An investigation of the clinical impact and therapeutic relevance of a DNA damage immune response (DDIR) signature in patients with advanced gastroesophageal adenocarcinoma.

BACKGROUND: An improved understanding of which gastroesophageal adenocarcinoma (GOA) patients respond to both chemotherapy and immune checkpoint inhibitors (ICI) is needed. We investigated the predictive role and underlying biology of a 44-gene DNA damage immune response (DDIR) signature in patients with advanced GOA. MATERIALS AND METHODS: Transcriptional profiling was carried out on pretreatment tissue from 252 GOA patients treated with platinum-based chemotherapy (three dose levels) within the randomized phase III GO2 trial. Cross-validation was carried out in two independent GOA cohorts with transcriptional profiling, immune cell immunohistochemistry and epidermal growth factor receptor (EGFR) fluorescent in situ hybridization (FISH) (n = 430). RESULTS: In the GO2 trial, DDIR-positive tumours had a greater radiological response (51.7% versus 28.5%, P = 0.022) and improved overall survival in a dose-dependent manner (P = 0.028). DDIR positivity was associated with a pretreatment inflamed tumour microenvironment (TME) and increased expression of biomarkers associated with ICI response such as CD274 (programmed death-ligand 1, PD-L1) and a microsatellite instability RNA signature. Consensus pathway analysis identified EGFR as a potential key determinant of the DDIR signature. EGFR amplification was associated with DDIR negativity and an immune cold TME. CONCLUSIONS: Our results indicate the importance of the GOA TME in chemotherapy response, its relationship to DNA damage repair and EGFR as a targetable driver of an immune cold TME. Chemotherapy-sensitive inflamed GOAs could benefit from ICI delivered in combination with standard chemotherapy. Combining EGFR inhibitors and ICIs warrants further investigation in patients with EGFR-amplified tumours.

The use of faecal microbiota transplant as treatment for recurrent or refractory Clostridioides difficile infection and other potential indications: second edition of joint British Society of Gastroenterology (BSG) and Healthcare Infection Society (HIS) guidelines.

The first British Society of Gastroenterology (BSG) and Healthcare Infection Society (HIS)-endorsed faecal microbiota transplant (FMT) guidelines were published in 2018. Over the past 5 years, there has been considerable growth in the evidence base (including publication of outcomes from large national FMT registries), necessitating an updated critical review of the literature and a second edition of the BSG/HIS FMT guidelines. These have been produced in accordance with National Institute for Health and Care Excellence-accredited methodology, thus have particular relevance for UK-based clinicians, but are intended to be of pertinence internationally. This second edition of the guidelines have been divided into recommendations, good practice points and recommendations against certain practices. With respect to FMT for Clostridioides difficile infection (CDI), key focus areas centred around timing of administration, increasing clinical experience of encapsulated FMT preparations and optimising donor screening. The latter topic is of particular relevance given the COVID-19 pandemic, and cases of patient morbidity and mortality resulting from FMT-related pathogen transmission. The guidelines also considered emergent literature on the use of FMT in non-CDI settings (including both gastrointestinal and non-gastrointestinal indications), reviewing relevant randomised controlled trials. Recommendations are provided regarding special areas (including compassionate FMT use), and considerations regarding the evolving landscape of FMT and microbiome therapeutics.

Clinical characteristics associated with the discrepancy between subjective and objective cognitive impairment in depression.

BACKGROUND: Patients with unipolar disorder (UD) commonly experience cognitive dysfunction during symptomatic and remitted phases. However, it is not necessarily the patients with the greatest subjective complaints, who display the largest objectively-measured deficits on neuropsychological tests. OBJECTIVE: This report investigated the demographic and clinical factors associated with the discrepancy between subjective and objective measures of cognition in two separate depressed patient populations in Denmark and New Zealand, respectively, using a new methodology. METHODS: Data from 137 depressed patients and 103 healthy controls including neuropsychological test scores, self-reported cognitive difficulties, and ratings of mood were pooled from two studies conducted in Copenhagen, Denmark, and Christchurch, New Zealand, respectively. Cognitive discrepancy scores were calculated using a novel methodology, with positive values indicating disproportionately more subjective than objective difficulties (i.e., "sensitivity") and negative values indicating more objective than subjective impairments (i.e., "stoicism"). RESULTS: In the Danish partially remitted patient sample, greater 'sensitivity' was associated with more subsyndromal depression severity (standardized Beta (std. ß )= 0.4, p < 0.01)), illness duration (std. ß = 0.4, p < 0.01), and younger age (std. ß = 0.6, p < 0.001). This association was replicated in the New Zealand sample of more symptomatic patients (p-values ≤ 0.05). LIMITATIONS: The cross-sectional design hampered causal inferences. We had obtained different measures of objective and subjective cognition from the two studies. CONCLUSIONS: Patients with more depressive symptoms and younger age overreported cognitive impairments across all illness states. The use of an objective cognition screener thus seems particularly relevant for these patients to assess whether subjective complaints are accompanied by measurable cognitive deficits.

