Assessing the benefit: risk ratio of a drug--randomized and naturalistic evidence.

Randomized evidence from clinical trials and naturalistic evidence collected from pharmacoepidemiology and pharmacovigilance activities both contribute to the initial and continuous assessment of the benefits and risks of a drug, ie, the balance between therapeutic efficacy and safety risks. Benefit-risk assessment (BRA) mainly relies on a qualitative assessment of quantitative data. Current attempts to quantify BRA are reviewed and discussed, along with the expectations of regulatory authorities such as the Food and Drug Administration and the European Medicines Agency. No method provides a fully satisfactory solution regarding BRA, because it is difficult to reduce its multidimensional aspect to simple metrics, in a context where other therapeutic alternatives play a role. Consistency and transparency are key in this assessment, which is performed throughout the whole drug life cycle. BRA is mainly based on randomized clinical studies during clinical development, and it is continued and consolidated by naturalistic data once the drug is on the market.

Opportunities and challenges in psychopharmacology
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This review addresses novel approaches for influencing the transcriptome, the epigenome, the microbiome, the proteome, and the energy metabolome. These innovations help develop psychotropic medications which will directly reach the molecular targets, leading to beneficial effects, and which will be individually adapted to provide more efficacy and less toxicity. The series of advances described here show that these once utopian goals for psychiatric treatment are now real themes of research, indicating that the future path for psychopharmacology might not be as narrow and grim as considered during the last few decades.
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Esta revisión aborda nuevos enfoques para influir en el transcriptoma, el epigenoma, el microbioma, el proteoma y el metaboloma energético. Estas innovaciones ayudan a desarrollar medicamentos psicotrópicos que alcanzarán directamente los blancos moleculares, llevando a efectos benéficos y que se adaptarán individualmente para proporcionar mayor eficacia y menor toxicidad. La serie de avances descritos aquí muestra que estos objetivos antes utópicos para el tratamiento psiquiátrico ahora son temas reales de investigación, lo que indica que el futuro camino de la psicofarmacología podría no ser tan estrecho y sombrío como se consideró en las últimas décadas.

Ce relevé de littérature porte sur les nouvelles approches permettant d'influencer le transcriptome, l'épigénome, le microbiome, le protéome et le métabolome énergétique. Ces innovations ouvrent une voie pour de futurs médicaments psychotropes qui atteindront directement les cibles moléculaires à l'origine de leurs effets bénéfiques, des psychotropes qui pourront être adaptés pour chaque personne afin de les rendre plus efficaces et avec moins d'effets indésirables. L'ensemble des développements cités montre que des buts antérieurement utopiques pour les traitements psychiatriques sont devenus des thèmes de recherches. Cela indique que le futur de la psychopharmacologie pourrait ne pas être aussi limité et sombre que cela fut considéré durant les précédentes décennies.

Alternative and complementary approaches in psychiatry: beliefs versus evidence.

While the legitimacy of medical treatments is more and more questioned, one sees a paradoxical increase in nonconventional approaches, notably so in psychiatry. Over time, approaches that were considered valuable by the scientific community were found to be inefficacious, while other approaches, labelled as alternative or complementary, were finally discovered to be useful in a few indications. From this observation, we propose to classify therapies as orthodox (scientifically validated) or heterodox (scientifically not validated). To illustrate these two categories, we discuss the place, the role, the interest, and also the potential risks of nonconventional approaches in the present practice of psychiatry.

Si bien la legitimidad de los tratamientos médicos se cuestiona cada vez más, se observa un aumento paradójico en las aproximaciones no convencionales, especialmente en la psiquiatría. Con el tiempo, se descubrió que las aproximaciones que la comunidad científica consideraba valiosas eran ineficaces, mientras que otros enfoques, etiquetados como alternativos o complementarios, se descubrieron finalmente como útiles en algunas indicaciones. A partir de esta observación, se propone clasificar las terapias como ortodoxas (validadas científicamente) o heterodoxas (no validadas científicamente). Para ilustrar estas dos categorías, se discute el lugar, el papel, el interés y también los riesgos potenciales de las aproximaciones no convencionales en la práctica actual de la psiquiatría.

