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The use of randomized clinical trials, in particular placebo-controlled trials, for drug approval, is the subject of long-standing debate in the scientific community and beyond. This study offers consensus recommendations from clinical and academic experts to guide the selection of clinical trial design in psychiatry. Forty-one highly cited clinical psychiatrists and/or researchers participated in a Delphi survey. Consensus statements were developed based on the findings of a published, peer-reviewed systematic review. Participants evaluated statements in two survey rounds, following the Delphi method. The expert panel achieved consensus on 7 of 21 recommendations regarding the use of randomized clinical trials. The endorsed recommendations were: (i) Results from placebo-controlled trials are the most reliable and (ii) are necessary despite the growing placebo-effect; (iii) it is ethical to enroll patients in placebo-arms when established treatment is available, if there is no evidence of increased health risk; (iv) There is a need to approve new drugs with the same efficacy as existing treatments, but with different side-effect profiles; (v) Non-inferiority trials incur an increased risk of approving ineffective medications; (vi) The risk of approving an ineffective drug justifies trial designs that incur higher costs, and (vii) superiority trials incur the risk of rejecting potentially efficacious treatments. The endorsed recommendations inform the choice of trial-design appropriate for approval of psychopharmacological drugs. The recommendations strongly support the use of randomized clinical trials in general, and the use of placebo-controlled trials in particular., Competing Interests: Declaration of Competing Interest Guy M. Goodwin is a NIHR Emeritus Senior Investigator, holds shares in P1vital and P1Vital products and has served as consultant, advisor or CME speaker in the last 3 years for Beckley Psytech, Clerkenwell Health, Compass pathways, Evapharma, Janssen, Lundbeck, Medscape, Novartis, P1Vital, Sage, Servier. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health. Michael Berk is supported by a NHMRC Senior Principal Research Fellowship (1156072). MB has received Grant/Research Support from the NIH, Cooperative Research Centre, Simons Autism Foundation, Cancer Council of Victoria, Stanley Medical Research Foundation, Medical Benefits Fund, National Health and Medical Research Council, Medical Research Futures Fund, Beyond Blue, Rotary Health, A2 milk company, Meat and Livestock Board, Woolworths, Avant and the Harry Windsor Foundation, has been a speaker for Abbot, Astra Zeneca, Janssen and Janssen, Lundbeck and Merck and served as a consultant to Allergan, Astra Zeneca, Bioadvantex, Bionomics, Collaborative Medicinal Development, Janssen and Janssen, Lundbeck Merck, Pfizer and Servier – all unrelated to this work. Andreas Meyer-Lindenberg has received consultant fees from: Boehringer Ingelheim, Elsevier, Brainsway, Lundbeck Int. Neuroscience Foundation, Lundbeck A/S, The Wolfson Foundation, Bloomfield Holding Ltd, Shanghai Research Center for Brain Science, Thieme Verlag, Sage Therapeutics, v Behring Röntgen Stiftung, Fondation FondaMental, Janssen-Cilag GmbH, MedinCell, Brain Mind Institute, Agence Nationale de la Recherche, CISSN (Catania Internat. Summer School of Neuroscience), Daimler und Benz Stiftung, American Association for the Advancement of Science, Servier International. Additionally, he has received speaker fees from: Italian Society of Biological Psychiatry, Merz-Stiftung, Forum Werkstatt Karlsruhe, Lundbeck SAS France, BAG Psychiatrie Oberbayern, Klinik für Psychiatrie und Psychotherapie Ingolstadt, med Update GmbH, Society of Biological Psychiatry, Siemens Healthineers, Biotest AG -All unrelated to this work. Terence A. Ketter has been a consultant to Otsuka Pharmaceuticals, Sunovion Pharmaceuticals, Abbvie, and Alkermes. Joseph Goldberg has been a consultant to BioXCel, Otsuka, Sage Pharmaceuticals, Sunovion, and WebMD, and served on the speaker boards for Allergan, Intracellular Therapies, and Sunovion. Rif S. El-Mallakh is on the speaker bureau of Alkermes, Eisai, Indivior, Intra-Cellular Therapeutics, Janssen, Lundbeck, Noven, Otsuka, Sunonvion, and Teva. Lakshmi N Yatham has been on speaker/advisory boards for, or has received research grants from Abbvie, Alkermes, Allergan, CANMAT, CIHR, DSP, Merck, and Sanofi Rasmus W. Licht has within the preceding three years served an advisory board of Janssen Cilag and Sagw, and received speaker honorarium from Astra-Zeneca, Jannsen-Cilag, Servier and Lundbeck Allan H. Young has been employed by King's College London; Honorary Consultant SLaM (NHS UK). Young has participated in paid lectures and advisory boards for the following companies with drugs used in affective and related disorders: Astrazenaca, Eli Lilly, Lundbeck, Sunovion, Servier, Livanova, Janssen, Allegan, Bionomics, Sumitomo Dainippon Pharma, COMPASS Allan H. Young's independent research funded by the National Institute for Health Research (NIHR) Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King's College London. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR, or the Department of Health.Consultant to Johnson & Johnson and Livanova. Received honoraria for attending advisory boards and presenting talks at meetings organized by LivaNova. Prof. Alessandro Serretti is or has been consultant/speaker for: Abbott, Abbvie, Angelini, Astra Zeneca, Clinical Data, Bo- heringer, Bristol Myers Squibb, Eli Lilly, GlaxoSmithKline, Innovapharma, Italfarmaco, Janssen, Lundbeck, Naurex, Pfizer, Polifarma, Sanofi, Servier. Ayşegül Yildiz has nothing to declare. Jean Michel Azorin has received honoraria or research or educational conference grants from Lundbeck and Otsuka. Othman Sentissi has received advisory board honoraria or research or educational conference from Otsuka, Lilly, Lundbeck, Sandoz, Janssen and Sunovion on an institutional account for research and teaching. Prof. Gordon Parker has received lecture fees and board member honoraria from Otsuka, Servier and Lundbeck. Dr. David Bond has received consulting fees and/or research grants from Alkermes, Myriad Genetics, the National Institutes of Health, the University of Minnesota Department of Psychiatry and Behavioral Sciences, and the University of Minnesota Foundation. Prof. Giulio Perugi has received grant/research support from Eli Lilly & Co.; is on the speaker/advisory board of Sanofi-Aventis, Bristol-Myers Squibb, AstraZeneca, Eli Lilly & Co., Jannsen-Cilag, and Lundbeck; and has acted as consultant of AstraZeneca, Eli Lilly & Co., and Lundbeck. Prof. Eduard Vieta has received grants and served as consultant, advisor or CME speaker for the following entities: AB- Biotics, Abbott, Allergan, Angelini, Dainippon Sumitomo Pharma, Galenica, Janssen, Lundbeck, Novartis, Otsuka, Sage, Sanofi-Aventis, and Takeda. Dina Popovic has served as a speaker and/or medical writer and/or consultant and/or has participated in advisory boards for Bristol-Myers Squibb, Dexel, Merck Sharp & Dohme, Janssen-Cilag, Lundbeck, Ferrer, and Forum Pharmaceuticals. None of the remaining authors have conflicts of interest to declare., (Copyright © 2022 Elsevier B.V. and ECNP. All rights reserved.)

