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Roger M PinderEditor-in-Chief, Neuropsychiatric Disease and Treatment, York, UKThere were three papers in Neuropsychiatric Disease and Treatment that attracted the most attention in the last year, all recording more than 10,000 hits since publication.Varying widely in subject matter, by far the most popular of the trio, with almost 30,000 hits, was a publication on a new physical method for treating psychiatric disorders, in this case bipolar disorder,1 while publications on alcohol consumption and cognitive risk2 and dietary treatment of attention deficit hyperactivity disorder (ADHD)3 were in second and third place, respectively.

Roger M PinderEditor-In-Chief, Neuropsychiatric Disease and TreatmentSchizophrenia remains one of the most debilitating and intractable illnesses in psychiatry. Despite the availability of effective drug treatment since the beginning of the psychopharmacological era in the early 1960s with the introduction of the first antipsychotic chlorpromazine, the subsequent development of second generation or atypical antipsychotics, and the effectiveness of certain types of psychotherapy, many patients are unresponsive and remain unwell for several years or relapse after apparent response. Only clozapine has proven efficacy in treatment-resistant schizophrenia, but many patients still do not respond. Polypharmacy is common, with many physicians choosing to augment rather than switch medications. Schizophrenia may be in part a neurodevelopmental disorder and involve changes in brain structure, and credence has been given to the idea that the prodromal phase, before overt symptoms have appeared, should already have been addressed with aggressive treatment. Various aspects of schizophrenia and its treatment, as well as the associated use of antipsychotic drugs in the treatment of the manic phase of bipolar disorder and Tourette syndrome, have been covered in the pages of Neuropsychiatric Disease and Treatment during the first half of 2012.

1 Following a seven day drug-free period, 80 depressed outpatients were randomly allocated to receive mianserin 60 mg nocte or nomifensine 150 mg daily. Blindness was maintained by the use of a double-dummy technique. 2 All measures of efficacy showed a trend in favour of mianserin throughout the four week trial, including the Hamilton Depression Scale (HDS), the Beck Self-rating Depression Inventory (BDI), the Clinical Global Impression (CGI) and the Efficacy Index. 3 Significant advantages in efficacy for mianserin were observed at day 14 on the HDS and at days 7, 14 and 21 on the CGI. 4 Substantially more patients experienced marked or moderate improvement during treatment with mianserin than with nomifensine. Side-effects were low with both drugs. 5 On the basis of the present trial and a previous comparison, mianserin appears to be a more effective antidepressant than nomifensine. [ABSTRACT FROM AUTHOR]

1 S(+)-mianserin is the more potent enantiomer of mianserin in pharmacological tests indicative for antidepressant activity. Pharmacological tests indicative for sedation suggest that sedative effects are similar for mianserin and its enantiomers. 2 Of the three compounds, mianserin had the optimal therapeutic ratio of antidepressant-like activity versus sedative properties when assessed by computerised EEG in healthy volunteers participating in a double- blind placebo-controlled single dose trial. 3 Of the known metabolites, desmethylmianserin and 8-hydroxymianserin substantially retain pharmacological properties indicative for antidepressant activity but are less active than mianserin in tests indicative for sedation. Mianserin-N-oxide is inactive or only weakly active in most pharmacological tests. 4 Desmethylmianserin occurs in human plasma after both single and multiple dosage to an extent of about one-third that of mianserin. 5 Mianserin has optimal efficacy as the racemate. Desmethylmianserin and 8-hydroxymianserin are pharmacologically active metabolites and may contribute to the overall antidepressant effects of mianserin. [ABSTRACT FROM AUTHOR]

Waiting lists for elective surgery are increasing in the United Kingdom. We report a single-centre experience of disease progression of Dupuytren's disease while on the waiting list for surgery and its effect on the type of operative treatment required., Competing Interests: Declaration of conflicting interestsThe author(s) declare no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: Nonmelanoma skin cancers (NMSC) have an incidence of 152,000 cases per year in the United Kingdom (UK), which continues to rise. Incomplete excision rates for NMSC are estimated to be around 10 percent and result in patients having a higher risk of recurrence or having to undergo further treatment., Objective: The objective of our study was to determine whether the use of dermoscopy as an adjunct to clinical examination could improve the rates of incomplete excision in NMSC lesions., Methods: Electronic literature search of MEDLINE, EMBASE, and Cochrane Central databases plus manual reference checks of articles on dermoscopy use in surgery between inception and November 2020. Two levels of screening were used on 452 studies. A random effects model was used in the meta-analysis, with the DerSimonian-Laird method used to pool data., Results: A total of six fully extracted studies were included with a total of 592 patients; with five of these studies reported on basal cell carcinomas and one reported on squamous cell carcinomas. The odds ratio of incomplete excision when guided by dermoscopy was 0.29 (95%CI 0.25; 0.34). Heterogeneity was assessed with the I 2 statistic and was found to be 0 percent., Limitations: The number of studies included was small, with three of the studies from the same authors. Studies included are nonrandomized and as such hold a significant risk of bias., Conclusion: Incomplete excision rates were reduced when using dermoscopy to mark surgical excision margins in comparison to naked eye evaluation alone., Competing Interests: DISCLOSURES: The authors report no conflicts of interest relevant to the content of this article., (Copyright © 2022. Matrix Medical Communications. All rights reserved.)

