Article

Creatine monohydrate in resistant depression: A preliminary study

Authors:
  • Ben-Gurion University of the Negev, Beer Sheva Mental Health Center
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Abstract

Creatine plays a pivotal role in brain energy homeostasis, and altered cerebral energy metabolism may be involved in the pathophysiology of depression. Oral creatine supplementation may modify brain high-energy phosphate metabolism in depressed subjects. Eight unipolar and two bipolar patients with treatment-resistant depression were treated for four weeks with 3-5 g/day of creatine monohydrate in an open add-on design. Outcome measures were the Hamilton Depression Rating Scale, Hamilton Anxiety Scale, and Clinical Global Impression scores, recorded at baseline and at weeks 1, 2, 3 and 4. One patient improved considerably after one week and withdrew. Both bipolar patients developed hypomania/mania. For the remaining seven patients, all scale scores significantly improved. Adverse reactions were mild and transitory. This small, preliminary, open study of creatine monohydrate suggests a beneficial effect of creatine augmentation in unipolar depression, but possible precipitation of a manic switch in bipolar depression.

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... In addition to the larger associative population study mentioned earlier [111], a number of case studies [120] and smaller-scale clinical trials have been published investigating the possible efficacy of creatine supplementation for treating symptoms of depression [21,22,[121][122][123][124]. In addition, a recent extensive review focused on the use of creatine for the treatment of depression [125]. ...
... In addition, a recent extensive review focused on the use of creatine for the treatment of depression [125]. Many of the studies have included mostly female participants [21,22,[121][122][123][124]126]. Furthermore, most studies have looked at the augmentative effect of creatine to traditional pharmacological interventions [21,121]. ...
... Furthermore, most studies have looked at the augmentative effect of creatine to traditional pharmacological interventions [21,121]. Most studies have observed clinically relevant improvements and suggest further investigation into the use of creatine as an intervention for different forms of depression [21,22,[120][121][122][123][124]. However, others have not observed any benefit [126]. ...
Article
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While the vast majority of research involving creatine supplementation has focused on skeletal muscle, there is a small body of accumulating research that has focused on creatine and the brain. Preliminary studies indicate that creatine supplementation (and guanidinoacetic acid; GAA) has the ability to increase brain creatine content in humans. Furthermore, creatine has shown some promise for attenuating symptoms of concussion, mild traumatic brain injury and depression but its effect on neurodegenerative diseases appears to be lacking. The purpose of this narrative review is to summarize the current body of research pertaining to creatine supplementation on total creatine and phophorylcreatine (PCr) content, explore GAA as an alternative or adjunct to creatine supplementation on brain creatine uptake, assess the impact of creatine on cognition with a focus on sleep deprivation, discuss the effects of creatine supplementation on a variety of neurological and mental health conditions, and outline recent advances on creatine supplementation as a neuroprotective supplement following traumatic brain injury or concussion.
... As performance-related studies assessed health and safety markers, evidence began to accumulate that creatine supplementation may also offer some health and/or therapeutic benefits as we age [4,12,14,67,[69][70][71]131]. In this regard, creatine supplementation has been reported to help lower cholesterol, triglycerides and/or manage blood lipid levels [77,132,133]; reduce the accumulation of fat on the liver [133,134]; decrease homocysteine thereby reducing risk of heart disease [30,135]; serve as an antioxidant [30, [136][137][138][139]; enhance glycemic control [1,11,[140][141][142][143]; reduce the progress of some forms of cancer [8,17,18,135,[144][145][146][147]; increase strength and muscle mass [2,9,13,67,70,71,93,99,101,[148][149][150][151][152][153][154]; minimize bone loss in some studies [2,4,14,16,99,150,[155][156][157][158][159][160]; improve functional capacity in osteoarthritic and fibromyalgia patients [22,161,162]; enhance cognitive function particularly in older populations [3,27,28,69,94,127,131,159,[163][164][165][166][167][168]; and, in some instances, improve the efficacy of some anti-depressant medications [5,29,[169][170][171][172]. These findings support contentions that it is prudent for individuals to consume at least 3 g/day of creatine to support general health as one ages [1,50]. ...
... Reports since the early 1980s have suggested that creatine metabolism and/or availability may have antidepressive effects [312][313][314][315][316][317][318]. These studies and others have provided the basis for assessing the effects of creatine and/or creatine precursors like S-adenosyl-Lmethionine (SAMe) and GAA affect brain phosphagen levels, markers of depression, and/or the therapeutic efficacy of antidepressant medications [8,169,170]. For example, the creatine precursor SAMe has been reported to be an effective treatment for clinical depression. ...
... For example, Bakian et al. [324] recently assessed the dietary patterns from the National Health and Nutrition Examination Survey (NHANES) database and found a significant negative relationship between dietary creatine intake and depression among adults in the United States. Roitman et al. [169] reported in an openlabel study that creatine monohydrate supplementation (3-5 g/day for 4 weeks) improved outcomes in a small sample of patients with unipolar depression. Toniolo et al. [29] evaluated the effects of creatine supplementation (6 g/day for 6 weeks) in bipolar patients and reported on Montgomery-Asberg Depression Rating Scale (MADRS) remission rates (i.e., 66.7% remission in the creatine group vs. 18.2% in the placebo group). ...
Article
Full-text available
Although creatine has been mostly studied as an ergogenic aid for exercise, training, and sport, several health and potential therapeutic benefits have been reported. This is because creatine plays a critical role in cellular metabolism, particularly during metabolically stressed states, and limitations in the ability to transport and/or store creatine can impair metabolism. Moreover, increasing availability of creatine in tissue may enhance cellular metabolism and thereby lessen the severity of injury and/or disease conditions, particularly when oxygen availability is compromised. This systematic review assesses the peer-reviewed scientific and medical evidence related to creatine’s role in promoting general health as we age and how creatine supplementation has been used as a nutritional strategy to help individuals recover from injury and/or manage chronic disease. Additionally, it provides reasonable conclusions about the role of creatine on health and disease based on current scientific evidence. Based on this analysis, it can be concluded that creatine supplementation has several health and therapeutic benefits throughout the lifespan.
... Furthermore, one adult and one adolescent open-label trial have shown improved mood in TRD patients with the addition of 3-5g of creatine to treatment regimens [113,114]. Roitman et al. [113] showed in their small, preliminary, open label study of creatine monohydrate that significant improvement in seven out of the ten TRD patients enrolled significantly improved HDRS, HARS, and Clinical Global Impression scores, at weeks 1, 2, 3 and 4. Kodo et al. [114] studied five female adolescents TRD to fluoxetine using 4g of creatine in addition to fluoxetine and observed improved depression score and a significant increase in brain Phosphocreatine (PCr) concentration (p=0.02) on follow-up (31) P MRS brain scans. Clearly, for both of these studies the small sample size and lack of a placebo control group limit the interpretation of the data. ...
... Furthermore, one adult and one adolescent open-label trial have shown improved mood in TRD patients with the addition of 3-5g of creatine to treatment regimens [113,114]. Roitman et al. [113] showed in their small, preliminary, open label study of creatine monohydrate that significant improvement in seven out of the ten TRD patients enrolled significantly improved HDRS, HARS, and Clinical Global Impression scores, at weeks 1, 2, 3 and 4. Kodo et al. [114] studied five female adolescents TRD to fluoxetine using 4g of creatine in addition to fluoxetine and observed improved depression score and a significant increase in brain Phosphocreatine (PCr) concentration (p=0.02) on follow-up (31) P MRS brain scans. Clearly, for both of these studies the small sample size and lack of a placebo control group limit the interpretation of the data. ...
... PO OL (n=10) Trial showed significant improvement in depression scores at weeks 1, 2, 3 and 4 in seven out of the ten TRD patients [113]. ...
Article
Full-text available
Major depressive disorder (MDD) is a leading cause of disability worldwide. Current first line therapies target modulation of the monoamine system. A large variety of agents are currently available that effectively alter monoamine levels; however, approximately one third of MDD patients remain treatment refractory after adequate trials of multiple monoamine based therapies. Therefore, patients with treatment-resistant depression (TRD) may require modulation of pathways outside of the classic monoamine system. The purpose of this review was thus to discuss novel targets for TRD, to describe their potential mechanisms of action, the available clinical evidence for these targets, the limitations of available evidence as well as future research directions. Several alternate pathways involved in the patho-etiology of TRD have been uncovered including the following: inflammatory pathways, the oxidative stress pathway, the hypothalamic-pituitary-adrenal (HPA) axis, the metabolic and bioenergetics system, neurotrophic pathways, the glutamate system, the opioid system and the cholinergic system. For each of these systems, several targets have been assessed in preclinical and clinical models. Preclinical models strongly implicate these pathways in the patho-etiology of MDD. Clinical trials for TRD have been conducted for several novel targets; however, most of the trials discussed are small and several are uncontrolled. Therefore, further clinical trials are required to assess the true efficacy of these targets for TRD. As well, several promising novel agents have been clinically tested in MDD populations, but have yet to be assessed specifically for TRD. Thus, their applicability to TRD remains unknown.
... Além disso, estudos demonstram a eficácia antidepressiva da suplementação com creatina como augmentator (potenciador) do efeito dos antidepressivos inibidores seletivos da recaptação de serotonina (ISRS) na depressão refratária ao tratamento com antidepressivos convencionais (KONDO et al., 2011;LYOO et al., 2012). Ainda a suplementação com creatina tem demonstrado melhoras nos sintomas de pacientes que sofrem de estresse póstraumático, depressão e fibromialgia (AMITAL et al., 2006) e em pacientes com depressão unipolar resistentes ao tratamento com antidepressivos (ROITMAN et al., 2007). Ainda, S-adenosil-Lmetionina, um doador do grupo metil para a síntese de creatina, também apresenta efeito antidepressivo (PAPAKOSTAS, 2009) e aumenta os níveis de fosfocreatina (SILVERI et al., 2003). ...
... Uma paciente mulher com estresse póstraumático, depressão e fibromialgia resistente ao tratamento com o antidepressivo citalopram (40 mg/kg), por 1 ano, quando suplementada com creatina monohidratada (5 gramas/dia) por 4 semanas apresentou uma redução nos escores da escala de depressão de Hamilton. ROITMAN et al., 2007 Cinco pacientes homens e 3 pacientes mulheres com depressão unipolar resistente ao tratamento com antidepressivos de distintas classes, por 4 semanas, quando suplementadas com creatina monohidratada (5 gramas/dia) por 1-4 semanas apresentam redução significativa dos escores da escala de depressão de Hamilton. KONDO et al., 2011 Cinco adolescentes do sexo feminino com depressão unipolar resistente ao tratamento com fluoxetina, quando suplementadas com creatina monohidratada (4 gramas/dia) por 1-8 semanas reduziram significativamente os escores da escala de depressão em crianças. ...
... Alguns estudos ressaltam que a suplementação com creatina pode promover uma melhora nos estados de humor de pacientes depressivos (AMITAL et al., 2006;ROITMAN et al., 2007;KONDO et al., 2011;LYOO et al., 2012;STRAKOWSKI, 2012). Consistente com os achados clínicos, nossos resultados mostram claramente que a creatina administrada sistematicamente por via oral é efetiva em reduzir o tempo de imobilidade no TSC, indicando uma propriedade antidepressiva deste composto ergogênico neste teste preditivo de ação antidepressiva. ...
