Esketamine Nasal Spray versus Quetiapine for Treatment-Resistant Depression.

BACKGROUND: In treatment-resistant depression, commonly defined as a lack of response to two or more consecutive treatments during the current depressive episode, the percentage of patients with remission is low and the percentage with relapse is high. The efficacy and safety of esketamine nasal spray as compared with extended-release quetiapine augmentation therapy, both in combination with ongoing treatment with a selective serotonin reuptake inhibitor (SSRI) or a serotonin-norepinephrine reuptake inhibitor (SNRI), in patients with treatment-resistant depression are unknown. METHODS: In an open-label, single-blind (with raters unaware of group assignments), multicenter, phase 3b, randomized, active-controlled trial, we assigned patients, in a 1:1 ratio, to receive flexible doses (according to the summary of product characteristics) of esketamine nasal spray (esketamine group) or extended-release quetiapine (quetiapine group), both in combination with an SSRI or SNRI. The primary end point was remission, defined as a score of 10 or less on the Montgomery-Åsberg Depression Rating Scale (MADRS), at week 8 (scores range from 0 to 60, with higher scores indicating more severe depression). The key secondary end point was no relapse through week 32 after remission at week 8. All patients were included in the analysis; patients who discontinued the trial treatment were considered as having had an unfavorable outcome (i.e., they were grouped with patients who did not have remission or who had a relapse). Analyses of the primary and key secondary end points were adjusted for age and number of treatment failures. RESULTS: Overall, 336 patients were assigned to the esketamine group and 340 to the quetiapine group. More patients in the esketamine group than in the quetiapine group had remission at week 8 (91 of 336 patients [27.1%] vs. 60 of 340 patients [17.6%]; P = 0.003) and had no relapse through week 32 after remission at week 8 (73 of 336 patients [21.7%] vs. 48 of 340 patients [14.1%]). Over 32 weeks of follow-up, the percentage of patients with remission, the percentage of patients with a treatment response, and the change in the MADRS score from baseline favored esketamine nasal spray. The adverse events were consistent with the established safety profiles of the trial treatments. CONCLUSIONS: In patients with treatment-resistant depression, esketamine nasal spray plus an SSRI or SNRI was superior to extended-release quetiapine plus an SSRI or SNRI with respect to remission at week 8. (Funded by Janssen EMEA; ESCAPE-TRD ClinicalTrials.gov number, NCT04338321.).

Predictors of hospital readmission for patients diagnosed with delirium: An electronic health record data analysis.

INTRODUCTION: Delirium is an acute and fluctuating change in attention and cognition that increases the risk of functional decline, institutionalisation and death in hospitalised patients. After delirium, patients have a significantly higher risk of readmission to hospital. Our aim was to investigate factors associated with hospital readmission in people with delirium. METHODS: We carried out an observational retrospective cohort study using linked mental health care and hospitalisation records from South London. Logistic regression models were used to predict the odds of 30-day readmission and Cox proportional hazard models to calculate readmission risks when not restricting follow-up time. RESULTS: Of 2814 patients (mean age 78.9 years SD ±11.8) discharged from hospital after an episode of delirium, 823 (29.3%) were readmitted within 30 days. Depressed mood (odds ratio (OR) 1.34 (95% confidence interval (CI) 1.08-1.66)), moderate-to-severe physical health problems (OR 1.67 (95% CI 1.18-2.2.36)) and a history of serious circulatory disease (OR 1.29 (95% CI 1.07-1.55)) were associated with higher odds of hospital readmission, whereas a diagnosis of delirium superimposed on dementia (OR 0.67 (95% CI 0.53-0.84)) and problematic alcohol/substance (OR 0.54 (95% CI 0.33-0.89)) use were associated with lower odds. Cox proportionate hazard models showed similar results. CONCLUSION: Almost one-third of patients with delirium were readmitted within a short period of time, a more detailed understanding of the underlying risk factors could help prevent readmissions. Our findings indicate that the aetiology (as alcohol-related delirium), the recognition that delirium occurred in the context of dementia, as well as potentially modifiable factors, as depressed mood affect readmission risk, and should be assessed in clinical settings.

