, 102 patients were treated for 5 weeks with either white bright light (10 000 lux, 1 h daily) or red dim light (50 lux, 30 min daily). All patients were treated with sertraline in a fixed dose of 50 mg daily. The clinician-rated depression scales used were the Hamilton Depression Rating Scale (HAM-D17), Hamilton six-item subscale (HAM-D6), Melancholia Scale (MES) and the seven 'atypical' items from the SIGH-SAD. RESULTS: One-hundred and two patients were included in the study. Analyses showed that the reduction in depression scores in the bright light group was statistically significantly larger than in the dim light group on all scales. The scale most sensitive at endpoint was the HAM-D(6), which includes the core symptoms of depression. CONCLUSION: The study results support the use of bright light as an adjunct treatment to antidepressants in non-seasonal depression.

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. METHOD: In a randomized double-blind controlled trial, 102 patients were treated for 5 weeks with either white bright light (10.000 lx, 1 h/day) or red dim light (50 lx, 30 min/day). All patients received sertraline in a dosage of 50 mg daily. The self-assessment scales used were the Major Depression Inventory (MDI), the Psychological General Well-Being Scale (PGWB) and the Symptom Check List (SCL-90R). RESULTS: On all three questionnaires the score differences between baseline and endpoint were greatest in the bright light group. On the SCL-90R, the difference reached statistical significance. Results and effect sizes are compared with results from Danish national population studies applying PGWB and SCL-90R. CONCLUSION: The results advocate the use of bright light as an adjunct treatment of non-seasonal depression.

Continuous versus non-nightly use of zolpidem in chronic insomnia: results of a large-scale, double-blind, randomized, outpatient study.

New treatment strategies are encouraged in insomnia and, in particular, discontinuous treatment. The aim of this double-blind study was to compare, in a large primary care population of chronic insomniacs (> 4 weeks duration) the efficacy and safety of zolpidem 10 mg 5 nights/week and placebo 2 nights/week, to that of nightly zolpidem. Seven hundred and eighty-nine drug-free insomniacs, with a Total Sleep Time (TST) of 3-6 h/night were enrolled in seven European countries. After a placebo run-in period, treatment lasted 14 days. The primary criterion was the Clinical Global Impression improvement score (CGI-II) which showed that 65.2% of patients in the continuous and 58.6% in the discontinuous groups were rated 'much' or 'very much' improved. Even though the non-inferiority test did not show the equivalence of both regimens, the difference of 7% in responder rates does not appear to be clinically relevant. Other sleep parameters such as TST, number of nocturnal awakenings and Quality of Life scales showed marked, not significantly different, improvements in both groups. Both regimens were well tolerated and no adverse event which could be related to non-treatment nights was reported in the discontinuous group. Non-nightly zolpidem appears to be a feasible and safe additional option for the management of chronic insomnia.

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).

[Abuse of Ecstasy (3,4-methylenedioxymethamphetamine). Pharmacological, neuropsychiatric and behavioral aspects]. / Misbrug af Ecstasy (3,4-metylendioxymetamfetamin). Farmakologiske, neuropsykiatriske og adfaerdsmaessige aspekter.

Ecstasy (3,4-methylenedioxymethamphetamine) is a popular recreational drug, a "designer drug", which has been developed from the basic structure in amphetamine. Ecstasy has now reached the illegal drug market in Denmark via the US, Great Britain and Sweden. The drug is related to a certain youth culture from which it is estimated that many drug abusers have been recruited. The desired effects of ecstasy, namely enhanced openness, awareness and empathy, have previously been used in various therapeutic connections. In later years the drug has led to abuse which, in connection with certain cultural behaviour patterns (for example in discotheques), can cause dangerous psychiatric as well as somatic effects. The undesirable psychiatric effects range from fear through depression to actual psychoses, and the somatic effects vary from symptoms of increased sympathetic activity to malignant hyperthermia, disseminated intravascular coagulation, rhabdomyolysis, renal failure, and lethal hepatotoxicity. The last mentioned symptoms occur in connection with prolonged physical activities such as exhausting dancing sessions. The article discusses the available treatments for conditions of abuse and stresses the need for prophylactic efforts in the form of information and awareness of the problem.

