RESUMO
Preclinical and clinical research supports a role for neuroactive steroids in the pathophysiology of posttraumatic stress disorder (PTSD). We investigated ganaxolone (a synthetic 3ß-methylated derivative of allopregnanolone, a GABAergic neuroactive steroid) for treatment of PTSD in a proof-of-concept, multisite, double-blind, placebo-controlled trial. Veteran and non-veteran participants (n = 112) were randomized to ganaxolone or placebo at biweekly escalating doses of 200, 400, and 600 mg twice daily for 6 weeks. During an open-label 6-week extension phase, the initial ganaxolone group continued ganaxolone, while the placebo group crossed over to ganaxolone. Eighty-six and 59 participants, respectively, completed the placebo-controlled and open-label phases. A modified intent-to-treat mixed model repeated measures analysis revealed no significant differences between the effects of ganaxolone and placebo on Clinician Administered PTSD Symptom (CAPS) scores, global well-being, negative mood, or sleep. Dropout rates did not differ between groups, and ganaxolone was generally well tolerated. Trough blood levels of ganaxolone at the end of the double-blind phase were, however, lower than the anticipated therapeutic level of ganaxolone in >35% of participants on active drug. Pharmacokinetic profiling of the ganaxolone dose regimen used in the trial and adverse event sensitivity analyses suggest that under-dosing may have contributed to the failure of ganaxolone to out-perform placebo. Future investigations of ganaxolone may benefit from higher dosing, rigorous monitoring of dosing adherence, a longer length of placebo-controlled testing, and targeting of treatment to PTSD subpopulations with demonstrably dysregulated pre-treatment neuroactive steroid levels. Clinicaltrials.gov identifier: NCT01339689.
Assuntos
Pregnanolona/análogos & derivados , Transtornos de Estresse Pós-Traumáticos/tratamento farmacológico , Transtornos de Estresse Pós-Traumáticos/epidemiologia , Adulto , Estudos Cross-Over , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Pregnanolona/uso terapêutico , Estudo de Prova de Conceito , Transtornos de Estresse Pós-Traumáticos/diagnóstico , Resultado do TratamentoRESUMO
We report findings from a 12-week randomized double-blinded placebo-controlled trial of methylphenidate or galantamine to treat emotional and cognitive complaints in individuals (n=32) with a history of PTSD, TBI, or both conditions. In this small pilot study, methylphenidate treatment was associated with clinically meaningful and statistically significant improvement compared with placebo on the primary outcome, a measure of cognitive complaints (Ruff Neurobehavioral Inventory-Postmorbid Cognitive Scale), as well as on the secondary outcomes reflecting post-concussive (Rivermead Post Concussive Symptom Questionnaire) and post-traumatic stress symptoms (Posttraumatic Stress Disorder Checklist). Treatment was well tolerated. These results suggest the need for a larger RCT to replicate and confirm these findings. Design considerations for such a trial should include the need for multiple sites to facilitate adequate recruitment and extension of the treatment and follow-up periods.
Assuntos
Lesões Encefálicas Traumáticas/tratamento farmacológico , Lesões Encefálicas Traumáticas/psicologia , Galantamina/uso terapêutico , Metilfenidato/uso terapêutico , Transtornos de Estresse Pós-Traumáticos/tratamento farmacológico , Transtornos de Estresse Pós-Traumáticos/psicologia , Adulto , Sintomas Afetivos/tratamento farmacológico , Sintomas Afetivos/etiologia , Lesões Encefálicas Traumáticas/complicações , Transtornos Cognitivos/tratamento farmacológico , Transtornos Cognitivos/etiologia , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos , Projetos Piloto , Transtornos de Estresse Pós-Traumáticos/complicações , Resultado do TratamentoRESUMO
Recent advances in molecular genetics have greatly increased the understanding of the pathophysiology of certain neurobehavioral disorders and the core symptoms of these disorders. This paper reviews key concepts important in understanding the genetics of neuropsychiatric disorders, and gives an overview of several different types of genetic disorders, including trinucleotide repeat disorders, and functional polymorphisms of monoamine neurotransmitter systems.
Assuntos
Encefalopatias/genética , Transtornos Mentais/genética , Polimorfismo Genético , Animais , Monoaminas Biogênicas/metabolismo , Transporte Biológico , Encefalopatias/fisiopatologia , Encefalopatias/terapia , Humanos , Proteínas de Membrana Transportadoras/genética , Proteínas de Membrana Transportadoras/metabolismo , Transtornos Mentais/fisiopatologia , Transtornos Mentais/terapia , Receptores Colinérgicos/biossíntese , Receptores Colinérgicos/genética , Receptores Dopaminérgicos/biossíntese , Receptores Dopaminérgicos/genética , Receptores de Serotonina/biossíntese , Receptores de Serotonina/genética , Expansão das Repetições de TrinucleotídeosRESUMO
The diagnosis and treatment of individuals with problems involving both psychiatry and neurology have become more sophisticated in recent years, but these advances may be difficult to implement in the modern health care environment. For 16 years, an inpatient Geriatric Treatment Center within a state mental hospital has been used to diagnose and treat older persons with complex neuropsychiatric disorders. Eight illustrative cases are presented of patients with major behavioral dysfunction that could not be managed effectively in other health care facilities. After neuropsychiatric evaluation and behavioral neurology consultation, all had neurologic diagnoses established as the cause of their presentation. Seven improved with appropriate treatment, of whom one could return to independent living, and the eighth died and had an autopsy diagnosis of his disease at a nearby academic medical center. This series highlights the value of collaboration between psychiatry and neurology for evaluation and treatment of older patients with neuropsychiatric problems not easily accommodated by many existing health care settings.