Sex-related effects in major depressive disorder: Results of the European Group for the Study of Resistant Depression.

BACKGROUND: Sex-related effects on the evolution and phenotype of major depressive disorder (MDD) were reported previously. METHODS: This European multicenter cross-sectional study compared sociodemographic, clinical, and treatment patterns between males and females in a real-world sample of 1410 in- and outpatients with current MDD. RESULTS: Male MDD patients (33.1%) were rather inpatients, suffered from moderate to high suicidality levels, received noradrenergic and specific serotonergic antidepressants (ADs) as first-line AD treatment, generally higher mean AD daily doses, and showed a trend towards a more frequent administration of add-on treatments. Female MDD patients (66.9%) were rather outpatients, experienced lower suicidality levels, comorbid thyroid dysfunction, migraine, asthma, and a trend towards earlier disease onset. CONCLUSIONS: The identified divergencies may contribute to the concept of male and female depressive syndromes and serve as predictors of disease severity and course, as they reflect phenomena that were repeatedly related to treatment-resistant depression (TRD). Especially the greater necessity of inpatient treatment and more complex psychopharmacotherapy in men may reflect increased therapeutic efforts undertaken to treat suicidality and to avoid TRD. Hence, considering sex may guide the diagnostic and treatment processes towards targeting challenging clinical manifestations including comorbidities and suicidality, and prevention of TRD and chronicity.

Changes in White Matter Microstructure After Electroconvulsive Therapy for Treatment-Resistant Depression.

BACKGROUND: Treatment-resistant depression is among the most debilitating conditions in psychiatry. Recent studies have associated alterations in white matter microstructure measured with magnetic resonance imaging with poor antidepressant response. Therefore, the extent to which electroconvulsive therapy, the most effective therapeutic option for treatment-resistant depression, affects white matter microstructure warrants investigation. METHODS: A total 13 patients suffering from severe unipolar treatment-resistant depression underwent magnetic resonance imaging with a diffusion tensor imaging sequence before and after undergoing a series of right unilateral electroconvulsive therapy. Diffusivity metrics were compared voxel-wise using tract-based spatial statistics and repeated-measures ANOVA. RESULTS: A total 12 patients responded to electroconvulsive therapy and 9 were classified as remitters. An increase in axial diffusivity was observed in the posterior limb of the internal capsule of the right hemisphere (PFWE ≤ .05). The increase in this area was higher in the right compared with the left hemisphere (P < .05). No correlation of this effect with treatment response could be found. CONCLUSIONS: The strong lateralization of effects to the hemisphere of electrical stimulation suggests an effect of electroconvulsive therapy on diffusivity metrics which is dependent of electrode placement. Investigation in controlled studies is necessary to reveal to what extent the effects of electroconvulsive therapy on white matter microstructure are related to clinical outcomes and electrode placement.

Clinical Correlates and Outcome of Major Depressive Disorder and Comorbid Migraine: A Report of the European Group for the Study of Resistant Depression.

BACKGROUND: The present multicenter study aimed at defining the clinical profile of patients with major depressive disorder (MDD) and comorbid migraine. METHODS: Demographic and clinical information for 1410 MDD patients with vs without concurrent migraine were compared by descriptive statistics, analyses of covariance, and binary logistic regression analyses. RESULTS: The point prevalence rate for comorbid migraine was 13.5% for female and 6.2% for male patients. MDD + migraine patients were significantly younger, heavier, more likely female, of non-Caucasian origin, outpatient, and suffering from asthma. The presence of MDD + migraine resulted in a significantly higher functional disability. First-line antidepressant treatment strategy revealed a trend towards agomelatine. Second-generation antipsychotics were significantly less often administered for augmentation treatment in migraineurs. Overall, MDD + migraine patients tended to respond worse to their pharmacotherapy. CONCLUSION: Treatment guidelines for comorbid depression and migraine are warranted to ensure optimal efficacy and avoid possible pitfalls in psychopharmacotherapy, including serotonin syndrome.

Structural changes in amygdala nuclei, hippocampal subfields and cortical thickness following electroconvulsive therapy in treatment-resistant depression: longitudinal analysis.

