Safety and tolerance of combination of monoamine oxidase inhibitors and direct dopamine agonists in adults and older adults with highly resistant depression.

INTRODUCTION: Dopamine (DA) is likely to be involved in some depressive dimensions, such as anhedonia and amotivation, which account for a part of treatment-resistant forms. Monoamine oxidase inhibitors (MAOI) and direct D2 and D3 receptors agonists (D2/3r-dAG) are known to help, but we lack safety data about their combined usage. We report on safety and tolerance of the MAOI+D2r-dAG combination in a clinical series. METHOD: All patients referred to our recourse center for depression between 2013 and 2021 were screened to select those who did receive the combo. Data were extracted from clinical files. RESULTS: Sixteen patients of 60±17 years of age (8 women, 7 with age>65years, all suffered from treatment resistant depression, 7 with bipolar disorder) received the combo. There were no life-threatening adverse effects (AE). However, AE were reported by 14 patients (88%) most of which were mild and consisted of insomnia, nausea, nervousness, confusion, impulse control disorder and/or "sleep attacks". One patient presented a serious AE requiring a short hospitalization for confusion. Intolerance led to failure to introduce treatment in two patients (13%). The retrospective non-interventional design, the variety of molecules, and the modest sample size limited the scope of these results. CONCLUSION: There was no life-threatening safety issue in combining MAOI and D2/3r-dAG, especially regarding cardiovascular side effects. The systematic screening of AE might account for their frequency, but these precluded the treatment in only two patients. Comparative studies are needed to assess the efficacy of this new combination.

Compassion-focused therapy (CFT) for the reduction of the self-stigma of mental disorders: the COMpassion for Psychiatric disorders, Autism and Self-Stigma (COMPASS) study protocol for a randomized controlled study.

BACKGROUND: People with mental disorders face frequent stigmatizing attitudes and behaviors from others. Importantly, they can internalize such negative attitudes and thus self-stigmatize. Self-stigma is involved in diminished coping skills leading to social avoidance and difficulties in adhering to care. Reducing self-stigma and its emotional corollary, shame, is thus crucial to attenuate the negative outcomes associated with mental illness. Compassion-focused therapy (CFT) is a third-wave cognitive behavioral therapy that targets shame reduction and hostile self-to-self relationship and allows for symptom improvement while increasing self-compassion. Although shame is a prominent part of the concept of self-stigma, the efficacy of CFT has never been evaluated in individuals with high levels of self-stigma. The purpose of this study is to evaluate the efficacy and acceptability of a group-based CFT program on self-stigma, compared to a psychoeducation program for self-stigma (Ending Self-Stigma) and to treatment as usual (TAU). We hypothesize that diminished shame and emotional dysregulation and increased self-compassion will mediate the relationship between self-stigma improvements post-therapy in the experimental group. METHODS: This seven-center trial will involve 336 participants diagnosed with a severe mental illness and/or autism spectrum disorder and reporting high levels of self-stigma. Participants will be randomized into one of three treatment arms: 12 week-treatment of compassion-focused therapy (experimental arm), 12 week-treatment of Psychoeducation (active control arm), and TAU (treatment as usual-passive control arm). The primary outcome is the decrease of self-stigma scores on a self-report scale, i.e., ISMI, at 12 weeks. Secondary endpoints include sustainability of self-stigma scores (ISMI) and self-reported scores regarding target psychological dimensions, e.g., shame and emotional regulation, social functioning, and psychiatric symptoms. Assessments are scheduled at pretreatment, post-treatment (at 12 weeks), and at 6-month follow-up. Acceptability will be evaluated via (i) the Credibility and Expectancy Questionnaire at T0, (ii) the Consumer Satisfaction Questionnaire for Psychotherapeutic Services posttreatment and at 6-month follow-up, (iii) attendance, and (iv) dropout rates. DISCUSSION: This study will evaluate the potential efficacy and acceptability of a group-based CFT program on the decrease of self-stigma and thereby contribute to the continuing development of evidence-based therapeutic interventions for the internalized stigma of mental and neurodevelopmental disorders. TRIAL REGISTRATION: ClinicalTrials.gov NCT05698589. Registered on January 26, 2023.

Psychotropics and COVID-19: An analysis of safety and prophylaxis.

