Escitalopram in seasonal affective disorder: results of an open trial.

OBJECTIVE: The aim of this study was to evaluate the efficacy and tolerability of escitalopram in the treatment of seasonal affective disorder (SAD, fall-winter depression). METHODS: Twenty SAD patients were included in an 8-week drug surveillance. Patients were treated with open-label escitalopram at a dosage of 10 to 20 mg per day. Efficacy assessments included the Structured Interview Guide for the Hamilton Depression Rating Scale (SAD version; SIGH-SAD), the Clinical Global Impression (CGI) and the Social Adaptation Self Evaluation Scale (SASS). Side effects were monitored with the UKU Side Effect Rating Scale. RESULTS: From week 2 onwards, escitalopram significantly reduced SIGH-SAD score and CGI severity score (p<0.001). From week 4 onwards, the SASS score was also significantly improved (p<0.05). The response rate (SIGH-SAD<50% of baseline value) after treatment for 8 weeks was 95%, the rate of remission (SIGH-SAD < or =7) was 85%. Side effects were mild to moderate and did not lead to cessation of therapy. CONCLUSION: These results suggest that escitalopram is an efficacious and altogether safe treatment for seasonal depression.

No association of clock gene T3111C polymorphism and affective disorders.

CLOCK was hypothesised to be related to susceptibility of affective disorders. To test subsamples of affectively disordered patients, we examined age of onset (AoO), numbers of episodes and melancholic type of clinical manifestation. Using PCR and RFLP, we investigated in patients with unipolar depression and bipolar disorder (BP) whether the CLOCK T3111C SNP is associated with affective disorders (n=102) compared to healthy controls (n=103). No differences were found either in genotype or allele frequency distributions of T3111C polymorphism between patients compared to healthy controls (p>0.2). No deviations from Hardy-Weinberg Equilibrium (HWE) were detected either in patients, or healthy controls. Results suggest that there is no association between the T3111C SNP and affective disorders in general. Data of our sample replicate prior findings of Desan et al. [Am. J. Med. Genet. 12 (2000) 418]. Subsamples of patients with high numbers of affective episodes did show some deviations in genotypes (p=0.0585).

A polymorphism (5-HTTLPR) in the serotonin transporter promoter gene is associated with DSM-IV depression subtypes in seasonal affective disorder.

Serotonergic mechanisms are thought to play an important role in the pathogenesis of seasonal affective disorder (SAD). The expression of the serotonin transporter (5-HTT) is regulated in part by an insertion/deletion polymorphism in the serotonin transporter gene promoter region (5-HTTLPR). The 5-HTTLPR short allele (s) has been associated with anxiety-related personality traits and depression, and one study observed an association between the 5-HTTLPR s-allele and SAD and the trait of seasonality. We genotyped 138 SAD patients and 146 healthy volunteers with low seasonality for 5-HTTLPR. No difference between patients and controls was found for genotype distribution and s-allele frequency. However, genotype distribution and allele frequencies were strongly associated with DSM-IV depression subtypes. Melancholic depression was associated with the 5-HTTLPR long (l) allele and atypical depression with the 5-HTTLPR s-allele (two-sided Fisher's exact test: genotype distribution: P=0.0038; allele frequencies: P=0.007). Our data are compatible with the hypothesis of a disease process that is not causally related to 5-HTTLPR, but involves 5-HT neurotransmission and 5-HTTLPR somewhere on its way to phenotypic disease expression.

[Seasonal affective depression in 2 German speaking university centers: Bonn, Vienna. Clinical and demographic characteristics]. / Saisonal abhängige Depression in zwei deutschsprachigen Universitätszentren: Bonn, Wien. Klinische und demographische Charakteristika.