Major Depressive Episode (MDE) is a transdiagnostic nosographic construct straddling Major Depressive (MDD) and Bipolar Disorder (BD). Prognostic and treatment implications warrant a differentiation between these two disorders. Network analysis is a novel approach that outlines symptoms interactions in psychopathological networks. We investigated the interplay among depressive and mixed symptoms in acutely depressed MDD/BD patients, using a data-driven approach. We analyzed 7 DSM-IV-TR criteria for MDE and 14 researched-based criteria for mixed features (RBDC) in 2758 acutely depressed MDD/BD patients from the BRIDGE-II-Mix study. The global network was described in terms of symptom thresholds and symptom centrality. Symptom endorsement rates were compared across diagnostic subgroups. Subsequently, MDD/BD differences in symptom-network structure were examined using permutation-based network comparison test. Mixed symptoms were the most central and highly interconnected nodes in the network, particularly agitation followed by irritability. Despite mixed symptoms, appetite gain and hypersomnia were significantly more endorsed in BD patients, associations between symptoms were highly correlated across MDD/BD (Spearman's r = 0.96, p<0.001). Network comparison tests showed no significant differences among MDD/BD in network strength, structure, or specific edges, with strong edges correlations (0.66-0.78). Upstream differences in MDD/BD may produce similar symptoms networks downstream during acute depression. Yet, mixed symptoms, appetite gain and hypersomnia are associated to BD rather than MDD. Symptoms during mixed-MDE might aggregate according to 2 different clusters, suggesting a possible stratification within mixed states. Future symptom-based studies should implement clinical, longitudinal, and biological factors, in order to establish tailored therapeutic strategies for acute depression., (Copyright © 2020. Published by Elsevier B.V.)