Assessing and addressing cognitive impairment in bipolar disorder: the International Society for Bipolar Disorders Targeting Cognition Task Force recommendations for clinicians.

OBJECTIVES: Cognition is a new treatment target to aid functional recovery and enhance quality of life for patients with bipolar disorder. The International Society for Bipolar Disorders (ISBD) Targeting Cognition Task Force aimed to develop consensus-based clinical recommendations on whether, when and how to assess and address cognitive impairment. METHODS: The task force, consisting of 19 international experts from nine countries, discussed the challenges and recommendations in a face-to-face meeting, telephone conference call and email exchanges. Consensus-based recommendations were achieved through these exchanges with no need for formal consensus methods. RESULTS: The identified questions were: (I) Should cognitive screening assessments be routinely conducted in clinical settings? (II) What are the most feasible screening tools? (III) What are the implications if cognitive impairment is detected? (IV) What are the treatment perspectives? Key recommendations are that clinicians: (I) formally screen cognition in partially or fully remitted patients whenever possible, (II) use brief, easy-to-administer tools such as the Screen for Cognitive Impairment in Psychiatry and Cognitive Complaints in Bipolar Disorder Rating Assessment, and (III) evaluate the impact of medication and comorbidity, refer patients for comprehensive neuropsychological evaluation when clinically indicated, and encourage patients to build cognitive reserve. Regarding question (IV), there is limited evidence for current evidence-based treatments but intense research efforts are underway to identify new pharmacological and/or psychological cognition treatments. CONCLUSIONS: This task force paper provides the first consensus-based recommendations for clinicians on whether, when, and how to assess and address cognition, which may aid patients' functional recovery and improve their quality of life.

Methodological recommendations for cognition trials in bipolar disorder by the International Society for Bipolar Disorders Targeting Cognition Task Force.

OBJECTIVES: To aid the development of treatment for cognitive impairment in bipolar disorder, the International Society for Bipolar Disorders (ISBD) convened a task force to create a consensus-based guidance paper for the methodology and design of cognition trials in bipolar disorder. METHODS: The task force was launched in September 2016, consisting of 18 international experts from nine countries. A series of methodological issues were identified based on literature review and expert opinion. The issues were discussed and expanded upon in an initial face-to-face meeting, telephone conference call and email exchanges. Based upon these exchanges, recommendations were achieved. RESULTS: Key methodological challenges are: lack of consensus on how to screen for entry into cognitive treatment trials, define cognitive impairment, track efficacy, assess functional implications, and manage mood symptoms and concomitant medication. Task force recommendations are to: (i) enrich trials with objectively measured cognitively impaired patients; (ii) generally select a broad cognitive composite score as the primary outcome and a functional measure as a key secondary outcome; and (iii) include remitted or partly remitted patients. It is strongly encouraged that trials exclude patients with current substance or alcohol use disorders, neurological disease or unstable medical illness, and keep non-study medications stable. Additional methodological considerations include neuroimaging assessments, targeting of treatments to illness stage and using a multimodal approach. CONCLUSIONS: This ISBD task force guidance paper provides the first consensus-based recommendations for cognition trials in bipolar disorder. Adherence to these recommendations will likely improve the sensitivity in detecting treatment efficacy in future trials and increase comparability between studies.

No change in neuropsychological dysfunction or emotional processing during treatment of major depression with cognitive-behaviour therapy or schema therapy.

