The anatomy of excitement:Understanding and improving the effectiveness of electroconvulsive therapy

Electroconvulsive therapy (ECT) is an effective treatment for severe depression. In this thesis, I studied electroconvulsive therapy (ECT) research with the objective to improve the clinical outcome after treatment and to gain a better understanding of its working mechanisms. Multiple methods in ECT research were explored, varying with respect to sample selection (i.e., single- versus multi-center data), study design (i.e., observational retrospective study versus prospective RCT, controlled versus non-controlled), type of data (i.e., clinical, EEG, and [f]MRI), and the applied statistical models to analyze the data (i.e., frequentist versus Bayesian models). Additionally, I proposed a taxonomy of ECT research. The main chapters can be considered as specific case-examples of the child-nodes of this taxonomy. Thereby, this thesis contributes to improving the clinical outcome and understanding of the working mechanisms of ECT. Based on the findings in this thesis, I have discussed the methods that are commonly used in ECT research and which future directions this may take

Restoration of postictal cortical activity after electroconvulsive therapy relates to recovery of orientation in person, place and time

Background. Most patients show temporary impairments in clinical orientation after electroconvulsive therapy (ECT)-induced seizures. It is unclear how postictal reorientation relates to electroencephalography (EEG) restoration. This relationship may provide additional measures to quantify postictal recovery and shed light on neurophysiological aspects of reorientation after ECT. Methods. We analyzed prospectively collected clinical and continuous ictal and postictal EEG data from ECT patients. Postictal EEG restoration up to 1 h was estimated by the evolution of the normalized alpha–delta ratio (ADR). Times to reorientation in the cognitive domains of person, place, and time were assessed postictally. In each cognitive domain, a linear mixed model was fitted to investigate the relationships between time to reorientation and postictal EEG restoration. Results. In total, 272 pairs of ictal-postictal EEG and reorientation times of 32 patients were included. In all domains, longer time to reorientation was associated with slower postictal EEG recovery. Longer seizure duration and postictal administration of midazolam were related to longer time to reorientation in all domains. At 1-hour post-seizure, most patients were clinically reoriented, while their EEG had only partly restored. Conclusions. We show a relationship between postictal EEG restoration and clinical reorientation after ECT-induced seizures. EEG was more sensitive than reorientation time in all domains to detect postictal recovery beyond 1-hour post-seizure. Our findings indicate that clinical reorientation probably depends on gradual cortical synaptic recovery, with longer seizure duration leading to longer postsynaptic suppression after ECT seizures.</p

The effectiveness of nitrofurantoin, fosfomycin and trimethoprim for the treatment of cystitis in relation to renal function

Objectives: We evaluated the effect of renal function on clinical failure rates of nitrofurantoin, fosfomycin and trimethoprim for the treatment of cystitis in primary care. Methods: Data were retrospectively obtained from 78 Dutch general practitioner (GP) practices between 2013 and 2019. Eligible episodes in patients (>11 years) were those requiring 5 days of nitrofurantoin (NF5), single-dose fosfomycin–trometamol (FT1), 3 days of trimethoprim (TMP3) for uncomplicated cystitis, or 7 days of nitrofurantoin (NF7) or trimethoprim (TMP7) for complicated cystitis. Clinical failure was defined as second antibiotic prescription for cystitis or pyelonephritis within 28 days post-prescription. Mixed effects regression analysis was used, with patient and GP practice as random effects and demography, comorbidity, and cystitis history as fixed effects. Results: Adjusted odds ratios (aORs) for clinical failure per 10mL/min decrease in estimated glomerular filtration rate (eGFR) were 1.05 (95% CI: 1.01–1.09) for NF5 (n = 24,591), 0.96 (95% CI: 0.92–1.01) for FT1 (n = 5359), 0.98 (95% CI: 0.89–1.08) for TMP3 (n = 1064), 1.05 (95% CI: 1.02–1.09) for NF7 (n = 10,628) and 1.02 (95% CI: 0.93–1.14) for TMP7 (n = 831). In uncomplicated cystitis and eGFR ≥60 mL/min, clinical failures occurred in 14.6% (1895/12 980) of NF5-treated, 20.7% (266/1283) of FT1-treated (aOR versus NF5 1.37, 95% CI 1.18–1.59) and 20.8% (66/318) of TMP3-treated patients (aOR 1.42, 95% CI 1.07–1.87 versus NF5). In uncomplicated cystitis and eGFR <60 mL/min, FT1 resulted in 16.0% (39/244) and NF5 in 23.3% clinical failures (110/472), aOR: 0.61, 95% CI: 0.39–0.95). Conclusions: In eGFR ≥60 mL/min treatment with fosfomycin or trimethoprim for uncomplicated cystitis was associated with more clinical failure than treatment with nitrofurantoin, while in eGFR <60 mL/min nitrofurantoin was associated with more clinical failure than fosfomycin–trometamol. Renal function, if known, should be considered in the clinical decision-making for cystitis treatment

