The Psychopharmacology Algorithm Project at the Harvard South Shore Program: An update on management of behavioral and psychological symptoms in dementia.

Geriatric patients with dementia frequently present with agitation, aggression, psychosis, and other behavioral and psychological symptoms of dementia (BPSD). We present an update of our previously published algorithms for the use of psychopharmacologic agents in these patients taking into account more recent studies and findings in meta-analyses, reviews, and other published algorithms. We propose three algorithms: BPSD in an emergent, urgent, and non-urgent setting. In the emergent setting when intramuscular (IM) administration is necessary, the first-line recommendation is for olanzapine (since IM aripiprazole, previously favored, is no longer available) and haloperidol injection is the second choice, followed by possible consideration of an IM benzodiazepine. In the urgent setting, the first line would be oral second-generation antipsychotics (SGAs) aripiprazole and risperidone. Perhaps next could be then prazosin, and lastly electroconvulsive therapy is a consideration. There are risks associated with these agents, and adverse effects can be severe. Dosing strategies, discontinuation considerations, and side effects are discussed. In the non-emergent setting, medications are proposed for use in the following order: trazodone, donepezil and memantine, antidepressants such as escitalopram and sertraline, SGAs, prazosin, and carbamazepine. Other options with less support but potential future promise are discussed.

Incident psychopharmacological treatment and psychiatric hospital contact in individuals with newly developed type 2 diabetes - a register-based cohort study.

To investigate the association between newly developed type 2 diabetes (T2D) and incident psychopharmacological treatment and psychiatric hospital contact. Via Danish registers, we identified all 56 640 individuals from the Central and Northern Denmark Regions with newly developed T2D (defined by the first HbA1c measurement ≥6.5%) in 2000-2016 as well as 315 694 age- and sex-matched controls (without T2D). Those having received psychopharmacological treatment or having had a psychiatric hospital contact in the 5 years prior to the onset of T2D were not included. For this cohort, we first assessed the 2-year incidence of psychopharmacological treatment and psychiatric hospital contact. Secondly, via Cox regression, we compared the incidence of psychopharmacological treatment/psychiatric hospital contact among individuals with T2D to propensity score-matched controls - taking a wide range of potential confounders into account. Finally, via Cox proportional hazards regression, we assessed which baseline (T2D onset) characteristics were associated with subsequent psychopharmacological treatment and psychiatric hospital contact. A total of 8.3% of the individuals with T2D initiated psychopharmacological treatment compared to 4.6% of the age- and sex-matched controls. Individuals with T2D were at increased risk of initiating psychopharmacological treatment compared to the propensity score-matched controls (HR = 1.51, 95% CI = 1.43-1.59), whereas their risk of psychiatric hospital contact was not increased to the same extent (HR = 1.14, 95% CI = 0.98-1.32). Older age, somatic comorbidity, and being divorced/widowed were associated with both psychopharmacological treatment and psychiatric hospital contact following T2D. Individuals with T2D are at elevated risk of requiring psychopharmacological treatment.

How a Psychopharmacology Clinical Trial Site in the Seattle Area Managed Clinical Trials and Patient Care During the COVID-19 Pandemic.

OBJECTIVES: As the COVID-19 pandemic developed in March 2020 in greater Seattle, our clinical trial site faced several ethical and clinical dilemmas. We remained open to research patients including high-risk elderly patients and adapted to changing health recommendations. METHODS: Beginning March 14, 2020 we developed an in-person evaluation for potential risk of COVID-19. Included are the first 3 weeks of screening by our physicians for potential exposure to COVID-19, common symptoms, temperature, blood oxygen saturation, and heart rate. Individuals with higher risk (n = 23) were identified and managed. RESULTS: The 825 evaluations included 37 staff, 167 patients, and 152 visitors. No one needed isolation or transfer to acute care facility, staff attendance was 95%, all 33 geriatric patients continued in phase II trials, and others decreased by 5%. CONCLUSION: We share how we incorporated COVID-19 Center for Disease Control health recommendations to a clinical trial center and addition of pulse oximetry.

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.

