Lithium Therapy in Old Age: Recommendations from a Delphi Survey.

INTRODUCTION: While lithium (Li) has been well established for the treatment of bipolar disorder, geriatric patients require special attention when it comes to issues of drug safety. Declining renal function, amongst other medical conditions, and polypharmacy may pose increased risks. Only a few previous studies have addressed the management of Li in geriatric patients. METHODS: Twenty-four German medical experts on geriatric medicine and Li treatment participated in a Delphi survey, consisting of two rounds of questionnaires and a final formulation of treatment recommendations. Three major issues of Li therapy were outlined: initiation of treatment, monitoring of ongoing therapy, and withdrawal due to medical reasons. Final recommendations were consented to at a threshold of at least 80% expert agreement. RESULTS: Final consensus was achieved on 21 clinical recommendations. The approved recommendations covered aspects of necessary laboratory checks, concomitant medication, and target Li serum concentration in geriatric patients. Concerning the termination of Li therapy, an agreement was reached on the appropriate time span for tapering and on potential alternatives to Li. No consensus was achieved on whether concomitant dementia or frailty should be considered contraindications for Li treatment and the appropriate threshold of the estimated glomerular function rate for withdrawing Li. CONCLUSION: According to the view of German experts, Li may be used in geriatric patients, but it should be monitored carefully. However, the lack of consent in several specific treatment situations underlines the need for research on specific issues of Li therapy.

Evidence and expert consensus based German guidelines for the use of repetitive transcranial magnetic stimulation in depression.

INTRODUCTION: Non-invasive brain stimulation techniques such as repetitive transcranial magnetic stimulation (rTMS) offer a promising alternative to psychotherapeutic and pharmacological treatments for depression. This paper aims to present a practical guide for its clinical implementation based on evidence from the literature as well as on the experience of a group of leading German experts in the field. METHODS: The current evidence base for the use of rTMS in depression was examined via review of the literature. From the evidence and from clinical experience, recommendations for the use of rTMS in clinical practice were derived. All members of the of the German Society for Brain Stimulation in Psychiatry and all members of the sections Clinical Brain Stimulation and Experimental Brain Stimulation of the German Society for Psychiatry, Psychotherapy, Psychosomatics and Mental Health were invited to participate in a poll on whether they consent with the recommendations. FINDINGS: Among rTMS experts, a high consensus rate could be identified for clinical practice concerning the setting and the technical parameters of rTMS treatment in depression, indications and contra-indications, the relation of rTMS to other antidepressive treatment modalities and the frequency and management of side effects.

Challenges and pitfalls in anesthesia for electroconvulsive therapy.

Electroconvulsive therapy (ECT) refers to the application of electricity to the patients' scalp to treat psychiatric disorders, most notably, treatment-resistant depression. It is a safe, effective, and evidence-based therapy that is performed with general anesthesia. Muscle relaxation is used to prevent injuries related to the tonic-clonic seizure caused by ECT. Hypnotics are administered to induce amnesia and unconsciousness, so that, patients do not experience the period of muscle relaxation, while the generalized seizure is left unnoticed. For the anesthesiologist, ECT is associated with the challenges and pitfalls that are related to informed consent, social acceptance of ECT, airway management (especially in COVID-19 patients), and the interaction between ventilation and anesthetics from one viewpoint, and seizure induction and maintenance from another. The exact mode of action of the therapy is as unknown as the optimal choice or combination of anesthetics used.

Effects of magnetic seizure therapy on anterograde and retrograde amnesia in treatment-resistant depression.

