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Nascimento, Érica Cristina Moreno - One of the best experts on this subject based on the ideXlab platform.
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Estudo do mecanismo de ação das moléculas agonistas e antagonistas para o tratamento do mal de Alzheimer e da depressão
2015Co-Authors: Nascimento, Érica Cristina MorenoAbstract:A Doença de Alzheimer (DA) é um tipo de demência degenerativa e progressiva de grande preocupação social. Estima-se hoje que, 45 milhões de pessoas no mundo apresentem algum tipo de demência, dentre essas, 25 milhões apresentam sintomas característicos da doença de Alzheimer. O estilo de vida imposto pela situação social e econômica e alterações no estado emocional causadas por traumas e doenças vêm contribuindo para o aumento dos casos de pessoas onde são observadas modificações no seu estado comportamental (estados depressivos: ED). Dados da Organização Mundial de Saúde indicam que mais de 20% da população mundial sofra fisiologicamente com alterações no seu estado emocional originando estados depressivos de alguma natureza. Por não terem suas causas determinadas e nem serem conhecidos os mecanismos que desencadeiem estas alterações nos estados neurológicos dos pacientes, estratégias de tratamento são empregadas para tentar sanar o problema, ou trazer melhora no estado de vida dos pacientes. As estratégias mais utilizadas para tratar pacientes com DA e ED estão relacionadas ao uso de drogas que atuem nas sinapses de maneira a inibir a função de enzimas responsáveis pela ativação e desativação dos neurotransmissores envolvidos diretamente nos processos que ocasionam as demências e o ED. A estratégia mais usada para tratar pacientes com DA é a terapia colinérgica, que consiste no uso de fármacos com ação inibitória frente à acetilcolinesterase (AChE) para impedir o decréscimo da concentração da acetilcolina nas fendas sinápticas. As drogas tacrina, donepezil, galantamina e a rivastigmina são drogas aprovadas para o tratamento da DA, classificadas como inibidoras da acetilcolinesterase (AChEI). Outras drogas como o metrifonato, diclorvos, huperzina A, fenserina e o dímero da tacrina estão em fases de teste clínico. O tratamento clássico da depressão é feito com o uso de medicamentos que promovam o aumento da serotonina nas regiões sinápticas, seja inibindo a ação das enzimas monoamina oxidase A e monoamina oxidase B que degradam o neurotransmissor, seja pela inibição seletiva de recaptura deste neurotransmissor pelos receptores específicos a essa função. As drogas moclobemida, Isocarboxazida, iproniazida, tranilcipromina, fenelzina foram amplamente utilizadas no tratamento de ED, porém seus efeitos colaterais severos as classificam como drogas restritas ao uso, caso outras drogas não sejam eficientes. As drogas inibidoras das isoformas da monoamina oxidase de segunda geração, Clorgilina, Nialamida selegilina e rasigilina foram desenvolvidas para amenizar o tratamento do ED. Na tentativa de produzir drogas multi-alvos foi proposta a droga hibrida ladostigil, como potente inibidor da acetilcolinesterase e da monoamina oxidade B. Neste trabalho, foram realizados diversos estudos teóricos quânticos no intuito de elucidar o perfil farmacofórico de conhecidas drogas empregadas no tratamento da DA e do ED. Para isso foram realizados cálculos no vácuo e em meio solvatado no nível semi-empírico e ab initio para determinação de parâmetros estruturais, eletrônicos e espaciais dos inibidores das enzimas. Outra série de estudos, simulando o ambiente intracelular in sílico, foram também realizados para compreender o mecanismo de inibição da AChE, quando a enzima interage com alguns de seus inibidores. O método de multivariáveis de análise das componentes principais (PCA) foi aplicado a 20 parâmetros, das drogas citadas, para determinação do perfil farmacofórico dos inibidores das proteínas aqui estudadas. Os parâmetros foram obtidos através dos cálculos no vácuo e no modelo de solvatação CPCM em nível B3LYP/6- 31+G(d,p). O estudo da PCA foi realizado para reduzir o espaço amostral de propriedades, a fim de obter as propriedades que são relevantes e comuns entre essas drogas, que têm estrutura molecular diferenciada e, no entanto, apresentam os mesmos alvos. Com o intuito de determinar qualitativa e quantitativamente as interações entre a acetilcolinesterase e alguns de seus inibidores foram realizadas uma série de simulações utilizando o método híbrido QM/MM MD e vários cálculos teóricos usando o método FEP nos níveis AM1/MM empregando a biblioteca fDynamo. Propriedades eletrônicas, como a energia do orbital HOMO-1, dipolo e propriedades estruturais como, o tamanho da droga e a distância entre os dois hidrogênios mais ácidos da molécula são algumas das componentes principais participantes do perfil farmacofórico que correlacionam as drogas estudadas. As energias livres de interação dos sistemas proteína-ligante foram calculadas e observou-se uma grande contribuição da componente de van