The use of psychotropics during the COVID-19 pandemic has raised two questions, in order of importance: first, what changes should be made to pharmacological treatments prescribed to mental health patients? Secondly, are there any positive side effects of these substances against SARS-CoV-2? Our aim was to analyze usage safety of psychotropics during COVID-19; therefore, herein, we have studied: (i) the risk of symptomatic complications of COVID-19 associated with the use of these drugs, notably central nervous system activity depression, QTc interval enlargement and infectious and thromboembolic complications; (ii) the risk of mistaking the iatrogenic impact of psychotropics with COVID-19 symptoms, causing diagnostic error. Moreover, we provided a summary of the different information available today for these risks, categorized by mental health disorder, for the following: schizophrenia, bipolar disorder, anxiety disorder, ADHD, sleep disorders and suicidal risk. The matter of psychoactive substance use during the pandemic is also analyzed in this paper, and guideline websites and publications for psychotropic treatments in the context of COVID-19 are referenced during the text, so that changes on those guidelines and eventual interaction between psychotropics and COVID-19 treatment medication can be reported and studied. Finally, we also provide a literature review of the latest known antiviral properties of psychotropics against SARS-CoV-2 as complementary information.

Drugs for preventing postoperative nausea and vomiting in adults after general anaesthesia: an abridged Cochrane network meta-analysis.

Postoperative nausea and vomiting is a common adverse effect of anaesthesia. Although dozens of different anti-emetics are available for clinical practice, there is currently no comparative ranking of efficacy and safety of these drugs to inform clinical practice. We performed a systematic review with network meta-analyses to compare, and rank in terms of efficacy and safety, single anti-emetic drugs and their combinations, including 5-hydroxytryptamine3 , dopamine-2 and neurokinin-1 receptor antagonists; corticosteroids; antihistamines; and anticholinergics used to prevent postoperative nausea and vomiting in adults after general anaesthesia. We systematically searched for placebo-controlled and head-to-head randomised controlled trials up to November 2017 (updated in April 2020). We assessed how trustworthy the evidence was using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) and Confidence In Network Meta-Analysis (CINeMA) approaches for vomiting within 24 h postoperatively, serious adverse events, any adverse event and drug class-specific side-effects. We included 585 trials (97,516 participants, 83% women) testing 44 single drugs and 51 drug combinations. The studies' overall risk of bias was assessed as low in only 27% of the studies. In 282 trials, 29 out of 36 drug combinations and 10 out of 28 single drugs lowered the risk of vomiting at least 20% compared with placebo. In the ranking of treatments, combinations of drugs were generally more effective than single drugs. Single neurokinin-1 receptor antagonists were as effective as other drug combinations. Out of the 10 effective single drugs, certainty of evidence was high for aprepitant, with risk ratio (95%CI) 0.26 (0.18-0.38); ramosetron, 0.44 (0.32-0.59); granisetron, 0.45 (0.38-0.54); dexamethasone, 0.51 (0.44-0.57); and ondansetron, 0.55 (0.51-0.60). It was moderate for fosaprepitant, 0.06 (0.02-0.21) and droperidol, 0.61 (0.54-0.69). Granisetron and amisulpride are likely to have little or no increase in any adverse event compared with placebo, while dimenhydrinate and scopolamine may increase the number of patients with any adverse event compared with placebo. So far, there is no convincing evidence that other single drugs effect the incidence of serious, or any, adverse events when compared with placebo. Among drug class specific side-effects, evidence for single drugs is mostly not convincing. There is convincing evidence regarding the prophylactic effect of at least seven single drugs for postoperative vomiting such that future studies investigating these drugs will probably not change the estimated beneficial effect. However, there is still considerable lack of evidence regarding safety aspects that does warrant investigation.

Racing and crowded thoughts in mood disorders: A data-oriented theoretical reappraisal.