BACKGROUND: Impaired neuropsychological functioning is a feature of major depression. Previous studies have suggested that at least some aspects of neuropsychological functioning improve with successful treatment of major depression. The extent to which medications may affect the degree of normalization of these functions is unclear. The aim of the current study was to examine the course of neuropsychological functioning during treatment of major depression with cognitive-behaviour therapy (CBT) or schema therapy (ST). METHOD: A total of 69 out-patients with a primary diagnosis of major depression and 58 healthy controls completed mood ratings, neuropsychological measures, and measures of emotional processing at baseline and after 16 weeks. Participants were randomized after baseline assessment to a year-long course of CBT or ST. Patients reassessed at 16 weeks were medication-free throughout the study. RESULTS: Significant neuropsychological impairment was evident at baseline in depressed participants compared with healthy controls. After 16 weeks of psychotherapy, mean depression rating scores fell more than 50%. However, no neuropsychological measures showed convincing evidence of significant improvement and emotional processing did not change. CONCLUSIONS: Persisting impairment in neuropsychological functioning after the first 16 weeks of CBT or ST suggests a need to modify psychological treatments to include components targeting cognitive functioning.

Cutaneous ulcers in a returning traveller: a rare case of imported diphtheria in the UK.

We describe a case of cutaneous diphtheria in the UK, presenting as lower leg ulcers in a returning traveller, and discuss the epidemiology, significance and public health implications of this disease and the therapeutic options available. A 65-year-old woman presented with a 6-week history of multiple ulcers appearing on her legs following a holiday in Kenya. Culture of biopsy tissue grew Corynebacterium diphtheriae. A cascade of therapeutic and public health interventions followed, many of which were terminated once the isolate was confirmed as nontoxigenic. Cutaneous diphtheria is a rare, notifiable disease in the UK, but is common in tropical countries, and is most often seen in the West as a traveller's disease. Corynebacteria are common skin commensals, and without appropriate clinical details, laboratories may not recognize C. diphtheriae/Corynebacterium ulcerans. This is likely to have led to under-reporting and under-recognition of the condition.

Does Bowel Preparation for Colonoscopy Affect Cognitive Function?

Colonoscopy is a common procedure used in the diagnosis and treatment of a range of bowel disorders. Prior preparation involving potent laxatives is a necessary stage to ensure adequate visualization of the bowel wall. It is known that the sedatives given to most patients during the colonoscopy cause a temporary impairment in cognitive function; however, the potential for bowel preparation to affect cognitive function has not previously been investigated. To assess the effect of bowel preparation for colonoscopy on cognitive function. This was a prospective, nonrandomized controlled study of cognitive function in patients who had bowel preparation for colonoscopy compared with those having gastroscopy and therefore no bowel preparation. Cognitive function was assessed using the Modified Mini Mental State Examination (MMMSE) and selected tests from the Cambridge Neuropsychological Test Automated Battery. Individual test scores and changes between initial and subsequent tests were compared between the groups. Age, gender, and weight were also compared. Forty-three colonoscopy and 25 gastroscopy patients were recruited. The 2 groups were similar for age and gender; however, patients having gastroscopy were heavier. MMMSE scores for colonoscopy and gastroscopy groups, respectively, were 28.6 and 29.5 (P = 0.24) at baseline, 28.7 and 29.8 (P = 0.32) at test 2, 28.1 and 28.5 (P = 0.76) at test 3. Motor screening scores for colonoscopy and gastroscopy groups, respectively, were 349.3 and 354.1 (P = 0.97) at baseline, 307.5 and 199.7 (P = 0.06) at test 2, 212.0 and 183.2 (P = 0.33) at test 3. Spatial working memory scores for colonoscopy and gastroscopy groups, respectively, were 14.4 and 6.7 (P = 0.29) at baseline, 9.7 and 4.3 (P = 0.27) at test 2, 10 and 4.5 (P = 0.33) at test 3. Digit Symbol Substitution Test scores for colonoscopy and gastroscopy groups, respectively, were 36.3 and 37.8 (P = 0.84) at baseline, 36.4 and 40.0 (P = 0.59) at test 2, 38.6 and 40.8 (P = 0.76) at test 3.This study did not find evidence of cognitive impairment resulting from administration of bowel preparation before colonoscopy.

Neurocognitive intra-individual variability in mood disorders: effects on attentional response time distributions.

