The STAR*D trial: Revealing the need for better treatments

National Institute of Mental Health, Bethesda, MD 20892-9669, USA.
Psychiatric services (Washington, D.C.) (Impact Factor: 2.41). 11/2009; 60(11):1466-7. DOI: 10.1176/
Source: PubMed


STAR*D (Sequenced Treatment Alternatives to Relieve Depression) continues to stimulate debate. The landmark trial demonstrated the feasibility of large-scale, community-based studies conducted without pharmaceutical company support. The results provided insight into nonresponse to initial treatment with selective serotonin reuptake inhibitors and alternatives for second- and third-line treatment options and suggested opportunities for personalized approaches to depression care. However, initial and one-year remission rates (28% and 70%, respectively) suggest that important goals for treatment of this disabling disease remain out of reach and that the bar for antidepressants has been set far too low.

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    • "In the United States alone, MDD remains the second highest contributor to years lived with disability, and recently rose to the fifth leading contributor to disability-adjusted life years according to epidemiological studies from 1990 to 2010 (Collaborators, 2013). The mental health community is largely in agreement that current antidepressant drugs are not adequate due to the long treatment time course required to reach full efficacy (weeks to months), and their limited response in treatment-resistant patients (Insel and Wang, 2009). Many depressed patients, especially those who are at risk for suicide, require an effective, fast-acting antidepressant. "
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    ABSTRACT: A debilitating mental disorder, major depressive disorder is a leading cause of global disease burden. Existing antidepressant drugs are not adequate for the majority of depressed patients, and large clinical studies have demonstrated their limited efficacy and slow response onset. Growing evidence of low-dose ketamine's rapid and potent antidepressant effects offers strong potential for future antidepressant agents. However, ketamine has considerable drawbacks such as its abuse potential, psychomimetic effects, and increased oxidative stress in the brain, thus limiting its widespread clinical use. To develop superior antidepressant drugs, it is crucial to better understand ketamine's antidepressant mechanism of action. Recent preclinical studies indicate that ketamine's antidepressant mechanism involves mammalian target of rapamycin pathway activation and subsequent synaptogenesis in the prefrontal cortex, as well as glycogen synthase kinase-3 beta (GSK-3β) inactivation. Adjunct GSK-3β inhibitors, such as lithium, can enhance ketamine's efficacy by augmenting and prolonging its antidepressant effects. Given the potential for depressive relapses, lithium in addition to ketamine is a promising solution for this clinical issue.
    Full-text · Article · Aug 2015 · Frontiers in Neuroscience
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    • "Depression in individuals with either major depressive disorder (MDD) or bipolar disorder (BD) is one of the leading causes of the global disease burden. Almost all current antidepressant drugs in clinical use require weeks to months to take full effect (Adell et al., 2005), and a significant proportion of patients do not respond to available agents (Insel and Wang, 2009). Ketamine, a noncompetitive N-methyl-D-aspartate receptor antagonist, has been safely used as an anesthetic and analgesic agent for many years. "
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    ABSTRACT: Evidence suggests that mammalian target of rapamycin (mTOR) activation mediates ketamine's rapid but transient antidepressant effects, and that glycogen synthase kinase-3β (GSK-3β) inhibits this pathway. However, ketamine has associated psychotomimetic effects and a high risk of abuse. The mood stabilizer lithium is a GSK-3 inhibitor with strong anti-suicidal properties. Here, we used a mouse stress model to investigate whether adjunct lithium treatment would potentiate ketamine's antidepressant-like effects. Mice received chronic restraint stress and long-term pre- or post-ketamine lithium treatment in drinking water. The effects of lithium on ketamine-induced antidepressant-like effects, activation of the mTOR/brain-derived neurotrophic factor (BDNF) signaling pathways, oxidative stress, and dendritic spine density in the brain of mice were investigated. Sub-therapeutic (600 mg/L) lithium-pretreated mice exhibited an antidepressant-like response to an ineffective ketamine (2.5 mg/kg, i.p.) challenge in the forced swim test. Both the antidepressant-like effects and restoration of dendritic spine density in the medial prefrontal cortex (PFC) of stressed mice induced by a single ketamine (50 mg/kg) injection were sustained by post-ketamine treatment with 1200 mg/L of lithium for at least two weeks. These benefits of lithium treatments were associated with activation of the mTOR/BDNF signaling pathways in the PFC. Acute ketamine (50 mg/kg) injection also significantly increased lipid peroxidation, catalase activity, and oxidized glutathione levels in stressed mice. Notably, these oxidative stress markers were completely abolished by pretreatment with 1200 mg/L of lithium. Our results suggest a novel therapeutic strategy and justify the use of lithium in patients who benefit from ketamine. Published by Oxford University Press on behalf of CINP 2014. This work is written by (a) US Government employee(s) and is in the public domain in the US.
    Preview · Article · Dec 2014 · The International Journal of Neuropsychopharmacology
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    • "The growth of large trials of intervention in mental illness has been impressive over the last 25 years. Very large studies such as the CATIE (Lieberman et al. 2005) and STAR-D studies in the US (Insel & Wang, 2009) and CUtLASS in the UK (Jones et al. 2006), all carried out independently of pharmaceutical company support, have changed our thinking about the use of antidepressants and antipsychotic drugs and smaller but high-quality equivalent studies of psychological treatments have led to the adoption of psychological treatments such as cognitive behaviour therapy en masse in the UK in the growth of the improved access to psychological treatments programme (Clark, 2011). The introduction of specific topic networks, including one for mental health, has assisted this greatly, as multicentre studies have been resourced by trained staff, clinical studies officers, who facilitate recruitment, assist with research governance and provide extra input to studies that are recruiting below target. "
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    ABSTRACT: Background: Loss of cortical volume in frontotemporal regions occurs in patients with first-episode psychosis (FEP) and longitudinal studies have reported progressive brain volume changes at different stages of the disease, even if cognitive deficits remain stable over time. We investigated cortical changes in patients over the 2 years following their FEP and their associations with clinical and cognitive measures. Method: Twenty-seven patients after their FEP (20 with schizophrenia, seven with schizo-affective disorder) and 25 healthy controls matched for age and gender participated in this study. Magnetic resonance imaging (MRI) was performed on a 1.5-T scanner both at baseline and after 2 years. Area and thickness of the cortex were measured using surface-based morphometry (SBM). Patients also underwent neuropsychological testing at these two time points. Results: Progressive cortical thinning in the superior and inferior frontal and, to a lesser extent, superior temporal cortex was observed in patients. Cortical area remained constant. Cortical thinning was associated with duration of treatment at a trend level and was predicted by baseline measures of IQ and working memory. Cortical thinning occurred in the absence of clinical or cognitive deterioration. Conclusions: The clinical implications of these cortical changes remain uncertain, but patients with less cognitive reserve may be more vulnerable to developing cortical abnormalities when exposed to medication or other disease-related biological factors.
    Full-text · Article · Jul 2014 · Psychological Medicine
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