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PURPOSE/BACKGROUND: Using data from KINECT® 4, a phase 3, 48-week study of valbenazine, post hoc analyses were conducted to assess long-term outcomes that are relevant to the real-world management of tardive dyskinesia (TD). METHODS/PROCEDURES: Post hoc analyses of the participants of the KINECT 4 study who completed 48 weeks of open-label valbenazine (40 or 80 mg) treatment were conducted. Valbenazine effects on TD were evaluated using the Abnormal Involuntary Movement Scale (AIMS), Clinical Global Impression of Change-TD (CGI-TD), and Patient Global Impression of Change (PGIC). FINDINGS/RESULTS: Of 103 participants completing 48 weeks of treatment, 55% experienced clinically meaningful improvement (defined as ≥2-point reduction in AIMS total score [sum of items 1 - 7, evaluated by site raters]) by week 4; at week 48, 97% met this threshold. The percentage of completers who achieved AIMS total score response thresholds of ≥10% to ≥90% increased over time, with 86% of completers reaching ≥50% improvement. Of the 40 (39%) completers with AIMS ≥50% response at week 8, 38 (95%) sustained this response at week 48; 81% of those who did not meet this threshold at week 8 had achieved it by week 48. At week 48, more than 85% of completers achieved CGI-TD and PGIC ratings of "much improved" or "very much improved." IMPLICATIONS/CONCLUSIONS: The majority of participants who completed 48 weeks of treatment with once-daily valbenazine experienced substantial clinically meaningful and sustained TD improvements. These findings indicate that valbenazine can be a highly effective long-term treatment in patients with TD.
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Discinesia Tardia , Tetrabenazina , Valina , Humanos , Tetrabenazina/análogos & derivados , Tetrabenazina/farmacologia , Tetrabenazina/administração & dosagem , Tetrabenazina/efeitos adversos , Discinesia Tardia/tratamento farmacológico , Masculino , Feminino , Pessoa de Meia-Idade , Valina/análogos & derivados , Valina/administração & dosagem , Valina/farmacologia , Valina/efeitos adversos , Idoso , Resultado do Tratamento , Adulto , Escala de Movimento Involuntário Anormal , Antipsicóticos/efeitos adversos , Antipsicóticos/administração & dosagemRESUMO
BACKGROUND: Little is known about the determinants of community integration (i.e. recovery) for individuals with a history of homelessness, yet such information is essential to develop targeted interventions. METHODS: We recruited homeless Veterans with a history of psychotic disorders and evaluated four domains of correlates of community integration: perception, non-social cognition, social cognition, and motivation. Baseline assessments occurred after participants were engaged in supported housing services but before they received housing, and again after 12 months. Ninety-five homeless Veterans with a history of psychosis were assessed at baseline and 53 returned after 12 months. We examined both cross-sectional and longitudinal relationships with 12-month community integration. RESULTS: The strongest longitudinal association was between a baseline motivational measure and social integration at 12 months. We also observed cross-sectional associations at baseline between motivational measures and community integration, including social, work, and independent living. Cross-lagged panel analyses did not suggest causal associations for the motivational measures. Correlations with perception and non-social cognition were weak. One social cognition measure showed a significant longitudinal correlation with independent living at 12 months that was significant for cross-lagged analysis, consistent with a causal relationship and potential treatment target. CONCLUSIONS: The relatively selective associations for motivational measures differ from what is typically seen in psychosis, in which all domains are associated with community integration. These findings are presented along with a partner paper (Study 2) to compare findings from this study to an independent sample without a history of psychotic disorders to evaluate the consistency in findings regarding community integration across projects.