Tandis que la légitimité des traitements médicaux est de plus en plus mise en question, on constate une augmentation paradoxale des approches non conventionnelles, notamment en psychiatrie. Avec le temps, des approches qui étaient considérées de valeur par la communauté scientifique se sont révélées inefficaces, tandis que d'autres, étiquetées comme alternatives ou complémentaires, ont été décrites comme efficaces dans quelques indications. À partir de cette observation, nous proposons de classer les traitements soit comme orthodoxes (validés scientifiquement) soit comme hétérodoxes (non validés scientifiquement). Pour illustrer ces deux catégories, nous commentons la place, le rôle, l'intérêt et aussi les risques potentiels des approches non conventionnelles dans la pratique actuelle de la psychiatrie.

Plasma corticosterone, dexamethasone (DEX) suppression and DEX/CRH tests in a rat model of genetic vulnerability to depression.

The hypothalamo-pituitary-adrenal (HPA) axis is hyperactive in major depressive disorder (MDD), and baseline cortisol levels are usually elevated in MDD patients, with alterations of the circadian hormone secretion pattern. The dexamethasone (DEX) suppression test (DST) has been extensively applied to diagnose a dysregulation of the HPA axis in MDD, but it has only a limited sensitivity to, and specificity for, depression. The DEX/CRH test, which combines the DST with a corticotropin-releasing hormone (CRH) challenge, has proved more reliable to show HPA axis dysfunction in MDD. We have applied these two tests to a putative model of vulnerability to depression in rodents, the Roman high-(RHA) and low-(RLA) Avoidance rat lines. As compared to RHA, RLA rats are behaviorally inhibited, they show an exaggerated response of the HPA axis to stress, and are more prone to develop depressive-like features when exposed to chronic stress. Our results show that (a) there were no significant differences in circadian plasma corticosterone (CORT) levels and/or secretion patterns between the two lines; (b) in the DST test, CORT was suppressed to the same extent in RHA and RLA rats; and c) in the DEX/CRH test, areas-under-the-curve (AUCs) and CORT delta (peak minus baseline) responses were significantly larger in RLA rats. One possible interpretation of these data is that an increased response to CRH could be a trait marker (or endophenotype) for depression, whereas alterations of circadian glucocorticoid secretion patterns and non-suppression of the daily glucocorticoid rise by dexamethasone could be state markers, i.e. features that are only present during depressive episodes.

Biological clocks and the practice of psychiatry.

Endogenous biological clocks enable living species to acquire some independence in relation to time. They improve the efficiency of biological systems, by allowing them to anticipate future constraints on major physiological systems and cell energy metabolism. The temporal organization of a given biological function can be impaired in its coordination with astronomical time or with other biological functions. There are also external conditions that influence biological clocks. This temporal organization is complex, and it is possible that a series of psychiatric disorders and syndromes involve primary or secondary changes in biological clocks: seasonal and other mood disorders, premenstrual syndromes, social jet lag, free-running rhythms, and several sleep disorders are among them. In this review, we describe the main concepts relevant to chronobiology and explore the relevance of knowledge about biological clocks to the clinical practice of psychiatry.

Cortisol hypersecretion in unipolar major depression with melancholic and psychotic features: dopaminergic, noradrenergic and thyroid correlates.

Evidence supports that hyperactivity of the hypothalamic-pituitary-adrenal axis has a pivotal role in the psychobiology of severe depression. The present study aimed at assessing hypothalamic-pituitary dopaminergic, noradrenergic, and thyroid activity in unipolar depressed patients with melancholic and psychotic features and with concomitant hypercortisolemia. Hormonal responses to dexamethasone, apomorphine (a dopamine receptor agonist), clonidine (an alpha 2-adrenoreceptor agonist) and 0800 and 2300 h protirelin (TRH) were measured in 18 drug-free inpatients with a DSM-IV diagnosis of severe major depressive disorder with melancholic and psychotic features showing cortisol nonsuppression following dexamethasone and 23 matched hospitalized healthy controls. Compared with controls, patients showed (1) lower adrenocorticotropin and cortisol response to apomorphine (p<0.015 and <0.004, respectively), (2) lower growth hormone response to clonidine (p=0.001), and (3) lower responses to TRH: 2300 h maximum increment in serum thyrotropin (TSH) level (p=0.006) and the difference between 2300 and 0800 h maximum increment in serum TSH values (p=0.0001). Our findings, in a subgroup of unipolar depressed inpatients with psychotic and melancholic features, are compatible with the hypothesis that chronic elevation of cortisol may lead to dopaminergic, noradrenergic and thyroid dysfunction.

