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.

Electrocardiographic Changes During Initiation of Lithium Augmentation of Antidepressant Pharmacotherapy.

PURPOSE/BACKGROUND: Lithium augmentation of antidepressants represents a common strategy to overcome treatment resistance in patients with major depressive disorder. The use of lithium has been associated with cardiovascular adverse effects such as QTc prolongation and tachyarrhythmia. Although the previous studies investigated monotherapy with lithium, the aim of this study was to investigate electrocardiographic changes in LA. METHODS/PROCEDURES: A 12-lead surface electrocardiogram (ECG) was obtained from 38 patients with major depressive disorder before and during LA. Changes in heart rate, PQ, QRS and QTc interval, QT dispersion, ST segment, and T- and U-wave alterations were analyzed using a linear mixed model. FINDINGS/RESULTS: The ECG readings of 33 patients were evaluated. Lithium augmentation was not significantly associated with changes in heart rate, QTc, PQ, or QRS interval. We found a significant decrease in QT dispersion. These results were independent of sex, age, stable comedication, and comorbidities. During LA, we observed 9 cases of T-wave alterations and 2 cases of new U waves. CONCLUSIONS: Our data provide no evidence for serious ECG abnormalities at therapeutic serum lithium levels in patients treated with LA. In particular, we did not find evidence for QTc time lengthening or tachyarrhythmia, such as torsades des pointes. The recommended intervals for ECG checks should be considered to detect long-term effects of LA.

Faster speed of onset of the depressive episode is associated with lower cytokine serum levels (IL-2, -4, -6, -10, TNF-α and IFN-γ) in patients with major depression.

INTRODUCTION: Cytokines might play a key role in the pathophysiology of major depressive disorder (MDD). The speed of onset of depressive episodes has been discussed as an important clinical parameter in MDD. The aim of this study was to investigate a potential influence of the speed of onset of the depressive episode on cytokine serum levels. METHOD: Serum level of the cytokines interleukin (IL)-2, IL-4, IL-6, IL-8, IL-10, tumor necrosis factor alpha (TNF-α), interferon-gamma (IFN-γ) granulocyte and monocyte colony stimulating factor (GM-CSF) were measured in a total of 92 patients with MDD that did not respond to at least one previous antidepressant treatment. Patients were retrospectively divided in two groups: Faster (≤4 weeks) and slower (>4 weeks) onset of the depressive episode defined as the time passing from the first depressive symptoms to a full-blown depressive episode by using information from a clinical interview. RESULTS: We found significantly lower serum levels of IL-2, IL-4, IL-6, IL-10, TNF-α and IFN-γ in patients with a faster onset compared to patients with a slower onset of the depressive episodes. Furthermore, lower cytokine serum levels of IL-2, IL-8, IL-10 and IFN-γ were found in patients with a shorter duration (less than 6 months) compared to a longer duration (6-24 months) of the current depressive episode. This effect on cytokines was independent from the effect of the speed of onset of the depressive episode. CONCLUSIONS: Patients with faster onset of the depressive episode might represent a biological subtype of MDD with lower serum levels of IL-2, IL-4, IL-6, IL-10, TNF-α and IFN-γ.

Correction: Negative mood induction: Affective reactivity in recurrent, but not persistent depression.

[This corrects the article DOI: 10.1371/journal.pone.0208616.].

Negative mood induction: Affective reactivity in recurrent, but not persistent depression.

BACKGROUND: Despite the high clinical and epidemiological relevance of persistent depression, little is known about its specific psychopathology and whether it is distinct from recurrent depression. Depression in general has been associated with blunted affective reactivity but the evidence from previous studies is inconsistent. Here, we asked whether affective reactivity might differ between persistent and recurrent depression. METHODS: Twenty patients with persistent depression, 20 patients with recurrent depression and 20 healthy controls (HC) were recruited. Both patient groups showed moderate symptom severity. All participants underwent a sad mood induction procedure. Affective reactivity was assessed with the Positive and Negative Affect Schedule (PANAS) before and after mood induction. RESULTS: We found a striking difference in affective reactivity between patient groups. While the persistent group showed blunted reactivity to mood induction, the recurrent group demonstrated an affective response that was comparable to HC, with an increase in negative and a decrease in positive affect. Blunted affective reactivity was thus specifically associated with persistent in contrast to recurrent depression. CONCLUSIONS: These results highlight affective reactivity as an important psychopathological feature that differs between the two patient groups. Preserved affective reactivity to emotional stimuli in the recurrent group might reflect a resilience factor against persistence of depression.