Six hundred ten patients with seasonal affective disorder (SAD) were diagnosed and treated at the university hospitals for psychiatry in Bonn, Germany (1989-1992) and Vienna, Austria (1993-2001). The aim of this study was to compare our sample with other SAD populations in the literature and to investigate differences between the two study locations. We found female:male sex ratios of 5.0:1.0 in unipolar depressives and 1.5:1.0 in patients with bipolar affective disorder. Of our patients, 21.7% suffered from bipolar II disorder, and 1.3% were diagnosed as having bipolar I. Our patients obtained a mean global seasonality score (GSS) of 15.4. Women had a higher GSS than men (t = 2.127, P = 0.035), and Viennese patients had higher scores than patients in Bonn (t = 3.104, P = 0.002). Totals of 66.3% of all patients suffered from atypical depression and 17.8% from melancholic depression. Patients with atypical depression were more frequent in Vienna, whereas patients with melancholic depression predominated in Bonn (chi 2 = 54.952, df = 2, P < 0.001). The demographic and clinical characteristics of the patients described in this article confirm the findings of other epidemiological investigations obtained in non-German-speaking samples.

Changes of clinical pattern in seasonal affective disorder (SAD) over time in a German-speaking sample.

OBJECTIVE: The goals of this study are to provide estimates of clinical and demographic variables of patients with seasonal affective disorder (SAD) in Germany and Austria, to compare our results with those of previously published SAD studies, and to find out whether the clinical pattern of SAD remained stable over several years. METHOD: We investigated 610 SAD patients from the outpatient clinics in Bonn (n = 190) and Vienna (n = 420). Patients in Bonn were recruited in the fall-winter season of the years 1989-1992, those in Vienna in the years 1993-2001. RESULTS: We observed a change in the clinical pattern in our patients: patients from Bonn, who were diagnosed and treated about 5 years earlier, were more likely to suffer from melancholic depression, whereas Viennese patients rather suffered from atypical depression (chi(2) = 54.952, df = 2, p < 0.001). The symptoms of hypersomnia, daytime fatigue, increased eating and carbohydrate-craving were more frequent in the Viennese sample, anxiety and deterioration of patients' capacity to perform at work predominated in Bonn. In addition, patients from Vienna obtained a higher GSS (global seasonality score, measured by the SPAQ - Seasonal Pattern Assessment Questionnaire) than those from Bonn (15.7 +/- 3.3 and 14.6 +/- 4.1 respectively; t = 3.104, p = 0.002). Taken together, our results were in good accordance to other published SAD materials, but we were able to demonstrate that our patients reported "feeling worst" (measured by item 13H of the SPAQ) in November and December, whereas SAD patients in the USA clearly had their worst months in January and February. CONCLUSIONS: We suggest that an increase in awareness of fall-winter depression in the last decade by both doctors, who referred patients, as well as patients or the entire population must have caused patients to sign up for light therapy at the Viennese SAD clinic because of having heard about the atypical symptom profile. This increased awareness of SAD can also be measured by a statistically significant reduction in the diagnostic latency (from the age of onset to the diagnosis of SAD) when comparing the two study locations.

[Pharmacotherapy of seasonal depression]. / Die Pharmakotherapie der saisonal abhängigen Depression.

Seasonal affective disorder (SAD), first described in 1984, is a condition characterized by recurring depressive episodes in fall and winter alternating with nondepressive episodes in spring and summer. Various neurotransmitters have been implicated in the etiology of SAD, with the strongest evidence for an involvement of serotonin. Moreover, researchers have focused on the development of treatment modalities for SAD. Despite the proven efficacy of light therapy in SAD, some patients do not experience sufficient relief of depressive symptoms with light, and a number of them feel unable to comply because of logistical difficulties in administering bright light therapy. Comparatively few studies have examined the role of pharmacotherapy in the treatment of SAD. So far, selective serotonin reuptake inhibitors and possibly compounds with a distinct noradrenergic mechanism of action seem to be the treatment of choice for seasonal depression. There is, however, a clear need for further placebo-controlled studies to evaluate pharmacological treatment options for SAD.

Intravenous mirtazapine in the treatment of depressed inpatients.

Mirtazapine is a novel antidepressant with a noradrenergic and specific serotonergic mode of action. So far, mirtazapine has been administered orally. This naturalistic study evaluates the antidepressant efficacy, safety, and tolerability of mirtazapine 15 mg/day administered intravenously to 27 inpatients with moderate to severe major depression. Compared with baseline, we found a significant decrease of the Hamilton Depressive Rating Scale (HDRS) total score (P<0.001). Side effects were mild and transient. Altogether, the results of this preliminary study show that intravenous mirtazapine is an effective, safe and well tolerated treatment for depressed inpatients.

