Roland Ricken

Hyporeactivity of ventral striatum towards incentive stimuli in unmedicated depressed patients normalizes after treatment with escitalopram

Major Depressive Disorder (MDD) involves deficits in the reward system. While neuroimaging studies have focused on affective stimulus processing, few investigations have directly addressed deficits in the anticipation of incentives. We examined neural responses during gain and loss anticipation in patients with MDD before and after treatment with a selective serotonin reuptake inhibitor (SSRI). Fifteen adults with MDD and 15 healthy participants, matched for age, verbal IQ and smoking habits, were investigated in a functional magnetic resonance imaging (fMRI) study using a monetary incentive delay task. Patients were scanned drug-free and after 6 weeks of open-label treatment with escitalopram; controls were scanned twice at corresponding time points. We compared the blood oxygenation level dependent (BOLD) response during the anticipation of gain and loss with a neutral condition. A repeated measures ANOVA was calculated to identify effects of group (MDD vs. controls), time (first vs. second scan) and group-by-time interaction. Severity of depression was measured with the Hamilton Rating Scale of Depression and the Beck Depression Inventory. MDD patients showed significantly less ventral striatal activation during anticipation of gain and loss compared with controls before, but not after, treatment. There was a significant group-by-time interaction during anticipation of loss in the left ventral striatum due to a signal increase in patients after treatment. Ventral striatal hyporesponsiveness was associated with the severity of depression and in particular anhedonic symptoms. These findings suggest that MDD patients show ventral striatal hyporesponsiveness during incentive cue processing, which normalizes after successful treatment.

A preliminary study of increased amygdala activation to positive affective stimuli in mania

OBJECTIVES The present study in hypomanic and manic patients explored how amygdala responses to affective stimuli depend on the valence of the stimuli presented. METHODS We compared 10 patients with 10 matched healthy control subjects. We measured blood oxygen level-dependent (BOLD) responses in the amygdala while subjects passively viewed photographs taken from the International Affective Picture System. After the fMRI session, subjects saw the pictures again and subjectively rated the emotional valence and intensity of each picture. RESULTS Compared to healthy individuals, hypomanic or manic patients showed higher valence ratings in positive pictures and associated larger BOLD responses in the left amygdala during positive versus neutral picture viewing. This enhanced amygdala activation was correlated with Young Mania Rating Scale scores and with euphoric as opposed to irritable symptom presentation. CONCLUSIONS Increased valence ratings and amygdala responses to positive affective stimuli may reflect a positive processing bias contributing to elevated mood states characteristic for euphoric mania.

Do locked doors in psychiatric hospitals prevent patients from absconding

Background and Objectives: In the acute treatment of acute psychiatric patients coercive measures are often required and therapeutic relationships can be affected by such measures. In this study we assessed whether opening the entrance door of an acute psychiatric ward influences absconding behaviour. Methods: An acute psychiatric ward was primarily closed (91.4%) for six months and primarily open (75.6%) for six months over the time period of one year. In this one year period, 337 patients were treated (206 male, age: 40 ± 16 years): 60.2% of the patients had schizophrenia, 13.6% had affective disorders, 11.6% suffered from addiction and 14.5% displayed other diagnoses. Results: In terms of age (t = 0.026, df = 335, p = 0.979), gender (chi2 = 1.6, df = 1, p = 0.13), di- agnoses (chi 2 = 7.337, df = 1, p = 0.062) and duration of stay (t = -0.90, df = 335, p = 0.928), we found no significant differences between the patients admitted in the closed and those ad- mitted in the open ward period. Absconding (df = 1, chi2 = 5.107, p = 0.029), aggressive inci- dents (chi 2 = 4.46, df = 1, p = 0.050) and coercive medications (chi 2 = 4.646, df = 1, p = 0.037) were observed significantly more often in the closed door period. Moreover, the dura- tion up to readmission was reduced in the closed time period (t = 2.314, df = 54, p = 0.025). Conclusions: We hypothesize that open doors reduce patients discomfort, improve ward atmosphere and aggressive acts and do not appear to increase the risk of absconding.

Reduced Brain-Derived Neurotrophic Factor Serum Concentrations in Acute Schizophrenic Patients Increase During Antipsychotic Treatment

Introduction: Brain-derived neurotrophic factor (BDNF) is not only involved in the development, differentiation, and survival of dopaminergic neurons; it also regulates fast neurotransmission and neuronal activity. Methods: In this study, 22 patients with acute schizophrenia and 22 age-matched healthy volunteers were recruited, and BDNF serum concentrations were measured in unmedicated patients and after 2 weeks and 4 weeks of medication. Results: Brain-derived neurotrophic factor serum levels of unmedicated schizophrenic patients (n = 22; 4.38 ± 2.1 ng/mL) were significantly decreased compared to the age-matched healthy volunteers (n = 44, df = 42, P = 0.029). In a mixed-model repeated-measures analysis of variance, a significant BDNF increase has been found during treatment (&khgr;2 = 2.91; df = 1; P < 0.0001). The percental change of BDNF (increase, 173% ± 110) correlated negatively with the percental change of PANSS score (decrease: 75% ± 22; n = 18; r = −0.554; P = 0.032). Conclusions: Our study replicates studies showing that unmedicated patients with schizophrenia have decreased serum BDNF levels compared with healthy controls. Brain-derived neurotrophic factor increase during treatment seems to parallel positive and negative symptom improvement.