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.

Psychotherapy of Borderline Personality Disorder: Can the Supply Meet the Demand? A German Nationwide Survey in DBT Inpatient and Day Clinic Treatment Facilities.

The present study aimed to assess (1) the amount of inpatient and day clinic DBT treatment places for patients with borderline personality disorder and (2) the relationship between supply and demand in a given study region. Survey of inpatient and day clinic facilities in the German DBT network. 42 inpatient units and day clinics responded, representing 75 % of the DBT network members contacted. These institutions offer 527 DBT treatment places and treat about 2310 patients per year. The mean waiting period prior to treatment was 14.3 weeks. 700 DBT inpatient or day clinic places exist in Germany in 2011. 3000 patients receive DBT inpatient or day clinic treatment per year. This approximates a ratio of 820 borderline patients for one existing DBT inpatient or day clinic place in Germany. The long waiting time reflects the great demand for this treatment and could be interpreted as an imbalance between supply and demand.

Pavlovian-to-instrumental transfer effects in the nucleus accumbens relate to relapse in alcohol dependence.

In detoxified alcohol-dependent patients, alcohol-related stimuli can promote relapse. However, to date, the mechanisms by which contextual stimuli promote relapse have not been elucidated in detail. One hypothesis is that such contextual stimuli directly stimulate the motivation to drink via associated brain regions like the ventral striatum and thus promote alcohol seeking, intake and relapse. Pavlovian-to-Instrumental-Transfer (PIT) may be one of those behavioral phenomena contributing to relapse, capturing how Pavlovian conditioned (contextual) cues determine instrumental behavior (e.g. alcohol seeking and intake). We used a PIT paradigm during functional magnetic resonance imaging to examine the effects of classically conditioned Pavlovian stimuli on instrumental choices in n = 31 detoxified patients diagnosed with alcohol dependence and n = 24 healthy controls matched for age and gender. Patients were followed up over a period of 3 months. We observed that (1) there was a significant behavioral PIT effect for all participants, which was significantly more pronounced in alcohol-dependent patients; (2) PIT was significantly associated with blood oxygen level-dependent (BOLD) signals in the nucleus accumbens (NAcc) in subsequent relapsers only; and (3) PIT-related NAcc activation was associated with, and predictive of, critical outcomes (amount of alcohol intake and relapse during a 3 months follow-up period) in alcohol-dependent patients. These observations show for the first time that PIT-related BOLD signals, as a measure of the influence of Pavlovian cues on instrumental behavior, predict alcohol intake and relapse in alcohol dependence.

Patient satisfaction with inpatient psychiatric treatment and its relation to treatment outcome in unipolar depression and schizophrenia.

OBJECTS: Patient satisfaction with psychiatric treatment has emerged as an important factor with respect to the quality of health care. METHODS: Patient satisfaction using the Zurich Satisfaction Questionnaire (ZUF-8) as well as symptom severity (measured with the Hamilton Depression Scale [HRSD], Brief Psychiatric Rating Scale and Clinical Global Impression Scale) was assessed at admission and discharge of inpatient treatment in patients with a major depressive episode (MDD, N = 217) and schizophrenia (N = 75). Differences between the two diagnostic groups (using T-tests) and correlations of patient satisfaction with different social and treatment variables were calculated (Pearson product-moment correlation). RESULTS: The mean score of patient satisfaction was 26.8 points (ZUF-8; range 8-32 points), without differences between MDD and schizophrenia (t = 0.45, p = 0.78). Patients with MDD and personality disorder showed lower satisfaction than patients with MDD without personality disorder (t = 2.31, p = 0.03). Patient satisfaction correlated negatively with severity of depressive symptoms at discharge (HRSD: r = - 0.38; p < 0.01) and number of comorbidities (r = - 0.42; p < 0.01) in MDD. Number of prescribed drugs correlated negatively with patient satisfaction in both groups (depression: r = - 0.28, p = 0.02; schizophrenia: r = - 0.24; p = 0.03). CONCLUSIONS: Patient satisfaction was high without differences between MDD and schizophrenia. Severity of disease and comorbidites in MDD and number of prescribed drugs in both groups were related with reduced patient satisfaction.

[Effectiveness of Dialectical Behavior Therapy (DBT) in an outpatient clinic for borderline personality disorders - impact of medication use and treatment costs]. / Effektivität der Dialektisch-Behavioralen Therapie (DBT) in der tagesklinischen Behandlung der Borderline-Persönlichkeitsstörung - Bedeutung von Medikation und Behandlungskosten.