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Pessoas Mal Alojadas , Transtornos Psicóticos , Veteranos , Humanos , Integração Comunitária , Veteranos/psicologia , Motivação , Estudos Transversais , Transtornos Psicóticos/psicologia , CogniçãoRESUMO
BACKGROUND: In an initial study (Study 1), we found that motivation predicted community integration (i.e. functional recovery) 12 months after receiving housing in formerly homeless Veterans with a psychotic disorder. The current study examined whether the same pattern would be found in a broader, more clinically diverse, homeless Veteran sample without psychosis. METHODS: We examined four categories of variables as potential predictors of community integration in non-psychotic Veterans: perception, non-social cognition, social cognition, and motivation at baseline (after participants were engaged in a permanent supported housing program but before receiving housing) and a 12-month follow-up. A total of 82 Veterans had a baseline assessment and 41 returned for testing after 12 months. RESULTS: The strongest longitudinal association was between an interview-based measure of motivation (the motivation and pleasure subscale from the Clinical Assessment Interview for Negative Symptoms) at baseline and measures of social integration at 12 months. In addition, cross-lagged panel analyses were consistent with a causal influence of general psychiatric symptoms at baseline driving social integration at 12 months, and reduced expressiveness at baseline driving independent living at 12 months, but there were no significant causal associations with measures of motivation. CONCLUSIONS: The findings from this study complement and reinforce those in Veterans with psychosis. Across these two studies, our findings suggest that motivational factors are associated at baseline and at 12 months and are particularly important for understanding and improving community integration in recently-housed Veterans across psychiatric diagnoses.
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Pessoas Mal Alojadas , Veteranos , Humanos , Veteranos/psicologia , Integração Comunitária , Motivação , CogniçãoRESUMO
Schizophrenia is a common, chronic and debilitating neuropsychiatric syndrome affecting tens of millions of individuals worldwide. While rare genetic variants play a role in the etiology of schizophrenia, most of the currently explained liability is within common variation, suggesting that variation predating the human diaspora out of Africa harbors a large fraction of the common variant attributable heritability. However, common variant association studies in schizophrenia have concentrated mainly on cohorts of European descent. We describe genome-wide association studies of 6152 cases and 3918 controls of admixed African ancestry, and of 1234 cases and 3090 controls of Latino ancestry, representing the largest such study in these populations to date. Combining results from the samples with African ancestry with summary statistics from the Psychiatric Genomics Consortium (PGC) study of schizophrenia yielded seven newly genome-wide significant loci, and we identified an additional eight loci by incorporating the results from samples with Latino ancestry. Leveraging population differences in patterns of linkage disequilibrium, we achieve improved fine-mapping resolution at 22 previously reported and 4 newly significant loci. Polygenic risk score profiling revealed improved prediction based on trans-ancestry meta-analysis results for admixed African (Nagelkerke's R2 = 0.032; liability R2 = 0.017; P < 10-52), Latino (Nagelkerke's R2 = 0.089; liability R2 = 0.021; P < 10-58), and European individuals (Nagelkerke's R2 = 0.089; liability R2 = 0.037; P < 10-113), further highlighting the advantages of incorporating data from diverse human populations.
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População Negra/genética , Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla , Hispânico ou Latino/genética , Esquizofrenia/genética , Feminino , Loci Gênicos , Humanos , Masculino , Polimorfismo de Nucleotídeo Único/genéticaRESUMO
BACKGROUND: Individuals with tardive dyskinesia (TD) who completed a long-term study (KINECT 3 or KINECT 4) of valbenazine (40 or 80 mg/day, once-daily for up to 48 weeks followed by 4-week washout) were enrolled in a subsequent study (NCT02736955) that was primarily designed to further evaluate the long-term safety of valbenazine. METHODS: Participants were initiated at 40 mg/day (following prior valbenazine washout). At week 4, dosing was escalated to 80 mg/day based on tolerability and clinical assessment of TD; reduction to 40 mg/day was allowed for tolerability. The study was planned for 72 weeks or until termination due to commercial availability of valbenazine. Assessments included the Clinical Global Impression of Severity-TD (CGIS-TD), Patient Satisfaction Questionnaire (PSQ), and treatment-emergent adverse events (TEAEs). RESULTS: At study termination, 85.7% (138/161) of participants were still active. Four participants had reached week 60, and none reached week 72. The percentage of participants with a CGIS-TD score ≤2 (normal/not ill or borderline ill) increased from study baseline (14.5% [23/159]) to week 48 (64.3% [36/56]). At baseline, 98.8% (158/160) of participants rated their prior valbenazine experience with a PSQ score ≤2 (very satisfied or somewhat satisfied). At week 48, 98.2% (55/56) remained satisfied. Before week 4 (dose escalation), 9.4% of participants had ≥1 TEAE. After week 4, the TEAE incidence was 49.0%. No TEAE occurred in ≥5% of participants during treatment (before or after week 4). CONCLUSIONS: Valbenazine was well-tolerated and persistent improvements in TD were found in adults who received once-daily treatment for >1 year.