Dopamine transporter availability in symptomatic depressed patients with seasonal affective disorder and healthy controls.

BACKGROUND: During recent years hypotheses about the pathophysiology of seasonal affective disorder/winter type (SAD) have focused monoaminergic mechanisms. There is substantial evidence that serotonergic systems play an important role. The potential role of catecholaminergic pathways has not been fully explored. METHODS: Eleven drug-free, symptomatic depressed patients with SAD and 11 healthy age- and gender-matched healthy controls were invited to participate in a 123Ibeta-CIT single photon emission computed tomography (SPECT) study to assess striatal density of dopamine transporters (DATs). The cerebellum was used as reference region. Ratios were calculated between mean counts in left and right striatum and cerebellum. These ratios minus I represent specific/non-displaceable binding and are assumed to be directly related to DAT availability at the time of binding equilibrium. RESULTS: Displaceable 153Ibeta-CIT binding in the area corresponding to the left striatum was significantly reduced in SAD patients compared to healthy controls (10.49+/-0.91 v. 1195+/-1.54, respectively; 2-tailed P = 0.017, Mann-Whitney U test). CONCLUSIONS: These data suggest reductions in the availability of striatal DAT binding sites in untreated symptomatic depressed SAD patients. It remains unclear whether these reductions represent a primary defect or an attempt to overcome a state of possible lowered dopamine availability in the synaptic cleft during a depressive episode of SAD. However, these findings provide evidence that brain dopaminergic systems may be involved in the pathophysiology of SAD.

No evidence for in vivo regulation of midbrain serotonin transporter availability by serotonin transporter promoter gene polymorphism.

BACKGROUND: A polymorphism in the serotonin transporter promoter gene region (5-HTTLPR) has been shown to influence the quantity of serotonin transporter expressed in human cell lines: the 5-HTTLPR short allele (s) has been associated with reduced 5-HTT expression when compared to cells carrying the 5-HTTLPR long allele (l). We performed a single photon emission computed tomography (SPECT) study using the ligand [(123)I]-2-beta-carbomethoxy-3-beta-(4-iodophenyl)tropane ([(123)I]-beta-CIT) to measure 5-HTT availability in 16 healthy subjects genotyped for 5-HTTLPR. METHODS: SPECT scans were performed 24 hours after tracer injection, regions of interest anatomically corresponding to the thalamus-hypothalamus and mesencephalon-pons areas were compared to the binding in the cerebellum, representing the nondisplaceable [(123)I]-beta-CIT-binding (results expressed as target activity minus cerebellum activity/cerebellum activity). DNA from peripheral nuclear blood cells was genotyped for 5-HTTLPR using standard polymerase chain reaction methods. RESULTS: Specific binding ratios in the thalamus-hypothalamus were 2.65 +/- 0.4 in subjects with the l/l genotype (n = 3), 2.76 +/- 0.5 in subjects with the l/s genotype (n = 9), and 2.77 +/- 0.4 in subjects with the s/s genotype (n = 4). Binding ratios in the mesencephalon-pons were 1.43 +/- 0.3 (l/l; n = 3), 1.37 +/- 0.3 (l/s; n = 9), and 1.28 +/- 0.3 (s/s; n = 4). None of these differences was statistically significant. CONCLUSIONS: Our data provide no evidence for in vivo functional regulation of 5-HTT availability by 5-HTTLPR in the thalamus-hypothalamus and mesencephalon-pons of healthy subjects.

Prevalence of premenstrual dysphoric disorder in female patients with seasonal affective disorder.