OBJECTIVES: Speed of thought is a central phenomenon in mood disorders. We aimed to provide an update on the topic ten years after a first narrative review published on racing and crowded thoughts in mood disorders. This update is based on recent publications, including recent works of our group. METHODS: Narrative review based on publications from the last ten years including publications of our group and a systematic research of references on PubMed. RESULTS: The traditional dichotomist view of racing versus crowded thoughts is not refuted but appears to be more complex, as revealed by validation studies of the Racing and Crowded Thoughts Questionnaire. Moreover, this dualistic view can no longer be conceptualized in a simple bijective concordance with the distinction of hypomania versus mixed depression. We also show that racing/crowded thoughts are strongly associated with mixed depression and not with non-mixed depression, that they tend to be more associated in hypomania to irritability than to the typical symptoms of energy and activity increase and that they are clearly distinguishable from ruminations. Yet, although tightly linked to mood disorders, racing/crowded thoughts appear to be associated to anxiety as well as attention deficit/hyperactivity disorder and insomnia. CONCLUSIONS: Racing and crowded thoughts should be studied in a dimensional perspective as an important facet of mind activity within and beyond the field of mood disorders.

Practical considerations for the evaluation and management of Attention Deficit Hyperactivity Disorder (ADHD) in adults.

Attention deficit with or without hyperactivity disorder (ADHD) is one of the most frequent neuropsychiatric disorders, and affects 2-4% of adults. In contrast with many European countries, the identification and management of adult ADHD remains underdeveloped in France, and a subject of controversy. This review provides a practical update on current knowledge about ADHD in adults for French-speaking professionals who have to detect or manage adult patients with ADHD. ADHD is classified as a neurodevelopmental disorder in the recent update of the international diagnostic classification. While symptoms and impairment due to ADHD are frequently severe during childhood, they often evolve as children grow older, with frequent persistent disabilities in adulthood. In adulthood, the clinical presentation, as in childhood, involves the symptom triad of inattention, hyperactivity and impulsivity. However, differences are noted: hyperactivity is more often internalized, symptoms of inattention may be masked by anxiety symptoms or obsessive-like compensation strategies. ADHD is often diagnosed during childhood, but it is not rare for the diagnosis to be made later. Failure to recognise symptoms resulting in misdiagnosis, or alternatively well-developed compensation factors could be two underlying reasons for the long delay until diagnosis. Other symptoms, such as emotional deregulation or executive function-related symptoms are also usually observed in adults. In addition, in adults, ADHD is often associated with other psychiatric disorders (in 80% of cases); this makes the diagnosis even more difficult. These disorders encompass a broad spectrum, from mood disorders (unipolar or bipolar), to anxiety disorders, and other neurodevelopmental disorders and personality disorders, especially borderline and antisocial personality disorder. Substance-use disorders are very common, either as a consequence of impulsivity and emotional dysregulation or as an attempt at self-treatment. Sleep disorders, especially restless leg syndrome and hypersomnolence, could share common pathophysiological mechanisms with ADHD. ADHD and comorbidity-related symptoms are responsible for serious functional impairment, in various domains, leading to academic, social, vocational, and familial consequences. The impact on other psychiatric disorders as an aggravating factor should also be considered. The considerable disability and the poorer quality of life among adults with ADHD warrant optimal evaluation and management. The diagnostic procedure for ADHD among adults should be systematic. Once the positive diagnosis is made, the evaluation enables characterisation of the levels of severity and impairment at individual level. A full examination should also assess medical conditions associated with ADHD, to provide personalized care. In recent years, a growing number of assessment tools have been translated and validated in French providing a wide range of structured interviews and standardized self-report questionnaires for the evaluation of core and associated ADHD symptoms, comorbidities and functional impairment. The treatment of ADHD in adults is multimodal, and aims to relieve the symptoms, limit the burden of the disease, and manage comorbidities. The most relevant and validated psychological approaches are psycho-education, cognitive-behavioural therapy and "third wave therapies" with a specific focus on emotional regulation. Cognitive remediation and neurofeedback are promising strategies still under evaluation. Medications, especially psychostimulants, are effective for alleviating ADHD symptoms with a large effect size. Their safety and tolerance are satisfactory, although their long-term clinical benefit is still under discussion. In France, methylphenidate is the only stimulant available for the treatment of ADHD. Unfortunately, there is no authorization for its use among adults except in continuation after adolescence. Hence the prescription, which is subject to the regulations on narcotics, is off-label in France. This article aims to provide practical considerations for the management of ADHD and associated disorders in adults, in this particular French context.

[IDEM-depression: Characteristics and evaluation of an open group that combines psychoeducation and cognitive-behavior therapy]. / IDEM-dépression : caractéristiques et évaluation d'un groupe ouvert combinant psycho-éducation et thérapie cognitivo-comportementale.