Many factors have been proposed to contribute to the risk of recurrent tenosynovial giant cell tumours (TSGCT); however, we remain unable to predict those at risk, which formed the rationale for this multicentre retrospective case-control study of 28 patients with recurrence. We included cases of recurrence in a 1:1 ratio matched for age and sex with controls over 10 years. Using Cox regression, we present hazard ratios (HRs) for recurrence with 95% confidence intervals (CIs). Out of 285 cases, 28 individuals developed recurrence after a median of 2.4 years. Recurrent TSGCT had a higher mitotic count/mm 2 in the primary tumour (median increase of 3 [IQR 1, 7]). Mitotic count in the primary tumour was associated with the risk of recurrence (adjusted HR 1.1 [95% CI 1.1, 1.2]) meaning that for every additional mitosis, the risk of recurrence increased by 10% per annum. We recommend a prospective cohort study to validate our findings., (Copyright © 2019 British Association of Plastic, Reconstructive and Aesthetic Surgeons. Published by Elsevier Ltd. All rights reserved.)

Background: Nail-bed injuries are the most common hand injury in children. Surgical dogma is to replace the nail plate after repairing the nail bed. Recent evidence suggests this might increase infection rates and returns to clinic. The aim of this feasibility trial was to inform the design and conduct of a definitive trial comparing replacing or discarding the nail plate after nail-bed repair., Methods: This study recruited participants from four hand units in the UK between April and July 2015. Participants were children under the age of 16 years with a nail-bed injury requiring surgery. They were randomized to either having the nail plate replaced or discarded after nail-bed repair. The follow-up method was also allocated randomly (postal versus clinic). Information was collected on complications at 2 weeks and 30 days, and on nail-plate appearance at 4 months using the Zook classification. Two possible approaches to follow-up were also piloted and compared., Results: During the recruitment phase, there were 156 potentially eligible children. Sixty were randomized in just over 3 months using remote web-based allocation. By 2 weeks, there were two infections, both in children with replaced nail plates. The nail-replaced group also experienced more complications. There was no evidence of a difference in return rates between postal and clinic follow-up., Conclusion: Recruitment was rapid and nail-bed repair appeared to have low complication and infection rates in this pilot trial. The findings have led to revision of the definitive trial protocol, including the mode and timing of follow-up, and modification of the Zook classification., (© 2017 The Authors. BJS published by John Wiley & Sons Ltd on behalf of BJS Society Ltd.)

Purpose: To determine by systematic review the optimal treatment of scaphoid nonunion., Methods: We conducted a systematic review of the literature with a meta-analysis of proportions to investigate the comparative effectiveness of different surgical techniques., Results: A total of 48 publications (1,602 patients) met the eligibility criteria. Vascularized and nonvascularized bone grafts had an estimated union incidence of 92% and 88%, respectively. Distal radius and iliac crest bone grafts had similar union rates (89% and 87%, respectively) but harvesting of iliac crest bone grafts had more complications. Both screw and K-wire fixation had a higher incidence of union (88% and 91%, respectively) than no fixation (79%). No approach was statistically different. Patients fixed with screws were mobilized earlier than those with K-wire fixation., Conclusions: Current evidence does not demonstrate a significantly superior method for the treatment of scaphoid nonunion. A multicenter randomized trial would be ideal but the large numbers that would be required may make this unrealistic. We recommend the continued reporting of series with specific assessments and outcome measures to optimize future comparisons in an attempt to determine the best management of scaphoid nonunion., Clinical Relevance: The use of bone grafts and the methods of their fixation for scaphoid nonunion are debated issues in hand and wrist surgery, with multiple methods employed. There is no current consensus on optimal treatment. A meta-analysis of proportions of available data from recent studies was deemed the most appropriate way to assimilate the available evidence with the view to inform surgeons of the optimal treatment according to the evidence base., (Copyright © 2015 American Society for Surgery of the Hand. Published by Elsevier Inc. All rights reserved.)

We describe the largest reported epineural ganglion of the ulnar nerve arising in the cubital tunnel. A 54-year-old male, driver presented with progressive symptoms of left sided cubital tunnel syndrome. Surgery demonstrated a 11 × 3 cm ganglion which was successfully removed. Post-operatively the patient demonstrated partial recovery with no recurrence of the ganglion., (Crown Copyright © 2012. Published by Elsevier Ltd. All rights reserved.)