Resistance and worsening of depression in response to antidepressants (ADs) are major clinical challenges. In a large international sample of patients with major depressive disorder (MDD), we aim to explore the possible associations between different patterns of response to ADs and bipolarity. A total of 2811 individuals with a major depressive episode (MDE) were enrolled in the BRIDGE-II-MIX study. This post-hoc analysis included only 1329 (47%) patients suffering from MDD. Patients with (TRD-MDD, n = 404) and without (NTRD-MDD, n = 925) history of resistance to AD treatment and with (n = 184) and without (n = 1145) previous AD-induced irritability and mood lability (AIM) were compared using Chi-square, t-Student's test and logistic regression models. TRD-MDD patients resulted significantly associated with higher rates of AIM, psychotic features, history of suicide attempts, emotional lability and impulsivity, comorbid borderline personality disorder and polipharmacological treatment, compared to NTRD-MDD group. In comparison to NAIM-MDD patients, subjects in the AIM-MDD group showed significantly higher rates of first-degree family history for BD, previous TRD, atypical features, mixed features, psychiatric comorbidities, lifetime suicide attempts and lower age at first psychiatric symptoms. In addition, patients with AIM presented more often almost all the hypomanic symptoms evaluated in this study. Among these latter symptoms, logistic regressions showed that distractibility, impulsivity and hypersexuality were significantly associated with AIM-MDD. In conclusion, in MDD patients, a lifetime history of resistance and/or irritability/mood lability in response to ADs was associated with the presence of mixed features and a possible underlying bipolar diathesis., (Copyright © 2019. Published by Elsevier B.V.)

According to the DSM-5, "reduction in the need for sleep" is the only sleep-related criteria for mixed features in depressive episodes. We aimed at studying the prevalence, clinical correlates and the role of hypersomnia in a sample of acutely depressed patients. Secondarily, we factors significantly increasing the odds of hypersomnia were studied. We conducted a post-hoc analysis of the BRIDGE-II-Mix study. Variables were compared between patients with hypersomnia (SLEEP+) and with insomnia (SLEEP-) with standard bivariate tests. A stepwise backward logistic regression model was performed with SLEEP+ as dependent variable. A total of 2514 subjects were dichotomized into SLEEP+ (n = 423, 16.8%) and SLEEP- (n = 2091, 83.2%). SLEEP+ had significant higher rates of obese BMI (p < 0.001), BD diagnosis (p = 0.027), severe BD (p < 0.001), lifetime suicide attempts (p < 0.001), lower age at first depression (p = 0.004) than SLEEP-. Also, SLEEP+ had significantly poorer response to antidepressants (AD) such as (hypo)manic switches, AD resistance, affective lability, or irritability (all 0<0.005). Moreover, SLEEP+ had significantly higher rates of mixed-state specifiers than SLEEP- (all 0 < 0.006). A significant contribution to hypersomnia in our regression model was driven by metabolic-related features, such as "current bulimia" (OR = 4.21) and "overweight/obese BMI (OR = 1.42)". Globally, hypersomnia is associated with poor outcome in acute depression. Hypersomnia is strongly associated with mixed features and bipolarity. Metabolic aspects could influence the expression of hypersomnia, worsening the overall clinical outcome. Along with commonly used screening tools, detection of hypersomnia has potential, costless discriminative validity in the differential diagnosis unipolar and bipolar depression., (Copyright © 2019. Published by Elsevier B.V.)

Approximately 10% of patients presenting with Lyme disease experience fatigue, musculoskeletal pain, concentration disorders, or short-term memory deficits in the six months following treatment. This entity has been defined as post-Lyme disease syndrome or post-treatment Lyme disease syndrome. The pathophysiology of this syndrome is unknown, but neither persistence of the bacterium nor effectiveness of antibiotics are currently reported in the literature. The French High Council for Public Health (French acronym HCSP) has recently defined a new entity called "persistent polymorphic symptoms after a tick bite" allowing for designing studies to better understand these subjective presentations, for which objective biomarkers are currently lacking. This entity encompasses patients experiencing fatigue and generalized pain in the months following a tick bite and can be associated with several subjective symptoms with major impact on the quality of life. In the field of somatoform disorders, this article reviews functional neuroimaging studies in patients presenting with subjective complaints and discusses potential clinical implications for persisting symptoms after tick bites and post-treatment Lyme disease syndrome., (Copyright © 2019. Published by Elsevier Masson SAS.)