BACKGROUND: Electroconvulsive therapy (ECT) is the treatment of choice for severe mental illness including treatment-resistant depression (TRD). Increases in volume of the hippocampus and amygdala following ECT have consistently been reported.AimsTo investigate neuroplastic changes after ECT in specific hippocampal subfields and amygdala nuclei using high-resolution structural magnetic resonance imaging (MRI) (trial registration: clinicaltrials.gov - NCT02379767). METHOD: MRI scans were carried out in 14 patients (11 women, 46.9 years (s.d. = 8.1)) with unipolar TRD twice before and once after a series of right unilateral ECT in a pre-post study design. Volumes of subcortical structures, including subfields of the hippocampus and amygdala, and cortical thickness were extracted using FreeSurfer. The effect of ECT was tested using repeated-measures ANOVA. Correlations of imaging and clinical parameters were explored. RESULTS: Increases in volume of the right hippocampus by 139.4 mm3 (s.d. = 34.9), right amygdala by 82.3 mm3 (s.d. = 43.9) and right putamen by 73.9 mm3 (s.d. = 77.0) were observed. These changes were localised in the basal and lateral nuclei, and the corticoamygdaloid transition area of the amygdala, the hippocampal-amygdaloid transition area and the granule cell and molecular layer of the dentate gyrus. Cortical thickness increased in the temporal, parietal and insular cortices of the right hemisphere. CONCLUSIONS: Following ECT structural changes were observed in hippocampal subfields and amygdala nuclei that are specifically implicated in the pathophysiology of depression and stress-related disorders and retain a high potential for neuroplasticity in adulthood.Declaration of interestS.K. has received grants/research support, consulting fees and/or honoraria within the past 3 years from Angelini, AOP Orphan Pharmaceuticals AG, AstraZeneca, Celegne GmbH, Eli Lilly, Janssen-Cilag Pharma GmbH, KRKA-Pharma, Lundbeck A/S, Neuraxpharm, Pfizer, Pierre Fabre, Schwabe and Servier. R.L. received travel grants and/or conference speaker honoraria from Shire, AstraZeneca, Lundbeck A/S, Dr. Willmar Schwabe GmbH, Orphan Pharmaceuticals AG, Janssen-Cilag Pharma GmbH, and Roche Austria GmbH.

Changes over time of the diagnostic and therapeutic characteristics of patients of a psychiatric intensive care unit in Austria.

OBJECTIVE: The aim of this repeated cross-sectional study was to compare patients from a psychiatric intensive care unit (PICU) over ≫30 years regarding their diagnostic and therapeutic characteristics. METHOD: Three samples including 100 consecutive inpatients each from the Viennese PICU were submitted to a chart review: sample no. 1 from the years 1985/86, no. 2 from 1995/96 and no. 3 from 2007/08. RESULTS: Changes in referral modes were associated with a decrease of patients with substance induced disorders and an increase of patients with affective disorders over time. The rate of admissions after accidents and suicides was stable. The use of cranial MRI increased, while intravenous psychopharmacotherapy and parenteral nutrition decreased. Involuntary admission occurred in 43% and in 37% of patients physical restraints were necessary. We saw a shift from tricyclic antidepressants to SSRIs and SNRIs from sample 1 to 3. Likewise, we observed the emergence of atypical antipsychotics and a reduction of use of typical neuroleptics mainly from sample 2 to 3. The percentage of patients receiving benzodiazepines increased over time, while the mean dosage of benzodiazepines decreased. 7% of patients received electroconvulsive therapy. CONCLUSIONS: The changes over time in our samples reflect the medical progress made during the last decades. Future studies should focus on evaluation of efficacy of psychiatric intensive care using standardized measurements.

Electroconvulsive therapy with S-ketamine anesthesia for catatonia in coexisting depression and dementia.

Information on efficacy and safety of electroconvulsive therapy in patients with dementia is sparse. The current case report describes a patient suffering from severe depression and dementia who received electroconvulsive therapy with S-ketamine anesthesia at our psychiatric intensive care unit for the treatment of her therapy-resistant catatonic stupor. The patient's condition improved remarkably through the treatment. By the end of 16 electroconvulsive therapy sessions, her catatonic symptoms remitted entirely, her affect was brighter and she performed markedly better at the cognitive testing.