BACKGROUND: Attentional impairment is a core cognitive feature of major depressive disorder (MDD) and bipolar disorder (BD). However, little is known of the characteristics of response time (RT) distributions from attentional tasks. This is crucial to furthering our understanding of the profile and extent of cognitive intra-individual variability (IIV) in mood disorders. METHOD: A computerized sustained attention task was administered to 138 healthy controls and 158 patients with a mood disorder: 86 euthymic BD, 33 depressed BD and 39 medication-free MDD patients. Measures of IIV, including individual standard deviation (iSD) and coefficient of variation (CoV), were derived for each participant. Ex-Gaussian (and Vincentile) analyses were used to characterize the RT distributions into three components: mu and sigma (mean and standard deviation of the Gaussian portion of the distribution) and tau (the 'slow tail' of the distribution). RESULTS: Compared with healthy controls, iSD was increased significantly in all patient samples. Due to minimal changes in average RT, CoV was only increased significantly in BD depressed patients. Ex-Gaussian modelling indicated a significant increase in tau in euthymic BD [Cohen's d = 0.39, 95% confidence interval (CI) 0.09-0.69, p = 0.011], and both sigma (d = 0.57, 95% CI 0.07-1.05, p = 0.025) and tau (d = 1.14, 95% CI 0.60-1.64, p < 0.0001) in depressed BD. The mu parameter did not differ from controls. CONCLUSIONS: Increased cognitive variability may be a core feature of mood disorders. This is the first demonstration of differences in attentional RT distribution parameters between MDD and BD, and BD depression and euthymia. These data highlight the utility of applying measures of IIV to characterize neurocognitive variability and the great potential for future application.

Faecal microbiota transplantation for Clostridium difficile infection in the United Kingdom.

Faecal microbiota transplantation (FMT) has been shown to be highly effective in treating recurrent Clostridium difficile infection, but to date there have been no data from the United Kingdom. An electronic survey was developed at Portsmouth Hospitals' National Health Service (NHS) Trust and sent out to UK hospital specialists utilizing the contact databases of the British Infection Association and the Royal College of Gastroenterologists. A total of 162 responses were received, representing nearly one in every seven of the United Kingdom's infection specialists and a response from one in every two UK NHS acute trusts or boards. Ninety-six per cent believe that the evidence base supports the use of FMT, and 94% reported consulting on at least one patient a year in whom they would recommend FMT. However, only 22% reported FMT use in their institution in the last 10 years, and 6% reported performing more than ten FMTs in the last 10 years. Concerns with patient acceptance, donor selection, availability of screened faecal solution, feasibility of procedure and availability of local expertise were reported as inhibiting the use of FMT. More than 90% of respondents would like access to regional guidelines, prescreened faecal solution and expert advice to facilitate implementation, and more than two thirds of respondents would support a regional FMT referral centre. A large gap exists in the United Kingdom between physicians desire to use FMT and the ability and facilities to provide it as a therapy at the bedside.

The oral management of patients who have received radiotherapy to the head and neck region.

Several thousand patients are diagnosed annually with head and neck cancer (HANC) in the United Kingdom. This represents a significant proportion of all cancers that are diagnosed and a common treatment modality for this is radiotherapy to the head and neck region. Radiotherapy can be highly successful in managing HANC but also has several side-effects in the oral cavity and associated structures. These sequelae present considerable short and long-term problems for dental professionals involved in the care of HANC suffers.

The MoCA: well-suited screen for cognitive impairment in Parkinson disease.

OBJECTIVE: To establish the diagnostic accuracy of the Montreal Cognitive Assessment (MoCA) when screening externally validated cognition in Parkinson disease (PD), by comparison with a PD-focused test (Scales for Outcomes in Parkinson disease-Cognition [SCOPA-COG]) and the standardized Mini-Mental State Examination (S-MMSE) as benchmarks. METHODS: A convenience sample of 114 patients with idiopathic PD and 47 healthy controls was examined in a movement disorders center. The 21 patients with dementia (PD-D) were diagnosed using Movement Disorders Society criteria, externally validated by detailed independent functional and neuropsychological tests. The 21 patients with mild cognitive impairment (PD-MCI) scored 1.5 SD or more below normative data in at least 2 measures in 1 of 4 cognitive domains. Other patients had normal cognition (PD-N). RESULTS: Primary outcomes using receiver operating characteristic (ROC) curve analyses showed that all 3 mental status tests produced excellent discrimination of PD-D from patients without dementia (area under the curve [AUC], 87%-91%) and PD-MCI from PD-N patients (AUC, 78%-90%), but the MoCA was generally better suited across both assessments. The optimal MoCA screening cutoffs were <21/30 for PD-D (sensitivity 81%; specificity 95%; negative predictive value [NPV] 92%) and <26/30 for PD-MCI (sensitivity 90%; specificity 75%; NPV 95%). Further support that the MoCA is at least equivalent to the SCOPA-COG, and superior to the S-MMSE, came from the simultaneous classification of the 3 PD patient groups (volumes under a 3-dimensional ROC surface, chance = 17%: MoCA 79%, confidence interval [CI] 70%-89%; SCOPA-COG 74%, CI 62%-86%; MMSE-Sevens item 56%, CI 44%-68%; MMSE-World item 62%, CI 50%-73%). CONCLUSIONS: The MoCA is a suitably accurate, brief test when screening all levels of cognition in PD.

