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Objective: To collect descriptive data on the treatment of Alzheimer’s disease with galantamine under naturalistic conditions. Study design: This was a prospective, open-label, observational study. Patients: Subjects (n = 345) with mild to moderately severe dementia of the Alzheimer’s type were recruited from 48 hospitals in Australia. Methods: Subjects were enrolled and received treatment with galantamine for 6 months in a clinical practice setting. Subjects were assessed at baseline and 3 and 6 months after starting treatment using the Mini-Mental State Examination (MMSE), the Clinician’s Interview-Based Impression of Change plus Caregiver Input (CIBIC-plus) and the Alzheimer’s Disease Assessment Scale-cognitive subscale (ADAS-cog) [the latter only if the baseline MMSE score was at least 25]. Subjects were also assessed using an abridged Instrumental Activities of Daily Living (IADL) questionnaire that included questions on using the telephone, ability to travel more than 1km outside the home, taking medications and managing money, and an 11-item behaviour assessment scale that measured aggression, sleep disturbance, disinhibition, personality changes, irritability, depression, agitation, apathy, inertia, hallucinations and aberrant motor behaviour. Results: Of the 345 subjects who were enrolled in the study (intent-to-treat [ITT] population), 229 completed the baseline, 3- and 6-month visits (per-protocol [PP] population). The mean age of the PP population was 78.0 ± 6.8 years. At 6 months, most PP subjects (70%) showed an increase in MMSE score compared with baseline, with a mean increase in score of 2.0 ± 3.1 points from a baseline of 20.8 ± 4.2 points. In the ITT population, 44% of subjects (151/345) showed an increase in MMSE after 6 months. If data were unavailable the patient was classified as a nonresponder. Of the 21 PP patients who were assessed using ADAS-cog, 18 (86%) demonstrated a decrease in the ADAS-cog score, reflecting an improvement in cognition. Of the ITT population, 33% (19/57) had a decreased ADAS-cog score after 6 months. Most PP subjects (86%) were considered responders according to the CIBIC-plus score, with 65% showing some improvement over 6 months of treatment. Of the ITT population, 54% (187/345) showed no deterioration in CIBIC-plus score after 6 months. No deterioration in IADL or behaviour assessments occurred in the majority of PP subjects over 6 months. Conclusions: In a clinical practice setting, the majority of subjects receiving galantamine who completed the study maintained their ratings of cognition, function, behaviour or global assessment over the 6-month period.

Antiepileptic drugs are commonly given for perioperative prophylaxis after brain tumor surgery, and there has been growing interest in levetiracetam, a second-generation antiepileptic drug. This retrospective study compared the seizure outcomes, side effects and durability of levetiracetam with valproic acid after a craniotomy for supratentorial brain tumors. Between 2009 and 2012, 282 consecutive patients with a supratentorial brain tumor underwent a craniotomy at Seoul National University Bundang Hospital. Of these patients, 51 (18.1 %) and 231 (81.9 %) were pre-operatively administered levetiracetam and valproic acid, respectively. The postoperative seizure outcomes (within 1 month after surgery) and the long-term side effects of both drugs were evaluated. Of the 51 patients in the levetiracetam group, 4 (7.8 %) experienced postoperative seizures after brain tumor surgery, and 15 (6.5 %) of the 231 patients in the valproic acid group experienced postoperative seizures (p = 0.728). The long-term complication rate of the valproic acid group (26.8 %; 62/231) was significantly higher than that of the levetiracetam group (9.8 %; 5/51) [p = 0.010]. In the valproic acid group, 10 hepatotoxicities, 20 hyperammonemias and 10 hematologic abnormalities (6 thrombocytopenias, 3 pancytopenias, and 1 leucopenia) occurred. Moreover, 89 patients (38.5 %) in the valproic acid group changed or added other anticonvulsants because of side effects or uncontrolled seizures, whereas only 9 patients (17.6 %) in the levetiracetam group changed or added other anticonvulsants (p = 0.005). The postoperative seizure control rates of levetiracetam and valproic acid were not statistically significantly different; however, levetiracetam may be superior to valproic acid in terms of its safety and durability after supratentorial tumor surgery.

Eszopiclone (Lunesta®), the S-enantiomer of racemic zopiclone, is a nonbenzodiazepine hypnotic agent that is approved in the US as an oral, once-nightly therapy for insomnia in adults; eszopiclone is also currently under review by the European Medicines Agency. Eszopiclone is rapidly absorbed after oral administration without any next-day clinical residual effects being detected. Large, well designed trials of up to 6 months’ duration have shown that eszopiclone significantly improves both sleep onset and sleep maintenance compared with placebo in adult and elderly patients with primary insomnia. Eszopiclone for 4–8 weeks also significantly improved sleep parameters compared with placebo in patients with insomnia coexisting with other conditions that also disturb sleep (co-morbid insomnia), and improved certain measures of the co-morbid conditions to a greater extent than the standard therapies alone. Short-term eszopiclone produced improvements in daytime functioning in patients with co-morbid insomnia. Six months’ therapy in adults with primary insomnia improved daytime functioning and health-related quality of life. Eszopiclone was generally well tolerated. There was no evidence of tolerance during 12 months of treatment with this agent. On discontinuation of eszopiclone, there was no rebound insomnia or serious withdrawal effects. Well designed, comparative trials with other nonbenzodiazepine hypnotics are needed to determine its relative efficacy and tolerability. A cost-utility analysis suggested that eszopiclone is cost effective for the treatment of primary insomnia in the US. Therefore, eszopiclone is a useful therapeutic option in the management of adult and elderly patients with primary or co-morbid insomnia. Unlike most other hypnotics, eszopiclone is not limited to short-term use.

