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1.
Annu Int Conf IEEE Eng Med Biol Soc ; 2020: 5510-5513, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-33019227

RESUMO

Major depressive disorder or clinical depression is a mental disorder characterized by daily low moods, which occur across many situations. Individuals suffering from depression are typically treated with counseling and antidepressant medication. This paper presents a computing approach for visualizing the dynamics of pairwise interactions of moods in personalized depression under and without medication. The methods of fuzzy cross recurrence plots of time series and their tensor decomposition offer a new way for gaining insight into the causality of the complex behavior of depression and its treatment.


Assuntos
Transtorno Depressivo Maior , Afeto , Antidepressivos/uso terapêutico , Depressão/tratamento farmacológico , Transtorno Depressivo Maior/tratamento farmacológico , Humanos , Recidiva
2.
Artigo em Inglês | MEDLINE | ID: mdl-32942346

RESUMO

Introduction: Bipolar disorder is a complex mood disorder characterized by a chronic and subtle course of fluctuating manic/hypomanic and depressive symptoms. Cariprazine, a dopamine D3-preferring D3/D2 receptor partial agonist with serotonin 5-HT1A receptor partial agonist and serotonin 5-HT2A antagonist properties, is approved to treat manic and depressive episodes of bipolar disorder. Post hoc analyses evaluated efficacy across symptoms in bipolar depression. Methods: Pooled data were analyzed from 3 phase 2 or 3, randomized, double-blind, placebo-controlled studies of adults with bipolar disorder and a major depressive episode. Mean change from baseline to week 6 in Montgomery-Asberg Depression Rating Scale (MADRS) total score and individual item scores were analyzed in individual dose groups (1.5 mg/d, 3 mg/d) and overall cariprazine (1.5-3 mg/d). Pooled safety was evaluated via adverse events. Results: A significantly greater difference in mean change from baseline in MADRS total score was seen for each cariprazine dose group versus placebo (least squares mean difference vs placebo: 1.5-3 mg/d = -2.6, 1.5 mg/d = -2.8, 3 mg/d = -2.4) (P < .001 all). Significant differences versus placebo were seen on all individual MADRS items except inner tension for the overall cariprazine group (P < .05). Cariprazine was generally well tolerated. Conclusions: Cariprazine demonstrated broad efficacy across symptoms of depression in bipolar disorder. In previous post hoc analyses, cariprazine also demonstrated broad efficacy across manic symptoms, suggesting that it is effective across the wide range of symptoms on the bipolar spectrum. A 1.5-mg/d starting dose and slow titration resulted in lower rates of some adverse events in the bipolar depression studies versus the mania studies. Trial Registration: ClinicalTrials.gov identifiers: NCT01396447, NCT02670538, NCT02670551.


Assuntos
Transtorno Bipolar/tratamento farmacológico , Transtorno Depressivo Maior/tratamento farmacológico , Neurotransmissores/farmacologia , Piperazinas/farmacologia , Adulto , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neurotransmissores/administração & dosagem , Neurotransmissores/efeitos adversos , Piperazinas/administração & dosagem , Piperazinas/efeitos adversos , Resultado do Tratamento
3.
Adv Pharmacol ; 89: 103-129, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32616204

RESUMO

Depression represents one of the most common and debilitating mental illnesses in the world today. Despite this pressing issue, the majority treatments for depression give patients therapeutic response only approximately half of the time, with many not responding at all. In part, this stagnation has been due to the dominance of the monoamine hypothesis that guides the current approach to understanding and treating depression. While therapies that increase levels of monoamines have been useful, clearly a more complete understanding of the neural circuits and treatments is needed to better help patients. Recent work that exploits the glutamatergic system within the brain has demonstrated a functional role for glutamate in combatting depression. While more research is required to understand the specific glutamatergic pathophysiological mechanisms within depression, emerging clinical work has already demonstrated promising results. Current treatments that target the glutamatergic system, especially NMDA receptor antagonists have already shown efficacy in several clinical trials. In this chapter we briefly introduce a mechanistic basis for a role of glutamate in the pathophysiology of depression. We further review basic and translational studies that describes potential mechanisms and roles for glutamate. A discussion of the first promising NMDA receptor antagonist for depression, ketamine, follows afterward. The development of NMDA receptor antagonists for treatment of depression is chronicled, from initial studies up through the recent FDA approval of intranasal esketamine as well as other newer compounds that have shown recent promise in clinical trials.


