RESUMO
This single-center study administered MIJ821 (onfasprodil) as an intravenous infusion to healthy volunteers and included two parts: a single ascending dose study (Part 1) and a repeated intravenous dose study (Part 2). Primary objective was to evaluate the safety and tolerability of single ascending intravenous doses infused over a 40-min period and of two repeated doses (1 week apart) of MIJ821 in healthy volunteers. Secondary objectives were to assess the pharmacokinetics of MIJ821 after intravenous infusion in Part 1 and Part 2 of the study. Overall, 43 subjects in Part 1 and 12 subjects in Part 2 were randomized in the study. Median age in Part 1 and Part 2 was 45.0 and 43.5 years, respectively, with the majority being Caucasian (Part 1: 84%; Part 2: 92%). 19 subjects (44.2%) in Part 1 and 8 subjects (66.7%) in Part 2 experienced at least one adverse event (AE). Following single dose in Part 1 and Part 2, the AUCinf values of MIJ821 increased in a dose-proportional manner across the dose range 0.016-0.48 mg/kg and the Cmax values in a slight overproportional manner across the dose range 0.048-0.48 mg/kg. At the highest dose of 0.48 mg/kg, the geometric mean AUCinf was 708 h ng/mL and the geometric mean Cmax was 462 ng/mL. Inspection of 1-h post-dose resting electroencephalography activity across cohorts showed a relationship to administered dose, providing exploratory evidence of distal target engagement. In conclusion, MIJ821 showed a good safety and tolerability profile in healthy volunteers. Dissociative AEs were mild, transient, and dose-dependent.
Assuntos
Infusões Intravenosas , Humanos , Método Duplo-Cego , Área Sob a Curva , Voluntários Saudáveis , Relação Dose-Resposta a DrogaRESUMO
ABSTRACT: Adult attention-deficit disorder (ADD) is a common diagnosis, and amphetamine medications are increasingly used. Recent reports suggest high prevalence of affective temperaments, such as cyclothymia, in adult ADD. This study reexamines prevalence rates as reflecting misdiagnosis and reports for the first time on the effects of amphetamine medications on mood/anxiety and cognition in relation to affective temperaments. Among outpatients treated at the Tufts Medical Center Mood Disorders Program (2008-2017), 87 cases treated with amphetamines were identified, versus 163 non-amphetamine-treated control subjects. Using the Temperament Scale of Memphis, Pisa, Paris and San Diego-Autoquestionnaire, 62% had an affective temperament, most commonly cyclothymia (42%). In amphetamine-treated cases, mood/anxiety symptoms worsened notably in 27% ( vs. 4% in the control group, risk ratio [RR] 6.2, confidence interval [CI], 2.8-13.8), whereas 24% had moderate improvement in cognition ( vs. 6% in the control group; RR, 3.93; CI, 1.9-8.0). Affective temperaments, especially cyclothymia, are present in persons about one-half of persons diagnosed with adult ADD and/or treated with amphetamines.
Assuntos
Transtorno do Deficit de Atenção com Hiperatividade , Transtorno Bipolar , Adulto , Humanos , Temperamento , Transtorno Bipolar/psicologia , Transtorno do Deficit de Atenção com Hiperatividade/diagnóstico , Transtorno do Deficit de Atenção com Hiperatividade/tratamento farmacológico , Transtorno do Deficit de Atenção com Hiperatividade/epidemiologia , Prevalência , Transtorno Ciclotímico/diagnóstico , Transtorno Ciclotímico/epidemiologia , Transtorno Ciclotímico/psicologia , Inquéritos e Questionários , Inventário de PersonalidadeRESUMO
William Osler (1849-1919) is often considered the most influential physician in the emergence of science-based medicine. However, his approach to clinical medicine tends to be misunderstood, and its relevance to psychiatry has not been explored systematically. Osler's approach to the patient had four components: biological reductionism about disease, a scientific approach to clinical diagnosis, therapeutic conservatism, and a humanistic approach to the person. These concepts conflict with the pragmatic, eclectic, anti-reductionistic assumptions of contemporary psychiatry, as codified in its interpretation of a "biopsychosocial" model. This model leads to unscientific practice, with excessive use of medications given for symptoms, and inattention to identifying and treating diseases. This article suggests that implementing Osler's philosophy of medicine in psychiatry would greatly benefit the latter. It would inaugurate a new "biohumanistic" approach to psychiatry.