Safety of high-intensity treatment with the irreversible monoamine oxidase inhibitor tranylcypromine in patients with treatment-resistant depression.

INTRODUCTION Because the irreversible monoamine oxidase inhibitor tranylcypromine (TCP) was introduced nearly 50 years ago, only few studies exist on todays clinical prescribing practice together with 2nd and 3rd generation psychotropic drugs. METHODS We performed a practice-based observational study of patients with depression treated with TCP in two psychiatric departments in Berlin to assess side effects, effectiveness, comedication and acceptance of the low-tyramine diet. RESULTS We identified thirty-two patients treated with TCP at a mean dose of 51.9 mg/day after an average of 3.3 pre-treatments in the current episode. Dosing of TCP and the use of multiple psychotropic comedications indicate a high-intensity treatment. The most frequent side effects resulted from arterial hypotonia (28%). Dietary restrictions were mainly rated as moderate. 59% of patients remitted (HAMD- (21)<9 or CGI-I=1) and 22% responded (HAMD- (21) reduction >50% or CGI-I=2). DISCUSSION A high-intensity treatment of inpatients with TCP is clinically feasible, i.e., the use of high doses and multiple comedications with a good benefit-risk-ratio. Prospective data aiming at comparisons with modern antidepressants and clarifying further safety issues are warranted.

Supraphysiologic doses of levothyroxine as adjunctive therapy in bipolar depression: a randomized, double-blind, placebo-controlled study.

OBJECTIVE Suboptimal availability of circulating thyroid hormones may contribute to the high rate of treatment failures in bipolar disorder. This study tested the efficacy of adjunctive treatment with supraphysiologic doses of levothyroxine in patients with bipolar depression and the hypothesis that women would display a better outcome compared to men. METHOD The aims of this multicenter, 6-week, double-blind, randomized, placebo-controlled fixed-dose (300 μg/d) trial conducted from 2004 to 2009 were to assess efficacy and tolerability of levothyroxine adjunctive to continuing treatment with mood stabilizer and/or antidepressant medication for patients with bipolar I or II disorder, currently depressed (DSM-IV), and to investigate gender differences in treatment response. The primary efficacy variable was mean change in Hamilton Depression Rating Scale (HDRS) score. RESULTS Of 74 patients enrolled in the study, 62 (35 with bipolar I; mean age = 44.9 years) were randomized. Mean change in HDRS score from randomization to week 6 was larger in the levothyroxine group compared to the placebo group, with a 2.7-point difference (decline of -7.8 [38.3%] vs -5.1 [25.5%]; last-observation-carried-forward analysis). The course of HDRS scores over time from randomization to week 6 was significantly different between groups at week 4 (P = .046) but not at the end of the placebo-controlled phase (P = .198). The secondary analysis of women (n = 32) revealed a significant difference between groups in mean change in HDRS score (-16.6% placebo vs -42.4% levothyroxine, P = .018). A mixed-effects model for repeated-measures analysis showed a significant between-group difference in HDRS score (6.8, P = .012) for women. High thyroid-stimulating hormone levels, indicating suboptimal levels of circulating thyroid hormones, were predictive for positive treatment outcome in women treated with levothyroxine in a linear regression model (F3 = 3.47; P = .05). DISCUSSION This trial demonstrated that patients treated with levothyroxine did numerically better than those treated with placebo; however, the study failed to detect a statistically significant difference between the 2 groups in the primary outcome measure due to a high placebo response rate. Previous findings that women show better improvement in depression scores with levothyroxine compared to men were confirmed. TRIAL REGISTRATION ClinicalTrials.gov identifier: NCT01528839.

Brain-derived neurotrophic factor serum concentrations in acute depressive patients increase during lithium augmentation of antidepressants.

Abstract In recent years, lithium has proved an effective augmentation strategy of antidepressants in both acute and treatment-resistant depression. Neuroprotective and procognitive effects of lithium have been evidenced. Brain-derived neurotrophic factor (BDNF) has been shown to play a key role in the pathophysiology of several neurological and psychiatric disorders. The BDNF hypothesis of depression postulates that a loss of BDNF is directly involved in the pathophysiology of depression, and its restoration may underlie the therapeutic efficacy of antidepressant treatments. Brain-derived neurotrophic factor serum concentrations were measured in a total of 83 acutely depressed patients before and after 4 weeks of lithium augmentation. A significant BDNF increase has been found during treatment (F2,81 = 5.04, P < 0.05). Brain-derived neurotrophic factor concentrations at baseline correlated negatively with relative Hamilton Depression Scale change after treatment with lithium (n = 83; r = −0.23; P < 0.05). This is the first study showing that lithium augmentation of an antidepressant strategy can increase BDNF serum concentrations. Our study replicates previous findings showing that serum BDNF levels in patients with depressive episodes increase during effective antidepressant treatment. Further studies are needed to separate specific effects of different antidepressants on BDNF concentration and address potential BDNF downstream mechanisms.