Neurotransmitters and electroconvulsive therapy.

OBJECTIVES: Electroconvulsive therapy (ECT) is a well-established effective treatment strategy in treatment-refractory depression. However, despite ECT's widespread use, the exact neurobiological mechanisms underlying its efficacy are not fully understood. Over the past 3 decades, extensive work in rodents, primates, and humans has begun to delineate the impact of electroconvulsive seizures (ECS) and ECT on neurotransmission systems commonly implicated in depression. In the current review, we will focus on two major biogenic amine systems, namely serotonin and dopamine. METHODS: The database of PubMed was searched for preclinical studies describing the effects of ECS on the serotonergic and dopaminergic system using behavioral sensitization paradigms, in vivo brain microdialysis, messenger RNA and protein expression, electrophysiology, and positron emission tomography. Additionally, human data describing ECT's effects on neurotransmitter turnover, receptor binding, and functional imaging were reviewed together with relevant genetic association studies. RESULTS: Literature research resulted in 40 published original studies related to ECS/ECT and the serotonergic system, whereby only three were studies in humans. Regarding dopamine, 15 preclinical and 12 human studies were found in PubMed database. CONCLUSIONS: Converging data obtained from genetic and imaging studies in humans have corroborated many of the earlier preclinical and clinical findings relating to enhancement of serotonergic neurotransmission and activation of the mesocorticolimbic dopamine system after ECS/ECT. Moreover, it seems that these effects are evident at various levels, including neurotransmitter release, receptor binding, and overall neurotransmission. Future studies combining convergent modalities could enhance our understanding of the mechanisms underlying ECT's profound antidepressant effect and would support the development of better pharmacological and somatic treatment approaches for refractory depression.

Perspectives in treatment-resistant depression: esketamine and electroconvulsive therapy.

Modern electroconvulsive therapy (ECT) and the approval of nasal esketamine for clinical use have significantly improved the approach to treatment-resistant depression (TRD), which is defined as non-response to at least two different courses of antidepressants with verified adherence to treatment, adequate dosage, and duration of treatment. The goal of this literature review is to present the newest evidence regarding efficacy and safety. Furthermore, we aim to provide an overview of future perspectives in this field of research, for example, regarding structural and molecular effects. Both treatment methods will be critically evaluated for their individual advantages, disadvantages, and response rates. Firstly, we will discuss the well-established method of ECT and its different treatment modalities. Secondly, we will discuss the properties of ketamine, the discovery of its antidepressive effects and the route to clinical approval of the esketamine nasal spray. We will comment on research settings which have evaluated intravenous ketamine against ECT. The decision-making process between esketamine nasal spray or ECT should include the assessment of contraindications, age, severity of disease, presence of psychotic symptoms, patient preference and treatment accessibility. We conclude that both treatment options are highly effective in TRD. If both are indicated, pragmatically esketamine will be chosen before ECT; however, ECT studies in ketamine non-responders are missing.

Effects of lockdowns on neurobiological and psychometric parameters in unipolar depression during the COVID-19 pandemic.