Neuroendocrine predictors of the evolution of depression.

Depression is both clinically and biologically a heterogeneous entity. Despite advances in psychopharmacology, a significant proportion of depressed patients either continue to have residual symptoms or do not respond to antidepressants. It has therefore become essential to determine parameters (or predictors) that would rationalize the therapeutic choice, taking into account not only the clinical features, but also the "biological state," which is a major determinant in the antidepressant response. Such predictors can derive from bioclinical correlates and, in this context, the neuroendocrine strategy appears particularly suited. Numerous studies have investigated neuroendocrine parameters--derived mainly from dynamic challenge tests--in order to (i) determine the predictive profiles of good clinical responders to given antidepressants; (ii) monitor the progression of markers in parallel with the clinical outcome; and (iii) evaluate "in vivo" in humans the mechanisms of action of antidepressant compounds (before, during, and after treatment). This article does not attempt to be exhaustive, but rather uses selected examples to illustrate the usefulness of the investigation of the adrenal and thyroid axes and the assessment of central serotonergic, noradrenergic, and dopaminergic systems by means of neuroendocrine tests. Given methodological constraints, most of these investigations--except for baseline hormone values and the dexamethasone suppression test--cannot be used routinely in psychiatry. Despite these limitations, the neuroendocrine strategy still offers new insights in biology and the treatment of depression. Its possible expansion depends mainly on the development of specific agonists or antagonists for better investigation of the receptors supposedly involved in the pathophysiology of depression. These investigations will help define more homogeneous subgroups from a bioclinical and therapeutic viewpoint.

Chronic corticotropin-releasing hormone and vasopressin regulate corticosteroid receptors in rat hippocampus and anterior pituitary.

Corticotropin-releasing hormone (CRH) and vasopressin (AVP) participate in the endocrine, autonomic, immunological and behavioral response to stress. CRH and AVP receptors are found in hippocampus and anterior pituitary, where mineralocorticoid (MR) and glucocorticoid (GR) receptors are abundant. We investigated the possible influence of CRH and AVP on the regulation of MR and GR in both tissues. CRH, AVP, or their antagonists were administered to adrenalectomized rats substituted with corticosterone, to avoid interference with adrenal secretion. Repeated i.c.v. oCRH injections (10 microgram) for 5 days significantly decreased MR and GR mRNA in hippocampus and MR mRNA in anterior pituitary. AVP significantly increased both corticosteroid receptor mRNAs, as repeated i.c.v. injections (5 microgram) for 5 days in hippocampus, and as continuous i.c.v. infusion (10 ng/h/5 days) in anterior pituitary. The i.c.v. infusion of 5 or 10 microgram/day of the alpha-helical CRH antagonist during intermittent restraint stress (5 days), induced a significant decrease in hippocampal MR binding. In anterior pituitary, 5 microgram/day significantly decreased MR binding, while 10 microgram/day significantly increased GR binding. Under the same conditions of stress, the infusion of 15 microgram/day of the vasopressin V1a/1b receptor antagonist [dP Tyr (Me)(2)AVP] significantly increased MR and GR binding in hippocampus and anterior pituitary; 5 microgram/day significantly decreased pituitary MR binding. Our results show that CRH and AVP regulate MR and GR in hippocampus and anterior pituitary. This reveals another important function of CRH and AVP, which could be relevant to understand stress adaptation and the pathophysiology of stress-related disorders like major depression.

Clonazepam and lorazepam in acute mania: a Bayesian meta-analysis.