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Inibidores da Captação Adrenérgica/uso terapêutico , Discinesia Tardia/tratamento farmacológico , Tetrabenazina/análogos & derivados , Valina/análogos & derivados , Idoso , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Satisfação do Paciente , Tetrabenazina/uso terapêutico , Resultado do Tratamento , Valina/uso terapêuticoRESUMO
OBJECTIVE: We provide a closer look at the result of a randomised, placebo-controlled, active-reference (quetiapine XR), flexible-dose, 6-week study of brexpiprazole in schizophrenia, which did not meet its primary endpoint - change from baseline in Positive and Negative Syndrome Scale (PANSS) total score. We also investigate potential expectancy bias from the well-known side-effect profile of the active reference that could have affected the study outcome. METHODS: Pre-specified sensitivity analyses of the primary end point were performed using analysis of covariance (ANCOVA) last observation carried forward (LOCF) and observed cases (OC). Post hoc analyses of change from baseline in PANSS total score were performed using the mixed model for repeated measures approach with treatment groups split by having typical adverse events with potential for functional unblinding, for example, somnolence, increase in weight, dizziness, dry mouth and sedation. RESULTS: Pre-specified sensitivity analyses showed separation from placebo for brexpiprazole at week 6: LOCF, ANCOVA: -4.3 [95% CI (-8.0, -0.5), p = 0.0254]. OC, ANCOVA: -3.9 [95% CI (-7.3, -0.5), p = 0.0260]. Patients treated with brexpiprazole experiencing typical adverse events with potential for functional unblinding before or at Week 2 had a least square (LS) mean PANSS change of -29.5 (improvement), with a difference in change from baseline to Week 6 in PANSS total score between brexpiprazole and placebo of -13.5 [95% CI (-23.1, -4.0), p = 0.0057], and those who did not had an LS mean change of -18.9 and a difference between brexpiprazole and placebo of -2.9 [95% CI (-7.2, 1.4), p = 0.1809]. CONCLUSION: Pre-specified sensitivity analyses showed separation from placebo for brexpiprazole at Week 6. A post hoc analysis suggested a potential confounding of efficacy rating towards symptom improvement in patients who experience known side effects of quetiapine XR.
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BACKGROUND: Mismatch negativity (MMN) is an event-related potential (ERP) component reflecting auditory predictive coding. Repeated standard tones evoke increasing positivity ('repetition positivity'; RP), reflecting strengthening of the standard's memory trace and the prediction it will recur. Likewise, deviant tones preceded by more standard repetitions evoke greater negativity ('deviant negativity'; DN), reflecting stronger prediction error signaling. These memory trace effects are also evident in MMN difference wave. Here, we assess group differences and test-retest reliability of these indices in schizophrenia patients (SZ) and healthy controls (HC). METHODS: Electroencephalography was recorded twice, 2 weeks apart, from 43 SZ and 30 HC, during a roving standard paradigm. We examined ERPs to the third, eighth, and 33rd standards (RP), immediately subsequent deviants (DN), and the corresponding MMN. Memory trace effects were assessed by comparing amplitudes associated with the three standard repetition trains. RESULTS: Compared with controls, SZ showed reduced MMNs and DNs, but normal RPs. Both groups showed memory trace effects for RP, MMN, and DN, with a trend for attenuated DNs in SZ. Intraclass correlations obtained via this paradigm indicated good-to-moderate reliabilities for overall MMN, DN and RP, but moderate to poor reliabilities for components associated with short, intermediate, and long standard trains, and poor reliability of their memory trace effects. CONCLUSION: MMN deficits in SZ reflected attenuated prediction error signaling (DN), with relatively intact predictive code formation (RP) and memory trace effects. This roving standard MMN paradigm requires additional development/validation to obtain suitable levels of reliability for use in clinical trials.