Defying the COVID-19 pandemic required restriction measures of unprecedented scale, that may induce and exacerbate psychiatric symptoms across the population. We aimed to assess in vivo dynamic effects of mitigation strategies on human brain neurobiology, neuroplastic as well as psychometric parameters. Three structural magnetic resonance imaging measurements, serum brain-derived neurotrophic factor (sBDNF) analyses, and psychometric assessments (Beck Depression Inventory-II and Perceived Stress Questionnaire-20) were performed in healthy individuals and patients with a recurrent major depressive disorder in the period from September 2020 to July 2021. Group differences and changes over time in structural imaging, neuroplastic and psychometric parameters were assessed with linear mixed models. Analysis of data from 18 patients with a recurrent major depressive disorder and 28 healthy individuals showed clinically relevant scores for depression and stress in the patient group as well as significant cross-sectional differences in depression scores (F = 30.89, p < 0.001) and three subscales of the Perceived Stress Questionnaire (Worries: F = 19.19, p < 0.001, Tension: F = 34.44, p < 0.001, Joy: F = 12.05, p = 0.001). Linear mixed models revealed no significant changes over time in cortical thickness of the prefrontal cortex, anterior cingulate cortex, hippocampus, and amygdala (F = 0.29, p > 0.1) and no interaction with group (F = 0.28, p > 0.1). Further, analysis revealed no main effect of time and no interaction of time x group in depressive symptoms, perceived stress subscales, and sBDNF (all p > 0.1). Despite the limited sample size, the strength of this investigation lies in the multimodal assessment of peri-pandemic lockdown effects. Nine months of varying restrictions measures did not result in observable changes in brain morphology nor impact depressive symptoms in either psychiatric patients with a recurrent major depressive disorder or healthy individuals. While these neurobiological and psychometric data stand in contrast to initial expectations about the effects of restriction measures, they might inform future investigations of longitudinal effects of restriction measures on mental health.

Case report: Interstitial pneumonitis after initiation of lamotrigine.

The second-generation anticonvulsant lamotrigine is widely used in the psychiatric field as a mood stabilizer or antidepressant augmentation therapy. Although particularly older anticonvulsants are known for their potential to cause hypersensitivity syndromes, newer antiepileptic drugs do hold a certain risk as well. Presenting a case of a 32-year-old male inpatient of African ethnicity suffering from a primary severe depressive episode in the course of a recurrent major depressive disorder, we report the occurrence of a rapid-onset drug-induced pneumonitis. Herewith, the interstitial pneumonitis occurred after the initiation of 25 mg lamotrigine as an augmentation therapy. Except for the clear temporal correlation between the administration of lamotrigine and the onset of pneumonitis, we did not reveal any further potentially causal diagnostic hints. Importantly, no relevant genetic variations of metabolizing enzymes or drug interactions resulting in lamotrigine overdosage as a potential cause of toxicity were identified. Our experience with a potentially life-threatening adverse drug reaction shortly after the initiation of the largely well-tolerated lamotrigine suggests a potential side effect under the second-generation anticonvulsant although similar adverse events are deemed to be very rare.

Case report: Hyperactive delirium after a single dose of zolpidem administered additionally to psychopharmacotherapy including clozapine.

The non-benzodiazepine hypnotic zolpidem is frequently administered as a short term psychopharmacotherapy for insomnia. Although it is well-established in a broad clinical routine and often well-tolerated, severe delirium and complex sleep behavior were reported in rare cases. Hereby, it remains unclear whether zolpidem's potential for delirium might be enhanced when combined with further psychopharmacotherapeutics. The present case report portrays a young male Caucasian inpatient with schizoaffective disorder, who was admitted due to severe hyperactive delirium after a single dose of zolpidem 10 mg that was administered in addition to already established psychopharmacotherapy including clozapine 200 mg/day, aripiprazole 15 mg/day and cariprazine 4.5 mg/day. In detail, disorientation, agitation, confabulations, bizarre behavior, and anterograde amnesia occurred shortly after ingestion of zolpidem and gained in intensity within a couple of hours. Once zolpidem was discontinued, the abovementioned symptoms subsided completely and did not reoccur. Since a clear temporal association could be drawn between the intake of zolpidem and the onset of hyperactive delirium, the present clinical experience should serve as a cautionary note for combining potent sedative-hypnotics and substances with anticholinergic properties, even in young adults in a good general condition. Moreover, our case argues for the necessity of further research into the pathomechanism of the interaction potential of non-benzodiazepines as zolpidem, especially with substances exerting anticholinergic properties, which are known for their potential to precipitate delirium. Therefore, the metabolic pathways of the concurrently administered substances should be further taken into account.

Combining image-derived and venous input functions enables quantification of serotonin-1A receptors with [carbonyl-11C]WAY-100635 independent of arterial sampling.