Genomics and the future of psychopharmacology: MicroRNAs offer novel therapeutics
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MicroRNAs (miRNAs) are short, noncoding RNAs functioning as regulators of the transcription of protein-coding genes in eukaryotes. During the last two decades, studies on miRNAs indicate that they have potential as diagnostic and prognostic biomarkers for a wide range of cancers. Research interest in miRNAs has moved to embrace further medical disciplines, including neuropsychiatric disorders, comparing miRNA expression and mRNA targets between patient and control blood samples and postmortem brain tissues, as well as in animal models of neuropsychiatric disorders. This manuscript reviews recent findings on miRNAs implicated in the pathology of mood disorders, schizophrenia, and autism, as well as their diagnostic potential, and their potential as tentative targets for future therapeutics. The plausible contribution of X chromosome miRNAs to the larger prevalence of major depression among women is also evaluated.
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Los microARN (miARNs) son ARN cortos y no codificantes que funcionan como reguladores de la transcripción de genes que codifican proteínas en los eucariotes. Durante las últimas dos décadas, los estudios sobre miARNs señalan que tienen un potencial como biomarcadores diagnósticos y pronósticos para una amplia gama de cánceres. El interés de la investigación en los miARNs se ha extendido a otras disciplinas médicas, como los trastornos neuropsiquiátricos, donde se compara la expresión de los miARNs y los blancos de ARNm entre las muestras de sangre de pacientes y controles y los tejidos cerebrales postmortem, como también en modelos animales de trastornos neuropsiquiátricos. Este artículo revisa los hallazgos más recientes sobre los miARNs implicados en los trastornos del ánimo, la esquizofrenia y el autismo, así como su potencial en el diagnóstico y como blancos experimentales para futuras terapias. También se evalúa la eventual contribución de los miARNs del cromosoma X a la mayor prevalencia de depresión mayor entre las mujeres.

Les micro-ARN (miARN) sont de courts ARN non codants, fonctionnant comme des régulateurs de la transcription des gènes codant la protéine dans les cellules eucaryotes. D'après des études menées au cours des dix dernières années, les micro-ARN ont un potentiel en tant que biomarqueurs diagnostiques et pronostiques dans une large gamme de cancers. Les centres d'intérêt de la recherche sur les miARN se sont élargis à d'autres disciplines médicales, dont l'étude des maladies neuropsychiatriques, en comparant l'expression des miARN et des ARNm cibles dans des échantillons de sang de patients avec des échantillons de contrôle, dans des tissus cérébraux post-mortem, ainsi que dans des modèles animaux de maladies neuropsychiatriques. Cet article passe en revue les découvertes les plus récentes sur les miARN impliqués dans les pathologies des troubles de l'humeur, la schizophrénie et l'autisme ainsi que leur potentiel diagnostique et thérapeutique en tant que cibles expérimentales pour de futures thérapies. Il y sera également étudié la possible implication des miARN du chromosome X dans la prévalence plus grande de la dépression majeure chez les femmes.

How evolutionary psychiatry can advance psychopharmacology
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The prevailing paradigm for psychopharmacology focuses on understanding brain mechanisms as the key to finding new medications and improving clinical outcomes, but frustration with slow progress has inspired many pleas for new approaches. Evolutionary psychiatry brings in an additional basic science that poses new questions about why natural selection left us vulnerable to so many mental disorders, and new insights about how drugs work. The integration of neuroscience with evolutionary psychiatry is synergistic, going beyond reductionism to provide a model like the one used by the rest of medicine. It recognizes negative emotions as symptoms, that are, like pain and cough, useful defenses whose presence should initiate a search for causes. An integrative evolutionary approach explains why agents that block useful aversive responses are usually safe, and how to anticipate when they may cause harm. More generally, an evolutionary framework suggests novel practical strategies for finding and testing new drugs.
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El paradigma común para la psicofarmacología se centra en entender los mecanismos cerebrales como la clave para encontrar nuevos medicamentos y mejorar los resultados clínicos, pero la frustración con el lento progreso ha inspirado muchos motivos para nuevas aproximaciones. La psiquiatría evolutiva conlleva una ciencia básica adicional que plantea nuevas preguntas sobre el por qué la selección natural nos dejó vulnerables a tantos trastornos mentales y aporta nuevas perspectivas sobre cómo funcionan los fármacos. La integración de las neurociencias con la psiquiatría evolutiva es sinérgica, y va más allá del reduccionismo para proporcionar un modelo como el que utiliza el resto de la medicina. Reconoce las emociones negativas como síntomas, que son, como el dolor y la tos, defensas útiles cuya presencia debe iniciar una búsqueda de causas. Un enfoque evolutivo integrador explica por qué los agentes que bloquean las respuestas aversivas útiles suelen ser seguros y cómo anticipar cuándo pueden causar daño. De manera más general, un marco evolutivo sugiere nuevas estrategias prácticas para encontrar y probar nuevos medicamentos.