Thesis
Full-text available
A creatina modula a bioenergética celular e apresenta efeito antiexcitotóxico, antioxidante e apresenta propriedades neuroprotetora e antidepressiva, no entanto, os mecanismos intracelulares responsáveis por esses efeitos ainda não estão bem estabelecidos. No primeiro captítulo desta tese foi analisado o efeito da administração de creatina (p.o.) em camundongos no teste de suspensão pela cauda (TSC), um teste preditivo de atividade antidepressiva. Além disso, foi avaliado o envolvimento dos sistemas de neurotransmissão dopaminérgico, serotonérgico, noradrenérgico, glutamatérgico, bem como as vias de sinalização intracelular mediadas por L-arginina/óxido nítrico (ON), proteína cinase A (PKA), proteína cinase C (PKC), cinase da cinase ativada por mitógenos (MEK)/cinase ativada por estímulos extracelulares (ERK) 1/2, cinase dependente de Ca2+/calmodulina (CaMK-2), fosfatidilinositol 3 cinase (PI3K)/proteína cinase B (AKT), glicogênio sintase cinase 3β (GSK-3β), proteína alvo da rapamicina em mamíferos (mTOR) e hemeoxigenase-1 (HO-1) implicadas no efeito antidepressivo da creatina no TSC. A administração de creatina (0,1-1000 mg/kg) reduziu o tempo de imobilidade em camundongos submetidos ao TSC, sem alterar a atividade locomotora. O efeito anti-imobilidade promovido pela administração de creatina no TSC foi bloqueado pelo pré-tratamento dos camundongos com ρ-clorofenilalanina metil éster (PCPA; 100 mg/kg, i.p., por 4 dias consecutivos, inibidor da síntese de serotonina (5-HT)), α-metil-ρ-tirosina (AMPT; 100 mg/kg, i.p., inibidor da enzima tirosina hidroxilase), haloperidol (0,2 mg/kg, i.p., antagonista não seletivo de receptores dopaminérgicos), SCH23390 (0,05 mg/kg, s.c., antagonista de receptores dopaminérgicos D1), sulpirida (50 mg/kg, i.p., antagonista de receptores dopaminérgicos D2), prazosina (1 mg/kg, i.p., antagonista de receptores α1adrenérgicos), N-metil-D-aspartato (NMDA) (0,1 pmol/sítio, i.c.v.), D-serina (30 µg/sítio, i.c.v., agonista do sítio da glicina do receptor NMDA), arcaína (1 mg/kg, i.p., antagonista do sítio das poliaminas dos receptores NMDA), L-arginina (750 mg/kg, i.p., precursor de ON), SNAP (25 μg/site, i.c.v, doador de ON), 7-nitroindazol (25 mg/kg, i.p., inibidor da enzima óxido nítrico sintase neuronal), H-89 (1 μg/sítio, i.c.v., inibidor de PKA), KN-62 (1 μg/sítio, i.c.v., inibidor de CaMK-2), queleritrina (1 μg/site, i.c.v., inibidor de PKC), U0126 (5 μg/sítio, i.c.v., inibidor de MEK1/2), PD09058 (5 μg/sítio, inibidor da MEK1/2), LY294002 (10 nmol/sítio, i.c.v., inibidor de PI3K), wortmanina (0,1 µg/sítio, inibidor de PI3K), rapamicina (0,2 nmol/sítio, i.c.v., inibidor de mTOR), protoporfirina de zinco (10 µg/sítio, i.c.v., inibidor da enzima heme oxigenase-1). Além disso, creatina (0,01 mg/kg, dose sub-efetiva) em combinação com doses sub-efetivas de SKF38393 (0,1 mg/kg, s.c., agonista de receptores dopaminérgicos D1), apomorfina (0,5 mg/kg, ip, agonista preferencial de receptores dopaminérgicos D2), fenilefrina (0,4 μg/sítio, i.c.v., agonista de receptores α1-adrenérgico), WAY100635 (0,1 mg/kg, s.c., antagonista seletivo de receptores 5-HT1A), 8-OH-DPAT (0,1 mg/kg, i.p., agonista de receptores 5-HT1A), fluoxetina (5 mg/kg, p.o., antidepressivo inibidor da recaptação de serotonina (ISRS)), paroxetina (0,1 mg/kg, p.o., ISRS), citalopram (0,1mg/kg, p.o., ISRS), sertralina (3 mg/kg, p.o., ISRS), amitriptilina (1 mg/kg, p.o., antidepressivo tricíclico), imipramina (0,1 mg/kg, p.o., antidepressivo tricíclico), reboxetina (2 mg/kg, p.o., antidepressivo inibidor seletivo da recaptação de noradrenalina, ISRN), bupropiona (1 mg/kg, p.o., antidepressivo inibidor da recaptação de dopamina e noradrenalina), MK-801 (0,01 mg/kg, p.o., antagonista de receptores de NMDA), cetamina (0,1 mg/kg, i.p., antagonista de receptores NMDA), AR-A014418 (0,01 µg/sítio, i.c.v., inibidor seletivo da enzima GSK-3β), cloreto de lítio (10 mg/kg, p.o., inibidor não seletivo da enzima GSK-3β), protoporfirina de cobalto (0,01 μg/sítio, i.c.v., indutor da expressão de HO-1) reduziu o tempo de imobilidade no TSC, em comparação com qualquer um dos fármacos administrados isoladamente. Este conjunto de resultados sugere que o efeito antidepressivo da creatina no TSC seja mediado por uma ativação de receptores dopaminérgicos D1 e D2, bem como dos receptores 5-HT1A e α1-adrenérgico, e uma inativação de receptores glutamatérgicos NMDA, além de envolver a ativação de PKA, PKC, MEK1/2, PI3K/AKT, mTOR, HO-1 e uma inibição de GSK-3β. Tendo em vista que existe uma grande comorbidade entre a depressão e a doença de Parkinson (DP), e sabendo que antidepressivos de distintas classes protegem da morte celular induzida por toxinas dopaminérgicas, como a 6-OHDA, o segundo capítulo desta tese investigou o efeito neuroprotetor da creatina frente a morte celular induzida pela toxina dopaminérgica 6-OHDA. Esta diminuiu a viabilidade de células de neuroblastoma humano SH-SY5Y, bem como de fatias de estriado cerebral de ratos. A creatina apresentou um efeito protetor contra a toxicidade induzida por 6-OHDA (10–5000 μM) em células SH-SY5Y e este efeito foi revertido por diferentes inibidores de cinases: LY294002 (10 µM), KN-93 (1 µM, inibidor de CaMK-2), H-89 (2 µM), PD98059 (10 µM) e queleritrina (0,1 µM). Além disso, 6-OHDA reduziu a fosforilação de GSK-3β (Ser9) em células SH-SY5Y e a incubação com creatina reverteu este efeito. Ainda, 6-OHDA (50-300 µM) reduziu a viabilidade celular em fatias de estriado de ratos e creatina ou fosfocreatina (2,5-10 mM) reverteu este efeito. Ainda, verificamos que 6-OHDA aumenta a produção de espécies reativas de oxigênio e induz uma diminuição na fosforilação de AKT (Ser473) e GSK-3β (Ser9) em fatias de estriado de ratos, sendo que a creatina ou fosfocreatina (5 mM) reverteu este efeito. O inibidor da PI3K LY294002 (30 µM) reverteu o efeito da creatina e da fosfocreatina sobre a viabilidade celular e produção de espécies reativas de oxigênio em fatias de estriado expostas a 6-OHDA. Além disso, 6-OHDA diminuiu o imunoconteúdo de tirosina hidroxilase e creatina ou fosfocreatina reverteu este efeito. O efeito protetor de creatina ou fosfocreatina na modulação do imunoconteúdo de tirosina hidroxilase em fatias de estriado de ratos expostas a 6-OHDA parece ser dependente da ativação da via de sinalização intracelular PI3K/AKT, uma vez que LY294002 (30 µM) reverteu este efeito. Este segundo conjunto de resultados sugere que a creatina apresenta efeito neuroprotetor frente à morte celular induzida por 6-OHDA e este efeito parece ser devido a propriedades antioxidantes e ativação das vias de sinalização intracelular mediadas por PKA, PKC, MEK1/2, PI3K/AKT e uma inibição de GSK-3β. Esta tese sugere que a creatina pode ser uma nova alternativa terapêutica para o tratamento da depressão e da DP.
... In this study, the patient submitted to an adjunctive treatment with creatine and citalopram for 4 weeks showed an improvement in the symptoms of depression and fibromyalgia lasting up to 8 weeks after the end of treatment (Amital et al., 2006). These results were reinforced by a study that showed that 8 unipolar and 2 bipolar patients with treatment-resistant depression treated for four weeks with creatine significantly improved their symptoms, and one patient had improvement in only one week of treatment (Roitman et al., 2007). In another study performed in 5 female adolescents who had been on fluoxetine for more than 8 weeks, but continued meet diagnostic criteria for depression, the Children's Depression Rating Scale-Revised scores was decreased by 56% of its value following adjunctive treatment with creatine for 8 weeks (Kondo et al., 2011). ...
... With regards to the possible beneficial effects of creatine for the management of bipolar disorders the results are still preliminary and scarce. To the best of our knowledge, two studies acknowledge this point (Roitman et al., 2007;Toniolo et al., 2017). Briefly, in a study performed by Roitman et al. (2007) eight unipolar and two bipolar patients with treatment-resistant depression were treated for four weeks with 3-5 g/day of creatine monohydrate in an open add-on design. ...
... To the best of our knowledge, two studies acknowledge this point (Roitman et al., 2007;Toniolo et al., 2017). Briefly, in a study performed by Roitman et al. (2007) eight unipolar and two bipolar patients with treatment-resistant depression were treated for four weeks with 3-5 g/day of creatine monohydrate in an open add-on design. As result of these clinical trial, both bipolar patients developed hypomania/mania. ...
Article
Depression, a highly prevalent neuropsychiatric disorder worldwide, causes a heavy burden for the society and is associated with suicide risk. The treatment of this disorder remains a challenge, since currently available antidepressants provide a slow and, often, incomplete response and cause several side effects that contribute to diminish the adhesion of patients to treatment. In this context, several nutraceuticals have been investigated regarding their possible beneficial effects for the management of this neuropsychiatric disorder. Creatine stands out as a supplement frequently used for ergogenic purpose, but it also is a neuroprotective compound with potential to treat or mitigate a broad range of central nervous systems diseases, including depression. This review presents preclinical and clinical evidence that creatine may exhibit antidepressant properties. The focus is given on the possible molecular mechanisms underlying its effects based on the results obtained with different animal models of depression. Finally, evidence obtained in animal models of depression addressing the possibility that creatine may produce rapid antidepressant effect, similar to ketamine, are also presented and discussed.
... Compared with placebo, creatine was associated with a significant reduction in depressive symptoms in PD patients following a 2-year treatment course 16 . Recently, creatine monohydrate has been studied as an adjunctive treatment for depression with antidepressants in open-label [17][18][19][20] and randomized clinical depression trials [21][22][23] . These studies have largely [17][18][19][20][21][22] , but not entirely 23 , demonstrated that creatine supplementation enhances and/or accelerates antidepressant response. ...
... Recently, creatine monohydrate has been studied as an adjunctive treatment for depression with antidepressants in open-label [17][18][19][20] and randomized clinical depression trials [21][22][23] . These studies have largely [17][18][19][20][21][22] , but not entirely 23 , demonstrated that creatine supplementation enhances and/or accelerates antidepressant response. Of note, the majority of clinical creatine studies have focused on antidepressant augmentation in adolescent and adult women. ...
... While observational research has examined the relationship between specific nutrients including omega-3 fatty acids 27,28 and dietary B vitamins [29][30][31] and depression, the association between dietary creatine intake and depression risk is currently unknown. Based on reports of creatine's antidepressant effects independent 16 of and in combination [17][18][19][20][21][22] with antidepressant administration, the current study extends this line of investigation to a large, population-based, U.S. sample to determine creatine's relationship with depression within the context of the North American diet. Using data from the Centers for Disease and Control and Prevention's National Health and Nutrition Examination Survey (NHANES), we (1) measured the prevalence of depression among community-dwelling adults in the U.S. across quartiles of dietary creatine intake, (2) examined the relationship between average daily dietary creatine intake and selfreported symptoms of depression, and (3) investigated potential modification of the association between average daily dietary creatine intake and depression by sex, age, and antidepressant/anxiolytic medication use. ...
Article
Full-text available
Creatine monohydrate is actively being researched for its antidepressant effects, yet little is known about the link between dietary creatine and depression risk. This study examines the association between dietary creatine and depression in U.S. adults, using data from the 2005 to 2012 National Health and Nutrition Examination Survey (NHANES). Patient health questionnaire, dietary creatine intake and covariates were obtained on 22,692 NHANES participants ≥20 years of age. Depression prevalence was calculated within quartiles of dietary creatine intake. Adjusted logistic regression models were formulated to determine the relationship between dietary creatine intake and depression risk. Additional covariates included income to poverty ratio, race/ethnicity, sex, age, education level, body mass index, healthcare access, smoking status, physical activity, and antidepressant/anxiolytic medication use. Models were further stratified by sex, age group, and antidepressant/anxiolytic medication use. Depression prevalence was 10.23/100 persons (95% CI: 8.64–11.83) among NHANES participants in the lowest quartile of dietary creatine intake compared with 5.98/100 persons (95% CI: 4.97–6.98) among participants in the highest quartile (p < 0.001). An inverse association was measured between dietary creatine and depression (adjusted odds ratio (AOR) = 0.68, 95% CI: 0.52–0.88). Dietary creatine’s negative association with depression was strongest in females (AOR = 0.62, 95% CI: 0.40–0.98), participants aged 20–39 years (AOR = 0.52, 95% CI: 0.34–0.79) and participants not taking antidepressant/anxiolytic medication (AOR = 0.58, 95% CI: 0.43–0.77). Study results indicate a significant negative relationship between dietary creatine and depression in a nationally representative adult cohort. Further research is warranted to investigate the role creatine plays in depression, particularly among women and across the lifespan.
... Furthermore, one adult and one adolescent open-label trial have shown improved mood in TRD patients with the addition of 3-5g of creatine to treatment regimens [113,114]. Roitman et al. [113] showed in their small, preliminary, open label study of creatine monohydrate that significant improvement in seven out of the ten TRD patients enrolled significantly improved HDRS, HARS, and Clinical Global Impression scores, at weeks 1, 2, 3 and 4. Kodo et al. [114] studied five female adolescents TRD to fluoxetine using 4g of creatine in addition to fluoxetine and observed improved depression score and a significant increase in brain Phosphocreatine (PCr) concentration (p=0.02) on follow-up (31) P MRS brain scans. Clearly, for both of these studies the small sample size and lack of a placebo control group limit the interpretation of the data. ...
... Furthermore, one adult and one adolescent open-label trial have shown improved mood in TRD patients with the addition of 3-5g of creatine to treatment regimens [113,114]. Roitman et al. [113] showed in their small, preliminary, open label study of creatine monohydrate that significant improvement in seven out of the ten TRD patients enrolled significantly improved HDRS, HARS, and Clinical Global Impression scores, at weeks 1, 2, 3 and 4. Kodo et al. [114] studied five female adolescents TRD to fluoxetine using 4g of creatine in addition to fluoxetine and observed improved depression score and a significant increase in brain Phosphocreatine (PCr) concentration (p=0.02) on follow-up (31) P MRS brain scans. Clearly, for both of these studies the small sample size and lack of a placebo control group limit the interpretation of the data. ...
... PO OL (n=10) Trial showed significant improvement in depression scores at weeks 1, 2, 3 and 4 in seven out of the ten TRD patients [113]. ...
Article
Full-text available
Major depressive disorder (MDD) is a leading cause of disability worldwide. Current first line therapies target modulation of the monoamine system. A large variety of agents are currently available that effectively alter monoamine levels; however, approximately one third of MDD patients remain treatment refractory after adequate trials of multiple monoamine based therapies. Therefore, patients with treatment-resistant depression (TRD) may require modulation of pathways outside of the classic monoamine system. The purpose of this review was thus to discuss novel targets for TRD, to describe their potential mechanisms of action, the available clinical evidence for these targets, the limitations of available evidence as well as future research directions. Several alternate pathways involved in the patho-etiology of TRD have been uncovered including the following: inflammatory pathways, the oxidative stress pathway, the hypothalamic-pituitary-adrenal (HPA) axis, the metabolic and bioenergetics system, neurotrophic pathways, the glutamate system, the opioid system and the cholinergic system. For each of these systems, several targets have been assessed in preclinical and clinical models. Preclinical models strongly implicate these pathways in the patho-etiology of MDD. Clinical trials for TRD have been conducted for several novel targets; however, most of the trials discussed are small and several are uncontrolled. Therefore, further clinical trials are required to assess the true efficacy of these targets for TRD. As well, several promising novel agents have been clinically tested in MDD populations, but have yet to be assessed specifically for TRD. Thus, their applicability to TRD remains unknown.
... 28 Creatine intake improved the antidepressive-behavior in animal models 29-31 and working memory scores 28 as well as the Hamilton Depression Rating Scale (HAM-D) score in humans. 32 In another recent study, treatment combined with creatine and antidepressants was effective in depressed patients. Receiving both creatine supplementation and escitalopram has been shown to improve depression symptoms. ...