der Waals para as interações entre a acetilcolinesterase e seus inibidores. ___________________________________________________________________________ ABSTRACTAlzheimer's disease (AD) is a degenerative and progressive type of dementia of great social concern. The latest worldwide estimate shows that 45 million people have some form of dementia, among these 25 million have symptoms of Alzheimer's disease. The lifestyle imposed by social and economic conditions and changes in emotional state caused by trauma and disease have contributed to the increase in cases of people where changes in behavioral state (depressive states: DS) are observed. The World Health Organization estimates that more than 20% of the world population suffers physiologically with changes in its emotional state resulting in depressive states. The AD and DS specific causes and the mechanisms that trigger these changes in the neurological status of patients are not known, thus treatment strategies are employed to try to minimize the effect, or bring improvement in the state of patient life. The most common strategies used to treat patients with AD and DS are related to use drugs that act at the synapses so as to inhibit the function of enzymes responsible for the activation and deactivation of the neurotransmitters directly involved in the processes that cause dementia and the depression. The most used strategy to treat patients with AD is the cholinergic therapy, which consists in use drugs with inhibitory effects against acetylcholinesterase (AChE), in order to prevent the decrease of the concentration of acetylcholine (the neuroreceptor) in the synaptic region. Tacrine, donepezil, galanthamine and rivastigmine are drugs approved for treatment of AD and are classified as inhibitors of acetylcholinesterase. Other drugs such as metrifonate, dichlorvos, huperzine, phenserine and the tacrine dimmer are in stages of clinical testing. The classical treatment of depression is done with the use of drugs that promote the increase of serotonin in the synaptic cleft, either inhibiting the action of the enzymes monoamine oxidase A and monoamine oxidase B, that degrades the neurotransmitter, or by selective inhibition of the reuptake of this neurotransmitter by specific receptors to such function. The drug moclobemide, Isocarboxazid, iproniazid, tranylcypromine, phenelzine, have been widely used in the treatment of DS. Nevertheless, its severe side effect classifies as restricted to use, only if other drugs are not effective. The second generation drugs that inhibit monoamine oxidase isoforms Clorgyline, Nialamide selegiline and rasagiline were developed to help the treatment of depression. In an attempt to produce a multitarget drug, ladostigil a hybrid drug was proposed as a potent inhibitor of acetylcholinesterase and monoamine oxidase B. In this work several quantum theoretical approach were undertaken in order to elucidate the pharmacophore profile of known drugs used in the treatment of AD and DS. For this purpose calculations in vacuum and solvated medium at the semi-empirical and ab initio level were performed for determination of structural, electronic and spatial parameters of enzyme inhibitors. Another series of studies simulating the intracellular environment in silico was used in order to understand the mechanism of acetylcholinesterase inhibition, when enzyme interacts with some of its inhibitors. The multivariate method of the principal components analysis (PCA) was applied to selected 20 parameters of drugs cited before to determining the pharmacoforic profile of those protein inhibitors. The multivariate method of the principal components analysis was applied to selected 20 parameters of drugs cited before in order to determine the pharmacophoric profile of these protein inhibitors. The parameters were obtained from the calculations in vacuum and CPCM solvation model at the DFT B3LYP/6-31+G(d,p) level. PCA study was applied to reduce the sample space of properties to obtain the most relevant properties common to these drugs, which have the same target but have different molecular structure. A huge number of simulations were performed using the hybrid method QM/MM MD in order to qualitatively and quantitatively determine the interactions between acetylcholinesterase and some of its inhibitors. Additionally several theoretical calculations applying FEP method using the fDynamo library in AM1/MM level to compute the free binding energy of the systems acetylcholinesterase-inhibitor were performed. Electronic properties such as the orbital energy of HOMO-1 and the dipole momentum; structural properties such as the size of the drug and the distance between the two most acidic hydrogens of the molecule are some main components of the pharmacophoric profile correlating the drugs studied here. Free energies of interaction of the protein-ligand systems were calculated and revealed a major contribution of the van der Waals component to the interactions between acetylcholinesterase and its inhibitors