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Atenção/fisiologia , Eletroencefalografia , Potenciais Evocados Auditivos/fisiologia , Rememoração Mental/fisiologia , Esquizofrenia/fisiopatologia , Psicologia do Esquizofrênico , Adolescente , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Esquizofrenia/diagnóstico , Adulto JovemRESUMO
PURPOSE/BACKGROUND: Valbenazine is approved to treat tardive dyskinesia (TD) in adults. KINECT 4 (NCT02405091) was conducted to explore the long-term effects of once-daily valbenazine in patients with TD. METHODS/PROCEDURES: The study included a 48-week, open-label treatment period and 4-week washout. Dosing was initiated at 40 mg/d, with escalation to 80 mg/d at week 4 based on efficacy and tolerability. Standard safety methods were applied, including treatment-emergent adverse event (TEAE) reporting. Valbenazine effects on TD were assessed using the Abnormal Involuntary Movement Scale (AIMS), Clinical Global Impression of Change-TD, and Patient Global Impression of Change. FINDINGS/RESULTS: After week 4, <15% of all participants had a serious TEAE (13.7%) or TEAE leading to discontinuation (11.8%). Participants experienced TD improvements during long-term treatment as indicated by mean change from baseline to week 48 in AIMS total score (sum of items 1-7, evaluated by site raters) with valbenazine 40 mg/d (-10.2 [n = 45]) or 80 mg/d (-11.0 [n = 107]). At week 48, most participants had ≥50% improvement from baseline in AIMS total score (40 mg/d, 90.0%; 80 mg/d, 89.2%), Clinical Global Impression of Change-TD rating of much or very much improved (40 mg/d, 90.0%; 80 mg/d, 95.9%), and Patient Global Impression of Change rating of much or very much improved (40 mg/d, 90.0%; 80 mg/d, 89.2%). No dose effects were apparent by week 36. Week 52 results indicated some loss of effect after washout. IMPLICATIONS/CONCLUSIONS: Valbenazine was generally well tolerated, and no new safety concerns were detected. Substantial clinician- and patient-reported improvements were observed in adults with TD who received once-daily valbenazine for up to 48 weeks.
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Antipsicóticos/efeitos adversos , Transtornos do Humor/tratamento farmacológico , Avaliação de Resultados em Cuidados de Saúde , Transtornos Psicóticos/tratamento farmacológico , Esquizofrenia/tratamento farmacológico , Discinesia Tardia/tratamento farmacológico , Tetrabenazina/análogos & derivados , Valina/análogos & derivados , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Humanos , Pessoa de Meia-Idade , Discinesia Tardia/etiologia , Tetrabenazina/administração & dosagem , Tetrabenazina/efeitos adversos , Tetrabenazina/sangue , Tetrabenazina/farmacologia , Valina/administração & dosagem , Valina/efeitos adversos , Valina/sangue , Valina/farmacologia , Adulto JovemRESUMO
We live in an age of psychopharmacology. One in six persons currently takes a psychotropic drug. These drugs have profoundly shaped our scientific and cultural understanding of psychiatric disease. By way of a historical review, we try to make sense of psychiatry's dependency on psychiatric drugs in the care of patients. Modern psychopharmacology began in 1950 with the synthesis of chlorpromazine. Over the course of the next 50 years, the psychiatric understanding and treatment of mental illness radically changed. Psychotropic drugs played a major part in these changes as state hospitals closed and psychotherapy gave way to drug prescriptions. Our review suggests that the success of psychopharmacology was not the consequence of increasingly more effective drugs for discrete psychiatric diseases. Instead, a complex mix of political economic realities, pharmaceutical marketing, basic science advances, and changes in the mental health-care system have led to our current infatuation with psychopharmacology.