BACKGROUND: Electroconvulsive therapy (ECT) is the gold standard for treatment-resistant depression (TRD). However, cognitive side effects, mainly anterograde and retrograde amnesia, frequently occur. Magnetic seizure therapy (MST) is tested using more focal seizure induction. However, the suggestion MST may be more beneficial than ECT because it causes fewer amnesia have not yet been comprehensively investigated using common neuropsychological testing specifically for ECT. We aimed to examine whether MST causes anterograde and retrograde amnesia. METHODS: Ten patients with TRD were treated with MST (8.9 [2] treatments) at 100% machine output, a frequency of 100 Hz and 657.4 (62) pulses per train. The short form of the Autobiographical Memory Inventory was administered to test retrograde amnesia. Furthermore, an extended neuropsychological test battery, including verbal and nonverbal recall as well as recognition tasks, was used. RESULTS: We observed changes in retrograde amnesia, although they were not clinically relevant (mean: -0.42 ± 0.14). Furthermore, no anterograde amnesia as well as no effects on global cognitive status, attention, language, and executive functions after MST were measured. CONCLUSIONS: The cognitive safety and efficacy of MST in patients with TRD were indicated. However, the main limitations of the present study were the small sample and as a consequence, the low statistical power to detect changes after treatment. Therefore, our findings require replication in further studies. In addition, a direct comparison between MST and ECT in a larger sample should be performed before MST can be discussed as an alternative treatment approach to ECT in clinical practice.

Superolateral medial forebrain bundle deep brain stimulation in major depression: a gateway trial.

Short- and long-term antidepressant effects of deep brain stimulation (DBS) in treatment-resistant depression (TRD) have been demonstrated for several brain targets in open-label studies. For two stimulation targets, pivotal randomized trials have been conducted; both failed a futility analysis. We assessed efficacy and safety of DBS of the supero-lateral branch of the medial forebrain bundle (slMFB) in a small Phase I clinical study with a randomized-controlled onset of stimulation in order to obtain data for the planning of a large RCT. Sixteen patients suffering from TRD received DBS of the slMFB and were randomized to sham or real stimulation for the duration of 2 months after implantation. Primary outcome measure was mean reduction in Montgomery-Åsberg Depression Rating Scale (MADRS) during 12 months of DBS (timeline analysis). Secondary outcomes were the difference in several clinical measures between sham and real stimulation at 8 weeks and during stimulation phases. MADRS ratings decreased significantly from 29.6 (SD +/- 4) at baseline to 12.9 (SD +/- 9) during 12 months of DBS (mean MADRS, n = 16). All patients reached the response criterion, most patients (n = 10) responded within a week; 50% of patients were classified as remitters after 1 year of stimulation. The most frequent side effect was transient strabismus. Both groups (active/sham) demonstrated an antidepressant micro-lesioning effect but patients had an additional antidepressant effect after initiation of stimulation. Both rapid onset and stability of the antidepressant effects of slMFB-DBS were demonstrated as in our previous pilot study. Given recent experiences from pivotal trials in DBS for MDD, we believe that slow, careful, and adaptive study development is germane. After our exploratory study and a large-scale study, we conducted this gateway trial in order to better inform planning of the latter. Important aspects for the planning of RCTs in the field of DBS for severe and chronic diseases are discussed including meaningful phases of intra-individual and between-group comparisons and timeline instead of single endpoint analyses.

Plasma brain-derived neurotrophic factor (pBDNF) and executive dysfunctions in patients with major depressive disorder.

Objectives: Executive dysfunctions are frequently seen in patients with major depressive disorder (MDD) and normalise in many cases during effective antidepressant therapy. This study investigated whether a normalisation of executive dysfunctions during antidepressant treatment correlates with or can be predicted by clinical parameters or levels of brain-derived neurotrophic factor (BDNF).Methods: In 110 MDD patients with executive dysfunctions (percentile <16), executive functions and plasma BDNF levels were analysed at baseline, and days 14 and 56 of an antidepressant treatment. BDNF exon IV and P11 methylation status was studied at baseline.Results: Eighty patients (73%) experienced a normalisation of executive dysfunctions, while 30 (27%) suffered from persistent dysfunctions until day 56. Patients with persistent dysfunctions had significantly higher HAMD scores at days 14 and 56, and lower plasma BDNF levels at each time point than patients with a normalisation of dysfunctions (F1= 10.18; P = 0.002). This was seen for verbal fluency, but not processing speed. BDNF exon IV and p11 promoter methylation was not associated with test performance.Conclusions: Our results corroborate a concomitant amelioration of executive dysfunctions with successful antidepressant therapy and support a role of BDNF in the neural mechanisms underlying the normalisation of executive dysfunctions in MDD.ClinicalTrials.gov number: NCT00974155; EudraCT: 2008-008280-96.

