Acute effects of lithium augmentation on the kidney in geriatric compared with non-geriatric patients with treatment-resistant depression.

INTRODUCTION: Lithium augmentation (LA) of antidepressants is a first-line therapy option for treatment-resistant depression (TRD). Nevertheless, it is rarely used in geriatric patients mostly because of the fear of kidney toxicity. The purpose of this study is to investigate estimated glomerular filtration rate (eGFR) changes and number of acute kidney injuries (AKI) using LA in geriatric compared with non-geriatric patients. METHODS: In a prospective multicenter cohort study, eGFR changes were measured in 201 patients with unipolar depression (nage≥65years  = 29; nage<65years  = 172) at baseline and over 2-6 weeks of LA. We used linear mixed models to investigate changes in eGFR upon LA and assessed the number of AKIs, according to the Kidney Disease: Improving Global Outcomes (KDIGO) guidelines. RESULTS: Both age groups showed a significant eGFR decline over the course of treatment with lower eGFR in geriatric patients. The lithium serum level (interpretable as "effect of LA") had a significant effect on eGFR decline. Both effects (age group and lithium serum level) on eGFR decline did not influence each other, meaning the effect of LA on eGFR decline did not differ between age groups. Two AKIs were observed in the geriatric age group when serum lithium levels exceeded the therapeutic range of >0.8 mmol/L. CONCLUSION: This is the first study investigating eGFR change and AKI upon LA for TRD in geriatric compared with non-geriatric patients. Our data suggest that LA, as an effective treatment option in geriatric patients, should be closely monitored to avoid AKIs.

The big five model in bipolar disorder: a latent profile analysis and its impact on longterm illness severity.

BACKGROUND: Using a personality typing approach, we investigated the relationship between personality profiles and the prediction of longterm illness severity in patients with bipolar disorder (BD). While previous research suggests associations between BD and traits from the NEO-FFI profiles, the current study firstly aimed to identify latent classes of NEO-FFI profiles, and, secondly, to examine their impact on the longterm prognosis of BD. METHODS: Based on the NEO-FFI profiles of 134 euthymic patients diagnosed with BD (64.2% female, mean age = 44.3 years), successive latent profile analyses were conducted. Subsequently, a subsample (n = 80) was examined prospectively by performing multiple regression analysis of the latent classes to evaluate the longitudinal course of the disease (mean: 54.7 weeks) measured using a modified Morbidity Index. RESULTS: The latent profile analyses suggested a 3-class model typifying in a resilient (n = 68, 51%), vulnerable (n = 55, 41%) and highly vulnerable (n = 11, 8%) class. In the regression analysis, higher vulnerability predicted a higher longterm Morbidity Index (R2 = 0.28). CONCLUSIONS: Subgroups of patients with BD share a number of discrete personality features and their illness is characterized by a similar clinical course. This knowledge is valuable in a variety of clinical contexts including early detection, intervention planning and treatment process.

Adjuvant psychotherapy in early-stage bipolar disorder: study protocol for a randomized controlled trial.

BACKGROUND: Bipolar disorders are serious illnesses with a chronic course and a high rate of relapse. Typically, bipolar disorders onset during adolescence or early adulthood, with patients experiencing significant personal and social costs as a consequence of their illness. Despite this, to date, there is limited (controlled) evidence regarding the effectiveness of psychotherapy during the critical stages of the disorder (e.g., early onset). Some preliminary studies suggest that targeted, tailored early interventions in particular may improve disease prognosis. The proposed study examines the effectiveness of group psychotherapy on relapse prevention, global adaptive functioning, and neuropsychological functioning in early-stage bipolar disorder. METHODS: In this multicenter randomized controlled trial (RCT), 300 patients with bipolar disorder are randomized to one of two group psychotherapies: Specific Emotional-Cognitive Therapy (SECT; intervention group) or Emotion-Focused Supportive Therapy (EFST; active control group). Each therapy comprises of a total of 48-h sessions (delivered once a month) over a period of 4 months. Assessments take place at baseline (t1); 6 months follow-up, i.e., post-intervention (t2); 12 months follow-up (t3); and 18 months follow-up (t4), whereby 18 months follow-up is the primary time point of interest. DISCUSSION: The goal of this study is to test the effects of an innovative, specific group therapy relative to an active control condition in terms of rates of relapse, global functioning, and neuropsychological functioning. Pending the outcomes of the trial, it will be possible to establish a firm evidence base for accessible group psychotherapy adjuvant to routine psychiatric care for individuals with bipolar disorder. TRIAL REGISTRATION: USA: ClinicalTrials.gov NCT02506322 . Registered on 19 December 2014; Germany: German Clinical Trials Register DRKS00006013 . Registered on21 May 2015.