INTRODUCTION: Depression is a highly prevalent mental illness that is associated with high rates of morbidity and functional impairment. At the psychiatric unit of the University Hospital of Strasbourg, France, we have developed an open group that combines psychoeducation and cognitive-behavior therapy (CBT), the information, discovery, exchange and mobilization for depression group (IDEM-depression). IDEM-depression is composed of 17 thematic, structured, and independent sessions, which address different aspects of depression (i.e., rumination, pharmacological treatments). Because of its flexible format, patients with varying degrees of depression severity (from remission up to severe depressive symptoms) and whose depression might be bipolar or unipolar, are able to participate in the group. Thus, the group is well suited to a large number of patients with major depression. In the present study we aimed at describing the IDEM-depression group and presenting results regarding patients' overall satisfaction, assessed via two self-report questionnaires (the Client Satisfaction Questionnaire, the CSQ-8, and the IDEM ad hoc questionnaire), as well as its effect on mood following each session assessed via a visual analog scale (VAS) ranging from 0 up to 100. METHOD: Sixty-five patients participated in 50 sessions of the IDEM-depression group in two hospitals in Alsace. 61% of the patients had bipolar disorder, and 41% of them were inpatients. Sessions took place on a weekly basis, lasted 2hours and were proposed by a CBT-trained clinical psychologist. Patients were asked to fill-out the VAS at the beginning and at the end of each session. Moreover, they were asked to fill-out the CSQ-8 and the IDEM ad hoc questionnaire when they left the group. Other than one session ("yoga and mindfulness"), all the sessions (16 out of 17) were structured on a Powerpoint© presentation. During the first hour information was given regarding the topic (i.e., rumination), and a shared CBT conceptualization of the topic was formulated by the participants and the psychologist. For most sessions, the first hour was therefore communication and information-based, whereas during the second hour participants were asked to participate in in-session behavioral experiments and/or to evaluate specific aspects of their behavior (thoughts, emotions, activity, mindful behavior) during the last few days. The therapist manual and the slides for each session are available via e-mail to the first author. RESULTS: Regarding the results, self-reported mood on the VAS was compared between the onset (225 VAS) and the end (225 VAS) of each session. Overall, results suggest that self-reported mood is significantly improved following the participation in sessions (t=-5. 87, P<0.001). Moreover, mean results on the CSQ-8 suggest that patients are highly satisfied with the group (M=24.46, SD=6.42). Among them, 82% reported a moderate-high satisfaction with the group. On the IDEM ad hoc questionnaire, patients reported an overall high satisfaction level regarding (i) the content of sessions, (ii) the duration of sessions, (iii) the frequency of sessions, (iv) how much they felt they could express themselves during sessions. In the qualitative comments of this questionnaire, patients reported that the group helped them to gain an understanding of the mechanisms involved in depression; to feel less isolated and guilty; and to learn about specific psychotherapeutic tools (i.e., mindfulness) and to try to implement them. CONCLUSION: Our results suggest that an IDEM-depression group is well suited to a wide-array of clinical pictures associated with depression (varying severity, bipolar or unipolar, inpatients and outpatients). This is probably due to its open-group format which is particularly well-adapted to the dynamic symptomatology associated with major depression, and may stimulate decentering in patients who have different levels of severity of symptoms but participate in the same session. Moreover, its impact on mood improvement, and the high satisfaction level reported by patients, seem to be related to its CBT and psychoeducation-based content on the one hand, which has shown its efficacy in depression. On the other hand, IDEM's structured open-group format might have also contributed to the improvement in mood and the overall good satisfaction reported by patients, through the social support provided by the group, improved feeling of self-efficiency, and its effect on stigmatization. Thus, IDEM-depression group is an efficacious, flexible, low-cost, and easy to implement (in different clinical settings) psychotherapeutic option for major depression.

Effects of epidural volume extension by saline injection on the efficacy and safety of intrathecal local anaesthetics: systematic review with meta-analysis, meta-regression and trial sequential analysis.