... 38,39 In human studies, creatine intake over 4 weeks (3-5g/day) showed antidepressant effects in tests for depression and anxiety. 32 In addition creatine plus the SSRI escitalopram improved the depressive symptoms and provided superior efficacy, relatively good tolerability, and minimal side effects in depressive disorders. 33 Specifically, exercise increases 5-HT synthesis and metabolism as well as beta-endorphins to improve the clinical efficacy of exercise treatment of depression and anxiety disorders. ...
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[Purpose] The effects of creatine and exercise on chronic stress-induced depression are unclear. In the present study, we identified the effects of 4-week supplementation of creatine monohydrate and/or exercise on antidepressant behavior and raphe 5-HT expression in a chronic mild stress-induced depressed mouse model. [Methods] Seven-week-old male C57BL/6 mice (n=48) were divided randomly into 5 groups: (1) non-stress control (CON, n=10), (2) stress control (ST-CON, n=10), (3) stress and creatine intake (ST-Cr, n=10), (4) stress and exercise (ST-Ex, n=9), and (5) combined stress, exercise, and creatine intake (ST-Cr+Ex, n=9). After five weeks’ treatment, we investigated using both anti-behavior tests (the Tail Suspension Test (TST) and the Forced Swimming Test (FST)), and 5-HT expression in the raphe nuclei (the dorsal raphe (DR) and median raphe (MnR)). [Results] Stress for 4 weeks significantly increased depressive behaviors in the mice. Treatment with creatine supplementation combined with exercise significantly decreased depressive behaviors as compared with the CON-ST group in both the TST and FST tests. With stress, 5-HT expression in the raphe nuclei decreased significantly. With combined creatine and exercise, 5-HT positive cells increased significantly and had a synergic effect on both DR and MnR. [Conclusion] The present study found that even a single treatment of creatine or exercise has partial effects as an antidepressant in mice with chronic mild stress-induced depression. Furthermore, combined creatine and exercise has synergic effects and is a more effective prescription than a single treatment.
... It is believed that there is an increase in energy demand with depletion of PCr stores at the onset of disease [124,249]. In clinical trials with depressed patients [250][251][252], a positive effect on subjective impairment after adjuvant creatine supplementation could be demonstrated. The higher the increase in cerebral PCr after creatine supplementation, the lower the depressive or manic symptoms [253]. ...
... There is, however, ongoing debate on higher dosage for a needed benefit in these sub-groups [258]. Table 7 presents a summary of the literature related to the effects of creatine supplementation on individuals with psychological disorders [251,252,255]. ...
Article
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Creatine monohydrate (CrM) is one of the most widely used nutritional supplements among active individuals and athletes to improve high-intensity exercise performance and training adaptations. However, research suggests that CrM supplementation may also serve as a therapeutic tool in the management of some chronic and traumatic diseases. Creatine supplementation has been reported to improve high-energy phosphate availability as well as have antioxidative, neuroprotective, anti-lactatic, and calcium-homoeostatic effects. These characteristics may have a direct impact on mitochondrion’s survival and health particularly during stressful conditions such as ischemia and injury. This narrative review discusses current scientific evidence for use or supplemental CrM as a therapeutic agent during conditions associated with mitochondrial dysfunction. Based on this analysis, it appears that CrM supplementation may have a role in improving cellular bioenergetics in several mitochondrial dysfunction-related diseases, ischemic conditions, and injury pathology and thereby could provide therapeutic benefit in the management of these conditions. However, larger clinical trials are needed to explore these potential therapeutic applications before definitive conclusions can be drawn.
... Two open-label investigations with small sample sizes (in one study, participants were 10 adults of both sexes who were non-responders to AD and/or mood stabilizer therapy; in the other study, the participants were 5 female adolescents who were non-responders to at least 8 weeks of fluoxetine treatment) found creatine to be an effective add-on to AD (and/or mood-stabilizer) treatment in patients with MDD. We would like to remark that in one of these studies (Roitman et al., 2007) 2 out of the 10 study patients suffered from a depressive episode within the context of bipolar disorder (Kondo et al., 2011;Roitman et al., 2007). Finally, the results of a recently published open-label study suggest that combined augmentation of SSRI or SNRI therapy with creatine and 5-HTP in females with insufficient response to prior AD treatment lasting at least 8-weeks may be an effective augmentation strategy (Kious et al., 2017). ...
... Two open-label investigations with small sample sizes (in one study, participants were 10 adults of both sexes who were non-responders to AD and/or mood stabilizer therapy; in the other study, the participants were 5 female adolescents who were non-responders to at least 8 weeks of fluoxetine treatment) found creatine to be an effective add-on to AD (and/or mood-stabilizer) treatment in patients with MDD. We would like to remark that in one of these studies (Roitman et al., 2007) 2 out of the 10 study patients suffered from a depressive episode within the context of bipolar disorder (Kondo et al., 2011;Roitman et al., 2007). Finally, the results of a recently published open-label study suggest that combined augmentation of SSRI or SNRI therapy with creatine and 5-HTP in females with insufficient response to prior AD treatment lasting at least 8-weeks may be an effective augmentation strategy (Kious et al., 2017). ...
Article
Given the moderate efficacy of the currently available antidepressants (ADs) in the treatment of major depressive disorder (MDD), the identification of agents that are both able to enhance the effectiveness of ADs and have a good safety profile is a reasonable task for current psychopharmacology. In addition to the well-known drugs (second-generation antipsychotics, levothyroxine, dopaminergic agents, etc.) for augmentation, investigations suggest that several nutraceuticals and over-the-counter (OTC) drugs may be effective and safe as adjunct therapeutic agents to conventional ADs. To identify such active ingredients we first performed a systematic literature search using PubMed and then conducted both backward and forward citation searches. For the PubMed search, we used the following combinations of keywords: 1) “adjunctive” + “therapy” + “antidepressant”; 2) “add-on” + “therapy” + “antidepressant”; 3) “supplementation” + “therapy” + “antidepressant”. As a result of those efforts, we found more than 20 agents (e.g. S-Adenosyl-L-Methionine; folate; ω-3 fatty acids; curcumin; N-acetylcysteine; saffron; 5-hydroxytryptophan; NSAIDs) that are supposedly effective in the augmentation of standard AD treatment. We discussed the possible mechanisms of the antidepressant actions of those agents, as well as the preclinical and clinical evidence for their efficacy as stand-alone and adjunct treatments for MDD.
... In this study, compared with the normal control group, the levels of citrate, α-Oxoglutarate and malate in the rats with depression were significantly decreased, suggesting the effects of the CUMS. Creatine has an important protective effect on mitochondrial energy metabolism, and plays a key role in brain energy homeostasis [45]. A decrease of creatine level is suggested to be related to the pathophysiology of depression [45,46]. ...
... Creatine has an important protective effect on mitochondrial energy metabolism, and plays a key role in brain energy homeostasis [45]. A decrease of creatine level is suggested to be related to the pathophysiology of depression [45,46]. Creatine synthesis is closely related to glucose metabolism. ...
Article
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Background: It is known that bioenergetics of aerobic and resistance exercise are not the same but both can effectively improve depression. However, it is not clear whether and how different types of exercise can influence depression through the same metabolic regulatory system. Metabolomics provides a way to study the correlation between metabolites and changes in exercise and/or diseases through the quantitative analysis of all metabolites in the organism. The objective of this study was to investigate the effects of aerobic and resistance training on urinary metabolites by metabolomics analysis in a rodent model of depression. Methods: Male Sprague-Dawley rats were given chronic unpredictable mild stress (CUMS) for eight weeks. The validity of the modeling was assessed by behavioral indices. After four weeks of CUMS, the rats that developed depression were randomly divided into a depression control group, an aerobic training group and a resistance training group. There was also a normal control group. From week 5, the rats in the exercise groups were trained for 30 min per day, five days per week, for four weeks. The urine samples were collected pre and post the training program, and analyzed by proton nuclear magnetic resonance (1H-NMR) spectroscopy. Results: Both types of training improved depression-like behavior in CUMS rats. Compared with normal control, 21 potential biomarkers were identified in the urine of CUMS rats, mainly involved in energy, amino acids and intestinal microbial metabolic pathways. Common responses to the training were found in the two exercise groups that the levels of glutamine, acetone and creatine were significantly recalled (all P<0.05) Aerobic training also resulted in changes in pyruvate and trigonelline, while resistance training modified α-Oxoglutarate, citric acid, and trimethylamine oxide (all P<0.05). Conclusions: Aerobic and resistance training resulted in common effects on the metabolic pathways of alanine-aspartate-glutamate, TCA cycle, and butyric acid. Aerobic training also had effects on glycolysis or gluconeogenesis and pyruvate metabolism, while resistance training had additional effect on intestinal microbial metabolism.
... Creatine is the precursor of phosphocreatine (PCr), which has an important role in brain energy homeostasis through the phosphocreatine circuit and has been shown to have antioxidant properties (Pereira et al. 2018). In a small sample of patients with unipolar and bipolar treatment-resistant depression, open label adjunctive treatment with creatine monohydrate led to significantly improved depressive symptoms; however, in both bipolar disorder patients, there was a momentary switch to elevated mood (Roitman et al. 2007). ...
Article
The biological bases of bipolar disorder include aspects related, among others, to neurohormonal pathways, neurotransmission, signal transduction, regulation of gene expression, oxidative stress, neuroplasticity, and changes in the immune system. There is still a gap in understanding its complex neurobiology and, consequently, developing new treatments. Multiple factors probably interact in this complex equation of pathophysiology of bipolar disorder, such as genetic, biochemical, psychosocial, and environmental stress events, correlating with the development and severity of the bipolar disorder. These mechanisms can interact to exacerbate inflammation, impair neurogenesis, and increase oxidative stress damage, cellular mitochondrial dysfunction, changes in neurotrophins and in epigenetic mechanisms, neuroendocrine dysfunction, activation of neuronal death pathways, and dysfunction in neurotransmission systems. In this review, we explore the up-to-date knowledge of the neurobiological underpinnings of bipolar disorders. The difficulty in developing new drugs for bipolar disorder is very much associated with the lack of knowledge about the precise pathophysiology of this disorder. Pharmacological treatment for bipolar patients is vital; to progress to effective medications, it is essential to understand the neurobiology in bipolar patients better and identify novel therapeutic targets.
... A growing collection of evidence supports that creatine supplementation may improve health status as individuals age [41,[43][44][45]195]. In this regard, creatine supplementation has been reported to help lower cholesterol and triglyceride levels [67,196]; reduce fat accumulation in the liver [197]; reduce homocysteine levels [198]; serve as an antioxidant [199][200][201][202]; enhance glycemic control [132,[203][204][205]; slow tumor growth in some types of cancers [32,198,206,207]; increase strength and/or muscle mass [37,41,44,45,82,[208][209][210][211][212]; minimize bone loss [211,212]; improve functional capacity in patients with knee osteoarthritis [213] and fibromyalgia [214]; positively influence cognitive function [43,83,195]; and in some instances, serve as an antidepressant [215][216][217]. ...
Article
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Creatine is one of the most popular nutritional ergogenic aids for athletes. Studies have consistently shown that creatine supplementation increases intramuscular creatine concentrations which may help explain the observed improvements in high intensity exercise performance leading to greater training adaptations. In addition to athletic and exercise improvement, research has shown that creatine supplementation may enhance post-exercise recovery, injury prevention, thermoregulation, rehabilitation, and concussion and/or spinal cord neuroprotection. Additionally, a number of clinical applications of creatine supplementation have been studied involving neurodegenerative diseases (e.g., muscular dystrophy, Parkinson’s, Huntington’s disease), diabetes, osteoarthritis, fibromyalgia, aging, brain and heart ischemia, adolescent depression, and pregnancy. These studies provide a large body of evidence that creatine can not only improve exercise performance, but can play a role in preventing and/or reducing the severity of injury, enhancing rehabilitation from injuries, and helping athletes tolerate heavy training loads. Additionally, researchers have identified a number of potentially beneficial clinical uses of creatine supplementation. These studies show that short and long-term supplementation (up to 30 g/day for 5 years) is safe and well-tolerated in healthy individuals and in a number of patient populations ranging from infants to the elderly. Moreover, significant health benefits may be provided by ensuring habitual low dietary creatine ingestion (e.g., 3 g/day) throughout the lifespan. The purpose of this review is to provide an update to the current literature regarding the role and safety of creatine supplementation in exercise, sport, and medicine and to update the position stand of International Society of Sports Nutrition (ISSN).
... Because it alters brain high-energy phosphate metabolism, creatine supplementation may be a novel approach for treating BD. Adjunctive treatment with 3-5 mg/ day of creatine monohydrate in patients with either MDD or bipolar depression significantly improved depressive symptoms (Roitman et al. 2007); however, two patients with bipolar depression experienced a transient switch to hypomania. Another study found that creatine improved depressive symptoms in comorbid depression and fibromyalgia (Amital et al. 2006). ...
Chapter
Currently available therapeutics for bipolar disorder (BD)—and bipolar depression in particular—are scarce and often ineffective. This is particularly troubling because the long-term course of bipolar depression comprises recurrent depressive episodes and persistent residual symptoms. Glutamate and its cognate receptors have consistently been implicated in the pathophysiology of mood disorders, as well as in the development of novel therapeutics for these disorders. Since the rapid and robust antidepressant effects of the glutamatergic modulator ketamine were first observed, similar agents have been studied in both major depressive disorder (MDD) and BD. This chapter reviews the clinical and preclinical evidence supporting the use of novel glutamate receptor modulators for the treatment of bipolar depression. We also discuss other promising, non-glutamatergic targets for potential rapid antidepressant effects in mood disorders, including the cholinergic system, the melatonergic system, the glucocorticoid system, the arachidonic acid (AA) cascade, and oxidative stress and bioenergetics. The chapter discusses several specific agents, including N-acetyl cysteine (NAC), scopolamine, biperiden, agomelatine, riluzole, ketamine, memantine, creatine, metyrapone, ketoconazole, mifepristone, and celecoxib. Non-pharmacological somatic treatments are not reviewed.
... Creatine, endogenously synthesized from arginine, glycine, and methionine, was decreased in this study. Some studies have suggested that creatine plays a pivotal role in brain energy homeostasis (Roitman et al., 2007), and that cre-atine supplementation alters depression-like behaviors in rodents (Allen et al., 2010). However, the exact role of 1-methylhydantoin in the pathogenesis of depression is still unclear. ...
