RESUMEN
Criteria for treatment-resistant depression (TRD) and partially responsive depression (PRD) as subtypes of major depressive disorder (MDD) are not unequivocally defined. In the present document we used a Delphi-method-based consensus approach to define TRD and PRD and to serve as operational criteria for future clinical studies, especially if conducted for regulatory purposes. We reviewed the literature and brought together a group of international experts (including clinicians, academics, researchers, employees of pharmaceutical companies, regulatory bodies representatives, and one person with lived experience) to evaluate the state-of-the-art and main controversies regarding the current classification. We then provided recommendations on how to design clinical trials, and on how to guide research in unmet needs and knowledge gaps. This report will feed into one of the main objectives of the EUropean Patient-cEntric clinicAl tRial pLatforms, Innovative Medicines Initiative (EU-PEARL, IMI) MDD project, to design a protocol for platform trials of new medications for TRD/PRD.
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Trastorno Depresivo Mayor , Trastorno Depresivo Resistente al Tratamiento , Depresión , Trastorno Depresivo Mayor/tratamiento farmacológico , Trastorno Depresivo Resistente al Tratamiento/tratamiento farmacológico , HumanosRESUMEN
Brexpiprazole is an oral antipsychotic agent indicated for use in patients with schizophrenia or as adjunctive treatment for major depressive disorder. As obesity (body mass index ≥35 kg/m2 ) has the potential to affect drug pharmacokinetics and is a common comorbidity of both schizophrenia and major depressive disorder, it is important to understand changes in brexpiprazole disposition in this population. This study uses a whole-body physiologically based pharmacokinetic model to compare the pharmacokinetics of brexpiprazole in obese and normal-weight (body mass index 18-25 kg/m2 ) individuals known to be cytochrome P450 2D6 extensive metabolizers (EMs) and poor metabolizers (PMs). The physiologically based pharmacokinetic simulations demonstrated significant differences in the time to effective concentrations between obese and normal-weight individuals within metabolizer groups according to the label-recommended titration. Simulations using an alternative dosing strategy of 1 week of twice-daily dosing in obese EMs or 2 weeks of twice-daily dosing in obese poor metabolizers, followed by a return to once-daily dosing, yielded more consistent plasma concentrations between normal-weight and obese patients without exceeding the area under the plasma concentration-time curve observed in the normal-weight EMs. These alternative dosing strategies reduce the time to effective concentrations in obese patients and may improve clinical response to brexpiprazole.
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Antipsicóticos/farmacocinética , Citocromo P-450 CYP2D6/metabolismo , Obesidad/epidemiología , Quinolonas/farmacocinética , Tiofenos/farmacocinética , Antipsicóticos/administración & dosificación , Antipsicóticos/uso terapéutico , Área Bajo la Curva , Índice de Masa Corporal , Simulación por Computador , Esquema de Medicación , Femenino , Humanos , Masculino , Modelos Biológicos , Quinolonas/administración & dosificación , Quinolonas/uso terapéutico , Esquizofrenia/tratamiento farmacológico , Tiofenos/administración & dosificación , Tiofenos/uso terapéuticoRESUMEN
Accounting for subject nonadherence and eliminating inappropriate subjects in clinical trials are critical elements of a successful study. Nonadherence can increase variance, lower study power, and reduce the magnitude of treatment effects. Inappropriate subjects (including those who do not have the illness under study, fail to report exclusionary conditions, falsely report medication adherence, or participate in concurrent trials) confound safety and efficacy signals. This paper, a product of the International Society for CNS Clinical Trial Methodology (ISCTM) Working Group on Nonadherence in Clinical Trials, explores and models nonadherence in clinical trials and puts forth specific recommendations to identify and mitigate its negative effects. These include statistical analyses of nonadherence data, novel protocol design, and the use of biomarkers, subject registries, and/or medication adherence technologies.