Assuntos
Padrões de Prática Médica , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Antidepressivos/farmacologia , Transtorno Depressivo Maior/tratamento farmacológico , Transtorno Depressivo Maior/fisiopatologia , Ácido Glutâmico/uso terapêutico , Humanos , Ketamina/uso terapêutico , Receptores de N-Metil-D-Aspartato/metabolismo
4.
Adv Pharmacol ; 89: 163-194, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32616206

RESUMO

A paradigm shift in the conceptualization of the neurobiology of depression and the serendipitous discovery of ketamine's rapid-acting antidepressant (RAAD) effects has ushered in a new era of innovative research and novel drug development. Since the initial discovery of ketamine's RAAD effects, multiple studies have supported its short-term efficacy for fast-tracked improvements in treatment-resistant depression. Evidence from MRI studies have repeatedly demonstrated functional connectivity alterations in stress- and trauma-related disorders suggesting this may be a viable biomarker of chronic stress pathology (CSP). Human mechanistic studies further support this by coupling functional connectivity to ketamine's RAAD effects including connectivity to glutamate neurotransmission, ketamine to normalized connectivity, and these advantageous normalizations to symptom improvement/ketamine response. This review provides an abridged discussion of the suspected neurobiological underpinnings of ketamine's RAAD effects, highlighting ketamine-induced alterations in prefrontal, striatal, and anterior cingulate cortex functional connectivity in major depressive disorder. We present a model of CSP underscoring the role of synaptic loss and dysconnectivity and discuss how ketamine may be used both as (1) a treatment to restore and normalize these stress-induced neural alterations and (2) a tool to study potential biomarkers of CSP and treatment response. We conclude by noting challenges and future directions including heterogeneity, sex differences, the role of early life stress, and the need for proliferation of new methods, paradigms, and tools that will optimize signal and allow analyses at different levels of complexity, according to the needs of the question at hand, perhaps by thinking hierarchically about both clinical and biological phenotypes.


Assuntos
Transtorno Depressivo Maior/tratamento farmacológico , Transtorno Depressivo Maior/fisiopatologia , Ketamina/uso terapêutico , Rede Nervosa/fisiopatologia , Estresse Psicológico/fisiopatologia , Antidepressivos/farmacologia , Antidepressivos/uso terapêutico , Doença Crônica , Humanos , Ketamina/farmacologia
5.
J Clin Psychiatry ; 81(4)2020 06 23.
Artigo em Inglês | MEDLINE | ID: mdl-32603560

RESUMO

OBJECTIVE: To determine whether concurrent posttraumatic stress disorder (PTSD) should affect whether to augment or switch medications when major depressive disorder (MDD) has not responded to a prior antidepressant trial. METHODS: Patients at 35 Veterans Health Administration medical centers from December 2012 to May 2015 with nonpsychotic MDD (N = 1,522) and a suboptimal response to adequate antidepressant treatment were randomly assigned to 3 "next step" treatments: switching to bupropion, augmenting the current antidepressant with bupropion, and augmenting with the antipsychotic aripiprazole. Blinded ratings with the 16-item Quick Inventory of Depressive Symptomatology-Clinician Rated (QIDS-C16) determined remission and response by 12 weeks and relapse after remission. Survival analyses compared treatment effects in patients with concurrent PTSD diagnosed with the Mini-International Neuropsychiatric Interview (n = 717, 47.1%) and those without PTSD (n = 805, 52.9%). RESULTS: Patients diagnosed with PTSD showed more severe depressive symptoms at baseline and were less likely to achieve either remission or response by 12 weeks. Augmentation with aripiprazole was associated with greater likelihood of achieving response (68.4%) than switching to bupropion (57.7%) in patients with PTSD (relative risk [RR] = 1.26; 95% CI, 1.01-1.59) as well as in patients without PTSD (RR = 1.29; 95% CI, 1.05-1.97) (78.9% response with aripiprazole augmentation vs 66.9% with switching to bupropion). Treatment comparisons with the group receiving augmentation with bupropion were not significant. There was no significant interaction between treatment group and PTSD on remission (P = .70), response (P = .98), or relapse (P = .15). CONCLUSIONS: Although PTSD was associated with poorer overall outcomes, the presence of concurrent PTSD among Veterans in this trial did not affect the comparative effectiveness of medications on response, remission, or relapse after initial remission. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01421342.


Assuntos
Transtorno Depressivo Maior/tratamento farmacológico , Transtorno Depressivo Resistente a Tratamento/tratamento farmacológico , Transtornos de Estresse Pós-Traumáticos/tratamento farmacológico , Adolescente , Adulto , Antidepressivos/uso terapêutico , Aripiprazol/uso terapêutico , Bupropiona/uso terapêutico , Transtorno Depressivo Maior/complicações , Resistência a Medicamentos/efeitos dos fármacos , Quimioterapia Combinada , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Método Simples-Cego , Transtornos de Estresse Pós-Traumáticos/complicações , Adulto Jovem
6.
J Clin Psychiatry ; 81(4)2020 07 07.
Artigo em Inglês | MEDLINE | ID: mdl-32659874