Assuntos
Psiquiatria , Psiquiatria/história , Humanos , História do Século XX , História do Século XIX , Filosofia Médica/história , Transtornos Mentais/história , Transtornos Mentais/tratamento farmacológicoRESUMO
BACKGROUND: In the 1970 s, scientific research on psychiatric nosology was summarized in Research Diagnostic Criteria (RDC), based solely on empirical data, an important source for the third revision of the official nomenclature of the American Psychiatric Association in 1980, the Diagnostic and Statistical Manual, Third Edition (DSM-III). The intervening years, especially with the fourth edition in 1994, saw a shift to a more overtly "pragmatic" approach to diagnostic definitions, which were constructed for many purposes, with research evidence being only one consideration. The latest editions have been criticized as failing to be useful for research. Biological and clinical research rests on the validity of diagnostic definitions that are supported by firm empirical foundations, but critics note that DSM criteria have failed to prioritize research data in favor of "pragmatic" considerations. RESULTS: Based on prior work of the International Society for Bipolar Diagnostic Guidelines Task Force, we propose here Clinical Research Diagnostic Criteria for Bipolar Illness (CRDC-BP) for use in research studies, with the hope that these criteria may lead to further refinement of diagnostic definitions for other major mental illnesses in the future. New proposals are provided for mixed states, mood temperaments, and duration of episodes. CONCLUSIONS: A new CRDC could provide guidance toward an empirically-based, scientific psychiatric nosology, and provide an alternative clinical diagnostic approach to the DSM system.
RESUMO
BACKGROUND: Current psychiatric drug discovery and development has not produced very effective medications in the past few decades. Conventional wisdom provides reasons for failure that do not address major structural obstacles to true innovation for psychiatric drugs. METHOD: Narrative review based on analysis of the scientific literature augmented by personal experience in academic clinical research as well as in the pharmaceutical industry. RESULTS: The largest obstacles to drug discovery and development are the biological invalidity of most DSM diagnoses, the economic incentives to produce short-term symptomatic treatments with blockbuster profit potential, and very low thresholds set by the FDA for ending drug discovery due to toxicity. Since these larger structural socio-economic obstacles to drug development will be difficult to change, a new proposal is made for a parallel non-profit drug discovery paradigm, to be funded by governments, akin to the development of vaccines for the Covid-19 pandemic. The key public health implications are highlighted in the example of developing new drugs for Alzheimer dementia, and the potential utility of an anti-tau agent like lithium, currently ignored in drug development in favor of much more expensive and questionably effective amyloid-reducing agents. CONCLUSIONS: Given the key structural problems of psychiatric drug discovery and development, a parallel non-profit drug discovery paradigm is needed to meet all public health needs, as well as to reinvigorate truly innovative and transformative research.
Assuntos
Vacinas contra COVID-19 , COVID-19 , Humanos , Descoberta de Drogas , Indústria Farmacêutica , Desenvolvimento de MedicamentosRESUMO
OBJECTIVE: Drugs can be divided into two major categories, symptomatic and disease modifying. This review explores whether and how psychiatric drugs fall into one or the other of those categories, and the implications of those results for clinical practice and research in psychopharmacology. METHOD: Narrative review. RESULTS: Most psychiatric drugs have only short-term effects of improving active symptoms. They do not show long-term benefits for the underlying disease, such as improving the course of illness and improving mortality. Evidence is provided for this claim in the treatment literature of antidepressants for depressive illness and antipsychotics for schizophrenia. Developing truly beneficial drugs for disease modification also is limited by the poor clinical and biological validity of Diagnostic and Statistical Manual diagnoses as well as the use of invalid falsely positive maintenance efficacy randomized discontinuation trial designs. CONCLUSIONS: Current psychopharmacology is limited mostly to symptomatic effects, not transformative treatments for the diseases underlying those symptoms. A change in approach is needed in psychopharmacology practice and research, focusing on long-term disease modification rather than short-term symptom improvement.