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Ensayos Clínicos como Asunto/normas , Internacionalidad , Cooperación del Paciente/psicología , Ensayos Clínicos como Asunto/métodos , Femenino , Humanos , Masculino , Cumplimiento de la Medicación/psicología , Participación del Paciente/métodos , Participación del Paciente/psicologíaRESUMEN
The success rate in the development of psychopharmacological compounds is insufficient. Two main reasons for failure have been frequently identified: 1) treating the wrong patients and 2) using the wrong dose. This is potentially based on the known heterogeneity among patients, both on a syndromal and a biological level. A focus on personalized medicine through better characterization with biomarkers has been successful in other therapeutic areas. Nevertheless, obstacles toward this goal that exist are 1) the perception of a lack of validation, 2) the perception of an expensive and complicated enterprise, and 3) the perception of regulatory hurdles. The authors tackle these concerns and focus on the utilization of biomarkers as predictive markers for treatment outcome. The authors primarily cover examples from the areas of major depression and schizophrenia. Methodologies covered include salivary and plasma collection of neuroendocrine, metabolic, and inflammatory markers, which identified subgroups of patients in the Netherlands Study of Depression and Anxiety. A battery of vegetative markers, including sleep-electroencephalography parameters, heart rate variability, and bedside functional tests, can be utilized to characterize the activity of a functional system that is related to treatment refractoriness in depression (e.g., the renin-angiotensin-aldosterone system). Actigraphy and skin conductance can be utilized to classify patients with schizophrenia and provide objective readouts for vegetative activation as a functional marker of target engagement. Genetic markers, related to folate metabolism, or folate itself, has prognostic value for the treatment response in patients with schizophrenia. Already, several biomarkers are routinely collected in standard clinical trials (e.g., blood pressure and plasma electrolytes), and appear to be differentiating factors for treatment outcome. Given the availability of a wide variety of markers, the further development and integration of such markers into clinical research is both required and feasible in order to meet the benefit of personalized medicine. This article is based on proceedings from the "Taking Personalized Medicine Seriously-Biomarker Approaches in Phase IIb/III Studies in Major Depression and Schizophrenia" session, which was held during the 10th Annual Scientific Meeting of the International Society for Clinical Trials Meeting (ISCTM) in Washington, DC, February 18 to 20, 2014.
RESUMEN
Schizophrenia is a complex, heterogeneous, multidimensional disorder within which negative symptoms are a significant and disabling feature. Whilst there is no established treatment for these symptoms, some pharmacological and psychosocial interventions have shown promise and this is an active area of research. Despite the effort to identify effective interventions, as yet there is no broadly accepted definition of therapeutic success. This article reviews concepts of clinical relevance and reports on a consensus conference whose goal was to apply these concepts to the treatment of negative symptoms. A number of key issues were identified and discussed including: assessment of specific negative symptom domains; defining response and remission for negative symptoms; assessment of functional outcomes; measurement of outcomes within clinical trials; and the assessment of duration/persistence of a response. The group reached a definition of therapeutic success using an achieved threshold of function that persisted over time. Recommendations were agreed upon with respect to: assessment of negative symptom domains of apathy-avolition and deficit of expression symptoms; thresholds for response and remission of negative symptoms based on level of symptomatology; assessing multiple domains of function including social occupation, activities of daily living, and socialization; the need for clinical trial data to include rate of change over time and converging sources of evidence; use of clinician, patient and caregiver perspectives to assess success; and the need for establishing criteria for the persistence of therapeutic benefit. A consensus statement and associated research criteria are offered as an initial step towards developing broad agreement regarding outcomes of negative symptoms treatment.
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Esquizofrenia/terapia , Conferencias de Consenso como Asunto , Humanos , Psicología del EsquizofrénicoRESUMEN
BACKGROUND: There is growing research interest in studying motivational deficits in different neuropsychiatric disorders because these symptoms appear to be more common than originally reported and negatively impact long-term functional outcomes. However, there is considerable ambiguity in the terminology used to describe motivational deficits in the scientific literature. For the purposes of this manuscript, the term "amotivation" will be utilised in the context of mood disorders, since this is considered a more inclusive/appropriate term for this patient population. Other challenges impacting the study of amotivation in mood disorders, include: appropriate patient population selection; managing or controlling for potential confounding factors; the lack of gold-standard diagnostic criteria and assessment scales; and determination of the most appropriate study duration. METHODS: This paper summarises the search for a consensus by a group of experts in the optimal approach to studying amotivation in mood disorders. RESULTS: The consensus of this group is that amotivation in mood disorders is a legitimate therapeutic target, given the magnitude of the associated unmet needs, and that proof-of-concept studies should be conducted in order to facilitate subsequent larger investigations. The focus of this manuscript is to consider the study of amotivation, as a residual symptom of major depressive disorder (MDD) or bipolar depression (BD), following adequate treatment with a typical antidepressant or mood stabiliser/antipsychotic, respectively. DISCUSSION: There is a paucity of data studying amotivation in mood disorders. This manuscript provides general guidance on the most appropriate study design(s) and methodology to assess potential therapeutic options for the management of residual amotivation in mood disorders.