Efficacy of cognitive-behavioral group therapy in patients at risk for serious mental illness presenting with subthreshold bipolar symptoms: Results from a prespecified interim analysis of a multicenter, randomized, controlled study.

OBJECTIVE: Most patients with bipolar disorders (BD) exhibit prodromal symptoms before a first (hypo)manic episode. Patients with clinically significant symptoms fulfilling at-risk criteria for serious mental illness (SMI) require effective and safe treatment. Cognitive-behavioral psychotherapy (CBT) has shown promising results in early stages of BD and in patients at high risk for psychosis. We aimed to investigate whether group CBT can improve symptoms and functional deficits in young patients at risk for SMI presenting with subthreshold bipolar symptoms. METHOD: In a multicenter, randomized, controlled trial, patients at clinical risk for SMI presenting with subthreshold bipolar symptoms aged 15-30 years were randomized to 14 weeks of at-risk for BD-specific group CBT or unstructured group meetings. Primary efficacy endpoints were differences in affective symptomatology and psychosocial functioning at 14 weeks. At-risk status was defined as a combination of subthreshold bipolar symptomatology, reduction of psychosocial functioning and a family history for (schizo)affective disorders. A prespecified interim analysis was conducted at 75% of the targeted sample. RESULTS: Of 128 screened participants, 75 were randomized to group CBT (n = 38, completers = 65.8%) vs unstructured group meetings (n = 37, completers = 78.4%). Affective symptomatology and psychosocial functioning improved significantly at week 14 (P < .001) and during 6 months (P < .001) in both groups, without significant between-group differences. Findings are limited by the interim character of the analysis, the use of not fully validated early detection interviews, a newly adapted intervention manual, and the substantial drop-outs. CONCLUSIONS: Results suggest that young patients at-risk for SMI presenting with subthreshold bipolar symptoms benefit from early group sessions. The degree of specificity and psychotherapeutic interaction needed requires clarification.

Leptin gene polymorphisms are associated with weight gain during lithium augmentation in patients with major depression.

Weight gain is a common adverse effect of lithium augmentation. Previous studies indicate an impact of genetic variants at the leptin gene on weight gain as a consequence of psychopharmacological treatment. The primary aim of our study was to identify variants at the leptin locus that might predict lithium-induced weight gain. The secondary aim was to investigate if these variants modulate leptin levels. In 180 patients with acute major depressive disorder, body mass index was measured before and after 4 weeks of lithium augmentation, in a subsample also after 4 and/or 7 months. In a subsample of 89 patients, leptin serum concentrations were measured before and during lithium augmentation. We used linear mixed model analyzes to investigate the effects of 2 polymorphisms at the leptin locus (rs4731426 and rs7799039, employing the respective proxy SNPs rs2278815 and rs10487506) on changes in body mass index and leptin levels. For both polymorphisms, which are in high linkage disequilibrium, body mass index was significantly lower in homozygous A-allele carriers than in carriers of other genotypes at baseline. Over the follow-up period, body mass index increased less in homozygous A-allele carriers of rs4731426 than in carriers of other genotypes. This was not the case for rs7799039. Neither polymorphism modulated leptin protein expression. Our study strongly supports the hypothesis that genetic variability at the leptin locus is involved in lithium augmentation-associated weight gain in major depressive disorder. Furthermore, Genotype-Tissue Expression data provide strong evidence that rs4731426 influences the expression of leptin messenger ribonucleic acid in fibroblasts.