RESUMO

OBJECTIVE: A recent randomized controlled trial of repetitive transcranial magnetic stimulation (TMS) for major depressive disorder (MDD) in veterans raised the question of whether comorbid posttraumatic stress disorder (PTSD) negatively impacted the outcome of TMS in veterans. To address this, a quality database was analyzed to compare outcomes of MDD treated with TMS in veterans with and without comorbid PTSD. METHODS: The clinical outcomes of all consecutive veterans with MDD treated with TMS at the James A. Haley Veterans' Hospital as outpatients from October 2013 through September 2018 were included. Patients were initially evaluated by an experienced psychiatrist, and the diagnosis of MDD was made by clinical evaluation per DSM-IV-TR/DSM-5 criteria. At the start of treatment, after every 5 treatments, and at the end of treatment, patients were assessed with self-report and clinician-rated scales of depression. All data were abstracted from an existing quality database. RESULTS: Among the 118 patients treated with TMS for depression, 55 (47%) had comorbid PTSD and 63 (53%) had no comorbid PTSD. Response and remission rates by score on the Montgomery-Asberg Depression Rating Scale were similar between patients with PTSD (52.5% and 40.9%, respectively) and without PTSD (53.8% and 35.6%, respectively). No seizures or persistent adverse effects were observed or reported in either group. CONCLUSIONS: Comorbid PTSD did not impact the outcome of TMS for depression in this sample of veterans. Future studies should include formal ratings of PTSD to determine if the severity of PTSD affects the outcome.


Assuntos
Transtorno Depressivo Maior/terapia , Transtornos de Estresse Pós-Traumáticos/terapia , Estimulação Magnética Transcraniana , Veteranos/psicologia , Adulto , Idoso , Terapia Combinada/métodos , Bases de Dados Factuais , Transtorno Depressivo Maior/complicações , Transtorno Depressivo Maior/tratamento farmacológico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Psicotrópicos/uso terapêutico , Transtornos de Estresse Pós-Traumáticos/complicações , Transtornos de Estresse Pós-Traumáticos/tratamento farmacológico , Estimulação Magnética Transcraniana/efeitos adversos , Resultado do Tratamento , Adulto Jovem
7.
J Clin Psychiatry ; 81(4)2020 07 14.
Artigo em Inglês | MEDLINE | ID: mdl-32663909

RESUMO

OBJECTIVE: To assess putative antidepressant and procognitive effects of decoglurant, a selective metabotropic glutamate receptor type 2/3 (mGlu2/3) negative allosteric modulator, as adjunctive treatment to selective serotonin reuptake inhibitors and/or serotonin-norepinephrine reuptake inhibitors (SSRIs/SNRIs) in patients with partially refractory major depressive disorder (MDD), diagnosed using DSM-IV-TR criteria. METHODS: This randomized, placebo-controlled, double-blind, multicenter phase 2 trial consisted of 4 weeks' screening, 6 weeks' treatment, and 8 weeks' follow-up between September 2011 and June 2014. Individuals with Montgomery-Åsberg Depression Rating Scale (MADRS) score ≥ 25 and Clinical Global Impressions-Severity of Illness scale score ≥ 4, despite up to 2 adequate trials of an SSRI/SNRI and compliance confirmed by positive SSRI/SNRI blood levels, were randomized to decoglurant 5 mg (n = 101), 15 mg (n = 102), or 30 mg (n = 55) daily or placebo (n = 99) as adjunct to ongoing treatment with 1 SSRI/SNRI. An adaptive design was used with an interim analysis after 30 patients in each group had received 6 weeks' treatment. The primary outcome variable was change in MADRS total score from baseline to end of treatment. Primary assessments were performed by fully blinded centralized raters. RESULTS: Of 357 participants, 310 completed 6 weeks' treatment. At 6 weeks, no significant differences between any active treatment arm and placebo in reducing MADRS total score or response or remission rates were observed. Decoglurant exerted no significant effects on Cambridge Neuropsychological Test Automated Battery cognitive accuracy and cognitive speed composite scores or on secondary measures of mood and functioning. A relatively high placebo response was observed, which may have constrained the ability to detect treatment effects. No deaths occurred; few patients reported serious adverse events. CONCLUSIONS: Decoglurant was well tolerated overall but did not exert any antidepressant or procognitive effects. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01457677.


Assuntos
Transtorno Depressivo Maior/tratamento farmacológico , Transtorno Depressivo Resistente a Tratamento/tratamento farmacológico , Adulto , Regulação Alostérica/efeitos dos fármacos , Antidepressivos/uso terapêutico , Método Duplo-Cego , Quimioterapia Combinada , Antagonistas de Aminoácidos Excitatórios/uso terapêutico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento
8.
J Clin Psychiatry ; 81(4)2020 07 21.
Artigo em Inglês | MEDLINE | ID: mdl-32726521