The quest for biomarkers in suicidal behaviors has been elusive so far, despite their potential utility in clinical practice. One of the most robust biological findings in suicidal behaviors is the alteration of the serotonin transporter function in suicidal individuals. Our main objective was to investigate the predictive value of the serotonin transporter gene expression (SLC6A4) for suicidal ideation and as secondary, for suicide attempts in individuals with a major depressive episode (MDE). A 30-week prospective study was conducted on 148 patients with a MDE and 100 healthy controls including 4 evaluation times (0, 2, 8 and 30 weeks). Blood samples and clinical data were collected and SLC6A4 mRNA levels were measured from peripheral blood mononuclear cells using RT-qPCR. We first demonstrated the stability and reproducibility of SLC6A4 mRNA expression measures over time in healthy controls (F=0.658; p=0.579; η 2 =0.008; ICC=0.91, 95% CI [0.87-0.94]). Baseline SLC6A4 expression level (OR=0.563 [0.340-0.932], p=0.026) as well as early changes in SLC6A4 expression between baseline and the 2 nd week (β=0.200, p=0.042) predicted the worsening of suicidal ideation (WSI) in the following 8 weeks. Moreover, changes in SLC6A4 expression between the 2 nd and 8 th weeks predicted the occurrence of a suicide attempt within 30 weeks (OR=10.976 [1.438-83.768], p=0.021). Altogether, the baseline level and the changes in SLC6A4 mRNA expression during a MDE might predict the WSI and the occurrence of suicidal attempts and could be a useful biomarker in clinical practice., (Copyright © 2017 Elsevier B.V. and ECNP. All rights reserved.)

Background: Little is known about the sequence of onsets in patients affected by comorbid alcohol use and bipolar disorder. This study examines the risk factors associated with their co-occurrence and order of onset., Method: The demographic, clinical, and temperament characteristics as well as the course of illness were analyzed within our sample of 1090 DSM-IV bipolar I manic patients. Our sample was categorized according to the presence of comorbid alcohol use disorder and the sequence of onsets of bipolar and alcohol use disorders i.e., alcohol first (AUD-BD) and bipolar first (BD-AUD)., Results: Regression analyses revealed that alcohol use disorder (52.5%) was associated with the male gender, additional substance use disorders, as well as an irritable and a hyperthymic temperament. The AUD-BD group (6.6%) was older than the BD-AUD group (45.8%) and showed higher rates of comorbid sedative use, organic, and anxiety disorders with higher levels of irritable temperament, and a bipolar subtype characterized by depressive polarity at onset. The BD-AUD group had high levels of hyperthymic temperament with higher rates of comorbid stimulant use disorder and a manic polarity at onset., Conclusions: In the AUD-BD group, alcohol might have been used to reduce stress and tension caused by the presence of an irritable temperament as well as anxious and organic disorders, leading to first depressive episode. In the BD-AUD group, stimulant use might have triggered the first manic episode, and alcohol abuse result from mania severity., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Bipolar disorder is associated with impaired decision-making. Little is known about how treatment, especially lithium, influences decision-making abilities in bipolar patients when euthymic. We aimed at testing for an association between lithium medication and decision-making performance in remitted bipolar patients. Decision-making was measured using the Iowa Gambling Task in 3 groups of subjects: 34 and 56 euthymic outpatients with bipolar disorder, treated with lithium (monotherapy and lithium combined with anticonvulsant or antipsychotic) and without lithium (anticonvulsant, antipsychotic and combination treatment), respectively, and 152 matched healthy controls. Performance was compared between the 3 groups. In the 90 euthymic patients, the relationship between different sociodemographic and clinical variables and decision-making was assessed by stepwise multivariate regression analysis. Euthymic patients with lithium (p=0.007) and healthy controls (p=0.001) selected significantly more cards from the safe decks than euthymic patients without lithium, with no significant difference between euthymic patients with lithium and healthy controls (p=0.9). In the 90 euthymic patients, the stepwise linear multivariate regression revealed that decision-making was significantly predicted (p<0.001) by lithium dose, level of education and no family history of bipolar disorder (all p≤0.01). Because medication was not randomized, it was not possible to discriminate the effect of different medications. Lithium medication might be associated with better decision-making in remitted bipolar patients. A randomized trial is required to test for the hypothesis that lithium, but not other mood stabilizers, may specifically improve decision-making abilities in bipolar disorder., (Copyright © 2015 Elsevier B.V. and ECNP. All rights reserved.)