UNLABELLED: image- derived input functions (IDIFs) represent a promising technique for a simpler and less invasive quantification of PET studies as compared to arterial cannulation. However, a number of limitations complicate the routine use of IDIFs in clinical research protocols and the full substitution of manual arterial samples by venous ones has hardly been evaluated. This study aims for a direct validation of IDIFs and venous data for the quantification of serotonin-1A receptor binding (5-HT(1A)) with [carbonyl-(11)C]WAY-100635 before and after hormone treatment. METHODS: Fifteen PET measurements with arterial and venous blood sampling were obtained from 10 healthy women, 8 scans before and 7 after eight weeks of hormone replacement therapy. Image-derived input functions were derived automatically from cerebral blood vessels, corrected for partial volume effects and combined with venous manual samples from 10 min onward (IDIF+VIF). Corrections for plasma/whole-blood ratio and metabolites were done separately with arterial and venous samples. 5-HT(1A) receptor quantification was achieved with arterial input functions (AIF) and IDIF+VIF using a two-tissue compartment model. RESULTS: Comparison between arterial and venous manual blood samples yielded excellent reproducibility. Variability (VAR) was less than 10% for whole-blood activity (p>0.4) and below 2% for plasma to whole-blood ratios (p>0.4). Variability was slightly higher for parent fractions (VARmax=24% at 5 min, p<0.05 and VAR<13% after 20 min, p>0.1) but still within previously reported values. IDIFs after partial volume correction had peak values comparable to AIFs (mean difference Δ=-7.6 ± 16.9 kBq/ml, p>0.1), whereas AIFs exhibited a delay (Δ=4 ± 6.4s, p<0.05) and higher peak width (Δ=15.9 ± 5.2s, p<0.001). Linear regression analysis showed strong agreement for 5-HT(1A) binding as obtained with AIF and IDIF+VIF at baseline (R(2)=0.95), after treatment (R(2)=0.93) and when pooling all scans (R(2)=0.93), with slopes and intercepts in the range of 0.97 to 1.07 and -0.05 to 0.16, respectively. In addition to the region of interest analysis, the approach yielded virtually identical results for voxel-wise quantification as compared to the AIF. CONCLUSIONS: Despite the fast metabolism of the radioligand, manual arterial blood samples can be substituted by venous ones for parent fractions and plasma to whole-blood ratios. Moreover, the combination of image-derived and venous input functions provides a reliable quantification of 5-HT(1A) receptors. This holds true for 5-HT(1A) binding estimates before and after treatment for both regions of interest-based and voxel-wise modeling. Taken together, the approach provides less invasive receptor quantification by full independence of arterial cannulation. This offers great potential for the routine use in clinical research protocols and encourages further investigation for other radioligands with different kinetic characteristics.

Actigraphic measurements in opioid detoxification with methadone or buprenorphine.

The objective of the present naturalistic study was to assess the differential effects of opioid detoxification with methadone or buprenorphine on activity, circadian rhythm, and sleep. Forty-two consecutive inpatients with opiate addiction were switched to either methadone or buprenorphine and gradually tapered down over the course of 2 to 3 weeks. There were no significant differences in comedication (lofexidine, quetiapine, and valproic acid) between the methadone and buprenorphine groups. Patients in the methadone group showed 11% lower activity and were 24 minutes phase delayed as compared with buprenorphine-treated patients, whereas the latter had 2.5% lower sleep efficiency and 9% shorter actual sleep time. These significant group differences were most pronounced for the lowest doses (≤20% of maximum individual daily dose, ie, at the end of withdrawal representing late withdrawal effects). Furthermore, for the total sample, we found a significant decrease in the relative amplitude of the sleep-wake cycle and worsening of all actigraphic sleep parameters from the higher (100% to 20%) to the lowest doses (20% to 0%). The acrophase of the circadian rhythm displayed a phase advance (-88 minutes) from the highest (100% to 80%) to the lower doses (80% to 0%) in methadone-treated patients. Opioid tapering with methadone or buprenorphine leads to characteristic changes of the rest-activity cycle, but further study is required to validate these results.

The Toxicity Potential of Antidepressants and Antipsychotics in Relation to Other Medication and Alcohol: A Naturalistic and Retrospective Study.