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Apatía , Trastorno Bipolar/psicología , Trastorno Depresivo Mayor/psicología , Motivación , Proyectos de Investigación , Antidepresivos/uso terapéutico , Antipsicóticos/uso terapéutico , HumanosRESUMEN
OBJECTIVE: The maintenance efficacy of antidepressants is usually assessed in postmarketing studies with a randomized withdrawal design. This report explores differences in relapse rates, trial characteristics, and success rates in maintenance efficacy studies submitted to the US Food and Drug Administration (FDA) over a 25-year period. DATA SOURCES: Clinical data from all maintenance trials with antidepressants submitted to FDA between 1987 and 2012. STUDY SELECTION: Efficacy data were compiled from 15 maintenance clinical trials in adults diagnosed with major depressive disorder according to DSM-III or DSM-IV criteria. DATA EXTRACTION: Trial characteristics, relapse rates, and time to relapse in each study were examined. RESULTS: Relapse rates were significantly lower (P < .05) in the drug arm than in the placebo arm in every study, with a mean relapse rate difference of 18% and an average percent reduction in relapse rate of 52% compared to placebo. Only 6% of the relapse events occurred in the first 2 weeks of the double-blind phase. The separation between treatment arms continued to increase throughout the double-blind phase only in the trial with longest response stabilization period. CONCLUSIONS: Antidepressant maintenance trials have a high rate of success, indicating a benefit of continuing drug treatment after initial response to an antidepressant. This benefit appears to result mainly from a decreased rate of recurrent depression rather than from an effect of drug withdrawal in the placebo groups.
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Trastorno Depresivo Mayor/tratamiento farmacológico , Ensayos Clínicos Controlados Aleatorios como Asunto/estadística & datos numéricos , Resultado del Tratamiento , United States Food and Drug Administration/estadística & datos numéricos , Privación de Tratamiento/estadística & datos numéricos , Adulto , Trastorno Depresivo Mayor/prevención & control , Femenino , Humanos , Masculino , Persona de Mediana Edad , Prevención Secundaria , Factores de Tiempo , Estados UnidosAsunto(s)
Ensayos Clínicos como Asunto , Trastorno Depresivo Mayor , Estrógenos , Reproducción , Afecto/fisiología , Ensayos Clínicos como Asunto/métodos , Ensayos Clínicos como Asunto/normas , Interpretación Estadística de Datos , Trastorno Depresivo Mayor/metabolismo , Trastorno Depresivo Mayor/terapia , Estrógenos/metabolismo , Estrógenos/uso terapéutico , Femenino , Humanos , Selección de Paciente , Encuestas y CuestionariosRESUMEN
OBJECTIVE: This article captures the proceedings of a meeting aimed at defining clinically meaningful effects for use in randomized controlled trials for psychopharmacological agents. DESIGN: Experts from a variety of disciplines defined clinically meaningful effects from their perspectives along with viewpoints about how to design and interpret randomized controlled trials. SETTING: The article offers relevant, practical, and sometimes anecdotal information about clinically meaningful effects and how to interpret them. PARTICIPANTS: The concept for this session was the work of co-chairs Richard Keefe and the late Andy Leon. Faculty included Richard Keefe, PhD; James McNulty, AbScB; Robert S. Epstein, MD, MS; Shelby D. Reed, PhD; Juan Sanchez, MD; Ginger Haynes, PhD; Andrew C. Leon, PhD; Helena Chmura Kraemer, PhD; Ellen Frank, PhD, and Kenneth L. Davis, MD. RESULTS: The term clinically meaningful effect is an important aspect of designing and interpreting randomized controlled trials but can be particularly difficult in the setting of psychopharmacology where effect size may be modest, particularly over the short term, because of a strong response to placebo. Payers, regulators, patients, and clinicians have different concerns about clinically meaningful effects and may describe these terms differently. The use of moderators in success rate differences may help better delineate clinically meaningful effects. CONCLUSION: There is no clear consensus on a single definition for clinically meaningful differences in randomized controlled trials, and investigators must be sensitive to specific concerns of stakeholders in psychopharmacology in order to design and execute appropriate clinical trials.