Background: Free tissue transfers must survive in order to achieve their surgical goals. There is little consensus about managing the 'failing' free flap, and practice is often guided by anecdote., Material and Methods: We have prospectively collected data about all free flaps performed within our department between 1985 and 2008 (2569 flaps). We identified 327 flaps which were re-explored a total of 369 times. We analysed these flaps with regard to indication for re-exploration, operative findings and outcome., Results: Thirteen percent (327) of free flaps were re-explored. Of these, 291 (83%) had a successful outcome. Successful re-explorations took place at a mean 19h post-op and unsuccessful re-explorations at a mean 56h post-op. Clinical diagnosis prior to re-exploration was confirmed operatively in 91% of cases., Conclusion: We have considered the factors that allowed us to achieve the salvage rates described over a prolonged period, and identified two key areas. Firstly, we favour a model for free flap monitoring with clinical judgement at its core. Secondly, we feel the facility to recover patients post-operatively in a specialised, warmed environment, and return them to theatre quickly should the need arise, is essential. These two simple, yet institutionally determined factors are vital for maintaining excellent success rates., (Copyright 2009 British Association of Plastic, Reconstructive and Aesthetic Surgeons. Published by Elsevier Ltd. All rights reserved.)

Experience shows that young children are favourable candidates for microsurgical reconstruction, having few of the established risk factors for flap failure. In children's reconstructive surgery free tissue transfer (FTT) permits reconstruction whilst retaining growth potential, and reduces the overall number and duration of care episodes, and their related distress to the child and family. We present one centre's experience of free tissue transfer in children less than 2 years of age, over a 15-year period, demonstrating that free tissue transfer can be successfully employed in children under 2 years old. Salient aspects of patient selection, pre-operative counselling, and per-operative management are presented. Data from all free flaps in children under 2 years of age at the time of surgery were collected prospectively. Forty-seven flaps were performed as 37 separate procedures, in 32 children under 2 years of age. In ten patients, double transfers were performed in single procedures. Free tissue transfers were performed for reconstruction of congenital defects, following trauma and meningococcal septicaemia. All but one flap survived. In our series operative and ischaemia times, re-exploration, complication and flap failure rates were not higher than in comparable adult or older paediatric series from this unit, suggesting that there is no microvascular, or other, factor inherent to the infant that should preclude the use of free tissue transfer. Individual microsurgeons with appropriate facilities should not be inhibited from performing free tissue transfers which are humane and cost effective when compared with alternatives for very young children., (Copyright 2009 British Association of Plastic, Reconstructive and Aesthetic Surgeons. Published by Elsevier Ltd. All rights reserved.)

Noradrenaline has long played a key role in the way the etiology of depression is conceptualized and in the mechanism of action of many current antidepressants. Tricyclic antidepressants (TCAs), monoamine oxidase inhibitors (MAOIs), serotonin-noradrenaline reuptake inhibitors (SNRIs), selective noradrenaline reuptake inhibitors (NRIs), the noradrenergic and specific serotonergic antidepressant (NaSSA) mirtazapine, and many atypicals, like mianserin and bupropion, influence, at least in part, central noradrenergic function. Enhancement of noradrenergic function may be particularly helpful in patients with melancholia. However, while noradrenaline will continue to be a target for research into the etiology and treatment of depression, it is unlikely that antidepressants acting solely on noradrenaline will be pursued.

The relative risks of coronary heart disease (CHD) and overall mortality are reduced by moderate consumption of alcoholic beverages, particularly wine, which has major implications for public health. It appears likely that this beneficial effect of alcohol will soon be extended to some mental disorders. Although data on psychosis and mood and anxiety disorders are currently lacking, it appears that the relative risks of developing ischaemic stroke and Alzheimer's or vascular dementia are also lowered by moderate alcohol consumption. Such findings are still tentative because of the inherent methodological problems involved in population-based epidemiological studies, and it is unclear whether the benefit can be ascribed to alcohol itself or to other constituents specific to wine such as polyphenols. Plausible biological mechanisms have been advanced for the protective effect of alcohol and wine against CHD, many of which will also play roles in their protective actions against cerebrovascular disease and dementia. The specific antioxidant properties of wine polyphenols may be particularly important in preventing Alzheimer's disease. Because of the substantially unpredictable risk of progression to problem drinking and alcohol abuse, the most sensible advice to the general public is that heavy drinkers should drink less or not at all, that abstainers should not be indiscriminately encouraged to begin drinking for health reasons, and that light to moderate drinkers need not change their drinking habits for health reasons, except in exceptional circumstances.