Effects of acute tryptophan depletion on neuropsychological and motor function in Parkinson's disease.

Interactions between the 5-HT system and the dopaminergic system and cholinergic system may be important in determining cognitive function and motor function in Parkinson's disease (PD). Previous studies have shown effects of reducing serotonin function, by acute tryptophan depletion (ATD), on neuropsychological function. In particular, an adverse effect on verbal memory has been demonstrated. This study compared with the effects of ATD on cognitive and motor function in PD and healthy control subjects. The effects of ATD were investigated in a double-blind, placebo-controlled, counterbalanced, cross-over, randomised design in 20 patients with PD and 35 healthy controls matched for age, gender and premorbid IQ. There was a differential group effect of ATD on global cognitive function whereby the mean score on the modified mini mental state examination during ATD was lower than placebo in PD but higher in controls. There was a similar pattern of effects on verbal recognition. In a visual recognition task, ATD improved performance in the PD but not in the control group. In terms of psychomotor speed, there was also a group-specific effect with reduced latency of response during ATD in the PD group but increased latency in the control group. ATD has subtle neuropsychological effects, which differ significantly between PD and healthy control subjects. This suggests that the dopaminergic and cholinergic deficit of PD significantly modulates the effects of serotonin depletion, resulting in positive effects in some domains. Further investigation on the effects of specific serotonin antagonists may be merited in PD.

The effects of acute tryptophan depletion on mood in patients with Parkinson's disease and the healthy elderly.

Reduced serotonergic tone may be a compensatory adaptation to reduced dopaminergic activity in Parkinson's disease (PD) and may result in vulnerability to depression. To test this hypothesis this study examined the effects of serotonin depletion, using the technique of acute tryptophan depletion (ATD) in PD. The effects of ATD were investigated in a double-blind, placebo-controlled, counterbalanced, cross-over, randomised design, in 20 patients with PD and 32 healthy controls matched for age, gender and pre-morbid IQ. The primary outcome was change in scores on a modified Montgomery-Asberg Depression Rating Scale (MADRS). ATD resulted in a small but statistically significant increase in score on the MADRS, but there was no effect specific to the PD group. The results do not support the hypothesis that low serotonergic tone results in vulnerability to depression in PD and are in accord with an earlier study using the same technique in PD.

A comparison of neurocognitive impairment in younger and older adults with major depression.

BACKGROUND: Neurocognitive impairment is a well-recognized feature of depression that has been reported in younger and older adults. Similar deficits occur with ageing and it is unclear whether the greater deficits in late-life depression are an ageing-related phenomenon or due to a difference in the nature of late-life depression itself. We hypothesized that ageing alone would not fully explain the increased neurocognitive impairment in late-life depression but that differences in the illness explain the greater decrements in memory and executive function. METHOD: Comparison of the neuropsychological performance of younger (<60 years) and older (60 years) adults with major depressive disorder (MDD) and healthy comparison subjects. Scores for each depression group were normalized against their respective age-matched control group and the primary comparisons were on four neurocognitive domains: (i) attention and executive function; (ii) verbal learning and memory; (iii) visuospatial learning and memory; and (iv) motor speed. RESULTS: We recruited 75 subjects with MDD [<60 years (n=44), 60 years (n=31)] and 82 psychiatrically healthy comparison subjects [<60 years (n=42), 60 years (n=40)]. The late-life depression group had greater impairment in verbal learning and memory and motor speed but not in executive function. The two depressed groups did not differ in depression severity, global cognitive function, intelligence or education. CONCLUSIONS: Late-life depression is associated with more severe impairment in verbal learning and memory and motor speed than depression in earlier adult life and this is not due to ageing alone.

Upstream genetic variant near INSIG2, influences response to carnitine supplementation in bipolar patients with valproate-induced weight gain.