Background: In bipolar disorder (BD), little is known about how deficits in neurocognitive functions such as decision-making are related to phase of illness. We predicted that manic, depressed, and euthymic bipolar patients (BPs) would display impaired decision-making, and we tested whether clinical characteristics could predict patients' decision-making performance., Methods: Subjects (N = 317; age range: 18-65 years) including 167 BPs (45 manic and 32 depressed inpatients, and 90 euthymic outpatients) and 150 age-, IQ-, and gender-matched healthy control (HC) participants, were included within three university psychiatric hospitals using a cross-sectional design. The relationship between predictor variables and decision-making was assessed by one-step multivariate analysis. The main outcome measures were overall decision-making ability on the Iowa Gambling Task (IGT) and an index of sensitivity to punishment frequency., Results: Manic, depressed, and euthymic BPs selected significantly more cards from the risky decks than HCs (p < .001, p < .01, and p < .05, respectively), with no significant differences between the three BD groups. However, like HCs, BPs preferred decks that yielded infrequent penalties over those yielding frequent penalties. In multivariate analysis, decision-making impairment was significantly (p < .001) predicted by low level of education, high depressive scores, family history of BD, use of benzodiazepines, and nonuse of serotonin and norepinephrine reuptake inhibitor (SNRI) antidepressants., Conclusions: BPs have a trait-related impairment in decision-making that does not vary across illness phase. However, some subtle differences between the BD groups in the individual deck analyses may point to subtle state influences on reinforcement mechanisms, in addition to a more fundamental trait impairment in risk-sensitive decision making., (Copyright © 2011 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Background: Lithium carbonate and valproate semisodium are both recommended as monotherapy for prevention of relapse in bipolar disorder, but are not individually fully effective in many patients. If combination therapy with both agents is better than monotherapy, many relapses and consequent disability could be avoided. We aimed to establish whether lithium plus valproate was better than monotherapy with either drug alone for relapse prevention in bipolar I disorder., Methods: 330 patients aged 16 years and older with bipolar I disorder from 41 sites in the UK, France, USA, and Italy were randomly allocated to open-label lithium monotherapy (plasma concentration 0.4-1.0 mmol/L, n=110), valproate monotherapy (750-1250 mg, n=110), or both agents in combination (n=110), after an active run-in of 4-8 weeks on the combination. Randomisation was by computer program, and investigators and participants were informed of treatment allocation. All outcome events were considered by the trial management team, who were masked to treatment assignment. Participants were followed up for up to 24 months. The primary outcome was initiation of new intervention for an emergent mood episode, which was compared between groups by Cox regression. Analysis was by intention to treat. This study is registered, number ISRCTN 55261332., Findings: 59 (54%) of 110 people in the combination therapy group, 65 (59%) of 110 in the lithium group, and 76 (69%) of 110 in the valproate group had a primary outcome event during follow-up. Hazard ratios for the primary outcome were 0.59 (95% CI 0.42-0.83, p=0.0023) for combination therapy versus valproate, 0.82 (0.58-1.17, p=0.27) for combination therapy versus lithium, and 0.71 (0.51-1.00, p=0.0472) for lithium versus valproate. 16 participants had serious adverse events after randomisation: seven receiving valproate monotherapy (three deaths); five lithium monotherapy (two deaths); and four combination therapy (one death)., Interpretation: For people with bipolar I disorder, for whom long-term therapy is clinically indicated, both combination therapy with lithium plus valproate and lithium monotherapy are more likely to prevent relapse than is valproate monotherapy. This benefit seems to be irrespective of baseline severity of illness and is maintained for up to 2 years. BALANCE could neither reliably confirm nor refute a benefit of combination therapy compared with lithium monotherapy., Funding: Stanley Medical Research Institute; Sanofi-Aventis., (Copyright 2010 Elsevier Ltd. All rights reserved.)