RESUMO

OBJECTIVE: To review the efficacy of antidepressants and other therapeutic agents for the treatment of cognitive impairment in adults with major depressive disorder (MDD). DATA SOURCES: We conducted a database search of MEDLINE, PsycINFO, and Embase through Ovid on May 7, 2019. The year of publication was not restricted. The search terms "Major Depressive Disorder," "depress*," "cognit*," and "therapeutics" were used. STUDY SELECTION: The studies included in this review were clinical trials of antidepressants and other therapeutic agents in MDD populations. Participants were aged between 18 and 65 years and had a DSM-III, -IV, or -5 diagnosis of MDD. In total, 2,045 research papers were screened, 53 full-text articles were assessed, and 26 articles were eligible to be included in this systematic review. DATA EXTRACTION: The data and quality of research papers were assessed and screened by 2 independent reviewers. Discrepancies were resolved through a third reviewer. RESULTS: Overall, studies demonstrated that tricyclic antidepressants do not have procognitive effects, while vortioxetine and bupropion have demonstrated procognitive effects in MDD populations relative to selective serotonin reuptake inhibitors and serotonin-norepinephrine reuptake inhibitors. Several non-antidepressant agents, such as modafinil, amphetamines, and erythropoietin, have also demonstrated significant positive effects on cognition in depression. CONCLUSIONS: Present-day antidepressants and other agents have demonstrated procognitive effects in MDD, but the findings between various agents are mixed. Further research looking at objective measures of cognitive performance would be helpful to obtain more definitive results regarding the efficacy of therapeutics for cognitive impairment in MDD.


Assuntos
Antidepressivos/uso terapêutico , Disfunção Cognitiva/tratamento farmacológico , Transtorno Depressivo Maior/tratamento farmacológico , Psicotrópicos/uso terapêutico , Disfunção Cognitiva/complicações , Transtorno Depressivo Maior/complicações , Humanos
9.
Expert Opin Pharmacother ; 21(14): 1685-1698, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32584616

RESUMO

Introduction: Postpartum depressive disorder (PPD) is a burdensome medical condition. To date, only one treatment (Brexanolone) has undergone registrational trials and is approved in the United States with an indication for the treatment of PPD. However, other treatments are prescribed and have been tested for this condition. Herein, the authors review the available scientific evidence pertaining to the somatic treatments of PPD. Areas covered: The authors evaluate the published open-label and randomized controlled trials (RCTs), examine the biological mechanisms of PPD treatments, and evaluate how the available data translates into information that may be useful for clinical practice. Expert opinion: Antidepressants have long been the mainstay of PPD treatment, despite the limited evidence from randomized clinical trials that supports this practice. Brexanolone improves treatment options for women with PPD. However, the relatively burdensome administration and monitoring protocol, along with the high cost of the medication, limit the possibility for an extensive use of this medication. Large, randomized, controlled trials of hormonal treatments in patients with PPD are warranted. Also, treatment with mood stabilizers and/or antipsychotics in women with major depressive disorder, who meet the DSM-5 mixed features specifiers in the post-partum period, should be tested in controlled clinical trials.


Assuntos
Antidepressivos/uso terapêutico , Depressão Pós-Parto/tratamento farmacológico , Transtorno Depressivo Maior/tratamento farmacológico , Pregnanolona/uso terapêutico , beta-Ciclodextrinas/uso terapêutico , Antidepressivos/administração & dosagem , Antidepressivos/efeitos adversos , Depressão Pós-Parto/metabolismo , Transtorno Depressivo Maior/metabolismo , Combinação de Medicamentos , Monitoramento de Medicamentos , Estrogênios/sangue , Feminino , Humanos , Ocitocina/sangue , Pregnanolona/administração & dosagem , Pregnanolona/efeitos adversos , Ensaios Clínicos Controlados Aleatórios como Assunto , Estimulação Magnética Transcraniana , Resultado do Tratamento , Estados Unidos , beta-Ciclodextrinas/administração & dosagem , beta-Ciclodextrinas/efeitos adversos
10.
J Clin Psychiatry ; 81(4)2020 06 09.
Artigo em Inglês | MEDLINE | ID: mdl-32558402

RESUMO

OBJECTIVE: The neuroactive steroid metabolite of progesterone, allopregnanolone, is a positive allosteric modulator of γ-aminobutyric acid-A (GABAA) receptors and a putative treatment for mood disorders. This pilot study was performed to determine whether an oral allopregnanolone analog (ganaxolone) may be effective adjunctive therapy for persistent depression despite adequate antidepressant treatment in postmenopausal women. METHOD: Ten postmenopausal women (mean ± SD age: 62.8 ± 6.3 years; range, 53-69 years) with persistent depression despite adequate antidepressant treatment (current DSM-IV-TR major depressive episode per the Structured Clinical Interview for DSM-IV-TR, Montgomery-Asberg Depression Rating Scale [MADRS] score ≥ 16, and treated with an adequately dosed antidepressant for ≥ 6 weeks) were studied from December 2016 to April 2018. Open-label ganaxolone (225 mg twice daily, increased to 450 mg twice daily if tolerated) was administered for 8 weeks, followed by a 2-week taper. RESULTS: Mean ± SEM total MADRS score (primary endpoint) decreased by 8 weeks (24.4 ± 1.6 to 12.8 ± 2.9, P = .015), and the decrease persisted over the 2-week taper (P = .019); of the 9 subjects who completed the full 8-week treatment period, 44% (4/9) experienced response (MADRS score decrease ≥ 50%) and remission (final MADRS score < 10), which persisted in 100% and 50% of subjects at 10 weeks, respectively. Secondary endpoints showed significant improvement, including Inventory of Depressive Symptomatology-Self-Report score (P = .003), MADRS reduced sleep subscale score (P < .001), total Symptoms of Depression Questionnaire (SDQ) score (P = .012), and scores on SDQ subscales for disruptions in sleep quality (P = .003) and changes in appetite and weight (P = .009) over 8 weeks. No significant effects were observed on quality of life or sexual function. All subjects experienced sleepiness and fatigue; 60% experienced dizziness. CONCLUSIONS: In this open-label, uncontrolled pilot study, adjunctive ganaxolone appears to exert antidepressant effects but produces sedation with twice-daily dosing. Ganaxolone may also improve sleep, which may be useful in patients with depression and insomnia. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02900092.