QT interval prolongation and ventricular tachyarrhythmia are potential adverse effects of antidepressant (AD) and antipsychotic- (AP) agents, especially when overdosed. Since AD and AP agents are often prescribed to patients suffering from suicidal intentions, it is essential to estimate these risks in the context of intoxications. This retrospective and naturalistic one-year registry study included 105 patients treated for oral intoxication at the University Department of Emergency Medicine in Vienna, Austria. AD/AP intoxications were present in 26 patients, while in the control group (n = 79) non-AD/AP drugs (n = 54) and exclusively alcohol (n = 25) were the toxic agents. QT intervals, the necessity of intubation, the extent of conscious state, and the subsequent discharge management were compared. The mean age was 34.94 ± 14.6 years, 62 patients (59%) were female. There were no significant between-group differences regarding QT prolongation >470 ms using Bazett's correction (p = 0.178), or >440 ms using Fridericia's correction (p = 0.760). No significant group differences concerning the need for intubation were observed (p = 0.747). The AD/AP and the control group did not significantly differ regarding Glasgow Coma Scale scores (p = 0.439). Patients with AD/AP intoxication were significantly more often transferred to the psychiatric department, while discharge to home was more likely in the control group (p = 0.002). These results suggest that the risk of a potentially life-threatening outcome in cases of intoxication with AD/AP is not substantially higher than in other easily available toxic agents, in line with the advantageous risk/benefit ratio of newer ADs and APs.

Meta-analysis of brain structural changes after electroconvulsive therapy in depression.

BACKGROUND: Increases in the volume of the amygdala and hippocampus after electroconvulsive therapy (ECT) are among the most robust effects known to the brain-imaging field. Recent advances in the segmentation of substructures of these regions allow for novel insights on the relationship between brain structure and clinical outcomes of ECT. OBJECTIVE: We aimed to provide a comprehensive synthesis of evidence available on changes in brain structure after ECT, including recently published data on hippocampal subfields. METHODS: A meta-analysis of published studies was carried out using random-effects models of standardized mean change of regional brain volumes measured with longitudinal magnetic resonance imaging of depressive patients before and after a series of ECT. RESULTS: Data from 21 studies (543 depressed patients) were analysed, including 6 studies (118 patients) on hippocampal subfields. Meta-analyses could be carried out for seven brain regions for which data from at least three published studies was available. We observed increases in left and right hippocampi, amygdalae, cornua ammonis (CA) 1, CA 2/3, dentate gyri (DG) and subicula with standardized mean change scores ranging between 0.34 and 1.15. The model did not reveal significant volume increases in the caudate. Meta-regression indicated a negative relationship between the reported increases in the DG and relative symptom improvement (-0.27 (SE: 0.09) per 10%). CONCLUSIONS: ECT is accompanied by significant volume increases in the bilateral hippocampus and amygdala that are not associated with treatment outcome. Among hippocampal subfields, the most robust volume increases after ECT were measured in the dentate gyrus. The indicated negative correlation of this effect with antidepressant efficacy warrants replication in data of individual patients.

The Role of Relationship Status in Major Depressive Disorder - Results of the European Group for the Study of Resistant Depression.

BACKGROUND: While the association between relationship status and the development of depressive symptoms in the general population were reported previously, its relation to the severity and the course of major depressive disorder (MDD) as well as the treatment patterns and response rates needs to be elucidated. METHODS: The present international multicenter cross-sectional study performed by the European Group for the Study of Resistant Depression (GSRD) investigated socio-demographic and clinical patterns of relationship status in a real-world sample of 1410 adult in- and outpatients with MDD as primary diagnosis. RESULTS: While 49.9% of all MDD patients were partnered, 25.4% were separated, and 24.8% were single. Single relationship status was linked to younger mean age, earlier mean age of onset, and current suicidal risk. Being separated was related to older mean age, unemployment, greater symptom severity, current suicidal risk, and add-on treatment strategies. Partnered relationship status was associated with less frequent current suicidal risk. LIMITATIONS: The retrospective assessment of treatment response that was exclusively based on psychopharmacotherapeutic strategies should be critically considered and weighed while interpreting the present results providing novel insights into the complex interaction of relationship status with the clinical phenotype of MDD. CONCLUSIONS: Although MDD patients living in relationships do not seem to be omitted from the evolution of MDD, they may be spared from chronicity and suicidality. Hence, being aware of the current relationship status might support clinicians in the diagnostic and therapeutic process towards optimized management of such challenging clinical phenomena and their negative consequences.