Article
Major depressive disorder is a serious psychiatric condition associated with high rates of suicide and is a leading cause of health burden worldwide. However, the underlying molecular mechanisms of major depression are still essentially unclear. In our study, a non-targeted gas chromatography-mass spectrometry-based metabolomics approach was used to investigate metabolic changes in the prefrontal cortex of the learned helplessness rat model of depression. Body-weight measurements and behavioral tests including the active escape test, sucrose preference test, forced swimming test, elevated plus-maze and open field test were used to assess changes in the behavioral spectrum after inescapable footshock stress. Rats in the stress group exhibited significant learned helpless and depression-like behaviors, while without any significant change in anxiety-like behaviors. Using multivariate and univariate statistical analysis, a total of 18 differential metabolites were identified after the footshock stress protocol. Ingenuity Pathways Analysis and MetaboAnalyst were applied for predicted pathways and biological functions analysis. “Amino Acid Metabolism, Molecule Transport, Small Molecule Biochemistry” was the most significantly altered network in the learned helplessness model. Amino acid metabolism, particularly glutamate metabolism, cysteine and methionine metabolism, arginine and proline metabolism, was significantly perturbed in the prefrontal cortex of learned helplessness rats.
... Olesoxime did not improve motor or metabolic function but did improve cognitive and mitochondrial pathology in a Huntington's rat model, BACHD [ 164 ]. Although creatine is known for preventing muscle fatigue, it has also been shown to reduce mental fatigue [ 165 ]. Due to its low toxicity, high dosages of creatine have been added to treatments for neuropsychiatric disorders [ 165 , 166 ]. ...
Chapter
Amyotrophic lateral sclerosis (ALS) is a debilitating disease characterized by progressive loss of voluntary motor neurons leading to muscle atrophy, weakness, weight loss, and respiratory failure. Evidence suggests that various molecular mechanisms including oxidative stress, mitochondrial dysfunction, apoptosis, glutamate excitotoxicity, proteasomal dysfunction, and inflammation are responsible for ALS pathogenesis. In this chapter we summarize the various therapies tested on animal models targeting the above molecular mechanisms and compare their effects on body weight loss, muscle damage, disease onset, duration, and survival. We also review drugs that prevent body weight loss in animal models of ALS and analyze their structure-activity relationship.
... In BD, decreased PCr concentrations have been reported (Stork and Renshaw, 2005). Furthermore, creatine has been shown to have antioxidant properties in animal models of oxidative stress (Sullivan et al., 2000;Tarnopolsky and Beal, 2001;Lawler et al., 2002) A 4-week open-label trial with 10 participants experiencing treatment-resistant depression (8 unipolar and 2 bipolar) showed improved depression scores with 3 to 5 g/d creatine monohydrate augmentation, provoking switch to elevated mood in both BD patients (Roitman et al., 2007). Two trials focusing on a combination of cytidine and creatine in bipolar depression are currently being conducted (NCT01543139; NCT02625779). ...
Article
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Background: Bipolar disorder is a chronic and often debilitating illness. Current treatment options (both pharmaco- and psychotherapy) have shown efficacy, but for many leave a shortfall in recovery. Advances in the understanding of the pathophysiology of bipolar disorder suggest that interventions that target mitochondrial dysfunction may provide a therapeutic benefit. Methods: This review explores the current and growing theoretical rationale as well as existing preclinical and clinical data for those therapies aiming to target the mitochondrion in bipolar disorder. A Clinicaltrials.gov and ANZCTR search was conducted for complete and ongoing trials on mitochondrial agents used in psychiatric disorders. A PubMed search was also conducted for literature published between January 1981 and July 2017. Systematic reviews, randomized controlled trials, observational studies, case series, and animal studies with an emphasis on agents affecting mitochondrial function and its role in bipolar disorder were included. The search was augmented by manually searching the references of key papers and related literature. The results were presented as a narrative review. Results: Mitochondrial agents offer new horizons in mood disorder treatment. While some negative effects have been reported, most compounds are overall well tolerated and have generally benign side-effect profiles. Conclusions: The study of neuroinflammation, neurodegeneration, and mitochondrial function has contributed the understanding of bipolar disorder's pathophysiology. Agents targeting these pathways could be a potential therapeutic strategy. Future directions include identification of novel candidate mitochondrial modulators as well as rigorous and well-powered clinical trials.
... In animal studies, Cr supplementation seemed to have positive antidepressant-like effects [77,164]. In depressed patients, relatively low doses of Cr (3e5 g/day) ameliorated symptoms of depression even in patients resistant to standard anti-depressants [165,166], and increased brain PCr, as measured by 31 P MRS [167]. ...
... In a preliminary study (N=8) published by Roitman et al. (2007), creatine was associated with a significant reduction of depressive symptoms in unipolar depression, but it precipitated manic episodes in two bipolar subjects approximately three weeks post-creatine treatment. Although creatinine administration can be considered mechanistically feasible for the management of BD, larger studies are necessary to determine in which mood state (clinical timing) and dosage it might be ideal to exert its neuroprotective effects. ...
Article
Bipolar disorder (BD) is a chronic psychiatric illness characterized by severe and biphasic changes in mood. Several pathophysiological mechanisms have been hypothesized to underpin the neurobiology of BD, including the presence of mitochondrial dysfunction. A confluence of evidence points to an underlying dysfunction of mitochondria, including decreases in mitochondrial respiration, high-energy phosphates and pH; changes in mitochondrial morphology; increases in mitochondrial DNA polymorphisms; and downregulation of nuclear mRNA molecules and proteins involved in mitochondrial respiration. Mitochondria play a pivotal role in neuronal cell survival or death as regulators of both energy metabolism and cell survival and death pathways. Thus, in this review, we discuss the genetic and physiological components of mitochondria and the evidence for mitochondrial abnormalities in BD. The final part of this review discusses mitochondria as a potential target of therapeutic interventions in BD.
... 30,31,60 Also, in animal models chronic administration of the antidepressant paroxetine enhances mitochondrial function, 61 whereas in humans several studies reported an antidepressant effect of mitochondrial modulators such as creatine and melatonin. [62][63][64][65] Mitochondrial function in MDD patients has been measured in platelets and peripheral blood mononuclear cells and was found to be significantly impaired. 66,67 Furthermore, mitochondrial dysfunction was associated with the severity of depressive symptoms. ...
Article
There is ample evidence that glucose metabolism in the pregenual anterior cingulate cortex (PACC) is increased in major depressive disorder (MDD), whereas it is still unknown whether glucose levels per se are also elevated. Elevated cerebrospinal fluid (CSF) lactate concentrations in MDD patients might indicate that increased glycolytical metabolization of glucose to lactate in astrocytes either alone or in conjunction with mitochondrial dysfunction results in an accumulation of lactate and contributes to pathophysiological mechanisms of MDD. However, until now, no study investigated in vivo PACC glucose and lactate levels in MDD. Proton magnetic resonance spectroscopy was therefore used to test the hypothesis that patients with MDD have increased PACC glucose and lactate levels. In 40 healthy and depressed participants, spectra were acquired from the PACC using a maximum echo J-resolved spectroscopy protocol. Results show significant increases of glucose and lactate in patients, which are also associated with depression severity. These findings indicate impaired brain energy metabolism in MDD with increased fraction of energy utilization via glycolysis and reduced mitochondrial oxidative clearance of lactate. Targeting these metabolic disturbances might affect the balance of metabolic pathways regulating neuronal energetics and result in an attenuation of the elevated basal activity of brain regions within the neural circuitry of depression.Molecular Psychiatry advance online publication, 17 May 2016; doi:10.1038/mp.2016.73.
... social anxiety and bipolar disorder) [30,31]. In fact, a previous study had reported that creatine supplementation can have a beneficial effect in the treatment of emotional symptoms of patients with resistant depression [32]. ...
Article
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Chronic exposure to excessive glucocorticoid (GC) concentration in Cushing's syndrome (CS) can affect the brain structurally and functionally; ventromedial prefrontal cortex (vmPFC) is rich in GC receptors and therefore particularly vulnerable to excessive GC concentration. Proton magnetic resonance spectroscopy ((1)H-MRS) is a sensitive, non-invasive imaging technique that provides information on brain metabolites in vivo. Our aim was to investigate metabolite concentrations in vmPFC of CS patients and their relationship with clinical outcome. Twenty-two right-handed CS patients (7 active/15 in remission, 19 females, 41.6 ± 12.3 years) and 22 right-handed healthy controls (14 females, 41.7 ± 11 years) underwent brain MRI and (1)H-MRS exams at 3 Tesla. Concentrations of glutamate (Glu), glutamate + glutamine (Glx), creatine (Cr), N-Acetyl-aspartate (NAA), N-Acetyl-aspartate + N-acetylaspartylglutamate (total NAA), choline-containing compounds (Cho) and myoinositol (MI) were determined. Moreover, anxiety and depressive symptoms were evaluated with the State-Trait Anxiety Inventory (STAI) and the Beck Depression Inventory-II (BDI-II) test, respectively. CS patients had lower concentrations of glutamate and total NAA in the vmPFC than healthy controls (8.6 ± 1.2 vs. 9.3 ± 0.7 mmol/L, and 6.4 ± 0.8 vs. 6.8 ± 0.4 mmol/L, respectively; p < 0.05). Duration of hypercortisolism was negatively correlated with total NAA (r = -0.488, p < 0.05). Moreover, the concentration of total NAA was negatively correlated with anxiety state (r = -0.359, p < 0.05). Brain metabolites are abnormal in the vmPFC of patients with CS. Decreased total NAA and glutamate concentrations indicate neuronal dysfunction that appear to be related with duration of hypercortisolism and anxiety.
... Strategies to boost mitochondrial bioenergetics and/or redox functions alone or in combination with existing therapies improved symptoms of stress-related disorders in human and animal models. For example, 3 of 4 clinical trials with creatine monohydrate in combination with antidepressant drugs accelerated the efficacy of treatment modalities without improving the maximal therapeutic benefits in an overall small sample size [101][102][103][104]. Remarkably, the use of antioxidants (e.g., Zinc, N-acetyl cysteine, vitamin E, and coenzyme Q10) as supplements in the treatment of neuropsychiatric disorders also provided some promising results in major depression and bipolar disorder [105]. ...
Article
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The brain evolved cellular mechanisms for adapting synaptic function to energy supply. This is particularly evident when homeostasis is challenged by stress. Signaling loops between the mitochondria and synapses scale neuronal connectivity with bioenergetics capacity. A biphasic “inverted U shape” response to the stress hormone glucocorticoids is demonstrated in mitochondria and at synapses, modulating neural plasticity and physiological responses. Low dose enhances neurotransmission, synaptic growth, mitochondrial functions, learning, and memory whereas chronic, higher doses produce inhibition of these functions. The range of physiological effects by stress and glucocorticoid depends on the dose, duration, and context at exposure. These criteria are met by neuronal activity and the circadian, stress-sensitive and ultradian, stress-insensitive modes of glucocorticoid secretion. A major hallmark of stress-related neuropsychiatric disorders is the disrupted glucocorticoid rhythms and tissue resistance to signaling with the glucocorticoid receptor (GR). GR resistance could result from the loss of context-dependent glucocorticoid signaling mediated by the downregulation of the activity-dependent neurotrophin BDNF. The coincidence of BDNF and GR signaling changes glucocorticoid signaling output with consequences on mitochondrial respiration efficiency, synaptic plasticity, and adaptive trajectories.
... The behavioral effect of a single administration of creatine or ketamine was similar to the one elicited by chronic fluoxetine administration. Notably, some clinical studies report that creatine may reverse symptoms of depression in 1 [37], 2 [38], and up to 3 weeks [58,59], a relatively short period when compared to those necessary for elicit remission by the conventional antidepressants that are usually 4 to 5 weeks [60]. In addition, regarding ketamine, although the data reported in the present study are not surprising since they are in agreement to several previous studies [22,23,61,62], it extends literature data by showing its rapid effect in another model of depression that mimics the exposure to chronic stress. ...
Article
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Ketamine has emerged as a novel strategy to treat refractory depression, producing rapid remission, but elicits some side effects that limit its use. In an attempt to investigate a safer compound that may afford an antidepressant effect similar to ketamine, this study examined the effects of the ergogenic compound creatine in a model of depression, and the involvement of phosphatidylinositol-3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/Akt/mTOR) pathway in its effect. In order to induce a depressive-like behavior, mice were administered with corticosterone (20 mg/kg, per os (p.o.)) for 21 days. This treatment increased immobility time in the tail suspension test (TST), an effect abolished by a single administration of creatine (10 mg/kg, p.o.) or ketamine (1 mg/kg, i.p.), but not by fluoxetine (10 mg/kg, p.o., conventional antidepressant). Treatment of mice with wortmannin (PI3K inhibitor, 0.1 μg/site, intracerebroventricular (i.c.v.)) or rapamycin (mTOR inhibitor, 0.2 nmol/site, i.c.v.) abolished the anti-immobility effect of creatine and ketamine. None of the treatments affected locomotor activity of mice. The immunocontents of p-mTOR, p-p70S6 kinase (p70S6K), and postsynaptic density-95 protein (PSD95) were increased by creatine and ketamine in corticosterone or vehicle-treated mice. Moreover, corticosterone-treated mice presented a decreased hippocampal brain-derived neurotrophic factor (BDNF) level, an effect abolished by creatine or ketamine. Altogether, the results indicate that creatine shares with ketamine the ability to acutely reverse the corticosterone-induced depressive-like behavior by a mechanism dependent on PI3K/AKT/mTOR pathway, and modulation of the synaptic protein PSD95 as well as BDNF in the hippocampus, indicating the relevance of targeting these proteins for the management of depressive disorders. Moreover, we suggest that creatine should be further investigated as a possible fast-acting antidepressant.
... The present findings could partly explain why increasing creatine levels via administration of creatine supplements has been shown to have potential in alleviating depressive symptoms in depressed patients (Kious et al., 2019;Kondo et al., 2011;Lyoo Nemets and Levine, 2013;Roitman et al., 2007). However, while Kondo et al. (2016) examined the effects of daily administration of 2, 4 or 10 mg creatine on both depression and prefrontal creatine, they did so in only seven, eight and seven participants, respectively, meaning that the authors may have been underpowered to determine whether baseline prefrontal creatine concentrations can predict the observed treatment-induced improvements in mood. ...