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Serviços de Saúde Mental/história , Psiquiatria/história , Psicofarmacologia/história , Psicotrópicos/história , História do Século XIX , História do Século XX , História do Século XXI , HumanosRESUMO
OBJECTIVE: Oxidative stress is implicated in the aetiology of schizophrenia, and the antioxidant defence system (AODS) may be protective in this illness. We examined the major antioxidant glutathione (GSH) in prefrontal brain and its correlates with clinical and demographic variables in schizophrenia. METHODS: GSH levels were measured in the dorsolateral prefrontal region of 28 patients with chronic schizophrenia using a magnetic resonance spectroscopy sequence specifically adapted for GSH. We examined correlations of GSH levels with age, age at onset of illness, duration of illness, and clinical symptoms. RESULTS: We found a negative correlation between GSH levels and age at onset (r = -0.46, p = 0.015), and a trend-level positive relationship between GSH and duration of illness (r = 0.34, p = 0.076). CONCLUSION: Our findings are consistent with a possible compensatory upregulation of the AODS with longer duration of illness and suggest that the AODS may play a role in schizophrenia.
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Glutationa/metabolismo , Córtex Pré-Frontal/metabolismo , Esquizofrenia/metabolismo , Adolescente , Adulto , Fatores Etários , Idade de Início , Doença Crônica , Feminino , Humanos , Espectroscopia de Ressonância Magnética , Masculino , Pessoa de Meia-IdadeRESUMO
BACKGROUND: Although predominant negative symptoms of schizophrenia can be severe enough to cause persistent impairment, effective treatment options are lacking. We aimed to assess the new generation antipsychotic cariprazine in adult patients with predominant negative symptoms. METHODS: In this randomised, double-blind, phase 3b trial, we enrolled adults aged 18-65 years with long-term (>2 year), stable schizophrenia and predominant negative symptoms (>6 months) at 66 study centres (mainly hospitals and university clinics, with a small number of private practices) in 11 European countries. Patients were randomly assigned (1:1) by an interactive web response system to 26 weeks of monotherapy with fixed-dose oral cariprazine (3 mg, 4·5 mg [target dose], or 6 mg per day) or risperidone (3 mg, 4 mg [target dose], or 6 mg per day); previous medication was discontinued over 2 weeks. The primary outcome was change from baseline to week 26 or end of treatment on the Positive and Negative Syndrome Scale factor score for negative symptoms (PANSS-FSNS) analysed in a modified intention-to-treat population of patients who had follow-up assessments within 5 days after last receipt of study drugs with a mixed-effects model for repeated measures. Safety was assessed in all patients who received at least one dose of study drug. This study is registered with EudraCT, number 2012-005485-36. FINDINGS: Between May 27, 2013, and Nov 17, 2014, 533 patients were screened and 461 (86%) patients were randomised to treatment (230 for cariprazine and 231 for risperidone); 460 were included in the safety population (one patient discontinued before study drug intake). 227 (99%) of 230 patients in the cariprazine group and 229 (99%) of 230 patients in the risperidone group were included in the modified intention-to-treat population (178 [77%] in each group completed 26 weeks of treatment). Mean daily doses were 4·2 mg (SD 0·6) for cariprazine and 3·8 mg (0·4) for risperidone. Treatment-emergent adverse events (eg, insomnia, akathisia, worsening of schizophrenia, headache, anxiety) were reported in 123 (54%) patients treated with cariprazine and 131 (57%) patients treated with risperidone. Use of cariprazine led to a greater least squares mean change in PANSS-FSNS from baseline to week 26 than did risperidone (-8·90 points for cariprazine vs -7·44 points for risperidone; least squares mean difference -1·46, 95% CI -2·39 to -0·53; p=0·0022; effect size 0·31). One patient in the risperidone group died of a cause regarded as unrelated to treatment. INTERPRETATION: Our results support the efficacy of cariprazine in the treatment of predominant negative symptoms of schizophrenia. FUNDING: Gedeon Richter Plc.