BACKGROUND: Both seasonal affective disorder/winter type (SAD) and premenstrual dysphoric disorder (PMDD) are cyclical disorders characterized by so-called atypical depressive symptoms. In the present study we compared the point prevalence rates of PMDD between a sample of premenopausal female patients suffering from SAD and healthy female controls. METHODS: Forty-six female patients with SAD and 46 healthy controls were included in our study. All subjects underwent a semistructured clinical interview according to DSM IV criteria and completed the Seasonal Pattern Assessment Questionnaire. PMDD was diagnosed in a self-rating interview for PMDD according to DSM IV criteria. To verify the diagnosis of PMDD, all patients were followed up in stable summer remission using daily self-rating scales for two full menstrual cycles. RESULTS: Patients with SAD fulfilled significantly more often the diagnostic criteria for PMDD than female healthy controls (46% vs. 2%, respectively; chi-square: P<0.001). CONCLUSIONS: These results provide preliminary evidence for a high point prevalence rate of PMDD in premenopausal females with SAD. CLINICAL IMPLICATIONS: It would be worthwhile to investigate whether an additional diagnosis of PMDD has an impact on the clinical outcome and the response to bright light therapy in female patients with SAD.

Reboxetine in seasonal affective disorder: an open trial.

Seasonal affective disorder (SAD), winter type, is a condition characterized by the annual recurrence of depressive episodes during fall/winter, alternating with spring/summer euthymia or hypomania. Various neurotransmitters have been implicated in the etiology of SAD, the strongest evidence involving serotonin. Recently, increasing attention has been paid to the potential role of catecholaminergic pathways in the pathophysiology of SAD. We investigated the efficacy and tolerability of reboxetine, a selective noradrenaline inhibitor, in patients with SAD. Eleven out of sixteen patients who were included in a 6-week drug surveillance during winter season experienced full remission of depressive symptoms. Nine patients reported a rapid relief of preexistent severe atypical depressive symptoms within the first treatment week. Reboxetine might therefore be an effective and well-tolerated treatment option for SAD patients. In conclusion, our preliminary results are in line with evidence from recent studies suggesting that catecholaminergic systems might also be involved in the pathophysiology of SAD.

Monoaminergic function in the pathogenesis of seasonal affective disorder.

Seasonal affective disorder/winter type (SAD) is characterized by recurrent depressive episodes during autumn and winter alternating with non-depressive episodes during spring and summer. Light therapy with full-spectrum, bright white light has been shown to be effective for this condition. Several hypotheses have been discussed in the literature about the pathogenesis of SAD. The most prominent includes disturbances in central monoaminergic transmission. Evidence can be inferred from studies showing a seasonal rhythm of central and peripheral serotonergic functioning which may be a predisposing factor for SAD. Some of the symptoms of SAD are believed to represent an attempt to overcome a putative deficit in brain serotonergic transmission. Moreover, 5-HT receptor challenge studies suggest altered activity at or downstream to central 5-HT receptors. Monoamine depletion studies support hypotheses about serotonergic and catecholaminergic dysfunctions in SAD and suggest that light therapy may well compensate for this underlying deficit. Further, albeit indirect, support for the importance of monoaminergic mechanisms in SAD and its involvement in the mechanism of the action of light therapy comes from studies showing antidepressant efficacy of serotonergic and noradrenergic antidepressants in the treatment of SAD. Altogether, disturbances in brain monoaminergic transmission seem to play a key role in the pathogenesis of SAD; monoaminergic systems may also play an important role in the mechanisms of the action of light therapy.

Occurrence of mirtazapine-induced delirium in organic brain disorder.

Mirtazapine is the first of a new class of antidepressants, the noradrenergic and specific serotonergic antidepressants. Its antidepressant effect appears to be related to its dual enhancement of both noradrenergic neurotransmission and serotonin 5-HT1 receptor-mediated serotonergic neurotransmission. Mirtazapine has demonstrated superior tolerability to the tricyclic antidepressants, primarily on account of its relative absence of anticholinergic, adrenergic and serotonin-related adverse effects. We observed mirtazapine-induced delirium in one organically depressed and two major depressed patients with subclinical brain disease. The appearance of hallucinations, psychomotoric agitation and cognitive changes after initiation of mirtazapine, and their prompt improvement after drug discontinuation, led to the impression that these were drug-induced phenomena. One possible hypothesis for the observed deliria is a central increase of norepinephrine after acute administration of mirtazapine. Subclinical brain disease might have favoured the occurrence of delirium in the three cases.