Assuntos
Antidepressivos/uso terapêutico , Transtorno Depressivo Maior/tratamento farmacológico , Transtorno Depressivo Resistente a Tratamento/tratamento farmacológico , Pregnanolona/análogos & derivados , Idoso , Quimioterapia Combinada , Feminino , Moduladores GABAérgicos/uso terapêutico , Humanos , Pessoa de Meia-Idade , Projetos Piloto , Pós-Menopausa , Pregnanolona/uso terapêutico , Resultado do Tratamento
11.
J Clin Psychiatry ; 81(4)2020 06 16.
Artigo em Inglês | MEDLINE | ID: mdl-32558407

RESUMO

OBJECTIVE: Differential predictors of response to alternative treatment options are needed to improve the outcomes in major depressive disorder. The symptom dimension comprising loss of interest and reduced activity has been reported as a predictor of poor outcome of treatment with antidepressants. We hypothesized that augmentation with partial dopamine agonist aripiprazole will be effective for individuals with pronounced interest-activity symptoms. METHODS: We tested the hypothesis in the 2-phase Canadian Biomarker Integration Network in Depression trial 1 (CAN-BIND-1). All participants had a primary diagnosis of major depressive disorder confirmed with the Mini-International Neuropsychiatric Interview. In phase 1, 188 individuals received escitalopram monotherapy 10-20 mg daily for 8 weeks. In phase 2, nonresponders received augmentation with aripiprazole 2-10 mg daily while responders continued escitalopram monotherapy for another 8 weeks. Outcomes were measured with the Montgomery-Åsberg Depression Rating Scale (MADRS) every 2 weeks. Effects of baseline interest-activity symptoms on outcomes were tested in repeated-measures mixed-effects models. RESULTS: Higher baseline interest-activity score (indicative of more severe loss of interest and reduction in activity) predicted worse outcome of escitalopram monotherapy in phase 1 (b = 1.75; 95% CI, 0.45 to 3.05; P = .009), but the association disappeared with the augmentation option in phase 2 (b = -0.19; 95% CI, -1.30 to 0.92; P = .739). A significant interaction between the baseline interest-activity score and aripiprazole reflected the opposite direction of the relationship between baseline interest-activity score and degree of improvement with escitalopram monotherapy versus aripiprazole augmentation (b = -1.60; 95% CI, -2.35 to -0.84; P < .001). CONCLUSIONS: Individuals with prominent loss of interest and reduction in activity benefit less from escitalopram monotherapy and more from aripiprazole augmentation. Future trials may test the benefits of early prodopaminergic augmentation guided by interest-activity symptoms. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01655706.


Assuntos
Aripiprazol/uso terapêutico , Citalopram/uso terapêutico , Transtorno Depressivo Maior/tratamento farmacológico , Letargia/tratamento farmacológico , Adolescente , Adulto , Antidepressivos de Segunda Geração/uso terapêutico , Transtorno Depressivo Maior/complicações , Agonistas de Dopamina/uso terapêutico , Quimioterapia Combinada , Feminino , Humanos , Letargia/complicações , Masculino , Pessoa de Meia-Idade , Adulto Jovem
12.
Neuron ; 106(5): 715-726, 2020 06 03.
Artigo em Inglês | MEDLINE | ID: mdl-32497508

RESUMO

Ketamine exerts rapid antidepressant action in depressed and treatment-resistant depressed patients within hours. At the same time, ketamine elicits a unique form of functional synaptic plasticity that shares several attributes and molecular mechanisms with well-characterized forms of homeostatic synaptic scaling. Lithium is a widely used mood stabilizer also proposed to act via synaptic scaling for its antimanic effects. Several studies to date have identified specific forms of homeostatic synaptic plasticity that are elicited by these drugs used to treat neuropsychiatric disorders. In the last two decades, extensive work on homeostatic synaptic plasticity mechanisms have shown that they diverge from classical synaptic plasticity mechanisms that process and store information and thus present a novel avenue for synaptic regulation with limited direct interference with cognitive processes. In this review, we discuss the intersection of the findings from neuropsychiatric treatments and homeostatic plasticity studies to highlight a potentially wider paradigm for treatment advance.