Article
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Background: Depression and low mood are leading contributors to disability worldwide. Research indicates that clinical depression may be associated with low creatine concentrations in the brain and low prefrontal grey matter volume. Because subclinical depression also contributes to difficulties in day-to-day life, understanding the neural mechanisms of depressive symptoms in all individuals, even at a subclinical level, may aid public health. Methods: Eighty-four young adult participants completed the Depression, Anxiety and Stress Scale (DASS) to quantify severity of depression, anxiety and stress, and underwent 1H-Magnetic Resonance Spectroscopy of the medial prefrontal cortex and structural magnetic resonance imaging (MRI) to determine whole-brain grey matter volume. Results/outcomes: DASS depression scores were negatively associated (a) with concentrations of creatine (but not other metabolites) in the prefrontal cortex and (b) with grey matter volume in the right superior medial frontal gyrus. Medial prefrontal creatine concentrations and right superior medial frontal grey matter volume were positively correlated. DASS anxiety and DASS stress scores were not related to prefrontal metabolite concentrations or whole-brain grey matter volume. Conclusions/interpretations: This study provides preliminary evidence from a representative group of individuals who exhibit a range of depression levels that prefrontal creatine and grey matter volume are negatively associated with depression. While future research is needed to fully understand this relationship, these results provide support for previous findings, which indicate that increasing creatine concentrations in the prefrontal cortex may improve mood and well-being.
... While nothing can be asserted regarding a possible causal role of creatine in these events, we could reasonably expect that boosting mitochondrial energy generation may trigger manic symptoms, as we hypothesize that bipolar disorder may consist of a biphasic disorder of energy generation, increased in mania and decreased in depression (Morris et al. 2017). In the open trial published by Roitman et al. two patients with bipolar disorder that were included in the mixed sample of participants with bipolar-and unipolar-resistant depression turned to hypomania and mania before the 4th week of treatment with creatine monohydrate (3-5 g/day) (Roitman et al. 2007). Regarding the two patients who received creatine that were discontinued from the study due to worsening of depression, it is important to note that they did not present significant mixed features at baseline (total scores on YMRS = 0 and 2). ...
Article
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Depressive episodes are a major cause of morbidity and dysfunction in individuals suffering from bipolar disorder. Currently available treatments for this condition have limited efficacy and new therapeutic options are needed. Extensive research in the pathophysiology of bipolar disorder points to the existence of mitochondrial and bioenergetic dysfunction. We hypothesized that creatine monohydrate, a nutraceutical that works as a mitochondrial modulator, would be effective as an adjunctive therapy for bipolar depression. We conducted a double-blind trial in which 35 patients with bipolar disorder type I or II in a depressive episode by DSM-IV criteria and in use of regular medication for the treatment of this phase of the disease were randomly allocated into two adjunctive treatment groups for 6 weeks: creatine monohydrate 6 g daily (N = 17) or placebo (N = 18). Primary efficacy was assessed by the change in the Montgomery–Åsberg Depression Rating Scale (MADRS). We did not find a statistically significant difference in the comparison between groups for the change in score on the MADRS after 6 weeks in an intention-to-treat (ITT) analysis (p = 0.560; Cohen’s d = 0.231). However, we found significant superiority of creatine add-on vs. placebo when we considered the remission criterion of a MADRS score ≤ 12 at week 6 analyzing the outcome of the 35 randomized patients on ITT (52.9% remission in the creatine group vs. 11.1% remission in the placebo group) and of the 23 completers (66.7% remission in the creatine group vs. 18.2% remission in the placebo group) (p = 0.012; OR = 9.0 and p = 0.036; OR = 9.0, respectively). Two patients who received creatine switched to hypomania/mania early in the trial. No clinically relevant physical side-effects were reported or observed. This proof-of-concept study, aiming to restore brain bioenergetics using an adjunctive mitochondrial modulator, is not conclusive on the efficacy of creatine add-on for bipolar depression, but suggests that this compound may have a role in the adjunctive treatment of this phase of the illness. Further investigation through randomized controlled trials with larger samples should be conducted to verify the efficacy of creatine supplementation for bipolar depression and also for subsyndromal depressive symptoms.
... Because it alters brain high-energy phosphate metabolism, creatine supplementation may be a novel approach for treating BD. Adjunctive treatment with 3-5 mg/ day of creatine monohydrate in patients with either MDD or bipolar depression significantly improved depressive symptoms (Roitman et al. 2007); however, two patients with bipolar depression experienced a transient switch to hypomania. Another study found that creatine improved depressive symptoms in comorbid depression and fibromyalgia (Amital et al. 2006). ...
... A growing collection of evidence supports that creatine supplementation may improve health status as individuals age (7,12,15). In this regard, creatine supplementation has been reported to positively influence cognitive function (12,15) and in some instances serve as an anti-depressant (17,20). ...
Article
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The purpose of this study was to determine the effect of 16 wks of resistance training and creatine supplementation on strength and cognition in 26 older adults (5 male and 21 female) who were randomly assigned to the Control Group (CG, n=13) or the Intervention Group (IG, n=13). Weight and height were measured. The JAMAR™ hand dynamometer was used for the dominant and nondominant handgrip. Cognitive performance was measured with the MoCa questionnaire. Resistance training plus 5 g•d-1 of creatine supplementation were applied as the intervention protocol for 16 consecutive wks. After the 16 wks of intervention, the IG improved in both the handgrip strength (P<0.05) and cognitive performance (P<0.05). The findings indicate that 16 wks of resistance training and creatine monohydrate supplementation improved older adults' handgrip strength and cognitive performance.
... Recent studies have shown that the nutraceutical compound creatine produces a promising antidepressant effect in animal models (Allen, 2012;Allen et al., 2010, Cunha et al., 2012, 2013a, 2013b, 2014a, 2015a, 2015b, 2017, 2017 and clinical trials (Kondo et al., 2011(Kondo et al., , 2016Lyoo et al., 2012;Roitman et al., 2007;Yoon et al., 2016), suggesting that creatine supplementation may be a novel approach for the treatment of MDD. Although the mechanisms underlying the antidepressant effect of creatine remain not fully elucidated, the monoamine and adenosine receptors activation, NMDA receptor inhibition, and the activation of several intracellular kinases have been implicated in its effect (Cunha et al., 2012(Cunha et al., , 2013a(Cunha et al., , 2013b(Cunha et al., , 2014a(Cunha et al., , 2015a(Cunha et al., , 2015b. ...
Article
Creatine has been shown to play a significant role in the pathophysiology and treatment of major depressive disorder (MDD) in preclinical and clinical studies. However, the biological mechanisms underlying its antidepressant effect is still not fully elucidated. This study investigated the effect of creatine (p.o.) administered for 21 days in the behavior of mice submitted to tail suspension test (TST), a predictive test of antidepressant activity. Creatine reduced the immobility time in the TST (1–10 mg/kg), without affecting locomotor activity, a finding consistent with an antidepressant profile. Creatine administration increased the ubiquitous creatine kinase (uCK) and creatine kinase brain isoform (CK-B) mRNA in the hippocampus of mice. Taking into account that PGC-1α induces FNDC5/irisin expression mediating BDNF-dependent neuroplasticity, the effect of creatine administration (1 mg/kg, p. o.) on the hippocampal PGC-1α, FNDC5 and BDNF gene expression was investigated. Creatine treatment increased PGC-1α, FNDC5 and BDNF mRNA in the hippocampus as well as BDNF immunocontent. The involvement of BDNF downstream intracellular signaling pathway mediated by Akt, proapoptotic proteins BAX and BAD and antiapoptotic proteins Bcl2 and Bcl-xL was also investigated following creatine treatment. Creatine increased Akt (Ser 473) phosphorylation, and Bcl2 mRNA and protein levels, and Bcl-xL mRNA, whereas BAD mRNA was decreased following creatine administration in the hippocampus. Altogether these results indicate that creatine antidepressant-like effect may be dependent on Akt activation and increased expression of the neuroprotective proteins in the hippocampus of mice. The obtained data reinforce the antidepressant property of creatine and highlight the role of these molecular targets in the pathophysiology of MDD.
... Regarding brain health, creatine supplementation was reported to affect cognitive and emotional function 15 . Creatine intake attenuated depressive symptoms in experiments with ani- mal and human subjects [16][17][18] . However, the molecular mechanism underly- ing the antidepressant effects of creatine remains elusive. ...
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[Purpose] Chronic stress can lead to mood-related psychomotor behaviors such as despair. Decreased hippocampal neurogenesis has been observed in patients with depression and in animal models of depression. Exercise enhances the population of the new born cells in the dentate gyrus (DG). A few studies have demonstrated that creatine has antidepressant effects in humans. However, the mechanism underpinning these effects is poorly understood. Therefore, we examined whether regular exercise and/or creatine was closely associated with the activity of the Wnt/GSK3β/β-catenin pathway in the hippocampal DG. [Methods] Mice were subjected to 4 weeks of chronic mild stress starting a week prior to the start of a 4-week protocol of treadmill running and creatine supplementation. Tail suspension (TST) and forced swimming tests (FST) were carried out 2 days after the final treadmill running session. Immunohistochemical and western blot analyses were conducted to evaluate hippocampal neurogenesis, GSK3β activity, and nuclear β-catenin protein levels in the DG. Furthermore, Wnt signaling antagonism in the DG using stereotaxic injection was performed. [Results] Chronic mild stress-induced increase in immobility in the TST and FST were restored by treadmill running and/or creatine supplementation. The number of Ki-67+ and doublecortin (DCX)+ cells were decreased by chronic stress, and this decline was reversed by the exercise and supplement regimen, along with the changes in GSK3β activity and nuclear β-catenin protein levels in the DG. Local antagonism of DG Wnt signaling caused an increase in immobility even 5 days after injection with C59. [Conclusion] Regular exercise combined with creatine supplementation had a greater effect on hippocampal neurogenesis via the Wnt/GSK3β/β-catenin pathway activation compared with each treatment in chronic mild stress-induced behavioral depression.
... In the clinical environment, supplemental creatine improved symptomatic and endoscopic indices of Chron's ileitis (Roy & Lee, 2016), increased muscle mass in rheumatoid arthritis (Wilkinson et al., 2016), improved muscle function in fibromyalgia patients (Alves et al., 2013), patients with congestive heart failure (Kuethe, Krack, Richartz, & Figulla, 2006) and Duchenne muscular dystrophy (Felber et al., 2000;Louis et al., 2003;Banerjee et al., 2010), improved developmental outcomes in CDS (Ganesan, Johnson, Connelly, Eckhardt, & Surtees, 1997;Leuzzi et al., 2000;Schulze, Ebinger, Rating, & Mayatepek, 2001;Battini et al., 2006;Ndika et al., 2012) and mitochondrial encephalopathy (Barisic et al., 2002), made better outcome measures in resistant depression (Roitman, Green, Osher, Karni, & Levine, 2007), and showed beneficial effects on neuromuscular symptoms and performance in glycogenosys type V (Vorgerd & Zange, 2007). ...
Article
Creatine is a non-proteinogenic amino acid available from various animal-based foods or synthesized endogenously in the human body. A number of recent population-based studies demonstrate a lower-than-expected dietary creatine intake across age- and gender-specific cohorts, with low creatine consumption accompanied by various health risks. Those studies suggest that the general public may benefit from creatine to prevent and manage various health conditions or to ensure advanced growth. Favorable safety and promising impact of supplemental creatine on human well-being and functioning emanated from plenty of small-sampled interventional studies perhaps suggest a need for recommending creatine to the general public. In this opinion paper, I have outlined the possible rationales for endorsing supplemental creatine ubiquitously, and discussed opportunities and challenges for population-wide creatine use.
... supplementation for 4 weeks (3 g/d the first week, 5 g/d afterward). Because of the net improvement (Hamilton Rating Scale for Depression reduced from 24 to 16, "Visual Analog Scale" for fibromyalgia reduced from 80 to 40), it was decided to continue with creatine supplementation even later.An add-on open-label study of 10 patients with mood depression resistant to psychopharmacological therapy (two with bipolar disorder and eight with major depression)128showed improvement in all patients, both from a clinical point of view and from the point of view of all the measurement scales used. It is particularly interesting that in this study both patients with bipolar disorder showed a manic or hypomanic overshoot upon creatine administration. ...
Article
Creatine is pivotal in energy metabolism of muscle and brain cells, both in physiological and in pathological conditions. Additionally, creatine facilitates the differentiation of muscle and neuronal cells. Evidence of effectiveness of creatine supplementation in improving several clinical conditions is now substantial, and we review it in this paper. In hereditary diseases where its synthesis is impaired, creatine has a disease‐modifying capacity, especially when started soon after birth. Strong evidence, including a Cochrane meta‐analysis, shows that it improves muscular strength and general well‐being in muscular dystrophies. Significant evidence exists also of its effectiveness in secondary prevention of statin myopathy and of treatment‐resistant depression in women. Vegetarians and vegans do not consume any dietary creatine and must synthesize all they need, spending most of their methylation capacity. Nevertheless, they have a lower muscular concentration of creatine. Creatine supplementation has proved effective in increasing muscular and neuropsychological performance in vegetarians or vegans and should, therefore, be recommended especially in those of them who are athletes, heavy‐duty laborers or who undergo intense mental effort. Convincing evidence also exists of creatine effectiveness in muscular atrophy and sarcopenia in the elderly, and in brain energy shortage (mental fatigue, sleep deprivation, environmental hypoxia as in mountain climbing, and advanced age). Furthermore, we review more randomized, placebo‐controlled trials showing that creatine supplementation is safe up to 20 g/d, with a possible caveat only in people with kidney disease. We trust that the evidence we review will be translated into clinical practice and will spur more research on these subjects.
... Noteworthy, several clinical studies have also demonstrated the beneficial effects of creatine in patients with MDD. [100][101][102][103][104][105] Particularly, Lyoo et al. showed an improvement in depressive symptoms in 52 patients with MDD that received creatine combined with escitalopram for eight weeks, as early as week 2 of treatment. 104 These findings were later reinforced by another study performed by Hellem et al., which showed that 14 patients with MDD in an eight-week open-label trial of daily creatine treatment presented a significant reduction in depressive symptomatology as early as week 2 when compared to baseline scores. ...