Epidural volume extension, a modification of combined spinal-epidural anaesthesia, involves the epidural injection of saline in order to increase the spread of drugs given intrathecally. Results from individual studies have so far been contradictory and we aimed to gather the available evidence for this technique. We performed a systematic literature search for randomised, controlled trials comparing epidural volume extension after spinal injection with a control group without epidural injection in patients undergoing surgery. Conventional meta-analyses, trial sequential analyses and meta-regression were performed, with the Grading of Recommendations on Assessment, Development and Evaluation (GRADE) approach used to express reliability of outcome estimates. We included 15 studies with 1177 participants. Meta-analyses for the primary outcomes, such as maximum sensory height (6 studies, 274 participants, mean difference (MD) (95%CI) -0.59 (-1.24 to 0.07) dermatomes, low-quality evidence) and hypotension (10 studies, 683 participants, risk ratio (95%CI) 0.84 (0.66-1.07), low-quality evidence), did not differ significantly between the two treatment arms, but trial sequential analysis suggested insufficient evidence to be certain of these findings. Meta-regression suggested a volume-dependent effect, with higher volumes causing a higher spread of intrathecal drugs and a higher incidence of hypotension. A sub-group analysis indicated a pronounced effect on motor block recovery time when a lower anaesthetic dose plus epidural volume extension was compared with a higher anaesthetic dose without epidural volume extension, the MD (95%CI) being -66.75 (-76.0 to -57.5) min, with trial sequential analysis suggesting the evidence was sufficient to draw this conclusion. In trials using the same anaesthetic mixture in the epidural volume extension and the control groups, motor block recovery time did not differ between groups, with a MD (95%CI) of -1.06 (-5.48 to 3.36) min, although trial sequential analysis suggested insufficient evidence. In summary, there is not enough evidence to draw definite conclusions on the effect of epidural volume extension. The quality of the current evidence is low for both efficacy (maximum sensory height) and safety (hypotension). However, there may be a significantly shorter motor block recovery time when different anaesthetic mixtures are used in epidural volume extension and control groups; this warrants further investigation.

Patient-controlled analgesia with remifentanil vs. alternative parenteral methods for pain management in labour: a Cochrane systematic review.

We aimed to assess the effectiveness of remifentanil used as intravenous patient-controlled analgesia for the pain of labour. We performed a systematic literature search in December 2015 (updated in December 2016). We included randomised, controlled and cluster-randomised trials of women in labour with planned vaginal delivery receiving patient-controlled remifentanil compared principally with other parenteral and patient-controlled opioids, epidural analgesia and continuous remifentanil infusion or placebo. The primary outcomes were patient satisfaction with pain relief and the occurrence of adverse events for mothers and newborns. We assessed risk of bias for each included study and applied the GRADE approach for the quality of evidence. We included total zero event trials, using a constant continuity correction of 0.01 and a random-effect meta-analysis. Twenty studies were included in the qualitative analysis; within these, 3713 participants were randomised and 3569 analysed. Most of our pre-specified outcomes were not studied in the included trials. However, we found evidence that women using patient-controlled remifentanil were more satisfied with pain relief than women receiving parenteral opioids (four trials, 216 patients, very low quality evidence) with a standardised mean difference ([SMD] 95%CI) of 2.11 (0.72-3.49), but were less satisfied than women receiving epidural analgesia (seven trials, 2135 patients, very low quality evidence), -0.22 (-0.40 to -0.04). Data on adverse events were sparse. However, the relative risk (95%CI) for maternal respiratory depression for patient-controlled remifentanil compared with epidural analgesia (three trials, 687 patients, low-quality evidence) was 0.91 (0.51-1.62). Compared with continuous intravenous infusion of remifentanil (two trials, 135 patients, low-quality evidence) no conclusion could be reached as all study arms showed zero events. The relative risk (95%CI) of Apgar scores less than 7 at 5 min after birth compared with epidural analgesia (five trials, 1322 participants, low-quality evidence) was 1.26 (0.62-2.57).

[Trial sequential analysis : Sample size calculation for reliable meta-analyses]. / Sequenzielle Studienanalyse : "Fallzahlberechnung" für verlässliche Metaanalysen.