Impulsivity predicts illness severity in long-term course of bipolar disorder: A prospective approach.

BACKGROUND: Bipolar disorder is a common, severe and chronic mental illness. Despite this, predictors of illness severity remain poorly understood. Impulsivity is reported to be associated with bipolar disorder and aggravating comorbidities. This study therefore sought to examine the predictive value of impulsivity for determining illness severity in euthymic bipolar disorder patients. METHODS: Baseline trait impulsivity of 120 bipolar euthymic patients (81 bipolar disorder I [68%], 80 female [67%]) and 51 healthy controls was assessed using Barratt Impulsiveness Scale 11. The impact of impulsivity on illness severity (measured with morbidity index) was prospectively tested in 97 patients with sufficient follow-up data (average observation time: 54.4 weeks), using linear regression analysis. RESULTS: Barratt Impulsiveness Scale 11 total (ß = 0.01; p < 0.01) and in particular Barratt Impulsiveness Scale 11 attentional subscale scores (ß = 0.04; p < 0.001) predicted illness severity in bipolar disorder, while controlling for other clinical variables. Only age at onset persisted as an additional, but less influential predictor. Barratt Impulsiveness Scale 11 total scores and Barratt Impulsiveness Scale 11 attentional subscale scores were significantly higher in euthymic patients compared to controls. This was not observed for the motor or non-planning subscale scores. LIMITATIONS: The average year-long observation time might not be long enough to account for the chronic course of bipolar disorder. CONCLUSION: Trait impulsivity and particularly attentional impulsivity in euthymic bipolar patients can be strong predictors of illness severity in bipolar disorder. Future studies should explore impulsivity as a risk assessment for morbidity and as a therapeutic target in bipolar disorder patients.

A standardized stepwise drug treatment algorithm for depression reduces direct treatment costs in depressed inpatients - Results from the German Algorithm Project (GAP3).

BACKGROUND: In a previous single center study we found that a standardized drug treatment algorithm (ALGO) was more cost effective than treatment as usual (TAU) for inpatients with major depression. This report aimed to determine whether this promising initial finding could be replicated in a multicenter study. METHODS: Treatment costs were calculated for two time periods: the study period (from enrolment to exit from study) and time in hospital (from enrolment to hospital discharge) based on daily hospital charges. Cost per remitted patient during the study period was considered as primary outcome. RESULTS: 266 patients received ALGO and 84 received TAU. For the study period, ALGO costs were significantly lower than TAU (ALGO: 7 848 ± 6 065 €; TAU: 10 033 ± 7 696 €; p = 0.04). For time in hospital, costs were not different (ALGO: 14 734 ± 8 329 €; TAU: 14 244 ± 8 419 €; p = 0.617). Remission rates did not differ for the study period (ALGO: 57.9%, TAU: 50.0%; p=0.201). Remission rates were greater in ALGO (83.3%) than TAU (66.2%) for time in hospital (p = 0.002). Cost per remission was lower in ALGO (13 554 ± 10 476 €) than TAU (20 066 ± 15 391 €) for the study period (p < 0.001) and for time in hospital (ALGO: 17 582 ± 9 939 €; TAU: 21 516 ± 12 718 €; p = 0.036). LIMITATIONS: Indirect costs were not assessed. Different dropout rates in TAU and ALGO complicated interpretation. CONCLUSIONS: Treatment algorithms enhance the cost effectiveness of the care of depressed inpatients, which replicates our prior results in an independent sample.

Cytokine serum levels remain unchanged during lithium augmentation of antidepressants in major depression.