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Antipsicóticos/uso terapêutico , Sintomas Comportamentais/tratamento farmacológico , Piperazinas/uso terapêutico , Risperidona/uso terapêutico , Esquizofrenia/tratamento farmacológico , Psicologia do Esquizofrênico , Adulto , Sintomas Comportamentais/etiologia , Sintomas Comportamentais/psicologia , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Esquizofrenia/complicações , Resultado do TratamentoAssuntos
Antipsicóticos/uso terapêutico , Esquizofrenia , Antipsicóticos/efeitos adversos , Terapia Combinada , Manual Diagnóstico e Estatístico de Transtornos Mentais , Dopamina/metabolismo , Humanos , Modelos Neurológicos , Psicoterapia , Esquizofrenia/diagnóstico , Esquizofrenia/etiologia , Esquizofrenia/metabolismo , Esquizofrenia/terapiaRESUMO
OBJECTIVE: Review efficacy, safety, and tolerability of brexpiprazole in patients with schizophrenia in short- and long-term phase 3 studies. METHODS: Patients experiencing a current exacerbation of schizophrenia received brexpiprazole in two fixed-dose (2 and 4 mg), 6-week, placebo-controlled studies, one flexible-dose (2-4 mg), 6-week, placebo-control and active reference study, and one fixed-dose (1-4 mg), 52-week, placebo-controlled maintenance study. RESULTS: The efficacy of brexpiprazole was demonstrated in the two short-term fixed-dose studies with statistically significant improvements from baseline in Positive and Negative Syndrome Scale (PANSS) total score compared with placebo. In the flexible-dose short-term study, treatment with brexpiprazole resulted in numerically greater improvements in PANSS total score than with placebo that approached statistical significance (p=0.056). A meta-analysis of these short-term studies showed a mean change in PANSS total score of -20.1, reflecting a clinically meaningful reduction in symptoms. In the maintenance study, brexpiprazole had a beneficial effect relative to placebo on time to exacerbation of psychotic symptoms/impending relapse (p<0.0001). For all studies, brexpiprazole demonstrated clinically meaningful treatment effects on the Personal and Social Performance scale. Brexpiprazole had a favourable safety profile, with a relatively low prevalence of activating and sedating side effects. Weight gain in the short-term studies was ~1 kg greater than placebo. No safety concerns were observed with brexpiprazole in laboratory values, electrocardiogram, or vital signs. CONCLUSIONS: Overall, the results indicate brexpiprazole, used either short-term or as part of a long-term maintenance treatment programme, is an efficacious therapy option in adults with schizophrenia and has a favourable safety/tolerability profile.
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Antipsicóticos/uso terapêutico , Quinolonas/uso terapêutico , Esquizofrenia/tratamento farmacológico , Tiofenos/uso terapêutico , Adulto , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Resultado do TratamentoAssuntos
Ensaios Clínicos como Assunto/métodos , Esquizofrenia/diagnóstico , Esquizofrenia/tratamento farmacológico , Pesquisa Translacional Biomédica/métodos , Incerteza , Antipsicóticos/farmacologia , Ensaios Clínicos como Assunto/tendências , Terapia Cognitivo-Comportamental , Humanos , Terapia de Alvo Molecular/tendências , National Institute of Mental Health (U.S.) , Esquizofrenia/genética , Pesquisa Translacional Biomédica/tendências , Falha de Tratamento , Estados UnidosRESUMO
BACKGROUND: It is widely believed that relapse in first-episode psychosis (FEP) causes illness progression, with previous reviews suggesting that treatment non-response develops in one in six patients who relapse. This belief contributes to the primary treatment goal in FEP being relapse-prevention, often in favor of other recovery-oriented goals. However, previous reviews primarily reported on naturalistic studies in chronic schizophrenia and predated multiple major studies with higher-quality designs. METHODS: We conducted a narrative review of studies of any design that examine the impact of relapse on medication response and other symptomatic and functional outcomes in FEP. RESULTS: We identified eight relevant studies, five of these published since the last major review on this topic. Observational studies show a clear association between relapses and worse response to medication, but poorly control for confounding. Three higher-quality studies (two randomized) generally do not find worse symptomatic or functional outcomes among medication reduction/discontinuation arms compared to maintenance controls, despite significantly higher initial rates of relapse. CONCLUSION: While the social and psychological consequences of a relapse should not be dismissed, clinicians should demand high-quality evidence about the risks of relapse on long-term outcomes. The conventional notion that relapse leads to treatment non-response or worse long-term outcomes is generally not supported by the highest quality studies. These findings can help clinicians and patients weigh the risks and benefits of competing treatment strategies in FEP.