BACKGROUND: Clonazepam and lorazepam are used in the treatment of acute mania but trial results are conflicting. METHODS: Studies were identified by searching MEDLINE and EMBASE for lorazepam or clonazepam in acute mania between 1966 and 2000. Seven randomized controlled trials were found comparing clonazepam or lorazepam to placebo, haloperidol or lithium in acute mania. Data on 206 patients were analyzed. RESULTS: The heterogeneity of trial designs and the use of different comparators necessitated a Bayesian hierarchical meta-analysis with three models: (a) random trial effect and fixed treatment effects, (b) random trial and treatment effects, (c) random trial and treatment effects with trial variance unknown. With all models, clonazepam decreased psychopathology scores statistically significantly with the following standardized responses: model (a): 1.26 (95% predictive interval (PI) 0.33 to 2.28), model (b): 1.21 (95% PI 0.08 to 2.53), model (c): 1.41 (95% PI 0.12 to 2.67). Lorazepam did not yield statistically significant standardized responses for any of the three models: model (a): 0.79 (95% PI -0.29 to 1.89), model (b): 0.77 (95% PI -0.57 to 2.24) and model (c): 0.74 (-0.82 to 2.20). Haloperidol yielded statistically significant standardized responses in the three models but lithium effect was statistically significant only in model (a). Safety data were in line with the usual safety profile of benzodiazepines. LIMITATIONS: Trial designs were heterogenous and patient number was limited. CONCLUSIONS: This meta-analysis suggests that clonazepam is efficient and safe in the treatment of acute mania, but the results remain inconclusive for lorazepam.

Clinicians' predictions of patient response to psychotropic medications.

Clinicians prescribe a medication when they assume that there is a reasonable probability of its success. There are many studies on the predictive value of social or clinical information, but these studies do not include the prognosis made by psychiatrists before treatment. These studies indicate that a small to moderate proportion of the total variance of outcome can be predicted from social or clinical information. It is peculiar that there are very few studies on the accuracy of psychiatrists' "bets" about the effects of psychotropic drugs when they use the clinical characteristics of patients as predictors, considering the practical relevance of predicting the outcome of a psychiatric treatment. The absence of studies on the accuracy of clinicians' bets or predictions in psychiatry is unfortunate.

The clinical pharmacology of depressive states.

Antidepressants have good efficacy in the treatment of mood disorders, with effect sizes that have consistently been found to be greater than those of placebo. The more recent antidepressants do not have better efficacy than the compounds discovered 40 to 50 years ago, but they do have a more favorable configuration of side effects, leading to fewer dropouts. This favorable situation has made it possible to prescribe the newer antidepressants in less severe depression and in several anxiety disorders, with considerable benefit to patients. During the last decades, research into the pathophysiology of mood and anxiety disorders has provided much information on the brain circuitry, neurohormones, and neurotransmitters involved in these disorders. In parallel, biological and behavioral work on antidepressants, using animal models and new biochemical techniques, has led to a broader understanding of the mode of action of these drugs. Despite this impressive list of discoveries, much research remains to be done on the clinical, psychological, neuropsychological, physiological, and neurochemical aspects, before we can obtain a coherent description of the pathophysiological mechanisms of depression and its treatment. This will lead to a better ability to predict the quality of drug response and, therefore, to the individualization of treatment.

Neurobiology of circadian systems.

Time is a dimension tightly associated with the biology of living species. There are cycles of varied lengths in biological activities, from very short (ultradian) rhythms to rhythms with a period of approximately one day (circadian) and rhythms with longer cycles, of a week, a month, a season, or even longer. These rhythms are generated by endogenous biological clocks, i.e. time-keeping structures, rather than being passive reactions to external fluctuations. In mammals, the suprachiasmatic nucleus (SCN) is the major pacemaker. The pineal gland, which secretes melatonin, is the major pacemaker in other phyla. There also exist biological clocks generating circadian rhythms in peripheral tissues, for example the liver. A series of clock genes generates the rhythm through positive and negative feedback effect of proteins on their own synthesis, and this system oscillates with a circadian period. External factors serve as indicators of the astronomical (solar) time and are called zeitgebers, literally time-givers. Light is the major zeitgeber, which resets daily the SCN circadian clock. In the absence of zeitgebers, the circadian rhythm is said to be free running; it has a period that differs from 24 hours. The SCN, together with peripheral clocks, enables a time-related homeostasis, which can become disorganized in its regulation by external factors (light, social activities, food intake), in the coordination and relative phase position of rhythms, or in other ways. Disturbances of rhythms are found in everyday life (jet lag, shift work), in sleep disorders, and in several psychiatric disorders including affective disorders. As almost all physiological and behavioural functions in humans occur on a rhythmic basis, the possibility that advances, delays or desynchronization of circadian rhythms might participate in neurological and psychiatric disorders has been a theme of research. In affective disorders, a decreased circadian amplitude of several rhythms as well as a phase advance or delay have been described, leading to hypotheses about changes in biological clocks themselves or in their sensitivity to environmental factors, such as light or social cues. Molecular genetics studies have suggested the involvement of circadian clock genes, but no tight association has yet been found. Agomelatine is an antidepressant, agonist at melatonergic MT(1), MT(2) receptors and antagonist at 5-HT(2C) receptors, and is able to phase advance circadian rhythms in humans. The fact that non-pharmacological (light therapy, sleep deprivation, rhythm therapy) and pharmacological (lithium, antidepressants, agomelatine) therapies of affective disorders influence circadian rhythms indicates that biological clocks play a role in the pathophysiology of these disorders.