[123I]-beta-CIT SPECT imaging shows reduced brain serotonin transporter availability in drug-free depressed patients with seasonal affective disorder.

BACKGROUND: Numerous findings indicate alterations in brain serotonin systems in seasonal affective disorder (SAD). [(123)I]-2-beta-carbomethoxy-3-beta-(4-iodophenyl)-tropane ([(123)I]-beta-CIT) labels serotonin transporters (5-HTTs) in the midbrain. We performed a [(123)I]-beta-CIT single photon emission computer tomography (SPECT) study under the hypothesis of lower [(123)I]-beta-CIT binding reflecting reduced central 5-HTT availability in depressed SAD patients. METHODS: Depressed SAD patients and healthy control subjects were investigated using [(123)I]-beta-CIT SPECT 4 hours and again 24 hours after tracer injection. Subjects had either never used psychotropic medication or had been drug-free for at least 6 months prior to the investigation. Specific-to-nondisplaceable partition coefficient (V(3)") was calculated for the thalamus-hypothalamus and the midbrain-pons; the cerebellum served as a reference region. RESULTS: Patients showed a reduction in V(3)" in thalamus-hypothalamus (2.41+/-0.3 vs. 2.84+/-0.4; p = .026) 24 hours post tracer injection (p.i.). No difference between patients and control subjects was found in midbrain-pons (1.31+/-0.2 vs. 1.42+/-0.2; p = .39). No differences were detected in the SPECT acquisitions 4 hours p.i. CONCLUSIONS: Depressed SAD patients showed lower specific-to-nondisplaceable [(123)I]-beta-CIT binding in the region of interest (ROI) thalamus-hypothalamus. The small size of the midbrain-pons ROI may have contributed to the failure to show a difference in this ROI as well. Similar to reduced midbrain 5-HTT availability in nonseasonal depression, depression in SAD seems to be associated with reduced 5-HTT availability to the thalamus-hypothalamus.

Atypical epithelial cells and specimen adequacy: current laboratory practices of participants in the college of American pathologists interlaboratory comparison program in cervicovaginal cytology.

CONTEXT: The Bethesda System for reporting cervical/vaginal cytologic diagnoses introduced terminology for atypical squamous and glandular cells and categories for specimen adequacy. OBJECTIVES: To analyze current laboratory reporting practices and compare trends to previous surveys. DESIGN: Questionnaire surveys were mailed to 2000 laboratories in 1996 and 1997. PARTICIPANTS: Laboratories enrolled in the College of American Pathologists Interlaboratory Comparison Program in Cervicovaginal Cytology. MAIN OUTCOME MEASURES: Laboratory policies, criteria, and reporting rates for Bethesda System categories. RESULTS: The 1996 specimen adequacy survey had 1166 respondents, and 768 laboratories returned the 1997 questionnaire focusing on atypical squamous cells of undetermined significance (ASCUS) and glandular cells of undetermined significance (AGUS). Nearly all laboratories (92%) routinely reported specimen adequacy, an increase from the 66% rate in 1991. The median rate for unsatisfactory specimens was 0.5% (mean 0.95%), and the median rate for the satisfactory but limited category was 5.8% (mean 9.3%). The Bethesda criteria for designating a specimen unsatisfactory were used by more than 90% of laboratories. Nearly all laboratories (97%) used the term ASCUS in 1997, and more than 80% of laboratories used the Bethesda criteria for this category. Median reporting rates for epithelial abnormalities were as follows: ASCUS, 4.5%; AGUS, 0.3%; low-grade squamous intraepithelial lesion (SIL), 1.6%; and high-grade SIL, 0.5%. The median ASCUS/SIL ratio was 2.0, with 80% of laboratories reporting ratios between 0.64 and 4.23. The median ASCUS rate and ASCUS/SIL ratio were higher than 1993 survey results. Nearly all laboratories attempted follow-up studies on patients with abnormal cytology results, and midsized laboratories achieved the highest rates of follow-up. Median rates of abnormalities following an ASCUS or AGUS diagnosis were 20% and 15%, respectively. Laboratory respondents commonly used written recommendations in ASCUS/AGUS reports. CONCLUSIONS: Most laboratories that responded to the surveys had adopted Bethesda terminology and criteria for specimen adequacy and ASCUS/AGUS. Reporting rates for SIL and adequacy categories have remained stable, but median ASCUS rates and ASCUS/SIL ratios are higher than in 1993. The AGUS category is reported infrequently, but can be associated with significant pathology.