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The available medications for the treatment of major depressive disorder have limitations, particularly their limited efficacy, delayed therapeutic effects, and the side effects associated with treatment. These issues highlight the need for better therapeutic agents that provide more efficacious and faster effects for the management of this disorder. Ketamine, an N-methyl-D-aspartate receptor antagonist, is the prototype for novel glutamate-based antidepressants that has been shown to cause a rapid and sustained antidepressant effect even in severe refractory depressive patients. Considering the importance of these findings, several studies have been conducted to elucidate the molecular targets for ketamine’s effect. In addition, efforts are under way to characterize ketamine-like drugs. This review focuses particularly on evidence that endogenous glutamatergic neuromodulators may be able to modulate mood and to elicit fast antidepressant responses. Among these molecules, agmatine and creatine stand out as those with more published evidence of similarities with ketamine, but guanosine and ascorbic acid have also provided promising results. The possibility that these neuromodulators and ketamine have common neurobiological mechanisms, mainly the ability to activate mechanistic target of rapamycin and brain-derived neurotrophic factor signaling, and synthesis of synaptic proteins in the prefrontal cortex and/or hippocampus is presented and discussed.
... To our knowledge, the first trial to examine creatine for the treatment of depression was conducted by Roitman and colleagues [187]. They examined eight patients with MDD and two patients with BDU and treated them with open-label creatine at 3-5 g/day for four weeks, as an add-on to their existing antidepressants or mood stabilizers. ...
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Depressed mood, which can occur in the context of major depressive disorder, bipolar disorder, and other conditions, represents a serious threat to public health and wellness. Conventional treatments are not effective for a significant proportion of patients and interventions that are often beneficial for treatment-refractory depression are not widely available. There is, therefore, an immense need to identify novel antidepressant strategies, particularly strategies that target physiological pathways that are distinct from those addressed by conventional treatments. There is growing evidence from human neuroimaging, genetics, epidemiology, and animal studies that disruptions in brain energy production, storage, and utilization are implicated in the development and maintenance of depression. Creatine, a widely available nutritional supplement, has the potential to improve these disruptions in some patients, and early clinical trials indicate that it may have efficacy as an antidepressant agent.
... Psychosocial defeat reduced brain Cr in tree shrews [21,22]. In humans, Cr supplementation improved Hamilton Depression Rating Scale (HAM-D) scores in individuals with treatment-resistant depression [23]. Combination treatment with escitalopram and Cr increased HAM-D scores and led to a more rapid onset of symptom relief than women treated with a selective serotonin (5-HT) reuptake inhibitor (SSRI) alone [24]. ...
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Approximately 20% of adults in the U.S. will experience an affective disorder during their life. While it is well established that serotonin (5-HT) is a crucial factor in mood, impaired cellular bioenergetics are also implicated. Creatine (Cr), through the Cr/Phospho-Cr (PCr) shuttle, maintains high ATP concentrations in the neuron. This system may be implicated in the etiology of affective disorders, as reduced Cr, PCr, and ATP are often seen in the brains of affected patients. To address this issue, Cr transporter (Crt) deficient male mice (Slc6a8-/y) and female mice heterozygous for Crt expression (Slc6a8+/-) were used to evaluate how a Cr deficient system would alter affective-like behaviors. Slc6a8-/y and Slc6a8+/- mice had faster escape latencies in learned helplessness, indicating a potential resilience to behavioral despair. Slc6a8-/y had decrease latency to immobility in the tail-suspension test and Slc6a8+/- had increased open entries in elevated zero maze, but all other variables matched those of wildtype mice, however. Slc6a8-/y mice have increased 5-hydroxyindoleacetic acid content in the hippocampus and striatum and increased monoamine oxidase protein and tryptophan hydroxylase-2 protein content in the hippocampus, while 5-HT levels are unchanged. This indicates an alteration to the 5-HTergic system in Cr deficient mice. Our results indicate that Cr plays a complex role in affective disorders and 5-HT, warranting further investigation.
... There were significantly greater improvements in Hamilton Depression Rating Scale (HAM-D) score, with improvements observed after 2 weeks in females consuming 5 g·d −1 of creatine for 8 weeks [84]. This response time accelerates the effectiveness of antidepressant medications compared to the typical 4-5 weeks acclimatization to detect/identify effects with these therapeutics alone [88,89]. Dietary creatine intake is inversely proportional with depression occurrence; with a 31% greater incidence of depression in adults in the lowest quartile of creatine intake [90]. ...
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Despite extensive research on creatine, evidence for use among females is understudied. Creatine characteristics vary between males and females, with females exhibiting 70–80% lower endogenous creatine stores compared to males. Understanding creatine metabolism pre- and post-menopause yields important implications for creatine supplementation for performance and health among females. Due to the hormone-related changes to creatine kinetics and phosphocreatine resynthesis, supplementation may be particularly important during menses, pregnancy, post-partum, during and post-menopause. Creatine supplementation among pre-menopausal females appears to be effective for improving strength and exercise performance. Post-menopausal females may also experience benefits in skeletal muscle size and function when consuming high doses of creatine (0.3 g·kg−1·d−1); and favorable effects on bone when combined with resistance training. Pre-clinical and clinical evidence indicates positive effects from creatine supplementation on mood and cognition, possibly by restoring brain energy levels and homeostasis. Creatine supplementation may be even more effective for females by supporting a pro-energetic environment in the brain. The purpose of this review was to highlight the use of creatine in females across the lifespan with particular emphasis on performance, body composition, mood, and dosing strategies.
... In addition to its role in brain development and function, meat consumption may have specific nutritional benefits for adult men. Meat contains creatine, (naturally occurring only in animalsourced foods), which improves muscular strength, size, and physical and neural performance (Kreider, 2003;Rae et al., 2003;Roitman et al., 2007). Meat has a more complete profile of amino acids than do plant-based proteins (Hoffman and Falvo, 2004). ...
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Modern attitudes to meat in both men and women reflect a strong meat-masculinity association. Sex differences in the relationship between meat and masculinity have not been previously explored. In the current study we used two IATs (implicit association tasks), a visual search task, and a questionnaire to measure implicit and explicit attitudes toward meat in men and women. Men exhibited stronger implicit associations between meat and healthiness than did women, but both sexes associated meat more strongly with ‘healthy’ than ‘unhealthy’ concepts. As ‘healthy’ was operationalized in the current study using terms such as “virile” and “powerful,” this suggests that a meat-strength/power association may mediate the meat-masculinity link readily observed across western cultures. The sex difference was not related to explicit attitudes to meat, nor was it attributable to a variety of other factors, such as a generally more positive disposition toward meat in men than women. Men also exhibited an attention bias toward meats, compared to non-meat foods, while females exhibited more caution when searching for non-meat foods, compared to meat. These biases were not related to implicit attitudes, but did tend to increase with increasing hunger levels. Potential ultimate explanations for these differences, including sex differences in bio-physiological needs and receptivity to social signals are discussed.
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Mitochondria are cellular organelles involved in several biological processes, especially in energy production. Several studies have found a relationship between mitochondrial dysfunction and mood disorders, such as major depressive disorder and bipolar disorder. Impairments in energy production are found in these disorders together with higher levels of oxidative stress. Recently, a number of agents capable of enhancing antioxidant defenses or mitochondrial functioning have been studied for the treatment of mood disorders as adjuvant therapy to current pharmacological treatments. A better knowledge of mitochondrial physiology and pathophysiology might allow the identification of new therapeutic targets and the development and study of novel effective therapies to treat these specific mitochondrial impairments. This could be especially beneficial for treatment-resistant patients. In this article, we provide a focused narrative review of the currently available evidence supporting the involvement of mitochondrial dysfunction in mood disorders, the effects of current therapies on mitochondrial functions, and novel targeted therapies acting on mitochondrial pathways that might be useful for the treatment of mood disorders.
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Objective: Depression among methamphetamine users is more prevalent in females than males, but gender specific treatment options for this comorbidity have not been described. Reduced brain phosphocreatine levels have been shown to be lower in female methamphetamine users compared to males, and, of relevance, studies have demonstrated an association between treatment resistant depression and reduced brain phosphocreatine concentrations. The nutritional supplement creatine monohydrate has been reported to reduce symptoms of depression in female adolescents and adults taking antidepressants, as well as to increase brain phosphocreatine in healthy volunteers. Therefore, the purpose of this pilot study was to investigate creatine monohydrate as a treatment for depression in female methamphetamine users. Methods: Fourteen females with depression and comorbid methamphetamine dependence were enrolled in an 8-week open label trial of 5 grams of daily creatine monohydrate and of these 14, eleven females completed the study. Depression was measured using the Hamilton Depression Rating Scale (HAMD) and brain phosphocreatine levels were measured using phosphorus magnetic resonance spectroscopy pre- and post-creatine treatment. Secondary outcome measures included anxiety symptoms, measured with the Beck Anxiety Inventory (BAI), as well as methamphetamine use, monitored by twice weekly urine drug screens and self-reported use. Results: The results of a linear mixed effects repeated measures model showed significantly reduced HAMD and BAI scores as early as week 2 when compared to baseline scores. This improvement was maintained through study completion. Brain phosphocreatine concentrations were higher at the second phosphorus magnetic resonance spectroscopy scan compared to the baseline scan; Mbaseline = 0.223 (SD = 0.013) vs. Mpost-treatment = 0.233 (SD = 0.009), t(9) = 2.905, p < .01, suggesting that creatine increased phosphocreatine levels. Also, a reduction in methamphetamine positive urine drug screens of greater than 50% was observed by week 6. Finally, creatine was well tolerated and adverse events that were related to gastrointestinal symptoms and muscle cramping were determined as possibly related to creatine. Conclusions: The current study suggests that creatine treatment may be a promising therapeutic approach for females with depression and comorbid methamphetamine dependence. This study is registered on clinicaltrials.gov (NCT01514630).
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Deficits in mental energy negatively impact mood, motivation and cognition, and may significantly affect quality of life in a large portion of the general population. Central to the maintenance of optimal mental energy is the role of the mitochondria in energy metabolism. The mitochondria play a fundamental role in maintaining neuropsychiatric function with evidence suggesting a relationship between impaired mitochondrial function and deficits in mood, cognition and mental vitality. The enhancement of brain energy metabolism with nutritional factors such as creatine, acetyl-l-carnitine, multivitamins and polyphenol rich diets may be a novel strategy for reducing mental fatigue and improving mood and cognition, having wider relevance to neuropsychiatric and neurodegenerative illness, such as major depression and Alzheimer's disease.
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The understanding of the pathophysiology of bipolar disorder (BD) remains modest, despite recent advances in neurobiological research. The mitochondrial dysfunction hypothesis of bipolar disorder has been corroborated by several studies involving postmortem brain analysis, neuroimaging, and specific biomarkers in both rodent models and humans. Evidence suggests that BD might be related to abnormal mitochondrial morphology and dynamics, neuroimmune dysfunction, and atypical mitochondrial metabolism and oxidative stress pathways. Mitochondrial dysfunction in mood disorders is also associated with abnormal Ca²⁺ levels, glutamate excitotoxicity, an imbalance between pro- and antiapoptotic proteins towards apoptosis, abnormal gene expression of electron transport chain complexes, and decreased ATP synthesis. This paper aims to review and discuss the implications of mitochondrial dysfunction in BD etiology and to explore mitochondria as a potential target for novel therapeutic agents.
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The development of fast-acting antidepressants is crucial considering that conventional antidepressants require a long period to elicit therapeutic effects. Creatine, an ergogenic guanidine-like compound, stands out as a candidate to exert fast antidepressant-like responses. The present study investigated whether a single dose of creatine elicits a fast response in mice submitted to the novelty-suppressed feeding (NSF) test, a paradigm that may assess depression-like and anxiety-like behaviors. Ketamine, an NMDA receptor antagonist that has rapid antidepressant effects, and conventional antidepressants were also tested. The involvement of the mTORC1 signaling pathway in the behavioral responses was also investigated. Biochemical analyses included hippocampal BDNF level (ELISA) and total and phospho-mTORC1 (Ser²⁴⁴⁸), PSD95 and synapsin immunocontent (Western Blotting). Creatine (10 mg/kg, p.o.) or ketamine (1 mg/kg, i.p.) reduced the latency to feed in the NSF test. Conversely, fluoxetine (10 mg/kg, p.o.), imipramine (1 mg/kg, p.o.) or bupropion (10 mg/kg, p.o.) did not alter this parameter. The administration of rapamycin (mTOR inhibitor, 0.2 nmol/site, i.c.v.) abolished the effects of creatine or ketamine in the NSF test. Creatine or ketamine-treated mice presented increased hippocampal BDNF level, an effect abolished by rapamycin. The hippocampal phospho-mTORC1 (Ser²⁴⁴⁸) immunocontent was increased by creatine, but not by ketamine. However, ketamine, but not creatine, increased PSD95 and synapsin immunocontent. Creatine and ketamine elicit a rapid response in the NSF test by a mechanism dependent on the mTORC1 signaling pathway.
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ABSTRACT CREATINE MONOHYDRATE SUPPLEMENTATION CAN INCREASE TOTAL CREATINE AND PHOSPHOCREATINE STORES FOR RESYNTHESIS OF ADENOSINE TRIPHOSPHATE. ALTHOUGH MOST EXISTING LITERATURE HAS INVESTIGATED CREATINE TO IMPROVE STRENGTH AND BODY COMPOSITION, IT HAS ALSO BEEN SHOWN TO PROMOTE BRAIN ENERGY HOMEOSTASIS AND IMPROVE COGNITIVE PARAMETERS. THIS MAY BE ANOTHER MECHANISM FOR PERFORMANCE ENHANCEMENT BECAUSE EXERCISE IS BOTH PHYSICALLY AND MENTALLY DEPLETING. THIS ARTICLE AIMS TO (A) REINFORCE THE EFFICACY OF CREATINE SUPPLEMENTATION IN ATHLETES, (B) SHOWCASE CREATINE'S ROLE AS A COGNITIVE ENHANCER, AND (C) ESTABLISH THE NEED FOR FUTURE INTERVENTIONS IN CREATINE'S EFFECT AS A COMPREHENSIVE ERGOGENIC AID (COMBINING PHYSICAL AND COGNITIVE BENEFITS).