A major change of prescribing pattern in absence of adequate evidence: benzodiazepines versus newer antidepressants in anxiety disorders.

We performed a systematic review of controlled trials on anxiety disorders treatment (generalized anxiety disorder, panic disorder, social phobia and post-traumatic stress disorder) published from 1980 to 2006, and identified trials comparing the efficacy of benzodiazepines (BZD) with that of antidepressants, in particular comparisons between BZD and newer antidepressants. Among 969 publications, 274 double-blind randomized controlled studies remained after using our exclusion criteria. These studies comprised altogether 439 comparisons. There were in total 23 comparisons of antidepressants versus BZD. Among these, 22 compared the efficacy of older antidepressants versus BZD, whereas only 1 concerned the comparison of a newer antidepressant versus BZD. It showed comparable efficacy between venlafaxine and diazepam in the treatment of generalized anxiety disorder. Our study shows that the major change of prescribing pattern from BZD to newer antidepressants in anxiety disorders has occurred in absence of comparative data of high level of proof.

Mineralo- and glucocorticoid receptor mrnas are differently regulated by corticosterone in the rat hippocampus and anterior pituitary.

In most cell lines and animal tissues, glucocorticoid receptors undergo downregulation after exposure to corticosterone. However, corticosterone treatment has not shown a consistent effect on mineralocorticoid (MR) and glucocorticoid receptors (GR) in the hippocampus, and it has been rarely assessed in the anterior pituitary. In this study we investigated dose-dependent effects of corticosterone on MR and GR mRNAs in the hippocampus and anterior pituitary. Adrenalectomized rats substituted with corticosterone in drinking fluid were injected subcutaneously with vehicle or 1, 10, 50, 100, or 200 mg of corticosterone, and sacrificed 4 h later. In the hippocampus we found a progressive decrease in MR and GR mRNAs with increasing doses of corticosterone. This was significant with 50 and 100 mg corticosterone for MR mRNA and with 10-200 mg corticosterone for GR mRNA at plasma corticosterone levels above 30 microg/dl. The anterior pituitary did not show significant changes at any dose. A time-course with 2 mg of corticosterone (non-response dose range at 4 h) revealed a significant decrease in MR and GR mRNAs in the hippocampus 8 h after the subcutaneous injection. In the anterior pituitary both mRNAs showed an increase that was significant 24 h after injection for MR and from 8 to 24 h for GR. In the hippocampus, adrenalectomy (absence of corticosterone) induced a significant increase in MR and GR mRNAs on day 3, but not on days 1, 8 and 21 after adrenalectomy. In the anterior pituitary there were no significant changes at any time after adrenalectomy. In summary, we have found an in vivo corticosterone dose- and time-dependent downregulation of MR and GR mRNAs in the hippocampus, whereas anterior pituitary MRs and GRs seem relatively insensitive to the excess or the absence of corticosterone, suggesting the lack of an autoregulatory effect in this tissue. Significant mRNA changes appearing later in time could suggest a secondary response via a glucocorticoid-induced gene product. Corticosteroid receptor downregulation in the hippocampus could prevent overstimulation or tissue damage when plasma corticosterone is high, while increased corticosteroid receptors in the anterior pituitary could buffer the excessive brain drive on the pituitary during chronic stress or pathological conditions associated with increased plasma glucocorticoids, such as depression.