Assuntos
Antidepressivos , Antipsicóticos , Antidepressivos/farmacologia , Antidepressivos/uso terapêutico , Antipsicóticos/farmacologia , Antipsicóticos/uso terapêutico , Manual Diagnóstico e Estatístico de Transtornos Mentais , HumanosRESUMO
BACKGROUND: Antipsychotic medications have limited benefits in schizophrenia, and cognitive behavioral therapy may be beneficial as an adjunct. There may be potential for implementing mobile cognitive behavioral therapy-based treatment for schizophrenia in addition to standard antipsychotic medications. OBJECTIVE: This study aims to determine whether PEAR-004, a smartphone-based investigational digital therapeutic, improves the symptoms of an acute psychotic exacerbation of schizophrenia when it is added to standard treatments. METHODS: This was a 12-week, multicenter, randomized, sham-controlled, rater-blinded, parallel group proofofconcept study of 112 participants with moderate acute psychotic exacerbation in schizophrenia. This study was conducted in 6 clinical trial research sites in the United States from December 2018 to September 2019. The primary outcome, change in Positive and Negative Syndrome Scale (PANSS) from baseline to week 12 or the last available visit, was analyzed using the mixed-effects regression model for repeated measures, applied to an intent-to-treat sample. RESULTS: The total PANSS scores slightly decreased from baseline over the study period in both groups; the treatment difference at day 85 between PEAR-004 and sham was 2.7 points, in favor of the sham (2-sided P=.09). The secondary scales found no benefit, except for transient improvement in depressive symptoms with PEAR-004. Application engagement was good, and patient and clinical investigator satisfaction was high. No safety concerns were observed. There was some evidence of study site heterogeneity for the onboarding processes and directions on PEAR-004 product use at baseline and throughout the study. However, these differences did not affect the efficacy results. CONCLUSIONS: In the largest-to-date randomized, sham-controlled study of a digital therapeutic in schizophrenia, PEAR-004 did not demonstrate an effect on the primary outcome-total PANSS scores-when compared with a nonspecific digital sham control. The secondary and exploratory results also did not demonstrate any notable benefits, except for possible temporary improvement in depressive symptoms. This study provided many useful scientific and operational insights that can be used in the further clinical development of PEAR-004 and other investigational digital therapeutics. TRIAL REGISTRATION: ClinicalTrials.gov NCT03751280; https://clinicaltrials.gov/ct2/show/NCT03751280.
RESUMO
Clinicians and patients often try a treatment for an initial period to inform longer-term therapeutic decisions. A more rigorous approach involves N-of-1 trials. In these single-patient crossover trials, typically conducted in patients with chronic conditions, individual patients are given candidate treatments in a double-blinded, random sequence of alternating periods to determine the most effective treatment for that patient. However, to date, these trials are rarely done outside of research settings and have not been integrated into general care where they could offer substantial benefit. Designating this classical, N-of-1 trial design as type 1, there also are new and evolving uses of N-of-1 trials that we designate as type 2. In these, rather than focusing on optimizing treatment for chronic diseases when multiple approved choices are available, as is typical of type 1, a type 2 N-of-1 trial tests treatments designed specifically for a patient with a rare disease, to facilitate personalized medicine. While the aims differ, both types face the challenge of collecting individual-patient evidence using standard, trusted, widely accepted methods. To fulfill their potential for producing both clinical and research benefits, and to be available for wide use, N-of-1 trials will have to fit into the current healthcare ecosystem. This will require generalizable and accepted processes, platforms, methods, and standards. This also will require sustainable value-based arrangements among key stakeholders. In this article, we review opportunities, stakeholders, issues, and possible approaches that could support general use of N-of-1 trials and deliver benefit to patients and the healthcare enterprise. To assess and expand the benefits of N-of-1 trials, we propose multistakeholder meetings, workshops, and the generation of methods, standards, and platforms that would support wider availability and the value of N-of-1 trials.