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Estudo do mecanismo de ação das moléculas agonistas e antagonistas para o tratamento do mal de Alzheimer e da depressão
'Biblioteca Central da UNB', 2014Co-Authors: Nascimento, Érica Cristina MorenoAbstract:Tese (doutorado)—Universidade de Brasília, Instituto de Química, Programa de Pós-Graduação em Química, 2014.A Doença de Alzheimer (DA) é um tipo de demência degenerativa e progressiva de grande preocupação social. Estima-se hoje que, 45 milhões de pessoas no mundo apresentem algum tipo de demência, dentre essas, 25 milhões apresentam sintomas característicos da doença de Alzheimer. O estilo de vida imposto pela situação social e econômica e alterações no estado emocional causadas por traumas e doenças vêm contribuindo para o aumento dos casos de pessoas onde são observadas modificações no seu estado comportamental (estados depressivos: ED). Dados da Organização Mundial de Saúde indicam que mais de 20% da população mundial sofra fisiologicamente com alterações no seu estado emocional originando estados depressivos de alguma natureza. Por não terem suas causas determinadas e nem serem conhecidos os mecanismos que desencadeiem estas alterações nos estados neurológicos dos pacientes, estratégias de tratamento são empregadas para tentar sanar o problema, ou trazer melhora no estado de vida dos pacientes. As estratégias mais utilizadas para tratar pacientes com DA e ED estão relacionadas ao uso de drogas que atuem nas sinapses de maneira a inibir a função de enzimas responsáveis pela ativação e desativação dos neurotransmissores envolvidos diretamente nos processos que ocasionam as demências e o ED. A estratégia mais usada para tratar pacientes com DA é a terapia colinérgica, que consiste no uso de fármacos com ação inibitória frente à acetilcolinesterase (AChE) para impedir o decréscimo da concentração da acetilcolina nas fendas sinápticas. As drogas tacrina, donepezil, galantamina e a rivastigmina são drogas aprovadas para o tratamento da DA, classificadas como inibidoras da acetilcolinesterase (AChEI). Outras drogas como o metrifonato, diclorvos, huperzina A, fenserina e o dímero da tacrina estão em fases de teste clínico. O tratamento clássico da depressão é feito com o uso de medicamentos que promovam o aumento da serotonina nas regiões sinápticas, seja inibindo a ação das enzimas monoamina oxidase A e monoamina oxidase B que degradam o neurotransmissor, seja pela inibição seletiva de recaptura deste neurotransmissor pelos receptores específicos a essa função. As drogas moclobemida, Isocarboxazida, iproniazida, tranilcipromina, fenelzina foram amplamente utilizadas no tratamento de ED, porém seus efeitos colaterais severos as classificam como drogas restritas ao uso, caso outras drogas não sejam eficientes. As drogas inibidoras das isoformas da monoamina oxidase de segunda geração, Clorgilina, Nialamida selegilina e rasigilina foram desenvolvidas para amenizar o tratamento do ED. Na tentativa de produzir drogas multi-alvos foi proposta a droga hibrida ladostigil, como potente inibidor da acetilcolinesterase e da monoamina oxidade B. Neste trabalho, foram realizados diversos estudos teóricos quânticos no intuito de elucidar o perfil farmacofórico de conhecidas drogas empregadas no tratamento da DA e do ED. Para isso foram realizados cálculos no vácuo e em meio solvatado no nível semi-empírico e ab initio para determinação de parâmetros estruturais, eletrônicos e espaciais dos inibidores das enzimas. Outra série de estudos, simulando o ambiente intracelular in sílico, foram também realizados para compreender o mecanismo de inibição da AChE, quando a enzima interage com alguns de seus inibidores. O método de multivariáveis de análise das componentes principais (PCA) foi aplicado a 20 parâmetros, das drogas citadas, para determinação do perfil farmacofórico dos inibidores das proteínas aqui estudadas. Os parâmetros foram obtidos através dos cálculos no vácuo e no modelo de solvatação CPCM em nível B3LYP/6- 31+G(d,p). O estudo da PCA foi realizado para reduzir o espaço amostral de propriedades, a fim de obter as propriedades que são relevantes e comuns entre essas drogas, que têm estrutura molecular diferenciada e, no entanto, apresentam os mesmos alvos. Com o intuito de determinar qualitativa e quantitativamente as interações entre a acetilcolinesterase e alguns de seus inibidores foram realizadas uma série de simulações utilizando o método híbrido QM/MM MD e vários cálculos teóricos usando o método FEP nos níveis AM1/MM empregando a biblioteca fDynamo. Propriedades eletrônicas, como a energia do orbital HOMO-1, dipolo e propriedades estruturais como, o tamanho da droga e a distância entre os dois hidrogênios mais ácidos da molécula são algumas das componentes principais participantes do perfil farmacofórico que correlacionam as drogas estudadas. As energias livres de interação dos sistemas proteína-ligante foram calculadas e observou-se uma grande contribuição da componente de van der Waals para