RESUMEN
The aim of this study was to develop a placebo model for bipolar disorder to help optimize clinical trial designs for studies targeting manic episodes in bipolar disorder. A bipolar disease database was built based on individual longitudinal data collected from over 3,000 patients in 11 clinical trials for 5 approved bipolar drugs. An empirical placebo effect model with an exponential decay process plus a linear progression process was developed to quantify the time course of the Young Mania Rating Scale total score based on only placebo data from the database. In order to describe the dropout pattern during the trials, a parametric survival model was developed and the Weibull distribution was identified to be the best distribution to describe the data. Based on the likelihood ratio test, it was found that patients with higher baseline score, slower disease improvement and more rapid disease progression tended to dropout earlier, and the trial features such as trial starting year and trial site were also significant covariates for dropout. A combination of the placebo effect model and the dropout model was applied to simulate new clinical trials through Monte-Carlo simulation. Both the placebo effect model and dropout model described the observed data reasonably well based on various diagnostic plots. The joint placebo response and dropout models can serve as a tool to simulate the most likely level of placebo response with the expected dropout pattern to help design a new clinical trial.
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Antipsicóticos/uso terapéutico , Trastorno Bipolar/tratamiento farmacológico , Modelos Psicológicos , Pacientes Desistentes del Tratamiento , Efecto Placebo , Ensayos Clínicos Controlados Aleatorios como Asunto , Antipsicóticos/administración & dosificación , Trastorno Bipolar/psicología , Bases de Datos Factuales , Humanos , Método de Montecarlo , Pacientes Desistentes del Tratamiento/psicología , Pacientes Desistentes del Tratamiento/estadística & datos numéricos , Escalas de Valoración Psiquiátrica , Ensayos Clínicos Controlados Aleatorios como Asunto/estadística & datos numéricosRESUMEN
The Food and Drug Administration recently approved Invega for the treatment of schizophrenia in adolescents 12 to 17 years. If dosing recommendations for this population would have been based only on the results of the single efficacy trial included in this program, paliperidone dosing in adolescents might have been limited to 3 mg/d in adolescents less than 51 kg and to 6 mg/d in adolescents greater than or equal to 51 kg. This article provides an illustration of a more integrated approach to arrive at dosing recommendation that included practical considerations, modeling and simulation of data from the clinical trial, and the totality of evidence for both paliperidone and the parent drug, risperidone. On the basis of this integrated approach, the agency approved a starting dose of 3 mg/d in both adolescent weight groups and subsequent dosing in a range of 3 to 6 mg/d for adolescents less than 51 kg and 3 to 12 mg/d for adolescents greater than 51 kg, although the 3-mg dose was not evaluated in the greater than or equal to 51-kg group.
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Antipsicóticos/administración & dosificación , Isoxazoles/administración & dosificación , Pirimidinas/administración & dosificación , Esquizofrenia/tratamiento farmacológico , Adolescente , Factores de Edad , Antipsicóticos/uso terapéutico , Niño , Simulación por Computador , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Aprobación de Drogas , Estudios de Seguimiento , Humanos , Isoxazoles/uso terapéutico , Modelos Biológicos , Palmitato de Paliperidona , Pirimidinas/uso terapéutico , Estados Unidos , United States Food and Drug AdministrationRESUMEN
OBJECTIVE: The occurrence of pimozide-induced arrhythmias is concentration dependent. Hence, it is important for prescribers to consider causes of increased pimozide exposure. This article summarizes the U.S. Food and Drug Administration's (FDA's) review of drug interaction and pharmacogenomic studies and discusses pharmacokinetic simulations we performed to develop new cytochrome P450 2D6 (CYP2D6) genotype-guided dosing recommendations for pimozide. METHOD: Pharmacokinetic parameters by CYP2D6 genotype were derived from a published single-dose pharmacogenomic study of pimozide. We simulated what pimozide exposures would result from a multiple-dose scenario in different CYP2D6 genotype groups: extensive, intermediate, and poor metabolizers. The maximum dose for poor metabolizers was defined as the dose that would not exceed pimozide concentrations following 10 mg daily in extensive metabolizers and intermediate metabolizers (the current maximum dose in an unselected population). RESULTS: Dose-ranging analyses revealed that 4 mg daily in CYP2D6 poor metabolizers was the maximum dose that would not result in plasma concentrations in excess of those observed in extensive metabolizer and intermediate metabolizer patients receiving 10 mg daily. CYP2D6 genotyping is now consequently recommended in the pimozide product label before exceeding 4 mg of pimozide daily in adults or 0.05 mg/kg/d in children. Previously, dose adjustment was recommended every 3 days to achieve the desired clinical response for all patients. The label was modified to subsequently reflect that pimozide doses should not be increased earlier than 14 days in patients who are known CYP2D6 poor metabolizers. CONCLUSIONS: Given the risk of increased pimozide concentrations and longer time to steady state in CYP2D6 poor metabolizers, the FDA has revised the pimozide label to provide clinicians with clearer dosing, titration, and genotype testing recommendations. The new information is intended to enhance therapeutic individualization of pimozide in pediatric and adult patients.