Prevention Of Xerophthalmia By Oral Massive Dose Vitamin A: (A Preliminary Report)

Untuk menilai efektivitas pemberian vitamin A dosis tinggi (200.000 IU vitamin A dan 40 IU vitamin E) secara masai dalam USAha pencegahan xerophthalmia, dilakukan penelitian terhadap seluruh anak umur 1-5 tahun di tujuh RK kotamadya Salatiga dan lima desa kabupaten Semarang, oleh suatu team ophthalmologi. Pada pemeriksaan awal ditemukan 132 penderita xerophthalmia diantara 2812 anak (4,7 persen). Kepada 2680 anak yang tidak menderita xerophthalmia sebagian diberi kapsul vitamin A dosis tinggi dan sebagian lain diberi kapsul placebo yang identik, secara "double-blind" diperiksa ulang sesudah enam bulan. Ternyata bahwa 7 diantara 1286 anak penerima vitamin A yang diperiksa (0,5 persen) menunjukkan tanda-tanda xerophthalmia. Sedang diantara 1183 anak penerima placebo yang diperiksa ternyata terdapat 43 penderita xerophthalmia (3,6 persen). Secara statistik bedanya amat bermakna. Tanda-tanda utama yang ditemukan adalah kombinasi dari buta-senja, xerosis conjunctiva, dan bercak Bitot. Kedua tanda yang terakhir ini terdapat pada 90 persen dari penderita, sedang buta-senja hanya 15 persen. Pada pemeriksaan ulang 132 anak penderita xerophthalmia yang telah diberi kapsul vitamin A dosis tinggi ternyata bahwa 91 persen dari yang diperiksa tidak lagi memperlihatkan tanda-tanda xerophthalmia. Jumlah anak yang tidak dapat diperiksa kembali jauh dibawah angka perkiraan. Sebagian besar karena telah pindah alamat, sebagian kecil meninggal. Antara golongan placebo dan vitamin, jumlah anak yang tidak dapat diperiksa kembali ini sama besar. Penelitian ini membuktikan bahwa kapsul vitamin A dosis tinggi efektip sekali untuk mencegah timbulnya xerophthalmia dan menyembuhkan gejala-gejala xerophthalmia ringan

Desmopressine voor de behandeling van nycturie bij ouderen: ongewenst door hoog risico op bijwerkingen?

Desmopressine, een synthetische analoog van het antidiuretisch hormoon, wordt gebruikt ter behandeling van nachtelijke incontinentie bij kinderen en sinds enkele jaren ook in de behandeling van nycturie bij ouderen. Nycturie bij ouderen veroorzaakt slaapstoornissen en is geassocieerd met een hogere kans op vallen en een hogere mortaliteit. Desmopressine leidt bij ouderen tot een significante afname van de nycturie en daarmee tot een betere slaapkwaliteit. Hierdoor wordt het steeds meer voorgeschreven bij ouderen. Desmopressine veroorzaakt bij volwassenen in 15% een borderline hyponatriëmie (Na=130–135mmol/l) en in 5 % een ernstige hyponatriëmie. Predisponerende factoren hiervoor zijn een hogere dosis, leeftijd > 65jaar, een laag-normaal serum natrium, een hoog basaal 24-uurs urine volume, co-medicatie, zoals thiazidediuretica, tricyclische antidepressiva’s, specifieke serotonineheropnameremmers, chlorpromazine, carbamazepine, loperamide en NSAIDs (Non-Steroidal Anti-Inflammatory Drugs). Een hyponatriëmie kan, indien ernstig en snel ontstaan, klachten geven zoals hoofdpijn, misselijkheid, braken, duizeligheid en het kan in ernstige gevallen leiden tot somnolentie, bewustzijnsverlies en overlijden. Wij presenteren twee patiënten waarbij desmopressine-gerelateerde hyponatriemie aanleiding was voor ziekenhuisopname. Vanwege het hoge risico op hyponatriëmie bij ouderen na gebruik van desmopressine, moeten alternatieve behandelingsstrategieën voor nycturie eerst worden overwogen. Indien desmopressine toch wordt voorgeschreven, is nauwgezette controle van het serum natrium noodzakelijk

Negative cognitive schema modification as mediator of symptom improvement after electroconvulsive therapy in major depressive disorder