Concern about disappointing results from recent multi-center trials of new antidepressants prompted several ACNP workshops on "improving the technology of clinical trials." The workshops focused on technical problems, such as patient screening, reliability of clinical ratings, and the role of the placebo control. They aimed to determine how to more effectively apply the current clinical trials model for evaluating antidepressant drugs. The problems confronting the field of clinical trials, however, extend beyond technology. They also included conceptual issues concerning changes in the understanding of depressive disorders and of the multiple actions of antidepressant drugs. Such problems have been further complicated by the rapidly changing field of drug development itself, which is continually refining the targeting of new antidepressant agents. Drugs are increasingly being developed to try to change specific behavioral facets more rapidly and may be less likely, therefore, to act initially on "whole" disorders. To address such issues, a symposium was held in Rhodes in 2000 that focused on such conceptual changes with the goal of developing recommendations to revise the clinical evaluation model. Its purpose was to integrate new knowledge on depression and the mechanisms of action of antidepressant drugs toward developing more efficient methods of drug development. Since the evaluation process will eventually require changes in governmental policy, senior staff from the National Institute of Mental Health (NIMH) , Unites States and Food and Drug Administration (FDA), Unites States participated as well as members of academia, industry and clinical practice. Recommendations for altering clinical trial methodology were made in four areas: patient selection, methodology of evaluation, measuring onset of action, and FDA and NIMH perspectives on current practice. This article discusses these four areas and presents the consensus of the panel participants.

Background: The delay in the therapeutic effect of antidepressants is a considerable impediment to their successful clinical use, and attention has recently been focused on antidepressant drugs that may have a faster onset of action., Data Synthesis: Several methodologies exist for evaluating differences in time to response between antidepressants including the identification of the timepoint at which statistically or clinically significant differences between treatment groups emerge, pattern analysis, and survival analytical approaches. All have conceptual as well as practical advantages and disadvantages., Conclusion: The survival analytical approach is generally considered to be the most rigorous and sensitive in detecting differences in the speed of response of antidepressants, but the other methodologies provide useful information.

Modern antidepressants lack many of the side-effects and much of the toxicity of the first generation tricyclics and monoamine oxidase inhibitors. Knowledge of the receptor interactions that are responsible for poor tolerability and potential lethality in overdosage has enabled the design of agents that have low or no affinity for such receptors. Nevertheless, even the second generation selective serotonin reuptake inhibitors (SSRIs), the serotonin noradrenaline reuptake inhibitors (SNRIs) and the noradrenaline and serotonin specific antidepressants (NaSSAs) have not substantially improved upon the efficacy of the older agents. They still take some time to be effective, although venlafaxine and mirtazapine may be faster in onset than SSRIs, and they leave a substantial minority of patients unaffected.Innovative new antidepressants may be based upon a variety of mechanisms, including receptors, G-proteins, second messengers, gene transcription factors and the hypothalamic - pituitary - adrenal axis, but their availability may be hindered by recent advances in pharmaceutical research technology. Thus, the creation of large chemical libraries containing millions of new entities has increased structural diversity, but pharmacological evaluation has narrowed down to simple assays in high-throughput screening systems. Such assays depend to a major extent on how well they reflect the biological aetiology of the disease under study. While new antidepressant moieties will undoubtedly emerge, optimal use of the new research tools will necessitate a more sophisticated level of knowledge about the true causes of depression. Copyright 2001 John Wiley & Sons, Ltd.

Activation of 5-HT1A receptors has been shown to attenuate catalepsy induced by typical antipsychotic compounds. Since mirtazapine (Remeron; Org 3770) has indirect 5-HT1A receptor stimulating properties as well as antagonist properties at alpha2-adrenoceptors and 5-HT2 receptors, it was of interest to investigate how the compound could modulate the effect of haloperidol on apomorphine-induced climbing behaviour in mice and haloperidol-induced catalepsy in rats. In the apomorphine climbing test, it was found that mirtazapine (2.2-22 mg/kg) did not change the climbing behaviour of mice induced by 1 mg/kg of apomorphine. However, when given as a co-treatment with haloperidol, mirtazapine (1 and 10 mg/kg) dose-dependently augmented the inhibiting effect of haloperidol on this climbing behaviour. Co-treatment with the 5-HT1A receptor agonist 8-OH-DPAT (0.1 mg/kg) also augmented the effect of haloperidol. Catalepsy induced by haloperidol (4.6 mg/kg) was attenuated by mirtazapine (2.2-22 mg/kg). The strongest effect was seen at 90 min after haloperidol treatment. The results obtained in these experiments suggest that co-treatment with mirtazapine may enhance the antipsychotic effect of haloperidol and reduce its extrapyramidal side effects, thereby widening its therapeutic window.