Clinical Predictors of Response to Magnetic Seizure Therapy in Depression: A Preliminary Report.

OBJECTIVES: Magnetic seizure therapy (MST) is a novel convulsive brain stimulation method in clinical testing, which is used as an alternative for electroconvulsive therapy in patients with treatment-resistant depression (TRD). Preliminary studies have suggested that MST leads to fewer cognitive adverse effects than electroconvulsive therapy but has similar efficacy. However, the clinical predictors of response to MST have not been evaluated yet. This study aimed to investigate whether these predictors can be identified in patients with TRD. METHODS: Thirty-eight patients with TRD were included. As clinical predictors for treatment response, we used the diagnosis, sex, age, family history, and severity of depression, as well as the melancholic, psychotic, anxiety, and atypical depression symptoms. A response was defined as an improvement higher than 50% on the 28-item Hamilton Rating Scale for Depression. The binary logistic regression, stepwise linear regression, and effect sizes were calculated. RESULTS: We found that 68.4% of the patients responded to MST. The responders had significantly fewer previous depressive episodes, less severe depression, and fewer melancholic (anhedonia) and anxiety symptoms than the nonresponders. In addition, responders were more likely to have a positive family history of depression than nonresponders. In particular, the number of previous episodes and a family history of depression were significant predictors of the response to MST. CONCLUSIONS: We demonstrate that the chronicity, severity, and family history of depression, as well as the presence of melancholic and anxiety symptoms, can serve as clinical predictors of the response to MST. Further research with a larger sample size will be required to verify these preliminary findings.

Deep brain stimulation of the supero-lateral branch of the medial forebrain bundle does not lead to changes in personality in patients suffering from severe depression.

BACKGROUND: Reports of changes in patients' social behavior during deep brain stimulation (DBS) raised the question whether DBS induces changes in personality. This study explored if (1) DBS is associated with changes in personality in patients suffering from treatment-resistant depression (TRD), (2) how personality dimensions and depression are associated, and (3) if TRD patients' self-ratings of personality are valid. METHODS: TRD patients were assessed before DBS (n = 30), 6 months (t2, n = 21), 2 (t3, n = 17) and 5 years (t4, n = 11) after the initiation of DBS of the supero-lateral branch of the medial forebrain bundle (slMFB-DBS). Personality was measured with the NEO-Five-Factor Inventory (NEO-FFI), depression severity with Hamilton (HDRS), and Montgomery-Åsberg Depression Rating Scale (MADRS). RESULTS: Personality dimensions did not change with slMFB-DBS compared with baseline. Extraversion was negatively correlated with HDRS28 (r = -0.48, p < 0.05) and MADRS (r = -0.45, p < 0.05) at t2. Inter-rater reliability was high for the NEO-FFI at baseline (Cronbach's α = 0.74) and at t4 (α = 0.65). Extraversion [t(29) = -5.20; p < 0.001] and openness to experience [t(29) = -6.96; p < 0.001] differed statistically significant from the normative sample, and did not predict the antidepressant response. CONCLUSIONS: slMFB-DBS was not associated with a change in personality. The severity of depression was associated with extraversion. Personality of TRD patients differed from the healthy population and did not change with response, indicating a possible scar effect. Self-ratings of personality seem valid to assess personality during TRD.

Degree of Postictal Suppression Depends on Seizure Induction Time in Magnetic Seizure Therapy and Electroconvulsive Therapy.