Background: Electroconvulsive therapy (ECT) is a potent option for treatment-resistant major depressive disorder (MDD). Cognitive models of depression posit that negative cognitions and underlying all-or-nothing negative schemas contribute to and perpetuate depressed mood. This study investigates whether ECT can modify negative schemas, potentially via memory reactivation, and whether such changes are related to MDD symptom improvement. Method: Seventy-two patients were randomized to either an emotional memory reactivation electroconvulsive therapy (EMR-ECT) or control memory reactivation electroconvulsive therapy (CMR-ECT) intervention prior to ECT-sessions in a randomized controlled trail. Emotional memories associated with patients' depression were reactivated before ECT-sessions. At baseline and after the ECT-course, negative schemas and depression severity were assessed using the Dysfunctional Attitude Scale (DAS) and Hamilton Depression Rating Scale HDRS. Mediation analyses were used to examine whether the effects of ECT on HDRS-scores were mediated by changes in DAS-scores or vice versa. Results: Post-ECT DAS-scores were significantly lower compared to baseline. Post-ECT, the mean HDRS-score of the whole sample (15.10 ± 8.65 [SD]; n = 59) was lower compared to baseline (24.83 ± 5.91 [SD]). Multiple regression analysis showed no significant influence of memory reactivation on schema improvement. Path analysis showed that depression improvement was mediated by improvement of negative cognitive schemas. Conclusion: ECT is associated with improvement of negative schemas, which appears to mediate the improvement of depressive symptoms. An emotional memory intervention aimed to modify negative schemas showed no additional effect

Effectiveness of Emotional Memory Reactivation vs Control Memory Reactivation Before Electroconvulsive Therapy in Adult Patients With Depressive Disorder A Randomized Clinical Trial:A Randomized Clinical Trial

Importance: Although electroconvulsive therapy (ECT) is often effective, approximately half of patients with depression undergoing ECT do not benefit sufficiently, and relapse rates are high. ECT sessions have been shown to weaken reactivated memories. The effect of emotional memory retrieval on cognitive schemas remains unknown. Objective: To assess whether emotional memory retrieval just before patients receive ECT sessions weakens underlying cognitive schemas, improves ECT effectiveness, increases ECT response, and reduces relapse rates. Design, Setting, and Participants: In this multicenter randomized clinical trial conducted from 2014 to 2018 in the departments of psychiatry in 3 hospitals in the Netherlands, 72 participants were randomized 1:1 to 2 parallel groups to receive either emotional memory reactivation (EMR-ECT) or control memory reactivation (CMR-ECT) interventions before ECT sessions. The Hamilton Depression Rating Scale (HDRS [total score range: 0-52, with 0-7 indicating no depression and ≥24 indicating severe depression]) was used to measure symptoms of depression during and after ECT, with a 6-month follow-up period. Participants were between ages 18 and 70 years with a primary diagnosis of unipolar major depressive disorder (MDD) according to the Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition, Text Revision) and in whom ECT was indicated. Data analysis was performed from July to November 2019. Interventions: EMR-ECT or CMR-ECT interventions prior to ECT sessions. Main Outcomes and Measures: Depression scores and relapse rates within 6 months were assessed with the HDRS and analyzed using logistic and linear multiple regression analyses. Results: A total of 66 patients (mean [SD] age, 49.3 [12.3] years; 39 [59.1%] women) were randomized to the EMR-ECT group (n = 32) or the CMR-ECT group (n = 34). Regardless of the memory intervention, 42.4% (28 of 66) of patients responded (≥50% decrease of symptom severity on the HDRS). Of patients who responded, 39.3% (11 of 28) relapsed within 6 months. Remission rates (CMR-ECT group, 29.4% [10 of 34] vs EMR-ECT group, 25.0% [8 of 32]; P = .58), mean (SD) HDRS scores after the ECT course (CMR-ECT group, 14.6 [8.6] vs EMR-ECT group, 14.9 [8.8]; P = .88), total mean (SD) number of required ECT sessions for response (CMR-ECT group, 14.9 [7.9] vs EMR-ECT group, 15.6 [7.3]; P = .39), and relapse rates (CMR-ECT group, 46.7% [7 of 15] vs EMR-ECT group, 30.8% [4 of 13]; P = .33) were not significantly altered by the intervention. Conclusions and Relevance: Study findings suggest that the EMR-ECT intervention just before patient receipt of ECT for depression did not improve effectiveness, increase speed of response, or reduce relapse rates after the ECT course compared with patients receiving CMR-ECT. Trial Registration: Trialregister.nl Identifier: NL4289