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Major depressive disorder (MDD) often begins during adolescence and is projected to become the leading cause of global disease burden by the year 2030. Yet, approximately 40 % of depressed adolescents fail to respond to standard antidepressant treatment with a selective serotonin reuptake inhibitor (SSRI). Converging evidence suggests that depression is related to brain mitochondrial dysfunction. Our previous studies of MDD in adult and adolescent females suggest that augmentation of SSRI pharmacotherapy with creatine monohydrate (CM) may improve MDD outcomes. Neuroimaging with phosphorus-31 magnetic resonance spectroscopy ((31)P-MRS) can measure the high-energy phosphorus metabolites in vivo that reflect mitochondrial function. These include phosphocreatine (PCr), a substrate for the creatine kinase reaction that produces adenosine triphosphate. As part of the National Institute of Mental Health's experimental medicine initiative, we conducted a placebo-controlled dose-ranging study of adjunctive CM for adolescent females with SSRI-resistant MDD. Participants were randomized to receive placebo or CM 2, 4 or 10 g daily for 8 weeks. Pre- and post-treatment (31)P-MRS scans were used to measure frontal lobe PCr, to assess CM's target engagement with cerebral energy metabolism. Mean frontal lobe PCr increased by 4.6, 4.1 and 9.1 % in the 2, 4 and 10 g groups, respectively; in the placebo group, PCr fell by 0.7 %. There was no group difference in adverse events, weight gain or serum creatinine. Regression analysis of PCr and depression scores across the entire sample showed that frontal lobe PCr was inversely correlated with depression scores (p = 0.02). These results suggest that CM achieves target engagement with brain bioenergetics and that the target is correlated with a clinical signal. Further study of CM as a treatment for adolescent females with SSRI-resistant MDD is warranted.
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Major depressive disorder, with serious impairment in cognitive and social functioning, is a complex psychiatric disorder characterized by pervasive and persistent low mood and a loss of interest or pleasure. However, the underlying molecular mechanisms of depression remain largely unknown. In this study, we used a non-targeted metabolomics approach based on gas chromatography-mass spectrometry of the prefrontal cortex in chronic restraint stress (CRS)-treated rats. CRS was induced in the stress group by restraining rats in a plastic restrainer for 6h every day. This stress paradigm continued for 21 days. Body weight measurement and behavior tests were applied, including the sucrose preference test for anhedonia, the forced swimming test for despair-like behavior, and open field test and the elevated plus-maze to test for anxiety-like behaviors in rats after CRS. Differentially expressed metabolites associated with CRS-treated rats were identified by combining multivariate and univariate statistical analysis and corrected for multiple testing using the Benjamini-Hochberg procedure. A heat map of differential metabolites was constructed using Matlab. Ingenuity Pathways Analysis was applied to identify the predicted pathways and biological functions relevant to the bio-molecules of interest. Our findings showed that CRS induces depression-like behaviors and not anxiety-like behaviors. Thirty-six metabolites were identified as potential depression biomarkers involved in amino acid metabolism, energy metabolism and lipid metabolism, as well as a disturbance in neurotransmitters. Consequently, this study provides useful insights into the molecular mechanisms of depression.
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Ethnopharmacological relevance Zhi-zi-chi decoction (ZZCD) has been used for treating depression for centuries as an effectively traditional Chinese medicine. Until now, studies on pharmacological research of ZZCD mostly centered in pharmacokinetic and network pharmacology level. Little was known about its pharmacological mechanism of relieving depression. Aim of the study This study was to evaluate the effect of ZZCD on relieving depression via behavioral tests, serum metabolomics and signaling target expression analysis on chronic unpredictable mild stress (CUMS) model mice. Materials and methods In this study, 70 male Balb/c mice were randomly divided into seven groups. The CUMS exposure lasted 7 consecutive weeks. The mice were administrated with ZZCD for the last 3 weeks. Behavioral tests (body weight test, sucrose preference test, tail suspension test, open field test and forced swimming test) were applied and a serum metabolomics method based on UFLC/Q-TOF-MS with multivariate statistical and global metabolic network analysis was performed to identify potential endogenous metabolites and pathways which may be relevant to depression. Finally, the protein expression of PKA, p-CREB, BDNF, TrkB and PSD-95 in mouse hippocampus was determined by western blot to verify the metabolomics deduction. Results The body weight and sucrose preference were significantly reduced while the immobility time, total distances and time in center were visibly increased in the CUMS mice at the 4th week. After 3-week administration, high and medium dosage groups mice showed status improvement compared to the model group. 76 metabolites were identified as potential biomarkers from the metabolomics profiles in C18 and Hilic systems, of which 48 were trending up and 28 were trending down after administration with ZZCD. In addition, 9 significant pathways related to changed biomarkers were conducted, of which five were lipid metabolism pathways, two were amino acid metabolism pathways, one was translation pathway and one was carbohydrate metabolism pathway. The pathways were closely connected by O-phosphoethanolamine, phosphatidylcholine, L-glutamine, L-aspartic acid, L-arginine, L-glutamic acid, L-proline, gamma-aminobutyric acid and oxoglutaric acid. All of the target contents were significantly reduced in the model group compared with those in control group, while fluoxetine and ZZCD treated groups showed corrections after 3-week administration. The results revealed that the anti-depression efficacy of ZZCD might be associated with PKA-CREB-BDNF-TrkB-PSD-95 pathway influenced by metabolic changes, verifying the pathway annotation speculation. Conclusion This study demonstrated that the establishment of CUMS depression model was successful and ZZCD had a positive treatment effect on depressed mice. Metabolomics results revealed the holistic and interconnected metabolic changes of ZZCD in CUMS mice. The metabolic pathway annotation suggested that the anti-depression mechanism of ZZCD might be related to signaling pathway in brain. PKA-CREB-BDNF-TrkB-PSD-95 signaling expression was a verification and complement to the metabolomics results and provided vital evidence for the anti-depression efficacy of ZZCD.
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Objectives Milletia speciosa Champ (MS), a traditional Chinese medicine, has the abilities of antistress, antifatigue, anti-oxidation and so on. In our previous study, MS was found to antidepression while the underlying mechanism of which needs further elucidation. Methods Here, a proton nuclear magnetic resonance (1H-NMR)-based metabonomics combined network pharmacology research approach was performed to investigate the antidepressive mechanism of MS act on mouse with chronic unpredictable mild stress-induced depression. Key findings Results showed that MS could alleviate the ethology of depression (including sucrose preference degree, crossing lattice numbers and stand-up times) and disordered biochemical parameters (5-hydroxytryptamine, norepinephrine and brain-derived neurotrophic factor). Metabonomics study and network pharmacology analysis showed that MS might improve depression through synergistically regulating five targets including Maoa, Maob, Ache, Ido1 and Comt, and three metabolic pathways such as tryptophan metabolism, synthesis of neurotransmitter and phospholipid metabolism. Conclusions This study for the first time preliminary clarified the potential antidepressive mechanism of MS and provided theoretical basis for developing MS into novel effective antidepressant.
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The author presents the perspective that orthomolecular treatments possess psychoactive effects that result in potentially desirable physiological changes (e.g., sedation, psychomotor slowing, activation, and/or altered sense perception). The psychoactive effects of a broad range of commonly-recommended orthomolecular interventions are listed. This perspective can be integrated into a more expansive understanding of how orthomolecular interventions work, without claiming specific biochemical alterations. Lastly, several key advantages are delineated to support the use of orthomolecular interventions for their psychoactive effects.
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Depressive disorders cause large socioeconomic effects influencing not only the patients themselves but also their family and broader community as well. To better understand the physiologic factors underlying depression, in this study, we performed metabolomics analysis, an omics technique that comprehensively analyzes small molecule metabolites in biological samples. Specifically, we utilized high-resolution magic-angle spinning-(1)H NMR (HRMAS-(1)H NMR) spectroscopy to comprehensively analyze the changes in metabolites in the hippocampal tissue of rats exposed to chronic stress (CS) via multi-step principal component analysis (multi-step PCA). The rats subjected to CS exhibited obvious depression-like behaviors. High correlations were observed between the first principal component (PC1) score in the score plot obtained using multi-step PCA and measurements from depression-like behavioral testing (body weight, sucrose preference test, and open field test). Alanine, glutamate, glutamine, and aspartate levels in the hippocampal tissue were significantly lower, whereas N-acetylaspartate, myo-inositol, and creatine were significantly higher in the CS group compared to the control (non-CS) group. As alanine, glutamate, and glutamine are known to be involved in energy metabolism, especially in the TCA cycle, chronic exogenous stress may have induced abnormalities in energy metabolism in the brains of the rats. The results suggest that N-acetylaspartate and creatine levels may have increased in order to complement the loss of energy-producing activity resulting from the development of the depression-like disorder. Multi-step PCA therefore allowed an exploration of the degree of depression-like symptoms as represented by changes in intrinsic metabolites.
Chapter
People with bipolar disorder (BD) all too often have suboptimal long-term outcomes with existing treatment options. They experience relapsing episodes of depression and mania and also have interepisodic mood and anxiety symptoms. We need to have a better understanding of the pathophysiology of BD if we are to make progress in improving these outcomes. This chapter will focus on the critical role of mitochondria in human functioning, oxidative stress, and the biological mechanisms of mitochondria in BD. Additionally, this chapter will present the evidence that, at least for some people, BD is a product of mitochondrial dysregulation. We review the modulators of mitochondria, the connection between current BD medication treatments and mitochondria, and additional medications that have theoretical potential to treat BD.
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Functional brain imaging studies in unipolar and secondary depression have generally found decreased prefrontal cortical activity, but in bipolar disorders findings have been more variable. Forty-three medication-free, treatment-resistant, predominantly rapid-cycling bipolar disorder patients and 43 age- and gender-matched healthy control subjects had cerebral glucose metabolism assessed using positron emission tomography and fluorine-18-deoxyglucose. Depressed bipolar disorder patients compared to control subjects had decreased global, absolute prefrontal and anterior paralimbic cortical, and increased normalized subcortical (ventral striatum, thalamus, right amygdala) metabolism. Degree of depression correlated negatively with absolute prefrontal and paralimbic cortical, and positively with normalized anterior paralimbic subcortical metabolism. Increased normalized cerebello-posterior cortical metabolism was seen in all patient subgroups compared to control subjects, independent of mood state, disorder subtype, or cycle frequency. In bipolar depression, we observed a pattern of prefrontal hypometabolism, consistent with observations in primary unipolar and secondary depression, suggesting this is part of a common neural substrate for depression independent of etiology. In contrast, the cerebello-posterior cortical normalized hypermetabolism seen in all bipolar subgroups (including euthymic) suggests a possible congenital or acquired trait abnormality. The degree to which these findings in treatment-resistant, predominantly rapid-cycling patients pertain to community samples remains to be established.
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Intense debate persists about the need for placebo-controlled groups in clinical trials of medications for major depressive disorder (MDD). There is continuing interest in the development of new medications, but because effective antidepressants are already available, ethical concerns have been raised about the need for placebo groups in new trials. To determine whether the characteristics of placebo control groups in antidepressant trials have changed over time. We searched MEDLINE and PsychLit for all controlled trials published in English between January 1981 and December 2000 in which adult outpatients with MDD were randomly assigned to receive medication or placebo. Seventy-five trials met our criteria for inclusion. Data were extracted from the articles by 2 of the authors and discrepancies were resolved via discussion and additional review by a third author. The mean (SD) proportion of patients in the placebo group who responded was 29.7% (8.3%) (range, 12.5%-51.8%). Most studies examined more than a single active medication, and, in the active medication group with the greatest response, the mean (SD) proportion of patients responding was 50.1% (9.0%) (range, 31.6%-70.4%). Both the proportion of patients responding to placebo and the proportion responding to medication were significantly positively correlated with the year of publication (for placebo: n = 75; r = 0.45; 95% confidence interval [CI], 0.25-0.61; P<.001; for medication: n = 75; r = 0.26; 95% CI, 0.03-0.46; P =.02). The association between year of publication and response rate was more statistically robust for placebo than medication. The response to placebo in published trials of antidepressant medication for MDD is highly variable and often substantial and has increased significantly in recent years, as has the response to medication. These observations support the view that the inclusion of a placebo group has major scientific importance in trials of new antidepressant medications and indicate that efforts should continue to minimize the risks of such studies so that they may be conducted in an ethically acceptable manner.
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This 12-week study of two elderly, depressed subjects investigated the effect of acetyl-L-carnitine (ALCAR) treatment on the Hamilton Depression Rating Scale (HDRS) and on measures of high-energy phosphate and membrane phospholipid metabolism. Two mildly depressed (HDRS 15-20), non-demented male subjects 70 and 80 years old were compared with six non-demented controls (all males, mean age of 73.6 +/- 3.6 years). High-energy and membrane phospholipid metabolites were measured by phosphorus magnetic resonance spectroscopic imaging (31P MRSI) analysis. HDRS and 31P MRSI measurements were taken at entry, 6 and 12 weeks for the depressed subjects. 31P MRSI analysis revealed elevated levels of phosphomonesters [PME(s - tau(c))] in the prefrontal region of these mildly depressed subjects, which decreased with ALCAR treatment and showed a trend for correlation of the PME(s - tau(c)) levels with HDRS. ALCAR treatment also resulted in increasing levels of the prefrontal phosphocreatine (PCr), which correlated with HDRS. In the prefrontal region, the mildly depressed subjects compared with controls had elevated PME(s - tau(c)) levels which normalized after 12 weeks of ALCAR and increased PCr levels after ALCAR treatment. These preliminary findings suggest further studies are warranted.
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Neurophysiological studies of major depression performed using PET imaging have shown abnormalities of regional cerebral blood flow (CBF) and glucose metabolism in multiple prefrontal cortical and limbic structures that have been more generally implicated in emotional processing. The current study investigated the effects of antidepressant drug treatment in these regions using PET measures of glucose metabolism. Subjects with primary MDD (n=27) were imaged while unmedicated and depressed, and, of these, 20 were rescanned following chronic antidepressant drug treatment. Regional metabolism was compared between unmedicated depressives and controls and between the pre- and post-treatment conditions in regions-of-interest (ROI) where metabolism or flow had previously been shown to be abnormal in unmedicated depressives. At baseline, the mean metabolism was increased in the left and right lateral orbital cortex/ventrolateral prefrontal cortex (PFC), left amygdala, and posterior cingulate cortex, and decreased in the subgenual ACC and dorsal medial/dorsal anterolateral PFC in the unmedicated depressives relative to controls, consistent with the results of previous studies. Following treatment, metabolism significantly decreased in the left amygdala and left subgenual ACC, and corresponding changes in the orbital and posterior cingulate cortices approached significance. The metabolic reduction in the amygdala and right subgenual ACC appeared largely limited to those subjects who both responded to treatment and remained well at 6 months follow-up, in whom the reduction in amygdala metabolism tightly correlated with the reduction in HDRS scores. The magnitude of the treatment-associated, metabolic change in the amygdala also correlated positively with the change in the stressed plasma cortisol levels measured during scanning. These data converge with those from other PET studies to indicate that primary MDD is associated with abnormal metabolism in limbic and paralimbic structures of the mesiotemporal and prefrontal cortices. Chronic antidepressant drug treatment reduces metabolism in the amygdala and ventral ACC in subjects showing a persistent, positive treatment response. In contrast, the persistence of the abnormal metabolic deficits in the dorsomedial/dorsal anterolateral PFC in MDD during treatment may conceivably relate to the histopathological changes reported in these regions in post mortem studies of MDD.