OBJECTIVE: Investigation of the clinical effectiveness of dialectical behavioral therapy in a day clinic setting (DBT-DC) for borderline personality disorders (BPD), and impact of medication and daily costs. METHODS: In a prospective, naturalistic, open and uncontrolled design BPD patients were enclosed in a 12-week DBT-DC. This DBT-program was certified by the German network of DBT. We collected data from the Symptom Checklist (SCL-90), the Beck Depression Inventory (BDI) and the Borderline Symptom List 95 (BSL-95) in the first and at the end of the 11th week. The concomitant medication and its changes were described. RESULTS: 31 cases were included (9 drop-outs: 29 %). The average age was 33.3 years (18 - 52, SD = 10.6). 21 females and one male completed the program. There was no relationship between changes of BDI, SCL-90 and BSL-95 scores (p < 0.001) and medication (and its alteration). The BDI scores improved by 50.8 % (p < 0.001), the SCL-90 by 42.9 % (p < 0.01) and the BSL-95 by 48.4 % (p < 0.001). The power was 0.99 (α = 0.05), the effect size was 1.41. In our setting the daily costs showed a reduction of about 6500 € per case compared to an inpatient DBT. Medications played no significant role for improvement. CONCLUSIONS: For the first time a partial remission for BPD patients after 12 weeks has been shown to be achieved in a DBT-DC setting. DBT-DC reduces the primary costs of BPD compared to a specific inpatient therapy.

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.

Acute and long-term treatment outcome in depressed inpatients with vs. without anxious features: results of a one-year follow-up study.

BACKGROUND: Anxious depression (AD) is common in patients with unipolar depression. It remains unclear if they have a higher level of depressive symptoms, a higher risk of non-response, a poorer prognosis and a higher relapse rate compared to non-anxious depressed (non-AD) patients. METHODS: 168 patients took part in all three measurement points: (1) intake, (2) discharge and (3) follow-up. Patients fulfilled the criteria for anxious depression if they had a baseline score >7 on the anxiety/somatisation factor of the Hamilton Rating Scale for Depression (HRSD). Patients with AD and non-AD were compared regarding symptom reduction from intake to discharge as well as from discharge to one year after discharge. Primary outcome measure was the HRSD. RESULTS: The prevalence of AD was considerably high (81%). At intake, patients with AD had a significant higher score in the modified HRSD (M=20.67±4.12 vs. M=14.35±5.06). Both patient groups showed a significant and comparable intake-to-discharge symptom reduction in all inventories. Remission rates at discharge did not differ between AD and non-AD patients. At 1-year follow-up, AD patients showed a similar symptom severity compared to non-AD patients. CONCLUSION: Symptoms of anxiety are common in depressive disorders are associated with higher depressive symptoms at the beginning of treatment. Acute and longer-term treatment outcome of AD patients was comparable to that of non-AD patients. LIMITATIONS: Limitations of this study are the naturalistic design, treatment was not standardized and comorbid anxiety disorders were not assed using a structured interview.

Effectiveness of cognitive-behavioural therapy plus pharmacotherapy in inpatient treatment of depressive disorders.

BACKGROUND: Meta-analyses show benefits for patients from a combination of medication and cognitive-behavioural psychotherapy. However, it is still unclear whether or not additional cognitive-behavioural therapy (CBT) also produces a better treatment outcome in a naturalistic psychiatric setting. METHODS: Two-hundred six consecutively registered acute psychiatric inpatients with a unipolar depressive disorder were treated with additional CBT. This combined therapy was then compared with psychiatric primary care in an inpatient setting (clinical management). In addition to pharmacological treatment, 105 of the 206 patients also received symptom-focused CBT after hospitalization. Seventeen-item Hamilton Rating Scale for Depression (HAMD, primary outcome criterion), Beck Depression Inventory (BDI), Dysfunctional Attitude Scale, Clinical Global Impression Scale and the Global Assessment of Functioning were performed with all patients. RESULTS: Patients who were treated with additional CBT revealed a considerably greater reduction of depressive symptoms than in patients who received inpatient primary care only (HAMD: -22.21 versus -19.86, p = 0.027; BDI: 14.99 versus 11.36, p = 0.031). Moreover, remission rates were significantly higher (HAMD: 72% to 51%, p = 0.045; BDI: 58.8% versus 43.1%, p = 0.044) in the combined treatment group than in the primary care only group. LIMITATION: The naturalistic design and the inconsistent pharmacological treatment are design flaws. CONCLUSION: The results show that additional cognitive-behavioural treatment of depressive disorders notably improves outcome over standard procedure in acute psychiatric treatment. KEY PRACTITIONER MESSAGE: There is a need for treatment strategies to accompany medication. In the Sequenced Treatment Alternatives to Relieve Depression trial (STAR*D), only 33% of the patients reached remission criteria after the first antidepressant treatment step and only 50% after the second step. The strict inclusion criteria of randomized controlled trials often render their patient populations unrepresented. For an accurate view of treatment effectiveness, their results need to be complemented with results gained from trials in clinical practice. Additional cognitive-behavioural treatment notably improves treatment outcomes compared with standard treatments in the acute psychiatric treatment of depressive disorders. The results of this study under naturalistic conditions are an important addition to findings from randomized and controlled studies.