Assuntos
Atenção à Saúde , Ecossistema , Humanos , Resultado do TratamentoRESUMO
Second messenger systems, like the cyclic nucleotide, glycogen synthase kinase-3ß, phosphoinositide, and arachidonic acid cascades, are involved in bipolar disorder (BD). We investigated their role on the development of novel therapeutic drugs using second messenger mechanisms. PubMed search and narrative review. We used all relevant keywords for each second messenger cascade combining it with BD and related terms and combined all with novel/innovative treatments/drugs. Our search produced 31 papers most were reviews, and focussed on the PI3K/AKT-GSK-3ß/Nrf2-NF-ĸB pathways. Only two human randomized clinical trials were identified, of ebselen, an antioxidant, and celecoxib, a cyclooxygenase-2 inhibitor, both with poor unsatisfactory results. Despite the fact that all second messenger systems are involved in the pathophysiology of BD, there are few experiments with novel drugs using these mechanisms. These mechanisms are a neglected and potentially major opportunity to transform the treatment of bipolar illness.
Assuntos
Transtorno Bipolar , Humanos , Transtorno Bipolar/tratamento farmacológico , Transtorno Bipolar/metabolismo , Glicogênio Sintase Quinase 3 beta/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Fosfatidilinositol 3-Quinases/uso terapêutico , Sistemas do Segundo MensageiroRESUMO
OBJECTIVES: Polypharmacy is common in maintenance treatment of bipolar illness, but proof of greater efficacy compared to monotherapy is assumed rather than well known. We systematically reviewed the evidence from the literature to provide recommendations for clinical management and future research. METHOD: A systematic review was conducted on the use of polypharmacy in bipolar prophylaxis. Relevant papers published in English through 31 December 2019 were identified searching the electronic databases MEDLINE, Embase, PsycINFO, and the Cochrane Library. RESULTS: Twelve studies matched inclusion criteria, including 10 randomized controlled trials (RCTs). The best drug combination in prevention is represented by lithium + valproic acid which showed a significant effect on time to mood relapses (HR = 0.57) compared to valproic acid monotherapy, especially for manic episodes (HR = 0.51). The effect was significant in terms of time to new drug treatment (HR = 0.51) and time to hospitalization (HR = 0.57). A significant reduction in the frequency of mood relapses was also reported for lithium + valproic acid vs. lithium monotherapy (RR=0.12); however, the trial had a small sample size. Lamotrigine + valproic acid reported significant efficacy in prevention of depressive episodes compared to lamotrigine alone. CONCLUSIONS: The literature to support a generally greater efficacy with polypharmacy in bipolar illness is scant and heterogeneous. Within that limited evidence base, the best drug combination in bipolar prevention is represented by lithium + valproic acid for manic, but not depressive episodes. Clinical practice should focus more on adequate monotherapy before considering polypharmacy.
Assuntos
Transtorno Bipolar , Antimaníacos/uso terapêutico , Transtorno Bipolar/tratamento farmacológico , Humanos , Compostos de Lítio/uso terapêutico , Polimedicação , Ácido Valproico/uso terapêuticoRESUMO
While serotonin reuptake inhibitors are sometimes used in clinical practice to treat acute bipolar depression, the neurophysiological substrates underlying their efficacy are little studied. In the context of a larger clinical efficacy trial, the present study explored neural mechanisms associated with citalopram versus placebo treatment for bipolar depression. FDG-PET imaging examined whole-brain metabolic changes before and after treatment. Clinical efficacy was similar for citalopram versus placebo. Neuroimaging results demonstrated greater glucose metabolism in the left orbitofrontal cortex (OFC) before treatment (combined citalopram and placebo subjects) relative to after treatment, but did not correlate with clinical recovery. Glucose metabolism in the left OFC was also a predictor of depression severity when baseline scans were regressed with baseline MADRS scores. Despite of our small sample size and possibly underpowered whole-brain analysis approach, these preliminary results suggest the OFC, a key region involved in reward circuity, may be a neural substrate for depressive symptom improvement in bipolar depression, regardless of whether due to active treatment or placebo.