as interações entre a acetilcolinesterase e seus inibidores.Alzheimer's disease (AD) is a degenerative and progressive type of dementia of great social concern. The latest worldwide estimate shows that 45 million people have some form of dementia, among these 25 million have symptoms of Alzheimer's disease. The lifestyle imposed by social and economic conditions and changes in emotional state caused by trauma and disease have contributed to the increase in cases of people where changes in behavioral state (depressive states: DS) are observed. The World Health Organization estimates that more than 20% of the world population suffers physiologically with changes in its emotional state resulting in depressive states. The AD and DS specific causes and the mechanisms that trigger these changes in the neurological status of patients are not known, thus treatment strategies are employed to try to minimize the effect, or bring improvement in the state of patient life. The most common strategies used to treat patients with AD and DS are related to use drugs that act at the synapses so as to inhibit the function of enzymes responsible for the activation and deactivation of the neurotransmitters directly involved in the processes that cause dementia and the depression. The most used strategy to treat patients with AD is the cholinergic therapy, which consists in use drugs with inhibitory effects against acetylcholinesterase (AChE), in order to prevent the decrease of the concentration of acetylcholine (the neuroreceptor) in the synaptic region. Tacrine, donepezil, galanthamine and rivastigmine are drugs approved for treatment of AD and are classified as inhibitors of acetylcholinesterase. Other drugs such as metrifonate, dichlorvos, huperzine, phenserine and the tacrine dimmer are in stages of clinical testing. The classical treatment of depression is done with the use of drugs that promote the increase of serotonin in the synaptic cleft, either inhibiting the action of the enzymes monoamine oxidase A and monoamine oxidase B, that degrades the neurotransmitter, or by selective inhibition of the reuptake of this neurotransmitter by specific receptors to such function. The drug moclobemide, Isocarboxazid, iproniazid, tranylcypromine, phenelzine, have been widely used in the treatment of DS. Nevertheless, its severe side effect classifies as restricted to use, only if other drugs are not effective. The second generation drugs that inhibit monoamine oxidase isoforms Clorgyline, Nialamide selegiline and rasagiline were developed to help the treatment of depression. In an attempt to produce a multitarget drug, ladostigil a hybrid drug was proposed as a potent inhibitor of acetylcholinesterase and monoamine oxidase B. In this work several quantum theoretical approach were undertaken in order to elucidate the pharmacophore profile of known drugs used in the treatment of AD and DS. For this purpose calculations in vacuum and solvated medium at the semi-empirical and ab initio level were performed for determination of structural, electronic and spatial parameters of enzyme inhibitors. Another series of studies simulating the intracellular environment in silico was used in order to understand the mechanism of acetylcholinesterase inhibition, when enzyme interacts with some of its inhibitors. The multivariate method of the principal components analysis (PCA) was applied to selected 20 parameters of drugs cited before to determining the pharmacoforic profile of those protein inhibitors. The multivariate method of the principal components analysis was applied to selected 20 parameters of drugs cited before in order to determine the pharmacophoric profile of these protein inhibitors. The parameters were obtained from the calculations in vacuum and CPCM solvation model at the DFT B3LYP/6-31+G(d,p) level. PCA study was applied to reduce the sample space of properties to obtain the most relevant properties common to these drugs, which have the same target but have different molecular structure. A huge number of simulations were performed using the hybrid method QM/MM MD in order to qualitatively and quantitatively determine the interactions between acetylcholinesterase and some of its inhibitors. Additionally several theoretical calculations applying FEP method using the fDynamo library in AM1/MM level to compute the free binding energy of the systems acetylcholinesterase-inhibitor were performed. Electronic properties such as the orbital energy of HOMO-1 and the dipole momentum; structural properties such as the size of the drug and the distance between the two most acidic hydrogens of the molecule are some main components of the pharmacophoric profile correlating the drugs studied here. Free energies of interaction of the protein-ligand systems were calculated and revealed a major contribution of the van der Waals component to the interactions between acetylcholinesterase and its inhibitors
Scott E. Walker - One of the best experts on this subject based on the ideXlab platform.