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BACKGROUND: PDE10A inhibition represents a potential mechanism for treating schizophrenia. PDE10A inhibitors increase cyclic nucleotides in striatal neurons, thereby mimicking the effects of dopamine receptor D2 antagonists and D1 agonists. We evaluated the PDE10A inhibitor MK-8189 for treating schizophrenia. METHODS: Randomized, double-blind, placebo and active-controlled, phase 2a, multicenter, inpatient trial in adults experiencing an acute episode of schizophrenia. Participants were randomized 2:2:1 to once-daily MK-8189 12 mg, placebo, or risperidone 6 mg (active control) for 4-weeks. The primary outcome was change-from-baseline in total score on the Positive and Negative Syndrome Scale (PANSS) at 4 weeks. RESULTS: The number of treated participants was 90 for MK-8189, 89 for placebo, and 45 for risperidone. MK-8189 demonstrated a trend towards improvement versus placebo for change-from-baseline in PANSS total score after 4 weeks (difference = -4.7 [95 % CI: -9.8,0.5], P = 0.074). The active control risperidone was superior to placebo on PANNS total score (difference = -7.3 [95 % CI: -14.0,-0.6], P = 0.033), demonstrating assay sensitivity, while MK-8189 and risperidone did not significantly differ (difference = 2.6 [95 % CI: -4.0,9.2], P = 0.440). MK-8189 had a nominally significant effect on PANSS positive subscale score compared to placebo (difference = -2.2 [95 % CI: -3.8,-0.5], P = 0.011). Discontinuation of MK-8189 treatment due to an adverse event was low (<10 %). Extrapyramidal symptoms occurred with MK-8189 but were mostly mild and transient. Compared with placebo, MK-8189 reduced body weight while risperidone increased weight. CONCLUSIONS: These findings suggest that PDE10A inhibition may produce antipsychotic effects and associated weight loss and that further trials with PDE10A inhibitors are warranted. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT03055338.
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Antipsicóticos , Diester Fosfórico Hidrolases , Pirimidinas , Risperidona , Esquizofrenia , Compostos de Enxofre , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem , Doença Aguda , Antipsicóticos/farmacologia , Antipsicóticos/efeitos adversos , Antipsicóticos/administração & dosagem , Método Duplo-Cego , Avaliação de Resultados em Cuidados de Saúde , Inibidores de Fosfodiesterase/efeitos adversos , Inibidores de Fosfodiesterase/farmacologia , Inibidores de Fosfodiesterase/uso terapêutico , Diester Fosfórico Hidrolases/metabolismo , Estudo de Prova de Conceito , Pirimidinas/efeitos adversos , Pirimidinas/farmacologia , Pirimidinas/uso terapêutico , Risperidona/farmacologia , Risperidona/efeitos adversos , Risperidona/administração & dosagem , Esquizofrenia/tratamento farmacológico , Compostos de Enxofre/efeitos adversos , Compostos de Enxofre/farmacologia , Compostos de Enxofre/uso terapêuticoRESUMO
Individuals living with psychosis are often underserved in the United States, partly due to the dearth of providers trained in evidence-based practices for this population. One such practice is Cognitive Behavioral Therapy for psychosis, which the Substance Abuse and Mental Health Services Administration has identified as a standard of care for this population. The explosion of telehealth, in large part due to the COVID-19 pandemic, has led to increased opportunities for virtual psychotherapy. Telehealth offers a number of benefits, such as the ability to address service inequities, including lack of access to a local provider well-trained in the modality of therapy needed. The current article describes the National Psychosis Telehealth Program within the National Expert Consultation and Specialized Services (formerly VA National Telemental Health Center) program, U.S. Department of Veterans Affairs. The goal of this telehealth program is to utilize an expert consultation model and offer a remote individual, time-limited Cognitive Behavioral Therapy for psychosis protocol to Veterans across the nation in order to decrease access disparities to this relatively scarce service. We share our initiation activities and lessons learned as we developed this program in hopes of encouraging others to consider similar efforts at their sites. We also include a typical, complex case that serves to illustrate the challenges and benefits of this approach. (PsycInfo Database Record (c) 2024 APA, all rights reserved).