Calcium homeostasis in fibroblasts from patients with amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a chronic neurodegenerative disorder of the motor system in the CNS characterized by motor neuron death in the spinal cord, brain stem and cortex. Readily available tissues such as fibroblasts from ALS patients can serve as simple model systems to study the molecular mechanisms leading to degenerative disorders. We have used Fura-2 fluorescence microscopy and single-cell imaging to study the spatiotemporal dynamics of intracellular free calcium ([Ca2+]i) in primary cultures of fibroblasts from skin biopsies from ALS and normal subjects. Increases in [Ca2+]i were induced by stimulation with bradykinin (100 nM); neurotensin (50 nM); N-formyl-Met-Leu-Phe (chemotactic peptide) (1 microM); [Arg8]-vasopressin (1 microM) and histamine (10 microM). The levels of [Ca2+]i in 80-120 individual cells per agonist were monitored for 15 min. No significant differences were found in the resting levels of [Ca2+]i in control (102 +/- 4 nM) and ALS (98 +/- 6 nM) fibroblasts and in the maximal [Ca2+]i levels after stimulation with N-formyl-Met-Leu-Phe, [Arg8]-vasopressin, and histamine. Significantly lower [Ca2+]i transients were found in fibroblasts from ALS donors compared to controls when stimulated with neurotensin (p < 0.002) and bradykinin (p < 0.005). The percentage of individual cells reacting to a given agonist (40-100%) was similar in both groups. The molecular basis of the impaired calcium homeostasis in fibroblasts from ALS patients is not known, but a generalized membrane defect can be excluded since the [Ca2+]i responses are defective only when bradykinin or neurotensin are used as agonists.

Zolpidem: clinical experience in psychiatric settings.

Zolpidem, a new short-acting non benzodiazepine hypnotic with high selectivity for benzodiazepine--1/Omega-I receptors and with lack of tolerance and physical dependence in animal models and lack of withdrawal phenomena even after up to 180 days treatment has recently been introduced. Data from clinical trials show a comparable effectiveness in inducing and maintaining sleep to comparative drugs (benzodiazepines) and besides that, it seems to preserve--even improve sleep-architecture and lastly preserve daytime wakefulness. Very few studies have been conducted in psychiatric patients, but also in this group effectiveness has been shown, and from daily clinical experience, this picture seems to hold. It must be remembered, that psychiatric patients have a high level of symptomatic benzodiazepine and/or alcohol misuse disposing to withdrawal and abstinence states in which zolpidem is less effective presumedly reflecting its selectivity. Having passed the withdrawal states, zolpidem can be used as an effective and safe hypnotic.

Inhibitory effects of amitriptyline on the stimulation-induced Ca2+ increase in parotid acini.

The present study demonstrates the effects of the antidepressant, amitriptyline, and the acetylcholine antagonist, atropine, on the stimulation-induced rise in cytosolic, free Ca2+ (Cai2+). The changes in Cai2+ of collagenase-isolated rat parotid acini were measured by means of the Ca2(+)-sensitive dye, fura-2. It was found that stimulation by carbachol resulted in a maximal increase of 582 +/- 34 nM (mean +/- S.E.) in Cai2+ with a ks of 5.8 +/- 1.3 microM. Adrenaline caused a rise of 380 +/- 22 nM in Cai2+ with a ks of 0.5 +/- 0.2 microM. Amitriptyline and atropine were found to inhibit the carbachol-induced rise in Cai2+ with dissociation constants (kI) of 105 and 1.25 nM, respectively, in the absence of agonist. The adrenergic-induced rise in Cai2+ was inhibited by amitriptyline with a kI of 45 nM. Amitriptyline was found to inhibit both receptor classes by a competitive or mixed type of inhibition. Similarly, atropine exerted the same type of inhibition on the acetylcholine receptor. Amitriptyline and atropine were found to be mutually exclusive for competing for substrate binding on the receptor. These findings are consistent with a common binding site for amitriptyline and atropine on the acetylcholine receptor, possibly in close proximity with, but different from the substrate binding site. The stimulation-induced cell shrinkage evoked by the loss of electrolytes and water from the acini was measured by a 90 degree light scattering signal. It was found that this method makes possible the detection of autonomic side-effects of antidepressants on acini suspended in protein-containing media.

Anticholinergic effects of cis-chlorprothixene characterized in rat parotid acini.

The anticholinergic effects of the antipsychotic drug, cis-chlorprothixene, on the secretory events underlying the formation of primary saliva were investigated. The neuroleptic, cis-chlorprothixene, is used extensively as a major tranquillizer but shares side-effects such as xerostomia with most antidepressants. The inhibitory effects of cis-chlorprothixene upon the cholinergic-induced rise in Ca2+ as well as on O2 consumption and Cl- loss were investigated in isolated rat parotid acini in order to characterize its anticholinergic effects quantitatively. The cholinergic-induced rise in cytosolic, free Ca2+ was inhibited by cis-chlorprothixene with half-maximal effect at 1.9 microM and maximal inhibition at 10 microM. When the cytosolic, free Ca2+ was enhanced in the presence of 10 microM cis-chlorprothixene by means of the Ca2+ ionophore A23187, a loss of Cl- was observed similar to that observed during cholinergic stimulation in the absence of cis-chlorprothixene. The findings are consistent with the possibility that cis-chlorprothixene exerts its effects on the steps leading from agonist binding to the acetylcholine receptor and to the increase of cytosolic free Ca2+. Thus, measurement of the stimulation-induced rise in cytosolic, free Ca2+ in the presence of neuroleptics such as the thioxanthenes represents a fast and reliable method for detecting inhibitory effects on autonomic receptor activation.