Assuntos
Antimaníacos/farmacologia , Transtorno Bipolar/tratamento farmacológico , Transtorno Depressivo Maior/tratamento farmacológico , Antagonistas de Aminoácidos Excitatórios/farmacologia , Homeostase/efeitos dos fármacos , Ketamina/farmacologia , Compostos de Lítio/farmacologia , Plasticidade Neuronal/efeitos dos fármacos , Animais , Antimaníacos/uso terapêutico , Transtorno Depressivo Resistente a Tratamento/tratamento farmacológico , Antagonistas de Aminoácidos Excitatórios/uso terapêutico , Humanos , Ketamina/uso terapêutico , Compostos de Lítio/uso terapêutico , Transtornos do Humor/tratamento farmacológico , Sinapses/efeitos dos fármacos
14.
BMC Psychiatry ; 20(1): 208, 2020 05 08.
Artigo em Inglês | MEDLINE | ID: mdl-32384884

RESUMO

BACKGROUND: IGF-1 is an essential neurotrophin produced peripherally and in the brain. Impairments in the brain IGF-1 concentrations might be responsible for some aspects of major depressive disorder (MDD) pathogenesis, whereas peripheral IGF-1 could have the marker value. We aimed: 1) to compare serum IGF-1 levels in MDD patients and healthy controls (HC); 2) to elucidate possible associations between changes in IGF-1 expression and crucial characteristics of the current depressive episode, MDD course; 3) to evaluate IGF-1 dynamics after 8 weeks` vortioxetine treatment. METHODS: Seventy-eight MDD patients (according to DSM-5) and 47 HC were enrolled. Serum IGF-1, psychopathological (MADRS, CGI) and neuropsychological parameters (PDQ-5, RAVLT, TMT-B, DSST) were analyzed in all subjects at admission and 48 patients after 8 weeks` vortioxetine treatment. AUC-ROCs were calculated to determine if the value of serum IGF-1 could separate MDD patients from HC. Multiple regression models were performed to explore relationships between IGF-1 and depressive episode's symptoms. RESULTS: MDD patients had significantly higher serum IGF-1 levels than HC (228 (183-312) ng/ml vs 153 (129-186) ng/ml, p < 0.0001). IGF-1 had a good diagnostic value for predicting MDD in the whole sample with AUC of 0.820 (p < 0.0001). For a cutoff of 178.00 ng/ml, the sensitivity and specificity were 83 and 71%, respectively, and the number needed to misdiagnose was 5, indicating that only 1 of 5 tests give an invalid result. Among MADRS items, only reported sadness, inner tension, and concentration difficulties were significantly positively associated with serum IGF-1 concentrations. Vortioxetine treatment significantly attenuated IGF-1 levels and improved all psychopathological, neuropsychological parameters. CONCLUSIONS: Significant associations between IGF-1 levels and hypothymia, anxiety, and cognitive disturbances may indicate a pathogenic role of IGF-1 for the mentioned symptoms. We assume that the activity of the cerebral-hepatic axis increases in response to insufficient IGF-1 brain expression in MDD patients, whereas, vortioxetine treatment restores cerebral IGF-1 concentrations and, consequently, decreases its compensatory production by the liver. TRIAL REGISTRATION: registered at ClinicalTrials.gov (NCT03187093). First posted on 14th June 2017.


Assuntos
Transtorno Depressivo Maior/diagnóstico , Transtorno Depressivo Maior/tratamento farmacológico , Fator de Crescimento Insulin-Like I/metabolismo , Vortioxetina/uso terapêutico , Adulto , Biomarcadores/sangue , Estudos de Casos e Controles , Transtorno Depressivo Maior/sangue , Método Duplo-Cego , Feminino , Humanos , Fator de Crescimento Insulin-Like I/análise , Masculino , Reprodutibilidade dos Testes , Resultado do Tratamento
15.
JAMA Netw Open ; 3(5): e205308, 2020 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-32432711

RESUMO

Importance: In the absence of readily assessed and clinically validated predictors of treatment response, pharmacologic management of major depressive disorder often relies on trial and error. Objective: To assess a model using electronic health records to identify predictors of treatment response in patients with major depressive disorder. Design, Setting, and Participants: This retrospective cohort study included data from 81 630 adults with a coded diagnosis of major depressive disorder from 2 academic medical centers in Boston, Massachusetts, including outpatient primary and specialty care clinics from December 1, 1997, to December 31, 2017. Data were analyzed from January 1, 2018, to March 15, 2020. Exposures: Treatment with at least 1 of 11 standard antidepressants. Main Outcomes and Measures: Stable treatment response, intended as a proxy for treatment effectiveness, defined as continued prescription of an antidepressant for 90 days. Supervised topic models were used to extract 10 interpretable covariates from coded clinical data for stability prediction. With use of data from 1 hospital system (site A), generalized linear models and ensembles of decision trees were trained to predict stability outcomes from topic features that summarize patient history. Held-out patients from site A and individuals from a second hospital system (site B) were evaluated. Results: Among the 81 630 adults (56 340 women [69%]; mean [SD] age, 48.46 [14.75] years; range, 18.0-80.0 years), 55 303 reached a stable response to their treatment regimen during follow-up. For held-out patients from site A, the mean area under the receiver operating characteristic curve (AUC) for discrimination of the general stability outcome was 0.627 (95% CI, 0.615-0.639) for the supervised topic model with 10 covariates. In evaluation of site B, the AUC was 0.619 (95% CI, 0.610-0.627). Building models to predict stability specific to a particular drug did not improve prediction of general stability even when using a harder-to-interpret ensemble classifier and 9256 coded covariates (specific AUC, 0.647; 95% CI, 0.635-0.658; general AUC, 0.661; 95% CI, 0.648-0.672). Topics coherently captured clinical concepts associated with treatment response. Conclusions and Relevance: The findings suggest that coded clinical data available in electronic health records may facilitate prediction of general treatment response but not response to specific medications. Although greater discrimination is likely required for clinical application, the results provide a transparent baseline for such studies.


