Family History of Alcohol Dependence and Initial Antidepressant Response to an N-methyl-D-aspartate Antagonist

Laboratory of Molecular Pathophysiology and Experimental Therapeutics, Mood and Anxiety Disorders Program, National Institute of Mental Health, National Institutes of Health/DHHS, 10 Center Drive, Bethesda, MD 20892-1282, USA.
Biological psychiatry (Impact Factor: 10.26). 12/2008; 65(2):181-4. DOI: 10.1016/j.biopsych.2008.09.029
Source: PubMed


A high rate of comorbidity exists between mood disorders and alcohol dependence. Furthermore, both ketamine, a dissociative anesthetic with a recently described rapid-onset antidepressant effect, and ethanol are N-methyl-D-aspartate (NMDA) receptor antagonists. Previous investigations of healthy individuals with a family history of alcohol dependence have found that these individuals have an attenuated response to ketamine's perceptual disturbance and dysphoric effects similar to that found in individuals with a self-reported history of alcohol dependence. This study investigated whether a family history of alcohol dependence influences ketamine's initial antidepressant effect.
Twenty-six subjects with DSM-IV treatment-resistant major depression were given an open-label intravenous infusion of ketamine hydrochloride (.5 mg/kg) and rated using various depression scales at baseline, 40, 80, 120, and 230 min postinfusion. The primary outcome measure was Montgomery-Asberg Depression Rating Scale (MADRS) scores.
Subjects with a family history of alcohol dependence showed significantly greater improvement in MADRS scores compared with subjects who had no family history of alcohol dependence.
A family history of alcohol dependence appears to predict a rapid initial antidepressant response to an NMDA receptor antagonist.

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Available from: David A Luckenbaugh, Feb 04, 2015
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    • "ts , and changes to the glutamatergic system and NMDA binding has been implicated in both disorders [ Petrakis et al . 2004 ] . Phelps and colleagues used linear mixed models to evaluate differential response in 26 MDD participants with and without a ( self - reported ) family history of alcohol dependency to open - label ketamine administration [ Phelps et al . 2009 ] ."
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    ABSTRACT: The burden of depressive disorders and the frequent inadequacy of their current pharmacological treatments are well established. The anaesthetic and hallucinogenic drug ketamine has provoked much interest over the past decade or so as an extremely rapidly acting antidepressant that does not modify 'classical' monoaminergic receptors. Current evidence has shown several ways through which it might exert therapeutic antidepressant actions: blockade of glutamatergic NMDA receptors and relative upregulation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) subtypes may alter cortical connectivity patterns; through intracellular changes in protein expression, including the proteins mammalian target of rapamycin (mTOR) and brain-derived neurotrophic factor (BDNF); and alteration of intracellular signalling cascades. The clinical evidence demonstrates rapid improvements in mood and suicidal thinking in most participants, although study numbers have generally been small and many trials are unblinded and methodologically weak. There is a small body of work to suggest ketamine might also augment electroconvulsive therapy and potentially have a role as a surgical anaesthetic in depressed patients. A major problem is that the effects of ketamine appear temporary, disappearing after days to weeks (although longer benefits have been sustained in some), and attempts to circumvent this through pharmacological augmentation have been disappointing thus far. These exciting data are providing new insights into neurobiological models of depression, and potentially opening up a new class of antidepressants, but there are significant practical and ethical issues about any future mainstream clinical role it might have.
    Therapeutic Advances in Psychopharmacology 04/2014; 4(2):75-99. DOI:10.1177/2045125313507739 · 1.53 Impact Factor
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    • "In 2009, four open-label studies showed one-time intravenous ketamine led to rapid improvement of treatmentresistant depression [106] [107] [113] [114]. Quickest significant antidepressant response was noted within 40 minutes [106] and slowest within four hours [113]. "
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    ABSTRACT: Major depressive disorder (MDD) is a serious mental disorder that ranks among the major causes of disease burden. Standard medical treatment targeting cerebral monoamines often provides only insufficient symptom relief and fails in approximately every fifth patient. The complexity of MDD therefore, reflects more than monoaminergic dysregulation. Initial research argues the case for excessive glutamate levels, suggesting that antiglutamatergic drugs might be useful in treating MDD. Ketamine is a non-selective, high-affinity N-methyl-D-aspartate receptor (NMDAR) antagonist most commonly used in pediatric and animal surgery. In the past, ketamine has gained popularity because of its ability to rapidly elevate mood, even in treatment-resistant and bipolar depression. However, there are still many obstacles before widespread clinical approval of ketamine treatment could become reality. In this review, ketamine’s powerful antidepressant effects are discussed and further research necessary for therapeutic application is outlined. NMDAR antagonists provide an entirely new way of treating the manifold appearances of depression that should not be left unused.
    Current Neuropharmacology 01/2014; 12(1):57-70. DOI:10.2174/1570159X113119990043 · 3.05 Impact Factor
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    • "Polovina pacientù zaznamenala po infuzi ketaminu signifikantní zlepšení nálady déle než jeden týden (C. A. Zarate, Jr. et al., 2006). Ètyøi otevøená sledování z roku 2009 potvrdila rychlé zlepšení nálady po jednorázovém intravenózním podání ketaminu u rezistentní deprese (Machado-Vieira et al., 2009; Mathew et al., 2010; Phelps et al., 2009; Salvadore et al., 2009). Nejrychlejší antidepresivní odpovìï byla zaznamenána bìhem 40 minut (Machado-Vieira et al., 2009) a nejpomalejší bìhem ètyø hodin (Mathew et al., 2010). "
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    ABSTRACT: This literature review begins with a rationale for the development of new therapeutic approaches for the treatment of depressive disorder. In the following sections the history of the finding of ketamine‘s antidepressant effect, its pharmacological properties and application routes are summarized. The following is an overview of the existing scientific evidence of ketamine’s efficacy in patients with unipolar and bipolar depression, suicidality and the adjuvant use in electroconvulsive therapy. Finally, the author discusses acute and chronic side effects, safety of repeated administration of ketamine and possibilities of extending the antidepressant effect. The last section summarizes recent findings on the mechanism of the antidepressant effect of ketamine on the molecular level and its effect on neuronal plasticity.
    Psychiatrie 01/2014; 18(4):193-205.
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