OBJECTIVES: Anesthesia is required for both magnetic seizure therapy (MST) and electroconvulsive therapy (ECT), although it has anticonvulsant properties. In this case, bispectral index (BIS) monitoring, a specific electroencephalogram-derived monitoring, can be used to find the optimal seizure induction time during anesthesia to elicit adequate seizures. A measurement of seizure adequacy in electroencephalogram is the postictal suppression. The purpose of this study was to investigate the influence of seizure induction time on the degree of postictal suppression by comparing BIS versus no-BIS monitoring in MST and ECT. METHODS: Twenty patients with treatment-resistant depression were randomly assigned to either MST or ECT. Each patient underwent 3 treatments with the determination of seizure induction time by defined prestimulation BIS (BIS condition) and 3 treatments with determination of seizure induction time by controlled clinical trial protocol (no-BIS condition). Statistical analysis was calculated by repeated-measures analysis of variance. RESULTS: The degree of postictal suppression was more pronounced in both MST and ECT, with BIS monitoring. In this connection, no differences between MST and ECT were found. Seizure induction time was significantly later in the BIS condition (181.3 ± 6 seconds) compared with the no-BIS condition (114.3 ± 12 seconds) (P < 0.001). CONCLUSIONS: Adequacy of seizures, in the form of the degree of postictal suppression, was superior by determining the seizure induction time with BIS in both MST and ECT. Further research is needed to investigate the correlation between the degree of postictal suppression and treatment response.

Deep brain stimulation to the medial forebrain bundle for depression- long-term outcomes and a novel data analysis strategy.

BACKGROUND: Deep brain stimulation (DBS) of the supero-lateral branch of the medial forebrain bundle (slMFB) in treatment-resistant depression (TRD) is associated with acute antidepressant effects. OBJECTIVE: Long-term clinical effects including changes in quality of life, side effects and cognition as well as long-term data covering four years are assessed. METHODS: Eight TRD patients were treated with DBS bilateral to the slMFB. Primary outcome measure was a 50% reduction in Montgomery-Åsberg Depression Rating Scale (MADRS) (response) and remission (MADRS <10) at 12 months compared to baseline. Secondary measures were anxiety, general functioning, quality of life, safety and cognition assessed for 4 years. Data is reported as conventional endpoint-analysis and as area under the curve (AUC) timeline analysis. RESULTS: Six of eight patients (75%) were responders at 12 months, four patients reached remission. Long-term results revealed a stable effect up to four years. Antidepressant efficacy was also reflected in the global assessment of functioning. Main side effect was strabismus at higher stimulation currents. No change in cognition was identified. AUC analysis revealed a significant reduction in depression for 7/8 patients in most months. CONCLUSIONS: Long-term results of slMFB-DBS suggest acute and sustained antidepressant effect; timeline analysis may be an alternative method reflecting patient's overall gain throughout the study. Being able to induce a rapid and robust antidepressant effect even in a small, sample of TRD patients without significant psychiatric comorbidity, render the slMFB an attractive target for future studies.

Deep brain stimulation for bipolar disorder-review and outlook.

Research on deep brain stimulation (DBS) for treatment-resistant psychiatric disorders has established preliminary efficacy signals for treatment-resistant depression. There are only few studies on DBS that included patients suffering from bipolar disorder. This article gives an overview of these studies concerning DBS targets, antidepressant efficacy, and the occurrence of manic/hypomanic symptoms under stimulation. First, promising results show that all patients experienced significant improvement in depressive symptomatology. In a single case, hypomanic symptoms occurred, but they could be resolved by adjusting stimulation parameters. Furthermore, this article highlights important clinical differences between unipolar and bipolar depression that have to be considered throughout the course of treatment.

Walking away from depression-motor activity increases ratings of mood and incentive drive in patients with major depression.

Reduced motor activity is associated with depression. Lewinsohn's cognitive behavioural model of depression assumes a lack of positive experience due to a reduced level of activity as a key aspect of depression. The acute relationship between motor activity and mood as well as between motor activity and incentive drive (the motivation to engage in activities) is unknown. An augmentation of mood and incentive drive could precede or follow motor activity. We examined (1) whether motor activity would be correlated with the course of depression and (2) the temporal relationship between motor activity and acute changes in mood and incentive drive. Motor activity was measured with actigraphy in 12 patients with depression for one week. Severity of depression was assessed before and at the end of the study with depression rating scales. The patients reported mood and incentive drive once per hour. With lag sequential analysis, the temporal relationship between motor activity and mood and incentive drive was evaluated. Higher motor activity was associated with depression improvement. Motor activity had an acute association with mood and incentive drive, especially one hour after activity. The results support the Lewinsohn's model of depression and underline the impact of behavioural activation in antidepressant treatment.