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Current Place of Monoamine Oxidase Inhibitors in the Treatment of Depression
CNS Drugs, 2013Co-Authors: Kenneth I. Shulman, Nathan Herrmann, Scott E. WalkerAbstract:This paper reviews the discovery and history of the use of irreversible monoamine oxidase (MAO) inhibitors (MAOIs) such as phenelzine, tranylcypromine and Isocarboxazid, as well as the second generation selective and reversible MAOIs such as the MAO-A inhibitor, moclobemide and the MAO-B inhibitor, selegiline. Data for review were identified from a literature search of OvidSP Medline and PsycInfo performed in July 2012, using the subject terms and keywords of ‘monoamine oxidase inhibitors’, ‘major depression’, ‘depressive disorder’ and ‘depression (emotion)’. The search was limited to papers published in the English language and from 2007 onward only. Irreversible MAOIs have the potential to treat the most challenging mood disorder patients including those with treatment-resistant depression, atypical depression and bipolar depression. Unfortunately, the use of irreversible MAOIs has been declining sharply due to lack of marketing and the excessive fears of clinicians. Moreover, few clinicians now have any experience, let alone comfort, in prescribing this class of antidepressants. The newer MAOIs are available as another option for the treatment of major depression but have not replaced the irreversible MAOIs for the specific sub-types of depression for which they are now recommended in most consensus guidelines and treatment algorithms. The pharmacology, drug interactions and dietary recommendations associated with the use of MAOIs are reviewed. With the appropriate dietary restrictions and attention to potential drug interactions with serotonin and noradrenaline agents this class of drugs can be used effectively and safely. The MAOIs still represent an important element in our therapeutic armamentarium. Despite recommendations by opinion leaders and consensus guidelines for the use of MAOIs in specific sub-types of depression, the prescription rate of MAOIs is far less than expected and is decreasing. The “bad reputation” and the lack of industry support for this class of agents (especially the irreversible MAOIs) must be overcome in order to continue to provide a potentially useful treatment for a very vulnerable yet substantial sub-population of mood disorder patients.
Kenneth I. Shulman - One of the best experts on this subject based on the ideXlab platform.
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Current Place of Monoamine Oxidase Inhibitors in the Treatment of Depression
CNS Drugs, 2013Co-Authors: Kenneth I. Shulman, Nathan Herrmann, Scott E. WalkerAbstract:This paper reviews the discovery and history of the use of irreversible monoamine oxidase (MAO) inhibitors (MAOIs) such as phenelzine, tranylcypromine and Isocarboxazid, as well as the second generation selective and reversible MAOIs such as the MAO-A inhibitor, moclobemide and the MAO-B inhibitor, selegiline. Data for review were identified from a literature search of OvidSP Medline and PsycInfo performed in July 2012, using the subject terms and keywords of ‘monoamine oxidase inhibitors’, ‘major depression’, ‘depressive disorder’ and ‘depression (emotion)’. The search was limited to papers published in the English language and from 2007 onward only. Irreversible MAOIs have the potential to treat the most challenging mood disorder patients including those with treatment-resistant depression, atypical depression and bipolar depression. Unfortunately, the use of irreversible MAOIs has been declining sharply due to lack of marketing and the excessive fears of clinicians. Moreover, few clinicians now have any experience, let alone comfort, in prescribing this class of antidepressants. The newer MAOIs are available as another option for the treatment of major depression but have not replaced the irreversible MAOIs for the specific sub-types of depression for which they are now recommended in most consensus guidelines and treatment algorithms. The pharmacology, drug interactions and dietary recommendations associated with the use of MAOIs are reviewed. With the appropriate dietary restrictions and attention to potential drug interactions with serotonin and noradrenaline agents this class of drugs can be used effectively and safely. The MAOIs still represent an important element in our therapeutic armamentarium. Despite recommendations by opinion leaders and consensus guidelines for the use of MAOIs in specific sub-types of depression, the prescription rate of MAOIs is far less than expected and is decreasing. The “bad reputation” and the lack of industry support for this class of agents (especially the irreversible MAOIs) must be overcome in order to continue to provide a potentially useful treatment for a very vulnerable yet substantial sub-population of mood disorder patients.