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Citocromo P-450 CYP2D6/genética , Antagonistas de Dopamina/administración & dosificación , Antagonistas de Dopamina/farmacocinética , Síndrome de QT Prolongado/prevención & control , Pimozida/administración & dosificación , Pimozida/farmacocinética , Polimorfismo Genético , Medicina de Precisión , Síndrome de Tourette/tratamiento farmacológico , Síndrome de Tourette/genética , Adulto , Niño , Antagonistas de Dopamina/efectos adversos , Relación Dosis-Respuesta a Droga , Etiquetado de Medicamentos , Monitoreo de Drogas , Pruebas Genéticas , Humanos , Síndrome de QT Prolongado/inducido químicamente , Dosis Máxima Tolerada , Tasa de Depuración Metabólica , Pimozida/efectos adversos , Guías de Práctica Clínica como Asunto , Estados UnidosRESUMEN
OBJECTIVE: There has been concern about a high rate of placebo response and a decline in treatment effect over time in schizophrenia trials as well as the implications of increasing conduct of such trials outside North America. This report explores differences in efficacy data over an 18-year period from randomized placebo-controlled trials submitted in support of new drug applications (NDAs) for the treatment of schizophrenia and differences in results between trials conducted in North America and elsewhere. DATA SOURCES: Clinical trial data that were submitted to the US Food and Drug Administration (FDA) as part of NDAs for the indication of schizophrenia between 1991 and 2009. STUDY SELECTION: Efficacy data were compiled from 32 clinical trials with 11,567 evaluable patients with schizophrenia. Data from completed, randomized, multicenter, double-blind, placebo-controlled, 4- to 8-week clinical trials in adult patients diagnosed with schizophrenia according to DSM-III or DSM-IV criteria were included. DATA EXTRACTION: Baseline demographic and disease characteristics, including mean Positive and Negative Syndrome Scale (PANSS) total scores, were summarized and compared between North American and multiregional trials. Mean change from baseline to endpoint in PANSS total scores was utilized as the primary outcome of interest. We explored differences in treatment effect and success rate of these trials based on when and where the studies were conducted, sample size, trial duration, and baseline patient characteristics. RESULTS: Twenty-one of the 32 trials were conducted solely in North America, and 11 were carried out in multiple regions. Of those 11 multiregional trials, 2 were conducted exclusively in foreign countries. Although the observed responses (change from baseline) in placebo and drug-treated groups in multiregional trials tended to be larger than in North American trials, the treatment effects (drug-placebo difference) were -9 and -8 PANSS units for North American and multiregional trials, respectively. When time of trial conduct was taken into account, an increasing placebo response and a diminishing treatment effect over time were observed in North American trials from -10.8 PANSS units for the first period (1991-1998) to -6.0 PANSS units for the later period (1999-2008). The overall trial success rate over the almost 2 decades was 78%, declining slightly in trials conducted after 1999, the time period during which multiregional trials were first conducted (74% for 1999-2008 vs 85% for 1991-1998), despite increasing sample sizes in the later period. The mean baseline PANSS total score was in the range of 87-100 for most of these trials. Trials in patients with higher mean baseline PANSS total scores tended to show larger treatment effects than those in patients with lower scores. The mean body weight and body mass index (BMI) were higher in patients in North American trials and North America-predominant multiregional trials compared to those in foreign-predominant multiregional trials (mean body weights of 85 kg and 81 kg vs 72 kg, and BMIs of 29 and 27 vs 25, respectively). Treatment effects decreased as body weights increased, especially in North American trials. In foreign-predominant multiregional trials, there were higher proportions of women than in North American trials and North America-predominant multiregional trials (40% vs 22% and 27%, respectively) and a relatively larger proportion of Asians (21% vs 1% and 8%, respectively). CONCLUSIONS: A high and increasing placebo response and a declining treatment effect are of great concern in schizophrenia trials conducted in North America. In this era of global clinical trials, close attention is needed to the design and conduct of these trials.