An overview on clinical aspects in magnetic seizure therapy.

The aim of the presented work is to provide an overview on the clinical data of the promising convulsive brain stimulation technique, the magnetic seizure therapy (MST). We review the advantages and disadvantages of MST, focusing on rationale, development and current treatment procedure. We also provide a summary of the current literature including clinical trials and case reports found in the PubMed database. Furthermore, we consider effectiveness and side effects, emphasizing on crucial issues to be addressed for a better understanding of this potential new treatment option in treatment-resistant depression (TRD).

Effects of electroconvulsive therapy and magnetic seizure therapy on acute memory retrieval.

OBJECTIVES: Electroconvulsive therapy (ECT) is currently the most effective treatment for severe depression. However, it is frequently associated with negative cognitive side effects. Magnetic seizure therapy (MST) depicts an alternative, although experimental, convulsive treatment for major depression. Initial results suggest comparable antidepressant effects accompanied by a better side effect profile. However, no studies up to now have addressed acute retrieval disruption after MST in comparison to ECT. Therefore, we intended to broaden insight into the side effect profile of MST compared to ECT by examining the disruption of acute verbal memory processes after treatment. METHODS: Twenty depressed patients were randomly assigned to either MST (10 patients) or ECT (10 patients) treatment. On 2 treatment days and 2 treatment-free days, the patients memorized words using a controlled learning paradigm derived from the Batchelder and Riefer storage retrieval model. Four hours after memorization, the patients were asked to retrieve words freely (delayed recall) and a second time with the help of an additional cue constructed out of a hypernymic category (cued recall). By comparing memory performance on treatment days to control days, treatment-induced memory disruption was evaluated. RESULTS: After ECT, delayed recall was disturbed, whereas after MST, it was not. However, this difference in performance was no longer apparent upon cue application (cued recall). CONCLUSIONS: This study demonstrates that ECT-induced acute memory disruption measured by delayed recall is absent after MST, confirming its superior side effect profile. We hope that confirming advantages of MST over ECT will improve therapy options for patients with severe depression.

Deep brain stimulation of the human reward system for major depression--rationale, outcomes and outlook.

Deep brain stimulation (DBS) as a putative approach for treatment-resistant depression (TRD) has now been researched for about a decade. Several uncontrolled studies--all in relatively small patient populations and different target regions-have shown clinically relevant antidepressant effects in about half of the patients and very recently, DBS to a key structure of the reward system, the medial forebrain bundle, has yielded promising results within few days of stimulation and at much lower stimulation intensities. On the downside, DBS procedures in regions are associated with surgical risks (eg, hemorrhage) and psychiatric complications (suicidal attenuation, hypomania) as well as high costs. This overview summarizes research on the mechanisms of brain networks with respect to psychiatric diseases and--as a novelty--extrapolates to the role of the reward system in DBS for patients with treatment-resistant depression. It further evaluates relevant methodological aspects of today's research in DBS for TRD. On the scientific side, the reward system has an important yet clearly under-recognized role in both neurobiology and treatment of depression. On the methodological side of DBS research in TRD, better animal models are clearly needed to explain clinical effects of DBS in TRD. Larger sample sizes, long-term follow-up and designs including blinded sham control are required to draw final conclusions on efficacy and side effects. Practical research issues cover study design, patient tracking, and the discussion of meaningful secondary outcome measures.

Comparable seizure characteristics in magnetic seizure therapy and electroconvulsive therapy for major depression.