BACKGROUND: Meta-analyses have a great impact on medical decision-making. Random errors are, however, often the reason for misinterpretation of interventional effects in meta-analyses. OBJECTIVE: The aim of this article is to introduce authors and readers of meta-analyses to the problem of random errors. The article presents trial sequential analysis (TSA) as a suitable and user-friendly method that adjusts for the risk of random errors in meta-analyses. MATERIAL AND METHODS: The practical application of TSA is illustrated and exemplified using regional anesthesiology procedures versus conventional pain therapy with respect to the prevention of persistent postoperative pain after breast cancer surgery or thoracotomy. The results were compared with those from conventional meta-analytical methods. RESULTS: Conventional meta-analytical methods showed a significant advantage for patients after breast cancer surgery as well as after thoracotomy for regional anesthesia procedures with respect to the reduction of persistent postoperative pain. By means of TSA it could be concluded for thoracotomy that the evidence of this meta-analysis was sufficient. In contrast, the TSA for breast cancer surgery showed that based on the current data set and on the basis of relevant assumptions, it is potentially a false indication of an effect. There is currently no evidence that regional anesthesia leads to a significant reduction of persistent postoperative pain. CONCLUSION: The TSA is a suitable tool to minimize the risk of random errors and for a more reliable assessment of the evidence for the results of a meta-analysis.

Efficacy and safety of intravenous lidocaine for postoperative analgesia and recovery after surgery: a systematic review with trial sequential analysis.

BACKGROUND: Improvement of postoperative pain and other perioperative outcomes remain a significant challenge and a matter of debate among perioperative clinicians. This systematic review aims to evaluate the effects of perioperative i.v. lidocaine infusion on postoperative pain and recovery in patients undergoing various surgical procedures. METHODS: CENTRAL, MEDLINE, EMBASE, and CINAHL databases and ClinicalTrials.gov, and congress proceedings were searched for randomized controlled trials until May 2014, that compared patients who did or did not receive continuous perioperative i.v. lidocaine infusion. RESULTS: Forty-five trials (2802 participants) were included. Meta-analysis suggested that lidocaine reduced postoperative pain (visual analogue scale, 0 to 10 cm) at 1-4 h (MD -0.84, 95% CI -1.10 to -0.59) and at 24 h (MD -0.34, 95% CI -0.57 to -0.11) after surgery, but not at 48 h (MD -0.22, 95% CI -0.47 to 0.03). Subgroup analysis and trial sequential analysis suggested pain reduction for patients undergoing laparoscopic abdominal surgery or open abdominal surgery, but not for patients undergoing other surgeries. There was limited evidence of positive effects of lidocaine on postoperative gastrointestinal recovery, opioid requirements, postoperative nausea and vomiting, and length of hospital stay. There were limited data available on the effect of systemic lidocaine on adverse effects or surgical complications. Quality of evidence was limited as a result of inconsistency (heterogeneity) and indirectness (small studies). CONCLUSIONS: There is limited evidence suggesting that i.v. lidocaine may be a useful adjuvant during general anaesthesia because of its beneficial impact on several outcomes after surgery.

[Mixed depression and DSM-5: A critical review]. / Dépression mixte et DSM-5 : mise au point critique.

BACKGROUND: Mixed depression is a depressive syndrome characterized by the presence, along with the typical depressive symptoms of depression, of those of over activation and excitation. If sometimes this activation is expressed by classical hypomanic symptoms, it is often observed by means of more subtle expression: inner tension, crowded thoughts, dramatic expression suffering, and unproductive agitation. It is important to identify mixed depression because such patients are particularly at risk of suicidal behaviors, substance abuse and therapeutic resistance. Even if therapeutic strategies continue to be discussed, treatments should rely on mood stabilizers and antipsychotics instead of antidepressants as in pure depression. Even though the concept of mixed depression has been described for more than twenty years, first by Koukopoulos and then by other authors, it had been little studied, especially because it did not appear in international psychiatric classifications. The DSM-IV supported a very narrow conception of the mixed states because the criteria required simultaneous full manic and full depressive syndromes, corresponding only to some dysphoric manias. The recently published DSM-5 proposes modifications in mood and bipolar disorder classifications, and especially introduces the possibility to specify depressive and manic episodes with "mixed features". To diagnose depression with mixed features, a full depressive syndrome has to be present together most of time with three hypomanic symptoms, except symptoms that are considered as overlapping (that can be observed either in mania or in depression), i.e. agitation, irritability and distractibility. METHODS: Critical analysis of DSM criteria and review of literature. RESULTS: We first analyzed the clinical relevance of the definition of depression with mixed features which could correspond to mixed depression. The problem is that the hypomanic symptoms allowed by the manual lead to symptom associations that are rather illogical (as euphoria with depression) or improbable (as increased or excessive involvement in activities that have a high potential for painful consequences). Also, some more specific symptoms that can be observed in mixed depression are not mentioned (such as hypersensitivity to light or noise, absence of motor retardation, dramatic expressivity of suffering). The DSM-5, as did DSM-IV, refers to an understanding of mixed depression as a simple addition of depressive and manic symptoms. The classification does not take into account that the symptoms could be rather different from hypomania, as the expression of an overactive thought in a depressed mind. Secondly, we reviewed cohort studies using the DSM-5 criteria (or similar criteria with the exclusion of overlapping symptoms), and as a consequence of the poorly defined symptoms, we found that the diagnosis of mixed depression according to DSM-5 is almost impossible, either in unipolar or in bipolar depression. CONCLUSIONS: We think, with others, that the definition of the mixed depression by the DSM-5 is not clinically relevant and misses important information about the concept. Clinicians can be attentive to the identification of mixed character in depression, even if DSM-5 criteria are not fully met. Unfortunately, the DSM-5 definition could undermine research efforts for a better understanding of epidemiology, phenomenology and therapeutics of mixed depression. We propose and discuss alternative solutions for defining mixed depression, such as the absence of exclusion of "overlapping" symptoms, a more insighted phenomenology, or a dimensional approach.