Assuntos
Transtorno Bipolar , Citalopram , Transtorno Bipolar/diagnóstico por imagem , Transtorno Bipolar/tratamento farmacológico , Citalopram/uso terapêutico , Depressão , Método Duplo-Cego , Humanos , Efeito Placebo , Inibidores Seletivos de Recaptação de Serotonina , Resultado do TratamentoRESUMO
OBJECTIVE: To assess the efficacy and safety of citalopram in the acute and maintenance phases of bipolar depression in a randomized, double-blind, placebo-controlled trial. METHODS: Between 2007 and 2014, 119 subjects with acute major depressive episodes diagnosed with DSM-IV bipolar disorder, type I or type II, were randomized blindly to citalopram or placebo, added to standard mood stabilizers. They were followed for 6 weeks for acute efficacy (primary outcome) and up to 1 year for maintenance efficacy (secondary outcome) using scores on the Montgomery-Asberg Depression Rating Scale (MADRS) and the Mania Rating Scale of the Schedule for Affective Disorders and Schizophrenia (MRS-SADS). The study was powered for a clinically meaningful effect size. RESULTS: Mean ± SD MADRS scores changed from a baseline value of 27.4 ± 9.1 to 13.1 ± 8.4 at the end of the acute phase for citalopram versus a change from 27.4 ± 7.3 to 15.2 ± 9.9 for placebo, a clinically and statistically nonsignificant difference. Maintenance efficacy also was not better with citalopram than with placebo. Acute manic/hypomanic episodes were similar in both groups, and subjects with type II illness did not have better outcomes than subjects with type I illness. In maintenance treatment, MRS-SADS scores were greater overall, especially in subjects with a rapid-cycling illness course, with citalopram versus placebo. CONCLUSIONS: Citalopram, added to standard mood stabilizers, did not have clinically meaningful benefit versus placebo for either acute or maintenance treatment of bipolar depression. Acute mania did not worsen with citalopram, but maintenance treatment led to worsened manic symptoms, especially in subjects with a rapid-cycling course. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00562861.
Assuntos
Antidepressivos de Segunda Geração/uso terapêutico , Transtorno Bipolar/tratamento farmacológico , Transtorno Bipolar/prevenção & controle , Citalopram/uso terapêutico , Doença Aguda , Adolescente , Adulto , Método Duplo-Cego , Esquema de Medicação , Quimioterapia Combinada , Feminino , Seguimentos , Humanos , Quimioterapia de Indução , Análise de Intenção de Tratamento , Quimioterapia de Manutenção , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento , Adulto JovemRESUMO
BACKGROUND: Depression is a leading cause of disability. International guidelines recommend screening for depression and the Patient Health Questionnaire 9 (PHQ-9) has been identified as the most reliable screening tool. We reviewed the evidence for using it within the primary care setting. METHODS: We retrieved studies from MEDLINE, Embase, PsycINFO, CINAHL and the Cochrane Library that carried out primary care-based depression screening using PHQ-9 in populations older than 12, from 1995 to 2018. RESULTS: Forty-two studies were included in the systematic review. Most of the studies were cross-sectional (N=40, 95%), conducted in high-income countries (N=27, 71%) and recruited adult populations (N=38, 90%). The accuracy of the PHQ-9 was evaluated in 31 (74%) studies with a two-stage screening system, with structured interview most often carried out by primary care and mental health professionals. Most of the studies employed a cut-off score of 10 (N=24, 57%, total range 5 - 15). The overall sensitivity of PHQ-9 ranged from 0.37 to 0.98, specificity from 0.42 to 0.99, positive predictive value from 0.09 to 0.92, and negative predictive value from 0.8 to 1. LIMITATIONS: Lack of longitudinal studies, small sample size, and the heterogeneity of primary-care settings limited the generalizability of our results. CONCLUSIONS: PHQ-9 has been widely validated and is recommended in a two-stage screening process. Longitudinal studies are necessary to provide evidence of long-term screening effectiveness.