Assuntos
Antidepressivos/uso terapêutico , Transtorno Depressivo Maior/tratamento farmacológico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Transtorno Depressivo Maior/diagnóstico , Transtorno Depressivo Maior/psicologia , Registros Eletrônicos de Saúde , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Modelos Estatísticos , Indução de Remissão , Estudos Retrospectivos , Resultado do Tratamento , Adulto Jovem
16.
Lancet Psychiatry ; 7(6): 515-527, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32445690

RESUMO

BACKGROUND: Several small studies suggest that the adjunctive use of anti-inflammatory agents might improve depressive symptoms in bipolar disorder. However, there are few well designed, appropriately powered clinical trials assessing the efficacy of these novel treatment strategies. We aimed to assess the efficacy of adjunctive minocycline or celecoxib in this setting. METHODS: This double-blind, 12-week, randomised, placebo-controlled trial was done in four outpatient psychiatric clinics in Pakistan. Eligible participants were adults (aged 18-65 years) with DSM-5 bipolar disorder (type I or II) and a major depressive episode. In a 2 × 2 factorial design, participants were randomly assigned (1:1:1:1) to receive either active minocycline plus active celecoxib, active minocycline plus placebo celecoxib, placebo minocycline plus active celecoxib, or placebo minocycline plus placebo celecoxib. The primary outcome was the mean change from baseline to week 12 in score on the 17-item Hamilton Depression Rating Scale (HAMD-17), assessed in all randomised participants (missing data were imputed and assumed to be missing at random). The trial was registered with ClinicalTrials.gov, NCT02703363. FINDINGS: 266 (17%) of 1542 patients assessed between May 1, 2016, and March 31, 2019, were randomly assigned to receive minocycline plus celecoxib (n=68), minocycline plus placebo (n=66), celecoxib plus placebo (n=66), or placebo plus placebo (n=66). From baseline to week 12, depressive symptoms as per HAMD-17 reduced in all four groups (from 24·5-25·2 to 11·3-12·8), but these reductions did not differ significantly between the groups. In terms of main effects, reductions in HAMD-17 did not differ for patients treated with minocycline (mean adjusted difference vs non-minocycline 1·48 [95% CI -0·41 to 3·36]; p=0·123) or for celecoxib (mean adjusted difference vs non-celecoxib -0·74 [-2·61 to 1·14]; p=0·443). Rates of serious adverse effects did not differ between groups (31 participants had a manic switch, two self-harmed, and one died in a motor vehicle accident). INTERPRETATION: We found no evidence that minocycline or celecoxib was superior to placebo for the treatment of bipolar depression. This large trial casts doubt on the potential therapeutic benefits of adjunctive anti-inflammatory drugs for the acute management of bipolar depression. FUNDING: Stanley Medical Research Institute.


Assuntos
Antibacterianos/uso terapêutico , Anti-Inflamatórios não Esteroides/uso terapêutico , Transtorno Bipolar/tratamento farmacológico , Celecoxib/uso terapêutico , Minociclina/uso terapêutico , Adulto , Antibacterianos/administração & dosagem , Anti-Inflamatórios não Esteroides/administração & dosagem , Transtorno Bipolar/psicologia , Estudos de Casos e Controles , Celecoxib/administração & dosagem , Transtorno Depressivo Maior/tratamento farmacológico , Transtorno Depressivo Maior/psicologia , Manual Diagnóstico e Estatístico de Transtornos Mentais , Método Duplo-Cego , Quimioterapia Combinada , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Minociclina/administração & dosagem , Paquistão/epidemiologia , Placebos/administração & dosagem , Escalas de Graduação Psiquiátrica , Resultado do Tratamento
17.
J Clin Psychiatry ; 81(4)2020 05 26.
Artigo em Inglês | MEDLINE | ID: mdl-32459407