Add-on benzodiazepine treatment in patients with major depressive disorder - results from a European cross-sectional multicenter study.

Since many patients with major depressive disorder (MDD) do not satisfactorily respond to initial antidepressant monotherapy, add-on treatment strategies with other psychiatric compounds are often established. The present European multicenter cross-sectional study comprising 1410 MDD in- and outpatients investigated the prescription pattern of benzodiazepines as add-on treatment in the psychopharmacotherapy of MDD. Analyses of variance, chi-squared tests, and logistic regression analyses were conducted to examine differences in socio-demographic, clinical, and treatment characteristics between benzodiazepine users and non-users. The prescription rate for adjunctive benzodiazepine treatment amounted to 31.35%. The most often administered benzodiazepines were lorazepam (11.13%), clonazepam (6.74%), and alprazolam (6.60%). Benzodiazepine users exhibited more severe depressive symptoms expressed by a higher mean Montgomery and Åsberg Depression Rating Scale total score at study entry (26.92 ± 11.07 vs 23.55 ± 11.23, p<.0001) and at the beginning of the current major depressive episode (35.74 ± 8.08 vs 33.31 ± 7.40, p<.0001). Furthermore, they were characterized by a higher proportion of patients receiving additional augmentation/combination medications with antidepressants (40.95% vs 24.28%, p<.0001), antipsychotics (41.63% vs 18.39%, p<.0001), and low-potency antipsychotics (10.18% vs 4.75%, p<.0001). Moreover, benzodiazepine prescription was associated with older age, unemployment, inpatient treatment, suicide risk, psychotic and melancholic features, comorbid panic disorder, agoraphobia, social phobia, and obsessive-compulsive disorder. Taken together, our findings indicate that benzodiazepine augmentation in MDD is first of all established in severe/difficult-to-treat conditions and serves as predictor for the use of additional augmentation/combination treatment strategies.

Acute and subsequent continuation electroconvulsive therapy elevates serum BDNF levels in patients with major depression.

INTRODUCTION: The induction of brain-derived neurotrophic factor (BDNF) release and subsequent restoration of neuroplastic homeostasis may underlie the effects of electroconvulsive therapy (ECT). OBJECTIVES: We aimed to assess serum and plasma BDNF levels during the course of acute ECT, as well as before and after subsequent continuation ECT, in patients with depression. METHODS: We included 24 patients with major depressive disorder (mean age ±â€¯SD: 54.5 ±â€¯13.7; f/m: 17/7; baseline 17-item Hamilton Depression Rating Scale score of 26.79 ±â€¯4.01). Serum and plasma BDNF (sBDNF, pBDNF) levels were assessed at nine time-points before, during, and after acute ECT series. Data were analysed using linear regression and linear mixed models, which were adjusted for multiple comparisons via Bonferroni correction. Five patients received continuation ECT subsequent to the acute ECT series. In these patients, BDNF levels were assessed before and after each two continuation ECT sessions using Wilcoxon signed-rank tests. RESULTS: Relative to baseline (mean ng/ml ±SD: 24.68 ±â€¯14.40), sBDNF levels were significantly higher 1 day (33.04 ±â€¯14.11, p = 0.013, corrected), 1 week (37.03 ±â€¯10.29, p < 0.001, corrected), and 1 month (41.05 ±â€¯10.67, p = 0.008, corrected) after the final ECT session, while pBDNF levels did not significantly differ (p > 0.1). Furthermore, our results indicated that sBDNF levels increased after each continuation ECT session. There was no significant association between sBDNF levels and clinical parameters or treatment response. CONCLUSION: The absence of an association between changes in sBDNF levels and depressive symptoms challenges the proposed concept of sBDNF/pBDNF as key markers of the effects of ECT.