Large (big)-conductance calcium-activated potassium (BKCa) channels are expressed in migraine-related structures such as the cranial arteries, trigeminal ganglion and trigeminal spinal nucleus, and they play a substantial role in vascular tonus and neuronal excitability. Using synthetic BKCa channels openers was associated with headache as a frequent adverse effect in healthy volunteers. Additionally, BKCa channels are downstream molecules in migraine signalling pathways that are activated by several compounds known to provoke migraine, including calcitonin gene-related peptide (CGRP), pituitary adenylate cyclase-activating polypeptide (PACAP) and glyceryl trinitrate (GTN). Also, there is a high affinity and a close coupling between BKCa channels and ATP-sensitive potassium (KATP) channels, the role of which has recently been established in migraine pathophysiology. These observations raise the question as to whether direct BKCa channel activation can provoke migraine in migraine patients, and whether the BKCa channel could be a potential novel anti-migraine target. Hence, randomized and placebo-controlled clinical studies on BKCa channel openers or blockers in migraine patients are needed.

Early non-response is a well-established prognostic marker but evidence-based and consistent recommendations to manage it are limited. The aim of this systematic review and meta-analysis was to generate evidence-based strategies for the management of schizophrenia patients with early non-response to 2 weeks of antipsychotic treatment. We conducted a systematic review and meta-analysis of randomized trials comparing antipsychotic dose escalation, switch, augmentation and continuation in individuals with study-defined early antipsychotic treatment non-response. Eligibility criteria were (1) clinical trials of primary psychosis treating for at least 2 weeks with antipsychotic monotherapy with study-defined operationalized criteria for early non-response; and (2) randomization to at least two of the following treatment strategies: dose escalation, switch, augmentation, or treatment continuation. Information sources were Pubmed, PsycINFO, and EMBASE, and risk of bias was assessed using Jadad scores. Results were synthesized using random-effects meta-analysis, comparing each intervention with treatment continuation for total symptom change as the primary outcome, generating standardized mean differences (SMDs) and 95% confidence intervals (CIs). Studies meeting the selection criteria but providing insufficient data for a meta-analysis were presented separately. We screened 454 records by 1 August 2022, of which 12 individual datasets met the inclusion criteria, representing 947 research participants. Of those studies, five provided data to include in the meta-analysis (four with early non-response at 2 weeks, one at 3 weeks). Early non-response was defined within a timeline of 2 weeks in eight datasets, with the remaining datasets ranging between 3 and 4 weeks. The rates of early non-response ranged between 72.0 and 24.1%, and the endpoint ranged within 4–24 weeks post randomization. Quality was good (i.e., Jadad score of ≥3) in 8 of the 12 datasets. Overall, three studies compared antipsychotic switch versus continuation and two compared antipsychotic switch versus augmentation, in both cases without significant pooled between-group differences for total symptom severity (n = 149, SMD 0.18, 95% CI −0.14 to 0.5). Individually, two relatively large studies for antipsychotic switch versus continuation found small advantages for switching antipsychotics for total symptom severity (n = 149, SMD −0.49, 95% CI −1.05 to −0.06). One relatively large study found an advantage for dose escalation, although this finding has not been replicated and was not included in the meta-analysis. None of the alternatives included antipsychotic switch to clozapine. Despite robust accuracy of early antipsychotic non-response predicting ultimate response, the evidence for treatment strategies that should be used for early non-response after 2–3 weeks is limited. While meta-analytic findings were non-significant, some individual studies suggest advantages of antipsychotic switch or dose escalation. Therefore, any conclusions should be interpreted carefully, given the insufficient high-quality evidence.

Leptomeningeal metastases represent an aggressive stage of cancer with few durable treatment options. Improved understanding of cancer biology, neoplastic reliance on oncogenic driver mutations, and complex immune system interactions have resulted in an explosion in cancer-directed therapy in the last two decades to include small molecule inhibitors and immune checkpoint inhibitors. Most of these therapeutics are underexplored in patients with leptomeningeal metastases, limiting extrapolation of extracranial and even intracranial efficacy outcomes to the unique leptomeningeal space. Further confounding our interpretation of drug activity in the leptomeninges is an incomplete understanding of drug penetration through the blood–cerebrospinal fluid barrier of the choroid plexus. Nevertheless, a number of retrospective studies and promising prospective trials provide evidence of leptomeningeal activity of several small molecule and immune checkpoint inhibitors and underscore potential areas of further therapeutic development for patients harboring leptomeningeal disease.

Despite significant progress in the understanding of the frontotemporal dementias (FTDs), there remains no disease-modifying treatment for these conditions, and limited effective symptomatic treatment. Behavioural variant frontotemporal dementia (bvFTD) is the most common FTD syndrome, and is characterized by severe impairments in behaviour, personality and cognition. Neuropsychiatric symptoms are common features of bvFTD but are present in the other FTD syndromes. Current treatment strategies therefore focus on ameliorating the neuropsychiatric features. Here we review the rationale for current treatments related to each of the main neuropsychiatric symptoms forming the diagnostic criteria for bvFTD relevant to all FTD subtypes, and two additional symptoms not currently part of the diagnostic criteria: lack of insight and psychosis. Given the paucity of effective treatments for these symptoms, we highlight how contributing mechanisms delineated in cognitive neuroscience may inform future approaches to clinical trials and more precise symptomatic treatments for FTDs.