RESUMO

OBJECTIVE: Esketamine, the S-enantiomer of ketamine, was recently approved as a rapid-acting intranasal therapy for depression and is currently under development for suicidality. The authors sought to determine the efficacy of adjunctive intranasal esketamine in major depressive disorder (MDD). DATA SOURCES: A systematic search of PubMed/MEDLINE was conducted up to January 2019, in addition to abstracts of major psychiatric meetings held since 2010. Searches were conducted by cross-referencing the term intranasal with the term esketamine. Where necessary, authors and/or study sponsors were contacted in order to obtain a copy of the presentation as well as any pertinent study details. STUDY SELECTION: 241 study abstracts were initially identified and reviewed. Selected studies were randomized, double-blind clinical trials comparing adjunctive intranasal esketamine to adjunctive placebo for MDD. DATA EXTRACTION: Data were extracted independently by two of the authors. A random effects model was used to calculate the standardized mean difference (SMD) between esketamine and placebo (intranasal saline) in the Montgomery-Asberg Depression Rating Scale (MADRS) score change from baseline to endpoint, serving as the primary outcome of the study. RESULTS: Five trials with 774 patients were pooled. Adjunctive esketamine was significantly more effective than placebo for MADRS score change, response, and remission (N = 774, SMD = 0.36, 95% CI = 0.24-0.49, P < .0001; response: risk ratio [RR] = 1.40, 95% CI = 1.22-1.61, P < .0001; remission: RR = 1.45, 95% CI = 1.20-1.75, P < .0001). Results remained statistically significant regardless of differences in the study sample, fixed vs new/optimized baseline antidepressants. CONCLUSIONS: Adjunctive intranasal esketamine for patients with MDD who are either treatment-resistant or acutely suicidal appears to be an effective treatment strategy.


Assuntos
Transtorno Depressivo Maior/tratamento farmacológico , Ketamina/uso terapêutico , Administração Intranasal , Antidepressivos/administração & dosagem , Antidepressivos/uso terapêutico , Transtorno Depressivo Resistente a Tratamento/tratamento farmacológico , Quimioterapia Combinada/métodos , Humanos , Ketamina/administração & dosagem , Resultado do Tratamento
18.
J Clin Psychiatry ; 81(3)2020 05 05.
Artigo em Inglês | MEDLINE | ID: mdl-32369683

RESUMO

​​ Measurement-based care (MBC) is an important strategy in the treatment of patients with major depressive disorder who have inadequate antidepressant response. The rating scales used in MBC can assist clinicians at critical decision points, such as when to declare a treatment failure, what to do with partial improvement, and how long to continue successful treatment. Measurement has two benefits: it gives the clinician an objective basis for comparison of symptom severity over time, and it helps patients to have insight into their illness course. Further, many of these tools do not add substantially to the length of the clinical visit. MBC can also be used to monitor and address residual symptoms such as fatigue and irritability that impact patients' functioning and quality of life.​ ​.


Assuntos
Antidepressivos/uso terapêutico , Transtorno Depressivo Maior/tratamento farmacológico , Transtorno Depressivo Maior/diagnóstico , Transtorno Depressivo Maior/psicologia , Humanos , Escalas de Graduação Psiquiátrica , Falha de Tratamento , Resultado do Tratamento
19.
J Clin Psychiatry ; 81(3)2020 05 05.
Artigo em Inglês | MEDLINE | ID: mdl-32369684

RESUMO

​​ ​​ Being able to recognize inadequate response to antidepressant treatment and distinguish it from treatment-resistant depression is key in order for clinicians to provide appropriate therapies. Although definitions vary, nonresponse is often defined as less than 25% improvement on a standardized rating scale, and partial response, as more than 25% but less than 50% improvement. Residual symptoms characteristic of inadequate response (less than 50% improvement) include low mood, anxiety, irritability, guilt, and somatic symptoms. Various factors that may contribute to inadequate response to an antidepressant include inadequate dose or duration, poor adherence, and misdiagnosis. ​.


Assuntos
Antidepressivos/uso terapêutico , Transtorno Depressivo Maior/tratamento farmacológico , Transtorno Depressivo Maior/diagnóstico , Transtorno Depressivo Maior/psicologia , Humanos , Escalas de Graduação Psiquiátrica , Falha de Tratamento
20.
J Clin Psychiatry ; 81(3)2020 05 12.
Artigo em Inglês | MEDLINE | ID: mdl-32412697

RESUMO

​​​​ About 30%-50% of patients experience inadequate response to antidepressant therapy, and treatment choices for these patients include augmenting the antidepressant with another therapy, increasing the dose, switching to a different antidepressant, or combining antidepressants. Clinicians should tailor treatment strategies based on patients' response, tolerability, and disease severity. In this activity, augmentation and adjunctive strategies involving atypical antipsychotics, as well as off-label options including buspirone, stimulants, thyroid hormone, and lithium, are reviewed.​ ​.


Assuntos
Antidepressivos/uso terapêutico , Transtorno Depressivo Maior/tratamento farmacológico , Antidepressivos/administração & dosagem , Transtorno Depressivo Maior/diagnóstico , Substituição de Medicamentos , Humanos , Escalas de Graduação Psiquiátrica , Falha de Tratamento
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