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Antipsicóticos/uso terapéutico , Aprobación de Drogas/estadística & datos numéricos , Ensayos Clínicos Controlados Aleatorios como Asunto/estadística & datos numéricos , Esquizofrenia/tratamiento farmacológico , United States Food and Drug Administration/estadística & datos numéricos , Método Doble Ciego , Humanos , Internacionalidad , Estudios Multicéntricos como Asunto , América del Norte , Efecto Placebo , Escalas de Valoración Psiquiátrica/estadística & datos numéricos , Ensayos Clínicos Controlados Aleatorios como Asunto/psicología , Ensayos Clínicos Controlados Aleatorios como Asunto/tendencias , Estados UnidosRESUMEN
OBJECTIVE: Vilazodone was recently approved by the US Food and Drug Administration (FDA) for the treatment of major depressive disorder (MDD). The purpose of this review is to summarize the FDA's approach to its review of the clinical pharmacology and the clinical efficacy and safety data for this new drug application, important issues in its decision-making, and its conclusions. DATA SOURCES: The data sources for this review were the original raw data sets for all clinical trials included in the development program for vilazodone, as well as the sponsor's original analyses of these data. STUDY SELECTION: Data were available from 24 human trials involving vilazodone, and included a total of 2,898 human subjects exposed to 1 or more doses of this drug. DATA EXTRACTION: The FDA had access to original raw data sets for these trials. RESULTS: Vilazodone is effective in treating MDD at a dose of 40 mg/d, but it needs to be incrementally adjusted to this dose to minimize gastrointestinal symptoms. It needs to be taken with food to ensure adequate plasma concentrations. Vilazodone's profile of adverse events is similar to that seen with selective serotonin reuptake inhibitors. No dose adjustment is needed based on age, gender, or renal or hepatic impairment. It is recommended that the vilazodone dose be reduced to 20 mg when it is taken with strong cytochrome P450 (CYP) 3A4 inhibitors, eg, ketoconazole. Vilazodone is not expected to have important effects on the clearance of other drugs that are cytochrome P450 substrates. CONCLUSIONS: Vilazodone is a new treatment for MDD, but it is unknown whether it has any advantages compared to other drugs in the antidepressant class.
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Benzofuranos/uso terapéutico , Trastorno Depresivo Mayor/tratamiento farmacológico , Indoles/uso terapéutico , Piperazinas/uso terapéutico , Inhibidores Selectivos de la Recaptación de Serotonina/uso terapéutico , Benzofuranos/efectos adversos , Benzofuranos/farmacocinética , Ensayos Clínicos Fase II como Asunto , Ensayos Clínicos Fase III como Asunto , Ensayos Clínicos Fase IV como Asunto , Aprobación de Drogas , Femenino , Humanos , Indoles/efectos adversos , Indoles/farmacocinética , Masculino , Piperazinas/efectos adversos , Piperazinas/farmacocinética , Inhibidores Selectivos de la Recaptación de Serotonina/efectos adversos , Inhibidores Selectivos de la Recaptación de Serotonina/farmacocinética , Disfunciones Sexuales Fisiológicas/inducido químicamente , Estados Unidos , United States Food and Drug Administration , Clorhidrato de VilazodonaRESUMEN
Primary "cognitive" disorders (e.g., Alzheimer's disease) often have behavioral features, just as primary behavioral disorders (e.g., schizophrenia) often have cognitive features. Drug research in recent years has expanded into targeting the full range of symptoms of both types of disorders. DSM-5 should include these associated features of each type of disorder, because acknowledging the full range of symptoms for each type of disorder has important research and treatment implications.