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Alterations in brain high-energy phosphate metabolism, determined by in vivo magnetic resonance spectroscopy (MRS), have been reported in subjects with a number of brain disorders including major depression, schizophrenia, and substance abuse. It is not clear to what extent these changes can be modified by pharmacological or nutritional means. To address this possibility, we evaluated changes in brain chemistry that were associated with oral creatine (Cr) administration. We hypothesized that oral Cr supplementation, by increasing brain creatine and high-energy phosphate stored in phosphocreatine, would result in an increase in the creatine resonance, as measured using proton 1H-MRS, and a decrease in the beta-nucleoside triphosphate (NTP) peak and an increase in the phosphocreatine (PCr) peak, as measured by phosphorus 31P-MRS, in brain of healthy human subjects. Fifteen healthy male subjects (age=22.9+/-2.2; body mass index=22.9+/-1.7), who were without any axis I disorders or physical or neurological illness, were recruited. Ten subjects took creatine-monohydrate, 0.3 g/kg/day for the first 7 days and 0.03 g/kg/day for the next 7 days (creatine group). Five comparison subjects took equivalent amounts of sucrose as placebo (placebo group). Both 1H- and 31P-MRS scans were acquired at baseline, as well as at day 7 and day 14 of oral supplementation. 1H-MRS: Water suppressed localized spectra were acquired using a single-voxel (1.5 cm x 2 cm x 2 cm) proton MRS PRESS sequence in the left frontal lobe. 31P-MRS: Phosphorus spectral data were recorded from a 5-cm-thick axial brain slice using a short-TE slice selective spin-echo pulse sequence. The creatine group had significantly increased brain creatine levels (8.1% and 9.3%, in creatine/N-acetyl aspartate and creatine/choline ratios, respectively) compared to the placebo group over the 2-week period. The creatine group had significantly decreased beta-NTP levels (7.8%) and marginally increased PCr (3.4%) over the same period. In addition, the brain inorganic phosphate level increased over the same period in the creatine group (9.8%). The current study is the first multinuclear (1H and 31P) MRS study to evaluate changes in brain high-energy phosphate metabolism following oral creatine supplementation in healthy human subjects. These findings suggest the possibility of using oral creatine supplementation to modify brain high-energy phosphate metabolism in subjects with various brain disorders, including major depression, schizophrenia, cocaine and opiate abuse, where alterations in brain high-energy phosphate metabolism have been reported.
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S-adenosyl-L-methionine is an effective treatment for clinical depression, although the mechanism underlying this effect is unclear. Presently, in vivo phosphorus magnetic resonance spectroscopy (31P MRS) and brain transverse relaxometry were employed to test if S-adenosyl-L-methionine supplementation alters brain bioenergetics and/or transverse relaxation time (T2RT) in a nondepressed cohort. If these magnetic resonance techniques are sensitive to S-adenosyl-L-methionine induced alterations in neurochemical processes, these methods may be used in cases of clinical depression to elucidate the mechanism underlying the antidepressant effect of S-adenosyl-L-methionine. Twelve subjects self-administered 1600 mg of oral S-adenosyl-L-methionine daily. Phosphorus spectra and transverse relaxation time were acquired at baseline and after treatment using a 1.5 Tesla scanner. Phosphocreatine levels were significantly higher after treatment, whereas beta nucleoside triphosphate levels, predominantly adenosine triphosphate in brain, were significantly lower after treatment. A surprising gender difference in T2RT emerged after supplementation, with women exhibiting significantly lower T2RT than men. Alterations in phosphocreatine and beta nucleoside triphosphate are consistent with the report that S-adenosyl-L-methionine is involved in the production of creatine, which in turn is phosphorylated to phosphocreatine using adenosine triphosphate. These findings suggest that S-adenosyl-L-methionine alters parameters associated with cerebral bioenergetic status and that some effects of S-adenosyl-L-methionine (T2RT) occur in a gender-specific manner.
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Metabolic changes in the hippocampus formation can be investigated with in vivo magnetic resonance spectroscopy (MRS). Learned helplessness (LH) is a well validated animal model of depression which we established in Sprague-Dawley rats defining some as "learned helpless" (LH) or not "learned helpless" (NLH). Helpless and non-helpless rats received a course of daily administered electroconvulsive shocks (ECS) for 6 days. MRS measurements were performed on a 4.7 T animal scanner with an average voxel size within the rat hippocampus of 10 microl. In LH rats hippocampal creatine/NAA rose significantly (14%) whereas creatine/NAA of NLH rats showed no increase at all. A possible connection between hippocampal creatine levels and major depressive disorders as a reflection of changes in energy metabolism is discussed.
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Placebo effects in major depressive disorder (MDD) have received much interest in the medical literature. However, few quantitative analyses have been done in homogeneous populations. To determine efficacy rates for placebo in patients with MDD; to quantify the correlation between efficacy and publication year, as well as between placebo and drug response rates. Searching MEDLINE (1966-December 2000), EMBASE (1998-February 2001), HealthSTAR (1975-December 2000), and Cochrane (1980-December 2000) databases, randomized, placebo-controlled trials were retrieved including patients with MDD as defined by Diagnostic and Statistical Manual of Mental Disorders, 3rd and 4th editions criteria, Hamilton Rating Scale for Depression score >/=18 or Montgomery-Asberg Depression Rating Scale score >/=16, reporting successes as 50% decreases in scores after 6-8 weeks of treatment. Response rates were summarized using a random effects meta-analysis for per protocol (PP) and intent-to-treat (ITT) results. We included 24 of 134 potential studies examining 4459 patients, 1786 on placebo and 2673 on an antidepressant. Placebo response rates were 45.5% (PP) and 26.9% (ITT). Correlations were significant between year and rates (PP rho 0.448, p = 0.042; ITT rho 0.557; p = 0.006), but not for active drugs. Placebo and drug rates were correlated (PP r 0.397, p = 0.020; ITT r 0.539; p = 0.002). These placebo rates confirm those reported previously, but were from a homogeneous population. Although statistically significant, the correlation between drug and placebo rates was lower than others reported. During the study period, placebo rates increased linearly; active drugs did not. Correlations between placebo and drug response rates reflected moderate to strong effect sizes. We suggest that current methodology has been unsuccessful in achieving unbiased double-blind conditions not influenced by extra-trial factors, including time.
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Bipolar disorder (BD) has substantial morbidity and incompletely understood neurobiological underpinnings. To investigate brain chemistry in medication-free individuals with BD. Two-dimensional proton echo-planar spectroscopic imaging (PEPSI) (32 x 32, 1-cm(3) voxel matrix) acquired axially through the cingulate gyrus was used to quantify regional brain chemistry. The Center for Anxiety and Depression at the University of Washington in Seattle and the Bipolar Research Programs at McLean Hospital and the Massachusetts General Hospital in Boston. Thirty-two medication-free outpatients with a diagnosis of BD type I (BDI) or BD type II (BDII), predominantly in a depressed or mixed-mood state, were compared with 26 age- and sex-matched healthy controls. Tissue type (white and gray) and regional analyses were performed to evaluate distribution of lactate; glutamate, glutamine, and gamma-aminobutyric acid (Glx); creatine and phosphocreatine (Cre); choline-containing compounds (Cho); N-acetyl aspartate; and myo-inositol. Chemical relationships for diagnosis and mood state were evaluated. Patients with BD exhibited elevated gray matter lactate (P =.005) and Glx (P =.007) levels; other gray and white matter chemical measures were not significantly different between diagnostic groups. Isolated regional chemical alterations were found. An inverse correlation between 17-item Hamilton Depression Rating Scale scores and white matter Cre levels was observed for BD patients. Gray matter lactate and Glx elevations in medication-free BD patients suggest a shift in energy redox state from oxidative phosphorylation toward glycolysis. The possibility of mitochondrial alterations underlying these findings is discussed and may provide a theoretical framework for future targeted treatment interventions.
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While several studies have suggested a relationship between the hippocampus and psychosis in schizophrenia, fewer studies have specifically investigated the presence of psychosis in mood disorders from a neurobiological perspective. Moreover, a limitation of these earlier studies is that the majority of them were performed in chronic patients. The present proton magnetic resonance spectroscopic imaging (1H-MRSI) study assessed neuronal integrity (as assessed with N-acetylaspartate, NAA) in the hippocampus of patients with a first episode of mood disorders with psychotic symptoms. We studied 17 patients and 17 healthy subjects matched for age and sex. Subjects underwent 1H-MRSI, and measures of NAA, choline-containing compounds (CHO), and creatine+phosphocreatine (CRE) in 11 brain regions were obtained, i.e. hippocampus (HIPPO), dorsolateral prefrontal cortex, superior temporal gyrus, inferior frontal gyrus, occipital cortex, anterior and posterior cingulate, centrum semiovale, prefrontal white matter, thalamus and putamen. NAA/CRE ratios in HIPPO of patients were significantly lower than in controls. Sporadic and non-hypothesis-driven results were found in occipital cortex and prefrontal white matter as a main effect of diagnosis, and in superior temporal gyrus as a hemisphere by diagnosis interaction. These results would not survive a Bonferroni correction for the number of ROIs. No correlations were found with the available demographic and clinical data. Therefore, hippocampal neuronal abnormalities are present at the onset of mood disorders with psychotic symptoms. These data suggest that neuronal abnormalities in HIPPO may be associated with psychosis in mood disorders. Since these data were obtained in patients at first episode, they cannot be explained by chronicity of illness or pharmacological treatment.
Article
Neuroimaging and postmortem studies have suggested the involvement of the dorsolateral prefrontal cortex (DLPFC) in the pathophysioloy of unipolar disorder. We examined with in vivo 1H magnetic resonance spectroscopy (MRS) the levels of specific metabolites in the DLPFC of adult unipolar patients and the role of illness chronicity on DLPFC abnormalities. Nineteen unmedicated unipolar mood disorder patients and 19 age- and gender-matched healthy controls underwent a short echo-time 1H MRS examination localized to an 8-cm3 single voxel placed in the left DLPFC. There were no significant differences in metabolite levels, including N-acetylaspartate (NAA), phosphocreatine plus creatine (PCr+Cr) and choline-containing-compounds (GPC+PC), between the two groups. However, NAA/PCr+Cr ratios were significantly lower in the chronic than in the less chronically ill patients and healthy controls. The low levels of NAA/PCr+Cr ratios in the left DLPFC of unipolar patients who had been more chronically ill suggest a potential role for illness chronicity in neuronal abnormalities in the DLPFC in unipolar disorder. This could possibly be accounted for by neurodegenerative processes arising with the progression of the illness. Future 1H MRS investigations should longitudinally examine the role of illness chronicity on DLPFC abnormalities and their relationship with the symptoms of unipolar disorder.
Article
Magnetic resonance spectroscopy studies (MRS) reported abnormally low levels of N-acetylaspartate (NAA, a marker of neuronal integrity) in dorsolateral prefrontal cortex (DLPFC) of adult bipolar patients, suggesting possible neuronal dysfunction. Furthermore, recent MRS reports suggested possible lithium-induced increase in NAA levels in bipolar patients. We examined with in vivo (1)H MRS NAA levels in the DLPFC of adult bipolar patients. Ten DSM-IV bipolar disorder patients (6 lithium-treated, 4 drug-free) and 32 healthy controls underwent a short echo-time 1H MRS session, which localized an 8 cm3 single-voxel in the left DLPFC using a STEAM sequence. No significant differences between the two groups were found for NAA, choline-containing molecules (GPC+PC), or phosphocreatine plus creatine (PCr+Cr) (Student t-test, p > 0.05). Nonetheless, NAA/PCr+Cr ratios were significantly increased in lithium-treated bipolar subjects compared to unmedicated patients and healthy controls (Mann-Whitney U-test, p < 0.05). Relatively small sample size may have reduced the statistical power of our analyses and the utilization of a single-voxel approach did not allow for the examination of other cortical brain areas. This study did not find abnormally reduced levels of NAA in left DLPFC of adult bipolar patients, in a sample of patients who were mostly on medications. However, elevated NAA/PCr+Cr ratios were shown in lithium-treated bipolar patients. Longitudinal 1H MRS studies should further examine NAA levels in prefrontal cortex regions in untreated bipolar patients before and after mood stabilizing treatment.
Article
Few studies have examined the neurochemical abnormalities that might be associated with pediatric bipolar disorder. The aim of this study was to use magnetic resonance spectroscopy to evaluate several brain regions implicated in bipolar disorder in children with a mood disorder and a familial risk for bipolar disorder. We hypothesized that these children would exhibit neurochemical differences compared with healthy children of parents without a psychiatric disorder. Specifically, decreased N-acetylaspartate (NAA) and creatine and phosphocreatine (Cr) of the prefrontal cortex and cerebellar vermis would reflect impairments in neuronal function and cellular metabolism, and elevated myo-inositol (mI) would reflect impaired phosphoinositide metabolism, potentially representing early markers of neurophysiologic changes that might underlie the development of bipolar disorder. Children with a mood disorder and at least one parent with bipolar disorder (n = 9) and healthy children (n = 10) group matched for age (8-12 years), race, sex, education, and Tanner stage were evaluated using the Washington University in St. Louis Kiddie Schedule for Affective Disorders and Schizophrenia. Proton magnetic resonance spectroscopy was acquired using 8-cc volumes within the frontal cortex, frontal white matter, and the cerebellar vermis. Metabolite ratios (NAA/Cr, cholines (Cho)/Cr, mI/Cr, NAA/Cho, NAA/mI, and Cho/mI) and concentrations (NAA, Cr, Cho, and mI) were calculated and compared between groups. The trend in