A 44-year-old man presenting with atypical maniac behavior and hypokaliemia was diagnosed with Cushing's syndrome and treated in emergency by bilateral adrenalectomy. Endocrine investigations were suggestive of an ectopic adrenocorticotropic (ACTH) secretion, both at baseline (mean ACTH levels = 215 pg/mL, beta-lipotropic hormone = 2329 pg/mL; molar ratio > 5) and after pharmacodynamic testing (lack of inhibition of ACTH by dexamethasone, blunted ACTH response to corticotropin releasing hormone). Ectopic ACTH secretion was investigated while pituitary ACTH secretion was suppressed by dexamethasone. A paradoxical rise of ACTH from 384 to 717 pg/mL was observed after subcutaneous administration of 500 micrograms octreotide. A right lung tumor that remained occult for 7 years was only revealed by octreotide scintigraphy, despite annual chest tomodensitometric examinations. Right inferior lung lobectomy allowed allowed for removal of a 13 mm tumor corresponding to a bronchial neuroendocrine carcinoma with positive immunostaining for ACTH. Mediastinal lymph nodes were histologically normal. Perioperative ACTH measurements, showing a more than 50% decrease from baseline at 15 minutes after tumor resection, were suggestive of complete tumor removal. This was confirmed 10 days postoperatively by undetectable ACTH levels and by a negative octreotide scintigraphy after surgery. This case report of an occult ACTH secreting bronchial neuroendocrine carcinoma illustrates the diagnostic value of octreotide scintigraphy, and the prognostic value of perioperative ACTH measurements in such cases.

Atypical neuroleptics can be defined as dopamine receptor blockers which differ from typical neuroleptics in that they have a markedly lower or absent propensity for the induction of parkinsonian side effects or tardive dyskinesias. The authors are studying varied molecules considering their mechanism of action. The differences between atypical and typical neuroleptics may relate to regional specificity in site of actions and receptor binding profile. The authors insist on clozapine, which is a D2 antagonist and in which many other systems might be involved. New neural models may help understand these interactions. The Swerdlow and Koob's model is a unified hypothesis of cortico-striato-pallido-thalamic function which can explain psychoses, depression, dyskinesias and Parkinsonian disorders. The authors make a linkage between this model and Davis's hypothesis. This author hypothesizes that schizophrenia is characterized by abnormally low prefrontal dopamine activity leading to excessive dopamine activity in mesolimbic dopamine neurons, that explains the both negative and positive symptoms coexistence. For the authors, new ways are then opened for an integrative conception of psychosis and affective disorders. This conception might be integrated into the bio-psycho-social model based on chaotics, evocation of which is the author's conclusion.

Basal level and isoproterenol-induced response of cyclic adenosine monophosphate (cAMP) were determined in mononuclear leucocytes from 17 drug-free patients with major depressive (n = 9) or dysthymic disorders (n = 8) and 20 normal controls. No significant difference was observed between basal cAMP levels from depressed and control subjects. The cAMP production in response to maximal stimulation by isoproterenol (ISO), a beta-agonist, was significantly lower (-34.7%) in depressed patients than in controls, and was significantly negatively correlated to the severity of the depression as assessed by the Hamilton depression rating scale score (r = -0.62; p < 0.003). When the depressed group was subdivided on the basis of the DSM-III-R (APA 1987) diagnosis criteria into major depressive and dysthymic disorders, the ISO-stimulated cAMP levels in the two groups were indistinguishable. When evaluated at the same time than the density of beta-adrenoreceptors in eight depressed patients, the ISO-stimulated cAMP levels were highly significantly correlated with the Bmax values (r = 0.89; p < 0.003). The results indicate that the decrease in beta-adrenergic responsiveness of mononuclear leukocytes can be present in depressed patients whatever the nosographical subtype of the depressive disorder and is quantitatively related to the depression severity. Based on these data, it seems that the blunted beta-adrenergic sensitivity observed in mononuclear leukocytes (MNL) cells of depressed patients is closely associated with a loss of beta-adrenoceptors.