Le modèle prévalent de la psychopharmacologie se concentre sur la compréhension des mécanismes du cerveau comme la clé pour découvrir de nouveaux médicaments et améliorer les résultats cliniques, mais la frustration ressentie devant les lents progrès de cette méthode a inspiré de nombreux plaidoyers pour d'autres approches. La psychiatrie évolutionniste apporte une connaissance scientifique fondamentale supplémentaire qui pose de nouvelles questions sur la raison pour laquelle la sélection naturelle nous a laissé si vulnérables à tant de troubles mentaux, et des idées nouvelles sur la façon dont fonctionnent les médicaments. L'intégration de la psychiatrie évolutionniste aux neurosciences est source de synergies, allant bien au-delà du réductionnisme en fournissant un modèle semblable à celui utilisé par le reste de la médecine. Il reconnaît les émotions négatives comme des symptômes, exactement comme le sont la douleur et la toux, défenses habituelles qui doivent initier une recherche des causes. Une approche évolutionniste intégrative explique pourquoi des agents qui bloquent des réactions pertinentes d'aversion sont généralement sans danger, et comment anticiper lorsqu'ils pourraient causer un préjudice. Plus généralement, un modèle évolutionniste propose de nouvelles stratégies pratiques pour trouver et tester de nouveaux médicaments.

Treating psychiatric symptoms and disorders with non-psychotropic medications
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A few drugs prescribed in internal medicine, ie, non-psychotropic drugs, can be used to treat certain neuropsychiatric disorders. For most of these situations, the level of evidence remains low. But when sufficient data becomes available, these molecules are then included in official guidelines for the treatment of neuropsychiatric disorders. In this article we review interesting drugs which may be relevant from an evidence-based medicine point of view, and could become part of psychiatric practice in the future.
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Drug discovery in psychopharmacology: from 2D models to cerebral organoids
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Psychiatric disorders are a heterogeneous group of mental illnesses associated with a high social and economic burden on patients and society. The complex symptomatology of these disorders, coupled with our limited understanding of the structural and functional abnormalities affecting the brains of neuropsychiatric patients, has made it difficult to develop effective medical treatment strategies. With the advent of reprogramming technologies and recent developments in induced pluripotent stem (iPS) cell-based protocols for differentiation into defined neuronal cultures and 3-dimensional cerebral organoids, a new era of preclinical disease modeling has begun which could revolutionize drug discovery in psychiatry. This review provides an overview of iPS cell-based disease models in psychiatry and how these models contribute to our understanding of pharmacological drug action. We also propose a refined iPSC-based drug discovery pipeline, ranging from cell-based stratification of patients through improved screening and validation steps to more precise psychopharmacology.
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European college of neuropsychopharmacology network on the prevention of mental disorders and mental health promotion (ECNP PMD-MHP).

Prevention is the most promising way to reduce the high personal, familial, societal, clinical and economic costs of mental disorders in Europe and worldwide. A complementary approach is to go beyond the prevention of mental ill health, to promote good mental health. This manuscript highlights the first European consortium fostering cutting-edge multidisciplinary research in these two areas. The ECNP-funded Network on the Prevention of Mental Disorders and Mental Health Promotion (ECNP PMD-MHP) brings together European sites of excellence with different expertise for translational research collaboration, including partnerships with the industry. The ECNP PMD-MHP Network adopts a transdiagnostic, lifespan, clinical staging model which cuts across different mental disorders and different methodologies. The main aims of the ECNP PMD-MHP Network are to facilitate multidisciplinary collaboration, enhance knowledge and data sharing, standardise core assessment and outcome measures, promote clinical research, apply for grant funding, and generate research reports. By supporting collaborative research, the ECNP PMD-MHP Network will be vital for fostering European psychiatry in the field of prevention of mental disorders and promotion of good mental health.

Clinical guidelines for the management of treatment-resistant depression: French recommendations from experts, the French Association for Biological Psychiatry and Neuropsychopharmacology and the fondation FondaMental.

BACKGROUND: Clear guidance for successive antidepressant pharmacological treatments for non-responders in major depression is not well established. METHOD: Based on the RAND/UCLA Appropriateness Method, the French Association for Biological Psychiatry and Neuropsychopharmacology and the fondation FondaMental developed expert consensus guidelines for the management of treatment-resistant depression. The expert guidelines combine scientific evidence and expert clinicians' opinions to produce recommendations for treatment-resistant depression. A written survey comprising 118 questions related to highly-detailed clinical presentations was completed on a risk-benefit scale ranging from 0 to 9 by 36 psychiatrist experts in the field of major depression and its treatments. Key-recommendations are provided by the scientific committee after data analysis and interpretation of the results of the survey. RESULTS: The scope of these guidelines encompasses the assessment of pharmacological resistance and situations at risk of resistance, as well as the pharmacological and psychological strategies in major depression. CONCLUSION: The expert consensus guidelines will contribute to facilitate treatment decisions for clinicians involved in the daily assessment and management of treatment-resistant depression across a number of common and complex clinical situations.

Computational psychopharmacology: a translational and pragmatic approach.