[Selective and safe. Review of new antidepressive drugs]. / Selektiv und sicher. Die neuen Antidepressiva im Uberblick.

Epidemiological studies suggest an incidence of major depressive disorders between 6% and 17%. A number of therapeutic modalities, including modern antidepressants, have been shown to be effective treatment for these conditions. Modern antidepressants are significantly more effective than placebo in the treatment of depression, and are equally as effective as the older tricyclic and tetracyclic antidepressants. Modern antidepressants, however, show superior efficacy for the long-term treatment of depression, probably because of their favorable side effect profile.

Interobserver variability in subclassification of squamous intraepithelial lesions: Results of the College of American Pathologists Interlaboratory Comparison Program in Cervicovaginal Cytology.

OBJECTIVE: To determine whether, on a national cytology proficiency test, a competent cytologist can consistently distinguish grades of squamous intraepithelial lesions. DESIGN: Results for low- and high-grade squamous intraepithelial lesion referenced slides from the College of American Pathologists Interlaboratory Comparison Program in Cervicovaginal Cytology for 1996 and 1997 were analyzed including educational, nongraded vs graded validated slides. RESULTS: The discrepant rate between low- and high- grade lesions ranged from 9.8% to 15% for cytotechnologist, pathologist, laboratory, and all responses. There was a statistically significant difference in performance on graded, validated slides vs educational slides with better performance on validated slides. CONCLUSION: This significant interobserver variability in subclassification of squamous lesions should be considered in management guidelines for abnormal Papanicolaou test results and implementation of national cytology proficiency testing.

Evaluation of systolic performance by automated impedance cardiography.

Impedance cardiography (ICG) is a noninvasive method for evaluating cardiac function. Left ventricular stroke volume (SV) is the basic hemodynamic parameter derived from thoracic bioimpedance curves. Issues of our study were to investigate the diagnostic value of other indices of left ventricular systolic performance, such as ejection fraction (EF), index of contractility (IC), peak flow index (PFI), and acceleration index (ACI), which can also be calculated by ICG. Forty patients (PTS) with suspected coronary artery disease (CAD) were monitored by automated ICG during pharmacologic stress testing with dobutamine. All PTS underwent subsequent cardiac catheterization. In PTS with single vessel disease, the dobutamine-induced changes of SV, EF, IC, PFI, and ACI were comparable to those of PTS without CAD. In PTS with multivessel disease, the impaired systolic performance during dobutamine stimulation could be clearly demonstrated. We conclude that automated ICG is a useful method for monitoring SV and other indices of left ventricular systolic performance for detecting PTS with ischemic left ventricular dysfunction during cardiovascular stress.

Monoamine depletion in non-pharmacological treatments for depression.

Non-pharmacological treatments such as light therapy for seasonal affective disorder or sleep deprivation for non-seasonal depression have been shown to treat depression effectively. With the use of the tryptophan depletion paradigm and the catecholamine depletion paradigm we assessed the role of brain serotonergic and catecholaminergic systems respectively. We found that disturbances in brain serotonin systems play a key role in the pathogenesis of seasonal affective disorder and that light therapy may compensate for the underlying deficit. Moreover there is evidence that catecholaminergic systems may be involved in the mechanism of action of light therapy. Tryptophan depletion studies suggest that sleep deprivation does not exert its antidepressant effects by involving brain serotonin systems alone. Interestingly, tryptophan depletion prevented the relapse after the recovery night, possibly by enhancing brain serotonin transmission after the depletion procedure.