Platelet tritiated imipramine binding (Bmax) was studied in 33 depressed patients, before and after 1 and 4 weeks of antidepressant treatment, and in 34 healthy volunteers. The Bmax was significantly lower (-21%) in drug-free depressed patients than in controls and increased significantly as early as the first week of treatment to reach the control value, in parallel with a 38% decrease in the Hamilton depression rating scale (HDRS) score. After 4 weeks of treatment, the Bmax was still normal and remained significantly higher than the baseline value, while the clinical state of the patients had greatly improved (a 63% decrease in the HDRS score). However, an increase in the Bmax also occurred in non-responders to treatment. In addition, we observed that the ability of the treatment to increase the Bmax depended on the pharmacological profile of the drug used. The present results show that, in patients on antidepressant medication, platelet tritiated imipramine binding normalization cannot be considered as a marker of clinical remission.

Binding parameters of (-)-iodopindolol to beta 2-adrenoceptors were determined on intact mononuclear cells in 41 untreated patients with different DSM-III subtypes of depression. Both maximal beta-receptor density (Bmax) and dissociation constant (Kd) were not significantly different between control and all depressed subjects. However, Bmax was significantly decreased in unipolar patients as compared to controls (p less than 0.001) whereas no significant difference was found in bipolar or dysthymic patients. In unipolar patients, a very strong association was found between Bmax values and the severity of the depression as assessed by the Hamilton Depression Rating Scale score (r = -0.75; p less than 0.005). This correlation was also highly significant in the entire depressed population (r = -0.58; p less than 0.0009). These results suggest that the lower number of beta-adrenoceptors in intact leukocyte cells of depressed patients is related to the depression severity.

Not being able to equilibrate affirmations and negations, the schizophrenic patient accedes only exceptionally to the majoring equilibrations of the second and third levels. In the logico-mathematic field, he does not approach the constructive synthetizing generalisations of reasoning. Lacking reflective abstraction, he cannot balance his logico-mathematic reasoning and differentiate what is structurally possible from what is materially possible, thus explaining his inaccessibility to perceive logic necessities, contrasting with the certainties of his delirium. In the logico-experimental domain, he reaches only rarely clause reasoning generalisation, and relapses regularly to the level of inappropriate generalisations of the extended inductive type. It is useless to try to find the "primum movens" of his difficulties, either in his imbalance assimilation/accommodation, or in his impossibility to see his contradictions, or even in his incapacity to equilibrate affirmations and negations. The majoring equilibrations, of which he is unable, are the functional expression of structures which do not follow the linear causality of Laplace's determinism but the circular causality characteristic of teleonomic processes. After a month of neuroleptic treatment, the decompensated schizophrenic's balance between assimilation and accommodation is partially restored.

In the treatment of depression, when antidepressant drug choice is made according to alterations of erythrocyte membrane transport of L-tyrosine and L-tryptophan in the individual patient, the clinical results are superior to those obtained when drugs are prescribed according to the physician's judgment. This is demonstrated by comparing three experimental groups: I, 100 patients treated in relation to their L-tyrosine and L-tryptophan transport; II, 30 patients treated according to the clinician's experience; III, 38 subjects treated against the L-tyrosine and L-tryptophan transport indications. In these groups, the frequency of patients improved by more than 70% is 77%, 47%, and 16%, respectively.

The concept of pseudodementia was coined in the late XIXth century to refer to a syndrome mimicking dementia, but without underlying neurological lesions. Depressive disorders represent the main etiological factor and may present under two different forms, either "depressive cognitive disorders", or the more severe feature of "Wernicke's pseudodementia". The main issue remains diagnosing pseudodementia form organic dementia, especially from cortical degenerations of the Alzheimer type. Thus, the recognition of this clinical syndrome represents an alternative to the diagnosis of dementia which may lead to earlier and more effective psychiatric treatment. Recently, diagnostic criteria have been proposed to facilitate this distinction. Such criteria include clinical history, neuropsychological features, biological findings (dexamethasone suppression test and plasma MHPG) and electroencephalographic sleep studies. Finally, from a theoretical point of neurological conception of depression as well as for current hypotheses on the relationship of this last one with dementia.

Paranoid schizophrenics are unable to balance affirmation and negation. Using the terms of Jean Piaget, they therefore only partially achieve the "équilibrations majorantes" of level II and never those of level III. In their thinking, they have access to the "généralisations inductives" (often excessive ones), but rarely to the "généralisations constructives complétives". They do not have access to the "généralisations synthétisantes" or to the feeling that logic is necessary. They oscillate between the positivist need to measure or verify and absolute beliefs issued from magical thinking.