Yuliya O Kuchkovska - One of the best experts on this subject based on the ideXlab platform.
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regioselective synthesis of functionalized 3 or 5 fluoroalkyl isoxazoles and pyrazoles from fluoroalkyl ynones and binucleophiles
Journal of Organic Chemistry, 2019Co-Authors: Bohdan A Chalyk, Andrii Khutorianskyi, Andrii Lysenko, Yulia V Fil, Yuliya O KuchkovskaAbstract:A facile synthetic route toward either 3- or 5-fluoroalkyl-substituted isoxazoles or pyrazoles containing an additional functionalization site was developed and applied on a multigram scale. The elaborated approach extends the scope of fluoroalkyl substituents for introduction into the heterocyclic moiety, and uses convenient transformations of the side chain for incorporation of fluoroalkyl-substituted azoles into the structures of biologically active molecules. The utility of the obtained building blocks for isosteric replacement of alkyl-substituted isoxazole and pyrazole was shown by the synthesis of fluorinated Isocarboxazid and Mepiprazole analogues.
George I Papakostas - One of the best experts on this subject based on the ideXlab platform.
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efficacy of antidepressants for late life depression a meta analysis and meta regression of placebo controlled randomized trials
The Journal of Clinical Psychiatry, 2011Co-Authors: Enrico Tedeschini, Yeciel Levkovitz, Nadia Iovieno, Victoria E Ameral, Craig J Nelson, George I PapakostasAbstract:OBJECTIVE Late-life depression is an important public health issue, given the growing proportion of the elderly relative to the general population in the developed world. The purpose of this study was to examine the efficacy of antidepressants for the treatment of major depressive disorder (MDD) in elderly patients. DATA SOURCES PubMed/MEDLINE was searched for randomized, double-blind, placebo-controlled trials of antidepressants for treatment of both adult (nonelderly) MDD (patients aged < 65 years) and late-life MDD (patients aged ≥ 55 years). The search was limited to articles published between January 1, 1980, and March 3, 2010 (inclusive). The year 1980 was used as a cutoff in our search to decrease diagnostic variability, since the DSM-III was introduced in 1980. Our search cross-referenced the term placebo with each of the following antidepressants: amitriptyline, nortriptyline, imipramine, desipramine, clomipramine, trimipramine, protriptyline, dothiepin, doxepin, lofepramine, amoxapine, maprotiline, amineptine, nomifensine, bupropion, phenelzine, tranylcypromine, Isocarboxazid, moclobemide, brofaromine, fluoxetine, sertraline, paroxetine, citalopram, escitalopram, fluvoxamine, zimelidine, tianeptine, trazodone, nefazodone, agomelatine, venlafaxine, desvenlafaxine, duloxetine, milnacipran, reboxetine, mirtazapine, and mianserin. We also reviewed the reference lists of all studies identified through the PubMed/MEDLINE search. STUDY SELECTION Articles were selected that reported on randomized, double-blind, placebo-controlled trials of antidepressants used as monotherapy for treatment of MDD and that met numerous a priori criteria pertaining to MDD diagnosis criteria, study duration, study design, drug formulation, original data, age thresholds, primary and secondary outcome measures, and exclusions of other disorders. Final inclusion of articles was determined by consensus between the authors. Seventy-four articles were found eligible for inclusion in our analysis (15 late-life MDD trials and 59 adult MDD trials). RESULTS Antidepressants were found to be efficacious for late-life MDD (age 55 and older; P < .0001), although there was evidence for heterogeneity across studies (Q22 = 67.302, P < .001). However, antidepressants were not found to be efficacious in the subset of studies using age thresholds of 65 years or older (older late-life MDD) (P = .265). Finally, when we controlled for study design characteristics, antidepressant but not placebo response rates were lower among late-life MDD patients than among adult MDD patients. CONCLUSIONS The present meta-analysis suggests that antidepressants are efficacious in late-life MDD, but significant study heterogeneity suggests that other factors may contribute to these findings. A secondary analysis raises the possibility that efficacy of these agents may be reduced in trials involving patients aged 65 years or older. Why antidepressants may be less efficacious in elderly versus younger subjects remains unclear.