RATIONALE: Psychopharmacology needs novel quantitative measures and theoretical approaches based on computational modelling that can be used to help translate behavioural findings from experimental animals to humans, including patients with neuropsychiatric disorders. OBJECTIVES: This brief review exemplifies this approach when applied to recent published studies of the effects of manipulating central dopaminergic and serotoninergic systems in rodents and marmoset monkeys, and possible comparisons with healthy human volunteers receiving systemic agents or patients with depression and schizophrenia. METHODS: Behavioural effects of central depletions of dopamine or serotonin in monkeys in probabilistic learning paradigms are characterised further by computational modelling methods and related to rodent and human data. RESULTS: Several examples are provided of the power of computational modelling to derive new measures and reappraise conventional explanations of regional neurotransmitter depletion and other drug effects, whilst enhancing construct validation in patient groups. Specifically, effects are shown on such parameters as 'stimulus stickiness' and 'side stickiness', which occur over and above effects on standard parameters of reinforcement learning, reminiscent of some early innovations in data analysis in psychopharmacology. CONCLUSIONS: Computational modelling provides a useful methodology for further detailed analysis of behavioural mechanisms that are affected by pharmacological manipulations across species and will aid the translation of experimental findings to understand the therapeutic effects of medications in neuropsychiatric disorders, as well as facilitating future drug discovery.

British Association for Psychopharmacology consensus statement on evidence-based treatment of insomnia, parasomnias and circadian rhythm disorders: An update.

This British Association for Psychopharmacology guideline replaces the original version published in 2010, and contains updated information and recommendations. A consensus meeting was held in London in October 2017 attended by recognised experts and advocates in the field. They were asked to provide a review of the literature and identification of the standard of evidence in their area, with an emphasis on meta-analyses, systematic reviews and randomised controlled trials where available, plus updates on current clinical practice. Each presentation was followed by discussion, aiming to reach consensus where the evidence and/or clinical experience was considered adequate, or otherwise to flag the area as a direction for future research. A draft of the proceedings was circulated to all speakers for comments, which were incorporated into the final statement.

Clinical guidelines for the management of depression with specific comorbid psychiatric conditions French recommendations from experts (the French Association for Biological Psychiatry and Neuropsychopharmacology and the fondation FondaMental).

BACKGROUND: Recommendations for pharmacological treatments of major depression with specific comorbid psychiatric conditions are lacking. METHOD: The French Association for Biological Psychiatry and Neuropsychopharmacology and the fondation FondaMental developed expert consensus guidelines for the management of depression based on the RAND/UCLA Appropriatneness Method. Recommendations for lines of treatment are provided by the scientific committee after data analysis and interpretation of the results of a survey of 36 psychiatrist experts in the field of major depression and its treatments. RESULTS: The expert guidelines combine scientific evidence and expert clinician's opinion to produce recommendations for major depression with comorbid anxiety disorders, personality disorders or substance use disorders and in geriatric depression. CONCLUSION: These guidelines provide direction addressing common clinical dilemmas that arise in the pharmacologic treatment of major depression with comorbid psychiatric conditions.

The Psychopharmacology Algorithm Project at the Harvard South Shore Program: An Update on Unipolar Nonpsychotic Depression.

BACKGROUND: The Psychopharmacology Algorithm Project at the Harvard South Shore Program presents evidence-based recommendations considering efficacy, tolerability, safety, and cost. Two previous algorithms for unipolar nonpsychotic depression were published in 1993 and 1998. New studies over the last 20 years suggest that another update is needed. METHODS: The references reviewed for the previous algorithms were reevaluated, and a new literature search was conducted to identify studies that would either support or alter the previous recommendations. Other guidelines and algorithms were consulted. We considered exceptions to the main algorithm, as for pregnant women and patients with anxious distress, mixed features, or common medical and psychiatric comorbidities. SUMMARY: For inpatients with severe melancholic depression and acute safety concerns, electroconvulsive therapy (or ketamine if ECT refused or ineffective) may be the first-line treatment. In the absence of an urgent indication, we recommend trialing venlafaxine, mirtazapine, or a tricyclic antidepressant. These may be augmented if necessary with lithium or T3 (triiodothyronine). For inpatients with non-melancholic depression and most depressed outpatients, sertraline, escitalopram, and bupropion are reasonable first choices. If no response, the prescriber (in collaboration with the patient) has many choices for the second trial in this algorithm because there is no clear preference based on evidence, and there are many individual patient considerations to take into account. If no response to the second medication trial, the patient is considered to have a medication treatment-resistant depression. If the patient meets criteria for the atypical features specifier, a monoamine oxidase inhibitor could be considered. If not, reconsider (for the third trial) some of the same options suggested for the second trial. Some other choices can also considered at this stage. If the patient has comorbidities such as chronic pain, obsessive-compulsive disorder, attention-deficit/hyperactivity disorder, or posttraumatic stress disorder, the depression could be secondary; evidence-based treatments for those disorders would then be recommended.