Lithium augmentation (LA) of antidepressants is a first-line therapy in treatment-resistant depression. Immunomodulatory effects of lithium have been described. The cytokine hypothesis of depression postulates that cytokines play a key role in the pathophysiology of depression. Concordantly, it has been shown that proinflammatory cytokine serum levels decrease during antidepressant treatment. The aim of this study was to investigate changes in cytokine serum levels during LA. Serum concentrations of the cytokines interleukin (IL)-2, IL-4, IL-6, IL-8, IL-10, tumour necrosis factor alpha, interferon-gamma, granulocyte and monocyte colony stimulating factor were measured in a total of 95 acutely depressed patients before and after four weeks of LA. Changes in cytokine levels were corrected for the confounding factors severity of depression, treatment response, lithium serum level, gender, age and body mass index in a linear mixed-model analysis. We did not find a significant change in any of the measured cytokine serum levels during LA (p > 0.05). In conclusion, our study does not support the role of cytokine serum levels as a state marker in treatment of depression with LA.

Ghrelin Serum Concentrations Are Associated with Treatment Response During Lithium Augmentation of Antidepressants.

Background: Lithium augmentation of antidepressants is an effective strategy in treatment-resistant depression. The proteohormone ghrelin is thought to be involved in the pathophysiology of depression. The purpose of this study was to investigate the association of treatment response with the course of ghrelin levels during lithium augmentation. Method: Ghrelin serum concentrations and severity of depression were measured in 85 acute depressive patients before and after 4 weeks of lithium augmentation. Results: In a linear mixed model analysis, we found a significant effect of response*time interaction (F1.81=9.48; P=.0028): under treatment, ghrelin levels increased in nonresponders and slightly decreased in responders to lithium augmentation. The covariate female gender had a significant positive effect (F1.83=4.69; P=.033), whereas time, response, appetite, and body mass index (kg/m2) did not show any significant effect on ghrelin levels (P>.05). Conclusion: This is the first study showing that the course of ghrelin levels separates responders and nonresponders to lithium augmentation. Present results support the hypothesis that ghrelin serum concentrations might be involved in response to pharmacological treatment of depression.

Autobiographical Memory in Bipolar Disorder and Its Link to Neuropsychological Functioning.

OBJECTIVE: The aim of this study was to examine the specificity of autobiographical memory (AM) in bipolar disorder (BD) and to investigate the association between AM and neuropsychological functions. METHOD: Twenty bipolar patients and 22 matched healthy controls (HCs) were included in this study. AM was assessed with an extended version of the Autobiographical Memory Test (AMT) including rejection cue words. A neuropsychological test battery was used to examine verbal memory, executive functions, and attention. RESULTS: Across both groups, the number of specific memories in the AMT was significantly smaller in response to rejection cue words and positive cue words than in response to negative cue words. Participants with BD and HCs did not differ significantly in neuropsychological measures. Across both groups, scores of verbal memory, executive functions, and attention were significantly correlated with specificity of retrieved memories. LIMITATIONS: Although our clinical sample consisted of clinically stable outpatients, 6 out of 20 patients were not rated as euthymic but as mildly depressed. All BD patients were medicated. CONCLUSION: Contrary to previous results, patients with BD did not differ in the number of specific memories compared to an HC group. Our findings suggest that neuropsychological functioning is associated with AMT specificity. Further research is required to gain a better understanding of the underlying mechanisms which may influence the ease of memory retrieval.

How Effective Is Algorithm-Guided Treatment for Depressed Inpatients? Results from the Randomized Controlled Multicenter German Algorithm Project 3 Trial.