Assuntos
Terapia Cognitivo-Comportamental , Transtornos Psicóticos , Telemedicina , United States Department of Veterans Affairs , Humanos , Terapia Cognitivo-Comportamental/métodos , Transtornos Psicóticos/terapia , Estados Unidos , COVID-19 , Veteranos , Encaminhamento e Consulta , Acessibilidade aos Serviços de SaúdeRESUMO
BACKGROUND: There is no consensus on defining relapse in schizophrenia, and scale-derived criteria with unclear clinical relevance are widely used. We aimed to develop an evidence-based scale-derived set of criteria to define relapse in patients with schizophrenia or schizoaffective disorder. METHODS: We searched the Yale University Open Data Access (YODA) for randomised controlled trials (RCTs) in clinically stable adults with schizophrenia or schizoaffective disorder, and obtained individual participant data on Positive and Negative Syndrome Scale (PANSS), Clinical Global Impression Severity (CGI-S), Personal and Social Performance (PSP), and Social and Occupational Functioning Assessment Scale (SOFAS). Our main outcomes were PANSS-derived criteria based on worsening in PANSS total score. We examined their relevance using equipercentile linking with CGI-S and functioning scales, and their test-performance in defining relapse with diagnostic test accuracy meta-analysis against CGI-S worsening (≥1-point increase together with a score ≥4 points) and psychiatric hospitalisation. FINDINGS: Based on data from seven RCTs (2354 participants; 1348 men [57·3%] and 1006 women [42·7%], mean age of 39·5 years [SD 12·0, range 17-89]; 303 Asian [12.9%], 255 Black [10.8%], 1665 White [70.7%], and other or unspecified 131 [5.6%]), an increase of 12 points or more in PANSS total (range 30-210 points) corresponded to clinically important deterioration in global severity of illness (≥1 point increase in CGI-S, range 1-7) and functioning (≥10 points decline in PSP or SOFAS, range 1-100). The interpretation of percentage changes varied importantly across different baseline scores. An increase of 12 points or more in PANSS total had good sensitivity and specificity using CGI-S as reference standard (sensitivity 82·1% [95% CI 77·1-86·4], specificity 86·9% [82·9-90·3]), as well as good sensitivity but lower specificity compared to hospitalisation (sensitivity 81·7% [74·1-87·7], specificity 69·2% [60·5-76·9]). Requiring either an increase in PANSS total or in specific items for positive and disorganization symptoms further improved test-performance. Cutoffs for situations where high sensitivity or specificity is needed are presented. INTERPRETATION: An increase of either 12 points or more in the PANSS total score, or worsening of specific positive and disorganisation symptom items could be a reasonable evidence-based definition of relapse in schizophrenia, potentially linking symptoms used to define remission and relapse. Percentage changes should not be used to define relapse because their interpretation depends on baseline scores. FUNDING: German Research Foundation (grant number: 428509362).
Assuntos
Antipsicóticos , Transtornos Psicóticos , Esquizofrenia , Adulto , Masculino , Feminino , Humanos , Antipsicóticos/uso terapêutico , Escalas de Graduação Psiquiátrica , Esquizofrenia/diagnóstico , Esquizofrenia/tratamento farmacológico , Transtornos Psicóticos/psicologia , Testes Diagnósticos de RotinaRESUMO
The Genomic Psychiatry Cohort (GPC) is a longitudinal resource designed to provide the necessary population-based sample for large-scale genomic studies, studies focusing on Research Domain Criteria (RDoC) and/or other alternate phenotype constructs, clinical and interventional studies, nested case-control studies, long-term disease course studies, and genomic variant-to-phenotype studies. We provide and will continue to encourage access to the GPC as an international resource. DNA and other biological samples and diagnostic data are available through the National Institute of Mental Health (NIMH) Repository. After appropriate review and approval by an advisory board, investigators are able to collaborate in, propose, and co-lead studies involving cohort participants.