BACKGROUND: The protein product of INSIG2 is involved in cholesterol and triglyceride metabolism and homeostasis. Variation at rs7566605 near the gene INSIG2 has been associated with increased BMI. OBJECTIVE: To evaluate the effect of rs7566605/INSIG2 genotype on the ability of valproate-treated bipolar patients (BMI ≥ 25 kg/m2) to lose weight using carnitine supplementation during a 26-week lifestyle intervention study. DESIGN: Forty-eight bipolar patients with clinically significant treatment emergent weight gain were genotyped at the rs7566605 SNP. Participants were randomised to l-carnitine (15 mg/kg/day) or placebo for 26 weeks in conjunction with a moderately energy restricted, low-fat diet. Weight and body fat percent were measured fortnightly. Waist circumference measurements and dual-energy X-ray absorptiometry were used to assess changes in body composition. Obesity-related biomarkers were measured at baseline and 26 weeks. RESULTS: There was a significant interaction between rs7566605/INSIG2 genetic status and treatment with carnitine or placebo. Carnitine had no significant effect on body composition measures in G allele homozygous patients who lost between 0.97 and 2.23 kg of fat. However C allele carriers on average gained 2.28 kg when given a placebo. Carnitine supplementation in this group enabled average weight loss of 2.22 kg of fat (p = 0.01). Approximately half of this mass was in the vital truncal compartment (p = 0.002). Bioinformatic analysis detected that the SNP lies in a highly conserved 336 bp sequence which potentially affects INSIG2 gene expression. CONCLUSIONS: C-carriers at rs7566605, possibly regulating the homeostasis gene INSIG2, lost significantly less weight in this lifestyle intervention study. This effect was reversed by carnitine supplementation.

Randomized, multicenter, dose-ranging trial of retigabine for partial-onset seizures.

OBJECTIVE: To evaluate the efficacy and safety of retigabine 600, 900, and 1,200 mg/day administered three times daily as adjunctive therapy in patients with partial-onset seizures. METHODS: A multicenter, randomized, double-blind, placebo-controlled trial was performed. After an 8-week baseline phase, patients were randomized to a 16-week double-blind treatment period (8-week forced titration and 8-week maintenance) followed by either tapering or entry into an open-label extension study. Primary efficacy was the percentage change from baseline in monthly seizure frequency and compared across treatment arms. Secondary efficacy comparisons included the proportion of patients experiencing >/=50% reduction in seizure frequency (responder rate), emergence of new seizure types, and physician assessment of global clinical improvement. Safety/tolerability assessments included adverse events (AEs), physical and neurologic examinations, and clinical laboratory evaluations. Efficacy analyses were performed on the intent-to-treat population. RESULTS: Of the 399 randomized patients, 279 (69.9%) completed the double-blind treatment period. The median percent change in monthly total partial seizure frequency from baseline was -23% for 600 mg/day, -29% for 900 mg/day, and -35% for 1,200 mg/day vs -13% for placebo (p < 0.001 for overall difference across all treatment arms). Responder rates for retigabine were 23% for 600 mg/day, 32% for 900 mg/day (p = 0.021), and 33% for 1,200 mg/day (p = 0.016), vs 16% for placebo. The most common treatment-emergent AEs were somnolence, dizziness, confusion, speech disorder, vertigo, tremor, amnesia, abnormal thinking, abnormal gait, paresthesia, and diplopia. CONCLUSION: Adjunctive therapy with retigabine is well tolerated and reduces the frequency of partial-onset seizures in a dose-dependent manner.

Effects of acute tryptophan depletion on cognitive function in Alzheimer's disease and in the healthy elderly.

BACKGROUND: The cholinergic system is profoundly impaired in senile dementia of Alzheimer type (SDAT) and replacement therapy produces only modest clinical benefits. The serotonergic system is also impaired and may contribute both to cognitive and non-cognitive symptoms in SDAT. To investigate this further we assessed the effects of lowering brain serotonin using the technique of acute tryptophan depletion on cognitive function in patients with SDAT and in age matched control subjects. METHOD: Sixteen patients with probable SDAT and 17 healthy elderly subjects received two amino acid drinks in a within subject, double-blind, placebo-controlled, counterbalanced, crossover design. One of the drinks was nutritionally balanced and contained tryptophan (placebo), the other was identical but contained no tryptophan. A battery of detailed neuropsychological tests was performed between 4 and 6 h after the drink. Mood rating scales and other ratings of behavioural and emotional symptoms were also performed on both occasions. RESULTS: Acute tryptophan depletion resulted in impairment on tasks of working memory in both groups. There was no group specific effect. Female SDAT subjects performed better on a task of pattern recognition during acute tryptophan depletion compared with placebo. There were no changes in behavioural symptoms during acute tryptophan depletion in either group. CONCLUSION: Compromised serotonergic function may be an important contributor to cognitive decline in SDAT and in ageing. Strategies targeting specific 5HT receptors may be helpful in SDAT.