Use of an oncolytic vaccinia virus for the treatment of canine breast cancer in nude mice: preclinical development of a therapeutic agent.

Mammary cancers together with cancers of the skin account for about 60% of the total cancers occurring in dogs. The veterinary options for therapeutic management of canine mammary cancer are limited and prognosis for such patients is poor. In this study, we analyzed the functionality of the oncolytic vaccinia virus strain GLV-1h68 as a possible therapeutic agent for canine mammary cancer. Cell culture data demonstrated that GLV-1h68 efficiently infected and destroyed cells of the canine mammary adenoma cell line ZMTH3. Furthermore, after systemic administration this attenuated vaccinia virus strain primarily replicated in canine tumor xenografts in nude mice. The efficient tumor colonization process resulted in inhibition of tumor growth and drastic reduction of tumor size. This is the first report demonstrating that vaccinia virus is an effective tool for the therapy of canine mammary cancers, which might next be applied to dogs with breast tumors.

Postmortem diagnosis of hemoglobin SC disease complicated by fat embolism.

A case is reported of a previously healthy 52-year-old African American male who presented with acute onset of abdominal pain. Progressive increase in his abdominal symptoms led to an exploratory laparotomy; however, no pathology was discovered. Postoperatively, the patient became hypoxemic which progressed to diffuse infiltrates on chest x-ray, suggestive of adult respiratory distress syndrome. He had a rapidly fatal course. Autopsy showed bone marrow infarction, fat embolism, splenomegaly, and widespread congestion with sickle erythrocytes. Hemoglobin electrophoresis done postmortem showed hemoglobin (Hb) SC disease that was undiagnosed antemortem. To the best of our knowledge, it is unusual for Hb SC to be diagnosed postmortem in adults. This case suggests that sickle cell disorders should be ruled out in patients at risk for hemoglobinopathy in the presence of signs and symptoms compatible with the disease, irrespective of age.

Opiate modification of intracranial self-stimulation in the rat.

Studies were conducted to confirm the involvement of central opiate receptors in the expression of opiate modulation of intracranial self-stimulation (ICSS). Biphasic, dose-related changes in ICSS responding are described following IP administration of morphine sulfate (1-25 mg/kg) and levorphanol tartrate (LEV, 0.5-5 mg/kg). Similar patterns of response modification are reported following intraventricular (IVt) administration of LEV (0.01-0.2 muMoles) LEV's enantiomorph, dextrorphan, was not found to elicit comparable effects after either IP or IVt administration. Both the facilitatory and the depressant phases of LEV's action were antagonized by naltrexone (10 microgram, IVt), which had no apparent effect on ICSS by itself. Complete tolerance developed to the suppression of responding by 2.5 mg/kg LEV (IP) but not to the facilitatory effect of 0.5 mg/kg (IP), during a 5-day course of administration. The implications of these results for opiate reinforcement theory are discussed and possible mechanisms are advanced.