The effects of a clinical care pathway for schizophrenia: a before and after study in 114 patients.

BACKGROUND: The implementation of clinical guidelines in care pathways is being promoted for quality assurance in psychiatry and psychotherapy, as in other medical fields. The achievable benefits are disputed and are generally thought to be small. There have been hardly any studies of the effect of clinical care pathways on the costly inpatient treatment of schizophrenic psychoses. METHODS: We conducted a prospective, controlled, before and after study in 114 patients with schizophrenia to determine whether the implementation of a pathway would improve diagnosis and treatment in conformity with published guidelines, and whether there would be any associated improvement in outcome. The patients' course was extensively documented with a number of structural, process-related, and outcome-related variables in the years before and after pathway implementation. Moreover, two different intensive methods of pathway implementation were tested. Data were collected from 2003 to 2005. The primary indicators of outcome quality included pharmacotherapy-related variables and assessments of treatment efficacy by the physicians, the nurses, and the patients themselves. RESULTS: After pathway implementation, some diagnostic tests that had been performed only rarely beforehand were performed much more often. The percentage of over- or undermedicated patients, as defined by the treatment pathway, declined markedly. Surprisingly, however, the patients' multidimensionally documented psychopathological course and their subjective judgments of their condition were worse after pathway implementation than before on all four scales that were used to assess these variables. CONCLUSION: The implementation of a treatment pathway brought about a robust change in process-related variables. The findings of this study furnish no explanation for the observed decline in treatment efficacy.

Adherence to guidelines and effectiveness of inpatient treatment for unipolar depression.

OBJECTIVE: This naturalistic study is a contribution to randomized controlled trials which reflect only a very limited part of patients of the clinical practice and the relevance of guideline recommended treatment. METHODS: Adhering to quality assurance and development of treatment guidelines, 224 patients were evaluated for the effectiveness of inpatient treatment of unipolar depressive disorders by assessing admission and discharge depression scores, response and remission rates. Furthermore patients who were treated according to current guidelines (duration of treatment, dosage of antidepressants, combination of medication and psychotherapy) were compared to patients who did not meet those criteria. Primary outcome measure was the 17-item Hamilton Rating Scale for Depression (HAMD). Secondary outcome measures included Beck Depression Inventary (BDI). RESULTS: Mean HAMD-17 total score decreased from 28.9 to 8.0. Effect sizes d were similar to other naturalistic studies (d(HAMD) = 2.9; d(BDI) = 1.4); 84.4% of the patients could reach complete or partial response criteria for the HAMD-17. Patients treated according to guidelines could reach remission in 73% of cases (HAMD) vs. 59.6% remission rate for non-guideline patients. CONCLUSION: This trial shows high remission rates in inpatient treatment of depression compared to similar effectiveness studies. Guideline according treatment might be superior to other treatment strategies.

Smooth pursuit eye movements of patients with schizophrenia and affective disorder during clinical treatment.

BACKGROUND: Smooth pursuit eye movement dysfunctions are considered a biological indicator for vulnerability to schizophrenia. This study examines test-retest stability of specific eye movement variables such as velocity gain and different saccadic categories. METHODS: Smooth pursuit eye movements of 27 schizophrenic patients and 30 patients with major depression were examined three times during clinical treatment using high-resolution infrared oculography. Forty-one normal controls were retested after four weeks. RESULTS: Intraclass correlation coefficients as a measure for retest-stability were highly significant in each group for all time-points, except for anticipatory saccades in schizophrenics. No significant correlations were found between psychopathological status, neuroleptic medication and eye movement variables. CONCLUSIONS: Our results indicate that the most important measures of eye tracking performance in psychiatric patients are not significantly influenced by neuroleptic medication or clinical state and are stable across time.