Assuntos
Transtorno Depressivo Maior , Questionário de Saúde do Paciente , Adulto , Estudos Transversais , Depressão/diagnóstico , Humanos , Programas de Rastreamento , Atenção Primária à Saúde , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Inquéritos e QuestionáriosRESUMO
Not required.
Assuntos
Betacoronavirus , Infecções por Coronavirus/complicações , Pandemias , Pneumonia Viral/complicações , Psiquiatria/métodos , Transtornos Psicóticos/complicações , Telemedicina/métodos , COVID-19 , Infecções por Coronavirus/epidemiologia , Humanos , Pneumonia Viral/epidemiologia , Transtornos Psicóticos/psicologia , Transtornos Psicóticos/terapia , Consulta Remota/métodos , SARS-CoV-2RESUMO
INTRODUCTION: A new mood rating scale for mixed states of depression along with manic-like excitatory symptoms, the Koukopoulos Mixed Depression Rating Scale (KMDRS), was assessed in a post hoc analysis of a randomized clinical trial of lurasidone versus placebo in major depressive disorder (MDD) with mixed features. METHODS: The KMDRS was compared with the Montgomery Asberg Depression Rating Scale (MADRS) and the Young Mania Rating Scale (YMRS). Item weighting was performed and compared with an original KMDRS validation data set. Weighting was used to provide imputed KMDRS scores in the lurasidone study, based on observed MADRS and YMRS scores. RESULTS: Standardized effect sizes were larger for MADRS (0.61) and YMRS (0.79) than for KMDRS (0.44, Cohen d). CONCLUSIONS: This analysis did not find that the KMDRS produced a larger effect size than the MADRS in Diagnostic and Statistical Manual for Mental Disorder-5 (DSM-5) defined MDD with mixed features. The lower utility of KMDRS may be due to the imputed nature of this analysis, or also to the DSM-5 defined patient population, which may reflect mixed hypomania rather than mixed depression.
Assuntos
Afeto/efeitos dos fármacos , Antidepressivos/uso terapêutico , Transtorno Depressivo Maior/tratamento farmacológico , Cloridrato de Lurasidona/uso terapêutico , Escalas de Graduação Psiquiátrica , Antidepressivos/efeitos adversos , Transtorno Depressivo Maior/diagnóstico , Transtorno Depressivo Maior/psicologia , Humanos , Cloridrato de Lurasidona/efeitos adversos , Valor Preditivo dos Testes , Fatores de Tempo , Resultado do TratamentoRESUMO
Excipients, considered "inactive ingredients," are a major component of formulated drugs and play key roles in their pharmacokinetics. Despite their pervasiveness, whether they are active on any targets has not been systematically explored. We computed the likelihood that approved excipients would bind to molecular targets. Testing in vitro revealed 25 excipient activities, ranging from low-nanomolar to high-micromolar concentration. Another 109 activities were identified by testing against clinical safety targets. In cellular models, five excipients had fingerprints predictive of system-level toxicity. Exposures of seven excipients were investigated, and in certain populations, two of these may reach levels of in vitro target potency, including brain and gut exposure of thimerosal and its major metabolite, which had dopamine D3 receptor dissociation constant K d values of 320 and 210 nM, respectively. Although most excipients deserve their status as inert, many approved excipients may directly modulate physiologically relevant targets.