Electroconvulsive therapy (ECT) is highly effective for treatment-resistant depression (TRD); however, its use for less severe forms of depression is somewhat limited by a lack of control over current spreading to medial temporal lobe memory structures, resulting in various cognitive side effects. In contrast, magnetic seizure therapy (MST), which uses high frequency repetitive transcranial magnetic stimulation (rTMS) for local seizure induction, has been associated with reduced cognitive side effects. To assess whether different characteristics of seizures induced by both methods are responsible for the differences in neuropsychological side-effect profile, we studied seven TRD-patients undergoing both MST and ECT in an open-label, within subject, controlled crossover pilot study. Comparison parameters included seizure-related ictal characteristics, including motor activity, electromyogram (EMG), electroencephalogram (EEG), and postictal recovery and reorientation times.Our results showed no differences in motor activity or EMG and EEG characteristics, thus implicating similar electrophysiological processes in seizure induction with MST and ECT. In line with previous studies, we observed shorter postictal recovery and reorientation times following MST.The ictal characteristics of induced seizures were found similar with ECT and MST suggesting that the more focal seizure induction associated with MST may account for the more beneficial neuropsychological side effect profile of MST.

Rapid effects of deep brain stimulation for treatment-resistant major depression.

BACKGROUND: Treatment-resistant major depressive disorder is a prevalent and debilitating condition. Deep brain stimulation to different targets has been proposed as a putative treatment. METHODS: In this pilot study, we assessed safety and efficacy of deep brain stimulation to the supero-lateral branch of the medial forebrain bundle in seven patients with highly refractory depression. Primary outcome criterion was severity of treatment-resistant major depressive disorder as assessed with the Montgomery-Åsberg Depression Rating Scale. General psychopathologic parameters, social functioning, and tolerance were assessed with standardized scales, the Global Assessment of Functioning scale, quality of life (Short-Form Health Survey Questionnaire), and neuropsychological tests. RESULTS: All patients showed strikingly similar intraoperative effects of increased appetitive motivation. Six patients attained the response criterion; response was rapid--mean Montgomery-Åsberg Depression Rating Scale of the whole sample was reduced by>50% at day 7 after onset of stimulation. At last observation (12-33 weeks), six patients were responders; among them, four were classified as remitters. Social functioning (Global Assessment of Functioning) improved in the sample as a whole from serious to mild impairment. Mean stimulation current was 2.86 mA; all side effects (strabismus at higher stimulation current, one small intracranial bleeding during surgery, infection at the implanted pulse generator site) could be resolved at short term. CONCLUSIONS: These preliminary findings suggest that bilateral stimulation of the supero-lateral branch of the medial forebrain bundle may significantly reduce symptoms in treatment-resistant major depressive disorder. Onset of antidepressant efficacy was rapid (days), and a higher proportion of the population responded at lower stimulation intensities than observed in previous studies.

Long-term effects of nucleus accumbens deep brain stimulation in treatment-resistant depression: evidence for sustained efficacy.

Deep brain stimulation (DBS) to the nucleus accumbens (NAcc-DBS) was associated with antidepressant, anxiolytic, and procognitive effects in a small sample of patients suffering from treatment-resistant depression (TRD), followed over 1 year. Results of long-term follow-up of up to 4 years of NAcc-DBS are described in a group of 11 patients. Clinical effects, quality of life (QoL), cognition, and safety are reported. Eleven patients were stimulated with DBS bilateral to the NAcc. Main outcome measures were clinical effect (Hamilton Depression Rating Scale, Montgomery-Asperg Rating Scale of Depression, and Hamilton Anxiety Scale) QoL (SF-36), cognition and safety at baseline, 12 months (n=11), 24 months (n=10), and last follow-up (maximum 4 years, n=5). Analyses were performed in an intent-to-treat method with last observation carried forward, thus 11 patients contributed to each point in time. In all, 5 of 11 patients (45%) were classified as responders after 12 months and remained sustained responders without worsening of symptoms until last follow-up after 4 years. Both ratings of depression and anxiety were significantly reduced in the sample as a whole from first month of NAcc-DBS on. All patients improved in QoL measures. One non-responder committed suicide. No severe adverse events related to parameter change were reported. First-time, preliminary long-term data on NAcc-DBS have demonstrated a stable antidepressant and anxiolytic effect and an amelioration of QoL in this small sample of patients suffering from TRD. None of the responders of first year relapsed during the observational period (up to 4 years).