Background: Treatment algorithms are considered as key to improve outcomes by enhancing the quality of care. This is the first randomized controlled study to evaluate the clinical effect of algorithm-guided treatment in inpatients with major depressive disorder. Methods: Inpatients, aged 18 to 70 years with major depressive disorder from 10 German psychiatric departments were randomized to 5 different treatment arms (from 2000 to 2005), 3 of which were standardized stepwise drug treatment algorithms (ALGO). The fourth arm proposed medications and provided less specific recommendations based on a computerized documentation and expert system (CDES), the fifth arm received treatment as usual (TAU). ALGO included 3 different second-step strategies: lithium augmentation (ALGO LA), antidepressant dose-escalation (ALGO DE), and switch to a different antidepressant (ALGO SW). Time to remission (21-item Hamilton Depression Rating Scale ≤9) was the primary outcome. Results: Time to remission was significantly shorter for ALGO DE (n=91) compared with both TAU (n=84) (HR=1.67; P=.014) and CDES (n=79) (HR=1.59; P=.031) and ALGO SW (n=89) compared with both TAU (HR=1.64; P=.018) and CDES (HR=1.56; P=.038). For both ALGO LA (n=86) and ALGO DE, fewer antidepressant medications were needed to achieve remission than for CDES or TAU (P<.001). Remission rates at discharge differed across groups; ALGO DE had the highest (89.2%) and TAU the lowest rates (66.2%). Conclusions: A highly structured algorithm-guided treatment is associated with shorter times and fewer medication changes to achieve remission with depressed inpatients than treatment as usual or computerized medication choice guidance.

Leptin serum concentrations are associated with weight gain during lithium augmentation.

BACKGROUND: Meta-analytical data show lithium augmentation (LA) as an effective treatment strategy in major depression. Weight-gain is a common side effect of LA. The proteohormone leptin is discussed to be involved in the pathophysiology of weight gain induced by psychopharmacological treatment. The purpose of our study was to investigate the association of leptin and body mass index (BMI) during LA in a prospective cohort study. METHODS: Leptin serum concentrations and body mass index (BMI) were measured in a total of 89 acute depressive patients before and then after four weeks of LA. RESULTS: In a linear mixed model analysis the following variables had a significant positive effect on BMI: time (equal with "treatment effect of LA"; F1.83=6.05; p=0.016) and leptin (F1.111=13.83; p=0.0003) as well as the covariates male gender (F1.89=5.08; p=0.027) and adiposity (F1.85=105.13; p<0.0001). LIMITATIONS: If the reported effect of leptin on BMI is specific to LA remains unclear without a control group. CONCLUSION: Leptin signalling might be involved in lithium-induced weight-gain.

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.

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.

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.

Serotonin transporter gene and response to lithium augmentation in depression.

BACKGROUND: The serotonin (5-HT) transporter gene-linked polymorphic region (5-HTTLPR) is associated with better response to selective serotonin reuptake inhibitors in Caucasian patients carrying the long (l)-allele. In contrast, augmentation of antidepressant drugs with pindolol has been shown to improve responsiveness to antidepressants in short (s)-allele carriers. Lithium augmentation is a well-established strategy for overcoming treatment resistance. In this study, the 5-HTTLPR allele variant's effect on lithium augmentation was analyzed in antidepressant-nonresponsive patients. METHODS: We measured remission rates during lithium augmentation in 50 depressed patients genotyped for the 5-HTTLPR. All patients took part in phase II of the German Algorithm Project, a prospective study for the evaluation of a standardized stepwise drug treatment regimen. For statistical analysis, the Cox regression model including several clinical factors besides the 5-HTTLPR was used. RESULTS: Only the genotype of the 5-HTTLPR (P<0.006) showed a signficant influence on remission. Patients homozygous for the s-allele had a more favorable response compared with those heterozygous (hazard ratio=6.9; P=0.005) or homozygous for the l allele (hazard ratio=4.5; P=0.003). CONCLUSION: The findings support a differential effect of the 5-HTTLPR gene on primary treatment with antidepressants and treatment augmentation. Similar to the observations with pindolol, s/s-allele patients showed a higher benefit from lithium augmentation than did patients carrying other 5-HTTLPR genotypes. Thus, the s/s genotype might predict an individual's risk of antidepressant nonresponsiveness and sensitivity to augmentative drugs such as lithium.