The FKBP5 polymorphism rs1360780 influences the effect of an algorithm-based antidepressant treatment and is associated with remission in patients with major depression

Objective: The FKBP5-gene influences the HPA-system by modulating the sensitivity of the glucocorticoid receptor (GR). The polymorphism rs1360780 has been associated with response in studies with heterogeneous antidepressant treatment. In contrast, several antidepressant studies with standardized antidepressant treatment could not detect this effect. We therefore compared patients with standardized vs naturalistic antidepressant treatment to (a) investigate a possible interaction between FKBP5-genotype and treatment mode and (b) replicate the effect of the FKBP5-genotype on antidepressant treatment outcome. Methods: A total of 298 major depressive disorder (MDD) inpatients from the multicentred German project and the Zurich Algorithm Project were genotyped for their FKBP5 status. Patients were treated as usual (n=127) or according to a standardized algorithm (n=171). Main outcome criteria was remission (Hamilton Depression Rating Scale-21<10). Results: We detected an interaction of treatment as usual (TAU) treatment and C-allele with the worst outcome for patients combining those two factors (HR=0.46; p=0.000). Even though C-allele patients did better when treated in the structured, stepwise treatment algorithm (SSTR) group, we still could confirm the influence of the FKBP5-genotype in the whole sample (HR=0.52; p=0.01). Conclusions: This is the first study to show an interaction between a genetic polymorphism and treatment mode. Patients with the C-allele of the rs1360780 polymorphism seem to benefit from a standardized antidepressant treatment.

Algorithm-guided treatment of depression reduces treatment costs — Results from the randomized controlled German Algorithm Project (GAPII)

BACKGROUND The German Algorithm Project, Phase 2 (GAP2) revealed that a standardized stepwise treatment regimen (SSTR) results in better treatment outcomes than treatment as usual (TAU) in depressed inpatients. The objective of this study was a health economic evaluation of SSTR based on a cost effectiveness analysis (CEA). METHODS GAP2 was a randomized controlled study with 148 patients. In an intention to treat (ITT) analysis direct treatment costs for study duration (SD) and total time in hospital (TTH; enrolment to discharge) were calculated based on daily hospital charges followed by a CEA to calculate cost expenditure per remitted patient. RESULTS Treatment costs in SSTR compared to TAU were significantly lower for SD (SSTR: 10 830 € ± 8 632 €, TAU: 15 202 € ± 12 483 €; p = 0.026) and did not differ significantly for TTH (SSTR: 21 561 € ± 16 162 €; TAU: 18 248 € ± 13 454; p = 0.208). CEA revealed that the costs per remission in SSTR were significantly lower for SD (SSTR: 20 035 € ± 15 970 €; SSTR: 38 793 € ± 31 853 €; p<0.0001) and TTH (SSTR: 31 285 € ± 23 451 €; TAU: 38 581 € ± 28 449 €, p = 0.041). LIMITATIONS Indirect costs were not assessed. Different dropout rates in TAU and SSTR complicated interpretation of data. CONCLUSION An SSTR-based algorithm results in a superior cost effectiveness at no significant extra costs. Implementation of treatment algorithms in inpatient-care may help reduce treatment costs.

Characterizing the phenotype of multiple sclerosis–associated depression in comparison with idiopathic major depression

Background: Depression is a common co-morbidity in patients with multiple sclerosis (MS). While somatic symptoms of MS correlate with depression levels, it is unclear whether the clinical presentation of MS-associated depression differs from patients with “idiopathic” major depressive disorder (MDD). Objective: To compare the clinical phenotype of depression among MS and idiopathic MDD patients. Methods: Mean relative contribution of individual Beck Depression Inventory-II (BDI-II) items was evaluated among n = 139 patients with relapsing-remitting MS and n = 85 MDD patients without somatic illness. Next, comparisons were repeated in n = 38 MS with clinically relevant depressive symptoms (BDI-II > 19) and n = 38 MDD patients matched for sex, age, and depression severity. Finally, the underlying construct of depression was compared across groups using confirmatory factor analysis (CFA). Results: Comparisons on a whole-group level produced the expected differences along somatic/non-somatic symptoms. However, when appropriately controlling for depression severity, age, and sex, only four items contributed differentially to BDI-II total scores in MS versus MDD. CFA suggested that the underlying depression construct is essentially identical in both groups. Conclusion: The clinical phenotype of “idiopathic” MDD and MS-associated depression appears similar when adequately examined. The relevance of these findings for psychotherapeutic approaches for MS-associated depression should be explored in future studies.